o

.J.
.-

)1...;'"
...h.
... t - 1/2(R2Mg+MgX2)

o
. Il.,.
Contenta
Pu(act
ConlrihU/QU
l . 111' ....... ...,10.
Philip E. &kilQ
PUT 1: INFRODl CIlON
l. Historical Background
11. Thc Naturc ot he Grignard Rueol
111. ScoPC ot tbe Grignard Reaedon
IV. Organiu,tion 01 Ihis Book
Refcrcnm
PART 11: ME1]fODS OF GRIGNARD IEAGENI PREPARATION
1. General DiscuS$ioll 011 Ihe Reaction oC Mancsium Ind RX
11. Elfccl ot Water aOO Oll.yaen 011 Grignard Rugenl Preparatioll
ni
I
I
l
l
6
7
,

10
..
JlI. Elfect or Solvent on Grignard Rugent Preparalion
IV. ElfeCl of RX on Grianard Reaent Preparation
v. Preparalion of II-BulylmagnQium Chloridc
VI. Alternative e t h o ~ h for Grignard Reaenl Preparadon
Rcfcremu
I Introduct jon
4. Mapesh!m Ailalioll
hu"," D. Ritler and Mal/Mili S. Srll
I Inl roductjon
PART 111: SAFE HANOI ING PUCfJCES

5. Safe Ha.l'" Praetiets of I ... trlal Snle Crl .... nI Rnants
Philip E. Ralcitu
I InlUvl uclQo
COOI'Jhh
10
13
IS
17
20
"
53
79
79
,
Coa.n"
PART IV: ANAl.ySFS OE GRIGN!RD REAGENTS
l. Quantitative Wel Analyses
11. Procedul'e$ ror Quantitatiw: Wet "naipes
A. Preparat ion aod Standardiution or 2 Butanol Solution
B. Dctennination of Grignard Rcaacn! Activily
C. Dctermination or Grignard Reagent Acid-Base Value
Rcfettncrs
"
..
..
91
91
92
7. In(rar .... Ramall S.lL.Ii"_ .. .,""'-________________ . 1 l
faul ChabO!
10.1
Jo-Anrrc K 8o..,.rtrel
C. Schlenk Equilibrium 109
IV, Catboo.13
A, Oycrview
B, Chcmical Sbifls
Refercoces
CClIT' .... IS
111
111
11 2
lIS
PART V: MECHANlSMS ANO STRUcrURE-REAcrtVITV RELATlONSHIPS
lO. Mech.alsm orGricnud RUlcn! Form.Uon 145
Cha{iq Hamdouchi and Ha"" M. Walborsk"
J. Introductjon 145
80th Diffusion Conccpt and Nalurc or lhe Reactive surracc 187
."
C. Disagreement Between lhe C.lculatcd _00 he Ex.perimental
Resulg 189
V. Further Evidencc fo r he Surfacc Nature of Grignard Resgenl
Eomal jan 19S
A. Formalion ofGrignard Reagenl in the Presenoc af
MQoodeu1erated Almbol.
C. Ooly lhe Suacc Nature of he Reaction Could Prcdict
Rclcnlion 708
RcfCttI1Q'1 214
11. McehanismJ of RHctlons In GrigDud RUleno
2"
Corneli3 BlomlN'(1
1.
Inlroondl:ln 219
11. Me(:hanism af lhe Carbonyl Addilion Reaction
'"
A. Homolytic VCl"5Ul1 Conccrtcd McclIanisnu
'"
B. Devclopmcnt of a Rcactivity Spectrum 227
e f'onlZl1cd Ma:baoism 231
D. Reactivity af Various Magnc:5ium Species
2"
111. Candll.jon 246
Rcfcn::nrrs 246
1L SU'UCture-RacliYIII Rehltlo.hl,.
,..
Cornell.J BlomlNra
1. Inlrodurtion 271
11. Faclo" AfI'ectiog !he ComposllOD af Grignard Reagcnts in Sohl tion 273
A Salvenl .ud Conc:entral jon Ef:cls 271
111.
,.
GmJUJ Parkin
1. 101[0<I"cljoo
11. Synlheses and Slructur= of Monomeric Four-Coordinate
PART VI: GENERAL RUcnONS OF GRIGNARD REAGENTS
15. Nlldeopllilil: S.b.litatiocl .. lb E!tropllille Orpc, M.in Group, .. d
Tra..t,M Metal Spcda
Gary S. S i l ~ m O l l
1 Int rodllc!ion
8. Effcct or Leaving Groups
C. Nucleophilic Aromatic Subslilulion
D. Epoxidc (Oxiranr) Ring Openings
111. E1cctrophilic Main Group Species
A Porrn1ja! Problems
B. Polcntial Solutions 10 Minimize Competina Reactions
IV. Elcclfophilic Traruilion Metal Species
A PotcO!;!! prohlcms
16. NIICleopllilk Allklltloa 10 UnronjIIpled C-C Maldplt 80Dds
Phllip E. Roklla
1 Inuodllct jon
11. Factors Alfecti ng the Addition or RMa:< lo Unconjugalcd C-C
Multipk 80mb
111. Inlf1l molccular MMagneshlm-ene
M
Reactioo
Co .. M,;ibL
'"
291
298
J07
107
309
J17
322
32S
325
326
334
314
'"
355
35S
3>6
IV. Stereochernistry of Addition
V. Addition lo Simple Alkenes
1
"o
""
3S7
3S7
17. Nucleo,llilic AddltlOll lo Clrbca Heteroalom Mlllriple Bar ' r O, S, N, P 36.
U o n ~ Mlginiac
1. Introduction
11. Nucleophilic Addition 10 C=O Bond!
A. Aldehydes and KeloDeS
8. Eslers, Acyl Chlarides, Anhydridcs, and Amides
e CartlOD OjOJjdr and Derivatives
B. Djtbioeslcrs
c. Cubo" Djsulfide and CamOD Sulfidc
IV. Nucleopbilic Addilion lo C=N Bonds
A. Aldjmjnes and Kctjmjnes
8. Tminium SalOl
C. Iminoctbcn and Imjnolhjoctbcrs
D. Imi"9f"rbonates
E, Carbodjjmjdes
v. Nuclcophilic Addition lo cseN Bond.
VI. NucJcophilic Addition lo C- P or e P 80mb
References
18. NlICleo,lIilic: "'''lito. Co Mtlll-CarbcMI M.tlpIe Bod.
1 1M A Mnrwrdo and Po .. ! &hrcamfo
1. Introductjon
TI . Transition Metal Carbene Comple:tes
111. Transilion Metal Carbyne Complexes
IV. Condusion
Rcfcrenm
Philip E. &kila
1. Introductioo
A, 1.3-0iencs
B, Olher Coniugaled Olefins
c. Enones
D. Metal-Complexed Systems
V, Addition lO Aromatic Nuclei
A. Substituted Arenes
3"
361
361
363
364
365
]66
366
166
367
368
""
369
36'
36'
370
373
373
m
l77
379
379
381
381
lal
J ~
385
386
386
386
B. Aryne Quenchins
VI. MiSJ'lIanMul
Referenccs
20. NlICkophilic A4tlldoll to Carbu
O, S. N
Uone Miginiac
386
381
388
39'
1. lnuOOucl iQo 391
11. Nucleophi lic AdditioD 10 Conju&aled C=O Bond! 391
A. Coojugated Aldehydes and Ketones 391
B. Conjugaled Eslers 392
C. Conjugaled Amides 393
D. Alkylidene Malonates .nd Cyanacelales 39]
References 395
21. Adtlilkln lO OrpllOmelallic _lid Allyl Compkns 397
LiMl A. Ml'rcanda and Pau{ Mercando
Introduction 391
Transition Metal 391
Rcfcrt'nces 40]
pART VII: SPto,U. TOprcs: APPI .ICADONS ANO REActlONS OF
GRIGNARO REAGENTS
Davjd A. Burro
1. Inlrodllcljoo
11. Ma,:hani sm
111. Addition Reaelioos
D. Witb Kelones and Salurated Halida
IV. Cydizat ioo Reactioos
V, Coupling ReactioDS
YI. Djmerirntions
VII. Wittig-Type Reactions
.os
406
407
411
41'
411
417
'18
VIII.
Phospborw and Other Me"l.
418
A. Pbospborus
...
B. Tin
41'
C. Gcrmanium
'l'
D. Lead and Gallium
' 20
IX. Organosilane Reaajons
'20
A. Addition Reaajons
'20
B. Caroon and Oxyen Silyllljon
'" C. Cyclizaljon Reaclions
426
D. Coupling ReactiolUl
428
X. Ultruontc Reactions
434
Xl. Reaction witb Olher Metals and Metal Halides
'"
Refc:rences
'"
II Gria:nanl RnataCS u a.sr:
441
Wolltr Kosa,
lo Introduction
441
11. Basici ty Thcory and Measurement
442
111. Metallation
443
A. Intramolecular Rearrangc:mentl
443
B. Enolates
44'
C. Misccllaneou5 Reactions
4SO
IV. Elimination$
451
V.
Summary
'" References
'"
U . Sr"l Vt._ Sr"l'
'"
r ~ I O Figadi, t o1ld Xav!t, Fr01lde
lo Introduction
'"
11. Reactions with Organomagnesium Reagents
'" A. Allylic Halides
'" B. Allylic Pbosphates
4"
C. AlIylic Elhen
'"
D. Allylic Ammonium Salts
".
E. Propargyl Aloobols
""
F. ProparlYl Halides
"" G. Propargyl Aodates
461
H. Propargyl Elhen
462
lo ProparIY1 Oxiranes
""
J. Vinyl Oliranes
463
K. Intramolecular ReactiolUl
463
111. ReactioTU Catalyzed by Copper
464
A. Allylic "alides
...
B. Allylic Phosphllcs
467
C. AlIylic Ethen
469
D. Allylic Caroolylalcs
471
E. Vinyl Oliranc:s
476
F. Allylic Aziridines
478
G. AUylic Ammonium Salts 479
H. AlIylic Sulfides 479
1. AJlylic Sulrones 481
J. AlIylic Tosylates 483
K. Propargyl Oxirancs 483
L. Propargyl Etncrs
",
M. Propargyl Acetates 481
N. Propargyl Sul!inates 488
o. Propargyl Tosylates 488
IV. Reaclions Catalyzed by Palladium 489
A. Allylic Halides
"9
B. Allylic Acetates
"9
C. AlI ylic Ethers
"9
D. AlIylic Sulfides
"9
E. Propargyl Halides
49"
V. ReaClions Catalyzed by Other Transition Metals Fe, Ca, Mn)
49"
A. AlIylic Alcohols
49"
B. AII)'lic Phosphales 491
C. Allylic Sulfides
49'
D. Propargyl Chlorides
49'
VI. Candusion
49'
Rderenccs 494
2S. Di ... Jkk-Deri,ti Ol-Gripanl Rea&mts: Prepll ralion . ncI RculkHts "97
Kct'in C. CtulnQn and Grant R. Krow
1, Introduction 497
11. Alkyl Oi-Grignard Reagen!! 491
11 1. Reaelion! or Benzyl and Miled RenzylAryl Di-Grignard ReagenlS Si l
IV. Reaelion or Vin)'1 and Mi:ted Vinyl-Alkyl Di-Grignard Reagenl! SIS
V. Reaction or Diar)'1 Di-Grignard Reagenl! SI7
VI. Reaclions o Acet)'lenie and Mi.l.ed Ar)'lAcetylenic DiGrignard
Reagcntl 520
VII, Reaetions of AHyl DiGrignard Rcagcnts 521
Rcfcrem:es S22
26. FormalicNl. ncI Reae!_ or S.b5til_tet! (2-Butene- I,-4-4iyl)mal ts.m
ComP'exes
RtUMn D. Ril'kl' and MallMw S. Stl!
l. Introdlletion
11.
111.
IV. Preparat ion of Hcterocycies and Spiro Compounds
V, Preparation of l ,3-DicRC$
VI. Preparation of Cyelie Oienes
Rcfcrcnces
S27
'"
'29
S33
,,,
m
'"
27. Spil'Olllln.lat'- Vii., Sa.rihlt (z...htNe-I,4-4iyl)ms1 Ikm Compluet 539
D. Rielcr rmd Maultr.,., S. &//
l. Introduction 539
11. Reactions of 1,2Oimethylene CycIohexane-Magnesium Complell 539
A. With Bis-electrophiles 539
B. With Bromoallr.ylnitriles 540
C. Reaction with -Ethyl Acetate 542
111. Synthesis of Fused Carbocycles 543
A. Synlhesis of Spiro y-Lactones S46
B. Syothesis oC Spiro 6-LactODCS 548
IV. Generation of Quaternary Carboo Ceoters 549
A. Synthesis of Alcohols 549
B. Synthesis or 7-Lactams 550
References 554
l8. Asymmelik Syaomb V ... Ra .. tI 557
Joh" T.
1. Introduction 557
11. Addition 10 Carbonyl Derivatives 558
A. 1,2-Additions 558
B. 1,4-Additions S65
111. Nucleophilic Substitution Reactions with Grignatd Reagents S68
IV. Miscellaneous Reactions 570
V. Summary 573
Referenccs 573
29. Metal-Catalyu4 Rn.c-doDl 577
Hj,okazu U,abr a"d $610
1. Introduction 577
11. Copper..(:atalyzed Reactions 578
A. Substitution ReactioD S78
B. 1,2-Addition Reactions 10 Carbonyl Compounds 592
C. 1,4-Addition Reaclion 10 Carbonyl Compounds 592
D. Carbonmagnesation ofOlefins and Acetylenes 599
111. Niclr.el-Catalyzed Reactlons 599
A. Substitution Reaction 599
B. Carbonyl Addition 611
C. H)'dro- aOO Carbomagnesation oC Olefins and Acetylenes 611
IV. Palladium-Catalyzed Reactions 611
V. Titanium-Calalyzed Reactions 615
VJ. Misce11aneous Metal-Catalyzed Reactions 617
Glossary 621
Rcferenoes 622
JO. TIIe Pliparatioll or 1,1-BlrnHlllUcs of Mal aI.u alld Zlac
Pauf KnOlhrf
1. Introduction
63'
613
... ,
11. Preparalion of Mixed I,I-Bimetallics of Magnesium and Zinc
111. R.eactions af Milled 1, I-BimctaUics of Magnesium and Zinc
A. ScJective Reactions wilh Electrophiles
B 01e6081;00 Rcaetiaos
C. Oxidation of 1,l-BimetaJlics of Magncsium and Zinc
IV. Relatcd ReaFnts
Refcreof'M
31. Alkynyl Gria ... nI Ruacnb ... 'Their Usa
M(UQvuki U_no and Akio Suzukl
111.
63'
.,.
63.
637
640
641
642
""
647
D. Acelylenic Carbollylaion and Acytalion 6SS
E. Nucleophilie SubstilUlion Reactions 656
F. Conjugated Alkyncs and Polyalkynes 651
G. Organornclallic Acctylene Compounds with Metal Halides 658
H. Reacti ons oC Pro parar] Bad fu Protected Grignard Realen's 660
V. Protecting Melhods for Acclylenic Compounds 661
31. Grlpa RnaeAts 1M SU._
fkrry A r k / ~
1. Introduction
11. Formadon of he Silicon-Carbon Bond
A. Background
B. Reacti vily Tn:nds for Grignards and Si lanes
C. Process Chcmislry with Elhers
D. Prooess Chemistry Without Ethen
111. Silane-Blocking Asents
IV Cooclllsioo
Rdereoces
33. ZWe,ter-Nltll Cllllysis
8rjqnWS ~ r
J Introdl!ction
11. Grignard Reagenls as a Seoond Componen!
662
667
667
667
667
669
671
672
672
673
674
677
.78
34. Orpnomaa rsium eom,.... ' ir as PoIyilkib.ldolt laitlaton
x Quier Dr/ljOll
.'"
l Introduction 685
11. Polyrncrization of Methyl Mcthaa}'latc Usins Orpnomasnesium
Intiaton 686
A. Deseription of Stereoregularity in Poly(mcthyl methacrylatel 686
B. Forcca of Stereoregulation in Mcthyl Methacrylatc
Polymerization 686
C. Polymerizalion of MClhyl Methacrylatc Usiog Oraanomagnesim
Tnjtjators 688
111. POlymerization ar Other Acrylic aDd Methacrylic Esters Usiog
Grignard Reagents 692
IV. Anionic Polymcrization of Other Unsalurated Monomers Usios
Organomagnesium Compounds 694
A. Nilrogcn-Cootaining Mon01m1'$ 695
B. Halogcnated Monomers 697
C. Styrenic Monorncrs 697
/l1deX Wl
Contrlbutors
Barry Arkles, Ph.D. Presiden!, Geles! Ine., TuJlytown, Pennsylvania
Corndis BJomber, Pk.D. Free Univenily. Amsterdam, The Netherlands
Jo-Aan.e 1(. BOUlltel, Pb.D. Group Supervisor, Molecular and PolymerCharacterization,
Deparlmenl or Research and Dcvclopment.Centtal Analytica1 Chemistry, E1f Atocbem
Nonh America, Ine., King of Prussia, Pennsylvania
KHin e CanDOR, n.O. Research Scicntist, Spedalt)' Chemicals Group, Elf Atoc;hem
North Amenea, Tnc., King of Prussia, Pcnnsylvania
Paul a..bot, PlLD. Research Scientist, Depanment of Central AnaJytical Chcmistry, El(
Atochem Norlh Ameriea, Inc., King of Prussi .. Pennsylvania
Xavicr Drujon, Pb.D. Groupement de Rechcrches de Lacq, Elf Alochem S.A., Lacq,
France
BruIllO Fladere, Dr.5c. Department of Organic Chemisuy, Facult de Phannacie,
Universit Paris-Sud, ChAtenayMalabry, Franee
Xavler Fta.ck Doctoral Candidatc, Departmenl of Organic ChemiSlrY, Faculte de
Pharmacie, Univcrsite Paris-Sud, ChAtenay-Malabry, France
Ch.tlq Hamdottcl, Pk.D_ Research Scientist, LilIy Research Center, S.A., Madrid, Spain
.. ,
1l1l11
Pul kllOCltef Professor Doctor, Dcpart ment of Chemistr)', Vniversity of Marburs,
Marburs, Germsn)'
Bri W, S. kolthamllltl", Ph.O. Associate Scientist, Dc:panment of Pol)'olefins and
Elastomen Research, The Do .... Chemical Compan)', Frc:eport, Tuas
W."er Kosar, Ph,D. Restsrch Scientist, Dc:partment o[lndustrial Spc:cial ties, Elf Atachem
Nonh America. Inc., KinS of Prussia, PenflS)'lvania
G",II! R. Krow, Ph.O. Professor, Dc:partment of Chcmist r)', Temple Univcnit)'.
Philadelphia, Penns)'lvania
l..Jsa A. Merundo, Ph.O. Senior Research Chemist, Air Products and Chemicals, lne.,
AlIento .... n. Pennsylvania
Plul Merando, PILO. Scientist. Specialt)' Chemicals Group. Elf At achem Nonh Amerita,
Ine., KnS of Prussia, Pcnnsylvania
u- Mitin"c Professor, Laboratoire de S)' nl hese Organique, Faculte des Sciences,
Vnivenite de Poi tien, Poitien, France
GH"lnI Plrkin, O.PhiL Professor, ))epartmenl orChemistr)', Columbia Vniveni ly, New
York, New York
Philip E. Rl kitl, Ph.O. Business Manaser, Elr Atachem ASri, S.A., Plaisi r, France
Reubt n O. Rieke, Pb.D. PTofessor, Oc:partmcnl of Chemistry, University o Nebraska and
Rieke Metals, Inc. , Lincoln, Nebraska
Johl T. Robtrts. Ph.D. Director. Chemicals Research, Chemical Specialt ics and Plastic
Additives, Elf Alochem North America. lne.. King of Prussia, Pennsy/vania
Olyld A. RImO, Pb..D. Research Scientist, Spc:cialt)' Chemicals Group, Elf Atochcm North
America, Ine.. King of Prussia, Pennsylyania
Fumie Salo, Ph.O. Professor. Dc:partmcnt of BiomoleculllT Engineerins, Tokyo Instit ute
ofTechnology, Yokohama. KanaSllwa, Japan
l\bllhew S. Sel! Research Chemist, Ri eke Metal!, Inc., Lincoln, Nebraska
Glry S. Sihmnall, n.O. Pri ncipal Seicntis!, Specialt)' Chcmicals Group. Elf Atachem
North Amcrica, lne.. KinS of Prussia, Pennsylvsnia
Akio Su:r.ukt, Ph.D. Senior Technicat Ad"isor, Fine Chemicl ls Oi"ision, Hokko
Chemlclllndustry Co., Lid., Tokyo, Japan
'"
c--...
Hull'on L. Uhm. n.D. Scientisl, Spccialty Chcmicals Group, Elf Atochem Nonh
Amerita, Tnc., King or Prussia, Pcnnsylvania
Mauyukl Umeno Manager, Process RC$carch, Fine Chemicals Resean:h Laboratories,
Hokko Chemital 'nduslr)' Co., LId., Alugi, Kanagawa, Japan
Hlrokuu Urabe, Pb.D. Assistant Professor, Deparlmenl of Biomolecular Engineerin,
Tokyo Institule of Techonlog)', Yokohama, Kanagawa, lapan
Ihrry M. Walbonky, Ph.D, Professor, Depanment of Chemistry, The Florida Slalc
Uni vcrsity, Tallahassee, Florida
1
Introductlon
PHIUP E. AAKITA
A/clJlrlmtJ CMmlcallndwlrwJ Co . LId., ToIcyo, JDpQII
l. HISTOAICAL BACKGROUND
Of aU the "name reactions" in chemistry, tbere is arguably none better known lhan the
"Grignard reaclion." It is hardly aD exageraton 10 u)' Iha! virtually every chemist, al
sorne lime or anothcr in bis or her professionallife. has carnee! out a Grignard rcaction.
The great scope and the versatility of Ihis reaction has made it a r ~ u e n t choice for
laborator)' synthesis ando increasingly, for lhe industrial production oC high-value-added
specialty chemicals used as calalysts or for intermediates in lhe food, flavor, fragrance,
and pharmaceulical industries.
The terrn Grignard rtadion actual])' reren 10 two separa!e steps:
1. The formalion oC a Grignard reagent from Ihe rea.elion of magnesium with aD
organic halide in a suitable solveo! [Eq. (I)).
RX -+- Mg -+- nS -Jo RMgX'S
n
(1)
2. The subsequent reaction oC Ihis reagenl with an organic or inorganic subslrate
lo yield a producl by eilher addition [Eq. (2)] or subslitulion [Eq. (J)].
RMgXoS
n
+ AZ ~ RAZMgXoS
n
RAZMgXoS
n
+ H
2
0 -+ RAZH + MgXOH + Sn
RMgXoS
n
+ AZ -+ RAZMgXoS
n
RAZMgXoS
n
-+ RA + ZMgXoS
n
(2)
(3)
f
~ '"
,
.....
In Eq. (2), the workup typi<:ally nvalva a water c!cavage ol he MgZ bond, whereas for
Eq. (3). here is a sponlaneous cl imination oTlhe magnesi um-c::ontaining rragment. Togethcr
(cither 1+2 or 1+3) these !teps constitulc whal toda)' i, mean! by a Ongoard reaction.
Thc fin! cxamptc of "", hal i5 now knnwn as a Grignard reaclion was observed, in
1899. by Barbicr [1 ]. He reported Ihal a mixture of methyl iodide. a methyl kctone, and
magnesium metal in dicthyl cl her produce<! a teniar)' alcohol. He assigned 10 his sludcnt,
Victor GTignard, he task af unravtling he mechanism of Ihis unusual result. The dctailed
ludies by Grignard [ 2], finl publ is hcd in 1900 and prescnted in his doctoral Ihcsis in
1901. established Ihat he reaction observe<! by Barbier could be separated inlo hree
distinct steps:
/ "
, ... J '

/H,
/ '
___ o
I ' -', /
" .0 _____ ~ ",1(011)
(4)
(' )
(6)
The real valuc or his observation was he =snition Ihat Ihis sequence was quite general
and oould be used lO prepare an e:tlraordinary variel y of ncw oompounds. Grignard
devole<! much of he rest of his carecr lO broadcning he soopc and underst anding of Ihis
rcaelion and was rccogni z.ed ror his achievements wilh the Nobel Prize in Chemisuy in
1912 al he age of 39. In he )'ean Ihat fol1owed, he Grignard reaction was increasingly
cmployed as aconvcnicnt aOO w:rsatilc tool for Iabornlory !ynlllesis. Howevcr, he relativc:ly
high COsl of magncsium and Ihe more reactive organic bromides and iodidcs, as wdl as
lhe: haurds associated with diethyl ether as a SOlvenl, proved 10 be limitatioos lO
cornmercializat ion on an industrial scak
Starting in he 195Os, several <kvc:lopments cad 10 improvcd industrial prooedures.
Thesc ndude<! lhe substitut ion of tetrahydrofuran (THF) [3) fo r dielhyl et her, together
with lbe recogni tion t hat t he Icss n:active, but signifi&antly less expensive, organie chlorides
could be Illccessfully used in place of the btomides or iodidcs [4--7). Several companies,
ineluding Arapahoe Cbemicals (now parl of Synlex) and M&T Chemicals (now parl 01
Elr Alochem) among olben, beo;arne TIl(:rchanl suppliel'$ ofGrignard rcagents in prodw:;tion
quantities lo Ihe fine chemi&al industry for Ihe manufacture of fl avor, fragrance, and
pharmaceul ical intermediates..
Today, less Ihan 100 ~ a r s afler Ihe first di scovery of this n:act ion. Ihe chemical
lileralure contains leos of Ihousands o n:fcn:nces to Ihis n:aclion. and Ihe indust rial
product ion of Grignard Teagents for caplive use or merchant sale is eslimated 10 excced
50,000 tons annually (8). The scope and potential ror Ihe Grignard react ion continues 10
grow and new discoveries and improvemenls in mcthod an: regularly reported. Tbe balance
of Ihis book i5 devole<! 10 delailed n:ports on Ihe pn:paralion. analysis., sl ructure, and
reactivi ty ofGrignard reagent! Ind I $Clecl ion ofta pies and applicatians of curn:nt inleres\.

,
11. THE NATURE OF THE GAIGNARD AEAOENT
The original formula, RMaX, fiI1llt propase<! for Ihe Grignard reagcnl, by Viclor Grignard
himselr, has a convenienoe and economy of sl)'le Ihat belies i1$ true naturc. Following lhe
nitial rcports, il bccame quickly apparcnt Ihat Ihe actual struclurc il far more complex,
both in 50lution and in Ihe salid stale. One early suggestion [9] was an equilibrium of
Ihe type:
2RMgX e:> R
2
Mg + MgX
2
(7)
Supporting Ihis vicw was Ihe observation Ihat dioxane could be use<! lo precipitate MgXl
from Grignard solutions. (This lo in fael, a convenient mClhod for Ihe prcparalion of
solutions of diallcyl magnesium.) What followed was an eJltensive series af sludies by
Schlenk and Schlenk [lO). The)' proposed a se! of equilibria, in which Eq. (1) was
accompanied by Eq.
(8)
lo describe Ihe behavior of Ihe Grignard reaaen! in solution. Olher studies, ineluding
eonduelivi lY, electrolysis, and isotopie e10ehange reactions, gave resull! Ihat could vanously
be interprcted as $upporting or contradieting the elassie Schlenk equilibna. The carlier
worl: was reviewed by Ashby, in 1974 [11), and !Upported Ihe conelusion Ihat all of the
reported compositions of the Grignard rcagenl could be found, 10 some degn:e, depending
on Ihe nalure of organie group. halide, solvent. concentration, and so rorth. Neverthelcss,
for virtually all practical purposes, the simple, sloichiomelric struetun:, RMaX, is sufficient
lo describe he Grignard rcagent.
111. SCOPE OF THE OAIONAAD AUcnON
The grcal value or Ihe Grignard reaelion 10 the synlhetic ehemisl is ils generality as a
building block ror an impressive Tange of Slructures and runctional group$. Similar lO
other organomelallie compounds of the group 1, 11, and JII clemenlll (for e1Oample,
organoli lhium and organoaluminum compounds), Grignard reagenlll act as bolh (1)
prototypical carbon nuc1eophilcs thal can undergo addilion or substitution reactions and
(2) Slrong bases Ihat can deprotonatc acidie substrates, giving conjugate bases or produets
or clirnination reaetions. A elassic, rby now somewhat daled compendium of the reactions
of Grignard cornpounds with non rnetallie lubstances il Ihe volumc by Kharasch and
Reinmuth [12J.
Grignard reagents rcael wilh mOlI organic functional groups conlaining polar rnulliple
bonds (c.g., I:etones, nitriles, sulfones, imines), highly slraiocd rings (c.g., epo1Oides and
sorne eyeloall:encs), acidie hydrogens (e.g., alkyncs), and sorne higbly polar single bonds
(c.g., carbon- halogcn or A summary list is pn:senlcd in Table 1. AlIhough
Ihis lable is by no means uhaustive, il iIlustrates the breadth and richncss of possibi lilics
available with Ihe Grignard reaClion. To givc ooly two cnmplc:s. a varialioo or reaction
conditions pcrmils he convenion ofan ester 10 eilher a tertiary alcohol(sce Table 1, entry 9)

(9)
+ Z MH,X
'"

Tibie t
,,,
,"
,,,
,,,
,"
,"
,,,
1","
,,,
10"
\S"
11
10
Reaction of RMgX .... ilh Substrltes
...... H
, ,
,',
"'" ,
,
Il, llll '
,
Il LI., al-
,
R' ll..
crII
"
,
1,u...O1I
o

,

J RH,X
2 IlH,X
Cul,<
2 '"IX
"
"
".
',""

lt 0-11
Il?<a
,
liAR
lO- K
IX!
I 0-11
RXIl
11 _0 K
,X;,
,
,,)t..
,
'.
6-,
, ,

11 R' 0.
11
.....
T.bIe I
ln<rx
11 "
22'("
21 "
24
U
HU
a"
' . 0
l O"
COIICillued
Rue"n'
"
)=C:O
"
O
"
. S ....... 1
" O
II'Ut'
,
,
<S.
11' - 11-1:_'
,-"
R'.!!."
')b
"
"
-
-
"
-
-
,

"-enU
2 IM,I
2 111,1
O
")l.,
" O
"
, ..
R' '1
u<
uu
.. ,


O
..
..... S ... O II
,
" .Jl..
'NK I
O
R,ll.
,
"O.!
l' l'
.0
..... """ -- '11
"
-
-
'.
,
"
F ' =

Sowu: Ah elChe""""al radioru ...... takCtl from EltAIochem. n.. Hm ......
olGr/flr<lNl Rut:llOfts, 2nd od. 1m 11

, .... ,

or a kctonc (scc Table 1, entr)'
o
11
R' - C - DR- + RMgX
.....
o
11
... R' - e - R
(lO)
Likcwise. Ihe rcaclion of a Grignard reagenl wilh a cyclohuenone can resul! in eilller
1,2-addition 10 produce a lub5t ituted cyclohcxenol (sce Table 1, cntry 18)
o
(1 1 )

or 1,4-addition lO give a 3-substi tuted cyclonexanone (see Table 1, cnlr)'
o o
(12)
+ RMgX
cal.
The specific reaellon!, classified acoording 10 type, are discussed in greatcr detail in
Scction VI (Chapters
IV. OROANIZATION Of THIS BOOK
General methods for lhe preparation of Grignard reagents are in Chapler 2,
lheir prcparation from oldios in Chaptcr 3, and Ihe special features ofmagnesium aetivation
in Chaplcr 4. Sare-handling prooedures are described in Chapter 5 and classic wel mClhods
of anal)'!is in Chaplcr 6. The spect roscopic anal)'sls of Grignards by iorrare<! (Chaplcr 7)
and nuclear magnclic resonancc (Chapler 8) revea[ infonnal ion concerning Ihe struClures
present in $Olution, whereas X-ray crystallographic studies (Chapter 9) presenl lhe resulta
in the $Olid state.
Further in5igbl 10 the nalUTe 01 Ihe Grignand reagent can be ohtained from sludies
orthe mechanism orronnation (Chapter 10) and reaclion (Chapter 11) ol Grignard reagents,
and the relalionships belween slruClure and reaclivily (Chapter 12). These are preseolcd
io Pan V, along with a rcview orlhe Sehlenk equilibrium (Chapler 13) aod Ihe eITeel
of polypyrazoylborate ligands (Chaptcr This i5 lollowed by discussioos of the general
clusel of reactions (both substitulion and addilion reactions) io Pan VI. Substilution
reaclions al single bonds are reviewed aooording 10 whel her lhe electrophilie subslrate is
an organic majn group clement (Chaptcr IS) or a transilion metal oompound. Nucleophilie
addilion reaclions al multiple boods are dassified aooording lO whelher Ihe multiple bond
is unoonjugated carbon--carbon (Chapter 16). carbon- heteroatom (Chapter 17). or
carbon- metal (Chapter 18); or conjugaled carbon--carbon (Chapter 19). carbon-heteroatom
(Chapter 20). or carbon-rnelal (Chapter 21).
P"'OC
1
Finall )', Parl VII (eh.plell 22-34) il devoted 10 nrin of I pec:i .1 topie, in
Orignard clM:misuy, highJighting $Cveral areas or " :earch nlerest, activit ie5, and
applications.
REFERENCES
L P. Barbicr, Compl. R,,,d. /18:110
2. V. Grignard, Compl . RIM. 1)0: 1322
3. Tetrahy<lroful"I.na,. Reac:tion Solvent, E.tdu Pont de Nemours&Co. Wilminton DE. 1%0.
4. H. E Ramsden. U.s. PatcO! 2,79S,628, J UM 11, 19S7, 10 Metal ,00 Tbermit Corp.
S. H. E. Rilmsden, U.S. Pllent 2,813,27.5, Febtuary 10. 1959, lo Metal In<! Thermit Corp.
6. E. Kaiser and L Sporlr, U.S. Pllenl 2.8.8 1,225, April 7, 19S9 10 Armour Ind Co.
7. H. E. Ramsden and A. Balint, U.s. Pltent 1,9S\l$6. November 8, 1960, 10 Metal and "Thermit
Carpo
8. G. S. Silverman , 00 P. E. Raldt .. Orign.rd reactiona, Klrk-ollr_r &cydop.tdiG .,1 Cltmrictll
Th"oIog)'. Vol. 12, 4th ro. p. 768, 1994.
9. R. Abeg. Chmo. &r. M:4112 (90S).
10. W. Schlcnk ,00 W. Schlcnk. Jr., ChmI. Ber. 618:920 (1929).
11. E. C . .... shby, J. Laemmdc,.nd H. M. Ncumann, Ae(". CMm. Ru 7:272 (1974).
12 M. S. Kharas<:h.nd O. Reinmuth, Grignard Rncfiotu o[ N_fallic Subslanul, Prcnliec-H.U.
Enlllcwood ailfa, NJ, 19S4.
13. T. G. B, ilkina Ind V . ..... Shusbunov, /mmiotu COII1pouttds wjh OXY9"' fIIId
Pt rox;tkl, Chcmkal Rubber Company Pn:ss, OH, 1969.
14. M. E. Volpin Ind l. S. Kolomnikoy, Or9O_1. Rncl .. 1;)1) (197S}.
lS. J. Nolles, 8ull. Soc. Ch;",. Fr. 21S1 (1972).
16. T. l mamoto, N. T.kiy.ma, Ind K. Nak.mura, Tt lraMdrl1ll II. 16:4763 (198S).
17. G. 01. h, G. K. S. Prakuh, .nd M . .... rv.Mlhi. SynIMIU, 228 (1984).
18. J. Fauv.rquc, J. Ducom, I nd J. F. COItIpl. /WId. (e) 17H1 1 (1972). But scc,.1so
V. Fiandanese, V. Marchese, G. Manina,.nd L Ronzini, T,fraMdrl1ll II. 15:4805 ( 1984).
19. J. Mlrch, AdrJo"crd Orflllllk Otmisrry, John Wilcy &. Sons, Ne .. York, NY, 1985.
20. S. O. Lawc:sson.OO N. C. Y.n" J. Am. eMm. Soc. 81:4230(l9S9). But leC allO S. O. La_n,
c. Frisell. D. Z. Denney, aOO D. B. Oenney, T,'fQMdrOll. 19: 1229 (1963).
21. E ... . Org_Iol/la In Orfll1ll;C SynrMlis, Jolln Wiley &: Sons, Ne .. York, 1980.
22 C. L Raslon .nd G. Salem, Preparation Ind \IX of GrilJllrd .00 group 11 orpnomet.llic:l
in orpnie Iynlhe:sis, .,.", Clttmisl' y o[ 1M Mtlalearbolo /kM/, Vol. 4 (F. R. H."ley, ed.). John
Wiley &: Sons, New York, 1981, Ch.p. 2.
23. R ...... Kjonaas .nd E. W. Vawtet", J. Org. e'-'. 5/:3993 (1986).
24. J. CoIongc .nd R. M.rey, Orga"lc Sy"'Mlis IV, 601 (1963).
25. D. N. H.rpp, S. M. Vincs, J. P. Montillier,.1Id T-H. Ch.n, J. Org. CM",. 4/ :3987 (1976).
26. S. Patai. T1tt CM",isl' y o[ 1M 111101 Group. Pa" 1, John Wilcy &: Sonl, He", York, 1974.
27. D. Plquer, 8ull. Soc. Olm. Fr. 1439 (197S).
28. W. Kitchi nl lOO C. W. Fon" OrgallOfMl. elrtm. Rn. 51. A 5;28 1 (1970).
29. F ..... singcr, P. Lalle, B. Fell,.OO G. Gubelt, Clttm. lJt . /00:1696 ( 1967).
30. P. C.nonne, G. B. Foscolos, I nd G. Lemay, TttraMdrOIIlI. ll;1SS {1980).
31. S. Plt.i, T1tt Cllrmisl.)' of 1M Doubk Bond, Inlencience. New York, 1970.
32. G. 8oircau, O . .... benhaim, J. L Nlmy,lnd E. Henry-8nch,Zhur. Org. KJrfm. /1: IMI (1976).
J3. R . .... ndef1Ol1, J. Am. CM"'. Soc. 9.2:4978
34. T. JelferyLuonllnd G. Unstrul"I"\elle, TtlrtlMdrl1ll lI.11:SOI9
'"
2
Common Melhods 01 Grlgnard Raaganl
Preparallon
GARY l . SILVERMAN
EIf ArocMm Norflr AlllffiCll. 1m:" King of I'nlJf6, I'tmUyltJQII/(l
l. GENERAL DIBCUSSION OH THE AU.cnOH OF MAQNI!81UM AND RX
The prololypical GriJIlard reagenl preparation involves he reaction ol ao allt)'1 oc aryl
halide (RX) wilh magnesium (Mil in an elhercal solvent, uoder renuJ: conditions [1,2].
nitiation af Ihis reaction should occur wilhin he firsl 10-20 wl"'" addition af lhe RX
solution. Evidencc for Ihis nitiation i$ I large uothenn, and a visual change o lhe
magnesium lumings from briht-shiny lver color lO a duU gray-blacl;. M.o)' chemub
look for Ihis color ehaoge in he magnesium or 5Olution, bul Ihis can be misleading ir the
aptation is strong enough 10 shur lhe magnesiurn (see ehapler ~ Until nilialion hu
tx:cn confinned, no more Iban 20 wl "-. orlhe RX charge should be addcd lo lhe reactor.
Otherwise, one riskl njtiation af Ihi. clI:olhermic reaction .ner a1l or Ihe RX has beco
added. ThiJ is one or lhe major hazardJ in Ihe Grignard reaenl preparalion, because lbe
mulling rapid exOlhellll will cause a release or lhe reactor conlenta inlO the atnlosphere.
Therefore, an appropriale hazard revlcw should be conduele<! before carrying 01.11 Ihis
reaclion [3,4]. From a laboralory safely paiol or view lhe following precaulions are
recommended:
1. lsolale reaction selup in a hood.
2. Place a lpilll ray benealh lhe l\as.k.
3. Inslall a venl relief and a surge flask lo prevenl lhe release of lhe RX-$()!venl
mixture lo the environmeoL
4. Use telrahydrofuran (THF) inslead oC diethyl ether (ElzO).
5. Use activity measuremenlS (see Chapter 6) to determine if nitiatioD hu occurred.
,
p' m
"
SllJhIllMl
The handling technique and choice of RX, solvt:nt. and magnesium can havc a
significanl effcct on he preparation and yieJd of llle Grignard rea&<,nt. Sorne o(the potentiaJ
problems are homocoupled product, intramoJccular rcactions, formali on or
and Ihe noni nitiated rcaction or RX with Mg. Thererore, propcr manipulation and drying
(Ir each componen! mUSI be carried out.
11. EFFECT OF WATER ANO OXYGEN OH GAIONAAD AEAGENT PREPARATIOH
The reaclion apparatus. RX, $Olvent, and Mg muSI be dry (J.ess Ihan 0.02 wt Y. of H:O)
and free: of O. Ir lhe HlO conten! is aboye 0.02 wt%, lhen Ihe reaction or Mg and RX
will no! nitiate propcrly. exc:ept for 3n exlremely reactive RX species, such as henzrl
bromidc.
Unrortunately, Ihe presencc or HIO Iypically lcad! lo a sudden nitiation after all
of lhe RX hu been added. This laltes place bccausc lhe residual H10 i5 azeolropcd
oul of the mixlure during reHux, or lhe H10 i5 actually consumcd by residual Grignard
rugen! in Ihe flask, and lhe solulion evcntually rcachc5 a dry, inen state, al which lhe
reaction can initiale. TIae conscquence is a sudden initialion, with a large exolherm that
cannol be handlcd by Ihe condenscr, resulting in lhe reaClion flask contents being spcwcd
into Ihe almosphere. This is oroe of the mOSI common mistakcs Ihal a novice Grignard
ehcmist will make.
To plllvcnl Ihe foregoing secnario, all solvents and reaclanls should be dricd and
manipulalcd under nitrogen (argon) by slandard Schlcnk or g1oyebox lechniqucs [j]. Since
HJO reacts with Grignard reagents 10 fonn the resulting prol onatcd produet [Eq. (1)]
[ 1,2], then H
1
0 can be eliminatcd by Ihe addition of Ihe same Grignard rcagent from a
previou! rcaelion. In fael Ihis method of climinating HO i! the mos! cost-cffectiye way
10 make Grignard reagenls on an industrial seale (6].
RMgX + H10'--, R- H + MgX(OH) (1 )
Other prccaulions Ihal should be laken are to confirm nitialion (exothenn and an
actiyilY litralion) and, under aU circumslance:s, no more Ihan 20 wt"1o of Ihe RX should
be added unti l ioitiation has becn confirmcd.
Although advcntilious O will not retard lhe intialion process. lhe 0
1
will reael
with the Grignard reagent to form an RMgOX specics{sce Chaplcr 14). TIai! pcroxo-speel::s
can oxidizc ot hcr reaclanl$, ligands. calaly! l, or final product in Ihc subsequenl coupling
llIaction. Furthennore, upon hydrolysis, the oxidizcd Grignard reagent will form an ROH
spccies Ihat may alUSC purificat ion problems.
An example of Ihis oxidation problem is obscryed in the preparation or
lriphcnylphosphine usi ng 3.1j equivalents of Grignard llIagent [Eq. (2)) [7- 9]. If Ihis
rcael ion i$ hydrolyzcd in air instcad of an incrt N
l
atmospherc, then the amount or
triphenylphosphine oxide will increase from less than t mot-!o 10 grealer Ihan 1 j mot-! .
Whcn Ihcre is no exCCS5 of lhe Grignard reagent, Ihere is no inerease in the amoun! of
triphenylphosphine oxide fonncd in air (less Ihan 1 TIais indi catcs that oxidalion
of lhe Grignard reagcnl is fasl, probably diffusion-conlrolled, and Ihal Ihe pcroxo-specics
is a bctter oxidant for triphcnylphosphine Ihan 0
1
.
O)P+3.1K,H,MgCl ,0.Ij(C. H,hPO+0.8j(C.H,)P (2)
111. EFFECT OF SOlVENT ON GAIGNAAD RUGENT PAEPAAATION
Diethyl ether has becn Ihe solyent of choice unlil altemative ethers bccame commercially
ayailable, in particular THF [10,1 1]. Virtually alt elncreal solvenls haye becn evaluated
"' .' ..
"
as wcll as vanOUi nonpolar hydrocarbons. 1crdore, preliminary thought should
be spent on choosing the appropnale salvenl for lhe Grignard reagenl preparation and
subsequent ooupling reaction. There are rour ke)' oonsldeTations in choosing a salven!:
chemistr)', safel)', economia, and rtactivil)'.
The solvenl can significantly affccl Ihe cbcmislty of lhe GriBnard reagenl, such as
)'ield impro'l(!UKnlS (Eq. (3): 12), slereochemical (Eq. (4): 13] and reJiochemical oontrol
[Eq. (5): 14], and Ihe formadon of dialkylmasncsium !pecies [Eq. (6): I S). 1"hest solvent
effccu can be attnbulcd 10 Ihe solven!'! polanlY, basicity, steric hinderance" and shift. in
Ihe Schlenk equilibrium (see Chapter
4C," J Br + 4MB + BF )O(Eth,--." (e," ,).BMgBr + 3MgBt(F)
,...,
,
,
X'"
,
+

THF . %%
EI,O %
......,..-
,.
na 15 11: 12
." 62:]'
,
'"
(3)
(4)
(5)
(6)
Safely issues are dircclly relalcd 10 the solvent'. flash point [6,16). From Ihis point
of view, dielh)'l elher is Ihe worst choice for a salvenl rrable 1). Mast industrial Grignard
T.bIe 1 Scleo;tcd Solven! Propcrticl'
Properry
Flash poinl (oC)
TLV (ppm)
BIIlicily (B)
[17,18]
Diele<:trie
ronstanl
Bolin, poinl"C)
Densily (J/m)
THF
->4
lOO
'"
7.54
66
0.89
DlI. fmm Rd. 6J.
EI,O
",
' .l4
"
0.71
IIHeulle
-22
"
.. "
68
0.66
Toluene

,""
D78
'" 0.87
Xylene
21
,""
1,4-Oioune
"
"
uo
,,,
....
'"
SItowun
proreS' e5 have JwilChcd 10 THF in lieu of diethyl ether bccaU5C or he ftuh poinl issuc.
Other safely consideratiool an: the followina: the raw material. (TL V), the n:ac:tive Grilllard
rtIllent, and pcroxide fonualion in the elhers. Thercforc, the Malerial Sl1fely Data Sheel
of Ihe solvenl and all of lhe reactanll should be carefuUy rcad and uDdcrstood by lhe
chcmisl, so that lhe appropriate prccaulions an: talr.en.
E!conomie considerations are not an is"ue for t.lploratory worlr. carricd OUI in the
labaratory. Howcver, these issucs are pcrtinent from a business pcrspoctive. The rollowing
faetors nced lo be evalualcd: cosl of Ihe solvenl, case and cosl of rtCycliog the solvent,
volume efficiency (1OIubility, cspccially for RMgCI derivalivcs), and rcquircd tempcraturcs
for pn:paration aOO l ubscqucnt coupling reactionl. Given Ihese mleria, dicthyl elher falls
short bccausc of iocfficient reoovery, low reftull lempcralurc limil al almospheric prmurc,
and low RMgCI sol ubility rclativc 10 THF. The RMgCI is rcquircd bccause oftbe significan!
economic advantage Ihat RO has over RBr or RI.
Thc lasl considerali on is the rtactivity or the Grignard rtagent wilh the solvenl ilself.
Dclelerioul reactions of the Grignard rcagcnl with clhercal solvents occurs only under
extreme condiliool and has becn obscrvcd, lo some ellleol, in dielhyl elher, di-o-butyl
elher, THF, '.bulylmelhyl elher, anisole (155"C), DME, and allylphenyl ether [Eq. (7);
19- 24]. Sincc Ihese reactions occur ooly under t.llreme conditions, the cthcreal solvenls
are prcferrcd bccause of lhe high Grignard reagent solubi li ty (up lo 4 M).

(7)
Amines can be uscd for Grignard rtagent prcparalion. but Ihe solubility il poor (Iess
Ihan I M) and, occasionally, formalion oflhe ammonium salt will cause problcms [1,25,26].
Hydrocarbon solvents, Juch as ht.lane and loluenc, do nOI solubilizc MgX cffectively,
m ulling in lhe formalion of diorganomagncsium derivalivcs. This is a cost--elfective method
lo prcpan: diorganomagncsium derivativcs [1 5,27- 30]. The insolubility of lhe MgXJ is
also ob$ervcd with 1,4-di oxaoc and, 10 some degrcc, with chelat ing solvenl5 such u
TMEDA and hexamcthylph05phoramide In fael the addilion of 1,4-dioJlloc il
a common Icchniquc lo mah halMic-frcc RJMg [Eq. (8); 31 - 33)].
0-
o
(8)
Talr.ing lhe ehemistty, safety, cconomics, aod n:activity ioto aecaunt complicales lhe
solven! choice and typically compromi5es must be made in al !eaJ1 one oC the facto" lo
meel the requin:mcnl5 for Ihe applicalion. The elhercaJ solvents are Iypically prcferrcd
because of lhe Grignard reagcnt'. high solubility. From a safety, economic, aOO usual1y,
a ehemical pcrspoctivc, THF il the best all-around solvenl for Grignard rcagenll. However,
THF does have limitatiOlU similar lo Inc nonpolar solventa when RMgJ spccics are desired
(i.e., low solubi lily oC Mgl
l
rtSulting in Ihe rormalion of RJMg).
,-, -
"
IV. EFFECT OFAX ON GAIGNAAD AEAGENT PAEPAAAT10N
80th the halogen and the R group wiU affect the Grignard reagen! pn:paralion. For the
halogen, the r.te of disappear ....... of Mg follows the general order I > Br>OF.
Unforlunalely, the rate ofdisappcaranceofMldocs nol alw.y.correlate with the formation
of active Grignard Typically, he more reactive Ihe RX is, lhe higher the probability of
ronning a homocoupJcd producto Thcrdorc, wbcn choosing X. the rate of rcactivity,
sol ubi lily, produCl selectivilY, and COSI muSI be laken inlo account.
Thc general efl'ect of R on lhe rate of disappc.ram;:c of Mg is allyl, bcnzyl > primary
alkyl> $CI;Ondary alkyl, cycloalkyl ;' lertiary aromatic> yi ny!. Apio, the more
n:aeliYe R is, the more probable Ihe fonnalion ofhomoooupJcd product Another importanl
consideration for the R group is the compalibility of functional groups in . the orpnK:
halide. BccaU5C of the rcactivity of the Grignard reagenl (scc Chaplers 1, 15-21).
noncompatible functional groups nced lo be prolCClcd. sorne ehemisls design a
rcactive functionality into Ihe organK: halide 10 carry oul an intramolccular cyclizalioD
($Ce Chapters 25-27).
Sinoc: the ruetion of RX with Mg lo gcncrate RMgX is a formal oxid.live addition,
then a hcuer w.y lO look .t lhe rcactivity is 10 consider Ihe rcduction potenlial of Ihe
RX. For the rcaclion 10 be thermodynamically fcasible, lJ.E must be po!Jitiye (i.e., p-lJ.G).
This mcans Ihal Ihe rcduction potential ror RX musl be more positive Ihan the rcduetion
pllential of Mg2+ lO Mio which hl5 a slaDdard rc<luction pltcnlial or - 2.37S V [34].
Sinoc: the rcduction polenlials are really affected by solvcnt and rcference electrodc,
comparisons and discunion oftrends musl be mlde under the same elcclrochcmical sy!lcm
(rabIe
The reduction potentials, within tbe same elcctrochcmical systcm, an: cdnsiSlenl with
the pn:yiously statcd lrends for the halogcns (sce Table 2, cntrles 8-10 or 19-21) .nd R
groups (sce Table 2, entnes 26, 9, 13, 14, IS, 17, 7). Use of Ihe rcduedon potentials
alJows the cbem$t lo combine Ihe rcactivity elfCC\!l 01 tbe halogen aOO the R;group 10
anticpate Ihe polenti.1 difficulty in m.king a Grignard reagent. Generalilics aboul Ihese
rcduclion polenliab (DMF'SCE) ror Orign.rd reagent preparation are
Grealer than - 2.0:
- 2.0to - 2.3:
Len than -2.3:
facile reaclion and high homocoupling
modcrate rcactivity .nd low homocoupling
sJuggi5h reaction and no homocoupling
In highly reacliye RX species, such as benzyl bromide (BzBr). lhe: rormation or high
leyels of dibcnzyl (Bz
J
) is typica!. In fact, 8Z
2
can be made quantital iyely rrom Ihis rcaction.
The leve! of BZ
2
can be minimiud by docrcasing the foll owing reaction paramelers:
lempcralure, concenlration, and addition rate. Increasinl the Mg surfaoc: area .nd man
tran5fer wiJI al$O decrcasc Ihe 8z
2
formation. All of thesc parameler adjUSlments .re aimcd
at fayoring an intennolecul. r rcaction of Mg and BzBr 'versus tbe intermolecul.r rcaction
of BzMgBr with BzBr.
In sluggish rcactions,5ueh as lhe rcaction of magncsium wilh chlorobenicne (PhQ).
there are several process conditions th.t can belp racililale lhe rcaetion. As in the preceding
examplc, tbe followiDg reaction parameten can be u5Cd: agilalion rale, tcmpcrature,
addilion rate, concenlration, MI sudace arca,.nd mass transfer. To optimize Ihe reactioD
of RX .nd Mg a high Mg sudace arca (see Chapler 4) and hlgh agilation (good ml5S
lransfcr) is rcquim!. Thc Icmpcrature can be rai5Cd 10 ncar reflul (6O"C in THF) 10 providc.
the actiyalion energy for Ihe reaclion. This lechnique js particularly effcctive with .rom.tic
chlorides. Thcse aromatie rcactions can be run at a highc:r concentralion and rasler addil ion
"
5/Aa .. I1M
T. ble 2 Selecled Reduct ion POlcnl iall or RX'
.. I ..... I IIoIU_ ....
bhc...,. rot..,u.
b'"
,
,,,.d l ecU_

loof ........
,
"'.'
OI.CIIU'UII/ICI
_1.31
" ,
al., .. _lftAal/lCI
- 1. "
"
,
01,1;1 _('ftUI/la -2. 1'
"

01,01,'
CII, CII(IUI)/la - 1.)6
"
,
C.,CII
,
_
al,CII(ftAII)flCI 1.12
" DMI'(ftAI )/.CII -2.11
"

1..aI, CIII. I .. 7 ~ DO{ftIoI )"a -l. 52
"
,
?'-I ..
7S- IIO{nul/ICI -2. U
"
~
15' DO(TIAP)flCI
_I.n
"
~ ..
75' DO(IUP)/ICI _l. 2t
"
_ ( IUT' I/leI -1.29
"
"
:--Cl
15' IIO(TUr)a:CII
-1. ,.
" _CIUT')/I'ar - 2.0!
"
U OI , CII,CII,I .. DMI'{'ftAIl!JCI -z. n
" U
aI. '*Ck)CII.
_(ftoU)/SCII _l.r!
" U
CII.(lII,'.'"
_(TIW)/ICI
- 1. "
"
,.
c:.. CII (Ir) CII. CII. _<nu)/ICI - 2. )4
"
"
(CIIII . Clr ,l,.(ft.U')/.CI
-2."
"
DMl'lftAI)/ICI _2. 1'
"
U
0-'
7S. DO{ftU)/'CI
_1 . 62
"
, ,
_(TUI )"" _ 1
- I . JI
" al,CI'( nAlI/Acl ...
-1.21
"
" r:Jr'"
7S. DO{ftAI)/1CI -2. J2
"
, ,
_(TUI}!"""'"
- l . 11
"
"
0-"
_(ftAllflC& _2. SI ..
, ,
IWI1'UIUAI/"I.
-t .n
"
"
-0-'
, ,
DMl'CftAa)/Acllctr - l . la
"
"
-0-"
, ,
DMl' l tul l/AclIck
-1.14
"
"
-O--CI
_lftAa)/J&lAlr
-2. 11
"
"
O-{}-I
_(TUII1/ AclIck - 1. f5
"
, -
"
,..O-@-I"
DMl'CftAlJ/A&I",I ..
-1.14
"
..
O--CI
_lftU)/AcI", ... - Z. 1S
"
, -
"
),
aI.CII(nM,/JII _1 _0. 2'
"
P"NO"
T.We 2 Continued
hU)'
"
"
Selv ... tl
.. t .. ."el

DO(TIAI'J/'c&

ILoltvno
h'.ntlal
,
-1.21
- O. "
- 1. '1
- l. Sol
" .. ,
..
"
"
"
"
'1" .. llhe potenl ;'1s were measuml by poI.Il1II"'ph "';nl 1'1 _mini
lhe lupportinl tlecuo1yle. in pamltheail.. <:oncenll1ltion .Iried rrom 0.01 /ti
10 ulul1loon ...:I 15% DO I n% dioune "';th 25% H,O. rO. moR: "rormllion ....
""-
rate rclalive lo the ben:zylic sySlems. However, the addilion rale should never be fasler
Ihan Ihe reftux rale.
Typical1y, Grignard reagenls made from the addilion of RX lo magnesium can be
made in higher Ihan 90'"1. yield as long as any reactive functional ily in Ihe substrale has
!:leen prolected and Ihe paramelers discuJSed previously have !:leen optimized Ihrough
statistical experimental designo Although the solvent syslem may vary, owing lo solubi lity
problcms. sorne commercial eumples of Ihis high yield reaction follow (reater Ihan 90";'
yield and concentralions of 1- 3 molfkg).
CH)MgC1 (Br, 1)
CH
1
CH
1
MgQ (Br)
CH1- CHMgCl (Br)
CH
1
- CHCH
1
MgCl
CH,CH
1
CH
1
MgCI
(CH
1
)CHMgC1
CH
l
(CH
1
hCH
z
MgO
CH
1
CH
1
CH(CH)MgO
(CH,hCMgO
CHiCH
1
hCH
1
MgBr
CH,(CH
1
). CH
1
MgBr
C. H"MgCI
(Br)
4-ClC&H, MgCI
V. PAEPAAATlON Of ".8UTYLMAGNESIUM CHLOAtDE
C. H,CHJMgCI
2--CH
1
C.H,MgCl (Br)
4-CH,C. H, MgO (Br)
CH,(CH
1
).CH
J
MgC1
C. H,CHJCHJMgCI
C, H,qCH)hCHzMgCI
This scction describes Ihe preparation of a prototypical Grignard reagent, n-bulyl-
magnesium chloride. The remov81 of 0 , and H
2
0 from Ihe ruetion tlask selup, salven!,
RX, and Mg is essential. Therefore, all operalions were performed under a dry nitrogen
or argon atmosphere, using a standard Schlcnk line or dry bol techniques (S).
The THF was distilled from sodiumfbenzophenone and ! Iored under an argon
atmO$phere. Chlorobulane and 1,2-dibromoethanc were dried wilh 4 molecular sicvct
(0.02 wt /. by KaTI Fisber litrallon), followed by freez.e-pump-Ihaw deg.asing of RX
(repeated 3 Thc dry and degased RX reactanu were Ihen placed under an argon
atmosphere. The Mg lumings and the glassware for lhe reaction wcrc placed in a 1 (re
oven overnight (10- 14 The glanware was tben a5Semblcd hOI wilh a Ilrong SITeam of
argon flu$hing the reaction flask setup (Fig.
A S3.5-G (22 mol) sample of magnesium lumings was addcd hOI to Ihe flask, wilh
a 5trong Slream of argon Howi ng Ihrough an open joint Ihal was subscqllelllly capped
wilh a septum. The reaclion fl uk selup WII placed under vacuum (kss Ihan 0.1 ton ) for
10 min and the vacuum wu broken with argon (repeal lhrce limes). A tol81 of S81 .4 g of
THF was added to the ftask and Ihe mechanical slirrer was lurned on. To ensure tbe
"
lJ/IthillM/
Ftaure I Reaction ftask setup for standard Grignard rugenl prep;lration.
A. VacuUmjN, iolet
B. Bubb1er fo. n:Jicf
C. Surge fluk
D. Condense. (i nen rooling
E. Mocllanical agitalO!"
F. Addition funocl
G. or thermocouplc with heat oontroUcr
H. Seplum-<.::Oycred port for MI addilion
l. Sealed reaction ftask with , upport
J. Healing manlle
K. l.aborllory jack
L SpilJ Iny (Iufficicnt for reactor contcnU)
activation of magncsium (sce Ch. pie. 4), 5.0 i (0.027 mol) or 1,2-dibromoelhanc Wll$ added
10 Ihe ftlllk by syringc. A j OC clIol hcnn was ob$erved, with an ncrease in gas fl ow Ihrough
Ihe bubbkr (Le., he relt ase of cthen!:). A mixture or 185 8 (2.0 mol) or chlorobutanc .nd
18S 8 THF was added 10 lhe addition funnel. An initia] chaTgc or approximalcly 30 g or
Ihis mixtul"(: was added 10 Ihe flask and Ihe exotherm drovc Ihe reaa ion 10 reflul. The
aclivil y analysis confirmed Ihat, indeed, sorne Grignard reagent had formed. The remainder
of Ihe was added al a rale lo conl rollhe rale al lhe condenser (2h addition
After lile addilion was complele, ulernal healing ""as applied for 2 h 10 mainlain
"
lhe rcaction al reflux. The resction was aUowcd 10 0001 10 ambient temperature.
Subsequently, the mechank:al stirrer was lurncd olf aod lbe residual magnesium was
.lIowcd 10 seltle. The solution was transferred by cUlnula 10 obtain 994 g nf
n-butylmagnesium chloride $Olution. 1lie solution W8S analyud for aetivity {1.9J mol/kg}
and acid- base litration (2.01 moJ\:g) 10 give a 96"/. ratio and a 9S.9% yield, based on
chlorobulam:. No chlorobulane was deteclcd by gas chromatography {oq anal)'si .
11Iis procedurc has beco rcpcaled in our labor.tory and in production (modified
versian) hundreds of times, and the average for 1993 activityfacid-basc ratio WI! 96"/. ,
wilh a standard devialion Df 2." . Thia indicalC$ hat, if he propcr procedu!'e il followcd,
then a reproducible )'icld of Grignard reagenl can be InaiDcd. Thc mos! common variation
on Ihis preparadon Is lhe typc of Mg activation (see Chaptcr 4). Otiler rccommendcd
preparalion! can be found within thi s book (sec espccially Chapters 3 aOO 4) and in the
literature [conti nuou5 proc:ess Rcf. 41 and batch process Rcfs. 42. 4]].
VI. ALTERNATtVE ME1liOOS FOR GRlGNARO REAGENT PREPARATlON
By far Ihe mOlt common way o( making a Grianard reagcnl il the oxidalive Iddition ol
RX 10 magncsium. Howcvcr, bccausc of homocoupling difficultics (benzylic: systcms).
unavailable or non-acees,ibk RX spccies, and cconomk bencfits, olher Iynlhelic: routcs
are more tavourable. There are several practical altemative synthelic: melhods lo makins
Grignard rcagenl!: metal-mctal cxchangc reaclons [Eq. (9); Tibie], enlries 1- 7), lcid- base
reaclions of RH wilh a Grignard rcasenl (Eq. (10); ser: Tibie 3, entncs 8-12].
oxidativc--rcduclive transmetallation (Eq. (11); sec Table ], mtrics n - IS], mctaIX- X
'
exchangc [Eq. (12); sec Table 3 entries 16-20] and preparation (rom olefins (sec Chapler
3). The Grignard rcagcnts gcncratcd by lhese melhods are rarely SOIIIe(!, and the yiclds
reportcd in Tibie 3 refer to Ihe couplinS reaction of the resultin Grignard reagcnt
inlenncdiate and the sub5lrate o( interest. Thereforc, the yields aClUaUy rcflcct the couplins
rcaction of Grignard rcagcnl aOO sub5trale. Sinoe lhere are high yieldl with sorne of Ihe
subst rates, it is reasonable 10 assume lhat Ihe yiclds of thcsc method!; can approach !he
sreater Ihan 9()'Y. yields of the oxidative addilion of RX 10 magncsium.
R.M + IIMgC1 IIRMgCl + Ma.
M- Na, L, Hg
RH+R'MgX IRMsX+R1H
RMX+MS RMgX+M
(9)
(10)
(11)
(12)
The metal exchanse reaclionl are straightlorward, and one can cui ly prepare MRJ
by this Toute. This melhod il Iypically uscd when !he Grianlrd reagent il difficult to
prepare trom RX, lusoeptibJe to homocoupling, or a diorganomagnesium reagcnl is dcsircd.
An interestng application is in asymmetric synthesis by which chira! Grignard reageDI5
can be preparcd (sec Table 3, mlries 1- 3). The obvious disadvanlage il that Ihis mule s
nol cconomical1y favorable relativc 10 Ihe standard melhod of preparalion and adds a
step in the ynthesis (Le., preparation of the organomctallic reaclan!, R.M).
The acid- base preparation melhod il Iypically used 10 make Grignard reasenl5 of
terminal alkyncs. The advantage is Ihat an inexpeosive Grignard reagenl can be uscd 10
make an unaO"L"Ssiblc or prohibitivcly expcnsivc Grignard reagcnt. 1lIc major limitation
il Ihat RH musl be more acidic Ihan R 'H for Ihis reactioD 10 occur (sce ChapteT ]1).
"
T.bIe J Selecto:d EJllmples of Ahernacivc Metllodt ror Grinud Re_genl
Preparation
"
"
..
.'
"
n'
,
U'

I
u-.('",
U
. - ,
,
,
0<,
,
. "
,
-"
:1 ~
' .. .
"
.. I
. ,
"--O

l

Jl .......
J
"
,-.;- =--"
- \1
....
,
..

, ,
0-..

32 - ~ o
~ ( 100 DI) ..
"
u-u ..
"
..
S4-f7
"
60 - 75 ..
"
..
"
" "
"-M
s_
"NO"
T.bIe 3 Con,i nued
.. '
n'
n'
n'
...
MI B"
I J-k
-11-(
I ""'Ir
*
'
r ,,-1. 111
, '
I '
-.+,
I
Q

.
O] e<Uivllenll MIO"
cNo,C, .H.
CH,(CH,).MC!
t CH,CH,MIB'

,
,
l .. ...
,
..
,
."
I
-'+'1
I I el
Rcporled yield. ,he Gripord_THF complu
" 2 cquiv.lcnll o( MI
, M-
, C. H,M,B,

"
" . ti "
>"
" "
to "
" "
10 n ..
n
n
"
SllwI men
The oxidative-reduc::tive transmetallalion can be carrie<! out with organomelall ic
reagen!! that have 11 reduction potential more positive Ihan magnesium V). Sincc
lhese reactions are typicall y carried out with organomercury derivatives, !htre i! a major
envi ronmental SSUt with formalian of HgO, result ing in Ihis method rarel)' being used,
even in Ihe laboratory.
The metal X- X' " .. change relelion s dependen! DO Ihe polarization of R I XL. Thcrefore,
lhe be!lcr Ihe leaving group X' s, Ihe more probable Ihis Teaclion will work. The ad vantages
or Ihis melhod are the same as [hose for Ihe metal (xcllange reae!;on. Tm: disadvantages
are that JXltentially two different Grignard Teagent! are in solulioo [Ihe Teac!ion in
Eq. (12) is an equi librium betwccn Ihe two Grignard spcciC$] and Ihe act ual coupling react ion
10 form R- R',
REFERENCES
1, M, Kha.rasch and O, Reinmulh, Griglt<1Td RelKtiOlts 01 N_lallir S .. bslWU'tJ, Punlico: Hall,
New York,
l V. Grignard. ComP/. Rlnd. IJO:IJ22 (1900).
J. H. Gerritsen and M. Cornells. Iltd. EIIg. Praan [NJ. {)n. 14,893 (1 985).
4. M. Jor>eS, P/{JlIII Op. Pr. 8:200 (1989).
S. D. Shriver and M. Dm:dwn, TM Mm;pu/a/Wt! (JI Alr !*/UI/i<'l Campault<, 2nd eII., John
Wile)' &: Sons. Ncw Yo/k. 1986.
6. G. ano:! P. Rakil .. Grigltard rtOClitmJ. KiTlcOlh_r al CMmkal
TlonaIogy, 4th ed. (J, KrOKhwitz and M. Howe-Grant, edl.). John Wilc)' &: Son5, New York,
1994.
7. R. Han and G. J. Am. Chtm, $. 114:748 (1992).
8. S. Czcrnedi. C. Georgoulil. and E. Michel. J. Organo_r. Chtm. 140: 127 (1977).
9. G. Silvcrman and M. DiFitipantonio, Elf Atocllcm N. A. [internal publication). 1981.
10. tu Il &oc/ion Sol""ltr, E. 1. du Ponl Ncmoul'l &: Co. Wilmington, DE, 1960.
11. H. Normant. O. R. IItbd. !*altCt Acod. S. 219: 1510 (1954).
12. H. Drown I nd U. Rachcrla, Orgtmamt'fo/licl J:391
13. H. Naglno. M. Ohno, Y. Mi)'amae, and Y. Kuno. Bull. Clwm. Soc. Jplt. 6J:2184 (1992).
14. J, 8ackvall, M. Sellen. D. Grant. J. Am. Chtm. Soc. 1/2:6G15 (1990).
1 S. L. Fannin. C. Crapo. D. U.S. Patcnt 4,615,843, Oct. 7 1986, to Tuas Alkyls. 1 nc.
16. P. Rakila, J. Aultman,.nd L SI.pelton. Clltm. &g. p. 110 (1990).
17. 1. Koppcl and T, Palm, AduanctJ lit Untar f TU Energ), RtlllllorultipJ (N. Chapm.n and J.
Shoncr, edl.). Plcnum Press, New York, 1972. Chap. 5.
18. P. Rakita, J.Aultman, an<! L Staplelon, Thc mcuun: of basicily is lhe infrarcd hin, twoo-
;n e H,OD complcxed wIh the bo.!IC, Clt!om. Eitg. p. 110 (1990).
19. L Jonn. S. Kirby, D. Kean, and G. Campbcll , J. Clt!om. 284: 159
2(L E. Banmann. J. O'gQItamt'/. Chem, 184:149
21. A. Macreker, AlIgt .... Chem. /11/ . EJ. Ellgl. 26:912
22. F. Fn:ijce, G. Schat, R, Mierop, C. Blombcrg. and F. Bickelhaupl . IftltrIX)'du 7:237 (1977).
23. A. Macreker. CIrcnr"Zlg. 97:361 (1973).
14. H. Bodewilz. 8. Schaan, J. Niet, C. Dlomllcrg, and F. 8ickelhaupt. TtlrQMdrQ/t. 34:2523
25. E. Ashb)' and F. Walker, J. Or , Chem, 33:3821
26. J. Rabcsiaka. Bull. $. CIIim. f,. 579 (1969).
27. W. Smith, J. O'glllt_" CIrtm. 64':25
28. D, WakcflCld, O'gllllQmtl. 1Uv. J:13 1
29. W. Glaze and C. Selman, J. Orgllno",,,, Clltm. J :477 ( 1966).
30. D. BryccSmith and E. BluC!, Org. Sy",h. 47: 113 (l96n
3L W. Sehlcnk aOO W. Schlcnk, Jr., Ber. 628:920 (1929).
32. R. AndcT10n and G. Wilkinson, llttJf'g. 1P:262
'"
,
,
33. C. RUlon aOO G. Salero, T'M Cltemistry o/ M",(O..cubtNo BONJ (F. Hartley, ed.), 1981, 1$1'.
34. O. eRe HwuJbooIcofCMmI.JtryOlld pI/ysla,eRe PI " Boca Raton,l992,Chrop. 13.
JS. L Meiles _lid P. Zuman, eo;I . e Re Handbook Serie:t in Orpnie Elcctrodtc:misul. eRe P. "
Ocvcland, OH, 1977, Chapt. 1- 3.
36. M. von Stackelber.1Id W. Stradc, Z. Ekklroc'-t. 51:118 (1949).
37. F. umbert, J. V.g. CMn. J/:4184 (1966).
38. F. Lambcrt .00 K. Kobayuhi, J. Am, CIImI. 5. 81:5342 (1%0).
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Cltemlsl'y, 5th ed., Lonman, Essu. 1989, pp. SlI- S.tI.
43. A. Holmes ano:! A. PIIer, 0,,< 5)'11110. 65:61 (1987).
44. H. Walborslty .nd A. VOUDIo J. Am. Cltm!. Soe. 86:]2811 (1964).
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46. P. Zhan, and R. aa.ley. Tt:mwdroll Lm, J1:294S (1992).
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48. A. MinalD, K. Tamao, T. HI.)'ashi, K. SW:llki,andM. Kllmada, TmWdr"" Lm.l1:S319(198n
49. J. Kenncd)', H. Kllivila, F. Pcmr,R. Tien.,J.ConsidiDe, J. O,g_t. Chmt.6J: 161(1973).
SO. T. Husel and D. Seebach, 91:427
SI. C. 8ishop and G. Morrow, J. Org. CMnt. 48:6"
52. S. O. Daviea and M. L. H. Oreen, J. Soc., IJIIOII Trans. 1SI0
SJ. G. Ditchfield and A.. Pedler, J. l'"IrlorilM CIInn. 10:447 (1977),
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55. L COI'" and G. Whilcsidea, J. Am. CM"'. Soc. 99:2)90 (1977).
S6. E. Manel and M. Vl.racbe, J. OrgeUl()mn 4O:CS3
57. D. Delpa, S. Stem, and S. Cohen. l . "'-iM 1:379
S8. H. Nishiyama, K. bah, K. Iloh, K. Ohno, H. Napse. K. MI."lImOlO, and H. Yoshiwl.ra, l .
O,g. CM"'. $1:401 (1 992).
S9. D. Seyfcrth and R. l . OrgllllOl'MI. CIInn. 54:54 (1973).
60. N. RedwlDe, P. MOre&1I, and A. Commeyru, J. CIInn. 1O:69\I (1982).
61. E. Colomer and R. Cornil, l . Org/J1lOfMI. /JJ:1S9 (1977),
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63. .. ron, S/O,., " " d HOIIdJing, O\JPonl Cbemicab, 1991.
'"
3
Preparatlon 01 Grlgnard Reagents Irom
Olellns and Acetylenes
FUMIE .... TO . 1Id HIROKAZU URAee
ToIc)"o 01 T/"wIOfY, JQpa1I
l. INTAODUcnON
The synthesis 01 Grignard rcagenls Irom olefiIl$ or acetylenes compkmenu ,he standard
reduc:tivc method for preparation 01 Ihese reagents from alkyl halides and magnesium
metal [1, 2]. When alkyl or alkenyl halides are tatber difficulllo obllin relative 10 lile
correspondng oJefins or acelylenes, or whcn a Grignard reagcnt is han! 10 prepare by
the aclion of magnesium on an organic haJide, Ihis mcthodology is especially useful.
Moreover, cherna-, regio.., and stereochemical considcl'1ltions often lavor Ihis methodology.
The reac::lions dcscribed in Ihis ehapler will be limitcd lo Ihe dircct formation 01
carbon- magnesium bond! usng olcfin or acetylenic subslrates. Generation ol Grignard
rcagcnts from any isolable intermediates, such IU alll:yl (alkcnyl) haUdes or olhcr
organometalli<: compounds obtained from olefil15 or acct)'lenes, Ind fonnalion of
magnesium acct)'lides from tenninal accl)'lenes are excluded.
The reactions appearing in Ihis chapler wiU be classified into four t)'ptS: (1)
h)'dromagnes8lion oC olefins or acct)'lenes, (2) carbomagllcsation oC oldins or Iccl)'1enes,
(3) reductive magnesalion of dimes, I nd (4) isomerizalion of unsaturated Grinard reaenlS.
Scheme 1 shows an iIIustrative descriplion of lhese reBaions. Sorne of these 10pK:s liad
beco airead)' diK"ussc:I in revkw articles [1-17]; herein particular attenlion will be paid 10
current literature reports. The reagent orIlle I)'pt RlMa is. strictly lpeakin. nOI a Grignlrd
reageot (RMgX), bUI il is discussc:d logelher in Ihis section. becausc RMgX aOO RMa
are oflen closel)' related through the Schlenk equilibrium..
;1.
111.
, .. r4'
'-- o
-.,
.'
U
MIX
Scheme I Preparal;on of Grignard reatenlS from olcfiru and acelylcnes
11. HYDROMAGNESATlON OF OlEFINS ANO ACETYUNI:S
The most simple method ror the preparadon of Grignard reagcnts from olefins or
acetyknes is lhe formal addit ion of HMgX species 10 sueh unsalurated carbon-g,rbon
bonds. In fael, lhe most fundamental inorganie magnesium salt. MgH. has becn reported
10 add el hylene under drastic reaction candilions [ 18]. However. as Ihe double bond il
uluall y resistant 10 sueh addit ion reaCl ions, Ihe mel hod of thi! rcaelion il nol general.
However. in 1978 Ashby tt al. [ 19] reported Ihal hydromelallat ion of l-octenc wit h MIH,
was greatly promoted by Ihe addition of a catalyt ie amounl of ep TiCl
l
, as c:videnced
by Ihe faet Iha! quenching the: Te!lul tanl organomagnesium reagenl with deuterium oxide
or I gave deutcrated OClane or l-iodooctane according 10 Eq. Titanium
lriehloride and zrCJ. were reported nOI to be effective cataly!t! for this reaetion.
(1
MI " (1 cqyl.)
.
CPl TICl) (5 mol'l)
nlP. 60 OC. 1 h,
(1)
Other uamples are summarized in Table l. Terminal olefinl nicely part icipated in Ihit
reaedon as shown in Eq. (1) and entries I and 2 in Table 1. Styrene showcd a revenal of
regioselection relal ive lo the pasilion of Ihe ncwly formed carbon- magnesium bond.
However, sterically hindered olefins afforded an increasi ng amount of hydrogenatcd
producto even alter trcalment of Ihe react ion mixture wilh DlO (sec Table 1, entres 3
aOO Finally, no deuleratcd hydrocarbons oblai ncd from /ral'!.\' and lrsubstilutcd
olefin$, even Ihough Ihe starting malerials were almost completely consumcd (sec
Table 1, enlries S aOO 6).
'"
T.bIe I Cp,rlCl,-Cal.lyzed Hydronuolnesatioll 01 Olefi ... ano:! Acetylenel
,
,
,

,

,

M,H
CpTICI
THF, t.O -e
0=
c"Hu-'=
I (u.)
..
..
"
"
1 (U. )
9 C,II,-'='-C,H, 1 (r.l.)
Ref 19.
.'
"" .. M (94)
""El (100)
41b ..... (19)
I'IoCIlDeIl, (90)
I'IoCllzCll,O (10)
dl l ...
clc1oh ... ft. (95) ... u (60)
.eu"" (66) d, . ..... n. (20)
fru, l Ioc e (16)
he .... (70)
d,l ..., ft. (l .')
] . ,.,!.
pllfte
''''''MI (60)
, ...,. ,,," ((01
d, . ) . , !.
(O)
d 1..., ,," UOl
d, ! o.!, ... (40J
Sdunlt 1 Ordcr or Ractivily ror hydrom.",mtion
Thc relative reaclivi ly fOf hydromagnesalion of olcfins. as eslimaled by deuteralion
sludies, decreases in the following order (Scheme 2). Relaiyely long reaclion periods
neccssary for the convenion of hindered olefins, durilll which aclive magnesium 5pecies
deleriorale. account for Ihe low or no uptake of deuterium in the producl5 following Ihe
addition of 0 ,0. Allhough an nlemal acelylene uOOerwenl Ihis hydromagnesalion 10
give a deuteraled eu-olefin in good ylc:ld afler 10 0,0 {see Table 1, enlry
with a terminal aoetylene, formalion of magnesium acetylide hindered further convenion
of the subslrate (sce Table 1, enlry g).
1I was al50 reporte<! (6.20] Ihat MgH, prepared from MI aOO Hz under ehromium
or titanium catalysis hydromagnesiated Ialkenes in 1000 yields in (he presenoe or a
zirconium salt. fOf which lrl. was particularly useful. As in the earlier eumple reporte<!
by Ashby (19), the reactions with 1, 1- and 1,2-dialkylet hylcnes were very slow. The resultinl
dialkylmagnesium. whkh consiste<! of a I-alkylmagnesium compound wilh greater Ihan
99.1"/. regiochemical purilY and may be i50lalcd if n....,..,sary, was used for thc synlhesis
of tetraalkylt in, carboxylic acid, or lrialkylphosphine [Eq. (2)]. These hydromagnesation
'"
reactions were also applicd 10 a functionaJized okfin [21] and lo dienes (22). Othcr
.magnesium hydrida, such as Et,NMgH, were examincd, bu! were les!! usd'ul Ihan MgH. [6].
Sn7
( R----t,s"
. ..."
MIli, (1 "'Iul.)
( R-""12M
ro, ,
R ............... CO:!"
,
(2)
z.j (tOl.)
(2.3 c<julv)
T'"
71)101(, ylcld
"'..
( ''''1;'
RaoEl.C6III)
99.1'
Ilomc,icllIl
puc
Grignard ll:agc:n!S huing a p-hydrogcn are known 10 be in equi librium wilh another
olcHo aod a sccond Grignard reagcnl in thc presence of a cer!ain transi tion metal catalysl,
as shown in Eq. (3).
.'
............... MIX
(3)
This rcactlon is superfidally understood as a formal of elcment from
a Grignard reagco! to ao olcHn undcr catalysis of such a traosition metal comple. (Schcme
In 1962 [23], Cooper and Finkbeincr st udied this reaction in detail by taking
Irlllnsition melal catalysll involving TiO., CP. Tia" ZrCl., and va. [24].
TypicaJly, a mi.tuTe o( an oleHn and PrMgBr in elher was healed al refluJ in Ihe prescnoc
ofTiO. lO atrord Ihe new Grignard reagc:nl resulting from the added olelin. The rnechanism
o(lhis reaction was proposed, as shown in Schcme 4, in which a titanium hydridc, al TiH,
played an important role (25).
The newly formed Grignard reagenl can be lrapped regioselectivcly wilh a variety
of clectrophiles, such as aldehydes, ketones, carboo di oxide, orthoesters, silyl chloridc, and
o.ygen. Tables 2 and 3 surnmariu Ihe results of these and several additional
examples.
The use of a low molecular wcigh! Orignard reagcn!, such as Et-, Pro, _Pro, or
fBuMgX is rccommended as Ihe R1CH.CH,MgX in Eq. sinoc: lhe olefin formed by
lhe Grignard equilibrium (R'CH _ CH,; el hylene, propylene, or isobutenc. respectivel)')
\'

-II M,X-
-IIM,X-
.'
............... M'X
I
SdKme" Propoacd ruction oourse for titaniurn..::atalyzed Grignard reaction
T.bIe 1 GeTICTlItion and ReaClionl or I-Alkyl Gn.nard Reasenu from Alkenes
by Hydtomagneu.tion
.'
r.. B.,
f ..... /_ 8_
,
R'R'lqOM)CH) ,
' -B.M,a CPlTiCl,
R1RQOltr 4' -11
"
,
e, H 1). AlCl II', P,MI B. TiCI. 00, 21-62 1 21
<-C,H" .
O'
,
R'R1O:OUh EIMCI q.,TiCl, ro,
"'..-
!j.
" JI. ' R l C'(OHlCl t).,
",'R1CCOII KCII).
,
C.H1) 1',MIBr na. (ElO), ClI (l>IO)}CH-
" "
""

er'
EIM,B. CpinOI M.,s1Cl Me,SI
"
"
,
O'
1', 101 1 0 na.
'"
40-45
"

'""
prodOlC" ... loclOflel l. poul"!..
Z7
TaW,3 Genellllion and Reactionl 01 or IiI-SiJyJalkyl Gri,nard Reap:nls
rrom Slyrena o' a VinylsiJane by HydromalPleulion
".'
"
, A"
RM.X
,A
"'
,J. ...
,
<0,.1,.,
E-Irl
,
RM.X
C'''',.,
s '
"
Yi.ld '!lo) R.f.
... . A, P. M.B. , Cp,TiCt,
"'"
"
40-" 29.30.
P.M.!"_
"
, _h M.O
,
...
"".
n 5I
"
, -( M.OJC,U
,
, -(M.,C_CIIClIvc,lr P,M. 8. Cp,'rICI,
""
"".
n
"

..
,
na, o, a< ..
"
,
,
,
CplTIa, o, a<
"
"

I P,M,O. CpITiCt, HJO

" ,
, ,
"'"
D
,

, ,
M<ISia Me,Si
,
can be expelled from the reaction mixture lO 5hift the equilibrium 10 Ihe riglll [see Eq.
(3)]. For the lilanium calalysl, e pI Tia, could be use<! equally well. The exclusive formadon
of Ialkyl Grignard reagents was nOled for lhe terminal alkeDCS (see Table 2) exoepl for
styreoes and a silylelhylene Ihat afl'orded secondary (Le_, benzyl or Isilylalkyl) Grignard
reagents (see Table Similar lo lhe aToremcnlioned hydromagncsation wilh MgH"
terminal oJefins .Iso Ihe melallalion quite rapidly, which enables a
chcmosclective hydromagesation bclwcen different 1)'peS of olefins (see entoo 3 and 7,
Table 2; entry 3, Table None of the following olcfins------<yclohexene, 2-pcnlene,
IrO/lS-slilbcne, liI-methylslyrene. p-melhylslyrene, or 2mclhyllpcntene.-entered the
Grignard ClIchange reaction, even under rorcing reaction condili ons (PrMgBr, Tia.) (24].
A rew runctional groups in the olefinic subslrate, such as ether, hydroxyl (which exilta as
alkoxide in reaclion or internal oleli n, did nol inlerfere wilh lhe reaction (see
enlric$ 2. 4, and 6, Tabk Ti tanium catalyzed isomerization oT lerminal olelins to
unrcact ive, internal oncs as illuslrated in Eq. (4) (27) can lower Ihe yield or Ihe eJl.changed
Grignard reagenl.
(4)
". ". ".
Thus, the reponed product yields so far are modc:rate to goad (usually lower
than 50%). n il disadvantage was circumvented by the use of dienes or aoetylencs al
described later. since thcse substratc:s afl'ord slructurally or elect roniaally more Ilable
intermedia tes, such as allyl- or alkenylmelals, compared wil h alkylmclall, which not only
TIbie 4 Genertlion Ind Rcactioll!l 01 AUyl Ori&nMd Ruentl (mm [)lena
by Hydromlgneulion

"o


n ,I,X ,
__
"......v Ar

CPlTlCll
'"
(J)El


k'MIX
.0
"
P,odll<U <', kd,
,
"
P,MI8,
"'"
"
,us 2 (13),
" "_l (Il), l Ul)
,
M. o
"'"
"
1 (ll), l (16) o
,

o M.,qOU)-
,
(79.95) o

Mo, El. 11. 1_1111104,81
"'"
"'"
1 (71 . 11)
"
,
Mo. El. 1111.
o
HCO:tM.II, 1 (H_M)
n.n
M.Sl
malu:s lhe reaction oC Eq. (3) no longer in cquilibrium [29]. bul a1so prevenu lhe Coregoina
undesifed isomerization.
Sato tI DI. showed Ihal Ihis titanium-catalyzed rcaction oC olefins and low molecular
weight Grignard reagenu couJd be extended 10 conjugated dieoes and aoetylenes, provided
Ihal epI TiO
I
was used as Ihe calalysl in place oC TiO. (5). The expected product from
2-alkylI,3butadiene il an aJlyl Grignard reagent and, in fact, lhe elcan formation of a
sinjle aJlyl Grignard reagent, as shown in Eq. was verified by the subscquent reactions
wilh eleclrophi les [29] (Table

XM ......v ('1
The high yields and the ex.cellent regiose1ectivities oC Ihis hydromanesalion, as weJl as
lhe versalilily of Ihe resultanl a1lylmelal reagenlS [34,35]. mue Ihis melhod valuable in
organie synlhesis.
Acel)'lenes also underwenl a similar hydromanCS8lion rcaelion in Ihe presence of
epI TiO
l
10 give alkeDyl GriJliard reapla haviDg I dcfined regio- and slercochcmistry.
dependent upon the sub5trale [36]. ThercaclioDlarecollectcd iD Tibies 5and 6. A few poiDI.
are Doleworthy. Disub5tiluted accty1enes selcctively alforded 1,2-d.s-disubslituted viD)'1
Grignard reagents, in which lhe carbon-mIJDeSium bond occupies lhe position elose lo
pheDyl or but remote from t -h)'droxyalk)'1 (see Table Thc directiDg clfcct
oC pbcnyl prevailed over Ibat oC lhe slyl (see entries ti and 12. Table Trimclh)'lsilyl-
propargyl akohols are ellceplional lo obtain lhe t ,2-trllfl.S-disubsli tuted ViDyl Grignard
reaacnt, even Ihoup lhe rcgia.c1ectiOD satisfies lhe forcgoing rule (see Table 6). Thcse
sc1ectivc mclhods for the prcparation oC alkenyl Grignard reageDts bave found widespread
use in organic synlhesis.
The mechanism oC!he CoregoiDI reactiOfLl oC dieoes IDd acclykncs should rescmble
Ihal of Ihe olefinic case (see Scbemc 4, on tbe U$umptioD Ihal Ihe calaJyljcaJly active
Tibie 5 Gcnt;ll.ti(ln and Reactionl af Alkcnyl Grignl.rd from Aoetylene
,
,
,
,
,

,


"
"
"
"
"
"
"
"
"
"
"
"
M.


"

11.
1
R'
)=1 ,
o
O"
o'
"
"
"
"
Vlold ('lo) II.d.
(9:1 100) ]7
11OO'lloZ1
5

(91. 100) n,3'
1>99'IIoZ)
(OI.ltOlI ... 1".. H.o
"
4 (lOO)
1>9lI'11oZ1
"
"
M.





"



(CH,Il0H
c,n"

Mo. Bu, 1'10, OI,oN
/ 0 .
Orl,.o.d.









",o
"
,,o
D
M_O M,
",o
"
,
",o
"
,
M,
' '' yl . lh 011 , 1
n.
4 (92 100)
''''''''
"5 (15)
[":121
4,5 (10)
190;101
4 ( "N;)
t>9lI'roZ(
4.5 ( .. )
t U :} )
"'"
(>9oI'1oZ)
4,5 ( . . )
196:4)
4 (\11 )
19J .. ZI
4 (191
(11)
1"'foZ)
"







"


MeCHO.ct lO -CHMeCHO 4 ( . ... SO) 11

Bol/C. I B. 4 (106)
C,II1101O Cj H"CII(OH). 4 ( .. )
} hl .. , I 4 (16)
11 4 (60. 100)
"
"
"
4 1. 42
!I 104 .
" .
23 h
CH(Et)OH
"""'" .
"'''' .


"
M"


o
M,
4 (96-100) 41
4 (96. 100)

14 8
"
. aoM'OI,
' ''''''ICI


T.ble 6 Hydrom'nes&lion of Trimclhylllilylpropary1 Alcohob
Me,.' i"'f"yR .!!:... Mo,SI'f'(R
R' MIX
, "
j. B"M,O
, ,
' .8.104,0'
,
o

Me, CI H".
<- C.HII",
f'bCH,OCHI".
""eH(OH)
M,;!!; OM(X El OH
S'
O YI.ld ( .. , Ref.
",o
"
'"
"
M"
M, ..
o
n.I/C.1
"
I9IE >9'110)
II;IR
1
oo
''eN
R 111;2qOIl).
lO-U
.,
(R'C(- NII ,..") 32-16
7(-91
"...,
!
IJI
+ 1)
""')'
,
c,lI"
el)
(cCtIl,, )01
e"
PerlO<! 11r)
,
u . IOO
o
'"
<L'
o
,
o o
,.,
"
o
"
"
o
"
o o
90 ..
o
"
"
.
"
o o
"
Schtme 5 Equilibralion of acety!c:re ' 00 .Ikenyl Grignard reagenl under hydromagnesation
conditions
species is epI TiH in place of a, TiH) (29). Recent .tudy showed lhat there WI\.I an
equilibrium bctwecn a Itarting acclylcne and the alkenyl Grignard rugen! produced by
the hydromagnesation, provided lhe acetylenc w.s lilylated [47]. ThUI, lhe addition of a
difl'erenl acctylene 8 10 lhe silylalkenyl Grignard Teag<:ot 7, pre-formcd rrom Ihe
corresponding silylacetylcne 6 and -BuMgDr under Cpl TiCl
1
catalysil, formed a new
. Ikcnyl Grignard rugent 9 and the nidal acetyknc 6 in the reune or prolonged reactioD
perlod (Scheme
More interesti ngly, the same study showed Ihat change or electrophiJes (Ihus, Ihal
of the perlods necesspry for Ihe oomplelioD or lhe reaction) a1tem:l Ihe regioselectivily
"
-_ .....
M,n,
,,'
Mc,SJEI

C,II ,
$iMe,
C,It"
,

" "
1194 Clclusivc
Ijl '_""M In:
"
0,0 MeSiOTf
R'R1CO
CB
CPITiCh
,D'
(Mc,Si) ( R'R1qOIl ).) (8.)
,
e,lI"
3] 100'110
" "
19 6 'ncc
yicld
Mc,si
".
Mc,si
c'II,1MID.
c,II,flll

Se.me ti Regiosclectivity dcpendin on clectrophiles
found in Ihe final products owing 10 a rapid equilibrium between Ihe two rcgioisomers
of the alkenyl Orignard reagenl Ihrough Ihdr paren! acelylene
In 1969 [ 23], Mark6 reporte<! detailed investigation on a si milar hydromagnesation
or I-alkenes and $Iyrcnc wilh PrMgBr. by Na] [48- 50). From the former, a
l-allr.yl Grignard rcagen! WI.$ obtained., whereas , Iyrene the secondary (benzylic)
Grignard rcagent. Simple olefi ns gave modcrate yklds of the Grignard rcagenls, bul the
yields 01 tbe products werc somewhat improved wi,h an allyl alcohol and a slyrene. which
werc used as slart ing material! in Ihe of a laclone [Eq. (6): 4J, and an
llI-arylalkanoic acid [Eq. (7): 31). In Ihe lasl transformat ion, lhe yicld was ma imized.
J . ld
El: D(H. ) : I
"? _ I'.M,a. XM'Y 00:t o o
, , -y'--""':;' )0110 JI.ld
NIOt. "MI'A /o4,X U
"""," "

lO'llo JI.ld
....
"
11'110 ,!cId
(6)
(7)
The mechanisms of Ihe reaction hu becn considere<! lo be as shown in Scheme 1,
in which a Ni." species, produced by P- hydride elimination from an alkyl-nickel
inlermediale, catalyzes the key step (4].
A silylacclykne was reported lO enter the similar nk:kel-catalyze<l reaction [Eq. (8):
51]. However, butadieoe gave a cyclic Grignard rather than lhe simple allyl
I
Sdteme 7 Proposcd rea<:lion ooune fo. nickel-catalyzed Grignard cu:llanp reactions
Grignard reagen! afie, ib telomerizalion followed by cydoisomcrizatioD [Eq. (9); 52].

SIM.D,. Me,Sl\........./CJ11I!!.. Mt:,S'\........./c.H1J
HI(aco.". ,-
Dlhl a,M, El
P,M,8.
(I'fl,PhNICI,
El.JO. r.t.
EI+(EI) .. HtO(HI.o,o(O). 50 63'10 ,Icld
McCHO<McCH(OH)-)
;--<",--M'" O ,
\.-l....,..WB.
(')
(')
Likc other hydromagncsati oDS C81a1yud by ron [l,53,54] or coball [SS], furtber syntbctic
appUcations of these nickcl-catalyzcd Grignard uchange reactions were nol clImined in
more detail.
or Ihe aforcrncntioned traosition rnetal-cataJyzed Grignard exchanJ( reactions, lhe
mas! standard method Ihal has Ihe broadest applications in orpoic .)'ntilesi, is perhaps
a titanium-catalyze<! hydromag.ncsation of olcfins and aottyJenes wilh Jow molecular weight
Grignard rcagcnl$.
111. CAABOMAGNII!:8ATION OF OlEF1NS AND ACEIVLt:NES
Vicinal runctionalization or oldins o. is an efficient manipulation of Ihese
functional groups, as Ihey have Iwo consecutive reactive oenters. From this standpoi nt,
carbomelal1ation of olefins aOO acetylenes i. an Itltlctive traruformation, owing lo the
concomi tln! formation oC a new carbon-carbon bond at one terminUll Ind Grignard
reagent at another po!ition, the latler or which penniu an introduction or a variety oC
carbon or heteroatom dectrophiles [&j . (10)).
... '

." . '
R, r l'
".'
s'
(10)
Tibie 7 Allylmagnenlion of Allyl Alcohols .nd Amines'
"
:?+'
Ykt

11 ' 11' (II.)CIM. R' E-
" "
"
"
,
R' X'
" ,
E"1
" " " "
,
.'

Yiold ,O) Rd.
, , , ,
'"
, ,o
,
"
"
,

""
n

,
ro,
ro,,,



... ,ro M.CCOH)
,
M.
",o
"
<>
,
"
M.

"

,

"
M,
"

.,,.A ,n_': I I

.-
,

..
"
,
"

..
"

"
}9.60
"

" "
NHr.


" "
"
.-
",

"
61 .61
"
.- NMol
..
"Jteaeliont ol.,.,lfa 1_10 -... pe1fo, Ud in elhcr 11 . L.rdlu.l, "hile lboec olenlfa
11- 12 in ..,lIulin, THF or THF lolucne.
' n.. product obuined in \ow ,;etc! lhowed lile ..,Y1=nod rq:iosdec:"Ii"';ll.
0 le6ns are gcnerally quite inert agailUt the addilion of Grignard reagenlt under
ordinary reaclion coDditions. Additionl of Grignards lo unaelivaled olefins usually
.-.,quire sueh dnulic reaction conditions Ihallhey are of limilcd use [2,7]. However, proper
ehoice in subslratcs allowed such reactions lo procccd under aooeptabJc coDdi lions.
Eumples incJude the reaeliollJ of allyl Grignard reagents wilh oJcfins or diencs
[2,7,8, 11 ,12,]4], and inlramolecular ofGrignard reagenu 10 mulliplc bond. (i.e..,
isomeriution of unsalursled Grignards, sce lhe foUowing seclion) [2,7,9,10,16, 17]. Equation
(11) shows IUyl Grignard addition lo ethylene and l-OClene, Ihe yields of whi<:h varied
widely Higher yields were rccordcd for elhylenc. Polymeriution and rearrangcmenl
of Ihe resultan! unulUraled Grignard reagenls under lhe reacli on condillons may accounl
for lhe moderale yields in these reaelions.
"
" "

,-6.,
1110

, A,
,
(11)
:zo. 120 OC
RolI.c.Hn
R"H.Me
2112. , 1.ld
A certain subsl ituent elote to or 00 Ihe Teaeting double bond further eohances jls
reactivily. These l ubslituents aUylie (rabie 7) OT homoallylic [Eqs. (12). .59,63; (13).
64: and ( 14) 64] hydroxy, all ylic amino (sce Table 7). and lhe vinylie pheoyl (sce enlry 8,
Table 7) groups.
OH
.;-....,M.Br
OH

B.o
.
"'
..
EltO. 25"C
"
(12)
".
ylald
OH
,.....,.",. MIBr
6
H,o
.
( 13)
C,H6. reno
10110 ,',Id
clJ/. r ...... O:1O
El'
-
OH
(14)
ELLO . .. n
El'. HtO. (Xh. ,. DuOCOPb
El .. H. CO:zH. , h O
(lac, oniud)
The slcreochcmieal oulcome of the fOTegoing reaclions was discuSled in tenns of lhe
hydrox)'l -assiSled mec:hanism. A vioylic sil)'l group secrned to promote the addi tion step
and ddinitely controlled tlle regiochemistry or lhe reaction [fA. (1 S); 65].
RM.Br H,o
Me,sl EttO
90- 100 OC
bEL U,..,. p,
,
(1 S)
A synthctically useful Iransformation, in which lhe allylic hydrolY and vinylic sil)'1
subslitucou doubly faci lilalc Ihe allyl Grignard addition, is nOlcworthy aOO is shown in
Eq. (16) (66] {sec cntry 7, Table n
""" """'Y
OH
. '
"",'
H, fiJ I!l I
J-o .... , - "-'-'VV
1.,-&
( miJo. ) ( 1III JO')


Mc,SyY + Mc,Si
El OH
(""Jor) ( l ') (1II.0 .)
2919" ,>cId
5'. HzO. 0zQ, NBS. (PbS'. PloCOO. R' ,rOO. hB.
El_ H. o. Br, PhS, PhCO-, k
1
k
1
qOH)., OO).H. Bn
(16)
The diaosten:oselectivity or he prolonaled producl [lO; EI_ H] 'Nal abaul 9:1, and the
major isomer 'Nas proposed 10 arise rrom the inlramolecular delivery or the all )'1 group.
as shown in Eq, Moreover, the deuterated product (EI _ D) showed an 8:1
Tibie 8 Elhylmannalion of Olellllll with EI,Ma
E"Ma
,A.
R.J....,Mle
c" ZtC1,

,
Yield
lO'
Rd.
,
' ... OI,Cl t. OlCMr u . 90

,
MOlSi e l/, ..
,
BuOCI I
"


ClI,-tllellOClI,.
"

,
cf.-"',
"


".u-
..
,
".",. Ir -c..H, , )OCH .eu. e H I el/.n
"


".",. t.4 oOCH,cl l _eHI el 1, ) , .
"

,
r hOCH-
,

"
,'a", I'hOC H eH . c n( cn }J-
"

"
IIOCH,
,

"
,,,."' . I/OCtl ,CII-CI I(CI I 1,
"

"
ElI'ICI/,
' 00

"
"u, CNCU,CIIooCI IICl I,,..
"

"
CM-otcHSCM-
"

" '"
u . lO"
"
"",t + PII .............. ,
113:171
"The prodUCI."" lbe ,id<! Ihown ... IIIoIec alter bydrol)'W 01
.......
diastereoseteclivi ty for deuterium aOO the al1yl group. A variety of electrophites coutd reaet
with the rt:!I ultan! magnc:sium reagent.
In addition to these uncatalyzed rcactions, certain transilion metals are known to
promote the addition orGrignard reagent to olefins. For a:.ample, nickel0(:3lalyzed addilion
of PhMgBr to ethylene has becn documented, bUI the reaetion itsetr was ralher messy
and or a tow synthelic utility (23,48,49,50). Whercas a titanium catalyst, ueh 115 Tia. or
ep TiCI , elfected the lIydromagnesation of oteHns and acetylenes wjth Grignard reagenLl,
as described in the preceding section, use or a suitable zirconium catatysl altowed a
carbomagnesation uOOer simi lar Teaetion coOOitions.
Thc fi nl rcport 00 carbomagncs.alion calalyzed by zircooium was madc by Dzhcmilcv
.el al., who carned out Ihe rcaclion by taking oleHo, EtMgZ (z, see Eq. (17)), and a
catalytie amount ofCpZrO al near room temperalure 10 obtain 2-ethylalkylmagnesium
reageo! with a goad selcctivity (Eq. 6).
(17)
9]:1 . 9J:5
TI bie' GeIM:IlIl;on.nd ReactiollSofGriJlUlrd Reaaent. by Ziroon;um.
CataJ.r=I Eth.yhmogncsation

."'"
E1M,X
R.A-M,X
s'
- O
CN'l,Ol

En"1


O' a Y.ld('Io) RIf.

.,
",o
,
..
"
,
e.Hn a
""""
McCH(OH)- "
"
, , ,
II(OMohllll01
'" "
,

, ,
"'"
.,
"
,
,

'.
, ,,_,.
69,71


"
M"
M,
"
..


011,1 . 8 . 111,.
"


e"'",
(Mdh
M"
..
"

R
1
R1w
R lp,
l
ecOIl). lI-SI
"

""",ro
- "

"

..
".
"
II.M,o....,..l,
,
V .. ld f.r ... la ha. or O',ut4 ....... 1.
"
Thi! carbomagnesalion was cumined moslly wi lh EIJM as EtMgZ ami, accordingly,
Ihe products are dialkyimagncsiums. whicb are shown in Table 8. As Ihe aforementioned,
litanium-catalyud hydromagnesations, Ihis ziroonium-calalyzed cthylmagnesation was
also mOS! SIJ1xtOlfuUy applied lo terminal okfins and permitted a chemosck:ctive
metallation ofbis-olefinic subslances. Many luch cxamples can be sceo in Table 8.
several functional groups contaioing tlber, amine, lulfidc, and smcon groups did nol block
Ihe reselion. Howcver, aJlylie pheJlOly and hydrolY groups ortbe rescting terminal olefink
moietics totally inhibited the reaction (entrics 9 and 11, Table Styrcnc showed a reversal
regiosc]cctivity against alkenes (scc cntry 16. Table wrueh is in accord wil h t be lendeney
or this particular substrale, as also nOled in the prcvious hydromagncsation.
In addilion 10 Ihe buie rescarch jusI desCi ibcd., I rew differcnt groups [61- 10] quite
recenlly invesligaled this reselion in more detail by using ethyl Grignard rcagcnt, rather
Ihan diel hylmagncsium. This brought the vlluc of Ihis series or reactions lo lhe altenlion
of organic ehemists. The resullanl Grignard reagents have reactcd nicely wilh a variety
of elcctrophilcs, as summarizcd in Table 9.
Hoveyda el al. funher orientcd Ihcir invesligadon on Ihis zirconium-calalyud
ethylmagncsalion lo Ihe i"ue or 1,2-asymmelr1c induction in he step or elhyl addition lo
SUbslil Uled olefin as elCmplificd in Eq. (18) [10). Thus, el hylmagnesalion or various allyl
QMoO
X.M
'YMoO
O.

EtNICI El
CpIZ.C1 (18)
U mol")
.,..
0,0
'YMoO
"" ..
(u/I)
alcohols alfordcd $yn-diol aner Ihe oxidative work.up of lhe produced Grignard reagenl
wi lh O, (Eq. (19)). Tbe $,-,,selecti vity was reinforced when the readion wu perfonncd
in a solvent wi lh less coordination abilily (from THF, lo 2.5-DMTHF. lo ether). which
$uggesll Ihal Ihe SCIe<:livily was conlra lcd by chclal ian bctwecn the hydroxy graup
(alkoxide in Ihe readion media) and the reacling metal cenler.
O"
) _
CPlZrC!,
(S mol")
2SC, 12
R*C, II W. -C,II, ,CH, .
!In. < C, H 11. PI!

1.S DMTlIF
n"
95: 5 . 15:25
19: 11 - 15: 15
75:15 . 50:50
(19)
On the conlrary, a wide varety a f ather terminal alkenes having allylic 81koly or
methyl group a11'ardcd ",,i-diob after lhe et hylmagnesalian followcd by the same workup
[ Eq. (201). In lhese cases. vi nually no change a f dilllllereosclectivities was observcd
by switching the salvenl from TH F 10 elher. showing Ihallhe a rigin of Ihis dilllltereosclcction
comes from sleric repulsion of substiluenLS around lhe reaclian <:entero
,
,N
El,O ot Tllf
Ih ,C,1l )CH,. ,
C, 1l " cmo!! j - .
C, U "CU(OMEM)-,
h .<.C,II
, I
.Ph
X.Me.M.O.MEMOJDuO.DnO
o,
, C
,

;,
, <Id
>w, < 1 . 50:50
)20)
A bulky TBS group 10 Ihe terminal alefin blockcd the reaclia n, which
enabled Ihe rollowingchcmoseJect ive readian [Eq. 71). However, an addil ional
runctianalil Y near Ihe reaction cenler assists he elhylmagnesation 10 agai n proc:eed [ Eqs.
(22) and 70].
en"

CPIZ,O,
(5 mol")

B(OMej

No .... ,Ioft
en"


(21)
(22)
, ....

lu",I""
,

!>IM,O, Q

Cp,a,
",,3
(S ...... "')
(23)
c,H"
O><
'""'"
L
10'110 r1dd
"" >95:5 .dectl.ltr
Norbomenes also underwent regio- aOO slcreoseJective cl hylmagnesation, even Ihough
Ihe synthetic applicabi lily is rather restricted [Eq. (24); 73).

ElM&CI H'
" -

CplZrC1J
(24)
'0
ElzOorntF
RaH.MEM
4591'110 yi.ld
'>99:<1 .80:20
Study on Ihe mechanism of Ihis reaction revealed a reaclion pathway involving
reorganil.3.lions ofsevera] active species. A ! Iud), using deulcrium-labeJcd CH)CD
1
MgBr
rcvcalcd Ihat deutcrium was inoorporalcd on both carbons of lhe ncwly introduced cthyl
group al a ratio of so:SO ( Eq. (25) aOO (26); 70].
O.

(25)
..

.J,
'"
ClJ.
:: o/ .... Mo _!i01IO o
(26)
Thc mos! likcly rcaction COUI'$e Ihrough lbe intermediar)' ziroona-cyclopropanc 11
aDd -cyclopentanc 12 WIU propose<! (Schcmc 8) and could rationalizc lhe 1055 o( positional
idenlil)' of both carbon! 01 lbe clhyl Grinard reagcnt. Moreovcr, Ihe OrigiD of the
aforementioned stereO$Clectioru [Ste Eq$. (18-20)) has bocn weJl e:lplained in temu of
chelation or steric repulsion in the intermediate species in thil mechanism [70].
When ethyl Grignard teagent in the foregoing carbomagnesation was replaced by
PrMgBr, the reaction probably took phu;:e through zircona{methylcyclopropanc:)' to yield
a mixture of produc::ts having 11- 8nd i-propyl groups. Thc latter is the major ur exclusive
oonstituent [Eq. (27); 69,74].
PrM,8f

",,,",,,
(J
1l1P, 1!I"C
",o
(27)
"'"


Cp,ZrC1,

2 ElM,cI
.""
Cp,Zr-1I ( 11)
(. "",(])

Stlkme 8 Proposed reaction course for zirwnium.glalyv:d cthylmantsation
The use of a chiral zirconium catalysl may elltend these reactions lo asymmetric
synthesis. An example Ihal achievcd a chiral IransIcr al a very high level was reporled,
but a Grignard reageot was ovolved io ooly a transitot species. nol io lhefinal product (14).
Carbomagnesation of acetylenes with Grignard reagents affords thc correspoodioa
alkenyl Grignard reageots, possibly with a defned regio- aOO stereo-chemislry [2,1, 11 ,11,34).
Thil resclion work! wdl for iolernal acelylenes haviog a hydrolY or amino group proximal
10 the lriple bond, as in the olefinic subslrates discussed earlier. Equalion (28) formulates
the reactions, in which the regio- and slereochemislries of the resul!iog magneslum specics
have btto conlrol1ed, as depieted by high selecti vities. Table 10 summariz.es Iypical reactions.
(28)
Ahhough propargyJic hydrollY groups oicely direclcd Ihe regioselective addition of
Grigoard reageols, amino groups seemed lo be less effective, aod Ihe
regioselection. The addilioo of Grigoard reagenls lO acelyleoes haviog a funcliooal group,
such a5 hydrOllY, amino, or alkylthio, al each of bolh propargylic lermini was also
iovesligatcd (78-81)' Homoproparyl alcohols are IliIl su.steplible to Ihe aUyl Grignard
addition, bul Ihe high regio- and stcreosc:leetivilies oblained wilh propargyl derivatiVC$
are orten lost [60,64,76,77]. The subslrale having a hydroxyl remote Trom Ihe triple bond
by more Ihan Ihree rnethyJenes 5eemed nol lo be attacked by al1yl Grigoard reagent under
conditions comparable wilh Ihose applicd lO the reaclion! of Eq. (28) [76J.
A transition metal catalyzes a similar carbomagnesal ion reaction, which has broaden
the synlhetic usefulllCS5 of Ihis rnethod for synthesis of alkeoyl Grignard reagenls. Among
melal sa1ts Ihal were reporled lo calalyzc carbomagnesalkm 01 acelylcncs
[7,51,82- 84], copper nlls are most popular [7,13- 15). A variely 01 acelyJenes, including
ac:elyJene itsclr (85], as weU as subslituted ones participaled in Ihis reaction. Sorne
representalive reaclions are summariud in Table 11.
Although lhe applicabilily is limiled lo Grignards haying no ,B-hydrolen, namely
MeMgX and PhMX. nickel-catalyzcd carbomagnesations of aoclylenes becn
documenled [Eqs. 84 and (JO); SI).

T.bIe 10 CorbomalftU'llion oIPmP"'lIY1 Alcobols.nd Aminc:lwit h Grianard
R ....... I$
"
, _ __ 1-11'
R -' =',
,
".
-
1 HHHCfI
,
,

,


,
'"
"
"
M,




M,
M,






M,
M,
...
... ctonUed.








NPI!
NMel
''-M'"
el' 'fR'
,
( U )
El' El Yldd (,,)
EINI8. li20 H U (lO)
1II,'.M,CI . lJ (26_U)
(J) COJH" _.
104._. ,. &.., H


II (O)
13 (60)
Rd.
"
7S,16.11
"


Me_,E. .

13 (45-59) 71
/_ Pr .
PhM,X
1II,. M,Cl
111 ,1.,

.., . Meel
111)'1.Il0l,8
ElidiD.
Er,

. P, . MIOr
all, I M,CI



Il
13 02)
"
"
"
oo ...
13+14 7'
(10,90':951
I J+14 (40-60)
[15:151

IJ 61.62
'Sa! orle", " lO' oXl.li!ed clixussiotl.
ZIE. DOIlpcci6cd.
")==<"
PIi MIO.
EI-=-a
Ph MBr

(PhJPhNI01

lO" ,1014 ,
,
Si",",
Me-,Si>==<.G.H11
Mepi Me
,
MeMIB.

)=(
111



Ni ( l cach
X
""
X (;Jf"
,
-AIMe)
CoH"
X" M
I
8')Et
"
.'
"
Rlllo VI.ld!")
0,0 D
, : I
"
"""
RCH(OH}- ":15.90:10 "-lO
ro, co,H

,
,
"
'.
,
ji : I
"
"
(29)
(30)
S.1o end Urebe
T.bk 11 Carbomasne$a\ion of AlkyrlCll wi!h Orinard Reasen!' Ca!alyud by
Coppcr
RM. X
R' R' R' MJlI. '
"
"
"
"
R'_.=._.1
,
>=< " I >=< ..!!.-
H'
r<.,
"'"
R M.X R R
' , "
( 15) (U)
I!.II,
.'
.'
... '
"'"
"'
"
Yi.ld ( .. ) .ef.
,
"
"
CI Hu M,B. C.D. EtCH(OH)
" " ,
M . lll.IP .
""
M. .E ... Cd,. M.o
"
15 (769J) ..
1'Io CU-CIl .
' 1'1 "
e.'
R'C.c

,
"'''''' "
,11, I. M,x. e.,
,,'"
" "
(ll IO)
"



,

,
",o
"
(ll IO) ..
,

, ,
ro,"
"
(:J() 61) ..

, ,


.IRIco R ,.lqOIll U
,

on,I l ku,l.

"
(10 10;1) 11.11


"
CH(h4c)OH I'hM,O.

"
(H)

"
",",,,"

"
(ll)
"
CM,oMI8. MIBr E'MI8
"
(HJ I)
" ". MIO .
( . '.0)
,IIlI. MIO.
"P","oCL, I,olol<d ... I''':lon ...
Thesc: uncatalyzed and transition melal-catalyzed carbometallations enable the use Or
vanouI Grignard reagenll 10 give al ken}'1 Grignard reagents or high regio- and
51ereochemical pur;tin. dependent on Subslrales. This method enables Ihe synt hesis or
steTeodefined olefins round in many naturall y occurnng producls.
IV. REDUCTIVE METALLATION OF DlENES
Reductive metallation or 1.3butadienc with magnesium in aprotic media afforded u kind
or allyl magnesium Teagent, (2butene I,4-diyl)magnesium. which has sorne use as a start ing
material for other organometallic compounds [91.92]. However, lhe smoolh me(ullation
was limited lo butadiene. Ot hcr typc5 or l.3-dieoes uluall)' suffered dimenzalion,
polymenzalion, and otller side reaclions under similar readioo oondi lions (93). Rieke er
Q/. this diflkulty by using a ver}' active magnesium, Mg" calle<! YRielce- Mg
H
[94J. prcpared by lile reduclion or MgO with lit hium metal in the prcsencc or naphthalene
or lithium naphthalenide in THF. In ract, $Cveral typical dicnc:s or the folJowing $t rudurcs
underwenl Ihe clean reductive metallation 10 give the dienc-magnc:sium rcagenU [17; Eq.
(31)].
[ ''C
M
. [
m'
''C"' 't
':( ''C'" -
I .... ;1( MX.
El' "'IX' I 1;1'
(17)
.' I
m' I .' I
El' I
''Cm'
't>
':( ''C' I aJ,I:,
I El'.




.'
':t., ''(s,
s'
Sclitrne 9 Reaclion of(2bulcnc-l,4-diyl)manesium 11 willl twodilrcl'CTll cltrophiJes, El ' Ind El'
M,'

, CM"
(17) f1I
':. X o: (31)
R. Me.
Y""".
'"
Sino: Ihese species WCTe difficult lo oblain before lhe developrnent oflhis improved rnethod,
thdr yolhet .. application has DOI beco ex.plored [95,96). As lile resulting magnesium
spa;ies has (wo carbon-magnesiurn bond" il may rcaCl Willl I\VO dilferent electrophiles,
EJI Ind El', in a stepwise manDtr 10 gve a possible mixture oC threc regioisomen, ir lhe
starting diene is symmetric, or a mixture oC s i ~ ir ji is uDsymmelric (Scbeme ~ Howcver,
Ihe actual reactions of 17 wil l! dcctropbi lc usually talr.e plao:: in a highly regioselcctivc
manner lO reduce the number or Ibe product(s) 10 one or l\Vo. Table 12 shows representative
rcactions based on Ihe diene-magnesium reagcnl
The mosl nleres!ing applicalions of 17 are certain cycl iulions aOO spiroannulations
(98-100). The trcatrnent of the rcagenl with I bifuDctional electropbilc, such as X(CH}).X,
X(CHJ).CN, RBX}, RPCI
J
, RJSiOJ. or SiC!.. or with a combination of two dilfercnt
ones, ineluding RIR1CO+CO
J
or elhyleDe oxide+CO
J
, effccts carbocycliution,
helerocyeliution, and lacloniulion, iDeludiDg a spira.fashion, as shown in Scheme 10.
A supcrficially analogous cyelomagnesatioD o 1,6- and 1,7-dienes pror.ccded with
BuMgX or BuJMgX in the presenoe o Cp1ZrCl
1
cata1ysl. as shown in &j . (32) [67,101).
All hough mosl cumples inelude simple hydrolYlic workup of lhe rcaclion mixture.
T.We 12 Represent ative Rcactions of (2_Bulene_ I,4-diyl)magn.esium, .... ilh
Eleclrophiles
[ :::o.!
1) !;l '
J) !;l'
"
, M.

, .

J (CII " ,




..... PII.
"
El ' m'
R I O ti'

ArCII" ,

A.. .. ' Ko.. 11"

, ..
1oI.,sICl
.. ,sICl
o

.

X (HII, "
"
(419{1)

,
XCOMo(I'II) (6011'
"
ml')


"A.
SIR.
(11:21100:01
inlerceplion of Ihe inlermediale with D10 or 10 yield the oorresponding
bisdeulerated hydrocarbon or diol oonfirmed Ihe presence or the bis magnesiated species 18.
zj: L
Z.Ctlz, .CRIR
l
., I'hN
b"
yicld
Ir .. u /c/ . .. 91:3 J ) : 61
z,. :x::x; R_Me
..... yk:ld
,

IJ"MIO equi .. )
.,. 1J"2M, (1.5 cqui .. )
CPIZ.Ct (1.' 10 mol")
EllO. ' .1.
,
Zr-t"'MIX

(U)

".
-
Z .. (ClIln .
EI'(EI}-[)zO(O).o,(OIl)
61'0" ,Icld
,rdtUlcl,. I ' :12-10;10
(32)
"
RBX or
II,SIO,
lid. 9J,95
'''''
R.r. 96
I
XCOIl>.X
R_ Ij
lid. 9].9.
BI(CH,)"Ctf
. _ I }
II.r. 93,9'
------
."-',-""'
1:::0.'
(I7)

"ro,
lid. 99
",+-
o
"A,
o
"11/-\11'
'\. "ro,
'\. R.r. 100
"
"v
"
o
SdHn.e 10 Cyclizuion alld spiro-annulalion b'11d on 17
The mechanism of Ihis rcaction il clogly related lO Ihal of the or
oJefios with EI1Mg or EtMgX, as deseribed io the foregoing seclion, bul the use of
bulylmagoesium reagent, ralher Ihan is the key. The use of bulkier bUlylmagoesium
reagents prevcnts the formalion of zirconacyclopenlane 13 (right half of tbe Scheme 11).
II does allow Ihe ligand exchange between butene and lbe added 1,6- and 1,7-diene 19 on
the zirconium 10 make lhe rcaclion proc::eed 10 11 (len portion ofScherne 11), which finally
fumishes a desired bismagnesium rcagenl 18 [67].
V. ISOMEAlZAnoN OF OLEFlNIC AND ACETYLENIC OAIONAAD
AEAGENTS
In contrasl 10 inlermolecular addilions of Grignard reagents 10 unsaturaled bonds, tbe
Iype of reaclions in an inlramolecular fashion (i.e., isomerization of olefinic or
acelylenic Grignard reagenll wi lh an appropiate struclure) rould prooeed much easier
[2,7,9,10). Exhauslive reviews Ihal s)'Slemalic:ally IUrvey Ihese reaclion! from Ihe
standpoinls of organic [ 10] and physical orSlnk chemislry [9] are quite informalive. A
general suideline on lhe rate and direction of lhe cyclizations has bcen described in Ihese
reviews. A few, synl helically inlereslins examples are shown in Eqs. (33) [ 102], (34) [90],
(33)
C,<: h ......... , .. .
<>l dla>c: l '
r-fI.lI
X
( 11)
v........1.I.X
(22)

= ".=
. :-


.. r .1_."" 2.
(21)
Schrne 11 Dilfc.encc in proposed catalylic cy<:les of cycloma,nesalion or dienes ,lid
ethylma,nesation of alkenes
1,8.
"
D'
-

(34)
M18.
"
OM", 0"
EI"(B): 11I,1. 8 . (.l l yl)
Yl dd:
d."19."0:2I.
".
and (35) [103], which show that both and j -endo-trig ring closures [ 104] are
pmsible.
Me,Si

D'

".
H'"
(35)
111M, Mol El Mc,l
"' "
" "
El' (EI ): O:2O(D), 111,1. 8 '(1 11
,
1)
Y<:ld: .....
" .
The most syntheticaUy useful transformation belonging to this elass of rcactions would
be he magnesio-enc rcaction [Eq. 16,17].
M,lI:
, .
. '
..
o
(36)
T.We 13 Ma:n jo, ene and Sublequent Rcaction witb E5ectro-
", ...
Q a
a
E. ",
h, ,,,.,. O'
r ....... ' ( .. , a. f.
,
f""
..
....

(un,
..
,
..
4(
(6' )
,
)

,
''t('" ""'"
f4 . 0I
", ((0_11'
"
C! , .2.3
a

(12 )
10U' G
,


",


}..-,'
"',:I.CI
-
( O U)
,,,
" "
,
a
1.1 " ... .I. II ..... . PI!

- ,
Mc:,:I.CI
U, ... ,
( a )
,
o
, (
c:(.
( .. )
'"
/IIIB.
.....JO:.

-
""'"
,,,
c.t. ""ED" (1"
"
.....
(JI ,
,,,
T." IJ Conttnued
e'

"
(JO)
,,,
"
(62)
'"
"
( 47)
'"
'TIII. 0.;",.,., "' .... , .... ,,,,,,mi b, ..... , .... "'-1.
Typically Ihe IIl1yJmagnesium reallents are generated from Ihe correspoodinll allyJ chloridcs,
al a low temperature.. wi lh magncsium, which is preferably aClivaled before Ihe reaction
by an appropriate method [94, IOS, I06]. The ene reaction WII5 allowed to complete al
room lemperalure or as hillh as 13O"C. Table 1) colleeu several examples, Ihat demonslrale
Ihat Ihis melhod is panicularly useful for lhe consl ruction of carbocyclic rings. The
slereoselectivi ties of the 5ubstituents are oflen higll and lhe remainin; orllanomelllllic
moieties are helpfuJ for funher synthetic elaboration. These advantallcs have becn amply
hillhlighted in Ihe concise synthesct of lerpenes [16,17, 107- 111 ,11l-1 17].
Isomerizal ion of acctylenic Grignard reagenLS alroeds Ihe correspondinll cyclic alkenyl
Grillnards [2.7). Mllny cyclizalions of acelylenic Grignard reagen!! are found in Ihe
lilenlure [9]. Equalions (37) [1 18, 119] and (38) [ 119] represent recent, synl helically usd"ul
elamp!es, in which Ihe silyl IlrouP play! a dual role lo facililale the cyclization and 10
increase lile slereoselectivity.
M. 11>==(3
B'
R>==(3III)' II- = -{O' ),,-x (CII J.
'M.
"
, ,
"
Sol . CDftdiLIgftl B'
"
Yidd( .. )
Iln
8.
,
T1rF
..
ollJI . II, on,1



0,0
, .,


" ",
a
m,
IOO"C; 6d
",o
" "
MOISI B, , ,",o ,.n.:
..
oIlJ I B IIJI ..
EI,$I-. =
".
,,-,"
99'110 yldd 191: 11
,
0,0
rI
El,5i ElISI
(38)

,
ElISI- .::,?
".
,,-,D'
9'" Jlclo! 1 ):911
, ,
0,0
,erl
.,
Inll1lmolecular addilion of a Grinard 10 a triple bond il also catalyu:d b), a coppct
salt , as in Ihe intermoleo::ular addition (S;. 15].
OItw.n
0Itw.. producto
D" 70 : )O
(39)
95"D .. yicld
VI . CONCLUSION
Preparation of Grignard teagent! from okfins and aoclylenes nOI only complemenls the
convenlional methods, but aiso enables a cherno-, regio-, and stereo:selcctive formation of
Grignard reagenu Ihat are olherwi:se diffieuJt to prepare. Moreover, Grignard teagen!!
with stereogenic centers, obtained taJily from suitably substiluled olefins. conlribute an
easy access 10 synthetically versatile intermediates.
ENDNOTE
The following abbreviations are used Ihroughout Ihis seetion: El, Pro /I-ptop)'1 unless
otherwise indexcd; 8u, /I-bulyl unles! otherwi:se iDdexcd; C.H
2
.. l' /I-alll:yl un]ess otherwise
indexcd; 8n, PhCH
2
; Ph, aryI;Cp.,,'-cyclopentadienyl, unlc:ss othetw;,e indexed;
/1-. normal; j-, so; $-, secondary; f-, teniary; (-, eyelo; "., para; 11--, rn-hapto; THF.
letl1lhydrofuran; 2,5-DMTHF, 2,S-dimethyltelrahydrofuran; T85, t-8uMelSi ; MEM,
methOllyethollymethyl; TI, CF lS01-; acae, aocty1aoclonale; Dibal, diisobutylaluminum
hydride. Quite recenlJ)', a repon on Ihis meehanism of titaniurn-calalyzed hydromagnesa-
tion of aOClylenes appeartd (120].
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4
Magneslum Actlvatlon
REUBEN D. RIEKE
Unlwrslry and Meta, Inc., Lincoln. N,brasM
MATTHEWS.SELL
Rieu Mtfa/s. lne., Lincol". Ntbrada
1. INTAODUCTION
Organometallic compounds and metal-mcdiated transformatioru are among Ihe mas!
powerrul lools in Ihe s)'ntbctic orpnic cbemists' arsenal. The teratufe involving
organometallic ncnnediales has iterally explodcd in he past 30 yeal'l, and he tate of
publicalion in Ihis arca oontinucs 10 accelcrale. Although man)' Iransrormalions involvc
hetcrogeneous conditions interface). mas! of bese rcactiODS involvc discrete
organomctallic spccies.
The significancc or he: Gnlnar<! reaction is cleady upmsed in he following
quotation: ... c:very chemist has carried out Ihe Grignard reaction al leas! once in his
iretime .. ," (1). In lighl of Ihis ubiquily, the gencration of new Grignard reagenls 15 indecd
a worthwhik: cndeavor. Although the fonnation ofGrignard reagen!! is ostensibly thought
10 be eompletcl), (Mn: are m.n)' organie halides thal do not fonn Grignard
reagen!!. The preparalion of Grignard reagenls from primar)', secondary, and tertiar)'
halidC$, u well as from aryl iodides and bromides using ordinary metaUie magnesium
lurnings can be accomplished in low-boiling solvenl, sueh as dielhyl elher. However,
man)' organic halides, ncluding bie)'clie bridgehcad halides, aryl ehloridcs, and vin)'l
ehloridcs, exhibt a low propensit)' for the fonnation of their correspondng Grignard
reagen!! from ordinary magnesium turnings. Also, thcre are man)' alk)'l and aryl bromides
that appear 10 be likel)' candidates for Grignard fonnation, bul fajl because ortbe prescnce
of certain funct ional groups. Jueh as ethers. M"reover, organie lIuorides are generally
considercd lO be inert loward ordinar)' magnesium. Also, occasionall)' theGrignard reagenl,
are unslable under Ihe reaction condili"ns Ihal comm"nly involve refluxing in
tClrahydrofuran fTHF).
Clearly. any technique Ihat could make thcsc more difficull organie halides acces'ible
lo Grignard rcagenl formation is desirabJc. To thi s end, ir ordinary magnc:sium could
somehow be (either physieally or chemically), of these difficutlty a,.,....ssiblc
Grignard reagents coutd be prepared. Severat melhods are currenlly at Ihe disposat of Ihe
synthelic ehemist. which have greally expanded he range o( organic halides hal are
amenable 10 Grignard reagenl prcparalion. It i5 Ihe of magnesium Ihat il Ihe
$Cope of his chapler.
11 . GENERAL METHOOS OF MAGNESIUM ACTlVATION
A. Remo.e l 01 O.lde '--re, .
Sina: Grignard reaetions of alkyl iodides and bromides are ditrusion-cont rolled aficr Ihei r
Ihe rcaclion rale il di rectly proporlional lo Ihe availablc mctal , urface arca
[2). The simplesl for cnforcing Ihe iniliation of magnesium-i nduced reaclionl by
increasing he surface arca is removal or oxide layers by washing with mineral
llcids; hen, fi ling, grinding, and milling [3). Allhough removal of Ihe oxide tayers and
augmenlation or the surface arca wi1l increase the reaclivity o( ordinary magnesium, the
production of Ihe finesl particles or, in the ideal case, eYen of large cl uslers, is far from
bcing achieved using Ihis melhod.
B. The " O,y-SII," Melhod
Scauered reporu have appeared in the literalure of magnesium activation by Sl irring Ihe
solid under an inerl atmosphere. The melhod is exemptified by Ihe synthesis of Ihe aromal ic
Grignard reagent shown in Figure 1, which frustraled altempls at ils preparalion by
convenlional techniques [4). The development of this method has proved very effective
in Ihe synthesis of several aUyl- and benzylmagnesium hal ides [S].
To lest the dry- sl irring procedurc. a batch of commercial turnings (Fison's) was
mechanicaUy slirred with a Teflon bar in a wide-bore 5chlenk lube, under a nit rogen
almosphere for 15 hr. This Ied 10 gross changes in Ihe appearance of he magnesium. The
parliclc sizc was reduced, the color was much darker gre)'-black. and a magnesi um mi rror
had becn deposi led on the lower walls of Ihc Schlenk tube. Al Ihi s stage, the mel al WIU
covered wil h dry dielhyl elher, mainlaining the inerl almosphere. A solul on of freshl)'
dislillcd rx-phenelhyl chJoride in diethyl elher was added dropwise 10 the cenler of Ihe
vorlex of the tirred magnesium slurry and generaled the corresponding Grignard reagen!
shown in Figure 2, al O"C over a periad of 3-4 hr. The quantit)' of magnesium constiluted
a livefotd cxcess over Ihe haJide. In this way, a clear sotut ion was maintained. This contrasts
wi lh he normal appcarance orlhe reaclion mixlure during Ihe preparalion orlhe Grignard
reagent shown in Figure 2, when substanlial precipiation or MgCI is formed as a resull
of homocoupling, leading 10 cloudinc:ss and eventuaU)' a while precipitate.
Figure> I Aromalic Grinard rcalent formro usinl the dl)'-t'lir melhod of manesium activalion.
"
I MgCl
h
Filllre 1 Fonnation of lile Grignard reagent From ex-pbenelhylchloride aOO magnesium le. ivalec!
by he dry-slir method.
MCI
/->", )
I
h
Figure 3 Form;ttion of Ihe benzyl Grinard !'algcOI u.sing mancsium activated by Ihe dl')'-llir
mcthod.
Fil1ll't!" Formalion of lhe benzyl-Iubnituted Grignard reagcnt u';ng magnesium activated by
lile drJ-Ilir melhod..
After addition was complete, the Grignard solution was filtered through a frit, under
positive nitrogen prcssure, ami made up 10 a standard voJumc with dry diclbyl clller in
a second Schlcnk lube.
It was eslablished Ihat Ihe nitrogen atmosphere can be replaccd with afgon. wi lhoul
alfccting he activat ion process. Thi! demonst ratcs Ihat surface magnesium nilrides do nol
playa role. The successrul application of dry-stir activation 10 lhe synthesi, orlhe Grignard
reagen! shown in Figure 2 spurred a series of experiments in which aUyl a f benzyl chlorides
werc: converted into their correspondng Gngnard rcagents.
Among the benzyl magncsium chlondes prepare<!, the synthesis ofthe benzyl Gngnard
rcagent shown in Figure 3 was straightforward, whcrcas the formation of iu denvative
(Fig. 4) had to be carned out with careful control of the rate of addition to avoid coupling
side products.
Ci nnamylmagncsi um chlonde (Fig. S) can be synthcsized very clcanly by prescnt
tcchniqucs, allhough rcaction of the chlonde shown in Figure 6 [6] with dispcrscd Mg
had beco reported to yicld lillle or no Grignard rcagcot [7].
Synt hcsis of the Il-silylated rcagcnt (Fig. 7). widcly utilized in asymmetric
cross-coupli ng [8J, Wllll straightforward, aJthough, herc. the rc:agcnt can be prepare<! in
high yield by standard procedures.
The propargyl halide (Fig. 8) can be convcrted into ilS correspondng Grignard
rcagcnt (Fig. 9) in 63-". yicld by the dry-stir technique. Prcviously, this rcagent had bcen
Fiaurt 5
method.
Cinn:amylm.a;neJium chloride prcplrcd U$;na; mancs;um actiYllcd by lhe dry-slir
Fiaurt 6 Reaction of cinnamyl cllloridc wilh di$peucd mB&r\CSium has been rcporlcd 10 yicld
Ihlle or no Orill1:ard l'eaa;cnl.
Formalion of lile -silylalcd Orlananl r c ~ n l u,ina; maa;ncsium adivalcd by lhe dry-slir
I
FIp" 8 ProparIY1 chloride can be oonvcncd 10 itl oorrcapondirlfl Orlananl rcagenl U$na; m:
dry- lIir echnique.
Fip" 9 Orignard rcagenl prcparcd in 63% yicld from iu correspondina; proparvl chloridc (lee
Fi" 8) lI.ina; maa;neJium activated by 1m: dry-slir mclOOd.
Flpre 10 A c c t ) ~ WIllI dctcclcd lllI an impunly in elle formation or lhe proparyl Grignard
rc:agent (_ Fi. 9 ~
H
ritllH 11
(see Fig. 9 ~
Aliene was dt:eecccd u an impunt)' in the formalion orlhe propari)'l Gngnard reagenl
prepared only by resourc:c to a cyclic reactor, Wling amalgamaled mag.nesium (9). 1be
impurilies observed in Ihe uC-spcctrum were acctylene (Fig. lO) and alIene (Fig. 11) rather
Ihan Ihe homoooupling producls; passibly lhe propargyl radical formed initially is capable
of hydrogen atom abslraction from solvent.
FinaJly, lhe method was used 10 prepare allyl- aOO melhallylmag.nesium chlondes,
the uC_spectra ofwhich were consislenl wilh lhe expected dynamic ,,1_,,1 al1yl struClure
[lO).
C. Gllm.n C.t.tysl
One of lhe earliest magnesium aClivalion methods used in Ihe preparalion of Grignard
reagents was Ihe Gilman calalysl (I
l
) (11). This method has bc:en widely used, owing to
its convenience and $lfety for larg<:-scale prcparalion of activated mag.nesium. Today, il
remaios the melhod of choice for activaling orelinar}' magnesium lumings. This mclhod
works for a \Vide vanely of organic halides, bul nol for Ihose halides for which il is
tradilionally difficult lo prepare thcir corresponding Grignard reagents. Typically,
magnesium tumings (S S) are added under nilrogen lo benz.cnc (100 mI). followed by iodine
(2S g). Diethyl elher (S mI) is added dropwisc lo initiale Ihe activation. The mixture is
stirrcd unti! Ihe iodine colordisappean. The solvents are removed lO dryness by distillalion.
The aClivaled magncsium can be slored aud reactivated irnmediately before use by heating
until Ihe characterislic iodine color appean. A smaU amount oC iodine may be addcd lO
bulk magnesium lO initiate difficult reactions. Frtquenuy, Grignard reactions can be
iniliated simply by lhe direct addition of a small amounl of iodine lo Ihe reaction mixture
al lhe beginning slage of Ihe Grignard teagenl preparadon.
The proposed mcchanism to rationalin: lhe enhanccd reactivily of iodineaclivated
magnesium involves lhe formalion of magncsium(l) iodide, which fuDCtions as lhe active
ag<:nl in Ihe formalion oC lhe Grignard reagent [12). Magnesium(l) iodide is more soluble
Ma+Ml2 lt.!I
R-X + MgI .. R'. XMgI
XMsI + Mi .. MX + Mal
R" + MX .. RMX
FIgurC' 12 Prop;ll!d mechanism for lhe aclivation ofmagnesium by iodin ...
and more reactive Ihan magnesjum metal, and since jt is regenC'raled dunng Ihe reaetion,
jI may aCI as a catalyst. Stc Figure 12 for a proposcd mcchanism for Ihe of
magnesium by iadinc,
O. Vltrlo. Acldltlon
Vi lride, which can be' purchased from Hucel Chemical Praducts, is a reducing agenllhal
has becn shown lO activate magnesium (13). Vilride, NaAIH
1
(OCH
1
CH
1
OCH
l
)" is
sodium aluminum solulion in loluene. Vilnde is a
novel and unique Grignard activator Ihal is gencrally applicable [14]. It eliminales the
nee<! for drying and purillcalion of the solvent, removng quant il atively moist ure, alcohol!,
and pcroxides, and it also actvales he magnesium. A minute quantity ofVi lride is required,
and cessation of Ihe evolulon indicales Ihat the is properly aClivaled.
An excess of Vilride docs not nterfere with the Grignard proccss. This process is superior
10 any other Grignard iniliation melhad, ami commercial cllemicals can be use<! ,
E. M.vne,lum Aetlv.tlon by Enlr. lom.nl
Another classic methad for magnesium activation is entrainment. Entrainment involvcs
using catalylic amounts of a vcry reactive alkyl halide in oonjunction with an unreactive
one 10 initiate Ihe reaction in lile preparation of Grignard reagents. However, in many
instanees where inerl organie halides are used, molar quantities of he very reactive alkyl
halidesare required asenlraiucrs 10 provide continuousaetivation oflhe metal ! Urraa:. Thus,
two equivalents of magnesi um turnings are used when the entrainment or methad of
magnesium activation is pract iced. The reactive organie halide is belleved lo clean and
actvate the l urface of the magncsium and, Ihereby, encourage Ihe incrt organie halide 10
5ubsequenl ly reael. Melhyl iadide (15] and ethyl bromide [16] have bolh becn used fo r
this purposc. The obvious disadvantage of using these halidell is Ihe formation of a sccond,
eKtri nsic Grignard reagenl that wiJI reael with added organie substrate.
Pearson tI al. in 1959 developed an improved methad 01 ent rainment (1 7). Pearson's
melhad, instead of usi ng reacl ive al kyl halides, used 1,2-dibromoclhane as Ihe entrainer.
Tite advanlage of using 1,2-dibromocthane over bromocthane is thal upon reaetton wit h
the magnesium, magnesium dibromide is formed, wi th lhe concomitant liberat ion of
elhylene gas. Hence, no sccond, extraneous Grignard reagC' nt is present in the reaclion
mixture. The magnesium dibromide thal is formed is an activator. The reaClion of
1,2-dibromoclhane with magnesium is believed lo procced according 10 the p8lhway shown
in Figure ]J [1 8).
The preactivation of magncsium i$ a madified entrai nment activation proccdure that
was Ilrsl developed by Ehrli<:h and Sachs ( 19]. Thi! methad involves tite alidi tion of a
,
..,.,:: .. Ium AdW.&In
-- Br-t.fa-<:Hz-CH2-Br
- _ .. H2<='CH2 + MaBr2
Figure 13 Proposcd mechan$m for ,he reaction of t,2-dibromodh.nc with magnesium in Ihe
enlr.inmenl mcthod 01 ma8JlCfium .ctivltion .

Q=.
. '''-
. '-'-
I .

1) .." TMI', .. ,tCc.tlt. rt, lh; 11) r .... 11-1511 (JI"'): el In.
.. WI: "., NO(":'-'.OH, 1,:111; _, N/e, ItOU, ... otf, lb (1""'"
Sclleme 1 Synlhesis ol olOllUOln;1IC usng lhe entrainmenl melhod o magnesium actival'on.
$rn.ll amounl of reactive organie halide 10 mag.ncsi urn lumings in diethyl clller. Once lhe
ruction begins, 5OIution contaioing be rormed Grignard rugen! from Ihe reactive
organie k.lide is dccanted. The residuc is rinsed with diethyl tlher scveraltimes, rollowcd
by tbe addition o thc unreactivc halide. The activation or magnesium by Ihis approach
ma, be ascribed 10 cleani ng Ihe metal surface and ncreasing Ibe number or sites o{
imperfection.
Rcc:cntly, Meren and Hutchings cmployed the cntrainment or magncsium as a key
step in the total synt hesis of lllII shown in Scheme 1 [20).
The corresponding Grignard of bromoindolilMi 6 WaJ generated by treating 6 with
magnesium tumings in THF containi ng 1,2-dibromotetrafluoroethane as an entrainer.
Grignard format ion Wlllll complete alter 1 hr, as evKienccd by gas chromatography (GC),
showi ng complete consumption of the 'taning material. Addition oC the oJlazoline 7
followed by beating ovemight led 10 lbe coupled product 8 in 71 -;. yield. Thia eJlample
displays the usefulness oC the entrainment method in lhe synthesis oC molcculcs.
In Ihe batch manufacture of Grignard tbe most salisf"actory prooedure 15
lO relain an eJlCCSS oC magocsium from the preccdiog batch (activated bc:el) and 10 add a
small amounl oC the Grigoaro solution. This process will eliminate H
1
0 and from
Ihe magnesium tumings, subsequently, activating the magnesium, In Ihis fashioo littlc
diffkulty i5 usually encounlered in injt ialiog the reaclion [21).
lO
F. M.hlt Alom V.porIz.tion
Several physieal tcchniques foc he activat ion of rnctab can Iso be l,lsed for aetivatng
magnesium. Onc of l hac techniques i, metal atom vaporization. The firs! repor1 or he
prcparalion or organometallic compounds by usiog vaporiztd metal aloms 10 reacl wilh
organi<: ligands was published by Tirnms in 1969 (22). Before Timms' work, a similar
technique had beco used by Skcll and co-workcrs (23] fOf lhe vaporization or reactive
caToon species on carbene chcmistry. Metab are largely monoatomie afier vaporization
[24]. The lechnique Iha! has beco gcneralJ y adoplcd for reaeling Ihcrmally generaled
metal a[oms wilh orgaoie oompounds can be sumrnariztd as folJ ows: (1) The metal is
vaporized al a controlled rate by heating under high vacuum. (2) Thc metal atoms are
trapped by lhe vapor of an organie substrate Of oondcnsed into a 50luloo of lhe reaclanl
in an inen al low lemperalll re [25].
The tirst report on the oxidation of melal aloms 10 form organomelalHe oompounds
was made b), Skell and Girard [26]. The)' evaporaled magnesillm f10m a crueible al 5ClO'"C
aOO oondenscd lhe vapor with a vanet)' of slraight-<;hain aOO branehed-ehain alk)'1 halides.
The oondensate al - 196
Q
C was blaek, bllt bcc:ame colorle$s on warming as Ihe prodllels
RMgX, unsoloottd Grignard reagenls, were rormcd.
A varialion of Ihis melhod is the coeondensalion of vaporixed melal aloms wilh
sohents slleh 8lI benzene. THF, or hexane, which W8ll first developed b), Klabunde [27].
Klabunde cocondensod magnesium vapors wi lh THF al liquid nilrogen Icmperaturc. Al
_ 196C, he magnesium was dark blue when cocondenscd wilh THF. Thi, has becn
attributed lo the formalion of a eharge-Iransfer complex. Upon sJight wanning, the
Mg- THF matrix lurned into a blaek ,Iurr)'. The THF could be pumped off, leaving an
extremel)' powder. Slurries of aClivaled magnesium powders acquired b), Ihis
tcchnique exhibited high reactivit)', particularl)' loward oxidal ive-addition reaclions [ 28].
For cumple, lrealment of Ihe magncsium slurry wi lh chlorobenxene at room lemperature
for ) h afforded benzcne aner h)'drol)'sis in 85". )'ield. In oonlras!. ordinary magnesium
was unreactivc loward chlorobenxene under the same oondi!ions.
B)' using magnesillm preparcd b)' he metal alom vaporizalion mcthod, difficult
Grignard reag<:nls becn prepared. Fo! examp!e, lhe aU)'Iic:: Grignard reagenl shown
in Figure 14 can be s)'nthesized from Ihe correspondng al1)'1 ehloride in 6IW. )'ield,
although ils s)'nlhcsis P10ved impossible b), convenlional techniqllcs [29]. The abiti!), lo
prepare Ihese difficultl), accessible Grignard reagenls displa)', the lI$Cifulness of Ihis proccss
Onc advanlag<: Ihis aclivat ion melhod has over olher melhods is Ihal Ihe gcncraled
melal su!pensions are complelel)' free or halogen, and arenes. Wil h Ihe proper apparatus,
larger amounls of melal can easil)' be activaled. However, comparalive stlld)' has
shown that magncsium activaled b), such vaporizalion is nOl 8ll react ive as Rieke magnesium
[lO). Unked wi lh Ihe undoubtedly grealer rosl ort he equipment, Ihis oould be responsible
for lhe few recent applications of Ihis lechniqlle in organie s)'nlhesis [31].
MgCI
Fipre 14 AlIylic Grinard formed from lhe cor=ponding allyl ddoride lIIin, magnesillm
by he metal 110m v.poriz.llion method.
'.
O. Ultr .. ounc! MlIgIMlUm ActI".tlon
Ullrasound Ictivation is a physical technique that ean be employed 10 activate magnesiul'll.
Ultrasound can be delivered safel)' aOO convcniently ,...jlh inexptnsive cquipment, and Ihis
Icchnique has generated a field of study kllown u sonochemistry. Ullrasound can clfcct
chemical resellon! al a mClaI-40lulion intcate when lbe 10und waves induce
or be formllion, growlb. and luddcn conapse of very fine bubbles of gas 1I he
metal-sol uli on interface. This rapid oollapsc !cad! 10 ilIense, localized prc:ssure and
lemperalure differcntial5, as well al electric diJcharges. In rnultipha5e 1)'$lem$, Ihis produces
shockwaves, whith increase mass lraml'er and can lead 10 erosion al Ihe sudlce of a solid.
In addition, Ihe !trong turbulenoc gives rise lo oollisioD5 of Ihe particJes distributed in Ihe
solvent, whith can lead lo considerable morphological chango, either by disinlegralion
of Ihe part icles or even by Ihor fusng logelher owing lo local oyerhealing on collilion
[32]. Such collisioru are al50 belieYed 10 be responsible for lhe degradalion, or eyen Ihe
complele deslruction, of surface oxide layert. In such cases, 5Onicalion of lhe metal before
ils use had an aCliyalion effoct comparable wilb $Cnalion of the wbole reaction miJlture.
Principal uses have included lhe generadon of organomagnesium reagenlS [33].
Renaud firsl reported Ihal improyed yields of Grignard reagenls could be oblai ned
by sonolysis of Ihe rcagents in undried diethyl el her. These results were fi rsl published in
19so, bul did nol Ilimulale furtber inleres! in tbe use of ullruound lO aQClelerate ebcmical
reactions ( 34). Renaud's inilial resulls were lalee followed up by Sprich and Lewandos,
who examined the reaction between magnesium and 2-bromobutane in dietbyl elber
conlaining difl'erenl pcn::cntagcs of water [3SJ. The resulta indcaled Ihal ullrasound had
a profound efl'ccl on lhe initialon of lhe reaClion, although the overall yield al Grignard
reagenl was unchanged. Sonication was carried out in a $Cnialting cleaning balh, and it
is significanl Ihat sonication of Ihe melal before addition of lbe organic bromide had no
effcct on initiation lime. Thi! suggests Ihat Ihe primary efl'cct or the ultra50und js lO remoYe
adsorbed water from Ihe metal surface, rather than any surface-cleaning efl'cct. A practical
adyanlage ofmctal actiyation by ultrasound lies in Ihe ract Ihat frequenlly (he conventional
ultrasonic purification balhs used in the laboralory alrcady suffice lo achieYe a salisfaclory
efl'ccl. The res ulting magnesium, however, in no way approaches Ihe high leycl of reactiyity
demonsl ralcd by Rieke magnesium. The simple and hannlcss application of ullr&50und
on a large-scale is sure lo guarantee Curther use and developmenl of Ihis Icchnique in !be
future. Howcyer, al presento 5Onicalion has limiled use witb organie halides Ihal have
dcmonslrated difficulty in Grignard formation (Le., alkyl aDd aeyl fluoride:$).
The 5Onication method of magnesium actiyation has been employed 10 initiate
sluggish Grignard reactions in clber. Sonicalion is Ihe prefel1'Cd tcchnique for elfccting
lhe Barbier varialion, in which the dectrophilic spccies and organohalide are inlroduced
concomitantly, and lhe Grignard rcagenl is then inlen::cpled as fasl as il is formed
(Fi g. IS) [36].
PC!) + )f'tBr
1) Mg
","'
2)_
Figure 15 Formalion of lriphenyl phOlphine lISio. sonication.
"
H. M",,,"lum M.lhodl
Anlhracene and SOTm of ilJ <kriyalivcs Il:act with mel,lIie magnesium in THF lo form a
compJell: or ype 1, as shown in Figure 16. Spectrosc:opi<: and cncmical properties of
lhe complell beco inYe$ligated in detail [J7].
Thc X-ray slruclure analfsis of a rcpn:sentative oflh, series shows penlacoordinated
magnesium wilh unusuaJly long bonds lO Ihe carbon atoms (2.32 A) and a significant]y
bcnd dihydroanl hraccnc lil nd (38). In view of hese ,Iruelura] fcat ures, Ihe low hennal
stabilily of Ihe mclallacyelc ia erilieot, which j, furthc r reduccd by substitutol!, cspec;ial ly
in lhe 11- or IO-position. or bolh, of Ihe anthraccne [ 19J. The unusual structure of this
oomplex is parallckd by ilS widcly divcrsc chcmical bchavior. Complex I rcacts wilh many
clcctrophilcs (e.g.., CO
2
alkyl halides, 1I:clooes. Ol clancs, dichlorO!l ilanc:s and dichloro-
slannanes, and CPlTia) as a (di)nueleophile. bul aels as an donor for aryl
halides and as a source of "soluble" magnesium for allyl and benzyl halides, thereby
enabling lhese subslrales lo be converted efficienlly inlo the corresponding Grignard
reagenu [40). Even loluene j5 aui table as solvenl. Furthennore, in contrasl 10 Rieke
magncsium, I pcrmits the mctallalion ofpolyslyrcne bearing p-{chloromclhyl) groups [41].
Propargyl chloride i5 smoot hly converled inlo atlenylmagnesium chloride by 1, which is
quite rcmarkable, given lhe considerable difIk ulties with which lhe preparalion of Ihis
rcagent was fonnerly llSSOCalcd [40]. This "magnc:sium SOUI'QC" can also be polymerically
bound 10 a polyslyrene functionaJ izcd with anlhracene residUdl [47a].
Complex I i, Ihermally unslable and afl"ords highJy reactive pyrophork magnesi um
powders with eXlraordinarily high spccifk surface arcas (up lo 110 m' g- J) and
corrupondingly high rcactivity wllcn healcd in inert solvents or when heatcd neal under
vacuum [42]. These powders likewise afl"ord Grignard reagents in very good yiclds on
reaction wjth a series of difl"erenl halohydrocarboJU in THF. toluene, and in sorne cases,

m

Filurt 16 ReaClion of anthracenc and magnesillm,
.. '
-'
";
-
.. ,
SeMme 2 A reaction.

" ... /un! Ad/Y.1Ion
Table I Result. from lhe Mqnesium-ene Reaction Shown in Sc ' llIIIe 2 U.ing V.por.Act;vlled
Magroeaium. Antllracene-Manesium .nd Rieke f.hancsium
Vlpor-activated Antbraoene- Rieke
"
E M,I"!.) Mil"!.) MIl "!.)
I OH
"
" " I CONHPh 71 67
"
2 OH
" "
..
2 CONHPh 72
" "
I MX. ..... ul'. ,",xl
,
11. , ..... , (d.!""
Scheme 3 Proposcd catalytic C)'de for lile formation of aclivllcd metals.
ew:n in heplane. MagnesiLlffi powder obtained in Ihe tbennal decomposition o( activated
MgH
1
has proved to be onlr 5ligb!ly Iess reactive [43].
In any event, the activity of !ueh magnesium samples is far superior lO Ihal of
commcrcially Ivailable metal turnings and compares fayorably with Ihal of Riekc
magncsiuffi a f of magncsiurn that has beco activaled by metal vapor tcchniques. Thia has
been cltarly demonstrated, for cumple, by a comparative study resctlon
shown in Schelll(! 2 [44]. Table 1 depictJ lhe resulu obl:ained in Ihis rcaclion LiSinS
vapor-aclivated magne5ium, anthracenc-magnesium, and Rieke magncsium.
Sincc the preparative oUllay for cach of the individual activation mcthods dilfen
considerably, yet the rcsulu oblaiDCd are comparable. thei r respective can be
estimatcd.
In the Riek-e proccss for the reduction or salts, magne5ium is $uitablc only in
clIccplional cases as a subslilute for polassium. HowevCf, the ready formalion of Ihe
anlhraccne complcx I can also be cxploi lcd for Ihis purpose. As shown in Schcme 3, not
only aclivalcd metals can be gcneralcd by a calalylic cyc1e. bul also, in Ihe presencc of
suitable ligands, complcxes wilh a uro- or low-vaknt ccntral atom, such as [M(codh,)
(M _ Ni, (Cp,M) (M _ V, Ca, Fe). and (Pd{PPhJh ) , aOO [Mo(butadicne)11 can be
preparcd (45).
..
""""
",.
'" '"
I
; ;
Fip"! 17 Thc Grignard reagent or 9-<:hloromethylanlhracc"., m:pared rrom Ihe
anlhlllcenoc c:ompk".
The Ivailability of magnesium- anthracene provided a major advaooe for Ihe synlhesis
or reactive Grignard reagents [46]. Thi, orange, THF-soluble adducl js especially eft'eclive
for Ihe preparation or benzylmagoesium halides, sorne of which are olherwisc difficult 10
synlhcsizc [47]. The Grignard Teagenl or9<hloromelhylanthracene (Fig. 17) \Vas prcpared
by Ihe slol\' addition or a sol ulioo of lhe orgaDic halide in THF 10 a suspension of a
stoichiometric amoool of Ihe magnesium- ant hraccne oomplcx in THF al 2O"C. A dccp
blue color persim unlil Ihe addilion j, complete [48].
This rugen! is ea!ily prepared, bUI Ihe farmltion of I mol of anthr.cene farcach mole
of Grignard reagenl formed when Ihe stoichiometric reagen! is use<! presents a drawback.
l. Cholc. of Solvent
Historicall y, dict hyl ether was the common ",Ivent uscd in the preparation of Grignard
reagcn15 (48]. The drawbackl of u,ing dk:thyl ether include its CJ: tn:me flammability and
relatively lowboiling point, which prccludes i15 use in reactions with high working
tempcratun:s.
Sino:: the advcnt of tetrahydrofuran (THF), worlr. involving diethyl elhcr has greal ly
diminishcd. Telrahydrofuran is a nfer a1lemalive solvenl Ihat has becn widely uscd lince
lhe 19SOs in Ihe commercial-scalc production and use of Grignard reagcnls. 1I is a cyelie
elhcr wilh greater ",valing power, which n:nder! the formallon of Grignard reagenls
more radie. Also, the boiling poinl of THF 15 IS.soC (6O"F) greater Ihan Ihat of dicthyl
elher. As n:sull, THF il ckarly the salvenl of choio:: ror the produclion of Grignard
reagcn15 as well as Rieke magnesium.
Hydrocarbon salvents havc alsa becn uscd ror Ihe pn:paration of Grignard reagcntl.
Advantages have becn clajmcd ror the uses of sueh salvents, but the organomagnesjum
halide usually precipitatcs, which renders jls trand'er and analysis difficull [21]. Tertiary
amines becn uscd to Grignard reagen!. in aromatic salvent!. Hydrocaroon
solvents an:, however, frcquentl y uscd in the Jubscqucnt reactions or the Grignard rcagent
wilh caroonyl and olher subslrates. Oa:a, ionally, a millture or THF and toluem: is uscd,
as toluem: improves Ihe solubility of sorne Grigoard reageots.
111. MAONe:8IUM ACTIVAnON BY THE RIEKE METHODS
A. Hla'lo.-,
lo 1912, Rieke and associates n:portcd a general approach ror pn:paring highly
metal powdcrs by reducing metal salts in cthereal or hydrocarooD solvents usi ng aklli
metals as reducing agenll (SO]. Scverll buje approaches are possible and caeh has its
OWD particular advantages. For sorne metals, all approaches can lcad 10 melal powders
..
MX,,' '" --.. M" + nKX
F i g u ~ 18 FormatiaD of In actiwlled metal by lile mluction 01. metal ult using polassillm.
of idcntical rcadivil)'. Howcver, for olhcr metal" one method can cad lo far superior
reaclivly. High reactivity, for the mos! part, rden lo olM1ative-a.ddition reactions. Sinoe
Ihis initial reporto several olher reduction mcthods have bcen reported, including
rnctal- graphitc compounds, magnesium- anthraccnc complex, and dissolvcd allr.alides (51 J.
Allhough Re"c's nitial CDlry into Ihis arca ofslud)' nvolved lhe reduetion of MCI1
",,Ih potassium bipnenylide, cafl, work concentrated on rcductions ""itboul lhe use oC
electron carricrs [S2]. In Ihis approach, reductions are convcnicntly carricd out with an
alkali metal Ind a solvcnt, lhe boiling poiol oC which u ettds Ihe mclting poiol of
lhe .Ikali metal. Thc metal sal l 10 be reduoed mus! also be parti.U), soluble in lhe solvcnt
and lhe reductions are carried out under an argon almO$pbere (Fig. 18).
Tbe rcductions are exothennic and gcnerally are complete wllhin a rew houn. In
addition lo lhe: metal powdcr, I mol, or more, or alhU $lIt lre gcneratcd Convcruent
systems or rcducing agcnts aOO solvents inelude potassium-THF, aOO sodium- I,2
dimclhollyclhanc (OME). F or many mctal salts, solubiUty considcrations reslnct rcductions
to cthcreal solvents. Also, for some mctal salts, rcductive e1eavage ol lbe ctherelllOlvents
rcqui res reductions in hydrocarbon solvents, such as bcnzene or loluenc. This is true for
~ In, and Cr [53]. Tbe finely dividcd melals prepared by Ihis approach are a composile
of lhe melallll welllll the alkali $Ilts. The comilllure appean lo keep lhe small Cl'}'stallites
from sinlering inlo largcr crystlls and, thus, altenuating their chemical reactivity. Thc
alleali alts also may serve 111 elcctrolytes and racilitatc electron Iransfer in the initial stcp
or Ihe ollldative-addition reaction.
R, COfIt.mpof ..,. Mlhod.
A seoond general approach for lbe eneralion of Ricke magncsium involves using an alleali
metal in conjunclion wilh an electron carrier, such as naphthaJene. TIte electron carrier
is nonnaUy used in less Ihan stoichiometnc proportions, generaJly S-IO% by mole, based
on (he alkali metal. This procedure allows reductions lo be carricd out at ambitnl
Icmperalul'CS, or al least al lower lemperatun:s, Ihan with Ihe prcvious approlch,
which rcquires refluxing. A convenicnl reducing metal is lilhium. Not only is the procedure
much safer when lil hium is used, ralher Ihan sodium or potassium, bul lrcquently Ihe
reactivity ol the melal powder is realer.
The current methods used for the preparalion ol Ricke magnesium (Mg-) involves
a onepol proocdure and use:s a catalytic amount of naphlhalcnc. An oven-dricd, 50 mi,
two-necked. roundbollomcd !lask cquippc:d wilh a Teflon-coalcd magnetic stirring bar,
an argonfvacuum manifold adapter and a rubber scptum is chargcd wilh anhydrous
magnesium chloride (0.402 g, 4.22 mmol), lithium (cut foil, 0.061 g, g.g6 mmol), and
naphlhalene (0.170 So 1.33 mmol) in a Vacuum AtmO$phel'CS Company dfJ boll undcr
argon. The !lask is then conncctcd Ihrough the adapler lo a doublc manifold providing
vacuum and purificd argon. and lhe nask is evacuatcd and backfillcd wilh argon three
limes. Freshly distillcd THF (15 mI) rrom Na/K. alloy under argon is addcd by syringe.
The mi;l;lure is vigorously stirred al room Icmperature undcr argon unlil the solution
bccomes dark grecn (ca. 3 h). Stirring is continued for anolher 30 mino Thc newly rormcd
magnesium sJurfJ is allowcd 10 sell le for 3 h aOO Ihe superoalant is removed by cannula.
..
Frcshly dis tilled THF ( lO mI) j$ added 10 the active magnesiuffi (black powder). followed
by Ihe approprialc Jl,lbstrate. Thi s ;$ (he currenl melhod of choice fOT he prcparalion of
Rieke magncsium [54).
A t hird approach fOT Ihe gcnecation of Rk: ke magnesium is 10 use a stoichiometric
amOllO! of preformed lilhium naphthalenide. This approaeh allo",! a very rapid gcncration
of Ihe melal powders, becausc he reduclions are dilfusion-controJIed. Very lo", 10 ambienl
temperalUres can be used for he rcduction. In !lOme cases.. Ihe reduct ions are slo",cr al
lo", tcmperatures becausc of he 10'" so[ubility of Ihe metal sal!$. In a Iypical prcparation
of Ricke magnesium IIsiog prdormed lithium naphlhalcnide, lhe Jame general proccdurc,
as outlined in lhe farego;ng. i5 rollowed, ",ilh a fe.., cxceptions. Uthium (10.0 mmo!) and
naphlhalcnc ( 10.8 mmol) in freshl y dislilled TH F (15 mI) an: sli rred under argon unlH 1m:
lilhium is oompletel y oonsumcd (ca. 2 The resulling dark grcen lilhium naphlhalenide
is Ihen transferred by cannula inlo a THF wlulion (10 mi) of anhydrous magnesi um
chloride {4.8 The mixlure is at room lemperalure fo r 30 mino
The newly formed aClive magnesi um (black powder) is allowed lO seule for 3 h, and lhe
5upernalanl is drawn off" by cannul a, followed by replacement wi lh freshly di slilled THF
( 10
Allhough each of Ihese melhods will generale aClive magnesium, melhod 2 is Ihe
melhod of choice, as il facilitates workup. There docs nOI appc:ar 10 be any appredable
diff"erence in lhe reactivity of Ihe active magnesium when praclicing any of Ihe Ihree
melhods. The inherent advanlages of met hod 2 are Ihal il is a one-pol process, and il
uses a minimum amounl of eleclron carrier, which aff"ords Ihe separal ions lo be more
facile. Ir Ihe reader is usi ng melhod 2, il is importanl Ihal Ihe reaclion is slirred vigorow/y
10 prevenl Ihe magnesium powders from coaling the lilhium and Ihereby relarding Ihe
reduclion. Alw, Ihe Slirring was mosl effecl ive ",hen lhe reaclion naslr: was sel slighlly
a"'ay from the cenler of lhe magnelic sli rreT.
For alllhrce mel hods, Ihe finely divided blaek magnesium powder will seUle afler
standi ng for a few hours, leaving a dear and, usually, colorless, wl ulion. Thus, lhe
magnesium powder can be . w8.llhed lo remove Ihe elect ron carric:r as well as Ihe al kali
salt, especia]]y if il is a lilhium salt. Moreover. a differenl solvenl may be added al Ihis
poinl, providing versalility in the wlvent choice for subsequenl reacli ons.
A fourlh procedun: Ihat "'as devd oped early in Ihis sludy nvolved lhe al
magnesium ehloride ",ilh polassium in Ihe presence of potassi um iodide. Allhough lhe
oplimum ralio of magnesium ehloride 10 polassium iodide is 1:1, much Imaller quantil ies
of polassium iodide are nearly as effcctive (Table 2). Thi s suggesls Ihal lhe polassium
iodide is aeling in a catalylic rashi on. One possible mode of aellon is Ihat Ihe Rieke
magnesium catalyzes a halogen..cxchange reaction with Ihe aryl ehlorides. In any evento
the rnagnesiurn prepared by Ihis rOUle is nearly as reactive as lhe magnesium prepared
by lhe lilhium reduction approach. Because the lilhiurn rcduct ions are more oonvenienl
and safer, lhere has becn lillle ehemislry carried oul ",ilh Ihe MgCl.-KI procedure. One
of Ihe mas! notable reactions reponed was Ihe conversion of ".. nuorololueOl: lO lhe
corresponding Grignard reagen! in I hr in reftuxing THF [5Gb].
Anolher inleresling variation of Ihe potassium- magnesium chloride reduction il to
carry oul lbe reduclion in a mixed solvenl syslem of THF and trielhylamine (ralio
Thi s melhod also yields a forro of magnesium Ihat is nearly as reaclive as Ihe lilhium
reduclion procedure. Table 3 shows reactions of p<hlorotol uene ",ith Rieke magnesium
prepared in THF EtJN. Fe'" reporlS have appeared using Ihis rorm of highly reaclive
magnesmm.
Conceivably, any metal on Ihe periodic lable can be act ivate<! by lhe Rieke melhod.
T.bkl Rcdu<;tion of Magnesium Chloride "';Ih Potuaium in lhe Pracooc: 01 Potusium lodide
~ . yield Grignard al rclo;tion
Readn.
time (min) or
Readn. Mil ,=.
~ . MX MX re)
,
"
JO
.,
120
"
N ~
"
o o 14 50 15
17 ur
"
o
,
"
76 9l
18 tia
"
o 7
" "
..
"
N.,
"
o o JO
..,
87
20 N.a
"
o o
"
58 8l
21 NaSr 2l o o 13
,.,
..
12 N.I
" "
9l 98
"
100
II
K'
"
o o 7 JO ..
24 Ka
"
o
,
34
..,
"
"
Ka
"
o

"
67
"
26 KB,
"
o o 11 .. 15
27 KD,
"
o o
,
"
78
28 KI
"
87 9l 98
"
100
"
KI
"
o
,
"
"
8l
JO KI
" "
.. 92 97 100
31 KI 2
" " "
97 98 100
12 KI 20
" "
76
"
97 100
)J
KI
o.,
2l
" "
97
"
100
34 N ~ o o o o o o
II KI
"
o
,
17 55 15 8l
J6 KI

o 14
"
6l 76
" 37 KI 2 o 26
"
7l 8l
"
"
KI 1 o
"
" "
"
9l
JO KI
o.,
o
"
" "
8l 9l
.. Uf 2 o o o o o 11
"
N, I
2 o o
,
21
"
70
"
0.1 2 o
,
12
"
13
"
"
1, 20 o
,
"
..
"
..,
.. K. SO 1
"
13 II 69 87 05
"
K. SO. 20 2l o
,
"
76 90
.. CuSO. 20
"
o o o 7
"
ZnSr, 20
"
o
"
31
" "
.. MsO,
o.,
"
o o
,
12 ..
~
MsO,
o.,
"
o o o o o
Indeed, maoy metals otber tban magnesum have beeo actvate<! and use<! in the synthesis
or many organic compounds [SS]. Mast notably, copper, zinc. calcium, indiurn, cadmium,
nickel, aluminum, and blrium have been activaled and u5Cd in the synthesis of many
compleJt moleroles [ ~ ] .
An important aspcct or the actve magnesium by Ricke methods is its convcnicnt
prepara don. The apparatU5 rcquircd js very incxpcnsivc aod simple. Thc rcductioDS are
DormaUy carricd out io a two-neck flask equipped ""ith a condenser (ir noccuary), magnetic
stirrer, under an argon atrnospherc. In general. il is nOI possible to prepare anhydrous
..
Table 3 Ro:actiolll o( p-01lorotoluenc ... Ih. Ricke M"ncsium Pttpared in THf'-Et,N
% yicld Grinan:r
al runion time (min) or
Reactn. THF Et,N MCI, % time
Mil
",.
(mi) (mI)
.. "'"
(ltT)
K'
,
"
JO
.,
'lO
"
50 O
"
J O O .. 50
"
" " " "
J O 12 J8
'"
"
"
" " "
J 47 77
" "
"
" "
"
J
,
7J 87 97
'00 ' 00
" " " "
2l O O O O O
"
, .,
"
2l O O O O O
.,
O 50
"
21 MgCll nol reduoed
"
O 50 20 2l MgCI, no! rcd.......:d
'"
" " "
J O O O
"
J2
magnesium halides by healiog Ihe corresponding hydrates under vacuum. In general, Ihis
will Iead 10 11 of olides and hydroxides that canno! be completel)' reduoed. It is
essential thal anhydrous magnesium salls be used. The Ilnhydrous magnesium salts can
be purchased or can be easily prepared from ordinary magnesium tumings and
1.2-dibromoethane or 1,2-dichloroclhanc.
A convenienl proocdure for lhe preparati on 01 tiK:se anhydrous magnesium $IIllS has
bccn publishcd [57]. Thc magnesium turnings aOO 1,2-dibromoethane used were purchucd
from J. T. Baker Chemical Company and Aldrich Chemical Company, I ne., respectivel)'.
A 200-ml, Ihue-necked, roundbottomcd lI asl: is equipped with a magnetic stirring bar,
two stoppcrs. and a condenser connccted to an argon inlet. The flask i5 charged wilh 0.35
g (0.01 44 mol) ofmagnesium turnings, SO mi of telrahydrofuran. and lO g (0.016 mol) of
1,2-dibromoethane. suspension is warmed gently to initiate the react ion. Aner
initially exothermic reaction subsides, Ihe mixture is heated al reftux for SO min. The
solvent is evaporaled under a re<!uced pressure of argon or nitrogen, leaving a white solid.
The ft ask , then evacuated and heated in an oil balh al ISO"C for I h. The dry magnesi um
bromidc is ready for the ensuing preparation or Rieke magnesium and can be prepare<!
in the u me vesscl.
Equally important is Ihat extreme caution should be e:a:ercised when working with
Ihese material.s. Although Rieke and co-workers haye never had a tire or e:a: plosion caused
by Ihe active metal.s, one should handle Ihem with careo Unt il one bccomes familiar wilh
Ihe characterist ics or Ihe melal powder involved, careful coll$ideration should be taken al
every ,tep. To dale, no metal powders Ihat Rieke and co-workers have generaled have
spontaneously gnited ir removed from the reaction vessel while I till wet with solvent.
They do, however, react rapidly with o:a:ygen and moisture in Ihe airo Acoordingly, Ihey
should be handled under an argon Ir the metal powdcrs are dried before
being exposed lo Ihe ai r, many will begin lo smoke or will ignite. Perhaps he masl
dangeroUll step in the preparalion of Ihe aclive metals is Ihe handling of sodium or
potusium. Thi! can be avoided for masl metals by using lithium as the reducing agen!.
..
C. GrtgMrd ltelng Mag,...Iu",
The reactions ol Rieke magoesium with varioU5 ha1ides and dihalide$, SORlC ol which react
wilh difficulty undcr lile conditions ol normal Grignard preparationa, wcrc invesligaled
[S8]. lbe results are summarized in Tibie 4. The yicld, obtained by OC afler bydrolysis,
and the yields of acids ablain! afier COz quem::h are shown.
1I should be: Doled Iha' Ihis reportee! chemistry wu peormed with Riekc magnesiurn
preparcd by lhe MgClz- KI-K- THF .yslem.. Rielr:e magne$ium prepared by lhe &afer
lithium naphthalenide reduclioD approach sbould be upected lO give he 51I1le ar evcn
improved I'C$ults compared wilh what is rcportcd bcre.
Previous clforts 10 prepare dimagnesium derivatives of benzenc have becn slIcccssful
onl)' wilh dibromo- al bromoiodobcnzcne, required fordoS conditions, and typically
resulttd in Ihe monomanesiurn derivative as lbe major producto lbis work has becn
survcyed by lolfe and Nesmayanov [59]. With lile MgClJ-KI-K-THF 'ystcm, Ihe
preparalioo of Ihe di-Grignard of p-dibromobcnzcDC in 100% yield io 15 mio al room
Icmperalure is posstblc. The yickt was delennincd by GC af"Icr hydrolysis and was bascd
on Ihe disappcarancc or Slartios malerial and bromobcnzcoe and lbe formalioo of bcnzcnc.
lo carlier work, only ODC halosen alom or dichloro derivllivcs or bcnr.cne and oaphlhalcne
reactcd with magncsium (60], and tbe chlorinc of p-chlorobromobcnzene was completely
unrcactivc [61]. By usins Ihis melhod, a 100% yieid was obtained of the mono-Grignard
and a 10-;. yicld of the di-Grignard of p-chlorobromobcounc io 15 mio at room
temperalure. Afler 2 hr the yield of di-Grignard was 100/ . With p-dichlorobcnzenc the
yieid oC di-Grignard was 30% in 2 hr. Use of a lowcr M/halide ralio pcrmittcd the rapid
Tibie .. Reactiom of Rieke MInesium wilh VlriOUl Halides l OO Dihalides
._- ._-
7. ,..IoIO' ..... d l-:,;.w
-......
Mllkl ..... oc
-- --
-ro,o,

n

o o u
"

n "
o o
" "

"


"
,.

o
)if'
o o u
"

"
,.

ff'
o o u
,



,.

,

o

o u
,

"
+
o u
"


"
tP
LO o
"
"

"
'"
" "
).Jo o u
"
)-"
o u
,

"
"
and sclcctivc formalian of lhe mono-Grignard of p-dichlorobenzene, .... hien ""as oonvcrted
10 4-<:hlorobenzoic acid in 89'Y. yick! by CO, queDeh.
Significantly, when p-dibl"omobenzc:rn: W3.!I lreated wilh one equivalen! of Riekc
magnesiurn al _ 78C. oolr lhe mono-Grignard "'as formed quantitatively in 15 mio [62].
Thc yield was dclcrmined by GC afie! hydrolysis and "'as bued on Ihe diaappearaoce of
slartiog matcrial and lhe formalion of bromobenzcnc. Thi! ia in Ilark conlrasl 10 Ihe
ruction of p-dibromobenzene ",ilb ordinary magnesiurn, whien affonb a mixture of Ihe
mono- and di-Grignards, as wcU as unreaeled Itartiog materi al [63].
A primary halide. l bromooctane. reaeled as expectcd lO givc IOO'Y. yicld in
10 min and Wtu oonverted to pivaJic acid in 52% ykld after 1 hr of rcaction.
I-Chlorobicycl o[2.2. IJheptane reacled IIowl1 al room lemperature, so Ihis was rerun in
tenu"ing THF. Apio, Ihe Grignard preparalion was slow, giving 7 .. 'Y. yitld alter 6 hr
of reflux. The Orignard Wllll Ihen quenched wilh eOlIO give l-bK:yclo[22IJheplane-
carboxylic acid in 6J'Y. yield. Siller and Nicmann [64] preparcd l-bicyclo(U.I]-
heplanecarboxyli<: acid from l-chlorobicyclo[2.21]heplane by convcrsion of lhe chloride
10 Ihe lilhium sall, followed by COI quench. The Rieke melhod appears 10 be superior,
,i nee il obviatcs the preparation of the lithium salt used in the procedure of Sixler and
Niemann.
An allyl halide, 3-chloro-2-melhylpropenc, was converled 10 3met hyl-J-butenoic
acid in S2'Y" yield afler 1 hr of reael ion at room lemperature. Wagner (65] convcrted
3-chloro-2-methylpropene lo lhe Grignard in SI";' yicld afler 10 hr at 14-16C, and
oblained J-mct hyl-J-bulenoic acid from Ihe Grignard in 4O'Y. yicld afier COI qucneh.
Finally, Ihe vinyl bromide 2-bromopropene was converted 10 lhe Grignard in 100%
yield in only S min at room Icmperature using the MgCl,-K- THF system. The Grignard
of vinyl bromide 2-bromopropene was lhen coovcrted 10 methacrylic acid in 71% yield.
Normanl, in his pioneering work 00 vinyl Grignard preparation$, has rccommended a
4O--SO"C range for halide addilion 10 magnesium in THF, foll owed by heating for 0.5-1
hr al 7O-8Q' C [66]. Sy Ihis proccdure, he was able 10 oblaio yields of 95--97'Y. in the
preparation of vinylmagoesium bromide. The Rieke magnesium appears lo be an
improYemenl of Normanfs melhod, since il allows Ihe preparalion of vioyl Grignard
reagenu al room temperature snd below.
Walborsky has receotly reported on the formstion of the chi ral 1-methylspiro[2.S]-
oclylmagncsium bromide Grignard reagenl, which was gencrated by Rielte msgnesium
(67]. Walbonky concludl thallhe reaction of Ihis chira! Grignard reagen! occurs mainly
al lhe surface of lhe magnesi um.
TIte preparali on of l-bromo-l -met hylspiro(2.S]oclane (Fig. 19; 13) was described.
To determine product di stl"i,t,ution, the racemic bromidc 13 was lrealed with Rieke
magntlli um in elher (68] in the presence nf r-BuO-D as shnwn in Figure 19. The reactinn
alforded a 70'Y. yicld of !-melhylspiro[2.5]oclane which Wllll 33% deuteraled according
10 NMR ana!ysi$, as the main products. This indicales thal lhe yield in lhe Grignard
reagenl formalion slep i$ 23 %. Olher producls found were 2,J-dielhoxybutanc (dielhyl
el her dimer, lt; Ihe cyclopropyl radical dimer 17 and a polymerie
residue, which by NMR was shown lo contain aliphalic prolons and sorne elher moieties.
The volalik producu wcre ilOlalcd by prcparalivc gaschromalography. and their st ruct uTCI
were proved by speclroscopie analyses and comparison wilh authentic samplCll. Thc
aulhentic sample of spiro hydrocarbon 15 was obtained in 70% yield from bromidc IJ
by lithium-hal ogen ClIchange with ItrIbulylli lhium fotlowed by protonation wilh rrn:thanol.
The aulhentic sample oflhe clhyl dimer 1t was preparcd according 10 a literalure proccdure
[69].

/\(H
,e:-y CH,
(!}lStH'II)
A
C::J I
. , .... '"
"

d<;,
(t). UO (ll" I

Fipre 19 Treatment of raccmic bromide 13 with Rickc magnesium in the pracncc of I- BuO-D.
:'::J
A,
'oH

1\. .. COOH
,. Mol;
:'. J4.""
te
(S}(.}1l
(S}(.).!'
"'"
IOlvent tim., b
yi.ld, "
optlca1 purit)', "
1 eiber 2
,.
10
2 THF 2 58 13
Fiure 10 Treatment oftheoptically purc bromide with Rickc magnesium foll owcd by <;lrbon.tio!I.
As in Ihe previoll51y investigaled Grignard reaction of cyclopropyl bromide [70],
Ihe exocyclic cyclopropyl olefin 18 could not be solated from lhe reaction mixture. Since
it WIU suspected Ibal olefin 18 would not be stable under the Grignard reaction condlions,
an aulhentic sample WIU synthesized in 60% yicld by zinc-induced eJiminalion of (he
losylate precursor in DMF. The Grignard reaction of 13 was repeated in lhe presence of
Ibis olmn and under he $ame condiltons (1 hr al room Thc olefin 18 wu
shown 10 undergo complele polymeriution.
To eslabl ish Ihe slereochemislry of lhe rcaction, oplica.lly pure (S)-{ + } 13 was lreated
with Rieke magnesium al room lemperalul"C in bolh elner and THF and Ihe reaclion
mixture carbonated. The results are shown in Figure 20.
The reaction in elher resulled in a 25"1_ yield of optically active acid 19 along with
42% of raccmic hydrocarbon 15. Since the specific rotalion of 19 was very small, Ihe
oplical purily of Ihe acid was delennined by the more accurale NMR procedure. Hence,
(S)( - )-a:-methylbenzylamide was prepared; lhe diaslereoisomern: excess delennined by
NMR from Ihe signals correspondng 10 Ihe cydopropyl protons was 10"1_. Reaction in
THF afforded a much higher yield orthe Grignard reagcnl (S8"1_) and only 20-/0 ofraoemic
hydrocarbon 15. The oplical purily oC Ihe acid 19 WIU 13"1_.
To establish the absolule configuration of the acid formed after Grignard reaction
(Fig. 21) oplically pure (S)-( + H3 WIU lreated with It'rt-bulyllithium in ether soluli on,
followed by carbonation 10 yield optically pure (+}l9 as detennined by NMR analysis
of its (S)-( - )-a:-mel hylbenzylamide derivative. Sincc lithium- halogen exchange followed
by carbonalion proceeds with complele retcntion of configuration (71] Ihe (5) configuration
is assigned lo (}I9; Ihis establishes that Ihe Grignard reagenl formalion rcaClion prooceds
with relenlon or configura tion. In contrast, when oplically pure bromide 13 was reduocd
"71\(COO.
1" _ CH,

... "
(S}(+)-I'
Fipre 21 oft he opliaolly puI"C brQmide .... ilh Im-bulyllithium follo-.1 by carbonalion
aOO lhe rrouctioo of the oplicaUy purc bromidc followed by carbonation.
Table.5 ResullS r,om lhe Trntment oflhc Oplically Pure Bromidc w;lh Ricke
MI gnesium in lhe PTexnoe of ,-8uO0


Ructioft el (SH+)-I ..w. lUouM. " nO'ha..o.o.
...
r. "C tByC).Q "",Ir
Ylcld ..
.., ,
..
, ..,

..
, .., ,.,
..

.,.

"


lU
"
"
"
"
o p, "
"
"
"
"
under homogeneou5 conditi ons .... ilh lithiurn naphthalenidc (1 cq) [72J. in THF al room
temperatare, Ihe resullin, acid 19 isolated in 21"1. yicld arter carbonatlon .... as completely
raccmic. These resultll are consisten! ""Ih and supportivc of Ihe sunace OBt ure or Ihe
Grignard rormalion.
Wal bonky and Rachon have also reported on the U$C or Ricke magnesium looblain
reaclion .... ilh (5)1 + H bromo- lmethyl2,2-diphenylcyclopropane al - 6S
Q
C lo alford a
chital Grignard reagent Ibat is )3--4) -;" oplically pure [73). In 1961, Young aOO Walborsky
[74] demonst ralcd Ihat Ihe reaclion of chi ral (S)-( + }-1-bromo- l-metbyl-2,2-di phenyl-
cyclopropane (Table S; 1) wilh magncsium powder resultcd in the formation of a chiral
Grignard reagenl as evidenced by lhe fact Ihal on carbonation of Ihc reaclion mixture
an oplica1ly activc acid was oblai ned with an oplk:al punly of approximalc:ly
Ricke magncsium, is a highly reactive form of magncsium Ihat enablcs one lO form
Grignard reagcnls at - ur lowcr. The reaclion of (S)-( + ) - 1 with Ricke magncsium
was conduclcd in THF in Ibe presenOli of 1-8uO-0 . The resu!l. are summari.w.t in Table
S. 11 js clear from Table S that Ihe isolalcd yiclds of 2 are almos! quantitative, wilh a very
high dculerium conlen\. Morcover, at the uplical purily ranges from )) 10 4J'Y .
Furthcrmore, under Ihe feregoing conditions, bul usi ng powdcrcd magnesium, inltead of
Rieke magnesium, no rcaclion occ:urred. \Iso of significance js the decreasc in oplical
punly lo 18% whcn he rcaction i5 carried oul al + lO"C. Thc Rickc magncsium, Iherefore,
plays an importanl role in Ihe inili al electron Iransfer Slep, since lhe optical punly al 2
at + 2O"C is the same for both Ricke magocsium and ordinary powdcred magnesium. The
high deutenum incorporali on i5 11 reflecl ion of the degree al Gngnard reagent formadon
"
and is a qualitativc affinnation Iha! vc:ry littk reaction of the radical with other hydrogen
atom SOUI'CClI occurs undcr thC!le conditionJ.
A simple cllamplc oC lhe advantage nr gcnerating Grinard reagenl! al low
!tmperajures is Ihe reaction orJ.halophenoxypropane [75]. Although he Grignard rugenl
;, casy 10 encrlle al room tcmperature or above, il displaces tbe pnenolY roup by an
SN2 reaction 10 gcncrate cyclopropanc. This reaction is, in tact, a standard way 10 prepare
cyclopropanes, and the C:ytliulion eannol be slopped; howcver, by using Riekc magnesium,
he Grignard reagenl can be prepared al -7S C, and il does nol C}'l:Jize ar hese low
Itroperatures. 1\ can Ihen be added 10 a variel)' nr olher substrates in standard Grignard
reactions. Olher attempts al lowtemperature formalioD nf Grignard reagents nvolved
molecules containing nitrile, kCIODC, Ind esttr tunetional groups [76]. These reactions
weTe [argel), unsurcesdul, U)I in Ihe case of S-bromOOClanc:nitrile. In Ihe alk)'1 syslems,
elh)'ll-bromopropionale. 4-bromobul)'ronilrile, and S-bromovaleronitrile, the heteroaloms
ooordinaled strongly lo Ihe magnesium surfacc al the temperatures required lo prevenl
atlad. ofGrignard reagenb on lhe functionality presenL Tbus, Grignard reagenl formation
was inhibilcd b)' Ihe oocupation of the aclive sites on the magnC:5um surfaoe, allhough
S-bromooctanenilrile reaclcd rapidly with Rieke magnesium at - 7S"C lo give 74Y.
conversion lO lhe Grignard reagen!. Carbonation gave 3-cyanooctanoic acid in )'ield,
basc:d on Grignard rcagen!. Tbis appe8n 10 be the fint eumple of a Grignard reagent
Ihal conlains Ihe nitrile functionaJit)' . InleteSlingl)', Ihe nitrile functionality ooordinatcs $1)
strongl)' lo Ihe magnesium surface Ihat reaction with organic halides iscompletel)' inhibited
until 2O"C il reached. 4-Bromobut)'ronilrile did not react at alt with Rieke magncllium at
- 7SC. When the temperalure was Ilowl)' raiscd, no reaction was obscrved until 2O"C,
at which time polymerizalion oocurred. In confirmatory uperimenh. t-bromopentane
reacted quantitativel)' wilh Ricke magnesium in I min al - 7SC. The resulting Grignard
reagenl did not react with lubsequentl)' added butyronitrile even afler I hr al - 7S"C. If
bulyronitrile was added lo the Rieke magnC:5um al - 7SoC, followcd b), addilion of
bromopenlane, no Grignard reagent was formed after 2 hr. Tbis demonslrales Ihe strong
adsorption of the Lewis base (but)'ronilrile) on the metal Jurfaoe, which is aeting IU a
Lewis acid.
When benzonitrile was reacted with Rieke magnC:5um in refhuing glyme. a doep
red color developed afler I hr. Gas chromatography revealcd mosl oC Ihe Slarting material
10 be unconsumed. Afler reftuxing ovemight, lhe reaction mixture lumed brown, aDd most
of the 'Iarting material was c:onsumed. An aliquo! injocted directl)' inlO the gas
chromatograph did nOI reveal benzil fonnalion. Workup showed IwO main products:
2,4,6-lriphc:n)'l-I,1.S-triazinc: and 2.4.S-triphenylimidazole. in 26"/0 and 27"/ yields,
respectivel)' {Fig.
Figure 12 Two producu rrom he n:action ofbc:nzonilrik wilh Ricke m.snesium in glyme.

[1 Ii
:x:



b
&Inai:on " ,F'.18I:d 10 bm iri'sr'm
Coid ..... (alntir;.,i 'be, e ; (b)
. ..,.....
SdInne .. Two urrWlion rearoons used 10 rorm imidawles.
rabie ti A Summary of he V.riOWl Melhool UKd in Ihe Trirncrtz.aion of "rom.tic Nitriles
Reagenl Condition, % yicld
Cblorosulfonic a.;id O"C, 12 hr
.,
AtO) 140-16O"C
..,
POJ flO 24 hr
"
M.oH 100-123C, 7SOO alm 74-82
N.
e.H. N OIK iven
RMgX Boilin )llene
" RU
"
The imidazole was quite uncxpcclcd, bu! nc:vertl'leless present as Ihe maS! abundan!
producl. A product wilh a TLC R, equivalenl 10 benri l wal abo presen! in css Ihan S
mol% yield. as were numcrous olher unidentilicd producu in low yields..
The imidazole was 5hown 10 arise, al least in parl, rrom Ihe triazine. 2,4,6-Triphenyl-
1.3,S-triuine relelcd with Rieke magnesium in refluxing THF lO afford 2,4.5-
tripbenylimidawk in yield; 6S'Y. was unreactcd startiog material; 8'Y. was
unaccountablc.
Giordano and 8e1li hay!: rormed imidaroles from 2,4,6-lriaryl-4Il-I .J,S-lhiadiuines
by a base-calalyzed eJllrusion of sulfur [77]. Schmidt d al. also refer 10 an analogoua
eJluusion of oxygen from Ihe 4H-I,l-oxazine [78]. Scheme 4 dcpictllWO eJltrusion reaclions
used 10 fOml imiduoles.
Radzisewski prepared imidazoles by Ihe extrusion of nitrogen from lriazines using Zn in
rclluxing aOC:lic acid [79J.
The trimerizalion of aromalie nitriles 10 give symmetrK: triarines is nol unknown,
but generaUy, the rcac1ions musl be catalyzed by slrong aeida or a wcak base and undcr
e:memely high pressurc. The aelioo of preforrntd Grignard reagcnta also gives symmelrie
lriarines. Organoalkalis also gve lrimers, bUI not symmelre lriazines. A summary of lhe
v.rious mcthods Ihat have becn employcd in the lrimerization or aromatie nitriles is given in
Table 6. This dircct rcac1ion of magnesi um 10 alford symmetrK: triazines is uoprecedenlcd
in the literature.
04lil ........ 111 Attlullon
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5
Sala Handling Practicas 01 Industrial
Scale Grlgnard Reagants
PHllIP E. RAKITA
El! AItKMm Agri. S.A .. Plaisir. FrJ/lU
l . INTRODucnON
The use ofGrignard reagenlS 00 an industrial scale poses additional and differcnl oonccms
from those: found in tbe: laboralory. Thcsc dilfercnccs occur al several poiots during lhe
prooess of preparation and use of a Grignard rcagent. In an industrial situation, ofien
involving severa! hundred kilograml of reasen!s, Ihe equipment is dilfercnt from Ihat
employed in tbe rcscarch Iaboratory. Industrial produClioD typica1ly uses steel vessels or
differcnt shapes. with dilfercnt oonfigurations for Ihe addition or rcmoval oC rcagenls,
compared wilh laboratory glasswarc. The capabilil)' 10 modify he contiguration of lhe
reaclion vessel is oflen less. Agitation methods are differ<:nt. In he industrial sclting. he
importan! engioeering parameters, neluding surface/ volume talios (which inlluence rales
or hes! transfer), are substantially different from those in the laboralory. Characteristics and
qualitict of avai lable reagents may be different. Rcaction times may differ lubstantially,
and indust rial production may be influeneed by such nonscientific considcrations as Ihe
cconomics of produclion schcduling an<! the exigencics of Ihe industrial workweck.
Although industrial-seale Grignard reagents are oflen use<! ill , ;UI without isolation,
an imponanl 5egnlcml or Ihe worldwide production (e;timalcd al teos of Ihousands of
melric tons annuaUy) is deslincd for mell:hanl sale. Thi, introduces lbe additioDal issucs
of sare storage and transportation nol normany encountered in lhe laboralol')'. Also 10
be considercd are matteT1 of compliance with nationa! ar intemaliana! regulatol')' bodies.
Finally, by Ihe sheer volumes of reagents involvcd, waste disposal for the industrial Grignard
chcmist is an important cconomic and sarety oonsideralion.
The purposc or Ihis chapter is 10 ideDtify and outlinc some of lbe critical 5Ifety
issuC$ Ihal must be oonsidered when planning 10 oonduct a Grignard reaction on an
industrial seale.
"
lO
.....
11 . PAINCtpLES OF THE INDUSTRIAL MANUFACTU'IING PROCEsa
In .pito: of lheir industrial use ror many ycara, lhe cornmemaJ-scale production of Grignard
reagcnts has nOI becn cxtensively describe<! in detall. Waugh and Waugh [1] reported lhe
general features of a Imall produclion un;l, and Colin and GilIin [2] described a pilot-siud
operalion .uit.blt 10r pharmaoeutical appl ications. A oontinuoIU syslem, practical ror
small - or mcdium-scalc production, WaI patente<! by Holfman-La Roche [ 3], bul apparenlly
was ncver commcrcializcd. Tho: 0011 practically importanl mcthod is he three-stcp batch
mclhod describe<! by Viciar Grignard in 1900. namely (1) [armalian af Ihe Grignard
re_genl, (2) reaction wilh a substrato: followed by (3) of Ihe reaction mixture.
A simplificd schcmalK: diagram oC Ihe industrial proccss is shown in Figure L
1110: equipment can usually be constructed or carbon stce!. ucept for the hydroly,i!
yessel, which il more lypicalJy gla" lioecl 10 ayoid C()lTQ5ion by aqucouI acids. It il
preferable lO use stainJess sleel or, ideaJly, glass-lined vesscls Ihroughout. AII vessels musI
be suppl ied wilh an iocrt gas (ni l rogen or argon) for purging and blanketing and are lO
be vented 10 release off-gases. 1I is imperalive thal Ihe teacl ion vesscl be prolecled wilh
a ruplUre disk.
A. ForrrMIllOfI 01 1M Grlvn-rd A.agenl
In the daS!iic melhodology, for lbe slart-up of a batch proocss (sce Fig. magocsium
lumings or chips are chargc:d lo yessc:1 R-l. Afler Ihorough purging wilh an iocrt gas. a
porlion of lhe solven! i, addcd, followed b), a fraclion of lhe: halide charge from vesscl
R-1. The chic:f hazard associaled wilh Ihe manufaClure o Grignard reagentl occurl al Ihis
slage-Ihe difficull)' in niliating Ihe ruetion. If lhe addilion of Ihe halide is continued
before inilialion lakes place, Ihe prc:sence of halide when Ihe reaclion does beain,
will generale such a large uOlherm Ihal Ihe cooling S)'llcm ma)' be overwhelmcd. This
may result in a dangerous pressure buildup aOO lhe: polenlial for an explosion.
To minimizc Ihi s dilficull)', an nilialor is frcquenll)' emplo)'ed. Among Ihe numerous
suggeslions in Ihe lilerature, Ihe mosl satisfaclory industria! procedure is lo relain a portion
of Ihe Grignard from Ihe precedng balch and lo add Ihis portian lo Ihe inilial solvenl
charge. Thi, serYes 10 eliminate residual water and lo dean lhe: magnesium surface. Once
Ihis has becn added, Ihe halide i. addcd al a rale dctermined b), lhe lemperature
and Ihe pressure in lhe reaclion vessel.
Canling i, roulind)' appl ied, eilher wilh ambien! proce51 waler ir Ic:lrah)'drofuran
(THF) il Ibe solven!, or witb cbil1ed brinc if dic:lhyl elher il usc:d. Since Grignard reagenlS
are particular!)' reaclive with waler, liquid h)'drocarbon coolants ma)' be prcIerred, to
eliminale Ihe risk Ihal could arise from a cooling systc:m Icak.
11. A edon 01 1M Grign.rd A ..,.nI wfth S",b'b'"
For lhe: process represenled b)' Figure 1, lhe Grignard reagenl il usuall)' lransrerrcd from
lhe reaction vcssel R-2 lo Ihe Mcoupling
ft
vcssel R-l for !he reaClion wilh Ihe substrale. 1I
is usuall )' adyisablc lo rcmove particlcs or iesidual magnesium by filtralion. The IUMlrale,
dissolvc:d in an elher or hydrocarhon 5Olyenl, il Ihen added slowl)' from !he reed lank
(wi th canling of Ihe react ion The addi lion can al50 be reversc:d (Le., addi lion or
lhe Grignard reagent slowl)' from yessel R-2 lo a 5Olul ion of lhe subslrale in vcssel
The choice of direct or revene addi lion is dictaled b)' leyeral faclon alld is usually
established b)' suilablc process and pilol plan! sludies befare reaching Ihe plan! slage.
Aner Ihe reaclion iscomplete, masl orlhe solvenl is removed by disliIlalion, wilh or wilhoUI
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he addition ofcllough hydrocarbon 10 R-] 10 mainlain adequate agitat ion. Al Ihis poiol
he: cont enta of R ) are pumped 10 R-4 foc {urlnce pr0ces5ing.
C. H,drol,.I. of ltMt Relldlon MllllUr.
Apart from lhe reaclion ofGrignard reagents wi th organic or inorganic balides. he reaclion
in slep 2 gives a comple:t Ihat requires a slep lO releasc he desired producto
Water has sufficient acidit, lo hydrolyu: l he complex, bul lhe basic magnesium salts
forrncd in lhe qucnching reaclion ofien produce a gel Ihat can be diffieul! 10 manipulate.
This problem can be overoome through he addilion of a slrongcr acid 10 nculralize (he
basic salu and produce water-soluble magnesium salls. Sulfuric and hydrochl oric acids
are commonly employed, bUI mar Iead, particularly in (he case af sorne teniaey alcohols,
10 dehydratioo. In thesc cases, Ihe use of a weaker acid, sueh as acel ic acid or ammonium
chlonde, permits the recave!')' oC the desired alcohol. After Ihe hydrol)'ss step i, complete,
the aqueoUll pha.sc is separaled from the organic phase and Ihe product is Ihen isolated.
When h)'drolysis is nol required, the metalhelical reaction lcads di rectl)' lo lhe
product (plus magnesi um halide) in the solvenl Volatile products ma)' be removed b)'
direct distillalion, or he solid magnesium hal ide ma)' be removed by fi llration, before
evaporalion oC Ihe solvent. U the final product is nOI watersensijve, waler-washin(! oC
lbe final reaction product mixture usuall)' convenientl)' removes the salts.
Special handlin(! procedures have becn describcd [4] ir the Grignard reagenl has
becn purchascd commercial1 ), (eilher in drums or bulle) for use in a separate Cacilty.
Several conli nuous processes for Ihe manufacture and use of Grignard reagenu bave
becn proposed [S], bUl they enjo)' no currenl commcrcial significante.
111. S"'FETY CONSIDER ... TIONS
.... ScllIe-up
The transfcr of a reaclion $Cquence involving a Grignard reagenl from he laborator)'
throu(!h the pilot planl and inlo production involves Ihe same consideralions oC scale-up
in design an<! practioe as Ihal oC olher inherentl)' exothermic reaclions. Considerations oC
rates oC agitation, heal Iransfer, pressure buildup, and ol her safel)'relaled parameters
should follow standard chemical engineerin(! design principies.
B. Handllng.nd Stot'lIg.
Merchant Grignard reagents are supplied cornmcrciall ), in SS-gal1on (200 16-gauge
Ilainless steellighlhead drums (DOT17C in lhe United Slales, TATA IA2 intemal ionall)'),
with double-we1ded top and body seams. Hcads wilh a mnimum convexly of 3/8 in., bul
not extendin(! bc:)'ond Ihe level oC Ihe chimes, are required in lhe United SlaleS. Threaded
melal plugs are required and must engage al least tbree threads with a gaskel in place.
[Propr1el ary designs also exisl Cor relumable, refillable bulle conlaners suitable for shipmenl
of Grignard reagcnts.]
The properuily ofOrignard reagents lo reaCI vi(!orously wilh waler manda tes extreme
care in drum handling. Any damage lo the conlainers could cause !caleage oC the contents
and conlact witb waler, wilh the potential of a fast, volatilc reaction and the rapid evolut ion
oC Hammable !IOlvent vaporl.
.,
s-. AV SIt/MoHr n", "'2:1\ ..
A bJankct of inctt su. s\1Ch as oty nilrogen or 8' 80n, is required fOl the packagill&
handling. and lranspart oC Grignard reagenlS lo reduce reactivily. lbis ncM atmospherc
musl be mainlained throughout tbe production and UJC of he rugenl. bolh 10 maximizc
safcly and optimize yields.
C. n.o"'r Prac.du ....
When seu;oS up a sfslem 10 transrer Grignard rugcnlS from drums 10 a roed taoll:, lhe
unopened drum of Grignar<! reagent musl be lI'ounded and mechankally bonded before
the atlat:hment oC any tmnder fittings, 10 ensure a metalto-metal contaCl with he round
cable (Fig. 2).
Typically, the 2-io. drum bung is sel up as lhe feed a utlel, and lhe 3/4-io. opeoing
is se! up as he ven!. This ven! ;5 equippcd with low-prcssure, regulated nitrogen or argoD
lo provide an incrt almosphcre in the drum and Ict as a folloW(:r gas in the feed lines.
The 3/4-io. venling sySlem should nelude a solvent flush for riruing residual Grignard
reagent from thr: feed line:s. This will enlure sale opening of the quick-eonncct junctions
typically found in luch systems. A pressure relief valve is also needed 10 prevent
overpressurization of the drum.
D. DI..,., .. I 01 w _
Before disposal of lhe drum, it should be ftushed with severa! portions of dry solvent Tbe
line lo Ihe l'CQCiving lank. should be ftusbed as well. Thi! is followed by a ftush of dry
inert SU 10 emply lbe line. 000: the pipe and fitting! are removed, the drum is capped
and transferred to a waste-handling pad equipped wi!h a grounding syslem, water, ud
proper wasle solvenl-handJing facilitC$. The drum can tben be $&lel)' filled with cok! water.
Water should be allowed to overflow for 5 min lo ftush oul an)' remaining solven! or
reagent After thorough drainase, the drum is ready ror saCe disposai.
Grignard reaClions are generaU)' tun using an exccss oflbe reagent to ensure complete
consumplion or the substratc. AClXlrdingly, wbm the reaClion is complete, lherc t)'pically
remains 5-25-;. unrcaCled Grignard reagent in the rcaction _! that musI be disposed
of properly. 80th the quenching oC lhe coupled Grignard reagent and the disposal of he
unused reagenl kft in the drum require an initial hydro!ysis step 10 remove the magnesium
halide.
The hydrolysis slep required 10 dispose of excess Grignard reagenl is perl'ormed in
the pl'OCCS$ vessel, which should be vented through a flame arrestor. Sufficient acidified
water (enough to fono al ltut a 25-;. MgCll solulion) is added care!ully, with good
agitation and full cooling on Ihe jacket.
When perfonoed on lhe reaClion mus in !he reactor vesse!, Ihis hydrolysis slep will
create IWO separate, immisdble layen: the product in Ihe orgarnc salvent and aqueouJ
magnesium ha]idc. The (general]y) heavier aqueouslayer seules lo lhe bollom of the vessel
where it ean be drained oul. .
The desired prodUCl is Ihen further i$O!aled by removing Ihe volalile solvenl. The
solvenl can be dislilkd from the produCl by stripping. or removed mC(:hanically by
cxlraction. Tbe recovered salvenl is then burned in In approved facililY, or ir il is to be
reused, is typically distilled to ensure lile required purily for Ihe next batch.
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IV. HAZARD CONTROL ANO MANAOEMENT
A. Splll.
..
Spills of Grignard reagent! should be contained with ncM absorbenl material, such as
dry sand or earth, and tralUferred with nonsparking bronu, brass, or plasde 10015, making
sute Ihat he container is properly grounded.
Any spilJed Grignard reagenl mus! be disposed 01 as a solid waste, in aa;:ordancc
with all ap"licable rcgulatioDL Spilled Grignard reagenta COIIIWl be so/oogtd, since
contaminadon and c:cposurc 10 lir renden Ibero unsuitable for use.
B. Flr..
Tbc hazards associated wilh lhe manufacture, transpon. and use or Grignard reagcnts are
relate<! lo lhe flammabiJity ofthc: solventa employed alld thc cxothermic reactions nvolved
in tbeir preparalion and use.
Historicall)', diclhyl tlher was lhe common salven! used iD Ihe preparation 01 Grignard
reagenl$. Commcrcially, howevcr, ila use i.s limilcd by S extreme flarnmability and relatively
low-boiling poiot, which procludes lts use in reactions wilh higher working Icmperatures.
Sina: the 19SOs it has becn largely replaced by Ielrahydrofuran tTHF') in oommercial-scak
production. Tetrahydrofuran il a cyclic ether, wilh a boiling poinl 3Q"C higbcr Ihan Ihal
of diethyl elher and a Oash poinl oC - t 7"C, compared with - (S"C Cor diclhyl elher.
As reaetions involving the manufacture and use oC Orignard reagenu are eXOlhennic,
the associaled heat musl be controlled. Typically, these reacti on! are<:allied oul injackeled,
g1ass-lincd leel reaeto", equipped with coaling, explosion-proof ekctrical wiring, explOlion
disks, and inert almOlphere ror purging and blanketing. To conlrol the beal of ruedon
when THF solvenl is employed, ambient oold water may l Utria:. For reaelioas usi ng dielhyl
elher, ehiUed waler or brine iJ required to keep the reaetion mass below the boilin, poinl
Since Grignard reagenlS are particularly reactive with water, quid hydrocarbon coolant.s
(e..g., kerosene) may be substiluled 10 eliminate the risk oC a water leak. Similar precautions
apply ror Ihe use of oommercial Orianard reagent.s.
Grignard reagenl! reaet exothennically wilh air, waler, aOO COl . However, duriag
a reagent tire, the major source of heal generated will be from the bumiDg solven\. As
with any solvent tire. the Ihree primar)" concem. should be
1. Removing the SOUfQC of ignition
2. lsolaling and extinguishing Ihe lire
3. Conlrolling the evolution oC Oammable vapors
Because Grignard reagents are highly reactive. eXlinguishen containing carbon
dioxide, ehlorinated hydrocarbons, or water muS! nOI be used. Dry ehemical lire
extinguishen are preCerred Cor the tightiDg oC Grignard lires. Additionally, full
personal-protective elothing, neluding self-contained breathing apparatus, is required.
C. Toa+clt)' and Toale B,-producta
Because of lheir high reactivily, there is liule meaningful informadoo 00 the health
hazards oC Grignard reageDIs ptr M. Rather, conJideralion needs lo be given lo the
starting reagenU employed, inc1uding the solveols aod tbe products (or by-producu)
oC the reaetion. Sorne starting materials, Cor eumple, orpDie halides (notably melhyl
bromide and vi nyl chloride), are particularly toxie. Hydrolysis oC a phenylmagnesi um
halide produces benzene.

.....
By-products of lhe decomposition of Grignard reagcnls are aD additional concero.
As with flammable oranie halides, lhere is a potenlia! Tor lhe rdeax of hazardOU5
hydrogen halide vapors (Ha. HBr). Ir lhe lire involvcs certai n Grignard reagenfl
(notable phenylmagnesium he hazardoUll hydrocarbon, benzcnc, may be
releascd.
V. REOULATOAY COMPLlANCE
A. Commen::I.1 U
Industrial use of a Grignard Teagen! in Ihe United Slates Tequires Iha! il Ix induded 00
he Envi ronmental Protcctio n Agency (EPA) Isl of Chemical S"bslOnccs in COIIfIntru. A
correspondng registralinn exists ror lhe European Cornmunity and ror Jopan. Table 1
gives Ihe Chemical A bstracts Servio:: leAS) numbcrs of hose liste<! by lhe EPA as of 1994.
For chemicals Ihat do nOl appear on he U.S. EPA lisl af Chemicol Substonces in
CCH/1mf!r u, il is nccC!sary 10 suhmil a Premanuracture Not ification (PMN) 10 lhe EPA
before making the new material for commercial purposcs. Thc EPA approval is bascd on
adcquate documenlation of planned manufacluring procedures, anticipated by-producl$,
hcalth and cnvironmental effecls test data, and procedurcs for safe use, handling, and
disposal.
B. Alr, Wller, 8oI1c1 W ....
Before a chemical manufacturer in the Uni tcd States can scale up production of Grignard
reagenlJ from the laboralory 10 the planl, approprialc federal, ,late, and local air,
wastcwatcr, and solid waste permits musl be obtained, or e)l istng permits modifled.
Requi red approval periods will vary depending on Ihe j urisdiction.
T.bIe 1 Gri8nard Lisled on Ihe UOS. EPA To.jo: Sublilances Conlrol Ael (TSCA) Lisl
Nlme
Mel hylmagncsium chlondc
MClhylmagncsium bromidc
MClhylmagncsium iodidc
chlonde
Ethyl m''1nesium bromide
nPropylm'8nesium chlolde
bopropylmagneJium chloride
n_Buly1ma8nesium chlc)ridc
.... c- Butylm.8nesium chloride
II-PcntyJma8nesium bromide
n-Huylm'8nesium bromide
Vinylml811csium bromide
Phcnylmagncsium bromide
Pheny1ml81"1eSium chloride
Ben!ylmancsium chloridc
J>-Toly1ma8f1C!1ium bromidc
Tolylma811C1um chloride
RMsX formula
ClI , MC\
CH, MIIBr
CH, M81
CH,CH, MgCI
CH,CH, MIBr
CH,CH,CH, MgCl
(CH,),CHMla
CH,(CH.),CH, MgCI
CH,CH,CH(CH,)MgCI
ClI ,fCH,J.MIBr
CH,(CH,I, M8Br
CH, ... CHM8Br
C. H, M8Br
C. H, MgCI
C. H,CH,MCI
4----CH,C.H.MgBr
2---CH,C. H. MgCI
CAS rei,ry
numlxr
[646-58-4]
(75-16- 1)
[9 17-646]
[ 2386-64-3]
[925.90-6]
[U34-82-4J
[10611-55-9]
[69J.{l4..9]
( 15J66.08-02]
{693-2S-4]
[376 192-0]
( 1126-67 1]
( 100-583]
[ 100-59-4]
[6921-34-2)
[4294-57-9]
[33872-80-9]
C. Tranaport.llon
Sincc Ihey are elassificd as lIammable liquid!!, Grignard rcagenlS in Ihe Uniled States musl
be paekaged in drums or olher suitable conlainen bcaring a red U.5. Dcpartmenl of
Transportation label. Thc: a""ropriate interoational designation of Grignard rcageDIS is
UN-I993. Conlainer sizc reslnelioD! a""ly for occan shipmenl of Grignard rcagenlS Ihal
generale gascous by-producls (C
I
lo C. hydrocarbons) on hydrolysi s.
Whcn shipping Grignard rcagcnl!l, one should revjew internalional lransportalion
regulalions. The UDiled Slales import and elport reslrictions on Grignard reagcnls are
lisled in Ihe T o ~ i c 5ubstanccs Conlrol Ael (TSCA). Section 12 For export, reslrictions
may be imposed by (he rcceiving counlry. Note Iha! (he majority of Ihe regulalory
considerations for (he use of Grignard reagcnlS will a"ply 10 Ihe solvenlS used, ralher
Ihan Ihe Grignard rcagcnts themsclvcs.
D. Slor.""
As wjth any polenlially lIammable material, Ihe best sloragc raci lily js a well-vcotilatcd.
tire-resiSlan! building, , uieable for flammablc chemicals, Ibal is away from main buildings
and of&,es.
REFERENCES
l. T. Waugb and R. Waugh, A.m. CMtrr. Se,. lJ:73 (1959).
2. P. Colin and J. Gittin, CMm. ~ PrOQ. J6:71 (1960).
J. J. KotlonilJl:b, AM. H. Y. Acad. Sci. /15:161 (19M).
4. P. Rakita, J. Aultman, and L Slapel ton, CIItm. EnrI. 97: 110( 1990).
~ G. 81ackman. C. Wrigbt. and R.Smilb, U.s. Patcnl J,9 11,oJ7,Oct. 7,1975. to NakoCbemicalCo.
6
Wet Analyses 01 Grlgnard Reagents
OARY S. SJlVERMAN
El! AtOCMm Nortll Inc . KIIIg ofPnusIQ, P,,,1ISylvanID
l. QUANTlTATIVE _El AHALYSES
Thcre are tbree potential problems Ihat may OCCUf durioS lhe Grignard reagenl prepllnltion:
olidation by OJo bydrolysis by HJO, ar homocoup1ina durina lhe addition of alkyl or aryl
halide. Oxidadon Ind hydrol)'sis will &:crease Ihe active Grignard reagenl. whilc
maintaining he nme equivalents o(base. Bccause ofthesc hree problems., lhe concentradon
of a Grignard reagent should nol be assumcd based on he reactants. By no! aDalyzing
he Grignard reagent, one ar more of lhe following problems ma)' occur. impropcr
stoichiometry, potcntial deleterious side reactions, highly clIolhcnnic qucncbing process,
phase split. wastc di5posaL and ros! problems. Therefore. lbe IDalytical tcchniquc mus! be
ablt 10 dilTertntiate between active Grignard and total basicil)'.
Thcre is a plethora of methods available 10 measure lbe active Grignard The
metbod! range (rom titratioD lo c1edropbilic qucDcbing lollowcd by gas chomalograpbic
(OC) anal)'Sis. Potenliornetric titratioD (1- 3J lUiDg 2-butanol as the lilranl is rccommendcd
as the general melbod for delermining the actjvly oC Grignard reagcntl. The advanlages
oCthis mcthod are Ihal il docs nOllit rate Mg-OH or Mg-OR species; jI gives reproducible
rcsults (J standard devjations _ 0.6% oC value); di red analysis of solution. ami analysi!
takes less Ihan 10 miDo
Standard litration lechniqucs, using indicators (4,5,13J wilh 2bulanol as the tilran!,
have greater elTor (3 standard devialions _ 1- S-J. oC valuc). bul usually Ihis is Itill acceplable.
The real advanlage ollbese indicalor mctbods is Ihat virtually no capital inveslmcnt is
rcquired for lhe equipmcnl. The equipmenl for Ihe more aocurale potentiometric lilration
method can cost upward ol 15,000 dollan. This is why tilratioll! using 2,2'bipyridyl or
are more prevalent in the ilerature.
Elect rophilic queneb followcd by OC analysis can give Ihe accuracy and preelsion
oC a polentiometric titration Howcvcr, each slartiog material and ilS product must
lO
lO
be calibrated versus a GC standard. This requires ti time-consuming GC melhod
development prOCle$l. Abo (bese melhods Iypically take 11 mnimum of I h from lhe starl
of the quench procedure lo obtaining he final chromatogram. The advanlage or he OC
mcthod is Iha! a direct measuremenl or t he homoooupled product, ollidixcd Grignard.
hydrolyud Grignard, and unreacled alkyl or aryl halide, all can be made.
Gas evolution from the hydrolysis or Grignard rcagcnll can be used for he aclivily
anal y!;!!. However, can: muSI be taken in he calibrati on of standards. becausc he resulting
gas will have sorne so[ubility in the solvent . Typically, lhe gas is analyz.ed by GC, laldog
he gas from he headspace of a closed s)'slern. The obviou! limitalion in Ihis method is
Ihat nnl)' a selected amOllO! of Grignard Teagent! (C. or less) can be used. owiog 10 the
Yolalili ly of Ihe hydrolysis products.
Total basicity i$ meuurcd by standard acid- base titration techniques. The activity
divided by the total basicily should be greater than 9O'Y . Ir it is noto then the Grignard
reagent should be checked for unreaeted alkyl or aryl hatide, homocoupled produet,
hydrolysis products, and oxidat ion products.
11 . PROCEDUAES FOR QUANTITATIVE WET ANALYSES
This sect ion ineludes Ihe pr<X:Cdures for Ihe anatyscs of Grignard reagents. AH reagents
and 50lvenUl were dried (Karl Fischer titration must be Iess than 0.02 wt 'Y. degased,
and placed under a nilrogen atmosphen:. AH operat ions were carried oul under an inert
atmosphere usinS a Brinkman 682 tilroproccssor, a sealed laS! electrode Ihat contained
the working and aUlliliary electrodes and a silver reference eJect rodc. For
nonpotenti omet ric lit rat ions the same buret (Brinkman dosimat 665) and ccll were used
with lhe speci lie indicator.
A. p,.p.r.t1on.nd Stllnd.rdlz.Uon of 2-Butllnol Solutlon
This mclhod is used 10 standardixe l-bulanol solutions in xylenes and is based on acelylalion
of Ihe alcohol. To make Ihe slock 2-bul anol solution. add 74 g uf l-bulanol lo an inert I-L
voJumel ric f1ask and diJute 10 ] L with xylcnes. Mix Ihoroughty and lrander under nitrogen
10 a U-L storage Hask oonlainins 4 molecular sleves. Desas the so[ut ion by Ihe
freelC-pump-Ihaw technique (Ihree times) and place Ihe storage Hask under nitrosen.
The titranl is a standardized NaOH solution of approximately O.S N. and Ihe indicator
is a 0. ] wl /. 1:1 mili of cresol red and thymol blue in methanol. The color change will be
from a lighl yellow 10 violel for Ihe end poinl.
The reagenl solulion is prepared by pipett ing I mi of 70% perchloric acid into a
1000ml volumetric ft ask, add 7S mi of el hyl acelale, and shake well . Add 10 Ihe mark wilh
acelic anhydridc. Note Ihal Ihis il an exolhermic dilulion and an ice balh may help spccd
up Ihis proa:ss. However, Ihe solution should be al ambient temperalure before final
dilution and actual use. Thi! reasenl il ! Iable for al leasl 1 wcek.
Once all orlhe solution! have becn prepared. use the roll owing prooedure. Pipene S mi
01 Ihe acelic anhydride reagenl soludon iolO each of IWO oven-dried Erlcnmcyer flasks,
followed by pipetting S mi of the l-bulalloJ 501ulion ioto only one of Ihe Haskl and mark
il Hask B. Sl opper bol h Hasks alld mix thoroughly for al Jeasl J 5 mino Carefully pipeue
mi orHzO ovcr 2- 5 min and allow lhe Hask 10 coal 10 ambienl lemperature (S-IO
Add 5 drops or Ihe indicalor solulion and litrale with the NaOH solution to the yiolel
"
end poinl. Calculatc he molarilyofthe 2-bulaDol solut ivo using therollowingcquation:

M -
.""".... 5.00 mi
Tho: molaril), should be approximalely 1 based 00 ma$S or 2-bulanol and he
rc:commendcd diluti on vol ume.
B. Del. rmlo. tla D of Grlgo. rd A gent Actlvlty
Clcan, dry, and oert a SO-ml itration ftuk contaioing a working/auxiliary elect rode, a
refcrencc elcct rode, buret tip (or subsurfacc (ced, septurn, stir bar, and a nitrogen inlet,
wilh a bubblcr {or pressUI'C relid. Add enough sol ven! 10 Ihe Hask 10 cover Ihe electrodes
and he bure! tip, which is approximately 25 mi ortetrahydroruran (THF; len Ihan 0.02
H10) and 513rt he sliner. Weigh out, in milligrams. appwximatcly 2 8 of Grignard reagen!
by syri oge and add lo Ihe flask. Reweigh he syringe 10 gel he precise mass or Grignard
rugent added to the lIask. Start the titration with the standardiz.ed 2-butanol solution (see
Section U.A). A sharp deerease in polential, u well u fonnalion of a white solid, indicale
that the endpoint has been reached. The first derivative oC the S-shaped curve is the actual
endpoint,and IheGrignard rugen! activty ean becalculated by the CoUowingequalion:
. . ACllvlly (mo , .. g) __
Grignard Teagent mass(kg)
Thcre are several reasons why the Grignard reagen!'! mass is used. inSlead oC the
volume (Jiters) lO give Ihe aCli vi!y. The major reason is mass measurements in mos! synthetic
laboralories are significanlly more accurate than volume measurement$, owing 10 Ihe lack
oCavailabi ltyofinerl volumelric pipelte5.. For commercial production ofGrignard reagen!s,
these eomment! are magnified, and the mass measurement is the most appropriate.
There are severa! adequate indicators that can be used instead ollhe eJeelrode syslem.
The most common are 2,2'-bipyridyl and I,IO-phenathroline. In the presern:e of active
Grgnard reagenls hese indiealors will Conn colored charge-lransfer compkxes.. Alter
quenching with 2-butanol, the complex is broken, subsequent ly he color disappears. The
color will vary from yellow loa dark orange-brown,dependingon the Grignard reagen\.
An nteresting qualitative test for organoJithium reagents in he Grignard reagenl!
is 10 add a few milligrams of 2,2'-bipyridyl to the active reagent [13]. Ir the solution is
red-purple versus a yellow-orange, Ihen here is an organolihium presento Thi! is an
important tesl, espet:iaUy ir Reike Mg, generated from lihium, is used (see Chapler 4).
C. D. t.rmln. llon of Grlgn. nt " 9*01 Ac!d-B ... V. lu.
This determination is a standard aeid-base titrltion, and thc ratio of Ictivity(see Stion
II.B)/acid- base should be greater Ihan 9J'Y . An eumple of this procedure is described in
the following.
Clean and inert a 2SO-ml titration flask containing Iwo buret lips for $ubsurfacc leed.
septum, stir bar, and a nit rogen inlet, wilh a bubbler for pressure telid. Add lOO mi of
degased. HjO 10 he lIask and lum on stirrer. Weigh out, in milligrams. aprro:timately 5 g
of Grignard reagen! by syringe and add to Ihe flask slowly. Reweigh lhe syringe 10 gel
Ihe preci se mass of Grignard Teagent added lo Ihe lIask. Add approximately 5 mi ofO.5 M
HCI from buret I and rinse the sides of the lIask with !he $Olulioo uotil there are no visible
solids. Add 3 drops of phenolphlhakin to Ihe flask and titrale J.-.4 mI pas! Ihe endpoint
' 1IIi1.."
(colorless). AlIow the solution to stir for j mino Add J drops of met hyl red indicator. Titrate
with standardized 0.1 M NaOH in 2 lo he eodpoiot (disappearaocc of red color).
To calculate the acid- base value use the folJ owiog equation:
Acid- base (moJ\g)- (MIIOVIIa - M...atIVNoOH)
Grignard reageot mass{kg)
REFEAENCES
l . K. K hamo C. Chevrol. J. Folelt. M. and J. Perchon. Bull. SOCo Ch/m. F,. 4:243 (1971).
2 K. Botlaludur ,lid P. 8ranipn. Elf Atochem N. A., internal standard test mctbod (l 97n
3. G. S. Silvcrman aOO P. Rat ita. Griflnard ructiont. Ki,kOllrme, Enc)'loNw o[ ClonnktJl
T JtnoIogy, 4th ed. (J. Krosdlwitz aOO M. Howc..(}ranl. em) Joho Wiley & Saos, New
York, 1994.
4. D. Berflbreiter and E. Penderrau. J. O'g. 46:219
j . V. Ato, H. V.mashita. T. Ot.Jubo,'OO F. Oflura. J. O,g. CIonn. 54:5627
6. M. Winkle, J. Lansingcr, and R. Ronald, J. CM,... Soc. Cltem. C_. p. 87
7. S. Watson and J. Eastham, J. O,(JIlNHMI. CM,... 9: 165 (l96n
8. H. House and W. Respesl. J. 0'V-1. Cite,... 4;9S
9. R. Hollandcr aOO M. Anteunis, BulI. Soc. Chim. Iklg. 71: 77
lO. A. Wowl; and S. Gionnni. Allal. Cltem. 38:742
11. M. Molinar, J. Lombardo, O. Lite$, and G. Videla. AII. A.!Soc. Quim. 48: 140
12 V. Chcmoplekova. V. S.kh,rov, Ind K. Russltm CIonn. Rn. 41:1063
13. 8. Fumi ... A. Hlnnl ford. P. Smith. I nd A. Th.tchell, 01 PrOCI/c(l/ O,g(Jllk
CltemU/ry, 5th ed, Longmln, E4scK, 1989, pp. 44}-445.
7
Inlrared and Raman Spectroscopy
Paul Chzbot
El! Aloc/tvn Amt ricrJ. lile., King 01 Pnusia. PC1IJIJy/wlllll
l. AlIPHATlC OAIONAAD AEAGENTS
The structure and properties oC lhe Grignard reagent! are a funct ion or Ihe organic group
allached lo the metal atom. Plum, in 1937, was Ihe first 10 Sludy lhe influcnce oC
lhe organic group using iorrared spoctrmeopy (1). The Grignard reagcnts studied were
diethyl tlher solutions ofethyl- and phenylmagnesium bromide and iodidc. Even though
several absorption bands Ihal could be a!tributed to Grignard reagents were observed,
no definite ass gnmenl! could be made.
The group of SaHnger el al. compared lbe iofr.red spcctra of Grignard reagents
in solution in tctrahydrofuran (THF) and diethyl tlher (R _ Me. El, or Ph;
X .. Br(THF, CI(iHf), (RIJO [2]. When pure RJMg and MsXz were mixed, l' was
observe<!, aRer S min, lha! lhe spcctra oC lbe reaction mixtures were identical with Ihat
of the Grignard 1I was aOO observed that the nalure of lbe halogen alom did
nOI have a large inftuenee on Ihe inrrarcd speara. And finally, a in ooneenlration
did nol modify Ihe infrarcd spcctra significantly. For lhe alkyl Grignard an
absorption band was obscrved bctwccn S3S aOO SOO cm -1 and was assined lo lbe C-Mg
sl retching vibration. For phenylmagnesi um compoundJ, Ihis band shifte<! 10 lower
frequencies, and was obscrvcd bctwccn 383 and 36S cm -l. The resulta of Ihis . Iudy were
uscd lo show lhe elislcnoc of Ihe Schlenk equibrium in Grignard soIutioDS. Furthermorc.
this sludy indicales Ihat the nature o( tbe alky! or ary! group, the atom. and the
solvent, al1 have an efl'ect on the Itructure of lhe Grignard
The efl'cct of the chain lcngth of an aliphatic groups attached lo Ihe magncsium
atom was sludie<! thoTOughly by Kress and Novak [3-,SJ. Thc analy.is of the infrarcd
and Raman spcctra or melhyl and cthyl Grignard rcaenll, oombincd with the analysis
of the corresponding deuterale<! compounds and different groups has Icd lo a
complete vibratonal assignment. For C
2
H, MgX' 2(C
l
H,hO (X - Br, 1) in the solid state
..
Flpre I CryslaUine Ilruclure or C, H,MaX'20(CH,CH.),. )( _ Br or l.
T_We 1 01 lhe Infrared 8andl Otue,.'C<! ror lile
Vibratiollll Involvinglhe Magnesium Atom in C, H,MIX'2(C, H,}O
a' 90 K
Inframl Raman
Auinmcnt C, H,MBr C, H, MgI C, H, MgBr C, H, MgI
,M&-C
."
."
..,
."
"...,. MIO, JI7
". ".
'"
1'..,. MgO,
JO,
'" '"
29J
,M,x
'"
m
'48
m
' MCC
'"
l79sh
6M&O,
-
""
14Ssh
al 90 K, lhe", is a tctrahedral arrangemenl or lhe cthyl raup, he atom, and the
I\VO cthyl t lber molecules around Ihe magnesium alom (Fig. 1) [3]. Tite: dielbyl tlher
molecules are always in lhe CG conrormalion lor these compounds, a oonformali on Ihal
is nOI 1r.nown for pure diet hyl ether. The reason for the conformatianal ehangtl is the
coordination af lhe di<lthyl tlher molecuJes wilh he magnesium alom. lbe coordination
efrect ncreases he frequency ar he eH, slrclching and lauion vibradoR! aOO dccreC5
lhe frequcncy 01 lhe slr.elcton vibrations Ihrough a eharge transrer rrom the oxygen to the
metal atom. Dicthyl ether absorplion bands are not particularly scnsi live to lhe deuleralion
or Ihe organic group or Ihe Gngnard compound or 10 the ehemical subslitution or the
halogcn atom, cxccpt ror thc C-O---C dcl"onnation vibration band al SOS cm - 1, ror
whieh a s.Iight rrcqucncy shift can be observcd as a runC1ion or lhe compound studicd.
According]y, the clhyl group attaehcd 10 thc magncsium alom is nOI vcry scnsitivc to thc
dcutcrat ion or lhe diclhyl clhcr, or 10 lhe nature or Ihc halogen. But Ihc rrcqucncies
observcd ror the Cl H$ group were diffcrcnt rrom thosc observcd ror corresponding
hydrocarbons. Thc rrcqueneies or Ihe C-H stretehing and ddormation vibrations are
lowcr than ror hydrocarbons, and the skeleton !trelehing vibrat ions rrequencics are slighlly
higher.
The bands correspondi ng 10 the vibrations or cthylmagnesium halidcs involving lhe
magnesium atom are round al rrequcneies lowcr than 500 cm-l. Table 1 shows a companJOn
or tbese rrcqucn<:es ror Ihe inrrarcd and Raman spcctra (X _ Dr, 1). Thc analy,i! or the
rrcqucncics show! that the tctrabcdral arrangcrrn:nt around thc mclal atom is very simi lar
ror bolh compounds. It alJO shows Ihal thc nalurc or the haJogen has a Jargc influcnce
on lhe Mg-X slretehing vibration. with a shin or 20 cm - I rrom the bromidc lo he
iodidc. The other vi bration! involving the Mg atom are only slightly alfcctcd.
Tibie 1 Frequencies oflhe M.-X Stn:tchio Vibr.tion Bandl
in thc Raman Speclra of C. H.MgX-2(C. H.hO ex .. Br and 1) in
ItIc Solid (90 K) and Uquid (JOO K) Slale
SI.te EtMBr-2(EtJ.O EtMaI-2(Et).O EtMICl"2(EthO
Solid 248 224 225
Liquid 244 227 263+241
FaPR 2 Cryllalline 1lr1lClun: oIC,H,MsO-20(CH,CH.),.
..
The analysi! of lhe same oompounds, in lhe iquid state, al 300 K did nOI
enough difl'crences lO $uggesl a change in thcir struclun:. The speclra of Ihe samples in
the salid flale (90 K) have a bcUer resolulion, which is due 10 Ihe cr}'1taUinc com:lation
effect and Ihe decreasc in lemperature. The si milarity of the frequencies observed fOl lile
Mg- X sln:tching vibration bands in lhe Raman spectra (Table 2) of Ihe liquid! and solids
confirm the similarities of Ihe slruclure5. In Ihe Iiquid state, lhe dictbyl elher molecules
are slm in lhe GG oonronnation.
Tm: Raman spcclra of C
1
H,MgBr-2(C
I
H,hO in the liquid slale and in a diethyl
elher 5OIulion atso compared, The speclrum of Ihe 5Otulion corresponds 10 a
superposilion of the spec1ra of pure dielhyl elher and of C
1
H
s
MgBl'2(C:H,hO. No
concentralion elfec!5 were observed, indicaling that Ihe Sch!enk equi!ibrium favon Ihe
Grignard form for Ihe ethylmagnesium bromide.
The compound C,H,MgC!':CzH,hO was also !Iudie<! in the liquid and crystalline
Ilate and in solulion in diethyl elher by Kress aOO Novak, using infrared and Raman
speclroscopy [4]. In Ihe liquid tale (300 K) aOO in the vitreous slate (90 Ihis
monoelherale has a dimeric cyclic obtained Ihrough Ihe formation of chlorine
bridgcs (Fig. The dielhyl elher moleculcs are in a GG conformation.
The Mg---Ct slrelching vibration band i$ Jocated between 290 and 270 cm -1 in the
infrared spectrum (at 90 K) and al 263 and 241 cm- in the Raman spectrum {al 300
The lacalion of Ihese bands and heir mulliplicity u compatible with tbe dimer
model proposed for this compound. The band.s assigncd lo othcr vibralional modes
involviog Ihe magncsium atom, namely the e-Mg and Mg-O vibrations
and the C---C-Mg deformation vibratioD, very similar lo Ihose observed for
C
z
H,MgBl'2(C, H,hO. This observation i5 also consistenl with Ihe dimer model. The
replacement of Ihe bromine alom by a ehlorine alom and !he ehaoge in lhe degree of
solvalion of Ihe molecule initiale only 51igbl frequeocy shifts of Ihe inlemal vibralions of
Ihe elhyl group altaehed lo lhe magnesium alom and of lhe dielhyl elher moleculcs.
The Raman spectra of dielhyl elher 5OIulioos of elhylmagncsium chloride werc very
similar 10 Ihat observed for Ihe liquid. Furthermorc, a change in the concentradon of he
"
IOlution from I 106M did nOI modify lhe spcctrum ,ignificantly. Thcsc resulta sholll Ihat
lhe Sehlenk equilibriurn again favors he Orilnard re8.gcnt formo
The spectrum of the crystal1ine form of the cthylmagncsium chloridc is diffcrent from
those obsenred for lhe liquid and for dict hyl clber solutions. Major frequency shilts were
ohscrvcd for C- H aymmctric stretchin Ind CH
1
waggin vibralion bands, and also for
lhe C-C aOO lhe Mg--C slretchin vibral ion bands of l he clhyl grollp luached 10 lhe
magnesium alom. Five absorplion bands ""ere observed in lhe Raman speclrum of Ihe
crystallinc rorm that could nol be faun<! in lhe spcctrum of he liquid. The oomparison
af the spectrum of lhe crystal line form with Iha! af EIIMg and EtMS"EIO showI Ihat
lhe new bands can be assigned 10 vibrallons of lile ct hyl rOllp attached 10 he magnesium
atom, bul in a bridging pasilion. There j, also sorne cvidence Ihat lhe chlori nc atoms
lIilI in bndging posilions belwcen magnesium aloms. il was concluded that the
cryllaline form consim of a complex association betwoen Iwo or more dimers Ihrough
lhe formalion oC ethyl bndges..
The elfect orthe length of lhe organic group on Ihe vibrational spectra orlhe Gngnard
reagents was completed by Kress and Novak Ihrough the st udy of CH)MgX2(C
l
H,hO
(X - Br, 1) [5]. Al 90 K, Ihe Raman spectra show thal CH
J
MgBr-2(C
l
H,hO exhibils
Iwo cryslalline forms (1 and TI), whereas for CH, Mgl'2(C
2
H, hO, only form I
oould be observe<!. Tbe Ilruclure of the torm ) crystlls is very similar lo thal observed
tor C
1
H,MgBr2(C. H,hO, wit h a tetrahedraJ arrangement of the halogen alom, melhyl
group, and the t wo diethyl elher moJccules around the magnesium alom. For Ihis crystaJline
form, the diethyl elher mokcules are slill in I GG conformation. The nature of lhe halogcn
atom and Ihe nature ot the organk: group (deuleraled or nOI) atlached 10 Ihe magnesium
atom do nOl have much in"uence on the frequencies and intensi lies of Ihe bands assigned
lo Ihe inlemal vibralions of Ihe diclhyl el her molecu!es. The frcquency shin observe<! for
Ihe c-o-c deformal,on vibralion is caused by the coupling wilh lhe Mg-C
vibralion.
The deuleration of the melhyl group or Ihe methylmagnesium bromide has le<! 10 I
complele vibral ional assignment. The frequencies of Ihe bands assigned lO he methyl
grolip are almosl identical for he bromide and t he iodide; however, Iheir frequencies
much lower Ihan lhe torresponding vibralion! of alhne melhyl groups. !uth as el hane
or propane. This is probably due lo Ihe ionit t haraeler of he melhyl group atlachcd lO
an elcclroposilive magnesium atom.
The vibrations involving lhe magnesium alom of CH) MBr- 2(C
2
H,l.O are found
below 600 cm - l . Table 3 sho ..... s the rrequency of these vibralionl. From Tables I and 3,
it can be observe<! Ihat the rrcquencies of lhe nfraced and Raman bands correspondng
10 Ihese vibralions ace very si milar, eXDq)1 for lhe Mg-C slretching vibralion band, which
is higher for lhe methyl groups Ihan for Ihe el hyl grou"" owing 10 the lower molecular
weight of Ihe melhyl groups. A sJight rrcquency shin is also obscrvcd for lhe MgO
l
slcelching vibrations, which is probably due lo a coupling effcct or lhe melhyl group.
Thc large differenoes observe<! bet wcen lhe Raman spectra of form I and form n
cryllals of CH) MgBr-2(C
2
H,)O indicale lhe vanllions in Ihe molecular SlruCluce.
Frequency shifts wece observcd mainly fOT the bands assigned lo vibral ions or lhe dielhyl
ether molc:cules. Small shifls wece al$O observed ror olher vibralions, namely, Mg-C
slcetch,ng vibrafon aOO Ihe MgO
l
asymmel ric stretthing vibradon. )1 was SUggesled Ihat,
in form 11, Ihe dielhyl ether molecules adopt a TG or TI conformat ion. An equilibnum
bet wcen lhe gauchr and 'rallJ oonformations wal proposed lo cJ: plain t he spectraj results,
along wi lh he ,imilanty or lhe volumcs oocupied by thc Br and CH, grOUp5.
The analysis of Ihe apect ra obtained for Ihe liquida (al 300 K) aOO Ihe diethyl etbcr
.. , ....
TaWe l FrequenciCl of lhe Infrared 8ands Obser"Od lor lbe Vibral;".,.
Invotvin,lbe Ma,nail,llR Alom in CH,MgX2{C,H,.O al 90 K
Infran:d

CH,MBr CH.M&f CH,MBr CH,M,Br CH,M&f
AuiJllmcnl (fonn n (Iorm 11)
,MgC
'10
'"
'99
515sh
"-- MgO,
3J>I
''',h
'"
,..
Po,. MgO,
'"
281
".
'" ,M,x
'" '" '" '"
2JJ
& MgO, 1 .. 1<0
&CMX
11'
m
Table -4 Frequencies of lbe New Bandl Obsu ,ec! Irom Dilferenl
Reaaio.,. UDder ACSOn
Reaaion
I' .... C-H _C-H &..,.CH, &_CH
J
MII+CH,1
""
2800 IJOl
,.,
MII+CD,1 ' 102
'0'"
990 <J8
M,+CH,Br
, .. ,
2800
" 1
MII+CD,Br 2102
-
41'
MII+CH,CI 280l
1'" "0
C.+CH,I
1'"
420, JIIO
Sr+CH,1
1'" "0
Sr+CH/Br
"0
salutions of form 1 and 11 shows that Ihe)' similar 10 Ihc cth)'lmagncsium bromide
spcclra. Onl)' a sHghl WII5 observed belwccn Ihc spcctra of Ihc liquids al 300
K and Ihose of the form T crystals al 90 K. The slructure or lhc meth)'lmagncsium bromide
and iodide in Ihe liquid rorro is similar lO ethylmagnesium bromidc. The dilfcrcnces betwccn
lhe quid! and lhe salid! were cilplained in lemu of lempcralure varialions and changes in
lhe ph)'sical sta te. No significanl changc was observcd in Ihe Raman spcctra oflhe solul iom
as a runction of the concenlration.
To slud)' unsolvaled Grignard spccies, Ault eumincd Ihe reaction ofmagll6ium wilh
melhyl halides in afgOn matrices [6]. The reaction olmagncsium wilh CH,I, eD,I, CH,Br,
eOJBr, and CH,C\; lhe reaction or calcium, strongium, or zinc wilh CH.I; aOO lhe reaction
01 strontium wilh CH,Br. Ied lo infrared spcctra wilh absorption bands Ihat could nol
be assigncd lo the paren! mcthyl halide, sugesting a distinct reaction in which the
carbon- halogen bond is rup!ured. lbe frequcncy and proposed assignment of tbese bands
obtaincd Ihrough Ihe dilferen! reactions are given in Table 4. From these results. a 1:1
reaction complex WII5 suggeslcd; bu! no conclusion could be made as rar as the structure
01 Ihe product was concemcd, sinoe no carbon- melal or melaJ-halogen bond could be
observcd.
11 . ALl YUC OAIGNAAD AEAGENTS
The innuence of Ihe nalure of the halogen, of the solvent. and of the concentration on
the C_C 5Uetehing vibration region of the vibrational spect ra of a1Jylie Orignard reagent!
(Cl H, MgX) was sludied by Gross (7]. It was found that the concentration of the diethyl
ether solulion docs nOI bave any nfl uence on the frequeney orthe C_ C stretching vibral ion
band oC CH._CH-CH1_ Mg_ Br, for concenl rat ions ranging rrom 0.5 to 25 N. Bul
unlike whal was found fo r Ihe aliphalie Grignard reasenls, the nalure: of Ihe halogen atom
docs have a larse influe nce on Ihe vibralion or Ihe orpnie group. The frequeney of the
C_C stre:tehing vibral ion band shin, from 1591 cm- ' fo r Ihe allylmagnesium iodide in
ao elhyl elncr solulioll, 10 IS88 em- ' lor the aHylmagnesium bromide. to 1580 em- ' lor
lhe ebloridc derivative.
The solvent also has a slrong influence on Ihe posilion orlhe C_ C stre:lehing vibration
band or the all ylic Grignard. The rrequeneies observed ror severa! solvents and differe:nt
halosen groups are given in Table 5. The role 01 both Ihe solvent and Ihe halogen atom
on Ihe strueture: oC the allylic Grignard was e)(plaincd by the nuclcophi!ic eharaeter of
Ihcsc groups aod Iheir aetion on the emp!y eleclronic shells of Ihe magnesium alom. The
competi tion hetwcen tbe donor eharaeter of Ihese groups sbifts toward Ihe solvent in more:
basic solvents, and lowaro the halogen alom in less basic solveots. No conelusioo was
given for tbe environmenl of the magnesium alom and ils bonding to the al1yl group.
A mi)(ture: of l-bromo-2-butene, ci:t- and raIl3-. and of 3-bromo-l-butenc was re:acted
wil h magncsi um and analyzcd usi ng infrarcd spoc::t roscopy. The erolyl bromidc has an
absorption band al 1666 cm- ' , with shoulders at 1654 and 1637 cm- '. These bands are:
assigncd 10 tbe C_C stre:tehing vibralon 01 l-bromo-2-trallS-butenc, l-bromo-2-cis-butenc.
and 3-bromo- l-bulenc, respeclive!y. The infrared speclrum oflhe Orignaro rcascnl formcd
rrom these: compounds shows a single band al 1535 cm - 1 for Ihe uMOlvaled spccies, and
two bands al 1611 and 1632 em-
I
fo r Ihe solvatcd spccies in diet hyl elher solulion. The
smaller shift obsc:rved after Ihe format ion oll he Grisnard re:agenl ror Ihe crotylmagncsi um
bromide Ihao for Ihe allylmagnesi um bromide can he by lhe electron donor
ebaraeter of the met hyl group 01 the erotyl. 1t is even more: obvious in the 'rallS-crolyl
than for the cis-form, owing to Ihe easier electron transfer aloo& a Ira1l.1-compound. Thi!
assumptioo is also supportcd by he single absorpt ion band covercd at 1637 cm-
I
for
Ihe Grigoard rc:agent pre:parcd rrom (CHlhC- CH-CH. Br, where: no cl.H ra1l.1-isomen
exis!.
The ;rotyl mag.nesium ;hloride prcparcd Irom the same slaning rcasenls shows
inrrared specl ra in the 1600 cm - , regioo limilar l O Ihe bromide. Ooly small frc:q uency
Tabk 5 Inlluence aflhe Solvent aOO afIlie
Halogco Alom 011 the Frequency af lhe
e .. e Slrelchinl VibrtliOJl Band af Allylic
Grinard Rugents
SoIYenI RMa1 RMgBr RMgO
Elhyl clhc:r 1 ",
, ..
THF 1518
'"
BUlyl cther
Triclhylamine 1588
T.We 6 InHucnc:c of he Nalure of lhe Halo,en on he Frequem:y of
he Masne5ium-Halides Vibrations for Allylmagnesium H&lides
Inr ... red
l' Mg-X 250 210 260 210
6 Mg,X, 130 110 100 80
..
shifts (5 cm - 1) can be observed, oC the same order of magnitude IU lhe shirts observe<! in
he allylmagnesi um halidcs lor diffcrent halogen atoms.
The vibrationa] spectra or allylmagnesium chloride and bromidc in THF and in
diethyl elhcr, and in he solid slate: were invest igated by Sourisscau el al. [8.9] 10 oblain
more informatlon about he 5truclure of he el H; ion, aOO lo verily the oature of the
metal-allyl bond. The amenee oC a e-e strelching vibration band around 1620 cm-
I
,
he abscncc oC he out-of-planc C-H deformation vibratioll band, between lOOO.nd 900
cm - 1 and he abscncc oC characlcrisdc vinyl CHz vibration! indicatc Ihat he pi eJectrOlU
all: delocaliud along he entire allylic skeleton, and Ihat both C-C vibratiolU and both
CH
2
end groups are si milar. However, lhe oblained spectra for lhese compounds are very
ditrerent from Ihose oblained for pi a1lylic comp1ell:e!JI of lramili on metaJs.. ThUJ, il iJ
SUggesled Ihal Ihe inleraetions are of a difl'erenl type, even tbough ionie in eharacter.
The st udy of olher a1lylmelal (magnesium, lilhium. sodium) compounds in Ihe solid
state showed Ihallhe lrequency ol the strelching vibralion. of lhe allylgroup is dependenl
on Ihe melal. It was proposcd Ihal Ihe depcndence is due 10 lhe ncg&live charge ol lhe
ion, which ncreases {rom Ihe magnesium compound 10 lhe lithium and sodium compounds.
The low-trequeney infrafl)(i speclra of Ihe aJlylmagnesiums show an inlense absorplion
band near 320 cm - 1 and anolher, Icss intense, band near 160 cm - L. The Raman speclra
of lhe same compounds showed Ihree inlense bands belwcen 430 and 310 cm - 1 and three
weaker bands between 190 and 120 cm - L. The higher-frcqueney absorptions were assigned
10 allylmagncsium strelching vibradons, whereas lhe lower.frcqucncy absorptions were
assgne<! 10 the deformadon vibratons.
For Ihe aUylmagnesium halides, two ol her bands were observe<! in the low-frequcncy
region of lhe infrared and Raman spect ra. The frequeney of lhe bands was dependen! on
Ihe nalure of Ihe hal ogen group (Table ~ The higher-frcqucncy band was assigncd 10
Ihe Mg-X slrelching vibralion. although lheir frequcncy was mueh lower Ihan those
obscrvcd for olher magnesium- halide complexe!JI. The presence of halide bridge! was
proposed lO ell: plain Ihe differenccs. The lower-frequency band was then assigned lo the
ddormation of the Mg
1
X
2
bridge!.
The THF and dicthyl elher sol utions orlhe allylmagnesi um halidcs were al50 studicd
belwcen 0.3 and 3 M. Dilferences belwcen lhe inrrared speclra of Ihe IwO $Olut ions were
assigned lo Ihe differencc or $Olubilily or lhe Grignard reagenls in both rolvenllll. The
absorpti on bands observe<! for Ihe THF solution were very similar lo those obscrved for
lhe salids, bul were located al higher frequencies. Thus, il was proposed thal the a1lyl
group has a struct ure similar lo thal orIbe elH; anion. Furthermore, two new absorplion
bands were observed near 470 and 400 cm - l. These band5 were assigned 10 C-Mg
Slrelt hing vibralions, and were u5Cd 10 explain Slronger interactions betwcen some new
, ..
species of lhe all)'1 groups and the magnc::sium atom in Ihe solutions. Thcse .trongcr
intel1lct ions do nOI have 11 pUfe covalent RSsignmcnl.
In another alud)', Sourisscau el al. oomparcd Ihe jorrare<! and Raman spec:tra of t he
aUylmagnesium halides wi th those of cyclopentadienc-metal oomplexcs [9]. Although liD
average valuc of 320 cm- ' was Cound ror l he e- Mg 51rctching vibration or the
allylmagm:sium compounds, Ihe C, H;-Mg ,{retching vibrlnion appears al 360 cm- l.
Thi! indicates Iha! the magnesiurn-<:yclopcntadiene bonds are strongcr Ihan {he
aUyl-magnesium bond,. A oovalcnt bond between the cenltr oC the c)'(:lopentadicnc group
and Ihe metal alom, and In iODie bond bctwecn Ihe Cl H; roup 8nd Ihe metal atom
was suggested 10 explain l he observed djlference.
111. OTHEA OAIONAAD COMPlEXES
The reaclion of benzoyl pcroxide (BPO) with phenylmagnesi um bromide !cads 10 the
formtion of two dilferent [10]. Complex 1 is produced when the molar ratio
of [ PhMgBr]/[BPO] is 1.33: 1.0, and is believed to exist as a dimeric state (Fig. whereas
complex JI (Fig. 4) is obtai ncd when the molar ratio is 0.66:1.0. The THF so[ut ions of
I and 11 have very similar absorplion bands, but dilfer signi licantly from tbe
THF so[ution of BPO. The inrrare<! spect rum of the BPO solution shows three absorption
bands at 1792, 1770, and 1214 cm - l. The inrrare<! spoclra or the complex 1 and 11 soluti ons
show IwO absorption bands al 1640 and cm- L. The 1640 cm-
I
js assigned lO Ihe
o

-;70" : "Sr ....... : /0>-
Ph-C..... 'Mg' ,MsI, Ph
..... /"........ " , '.
o,er,o

O O
Flcure J 51rlK'lure of oomplex I of [PhMgBr]:[ BPO] .
FlaIll'C 4 StrlK'lure of oomplex 11 of [PhM Dr]:[DPO) .
, ..
Flpre! Grillo.ni reagent oblained from lhe of mesil)'1 methyl ketone and tthylmanesium
bromide.
OEI
J
I
/O-MgBr
,)--C

I
H
Figure 6 Slruct ... of form I (Z) of lhe: mlnesium enolale.
carbonyl stretching vibration{l792- and 177()..cm -1 bands in BPO). whereas lhe 14I S..gn- 1
band is assigned lo he C-O s!retching vibration (1214 cm-
I
in BPO). Tbe observed
shilis are due 10 lhe dilference oC bonding energics from BPO 10 Ihe complexes.
The Grignard reagenl derivcd from lbe reaction of mesil)'1 mClhyl kctone aOO
el hylmagncsium bromide was studicd by Pinkus el al [11]. From elemental anal)'!i$, iI
was found Ihat the product fonncd wu as a monoetberate. The dirncric
slate or the product was derivcd from a molecular weighl analysis. The infrared analysis
of Ihe product showed lhe abseno: of a e-o stretching vibralion, bul Ihe presence of
two bands al 1645 and 1667 cm- ' lbal were assigned lO a e-e cooUe stretching vibradon.
aromatic e- e stretching vibration was airo observed at 1603 cm .,. From Ihis data,
along with lhe NMR anal)'sls. the dimeric stale structure (Fig. 5) was suggested.
The enoliution oC severa! ketones using Grignard reagenls was followed b),
Maroni Bamaud el al. [ 12]. Several dilferent structures were idenlified. depending on the
51arting ketone and Ihe Grignard reageot used. Only Ihe e-e slretching vibration regions
oC the inCrare<! speclra were invesligaled. Three dilferenl specl ral regions were idenlified.
The 1625 to 163S-an
'
region wu lWigned lO lhe presenCIe oC conjugated dienes. The
16SQ.. lo 166O-cm - 1 regi on was assigned lo tbe e-e slretching vibration oC an Ometal
species. It was airo observed that tbe inteosi!y oC tbe band found in lhis speclral region
was increasing wilh Ihe enolate content. A third specl ral region wu also idenlified
(1670-1690 cm-'), bul no correlation wi lh an)' Jlructure could be derive<!.
'"
DE'_
I
/O-MgB,
_c

I
'''"''
Flsure 7 Slruclure of form 11 (E) of lhe ml,ne:s;um cn<;>late..
Thc slruc1ure oC two different magnesiuffi cnolates (1 and 11) was studied by Pinltus
and Wu u.o;ing IR and NMR [13]. Form 1 (fig. 6) which has a Z configuration, was
obtaioed hrough Ihe reaclion or bcnzalacetomesitylcne and phenylmagnesium bromide.
Form 11 (Fig. 7) hu an E conligurati on and was obtained from Ihe reaClion or
2.2-di phenylelhyl 2,4,6-trimethylpbenyl ketone with ethylmagnesium bromide. The baods
al 1658 and 1650 cm - 1 observed in lhe c- e st rclching "ibration region oC lhe infrarcd
spcctra or bol" magncsium cDolates are in exccllent agreemenl with Ihose observed
previou! l)' for alkylmesityl ketones [11].
AEFEAENCES
l. W. B. PI"m, J. Cltmt. PIrJ'I. 5;172 (1937).
2. R. M. S.linger . OO H. S. Mod!er, J. Am. CMnt. Soc. 86: 1782
3. J. Krus aOO A.. Novak, J. OrgattOOilct. CIwm. 86:281 (197S).
4. J. Krus.OO A. J. Orfl<lltOl'tl'l. CMm. 99:23 (191').
,. J. Krt::5I . nd A. NOVlk, J. CIrcrt. 99: 199 (1915).
6. B. S. Aull, J. Am. Clwm. Soc. 101:3480
1. B. Groa, BulI. Soc. C"Im. Fr. 100360S (1961).
8. C. SoUI"lXI U, B. Pasquier, I nd J. Hervieu, Spnlrodlm. ACla JIA:287 (191S).
9, C. Sourissc:.u, J. Guillerrnet, Ind B. Pasquier, C. R. Acad. Sei. Paru 8:239 ( 1974).
lO. M. Okubo, K. Mlru)'al'lll, Ind J. Osu';' IMI. CMm. Soc. 44:136'
11. A. G. Pinklll, J. G. Lindbe .... . nd A.-B. Wu, CItmr. CommlUl. p. 13S1 (1969).
12. Y. Muoni-Bamlud, J. Berltlnd, F. Ghozland, L GorTiehon-Guisnorl, Y. Koudili, P.
R.. Ind H. NOrm.lnl, C. R. AnJd. Sd. PQTU p. 221 (191$).
13. A. G. Pinkus 100 A.-B. Wu, J. Org. CMm. 40:2816 (197S).
8
Nuclear Magnetlc Resonance Analyses 01
Grlgnard Reagents
JO-ANNE K. BONESTUl
ElI AfOCM'" Nonh AlINr /cQ, Inc XJ. ofPnuslo.
l. INTRODUCTION
Since Ihe 19SOs, nuclear magneti<: resonancc (NMR) has found widc application in Ihe
$Olution of chemical probJems. including numerous applications in tbe field of Grignard
rcagenlS. Chemical shitt and spin-spin-coupling data cDable Ihe chemiSI 10 detcnninc lbe
location of magnetically acti ve nucki in a molccule of inlcrcst, and lo ohllin preliminary
slructural infonnation aften nol readl)' deducible by othcr methods of spectroscopy.
Bc:cause or he quantum mechanical lime scale of lhe NMR nstrument, one can
slud)' ccrtain lime-dcpendenl phenomcna Ihat are nol generaU)' aCQe'lsible lO Ihe other
branches of specttoSCOpy. 80t h molecular motion and chemical e:lchange mar alfecr. Ihe
appcarancc of NMR spectra. This uniquc characlcristk hall importan! implicatiolU in !he
stud)' ofGngDan:! reagenu. This ehapter is designed lO provide infonnalion l o Ihe ehemisl
who uses NMR as an investigative tool. 11 i5 auumed that the readc:r has a buje
underslanding of Ihe theory snd praeljce o NMR spectroscopy. Those who do Dot may
find it helpful lO consul t onc of several exccllent texlt on NMR speclroscopy [ 1- 13].
In the experimenlal lpeclra and tibies shown in Ihis ehapter, lbe chemlcal shin.
given are Ihose measured from the particular referencc, wilhout susa:ptibility corrections..
11. PAOTON CHEMICAL SHIFTS IN GRtGNARD AEAGENTS
A. 01/.,..,1
Two pbenomenl have the most profound effect on the ehemical shifts of protons [19].
",
'"
These paramelen are:
1. The local dianUl9nefic contribution of the elo:<:lroo eloud around tbe prOlon under
oonsidcration
2. The effect of neighoori"9 atoms and groups 0 0 Ihe mokcule (IJ')
Within Ihis approximation, the influence oC substitutol! and ncighboring aloms is
tworold. Fint, lhe)' will alreel Ihrough ehaogcs of the electron densi!)' al lhe proton,
causcd by inductive aud mesomeric mechanisms. Sccond, electron circulation induced by
he u lernal magnelic licld, Bo. wilhin hese neighOOMng aloms aud groups will give rise
10 magnclic momen!! (i.c., sccondary ficlds Ihat changc 8 .... , al he prolon). Additonally,
clecl ric field and van der Waals effects ma)' be considcrcd, as weU as Ihe influcncc oC lhe
surrounding medium. Consequcntly, aD)' changl' in prolon screening ma)' be exprcssed as
a lum oC several Icnns:
( 1 )
whcre Ihe last four cont ributions stand for the magneti<: fi eld, electric field, van der Waats,
and medium el'fects.
8. mt.m.1 Dyn. mlc8 of Orpnle Mo*ulel
J. Dynamlc Proc.ss.s In Organomagnaslum Compounds snd Csrbocallons
InitiaJ measurements oC ethcr solutions uf methylmagnesium bromide and dimethylmagne:sium
are presented in Table 1 (14]. I n agrcement with earlier ob$er vations for alkylmagne:sium
bromide:s and the corresponding dialkylmagnesiurns [1 5-19], lhe: spcetra of methylmagnesium
bromide a nd of di methytmagnesium are very simitar. ool h in posilion of chemical shift
and in L l e- L H-coupl ing constanls. The posi t ion or the: methyl signal ror dimethylmagne:sium
was dependent on concentradon [ 16,17] and moved to a higher field as the cona:ntration
Tibie 1 Proton Chemical ShiIU oI"Methyl Magnesium Compounds
in Ether Solution'

Compound molll 6'!ppm
J L ' (>II/H.O
Temprq tJHz
CH,MgBr
,'"
- 1.50' 107
_ JO .,
CII MgBr .ro - 1.50' 107
_ JO .,
CH,MgBr 0.20 - 1.53 107
_JO .,
CH,Mgl l. .. -1.53 107
_JO .,
(CH.h Mg
."
- 1.38
_ JO .,
(CH,). Mg 0.18 -1.61 10S.S
_ JO
.'
(CH,IIMg O .... - 1.41 10H - JO
.,
(CHJIIM, 0.028 - 1.50 10S.S
_JO
.,
(CH.hMg O ... - IAI] IOS.S 3J
.,
(CH.I. Mg O ... - 1.41
IOS.S - 29
.,
(CH.hMg O ... - 1.47 10S.S
-"
"'
"""I"M ptOIon NMR dala aequ;'l>d on V.n.n A-60 SpCClromel ",i,h
TMS .. In inte,n.llI.ndard.
' UM ,.;,;!Ib . l lleiabt
$owC<': Re(. 14.
'"

, ..
""as lowcrc:d, luggesling Ihat lbe eXlenl of salvalian or he degree 01 associalion of
dimethylmagnesium varied with coocentration.
a. rntramolc(ular Exchangt Procu.sts
The allylmagnesium bromidc I consista of a quintel al ~ 6.2 and a doubkt al 6 2.5 ppm
in an intensity ratio oC 1;4, indicaling Ihe prescoce 01 an AX. syslem [20). This observation
is consistenl wilh rapid c:quilibriurn involviog he two sornen h and lb.
I 2 3 I 2 3
CH
2
CH--CH
2
-MgBl";:BrMg-CH=CH
l
-CH
l
t. lb
erolrl bromide and a-methylallyl bromide reacted with magnesium in tlber 10 yicld
Ihe same butenyl Grignard reagent (21). Given Ihe extraordinary behavior of Ihe butenyl
Grignard reagen! in a variety nf chemica] reactions, Young and Raberts (22. 23] inferred
Ihat Ihe corree! slructure was crotylmagnesium bromidc, as confinned by Ihe
iorrare<! evidencc (24] and IH.spectrum (21).
b. Temperalure Deptndenct
The applicalion of 'H_NMR spcctl'O$COpy 10 the sludy or Ihe struclure of Grignard
reagenls is rendered difficult by Ihe rapi<! inlra- an<! inlermolecular nchange procCl5eS
Ihal normany occur al room temperalure. Evans el al. (25] altempted lo overcome Ihis
difficulty Ihrough lhe use or fluorine-19 NMR spectroscopy, in lhe slOOy of fluoroaryl
Grignard reagenl5 alioli' lemperatures. Next, lbey described Ihe low-Iemperalure
' H-spectra ofseveral Grignard reagenl5 in lelrahydrofuran (THF) aOO diel hyl elher (OEE).
from which il was possible 10 dislinguish ~ R M g X M aOO ~ R 1 M g species.
Ashby el al [27] carried oul a similar lIudy on mclhylmagnesium bromide in dielhyl
elher. Unfortunalely, precipitalion precluded Iny quanlilllive measuremenl5.
Evans el al. (28] reporte<! Ihe ' H-NMR SpccUI 01 a vanely of alkyl and aryl reagents
in a number of coordinadng solvents. 1bese measuremenls were cailie<! out over 1
considerable temperalure range lOO, al lhe lowest temperatures, chemical exchange wal
on the ' H-resonante time 5CaIe.
For 3,l-dimelhylbutylmagnesium chloride 2, the prolon spcclrum has becn observe<!
10 be temperature-dependenl (29,30). Al - 53"e, an AA' SB' syslem is oblained, whereas
CH.
I
H,C- e -CH,- CH, N,cI
I
e".
2
3,J-dirnethylbutyt"'ll" dum chIoride
al 32"C, one observes a spectrum of the AlX
1
Iype (Figure 1). For a simplified explanation,
il may be a$Sume<! Ihat, alioli' lemperature, lhe compound exisls predominantly in lhe ',afU
cQtiformatlon 3. The observalion of an AA' XX' syslem is consistent wilh this conclU$ion.
The transilion 10 an AlX
l
means Ihat, al high temperalures, Ihe elfective chemical shif,
dilferencc becomes zero. Thi! indica les Ihal for Ihe spin-spin inleraction between the
A and X prolons only one coupling constanl exists. Thererore, the protons A and A' Ind
...

H
3
X and X' musl be magnetically equivalen!, Iha! is l bey exthange magnetic sitcs wilh one
anolher. TIte mosl plausible mechanism for such an exchange i, he inV1:rsion of the
carbanion . .. S, Ihat is isoelectronic with an amine. The activation entray ror Ihis process
1m. $
mlatlon
4
s
was detcrmined from he temperature-dcpendent Hne shape of !he: spectrum 10 be:
4fI8 kJ mol- ' (1I 2 kcal
"ta
.,.
k
',1.'

-10&'
Fipre I Spectra of CH)M p'0IOIlt of chloride in THF u
I runction of tcmpcraturc:. (From Rcr. 3(1)
'"
T.bIe 1 The H'- NMR Methyl Signals ror Mbhnts ofOrplK)IJIe\.lIic
Compounds in Ethcr Solution
Compoull<h (COIK., molfL) 5' / ppm
J nc.I\iM.
Temp re
(CH)I,M (0.26)+ LiDr (0.51)
-,..,
.-
-JO
CH,MgBr OS)+CH.U (O. 14) - 1.49
"
_JO
CH.MBr (O.35)+CH.U (0.35) - 1A1
_JO
CH,MaDr (O.14)+CH.U (0.56)
- 1.59
_.
_ JO
MaBr, (I .421+CH,Li (0.95)
- 1.55
'08
_JO
MaBr, (U3)+CH.U (1. 14)
- 1.52
' 08
_JO
MIBr, (o.7 1)+CH. U (1.42) - 1.38
10'
-JO
MIBr, (O.40)+CH.U (1 .63) -1.60
lO'
_JO
MiBl, o.01)+CH, Li (0.70) - 1.75
_.
_ JO
'l'e prolon NMR cbl.l wen: a:quircd .,., I V.rialI A-60 Spr:clromelcr .. lb
TMS .. u inlClllallU1ldard.
Sottr: ReJ".
'"
The 'H spect rwn of the mcthylenc roup of 2-pbenyl-)-mclhylbulylmagnesium
chloride [JO] Uso Ihows a tempcralure vari.tion suggcsliog changes in the rale ofinvcnion
(fig. In Ihis case, Ihe inverson al he -CHJ-M, cenler il slow cvco al + 66
e
C, and
Ihe !wo mcthylcne protons are magnclically nonequivalenl owing lo Ihei! proximilY 10 a
cenler of molecular asymmetry [JI).
c. l ntermolecul/Jl" E.u:nange Pro.:tJMS
Whi lesides el al. [14] elamine<! lbe 'H-NMR mel hylsignals of elher IOlutions contalning
the yarious mixtures oC magncsi um and Iitbium compoundl. 111e data are summaril.cd in
Table 2. Tbe cbcmical shifts and 'JC-'H-wupl ing constanl \lalues obscTved for the yarioUl
mixtures containing magnesium bromide suggcst the prcselJCe of equilibria [Eq. (1 and 2)]
Ihat are shiflcd lO the right.
2CH
l
Li + +(CH,hMg
CHl Li +
(1)
(2)
111e possible spccies prescnt in solulions oC Grignard reagents (small concenlrations oC
iOM being ncglectcd) can be represcnled by ID extended Schknk equilibrium [25,32,]]].


/
I
2M'9X
'--<:-.
_.-
./, JO
y'"
"
I
'--<:-,

, ..
Molecular weight dcterminations [34,35] indicate Iha! Grignard reagcol. in THF are
mODomeric; oonsequcntly. only lhe simple Schlenk eqllilibrium (Eq. (3)] necd be considered.
R
1
Mg+ MgX,=2RMgX (3)
However, in diethyl tlher, dimeric or polymeric specics all: apparently presen!, except al
low concentralions (bclow 0.1 M).
111. MAGNESIUM25
A. Overvl
The earlicst 'lUdies or "Mg NMR were explora!ory and used continuous-wavc
NMR technoJogy [36-40). In general, thcsc sludies sufrere<! from a lack of inst rumental
scnsit ivity. Ncvcrtheless, these exploratory !Iudies dcmonstrated the ability of l'Mg NMR
lo provide informalion on he chcmistry or complexation. One of he first applicalions or
Fourier transrorm I:hniques 10 UMg-NMR WIU 00 aqueous Ma
ll
electTolytes (e.g., MgBr,
and MgCl l) [41). Fouricr Iransform NMR made il possible 10 .!udy concentrali ons as
low as 0.002 M in natural abundance Mg
H
solutions in less than 12 h.
Mast earlier HMg_NMR investigat ions eoncenlrated on biological 'ystems and
inorganie complellCS (3,4,9,12, 13]. Roccnlly, the ehemical shin range of organomagnesiurn
compound5 has becn detennined (42,43). Thc: 15Mg chemical shifts and lioe widths at
halfheighl. can be used 10 clarify the mul tiple bonding, coordinat ion, and association
behavior of organomagnesium compounds [42]. Thc importance of the solven! and the
temperaturc al whieh Ihe NMR mcasurcment is laken should nOI be undcrcstimaled,
because these paramelers will afl"ect the Iype of specics prestnt in solution. lhe chemical
,hin, 6, and Ihe lioe width of the observed peak of Ihe specics.
8. Chernal Shltb .nd L!IMI Wldth,
Table 3 presenls 'Mg Jine widlh and chemical shif, dala obtained as a (unelion of Ihe
concentration of MgBr, and MgCll [41]. Also included in Table 3 are the visoosi ties of
the solulions investigated. Thc chemical , hifts, when correcled for bulk susccptibilily elfects,
Yary over a tOlal range of less than I PP'".
In THF, Ihe compounds R.Mg, RMgX, and MgX" wherc R is either an alkyl or
an aryl group and X is a halogen. are monomerie oyer a wide range of concentratiornl
[44). The yal ues of the 15Mg ehemical , hifts, 6 e' Mg), in THF for the alkyl aryl MgBr,
and dibromide compounds rclalive lo MgSO.7H. 0 in 0 . 0 , are bctwccn O and + 100 ppnt,
whercas the eyelopentadienyl (Cp) compounds are bctwccn - 30 and - 90 ppm (Fig. 2
and Table 4). The Jine widths at half height, .1/1' or Ihe 15Mg NMR signal of MgBr. in
THF vanes bclwccn SO Hz al 280 K 10 SS Hz at 340 K, with a minimum of 3S H1. at 330 K
[45]' This ndicates a transilion from a quasi-oclahedral [46] 10 a tetrahedral coordinated
species as a consequenoc of the eliminalion of two mokeules orTHF at higher temperalures.
The struelure for allylmagnesium species has becn studied experimentally and
theorctically [47, 48). Thc HMg_NMR of {C.H, h Mg indicates Ihat Ihe allyl groups are
!1-bondcd 10 he magncsium (see "C-NMR discussion).
BiscyclopenladicnyJ magnesium spccies have an unusually narrow .". of 100-500 Hz.
This is rationalized by penla-haplo bonding, ''1-Cp--Mg [42,43]. In these Iystems,
HMg-NMR spectroscopy provides a dircct contribulion 10 the discussion of whelher the
bonding is ionie or covalent [45].
NMR art wi'd Rw; ... ,.
T. bIe 3 Ma8"C"ium-15 NMR Dat.' ro. Aq"eO'lI
Mapc:si llm Sal! Solutions
Con<:. (m)"
b ..... '" (Hz)" "
6 (ppmJ"
MaBrl
2.70 6.s:OJ
'.0<
O.,
2.30 6. 1 o.2 1.17
.,
1.97 5.4 Q2 1.S7 ..
1.64 S.OO.2 1.43 0 3
0.90 J.9fO.2 1.19 O,
0.41 3.6fO.2 1.10 00
010 2.7O.J
lO'
00
M""
4.10 7.HO.) l .l 0.0
3.60 S.HO.) ... ,S
- 01
320 SJO.2 3.72 00
2.19 4.8o.:z 3.02 00
'.30 ".HOJ
, ...
0.0
1.30 3.8o.2 1.65 0.0
0.47 3.2O.2 1.11 0.0
0. 10 lHO.) 1.05 0.0
'N.tu", .bundance "M,,, ' .51 Mal.
'Cm"", .. tn.tion in moIaHIJ.
'UIK lridlha oont: detcnnincd u lhe ful"";':Hb .1
half.beht T.bul.ted nl_ le", lIt he .. oh!
I .... t , h_ dctmninat;"'" ";Ib \he error limiu lhe
",-"".n! deYi.tion 01 \he meuu ..... t nt.
"cbcmical shifu (tU ppm) reJa';ft lo lhe asnal ror
M.aoJ._ utrlpolltcd lo ;nftnit. dilulOII. More
posilioe .ll .... rd'cr 10 allieldina. Bulk MIIOePIibiJity
Wi, ... ioN h .... beocI ....
Sow<:t: Rd . l.
HgSO. -7K
1
D 1n 0: 0

" , - 10 !la
ItlB.
&UIg' Bt Mqlr2
" "
H . l
" .
3200 H!..L
-L ..J........I..
,


".
,.

..
'.
,>,,,
-u.,
"

l aS RJ
...L

-,.
-no
Flpre 1 Rangc or dlcmital Ih,1b for HMg derivat; YeI. (From Rd. 42.)
C. SdlIenk Equlllbf'lum
'DI
Spectrosoopy by lSMg_NMR has considerable adyantages oyer IH_ and 1JC-NMR
spectroscopy [41, 49, SO) in the study or the SchJenk equ.ilibria (ICe Chaptcr bc:cause
an three spedcs that are typically associated with the equilibria can be reoorded and
identilicd by thci r charactcristic chemical shif!:s.
".
_MIJ'U
T.bIe .. Magnesium-2S Nuclear Ma,Mti<: R_ncc Data' ro. Orpnic 5011llionl
of Maanes;"rn Compoundl Rclative lo MaSO.' l H,O 0.18 mol,lL) u Externa'
Rderenoe
Compound Solvenl Temp (K) 6 (lOMa) (ppm)
,v' /I
R,Ma
(C,H. ),M. THI" 310 99.2 3200
(nPr),M .. TMED .......
TMED'"
'"
110.0
'700
(e,H, ),M,' THF 310 10A 2000
Ph,MI' Diollne' DioulIe
'"
108.0 2800
Cp, MI' Toh.lC'ne' 310 - IS."
,OS
Cp,M,"nTHF THF 310 - 33.8 90
ep,M, THF 310 - 78.3 350
Cp, M,'TMED' TMED' 310 - 2S.8 50
Cp,M .. TMB()I Toluene m - )1.0
,.,
Cp,M'Oioxane Oioll.ne 310 - 48.5 - 300
Cp,M.'OME' DME' 310 - 49.4 73
Cp,M,'nPMc.' PMc,' 310 - 60.9 220
Cp,Ml'nOEI,' El,O'" 310 - 75.3
'50
epI"""
310 - 79.6 750
"cp,M,"nTHF THF 310 - J6.1 250
(Mg(ataChr THF 310
.,
650
RMR'
CpMIEt'" THF 310 - 4.0
' lOO
CpMJ(C. H, )"-' THF 310 - [4.7 710
CpM,Et
o
., THF 1I0 - 10.0
'lOO
{Indenyl)MEt' THF
3"
2 .. 900
CpM.MC'TMED" ...... TMED'" 310 15.0
, 1110
CpM,.OEt,- OEI, - 310 - 14.1 ,ro
aMaD.
MeMBr' THF 310 67.8
'900
EtMsBr" THF
,.,
56.'
, 1110
(C
J
H. )MS8 ... THF 310 19.7 1100
CpM,a .. THF 310 -26.8 ro
"CpMIBrTMEDA ... TMEDA' 310 - 15.0 300
(CpMBr<>Et , ), T"_ 1I0 - 31.9
,.,
MX,
MgCI , THF 310 16.4 350
MgBr, THF 310 14. 1 36
"N.tu .. 1 .bundanec "MI al 2 .... 9 MHz (11.. t ....
'OME _ dimetho.ylcl luo ....
.. hydrofu ...... ' PM .... trimothylphoophinc.
nPt _ ... propJl "OEI, _ (C, HJ, O.
"TMEOA .. wramethl1 diami.w. "C",,' -1.2. CH ,) , ]C, H , .
"C.H,: H,C .. qCH.JCH . " ...., _ (CH, COj,CH .
'1'11 - phenyl.
EI _ .lhyl.
'Cp:c]'dopent.d .... yI _ C. H . oep' _ (CH, I.C. _ M. ,C .
"SoIY<:nl" a mixlure of toIueae.1Id douLe:rlo1eCllol"".w.
' Me _ me\hl1.
'TMEO .. 1.2-biI( dime\hyt,..".lno):thlnc. 'C,H, _ H, C_ CHCH .
I"fMBO _ I.).bit(dimetbyl.minolbutano.
&w : Re&.. 42. .J. " .

'"
"

/\
"
-
,
10lm
,
r.n
..
fdlSK
"

Tol_
, ,
..


Fil'll"e J "Mg-NMR .pectra (24.49 MHz) of. 3.6 M lOI utlon or EIMgBr in THF a, varlout
lemperalure. Al 310 K (A) Ihe RMgX and MX. JpecieJ are directly identificd in lile jii StnCC of
OrK anotllcr. Thc prexllCC uf II..M, follOW$ frQm lhe ooalesa:na: behavior (8-0 ), and lhe
hish-temperaluTe spectrum lE). (From Rd, 42.)
The HMg_NMR .peclna ol organomagncsium halides (Grignard compollnds) IR: a
function of he concentration and lemperatun:I [44,SI]. For EtMgBr, Ihree spccics of lhe
Schlenk equilibrium can be detected concurrently al 310 K [41] (Fa. The rcsonanoes
for EIMgBr (6 _ 62) and MgBr. (6 _ 12) are resolved TIw: broader sinal ol EI1Mg is
overlapped by lhe EIMgBr signaJ. Direct evidc:noe for lhe presenCIe ol Et1Mg il provided
by he spe<:t rum al 340 K (see Fig. With ncreas-d lempcralure, thc equilibrium shitts
in he direction of EtMgBr [28,44). In average si&nal is [ouoo It 54 ppm. Furtber proof
is obtained by comparing lhe HMg_NMR data or EIMgBr wilh Ihal of MeMgBr. Tbe
equilibrium constanl for MeMgBr is larger Ihan EIMgBr (K 111::30 VI. K _3.1) [28,44], wilh
Ihe rcsulting HMg_NMR averaged signal for MeMgBr of 6-67.8, even al 300 K.
For CpMgBr, Ihe HMg_NMR signa! is funher removed from MgBrz, and the IiDe
width i$ narrow enough 10 quantiry lhe Schlenk equilibria conslants [42]. For a 1.38 M
soluti on of CpMgBr in THF, there are signals al 6_16.3 (2 mol %, MgDr,) and -26.8
(98 moW., When a 1:1 miJL:ture ar Cp1Mg and MgBr, is made in THF, lhe
nme ehemical shirts, line widths. and inlegration are rormed. The equilibrium conslant
is estimaled at K- lO', which is in agrec:ment wilh the value obtained by extrapolalion
lo 298 K.
IV. CARBON 13
A. o.ervt
Carbon 13-NMR is a routine means of eharacterixing organometallic compounds. as well
as a mechanislie probe [ S2- S6]. Tbe sensitivity of IlC-NMR is reflected in Ihe wide range
of ehcmical shifts and sea]ar coupling constants, J c-x, Ihat alloW$ for evaluation of Jubile
ehanges in the organomelallic species at tbe M-C bond. This sensitivilY has aOom
organomelallic chemiSls 10 evaluate fluxional processes and electron deloc::alizalion in
'"
paramapelie species. Sorne of {he advantages of 13e- IH_NMR for orgaDomelallic
pedes are direct M-C bond evaJuation, evaluation or unsalurated orllaDie Ipc:cics, signal
dispersion is much 8reater (ehemical .hift), and hybridization of lhe carhon aloms can be
obtained from Ihe IJQt-coupling constanL
B. Chemle.-I Shltb
1. Background
To a good approllimalion.1hree temn domnate Ihe IlCNMR chemical shirts: diamagnetic,
paramagnetic, and anisotropy ,hiclding ( 57]. Lamb dcvelopcd a tbeoretical
cllpression for lhe ditmltlf}Mlic tcnn Ihal focuses 00 Ihe electron densil)' al a spcdfic nuclcus
[S8]. Thcrcfore, one would expcd Ihe carbon's hybridizalion 10 have a aTge chemical shifl
clfed. Obviously. electron dcficicncy in a carbocation will proroundly clfcct lhe cheroical
shift [59-62).
The paramagnetic: lerm depcnds on Ihe num1x:r of eleclroos in Ihe 2p orbital and
multiplc oond contribution. ll1I ""di aJ the average excitation energy Af.. Thcrefore,
(erm wiJI have a significant dtllhielding effcet on 1[ For further di$CUS$ion the
n:adcr is referred 10 POple'l referencc [63].
Thc Ihird term anl$olropy includes the conlribution of electron currenlJ on neighboring
alOm$ or functional groups. This neighboring-group effcel il mOSI pronounccd at the
CII-carbon and diminishes by the inverse cube of the dislalH:C [51). Molecular gc<lmelry
also contributes to lhe anisol ropy termo Increasiog Itene bulk or the alkyl groups or
incrcasing the eleetron-wilhdrawing groups generate a downficld shift [64). Crowding of
shiclding helel"Ollloms rcinforccs an upficld ,hin. Intramolecular hydrogen bonding will
also afreel Ihis termo Thercfore, tllen: can be significant elrcets on the chemical shin by
chaogcs in conccntration, solvent, pH, and luch.
2. Experimental
Roberls et al. [6S] sludie(! aliphatic Grignard n:agenls in Ihe prescncc or huamc:lhyl -
phosphoramide (HM PA; Table S). Thcsc solutions werc thought to exisl as RMgX on the
basis of uC_NMR data, which is consistent wi th l he 'H-NMR data. Regiochcmical dala
can be oblained by ' lC_NMR analysis, as in he rcaction product or ciJ-4..f-bulylcyclohexyl
ehloride and magnesium. In this case. therc werc no I,J-diaxial steric compTC!Sion shin"
indicating that only lhe lrll1l.1-isomer was formed. Inilial work on allylmagnesium bromide
indicates tlle existencc or an ion pair (C1H;XMgBr*) in diclhyl etller solution.
Schlosscr et al. [47) attempted to elucidate Ihe bonding bctwccn lhe melal and Ihe
tarbon skeleton for organomelallie allylie spcciC5 (Structure Using Ihe isot opie
perturbadon te<:hnique dcvclopcd by Saunclcrs el al. [66--68), Schlosscr soughl lo distinguish
betwccn clmic and nonclassic carbocations. The lower zero poiol entrgy of lhe C-D
bond n:lalivc 10 the C-H bond [69, 10] rcsulls in a prcfercncc for ao olcfinie C--D bond
versus a saluraled C-- D bond. Thcrcfore, with the introduclion of deulerium ioto one of
tlle allylie lermioi, lhe proportion oflhe metallomc:r (Fia. 4b) should illCrease al Ihe upense
of e (scc Fig. 4) if they are preseot in equilibrium (dyoamic isolopic Indcpcndeotly
or the exehangc rate, scparate sigoals should appcar for the two lerminal carhon nuelei
lO l he right and len of the original signal. In Ihe symmlric sl ructun: (scc Fig. 4a), Ihe
deulerium would !cad 10 a slight, isotopic spccific, upfield shift (static isolopic
Thcdata from the spectra arcshown in Table 6. Thtl monohapto structure (a-complex)
is observed for allylmagnesium bromide in THF or dicthyl elher. The ehcmical !hirt ehangc
NMR A".".. (11 Q t",.nI Re;. 1111
nble5 Chemical Shllll 01 Alkyl OrilDan! C o m ~ ~
Complex ql) q2}
CH,M,I 14.S
C1H, MISr" - >9
1"
1I-C. H, MI Sr" 11.) 21.1
1I-C. H, MIBr"
, .
31.6
1I-C, H" MIBr" 7.' 21.5
i.w-C. H, MSBr"

22..
CydOhelylMCI"
24,4
".0
4+butylcyclohe.yl MaCI'" 22.9
"S
AHyl MIBr" S7.S 113.1
Cy<;lopmtadlcnyl MIBr" 10S.S
Cy<;Jopentadlcnyl MCl 103.1
CH.C, H. MCI 116.1 HM. I
l.J.dimc:thylcyelopentadio:nyl MISr".r 114.4 103.2
'All ehemielll $hin, in paru per mil1ion.
"O.t. coovertcd rrom CS.llandan! (192.8 ppm).
'C(CH,h, .J. 32.0 ppm; QCH,)., .J_27.6 pprn.
"CH ,.J. 11.1 ppm.
'Soc dlalralTll for numbering.
'CH,.J _ 1I.2 ppm.
/ . ~ .--, .....
lO
111: 11. H
fII : (Ht(Htl:l
111. (I(H,I,
'"
x H, O
",
ql}
21.1
lO.'
".l
lO.'
JU
SU
101.6
q.}
q"
."
"
"
"
13,2
"
m 13.4
"
"
" .
"
49.6
"
"
"
..
..
101,4 ..
Fipre 4 Equilibr.tion 01 lhe allyl roup in an orpnometallic romplel. (From Ref. 47.)
".
indicales IIn equilibrium distribution of (1 b)-MgBr/{l(c}-MBr of SI:49-52:48. The crotyl
and prenyt species gave simi lar results. Thus, as was already delermined by RobertJ el al.
[20,21,71] on lhe basis of proton NMR, the O'-complex with the mllgnesium Illtached to
lbe primary carbon is lhe prderred _Uylic Grignard reagent structure. The relative upfield
shin orI be 6(Cl) signalluggests a certain accumulation ofeJectron density at the .ubstituted
end of the .lIylic moiety. A polariring inleraction belwwu the metal and doubie bond
(partial valena:) may _iso be coruldered since lhe downfield Ihin of lbe 6(C
1
) ligna15 is
consistenl wilh Ihis etrecL
Granl el al. [73] attributed the large chemical shifis of q l ) and 02.6) in lne
IlC_NMR of pheytmagnesium chloride 10 Ihe changes in the average exatation CllCrgy
(Table n Another system, cyelopentadienylmagnesium halide (C, H, MgX) d0C3 nol
distinguish any of the inlermediate species that mighl exilt. and only one peak ji observed
T. bk 6 C.rbon-1J NMR Chemical Sltifl D.la or Grignard Re.genlo in
THF al 2$"C'
M X SI""IU!"!: oS (C') oS (C') 6 (C') oS (CH,) oS (e')
H' H Propene
MI O. H Altyl
MO. D' AlIyl
MIO. H' Altyl
MgO. IY Altyl
H' H 2- Oulene
2 0ulene
MgOr' H CrOI)'1
H' H 3-Meth)'I-2-bulene
MIOr' H P!"!:nyl
"01<111;""1 lhitts teIotiw: lO TM5.
" S7S
".0
58.7
S9.1
"
"
"
13.5
149.5
149.5
148.2
148.3
,,.
'"
'"
'"
'"
",
"Chemical lhift. el h)'dl"OCllrbolll ore Jiw:n ror DDmpl.n,.,n.
'" 57S
".6
58.1
57.1
,,.
"
'" "
'"
"
'"
" "
'"
26
"
",
,
"
<Milt<! oilllll .. risin. by O faS10nd fCWl1ible l .... n.,licn bel""n lWO m' rror-im.e . lrUC'U_
fr_n I lruo1" ..... """"Id Ippea. 11 22 Ind 92 PI"" ro. d (C' lo"" d ..... pecliw:ly
O'"' ..... licn in ,be X P"'i,ioft leado lO ,pI'llin, el , ... .!jO ....... 1 'o 1 :U I,iple'
(J _ 21 _21
"'c NMR chm!;""llhill in dicthyl e' .... soIutions fmm Rd. 12.
' W"'re 'wo Kric:I el ""m ..... lre Ji- fo. 1 .;roI,1 dc:ri' ''live. lhe uPI"I"' .. 1_ Ipply lu
1'" tIIJo-ianmc, Ind ,he "' ... " ror ,be n ... isnmcr.
rtht uppcr .. 1 ... in 1M .!jCH,1 nolumn el prenyl dc:riv.liva .de .. ' o ,be ..JI). .1Id 1M
"'_r .. 1 ... fo. , ... <ro i-"a, .
' No! f<COIIIiublc .1 U"C O .. inl 'o <:Icc:u.iw: btoadin, "" cook , IIICI!; (IfI nooIin (' o
- .lO"O , .. o 1OCJ'II .... 'c ...... b . P\lCfo' 11 18 Ind 26 ppm (11oe tlllcr by THf) Ind"
22 ppm " """ ... flni ....
Sawa: . .... 47.
T.ble 7 Chernical Shifu" of Al kyl Grignud
Complex
Q'I
02.6) 03,5)
Q')
07) QS) 09) Rd.
e.H,MgO'" 164.3 139.9 125.8 12"'5
C. H,eH,MgO'" ISS.1 123.4 127.3 116.1
(C. H.eH,hM .... IH.2 123.2 127.4 115.9
C,H, CH, MgOfH M PT"" 143.0 123.2 127. 1 1\3. 1
C.H.eH,CH. MgB ..
149.6 127.0 121.0 123. 1
C.H.(CH, ). MaB .... 144.3 127. 1 127.9 124. 1
'AII . hill. in ppm.
' Oo!. nonvertod (rom __ ... ndard U2tl.)
' 0.11 rmm es, ,,"ndOrd (1921
' FOI" n"mbrrin")'I1aD .... dlot...,.,..
.so. .... Rd . 13.
, . .
40CHaCHaCH' ''''8r
l "
" 22.2 6S
21.9 6S
24.6 6S
35. 1 10.8 6S
44.6 31.9 7.9 6S
p' m
Benzylmagnesium
chloride
Dibenzylmagncsium (ppm)
7
'"
in Ihe "C-NMR. This j, due lO tlK: ftuxiona.l bchavior of Ihe e,H, nng and he NMR
experimental time frame being too long 10 observe Ihe intermediate species.
Roberl! el al. [65] fOllnd Ihat the chemicallhilts of bcnzylmagncsium chloride and
dibcnzylmagncsium were ncad)' identical [Fa. 7]. This suggests Ihat both existed primaril)'
as RJMg in dicthyl etMf solulioD. The besl qualitative description orthe benzyl group rrom
Ihe bcnzyl Grignard reagenl is as a bcnzyl anioll. To support Ihi s description Roberts
[65] calculll.ted Ihe electron densi'y ror a bcnzyl anion and correlated Ihe electron
densi!y with a simulated IlC.NMR, which correlalCS wilh the observed spcctra ror
bcnzylmagncsium halide. Howcvcr, here is sorne covalent character in lhe MC-C bond
Ihat prevents a precise matth,
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n.
26. D. F. Evan. and G. V. Faukeny, Cltmt. Comm ..... p. 974
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40.. R. O. Bryanl. J. Mag". 6: 15!J
-4 1. L Simerat 100 G. E. Maciel, J. PI/y" CM,". 80:552
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-43. K. Mebler, Lehmkuhl, R. Benll, A. RuHnska, Ind C. Kruger, CMm. Btr. JJ9: 105-4
44. E. C. Ashby, Q. Rn. CIw",. 5. 21:59 ( 1%7}.
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-46. F. SehrOder '00 L Spandau, Na/u""WnucIoafttn H:360
47. M. Scbtouer aoo M. SlJihle, Angt' .... CIItm. hltl. EJ. &!g/. 19:487
018. T. Oark, C. Rhode, Ind P. von R. Or[JQllomelalllcJ 2:1 344
49. W. Ford 100 J. Orulvlcr, J. Or[J. CM"' . J7:2S61
so. G. Parris and E. Ashby, J. Am. CMm. Soc. 9J:1206
51. R. Benn, H. Lehmkuhl, K. Mebler, and A. Ro.I nska, J. O'{lQllomt'l. CMm. 1\IJ:1 ( 1\185).
52. B. E. Mann, Adu. O'[Jtlllomer. CIwm. 12: 135 (197-4).
S3. M. H. Cbisbotm 100 S. Prog. l/IOI"fJ. Clwm. 20:299 (11116).
5-4. O. A. Gansow and W. O. Vemon, To, Car/xJlt-/J NMR Sptclrosc. C 2:269
SS. L 1. Todd and J. R. Wilkinson, J. O'fJanonte/. CMm. n , l (l91-4).
S6. P. W. Jotly and R. MyllOtl, Adu. OrfJ01tO"'t/. CIovt<. 19:251 (1981).
57. E. Breitmaier and W. Voelter, ClU/xJIt-/J NMR SptClroscopy: Higl/ RtJoiJIrlOOl tvtd
ApplICIJ//OftJ '" Or[JQIIIc CMmis/'Y /Uld BIocM,"/'Y, 3rd (ldn . VCH PublilMIl. Ncw York, 1987.
58. W. E. Lamh, PI/yJ. Rn . 60:817
S9. G. A. OJah I nd A. M. While, J. A",. CIwm. Soc. \1/:5804 (1%9).
60. G. A. Olah, CIwm. 11/1. EJ. &g/. /2:173 (1973).
61. O.E. Macid and O. A. Bcally, J. Plly, . CMm. 61:3920 (1% 5).
6.2. F. Wchrle, J. de Hu n. A. Keu$ernaltl, O. ner, and W. Simon. Hcro. CI/lm. Acla. 52: 103 ( 1969).
63. J. Popte, Mol. pI/YI . 7:301 (1\1604).
64. D. M. Oranl and V. B. Cheney. J. A", . CIwm. Soc. 89:5315 {I %7}.
65. D. Leibfritz, B. O. Wasner. 100 J. D. RobcrtJ, JIU/W AM. CM"' , 76J, I7)
66. M. Saunden, L Ind M. Klles, J. Am. CMm. 99:8070
61. M. Saunden 100 M. Kates, J. A",. CM",. Soc. 99:807 1 (1977}.
68. M. Saunden, M. Kates, K. Wiber" and W. Pral!. J. A",. CM",. 99:8012 (1977}.
69. L Mclander, EJfu 011 Rcocliolr Ronald Press. New York, 1960.
70. M. Dewar. HyprrCfHlju(Jalion, Ronald Preq, New York, 1%2.
71. O. W. Whitesides, J. E. Nordlander, Ind J. D. Roberts, J. Am. CMm. Soc. "4:2010
72. G. D. Slucky, J. A", . CM"' , Soc. 92: 1150
73. A. Jones. O. Gran!. J. Ruuell, . nd G. J. Pllys. CMm. 7), 162-4
P"NO"
9
Crystal Structures 01 Grlgnard Reagents
ItAEWON L UHM
El! Atocltit", Nonh A_rica. lile., KIIII ofPnuskl,
1. INTAODUCTIOH
TIlo: natUTe of Grignard rtagcn!s hu beco sludicd by both physical and 5pa::lroscopic
techniQues. Thcse havc shown Ihat he reagent bccomcs a complcx mixture of variouI
magncsium compounds in saludon [1). TIte isolation and Ihe characterizalkm of hese
dilferent compounds havo: helped in understanding Ihe composition oribe Grignard reaeol
solution. In recenl )lean, cryslallographie metbods havc given conclusive evidcooe for lbe
presence of some of lhe componenls.
In simple lennl, soluliollll of Ihe Grignard reagen! follow Ihe: Schknk equilibnum
[Eq. (1 ): 1]. The chemistry is dependen! on many faclors(e.g., solvent Thc compoundJ
presenl in snlution consi,! oC he compounds dcpiclcd in &j. (1) as wcll as compounds
fonned Trom lhe aggregation oft hese basie organomagnesium monomers inlo Ihcir dime.."
!rimen. and so on.
(1)
A considerable amounl of importanl dala can be gained from Ihe crystal slructures
of organomagnesium compounds. The bonding and ooordinalion modes of Mg
observcd in Ihe cryslal Slructul"C$ ive evidence for lhe pouible SlructUI"C$ or lhe compouDds
in solulion. The reactivilY of Ihe complexts can abo be intel,ed from lhe slructure of lhe
organomagnesium complexes. However, il muSI be realized Ihat Ihe cryatals do not
nec:essarily reflect Ihe components m solution, and conclusions should be drawn only in
conjunction wilh olher data [e.g., nuclear magntlic rcsonancc; NMR (lite Chapler g) and
associalion mea.suremenU].
. Briefty, severa! methods have proved successful in providin X-ray-grade organo-
magnesium crystals. These methods indude slow sublimation, It!CJ")'lIallization from
nonpolar solvenls (al kanes or toluene), and mixed solvent ayslems in which a nonpolar
'"
'"
solven! is added 10 a Grignard solut ion. Auempls 10 remove lhe coordinated by
!!ealiog IInder V8cuum U$ually leads 10 he dl.'COmposition of lhe R group. Desolvation of
RMgX (R .. Me. El; X .. Cl, Br) gives a of MgX1 and [MiRJ]. [2]. The
disproport ionation is racile and follows he order Cl > Br > I and Me > El. Thi! rellects lhe
propensity for ligand bridging.
Grignard reagents refcr 10 compounw or lhe type RMgX. bul lhe SchJcnk equilibrium
has indicated Iha! diorganomagncsium compound$ and MgX are also prescol in Gripard
solutions. An un<krstanding of he chcmical bandiog rcquircs he X-ray struclurcs of bot h
organomagnesium compounds and magnesium dihalide compounds; a discussion of aH
lhese compounds will be given in Ihis chaptcr.
11. STRUCTURES OF HALOORGANOMAGNESIUM COMPOUNOS
The crystall ine forms orGrignard reagcnl! are eompouDds of lhe: typc RMgX. However,
these: compounds have proven to be diffieult to crystallize. The erystall ization process
u$ualJ y gave a MgX, precipitate a nd a soluble organomagnesium oompound with a probable
[Mg R) X] composition [3]. Sueh difficulties were surmounted by studying the Br
derivatives.
A list of haloorganomagnesium oompounds, wilh ltnown crystal strucluces and lhei r
bond Ic:ngths and angles, i5 given in Table 1. Also included in Table I are oompounds of
t he Iypc R M gX ' L, in which the coordinaling solvenl is replaoed by a stabi lizing ligand, L
A. Trlc:oordln.led H.loorpnomqneslum
Steric faetors lead 10 deviatiom from the normal telrahedral coordination around the Mg
a lom. The eryslal Slrueture of chloridc monodiethyl
ctherate ( Compound 1] indicates Ihat the oompound has a trigonal planar eometry [4].
The unus ual coordination resul lS from Ihe sterie bullt or the lrimelhylsilyl group which
prevenl! the eoordina tion of a sec.:ond el her solvent.
Compound 1
B. TetrlCoordlnllled Halogenoorganomqn .. lum
Most of the er)'s .. ! struetures or Grignard compounds a re four-<:oordinate and have a
distorted tetrahedral st ruc1un::. The monomerie oomplex has Ihe struclure RMgXll
( Compound 2J whcre R is the organie group, X is the halide, and l is the coordinating
solvent THF or ethel'1) [ 1]. The compounds deviate sl ightly from ideal letrahedral
gmmelry. The C-Mg- X bond angle is reater Ihan Ihe regular lelrahedral values and
Ihe l-Mg- L bond angle is smaller. An examplc is lhe er)'!lel slruelure or EtMgBIiOEt1)1
[ Compound 3], which has typical values fOf Ihe bond lengths of Mg- Br (2.48 Mg-C
p' m
".
T.bIe I Relevan' Bond ungthl (jand Bond Anllc!lr)from theCryttal SlrUC1U1l'1 al Haloorpno-'
mlIllnes;um Compounds
Compound C-Mg--X L--Mg--L M-C MS-X MS-L Rd.
MgBrEI(OEI,h l2S 101 W 2.48 l04 l
MgBrPh(OEI,} , . ,..

l .. lOJ l8
MgNrEt[( - )-partcinc] 11l 84
l"
l48 III

MgCI(r-Bulyl)- I1l 84 ll' lJ3 l17 17
(( - )-sPlrteincJ
MaDrEI- 112 l22 III ll.
" [( - )-asosparteine]
MgOrEI- 111
"
l34 III ll' oo
[( +
[ MgBrEI(NEtJh ll'
l""
2.18 lO
2.567
(M.BrEI(OEI,)), ... 93.2 2.1\9 2.019
'1
[(Np,Mg), {NpMgBr),l. 118.6,100.6, UO-2.29,
l", -
12
108.1,122.6 2.33--2..42 2.818
(EtMgCI MgCI,{THF),], 9S.4,125.9 89.6
ll'
l .. , 2.[ 4.2.11, l.
lOO l04
[(1-BrMg-2-pivaloyl- 104.3 91.9, 82.1 224S l622 2. 146,
l'
tel rah ydroq u i noline" 2.136, 2.236
[THF),
S- 128.2 llO 2517 2. 12, 2.13, 11
cro"'n-4
2.33, 2.49
2- BrMg- I,3-l.ylyl-18- 2.176 2.597 2.126--2,331 17
cro .... n-S
CpMgBr- 12l
"
l21 2.63 1
EI,NCH,CH,NEt,
]- 12l
"
2167 2.52 2.269.2.230

MDr-TMEDA
[('1'-AUyl)MgCI'TMEDA], 12129 80.28 l179 2.400.
Il
l'"
(Ph.qMgBI'(OEI,h [[6.4 101 .5 12l 2,465 2.02, 2.04

(21 and Mg-O {2.03 and 205 Al liS well as bond IIngles or Br- Mg-C ( 125.0") IInd
O---Mg-O ( 101) [5].
CompouMs 2 . nd 3
Crystal structures are more numerous ror compounds or Ihe RMgXL" in which L
i5 nol reslriclcd lO coordinaling solvenls, bUI can inelude any neutral ligand. These
compounds are: generally solida and easier 10 cryslallize inlo X-ray-grade single crystals.
12.
....
The cryslal structures are pseudotetrahedral, with he dislorlion beinl! dependenl 00 lile
stcric requiremenls of he ligand L. Thc eJect ronic ctrect of L can al$O resull in varialions
in lile bond leoglhs. The ayslal struetures of Grignard complc:tes with optically active
sparleinc ligandl charactcriu: he variatiool hatean oocur [6]. The EtMgBr - )-sparteine]
oompound [Compound 4] has a typica! M-Br of 2.48 A, a Mg-C (2.24 and
Mg-O bond IeDglh! (2. \S The bond angles are smaller, probably duc 10 he grealer
Sltri<: constraints mpo$! by lhe sparteine ligand.
r
" /"
'-../ '",/
\
9i-'1Ii El
Compo;! f"
A s.imilar distortcd tettabc:dral geomc:lry was obscrved in lhe Cl)'$ta1 structurc of Grignard
compouDds with delocalized anionic ligandl. The strUClurc ofCpMgBr(Et JNCH leH lNEt J
(Compound 5] has Ihe eJlpcctcd large Cp-Mg---Br angle (1251. bul a mueh smalk:r
N- Mg- N angle (83") [7). The iODie Cp ligand results in a longer Mg- Br bond (2.6)
A similar cryslal Slruclun: was determined for lhe subsliluted Cp derivative, (,, ' _1,2,4-
(Me)Si)Cp]MgBr-TMEDA (8].
Compllu'" 5
The normal dislorted tetrahedral gcometry was also determined iD Ihe cryslal structurc
or (PhlClMgBr(OEI))z (Compound fi] (9]. JI i5 of inlerest becausc il docs nol dissociate
inlo its ionie: parts (untike PhlCLij, and Ihell: i1 no interaction belween Ihe M and Ihe
phenyl roup5. Thc negalive charc from Ihe organic roup i, partiatly dcl ocalized and
mults in a loncr Mg-C bond length (2.25
CompollDll fi
'"
Grignard compounds can a1so cr)'slallize 8JI dimen. usually when Ihe recrystallization
solvenl is wcakly coordina!ing (c.g., tricthylaminc or isopropyl ether). Tbe slruclun: con,i,t,
oF two tctrahcdral Mg aloms Ihat are bridged by IWO haJogen (X) aloms, and each Mg
atom hll5 onc terminal R group Ind one coordinating SOIVCDL 11Ic cryltal structurc of
[cthylmagnesium bromide-triethylamine]J (Compound 7] hu Mg- Br bonds of almos!
equa] length (2.566 and 2.561 A) and lhe Mg
J
8r
J
has a sqUln: typc formalion
(Mg-Br_ Mg_ 86.8
D
nd Br- Mg- Br _ 9J.2) (10].
Com,tF ,td 7
Grignard compoundt with ,Iltoxy orpnic rou", do nol have Ihe same halogen
bridgcd structure. An X-ra)' structure oC [MBr{OBu'XOEtIllz (Compound 1] has
demoDstraled Ihat il il an alkolly.bridged dimer [11].
Comp:a ,, 8
Grignard compounds of Ihe Iype RMgX. wilh no coordinaling solvcnt molecules.
are inclined toward polymcmation (12]. Growing single crystals oC polymers i.s very
diffk:ult. The crystal structure of an adducI, [(NpzMsh{NpMsBr)lJ. [Compound 'J,
indicated Ihal it wu a polymer cbain of Ihree MgNpZ rinp altcrnating with onc MJzBrz
nng [12]. 1I WaJ lhe finl crystal struclure of a simple alkylmagnesium halidc wilh no
solvcnl molecules.
"
C. Plnt.COMdIn8te4 HlloorgPOmI"".,lum
geomelry is observed ror Grignard reagents Ihat nelude mall lipOOl.
T!tey U$ually allain a distorted lrigonal bipyramidalslructure and a lisl of lbese compounds
js given in Table 1. A Iypica] monomerie aysla] slruelure is given by melhylmagnesium
bromide Iris(lelrahydrofufanate) [Compound 10] {n]. The Me and Br ligands remain in
a cis-oonfiguralion, and l!tey are mutuaJly exehangeable. The Mc-Mg- Br angle of' 126
0
is grealer Ihan
Compo4lnd 10
Pentacoordinalion can also resull (rom aggregalion or Mg compoundl. One SlIch
compound i$ an elhylmagnesiLlm chloride-magnesium chloride adduct, [EtMga-MgO'
(THFhJl {ComK)und 11] [ 14]. The cryslal st ructure confirms Ihal il is a telramer wilh
chlorine-bridged Mg aloms. Two of Ihe Mg atoms are penlacoordinaled lO three e ls, ODe
El group, and one lelrahydroruran solvent. The remaining Mg aloms are boLlnd 10 four
a ligand! and Iwo lelfahydrofuran ligands in an pseudooctahedral symmelry.
CompolUl!d II
TIlc ((,,'-allyl)MgCI'TMEDA]1 eomplel [Compound 12) has a ehlorine-bridged dimerie
SI TUcture [ 15]. Tht compound can be considered as an associal ion of Iwo monomers,
since the Mg--CI bridge$ are nol ' ynunetric (2.400 .00 2.694 A). Tbe Mg-C bond i$
typical, and thcre is no interac::tion betwecn Mg and the other carbon atoms.
D. H ... c:oordlnall'Cl Haloorganomagne.tum
Hc:xs(:()Ordination around the Mg atom OC:CUI"$ when an intramolcc:ular (:()Ordinaton takC5
place. An cumple or an oc:tahedral-type structure is given by l-bromomagnesio-2-pvaloyl-
tetrahydroisoquinoline{fHFJ, [Compound 13] [16]. The Br and organic group of he
quinoline are io Ibe cls-ooofiguralion, wbich is Iypical of Grgnard reaseots. Agaio, the
C- MS- X angle or 1 4 ~ is larger Ihan tbe anticipated 90". The lack of steric c::oostraiots
allo ..... s ror bisher c::oordioation. The I h ~ THF ligaods are in the rcmaioios axial aod
equltoral positiol1$ .. Tbe preferencc: for hcxacoordination problbly.iso l"C$ults from thc elttr"ll
stabilization that is achieved by [onnation of the chelating ring.
Compound. 13
One group of crystal structul"C$ of hc:xaroordinatc:d Grgnard c::ompounds involves
crown ethen, and an example i.s the compound. 2-bromomagnesi o-I.3-xylyl-I S-c::rown-4
[Compound 1 ~ ] (17]. The ay!lal structures of tbis Ind othcr ero""'n ether compounds
Compound 14
, ... ,,"
".
give a distortcd octahedron consistiDg of Br, e, Bnd lhe four oKygen aloml bollnd 10 Ihe
Mg atom. The oxygen aloms Deares! lhe JI)'l)'1 roup are onl)' weakly bound 10 Mg.
Hexacoordinated Mg can also be attained wilh opeo polyethcr ligands. Disloned
OC1ahcdra] gcometr)' results when Ihe polyether group has Iwo, hree or fOUT
intramolecularly bonded ox)'gen atoms. A Iypical cryslal structure is given by
o-[CHJ(OCHJCHJ)JOMeJ-subsliluted phcnylMgBr [Compound 15][18]. The Mg atom
is bouad 10 one phenyl carbon snd Iwo oxygen atOIllll of lhe polyelhcr ligand in lhe
equatorial plane, with he third oxygcn occupying an u.ial positioo around Ihe Mi atorn.
Thc remainiog coordination sites are takcn up by lhe halide (Br) Bnd tetrahydrofuran
ligandl. Thc numbcr of ooordinatcd solvent molecules is dependen! on lhe numbcr of free
coordination si les arollnd lhe Mg alom in ils psclldooctahcdral ,tale.
,
O
Compound IS
The highesl coordination slate of Mg i, hexacoordinatc. even when further
inlramolecuJar coordination i, possible. The MS of Ihe crown tlher oompound,
2-bromomagnesio-1.3-xylyl- IS-crownS [Compound 16] [17], is coordinalcd 10 only four
of Ihe live oxygcn atoms as weJl as lhe Br and lhe aromat; carbono
CornJII'*M 16
Aggregation has nOI becn obscrvcd in hexacoordinated Grignard rcagenls., probably
becausc of bolh cJ.ectronic and , Ieric oonstraints.
111. STAUCTUAES Of DIOAGANOMAGNESIUM COMPOUNDS
The oomposition or a Grignard reagc:nl in solulion also ineludes ,mall amounts of
diorganomagncsum oompollnds (MgRJ) jn jls monomem, dirneric, ami highcr aggregale
rorlll$ (2). Crystals of diorganomagncsillm oompounds are mllch ruier 10 obtain relative
10 Grignard eompollnru. The compounds can be cryslallized from a polar solven! (ether)
la
Table 2
Relevanl Bond Lengtlu (A) and Bond Anglea rJ rrom lile Slrudutel of Diorgano-
magnesium CompouMI
Compound C-Mg-C L-Mg-L Ms-C
Mg-L Rcr.
MMerfTMEDA)
D'
"
W l2<
"
MgPhpMEDA)
'"
83 W U
"
Mg(o-CH
1
carboranyl) (p-
'"
'00
".
2.'"
..
dionnc)
MgMe,(quinuclidine), 12.
".
".
2.24
"
122
"
2. 13 2.03
" M /Ilp-tol )'1) lIT H F) 1 1224
" .2
2. 127 >OJO 26
[Mg(p-lolylhrrHFJ,l 102.S ns 2.313,22.(5, >020 26
2'JO
[ MMe.J.
IOl 7l 224 38
[MgEt,].
, ..
72 226 38
[p- 128
"
32
dioune]
[(CH,), Mg{THf),), 141 ,S
" .
2. 15,2.l J 2.089.21 10 31
[o-XylidcncMg-(THF).], m.a, 94.1, 94.0 lLS4,5.158. Lon, 2.063, J6
3O.S 2.17Q
2'"
(1,8 NapthalcnediylMI"
-
2.IS, 2.28, 201
" THF].
2"
[(Me,Si),], Mg
'80
2.116 21
[(Me ,SihN Mg(s.Bu)], 92.9 2 ..
2,118 22
, Ph C=C), M,iTHF). 88.2 2. 175 2.382. 2.)74
"
(fh
'80
.. 2.176, 2.200 2.375 42
(f. Bulylclhynyll, M" 2.115 2.372, 2374
"
(n.1EDAI,
(E I M &(2.2.1-cryptand)], 106.8, 2.36. 2.238, 4J
EI , M8, 114.4 2209
[NpM(lll-<:'1Pland)],' 11M, 11 7.6, 2. 121,2.240, 4J
NP.M 124.8
2'"
Che<:k name 121.8 89.0 2. 127.2. 1S4 2. 142, 2.377
" [McMg{l S-cmwn-1)' 10U- 2. 140, 2.25- ..
Me. MI,].
llS.2 2.391, 3.21
[El, 18-cown-6)]
'80
"'"
2.767,2.792,
"
2.778
MgCCp) .. aas
,..
2.339 2008
"
M(Me,Cp' gu
,..
234'
2.011
"
M(Np).-gu
-
2.126 1.S41 20
M(CpKNp.,gas
' 80
"a
212 20
and can also be healed lo crystals. Hence, more cryltal IlruclUrcs are
known for diorsanomagncsium compounds Ihan ror Grignards. A list of lhe bond Icnglhs
and angles of crystal structures of diorganomagnesium compounds is in Table 2.
A. 01- . nd Trieoordlrq,,", Dlof"g.nomIIgne.tum
Thc simplesl organomagnesium eorqKlUlllis consist of Mg atoms coordinated 10 IWO
organie groups (MgR,) in a li near fashion. Gas-phasc electron difl"raction has bcen used
,..,
10 study the cycJopentadicnyl [Compound 17) [ 19] nd Deopentyl (Compound (8) (20)
dcrivat ives. This method is limited by lhe hennal inltability al many orsanomagnesium
compounds. Thc hcal requircd foc volati lizalion cau!iC$ man)' of l he compounds 10 lose
heir coordinated solvent and fnnn a nonvolatile polymer.
,
,
,
'"
,
\ (:'5 1
CompilEnds 17 .nd 18
Unlike Grignard reagen!s, crystal structures of dicoordinated organomagnesiurn
compounds are known. These are formed when stcricaUy hindercd [inds cause uce5lIive
crowdin in he cnvi ronment aroli nd he Mg atom and preven! lhe coordinalwn of an)'
$Olvenl moleculcs. Thc X-ca)' st ruC1ure of bi s[tris(trimethylsilyl)met hyl]magnesiurn
[Compound 19] ndicales Ihat he compound is linear (C- M-C_ 18O") and il
centrosymmctric around lhe MS alom [21]'
oo,
~ 13
-
- ~ , . ~ .
\',..,'
S"
Is
Com,ound 19
Tncoordinated organomagnesium species resllll from lhe replaccment of the salvent
by 1 slericaUy oonstrained R grollp. CrysllJS can be obtained by the use of In apolar
cryslallizio solvent. A typical crystal $I ructllre of a lricoordinale spccies is Ihat or
src. blllylmagnesillm hexamelhyldisilazanc [Compollnd 20], which has a symmetric
four-membered Mg, N cyclc (i.e., all Mg- N bond Icnsths are ick:ntical) [22].
Compoulld lO
Pseudo di- and tricoordinated cry5tal structllres are known for Mg oomplelles wilh
cyclopentadienyl and indenyl grollps. The magnesoccne oompound CPIMg [Compound
11] hu a linear Cp--Mg--Cp strllctllre in which lhe Cp groups are staggered [23]. The
tricoordinate inden)' 1 compounds [Compounds 12 and 23] have two di lferent crystaUinc
p' m
07' 1' $InIt;turH 01 Grlptlfi'd R .. , , "t.
environmenl5, both of which have a monomc:ric: MlICinden),l}J struclure [24]. The MI
atom io Compound 22 i5 ,,'-honda! lo one indenyl group and ,, ' -bound 10 IWO iodenyl
groups. Compound 23 has ODe ,,' Mg-iodenyl bond and two ,,1 Mg-jndenyl bond$. These
novel l lructures probably result from the packiog orthe indenyl groups in Ihe cryslallattioe.
CompouLMIs 21, 22, .... 23
B. rltTloeoordln.t.d DlorglrlOm."",.lum
The normal mnde of coordination for organomagnesium is much Ihe same
as for Grignard compounds [1]. The crystal sl ructures are oC the form MgRR' L, in whicb
R and R' are the samc: or dilferent organic groups and L refers lo a salvenl or a neutral ligand.
The crystaJ Itructure of diphenylmagnesium'bis(telrahydrofuranate) [Compound :W]
has bond Ieogt hs and angles tYpK:al of diorganomagnesium compounds. The C-M-C
angle oC 122.4 is latger Ihan in the Grignard compounds and lhe O-Mg-O or 94.2" is
smaller (25]. An uousual feature of lhe p-tolyl analogue il Ihe presence of both Ihe
monomer [Compound l!] and lhe dimer (Compound 26] in Ihe crystalline slate [26].
This jndicales Ihal bolb monomen and dimen are presenl in soIution. The crystaJ slructure
of Ihe monomer is similar lo Ihe pbenyl complex. The Mg alOnu in Ihe dimer are bridged
by Ibe lViO lolyl groups Ihrough a three-ccnter, two-electron bond. However, lhe bonding
is unsymmetric with one long (2313 A) aOO one Ihon (2.245 A) M-C bond per MI
alom and bolh are longer thao the terminal M-C bond length of 2 130 A. The dimer
could Ihus be considered as Iwo Ilrongly associaled monomen.
Comp4lZEl dl U, 25, ... l6
The crystal packiog of organomagnesium compounds has shown Ihal inlramolecular
coordination js preferred over IOlvenl coordinatioo. Thesc oompounds have a tetrahedral
geomelry. The cryslal struclure of [MeO(CH1),hMg [Compound 27) odicaleS thal Ihe
,,.
MI has a distortcd lelrahedraJ envimnment, .... ilb a large C-Mg--C angle 01 140.2
0
Ind
a . mall O-Mg-O angle of 96.4
0
[27). The ( o- pyridyIXMcJSih C]zMg compound
[Compound 28) also has a distorted tetrahedra geomelry around Ihe Mg alom [28].
However, a greater rina slrain result, froro he four-membered r;ngs and, hence, there 1,
a Jarger variation in Ihe bond angles.
ComP'"'ds 27 ,lid 28
Thc X-ra, slructurc 01 ([2,4-dimcthyl-2,4-pentadienyl}zMg-TMEDA] [Compound
29] show! that an I _ t y ~ Mg--C bond ia presen! [29]. No inleraclion is observcd bctwecn
Ihe Mg alom and Ihe remaining carOOn atoms 01 Ihe pcntadicnyl lipodl. A 'ypical
tetrahedral coordinalion and normal Mg-C and Mg-N bond Ien,lhs oa;:un.
Monomeric tctrahedral oompounds can also be achieved by Ihe use 01 triJ-<:belating
Iigands. The cryslal structures of several [triJ(pyrazolyl)hydroborato]alkylmagncsium have
sho""D that hey have allorter Mg--C bond lenglhs (2.10--2. 18 A) and a Iypkal uample
is given [Compound JO] [JO).
Compcl .... 30
Dimeric diorganorganomagnesium compounds also have dislorted tetrahedral
eom<:tries. The compounds [MgPh}(OEI1)1) and [MgEt}[OEIJlJ art known 10 be
".
dimeric in solution, bul CT)'slallizc as monomcI1I. This predominanoe for dimcric spccics
in 1IOII.IIIon ulually givcs rile: 10 polymeric 01 cyclic complexct. The Cl')'JlaI slructure af
(Compound JI] ShOWllhat lhe Mg atoms are in a 12-membcred cycle
(Le., lhe organie group linhlhe two lelrabedraJ Mg atoms) [31). Tbi. results from the
Contpu di 31
association af the monomcn. Thcnnod)'Damica1ly, lbe eolbalpy factor (ring strain) prefcn:
he six-membered cy<:lic monomer, wberea. lbe dimcric compound is favored entropically.
A similar compound, [Mg(CH
z
4(p-diollaneIJz{p-diollaDc] [Compound 32], .Iso has Ihe
same dimeric structural base [32). Howcver, Ihe oompound forms polymer nctwork
through Ihe dioune oxygen aloms. Crystal structures ol Ihis Iype are rare, siDee lhe
ill$OlubiJity of noncyclic polymeric .peca mate lbem difficult 10 solate as sinlc: crystals.
".
Campen d 32
The crystal structure al (N,N-dimcthyl-l.ami nopropyl)MgEtlz [Compound 33]
indicates that the Mg atoms are bridged by the organic group through two-dectron,
thrce-center bond, in which lhe carbon atom has a pendant group that intramolecularl)'
bond! lo the Mg alom [33]. This fulfills lhe tetrahedral geometr)' around Ihe Mg atom.
A nitrogen analogue, [Mc
1
NC
1
H.N(Me)MgMe]1 [Compound 30'], has a si milar structurc
(34].
Com,.....- 33 .... 34
''''
Thc [(o-anis)'lhMg(THF)], complcll [Compound 3!] has an unusualJy compJcll
crystal 5truclure [J5]. The dimer conlains one Ictrahedral MI an<! one
pcnlacoordinated MI atom. Two anls)'] rollp! are bonded solcly thmugh the o-caroon
alom, bul lhe rcmaining groups are bound Ihrough bolh the oxrgen alom aud lbe o-carbon
atom eitllc:r 10 one Mg alom Of 10 bolh Mg atoms as shown. Thi! results in a partial
positive charge on Ihe pentacoordinated Mg atom and a parti al negative charge on !he
othcr Mg atom.
Corn,"," -1 JS
The cycl ic rimerie spedes, (o-xylideneMgtTHFhl
J
[Compound 3(;], has a
trimagnesacycloptnladcc::ane structurc [ 36]. The preferente fOf Ihe trimer probably arises
from he greatcr ability of he Mg atom 10 achicve a letrahedraJ geometry in he lrimer
relative 10 he dimer.
Cornp ... " 36
Contrar)' lO lhe roregoi og cyclic compounds, ((I ,8-naphthalenediyl)Mg(THF)].
[Compound 37] is a tetrameric cluster in which the Mg atoms are bridgcd through he
,JI
naplhalenc by olle ti bond .nd Iwo thrce.centcr, two-electron bond.. Association
mcasuremcnts have ,hown Ihat Ihis tetramcrK: spccics ilI also present in saludon [37].
Compo" d 37
The nonsolvatcd eompounds, MgR
1
(R _ Me or El) [Compouod 38], arer:lyrncrs
wilh symmclrically bridging aJkyl groups. The Ms-C bond Jenglhs are 224 ror Me
dcrivative and 226 A for lhe El dcrivalive [l8]. The C-Mg--C ang)e all: CONtaD! .1
lOSO and 1 0 8 ~ respectivel)'. The R bridges an: threc-unter, two-electron bonds; tberdore,
lhe MI atoms are ablc lo retaio thcir tctrahcdral ooordination. The presenoe of Mg-M,
bonda has nol beco determincd, a1though sorne MI-M, intcracdon hu beco observed
in (MaMe] .
"
C. Pe" .. .nd H KOOidlnated DlCM'ganom.gnealum
A pentacoordinated Jtruclure cJ.isls whcn an intramolccularly bound igand is prescot
Thc l-oxa-6-magnesadibenzo(4,S,6)cyclodecadienc-THF
1
compound [Compound 39]] has
a distorled trigonal bipyramidal geometry [39]. The lrischclating dipbenyl ligand has
small C-Mg--O angles or -SS' and Ihe small bile or the ehelale aUow! lhe coordinadon
or a IICCOnd THF molccule.
Compound J9
The crystaJ sl ructure or(J-Cu-PhCH _ CHCH -CHPhJMg(THF}J [Compound 40]
hu shown Ihal the organic group chelates lO lhe Mg alom and has a dislorted lrisonal
bipyramidal slruclure [40]. Thc inlereslin. realure comes from lhe prcscnce ol lhe double
bond which gives Ihe ligand a partial ". coordinalion 10 Ihe Mg alom_
THF
... ,-<:'--:>-'"
"'.
, ' ; ~ T H F
TH'
Complid 40
A he:taooordinale geometry is observed ror bis(phenylelhynyl)magnesium. An X-ray
delermination or (Ph-C- OJMg(THF). demonslrates Ihe presence ol two isomeric
compounds in which Ihe organic groups are either Irllm or cu 10 each olher [41]. The
cf)'slal st ruclure of an analogou! compound, (Ph-C-C)
J
Mg{TMEDA1, [Compound "1],
""
Compound 41
Q,H.ISItvctvrn ot OI.,.rd """111'&
".
shoWI Ihat it conlains only lhe rrlllU-isomer (C- Mg-C of 180") [42]. Each TMEDA
has a N- Mg- N angle of 80", which results fmm itl chelaring elfect. Tllerdore, lhe
cquatorial angles art: distorted and tlle Mg-N bond leogths art: longer than anticipated.
D. Pol,..Ih.,.com.lnlng OrptlClfl\agneltum
The complexalion of organomagnesi um compounds wilh polyethcr ligands has given rise
lo unusually high coordination geometries and lo I disproponionalion inlo alkylmagnesium
calions and magnesate anioos. The Iwo elfects an: exemplified iD lhe cryslal slructure of
[ EtMg(2,2,I-crypland)] J[EI. Mg
J
] [Compound 41] [43]. The crypland facililales he
disproportionation of lhe Mg dimer ioto EtMg" and EI.Mgi". The dialk:ylmagnesium
anion itselfhas no din:ct inleraction wilh Ihe cryptand. These compounds havean unusually
high reactivity by which rales can be accelerated by $Cveral orders of magnil ude .

(9
,-
El, ~ E \ t . , / Et
/ 'El':M4.......!I
"
V
,
Coropou
,u
A similar separalion of he organomagnesium species occurs in the crystal structure
of (NpMg(2,I. I-cryptand)][NP
l
MgJ [ Compouod 43] [43]. The anion is nol symmetric
as anticipaled, bul has a distoned trigonal planar geometry. On heatin& the NpJMg
becomes protonated and a di meric slructure [ Compound 44] is rormed. The crystal
struct un: demonstrales Ihat cleavage of sorne of the bridging ligands has laken place .

-
~ .... - ..
.;
ComPll 43 .... 44
".
Thc cr)'stalltructUn: of [MeMg(IS-crown-5)- Me. M81J. [Compound 4.5] indicatcs
tila! a pardal diuociation afI lie compound has aken place [ 44]' Te Mg alom lies 0.42 A
0111 ollhe erown t lller plane and has a wcak interaction wit h a terminal met hyl group
of Ihe polymctic magnesate anion.
Compound 45
IODie pairin is nol ob5erved for MgEIJ{18-crown-6) [Compound 46J [45). Tite
CT)'stal st ruclun: revcals a linear C-Mg-C bond, with Ihe crown tl ller residing in lhe
cquatorial planc. The Mg atom occupics the cenltr of Ihe erown elher Ihrough wealr.
Mg-O bonds. A similar "threaded" ItructUn:;5 known for MgPhI11,J-xylyl- l8-crown-S)
(Compound 47] [46]. Thc Ph-Mg-Ph angle is agai n li near, allhough Ihe prescna: or
lhe .),Iyl group rtsults in irregular Mg-O bond lengths. with Ihe s!mngesl bonds
fa Tlbesl from lbe :trl)'l group. Thc slcric bulk of Ihe phenyl group prevent! it from
pcnctr&ling lhrough Ihccrown elhc:r n ng and, Ihercfore, isconsidercd a !tructure,
in whi<:h l be MgPh
1
undcrgoes incJusion Ihrough mull$. Jts formal ion
probabJy occurs through an nilial dissociation inlo ion pai..,. Thc rOlaxanc sl ruclurc i!
Compoands 46 .1Id 47
'"
".
observe<! for (Compound 48] [47]. Thc: l-
butylphenylgTOup canool "thread" through Ihe erown clhercavily and, therefore, probably
gocs through a magnesate spedes.
The crystal st ructure of ((P-I-bulylphenyl}zMg] l( 1,3, 16, I S-dixylyl-3O-crown-8) [Com-
pound 49] iodicates Ihat Ihis crown ethcr has greater flcxibility, giving rise 10 uDique
coordination environments around Mg [47]. The two diarylmagnesiurn unils bond 10 lhe
crown ether 00 cither sidc or Ihe IwO lIylyl groups. Tbe same geometry is ob$crved in
Ihe cryslal st ructure of (p-t-butylphenylh Mg(diglyme) [Compound which is
pcnlacoordi nate with Mg and O in one plane [47). 1be (p--butylphenylh Mg(tetraglyme)
CompcMlds 49 .1Id SG
".
Uhm
compound has a similar geometry llfOund Ihe Mg alom. Three different conformen resull
from lhe different pIIcking of lhe unoonded ethcr groups.
Subst itutcd polycthcr and crown tlllers!;ll D also undergo int ramoJocular bondng with
Mg tbrough an organic substitutot. Derivatives or Ihis oature nave reater reactivit)'
relatve lo othe. diorganomagnesium comxlI,mds. The crystal structure nf 2-((p-r-
[Compound 51) displays a diSlorted trigonal
bipyramidal geometry around he Mg atom [47]. Two olygen atoms have regular banda
10 the Mgalom, two olnen are weakly bound, and onc alom rernains nonbonded.
CompollM 51
IV, BIMETALLlC MAONESIUM COMPQUNDS
Several errstal structures of magnC!lium compound, complexed lo tithe. maio group o.
transilion mctab have beco determine<! in recenl yeaO'. Since Ihe number of , ueh st ructures
is limiled, Grignard and organomagnesium 51ruelures will be discussed logelher. A liSI orIbe
bond lengths and angles or Ihe compounds are given in Table 3-
Organomagnesium compounds oomplexed wilh organolilhium complexes are formed
Ihrough organie bridges betwecn tbe Mg and ti atoms. The cry5taJ slruelure of
(TMEDM..I1:fJ.t-CHJ.Mg [Compound 51] sOOws Ihal lhe tetrahedralletramcthylmagJ\(3ale
is capped by Iwo TMEDA<oordinatcd ti aloms [48]. A lroe: tetrahcdral geometry around
Ihe Mg is observe<! where lhe Mg-C bond lengths range from 2.23 10 2.29 A and
C- Mg-C bond angles ranc from 108.4 10 10\1.9". These values indicate that there 11
no charge separal ion inlo alkali melal cation and magnesate anion species. However, such
slruClures can be perceivcd as an associal ion or Ihe magnesate unil with lhe alkali melal
solvalcd by a ehelalins Lewis base 11Ie sodium aoalogue has a !imilar struelure,
wilh Ihe nnly difl'erencc arisiog {rom the preferred pcntacoordinalion of Ihe sodium [4S].
11Ie replaccmenl orTMEDA by Ihe lridenlale ligand, PMOTA,gives the {PMOTANaJiI'"
Ph).MS complex [Compound 53] [49].
Com]lOlM4s 52 Ind 53
CI,."" Slnlctlltn tII Qn,,'wrYI R .. , ... "
'"
Table 3 Relevanl Bond Lengl lLs (A) and Bond Anla rJ rrom lhe Cryslal SIn.w:turn oI8imetallic:
Manes;um Compounds
Compound C-MO-<: MO-<: MS-X MS-L Od.
[TMEDALi),{I- MeJ.M 108.4-109.9 2.23-2.29
-
2.616, 2.615 ..
[TM EDA Lt1h-Pb),(M- 106.0-112.1 2.29,2.33
'" I- Pb),h
[PM DT A 101- 11 5 2.21- 2.31 49
[Li(TM E DA),] [(bo:ruyll. - 105--1 14 2.3 1, 2.32
-
211.9(U)
"
MI'Li(TMEDA))
89.3, 1)2.8 218, 2.31 2.3S, 2.20
"
Li(TMEDAlh
[TMEDA(I- %.S. 96.9, 2. 161,2173, 2.520. 2.254 49
bulylc:tbynyllJM N. J, 134.1 >257
[PMDTA1r- 91.5.96.1. 2. 184.2.247.
-
2.45 1, 2.299 49
bUlylelhynyll, M' Na 1, 130.3 2.191
(TMEDAhM(I- 2.115 2.382, 231.4 49
bUlylelhynyl),
[( Mc,Si)C](THF)M l.I9 2m,
2"'"
73
(l. 8r), Li(THF), 25/S
Cu.MiJI- PhJ.
-
'"
-
....
" CpCo{C, H.K.-Ph)MBr-
,..
2.512 2.S63(Co)
"
[THf],
(H.C,J,Ni(-Me)MMe- 1125 2.294, 2. 1 so
-
2252, 2264
"
TMEDA
(Cp'U(O)(CH,PPh,CH,), W
."
1.94
"
MC1,(CH,PPh,CH ,JJ 2.23 (C)
[Me,SI(p-OMe),J,M- 20S. 2.24
"
(p-dionne)
(H.81,MfHFJ
J
." B
209 (O) 77
W(Oll, Mg 2.01 78
[THF!. 2.10 (THF)
(Me.RI:(O)J, Mg(THF). 2.029, 2.09
"
{( Me,SiJ. Re(OlhMg
- -
1.923
" (THf). 2.02 1 (THF)
(MgCl(THF),HFeCI.l
m. W so
[MCI(THF).H AlCI.l
""
w ..
(Mg!,THF).I-CU,FeCI.J
."',
l.O9 81
((THF), M iJI-C\)JMI'
. '"
...
" (THF),}[TiO.ffHF)]
Changing Ihe Sloiehiomelric ratios of Ihe roregoi ng reagents lo equimolar quantities
of the magnesium and Iilhium compounds yields [TMEDA' Li],{J4-Ph),Mgl- PhJ:Mgl-
Phj, [Compound S.] (SO). The eryata! !lructure showa Ihat the compouoo is a dimerie
,,.
phenyl-bridged maglJe5ium $pecics Ihat is cappcd by TMEDA ooordinated U as in
Compounds 52 Dnd 53. A separa' ion of hc magnesium and lithium into anione and
cationicspecics;$ ob$Crved for Ihc bcnzyl analogue. Thccryslal slruclure of [rrMEDAh"Li]
[(bcm:yl). MS"Li(TMEDAJ] (Compound 5.5] Ihat organolithium is preKnt boh in
lhe cation and in Ihe ani on whcre il js bcnzyl-bridged 10 Ihc magnesiurn (ji). The geometry
aTound lhe Mg atom is a dislorted tetrahedron with Mg-C bond lenglhs of 2.32 and
2.31 rorlhe bridging bcnzylgroups and 2.22 and 2.26 A for hc tcnninaJ bcnzyl groups.
Compouncl 55
Varial] on! on he R group can ive ose 10 ptnt8coordinated Mg. A typical crystal
struclure is given by ((PhC-ql MS"Li(TMEDA)], (Compound 56] [j i ). Thc Mg alom
is in a pseudotrigonal bipyramidal geomelry wi t h two of Ihe alkyoyl ligands in lhe
equalorial plane (Mg-C of 2.IS ) and a Ihird lUIial alkynyl group (Mg-C of 2.13
The remaining Iwo positions are oa;:upied by the chelaling TMEDA Jigand, The two ti
aloms bridge lhe two Mg uniu through interaclions wilh the 11 bond or the alkynyl group,
A similar crystal 5truclure was ror [TMEOA(I-bulylethynylhMg' Na]z [49]'
-'"
COI'II,""," 56
Complexes oonlainins both Mg and a transi lion metal (M) have becn characlerized
5Ifucturally ( 1). Sonding usually lakes place by bridging organic grouf", and ' through
dinx:t Mg- M bonds which are observed when large differenoes in electronegativities exist
bclween Mg and he transi t ion melal. An cumple or both Iypes or bondng is setn in lhe
1#
erys!al slrocture of CpCo(C
1
H .. KII-Ph)MgBrTMEDA (Compound 57] [52). A direcl
Mg-Co of 2.56 exisu and the phenyl group on the Cn is weakly coordinatcd 10 he
pentacoordinatcd Mg atom {Mg-C 2.56 , Co--C 1.98 Al. The crystal strudure or he
compound, (H .. CzhNi(jl-Me)MsMc-TMEDA [Compound 58J, ndicates Ihat bere is a
dim:t g ~ N i bond or 2.615 and a bridging Me group (Mg-C 2.295 , Ni-C 2.031
l [S3]. Thc pcntaooordinated Mg atom is a1so coordinated 10 TMEDA and a tcnninal
Me group.
ComprF h 57 ... 51
Two unusual structures are obtaincd rrom tbe:: coordinatioo of Grignard reagents
10 CP1Mo rt::5iduc:s [54,55]. The fiDI crystal struelUTe of CPIMo(H)MgBr-{OC .. H,h
[CompouDd .59] shows Ihat tltere is a regular lelrahedral geometry around he MI atom,
bUI no organic group is bonded 10 he Mg [54]. A direct Mg-Mo bond replaccs he
Mg-C bond usually presen! in organomagnesium compounds. A second sel of cryslals
present gave a cluster in which two Mo aOO rour Mg atoms are presento The crystal
struct ure or [(CpzMoHHRMIdJ-8rhMg(OE!z)}]z [Compound 60] cantains four-
membered MgzBr: riogs bridged by two CpzMoH reslducs with Mg- Mo---M angles
or lOa.So [SS). Teuahedral geomelries exi!t arouOO tbe Mg aloml al which Iwo of the
Mg atoms are bouOO to thecyelohexyl groups and !he remaioing Mg atoms are coordinaled
to elher group!!.
v. STRUCTUAES OF MAONESIUM DtHALIDE AND OTHEA MAONESIUM
COMPOUNDS
Although magnesium dihalides are not organomagnesium compounds, tbey do exist in
al! Grignard solutioru and, therefore, are inelude<! in Ihis review. Tbey aOO give valuable
, ..
nble4 Relevanl Bond I...entlu (A) and Bond AnsJes (")
rrom 1he Crystal Struclutel al Manesium Dihalide Compounds
Compound Mg-X
MS-'
.d.
MgBr, {fHF). 2.625 2.16
"
MaBr,-(THF), 2.613,2.199 2. 126 8J
{M.-rHF).{H,Ohl
B
"
4.65 1 2.042, 214 8J

2.463, 2.483 2.26, 2.28 ..
MgDr ,'{pyridinc). 2.767 W
" MgBr,i-S,7. 2.623 2127,2152,
" H,dibenq: , ... 2.183
MaO,"(( - )-spartcinc] 2.269. 2.219 2. ISO.2.I60
" M,Br,' [{ +)-6- 2.45, 2.47 2.08, 2. 11
.,
betuylspandne]
T.We5 Relevanl Bond l.en"hs (A'.nd Bond Anlcs ("1 rrom
lile Crystal Slructure of Mancaium Compounds Othc, Ihan hose
in PJoeviout Tables
Compound Mo-X
MS-'
.d.
(Me,Si). Maiglymc) alO 2. 124 87
(Mc,Sil, MI'TMEDA l628 2.192 ..
(Mc,GeI,Mg{lymc:l. VIII 2.22
"
(H. B.)M,iTHfJ. 13&. 2.48 2.019 90
[(I- BuC(O)CHCH, ) MgUr 2.417 2.049. un
" IOEt,)].
[- BuOMgBr'Et,J, 2.01,1.91 92
rTHF}. M.,Brzl- 2.474 1078. 2.066.
"
B - e Ph ,).,(I-T H F) 2.453
((N ,N' El h Y Ienebis- 2.12, lOO
"
(aoel , 'acclonei mine-
cnolatc)MaJ.
(6,',15,17-Me,dibenzo..
(bJ]{1,4,8,1l]-N .. - 2..041(0)
cydOlelradecine) M '
(THF)
MkN(NHH'). 2.. 148.2..0'13
"
( Mc,Xi(Bu'N) MS"THF] , 2..049(0).
" 2.. IS, 1.993
[( Mc,AI)Me,Si(NBu'l" 2SJ 228 ..
MII'-I)],
[Hu'NSiN(BI')SiN(Bu')] M," 2..12(0).2..0S(N) 97
(THF),
[(o-Me,SiN),C. H .. )MI" 2..041(0 ). 98
(OE,), 1.997, 2..083
[ Phenazinc-N ,N' --( M, Br 2.513 2.. 12(0).
"
THF ,hl'[M,HrTHF.J
'"
'"
in,ight inlO Ihe reactivity or Ihe Gnlllard reagcnlt. A lis! oC Ihe bond lengths and angles
oC some magnesium dihalidea a given io Table ... Aa cumple is the crystal Itrudure oC
MgBrJ{THF)4 [Compound 61], in which Ibe Malom is in In octabcdral environmtnl wjlh
he 8r 110m! oa:upying Ihe alial posilioDI aOO lhe rour THF groups are in the equalorial
planc (S]. However, tbe four cqualorial positions are notalways oo;upicd by lhe so!vcnt
roups. Thc crystal structure oC MgClJ{( - rspartcine] [Compound 62] shows lhal the
geometry around Ihe Mg alom is tctrahedral with lile sparteine igand occupying IwO oC
he positions [57].
"
THFh", I .,,,,THF

THF ...... ' ...... THF
"
Comp" ' IJ 61 ... 62
111e crystal st ructures of anolber group or magnesium compounds wilhaul Mg-C
bonds are also relevant, and sorne oC Ihe bond lengllu and Ingles are given in Table S.
AEFEAENCES
l . P. R. Mlrkies, O. S. Akkermln, and F. Bickelhaupt, Am.. Org<lllOllWl. CIIon. J1: 141 (1991).
2. E. Weiu. Cltmt. &,. 98:2305
3. B. l . WakefK:1d, Or9f11'O'l'/'t1. Rn . 1:131 (1966). E. C. At hby. 8ull. Soc. Ch;.". F,. p. 2133
Pu,t App!. Che", . (1980).
4. R. ShakiT aOO J. 1.. Atwood, A". . C, ymllog, . As.J. Se,. 6:11 (1918).
S. 1.. J. Gugcnbcrgcr aOO R. E. RuJldIe, l . Am. Clrtm. Soc. L. J. Gugcnbcr.:'
aOO R. E. Rundle, J. Am. Cltmt. Soc. (1968).
6. H. Kate)'ama, K.. Miki, N. Tanaka, N. Kasai. Y. Okamoto. aOO H. Yuki, &/1. Cltmt. Soc.
JJHI .56: 131 9 (1983).
7. C. JohlUOn, J. Tone)', and G. D. Sud)'. l . Or(lOllO#MI. Cltmt. W:CII (1972).
8. C. P. Morle)', P. lutD, C. Krilacr. aOO J. M. Wallis. Org_'DlliQ 6:1(18.4 (1981).
9. L. M. En.:lhardl, S. Harvey. C. L RUlan, aOO A. H. Whitc,J. Orgt11lOlMI. Clltm. J4/:39 (1988).
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'"
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10
Machanlsm 01 Grlgnard Raagant Formatlon
CHAF1Q HAMDOUCHI
Ully &ltarch C,,,ter, S. A., Madrid, Spalll
HARRY M. wAL.8ORSKY
1M FloridaS/alt U,,/ytrllty, TQ/la}wstt, Florida
l. INTRODUcnON
111e seminal discovcry lhat orpni<: halidcs rcact with mag.nesium metal dates baclr. 10 he
lurn or Ihe CCDlury (1). Thc product of Ihis reaction has becn given be appellalioD of
Grilllard reagen! .fier ilS discoverer, Ihe Nobcl Laureate Victor Grignard. The question
or how Ihis rugen! is forme<! or, lO pul il anotber 'Nay, how he magnesium is inserte<!
between the carbon- halogen bond is a subject lhat is 'liJI bein debated.
RCHX+ Mg ..... RCHMgX
One or lhe firsl suggc:slions 'Nas advlnoed in 1904 by TlChclinzeft' [2), who believcd
lhat lhe intcnnediates in Grinatd re&Jttlt formation wcre oxonium 01 quaternary
ammonium sall5. lbis assumplion was quickly ICjectcd by Grignard himsclf in 1907 [1).
Thc tllclusion of an ionic proceso ror the mecbanism or Grignard reagen! formalion was
demonstrated by tbe WOllr. oC Kondyrew (3] in 1925 and Brun (4] in 1939, who showed
Ihal very 1ittle currenl was passed when mancsium "dissolves
w
in an elheral SOIUlioD oC
elhyl bromide.
An eariy obscrvation by Grignard (S] thal iodine could be uscd as an activator in
iniliating the reaction opencd up an era oC investigations and .peculations on Ihe mccbanism
oC Grignard reaent Cormation. Dala collected over a SO-year period were evaluatcd by
Kharasch and Reinmuth [6], who suuested in 19S4 thal organomagflC$ium halidc
Cormation is a radN:al reaction involving "suace adherent radicals, al least iD p a n ~
Kinetic studies on Grignard reagent rormation by Kilpatrick ami co-workers (1] dearly
demonSlrated Ihal iodine Cacilitatcs lhe preparation of Grignard reagenll by reducing lbe
inductiOD periodo without alfccting Ihe rale orthe reaction. To accounl for this obscrvation
Kharasch and Reinmuth suueslcd Ihat an aclivalor, Iuch as iodine, mus! ad eilbcr by
clcansing lhe magnesium suate. or by introducing free radicals, or bolh. Thcy also
, ..
".
concluded Ihat he resullS of Gomberg and Bachmann [8) as wel! as hose of Gilman and
co-workcrI [9J wel't' consistenl with magnesium haJide activat;ng he magnesium in lhe
samc manncr as iodine. Thus, the activator in he presence of iodine cOllld actually have
beco magnesiou, iodide:
RX+IMg ..... IMgX+R
IMgX+ Mg ..... MgX+ IMg"
R" + "MgX_RMgX
Without an activator he reaction is assumcd lo be nitiated by a cata!ylic amOllo!
of magnesium haJide MgXl resulting from a Wum:-type reaction, which would. following
Kharasch aud Reinmuth, acoount fOf he disproportionation produclS as well:
2RX +Mg ..... MgX
1
+R
1
2RX+ Mg_MgX + RC.H)+ Re _m
MgXl+ MS ..... 2XMg
RX+XMg' _MgX, + R'
R +XMg .... RMgX
Al Ihi s poiol KhaTll$Ch- Reinmuth ooncluded M here would appear lo be no campell ing
re3iliOn lo regard lhesc radicals as 'free' in the scnse Ihat hey oo::ur in significant numben
in Ihe body of Ihe 5Olulion. The processes described mighl very well lake place al Ihe
solid- liquid
Persuaded by Ihe fael Ihat disproporlionalion and coupling reactions oould nOI be
Ihe rcsull of Ihe reaetion of the halide wilh i15 Grignard reagent under Ihe oonditions
used 10 prepare Ihe reagenl, hey added Ihal Ihe surfate accounls for the disproportionation
and may involve a free radical mechanism. The mechanism they ,uggested, which i5 a
modified version of the Gomberg and Bachman scheme. poslulaled a surface ofmagnesium
oontai ning of surface unsaturalion" (Mg).(Mg'h,. 11Ie reacliol1 would be viewed
as foUows:
l. (MgJ.(Mg)J, + RX .... [( MgJ.(Mg)l, _,(MgXJ+ R ']
.... (M gJ. _l( Mg' h,( M gXXMgR)
2. (Mg)._l(Mg },(MgXXMgRj+ RX .... (MgJ. _.(Mg),,+l + 2RMgX
3. (MgJ. _ !(Mg' ),,(MgX)( MgR) + RX .... (Mg). _.(Mg), , + J + MgX! + RJMg
4. (Mg). _l(Mgh,( MgXXMgR) + RX .... (MgJ. _,( Mg JJ.+l(MgX)(MgR)+ RMgX
Kharasch and Reinmuth also dcemed il improbable that highly reactive free radicab
in solulion would undergo ooupling reaclions before reacting with Ihe usual Grignard
solvel1ts. Thus, surfaceattached radical$, by means of Iheir of surfaoc
would accounl for Ihe Wurtz and disproporl ionalion reaclions, and Ihey ooncluded Ihal
secms alt ogetbcr probable Ihat Iwo adjaocnt radicals mighl form a
(Mg). _,( Mg ),+ J(MgR), .... (Mg). _ , (Mg' )" +. + Rl
,
or/and
(MgJ, _,(Mg')I,+ I( MgRlz + RMgX .... [( Mg). _ .{Mg'h, . )(MgR) + 'MgX + R
I
]
.... (Mgl. _6(Mg').,+,.{MgX)(MgRJ+ Rl
m
The disproponionalion ",aelions being conlrolled by Ihe Ame faetora as Ihe coupling
reaelion would be repJ"e$Cnled by !he Mme equadon. FinaUy, relative lO lhe attaek on
solven! by radicals that mighl escape into solution, they me",ly stated that il would depend
on the design of the experimenl (i .e., the nature of the free radical! and the nature of the
solvent
The prcccding i.s a resume of the analysis made by Kharasch and Reinmulh 10
aceount for the qualitadve and quant itative observations on Grignard rcagcnt formatioo
made over a period of SO yean by the scientifie oommunity. Would these spcculations be
useful in lhe development of a tenable mechanism for Grignard reagent formadon?
1I was shorlly afler publication of the Kharasch and Reinmulh book Ihal our group
llegan Iheir invt$ligalions on !he mel;hanism of Grignard rcagcnl formation.
11. WHY WEAE CHIAAL CYCLOPAOPYl ANO VINYl SYSTEMS SELECTEO FOR
INVESTIGATING THE MECHANISM OF OAGANOMETALUC COMPOUNO
FOAMATION?
Thi5 ilCClion providt$ the rationale ror the selection or the chiral cyclopropyl and vinyl
syslems in the investigalioD of the mel;hanism of organometallic compound rormation.
The absolule configuralions and oplical puritit$ or thcse systems have becn t$tablished.
Thc ability of these syslem. lO perform as effective probes in such mel;hanistic !tudies
resides in the knowlcdgc orthe: stcreochemistry nf their radical and carbanion intermedialcs.
Do the radical and carbanion intermedialcs relaio or lose lheir configurations?
A. CycloPl'op)'l.rtd Vln)'1 Radleal,
, . S/ereochemls/ry ol/he Vinyl Radical
The stereochemistry of rree radicals and Ihe qucslion of the:i r gcomctry and reaclivily have
bcen Ihe subjel;t of several reviews [10]. Whether the: unpaired elel;!ron of vinyl radicals
is in a p lt-orbital (linear) or in an spJ a-orbital (nnnlinear) has bcen a $ubject of interest
for many yeara.
Electron spiD rcsonance {ESR) st udies on vinyl free radicals by Fcsscnden and Schuler
[ 11] in liquid ethylene-ethane and by Cochran and associatcs [ 12] in an argon malrix
were com::lusive. The ESR spectrom of lhe vinyl radical reportcd by Ihe !aUer group
cxhibitcd eight broad overlapping lincs Ihat were aS5igncd 10 lhe hypcrfine interaetion of
the unpaircd electron wilh three noncquivalcnl prntonlJ. The Ihree protOnll in this radical
were nonequi\lalcnt, wilh values for the: coupling CODSlants of and
11
11
,,,-,,,,68 G, respectively. Fessenden and Schuler reported two distincl ,8-coupl ings
constants (58 and JJ G) ror Ihe l-melhylvinyl radical al _ 172C ( 11]. This is funher
evidence that the vinyl radicals are not linear at Ihe radical cenler and, the",forc. have
an clel;lronic configuration diffc",nl from eil her alkyl radicals or conjugated "" radicals.
The invel'5ion barrier of the vinyl radical CHJ=CH' al the radical centCl' was est imatcd,
in Ihese sludics, lO be 2 kcaJ/ mol, wilh a rale or invel'5ion of configuradon wi lh uppcr
and lower limil! o(3)( 10-
1
Ind J)( 10-.
0
al - I7O"C, whieh is on Ihe order or diffusion
conlrol. It was also suggcslcd that invel'5ion of the vinyl radical lakes place by a tunneli ng
process, which i5 rdatively lemperaturc-insensilive.
The high inversion rate would miJitate agajnst the trappi ng of a vinyl radical in
solulion, even in the prescnce of a good radical trap and, indced, this was ShOWD 10 be
lroe by Walbol'5ky and RachoD [iJb]. Thus, Ihe tri-II-butyltin hydride radical chain
...
'l"
...... r .-J O/ _
I 8,
a. Bu,5nH , .

($H+H
1

j
'H
(t}-J
Sch!mt 1
rcduction of (S}( +)-1 ave completel)' raoemic (4-methyk:yc1oneJL:ylidene}-<:thane J
(Schemc n
2. SI.reochem/a/ry o, Me Cyclopropyl Redlcel
Thc high strain in cyclopropyl systems hu beco attributcd 10 bond angle distortion (Baeyer
suain) aOO nonhondcd repulsions (Pitzer To decreasc bond anak: distortion, lhe
g,use or internal st rain, the cyclopropyl radical, in contras! with olner c)'l:lic and acyclic
radicals, is a 11 radical [11]. It was 00 lhe buis or the earlier electron spio resonance
sludie! carricd out by Fessenden and 5chuler [ lla] Ihat the smilarily in the electronic
SlruClurc of cyclopropyl aOO vio)'1 radicals wu suggCSled. The cyclopropyl radical electron
paramagnctic resonana: (EPR) spectrum cllhibiled ten lines, characterittic of one "
(a
H
. -6/51 Gl ami fOUT fJ couplings (a
H
,-2J.42 which indicated Ihat its clect ronic
llructure was ditrerenl [mm Ihal of alkyl and cycloalkyl radicals and claser 10 Ihat oC a
vinyl radical wil h Inc Cl-hydrogen alom out of the planc of lhe nns. An exceUenl later
anicle by Ingold and co-workers [14] reported Ihe EPR spect ra of both cyc1opropyl and
I-melhylcyclopropyl radical!. Tbc IH and !le hyperfinc sp1itting (hes) was mcasured for
bolh radicals aOO dcmonstrated, unambiguousIy, thei r nonplanarilY and thcir similar
dcgrce of devialion from planarilY (Table
The hfs caused by Ihe protons on Ihe methyl group of the I-methykyclopropyl
radical would secDl 10 be quite similar 10 Ihal or lhe I-melhylvinyl radical (19.48 G) [1 la],
which was aIso shown 10 be a benl (J radical. The ncl difference or OH. betwccn lhe
cyclopropyJ (-6.7 G) lOO vinyJ radicals (+ 13.4 Gl [ lIa] also indicalCJ Ihat the vinyl
radical is more benl lhan lhe cyclopropyl radical. Thc rale constants for lhe invenion oC
bol h cyclopropyl and J-mcthylcyclopropyl radicals wcre liso detcnnincd [ 14J by chemical
Table I IH .nd"C Hypcrlinc: Spliuinp
(Oauss; G) ror Cyc;\opropyl .nd I_Methyl_
cyclopropyl Radical in Cycloprop.nc: a'
- 1I1'C
Radical
" ..
6.7( IH)
19.5(JH)
23.5(4H) 95.9
21(4H) 98
'"
trappiog with COJBr. TIte nversiao proces.s of these radicals was so rapid Ihal il appcared
10 be impossiblc, as wc VliU lOe laler, 10 trap Ihese radical, in solutioD before complete
tquilibration. Al 11 C he cyclopropyl radical invertl ita conliguration with mlc con.tant
ca. 10
11
sec-
L
, sihUy raster Ihan .mcthylcyclopropyl radical 21 x 10
11
sec-
L
[14] and
closc 10 tl'le ditrUJion rale(I0
11
sec '
l
) (15).
00 IN:: olhcr hand, on lbe bui. or ah inilio calculations on lhe cydopropyl radicaL
Dupuis and Pacansky [16) showed Ihat he G!-CH bond is bent. with an out-oC-plall<l
a-CH angle or 39.3
0
and an nvenioo bamcr al 3.0 kcal mol -
t
, In .ddition, hejr results
indicated Ihat the ,,--CH bond knglh (1.47 Al in the eyclopropyl radical was ,Ughtly
shortcr Ihan lhe C-C bond Jenglh (1.501,1,) in cyclopropane and Ihat Ihe fJ-CC bond
cnglh (1.54 Al WIllI looger, which mcans Ihat Ihe a radical causes strengthening of the
([-CC bond and weakening of tbe fJ--CC bond. Thi, is consistent with the observed
mode of rearrangement of the cyclopropyl radicalto the allyl radical, as will be discussed
later. Usin! an ab initio spin-unrcstrieted Hartrec-Fock (UHF) IN:thod. Zgierski and
co-workers [17] calculated the geometr)' and tbe inversion frequency for {he 1
methylcyclopropyl radical. The lobal minimum eKhibited a pyramidalization ang,k: of
(C.C,C
2
C, - the bond length. were C,C
2
=C,C
J
_ 1.469 and the nvenon, which
was accompanied by mcthyl rotation, had a frequency of9 x IO'J sec- ' at - 17Je.
Again, given the extraordinary high invemon frequency for the cyclopropyl Bnd
melhylcyclopropyl radicals, one would expect complete 10$5 of conliguration when tbese
radicals are generated in salutian, regardlcss of tbe radical trap {hat is p,esenl. Henc:e, il
is not surpri,ing that total 1055 of optical activity was observed when (he l-mcthyl2,2
diphenylcyclopropane radical was generated in salutioD by a variety ofmcthods cmploying
chital prccurson:
1. ThermaJ daxlmposition orIbe diacyl perollide of(R)-( +
carbollylic acid 11 without or in lbe praence of a good radical trap, as iodinc
or thiophcnol [18] (Schcmc
"'>-.te
.. 'V' ..
. ce",

(:tri!
f ", I'IISH
. ,
""
(R.)-(+)o11
+'_'0"'"
"'>-.t'
.. 'V ...
(i:)-14
Schtme 1
(1)- 13
",.
2. Decarooxylation ofacid (R)-{ + K I7) with lead tetraacetatc-iodine (19] orwith HgO Br!
[20] (Scheme J).
H,o.'B.
,
(:1:)_ 14 (RH+H1 (1)-11
Sclttme 3
J. Rcduction or (R)-{ + )-I-bromo- l -rnethyl-2,2-diphenylcyclopropane 18 wih tri-n-
bulyltin hydride as solven! [18, 21] (Scheme 4).

"'V',,,
(R}{-)- I'
Sclwme
'..,.-./
"'V',,,
(tH]
Total l0" of a pl ical activily of Ihe cyclopropyl radical WalI also recen!! y by
Walbonky el al. [22J for a chiral aliphatic cyclopropyl system. When opticaUy pUIlI
(S)-( + r l-bromo--methylspiro[2,S]octane 19 was reduced under homogeneous coodillons
with ilhium naphlhalenide in tetrahydroruran (THF) al room temperalUre he resulting
acid 12, isolated afier carbonallon, was completely racemic (Scheme 5).
L.i Naph

(SH+H'
ro,
(i r 21
ScMme S
3. Rfl8ClMty 01 Cyclopropyl and Vlnyl Radical
Another interesting feature related lo the (f nalure of the cydopropyl and vi nyl radical!
is their reactivity. In general, (f radical! are more reactive and les! sclect ive Ihan x radicals.
Phenyl, yinyl, and cyclopropyl fT radicals will abstract hydrogcn atoms rrom n turated
hydrocarbons al 77 K, conditions under whkh x radical! are unreactive [23]. In Rchardt's
(24) radical rcacliyi ty daS$ification, bascd on Ihe reaclion or a series or (f ami x radicals
wilh Brea, and C0
4
, Ihe cyclopropyl radical, an inycrting (f radical in an spZ_ hybridized
orbital, closely rcscmbled thc noninycrting phenyl radical. Furthcr support for Ihis finding
Table 1 Absolute Rate COl\St . .. lS (or Reactio,.. al Vario ...
Radical, with Tri-.... bulylgermanc al Ambient Tempcraturc
Radical Tcmp f e}
10- "o. (M - ' sec- ')
~ k =
e. H,_
"
26028 2
(Mc),C=CH"
"
lH5 10
e-C, H,. JO 132 7
CH, .
"
O., 20
RCH
1
CH
2
_
"
0.1 24
Sco. ,: Rol. 266.
'"
was supplied by uperiments of Shono and Nishiguchi [2S), who also poio! out Ibat the
cyclopropyl radical behaves more like a phenyl u radicallhan a 11" cydobexyl radical.
Definitive kinetic data for he rcaclivity of cyclopropyl and vin)'1 radicals werc
provided by work or Ingold and oo-worken [ 26a,b]. Thcir investigation of he reactivil)'
or sorne carbon-ccntered radicals with tri-n-butylstannanc al 3O"C [27] showed Ihat he
absolule rale constan! for hose reactions decreased along (he series: C,H; (59")
(CH)hX=CH' (3Sc-C)Hj (8.SCH; (L2 RCH
2
CHi (O.27(CH
l
hCH' (0.15) (o:
rate constan! 10- ' k_ M- ' sec - ' at 3O"C).
The $ame: order of aOOolule rale constants was nOled for lhe reactivjties of radicals
wilh Iri-n-bulylgermane [27] (Table 2).
4. Rearrangement o, Cye/opropyl Radlcsl
Anolher feature Ihat di slinguishes Ihe cydopropyl radical is jls propensity lo react with
salvenl before il can rearrange 10 Ihe more slable allyl radical when jI is gencratcd '"
so/u/ion. This is becau$C the activation eDCrg)' for rcarrangemenl is higher Ihan for il.!
react ion wilh salvenl. Forexample, an unsubslituled cycJopropyl radical requires an eDCri)'
of 22 kcal mol - ' [28.29] to uarrange 10 an altyl radical, whereas a cyclopropyl radical
rcacls with salvenl by abstracting hydrogen, with an activalion energy Ihal is reported
(29] lo be 7 kcal mol - ' .
7 kcal mol-' 22 kcal mol - '
cycJopropane_cyclopropyl radical .... allyl radical
The rearrangemenl ofa cyclopropyl radical to an allyl radical in salul ion was reportcd
for Ihe firsl time by Walborsky et al. [18] in lbe thenna! decomposition of
l -methyl-2,2-diphenylcyclopropanecarbonyl peroxide [11] (Sc::heme 6 ~ Thc l-mctbyl-2,2-
diphenylcyclopropyl radical [ 16] reacted by both abstracting hydrogen from Ihe salvenl
[:>v<:t
'" ..
,,>.,6 '"
'" ..
,,>v<.
(1HI ..
(1)- 1l
I
" .,
"X.
n
Scheme 6
'"
and by rearran,ing 10 he 1, I..;Iiphenyl-2-melhylpropenyl radical [23], which dimerized
10 yield 1, 1,6,6-tetraphenyl-2,S-hcndicn.e (24]. Thc proportion of dimeric productlo Ihat
of cyclopropane WaI dependen! on lhe IOlvcnl. Ir a good radical sca\'Cngcr, such as
chlorororm. carbon tet rachloride, Of thiophenol, is l,lsed, onl)' lhe unrearranged
cyc\opropanc ji ohtaincd. The rearrangcmcnt of 16 lO 13 has become a usdul diagnostic
1001, as will be socn in Ihe seque!.
5. Summary
80th cyclopropyl and vin)'1 radicals are cr- radicals wilh invcnion frequencies near Of al
diffusion control and with simi lar absolutc rale constanl $, as cvidcnccd by loor rcactivity
toward tri -,.-bulyJstannanc aOO tri,,butylgcrmane.
B. CycIOfM'GpyI.nd VIII,. C.m.nlon nd Of9.nomelaUIc:
AvaiJablc rncthods tor generaling cyclopropyl and vinyl anions from thcir corresponding
cyclopropyl and vinyl halides an:: reatt ion, with metal surfatx:S, with dissolving metals,
by halogen- metal exthange, and by electrochemkal reduction. In Ihis section we examine
Ihe cirtumstant:eS under whit:h free radial ls are nOI formed as ntemediales during lhe
fomat ion of Ihese CIIrbanions and organometaJlit reagenls.
In oontrast with lhe lilhium-hal ogcn ext hangc reactions of lelrahcclrally hybridized
alkyl iodides in whith free alkyl radicals have bcen delccted as intermediates by ESR [30],
t bcmk:ally induccd dynamit n\lt:lear polariulion (CJONP) [31], and by cllemk:al trappin
oflhe radicals [32], radical. werc not dClcctcd for cyclopropyl.nd iodides. In general
the oplical slabUi ty or tetrahcdrally (Spl) hybridiz.cd organolithium oompounds i5 both
Icmpcralure- and solvcnt-dependent. The halogen melal exchangc bctwocn (- }-(Rr2-OClyl
iodidc and .J-bulyllithium in petroJeum cthcr-i:lher al - 70"C, followed by carbonation,
gave ( - )-(R}-2-melhyloctanoic add Ihat was SO"/. racemiz.cd [ 33]. Thc optical purily
dccreased wilh increasc in tcmper.luTe, and time allowed for lhe exchangc, lhereby
indicalng the conligurational instabiJity oC the optically active 2-oclyllithium reagent . Alto
addition of dielhyl elher ncreases the rale of raccmization [34].
l . o( Vlnyl C. rbanlon
Trigonally hybridizcd vi nyllithium derivatives are charactcrizcd by highcr conligurali onal
stabiJily [34,35). Pantk [36] dcmonsl rated Ihat (e) and (Z)-l-Iithium-I -phcnyl-I-butene
oould be preparcd Itcrcospccifically, with retcntion oC oonfiguralion, by a lilhium- halogen
cxchange reaction bclwccn II-butyllithium aOO (Z) and (E}-I-bromo-I-phenyl- I-butenc,
respective1y (Scheme n 80th lithi um dcri valives are oonfiguralionalJy stable at
"'>=<"
...... s..u
8. H
,
"'>=<"
...... SuBr
U H
" "
room temperature in hexane solutions. HowevcT, ciHraltl-isomerizat ion oocurred in
hcxane-THF mixtures.
When the Iit-substitucnts are alkyl groups [34,35a] and hydrogen [37], nllcad of phcnyl,
thc vinyUithiums are configurationally Ilable, evcn in coordinating solven!s. Thc
".
configurali onal slabilil)' ofvinyUilhium w .. uamincd by Walbonky .nd Banks (38], who
showed Ihat he tlcreochcmical slabiJily 01 lbe vinyllithium reApl in diethyl ctbcr waa
temperature-dependent HaJogen-rnetal exeb.nSi: 01 t-bulyUitbium with oplicaly pure
(S)-( + )-4-mclhykyclohcxylidcoebromomcthant 'n in dicthyl tlher al - 6S C produced
4-mcthylcyclohcxylidenemethyllithium, which was carbonate<! al dirrcrenl temperatun:II 10
rorm the correspondng acid (Schemc Carbonatian al -6SC save In acid, (5)-( + ,.29,
wilh an oplical purilY greatcr than . However, "'neo lhe villyllithium IOlution was
allom 10 warm 10 <re ami remain al Ihat tcmperature for 2 hr, Ihe optical purily of
resutting leid, solated afier carbonation, dropped lo 79-; .

,_"'"
,
co,'
Se:' mllt.
2. Stereoc:hemlstry o, Cyclopropyl Cerban/on
Ik :ause af (he reater s charactcr or cyclopropaoc's tll:cocyclic orbitals [39] (spu,). lbe
cyclopropyl carbanion might be cxpecled 10 bchave . imilar 10 lhe t rigonally bybridized
(Sp1) vinyl Qlrbanion. This was indced sbown 10 be so by Walbonky el al. (40], who
invesligatcd the halosen lithium intercbanse between (S)-( +
diphenylcyclopropane 18 and ".butyUilhium under a variety of condilions (Iemperature,
soIvent, and reaction They demonstrated thall .methyl-2,2-diphenylcyclopropyllilhium
was capable ofmaiDwniDg its configurallon, asjudged by lbe oplical purily oribe products
obtained when it was allowcd 10 !"eIel wilh methanoI, water, carbon dioxide, bromine,
and iodine (Scheme Moreover, solvent, lemperalure, aud reaction time bad very Hllle,

%,
(5)0(+)- 11
"

Scl une 9
'"
T.bIe 3 Solvent and Tnnperat ure Effect on lhe
Stereocbemittry of Cyclopropyl C.rtNonion
T=p Time Opt. punIr
Solvenl
(oC
(min) ('lo) ('lo)
E,,.,
28 lO
"
100
28-29 10
"
100
Elller
-.
JO
.,
100
THF
-.
20 J9 100
ir any, elfect on lhe: a plical punIr (Table 3). Tite lithium derivativc reBele<! with 5O!vcnl
in Ihe arder 1,2-dimclhoxycl hanc: > Ittrahedrofuran >dicthylet hcr. When di mctho.lyethanc
was uscd, carbonallon of Ihe reaclion mixture railed lo yicld any l -mcthyl-2,2-
diphcnylcyclopropanecarboxyli<: cid 11. The 0(1)' producl isolated W8.lI Ihe hydrocarbon
13 in 85'-. oplica! punly. Thi! observat ion wiIJ be uscd lo advantagc laler.
A ,imilar result was obse ..... ed with a completel)' aliphatic substitutcd cyclopropyl
derivativ!: (Schemc: When optically pure: (5)-( + }-1-bromo-l -melhylspiro[2,S)octane 19
was lreale<! witb I-butyllithium in tlher solution al - 7S"C for 30 min, the acid 22 obtai ned
on caroonat ion was i50lated, wit h complete retention ot oplical aCl ivity and configuration
[22]. Thi. indicatcs Ihal I-met hylcyclopropyllithium derivativcs are configuralionaUy more
stable Ihan al kyllilhium (Spl) reagellls and Ihose vinyllilhium reagenl, that contain a
phenyl group in lhe g-po,ilion. TIaeir !Iabilily is comparable wilh Ihal or alkyl-subsli luled
vi nyllithium reagents.
t- <J." Ik
-
"'
l . _BIIU
'-ro,
Sc:lltme 10
e :Ti .. ,COIH
M,
(SH ..
The foregoing Icchnique allows one lo prepare other organometallic compounds,
5uch as organomagnesium, orgallosamarium [41], and organocalcium [42] derivalives,
with complele relcnlion of oplical ao:;livi ly and configu ral ion. TIai, can be accompl ished
by simply lreali ng Ihe configurationaJly s table cyclopropyl a r vinyltilhium reagenl wilh
lhe cor respollding metal halide.
3. Summary
II has becn dcmonslraled Ihal cyclopropyl and villyl radical intermediales call1lol mailllain
their collfigurations when generaled in 5Olulioll, whereas Iheir corrcsponding anions, as
organomctallics, do. TIaus, these systcms ser ve as convenient probes for investigating the
mcchanism of organometalliccompound formalion. TIaese I"catures were ulilized and serve<!
as hasi, for investigaling and establishing Ihe mcchanism of Grignard reagenl formatio n.
".
111. THE MECHANISM Of' GAIGNARD REAOENT FOAMATfON
A. Int. .. ".dlacy of Aadk:li" encl P,,, ,. Lladlng to AMal, ,lid lo
Orlgnerd Aeaglnt Opt!.lty ActI Orlgnllrd R"IiI'"'
The fint suo;:cnCul formation of an aplicaUy active Grignard reagenl in which lhe
magnesi um 15 directJy altache<! lo Ihe chical cenlt r was reponed in a shart communication
in 1961 [43]. followed by a full paper in 1964 [44]. Previous attempts 10 prepare optically
active Grignard reagents from acyclic halides such as (-"2-iodobutane (45], ( - )-2-
bromooctane [46, 47) ami optically active I-phenylethyl bromide (48). as wcllu a cyctic
halide ( - )-3,3-di mc:thylcyclohe.a:yl chloride [48], all had giten rise 10 raoemic products.
The fi n l chiral halides use<! by Walbon,ky and Young [43,44] were optically active
l-bromo-l-melhyl-2,2-diphenyk:ydopropane 18, l-chloro- l-methy"2,2odiphmyk;ydopropane
11, and .iodOol -methyl.2,2-diphenyk:ydopropane 14, Ihe absolulc configuralions and
aplical purities o which were established [40.49) as were those of lheir derivalives,
r -mclhyl-2,2-diphenylcyclopropane 13 and l-mel hyl-2,2-diphenylcyclopropanccarboxylic
aeid 17.
When (S)-(+}-I-bromo-l -melhyl-2,2-diphenylcyclopropane lB was trcaled wilh a
powdered magnc:sium- magnesium bromide mixture in reftuxing lelrahydrofuran and
tbe reaelion mixture carbonatcd (Scheme ~ Ihe telulting product. 1-mclhyl-2,2-
diphenylcyclopropanecarboxylic acid 17 and l -melhyl-2,2-di pbenyleyc1opropanc 13 were
optically active, wilh predominant retenti on of oonfigufation. This was the lirat
(S)-(+HI (SH-H1
Sdltmt II
"',---,,"'"
,,/ V'H
demonstral ion of an oplically aelive Grignard reagenl. Neilher solvenl, lemperature, Dor
reaction lime greally alfecled the oplicaJ puri lies of the products (Tablc 4). The yield or
acid incn:ascd along wilh a corresponding dccrcase in hydrocarbon when going rrom etber
lo THF. Also, the particle size and purily ol magnesi um had liule, if any. elfect on the
stef'CO(:hemiSlry ol Grignard reagent fonnalion.
The fil'lll queslion Ihat arase from Ihese rcsults wu lbe following: Al which point
in the reaction had Ihe racemization occurrcd7 That Ihe unrcacled amounl of
(R}-{ - }-l-bromo-J-melhyl-2,2-dipbenylcyclopropane I'COOvered afler the reaction had
undergone no 10$$ ol oplical activity removed Ihe passibi lity Ihat racemizal ion was due
lo racemization of starting malerial under he reaction condilions [44]. However, lo
ascerlain whet ber or not Ihe racemization oocurred afIer Ihe Grignard reagenl was
Cormed, il was necessary lO prepare an aut henlic sample of tbe oplically active
Grignard rcagcn!. This was aehieved by Ihe reaction of oplically !Iable -melhyl-2,2-
diphenylcydopropylli lhium 30 wilh an elheral solut ion ol anhydrous magnesium bromide
(Scheme r 2 ~ To assurc that no unreacted lilhium rcagenl rcmained, dimethoxyet hane,
whieh was known lo decompose 30, was added. Carbonalion of Ihe rcaelion mtlurc
produced Ihe corresponding acid 17 wilh complete rclenlion ol oplical aelivily and
configurat ion [44), thercby demonslraling Ihat. once lonned, Ihe Grignard reagenl 31 i5
".
#Mmdll l : tI .nd ..... .,." .. ,.
T.IM .. SrereochemiSlf)' ofGri,nard RUlIern Formalon from OptiCIIJly ACl ive I-Methyl- -bromo.

Acid Hydrocarbon
Temp.
Solven!
ro
(min) Yield (%) OpL purily W. Yield (%) Opt. purit, ('Yo )
Et ,O"
"
20
,.3
14.S
"
,.
Er ,Oo..
"
" "
20.' 22' 3'
THP" 25-21.3 40 4l 12.
"
10. 1 S
THfo .....
"
20
"
I S.2
"
loS
rnp' ..
"
JO J2 18.8 44 123
THP' "
"
JO
"
I S.S 20 13.7
THP "
" "
7Q
18.S
. ,
' .2
THP' "
"
18'
41 15.3 J2 12.
TH!"
"
18'
"
16.2

' .2
THP
" "
16.0
, .
' .1
THp
"
4l I S.O
'In 1110 a.,licr lIudieo reaction mlllure ..... carbonalCd in lbe c:onY<1lIOll.1 manner by pourin jI
nuo. ufl)' o( dI} ice, .. hicl! nuy "'"' Iood 10. J.rae lmou.nl <Ji l-melhyl-2.2-<lipheQYkydo,)ropane, ""uhinl
From. hydrolysa 01,,,,, Gri",. ,. releen' durinS!be ".,bonation. Under lhese COftditiona il . u IlOl pouiblo lo
delmn' ''' , ... Opliaol puril, ot ,he: hyd,oc:arbon fo"""' durin. Oripard rasml ro""",ion.
"Ml lftr:lium po..,x u usecL
' Reoc:liona _re Clrricd oul in . vlCUum manifold l)'Ilem. .. hieh enlblcd 11M: formal ion . "" ca.bonllion '" lbe
orpl\Ol"llellllicllO be OOIIdllCled \tftder oondilio", Ih.ol ud\>ded rnoisture mi.rure _lid lit [$O).
' Elhyle ... dibromido: wu Idded lo bromido 100 masneoum.
' MInetum tumi,... _re U!ol.
' Mopaium 0199.9995% purily .. u.-d.
"' .... PfJ>v<Me Mle.! .
"').;;fMe
Ph>V<e,
I.e,,! 1
-
" U
f'b M,e.
{SH )-1I
" "

'00,
"')..;f.Me
"' 00,"
(SH+17
Sdlrme 11
configurationall )' stable. Henoe, the eltensive raccmization obscrvcd must have OOC\Irrcd
in the Grignard N:agent (ormati on step in which radicals aN: known 10 be involvcd.
How docs one aCCOunt for the observcd N:tenlion oC confillurati on? Could N:tent ion
have bccn a N:sult of haJolICn-metal inter<:hanlle with Grignard reallCnts? In this manllCr
the formation of Grillnard TCallCnU tould involve oomplete raccmization, ll5 has becn
obscrvcd wilh ot her oplicall)' attive halides (47], but ir Ihe raccmic Grillnard reagcn! was
",
Ibcn lo undergo halogcn- metal intcrdlange witb WI1'e8Ctcd optically actil'!: halidc (a rclenlion
stcp). Ihis would resull in he forrn.tic:ln of paro.Uy active Grinard rc',elll, lIlI wu
obscrved (Scheme J ~ Moreover, lhe resuhs of Zakharin et al [SI] would be in support
of Ihis assumption, since lheir sludies OD Ihe e:l(:hange of Grignard reagents wilh alkyl
and aryl halides suggesled Ihat the halosen- metal illtcrchange lUetion is he lame fOT
both organomagnesium aOO organolithium compounds. This would imply Ihat lhe
organomagnesium exchange ,Iso proceedJ with retention of conliguration.
Pb\.--!,*
"'V',,
(SH+)I
">-.tOO
""V'"
(i)-ll

(:t}31
"\._.J'/Iok
""V'"",
"
Sc"une 13
This question wu addremd by Walborsky el al. [SO] in Ihe foUowing clI.perimenl.
A IOlution ofracemic Grilllaro rcajenll} was prepand rrom racemic t . methyl-t-bromo-
2,l-diphenylc)'clopropaoc 18 in THF and sep&nlled from unreacted manesium. Thc
raccmic Grignard reaen! WIIJ then addcd 10 a solution of oplical)' active brornwe lB.
When lhe reaction mixture was refluxed ror 3 hr and Ihen (realed wilh carbon diollide,
lhe resulling acid 17 was complelely racemic. Thus, halog<:o-melal interchange can be
eJ:eluded as a 50Uroe of Ihe observcd oplical activity.
Al Ihis point, il appeared that lhe radiall inlennediale was nol enlirely free. This
resulled in lhe fint propasal ror Ihe palhway lcading 10 Gngnard reag<:nl formalioo. 1I
was postulaled Ihal elcdron lrand"er oa:un Crom lhe metal . uace inlo lhe carboo--halof!C1l
bond lo tcad lo a lighl QII;OtI ,adical-cat;OfI radical pairo lhe eoll.psc or whieh on lhe
, urfaee yielded Grign.rd reag<:nt wilh oomplete relenlion oC coofigutlllioo. Raeemizalioo
would ~ u l l rrom coll.pse or lhe liahl anion radic:lll-calion radical pair lo. loase radical
pair, or mighl also resull dircclly from inilial electron transfer. lbi. propolal was 'upPOrled
by a sludy of Ihe effect of vanous halog<:ns 00 Grignard rcagcnl formalioo, whiclJ will be
discussed laler.
The olher syslem iD whicll Ihe slereochemislry oC Grignard rcagenl formal ion was
investigated involved use of a ehiral vinyl bromidc selcctcd for lhe reasons diw'ucd
prcviously. Walborsky aOO Banks (38) reportcd formation of Grignard rcaacnl Jl from
ehiral (5)-( + }4-mcthyk:ycloheJ:yl)dcnebromoDIClhanc 27 (Scbeme 4 ~ OplicaJly aeliw:
(5)-( + H4-methylc:yelohexylidenc) bromomelhane WIS eoow:rted lo lhe Gngnard reag<:nt
by rcaction with magncsium powder in TAF. Carbonalion oC lbe Grignard rcagcnt ave
lbe aed 29, whieh was 42-;. oplic:lllly pureo As with cyeJopropyl bromide 18, the unrcaeled
,,.
i "ar
"
Schtme 14
bromide could be recovered with complete rclenlion of its nilial oplica! acivil)'. This,
again, showed Ihat the IOS$ of oplical aclivil)' observed in he vioyl Grignard reagent was
nOI due 10 raoemiution ofthe sub5trate vio)'l bromide 27 under he reaction condiiolU.
Al in he cyclopropyl s)'stem, 10 determine whelhcr raoemization occurred antr lbe
Grignard rcagenl was formed. he correspondng yio)'l Grignard reagent \Vas prepare<! by
realing optically active 28 with exccss magnesium
promidc in THF- he:une solution (Scheme I Tite rcacion was allowed lO warm 10 room
lempcrature and hen carbonated, whereupon acid 29 was i50lated with 91 % overall
relention or configuradon. Tt is importanl 10 recalJ Ihat he observed small 10$11 or oplica]
activity had aClually ocwrred in lhe vinyllithiurn teagen! before reaction with magnesium
bromidc.
,OoU
,
M,Br,
.
COI .
"
Sehen" 15
The formation oC vinyl Grignard rcagent by direct interaction oC optically active
(4-rrn:thyleyclohellylidene)bromomethane 27 with magnesi um melal al$O occun wilh partial
raeemizalion. Here, loo. Ihe raoemizalion occurred in the Grignard Cormalion step.
The stereoseleclivily oC lhe reselion oC vinyl bromide 27 with magnesium metal is
oonsiderably higher Ihan Iha! observed for lhe cyclopropyl bromide. 1I has becn suggesled
[38] Ihal the stereoselectivily o Ihe reaction oC magnesium metal with chi ral organic
halides increases wilh !he amoun! or !-Charaeter of the carbon- halogen bond (Table
The correlation of carbon- halogco bond strength with the slereoselectivity or chiral
Grignard reagenl formalion implies Ihat electron tran5fer l o vinyl haJides is followed by
a more coneerted oollapse orlhe light anion radical-cation radical pair leadinglo retention,
rather Ihan in Ihe corresponding step for the reaction oC cyclopropyl or alkyl sub$lrates.
".
T.bIe 5 Tnfluence oIlbe Hybridization Slale on Ihe Slereochemistry al Grignan:l RQsenl
Temp. Opt. punIr O/.cid Hybridization
R- X rq SolvcI"
("/o) of chiral e
eS}( +)-27
"
TH'
42 .p'
(S)-( +}-18
"
TH'
l'
5p',U
(c-Hexyl)CHOCH, [46, 47]
"
El,O o .p'
T.Wt6 Effixt of HaJogen on he ofGrignard Reagenl Formalion fmm Optically
Pun: l -MctbylcydoPfopyl Halides in THF
Acid Hydnx:arbon
Tcmp. Time
Halide r q (min) Yield W.) Opt. punIr (%) Yield (%) Opl pu,; ly (%)
a
" "
.1 25.7 1.3 6.6 (inv,)
a
"
1"
"
25.4 1.0
s.) (iDV.)
8.
" "
7<1 1<5
.,
6.2 lrel.)
B.
"
lOO
"
1<2

4.2 (ret)
1
"
,.
..
1.'
(4.4) 0.8 (re!.)
1
"
190 36 1.9 19.0 1.0 (re!.)
B. Halogen E"-d on lb. Smaochllml"y of thII a,lgMnI FonnatIon A .... llon
That halogcn has In clrcel 00 he slereochemistry ot Grignard rcagcnt fonnation wa5
rcporled in he earl ier studies [44, SO). Oplically active l -mclhyl-2,2-diphcnylcyclopropyl
chloride 12, bromide 18, and iodidc 14 wcrc converted lo be;r corresponding Grignard
reagcnts and carbonated (Scheme The results are shown in Tabk 6.
X..a.(RK+J2
X-o..(RK,,,,1
X_1. (RK+I.
(RK+H7 (S)-(' Hl
In alJ acid 17 was oblaincd wi lh ovcrall retention of configuradon. An
inlel"CSling cffcct of the halogen is revealcd. Relenlion of oplical activily or configuration
decrcases in Ihe dircction O> Br 1, with cydopropylmagncsium iodide being cssentially
racemic. The yield of acid vanes in Ihe same dift:Cl.ion, O>Br l. and the producl
hydrocarbons are very ncarly racemic.
Thc enerBY of lhe carbon- halogcn bond as weJl as lhe reduction polenlial decreases
in Ihe order e l > Br > 1, as do he oplica] punties and yields of Ihe Gngnard reagents.
'lO
Thi s is consisten! with tbe conclusion Ihat he amOllO! of loosc radical pair formed is
delcrmincd by lhe slrength of lhe carbon- halogen bond. As Ihe halogen is changed from
iodide, 10 bromide, 10 chloride, Ihe bond $Irength increases and more enerBY i$
10 add 3D additional elect roo lo he caroon- hatogcn bond. Conse<uenl ly, Ihe lirelime of
Ihe intermediale radical ion decreases in Ihis a rder. and Ihe reaction becomes more
concerted. wilh !he oonsequcncc Ihat there is less loose radical pair forme<! and, hus, leu
raccmiuuion and 10$5 of material 10 side processes.
The roregoin reslllls highlight !he questions of Ihe cxac! oature of tbe radicals
nvolved in Grignard teagen! formation 8nd why t be amOllO! of hydrocarbon formcd
ncreases wben chaoging solvenl from TH!" lo c:ther.
C. N.tue. 01' the A"IcIII.
, . Produc, Ana/yals
In addition 10 stereocbemical analysis ofGrignard reagenl formalion from optically aetive
l-melhyl-2.2-diphenylcyclopropyl halidcs, e:llmination and idenlilicat ion of lhe minor
producls were Ihoughl 10 provide helpl"ul information for understanding Ihe nalure of lhe
radicals involved in Ihis pr0ce5S. Thus, a thorough analysis of the acid and hydrocarbon
fraclions alter carbonalion of Ihe Grignard rc:agent formed from racemic l-methyl-2,2-
diphenyleyclopropyl bromide 18 in ether was undertaken [SO] (Scheme 17). Al ong wilh
l-methyl-2,2-diphenylcydopropane carboxylie acid 17, formed in 34% yicld [mm the
cyclopropyl bromidc, 1% of 2,2-diphenyl-3-methyl-3-butanoic acid 33 was isolated and
idcntified (Scheme 17), lbe lalter being formed by isomerization of Ihe cyclopropyl radical,
either in solution or on lhe magnesium suace, 10 form an allylic Grignard reagenl
(Schcme 18). Allhough lhe isomerizalion mighllead lO l he primary Grignard reagenl [52],
carbonalion would yield lertiary acid 33.
Ph>v<Me
" .
(1)-1'
I'II)..-.{Me
,,'V'H
(1)- U
(23")

I.MfI'&hcr
Ph Me
";,--<


,. ro,
Ph CO Me
:v
"
"'"

Sdwme 17
\
(t ). 17
("' ..
"
(l,.)
,
"
O")
Y
J
odd fnI:ooo

.. ""
;,/,7'"
"
(4")
The hydrocarbon fraetion was composed of23-;_ l-methyl-2,2-dipbenylcyclopropane
13, 9-/. 2,2-diphenylmelhylenecyclopropane :W, 3% l-rncthyl-2,2-diphenylcyclopropcne 3!,
alon wilh 4-;. of a higher molecular weighl malerial Ihal tumed Oul lO be lhe Mdimer"
1, l-disubslituted-2,2-diphcnyleyclopropane 36. AIl attcmpts 10 dCI:t lhe preseoce of ot her
possible dimeric material sueh as :u and 37 rai led.
, ..
:.vMe


,
.... t;H,
" ..
..
" ....
. "'"

.. "

'" ..
"
,eo
Pb>=<Ofi'lcX
co,"
Sdlmc: 18
On Ihe olher hand, tborough cxamination or he products rormro afler reaction or
racemic 4-methylcyclobexylidenebromomethane 27 in THF with magDe$ium powdcr
followed by hydrolysis or lhe rcaction mixture wilh deulenurn oxide {Scheme 19} furnished
4-methylcyclohexylidenemethane 38 along with bis-1,2-(4-mtt hykyclohcxylidenc)clhane J9
in 7: 1 ratio. The amOllO! of vio)'1 Grignard reagen! ronncd WIIS 79-;., as judged by
approximatcly 9OY. deulerium iocorporation in olefi n 31.
r -B. I

"
S: 1M: 19
..... r . )
v
"
17 .. -) ...
? -
Thus, jI appcars thal lhe side produCLt for both cyclopropyl and vio)'1 Iyuems ditrer,
in both olture and quantily, from hose obtained wbcn thc radical. are enerated
in solution. This is eJlplained in temu ol a JUTfau-bound radical.
However, il il diffieul! 10 dislinguUih unambiguously between tbe amOllO! or
hydrocarbon aming from the disproportioDl lion reaClioD between two radical! and lhe
amoun! arising from solvent cleavage. To dilJ'erentille belwocn the two possibilities. Ihe
formation of Grignard reagenU in perdeuterated etben was investigated [SO).
2. Formarfon 01 Grlgnsrd Rugenr In PerdtWfer.t&d Ether8
Thee:a:tent ofsolvenl cleavage in Grignard reaent fOrmltion wasdetermincd b), Wllborsk)'
and AronolJ' (SO]. In tbe lonnation of Grignard rcagent lrom oplicall)' active
l-melh)'I-2,2-diphen)'lc)"clopropyl bromide in THF- D. aOO diethyl ether- D
,o
solvent
cleavage WIIS indicated b)' the amoun! ol deulerium incorporation in lhe hydrocarbon,
l-melhyl -2,2-diphenylcydopropane 13. The resull., (Table 7) . how lbat aJthough solvcnt
cJeavage in THF il trivial (onl)' I the amounl of deulerium ineorporalion is 28.5%. In
dielhyl elher over 20-/0 of 13 is lonned, bUI tbe amount of deuterium ineorporllion .
10"11', 6. . These observalons ha ve a significan! bearing on our laler discussion olOrignard
fonnalion lrom cyclopropyl bromide.
,,,
T.bIe 7 Fornunion ol Grilnard Rugenl 'rom (+ ,- 1-Melhyl. l-bromo-2.2-diphcnykycJopropalle
in Deuleraled EIMU
Acid Hydrocarbon
Temp. Yie!d OpL punl, yield RO in He Opto punly
SoI\lt:nl rq
"" ""
RII + RD (%y {%y
f%r
THF-D.
"
..
"
, .0
28.5 9.0
EI,O-D,a
" "
,<2
20.2
.,
4.'

As can be ICen, the resu!!! obtained in ether D, Q no significan!
ditTerences in lhe yiclds and aplical puritics or Ihe acids and hydrocarbons rrom hose
obt:aincd in nondeuleraled etlK:r. This is consistenl wilh Ihe betier Ihat $Olvent cleavage
in Ihis IOlvcnt is unimportanl, then:rore, one would nol expecl lo observe any appreciable
kinetic i$Olopic
Howcvcr, a si gnificant diffcrencc in yicld and aplical punIr or 11M: acid rormcd 00
carbonalion could be DOled bctwcen expcrimenls carricd oul in THF- D. and t hose in
ordinary THF. In ordinary THF, he Grignard rcagenl, as measured by Ihe amOllo! oC
acid produce<!, was formed in I S.". higlter and S.". lower optical puril y. By oontrast, tite
yield of l-methyl-2,2-diphenyk:yclopropane in THF- D. was significantly lower Ihan in
nondeuteratcd THF, whcreas the opt ical purity iocreascd. The dilfcrences in yiclds and
oplical puril ics in THF- D. oompared with THF are consistenl wilh a deuteri um isotopic
elfeo;l. In prolonaled THF, solvenl cleavage by a raccmic intermediale would largcly
a<:counl ror Ihe formalion or l-mclhyl-2,2-diphenylcyclopropane (path A or Sclteme
00 Ihe olher hand, a kinetic isOIOpic elfcel in THF- D. mighl have rcsulled in lhe raccmic
inlermediale being diverted to raccmic Grignard reagcnt, the prccunor of raccmic acid
(palh Conscquenl ly, in lhe THF- D. expcriment an increasc in Ihe yield of Ihe acid
and a dccreasc in ils oplical purily would result.
3. $url.ce-8ound Radical
What do both product analy,i, and the formadon of Grignard reagent in pcrdeutetatcd
as dC$Cribcd in Ihe foregoing. dcmonSlrale1 Formation or dimer 36 provides
, Irong cvidenoc for the involvcmcnl of radi cal intermediales Ihat are nol rree in SOlulion.
This, oombined with lhe lack of solvent cleavage, Ihe resulls of slereochemical analysi5,
and Ihe nature of products formed in pcrdeuleratcd ellter, are slrong indication! of lhe
, udace-bound nature of all lhe inlermediates involved in Grignard reagenl rormalion.
Thcre iJ liule doubt thal r lhe l-melhyl-2,2-diphenylcyclopropyl radical 16 were generaled
n solut ion, it would eitlter cleave tite solvenl lO form cyclopropane 13, or undergo nng
opening 10 Ihe more 51able allyl radical, which would dimerizc to yicld 24. Only a very
, mall amount (1 %) or product that oould he auributed to the allyl radical was detccled,
and nei lhcr dimer 24 nor dimer 37 was ohserved. very lillle solvent c!eavagc
was round.
p' m
Ph\,........,.(Me
,,'V'.
(t). 13
f ofup ...... 'im ......
">--.<.""
,,'V"
"
Ph Me
Pb>V<MaBf
().)I
s.
so
..... Al
ro,
" ""
pt,'>\<H (<<D)
(.t)-13
(:tH1
'"
D. Kharlsc:h-Aelnmu1h-W.lbonkr M.manlllm Ior Orlgnard R.llllm F-.tIOn
Given lile faels outlined in he roregolng detalled discussion, Walbonky and bis
ootlaborators proposed he following mechanism of Grignard reagent formalian (Fig. t I.
AIl pro<:t:S$CS jnvolved in formation of the Grignard reagent are assumed lo occur al 11M:
magnesium surfaoc. The finl and ratc-detcrmining step involves an electron transfer from
he magncsium suacc into (J . antibondng orbital of lhe carbon-haloen bond
,.
71
7;-;
'ti""
/" 1IIIIilllll

.. ttgx
/1111i/jj7!1111
Ch; el" .. ,=-.. "gV
4
Wg'"

Figure I The Khanscll-Reinmulh- Walbonky mechanitm of Gri."ard reagent farmalion.
'"
'H
(palhway 1) 10 produce a lighl radical anion- radical cation pair as a transition state or
intennediate [55, 56]. Free radicals are generated ci lher by a concerted electron trarufer
bond breaking from he magnesium 5urface (palhway 2). or by dissociation- if il is an
inlermedialc--of lile ligb! radical aninn- radical calion (pal hway 3) lo produce a loose
radical pair adsorbed on Ihe suate. Tbe amouo! of Ihe lattcr depcnds on Ibe slrength
of 1M carbon- halogen bond. Thc ,""caker Ihe bond (Ihe lowcr he reduction polenlial). he
realer lhe amouol of loose radical pairs. In olher words, in Ihe mechanism proposed,
the amounl of these pain would be predicted 10 increase in going from e a, 10 C-Br,
10 C-I, and 10 ncrease frorn Spl charaeter of Ihe carbon bonded lo he halide, lo Spl .U.
10spJ.
Ir Ihe halide were al a chiral center and Ihe substrate optically active, collapse of
Ihe lighl anion radical--a.tion pair would lead 10 formalioo of Grignard reagcnl wilh
complele relenlion of configuradon (palhway 4 ~ On Ihe olher hand. a loose radical pai r
would mainly lead 10 racemic Grignard reagenl by a sao rOlation of the carbon radical
relative to the ,uace and subsequent combination with the magnesiouJ halide radical
(pathway S ~ The organic radical! may also escape capture by magnesius halide and
undergo di sproportionation and dimerization at the suace. Very small amoun!s of these
radicals lcave Ihe suace lO lose Ihemselves wilhin bulk solvenl, and a few {l Y. in lhe
case of cyelopropyl syslem. as detceled by Ihe amounl of Grignard reagenl arisin from
ring opeoing} may relurn 10 lhe suace 10 form Grignard reagent.
E. Gener Acceptlu'letl .1Id Support
That radicals are involved in the format ion of Grignard reagents has found general
aoceptance, and further evidence has becn provided for the suacebound nature of lhe
radical. The palhways Ihat describe the mechanism for Grignard reagent formalion shown
in Figure I have becn confirmed, eilher IJlIrtially or entirely, by several investigalors whose
work covers varioul aspeclS, 5ueh 15 proclucI and stereochemical analyscs, kinetic and
sptClroscopic sludies, invesdgadon of Ihe morphology of lhe magnesium, and inidal
calculalions.
1. AQreemenf with Ofher Sy3fem3
Formalion ofbiphenyl in lhe reaction of magnesium with bromobenzene (S7] was reponed
by Brycc-Smi lh and Col (S8]. Disproportionalion and coupling observe<! in lhe reaclion
of ,8,,8-dimelhylphenelhylehloride with magnesium was reported by Rilchardt el al. (S9].
Groolvcld, and associates [60] sl udied Ihe procluets formed during Ihe reaclion of
l-elholybromonorbomane wilh magnesium in THF (Scheme 2 ~ The appreeiable amounl
(12Y.) of coupling praduct, nOI only supporled Ihe inlermediacy of radicab, bUI wa, al50
consislenl wilh Ihe suace nalure of Grignard reagenl rormalion.
;
1) MI
;SO)
J;

""

00 0,0 00 00 00
,
.. ..
" "
( .... ) (U".
(l.''''.
Selttllle 21
,
,,.
Thc cons.iderable amount orphenyl group migradon observe<! by GrovclI5tein [61]
duriog ,he preparation or Grignard reagcnU {rom reaclioD of magnesium wilb
S-chlor04,<kiiphenyl-l-pcntene 44. 2-chloro- l,I,I-triphenylethane 45, an<! l-chloro-2,2,3-
triphcnylpropanc 46 in dicthyl ethcr and in THF (Schemc 22) i, abo bclievcd 10 be he
result of intermediatc radicals nvolved in tbese pror.c nes


..
Ph,ccHMaO
,
..

f'b,ccHCOH
"

..
U"""

o
Ph,ccHi --
"
".,ccH," .0_-
o
"""
"
.......
Sct.nte 11

..

PbC-CHtf'lI
..


,
"'" ..
Thi! hypothesis was actually teste<! by sbowing Ihal Orignard reagenls .., and .50,
rormed by reaction of 2.chloro- l,I,I-triphmylelhane ..... ilh magnesium in diethyl cther,
stable; therefore, phcllyl migration did nol occur afier lhe Grignard reaent was fo. lCd.
Moreovcr,lIrongchemical support for lbe radical-turfaoe nature ofGrignard rugen!
formalion WII5 providcd by romparing Ihe results oC Grovcnslein (61], {rom c10perimcnts
in which Ihe radical! upccted 10 be formcd Ind 10 remain al Ihe surface or Ihe
magnesium. with those of Curtin [62J. in which the Slme radicals were generaled in
solution (Scheme 23). In Ihe lalter case. radical 47 "'as aenerated under homogeneous
conditiolU by decarbonylalion of lhe oorrespondin a1dehydc .53. In contl'lst witb the
Grignard reaent, radical..,.. formcd by dccarbonylation, rearrancd complctely lo radical
41, as demonslrated by lhe amouol of hydrocarbon 54.
,0
I. Bu(XlI.BII .
Ph ccti,c: PhlCCH
1
'
, "
"
"
I

Ph,cHCH.,..
o
Ph,c-CH)Ph
.. ..
Stkrne 13
, ..
"

..
"""
. ,
-
,
Ph - C- CH,'
,

u
I
..
,
Pb-CH.C-
,
..
"
..
,
,
PII-CMC1
,
..
..
leo,
..
,
Ptr. - c:co.H
..
"
(" .. )
Evidence for a $urface-bound radical WIS also provided by work of Rchardt tI al.
[59J Rcaction 01 neophyl chloride 55 with magnesium Jed, aftcr carbonylali on, 10 acid
61 in 65% yield, without any contamination by acid 60, which could have arisen by
rearrangement of radical 56 10 radical 7 (Scheme 24).
Howcver, whcn he samc radical was scnerated in 5OIution under homogencou5
conditions, eilher by he radical dccarbonylation reaction of Winstein nd Seubold [63]
of aldehyde (jl (Schemc 25) or by hermal decomposition ofthe { bulyl perestcr 65 (Schemc
26). lhe !'CII ult WalI dilfcrenl.

I'tI- C- CHCHO
,

"
"''''')

,
.. "")
Se_mI: 15
"
In he former instance, he Teactioo gave rise 10 a 1:1 of hydrocarbons 6J
and 64, which indicated Ihat lhe primary neophyl radical 56 had partan)' rearranF in
sol uti on 10 lhe terliary radical 57. SimiJarly, thermal deoomposiion or perester 65 yic:lded
M,
,0
,

,
"'
"
"
( 11")
M,

, ,



.. ...
.,

(21,,)
(63")

SclKllie 26

M,
"'
a mixture oC hydrocarbons 63 and 64 as B resull oC hydrogen capture by unrcarranged
radical 56 and rearrangcd radical 57. Thesc produCls wcrc nol produoed under lhe
helerogcncous conditiODS in which tbe radicals are bollnd lo he lunace.
Rchardt el aL abo observed (59J, tbal lhe product dJlribulion obtained from
reaction oC l-chloro-2,2-dimethyl.J-phenylethanc (68] with magncsium followcd by
carbonation (Schcme 27) wu quite similar 10 lha! obtained in Ihe reaction oC raccmic
l-methyl-2,2-diphenylcydopropyl bromidc 18 wilb magncsium in tlber, ShOWD in Scheme
17.
M,
,
PhCH,c:c
"'
"
(B")
':fe ':k
PbCH1'j=-COOH .. 1'!ICHp!
M,
"
(1,,,,
Only lhe lunace oature oribe ructian could account for such a product distribution.
Here again, Ihe Icrtiary radical formed al Ihe lurfaoc underwcnt sudao: disproportionation
and dimcriution lo give rise 10 hydrocarbons 73, 71, 72, and part or hydrocarbon 70. A
rraction or the latter might be the result or reaction with 501vent.
'"
Furlher suppon fOI a lurface-bound radical can be round in work by Derocque and
Sundennann (64] on he reactioo of cyeJopropylidenemelhyl bromide 61 wjlh magnesJum
in ether (Scheme 28). Undcr eondilions in which radical 69 ,",as genef.IM al he magnesium
surface and WlllI CXpecled 10 remain al tbe surfacc, he reactioD had Ied 10 a mixture of
unrearranged Grignard reagen! 70 and rearrangcd Grignard rcagcnt 71 in approximatcly
1:1 ratio. However, wheo the lame radical intermediate" "'as produced in solution by
means of lin hydridc mluction in tlher, he ratio ofhydrocarbons 71 and 73 ,",as considerably
different
[:;
(ti
"1
[:;

,
"
...... 8r
IIMIIII/
..
A
..
----
lI)d ... ... hu
[:; t'
-
C",

M,Br
eHM,ar
[:;
,"
" "
(1: 1)
/
""-
t'
[:;
"
CH,,"
"
"
n
(9:1)
Sclwme 18
Grignard l"Cagcnl formation {rom geomelricaUy isomenc viDyl halides bas bceo
Iludied by severa] groups [65.-67), ",hose resulta ",ere consisten! wilh Ihe me<:hani!m
shown in Figure 1.
Yoshino and co-worken [65a] reporled that reaclion of ci.t-,8-bromosl)'renc wilh
magncsium in THF resulted in 95% retcntion of oonfiguralion and Ihat reaction of
r'OlI.!"-,8-bromost)'rene prooceded with 91 % relention. On Ihe other hand, in diethyl elher,
the ci!J.slyryl Grignard reagen! was formed wilh only 68% reknlion of configuralion,
and lhe Irans-isomerwu formed wilh retenlion. The 10Sl ofoonfiguration wu shown 10
lake place during formalion of the Grignard reagent They also obtained beUer yields of
Gripard reagenl Trom Ihe ,8-bromoslyrenes and fewer side producls in THF, compared
with reaclion in elher. No deulerium inoorporation wu delected in Ihe side producu
wru:n Ihe Grignard reagent wu formed in THF. D,.
A similar nonslereosxcificil)' has bcen observed in Ihe formalion ofGrignard reagents
from a series of comelric isomen of vin)'l bromides. le groups of Martin and Mcchin
and Martin [66,67] reponed lhe direct measuremenl of Grignard reagents prepared from
luch compounds. For ClIample, cu-I-bromo-I-hexene gave a Grignard rugenl containing
85% of the ci.t-isomer and Ihe t,ans- I-bromo-I-hexene yjclded a Grignard reagenl
I,ans. The dala from six vill)'l halidcs provided deflnitive evidence that Ihe metion
of isomericall )' pUN: vinyl bromides with magnesium is nonslereospeci fic. The stereo-
'lO
seJectivily of formation af vinyl Gri3llard reagenl l from ciJ- and frQ/U-vio)'1 h.lides
depends on che siu af Ihe alk)'1 substituents;; 81so, Ihe (ormalion af Grignard reagents
from c1, -vinyl h.lides ji more stcreosckctive Ihan Ihat from rram-isomen.
In anolher Iud)' a f Grignard reagen! formation by Buskc aud Ford [68], the high
stcreoselectivity observed in lhe preparation of olllf 7-benzonorbomadienyl Grignard
rcagenl! n. and m (Schcmc 29) supports mecllanisrn in which thc rate-limiting stcp
is electron traDsrer froro Ibe metalla lhe alkyl haJide, ludioS 10 radicals bond 10 lbe
magnesium lurface. Allli-7-bromo- and chloronorbomadicne 741 and 76 rcacted
with variouI types of rnagnesiurn in reftuxing THF 10 yield, alter dcutcrolysis.
benzonorbornadicne in 70 and yield, The umymmclric dimer 79 wu
lbe onl)' sidc producl isolated aOO idcntified.
,.
(pollo ',4)
"
o
o
,."." x-Br;
-
7 7 ' ....... ,
_ x.a:.
(5K t t ......,.
p' m
".
Two nleraling aspecLS of Ihis work are consisten!. wl" Ihe results i51M earlier in
Table 6 [SO). Fint, Ihe yield ofGrignard reagcnl , determine<! (mm the amouo! ofdeulerium
incorporalion, turned oul 10 be highcr (rom Ihe Imtl-chloridc 7"b (58%) tban (rom lhe
11II/I-bromide 7 ... A sewnd, and more interesting. I15pcct 15 Ihe cfreel of halogcn
on the slcrcoscJectivity. The Grignard reagcnt formed from anri-bromide was 86,.. an//,
wbercas that from lhe IInll-chloridc was more than 90% IIn/l. The higher stereoseJectivily
observcd in Ihe lattcr u abo consisten! wth the greatcr tcndene)' of RCI lO form a gil!
radical pair (scc pathway 1; Fig. rathcr Ihan a loosc radical pair {sec palhway 2;
Fig. ,ince lhe slrenllh of lhe caroon- halogen bond is in Ihe order C1> Or > l.
It was also made citar in Ihis rcporl [68] that Ihe stereoselcc,:tivi ly did no! dcpeod
on Ihe partiele sizc nor purily of lbe magncsium used. Thi! oonfinns earlier observadons
(50]. The use of Reke magnesum also did nol change the stereosclect vity significant ly.
Od Ihis sleTCOselcclivily occur afler be Grignard Teagen! was formed as a rcsult of
equilibrium bclween a millure of Jyl'l- and Ul'Ifi-Grignard reagenlil, as might havc bocen
elpecled from a sccondary Grignard reagenl [45-47.69)1 The answer was no, because the
Grignard reagenl5 (JIIti-77. and nb, as well as Ihei r corresponding 5yn-isomcrs werc
configuralionally slabk: under Ihe condilions of Iheir prcparalion, as well IU under Ihe
trapping elpcrimenl condilions.
Evidencc ror a surfacc-bound radical Ihal had accounted for the stercosclectivity
was prorided when unll_RDr 7'" and 74b werc reacted with a sodium naphthalenidc- MgXl
mi:tture(NaNaphjMgXl; Scheme JO). Thc preparation ofGrignard rcagenll; by Ihis method
is known lo prooeed by free radicals in 5Olulion. In conlrasl with rcaclions occurring
at the surfacc, aTter deuleriolysis, Ihe NaNaph/ MgX, reaction yiclded a mixlure or QIlI-D
and 5yll-D product in almost identical yicld (Schcme JO). Moreover. Ihe tack of
stcreosclectiyity in Ihis rcaction was nOI duc 10 an isomerization of Ihe Grignard rcagent
by an C:lCCSS of NaNaph [68]. Interestingly, Grignard reagent fo nnation from even the
saturatcd Ql'Ifj-7-bromobcnwnorborncne 7 .. procecd with high retention. This ucluded
Ihe possibi lily Ihat he doublc bond in 7 .. lod 74b <;;ould haye stabi lizcd the Qnti-Grignard
rcagcnt by coordinatng with he magnesium alom.
,
"

,
"'"
O
NoNopM:1.X
O
X.n..l"
x ..
1,0
o
O
O
"
( 1 ; 1)
Sebtme 30
P"NO"
Thc high 5lereosclc:ctivily could aCluaUy have Iwo origins: 1e first musl he due 10
palhways ( 1,4] that had accounled for Ihe retcnlion obscrve<l in the chiralsystems studicd
by Walborsky el al. [38.43,44,5OJ. lbis cou)d o;plain the efl'cct of halogen on lhe
stercoselcclivily. As to Ihe sccond cause, Buske and Ford [68] suggesled that Ihe rcaction
of /lm/RBr 74. and /lnriRO 74 might procccd by a ratelimiling electron lransfer 10 fonn
a 7 henlonorbornadienyl radical .1 Ihe magncsium suace. Here, the magllCllium would
trap lhe 01111 suacebound radical before cquilibralion to Ihe syll surfaoe-bound radical
could occur (scc Scheme
Landor and co-workers [70] sludicd Ihe rcaction of (S)-(+}-Ibrom0-4,4,4-
trimethylpcnla.t,2-diene 80 wilh magncsium activaled by mercuric ehloridc in THF
(Scheme RealTangcd and chiral acctylenie acid 81 along with unrcarrangcd chiral
allcnic acid 81 were obtaincd afier carbolylation. lbe latlcr was fonned wilh partial
relenlion of configuralion. Both prodUClS could be formcd Ihrough radicals boulKl lo the
magncsium surface. bul the amount of retention mUSI have bcen Ihe rcsull or Ihe ligbt
radical anion- radical calion pair forme<! Ihrough palhwlY 1.
IBu ==<,"
t.k>=' B<
(SK+l-to
Sclwmt 31
I-Bu "
...>-""""'CO," +
(SK+rtl
(R}(+)-Il
Additional support for Ihe surface nature of lhe rcaelion emerged from a sludy by
Richey and Moses [71] of Ihe configuralional slabilily of a eyelopropyl Grignard teagcD!,
thereby providing a sccond cumple [43, 44] of a cycJopropyl Grignard rcagcnl Ihal
partaJly retaiDCd iu conliguration during its {ormalion by direct iDleraclion of cyclopropyl
bromide wilh magncsium. In Ihis case, Ihe magncsium was auacbcd lO sccondary d-c3rbon,
a 74:26 milllure of83 and 84 bcing treated with magnesium iD elher al ambicnl tempcralurc.
Afier deulerolysill lhe reaelion yicldcd a 77:'2] mixlure of SS and 86 {Schemc
This rcsull shows thal lhe Grignard reagcnU wcre formed, wilh almoS! complele
relenlion of configuralion. lbe 85:86 rado did nOI ehangc significanlly, even afier the
solution of Grignard rcagcnt had bcen healed at rcfIUl for 16 hr
lbe exlensivc retcnlion observed in Ihis cyclopropyl syslem, comparcd wilh the
cyclopropyl syatems studied by Walborsky, could be ellplaincd in lerm of ditrereol degrces
or mobilily or Ihe radicals 0 0 Ihe melallic suaoc. lbus, in Walborsky's syslem [43, 44],
lhe absencc of a heleroalom providcd for I racile 180" rolation of Ihe eyelopropyl radical,
lcading alter combinalion wilh BrMg' 10 Ihe dcgrec of raccmizalion aClually observe<!,
whereas Ihe melalJated hydrolyl group prcscnl in lhe radicals formcd from 8J aod 84
mighl he involved in chclalion with the magncsium surfacc, lhereby kceping Ihe radical
from rOlaling on Ihe surfacc.
".

Me: )'", ,,CH,oMIBr
8r fI


O H
"
(74:26)
, .. '-
' .. >,0


Me'X"CHOD
H O
(77:lJl
Scbeme 32
..
2. Cycllzable Radical Probes
Thc rcaclion of 6-bromo-l-ncxene 110 wilh magnesium was studied by several grDUpa
(72), whose results were in perfect agreemenl wilh lhe audace nature of Ihe Grignard
reagen! formation. The maio product formed aftcr hydrolysis was I-hexene 111 in 85-9S"/.
yield, whereas the amo un! ofmethylyclopentane 112 was reporte<! lO Ix 3-7'"1. (Scheme
lJMI@het ,

;

2) Hp
",
",
'"
.(01;


",
'"

'"
&:kme JJ
IntcrestingJy, he S-hCJIcnyl radical, which is bctieved 10 cyclizc quickly, wilh a rate
constan! on he order of k. _ JO' scc - I ( 73,74], had led 10 a high yicld of cyclizcd product
wheo gcneratcd in solution (75). For example, reduction of 110 ",ilh tri-/l-butyltin hydride
providcs 111 in 78% yicld and onlr 7% of lhe Itraighl-chain nlcHn 111. Thi! contrast!
with whal was aelUal1y observed in formalion of Ihe Grignard reagenl by reaedon of 110
with magnesium. in spite orthefact Ihat Ihe Shellenyl radical is involved in bolh nnances.
Tbe innuence of salvenl on Grignard reagenl formalion in Ihe 5-hellenyl system was
sludied firsl by Dodewitz and mociales (76] and 1) yean later by Ashby and Oswald
oIG1/hIlM1IfHerntFomNftIoIr
'"
Table 8
YieJd of Gripard Compounds and Side Producu in lhe Reaciion of 6-Bromo-J-huene
"';th MI gn.csium
M .
50tHnt ratio ViKOS;ty
Et,O
TMF
THFOBE I/I .n
DBE
DPE
THFfbcru:enc 1/6.7
R .. , It .. iaht eh.in; R.. eyelM:.
500;",: Re. 16..
0.19-(
0.389
0.461
O ...
0.80
O ...
AbsoIutc yieldJ" (%)
R .. MIBr R.MgBr R ....
8s.5
"
9.0
" .0
"
'.0
... ,
9.0 ' .0
73.5 18.0 7.0
65.5 21.0 '.0
54.0 19.5 17.5
RetaliH yields' (*.4)
R"R ..
R.R, R.R.
6"
18.0 7.'

29.0 17.0
45.5 31.5 210
39.0
".0
21.0
35.0 38.5
,.,
... 0 36.0 11.0
(77]. The DUlch group (76] has: d its conclusions on producl dist ribulion and correlalion
wilh lhe iDlensily or lhe CIDNP spcctra of lhe Grign.rd reagent, whereas Ashby and
Oswald (77] sludie<! only product dislribulion after qucnchinJ lhe reaction wilb DlO.
Similar conclusions were reaehed by both groups, who Cound lhal lhe nalure or lhe solvenl
(Le., ils viscosi ly, basicily, and 1r-eICl;tron-4onalin .bUiIY), influenced, 10 a oenain
Ihe evolulion ollhe loase radical pair (R J MX) al lhe aite of tbe elect ron Iransler, wbich
afi"ects 1M: oompetilion belwoeD palhway S ol Fiure 1, 1eadinIO Gligoard reagent, and
palhways 6 aOO 7, leadin lo disproportionalion, dimerizalion, iJomerization, .nd so oo.
P.lhway 5 wu more imponanl iD more basic IOlvents, luch u THF, which is known
lo be good solvenl for Grilllard reaenl rormalion.. Masl of Ihe radical5 rormed in Ihis
solvenl reacted 10 fono Grignard reageDI (85%), Wheleas lower tOlal yields or dimen;
were observed (Table This could be attribuled 10 Ihe ablly ollhis solvent 10
magnesious halide (XM') al the metal suace, Ihus racilil'liu its combination witb a
radical lo lorm R.,.MX. However, in lesa buie soIveots, such u diethyl elher
aOO di-n-butyl ether, Ihat do 001 solvale XM as weD as THF, lhe radtcaJ R' could lcave
the si le or lhe sillle .. dectron transCer, tbc:reby enabl.in il 10 react more casily wilh anolher
radical R' al the surfacc: 10 produce more sid( productJ (soe palhway 6; Fia. 1). In
accoldanoe wilh Ibis vjc:w. higher yie1ds of dimen and, consequc:ntly, low yic:1ds o
Grignard reagc:nl were actuaDy observed in such solvents.
On lhe olher hand, lhe amounl or cyclu.ed product depended Ilrongly on lhe viscosily
or lhe solvenl used (76, 77]. An increase in solvenl viscosily would be expc:cled 10 inaease
lhe lirelime or radicals, thus facilitating lbe cycliution proccss al lhe sile oC siDgle-eICl;tron
transfer (SEl'), wilb subsequent formalioD ol cycli7ed Grianard, aOO would reduce: Ihe
mobilily of R' at tbe metal suacc:, Ihereby preventing Ihis radical Crom enoounterin
olher radicals (soe Table
Di lulion ofTHF wilh a II"-electron-donaling solvent, such u bell1..CDe [76], dc:creased
Ihe reactivity or R' wilh XMg' lo form Grignard reasenl al lhe site or Ihe ainJe-dcctron
transfer (soe T.ble 8). Conscquently, lhe lotal yield of slraihl-chain Grianard reagenl
docrelUd, wherea. the 10lal yie1d or dimcrs increasM
Increl5C in lhe benzene(IlfF ratio would reduoe lhe tendency or THF lO complex
XMg' necessary ror form.li on of Grignard reagent al lhe lite or Ibe SET, aided by a
possible inleracton belwcen lhe radicals and a Ir-electroo-rich solveD!. This would increase
,,,
the tendem::y of the straighl-chain radical 10 [cave the , de of Ihe SET and move away on
he magnesium suace, befare cycJizalion, so Ihat it oouJd meel _nOIMr radical.
Ashby and Oswald [71] nduded Ihe cffecls of activadoD of he magne!lium,
temperature, stoichiomctry, magnesium punl)', and oature of he halide in heir study.
Duriog he reaction of 110 with magncsium in THF, actvate<! by EtBr, 1
2
Of sonification,
5ligh! increase (J-4Y.) in lhe amOUO! of Grignard Teasenl took place, 85 measured by
lhe deuteriurn conten! aftcr quenching with 0
1
0 . In ract., an alkyl halide, iodine, or
$Onificalion activa les magnesium by incrcasing the number of unsaluraled &iles, or by
cleaning he sudace. Varying the temperature from 22 10 61C, Of t hanging the duradon
of he reaction, had linle elreel. On he other hand, ID ncrease in he concentration of
110 slighdy decreased the yield of I-hexene from at 0.001 M, while increasing the
yield of dimer from O to 3., -;_. However, the n:lative yields ofGrignard reagent, as indicated
by the amount of deuterium incorporation, were not affected by a change in concentration
of alkyl halide. Tncreasing the magnesiurnJalkyl halide rati o did not influence the relative
yield of Grignard reaSenlo but did slight1y increase the total yield of I-hexene, as well as
lhe total yield of methylcyclopenlane. Also, more straight-chain Grignard reasent and less
cyclic Grignard reasent were formed from chlorohexene, compared with bromohexene.
4. Klnetlc Ane/ysis
In the Jale 19705 aOO eany 198Os, two groups altempled by mean! of kinelic sludies lO
delermine the rale-delermining sleps in Ihe reaction leading 10 formalion of Grignard
reagen!. Al thal time, the kinetic ludies in queslion sulfercd from a lack af informalion
on the rcduction of organic haMes [78.79].
Volger and co-workers [SO) made an atlcmpt 10 decide betwecn Ihe Iwo allemativc
ralc-delermining slepl 1 and 2 of Figure 1, pathway 1, which leads to a ligbt anion
radica\--eation and pathway 2, which leads to the loosc radical pairo 80th palhways
were viewed as electron-transfer reaclions..

R-X+Mg ----SET ..... [R_X' - Mg
2
+]
R-X+Mg ----SET ... R'+'MgX
( 1)
(2)
Mcasun:mcnt af Ihe carbon kinelic i$Otope elrecl in Ihe n:action of methyl iodide
wilh magnesium in diethyl elher and comparison with a cak::ulation ol Ihe theoretical
equilibrium isotopic effecl for the homolysis of mcthyl iodide led Volger and co-workers
[8] 10 suggest that palhway 1, rather than palhway 2 (tcc Fig. 1). was the rate-dctermininl
step in formation of an alkyl Grignard reagcnt. Afluing Iha\ a caTbon isolOpic cffcet
would be expected if pathway 2 were involved, their experimental results showed that
formation of Ihe Grignard reagent proc:ecded wilh no delectable i$Otopic elfect
(uk
u
/ k,, _ O.9992 O.OOO5). On the olher hand. the calculated equilibrium isolopic elrcel
for the equat ion, CHlX ... CHl .+X' , lor which he methyl radical was taken as model
for the intcrmediate in palhway 2, Hes betwecn 2 and 3-/0. Although thesc studics
5UppoTled Ihe belieflhat palhway I was involved in the ratc-dctcrminingstep, the modcl used
for lhe calculation to lest palhway 2 was really noln:presentative of the pathway in qUCIlion.
Subsequently, kinctic "udies n:ported by Whitesidcs and collaborators [81] provided
rurtber support ror Ihe view Ihat tbe rate-determining slep in formalion of alkyl Grignard
rcasenlS involves eleclron lransfcr from Ihe melal suace. The netics of (he reaction ol
an organic halide R, X with magnesium were described by Eq. (3). in which S ... aocounlcd
for Ihe characteristics ol magnesium surface Ihat inftuence Ihe rate, and an analogoua
,
expressioD [Eq, (4)J for another orgallc halKle R1X. usi ng lhe same valut of S,,""
- d(R,X) le (R X .. S
dI - JI/NI
'"
(J)
(4)
Utwo oTgaoie halidcs in lhe lame rcaction mixture compete for a common magnesium
$urface, the expression derivcd froro Eqs (3 and 4) by assumiDg - I aOO integralios would
be Eq.

By usiog Ihis competitive lechnique for (he reaction of alkyl halides with magnesium,
the plol! of Eq. (S) exhibited a linear character as iIIustrated in Figure 2. The reJative rates
(k ,/ k}) were independent of lhe conoentration of al"yl halide or t he Iype of magnesium
used, the , izc, Ihe punly, Ibe suacc area, and Ihe quantily.
or furlher nleres! is a comparison [81 b] ohlle structure-reactivity profiJe for several
rtaCllon Iypes (Fig. 3), such as {JJ Ihe Grignard reagenl or organic halides wilh magnesium,
(2) a reaction ovolvi og a carbanion intermcdiate, such as a metal--halogcn interchange;
(3) an SN' react ion such as displacement of bromine ion from an alkyl bromide by iodide
ion; (4) an SN,-tYPC rcaction involvi ng a carbocation, such as thc solvolysis of
I-met hyl- I-chlorocycloalkanes; (5) the free radicaJ reduction of alll: yl bromidcs by
tri-n-butylti n hydridc.
The 81kyl iodides and most of the alkyl bromidcs sludicd reaclcd wilh magnesium
in dielhyl elhcr al almosl idcntical rates (sa:: Fig. As can be seen, Ihe rale of the
Grignard rcagcnt was leasl sensitive lO Ihe sl ruclurc of the organic hal idc. The
difl'ercnce between Ihe structure-rcaclivily profiles for the Grignard reag<:nt and the
.
X
-
a:
";;
X
-
a:
1.2 U
Figure 1 Four repruentltive Grignard rugenll ploued accordins lo Eq. (5); bromide
n.cydopenlyl bromide(e); cyclopentyl chloridc V$. cydopentyl bromide npeDtyl chloride V5.
thloridc neopentyl bromide VI. cyclopmlyl bromide (O). (From Ref.lllb.)
'l'
' .0
' .0
-

.
0.0
"

."
S, 2
-

..
E
.0
:: t
/'(
I tcHtInqCH,lCl looIw!
"
...
"
...
' .0
Ftcure J Comparison oftM strocture-reactivity profil!: for reaclion Iypes. (CsCHA, =ium
(From Rd . Bib.)
Sl ructure---reaetivity profi les for Ihe reaclions or Ihe ot her models was in agreemcnl wilh
carler findings of Walborsky el al. (44,50J thal Grignard formation does nOI
invol,,!: froe carbanions Of carbonium ions (51'1 ') as inlermediates and tha! a Iransi tion state.
sueh as Ihal nvolved in an S,., rcact on, oould also be cxcl uded rrom Ihe mechanism.
Thc ume aUlhan again conccrned hemselves [81d) wilh Ihe queslion orlhe existencc
of alkyl radical anions as discrete intcrmediates aJong Ihe rcact ion coordinal!: and whethcr
Ihe reaclion of alkyl halides wit h magnesium proceeds by pathway I or 2 (_ Fig. In
contras! lO (he "iew or Volger el al. (SO], who rercrrtd 10 palhway 2 as an cleclron-I ransrcr
proocss [ Eq. (6)] as origi nally described, Whilesides el al. viewc:d palhway 2, ir il has an
c:xiSlence, as a halogcn abslrac1ion [Eq. (7)).
To decidc: belwcc:n Ibc$c two models, thc:y compared ratc:--st ruelun: proli les ror the
disappearance or al kyl halides in eontael wit h magnesium wi th ratc:--struclUrc profiles ror
others models of reduct ion. These ineludc:d (1) rate-slrueturc proli les ror the rree radical
reduet ion or alkyl ehlorides wit h lri-n-bul yl tin hydridc in diethyl cther [ 33], assumi ng
T.bIe 9 Correlalion CodIicienIS (and Leul-Squares Slopc:l) CharKIeri:tinl UDear Free Enero
Com:lalionl Bclwcen Reactions Thal redUCle Atkyl Halides'
"""
"'"""" """"'"

_ ..
RCI{BuJSnH) O.9(l.S)
(EI
I
O,3S' C)
RBriBu)SnH) 0.82(3.2) 0.97{lO)
(EI,O,o-O
RBriCH)C. H.),COU) 0.93(0.78) 0.94(0.62) 0.87{O.31)
(RHF, 24' C)
RCI{E,z) 0.99(6.S) 0.96(6.3) 0.91(3.1) 0.93(9.S}
CC, DMF, 2S' C)
RBriEuzl 0.74(9S1 0.73(4.3) 0.81(8.4) o.93(1J} 0.8.5(0.69)
(Hg. DMF, 2S' q
'Theoo P'l'I.f<\d'" ore dori'led ('0lIl t"" pIou 01101; 1". .... loa 1"., Of rNM los l:", ... E". ror qdopmt)'l.
qcIohc1)'1. cyduod)'l. ... pcnt)'l. l.haJo. l .tkylcthl.nc, and 2. baIo-Z ... lkylproponc.
Ihal Ihi , was a model for homogeneou$ halogen abstraction in an innerspherc
proocu [84]; (2) rale-slruclurc proliles for Ihe rcduction of alleyl bromides wilh lilhium
4,4'dimelhylbcnzophenonc leelyl [SS] in THF, assuming Ihat Ihis was a model for
homogencou$ electron IransIer in an outerspherc prON'SS; and (3)
profiles for the elcctrochcmical rcdudiOn of alleyl halidcs al merc:ury and glassy carbon
electrodes [86], as a model for a hcterogencous eJcctron lransIer pl"OCCS3.
Linear correlations were observe<! belwcen reaclions of alleyl halide3 wit h alt of lhe
reducing agenls, as also demonstrated by the rorrclation coefficicnts shown in Table 9.
Thcse correlalion! were taleen 10 indicale that Ihe slep(s) involving carbon- halogen
bond breaking in aJl hese rcduction pfO!nses mus! be similar, which means, following
hese aUlhors, Ihat Ihere musl be a common palh Ihal does nOI involvc an inlermcdiale
in the rate-delermining slep. The highest corrclatiOD observe<! was between the
profile for elcclrochemical rIuclion of alleyl chlorides al a glassy
carbon elcctrode and the rate-structure profile for lhe reaction or alleyl chlorides with
magnesium. Thi! point is of significance and wiJl be elaboratcd on in Ihe elcct rochcmical
section.
However, although the resull! were ofinleresl, these analyscs of rale-slrUClure profiles
for reaclions of organie halides would nol distinguish betwcen a path in which
carbon- halogen bondbreaking occurs by halogen abslraction froID the alleyl group by
Ihe melal (an inner-sphere process) and a palh that involvcs a single eJcclron Iransfer 10
Ihe organic halide from the melal <an ouler-sphere Such a dccisioD, ji was
concluded, be made made by an experimenlal approach bascd on qualitative
comparisons of rale-slrUClure profiles with those for reactions whieh mighl be expcctcd
10 exemplify Ihese mcchani!tic limils since aJl Ihese profiles appearcd lo be Jincar1y
corrclatcd with cach ot her and lince iDner and oUI -sphere processcs may exhibil
lnearly-corrc[atcd rale-slruclure profilcs."
A sccond approach, used by the Whitesidc group, employcd the conslanl- surfacc
technique [8Ib), which involvcs followinglhc disappearanoc, with lime, of one orpnic
halide in contact wilh a largc mass of magnesium, replacing Ihc solulion of lhe ini lially
formcd Grignard reagenl wilh a solution of a sccond halide and following ils disappearance
with time, all wit houl chaDginglhe surface arca of Ihe magnesium. UOOcr these coOOi lions
'"
T.We 10 Relativc Rale:l of Reaction
.00 Cyclopentyl Chloride wilh Ma,ncsium in Severat SolventJ
Relative n.le"
oomponition '1, cP RB, RO
El,O 0.33
,
(80:20) 0.33
''''
THF
"55
...
RMIBr (0.6 MI
(Et,O-pentane.80:20) 0.5& 0.06 0.03
Bu, O .7
O.'"
El,O-Nujol (80:20) .72 0.47
Bu,o-..:ydohuane (7S:25) .77 0,49
THF- HMPA (75:25)
"79
0.47
RMBr (1.0 MI
Et,O-pc:nt.ne (70:30) 0.80 0.58
RMIB. (1.0 MI
El,O-penllne (80:30) 0.86 0.47
RMsBr (0.6 M)
EI,O- pcntane-Nujol (80;10:10) 0.89 036
RMIB. (0.6 MI
Et ,O-paraffi n ol (80:20)
L'
0.29
RMaS, (0.6 M)
Et ,O-Nujol (80:20)
L'
0.27 0.05
RMIB. (1.0 MI
Et ,O-penlane (80:20) LS 0.20
'Relll;.., lo !he .. le o( dielhyl Clbe .
St-n-: Rof. 81r.
he Tates of reaclioo of cyclopentyl bromidc aad cyclopentyl chloride with magncsium
were proportiona] 10 Ihe cxpose<! surface arca SM." of he metal.
_ d(RX) _ k.,.{RX)S ..
d,
(S)
This suggested tha! lhe rate-dctermining slep musl involve reaclion of Ihe organic
halide al the surface. ThU5, a mechanism involving a soluble magnesium species Mg' was
excluded, and one could conclude that Grignard reagent formation takes place al Ihe
mctal-solution interface, at kast for Ihe rale-dctermining elcct ron-ttansfer slep.
Furthet won: [SIf), which dcmonstrated that the rates of reaction of cyclopentyl
bromide with magnesium lit the kinetic fealures of a transport-limited heterogenroUI
reaction, was bascd on two SCtJ of cxperimenli. Fint. the relative rates of reaction of
cycJopenlyl bromide and cyclopentyl chloride with masnesium in solvent. of dilfercnt
viscosilies [81f) were examined by applying the constant-surfaoe kinctics lechniquc. Thc
results an:: . ummarizcd in Table 10. These demonstratc Ihat Ihe relative rates of n::action
of cyclopcnlyl bromide wilh magnesium in a series of solvents "'ere proponional lO Ihe
nverse of the solvent shear viSCO!ity (,, - 1). whereas the reaction of cyclopentyl chloridc
was 10
1
slowcr and inscnsitive to solvenl viscosity. This was taken as cvidence Ihal lhe
''''
rcaclions are Iran,porl-controllcd lar cycJopentyl bromide and nOI forcyclopentyl chlande.
evcn Ihough he latler js known lo have a 5lighll)' larger dill"usion coefficicnt and ia
supposed 10 react more rapidly in a diffusion-controlkd proo J'
Second. he relalive rates 01 he reactions 01 bromide 8nd cyclopeDtyl
chloridc with magnesium wcre eJlamincd as a lunction 01 stirring Tate (w) [SU]. II was
assumcd Ihat ir lhe reaaian! were Iransport limited, an ncrease in slinio! rate would
decrease he thicknes.! of he boundary layer and, therdore, increuc lhe rate al which lhe
alkyl halide reaches he metal surfacc. Indecd, lhe ralc oC disappearancc 01 cyclopenlyl
bromide was dependenl on (IJ, wnereas he ralc 01 reactloD 01 cyclopcntyl chloride wu
ndependent. In a vanation ofthcseupcrimenu, lhe ratc 01 reactlon 01 cyclopentyl bromide
in diclhyl ethcr depended 00 he angular velocity 01 a rotalieg disk er magnesium, whi4::h
was taken aJI evidence for a mus transport-limited reaction. Tbese results Ied te lhe
conclusion [811] that tbe rales ef reactien or organic iodides and most organic bromides
with magnesium are either mass transport- or dilfusion-limiled. Less reactive organic
bromides, such aJI atrl-, neopc:ntyl-; and e)'cloprop)'1 bromide, react al rates Iess ihan mass
transporto The rates of reaction of alk),l chlorides wilh magnesium are slower and are
not mass transport-limited.
In a similar altempl 10 delermine lhe nature of !he rate-determiniog step in Ihe
reaelion of aryl halides wilh magnesium, the kinctics of tbe reaction of Jubstitutcd aryl
bromides with ma8nesium and wilh lri-n-bulyltin hydride in elhereal solvenlll wcre
enmined [SIc], using competi tive kinetics techniques, and were correlatcd with lhe
p,bstitucnt effect IlSing Hammctt u paramtten;. A Hammctt plOl: lOS (lcJlcJ-f(uJ Ihen
providcd Ihe value of the Hammett constant p for the reactions of ar)'1 ha1ides with
magnesium ami wilh Iri-n-but)'ltin h)'dride in vanoul solveolll (Fig. 4 aOO Table 11).
Jnspeetion ofTable JI show! Ihal p for the reactien of aryl halides wilh Iri-n-bu,)'llin
h)'dride was not solveel-dependcnl, whereaJ p for the reaction with magnesium was.. The
small values of p for he reactioe of aryl bromide wilh magnesium in a polar $Olvent were
again inlerpn:lcd [SIc] io lerms of a mass traosport-limitcd proocss. Thus reactions of
aryl bromides woukl be transport-limi ted in THF and more polar salvenls, but nOI io
dieth)'1 elhet and less polar solvenl. On Ihe otber haod, Ihe rate of reactioo of aryl iodides
wilh magnesium socmcd to be lranspon-limilcd, even io dielh)'1 elher, wben:as the rale
of rcaClion of ehlorobenzenc with magnesium, whieh WaJI l<r slower Ihao that of
bromobtnzenc, was noto
Al Ihis poinl, Whitesides and co-workers concludcd [Si c] thal il was unlikely
Ihat the rate-delermining step ovolved ttansilion s'ates, such as startiog malerial,
physiosorption, aryl cations, ar carbaoionic structures.. Thc Hammcll values of p, tegetber
wilh the observalion that the rates of lhe reaction of aryl bromides with magnesium in
elher, correlatcd wilh the tales of abstractioo of brominc by tbe lri-n-butyl tin radical, as
well as wilh Ihe half-wave reductian poleotial$, Icd tbem [8Ie] lo suggest Ihree probable
limiting struetures for Ihe rate-delerminin8 step in Grignard rcagcnt formation Crom aryl
halides. Thc fjrst possibility was an electron transfer from lbe metal to aryl bromide,
lcad;ng lo a radical anion, the second Wa! bromine abstraction by magnesium, which
produces ao aryl radical, and the thin! an insertion of magnesium into lhe carbon- bromine
bond. Thus, Ihis work did nOI anser tbe original questiao 00 whether Ihe rate-delermining
slep was pathway I or palhway 2 e r bolh (101: Fig. n
5. Spectroscop/e Stud/es
Funher and direct evidence for Ihe occum:nce of radicals aOO also prno! for radicals pair
as illlermediates in formalion of Ihe Grignan! reagcnl was providcd by chcmically indueed
'lO
A
-t-+-i-',
Figure" Two cumples or Hammelt plOIS; (A) Hlmmoll ploll for reacti(lns of lubiltiu"cd
bromobenzenes with Iri-,,-blllyll;n bydride ;11 dietllyl o:thcr. (B) HammcU plOI$ for rudions or
Jubstiluted bromobcnzenes "";h MI in diethyl tlllC'!".
Tibie 11 Hammell Values for Reactions or A.yl Hatioka .... ilh
Magnn;um and ",lb Tri-,,-butyltin Hydride
ArO+MI
ArI + Mg
ArBr+Ms
ArBr+BuJSnll
Sourc.-: Re{. SIe.
Hamrnctt v;lucs (PI
THF TItP
<o.s <0.6
I.J O.2
2.0o.2
O.2O.2
1. 1 0.2
l.4O.2
3Bu,O-IC.H, .
lOO.3
dynamic nuclear polarization In a tcries of reports Bodewitz and associates
[60,76,87.- 81c] cumincd the ClDNP 'HNMR spectra produced dunng Grignard reacnt
fonnation by reaclion or ".riOIl5 alkyl halidcs ",ilh magnesium in THF and clher. The
main fealure or Ihis method is tbat il allows one 10 rccognizc Ihe producls that are
,,,
I ! , I , I , , , , ! 1 ! , , I I I I I t I r I I! I
U f.O U u 'O 0.1
FiJuu 5 A ' H-NMR CIDNP lpectrum dunna lhe raction of I-iodopropane "'Ih
magnesium in di-II-bulyl CHJCHJCH.Mal; {, . 7-6.16--CH,=CH-CHI_ (From Rcr. 87b.)
{rom radicals. By Ihis means radicals may be delected arter a penod much longer Ihan
tlld. Iirel1me.
A CIDNP phcnomenon was a1ways observed in sigoalsemanating from Ihe - proton!
or lueh Grignatd reagents. oocasionally when lhe signals or lhe solven! did nol
ntenere, Ihe elTect C()uld also be observe<! in lhe proton signals or Ihe di sproportionation
and coupling producls, Ihcreby indicating Ihe position al which lhe process bad oocurred.
One or Ihese ;ases js iIIustrated in Figure !l. Thi. nol only stronal)' supported Ihe radical
nature of lhe reaction, bul abo provKted further proof for Ihe occurrencc oC radical pain
as inlcnnedi ates and for a suacc- bound radical
Consisten! wilh palhways 1, 2, S, 6, and 7 in Figure I or Ihe mecllanism proposed
by Walborsky and co-workers, Bodcwitz el al. [60,76,87a-37c] carne 10 the conclw;ion
Ihal Ihe ruction of an aryl halide with magnesium procC!ecl! by a single eleclron Iransrer
from lhe aunace of Ihe metal 10 Ihe carbon halogen bond lo produce a radical anipn
absorbed allhe metal suace by electroslal;'; inleraction and uniposilive magnesium M" ..
(see pathway 1; Fig. 1). RapKi dooomposilion of Ihis anion radical aOO combinalion of
X- with the uniposilive magnesium would lead lo lhe radical R" and Ihe magnesious
halide XMg; (see palhway 3: Fig. Thc latter was described as "s" meaning "a
suacc-bound non-free radical." In agreemenl wilh Walborsky's mechanism, lhey also
indicaled Ihal mOSI of lhe radicals underwent a fasl reaction al lhe lile of lhe eleclron
Iran5fer wilh XMg; 10 form lhe Grignard reagent (see palhway S; Fig.
Howcvcr, lOe CIONP spect ra did nol show that Ihe radical pair involved in the
formalion of lhe polarized Grignard reagenl was R' 'MgX. This was attributed lo a lack
of lhe required degrees of frccdom of XMg; lo take par! in singlel triplel mixing in a
radical pair R' 'MgX and Ihe fast prones! of coupling. Alternativcl y, radical R' could
escape From lhe site of lhe eleclron lran5Fer where il is forme<! aOO undergo hydrogen or
halogen abstraction (!ICe pathway 6; Fig. 1). Anotner route oF escape for lhe radical would
be associalion wilh anolher radical lo form a radical pair R' 'R, which would result in
Ihe polari:talion observed in lhe alkyl group (see pathway S; Fig. 1). Such a"oc1alion
would also account for the di sproporti onation and coupling proouCU {sec palhway 6; Fig. 1
An argument could be made Ihal Ihe radicals dilfuse apart when ruction by palhway
6 does nOI occur. Here, the resull ing free radicals might undergo association with XMg;
10 yield Grignard reagcnt and hydrogcn or halogen abstraelion. However, such a possibitity
appears unlikely, since il would not accounl for Ihe amounl of Grignard reagent formcd
(98/.). As Bodewilz and oo-workers poinlcd oul, if Gri8nard reagent were formcd by
radical pai rs R' 'R, or if Ihe radical did nOI reacl al (he site of il5 (ormation, a much
lower yield of RMgX would be: expoctcd owing to disproporlionalion, coupling. and such.
This providcs support for the original mechani sm proposed by Walborsky and co-workers
in whieh the surface-bound radical play! the major role in Ihe formation of Grignard
reagenl, and hey commenl Mwe fecl that Ihe direct reaction at the site of Ihe electron
trander is by far the most important roule leading to the Grignard reagcnt.
K
Al so of interest are the results of Scrgccv and co-workers [8S] who investigatcd Ihe
solid-phase reael ions of magnesium wilh ary! and allr.yl halides at low temperalure by
means of EPR. Their invcstigation of Ihe reaclion of magnesium alom with orpnic
ehlorides [88b] supports Ihe existence and participalion of radical anions and radical. as
well as Ihe suace nalure of the reaction and provides further evidence Ihat the ratio of
inlermedialC!, radical anion-radical pair, formcd by palhway l and palhway 2 (Fig. 1) is
slrongly dependenl on the earbon-ha!ogen bond strength.
In general, Ihe EPR spectra of condenscd magnesium wilh alkyl and aryl hal ides
exhibited two Iypes of signall, depending mainly on the nalure of lhe halogen.
Fluorobcnzene. with a carbon- fluorine bond ellCrgy of 122 kcaljmol, exhibi lcd a si nglel
eharaeleristie of the ani on radical RX' - Mg' whereas bromobenzcne (15 kcal/mol)
showed supcrposition of a broad signal and a multiplet The latler was assigned to the
radical. On Ihe ot her hand, the EPR spectrum of condensed magnesium wilh fl uorooctane
(carbon- f1uorine bond, 101 kcalfmol) showed a sextet, with a superimposcd singlel, whereas
bromobutane (68 kcaljmol) exhibited a sexlel. These dala would lead one 10 the
inlerpretat ion Ihal an increase in the carbon-halogcn bond strength induces an ncrease
in t]}e yield of the ligbl radical anion- radical cation. Formalion ofGrignard Teagent would
occur largely by pathways 1 and 4,(see Fig. wit h a concomi tant docrease in the formalion
of radical pairs (soc pathways 2 and 5). This is reflected in Ihe fael thal Ihe highesl
retention of configunuion in Grignard formalion in the reaction of l-halo-l-melhyl-2,2-
diphenylcyclopropane was observed when lile halogen was chlorine. On lhe olher hand,
weakening of the carbon- halogen bond would !cad to a very low yield of lhe light anion
radical-cation and rormalion of the Grignard reagent would occur maioly by
pathways 2 and 5. Indccd, Ihis is what was observed; absence in Ihe EPR spect rum orthe
singlet charaeterislic of the ion-radical pair in Ihe rcaclion of magnesi um condense<! wilh
iodobutane is coupled with the lack of retent ion of configuration in the reaetion of
l-iodo-l-met hyl-2,2-diphenyleydopropane wi th magncsium.
Support for Ihe surface nature of the reaction was also provided by Molle and
oo- workeT5 [89a,b] who sludied changes in Ihe metal surface during formalion of lhe
Grignard reagcnt from I-bromoadamanlane and observcd formation of a black layer 00
the melal suace, with a thickncss reaching 111m. The magncsium turnings coalcd wilh
Ihis deposil were subjected 10 XPS analysis and ion bombardment [90J to analyze the
element! presenl al differenl depths and 10 obtaio information on the phenomena occurring
al Ihe melal-solulioo inlerfaa: when an alkyl hal ide reaets with magncsium. Figure 6
ilIustratcs Ihe evolulion or the signal inten!it y ratio R l or eh and Mg
I
electrons as well
as the signal intenslY ratio RI of and Mg
l
electron,. These ralios eorrespond lo
the ratios of the componenl5 in Ihe deposil al dilferenl depths. The layer al Ihe surface
was divided inlo three important regions. At Ihe oul$C1 il should be noted Ihat the XPS
spectrum recorded afier reaehing lhe ,urface ilself was iclcntical wilh Ihat of a scoured
magnesium turnin (R ,= R1=O). The XPS sludy of Ihe so-callcd lower region (up 10
,,,
N(E)
1
0"
'"

N(E)
3



'.
TH( _.-

(.) (b)
Figure 6 ' al An cumpk of XPS lpectlll 01 Ms!urnings before Ind . fkr lhe reaClion ilI nl lated
wilh dibromoethanc .00 . lter reaction wi lll I-bromoadamantanc. lb) XPS . naI YI;1 orIlle componenll
in lhe dcposit al diffcrcnl dcpths (R" [C
1
.VMI2J; R: . [BruJf[MgJ.
4 prn of thiclr.ness) showed that Ihis regioo was oompostd maioly of and
I,I'-diadamanlane. In l his regioo both ralios R, and RJ incn:a.!ied. indicati ng ils
helerogeneouJ character. The prcsence or highly reactive magnesium Mg" alons wit h
diadamanlanc in Ihis region nOI ooly showed herir oommon origin, Ihe loosc radical (R'
' MgX) having bten formed and reacted largcly al tbe sulface. bUI also supponed Slrongly
palhways 6 and 7 (scc Fig. 1). Thus, as predicted by Ihe mechanism discussed earlier, lhe
adamant)'1 radical dimerized (sec pat hway 6) al tbe metal SUrflce 10 give the ooupling
, ..
product, ""hile MgX disproportionated (_ pathway 7) lo yicld highly react ive magncsi urn
Mg- and MgBr._ Thc intermediatc rcgion aboye 4 pm containe<! Ihe same oomponcnls,
huI character, as ahown by Ihe constancy of bolh ratios R, and
R,. Thc third, upper regioo, which began al 6.95 and cnded al 7 11m was maioly compose<!
afMgBr ,. as indicatcd by lile increase nf RJ up lot he known valueofMgBrl which s8.
Othcr work in Ihis arca Ihal dcscrvcs lo be citcd is a report by Ault [ 91] 00 he
formalion aOO speclroscopic charactcrization of unsolvatcd Grignard rcagenlS by
isolation. Although a gas phase model has li ule 10 do wilh cvcnt s Iha! occur when Ihe
Grignard reagcn! is prepared in a salvent, he resul t tseU relle<:ts he major role pIar e<!
by lhe surface orlhe magncsium. Magnesium metal was codcpositcd wil h samples of melhyl
hal ides (CH.X: X_C!, 8r. l) in un argon malrill. and Ihe producls formed were analyzcd
by infrare<! spcclroscopy. New bands (S43, 1305,2800,2892 cm-tI were delOClcd arter
every reacl ion. This thal, even in inert mal rices, Ihe insertion of magnesium
inlo carbon- halogen bond lake5 place 10 lead 10 an unsolvated Grignard spccies.
6. Ab /nll/o Sludy of 'he Mechenlsm
Ab inilio calculalions by David (92J on nsertion of an $Olated magncsium alom into
Ihe carbon- halogen oond of fluoromelhanc and chloromelhane includcd calculalions of
transil ion ! tale energies, gcomelries, and vibradonal rrequencies. 80th syslems ellhibited
si milar gcomelries for Ihe l ransition st ale wilh C. symmetry (Scheme


The tramition ! Iate for Ihe reaclion was located at SCF and correlated levels. Geomelrie
parameters and encrgies for Ihe transit ion stale were comparcd with hose of Ihe Grignard
reagenl CHlMgCl, t he lalter also arri ved al afler full optimizalion al both lhe SCF and
corrcl ated levcb.
As can be IleCn from Table 12, Ihe Mg--CI bond diltance in lhe lransilion slale i.
quile close 10 that of lhe Mg-CI portion in the Grignard reagenl CH. MgCI. !bis was
T.ble 12 Par.meten and Energics for Tnuuition Slate (H.CCI M)# aOO lile
Grignard Molecule CH. MgO
(H.CCl Mg)# CH1MgO
Paramelera
SC,
MP2 SC, MP2
C- Mg (A) 29862 2.7471 2.090
"799
C-C1 2.S174 2.2SS4
Mg-O 2.392 2.38 11 2.2]7 2. 1917
(Mg-C-O) (degrces) SO.65 55.81
(H-C-M&) lIt. 7 11 1.46
Energy (IIarlrees) - 698. 649 -699.182 - 69&.764 - 699.338

11$
85Cribcd 10 (he slroog interaction betwocn the magnesium and the halogen in the transidon
llatc. Thc ncl alomic charge was determine<! by a Mulliken populalion anal)'sis fOf lhe
Grignard reagen! and for he transidon slate. Thc charse- found VIere C. -08.18; Mg,
0.911; a, - 0.522, fOf he Grignard reagen!, and C. -0.]16; Mg. 0.107; a, - 0.44, for he
rlnsition Slale.
IV. A MATHEMATtcAL APPROACH TO IESTABUSHING A MECHANISM
Anotiler vicw of he mcchanism of Grignard reagenl formation was advanced by Oa,.,1
and co-workers in 1986 [93].
A. Dltru,lon Moct.l CIIlculallon .nd "'Isumpdona
The view, lO be djscuMed in Ihis section, nvolved a mathematical model calle<! he difJusion
(O) model, based on kinctic data and lhe product distribwtion found in several Grignard
reagent!. 1I Vlas agreed Ihat the fin! !tep in Orignard reagcnl farmltion ia an electron
trander from he magnesium sunaee 10 Ihe carbon-halogen bond, leading to a radical R' ,
The radical i, formcd in solulion al conslanl flull u, in aplane parallello Ihe sunaee and al
a dislanee J belween Ihis plane and lhe sunao:: allhe lime ofil! (ormalion, 1I was postulatcd
(1) Ihat all radical inlermcdialcs dilfuse freely in solution al all limes as if they werc
produccd in a mcdium, none of them being bound lo lhe metal sunacc; (2)
that isomerilJltion of R' in solution lo Rj (a rcarrangcd radical) is followcd by rcaction
of a rraction of both R' and Rj wilh lhe salvenl SH lo produce RH, R,H and S'; (3) that
a fraction of these Ihree radical inlenncdialC5 would rcact wilh each olher, lcading lo Ihe
coupling products RR, RR" RS, R,R" R,s, and SS; and, finally, (4) Ihal lhose radicals R',
R', Ind S", which liad escapod. rcactioD with solveDt and otbu sidc reactions, but werc
stiJI in Ihe body of Ihe solven!., would relurn 10 the magncsium surfaee 10 reacl and fonn
RMgX, R,MgX, and SMgX (Fig. 7).
The l).mooel was fur1her bascd on Ihe assumplion Ihat alt radical inlenncdiatcs R',
R, Ind S' posscssed idcnlical relclivilics and ralcs or dilfu.sion: Firsl, Ihey would al! have
Ihe same rale constanl for rcaclion wilh the solvenl k. (scc-
I
). Scconei, they would have
the nme dilfu.sion coefficienl D (cm! scc - 'J. Third, lhey would have lhe ume rale constant
k. (cm' mol -
I
) for rcaction with cach olher. FinaUy, Ihey would retum to Ihe surfaee lo
rcact in an identical manner and witlllhe same rcactivity parametcr (Fig.
Thc firsl version oflhe model (93a] was suggestcd as an cfficient mcthod for prcdk:ting
thc ratios RiMgXIRMX in tbe Grignan1 n:acti<M d lIkyI. halides In this vcrsion,
side rcactions, such as solvent altack, coupling, 100 disproponionalion, were nol taken
inlo account. On Ihe assumption Ihat all isomerizations lcok place in the body of the
solvenl and that bolh R' and Rj wcre free in solution al atl times, il was Ihoughl plausible
10 compare Ihe first-order rale conslanl k for a homogcncous reaction- here, lhe known
ralcs of isomerization of alkyl radical, anei, more specifically, Ihose formcd from jhuenyl
bromide, norbomylethyl bromide, and cyclopropylcarbinyl bromide in
solution- with the known product distribulion for lhe Grignard rcaclion of jhueny!
bromide [75,95], norbornylelhy! bromidc [96], and cyclopropylcarbinyl bromide [95,97].
By using, with modification, cquations developcd by Noyes (98] and Naqvi [99] for lhe
Iheorelical lrealment of dilfusion-mcdiatcd rcactions, Garst el al arrived al Eq. (9) 10
describe lhe relalionship of the rale constanl k, lo Ihe yield ralio R,MgX{RMgX wherc
IN
JAA '(

I
o
I
R;M,X
--o. "
Figun 7 D-model for Grignard. rugen! rOfml.tion. Since RO, Ro' . and S' were usumcd lo !laYe
idcnlical propcrlies. c:ould be Inated as I sinale ;ntcrmediale T. which may dthcr retum 10
lhe IUrface and react wIh magnesium or ullderao coupli nl in soIution. Difrcrcnca in lhe nalure of
Ihe radical R', Rh and S' """re ,nored.
Filure 8 Dmodd for lhe single reactive inlcrmedialc T.
[108 1/.5+s- 0.5 108 D) is a constant.
{
RoM"') { I )
lo - O.Slogk, +lo - - 0.5 log O
RMgX +s
(')
In EQ. (9), .5 is Ihe rt:activit v para meter of lhe radical witli Ihe surfacc, O is lhe
diffusion c:ocfficicnI and s < or equal "A The pIoc d Iog RiMgXlRMgX versus k)g k;
ror Ihe Ihm: alkyl halides was drawn as a straighl line, which was taken 10 impl y that
was equallo 0.01 1, lince D was taken as 3 Jo< lO' 1 sec- ' . However, as may be scen
from Fi&ure 9 lhe elTor in Ihe value of Ihe constanl [log( I/.5+$) - 0.5 lag D), from which
is derive<!, is almosl 25-30%.
On hi! basis onc would conclude Ihal ir one knows Ihe rale conslanl ror isomerizalion
of a radical under homogeneous condilion. one shoukl be able 10 predict lhe yield ralio
",
., r--------------------,
"

,
"
'"

IlOPE . 111
-
a:
a:
~
.,.

logk(Ro -R;)
Fipre 9 Test of Eq. (9) ror oomcriuttons ODCIIrring durng the Orign.rd reagc:nl formation in
El l O from primar)' .n'yl bromidc.
RMgXfRMgX fol' he Grignard reaction of an)' alkyl halidc., cilher by calculation, using
Eq. (9) or directly from Ihe log/log plol of Figulli 9.
B. D-ModeI ~ o tn 1M Klnetlc TI' .. b ... nl ene! Error In 80th Dlftu.lon
Concept .nd Nature 01 ttM A .. : 11,. Surt_
To calculate Ihe producI distribution fol' Grignard reagent formalion fmm $.hclcnyl
bromide. Garsl el aL [93b,c:) used Ihe folJowing cquatioru and compared Ihe results with
l he experimental data of Bodewitz el al [76] for lbe Il:action of S-hexen)'l bromide wilh
magnesium (see Sc:c. m .E.2).
G
1
- 1_ kJk,
V .. [4k j 3(k.:D)" l ]O
1l _ (Dl kJLll,s
v, .. [4kJ3{kfO) l/l]u
4 _IDl kJ
1I1
6
0
1
_ 1 ;5 lile scalcd radical isomeriution rate conslanl, V rcprcsents Ihe scaled
initial-step flu:t, and 6. lhe scaled reactivity oftbesurfaoe toward Ihe radical. The paramelers
k
l
, k" k., and D, were either tuen from the Iilerature or estimaled wheD lbe dala ",ere
nol available. Sinoe a value for tbe Hu:. 11 "'as nol Imown for S-huenyl bromide. a value
of 2)( 10- s mol cm - 1 sec -
I
was applied to t he 2.1 M SOlulioD of S-hexenyl bromide used
by Bodewilz el al. [76]. Finally, Ihe value of 0.01 A - 1 for ~ was taken from the plol of
10g(R,MgXfR.MX) w:nus log le for lbe Ibree alkyl halides (see Fig. 9).
Table 13 compares Ihe product distribution calculaled in Ihis rashion wilb Ibe
experimental results oC Bodewitz el al. It is secn Ihat Ibe calculation where three oC Ihe
sil parameten (v, d. and k.J were given estimated values almost elaclly reproduClC$ lbe
, ..
13 Produce Dimibution for lhe Ruction or
S- Huenyl 8romidc wilh Magneaium in Eche. al 4O"C

RMgBr
R, MIOr
PP"
RII "
R,H"
RRjPP
RRJPP
R,RJPP
Calculated (%) Esperimental
88 lB
J 2.5
8.1 9.0
0.068
0.059
66 64.5
26 18
8.2 7.5
.p ill c:oIlccti", .ymbol ro. R .1Id chus PP ndudes RR.
R, .nd RIRj.
"F rOm 1M rcaction of R' or R, . ... Ih Ihe soIvenl; lhe amounlS
of RH or R,H IIIaI could derive from disproportionation
... en: nOI caken into accounL
experimental yiekls and Ihe prodUCI diSlribulion. Howevcr, ll5 was pointed out [93<:], Ihe
calculations of product distribution wen: quite sensitive lo variations in Ihe 111,111 v. Thc
qucstion Ihat may Ihen be asked is where di<! Ihe valuc of D used in lhe calculations come
from? As slaled by Ihe authors lnemselves, il was [9k. p. 245) Ihat Ihe
cst mate<! ti valuc (2x mol cm-
2
sec- ') was close 10 lhe vaJuc Ihat gave ,he bes!
agreemeot with experi meot.
Calculalioos lor Grignard reagerlt formalioo lrom 5-hexeoyl bromide aod product
dislribUlion in other such as THF, OBE. OPE, using similar a5lumplion, and
neglecting lhe reactions ol radical5 wilh solvents were also compared in each case wilh
lhe experimenlal !'CSults ol Bodewitz el al. (16] to supporl lhe argumenl lor Ihe greater
predictive competence of the D-model.
One ol lhe mosl significanl erron in lhe kinetic lrealmenl leading 10 Ihe D-model
is lhe assumplion ol a unifonnly reactive ! uaoe and linear diffuli on. 11Ie magnesium
suace is lrealed u iril were uniform [93a- 93<1], in spite ofconsiderable evidenoe militaling
againsllhil. Hi1I el al . [IOOJ had earlier examined Ihe surfaoe morphology of magnesium,
alter reaelion .",ilh organie halides in etheral soludon, using oplical microscopy and
scanning sleclron microscopy It was demoo5traled Ihat lhe fint Ilage oribe reaction
took place al small reactive sites caused by defects on Ihe magnesium and dislocalions.
Small pits were ob$crved on the magnesium suaoe Ihat grow as thc reaction procccds
unlil Ihey overlap and lose their individual idenlity. Most of Ihe magnesium suaoe was
unreactive, aOO Ihe numher of sites available for initiation was ndependent of the actlon
ol aclivalol'1. Also, inlerestingly, under similar condilions higher pil densities wcre observe<!
in the al kyl chlorides Ihan wilh alkyl bromides [100). The halide ion 'Nas involved in he
release of some ol he magnesium aloms from lhe 5uaoe. AI ro reaelions in diethyl cther
produoed higher pit densi ties Ihan in THF.
More rea:nlly, Bowyer el al. (101] photographed Ihe magnesium suate arca dunng
Grignard reagenl formalion. Leuco eryatal violcl [LCV; 4',4',4"-melhyldiyne-tri5(N,N-
dimelhylaniline)] (Scheme 35), in Ihe presente or oxygen, was uscd as an indicalor lor lhe
Grignard reagenl. 1111,15, Grignard reagen! reaels as a base with LCV, whieh is colorless,
10 give an jntermediale Ihal js oll.idized by oll.ygen 10 give dark bluc CV [101], Ihus
.ftdl.,'P'HI 111 0rl .. IJtllll.q2a' {r ... ulbl
,,.
, -o-l'
/'1 f -H
/ -
1) RMcX ,
2) O:! (-le"")
cv
Sellc:me 3S
pennitting one lo delect and follow Grignard Teagent formalion by obsemng Ihe dark
blue lpott Ibat appear on Ibe magnesium lurfao:. In the eadier Itaes of Ihe reaction, lhe
si tes were Imall. A pbotomicrograph of lbe magnesium lunaa: taken arter 18 min of lbe
reaction of magnesium wilh bromOClhane deady demonslratcd Ihal mOSI of lbe lurfaa:
of lhe magnesium was unreactive. This conlradicts lhe hypolbesis of a uniformly reactiw:
Jurfaa: assumed by lbe D,model. [nllead lbe experiments of Bowyer el al. [101] showcd
lhe presence or only a few, aOO very Imall, reactive lites at lbe besinning of the ruction
and dcmonslraled Ihal Ihe reacdon prooeed.cd mostly by groWlh of tbese reactive liles
and Ihat, early in the rCllclion, lbe diffusion of reactants aOO producu was spherical, Talher
lhan linear, as assumcd by lhe I).model. Thcse worken concluded lbat. based on Ihar
cllpcrimenlal observaliolll, Mit is remarkable thal a medel assuming linear difl'uslon can
so accuralely predict product ratios."
C. DI .. ",.,_nl a,la'ln ... c.k:u&eMd and ... El, ,rlml .. 1&I1 AHUttI
Thc discussion of Ihe D-model presenlcd in lbe previoul seetion demonstrated that this
model was based on assumplio"" accommodalions io lhe kinelioc treatmenl, aod error io
bolh dilfusioo concepl and nalure of lhe reactiw: lunaoe. lo Ihis seclion we present
experiments Ihat were designed lO lest Ihe hypothesis Ihal &11 radicals dilfusc from tbe
magnesium l unaa: and flow freely in solution.
1. Attempl& lo rrlJp Fr" Radlcal& al Ihe Maf1ntnl um Surlace
literature records varioul studies on the lrapping ofradicals by melal sunaces. Ga.scous
mcthyl froe radicals were earlier [102,103] shown lO rcact witb metalltc miTrOn, such as
kad, anlimony, and zinc, and to ollidizc g&JCOus metal aloms, luch IJ bismuth, tin, mercury.
cadmium, germanium [104], as wel! as calci um and slrontium [lOS). Thcse findiogs
promptcd an interesting question on lhe reactivily ofradicals with magnesium. Whal would
Ihe silualion be in solution? In olher words, would froe radicals eneraled in solulion
have enough lime lo diffuse Ihrough Ihe bulk mediurn, rcach the magnesium sunace, and
fonn Grignard reagenl? The answer lo Ihis question would decide lbe validity of one of
lbe assumptions oC Ihe I).model.
Illhould be poinltd OUI fil'Sl Ihat. according 10 tbe I).modcl, an &lkyl radical may
lravel 17,000 A aOO slill retain a hih probabili ty of retuming to the magncsium suaoc
10 form Grigoard reagenl [91c]. This distaDClC was calculated usins Ihe followins equatioos
where P is the probabilily Ihal a
p- e- '/- t1_(DI/cJ I/J
radical at a dil lanoc r from a reactive surfaa: wiU dilfuse lO Ihe magne:sium sunaoc nllead
, ..
of reacting ",ilb solvent, and (1 js called he space constant. TIle value of k" taten [rom
Ncwcomb's wurk [106] for (he R:action of oclyl radicals with EI.O al 2:rC, "'as 10'
and D was lhe dilfusion constan!, which was est imatcd as))( lO" A' sec-
l
. In
Ibis manncr, lhe space constan! "'as cakuJated 10 be 11,000 A. This would mean Iha! an
alkyl radical Ihat has lraveled a distance r _ 17,000 ' rom Ihe sudace has a 40% probability
10 relurn and fonn Grignard reagent because ... ould be equal lo , - L,
To test Ihi$, we carried out cllperiments [J07] designe<! lO determine ir Ihe magnesium
surface could serve as an clrcclivc radical trap capabk of modifying the normal behavior
of radical, produced in $Ol ulioo. A free radical c]ock, radical 101 (Scheme 36), forme<! by
photolytic decomposition of 820 precursor 100 [14, 95, I08J, ... as crnployed as a probc
for Ibis invesigation [ 107]. In general, tcrliary aro oompounds known 10 decomposc
smool hly and wilh real facililY, owing 10 Ihc 51abi lily of Ihe radical formcd and lhe
ground-slale slrain [1 07], and lhey also slable loward Grignard reagents {109J. When
100 wa5 photolyzcd in diethyl et her solution at 23' C {I07J, three: hydrocarbon products
fonned: 6-methyl-l -heptene 102; 1, I,l-trimethyl;yclopcntane 11M; and 2-met hyl_I,6-
heptadicne (see Scheme 36).
, ..
,

C'
'"

'" '"
I
"
'"

'"

'"
Schtme J(i
Product rati os given in Table 14, Allhough lhe total yicld was much lower al high
oonccntralions or 100, Ihe product ralios did nOI change appreciably wilh oonccnt ration.
Evidencc Iha! the I, I-dimethyl-S-hexenyl radical 101 was gencrated under these oondi lions
was provided (1) by the largc amount or cycliud product 104, Ind (2) by a Irapping
CJlperiment wi lh diphenylphosphine. The large amounl or 102 in lbe trapping
rabie 14 Pbotol)'l;' orl('O a' 350 nm in Oicthy! Elite. l' 2JoC
ProdllCl nllio (% yield)
Total yield
Entry 1M) (br) (%)
, ..
lO'
JO,
,
6
"
1(43) 0.6(26) 0.52(22)
,
0.25
"
57 1(2S} 0.72(18) 0.5(,(14)
"
0.25
" "
I(l) 12,7(41) 1.7(12)
'In !be praencc el , Eq 01 dip ..... "plloophinc.
Sottrct: Rcf. ]07.
Tibie 15 Pb()(olysil of I 1I 350 nrn in Diclhyl Ether in lbe Praenoc of Mlgnesium
Produet ratio (% yie:ld)
Conc. Total yidd
Enl!)' 1M) (br) (%)
, ..
'"
JO,
"
0.02S 6
"
1(43) 0.6(26) 0.52(22)
,"
""
" "
1(11) 0.72(8) 0.55(6)
"
0.25
" "
1(26) 0.69( 18) 0.504(14)
O' 0.25
"
"
1(27) 0.68( 18) 0.54(14)
"
0.2:5
"
II 1(23) 0.65( 18)
'In lhe PI : 1: 1Qt 01 , Eq el mq:nesum powder tMt .... lcIi .. tcd by oUniJll under IrotI.
"In lbe pi'''''''''' of ' Eq ol .... nQium aeti .. ted by etbyletle bfOlllidc (0.$ Eq al M,SrJ.
'"
' [n lhe preso""" o' Eq powder actinlCd by elbylefte broI2Ii<It. .rwllhe .... paium brontid< Wu
wuhcd out.
' In lhe prae_ 01 _anaium Ibll .... Kli ... ted by Me!. ,00 M.MII .......... hed out.
' [n lhe pi 'oa: el JJH.. -a-illft\.
Sovrn: Rd . ] 11.
experiment could De explaincd by assumin Ihat lhe rale ol ab$traction of hydroen {rom
diphenylphosphine (k" _ 10' sec -
I
) [ 106] is higher than the rate oC cyc1ization (k,,_IO'
sec -
I
) [ 11 0). The close correspondenoe in the yields of 102 and 105 indicated that these
products arose by disproportionalion oC the intermediale radical 101.
We now tum lo consider Ihe effoct Ihat a magnesium surfacc might have on the
rearrangemenl of free radicals in solution. Does radical 101 or the radical 103, when
in the presenoe of magnesium, react with il? If res. Ihe fonnation of sorne
Grignard reagenl 106 or 107, or bolh, or al leasl a change in Ihe product ralio would be
expecled. Table 15 shows whal ocaIrs wben tbe phololysis of 100 is carned out under lhe
same oonditions, but in the presenoe oC various types oC activated magnc:sium.
A comparison oC Tables 14 and 15 demonslrales Ihal Ihe nalure, Ihe yields, and the
ralio oC produCls are identical, whether 100 has bcen phololyzed in Ihe presenoe or absenoe
of the magnesium surface, regardless of how one attempla lo activale the magncsiurn,
which includes the use oC highly reactive Rieke maocsiurn [ 11 1].
Qne oould arue Ihat Ihe condilions used in Ihese experiments did nol exactly
rescmble the: oondilions under which Ihe D-modcl wa.s supp<ed to operatc. Radicals werc
produced in 5OIution and were caplured whether or nol lbey had reached the surface,
,.,
wncrcas in lhe D-model, radicals. arter beng produoed al he magnesium lun_ce, are
assume<! lo lcave lhe lurfaa:, lo diffusc: freely in soll.ltion, aad lheo 10 retllm 10 ronn
Gripar<! The kinetica wau]d obviously be differenL HOYfever, ir one considcrs
two of Ihe lUSumptions on which lhe D-modc:l 'Nas base<!, OM wauld have 10 coruider
he design of l hesc expcriments as a good I'f:prescntat ion or lhe model. First, as disC''''vd
eaflicT. lhe D-model a!Sumes unironnity of lhe magnesiurn surface as well as a linear
diffusion procesa; second, il folloW5 from the modd Ihat lhe octyl radical could travel a
distaDoc of 17,000 A inlo he solution and slill haye a 4O'Y. chance of rclurning lO lhe
manesium luate befare reacti ng with tlher solvent.
Now in Ihe pIIotol>"is of 100 in Ihe prcsence of Reke magnesiurn, all radicals were
gcneratcd closc 10 lhe magnesiurn surface within a spherc of r.diuI 1500 , as shown by
a calculalion based on the known values of the average panicle . ize of Rieke magnesium
(10-' cm) [l il e], Ihe density or magnesium (1.14 g/cm'). the amount or magnesium used
in the uperiment.s, and the total volume of Ihe soI ution. lf we COlUlider these faels, use of
Rieke magnesium ptovided an e:u:ellc:nt lesl for Ihe O-model, since, acoording 10 lhe model.
lrapping by lhe surfacc in Ihis case would be possible. By using Ihe equalion on p. 189 ror
determining lhe probabi lity 40, lhal a radical at dislancc r from Ihe reactive surfacc wiU
form Grignard reagent inslcad of rcaedng wil h lhe solvenl, wilh r _ l500 A, we oblain
4o, _ e -
o
.
ou
_0.92 which means that the yeld of Grignard
and a_ {Dlki
I J
reagent expected from Ihis experimenl would be 92"/. if lhe O-model were correct. Sincc
lhe oclyl radicab did not interael in any way wi th [he magnesi um surfacc, any modd Ihat
assumes that radicals could trave! 1500 A (or even kss [107]) from the surfacc and relurn
to form Grignard reagenl would be: exeluded.
Lel u, now consider the bchavior of radical 101 whcn formed at distancc zero from
the urfacc, as in Ihe rcaccion of 6-chloro-6-rml hyl-l-heptene [ 108] wi th magncsium 10
form lhe corresponding Grignard rcagen! (77]. Al 22"C in THF and wort.up with OJO,
108 furnished Ihe producu shown in Schcme J7. 6-Mct hyl-l-heplene (102], which indicaled
the amount of thc straight-chain Grignard reagenl formed during the rcaelion, was formed
in 67% yield and incorporated 8S.S'!!. of dculcrium, whereas lhe yicld of 1,1,2-
Irimclhyleyc10pcnlane (104] was only 11.8% and contained 90.6% of dcutcrium.
,.
1) Maf!lO' ,
'''>,0

.. (J'.
'"
11.1(90."'
?y
HlD
) . . L,
V
.. Dimen.
9. 1"
SelKllte J7
la
These resul15 seem lo show Ihat, ifradical lOI had traveled I500 (rom lbe magDeSium
,urfaee, it would nOI havc any chance 10 fOflll Grignard reaJeflI and Ihat lbe ratio of
produ<:u should be similar, 10. oertain CJltent, 10 those Ihown in Table ,,,. lostead, 85.S%
of Grignard reagenl was formcd from lhe straighl chain and ool r 11 .8Y. from Ihe cyclized
producto
2. Cyc/opropylmagnaslum Brom/de: Product 8a/ancN. C./cu/.,oo and Found
More recently, lhe aUlhon nf tbe [).model invesligaled lbe reaction orbromocyclopropaoc
133 with magnesium (93e), using apio Ihe equatioDS
mentioned carler 10 calculatc Ihe product dislribution, bUI luhlli luting anolhcf composite
parameler F for 11 and lIsing lhe same values, questioned earlier for S-hexenyl bromide,
now fo r cycJopropyl
4' 3D
'
6
l
F .. - -7.:-::-
V 4k.u
bromidc. TIlus, lhe flux r was apin cstimated as 2)( 10- ' mol cm - 1 sec -
I
, lhe difl"usion
cocfficicnl D as lO x 10- ' cm
1
sec -
I
, and the rate constant ror the coupling reaction 2k,
as 3.0 x 10' M -
1
5C(: - 1, tbese valuC$ constitutin in lhe authors' words Mprobably an
eJlccllenl approxi malion.
M
le value ohhe rate constanl ror lhe reaction or lhe cyclopropyl
radical with lhe salVeDt *,-10' sec -
I
was derived rrom the D-mocl analysis (Fig.
Thi, was luen to show that Ihe cyclopropyl radical wu 1000 limes more reactive loward
the salvent Ihan a primary alkyl radical. The value of lhe reactivily parameler 6 ror
cyclopropyl (O.OOS .4.) , halr or the one reported earlier These parameters were
lI.5Cd lo calculale the product dislribulion ror the reaction or cyclopropyl bromide wilh
v
F
F"ipre 10 Cakulatl yields (mol/ lOO mol of RBr) al RMgX (horiwnlally and RH
rrom I(llvenl Ittact by R" (l'enically Irmdinl lioes), aooordinl 10 I n ideali ..... D-model in wbicb
lhe inlermediale radical, R' lmi S' hal'e lhe lalIIe dilfuaion coefficienta Ind reBCtiwilils in
"'000. "CS
,.. H.....mucll Mtd W.1Ion.ty
Table 16 Compl103on ofCakulatcd . nd Obscrwd Yield! fo. the ReaClion al"
... ilh Magncsium
CpMBr
"
"
CpH"
"
lO-lO
CpCp'
,.,
I.l
CpS
.,
> 4.6
'Amount (mol) ol pmduct f<Jrmed ror 100 mol o( Uf ..,.,. .. rned.
' Amounl o( CpH ronned r,om rhe IUClOII 01 Cp ... ilh dielhyl ellter.
' Indudet producu of ... dical disproPQrtionation .nd <:ouplillg.
Souru: Ref. !He.
ss
" >1,3
6
.005
"
4.4 >< 10-
magnesium and compare!! wi lh Ihe: experimental result for lhe reaclion of magnesium
with bromocyclopropane in diethyl elher al reflux. Tbe result.s are shown in Table 16.
Again, Ihe calculation reproduced almos! uactly Ihe experimental results. Moreover,
bolh cakulation and experimcnt accounted for almos! 100-;. or lhe cyclopropyl roup,
lhe possi ble farmalian or cyclopropene being completely excluded.
On lile basis of Ihele lindings, he aulhon concluded Ihat cyclopropyl bromide ;$
convcrted 10 he cyclopropyl radical, which eaves the surface and difTuses inlo soluti on,
where it reacu mainly by hydrogen abstraction from lhe salvenl (le.. .. 4.4 x 1Q6 M - ' sec - ')
10 form cyclopropane and by coupling. The remaining radicals relum lo lhe magnesium
suacc: lO form Grignard reagc:nl
However, lhe conclusioll$ based on Ihese C.lpcriments ami Ihe calculations may be
queslioned as a l"C!Iu ll ofrecenl work in our laooratory [112] carried oullo mi lhe source
of the hydrogen atoms donated 10 Ihe cyclopropyl radical (Scheme The resullS are
shown in Table 17. In lhe D model Ihe mai n SOUfCC: of these hydrogen aloms would be
MI
\7'
-
\T"M. Br

'VI
m
ICH'OO
\7'01
....... "
lhe solvenl, whercas on the hasis of Ihe mc:chanism depiclcd in Figure 1, one woukl ClI:p:1
that disproporlionalion on the suacc: would be lhe mast probable source for cyclopropane
formatioll. Thc: yield of cyclopropane was determincd by efficicnt lrapping of Ihe gas (bp
- 33q. The amount ofGrignard reagenl was determined byquenching wilh melhanoJ O D
at O"C and lrapping of Ihe l -deuteriocyclopropanc. Use of ' HNMR $pcclromelry casily
distinguishcd bclwcen cyclopropane and l-deuleriocyc\opropanc:.
In hese ClI:perimenU [ 112], lbe yields of Grignard reagenl and of cyc\opropane were
significantly differenl rrom Ihose published by Ihe aUlhol"l of lhe I).model, oolh by
calculalion aOO experiment. The average of ve ruDS showcd Ihal only 26Y. cyc\opropanc:
,,.
T.ble 17 Yields orCydopropanc Formcd Dirco;tly Durin,
Fonnar;on al Cydopropylmancsium 8romide
;,
o.
Rellction of Cydopropane with MaJllellium
EJ.p. no.
, ,
3 4 l
A,_
In etbeT
Cp, 'lo yield' 30 2l 24 JI 24
"
CpMBr. % yield" 21 27 2l
,.
JI 24
In THF
Cp, % yield'

10 11 12 10
CpM,Br, % yield" 33 4l 2J
"
II
'C._
'lkterminecl by qucncllin, wjlh methallOl-O-O.
and 24% cyclopropylmagnesium bromide wcrc formed TIlc startin, material cyclopropyl
bromide was no! dctectcd alter lbe reaclion, so incomplctc reaction WIS nol lhe I'CII.$OD
for lbe di!fcrence in the yields. In contrasl lo Ihe dala moWD iD Table 16, bere 4G-45%
oC he cyclopropyl rcsidues wcre missi n" which kd lO lhe con<:lusion that a portion oC
Ihe lOS!, - 2O'Y., was he resull oC disproportionation oC lbe cyclopropyl radic:a.J on (he
magnC!lium surface Ihat leads lO fonnation of lhe unstable cyclopropenc. Again, Ihese
results turned out lo be in disagrecment with he predictive power oC the Omodel.
V. FUATHIER EYrDENCE FOR THI! 8URFACE NATURE OF ORIQNARO REAGENT
fOAMAnON
A. FOrndlllon of OrlgrMlrd Ruglnt In'" P ....... of M_,huN.alld Alcohol.
1. Resellon o( Organ/e Sroml rles Magnesl um /n Mefhanol..()..D
It has been demonstraled earlier Ihat the cyclopropyl radical 16, ..... hen generated in
methanol by deoomposition of Ihe precursor diacyl pcroxide [113], on tbe one hand,
abslracu a hydrogeo alom rrom met.haool 10 give 13 and, 00 lbe otber hand, yiekb
approximately an equal amounl or ring-opened dimer 14. The vinyl radical ..... as even more
reactive Ihan Ihe cyclopropyl radical (26). lbis led 10 a runher test ol Ihe assumplioD of
lhe D-model Ihat lhe radicals generated in Ihe reaction olan organic halide with magnesium
dilfuse fmlly inlo the $Ol uli on al aJJ limes and relum lo the magnesium lo form Grignard
reagcnt. lbe reaction of an organic halide with magnesium in MeCO ..... ould be good
probe for Ihis. Thus. ir reactive radicals. such as cyclopropyl or vinyl tT radicalt left lbe
surface of lbe magnesium, lbey ..... ould be expccted to react wjlh HCA,OD by abstracting
a hydrogen alom [1 14] rrom Ihe melhyl group. lo give RH. Additionally, lhe hydrocarbon
product ","ould be racemic in cases involvng chiral compounds and, ira cyc!opropyl radical
\Vere involved, a considerable amount of ring-opened derivatives ","ould be expccled lo be
rormed. Ir, on the otller hand, lhe radk:a.l did nol leave the surfaoe, bUI produced lhe
Grignard reagent on the lite of tbe SET, the reagent ..... ould be quenched by CH,OD 10
give deuterated product RO. Let us analyze the results or five selected 'ystems, for which
, ..

,

,
"

t:.
...... : . /
-- .
($)-(+HI \ $)-( +)- 130
(R)-(-)- IJ4
CO,Mo
"
($H+)-131
Sebcme 39
",
,_,CH,
H"V'"CO,M<
,
""".
E 13l
EI36
"

'"
Ihe reactiolU wilh magnesium in monodeuterated methanol were sl udied. The 'ySltmS are
sbown in Scheme 39.
React ions of Ihree aplically active a rganic bromides ""ilh magnesium in MeDO were
reporte<! by our group in 1989 [ 13]. (s)-(+H8 and (S)-(+}-IJO, which givc rise 10 (1
radical$, and (5)-( + r UI, which would produce a l[ planar dc:localu:ed radical, ""ere reacted
""ilh magnesium powdcr in mClhanol-O-D. Thc fourlh c:tample was reporled earlicr by
KirmseaDd co-workcl'1 [l iS], who reduced geometricalJ y pUft cyclopropyl bromide (E)-132
with magnesium in MeOD, while he fifth examp]e, he reaction of cyclopropyl bromide
133 wilh magnesium in methanol-O-D [112), has already bcen cited cadicr. The resulu
are shown in Table 18.
Consider now (he claim Ihat radicals produced during formation of the Grignard
reagent ditruse in solution all the time, in vk:w of the results shown in Table 18. In every
instanoe the products incorporate<! very littlc if any hydrogcn derive<! from Ihe methyl
group orHCHJOO. There is no law that would have prevente<! such radical! rrom ronniog
significant amounts of RH ir they were really in saludon, regardless of Ihe kinetics.
Moreovcr, 00 ring-opened products derive<! from 18 or I3Z were detecte<!. Thus, lhe main
products formed in 93-100% yield resulted from deutcrolysis for he correspondiog
Table 18 Raction of Q.Sanic Bromides (RBr) with in Meth8r>Ol-QD
RH+RD RO Configuralion
RB,
(yieJd (yield ";.) Opt. punly (%) Nalure of majar isorne. RO.
{SH+}-II 87 100
,.
Retention (RHHIJ D I3b
ISH + )-138 70 9J .. Retention (RH-}-I14 D I3b
(SH + )-131 94
" "
Inversion (SH+}-IJ5 D I3b
{ErlJl 9J
'00
(EfZ ... Relention E-IJ6 D
",
IJJ 33
"
'"
'"
T.We 19 Rcact;on aI{$}( + H' with Alk.li Mclab
in Akohol Solvent>
(RH- r 1
M" Salvenl (yieId %) Opl purilr I%J
U ' PtOH
" "
U 1-8110H 100
" N. M.oO
"
N. PTOH 100
" N. '-8uOH 100 ..
K . PrOH lO ..
K 1-8uOH
,
..
Rol: 94.
Grignard reagents. As in Ihc aprotic IOlvenlJ earl ier, hydrocarbons 13 and 134,
thc: fOTn1l1tion of which oa:urs partiaJly through (J radical!, fonned wilh significanl
n:lcnlion of configuralion (Ilb]. MortOV()r, in lhe reaclion dc:sc;ribcd by Kinnsc [ 115],
product E- tlfiD, Iso involvng a Vlas fomed wilh almos! complete rctcntion
of oonfiguration Finall}', cvcn (S)-( + )-131, whien would undoubtedly giV() rise 10 a
planar delocalized If radical intcnnediate, produccd (5)-( + )-IlSD wilb significan! optical
aelivi,y (11 -.J. When (S)-{ + )-131 wa.s reacted wilh tri-lI-hUlrltin hydridc, Ihe resulting
produCl (SH + )-I35H, VIal completely raoemic which showl that under homogeneous
coodilions Ihe radical inlermcdiale was, in fact, aehital.
It i, unreasonable lO bclleve that a modellhal assumes lhallhe radicals diffusc frcely
in solution could aecount for suda rcsulu. 00 lbe oher hand, a lurface-bound radical i5
fully in aecord wi h tbelD. Compound (5)-( +)-18 bchaves similarly when exposed lo metal
suaca of alkali metals in hydroxylic solvents [94]. As in lhe Grignard reagenl formalion,
when a solution of (5)-( + }- 1.bromo-l . melhyl.2,2-diphenylcydopropane 18 in melhanol,
isopropyl alcohol, or fbulenol was exposcd lo an alkali metal, such as lithium. sodium,
or potassium, the rcsultinl hydrocarbon (R)-{ - }-l. methyl.2,2-diphenylcyclopropane 13
was ,hown to be optically active and with retaiDCd configuralion, as shown io Table 19
and Scheme 40.
"' ,'"

(SH+) II
M"
ROH

,.,,- V -H
(RH+U
When monodeuleratcd melhanol MeOO was used as solvent hydrocarbon (R)-{ - }-l was
rormcd., with more Ihan 95-/0 deuterium incorporatioo in lhe I-position.
2. Resellon o, Orf/tlnle Sromldes wl th MSf/neslum In E/h"rll In the PffJlltIfIC" o,
Sutyl-QO
The so-callcd Rleke magnesium ( 111 ), which is prepare<! by miuclion of magnesium
bromide with polassium, i. highly reactivt: aod allow. preparalioo of Grignard realenlS
'lO
al low temperaturcs (- 7Soq . This high reactivi l)' es believed 10 be Ihe resuh of jls
gteater surface area (particle siu 0.1 Jl m). The reaclion 01 Drganie halidcs with Reke
magncsium in Ihe preseoce 01 t-butyl-OD, usi ng the cyclopropyl S)'Slem as a probc, has
beco rcported (1 3a,22]. Here again, lhe Grignard reagcnl, once (o rrned wo uld be q uenched
by I- Bu-OO. whcreas ir Ihe (1 radical! diffused in soludon, Ihey would be expected 10
abstraet a hydrogen atom from Ihe sol vent . Obvious]y, complete racemizat ion would be
eXpec1ed lthe Jalter oc:curred. Howevcr, when ($H + )-18 was txposod lO Rel::e magnesium
in TH F in the prcsencc 014 Eq 01 -Bu-OD al 6SoC, Ihe resulting producl (RH - )-I3D
forme<! in 94.". yield, wilh 92"/. deuterium incorporation and 43% oplical purl),
(Scheme The oplical activil )' decreased 10 IS"/. when Ihe reaellon was oonducted
under the lame condilions. bUI at 2O"c. This implies that, at lower lemperalures, the
rate differences betwcen pathways 1.4 and 2,5 of Figure I are higher and in favor of
pathways 1.4. leading to Ihe higher optieal purity observed at - 6S C versus 20"C. This
would be consistent with Ihe relative enthalpies of he two palhways as will be discussed
sub$cquenll y_ The oplical purity. using powdercd magncsium (200 11M) 20" was similar,
but no react ion was observcd at - 6SC.
THFfI-B..oo
IUo:b M,

Ph Me
",,">\1-
0
(SHt )- U (RH+1lO
41
G rignard formation in the presence or ,-Bu' OO also allowcd the determinali on
of the nature of inlermediales for a purel y aliphatic cyclopropyl ystem, as shown in
the product distribulion from reacli on of l-bromo-l-methylspiro[2'sJoctane 19 wilh
magnesi um (Schemc 42) (22). Trcalment of ( )-I9 with Reke magncsi um in elher in he
presncce of [-bulyl alcohol-OO gave rise in 70"1. yield 10 l-methybpiro(2,5]oclanc, 1st,
which was n"l. deuleratcd. This indicaled Ihal lhe yicld in Ihe Grignard reagenl formation
slep was Olher products detceled 2,J-dielhoxybutane (diethyl ether dimer,
he cyclopropyl radical dimer t!\6 and a polymeric residue Ihat arase from olefin
I SS. The undeulerated cyclopropane 154 arose from dispropon ionation or Ihe cyclopropyl
radical on Ihe suace of magnesi um and from reaclion wilh solven!. The % o( dimer 1!\6
accountcd for 6Y. of lhe cyclopropyl group!i. The lotal material balance was 76%, which
lefl up 10 24"1. unaccountcd foro This was ascriba! lO olefin ISS, which once formal, was
consumed to give rise 10 a mixture of polymers. In Ihe Grignard rcact ion of magncsium
wilh -bromo-l-methyl-2,2-diphenylcyclopropane 18 in ether (sce Schcme a similar
product distribution was observed.
Sinte lhe 2- norbornyl radical ( 11 7J and the S- norbornenyl radical (l iS] have becn
Ihoroughly Sludied and heir behavior in solution is weJl known, sludies of Grignard
reagent formation usi ng the 2norbornyl and norbornenyl systems scemcd weJl wonhwhile
(1 16J. Relative lO the nature of Ihese radicals. they are planar I( radicals.
Let us finl consider thcsc radicals under condil ions when they are free in solulion
with a certain lirelimc. From Ihe large available data one may conclude Ihat the 2- norbornyl
radical 141, when produccd in solut ion, always reacts more casily from Ihe Icss-hindcrcd
(1H'

(4710)
--x 1
C-<1 I L_":
-J T V
..
".
DO>
Schtme 42
'"
"'O>
".
O .. )

txO'-side. The uo/trtdo ratio of the producu docs nOI dcpend on the stcrcochemistry,
whether uo or endo, oC 51arting and lbe mixture or products alwlyl conllins
more txo- Ihan tndo-adduct. For cumple lhe bromodecarboxylation or subsltuted
2-norbomanecarboxylic acid 10 he correspondng 2-norbornyl bromides by lbe
Hunsdicckcr, ar related ruction! [119], produces tbe same product ralio, txo/endo, 69:31,
ndependenl l)' or 51arting material. Similar observadons wcrc reported by David and
Robert! [ 120] ror he oxidalion or tri-2-norbornylboraDe with ollygen, II!I wdl as for tbe
auto-oliidation or l he 2-norbornylmagnesium halides. In both cases a 76:24 ratio or
lI!'Xojclldo- norbomanol was obtained.
Somcwhat later Whitesides and San Filippo [121] sludied Ihe behavior of (he
2-norbomyl radical 141, when gencraled under free radical oondilions, by oompanng Ihe
slereochemislry, yield, and isotopic compasilion of the mixtures of l!ndo- and uo-
Tabie29 Reductio" 01137, IJI, 139, ilnd l 40 b1 Hydrides Undcr F.--Radic&1 eo"ditiolUl
I$otopic
RX Rwucin'lp:nt SoIvcnt Yicld (%) E.xoll!Nlo wmposition (%)
",
NIBD, 3: 1 rnFfH,O .. 90:10 ..
",
EI, AIO El,O
"
92:8 ..
",
OCuPBu, 3:1 TIlF/EI,O 6l 91:9 ..
",
Bu,SnO
N9'
100 90:10
'00
1"
N.BO. 3:1 THFfH,O .. 90: 10 87
1"
Et ,AIO EI,O
"
89:11
"
'"
OCuPBu, );1 THF/Et ,O
"
91:9
"
'"
Bu,SnD
NQ'
100 90:10
"
".
Bu,SnD N", 84:16
,.
lO'
Bu,SnO
Na'
84:16 94
$,," C'f'. R .... 12J
d:t.

a
'"

'"
c4.,., /'
'M' d{
",'

,.
=
'"

o
,..,
'"
noroornancs obtai ned by teduction of 137. 138, 139. and 140 wih various reducing agents
(Seheme In eaeh case, Ihe pun: i$Omer was u$Cd as slan iog material. Thc resull! are
in Table 20.
From Ihe dala in Table 20, four important poiol! should be kcpl in mind. First,
free radical reduction of 139 and 137 with all reducing as wcll as lhe lin hydridc
teduction or 138 and 140. occurted wjth he expecled 1055 or slereochcmimy. Second, lhe
ratio or u o-/cMo- norbomane2-D obtaiocd from hese rcductions was ndependen! of lbe
stereochcmistry of stanina material. Third, almosl i&nticaJ ralios of u o-/clldo- noroomanc-
2-0 obtained from lhe four ,tarliog material$. Finall)'. Ihe ralio of u o-/cndo-
norbomaoc-2-0 was independcnt af l he oalure or he metal.
Now Ihat we havc a elear idea on how the 2-norbarnyl radical 141 behaves in
solulion, Jel us relurn 10 Grignard reagcnl {ormalion and see how lhe same radical bebaves.
As in Ihe cumple deaJing wilb Ibe eyclopropyl syllem (lJa,22], botb t Mo- and
uo-2-norbornyl bMmide were exposed 10 Rieke magnesium in elber in Ihe prescnoc of 4
Eq of j-bulyl aloohol-OD al 70"C. Use of Ihis alcohol nOI only assures rapid quenching
of Ihe organomagnesium species bUI also prov<ks a marker for analytical purposes, On
lbe olber hand, il reduces lhe poni bili ty Ihat lhe: Grignard rea.gent migbl epimerize. In
fael, spl_hybridiz.ed seoondary carbon- magnesium bonds are known lo undcrso 510w
inverston, even on lhe: NMR time fC31e.. The equilibrium for 2-norbornyl
magnesium halides is actually reached artcr I da)' al ambient Icmpcralure [ 122). For
2-norbornylmagnesium bromidc, Davies [120J and 1cnseD [122] found an U D/ t MO ratio
of 41 :S9 al equilibrium; in OUT hands (116), lhe: uD/tildo ratio was 53:47 al equilibrium,
5tarting from Ihe tXo- bromidc, and S2:48, Ilarnng from Iht t lldo-bromidt.
'"
d?"
M,..t!I,.o-c-B..oo
d?
-= ,
,
'"
'"
d?, t!.

t!,
"
,
D
'" '" '"
"'"
,.. ,..
&hmc: 44a
As could be prcdicled from he 5urfacc oature of he reaction, when il!Jw-2-norbornyl
bromide . ... was e,;posed 10 Riekc maoesium al -70"C in the presencc of t-bulr!
aloohol -OD, the resulting producl W8S exclusively ,uo.norbomane-Z-D, 142. 00 (he Olhe!
hand, when tlldo-Z-norbomyl bromidc was reactcd uDder lhe same condilion, a .50:50
mixture of endo- and uo-norbomane-2-D, 143 aOO 142. W85 formed (Schemc 44a).
1I is ckar {rom Ihis result Ihallhe bchavior of Ihe radical produccd dunng Grignard
reagenl fonnaliOD is quite diffcrcnl from Ihat of the free radical in 5Olulioo. The uclusivc
retenlion observed when ,taniog from t.l:o-l44 might be duc lo more Ihan Ihe simple
conlribution or palhway 1,4 (sec Fig. 1) and might also be dllc 10 minimization of 1m:
nltraction bctween lOe x-planar radical 141, formed by pathway 2 (sc:c Fig. 1). wilh Ihe
surfll.cc Ihal Jeads lO equiJibration. Consequenlly, Ihe combinalion 01 R' and XMS' 10
form GriSllard would occur prcdomillantly from lhe lesshindered side, !cading
10 more exo-lIorborllylmagnesium bromide 146 (Scheme 44b).

illlt" ,..,,8.
M.
, ..
"'
-

...
4,
7il/fi"' "",8.
M.
1
tb ... ,
'"
...
"'"
Stbunc: 44b


Here again, a temperature e/fcel was noted. When Ihe same reaclions were conducted
al ambient lemperature, uo-bromide , .... led 10 a mixlure of of uo- I41 and 12%
of Itlldo-l43. However, 79,.. of 141 and 21 % of 143 were formed, Slarli ng from tndo-bromide
145.
As airead)' menlioru:d, Ihe Jecond s)'slem 10 be sluded [I16J was Ihe S-norborncnyl
5yslem. The radical clock-S-norbornenyl 149 ( 118J is known 10 rearrange to lhe
3-nortricyclenyl radical wilh a rale constant, determined by EPR, on Ihe order of 6 x 1()2
sec -
I
al - JO"C and 10
6
_10' sec -
I
al 2S C (123, 124]. II has becn firmly eslablished
from numerous e:tamplesoffree radical reduclions involvog thissystem that Iheequilibrium
in solution is in favor of radi cal 150. For example, a rcport by Davie!l (12S] demonslrated
Ihat whether one started from S-bromo-2-norbornene 148 Br Of from 3-bromonortricyclene
153 Br when carrying oul a coballous chloride-calalyzed rcaetion wilh melhylmagnesium
bromide, one obtains a mixture of 30% 2-norbornene ISI and 70% oorticyclene IS2
(Scheme
'lb
r ....
I
'" a-hllidoa


"
'"
, ..
".
a-IWic\a
'" '"
IU Br. a" Or

"
'"
m
"'"
".
Se_me 458
A similar equilibrium milllurc of products was aclually oblaincd by Kui viJa and
Alnaijar (124] from lhe free radical reaclion of S-norbornenyl and 3-nortricycleoyl halides
148 and 153 wilh lrimelhyltin sodium, and by logold and CarlS50n (73] from Ihe tio
hydride reduction of lhe same sysltms.. On Ihe olher hand, when exo-S-norborru:nyl
bromide 148 Br was reacled with Ricke magru:sium in elher in Ihe presencc of r-bulyl
alcohol-OD al -1O"C (Scheme 4Sb) Iwo principal products were oblaincd, 6S/.
exo-s-deulerionorbomene and 35% deuterionortricyclcne ( 11 6]. Again, lhe high deg=:
of deulerium incorporalion in 151 and 151, considcred logelhcr wilh Ihe coosiderably
large amounl of ISI compare<! with lhe work shown in Schcmc 46&, cxcludes a mechanism
Ihal poslulales Ihal Ihe radicals diffuJe al all times during Grignard rormation.
141 B.
B. Radlcel-Trapplng Experlm.,,"
H
U'' D
".

Ino
'SO
A well-de$igned radieal-trappins upcriment c:ould be a means for deciding wbetber
or no! radicals, produc:ed durin farmalion or lhe Grignard reagent, leave the
magnesium sudace and would also be a way oC dctcrminiDI heir amount An atlempl
lo Ibis elld was made by Whilc:sidcs and oo-workers ( 126), who belicvcd Ibat
2,2,6.6-tcll"lIrncthylpipc:ridine nitro;!;)'1 (TMPO') was an efficicnt free-radical scavenger,
capable oC reacting selectivc:Jy with an alkyl radical R' lo form O-alk)'I-2,2,6,6-
tctramcthylhydrOllylamine This ruelion is ver)' Cut, with a rate constan! on
lbe order oC 10
9
L mol -
I
.sec- J [128]. Thus, by conducting tbe reaclion oC alkyJ bromides
wilh magnesium in a solution containin8 botb TMPO' and .-bul),1 alcoholthey thougbt
10 preven! he Grignard reagents from reacling with (be radical scavenger, because il wu
beli cvcd Ihat he reaclion or RMIBr with ,DuOH was ten limes rasler Ihan Ihe Il:aelion
wilh TMPO. Their finl Il:porl [126a] dcscribcd lhe reaetion of eyelopcntyl bromide wilh
magnesium in elher in Ihe prcscno: of TMPO' Of I-DuOH. In thc abscnoe of ,-DuOH
(react ion lhe almOSI e;lelusive produet WIllI TMPOR (R-eyelopcntyl) in 96'/. yicld.
TMPOR was also formcd in high yield (84%) when the reaetion was condueled in lhe
presenoe orTMPO' logether with ,-DuOH (reaetion (11)]. On lbe hypolhcsis lhat RMgDr
reaets prcferentially with I-DuOH, lhey concludcd that more than of lhe radicals
wcrc Irappcd by TMPO bcfore bcing converted into eyelopcntylmagncsium bromidc. Thus,
more Ihan 80-J, of the radicals werc $upposed to have becn free bcrorc lormalion of he
Grignard reagcn!.
c-C,H,Dr +Mg+ ITMPO .... RH + R(-H)+RR + TMPOR (1)
<2% 2"/0
c-C,H,Dr+Mg+ITMPO'+IOt-DuOH_RH + R( - H) + RR + TMPOR (11)
<2-J. 84%
That eyeloheplyl bromide reacu with magncsium in a ver)' similar way as eyelopcntyl
bromide was reponed subscquently [126b]. By uJing lhe conslanl-surfaoc" kinelic
tcchnique 10 measurc Ihe rate of rcaetion wilh magncsium. Wbilcsidcs and co-worken
eslimated Ihal Ihe rale of rcduetion of TMPO' would be three times a[owCT Ihan lhe rale
of reaction of cyeloheptyl bromide with magncsium. Howcver, lhe validily of this eslimale
ia unelear. Thc kinctie:s of Ibe system is ver)' comple. owing lO competition among the
$Cveral rcaelioM, shown in Seheme 46, whieh were not colUidcrcd. The aulhon [16b)
mcrcly plolted the yield ofproduct from the rcaetion of eycloheptylbromidc with magncsium
in the prcsellOe ofTMPO' and ramyl alcohol as funetion of time, observed the formation
of95% ofTMPOc-C, " 1) ' atated Ihat thcsc results wcrc incompatible with a Jurfaoe-bound
......
RO, .. M,
,
R' , M,Sr
111111
M.
Schcme 46

TMI'O"
H.",dfluCL'N and ..... eI, ... ,
RM,O,
in "",ion

RMX' .. TMPO'"
I
(R'J"'M,X
in "1JIion
radical and concludtd that 95"10 of [he cyclohcptyl radicals weI'C free, [hcreby ignori ng
proccsses that compete with trappng by the TEMPO radical.
As admiutd by Whitcsides and co-workers, MgO reduces TMPO' [O [1M: anon
TMPO- at a rale compelil iye wilh Ihe reaction bclwecn RBr and MiO (1 JO], whiJe, on
Ihe olher hand, oidalion of Grignard rcagenls in Ihe presence of such agenls js also well
documenled (1 29, 131]. An example js a recenl publica[ion by Gred and Eberson (127],
who sludied Ihe rcaclion of a series of Grignard reagents wilh a njlrone. The process
inyolyed a si ngle electron Iransfer from RMgX lO Ihe N-oide and subscquenl clc:ayage
oflhe C-Mg bond, producing radical R' , which was trapptd with a radical SC8yenger,type
aminoyl. Conscqlienl ly, one is len with Ihe qucstion of what spccies has aclually reacted
with TMPO' and thcsc expcrimcnts do nOI answer tlM: quc:sli on of whOI pcrcentagc of
radicals cave Ihe lurface during formalion of lite Grignard rcagenl.
However. Ashby and Oswald (77] described a SOlUlioD for this problc:m by selecling
dicyclohClylphosphine (DCPH) as lite Irapping agen! capable of donalng a hydrogen
alom 10 a free radical. To ascertain whellter or nol ol her reactions competed wilh tite
reaction of DCPH with radical, lhe aulhors carried oul Ihe rcaction of bromooctane with
magnesium linder Ihe condilioll5 described in Table 21. As may be secn. three propertles
of DCPH were dcmonslratcd convincingly; (1) DCPH did nOI ceaCI with bromooctane,
T." 21 Slabili ly or DCPH Toward Alltyl Halide lOO Grignard Reap:nt:
RccaClion or Bromooc:tanc: Wilh MIgnesium in lhe Prcsence of DCPH
Time (hr) "Bromooct8ne ("lo) Octlne ("l. ) (1 D+ IH)" Deutcrium ( %)
O.S 97.6 O
O.,
1.' ".,
1.0 O %.1.
16.0 O 92,0
".0
O 92.0
'Reaetioou; _re ""rriod .... 1 i n nl F al 2r c, lhen q....-.cbcd with 0,0,
"Dlonk lal lo determine lhe O l a b i ~ '" tho mutu ... DCPH/bIoo"""l.I ....
80.9
74,8
74,0
74,3
MIL! 7' __ of Q'IJInr yJ 1171.7'" Fo""II\loI,
(2) OCPH did nOI ruCI wilh Grignard reagcnt, and (J) the Grignard Illagcnt was stable
in the presence or OCPH, even arter 60 h. Thu$, in c::ontrast with TMPO', lhe propertics
of OCPH made Ihis radical lrap a 8000 candidale for delermining Ihe amounl of radiad
on Ihe ,uace and for furlher lesling the hypolhcsis of Ihe D-model Iha! al! radicals
generaled dunng Orignard Illagcnl formalion mus! leave Ihe surface, dilfu$e freely in
solulion, and then reluro to the surface lO forrn the Orignard compounds.
We now luro 10 tbe reaction of 6-bromo-l-hcIane 110 wilh magncsium in THF in
the presente of OCPH, sludied by Ashby aod Oswald [77] (Schemc 47). Companog Ihe
resull wilh Ihe earlier discuuion in Seclion m.E.2, il il clear that .11 radicals Ihat escape<!
Ihe magnesium 5urface were lrapped by OCPH, which for Ihe heIenyl radical was no
more Ihan 25-; . The formalion of cyclized hydrocarbon 111 (4.7-;.) WIJ ascribed lo
cycli%alion occurring al lbe lurface, since a helenyl radical leaving lhe surface was eIpecled
lo reael wilh OCPH before il could cyclize.

Se' une 47
H(O)
4.7(2"0)
'"
Olher resul!! 10 be discussed now also SUggcsl Ihat il would be unreasonable lo cal!
on freely dilfusing radicals in Grignard reagenl formalion. One of Ihese Slemmed from a
sludy of Ihe reaction of 144 and 14' with Rieke magnesium in elncr al 23 C [1 16] in lhe
presence of deuteraled dicydohexylphosphine OCPO, which would be expecled lo trap
free radicals in solution lO giv.: 142D Ind I43D mpectively. The additional prescnce of
I-bulyl alcohol would resull in rapid quem:hiog of any Grignard rcalenl formed lo give
.42 and 143 (Scheme
The txo-l44, under Ihesecondilions, furoished norboroane .41. wilh no iocorporalion
of deulerium. On lhe olher haod lhe mixlure mulling fmm endo- l4S showed only 8-;.
of deulerium incorporalion. Thus, in lhe !alter, 8-;. of radieal has cscaped lhe magnesium
10 become Irapped by OCPD.
cb ..
cf:tH
H
...
.. ,
J:
cl:zH(DI
"
.. ,

Sclmne 48
Simi larly, Ihe reaclion of uo-5-l1orbornenyl bromidc 148 Sr (scc Scheme 45b) wilh
Ricke magncsium, under the same condilions, gave risc to a of two products,
norbornene 151 isolatcd il1 65". yield, containing 2% of deuterium, logelher with 35"/. of
norlrieyckne 152, which was 22". monodeulerated. Thi! would eorrespond lo abouI 8".
tolal dcuterium inoorporalion.
Lel U5 now relum 10 Ihe cyclopropyl system, whieh consl itutcd one of Ihe eenlen
of controversy over Ihe difference bctwecn caleulalcd and observcd resulls [93eJ. In a test
or Ihe pudielion or Ihe Dmodel ror Ihe amount of eyclopropyl radical departcd from Ihe
mar,nesium surface during Ihe Grignard reagent, it was demonstratcd rcccnlly [ 11 2]. using
DCPD as the radicallrap, Ihat when eyclopropyl bromide 133 IUctcd wi lh mar,nesium
turnings in elher in he prescncc of OCPD a 26". yicld or eyclopropane contai ning 15".
of deuterium resullcd. This oonstilules a 4% yield of deuleratcd material, base<! on the
amount of the eyclopropyl bromide eonsumcd. Thlls, again 4". of Ihe cyelopropyl radicals
cscapcd Ihe surface and werc Irllppcd by DCPD. When OCPD was replaccd by diethyl
elher-D,Q' the reaelion of eyelopropyl bromide wilh magnesillm in dicthyl cthcr-D,o
furnis hcd 23"/. cyc!opropanc, of whieh 13% was deuteratcd. This again indicales that onl y
3"/0 of the eyclopropyl bromide consumcd has produced radicals Ihat reaetcd wi th lhe
solvent .
Trappi ng elpcrirnenls in Ihe reaet ion of ( )- 1-bromornet hylspiro[2,5]octane 19 wilh
magnesium gave similar res ults [22]. Reaelion wi th Ricke magnesium in the prescncc of
DCPD resul lcd in 154; with 6% incorporalion of dculerium in produet 154, whereas in
lhe rcaetion or 19 with mechanically aclivatcd magnesium in dicthyl ether-D, o. 13". of
lhe radical! lerl the , urfaee and were Irappcd by solvenl, as judgcd by the dcuterium
incorporat ion inlo product 154. Thus, onl y a small fraclion of Ihe radicals cave the surface,
and most of Ihe cyclopropanc fonncd resultcd from disproporlionation on the surfaee.
The J).modcl prediclS that the major source of cyclopropanc i5 react ion or cyclopropyl
radica! with solvent, which is inconsistenl wit h ellperimenl.
VI . THE QUESnOH OF AH AHIOH AADtcAL
A. 811d1ground
TIle reader should fint be remindcd that pat hway 1,4 or Figure 1 involves formalion of
a tight radical anion- radical calion ion pair on the magncsium surface, which lead, 10
relention or oonfigurat ion. The Jiteralure providcs evidencc Ihan an anion radical cannol
be formcd as intcmediate by a single eleclron lransfer 10 alkyl halidcs. On Ihe basis of
cllperimenlal data [132J and Iheorelical calculations (1 33) si ngle-cleclron trander inlo a
carbon- halogcn bond it either purcly dissociativc (pathway 2) or proceeds by
short livcd spccies [134]. Savant concl udcd Ihat reductive clcavagc of lhe carbon halogen
bond in aUphalic haJidcs, either by dirccl electrochemical reduction al an inert elcct rode
undcr helerogeneous condilions, or by eleclrocbemical reduction mcdialcd by aromatic
anion radical" involves a concertcd electron trander bond-brcaking mcchanism in which
Ihe driving force is the , Iandard polenlial of the RX/R X- and not that of Ihe RX/RX' -
couple. Supporters of the D-modcl [1 34] also poinl out Ihal ir anion- radical intenncdialcs
Cllist. their !iretimes would be elllremcly 5horl (10-10 scc). Ab inilio (gas pha!1e) studies oC
the ilUCrtion oC magncsium inlo Ihe carbon- halogen bond do not predK:1 formation of
anion radicals with aliphatic [92], as previously discuned. or vinyl (135) halidcs.
,.
'"
8. Crltlclam
JI has beeo sugeste<! Ihat he retention of CQofiguralion obscrvcd in lhe case of
l-bromo-J-methyl-2,2-diphenylc;yclopropane II resulte<! {rom lhe IInusual stability of.n
intermediate anion radical whicl!. in lum. WIllI due 10 he phcnyl groups. The chiral vinyl
systcms wcrc also referred lo as [93d, 93<:]. To aceounl {or lbe relcotion observcd
in 1, 12, 18, 27, 131, and 158 duriog Grignard reagen! fonnation. Ihey cilcd work by
Boche, wha observe<! partal retcntion in Ihe reduclion oC la. 12, and 14 by alkali
naphthalenides in homogeneous solution [136] .. evidcmoc Ihat he l-mcthyl-2,2-
diphcnyk;yc::lopropyl radical is capable of partially maintaining its configuration in IOlulioo.
Thiscould account ror lhe Grignard resul! aOO may be supportivc orthc D-model. Howcvcr,
slcreochemistry of the radical! encrale<! from thesc Iystcms in solution indicates lhat Ihe
rcduction by mc::an5 of alkali naphlhalenide is halogen-dependenl. and Ihal the retention
or configuralion observcd is in the order I > Br > CI, whereas in Grignard reagenl format ion
il is jusI Ihe rcverse. e l > Br > 1. The rclenlion observcd by Boche was attri bulcd 10 the
lower reduc.::lion potenlial of [he: two geminal aromalic rings, compared with Ihe reduction
potential of Ihe c.::a rbon- halogen bond, so that the finl electron 5upplicd by 1M rcducing
agenl will enter Ihe aromatic moiely and 1M second inlo Ihe eJ- anliboding orbilal;
Iherefore, il Wlll proposcd Iba! Ihe obsenc:d retenlion was !he result or an inlramolcc.:ular
elcc.:uon uaosrer 10 yield !he configuralionally stable anion. Oearly, Boche', results have
no bearing on Grignard reagent formation; il should also be noled Ihat magncsium metal
docs nol resc.::1 with Ihegeminal pMnyl roupsinl-melhyl-2,2-diphenylc.::yclopropane 11.
Moreover. in our recenl study of the: rormalion of organocalcium reagents by direct
reaction of Ihe cyclopropyl haHdcs (S}( +}-I8 and (S)( +)-11 wilh calcium-aromatk anion
radic.::als (Scheme 49), raoemization look place in bolh nstanees [42]. As shown in Table
22. rcduction or (S)( +)-18 aOO (S}{ +)-11 wilh c.::alcium-aromatk anion radic:a.ls, encralcd
by rcac.:: li on of preformc:d lithium biphenylide (LiBPh
l
) and lithium naphthaknide (LiNph)
wilh c.::alcium bromidc: yieldcd, after quendling with Ha, 1-mc::thyl-2,2-diphenylc.::yclopropane
[13] or, after c.::arbonation, Ihe corresponding l -melhyl-2,2-dipbenylcyclopropancalrboxylic
acid [17]. In every nstanee prodUcll wel1: completely racemic. Thcse reactions are believcd
10 O!XUr by elcc.:lron IransIer in a homogcncoWl mcdium [42].
Thus, as delaiIed in Sc::hemc:: 49, the racemiution involvcs lhe inlermcdiacy of
c.::yclopropyl free radic.::a116 gencraled by a single electron lransfe! ftom the calcium-aromalic
anion radic:a.1 into the carbon-halogen 0'- antibonding orbital The cyclopropyl radic.::al
T.bIe 12 Redrn.:tion oI(SH + H8 and ($H +)
11 by Ca(Nph)j and Ca(8phh
X Timc (hr) Temp.(C)

O.,
Sr"
0.5
Sr"" 0.15
Br'" 0.75
'OpIicaJ purily.
' Reaaion .;lh Ca(BpIl!, .
<Ructio!l . ;tll Ca( Nph), .
"Quenchcd "';lh " ,O' .
-Carbonaled..
Sowcr: Ro( 42.
- lO
- 20
-78
- 78
"
"
45(0)

48(0) 21(0)
49(0) 26(0)
""',{S}-(+}-II
X..ct.(S}-(+}-U
I
O",

lE[
l "Ca"'"


"
1'"
I'II'>\<CH)
"
(UU
" .......
produccd in solution reachcs its inversion equilibrium befare being trapped by a
electron transfer 10 yicld cyclopropyl calcium, which when quenched with COl' gives the
raecmic carbollylie acid 17, or by reaetion with THF yiclds raecmic 13.
To complcmcnt all the data available from the literalUre, we designcd two additional
series of cllpcrimcnts 10 answer Ihe crilicism related lo the use of Ihose syslems. The
firsl, reporled recently (22J, dal! wi th Grignard reagen! formalion from a purely
aJiphal ic and lerliary chiral cyclopropyl bromide. This molccule does nOI contain any
"pscudoconjugalion", owing lO an aromalic or vinyl moiely Ihat might be responsible ror
Ihe al1eged unusual stabi lily of an inlermediale anion radical during formalion of a Grignard
reagent. Al Ihe same time, lhe presence of lhe cyelopropyl ring ensured thal Ihe Grignard
reagenl rormed from Ihis bromide would be configuralionally stable as had becn Ihoroughly
dcmonstraled earlieT. The was an elcctrochemical sludy (56] designed 10 clarify
Ihe queslion of ani on radicals in al] syslcms Ihat had becn subjcct lO criticismo
c . Only 1M Surt_ Nature of ltIe AellCtlon Could PrecUd Aetentlon
To establish lhe slereochemislry or Ihe reaelion, optically pure (SH + H bromo-
methylspiro(2SJoclanc 19 was treated with Rieke magncsium al room tempcralure in both
ether and THF. and the react ian mixture was carbonated [22] (Scheme The results
are shown in Table 23. The react;on in elher resulte<! in a 25/. yicld of oplically active
acid 22, Ihe res ul l af aplically act ive Orignard reagent, and 42% of raccmic hydrocarbon
154. Reaet ion in THF alforde<! a mueh higher yicld afhe oplical1y active Grignard reagent
(58%) and only 20'Y. or racemic hydrocarbon 154. As predicle<! by Ihe suace nature or
c ::r1.,'B .
..
($H+}-I'
.fI,' E "-01 011,: M'd ,,-.,.nI Fc:oUW"ClliI
Tibie 13 SEereochcm;,cr)' 01 Gripar<! ReqenE
Formation
Solvent Time(hr) Yiekl ('AI) Opt. pUI)' (%)
etlO 2 2S 10
THF 2 S8 1)
So--ct: Ref. 22.
Grignard rcagenl formalion, the:: reaction or (S)-( +)-1' wilh Rkke magnesium, al room
lemperalure in dller and in THF, in bolh caS,"" gave an oplically active Grigoard reaenl
Ihal, alter carbonation, gave an acid ahoMog nel relenlion of configuration. ThiJ il clcar
evidenc:e Ihat Ihe sudace II rF"'<'e'''ry for lhe retention of coDfiguralloD observed, and Ihal
Ihe crilicism by the:: proponen!! of Ihe IJ..model wu nol justified (93d, 9le). ODly lhe::
sudac:e nalure oC lhe:: reaction could prcdict tbe observed reteation.
D. EI"'bodEemal ,l,Plwuch
The questions lhat needed lo be answcrcd [.56] were the foUowing: Is bond-breakin a
oonoerled or stepwise prooess when elc:ctroldl are lransferred f10m metal sunaCCl 10 die
carbon-halogen bond? Are radical anioM formed as inlermediateil Do the '21- orbitals of
lhe:: atomalic moiety in 18.131, and 1.511 complete with thc:: 21- orbital oClbe <:aubon-halogen
bond durins the eJectron-lraldlfer prooess from lbe sudace, lhereby ausins Ihese systems
10 be atypical [93d, 9le]?
The masl cooclusive st udies devised lo asc:crtain wbetber electron 171Insfer and
bond.breakina are conoerted or stepwise bave bc:en conducted by Savnt and co-worken.
who uamined thc:: electrochemicaJ rcductive cleavase of tbe carbon-haloen bond al inert
eleclrodes, usinS a variety of aromatic and a1iphatic halides [132]. An elegant aOO delailed
description of tbe dissocialive electron transfer dynarnics, as well as the slepwise venian
is given in Ihis paper, which also contains a large body oC experimental dala for tesliDg
the modeJ that are based on the electrochcmical rcduction (under homogencous aOO
heteroencous condil ions) of alkyl, aryl, and bcnzyl halides, u wcU u olher organk:
substrates.
To determine whether or not an anion radical wu formed as an inlermediate in the
cxpcriments used durina our invcsligation oC tbe Grigoard reagent formalion, we
inveslisate<! the re<!uctive deavage of the carbon- haloen bond iD our systcms by cyclk:
voltammetry (Sli].
Cyc!ic volt ammetry of the substratcs was pedormed at a lassy carbon clectrode
which, in contrasl with mercury or ot her reactive electrodes, was believed lo be lufficiently
ioen toward chemical reactions with radical intermediates fonne<! durina the rcduction
process [132]. The compounds studied are shown in Scheme 51. Figure 1I and Table 24
show the mosl relevan! infonnation rrom Ihe electrochcmical reduction oC substrates 18,
1.58, 1', and 131.
Wilh onc exc:eption, Ihat of 1.lluoro-l.methyl2,2-diphc:nykyclopropaoe 160, which
exhibite<! no rcduction beror(: confomilant rcduction of either the salvenl or tbe lupportinS
electrolyte, a sinle irreversible calhodic wave was always observed. The values oC the
lransfcr coefficicnts wcre deri ved from Ihe cydic voltammetric peaks' widthl, lUSumins
Ihat Ihe ButlerVolmer kinetics apply: 1Z - 1.85(rl!F)(E,,/J- E,J [J32s.h]. Of interest was
'"

",\.-.:_,CHOCH
Pb"V '"B,
{SK+HSI

'"
"

tRH+ 1l
(R).(-}_159
ro A .. H
...
(R}-I54
Sdltllle SI
[hat Ihe valucs of he Ifansfer cocfficient. which werc shown lo be ndependenl of l he sean
rale [132g,h), were small for all subsl rales (belween 0.5 and 0.32).
Si milar observat!ons hay!: been reporled by Savtant el al. in hei r studies on Ihe
electrochemical reduction or simple aliphatic haJides [ 132gJ (11- , 5-, and I-bulyl halides) al
a glassy caroon electrOOe. CycJic vollarnmetry of he butyl halides showed orn: or two
waves, dependng 00 the relalive reducibil ity of lhe alkyl halidc RX and or
lhe radical R' . Al! t ransfer cocffi cients reported were smallcr Ihan O.S (betwocn 0.2 and
0.32). Thc rael hat lile tcander cocfficient was small was takcn as furlher evidcnce that
lhe rcduclion pathwl)'$ do nol involvc lhe RX'" anion radical as an inlermediale. Our
ob$ervations from Ihe electrochemical reduction of 18, 158, 19, and 131 al a g1assy ca. rbon
electrooe are in agreemenl with Ibis. The cycl ic voltammetric sbape. the peak widlh
E"l- E, _ (180-ISO) rnV, and Ibe value of (1 _ 0.25-0.32 at dilferent sean riles [137]
showed, wilhoul qucstion, Ihat electron tmnster and dc:composi tion of Ihe anion radical
al Grl...,.rd R.L'Il '''' ""' ..... IIM

I
...
..
O ' V"
, , ,
I

,
E (VISeE)
.. ':>.-.COI,ooc,
.' V'
..
'1""1"
.. -
.. -
, ,
I
..
r
, I
.,
..

'.<l
CJXiIIo

E (VIseE)
FIIlII'e 11 Cydic vollammctry of substratcs 11, 19. 158, and 131 (5 mM) on g1U11y carbon cJoctrooe
in ao;etonitriJe+o'l M n-Bu.NBF4 al 2.'l"C; ICIn Tale 0,1 V SCI;: - ' , Vertical lClle in p; horizontal
sc:ale in V Vii. sca
for these subslratcs is concer1cd. Ir a radical anion were fonncd as intenncdiatc, a
RX+e- ... R+X-
transfer t:ocfficienl doser loor larger Ihan 0.5 would be observcd [132j]. si nce the standard
potential of RX/ RX - must be mUl.!h more IK!gative Ihan Ihal of RX/R +X- , as in Ihe
case of aromatit: halidcs [132j] and ring-substitutcd nitrobenzyl halido [132J. for whit:h
a stepwise mcchani sm involving Ihe intermcdiat:y or anion radical was ahown

RX - .... R +X-
10 take place. It is also of intelat Ihat Ihe case of rcdut:\ion, iU shown by Ihe peak potential
or he wavc, is in he order 131 > 159> _ 18> 19.
f'rl\c) L E hI .wI ..... lIty
T.We lA C)dio; VoItarnmcln.. I'aIt PolCntiar.nd Trtlllkr Coefficicnt
.. ro.. SubOltrtte . 1, I!I, I, . nd Il l o
Na
eh.&llICIeriJlic -E
E Efi1 -
E

Compd.
.. -
(V VI. SCE) (V v'" SCE) (mV)

"
I im:venlble W
",
lOO 03
IS. I im:venlble
'61
2.43 m 0.21
Slcreochemical obscrvations also support the analollY betwcen electrochcmical Teadions
[S, 138] and orsaomcillJie Teagent rormalion of orsanic halides al metal . urfaccs
[22,42-44,94,116].
Rcduction of (R)-( -}-I!8 yields (S)-( + }-I59, with overalJ relention or configuration
and an optical purity of 31 % al a mercury eJeclrode [1391] and reduction in methanol
on a magnesium surfacc [140]. for which Ihe optica.J purity is 23% (Scheme 52).
(RH-H5I
M.

(SH+rU'
., O.P. _ 23
., ,10101_.,.

,,,
., yie1d _ 22
(SH+r
15
'
.,O.P. _ JI
.,yield _90

'" "yie1d _ 10
A similar result is obtaincd in the reduction of (S)-( +)-1 8, leading lo Ihe formalion
of (R)-( - >-" with overall retaincd configuration and optical purilies of 26"/. [139b) and
24
0
/0 [13b). respcctively (Scbeme 53).
M.
" ..
" ..

Ph>v'B. Pb>0H
" "
M.o"
(RHH3 (SH+)- II (IQ.(+U
'!lo O.P. _2-4 '!lo 0.' . _l6
'!Ioyield_ 97
'!lo ,....,_19
Schtme !J
Finally. interist ingly, eVCD at an unreacti ve electrode, such as gla"y carbon, the
tetention observed i. high, 47% teten don of optical activity with overaJl tetention of
conJisuration [139]. Thi, ndates that I vcry fast second electron trander, lcading lo lbe
conlisurat ionally stlble carhanion, occun at the surface..
VII. CONCLUSION
Tbc preViOU5 plIges have describcd Ihe evidence lcading to a dcscription of Grignard
reascnt rormalion in lemu of lhe reaclloDs shown in Figure 1. Tbc mcchanism, briefly
referred 10 as Ihe surface nalure ofGrignard reagenl formation, is based on
analyses, radical-trapping elperimenll., and produet distribulion. Work 10 eoun!cr recen!
crilicisms Ihal he cyclopropyJ syslems used in e$lablishing and supporting that
mechanism are atypical is dcscribed as wcll u clperiments Ihat show that tlH: basie
assumption of the more recently proposed D-modd- Ihal all radical s generala! in Ihe
reaetion lcave the magnesium surface and diffu$l: freely in solulion- is unlcnable.
ACKHOWLEDGMENTS
Wc thank Professor Wcrner Hen for reviewing and a!iting this manuscript. We a re also
graterul 10 M s Raehel Kerlin who did he drawings aOO retypcd the manuscript .
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'"
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al tri. ,,_b\llyltin .. dical wilh an I nr.yI halide m.y 11.$0 OCI;Ur by an outer'phcn: aoo the
n:action of Ill<yl h.lidc .... ith 4,4' -dimclhyl Ir. ctyl by an inncr-sphere pl"QC:CS$. ThQ ""as clcared
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P"NO"
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10l F. and W. Hofcdi lZ, &r. iS1B: 1335 (J929).
]03. E. W. R. Stl:ar;;e, Atom" ami Frn Radical Reactlons, 2nd cd., Reinhold, New York, ]9S4.
]04. T. J. Juhlke, R. W. Braun, T. R. Bierschenk,and R. J. Lagow,J. Am. Clwm. 5. /OJ :
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130. A. R. Forrester, J. M. Hey, and R. H. Thompson O'lIank CltmtiJtry of Sl<IbI, Fr
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'"

11
Meehanlsms 01 Reaellon. 01 Grlgnard Reagenls
CORNElIS BL.OMBERO
Fru Uni....,rsJry. AlrUltrdDm, T1w NtlNrlands
l . INTRODUcnON
Investiga!!on! orlhe mechanislic aspeclS or (he reactions of organomagnesium compounds,
in general, and of Grignard rcagents, in particular, Ihat havc Icd 10 our modcm insighl
ioto Ihese aspcclS Ilartcd oruy rathct reeenlly (i.c., in lhe carly 196(1).
Several problems finl bad 10 be ovcrcome and several relevanl questions 10 be
answcred before specilic types of reactioDs could be approachcd. Among luch problema
and q ucst ions wcrc Ihose eonccrning Ihe dcsc. iption or lhe dilfcrenl organomctallic lpeciel
in soluli on in a varicly or solvent. ($Ce e.g.. Ch.pter 13); he purily of lhe material, neludiD!
Ihe quality of the magnesium used for Ihe preparalion or he rtagcnU; aOO Ihe tdentily
o the dilfercnt products fonncd during Ihe reaclions.
The role pl ayed by 1he coordinating solvent molecules in lhe dcvdopmcnt or
inlcrmcdialcs, as well as tbat of transition states during the progress 01 tbe rcactions, bas
becn subject or oontroveny and debatc evcr since the Grignard rcaent was int roduocd
in synthetic organic chemistry at the beginning oC Ibis ntuey. Thc limitcd uodentaOOing
01 coordinati on numbers of elernent .. or main vak:ncic .. and oC covak:nt bonds al Ibal
lime Icd 10 an unclear descriplion 01 lhe SlrUCIure of the solvatcd Grignard rcaenl aOO
of Ihc mechani st ic upects oC its reactioll$.
In 1901 81aise [1] suggestcd the ColJowing structure for the Grignard compound
RMgX(CH,hO
in wbicb, as hc Connulated il:
lile tlMr is nol jusI an ordinary $OIftnt; il lIu illelf .nicipaled in lile reaction and lhe
slability or lhe proouc;t shOWll lhal it intimately ",nited with tM rat 01 !he mole!:\lle.
FiKure I Proposed SlrllClUre ofBayer . OO Villiger for I solvlled melhylmagnesium iodideGrignard
reagen!. (From Rd. 2)
Soon olher slructures were proposed; si mitar lo Ihe onc proposed by Rayer and
Villiger [2] in 1902, (Fig. 1) for solvalcd melhylmagncsi um iodide.
For lhe finl phuc of Ihe react ion of RMgX wilh epoxyethane, Grignard, 1 year
later [3] , preferred the foUowing slruclure (Fig. 2) over the one suggested by Bayer and
Vi lliger:
Figure 2 SltUClute ptop<lld fo. lhe firsl phi"" oribe reaction wilh RMgX. (From
Rd. 3.)
Through calorimctric measuremenls, Chelinzc:1f [4], in 1906 and 1907, found Ihal
lhe addit ion of 2 molEq of elher 10 un50lvatOO Grignard . eagenlS resulted in considerable
evo)ulion of heal, which was negligible wheD more elher was added (sec also Lifschitz
and Kalberer ( j] and Hayes Heat evolulion indicates lhe rormalion of a
complex belween Ihe Grigna.d reagent and polar molcculcs, implying compelitive
solvalion-<:omplexation when more Ihan one polar species is prcsent beside lhe
organomagnesiurn compound.
In 1912, Sl raus (7] ! uggested thal Ihe fiTst slep in the reaclion ora Grignard reagenl
with a carbonyl compound was the replaocment of the ether in Ihe complex (analogous
lo what had earle. becn proposcd by Kohler (8]; sec also Grignard's vje", on lhe finl
slep of reaclions "'Ih epoxyelhane as reprcsented in Fig. 2) follo"'OO by the rormat ion of
the carbon-alrbon bond (Scheme It.
,
A"COMQ'"
'c H,
....... ,

1"
This concept of replaocment of an ether molecule in a Grignard complex by a
carbonyl oompound as a fi nl slep in itl reaai on gradually became gellCTlIlly accc:pled (sec
also Von Braun and co-workers [9]) after res ulls were published by Meisc:n!JcimeT and
Casper ( 10] as well as by Hess and Rheinboldl (11).
Mcisc: nheimer'. complex may be a common first slep in the sc:quence of reactions
that may finally !cad 10 lhe formalion of dilferenl producIs (sc:e also Kharasch and
Rcinmulh's commenLS ( 12)). Ho"'ever. orlhe following steps in the reactions
wilh Ihe many 5ubslralc:s invesligaled is considerable:. And, even 1he:1l, ji WaJI rroc:nlly
sU88CSled lhal il was nol eic:ar wbc:the:r lhesc compic:xes are Ifue Slc:ps on lhe reaction
palh, or whelher Ihey represenl Mblind aUeys" [13].
Olhef compl icaling faeton in lhe: general dilClmions aOO .yslc:matiC invesliplions
or lhe mechanislic aspc:cts of reaetions of Grisnard reagents inelude
l. The wide varic:ly of lubslrales and or orpnomagncsium reagenll applicd in sueh sludies
2. The number or lide reaetions lhal seemed 10 be possibic: in wh.l origi naUy looked
like a slraighlforward and simple reaet ion
Concerning poinl 1, il i5 nol 10 be C:Xpc:cled Ihal reaelions or reagenlS l ueh alkyl-,
allylic-, be:nzylic-, . nd many ol her types or ofganomancsium halides wilh sumlr.les
as varied as I-hexyne, dimesilyl kelOne, benz.onilrik, aOO so 00. should havc:
a similar pattem in thc:ir mc:chanisms. Relative to point 2, nc:ithe:r was it c:xpcctcd al
Ihe !tan of lhe: invesligatiorl.'J of lhe: reaetion or Grignard reagenl5 with ketones Ihal
in the reaetion of nc:opc:nlylmagnesium ehloride wilh belttOphenone, a
lrD/Ultr would be obsc:rvcd, !cading 10 a 20% yield of bc:ru:opinacol as well as of
2,2-dimelhylpropane [14], nc:openlanc:.
Bul apan froro MUnc:Xpc:cted" side reaetions, vanoUl well-known competing
reaetions, such as reduelion. conjugated addilion. and c:nolizalion reaetions, may well
hinder lhe sludies of mc:chanislic aspc:cts or Gngnard reagc:nl reaelions. In view of an
sueh unknown raetors, il may nol come as a 5urpnsc that io ODe of Ihe latest publications
on some mc:chanistic upecls or Grignan:! reatenl addition reacrions. in Ihe Journl
olOrgDnic Chtmi,J/ry, Ihe iwthon slarlN lheir report wilh lhe: remark Ihal
Allhough Ihe addilion alGrigruord reagenlllo c;:IIrbonyl oompound.l b a mljor Iynlhelic: reac:tion
and sorne elforU have hocn devolcd 10;11 mechanisrn, due lo lhe variable nature al the . pecil J
:n : .]11 in ",Iution, kw pooitive raulll hlvc: been obtaincd. (15)
As will be nOlieed from Ihe conlenta of Ihis ehapter, however, considerably more
than effons" have heen devolcd in lhe search for a bc:tler understanding of Ihe
mc:chanism(s) or Ihe reaelion(s) or Gngnard reagenls. Whelher or nol Ihese efforts have
Ic:d 10 "positive te$ult," is to be judgc:d by those researchen who have made use or them
or wiIJ be: using them for fulurt work.
Dcvclopments after lhe early 1%Os in lhe: sl udia; of mecbanisms for reaetions of
Grignard reagenls have made il pos:sibic: lo come to a eluref underslaDding or Ihe general
eharaeter of these mechanisms. A dilferentialwn between a radical eharaeter of sueh
rea.etions, on the one hand, and a concertc:d (polar) mc:chanism, on lhe e:ltreme olher hand,
is beeomi ng mort and more evident. Howevcr, the details on Ihe slmeture or inlermediales
and the sc:quencc: of Ihe difl"erenl reaelion Ieps Ilill require more sludies.
Earlic:r reviews on the subjecl or mechanisms havc heen l'netel'ltcd in sueh standard
works as lhe: Kharuch and Rc:inmuth te:ltbook [12], which appearcd in 1954, as well as
in the ehaplers on ofganomagncsium ehemistry in sueh general organomelallic le:llbooks
as the ones by Jofl"e and Nesmeyanov [16] aOO by Nttel [17]. Later reviewl in this area
are mueh more charaeteristic of accouDts of investiptiont by thc: different specialists in
Ihis (and relatcd) field(s) [18- 25].
The emphasis of Ihis ehapler will be on Ihe mechanisl ie aspc:cts or lhe ("normal" ?)
addilion reaedon of Grignard reagents 10 Ihe carhon-o:lygen double bond, as is found for
ketones. However, il will become clear thal for rcactions wilh othe:r suhslrates. lhe: general
mechanistie aspc:cts or Ihese carbonyl addition rcaetions are also applicable.
11, MECHANIIM Of THE CAA80NYL ADDITlON AEACTION
A, HomcNytIc Ve ..... a Concel1ed Mechanlama
Inilially, Grignard Teagenls WCR considered lO be nueleophiles reacting mainly in a polar
fuhioD, However, early in lhe: history of Grignard ebernistry the concepl originated Ihat
the reaetion could have a radical eharaeter, In 1913 (26] and sorne yean laler in 1922
[21] Ihe formalion of alkencs and alkanes in the rcaelion of haloalkancs wi th Grignard
reagents in dielhyl el her (Sehe:mc 2) had already becn auribuled 10 Ihe intermcdiacy or
whal W8S named, 1m alkyls.
R-X R'Hg X
Se_me: 1
The suggcstion Ihat radicals were responsible: for he prodUCIS fOl Uled in reaelions
or alkylmagncsium halides with a ketone was fi nt made in a publication that appeared
in 1929 [28]. Acc:ordi ng 10 the aUlhon:
Thc: ~ u c i n l action of aliphalic Gr;lnlrd realenll can be acrounled for if lile &S&umption
iI made lhal I"valenl carbon ndicals an produced al inlermedialc naction producu,
They reachcd Ihe con<:huiOn Ihal
It ... ould be upco:;tcd lhal lbese uhalcnl carbon rldicals ... ould be very unllable 100 Ihat
lhe:y might undero,.pontaneoU$ly, one or ibe lyJ!CI ofuan..sformalion whid! have been rouOO
10 be chaTklerislic for lrivalenl carbon nldicab or lhe: lriary\mcthyl Iyp", namely, addion,
mulual oxidalion alld reduction, and polarizalion,
The: rollowing reaction sche:me was presenled (Seheme ~
R' HqX
"
,
Considerable amounts (oflen more Ihan SOY. yields)ofreduccd ketones were oblained
with Grignard reagenls from I-bromopropane, 2-bromopropane, I-iodobutane, 2-me:thyl-
I-bromopropane, and 2-met hyl-I-bromobutane,
In Iheir artiele, Ihe authon rercrred 10 an earHer paper by Lagrave [29] in 1921,
who in his , ludies of Ihe reduelion or bem:oplK:none by Grignard reagenl .. suggesled Ihal
Ihc subslralc fint replaccd Ihe solvent molecule in the Grignard el hcrate (sc:c also earl icr
work by Grignard [30,31]), af'tcr which kthe complex ehanged inlo a slable rorm which
could tnen give: several dilferenl produet5,k
Lagravc presented lhe foll owing scheme for Ihis reaedon (Schcme 4), in which it is
diffieull for modem ehemisl! 10 grasp whal Ihe (doUe<!-line) bonds aelually represen!:

-o
Blicke and Powen mene<! lo Ihis intennediale as being the same Iype as the: radicals
hey had describe<! in Scheme 3.
Saon afier this publication. another report appeared (in 1932) on the: (radical) reduction
of benzophenonc (again!) by cyclohe:xylmagnesium bromide and iodide (32).
A serious problem arase wben il was discovc:red Ihal trace amounts 01 transition
metals, whcn added 10 methylmagnesium bromide. would prevent the formation 01 lbe
addition reaction produel and le<! lO high yields 01 benzopinacol (33). In lhe: yean Ihal
followed, Olle mighl even say unti! the beginning oribe 1970s.lbe wholc: COnoepl of radical
lormation in reactiolLl of Grignard reagenls wa. almOSI exelusiV(ly related lo Ihe prcsence
01 sueh metal ions in lhe reaction mixture. So much so, indced, that in a recently published
paper [25]. Ihe purpose of whieh was "lO give a brief review on recent sludies on lhe
Grignard addili oo reactions," Ihe remark was made Ihat "io those days, Le., Ihe %Os,
uorortunalely it was difficull for the radical mcchanism of tbe Grinatd reagent to aio
general acceptanee."
In 1964. Ihanks 10 Ihe devc:lopmeol 01 modem techniques, especially eJectron-spin
resonance (ESR), a direct proor could be given 01 Ihe occurreoce 01 radicals in the reaelion
01 Grignard reagc:nts, sueh as ethylmagnesium iodide, pnenylmagnesium bromide,
and para'lolylmagnesium bromide, in lelrahydrofuran (THF) with aromal;c ketones,
.ueh as 4-chlorobenzophenone. 4-aminobenzophenone. 4-methoxybenzopbenone, 4,4'-
dimcthollybenzophenone, acetophenone, and 4-bromoaoetopbenone [34].
Radicals were also detected in the reaction mixtures of lOme aliphatic ketones (sueh
as penta- and hCllamelhylaoetone) and of benzonitrile. At conc:cntrations 01 10- ' - 10-
M a yield 013.4-;. free radicah Wl$ obtained when cquimolar amouots 01 benzopbenone
and phenylmagnesium bromide were allowed 10 react al a "dI')' ioe-aoetone" temperature.
When, in Ihe same reaClion, a 2O-fold exoess of Ihe Grignard reagenl was u.sed, 24-;.
radicals (based on lhe amount of Ihe benzophenone) could be detected. Aboul lhe nalure
of Ihese radicals lhe aulhor staled Ihat
Ahhough it is elcar tllat the free: radical in cach GriJII.rd reagent is nol the ketyl which is
obtaincd Ihrough lhe mluction of lhe correspondin ca.bonyl compound ... itb Ma/Hg,
compamon of 11Id. ESRapeen. and visible ab$orpfiOll spedra indCIIlc Ihat tbey .re quite
similar.
In Ihat same year, a rather revolutionary publication appeared [35] on Tht Seopt
O/ 1M &acliOll 1It1"","" CarbaniOllS or NitranlOllJ and UNStIluraltd EllrOll
Many carbanions and nilraDions seemed lo reaet with uDsaturated molecules, sueh as
nitroaromatic:s, azobenzcne, and dial')'l kelones, 10 form the radical anioos derived Irom
the unsaturated compounds. The sameeffect was observed with n-butylmagnesium bromide
and lIbutyllithium. The radical anions were observed with Ihe aid ofekctron spin resonana:
Table I Tbe Inlhxnoc 01 00 Radical
Formation by Orpnomlnc:tium Compoundl ",ilh
Kctone:s [ J6]
Radical
Si,na! anion,(%)
(C, H,hO Very weak aOO unsllbIe
THF Weat but IIIble ailllllJ <O,
DME Rather u1lilltlble O.,
(C, H,hN Un,table ,02
HMPA' Stron, lOO Itlble J<i
(ESR) speclroscopy, as was seen wilh the previousJy mentioned reaction, The conclusion
was that proocsSC'S involving onc-elcctron tnlO5fcr must be important in many reactions
nvolving carbanions,M
Of particular nterest were the lafge oonccntrations of anions formed with
organometallic reagenl5 in certain inslanoes. In Ihcir diJCus.sion or the results the aulhors
slated: Mlt is of interest 10 speculale on lhe imporlanor: of electron-t ransJer proocsses in
the synt heticaUy importan! addition and condensat ion reactions al' carbanions, nitranioos,
or organometallic reagents.
M
A ehange in opi nion on the rarety ofradicals found in what was, unti llhen,
10 be normal carbanionie reactions, was gradualJ y laking place as will be dcmonslraled
in this seclion.
The inftuence of the solveDt on radical Cormation by organomagne.tium compounds
with ketones was made evident a few years later when dibern:ylmagnesi um 11'115 reaeted
with ftuorenonc [36] (Table n
Since RMgX ytelds unaller concenlralioDs oC radical anions Ihan the correspondiDg
RIMs. Curlhe! invesligations by lhe samc aUlhon were carried out ",,t h these
organomagnesium compounds. It was concluded that Ihe fonoalion of radical anions is
ravored when the ionie eharaeter oC the carbon- magncsium bond is inereased, u with the
slrong!y ba.sie HMPA. Thi! concl usion wu supporled by results obtained wi lh severa!
dilferent organomagncsium compounds. when il WlU found Ihal an increase in the formation
oC radical anions is caused by a increasing charge on the carbon alom bound lo the
magne.tium alom:
Me< El < Bu <i- Prop < /- Bu < benzyl
In Ihat same period neopenlane, toget her wit h benzopinacol, were among lile produets
[1 4J 01 lhe reaction oC neopentylmagncsium chloride and benzophenone as well as the
(i.e.., lhe n:act ion produet, Ihe lertiary alcohol (Scheme

x
Se' Fme S
Ru 110., Mad.nr.,.,. (11 Orr'Li.rd R ..... 11
Thc proposcd meenanism for Ihi, reaction included he rormatioD-by a one-eteclron
lransrer-or a benzophenone kelyl aDd a ncopenlyl radical in a solvenl cagc. M ",hich lhen
oould cither coflapsc 10 produce lhe normal produet or frorn which the radical. oould
escape lO rorm dilferent producls, . uch as benzopinacot and ncopentane (Scheme
Ph Co:"u..JI
0,
,


.
Ph,IIC-O- "gX
, '.
o,
jo,
[Ph, COHgX
j
o,
Ph,C-CPh,
"

, ,
kit r 1
XHIIO OH!lX
Sdl me 6
Inili.lly il was Ihoughl Ihal the bcnwpinacol fOilued in .uch reactions Wall jusI a
by-producto produced in a prooess that Wall in competitioll with a polar mechanism.
Oradually. Ihe new yiew deyeloped that tbe initial electron-trander prooess Wall the oommon
reaclion. wherea.s lhe polar-or helerolyt)c-reaetion, referred lo alI "ooncerted mechanism, M
took place only when special coodilions were lulfilled_
Since (substiluled) benwphenone(s) are widely used for mech.nistie sludies, for
dilferenl reasons (e,g., no rx-hydrogens, so no "enolization
M
is possible; high molecular
weight, so products are easily detectable; reaetion, aOO so on), tbere is a tendency
in modern publicalions to generalize reaclions with benzophenone .nd 10 announce work
as done wilh kelones in general.
Apan from ESR spectroscopy. kinelic 'ludies have .iso oonlribuled oonsmr.bly 10
a bctter undentaOOing of Ihe rcaetion mech.nisms of Orianaro rea.gent, as did lhe lIudM:s
of the oomposition and struelure of lhe products of lhe reaclions.
Because of the considerable technical difficuldes encountered when monitoring
reaction mixtures of Orlanaro reagents with kelones (Ihe rcaclion of methylm'IDesium
bromide and acctone was .Imost complete wilhin 10 sec. eyen al - IS"e). il look a while
before reports on luch investigations appeared relularly.
In 1961, kinelic sludies 01 methyltnagnesium btomide wilb benzophenone .nd
pinacolone, 3,3-dimethyl-2-butanone [37], confirmed lhe existing opinion at that lime [_
Re!. 38, for its origin). Fint. a complex was formed belween Ihe OTiIDaro reagent and
the kelone, The complex was lhen atlacked by a IICCOnd Orignard molecule 10 rorm lhe
addition product (Scheme 7):
..
1111 '(_0 II " HgX 4 1111' c...[). .. X
tldlldlon I
--.J
aldotiJot ion
Sckme 7
The reaclions (bolh with beru:ophenonc and with pinacoJone) folJow a third-order Jaw:
V- k, [Grignard][ketone]
The rale constant for Ihis reaction, however, was dependenl on lhe Grignard
concentralion, which, as il was fonnulaled, Mis probabJy due 10 a conccnlration-dependcnl
self-associal ion as wcll al wilh olher Grignard reagenl ronns which are believed 10 exisl,
and wil h Ihe reacllon producls as Ihe reaction Dimelhylmagncsillm was len
limes faster in iu react ion wilh benzophenone {39] Ihan rmthylmagnesium bromide ancl
stopped hal f-way when equivalent amounlJ of bol h reagents were used, When a double
amount or dimethylmagnesium was employed. lhe reaction was complete.
The init ia! complexation of magnesium species with ketone could be ckmonstrated
by measuring Ihe rate constant, of reactions or melhylmagnesium bromide wilh mixlures
of pinacolone and magne!iium bromidc; Ihe reaclion roll owed scoond-order law:
V .. k [Grignard][kelone]
Klhus demonslraling [according 10 lhe aulhor] Ihal Ihe mechanism is closely related 10
lhe (Scheme
K.lon.

h, ".,;01
-
.. ,
Utttont-HIlBr,1 "RHollr" ___ produ(j Hgllr
Schmt 8
In Ihis scl1emc: Mlhe tinl slep j5 a rapidly eslablished equilibrium, which, in alllikelihood.
is strongly displaced 10 the right; lhe scoond i, rale controlling,k
Almosl si mult aneously, in 1963, anolher research group reported on Ihe react ion
kinetics of methylmagnesium species wilh benwphenonc (40) (a preliminary communC8lon
of Ihis work had appeared in Thcsc aulhon carne lO conclusions Ihal differed
consickrably from Ihe previou! one!i, Very explicitly lhey expresscd as lheir opi nion Ihal
K . .. lhe conccpt or lhe Grignard reaetion wilh a kelone procceding via a !/able oomplex of
lhe Iypc described by Swain (sa: Rcf, 38) is nol supporled by the pubJished evidencc (41]
nor by the l'C5ulls of the presenl inve!iligation,K
1I II worlh reponing here in a modero lexlbook on Grignard chemislry, Ihal lhe
$lime aulhors !Ialed Ihal Ihis whole concepl of a slable complex belwa:n lhe Grignard
reagenl and Ihe kelone was based on a wrong lranslalion and a mi sunderstanding of a
report by Preiffer and Blank from 1939 [41] Ihal is oflen qUOled even IOOay, The crilicism
al the aulhors continued as rolloW$:
No qllanlilica, yields, analyses, or isolalion wcre reporta! 10 juslify in any "'Iy lhe conclusion
lhal the prccipilllc WIlS or .... rtin materiab. It is bealuse 01 Ihnc _ioUl defecu
thlt il is fdl lhal lhe CJlperimcnl does not meTI Ibe importance Ibal hu bcen allached 10 iL
This hu llready bcen poinlcd OUI by 100 (42], ",110 repelled PfWl'er
.00 Dllnk', work, bul isoIatcd Ihe precipilale irnmedillely, Thcy round Ihal lhe Jaller
upon hydrol)'1il, lhe desired carbinol in 79'" yield [40).
However, having said Ihis, they also concluded Ihal Ihe l'C5ulu or Iheir work did not
penol Ihem 10 draw any finn concl usions about a possible substitute. The ki nelics were
found lo be complex, and additional work was sliU required.

The proposcd oonccrtcd rnechanisrns, rontl-inin. e)'e/ic are no loner
of muen interesl today, linee tbese inelude complellcs with Grignard rea,cmlS Ihat were
bclievcd lo have the R
2
Mg' MgX 2 !trodure in accord with lhe general apioion IIlhat time.
Soon after tbese kinetic sludies, in lbe eafly 196Os, aiming al lhe elucidation of
rcaclion mechanisffis, Ihe existente of radicals as intennediates became evident. and il
became more and more clear Iba! eJectron-transfer mechanisms do play an importan! role
in the reactions of Grignanl reagenls.
Befare going into tbese mechanisms in more delail in the oext section (scc Sec.
mention should be made of an unexpected ,ide reaction Ihat was published in 1971.
Although lhe addition of ,-BuMgCI lo benzopnenone had beco reported [43] 10
yicld 63% oflbe c:lpedcd tertial'J alcohol. 1, l-dipbenyl-2,2-dimethyl- l-propanol. "diphenyl-
,_bulylcarblnol
ft
(no rtduction products, suc::h as benzhydrol and benropinacol. wcre found
then). it was shown that besidcs lhe normal addilion to lhe earbon-<lx)'gcn doubk: bood,
l,2-addition and aOO l,6-addilion had lalcen place, leading 10 Ihe formalion of an
allc)'ldih)'drobenzophenone [44] (Scheme 9);
l,2-lIdd itlon
",..

",..
1.6_addlrion
50%
Se' tmE ,
Also, a mall amounl of benzopinacol was isolated lbe conjugate addilion of Gngnard
reagcoll 10 Sleneall)' hindercd bcnzophenoncs had becn sludied earlier (sce. c.a., Rd. 45],
bUI it had never beco dc:lcclcd for benzophe:noDC ilJclf. lbis is probabl)' bccausc of the:
ioslabi1it)' ot lhe dih)'drobcozophenone, which al 8Q-9<rC dCCOm)'(lICI lo rorm
benrophe:nonc aod 2-meth)'lpropane. ID Ihe prcscfl9C of oKidiziog il undergocs
aromatizalioo to form 4-t-bul)'lbcnwphenone. Furtber studies iD Ihis field showcd Ihal
wilh other substitutcd bcorophenoncs, nol 001)' 1,2- aOO 1,6-additioo loole plaoc, but, as
also 1,4-addi lioo. lbis happencd io particular wilh 4,4'-<ii-t-bul)'l- aod
4,4' -<iichlorobenzopheoone.
Kinelic mcasuremenll of reactions of t-BuMCl wilh ISI different lubstitutcd
bcnrophe:noncs lcd lhe: aUlhors lo thc concJusion Ihat, in all of tbese reaclions., lhe: most
probable common ralc-limiting step is Ihe electroo lraolfer from tbe Grignard reagenl lo
the leelone lo form the Icet)'! radical anion aOO tbe t-but)'1 radicaL lbil broughl them 10
the slatement Ihal: "lbis would indicate that the: radkal path il nol a s)de reaction, bul
ralher conSlilutCl the main, if not lhe: onl)' mechanilm
H
[44].
B. o. .... lopm.nt ot. A .... It ... "' Splcl,um
Electron transter il an ox.idation--reductioo pr(loCQlS Ihat leads lo the formalion of an 1!Ie)'l
radical froro lhe alle),lmagncsium halide, and of a Icel)'l-a radical anion- from Ihe leelODC.
'"
1I1on'"lJIV
The qUClllion can then be raiscd as lo what extent 'lIch radicals are Mfree" 10 move. either
within (he solvenl cae-a ralher vaoe terminoJogy Ihal hidcs a cerlaio lack of knowledgc
aboul he actual sit uation-or oulsidc of Ihis solvcnt cage, farlher away from lhe ,i le of
transrer. either 10 produce he normal product, or 10 escape and form dift'erenl. Munexpectcd,"
products (1lIch as disproportionation products., solvent-attack products, and
00 he olher hand. in a conoertcd mechanism, bond (armalion, which neludes he
shin of two electrons al a time ror each bond 10 be formcd. takes place simultaneously
on different site: in Ihe complued reagenls (sec, as an example, he eyc1ic mc:chanism
presented in Scheme 7). These two mec;:hanisms are extremes in a complete pidure or how
bond formalion takes place in reacliollll of Grignard reagcnts with whatcvcr substrate! is
under discussion; a reaclivily spectrum bc:<:omes evidenl
If Ihe lirelime of the alkyl radical is nlremcly i hort, in otnc: r words. ir a cerlain
given radical is very unstable (i.e., very reactive), Ihe lifelime of a radical pair, eonsisting
of an alltyl and a radical, and homolysis, would be ntremely
short. eleclron transfer and radical combination follow eaeh olher, wilh
alrnosl no separation; no can be made between a Iwo-step eleclron'lransfer
mechanism and a one-5lep polar mechanism. For slerie reason!, one would npecl Ihe
following sequcnce ofreaetivities in a eoncerte<! mechanism: tertiary <sccondary < primary,
wnc:reas the is lo be for an electrontransfer mechanism, in view of the
slabi l;ly of radical,.
A knowkdge of electrochemical properties or Ihe Grignard would
aJlow a more accurate prediction or Iheir reaelivities toward one and the same ketone.
since (ET) involves Ihe transfer or one electron. It was hoped that il
would be possible lo relate reaetion rates 10 the anodie potential or RMgX.
To Ihat end, the logarilhms of the pscudo-first-order rate conslants for reaetions of
0.02 M Grignard reagenl with 0.25 M benzophenone were ploued againsl Ihe (correcled)
vollage or an anodie process at a eurrent density of 'D- O.06 A cm-
l
(110.0.) [46]. An
approlimate linear correlation was oblained for methyl-, ethyl-, isopropyl-, ' -bulyl-, and
benzylmagncsium bromidc, whieh, al the aulhor carefully worded il,
migll! indicatc Ihat 1M. ET mcchanism which was IUgtllled fo. fl"T1-bulylm.gnesi um bromide
[44] may be a n:levanl modct for mlny simple alkylmanesi um bromidcs.
demonslrating lhe uncerlainty Ihat in Ihis arca, he continued
Ths "'ould not mean Ih.1 free r.dicals In: actual intermedialcs. bul only Ihal he al kyl
assUmel I .ignificlnt Imounl of I1Idical Chll1lCter in he t.aosillon olale [46].
The reaclivity or sorne olher Grignard rcagents Ihal were invesligaled was nOI well
correlated with thedischarge il seemed Ihat ,B-branching. a5 in represents
more $Ieric hindrance for Ihe chemical than for the eleclrode prOOC$S. For aUyl- and
cyclopenlylmagnesium bromide, lhe rcaetion was faster Ihan would be predicted from Ihe
di scharge potentiais. The mechanism of reaclion for Ihese rcagenls may be dilferent, or it
may be a hybrid between the Ilepwisc eleclfon-Ifansfcr mechanism and the polar (concertedJ
mechanism.
A few yean later, by I differcnt rcsearch group, Ihe idea W85 proposcd 10 "trap. M or
Mobserve," the inlennediate radical or radical aoion (47). d.l"-Propenylmagnesium brornide,
a vinylie Grignard rcagent, rcacted wilh benzophenone 10 yicld the nonnal,
, ....
unisomcriud, tcrtiary alcohol (Seheme 10):
v
H9Br

Schemc 10
Likewise, no isomerizalion (cyclizalioD) was wheD S-helenylmagncsium bromidc,
a well -sludicd radical probe, was reacted wjlh bcnzopnenoDC. Thc aulhors concludcd Ihal
Ihis M ... indicalcs Ihal eilher Ihe is polar or, ir SET, no radical character il
exhibited."
On he other hand. when l,l-dimelhyl-S-hcxenylmagnesium chloride was rcacted
wilh bcnzophenone, Ihe following produclS werc obtaincd (Scbcmc 11):
_
lO%
Sd une 11

H%
,,%
Since products from lhe 1,6-addilion reactions are tonned in much argcr amounlS Ihan
those rrom Ihe 1,2-addition rcaction (38;72), and since no cyclization takcs place in lhe
laUer l he conclusion WIS made Ihal lhe 1,2-addition rcaclion product rcsults
from a collapsc of a radical anion (kelyl)-radical calion (RM",- +) pajr in which lhe group
R' of the Grignard is $liD Ijghtly bound 10 Ihe magncsium.
However. how '"free." is Ihe radical anioo in rcactions of bcnzophenonc? In Ihe
prcsencc of a radical anion scavcngcr, sucb as p-dinilrobcnzcnc [48). pinacol formalion
is totalty IUpprcssM in reactions of MCHl MBr" aOO "t-C. H, MgCI" [49) with
2-mcthylbcnzophenonc, bul Ihe same scavcngcr had no cfl'cct on the ralio or Ihe rate of
1,2- and 1,6-addition rcaction productJ. Thus, the formalion of thcsc products docs nol
involve a Mfrce kelyl." A sil13le-cleclron transfer (SET) intermediatc, 1, wa.s proposed
(Scheme 12)
Rl1gX 9 Ph I C_O., __
The SET inlennediate I could either directly form a 1,2-addilion reaction product (JCc
Scheme 13 palh a; no isamerization) or il could diS$Oclate lo form a radical anion and 11
free radical within Ihe $Olvcnl caSC. CoUapsc or Ihe IWO radicals !cads 10 lhe formadon
o( the 1,6-addidon rcael ion producu, whercas escape: from lhe salvenl cagc would lcad
lo radical resellon products. such as benzopinacol and R- H, Ihe rcsul l of salvenl atlaek
(Scheme I Jt.
1,2_lIddltlan
y
1
. e e .
IPh,C-OHgX RI-- 1, 6- addlt lan
I .".,. 'u.
pInato! RH
.. , ... , ....
Scheme 13
Elecl ronlransfer and polar mechanisms are exlremes in a reaelivi ly spect rum or Grignard
reagenu. Al! evidenoe indicalcs Ihal lhe reaelion or CHJMgBr wilh acelone is polar,
whereas Ihe rcaction o( r-C .. H, MgCl wilh benzophenone prooceds by an eleclron- Iransfer
mechanism. 1I is unclear lO which of Ihe Iwo possible mechanisms Ihe reael ons or
lhe cis-vi nylic Grignard resgenl and S-hcJ.enylmagncsium bromide belong. si nce no
isomerizalion look place. From Ihe work prcscnled. il beo::amc clear Ihat, ir Ihe rtact ion
prooceds Ihrough an elcclron- Iransfer palhway, a "free" radical is nOI involved. Thc aul hon
(47) conc1ude Ihal
[T]he iniliaUy propose<! by ... -Moshcr [ 14] and Fauvlrque [36) 100 laler
supported by Holm-Crossland [44] ._ .-d$ SODIC modificalion. A "free
w
radical .nd "free
kClyl M Qlnool rorm in lhe SET Slcp as wu propo:scd. Apparently . n inlermcdiale radical
anion- radical Qllion pair i, rormed which Qln collapse 10 Ive 1.2 addi lion product or diuociltc
10 forrn a radicalanion Ind I free radial wilhin lhe solvenl calC which in hlrn can collapse
10 conjugale addilion producu or escape lhe solvenl cage 10 form pinlcol.
A sublle new element had lo be inlroduced 10 accounl for Ihe rcsulls oblained: free radicals
in a cage, a salvenl cage.
In furln.:r work on Ihe el ueidalion orln.: mcchanism ol rcaeliOIU orGrignard reagcn!!,
almOSI 10 yean afi er lhe arorcmenlioned refinemenl or lhe original electron-trlnsfer
mechanism, use was made. among olhers, of electron paramagnetic resonancc or (EPR)
lechniqucs [50,51], by the same l ulhor who, for the finl lime, in 1964, found evidencc
for the oocurrcnce or radicals in sueh reaelions. In Ihe inl roduelion of Ihe papcr il was
staled thll
[T]hc $Iill mnains lo be ,illC'C! tbere is almosl no ddinile informllion on
Ihe rnCC:Mnism by whK:h I n alkyl or aryl group is transfe"ed 10 lhe initillly forrned I nion
radicals.
Apio, as before, only aromatic kelonel [benzil and (subsliluled) benzopn.:nones] were
Ihe subsl rales. To measurC pscudo-lint-order I"(:aelion rales a lenfold nces5 of Grignard
reagent over kelonc was Ipplied in Ihe mcasurcmenls. Sc:heme 14 represenl! lhe rcsulls
of these investigations:
"
2 Katona 2 RHQ Br 77-"-
l . l.
(
'''''j'.
K,tOM T I i Klto .. I
RHgBr
1

21ICdona-_ RHIjIBr
o
]
1
_
0',,--_
RHgBr
l. r.
Seh_ 14
"
.!. RHIjI Br
lbe initial elc:dron transfer from a Grignanl reagent to a ketooe resulu io Ihe
formatloo of a mooomeric ioo radical pair 1, which ioslaDtly forms a slable dimer 2: lhe
two anion radM:a1s are ioo-paired wilh lhe dimeric countercation of lhe Grigoaro reagen!,
and the resulliog ion pairs eJ[isl as a dimeric species. The kinelics oflhe dc:cay ofl, followed
by SIOppcd-ftow Icchoique, showcd that the observcd p$Cudo-first-order dccay rate
constanU were proportional lo Ihe inilial concenlrations of lhe Grignard reageolS. Thi.
indic:ates Ihal assistance by another ~ n e u t r r molecule of RMgX is DCCClUry for an alkyl
(or ar)'l) group IraDsfer within the complex 10 complele the additioo reaetion. The authon
were able 10 determine /el aOO /eJ by dirccl observation of2, whieh shows a well-resolved
ESR lpectrum.
A plol oC /el oC the reaetion! of methylmagnesium bromide, n-bulylmagnesium
bromide, and elh)'lmagncsium bromide versus the staDdard oxidation potential! oC tbese
Grigoard reagents gave I relalivel), straighl Une (COrtelatioD ooefficient r _ o.998) [sce abo
Ret. 46], which supports Ihe reliability of the le
l
measuremenl5, as wellll the corrcctncss
oC the proposed mcchlnism.
A new dimeosion was giveo lo he sludy oC lhe radical mcchanism by be same
group when, ratber receotly [25], nol only the addition rcactioo bul also lhe reductiOD
reaction were iDelude<! io the investigalions.. When:a.s the addition rcaetion required the
participation oC anolher neutral Grigoanl rcagenl molecule for an allr.)'1 radical-transIer
ptOCCSll in the !table anion-radical aggregate, reduclioo coukl prooccd witbout sucb In
assistance. This was bascd 00 lhe following two findins;
L The larger amounU orGrignanl reagcnl5,compared with lr.etoncs,!cad 10 the lonnation
oC greater amounlS oC addilion rcaction produets.
2. The reaetioD5 iD dielh)'1 elher, compared with those iD tetrah)'droCuran, give greater
amounts oC addition rcaelion producu..
Thc secood finding is eJ[plained in temu oC the existiDg Schlenlr.-t)'pt equilibria
(Schemc 15) or GrigDaro reagents in solution (sce also Chaptcr (3):
2 RHIjIX


,
,
So>t UM 15
In tetrahydroruran tllen: wiU be more monomenc RM"' , wllereas in dielhyl elller, lile
equilibnum lies more loward Ihe dimer [52]. According 10 lile reaclion sclleme, as presenled
by lbese aUlhon (Scheme 16). the addition reaction wiU be ravored under a highcr
conoentralion or RMaX or in Ihe presencc or dimeric Gngnard reagenl, boca.use alkyl
radical IraDsfer in Ihe dimeric anion- radical inlermediale will be facilitated by anothcr
nearby neutral Gngnard reagent (sec palhs b and
I<ilo.,. ,
R l1g Br il
C"')" .
1<"_1 11 1<110.,.1
RHgBr
l. T.
. I ri ......
"
1
"
RHQX 1
1",1, )
,
. -. ....., ..
"
t._I"

,,_l
"
Rtdvdlon ..... 0 Mdlllon produlI
Sekme 16
The very lasl line in Ihis publicalion, howcver, leaves open anolller possible mechanism
iD which exclusively monomeric RMaX I involved: "A po5SibJe parlicipalion of PllIII e
[$clleme 16) caDDOI be excludcd al Ihis stage."
Such an "assistanoe" by a neulral Grignard molecule 10 achieve 1.2-addition ilI a
rathcr surprising new devclopmenl in recenl mechanistk sludies of react ion. of Grignard
reagents. II had betn introduced earlier [sec Ref$. 17,37- 39J as lhe: TClult of kinelic sludies,
bUI, in Ihat same period, work by otilen [sec Ref. 40] could nOI confirm Ihis mccha.nism.
One queslions how lhe assistancc by anolher Grignard molecule from outside lhe dimeric
complcl could accouDI for lhe panial rearnngemeDts in lhe alkyl group. as WlU found
in reactions of 1, I-dimethyl-S-hexeDylmagnesi um bromide (sec Ref. 47]. Future work will
have 10 answer sueh questi ons.
From Ihe same rescan:h group, a repon recenlly appcared on sludies of Ihe caU5C
for the: difJerenc:es in yields ofaddition and reduction produelll in rcaetions of ,, propyl and
isopropylmagnesium bromide with . ubstilutcd benwphenones in three differenl salvent!
(c.a.. diethyl elher (DEE). letrahydrofuran (THF). and 1,2-dimethoxyclhane (DME); 53].
As 10 be expectod, lhe: main producl.l of reaction. oflhe ,, propyl Grignard rcagenl, having
Iwo ,6 hydrogen atollU, were Ihe rcduction rcaction products, Ihe benzohydrols. In a Iypical
example. lhe: reaeli on with benzophenone, Ihe foUowing results were reported:
In THF (%) In DME (%) In DEI:! W. )
,, PropMgBr
Reduclion 8l 79 68
Addit ion 11 21 J2
I-PropMgBr
Reduction 18 31 21
Addilion (1 ,2-; 1,4-; and 1,6-) 82 69 13
R,F 'r,;n ""r:iVfl/_, (11 Orl,,,,", RU,'4Ilr
The ovcraU rcsult, la! the aulborl 10 Ihe conchuion Ihal Ibe produe! dislribution wal
govcrna! by sevcral facton:
L The abilily of the benzopbenone
2. The degree of a .. ociation or Ihe Grignard reagenl
3, Tbc: , Iructure or lhe aIkyl group in tbis reagen!:
Witb increaJIing dala on rcsults of reactions and wilh an increasing numbcr or
a growing number or reaction schemes are elI:pcc::led 10 be inlroduoed Tbc:
inlerprelalion oC lhe origio oC Ihe dilfereooes in 'he product distribution was based on Ihe
following coosideratlons:
The Grignard can be inlo Ihree clanes aa;:ording 10 Ihe slrenglh
of Ihe carbon- magncsium bond! [54]:
Ir Schus, in which Ihe reagent has a SIIong C-Mg bond, bul has no alom;
Ihe bond energy IS higher Ihan 250 kcal/mol: MeMiBr and PhM,sr belong to Ihis class.
2. W-class, in which Ihe reagenl has a weak C-Mg bond. wilh I bond energy below 200
kcal/mol: t-BuMgBr bclongs lo this elass,
3, M-elass, in whicb Ihe reagenl has a C- Mg bond eoergy midway belwcen Ihose orlhe
s- and W-classes: EIMgBr and nBuMgBr belong lo Ihis elass,
For these Ihree classcs Ihe relclion pathways can be dcscribed as sbown in Schezne 17 in
which:
B"" benwphenone
ET, .. electron traosfer
CLV -C-Mg bond
11 S - chus
efJr[! OIH
e+GE,T,
e + Gq ,

R.d, : Add,
I

e-Hger,R'
I
G _ Grignard rcagenl
DlM _ dimerization
Add. r ..... u
Add. ' I."MI ......... u
Ro.
Sc:helM 17
In the )'ear! that foIlowed arter the !int time a radical mcchanism was luggested
for reaCl ions or Grignard reagenl5 and kelones, a few definile sleps are lo be marked:
L 1929: Blicke and Powers [2S] proposed carboll radicals as intermcdiate
reaclon products
M
(see Scheme 2).
2. 1965: Blombers alld Mosher [14) luggesl Mlhe Iransfer of one elcclrOIl which can take
place wilhin Ihe complex fonnc:d belwccn Ihe Grignard reagcnl and Ihe kelone
M
(sec
Scheme 6). Their conclusion was Ihal "il seerned possible that man)' reactiollS of
Grignard compounds have Ihe polential for such a radical course.'
3. 1968: Fauvarque and Rouel [36) concluded Ihal "[lheirJ results al10wed [lhemJ 10
proposc, in accord wilh Ihe colIClusions of Blombcrg and Mosher, Ihat pan of lhe
Iddilion rcaction developed according lO Ihe following schemc (Schcme IS)":
-1.8
1
Sclttme 18

-A n,.,.. .... 1401 ... 1 ....
1 ;" ........ Iololt

).c.o-
4. 1977: Ashby and Bowers [41] found Ihal, if Ihe reactions Ibey had studied prcx:ecded
by In SET palhway, a free radical is nol involved. "Apparenl ly an inlcrmcdiale radical
anion- radical calion pair is fonncd which can coIllpsc to give 1,2-addition product
or dissociale 10 fonn a radical anion and a free radical wilhin lhe salvent cage which
in lurn can collapsc 10 conjugale addilion product! or escape {he salvent cage 10 fonn
pinacol" (see Schemes 12 and 13j.
5. 1991: Maruyama and [53J proposcd Ihree mcchanisms for reaclions of
Grignard reagenlS with benzophenonc, in which dilkrenliation is inlroduccd for the
C-Mg bond slrenglh in the respective reagcnt (sec Scheme 11).
A re!inement or the mecltanism was scarchcd for in Ihe more recent lileralure when
a djlferentiation was made bctween whal was called "inner-spheTe" ET and "outer_sphcre
M
ET. 11 was assumed Ihat, in the reaction of a Grignard reagcnt wilh a ketonc (i.e.,
bcnwphenone). the elect ron 'rander was ralc-limiling [44); furlhennore, fOT a series or
Grignard reagents, a corrclat ion hld becn found bctwccn Ihe rcacli on rales aoo Iheir
oxidadon polential! (21). according 10 Ihe Marcus thcory fo r oUler-spherc ET ( SS).
Neverthelcss, it secmed qucslionable [56) whelher lhe electron Iransfer was an ilKkpelKknl
step (step$ \ .... 2 ..... 3 .... 4 in Scheme 19), OT whether il Wl$ concertcd with Ihe transIer of
Ihe magnesium alom ($Ieps ' .... 3 .... 4).
, ... ,,"

RHgBrl
\",., .......
"

.",,,,,,,,'e'_'-' LO' .-
lO'
. .-."
IIHgBr __
l.,
""""'i
....... , ...
Sebeme 19
I Pllle-OHIIBr +
1
R' J
produch

rladloD coordlnot.
The outer-sphere electron transfer (slep 1_2) mcchanism would supposedly require
a highcr encrgy oC activation than Ihe concertcd electron nnsfer (step 1 ..... Unge
magnesium forma a very slrong bond to Olygtn. 00 lhe one hand. from comparisoD of
Ihe heal oC formallon of lhe traMilion states (or reaellon! of alkylmagnerium bromides
with benzophenone and, on Ihe otber hand, Ihe sum of Ihe heats oC formation of the _Jkyl
radicals and magoesium Ihe conclusion was drawn Ihal Ihe rale-detcrmining
step in these reactions is electron transfcr concerted with magncsium transfer from caroon
to ox)'gto. With tcrtiary and seoondary reagcnts lhe alkyls were free 10 diffuse out oC lhe
solven! cage, whercas wilh primar)' alk)'1 and methyl reagents, weak bondin e:dSls belween
Ihe radicals (4- 10 kcalfmol), prevenlin diffusion out of lhe 50lvenl cage.
A !ruly cona:rted mochani,m t., ho_ver, indic:a!ed in !he reaction of phcnylmlgnesium
bromide ",,!h ace!one, .na:!he wcak doctron donar, pbenylmagneslum bromide. is
reactive: !oonrd !bis IUbslrtle [S6].
A differenl vicw 00 lhe rale-delennining step in Ihis type or reactions was published
1 year later [57] alter carbonyl carbon kinctic isotope effecu aDd rdativc reactivities or
orIllo-, mlM-, and para-substituted benzophenones were determined. Scbemc 20 presents
lhe reactions proposed by lbese lIulhors (lee al50 [49] and Schemes 12 and 13):

RHgX":" lPbIC-HgRI
X
J
01
1.6-adckrcl.
20
plncu:ol
T.bIe 2 RellClion Scqucnca lOO lile Rllc-DclcrmininStep
o( lile ReKlion o( Bcmophcnonc wilh Vlrio ... Gnllllr<!
ReqcnlJ [37)
Rcaclion Kqucncc step
McMgI .-,
,
PhMgBr .-,
,
AltylMgBr . -,

CrolylMg8r . -,

1-8uMsO a- b-(d, e, O b
Kinetie isotope effcclS were posilive for melhy!-, pheny!-, and arrho-tolyl Grignard teagcnl,
in die!hyl elher, wcak for benzylmagnesium bromi, and near zero for al1yl-, cro!yl-, and
rtrt-bulylmagnesum halides..
Table 2 lisI s the reaclion sequenoes and lhe rate-delcrmining step for lhe reaclions
of various Grignard reagcnl$ wilh benzophenone.
One mil/U uk [lile aUlhora en<! Ihdr Concluding Remarks], wbal ... ill happcn if 1"'0
siJlliflCllnt/y dilfcrcnl kelonel _re aUowed 10 reaCI Wilh, rar uample aUy/-MgBr; do Ihey
always react in simi'ar ratc:J?
The ans ... er t a. foUo ..... Wllen Ihe eloclron-aCQCpling ability o( kctone il lowered
by . ny pcrturllalion, lile llarrier afltep a becolJ\c:J only sli,hlly h,her In<! lile llamer of slep
b (ar el TICI rapidly. As !!Ir u SET" lhe for boIh ketones, Ihe reaclivily
dirfcrence ... ollld be , man. Ho_vu, wltrn lhe barricr o( lIep b (or e) bccomos higll e,,"ugb,
lile bKk ET bccollICS ,itnitiClnl Ind lhen lhe reactivity ditrerence of lWO keloncs bccomcs
largcr. Furlhcr drease in lhe e!e<:tron_accePlingabilily of lhe keloM makos Ilep b (or e) lhe
slep. Finany, lhe radicJ,1 ion polir inlermedialc beo.:omes 100 Unstlble 10 elisl
in a meaninpu/ lifelime Ind lbe mechanism merlOS ... ilh lhe pollr OM.
l ile idcnl illcalion al lhe rlle-dctcrmining Jlep for IUdion, o( dill"erent tetones is
nleresting in Ihi, cantuI aoo:l ... m he lhe lubjecl o( further IlIIdy.
In a roocnt publication [13] of Ihe resullJ of yel anolher ' tudy of carbonyl carbon
tinetie i$Olope errccts (KIE), sueh an elfe<:1 was foun<! howevcr, for Itrl-bulylmagnesium
chloridc, oonlrary 10 whal had carlicr bcen reportcd [57]. The aulhor justil1cd his work
as followl
Thc p!"I$Cnce al a carboo KIE for lile reaaion of melhy/ Ind ils abscncc far 1M Itrlbulyl
Grignar<! rcagcnl ...... howevu,surprisin'lincc il would indicatc Ihal thc readion mochanisms
for Ihe Iwo Grignard rcagcnta were quaJilllively diJ'fcrent, whiJc Ihe linear COlTClalioo or E ..
aoo:l lhe Iog rale IUqcsts ltuol lhey are q ... lil"ivdy I/ikc. Work "'U lhocrd"ore lIanro 10
determine ... helher lhe reportcd KIEs could be confirrncd [ /3].
The KIE found fo! Ihe reaction ol benzophenonc with ft,r-bulyl Grignard rcagenl
was nol significanlly lower Ihan the KIE for Ihe rcaclion of melhylmagnesium bromide.
The resullJ indicale that Ihe elfe<:1 observed is mai nly the KIE for Ihe ketyl formation,
whieh includes brcatin of !he 11 C=O bond with a simultaneous O-M, bond formalion.
bltl nor necessarily wilh a si multancous C-C bond rormalion. Whal is common ror tbe
mcchanillms is that lhe fundamental reamon is homolysis or Ihe C-Mg bond. induoed by
concertcd O-M bond formation.

111 BCCOrd wilh he previously reporla! resulta, iodeed no KIE W8.lI round for
1I11ylmagncum bromide reactillg wilh benzophenone. Quite opposilc carlier conchuiolU,
Ihis ndiales Iha! Ihe reaction is no! dissociative and lbal thcn: ia DO kelyl rormalioo. /lo
conocrted six-cenler reaction, nor an SE2' mechanisffi mus! be imajned wilh C-C bond
ronnalioD taking place simultanc:ousJy with (he breakin of Ihe Ir C=O bond.
Th( 6ndiol of KIEs of valllCl around un;l)' IDUSI 1'01, &1 Iw bcen done reputedly, be taken
as proof for, bUI I'JII\er as proof agailul the participation of ketyl as u intcrmodiatc [Il).
This being lhe situatioo in 1993, it does indecd look (sce also Ref. IS ll5 quoted
tarUer) as ir ooly ..... few positive resullS have beco obtaiDed." However, 5uch a disqualifying
slatement does not do much justice 10 tbe cxcellcnl work done in lrus field in Ihe past
30 yean. No doubt sorne more crucial c;I;periments have 10 be carried out befare mOS! of
he mechanislic aspccts of lhe mosl common of a11 reactioM oC Grignard rcagenu (i.e.,
the onc with ketoncs) is fuUy uDdc:rstood.
A ltul)' conoened mechanism ia, howcver, indio;aled in the rcaction or phen)'lm1lncsium bromidc
wilh aec:lonc, lince lhe weak electron doDOr, phcnylmaanc:sium bromidc, iI exlft'mdy reactive
loward Ihillubslralc [56].
TItis quotalion Crom lhe prcvious scction comes Crom a discussion oC lhe rcactions
oC various Grignard rcagcnu witb bcnzophenonc.
Pheoylmagncsium bromide is iocapablc ofhomolysis, phcnyl radjeals bcing extrcmcly
unstable. Abo, sincc lhe rcduction of accIone is much Jess ta5)' lhan the rcduction of an
aroma tic ketonc, 5uch as bcnzophc:oone, lhe Irander of onc single electron (as in a rcduction
rcaction) from phcnylmagncsium bromidc 10 aCCIone is vcry unlikcJy when olber rcaction
paths an: available. A conccrtcd rcaction is luch a palh.
Tbc classic publicalion or a conoencd mcchanism appcarcd in the carl)' 1950s (l8]; il
pickcd up the idea or"assistanoe" by a sccond moJcculc oC a magncsium spccics in rcactions
oCOrignard rcagcnts, as suggcstcd earlicr [" 1], bascd on effOOCOUS obscrvatioM (scc p. 226).
TIte reaction oC I molEq or n-propylmagncsium bromkle with I molEq or diisoprop)'l
ketone, a stemll)' crowdcd ketonc, gave Ihe normal addilion reaction product in onl)'
101'1 yields.; the major product of lhe rcaction 1'111 the rcduction mlCtion producto rormcd
b), the tcander oC a .8-hydrogcn Crom lhe Grigoard rcagent to lhe kctoDC. Owing to an
enolization rcaction (Scbcmc 21), 3% unrcactcd kelOnc could be isolaled:
".
...
& . . .el'
- 1,
When, in he same rcaction, mon: Ihan 1 molEq oC magncsium bromidc was finl addcd
lo tbe kelone, rolJowcd b), Ibe addilion of I molEq of lhe Grignard rcagcnt, lhe yields of
Iflll"""'"
Ihe produels ehanged considelllbly: {rom 30 10 65% addilion ruelion produel; from
63 lo 26% rcduction reaelion product: aOO from 3 10 enolization reaclion producto
The reaseming be:hind Ihis experiment was the followi ng: The mechanism for addilion
of Grignard reagents 10 kel oncs was supposed 10 involvc rcaclion of a previously formed
Grignard- ketooe complcx with a sccond molcculc or Grignard reagcnl (Scheme 22 depicts
the mcchanislic view of Ihe aUlhors as they presenled il in their origi nal paper [35]):
Se_me 22
Such a rnechanism prcdicts Ihal ooe should be: able 10 ncrease Ihe yield or lhe addition
reaction product 10 a hindcrcd kelone al Ihe expense of Iliduction by the simple expcdienl
of adding magncsium bromide lO Ihe keloDC before addilion of Ihe Grignard Ilillgent.
Magncsium bromide is a slightly slrongcr Lewis acid Ihan Ihe Grignard reagenl and
should complex preferentially wilh the ketonc. Thus, it would lend 10 play lhe role or the
finl rnolccule or Grignard reagcnl (which complexCII the kc:tone). The magncsium
bromidc-ketone complex would be: incapablc or rcduction by intramolccular Iliarrangcment,
bul possibly even mOIli IU$OCplible Ihan a Grignard- kclonc comple:t 10 altack by IIn
external molccule of Grignard Iliagenl
The aulhors triumphanlly finished their shorl paper wilh:
Thc 1\1(, 1 of Ilti, prediclion is .,kHlion.1 ev;dcncc rOl" he CQf=t1lCSl or Ihe mec;hnism on
which il was bu ""'.
The cyclie mcchanism, in which Ihe conccnedncss ofl he lliactioD is so dearlydepicted.
hu found applicatioDJ in several olher iDJlances in organomagncsium chemislry. Thi s is
panicularly troe for Ihe rcduclion reaclion Viilh lhe aid of Grignard compounds. 1I was
reponed in 19SO. in a paper on Ihe uymmetric rcduction of keloncs wilh lhe aid of ehiral
Grignard reagents [58). Ihat Whilmore had a1ready presc:nted the idea ora cyclic mcchanism
(Schcme 23) al an American Chemical Saciely meeting in 1943 [ 59] :
x.
x
'"
'"

I
'.
"O-H\

(00 lH,_ R (H,
.
e' R CH,
-
e

eoCH,
, ,
, "
, "
"
,
R HU, IH A H-C

,


Sdwme lJ
In lhat samc period, nteres! had grown in the 51ructulli of allylic Grignard reagen!!
in soJu!ion and in lbe mcchanism of their rcactionJ. To accounl for the resulls or tbe
reaction or ketones with the Grignard Iliagent pllipared from ero!yl bromidc {Ibromo-
2-bulene), Roberu and Youn (60) presented a mechanistie scnemc: (Scheme with two
possible roules 10 Ihe cr-melhylaJlyl derivatives Ihat were obtai ned:
Sdlemt 24
Sueh a eyelie mechanism wu - in the opinion ol Ihese aUlhors-quite similar to Ihat
proposed ror (what Ihey named) the Oaisen allyl elher rearrangement (Scheme

Quite l urprising was the di5COvery oC lhe n:vel"$ibilily oC he addition reaclion ot
crolylmagnesium bromide with slerically hindered ket ones [61], in which a cycJic
mechanism (Scheme 26) was also ,ugesle<! 10 playa tole:
"

The second slep in Ihi$ scheme involves a rour-cenler conoerled mechanism 10 allow
the erotyl structun: lo be retaincd in Ihe bromomagnesio alkollide. Alter a reaction lime
or j min Ihe CI-methy!allyl derivalive was formed in a1most 79% yie!d. togelher with
orthe cis- and Ir<ln.J-crotyl dcrivatives. Alter 193 hr oflhe cr-mcthylally! compound
had remained among Ihe n:action products. whereas lhe combined ci.f- and lran.J-producu
were Corroed in a yie!d ol83'Y.: IO'Y. unreacled IUI -buly! isopropyl ketone was lound in
Ihe react ion mixture in lhe prcscnoe o{ presumcd uoess Grignard reagcnl. Sorne yeal"$
!ater, such a revenibility \Vas also dernonstrated ror the rcaction olallylrnagnesium brornide
with /trl -buly! isopropy! kClone and di-fut-butylketone [62, 63].
No carbonyl carbon kinelie isolope efl'ect was foun<! for Ihe reaelion of
aUylmagnesium bromide wilh benzophenone [13,57]. The rale of Ihe homolylie
mechanism- whieh could be predicted on !he ba5is of lhe oxidalion poten!ial of
.Uylmagnesium bromide [46]- il slower Ihan Ihe concened six-cenler re.elion.
keeping wilh Ihis inlerprelalion,M lhe aUlhor coneluded that Ml he reaelion of
.1Iylmagnesium bromidc wilh benzophenone lakes place wilhoul any transienl coloration
(13r
in a recenl ly published, dctailed study on Ihe stereochemistry of llle addit ion
reaCl ion of al1 ylie Grignard reagents (mainly erotylmagnesium ehloride) witn ,,8-elhylenie
kelones (15], addilion 10 arylsubsliluted enoDes occurred without any selectivi ly al aU,
The authors sugesled that this Wllll due to a single-eleoctron Iransfer, aince poor
diaslereoseleclivity is obse"ed wllen a carbon-carbon bond i5 formed by a radical- radical
combinalion [64]. No funher me<:hanistie details on Ihis difference in reaCl ivily were given.
Sueh resulu. again, demonstrate Ihat Ihe occurrence of cleelron Ir.nsfer il also
determined. among otller reaCl ion condilions, by lhe case of reduclion of Ihe substrale.
Proof for single-cle<:tron lransfer in reactions of allyl. and erolylmagnesi um bromidc
with benzophenone had becn reporled a few ycan before, in 1988, based on me8$urements
of carbonyl carbon kinetie isolope elfocts (whieh were nonexistenl) and aubsliluenl dfecl
Ie<:hniques [65]. Doubt aboul Ihe correet interpretalion of lhe observed phenomenon was
discu55Cd carlier in Ihis ehapler (see p. 231
The mechanisms of reactiona of bem:ylmagnesi um haJides can be eilher homolylic
or concened. Al wilh allylic Grignan! rugenl$, also reversi ble addilion reactions with
benzylic Gngnard reagenls and carbonyl compounds nave becn reponed. In general, yiclds
I alcohols are oblaincd in mueh beller yields by use of
1 [67). However, in 1980, il was demonslmled Ihat,
by far, lhe besl quickesl res ults for lhe synlhesis of thc:se normal .ddition reaction
products are oblai oed by applying benzylic n.lides in Ihe one-slep U- Barbier react ion
under ultrasonie irradial ion [68,69).
Benzylmanesium bromide was among lhe Grignard reagents foun<! on Ihe Itmigbl
ioe when Ihd r anodie oxidal ion potentials were ploued against lhe logarithm of the
pseudo-finl-ordcr rate conslants of reaclions with benzophenone [21,46]. 11Iis was
considered 10 be good evideooe for a rate-Iimiting elect ron tran!l'er
M
(21).
8enzylmagnesium bromide is al so reponed 10 react by an elect ron-trandermc:chanism
[70] with pyridazin; however, a polar mechanism was in Ihe reaetion of
benzylmagnesium bromidc with benril [11].
Reactions of benzylic Grignard reagents with formaldehyde and with other a rbonyl
compounds have mel with greal inleresl ever since Gngnan!'. IiTlt publication in Ihis lield
[72) in 1903. More recent work has Ihown that Ihree producu are formed in varyin
amounls, depending on Ihe reaclion condilions [73, 14) (Fig. 3t, 1, Ihe normal addi lion
1 IJ
13."
O'"OH
111
Fipre 3 Th= prodllCll fonned rrom reaction or benzylic Grijllard 1'U&ents with rormaldehyde.


'"
reaction product, 11, Ihe so-caJIed abnormal o- toJylcarbinol, and 111, Ihe abnormal diol.
Thc normal product I j, consistenll,. mioor compoDellI 01 he final product oomposilion;
11 appcars as the major producl when low oon<:enlralions of formaldehyde were used,
whereas Ihe amounl of (he diol ID increases al high rormaldehyde conoentrations.
In a detai\ed mechanism, proposed much earHee in 1933 [75], a , ix-center transilion
state (Scheme 27) was suggested lO account for the formalion al 11 (Ihe o-toylcarbinol).
whereas (prohably) a four-ocoter transidon slate is nvolved in Ihe formation 01 the normal
proouct.
C""
6
'"
x ot1glC
, ,
.......
........... A O/'IgX __ ,='
U- 21 K
SclKlne 27
More recen! invtstigations [13, 74, 76-78) have revealed the formalion al lIltype
producIs in reactiolU al benzylic Grignard reagents B wilh carbonyl compounds C. When,
for clample (Scheme 28). he secondary benzylic Grignard reagent, l-chloromagnesio-I-
phenylelhane, B, was reacled ror I hr al O"C wilh elhanal e, 52-;, or lhe tmnic alcohol
Twas formed toelher wilh 41 '/. orlhe diol D, and 7-;, orlhe normal product N. Howevcr,
when Ihe reaclion was carried out at 2O"C ror 4 day!, no Toould be lktccted amoDg the
n:acti on producIs. whereas the yield oC D had incn:ased 10 72'/0 ( 78]. No mon: Ihan 10-;,
of the normal alcohol N was Cormed.
(S"QX.
,
21


21 H-

t
T
-
121 H-
,
-",
"g XI
'"
t
t I 11-
,
,
-
-
Scbeme 18
TM reaction oC l-chloromagnesio-I-phenylethane wilh benzopheDone was Ihe nnly
one among Ihe reaclions invcsligaled (nine carbonyl compounds ~ r e used) Ihat gave a
reasonable yield oC the normal producl: 5S-;,. or lhe benzophenone, 36% oould be n:covered
from Ihe reaction mixture. None oC lhe products D or T wen: delecled. Then:fon:, il is
BlGmhl'J
probable Iha! lhe react ion wilh be:nzophenone proceeds by an ek<:l ron-!ransfer mechanism
[sec: also pp. 225 and 240 aOO Rds.21.46).
The aulhor of Ref. [46] eommenled on his resullS in Ihe foll owing manner.
n i. would nOI mean IluII free radicals are actual inlermcd;ales. hUI only 11111 lile Ilkyl
aHumes I sinific:anl lmounl or radical cllaracter in lile lraJUilion Slale. TIIe Ilabilily of Ibe
radical lylX transilion Slale may be: in.crealCd by p.airing bc1wccn be:nzopllenone kelyl radical
and Ihe alkyl radical (46).
Thertfore, il can also be: eoncluded Ihal, for reaetions of allylie and be:m:ylic Orignard
reagenls. a concened mechani5m can be in compcli lion wi lh an ele<:lron-lransfer me<:hanism.
D. A.Ktlv!ty DI V.rlOUI MlI8lM1llum Specl
Ral her early in the hislo.., of organomagnes:ium ebemislry Ihe suggeslion was forwarded
Ihal RMgX was no! Ihe onl y spcdes in $Olutions or Orignard reagents. In 1904, Ihe
exislence or ilS dimer (RMgXh was luggesled (79]. In 1905, il was slaled [80J Ihal il
would be or importance 10 Iry 10 verify Ihe exislence or Ihe followi ng equil ibri um (Scheme 29);
2 R' HgHlg " HgHI9
1
HgRJ
SC"lW!I1e 19
Several years later [8 IJ, lhe: exislence or lhe complell. E12 Mg'Mgll was made likel y
on lile grounds or several ob5ervalions. sueh as lhe ea.y $Olubilily or dielhylmagnesi um
in a IOlution or magnesium iodide and the deposition of magnesium in the anade
compartmenl on elcclrolysis of a solulion of et hylmagnesium iodide (for a more delai led
discussion of Ihe compasilioo or IOlul ions of Grignard reageol! see Chapler
When consideri ng Ihe sl ruCluTeS or Ihe differenl magnesium species in IOlulioo, il is
obvious Ihal each one of Ihese will have its specifie react ivily loward variollS substrales.
Thereron:, il cornes as no surprise Ihat. rrom Ihe very begi nning or Ihe study or lile
me<:hanisms or reaction or Grignard reagenlJ, lhe: or lIIeir comp<Kition was
included. In the fonoulalion or sueh rcactions, Ihe Orignard compound was oFlen rtferred
lO as " RMgX,M leaving unspecifi cd iU aclual slruelure.
As early as in 1930, it was found- wi lh the: aid or the organomagnesium color
lesls-thal phenylmap,ne$ium bromide was 20 times raster Ihan diphcnylmagnesium in lIS
reaclion wilh l-cyanobutanc [82]. Such observations made il elear Ihal knowledge or Ihe
composil ion or the Grignard reagenl $OIulion5 under invcsligalion is or vital importanoe
for a correct understanding or Ihe mc:chanism of lhei r reactions. The firsl report on lhe
(quantilalive) ki netic:s of reactions or organomagnesium compounds wi lh kelones (83), 20
years laler, showcd Ihe reverse order or reac1ivily ror a Gri gnard reagent and Ihe reJated
diorganomagnesi um species: dimel hylmagnesium reaeted much raster wil h acelone Ihan
did melhylmagnesium iodide. The same order of reactivity was found for reac1ions or Ihese
Iwo organomagnesi um compounds wil h benzopbenone [38].
InconeJusive results were obtaincd for reaclive species in IOlulioo (see Schemes 7
and 8 Indoed was used in Scheme 8 in the reacl ion sequcnce Ihal ineluded
a preliminary compk:lI.IIlion or Ihe kelone (pinacolone) wilh magnesium bToroide.
A few yean earlier, Ihe kinelC! of a mueh slowcr reaelion (Scheme the
rnetal- hydrogen ell.change reacl ion, was sludied [84]; gas evolulion was followcd over
lime for the lower aJkyl magncsium halides in Iheir react ions wilh (Scheme
RH
ScJllftM: 3G
The rates of Ihe reaclioft s of equimolar quantities in I N dielhyl ether solutions of
ethyJmagnesium bromide and l-heJIyne, al lhe reftux lemperalure or Ihe mixlure.
measured. ASligoin! Ihe vaJue of 100 10 Ihe rale of rcaction or elhylmagnesium
bromide (base<! on Ihe halflife or Ihe reaction) the rales or reaction or olber
organomagnesium cornpounds could be determine<:!. The relative rates of reaction of
melhylma!nesium iodide and meth)'lmagnesium bromide, ror eJlample, were both 6, and
Ihat oC aJl)'lmagnesium bromide was 435.
Halogenfree diethylmagnesium rcacted with I.hexyoe Ihree times as fasl as
elhylmagnesium bromidc (85). By (pardal) removal oC magnesium bromide from such a
5Olulion, Ihrough the addilion orvarious amounls of 1,4-diolloe and measuring Ihe relalive
rate oC reaction of that solution with .hexyne, il was expected Ihal informalion could be
obtained ahoul the position or Ihe Schlenk equilibrium. Dioxane itself had .no influeDOe
on lhe rale of reaction or dielh)'lmagnesjum in dielh)'1 elher. The rcsults were ralhcr
inconc1usive.
The interpretation of such rate measurements repeatedly encounlered difficullies
relaled lO Ihe st ructure of the organomagnesium speeies Pi , ul in lhe $OlulioiU, in
particular, when $Olvents. such as tertiary amines or when magncsium bromide, were
added (86).
Trieth)'1 amine has no elfect on lhe rate of reaction of dieth)'lmagnesium with
I-hex)'ne, bUI jt has a significant elfect on Ihis reactjon of eth)'lmagnesium bromide (rclative
Tale ncrease<! from 100 to 493). It was IUgsCSled Ihat he amine influenced lhe bridging
betwn IWO magnesium spccics in complexcs formed in $Olution &lid. b)' $O doins.
influenced the rcactivity.
It became clear in Ihat period that a better knowledge of lhe composilion of the
Grignard reagenl was required. 1I wu &Iso in Ihal perioo t hat enoDCOUS rcsulll of
invcstigations Ied 10 Ihe cooclusion Ihat Ihe Schlenk equilibrium wu cucntiaUy nOQCxistenl
[87] (scc also Chapter 13). In rcporls oC kinetic investigalioiU or the rcaction or
methylmagnesium bromide with benzophenone, as mentioned carlier in Ihis chaPler [scc
Rd. 40], consislenl use was made orlhe mixed Grignard !tructurc R1Mg'MgXl 10 describe
Ihe transilion states for (he rate-determining steps., referring lo OtheT1 (88, 89).
An obvious way to oblain a better iosigbt into lhe importante or the Schlenk
equilibrium on Ihe mcchanistic aspects or the reactions or Grignard reagents with a wide
variet)' or substralcs js lo finl study tbcsc reactioiU ror lbe simpler dialkyl- (or for that
malter diaryl-) mancsium spccies.
One of the inlercslin and important aspect.s of lhe reaction or dialk)'lmagncsium
compounds with keloncs conternt Ihe nalure and rcaetivil )' of one or tbe intermediatcs
formed, which contaios bolh a manesium-ox)'gcn and a magoesium-a.rbon bond as
prescnted in Scheme 31:

RIHg rO "
R' R' OHgR
'x' '1'
R' OHgO Ir
SelKme 31
Thcsc compounds were also proposcd as intermcdialcs. 10rmed in reacliolL'l 01
Grignard compounds .. il h "'etonc:s [90,91]. Several compJexcd organomagnesill/ll
rugenls were ob$ervcd in Ihe reaction 01 dimelhylmagnc:siu/ll wilh an exoe:ss 01
2-melhylbcnzophenone [921 in diethyl elher (Scheme 32). With l he react ion 01bolh met hyl
groups in the organomagm:sillm reagenl. yiclds 01 the producl were quantitative.
(CHI',HO
u',,,
P,
u '
,
0,
P,
.", ..
0,
P,
R R R

},
O O
HgCH) (H,I'I;" "HIIOR
ROtt( )loOR
'O' 'O'
O

R R R
P, P, P,
Se.me 32
The reaction 01 dimethylmagnesium wilh eu:css ketone oon5ists 01 a series 01
pseudo-firsl-order reac:tions involving Ihe formalion oC IwO inlermcdiate producls. PI and
PJ before Ihe 10rmadon 01 lhe final product P, . Interprelalion of the kinelic dala did nOI
ncasurily lead 10 lhe oonclusion that a complex het"'een lhe ketone and lhe
organomagnesium species was required 10 bring aboul a reacl ion (case: 11): a bimolecular
callision nOI involving a complex (case: 1) also til lhe data. Nevertheless, in Ihe abstraet
01 Ihe paper lhe aulhors showed lhe Ihree equalions Ihal did involve complex formalion.
which may rentel thei r preference for lhe lradilional ooncept 01 Ihe preliminary formalion
01 a MMeisenheimer complex.
M
The paper oonlinucd as follows: lO dislinguish
bclwecn case I and case 11 iI relatively minor compared 10 lhe more C$senlia] features 01
lhe reaedon path whieh have becn elearly cstabli sbed.
M
A 10ur-ccnler concerted mechanism
was presenled in eaeh 011he carbon-<:arbon bond rormation Sleps in the delailcd mechanism
depi<:ted in the final !lCheme.
To ooncludc Ihis section, Ihe mcchaniltic aspecl5 01 lhe reaetion of melhylmagnc:sium
bromide wil h (a substituted) benzophenone will be di!ICU5SCd in detail. as it was investigalcd
in Ihe nme period [18,19.93).
KinelM:: Sludies wcre carried out in exocss kclone. It was importanl lo keep the
Grignard oonccnlration hclow 0. 1 M 50 that anocialcd spccies would nOI present a
problem in the inlerprelalioo of Ihe kinelic dala. 1t was also imporlanl lo prepare Ihe
Grignard reagenl 1rom unusually pure magnc:sium. since eveo parts per million of cerlain
lransi lion metal impuri lies in Grignard reagents cause Ihe formadon 01 by-ptoduels in
significanl amounll.
The results of lbese invesligalions led lo the fo llowing !lCheme of reaetions (Scheme
33) in whieh complexcs eh e
J
, and e
J
are supposed 10 be 1ormed. the finl IWO 01 which
wiIJ lead 10 a product in which a IH:W carbon-carbon bond hIU been fonned:
1 CH,IIOer
H,Ir,
k'Jf RI C-O k'Jf R,CO k'lf
0'
/H,
"
, . ,
R,C-O"Hg A C-0"'H9
R,C-O"' Hi
,
' ,
.,
'",
'"'
1 C,l 1(,1 IC ,1
" I " I
R'f-
OHgllr
R'f-OHg C JI,
'"' '"'
Sdw.mc: 33
The values or (Ihe iniCial rale con5lanl5) k, Ihal were fouoo ror reactions or 0.0124 M
CH,MgBr wilh 2-methylbenzophenollt in coooenlration ranges belween 0.0128 and 0.668
M weTe reasonably conslant (ranging from 0.0213 10 0.0284 L mol- ' sec- ' ). indicaling
Ihal Ihe proposed model was com:ct and Ihal all (he parameten sutnliluled in lhe rale
express ion were also corree!.
When magnesium bromide WIU added 10 lhe Grignard solution ol melhytmagnesium
bromide, much lo Ihe surprise ol!he aUlhor, Ihe firsl-order ptot, indicating lhe disappearance
or Ihe reagenl, was linear over a targe part ol (he progreu of lhe reacciono
This resuf/ WQS mOJ/ fortuna/e.
lhe aUlhor concluded: in Ihal il indicaled Ihal lhe ruson for the obtened eurvalurc in lhe
,*udo 1st order plot involving only lhe GriJllard rcapnl (no utra added MgRr.) is due 10
the fa<:! tbat the GriJDIrd rugenl i5 disappearing in a more comple.l way . whercas when
exceu MgRr, il added. lhe MgDr, senes 10 eJiminale Ih" complalion. "The . ugcslion al
Ihis poinl is Ihal Ihe GriJllard rcagcnl disappears in 151 orocr ru hion in itl ruction w;lh
kelOnc bul il .Iso disappcars by- cornplculion wilh lhe product lo form RMgX'ROMX;
howcvcr, when nceu MgRr, is presenl, lhe produce can complcx Ihe ttroogc-r Lcwil .cid
(MgRr,).OO hmce lhe GriJllard rugeol disappearl in a ll"\lC lit arder fuhion (19].
A rather detailed scheme was presented ot complexes formed between produclS and
organomagnesium species as wetl as magnesium bromide.
These kinelic sludies resolved two questions:
l. The controveny conoerning Ihe inlegral behavior oflhe Grignard reagent: tbe reaction
is firSl-order in organomagnesium compounds.
2 Tht qucsli on concerning the nature of lhe reactive species: in dicthyl ttber lhe reaction
procceds by reaction of both RMgX and R,Mg 10 aboul tbe $ame e.ltent.
Although Ihe reaClion of dimtthylmagnesium wilh kelone in diethyl ctber is
approximately ten limes fasler Ihan lhe reaclion of melhylmagnesium bromidc. there is
abou{ {en times more melhylmagnesium bromide Ihan dimcthylmagnesillm in an ether
solulion of Ihe Grignard reagenl preparro rrom bromomclhane and magnesium.
111. CONCLUSION
It beeomes evidenl in Ihis ehapter thal considerable progress hlU been made in Ihe past
25 yean in Ihe undentanding of lhe mechanisms or reactions of Grignard reagenlS (and,
ror Ihat maUer, of olher organomagncsium species) with !telones, the main substratcs in
the synthetic procedures in which organomagncsium compounds are lIsed. The rather
negative remark, quoled from a very reoent Pllblical ion [151 Ihat, Mrew posi live res ults
been oblained,M dcmonstrates lhe impalic:nce of the modern seicnti!1 for an even
bcUer undentanding of eaeh one of the complicalcd reaction steps of eaeh one of Ihe
possible reactive species. In the wide spcctrum of reaelivit ics, lhe extremes are 10 be found
in the e/ec/ron-/rans/er rta>:lion, on the one hand, and lhe polar or CQl1cc,frd mhtmi.Jm,
on the other hond. Reduetion aOO oxidalion polentials of bolh Ihe slIbslrales and the
organomagnesium specic:s, respeclively, determine 10 what extent Ihe reaelions observcd
belong lO Ihe elect ron-lransfer or lhe polar or concertcd groups of mechanisms.
An addilional complicaling faelor in the unraveling of mechanisms of reacl ions of
Grignard reagents is relaled 10 Ihe composition of the 5011I Iion of Ihe organometallie
Teagent as well as the reaelivity of each one of lile reaclive species present.
In view of lhe rapid developmcnls in Ihis field, it is appropriale lo end Ihi s chapler
wilh paraphrasing a statemenl published in 1980 [1 9J, by one of the rescarchen who
ha:s--to a considerable extenl- been rcsponsible for a bener underslanding of the problems
in Ihis ficld.
It i, a ronunate rael that Mwe
M
have at lhe momenl a.rived al whal ;, believed lo be lhe
beJinninl of. much beller uOOel'Jlar>dinl of Ihe mcchan:lms of reaelion, ofGnlnaro reagenta.
Thal was said more Ihan a decadc ago.
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2. A. Bayer and V. Vil1iger. Cltt-m. IH . J5;1202
3. V. Grignard. ComP/. RemI. /J6;1262 (1903).
4. (a) W. Cbclinzdr. CMm. &r. J9:119 (b) W. Chelinzdr. Clrtm. &r. 40: 1495 (1907).
S. J. Lifschitz .nd E. O. Kalbc..." , Z. Chem. 101:399
Ii S. Hayes. TltiR Parir; 1963.
7. F. Slnus. Atlna/eII . 191:24.
8. E. P. Kohkr. Am. CItt-..... J. 18:51 1 ( 1907).
9. (a) J. yon Bnun. K. Heicle/. 100 E. Miilkr. JJn. 50; 1637 (b) J. vOn Brauo aod
G. Kirscbbaum, Chn. &m. 51: 1725 (1919).
10. (a' J. Mcisenheimer and J. Cuper. Cltt-m. Ber. '4; 16SS (1921); (b) J. Meisenheimer. AM. 441: ISO

11. K. Heu and H. Rhcinboldl. Bn. 54;2043 (1921).
12. M. S. K haraiICh nd O. Reinmulh, G';gna,d RtQCfion.J 01 Su/mflllUs.
New York. 1954, P. 138.
13. T. Holm. J. Am. Chem. 5. 115:916
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'"
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"
12
Structure Reactlvlty Relatlonshlps
CORNELlS BLOMBERG
Fn, Un/wrllty. Am.rI,rdDm, 11w N"Mrlands
l. INTAODUCnON
II ha! bcen made cicar, in Chapler 11, Ihal lile nalure of lhe Grignard rugen! has a greal
influence on lOe mechaoisrn oC lt reaClions. The extremes in lile reactivity spedrum of
nTganomagnesium compounds in lhei r interaction wilh telones, ror cumple, are (1)
reaClions in whieh a single electron trandcr oa:urs u the first .Iep, or (2) reactions in
whieh a COnceTted bond-breaking- bond-maJdng takes place wilhin a c)'clic transillon state.
This chlpler will deal wilh Ihe predictabilily of lhe rcsulll of reactlon! of
organomagnesium compoundl, in general and of Grinard reagent.s, in particular. wilh
subslratcs oC diffcrenl kinds. 1I is ,video! thal such a predictability requircs a clear
undcrstanding oflne mechanisms oflhe reactions nvolved. For Ihe single-elect ron transfer
rcactions{seeChaptcr 11 for thediscussion oflbe mechanism ofsuch reactions),encouraging
n:sults have rea:ntly bcen obtained.
A ratller sua;e"ful 3fruClurt-rtaclil''Y scheme [1] was introduce<! for resctions
of a variely of reagent .. such as ArMgBr, ArSMgBr. ArNHMgBr, ArN(MgBrh,
and ArOMgBr, with Jubslrates, such as benzophenone, lubstituted nitrobenzenes,
benzoq uinones, and many ot hers. In Ihis .lructure--reaClivity scheme lhe values of differences
between oxidation peah and redUCIioD potentials were laken as an estmate of Ihe relative
efficiency of e\cctroD transeer, the
Thc prolotype ofthis approach was reported in 1974 [2] when reJatve amounts of
evolved hests of reaction of RMgBr wilh benrophenone were related to lhe overvoltages
required for electrolydc oxidalion of lhe (alkyl) Grignard reagenlJ. lbe results presented
by the authors and guided by the AE-approach will, as lhe authors stated,
rontributc la a COTnP"'betuive undenlandinl o reaction beh.viour.nd reactivity o mancsium
re.gentll. The unil'ied Itruc:IUre-lUCIiyity .nd moo,lifiClltion ractQf1 ate uldul as luidelines in
vicw 0/.111001 of roooolirlom and o/ lI.nel 11M of IlfIt DN romponh (polar aprotic
1 .. nlaUleiI _n llIIOIIIIlS [2].
Many reaelion! of N- Mg and G- Mg (Grignard) rcagenls were elassified in lemu of
of (SEl). From Ihe delailed study of produet dislribulion,
minor faelors arising from aggregalion of reagenl molecules- s nd from
wa-complexali on of reaelanl.C were di sdoscd.
Long before any nsighl inl o the mechanisl1c aspecll ofreaClion! ofGrignard reagenll
was attained, sl udies had begun in whic::h Ihe reactivil)' of these reagent.!l was invesligaled
10 acqui re sorne underslanding of a structurc-rcaclivit)' rdalionship in Grignard chemi slr),.
Among Ihe finl reports of such sludics were those b), Ivanoff and CQ- workers in 'he earl)'
193Qs (3]. These aulhon reasaned tha! Ihe rale of Ihe rcacliolU of Grignard reagcnt! was
a measure of lhe slrenglh of Ihe carbon- magnesium bond. A furlher di scussion of Iheir
results will follow in Sect ion II.A.
Sincc Iha' lime, considerablc progrc5s has becn made in Ihe elucidali on of Ihe
mcchani sms of reacli ons of Grignard rcagenls. SliII, lhe tOlal number of knctic
investigalion! of 5uch reaelion! is ver)' limilcd, compared wilh, for example, reael ioul
of solvol)'l ical1y gencralcd earoonium ions wilh nudeophiles.
rtla/iOlUhips, Iherdore, have becn under lIud)' in Ihis fi.cld for a considerable lenglh of
time, although more rectnl sl udC! sccm lO be crilical of lhe general validil)' of such
relalionships [4].
Thc applicalion of Ihc conccpl of reaclivil)' in such structurc-reactivil)' relalionships
has nol )'et becn firml)' eslablished in Grignard chemistr)'. Onl)' ralhcr recenll)' have
suco:ssful and reliable kinclic:: measurements becn published, and Ihei r applicalion in
atlempl s lO elucidate mcchanisms of reaclons of organomagnesium compounds has just
begun (se(: Chapler Detai lcd mechanislic studies, such as SlruCIUrcs oft ransil ion slales,
entropies of reactions, and so on, are IliIl scaree; furthermore, such informalion is rat her
haphazard.
It ma)' be iIlustralive for the present si tuation 10 quote from one of (he mosl recen!
papers on the reaetivit)'- selcctivil)' principie (4J in which- IIS a final paragraph-"AIl
experimental worken [were acknowlcdgedJ who have parlicipalcd in mc.alluring the 1600
rale conslants used in Ibis
Nevcrthele$$, arter having discussed Ihis wealth of mcchani$lic informalion, lhe
paper's condusion WIIS Ihal the reactivil)'-sclcctivil)' principie had lO be rejcclcd 3lI a
general rule. Thc res ullS of the lIud)' were not considercd b), lhe author, one of lhe leading
researchen in Ihis field, 10 becomplc:td)' negativc. The lasl Iwo lines oftheCondusion were:
... invesligarions of tclectivily and ib relalion lo reaclivity slwuld be conli nued and used
pouibly lO a certain Iypc <JI rcadion ()f a OI:rtain mhanism. Parti<:ular ' lIcntion
should be sivcn lO reatliOID wilh a well known mcchani,m [4).
This ehapter will presenl rcsulls of invcsli gations in which sorne specifie festures. in
Ihe widest sense, of Slruct ures of Grignard reagenls are broughl inlo relation with Ihe
oUloome of Iheir reaClions. 1I is hoped and exptcled Ihat such a presenlation will be
helpful in oblaining a c1carer insighl into Ihe struclure-react ivil)' relationship' Ihat are
gradually bccoming more evidenl in organomagnesium chcmiSlty.
11 . SPECIFIC FEATURES OF AEACTJVITY
A. RuctI.,1ty In o..-r.r

,.,
Among (he earlie$1 publicalions in the field of reactivity ludies of Grignard reagenl5 are
hose by Ivanon' [3] in the beginning oC lbe: 1930s. TIte relative rates oC the folloMog
rcactions (Scheme 1) with si;! different Grignard rugents (RMgBr, ext:epl Ihat oC he
mct hylmagncsium Grignard reagent, for whic:h Ihe iodide \\'115 used) were determined lo
investigate he relative strelllllhs of he carbon--magnesiurn bond nvolved [3a].

RH

U 5
ttgCL
Schtnte I
Thc reaer nn wi lh Ihe stcrically most hindcred Grignard reagent. i50propylmagnesium
bromide, was Ihe faslest, whcrcas the reaction with (he least-hindercd Grignard reagent.
melhylmagncsum iodide, Vlas Ihe ! Iowesl. For lbe: reactioDI of various Grignard reagcntl
(aga n all RMgBr, cxcept lhe rncthyl Grignard) wilh indene (Schcrnc (he Jame order
oC reactivitics was found. with a minor ehange: the methyl Grignard reagent was raster
!!ere than the isobutyl reagent [3b]:

AMgX A-M
AI L. rllhs: >1'198. > > > ,",t > jl1t'r
Sd ... lile 2
One year later, in 1934, Vavon and oo-workers [5] determined the relative reaetivi ties
or Grignard reagents with a different type or lubstrates: benzoie acid esters. Steric
requirements played a role when the alcohol component or tbe ester walI ehanged from
primary, to secondary, 10 tertiary; the reIative rates or reactions or ethylmagnesium bromide
werc 400:40: 1, respectively, Thc relative rates or rcaction or ethyl-, isopropyl-, ,,-butyl-,
and phenylmagnesi um bromide with ethyl benzoate dtaeaJed in this order, The reaetioD
wilh ttrf-bulylmagnesium ehloride was reponed 10 be Mextremely slow,"
Changes in Ihe . Ierie requiremenu of Ihe benzoic acid componenl of the ester dld
suggesl a slrong influencc on the reactivity; Ihe reactions or elhylmagnesi um bromide wi th
the cthylesters or benzoic acid, o-methylbenzoic acid, and 2,4,6-trimcthylbenzoie acid had
relative rates or 1000:30:1, An interesting series !tudied in the same paper oonsistcd of the
reactions of ,, _blJlylmaglleSlJm chloridc, bromide, and iodidc, with bUlyl Thc
relat ivc tates wcre chloridc:bromidc:iodidc _1 7:4.j :l.
As was demonstratcd in Chapter II,COl1!liderably more knowlcdgcon lhe mcchanisms
of reaet ions oC Grignard rugents has becn obtai ocd lince lhe Ivanoff and VaYOn periodo
The predictability oC relatiyc reaction Jales as well as of lhe products formed has improYed.
The neXI scct ions will discuS$ the Collowina aspc<:ts of the structure and propert ics oC
Grigoard in reladon 10 thdr reactiyities: sleric rcquiremcnts, lhe halidcs,
p-hydrogcn atoms, Schlenk cqlJilibrium, and solvenl cffCCIs.
, . Sterlc Requlrements
Among the moS! obvious propertics of In organomagncsium compound that influenoc itl
reactiyity are ils . tcric requiremcnu: the bulkier the Ihe more hindraooc there will
be io the approach of Ihe subslralc, and Ihis may cause a considerable io ilS
chcmical behavior. Whcreas mcthylmagncsium bromidc rcaell wilh bcnzopbcnonc
(Scheme 3) lo yield, on hydrolys;" tbe upcc1ed terliary alcohol,
in J()(W. yield,

Sc:h!me 3
Ihe comparable reaetion of ncopcntylmagncsium chloridc. also a primary Grignard reaaenl
(6], lcads 10 Ihe Cormation of 20% bcnzopinaool (bcsidcs tbe CJlpcctcd tertiary alcohol)
logcther wilh ncopcnlane ($chcme
X HgCl . X
Sinoc the side product, bcnzopinacol, usuall)' oriinatcs from a radical-typc reaction
[7,8], it sccms Ihal Ihe "normal, nonradical, carDonyl addition reaction throuh a conocrted
mcchanism is in compet idon wilh tbe rcaction that is lnduccd by a sinle-clcctron lcanseer.
The slowi ng down of the firsl rcaetlon mlJSI be ascribcd to Ihe slerie requircmenls oC lhe
ncopcntyl group.
The eyen morc stericaU)' hindered Orignard Itrtbutylmagncsi urn bromidc,
teaels with benzophcnone (Scbemc S) 10 giye a rina-slJbstituled product in high yieldl
[2b.9] in ayer)' fut reaction.

SO%
&' 1 ..... 5
Later reports on he ral .. of reaellon! of /trl-bulyl Orignard reag1:nts with benwphenone
indced indicated that sueh reBelion! are mueh faster than those ofme!hyl Grignard reagent5:
Whcn a I1vcfold exCC:S$ of lhe Grignard reagenl was use<! in reaction with benwphenonc
(0. 10 M and 0.02 M, respectively) in dielh)'] elher al NC. ltr,-bulylmagnesium bromide
was more than 130 times fUler than Ihe correspondng me!hyl Grignard rugen! [lO).
However, when bc:nzopllenone was in utess (0.25 M of lhe ketone an<! 0.02 M of Ihe
Gtignard reagenl in diethy! .. Iher al 20"0. ftl'l-butylmagnesium bromidc was more than
1200 times faster in ti ruction Ihan rnelhylmagnesium bromide [11]. 1I is relevant ha!
Vavon and co-workcrs [S1. when mea5uring relative rates of reselions of Orign.rd
compounds wilh eslers, found Ihal Ihe 'vl-bulyl Orign.rd reagen! reacttd Kexlremely
slowlyK compaoo with lhe reactivity of elhyl-, isopropyl and ,, butylmagnesium bromide.
Evidenlly, the two types of reactioll$-witb benzopbenone, on tbe Orte band, and eslen,
on Ibe olher hand- follow Iwo complelely difl'erenl mechanislic patla.
Such difl'erenoes in mechanisms caD also be derived from Ihe results oC rate
measuremenls (l'able J) oC reactiofllJ of varioul Orinard reagents wilh benwpbenone,
carbon dioxide, and acelone. respectively. The reactivity series of Orignard reagenlS
loward carbon dioxide [12] is comparable witb lhe series fOl acelone (13], which Ied 10 lhe
conclusion lhat bolh types oC reactions fol1ow lhe same m:hanislic palh: a conoened
mechanism. Slenc requirements. thereCore, are nol lhe only parameter in the predictabilily
of results oC reactions or Orisnard reagents and, in ract. are oC lillle help when no olher
information on the reaction mechanism is aVlilable.
Other interesting conc!usions can be drawn from the dala presented in TIbie "
among which are lhe exlreme!y greal reactivily oC benzylmagnesium chloride loward
benwphenone aOO an even greater, and actually immeasurable. reactivily oC allylmagnesium
bromide loward bolh benwphenone and accIone..
An inleresling SCrK::, of reactions were published in 1991 in which lhe sleric
requiremenlS ofthe Grignard reagenls involved are liso very c1early made manilesl [14].
When a Grignlrd reagenl was added 10 a suspension of benzylpyridinium chloridc in
lelrahydrofuran (THF), heat was evolved, and a clcar solulioo was olxained. Thc reaction
is presented in Scheme 6; cilher a 1,2 or a 1,4--addition reaelion OCCUI'!l:
R"gX

I
..
CrtR "gXC(
1,
T.We I RaleConslanll for ReactionaolVariouaGriglllrd
RUF"I. ",ilh BenrophellOM alld Ao=tone (W-- 'J [2b]
(0.50 !ti RM&X with M Kelone in Oiethyl EIIter al
2O"Cj .1Id ... ;Ih C.tbon Dio.ide (A..Jl. mol - ' _ - ') {12]
(O.0022-(I.(Xl36 M CO, wilh I2-Fold EJ:oess or RMaX)
in TllF al O"C
<O,
0.10 '.H
1.61
'.'
'.'
6.49
u
6.S9
l.l1UI
["
g
B.
4.JS
)..,1198'
"
6.n
".

"
l,a
'. ,
>l-",,,
..

0-
1191
'
'. ,

..
0"""98. ICtI " Us.ol

".
............. 9
.-" .. .,.
... ",1 .,.
The results of Ihe reactions of 5even different RMgX wilh bcnzylpyridinium
chloride are presente<! iD Table 2. II is mosl likely Ihal he large amoun!.! orlhe 1,2-addition
producls formed in lhe reaction with methyl and phenyl Grignard reagenll are, indeed,
due 10 Ihe decreased steric bulk or these
2. The Helldes In the Grlgnard Reagent
The grcalcr elcctronegalivity of Ihe earller halidcs in the pcriodic lable is expccted lO cause
an ncrease: in he polari ly of the carbon- magncsium bond and, hcnce, lo ncrease ils
reactivily.
T.bIe 1 Relative Product Distribulion { ~ from
he Reacion or RMgX wilh Bcnzylpyridinium
Chloride in THF (14)
Grignard reagenl 1,2-AddllCl 1,4-Adduct
CH, MgBr
"
I
(CHoJ.CHMgBr
,
"
C. H. MI Br
"'
..
(CH.hCHCH,M,Br
"
II
(CH,),CM&CI J6 ..
C,H, MgDr 91
,
C, H,CH, MgBr
"
"
In 1934, Vavon had already found Ihal n-bulylmagncsium chloride reacled four times
faster wilh n-bulyl benzoate than did Ihe correspondng bromide which, in turo, showed
lhe same increase in reacdvi ly when compared wilh the ioc:Hde [5). Large dilferenc:es in
reaclivi,ics for chloride and bromidc reagenu are aJlO shown in Table 1 in reacliooa with
bolh accione and benzophenane. Even more slriking dill'ercnces were found for
reaclions of p-tolyl IInd p-chlorophenyl Grignard rcagenU with ben:rophcnone (2b):
p-tolylmagnesium chloride reacled 700 limes faslcr wilh benzophcnone lhan did lhe
correspondng bromide; an<! p-chlorophenylmagnesium chloride was 1200 times rUler
Ihan Ihe corresponding bromide in ils reaction wilh benzophcnone.
Aparl from dill'erences in polarily of Ihe carboD-magnesium bond, lbere may be
olner reasons why organomag:nesium chlorides react rasler Ihan tbe olher organomag:DtSium
hal ides. This, Ihen, may also cause a change in Ihe composillon ot lhe rcaction products,
since slower rt:aclions have no chance to develop. u in lhe rcaclion ofneopenlylmagncsi um
chloride with benzophcnone in Scheme 4.
In Chapter 11, mention was made of a mechanislic proposal (15), in which
participali on of a MneulralM Grignard reagenl molecule was rcquircd for an alkyl radical
lramfer process within Ihe stable anionradical agg:rcg:ate Ihal WIII oriinally fonned (sce
Scheme 16, in Chapter In According lO Ihe aulhon of Ihi s mechaniSlic propasa!. a highc:r
degree of associalion of Grignard rcagents in $OJulion promotes the format ian of addilion
reaction producls. The degrce or association of organomagnesium halides is strongly
infl uenced by Ihe nalure of lhe halide [ 16), wilh the earller halic:les in Ihe pcriodic table
bcing more strongly associated. If Ihe proposed mechanism is correct, a st ronger association
of the Grignard reagent promotes an casier and, hence, faster rcac:tion. Tbis s: :ms to be
slI pporlcd by Ihe relatively few resulls availablc.
More detailcd information on rates and mechanisms of reactions would be of greal
vallle to develop a more precise fonnulalion ot lhe mcchanism jusI discussed. Originally
il was applicd lo account for lhe differences in yields of produCU of addition and reduction
rcactions. However, as repcaledJy staled already, lhe mechanisms involved in bolh Iypes
of rcactions (reduclion '15. addition) shouJd then have 10 be firmly cslabJished, ,i ll(Z
mechanistic chang:cs may .... eU Jead to dilferent resulla.
3. {J-Hydr0lJ8n Atoms In Grlgnard R8IIgents
Among the best known MabnonnaJ" rcactions of Grignard reagents is Ihe one in which
rcduction of Ihe Jubstrale occurs.
Grignard. in his pioneer paper on reactions of organomagnesium compounds [11],
reported the rormation of a ,mall amounl of benzyl alcohol (bcside or Ihe
majn product, the seoondary alcohol) in the reaclon of bc:nzaldchyde with
isoamylmagnesium bromide (Scheme 7t.
56"
Sdltrnt 7

"
d
-............ -
Although Ihis type of reduction ii mOSI frcquently observed in reaclions wilh carbonyl
compounds, several diITcrenl types of organic .ubslrales h,,"c bcen reporte<! 10 undergo
rcduction by a Grignard reagent.
In Iheir paper on the reducing aClion of Grignard reagenls Kharasch and Weinhouse
(18), in 1936, reviewing previou, reports on rcduction by Grigoard reagenls, rderred 10
the rcduction of lhe ethyl esler of trimelhylaectic acid rethyl pivalate1 as studied by
Lcroide, in 1921 [19]. Indeed. a secondary alcohol WIU found among the reaction products,
in addition 10 the tertiary alcohol (Scheme 8). Thi. secondary alcohol mUllt have
becn rorroed. however, in a reaction in which a ketone is reduced by the Grignard reagenl;
ketone ronnation is the first step in reaclions of Grigoard reagen!s with esters. Most likely,
the addition reaction or anolhcr Grignard molecule with an interroediately fonned ketone
is retarded for sterie reasons. which Ihen permits the reduetion reaction lo take place:.
Sclltillt 8
In view or what has becn discussed in lhe previous sect ion (see Seclion I1.A.2) on
Ihe influence of lhe halide in Grignard reagenls, l is of interest 10 menl on that Lcroide'
reporte<! the formalion of considerably more of Ihe reduclion reaclion producl wbcn the
iodide was used. when comparcd with Ihe results obtained wilh the ehloride and Ihe
bromide. The yield ratios or secondary alcohol versus tertiary alcohol were(see. alcohoVlerl.
alcohol) 1.2, 2 1. aOO lO. respcclively. for thechloride, bromide, and iodide Grignard reagenl.
The rcduction of a carbon--earbon double bond was obscrved in 1991 [2Q] in the
reac:lion of a slerieall r hindc:red I:nonc: wi lh In organomlgnc:sium haJide (Seheme 9);

'''' Sdihiile ,
The reduclion of azobenzene by Grignard reagents wilJ be discuS"d al lhe eOO of
Ihis section.
" Reduction by Grignard rea!tnlS is a very common resction," was a statement by
Kharasch and Weinhouse in Iheir paper [ 18). However, Whitmolll and George. a kw
resrs Jaler, in 1942 [21], in their chusic: paper on Ihis subje<:1 u.sed Ihe followin! title:
Ahnormaf Gr i(l1UJrd hactiof\J. Amon! olhen. tbey IlIporled:
h has been definilely estlblished Ihal in lhe luction 011 ketone wilh In lliphlUc GriDard
reagent I hetl_hydrogen in !he lile< is .,re: 11111 for red.udion. The Clilenl or lhe reduetion
depends on lhe nurr:bet" I nd dllraetc<" or .uch bet&-hydrop:n I tOlnl.
Table 3 presenlll l he results ofreactions of diisopropyJ keloDC wi lh Grignard reagenlJ,
as sludied by Whitmolll aOO George [ 21]. rn tbese reactions. nOI on/y addilion and
rcduelion occurs, bUI a1so enoliution, whieh fi naUy lud. lo lbe recovery of lhe startin!
kelonc:.
Thelll is no p..hydragen atom present in met.hyl- and ncoptnlylmagoesium halide;
therdore, no rcduction reaction producu are observed in tbcir reactions. The highesl yield
or rcduct ion reaclion product Wal obtained with 2methyl--propylmagnc:sium bramide,
whieh has ooe tertiary hydrogen alom on lbe J-position. In a foolnOle, !he aUlhon made
mention of an unpubUsbcd resull in whieh Ihe reactioD of diisopropyl kelonc: wit h
ttrt-bulylmagoesium halide, whieh has nine primary hydrogens in Ihe J-posilion, yielded
65"/. of Ihe rcduction reselion producto
The low yleld of addition reaeton product, obtained wilh the DCQpeJl lyl Grignard
reagent is most Iikely due lo the bulkiness of this teagen! <_ Scction I I A I ~ Although
Tibie 3 ResulLl or Reactions or GriJIIlrd Reapnll .,.,ilh
Diisopropyl Kelone [21]
Yields (%)
Grignard te1sen' Enolwlion Reduction Addilion
CH1MIBr O O
" C
1
H,MIBr 2 21 77
n-C1H, MIBr 2 ..
" (CH1l1CHMIBr
"
6l O
(CH1hCHCH1MgBr
, 1
"

(CH,hCCH
1
MO .. O

s-a: Re(, 21.
T.bIe 4 Compariwn or,be Propcniet or"-Propyl- .OO
lsopropylmagnnium Bromide
Reducin S'renllb or Slrenl,h of
Reasen' Ibilily C- M,bond
l/-v H bo"d
II-C. H, MsBr lo.
Slro"S Wu'
-C.H, MsBr Hiah Wu'
S,rons
Ihe total yield of product5 obtained with the "-propyl Grignard reagenl is almosl equal
10 tbe lolal y}eld obtaioed with Ihe ethyl Grignard reagent, Ihe JaUer reagent gave mainly
,he addi lion reaction producl (77-;_), whereas tbe former reagenl yielded mainly the
reduclion reac1ion product (60e_), The increase in the yicld of thi s product was atlributed
10 lhe secondary charaeter or Ihe hydrogens (21).
In lhe previou5 sect ion (11.A.2), menlion was made of proposals [1 5] for a reaction
mechanism in which participalion ot a wneul rar Grignard Teagenl mo1ecule was required
10 aecounl tor an alkyl radical transter process wilhin the slable anion-radical aggrcgale
thal was originally tormed (see also Seheme 16 in Chap,er 11), In lbese publications Ihe
aUlhon sludied Ihe change in lhe addilionJrcduclion producl ralios in reactions ot variou!
alkylmagnesium bromides wjth SUbsl iluled benzophenones. This ralio was I.SS for Ihe
reaction ot CJH, MgBr (0..159 M) wilh belllophenone (0.079 M) in EtJO and 0.214 for
the same reaclion, under lbe same condiliolU, in THF. Thc increase or reduclion reaction
products in diethyl elber was altribuled lO lhe higher degrce ot association ot lhe Grigoard
reagenl in Ihis solvent This makes a sccond neutral Grignard moleeule immedialdy
available fOT Ihe alkyl radical transter within Ihe anion-radical aggregale. When Ihe excess
ot lhe Grignard Teagenl in THF was rcduced (0.151 M C
2
H, MgBr and 0.314 M
benzophenone), Ihe additionJreduction ratio decrea.sed from 0.214 to 0.139. Thi! decrease.
again, was attributed lo the shortage ot neutral Grignard moJecules wilhin Ihe aggresale
10 assisl in he Iranster ot an alkyl radical. There was an even more dramalic change in
,he additionJreduction ralio (decrease from 3.38 10 1, 14 ( ISa]) for Ihe rcaction of
II-bulylmagnesiurn brornide with fluorcDone.
A comparison of lbe results ot reaetions ot II-propylmagnesiurn bromide and
isopropylmagnesium bromide with (suhsliluled) benzophenones [15b] led the aulhon lo
sorne ooncJusions Ihat are presenled in Table 4.
Another elfecl causcd by Ihe presenoe ot 1-hydrogen atoms in Grinard reagenlll is
the change in rates oT their reactions.. WheD the rates oT reaC1ioDs oi various Grignard
reagents with were cornpared (see Seheme 10; see also Scheme JO in Chapter 11 ,
Scction II.C), Ihe aulhon carne lo lhe conclusion Ihat "there appean to be a simple
correJation betwecn Ihe number of 1-hydrogens and Ihe reactivily, .e., isopropyl::. ethyl ::. ".
propyl ::.
11l1g)( --_ II-M .. - "g)(
All. .ah , 210
'" "

Sdttme 10
-
This could. in he authol1l' apiojan, possibly rdlect a dfect or Ihe sorl
suggested by Polany [23J. which is iIlustrated for lhe ethyl moleculc (22aJ in Scheme
Ila; HA stabilization of he incipient carbanion R: e by anionic hyperoonjugation," as il
WlllI described 2 years Jater i5 ptaented in Scheme lb [22b).
"
, '.
a\D
!!
K: ( : ( ' e .... -...


ScIKR'IC 11
Thc secondary fI-deuterium kine!ic solOpe effecu in rcactions af p-perdeutcrated
elhyl-, isopropyl- aDd lert.bulylmagnesium halides with four differcnt kClones werc
dc:scribed (24] aDd were lound lo be small (wil hin There, loo, hypeTCODjUgative
stabilizalioD was sUPJ)(lsed lo playa role, bul Ihis effect wu opposcd by he lIerie elfects.
The role of hypcrcorliugation in reactions of Grignard reag<:nts, Ihcrerorc, scems complicated
and requires rurlher sludies.
The reactioo of azobenzenc lead$ 10 several different producu (Schcmc 12) (25]
O-N=tt -O . RHgX

/1 t19 x
[
0-'-:-0 ' RO]
N"
"
, ,
,
0-:-:-0
H HgX
, R ...
0-,-:-0
N.'
, RO
". j ...
SckJlllC 12
Primary and secondary Grignard reagcntl all gave addilion rcaction producu in yields
belwcen 10 and 20",4, bUI Ihe rales of reaction increased by a factor of 10 for each hydrogcn
in the P-posilion. Table S presenu SQmt of Ihe results oblained. A six.oCenler transition
state seems indicated in which lhe p-hydrogen atom is very clase lo an azo..nilrogm.
Comparison of tb<: results oblained wilh benzophenone as the subslrate did nol lcad lo
satisfactory answers for Ihe exact mechanisms nvolved.
TaWe.5 blc Co,,
nanh ror lhe Reaclions 0. 1 M Azobcnzcne
wilh O,S M Alkylmaanoeslum Bromide in
OicIhyl Elher al 2O"C [2S)
CH
I
Mr. 8r
C. H. MaBr
... C .. H, MgBr
(CHv,CHMgBr
(CH.hCHCH,MaBr
(CH.),CMaBr
C. H. CH
1
MgBr
C. H. MgBr (aUyl)
os
',000
200
100,000
10
',000
JO
12 miliion
4. SchlfHI/f Equlllbrlum
The SchJenk equilibrium, and any eqllilibria nvolviog associalion among the varioul
species in solution, are complicating {acton in organomagncsium chemimy (Scheme 13).
..... ;01" .,,<1 2111'19)( = RMg H9X = . " .d.'" .,,,; ..
Se_1M Il
Mcchani51i<: !Iudies have becn fru!lraled iD Ihe pasl by Ihe possible diffi:rences in sorne
orlhe aspecu: of Ihe mcchanism or Iheir reacliOIUl and, furthermorc, addilional complicalions
were caused by lhe prcsenoe of eaeh one of the reactive magnesium spedes in solulion.
Sorne of Ihese probJems wcre discussed in Chaptcr 11. A delailed discu$lion oC lhe Schlenk
equilibrium oC orpnomagnesium balides in solution is preseoled in Chapler 13.
Thc inftuence of lhe SchJenk equilibrillm on lhe reaeli vi ly of Grignard reagenl, i,
seldom clearly lraoed in mcchanislic sludies. The different rcagt:nts involved. in the
equilibrium have differenl reaelivilies loward various subslrales. Generally , peaking. lhe
Iymmetric orgaoomagnesllm compound, R, M" i, mllch more reaclive Ihan the Grignard
reagenl. In one of the earlicr reports on reactivitics of organomagnOllum compounds [26],
however, Gilman and co-worken reporled Ihal phenylmagnesium bromide wu 20 limes
taster in its reaction wilh l -cyanobul ane Ihan was diphenylmagnesium. In Ibis particular
ca .... a qu.eslion can be rai$Cd concernin, lhe reliability oC Ihe melhod used 10 monitor
lhe disapPCIrance of lhe organomagnesium reaclant during the progress or Ihe reaction;
the color lest Ihat was Ipplied tor that purpose has never becn fully acccpled as I reliab1e
instrument for Ihese measuremenlS.
Al Ihe tOO of Chapter 1I lbe reaclivily of melhylmagndium compounds lowards
!telones was disc"ssed, in view oC the position or lhe Schlenk equilibrium (27). Although
lbe reaction 01 dimethyl magnesium wilh 2methylben!ophenone in dielhyl ether is
approlmatt!y len times faster Ihan the reaction of melhylmagncsium bromide, there is
aboul len times more melh)'lmagnesium bromide Ihan dimethylmagnesium in a dicthyl
elher solution of a Grignard teagenl prepared from bromornethanc and magnesium.
T.bk' P""udo-Firsl.order Rale eo .. 'antJ
[., (tee - ' )J or lhe Overall Rcaction of 0.05 M
ofKetone wilhO.S M Alkylmasncsium Bromide
in Dieth,! Ellter a' 2O"C (25b]
Rcagcnt Aa:lone

CH
J
Mg8r
3.' OJO
(CH.hMg
"
1.9
C,H.MgBr 7.' 7.2
(C.H.),Mg
" "-<:.H,MgBr U 3.2
(I'I-C.H,hMa
"
..
2ft
Thcrcforc, Iherc is roushly as much reactjon taking place by mcthylmagnesi um bromidc
as by dimcthylmagnc:sium specic:s. Although thu hu no furtber consequenocs for lhe
overall ouloome of the rcaclioll, il docs llave comequcnces for lhe elucidation of lhe
reaction mechanisms nvolved. In case R.M, rcacts diferently from RM'" wilh a giVCD
subslrale, IUCh. diffcrences !!.en Jead 10 a difrerenl product compasilion.
Several quantitativc values of absolulc reactivities of alkylmagne:sium halides and
of dialkylmagnesium compounds toward tetones have beco published. 11M: values listcd
in Table 6 are quoled from Rd. 25b. In general. lhe .ymmctric organomagnesium
compounds react Caster Ihan lhe corresponding Grignard reagenl.
Thc Schknk equilibrium, as represenled by Scheme 13 can be shifted 10 Ihe righl
by Ihe addilion oC 1,4-dio..ane 10 an elhereal 5OIul ion of a Orignard rcagen!. A prtcipitale
is Cormed o{ a complex oC the dioxane wilh Ihe magncsium halidc. When enough dioJaDC
is addcd mOSI, iC nol all, oC lhe halkle is removed Crom lhe solution.
In Ihe lale 19SOs, a sludy was undertaken oC Ihe dilferences in reactivily oC
dielhylmag.nesium and elhylmagnesium bromide toward J-hexyDC (sce Scheme lO Cor lhe
reaction wilh the Orignard reagenl) (28). Halide-Crw dielhylmagncsium reacts three times
as CasI as ethylmagncsium bromide (Ihe value oC 100 was assigned lo lhe reactivity oC Ihis
reagenl) (23). When portions oC 1,4-dioxaDC were added 10 a solulion oC elhylmagnesium
bromide, Ihe relative reactivily ofthis solulion loward l-hexyDe increased. Afterthe addition
oC 1.00 molEq oC the dioxane and several hours reftux oC lhe reaction mixture (lo complete
Ihe formation of Ihe magncsium bromido-dioxanc lhe relalive rate o{ reaction
orlhe solution toward I-hcxyne had increased from 210 10 260, indicaling Ihal il contained
mainly the symmetric organomagnesium compouod. Figure 1 ShOW5 the resulu of these
invcstigations. lt was nol clear, from Ihis publicalion, why lhe value 0{30010r lhe halide-lrce
diet hylmagncsium was Dol reachcd, even afler Ihe reaction mixlure had becn refluxed Cor
12 hr.
A slriking ex.aple ol lhe influenoe oC he Schlcnk equilibrium on Ihe progress oC
reaclions oC organomagncsium compouDds was observed iD, what was named, a
ligand-assisted nuclcophilic addition reaclioo in which Ihe substrate was a lithium
quinol alkoxide [29]. In a typical LANA reaction (Scheme 14) he lithium quinol alkoxide
is first preparcd in situ, afler which followl lhe sequenlial addilion ol l,3-dimclhyl-3.4.S,6-
tetrahydro-2(I1I}-pyrimidone (DPMU) and a Orignard reagcn!.

Di o .. ocIc!.

,

0,00 ...
,
o 0,25
., ,
o QSO ...
1
,
1,00
1

...
,
o
,
,
"
,
1

-
I

1

,
-
o
o
-
I

3 1
-

,


lO
ruel;.;"
Fipre I of clhylrnanesium oompolIlI,b towud in dk:thyl tlller on
.!ldilion el 1,4-dionnc 10. 101ulion of C. H, MBr. (From Rd. 28.)
",.0,,,
(I"' "oCI,
6";(1'
. -
Ph .....

'.,'O.'U
"
."" u ' ,

1 ....
Sdttmt 14
80th 1,2- and 1,4-addition take place in Ihis reaction and lhe sdectivi ty of he n:aclion
IleCmcd lo Whingc primaril)' on how lhe yanOUI reaction consli l ucnls alfect he posilion
of the Sch1enk as he aut hors pul l.
Thc progress of he react ion or Ihe quinol alkoxidc and rnclhylmagnesium chloride
al - was foUowed several hours. Within 5 min lhe reaelion had procceded 10
40-50"1. oompletion, with extremely high SCleclivily (1,4 addition/l,2 addition _ 9S:I). No
furlher ehanae was obscrved over a period of 24 hr. Alter lhe 5OIulion wu wanned lo
approximalel)' 2jC, furlhcr reaclion oa;urred al a much slower rale and wilh rnuch lower
Sclcc::livily (1,4 add.fl,2 add. - H:n
On grounds of additional evidcnce, lhe aulhor1 concludcd Ihat lhe reactive
intermediate i$ not lhe oomplel of a quinol alkoxide and a Grignard reagent. (nstead, a
lernary cornplex was proposcd Ihal oonsisled ortbe quinol alkoJ:idc. a dialkylmagnesium,
and a Lcwis acid (such as Ihe rnagncsiurn halide). By, whatlhe authOr1 namcd "manipulation
of Ihe Schlenk a confirmation of their oom:lusion was oblained.
Met hylmagllClIum chloride gave a 13.0:1 sc1cetivity ratio, whereas pure diTTK:lh)'l-
magnesium, although mucb more reactive, eJ:bibited onl)' modest scJectivily 4:1 10 6:1).
When a sol ulion of dimelhylmanesium was employod Ihal containcd 10% magnesium
chloridc. both a high reaction rale aOO high sclcctivily (30:1) wcre obscrved. When more
magncsium chloride was addcd lhe Sthlenk equilibrium was shiftcd to that or the normal
Grignard solution alKl a normal sclcctivity was attaincd.
Contrary 10 whal had bcen obscrvcd for Ihe reaction of the IWO methylmagncsium
spccies in lhe reaction of the Grignard rolution prepared from bromomethane and
magncsium with 2-rnelhylbcnzophenone (27), Ihe LANA reactioos of the two meth)'l-
magnesium spccics do, ndced, have dilferent rcsull$, such Ihal the overall outcome of the
reaction is determined by Ihe posilion of Ihe Schlenk equilibrium.
A more syslemalic scarch {or such dilferences in reactivities of bolh lhe symTTK:lnc
organomagncsum spccics and the Grignard reagcnt would !cad lO inleresting inrormalion
abouI the influence of the Schlenk equilibrium on Ihe course of reactions of Grignard
compounds.
5. Solven/ ,nd Reactlvlty
The 501vent in which reactions of Grignard cornpounds are pcrformed may have a
considerable elfccl on Ihe progress and the oulcome of such reactions. This should nOI
come as a great surprisc, si nce Ihe organomagnesium compound$ generally are sl rongly
solvated. Before reaction with a suhslrale molccule can lake place, probably onc (or more)
salvenl molceulcs muSI be replaced from the complex wilh tb<: organomagncsium
compound. Changcs in Ihe propcrtics of the 50Ivent may then cause a changc in the nlle
of Ihe reaction which, in tum, may cause sccoOOary reactions 10 occur Ihat otherwisc
would nOltake place,leading 10 dilferenl prodUCIs. Furtherm<>re, among ot her pammelers,
the degrces of associalion of the dilferent magnesium spccic.s in solulion as well as the
Schlenk cquilibrium are also deterrnined by lhe 5Olvent, and changcs in anociation may
influence the progrcss of the reactioo.
The variation in solvenls that are available for synthcsis with the aid of
organomagncsi um compounds is mlher limitcd; mosl of Ihe rcsearch in this ficld ia done
in elhereal50lvents, such as diethyl ether, di-n-bulyl elhcr, lelmhydrofuran, furan, ani501e,
and Sorne amines, such as tricthylaminc, dimelhylanilinc. and a fcw
olhers of Ihal Iypc. have also becn applicd.
In Ihis scction sorne or the cbanges in lhe mtes or reactioo, as well as in lhe product
compositioo. wiU be discusscd and, when possiblc, the Ihcorelical implications of thcsc
changes will be clarified.
Salvent elfcets were studied in lhe late 1950s ror reactions of alkylmagncsium
compounds with Ihexync in dicthyl cther. Thcsc reactions have aJready becn discussed
scveraltimes in Ihis aOO in Chapter 1I (scc Sthcmc lO) [22a). When 1.0 molEq tricthylaminc
was aclded 10 lhe reaction mixture. the relative reactivity of mcthylmagncsium iodide
toward I-hexyne, which is 7 (Ihe rcaclivity orelhylmagncsium bromidc was arbitrarily sel
Ta/lole 7 Relativo: or Elbyl
GrilJUlrd ReaenIJ wllb I . Hu)'llC in
Diclbyl EIt.er in Ibe PR!SCn<;C or Tertiary
Ami ..... (3 1]
'" "
,
' ''1
'"
,,,
,
"y
",
'"
l-)
'"
eS"
... ...
V)
'"
I . OlG
,
"''f
... .. 400
'ry
'"
...
"
'r"T[
'"
",
0')
'"
IIIIGllltJlJ '
00 lOO} iOClllased with a factor of almosl 200 (Ihe relalive rale became I3SO). On lhe
addilion of Ihe same amount of lnelhylamine 10 reaction mixlulll conlaio;n,
ethylmagnesi um bromide. lhe Illlalive Illaclivi ly ioclllased much less dramatically (from
lOO 10 &40). Thelll was no change in the reactivity of dicthylmagnesium (relative reactivity
300) on addition of trielhylamine. Further work on Ihis Illaclion wilh varioul amines [JI]
showed Ihal IIN: increase in relalve rales of reaction of hexyne wilh elhyl Grignard
reagents (bromide as well as iodide) increaKd with decllluing numben of (II hydrogen
aloms (Table 7).
This, according lO Ihe lulhor$,
may Ix auribuled 10 an increase in lbe indllcciY<: elfecc (el:lroo relcase) rQlllliol rrom Ihe
IlIbslilution or Ilkyl lfOllpiII in lhe ....... rbon 110m. Anoth<'r possiblo: expl .... lion i5 Ibat it may
be c::aused by anioDie hypo:n:onjllption. (3 1].
lo Scheme 11 chis hyperoonjugalion has becn shown for a carbaoion.
Table 8 Rales of Reaclions ol Grilnard Rea8'CTIu (RMIBr) with (Phenac) in
Dielhyl EIMr (EI,O) and in Tdrlhydrorurln (THF) [32J
i:,)( 10"
Solvenl (RM,BrJ Trq
(L mol - ' K(: - ' 1
PhM,Br EllO 0.19 0. 19
"
OJS
."
0.20
"
040
0.16
."
"
.30
0.20 .12
"
0.31
THF
."
0.23
l'
'"
0.23 0.23 Il 140
EtMgBr El , O .21 0.21
"
>02
0.21 0.21
"
1 14
0.20 0.39
"
".
0.20 0. 10
"
U7
0.20 .40
"
U7
0.20 0.10
"
>O.
Ref. 12.
When applied 10 leniary amina, U Ihe or .. -hydrogens decrea5e1 in a series o( amines,
Ihe number or hydrizaliQn pouibiil;e, would deeruJo: Ilnd Ihe electron pair on nilroaen
would becorne more ullabJe for eoordination. The reaCfivity loward a Lewill mil,
mllgne!lium in I Grignlrd rugenl, would increase unlillhe I lkyl groupI introduce
a IlerK factor (31].
Aocordin to Ihe rcsuhs prcscnted in Table 7 Ihis lIeric laClor bccomes
importanl in mcthyldiisoprop)'lamine. Further lubatitution or methyl groups, as in
eth)'ldiisopropylaminc, causes a significant rcduetion ol tbe reactivil)' (lor elhylmagncsium
brornide from 31410 AIro, tbesmall ehaneiD lbe relalive reactivil)' ofelhylmagncsium
bromide afier Ihe additioD of an aromatic amine i5 due to Ihe weak buicilies of sueh amines.
Intercsting publicalions of work undertakeD iD Ibis field oC reaetivity b), researeh
group in (what at that lime was part 01) tbe USSR, unfortunatcly, was publishcd mainly
in Tillher in9CQeSs;ble journals. 1bc rates ol reaction oC phenylacclylene with elhyl- and
pbenylmagnc::sium bromlde were mcasurcd in diethyl elber and in tetrah)'droluran,
respectivel)' [32]. The rcsults, prcsented in Table 8, elcarly show Ihe dramatic ehange in
lbe second-oroer rale constanls, wben dieth)'1 elher is replaccd b), lelrahydrofuran as the
salvent. The same effect had becn found in 1968 by olhen [33) for Ihe reaction ol
beru:)'lmagnesium ehloride with phenylaoet),lenc: al O'"C the secoDd-order rale constant
(k)( lit; L mol -
I
scc -
I
) was 0.008 in diethyl ether .nd 84 in tetrah)'droluran, a ch.ngc
by a factor of (more Ihan) 10 thousand.
Thc rcactions oC diarylmagncsium compounds wilh I-.Ikynes are aboul 10 Ihousand
times las ter Ihan Ihose of the correspondina: Grignard rcagcnts [34). 11Ie following rales
(L mol-
I
scc -' ) were found for lhe reaction of dipbenylmagnesium with I-hexyne; 114
in telrahydrofuran, 11.6 in diclh)'1 elher, aDd 8.1 in di-n-bul)'1 elher. 1bc authon did nol
comment on Ihis phenomcnon.
Another slriking rcsult ol this work was Ihat, on going lmm Orte solvenllo the otber,
onl)' minor changes were fouad in Ihe rcaction rates.. Thc aUlhon concludcd Ihal
Apparenlly, lhe increasing inlluence oIlhe dOllor molecule, eoordinllod ""ilh magnaium
110m. on the nucleophilic:ity ol lhe phcnyl rldicaJ iI o;ompensalod 10 I large eJ; lertl by in
'"
T.bIe 9 J>c,roentagcs of Radical Ani01l3 Forme<!
in RcaclionJ al Dilxnzylmagnesium (O.3n MJ
wilh Fluorenone (O.34S M)l" Variou,

(C. H.),O
THF
VME
(C. H. ),N
HMPA'
Signals
Ver)' weak aOO unstable
Wuk bul allIM
Rathcr ,tab/c
Unstable
Slron .nd stable
Radical
Inions("lo)
,01
O,
> 0.2
J6
' HMPA. buarnethylphoopboric acid uiamKk.
inlluencc: on lhe clel.:trophili<:ity or lhe manesium alom. ie., by prevent;n, wordination or
1he lal1cr wilh Ihe acetylenio;; oompound.
Afler SOIIlC c;ommcnts on what was named medum potarily and - 'he
medum diclectric ronstant
ft
Ihe authort carne lo lhe rollowing conclusioru: $uch
nucJeophilic addition reaclions or diphenylmagncsium compounds wilh tetones and
melallalion reactions ol I-alkynes have sorne common teature5. Apparently, Ihey can bolh
be considere<! as a spedal case: o aromalic clectrophi lic $ubstitution, differi ng from (what
Ihe a ... lhon named) 81he classical uamples of Ihis reaction,8 in that Ihe latter one has a
more pronounoed reagent-like lransition slale.
A strong solvent d'l'ect in a completely diffell:nt reaction was observed in 1968 (35)
in a ,tudy of single-electron Iransfer (SET) reaclions of organomagnesium compounds
wilh ketones (see also Chapler 1 J, Seclion In some instances lhe formalion of stablc
radical anions was observed in lhe ruction 01' dibenzylmagnesium with ftuorenone.
Table 9 presenl5 Ihe resulls. The authors concluded: MOne notes Ihat those solvenl5 Ihat
51rengthen the ionie chlracter 01' magnesium, promote the rormalion 01' lhe kelyl ra.dicaJ
Furthermon:, from lhe results obtained with other organomagnesium compounds,
melbyJ <elhyl <i- propyl < r-bulyl <bemyl, lhe aUlhon; concluded Ihat lhe increasing
cb.arge on lhe carbon alom bearing lhe magnesium l'avofIJ the radical rormalion.
Apart from Ihese SET reactions, solvent efl'ects in reactions 01' organomagnesium
Teagenl! wilh carbonyl compounrls have bcen sludied ralher extensively. Tbe reaelion or
ethylmagnesium bromi<k: with benzophenone (Scheme 1 S) in dielbyl elher yields 94-1. 01'
the eJl.pected addition reaction producl, I,I-diphenyl-I-propanol, and 6% benrliydrol,
resuJling I'mm a reduction reaction or the Grignard reagen! (36). In tetrabydrol'uran Ihis
ruction yields 21 and 17-1., 01' both products..

"
.....-i1g8r ...
'"
! , 'Y.
'''' 11 H-

,
'"
l 1H
Scllcme 1.5
Tibie 10 Rcsulu of Re":Uonl W. Yicld) of
". Propyl - .nd Iwpropylm.,nesium Bromide
with Bcnw phcnone in TC1rahydrofuran (THF).
[)jeth)'1 Ether(DEE).and 1,2-Dimetholydhanc
IDME) [ ISb]
nPropMgBr LroPropMg8r
Solven! Add. Rod. Add. Rod. Subst.
THF 17
" "
l. l.
DEE n ..
.,
26 JO
DME
" " "
JO
l'
'f1
The rcaclions of n-prop)'l- and isopropylmagnesi um bromide wilh (subslituted)
benzophenone(s) in diethyl clner, Itlrahydrofuran, and 1,2-dimetholyelhane werc C8rdully
studicd in 1991 [ 15b). Several produets werc obtaiDed. With n-propyl Grignard re8gcnl,
these werc lhe products of Ihe addition IU well as of lhe reduction reaction, bolh taldog
place al Iht carbonyl group. With lhe isopropyl Grignard reagent. besides these two
prooucts, a thi rd one was observcd: lhe aromatic ring--substilulion resction product (see
Scheme S The resuJts, presented in Table 10, show that lhe ratios of Ihese producu
werc soJvent-dependent
As mentioDed in Section 1l.A.2, Iht aulhors attributed lbese results 10 Ihe degml of
association of Ihe various magnesium ,pecies in solution {see also Oapter 11 for lbe
mechanistic aspecu ol Ihis
AnOlher side reaclion, caused by changes in the solvent composilion, WaJ Iludie<!
in 1980 (in lhe former USSR) and, unfortunalely, WIS also published in rather iDa<XT!siblc
joumals [37]. The rcactioru of phenylmagnesium bromide wil h the aliphatic ketones,
2-butanone and J,J-dimelhyl-2-butanonc: (methyl-Iur-butyllr.etone). were studie<!. Besides
Ihe carbonyl addilion reaction, leading lo a tertiary alcohol, enoliution also takes place
with Ihis type of kelones. The enolale, on hydrolysis, yields the startingketonc:; however,
before hydrol}'3is, in the reaction mi.ture of the Grignard rcagent and lhe ketone, the
enolale can react furtiler wilh the kelonc: lO fonn a conden5ltion product (Sc:heme 16).
o-HVllr .J.- _-",,"._ R-H
.... 21 He
Scbcmc 16
OHg8r 2
A.--
'"
The rates k ...Jk ... wen: 7 and 8, n:spectively, for the ruedons or phcnylmag.nc:si um
bromidc with 2-butanone and 3,3-dimet hyl-2-butanone, bul on (he addition or large
amount, oC Iriethylamine (ISO and 90-10. respectively, for the Iwo n:aeljons) lhese rates
were almost doubled: from 7 10 16 and from 8 to 14. The general condusion from Ihis
work WI\.S Ihat triethylamine did nol change the rate of the addi lion react ion, but doubled
lhe rale orlhe enoliut ion reaction. St ill, the infl uencc ort he ami ne on the rates oC reactions
wen: mueh smaller Ihan for the n:a;t ions with I-hexyne. as listcd in Table 7.
Anolher reaclion wilh a sl rong salvenl effect i5 the reduclion oC primary halides with
the aid or Grignard reagenl ! . The n:aCl ion of 3-phenyl-l-propylmagnesium bromide wilh
iododecane [38] (in lhe absencc of catalysts) yielded 96-/_ oC R- H and R(- H) in
letrahydroruran u lhe salvent. bUI only 10% oC he same producu in dielh)' 1 ether (Schemc
17). Allhough an extensive sludy oC Ihe mechanistic aspecls or Ihis n:aclion (including lhe
clfecl of palladium catal)'sts) wu made, no comments wcre given on Ihe origin of lhe
signilicanl salvenl elfecl.
0-
11
9
Br

L-... \..... ...... TII F/tl lfI'
'\ 1, 96%
1(11
0121
_
" ..
Sclk-me 17

, ,
"
,

..
,
,
The following conclusions can be drawn from Ihis seclion on solvenl elfects.
During lhe lasl Ihrcc decadC$, exlcnsive and ,ysltmal ic sludies have becn pubtished
on Ihe compasilion in saludon or organomag.nc:sium compound!, in and oC
Grignard reagenl!, in particular. Various solvenls were used in luch studies. Furthermore,
sludies were made or t he effects of salvent! on Ihe coursc of the n:aCl ions oC lhesc reactive
species. In Chapter 11, il was madc clear Ihal t he mcchanistic aspeclS of such reaclions
are slill nOI fully undcrslood and, as a conse<ucnoc. Ihis impl iC$ Ihat many aspecls oC the
role orlhe solvent on Ihe COUTIC oflhc:se reaciions sliII re<]uin: furlher stud)'. In faci, in only
one specific case was a relal ion suggesled betwecn t he slruciun: oC the organomagnesium
species in solulion and the outcome oC its n:actions: monomeric species tcnd lo yield less
additklO reaciion producls with kelones and more reduction reaciion products Ihan do
di- or (pc: rhaps) evcn pol)'meric species. Thc reaction mechanism requires the presenoc or
a second magnesium species (sec Table
1I is hopcd that more systematic studies or both the composilion of the salulions
and Ihe outcome of the reactions will ultimatcly lead lO a better underslanding oC lhe
effccts Ihat solvents play in these processes.
AEFEAENCES
L (a) M. Okubo, T. Tl ul!umi, A. lehimura, and T. Ki\112Wl, Bu/l. Clttm. Sec. Ipn. ' 7:2679
(1984); (b) M. Okubo, Tsuuumi, and K. Mauuo, Bull. Clltm. 5. I{NI. 15O:2OIIS (1987);
(e) M. Okubo.oo K. MaullO. RftI. HtltrOOlom CNm. 10:2 13 (1994).
2. (. ) A. Holm, T. Holm, 100 E. HugcJell$Cn, Aela Cfrem. $cand. B 18:78 ] (1974); (b) T. Hulm.
o4 el/l Clttm. S(/lIIII. B J7:561
, ',',"O
3. !a) D. Yanalf Ind A. Spaasolf, BuI/. Soco CAim. F,. Sir. /1' 5/:619 (1932); (b) D. vanoll" I nd
l. Abdouloff, C. R. Aftul. Sr/. / 116;.491 (1933).
4. o . e _ner, J. C""". St)C. Pvkin TrtIIIS 2, P. 973 (l 993).nd rel' ''M' quotcd themn.
$. G. Vavon, M. B.rbiCi", .nd G. ThiCbaut, Btdl. Soc. CAinI. Fr. Sir. V. 1:806 (1934).
6. C. Ind H. S. MOIhcr. J. 0,,_1. C""". B:$19 (19611).
7. M. S. Kllaru::h .nd F. 1... Lambm, J. Am. Cltem. Soc. 6J:23U
J. E. C. Ashby, F. W. Walkcr, and H. M. Ncumann, CIInn. Comm ..... p. 330
9. T. Holm and 1. CrossJand. AC/" Cltem. SawJ. 25:59
10. T. Holm, Atl" Cltem. SNtuJ. B 4'2:68S
11. T. Holm, Au" Cltem. Sama. B 2S:& (1 974).
Il H. Yamazaki Ind N. Hayuhi, CMm. LAI/. p. 525 ( 1993).
13. See liso unpublishee! resulll by T. HoIm as mcntioncd in {2b] in rootn.otc 22.
14. T. Holm. AC/" Cltem. &ana. 4'5:276 (1991).
IS. (a) K. Maruyama and T. Katagiri, J. PAys. Org. CMm. 2:2OS (1919); (b) K. Man,yama,
Y. Matano, and T. Katagiri, J. PhyJ. O". Chmr. 4':SOI
16. E. C. Ashby, l . Lacmmlc, and H. M. Neumann, Ace. CIIme. R"J. 7".272 (1974).
17. v. Grinard, AIIJ!. CMn!. Phys. 14':468 (1901).
18. M. S. Kh.ruch and S. Weinhouse. J. O". CJwn. 1:200 (1936).
19. J. u roide, A"/I . Ch;",. 16:)54 (1921).
20. F. Barbot. D. N'Goma, 100 P. Miginiac. J. OrgllllQtMI. CItmt. 4'Ut.277 (1991).
21. F. G. Whitmore and 1. S. Georc, J. Am. CMm. Soc. 64:1239 (1942).
22 (a) J. H. WOIiz, C. A. Hollinpwort h, 100 1. l)essy, J. Am. CIwm. Soc. 71:103 ( 195S); (b) R. E.
Dessy. J. H. WOIiz, and C. A. HoUinpworth, J. Am. CItt"ttr. Soc. 79-JS3 ( 19$1).
23. E. C. Bongham, M. G. EVIns, In.:! M. PoIanyi. TrtllIJ. F"rarJy Soc. 3?-.377 (1941).
24. T. Holm 100 0 . Madam, Ael" CM,". ScmuI. f'6:985 (1992).
25. (a) T. Holm and l . CrouJand, Ae'" CMm. Saued. B 33:421 (1979); (b) T. Holm, AfIO CItmr.
Samd. B (1983).
26. (a) H. Gilmln and R. E. J. Am. CItt"ttr. Soc. 5/:3149 (1929); (b) H. GilmllD and
R. E. Sro""D, J. Am. CNm. Soc. 51: 1181 11930).
27. E. C. Ashby, Pu, .. Appl. CMm. 52:54$ (1980) Ind m crence:s cilee! Ihc:n:.
28. J. H. WOliz, C. A. Hollinpworth, Ind R. E. Deny, J. Am. CItmr. Soc. 18:1221
29. K. A. Swits, D. C. Lioua, and C. A. Mlryanorr, J. Am. CItrm. Soc. J/2.-9J9J
30. J. H. WOliz. C. A. Hollinpwonh, R. E. Das" I nd 1... C. Lin, J. Org. CMm. 1J: 228 (19S1).
JI. J. H. Woliz, C. A. Holli ngswol1h, I nd A. W. SJmon, J. O" . CItt"ttr. 14':1202
3l A. Tuulmetl, N. Palm, M. Uilman, and S. Rang. Org. 16:440
J3. Y. Pocker and Y. H. J. Am. CItmr. Soc. 90:6764 (19611).
34. S. Kurrikoft" 100 A. Tuu]mets, Org. Rtm:I . 15:124
35. J.F. FluVln:ue .nd E. Rouget, C. R.. AelJd. Sr;. 267:136$ (19611).
36. F. A. Hartog, Thcsis, Vrijc Univt:Tlteit, Amslcrdlm, ]971.
37. A. Tuulmctt: .nd M. Kalbui, O". RNcr. /7: 112
38. K. Yuan and W. J. Seott, J. O" . C""m. 55:6188 (1990).
13
The Composlllon 01 Grlgnard Reagenls In
Solullon: The Schlenk Equlllbrlum and lIs Effect
on Reacllvlty
KEVIN C. CANNON
El! ArOC:Mm NOI1h AIMrlC'tl, 1M., Klng of PnuJIa, p, " nsytm1lla
GRANT R. KROW
T ~ m p l U"m"lty. Phllolklphia. PtnN)'lwmla
l. INTRODUCTtON
The CQmposition of Ihe Grignard reagenl hu intrigue<! rescarchers si noc ts discovery in
1900. 80th Ashby (1] and Wakefield [2] have wrillen exocllent revicws about the early
histor)' concerning he delenninalion of Grignard reagen! composition. Abegg, in 1905,
suggested Ihe possibility of an equilibrium lO de5Cribe Ihe composition of Ihe Grignard
reagen! in an el her $Olution, with R representing the alkyl group and X representing a
halide [3].
2RMgX!:JR, Mg+ MgX,
This equilibriurn wal Jaler expande<! by Schlenk and Schlenk 10 include molecular
associat ion of Ihe OtigDar<! reagenl, and Ihis equilibrium is 0010' commonly referred l O
as Ihe Schlenk equilibrium (4).
2RMgXt:J RMg+ MgX
RMg + MgX2f::JRJMgMgXJ
The addition or 1,4-diolllne to oerlain Grigaard rcagents results in the precipitati on
ofan MgXl comple", n:sulting in essentially aU ofthe halogen bcing removed rrom solution
m
(4]. The Bulhon believed Iha! he addition of 1,4-dio)(ane and he 5ubsequent precipitation
or MgX, oould be used lo determine he equilibriulII cornposilion, implyin Ihal the rale
or c;u;hangt: amoDS oomponentll in solut ion was S]OW, Howevcr, lalcr investigal;on.
demonstrated Iha! Ihe cquilibrium wu dynamic, by showing Ihat the amouo! of MgXl
precipitated was a r"Dction or time and mode of addition [5,6]. Thc MgX, pre<:ipitates
from solution as a bis-diounc complex, res,,]!ing in a shirt of lhe cqui librium and he
formation or RJMg.. Thi. precipitation lechniquc ;1 oneo cmploycd 10 sclectively synthcsizc
dialkyl Grig.nard reagcnts RMg (7-9). Thc reactivity of solate<! R,Mg may differ
. ignificantly from [he reactivily or he cqui librium compositioo or a Grig.nard reagen!;
sorne difl'erenccs in reactivity are discllssed later in Section 111. AlIemativcly, predpiation
of the dialkyl Grignard reagent while MgXJ remains in soluli on can also shifi lhe
equilibrium. For example, 1,2-, 1..1-, and 1,4-diGrignard reagenls, Iynthc:sizcd from lhe
reaction oflhe corresponding dihalide compound and magnesium, forro c::yclic bifunctional
organomagnesium compounds that insoluble in telrahydroturan [fHF) (I()..I 3). Thesc
cyc::lic bifunctional organomagnesium compounds (1- 3) are assumed lo be polymeric.
. .,
,.,
""
,.,


""

""
"

Mg8!)
..


[col.
. ...,

[el.
.-

A more c::omprehensive representalon or the Sc::hlenk c::qui!ibrium is shown in
Sc::hc::me l. Ab ,,tia molecular orbital calculalions for R_ Me and x- a aOO 8r were
performed 10 determine whic::h species in Sc::heme 1 were lhennodynamically pretened (14).
In the absenc::e of solvenls, lhe various {MeMgCI),-bridged dimers were all signilic::anlly
more slablc: Ihan the correspondng monomers. For lhe reaction
2MeMgClt:(MeMgOh
he I1Ho ranged from - 24.8 10 - 37.1 and I1Go ranged from -IS.8 10 - 33.0
kcaVmol. On the olher hand, in he presence of Ihe salvenl dimelhyl el her, calculalions
showed that the dirnerization procen was nearly thennoneutrat; !J.Go wa - S.I kcalfmol .
The aUlhon $uggested that the relatively mall negative !J.G" value indicated Iha he
position of lhe equilibrium could easily be shified in Scherne I lo favor the presence of
monomen by altcring lhe halide, lhe alkyl group, or the salven\. The 6ffO and !J.G" ror
.-..(;_.
/
I

...:"J'
, ""'"
RJUg +
v ..... x'
"
I
..... X
Sdtfnle 1
he reaclion
2MtMgO",(Me)zM + MIOl
was calculaled 10 be +5.7 and +4.5 kcaVmol, respectively. Substi tution of Br for a
yielded correspondiDa 4'o and 4eJO va!ucs 1.3 kcal/mol Jess endolhermic. CaJculations
Iha! neluded dimel hyl llhcr salvadon alM) indicaled a slightly more favorable reaction.
The resull$ or lhe /lb ni/io calculations corroborate sorne or lhe uperimental results
rrom precediDa inve$ligalionll of Grignard reagent composition. These inve5tigations have
shown Ihat, in addition lO the ",vent. lhe alkyl group (R). aOO halide (X), Ihe equilibrium
in Scheme I is affected by conc:entratioD and temperature as well. Experimental resulta
Ihat he factOr! lha! alfea Grignard reagen! eomposition and reactivity are
discussed in the rollowing.
11 . FACTORS AFFECTIHG THE COMPOSmoN OF OAIONAAD REAOENTS IN
SOLunON
A. SoNent and Cone: .il ..... on IEnlO.
The tqui librium in Scheme I and. therdore, tbe composi tioD oC Grignard reagenls in
solulion, is a funclion oflhe solvent and COOOCDlratioD. ID some inslanoes, Ihe composition
may vary bctwccn solvenlll bccausc of a solubility cfI'cct. An insoluble constilucnl oC lbe
equilibrium may piccipitate, shirling Ihe cquilibrium lo I composition diffCR1lt fmm lbat
obscrvcd if all constitucnts wcrc soluble. Such is thc CISC wjth di.Qrignard reagcnl 5 [ 12].
When 1,8-diiodonaphlhalcne 4 was rcaclcd with mancsium in 2-mcthyltelrahydrofuraD
(2-MeTHF) al room tempcrature, I homogcncous IOlution oC5 was Cormcd in 90% yicld_
Howcver, when the reaclion was pcrfonncd in THF, sparingly sol uble MgII prccipitltcd
irnmcdiately. As a result, Ihe THF solution containcd 2 and unreaC'lcd 4..
' ..
[col. .""

Solvenl may also alter Ihe composil ion of Grignard reagenls in Ihe abscncc of a
rolubi lily effecl. A comprehcnsive ebullioscopic investigalion of a variety of Grignard
reagc:nls (melhyl, elhyl, -propyl-, t- bulyl-, aod phenylmagoesi um hal ides) showed Ihallhe
degrec of associat ioo is profoundl y alfected by several faclors, ioeludiog solvent [15). Al]
alkyl- and arylmagncsi um chl ori dcs, bromidcs, Hnd iodides were delermincd lo be
mooomerie compleJIcs io THF over a wide conccotration raoge (0. 1- 3.5 M). In diclhyl
ether, however, Ihe alkyl- and arylmagnesium bromidcs and iodidcs wcre mooomeric al
conccntrations Iess Ihan 0.1 M. A general inerease in association was obscrved with
oonccnl ration; al 0.3 M, solulions are appro. imalely half monomcric alHi halr dimeric
[16). 8elween conoentrations of O.S and 1.0 M, comple.es are dimeric. Alkylmagncsi um
chl orides in diethyl el her form stable with Ihe a$$OCalion bcing inseosilive 10
cooccnlration changC5. The nature of Ihe associated Grignard rcagenl io dict hyl elher was
charactcrized by ' HNMR studies of mclhylmagncsium bromide and iodidc [ 17,18).
Bridging mclhyl signals were not observcd al ambienl temperalures, ieading Ihe aUlhors
to oondude Ihal halogcn is the predominanl bridging group in the associatcd
Bridging melhyl signab wcre obscrved in trace quaolities only after conliog lo - IOO"C
fOT melhylmagnesium bromide and to - 4O"C for melhylmagnesium iodide [ 18].
The dilfcrence in Grignard rcagcnl associalion behavior in THF aod diethyl elher
is attributed lo lhe rdative Lcwi s buicitics of Ihe two solvenl$. Solvent- melal bondng
oompetC$ wilh lhe bridgio(l characterislia; of the halide, and THF competes more favorably
Ihan dielhyl ethcr. The relative donicities ofTHF and dielhyl clher are 20.0 and 19.2 kal
mol-
I
, respectivcly [ 19]. Howcver. mclhylmagnesium fluoride and methylmagnesium
II-buloxide are dimeric in THF, owing 10 lhe stronger bridging eharacleristics of fluoride
and alkoxKk groupscompared wilh lhe larger hal ides [20,21]. The relalion hetween solvent
basicily aod a55Ociation WIU further dernonst ralcd by ' HI'
9
F_NMR st udies of the rales
ofcxchangc ofaryl groups betwocn bisaeylmagncsium oomplcxes 6, 6' and Ihecorresponding
arylrnagnesium brornide complc.es 7, 7' [22]. Thc equilibratioo oflhese complcxes requi res
lhe intermediacy oT an associalcd complex, depicted as structure 8:
At-1'9 .. Ar'UgIIr __

,

r r
Rapid uehange of lhe aryl groups was obscrved spectroscopically in both benzene and
diclhyl et he!. The addition oT NN N' N'-Ielraelhylelhylenediaminc (TEED) considerably
reduCC$ the rate oT aeyl (lfQup exchangc. This obscrvalion was auributed lo st rong
coordinat ion of TEED lo the mooomeric complexC5, lhereby inhibiling formation of Ihe
associalcd intermediale 8 [ 1]. The donici ly of TEED exoceds SS ka l mol I [19).
The equilibrium belween monomeric complexes in solulion,
is also a fuoct ioo of 1M solvenL Equilibrium constants of Ihis react ion for a variely of
Grignard reagents havc bcen reviewed [23]. Equilibrium conSlantl fOT sc: lccted alkyl- and
arylmagnesium bromides in THF and dielhyl clher are presenled in Table 1. Thc numerial
values were delermincd by several wilh varying dcgrecs oT accuracy, usi ng
calorimetric, kinctic, and spcctroscopic melhods. Even wit h Ihese limitations, the data
suggesl sorne clcar lrends. lo THF, cquilibrium constants range from 3.S 10 .... 9, whereas
-.
60: f"qI(If. ' [\J1 and .. EA 7 1M RNCfM1'I m
Tallk 1 Elfec:1 or SoIvent on lhe Equilibrillm Collltanl (K) aDd E1Ullalpy (AH) for lbe
of MOIIOI'lIC' ic Compleul, R, MI+ Ma:J( , Q2RMIX
Gnlnard
ruenl
MeMsBr
EtMJBr
BuMIBr
PbMBr
Solvenl
THF
El , O
THF
EI , O
THF
Ell O
THF
Ell O
K
3.S-<4.0
-320
'.09
-'SO
-.
- 10'
J.n ....... o
, .... ,
6.10
-J.1"
3.'
- 32
2.82- 3.2
- 202
Mcthod al
I nalpis
IR, NMR
Calorimclric
Calotimclnc
Calorimclric
Calorimecrie
Calorimetric
CaL. NMR
Corimelr1c
'd.
18, 2-4
"
"
27
"
21
22.26
27
in dielhyl tlher, hey range from 55 10 _10', The values of AH in THF are positive,
whereas Ihe values in dicthyl tlher are nesalive. 1I WIIS Jugcsted lhat Ihe dilfcrcnc:e in
lhe equilibrium in THF and diethyl tlher i. due 10 lhe increascd coordination number of
Ihe magoesium lpecies in THF; lhe dominan! cffcct was usodated ... ilh the solvltion or
magnesium dibromidc (23). 1bc equiibria, sho ... n as follows, were IUgested
by lhe lulhon 10 emphlSjzc be solvent dcpendency oC lhe interconvenion of monomeric
ffi agnesium cornpk:l;c:s.
R , Mg(TH F), + MgXjTH F). = R MX(THF)J + RMX(TH F)J + TH F
R J Ms( EIJOh + MgX, (Et ,O), =2RMaX(Et,Oj,
Accordinalo Ihe equilibrium constanlJ in Tibie 1, aDd olhers Ihat were reviewed,
111 Ihree monomeric complexcs (R,M. M"", aOO RMX) are prescnt in appreciable
concenlration in THF, The simultancoU$ uilleoce of RJMa and MaX, in IOlulion has
been challcnged, based on Ihe reaclivilY or magnesium dichloride in THF [29]. An
allemalive equiJibrium in THF prop!l5cd by Ihe aulhors (ahown below) requires lhe
preseoce of dilIll:ric complcJ:es, which have nol yel becn detected in usocialion
invC$ligation ..
4RM X(THF).= [(THf). Mg-CI), MgRJ + [R Ma,(p-CI),(TH F)J
An allemalive onie equilibrium has becn more reocDtly propon d, base d on lhe reactivity
of maanesium dichloride in THF (JO].
+ [MaCW' - +2(MCJ(THF}, ] +
Howevcr, conductance experilIll:nts have demonstraled thal lhe conocnlralion of onie
spccies cannol be ver)' significan\, OWiDa 10 Ihe Iow cooductivilics reponed ror Grignard
reaenlJ in cl hcr IOlulions [1].
Solvenl elrcets were more dramatic ror lhe I,S-di-Grignard reaenl , (31]. In
THF, Ihe equilibrium constanl for convenion or I,S-di(bromomanesio)pentane , 10
magnesiacyclohexane 10 and ma.nesium dibromide WIJ determincd as 299 31 (..H _ + 2
kcal mol-
I
, oiS _ +17 In dkl hyl elher, lhe equilibrium les compktel y toward
I,S-di(bromomagnesio)pentane , .
~
,
O
....
..
"
c."""" .nd K,.".,
EIfcas of nonct her solvent on the equilibrium betwecn monomeric complexes havc
rcceivcd liule luention. An IHNMR investigadon of the efTcct of N,N,N' ,N'
tetramethylethylcnediaminc (TMED) on THF .rol utions of ethylmagnesium bromidc
demonstrated ]itUe efl"cct on the equilibrium constanl at - SOOC [32); howcver, TMED
may inhibit complex '''ooalion required for reequilibration in the same manner that
TEED inhibited the formllion of 8 in aryl group exehanse (see foregoing).
No eonclusive data exisl concernins Ihe efl"ect of Grignard reagenl concenlralion on
lhe: equilibrium belwccn monomcrie eomplexes. An LHNMR sl udy of bulyl ehloride
Grignard reagenl in THF showed no deteclable ehanges in equilibrium belwoen 0. 12 and
3.1 Al [1 8). Oanges in Ihe NMR speclra of more concenlraled solulions from the same
investigation were inlcrpreted by tne authors as rcsulling from preferential formation of
bulylmagnesium ehloride (the RMgX component). bul no subscquent investigalions have
addrcsscd Ihis hypolhesis.
B. AnlOftIc NaMlllyl Ug.nd E h c ~
Thc composilion orGrignard rcagcnls in solulion is influcnced significanlly by the anionie,
nonalkylligand (ANAL) coordinated lo magnesium. The ANALs discussed in this seclion
include halide (X- ). alkoxide (RO -lo and tris(pyrazolyl)hydroboralo ('1l.HB(n:);) ligands.
Sol ution composilion may be affccled by Ihe low solubility of one or lhe components in
Schcme 1, ineluding lhe low solubi lily orMg(ANALh. Precipitalion of an insolublecomplex
pcrturb5 Ihe equilibrium, and Ihe compasilion will ehanse in response lO the perturbalion.
A .rolubilily effcd relalins lo Ms(ANAL), can be iIluslraled by expandng on lhe prevously
discu$5ed synlhesis of di-Grignard reagcnl 5 in Section U.A. The halidefree di-Grignard
reasenl 2 was synthesized in THF from 1,8-di(iodomagnesio)naphthalene'" as a result of
lhe precipitalion ofMgl} al room lemperalure [12]. In contnut , the halide-rree di..Qrignard
reagent could nol be synthesized from 1,8-di(bromomagnesio)naphthalenc .... under
identical reaelion conditions owing lO the greater solubilily of MgBr} in THF.
' ..

..

The effect of ANAlsubslitulion on Grignard reagenl assooation was also mentioned
in Seclion Il .A. Auocialed complexes are believed lo bridse predominantly Ihrough halide
and alkoxidc Subslilutcnts, based on 'H-NMR studies ofmethylmagnesium bromide and
iodide [17.18]. The degrec or Grignard reagenl association is determined by compeling
raelors of salvent coordination (donicil)') versus bridginS eharacteristiC$ of the ANAL
F1uoride and alk.oxide bridging prevails over salvent ooordination in both THF and diethyl
elher and. as a l"CIull, alkylmasnesium complexes with Ihese sub5lilucnlS are dimerie
IdIL'.",," Eqvltlt rlIIm MWlIIr EfJc elli "" Rile iTl'r-') Z17
TaWe :z EI'rect or Halidc: on 1M Equilibrium COl1lllanl
(K) for lhe Intcrronvc:nion or Monomcde
R,M,+M,xEo2RM,x
Grignard MClhod o
n:..,enl SoIvcnl K analysis Ro.
McMaCI THF 4.' IR
,.
McM.Br THF 3 . .5-4.0 IR, NMR 18, 24
EIM,cI THF S.S2 Calorimclric
"
EtMsBr THF
'.09
Calorimcuic
" PhM,cI THF 1.66 Calorimctric
"
PbMsBr THF ln-4.0 Cal., NMR 22. 26
E1MSI EllO .6JO Calorimclric 27
EIM,Br El lO
-...
Calorimctric 27
PhMSI EI
1
0
. 1'
Calorimelric 27
PhM,Br EI,O
'>-62
Colorimclric 27
(20,21). AIlr.yl- Ind Irylmagnesium chlondes behave ditrerently in THF and diethyl elher.
These Grignard rtagenlS are monomeric in THF and dimeric in diethyl elher [15). This
ditrerence in salulion compasilion is luribuled lo lhe realer donicilY of THF, compared
wilh Ihal of diclhyl elher. The TH F coordination competes ravorably with chlonde booging,
wbereas dielhyl elher coordinalion does nol. Bromide and iOOide bridging are weaker
still. Allr.yl- and arylmagnesium bromides and iOOides are monomenc in THF and, al
concent ralions lower Ihan 0.1 M, in dielhyl ether. AJ concenlration or the Gngnard reagenl
increues rrom 0. 1 10 O.S M, unifonn increases in auociation raeton (1) indicale lhe
gradual increase in dimer concentration (16].
Theefl'ecl orlhe halide subslituenl on lhe equilibnum belween monomcric magnesium
complexes is sman compared wilh lbe previously discusscd salvenl cffecu, bullhe mag.nilude
of lhis halide effect may itself be solvent-depcndent. Table 2 lisis cquilibrium constant.
(K) for melhyl-, elhyl-, aOO phenylmagntllium halides in THF and dielhyl elher [23].
Compansan or ehloooe versus bromide substitution of Grignard reagenls in THF shows
little difl'erenoe in lhe cquilibrium conSlanlS for the reaedon, espccially wblen lbe limilalions
of camparinll numerical values, delermined by severa] IUlhors usinll differen! melhods of
anl lysis, are considered. In conlrlsl, eomparison or bromide versus iOOide sUbslitution
for ethylmagnesum halide lOO phenylmagnesium laUde in diethyl etber shows I significanl
dilJerenoe in lbe calorimetrically caleuJated cquiJibrium constanU [27). However, aQ:;Ordipl
lO lhe aulhor .. Ihe cquilibrium constlnU for the iOOide-substituted reagenls are unoertain,
owing lo I observed concentralion dependence iD Ihe Inalyses. Further investigation is
required 10 quanliry lbe salvenl dependency, ir aDY, thal exiSIJ for lbe halide cffea.
Tris(pyrazolyl)hytlroborato ("l-HB(pt)l) lipnds have becn used 10 show Ihal
sterically demandinl ligands can affea tbe cquilibrium belween monomeric manesium
complexes (33,34). The monomeric tris(3,S-dimethylpyrazoyl)hydroboratomagnesium alkyl
derivatives 11 are stable complexes al room temperature. When bealed 10 8O-12O"C in
benzene. tbese derivati ves undergo lillllnd redistribution lO ronn RJMg Ind the
six-coordinate sandwich complelt 11, which was followed by 'HNMR spect roscopy.
., ....
'" .... , El. ,.,.., .... ""
" "
The reactions usually procceded 10 9I)Y. oomplction over a pcriod 01 da)',-
al which poi ol he authors bclievc he redistribution reached cquilibrium. Howcvcr,
substitul ion of lhe tris(3.5-dirnclh)'lp)'razolyl)hydrOborato ("JHB(3,5- Mc2Pz);) by the
more stcrically dcmanding tri*-butylpyrazoyl)hydroborato lisand (" J.HB(3-I-Bupz),) in
magnesium oomplcllcs 13 prevents ligand redistribu\ ion aftcr 1 da)'! al 12O"C.
,
R Mol, El. U'r ..... ""
.....
"
"" ,
".,.
TIIe '1l. HB(J.,. Bupz); ligand reslricts a metal tenter 10 a maximum of four coordinadon
si tes, whcreu lhe coordination of two "J.HBC3.S.MczP;); ligands lO magnesi um does nol
result in particularl)' excessivc slcric intcractions [ 34].
C. Alkyl.nd AryI Llpncl E"he.
Equilibrium constanls estimate<! ror he Schlf:nk tquilibria 01 cl hylmagnesium bromide
(iodide) and phenylmagnesium bromidc (iodide) in dicthyl ether are shown in Table 3.
Equilibria lie strongly 10 the side of Ihe alkyl- and arylmagnesium halidcs for both
SUbslilucnts (27).
'Q--
"
" "
P' m
T.bIe 3 Equilibrium Collllanl. (K)
for he Rcaccion 2RMX"" R, MI+
MISr, in Dicthyl ElheT
R X Molarity (M) K
E< B, 0.10 0.002
Ph B, .10 0.018
E< 1 OJO < 0.016
Ph 1 O.JO <0.067
Table " Equilibrium Con$tanU (10 ror lhe Rcaetion or
14"'15 + MI Br, in THF
StruclUnt R' R' K (298 K)
1"
H H 0134
1 .. CH,OMc H
" 1
1"
CH,OMc CH,OMc 1.1)61
1" Cff,CH,OMe H 0.10
1"
CH,NMc, H
8.51:0< 10-
1
1<f CH, NMe, CH, NMe, 6.06>< I O ~
1"
p-CH,OMc H 0.352
m
Equilibrium constanlS for he Schlenk equilibril ol arylmagnesium bromides in THF
are shown in Table 4 [35]. Equilibria lit predominantly on Ihe dele ol tbe arylmBncsium
bromide, except fo r l o4e. in whicb therc are cbelating elher substi tuents al both Ihe 2- and
6-positions. If we assume a six-coordinate ArMgX species 14<: in he convenion ol two
molecules ol ArMgX into six-coordinate Ar,Mg 1!!e and MBr,ffHF]., lhe number ol
Mg-O bond, and Ihe number ol THf molccuJes coordinated is the same on both sides
of Ihe balance<! equilibritlm. The 2,6-bis(dimelhylamioomethyl)phenylmagnesitlm bromide
14r is probably a four-coordinale SlructUre. The llene bulk of lhe amine function, as weU
as Ihe abilily of Ihe amine functions lo salisfy Ihe Lewis acidity of tbe magnesium alom,
precltldes furthe r coordination by THF. Sinc:e four molules ofTHF are nceded lO $Ol vale
the Mg8r z. enl ropy consideralions favor lbe arylmagnesium halide al equilibrium.



-
' k
The Schlenk eqtlilibritlm of Ihe di-Grignard reagent 16, is driven completely 10 lhe
magnesiacycle 17 by Ihe bridging oxygcn gand (36]. The diaryl di-Grignar<! species 18
also cllisu compk!ely as !he magnesiacycle 19 (JS). When !he s!able nonsymme!rk:
diarylmanesium Spcc1e!1 lO was admillcd wi!h manesium bromidc, a quan!i!a!ive
lO Ihe erown e!her Grignard Spcc1es 21 and p-'_bu!ylmanesium bromidc was
obsc:rvcd. Coordinalion of the posi!ive manesium i$ lavorcd, and stcric crowdin
is reduced in 21 [ 37].
"g&'

al C'l4CI W? 3
- g
0.) .-
..
"
.. ..

1< MiI...2') -0-'-&
-. Br MilBt 0)

oJ oJ

"
--0-....
For alkyl Grignard reaents, solvenl il Ihe mosl importanl factor in delerminin
lhe pasilion ol thc Schlenk equilibrium. However, NMR sludies
indicatc Ihat Lhe rate ol alkyl Clchane i5 primadly a funClion uf Ihe ol the alkyl
group and i$ ooly scoondarily a luncli on ol sal venl [18]. Oilute diel hyl ether solutions
(0.1-0.3 M) ol RJMg and M"' J (R- EL or Ph) react almost inl tanLancously on mixin
to ive RM'" and associatcd Spcc1e!1 [27]. In a comparison ol alkyl groups, melhyl group
exchange is much rasler Ihan ' -bulyl group exchange, alld tlM: exchange i5 raster in dielhyl
clher Ihan in the hihcr donici!y IOlvent THF. In Ihe rnixcd bridgcd species 11, considered
10 be imporlanl in alkyl group Clchange, branching in lhe a[kyl group (R) would be
expccted lO inhibit formation ol lhe bridge bond. Further consistent with Ihis poslulate
i. the observalion Iha! whcn bis[tris(lrirnethylsi lyl}mel hyl]rnagnC5ium 13 was scaicd in an
NMR tube wilh MgBr. in diethyl ether{benzene (!}: I) for S hr al 25C, no ehange wu
observcd [38].
S" f\ " R
"MI! !"a.
X Y 's
"
R Alky1

6. Salven!
V. HIIIIde, elc.
p' m
,ml .... E" n1111&1I .... n E P: "" "-d :1\.,
D. TemFIE.""" El" S
Tcmpeflllure elfcctl on lhe composision al OrilLlud re.ge:nlS in solusion can be tilher
kintlic or Ihcnnodynamic. Incrtallin temptflltureII usually result in I raster ellchlne
or tiglnds magnesium compluet, whkh tfllnslatcs 10 raller cquilibralton
fIItes. An cumple or Ihis kinelM: errcct is lhe cquilibr'lion or the
Tabk 6 Equilibrium Con,lanll
(K) al. Funclion
(n ror lhe Equilibrium (-Bu),Ma
+ MaQ, .. 2_BuMaQ in THF
T(e
."
-59
"
.,
))
Id. la.
K
7.54
).00
23<
1.74
1.l2
sitcs of lhe associaled species was absenl al 2O"c. Therefore, il appears Ihlt low lemperalure
shifts the monomer-dimer cquilibrium loward the dimeric dimethylmancsium complCl
in THF.
Thecquilibrium belween mODomeric magnesiacyclohexane 10 and ilsdimericcomplCl
24 was shown 10 be a functioD of lemperalure (31).
[o],
..
..
The mean yalue for he cquilibrium al was 531 81, whereas he mean yalue al
48.SO"C was 223 41. As with dimethylmagncsium, low lemperature shifll lhe cquilibrium
loward Ihe dimenc complex.
Temperature effects on the equilibrium betwecn monomerie complcxcs have also
becn documented. An ' H-NMR investigation of t-bulylmagnesium chloride in ei ther THF
or diethyl ethcr showed that low Icmperalure shift. Ihe cqui librium toward the dialkyl
oomplex [18].
(t- Buh Mg+ MgCl
1
.ti2-BuMgCI
Quanlitatiye resuJl 1 concerning Ihe position of Ihe cqui1ibrium in THF al yanoul
Icmperaturcs are ShOWD iD Table 6. Wilh melhyl halide Grignard reagenll in THF and
diclhyl elher altcmpts 10 quaDtify tempenllure effects by the same techniquc were fruslraled
by predpitation or MgX (18). The inlerpretation of qualilati ve elTecll in diethyl ether
were eompl.icaled by the existence of additional monomcr-dimer cqui libria. Howeyer, in
THFlIOlulions thateonlain only monomericcompl.excs, it was poslul aled Ihal the formalion
of dimethylmagnesium was partly due 10 Ihe prttipitation of MgX (1IOlubility elTcct) aud
partly lO a temperature-relaled Ihift in cquilibrium, base<! on analyses of the precipitalc.
Thc reactiyily of mcthyl ehloridc Grig.nard reagent , di$(:ussed later in Scction III.B,
corroboralcs Ihis intcrpretation of the temperalure effcct (40).
'"
111. S"f'NTHETIC USEFULNESS OF 8CHUNK EQUIUBAIA MANIPULAnOHS
The Schlenk equlbrium or dalkylmagnesium and alkylmagnesium halides. as well as Iheir
correspondng a!l$Ocialcd aOO solvent<oordinatcd specie5, an: functions oC Ihe substrate,
halide, solvent, tonnlralon, and temperature. In Ihis .section, eumples or manipulating
tbese variables lO influencc Ihe: Schlenk equilibrium to control reaction ste:n:ochernistry,
regioche:mistry, and resctjvity are dc:scribed.
A. l,2-C.rbonyl A6dltlona
The $lereochemiSlry of MeM or MeMgX (X .. F, a, or 8r) addtons lO 4+
bulylcydohe:xanone in THF was independenl oC reagenl and resullcd in predominanlly
equalorial attack 10 fonn mainly Ihe axial alcohol product l!{71- 7S%) [41). AII magnc:sium
species weremonomericexccpl MeMgF, which is dimericn THF. A separate stereochcmical
study in diethyl etner, carried out al concentralions al which MelMg, MeMgBr, and
MeMgl exist in equilibrium between monomeric .and dimeric spedcs, gave 6S, 61, and
54%, respectively, ofaxial alcohol l5. Monomeric spedes MeMgX (O.I M) in dielhyl elhcr
give more axial akoholl! Ihan the dimeric species (Oo8 M) [42]; ror examp1c. MeMgBr
gave: a 68:32 prc:ference ravoring axial alcoholl! in delhyl elher under condilions during
which Ihe: Grignard reagenl was associalcd as Ihe monomer, whereas when McMgBr was
pre5Cnt as the dimeric specics, a 62:38 preference ror the axial alcohol l! was observcd.
"_ OH
.60 ot ....
, , .... r / ..... ,.
J THf
,
I
y .... OH
X-F.O .
"
In studies or Grignard rea.genl addilions 10 ozhc:teroatom-subslilutcd ke:tolle$ and
aldehydes he choice oC solvenl and the halogen alom of the Grignard reagenl have
influem:ed slereochemical outcomes [43-47]. An cumple is the rea.clion of the
oz-aminoketone l6 wilh phc:nylmagncsium halides in THF and in benzene.ln THF reaclion
i$ relatively indcpendenl or halide. lo benzene phenylmagncsium bromide am!
iodide reactions have reversed selectivity. The stereochemical resulls can be rationalized
by considerations of Ihe Schlenk equilibrium or various magncsium spedes. Grignard
reagent additions lo U; are cootrollcd by slene racton aod are coosidered 10 occur by
resction Ihrough cither a cyclic model17 or a dipolar stmaure lB [48]. In THF, magncsium
comple:les are monomeric; the magncsium alo015 are coordinalcd primarily with solvent,
aod the cyclic mndel is disfavored. ID benzene, which does not coordinate magnesium


..... " N OH
-. ""
"":f)--<J:'

,

:r" .-"
..
..
RR R'S
&"'!'!I

SS S'&'
..,..

SS
BII:
""
a

"
--
o
"
..
&
"
.. &
n
" ,

"
"
"

.....
-,-<. i!'


"
.

....

H''''
o
..
comple:u:5, he subslrale intcratts more strongly with he magnesium metal tenter, and
Itere il a grealer pcrcenlage of producls rrom lile cyclic model.
Thc concenlralion of Grignard reagen! oould abo be a factor in lhe stereochemical
oulcome. The addition of ethylmagnesi um chlonde 10 26 in dicthyl elhcr was highly
sc: lect ive for he RORO sterwisomer al concentration, of O,09-{I.72 M The
chloromagnesium compound , 8ssocialed even al lo\\' concent rat!on!. Tbe stereoselecli vity
or addi tion 10 l6 by tlhylmagnesium bromide, which is monoffiern: al lo\\' concentration,
is oonccntraion-dcpendent. Selectivity for he RORO isomer varie<! from 74". al 0.70 M,
where he dipolar model18 should dominate, 10 55"/. al 0.044 M, al which lhe c}'elie
model 27 should be more importan!. Thc $Ierrosclectivity fOf reaclion of 26 wilh
elhylmagnesium iodide is also concenlration-dependent .
An aHempt WlU made lO Ihe propellllily for coordi nalion of the magnesium
atom of a Grignard rugent with an amine runctionalily lo control Ihe stereochemistl1' or
addil ion or Me Mg or MeMgBr 10 ketonc: 29 in dielhyl el hcr. However, both
di alkylmagnesium and alkyl halide Grignard rugenl! gave similar res ults; amine
participation had little effect on lhe stereochemical outcome. The major product 3(1 resulted
[rom addition 10 Ihe Iess- hindered race of the kelone [49]. The eomctry or 29 does nOI
appear favorable ror si multaneous coordinalion of nilrogen and carbonyl wil h a
magnesium alom.
"
..

ee : M
el : 311
A suooessful approach 10 exploi l Ihe chelating ablity 01 MeMgBr lO control addilion
10 the hydrazone JI was di!COvered when lhe Grignard ruction was carried out in tol uene
Si nce toluene is a noncoordinating Ind nonpolar solvenl , the magnesi um
coordinates wilh the substrate lO aClivate the hydrazone and conlrollhe racial seledivily,
as shown. A 94:6 {or Re tace allack 10 give 32 was observed aner I hr al 2O"c.
There was no react ion after 48 hr at reflul temperalure in THF [SO].

, X
MezN-N-,'!'l PI"I

"- UH PI!
" ' M.l(
"
"
SC>"JI. EquJ:Uerlumllntl". E .... fe _", .. ", ..
Mueh improved yiclds of kctoocs, fonned by reactioo of Grinud reagenl. wilh
nitri les 3J, have becn obtained when reaelion. were performed in benzene conlaioio
1 Eq of diethyl elher, rather Ihan in diethyl elher alone [51]. Under lhe modilied coDditions,
il is poslulate<! Ihlt reaction oocurs Ihrough I speciC's in which Ihe oilrile has displaced
I dielhyl elher IOlvenl molccule (rom a dimeric Grinard species.
RCN R'Mg8r (al
U R e c-CaH"
R' e o-CIil1
B. Conjugate Addltlon,
ElOEt (1.0 Eq.'
.",,,
R e Me. R' e PI>
R e R ' e
Re I-Pt . R' e c4i ..
The !U!;tion of Et1M or EtMIIBr wilh 2-cyclohexeoone 34 has becn carricd out in various
5Olvenls. The dialkylmagncsium reagenl Iddcd 10 primlri ly Ihe carbonyl roup in all
salvenls studied. Dioxanc Ilforde<! lhe besl yield Ind grcatcst regiosclcclivily for 35; lbe
ratio of proclucts 10'115 similar in THF. EIMBr or EI1Ms/MgBr l gave 53:39 lod 54:35
ralios of 1,235/ 1,4--36 addilion producl in TAF, lhe: solvenllhal providcd lbe muimum
amount of oonjugale addilion. Wilh EtM,Br in bexane or bcnzcne, only lraces (2'Y.) of
1,4-additioo producl 36 werc observcd [52].
o
O'
o
6
,
,
0"
..
"
..
(1JIo>t.-1 l1li : 2
(TI F) 05 : 2
EtMgBr (THF) !:3 : )Il
(( is nOI possi ble 10 gcncralizc lbout Ihe propcnsity for 1,2- vertUJ 1,4-addition (rom
Ihe resulls wilh cyclobcllenonc 34, sinte 'r/:lIU3-penten 2-onc 37 rearo mainly by
1,4-addition to ive JI. wilh bolh diethylmagncsium aOO elhylmagncsium bromide io THF.
The diethylmagncsium rcactanl give incrcascd 1,2 addition procluct J9 [52].
""'f0
n O'
,

"
" "
A prcfereoce ol 1,4-lddition by lhe I lkylmlgncsium haJide specics ralher Ihan Ihe
dialkylmagnesium species, was observecl duringlhe rcactions of di propylmagnesium and
;.propylmagnesium bromide in diethyl elher witb lbe Orquiool acetite 40 [53]. Bclween
concentrations of 0.06 aod 0.24 M io dicthyl cther, ooly 2e. of 1,4--addilion product 41
was observcd with the dialkylmlgncsium species. However, al 0.24 M concent ratioo of
i- propylmagnesium bromide in dielhyl ether, 19% of 1,4-addilion product 41 was observed_
Al concentralion! of I- propylmagnesi um bromide below 0.5 M, the yield or 1,4-addition
producl 41 droppecl sharply, and Ihe resulls were similar 10 Ihose or Ihe di-l
propylmagnesium resgcnl al 0.06 M [ 53].

..
When tb!: quinol alkolti!le 4l was rcacted wilh dimethylmagnesium and melbylm.agnesium
halide resgenls in diethyl elher, selecli vi lies observed for 1,4/ 1,2-addition (45/46, respectively)
were 5:1 with MeJMg, 7.7: 1 wilh MeMgBr, and 13:1 wilh MeMgCl. More careful study
indicaled that temperature pla)'$ a major factor in the regiochemical oulcome. When
MeMgC1 wasadded lo 4lat - 78(', the ruelion prooceded in 5 min lO 40-50;' complelion,
and lhen furtheT reaction ccased. A 95:1 Sdeclivily favoring 1,4-addilion product 45 was
Jqserved. As Ihe IOlulion was wanned 10 _ 25(', reaction resumed al a mueh slower rale
and with lower selectivi ly (5.5: 1). Allhough all of Ihe organomagnesium reagenls in the
IOlulion can coordi nate wilh the al ko:dde oxygen lo give ~ a l e ~ complex 43, onl y tb!:
dialkylmagnesium species .... can reael al - 78C. Al higher temperalUres Ihe remainder
of Ihe alkyl groups can react, bUI by a differcnt reaetive spccies (40).
By rurther cxperimentation. lhe 1,4-addilion of lhe MeJMg reagenl 10 lhe quinol
alkoxide 4l was conlirmcd 10 be assislcd by Lewil acid complexalion of lhe kelone carbonyl
wilh MgCl
l
. The Me
l
Mg in THF, with 10;' MgC1l added, afforded 30:1 regio- and
slereoselectivi ly for the 1,4-addition product 45 [40). Reaetion presumably occun via lhe
Male
M
complex ..... Al higher concentralions or added MgO
l
, the MelMg reaction
Ilereoselectivily shiru 10 Ihal observed fOf MeMgCJ. As Ihe 5111 shiru lbe Schlenk
equi librium, reaction occun via lhe ~ a l e complex 43.
-"""
U.UQCI

I

""
....
'-'
...
.,
"
_,,'
J .,..
I

o
o
Q ..

9 ..
,
OH
,
OH
..
..
.. .. ..
p' m
C. Dlaplan mant Auctlona
Telrabenzylvanadium 47 could be prepared. by reaction of dibem:ylmagnesium wilh
vanadium telrachloride in pentane at - 2O"C. 8enzylmagnesium halide reagcnt, rail in
this reaction. It has been poslulated Ihat bem:ytmagnesium halides bchave as Lewis acid!
and promote reduction in Ihe oxidalion state of vanadium [54].
(PhCHV:rMg ~

"
Grignard reagents prepared from R' X (R'- Me, Pr, Ph, -Pr, t- Bu; X_ Br, 1) react
in diclhyl elher wi lh I.aryl-)-chloropropenes 48 lo alford Iwo alkylalion products by
competilive 5 .. 2-5",2' pro", .ses in addition 10 dimers 'Conned by singk-electron Irenster
(5ET) processes. In diethyl elher RMgX i5 prevalent Thi. sJlC'cics can react by S",2 or
S",2' pathways, which are Cacilitated by Lewis acid coordination ol magnesium sJlC'cies
wil h the leaving chlori<k: graup. In THF, however, the s,.2 proces! dominates. In THF
Ihe more nucleophilic dialkylmagnesium RJMg i5 the major reactive spedes and favon
an S..2 process [ SS]. See Chapler 24 lor d;.,cussion ol 2 versus ~ 2 addi lion .
..... "
"'"'"
..


"'"'"
,h""
" o"",
.. "'"
"
""" ""
111 : 33
ObUl)'I EIIMr 52:<18
""
100 :
,
OIefIJ4EIIw 01 : 33
H
""
100 :
,
0161,1'1 EIIMr a7 : 13
'"'
100 :
,
..... " ..
110 : 1"
THF 100 :
,
--- ."

D. Aeductlv. Deh.log, netlon
Diastcreoselec;t ive exchange oC iodine Cor hydrogen has bcen elfectcd by reaction ol'
o..protected 1, I-diiod0-4-melhyl)penlanol derivalives 51 with dialkylmagnesium or alkyl
"
R' Mem, /o.P'rt.IQ8r. THF
R' 81"'-3, WlMCI(Bt). THF
J..Po:.OWg. THF
Pr,Mg, Ea-
71 : 20
~ : e o
33 : 01
25 : 15
halidc Grignard reagcnu ronowed b), aqucoul qucnching. Vatiation or reagent, had liulc
inllucnce on Ihc ttcrcoteJe<:tivily oompared wilh lhe choice or lhe prola:linggroup [56].
AEFEAENCES
1. E. C. Asllb)', Q. Reo. 11:259
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3. R. Abcg./k,. J8:4tI2 (1905).
4. W. &hknk . OO W. &hkmk Ir, /kr.
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(1994).
lO. 1. W. F. L. Scctz, O. S. AHmnan, and F. Bicklchaupt, TtlraMdrM UI/. 11:4857
11. J. w. F. L. Secu, F. A. H.rto .. H. P. Blom, C. Blomberg. O. S. Akkernl.n,'OO F. Bicklchaupl,
TmoMdrM UI/. 1J:I"97
12. M. A. G. M. Tinp, G. Sellal, O. S. AHerman, F. Bicklehaupt. E. Horn, H. Kooijml n.
W. J. J. Smectl, ' OO A. L. Spck, J. A.m. CItm!. 5. Jl5:2808
13. M. F. Llppcrt Ind T. R. Mlrtin, J. CMm. Soc. Dall"" TrQ ..... p. 1959
14. J. Alten. J. Troy, P. Jilna. M. Trachtman, 100 C. W. Bock, S'nlCI. CM",. 5:99
IS. F. W. WIJker .nd E. C. Ashby, J. A.m. CMm. 5. Sl/:3&45
16. El. C. Ashby _00 M. B. Smith, J. A.m. CMnt. Soc. 86:4363 (1%4).
17. El. C. Alhby. G. Panll, aOO F. W. W.lker. J. CMm. Soc. CMm. CMIIItUII . p. 1464 (1969).
1S. G. E. Parris.OO E. C. Asbby, J. Am. CMm. Soco 9J:I206
19. V. GUlmann. C()(ITdiltlJti(m CMm. Reo. 1":22S
20. E. C. Ashby.1Id S. H. Yu, J. Orf}o CIwm. 19:3J9
21. G. E. CoSIes, J.A. Heslop, M.E. Rcdwood. 100 D. Rcdlcy, J. CIrfflt. Soc. A P. 1118 (1968).
22. O. F. EvaDa .OO M. S. Klla!\, J. CMm. Soc. A. p. 1648
23. E. C. Asllby, l . Lacmmle, l OO H. M. Neuml nn, Ace. CIIon. Ro. 7:272
24. R. M. Salingcr aOO H. S. Mosber, J. Am. CMm. Soc. 86:1782
25. T. Holln, MIO CIIem. Sclllld. 1J:579
26. M. B. Smilh , 00 W. El. Bcdcr. TmllMmOll 1J:42I S (1967).
27. M. B. Smilh 100 W. E. Bcder. TtlralwdrtNf 11'.3027
28. T. Hol m, Aera CMm. &amJ. 20:2821
29. P. Sobota aOO B. Duda, J. OrgD/IOIMl. CIt#m. JJ1'.239 ( 1987).
JO. P. Sobota. PUrt Appl. CMm. 61:861
JI. H. C. Hollkamp, C. Blombcrg, and F, Bickcl haupl . J. Or(lQllMltt , CMm. 19:219 (1969).
32. J. A. MSlI1uson l lId J. D. Roben&, J. Org. CMm. J7:133 ( ISln).
lJ. R. Hi n I nd G. Parkin, J. Org_l. CIwrn. J9J:CO
l4. R. Hin I nd G. Parki!\, J. Am. O t m. Soc. 114:748
H, P. M. Mlrkies, R. M. Altink, A. Villcna. O. S. AHcmum, F. Bickclhlup1. W. lJ. Smccts, 100
A. L. Spck, J. O"flOO"llt. 401'.289 ( l99n
36. e Blombcr .. G. :khlt, H. H. Grool vcld, A. D. IIId F. Bickclllaupl, Utbi.J AM.
CM"" 76J: I43
J1. F. Bickelhlupl, Acta CMm. SctJlld. 46:409
38. S. S. Al.J uaid, C. Eaborn. P. B. Uilchc:ock, e A. McGt:ary, an<! J. D. Smi lll, J. CMm. Sac,
C_m. C......", .... . p. 273
39. l . Kras. J , O'gtl'l_I. CMm. IJI:I
40, K. A. S..,.i5l, D. C. Liona,.1Id C. A. Mary.noff. J. Am. CIwm. Soc. 111:919)
41. E. C. Asbby, S. U. Yu, l OO P. V. Rolins. J. O'f}. CMm. J7:1918 (1972).
42, P. R. Joncs. E. J. Goller . OO W. J. KulT'mllll, J . O,g. Clwm. J4:1S66 (1969).
43. D. J. Cram .nd D. R. Wibon, J. Am. Cllem, Soc. 8J:124S (1963).
44. J. H. Stockcr. P, Sidiluntllom.B, J. Bmj.min..ndC. J. CoJlins.J. Am. CIIem ..
4S. O. Arjon., R. Pcriz-Ouorio, A. Perel!-Rubalcab., .nd M. L Quirop. J. CIwn. Soc. P,,/iII
Trans. 11 p. S91 ( 1981).
46. M. P. Coutrot, C. R. Htbd. $tQf\CtIAcM. &l. $t,. C ]79:469( 1914).
47. H. N.gano, M. 01100, Y. Miy.mu,.nd Y. KUDO. Bull. Clwm. Soco JpII. 65:2814 (1992).
43. P. Audoye. A. Guet, '00 A. l..lttes. J. O'fIlJIIOMI'l. CIIem. &t.30J (1975).
49. H. O. HOUlC and W. M. Bry.nt, J. O'g. Clwm .10:3634 (1965).
so. A. Aleuki$, N, Lcnscn,I.-P. Tranchicr, .nd P. M.npnc)', J. O". CIwm. 57:4S63 (1992).
S1. P. enonne, G. 8. F"O$COIos,.oo G. Lema)', TmQNdrOlf Lm. ]1:1SS (198Q).
S2. M. Oocmcn Ind G. Souasan, J. OrglUlOtMl. Clrtm. 80:303 ( 1914).
53. B. MUler, E. R. M.tjcb OO J. G. H.qet!)', J. 0'/1, Clwrrt. 49:3121 (1984).
Sot, S. D. Ibckwc . OO J. My.tt, J. O,ganomtl. CIwm. JJ:C65 ( 1911).
SS. K. Muraok., M. Nojim., S. Kutlba)'ulli, .nd S. N.p .... J. Chtm. $oc, P, ,/iII T,QIU. 11 p.
761 (1986).
S6. R. W. Hoffmann.OO A. Kusclle. CIttm. Bn. 1]7:UII ( 1994).
14
Effecl 01 Trls(pyrazolyl)hydroboralo Llgallon
GERARO PARJI;IH
Co/omtbia .. York. Nt .. York
l. INTAODUcnON
Grignard reagen! solulions comprisc: a complex distribution of magnesium altyl and aryl
derivatives [1 ]. In its simples! fonn, lhe compasilion af a GtigDan:! reaent IOlution is
describe<! by he wellknown Schlenk equilibrium [Eq. (1): 2].
(1)
However, Ihis si mple model is complicated by a variely of olber facton (e.g., solvation
etrccts and oligomerization). as iIlustraled by X-ra)' difl'ractioD ludies on he species Ihat
crystallize froro 5Olution. For uample, Figure I summarizcs sorne orlhe complcles isolatcd
rrom Grignatd reagenl soIultons Ihal have beco charactcrized by X-ra)' diffraction. Thesc
compb:es include both the four- and five-coordinalc solvatcd mODOmers, RMgBr(QEI Jh
(R _ El (3). Ph [4])and MeMsBr(THFh [.5]; lhe halogen-brldgeddimcn [ EIMgBr(OJ>rlJJ
J
[6] and [EtMgBr(NEIJ)]J [7]; and also lhe letranuclear complel [EtMslOl(THF)lJl [8].
111e tetranuclear complel ma)' be considered as an adduct orthc Grignard reagent EtM,a
and the MgClJ that is rOlhiOO as a consqcqucncc or the Schlenk equilibrium. Allhough
Ihese slructural sludies do indicate Ihe complexity o/"Grilnard rugenlsolutions, it should
be recolnized Ihat Ihe spccics that Cf)'stallize rrom such solutions are not !lCeenril)'
representativc or either Ihe major, or Ihe reactive, componenl Nevcrthelcss, dcspi te the
aforemenlioncd compleltit)', and the uncenainly or the exact nature or the active spccics
present in solut ion, Grignard reaaents continue to be onc o/" the most useruJ reagcnll in
synthetic orlanie and orpnomctallic chcmiSlry. Jt is. thereforc, of some interest lO detcnninc
the rcactivil)' or the magncsium alkyl moiet)' in wcll-dclincd coonIination environments.
In this scction, the use of Iris(pyrazol)'I}h)'droboralo ligati on [9) lo provde a series of
well-delincd monomerK: mancsium alk)'1 derivalives wiU be dcscribcd, and the elfect or
such coordination on the rcactivit)' of the magnesium carbon bond wm be commenlcd on.
""'" ,/
..

Dlmeric
'm"
TelranudoBr
Filur" I Slruclurally charactcrized rompkxes hat cryslalliu from Gri8l1ard Ka",n! IIOlutions.
11. SYNTHESES AND STRUCTURES OF MONOMERIC FOUA-COOADINATE
TRIS(PYRAZOLYL}HYDROBOAAro MAGNESIUM ALKYL
DEAIVATIVES
A. Trl-<py,.zoly.}tIrdrobor. to Llganda
TrU(pyrazolyl)hydroboralo ligands [HB(3,S-RR' pzhr which were
introduoed by Trofimenko in 1966 (10]. are readily ohtained lllI lhe pota$$ium deri vatives
by Ihe direct reaction of KBH. with lhe appropriate pyrarok: RR' pzH [Ee. (2); 9].
IKJ +
(2)
or particular significaoce, a wide variel)' or tris(pyrazolyl)hydroborato ligands are avaitable;
hence, Ihe cfrcels or bol h l lene and electronic influcnces may be sludied. For cumple, Ihe
sleric demands of lhe trU(pyrazolyl)hydroboralo tigands ma)' be readi ly modified by
5ubstitution al he 3-position or the pyra:rolyl group. Steri<: demands of ligands are orten
described in temu or their rone angles, e (Fig. 2) [1 1], which increase substantially from
184
0
to 244
0
upon substitution or the J H for a Bu' substilUent in tbe tris(pyrazolyl)hydro-
borato ligand system [12]. The nomenclature adopted bere for tris(pytazolyl)hydroborato
ligands is base<! on Ihal described by Trolimenko [9a]. Thus, the tris(pyrazolyl)hydroborato
ligands are represente<! by he abbreviation Tp, wi th the alkyl substituents listed as
superscripts. The tris(pyra:rolyl)hydroborato igands describe<! iD this section, namely,
[TpW.,], [TphJ. and [Tp""] (Ar _ p-C. H. Bu') [9.12a, 13]. are summarizcd in Figure J. from
which il can be secn that coordinatioD of tbe three nit rogen donon to a magnesium cenler
provides a wel1-defined coordination environmenl for investigaling a series of monomeric
four-coQrdinate magnesium alkyl derivatives.
360"
1 Cone an8lcs of tris(pyrazolyl)hydrobo ... to lipnds.
Flure J Tri$(pyruolyl)hydrobo ... to magnesium alk)'1 deriVlrives.
In IIddition lO providing a slble coordination environmenl, Ihe alkyl substituenls
011 he pyrazolyl group provkle a useruJ and nvaluable spec1roscopic handk: for monitoring
he reactivity of hese complexcs.
B. SynlheHI of (lpIl..II'JMgA CotllpllXft
Tris(pyrawlyl)hydroborato rnagnc:sium alkyl derivatives [Tp"'lMgR are readily prepared
by he reactions or (M][Tpl] (M _ K, n) with solutions of the appropriate dialkyl-
magnesium [Eq. (3); 14-17]. The reaction is very general and a series of primal)', seooooary
tertiary, vinyl, and phenyl derivatives have bcc:n obtaincd, 8lI ilIuslralcd in Table 1. The
magnesium alk,,1 eomplexes are 111 white Cf}'SlaUine 50lids thal are soluble
p' m
. ." ..
Table I lIoIalee! rr"'''']MR Complc1e!1
[fp"'']MR [fp-:JMgR (TJY' '')MR
CH,

CH,CH)

CH,tCH,hCHI

CH{CH
v1

qCH.h

CH.SiMc.

CH=CH,

C. H.

in hydrocarbon solvenls., lIch as benunc.
AzMg + [MlTP"-" I
_ [MRI

(3)
Thc react ions between R,Mg and he thalJium reagenls T1{Tp"''] an: accompanicd
by tbe deposilion of TI metal owing 10 (he decomposition or [TIR] [18J, which Ihcreby
provides a very elfective dri ving fora: ror the reselion. In view 01 (he elfect ive driving fon;:e
Tor the Ihallium reagenl. the potassium derivative (K](Tp l'] ma)' be prcferred for be
synlhesis of magDeSium alkyl derivatives nf le" sterically demanding ligand" Tor which
di.ubstitution and (he fonna lion of (he six-coordinatc magnesium derivative {Tp . l] , M
ma)' be racHe. For cxample, (be polassium derivativc: [K](Tp""J is be reagent or choice
Tor (he synlhesis of because he thallium reagcn! may result in disubstilution
wilh Ihe formalion of [TpM"]l Mg [17]. In conlrast, complexes of Ihe more slerically
demanding I-bulyl-$ubsliluled ligand [Tp""']MgR are eleanJy prepared UJing the thallium
reagent. since lhe formalion of [Tp .... :bMg is nol possible for Ihis Jigand syslem (see Jater

Finally, il Is worth nOl ing that although an appropriate method of synl hesis or
[Tpl"]MgR complexes would appear lo involve the reaction or a Grignard reagenl RMgX
wilh [M][Tp"'], such a method , complicaled by lhe formali on of Ihe corresponding
magnesium halKie dcriYalive rrpl.l"]MgX as a resull of compelilion belwccn Mg- X and
MI- R bond melalhesis [17, 19]. Thc producls oblaine<! dcpeod upon lhechoicc ofGrignard
reagenl and reaClanl ratio, as summarized in Figures 4 and 5. Such a problem is obviously
alleviated by using R1Maas Ihe reagenl, which eleanly ives Iheallr:yl product rrpl"]MR.
c. Struc:tur .. and Sp"bol coptc: Propertl of Com.,..
Tbe molecular sl ructures of several rrp"'"]MR derivalives have becn determine<! by
single-cryslal X-ray diffraction. which confinns Ihat in each case Ihe moleculea are
solvenl-free monomcrs, and that tlle tris(pynu:olyl)hydroboralo ligand is "J-coordinaled
lo magnesiuro. TIIe coordinatioD environment aboul Ihe magnesium may be dc5Cribed as
, , ,

Fipre 4 Product dimibuliOfl or he reaclions or RMCI (R _ CH .. eH ,CH Jo CH(CH.),. qCH .h)
... jlb n[TpW] as a fulKtion of reactant mol ar ralio (Modified from Rd. 17.)
'00
..
aVl -f' ..
....

o , 2 3 4 5
CtyAoX/ T{Tp ..... )IfIO' -rallo
,
" %
[Tp"',tga
..
..
'00
Fipre 5 Proouct dinribution of lhe reactiolll of CH,M", (X - a, Br, 1) ",ilh as I
runcHon of mlelanl molar ralio (ModiflCd rrom Rer. 11.)
trillonally distoned IClrahedral ORTEP drawinp for [Tp---:JMgCH" [TpW]MgCH{CH
J
)"
and [Tp"')MgCH
2
Si(CH.h are !hoWD in Figures 6-8, and sclected bond Ientbs are
presc:nted in Table 2. The Mg-C bond lenlllh! are in he cange 1096(9)-1182(8)A. For
n:fcrcnc.; otl'ler four-coordinatc monomerie magnesium alkyl complexc:s of the type
RMgX(Lh llave Mg-C bond leng!h! in tbe range 2.15-UJ (20].
Thc complexo [Tp''')MaR llave a1so been characlcrized by 'H- and 'lC_nuclear
magnetk resonanoe (NMR) speclroscopy. For clImple, Ihe MS-CH. groups of lhe melh,,!
derivatives (Tp"'']MgCH" and (Tp""]MgCH, exhibil ' HNMR signals
al " - 0.05, - 0.58, and - 0.25 ppm, respectively, and I'CNMR signals al - 5.2
(l Jc-" - I09Hz), - 9.5 ('Jc-Il -I09Hz) aOO - 17.1 ('Jc-Il .. I09Hz) ppm, respectively.
Ihe resonances anribulable 10 lris(pyrazolyl)hydroborato ligaOO are also
2H
FiglIrf 6 MoIuJar structure of [Tp""'JMsCH . (From Rer. 17,)
Fipre 7 Molecular IlrllClure 01 (Tph'JMAPr'. (From Ref. 17.)
T.bIe 2 Selected Bond Lengtlls Al for [Tp"''')MR Complexe5
M,-C
MJ-N
2.118(11)
2 . 1 ~ 1 0
2.131(7)
2.137(7)
2.182(8)
2.157(6)
2.1 70(4)
2.170;4)
2.('%(9)
2.012(6)
2.1197(5)
2.1 19(6)
, .....

FIg.re 8 Molecular Itructure or [Tp"'']M,cH). (From Ref. 11.)
a valuable speclr<neopic handle for monitoriog reactlVlty. For example, each oC Ihe
complexes [Tp---:JMgR exhibit a single charactcristic resonancc in lhe range 6 1.34-- 1.44
for Ihe t-bulyl substitueols oC lhe [Tp"" ligand.
HI. AEACTIVm aTUDIES OF [Tp",II']MgA COMPLEXES
An nvestiptioo orIbe reactivity oC tbe complcxcs [Tp .... ']MgR is importanl bolh in temu
oC delermining Ihe reaclivily orlhe Mg-C bond in I ooordination cnvironment,
bUI also in temu of providing a comparison with Ihe reactivily of Grignard reagenlS.
Aspects oC Ihe reaclivi ly oC [Tp . l1MgR are considere<! in lbe foll owing sections [21].
A. Ugand R_Iatr1but1on
Thc complexcs (Tp . l']MgR may be considered 10 be modificationJ of Grignard rtagenls.
As luch, these oomplexcs may be expcctcd 10 be subjcct lo [he taciJe ligand redislributioo
reactions oC lhe Sehlenk cquilibrium. Indeed, although solutkms or lbe tris(3,5-
dimelhyJpyrazoJyJ)hydroborato <krivatives [Tp"'']MgR are JlabJe al room lemperature,
bealing lo 8O-120"C docs resuJI in Iigand redislribution aod lbe rOrmaliOD or Ihe
six-coordinate sandwich compJex [TpN")JMg [Eq. 21.u]
, H-O

(4)
However, on increasing Ihe sleric demands of lhe lris(pyrazolyl)hydroboralo ligand,
lhe slabi lily of lhe rediSlribulion produCI [Tp .. ]lMg
sufficienlly so Ihal Haand rcdislribulion of [Tp)MgR is nOI observe<!. For eumple,
solulions oC [Tp"']MgCH, show no cvidence of dccomposilion alter 7 day' al 12O"C. 1I
is worth cmphasizing that Ihe [Tph'J ligand hu becn describe<! as a "Ielrahedral enforcer"
owing 10 its ability lO reslrict a ceotcr 10 a maximum of four-coordination [12a].
ror Ihis reason, lhe slerically demanding [Tp""1MgR sy51em is more appcaling lhan less
slericaUydcmanding (Tp"'lMgR systems for defininglhe reactivity ofthe Mg- R group.
The foregoing rcdiSlribulion reactions are, evident ly, significantly sloll'er Ihan those
involved in lbe Scblenk equilibrium of Grignard reagcnls. Con$equenlly, a mixture of Ihe
alkyl derivalivcs (Tp""MgCH
J
and [Tp"',)MgC(CHJ)J does nol rcsull in he rormalion
of crossovcr products alter btaling at 8O"C for 3 days [Eq. (5)].
(Tp .... ]MgCH J + (Tp"''')MgqCH lh - X ..... MgqCH lh + [Tp""]MgCH J
(S)
B. R .etion, wlth C.rbonyl o.rI".ttv
Nucleophilic addilion lo carbonyl functional il ies undoubte<!ly represents olle of the masl
importanl reaclions of Grignard rtlgenls. One sucn is Ihe alkylation of carbon
dioxide 10 give carbo.ylic acid deriva ti ves. Analogous rcactivity is abo observe<! belween
[rp"']MgCH
I
and COl' which gives lhe acetate derivalivc [Tph'JMg("I.OlCCHJ) [Eq
(6)].
o e o

(6)
The corresponding wilh "CO
J
gives (TpIhJMg('1'-Ol Use of l'C_NMR
spcc.:troswpy has idenlied Ihal Ihe magniludc of Ine Jc-c coupling conSlanl is n Hz, a
value indicativc of a one-bond coupling, Ihereby confinoing Ibe formalion of the C--C
bond in Ihis reaction.
Howevcr, allhough Ihe reaclion belween [Tplo'MgCH
J
and COJ is similar lO Ihal of
Grignard lbe is significantly slower. The lower [rp"'MgCH
l
relative 10 Ihal 01 Grignard reagtnts is presumably a consequence 01 bolh the
demanding nature and slrong bindinll 01 the lris(pyrazolyl)hydroboralo ligand lO he
magncsium center. Reduction oflhe llene demands aflhe 3-substilutcnt would be
to promote reaclivity, al i5 indicated by preliminary sludies with
(Ar_p-C.H.Bu') (13b].
In contrasl 10 Ihc addition of [Tph'JMgCH, 10 COl' he rcaclion of [fp-]MgCH
J
with acelone il no! Iypical 01 Grignard reactivily. Thus, rather than forminll an alkoxide
derivativc [rp"]MgOC(CH,h, the reaction between [Tp--:!MgCH, and (CHlhCO gives
lbe enolate complex [rpflrJMg{'11_OQ=CH)CH,) and CH. [Eq. (7)].

(7)
Magnesium enolatecomplexes have previousJy been isolated only for kelones wilh uerically
demanding 5ubstiluenlll {e.g., Du'C(O)EI [2)) and (I,J,5-Me]C, H
1
)C(0)CH] [24]}, and
Ihe formalion of [Tp'''')MS{"I.QQ=CH1XCH
J
}} repn:scnlS an inleresling eumple of a
magnesium enolale derived from aoelone. The reaction appcars lo be general for methyl
kClones !inee CHJC(O)Bu' also reacts wilh [Tp""JMgCH
J
10 give Ihc enolale derivative
[Tp .... ]Mg{"L.OC( CHJXDu'}. The enolate derivalives
are readily charactcriz.ed by NMR and IR sludies, as summariz.ed in Tabk J. For
Ihe Iriplcl resonanee e Jo-
H
_155 Hz) observed at 683.1 ppm in Ihc LlC-NMR spectrum
of [Tp""JMg{'1'.0C(=CH1XCHll} is charactcriSlic or a [OQ- CH1XCH))] moiely,
whereas Ihe absorption at 1620an -
1
in lbe IR spcctrum ia auribuled 10 Vc-c-
C. R .eclon. _Ith Oaygen
The alkyl complell.cs [Tpl"')MgR (R- Me, El, Pr', Bu, reaCI with exocss 0
1
at room
temperalure lo givc alkylperoxo complell.es [Tp""JMgOOR [Eq. (8); 15,21].

(8)
Thc reactions are instantaneous for the derivatives [Tp""JMgR (R "" El, Pr', Bu'). wherealL
the reaction or Ihe melhyl derivalive [Tp""JMgCHl is significanlly slower, proceedin
over a period or day' al room temperature. Furthermore, lbe reaction of 0
1
with
[Tploo']MgCH
J
il also accompanied by an approximate deoompo$ition, 50 thatthe
producl (Tpa")MgOOCH
J
is not cleanly isolated [15,21].
The alkylperollo complexes have been characleriz.ed by spetttoscopic studies on
isotopicalJy labeled dcrivatives. Thus, the reaclion of 110
1
(41 "l.) with [rp""JMgR ives
the enricbed alkylpcroxo complexcs [Tp''']Mg
L1
0
17
0R Ihat havc becn investigated by
l7ONMR spetl roscopy. Each complcx exhibits two 'l()'NMR resonantes in Ihc ranges
6 102- 183 and 6 323-427 for he Iwo distinct oxygen atoms ort he alkylperoxo (Mg-()...()...R)
moicty (Tablc 4 and Fig. 9) [15,21]. Howevcr, tbe "()'NMR cbemical shift, or thc two
oll.ygen atoms 01 the alkylpcroxo group cll.hibit difl"crenl trcndl when varying Ihe alkyl
Table 3 Sdccted SpcclrolKXlpic Data ror he Enolate
Compleles [Tp--,Mg{,,'..oq CH,)RJ (R - Me, Bu')

' HNMR
UCNMR
IR
' 1, 'Jc_If_ISSH.
6(Cfu)

6@)
tc-c cm-'
"JJ. L J
C

H
" 149 and 156 Hz.
' .29
4.32
83.1'
161.9
",.
R_Bu'
J."
4.42
82.1"
172.4
161S
Table 4 "0_ NMR Data ror [Tp .... ] M&<>OR 10 H. " Oj
5 "o (ppm)
..
,
6(MIQOR)
m
<O,
37l
l2l
6(MgOQR)
'02
,JO
!l'
'"
,ooL--_---_--__ --_--
Flg_tt 9 "ONMR data for and ROH.
P ... 1n
substitutnl. 00 he basis of lhe observe<! trend for he " O-NMR chcmical shifl! or Ihe
corresponding alcohols, lhe se! of resonances al higher licld is suggested 10 corTeSpond lO
lhe P-Q aloms, and Ihat Ihe SC: ! of resonanCC!l al lower field coTTCSpond 10 he a-O atoms
of l he alkylperoxo moielY.
In general, Ihe reaclions of organometallH:: derivatives with oxyg<:o afien produce
complell mixtures (25]. Typically. Ihe isolated products or hese rractions are alkoxo
derivatives (l.MOR], wilh rclatively (el" cxample!! nvolvng isolation or aklylperoxo
complexa [l.MOOR) [ 26]. The Juecessful isolation of magnesiurn alkylperoxo complcJ,CS
(Tp")MgOOR by Ihe reactions or [Tp""']MgR wilh Ol is presumably a conscqucDCe of
the slerically dcmanding environment that is produced by he tril(pyrazolyl)hydrooorato
ligand (sa: later However, in contrast 10 Ihe formation of Ihe alkylpcrolo
complexcs in the reactions of Ihe alkyl derivalives [Tp1MgR (R _ Me, El, Pr, Bu') with
0l' Ihe analogous reaction of lhe lrirnethylsilylmelhyl derival ive [Tpl"1MgCHSiMel
with Ol is aa;:ompanicd by Si-C oond clcavage and lhe formation of lhe lrimelhylsiloxidc
dcrivalive [Tpft"1MgOSiMel [Eq. 27].
(9)

A precedenl for Ihis reacion is providcd by Ihe observation of organic products derivcd
from Si-C bond clcavage after auloolidalion of other trialkylsi lyl metal dcrivativcs. In
particular, Ihe Grignard reagenl MelSiCHIMgCJ reacu wilh 0
1
10 give .ignificanl
quantities of Me1SiOH, (Me1Si).0, and (CHIO).. afler hydrolysis [28].
The mechanisms of Ihe reaelions of oxygen wilh metal- alkyl derivalives have
previously becn IUggested to involve radical intenncdiales (Scheme 1) on the basis oC (1)
alkl y group rearrangement and racemization, and (2) iDhibition oC aUlooxidation by radical
traps [29]
L"M-R +
L"M<X>o + Ro (iflilialion)
ROO-
L.,M-R + RQOo L"t.4OOR t Ro
Scbeme I A mcchlniMn ror lutoxidltion of metal allr:::y la.
An analogous mechanism is al$O proposed for the reaelions of [rph']MgR wilh 0l' since
(1) the: reaelion of with 0
1
il inhibited by smaD quantities 01 lhe radical
trap lIalvinoxyL and (2) ccossover producu are observed using IWO different tri!(pyrarolyl)-
hydroboralo lipnds. Specifically, the reaction 01 O, wilh mixluR oC [fph']MgCH,
and [rpMo'] MgC(CH,h gives, amonll olben, lhe crossover product [Tp""'JMgooqCH,h
[Eq. (lO)].
(10)
Nolably. allr:::yl exchange between [fph']MgCH
1
and [rp""'']MgQCH,h does noc (l(:C\lC
in Ihe absence oC 0
1
over a period oC more Ihan a monlh al IIO"C.
The Cormallon o (he lrimethyui loxide product [rp"'MgOSiMc
l
in Ihe reaction of
[Tp""'JMgCH
1
SiMe, wilh O, is also prop<lICd lo occur by a radical prO(c' Thus,
eliminalion offormaldehyde from Ihe radical inlennediate Me
1
SiCH
1
0
1
' [Eq. (11)] woukI
generate lhe trimethyuiloxide radical MelSiO' , a rearraogement that would be promoted
by the formation oC a strong Si-O bond.
_ _ _ ...,Sl-<J'
o ,
CH. O
( 11)
The observation of efossover producl$ in Ihe reaelion ola mixlure of[rp""]MgCH1SiMe
l
and [rp8"]MgQCH,)l with 0
1
$UpporU Ihe proposed radical mechanism.
The alkylperoJto derivatives [fph']MSOOR are capable of transferring an oJtygen
alom to cerlain substrates, wilh the: ooncomilanl formalion oC lhe alkoxo complex
[fp"']MgOR. For eumple. oxygen alom transfer 10 a magnesium alkyl derivative occun
in (he reaction oC [rph']MOOPr' wilh [rp'''1MgPr' al 8O"C 10 give [rp""'JMgOPr'
[Eq. (12)].
(12)
'm"
However, il is noteworthy Ihat ol)'gen alom transfer lo Ihe magnesium alt)'1 derivative
does nol OC(:ur rapidly al room temperature. This ;, presumably one or lhe faclolll Iha! is
rcsponsiblc: for he ob5ervation lhal the reaclions of (Tph'JMgR wilh 0l are IIClective in
Ihe formalion of alkylpcroxo complc:u:s, racher Ihan the 811:0110 derivativcs. It is li"el)'
Ihat Ihi s ;1 a consequcncc of he slcrically encumbered nature of lhe magnesium ccnlcrs
in thcsc: complclIe5.
Thc alkylpcroxo oomplcxcs [Tp"']MgOOR Iso elfecl ox)'gen atom trander 10 PPh
J
al room tempcrature, Iving (Tp'''']MgOR and PhlPO [Eq. (13).
[Tph']MgOOR+ PPh
J
-> (Tph'JMgOR + PhJPO (13)
D. AellCtlonl wlth HX and AX
As would be anticipated, lhe magncsi um-alkyl bonds in (Tph']MgR are ver)' susceptible
toward reactions ""ilh prolic reagenls HX, which resuh in el iminalion 01 Ihe alkaDC and
formation of Ihe correspondins (Tph)MgX derivalivc. Allhough Ihese rcactions are nOI
panicularly uscful from a synlhctic orpnic ehcn\imy perspcc:livc, they are of imponancc
in lenn5 of providing a wid!: varicly of [rp""'JMgX derivati va, and al$O ror defining tbe
rcactivity or Ihe Mg- R bond in a conl rollcd environmcnl. Examplcs or protie rcagents
Ihat rcaet in this way include (1) RC_CH (R .. PI\, SiMe,,); (2) ROH (R ... El, Pr, Bu', Pb,
CHJSiMc), (3) Bu'OOH; (4) PhNHJ; (5) CH)SH; (6) HJS; and (7) Ha, 115
5ummari:w1 in Schemc 2
A vancty of nonprolie reagenls, sueh 115 dimethyldisulfide, alkyl halidC$, trimethylsilyl
dcrivativcs, and halogcn&, aI$O reael with (Tp-:lMgR, aOO some of these reaetions are
summarizcd in Schemc 3.
-
SdlCnlC 1 Reactivily of toward HX. (Modificd from Ret. 21.)
...-'
X-Oo '
""
SetM-me 3 Reactivity of RX. (From Re!. 21.)
ScIH:IM 4 Illkyl .nd wupling.
...
The reaclions between [Tph'JMgCH
J
and a yarielr of alkyland benzyl haJides (RX) an
nOI racile, aOO typically occur al about lOO-14O"C lO give lbe halide dcnvative (TpH]MiX.
Similar dcrivalives are also obtaincd by tbe reactions of [Tph'JMgCHl with trimethyIsilyl
dcrivatives Mc.SiX {X -o. Dr, 1, Ncs, 111e reactions 01 (Tph'JMgCH. with benzyl
halides, PhCHzX (X-O, 8r, l). cleanl)' givc Ihe halide derivativc [Tph'JMX. Howcver,
in addition lo Ihe fonnalion or PhCHICHJ. significan! quantities of bibenzyl
(PhCHJCHJPh) are also produced. Thc ronnalion of bibenzyl is suggestive of radical
pl"O'XISCS in lhe reactioru with RX, support for which n provided by the obse"ation nf
rina opeoiog in Ihe reactions of cyclopropylmethyl halide derivatives [JO). Furtber support
for a radical mechanism in these reaction! i. provided by the relative order of rcactivities:
for Ihe alk)'1 iodides [CH,I, CH)CH1I, (CH)hCHI. (CHJ,CI] lbe increasing order of
rcactivil)' is primar)' <secondary <lertiary, and ror Ihe bc:nzyl halides C.H,CH1X Ihe order
i$ chl oride An allernalive mccbanism for formalion orbibc:nzyl involva
inilial lransmelallalion lo give lbe bc:nz)'1 derivalive by rcaction
wilh PhCH1X. However, Ihere is no evidence 10 support Ihis pathway.
The reaclion bc:twecn [Tp""']MgCH, and labc:Ued uCH,1 demonslrales Ihat, io
addilion lo alkylation (10 give [Tph']Mgl aDd IJCH,CH,), ltK:re is abo a oompelitive
metalhesis process involving alkyl (10 givc [Tp"1Mg
IJ
CH
J
aOO CHJI). as
shown in Scheme 4. Similarly, Ihe reaction bc:twccn and CH,1 abo
rcsulls in a degrec oC alkyl exchangc, glving [TpW:MgCH,. ooncomitanl wilh lbe
irreversible formation or [Tp""Mgl. Tbe exehange of alkyl groups bc:lwccn Grignard
and simpl)' alklyl halKies js nOI wcll documented Howevcr, indircct cvdence has
Po"""
!:leen presented 10 suppon lhe occum:nce of alkyl wilh more complex derivat iVC!
(ll ,J2]. AlkyJ cJchangc bctwocn (Tph'JMgCH
J
wilh LlCHl l i5 reminisccnt of lhe
sigma-bond metalhesil cllchangc procclI rcporled for ("S-C,Me,hScCH
3
(33). huI (htre
i5 insufficicnl informalion aVlilable lO identify whethcr htre are an)' mechanisti<:
smi lafi lies.
JY. COMPARISON OF (Tp" .... 1MgR WITH OTHER ALKYl AND HYDAIDE
DERrv A nYl:S
Thc tris(pyrazolyl)hydroborato ligand s)'slcm ab;o provides a userul framework fo!
stabilizing a series or other four-coordinate alkyl and hydridc derivatives, SlIth &.1
[Tp ]ZnR [J4], [Tp"'1ZnH [lj). [fpR.l]BcR [36], [Tp . I']BeH [37], [Tp1 [l8],
(Tp"' ]CdH (39), and [40]. The isostructural natUTe of (bese complexc$ 15
of importance in providing a mean! by whieh lhe nlrinsie reactivilics or M- R and M- H
bond! ma)' be assessed. For example, since dialkylzine derivatives are two-coordinate
monomcrs, whereas diaJkylmagnesium derivalives are Iypically rour-coordinate polymem
(or $Olvatcd) species, a comparison orlhe reaelivitiesor lhesc complMc:s doc:s nol ne" darily
provide a good indicadon of lhe ;ntrinsie reactivity of the Mg- R versus Zn- R bond, In
contrast, a compari$On of lhe reaetivilic:s of Ihe iroslruclural lris(pyrazolyl)hydroborato
complellCS [fp)MgR and [fp)ZnR provides a much beuer indicalion orlhe inlrinsic
reaclivilKls af lhe respective M- R bonds. Far cumplc, [fp"'']MgCH
1
CH
l
reactl wilh
PhCH
1
1 appraximalely 1(r limes rasler Ihan Ihe correspondng reaelion belwec:n
[fp"'ZnCH
1
CH] and PhCH
1
1. Similarly, [fp""1MgCH
l
reaets with COl al room
lemperature, whereas no reaetion is observcd betwec:n [fph']ZnCH
l
and COl al 14O"C
["J.
V. SUMMARY
In summary, lris(pyrazolyl)hydroborato Iigalion provides a series of rour-coordinale
magnesium alkyl complelles, [fp") MgR, whieh are readity prepared by Ihe reaclion of
R
1
Mg with (Ml[fp"') (M _ K, Ahhough derivalives of lhe less slerica]]y demanding
tm(3,S-dimcl hylpyrazolyl)hydroboralo ligand, [fplolo']MgR, are subject 10 lhermalligand
rediSlribulion reactions analogous 10 Ihat of the Schlenk equilibrium (giving
derivalives af the more Slerica]]y dcmanding Iris(3-I-butylpyrazolyl)hydroborato ligand)
are Ihermally Itable. The alkyl complexes [Tp- ]MgR, Iherefore, provlde a
mcan! by whieh lhe reaelivi ly of the Mg- R bond may be studied in a wdl-defincd Iyslem.
The reaelivi ly of Ihese complexes il Iypically lower than Ihose of Grinard reagenll, a
faelor Ihat has aidcd isoladon of complexes 50t h as alkylperoxo derivalives. Funhermore,
in sorne cases. suth as reaclions wi lh rnethyl ketonc:s, the enolale reaelion products do
nol parallel the alkoxidc products of the corresponding Grignard reaclion,
ACKNOWlEOGMENT
1 wish 10 aeknowlcdge lhe Nalional Science Foundalion for support of lhe work Ihat is
dcscribed in Ihis scction, and also lhe students and postdoctoral a$SOCiales who
worked on Ihis projcct.
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p' m
l3. M. E. Thompson, S, M. lb.X1er, A. R. Bul lJ, B. J, Burger, M. e Nolan, B. D. Slnearsiero, W.
P. Sc:llaefer,.nd J. E. Ik,cu .. , J. A",. CM"'. Soco IOSI:203-21\1 (1\187).
34. l. B. A. Looncy, Ind G. Parkin, J . Chmr. S. .... C_"n. pp. 22()...222
35. R. Han, l. B. A. Looney.loo G. Plrtin,). CM"'. Soc. CItnt. Commll/l. pp. 111- 119(1991).
l6. R. Han 100 G. Partin, fnorg.
37. R. Han Ind G. Parkin, I_g. CItt",. J/:983-988
38. (a) A. Looncy, A. Sakh. Y. ZIIan, aOO G, Plrkin, l _g. Clitm, JJ: I1S8- I164, 19\14; (b) D. L
Reer and S. S. Muon, Org_,lIlllc.l /1:2600-2603
39. D. L RqcT, S. S. Muon, aOO A. L Rheinaokl, J. A"I. CM"'- Soc. IfJ:10406-11>'07 (1993).
40. a) A. J. Caney, N. J. Mincbin. J. M. Patriek. 100 A H. Wbiee, AI/Jf. J. CItmL 36:1107- 1103
lb) A. J. Canty. B. W. Skelton, and A. H. White, Au.U. J. CM.... 40: 1609-1611 ( 198n (e)
G. G. Lobbia, F. Bonati, P. Cecchi, and C. Pettina"" Gazz. CIlim.UaJ. 111:3$S-3$8 (1991).
15
Nucleophlllc Substltutlon wlth Electrophlllc
Organlc, Maln Group, and Transltlon Metal
Specles
GARY S. IILVEAMAN
E!I Norlh A_rka, lne.
IClng o/ huuw. PmlUy/rNlIIio
l. INTAOOUCTION
ThI:: chcmistry described in Chapten 15-21 is categorizcd by he synlhctic producl
In $Ome nstances Ihis ma)' be an ovenimplificalion and he readcr is cncouraged 10 refer
lo he chaplers in Part V for mcchanistie detals.
This chapter will cover he prololypical nucleophilic lubstitution rcactiollJ oC
Grignlrd with organic. main group, and transition metal eleetrophiles. &cause
of Ihe large volurnc oC work, il is virtually impossible 10 be oomprehcnsive. ThercIore, thc
focus will be on lhe application oC nudeophilic lubstitution reactions, what he competina
rcactions are and, ir po$Sible, hol\' lO minimizc 01 take advantagc oC thcsc competing
rcactions.
Allylic substitution resctions [1) will be discussed in he venus SN2' (see Chapler
cydization reactions from di-Grignard reagenls wiU be discuss:d in Chapter 25;
metal-catalyzed reaetioDI \'fill be cow:red in Chapters 29 aOO 30; Ihe ebemislry ofacetykOCll
and Si are covere<! in Chaplen 31 and 32; and while sorne uymmetric reaelions wiU be
discus.sed, Ihe reader il encouraged 10 perusc Ihrough Chapltr 28.
U. ELECTROPHILtc OAGANtc SPECIES
NueJeophilie substitution reaetions using Grignard reagenl$ are ubiquilouS Ihroughout the
literature and have imponanl commerciaJ applk:ations [Eq. (1). Thesc reactions are ravored
>DI
s,,.,.,,,,.,.
by a highly eleetrophilic carbono good leaving groups, forcing condil lons and, in specific
cases. Ihe re/id" or ring ,train eneq!y.

R,MeX +
"

(1 )
1 - IIooIOC'"
te _ 1_.1"" r_ ..eh , halo, .... Of., 11., ar, .tc .
One would bese nucleophilic substitution react ioos 10 procecd wil h invt:rsion of
configurat;on (SN2), bUI occasionally, compeltivc rtaClion! result in retentivo oi
configuration. Typically. he racemic producl is observed; Ihe stereochemical res ults are
discuued in morc dctail in Chaplcl'lI 10, ll. and 28. In additi on 10 hese stcrcochcmical
prohlcms, there are olher potcn!ial drawbacks for he nucleophi lic substitutioo reactioo.
owing 10 compcting reactioos such as MgX- LG cJchangc, c1imination, and 10 a smaller
exten!. eJectron-transfer react ioos.
Thc MgX- LG clchangc react ioo was bricll y discussro in ehapler 2 as an alternative
melhod ror lhe preparalion of Grignard TCagents. The same problcm of rorming Iwo
differenl Grignard Teagenls in solulion also exi,IS here, and polarizal ion or R- LG bond
cnhances bolh Ihe nucleophi lic substilulion as well as Ihe MgX- LG reaclion. A classic
colamplc of Ihe MgX- LG uchange is Ihe reaction or )Eq or phenylmagnesium bromide
wilh chlorororm [2], bromoform E)], or iodoform [4]' The reaclion wit h chlorororm [Eq.
(2)] proo:eeds as prediclcd, 10 give lriphenylmelhane in 7Q....80WI 'Y. yield. The MgX- LG
colchange is (avored with Ihe bromoform and iodoform 10 yield 1.I .2,2letraphenylelhanc
as Ihe final producl [Eqs. (3) and (4)J.
CI,CH + 3
,

"
,
,
" -
(2)
-
(J)
(4)
The exchange reacl ion becomes even more compcti tive when there arc .Ieric
oonstraints and when therc is Ihe polendal for resonanceslabilizcd ionl, as in
triphcnylmethylbromidc [Eq. (5); 5]. The presence of diphcnylbiphcnylmcthane indicales

"
,

Nwlsrlflhllk Sutmlluflotr R'J,II/1".
that Ihere i$ a resonanc:c-ttabiliz.ed intermediate Ihal allows altack al Ihe par/lp05ilion.
as wetl 8J Ihe MgRr- Br e.lchange reaction Ihal, afler hydrolysis, yields lhe e-H bond.
This indicalts Ihat lhere is a dc:licate balance between lhe reaction versus
nucleophili<: Jubstitution.
The secand potenlial problem is elimination reaclkms [Eql. (6) and (7); 6,7). These
reactions Iypically occur when there il a goad leaving group at the ,8.position relative to
an acidie prOIOn, or a good Jeaving group Ihal can undergo Ihe MgX-Lg exchangc (sce
Chapters 11, 12, and 23 for more When Ihere are IwO good Jearing groups al lbe
cr:'p(ni ti on, a carbenoid is fonned Ihat typically results in a linear insertion of a carbon
unit inMead of the typical eyclopropyl Ting Connation [Eq. 8].
ex
"
.. n-C,H.MBr
"

o
(6)
" , j,'
.Jyi . --..
l.::Jl 2O' e
2RCH
l
MgBr+CHBr, ..... RCH=CH
2
+ RCH
l
Br+2MgBrJ (8)
Electron lransfer, Ihe third Iype oC competitive reaction, is not as significant in
Grignard chemistry relatiye 10 organolithium ehemislry. The reduction potentials oC
Grignard rcagcnls are approximalely -2.0 10 - 2.S V (in etherea.l solvents measured venus
SCE) Ihat can undc:rgo reduelion ehemislry iC Ihe organic subslrate can be reduced under
the reaetion conditions. This is particularly troe with carbonyl deriyatiyCl, which are the
focus ror Chapters 17 and 20 [Eq. (9); S). ThereCore, lhe Subsliluenls on lhe subslnl le mx:d
10 be ehosen carefully (Le., the e1tclrochemkally sensilive groups needs 10 be masked or

,
.JY'
el el
/'- .Ir
..
B. Eftect of L vlng Groupe
" ( ,.
--... r+
el
)-t-
e1
M-O el M-O el
(9)
The general etrecl 01 the Jeayjng groups relalts 10 Ihe polarizalion oC the LG-C bond.
Tberefore. a genenll rate of reaelion, based on the Grignard-compatible leaving groups js
as roll ows: halogcn > OR ... SR, CN, . . .. Another issue Ihal was Dot discussed in the previou!
sec1.ion is Ihe protolypical addilion teactions (sec I 1, TIte: leaving group
and Olher funclionality on tbe substnlte must be compatible with Grignard rcagent,
or tbe reaelion rate of nucleophilic; substilution mU$t be mueh Ihan reaction
rate oC tbe addition reaction.
1. Halogens
The halogens will polarize Ihe R- X bond more Ihan moslleaving groups Ihat
wilh Grignard ehemislry. Subsequently, the halogen$ teOO lO be Ihe si le oC reaeliyity for
Slt ... . ". ..
SUOOlil uli on, MgX- X exchange, and so on. For cumple, chloromcthylmcthyl elher, an
asymmelnc el her, can be casil)' modi6cd by simply adding 11 Grignard rcagenl that wilJ
displace the chloride instead of Ihe metho.lY group [Eq. (10): 9]. Competition of a halide
ver1US a Ihiokclyl is shown in Eq. (11) [ lO). Again halide substitution is Ihe predominant
producto
"
C
' ---L , "
, - + RMgX


(11 U
XCl . , . 1

er"
Ph . '1>01, .0 . Bu' , tu'
X.r .el
(10)
(11 )
As e.lpccled, altering a reaclion parameler, such as lempcralurc. can facilitate nucleophilic
substitulion, Oyer lhe olher types of reaclions [ Eq. 11]. In Ihis al - SOOc.
nucleophi lic subsli tution prcdominalcs, wilh ItIc vinyl lIuoride undergoing sub!!tilution
with lhe benzylmagnesium bl"omide, inslcad of Ihe nucleophilic addi lion 10
the carbon)'1 or Ihe olefin.
+

( 12)
By taking adyantagc or lhe organic moicty, allylic (bcnzylic) Ver$UIi vinylie (aromalic).
TCgiosclcc,:tivily can be aooompl ished wi lh more Ihan ORe halide prt:5en1 in lhe orpnic
sub!!lralc [ Eqs.. (IJ) and (14): 12, 1l]. Not only are these reactions regiosclcc.:tive. bul now
thcre is a reactive halidc in Ihe product Ihat can be eonyerted into a Orignard reagenl ror
subsequenl reactions. Occasionally, the scoond halide is uscd for a intramolecular
eyclizat ion reaction (sce Chapters 2S-27).

+
(J
"L
+ RMgX
.I _ CI , I r


( 13)
( 14)
M.dupllllk: BIIIHIINIIcn RN:J1ow
'"
Somc sclcctcd nuclcophilie substitulion rcaelions with halollcns as thc lcavinllllTOup
an: shown in Table l. Intercslingly, few ir any elimination productt .ven: fonncd in IOc
cxample shown in Table 1, enlry 2 lbis is in sharp contrast wilh tbe 1,2-dibromohexanc
cumple [ scc Eq. (6)], which can be att ributcd lo lhe use of Ihe Iess-rcactive dichloride
and Ihe pyran rinll.
2. Alkoxy
Another common Jeaving group 15 the alkoxy group (QR). which can be a cyclized !cavinll
group. sueh as a kelal [Eq. 24], laelonc, or an epClxide (scc Scction Difl'erent
alll:oxy IIrouPS can be uscd for sclective substitution, as shown in Eq. (16) (25). In Ihis
cumple Ihe phenoxy group 1, sclectivcly displaced; ralher Ihan the elhoxy IIroup. In fael,
if Ihere il a 1l00d leavinll group. such as an aactale, l ubstilut ion will prevail over addition
10 the carbonyl or an olefin [Eq. 26].
+ EtMgBr
,


( 15)
,-,
'X'
" , " ,
+ !t""r
OP'XOEt
+ ItKll r




OPh OEt
,"

l' ,-
'" 1 -_o

"-
,-
'"

1

Typically lhe alll:oxy leavin group js lbe beUer Grinard-compalible leaving group
n:lative to other nonhalogcn leaving IIrouPS [27- 29]. In all hree of the folloMnll rcactions
lhe OR i5 the preferred-lcaving group venus the SR [Eq. (18)], NRJ [Eq. (19)], and CN
[Eq. (20). lbe reaction dcpictcd in Eq. (lO) is not a troe competition between Ihe CN
and OR groups. buI, as expeclcd, the OR is displaced lO yidd lhe produe:1 (scc Scction
II.BJ and Table: 3 for mon: information on the CN An intercsting rcaction resulting
in the altoxy displacemcnt and n:lention of Ihe CO) substitutnl is shown in Eq. (21) ( 30).
Hen: the ring slrain and Ihe weak s-o bond facilitales OR as lhe lcaving IlrouP. Sorne
ol her sclcctcd cxamples of pn:ferential OR substitulion are listcd in Table 2.



,
,
"' 1
oc
,
:::-..
(18)
'"
Entry S"Mlr.te 'M",
Proouct
,"
,,,
,"
."
,"
,"
,,,
,"
10"
ex
"
O "
1"+ " " t.,.. ~ n O
t .. CI
0,-0
~
"
,
r ~ C l
,
O
"6
"
"h
o
CIJ.y
"
~ ~
"
"
,
0'
"
"
,
Cll.-atHCl
"
0"
,
"
,
1- CH . I"'.Pb,O
~ . 2 equlv.l ent. or Crllnord r.o,ent u.ed for tb. reoetl.n.
t . I .. ctlon cerrled out ot _ 10C.
C. Corraeted TI.ld be d on 45\ roe.vored .tartlna .. torlol.

"
O
.-0
.v,
Yicld f%)
"
65 - 12
63 - ..
..
71 - 7$
"
"
20 - 57
,,'
"
'"
Tibie 1 Seb:lcd Eo;.",pIa ot C-O Bond Clava..,
Enlry Substllltc RMX P d ~ Yield (%)
,"
t - (CH.'.Cl
S] - 10
~
(CH.'.OCK,
'"""'
( 0I, ) .5a1.
~
~ I I ~
(CII, I .UCH,
..J
'"
."' ..
, .. ,A
10" . A


"
- ')--c-/
. /
I - C. "s.
r-'
50 - 90
, \ aI,C.H,
. \

I

"

,
"
1-.
. -C.H,
,
41 - U
CII,e.".

CII,CII,CII,CIi,

,
Iqulval.nt. oC Gr 1lftard r .,,&nt
,
Equlv..nt 01 CTI,nard lo u " to .bltraet ti alcoholle H
+ EtMgBr

Ar - Ph, 4.CIPh, 4-CH b
51 -10 ,
(19)
PhOCN + R'MgX
1'_
PhOH+R'CN
ti . '2 , )'iel"
(20)
p' m
'"
+ R'MgX

(21)
3. M/scellaneous
Other Icaviog groups IC$S sucx:essful, owiog lO inlufficienl poi_matico af lbe e- LO
bond, or becausc competilive reaction! predominate. A 800d cumple for competitive
resClions ia the cyanide (CN) lcaving group wbich. under tbe righ! conditions, is ao eIJectivc
leaving group [Eq. (22); 39]. Use oribe lame SUMlrate fram &j. (22) with Ihe correspondina
organolithium reagen! (RLi) results in addition lo tbe eN group [Eq. (23)].
"
r
+ 2
1
K&X

(22)
,

"
I
"0

(23)
, ,
I
I
Other examples of he cyanide as a Juving roup are shown in TabJe 3 (cntries
1e cbcmisuy shown in Table 3, entry J, indkatcs Ihat nOI only doc:s nuclCQphilic
substitution of a Ihiocyanale group displace tbe cyanide 10 {orm a thioetbcr, bul an extra
equivalen! or CHJMgl results in addition 10 lhe aldebydc and lubsequent dehydrolysis 10
yicld the final producto Typically additioD 10 the cyanide group is oompctitive, with
nucJeophilic substitution resulting in a miXlure of reaction produClS.
Mercaplo leaving groups, luch as SC,H, or SCH
J
, are elfective, especially whcn a
cross-coupling calalyll, such as NiQ(PPh,h. is u5Cd [Eq. 4S]. Iu eXpecled, an

NI Cat.
(24)
episulfide is susceptible 10 nucleophilic substitution becausc or Ihe ring Slrain, as well as
because or Ihe polarization or the C-S bond [Eq. (2S); 46]. Note thal in Ihis eumpk [Eq.
(2S)) eilher lhe allylic anion has rearranged or there is a MgX- LC exchange rollowed by
an St<2' reaclion (see Chapter The s-s bond or disulfides can be reduced by Grignard
reagents lo give Ihe expccted thioethers [Eq. (26); 47]. Otherexamples ofsulfoxides., sulfates,
and arylsulronic leaving groups are given in Table J (_ enlnes 4-7). Enlries ti and 7 are
'"
Enlry Subslrale
'M'"
ProdUCI Yioeld (%)
," ?'H.
.<>
..
,
," (CH,OI .CCII
0"'Br
(aI.O) ,c{ '>
..
,
c(;
,"

CH.".A
"
o"
(QI,CII111SO.
lfHCl

10 - 7!i
lf",
n
,"


SO - 51
I

- " ,
O-Q
(lr"IBf

"
:-.,. I S:-.,. I
"'r
,
"
!
"

, .. -

+ PhCHO
(LV
"
:-.,. 1 : :-.,. '
O""'ar

I '
"
"-
, "
,
+
0J

,
.qllhd.nu ., Cr1lnard n t
particular])' inlcresl ing becausc of he proposed pyridync intermcdiate that forms aner a
M"'- S(QlPh uchange.


C, F sSSO + C,H J MgBr ..... C,F ,SC
6
H J + e,H .se.H J
"
.....
"
(25)
(26)
..... ftO ,Ik. S"tuJ>'ltMclJt "urW..,.
C. Hucleophlllc AromatIc: SUlNtltutlOf'l
Aromatie 5ubstitution reactions are typically earried out in high yicld uling metal-eatalyzed
croSS-cQupling reactiofU (see Chapler 29) [48-50). lo particular, biaryl lUctioDS an:
difficult 10 oblaio high yield without a metal cataly!t. However, Ihere are some
non-mctal-catalyzed coupling slralegies Ihat can rcsult in highyiekl reactions.
Onc of he more sUOO"SsCuI biarykoupling reaclions 'Nas developed by lhe Mycrs
group, using ou.zolinc lo activate an orIllo- or a para-learing group, such IU metbol)' [SI ;
Eq. (21)]. Recently, Ihe Mycl"J group has adapted Ihis mcthod lo makc chiral biaryl (Table
4,entry 1). Thi! melhod is also clfective wilh primary, secondary, and tertiary alkyl Grignard
reagenUi ($Ce Table 4, entries 4 and 6).

(27)
The MiraDO group has modified the modcrately IUccessrul ester activation or In
ortlro-leavi ng group by usng a bulky 2,6-disubstituted phenol for the esler functi onalily
[S9; Eq. (28) and Table S). The problem encounlered wilh lhe previous work [60,61) was
Ihe competitive addition reaclion lo lhe carbonyl of Ihe ester, resultin in Jow 10 moderale
yields Use of a (- .. entho1ty as the leavio roup. wilh ao ortho buJky esler
activalin roup, resulta in hih yields (80-90%) or bioaphthyls, wilh an opdcal yield of
grcaler Ihan 97"/. (see Table S, enlries S and 6).
(28)
The same philosophy or usin sleric bulk has had sorne moderale success when a
bulky kelone is u$Cd as an activatina roup (see Table S, entires The kavina
roup can have a drama tic effect on the yield, and FUJOD's sludy indicates Ihal
-OPh;;a. - S02CHJ >-SOl Ph>-SPh >-5CHJ' As Clpected, lhe para-positioo is 11110
activated [Eq. (29)), with a similar dependency on Ihe leavin roup (see Table 5, enlries
14and IS).
+
"
+ ...

(29)
,
p' m
'"
T,,*,4 Ou:zolinc Act ivation fo, Aromatic SUMtitution
Eo<ry Submale RM,x Prodl,lCl Yio:!d ("lo )
-t-
-t-
-Sl-
- SI -
I

,
."
/ '
-(
"
-,
"
"
,
"
"
I
"
\
"
-

,/

,"
,
SO - 6O
\
,
B<N,
.+
-f-1
,
--h
. -,
,
R'Q
," ..
;+
H.r
.'+
."
."
"
,l
'-")
,
" I

LJ
Ir Q
'-',
,,,
"
-, /
I
/',

"
"
-h
" ,
..
C .. ", inwd
'"
T.bIe.. Conlinucd
Enlry Substrate
RM'"
Yicld (%)
'y;
,
"
,"
.,.
~
Tibie S Bulky ArollUlti<: Elle!' or K d O ~ AetivatOD
Entry Substratc
RM'"
Yiekl (%)
."
,"
6
..
~
~
,-
I
."
6
,-
I ,"
"

,-
I
I
>.

'"
T.We S (ConlinuedJ
Entry Subotrate RM,x
<
,"
6
I
,
r
I
~
.<
>'
,
."
,
~
>'
I
~
I
~
~
r
~
- ,
,"
- O<

,
"
,
Hentloyl -
,
,
"
,
,
"_nlh)'l
r
\
-
- ,
.<
."
\ h

, ,
,
"

Henoll,,!
,
)-
9
. 0<
6
,"
>'
"-
I'roduct
r
~
I
~
,
~
>'
I
~ \
-
\ /.
J" , \
,
\
Kenthy i
>'
~
I
'"
~ \
-
h
r \
-
~ \
-
\ /.
\
h
00
O \
;....
9
O
>'
"-
>' ~
I
"-
~
I
Yield (%1
"
"
"
"
( ' 7 u)
"
Conllnud
T.!M 5 (Conlinued)
Entry
."
,,,
10"
11
H
U"
Un
1'"
u"
Subslrale
0)1)
"
,
I
I
I
/.
u; - C,K.O
Le - eH_SOl
u; - C,K,SOl
t.C - C,K.S
t.C - CH_S
'M",
~
~
."
6
I
~
"
1
~
~
I
P r o d ~
I
')1)
,
I
~
/.
~
I
Yield (%)
..
"
..
..
"
"
"
Use of e N or NO) as lhe Qn/w.aclivaling grOllp gives moderale yields (50-80%) of
the producl [Eqs. (lO) and (31)), bUI does nOI worlr. wilh aryl artd lertiary Grignard
reagenls [67- 71). For t he NO!-activating group, the reaction , aClllally an
addilion reaclion. and lhe isolable intermediale must be oJ:idized bad 10 Ihe aromatic
product o
,
I I
'"

I
',-
,/
.... '

l . 1MtX. TH1. lsoe
20 10 J
Do Epoxlde (Oxlr.M) Al", OIMn/",.
,
I I
(30)
"'1
'"
,/

(31 )
The reaction of Grignard reagcnls wilh epoxidcs, al finl gJancc, appeal'l lo be an effeclive
method for a two-carbon homoligalion. However, there are severa] compet ing reaedons
t hat limit the use of this method. Thcse deleteriou, reactions are formalion of halohydrins,
rearrangements, pol)'Tmrizalion orthe epoxide, and in asyrnmetric epoxides, regioseJect ivi ty
!SuC!o
The formation or halohydri n wa, obscrved early on in Grignard reaelions with
epoxides [Eq. 5.72). Approaches 10 eliminate halohydrins I S the fi nal product includc
removing the diethyl ether and going to higher temperature5 [Eq. (33)] or by adding reater
Ihan 2 Eq of Grignard reagenL The excess Grignard reagenl should react wilh the
halohydrin t o give the desired proouet [Eq. (34)).
,
6 + CH,CH,MgBr
,
6+ CH.CH,MgBr
lt,O, 40
0
e
..

"
e,R"
10C
/'"'-/'-..
----.,. /'0-../0 .... "

(32)
(33)
(34)
The rearrangement oC an epollide 10 an aldehyde or letonc is c.a talyzed by Lewi,
acids Jueh as MXl [Eq, (35); 5]. Afier the Grignard reagent addition to Ihe
Ihis will re5UII in lhe hydrollyl gooup and Ihe R group oC Ihe Grignard being on the same
T.Ye6
Entry
,"
2" , "
,"
."
,"
7' , , e
ScICClcd E .. mplco of Ourane Readionl
Olir.n.e
,
D.
,
0-
,
,
RMoX
OK.(CK,),OK,Mlar
"
-
,
.,
6
CH."":,

e.".",1:
"
"
Producl
CK.(CII.) .CII,otI

I

,
Yjeld (%)
'0 - ' 2
"
"
"
"
n -

T.bIe 11 (Cont;nued)
Enl ry Oxi .. ne
."
-
RMIX
"
,

Prodoo
o
o
-
, <
c. Peunon ol .!1n.Uon lo. !1nal produet, Ir, lor E-Ia_r .nd
KII ror Z.1o ..... .
Yield ( %)
"
carbono Al lemalivdy, Ihere can be a hydride, alkyl or aryl1,2-shirt Ihat will yield lhe same
producl [Table 6, enll)' 6) [73.74].
+ 11&1" 2

(35)
Epoxides are u$ed in numerous induslriaUy importanl polyrner and coatng
applit:alion5, whereu Grignard reagents havc bocn mcd as anionie polyrnerization calalysls
(see Chapler 3 4 ~ Therefore, il is nOI surprising Ihat polyrnerization can occur during lhe
reacl ion of an epoxide wi lh a Grignard reagenl [75]. Obviously, Ihis polyrnerization or
oligomerizat ion readion is at the expense or lhe dcsired product [Eq. (36)].
In general, Ihe Grignard reagent will attaek IIIt most elect rophilie carbon Iroll.S lo
the epoxide functionality confirmation (see Table 6, entries J 6 ~ However, the
regiO$electivity for asymrnc:tric epoxidcs is nol straightforward, bccause bolh 5terie and
clectronie elfects are .trong. In sorne inslances.. Ihe slerie elfectt preclude l he Grignard
reagent frorn approaching he electrophi lic cenler. Sorne sc:lected examples are shown in
Table 6.
The Durst group has taken advanlage of these competing reactioru (halohydrin
inlermedialc, Lewil aeid-catalyzed rearrangemcnt, and regiO$electivily i" ucs) lo forro

V 1. n-' ''''!.
...
7. e
,
2.
,.

.-
I

>-
<"
/-
I
'"
- ar,l ....
Srherm I
<"
f'1
'"
'"
a'
-,
.,
<"
I
"'-
x - CfI"O
,.
Ya" to
2!>C
'----",
Scheme 1
bcnzoeyloalkenols (Sclw:mes J and In Scheme J Ihe rcgiochemislry of he eventual
hydrollyl group js dependenl on Ihe reactjon condillans [&4,8S]. Schemc 2 shows a drastic
in rcgiochcmisl ry bctwccn when MgBr
1
aOO an organolighium Teagen! are
combine<! Ilnd use of only the organolithium reagent. Presumably. Ihe di lfercooe is Ihe
propo$Cd Grignard intermediale. which allows for compJemenlary chcmimy.
111. ELECTAOPHILlC MAIN QAOUP SPEctES
A. Pot.nU. 1 Problems
As mentioned earlier in Sc:ction TI.A nucleophilic substitution rcactions using Grignard
reagcnts ate favored by highly elccl rophil ic centers, goo<! leaving groups. and forcing
condilions. Tite same competing reaclions Ihat werc discussed earlier (see Section
II.A)-MgX- LG clIchangc, elimination, aOO undesired electron transrer reactions-still
apply. Another consideration ror the main group (MO) electrophiles is whelher the reaction
is thermodynamically favorable. In genera1. l he MO elemenl musI be more eleclTonegat ive
than Mg, which means Ihat albli (group 1) and alkalinc (group 11) eart h melals are nOI
very efl'ective electrophilic ccnten for nucleophilic subslituli on. An exccpt ion lO Ihis
slatement is Orignard rcagc:nt reaclions with Be eloclrophilic ccntera, because Be is slig.hlly
more elcctronegalive Ihan Mg (Eq. 86]. l nleI'C!llingly, Ihe insolubilily orlhe by-product
MgXl can shirt an unfavorabk e<uilibrium 10 Ihe desiml product, whieh implics Ihal
non polar solvenu, sueh as heplane or loluenc:, may be advanlageoul 10 drive (hese
reaeli ons 10 complelion.
BeCI. +2RmMgX -o RISc + MXCI",
The MgX- LG exehangc: reaelions are difficull 10 conlrol, bec;aU5e grealer palamation
orlhe MG-LG bond favon bolh nudeophilie 5ubstitution as well as exehange.
As CJlpc:cled, slcrically demandin compounds will readi ly undergo lhe ellehane reaellon
[Eq. (381; 87]. This typicaUy kads 10 Ihe formalion of an MG-MG bond (Eq. (39); 88).
Ir lhe MG- MG bond is weak. Ihen HIO can add lIero" Ihis bond durina Ihe hydrolysis
slep, resultin in 11 complicaled product distribution.
- "
",1 _, ,
-
(38)
-
"
\ ..... CL

" \
"
Reduetion by lrander, Ihe thin:! Iypeof compctitive reaelion. is more prevalenl
ror main group ehemislry relative to the previously discussed organie chemiSlry, bul il is
nOI as significanl relalive 10 lransi (ion metal chemislry. An cumplc of a reduction reaelion
is shown in Eq. (40) (89].
Q , () /0 /

c{ I ...... I ......
(40)
The leaving group also has a subslantial on convenion 10 the desired product,
and commenlS from Sect ion 1 liso apply 10 the main group elements. The dilference in
the reaelivily of the leavin roup(s) enables Ihe enemi!1 10 ralionally synlhesize miJled
aryl- alkyl dc:rivatives.
B. POWfiti.1 Solutlon. lo Mlnlmlz. Competlng Reactlon,
As menlioned in the orpnic sc<:lion (Scction 11), adjuslin the or Ihe
leaving group will relat ivc reaelion rates of both nudeophiJie substilution as wcll
as MgX- LG exchange. The MgX- LG exchange 15 a problcm cspocially wit h group XIV
and XV elemenls. Therefore, a significant amount or effort has been expended on seJection
or the leaving Corriu's group has taken advanlage or catechol- germanium
complexes 10 gve high yiekls or lelraalkyl or letraaryl germanium compounds [Eq. (41);
90J relalivc 10 oca. [sec Eq. (39)J, which givcs significanlly lower yields owing 10 Ihe
formalion of digermanium compounds.
1('"
h
"
o . ...I ...
/o... ,
1
e
K, + <C C,H,MgSr
(4 1)
Alternative lcaving groups. such as lhe general elass ofalkoxy groups [Eq. (42); 9 1]
and mixed halogen- alkoxy or amino (Eqs. (43-45); 92], have also been uscd wilh similar
results. Ir an excess or Grignard reagenl is uscd, Ihe final produc1 is lhe trialkyl or lriaryl
phosphinc. An elcctrophilc with a chiral c:cntcr and 1eaving groups wilh differenl reactivitics
allows for asymmelrie synthesis [Eq. (46); 93]. (For general chiral phosphine synthesis sce
Rd . 94.)
(42)
" /
,-,
l \
+ 2 CH.MgBr

\ /
,- ,
/ \
(43)
(,_el + RMgX
(, .
,-
(44)

I
,
"

I
+ RMgX
I
11 = 1'
-=1'
(45)
I

I
"

"
"
S/"'-n
""
o
\
~
1. Ir.nhylKe1r
If
~ __ L
/'
l .
CH10II/H'
,/.
~
-
' -.
,.
~

I
'"
> 94 'ee
(46)
Temperature is anothcr imponant parameter that can improve the yield of
nucleophilic 5ubslitution by suppressing the competitive reactlons. Inlerestingly, 10'"
lemperalure can be usa! lO selectivcty make mi:ted aJ kyl or aryJ compounds [Eq. (47): 95J
This can be an effective one-pot synlhesis lo make a chiral. albeil raccrnic, phO$phine.
"
I
"
1. _7I
o
e. I , K,X
I
P
l. 25C. I lll&X
"
I
p

I
"
(47)
~
~
Solvenl is anolher key paramcler that can have an effecl on Ihe COUI'$C of lhe reaction.
Nonpolar 5Olvents, such as toluene or heptane, faci lilale nucleophille subslilution. and
these are typieally added lo the elheral 5011I1ion$ ( IClrahydrofuran (THF) or diclhyl el her).
These solvenls do nOI cffectively sol llbilizc MgCl, thereby minimizing lhe k", i!
acid-calalyzed reaedon! as ",el! as sorne cxchange reacl ions. Note Ihal thcse solvents ",ere
iniiallyadded lo irnprove phase splits, cspeciall y ",ith THF.
An nteresting wlvent effect (Scheme J) ",as obscr\'ed by Okhloby1oli n {%] and latet
by Bro",n [97]. In both cases Ihe use ofTHF ratncr than dict hyl elher allo",ed the complete
alkylalion or a grOllp XIII subslrale, ",hereas Ihe diet hyl ether react ion did nol go lO
cornpletion.
( CII CII )
R,TIX
TlX, + 3 RMX
TIR.
(CII CII )
R,H
BX. + .. RMSX
[ K,BHMsBr)'
SdWrM 3
~ '"
, . EJtamples and Appllr;atlons
a. Group x/u
AII of the elements within Ihi s group (Le., B, Al. Ga, In, and TI) undergo faciJe nueleophilic
iubsli lulion wilh Grignard reagents in moderale 10 higb yicld. However, al lernalive. more
onomical, synlhelic roules are Iypically use<:! on oommemal K.Ie, esper;i.lly for
.Ikyl.luminum derivalives [98]. One major oommemal use of Grignard reagenls wilbin
Ihis group i5 lo make lelraarylborales [99].
Inilially. 50dium lelraphenylborale was use<:! as a quanlilalive analylical reagenl 10
pn:dpilale group I elemenls [100]. This inilial use was moditied lo pn:dpilale group I
elements [ 100]. This inili al use was modified to pn:dpilate and remove lllCs radioaclive
w.sle [101].
Tbe developmenl of cal ionic catalysts necessilated lhe developmenl of unreaC1ive
reunleranions. which Iypically bad becn PF; and BF . Unfonunately. a ~ can be
transfern:d from eilher of Ibese counleranions 10 a bighly reactive cationic calaly" (102).
An initial n:sponse was to use Ihe letraphenylborate as a counterior, which eliminaled Ihe
nudwphi lic F- problem, bUI bad lhe problem of ekctrophilic addilion 10 Ihe aromatic
ring [103). A solulion lO Ihese problems is fluorinaled tetraarylborates that prevent
nucleophilic atlack of he ~ anion as weU as electrophilic a<klilion lo the aromatic ring
[104-107]. Slructurcs I aOO :z (1 05), are sorne eJlamples of Ibese reunleranion!.
,
,
r-'
,
,
I
. ,
,
",
\
""
.,
",
Other uses for tbe arylborates are UV cal ionic cure [108, 1(9), bi ological aClivi ty as
fungicides (structure 3) [110), and marine anlifoulants for nylon fisbing nets (sl ructuce 4)
(111]. In the UV calionic cure, !he reunleranion forms, after photolysis, a $uperacid
intermediale that c a l a l ~ e s an epoJtide or vinyl ether polymerization.
Sorne cumples of nuclwphilic 5ubstilution of Grignard rcagent s wilh group XIII spccies
are shown in Table 7.
b. Group XlV
The organogroup XIV spccies (Gc. Sn, and Pb) are Iypic:ally preparcd from Grisnard
reagenlJ in high yicld and are arsuably he larsest synthelic commercial applicalion for
Grignard reagents. 80th carOOn (sce Section 11) and silicon (sce Chapler 32) are discussed
."
'"
T.bfe 7 Sclted Eumplet al Group XIII Elcctrophilco
En!ry SlI bttrate RMX ProdLK;t Yield W.)
1
"
I "
"
"
,

CH.CII.ll&lr
~
.... ""'
..
lA , , ..
~
~ B ... Cl
" JI
I .. 1
,

-'
,
.-J
1
,-o
,
' \::
..
-
..
a,
10 " .
101 NaBF,
"
,
9
' ,
..
s .. BF, C.JI,Mllr
.. I
"
~
I
, C,I "
Ale l.
0-"'
"
!.
l;j"-f);
.. \ ,
COIII"urd
Tibie 7
Entry Substr.'c RM,X
7', '"
GaCI. t5'
"
I
(;rNI
le . .. .
Inel.
,'. H
TIX. ....

,
.""tvd. nu of RII&X.


equlnl ... u of 1lII&X
<. l oC tH&I .
T. ble 8 Selected Eumpla of Group XIV Electrophiles
Entry Substrate
-,
KM'"
CII , KX.
CII.at. IIX.
C.". NX.
e,N, NII
SI/N .... .,.
Producl Yicld (%)
-O
-
"
Cf
Ff
(j'"-
" \ .
"
TIR. 'Cood. Yhld'
PrOOUf;t Vicld (%)
10 U
I " ..
GeR. 69 17
Tlble 8
Enlry
....
5
u

,'lO
7" tU
1
1U
IConlinued)
Substrale
KM'"
[(C.H.),ln),O CI ..atCII.Na;ar
(C.K.),SnCI
\ -O- ,Ir
O /, Na;
(CI.).SnCl
InCI . d'"
SI\CI.

"
A. 2 equlvd ... u of Gr 11lUlrd u ..... t .
. """lvd ... t. of GrI,lUIrd ,,_,_t.
C. J """lyolonta of GrllftOrd r_,.et.
D. 2 """IYolonto ef eth,t ehlorlde .
Y"ld (%)
(C.H,),lnCH.ca.cK.
,-o/
O )r. 1.
"
'JI
...... sn ..
..
Q,"O
O '"
"htlh ,.1.1.1"
"ht,h ,.teld"
, ,
70 - lO
"
and Iram-eslenfication reactions. Oraanolin species are u5ed for chemical Yapor deposition
(eVO) on window gla" 10 achieve a low-erniMivily Ihal prevCflts reftected heal from leaving
Ihe house [1 19].
The majar use of organolead was telraelhyllead, as an anliknock for ga$Oline (Table
8, entries 9 and 10). However, Ihis addilive has been banned for enYironmcntal reasons.
Oraanogermanium has niche U5CS in lhe field of matenal.s and, apin. these compounds
are Iypically made by lhe Grignard synlhetk: route. Sorne sc:lected synthelic examplcs are
shown in Table 8.
p' m
( . GrQIlp$ XV and XVI
Nucleophi lic l ubst ilut ion reactions procecd in moderate 10 good yields for Ihe gmup XV,
(N, P, As, Sb, and Oi) and XVI (O, S, St, and Te) ela:lrophi les. However. Ihe compclilive
reaction of Mg.X- LG exchange is more prevalent rclalive 10 the group XIV clernents. This
exchangc reacl ion typically leads to lhe ronnation or an MG- MG bond [ see Eq. ()9)).
Sorne e!fampks of suco:ssrul nucleophilic substhUion reactions are shown in Tables \1 and
10 [sec also Tables 2 (C-O cleavage) and 3 (C- S cleavage)].
Frorn 11 cornrnercial slandpoint, the preparation of phosphorus speces consumes the
largest volume of Grignard reagents in this set ol elemen!s. Although t here are alternative
reactionl for thc preparat ion of phosphines, luch as hydrophosphination [ Eq. (48)], the
Grignard reaction il slill preferred when Ilcrically hindered phosphinel are desired
(Scherne 4).
PH, + 3 CH, _CHR - ~ ' ~ ' ~ ~ ' - ~ P(CH,CH,R). (48)
These phosphines are Iypically used as ligands for catalylic reactions such as
hydroforrnylation. hydrogenat ion, dimerization, and ot her metal-catalyzed react ions. Other
uses for t he phosphorus denvatives are Wi Hig chemistry (vitamin A and E). phase-t ransfer
calalysis, epoxy cunng, eXlractants, and agricultural and pharmaceutical intermedia tes.
An inleresting example of an ext ractant is n-OClylphenylN,N-diisobutylcaroomyl
methylphosphi ne oxide (SctH:me 5) ( 48). This nuclear Cl lractant can concenl rate nuclear
waste by up lO 10" and Dr. P. Horwiu from Argonne National Laboratories "Ion a IRIOO
award for Ihe development of t he TRUEX process [1 47). Monitoring the reaction by
IIpNMR indicates hat nucleophiJic substitution occurs lint. followcd by proton
abstraction tO form Ihe anion {148].
..
,
pe l, -+ J
0 ~
0-
9
----------
'b
O
PH, -+ J
Sc""me ..
Although Grignard reagcnlS are used tO maltc ot hcr organo-MG pccies of group
xv and XVI Ihcy are typicall y smallvolurne, valueadded products, typically used in
phannaceuticals, evo precursor!, and ol her niche applicat ion$.
IV. ElECTROPHILlC TRANSITION METAL SPECIES
A. POle n"el Probleml
I n addition to tOe previous roncernS that were discussed in Sect ions 1I and 11I (MaX- LG
Clchange, undesired elcclron lransfer ructions, and unfavorabie ela:t ronegalivity or the
dect rophilic elernent). transition melal aklyls can undergo . and p-climination react ions,
Tibie 9 Selecta! Eumplcs or Group XV EJectrophiJes
Enlry
I ' ..
lA. "'
s"S
,' ....
A, 1U
SUMlrale
"


lbel,
RM,x
1IM&1. I! -
C,M,.C,M.QI,.
C.M, . CH,CH,.CH,
...... ( II.r),
RHX -
.U"l . vhyl ,
_r_tl", U" .
1. (CH,).QlCl,-SO"C
2. 2 CH,Klr,OoC
+
'&l,
"'"
A. 1 oqulv.leat. of Crl,nord r o.,ont.
l . 2 oqulvolont. ot Cr ltnord r o.,ont .
C. HKPA addod to tha r .. "tlon.
ProdLld

' ""'---
--' ,-
I
,
,
..
-'-./
O
+
'G\),
Yield f %)
26 - IS
50 - .0
"
n-u
"
U -N
ti - .5
'"
TIbie JO $eleclro Enmples o/' Group XVI Eleclrophil"
Enlry Subslf1lle RMX
5 .. CH,I
2" I,S, C. ". II&I.
o
s,"
:"
... '
r;]i"
1.
4'"
2 CICII .OCII. Se("" r ).
s'"
h .. MI. .... M,I.
,'"
>o,
"
C." . ... lr
7'"
h, tr,
C. ". M,lr
,A, ...
5o(O)CI.
C. H.M&X
" ..
RH&X, -
C,". C.".
,
M,"
9
ID'" T ... (CII , I.S ICI

1 ,qulv.l.nto . 1 Crllfto.d nt .
ProdllCl
C'y'
U -
IC.".I).
o
t.,. '
.-,
b
S.(CII,OCII,) .
M'M

(C." ,S.J,
(C.K,),S,Y-

\
,
",,51 -O-
\.
Yield w.)
53 - 60
"
13 _ '2
.0 - 90
"
" "
64 - 10
"
>
"
ortllo-melal1ati on with aryl groups, rearrangement, and rcaclions. With
all of these al ternative rcaclions leading 10 products, il is no wonder Ihal
very few u-alkyl and a-aryl metal oomp(exes were made before 1965 [149].
The and reduction chemiSl ry i$ parlicularly prevalent in the early transition
metals (groups JU- VII). Sorne exarnples are shown in Eql. (49-S 1) [150- 1 S2]. Along wilh
p-elimination, Ihese dclelerioUll rcacli ons are the major relson for poor 10 rnoderate yields
(2<HiO%) in early transilion metal chemistry. It has bccn suggestcd that MgX, acls as a
Lewis acid sile hat will promote the reduction of Ihe transi tion metars ollidalion slate
+ C.H .. M,CI
Sdltme !
vel , + 4
'" _ _ n . J
CJ ' _I - 501 .. )
,
"
,-
" ""
V ..
JI. _ _ 100. 1
(110 p _II-.J
d"--' --. VCI. +
,
't- .....
""y"
o e ....
", _ _ n.s
(-1 ' _1 - S20 b)
+ C.H.,M Cl
Nb(O)CI. + CH. MeCI 'c',.
- 'Nb(O)CI.
10 _ 71.1<1
Cr(OC(CH.J.). + 4

(49)
(50)
(51 )
S/1Ywm1Ul
4[Mg(R)CI(THF),l + 2 [ZrCI ,(THF),l - ZrR, +
(52)
[Mg(THF).IZrcl.l + 3 [MgCI,(THF).J
[ISO). Recent work does indi<:ate that MgX, will transfer a halide to a transitioo metal
al lhe of letraalkyl-M [Eq. (52); 153.154].
The unfavorable electronegativily issue refen speci fieally to Ihc early IransilK:m metal
elemenls. espeeially the group 111 (Se. Y, aClinides, and lanthioides) elemenu. The more
clectropositive elements fonn an cquilibrium with Grignard reagents. giving the other
altcrnalive reaetions a chance to oocur, resulting in poor yields or the desired produCI.
t1-Eliminal ion ;s probably lile mosl common decompos;t;on pathway for transition
melal alkyls and, again. is very common ror the early traosit ioo metals. groups III- VII
(Eq. {53); 149,155- 157]. In faet, ir Ihe Grignard rugenl is a precursor 10 a volalile olclin.
sueh as 2-melhylpropene, then an Molefin can be carried out 10 give an
CplM(alkyl) (halide) derived from Ihe oonvolatile olcfin in high yield (Eq. (54); 158).
<Q( /'
@
c.",o"''''-'''''I
'- .
"

&7
\/"
_. .,'f-"
"
(53)
(JO .......

t. e ...
.. "
(54)
AJthough <I-climination is nol as common as 1-climination, it will typically lead 10
a metal carbene that is highly reactive (sce Chapten 18 and 21) [Ec. (55); 159]. Inlercstingly.
in lhe same paper, products consistent w;'h aromalic C- H activalion, orl"o---melallalion,
is observed (Ec. (S6)] resulting in a low yield of Ihe desired product.
IICI L

-

"-
(55)
1
-
p' m

,M)
Rcarrangements are common in tramilion metal ehemistry, and ji is nol within 1M
scope or thi.o discu$llion lO cover Ihis topie. However, man)' of these rearrangements (N;Cur
lO nerease Ihe eleclron densi!y on lhe metal center. An cumple ol Ihis coneept ts addilion
or aUylie Grignard reagenls 10 a mClal-c::cnlcred clectrophile. Typically an "J-complcl j5
formed, presu!Tll.bly (rom tbc o-bond, (ollom by coordination of !he olcfin
as a nbond, which is bcUer rcpresentcd as an "l-<:omplcl[ [Eqs. (57- 59); 160-162].
/\-"
el el
(RhCI(P( 'Pel,),].
."
"
z. ",Ir I


o
, .
4-
_, t ..
_A--_ .... _" _. ),-{
l--
(SS)
(59)
An ntcrestina competing rcaclion (addition 10 a cyclopentadicnyl ring) was rccently
reporta! by BickeJhaupt [&. (60); 163). In Ihis reaction, a bulky dication is rorme<!. by
Ihe addition of phosphinc ligands. Ihat does nol stcrically allow Ihe Grignard realcnl [O
approach lile 1'010 cleclrophili<: ocnler. Subscqucnlly, a Cp ring slippage occurs as Ihe
Grignard reagent adds 10 the nog. forming an "l--complcl.
p' m

regl,),
c9{/<
'/,


,
...... . _zco e
-

\

\

(60)
l . Potentl, Soluuonl 10 Mlnlmlz. CompeUnt A.eetl_
Decrcasing Ihe salvcn! polarity 15 an clfectivc strates)' 10 decreasc Ihe amollo! or MgX- LG
cxchangc and reduclion react ions. Two potcntial are a decrease in the
IOlubi lity of MgX'THF .. or a shift in lile Schlenk equilibrium (see Chapter
Sub5cqucntly, Ihere are no Lewis acid lites in soluli oo Ihat could catalyze lhese competing
rcactionl. For cumple Ihe addi lion or tolucne as a oosolvcnt can takc a rcaction Iha!
predominately undcrgoes reduction [8(W.,see Eq. (SO)) 10 yicld Ihe nucleophilic . ubstituti on
product [15"1.; Eq. UI).
Nb(O)CI, CH,MSI
C,II
I
Q1. CH Nb(O)Cl
- - - ... .
(CII,CH.l,O
(61)
Thc Schlenk equilibrium ma)' play an importan! parl in hese rcactions. as implied by lhe
comparison or Ihe rcactions of (C. H,CH}Mg (Eq. (62)J versus C, H,CHJMgO [sce Eq.
(49)] with vcl. [150]. In faet, di organornagnesi urn reagents are commonly used nstcad
of Grignard reagents lO cont rol the e:lehange aOO reduetion reaclions [Eq. (63); 164J.
Interestingly, sorne groups have made he diorganomagnesium reagent in si tu by using a
diounc-THF solvenl system that will (orm the diorganomagnesiurn reagenl aOO prccipilale
MgXz ' dioxane [Eq. (64); 16:5].
--_. (C,H,CH,l.V
VCI, + 2 (C. H,CH,),Mg
TI(OC.H,), + 2 (C, H,),Mg

(63)
(64)
Burn, and Buehwald talle advantage of the fact hat dioxane will preapltatc
MgXl 'dioxane 10 drive a group 111 nucJeophilic substitulion 10 compJetion in yjeld. grcater
NucllDphlllc Sub.mutIon " .. ,Noo"
Tablc: 1I (Contnued)
Enlry SUMlrale
". (OOT)ZrCI.
c9? ,...Cl
,'"
n

RM'"
. -
CH"QI.CH,.

""
.C<
"1 Cl
).
"
"
A. 2 equivalante 01 Crilnard rae,ant .
'.ZI'(g;rf)
cti( ..",Cl
\1)'
laaetlon earrlad out In taluena. by addlt l on .
C. 4 equivalante of Cr l ,nard roa,ont .
D. OOT - crcl ooctatatrano.
C. E mpl of AppUceOfl.
Yield (OM
"
..
"
Sorne selecte<! eumples of nueleophilic subslilulion for Ihe transition mctals are liste<! in
Tables I H4.
tnterestingly. mixtd alkyl or aromatic-halide complexC! ean be made in good yicld
ror Ihe carly Iransition metal elemenls (se; Table 11, enlnes 2, 3, and 8). Howcver, as
mentiontd carlicr, the rully alkylattd or aromaticsubstituttd species typically ve tow 10
moderale yeld, (se; Tabie 11, entries 1, 6. and 9). To oblain good yelds of the fully
alkylalcd or aromatic-Iubslilulcd species, precipitation or removaJ of MgXl is required
(se; Table 11. enlries 4 and
The oommcrcial applications 01 the organomctallic specics are typically in the arca
of calalysis (se; Chaplers 33 and 34) and preparalion of precursora lor ehemical vapor
deposition (201). An cxample 01 the .yothetic usefuloc:ss of Grignard reagenl! is
demonstraled in the preparation of the new brecd of melalJocene catalYl1 that are used
lor polyolefin production (Scheme 7) [106,2Q2,203].
Chemical vapor deposition applications range from lhe semioonductor-mK:roclectronics
induslry, lo Ihe coalings indust ry (or wear resi slanoe. A significanl ponion o(lhe precursors
are made by nueloophilic substilution rcactions wilh Gngnan:! reagcnlJ. The organie
Table 12 Sda:led Eumples of Group V . 00 VI Elect rophle:s
Entr)' Subslr.te RM.x
Yicld (%)
"
e l
,
.. ,.,I"
e l ..... l ......... el
V,'

17 _ 4.
/',,-
I_v_V_.
TH, 111 el
/


I
\
"
"
le,."
IIb( O)Cl. aI.",1
aI.Mb(O)el.
"
"
I ,
CTCl ,'"' ,

"
( e,K, ) CrCK. (10) I
eoo.! yhU"
\
P(aI, )
...,......- P(aI! l ,
1".....-

' ( CII. J.
I "
"
moicties modify the transition metal so il will have the desired propertics. such as volatility,
appropriate dccomposition temperalllTeS, and so forth [5ee Rer. 201 for more cntena].
V. SUMMARY
In general, nllcleophilie substitut ion with Grignard reagents can be an ef!'cctive synthetie
tool. However, there are a mullilude of competing reaction! that need lo be minimiud to
obtain salisfaetol'} yields.
One or Ihe Ir: ey faetors for yield improvement is to precipitate or remove MgXl from
solution. Thi s can be accomplished by goi ng to leu polar solventa. such as heptane, or by
rorming insoluble complexes. sueh as MgXJ' dioxane. Potential explanations for this ef!'cct
are remo val or a Lewis aeid, shifi in the Schlenlr: equi librium, or the change in salvent
polarity that alfects the nucleophi licity or the Grignard reagent.
Typical reaction parameters, such as tempenlture, addi lion rale, mass transIer, and
such, can also help eliminate Ihe competing reactions.
By making the elcclrophilic ocnter more elcclropositive through modificali on or Ihe
leavi ng group(s), nllclcophilic subslilion can be racililaled. However, slerically demanding
elccuophilic ocnlcrs withoul an open coordinalion sile should be avoided.
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16
Nucleophlllc Addilion lo Unconjugaled e e
Multlple Bonds
PHILIP E. AAKITA
El[ Agri, S.A . PfaLlir , F,anu
l. INTRODucnON
This chapter is dcvotcd 10 be general subject or nucleophi lie addition reaclions orGrignard
reagenl, with unoonjugated alkenes and al1r.ynes (i.t., isolatcd carbon-carbon doublc and
triple Rea;tions of Ihis 'ype iovolvng metal cata!)'s;s are discusscd in Chaplcr 29.
The use of nucleophilic addition reactioru 10 unconjugated olelins and alkynes for Ihe
.ynlhesi. of uymmeuic producu is revicwed in Chapler 28. Reactions orGrignard reagcnll
with oonjugated alkcnes or alkynes (ineJuding conj ugation wilh carbon-<:arbon double
bond carbon- hclcroalom multiple bonds, and aromate systems) are diEll55ed in Chlpler
19. NOI included are discUliSions ofhydromagnesat ion (see Chapter J) (1). Also nol nelude<!
are " Barbicr
H
(i n situ) type rcacti ons that may alJO involve an inuamolecular
magnesium-ene rearrangemenl.
There are several reriews covering various aspecU of lhe generallopic oflhe addilion
of Grignard reagenls 10 carbon--carbon mulliple bonds. HiII (2) provides a mechanislic
analysis of inlramolecular rearrangemenll. Pnuad and ?inai [3] rOCU! on Ihe synthetie
possibililiC!l of the addition of Grignard reagentl to i$Olate<! multiple bonds iD functionally
substituted compoundl. Thc addition of Grignard reagents tD carbon-a.rbon multiple
bonds has also becn brieDy remwed by He (4).
11 . FACTORS AFFECTlNG THE AOotllON OF AM"X lO UNCONJUGATEO
c-c MULnPLE BONOS
Grignard reagen!! are generally nol very reaclive toward i$Olaled carbon-a.rbon multiple
bond!. Thcre are, however, several faelon, bolh steric and eleclronic, that can enhancc the
....
precursor! for chrysanthemic acid ( 22; Eq. (5)].
X"
'-..,-..

(SI
Thc presence ofan elect ron-rich group(-OR or NR,) in he allylic position C(lntributes
10 tlNl reactivit y of Ihe double bond toward Grignard reagcnls. Thus, aH,! and bc::m:yl
Grignard reagcnts rcad!,. add lo aJlyl alcohol [23,24]. Phen)'1 Grignard reagenl rcacls
wilh 1,1 , 10 givl:. after workup. ethyl 3-phcnyl propionate. in 74"1. yil:ld
(2S; Eq. (6)] .
. "
...
+
HIPA. tact" THl,
2zOC,

(6)
Allylic Grignard reagents al50 add toallylic and propargylicamines. bu! he mctallatcd
amine funct ion islc$.5 elfective Ihal lhe comparable metallated hydroilt)' funclino in dire<:ting
lhe course of Ihe reactioo [26].
VI . "DDITION TO ALKYNES
A. Tennl".' AIII}'.,..
Rcaction of simple terminal alkynes DormaJly kads 10 transmetaJlation (27]. Howevcr.
sub$tituted pmpargly alC()hol IUclS wilh cyclohuylmagntsiurn bromidc 10 givc, ancr
IUrrangcmenl, lhe subsl iluled aliene [Eq. 28.29].
.'.
r
(7)


' " )'ldcl
B. Inlfl'n,1 Alkyn
IntramoJecular cydizat ion has bcen obscrved for the addition of a Grignard reagenl acros!
an internal alkync [ Eq. (8); 30).
p' m
Rn/"
4. C. He, fflUuur TongbDo 8:62...{,6 (l987); C. A. IQSI(J): 2235Jp.
5. B. J. Wakdield, Compounds of lile alklli and alkaline clrlh rnelalJ in orpnie .ynlhcsiJ..
CMml.my. Perpmon Pn:ss. Odord. 1982, Chap. 44.
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, . W. Oppolzcr. R. Piueloud. and H. F. Slrauu. J. A", . Chem. StJ<. 1().l:6416
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Schomburg, A"". CM",. p. 11 76
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16. J. F. Normant.OO A. Alc:nkis, Sy"rhtsis Po &41 (1981).
11. E. A. HiII. J. O. g""omn CMm. 9/ :123 (1915).
18. E. A. Hill an<! M. M. Myel"$, J. Org""omt'r. CMm. 17]:]
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4/:1191 (1976).
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22. H. lchrnkuhl and K. Mehlcr, ,("". CMm. p. 1841 (1978).
23. H. Felkin and C. Kaescbcrg, TtlrOMdron Lm. p. 4587 (1970).
24. H. G. Ri<;MY, Jr. and C. W. Wilkin$, Jr., J. Org. Cltmr. 4J:S027 (1980).
25. S. Chattcrjce aOO E. Negishi, J. D. g. CM"'. 5O".l406 (1985).
26. H. G. Ri<;hey, Jr., L M. MMe$. M. S. Dornalski, W. F, Eritbon. and A. S. Heyn, J. Org. CItem.
46:J773 (198n
27. L Hcslinga, H. J. J. Pabon, D. A. Va n Dorp, R . Tr(1lJ. Chint. P"ys Bas 91:287 (1973).
28. T. Mukaiyama aOO K. Ka"'a!a. CIrr",. Lm. p. 758 (1978}
29. T, Mukaiyama and K. Ka"'a!a, p"u Appl. CI"m. 51:1337 (1979).
JO. H. G. Ri<;hey, Jr. and A. M. ROlhman, Trlr"ltMrOll Lm. p. 1457 {l968).
J I. Y. bhino, K. Wa kamo!o, and T. Hir;uhima, Chtm. II. J :76S 11984).
J2 H. G. Richcy. Jr .. W. F. Ericbon. and A. S. Heyn, TrtraltrtirOll l-rll. p. 2183
'"
Recen! Te$O:arch has dcah wilh Dew substrates [Eq. (2); 11] or Dew Grignard reagents
[Eqs. (J) and (4); 12,13):
tI CM)-CH.CH"9lr, nlr
21 11. ' 11
2


eH 2.e .C-CIIOH-CH .CIi-CH J
1Me
1
yldd 55S
25 CII
2
wCC1CII
3
JwCH,J-CHOH-R'
)'1.1011 82_90$
(2)
(J)
(4)
Applicalions were dcvcloped recent1y 10 address this problem for he fields of
pharmacculicaJ [Eq. (5); 14] and pesticide chemistry [Eq. (6); 15].
1) C,HSf'lqlr.

2) 11"/11
2
0
11


"\i\
AI"
!''''l

CH
2
-CH_CH,
(')
(6)
With organomagnesium oompounds prcpared fmm allrlie or propargJyic halidn. Ihe
reaction takes placc readily and no enolization or reduction is observcd [Eqs. (7) and (8);
16,11]:
R' -ellO
1 )

HCaC-CH-CHOH_R' (7)
tH.Cli
2
55_(,4"
1) (CH1'2C,C'C"98r

eH}
HC aCi -eIlOHJ:H_nC JII7
"l
ylel 76S
(8)
In contras! with organozinc compounds. all yli<: Grignard reagents orten react wilh
kClones in an im:vcrsiblc manncr [IR). Thc: samc resUlt5 are obtaine<! wilh organomagncsium
For example [12]:
""
(16)
Occ:asionally. Ihe reaction belween an amide and a Grignard reagenl may give a
terl iary amine. U$Lllting from Ihe allaek on Ihe inilial inl ermedi ale by a sccond mole of
RMgX. Eq.
"'"
1I. ..t_lfl It Ml , -
, -
,
,.
1t..t.;11t )2 - !lN9x
"".

The reaetion or carbon and Grignard reagents inil ially gives a sal! or a carboxylic
acid Ihal i5 able 10 reae! fLlr!her with lhe reagen! [Eq. (18)):
"",.
<>-e.o
..,.
,


( 18)
In practice. the sccond reaeti on is slow. even al room lemperatLIre. and can be
e:sscntiaJly d imi nated by poLlring lhe Grignard solLl lion onlo finel y powdcred, st irrcd, solid
carbon dioxide (dry ice). After hydrolysis, a carboxylic acid is oblained (27,28]:
<>-e.o
1 ) C,H
S
-CH-CH-CH
2
I'1qCl
2J H*' H
2
0
CX:H
1
I:I9Cl
" .A.A

C,H
5
-CH-CH-CH
2
vhld 7S"
( 19)
(20)
yidd 5S1'
Whcn lhe reaction is realizcd wilh a large eXte$$ of RMgX and COI gu, tCrliary
alcohols wilh Ihrcc idenl ical grOLlps are i$Olalcd aft er hydrolysis. 5L1eh alcohols may also
be obt ai ned with dialkylcarbonalcs or phosgcne.
111. NUCLEOPHILlC AOOITION TO C S BONOS
In addition 10 he general reviews lready ciled, Ihe esscnlial rcsults oblained in this area
before 1975 are sLl mmariz.cd in a French revicw (29].
A. T1llolletone,
Usually, this reaetion leads 10 a mixtureofscveral prodLl cts A, B. and C [Eq. 21 29,30]:
11 R"'<IX
,

, "
"x,..

, "
V
RS"
(21 )
,
,
-
Saturated Grignard reagents. other Ihan melhyl, lend 10 give mOltly reduclion ,
wilh a preference ror Ihiophilic product e when addition OCCUrl. Methyl magncsium
bromide in THF gives thiophilic addilion C, whcrel5 the methyl magncsium iodide in
elher gives carbophilie addition R. Vinylmagncsium ehloride adds lo sulfur or lo carbon
ac.;ording 10 Ihe Ihiokelone; allylmagnesium bromide or allenylmagncsium bromide give
only Ihe carbophilie addition product R, which partially c)'CHus under Ihe reaclion
condilions.
B. Dlthloelllrs
Since 1926, il has bcen known Ihat Ihiols could be rormed by reaclion or 2 mol al" RMgX
wilh 1 mol of dithioester [3 1]:
(22)
2) "20
A delailed 'Iudy or Ihis reaelion [Eq. (2); 32] has shown Ihal two principal producls, D
and E, may appear, aecording 10 Ihe R group or RMgX and Ihe lemperalureorlhe reaction:
,
"
RKqX/THf
,
"

.'-e_SC"]



"
','
b,
(23)
_lkyl, phenyl
,
,
-
The Ihiophilic addilion D is preferenlial when Ihe temperalure is less Ihan - 11"e and
when R is anethyl or an i50propyl group; .imilar results are obscrved wilh Olherdit hiOC$ten
( 33). Wit h CHlMgBr or CHlMal, carbophilic addition ili preIerential ir Ihe reaction is
pcrformed al 20"C or al rellux, leading 10 Ihe thiol E.
Thiophilic addilion or EIMgl 10 dil hiOC$lers lcads 10 aeyl anion equivalenls Ihal
reacl ""il h electrophilie reagenlS 10 yield 10 dilhioacetail (34). The laller compounds may
be Iransformed inlo Ihe corresponding carbonyl compounds on hydrolysis (&. (24)].
SC
2
H
S
c6HS-CH2-CH2-{- SC2"S
.. '
1) (CH]) 2CH-eHO

21 H
2
0
yldd 901r0
(24)
Carbophilic addilion or prenylmagnesium bromide and olher aUrlie Grignard reagenl$ 10
Ihe Ihiocarbonyl group or dilhiOC$len occurs exclusively wilh rearrangemenl of Ihe aUylie
chain (3S):
CH) s

(CH) J 2C.CH-CH2"'9lk
r Hl fCH) CH)
CH
2
.c-CH
2
'i
SCH) eH]

Finally. the rcaction of Grignard reagen!.! with a dithiocarbonate leads 10 gem-
aminolhioel hen ( 36):
C. Carbon Ollullklti .nd Clrbon Sulllde
The reaclions of caroon disulfide wilh Grignard reagenls IIppear 10 be allogclher si milar
lO Ihe corl'C!lponding react ioll$ of caroon di oltide. Thus.. il is possible 10 prepare dilhioadds
[37- 39; Eq. (27)];
S.c.,
(27)
This melhod may be uscd lO prepare dit hioeslcrs by Ihe following scheme [ 4(}-44; Eq. (18)]:
SC. S
.... '

,.,

yhlda 4B_BS,;
R alkyl , aryl
(18)
Suc:cessivc react ioll$ of Grignard reagents with carOOn disulfidc, l'lrilluoromethylsulfonyl-
benrol riuole, and amines., atrord Ihe corresponding N-mono and N,N-disubslitutcd
thioamides in goo<! ylclds (4S). Wilh carOOnyl sulfide tbe reaction leads 10 a mixture of
RCOSH and (RhCOH ( 30).
IV. NUCLEOPHILIC ADDtTlON TO C=N BONOS
A. Akllmlnel Ind Kettmlnel
Imines arc analogous to carOOnyl compounds in Ihcir react ions with saluratcd Grignard
reagenlJ [46] t he addi tion rcaction competes with enolization and rcduction relclion!).
Wilh imi nes that contain no Cl hydrogens and with sat uratcd Grignard reagenls wilhout a
p. hydrogen. the reaction prooecds in Ihe usual way (Eq. (29)],lclldi ng lo secondary amines
after hydrolysis:
1) RflqlC
129)
p. m
sahs [72,73) and from N-alkoxycarboxylpyridinium salls (74,75].
o "".
Ck"
20' C
Q
, Cl -
o

.
o
(35)
oc_o
"
deynyl, . .. yl, " .
vinyl OS) , ylelda
" .
C.c-CH.CH-CH 20-1'I1P (74)

yldd
C. Imlnoelh. r nd Imlnolhloehr.
An N-aryl iminocther lIndergocs a reaction wit h 2 mol of RMgX 10 Icad directly 10 a
JCC()ndary amine with IWO idenlical groups [76; Eq. (36)).
1) 2 II-<:K-<:K-CK Kc;JB.. II ..cK-CH-<:K
2
+ 2 . e H - NK-lH1H-CH. CH2
2)H / HO 65
,
(36)
yleldt 60-74,;
Wi th an N-tosyliminoether [55], it is poui ble 10 obtai n a primary amine [Eq. (37)]:
,.
"
2 II MqX
l'
"
N. / NHJ
'"
,.
'rOt-N.l-OC
2
N
S
N
2
KJ: - 1I

'rot _NK-C_1I

(37)
"
H/H
2
O
,
"
H/H
2
O

"
yle1dt
Reactions belween substiluted atlylic Grignard rcagcnts and cyd; iminothioet hers or
iminoethers becn tried with 2-methylthio-2-thiazolines or 2-oxazolincs. Inlerestingly,
only one addilion-climination reaclion is ob$crved [77; Eq. (38)):
O
1",

",
11 (CKl'2c-CH..cK2HqCI
(38)
yldd 81,;
Similarly, symmetric or unsyrnmet ric disubstituted dcrivalivcs of 1,3,4-lhiadiazole are
prcpared (78) from 2,S-bis(methyllhio}- I,3,4-thiadiazole or S-melhylthio-I.3,4-t hiadiazol-
2( 3H}-thione [ Eq. (39)):
D. Imlnoc:.rbon ....

=r-"" (39)
yleld 8S"
Wilh hese compounds, Grignard reagenlS may reaet with he slIbstrale hree sequential
limes al the same carbon [79; Eq. (40)):
p' m
tI 3 CH2-CH-CH2"98r

2 ) 1\""2
CH
2
-CH-CH
Z
e ,HS-HHJ:-CH Z-CH..cH 2
tH
Z
..cH-CH
2
yi.ld !HS
(40)
As CJlpe<:ted, N-tosyliminocaroonates lead 10 N-tosylamines Ihen lo primary amines
HlN-qRh [ 55].
E. ClrbodllmlcSel
Even by lIsing a large cxccss of RMgX (R_saturatcd, phenylic or allylic group), only
1 mol of RMgX adds, leading lo amidincs [80: Eq. (41)]:
t I

C,HS-N ..
(41 )
yilld' 82_901
V. NUCLEOPHILlC ADOITION lO Cs N BONOS
Generally. Grignar<! reagcnt5 add once 10 a nitrile rollp [81- 86]:
(42)
Hydrolysis of he adducu produces ketimines. which are instable under he reaction
conditions and rapidly hydrolyze 10 ketones. Tbc use or benzene, contaioing I eq. or tlher
as solvent, !cad! 10 ncrease<! yields of hIODes, compare<! wilh mlu]l! in diethyl ether [81].
Also. Ihe addilion of Grignard rea!:nls 10 nitri les ma)' be ealalyzed by Cu' sahs (88).
Tandcm alkylalion- reduclion of a series or nitriles, by alkylating wi lh Grignard reagents,
rollowed by reduction with lithium- ammonia alrords the corresponding branche<! primary
amines in reasonable isolated yiclds [89]. By lJ5C or a large or RMgX, a tworold
reaction has OfXlIsionally been oblained, producing primary amines [90; Eq. (43)):
(43)
Similar resu!ts are observed wil h Grignard reagenls and !l-alkoxynitriles (91] and also
wilh allylmagnesium bromide and various nitriles [83,92].
VI . NUCLfOPHILlC AoomON ro C P OA Cas- P BONOS
Even in recen! reviews, the addition or Grignard reagents lo these runctions has nOI been
reported [93- 95]. However,an eumple wilh an organolilhium eompound [94; Eq. (49)]:
Ar-C.'
1) CH) L1 , THr, _7S'C

2) "20
al10ws a rorecasl or Ihe possible behavior or organomagnesium derivalives.
(44)
'"
REFfRENCES
1. V. Grinard. C. R. xi. Po,u /J0: 1322
2. M. S. Kharasch ar>d O. Rcinmlllh, G,ignara RNlClilms "1 No",,,e IQ/IIc Swbs/unn's. lIall,
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J. B. J. Wakeficld, Organot1tt,,,t. CIIe"" Rn , I:JlJ (1966) . nd rd erenS themn.
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lO. J. L Moreau. Organomelatlic of allma and ketenes. rhc Cheml.m y ..
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11. O. Me5nard and L Miginiac. J. O.glJJwmtl. CMm. <I<IQ;271
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23. H. Xiong aOO R. D. J . Am. CM"'. 5. / 14:4415
24, P. Canonn.e, R. BouJanll"r. lOO P. AnJllCTS. TtITalteJron UI/. 32:5861
25. O. L Comi ru Ind J. J. Herrio;k, UI/. }j:132J
26. R. Polt. M, A. Pt:lerson, and L de Youna, J. O.g. Cltt m. J?:S469
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28. W. H. Miles, S. L In(! J. D. Del R"",rio. TmDhtdr"" Lm. 33:305
29. O, Paquer. B,,/I. SIN. Chlm. F,. p. 1439
30. D, Paqucr lOO M. VazeUl, J. CM"', U(J:. 2H
31. H. Gi1mn, J. Robinson, and W. J. Baber. J. Am. Chtm. SOCo <18:2115
32. L Up'T Ind M. Saquel. Bul/. 5. Ch;,., . Fr. p. 657 (1975).
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35. p, Gosselin. S. Mauon,.nd A. Tm aMdrM Ul/. 19:2711
J6.. K. Akiba. H. ShiraishL 100 N. Inamolo. Bull. 5. CMm. J{NI. J2:1 S6
31. J. M. Bciner and A. Thuillier, C. R.. ArM. &1. Paru174C:642
38. H. WUytllnd K. Koeck, Bull. 5. Chin!. &1(1. <1/;196
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40. K.. A. Jensen and e Pedet$Cn, ArIO CM"'. SeOfld. 15;1087 (1961).
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43. H. Westmijal, K. Klein, 1. Meijer, and P. Vermeer. S,."IMSf p. 432
44, R, S. Sukhai and L Srandsma, S""/MIU p. 971
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'"
,
Nuc'uphNk A) 'ItIon /o e It..,..,./om
46. R. W, Layer, Clltm, Rn. 6J:'89 (1963).00 mc.,UItltS .hc:n:in.
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55. 1". Barbot, Tmallt<f,fIII Lm, .10: 185 (1989).
56. D. J. Harl Ind K. J. Or,. Clrtm. 47:1555 ( 1982)-
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'"
39. G. Cainelli, D. Giacomini, E. Mezzina, M, Panunz:io, 100 P. ZanntoncUo, UII.
U :2961
60. P. L. G. M. Plnunzio, G. Mlrtelli, Ind G. Spunta, J. 0,'1. CM",.
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61. l . Laduranty, F. Barbot, Ind L Miginiac, J. O'(lfIIIlNnt'l. CM",. JJ5:283 (1987).
62 J. Ladurlnly, F. Barbot, 100 L Miiniac, B,,//. Soc. F,. P. 837 (l9a7).
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64. N. L Hob, Comm .... . Ii:$39
65. J. L Robcm, P. S. Borromc:O,lnd C. D. Pouller, Tmolttdron Lm. 18:1299
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67. G. COli n o;" M. Harama, aOO P. Miginiac, J. Orflllnormr. CMm.11/1:275
68. G. Court0i5 lOO P. Miinial;, B,,/I. Soc. Fr. p. 11-395
69. G. Counois 100 P. Miginiac, &11. Soc. Ch;"'. F,. p. 11.21
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71. D. Mesnard Ind L Miiniac, J. Or(lQMmd. CM"'. J71: 1
72 O. L Com;ns.nd A. H. AbduU.h, J. 0'(1, Clwm . .,7,"l1S
73. G. Counois. A. Al Arnaoul, .nd L MilJiniac, Tmtdttdron UII. 26:1027
74. T. R. Wcbb, TtlrlJMdron L"'. 16;3191
75. A. Al Arnaoul, G. Couno;" In<! L MilJinilc:, l. CMm. JJ1:1l9
76. J. Ponxl and L MilJinial;, C. R. Acad. Sel. PlJ'is 27JQ381 (1970).
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82 J. Rabcsiah, BIIII, Soc, 01"" Fr. p. 1440
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9S. A. C. Gaumonl and J. M. t:knis, CIrt",. R!. 94:141 3
18
Nucleophillc Addlllon lo Melal--Carbon Multiple
Bonds
LISA A. MERCANDO
Alr Products amJ CM",lea/, . Inc .. tflltntown, Ptnnsylwmia
PAUL MERCANDO
E/f Alochf!m Norllr AfMrlca. lne., Klng 01 PMl.lSill. P"IrIs)'lvonia
l. INTRODUCTION
This chapter ... ill focus on lhe nucleophi lic addition reactions of transiton metal carbenc
and carbyne oomplues wlh Grignartl reagenh. The synlhesis and $(lmc general reactions
of these carbcne and carbyne complc;I;e$ will be presented. A more delaiJed description of
Ihe chemistry of Ihese complellcs can be found in l he lilcrature [ 1]' Thi5 chapter, althOllgh
nol cxhaust ivc, is dcscr1ptivc of Ihe prototypicaJ nucleophili<: addition reactions of
metal-caroon (M-C) multiplc bonru wilh Grignard reagenl,.
11. TRANSmON MIETAl CAAIENE COMPLEXES
Transit ion metal carbcnc complcxes are describe<! by lhe general formula L.M= CR,R
1

... hefe Ihe carbcne ligand (=CR,R
J
) is booded lo Ihe melal by 11 melal-arboo double
bond. The lirsl tmnsitioo melal carbene complex was reported by Fischer IInd Maasbl
io 1964 (2]. Subsequently, many ot her carbene complexe5 have becn synlhesized by Ihe
classic route or Fischer Ol by new synthetic melhods.
Convent ionally, carbene compkxe$ are grouped into two clnsses: Fischer (2) and
Schrock [l) carbenes. Fischer carbenes may be idenlified by lheir lI[-donor $ub$liluents on
lhe carbene carbon and having lI[-acceplor ligands bonded 10 a low-ol idalion slale,
late tmnsi lioo melal. These ligands may be Ihoughl or as singlel carbenes that donale a
'"
Figure 2
the Schrock carbene carbon, and is a typical reattion observed for these carbene complelcs.
In this specifu: example, an intermediate i5 rormed that then rearranges to produce the final
titanium enoiate complu.
Typicai reactivity of Fischer and Schrock carbene complucs with Grignard ragents
(where the Grignard reagent is acting asa nucleophile) is illuSITated in Eq. This reactivity
is base<! on the electronics and molecular orbital calculations ror these Iypes or complexes
[ 10]. An example from the literature iIlustraling Ihis Iype of reactivity belween a Grignard
Teagent and a carbene complel was reponed by Helquist and co-workers, as shown in Eq.
(S) [11]. In these reactions, alkyl or phenyl magnesi um bromide is added to the calionic
carbenecomplel [Cp(CO}zFe=CHSPhJ[PF
6
]. The result ingproduct is a neutral complex .
.......... -
."oc

Ft
J
.. RMgBr


THF
R. Me. Bu
n
Ph
(4)
(SI
In addition, GladyilZ and co-worker5 reported an example of a Iypical reaction involving
a rhenium carbene complex and Grignard reagents. i11ustr.lled in Scheme 1 (1 2). The
addilion of o- MeC,H.MgBr and mesilyl Grignard reagent 10 [CpRc(NO.ll.PPh
J
)
(=CH)J(PF ,J produocd rhenium alkyl complexes. The sterically crowded mesil)'1 complu
was observed 10 uhibil Ihe presence of rOlomen in Ihe IH_nuclear magnetic resonanoc
(NMR) as a resull oF a Re-C. rotalional 1 . Ihe nucleophi lic
addilion of phenyl Grignard t resulling
in lhe neutral metatlacycle Eq. (6)
Ph

""F. /
OC-Mo +
/ \ J
OC /'")",
M.
PhMg"
'1')'h M.
- -
/ \ -1
OC /'-",
M.
(6)
Grignard reagenls have also becn reporled lo be use<! in the synt hesis of
sorne carbene complexes. For eumple, Schrock and co-workers [14J reporled Ihe
'"
(""
,,.
".
",
o
o
Sdwme I
use of PhMe,CCH, MgQ 10 IIlkylate Re(NArhQJ. resulting in Ihe carbene complu ,
Re(NARhlCHCMe, PhXCH,CMc, Ph). in near quantitalivc yield [Eq. (7)). Anothcr
examplc of a carbenc complex synthcsized usng a Grignard rugenl was reported by
Wcrncr IInd co- workcrs [ 15]. In this reaclon (Scheme 2). Ihe osmium carbene complex,
[(m .. s)Os(=C{NHCH,)(C, H,))CeH,h) , probably res ults from nuclcophilic auaek of he
Grignard reagenl al Ihe iSO(:yanidc carbon atom, followed by protonation of Ihe nitrogen.
In addilion lo he carbenc: compleJ, che bromophenyl oompound.
RMgl
Os-CMe -
Cr-/
CI
OS-C-NMe+
R//
I
R- f'h. 30 %
R_ Me, 23 %
PhMgBr /NHMe
OS= C, +
I"t( ...... / Ph
'"
11 %
" %
75 %
OS-C-NMe

23%
p' m
Table I ROUIQ lo C. rbcne
Slarlin! reagenl
Cp,Tia.
CpWOiCl, R
Cp W(Q)CI,R
Grignard
CH,(MgBr)
Mc.SiCH,MgCI
PhCH,MgCI
Metal carbC'ne
epI TiCH, MgtBr)CI
CpW[ CHSiMc.)O)R
Cp W[ CHPh](O) R
..
, ..
lOb
lOb
'"
was isolated. Interestingly, also shown in Ihis equation is he dilTcrcnl activity obscrvcd,
dependng on Ihe Iype of Grignard reagent used. The rcacli on of RMg' (R _ Me. Ph) wit h
[he osmium isoeyanidc complex produces two producU; howcvcr, he mi,lture or products
is dilferent wlK:n PhMg8r s used. 5yntnel K: mutes 10 carbene complelles can be
found in he litcrature involving Grignard reagcnls aeling as met al alkylat iog agent!
(Table 1) (1 6).
Me O!p, I otI....-
+ 3 Ph
h
Me MgO 1) 40"c
11 _ IOmp.

0 _0,1
(7)
111. TRANSITION METAL CAABYNE COMPLEXES
Transiion metal carbync complexa are describe<! by the general Formula L.M=<: R whell:
the carbyne ligand ( CR) is bonded lo the melal by a melal-carbon lriple bond. Transi lion
metal carbcne oomplellC:S have found numerOU5 applK:ations in syntnetie organic enemislry
throuSh a variety of carbene transfer and cycloaddition reaetions ( 17). In contrast, carbyne
(L"M CR) and vinylidene (L.M=C=CRR') complex.c:s havc fa r rewer applicattons.. in
parl bccau$(: Iheir oyeran chemistry is significanlly lesa developcd [18]. Addition Il:actions
10 transi tion melal vinylidene oomplexes will be: discussed in Chapter 21 . The finl
succesdul synl hesis of a carbyne complex was reported by Fischcr aOO co-workers in 1973
(Eq. 19]. Subsequently. many olher carbyne complelles have been Iynlhcsized by the
classic route of Fischer or by new synthetic methoos (20].
Oc CO
OMe \/
(COI.sM..( BX) X---M-C-R CO [8X;:(OMel]
'>< 1\
(')
OC C
o
M - Cr,Mo, W

X _ aSr,1
Carbyne lipnds can also be: srouped inlo two classes: Fischer and Sc::hrock carbynes.
The metal-carbyne carbon triple bond (Fis. 3) for a Fischcr carbyne eomplex i5 formed
'"
Fleurt J
from lhe sp-hybridizcd 10m: pair elect ron! on Ihe catbync cllrbon, in conjunction wilh a
II-bond from singJy occupied metal-d and carbon-p orbitals and 7f- backbonding from a
fillcd metal-d orbital il1to a vacan! carbon-p orbital. The bonding scheme fOf Schrock
carbynes can be drawn in two ways. dependng on Ihe oxidalion slate of Ihe melal. Thc
lone: pair electron! Iha! I(-backbond from Ihe melal in Ihe Fischer carbyne can be moved
[O an emply -orbital on Ihe catOOn atom. 1t may also be drawn sueh that aH he electrons
come from Ihe carbyne carbono Since Ihe firsl reporto Il:SClIT'(:h in Ihe ficld of Ta nsition
metal carbync complelle5 has grown al a rapid Tale [20]. Howcvcr. Ihere art IIlill many
gaps in Ihe knowledgc of Ihe chtmistry and propcrties of carbynes. Carbyne oomplcllts
can be synthcsized in a variely of ways [ 18]. Thc interesting aspect of these complexcs is
that transition metal carbyne complexes may also reaet in a variety of ways. The
modcs of of carbyne are illuscratcd in Scheme 3 [21]. The lirst four
modcs of reaecivi Cy shown in :X:heme 3 are (1) si mple substitulion of che ligands bound 10
che metal. (2) or reduetion of lile metal. (3) modilicalion or exchange of the
carbyne substi tuent. and (4) transfer of lhe earbyne ligand ( 18]. The last Iwo modcs of
are nuelcophi lie and eleclrophilie addili on atlhe earbyne carbono These modcs
of reaet ivily some of the most cxtensivcly sludicd. The Iypes of nueleophiles that have
been lo rcaet with carbyne eomplexes althe carbyne carbon inelude phosphines.
isonilriles. amines. Grignards, pyridine. halogens. CN +. OCN - , SCN-. OR -, and SR-
(17]. In general, cationic carbync: complexes and neutral earbyne complexes. wilh
clcctron-wi thdrawi ng ligands, have been tlle mosl reactive wilh nuelcophiles. Neut ral.
elcclron-rieh carbync complexes with 5ueh eledrophilcs as H ' and Me ' 10 give a
variety of products. dependng on Ihe involved and Ihe eonditions under whieh
the reaelion! are run (18)' Qthcr Iypes or (eaelions nOI port raycd in :X:hcmc 3
eycloadd lion. alkyne melalhesis, and alkyne polymerizalion ( 18].
11 Substilution olligands
2) Oxidation or reduction of the metal
31 Modifi cation of lhe arbyne lubstituenl
4) Transfer al !he carbyne bgand
SI Addition 01 . nudeophile al lhe arbyne carbon
'1 Addition al ilI'I elbophi lc al lhe carby .... carboo
Sdwme 3
The reaetions of Fischer and Schrock carbyne oompleJles are of interest because they
may aet as intermediates in chemical synthesil. Typical react ivity of carbync complnes
wilh nuclcophiles (Le., alkyl lilhium reagents and alkoJlidcs) are consistenl with
(he elcctronics and molecular orbital calculations for Ihese Iypes of complnes (Eq. (9);
22]. The nuclcophile adds 10 (he carbync-CIrbon, rcsulling in Ihe formalion of a carbene
compleJl. The reaction of a Grignard reagenl wilh a carbyne complex is expected lo
demonSlrale similar reactivity.

(') '"
LnM e Rl

-
A.d., e ..".
Grignard reagents can be used in Ihe synthesis of 50me carbyne complcxes.. For
cxamplc, Chisholm and co-workers reporled a convenicnl method for synthesizing
trialkylalkylidyne tungsten compounds, based on the melalhesis reaction betwccn
alkyl-Grignard reagents and ('DuO), W CR complnes, shown in Eq. (lO) {H]. This type
of synlhesi5 111011'5 the use al a wide variety of R groups: however, it i5 limited 10 alkyl
igands Ihat lack ,6-hydrogen atoms owing 10 ,6-eliminalion reaelions.
,
R_ Bu
Si Me3
IV. CONClUSION
R' - PhCHz
Me:Ja:l-I2
Me)SiOi
z
IMo]CCH''WC
(10)
The rcaetions of Grignard rcagcnts wilh traMilion melal carbene and carbyne
i, certainly interesting ehemistry. HOWeVer, tbere is mueh more enemistry nvolvng Ihese
reagenls Ihal needs 10 be Grilnard rugenl! have bcen uscd lo prepare transition
metal carbene and carbyne oompleU$ [16.23]. Nuclcophilie addilion lo transition metal
carbene oompleJlcs has al50 becn reported in the !erature (12, 13]. The ehemisl ry or
Grignard reagenls and carbene and carbyne compleJlcs remairu a fertile ground for fUlUre
investigation.
REFERENCES
1. (a) J. P. Coliman, L S. Hegcdus, J. R. NOfIon, and R. G. Finke, Pri"ciplu fJIId Applifa/iOlls al
O' gaMtransitlOll Mtlal Chtmistf,. Univc:rsil)' Seience Boa ... , Mili Vllley, CA 1918; (b) R. H.
Crabl lU. TM O' ganQmtlQl!k C/remisl'y of 1M T,OIIs;'iotr Melal,. ohn Wilcy & Son .. New
York, 1988: (e) K. H. DoIZ, H. Fischer, P. Hotrmln, F. R. Krcissl. U. Schuberl, and K. WeiSt,
T,a/t.J"<Hi Aft ral ComplUtS, Verl., Chemie. Wei nheim, 1983: (d) M. P. Doyle, A.
Chfm. Rn 19:348 (1986): P. J. Brothel'J aOO W. R. Roper, CMm. Rn . 88:1293 (1988):
(O M. Brookh.n and W. B. SllId.baker. Chtm. Rtv. 61:.1 1 (1987): (g) D. J. Cardin, B. Cctinkay
M. J. Doyle, and M. F. Lappen, 5. Rtv. 1:fj9 (1 973); (h) H. LcBozcc, D. an<!
P. H. NATO ASI Ser. C(Adv. Met. C .. bcnc Chem.) 169:101 (1989).
2.. (a) E.. O. F;schcr and A. MusOOl, A"gn.'. Chem, 76:643 (1964); (b) E.. O. Fischer ind A. MaasbOl,
A .... CMm. 1",. EJ. Eng/. J :S30 (1964).
3. R. R. Schroc:k, J. A",. CMm. So.:. 96:6796 (1974).
4. J. P. Coliman. L S. Heaedus. J. R. Nor. on. and R. G. F;nke, Prlnriples ami ApplictJliOflJ 01
OrgO"Olrtnuil/(m Melal Clltmistry. Univcni !y Scicna: Books. Mili Valley. CA. 19711.
5. J. P. Coliman, L S. Hegcdus. J. R. Nonon, and R. O. Finkc, o"d ApplktJrio,1J 01
Orgl1Mlratuillon MrltJ/ Clrtmistry. Universi. y Scicna: Books. Mili Villey. CA. 1978. p. 120.
6, C. P. W, M. Milc:s. J. Clwm. 1'4:3l1 (1983).
7. S, K, Zh.o i n<! C. Helquisl. J. Am. CiItm. St>or. 111:8527 (l989).
8. J. P. Coliman. L S. lIegedus, J. R. Nonon, and R. O. Finke, Prlllciplt s '1IId App/ic(J/iOtLJ tJf
O,gono"tJ/Ulrl"" MrrtJl Clrtmutry, Uni versily Scicna: Boob MiU Valley, CA. 1978. p. 131.
9. J. R. Slille and R. H. Orubbs, J. Am, Che",. 5. 10':1664 (1983).
10, (a) R. H. Crabtlft, OrgOllOttl<'ltJlllc Chtmisrry oflhe TrtmSiriOll MtltJls. John Wi1ey &; Sons,
Nc .... Vork. 19811: (b) J. P. Coliman. L S. Hcsedus. J. R. Nonon. an<! R. O, Finke.
ona ApplicoliofLJ of OrgarwrronJilion Mt lol Clrt misl,y. Univcnily Scielltt Booh. Mili Valley,
CA, 1978.
11. C. Knors. O.' H. Kuo. J. W. Lauhcr. C. Eisenbrot. aOO P. Helquisl. O'gtJllO_l/lllkl6:988 (l 987).
12.. W. A. Keil and W. E. 0ladyu. ) :879 (1984).
13. H. Brunncr. A. Wachtcr, 1. fkrnal. O. M. Reisncr. aOO R. J. fkbb, J. O, gatWWWf. Cllem. 143:119
(1983).
14. R. TOll'ki, R. R. Schroc:k, an<! W. M. Davi s, J. Am. Clrml. $. 1U:3367
IS. H. Werncr, U. Wcckcr. M. Schullz. and S, Stahl 10:3278 (1fj9 1).
16. fa) J. W. Brujn. G. Schat. O, S. Akkcrman. aoo F. Bk kclhaupl. Trl'tJhedron UII . 36:3935
(b) P. Lcgzdins, E.. C. Phil1ips. S. J. Rell ig. L Snchcz. 1. TToller.lmI V. C. Vec. O'(ItJ_"",a/l1o
7:1877
17. {a) J. P. Coliman, L S. Hcgcdus, J. R. Norton, and R. G. Finke, ona ApplictJri<NU of
O'ganotromiliO/! Mm Chtmislry. University Boob, Mili Valley, CA, 19711: (b) 11. p,
Kim an<! R. J. Angelic. AIhr. CM"' . 17:51 (,) E.. O. FiKhcr. P. Hofman.
F. R. R. R. Schrock. U. Schubert. and K. Wci!ll. Corbrllt Comp/utJ. VCH Publishcrs.
Nc .... York. 1988.
18. (a) J. P. Coliman, L S. HcgNus, J. R. Norlon. aOO R. G. Finke, alld Applicol<HIJ of
O,gQ/lo"tJ .... il/(m Mrlal CIw",iSlry. Univcrsity Sciem:c Books, MiU Valley. CA. 1978: lb) H. P.
Kim an.d R. J. Angelici, AdI>, Orga_tf. ellem. 17:51 (1987); fe) E.. O. FiKhcr. P. Horman,
E R. R. R. Schrock. U. Schuben. an<! K. Wc;ss. Ca,by'" VCH Publi.hcts,
Ne .... York. 1988; (d) E. O. Fischcr, G. Krcis, C. G. Kreiter, J. Mllc" G. lI ullncr, aOO H.
Lorenz. Allflr ... CMm. 1111 . EJ. &gl. 11:564 (1913).
19. E. O. Fischc-r. O. Kll'is, e G. KI"C ter, J. Miiller. O. lI ull ncr. and H. A .... CMm.
Inl. EJ. Eng/. 11:564 (1973).
20. H, P. Kim aoo R. J. Angelici. Adv. O,ga_I. Clwm. 17:51
21. E. O. Fischcr. P. Hofman. F. R. Kmssl. R. R. 5chroek. U. Schuberl, an<! K. Weiu, Co,by",
VCH Publishcrs. Ncw York. 1988.
22.. a) E. O. FiKhcr, P. Hofman. F. R. R. R. Schrod:, U. 5chubert, aOO K. Wei!ll. CorbJ"'W
VCH Publi5hcts, Ne .... Vork, 19811: (b) 1. P. Coliman. L S. Hcgcdus. J. R. Nonon,
ami R. G. Finke. OIId Applicariaru o[ O'fI<IIIotromiriott MeltJ/ CMm/slrY. Uni vasity
Sciem:c Books. Mili Valley, CA. 1978: (e) R. H. Cr. btm:. Tht O,gollOttl<'fol/ir C/rtmimy of 1M
TrofLJil<HI Mefo/J. John Wilcy &. Sons, Nc .... York. 1988.
2J. M. H. Chisholm. J. C. Huffman, 100 J. A. Klan&. /'alylwdrott 9: 1271
,
19
Nucleophlllc Addlllon lo Conjugaled
Carbon-Carbon Mulllple Bonds
PHILlP E. AMurA
El! ArocNm ARrl. S.A .. Plai.Jir. Frana
1. IHTRODUCTION
This chaplcr deals with lhe nuclcophilic addition of Grignard reagcnt! lo caroon-<:arbon
multiplc bond! (alkenes and alkyocs) con;ugaled with other multiple bond systems
(ineluding other alkenes. alkynes. carbon- heteroatom multiple bond!, and aromalie
iystcms). Also included for oomplcleness are the nucleophilic addition reactions of
organomagnesium halides wilh arOmllK: .ystems (arenes and arynes). Rcactions for whi<:h
he primary emphao;is is on he effect of metal C8.talysis are discussed elscwherc (sec Chaptcr
29). Thc use of thesc reaction! for lhe synlhess of lUymmctric prodUCIS is rovere<! in
Chapler 28. A discussion of nucleophilic addition 10 lI/ICOnjugalcd carbon-<:afoon muJliple
bonds is given in Chaplcr 16. The case or 1,2-addition 10 enones (carbonyl addition) i$
revicwed in Chapter 17. Tb<: rea;tion ofmagnesium rrn:tal with dicnes aOO other eonjugated
olefins is diseussed in Chapter 26. The use of Grignard reagenls in lhe polymeriution of
olefins is presented in Chapler 34.
11. FACTORS AFFECTlNG THE ADDtTIOH
As noted in Chapter 16, Grignard reagents are generally unrea;tive toward isoJaled
carbon-carbon multipJe bonds. Conjullation wilh an adjacenl II-syslem can enhance Ihe
dellTee of reaelivilY, somel imes enonnousJy. Grignards add readily lO enones (a.,fJ-
unsalurated carbonyls) and, Jess readily, 10 carbon-carbon multiple bonds eonjugated wilh
arornalie rings or otb<:r carbon-carbon multiple bonds (1). Allylie Grignard regents ,ive
1:1 adductl wilh eonjugated dienes in the prescnce of lilanium calalyslS (2].
'"

+
The Il:aclions oC quinooe monoketals has also becn rcviewed (Scheme 1) [12].
(U"I.)
Schemc I
(4)
The theoretical study by Khan el .1. [13] 00 the stcreochemistry of nucleophi lic
addition oC organometallic:s lO unsaturated ! UMlrltes can also be applied 10 conjugaled
syslems. OC Ihe three majar factoR alfeelin he onentatino of he nucleophile 10 he
suhstrate (see Chapter 6 ~ Ihe abi lity or Ihe suhstrate 10 discriminatc bclwecn Ihe
nucleophilic and electrophilic charactcr oC lhe Grignard rugen! is lhe ont mos! 5usa:ptible
lO nlluente by conjugalion with an adjacent II'-system. They concluded thallhe aa.:essible
electrophilic lile (Ihe metal) is he soura: oC he stereochcmical preferenoe lor the
electron-rich 01l:6n Tace.
IV. ADDfTION TO ALKENES
A. 1,3-Dlenel
Grignard reagen!! exhibl wldely divergent behavior toward 1,3-dienes, dependng 00 lhe
oalure of the Grignard, the degra: or , ubsttuton or sterie erowdng on the dene (or
Grignard), the reaeton condtolUl neludnlllOlvent, presenee of metal catalysl$. and other
sub$trates. for example, f-butylmagnesum chlodde reaeU with 1,3-butadiene (n the
presencc of CP2ZrCI2J to give S,S-di methyl- I hexene tI ,2-addit ion) in Ihe 8S-/_ yield (Eq.
5 ~ 14]'
(S)
t.2 Addition accompanied by allylic rearrangcment was observed by Langlois el al.
( Eq. 6 ~ 15].
el.",
+
-
'-O
,-(
,
12 , yleld
(6)
In contrast, 1,4-additi on was obtained using butylmagnesium bromide and Ihe
highl y hindcrtd butadiene in Eq. (1) [ 16].
(7)
.,
+ X . ~ I + (!('Cl
." I\:
- -
6-0 , yhld
1.4Addilion was al50 observed for 5i lytsubstituted I,Jbutadicne [11J.
For the extended ",syslcm of Iropone, Ri gby and Wil50n observed a 1,6-addilion
acrou Ihe heJlatriene system [Eq. (S); 18].
"
I
".
(')
I 1 +
-
Fulvcncs al50 add Grignard reagenl!. This represents a useful route 10 subslilUlcd
cyclopcntadicnederivativC1,as the rcs ultingGrignard rcagcnt can reacled further lo produce
other metal cyc10pentadienyl compounds [Eq. (9j 19).
"
"
"
I "
" "
+ I,M
+ O'
(9)
' .
!
{
0
M
h
Mention should also be made or Ihe exlensive work o( calas and co-workers on Ihe
magnesium-induced silylalion o( olefins. Allhough Ihis is nol 51rielly chemislry,
as defined for Ihis volume, Ihe reac1ions he has studied may be vicwed conceplUally as a
rcaction,H namely, Ihe addilion of an in situ silicon analogue o( a Grignard
rcagenl Me.SiMgX aeross a double bond (20].
B. OttI.r ConJugat.cl DI.nn.
Grignard reagents add lo enynes wilh electron-donor substituents in lhe allylic position.
The highly hindered olefin in Eq. (JO) limpie addition of t-bulylmagnesium chloride
[21 ] .
I
I
-
-

\
"
I




(10)
.!l..

I I

- -
-
-
u _ yldd
C. Enon
The addition of Grignard reagenls (O enones has been elltensively studied and revicwed
[6- 12J (see also Chapter Enones can reac1 either as caroonyls or olefins, leading lO
1,2-addilion (lo Ihe carbonyl) or 1,4-addition (lO Ihe olefin; Scheme
,
. """
I

I

W!
1,4'
",
"
"
CH,CH,
" " CII(CB,),
" "
C(CB,h

'"
Se_me 1
Numerous sludies have shown Ihal mulliple reaclion mcchanisms operalc:, and Ihal
a number of ractors, bolh sleric and electronic, nfluence the 1,2-/ 1,4- ratio (6,22].
,.,
relgen!s and polyhalo bcnzenes. Their melhod is ba5ed on Ihe creation and sub5equcnt
capture of aT)lnes with Grignard reagent. (Scheme 3 ~
,
"
.. 'O + Arlf.lr I
. ~
Ila;lr,

The reaction proceeds by (1) organomclallic cKchange. folJowcd by (2) aryne farmalion.
and (3) a regiospecific nuclcophilic addition of lhe Ir)'1 Grignard lo (he aryne. Thesc slcps
can cxx:ur or re<:ur in landem ruhion 10 form from one 10 _IX he ..... carbon-carbon bond!
in a single opcration (33.34). Subsequently, thc method wasexlcnded 10 alten)'1 and alk)'o)'1
Grignards (35; Eq. (13)] and trimethylsilylvinyl Grignards [36].
I
.... "
"
"
.-
+

>-
"
.- .-
I I
>- ~
I
l'
I
:[ (13)
I
J,
I
.-
I
.-
I
.. ..
., '" 7
1d4
Trapping of the Grignard produoxl in slep 3 ($Ce foregoinS) ..... ilh aU)'1 halidc proved
10 be a useful route 10 811)'1-, vio)'!, 1.2-disubstituted arenes (37].
V1. MI$CELLANEOUS
Terminal alkynes lypicaHy umkrgo transmetallation wilh Grignard reagcnt$ 10 give Ihe
corresponding alkynyl Grinard (_ Chapler ~ However, Klcijn and co-worken [38]
reponed Ihal '-bUlylmagncsium chloride reaCle<! ... ilh phenylbuladiyne (albeil in Ihe
presence of Ag ion) 10 give Iheproduclsof 1,2-addilion 10 Ihe lerminallriple bond [Eq. (14)].
13. S, O. Kahn, K. D. Dobbt, and W. J. Hehre, J. Am. CItt;", . Sote. J/ 0:4fi02
14. E. Nelishi, J. Miller, and T. Yoshida, Tr l,wtlrfHI Lm, ]5:3407 (1984).
15. Y. Langlois. N. Y. Bae. and Y. Fall, Ttl,tJlwdron tr.1d: IOO9
16. R. C. Fuwn, H. A. Dewald, Ind R. Gaenncr. J. Or,. Chnn. 16:21
17. V. l. KOIhuli n, J. Gr><. CIwm. USSR (Ena. lranl.) 19:1986
11, J. H. Rilby and J. Z. WilOn, J. Am. CItt;",. 106:&217
19. R. e Fuw n aod O. York, Jr., J. O" . CM", .
20. J. Dunogue$, B. Arreuy, e Biran, R. Calas,lnd F. Pisciotti,J. O'(Jll_I.
21. R, C. Fuson and H. D, Poner, J. Am, Chrm. $,
22... E.- I. Negi5lti, O,gtlflotnclQllkJ In O'gtlflk SylllhrJU. Joho Wiley & Sons. NC"W York, 1980.
23. y , Aoki and l . Kawaji ma. Tt l,alttdrOff Lm. J/ :7451
24. A. J. PealSOn Ind V. D. J. O,g. CIwm. SJ:3395
25, T. N. Danks. D, Rabhil. aOO S. E. Thomas. J. CM"'. Sote. Prrltl" T,QiU. 1:209 1
26. S. Thomas. J. Chr",. Sote. CIwm, C_UII , p. 226 (1987).
27. D. Brya:-Smil h and B. J. Wakcfic:1d. TtlrallttlrOff !.tll. p. )295
28. R. C. Fuson. Adv. 0,,_1. Chrm. / :221
29. G. Barloli, M. Bos<. and G. J. O'g, Clttm. 4H22 (1980).
30. G. BarlOll, M. Rosco, G. ao6 R. o.lponw. Ttlraltt/rOll 40:3437
31. S. Ikntlcy and D. J. Milnc:r, J. CIItm. # 7: 1
32. H. HlrI I nd K. Hama. Ttl,aItt/rOll l', 16:29 (1985).
33. c.-J. F. Du. H. Hin, Ind K.-K. D. N" J. O,g. Clttm. J/:3162
34. T. GhOlh I nd H. Hart. J, O,g. CIItm. JJ:HS5
35. c.-J. F. Du 100 H. Hin, J. O,g. Clltm. 51""31 1
36. T. K. Vioad lOO H. Hart. Tt l,ahtJrOll II. 29:885
J7. H, Han and A. Sudnra. Spuh. COI>IIIfUII. 18:1749
.18. H. Kleijn. el 11. R . Chlm. PayJ- &JJ 100:337 (l98n
39. H. G. Richey, Jr., W. F. Erickson, 106 A. S. Htyn. Trt,a!tttlrOllfl . p. 2183
40. H. G. Ricltey, Jr" W. F. Erkkwn. aOO A. S. Heyn, Ttl,ilMdran II. p. 2187
41. D. J. Nelwn 100 W. J. Miller, J. Chrm. Snc. CIItm. CommUII. P. 444 (1973).
42. F. Wudl, el ACS Symp, Se,. 48/:161 (1992).
20
Nucleophlllc Addlllon lo Conjugaled
Carbon-Heleroalom Mulllple Bonds: 0, s, N
LtONE MIGINIAC
Un/wrslll Franc.
l. INTRODUCTION
Generally, Grignard reagenu are nol lo add lo caroon-arbon double Of triple
bonds; howcver, addit ion 10 these unsaturaled bonds docs occur, espcciaJly when 11M: C=C
or e e bond is activated by conjugation wi lh a neighboring eJectron-withdrawing group
5uch as C=O, C=N, Of group ( 1-6)'
'1. NUCLEOPHILlC ADDITION TO CONJUGATED C=O BONOS
A. Conluglte d AI6ehy6e1 .nd Kel_.
1,4 Addi,ion reaclions (Michael addition) can occur wilh (I,II-unsaluraled aldchydes Bnd
ketones. in oompetition wi l h normal 1,2-addition (Eq. (1)]:
, , I 11 +/11
2

'c I I
'.'
c_c...c_OMqX
. C-C_OK
/ ,

,.,,,
\l. ' li ZO
.L.t-OH}-
",
'.'
.!-c.t-<lfokJX ..!-{-<o.
I I
I I
I
(1)
,.,
... '

lO)
Th!: yiclds are generally increased by proceeding in the: prescncc of CuX (2,17) or CuO
alld McJSiO ([8]. Wit h a lI,jf-acetylenic ester, RMgX (R satUt8ted, phenylic) ives
1,2-addilion prcfcrcnl iall y (19). Also, allenylic [6] and 811yl1c [2,10) Grignard rcagenl,
rcal;!. wilh er,p-unsaturated eslers lo k:ad [O 1,2-addition products exdusivcly.
C. ConJuglted Amlde.
In contras! ",iln conj ugated kctones and esters, Ihe reaction betwcen conjugated amides
and aU Iypes of RMgX procced! throgh a 1,4..addition [1-4). particularly wilh Ihe allylic
(21,22] and allenylic [6] organomagnesim derivatives [Eq. (7)]:
1)

2) 1\. / 11
2

CII
l
-YH-CH
2
..(;O-NIC
2
H, ) 2
CH,-C:II-CH..c1l
2
yhld 6S1'
(7)
Also, 1,4-addition of RMgX 10 a"B-ethyJenic amides followed by a-alkylalion ma)' oonstitutc
a general and cRitiCO! synthclic procedurc: for [he ronnation of tWQ C-C bonds in a si ngle
step (23; Eq. (S)]:
CH)-CHaCH-Co-O
(S)
O. Alkylldene M.Ion.tes .nd Cy.nscet8tes
Grignard reagents give 1,4-addi ti on with these derivat1vcs ( 1-6,24-21], especially with Ihe
allenylic and aUylic ofganomagnesium derivatives:
1) CH2..cH-CH2"9k

2) H*' H
2
0

CM
2
-CH..cH
2
yl eld sos
(9)
111. NUCLEOPHIUC AoornON ro CONJUGAn:O e- s BONOS
OnJy a few slUdies have been made on this reaction. Saturated Grignard reagenls react
with a:,J-elhylenic Ihi okelones (28;9] lo 1ead 10 a mixture or severa1 products. 1lIey
principally resul! from thiophilic 1.2-addi tion, thiophilic 1,4-addi tion, and S-alkylation
(28,29].
l'
"
1)
,

-

(10)
Under similar conditions, no reacljon Is obscrved by using phcnyl, vinyl,
or et hynylmagnesill m bromidcs [28.29).
N. NUClEOPHILIC ADDITIOH TO CONJUGATEO C= N BONOS
O1,,8Et hylenic aldimint$ and ketimines readily rcacl with salll rated and vi nylic
organomagnesium derivatives lO lead lO 1,4-addition products [4.30]; Eq. ( 11 )):
11 lI."9x
(11)
Wilh al1enylic [6] and al1ylic [31,32J Grignard rcagenl$. o:.f.I-unsaturated aldimines give
secondar y amines. resulting from a 1.2addi tion [Eq. (12)]:
1)
,
2 ) M* / HZO
CH l-CH-CK-fH-IfH-CH ( CH) ) 2

yhld u ...
( 12)
However, Ihe 1,4-addilion ofal1ylmagnesium bromide 10 2slyryl pyridine has beendescribed
[33; Eq. (l3)]:
11 Cllz- CH-CMzHogllr

O
: 76145
CHZ...cH-CHZ...cH- CHZ
'Ihld 701'
(13)
V. N!JCLEOPHILtC AOOITION TO CONJUGATEO e 11 BONOS
Tbe reaclion belween O1,,8-uns.alurated ni triles and Grignard teagents \l/as sludied in a few
ca.5e$ (4). Witb <!Jj-ethylenic nilriles,s.aturaled [4,34-36] and vinylic [37] Grignard reagents
lead lo 1.4-addition products:
1I.'...cM..cH-calf ItMqx. 11.' 14*/ 14
2
. J -.,.
19. J. K1ein aOO N. Aminadav, J . Clrem. Soco C P. 1380(1970).
20. J. Munch-Petel"Rn. P. JorellXn. aOO S. Refn. Acro CMin. Scoltd. 1):1955
2\. G. Daviaud 100 P. Migi niac, TrlroMdrO#l Lm. p. 3251 (1971) arw;! Ihcmn.
22. F. Barbot. A. Kadib-ELban. and P. Miliniac. TtuOMdron Le/!. U :SOII9
23. G. B. MJ>l.nso. K. K. Mahalanabil, Z. alld V. Snicci<ul, TrlroMdron UIl.
1/:-4823
2-4. G. Daviaud aOO P. Migi niac. Bu/l. $0(0. Chi .... F . p. 1617
25. G. A. HoImberglnd R. SjOholm, AClo Clorm. !kond U:J490
26. F. S. Proul. R. J. Hartman. E. P. Y. Huang, C. J. Korpica. and G. R. Tichelaar. O.g. S)"ltlh.
CoIl. 4;93
21. G. Daviaud, M. MaUt 8arOOI, and P. Miginia.;, C. R. Arod. Sd Poru 171C:9fJ9
28. P. aPd J. Val1c. Bu/l. 5. Olm. Fr. p. 11Q3
29. D. Paqucr. 81111. Soco Chin! . Fr. p. 1439 (1975) and ",fcfellCeS Ihcrein.
JO. 8. MauzC alld L Migini.c, Bull. Soco Chin!. Fr. p. 1078
31. 8. Mau alld L Miainiac. Bull. Soco Chin!. Fr. P. 1082 (1913).
32. 8. Mauze Ind L Migirtiac, Bull. Sor. Chim. Fr. p. IIJI
33. J. J. Eisch , lid R. L Hl rrel, J. O'flllfl<JlMl. CItmt. 1/:21
J4. S. Wawwnck. J. Am. $0(0.
lS. J. H. Burd<IlaJlcr alld P. Kuralh, J . Am. CMm. 5. S/:J9S (1959).
MI. T. Eichcr aPd S. Bhm. Tt lrohtdron UII. 11:2603
37. T. euYigor Ind H. Normlnl, Bull. 5. Ch/m. Fr. p. 2423
38. S. BlcchcTl aPd T. Wirtk. TtlrolrtdrM uU. J1:7237
or reaclivily art: nucleophilic [9]. and elect rophilic [10] addil ion at lhe vinylidene Cl-carbon
and fJ-ca rbon, re5plively. Thesc modes of reaclivily are disculsed in more dctail bccause
of the inleresting reactivily of Ihe vinylidene ligand. In general, cationie and neutral
vinylidene complexes have becn mort: reactive wilh nucleophi lt'$; anionic aOO neulral,
eltron-rich, vinylidene complexa rt:acl wilh eleclrophiles. Other types of reactions nol
portrayed in Scheme I are cycloaddition reactionJ.
The vinylidene ligand is susceptible 10 bolh nucleophilic and electrophi lic allack;
thererore. Ihese complexo may be useful precurson for slereospecilic organic synthesis.
M olecul ar orbital calculalions for seleclcd organometallic vinylidene complexes have shown
Ihat the HOMO is 25-30'Y.localizcd on Ihc vinyl idene'l ,8-carbon and Ihe lUMO is SO-64W.
localizcd on Ihe vinylidcne's Cl-carbon (11]. Thesc caleulalions have becn supportcd by
experimenlal dala, in which Ihe \"I-carbon is the si lc of nucleophilic atlack and eleclrophiles
add lo Ihe p-carbon (l). Reger and Swifi [Eq. (2)] reported Ihal nueleophilic addition al
Ihe \"I-carbon alom of Ihe calionie vinylidenc (CP(CQ)(PPhl)Fe(=C=CMePh)]OSQ2CF l
produced CP(CO)(PPhl)Fe(CMe CMcPh) in quantilaliyc yield [ 12]. Rcaclivity belwcen
cal ionic vinylidene complexC$ and Grignard reagents is expected to be si milar lo Eq. 2 ~
however, nucleophilic addilions of Grignard rcagenl lo vinylidene complexes were nol
found in Ihe literalUre. The reaction of electrophiles with Ihe vinylidene ligand. to
form carbyne complexes, was reponed by Green and co-workers [Eq. 3 ~ 13].
Electrophiles (R _ Me, CH
1
CH
1
0 H, CH
1
0EI, COBu', SiMel' SMe) added 10 the
anionie vinylidcne Li[Cp(p(OMehhMo( C CHBu')] yielding Ihe mclal-a.rbyne
Cp(ptOMehhMo( CCHRBul
R_ 1'h R_tM yidd_45'"
R .. OiroCH R' _ Me y l ~ d '" SI "
R . ....
R" ... I'h yidd .. 100 '"

RX _ Mol
'''0''" ,.'roO
MoSiO
M.SSM.
R
(2)
(3)
We found only one reponed reacllon bctween a Grignard reagenl and a transilion
melal vinylidene complex. Wiedemann and co-workcrs [14] rcaclcd neutral vinylidene
complexes CIL
1
Rb(=C=CHR')(l", P(Pr'h; R' _ Ph, Bu') with Grignard reagcnts, and lhe
$ubsliluled produels wcre isolated in good yields (Eq. (4)]. The chloride ligand was Ihe
si le of reactivity for tbis complex. This reaction ilIuslrates lhe coupling or an alkyl, arrl.
or vin)'1 groupwilh a vinylidene unit, occurring in thecoordinalion sphere ofrhodium(l).
...
MId .... el"d:
L
H
L
H
/ /
CI - Rh-=-<

... ,x
R- Rh-::-<
(4)
/ R / R
L L
L - PlOf'i)3
R_ Me
R_'"
yield _87
R_'"
R_'" yieId .. el"
R-CH..cH2
R_""
yiad .. as"
R-'"
R' '" BU
yieId .. 87"
111. TRANSITIOH METAL ALLYL COMPLEXES
The allrl group 15 IIn I.lbiquitous ligand, and a wide variely of allrl complexes are known
(15). TM chemistry of allyl Grignard with lransi tion melal catalysts is thoroughly
diseussed in Chapler 29. The lltrl group (CH CHCHi) can bind lo a metal center in
one of two ways: lbe monohapto form (Fig. 21), in which he allyl 15 a X-type (le) ligand,
or he trihapto form (see Fig. in which Ihe an,l i5 a LX-Iype (le) liami [16]. The
rihaplo form of Ihe aUylligand is besl thought of in erm! orl he resonaooe fnrm! indicated
in Figure 3. The trihapto form [{,,'-ClH, )M] also contains rxo-hydrogen atoms and
atoms (Fa. As dcfined by Crabtrec, Ihe carbon-carbon bond. in lhe
melal "J-aJlyl complel are twisted, this places the txa-hydrogcns rarther away rrom the
metal and the tmia- hydrogens doser lo the melal alom [16].
Flpre :z.

... M
Fia;ure J
Figare ..

M
Fipre 2b
'"
'"
T.blr 2 Solvenl IkpcrKIcnt Rc:sults fo' Grignard Rcagcnls
NucIeopllik Reaction oonditions Vield W. l Ratio 2:3
!'IIMaD EI,O,O"C ro RT. 1 h.
"
70:30
PhMg8r CII , a "O"CIO RT,1 h.
"
55: 45
MeMgS. nlF. O"C 10 RT. 1 h.
"
30:70
McMgBr CIl , a" O"Cro RT, t!lr
"
20:1\0
MeMgB. EI , O,O"C 10 RT. 1 h. 90 70: 30
(Vinyl)MgBr CH,a"O"CIO RT,2 Iu .. 55: 45
(Vinyl)Mgll r El , O. !re 10 RT. 2 h.
"
75:25
(Allyl)M Dr CH,a"O"Cro RT. 2 11. 58 40:60
Table 2 liSIS lile results found fo r the Grignard investigare<!. In diet hyl trher
5Olulion. Ihe Grignard reagcnts prererentiall y add 10 Co l [2], whereu in tetrahydrofuran
(THFl and other solvents C-4 addi!ion dominares [3]. II was also reported that the addit;on
or complClti ng agenls sueh as 1'1,1'1,1'1' ,\I'. tct ramethyler hylenedi amine (TMEDA) or IIcu-
nlCthylphosphoramide (HM PA) in diethyl et her res ulted in the n:venal of selecti vity.
R- t!.1! /=0 R l!Jf ;::0
-=--.. Mo'cO " '--___ M'cO
, '

(7)

Then: are a variety of react ions reported in t he lileratu n: demonst rating t he n:acti vi l y
of aHyl romplCJ(CS with Grignard n:agenl5. A few oft hese are ill uslraled here. For u ample,
Ihe hi ghl y reactive unsalurated pcrmelhyllilanocenc allyl calion, shown in Eq. (8). rcacu
with PhCH. MgCI regioseleclively 10 add 10 Ihe central aHyl posi li on by nucleophilic
addilion, producing a melaHocycle complu in 76/. yicld [27]. Compctit ive addition 10
Ihe allyl lcrminal posl ion was not observed. In addtion, competiive addi lion 10 the metal
cenler was also nOI observed: masl likely owing 10 Ihe small onic radius and Ihe lower
elcctrophilicity assooaled with litanium.

PhCH
2
""sO
Q;
H

Ti
(8)

THF, 6"

_78C - R.T.
rle1d
Anol hcr cumple of an aHyl compleJ( n:acling wit h a Grignard reagenl was n:ported by
It oh and co- worken (Eq. (n 28). (CI McsJRuBr l(" l .CH,qR)CH1) [R _ H, Me) was
lreated with BrMg(CH
1
J"MgBr in etller 10 afford lile Ru"-alkyl-butadene romplcJ(es
(C, Mcs)Ru(,,"-CH1CHRCH1) [R - H, Me). Labcling eJ(pcrimenls have suggesled Ihal
the reaClion may procecd by an irreversible double p-hydrogen elimi nation rrom
ruthena(lV)cyclopenlanc intermediates and slepwise lransrer of Ihe hydroen aloms lo
hydrogenale Ihe "l_allylligand .

Ru
(9)
.th"
R _ H; 6S % yield
R R- Me; 69%yicld
IV. CONClU810N
Thc reactions of Grignard reagents with Iransilion metal vinylidene and anyJ CQmplexes
are cerlainly inleresting chcmislry. Howcver, Ihcre il much more chcmiSlry nvolving Ihese
reagenl. thal needs 10 be explored. The chemislry of Grignard reagent. with vinylidene
and aUyl complexes remain. a fenile ground for ruture investigation.
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...
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p' m
22
The Barbler Reaellon
DAVID A. RUSSO
Elf ArMMm Nor/J, Amni<: ... I"c.
KUlfl "i Pruu;.,. Pt ltlUylNltUJ
l . INTROOUcnoN
The Barbier reaction hu intrigue<! chemists from the time Barbier fint rcported lhe
prodl,lction or 2,6-dimethyl-6-hydroxy_2_heptcnc from the reaclion of melhyl iodide wilh
2-methyl-6-0xo-2-heptcnc and maensiurn metal in 1898 (1). AlIhough largely supplanted
by Ihe rnueh more versatik: Grignard reaction as a synthctic 1001, Ihis Mone-step," Mio situ
Grignard.- or "direct rcaction," has found sorne unique applicalions and is IlilI of nteresl
lo man)' rescarchers. Sorne large-scale industrial prooe$Se$ also cmploy lhe 8arbicr rcaction
for product ,}nlhesi!. This section wiJI try 10 convey Ihe hroad $Cope orIlle Barbicr reaction
and highlight sorne or the more useful applications. The reader is rderrod lo major work$
00 he Barbier rcaction by Blombcrg [188] and Hartog [ 189J, review articles by Blomberg
and Harlog [2J and Ralston and Salem (3) as _11 a, the annual reviews on magnesium
in the JournaJ oIOrgOIlOnttlaJ/,,: Chtmislry for additionaJ inrormation.
The Borblt r rtoe/lon will be de6ned in lbe classie $C1l5e 8nd will inelude any one of
lhe following reaclion sequences: (1) addition of an organic halidc to a miJllure of ma8JlC5ium
and an electrophi1ic coreaClanl such as a ketone, (2) addition or a miJlture or an organic
halide and coreactant. over time, to magnesium, or (3) Ihe combination or al! three reagcnls
al once.
This i, contrasted with lhe Iwo-step Grignard rcaction in which be fin! step enlalls
Ihe rormation or an R- MgX specie rollowed by addition or, or addilion to. a coreadant
in a second slep.
.,
.01
rcaetions [ IOJ is oIJere<! as proof fOT Ihe poslulated pathways. Tbc 8ulhors propose Ihat
by knowing he electron affinities of Ihe halides and carbonyls nvolved, one <:an prcdict
lhe mechanism of Ihe reaclion.
Atlhough Ihe mcchanism of lhe Barbicr !'eaelion is nOI completely resolved, Ihe bes!
evidcncc now indicales Ihat radical anion or radical 5peQes. or both, are nvolved. These
radit:al moieties mOSI likely are formed by SET reactions on Ihe metal surface and may
involvc Ihe electrophile as wcll as Ihe halide. The body of evidence indicates Iha! a short-lived
R-MgX spccies is nOI formed in mas! Barbier reactions..
m. ...DDITION AEACTIONS
A. Wlth Aldehyd ... n<t Un,.tur.ted H,IIcte,
Perhaps Ihe widest use of Ihe 8aTbier rcacli on has been in Ihe production of alcohols and
ketones from caTbonyl electrophiles and altenyl aOO bcnzylic haHdes. Usually, Ihe Grignard
reagent s or the halides are loo reactive, and unwanted side producls, owing 10 Wurtz
coupling, are rormed. With Barbier conditions. iodides, bromides, and ehlorides can be
used, and sorne reactions can be conducle<! al room lemperature. Aliphatie alld cyclic
etheflli are generally used assolvents, but hydrocaroons are being used in inereasing amounts,
particularly in industrial applieations. Electrophilic coreagenls ranged from aldchydes,
kcloncs. and csters, lo amides. silanes, and phosphonalcs. The major by-producls are eilher
dimcrs rrom Wurlz-type coupling of Ihe halide, or diol rormalion from ooupling of the
radical anion.
Thc general scheme for the one-Slep Barbicr addition reaclion of alkenyl and beozylic
halidcs wilh aliphalic or aromatic aldehydcs 15 shown in Eq. {n
-.
R- CHO+R' - X
.......
R'
I
R-<::-oH
I
H
(1 )
Sevcral aldehyde and halide combinations becn Sludied and reprcsenlalive
exampleJ are shown in Table l . The solvents of choice range rrom elhers, such as diclhyl
elhcr, tetrahydrofuran (THF) and ruran, 10 hydrocarbons. such as benz.enc, and
petroleum elher.
Yields of aloohols vary rrom 4S 10 irrespeclive of or halogen Iype.
However, when erolyl halidcs are used, lmethylallyl producls are isolated [20], along
wilh oceasional diaddition products [Eq. (2)).
CH,-<::H CH-<:: HCI +C, H,-<::HO -_, CH,=CH-CH(CH,)-CH-C
1
H,
I
OH
+
(CH=CH-<::H(CH,l),-C-CH,
I
OH
(2)
p' m
...
Tibie I
Addion Reactions of Unu tufltcd Halides 10 Aldehydes

""'
Xl,ld BOH R.t,
CH,CHZCH
Z
CI'Iz-ctl-cHzlr
"
11 . U
0I(CH
1
) . CII.
"
u
CHZ .. CI(
.. 14,15
CHJ-CK-c!l
J

".50 12,14,16

I I

"
U
CKJCHooCIlCHZCIIICIICH
Z

I I

" "
CHlCH .. CHC!I.CH1Cll-ctl
O-

" "
O-..

" "
e,",

..
"
---9-
-
CIIZ-ctl-CH,Cl
" "
00

.. 11,19
CKICII.
CIIJCII-.cHCHJlr
-
,
CII
J
CH.oCHCH
J
Cl
" "
CIIlCH.
"
8 . WIIh Aloe"yal Ind Salurated HaUde,
Whcn an al"' )'1 halide ts used in he reaclion with an aldehyde [2.21], bolh Ihe halide and
lhe solvent can nfluente Ibe products Ihat form in addition 10 !he cxpected carbinol.
Whcn el h)'1 iodidc is reacted wilh benzaldehyde in ether, Ihe expe<:ted elh)'l phenyl
carbinol j5 isol aled in a lower yicld Ihan lhe by-products benzyl alcohol and
el hyl phenyl kCl one (35-;.). In THF, benzyl alcohol is Ihe major product (50";.) wilh Ihe
carbinol $Olale<! in on1)' a 10.". yield, With elh)'1 bromide in clller, Ihe major product is
the ketone In THF, the carbinol is the predominant product, being isolated in a
70-;. yield [2].
The react ion or a l-butyl halide with but anal yiclds the ,- bulyl propyl carbinol in a
Tibie 2 (Colllinued)
l' l'
O
D-o
cr
I
"
CH
2
00CH-af,Br ..
(1110 onlr)

"
CHJ-aI-cHJIIr ..
.. ,
"
MI lIe
I I
,

Me 011
D. Wlth K.ton nct s.tura.t.d H.11dft
'"
n
"
15,as
"
..
Thcre are fcwer reactions wlh saturated halides tban ""ilh unsaturated halides. GencraUy,
lhe kctones and halides rrom C--c 'kyl and Ihe ClIpccted alcohols are produced
in 50--70"/. yields The samc salvenl! and metal activation procedures use<! wilh
the unsaturated halides are also applied in lhese reactions.
Sorne userul and nteresting compounds are produced under Barbicr conditions when
Ihe kelonc or Ihe halidc is SQmewhal out or Ihe ordi nary.
"""
RIR2Co -
o
al _ al _ pII.llyl
al _ K. .2 _ 4-.n1.yl
R_
R'
, , - _. HOi- iCH;.b N .... Z
;;t ...
Fi,ure I Reaction of halNlkylami!le with a ketoM under Barbier condilions. (From ReJ. 38.)
When acelone, 1, I-diiodo-2- phcnylcyclopropane, aOO magcnsium are reac1cd togcthcr,
2-phc:nyJcydopropyl dimethylcarbinol is produccd [37J.
Alkylami nc moietics art inlegral componenl ! of many bcneftdal drugs. Normally, a
Grignard reagenl is rormed (rom he haloalkyl hminc as lhe fin! slep in introducing Ihis
functinnal group ioto Ihe rest of Ihe moleeule. However, Ihe Grignard rcagcn! is difficuh
lO form and is wmtwhal unstable. Wit h Ihe in silu Darbier met hod, a ver)' fIable magnesium
oomplex of Ihe alkylaminc and Ihe t elone ti formcd and isolatcd (Fig, Workup of Ihe
Jeads 10 sorne ver)' pure products. in yields as high as 85% [38].
Spirolaclone moiet ies are important components of some biologically act ive steroid!
that posSC$S anltumor activity. A prelude l O rormation or Ihe unil i$ lhe int roduction
or an aUyl sidc c hain into a steroidal kelone. Thi s reaet ion can be accomplished in good
yicld by Ihe Barbier reaclion ofallyl bromide, kelone, and iodine-activated magnesium in
ether. With Sa-choleslan3one. SI and 48"/. of the epimcric aUyl alcohols are isolaled.
Wit h 3.8-{tctrah 98'/. of the allyl alcohol i5 solated
[39].
Anot her inlcresti ng cumple or the Barbier reael ion i5 Ihat or J-butylpyridine wil h
aliphatic kclones in he prescncc or amalgamated magnesium (40). Wilh ethyl methyl
ketone, 5-butyl \N:l hyl-l1methyl2 pyridine methanol is $Olated, in 70/. yicld. Thc
cor!'C$ponding <%,<lI-dimelhyl derivat ive is isolated when acelone is used as the ketone sourcc.
The kelyl-coupling ptodUCIS, R,R'C(OH)-C(OH)R,R', areal$O produced in bol h reaetions.
E. Wlth Eatera, AmlOea, Nltrll.a, Epoxld
Thc reael ion or esters, amides. nitriles, and he like, wi th alkyl or aryl halides under Barbicr
oondi tions gcnerall y produces alcohols and kcloncs, in mueh the same manncT as the
reacli ons wi th aldchydC5 aOO kclones ( Eqs. (8- 13)].
ET
_. I
C
J
H, I +C
6
H,-CO
J
-C H
J
C
6
H, - C-C
J
H, 73% [41] (8)
I
OH
53% [41]
(')
Runo
An interest ing addition ora metliylene moiety ac:ross a doublc: bond or an unsall.lrated
ket one undc:r Barbierc:onditions has becn reported bysome Frenc:h c:hemists [Eq. (16);48] .

Mq
,
( 16)
EIO,C COtEt
No 1.2- or 1.4-addition proouc:ts were isolalcd.
IV. CYCLlZATION REACTIONS
The 8arbier reac:tion has becn used ror the synthesis or akohols thal were diffkult 10
prepare by normal Orignard rcagent techniques. This is partK:ularly tcue foc Ihe preparat ion
orc:ydK: aloohol5 rrom halogenated kelones. Several rcsearc:hers [49- 51] have shown thal
c:yclobulanol s and c:ydopentanoll can be preparcd in good yield! rrom 6 and ~ i o o o and
bromokelonc:s in eit her solvents with Mg or MgJHgCI
1
[Eq. (17)).
"
--,
'"
( 17)
The yield il only 20% in dielhyl elher, but il improves lO 65";. when Ihe bromo analogue
or tetrahydroruran is used.
With they-bromoanalogues,c:yclobutanolsare obtained in 2S-6(W. yicid! [Eq. (18)].
R'
( 18)
""
When R L". pbenyl, or when the chloro analogue is used (R L "" e ~ only ooupling prooucts
from a poslulaled kelyl radical anion are isolaled [Eq. (19)].
- i
---lo e l (0111 ,-e-C-(CK1I Je l
JK JK
(19)
AnOlher interesling ket yl c:yelizat ion is that reported ror a 1 ,5-pcntanedione derivative
on reaction wilh magnesium [Eq. (20): 52].
M,
(20)
...
.
HgCI2. THF
, ..... C
Figure 3 P..,,,,,rat;on of a trK:yd oundeconol. (From Rd. S4.)
))). THF. 'JOC
. -
_ .......
Figure 4 Preparation of 11 tticydoundeeanone. (From ReJ. SS.)
Stereosclccti Yc, fl,lsed-ring alicydic alcohols are prepa..,d in 10-77% yidds rrom
haloalkylalicyclic ketones. cycJic ketones range fmm es lo C
7
with iodo-,
bromopropyl-. or bromobutyl -substitution in IIN:: 2-position. Bicyclo[3.3.0]octan-l-ol$,
[4.3.0]nona- I-oIs, [4.4.0)deca-I -oIs. Ind (S.3.0]decan-l -ols are also prepared. Wbcn he
sidc chain is extended 10 iodopenlyl. no bicyclic productll are obtai ned. Usually he nng
fusion is ci50id [S3].
Tricyclic compounds can also be prepared from haloalkyl bicyeJic ket ones under
Barbier tondilion! (Figs. 3 and 4) [54]. 80th he fralls- and d j -dcnvativc5 are isolatcd in
a combine<! yield of 43"' . Thc reaC1ion mechanisms for bolh products are clplained by
invaking SET alld DET reactions [SS).
Bi cyclobulanes can al$o be prepared under Barbier candili ons fmm halo-
eyclopropylmelhyl ethcrs or ehlorides in 32-45% yields [Eq. (21 ): 56J.

(21)
HaCI )El)
Sorne cyclobutene and 1,3 butadiene are also isolated.
If eyano-hal oalltanes are used inSlead or Ihe halo-Itet ones. eyclization ruelions lalte
place under Barbier conditions 10 produce !telones [Eq. 57]. However, lhe solvenl
and Ihe halogen seem 10 have a greater elfecl on Ihe product .
..
__ o
(22)
al _ .. , 1-Pr, 1-8uI _ M, "1 a
1
t2 _ cyclopropyl , cyclohexyl
Yields ranged from 61- 79-;', and no eyanoalkanes were isolated.
o
HgC!2. THF
00
Filare S Cydization of. mdhylenc halid.:. (From Rd. 60.)
Whcn he alkyl ehain is lengthenro by one rncthylene unt, are
produced, along wi l J $Omc eyanoal kanes [Eq. (23)).
.'
.. R'
I
'" +c, ...
>

(23)
.'
Et
3
0
"'
11
1
- h. i-Pr
11. 2 _ K.
Yiclds as lIigh as 75'-. for he kelonC5 and I SY. fot he alkancs are obtaincd. When TH F
is used and bolh R groups are Me, ketone and all:ane are isotalcd in on11 10/. yiclds.
whcreas lIe major product (70%) js the 1, 1, IO, IO-tctramethyl-I, Hkl icyanodccane.
When Sr is substituted for 1, lhe eydoheunone product ean be !Olale<! in
predominancc onlr when HMPT is he solvent. Ir lhe mcthylenc ehain is lenghcncd by
onc unt, he cyanohellanc and unrcacled slaft;ng material are Ihe major producls. Only
2". of a eyeloheplanone ;5 i$olatcd.
fel is subsliluled ror 1, no reaelon OCCUI'$ in dller or THF. Tlle aUlllol'$ posluJale
that a suaeemediatd reaction takes place, and be<:ause no positive Gilman test occurs.
no intermediate Grisnard reasent is Formed.
Cycrizalion reaelions under Barbier conditions can also occur with
halidcs ( Eq. (24) and Fig. 5; 58,59,60].

THF
(24)
Helerocyclcs can also be prepared by eycliution reaetions under Barbicr conditi ons.
An unellptCted dihydroquinoline derivative is isolated from lile rcaction of a
haloalkylaniline ""ith an aJdehyde [Eq. (25); 61].
o
(2S)
'"
'"

6 Coupling reaclion or cydic aUrlic halides. (From acr. 63.)
V. COUPUNG AEAcnONS
In sorne inslanocs, cross-coupling products I n: ohtained under Barbier condil ions [Eq.
(26) and Fig. 6; 62,63].
(26)
R - C.-C, o pnenyl, o- and m-tol)'l. or o-anisyl
VI. DIMERIZATIONS
Qne o Ihe benelits of he Barbicr reselion aver lhe Grignard reaction is generally lhe
praduct ion of produclS wi lh lillle or no R- k dimer rormalion. However, because of lhe
radical nature of Ihe rcaction; Wurtz-Iype dimer (armalian can be lhe primar)' reselion in
l he absence of an elec.:trophilic roreagenl Sorne Russiao chemi sl$ hayc rcported Ihe
dirncriUli on of halogenated alkenes 2nd alkanes using iodioe-activated magnesium wilh
silyer bromide [Eq5. (27) and (28); 64).
64:W.
56-;.
(27)
(28)
Thc ethylcne bromide reaclioo presenl5 8n nlcrating way 10 exlend Ihe chain Icngth or
the dimer,
Vin)'1 bromide dcrivalives can be dimerized under slightl)' differenl Barbiercondilions
usi ng magnesium a nd cuprous chloride in THF [&, (29); 65).
(29)
Aromalic and bem;ylic halides can lIso be dimerixed undc:r Barbier conditions.
2- Bromoll uorene dimeri:te5 in a 52% ),ield wilh Ihe magnesium-<:uprous chloride
cambinalion [66).
p-Vin)' lbenzyl chloride dimerizes 10 Ihe 1,2-bis(p-slyryl)elhane when reaele<! with
magnesium tone [67).
The rollowi ng three reaaions are not dimerizalions in the same sense as he previous
eumples. bul Ihe)' show the range or lhe produds Ihal can be oblained
rrom Ihe in si lu readion [Eqs, (30) and (31) aOO Fig. 1; 68--10].
(lO)
... 11,0
N C-CH=CH
z
' produel , NClCHz).CN (31 )

H H
Et-{--t=U -Bu
X

Figllre 7 dimc:rs from ,he n:.tliOIl of u!>\k: r oonditions. (from Ret. 70.)
VII . WlTTIGTYPE AEACTtoNS
Tbc reaction oF g .. m-dihaIOlllkanes with alkyl or aTyl aldchydes and kclones under Barbier
oonditions wilh M8IHg can be uscd 10 prepare unsalurated deri vativC$ in a Wiuig-Iypc
reaclion. Some Japanese rescarchen [11] show Iha! syrene and substituted s!yrenes. as
WtU as oclenes. ean be prepared in yiclds as high as 7S'/, using diiodomethane and Ihe
corrcsponding aldehydes (Eqs. (32) and (33)].
" oIH,
R- C
6
H
r
CHO+CH
1
1 , R-C, H .. -CH=CH (32)
R _ H. p-CH
l
, p-Cl
n-C, H, , - CHO - _ , II.C, H,.=CH
1
(33)
Si milar rtaclions are reporlcd wlh aliphatic and cyc10aliphatic keloncs and diiodomcthane
[Eqs. (34) and (35); 71.72].
CH,-CO-C1H, ' (CH,hCH=CH
c-C. H,o=O 'c-C
6
H, o=CH
Olher gem-di halides abo used ( Eq. (36): 73].
VIII . PHOSPHOAUS AND OTHEA METAlS
A. PholphOrul
(34)
(35)
(36)
Organophosphorus oompounds find wide use: in Ihe chemical induslry as calal ysls,
inlermediales, compJcxes, and end-use products. Arylph05phi nes and phosphine oxides are
oflen produced by Ihe reaclion of a prefo rme<! Grignard reagenl with a halophosphine or
phosphine oxide. Yields are reduccd by Ihe produclion or unwantcd side- reaction product s
such as biaryls. Thc:se unwanlcd prod ucls are reduccd when the is conducled
under Barbier conditions. When alkyl and aryl halides are Teacle<! wilh magnesium melal,
a nihaloph05phine or phosphine oxide, a metal halide or amine catalyst, in THF- hcnzcne
mixtures, al goOO yields of ph05phines or phosphine oxides are oblai ned [74). For
e:tample, triphenylphosphine can be: prepared in a 97.2V. yield rrom Ihe reaclion or
bromobenzene, Irichlorophosphine, magnesium metal, aluminum chloride. and sodi um
chloride in THF- hcnzcne at 7O-80"C.
B. Tln
Grignards have ofi en heen used for Ihe synthesis of many al t yl and aryl organotin
compounds. However, cerlain derivativt'S, such as Ihc perfluorinaled al kyltins, cannol be:
made in Ihis manner btcause Ihe Grignard reagenls are 100 reactive. Tradilional1y, Ihcy
have becn prepared by the cJeavage reaction or dilins with pc:rfluorinated alkyl iodidcs.
However, pc:rfluorinaled alkyllins can be prepaced by a Barbic:r reaction of a tin halide
wilh pc:rHuoroclhyl iodide and magnesium mctal in THF al room lempc:ralure. Dimcthyl
and dibulyl bis(pcrfluorocthyl)l:ins are prepared in Ihis manncr in 34 and 16'Y. yickb,
rcspcclively [75J. Thc diclhyl aOO divinyl analagues, al wcU as the ditthyl iodopcrfluorocthyl
and lrivinyl pcrfluorocthyl lins can also prepaced in 10% yiclds [76].
Tetraorganolins can be convenicnlly prepaced lrom lhe coupling reaction 01 aUyl
halides wilh organolin halidcs under ult rasonic-assislcd Barbicr conditions [Eq. (37}J.


R
, .. so-l>-
'"
R L _ H, Mc, Ph, vinyl, al1yl; R
Z
_ H; R\ R4 _ H, Mc
Tralls/ds-slercoisorncr yicld _ 100:0--55:45
Yiclds range rrom 52 10 100/., wilh the -isorner in pcedominance [77].
(37)
Another coupling reaction that produces an optical1y active tetraorganolin utitizcs
an arornalic halide and a triorganotin [Eq. 3 8 ~ 78].
(38)
In Iheir sl udies on the use 01 si lyl-substitultd ligands as thermal and o:lIidative
stabilizcrs 01 lransilion metal" Pannell aOO collaborators (19) show Ihat Iralu-I-
Irimelhylsilyl-3-"L-allyl(lrimethyl)t in can be prepaced in an approximale SQ'Y. yitld by lhe
Barbier rcaction of a Irialkyl or triarrlmetal chloride with magncsium metal and
1-lrirnethylsilyl-3-chloroprop-l-ene. Wilh nickel(TI} chloridc. magncsium, a trace 01
mercuric(lI) chloride, and 2-trimelhylsilyl-3-chloroprop-l-eoc, the thcrmally and oxidatively
,table bis("l -2-trimelhylsilylallylmickel derivative is prepared in 36'Y. yitld. Thc
unsubsliluled derivative is thermally unstable and ignitcs in airo
The Barbicr reacli ons involving germanium derivativcs are similar in many way. lo Ihose
noled in Ihe previous section. Thc work or Pannen [79] and C(IUaboralou abo produccd
Ira1l5-1-lrirnethylsi lyl-3-"L-allyl(triphenyl)germanc in a SQ'Y. yicld.
The production 01 diphenylmethyl trirnelhylgermane in 44'Y. yield is reported rrom
the reduclivc germylation or benzhydrol with trimethylchlorogermanc. magne5ium, and
HMPT [80].
Organogermancs can be prepared using a mclhod simi lar lo Ihal uscd for lhe
production orhypcrvalent silicon spccies. Hypctvalent germanium spccies are reacled with
magncsium and alkyl bromides 10 give tetra-alkylgermanes in yields from 28 lo 78-/.. The
hypel"\'alenl species are lilhium or potassium Iris(benlCne-l,2-diolato)germanale, and the
bromides range from melhyl, clhyl bUlyl, eyelohexyl, dibromobulane, and dibromopenlane,
lo vinyl. allyl, and pnenyL The reactions are earried oul in reHuxing THF and, in some
cases, lhe yields are beUer Ihan those oblained from the tradhiona] melhod or reacting
Ictraehlorogennane wi lh Grignard reagents (81].
Di- and Irigennanes haye becn synlllesiud in 73-75"1. yields by Ihe Wurlz- Iype-
eoupling reaedons or phenyl ehlorogennanc or phenyl dichlorogermane wit h amalgamaled
magnesium (82).
D. Leed .nd G.lIIum
Tetraorganolead dcrival ives, such as Et. Pb are prepare<! from Ihe reacl ion of Pb, Mg, and
al kyl halidcs (8JJ.
Trialkylgallium derivalivcs (RlGa) are prepared from Ihe reaelion of alkyl iociides
wilh a magncsi um- gallium alloy (84).
IX. DRGANDSILANE REACTlONS
Silylal ion reaelions ha\'e becn uscd ror many ycan lO prepare ncw and inlerest ing
organosilancs. ranging from thermall y stable Huids and polymers, to biologically active
material,.
Chlorotrimethylsilane (TMSCI) and olher chlorosilanes are oflen uscd 10 prepare Ihe
organosilancs by Ihe fami liar two-slep pracess employing a preforrrn:d Grignard or lilhium
reagent or Ihe in sil u pr0ces5.
The in silu pracess occurs in Ihe samc manner as described earlier employing SET
reaclions from Ihe magnesi um $urfaoe lO the reactanls. forming radical and radical anion
specics. The question or whether or nOI a shorl-lived Grignard spccies exisl! in Ihese
rcaetions is slill debalable. wi lh evidente ror and againsl slill being olfered. In addi tion 10
Ihe ether solvents generally employed. Ihe use of lhe highly polar solvento hexamel hyl-
phosphorolriamide (HMPT). grealJy enhanoes Ihe in silu reaclion. Reaelions are gencrally
run al reHux temperalures, wilh elher solvenls, and al Jower lemperalures when HMPT
is employed. Reaction limes vary from a fcw minules 10 hours.
A. AddlUon Reedlons
Funetionally subslituted benzylic, allyJic. and vinylic oompound$ oontaining aJkoxides,
csters, ethers, nitriles, or amides can be reacled wilh halosi lancl under Barbicr conditions
using HMPT lo yield C and O-siJylated produels, 1,2- or 1,4addi lion produets, as wcll
as reduct ive dimen. Radical and anionie inlcrmcdiates are po$lll Jated. based on SET
reaelions from thc mctal, and mulliple siJalcd sptCC$ can be oblained. The U$C of the
TMSCI- Mg- HMPT system hu becn cxlcnsillCly invcsligatcd by Calas' group [8S] al Ihe
Universi ty of Bordeaux. and Ihei r work hu greally advanccd Ihe scicncc of thc Barbier
reaelion with silanes.
,. 1.2-Addltlons
The addition reactions of TMsa 10 ketones under Barbicr condil ions, wilh HMPT as
solvenl. yicld a yariety of products, dependi nll on Ihe cqivaJents 01 TMsa use<! and Ihe
type of groups on the kelonc. Table 3 ilJUSlrales Ihe additi on rcactionl ror acclophenonc
and sorne of its analogues.
,
Table 3 1,2Addi\;on Reaclioru of TMSCI (MI- HMP1) wilh Kelones
I,ton.
Cquiy
,
0.5-1
,
2 (TMU)
,
TMU .. ' ........... hyl u .....
s.-cr. Rd$.
PE" ,yqt.
. a
C,",-C-C-C,",
baba
j 8

OH ...
...
C,K1-J-t-SII
!.
p-TllS-C,,,. C:O-t-1IU
C1H1-,:-t-1kI.
y.14
-
..
(111 4. 1/ "_1
-
-
"
"
Anion- radical spccieli are postulated as reaction intcrmediatcs {or lhe gcminal TMS
produets [85]. Howcvcr.ror he glycol products, a si lyl-Grignard intcnnediale is postuJated.
No radical anion are required because he reael ion does no! occur in Ihe absence
or TMSCI [86,87].
When he kClone contaos a bulky graup, such as tbutyl. a TMS containi ng alcohol
js ablaine<! instcad of a disuMtituted hydroearoon. Ir lhe il changcd (mm HMPT
10 tetramethylurea [fMU). lhe aryl rn, is ,ilylete<! and a kClone i, isolated [88). Whcn
less Ihan 2 Eq of TMSa are tmployed, Ihe rcactian producI$ contain no silaDe species.
Thc cyclopropyl aOO elhylenic benzene derivalives are poslutaled lo arise from a carbene
nserlion inlO Ihe I-Bu group and a Me group rearrangcmenl [88].
Ni lriles and imines are reduced in Ihe presencc: of TMSO- Mg- HMPT 10 yield
silylated amines (Eq. (39): 87,89].
p-R--C, HJ- C N -_, p-TMS--C,HJ--CH- N(fMS)z
I
TMS
"
p-TMS-C, HJ--CH- NHz
I (39)
TMS
.-
Whcn 1- or 2-cyanonaphthalene is si lylll led, lhe silylamine is prepared as weJl as YanouI
multiple silylated naphlhalene spccies (90).
"' or amines. he addit ion fotlow$ a si milar pal h [ Eq. 90,91).
"

,<O,
R . ,-Du, e,H,; R 1_0 . H, Me
When R - C
6
H, and R ' .. Me, a TMS group also adds 10 Ihe para-posillon of the aromalit
ring (90J.
Un53.turated csten yield a varicty of producls whcn reacted with TMSO- Mg- HMPT
[Eq. 92].
.'
.'
al al
, /
I I
O<

ntS- e - C-H
,
I I
. '
a' COl a
1-1"
R
'
_ H, Me, e,H,. COJMe
Rl_ H, Me, COl Me
R'_H, Sr, Me, COIEt, C
6
H,
R .. Me, El, II- Bu, CHIC, H,

a l Rl al al
I I I
,
( - C-eH),

H-e-C-"
(4 1)
, I
I I
a
2
COl. a' co, a
' . 5-70\ 2-10\
Thc and IJ-trirmt hybilylox)'$tyrcnes will add more than I Eq of TMS during
reaction with CJ.cess TMSCI- Mg- HMPT [ Eq. (42); 93].
.'"
C'" I - CH-CH- ( Tl'IS) 1
l., (42)
...
'"
Acylimidazolcs yicld IIcylsilanes when the int ermcdiates from the Barbier reaction
an: hydrolyzed [Eq. 94).
"
(43)
Phcnacylamines yicld si lylamincs, amides, and nonsi lylatcd amines whcn reactcd with
TMSCI- Mg in THF (Eq. 95).
p' m
nble4 (Continucd)
8! 8! 8! 1

Xille!.
144tt.1pn .,.'-Plpt
Q-..

.. ,
- -



(l alld)
-
. -
-1:
4
--
-
N'

J..
s.-<r. Refl. 96-100.
Some interesting vinyl alienes are produoed in yields from the Barbier teaetion
of alkenylpcnt yncs with TMSCI [Ec. (41): 102).
.'
.'
I I
RI-c-e-c-e-ca-cl

ftUC,
I ,

R1_ H, TMS
RJ_ RJ = H, Me, -(CHJ).-
R _ H, Me
..
....,
a,T.
'Z
"
>
/'
, ,
Ji
"- ('n
""
r\
a' .4
A mult iplesubstitutcd 1.6-heltakisffMS)but ,2-yne js obtained from the teaetion of
1,6-bis(TMS)bulaI,3-diyne with excess TMSO undcr Barmer conditions [1 03).
The bieyclic 8,8-dimethyl-8-silyl-bicyclo[3.2. I)ocla2,6-diene is the only produel
isolated from Ihe Barbier reselion of eylohepta-2,4,6-lriene wilh dimelhyldichlorosilane
[104).
11. Clrbon IncI Ollypn SlIylaUon
80th C and O-silyJalcd compounds are isoJated from the react ion of bcnzyl aOO aUyl
alcohols, elhers, and amines with TMSCI [Eq. (48): lOS).

RR ' R1COH+TMsa (48)
R _ H. C, H,; R 1 _ H, CH
J
, C. H,: R
J
-CeH,. SiMe
J
When a secoOO mole of TMSO js used, lhe ailane RR IRJCSiMe
J
is formed along with
I mole of hexarnet hyldisiloxane, A Ti, Fe, or Ni calalysl is usually requjred ror Ihe second
step.
R_
The general reaction can also occur ",ilh an c:lhcr or aminc [Eq. (49)).
RR ' RJCX+TMSCI , RR' RlCSiMcJ+XTMS (49)

when: X _ OTMS, OCH OCH.-CH=CH, NRJR' , Yields range from SO lo 9S'Y. [lOS).
For allyl aOO substitutcd allyl aleohols and c:thcrs, bolh and 5",2' reactioo prodocu
are formed [Eq. 105].
-.
R-CH=CH- CHOR' + TMSCI ' R-CH=CH-CHJSi McJ+ R- CH- CH=CH
" .. ,.,- I
Si Mc
J
(SO)
R .. H, Me, C.H,
R' _ H, alkyl. aryl
(Z+ E) 45'Y.
5S%
When R .. C, H,. onl1 Ihe Z + E somers (5,.2 reaction) an: produced. Whcn R., H, a second
mole orTMSa will sitrlale: Ihe J-position formiog McISiCH=CH- CHSi Mc) in a SS"/.
yicld.
Thc C and O-!i lylalcd products an: obtained ",hen Ihe fuoelional compound I!
highly halogenatcd [Eq. (SI); 106].
M,
I
el Me
I I
el Me
I I
O IC---C- OH + TMSO - _, McISi-C-C-OSiMc)+ H- C- C-OTMS+
I 1 I I I
M,
el Me C1 M,
Me a Me
I I I
CI.C-C-OTMS + TMs-c---e.-.oH
I I I
Me a Me
I
With bis(trichloromethyl)l:etone, lhe O-silylated prodllcl i5 oblained.
OC=C- CHO 50%
I
QTMS
With ehloral. CIJC-CHQ, lhe disilylated produel was isolated.
H
I
TMS-CwC-OTKS
J,
B only, 60-70'
(S 1)
Sorne interesting si lyl -eyelization reaetions oecur whcn reactive al kenes or alkenyl halides
react with halosilanes and magoesium metal.
1,3-Butadiene and substituted butadienes react with halosilanes in the presencc oC
activaled magnesium 10 yi<:ld silylspiroalkcnes or cydic si lylalkcnes in yiekls from 21 lo
80% [Eq. 107- 1(9).
..
--.

'l'HP, HMP'l'
Etc' 'OEI
(52)
R.Cl,M.,OEt
A similar Il:action with 1,3,Shelllriene and dimcthyldichlorosilane yields Ihe I,l-dimethyl
when THF and CulO
l
IIl: employecl [liD).
Silylacenaphthenes and I.silylphenalenes all: obtained in 54-71-/0 yields from the
reactions oC 1.8-disubstituled naphlhalenes with chlorosilanes and Mg in THF (EqL (SJ)
aOO (54); 111-113).
...
eH, R
o O . R"''''''

(S3)
C l H.zCI
Oa


(54)
A unique si lyliOOenc results from the reaction of
bcnune with MclSiO
J
and MI in THF (114].
Si lylcyclobulanc: dcrivatives all: i$Olaled from thc Il:action oC ccrtain dihaJosilancs
with MI in clher or THF .
. '

I ,

p' m
with halosilanes un<kr Barbicr condilions yiclds severaJ usefuJ start;ng materials for olher
reaelions [E<. (57)).

R. _.CCI. + Me,R'SiCl R. _.CC1. _,SiR'Me,

JO-rC
n-2, 3, 4
R_ H, Me, C.H" p-ClC.H
j
, ClJC-, aud Ihereof
R'_H, Me
Silancs such as CI,CTMS, HCI,CTMS, MeCI,CTM5, C.H,CCI,TM5, CJ,c=qCJ)TMS,
and MeCI,CSiMe,H can be prepare<! in yields as high as SO"/. [120).
Some inleresling mulliple ,ilylale<! species are prepared by Ihis method [Eqs. (58-61);
121 - 123).

CBr .. + Me,SiCI {Me,Sil .. C + (Me,SihSiH + (Me,SihCH,
THF 28"/0
CBr .. + p-Me-C.H,--5iH,CI ' {p-Me-C.H,--5i H,) .. C
(S8)
(S9)
(60)
Thc HJSi derivatives (H,Si) .. C and {H,Si),CMc, can be prepared by trealing lhe aryl
.ilanes with acid, followcd by reduclion wilh LAH [122].
TUSCO
..

(61 )
For Ihe reaction of vinyl chloride with dichlorodimelhylsilanc, a disilane is isolalcd,
nOI Ihe expeo;:lcd divinyldimclhylsilanc [Eq. (62); 124).
CH,=CH- CI + Mc,Sia, . CH, CH-Si{Mch- Si{Me),-CH CH, (62)
Allyl halides tcaCI in the expected SM2 manner [Eq. 125,126].
CH,-CH-CH, - X + R1R'R'SiCl - _, CH, =CH- CH,--5iR
1
R' R'
x _a, Br
R'- H. Mc, El
R' "" H, Me, El, o
R'. H,Cp
Solvents can be elher and THF, and yields rauge from SI lo .
(63)
Cydic aJlyl haJ ides, suth as 3-thlorwydopent-l-ene, react wilh TMSCJ under Barbier
condi ti ons lo yield 3-trimelhylsilyl derivalives in good yield [127].
Propynyl bromide gves both Ihe trimelhylsilyl propyne and allenc derivatives (3:1)
in a 71"/0 yield on teltlion with TMSa (128), and 1,4-bii!(lrimethylsilyl)bul-2-enc results
rrom Ihe TMSCI reaclion with 1,4-dibromobut-2-ene [129].
The reaC1ion al t rolyl thloride wilh TMSO under Barbier condit ions yields the same
ratio of prodUtlS as the reattion of Ihe preformcd crotyl Grignard reagenl with TMSO
in ether (Eq. (64); 130).
'"
Table S Couplinl Reactions or Aryl Halides witb TMSCl/MI/HMPT

,
11114
K
0'
"
"
"
..
H
" "
H'
,
"
2-/11.
e'
..
)-11. c< ..

e,
n
l-CP)
" "
4-CPJ e,
"
2,4-dtM.
" "
). '-dJJole
"
"
2.4.6-trJJI.

"


..
:-t-lI\l

"
l-t-IIU

"
4-t-lu

..
'-OCK,
"
"
'-H,

"
'-OCK,

"
l - SCH,

"
4-SCH,

n
4M( Neh

"
'.<1

"
'-<0
e, ...
4-CH-cK
2
c<
"
2-C,N.
e'
..
'0
"
,.,/"""\

"
\..../

However, in Ihe absence of silane, McOMgO forms and in a second slCp wi lh lhe
silanc 10 yicld Ihc same prodUCIS. These resul lJ givc addi tional supporl for lhe inlermediacy
of a Grignard species in the Barbicr reaction.
Chloromc:thyl hetcroc:ycles rcact wit h silanes under Barbier conditions lO yield Ihe
si lylmel hyl derivalives in good yields. and
S.met hyl-J-(chloromethyl)isoxazole couplc wi lh TMSO-Mg in THF l O yicld the
correspondi ng 4- and J- trimelhylsil ylmelhyl analogues in yields of60 and 40"/0, respectivdy
[138].
Silalranes unst.ble in the presence of Grignard reasenl$, but under Barbier
condi tions, chloromethyl$il at rancs rcact with si lyl h. ]ides 10 form silylmethylsiJatranes in
good yicld (54-78%) (Eq. 139).
OCHCH
/ "
-.
/
CICHSi-QCHCH- N + RR' R1SiCI RR' RSiCHS'"
(71)
" /
"
OCHCH
R .. Me; R' .. Me, O; R"", H, Me, O
Disilane-ooupling products obtaincd from the or some vi nyl and aryl
silyl chlorides with magnesium [Eqs. 140, 141 ).
AryI1Si(H)CI
M,
I
Vinyl-5i-CI
I
M,
M,
I
Vi nyl- Si-CI
I
M,
-.
Vinyl-O
HH
N. , r
(arylJ.Si- Si(aryl)
Me Me
-.
I I
vinyl-Si-5i- vinyl
'"
I I
Me Me
Me Me
M,
-.
I I I
vi nyl-Si-Si- vinyl + vinyl-Si-Si Me
l

I I
Me Me
28-;.
Me Me
I I
vinyl- Si--Si- vinyl
I I
Me Me
I
M,
(72)
(73)
(74)
(75)
.,
Me Me
I I
Mee l yinyl- Si- Si- vinyl
. 1 III4W.JCI, I!
Me Me
x. UL TRAsONte REACnONS
(76)
The use of ultrasonic techniques in virtualJy cvcry field of chcmi st ry has c pandcd reall)'
in recen! yean.. SODochemical mcthods nave probably becn most succesdul for
heterogeneous reactions in general and, in particular, for organometallic synthesis.
Ultrasonic synlhesis allow5 he use of saftr solvcnu Ihat need nol be anhydrolls, ehcaper
ehlaride startins material s and, frtqucntly, lower reaction tcmperatures. An tJ.ccllent rcview
on he use or sonochemistry in organic and organomclallic chcmistry is Ihat o( Einhorn
and oo-workcr'$ [141 ]. A second Einhorn publication on he ultrasonicaUy astiste<! Barbicr
react ion is al$Q very inTormative [142].
Sonochemical Icchniques nave becn uKd predominantel)' in he lithiurn- Barbicr
reaction [142- 14S).
MosI or the work wilh magnesium hu been aimed at prepari ng Grignard reagents
that are normall y difficull lo synthesize. However, one recent publication has shown Ihal
the sonoehemical Barbier reaction with magnesium can be useful on a large seale [Eq.
1 7 ~ 146],
.... m
n-C J H, Br + C
6
H ,-CHO --C.H , - CH{OHrC l H T (17)
Anol her eumple on the use of the ultnuonic lechnique with the magnesium-Barbier
reaction is reported by Einhom and Luche in Iher study of organomclallic intermediales
from isocyanales [Eq. 1 8 ~ 141).
M. j ))
....
(18)
Li su
]fa 7"
The solvenls can be ether or THF, and Ihe reaction occurs al room tempcralUre in llS
short a time as 15 mino
Ult rasonic assistance can also be effeclive in the Barbier reacti on of cenaio
heteroeycles wilh ketones [Eq. (79); 148].
THF. )))
(79)

MelCO
The yicld 01 the 2-carbinol derivative il 31 "/0, and none of Ihe 3-carbinol is isolatcd.
XI. REACTlON WITH OTHER METALS ANO METAL HALlDES
The Barbier reaclioll with olller melals can oocupy all entire volumc 011 its OWII ando hence.
WillllOI be reviewed in Ihis work. TIte interested reader should refer lO Ihe relerenoes cited
al Ihe beginning of Ihis lexl and Ihose nOled in lhe following for addilional inlormalion.
In Ihe last 10 years. Ihe Barbier reaction method has been ulilil.ed more with otller
metals Ihan wil h magnesium. TIte number of papen publilhed on the lithium- Barbier
reacl ion i$ three lo four limes that 01 magnesium [149-1 S7J. Reaclions can be carried out
al lower temperalures Ihan possible with Mg- Barbier reactions and yields are oflen very
high wilh fewer by-producU. Olher metab of nole are samarium, in the form 01 itl diiodide
[158--165], and zine [ 166- 169] , lhe melal of choice for the pre-Barbier one-ltep reaction,
and Ihe clauic Reformalsky reaction. In silu reactions have bocen reported for Al [170],
Ce (171 ). Cd [172,173], Ga [1 74], Hg [ 175], In [176]. Mn [177], Pb [178- 180] , Sb
(18I-1g3], Sn (184,185], and Ti [lg6]. An excellent paper by ti reviews Ihe Barbier
reaclionl of many melals in aqueous media [ 187].
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71. S. Miyano. el al . Nipf'OI'I KtIfltJku Ka/shl . 213 (1992); C. A. 76:IS15Sfi
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14. Jpn. Tokkyo Koho 80 39,558 1980; C. A.
'S. F. G. A. Stone and P. M. Treichel, CMm. /11<1. p. 8)7 (1960).
7iS. S. E. Ulrich.oo J. J. Zuckerm.n.lnl}'fl. Ch/m. Acta 34:161 (1979).
17. L. E. Overman O,g. Sylllh. 71:118 (1992).
15. M. Lequan and S. Qucroix, J. Orgll_l. CMm. 194:33 (1980).
79. K. H. Panrll:ll, J. O'f/ano",,,,- Ckm. 111:37 (1976).
131 L. A. Lo_ and E. D. Oro .... n, Ger. Olfen. 1029,504 (lo 00 .... Corninll 1971; C. A.
7t'i:12175k (1972).
133. J. Dunogue'scl al., J . O'g/momer. CM"'. Jj:l 21
134. O. A. Hluestcin a nd E. R. EVMns. U.S. Patenl 4.116.993 (to General Eleclric Comp;ilny), 1978.
V. Bazanl and M. Cerny, CoIlr. Cu(/t . CommlUl. 39:1728. 1735, 1880(1914).
lJ6. J. P. PK:ard, el a1.. J . Res. p. 54 (1971).
131. N. S. Naoxlkin, el al., Bull. RUM. Acod. Sci. f)iv. CItem. Se/. p. 1191 (1977).
138. R. Nesi, .1 al., J . CMm. 19j:275 0980).
139. V. GeI'O/gyan. el a1., J. OrgoMmn CIIml . 4/B:C21 (1991 ).
140. P. (;erval 1 al , Bul/. Soc. Chim. F,. PO,I 1 p. 1548 (1974).
141. C. Einhorn. el a1., p. 787
142. C. Einhorn, el al . U/lr<U(Hf.s /8:3 16
142. J. De Souza. Oarboza, el al., Tel.olledron UII. /8:2013
14l . J. De SouzaBarboza, el al., J. 0'(1. Chem. H :1212 (19881.
144. l. Hurko .... , el al., Ae/o Cllem. Seond. Ser. 8 &1/:215 (l 981).
145. J. L Luche and J.-C. Oamiano, J . Am. CMm. Soc. IOJ:7926 (1980).
146. J. l ock. CM"'. Ter/ . (Hfidt lbn(l ) 1/:154 (1992); C. A. 118: 149964e (1993).
147. J. Ei nhorn.nd J. l uche. Ttlro!ot-drOll ull. l7:501
148. T.S. Chou. el al. J . CItem. Soc. Clltm. Com""m. p. 1552 (19871.
149. M. Kihara. el al.. Tel, ohed,on ( 1993).
150. 1\. Guijarro aOO M. Yus, Tt l.uMdro" UII. J4:20II. 3487 (1993).
151. C. Gomez. el al.. Telroltedroo (1993).
152. J. lomas and S. Hriand. J . Chem. Soc. Prrltl" TronJ. 1 p. 191119921.
IH J.L Ouboi" el al. Tmlllledroo UII. 19:3955 (1988).
154. M. Kihbra, el al.. Ttl.olredron u/I. J/:5347 (1990).
IH. M. Kihara. el al.. Telraltedron UII. 48:67 (1992).
1.56. N. Y. Shih, el al . Tr/rolledr"" UII. 10:5.563 (1989).
157. D. Ramon. el al.. Tel,QMdrOI! UII. JJ:22 17
158. P. dePouitl y. el al.. 8,,11. SM. CM",. F,. IJ0: 2.56
159. J. Jungi. el al.. J. Al/oJ's Compd. /91:197 (1993).
160. D. Curran and M. Tolleben, J . Am. CIttm. Soc. IU:605(J (1992).
161. J. L Namy. el J. O,gonomel. CMm. J18:81 (1987).
162. G. Molandcr and J. McKie. J. O'g. CMm.
163. O. Anlonsc:n. el aL Ae/a CMm. SNma.
164. D. Curran aOO R. C. Wo1in, S)"" lm p. 317 (1991).
165. D. Curran, el al . p. 943 (1992).
166. H. Waldman. Utbigs A,,". Chem. Po 1317 (1991).
167. C. Francesc. ti al., J . Clorm. Soc. Cllem. Comm"". p. 642
168. C. Najera and J. M. Sansano, Tel.o!rNron
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110. H. T. naka. el MI., Ttlrolttdroo UII. 19:172 1(1 988).
171. T. lmamolo, el al.. J. 0'(1. Cllem.
172. S. el al.. J . Oem.
173. O. Sain, el al. Terrolltdron U/f. JJ:479S (1992).
174. S. Araki. el al., App/. CMm. 1:415
115. J. J. DeVoss, el .1.. Tt/ro!rNr()fl
176. S. Araki. el al . J. OrgOllOmtl. Chem. J69:291
177. G. Cahicz and P. Y. Chulnt, Tt/ralled,on UII . 10:1373
178. H. Tanaka l al.. Tel. oltedron LtII. J0:4l61
179. H. Tanaka, el al., EltrlrDOrgo" k S)"fulleslJ (R. D. titile and N. l. Wcinber. Mareel
Dekker, Ne .... York. 1990. Po 241.
1110. 11. Tanaka, el 11 . Che",. E.m. p. 1461 (1986).
ISI. Y. Butsugan. el al . Tel'olwa' oo lIl/ . 18:3707 (1987).
....
182. C. Den, el .1., Lm. 19: 139S ( 1988).
183. W. Wang. el al . !. Cite,.,. Soc. Pt,ld" T"",s. I p. 424
184. H. Yamalaka. el al . Bull. Soco !p" . 6j:214S
185. T. Imai and S. Nishida. Sy"lhtJiJ p. 39S
186. H. Tanah. el al., Ttl,Q.M,""" !.tll. J/:3023 (1990).
187. C. J. Li, CMnt. RtfJ. 91:2023 (1993).
188. C. Blombcrg. TIwt Ba-bkr Rtat:11on iJltd Rdattd O",..Sltp Springer. Vnlag. Ikrlin
Heidelbcr .. 1993.
189. F. A. HaMO" Tht Bo,blt' RtQ.CliOll, A MtchOltist;c Krips Repro Meppel, AmslerdaZTI,
1978.
23
Grlgnard Reagents as Bases
WALTER KOS"R
EIf Aloclrmt Norlll Amrrica, ',c.
King 01 PrJUSiD, Pr"ltSyhlaniD
l. INTAODUCTION
In addition lo heir well-known uses 81 alkylating agen!s, Grignard reagcnls have also
beco use<! as bases. There are Iwo general classes nf Origoard base reactions: metalJation
[Eq. (I)] and dimination [Eq. (2)). Discrete metallated specics may be uscd in intennolccular
addition rtlclioM, oc allowcd 10 undergo inlramolccular rearrangcmcnl 10 he desired
producto Elimination reactions involvc loss af a stable magnesiatc species, such as
or halide.
Mctallation
RMgX+R'ZH - _, RH+R' ZMgX ( 1)
Elimination
RMgX + R'CH(Z)CHlR
J
- _RH +ZMgX + R'HC_ CHR
J
(2)
Grignard reagcnls are vcry slrong bases, comparable with lilhium rc.gcnil, although
not as widely reporte<!. The mos! cornmon example involves deprotonation of alkYI\e$ lO
,ve he acetylcnic Grignard reagenl [Eq. (3)].
RC CH + R' MgX ,Re CMgX + RH (3)
This c1ass of compounds is reviewed in Chapter 32 and will not be discussed here. Physical
sludies of basicily \ViII be reviewed, along with specific applications in melallation and
dimination.
".
442 Kour
11 . BASICtTY THEORV AND MEASUREMENT
Important paramcters that determine base strength are solvent, strueturc, and eleetro-
negati vity. B:uici ty i5 inercased by polar solvents that can slabili.u Ibe anonic charge. Thc
degra: of association il also important, as monomeric organomagnesium specics are more
effectivc as bases. The abilit y of salvenu, sllch as letrahydmfuran {THF) and hexametbyl-
pbospharamide to stabi lize monomer Grignard reagents is a major reasan fOf
the hi gher basicity in Ihese solvents. Many dcpmtonation rcactions are rlln in THF to
take advantage of this inereased basieity. Tbe Grignard rcagent may be prepared as a
dict hyl ether salution, but;$ then diluted wi th THF;n the reaction medium 10 achievc the
dcsi red basicly.
Substitut ion on the organie moiety wit h clectron-rcleasi ng gmups abo inereaSC!!
basicity. However, bulky groups. sllch as ,-butyl. can introduce steric hindrancc. thcreby
reducing reactivi ty. On the other hand. bulky groups can also introduce regioseleet ivity
in deprotonati ons.
Base strengtb. expressed in pK, uni ts. has bcen delermined eleet rochemicatly by Ihe
Chevml group [ 1-4]. These sl udics correlale Grignard reagenl basici ly wilh Ihe reduclion
polenlial at a hydrogen c1eelrode. The ;nitial !Iudy destribcd clcclrochemical meuuremenlS
of several Grignard reagenlS in THF. A depcndcnce on partial pressure of hydmgen was
noted wi th atl comp<lunds u:cept i- PrMgCI and -BuMgC!. The p<ltcnlials oflhesc Grignard
reagenls could not be dclermincd wilh Ihi s particular metbod. A follow-up sl udy showed
tbat RMgCI compounds were sl ronger bases Ihan RMgBr (Table 1). The ionic dissociation
of RMgX was also proved.
Thesc aulhors also comparcd basici tics of olher magncsium rcagenls (dialkyl,
amidohalo, and alkoxybalo) with Grignard reagent s {Table 2). Exccss halide ion was used
to fully shift Ihe Schlenk equilibrium 10 RMgX. As expccted, lhe dialkyl magncsiums werc
dibasic. Thc dialkyl magncsiums had slightl y higher pK, values Ihan he monoalkyl
magnesium balides.. The measured pK. valucs different slight ly from prior rcsults [ 1), bul
fetl witbin the I pK,- unil variation.
Salvenl coordi nalon efreets werc demonslr,ued by addition or HMPA. Basici ty
increased when HMPA was added to THF Grignard $Olutions. This was rationalized as
a complex rormal on betwccn Grignard reagent and HMPA, inereasing the rcduclon
potentilll. A pK. -unil increase was observed when 1. $-2 mol HMPA was added per
mole of Grignard reagen!.
Grignard rcagenl
CH, MgO
CH,CH, MgC1
CH,MgRr
CH,CH, MgBr
CH,CH,CH, MgCl
CH,CIi ,CU,CH, MgO
C.Ii ,CH, MgO
C.H, MgCI
C.H, MaBr
Sooo.-....: Rcf. l .
,K.
J 1.2
JO.'
2!U
29.3
27.6
26.8
24.6
23.9
m
TIbie 2 pK. V.lues ofOlher M.8JIC$i um
B._
Magnesium base
(Mc),Mg
(EI ). Mg
PhNHMgCI
PhNHMgBr
II-BuOMgCl
II -BuOMgBr
Mg(OH), [ 1]
SoI.ffr. Rrl. 2.
TlbleJ AcidilicsofGrignard8aJe
Conjgale Adds
Conjgale .cid pK,
CH, ...
CIiICH,
. .,
fCH)I,CH ...
(CH,CH1CH,)NH ...
(CH,CH,), NH
."
111. METALu.nON
pK,
JO.'
JO.'
21.7
20.1
I S. 7
14.1
11.0
The mosl common Grignard Teagenl! for deprolonalion are melhyl, elhy!. and isopropyl.
Magnesium dialkyl amides (similar lO Ihe lilhi um reagents) are anolher importanl eJa" of
reagent!. Thesc: reagen!s may be casily prepared and are orten commercially available. The
lower alkyl derivalives form vola!ile by-produels Ihat are casily removed from Ihe ruction.
The.sc si mple alkyl- and amido-derivalives are also quite basic. as wilnessed by Ihe high
pK. values of the eon;ugale acids [S,6] (Table 3).
Alkoxymagnesium rugents are another popular basic reagen!. Thcse reagen!s
Ihemselves are detived by metallalion oC lhe apptopriale alcohol [Eq. (4)].
ROH + R' MgX _ _ o ROMgX + R' H
(4)
The following scctions will diSl;:uSS application5 of Grignard reagcnts for melaUation. The
general calegories are intramolecular rearrangemenls, enolales. and misccll aneous reaclionl..
Eliminadon! are coyered in a separale scction.
A. Inlr.molecul.r A rr.l\4iII.menb
Equalion (S) depicls an inlramolecular Rcformalsky reaclion. The aulllors prepared Ihe
ester-substiluted aziridines, Ihen deprolonaled at the aI-kelo- or N- H-posil;on. The resull;ng
anions IlIen underwenl !Canangemenl 10 open Ihe azridine and cyclize al Ihe ester gtOUP,
giving pyrolinonc product!. Use of lhe bulk), mesityl Grignard reagenl aye only producls
or deprotonation. Use or the leS$-hindered methyl Grignard rcagent n:Slled in 4S"/. )'icld
of mctllylalion al Ihe esler posil ion when Ihe G rignard reagenl was scd in tenfold exCCS$.
'"
'"
2,4,6-Trimethylphcnoxymagnesiurn bromide was used as lhe base lO catalyze Ihis
aldol condenntion [ 16; Eq. (12)]. Note Ihat Habstraclion can occur al he melhyl or
melhylene, pcrmittins kinetic control.
,
" ..
"
,
......",.r
+
.,..

( 12)
,
,
, ,


!
A series or Grignard reagents were reacled with aliphatio:: eslers, and enolization
occurred KkctiVi:ly atine less-hindered po5ition. Interestingly, lhe esler enolate eliminales
magnesium alkoxide, fonning a hlene intenncdiate Ihal Il:acts wilh a sccond equivalenl
of Grignard reagen! lO form keto-cnolates [ 17; Eq. (13)].
y,
I

_,11&1
,
....
,
/f
-Z
( 13)
Axial versus equaloriaJ attack of magncsium tert iary-enolates on substituted cyclo-
ncxanones is affected by salven! (i.e., HMPA ncreases axial substitution) [18]. Incrcascd
basicity ravorl axial attac". The cDolales wcre gencrale<! by reac:tion of PrMgCI with
t-butylacetate [Eq, (14)).
,
...--'
,
(14)
A more delailed sludy on selectivily of Grignard enolales reacting wilh t-bulylcyclo-
hexanone was conducted [ 19,20; Eq. OS)]. The enolales were acelic add derivalives: elhyl
,
,
+

,.'
(1.5)
The regiochemislry of Grignard rcagcnt allack on coumarins was evalualed using
bolh IheoreticaJ and labonlloTy uperimenls [23; Eq. (16)). 1e calculaled nucleophilicity
of lhe Grignard reagenls. along wi lh orbi lal cnergies of substlUled coumarins. prov<ted
a thcoretcal basis lO estmate poi nts of react ion. Deprotonation occurrc:d along wilh
addhion. Grignard Teagenu slUdied in<:Juded t- BuMgCl, I. PrMgO, diisopropyl magnesi um,
$- BuMgCI.
(YV
'0'-,"",
(16)
2. General Syn/hes/s wl/h Magnes;um Eno/a/es
Deprotonal ion of an ester led lo a Claisen condensat ion. giving a bis-anisylketo elIter
inlcrmediale [24]. Acidificalion and lhermal dccarbo.lylation Ied lO Ihe desiral bis-
anisyl kclone [Eq. (17)]. This product was an intermediale 10 a bieyclo[J.2.1)octadienc:
derivative used in a study of anionie homoaromatiei ly.
,
.
,.
. ,
/'
( 11)
StereOlipecific aldol synthesis of acid! dcrivcd (rom (R) - (+}..bulyl-p-
tolysulfinyl aceta te has becn reporlcd [25: Eq. (18)). The I- BuMgBr was crucial 10 the
enolate generation without racemization. Magnesium diisopropylamide Wa$ usa! in
preparation of Ihe acelate precursor.
o ......
J '..J
,,1 /'

.... 0 o X
"+!'-'
!J
" '-,
V \

( 18)
Equation (19) displays a regioselective route 10 2'-hydro.lychalcones by magensium
(26]. Selective 1,2-addi lion resultcd from reaction of bromomagnesium
0;111;1<
....

,_0

-'

,*
' .
,1
,
1
-
1 '.
'. 1, 1,
,
'. '.
,
1
'.
'.

'.

, ,
'.
( 19)
on cinnamic aldchyde. The magnesium was crilical in coordinaling Ihe
and aldehyde lO dircel regiochemislry. A Icrtiary amine was also required 10
oblain lhe desired seleclivity.EIMg8r deprotonlled lhe pheools lo gene"le lhe phenaxides.
An example of a magnesium Ihiocsterenolate is shown in Eq. (20) (27). These enolates
were generated by reaelion ofthiocsten wilh several bases, ineluding i-PrMgCl, Et,NMgBr,
and EISMgO. The Ihiocsler enolales were uscd in subscquent Claisen condensaliolU.
,
,
".
L (Q[.).aItlC1

(20)

...

Encaminc chcmislry, using Grignard !"Cagcnls as ba!lC$, has bc:en reviewed [28; Eq.
(21)]. Ineluded is the ehemistry of encamine Inions generated rrom Grignard bases (usually
EIMgBr and i- PrMgBr)' These mlgnesium encamine anions are effective in alkylalions,
allhough tbey requi rc hiher reaetion ICmpcralurcs Ihan lilhium anioos.
LU
y-'
(21)
Magnesi um-encamides can be used in he synthe$is of a chira] [29; Eq. (22)J.
,-Bulylmagnesium bromide was uscd lo deprolonale he slarting encamine. The chc:]aling
nalure of Ihe magnesium rcsullcd in partal racemizalioD, ivina lower oplica] yiclds
comparcd wilh li lhium-eneamine.
l .
I OJ'I.
2. U ..
Thi oureas are melallaled byelhylmagnesium bromide [30; Eq. (23)]. The magnesium-
Ihiourea i5 Ihen converted 10 a carbodiimide by reaclion with carhon disulfide. Lilhium-
Ihiourcas can abo be used, bUI give good yields only wil h bulky substituents on the
thiourca. Less hindered lithio-thioureas undergo reaelion 10 givc isolhiocyanales, whieh
he magnesio-derivatives do nol.
H,I ..
I 11&1 ..
... y:'..I--' O
O
. ....

"
'.
"
,
"
,-' ,
(23)
K_
C. MIKIII IIMOUI R.actlonl
Magensium amides hay!: beco preparcd and ludie<! for use as ba$eS ( 31; Eq. (24)]. Unlikc
lilhium amides, hese bases are rnuch more thermall y stable. The amine derivalives
diisopropyl and lelramclhylpiJXridyl wcrc dcprotonated using ci lhcr elhylmagnesiurn
bromidc OT dibulylmagnesium.
/' ,
L CI.CII,lIlr L ro,
o ,
o
'"
(24)
, .
C, K.(OO)OCII .
I
I ' .
01,11,
I
" "
Propylmagnesium bromide deprotonates several chiral aloohols (borneQl, isoboroeol,
These chiral magnesium alkoxides are use<! ror asyrnmelric
reduclion or phenylrifluoromelhylketone [ 32; Eq. (25)). The magnesiurn alkoxidcs
generally givc poorcr asymmelrK: induct ion Ihan aluminum derivatives.
,
,
'.
(25)
Alkoxy magnesium halides are prepare<! by eithcr alcohol)'si, of Grignard rcagenls
(MeMgl, BuMgCI. MeOH, EIOH, II PrOH, t BuOH) or pyrolysis of Mg(ORb/ MgX.
wcemenl$. AJcoholysis prOCttds by way or alkoxy- hal ide exchangc, rather than simple 1:1
deprolonaton [ 33; Eq. (26)). Bulkicr alcohol! reacted more complctely owng 10 lower
solvation of magnesium salts.
2RMSO+ R'OH - _ R'OMSR+RH + MSCI (26)
In dielhyl ether./PrMs Br partally dcprolonates a molybdcnum dihydrkle complex,
formns a d magnesio- molybdenum dimer [34; Eq. (27)]. The complex contains / PrMsBr
coordi naled Ihrough halosen brdscs lO anolher melalbound masnesium. In THF, Ihi s
complu breaks down inlo a much s mpler Mo-MgBr complt:l.
(27)
Olefins can be preparcd from (35). hydroxyfulsones are
prepared by alkylalion of melallatcd sulfones usi ng various aldehydes [Eq. (28)]. 80lh
magnesium aOO lilhium sulfones were evalualed, and the magnesium sulfone! had Ihe
'"
advantage of suppressing cnolization dudng reaction witn hc aldehydc. Ethylmagncsium
bromide was uscd as hc base.

(28)
lsopropylmagnesium ehtoride is used 10 deprotonatc Ihe and a-silyl nng prOlon
of McSi(Me.HC,) (HN-/-Bu) [36]. Thi, magnesium dianion is Ihen reacted with Tia)
[Eq. (29). The producl comple", is uscd as an olefm polymeriution catalysl.
-:.P
1I 1 1000l,CHMJCI
/ ........... M
-+-
Mee\' ),
l. TlCI,t_"
1. "Cel
MClhylmagncsium chloridc is use<! 10 deprotonate CH,(SOCF JI.! . Thc anion is Ihen
alkylaled with CF lSQ,F [37; Eq. (30)). Subscqutnt trealmen! with LiOH gives he lilhium
salt that is use<! as an clcctrolytc in conductiog polymcr films.
l. THf

2. cr.so.r
(30)
IV. ELlMINATIONS
Thc 5eCC)nd majar application ror magnesium bases is elimination. Thc st rong basicity of
Grignard reagents allow! a greatcr dcgrec of climinalion Ihan do wcaker bases.,
I-Aryl-I-cyclopropanols are preparcd by a Gtignard base eliminalion process [38;
Eq. (J I)). The key step is elhOlidc: elimination rrom Ihe manesium alkOlddc: inlermediate.
TlH: resulting cyclopropanone is lhen reacted wilh aryl lilhiums to give the final producto
> >
,
CII,K.c1
- ",IOCH, aI,
,

,
/;'"
C
Ol
.aI,l,O
/;'",1

(31)
6. A. S1rci1wicxr, Jr, C. '""rxJrM:IWn lo Orflll,,1 CJwmulry, 2nd ed., Macmillan. N_
York, 1981, pp. 135, 1198.
1. 8. Kryaka, A. Lauren1, aOO 8. Mlrquel, TtlroltcdrOll 34:3291 (1918)-
8. H. Kryaka, A. Laurcn1, and H. Mlrque!, TtlraMdrOll Lm . p. 31(1911).
9. R. Bannik. Y. Hilb, and A. Laurent, Ttlralttdl'f'" JJ:1219 (1911).
10. T. Kunl lnd C. GUIJcM, J. Org. CJwm. 4N069 (1978).
11 . J. Mlnriquez. P. Fapn. and T. Marb, J. A",. Sac. /00:)940 (1978).
12. T. Shono. Y. Ma"umura, S. Kuhimura, alld K. Hlll naka. J. A",. C/W"'. 5. fO/:4152 (1919).
13. B. Coslisella, J. ,nd H. GrtI$S, Ttlr.dron 37:1221 (1981).
14. A. Pinhs and W. Servou. J. C.wm. Soc. Ptrk/tl TrtmS. 11 p. 1600 (1919).
IS. A. Pinku. Ind A. Wu, J. Org. CMm. 40:2816 (19n).
[6. A. Po<:hini, G. Pullia, llId R. Unpro, Tt".drOll Lm. p. 3S91 (1919).
11. F. Huel, O. ,nd A. TttraMt/r(l#l/ }9;419 (1913).
18. M. Bellassoucd, F. Oaroill:. F. Gaudemar-lwlrllolK. M. Gaudem ... I nd N. Goasdouc,
TtlrQIwdrOtl J1:271J {l913).
19. N. Idrm, M. Petry, aOO Y. Maroni-Hamaud, Tt lrahttiron UII. p. 47 ( 1973).
20. Y. Koulhi aOO Y. Maroni. Bamaud, TtlrolttdrOll kll. p. 51 (1913).
21. J. DertraOO, L Gonicl!on, aOO P. Maroni, TttraMtIron Lm. p. 4201(1911).]
22. J. Dertrand, N. Carbal, L Gorrichon-Guilon, and Y. Maroni-Barnaud, TtlralttdrOtl kll.
p. 4683 {19m
2J. M. Abou-Assali, J. Roser, lOO J. Oreul. TttraMdrM 31:1661 {l976).
24. A. Tunaoy, L Lab!:ol,,':ndJ. Pawaik,J . Chtm. Soc. C/wm. Comnrwr. p. 1590(1988).
2S. C. Mioskowski lOO G. Sollldie. Tttraltcdron 36:227 (1980).
26. G. Casiragbi, G. E. Oradi, R. Meaouri. aOO G. SIInori. Tt lralttdrM 35:2061 (1919).
21. G. Wilson, Jr. and A. Hesa. J. Drg. CIwm. 45:2766 (1980).
28. J. Whiletell aOO M. Whiletell, SynlMJu pp. 517 ( 198J).
29. R. A"nunzilll, M. Cinquini, aOO A. Gilard;. S,.nIMJu p. 1016 (1983).
JO. T. Hujimami, N. Dllni, alld S. Saki, SynlMlu P. 899 (1977).
J I. P. Ealon, C. Lee, aOO Y. Xion&- J. Am. CIwm. 5. 111:8016 (1989).
32. O. Nasipuri IIId P. Blhlllacharya. J. Clttm. 5. Pt .k./tI TriBU. 1 p. 576 ( 1977).
33. N. Turova .1Id E. Turevskaya. J. Org_l. Clttm. 41:9 (1972).
34. S. Oavies IIId M. Oreen. J. CIwm. $. /kJII(}If TrQf/.J. P.
15. P. B. LylhOC,.1Id S. Ruslan. J. CItt",. Soco Pnk/tl Tratll. I p. 829 (1918).
36. European Pllenl 04168] S alld 0495375 (lo Do ...
17. O. Denrabah, J. Chtm. $oc. ForoNy Tratll. 89:15S (19'91).
38. H. Brown .nd C. Rao. J. Org. Otm. 41:3602 (]978).
39. N. J. D.g. Cht",. 41:2670 (1978)..
40. 1. Bumham, R. aOO E. Eiscnbnum, J. Drg. Chtm. 38".2783 (1973).
p' m
Table I
Diet hyl phosphatc RMgX Yield ("lo )
"
E{Z
"
Gcranyl 11 ,,C. H,.MBr
" "
'00,"

Gcranyl 11 PhMgBr 97
"
"{'
,
Geranyl II CH.=CHCtI ,MBr 80
' 00 '00,"
O
Gcranyl 1I PhCH.MBr 79
"
""
,
GcrInyl 1I PhC=CMBr 72
' 00
"{'
O
Neryl 12 /IC. H,.MgBr
" "
0/100 11
Nayl Il PbMg8r
" "
.,..
,
Nayl 12 CH,=CHCHJMBr 77
'00
0/ 100 O
Ncryl ll PhCH,MgBr 72
"
''''
2
Neryl 12 PhC=CMBr 66
'00
.,..
O
C. "llrlle: Elhen
In Ihc carly 19405, Luttringhaus [ 17] indicated Ihat oerlain arrl atlrl ethcrs and thiocthcrs
Il:aet wilh phen)'1 and alk)'1 Grignard HiII [18] has Ihown Ihat II hept)'lmagncsium
bromide reacts with lI-but)'1 ,...phenyl aU)'1 clher lo .!ford 52% of 5
N
2' product, namely
J-phen)'I-I-dccenc. Richct and Pecque [ 19] observed Ihat in Barbicr coOOitions, erot)'1
chloridc 18. on reaction wilh magncsium ,00 acrolci n in diclhyl elher, can a!ford citlM:r
the CKpeeted alcohol 20 (in 70-/_ yicld) o. a lriene 21 (- 15-J_) owing to the attack of Ihe
alkoxide l' finl formed b), an allylic Grignard inlermediate [Eq. (7)].
H, C- CH::CH-Oi: .. CI + Mil + H,C_CH_CHO
" H;C=CH-CH.CH-CH::C!-\ HzC!
---- 11 I
H;C= CH - CH- CH - CH:: CH;,
lB
I o{ eH;, 111
"",,'
j
"'"
D. Allytle: Ammonlum S ...
(7)
Guplon [20] rcported Ihat aU)'lie dicthyl amines do nol reacl wilh Grignard even
in Ihe prescnce of a calalytie amounl of Cul. However, their corresponding quaternar)'
arnrnoniurn salts 22 were effectivc rcaelanls wilh mclh), lmagncsium bromide and
pben)'lmagncsium ehloridc. sinoe tlM: expected produClS lJ and 14 wcrc oblained. ane.
purificalion, in 5S and 84% yield, respectivel)' [Eq. (S)]. Unfortunatcly, the regiochcmistr)'
was nOI sludied bcc::au5C of 11M: symetric nature of the startng Ihercrore, lhe s,..2
or 5,,2' mechanism by which lhe pr()(:eSS does (!(:Cur, cannO! be ccrtiflCd.
RMgX

1 J : R= Me; SS'),
14: R .. Ph; 84'Jo
(8)
E, Pt09'rgyl Alcohol'
The enhanced aelivi ly of allylie Grignard !'eagenlS enables Ihem 10 reael with
aleohols by an IHlli-addition [ 21]. In salvenls (EllO or THF), !'eael ions oocur
reai ose[ccl ive[y by assislance lo give lhe dcsired carbomctallalion reaelion producl
[Eq, (9,
ElfJ"rlHF

(9)
2S
"
17 R
In totuenc al 12O"C, the reael ion of allylmagncsium bromidc 2S with propyn- I-
cyclohcJlanol18 !cad 10 lhe 5,.2' produet 29 in &0% yicld [ 22; Eq, (10)].
OH '"
/" ( 10)
Mn <Jo
28 29
Van Dijck. el al. (23J rcpoftcd lhe fonnation of Ihe 5,.2' produel 31 by reaetion of
mcthylmagnesium bromidc with 5,6ft-cpoJly-J7Il1-propynyl-androstane, 3ft, , J7f.1-trioJ JO
[Eq, (1 1)].

. (
E1COO



o
OH

><>",
JI
"
.OH
( 11)
Gouin [24] also reported Ihat atk.Jymagnesium halides, afler oddition 10 hcptyn-l-ol 33.
can 10 some giye rise 10 !he 5,.1' produclS 35; namety. Ihe altenie dcrivalives, as
by-produeu of Ihe carbometal1alion reaelion (Eq, (12)].
".
",OH
RM'"
B'=(QH
B,)--C_ CI-\,


( 12)
"
R
carhomclilll;tctl S,.2 '
pfl'II/oc. 34
"
F, Prop,rgyl H,IIMI
Propargyl hat ides have becn used by Campbell [ 15] and by 8anigan (26) 10 prepare
acelylenic hydrocarbons. For cumple, 8anigan prepared di-r-butylacetylene by reaelion
of methylmagncsium bromide with ,-butyl-ethynyldimcthylehloromcthane [26]. li owever,
10"/. orthe final produet was an unidcntified compound, Meyers [17] tentalivcly idenlified
resulting from Ihe atlack of Ihe acetate funclion [Eq. (15)).
0"
Md>1;\
OH,
A,>=- -=<.CHs R,_ i
R,- I
R,_ I _
-
'"
)
'"
)
'"
.. e .. 7
'"
'"
'" '" '"
.,
..
"
..
( 15)
R,"R" CII . 12
'"
!7
R, ,, R,, -(CH/k 24
"
22
H. Prop.rg)'1 Eth.r.
Nelson [ 31J reporltd that 2_al kylel hynyl_ or 2-aT)'lelhynyl letrahydropyrans 49 \reated,
by Grignard reagents ror 24 hr al room lempcrature in EllO, Icad to high yields of
SN2' -coupJtd products 50; namely, the 5,6-allenic alcohols ( Eq. (1 6)).
R' M;B,
El p.
l. Prop.rg)'1 Olllrl_1
( 16)
[32] reported that propargyl 51 readily rt"aclcd wilh Grignard reagent!
10 afford uclusively lhe 5",2' produc1S: namely, Ihe allenic derivatives 52 and 53 [ Eq. (17)
and Table 2].

Q RMgX
, .
lb EllO
"
n7)
11 is nOleworthy hal ciJ-epoxidcs lead 10 the alll i-allenic product as the major
oompound. bul he natUTe of Ihe Grignard reagent halide can reverse Ihe selectivity when
bromide is used. For rralls..cpollides, he $)'II-producl il alway! the maja r compound.
whalevcr Ihe nalure of he oounteri on. In he sleroid IoC rics [33J, the cross-coupling of a
Ti bie 2
RM,x Yicld 52 +63 ('Y. alll l/s)'"
,.
N-Pent MgO
"
81 : 19
cis
"
38:62
<1, , BIIMgO
9l 83;1 7
,r.],.,

"
4:96
mI,.,
". PenIMI Br 9l 14:86
Ira,.,
' BuMCI
"
6:94
Grignard reagent with alkynyl oxiranes 54 is also very regioselect ive loward Ihe SN2'
producl SS, and the syn-process is Ihe sole process observe<! [Eq. (18)].
I
I I
( 11
H, M.
11, fl
"
'{
'{
I
I
I
---p
fi
fi
fi
"
,\,PI<
'\.P"
,\.PI<
( 18)

EI20


"
(SS: 60 56: O 57:40)42%
J . Vln,! Oxlran ..
Rickborn (34) reporlcd Ihal 58, on addilion of Grignard reagent,
gave only Ihe S,,2 produel 59 in 9.W. yield [ste Eq. (11)). Whereas Johnson [3S] found
Ihal butadicne monoc:poxide 60 reaele<! wi lh melhylmagnesium halides, affording the
S",2/S
N
2' produets 61 and 62. resptClively, with a ratio that sl rongly depended on tll<:
nalure of Ihe haJ ide (Eq. (19)l
I
B,
O
OH
6
--
5\1 Me

( 19)
Andel"$on (36] reporled Ihal Ihe producl dislribulions of 111<: reaclion of butadiene
monoc:poxide 60 wilh Grignard are also dependenl on Ihe nature or Ihe Grignard
reagent [Eq. (20)), whieh has becn also observed by Rose el al. [ 37].
,


"
R IilS,,2'
ti
(20)
Ethyl
"
J.'i
,,81.1Iyl
"
22
Phcnyl
,
R4
K. Intramoleeullr AaKtlon.
Fischer and Howden [38] found that ft,)'-unsaturated Grignard reagents bearing a -alkoxy
group undergo an inleresling oTganometallic rearrangemcnl, wilh a carbon-carbon bond
fOrmalion of a Ihrcc-membered ringo In an acycJic cumple, halides 65 OT 66. when lrealed
wilh magnesium lumings and cthyl bromide in anhydrous THF and healed 10 of
s,., v.,..,. S"r
[Eq. (23).
(23)
A complete reversed selcctivity has becn observcd by Yamamoto [46] who, more
recent ly, reported the chemoselcctive reaction of prenyl Grignard reagent 73 wi th primary
allylic chlondes 76, versus allylic acetates in the presence or CuCN 2LiO at O"C to give
the 5,.2' produCl 78 with high selectivity, as shown in Eq.

CllCN.2UCI
11lF
0"
7RSNZ"
...
Mn -",.2', \17,..
ZlE" MIIf>

>
0"
7'ls,.2

(24)
o,"
F urthennore, for secondary aUylic chlondes 77, additioo of the same Gngoard reagent
73 in the presence of a catalylic amount or CuCN 2LiQ, shows ao eveo higher ,clcctivity
in favor or Ihe s.r.2' product 80, bUI wit h a moderale slereoselectivi ly for the double bond
(ZIE- S4:16) [see Eq. (24)J.
Rachall [47] studied the chemo-- and regioselectivity of the substitution of allylic
chlorides in the presence or allylic atelates by Grignard in the presente or a
catalytic amounl or Li JCuCI. and showed that the reaction was chemoscleclive (the acetate
runction remains unchangcd). and he regioselcctivity was in favor of t he 5,.2' producto In
the cyclic compound, the reaction was al!lO allll-se)ective [Eq. (25)).
1ft S,.2 U
22
-O
,,SuM,Sr ; TIif -O
AcO a .. AcO tI ... Bu
UCuCl
r
40C
(25)
84 Stf285
,
;:;/'
.j)

(26) " 00 M.o .!
Stf2 8. s,..2'UPh
x-a
,
"
X=Sr
"
"
X=I J4 ..
Sachall [48) also 5IUdied the reaeti vity of ArCu(X)MgSr toward t he allylation wit h
aectOlly-4-ehl oro- l -eydohellene-2 87 as a funct ion of the nature of the halide X in the
ini lial copper sal! used for lhe preparation or Ihe organometallic spcdcs. This study shows
t he greal innuellCC or the halidc on Ihe producl dislributions of Ihe reaclion [&. (26)).
Thc formai on of lhe S,,2 product 89 doxreases with the ctoxlronegati vi ly of lhe
oountcrion of he copper spccies.
The regiosc]oxti vi ty ofthc alkylation of preformed organoooppcr spccies also depends
on he nalure ofthis organocopper spccies (48]. The organocopper eomplexes Ar lCuMgX
aOO ArCu(CI)MgX were oblained by reaction of ArMgBr wi th CuCI2LiCI in a 2:1 and
1:1 molar rat io, respective!y. Reaetion of Ph
1
CuMgBr with the cyclic all ylic chl oride 84
afforded a 54:46 mixture ofS .. 2 and S,,2' produets 90 and ') 1, whereas, with PhCu(CI)MgBr,
a regioseloxtive S .. 2' subst ituti on (9. '/.) oc<;urred as shown in Eq. (2n
"
.'"
" l'hCuMg8r" D'"
o
THF
'"0
.<> .. 2 110
"

,
. j)
AcO "
(27)
"
The regi oselect ivily orlhe reael ion also scems 10 be slrongly eorrelaled lO Ihe addition
lime of the Grignard reagent [47J, as shown in he foll owing sludy [&. (28)]
CuX t RMllX -_._ (RCuX) MllX
" (RCuX)MgX + R" Y
"
"
kl
o
'('" .. CuX + MgXY
R 93 '<>,.2
(RCuX)MgX + RMgX
"
o + MgX
1
..
(28)
Monoal kyk:opper oomplellcs preferentiall y give S,,2' alkylat ion of allylie ubslrates
(see Eq. (27)], whereas dialkylcuprates favor S,,2 wilh primary allylie subslrales [47.48].
Consequently, ir the Grignard reagenl ii added slowly or k, > /(1. the monoalk ylcoppcr
species 92 wi1l predominate. and he major oompound wiU be lhe S,,2' product (highcr
temperalure, more calaly!l, and a subst rate rcaeting rapidly wilh 92 will increase lhe S .. 2'

In the samc manner. ir Ihe Grignard reagent is added rapidly or /1:
1
>/1:" the
di alkyk::opper spccies 94 wiIJ be in the majoTt y, consequentl y. the S,.2 ptoduct wilJ be
enhanced. As an iIIustralive demonslralion of such eonclusions, a more react ive allylic
halide should give a high degm: of Ihe S,,2' product, .nd by changing the nalure or Ihis
halide from CI lo Br, Ihe S .. 2';S,,2 ratio should be modilied. That was previously observed
by Schmid [49J in the folJowing cumple [Eq. (29)).
'BrMg
"

. .,
ruickvall (48] also showed that Ihe regiosc\celivity of Ihe reaction of addition of a
Grignard reagen! on acyclic allylicchloride in Ihe presenoc ofCua -2LiCI, can be inll uenccd
by Ihe nalure of Ihe organomagnesium spccics (Eq. (JO].
a
"0
0
.
"
CuCl.2UC1 (l/J mol 'J,)
II-BuM;Br 111F -2U"C
Ift : SN2'>94%-"Su
I
CuCULiO ( In mol D
PhM:llr
lliF -lO"C A.cO AcO =.
"
110 : 1.7 f 111 : I
(30)
With phenylmagnesium bromide l he rtaclions is leu regioscJccli vc (1 .7:1) in favor of
Ihe 5,,2' product Ihan with butylmagnesium bromidc, bul lile al1ack ;5 in both ca5C1
Ilrtliselcctivc.
The sludy of Ihe addition time of ar)'1 magnesium bromides on aU)'1 chlorides shows
thal Ihe addi tion time play' a significan! role on Ihe Sp2fS
N
2' ratio [48] since a fas addiion
(1 minI gavt: a 60:40 ratio and a slol'l addition (10 hr) 21:73.
Tempcralure is also crucial [4aJ , ince the 5 .. 2:5 .. 2' dislribulion changed from 51:49
at - 4J C [O 26:74 al 5O"c.
For lhe same reaction, lhe variation or the amounl of CuC/ 2LiC/ was studied and
shows a signi fican! modificalion of the products distribulion (48] si nce wit h 0.05 Eq. or
CuCI 2LiCI. Ihe 5 .. 2:5 .. 2' TlIlio is 45:55 whereas ror I Eq. of CuO 2lia, the same ralio is
26:74.
B. Al/ylle Pho.ph ....
The use or he phosphate leaving group gives bener reSLI11s ror both the sterct)$electivity
and Ihe: Sr.2'/S .. 2 ratio observed than Ihe corresponding chloride [46).
Thc: natureorthc: oxygc:nated groups on t he phosphoru$ alom is crucial, si nce diphe:nyl
phosphate:s alforded better 5 .. 2'/5 .. 2 ralios Ihan diisopropyl phosphate:s (Eq. 31) and
Table: 3].
,
(31 )
-
S"l S"l'
T. ble S
Calalysl Condilon! Yield ( %) f>t2JS..2'
CuCN 2LiO - 78' C, 1 h.
"
1:99
"-BuCECCu - 1S' e, 1 hr
"
14:86
Cul 2LiCl n ' e, 111.
"
20:80
CuO., -7S' C. IlIr .. 20:80
Li ,CuO. - 7S' e. 1 h. 14
" :49
CuBr Mc,S -7S' e. 1 hr
"
66:l4
CIIOTf - 7S' C, 1 h. 62 SI: 19
CuSCN - 4J' e. 1 h.
"
91:9
(34)
Inlereslingly, Marshall [50-52] found Ihal on addilion of a Grignard reagcnl 10 Ihe
letra!ubstituled allyljc phosphate 11 1, in Ihe prcsencc of I Eq of eoppcr iodide in
and dimelhyl5ulfide, Ihe $Ole produel formed was the S",2-coupled
compound 112 in good yield (82".) [Eq. (35)].
"'
C. AUr lle Etne,..

DME
Cut (1.....,.)
DMS (6cq.)
-7Hlo -2O"C
(35)
112S,..2:82%
In Ihe prcsence of Cu
'
, aUyl dhers can be coupJed with Grignard reagcnls al room
tempcrature in good yieJd aOO wilh high regioselectivilY in favor of the product, plu,
an ucellenlslereoseleclivity toward Ihe E-isomer [53], when usi ng a 1:3 EI,O{THF
[Eq. (36)].
QM.
[
CH -CH = CH - CH,- CH,OH
1 I J(Z)

2O"C, IIIh


[
Qi: Qi - CH - CH,- CHzOH
11 4 _ J 15(E) (36)
RMgX ., CHIA: I 11 4: 72 <J,
RM;X " EtM;Br 115: (,11 'lo
The same year, il was nOled by Commen;on [54] Ihat lhe use of Ihe Cu' Br cataly!i!
fOf the reaelion of Grignard reagenl! wilh allyl melhyl ethen lead 10 the of S",2
and S,,2' products, according 10 the !Ierie hindrancc or Ihe substrate and Ihe geomet ry of
Ihe double bond (Eq. (37] and Table 6).
Ro
R,.... 1
C_CHC_ OR'+ " .DuM:CI
,
lit;
'"
'"
_
_ R, .... I o
C_CH' C_
no
(3n
"-
111 R;,
"'"
o RM;X ,
/" o 123 Cu( l )
RMEX I
0""-
Cu( l)
"4
R-CHa - CH'CH(CH1);rOH
125 : fi7'J,
(40)
With related compounds. 5uch as allrl;e aoetals. they react with 10lal allylic
transposi tion in goo<! yidds 10 alford lhe correspondi ng cnol clhcr1 (:57; Eq. (41)).
(41)
Acidic workup Icads lO he correspondi ng aldchydc. Thc addition of 2 Eq of P(QElh in
reJalion with Cu Br, allows lhe reac1ion lo be perfonned al + IO"C.
D. Allyllc C.rboJl:ylele.
1. Al/yUe Acetates
11 is also possiblc 10 subslitulc aJlylic acetates by a Grignard rcagenl. hUI in tlle presenoe
of copper catalyst. Fouqucl [SS] reporte<! Ihat lrllns-crotyl acetate 128 is convcrled
regio- and stcn:osda:tivdy by n-butylmagncsium bromidc into Irm 2,oclene DO, with
88'V. yicld, by an 5.02 process [Eq. (42).

129
1"
U"uO
T'- 4 .
niF:SP(S:4)
"4
(42)
!JO
Sehmid [49] made a simi lar observation, bul noticed the formation of or the product
roulting from he auaek of Ihe carbonyl of the acetate runction.
Allylic acetates can also give rise to the reduccd products in the case of cinnam)'1
acetale. Indeed, trealmenl of cinnam)'1 acetate by elh)'lmagnoium bromide in Ihe presencc
of a calal)'lic amounl of Cuor in THF Jed 10 16% of the reduced compounds and 84-;.
of Ihe 5,.2 producl in a 70% combincd yield (55].
More recenlly, Backvall (47] showed Ihal Juch reaClions are ver)' dependent on Ihe
nature of Ihe solvent, temperature. calal>,,!, aOO addition time of Ihe Gri/!.llard reagenl.
The calalysl Li.CuCI. is convenienl 10 use. since il is soluble in masl solvenl$ and i$
rapidly reduced in copper(T) by lhe Gri/!.llard reagent. even at - 7SOC. lbe innuencc o( Ihe
addition time of the Grignard reagent on the regioselcclivily of the react ion is provcd by
the following slud)' (Eq. (43) and Table 1].
PIlS-----....
'-" '
'-04e n-BuMgBr "--- .... 811
iHF .:111"('
lJl
!JI
S,.2
PIlSy-,
.B,
1J.l
S,.2
(43)
A slow addition of Grignard reagenl givC$ a !xtter S,."J:fS,.2 ralio in favor of Ihe 5
M
2'
Y. ble 7
Addition tilllC' or mol % of
'"'
S,.2
". SuMg8r Imin) Li,CuC1.
132(%) IJJW. )
, ,
" " 20
,
"
38
., ,
" " 20 S 23 77
.,
S
"
87
T. ble 8
Addition lime of Mol % or S,..2 (%) 5,.2' W. )
... 8u MgBr (m;n) Temp.("q Li,CuCl.
'"
13.
U - JO 2
"
,
20 - JO 2
"
"
.,
- JO S
" " 20 O S ..
"
.,
O S 38
" 'SO
O S
"
"
producl. An increase<! amount of lhe calalysl ravon lhe same 5,.. 2' producto The reaetion
i, also chemoselocti ve, since an allylic phenyl sulfidc docs nol react in l hesc condi lion,.
Wil h less reactive ubsl rales, lhe lemperalure has a dramal ic efreel on lhe sclectivil y:
10'111' temperalurc and raSI addi tion favoring Ihe 5,..2 product, whcrel5 higher lemperalure
and 510'111' addi tion give lhe 5,.2' producl as l he major compound (47; Eq. (44) and Table 8).
'''J
Once agai n, the reaclion is chemoseleclive. si nce allylic phenyl elhers do nOI react in lueh
condiions.
80l h cfreets. addition lime and lemperalure, are ill ustraled (47] by Ihe reaction or
geranyl acelate with n-bulylmagnesi um bromide in THF in Ihe presc:nce of a catalytie
amount or Li ,CuCI. [ Eq. (45)].
I J tI ". Bu
131
(45)

I J9.'\,.2'; 611 ". Su
Tibie 9
Mol ratio Li,CIIO. Reaction Distribution
141/1'4l fmol%) Temp.ro Yicld f%) 142/10/1"
l.,
,
O THF
"
100:0 :0
2
"
O THF
"
91:0:9
l.'

20 THF
"
9S:1:4
2
,
O Et,O
"
80:0 :20
5uzuki [.59] also shows the high 5,.2 selectivity of lhe reaclion belween allyl acetales
and Grigna.d reagents by UlCuQ. catalysis in THF; bul modifieation of the nalure of
the solvent, temperalure, quanti ty of catalysl, and Ihe Grgnard reagenl used, had a
moderate elfect on the regioselectivity [ Eq. (46) and Table 9).
% TIH'
Ph c:..cl.
140 14\
S,.2142 : 14l.Z:1:)

(46)
S,.2' t 44
However, Backvall [47] reponed a dramatic solvenl effect, but used CuCN, rathe. Ihan
U,CuO., as a calalysl. The reaclion in THF at -78"C gave only the 5,.2 product. and
bychanging Ihe solvenl from THF to EllO, Ihe seleclivilycan be 101all)' reversed [Eq.(47)).
137
".BuMrBr
OAc
10 % mnlCuCN
'J,
THF,O"C. St.21S,.2'.94:6
Elp, 211"C, S,.21S,.2'.

""
Very recently Biickvall and van Koten [60] reponed that or'ho-aminoarenethiolacto
coppc:r compounds are excellent catalysts for lhe cross<oupling or Grignard reagent! with
acy<:l ic allylie acetates. For examplc. with slow addi lion of lIbulylmagnesium iodide 10 a
solulion of generanyl acetate conlaininl orrho-Ihiodimet hylaminometh)'l bcnzcne in
calal)'t ic amount. the 5,.2<ouplcd producl was exclusively obtaincd, whcreas in THF al
- JO"C, a fast addition lead lO lhe sole formation ol!he 5,.2' product.
2. Al/file P/"I' aloates
Goering (61,62] underlook a stud)' oC alkylalion ol $(lveral Grignard reagen!s wih allylic
pivaloates in lhe presence of a copper catalyst, in EllO [Eq. (48) and Table lO).
'''''Y
RMgX
'''''Y


[CI'J, CIIX
oe, , ,
(48)
S,.2 S,.2'
' 45
",
'"
T.ble 10
RMgDr C.X (146) S,,2' (147) Yjcld 1%)
N_OuMaBr CuCN 2- } 97-98
""'00
N_OuMaOr c.a 89
"
78- 96
II RuM,o. Cu Or
"
"
" IIRuMgDr C. , ..
"
..
N-RuMgD. C..sCN
"
"
90
r BuMgBr C..eN 16-21 84- 73 81- 91
PhMgBr CuCN >99 <O 16
T. ble 11
Organoropper specic.l S,,2 (146) (1 47) Yic:)d W.)
BuCutCN)MgBr
"
97.8
" BuMgB.CuCN 2.6 97.4 99
( 100:1)
Bu,CuMgBr
" " " BuMgBr/CuCl 89
"
96
(100: 11
Acyelic allylic 'y'tcms are ' ufficient ly react ive Ihat pivaloates can always be used wilhoul
detectable carbonyl a!laclr. , With alkyl Grignard reagents, the CuCN-catalyzed react ion is
highl y regiospecifie and give5 eilher uclusively. or predominanl!y, the 5,,2' producls.
whereas copper haJides completely reversed the regi oselectivity of Ihe reaclion in favor of
the S,,2-coupled produet (scc Tabk: 10).
Furt hermore lhe CuCN calalysl is more ugiospecifi c wilh the use of /1_
butylmagnesium bromide than wi th ' -buty!magncsium bromide. The reaction wit h
phenylmagnesi um bromide also showed an regiosclectivil y in favor of Ihe 5,,2
product o
The di stribution of S,,2/S,,2' produets (I46JI47) for Ihe reaelion betwocn trallNI-
melhyl-)/""pbenyl allyl pivaloate 145 and n-bulyl magnesium bromide in El lO [see Eq. (4S).
was sludied as a fuocion or lhe nalure of Ihe organocopper species [61) (Table 11).
The resiochemisl ry o( lhe stoichiometric alkylation (2.2 :97.8) 15 Ihe Jame as Ihal for Ihe
catalyzed react ion with CuCN (2.6 :97.4) and is in favor of he 5,,2' product. No reaet ion
oa::urs wilh n- BuMgBr{CuO (1:1) because of the formalion of lhe insoluble n- BuCu. 80th
regioselectivitiesobscrved for the alkylation wit h n-Bu,CuMgBr (85: 15) and CuCI-calalyzed
reaction (S9 :11) are in favor of Ihe S,,2 product.
3. AI/ylle Mosltos/ss
In eyeli e compounds, the influenoe of the catalyst is the same as already ob$crved in aeycl ic
cases with all ylic [61 ; Eq. (49)].
Although CuC! gives a parti a! regioselecivity (61:39) in favor or the 5,,2' producl.
CuCN gives an eKclusive alkylalion wi lh, in bot h cases. an a/lli-addilion.

II -BuM;X
o


141% CuX
\. ... au
... el
O
(49)
4110
lMB
, "
1511
mM II "'mc.,i".",1C
CuX =CuCl .w
"
CuX '" CuCN
"

4. Al/rile LIJetones
Fujisawa [63] reponed the nucleophilic ring-opening reaction of five- and si.l.-membered
laclones with Grignard reagenls by a ooppcr catalysis [Eq. (SO) and Table 12].
RMgX + Cut (2mol"" R COOH

TI-lF:Mc S (2n: 1)
.;:lIl"C
'"
(50)
AII reactions gave clIceUcnt regiosdectivity in favor or he S .. 2'-coupled producls (since
nane S .. 2-couplcd produtt could be Alkyl Grignard tcagenls lcd 10 he S .. 2'
prodllCI in high yiclds. whcreas he vin)'I-, all)'I-, and phen)'1 Grignard reagenls gave lower
yiclds and a moocratc stcreoselcclivily in favor of Ihe E-compound. Thc same resu!ls werc
ob$ened with - vinyl-6-valcrolactonc (63].
More recenll)', Curran [64J reporled Ihat a Grignard reagen! with coppcr catalysis
oould rcae! and opcn 2H-cyclopcnta(b)ruranones 153 (Eq, (SI) and Table 13J.
"
COOH +
l:uX ,/ A,
I Hlte ,R,.,R-II
11 RI" II II. :-(.:II .
RI=CH) 11. :",11
.,,,A:
(SI)
This slud)' showcd that Cu Br o MeJS mus! be empl o)'ed in a sloichiometric quaDlit )' lo
obtai n good selecti vi')' in favor or the SN2' product ( > 98:2). since a catal)'lic amount lea.ds
lO a SO:SO mixlure of .he SN2fS .. 2' -coupled produCU-
T.ble' 12
Grignard ...,agenl Yicld (%)
ElZ
MeMgllr 87
92:'
,,_lluM,Br 9) 86:14
J- BuMlllr .. 83:17
- lluMI8r
"
18:22
PhMgBr 7l 62:38
(Vinyl)Mlllr
"
S1:43
(All yl)Mgllr
,
92:8
Ph,CuMgllr
"
82 :18
(Vi nylJ,CuMg8r ro 112: 18
(Allyl),Cu M gllr .. 86:1 4
The reaction il Itereosclective, as only the anll-product was forme<!.
Fuj isawa (67] found Iha! he introduclion or a prenyl alcohol moiely,
wilh an f-conliguration, into a vinyl oxirane was readiJy achieved by a copper-catalyzed
5",2' reacl ion. Thus, addition or a Grignard teasent IfO 10 a solution of isoprenyl
and copper(l) iodide (5 mol"!.) in THFfMeJS (20:1) al -2O"C alforded lhe allylic alcohol
161 in 95"-. yield in a 97:3 F./ Z ratio (Eq. (54)].
(54)
'60
5uch prcx:edurcs wefll applicd by Marshall [50-52] for ,he synthe$es or large
cycloalkancs [Eq. (SS)).
(CHulo
'"
RMl,lBr THF

2 C<j. Cul; 12 "'l . MCJ."
{
CH:I=CHCHP-I2M;'r.
RMgBr ti-Pl"hSiCEiCOf" ';&
BuMgBr
(SS)
'"
Wilh addilion of [(triisopropylsilyl)propargyl] magncsi um bromide-lppcr(1) iodide
to Ihe vinyl 162 in THF-dimelhylsulfidc, the lran3-allylic propargyl alcohol 163
j, primarily forroed, in 79% yicld. Addili on of Ihe analogous lrimethylsi!y! reagenl ave
risc lO considerable 5,.2' allenic product, rcsulling from r-attack ofl ne propargyl reagenl.
Mari no [68] showed Ihallhe si lyl enol etners of subst il ule<! 2,3-epoxycyclohcxanones
react wilh (PhCuCN)MgBr and (CzHJCuCN)MgBr 10 givc, respectively, the 5,.2' and 5,.2
products [Eq. (56)].
OTMS
(PhCuCN)M:Il,
p ...
S,.2 lS

'"

(56)
OTMS OTMS

.. ,",

"",
l\5'J,
, ..
More rccently, Hudlkky [69] reponed Ihe regio- and chemosclect ivity orthe react ion
bct ween homochiral vinyloxiranes and Grignard reagcnls in Ihe presc:noe of a catalYlic
amounl of coppcr iOOidc [Eq. (57)].
S,..l'
'w'

a




:X
McMCBr lO'J,Cul



THF , 711"C 10-4O"C
:Me

o 161


16'1: 511%

OH



H M,




,


o
ce
McMCBr III%Cul
X'
oX
(57)

:.
1lIF:l'.tC) -4(f'C
o M.

,
-
OH
OH

H
,
1711: 171: 11 %
o RMCBr Hl'JCuJ
'f
a:><
x .

o THF 1M"CIO- 111"C'
R '" yhnclhyl
i
OH .
172. K.l'JI
TIle s,..2' product is predominanlly rorme<! by nonhalogenated compounds, which
tack lhe bulky, electronwithdrawing halogen atom. The S,..2 product i, IImi, whereas the
S,..2' producl is syn (owing 10 Ihe sleric hindrance or Ihe
F. AlIylJc ",Irldln
AUylic aziridincs can be alkylated by Grignard reagent! in Ihe presence of stoichiome!ric
quanli!ies or copper cy.nide [70] 10 give Ihe alll;-S,..2' producl as (he major compound
[Eq. (58)).
R=i- Pr
R=iP)Si(Mc):CH
R=pF-c,.H,.cH
J
,
'"
"
"
(58)
Hudlicky (69) reported lhe openiog of vinyt aziridiocs io cyclic compound$ that, as
Ihei r corresponding cpoxydes, gave rise lo Ihe S,..2 product in moderale yiclds (Eq, (59)]
".
o o
:>
)
McM:llr ICuI
,
THF-El.:O -4S"C

'"
5,.2 118
(59)
SJ'J.
">
)
McMl!Br.(;ul
,
O
TIIF:Ettl -4S"C
...
i
S,.2 179
177
..."
23 ...
G. Allrlle Arnrnonl"", 8.1t.
Tert iar)' amines. whc:n treal;ng with Grignard reagents, with or without copper catal)'sis,
do nOI react, whcrcas the correspondng quatemary ammonium salls can be displaced
by organomagnesium rcagenls in he prescnc:e or a catalytic amoun! of Cul in THF [20;
Eq. (60)).
,."""'"
(C"
"",l
McM:Or tSrooI <:tCul
,
I
TH'
(ro)
r +NMe,
",..
..
"
13
Suzuki [59] reported Ihat alkylation of a Grignard rcagenl with geran)'1
triethylammonium iodide gave risc 10 the SN2 producl in cllccllenl yields [Eq. (61)).
lOO
H. AUylk: Sutil"
....... CuBr 4mnl'"
"' .....
TH'
141 15%
'-./ ____ '" (61)
142 S,.2(9S'iI> Zl
Primar)' allylic su/lides of derivatives of belttOlhi:u:ole-2-l hiol rcae! wit h Grignard Teagenls
in Ihe prcsence of copper(1) iodide 10 yidd olefins, wilh or withoul allylic rearrangcmenl,
depending on Ihe nature ofl ne salvenl and Ihcallylicsulfide [71 ; Eq.(62)and Table 14].
,A ..... BuMsBr. "Y
R
.. (62)
/ Bu
";'-5 1111 SN2' Ull SN2 UlJ
In elher, Ihe SN2' oouplcd product il ronncd predominanlly, whcreas in a mixlure or THF
and El l O, Ihe product iJ lhe major oompound, wil h rClenlion oflhc oonfigul"ll lion of
the double bond.
Cal [72) sludicd Ihe cffc:ct or lhe ratio of Grignard reagcnl/CuBr on the
regiose[cclivity in the cross-coupling of lhe 2-OCla-2,6-dicnyllhiobenzothiawJe wi l h
Tibie 14
Yidd

5,,2' (182) 5,,2 (183) (182 + 183)
'"
Elher
"
J
"
Ph (2:1)
,
"
8J

Elher
,
"
..

(2:1)
,
"
90

TUI" ro JO
T.ble
Producl aFler
,Eq,
s,.2JS,,2' IS mi n ( "lo)
1: 1 O.S: W.S
"
1:2 1:519
"
1: 1 71
1:0.1 50:50
" 2:1 70:30
"
4: I 519:1
"
bromide (Eq, (63)); the res ults are s ummarizcd in Table 15.
>S.
",.
>Ss

. '"
(63)
The 5,,2/S,,2' ralio depends on he CuBr concenlration. In a catalyl ic a mounl o CuBr
(0.2S the product distribut ion is in ravor or the 5,,2 produCl (99:1 whereas an
or CuOr (3 Eq) increaSC$ the S .. 2' product
Calo ( 72,73] also noled hat t he 5,,2fS .. 2' ratio depends on Ihe nature of lhe
organocopper specics [ Eq. (M)].
(64,
RI " U ... alkyl
R 2 '" H. aryl uf COOR
The 5,.2' product is favored by a low rat io orGri gnard reagenl/Cu Or and the S
N
2 producl
by a higher OMe.
p' m
rabie 17
Yield
5.'
R, R, R, R, R,
RM'" (S .. 2/S .. 2'I (El z)
H
"
H H H
" H
" "
H M. " -HuMaRr
"
-
"
H H M. H

"
98( 100;0)
H 11 H M. H "- HuMaCl
"
100(100:0)
H H M. H H "- HuMaBr
.,
74( 11:80)
H H M. H H
"
7S13:87)
H M. H H H
" "
"
B"
11 H M. EI M Br ro 20
H
B"
H H M. EI M Br(EI 1O) 40 4
"
H M. M.
"
1I-1'luMIRr l
"lO
H H M. M. H II- HuMgC1 20 100
"
H M.
C. H"
"
II- BuMaO JO 100(100: 0)
M. M. H H H 90 o
rabie 18
R, R, R, R, X SoIvenl Yield (%) S .. 2(EIZ)
H H H M. 8,
TH'
"
98(100:0)
H
"
11 M. a THF
"
100( 100:0)
H H H M. a EI,O 10 90( 100:0)
H H M. H 8,
TH'
40 74(11 :89)
H 11 M. H C1 THF
"
75(13:87)
M.
" "
H
8,
TH'
" "
M. H H H B, EI ,O 20
,
M. 11 H H C1 EI , O
"
,
allylic sulrone has becn sludie<! and reporte<! [75; Eq. (67) and Table 18].
. "
l' ,R) 1 )1.,
11o- C:-()4:C. +
"
, R, Cu(ocacll'J> 1 11.,
",
"
""
S .. 2'
(E.IZ)
-
l
o
26
"
84(40:60)

96(70:)())
o
o
o
100
S .. 2'(EjZ)
l
o
10
26
"
84(40:60)

94(61:39)
(67)
Organomagnesium t hl oride used in THF ave Ihe bes! SN2/SN2' ralio in hi,h yields.
compare<! wilh Ihe correspondins bromide. Secondary allylic !ulrones led primaril y to Ihe
5 .. 2' producl in moderate yield in THF and in low yields in EllO.
Trost ( 76) reported the alkylation or al1 ylit !ulrones wilh Grisnard reagents in the
presence or a calalylic amounl or CuCN in EI
2
0, wilh hiSh regio- and SlereOKleclivi ty in
favor of Ihe 5
N
2' producl [Eq. {68J].
'"
producto when the reaet ion is performed at low temperalUre [77. Eq. (72)).
"
"
"

,
,
uc=c O
/\""Ol zOll R, /\""OlzOll

K"C=C- ,\ 011
"c=e=c 011

'"
"
.. ,o
" \
" " yield SY" 212 ami 2 13
(C. HI1)zCuM,Br. 3O"'C
'"
. ,
...
(C.H9lzCuM, Ur Me S: ..6()"C
"
1
.,
(C,11
17
)zCuM,Br Me:S: .6I1"C
"
2
"
(C
1
HI 7)zCuM,Br Me:S: . J(I"C
"

%
(72)
Thc reaetion is completel)' regioseJectivc in favor of t he SI'f2' product, and Ihe eross-coupling
of proparg)'1 epollides wit h organocuprales give nearl)' an exclusive tllllI-product wlH:n
dimethyl sulfur is present, b UI gi\'e mixlures of s}'n- and tlllli-products in its absence.
More recenlJ )', (32] reponed the diastereoselecti vc S}'II- or tlll li-opening of
propargyl cpoxides, wi l h good to clccllent 5
101
2' selectivit )'. Addition of IWO equivalents of
phosphinc as a ligand can inHucnee Ihe stereoclH:mistry of Ihe elimination slep 10 afford
either !he syll- or ont l- producl, as shown in Eq. (73) and Tablc 19.
Ilu.. ti
"(
JI... llII
I(
" "
2 oq. BuMgX
0 1
(73)



$'lI CuBr. Li gand
-50 lO -lO"C
5,,1'


2\6
'"
m m
'"
..
""
<0.'
....... 'r-b;1
Thc best stercoisomcnc olla/ s}'1I ratio was oblained wit h two equivalents of ligand (pe,
eu salt) and PBu
J
was preferred. because lhe reael ion milllure remainc:d homogencous
throughout !he reacl ion. The nature of X in RMgX influellCC5 the stcreochemi str)', and
!he beS! resulU are obtained wilh X _ Ur.
Y_bit 19
"ntl/sl
n Yield (%)
RM'"
Ligand (21 5fl I6) 215 + 216 211('Y. ) 218( %)
n_BuMgB.
2p(OElh 46:S4
"
n-BuMaDr P{NMc,h 99: I
"
JO
n-BuMa Br 2p(NMe
l
h 100:0
"
10
,
n-BuMa B PBu, a8 : 12
'" "
10
n-DuMI Dr 2PBu 100:0
"
"
n_8 uMgO 2P8u, IM:6
.,
n-8uMgl 2P8u 90: 10
"
Table 20
c"
Ligan<! Addilive anrl/Jyn Yield ( %)
CuRr 21 POEl ,h EI,O 41 :S9 100
CuBr EI,O JS:6S
"
CuRr Benzenc: 20:80 ..
Cu Rr EI,O TM.o 24:74 82
c,a
EI,O TM.o 29:71 100
CuCN EI, O TM.o 38: 62 100
CuSPh EI,O TMSCl J7:63 100
CuRr EI,O-pentanc TM.o [2: 88 100
Cu Br Et , O (O"C) [0:90
"
It is possible to increase Ihe Jynanli ralio by addition of TMsa or by changing Ihe
salvenl [32; Eq. (74) and Table 20].
Duyll
""1( 000

2eo:. BuMgCl (74)


S% CuX. Ugand
soIvml addilivc
,<,.
-SOIO-2(l"C Ih

,
'1<
215
'" aJli
As shown in Table 20, the ligand hu a dekterious effcel on lhe amount of the
&ynadduet. and lhe pla)'1 a significant role on Ihe Jlereosclcclivi ly, since a Il:aetion
run in bcnzcne gave a 20:80 anllJyn ratio, comparcd with El , O (3S:6S); howcver. Ihe
ehemical yield il poorer (48 and 72, Addition of TMSCI improves both lhe
&J'n-selectivily and Ihe eombined yield. Wilh substitulcd alk)'ncs, lhe samc elfccts (Iigand,
additivc, salvenl) all: observed (32).
Rcaetion of acyc!ic propargyl epolides with Grignard Il:agcnts in Ihe presence or Cut
catal)'l! alfordcd Ihe producll exc!usiV(lly, wilh high ' Icre<lselcctivily toward lhe
sy,,product. For the Iraru-epoxidc, !he selectivilics are higher, particularl)' for lhe
sy,, -proccsl [32; Eq. (7S) and Table 21].
1 lea 11
liel 11
""",,o
'>=:1-'"
">=:1-'"
(7S)

4-

" "
. "
219
,,,. 220
1m'; 22 1
L. Prop,argyl Eh"
11 Wa5 noled by several aulhors [S3,78,79] Ihal propargylie elhers reael with Grignard
Il:agenls by a coppcr calalysis 10 alford a miltull: of the S.r2 and S.r2' produets, wilh an
occasional elimination produet [Eq. (76)).
.. CoM
'=( ."
'(.11
""
'"
EllO; .7R"C
X_I !lIIti prodUCl(:e:SlJI,
X..a ,,.. pmdUCI te;)!i'l.

,.,
.. "
)= c =(
, ..
(18)
lJ6
By Uliing a homochiral et her, and oonlrolling Ihe $yll- 01 oonditions of the
reaetion, pUfe alltnie derivalives can be obtaine<! in high oplical purity [SO], as showtl in
Eq. (79) and Table 22.
,.
2RMp:
- .
- "'II
R' '" penl or Bu
"'0):
,,,

, "
)= c =(
11 11.
23'1
(79)
Wilh primary alkyl Grignard reagenls, lhe syl1-pr0CCS5 predominalC$, whatcver he rcaelion
condillons are. Under Ihe bes! cnndilioos (PentMDr, 2p(OEth. EtO/penlane 1/ 1) he
aliene is obtained in up 10 93+/. oplical punIr. Wit h hindcred Grignard reagenls, Ihe
anrjprGCess is predominanl.
M. Properg)'r Acetal
Propargr] acetales. on addition of alkyl Orignard reagents in Ihe presencc or a C8lalytic
amounl of Cu'o afford exclusively the produCI; narm:ly, Ihe allenic derivatives by an
<lnri-process (SO). as shown in Eq. (SO).
..
,, -HcltM;Br
"" "
(: 1[
'):: c =(
-

mti a:::79'l.
I()<J, CuBr EllO
"
..
"'"
1<111
'"
(SO)
..

"
,,-BuMgCl
'):: c =(
- r-11

I1mi cc:96%
5%CuBr EtlO
"
...
2o:F 2p(Oal,
'"
T.bI,ll
Yicld Aliene OveraU
RMIX Lipnd Solvent W. ) ( %) ronfis. :.roo;eu
,,-PcnIM&O 2P(OEl h EllO 8l
"

,,..
n_PenlMgBr
2p(OEth El lO SO
"

,,..
n- PcntMIBr 2p(OEt), EI,O/ pcnlanc, 1:1 80
"
" ..
n-BuMgBr 2P(OE1 h El,O 66
"

,,..
EIM,Br 2p(OElh El,O .. 12

,,..
-BuOC.H.M, Br 2P(OEI).
''0
"

,,..
/- BuMI Br 2P(OEth EI,O/ pcnlane, 1:1 ..
"
S
<ln/
'BuMgBr 2PBu. EI,O 62
"
S
M"
'-BuMgBr 2PBu
J
EI,O
"
10 S
M"
c.e nnl ...........
rv. REACnONS CATALVZED BY PALLADlUM
allylie alkylalion by Iransmelallation wilh Grignard reagenlll is 1CS5
frequently encountered Ihan wilh aryl- and vinyllin reagents [8S]. However, a few eumples
are known from (he literature and reponed herein. In $Omt callJC5, if Ihe reaetivity of sueh
allylic--elhen or amines have betn reponed, the regi oselectivily was nol sludied because
of the Iymmel rie nalult! of the subslratc:s..
A. Allyllc Hllldll
Sumagi n el al. [86] noted that GriJDard reagenl5 reaeled with allylie halides in THf in
lhe presence of a calalytic amount of patladium triphenyl phosphine lelratds [Pd(PPh ,).l
al room lemperature [Eq. (84)].
Pd{PF'hjJ
... PbMeBr "
ruF.2O"C
(84)
253: 96 'Ir
The same study showed thal Pdo gives beuer results than Pd
ll
C8lalysis in the yields for
formalion of alkylated products. Unrortunalely, excepl fo! a single It!port , Ihe
regioselcctivity was nol examined. Indecd, when cinnamyl bromide was reaeted with
phenylmagnesium bromide in Ihe presence of Pd{PPh,). , lhe 5",2 coupled product lS5 was
Ihe only alkylated eompound observed. in 77"/. yield with 22% of biphcnyl [Eq. (8S)).

'"
B. Altrlle Ae.ta ...

... PhM,Br
ruF.2O"C

155; 77 'lo
(8S)
Negishi [87] found Ihat phenylmagnesium bromide reaeled wil h fE:krot yl acetate in Ihe
presence of Pd(PPh,). lo alford a nearly 1:1 milllureofs..2 and 5
N
Z produels [Eq. (&6)).
'- ....,....... .0Ae
-....".-........, ..
l!Ili nlF.1H"C

157; 4K 'Jo -t Ph lSg; S2 'lo
(86)
C. Altytle: Eh,.
Sumagin el al. [86] also reported Ihal allyl phenyl ethen can reaet wilh phenylmagne:sium
bromide in THf al room lemperature in lhe prcsence of Pd(PPh,). lO alford lhe desired
phenyl-l.propene-2 in 39'Y. yield. Unfonunalely, Ihe regiochemi sl ry of sueh a reaction
with ot her 5ubsl rates was nOI studied [Eq. (87)].
..d'... Pd(l't'h,l. --"- _Ph
fIY........ ... PbMgBr . ,.......,...
H' ruF,2O"C
D. AIt,11c SuIllOe.
f- Ph-I'h

(87)
Takei [88] examined Ihe calalytie aelivil, of Pd(PPh, ). and Pd0
2
(PPh
l
h on l he reaelion
of phenylmagnesium bromide wilh IlIyl isopropyl sullide; Ihe alkylated produels were
obtained in 52 and &6% yields, rcspeclively. Unforlll natcly, the regiochemistry of lhe
reaelion was nol sludicd [Eq. (88)].
(88)
E. Prop.rgyl H,llde.
Li nst rumeJle [89J reported that propargyl chlorides reael wilh Grignard reagcnts lO give,
as the soJe prodl,lel of Ihe reaedon, Ihe 5...,2' oompounds 26Z.-d; namely, lhe allenic
derivalives [Eq. (S9)].
(S9)
In the same report, lhe aUlhors showed that alJcnic halides reacl with Grignard TeaSenl$
lo give the allenic oompound, wilh fair to 1000 yields (Eq. (90)].
THF
-)-'=-"CI + CtoHnMgCl J-C--..,.
PdCl
1
tCI'), C.HI1 (90)
163 PPh, 20 $ 264: 98 'J>
HAU-Ou tO %
V. REACTIONS CATAlVZED BV OTHER TRANSITlON METAlS
(NI, Fe, Co, Mnl
Copper-calalyzed subslilll lion of allylic halides (and reJaled cases) wilh Grignard reagenu
has been extensively st udied (see .5ection To a lener the use of ol her transi tion
metal catalysl, sl,leh as Ni, Fe, Ti, Mn, Cr, remain! anecdotally stl,ldied.
A. Allyllc Alcohol.
A1Jylic aloohols do nOI reael wit h alkyl- and aryl-Grignard rcagenls [90]. However,
Swierczewski [91J reported Chat methyl-, phenyl-, and benzylmagnesium bromides reaeled
wjch al1ylic alcohol, in Ihe presence of a catalyt ic amounl or NiCl,( PPh,l, 10 give either
a miuure of S",2/S", 2'-coupled products. or when R, or R is equal 10 phenyl. 10 the $Ole
S",2 oompound [Eq. (91) and Table 2J). The same seleccivily has been observcd by Wenkcrt
in si milar condilions [92].

(91)
T.bIe 23
R, R, R, R s,.2 ( %) 5,,2' (%) Yield W. )
CH, H H
M,
'"
..
"
CH, H H Ph ..
"
,71
H CH, H
M,
... 90.2 80
H CH, H Ph 41.4
" .
,,,
H H CH,
M,
31.2 68.2 82
H H CH, Ph 55.9
"'.1
JI
Ph H H
M,
100 O 81
H Ph H M, 100 O 81
H H Ph
M,
100 O
" Ph H CH,
M,
100 O 74
For a cyclieoompound, when vinyl-l eydohexanol l68 is lrealed wilh methylmagnc:sium
bromidc, wilh 10 moje. or NiCI
1
(PPh,h, a 75:25 mixture or products 169 and
270 i5 oblained [Eq, (92)],
To ralionalizc tllcsc experimental results. lile aulllors [91] proposcd that the eommon
inlermediate is a III-allyl eomplex or nkkel 272 Ihat can give risc eilher lO Ihe 5,.,2-1Ype
ooupled produel 273, or 1M SN2' _Iype compound 27". dependins on lhe slerie demands
[Eq. (93)).
11.' A 11."

RMgX LNiX

\ Q!
y 5,..2'
"'R' )< ... R
\ 1
(93)
R' A R"

I . .
t.,NI'
273 R
'"
B. Allyllc Phoaptatea
YamamolO {16] examined Ihe transilion mctal-c::alalyzed reaelions or Grisnard TeasenlS
witll (F,}-2-dec:enyl- l-diphenylphosphonate in THF, The resulls 50 obscrved are summarizcd
in Eq. (94) and Table 24,
108
SN2 109
p' m
T.bIe 25
R, R, R, R Ni S.2
S,.2'
CH, H H
"
NiOl[Ph, P(CH ,),PPb,J .. ..
CH, H H Ph NiO,(PPb." ..
" H H CH, Ph Na , [Ph, p(CH ,hPPh ,) 33
"
H H CH, Ph NiCl,(PPh,),
"
J8
CH, CH, H Ph NCI,{Ph, p(CH ,hPPh,] 7 7
CH, CH, H Ph NCI,(PPh,) 62 JS
"
H H Ph NiO,[Ph, p(CH ')JPPh,J
"
O
Ph H H Ph(CH,h NiO,{Ph, p{CH ,hPPh,] 8J O
Tibie 26
R, R, R,
'M'"
FCR!alysl S .. 2- ",2
I H H H II-DuMaDr FeCl,
"
O
2 H H 11 .-e-DuMaDr FoCI, 10 O
) CH, H H II-DuMaDr FoCI, 80 O
4 CH, CH, H E1Mal FoCI, 80 O
5 CH, CH, H II-DuMaDr FoCI,
"'90
O
,
CH, CH, H II-BuMaDr Fc:(acac), ro O
7 CH, CH, H -,_DuMBr FoCI,
"
O
8 CH, CH, CH, "-DuMaDr FoCI , 87 O
,
CH, CH, CH,
,,-BuMBr FeOr, 80 O
10 CH, CH, CH, I-PTMaBr FoCI ,
"
O
1\ CH, CH, CH, McM' FoCI,
"
"
12 --(CH, ),- CH, McM1 FoCI ,
" "
Melhylmagnesi um iodide, in the presencc ola catalytic amount of FeCI
J
, reacted separalely
with two different propargyl chloridcs (sec Table 26, entrics 11 and 10 give a 1:1 mixture
of 5 .. 2 and 5 .. 2- products_ In Ihe same study, Pasto airo showcd Ihat FeBr, is an
calalyst (sec entry whereas Fc(acac), is nol as as FeCl
l
(sec entry 6).
VI_ CONClUSION
As we have secn, Ihe s..2fSr.1: ratio of the producls forme<! by nucleophilic subslitution
of a Grignard reagen! on allylic halidcs or relatcd oompounds is strongly dependenl on
several fadors (e_l-, lhe nature or he elcctrophi lic substrate, solvent, oounler-ion, Grignard
reagent, and calalysl used). Therefore, for he preparadon ora targel molccule. bycontrolling
all parameters ofthis high-yiclding lransformalion, IS shown in the roregoin&. il is possible
to obtain either compound wilh high chemo-, regio-, and slereoselcctiyily_ But further new
improyements are 51ill 10 come_
ACKNOWlEDOMENT
We Ihank theCNRS for financial support, and Professor A_ CaY for his encouragement_
...
81. EA. Negishi, S. Challcrjee. and H. Mal$u, hita, TflroMdr(HI Urt , }]:)7J7- 3140
88. H. Takei an<! H. Obmura, TtI.wdrOll Lm. J:142S--3426
89. G. Limtrumelle aOO T. Jelfery- Luong. Tr lriJMdrOfl UI/. 1/:S0111- 5020
90. H. G. Richey and F. W. N. von RMin. J. O'1l01Wmf'1. Cltrm. 20:32
11 1. C. Cbuil. H. Felfin. C. Frajennan, G. ROUlSi. alld G. Swiercuwl ki, J . O'IJD_I . CM"'.
/ 17: 371 - 384 (11171).
92. E. Wenkert. J. B. Fernandes, E. L Mic:keloui, and e S. SwindelL. Sp'/MSI$ pp. 701- 703 (1983)
and referenteS aIro themn.
25
Dihallde-Derived Di-Grignard Reagents:
Preparation and Reactions
KEVIN C. CANNON
El! AIOCMm No,.,' A-,"IcG. 1Il.
Krg o[ PrWJ.JIa, Pt"",ylooniD
GRAHT R. KROW
Tt mplt U"ilYrJllY
Pltilathlph;o, PttlfU)'/oonill
l. IHTRODUCnON
The special utility of dj Grignard reagent5 in the synthesis of cyclic
metallocycJes and carbocyclcs has require<J Ihat a special Kction be devoted 10 the
preparation and reaction of thcse species [1 .2]. Reactions of magnesium, especially Rieke
magnesium. with dienes 10 fo rm magnesiacycloalkanes and spiroannelat ion reactions of
di Grignard rcagenls are covered spcciflcally in Chaptcl'1 26 aDei 27, rcspectivdy. The
abilLly to form di-Grignard rugenl! is '.rgely a function of the positional relationship of
l.x {x _ l , 2, II).dihalide substi tuents on alll:)'l, Ilken)'l, alkynyl, aryl, and benzyl or aUyl
Jubstrates; therdore, lhe discussion will be based on dihalidc substrales. Di-Grignard
reagenl formation can be s!rongly dependen! on choK:e 01 halogen, solvent, concenlration,
and Iype 01 activaled magnesium.
11. ALKYl Dt-OAIGHAAD AEAGENTS
Slable geminal or melhylene di-Grignard reagcnl$ CHJ(MgXIJ have becn prepara! in
50--60% yiclds Irom CHJXJ (X _ Br, 1) and iodine-aclivaled magnesium, or beuer with
magncsium amalgam (Q5 - 3";') in 1:1 ether- benttne [3--5). An altemalivc, higher-yiclding
synthesi$ ollhe methylene di-Grignard reagent involved the reaction 01 CHJBrJ and
magncsium amalgam in isopropyl etber [6). Yiclds 01 6O--80-J. are reported. The soluble
...
by-producl methylmagnesium bromidc: was scparated rrom methylenedimagnesium
dibromide by decantation, IInd Ihe resultant 51uIT)' ... as subsequently di swlved in 1:\ diethyl
et her- hentenc. A mechanislic s\udy or Ihe reaclion or
",ilh magnesium in tetrahydrofuran {THF) wilh sonicalion showcd rapid formalion or
mainlya ciS- frans mixture or -jodomclhyl-2-iodo-l,J-dimelhylcydopenlane [7]. Reaction
producls were consisten! wilh a single-electron radical chai n mechanism.
Methylenc: di-Grignard reagenls methylcnatc /llt)'l and ar)'1 aldehydes and ketones.
in generall y reasonable yitlds, al room lempeTature in a few minutes. in benzene-dicthyl
t lher solution!l.. The reagents can be prepared in situ. Tite: Teagenl is sclcct ivc for reaction
at Ihe carbonyl group of 1, 10 give diene 2 [E<,. (1)] [ 3]. However,
3p-aceloxy 501 pregn-l 6-en20..0ne 3 affords a product 4, formed by Iwo successive
conjugale addition. in JO-". yieJd, wilh only Iraces of melhylenalion producl [Eq. (2)1 [ 3].
Methylenc dibromide has becn oonverled 10 melhylene dimagnesium bromide and reacted
in Sil u wilh ulose sugars in THF. The magnesium is aClivated by calalylic amounts of
iodine and mercuric chloride; Ihis mixlure serves as an alternalivc lo lhe use
of magnesium amalgam [ 8]. TIK: yicld in Ihe met hylenalion of kelonc S 10 afford alkene
6 [Eq. (3)] is superior lO Ihal of an allernat ive Winig reaclion.
,
,

o ' 0)(

' .... ,
..,.
(70"4)

CHz(MoBrb

"""

1.'41 ' 1, I fiIICII
O)
,

O
--- o
""
'0-'(
(3)

The conversion of Ihe melhylene di-Grgnard reagent CH1( MgBrj 7 10 a proposed
melhylenemagnesium- melhylcnedimagnesium dibromide reagent 8 (Eq. (4)) by n:pealed
washing wilh fresh THF enhanced Ihe rcaclivi ly of Ihe di-Grignard reagen!. This has becn
demonstraled in Ihe of dimelallomelhancs and polymelal1 oeycloalkancs of main
grollp XIV (IVA) elernents [9]. Thc THF-washed reagent demonstrated superior yields in
Ihe synl hesi! of biS{lrmethylsilyl)methane (55%) and biS{lrimelhylgermyl)rnclhane
rompan:d wilh Ihe unwashed reagenl (low aOO 61%, E.uaclion of MgBr
1
from di.Qrignard reagenl , abo allcm! Ihe product dist ribll lion in the synthcsis of the
polygermacycloalkanes. The reagent , yiclded Ihe fou r-, sil -, and eighl-membered rnS
compounds 9-11 in yields oC 12, 36, and 2.3-;., respc:ct ively; whereas rea8f:nt 8 yiclded 9-11
in yields of 32, 17.5, and 1.8-/0.
I

, I
G_"""\. I
1 Df
-
ra.-
'-p.! '
( Go_
_a. J
'Go )
I
(4)
..
, '

"
"
Ti tanacydobutancs have also becn svnthcsiz.ed using methylene di-Grignard reagent
7 (Eq. (S). The addilion of 1 equiVll lent of 7 10 CpTiCl
z
yields n (lOa]. Compound 12, an
analogue or Tcbbe's rea8f:nt, CPzTiCH[AICI(CHllzJ, was assigncd as an open Slrudure,
base<! on ' Hnuclear magnetie resonance (NMR)data. React ion of complea 12 with al kenes
and alkyncs yielded titanaeyclobulanes 13 and litanaeyclobutcnes 14, respec::tively [S].
Altempl$ lo reproduce this rcaelion sequence with zircooocene dicllloridc, hoWCVCf, were
no! sucoessful.
-

/,-----
,
"
..
(S)
Theaddition OC IWO cquivalents oClhe methylenc di Gri gnard reagent7 with Cp TiCl
yiclds Ihe tilanocene diGrignard reagcnt 15 (40-;.), which can be convcrlcd lO a variely
of I,JmetalJatilanaeycJobulanes 16 by reaetion with RI MCI [Eq. (6) and Table 1; IOb, 1 1).
Compcl ilive formalion of 1,3-di tilanacyc!obulanes W81 observed in lhe synlhcsis of lhe
germanium and tin oomplexcs (11).
,
"
",
1o!. 51. R .CH, 1111O"J1,)
'"
Io! . Ge. R. eH, (75't.)
",
Io! . Sn. R . eH, ( I$%)
'"
lo! _ TI. R CsHs (33't.)
",
Io!. Zt, R . CsHs (31't.(
'"
Io!. HI, R . (36%)
(6)
The lrimelhylsil ylsubsliluted methylenc di-Grignard reagenl 18 has becn prepared
by rcadion of lhe geminal dibromide 17a [Eq. (7)) with magncsium amalgam in isopropyl
et her (12) or, allcrnal ively, by Ircatment of dibromide 17. with zinc(Cu) in THF, folJowed
by healing of lhe res ultanl organorine eompound with magnesium for 2 days [1 J). Reaetion
o( dibromidc l1a in silu with magncsium amalgam in diclhyl elller followed by addil ion
17. R,. H, Rl" 101 .. 51
l1b A,. A,. M.oSI

I 0'0.
$DI
(7)
(8)), which has beco oblained From both ds- aud Irllrl.1.I,l-dibromocydopropane 21 wit h
magnesi um in dielhyl elMf in an cvacuated, sealed Iass apparatus. The reagenl 22 reacl$
wilh dioxidc 10 aITord lhe ci.'l-diacid 13 [17). Thc
reagen! 22 can be prccipitated from diclhyl tlher solution, bUI a dialkylmagnesium species
prccipitatcs from THF.
"
'" .
. ,..,
"
(8)
"
An 3')ldie l,l-di-Grignard reagenl, 1,2-di(bromomagnesio)c:thane 24, hu beco
8cncraled in situ al - IOO"C by Ihe teaction of e H)') with Jithium-p,p' -di-fert-bulylbiphcnyl
in he presenoe of MgBr) [18]. The yield of he l,2-dGngnard 24 was onll' 10"10. as
detcrmined by reaction of he IOlution with trimclhyltin chloridc. The 1.\ . aud
1,3di-Grignard reagent products 7 and 2S wcre forrncd in yiclds of 40 and 15"/0, respectively
[Eq. (')].
CHzI:z U068 - ... CHz<Mo6rIr x"","CHmMgx
(9)
,
..
Thc rtaclion of l,3-di halopropanes with magncsium is a usdul mule IOt::)'dopropane$,
as can be seeo in lhe reaction or trichloride Z6 10 alford acid 27 [Ec. 19]. Whilesides
el al. wcre finl able lo prepare I,l-di(bromomagnesiowropane 15 from allene in five steps
[lO). Purilied 15 [Eq. (11)) has beeo prepare<! in 30.". yicld {rom 1,3-dibromopropane and
triply subJimed magnesium in clner [21]. Removal or dicthyl tl her and addition 01 THF
alforde<! a precipitate 01 an oligomer 01 magnesiacyclobutanc l8. Extraetion 01 lhe
precipitatc with THF removed lhe 1,6-di(bromomagnesio)hexane (15/o
Addition 01 nactlr I mol 01 magnesium bromide in diethyl tlher 10 18 reforms he
di-Grignard reagenl 25. Reaction of he di-Grignard reagt:nt l5 wilh COl is usdul in he
laboratory-scale preparation or cydobutanone 29: lhe S1raightforward synthcsis is
competi tive in price with ot her mutes 10 29. If addition or carbon dioxide is 100 rapid,
glularic acid is obtained (22).
l . MQ / THF

2. HO
"
( 10)
'"
(11 )
B
Appltcation orthe purified magnesium method 10 U-di bromo-2.2-dimethylpropane
affords 15-- 18". of 1,3-di-Grignard reagent (23], whk h has !:leen reaeled wil h IWO mola:ules
of eyelohennone lO afford the expeclcd 1,3-diol [24]. However, the substil ution pallern or
the 1, 3-di-Grignard Il:agent is limilcd; one p-alkyl substil ucnt resulted in low yiclds and
high dccomposilion ralCS owing 10 in;reascd p-hydridc mobili l y ( 25).
The applicalion of 1, 3-di-Grignard Teagenls in he synthcsis of mctal1acyelobutancs
has becn reviewcd by Bk kclhaupt [25]. Table 1 provides an updalcd listing of
mctall acydobutancs and 4-met allaspi ro[3.3]hcptancs 5ynlhC5izcd from 1,3-di-Grisnard
TeaSenls. Faci le oligornerizalion or slannacyelobulanc derivolives made Ihei r
i$Olation unsuccessful [25,29]. In oonl raSI, reoclion of MeSbCl , with 1.3-di-Grignard
produced no slibacyelobutanc, bUI dircctly produccd distibacydooclanc [30). TMIl: was
no evldcncc for sl ibacyclobutane oligomerizati on. Low yiclds (1- 5%) well: also realizcd for
unsubstitutcd transition metal owing 10 ft-hydride climination of Ihe
mctall acyd obutancs, whkh occurrcd mpidl y al - 20"C.
11 has been possiblc lo prepare di-Grisnard reagents 31. and 31b rrom
1,3-di bromocyelobut ane 30M and U-dibromocydopcntane JOb usinS doubly sublimed
magncsium in dcithyl el her [Eq. (12): 13]. Yiclds are \l and 4S%, respeclively. The
cydopcnlyl di-Grignard reagent JOb dccomposes wi lh loss of MgHBr lo form an all yl
Grignard Il:agent 32. The di-Grignard Il:agenls 31 can be rcactcd with carbon di OJl.ide lo
fo rm diacids and wilh lrimct hylsilylt in chloride lO afford organolin compounds (13). The
bridgchead bromincs of 1,4-di bromo-dccafl uoronorbornane 33 reael in diethyl el her wilh
magnesium-aclivated mel hyl iodidc lo form a di-Grignard Il:agcnl, which prolonates on
addi lion of waler to g; vc flu oronorbornane 34 ( Eq. (1 3); 31).
..,


(CH,)"

'''''v.-
(CH,)"
'"
.- "
. -,
1\.
F
10
8r
"
, . t.I'ietlMlrlM.t.
2. Hp
".
'"
.- "
. -,
UODtH

"
(12)
( 13)
Di-Grignard Il:agents in whieh the magncsium halide functional it ics are in a
1,1l-ll:lationship all: easUy preparcd by rcaction of the oorresponding t,1l-dibromoalkane
(11 )3) wi th magncsium in diethyl et her or THF (32). The di -Grignard rcagent preparcd
from I,S-dibromopcnlanc is in equilibri um wilh the magncsiacyc!oheJl.ane or related
polymeric species (32]. and an X-ray 5t ructural dctennination of Ihe dimer i$Olatcd from
THF has becn Il:portcd [ 33]. Afler U hr, oJl. ygcn coordination drivcs the di -Grignard
reagent 35 10 form l -ou-S-magnesiacyc!ooctane 36 quant itat ivcl y ( Eq. (14); 34].
(J,) (14)
"
'"
lincar I.II-di-Grignard (11 - 4- 10) pre:parc:d by addition of
magncsium to I,II-dibromides in THF [3S]. The di-Grignard re:agent formed
from 1,4-dibromobutanc: n:acts with trimelhylsilyl in THF 10 form disilanc:
37 (Eq. (lS); 36J and linear di-Grignard reagenLS 38 re:act wi lh 2.3-dibromopropenc:
lo 39 by dialkylation al lhe posi lion (Eq. (16); 37.3g].
1.

:1:. Me,5lCl
8rMg(CH:I,.MgBr

"
(1 S)
( 16)
"
A sludy or the additions or I,n-di-Grignard re:agenU (n _ 4-6) wilh diisopropyl ketone
40 behavior, as isshown for n:action with 1,4-di(bromomagnesio)butane
[fA,. (17); 35]. A was formal consisting or slarting 40 arising from Grignard
n:agent-induced enolate formation; alcohol 41 formed by hydride rc:duct ion or starling
alcohol, 42 and 43. formed as products of di-Grignard addilion, followcd
by expulsion or inlramolecular formalion (prolonation); and diaddition
product 44. formal by addilion of kelone 40 10 both ends of lhe di-Grignard
" ..
M
Ha H

M
O

.. 40 (35%] .1 (1:MIo)
(17)
44 (1:M1o]
Of special inlerc:st 10 Ihis accounl are: he reaction$ of di-Grignard witl acid
,ince Iwo Grignard n:agenl addilion$ lO alom can lead 10 he formalion
of cyclic aloohol,. A sludy of ring closures of di-Grignard reagenls formed
from 1,4-dibromoalkancs 45 wilh clhyl eslen or aryl and alkyl acids 46 in THF. laI to
68- 88% yidds of cyclopenlanols 47 havng mainly (77-96";. slereosclectivily) cis-dialkyl
substitulion (Eq. (18); 39,49]. A specific e:tample is Ihe convenion of ethyl aoetate (46,
R' "" Me) and 1,4-di(bromomagnesi o)penlane (45, R _ Me) 10 a 96:4 mill.lun: of trons-OH
and d3-0H cyclopentanols 47 IR _ Me) in 77YI yield. Reactions werc carried OUI al 2, C 10
avoid precipitalion of ma80csium from lhe solution. The cycli:;alion n:aclion is
subjccl 10 a sleric eft"ecl. as shown by comparison of lhe rc:acli on of the 4-pyridyl eSler 48
[fA,. ( 19)J wilh 1,4-di(bromomagnesio)bulanc and 1,S-di(bromomagnesio)pcntanc (41).
Addilion of Ihe di-Grignard reagenl' 10 Ihe ester 48 forms keto-Grignard inlermalialcs
49, which undcrgo cydizalion 10 cydoalkanols inlromolccular rcduct ion 10 alkenols
p' m
51, or enolizalion 10 kelones 52 in Ihe ralios given in parenlheses. Cyclicalion 10 so. is
favored for Ihe Ilve-membered ring. bul Ir.tnsfer of a hydride from a posilion fJ 10 Ihe
magnesium 10 givealkenol51b is favored over formalion ofa six-membered ring50b (41).
,

1. MWTHF
2. R'COOEl

R. Me, El , Pr, &.1 R'. H, Me, El. Ph, p.CIPh
"
..
--

R 1> ... ,1<11'
0',1>

"
I_J
_ n.51'"'1
51.
511> n.5 1111%1
(18)
(19)
The di-Grignard melhod has also becn applied 10 reaclions of di subsliluled amino
[41 ,42], phenoxy, and phenyhhio eslers [42] 10 provide difunclional cycloalkanols;
cumples nclude Ihe conversion or eslers 53 10 cydopenlanols 54 [Eq, 42]. Similarly,
Iactones can be converted lO diols as in lhe formalion of cyclopcntanol 56 from laclone
55 [Eq. (2 1); 43].
-

.. Z<:ttt.leCOOEl

.,.
l.""
.... (87%)
'"
Z. -NJ
6ilb (158'11.)
(20)

lo "'"
"'" (154'!1o)
IWQ(CHz)"MgBr

J),o
o.OH (1''Il0l

(21 )
u ..
The conversion of 3,4,4-lrialkyli soxazol-S-ones lO oximes of
t:yclopenlyl)alkan-2-ones is evidenced by lhe reaclion of 57 wilh 1.4-di(bromomagnesio)
bUlane 10 alford oxime 58 ( Eq. (22); 44]. The reaclion can be conlrasted wilh Ihal or
mono-Grignard reagenls, which reaCI only once al Ihe carbonyl group of Ihc:se subst rates
[44].

(22)
"
..
Coumarins 59, which are oonjugated laetones, reaet with 1,4-di(bromomagnc:sio)butane
to give mixlures containing minor amount! of 4-alkyl-3,4-dihydrocoumari n 60, formed by
conjugate addition aOO hydrolysis, and major formation or I-{o-hydroxyslyryl)cyclopent anol
fi l, rormed by di additi on al the carbonyl group (Eq. (23); 4SJ. Reaet ion or coumarin 591:
wilh gave mainly conjugate addition produet 6OC". Te C-4
substiluted coumarins !9tl and 59.1 gave malnly cycloalkanol produets fi l b and ' Id wilh
eit her di-Grignard rea8f:nt.
..
R. H, n
R_Ml. n
A. H, n.$
A.MI, n_$
M7 d

ti"" , ....
,,,,,,

" ..
,.""
'''''1
" ...
" ...
(23)
Anhydrides react wilh 1,4-di{bromomagnesio)butane and 1,5-di(bromomagnesio)
pentane 10 form spirolactones [46-48). Steric and elcctronic faetON influencc this reaet ion.
as shown by the regiO$Clectivity in the reaction of anhydrides '2 and 6J in Eq. (24). Unlike
Ihe reaetions of eslers. anhydrides reacl with I,S-di(bromomagncsio)pentaoc lo give
generally userul yields or cyclohexane derivat ives. lsoloic anhydride 6U and U8isoloic
anhydride 64b react in the same way with 1,4- and I,S-di{bromomagncsio)cydoalkancs to
give sub$liluted cycloal kanols 65. and 'Sb [Eq. (25)): the I-t>-aminophenylcycloalkanols
65b are difficull lo prepare by olher mel hods [49].
"
O O
"
BrMgICH;,)"IoIg8r
o;:;io
o

"
""
11 " 4,5
U
3 : 1
11 .. 4 (73%)
11. S (SS%)
O
(24)
cQ0
BrMg(ct\J.M:l8r
""

O
u
n _ 4 {SS%I
n _ S (20%)
,...
(:(rO

NHCH,

""
""
(25)
O
... Y.OH
'" """
... Y.,
&5b (55%)
'"
A melhod for formation of unsaturatcd w,w' -dicarboxylic acids by reaclion or Ihe
di-Grignard reagent! formcd from or 1,8-dibrotllooct-4-eJle, and
N-methylglularimide has becn developed [SO). The formali(m of tlH: diamide 66, shown
in Eq, 26, is an example. The chain exlension melhod has also becn applied lo formalion
of diacids from long chain (C_9 and C-19) %,w-dibromoalkanes.
...

llhel
(19'11.)
(CHv.CO(CH.I,GONHCH,
[CHzl1COICHzI,GONHCH
..
(26)
CaTboxyl-labclcd dicarboxylic acid 68 has becn prc:pared from I
penlanc and labelcd carboo [Eq. (27); SI). However, when he di-Grignard reagenl
67 was heated with isotopically labc:led barium carbonate, labele<! 4-1-butylcyclohexanone
69 was isolated [52].
"co.IHP

,.,
''''''
..

'''"
,
Q
(27)
BI'''co:.
"
''''''
R.
o
..
Het erocydopentane dcrivatives of Si [SJ.S4), Oe [55), 8 [56), Oa (57), Al [ 51}, and
P [58] havc becn synthcsized ulilizing 1,4-di-Grignard reagents and aryl- or alkyl-
substiluled m:leroalom dichlorides or di bromides. Simi larly, helerocydohexane derivati vo
ofSi ( 59]_ Ge [60), As (61), Ga (57J, and Al ( 57] have beco rc:alized using I,S-di-Grignard
Tcagenl,. Dihalidcs, 5uch as (Me,Sil,SiCI, (53]. MeSiHCI, [54], (EI,N)8CI, (56],
CI,PlQ)OEI [58) have becn $uCCC5sfully used 10 provide ahernati\'e substituenu on tlle
heleroalom. Alkyl l rihalides, such as MeSi CIJ (54] and ,-BuOeC\J [60), have becn
succcssfull y rc:acted wi l h di-Grignards 10 produce Ihe cOTresponding halogen-substiluted
heterocycles 70 and 71 in good yields, as shown in Eq, (28).


()
X
"
128)
".
Bic)'dic compounds can be s)'nlhesized from the appropriate di-Grignard reagen!.
3-Germabicyclooctanes 73 have becn synthcsized from he di-Grignard Teagenl 71
,."
derivcd from cis-I,3-bis(bromomclhyJ)cyclopcntaoe in dielhyl elher [ 62]. Thc yit:ld or t he
diphenyl compound 7]. was . whereas (hal ofthe dimet hyl compound 7lb was 21"1.
[Eq. (29)].
Q:"'"'

"'''''''' .

MgBr
(29)
"
".
R _ "
".
R. Me
Spirobenzosilepines weTe prepare<! from Ihe reaclion or di-Grignard Teagen! 74 and
dichlorobenzylsi lcpine derivatives in diet hyl elher and THF [63]. Synthesis of spi roeycle
75 was achievcd with a yield or 31 "l. [Eq. (30)].

cceo
(JO)
"
"
Metallacydopentane derivativC5 76-78 or rhodium( lII), iridium( lII ). and coool[( III )
have beco synlhesized by reacling 1,4-di{bromomagnesio)bulane in THF al room
lemperature with dihal ide complexes (Eq. (J I): 64,65). Use of a dionne solution or
magnesiocyclopentane did not afree! (he yield or [he rhodacyclopentane 76 [64]. Several
]-al kyl and 3.4-dialkyl-i ridacyclopentane analoglle$ of 78 were synthcsized using
IA-di-Grignard reagent! prepared from the corresponding dichloroalkanes [66). Yie1ds
raogcd from So/e for the 3-isopropyl adduct 10 4S;' fo r the l 4-dimelhyl adducl .


".
(31 )

The di-Grignard reagenl 79, synlhcsized in a 60% yield from 1.2-di(bromomelbyl)
letramelhyldisi lane and magnesium in dielhyl elher, was suocessfuJly use<! in lhe synlbesis
of Ihe platinadisilacyclopentane SO, which was oblaincd in a 46% yield [Eq. 67].
Si milarly, a nickeladisilaeyclopenlane derivalivc was synl hesized in 20-/_ yic:ld, bUI il was
not isolalcd rrom Ihe Solulion. In Ihe [ormalion of Ihe di-Grignard reagenl 79, the novel
I,J-disilacyclobulane 81 was also isolalcd in 20-;' yield.
P' m
"
[COOJPlCI . BrMa ........ SIS ........ J,lgBr
"
"

'"
~ PIICOO] 80
-O"
,
(32)
Di-Grignard reagtnl$ E-(CH
2
CH
2
CH
1
MgXh (E - O, S, NMe) hayc becn lIsed lo
synthesil:c a vare!)' of metallaheterocyclooctanes. l-Stanna-j-oxa- and 1$lannaj
thiacyclooclanc dcrivatives 83 wcre synthesizcd by reaelion of Ihe corresponding
di-Grignard reagent! 82 wit h S n C I ~ in yiclds of JS and 10"'0, TC5pe<:l ive1y [Ec. (J3); 68).
~ . ~ ~ f.O.S
(33)
"
There havc beco report5 of I-metalla-S-au.-cyclooctanes of Al [S7], Ga [ S7) , In [ 51],
Sn [68], P [69], and Si [70] from lhe reaelion MeN(CH
1
CH
1
CH
1
MgX)z and dihalidc
compoUllds. The tri-Grignard Teagenl N(CH1CH1CH1MgXh has bet:n used lO make
I-galla- and l-aluma-S-azabic)'(:lo[ 3.3.J]undecanes 84. b [Eq. (34)]. in addition lo
[-aza-S-si la-S- mel hyl-bicyd o[ 3.3.3]undccanc lI4c (S1,70].
84. M.Ga
84b M .. AI
84c t.4 .. SiCH,
(34)
Dimctallacycloalkanes have becn prepaml by reacling 1,11-dj( bromomagncsio)alkancs
(11 > 3) wi lh di(halometalla)aJkancs, which also ha ve becn deri vcd from di-Grignll. rd reagcnls.
Schcme I outli ncs lhe synthctic methodology for digcrmacyd oal kanes 88 used by
, .

.. ..
ScMmc 1
Takeuehi el al. (11)' Dimetallaalkanes 86, produce<! in goods yidds from Ihe
rcaelion of halide dimethylphenylgermanium bromide with di-Grignard reagenl 85, were
eonverled 10 87 by reaeli on wilh HBr Compound 87
was Ihen reaeled wilh an equivalenl of diGrignard reagenl 85 10 produce digerma-
eydoalkane 88; yclds range<! from IS"I. (n_6) 10 9% (n _ S.IO). Yields of lelragerma-
cydoalkane 89 ranged from 1,-. (n - 5) lO 2% (n -
Kuivila el al. synthesizcd dislannaeycloalkancs 91 by Ihe rcaction of di(ehloroslanno)
alkanes 90 (11 - 1-4) and 1,4-di(bromomagnesio)bulane in THF al room tcmperaturc [&j.
12]. Yields of 91 dccrcascd as ring siu of Ihe distannacycloalkanes increase<!: n_ l ,
3S%; n- 2. 21%; n. 3, 2S%; n _ 4, 20'-.
(35)
"
..
Distannacycloalkanes 92 and distannabicydoalkanes 93 [Eq. 36] wcre preparcd using
n _ 6, 7, 8, 10, aDd 12 (13,74). Thc melhodology was si milar
lo Ihal presented in Scheme 1. The rcacton of triphenyltin chloride wilh a di-Grignard
rcagen yidded he correspondng distannoalkane. The selective cleavage of one phenyl
roup from eaeh lin atom was accomplishcd by rcaction with Ha or HBr.
Dislannaeyeloalkanes werc Ihen synlhesiud. in a subscquenl rcaclion with the samc
di-Grinard reaen!. Repeatin he scquenc:e of $elective cleavae and reaction wilh Ihe
di-Grinard reagenl yieldcd he distannabicydoalkanes.
(36)
..
"
Magncsium actvale<! by stimng in df)' nitrosen converts lX,(lH,tibromoperfluorobularu:
(94a) and -hcxane (94b) lo Ihe corresponding di-Grignard rcagents (9s.,b) in 45-50'-. yields
(Eq. (3n 75]. The di-Grignard reasenl 95b has becn prcparcd also rrom disiJane 9fi [Eq.
(38)] by exehange of magnesium for silicon usins elhylmagncsium bromidc (16). The
foonation oflhe halogenaled dicne 98 from I,S..ctiiodopernuorooctane and elhylmagnesium
bromide probably oa:ur! by thermal (-IO"C) elimination of manesium nuoride from a
di..Qrinard reaenl 97 fonnee! by an exchanse reaction [Eq. (39); 16] .
..
....
n<F
... ,
(3S)
...
'"
''"'"

(39)
"
A 1,5-di-Grignard relgen! 100 can be formed from disl.llfone 99 by removal or lhe
protoos ,,10 he sulfonyl groups wit h ethylmagnesium bromide as base: [Eq. (40): 11]. The
reagen! reaels with ketones or bTomine 10 alford diadducts in low yields.
lO
EtMg6r I

PI>SOzCjH{CH,n
1
KSO,Ph 172%)
Mgar 101gB<
(40)
'"
There have beco unsuooessful attempts 10 solate di-Grignard reagenls from cyclic
1,4-dihaloalkanes. For cumple, 1,4-dibromocyclohexane, 1,4-dibromocydooctane, and
1,4-dibromocyclononanc give mixtures arising from Ting c1eavage, reduction, elimination.
and cyclization processes [78,79].
The rcaclivity or di-Grignard !'eag!:n!! can be modified lIsiog a variely or metal
calalysls. Primary a.w-alkyl di-Grignard reagents, bes! prepared from alkyl dichlorides in
THF, reae! with siJver(1) lriHale 10 fOTm four. fivc, and si.l- me:mbcred rinp in reasonablc:
(40-90%) yie:lds. The reacl ion i5 less dfc:ctive for formalion of medium-sized rings, bul il
i5 applicable lo formal ion of norbornane: 102 from Ihe: dichloride 101. as shown in Eq.
(41) (80).
M
O o
.. "'"

(41 )
'"
Calal y tic amounlS of dichloro[ I ,3-bis(di phenylphosphino)propane ]nickel(lI )
[Ni(dpppJC1
l
1 e:nablc: di-Grignard Tcagenls lo sc:lc:clive:ly cydocouple wilh aromalic
1,3-dichloride$ in THF (81). Yields are beller for pyridinophane:s 103_ (I()....JJ%) Ihan for
mc:lllcydophllnc:s 10Jb (besl yie:ld 22% for n - lO) (Eq. (42)). The mClhod has becn applied
lo Ihe: synlhc:sis of macrocydic po[yel hers (81,82].
ClMCl +
v_ CH. N n .. 6-\0. 12


<
,
103a V.N
103b V.eH
(42)
Alkyl di-Grignard reagenll can be rellclc:d sc:Jectivdy with aliphlllic and aromalic
acid chloridc:s in Ihe presencc or Iris(acclylacclonale:)i ron(lII ) (83). The bes! conditions
ulilized Illkyl chloridc:s in TH F. F ormalion or alcohol! is avoidc:d in Ihis onc:-slC:p catalyzed
synlhcsis oC symmelric diketones 184 [Eq. (43)]. Phenyllhiocarbonyl chlonde also reacls
seleclively 10 alford long-chain diacid Ihiol esters 1M.
""""

R_tM,SPh
"""""",,,,,"
104 R.MI {71'J1,j
1111 R.SPh
(4))
umg.;hain dicarboxylic acids 106 have becn prepared Crom ,8-propiolaclone and
alkyl di-Grignard in Ihe o catalylic dililhium coppcr lelrachloride (Eq.
84). The method cKtenm the chain length or a 1,II-dihalide by sil carbon aloms. The
conversion oC alkyl di-Grignard reagcnts (n _ 5, 6, 9, 10) 10 dicadmium reagenls, rol1owed
by reaction with halF-esler acid chlorides has becn used lo prepare dikelo C,.-C
u
a:,w-dicarboxylic acid estcr! [8S]. Thc dicarboxylic acid esler 107 was prepared using Ihis
mClhod in concerl wilh a Wolff-Kishner reduction lo remove Ihe ketone carbonyl llroups
[Eq. (45)].
1. CdCIi' elher
2. CCOICHt!.COzet
3. Aeducllon

''"
'"
111. AEACTlONS OF BENZYL AND MIXED BENZYL-AAYL DI-GAIQNAAD
REAGENTS
(44)
(45)
Benzyl di-Grignard can be from halides located on Ihe same or dilferenl
rinp. To obtain di-Grignard reagenls from benzylic halides using magnesium powder,
concentrationsoFthc di'(}rignard cannotexoeed O.IM in THF, lemperalurescannol
excecd 35C, and tbey musl be prepared rrom benzylic chlorides [ 16,86$7). A MgQ)-rrce
lrimerie eomplex 108 [Eq. (46)] was reported 10 precipitale al room tempcralure
yield) whcn di-Grignard reagcnts exoeeded concentradons oro. 1M [88]. The sloichiomelry
was reported as Mg(CH.C.H.CH.-oXTHF) . Thc usefulncss of Ihis precipitale was
demonstraled by Ihe rormalion oflbe bimetallic compound 109 in yield from reaelion
with MeJSnCI. On rooling a solution of o-C.H.{CH)MgC!1. to -4O"C, a colorless
cryslalline compleK that analyzcd as Mg(CH.C
6
H.CH.-oXTHF) was oblaincd in a
yield; a erystal slructure showed Ihis complex 10 be trinu:ric {87] .

(46)
,..
'"
Although he dichloride 110. can be convcrled 10 lhe corresponding di-Grignard
reallcnl lila in yields using magnesium in THF, Ihe dibromitk IIlb alfords
p' m
coupled producl 11 2 [Eq. 89,90].1[, however, magnesium anlhraeene is used as Ihe
magnesium souree, ben:tylic di-Grignard reagenl, II h, b can Ix preparcd in high yicld
from chlorides ond brom;des. The method i5 tven sucoessful with I,S-dichloronaphlhalene
11 3 (Eq. (48)], which rails loform a di-Gri8llard reagenl wilh powdercd masntsi um (86).
'"o
Mo'
...
-
...
111 ',b
- (47)
,.Q
" ..
'"
.".
,. "
1.401 THF
c.
(48)
113
The di-Grignard reagcnl 114, synthesi:ted from magnesium anlhraeene and
(Q-CICH1C.H.h. dcmonstratcd an enhanccd reactiyi ty toward WCI. O comparcd with lhe
di-Grignard reagenl preparcd by the elassic method usi ng elemental magnesium (91). The
lungsten(V) complex II!I was synlhesi:ttd in 45'Y. yidd usi ng magnesium anthraccnc; Ihe
di-Grignard reagenl prepare<! by the elassic roule gave < IO'Y. [92]. Al higher reaclion
stoichiometries di-Grignard reagent 114 resulte<! in lhe formalion of the oxo-frec oomplex
11 6{Eq.(49)]. Thi, reaelion could nOI beduplicalcd from lhe elassicaUy deriycd dj-Grignard
reagenl, even under more forcing conditions.
3.SIq. lit
/ ..

".

'"
(49)
A nricty of metallacycles haye becn 'ynthesizcd usi ng benzyl di-Grignard rcagenls
preparcd using elemental magnesium. Examples of metal1acycles formed from Ihe rcaction
of thtsc di-Grignards with dihalidc oomplexes are gilltn in Table 2. Altemalivcly, Ihe
litanium bis(2-indcnyl)-l,l'-biaryl metalJocyele 11 8 was preparcd from diol 11 7 (Eq. (50)),
in which the cyclopentanol rings were formed hy addil ion or o-di(chloromagnesiomethyl)
ben:ttne lO a biphenyl diester [95].
p' m
T.blt 1 MetaUIC)'eks Synlhesim! rrom Bcnzyl Di-Qrignard Rcagcnll
Ind Dihalidc Complucs
CCPl(COOI SI'!!.
lO"
.s'!!.
""
(;C}-If'(OCHol.b
."
""
""
'''1
...
.. ,
..,
.. ,

O", ...
C"'''gC1
0:
'
CH "OC'

..
1
41
"'"
'"
'"
(50)
Benzyl di-Grignard reagenls have been used in Ihe synlhesis uf brdged bis(carbene}-
dmelal eomplues 119.-1; [Eq. (51); 96). The di-Grignard reagenl o-C. HiCH
2
MgClh
11'85 reaele<! 11'1111 W(CO). al room lemperalure in THF 10 synthesizc: tlle tungsten complex
119b (SI % yield). whereas Mg(CH.C.H,CH.-o)(THF) was reaeled wilh lhe appropriale
'"
c.nnon and Krow
complexes under he same reaction oonditions 10 produce he
(61 %) and molybdenum (nol determined) 119J and 11 9c.
118.
1111b M.w. n
(51 )
The synthesis or rnclallacydobutabenzenes using di-Grignard reagen!1 has becn
investigated by Bickelhaupt el al. The l.2-dihydro-l -magnesiabcnzocydobutene reagc:nt
122 was synthesized by the addit ion of ] -bromo-l--<:hloromcthylbcn!cnc 120 lo sublimed
magnesium powder in THF ( Eq. (52); 97,98]. Di-Grignard reagcnt 121 W3S niaU), formed
in yield; predpitation, two THF washes, and decantution produced magnesiacycle
111 in 84-90"/0 yield. based on he dihalide. TJc use of sublimcd magnesium powdcr and
dihalidc 120 in THF was critica! 10 avoid WUfIZ coupli ng and otller by-producl formation
[971 Thc magnesiabcnzocyclobulene 122 reacled wilh only a single moleo::ule of kel one
lO forrn Ihe chelale eomplu 123 [ Eq. (53)). Addhion of MgBrl lo Ihe opens lhe
chelale and enables reacl;on w;th a s.econd molecule of ketone lO occur Icad;ng u1timately
10 Ihc ;sochromanc 124 [99J.
((a

0:;0



TI"
(52)
n.
'" '"
[0=' .. ].
"
" R,CO
ro"
R,CO
CQ'"
,0
.. &
..
" "
(53)
'u 'H
m
Mctallacyclobutabcnzcnes synl he$izcd by reaction of reallen! 122 and metal dihalides
in TH F are li51M in Table 1 A profound elfeo::l of di-Grignard reagenl purity on the product
distribution was noled in lhe synlhesis of the germabenzocyclobutene and attempted
synthesis of the correspond ng slannabcnzocyclobutene; use of unpurilied 122 dramatically
increased unwanted dimer formalion (97). Di-Grignard reagent 121 has becn applied 10
the synlhesis of titanabenzocyclobutene 125 (Eq. (54)], which was obtaned in a 93% yield
( 101).
'"
""

'54)
Pretormed di-Grignard reagent 126 was for lhe synl hesis of I-$ila.
accnaphlhene 127 in 10-". yield [Eq. {55): 102]. However, a yield of 71 -". or 127 w ..
realizcd when 8-bromo-I -chl orome!hylnaphthalene and dirmthyldichlorosilane were
reacted in the presencc of magnesium.
p' m
'"
Grignard rcagents (rom moleeules contai oing two vinyl bromide moiet ics han: beco
prepara! using magnesium in THF {37,38,104]. Thesc di-Grignard reagen!! can be trapped
with aTOOn dioxide, 10 give diadds; aldehydcs, 10 give alcohols; or protons, lo gve alkencs.
The ,8-aminovinyl di-Grignard rcagcnt 131 (Eq. (57)] does no! undergo elimi nat ion lo give
aliene, bUI reaelS with bulanal lo alrord di ol 133 (104]. The vinyl dihalides 134, generaled
(rom rcaction or a di-Grignard reagen! with 2,J-dibromopropcnc, form vinyl di-Grignard
reagenl$, which reael with carbon dioxide 10 ronn unsaturated diacids 13.5 (Eq. (S8)) in
50-66"/. yields [37.38].
"-
n-C,HCHO. ... l'r-<::1
HO C;.H"n
(H)
'"
'"
l . Io4g1THF

COOH COOH
."1-",,,, J...
0_6-12
(S8)
'" '"
<kminal vinylic di-Grignard reagen!s can also be synthesiud (rom halidefroe
reagto!!. Thc reaction of magncsium and diphen)'lacel)'lenc in THF al - 100"C
produce<! Ihe di-Grignard reagenls 136 and 137 [Eq. 105]. A 3:2 ral io of 136 and
137 was formed aecording 10 produCI ral ios from reacl ion wilh DjO. Di-Grignard 136
was i$Olate<! exclusivel)' b), cryslaUiz.alion.
"" - ""
M,



,
(59)

'"
Newman and Kaugars reported a c)'clobutene synt hcsis during Ihe reaclion of Ihe
vinyl alkyl dichloride 138 wilh magnesium in dieth)'1 el her [106]. Quenching oflhe reaclion
with water gave alkene 139 (3S"/o), forme<! by protonalion of Ihe mono-Grignard reagenl
from Ihe primary chlorlde, and cyclobulene 140 (23"/.) (Eq. (60)]. Mixed alkyl vin)'1
di-Grignard reagcnts 141 have becn formed, however, from Ihe correspondng dibromides
by reaction wilh magnesium in THF [ 107]. Reaclion of di-Grignard Teagenl 141 wilh
maleic anhydride provides live- and six-membered rng spirolaclones 142, by Eq. (61). A
slel"CQspecilic reaction of di-Grignard reagent l oO with l-chloro-cyclopenlen-)-one affords
spirokelone 144 (Eq. (62)], a l uitable spiroscsquilerpene precursor (107).
".
",,-f\

(35"4)
no

''''''
(60)
""
(CHz}"CHMeMBr
c$
,fu,.,

o
(61 )
.. ,
,.,
n_2
R.M. , n_2
n.1
O
-
b-a

(62)
-
.. ,
...
V. REACTION OF DIARYL DI-GRIGNAAD AEAOENTS
Aryl di-Grignard reagent! are generally avai lable from dihalides with powdered magnesium
[16]. The halide atoms can be on the s.ame or on diITerent rings, and they can be substituent!
on heterocyclic rings [I(UI). Highly reactive Rieke magnesium, prepare.:! from polassium,
potassium iodide, and magnesium chloride, has bcen advantageous with less reactive aryl
chlorides [ 109]. Protol! exchange ming ethylmagnesium bromide lnverts 1.2,4,5-
tetraftuorobenzcnc to the lrresponding p-substituted di-Grignard reagent (110).
Transmetallation 01 o-phenylenemercury with magnesium in THF produocd o-phenylcnc:-
magnesium tctramer in 90% yield [lOS,] 11). Halogen exchange betwcen ethylmagnesium
bromide and hCJIabromobcnzcnc aIToro5 a mixture 01 par(l (6"1.) and mef(l (1 di-Grignard
reagenlS, bUI main!y a mono-Grignard reagent i5 formcd (112].
A variety ofapplicalions or aryl di-Grignard reagenu hu bcen reponed. For CJlample,
aryl di-Grignard reagenu neacl with carbon diollide lo rorm diacids [ 110] and wilh ketoncs
10 givc diols [109]. Low moJ.c:cular weight poly-p-5ilaphenylenes haw: bcen synlhcsized wilh
Ihcse di Grignard reagenu [1 13]. Thc 2,2'-biJ(diarylphO$phinyl)-I, I'-binaphlhyl lmpounds
1046 havc bcen synlhesizcd using lhe di-Grinard reagenl 145 derived 1rom U '-dibromo-
1,l'. binaphlhyl and manesium in THF [Eq. (63); 114,115]. Reaction yie]ds varied according
lO Ihe slerie effects or the aryl groups of lhe diarylphO$phinyl chloride. Yields ranged from
91 (Ar _ phenyl) to (Ar -
I
.... '

(63)
'"
...
Aryl di-Grignard reagen!s havc proved uscful in Ihe syntbesis of helerocye!es and
metallacycles, as in Ihe !yntheses or Ihe siladihydroanthracene 147 (&. (64); [ 16J and
iododihydrobcnzobisminc 148 [Eq. (6'); 117].
p' m
'"
'"
'"
M SiCli
J.
:1
J

'"'
,.,
--
M. M.
164)
'"
"
oc,
I
Q

I
''''
MIIClUgCI
(65)
".
Germa- and stannadihydroanthraccnes have Riso been synlhesized by Ihis
prooedure: Ihe stannadihydroanthraccnc analague of 148 ma)' lhen serve as a precunor
10 olner hetcrodihydroanthracenes by substituti on reaclions [ 118].
Dihydrodisilaanlhraoenes ISO [ Eq. (66)) were successfull y prepallld from l he aryl
di-Grignard reagents 149 synthesized, usi ng Ricke magnesi um and bis(o-<:hlorophenyl)
methyl5i1ane or bU(o-chlorophcnyl)dimcthylsil am: [ 120,121]. These aryl chla rides were
unrcactive toward granular or powdered magnesium.
, .
',,'
0"'0
rnF
O:"
RR"SiCl, ..

MgClUgeI R' "R'
",

,
, ..
" ..
H eH, H
"'"
1")
" ..
eH, eH, H
,,%
"'"
eH, eH, e><,
""
" ..
eH, eH, c. ...
,,%
, ..
e><, c. ... c. ...
<5%
Reaction oflhc dimethylsilane di.Grignard reagenl 14911 (Eq. (61)] wilh trichlofO!lilanc
resulte<! in Ihe formalian of Ihe bis(dimethylo(),o' -diphenylsilyl)spirosilane 151 in 47% yield
[121). The use orthe dimethylsilane di-Grignard reagenl 149b was ellended lO the synlhesis
01 dihydroheterosilaanthracenes [ 120). The dihydrogennasiJaanthracene 15211 and the
dihydrostannasi laanthracene 152b were prepared in yields of 3) and 56"/0, respectively.
AUempls 10 prepare Ihe lead derivative fmm Me
1
PbC1
1
re!lulted in the rormalion 01
elemental lead.
HOC,
'si
0:.:0
CCO
,.,
, ,
o::
, ,
'"
(67)
15211 lo! _ Ge
t52b M_Sn
'"
I
Mger MgB<
1. CuCI;:,

2. H,O'
( 15'4)
19
Examples of mixed aryl- bcnzy' di-Grignard rcagcnts wtre covered in Section 111.
VI. REACTIONS OF ACETYLENIC AND MIXED AAYL- ACETYLENIC
DI-GFUGNAAD AEAGENTS
(71)
Acetylc:nic di-Grignard reagcnls hay!: an advant age ovcr disodiurn Of dililhium reagcnts
in Ihat Ihey are readily prepared in organic solv!:n!s. A pm;i pi t3tC of aecl)'lent dimagnesium
bromide separates quant itatively following an cxchange reaction o( et hyl magnesi urn
bromide wi h acctylene in bcnune-diethyl et her [1 JO). The most oommon appl ication of
Ihis di-Grignard rcagen! has been in Ihe synthcsis of sil acycloalkynes. Reactioo of
1.4-dichlorooctamct hyltet rasi lanc wit h di(bromomagnesio)acctylcne 161 in THF yielded
Ihe tc:trasilacyclohcxyne 162 (52-lo) [Eq. D I]. Thc octasilacydododecyne 163
accounled rOf only 1% yield. The analogous penlasilacycloheplync (22
0
;0) [ 132] and lhe
hexasilacyclooclyne (46
0
1.) [132.133] were synlhesized in a si mitar manner.

'"
'"
, I 1 ....
\ .SI =-Si. I
-SI SI-
o o
-SI SI-
;' "" -=-Si '
-"'" - ....
I I
'"
(72)
In cont ras!. cycl izalion of acclylenic di-Grignard reagenl 161 and (CISi Meh(CH 1).,
(11-0--4) was reporled lo pn::ferent iall y yield cyd ocondensalion adduets. reslllting from
mll hiple intermolecular reaetions [ 134). For cumple, the primary product n:::lI lIll ing rrom
he reaclion of J Eq. of (CISi Meh(CH
1
h with 3 Eq. of t he di-Grignard reagent 161 was
a 21membered Ting adduel
The di-Grignard reagenl 164, forme<! from I ,2-dielhynyl- l, I ,2,2-letraal k yldi, ilane, hall
becn prepared by reaction wi t h ei lher el hyl- or isopropylmagnesium bromide ( Eq. (13);
Reaelions of di-Grignard reagenl 164 wi lh 1,2-dichl orolelraalkyldis ilanes and
1.3_dichlorohu.amethyhrisi lane produced eyelie polysilancs and 166, respect ively, in
yields that were Iypically 37- 73"10 [ JJS- 1J7).
1.4-dibromobulane and magnesium in diethyl cther [ 142]. The reaction of the di-Grignard
reagenl l72 generatcd from butadienc using Rieke magnesium affordcd a 20'-. yield of 173.
-

Q
, ,
(76)
Generalion in $ilu of t he di..Qrignard reagent 175, by reacli ng an eJ.ccss of magncsium
with CHl=QCHJOh in t he prescncc of tlle iron complex 174 and PMc
J
, afforded the
novel iron compleJo 176 [Eq. 93]. Di-Grignard reagent 175 is a cross-<:onjugated
trimethylcncmcthane (TMM) dianion. Addilion of the presynthesized di -Grignard Teagen!
175 to a T HF sol ution or iron 174 resulted in low yicld of iron complell 176.
""

.'"
(77)
m
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11 6. F. c. Jonpma, P. de Koe, R. lolln:ns. N. R. Mall, G. L vanMourik, H. V",,,,;c,,
aOO R. J. M. Weuslink. Te/ralttd,OfI J1:192 1
117. H. Suzuki. T. MUlllfuji, ami N. Azuma, J. Chtm. Soc. Pnk/le. Traru. 1 p. 159)
118. P. Jutzi., Chem. /k,. J().f: 1455
119. M. S. Goedheijl, O. S. Akterman. F. Biekelllaupt. P. W. N. M. VlIn Leeuwen., N. Vddman,
ami A. L Spek, Orf/aIlornt!/illlkl 11:29) 1 (1994).
120. w. Z. MeCanhy, 1. Y. Coll:)'. aOO E. R. Corey. Or(l<l1Wmtlallicl 1:255
121. J. Y. Corey aew;l W. Z. MeCanh)". J. O'(I(JIfQIMI. Chem. 27/,) 19
122. F. A. Han aoo F. G. Mann, ,. CIltn1. Soc. p. 39)9 (1957).
123. (a) H. Hcaney. G. G. M.nn. aOO I. T. Millar. J. Chnrr. Soc. p. 1 (19S); (h) H. Heancy, F. G.
Mann,.OO l . T. Millar, J. CIenn. Soc. p. )930 (1957).
124. L S. Yang. T. A. Ensler. 100 H. Shechter. J. ChmI. $. CMIII. C_. p. 866
125. Y. Fujioka, IM/. Clttnt. Soc. Jp". 57:34904
126. F. Voeg!le, F. Alfler, M. E. Sleckhan, ami S. Mavili. CIrtm. &,. /U:897 (1\191).
127. F. Voegllc ami K. Kadel Chem. Ikr. IU:9(J) (1991).
128. G. Vln KOlcn Ind J. G. Nohes, J. Orgil_l. Clrtm. 104:127
129. W. S. Ra pson, R. G. Shultlewonh, and J. N. van Niekerk. J. CItmt. Soc. P. 326 (19041).
130. E. R. H. Jones. L Skauebol, Ind M. C. Whiting. J. Chem. Soc. p. 4765
IJI . W. Ando. F. Fusao. S. 5ckigawa, N. Nakayama,ami T. Shi miro, 0'ganamt/aflicsll:1009( 1992).
132. W. Ando, N. NakaYlma, Y. Klbe.lnd T. Shimiro, TttrahtdrOfl ,/ . J/:3597 (1990).
p' m
Ca_ and Kro.
133. F. Hojo. S. Sekiga"a. N. Nabyama, T. and W. Ando, O,ga"OIMlOl/irs 11:803( 1993).
134. E. Kloster-Jensen Ind G. Aamdal Eliassc:n. Angt1L. Chtm. 97:587/19851-
M. IohibwI, T. Hatano. V. Huesa ... a. T. Horio. A. Kunai, A. Mir ai, T. lshida, T. Tsukihara.
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)89-.1 ( 1990).
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26
Formatlon and Reaetlons 01 Substituted
(2-Butene-1,4-dlyl)magneslum Complexes
REUBEN D. RIEKE
U"iwrllry ofNtbrasw and Rita MI/a/s. If/C., LlftCoJ" . N,brasw
MAtnlEW S. SELL
Ri, M,ra/l, Inc., Llneo/". Nt braJluJ
1. INTRODUCTlON
In 1967, Ramsden demonstrated Ihat, \Jnder fordng oondit ions. magnesium will reael w;th
I,). butadienes 10 generate a magnesium-diene o m p l e ~ ( 1]' The reactivily or lhe dienc
was nOI what ane would have prediet ed for a bisGrignard reqenl. Allhough lhi s appc:ared
lo be a promisi ng ncw area or s!ud)' in the 19705, lhe ehemistry advanced ver)' titile. The
primar)' cause of this was Ihe difficult)' associated wi lh Ihe preparadon of Ihe
diene-magnesium oomplclIes [see 2. ror Iliview].
The reaction or ordinary magnesium with l J -dicnes such as I,l-butadiene or isoprene
is Llsually accompanied by dimerintion, trimerization, and oligomerization. This reaction
may be calalyzed by al kyl halides or Iransi lion metal salts, bul is gene rally accompanied
by a variely of by-products and is very time-consuming. Consequently, the uti liution of
these reagent s in organie synthesis has bcen quite limited [1), except fo! 1,1-
butadiene- magnesium, which has found considerable application in organometallic
synt hesis [see Rtf. 4 for relevanl revicws]'
In contrast, Rieke magnesium reaCI! with (E,E)-I,4-di phenyl- I,1-butadiene, 2,1-
di met hyl-1.3- butadiene, isoprenc, myrccne, or 2-phenyl-t,l-buladiene in lelrahydrofuran
[fHF) al ambien! temperalure 10 afford he corresponding subslitutcd (2-butene- l.4-
diyl)magnaium complexes in near quantilative yields. The sl ruclures of hese complexa
have nol yct bcen determincd except for {1,4-<i iphenyl- 2-butene-t ,4-diyl)magnesium, which
has becn shown 10 be a fve-membered ring metallocycJe [5]. Accordingly, Ihe most likely
Slructures for these complexa are fve-membcrcd melallocycles or oligomers. 1\ is also
possible Iha! an cquilibrium exim bctwccn Ihese various rorms.
'"
11 . REACTlVITV
These magnesium-diene exhibit unusual reactivily. Although one mighl expecl
Ihe oomplexes lo reael as bis-Grignard !'eagenls. it is clear Ihallhey are mueh more powerrul
nueleophi les. Remarkably. Ihey reaCl with al],;yl bromides and chloride$ al lemperalUTe1
as low as - SO"c. They appear 10 reacl by a slandard 5,.2 mt(;hanism. However, lhey can
5ef\le as electron-transfer agents wilh cerlain reagenls sueh as melal sahs. Wi th most
elt(;trophilcs at;Wmmodating good leaving groups. clean S,..2 ehemistry is observe<!.
As shown in Scheme 1, soft e!ec:trophilcs sueh as organie halidesdemonstrate complete
regiosdt(;livity ror the 2-position. The rcsul!ing primary organomagnesium intermcdiate
can Ihen be reaelcd wilh a wide range of sccond elt(;\rophiles.
Harder deetrophi les sueh as monohalosi lanes, monohalostannanes, and lueh, react
eomptelely in 11M: I-pasitlon, as shown in Scheme 2. Addition of a second
elt(;lrophile primari ly in lhe 2-position.
Thc overall resull is Ihat one can elfeet a net 2,I-addilion or a 1,2-addition byehoosing
appropriate deeuophiles. Representative complex, highly runctionalized moleeulcs that
have been preparcd using Ihis approach are shown in Table I [6].
(E,E) 1,4-Diphenyl- I,J- butadiene has boen one o the mOSI reactive oonjugatcd dienes
lowards metaUic magncsium. Reaellon of Ihis diene with Rieke magncsium affords
(1 ,4-diphenyl- 2-bulene-I.4-diyl)magnesium 2, whieh can be lreatcd with electrophiles.
as shown in Scheme J.
However. reaellon! or 1 with l.n-dibromoalkanes resulted in eilher eycl ization or
reduetion or Ihe eleetrophile. depending on he inltial dibromides. For cumple, eydization
procccded rapidly at - in (he reaclion of 1 with 1.3-dibromopropane and
1,3-dichloropropane. yic:lding a si ngle product o Irlln$- I-phenyl-2-((E}2-phenylethenyl]
cyelopcntane 4, in 65 and 81% isolalcd yidd. respectivdy.
Similarly, reaelion of 1,4-dichlorobutane or 1.4-dibromobulu ne with 1 ave
rrallS- l-phenyl-2-((E}2.phcnylel henyl]eyclohexane J as Ihe only eycllzed produet in 51
and 40
0
1. isoJalcd yield. rcspeclively. Surprislngly, 1 eyclized wilh melhylene dichloride 10
generale only a thrte-membered eydie oompound. rrOIlS-1 phenyl-2-(1E)-2phenylelhenyJ]
cyelopropane 6 in 76'Yo isolalcd yidd. examples utilizing Ihis approach are
shown in Tables 2 and J.
-
El (101)

)k,
"'"
"

ScIrltIM 1 Rcaclion of 12.3-dimelhyl2-butcnc-I,4-diyl)rnagncsium with a SC)/'t clccttophile. follo .... ed
by I second cltttrophile.
Et(lwd)
"
-
,
Schemc 2 Rcaction of 12.3-dimelhyl-2.butcnc. I.4-<;1iyl)ma,neaium with I hard elcctrophlc:.
follo .... ed by a sec:ond clcctrophk.
Tibie 1 Stepwiso:: Reactions ol(2.3-Dimethyl-2-bulcne-I,4-diyl)nagncsium
f.Mry ,..-EI 5,'ih SP"'/F' , ':ih '10' ., '14 YioCd
,
BJtCH',B,
.-
,
II<fCH,I,8<
""coa
~ .

,
"'o(CII',B,
.-
~
"

Wo(CII,),B<
~
.,
,
.... ,s;a
.-
>:f
"

~
>j-
,
'P'
"

o : : ~

BCH,),OI .",
~

"
BrlOI,I,cW
>-9
"
"
Bf(CH,I,CN
>-Q "
O
111. AEGIOSElfCTlVITY
Trcalmcnl of (1,4-dipheJ!)'1-2-huleoe- I,4-di)'l)magnesium with I,II-dihalaalkanes provides
a convtnicnl melhod for the gencration of $ubstitulcd Ihrce-, live-, aOO 5ix-mcmbercd
carbocycles. Signilicantly, lhe; c)'clizalions are alwa)'s slcrcospccilic and completel)'
rcgiosclcc::live.
1I i5 particularl)' difficult to prepare asymmetric (2-hulene-l ,4-diyl)magnesium
oomplcxes from ordinal)' magnesium. Thc rcaclioD is usuall)' oomplic::a.lcd b), exlcnsivc
~
o o
o
,
,
Schtme J Cydization of (1.4-di phenyl-2-bulene-I ,4-diyl )magnesium with l..,-dihaloalhnes.
polyrncriUlt klll. 1I was reporlcd Ihal he UiIC of Rieke magnesium circumvcnU Ihi s probJem.
Forexample. an cxocs.s ofncwly gtnefale<! Rit'ke magncsium reacled whh isoprenc. myrcene.
or 2-phcnyl- I,3-buladicm: in THF al room lemperature in 2 hr 10 give he correspondng
asyrnmelric (2-butcnc- I,4-diyl)masncsium complexes.
The basic diffcrence in chemistry between asymmetric and symmelnc (2-bulcne- I,4
diyl)magnesium originales {rom Ihe fael Ihal the former pos.se55eS (our lotall y diITcrent
reactive si les, and he ]pUer hn onl)' two nonidcnlical nuclcophilic cenlcrs. Accordi ngly,
Ihe rc:giochcmist ry of c1ectrophilic a tlack ;5 om: of Ihe essenlial problems associated with
he readon! of hese asymmctric 12-bulcnc- I,4-diyl)magnesi um compltxes. lt WlU rrporttd
that treatment of the magnesium complexa with triorganosi lyl chloridc in THF at _ 78C,
followtd by cydohexanone at O"C, alforded a stepwi$C addi tion acroS5 a terminal doublc
bond, wi t h higli regioselcct ivit y, as shown in Scheme 4. The res ults of the regiosclccti vc
reaclions are $ummarizcd in Table 4.
l t was suggested that the initial a\tack of the complex on the organosil icon r e ~ n t
dctcrmi ned the stlcctivity, which was dependent on bot h the diene substl'1lte and the initial
elcct rophile. As shown in Scheme 4, react ion of (2-methyl2butene- 1.4-diyl)magocsium
wit h trimcthylsi lyl chl oridt resulttd in initial a\tack al the 4- or I-posi tion, produci ng two
asomen of allylic organomagnesium inlermediates. Treatmcnt of the intermedi ary allylic
organomagnesium complexa with cycloheJlanooc lcd lo overall additions acroS5 a termi nal
double bond. Workup gave a 77:23 mixture or products in 9 1"/. total yidd {see Table 4,
enlry n
TiMe 3 Read;"n, of (2.J.I>imethyl-2-buteM- 1,4-di yl)mane,ium
.... ith Orpnodihalides






,


..
Ir(OI,).lr
Cl(c:!I,),cl
CL(('II,I,CI
o.lr<:.II.OI,Ir

"
>--t'6
>--'.-""
...Jl.... 'Ph
1 lL.14
"
n (69)
..
-- (15)
..
- - ( Ul
. - (U)
"
->O
..
the sizc of the organosi licon reagcnl re$ultw in illCreascd regioselectivi ty.
Thi! was demonstralcd by usi ng tri-n-butylsi lyl chloride as lhe ini tial electrophile.
Larger substituents at the 2.position or the diene were also demonstrated lo increase
selectivily. As shown in Scheme 4, the magnesium complex of myrocnc reactcd with
trimethylsil yl chl oride. followed by cyclohexanone. 10 yield he IWO compounds shown in

h
...

- ."
,
h
Mi
2c:1t - CH)
ld: R - CH,cH;P..qOI)1:r:
le:Il - C,"s


(1) II')SCI
nw.-nac
(11' - Ot) .... WyI)
0=
llF,Oec
Sc:heme 4 Rtliotela.:tive rUClion, of asyrnmelnc (2-butcne-l,4.,1iyl)magllCSium rcagcnl' ",th 1"'0
diffcrc:nt eb:trophilcs.
TabJe 4, enlr)' J in 11 94:6 ralio. Furthcrmore. a single i$Omcr was obtained in excellenl
yield by rcplaci ng Ihe 6rst eleclrophilc wit h tri-II-bulylsilyl chlori<k.
Remarkably. (2-phenyl-2-butene-l.4-diyl)mane$ium reacted uclusively al 11M:
4-positi on ",ih eithcr a rganosilicon eJectrophile. as shown in Scheme 4. l1le resulting
allylic organomagnesiurn intermedia!e added 10 cyclohcxanone clclusivc1y in Ihe J-pos;!;on.
Reaclion of asymmetric (2-hutent-I.4-diyl)magnesium wi lh <l,W-alkylene dihalides
lI$Ually giV<:$ WO isomcric product$. For example. t realmen! or (2-phenyl-2-bulene- I,4-
diyl)magnesium wth I,J-dibromopropane al rollowed by warming lO room
temperalure, resulted in Ihe generation of two fhe-mcmbc:red earbocyeles, I-phenyl- I-
ethenylcyclopentaneand 1lI-cyclopenlylslyrene, wilh a ralio of 71:23, in a 76-/_ isolatcd yield.
fY, PREPARATtOH OF HETEROCYCLES AND SPIRO COMPOUNDS
One of the usdul appl ieations of sub5t itulcd (2-butene-l,4-diyl)magncsium complexes is
the facile synthesis of si licon-containing live-membcred cydic compounds. Thi! reaC1ion
has bccn repor1ed earl ier for lhe magnesium complex of I,J.-butadienc [7).
In contrast with lhe ofsymmetric(2-butene- I,4-diyl)magnesium
complexes with lI,w-alkylene dihal ides, reactions or bot h symmelric and asymmelric
(2-butene- I,4-diyl)rnagnesium complexes with diorganosi lyl dichlorides yield exclusivdy
overall 1,4-additions, generating silicon-contai ning livc-membcred rings. Sorne of hese
are summarizcd in Table S.
Tibie" Rcactiom of Asymrne1rie (2_Butc ... 1,4-.di)I)magnesium
",ilh T",o Dil'l'c:rcnl Ekcuophilcl
" ,
;o. ICH,},$iC1
"
'--

,
(CHJ,$iO
"
M" ...
...B.),s;tI
, 1>,., " . b "S". tCHJ,siCI
"
, 2,.,..,.' Uf",. 'O" ... ,$iCl
"
For example. dichlorodimethylsi lane reacted with (1.4-diphenyl-2-buleneI,4-diyl)
magncsium al -7S"C 10 give c/$-I,I-dimethyl-2,5-diphenylsilacyclopcnl-J-ene in 660/.
isolaled yield (Table 5, enuy n Asymmetrically subslitulcd silioon-containing heterocyclcs
can also be preparcd in this fashion (5 Table 5, entries
Significantly, double annelation can be aa:omplishcd in one slep by Ireating Ihe
magnesium wilh SiO .. lO form spirohelerocycles. Reprcsenlative cxamples of Ihis
Iypc of lransformalion can be scen in Scheme 5, as well as Table S, entrie:!! 6-8. Addi lion
of SiCI .. 10 the THF solut ion of (2-methyl-2-bulenc- I,4-diyl)magnesium al - 78' C caused
an instanlancous disappcarance of lhe pale orange color. Workup affordcd 2,7-dimelhyl-
S-siJaspiro[4.4]nona 2,7-diene in 75% isolaled yield, as shown in Table S, enlry 6. This
oompound has becn reponed 10 be diflkull 10 prepare [8]. Uli lizal ion of magnesium
oomplexes of 1,J...dienes allows the prcparation lo be clcanly carricd OUI under extremely
mi ld oondilions.
V. PAEPAAATION OF 1,3-DIENES
The rcactivily of I,J-dicnes loward mctallic rnagncsium nries greal ly among individual
I,J-dienes. Oienes pouessing extended conjugations through Ihe oonnection wi lh arornalie
T.bIe 5 o( Siliron-ContaininJ aOO Spiro
Compounds from Asymmet ric (2-Butrnc I,4-d.iyl)magnesium
&,.
,
,

,

,

-
t:JoocI ..........
""....//"L1'Io
Mt,siCI,
>--<
1'Io,5iCI,
h
1'Io,5iCI,
)=Fh
1'Io,5iCI,

h
o,w.
h


THr, - 78 Oc
..
h
Si<:>

THf. -78 Oc

Y,
R. CH
l


r" d tc!

.. 1\ ...
:Ls:1'Io

'es(:
.:




l)Ol.
I

......... .. '"
tL,' .",
..
Yi4Id
"
"
"
"
"
"
Sc:hemf 5 of ,i licon-containina hetero<:yctes aOO spiro compouOO$.
p. m
groups. l uch as {E,E)- I,4-diphenyt-I,3.butadiene, display higher reaetivity Ihan aliphatic
I.l-dienes. Furthermore, l,l-butadiene ~ hibits higher react ivily Ihan substil ulcd 1.3-dienes
wilh nonaromalic groupt. lo particular, those 1.3-dieoes aocommodating more than one
alkyl group aboul the double bond! reDel wil h ordioary magnesium only with great
difficulty.
The nontrivial formation of a magnesium complex from aclivated magnesium and
2,3-dimethyl-I,3-butadiene has becn achieved previously (9]. Complicaled manipulations
for activat ing oommercial magoesium and loog reacl ioo times (5 days) are reportedly
required for the preparal ion of Ihe 2,l-dimethyl- l,l-buladiene-magoc:sium adduct.
The use of the preformed 2,l-dimethyl- l,l- buladieoe-magoesium adduct as a reag1:nt
in oranie synlhesis has nol becn previously reported. The only case io which Ihe
diene-magoesi um reagent was po:s.sibte involved was Ihe react ioos belween dichlorosilanes
and 2,3-dimethyl-J,3_butadienc: mediated by magnesium (l O). lo Ihis proccdure, Ihe diene,
dichlorosilane, and mc:lallie magnesium were refl uxed in a THF- HMPT 50Ivent mll.ture,
producing a subsliluted l-si lacyclopcnl-3-ene.
In a typical preparation of (2,l-<limelhyl-2-bulene- I.4-diyl)magnesium 8, freshly
distilled 2,3-dimet hyJ-I.3-buladiene 7 is added 10 Ihe newly generated Rieke magnesium
in THF. as shown in Scheme 6. The mi u ure i5 s rred for 8 hr al ambien! lemperature to
give 8 as a soluble complell in THF. The color of lne 50lution i5 paJe orange. The reaclions
of Ihe resulting complcx with I,n-dihaloalkanes yield a number of highly oseful
IranSrormalions [6]. For example, cydizalionl or (2,1-dimclhyl-2-butene- 1.4-diyl)magncsium
8 wi lh a wide variely of organodihaJides gentrale four-_ fi ve-, and s!x- membered carbocycles.
Usually. lne initial adducts can be trapped by prolonation, fumis hing monoaJkylated
producls.
K
"'
Q
lI(ClIZ)zX
>-b

UF. "
,
"
J IIr(CH:z)". zBr
noc
>--b.
11 ( ... 1)
11 ( ... t )
Sc:heme 6 Reaaions of 12,l-dimelhyl .l bulene_l ,4-diyl)m.agncsium wilh organodibromides.
."
VI. PREPARATlON OF CYCLlC OJENES
For cX8mple, addilion of 1,3-dibromopropanc 10 Ihc THF $OJuElO" of 8 al - 78
Q
C forrned
!he ntemediate IhI, which cyclized. when wanned lo room lempcral ure, lo yicld
l-melhyl-I-(I-mclhylethcnyl)l;yclopcnlam: 13 (11). On the olhee hand. an acidic workup
of911 al - 3S C glvc a single monoalkylatcd product, 6-broma-2.3,3-trimclhyl-l-hexcne
11. in 720/. isolated yield. Similar ehemi ,lry WII$ observcd wilh 1,4-dibromobutane, exccpl
Ihat no cyclization would oc::cur without reflu:JIing conditions. Inlcrestingly, Ihe eyclization
or 9a lO 13 represenl$ a cross-coupling of In organomagnesium reagent wilh an alkyl
bromidc, which is normally observed only in Ihe presencc or certain traosit ion metal sa1ts
oreomplexes (12).
It was recentl)' discovcred Ihat Rkkc magnesium reacts wilh 1,2-dimcl hylcnecycla-
alkanes in THF al ambient temperature to alfon! the corresponding magnesium eomple.1.es
in high yields. Signilicantly, treatment of these diene-magnesium reagent! with
bis-clectrophilcs provides a unique approach 10 commonly cncountcred spirocyelie systcms
(13].
Allhough 1,2-dimclhylenec:yclopenlanc aOO I ,2-dimethylenecyeloheptane dienes have
becn u$ed in combinalion with Ricke magnesium, most work has concenlratcd on Ihe
1,2-dimethylcnecyelohexane-magnesium complex. AH three orthese eyclie dienes have beco
synthcsized by established prooedures [14J.
The preparalion of the magocsium complex of 1,2-dimet hylcnecyclohexanc was
clfecled by usiog Rieke magnesium. In a Iypical react ioo, 1,2-dimethyleoecyclohexane was
added lO ao excess of ncwly generaled Rieke magnesium in THF (typical equivalenl ratio
of magoesiumfdiene -U: I). Afler allowing Ihc mixture lo sti r for 3 hr al ambienl
temperalure. Ihe corresponding diene-magnesium adduel 11 was formed as a soluble
complex in THF, as shown in Scheme 7. The resulting yellowish gold THF soluli on of Ihe
complex was easi ly sequeslered from Ihe excess magnesium by transferring by cannula lO
"


[ (.j
....
....
~ . .
"
",o'
()Oac, .... I)
r I . ~ J )
m
"
.-

llI'.-llac
\ .... 1,2. onIJ)
:Xhemt 7 Preparation oIthc malnesium wmplcl of U-dirnethylcncqdohuanc.
another HlI.sk. The freshly prepared TH F solution of diene- magnesium eomple:t was
subsequently treate<! wilh Ihe appropriale electrophi lc(s). The Slruelutes of 1,2-
dimethylenecycJohenne-magnesium reagen!s are presumably si milar 10 Ihose of
magnesi um eomp1elles of open-chain l.3-dienes. In THF solulion, 17 exiSl! most likely as
five-membc:red metallocycle or orllll.nometallic olillomers.
Halide-free Otllanomagnesium compounds prepared from he direcl melallll.lion of
conjulIlI. le<! dienes wilh Rieke magnesium represents an imporlanl II.chievement in
orllanomallnesium chemistry [reviewe<! in 2]. from he viewpoint of nucJeophilic
reat!ivity, Ihese diene-mallnesium reallenl! can be tonsidered as magnesiurn l.3-diene
dianions Ihat allow the formation ortwo bonds with electrophi li<: subst rates in one synthelic
operation. Dependinll on the nature of variou! eleetrophiles, bolh 1.2- and 1,4-additions
lO lhe original dienes have been observed [ 6, 1 SJ. When two eleclrophilie centers reside in
om: electrophi le, the oyera]] proc:ess provides easy aceess lO cyclic molecules.
AEFEAENCES
t . R E. Ramsden aOO J. E. Engd hard. U.s. 3.351.646 C. A. 68:49723f
2. U. M. Dzhemilev. A. G. Ibragimov. aOO G. A. Tolsti kov. J. OrgUlIQmr/. Cltem. 406: 1 ( 1991).
3. G. E. Herberich, W. Bovelelh, B. M. HosMek. D. P. J. Kodret. H. Ohst. aOO D.
Sochnen. Chm . /H . 1/9:420
4. (a) G. Erker, C. Kruger. and G. Muller. Adv. Che"' . U: I 11. V.suda, K.
A. Naklmura, Arc. CItem. Rrl. 18: 120
S. Y. Kai, N. Kanc:hisa, K. MikL N. Kas.ai, K. Ma.hima. H. Vauda.. aOO A. Nakamul"lI. CJH.m.
uu. p. 1271(1982).
6. R. D. Ric ke and H. Xiong. J. Org. Chem. 56:3109 (1991).
7. W. J. RichteT. S)"ntlte3U p. 1102 W. J. Richter, J. OrgIIllOll'''- Cite",.
(e) R. G. Salomon, J. Org. CMIr!. 39:3602
8. D. Terumuna, S. HaUa, T. T. Ueki. T. Oka7.aki. and V. SUluki. Bull. Chem. Sot". Jpll.
50: 1545 (19771.
9. H. Vasuda. V. Kajihlra, K. Malhima, K. Nagasuna. K. l, and A. Na kamu,a. O'lJ'ltwhlf!llJ/lics
1:388
JO. G. Manuel . P. MazeroJ1a, .00 G. Cauquy, SillJ,1 S, ",h. I"o'g.
Metol-Org. Chem. 4:133 (1974).
11. The st,ucture of (2,J-di""'thyJ 28butene- I,4-diyllma81lCSium bas no,}'<', de1ermine<!. The
mast likely SlruC1Ures for aliphalic dieIK-magnesium complexcs are live-"",mbered ""'tallocycles
or organomelallic olilODlen.
12. (a, L F. Elsom. J. D. Hunt, aOO A. McKiUop. Or90""""". C/,r", . ReII. 8: 135 IJ972); (b) J. K.
Kochi , A"(". Clwm. Res. 1:3S I
13. H. Xionl and R. D. Rickc. TnrlJltedr01l un. 31:5269
J4. la) t w. van Stra1ro, J. J. van Norden. T. A. M. van Schaik, G. T. Frlnke. W. 11. de Wolf,
and F. BickeJhaupl, R. Trov. ChlII . PlJ)"J'&JJ (b) N. A. Le, M. Jones, J, .
F. Bickel bl upt. ami W. H. de Wolf. J. Am. Cltem. Sar. 11':849J
15. If. Xiong a nd R. D. Rieke, J. 0'9. Cltem . .14:3247
p' m
27
Spiroannulations Using Substituted (2-Butene-
1,4-diyl)magnesium Complexes
REUBEN O. R1EKE
Uni>'t'rsity 01 and Me/a. tic .. Uncol,. . Nebnuka
MATTHEW S. SELL
Rie },felal!. Inc .. LillCo/n. Nebraska
l. INTAODUCTION
Spiro cenltr! are found ""idel)' in natural producls, such as sesquilcrpcnes. Several melhods
haYe beco reported in he [ittrature using spiroannulation as ke)' stCp5 in Ihe synlhesis of
natural products. Far cumple, ( ... )-aoorenone B has recently beco synthesiud by a
spiroannulation reaCl ion lIsiog he (2.3]sigmatropi<: rcarrangement Ihrough a cyclie
alJylsulfonium ylide (1). Also, d'Angdo and FCTmud haye reporlcd an tfficicnl
spiroannulation prOCle$5 uliliri ng an varianl of asymmctric Michael
alkylati on [2). FinaJty, Burne1l and associales ha"e recenl ly reported Ihe synlhc:sis or
pentalencnc lIsing a novel Lewi! acid-catal)'led spiroannulalion approach [3].
11. REACTIONS OF 1.2-DIMETHYLENE CYCLOHEXANf-MAGNESIUM COMPLEX
A. Wlth BI ..... Iec:tTophll
As shown in Scheme 1, utilizalion orlhe unusual bis-nuclrophilicil)' of 1,3-diene--magnai um
oomplc:xe!I, react ion or 2 with biwlectrophile5 can Ic:ad 10 spiro or fused bicyclk molecules,
depending on Ihe regioselectivi t)' of Ihe cyclization. Trcatmcnt of magnesium complc:xes
of 1,2-di melh)'lencc)'clohexane wilh l,n-di bromoalkallC$ resulted in overalJ 1,2-cyclitalions
or he original dienes. a!fordin spirocarboc)'cle5 in good excellenl )'ic: lds [ 4]. Scheme I
, depicIs a general route for lhe spiro-oldin s)'nthesis, cmphasizin lhe rcactions of 2 wilh
1.n-dibromoalkancs. T)'pieall)', l,n-dibromoalkanc was addcd 10 the tetrah)'drofuran [fHF)
5OIul ion of 2 al - 7g' C, producing I n organomagnesium intermediale aCJmmodating a
bromo group J. The intcrmcdiale C)'clizcd when warmcd, a!fording Ihe corTC$pondi ng
spirocarboc)'cJc containi n an eloc)'cli<: doublc: bond.
....

TlI', "
,
v
-



,
",o'
()(I"C, .... I)
In. roP<l.ll
,


T1 f', -?I "C
' .... I .l . .,. JI

Scheme I Reacl;ons of he margllCSlum compkx or ",th argano-
dibromides.
Thc posi tion of nit ial alkylation was eslablished by prolonation of he inlcrmediatc
al Ihe appropriatc temperatull:. Far he reaction of 2 wth 1,3-dibromopropane. acidic
hydrol)'sis al - JO"C resulte<! in monoalkylati on, yielding he correspondin! bromoolefin
oonlaining a qualernar)' cenler. 0 11 Ihe other hand. he monoalkylated intcrmediatcs,
derive<! from he realmenl of 1,4-dibromobutanc and 1,5-dibromopcntane wilh 2. were
protonaled al room tCmpcralure, affordi ng he correspondng noncyclized produl:ls.
Thc spiroannulation approach described in Schcmc I has been easil)' 10
analogou$ 1.2-dimclhylenecy<:loa lkanes. A wide variely of spirocycles have becn
from the react ions of magncsium complexes of 1,2-di mcthylenecyclopenlanc and
1,2-dimethyleneeyc\oheptane with l.n-dibromoalkanes and are shown in TabJc l . Thererore,
the presen! spiroannuJation mel hod provides a vcry general approach lO a large number
of spi rocarbocycles with diffcrenl combinal ions or ring sius.
B. Wlth Bromo.lkylnttrll
Reaclion or Grignard reagents wilh nilriles is a elassic mClhod of preparing kelontl. A
significanl difference belwecn an ordinary Grignard reagenl and the 1,3-diene-magnesium
intermediate js that Ihe laller contains 111'0 formal bonds, providing
a modc ror ring annulation. Treatmcnt or (2,3-dimethyl2butene I,4diyl)magnesi um wilh
bromoalkylnilriles has afforded eyclic kelones ( S). Studies have also demonstrated Ihat
Ihe approach ror the eyclic kelone rormall on can be 10 Ihc 1,2-dimclhylenccyclo-
alkane-magnesium reagent . Thus, Ihe reaclions of 2 wilh bromoalkylni triles resulted in
Ihe generalion or spirocycles as shown in Scheme 2. -For example.
addition of 3 bromopropionitri le 10 the magncsi um of 1.2-dimethylcncxyclohexane
2 at - 78"C yieldcd an organomagnesium intcrmcdiatc conlaining a eyano gTOUp 4. This
inlermcdiale began 10 eyclizc even al - 78C, preventing the trapping of lhc monoalkylaled
adduet. Warming he rcaetion 10 room Icmperature, followed by hydrolysis; afforded
.. ,
Tabkl ReaC\ions of Magnesium ComplueI of 1,2-Dimetbyleneo;ycloalkanes wich Bis-eletlrophiles
OJ OM thet<ophl l. COn.OlU lo ...
,.-.e_
y l .ld
,
"
CH,J,I, TI "C '0
eX)
..
r. rI ""
,
"
I.(CH,',"
-H "C O ..
cb
J5 ,IU
ron ....
,
"
'rICM,!, 71 "C lO
do
15 In
._ u ...

"
[ell,I,I. _JI "C to

"
-l' "C

"
I<CM,),I, JI "C lo
do
USI
_ u..,.

.,
'hOICll, I,oro _l' "C to
do
$2 enl
._ t __
,
.. 1.lell,I,I. 11 "C lo
O
.. POI
.-t __

"
"(CII.oI,I. 11 "C to
dJ
11 (U
._ te"".
[ COl
,
'l.
,

,
Sdttme 2 Rcaction of Che manesium compkl of 1.2-dimcthykncl;)'dohuanc ",ilh bromo-
alkylnitrile.
6-methyJenespiro[ 4. S]dccan-2-one 5 in SI 'Y. isolatcd yicld (Table 2, enlry Representative
cumples or Ihi s reaC1ion can be seen in chis table.
In comparison wilh previoUJ mcthods, he use of 1,2-<1imethylenecycloalkane-
magnesium Il:agcnts provides a simple approach ror spiroannulation as acoen 10
a widc variel)' of spirocyclic Iyslena. Furthermore, prepare<! by Ihis
melhod conlain functional groups. such as Ihe exocyclic doubJe bond or a kelo group in
one of Ihe rings which may be used ror rUrl her elabor1llli on of Ihc:sc: moleculc:s.
The process for 1Iw: conversion al conjugalcd dienes lO five-membered rings is or
greal inleresl in synlhelic organic cllemislry. A common procedure lo accomplish Ihis
lransformalion involves carbcne addilion lo dienes and rearrangemenl of Ihe resuhing
vinylcyclopropanes (reviewed in 6]. TIIe usefulness of Ihis approach is Jimiled owing 10
Ihe high-tempcralure (hermol)'sis of (he vin)'lcycJopropanes. To obviale Ihis probJem,
Danheiser and co-worken have devc] opcd an eIlicienl melhod for lhe Iynlhesi, of
p' m
T. ble 2 RcaCliol\!l of MI lJ1eSium of 1,2Oimethyl
enyclo.lhnn with 8romoalkyl nitriles
-
1'>"
,
a:II,cN
"
,
ex
at(cll ,),CN
"
,
ex
1IflCH,},CN
"

ex
Ik(CIlJ,C1'i
"
,
a:
&t(CII,),CN
cXJ

ex
Bt(ClIJ.CI'I
"
cyclopentene rrom conjugaled dienes by alkoxy- or carbanion-acceleraled
vi nylcydopropane rearrangemenl [7].
[n the course of Ihe slUdies 011 the chemistry of I,J-di elle- magllesi um reagenls, Ihe
reaclions of Teagent! wi lh have provided a simple
approach 10 a .... ide varety of carbocydes [8]. These cydizal ions oa:ur gcncrally al 1.2- or
J.4-positions of Ihe original dienel. Thi, chemislry has becn CJllcnded lo Ihe corrcsponding
exocyclic. conjugaled diencs and has at10wed a one-pol melhod lo spirocarbocyd es [9].
Thc further objeclive on Ihe chemistry of 1.2-dimcthylenecycloalkane- magnesium reagenlS
2 .... as Ihe conslrucli on of fused rings. Ir overall 1,4-cyclizalions of Z could be e!Tected by
an appropriale one-carbon dielectrophi le, fused carbocycks contai ni ng a fivemembered
ring would be casily accessed. A facile melhod for Ihe synl hesis of fuse<! carbocyclic enol!
by lhe reacl;on! of Z wilh carboxylie eslen has becn dcscribcd (l O). Interesingly, these
reaClions can also be used lo prepare p.)'- unsaluratcd kelones, simply by controlling the
reaellon lemperature. Application or Ihe approaeh 10 (2methyl -3-phenyl-2butene- 1,4-
diyl)magnesium for the synlhesis of 5ub$lil uled 3-<:yclopenlenols has also bcen presented.
C_ R.act\on wlttl EttI)'1 Ac:.tettl
In early invesligal;on!, tTcalmenl or lhe magnesium eomplex of 1.2-dirnethylenccyelohCJIane
2 wth elhyl acetale allow temperature (- 78 10 - IO"C), and hen quenching lhe reaetion
at - lO"C, resulled in lhe fonnat ion of (2-melhyl-l -cydohexenyl)propan-2-onc in 72V.
isolated yicld. On the olher hand, warming the mixlure 10 rcnUl. followed by ""orkup.
affordcd a fuse<! bicyclie eno1, 2.3.4.t6, 7.hexahydro-2-methyl-lll-inden-2-oJ in excellent
'"
ex
.. '
l col
,
-
, ,
CIIJCOO"' l (.llOCIO
_IO"CI

Qf"'"
())<:, """'"
,.
, ,
m,
(-lOOC
m,
....
"
."

,
1 KomllO
,-
J -,a'
(-100C)
1 HJO+
[Qf::]
I

())('
m,
"


SdlCnR 3 Reaction of he complex or 1.2-dimelhylelleC)'dohellne ... ilh e1hyl ao;etate.
yield. These resulls suggesled Ihat Ihe adduct formed al low temperature was simply
derived from he fin! attack by elhyl acetate al the -pasillon of 1, producing an allylic
organomagnesium intermediate contain;ng a carbonyl group. Howcver, Ihis suggestion
was quickly rukd out by trapping lhe intermediatc with lcelyl chloride. A delailed
rationalization for Ihe reaction of 2 with tlhyl acetite is givcn in Scheme 3.
111. SYNTHESIS OF FUSED CAABOCYCLES
Trealment of Ihe magnesium CQmplex of 1,2-dimelhylencc)'(:lohuane with elhyl acetate
al low tcmperature re$ulted in Ihe formlllon of a magnesium sall of a ' piTocnol. containing
a cyclopropane rins 6. This intcrmediate undcrw<:nt nns expansion when warmed, yieldinS
lhe fused carbocyclic product 8. Alternalivcly, prolonation of 6 at - I O"C alforded the
correspondins spirocnol 9, which rearranged in S;III lo Ihe ,8,y- unsaturaled ket onc
10. Addition of acctyl ehloride to 6 at - 2O"C and workup alforded 11 as a mixture of
two cstablishing the idcntity of Ihe initial adduct.
Significantly, a basic hydrolysis of 11 also alforded the 10, again C(Infirming that
Ihe ,8,l'-unsaturated ketone 10 was formed by rearrangc:mc:nl of the spirocnol 9.
The rins enlarsemenl from 6 to 7 involves a vinylcycJopropane-<:yelopcntene nns
upansion, whieh has becn observed for Iilhium satu of2-vinylcycJopropanol systems [ 11 ].
On the other hand, lhe rearrangemenl of 9 10 10 il formally a 2-vinylcycJopropanol nns
optning, with a prolon lrander. This is lhe finl of sueh a rearrangc:ment, al lhough
l-vinylcyclopropanol -cycJobulanone have becn well documcnled [6].
Fused bicyclie syslems, C(Inlainins a substitlUed five-membered nng, can be
conveniendy by lhe reaelions of the magnesium complexes of 1,2-dimclhylene-
eycJoalkanes with carboxyl ic esten. This rcaction procccds by a magnesium salt of a
spirocnol Ihal conlains a cycJopropane rin&- Quenehing of the inlermediale al an
approprialc tempcraturc crcales an alternaliV1: pal hway ror Ihe reaction, !cading lo a
p' m
T. ble J Synthesi, Qr Fused C.rbclol:ydes. ".)'- Unsaturaled Kelol>e3 .nd
jCydQptnlenQI, ('Qm Diene-M. gl>e3ium ReaJenlJ
Entry produc t "
,
... CII,COOEt
" .

...
" .
>
...
'"
CII,coon
C;<->
"
'"
ao,='



...
'.p."
CO<:,
..


... ..


... Z OI,COCl
Cl;< ><l
..


Cc J. / tran.- l 4,tt,
,
... cK,CCH, l,cooEt

..


...
"


... Phcoon ..

.. ...
" .
COIItin..u
'"
T.bIe J jCOlI'!lnlltJl
o'on
.ro'
11 .ld" lIoh"
U ... CII,laI,),eoon.

..

..
u ... CII,ICH,),eoon.
"

u u. CII,ICH,),coon.

"

"
u. C:H,ICII,t ,c:oon
<Xl.--
..

..
, ..
..

u
",
"

"
",
"

'57. : ... ne: m; 1.2.Dimelbtk"""7Clopetll'roo:; 57<": 1.2Dime,h)l
101: t .3-buladiene.
"Al( _ COIIIpO.IlKIs haoc bren Mly charKItriml by ' HNMR. "CNMtl.. FfII lId
mH$ $pec11'11.
' 15OIaletl
" ICOX .. u added ID 1M nuncsium-dienc complu 1I -7I' e. brin. lIi,ruI 11
- 1IC rOllO mino ,he IQClion wu .... d ... ll, .......... 10 lhe pecifled Inn""",lul'll.
A: Fuscd bicydie prod ... 1 .... obtoincd al "nu B: Quenchi", lhe react;"'" al _ IO'C
1 k.IDDe. C: Elhy! _al .... a. addetllD ,he mqnco;ium compl .. o(
51. al - 78' C. n.. mi.lu" .. al uitmd al _71'(" rO. lO min. 1M .... d ... U, .... tmed
'D - loe a ....... 1. Acldll;"'" o( _yl ctd<>ride JI -2O"C a t'lordetl U. O: AcldilOD o( 2 Eq
of chlorick lo 57. 11 - 7lt 'e. klllowcd bl .. armin lo l'OCIfII Innpenlurc. P'" 'l.
E: added ID 11M: mq.naium compl .. o( 1M 11 - 71'(". n.. wu lIirnd
1I -78 C rOl JO min .lId lraduall, wanned 10 room InnpenluR followed by renu ..
regioselec:tive synt hesis of /1.)""unsaturatcd ketones. Representati vc reac:tions of Ihis type
an: pn:scnlcd in Tablc J.
Rca:ntly. this met hod has been expaDded to includc rcac:tion with lac:toncs 85 wdl
as Ihe use of as)'mmclric dicnes [ 12].
'"
A. S,nlh .. 11 of Splro r LKton
The difficultia aS$OCiated with the synthesis of spiro y-Iactones include Ihe gencration of
a qualcrnary carOOn ccnter and Ihe int roduclion of functionalities used for laclonizat ion.
Much work has bcc:n done: in an e:lfort 10 dcvelop userul synthelic roules [13]. Howevcr,
masl melhods Ihe use rcagenls and multi ple synlhelie sleps 10 accompl ish
Ihe O'o'erall process.
Recenlly. il was reported tbal spiro y-Iaclones conlaining a vi nyl group al Ihe
(j-posi t ion ean also be synlhcsized in a one-pot procedufC, basal on slcpwisc re:aclion of
dienemagnesium reagents wit h ketoncs. follol'l'ed by re:aelion with earOOn diollide [ 14].
Scheme 4 ilIust rales a roule for spiro ,..Iaclone synlhcsis from the magnesium of
1,2-bis(methylene)cyclohCllane 1. Initially, il was observed that treal menl of 1,2-
bis(melhylene)cycloh<:lIane-magncsi um 2 reagenl wilh one equivalent of acctone al - 78
c
C
resulted in Ihe: formation of a 1,2-addilion adducl 12, derivcd rrom lhe incorporalion of
one moleeule of acctone wilh lhe diene complex. Protonali on of t2 al - 78C yicldcd a
leniary alcohol. conlaining a quaternary ccnler 13. I1 was considered Ihal wilh warming.
intermediate 12 should undergo nucleophilic addition 10 anol her eleetrophile. ThuI. car bon
di oxide was chosen as Ihe second eleetrophile and inlroduced to Ihe rcacl ion mixture al
OCC 10 room lempcralure. As expecled, Ihe intermediate reacted quickly with carbon
dioxidc, presumably yieldi ng a magnesium sall of a y-hydrollY acid 14. Afle:r acidic
hydrolysis. fol1owed by slight warming. a spiro y-Iaclone, 4.4--dime:t hyl-6-methylenc:-)-
oxaspi ro (4.S]dC(:an- 2-one: 16 was obl ai ncd in 68". isolated yicld. The: y-hydroxycarboxylic
.. '
""
""
.. -
OcelOR
"
H:30 o ce
"
[oc .. ]
,
"
-
78ce
,"
O
"
-
_18oe
"
"
Schtme" Synlhesis of aspiro " laClone from lhe magncsium complel of l.2-dimclh)Jenecyclo
Itcune .,.tone, .r>d COI
p' m
Table 4 Synlhcsis ol Spiro )'- Lacloncs from Conjupled Dkrocs. Kelorocs. and CO,
.. .,
.-
..
,

CycIo
L
" L
"
o
o

Cydopcot. ..
,
"

.... " .... ..
B. S)'fItheala of Spl", 6- l.Kton.a
Tite synlhesis or spi ro }'-Iaetones has bcen extended 10 lhe s)'nlhesis of spiro -laclones.
This one-pol IransIormalion of 1.3-dicnes reacted wilh cpoxid, mcdiated b), Rickc
magnesium 10 spi ro d-Iaetones in good iSQlaled )'iclds, was recenlly rc:porlcd (1 5). Much
work has becn done 10 elucidalc novel synlhet ie roules ror Ihese Iypcs or molC(;ules (16).
In parcular. 6-substituted 6-laelone5 have rcoentty auraeled considerable aUent ion, mainl),
bccausc molccules oF Ihis elass inelude man)' natural produets Ihat exhibl subslanlial
bioloaical ac!ivi!y ( 17). However. moSI mcthods ror Ihe synlhcsis or lhesc: molccules require
ce,
D
,
"
.
o oc 1,:"1
Sc:hemf 6 Synlhe5is of aspiro 6-laclone from lhe magnesium or 1,l-4imel hylenecydo.
lleune, et hylene oxide. . nd COI
Ihe use of complcx reagenls and multiple synthctic sleps lo accomplish Ihe oyerall process.
One of Ihe more adcpt mClhodl involves Ihe treatmenl of bis(hromomagnesi um) atkanes
with dicarbOll:ylic anhydrides (18].
$chcmc ti ilIustrates a routc for Ihe spiro "-aclone synthes;s from Ihe magnesium
tomple. of 1,2-bis(mcthylenc)cycloheune 2.
nliall),. trealmen! of l,2-bis(melhylcnc)cyclohcxanc- magncsium reaseol 2 wilh an
CJlec" of ethylcnc oxide al - 18"C, rcsulted in lhe rormallon of Ihe 1,2-adduct 22, derivcd
from Ihe inoorporation of I Eq of epoxide wi'b Ihe dienc complex. Signiticantly. Ihe
bis-organomagncsium n:agcnt 2 rcacted with onl)' 1 mol of epoxidc. with 100"/.
rcgiO$electivity in Ihe 2-position, 10 afford intermcdiate 22. When warmcd 10 O"c, 22
reaeted with carbon dioJide lo yield presumably Ihe magnesium salt of a - hydroJy
carboJylic acid 23. Aci dic hydrolysis, foUowed by warmins lo 4O"C 8('neralcd the spi ro
.J-Iaelone, 7-melhylene-J-ou spiro(S.S]undecan- 2-one 2S, in 69-/0 isolaled yield. Olncr
eumples of Ihis Iype or are listed in Table S.
When unsymmetrical epoKides were employed as the primary eloctrophile, Sood
resioseloctivily was observed. The a!tack of the unsymmelrical epoxKle alway occurred al
the lesl sterically hindered carbono
This convenient, one-pot process for the synthesis of spiro "-Iaclones from 1,3-dienes
and epoJides, mediated by Rieke magnesium. provides a proficienl route 10 Ihis class of
complex organic molecules in good isolaled yieldl.
IV. GENERATION OF QUATf:RNARY CARBON CENTERS
The general ion of a qualernary carbon cenler is nol a trivial underlaking in organic
'ynlhesis. Mult iple synlhelic slep5 are onen required lO genel"llle a quatemary carbono
The hiSh-yieJd formalion of OOlh alcohol, and vicinal diols by a one-pot prooedure wi lh
Ihe concomitanl forma lion or a quatemary carban cenler was reccntly reported [ 19].
A. Synth 11 DI Ak;ot!ola
Scheme 7 oul lines the general approach for the preparadon or a primary alcohol Ihat
accommodates a quatemary carOOn cenler. Significantly, the organomagnesium reagent
2 agai n reac1ed with only I mol or epoxide, with 100-/0 regioseloc1ivily. Aga]n, ir
Table 5 Synlhesis of Spi ro 6Lac!one$ from Conjugaled Diene- MDlnC$ium
Realen!$, Epcuide$. and CO,
., ....
% YoId
o
,
"
,
..

,
n
unsymmetrical epoxides were used Ihe bis-organomagnesium reagent 2 was always
completely regiosclective for Ihe less-hindercd caroon alom. Representat ive examples of
Ihis reaclion are shown in Table 6.
The process described here provides a facile prcparation of alcohol! and vidnal di ol!
in one-pot in high yields..
B_ Synthflall 01 y-Lat;:e.m,
1-Lactams are important inlermcdiales in mules to five-membcrcd heterocyclic compounds.
Moreover, tetramc acids and 3-pyrrolin-2-ones represent a diversc: and profoundly
importan! fami ly ofbiologically active secondary mctaoolites. many ofwhich have potential
."
ex
,
D
7 ReaClion al lhe magnesium complc. or 1.2-dimcthylcnocydoheulK and clhylene olide
followed by acidic hydrolysis
Tabl, 6 Synlllesis of Alcohols from Co!1jugaled Diene-MIJ1ICSium
and Followed by Ao:idic Hydrolysis
.. ",
.-
Epo.ido Pt.d"",
'" VioId
ex
O
'"
0-

,
K
o
)
(- , '"
0-
K
o
)
( , ;;-
,
[;>
-
,
K
') (
\
-
-

OH
"
,
K
K""
r
",
"
"

ex: K"" "
use in OOII medicine and agricullun: [lO). Synlhelic nlerest in Ihis elass or molecules has
becn nlense, particular!)' in Ihe past decade [21].
Man)' approaches 10 y-lac1ams becn dependent on cyclization byac)'l--nilrogcn
bond formalion [22]. Cyclization involvingcarbon..-carbon bond (ormation is an alternative
route; howevcr, unti! recenl l)', Ihis potential melhodology has received tiule attention.
Mori and co-workcrs reported a palladium-catalyzed cyclization or N-all )'1 iodoacelamides,
in which Ihe intramoJccular addition rcaclion of Ihe carbon- iodinc bond 10 an olelinic
linkllge is a key slep (23].
Rocently, Nagashima and associales developed a new roule 10 y- Iaclams by Ihe
ruthenium-catalyxed cyclizalion of N-allyllrichloroacclamides (24). Also, Stork and Mah
reported the radical cyclizalion or N-prOlecled haloacclamidcslo yield N-protected lactams.
The prolecling groups can lhen be easily removed under a rangc or dilferenl conditions
(25]. This cfficient radical cyclizatioD route 10 cl.t-rused pyrrolidoncs and piperidoncs is
inlcrcsli ng becausc ofthc widespread occurrcncc of relaled systems in nalural products [26].
p' m
"
"
.-,,.
"
',0', [
,oc

ca,
,oc
".
"OC
"
-l'ce
"'OC
..
Schnne 8 Reatlion ol(2,3-dimethyl-2_butenc. I,4-diyl)mlIne:1iurn w;lh In mine and COI
[Q l
,noc
)----<
...

.'oc ,

,
n.
"
"
"
11,0'


,
""
"
"
"
Scllemt 9 Reactjon of (2.J-dimclhyl-2-butenc. 1 ,4.,Jiyl)malne:lium ... ;th an mine, follo .... ed by acidic

Recent l)' a cnnvenicnt, one-pol preparation or y-lactam$ by Ihe reattion or a 1,3-dieoe
and mim:, mediated by Rieke magnesium. was accomplished [ 27].
As shown in Scheme 8, or (2.3-dimethyl-2-butcne-I ,4-diyl)magnesium 18
... ith an mine alforded lhe 1,2-addition adduct 27, which after treatrncnt wjlh caroon
acidic hydrolysis, and subscqlU:nt helting afforded a y-Iactam 30 afXommodating
a quatcrnary t;:arbon ccnter in 62% isolated )'ield. For otber cumples or Ihis Iypt or
transrormation, 5eC Table 7.
As shown in Schcrnc 9, ... hen Ihe initia1 adduct 32 (formed by lhe trealmen! oC 111
with Ihe imine) underwcnl acidic hydrolysis. lhe secondary amine 33 was afforded in 96-/.
isolaled yield. AII or lhe amines formed by Ihi l proccdure wcrc isolaled in execUenl
chemical yields and are shown in Table 8,
This facik onc-pol Iransformalion of a 1,3-diene-magnesium inlcrmediale providC$
T.bl" 8 formalion of Secondary Amines rrom RcaCl ions
2-bule .... wilh Imines. FoIlowed by Acidic
... ' ,
,
,
h ct.-o
"-O
,
"


!-.f)
h ct.9
"
,

!
h


,




REFERENCES
1. F. Kido. T. Abiko, and M. Kalo. J. CIrrm. $oc. Prrkill Tra1l5. 1 p. 229
1. 1. d'Angdo and C. ferroud. Tttro1!,drOtl Lm. 10:6511
3. Y. Wu. Y. Zbu, Ind D. J. Burnell. J. Org. CIomo. J9:H)4 (1994).
4. R. D. Ricke l OO H. Xion, J. Orll. Clorm. J 7:6S60CI99n
5. R. D. Rio:kc.nd H. Xiong, J. Orll. Clorm. 56:3 109
6. Z. GoldKhmidl.nd B. Crammcr. Clorm. $oc. Rtp. 17:229
1. Cal R. L Danhdser, C. MarlinczDuila. and J. M. Mori n Jr., J. Org. Clorm. 4J:I.l4O
(b) R. L Danbciscr. C. Ma rt inez. Duila. R. J. Auchus. 100 J. T. Kadonaga. J. Am. Clotm. Soco
10):2443 R. L Danbeiscr. J. J. Bromon. and K. Okano, J. Am. CMm. $oc. 107:4579

8. (a)H. Xiong Ind R. D. Rickc. J. Org. Clwm. J / :3247 (1 989); (b) R. D. Ricke and H. Xiong, J.
Org. eNm. 56:3109
9. H. Xiong and R. D. Ricke. TmiJMdroto UII. )1:5269
10. H. Xiona and R. D. Ricke. J. Am. CMm. Soc. 1",:4415
11 . R, L Danhcsc:r. C. Manina-Davila. and J. M. Morin J. Org. Cltem. 4' :I.l4O
12. R. D. Reke. M. S. Sell, ano:! H. Xiong. J . Am. Cltnrt. 5. 1/7:5429
13. (a) D. Alooso, J. Fonl, lno:! R. M. Onuno, J. Or(}. CM",. 56:5S67 lb) W. E. fristad lno:!
S. S. Henhbcrger, J. O,g. CM"' , 50:1026 (1985); (e) P. CIMnne, O. Selanger, ano:! G. I...emly,
J. 0'(1. CIrmr. " 7:3953 (198n
14. H. Xion, lno:! R. O. Reke, J. 0'(1. CIrem. 57:7007 (1992).
IS. ,a) M. S. Sell , H. Xiong, I nd R. O. Reh, Tmalwdron Lm. J-I: 6007 lb) R. O. Reke,
M. S. Sell,.no:! H. Xion, J . Org. CM", . 60:5143
16. L Set, O. Cheshire, Ind O. L Oive, J . CM"' , 501;. CJwm. Commun. J7:I20S
17. ,a) K.. Mon, ""':3233 (1989) I mI refue .... eo cited therein: (b) N. C. Sarua. aOO R. R.
xhmidt, Sy'llMIU, p. 1067 (1986); ( .. ) C. M. Thompson, TtlroMdrO/t Lm. 18:4241 ( 1987).
18.. P. Canonne, D. Selaner, G. Lemay, aOO G. B. fO$COIO$, J. O,g. CMm. fll:3091 (1981).
19. M.5. Sell, H. Xiong, ami R. O. Rieke, Tmol!MrM Lm. # :6011 (1993),
20. A. I. la5kin aOO H. A. Microbial prodlltU, CRC HandlxxJlr. o[ Microbiology, 2nd
Vol. S, CRC Press, 1984, and ref=ooes therein.
21. L. A. Paquene, D. MatOanald, L G. AOOenon, ano:! J. Wright, J. Am. CMm. Soco /J/:8037
(1989) ano:! cited therei n.
22. R. L frank, W. R. 5chmitz, and B. Zcidmao, 0'(1. J:328 ( 195S),
23. M. Mori. l. Oda, 100 Y. Ibo, TmaMrQII ll. 1J:S31S (1982).
24. H. Nap$hima. H. WahmalJll, N. OukL T. IshiL M. Watanabc. T. Tljima. aOO K. Hoh, J.
Org. CIrmt. 57: 1682
25. G. Stork Ind R. Mah, 18:723 (1989).
26. (a) M. O. khi, F. frolow, aOO C. Homaen, J. Orf}. Chmr . .,8:1841 ( 1983); {b) l . K. Chal Ind
D. J. Hin. TtlroMdrOtl .,/:3959 (1985); (e) S. J. Danishefsky lOO J. S. Pl nel: , J. Am. Ch,,,,. 5.
109:917 (1987).
27. M. S. Sell. W. R. Klein.and R. D. Rete, J. Or(l. CM",. 60:1077 (1995).
p' m
28
Asymmetrlc Synthesls Uslng Grlgnard Reagents
JOHN T. R08ERTS
El! AlocM'" HOI11t AMUje,," In<;.
Xi"g o/Pnm(a, Ptlt1Uyivonla
1. INTflODUCnON
TIw: synlhcsis of oplicaJly purc matcrials has gaincd mporlance in recen! years. As scicntisu
have largcled syntheticalJy challenging molecules Ihat have biological activity. a kecn
nlereSI has dcveloptd in he mcthods of producing, characlerizing. and solaling chiral
materials. The formation of chira] or oplicall)' active materials from nonoplicall)' active
precUTSOrs is tille<! uym_lric nJuc/ion. Asymmctric ndue!ion can be casi l), acoomplished
usins Grignaro Teagenl! and a nucleophilic acceplor.
A recen! book detai ls sorne catalyud Grignard rcae!ions fo r asyrnmetric induction.
In ASj'/IIlnttric Ca/a/y!i! In Or91mic Syn,hlsu, No)'ori [1 ] rcpar!s Ihe cnantioselect ivc
addition of Grignard 10 carbooyl compoundl, calalyzed by chirally modificd
organomelallic compounds. Thi! book conlains several inleresling examples of asymmelric
induclion involvng complexo from Grignard reagenu and olher chiralligands. including
amines and phosphincs. For eumple, Ihe formation of an alcohol from lhe reaction of
BuMgCI wilh benz.aldehyde can be cal alyzed by a chiTal tertiary amine 10 yicld Ihe
R-enantiomer in 9S/. oplical yield.
In Ihis chaplcr, Ihe delai ls of selcclcd synlhcses of oplically pure or enanliomctrically
enrichcd compounds using Grignar<! reagents will be presc:nled. [For a fuller ellplanation
of the concept of chirality and nomenelalure, lhe readers are referrcd 10 Refs. I- S.] However,
as new lerms are introduoed, a brief explanation will be providcd. Tbc worlr. is dividcd
inlo Ihree seclions. The first secti on inel udes lhe major reaclions lO prepare pure or
enrichcd malcrials by addition lo a chiral or prochiral carbonyl wilh a Grignar<! reagen!.
Thcse reaclions are Iypically 1,2- or 1,4-addiltons. The $CCOnd section include react ions
of a sui lable an epoxide) and a Grignard. The Ihird section is a miscellaneous
section and covers the preparation orpure or enrichcd materials that contain heleroatoms,
such as ni trogen, oxygen, silicon. and phosphorus and other nactions.
R"'''
11. ADDITION TO CAABONYL DERIVATIYES
Typical addition of a Grinard reag!:nl 10 a tarbon)' 1 compound leads 10 an alcohol. For
example, reaction al he planarcarbonyl carbon of an achital (nol a plicaU)' active) aldehyde
gives two possible slereoisomers, which are nonsl.lperimposable minor mages. Since two
enantiomcrs or chi ral compounds are forme<!, Ihe tarbon alom is describe<! as a
Olom. Before rc:aclion. Ihe ca/boo)' 1 carboo is describa! as prruureogenic 01 prochira/,
becausc il can Icad [o two diIJerent isomers 01 cnanliomers. From a stat istical poi o! of
view, nnc would predict Ihal equal amount5 oreach enanl iomer should be formed. Howevcr,
ir nnc sorner is formed in reater yield, Ihe n:action mixture is describcd as $Ca/emlt , and
Ihe cnantiomeric purily of Ihe producl$ is Ihe cnantiomeric ex<:es$ (e.e.) of ooe sorner over
l he other. For ir one enanliomcr is rormed in 75;0 and lhe second in 25"0, Ihe
e.e. ia 50"0 (75;. - 2' ''. - Mosl or Ihe reaclions in Ihis chapler will presenl e.e. as
lhe indicalion or asymmetric induction in a reaclion. Certainl y, for a reacl ion 10 be
synlhctically userul, Ihe e.e. will be very hi gh; an ideal c:tample or asymmetric induction
will have an e.e. of 100% (lOO";. of one enantiomcr and 0% of lhe second).
U one or Ihe reactanl! has a !tereogen!c center, here t hen is a possibility of forming
two pai rs of dia'llereomers or Iwo pai rs of enantiomcrs, four differenl products. Depending
on a variely of faclors, we could distance e.e. or d.e. (diaslcreomeric ellceS!, the predominance
or pai r of diaSlereomers over t he second). A few auihon will describe Ihe ratio of Ihci r
producll.
A. 1,2Addltlon.
The results of Grignard additions lO a varicty of carbonyl compounds are shown in Table
l. Thc: common theme for each eumple i! the formalion of a secondary alcohol from an
aldehyde. The aulhors ci led in Table 1 use a variely of convent ions 10 indicale oplical
purily however, ir JlO5sible. ihese will be converted 10 Ihe convenl onal perccnlage
e.e., or lo the configural ion (R- or So) or (he somero
Shing and co-worken f_ Table 1, entry 1) reported he slereoselective synthesis of
Ihe secondary alcohol (rom he aldehydO-D-glucose for use as an inlermcdiale in Ihe
synl hesis of goniopypyrones, cytolollins lo human l umor celb [6). These intermediate
producIs "'ere the epimeric benzylic alcohols; Ihe major producl was lhe R-isomcr, (ormed
in 70Y. e.e. The author! propase an a-dlelale t rallsit ion !Iale 1, a sill-membered cheJate
ri ng, wilh lhe nucleophile aUacking Ihe carbooyl (rom the bouom face, relalive 10 the
coordinaling hy1irollyJ and kctyJ groups, as shown in Eq. (I ).
-
(1 )

p' m
66:33 ralio. Gawley also idenl ified a new ouzoline chi ral auxiliary, a camphor derivaliw:,
Ihal affords improvcd seleclivi ly, up lo in one inslanee.
In contr:ul, Casiraghi el al. [1 0] (see Table ], entry 5) reportcd lhe synl hesis of
lIIpyrrylaldilols :u precursors 10 heleroalom nuclcosides. Reaelion of lhe pyrrol Grignard
wilh 2,3-0-bopropyl idene-o-glyccraldehyde gave a miuure of produets, dependi ng on lhe
catalyst. When the react ion is assisled by a litanium sall. lhe major product is Ihe
o-uyfhro-glycerol wit h a small amount of the o-rhreo-isomer, 8%. Wilh a
cerium sal! Ihe major producl has Ihe opposite stereochcmislry: Ihe yield of o-Ihreo-isomer
is wilh only 7/0 of lhe I.>-Uyfhro- isomer. Thil slralegy will be discusscd in subscquent
sections.
Table 2 shows selected reaclions of kelones with Grignard reagenl!. In (he finl enlry,
Miles and oo-workers [ 11 ] used a chiral Grignard reagent as thc nucleophile in Ihe
diaslereosc:lect;ve preparation of ethcr alcohols. Here, an oplica1ly aclivc Grignard reagent
ives bol h possible diaslereomers in an approximalc yicld, with an e.e. of SO/o for
Ihe S-isomer. Reaction of the $lime Grignard wit h cyclopenlanone gives similar yields
and oplical puri ly (80%
Table 2, enlry 2, shows an cumple of Ihc work of Marco el al. (12]. Thty obscrved
Ihe diaslereosclcctive addit ion 10 prOlecled sugars as precursors lo macrolide anlibiolics.
In general, Ihe diaslereomerie ralio of the tcrliary alcohol s depended on Ihe reagenl, the
solw:nt, and lhe lemperalure. Pure enanliomeric erthrulosc: acet onides (ei lher R- or
S-isomer) gave a mixlure of the IWO possible diastcreomenc adducls in fair 10 exccllent
yield: the d.e. varied from 25:75 IR or S) SIR 10 75:25 (R or S) SIR usi ng Ihe Grignard
reagent al - 78C in dielhyl elher.
Nogano and co-workers ( 3J reporled similar examples of asymmetric induclion for
nalural producl ynlhes;s using prolCCled $ugaTS and a varely of R' MgX, where X _ a,
Br, or 1. In Tablc 2. entTe$ 3 and 4, lhe lelralase carbonyl can also conlain in Ihe R(
position an elher, esler, urelhane, all:yl, or aryl group ( 13]. The aulhors reporled Ihe
diaslereomeler ratio from Ihe R subslrale and Ihe labeled carbon-2 varied from 80:20 10
10:90 (2S!2R). The variabi lity w:u conlrollcd by Ihe nat ure of the nudeophile, Ihe solvent,
and Ihe tempcrature. The aul hors ralional ized the product distri buliorJ based on chelation
of Ihe metal and steric bull: of lhe Teactanls, favoring the R-isomer.
For Iheir approach lo oplically active aleohols, Mazzanti and co-workers [1 4] used
chi ral acylsilanes (sec Table 2, enlries 5 and Si nce Ihe slereogenic silicon auxiliary could
easily be removed by fluoride trealment ( 15]. Ihe aulhon hopcd Ihe alcohols had a high
d.e. Ihat would lcad lo a high e.t. They demonstraled Ihe concept, bUI Ihe overall e.e. was
Ie,s Ihan 30'-_. For cumple, use of ei lher a phenyl or melhyl Grignard with the chiral
,ilane !lave a range of d.t. (1 bul on hydrolylic workup Ihe highcsl d.e. products
gave an alcohol with a e.e. of 28-/ . Varialion of Ihe substi tuenls on the si licon and adding
steric bull: to Ihe kelone gave mi.led rcsults.
Pagc and co-workers ( 16) used a dial hiane oxide moiely bccause il allowed Ihe
slereocontrolled addil ion of nudeophi les wil houl Ihe 105.5 of Ihe prolcct ing group (sc:e
Table 2. entry 7). These authors demonSlflIted high diaslercoseleclivities, depending on
Ihe solw:nt and Ihe temperature. In tetrahydrofuran rrHF), al - 2O"C, a 92-/. d.e. was
oblained in almosl quanlilatiw: yield; lowcr selcctivities were oblained in diel hyl elber or
at higher Icmpcralures.
Schmid and Maliakel [ I7J reporled diaslereosela:l;ve Grignard react ions in their
synt hetic scheme 10 sphydrofurans, scoondary metabolites from various , Irains of
Streplomycete$. Allhough Eq. (2) depicts Ihe desircd sequencc as a si ngle equal ion. th.l
actual scheme has fOUT sleps. The aulhors used lhe silyl-protecled carbonyl with

T. ble 1 Chiral Producls from 1,2.Additiofll 10 Kelona
E.t<J
(Id . ...... ) !!Id
I ( JI )
2 (11)
J C IJ) ....
(U)
....
~ (14)
....
, (n)
, (16)
~ .
- - t ~
O O
'.
,
- - t ~
O
,
c...tI ...... u .. ,
0,01 .... 1 n.t.
1:. n : u
1S:11
90' ..
l . 711\ ..
:s . SS> ..
,1'\ ..
,.,
(35, 4R) configuration and Ihe allyl Grignard reallenl 10 ive a si ngle. ring-c::losed furan,
with a pendant ally1 group, in 6(W. yield as lhe fin! slep. Subsequcnt Wacker uaction
gavc Ihe sphydroruran.
/
(2)
;'
"
P' m
""
Fujioka el al. (18J prcpared a ntw chiral<Xjl-building block fOf use in lhe synthesis
of optically active antlu8cyclinonn [Eq. (J)). Reaction of he propenyl Grignard
with he chiral p-tctralone gave lhe alkynylalcQhol with 110 a./J-ring. Thc 8ulhol'll show
one product with he indicated sltreQ(;m:misl ry. Hydrolysis of he ketal ga,'c he desi rcd
intermcdiate .
. 'r<
, '
.""",.

O)


In relate<! work. Tamura el al. [ 19] reponed diaslereosclective addition of Grignards
10 cyclk: aOO acyclic (I-keloocelal5 10 prepare mevalolactones. With high yields ( > 8S-/.).
he ratio of di Ulereomcrs varied (rom 60:40 lO 100:0 (Eq. (4)). Similar 10 he n:action in
Eq. (2). lhe ker slep is lhe (orm1l110n of he optically active keloacclal, usng (2S.


:=(
lIIlI'.
:=(
tII,ln

TIIF, . "oC
(4)
"
"
,
Murabayashi and Makisumi (2OJ prepara! Ihe anlirungal [Eq.
(5)] by the reactivn of Ihe cormponding cycloheunone wilh aryl Grignard reagents.
YiddJ wen: moderalc lo high, and Ihc predominan! somer had Ihe $-configurat ion. For
tilher Ihe diaza- or lriaza-5ub!;l itu.cnl$ lile cI$/ tNJIIS ratio was vcry high, more Ihan 90:1.
Only the cil-diastereomcr was rormed whcn Ihe cyclohcplanone was used.

(S)
K _ al._
Takallashi et al. [21] reported the synthesis or isomeric butanols from lile lertiary
amine, (S)-4-amino- l-phenylbulanone [Eq. (6)). The sten:cx:hcmiSlry rormed al Ihe new
chiral cenler (2-S- or 2-R-) was dependenl on lhe reaction condi l ions.
.'
"
.'
"
(6)
Addilion of Ihe Grignard reagenl was calalyz.ed by a variely of organomelalJics in
lhe work reported by Ukaji [ 22]. High diastereosc:lectivities were oblaincd in Ihe reaclion
major isomer was the S-isomer, usualJy formcd in greater than 9(1"1. e.e. Thc aUlho,",
ralionalizcd the formalion of the S-isomer by a!tack from lhe Si face of Ihe imine, lince
the ester carbonyl and the imino group are held 3Y" by lhe magnesium ion.
Addilion or an aUyl Grignard rcagenl lO a ,6,y-epoJ.yimine 10 ghe epoJ.yamines was
accompl ishcd by Bcrcsford ct al. [28] (scc Table J, enlry Thc authors suggcslcd chelalion
conlrol of Ihe epoxide oxygen, and Ihe eleclron pair on the nitrogen allowcd backsidc
aliad on Ihe imine, giving Ihe R-configuration. Addition of a Lcwis acid also contribulcd
lo the high slereosclcct ivitics.
As parl of a ll5ymmelric synthesis of key Pl"e(:ursors 10 various morphan or
bcnzomorphan drugs, Marazano and co-worken [29] studicd Ihe formalion of chiral
tet rahydrapyridines with lipophilic counleranions from Ihe corresponding pyridinium sal ts
(scc Table J, entry 5). Addition or anisyl Grignard reagenl followcd by borohydride
rcduction gave Ihe R,S-diaslereomer in d.c. Varying the R-group or Ihe Grignard
reagenl still gave the R,S-isomer as Ihe predominanl producl.
Alexakis and co-workers [ 30] developcd a complementary rncthod fo r the prcparation
of chiTal r:a:ami no aldehydcs. Addition orthe Grignard reagent lo the imidazolinc hydrazone
ave a high selcctivily for the Risomer (ICe Table 3, enlry 6). For a vanety or Grignard
reagenl!, lhe rcsulting isomer typicaUy has the R-configuralion. The authors suggestcd
Ihat formalion of lhe preferrcd isomer WIl5 effccted by chclalion control by the lone pair
of one of Ihe 111'0 nilrogens of Ihe imidazolinc ring and Ihe hydrazone runctionalily.
Previously, Ihe aulhors prepared Ihe S-isomer from Ihe alkyl lilhium reagen\.
Barloli el al. [JI] reportcd the formadon of enanliomerically pure amines and
hydroJ.ylamines from oplically active nilroalkancs with allylic and bcn:zylic Grignard
reagenls. The inlermcdiale nilrones (scc Table)' enl ry 7) wcre mixtures of f.. aOO Z-isomers
from the prolcclcd nilroalkancs. AlIhough Ihe regiochemistry is compl icatcd. lhe
stercochemist ry of Ihe dOllblc bond was afl"cctcd by Ihe nalure of lhe Grignard reagen\.
The major isomer was always lhe Eisomer.
8 . l,4-Addltlona
Table 4 li m sorne examples or asymmetric l.4-additions of Grignard reagents to enones.
Spcscha el al. [J2] n::portcd the conj ugale addilion of butyl Grignard 10 2-cyclohexenone,
calalyz.cd by a coppcr- thiO$ugar complex (ICe Table 4. enlry n Thc chiral ligarni was
" HSSIGH--coppcr 1.2:5.6:di-O-i sopropylidene-3-thio-cr- O-glucofuran. The producl. 3-
butylcyclohexanonc, was formcd in greatcr Ihan 98% yicld, wjth an c.c. or 6<W .
Lippard and co-workers [33] n::portcd the same addition. but catalyz.cd by copptrl(l)
complcxes wilh bidenlate chiral auxiliary ligands (see Table 4, entry Tite producls., as
prccuTSOD to PTO$tagJandin synthesi!. wen:: fonncd in moderale yicld and 1011' e.e. when
Cu( R-CHIRAMT). a chiral aminOlropone mine, used.. However. higher enantiomeric
exccss puritics ( > were oblaincd when a silyl reagent and hexamc:lhylphO$phoramide
(HMPA) weTe addcd. NOI surprisi ngly. both calalysls ave si milar producls wilh si milar
enanliomeric purilics.
A S-silyl enone was n::ported lo give a mixlure of product.s from 1,2- and 1,4-addili on
[34]. The aulhors $uggcslcd Ihal mixlUres of diaslereomers wcre oblaincd, but with
uncharaclcrilCd stercochcmistry al Ihe 3- and S positioos.
Takei and co-workeD [35] also reported the coppt: r-catalyz.cd addilion 10 enones
(scc Table 4. entry 4t usin an R-clhylenethioacctal as Ihe polential building block, with
a copper sulfidc complex. Addition or Ihe Grignard reagcnl gavc lhe major ProdUCI. wilh
a (35. 4R)-configuration, indicat ing Ihat Ihe addition occurrcd primadly sY" to the Ihioacelal
T.IM 4 Chiral Prool,M;tl trom I.4- Addi lions
bt<1
.. I _.
<'.f ...
... ,x tl;. _ ! !!I!Uc. IIo!'

I Ol! C,H.",I
6
l . > " O


I U)
C,".",X
6
J. 1 4\
O O
1 (310)
... '
,
\,0,
/u
,
/,
O
4 (n)

U : 1
,
. ,
LJ
,
LJ
(
M ....
1

1
" .
'"
1 , IS
nI aI.aI . ....
' 1
'1


o


, I nI CH,H,I
CY,-P l(p
n ",o _

,_.
,-.
o

,
o..

l. . ..
J (,.)

"''
"'D
o"ygeo. Di astereoseleclivi ties rangcd from goOO (O clccllenl Interestingly, Ihe
use of bulky Grignard reagcnt5 Ied 10 lower ralios of SIR al Ihe prochiral carbono
Touel el [J6] prepared several lJ melhyl and flphe nylalkanoic acids, wilh high
eoanl iomeric purilies. The Michael addi tion of elhyl Grignard reagenl lO p.hydro"y.
cinoamamides in rai r 10 Cllccll enl yiclds (scc Table 4. cnlry In each case. hydrolysis of
Ihe cinnamllmide yielded lhe alltanoic acid wilh R-confguralion in very high c.c. (>
The aUlhors suggcsled Ihal. because Ihe magnesium binds bol h Ihe carbonyl oxygen and
he prolecled alcohol oxygeo. Ihe alkyl grOllp is delivered 10 Ihe double bond in a
lrIm.lfashion.
'"
""
Schu1t:t and Harrington (37] added Grignards 10 !Eamido enone (see Table 4,
enlr)' They obtai ned high diaSleromeric Clm5$CS with a variel)' of nucleophiles; for
example. wit h methyl Grignard reagenl, Ihe d.c. ranged rrorn 8S 10 9(W .
Sakai and ro-workers [38] studied he additions lo conjugate CIten protectcd wilh
a cycl ic diol as a chiral aU.li liary. The estcr is protected with cnanliorncmally purc (l R.2R)
rral'u-cyclohcxanc diol (sec Table 4, cnt ry n Addition orphcnyl Grignard reagen!. catalyzed
by Cul, produced a moderalc yicld (50%) or a mixture of Ihe Iwo diastereomeT5 (prochiral
carbon RjS_18'!1.:22"/.) with a d.c. or 55"/0. In contrasto he authors Iso reported Ihat
addition or Ihe phenyl lilhium cuprate gave 94:6 ratio wilh he majar producl haying lhe
S-configurntion for Ihe prochiral carbono Because of che differences in lhe slruel ures of
Ihe eomplexes. altaek from the Iithium cuprale comes from Ihe Re-face, whereas attack
from the copper-Grignard comes from the Si-faee.
A copper-calalyzed 1,4-addition was also describe<! by Oppolzer and Kingma [39].
Addition ofthe Grignard lo an enoylsultam [Eq. (lO)) eould possibly produet fou r produCIS
because Iwo slereogenic eeDlen are formed. The authon found a high yiekl (90";.) of a
mixl ure of diastercomeric pairs, idenl ified aFter in ,il u hydrolysis 10 recover Ihe sullam
auxiliary. The major products were Ihe S.s-aOO the R,R-di astereomen The aulhon
ralionalize the differences in Ihe observed stereochemistries by eoordination of the
magnesium and coppcr wilh lhe carbonyl and lhe oxygens oflhe sultam, thereby pcrmitting
addilion to lhe Re-faee.
/'
,

, ,
,
1
"


/'
,

, ,
,
(10)
,
"
Lippard, work (33J on Ihe conjuale addition, moderated by the addit ion of a
oopper catalyst and I ,ilyl reagen!. il describe<! in Table 4, enlry 2. Further reaclions oF
In oplically active 4-siloxy-2-o;:yclopenlenone is depicled in Eq. In Ihis reaclion-
addition of the Grignard reagent w;th the ooppcr catalysl, either Cu(S-CHIRAMT) or
Cu( R-CHIRAM1}--gave the major product in which Ihe alkyl group is delivered lrtmol
lO Ihe si lyl group. The previou$ argumenl was used 10 ral iODalile the Formation of the
producto
,
I
+ CM,-otIlr.

+\,-'

( 11 )
+\,-'
Najera el al. [40,41) reported addition reactions 10 a variety of aryl sulrones. Tite
Grignard reagent addilion 10 an JJ-un$aturated sulfone (an enoyl sulfone) is depicled in
Eq. In Ihis reaction, Ihe major product is forme<! from conjugate addition lO the
p' m
(l2)
sulfone, ral her Ihan to the carbonyl. All hough Ihe slereochemistry is nOI well oonlrolloo,
Ihe regiochemistry is.
111. NUCLEOPHILlC SUBSTITUTlON AEACTIONS WITH GAIONARD AEAGENTS
Table S lim several reaclions in which Ihe Grignard reagent i5 addoo 10 a syslem Ihal
allows nng-openlng or displacemenl, ralher Iha n the Iypical addition reaclion! de:scribed
previou5ly. Umeuwa (42) palenle<! an approach lo make long-chai n alcohol! from oplically
active epo.lides ($Ce Table S. enlry In this eumpk. they prepare<! oplically pure 4-decyl
alcohol in quanlilalive yield. The product was formed by lhe addil ion of a Grignard
reagenl lO thc epo.lide; a calalysl. oopper{l) iodide, was also used.
810ch and Bri llel [43] invesligaled Ihe Subslilution reacl ion of Grignard reagenl s
10 Iricycl ic laclol!. An example of 1.4-asymmetric induction to produce enanliomerically
pure diols is shown in Table 5, enlry 2. Addition of lhe Grigoard reageol 10 a TlIcemic
laclol gave only one diaslereomer in high yield (72- 80;.). which is CQnsislent wi th olher
lactol!. The aUlhors suggesled Ihal aUack of the nucleophile always occun on Ihe same
face oflhe carbonyl. oorresponding 10 the less- hindered face oflhe relalively rigid lridentale
ehelale.
Rollin and eo- workers (44) treale<! wilh a
variely ofGrignard reagenls 10 ive braoched propan-loO]! (see Table 5. enlry A]though
lhe yields were {ai r lo moderale Ihey depended 00 he chaio Jenglh of lhe
Grignard reagenl: Ihe longer the alkyl. Ihe lower Ihe yield. Surprisingly, lhe authors
discovered Ihat Ihe rtgiochemislry is CQnlrolle<! by lhe n:mole pyridyl and lhe Ihiomet hyl
moieties. They argued Ihat lhe mechaoism is probably a n:mole-controlJed subslitulion.
wilh simullaneou$ acelone eliminatioo (rom lhe more hi ndered nonkelaJ carbono They an:
currenlly evalualing Ihe slereochemical CQnsequences of Ihe reaction.
Albero!a el al. (45) reported lhe n:gioselect iye Ting opening of lel rahydro- l.3-oxazines
10 give y-amino alcohols (see Table S. entry wi lh a wide Yariely of alkyl-. alkenyl-. and
aryJmagnesium hatides. The major producI was Ihe ring-opened primary alcohol.
Wi1co,ll and co-workers (46] invest igaled he n:aclion of Grignard reagenl! ""ilh
dialkylaminofuranO$ides 3$ a hasis for their work 00 nucleosides and amino sugars. An
e.tample is !he reaction of Ihe et hynylmagnesium bromide wi lh dibenzylaminoglyooside
10 give a 95'Y. yield of a single diastereomer (see TabJe 5. enuy The product, !he
propargyl amine. has an R-configuration at lhe amine carbono A raoge of gylcosides and
furanosides rcacle<! wilh a variety of Grignard reagcnls lo give similar resull!. The aulhors
propose Iha! Ihe C-2 cenler conlrols the displacement process, and Ihe olher 111'0 slerogenic
carbons at C-3 and C-4 an: nOI important in Ihis process. These results proyide products
wilh slereochemistry opposile Ihat of the producls derive<! from lhe correspondi ng
aldehydes.
As parl or a synthetic campa;gn 10 prepan: chi ral precursors for biologically active
give: pyrolidine:s. For e:umple, react ion with with a
Grignard reagent ave chi Tal in 60-/0
yield (see TabJc S, enlry 7). Molec.:uJar modcl$ 5uge$llhal intcrnal oomplcution of
and thc two nitrogcns grcat ly cnhances thc yie:ld af the R-isomcr aftcr altack at the et her.
Grabowski and oo-workcl1l [49] dcsignod an cnantiosc:lec.:tivc synt hesis of ar,ar-diaryl-
2-pyrrolldincmelhanoJ that uses Ihc addition af a Gngnard rcagcnt to prolinc-N-
carbolllnhydride, ral1owod by s\lbsti l \ltion with thc sccond cquivalcnt af Ihe Gngnard
rcagent. lo ycld a tcrt iary alcohol, with 99% e.c., Eq. (13).
o
,
..
o
2 PbII&CI

. -{
. m. (13)
'-, o
In Eq. (14), Yoda ct al. [SO) studiod Ihe prcparalion of oplically act ive actones.
with t hn:c contigUOU5 stereogenic centcrs. from imides wilh two stereogenic ccnlers. The
precursor chi ral mide was easil y preparc:d from tartanc aeid. Silylation of the 2,3-diol
and addil ion of lipophi lic Grignard rcagents 10 Ihe: imide gave Ihe - hydroxy amidc. The
authors are invesl igaling Ihe slereochemical consequences of Iheir work.
+
'-" \ -t-
1...... SI
o o""" \

..... 'H
o
( 14)
In Ihc prcpaTaton of complex sugars, Dak el al. [ S 1] rcactcd glycofuranuTonolactoncs
with aUyl Grignard reagenlS. Addit ion 10 Ihe carbonyl followcd by ring apeni ng. ave
the obscrvod products. di astercomeric pairs of dideoxyoetenofuranoses (Eq. (1 S)).
+\'-0
-fsL
o

CH,-a.t,lr
/ 1.
o (1 S)
_o o
o
,
A
IV. MISCELLANEOUS AEACTlONS
This sect ion of the rcview (:Ovcn the undry reactions Ihal Grignards undergo 10 efl"cct a
variety of malec.:ular lransformali ons.
Consiglio and Indolesc:: [ 52] rcportod the allylation or Grignards with nickcl-
diphosphine catal ysts. Eq. The authors showod the cxcellcnt conversion of Ihc allyl
'"
ether 10 Ihe alkylated eycloalkene: he convenions were ll ! ualJy greater Ihan 900/. for Ihe
fivc-membc:red ring and average<! more Ihan SOo/. for lhe six-membc:m:I rng. Thc aulhor!
di 5Closcd Ihat lhe high cnantiosclect ivity (aplical yields up 10 940/.) dcpends more on slerie
faet oD Ihan on electronic faclors.
( 16)
cat . _
In a different di splacement reaction, Nat iv; el al. [53] demonslrattd he replacement
of an acelox)' gfOUp in a p-tatlam by a silylmethyl group. React ion of 4-acetoxy-2-
azalidinone with a variel)' of alkyl Gngna r<! reagenls gave CQmplcx mixtures and low
yields of lhe desired producto However, reacti on with trimct hyl$ilylmethyl Gngnard reagcn!
gavc he si lylated p-Iaclam in pealer Ihan SO.,... yicld. Eq. 1 7 ~ Thc nitial resul15 do nOI
look promisins as a melhod for preparing substituted fJ- laclams .

'"
-...,./
", ... Cl
\..1
1-
11
... 1 \

/
..
/ '"
(11)
\
"

\
"
Wong el al [S4] deKribed he regioconlrolled addition or melhyl Grignard reagenl
and diJplacemenl, C8lalyzed by Ihe Ni" oompleJI [Eq. (18)). Addition 10 lhe bislhiane was
C8lalyzed by Ni- bisphosphine complu .. A chelation complcx was proposed. giving a
regioscleclive producl by an d o double bond. lnterestingly, only one orlhe dit hio moielies
reaCIs.
CH,Kt;I. c.t .

["el,c'"',) ,1
( IS)
Furukawa and oo-workers [55] deKribes lheir work as [jgand-cxchange react ions
or arylpyridyl sulfoxidcs wilh Grignard reagenlS 10 generate a nel pyridyl Grignard reasenl.
An example is Ihe reaction of cyc!ohexanone wilh 2-pyridylphenyl sulfoxide in lhe presence
of elhy! Grignard reagenl 10 yield pyridylcyc!ohexanol. wilh unspccificd stereochernist ry
[Eq. ([ 9)]. Howcver, when the aulhon used an opticalJy active lulfoxide, Ihey obtaincd
lhe alkylpyridyl speciC$, aJong with lhe trOIl$-alkylatcd sulfoxide wilh the opposite
configural ion in 100% d.c. They proposcd Ihe formali on or an inlermcdiale in which only
one diastereorner is rormed.
p' m
'"
Rd., IV

-
,
' .., , Ii

.. C, M.",'.
" .
( 19)


As par! of a program lo devclop ncw melhodl o( synl hesis for lhe unsaluruled
backbone of Z-configured phermones. Kunesch el al. ( 56] converted cycle enol cthers 10
the unsaturated acetate [Eq. (20)]. This nidel'MsIste<! [NiCI.t Ph Jl'hl reacl ion produced
stcreoselectively (>95'/.) Ihe F..E.diene. Hen:, the Gngnard reagenl adds 10 he vinylic
carbon, wi lh a ring opeoog lO give the opcn-chain prOOm;t.
(20)
The purpose of lhe work reported by Kocienski and co-workel"!l [ H] was for he
preparation of he ' ypicall y inao::essible trisubstit uted alkenes uscd as precul'$Ol"$ for
anl ifunga! derivatives. They demonSlrated Ihe Ni-catalyud cross-coupli ng of a Grignard
reagenl and 5-alkyl-2.3-dihydroruran gave he addition 01 reduction products, dependng
on Ihe workup. The leasl selective GriJ!.l1ard reagent gave a 5:1 ralio of addition/reduction,
and the ralio of ZIE is dependent on Ihe chai n lenglh of Ihe Grignard reagent, Eq.
Kocienski also reporled [58] he formation or Ihe E-homoallyic alcohol in 82% yield [Eq.
(22)]. In Ihis case, y-5ubslitulion or an ether alJowed Ihe ehe1ation control required ror
the formation of he e-i somer.
-
'"
I . ad Z

+

+
t It , ,,*
(21 )
,
-
"

.... ,
00dd1\1
'-\'
--1-.
,
+ aI,lI&lt
(22)

-
" ,
,-,
'"
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J pp. )4)1- J.438 (1992).
59. R. Rcbicn: and H. Kopn, TCftohedrfHI Lell. JO:3659--3662 ( 19851).
60. (a, J. Can:y, M. Buke!", J. Bro",", and M. J. CIwm. Soco Perlem Troll . 1 pp. 831-83!1
(b) J. Bro",". J. c.rey. and M. Ru..sseU, TCfrohcdron 46:4871-4886 (1990).
reagenls seleetively reaeled with alkyl iodide and losylale al the Icss-hi ndered terminus
[38,46] in Ihe presence of Cul [Eqs. (9) and 38: sce abo Eqs. (15) and (lO)).
MeSi yM'Br
) 1 + Bul
BrM,O(eHlt

E"
X_Sr. I.OTs
c.,
c. ,
c.,

HO(CH
1
lt
, ... yield
l/E: _ 96:.
",O
-
",O
1<4''" Jidd
10 .. rield
20" yicld wilhGIII Cllj

() <:tlill
10 .. yield
+
e,H"
81 .. yield (E/Z _ 1: 1) .. yield
(83 .. yicld 20 (E/Z 1: 1) : &O wilhoul CuJ
c. ,

80-90.. ,ield
(5)
(6)
(7)
(8)
(9)
(lO)
The substratesare primary- [sce Eqs.(2)and (5-9)] orsccondary- [31,41] [Eq. 41]
alkyl, alkenyl [Eq. 25], or aryl iodides [Eq. 31). Primary-alkyl bromides
[22,27,43,47] [see Eq. (lO) and Eq. 22] and primary. and secondary-alkyl losylates
(23,32,33,48: see Eqs. (3) and 10)] stm alforded Ihe correspondi ng ooupling produclS in
goad yie1ds, bul Ihe use of ch10rides--ellcept a11yl (38,40-43; Eq. (IS); 38] and henzyl
[29,37; Eq. 37] chlorides--or teniary alky1 substratos is usually discouraged [31].
";O
,l

LilC"CI,
1 I
,
X C;;HIl
O
(JI )
O
x. Br
""
yield
,
89% yicld
,.
LlCuCt.
SuMe8.
"A,
o
M,a
UCuCI.

, ..
o
,
DuM;Br
o
PhMeOr ..
c.a
,
TMEDA
,.
"A,.

",

15" riel"
Du -C, II )
18110 yiel"
c.,
"/'-,,
al' rield
(12)
( 13)
(14)
(1 S)
60" rield
(16)
When alkenyl iodilk was uscd as he substratc, il! stereochemical inlegdly was
relained in he product [ste Eqs. (5) and (12l; 2S,JS]. bul a decrcased isomeric purilr
also becn ment ioned [Eqs. (17) and (18): 49]'
c.,
..
11 11
70 ; 30
(17)
10-10 .. riel"
c. ,
n
11 e. Hu
80 ; 20
( 18)
10'110 riel"
Among he foregoing substratts., primary-al kyl subslrales are more reactivt han 811:
sccondary ones [JO,31,41], and iodides and losylates are more reactive han bromides
(31,32,48]. Alkenyl and aTrl subslrales secm 10 be less reactive oomparcd with alkyl
oounlnparls and, in be former 1yPC. Ni- and Pd-catalyzed reaelions are much more
popular (see he following Alkanes having I,w-Ieaving groups, when ro is
Ihrcc or more. underwent lhe: displaccment 10 give I,w-bis-substitulcd alkanes [ Eq. (19);
+ B' ............... B'
IIMPA
MgOr
Cullr
(19)
1 '"
2 : I
.. yidd
,.,
50-52]. 1,2.Dihalidcs did nol .ivc (he bi,alkylatN compounds owing 10 clminatioD or
reduction Orlhe halide moiety [27]. A stcpwisc IUclion WlllI also possible (&. (20); 27,52,53).


KO .. yicld
(20)
Many funclionalized Grignard reagcnls as well as subst rates Ihat have halide [31.54;
Eq. (21); 54]; esler [ 31,.55; Eq. (22); SS]; nitrUe [31]; elher, neluding acetal [24,26.47.50,52,
55-59; 5CC Eqs. (2) and (23); 59]; hydroxyl (31,35,38.60.61; scc Eqs. (S) and (15)]: or carboxyl
groups [&. (24); 60) oould participalC in Ihi s rcaction, wilh (he additional funclional
group(s) rcmainiog nlael.

B,
COlO.
,
P(OEI))
R. Bu. C,Hn
/ - p,
/- Bu
Q +
M O,
RM,BI + 8 , (CII )"CO M,CI
R . C, Il
II
,J-8u. n. 1-10
PII (CHlh-
SO"" yicld
R ...............
OAC
7j-.0'4 YH:ld
H. yicld
O .. yldd
(2 1)
(22)
(23)
(24)
Uncalalyzed reaclions orGrignard reagenls with epoxides are not so straightTorward
that they give products resulting from ring opening with 81kyl (R) as wcJl as halide (X)
of R-MgX or those from rearrangement promoled by lhe Lewis acididly oT lhe magnesium
cation [62,70). However, epoxides [62- 71 ; Eql. (25) and 62,64], oxelane [Eq. (27);
RMX
ex
, OIl
"
(25)
R _ alkyl,prc:nyt.
<1O"" yicld
Bn lkenyI.Ph (R_OII. 6,. yield "'MIII C ..
p' m
62), and small- ri ng laetones [Eqs. (28) and (29); 72, H) underwent clean-roupling reactions
with Grignard reagcnls in Ihe presence ora copper sah lO give alcohols and carboxylie acids.
c.,
0 "
.'
.'
, , ,
R .R.R .. H.3Ikyl.1'II 829"", yield
R: Bu.allyl.Ph


. BuM,CI Jf
CwD
c.a

R ............... OII
ylCld
(R .. Du. 10 .. yitld
11 .. yitld
(61 '110 yitld ",ilh CuCO
84 .. yicld
(26)
(2n
(28)
(29)
An anyl Grignll rd reagenl eoupled with epoxide al lhe less-substituted terminus of
lhe Gngnard in the presence o[ Cul . is exemplificd in Eq. (30) [74.15]. This outcome is
consistenl with hose appearing in Eqs. (9), (10), and (15),
Ma.
0"
&
c. ,
r
0 "

(JO)
"
,
11 .. yicld
"
.
"
89 .. ,;cld ",;'h.,." CII) .
Regio- and chemoscla.:tivc aspccts of ring openi ng o[ epoxides havc bcen studied.
The ring-opening ruclions usuall y lend lO prooced at lhe Iess-substituted tcrminus of
epoxides [63,64,61-69,11). In other word$, terminal epoxides are more react ive than intemal
ones (69). An cxception is the reaction of sil ykpoxides., for which the epoxide opening
OCCUf$ sclcctively at the carbon beanng he sil yl group, which is apparenlly bulkicr than
lhe alkyl group [Eq. 65.16,17,18).
c. ,
,
CeE
0 "

!
ji, 6EE
> 11" ,icld
(3 1)
Reaction o[ Iclra-subslituted epoxide was sluggish and usually aft'ords complex mixture
of producls.
'"
,.,

RuMIOr.. I
OCN

. "''''''Y

OCOBu-
(96" ce)
ca. 6S"", yicld 79.S: 11.3 : l.2


I ("1 J
,
,.
(53)
63 .. ce
E.u :ellcnt regio- and ,tcrcochcmical cont rol was reccntly more gCDerally rcaJized.
Thus. Ihe addition ora varidy or Grignard rcagcnts involvi ng allt)'l, bcnzyl, allyl, -al lten)'!.
and I-alltroyl Grignard rcagcnt! lO al1 rl chlorides, ph05phates. acetates, or sulfonales was
controlled 10 be Y lo he leaving group (i.e., in SNZ' fashion) under the inftuence or a
calalytic amouo! or CuCN- 2LiO complCl [Eqs. (54) IInd (5S); 118- 121). This Obse"alion
indicate!i Ihe position or the attlck was dctermined by Ihe localion of the leaviog group,
rather Ihan Ihe slcric hindrance or bolh IJlrlic lermini.
R I n_.s_./_alkyl.
IlIyl ,8n.
CU1_CH_.1'h
HuM,el
R
1
!I ,an:,.
R
l

CuCN2UCI

..
R'
67:])>99:<1
(54,
19-<)9" yield
orns
>99" rc,lolclcClivc
87'" yidd

The substilution was also highly allli,slereoselective, which was verified wi th optically
active starting malerial!. as iUuslrated in Eqs. (56) and (57) (1 19,120).
'-.//',/''''
8uMICI + - I
OPO(OPf'/h
9 . ... cc
CuCNlliCl
rE/Z. :.99: <1


:.99... rCliosclcclin
.". "
89'110 yictd
(56)
-
MSO...-=----......OAt;
HMPA
=.=CSiMf;.
0-'<
82"'" yicld
(71 )
Diostcreosclectivc. coppc: r-catalyzed propargylic substitution by Grignard
to yicld optically allcnes has becn reportcd for substratcs having a chiral acetal
moiety (Eq. 138] (10.148).
Hrd.., .... ,
RilO"'"
lOO"'" yicld
R. Me. Bu. Bu, P"
del"'") '6. 70, 100 ,
(72)
The degree and direction or enatio OT diasterrosclcctivity or the aliene formation
described in the forcgoing cannot be discus.sed without undentanding the ene! mcchanism
or this reaetion. Alcxakis et al. carricd out dctailcd studies in this arca and prescntcd two
possibilitie$, which are summariud in Schcmc 2. The fint one. prcviously propcmd by
Vermccr e al (IJO], involves 'lIIti-displacemcnt of the propargyl-Icaving group with RCu'
spccie5, followcd by of the R group from coppc:r 10 aliene, wilh rctenlion or
configuration. The sccond consisI5 ofcarbocupration of acelylcne, followcd by fI-climination
of the melal and he leaving group in eilher 51"- or ollli-fashion. In faet, the stereochemica!
oUlcome or Ihe aliene formation by copper-calalyzcd Grignard addition 10 propargyl
$ubstratcs changcs S1" to Ollli by changing lhe: organometall ic spe<:ics and the Icaving
group. Since he second mcchanistic propasa! can reasonably explain Ihi s observation,
Alcxakis el al. suggeslcd hat this one is the mosl likcly for Ihe copper-catalyzed Grignard
additions. Thc ddailcd discussion has becn reviewcd [145,146).
,
'RCg
l
, H
\ ,
R-CU
Ill
H
"
) '! R'
v'-.=(
p.=( ;
---r
= . X)
"
I! R'
'lIIriproducl
RCu
l

, '"
. "

i

-
p .=( i i)
=.--
X
"
C
x
" "
II
uri p,oduct
R M,X
R
"

p.=(
R"
" "
"
.,,, prod uc,
SclKnlt 2
p' m
8 . l,2_Addltlon R.lCtlonalo Csrbonrl Compounda
Stoiehiometrie organocoppcr reasent! prepared from RMgX and a coppcr salt are uscful
for the kelone from aeyl halides (7). The advanlage of Ihis reaelion is Ihal Ihe
fonnalion of lerliary alcohob is usuaJl y nesligiblc. presencc of a sloiehiometric amounl
of Cuo was reporled 10 faci lilale Ihe couplins or a hindered Grisnard reagenl and a
hindered aeyl halide 10 yield a kelone (149]. However, a calalylie venion or Ihis rcaction
was nOI examined, probably for Ihe same rea$On dcscribe<! for reactions wit h aldchydes
(sce lalcr).
Addition of Grignard Tcagcnls 10 aldchydc in lhe presencc of a coppcr sah was
examincd in oonjunction with Ihc slcrcochcmical outoomc. Sloichiomctrie ooppcr reascnlS
preparcd from Grignard rcagcnts and ooppcr sal ls oflcn add 10 ehiral aldehydcs [ISO]
and an iminc [HI] in a reversa! sense whcn comparcd with Grignard reagcnl alonc.
Howevcr. ooppcr-calalyzed addi lion or Grignard rcascnl 10 carbonyl oompounds has nOI
becn examined. Thi, presumably is bec::ause a Grignard rcasent reaets much fasler wi lh
aldehydes Ihan the derived organocoppcr rcagcnt! and, Ihus, ooppcr-calalyzed reaelions
show no eharaelerulic advanlage.
AlthouSh 1,2addition ofGrisnard reasentlO N-alkyl/Vsilylfonnamide alforded lhe
Jamc Iypc of producl, imincs. in Ihe presencc or absence of a eoppcr sall , /V.phcnyl./V.
silylformamidc afforded a doubly alkylated amine in thc reaelion or Gri gnard
Teagenl under coppcr catalysis [ Eq. 152].
,
1 PI! 69.91110 yield

RM,lIr .. IICON(SiMc]) Ph - (n)
R alkyl Cullr
,
1 Ph 63.97110
R ........... N
"
oC. 1,"Addltlon R.aetIon lo .. lursted C.rbonyl Compouno.
Onc of Ihe mosl importanl fealUrcs or organocoppcr rcagenls is Ihei r capabili ly lo underso
1,4-addilion 10 an cr,punsaluraled carbonyl compound, whieh was first rcporled by
Kharasch and Tawney, in 1941 [ 15)). This rcacl ion il now recognizcd as befng quitc
gencral for a varely of subslrates, ineluding acyelie and cyclic, cx,p-oldint and II,p.acclylcnic
kctones and eslCrs. Significanl improvemcnl5 in applicabiJit ies as well as product yiclds
have becn broughl abotlt by many rcsearch chemists in lhese rcw decades. And, accordi ngly,
Ihis reaedon is now onc of Ihc mast important synlhclic Iransformations. as amply
demonSlratcd in several lotal synlhcscs of complcx molccules. Thcsc rcaelions have becn
exhauslively lurveyed by several revicw$ [ 7.8,15,1.54-156). [n addi tion, gcncral aspccls of
1,4addition reaclions with organocoppcr reagenl! havc becn rcvicwed in many arlieles
and books [17- 19,21,148,157- 159], which may al$O be very
Coppcr salts vary from si mplc inorgan;c and organie salts, such as CuO, Cu Br, Cul.
and CuBr o Mc1S, 10 morc $Ophisltated onC$, which will be discussed in Ihe followi ng lext .
As described in Ihc prcvious seelion, a Cu" is masl likely 10 be reduced in lhe
rcaction medium 10 a Cut spccies. which ealaly::es lile 1,4addilion. This Cu"-Cu' i" ue
was revisiled recently and, in accord with Ihe foregoing slatemenl, Cu' was rcconfirmed
10 be an active calalySl, cven IhouSh the added oopper salt was divalen! [160,161].
'"
o
(
y---"",B. A
o ).j,
M.O

n 1.2.1
R . H.Me
O'VY
o
(79)
74 17"- yidd
(50)
2(140 (66" : 1 : 1
(3 : 4 : I "'IMUI Cu)
R .
CH,_CH" Ph
c.a
c.,
... yicld
o
O
c. ,
6
.,0
El MI S.


N' a o N
N
,
co,O

(13'"
O O
8uM,8 ....

s
,
co,O
,cid 95 :
,
1 ield 36 : 60'
,
co,o
... ;1110111 Cu)
O O

B.
60110 ricld
(8 1 )
(82)
(83)
(84)
In general, Ihe reasibi lily of Ihe reaelions depcnds on lile reactivities of subslrales
and could be intcrprttcd in erm! of !Icric aOO electronic racton. InitlaUy. in he hi slory
of organocopper react ions, substrates werc limited 10 reJativdy unhindered, o:,Jl-unsaturated
keloncs and eSICl"J. Sinoe he p'Subsl lulion 10 "Jjunsaturated carbonyl compound relards
The 1,4-addition ofGrignard under copper cat alysis, followed by a trap of
the resultiog (magnesium) enolates with an appropriale eleclrophik, i5 a versalik melhod
fOf double funct ionalization or doubk carbon--carbon bond formalion DI the Ir- and
P-positions of an o!efinie bond Ihal bears a carbonyl group [Eq. (89)). Recently, Ihis 10pi<:
has becn reviewed ( 1 S.5J. ( 170. 173, 174] of Ihis nOlion are presented
in Eqs.. (77). (90) [ 170], and (91) [174].
o
r)\ 1
O 00
RM, X +
CW cal.
o'
z\o
..d
z\
I . ,
, , ,
(89)
O
rc5:1
&
McM,Br +
6
ClIl-8w) P Me)SiCl

(90)
10'11> )'idd
O
OM,Br

(y
C.,
[
J

"
MeS
(91 )
8rCHC01Bu
.. ' .......

. C0811
HMPA
'"
".
)'icld
OO. Ilc. eOlelcct;ye
An scquence on an a.p- unlalurated ester hawing a p- Ieaving
group was used ror Ihe preparati on of a p-alkyl-a,fi-uolaturated ester [ Eq,. (92) and
203) . Howevtr, Ihe integrity of Ihe starting materials was nOI necessarily
relained in the products.. As (ar as Ihe slereoselecli vi ly is eoncerned. a stoichiomelric
copper reagenl seems 10 afl"ord a superi or result [204,205). Alternal ively, a substrato having
a .8'-leaying group undergoes a similar scquence 10 give a
p'-alkyl-a,fi-unsaluraled estor [Eq. 98].
c. ,
C. ,
1 1_9 1. )' icld
100" Ihi. somer
15;15 . ]0;"10
6).1"; yldd
(92)
(93)
p' m
.. UrMN aMI Salo
he stereochemistry of he prooucl was cmphasiud in Ihe rtaclion shown in Eq.
becausc Ihe si milar rcaclion performed with Me,CuLi alforde<! Ihe produc1 he
revcrsed absolute configurallon.
"4<MI 8
EIMln
lijO'
,

o M<
13'111

OHC ...............
l
E,
1)" yicld
9) .. <e
(98)
A (sloichiometric) organocopper rcagen! having a chi ral ligand may promote an
asymmctric l,4.addition reaclion. Ligands derivtd from cll iral alkoxide, amide, amine,
pbosphine. aOO hiolate llave been applied [ 148]. However. in contrasl with lhe
stoichiometri<: use of hese clliral auxiliaries, a catalytic version of chis rtaetion 15 slill
quite imited. A conjugale addition of RMgX lo 2-cydohexcnonc in lhe presencc of a
small amOllnl of a chiral copper-<l iamine oomplcx wn investigaled and alforded a product
with up 10 74% cnantiomerc eJl ctSS (e.e.).. provided a cerlain silyl chloride was added al
tlle same time [Eq. 217]. Alternalively, an oplically active coppcr Ihiolate complcx
cataly;ecd asymmelric alkyl Grignard addi tion 10 OI,/J-Un$8IUralcd ketonCl [218- 222]. The
hight$1 degrcc or chiral induction in coppcr-c8taJyzed 1,4-addil ions or Grignard reagenl s
hu becn achieved with 2-cycloheptenone, in up lO 87% e.e. by t he U$e or a thi olalc-<:oppcr
complc.ll; shown in Eq. (100) [218,219].
o
nllMCI
6


HMPA
( 1011
HMPA
o
6.,.
51 .. yidd
, ... c.
(99)
( 100)
...
Ni .....
SO .. , icld
19 .. ce
Ni ( .. .

NiBI.
,
""
M'X' "".
" ,
NiCt,;
,
Me PPh
1

M,O
60'10 yldd
90'!'0 ce IR)
90 .. yicld
.. ce (S)
( 11 2)
(ID)
A propargyl chloridc was convcrtcd 10 an aliene .... Ih a Orignard rcagenl and a nickcl
catalyM $lI(: h as NiBr
1
af Ni(acach [Eq. 129].
BuMIBr '/-.=
a
NiB, '--- ,.
r'"" ( 114)
As bolh 5 .. 2 and SHI-typc substitut ions, whith worlc wcll ror alley! halides and
rclated compounds, are nOI applicablc 10 ,p" or sp carbon centcrs having a leaving grollp;
introduction or an alkyl grollp 10 -alken)'l, ar)'l, ar t-alleyo)'1 halides, and relatcd
compounds, as forrnulated in Eq. (l IS) ;5 seldom achieved by Grignard reagenl$ alone.
Thus, anothcr complctcly dilfcrcnt mechanisrn has boen required 10 .freel Ihese typcs of
reactions. A breakt hrough in Ihis contexl was brought about by 1""0 ndependen! groups
localed in Japan [Tamao el al., Eq, 244] aOO in Francc: [Corriu and Muse, Eq.
(117); 245] in 1912. They describcd that the addition of a cenain nickel sah, toselner wi l h
a Grignard reagenl, dramatically faci lilated the foregoing 5ubstitution reaClions. Since
Ihen, Ihe imponancc or Ihi s method has becn repealcdly shown in many critical stagC$ in
orSanie yntheses and i5 extensiv<:ly reviewed in many artieJes and books [2,3, 11 , 12, 14.
246-257).
-:::P"'- x' .
""", .


A"X. or
,
ArR
. " ( 115)
- ,.
= ,-
= .-R
'"
(dppe)NiC1l
(0 . 1- ' '' )
EllO, .en.
Ni(acach

PhEt
91"
"M,X + PIl ............

Ar subslof'll.
(O. 2")
EllO. lS"C

507S'KIo yicld
hel relll 'Om a t ic
,.,
(116)
(111)
Thc mechanism or Ihis feae!ion was proposcd by Kumada el al. and also by olher
rescarch groups [2.3,246). A simplified ilIu5Iration. which is generaJl)' accepted and can
rationalizc olhe. side reactions nvolving isorncrization or lhe alkyl roup or Grignard
reagent (path al and reduction of subSlrates (path j5 shown in Schcmc 4.
Rcaclion or LNiX with 2 eq orRMgX affon.b: LNiR. which lhen rcaels with ArY 10
givc L,Ni(Ar)Y Species(ollidalivc addition), with Q.trusion orR-R. SequenliaJ incorporalion
or RMgX (transmttallation) and ArY onlO lhe nickel cmler induces Ihe cataJytic cycle to
yield Ihe cr05s-<:oupled product R- A.r. Ir flhydridc eliminalion occurs in lhe R group of
intermediate LINi{Ar)R, a new spedes, L.Ni(Ar)H complexed by R' CH=CH
I
, is gencrated
($Ce Scheme4, path a). This species may give baek 10 Ihe slaning L1Ni(Ar)R or, altemalively,
may proceed to anolher LINi(Ar}R" having lhe isomerie alkyl group R-, ralhcr Ihan
original R. This path a accounts for isomerizalion 01 Ihc alkyl group 01 Grignard Teagen\,
whieh is one of Ihe major side reactioit.s. Anol hcr course 01 lhe IMX reaelion (see
Scheme 4, palh b) is reductive climinalion 01 Ar and H from L.Ni(Ar)H lo yield ArH ptus
olclin. Thus, Ihis oYeraU process is reduelioD of ArY.
The mosl common nidel calalysl5 are NiX
1
, Ni(acae} , and mueh more rrequenlly,
a group 01 bis(phosphine}nickel(n) hat ide! having 2PPh
J
, dppe, dppp. dppb, and dppf a5
Ihe phosphine moicly, 1m: rcact ivilics of which werc compared wilh each olhcr [Eq.
246). More elaborale complexcs, sueh as Ihose having opticaUy aelive phosphincs followed
tater (discusscd tater). The foregoing divalcnl nieket salts are bclieved lO be reduccd by
Grignard reagenl lo generalc aelive Ni
o
spccics in ,i tu. In fael, Ihe zero- valcnt niekel
M.XY
,,'
A'T
Y
A,
4
N
(

".,./oCMalyud R ,kv

)-MIBr
)"
{dmpe)NICh
'"

1 -' "'1
(122)


-'
".
"'cld
(dppp) NiCll
.
,.icld
(123)
For eumple, the reaction of .PrMgCl wilh PhO aft"orded Ihree producu, jPrPh, /tPrPh,
and Ph H, depending on a choice of he catalysl (sce Scheme which ilI summarized in
Eq. (124) [246,285). Bidenlale low-electron-donaling phosphine ligands such as dppp,
dppe, and, in addition. dppr [271,292] are particularly usdul 10 prepare desired
isopropyJbcnune.
I-PrM,CI

Ph CI
L1NiCIl

I_Pr _Pk

II . Pr-Ph

H- Ph
L, YieldC"") RIlio
dppp
"
96 : . : 0
dppe
,.
96 : .:0
dmpt .. 9 : .. : 1
(124)
dmpf .. .:7.: 1'
2PPh) .. 16 ; JO;S4
2P811)

2 ; 16:n
2PEI)
,
1 : 11:81
In Ihe reaction or /trt-butyl Grignard rcagent and p..bromoslyrcoe, (dppl)NiQl was
Ihe mosl eft"eclive calalysl in allowing the rcaction 10 proceed ckanly aOO give only the
desired producto Other phosphine-nickel calal)'sts afl'orded a varying amounl or the
i.so-bul)'lated product [El;. JO!].
(dppf)NiCIl
8 .. -r
yidd
(125)
The imporlanc;:e in the choice of niekeJ catalysts was . Iso menlioncd when oplically
active 2-melh)'lbutyl Grignard reagc:nt was a1lowed lo rcact wilh PhCJ. When (dppp)Ni0
1
was applied lo he ruction. littlc racemizalion ir any, of the oplically actiVil alk)'1 portion
ook place during he coupling reaclion, wbereas the use of (Ph
l
PhNi0
1
or (dmpe)NiOl
rcsultcd in an apprcciablc decreasc in he oPlical purily or he producl [Eq. 285].
P' m
...



llNiCI


(91" op)
111. [nl
H
10.1- 11 ,6'
( 126)
Ll : dppp 10.)'
dmpc 9.6'
A deo:rease in stcreochemical purily of a product when compara! with a starlng
alkenyl Grignard reagent was also observe<!. Thus, care should be talten, si nce [he ci&/ troM
ralio of lhe alkenyl portion or Grignard Teagcnt! will nOI necessari ly be renected in che
final products under certain reaction condi' lons (246). Equation (1 27) lI ustrales sueh an
cumple.
M\ ,Mler
(1 .1 cquiv)
VE. 96: -4
.. ArX
(1 cquiv)
PbCI l '
PhB r
L. Or-CIOH, 17
Ralio
o : 100
n ; 13
9$ : S
( 127)
Far he substrates, a variety or reaving groups, neluding all halides (1, Br. a, and
even F [246]) [Eqs. (128) and (129); 296: and earlier discusion]), carooxylates in I mall . ring
enol lacl ones (Eq. (130); 302,303). carbonates (Eq. (131 ); 304] alkoxides (292,JOS-312;
Eqs. (1J2); )()8,m and (lJl); 292], sullides [231 ,236,237.289.300,311 .313-329: Eqs. ( 134);
236: (135); 236: and (136); 322], sulfoxidc [E<. (137); 237,272,322], sulfones [237,330,331;
Eq. (138); 331], sclcnides [3 11,239: Eq. (139); 239]. tclJuridcs [251.311], phosphales [332- 334;
Eq. (140); 334]. sulfonales [335; Eq. (1 41); 304], ammonium sah [Eq. (142); 336], and so
on. bearingan Sp l carbon,can bedisplaccd by Ihis mc:thod lo accompli sh Ihc carbon-carbon
bond formal ion. A I-alkcnyl halidc, 5uch as l-bromo-2-{lrimelhyl si lyl)aCClyJenc, could be
subsl iluled wilh PhMgBr lo yield phenyl(lrimethylsityl)acclylenc ( 247).
LNiCI
EIZ .. 92: I 14n .. )icld
l .. dppp. dppc. dmpc: , l Ph P ElZ .. 90:1093: 7
PhM,BI .. 1'Il\-. .... / f
lIE .. 92: a
(d ppp ) NiCI:
'"' " '-'
100 .. Jield
lJE .. 9); 1
RM,X
l
(dppp) NiCJ

4) 9S'IIo ) ,cld

R ..
B.
(128)
(I N )
(130)
'"
",S-.>--
B,
ClM.(CH1hOM.CI BwM,Br
o
{dppt;)NiCl1 (dppclNiCl2
M,


olhul
EIM.Br
(tr lphoJ)NiCI (PF,
I
x.a
I
yicld

ykld
R
-B.
S
R ... .Ikyl
X
...

yicld
( 146)
PhM,Br
"
McM,Br
(dppe) NiC12
Ix."p,sl
(dppp)NiCh
" oC
,icld
(147)
R
c-O-)fI
S
ylcld
(148)
The modc of reduelion by jPrMgCl shown in Scheme 4 and Eq. (124) was employed
in stcreoscltive desulfurization of alkenyl and aryl sulfides. sulfoxides, Of sulrones
[237,314,331: Eq. 314]'
S",
"'o
"'
(149)
"
76 ... yic;ld
The nickcJ-catalyxed coupling rtaclion is Ililativcly unatrected by the Ilerie congcstion
of he rcaction partners. as cxcmplified in Eq. (1 SO) [3SI). In addition, il showl reasonablc
compalibilil,. of fundional groups that are susceplible 10 lhe Grignard addition. An
cumple j5 shown in Eq. (151) (187].

RMC\
o"'
<-> B,
{dppp) NiCI 2
(dppp)NiCIJ

cr
R
N
,
00,"
H(mr, ricld
' o'"
V V
- -
( ISO)
,
74"" yicld
(l SI)
.u
reallen! wn possibly oonsumed lo givc a proou<:1 of hilh c.c. Sorne insight inlo lhe
mechanisms of this reaction has beco reported (353,310). Anolher 50mewhat more
straightforward cumple is asymmelric coupling of an aryl Grignard reagen! wi lh an aryl
halide lO rorm an oplically active biaryl (Eq. 311] [351.371- 374].
B. Carbonyl Addltlon
Addition or Grignard reagenls lo carboxylic acids [E!. (156); 37SJ or phenyllhiochloro-
formale ( Eq. (I Sn 316] cleanly $Iopped al thecarbonyl stage in Ihe presente ofa nickeJ sal t.
(dppc)NiCtz

92 (1S1Io yicld) : ) : 5
( 16 ; ; 16 wiLhouI Ni)
RM,X +

aCOSPh RCO$PI.
R ,, ,s-alkyl ,
"
( 1 S6)
( 157)
Diastcreoselective 1,4-addition of Grignard rugen! lo a rnelhylencmalonic acid
dcrivativc was promoted by NiCI (. (158); 182.183]. Other metaUic salls such 8! zoel.
FeCl
l
and Cul were Icss I,Isdl,l l relalive lO (he diastereosekctivily.
o
0)',1'11
Hiel)
",o'
,.
RuMIRr

<:0,11
N '",
( I SS)
O

'"
92'10 1ield
" ...
C. Hydro- and Carbom80neNtion ot 0""0 and AceIyI.n ..
A certain nickel sall il known 10 catalyze hydro- or carbomagnc:sat ion of unsaturaled
bonds with Grignard reagenll (sec Chapler 3).
IY. PALLAOIUM..cATALYn:D AEACTIONS
Action of alkyl Grignard reaSen{S wilh a varicty of alkyl halides (excepl Me! , which
undergocs melhylalion [377)) in the prescna: of a palladium catalyst usually resul ted in
dean reduction of the halides, ralher than alkylation or elimination [Eq. 37S.379].
p' m
'"
In Ihis palladium-catalyzcd reaction. even a nropenl)'1 iodide, which laeh p-hydrogens.
did not affordcd he alkylatcd product s.
(dppOPdC1
1
R " -alkyl ,
ncopcnlyl
X 0.61.1

R. H
50.100'110 yi eld
( 159)
Palladium-catalyzed substitution al an all)'lic carbon having a Icaviog group wil h
soft carbon nucJcophiles, such as active rnethylene compounds, is wcll documcnted, and
immcasurabJe data have been accumulatcd on jls chemo-, and stcreocncmical aspccls
[241.380-387]. To he contrar)', hese rcacl ioM, in which Grignard reagcnls were used as
he nucJcophiles, are slilJ rare [94.230,388,389] and are usuall)' ignore<!. Howcver, recent l)'.
a ver)' high regio. and stereosclective aJlylic alkylation was reporle<! by he use or palladium
cataly!!. rather Ihan a nidel or copper catal)'s! [Eq. 391)' Thc nvenian or
conliguration obscrvcd here i5 wi th the previou' stud)' using e)'clie subst ratcs
and palladium catalysts [230; cl. Eqs. (109) and (110)].
MeMeBr +

01'0(00),
> 99l1t ce
R:
(dppf) PdC11
60-100 ... )'idd
> 96l1t SH2
9791l1t te
(160)
Ahhough, generall )' 5pcaking, niekcl or ooppcr i5 Ihe ealal)'!1 of choice fOT aU)'lie 5ubstilluion
with Grignard reagent$, as shown in the roregoing discU5Sions. the result of Eq. (16O)
clcarl ), demonst rales thal palladium !till fi nds an advantage in aU)'lle substitutions.
SN2' -t)'pc proparg)'l ie subst ituti on or proparg)'1 chl oridcs with alk),1 or aryl Grignard
reagenls oould be carried out wi th (he catal)'st gcnerated from PdCI- PPhJ"Dibal ( 1:2:1)
[Eq. (161); 392]. nteresli ngl)'. the reaet ion slaning rrom propargyl chloride showed a
higher isomeric puri t)' of (he aliene than that from he isomeric allen)'1 bromidc [ Eq. (162);
392].
(161 )
62l1t yicld 99 : 1
(l4l1t yicld 72; 28 .. iLhoUI Pd)
PdClr PPh30ib.1

60% yicld 90: 10 (162)
Palladium also calalyzes Ihe lubst itulion al sp' carbons having a leaving group with
Grignard reagcnl! [393,394]. Man)' artieles are avai lable 00 this topie [1l.l2. 14.
246.248-25O,2S2- 2S4.380,381,390).
A varel)' of Grignard reagent! primary [33,49,53, 108,258,261.271,272,290,
Eqs. (163) and {164k 393.394] and sccondary [49,261 .271,272,284.399,401]
alk)'1 [Eq. (165); 271], aU)'1 [Eq. (166); 398], henz)'1 [272,290,397; Eq. (167k 290], alkenyl
Manganese [ 444], such as MnCl, was reporlcd 10 facititate ketone [ormation [rom
acyl halide5 and Grignard reagent [Eq. (202); 445]. The actual sal! addcd befe il soluble
Li JMnCI . Another application is Ihal enol tfiHates were subslilutcd wilh Grgnard rcagent !
under Li MnCI . eatalysis [Eq. (203); 446].
RM.X

R " ,s .tkyl,
1 tkcny , Ph
R' " .J, lIk yl.
1. ltkcnyl , Ph
RMIX

'm
AC1oH11
R . " llkyl.llIyl ,
8n, Ph

UJMnCI.
RCllR'
R
AC1ol'!I
2. -92'-' yicld
(202)
(203)
Zine eomplexes. consistng of amine, amino alcohol, alcohol, sulfide, or phosphine
as ligand, catalyzcd 1,4-addition of Grignard reasent s to ox,p-unsaluratcd carhonyl
oompounds [ 447,448]. An opl icaUy ligand on aehievcd asymmetric 1.4-addition,
the besl res ult is presented in Eq, (204) (448].
o
I- PrMISr +
6
o ''O''
0",: (204)
3l'!lo ce
97 : 3
92 .. yicld
Zirconocenc dichloride was use<! as a catalyst fo. allyl ic displacement of aJl)' 1 ethcn
with Grignard reascnts [449]. An asymmetric venion of this ,.aelion by the use of a
catalytic amounl of a ehi ral zireonocenc di(:h!oride was independently reportcd, and il
ilchieved a ncarly complete chirality inducl ion [Eq, (205); 4SO).
H
EIMICI
O



(205)
O
( 10'"
O"
6S .. ycld
,. 97'!1o "
Other applications of zirconium catalysts in hydro- and earbomagnesalion with Grignard
rcagcnts are descri bcd in Chapter 3.
Addili on of Grigna,d teagcnls to ketones to form aleohols is a elaS! or lhe most
fundamental reael ions in organle synlhcsis, Mueh dala on sclcctivi tics of this reacti on are
available. Yamamoto et al. utilizcd a highly bulky organoalumi num oompounds as a
'"
I
ScIMo.M S
sterically shiclding clemen! thal controls and even Ihe stcrwchcmicaJ outcomc or
he addilion or Grignard Teagen! 10 a cyclohcxanone (451-453J. which is excmplificd in
Eq. (206) [454].
o
+ '.BIl....j;. --1
,.,
%AIMc:
Bu-'
,.
/.Bu....l
".
,icld 100
, ..
011
l-8u....t. - -rBU
.
O

wichou. Al)
(206)
Schemc S accounts ror Ihe obscrvation in Eq. (206). Al first, Ihe bul!:)' aluminum
reagenl oocupies a less-hindercd space of Ihe substrale 50 that an inooming nuclcophilc
should approach Ihe kctonc from its superficially more hindered sklt (Le., by axial
Thc change in sclcctivity here has becn considered lo arise rrom a Ilerie control. ralher
Ihan transmctallation of lhe Grignard reagen! 10 an aluminumatc complcx before lhe
addition. Othcr' sclectivc reactions based 00 Ihe same notion have also been dcvdoped
[451-453].
Other metal catalysts in Grignard reac1ions will enable a variety of unprcocdenled
reaclions or more drastic altemalions in selectivitics, which are fulure problems.
GLOSSARY
The rollowing abbreviations are use<! Ihroug.hout Ihis chapter:
El c!hyl
Pr II-propyl, unless o!herwise indexed
Bu II-bu!)'l. unless ot herwise indexed
L lI-alk)'l, unlcu otherwise indexed
Bn
Ph phcnyl
p' m
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'"
30
The Preparatlon 01 1,1-Blmetalllcs 01 Magneslum
and Zinc
PAUL KNOCHIEL
U"iCNSi,y pi MarbJ.,g, Ma,burg. Ct rmalt>"
1. INTRODUCTION
The preparalion, structural and chemical propenies of molecules having several metals
auachcd lo he sarnc carDon atom hay!: fascnate<! chcmists ror long time. Theoretical
predictions speculate Ihat sorne or hese molecules mar havc aplanar tctracoordinated
carboo atom [1 .2). Several polyrnetallatcd compounds such as CLi. [l) havc beco prepare<!
and Iheir propertics were carerutly investigated. Unfortunately. owi ng lo Ihcir high
rcaclivily, ver)' fcw synthctic appliatinos havc beeo found, and sequen!ial reaclons of
Ihe fOUT carboo- metal bond! wilh difl'erent eleclrophiles coukl nol be rcalized [3). 0 0
Ihe other hand, mixed 1, I bimetaJlics. in principie, should be able lo reael in a selectivc
way with two different electrophil es (E' and El) as long as the:: reai;t ivity of the::
fint t'arbon- metal bond (C- M ') is 5ubstant ially different from the reactivity of the second
t'arbon- metll l bond [C_M
1
; Eq. (1)). In 1971, Gaudemar discovered a very general and
prai;tit'a] preparation of m i ~ e d I.l-bimelallic:s of zinc and magncsium by peorming he::
addilion of an aUylie zinc halide lo alkenylmagnesium halidcs [4--6). This reaction allows
the convenienl sludy of the reactivily of ~ e d 1,I-bimetallics, and il was roon found by
Knochel [ 7- 14. 19]. Ihat Ihe sequenlial rcaction of these organomelallic rugenls wilh
various eledrophi lcs can be realized. Furthe::rmore, these compounds provcd lO be cxoellent
olefination reagents, al10wing he stereoselective preparalion of polyfunctional (E)- and
(Z}disubstituted oleHns [ 12- 14; Eq. (2)). This chapter describes the:: prcparat ion and
rcactivity of m i ~ d magnesium aOO zinc 1, I-bimetal1ics. Thc chemistry of some related
rcagenls will also be covered.
\". '
'.,
11 E'
\..E'
'E'
(1)
, ..
is $Otaled as!he $Ole product [E<. (18); 8]. In he presencc ofooppcr satIS, sueh as coppc:r
cyanide (9] or, beuer, ooppcr cyanide.....Ji lhium ehloride oomple. (26). a hiher reactivil)'
of Ihe zinc- lit hium bimetallics js obscrvcd. Thus, lhe reaction or 18 with all,l bromidc in
Ihe presena: of CuCN 2LiO (10 mol '!.) produces Ihe bisallylated produCI 20 in 85'1.
)'icld, whereu Ihe reaction with chlorotrimethylslannane produ0C5 he dislannanc 21 [85%:
9; Eq. (19)]. The SClec1ivc quenching or a lilhium une dimelallic wilh rncthanol produces
an organozi nc that rcactl in Ihe presence of a copper, palladium, or titaniurn
catal,s! with a range of clcctrophiles, as shown in Schemc l. Thc magncsium, zinc bimelal1ic
15 can also be oonverted stlectivtly 10 lhe a zinc:ated ni trile 21 by Ihe reaction wih los)'1
cyanide [Eq. (20); 21). A relatcd rcaction of a zinc I,I-bimelallic compound wilh
benunesulfonyl chlonde fumishes primary alkyl chlorides arter hydrolysis [28].
H ..
...
-
"
...
-
.0,0'
H ..
...
,
"
"

I I MeA
"
2) 0.01 N HCI
53% 11 H
H ..
1I Me.
Hu
..
Ho.
..... ,
, ,,.
H ...
....
..... ,
..... ,
21:85%
"
..""'"
CuCNCII .
,...eH
B. OlellrwtlOfl AeKtlone
"
"
20: 115 '"
H,O'
"
(1 S)
(16)
(17)
(18)
(19)
(20)
,,.
Although the seleclive reaCl ion with electrophi!es [7- 11 ,29] oonsli lules an inlerest ing
reactivity pallern, the most useful synthelic applicalion of 1, I-bimetaJliC$ are olcfination
reaCl ons [ 30-32]. Frst investigalions have shown that magnesium- l.nc I, I-bimetallics
reaCl with a mnge of aldehydes in the presence of sloichiometric amounls of boron
trifluoridc e{hemle, leadng to(E)-disubstituted olefins [Eq. 7]. Ketonesdo not undergo
H ..
..,

- -1, 8, e
.. ,
,
co,e,
..-Jyu

..... .,
n.
-
, ..
"
"""
o


l'
... ,,,,,
H ..

... ,C!<

...
".
, ..
Rtac:tion oondlions: A: UeOH (1 equtv.); B: CuCN (1 .... tv.): e: 2-(bomomethrllaoyllte: o;
tVItolly ....... : E: toIe,sncl CI 1qJIY.); F: lIIyI brumkIt: G: 1-ai0H 11 *",1\1:
(E)' .iI)do.,-buI_, Pd(PPhJI ea: 1: CIT1(OiPrh (211CJ11Y." b&Nlldehyde (1.5
tqUfv.).
Sd"l1>e I
lhe okfination reaet;on. and a stericaUy hindercd aldchyde. such as pi valaldehyde. rea.;!,
nnl )' al a higher lempcraturc ( - leading 10 the corresponding olcfi n in mockral e
yield (7). Tbe reaction or 15 with acid chlorides in he presencc of copper{l) cyanide leads
to enol esters. such 85 23. in good yields. The reaction procccds less sat israclorily in [he
abscncc or copper salts [Eq. (22); 8.9]. The bes! olefination procedure or magnesium- zinc
l.I bimetallics , realized by reacling them with al kylidcncmalonates 14 (Eq. (23):
12.13). This remarkable reaction products selectively {Z}-olefins. By us; ng a dimelhyl
alkylidenemalonate. such as 23, instead of the oorrespondi ng diet hyl alkylidencmalollate,
il is possible to obtain very high Z-select ivities (Eq. (24); 13].
... ,
..-Jy ....
,,-
... ,
..-Jyz,,",
" -
.
78%(E : Z .. 99 : 11
CuCN Hel 0C0Et

23: 74'4(E : Z_ 20:110)
TH'
""V,>
.3(IC. I ti
S3%(E : Z.18 : 82)
... ,
(21)
(22)
(23)
(14)
86 '4(E : Z.O ; I001


25 ' C
SS'llo:E : Z_ 9<1 : 8


THF

O'C, lh
THF
I
... C
""
G:'I
"lo
2) CuCN-2UC1
3) 90JI
PhSO:!0COrEI
35: 80 '110
119.8BN
""""
..
...
0'"'
32: 87 % (> 99.9 %,1
Sdormf J
c . Oxld_IIOf1 0I1,IBlme .. lllc. of M_,,_.lum _nd Zinc
The presence of IWO melal$ allached 10 Ihe same carbon allow! Ihe performance of novel
re:aclion$, IInd the conl rollcd of 1, Ibirnelallics wilh air provides an upeditive
convenion or Ihese organometaUic compounds to aldehydes ( 19,21). Carbon- zinc and
carbon-magnesium bonds are: re:adi ly o.lidized by airo Where:as Ihe dirc:ct oxidalion
of l.Ibimelallics !cads lo mixlure:s, lhe: tre:almenl of lhe magncsium- zinc
l,l-bimelall ic re:agenl wilh ehlorol rimelhylslannane (O"C, 15 min), followcd by Ihe addition
of dry air in Ihe prc:sencc of chlorolri methylsilane, produces the correspondng aldehydc
in ycld5 (Eq. (27); 21]. The reaction procecd5 finl through lhe fonnation of a
trimclhylSlannyl- rinc 1, IbimctaJlic re:agenl or Iype 36, which re:adi ly insc:rts oxygen inlo
the carbon- zinc bond, leading lO lhe si lylatcd hydropero.lide J7, whic;h undergoes a
re:arrangemenl, leadng to Ihe aldchyde 38 (Eq. (28); 21). Inlereslingly, lhe reaction can
be extended lO asi lylalcd organonc re:agcnl! and Ihe addili on of butyllit hi um 10
atrimcl hylsilylslyre:ne furnislles, aficr transmctalation wilh zinc bromide, Ihe benzylic zi nc
compound 39, which i$ smool hly o.lidized by dry air in Ihe presente ofchl orolrimclhylsilane
(- IO' C,5 min) and alfords Ihe kelone 40 in 84
0
/0 yield [Eq. (29); 21]. This O.lidal ion
procedure allowl the Itcreoseleclive preparalion of aldol producls. ThuI, Ihe addition of
J-ct hoxyallylzi nc bromidc 41 (J9,40] 10 I-oclenylmagnesium bromidc (EI Z = r 2:811) Icads
10 a mixture of two diaslereomeric bimetallic species 42 and 43 thal are wilh
."
dry air, Icad;ng 10 the two diaslereomeric aldchydes 44 and 45 (ratio 88: 12) in 56% overaJl
yield. There is a complete Irander of he stereoehemical nrormallon of he alkcnyl
magncsium compound 10 aldchydes 44 and 45 [Eq. (JO); 21). The use of an alkollY
substituto! fo r controlling the stcreochcmislry in the fonnation of I, I-dimctallics has becn
clcgantly dcvclopcd by Morek. showing hat he control of up lo three stcrcoccntcrs in
an acyclic chaio using the [3,J]-sigmatropic shifi is possiblc [Eq. (JI): 41-43]'

.;..""
r"l
ElO -ZnBr

"

1) Mt,SnCI,
O 'C, 15 mIn

2) cty u, Uf:50
. 10C.0.5 h
""

H
09 %
0..:, .... ,SiCI f\ .SnMe, -1oI.,srooSlot.)
- )(.0 .
R
>=0
H
'C O h H 'SiU.)
10 , .1
"
"
tI BuU $iMlt)
O. Mf35iC1
.. Jl""
au-k
ZnBr
21 ZnBr, l't1
tOC, O, lh
40: &4 "" ..
::X;o
H ..
,_,U(8r 1) .... ,sr.cI
,
-
Z) <>,:. 1oIe,S'CI
E : Z_ 12 : 8lI H
(27)
(28)
(29)
56 %; 44 ; _ 12: l1li
zn,.
"...... ..
r!.. Q-Bu
(JO)
(3 1 )
56 %; das!;.,.jo: .. 95 : 5
IV. AELATED REAOENTS
The n(eraelions be:lwecn the IWO carbon-melal bonds (carbon- magnesium and carbon-zinc)
lead 10 new rcaetvty patterns thal are not found eilher in organomagnesium or organozine
reagents. Sueh interaetons between carbon- metal bonds are also possible for some otller
bimctallic magnesium reagents [44,45]. Labaudnierc [46) has shown sorne inlcresting
aspei;ls of Ihe ehemistry of 1.3-bimelallic reagents and has found that lhese compounds
are eleient mult iooupling reagents (47,48]. ThUs. Ihe reaction or lhe lithium- zine I,lallylic
bimetallies 46, prepared by the reaelion of Ihe allenyllit hi um 4' wilh allylzinc bromdc,
reacts selcctively wilh two dilferent ekclrophiles, alfordi ng polyfunetionaJ mokcules of
Iype 48 n exccllent yields {Eq. 46). Intereslingly, the IWO carbon- metaJ bond! can
al() be: separatcd by several carbon atoms without a 1051 orseleclivity. Thus, the copper-zinc
31
Alkynyl Grlgnard Reagenls and Thelr Uses
MASAYUKI UMENO
1l0U0 Chtmlcal /ltdJmry Ca., LId., Atugl. KanagalflJ. Japtl
AKJO SUZUKI
Hoo CMmlcallMusny eC!. . Lid .. Tokyo. JaPCJn
1. INTRODUCTION: FUTUAE OF ACETYLENtc COMPOUNDS
The chemical and physical propcrties of acel)'lcn;c compounds are characterized by Ihei r
slrong aci dic acetylenic hydrogen, ull$alurated ttiplebond. and linear structures. The urong
acidit)' of Ihe hydrogen Ihat is bount 10 Ihe triple bond can be readily transforme<! 10 Ihe
correspondng organorml aJlic compounds. These organometallic species can be use<! for
generaling a new carbon-carbon bond oc converled 10 various functional groups by
subst huon oc additi on rcaclions. Sorne of Ihe typical reaellons of acetyJcnic compounds are
l. Replacement or metal acetylides Li, -Na K, .MgX
2. Addition lO Ihe triple bond
3. Addition lO olher unsaturated postions
4, Polymerizati on
Acctylenic compounds rcadily undergo reduction, addit ion, or cyclization at the
triple bond. The straight -chain structurc, with the triple bond in the center, and a high
degrec of unsaturation, can be upected to provide a versatile tool for the synthesis of
liquid cryslals and organoelectric condUClon. Acetylcne has the simpla t carbon-.carbon
triple bond structurc and, hi storicall y, has becn an important building block for the
chemical indultry. For example, c:ommercial production of vinylchloride, acetaldehyde,
acrylic acid. acrylonitrile, and pen::hloroelhylene was fint accomplished by the Reppe
reaclon. which use<! acetylene as the slarting material. Acetylene was also employed
conveniently for the produclion of acelone, its conven ion to methyl rubbcr, and dimerized
vinyl acelylcne was convened to chloroprcne rubbcr. Al presen!. acetylene chcmistry has
been largely rcplaced by lower-cost olefin chcmistry that U.$CS ethylcnc and propylcne for
masl of these processes. lu use has continucd in limited fields such as Ihe preparalion of
1,4-butanedi ol. vinyl acetate. and acetylenic alcohols [1].
11. GENERAL METHODS OF PREPARATION FOA ACETYLENIC COMPOUNDS
are several review arli eles on Ihe melhods ror acclylenic compounds.
d lher by Ihe eliminadon or halogen compounds.. or by Ihe displaccmenl or melal acelylides
[2].
A. Ell mlnsUon of H, drag.n Hslogenlde snd D.nslagsnsllan 01
Alk, l n. logen CompouncI.
lhe elimination or 1,2- or I, I-dihalogenoalkancs or thal of halogenoalkenes by base is
dfccti ve ror preparing alkyncs. lhis route is especially effcclive owing 10 a variety or
halidcs Ihal are commerdall y avai lable ror use as raw malerial s. Usually. causlic alkali ,
alkali alcoholate. alhli amide, or lIbulyl lilhium are used as Ihe base. Under ccnain
condilion! side react;on, occur, kading 10 ;somcr;zation or rearrangemcnl lO form more
slable internal alkynes or aliene derivativcs.
For the preparalion of aryl or helerOllryl acclylenic oompounds. Ihe reacl;ons proceed
in good yield. wilh litlle isomerization of Ihe producls. When a Iwo-slep pr0CC5s ;s used.
a highly stable vinyl halogenide forms in Ihe lirsl !Iep under mild condilion,. Dehalogenalion
w;lh a slrong base in the seeond slep yiclds Ihe corresponding al kynes [Eqs. ( 1- 8)).
KOH
J RCH-CHBr
R-CO-CH
2
R
1
PCI,
R-CCll-CHlR
1
+ R-CCI-CHR
1

RCsCR
1
(2)
RCI
CHi-CHCI
RCH
1
CHC1
-
RCoCH

(J)
RCHO
PhJP-CHX
RCH-CHX
-
RC-CH

(4)
RCHO
CBr4
PhJP
RCH-CBrl

RCooCH

RCHQ
LiCnCI
RClI-<:CI
Bu,
RCoCH

(6)
RCBr-CHBr
lo
RCoCH (7)
RR1CH-CHX
Base (rearrangemenl)
RCorCR
1
(8)
B. IntrO<tuctlon lo Acetylsnlc Group wllh M ... , Ac;:.t,.' 1de snd
Ac;:.t,.I.nlc Compound.
Acctylenie Grignard reagenu oflhe lyiX RC-CMgX or alkalimetal acclylidcs of RC-CM.
where M denotes ti, Na. or K, are widely uscd for Ihe or acclylenic compounds.
Acelylenic Grignard reagent s are normally prepared in dhercal solvenl! al ambienl
tcmp:raturcs, or al rellux lemp:ratures under almospheric prcssurc. by replaoemcnt wi lh
olher Grignard rcagenl!. However. Iheir reacl jvi lY js somelimes lower Ihan Ihd r
correspondi nl! alkafimdal acelylides. subscquenl ly tlieir appl;cal ion , rcslTCled in sorne
cases. On the other hand, acclyknic Grignard reagenls nave an advanlagc ror reaelion
...
The acidil r of che acelylenic hydrogen vares with Ihe R group [ 10]. alld higher
addity facilitares lite displacemcnl reactioll5. The n:act ion is especiall y fast fo r
alko.ly-acetylenes alld slow for oompounds wilh a side chai o al a position clase lO an
cl hynyl group [ 11]. The rclat ivc pK, {or acclylenes has Ihe rol1owing trelld, wit h Subsl il ulion
(Eq. (14)).
pKa: RC=CH ;> HC=CH >RCH=CI-C=CH ,. RC=C-C=CH- ArC;;: CH (14)
The reaction between hexync and various Grignard reagenls. RMgX, has been
studicd extcnsively, and Ihe rate has !:leen measured by using gas evolution alld
electrochemicaJ melhods al certain lime nlervals (Table Tbc rale of reaclion decrcases
in Ihe arder of R: all yl->i Pr-:> El:> Pr:> Ph:> Me., alld X: a :> Bf :> I [1 2].
Thc rcaction with diclhylmagnesium j5 accelcrated, 10 a greal ex!cnl. and Ihe
correlalion lo Ihe decompositi on polenl ial of Grignard reagenl! has bun poinled OLlI
( 13). Thc rtaction rale tends 10 decrease with lhe higher basici ty 01 employed,
bLltlhe differenc:e is nOllarge [14). The diffcrence in Ihe solLl bilily of acetylenic Grignard
reagcnts rormed by displacemenl rrcquenlly affects he subscquent reaetions (Table The
addit ion or amines (sueh as lriclhylamine) accelcrales thcse reaelions considerabl y
(Table 3) ( 15).
In rael, the solubilily of cerla;n acetylcnic Grignard reagt nts in dicthyl el her is 1010'
and, in some nslances, oily maller separalts from solut ion_ In this case. dielhyl elher may
be replaced by another with higher sol ubility, bUI oily or slurry- like Grignard
reagents [iUle effect on Ihe reaction Pl'()(csses. Telrahydrofu ran shows excellent
solubility properties and i5 used for the preparat ion of acclylenic Grignard
reagenlS.
A si milar di splacement reaction can be condLlcled for acclylcnic carbi nol eompounds
by protccting the active hydrOllyl roup as tctrahydropyranyl elher or with addit ion or
2 Eq or cthylmagnesi um bromide [Eq. (1 17). Ihis rcact ion is oflcn very slow
Dih)'dropynn &MIOr
RR'C(OH)O:CH ' AAt(O-TIlP)CiCH' RI,'qO-THP)C;:C-MgBr
, "" ...
-"="'-- . RR'C(OMgBr)OC-MgBr (1 SI
T.bW I Relative Reactivity of I-Huyne ",ilh R-MX (Reft ul- Ether, I-Huyne' RMX:Lj l )
p-CI PhMg8r

Et Mgl 11
MeMg!

EtMgBr
'00
MeMgBr

EtMgO
'"
MeMCI 16 - PrMgBr
'10
PhMgBr
"
(Et , Mg) JOO
PrMaBr
"
A.llylMaBr O,
p- MePhMgBr 60
Ti bie 2 Re1a tive RCIClivily or .,.,ilh EIMBr in Cerlain Elhers (I- Hclynej EIMBr, \0: 1)
- Pr ,O Bu, O El , O THF 2- Me-THF
EIM8Br
'"
"O
110
10'
37
p' m
EtMaBr (1 mol/L)
(0.5 molfL)
EtMal (l .0 mol/LI
EtMgCI (1.0 molt)
MeMaBr (l.O 1I\QVL)
MtM1 (1.0 1I\Q1fL)
EI,M (O.S mol/ lI
Et MaBr (1 .0 moVL)
EtMl1 (1.0 molt)
o
'00
..
('li)
'60
7
7
JOO
f- BuNMe,
6116
'''''
(4%)
1010
Addition Et.N (mol)
0.25
.50
210
16O
'000
O.l
""
,.,
750
'"''
Amines (0,25 mol/ RMaX)
Pr,N
'<3
,
lO'
".
126
1.0
...
52"
,<O
'50
1llO
JOO
and, lO acceJerate jI, cuprous chJoride is added [1 8]. HighJy act ive i-propylmagnesium
bromide is occasionaJly use<! imlead or ethyJmagnesjum bromide [19].
Al lhou8h nOI accepled as general methods. the roll owin8 direct or indirect methods
or using halogeno acctylenes as starting materials have been proposed [20; Eqs. (16-22)].
Ms ' TlIF (01" TetrIIlydlap) .... Od'Y' .....
R-Ci. e-X R-C=C-M;X (16)
R : AIk)oi. At\, vinyI X (. ti'I)) : 1 '" Br '" a
Ph-C=C-CI MeMfX, HO . Ph-C"CH
x : a 2'.6%, Sr \3.4%, I 1(.2%
Ph-C=- C-Br MeMaBr I Elr? Ph-C=C.MgBr Hf' . Ph-CiCH (19%)
McM&Br I CcO-EtO
Ph-C=C-Me (62%)
2 R MaS'
F-C=CH R-C=C-M&Br + R-" + MFBr
2 EI-MaBr
Br-CSCH ' BrMg-C=C-MgBr + El." + El-Sr
2 R-MtBr
I-C=C-I' BrMg..c:C-MgBr + lR'
EI-MBr I ti,., .... 1s-9J<C 2dIyI
[Na-C=CH : Et-MgBrJ
Bu-MBr I BuO t4O'C
Na-C=C-MgBr
(17)
( 18)
(l 9)
12<1)
(2 1 )
(22)
P"NO"
.50 UntMO .nd Suzultl
B. Eltlynylm.gne.lum H.IIde" BI,(h.logenom.gn .. lum}-Ketyl.ne
Of all acctyknie Grignard reagents. cthynylmagnesium bromide HC-CMgBr is the mosl
important reagen\. El hynylmagnesium bromide is preparcd by lhe: n:ael ion or acclylene
wi lh Cl hylmagnesium bromide in diet hyl elher (21J. or in diethyl elhcr- benzene, under
atm of acelyk ne wi lh vigorous $Iirring [22]. formalion of monosubstilulW
elhynylmagnesium bromide under these eondil ions has been rejeclw by many sludies
pcrformed since Ihen. In fael. Ihis reaelion yielded an insoluble oi ly produel in dielhyl
elher Ihal was laler found 10 be acclylene dimagnesium bromide 8rMgC-CMgBr. These
Grignard n:agenls wen: soluble in cerlai n solvents, such as ehloroform [23] and melhylal
[24], bul Ihey Wiln: nOI considered 10 be practica!. However, acclylene dmagnesium
bromide has been userul 10 prepare .several disubsliluled acclylene derivalives.
Today. lelrahydrorllran is lI.sed almosl as a salvenl ror preparation or
el hynylmagnesum bromide, bccause lhe Gr ignard reagent is highly soluble in Ihis solven\.
In pTllelicc. el hynylmagnesll m bromidc can be obtained by adding a tetrahydrofllran
sollltion or et hyl magnesium bromidc. dropwise. inlo a JO"C rcaelion vesscl thal bll bbles
in acclylene inlo lel rahydroruran al Ihe tale or eonsumption [25). For lhe synlhesis or
acclylene dimagnesill m bromide, Ihe lemperalllre muSI be raised to 4O-S(rC [26]. The
tet rahydrofuran solution or et hynylmagnesium ehloridc can be prepared by the reaelion
of ace:tykne wilh melhylmagnesi um ehloride or bulyl magnesi um chl oridc and is used
sllCCCssIully for the: reaclion involvi ng lrimelhylchlorosi lane [27). When methylmagnesi um
ehloride is employed as a n:ag<:nt, gaseous acclylcne can be inl rodllccd din:ctJ y inlo Ihe
letrahydrofll ran solll tion or the Grignard reagenl, by properly controll ng lhe temperature
(28]. Since: acclylene has aClive hydrogens on bolh sites, dis ll bstiluled acctykne
dimagnesium halidestend 10 increase by disproporl ionalion in lhe course of Ihe synlhetic
protess or in the: slI bsequent react ions involving the ehynyl Grignard n:agcnls
[Eqs. (23- 26)).
HC=CH HC:C.MaBr + EIH HC:C MgB.
""'"
BrMg-C: C-MgBr + EI .1j
(23)
1 IICC. M:B.-SrMg-C=C.MgBr + HC:CH BrMg-CC-MgBr-- McBr, +
RX
HC:C-MgBr RC:CH + M&XB<
BrMg-C;;:CMgB.
l R"
(24)
RC=: CH HC=: C-Mr,lr RC=C.MgBr + HCECH
RC:C-MaBr
"'.
(25)
(26)
IV. REACTIONS OF ACETYLENtc GRIGNARD REAGENTS
In general. ace:tylenic Grignard n:agents RC-CMgBr are low in reactivi ly compared wil h
olher Grignard n:agents. However, they are eapable of part icipali ng in Ihe us ual Grignard
reaelion5 and are widely used for producing lIscful organie chemical Sll bslancc:s (Table 4).
Some or Ihe lower reaetivi ly or acctylenic Grignard reagenlS are the
1.2-addit ion n:actions involv ng bem:oniuile (29], and nucleophilic subsl ilulion reaclions
wi th halogen compounds Ihat are lmiled lO Ihose highJy reaclive compoundl, such as
Alkynyl Grlg".rd RNflMIa 1$'
4 React;on of Acclylenic Grinard Rugenls
'0.
o. , ...1......"
.. _-,
PI I
.
-
k .
IIC5 001f;1lt P'I!CH.CHCHO rtoOIoCOCU(OH)(AOI
,-,
'"'
,
' BuC! CMaIlr
' &.CECCH,oH
"'""
111)
,
Ot,"'CHC!!OIfIlt CH,=CHCllcqoHlM<. <>,

"",,qQMJBt)C ..ct.I&1I<
Iok,qOO)CoCCH(OH)CoCqOll)l<ol.,
,
a.c;CM&Or
&.
e.c;0CII,at,ott (81")
1"1

cx... ....
O,
o:...Q
<''''
,.,
,
11C=CM&1It
0"''''''.
HCII cct(N1ok)C,1tOH .... ,




rtoClOIfOr
1')")



11C!0If1l<
P'IoOI,o:llOH

161)
nctt,o OCH,n
OH OCH,n
"
a.cI!CIoI&& <>(00,
"'''

"

""OO.
(EIO),CttC!E COt(OEt),
,.,
"
1IoC10lf&

IIttCIIC.QIO ..... ,
""
"
1) ( .... :."+), ",o



"
WcC5CMallt
"""",00'
w.c1CCM0Ei},
(11")
'N'
"
BttC1M,;& ro, IIttC!C.QXlH
<''''
,n,
"
(a..ciCJ,Mt &.CII C-COOH
(1),,)
"
BuClo.t&CI

BttCiC.a::11:
",.,
'"'
'"
rtoC=CIoI&& rtoC.!C<"OIoIHn .... ,
"
rtoC=CM,;&
1) OOt.-C"O-1oICO
l) NoCIH IoItOH
rtoCE:c.cotIH,
'"'

rtoC=CM,;8r
.""""'0
rtoC"OCII,lI,cl
,-,
'"'
"
BuC!!CM,;8r M<SO,-oCH,c=CIIo a..c;C-OI,CiCllo
"'''
,.,
,
1'ItCCNf;1It
""""
I'ItC!!C.Qln, ,.,,, ,.,
"
1'IIC10If1lt 0.J)
,
. ---Q
",.,
,.,
P' m
triphenylmethylchloride [JO). Althol,lgh aUylie halide!! or propargylie halides reaet with
eommon Grignard reagents without addition of calalysl, lhey do nOI reael wilh
ace!ylenie Grignard reagenls unless a calaly!I, such as cuprou$ chloride, is presenl [JI].
In a similar way, acetylenic Grinard reagcnlJ do nol react wilh metal halides, such as
eadmium chl oride, 10 form cadmium aeetylide. Neverlheless. lhey are I,lscful reagenl! for
rcaction5 wilh highly reaClive compounds, such tu acid chlorides.
A. 1,2.Addhlon R .cUon. wllt! C.rbonyl Compound.
Acctylcnic Grignard reagen!, react readi ly with aldehydc$ or ketones 10 form acetylenic
alcohols (sce Tabie 4, entrie!! 1-4) [J2--45]. This alcohol synthesis is one of the most
important proceS5Cs in the aoctylenic Grignard reaaions and is use<! for lhe production
of various pharmaeeutical and agrochemical compounds. The aoclylenic alcohols formed
are further con verted to olher fu nctional groups and are uscd for the tOlal synthesis of
natural organic subslanees. Almos! aU carbonyl compounds, including alky, aryl,cycloalkyl,
and heterocyclic compounds. can be employed withou! elceplion for this reaction. This
Grignard proocss is particularly effcctivc for carbonyl eompounds that are unstable with
base, for example, !IItelraloncs or !II-hal ogcnocarbonyl c:ompounds [J2.JJ). The reac:tion
of carbonyl compounds with acctylenc dimagncsil,lm bromide yiclds the corre:'lponding
symmc\ric acctylenie glyool5 in one step and is uscd ror preparation of polyyncs
[Eqs. (27- 29); 34,4O,42,4J].
HC=a-I
(27)
-
-
OH
tlO'CI NMP

(28)
OH

(29)
Ac:etylenic Grignard reagents are elfcclive for reaction with conjugated compound$
sl,lch as piononc, whieh is an important SEa nin8 material for Ihe preparati on 01 carotcnoids
tha! readi ly undergoes enotation I,lnder basic condilions. Somc cumples of 5ynthetic
proces.ses are given (Eql. (JO-J3); 46-49).
(30)
(J I)
(J2)
-"- ".' .MO"-. . -IIA ,
(JJ)
Th<'; Grignard etllynylalion or a carbonyl group is rrequently uscd as a simple met llod
or preparalion ror sleroids, as an allernalive 10 proccsses involvi ng sodillm acelylide in
liquid ammonia or acelylene in pola$Sium r-bulolide [Eq. SO].
o
Mcl lAJe1
(34)

Synlhesis of asymmclrk aoelylcnic compounds can be made by adding a runctional
group lo a monO'Sllbsliluled acclylenic oompound and Ihen converting lO lhe disubsliluled
aoetylenic compound by Gngnard ruelions (Eq. {)jI: S t ,S2]. Ol her al!:aH melal aoelyl ides
or lhe Iype RC-CM. wherc M denoles Li, Na, or K, also rcael with carbonyl compounds
10 give acclylcnic a[cohols. bUI Ihe reaclions are somclimes acoompanied by , ide rcael ions
involving enolalion call$Cd by Ihe rcleasc or 1tIc: t hydrogcn on !hc carbonyl group.
Conscqueo!ly ..... eak basic lithillm acelylides are rrequenl ly lIscd.
e,H Ik "e' ,"e"""'",,,--
IIC=CN. " . CSHlIC=CH - CSH ILC=CCH2OH
(35)
IkMcC =CC6lillCl I ClICI
- CSHIIC!!CCH2Br CSHII C!CCHlC=CC6H1ZC1
B. Nucleophlllc Addlllon lo Epoly Compoundl
As cxpccted, the nng-opening addition or cpo.y oompollnds wilh acclylenic Grignard
rcagen15 gives acelylenic aloohols. Elhylene o.ide, havng Ihe simples! epo.y struelUre,
reaelS rcadily wilh acclylenie Grignard reagents 10 form (j'-hydro.yethyl aoetylcnic alcohols.
io which lhe number of earbon aloms is inerea$Cd by IWO ( S3, S4J. Tllis reaetion has also
becn successfully applied 10 an epo.icyclollexane, or an epoxideon sCeroid nngs (sce Table 4,
enlrles S and 6) (Eqs. (J6) aOO SS,S7.S8].
formate (CICOOEt) give carboxylic esters RC-CCOOEt [71,72]. for thesc reactions,
beUer results were obtaincd wilh lilhium acclylides RC-CLi (n]. G<XKi prodllct yit:lds
were also obtaincd with reaClions or dalkynyl magnesium eompallnds in dionne (sn:
Table 4, entrles 15 ami 16) (74].
Acclylenic kelones can be prepara! in moderatc yield by Ihe reaction of acetylcnic
Grignard reagenlJ with acid chlorides or anhydridc:s (Eq. (41 ); 75-78). Alkynyl magnesium
ch!oride reacts with acclic anhydrKlc to give acclylenic kelones in g<XKi yicld (sn: Tablc
4, ent ry
o

EtC=CMgBr

TlIF .2(l"C
o
Et
(8S%)
(41 )
The of etolyacctylene, whic:h results fmm the reac\ion betwecn acclylenic:
Grignard reagents and carbony! eompounds, readi ly gives acetylcnic kelones and has many
applicatioru; [76]. Generally speaking, for Ihe preparalon or kelones from acid chlorides,
zinc compounds may give better resulls. Trimcthylsilyl acetylcnc compounds of the Iype
RC-CSiMc
l
, which are synthesizcd by the Grignard mclhod. undergo a Fricdcl-Crans
reac\ion with acid chlorides to rorm acclylenic kelones in g<XKi yield, and chis process i5
wKlcly lIscd as II simplilied mute 10 acctylenic kel Orles (E<. (42); 79].
BuC=CMgDr Me)Sit;J BuC=CSiMe3 MeCOCl- AICI11CS DuC=C-CQ.Me (15%) (42)
Isocyanates (RNCO) and isolhocyanates (RNCS) also react wilh acctylenie Grignard
reagents 10 give Ihe correspondn!! subst ituted acid amidcs (RC-CCONHR' ) and
Ihioamidcs (RC-CCSNH R') [80,81 J. The readQn of chloroacely! isocyanalC (ClCH .CONCO)
and Ihe Grignard reagents, folJowcd by hydrolys;!, yields aeid amide compounds directly
(sn: Table 4, enlries 18 and 19) [82].
E. Nlleleoptlllle Suo.tltuHon R.Ktion.
The reactivity of acetyknic Grignard reagenls is lowcr than that of alhli melal acelylides
for synl hesi! of acelylenic hydrocarbons by nuc\cophilic slI bstitut ion reactions. However,
good results were oblained when al kyl I""lolllenesulfonalcs, alkylmcthanc sulfonales, or
alkylsulronales were uscd [83-87). In general, eoupling reaelions do no! occur belwecn
aoetylenie Grignard reagcnu and alkyl halide$, but if highly reactive halides. $lIeh as
triphenylmclhyl chloride, beru:hydryl ehl oride, or 2rurfuryl cllloride, are used, the
corresponding ooupJing produets are obtai ncd [88,89]. For coupling of Icss
halides, alkalimetal aoelylidcs thal are prepared by melallalion wilh lIbutyllithium in
lelrahydrofuran are used in place or Ihe Grignard reagcnts (5eC Table 4, cnt rles 20-23).
The reactions of acelylenic Grignard reagenls wilh lIhaloelhers that ha\'e a
reactive halogen, su<:h as ehl oromcl hyl ethen [90-92], or 2-chlorotelrahydropyran (93],
fC5ull in Ihe expcctcd ooupling prodllcls (scc Table 4, cntrles Chlororormamidincs
(94J, chlorotriazine (95). or chloroolimc:s [96] reacl with lhe aoctylcnic Grignard reagent s
readily. The reaelion bctwecn dibromo or eycJooclalelraene by phenyl.
acetylenicmagnesium bromide rorm the corresponding eonjugatcd long-chain coupling
products (Eqs. (43) and (44); sn: Table 4, entries 27, 28; 94,97].
'"
".
Faf example. Ihe realmenl of 1,4-dichloro-2-bulyne with sodium hydroxidc TcsultS in
diacely1cne fHC-C-C-CH) in good yield (Stt Table 4, enlT)' 39).
Thc: /"Cuellon! involving he gencration oracctylcnic oonds 01 cxtension ofunsalur.ued
bonds are exlremely uscful in chemkal synt hcsis of unsalurated alcohols. carboxylic acid!,
IInd poly.yne acetal , [Eq. (47); 11SJ. Far Ihe preparali on of e!sential fatty acids. cxtension
of proparg)' 1 unil5, followed by hydrogcnaion in Ihe pn:sencc of Lindlar calal)', !, will
rcsult in he efficient formalian of all ds-type raUy acid! [Eqs. (48) and (49); 126, 127].
'"
a

"'"

1) P8!. 2)lIrMrC=cc(HIIC02MsBr I00CN
J)H,I I ' " ..
-
........... Br 1c.cN. nlf
DrMaC" =CCJU6COlMPlr
G. Orgenome"l1Ie Aeetylene Compound. wlttl Met., Helld
(47)
(48)
(49)
Several organometall ic acclylenc compounds are prepared by Ihe replacemenl of acclylenic
Grignard reagenlS or alkalimetal acclylides wilh metal halide$ (MX) where M is D, Al,
Si, Ge, Sn, P, As" Sb, Cu, or Ag [1 28- 131]. They are al50 synlhesized by melall alion of
metal halides and RJAl or RIHg (see Table 4, enlries 40 and Metal acctylides or lhe
Iype (RC-ChD or (RC-ChAI are unstable and are i$Olaled as wilh amines or
el hers. Note Ihat many of the pm:ious metal acclylides are ulremely and Ihe
appropriale precautions should be taken for Iheir handling and slorage.
Cuprou5 acclylide oompounds., that are oonvenienlly prepared from Ihe oorTe.'iponding
Grignard reagenl. are l ypicalJy tmpl oyed for variou5 synlhetic processes [Eq. 132].
Allernalively. acclylenic silicone compounds are use<! for electronic applicali ons, as well
as for synl hesis [Eq. (SI); 133). Trialkylsilyl acclylenie compounds (RC-CSiR
l
), which
are use<! frcquently for introducng an acctylenc group. art: prcpared by the rcaetion
bc:lween Irialkylsil yl halides and acclylenic Grignard reagenl! [Eqs. (S2) and 53);
134.136- 138) or alkalimelal aeetylides (ste Table 4. entry 42) [13S]. Thcy are also prcpared
by a one-slep ooupling reaction in Ihe presencc or calalylic amount of sil ver chloride and
base [139].
p' m
o-<:}
Me3SiC;iCSiMc3
COCI
AK:l, ICUCI,
R'\. ...R'\._ NaOH,
v-urCOCH2CH(OMc)2 o-<:}CII(OH)CH2CU(OMe)2
Ha aq/diodn, Q-O-CH'CHOUCHO
McJSiC:CSiMelICpCO(O?li...lSi
Me)Si
(71%)

H. R" ellon, ot . nd b Prolected Gr1lln. rd R genll
(S7)
(58)
Propargyl bromidc (UC-CCH, Br) has reactive si tcs--a primary bromidc group. a
triple bond, Il nd an acet y1cnic hydrogcn- making it an cJ.lremely versal;'!: chcmical
intermediat . Thc brominc alom ;5 highly reactive loward he formation of a Grignard
and is typK:ally uscd in pncromonc synlhesis [ Eq. 148- 151]. Propargyl alcohol
(HC-CCH,OH) is also rcacive; howevcr. ils hydroxyl group muSI be prol eclcd by . ilher
react ing lile alcohol with 2.S-dihydro-2H-pyran or adding cxctSS Grignard reag.o! lo make
he . her or Mg sall (Eq. (60): Table 5, cnlries 1 and 2: 152.153). Propargyl alcohol! or
lhe type Rc-<:CH,OH reacl wi l h Grignard reagents in he presence of a cuprous
halide calal ysl 10 formo by addition. allylic alcohols RR' C CCH10H (see Table 5.
enl ries 3 and 4) (154]. On he olher hand. a Reformalsky rc:aclion of propargyl bromide
wilh carbonyl compounds in lile presence of zinc givcs acelylenic alcohols. For examplc.
secondary acclylenic alcollols Ihal are obtai ned by Ihe reaetion of proparlyl bromide with
uldehydcs and zinc can be convcrted lo acetylcnic Grignard reagenlS which. afler fllrther
T. ble 5 Grignanl ReaClion of Proparyli<: Compounds
,
,

....
rtoCICCICCH,owc.1


(Aa) [I'll
1_) IlloOl
'"
is 10 indicale where Ihe Grignard rtmains a viable lechnoJogy for Ihe
of si lanes.
TIK: generulizcd Sl ructure of un organosilane is R.SiX'4 _' I' X is an
clectron-wi thdrawi ng group, Iypicall y halu.k In Ihc simplest and earliesl cumples of IIK:
chcmistry. silicon Iclraehloride Wll$ substitulOO by addt on of Grignard reagenlS.
such as eth)'lmagnesium bromde and phenylmagnesium ch lorde [U). In addition.
Grignard rcagent s substitule allc.o_ides (OR), ,0-5i). and nitr les (eN),
'o-- .
liCio -,-:...
liCio
t-a
o-t-o ., .. o,
o-?-o
o
(1)
The: general inablily 10 acoomplish clcan. integral, parlal subslilution lelldi ng to
organohalosilants is tlK: primar)'. but nOI Ihe only, resl rict ion or Ihe Grignard process.
The difficult separat ion of Ihc corrosive. hydrolytically sensit ive halosil anes from Ihe
the rcla1ively low product concentration. and Ihc technology
involved in removal of by-produC1s.. and Ihe rccyclc of solvenls post' significant des;gn
barricrs in process scak-up and resull in economic barriers for producl acceplance (4).
Ir Ihe largel compound is tetraalkylsil anc or equivalent, proccss conl rol is not as cri tical,
and waler workup is all owcd. Water workup is oflen fadlitatOO by the addili on of dilute
hydrochloric ucid. particularly when products art derived (rom alkoxysilancs.
Ahcrnativc lechnologies that are used to gencrate organosi lanes on a commercial
scaJe are the: RochowMii llcr direcl proccS$, which works besl with low molecular wcighl
alkyl and aryl haJides [S]:
c.
CHICI SI
300-450
MeSICl
1

MelSICI
1

"'Isrcr
(2)
The: hydrosilylation reaClion, which is limiltd by the avai labiJily of hydridosilanes and
olcfins [6):
RCH .. CH
1
HSICI
I
(J)
The Barry proccss. which is gcnerally limilro by thermal stabli ty ort he aryl precursors [7,8) :
o . HSlCI,
'0,
,
(4)
Although Ihe produclion of organosilanes by non-Grignard processes is al leaSI 1000
limcs greater Ihan wilh Grignard processes, Ihcy remai n enential for many of the speciahy
3. Substltutlon Versus Electfon-Withdfawlng GfOUp
Si-CN > Si-CI > Si-OR > Si-O-Si
For lhe sub51ilulion reaction. Ihe al koly group of lile silanc: ls praelicalJy limi led
10 lincar radicals, nolably met holy and etho. y. Al lhough substiull ion of chlorides
for most transformations. lhe: conversion of ehlorides 10 otller electron-wi thdrawi ng groups
provides Ihe abilily lO aller Ihc degrtt of $ubstilulion in reaellons [ 12, 13]. In sorne reaC1ions.
Ihe relatjvely slow reaC1ion of an alkoxy group rclalive 10 a chlorine is exploiled. For
uample. lhe largel compound divinyltetramelhyldisiloxane, an important endcappc:r ;n
silieone ehemislry. caMOt be prepared in practical yield by thc addition of I Eq of met hyl
Grignard 10 vinylmethyldichlorosilanc. fo llowed by hydrolysis. Altcrnatively. mono-
alkolylat ion of vi nyl mclhyldiehloTosi lane nereases Ihe sclect;vilY for subslitut ion by only
[ mol of Grignard. (This process is uti lized only when availabi1il y of dimethylchlorosi lane
fOT the allemale route of hydrosi lyation of acetykne does nOI meet demand.)
'i'"
tItCoCH-S1-a
,
e
'i'"

,
CH,
(6)
Control of sub$titution by partial alkoxylation i5 mueh las elfective when an
. Ikoxyehlorosilane with a si ngle organie substituent wit hout steric bulk is involved. For
mcthyldiisopropoxychl orosilane lill le selecl ivi ly bet ween lubsllution of ehloride versus
isopropoxide was observed (14). Although cyanosilanes are rarely uscd directly in Grignard
reactions, thc addil ion of 5 mol ol. of I cyanide salt often eatalyzes Grigmm:l subst itulion
reaetion! [1 5-11). Thiocyanl lc. Inother pstudohalogen. elerlS I similar elfecl [18].
yH,

,
CH,
yH,
a-51-a
,
CH,
CH CH
_
-,c"C ___ "
CH,a- C -Sl-CI
, ,
CH, eH,
4. The Inl,oduellon 01 SI- H Facilita/es Subslilullon 01 Hal /des
yH,
'i'"
no tMCtlon or
CH, - C- Mela

a - Si-a

all..,I".tlon
, ,
CH,
eH,
CH,
C' .

,
,


a - Si-a - CH,a- C - SI-a
eH,
, , ,
,
c, ,
5. Reael/on wlth Hydrldes
)7)
(8)
Despi le Iheir relat ive basici ty. Grignard reagents do nOI gencraJly Teael with hydridcs.
However, in telrahydrofuran at elevated tempcral ure and in the case or polyhydridosilanC1i
in dicthyl el her, Ihe hydride can also be displaced [19].
'91
when partal substil ulon of Ihe silane is required. An nample of a producl produced by
Ihe reverse addition is diphcnylmclhylmclhoxysi lane. In sil U rormalion of Ihe Grignard
in Ihc presencc or si lane is prererred when Ihe Grignard has poor solution slabilily or
poor solubi lity. An cumple of a produel produccd by Ihe in Si lu proccss is
aUyllrimcthylsilane. Some hydridosilanes and vinylic silanes are rcael \'e in lhe presencc
of magncsium melal and diClhyl clhcr. elimi naling Ihc in silu mct hod as an oplion. After
a brief ind uelion period, lrichlorosi lane reael! violcnlly wilh magncsium in clher and
lel rahydrofuran. Phenyl hydridochlorosi lancs [23) and (24)
undergo rcaetions similar 10 Wurll. eoupl ing wilh magnesium in lelrahydroruran. For
cxamplc. divinyllelramclhyldisi lane rorms rrom vi nyldimclhylchlorosi lane.
\""

&.,
( 14)
Commereially, eonlinuous or eontinuous balch versions of l/tese l/tree prolocols are
gene rally employed [25].
D. Proe ... Cn.ml.try Wlthout Eth ....
Chlorob<: nl.cnc and bromob<:nzcne can aet both as reagenl! and sol ven!! in !he fo rmation
of muhiply SUbSliluted phcnylehlorosilanes such as triphcnylehlorosilane [26,27). The
reael ons run al clcvated Icmperalurcs, 130-28O"C, undcr al mospheric pressure.
Telrnethoxysilane and telramet hoxysilane can aet as bot h and reaelant!
[28.29). or as eosolvenu-catalysts in eombinalion wilh benzene [JO). The use of
letraethoxysi lane as a solvenl - reaetant has been importanl for a variety of oonlnuous
Grignard proccsscs, since it allows IIn cmeient reeycle loop [J I). The conlinuous reactor
portion of one such proccss disclosed in detail by Russian workers for diel hyldiet hoxysi lane
is depicled in Figure 1 (32) and may be contrasled wi th an earlier baleh process [33].
Si milarly. melhylalkoxysilane and 0 1 her alkylal k: oxysilanes are reported as solvenlS- reactllnlS
in Grignard rce1ions. eliminal ing Ihe nced [or el here1 solvenlS (34].
111. SILANE-BlOCKING AGENTS
Silanc-blocking agcnls are employed 10 derival iu and proleel various subslralcs during
synthclic .sequencc:s. In a typical appl ical ion. a silane-blocking group replaces an act ive
hydrogen in a parcnl eompound. a series or ehemical transrormal ;ons arc performcd on
Ihe modilicd parcnl eompound. and fi nally. the blocking agenl is remo,cd.
11 ' 11'
11
0
-+-_ . H - peNnl_.,. ___ .,. H.pa"l\t(lftOclllI"'
.' ..
( 15)
Thc optimum blocki ng agcnl is one Ihat derinlizcs the parenl rcadi ly, wi thslands
lhe lransformlng reactlons, is readily dcblocked. and has reasonablc economcs. Grignard
subslitulion is one or lhe reaet ions rrequently performed on si lane-blocked intermediates.
The most common blocki ng group. Ihe Iri melhylsi loxy group. is not resistant 10 att aek
from Grignard reagcnls. For example, blocked phenoxybromides reaet wilh Ihemselves,
forming none of Ihe desired Grignard reagenl.
'"

Filure 1 Cont;m.lOus Iynlllesi, reactor ror ethylalltoxy$ilanes: 1, input for readion mixture:
2. input ror m&,ncsium; 3, OUlput lor proc!uo;t; 4, reactor body; S, slinn shan: 6. Ipiral: 7, tltermocouplc
wdl. (From Ref. 32)
( 16)
Tlle choice of proper blocking agenl lar Grignard chemistry depends on economics,
reaction conditioRs, and acoeptable oondilionl lor deblocking lhe final producto As
illustrated in Table 1, al1 bul lhe leasl stcrically hindered sitanc-blocking agenll have
reasonable resislance 10 attack by Grignardsand alkyl1ithiums [3S). However, lhe reactions
are reported for mild condit ions. Fa! example, lhe f 1/1 lor Ihe reaction of Irimethylsiloxy-
n-butanol with mcthylmagnesium bromide al room temperature j, 48 hr. In contralt, lhe
reltlion ol trimcthylsiloxy.n.butanol with metbylmagnesium chloride in renuling
tetrahydrofuran is virtuall y complete within 30 min.
IV. CONCLUStON
Althollgh it is no longer crucial lo the silicone indllStry, Grignard chemistry rcmains a
vital and versalilc mclhod for Ihe production of organosilanes. The lechnology of
organosilanes dcrivcd from Grignards hu been refincd 10 control degr of 5ubstitlltion,
about the book ...
Tbil ullfuI b. ndbook providel lbc: tbeoretical and practkaI in(onnation necew.ry to
cxplo.e oew applicationl for Grinard reacnts on I daY-I<KiIy basis-prcsenting a com-
pnb in overvicw of current rcseuch IClivitics in Grignard chcmiJUy.
Surveyin spdne rcactions and Ippl)catious of Grignard cbcmiJUy. thc H.d&ooI: o/
GtqIlUUtl "'-p. " mctbods of Grignard rcagcrn prcpantioo from organic
balidcs a.nd ok:flDl ... Cumi ..... both thc formation and rcaction mccbni.ms of Grignard
reacDlJ ... 1WIlDWizes thc spccttum. of rcaclions exhibitcd by Grignard reacnts in onc coo-
" .... el soun::t ... dcfmes general structutc- reacli"ity rclalionships . .. considcn thc modiflCl-
lion of Grignud rcagern tcaetivity usiDg Clwysts . .. di.sctwc. lIWHHiD insuumcntal metbods
of &DI.Iy.i., inchxl.iDg infratcd. spoctrCiscopy, magnctic rcsonaocc, and x-ray crysll.l.lograpby
.. .rocuses en industrial-scalc safe harxlliDg proccdUtcl .. . deuils lOpics o( ., I :111 intcrest
suc.h u !be Bubicr rcaction, uymmclric Iynlbcsis u.in Grignard reaCnlS, and Zicg1er-
Nana Clwy.i .. . and mote.
Furnishin ovcr 2630 ciwions to Ry sources in tbc Ii!eraturc, thc HMdtHk o/ G,;,1f4I"fI
1mII.1Ib is a useful rcfercoce for chcmical engincers; organic, inorganic , medicinal ,
pbarmaccuticll. , l.IlI.Iytital , indwtrial, . ynthetic, organomctallic , aOO applicd cbcmist.s; in-
dustrial enginects; and gr"lduatc studcou in !bese disciplines.
about the editora: ...
GARY S: Sll.VERMAH is Principal SeicntiSl al Elf Atocbcm North Amcrica, 1 .... , King of
Pnwia, Pennsylvania. Thc major (OCut of bis WQri: for Ihc pul 10 years has becn thc
modiflCltion of Grignard reaenI reaclivity. Dr. Silverman is thc aulbor or coaulhor of
numerous profcsskmal publicalVms in rus flcld of eJL:pertise . Hc receivcd thc B:Se. dcgrce
(1979) in cbcmisuy fmm Ihc University of Aorida, Gaincsville, and thc Pb.O. dcgrce
(1984) in orpnic: cbcmisuy (mm thc University of South Carolina, Columbia:
PHIl.IP E. RAIUTA is Business Manager al El! Atocbcm Agri , S.A:, Plaisir, Francc. le
autbor or coauthor of over 35 rcsearch pipen in thc f!Clds oC organomcllllic cbcmistty,
addilives for pl.asticl, and industrial cbcmisuy, Dr. Raicita is I mcmbcr of thc American
Cbcmical Society and thc AslOCiatioo oC Rcsean:h Direclnrs. Hc rcceived thc B.Se: dcgrce
(1966) ill cbcmiJUy froro tbc Case l!lStiru!e oC T"'ch!lOlOJ)' , Clcveland, Ohia, and thc Pb:D.
dcgrce (1970) in orglllOmctal.lic chcm.istry from tbc MU5Ichusens In.uirutc of Tcchnology,
Cambridgc.
Prinu d in of Amerjca
M.4.RCI.L DEKICEIl, lNe.
Nll! .... YOIlK &su