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01 1352193505 80382 PDF
01 1352193505 80382 PDF
01 1352193505 80382 PDF
All
necleophiles
are Lewis
bases.
Structure of
The kinetic evidence: Rate = k [RX][Nu] the SN2 transition state
Walden inversion:
(+)-chlorosuccinic acid
1 was converted to (+)
malic acid 2 by action
of Ag2O in water with
retention of
configuration, in the
next step the OH was
replaced by Cl to 3 by
reaction with PCl5. 4
Philips (1923)
2 2 2
2 3
o o o
2 2
There is a high probability that
(a), (c), and (d) proceeded
o
with retention, leaving (b) as
the inversion.
5
ESCHENMOSER ET AL.
6
Unimolecular Nucleophilic Substitution (SN1)
CH3 CH3
H3C Br + 2 H2O H3C OH + Br + H3O+ Reaction kinetics:
CH3 CH3
rate = k [RX]
H3C CH3
Ionization of the
H3C Br H3C C + Br
substrate is the rate-
H3C CH3
determinating step.
CH3 H3C H
H
SN1 H3C C + O H3C O t BuCl
t- B Cl t-Bu
B + + Cl-
CH3 H H3C H 630 kJ/mol (in gas phase)
H 84 kJ/mol (in water)
H3C H H3C
H3C O + O H3C OH + H3O+
H3C H H H3C
8
Ion Pairs in the SN1 Mechanism
i. SN2 process: a
complete inversion
ii. Intimate ion pair R+X:
SR SR x SR + (1-x)RS
(1 x)RS
total inversion if (a)
SH SN 2 SH (b) SH does not take place or
to a combination of
RX R+X R+ X SR + RS
SH inversion and
(a)
R+ + X racemization if there is
competition between (a)
RX X R+ X R+
andd (b).
SH SN 2 SH SH iii. Solvent-separated
R+X: more
RS RS x RS + (1-x)SR
(1 )SR racemization (perhaps
total)
A complete picture of the possibilities for
iv. Free R+: complete
p
solvolysis
l l i in i a solvent
l t SH (ignoring
(i i th
the racemization
possibilities of elimination or rearrangement).
v. The difference: SN1
RS and SR represent enantiomers; x = some and SN2 mechanisms is 9in
fraction. the timing of the steps.
The Neighboring-Group Mechanism
1 2 3
B
Br
H O HO O
C OH-
H
Me C O C C C C
Me H 10
O -
O O-
Me
EVIDENCE:
( ) Configurational
(i) g retention. Note that both p products are optically
p y
inactive and so cannot be told apart by differences in rotation. The
meso and dl dibromides have different boiling points and indexes of
refraction and were identified by these properties.
H CH3 CH3 H H CH3 CH3 H
HBr
B OH
Br + B OH
Br B Br
Br + Br Br
H CH3 CH3 H H CH3 CH3 H
dl
dl
Br
Br
Br H CH3 CH3 H
H CH3 H H
H+ H CH3 -H2O C C Br Br
H CH3 + Br Br
H CH3 CH3
CH3 H
OH Br- CH3 CH3 H
OH2
(2S,3S) (2R,3S) (2R,3R) (2S,3S)
(2S,3S) 11
CH3 H H CH3 H CH3
HBr
Br OH + Br OH Br Br
H CH3 CH3 CH3
H H
dl meso
Br
Br CH3
H CH3 -H2O CH3 H H Br
C C
CH3 H
H CH3 H Br
-
Br
OH2 CH3
12
(iii) Acetolysis of both 4-methoxy-pentyl
4 methoxy pentyl brosylate 1 and 5-methoxy-
5 methoxy
2-pentyl brosylate 2: the same mixture of products. In this case the
intermediate 3 is common to both substrates.
CH3
CH3 CH3
H H O H
O H H O H
OBs
CH3 H CH3 H BsO CH3 H
1 3 2
CH3 CH3
H H H
O O
OAc
AcO C 3
CH C 3 H
CH
60% 40%
H OTs H OTs
H OTs H OAc
AcO-
AcOH
k 1011 1
-TsO- H
H ONB H ONB ONB
AcO-
+ H3C H3C
CH3
k
13.2 148
1
O
NB C NO
O2 14
C. NUCLEOPHILIC SUBSTITUTION AT AN ALIPHATIC TRIGONAL CARBON.
THE TETRAHEDRAL MECHANISM
Acyl substitution is basically a two-step nucleophilic addition and
elimination
li i ti reaction.
ti B th reaction
Both ti steps
t are reversible
ibl reactions.
ti
When reactions
e tion Preliminary R C X + H+ R C X R C X
are carried out OH OH OH
in acid solution, Y
there Step 1 R C X + Y R C X
may also be a OH OH
preliminary and Y Y Y
a final step. Step
p2 R C X R C R C + X
OH OR OH
Y
Final R C R C Y + H+ 15
OH O
D. Reactivity
The Effect of Substrate Structure
mechanism branching at either the or the carbon
For the SN2 mechanism,
decreases the rate.
Table 1. Average relative SN2 Primaryy and secondaryy
substrates generally react by
rates for some alkyl substrates the SN2 mechanism and
R Relative R Relative tertiary by the SN1 mechanism.
rate
t rate
t
Methyl 30 Isobutyl 0.03
Ethyl
y 1 y 10-5
Neopentyl
p
Propyl 0.4 Ally 10
Butyl 0.4 Benzyl 120
Isopropy 0.025
l
Elimination is always a possible side reaction of nucleophilic
16
substitutions
b off tertiary substrates
b ( h
(wherever a hydrogen
h d is present).
)
Substrates
S b t t off the
th type
t RCOX are usually h more reactive
ll much ti than
th
the corresponding RCH2X. The mechanism here is always the
tetrahedral one. Explanation:
i. The carbonyl carbon has a sizable partial positive charge.
ii. In an SN1 reaction a bond must break in the rate-determining
step, which requires more energy than the shift of a pair of
electrons, which is what happens in a tetrahedral mechanism.
iii. A trigonal carbon offers less steric hindrance to a nucleophile than
a tetrahedral carbon.
Unsturation at the -carbon.
Table 2. Relative rates for the SN1 reaction between ROTs and
ethanol at 25C
CH3CH2- 0.26 PhCH2- 100
(CH3)2CH- 0.69 Ph2CH- ~ 105
17
CH2=CHCH2- 8.6 Ph3C- ~ 1010
NOTE
In general, SN1 rates at allylic substrate are increased by any
substituent in the 1 or 3 position that can stabilized the carbocation
b resonance or hyperconjugation.
by h j ti A
Among th
these are alkyl,
lk l aryl,
l and
d
halo groups.
SN2 rates for allylic and benzylic systems are also increased (See
Tab.1), probably owing to resonance possibilities in the transition
state.
-Substitution
Substitution resonance effect, field effect
ZCH2X SN1 relative rate
Z = RO,, RS or R2N- Veryy rapid
p
Z = RCO, HCO, ROCO, NH2CO, NC, F3C Decreased compared to CH3X
18
Table 3.
3 List of groups in approximately descending order of
reactivity toward SN1 and SN2 reactions. (Z = RCO, HCO, ROCO,
NC, or a similar group)
S 1 reactivity
SN1 i i S 2 reactivity
SN2 i i
Ar3CX RCHDX Ar3CX R3CX
A 2CHX
Ar RCHDCH2X A 2CHX
Ar ZCH2CH2X
ROCH2X, RSCH2X, C=CX ArCH2X R3CCH2X
R2NCH2X
21
The Effect of the Leaving Group
R OSO2 CH3
ROTs
ROT
p-Toluenesulfonates, Tosylates
R OSO2 Br ROBs
p Bromobenzenesulfonates Brosylates
p-Bromobenzenesulfonates,
R OH
organic + 4 +
phase
2
1
aqueous + +
3 + +
phase
+ + +
4 4
25
Ambident
A bid t Nucleophiles
N l hil / S
Substrates.
b t t R i
Regioselectivity
l ti it
C C C
O O
H Y O
Y H
R C CH2O R C CH2Y 26
Y R O
E. Reactions
RX + R
R'2NH RR 2N
RR'
RX + R'3N RR'3N+X
RX + OH ROH RX + R'CONH RNHCOR'
RX + OR' ROR'
C C + RNH2 C C
C C C C O OH NHR
Cl OH O
R OSO2OR
OSO2OR'' + OR
OR' ROR'
ROR
2 ROH ROR
RCOX + H2O RCO2H
RCOOCOR' + H2O RCO2H + R'CO2H
C C + ROH C C RCO2R' + H2O RCO2H + R'OH
OH OR RCONR' + H2O RCO2H + R'2NH (R = H,
H alkyl,
lk l aryl)
l)
O RCOX + R'OH RCO2R'
R3O+ + R'OH ROR' RCOOCOR + R'OH RCO2R'
RX + R'COO R'COOR RCOOH + R''OH RCO2R'' + R'OH
RX + OOH ROOH RCOX + RR'COO
COO RCOOCOR'
RCOOCOR
RCOX + H2O2 RCO3H
27
II Aromatic
II. A ti Electrophilic
El t hili Substitution
S b tit ti
28
A. The Arenium Ion Mechanism
In the arenium ion mechanism the attacking species may be
produced in various ways, but what happens to the aromatic ring
is basically the same in all cases. For this reason most
attention in the study of this mechanism centers around the
identity of the attacking entity and how it is produced.
produced
X Y Y Y Y
+
Y
X X X X
slow
complexes
Y Y arenium ions
X fast
- X+
X X X Y
+ Y Z Y Z Y + Z
29
The attacking species
is not an ion but a dipole.
Evidence:
i. No isotope effects
If the hydrogen ion departs before the arrival of the
electrophile or if the arrival and departure are simultaneous,
there should be a substantial isotope effect (i.e., deuterated
substrates should undergo substitution more slowly than
nondeuterated compounds) because,
because in each case,
case the CH
C H bond is
broken in the rate-determining step.
However, in the arenium ion mechanism, the CH bond is not
broken in the rate
rate-determining
determining step, so no isotope effect should
be found.
ii. Isolation of arenium ion intermediates
Me
Me Me
EtF-BF3 H Et
Et BF
80C 4
Me Me
Me Me Me Me
mesitylene o
(Mp -15 C)
30
B. Orientation and Reactivity
Monosubstituted
b d Benzene Rings
Z Z Z
H H H
Ortho Y Y Y
(A)
Z Z Z
Meta H H H
Y Y Y
Z Z Z
Para
H Y H Y H Y
(B)
Any group Z that has an electron donating field effect should stabilize
all three ions.
Electron-withdrawing groups will increase the positive charge on the
ring, and destabilize the arenium ion.
31
Field effects should taper off with distance and are strongest at the
carbon connected to the group Z. +I groups should stabilize all three ions
but mostly the ortho and para
Some substituents have a pair of electrons (usually unshared) that
may be contributed toward the ring. Not only to direct ortho and
para, but
b t also
l tot activate
ti t these
th positions
iti for
f electrophilic
l t tt 32
hili attack
k
Three Types of Groups:
i. Groups that contain an unshared pair of electrons on the atom
connected to the ring.
O, NR2, NHR,
NHR NH2, OH, OH OR,
OR NHCOR,
NHCOR OCOR,
OCOR SR,
SR the four
halogens, and SH (except for the case of thiophenols
electrophiles usually attack the sulfur rather than the ring).
Cl,Cl Br,
Br and I deactivate the ring,ring but they direct ortho
ortho-
para.
ii. Groups that lack an unshared pair on the atom connected to the
ring and that are I.
Approximate deactivating ability: NR3+> NO2 > CF3 > CN > SO3H >
CHO > COR > COOH > COOR > CONH2 > CCl3 > NH3+.
anomaly, since this group directs para
The NH3+ group is an anomaly
about as much as or a little more than it directs meta.
iii. Groups that lack an unshared pair on H
the atom connected to the ring and that H C H
are ortho-para-directing. H H
R, Ar, COO groups, which active the ring. Y Y
33
(E) (F)
Orientation in Benzene Rings with More than One Substituent
Generalization
ii. If a strong activating group competes with a weaker one or with a
deactivating group, the former controls.
Directing order: NH2, OH, NR2, O > OR, OCOR, NHCOR >, R, Ar >
halogen > meta-directing groups.
Sulfonation
Halogenation
H
O
SO3 -
+ -
- H+
X X FeX3
+ S O + SO3- X2 FeX
F X3
O
H X
H SO3H + - FeX4- H+
- H+ + X X FeX3
SO3H X
SO3H
Fridel-Crafts Reactions
+ -
R ClAlCl3 R Cl AlCl3 R+AlCl4-
AlCl3 - AlCl 4
CH3CH2CH2Cl PhCHMe2PhCH2CH2CH3 CH3CH2CH2Cl AlCl3 CH3CH2CH2 CH3CHCH3
70% 30%
CH3CH2CH2C O
H2SO4 H+ AlCl3
+ CH3CH2CH2COCl
HO
35
Zn-Hg
CH3CH2CH2CH2
HCl
III Aliphatic Electrophilic Substitution
III.
MECHANISMS
Aliphatic electrophilic substitution can be distinguish
unimolecular (SE1) and bimolecular (SE2). The bimolecular
mechanisms are analogous to the SN2 mechanism in that the new
bond forms as the old one breaks.
Step 1 H
R2HC C R' R2C C R' Step 1:
slow OH-
O OH R2HC C R' R2C C R'
Step 2 R2C C R' + Br Br R2C C R' + Br O O
OH Step 2:
Br OH
C R' R2C C R' + H R2C C R' + Br Br R2C C R' + Br
Step 3 R2C
Br OH Br O O Br O
36
IV Aromatic
IV. A ti Nucleophilic
N l hili Substitution
S b tit ti
L L Nu OCH3H7-n
n NHPh
+ Nu
NO2 NO2
-
Nu L- 180
+ PhNH2
38
The Benzyne Mechanism
H Ar H Ar H Ar H Ar
A +
Ar
1
H Ar H Ar H Ar
C
Coupling
li
2
1 2
H Ar Ar H Ar
Disproportionation
2 +
H H
1 3
H Ar Ar
R'
+ R'H
41
1
REACTIVITY IN ALIPHATIC SUBSTRATES
In a chain reaction, the step that determines what the
product will be is most often an abstraction step. What is
abstracted by a radical is nearly always univalent,
univalent it is
hydrogen or halogen for organic compounds.
Generalizations:
ii. All substituents
b increase reactivity at ortho
h andd para
positions over that of benzene. There is no great difference
between electron-donating
g and electron-withdrawing
g g
groups.
p
ii. Reactivity at meta positions is usually similar to that
of benzene, perhaps slightly higher or lower. This fact,
coupled with the preceding one, means that all substituents
are activating and ortho-para-directing; none are
deactivating or (chiefly) meta-directing.
meta directing
iii. Reactivity at ortho position is usually somewhat
greater than at para positions,
positions except where a large group
decreases ortho reactivity for steric reasons.
44
REACTIONS
Allylic Halogenation
Olefins can be halogenated in the allylic position by a number
of reagents, of which N-bromosuccinimide (NBS) is by far the
most common.
O
peroxides
CH C C + N Br C C C
CCl4
Br
O
NBS (Wohl-Ziegler bromination)
Coupling of Alkynes
pair or
W A
W
Y
C B A
A C A B
B
B
Y A
A
Y
C B
Anti addition B
A C
Anti addition W A B W
threo dl pair
B
W A A
the threo dl W B
C B
pair or
A C A Y
Y B 47
B
II.. Electrophilic
p Addition
There is much evidence that when the attack is by Br+ (or a
carrier of it), the bromonium ion is often an intermediate
and the addition is anti.
anti
49
When the electrophile is a proton:
ii. The
Th reaction
i i
is general-acid,
l id i l i
implying rate-determining
d i i proton
transfer from the acid to the double bond.
ii. The existence of alkyl substituent effects.
iii Open
iii. O carbocations
b ti are prone to
t rearrange.
H H
H A H
+ +
+ HA C C + A C C + A C C + C C
C C
A
50
Orientation Markovnikovs rule: For electrophilic attack, the positive
pportion of the reagent
g goes to the side of the double or triple
g p bond that has more
hydrogens.
O
CH3-CH=CH
CH CH2 CH3-CH-CH
CH CH3 H2O
+ H OSOH CH3-CH-CH3
OSO3H OH
O
CH3-CH-CH3
CH3-CH=CH2 BrH
+
Br H3PO4
CH3-CH=CH2 H CH3-CH-CH3
+ OH
OH
CH 3 -CH=CH 2 + H O C C H3 C H 3 -C H-CH 3
O
OC CH 3
O
Br
CH3CH2CH2 C CH2 HBr 51
CH3CH2CH2 C CH HBr CH3CH2CH2 C CH3
Br Br
Rearrangement
CH3 CH - CH3
HCl 3+ Cl
H3C C CH CH2 - HC C CH CH H3C C CH CH2
Cl 3 3
H H H Cl
1,2-H
CH3 - CH3
Cl
H3C C CH CH2
+
H3C C CH CH2
H Cl H
HgSO
g 4
CH3(CH2)5C CH + HOH H SO CH3(CH2)5C CH2 CH3(CH2)5C CH3
2 4
OH O
52
Markovnikovs rule also applies for halogen substituents or
the case where bromonium ions or other three-membered
three membered rings are
intermediates.
Y Y Y
Cl C C H + Y+ Cl C C H Cl C C H or Cl C C H
H H H H H H H H
More stable
Y Y W
W
H2C CHR H2C CHR
53
III NUCLEOPHILIC ADDITION
III.
A. Addition to Carbon-Hetero Multiple bonds
55
Mannich reaction
H R R
NH + C O + CH C N CH2 C C
H O O
56
Schiff base
57
Wittig reaction
Aldol reaction
58
Grignard reaction
59
B. Addition to Carbon
Carbon-Carbon
Carbon Double Bonds
O H
Nu O
Nucleophilic
Nu
conjugate addition: O O H+
Nu Nu O
H
Nu
60
Michael reaction (1,4-addition)
61
IV FREE-RADICAL ADDITION
IV.
63
6 3
6-3 Eli i ti
Elimination Reactions
R ti
I. E2 and E1 Mechanism
X
C C C C + X- + BH
H
B E2 Mechanism
- B-
B
R4 H
R4 R3 R1 R4
H R3 R4 R3 L-
C C
BH R2
R1 R2 R1 R2 R3
R1
L L 65
R2
For a six-membered ring, anti-periplanarity of the leaving groups
requires that they be diaxial even if this is the conformation of higher
energy.
Relative Product
rate
cis-HOOCCH=CClCOOH
i HOOCCH CClCOOH 1
HOOC-CC-COOH
trans-HOOCCH=CClCOOH 50
66
syn-Elimination
Br
The deuterated - HBr
DH H 94%
norbornyl bromide
H H
cis-isomer: HCl elimination is much
slower than from corresponding
nonbridged compounds.
trans-isomer: Syn elimination can
H Cl Cl H take place (dihedral angle about 0);
H Cl H Cl
reached about eight times faster than
cis-isomer trans-isomer cis-isomer.
Example 1:
pyrolysis
68
sulfonate ester of menthol
II E1CB MECHANISM (CARBANION MECHANISM)
II.
B- H
O2N CH CHR O2N C CHR O2NCH=CHR L-
H
L
L
Example 3.
3
70
III Orientation of the Double Bond
III.
i. No matter what the mechanism, a double bond does not go to a
bridgehead carbon unless the ring sizes are large enough (Bredts
rule).
l )
ii. Zaitsevs rule: the double bond goes mainly toward the most
highly substituted carbon.
71
iii. Elimination
iii Eli i ti from
f compoundsd with
ith charged
h d nucleofuges,
l f e.g., NR3+,
SR2+ (those that come off as neutral mlecules), follow Hofmanns rule
if the substrate is acyclic: the double bond goes mainly toward the
least highly substituted carbon, but Zaitsevs rule if the leaving group
is attached to a six-membered ring.
1RX 2 RX 3 RX
CH3COO-(CH3)2CHBr CH3COOCH(CH3)2Br-
E2S
N2
C2H5O-(CH3)2CHBr CH3CH2O CH(CH3)2CH2=CHCH3
Temperature
C2H5OH
(CH3)C BrC2H5ONa M 3C OEtCH2=CMe
Me CM 2
25 9SN1 91E1+E2
55 0% 100%(E1+E2)
74
6 4 Rearrangement Reaction
6-4
In a rearrangement reaction a group moves from one atom to
another in the same molecule.
molecule Most are migrations from an atom to
an adjacent one (called 1,2 shift), but some are over longer
distances.
76
Beckmann rearrangement
This is an acid-catalyzed rearrangement of an oxime to an amide.
Cyclic oximes yield lactams.
The mechanism is generally believed to consist of an alkyl migration
with expulsion of the hydroxyl group to form a nitrilium ion followed
by hydrolysis:
OH O
O N
H
H2SO4 N
NH2OH
77
Claisen rearrangement
The Claisen rearrangement is a powerful carbon-carbon bond-
forming g chemical reaction. The heating g of an allyl
y vinyl
y ether will
initiate a [3,3] rearrangement to give a , -unsaturated carbonyl.
78
Pinacol Rearrangement
79
Hofmann rearrangement
80
6-55 Organic Redox Reaction
6
In organic chemistry oxidations and reductions are different from
ordinary redox reactions because many reactions carry the name but
d nott actually
do t ll involve
i l electron
l t t
transfer
f ini the
th electrochemical
l t h i l sense
of the word.
Categories or simple functional groups arranged according to
oxidation state
81
I Organic
I. O i reductions
d ti
Several reaction mechanisms exist for organic reductions:
Direct electron transfer in Birch reduction
Hydride transfer in reductions, LiAlH4
Hydrogen reduction with a catalyst such as Lindlar catalyst
Disproportionation reaction such as the Cannizzaro reaction
H H
Birch reduction: Na
NH3 (l), ROH
H H
H
R O H H H H R O H H
C
H H
C C C
H H
e H e H H
82
83
II. ORGANIC OXIDATIONS
Several reaction mechanisms exist for organic oxidations:
Single electron transfer;
Oxidations through ester intermediates with chromic acid;
Hydrogen
y g atom transfer as in Free radical halogenation;
g ;
Oxidation with oxygen (combustion);
Oxidation involving ozone (O3) in ozonolysis;
Oxidations
O id ti involving
i l i an elimination
li i ti reactionti mechanism
h i such
h as
the Swern oxidation;
oxidation by nitroso radicals, fremys salt or TEMPO.
Na2Cr2O7, H2SO4
94%
OH H2O, Et2O
O
84
Ozonolysis
85
Oxidation by TEMPO
86