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H1
H1
electrocyclizations
cycloadditions
sigmatropic rearrangements
ene reactions
Pericyclic reactions are prevalent in synthetic organic chemistry as well as in biosynthetic processes. This can be seen in the case of the endiandric acids, biosynthetically synthesized by Nicolaou: Ph
COOCH3
H Ph H
COOCH3
endiandric acid B
Nicolaou, K. C. J. Am. Chem. Soc. 1982, 104, 5555; J. Am. Chem. Soc. 1982, 104, 5557; J. Am. Chem. Soc. 1982, 104, 5558; J. Am. Chem. Soc. 1982, 104, 5560.
The principle of conservation of orbital symmetry applies ONLY to concerted pericyclic reactions. In these cases it serves as a powerful predictive tool.
Electrocyclic Reactions
Woodward, R. B.; Hoffmann, R. J. Am. Chem. Soc. 1965, 87(2), 395-397.
"We define as electrocyclic transformations the formation of a single bond between the termini of a linear system containing k electrons and the converse process."
"In such changes, fixed geometrical isomerism imposed upon the open-chain system is related to rigid tetrahedral isomerism in the cyclic array. A priori, this relationship might be disrotatory or conrotatory." A C A B C B D D B D C C
CONROTATORY
DISROTATORY
B D
Electrocyclic Reactions of 1,3-Butadiene: Butadiene Molecular Orbitals Under Thermal Conditions Thermal Cyclization of Butadiene
A C
A B C D
LUMO
D A C A
CONROTATORY
B C
HOMO
B D
"Thus, in an ope an open chai open chain system chain syste the symmetry of of the highest the highest occupie highes is such th that a bondi a bonding inte bonding interaction be involve overlap between orbial envelopes on opposite faces of the sy system , andthis can only only be achie be achieved conrotatory process."
A C B D C
LUMO
B D
HOMO
A C
DISROTATORY
B D
B D C
"On the oth promotion of an electr an electron to excited state leads t leads to a reversal to a reversal of the t relationships in the orbitals the orbitals mainly orbitals redistribution, with t the conseq consequence that a sys undergoes a thermally thermally induced dis induced d transformation in the ground sta the ground state shou conrotatory course when photochemically excited, and vice versa."
Analogous analyses of larger -systems will allow determination of the stereochemical course of electrocyclic ring closings and openings under thermal and photochemical conditions.
DISROTATORY
C A
Thermal HOMO
"Conversely, in open systems containing 4n + 2 -electrons, terminal bonding interaction within ground-state molecules requires overlap of orbital envelopes on the same face of the system, attainable only by disrotatory displacements." A B C D B
CONROTATORY
D A
Photochemical HOMO
Based on these these observat observations for electrocyc for electrocyclic reactions of electrocyclic react electrocyclic reactions can be summarized in terms of the number of electron pairs involved in the cyclization or ring opening:
Disrotatory Conrotatory
h
Conrotatory Disrotatory
Odd-electron systems follow same stereochemical course as the even system containing one further electron. Charged systems should behave in the same manner as neutral systems containing the same number of electrons.
"It should be emphasized that our hypothesis species in any case which of two types of geometrical displacements will represent a favored process, but does not exclude the operation of the other under very energetic conditions."
X
H
H H
H H
H H
H H
X
H H
When these traditionally "disallowed" processes are observed they are usually occurring by non-concerted pathways, such as diradical pathways.
X
H A
CH3 CH3
CH3
Examination of the two pos the two possible t two possible transitio possible transition states for negative steric interaction in transition state A that is not seen in transition state B. Thus, only product B is observed. The preference of transition state A over transition state B is called torquoselectivity.
transition sta
For the ele electrocyclic ring op ring opening of the [4.2.0 opening of the [4.2.0] fused bicyc of the [4.2.0] fused the cyclooctatriene with two trans olens (B) will be highly disfavored compared to the cyclooctatriene containing only cis olens (A). H H H
H H H H
H A
X
H Ph
H B
Electrocyclic Reactions in Nature and Synthetic Chemistry: The Endiandric Acids CO2R H H H Ph H H H CO2R
endiandric acid B
[4+2] Thermal Cycloaddition (Diels-Alder)
Ph H
H H CO2R
endiandric acid F
Ph
Nicolaou, K. C. J. Am. Chem. Soc. 1982, 104, 5555; J. Am. Chem. Soc. 1982, 104, 5557; J. Am. Chem. Soc. 1982, 104, 5558; J. Am. Chem. Soc. 1982, 104, 5560.
Cycloaddition Reactions
Hoffmann, R.; Woodward, R. B. J. Am. Chem. Soc. 1965, 87(9), 2046-2048.
Whereas electrocyclic reactions involve the net intramolecular interconversion of one -bond and one -bond, cycloaddition reactions consist of the net intermolecular conversion of k -bonds to k -bonds to form a cyclic product.
m-2
n-2
The [4 + 2] Cycloaddition:
Diene
Dienophile
3
LUMO
2 2
HOMO
1 1
disrotatory cycloaddition
In the thermal [4 + 2] cycloaddition reaction, mixing occurs between the highest occupied molecular orbital (HOMO) on the diene component and the lowest unoccupied molecular orbital (LUMO) on the dienophile component. The formation of two new -bonds (at the expense of two -bonds) requires disrotatory movement of the frontier molecular orbitals.
The [2 + 2] Cycloaddition
Thermally, the [2 + 2] cycloaddition is geometrically forbidden, as the HOMO and LUMO of the participating olefins would not be able to achieve the orbital overlap required for -bond formation.
LUMO
HOMO
On the other hand, the photochemical [2 + 2] cycloaddition is allowed and leads to stereospecific cyclobutane formation.
HOMO
LUMO
Suprafaciality- when, in a pericyclic reaction, the bondforming interaction occurs on the same face of a -system, as in thermal [4 + 2]. Antarafaciality- when, in a pericyclic reaction, the bondforming interactions occur on opposite faces of a -system. ethylene [2 + 2]
H
H H H H H H H
ketene [2 + 2]
O H H H H H H
H H H H
O
symmetry allowed, geometrically allowed
Why does the thermal [2 + 2] fail with two alkenes but succeed with ketene?
Removal of steric bulk (H-atoms) around the -system (as in the ketene) allows antarafacial bond formation that is geometrically forbidden in the ethylene [2 + 2].
Based on these observations for cycloaddition reactions of -systems, the Woodward-Hoffmann rules for cycloaddition reactions can be summarized in terms of the number of electron pairs involved in the cyclizations:
Photochemical
suprafacial-suprafacial suprafacial-antarafacial
Thermal
suprafacial-antarafacial suprafacial-suprafacial
In the suprafacial-suprafacial cases, the cycloadditions are symmetry allowed and geometrically allowed. In the suprafacial-antarafacial cases, the cycloadditions are symmetry allowed and generally geometrically disallowed.
Type of Cycloaddition
Thermal
4+2
Photochemical
2+2 4+4 6+2
2-component
3-component
2+4+4 6+2+2
4+2+2
4-component
4+2+2+2
2+2+2+2
Above are some examples of known concerted cycloaddition reactions. While reactions involving more than 4 components are allowed by orbital symmetry they must overcome entropic barriers. For this reason, multicomponent systems with more than 4 -systems have not been observed.
Crisis of Nomenclature
Traditional convention has it that cycloadditions are named [m + n] to denote the number of atoms in each component. Woodward and Hoffmann altered this so that m and n refer to the number of electrons in each component. This does not impact neutral species, but has consequences with dipolar species. R N R N
Example: Ozonolysis
O O
R'
O O O R'
R O
O O R'
Cheletropic Reactions
R O
R O
suprafacial [4 + 2]
SO2 - Class of retrocycloadditions when one atom is extruded from a cyclic -system - Demonstrative of antarafacial vs. suprafacial selectivity because geometrical constraints are overcome in constrained cyclic systems.
R O S O R
antarafacial [6 + 2]
SO2 R R
LUMO
HOMO
HOMO
LUMO
[14 + 2] cycloaddition
CN NC NC CN CN CN CN H CN
LUMO
2
HOMO
1
Stereoselectivity of Cycloadditions:
The Endo/Exo Problem
minor
O O O H+ O O HOMO O
major
O O O
Secondary Orbital Overlap favors endo transition state; strong enough to override sterics
OR
O LUMO
HOMO
LUMO
exo TS
Examination of orbital coefficients allows prediction of the regioselectivity of [4 + 2] cycloadditions. Coefficients of similar size should be matched to give maximal overlap in -bond formation. HOMO EDG EWG EDG EDG EWG EWG EDG EWG LUMO
EDG EWG
The orbital coefficient effect of a substituent at the 1 position of a diene outweighs that of a substituent at the 2 position of the diene.
For a thorough treatment of orbital coefficients in cycloadditions: Fleming, I. Frontier Orbitals and Organic Chemical Reactions, Ch. 4. 1976; Wiley-VCH: Weinheim.
Sigmatropic Rearrangements
Woodward, R. B.; Hoffmann, R. J. J. Am. Chem. Soc. 1965, 8(11), 2511-2513.
"We define as a sigmatropic change of order [i, j] the migration of a -bond, flanked by one or more -electron systems, to a new position whose termini are i - 1 and j - 1 atoms removed from the original bonded loci, in an uncatalyzed intramolecular process." H
1 2 k
H
j
1
j
2 k
"In the first process, here designated suprafacial, the hydrogen atom is associated at all times with the same face of the system, and the transition state possesses a plane of symmetry, . In the second, antarafacial process, the migrating atom is passed from the top face of one carbon terminus to the bottom of the other, through a transition state characterized by a twofold axis of symmetry C2."
H R1 R2 R3 R4 R1 R2 R3 R4
The cationic [1,2] shift of a hydrogen atom is suprafacial with respect to both components in the system. It is important to note that migrating hydrogen atoms can only behave in a suprafacial manner due to the symmetry of a 1s orbital. systems, however, can behave in either a suprafacial or an antarafacial manner, owing to the plane of symmetry present in p orbitals.
H R H
H H
H H
h
H
H H
Photochemical Rearrangement
[1,5] suprafacial-suprafacial rearrangement
R1 R2
H R3 R4
R1 R2
H R4 R3
R1
H R2 R3
R4
Thermal Rearrangement
The [1,5] thermal rearrangement of hydrogen requires that both components are suprafacial. Therefore, it is geometrically allowed. [1, j] thermal sigmatropic shifts in rings
R1 R2 R1
R1 R2
R2
Y Z
Z X
Y X R1
Z X Y R1 R2 Z
R1 R2 R2
[1,5] supra-supra Retention of Stereochemistry Indicates Suprafacial Rearrangement When alkyl groups migrate in an entirely suprafacial manner, the net stereochemical outcome is retention of absolute configuration at the migrating alkyl group. [1,7] antarafacial-suprafacial rearrangements Y X R2 R1 Y Z R2 [1,7] antara-supra Inversion of Stereochemistry Observed [1,7] antarafacial-suprafacial thermal rearrangements are similar to their [1,3] counterparts and occur with inversion of the absolute configuration of the migrating alkyl group. The -system is the suprafacial component. Based on these observations for sigmatropic rearrangements of of -systems, the Woodward-Hoffmann rules for sigmatropic rearrangements can be summarized in terms of the number of electron pairs involved in the rearrangements: Z X Y Z X
R1
R1
R2
supra-supra supra-antara
h
supra-antara supra-supra
kallolide A
CH3 R
H3C
HO
HO
precalciferol
Vitamin D
Cope Rearrangement
Claisen Rearrangement
Cope, Claisen, and variants are all predicted to be [3,3] supra-supra thermal sigmatropic rearrangements
R R
R R R R
Divinylcyclobutanes and divinylcyclopropanes prefer to rearrange through boat transition states from their cis conformations. Trans divinylcyclobutanes and divinylcyclopropanes will isomerize through diradical intermediates to their cis isomers and then undergo [3,3] sigmatropic rearrangements.
O S
O Me HO O S Ph Me O S
Me Ph [2,3] HO
O TEA O Ph
mCPBA DCM
HO
O Me HO OH H O Me O O O H OH
Transition state:
O S Ph H H Me O OH H R H
(+)-pyrenolide D
Engstrom, K. M.; Mendoza, M. R.; Navarro-Villalobos, M.; Gin, D. Y. Angew. Chem., Int. Ed. 2001, 40, 1128-1130.
[2,3] Wittig Rearrangement OTBS O TBSO TMS OTBS O OTBS O TBSO Li TMS
n-BuLi, THF
[2,3]
prostoglandins
TBSO H HO TMS TBSO H C5H11 TBSO
First example of an asymmetric [2,3] Wittig rearrangement Formation of 3 contiguous chiral centers to give a single stereoisomer!
Nakazawa, M.; Sakamoto, Y.; Takahashi, T.; Tomooka, K.; Ishikawa, K.; Nakai, T. Tetrahedron Lett. 1993, 34, 5923-5926.
Ene Reactions
6 electron process suprafacial to all components involving: - 4 electron component, the ene (typically allylic) - 2 electron component, the enophile (-bond) H O
Carbonyl Ene
R H O R
Conia Ene R
H Me H H NC D D CN NC D H D CN H Me H O H R O H
R R
Metalla-ene
MgCl
ClMg
Hetero-ene O
Se Se H O O O
Me H H
Retro-ene
H NC D D CN R O O H R O O H
H Me
O H
Me
t-BuO Me
Me OH O
O H
()-columbiasin A
Harrowven, D. C. Angew. Chem. Int. Ed. 2005, 117, 12471248.
H Me
Me