Ch242b Scott Virgil

The Woodward-Hoffmann Rules and the Conservation of Orbital Symmetry

The Woodward-Hoffmann rules encompass the realm of pericyclic reactions:

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."

Butadiene Molecular Orbitals Under Photochemical Conditions

Photochemical Cyclization of Butadiene

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.

Thermal and Photochemical Cyclizations of 1,3,5-Hexatrienes:

A B C D B

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:

Number of electron pairs

Odd Even

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.

However, there are a few caveats that deserve mention!

"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."

Conrotatory (Thermally Allowed)

Conrotatory (Thermally Allowed)

X
H

H H

H H

Conrotatory (Thermally Allowed)

H H

H H

X
H H

Disrotatory (Thermally "Disallowed")

Disrotatory (Thermally "Disallowed")

H Disrotatory (Thermally "Disallowed")

When these traditionally "disallowed" processes are observed they are usually occurring by non-concerted pathways, such as diradical pathways.

Torquoselectivity in Electrocyclic Reactions:

In the ca case of cyc of cyclobutene cyclobutene electrocyclic electrocyclic ring opening, you may have processes that give different isomeric products. The principle of torquoselectivity guides us in deciding which conrotatory process will be favored for a given electrocyclic ring opening. H CH3 H H H3C TS A CH3 H H3C H CH3 H H H TS B CH3 CH3 B H

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)

8 Thermal Conrotatory Electrocyclization

CO2R

6 Thermal Disrotatory Electrocyclization

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

m and n are numbers of -electrons in each component

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.

Stereospecificity of the Thermal [4 + 2] Cycloaddition:

The thermal [4 + 2] electrocyclizaton is selectively disrotatory, allowing absolute elucidation of the product cycle's stereochemistry. Thus, this is a sterespecific transformation: A A B B A B A B B A B C C A A B B C B A A

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

The Thermal [2 + 2] Cycloaddition: A Closer Look

Previously, it was said that the thermal [2 + 2] cycloaddition was geometrically forbidden, not orbital symmetry forbidden. To understand this, two new concepts, suprafaciality and antarafaciality, must be introduced. The consequence of suprafaciality and antarafaciality is that many processes that are Woodward-Hoffmann allowed can be forbidden to occur because of geometrical constraints on the system.

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

symmetry allowed, geometrically forbidden

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:

Number of Electron Pairs

even (4n) odd (4n + 2)

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

6+4 8+2 2+2+2

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

1,3 dipolar cycloaddition

R'

Traditionally: [3 + 2] W-H alteration: [4 + 2]

R'

Some common cycloadditions: 1,3 dipolar cycloadditions

R Y X R

Example: Ozonolysis
O O

R'

Y R' R R' R R'

suprafacial with respect to both components formal [4 + 2] Cycloaddition

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

Carbene addition to olefins

R R R' R R R' R R R' R R HOMO occupied by 2 e- is sp3 orbital and interacts with olefin LUMO LUMO is vacant p-orbital and interacts with olefin HOMO - This dual overlap is why carbenes have a side-on approach instead of head-on R' - Carbenes have two orbitals interacting on one carbon in cycloadditions:

LUMO

HOMO

HOMO

LUMO

[14 + 2] cycloaddition

CN NC NC CN CN CN CN H CN

Inverse Demand Diels-Alder Cycloaddition:

In a normal electron demand Diels-Alder, the HOMO of the electron rich diene reacts with the LUMO of the electron deficient dienophile. The inverse demand DIels-Alder occurs between the LUMO of an electron poor diene and the HOMO of an electron rich dienophile.
Diene Dienophile

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 product is thermodynamic, therefore lower in energy

endo TS Regioselectivity and Substituent Effects

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 EDG EWG EDG

EDG EDG EWG

EDG EWG EDG

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

sigmatropic change of order [1, j]

"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."

[1, j] suprafacial sigmatropic reaction

[1, j] antarafacial sigmatropic reaction

Sigmatropic Rearrangements of Hydrogen:

[1,2] cationic suprafacial-suprafacial rearrangement H H R1 R2 R3 R4

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.

[1,3] antarafacial-suprafacial rearrangement R

H R H

H H

H H

Thermal Rearrangement Geometrically Disallowed!

In the thermal case, [1,3] hydrogen shifts require one component to be antarafacial. Since the migrating hydrogen atom must be suprafacial, the -system would be antarafacial. Geometrical constraints on the system, however, prohibit this process since the bond overlap achieved in the transition state would be inadequate for bond formation. Photochemically, this process requires two suprafacial components. This eliminates the geometrical constraints of having an antarafacial component and allows the [1,3] hydrogen atom shift to occur. H R H R 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

Symmetry and Geometrically Allowed

H R2 R2 R1 R2 R1 H R1 H

Symmetry Allowed BUT Geometrically Forbidden!

[1, j] shifts of hydrogen atoms within rings is geometrically allowed only if both componts react suprafacially. This is seen in the case of a [1,5] hydrogen shift in cyclopentadienes (top figure). If, however, one component reacts antarafacially, the rearrangement will be geometrically forbidden, as the migrating hydrogen atom would have to travel through a C-C bond on its path to the opposite face of the -system. This is observed in the case of a [1,7] hydrogen shift in cycloheptatrienes (bottom figure). [1, 7] hydrogen shifts in acyclic heptatrienes are observed because the length of the -system permits the geometrical constraints seen in the [1,3] thermal shift situation to be overcome.

Thermal Sigmatropic Rearrangements of Alkyl Groups:

[1,3] antarafacial-suprafacial rearrangement X Y X Z

Y Z

Z X

[1,3] antara-supra Symmetry and Geometrically Allowed!

Inversion of Stereochemistry Indicates Antarafacial Rearrangement

Unlike a hydrogen atom, a migrating alkyl group can behave antarafacially. Thus, in a [1,3] antarafacial-suprafacial thermal rearrangement, the alkyl group is geometrically able to migrate on the same face of the -system. The key is to recognize that the absolute configuration at the migrating alkyl group has inverted. This inversion of stereochemistry is the consequence of antarafacial migration by the alkyl group. [1,5] suprafacial-suprafacial rearrangements Y 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

Number of electron pairs

Odd Even

supra-supra supra-antara

h
supra-antara supra-supra

Sigmatropic Rearrangements in the Biosynthesis of Natural Products: Sigmatropic Rearrangement of Bipinnatin J:

CH3 H O H3C CH3 O O OH CH3 H3C O CH3 O OH O [1,3] supra-supra Retention of Stereochemistry

bipinnatin J Sigmatropic Rearrangement of Precalciferol: CH R

3

kallolide A
CH3 R

H3C

HO

[1,7] supra-antara thermal rearrangement

HO

precalciferol

Vitamin D

[3,3] Sigmatropic Rearrangements: The Claisen and Cope Rearrangements

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

chair transition state

When possible, the [3,3] sigmatropic rearrangements prefer to proceed through chair transition states. Stereochemistry is able to be translated through the transition state to the products.

boat transition state

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.

[2,3] Sigmatropic Rearrangements

R O S R R R R O R R S H R

O S

Mislow-Evans Rearrangement: [2,3] supra-supra thermal rearrangement

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!

Stork's prostoglandin intermediate

Transition state for rearrangement:

TMS H H OTBS O OTBS H

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

The Woodward-Hoffmann Rules for Pericyclic Reactions

Number of Electron Pairs Odd Even One final example: Total Synthesis of Columbiasin A Use the Woodward-Hoffman rules to explain the stereochemical outcomes of the pericyclic reactions used in the Columbiasin A syntheses by K. C. Nicolaou and D. C. Harrowven. Me O OMe HO Me O O S O chelotropic [4+2] [4+2] cycloaddition HO H Me Me O OMe Me Me Me O OH Me O H Me Me Me
Nicolaou, K. C. Angew. Chem. Int. Ed. 2001, 113, 2543-2547.

Number of Antarafacial Components h Zero Odd Odd Zero

H Me

O H

Me

t-BuO Me

Me OH O

Ot-Bu 4-electrocyclic ring opening 6-electroncyclic ring closing tautomerization H Me O Me

O H

()-columbiasin A
Harrowven, D. C. Angew. Chem. Int. Ed. 2005, 117, 12471248.

H Me

Me