2018 Chemical Synthesis Ch242b

Scott Virgil

Handout 1: The Woodward-Hoffmann Rules

and the Conservation of Orbital Symmetry

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

H H

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

H
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 π-
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 A A A
C C
CONROTATORY B DISROTATORY B
C D
B B
D C
D D
Electrocyclic Reactions of 1,3-Butadiene:

Butadiene Molecular Orbitals Under Thermal Thermal Cyclization of Butadiene

Conditions

A
A
C B
C

D
B
LUMO D

A A
C
CONROTATORY B
C
HOMO B
D
D
"Thus, in an open chain system containing 4n π electrons, the
symmetry of the highest occupied ground-state orbital is such that a highes
bonding interaction between the termini must involve overlap between
orbital envelopes on opposite faces of the system, and this can only
be achieved by a conrotatory process."

Butadiene Molecular Orbitals Under Photochemical Photochemical Cyclization of Butadiene

Conditions

A
A
C B
LUMO D

C
B
D

HOMO A A
C
DISROTATORY B
D
B
C

"On the other hand, promotion of an electron to the first excited state
leads to a reversal of terminal symmetry relationships in the orbitals
mainly involved in bond redistribution, with the consequence that a orbitals
system which undergoes a thermally induced disrotatory
induced d
electrocyclic transformation in the ground state should follow a
conrotatory course when photochemically excited, and vice versa."

Analogous analyses of larger π-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

DISROTATORY
B

C C
A

Thermal HOMO D
"Conversely, in open systems containing 4n + 2 π-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

B
CONROTATORY

C D
A

Photochemical HOMO C

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 Δ hν
Odd Disrotatory Conrotatory

Even 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 specifies 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 Conrotatory Conrotatory

(Thermally (Thermally (Thermally
Allowed) Allowed) H Allowed) H
H H H H
Δ H H
X X
H H
H H
Disrotatory Disrotatory
X (Thermally
Δ
(Thermally Δ Disrotatory
(Thermally
"Disallowed") "Disallowed") "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
CH3
H
X CH3
CH3
H H3C
H
TS A A
CH3
H CH3
H3C H
H
H
H CH3
CH3

TS B B

Examination of the two pos the two possible t two possible transitio possible transition states for transition sta
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.

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 olefins (B) will be highly disfavored compared to the cyclooctatriene containing only cis
olefins (A).
H
H
H H H

H H
H
H
H
X H
H
A B

Electrocyclic Reactions in Nature and Synthetic Chemistry: The Endiandric Acids

CO2R Ph
H

Δ H H

H H CO2R

H
Ph
endiandric acid B
8π Thermal [4+2] Thermal
Conrotatory Cycloaddition
Electrocyclization (Diels-Alder)
CO2R
6π Thermal H
Disrotatory
Electrocyclization Ph 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 σ-bond and one π-bond, cycloaddition
reactions consist of the net intermolecular conversion of k π-bonds to k σ-bonds to form a cyclic product.

m n m-2 n-2

m and n are numbers of π-electrons in each component

The [4 + 2] Cycloaddition:

Diene Dienophile

ψ3
LUMO
ψ2
HOMO
ψ2

ψ1
ψ1
disrotatory
cycloaddition Δ

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 σ-bonds (at the expense of two π-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
A

B
B B

A
A B
A

B
B

A A
B A
B B

C C
C

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 σ-bond formation.

LUMO
ψ2 ψ2

HOMO
ψ1 ψ1

On the other hand, the photochemical [2 + 2] cycloaddition is allowed and leads to stereospecific cyclobutane formation.

hν

HOMO LUMO
ψ2 ψ2

ψ1 ψ1
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.

Δ Suprafaciality- when, in a pericyclic reaction, the bond-

forming interaction occurs on the same face
of a π-system, as in thermal [4 + 2].

H Antarafaciality- when, in a pericyclic reaction, the bond-

H H forming interactions occur on opposite faces
H of a π-system.
H
H H ethylene [2 + 2] ketene [2 + 2]
H
H
O Δ O
H H
H

O H
H
H H
H
H O
H
H H symmetry allowed, symmetry allowed,
H geometrically forbidden geometrically allowed

Why does the thermal [2 + 2] fail with two alkenes Removal of steric bulk (H-atoms) around the π-system
but succeed with ketene? (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 π-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 Photochemical Thermal

even (4n) suprafacial-suprafacial suprafacial-antarafacial

odd (4n + 2) 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 Photochemical

4+2 2+2
2-component 6+4 4+4

8+2 6+2

2+2+2
3-component 2+4+4 4+2+2

6+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 π-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 R
N N
1,3 dipolar
Traditionally: [3 + 2]
cycloaddition W-H alteration: [4 + 2]

R' R'

Some common cycloadditions:

1,3 dipolar cycloadditions Example: Ozonolysis

R R
O O
X X O O O O
Y Δ Y

R R' R R'
R' R'

suprafacial with respect to both components

formal [4 + 2] Cycloaddition R O
O O
O
R O R' O
R'
Cheletropic Reactions

R R
Δ SO2
S R R
O O suprafacial - Class of retrocycloadditions when one atom
[4 + 2] is extruded from a cyclic π-system

- Demonstrative of antarafacial vs. suprafacial

selectivity because geometrical constraints are
Δ overcome in constrained cyclic systems.
SO2
S antarafacial
R R [6 + 2] R R
O O

Carbene addition to olefins

R'
R R' R
- Carbenes have two orbitals interacting on one carbon
in cycloadditions:
R R
• HOMO occupied by 2 e- is sp3 orbital and interacts
R' R'
with olefin LUMO
R R • LUMO is vacant p-orbital and interacts with olefin
R R
HOMO

- This dual overlap is why carbenes have a side-on

LUMO HOMO HOMO LUMO approach instead of head-on

[14 + 2] cycloaddition

CN
NC CN CN
CN
NC 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

ψ3 LUMO

ψ2
ψ2

HOMO
ψ1
ψ1

Stereoselectivity of Cycloadditions:

The Endo/Exo Problem

minor major
O H+ O
O O
O
O
HOMO O O
O

Secondary Orbital
Overlap favors endo OR HOMO LUMO Exo product is
transition state; thermodynamic,
strong enough to therefore lower
O LUMO in energy
override sterics
O
endo TS exo TS

Regioselectivity and Substituent Effects

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 σ-bond formation.

HOMO LUMO
EDG EDG EDG
EDG
EWG EWG EWG

EWG

EDG EDG
EDG EDG
EDG EWG EDG EWG
EDG EWG 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 σ-bond, flanked by one or more π-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 H
j 1 j
1
2 k sigmatropic change 2 k
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 π-
system, and the transition state possesses a plane of symmetry, σ. 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 H
R3
Δ R1
R1 R1 R3 R3
R4 R2
R2 R2 R4 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. π-
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 Δ H

H H H
R 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 π-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 hν H

R H H H

Photochemical Rearrangement

[1,5] suprafacial-suprafacial rearrangement

R1 R1
H Δ H R1 H
R2 R4
R3 R4
R2
R4 R2 R3
R3

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

H
Δ H R1 H

R1 R1
R2 R2
R2
Symmetry and Geometrically Allowed

H R2
Δ
R2

R2 H R1
R1 H
R1

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 π-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 π-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
Z Y Z
Y
Δ
X Y X
Z

[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 π-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
Y Z Z
X
X Y
X
Δ R1
R1 Z
R1
R2
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

Z X Y
Y
Z
Δ X
X

R2 R1
R1
R1 Y Z R2 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 π-system is the suprafacial component.

Based on these observations for sigmatropic rearrangements of of π-systems, the Woodward-Hoffmann rules for sigmatropic
rearrangements can be summarized in terms of the number of electron pairs involved in the rearrangements:

Number of
electron pairs Δ hν
Odd supra-supra supra-antara

Even supra-antara supra-supra

Sigmatropic Rearrangements in the Biosynthesis of Natural Products:

Sigmatropic Rearrangement of Bipinnatin J:

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

CH3 O
CH3
O O
O
bipinnatin J kallolide A
Sigmatropic Rearrangement of Precalciferol:
CH R 3 CH3 R
H3C
Δ [1,7] supra-antara
thermal rearrangement

HO HO
precalciferol Vitamin D

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

Δ O Δ O

Cope Rearrangement Claisen Rearrangement

Cope, Claisen, and variants are all predicted to be [3,3] supra-supra thermal sigmatropic rearrangements

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

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

O Me O
Me O S Me O S
Ph Ph [2,3] TEA
mCPBA
DCM HO
HO HO O Ph
S

O
Transition state:
Me O
O H H
O
(+)-pyrenolide D
HO O
S R
OH H H
Ph
O OH
OH
H H O
Me

Me

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 OTBS

O O [2,3]
n-BuLi, THF
TBSO TBSO Li

TMS TMS

O
OTBS

prostoglandins
TBSO H
TBSO H TMS
C5H11
HO
TBSO
First example of an asymmetric [2,3] Stork's prostoglandin
Wittig rearrangement intermediate Transition state for rearrangement:

Formation of 3 contiguous chiral TMS

centers to give a single stereoisomer! H
H

OTBS
OTBS
O 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: Carbonyl Ene
- 4 electron component, the ene (typically allylic) R R
- 2 electron component, the enophile (π-bond)
O O
H H

Conia Ene
R R
H H
O O
H R H R
Me Me
Metalla-ene
H
H
H
D
CN H D MgCl ClMg
NC NC CN
D D Hetero-ene
O
Se O
Se
Me O
H O
H
H
Retro-ene
H D
CN R O R O
NC
D O O
H H

The Woodward-Hoffmann Rules for Pericyclic Reactions

Number of Number of Antarafacial Components

Electron Pairs Δ hν

Odd Zero Odd

Even Odd Zero

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
Me O
chelotropic OMe
[4+2] Nicolaou, K. C. Angew. Chem. Int. Ed. 2001, 113,
HO Me 2543-2547.
H O
Me [4+2] HO Me
O H
cycloaddition O Me
S Me
O H Me O
Me OH

Me O Me
H
t-BuO Me Ot-Bu O Me
Me
Me 4π-electrocyclic H
ring opening
Me
H (–)-columbiasin A
OH O 6π-electroncyclic O
ring closing Me
H Harrowven, D. C. Angew. Chem. Int. Ed. 2005, 117, 1247-
tautomerization 1248.
Me
Me