2018 Chemical Synthesis Ch242bScott Virgil

Handout 1: The Woodward-Hoffmann Rulesand the Conservation of Orbital Symmetry

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

electrocyclizations cycloadditions sigmatropic rearrangements

H H

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:

COOCH3

Ph

PhH

H

H

H

endiandric acid B

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

"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."

CB

A

D

A

C

BD

CONROTATORYDB

A

C

A

C

BD

DISROTATORY

Woodward, R. B.; Hoffmann, R. J. Am. Chem. Soc. 1965, 87(2), 395-397.

COOCH3

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.

Electrocyclic Reactions of 1,3-Butadiene:

HOMO

LUMO

Butadiene Molecular Orbitals Under ThermalConditions

Thermal Cyclization of Butadiene

A

BC

D

A

C

DB

CB

A

D

A

C

BD

CONROTATORY

"Thus, in an open chain system containing 4n π electrons, the symmetry of the highest occupied ground-state orbital is such that a 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."

4nπ-electrons,highest occupied ground-sta

must

HOMO

LUMO

Butadiene Molecular Orbitals Under PhotochemicalConditions

Photochemical Cyclization of Butadiene

A

BD

C

A

C

DB

DB

A

C

A

C

B

DISROTATORY

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

a reversal of the termin reversal of the terminal symmetryorbitals mainly involved in b

induced disrotatory electrocyground state should follow a

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:

C

B

A

D

Thermal HOMO

DISROTATORY

C

B

D

A

C

B

A

D

Photochemical HOMO

CONROTATORY

D

B

C

A

"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."

Based on these these observat observations for electrocyc for electrocyclic reactions of electrocyclic reactions of conjugated polyene Woodward-Hoffmannelectrocyclic 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

Even

Disrotatory

Conrotatory

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."

Δ X

Conrotatory(ThermallyAllowed)

Disrotatory(Thermally

"Disallowed")Δ

H

HH

HH

HX

Conrotatory(ThermallyAllowed) H

HH

HH

H

Disrotatory(Thermally

"Disallowed")Δ

Conrotatory(ThermallyAllowed)

Disrotatory(Thermally

"Disallowed")X

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

In the ca case of cyc of cyclobutene cyclobutene electrocyclic electrocyclic ring opening, you may have ring opening, you may have noticed that there opening, you may have noticed that there are two possi you may have noticed that there are two possible conrotatoprocesses 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

H

CH3

CH3

H

CH3

H3C

H

H

HH

CH3

CH3

H

H

CH3

CH3

X

H

H

HH

HHH

H HHH X

H

H

H3C

CH3

Examination of the two pos the two possible t two possible transitio possible transition states for transition states for the ring opening of trans-dimethyl-cyclobutenenegative 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 bicycle below, t the [4.2.0] fused bicycle below, torquose [4.2.0] fused bicycle below, torquoselectivity pr fused bicycle below, torquoselectivity predicts that ri bicycle below, torquoselectivity predicts that ring opening leathe cyclooctatriene with two trans olefins (B) will be highly disfavored compared to the cyclooctatriene containing only cis olefins (A).

TS A

TS B

A

B

A B

Torquoselectivity in Electrocyclic Reactions:

Electrocyclic Reactions in Nature and Synthetic Chemistry: The Endiandric Acids

CO2R

Ph

Δ

PhH

H

H H

H

H CO2R

endiandric acid B

CO2R

Ph

HH

H

CO2R

endiandric acid F

8π ThermalConrotatory

Electrocyclization

6π ThermalDisrotatory

Electrocyclization

[4+2] ThermalCycloaddition(Diels-Alder)

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 ReactionsHoffmann, 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:

HOMO

LUMO

Δdisrotatory

cycloaddition

Diene Dienophile

ψ1

ψ2

ψ3

ψ1

ψ2

In the thermal [4 + 2] cycloaddition reaction, mixing occurs between the highest occupied molecular orbital (HOMO) on thediene 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:

B

A

B

A

A

A

B

A

B

C

B

A

A B

C

BA

A

B

B

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.

Δ

LUMO

ψ1

ψ2

ψ1

ψ2

HOMO

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

hν

LUMO

ψ1

ψ2

ψ1

ψ2HOMO

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. Tounderstand 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 ofgeometrical constraints on the system.

Δ

HH

H HHH

HH

ΔO O

H

H HHH

HO

Why does the thermal [2 + 2] fail with two alkenesbut succeed with ketene?

Suprafaciality- when, in a pericyclic reaction, the bond-forming interaction occurs on the same faceof a π-system, as in thermal [4 + 2].

Antarafaciality- when, in a pericyclic reaction, the bond-forming interactions occur on opposite facesof a π-system.

HH

HH

H

H

H

H

Osymmetry allowed,

geometrically forbiddensymmetry allowed,

geometrically allowed

ethylene [2 + 2] ketene [2 + 2]

Removal of steric bulk (H-atoms) around the π-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 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 ThermalPhotochemical

even (4n)

odd (4n + 2)

suprafacial-suprafacial

suprafacial-antarafacial

suprafacial-antarafacial

suprafacial-suprafacial

In the suprafacial-suprafacial cases, the cycloadditions are symmetry allowed and geometrically allowed. In thesuprafacial-antarafacial cases, the cycloadditions are symmetry allowed and generally geometrically disallowed.

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.

Type of Cycloaddition Thermal Photochemical

2-component

3-component

4-component

4 + 2

6 + 4

8 + 2

2 + 2 + 2

2 + 4 + 4

6 + 2 + 2

4 + 2 + 2 + 2

2 + 2

4 + 4

6 + 2

4 + 2 + 2

2 + 2 + 2 + 2

Some common cycloadditions:

1,3 dipolar cycloadditions

YXR

R'

YX

R'

R

O

O

O

R'

RO O

OR R'

OO

O

R'R

Example: Ozonolysis

Δ

suprafacial with respect to both componentsformal [4 + 2] Cycloaddition

Cheletropic Reactions

S

S

OO

OO

SO2

SO2

R R R

RR

R

R R

Δ

Δ

R

R

R

R

R' R'

R'RR

R'

RR

Carbene addition to olefins

LUMO HOMO HOMO LUMO

suprafacial[4 + 2]

antarafacial[6 + 2]

[14 + 2] cycloaddition

H

CNNC

NC CN

CNCN

CN

CN

- Class of retrocycloadditions when one atom is extruded from a cyclic π-system

- Demonstrative of antarafacial vs. suprafacial selectivity because geometrical constraints are overcome in constrained cyclic systems.

- Carbenes have two orbitals interacting on one carbon in cycloadditions:

• 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

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.

RN

R'

RN

R'

1,3 dipolar

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

OO

O

R R'

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 deficientdienophile. The inverse demand DIels-Alder occurs between the LUMO of an electron poor diene and the HOMO of an electron rich dienophile.

HOMO

LUMO

Diene Dienophile

ψ1

ψ2

ψ3

ψ1

ψ2

Stereoselectivity of Cycloadditions:

The Endo/Exo Problem

Regioselectivity and Substituent Effects

EDGEWG

EDGEWG

HOMO LUMO

EDGEWG

EWGEWG

EWG

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.

EDG

EWG

EDGEDG

EDGEDG EDG

EDG

EDGEDG

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.

For a thorough treatment of orbital coefficients in cycloadditions: Fleming, I. Frontier Orbitals and Organic Chemical Reactions, Ch. 4. 1976; Wiley-VCH: Weinheim.

OO OO

O

O OO

O

majorminor

Secondary OrbitalOverlap favors endotransition state; strong enough to override sterics

Exo product is thermodynamic, therefore lower in energy

H+

endo TS exo TS

OR

O

HOMO

LUMOO

HOMO LUMO

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 intramolecularprocess."

H H1

2 k

j 1

2 kj

sigmatropic changeof 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 atwofold axis of symmetry C2."

[1, j] suprafacial sigmatropic reaction [1, j] antarafacial sigmatropic reaction

Sigmatropic Rearrangements of Hydrogen:

R2R1

H

R4

R3

R2

R1

R4

R3

H

R2

R1

R4R3

H

[1,2] cationic suprafacial-suprafacial rearrangement

Δ

The cationic [1,2] shift of a hydrogen atom is suprafacial with respect to both components in the system. It is important tonote 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

H

R H H

H

HH

Thermal Rearrangement

H

R H

H

H

HH

Photochemical Rearrangement

Geometrically Disallowed!

R

RΔ

hν

In the thermal case, [1,3] hydrogen shifts require one component to be antarafacial. Since the migrating hydrogen atommust be suprafacial, the π-system would be antarafacial. Geometrical constraints on the system, however, prohibit thisprocess 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 antarafacialcomponent and allows the [1,3] hydrogen atom shift to occur.

[1,5] suprafacial-suprafacial rearrangement

R3R4

R1

R2

HR2

R1

R3

R4H

R1

R2R3

R4

H

Thermal Rearrangement

Δ

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

R2R1

HR1

R2

H

R1R2

H

Symmetry and Geometrically Allowed

R2

H

R1

R2

R1

H

R2

R1H

Symmetry Allowed BUT Geometrically Forbidden!

Δ

Δ

[1, j] shifts of hydrogen atoms within rings is geometrically allowed only if both componts react suprafacially. This is seenin the case of a [1,5] hydrogen shift in cyclopentadienes (top figure). If, however, one component reacts antarafacially, therearrangement 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 thegeometrical constraints seen in the [1,3] thermal shift situation to be overcome.

Thermal Sigmatropic Rearrangements of Alkyl Groups:

X

Y Z

ZY

X

X

ZY

[1,3] antara-supraSymmetry and Geometrically Allowed!

Inversion of Stereochemistry Indicates Antarafacial Rearrangement

Δ

[1,3] antarafacial-suprafacial 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 recognizethat the absolute configuration at the migrating alkyl group has inverted. This inversion of stereochemistry is theconsequence of antarafacial migration by the alkyl group.

[1,5] suprafacial-suprafacial rearrangements

R2R1

R1

R2

R1

R2

XY Z X

YZ

Z

X Y

[1,5] supra-supraRetention of Stereochemistry Indicates Suprafacial Rearrangement

Δ

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

R2R1 R2R1R1

R2

X

Y Z

ZY

XXZ

Y

[1,7] antara-supraInversion of Stereochemistry Observed

Δ

[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

Even

supra-supra

supra-antara

supra-antara

supra-supra

Sigmatropic Rearrangements in the Biosynthesis of Natural Products:

O

OO

H

H3C

OH

CH3

hν O

O

OH

CH3O

H3C

CH3CH3

Sigmatropic Rearrangement of Bipinnatin J:

bipinnatin J kallolide A

[1,3] supra-supraRetention of Stereochemistry

Sigmatropic Rearrangement of Precalciferol:

H3C

CH3

HO

Δ

CH3

HO

R R

precalciferol Vitamin D

[1,7] supra-antara thermal rearrangement

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

O O

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

boat transition state

Δ Δ

Δ

Δ

Δ

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.

Divinylcyclobutanes and divinylcyclopropanes prefer to rearrange through boat transition states from their cisconformations. Trans divinylcyclobutanes and divinylcyclopropanes will isomerize through diradical intermediates to their cis isomers and then undergo [3,3] sigmatropic rearrangements.

[2,3] Sigmatropic Rearrangements

OH

SO

R

R R

RSO

RS

R

O

R

R

R

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

H

OMe

HO

SPh mCPBA

DCM

OMe

HO

SPh

O OMe

HOO

SPh

[2,3] TEA

OMe

HOOH

O

O

O

O

H H

Me

OH

(+)-pyrenolide D

Engstrom, K. M.; Mendoza, M. R.; Navarro-Villalobos, M.; Gin, D. Y. Angew. Chem., Int. Ed. 2001, 40, 1128-1130.

S

O

Ph

H

R

O

Me

HH

H

Transition state:

Δ

OTBS

OTBS

TBSO

O

TMS

n-BuLi, THF

OTBS

TBSO

O

TMS

Li[2,3]

OTBS

TBSO TMSHHO

First example of an asymmetric [2,3] Wittig rearrangement

Formation of 3 contiguous chiral centers to give a single stereoisomer!

O

TBSO HC5H11

TBSO

prostoglandins

O H

TMS

OTBS

HH

Transition state for rearrangement:

Nakazawa, M.; Sakamoto, Y.; Takahashi, T.; Tomooka, K.; Ishikawa, K.; Nakai, T. Tetrahedron Lett. 1993, 34, 5923-5926.

Stork's prostoglandinintermediate

[2,3] Wittig Rearrangement

Ene Reactions6 electron process suprafacial to all components involving:

- 4 electron component, the ene (typically allylic) - 2 electron component, the enophile (π-bond)

H H

H

Me

H

D

CND

NC

H

Me

D

CND

NC

H

HMe

DCN

DNC

H

HO

OH

MgCl

HOSe

HO

OH

ClMg

HOSe

R R

Carbonyl Ene

R

R R

R

Conia Ene

Metalla-ene

OH

O

OH

O

OO

R R

Hetero-ene

Retro-ene

The Woodward-Hoffmann Rules for Pericyclic Reactions

Number ofElectron Pairs

Number of Antarafacial ComponentsΔ hν

Odd

Even

Zero

Odd

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.

O

O

OMe

Me

Me

H

S

Me

Me

HO

OO

MeMe

OMe

O

OMe

HMe

HO

H

chelotropic[4+2]

[4+2]cycloaddition

MeMe

OH

O

OMe

HMe

H

HMe

Me

OH O

Met-BuOO

O

Ot-Bu

Me

Me

H

Me

Me

4π-electrocyclic ring opening

6π-electroncyclicring closing

tautomerization

(–)-columbiasin A

Nicolaou, K. C. Angew. Chem. Int. Ed. 2001, 113, 2543-2547.

Harrowven, D. C. Angew. Chem. Int. Ed. 2005, 117, 1247-1248.