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Pericyclic Reactions and Woodward-Hoffmann Theory, Lecture notes of Organic Chemistry

National Chiao Tung University Organic Chemistry

An in-depth exploration of pericyclic reactions, a type of concerted reaction in which bonds are formed or broken in a cyclic transition state. Various examples of pericyclic reactions, including electrocyclisation, cycloaddition, and sigmatropic rearrangement. It also delves into the woodward-hoffmann theory, a method for predicting the stereochemistry of pericyclic reactions. Rich in diagrams and explanations, making it a valuable resource for students and researchers in the field of organic chemistry.

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Content modified from Understanding Organic Synthesis Course 2009-2010 by Prof. M. Wills

Pericyclic reactions and Woodward-Hoffmann rules for concerted cycloadditions,

electrocyclizations and sigmatropic rearrangements. FMO theory.

Additional reading:

Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. 1969,8, 781-853.

Fleming, I. “Molecular Orbitals and Organic Chemical Reactions,” Wiley, 2009.

Carey, F. A.; Sundberg, R. J. Chapter 10 in “Advanced Organic Chemistry: Part A,” 5th Ed.; 2007

Carey, F. A.; Sundberg, R. J. Chapter 6 in “Advanced Organic Chemistry: Part B,” 5th Ed.; 2007

Tantillo, D. J.; Seeman, J. I. Chem. Eur. J. 2021, 27, 7000-7016.

Zhou, Q.; Kukier, G.; Gordiy, I.; Hoffmann, R.; Seeman, J. I.; Houk, K. N. J. Org. Chem. 2024,

89, 1018-1034.

Discover Lecture notes of Organic Chemistry National Chiao Tung University

Partial preview of the text

Download Pericyclic Reactions and Woodward-Hoffmann Theory and more Lecture notes Organic Chemistry in PDF only on Docsity!

Content modified from Understanding Organic Synthesis Course 2009-2010 by Prof. M. Wills

Pericyclic reactions and Woodward-Hoffmann rules for concerted cycloadditions,

electrocyclizations and sigmatropic rearrangements. FMO theory.

Additional reading:

Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. 1969 , 8 , 781 - 853.

Fleming, I. “Molecular Orbitals and Organic Chemical Reactions,” Wiley, 2009.

Carey, F. A.; Sundberg, R. J. Chapter 10 in “Advanced Organic Chemistry: Part A,” 5th Ed.; 2007

Carey, F. A.; Sundberg, R. J. Chapter 6 in “Advanced Organic Chemistry: Part B,” 5th Ed.; 2007

Tantillo, D. J.; Seeman, J. I. Chem. Eur. J. 2021 , 27 , 7000-7016.

Zhou, Q.; Kukier, G.; Gordiy, I.; Hoffmann, R.; Seeman, J. I.; Houk, K. N. J. Org. Chem. 2024 ,

Introduction: Unexpected results of cyclisation reactions.

Pericyclic reactions are; “Any concerted reaction in which bonds are formed or broken in a

cyclic transitions state”. (electrons move around in a circle).

i.e. there is a single transition state from start to finish, in contrast to a stepwise reaction.

Transition state

reaction co-ordinate

Energy

starting

material

product

Concerted reaction

Transition states

reaction co-ordinate

Energy

starting

material

product

Multistep reaction

inter-

mediate inter-

mediate

Properties of pericyclic reactions:

(a) Little, if any, solvent effect (b) No nucleophiles or electrophiles involved.

(c ) Not generally catalysed by Lewis acids.

(d) Highly stereospecific. (e) Often photochemically promoted.

Examples of pericyclic reactions, continued:

Example of a cycloaddition to give a 6-membered ring:

3) Sigmatropic rearrangement reactions: These involve a concerted migration of atoms or of groups of

atoms. E.g. migration of a s-bond. The numbering refers to the number of atoms in the transition state on either

side of where bonds are made or broken.

H H

This would be classified as a [ 1 , 2 ]-sigmatropic

rearrangement (or shift).

[ 1 , 2 ]

This would be classified as a [ 1 , 5 ]-sigmatropic

rearrangement (or shift).

H

[ 1 , 5 ]

(one cis or Z alkene,

and a E,E- diene)

heat

O

One diastereo-

isomer is favoured.

(Diels-Alder reaction!)

Examples of pericyclic reactions, continued:

3) Sigmatropic rearrangement reactions: A high level of stereochemical control is often observed.

This would be classified as a [ 3 , 3 ]-sigmatropic

rearrangement (or shift).

only, no:

observed

heat

[ 3 , 3 ]

Other concerted reactions:

a) Ene reaction (synthetic chemists), or Norrish rearrangement (photochemists) or

McLafferty rearrangement (for mass spectrometrists).

b) Decarboxylation reaction:

O

H

O

H

enol

alkene

n.b. enolate = O

O

H

O C^ O^

H

O

What is happening in the cyclisation is that p-orbitals (which form the p-bonds) are combining

in order for a new s bond to be formed between the ‘ends’ of the conjugated system. However,

in order for this process to happen efficiently, it is necessary for the orbitals with the same

wave-function sign (phase) to ‘join up’. In order to work out where these are, a quick analysis

of the four molecular orbitals (formed from the 4 atomic – p – orbitals) is required.

Woodward-Hoffmann theory applied to cyclobutene formation.

Note: ‘n’ atomic orbitals, when combined, result in the formation of ‘n’ molecular orbitals.

Low-energy orbitals are generally bonding and high energy ones are antibonding. Because the

lower orbitals are filled in the butadiene system, the molecule is stable.

Note: the view of the

butadiene is 'edge-on'

with the single bond

'further back'.

H

H H

y 3

y 4

y 1

y 2

Energy

There are 4

electrons in this

bonding system.

Filling orbitals from

the lowest first soon

reveals the nature

of the outermost or

'frontier' orbital.

0 nodes

1 nodes

2 nodes

3 nodes

Woodward-Hoffmann theory applied to cyclobutene formation.

So it is now possible to see what happens when butadiene is converted to cyclobutene. In order for

the new sigma bond to be formed between the newly-connected carbon atoms, the ends of the

molecule have to ‘rotate’ in a very specific way for this to happen. We only need to consider the

highest-energy molecular orbital (highest occupied molecular orbital, or HOMO):

The result is that the ‘X’ groups end up trans to each other, as do the ‘Y’ groups.

Because this involves a concerted rotation of each end of the diene in the same direction (clockwise is

illustrated, although anticlockwise would give same result) this is referred to as a ‘ conrotatory ’

process. It is also referred to as ‘ antarafacial ’ because the orbitals which link up have identical signs

on opposite faces of the diene.

H

X

Y Y

y 2 X X

Y Y

X

Y

X

Y^ X

Y

H

X Y

X

Y

overall: X

Y Y

X

heat

X Y

Y X

Orbitals of same

sign form a bond

(HOMO)

Cyclisation under photochemical conditions: In the new HOMO, the ‘ends’ of the orbitals with

the same sign are on the same face of the diene, or ‘suprafacial’. In order for these to ‘join up’

to form a bond, the ends of the alkene have to rotate in opposite directions. This process is

described as ‘disrotation’.

i.e., A suprafacial , disrotation process.

n.b. Note that the hybridisation of the carbon atoms at the ends of the diene changes from sp

to

sp

in the process.

H

X

Y Y

y 3 X X

Y Y^ X X

Y

X^ X

Y

H

Y Y

X

overall: X

Y Y

X

Y Y

X X

Orbitals of same

sign form a s-bond

(photochemical

irradiation)

Woodward-Hoffmann theory applied to cyclobutene formation – conclusion:

It is now possible to understand all the stereochemical observations for the butadiene

cyclisations which were described at the start of the section:

Note how antara/conrotation go together, as do supra/disrotation. Logical really.

Note, also, that the rules also work in the reverse direction, e.g.

irradiation (hu) E,E cis

E,Z

Heat (D)

suprafacial

disrotation

antarafacial

conrotation

irradiation (hu)

Heat (D)

E,E

cis

trans

E,Z

Heat (D)

irradiation (hu)

suprafacial

disrotation

suprafacial

disrotation

antarafacial

conrotation

antarafacial

conrotation

Although it should be noted that sometimes stereocontrol is lost due to competing radical reactions.

Synthetic applications of electrocyclisation reactions:

The conversion of ergosterol to vitamin D2 proceeds through a ring-opening (reverse)

electrocyclisation to give provitamin D2, which then undergoes a second rearrangement (a [1,7]-

sigmatropic shift). Stereochemical control in the sigmatropic shift process will be described in a

later section of this course.

H H

HO

ergosterol

sunlight

photochemically-

promoted electrocyclisation

(antarafacial, conrotation)

H

HO

provitamin D 2

H

HO

H

[ 1 , 7 ]-sigma-

tropic shift.

vitamin D 2

Synthetic applications of electrocyclisation reactions:

A spectacular example of the power of electrocyclisation reactions is in the biosynthesis of

endiandric acids, which are marine natural products.

All of these are derived from the linear polyene shown below:

HO

C

E

Z

E

The double-bond stereochemistry is critical.

H H

HO

C

Endiandric acid D

H H

HO

C

Endiandric acid E

H H

HO

C

H

Endiandric acid A

Step 1:

Step 2:

HO

C

HO

C

conrotation

(antarafacial)

HO

C

HO

C

HO

C

H

4 n, thermal

H H

HO

C

Endiandric acid E

HO

C

disrotation

(suprafacial)

HO

C Ph

H^ H

R

H

HO

C

R

H H

HO

C

4 n+ 2 , thermal

Note: the product is racemic.

K. C. Nicolaou’s research group achieved a direct synthesis of endiandric acid A in the

laboratory. This was achieved by the reduction of the two alkyne groups in the molecule

below by Lindlar catalyst (cis- alkenes are formed selectively) which then formed the product

upon heating in toluene. A pretty impressive ‘one-pot’ cyclisation.

H H

MeO 2

C

H

Endiandric acid A

(methyl ester derivative)

MeO 2 C Ph

MeO 2

C

(not isolated)

H

2 Lindlar^ catalyst

(Pd/CaCO 3 , + Pb or quinine poison)

o C

Toluene

Nazarov cyclisation, cont....

O

H H

H

O

H

H H

O

H

H H

- H

enol - >

ketone

Stereochemistry in the key cyclisation step:

O H

4 n, thermal

hence

conrotation,

antarafacial

O H

H

O

H

H H

Note: although drawn as a localised cation, the positive

charge is spread over five atoms through a delocalised

p system of p-orbitals. There are a total of 4 electrons

in the p system (i.e. two in each alkene), hence it is a

4n electron system, and obeys the rules as usual.

Woodward-Hoffmann theory for prediction of the stereochemistry

of pericyclic reactions: Cycloaddition reactions.

In cycloaddition reactions, the situation is slightly different because a) two molecules are used

and b) electron flow takes place from the highest occupied molecular orbital (HOMO) of one

molecule to the lowest unoccupied molecular orbital (LUMO) of the other. The stereochemistry

therefore follows from the wavefunction signs of the orbitals on each molecule.

Consider the reaction of a butadiene with an alkene (the Diels-Alder reaction):

The reaction is usually heat-promoted,

but sometimes it is carried out photochemically.

1 ) Diene must be in the s-cis conformation:

s-cis s-trans

This will react: But not this:

(ends are too

far apart)

Pericyclic Reactions and Woodward-Hoffmann Theory, Lecture notes of Organic Chemistry

Related documents

Partial preview of the text

Download Pericyclic Reactions and Woodward-Hoffmann Theory and more Lecture notes Organic Chemistry in PDF only on Docsity!

Pericyclic reactions and Woodward-Hoffmann rules for concerted cycloadditions,

electrocyclizations and sigmatropic rearrangements. FMO theory.

Additional reading:

Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. 1969 , 8 , 781 - 853.

Fleming, I. “Molecular Orbitals and Organic Chemical Reactions,” Wiley, 2009.

Carey, F. A.; Sundberg, R. J. Chapter 10 in “Advanced Organic Chemistry: Part A,” 5th Ed.; 2007

Carey, F. A.; Sundberg, R. J. Chapter 6 in “Advanced Organic Chemistry: Part B,” 5th Ed.; 2007

Tantillo, D. J.; Seeman, J. I. Chem. Eur. J. 2021 , 27 , 7000-7016.

Zhou, Q.; Kukier, G.; Gordiy, I.; Hoffmann, R.; Seeman, J. I.; Houk, K. N. J. Org. Chem. 2024 ,

Introduction: Unexpected results of cyclisation reactions.

Pericyclic reactions are; “Any concerted reaction in which bonds are formed or broken in a

cyclic transitions state”. (electrons move around in a circle).

i.e. there is a single transition state from start to finish, in contrast to a stepwise reaction.

Properties of pericyclic reactions:

(a) Little, if any, solvent effect (b) No nucleophiles or electrophiles involved.

(c ) Not generally catalysed by Lewis acids.

(d) Highly stereospecific. (e) Often photochemically promoted.

Examples of pericyclic reactions, continued:

Example of a cycloaddition to give a 6-membered ring:

3) Sigmatropic rearrangement reactions: These involve a concerted migration of atoms or of groups of

H H

[ 1 , 2 ]

H

H

[ 1 , 5 ]

O

O

O

O

O

O

Examples of pericyclic reactions, continued:

3) Sigmatropic rearrangement reactions: A high level of stereochemical control is often observed.

[ 3 , 3 ]

Other concerted reactions:

a) Ene reaction (synthetic chemists), or Norrish rearrangement (photochemists) or

McLafferty rearrangement (for mass spectrometrists).

b) Decarboxylation reaction:

O

H

O

H

O

H

O C^ O^

H

O

What is happening in the cyclisation is that p-orbitals (which form the p-bonds) are combining

in order for a new s bond to be formed between the ‘ends’ of the conjugated system. However,

in order for this process to happen efficiently, it is necessary for the orbitals with the same

wave-function sign (phase) to ‘join up’. In order to work out where these are, a quick analysis

of the four molecular orbitals (formed from the 4 atomic – p – orbitals) is required.

Woodward-Hoffmann theory applied to cyclobutene formation.

Note: ‘n’ atomic orbitals, when combined, result in the formation of ‘n’ molecular orbitals.

Low-energy orbitals are generally bonding and high energy ones are antibonding. Because the

lower orbitals are filled in the butadiene system, the molecule is stable.

H

H

H

H

H H

Woodward-Hoffmann theory applied to cyclobutene formation.

So it is now possible to see what happens when butadiene is converted to cyclobutene. In order for

the new sigma bond to be formed between the newly-connected carbon atoms, the ends of the

molecule have to ‘rotate’ in a very specific way for this to happen. We only need to consider the

highest-energy molecular orbital (highest occupied molecular orbital, or HOMO):

The result is that the ‘X’ groups end up trans to each other, as do the ‘Y’ groups.

Because this involves a concerted rotation of each end of the diene in the same direction (clockwise is

illustrated, although anticlockwise would give same result) this is referred to as a ‘ conrotatory ’

process. It is also referred to as ‘ antarafacial ’ because the orbitals which link up have identical signs

on opposite faces of the diene.

H

H

X

X

Y Y