Molecular Rearrangements

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Molecular Rearrangements

1. Wagner – Meerwin Rearrangement

In this rearrangement an alcohol containing an alkyl or aryl group at - carbon

undergoes rearrangement with the migration of alkyl or aryl group and simultaneous

elimination of water molecule to give an alkene in presence of an acid.

C C

R3

R2

R1

R5

R4

OH

C C

R3

R2

R1

R5

(if R4 = H)

C C

R3

R2

R5

R1

R4

(if R has an H atom)

Initially a carbocation is formed and then rearrangement takes place as per the

mechanism given below.

C C+

R3

R2

R1

R5

R4

C C

R3

R2

R5

R1

C C+

R3

C

R1

R5

R4

H

H

H

C C

R3

CH2

R5

R4

R1

Due to the formation of carbocation, SN1 reaction conditions favour this

rearrangement rather than SN2 conditions. These types of rearrangements were first

observed in bicyclic terpenes.

CH3

CH3CH3

OH

1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol

Isoborneol

acid

CH3

CH3

CH2

2,2-dimethyl-3-methylidenebicyclo[2.2.1]heptane

camphene

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CH3 C.

CH3

CH3

CH2 Clbase

CH3 C.

CH3

.CH CH3

CH3 CH2 CH2 Br

AlBr3

CH3 CH CH3

Br

AlBr3mechanism

CH3 .CH2 CH2

+

+ AlBr4-

CH3 CH+

CH3

AlBr4-

Therefore in the last case there is a shift of H- ion not a bromide ion. Here the

leaving group may be H2O or any other group, but its loss should create a carbocation,

including N2 from aliphatic diazonium ion. The direction of rearrangement is towards

the most stable carbocation, i.e., tertiary > secondary > primary.

2. The Dienone – Phenol Rearrangement (Aromatization)

In this type of rearrangements cylic ketones with two double bonds undergo

rearrangement in presence of an acid to give phenolic compounds. For instance,

cyclohexadienone is rearranged to phenol. The driving force for this overall reaction is

the creation of aromatic system.

O

R R

acid

OH

R

R

Mechanism

O

R R

H+ C+

OH

R RC

+

H

R

R

OH OH

R

R

CyclohexadienonePhenol

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Rarely, with an electrophile phenol undergo a reverse rearrangement, i.e.,

phenol to dienone rearrangement as follows.

OH

BrBr

Br

+ Br Br

O

BrBr

Br Br

3. The Favorski Rearrangement

The rearrangement of an - haloketone in presence of a strong base such as

alkoxide to give an ester is called as Favorski rearrangement.

C C R1

O Cl

R2

R3

+ -OR4 C C R4O

O R1

R2

R3

haloketone

alkoxide

ester

Mechanism

C C R1

O Cl

R2

R3

-OR4

C C R1

O-

Cl

R2

R3

OR4

- Cl-C C R

1

R2

R3

OR4

O

C C R4O

O R1

R2

R3

Cyclic - haloketones give ring contraction when subjected to this reaction

conditions.

Cl

O

+ -OR1

2COOR1

2

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This reaction has also been carried out on - hydroxy ketones and on , -

epoxy ketones.

C. C C R1

O

R2

R4

R3

O

OH-

HOOC C C

R2

R4

R3

H OH

Mechanism

C. C C R1

O

R2

R4

R3

O

OH-

C. C C R1

O-

R2

R4

R3

O

OH

C. C C

O

R2

R4

R3

OH

R1

O-

HOH

- OH-

There was another mechanism proposed for this rearrangement which is given

below.

C C C

O

H

R6

R5

R2

Cl

R3

-OR4

- R4OH

C-

C

C

R2

R3

Cl

R5

O

R6 - Cl-

C

O

R5

R6

R2

R3 R4O-

R5

R6

R2

R3

O-

OR4

C C-

C

R5

R6

R2

R3

OR4

O

R4OH C C

C

R5

R6

R2

R3

OR4

O

H

If the intermediate is symmetrical then the 3-membered ring can be opened on

either side with equal probability of the >C=O group. In case of unsymmetrical

intermediates it should open on the side that gives more stable carbanion.

4. The Schmidt Rearrangement

The addition of hydrazoic acid (HN3) to carboxylic acids, aldehydes, ketones,

alcohols and alkenes is known as Schmidt rearrangement. The most common of this

type of rearrangement is with carboxylic acids.

RCOOH + HN3 acid

R - N = C = OH2O RNH2 + CO2

In these reactions, H2SO4 is the most common catalyst, but Lewis acid can also

be used. The reaction between >C=O group of ketone and HN3 is a method for

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inserting a NH group between >C=O and one R groups. Thus it converts a ketone into

an amide.

C

O

R1

RHN3

H+

CR NH

O

R1

The mechanisms for these rearrangements are described below.

1. Addition with carboxylic acids.

C OH

O

R

H+

- H2O

C+

O

R

HN3

C

O

R N N+

N

H- N2

CR

O

+N:

H

CO N R

H2O

NH2 R+ C OO

Isocyanate

2. Addition with >C=O group of ketones.

CR R1

O

acid C+

R R1

OH

HN3

CR R1

OH

NH N+

N

- H2O

CR R1

N N+

N

C+

R1

N R

H2O

CR1

N

OH2

+

Racid

CR1

N

OH

R

- N2

tautomerizationCR

1NH

O

R

Ketone

Amide

5. The Bayer – Villiger Rearrangement

The insertion of a oxygen atom to ketone for converting it into an ester using a

peracid or peroxo compounds is known as Bayer – Villiger rearrangement.

C

R R1

O

+ C

O

H5C6 OOH

C

O

R OR1

In presence of a mineral acid the ketone forms a carbocation first, which then

undergo an addition with peracids or peroxo compounds. The addition product

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successively eliminates a carboxylate anion and proton to give an ester finally. The

mechanism for this rearrangement is given below.

C

R1

R

O

acid C+

R1

R

OH

C

OH

R1

R

O O C R2

O

R2CO3H

- H+ - R2CO2-

C+

R

OH

OR1

- H+

C

O

RR1O

The evidence for this reaction is that the O18

labeled ketone gives an ester

entirely labeled in the oxygen of >C=O group and none in the alkoxy oxygen.

6. The Stevens Rearrangement

A quaternary ammonium salt having an electron withdrawing group, Z on one

of the carbon attached to nitrogen on treatment with a strong base rearranged to give a

tertiary amine. This reaction is referred to as Stevens rearrangement.

N+

Z - CH 2

R1

R3

R2

NaNH2

CH N

R3

R2

Z

R1

Quaternary ammonium salt 30 amine

The following type of radical pair mechanism has been proposed for this

reaction.

N+

Z - CH 2

R1

R3

R2 NaNH2

N+

CH-

R1

R3

R2

Z NCH-

R3

R2

Z.R1

NCH

R3

R2

Z.R1

CH N

R3

R2

R1

Z

(Solvent cage)

Here, the radicals do not escape since they are tightly held in solvent cage.

Another mechanism, which involves ion pairs in solvent cage instead of radical pair,

was also proposed for this kind of rearrangement as described below.

CH-

N+

R1

R3

R2

Z C+

N+

R3

R2

Z

R1(-)

Solvent cage

CH N

R3

R2

Z

R1

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7. The Wittig Rearrangement

The rearrangement of ethers with alkyllithium in presence of a strong base is

called the Wittig rearrangement.

R - CH2 - O - R'R"Li

R - CH - O-Li+

R'

+ R''H

Mechanism

CH-

R O R1

CH-

R O.R

1

CHR O-

.R

1

CHR O-

R1

Solvent cage

Evidences:

1. The rearrangement is largely intramolecular.

2. Migratory aptitudes are in the order of free – radical stabilities, not of

carbocation stabilities.

3. Aldehydes are obtained as side products.

4. Partial racemization of R’ has been observed.

5. Cross over products has been detected.

6. When ketyl radical and R. radicals from different precursors were brought

together, similar products resulted.

8. Wolf Rearrangement

The - diazoketones in presence of silver oxide eliminates N2 with

rearrangement to form a ketene. In this rearrangement a ketene is formed in the

absence of any nucleophile and hence isolated. But if it is carried out in presence of

H2O, -OH, -NH2, the ketene will be converted into –COOH, -COOR, –CONH2

respectively. The over all reaction is known as Ardnt – Eistert synthesis.

C ClR

O

C CH-

R

O

N+

N +2CH2N2

CH3Cl + N

2

C CH-

R

O

N+

NAg2O

- N2

CH C OR

- diazoketone

ketene

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CH C OR

ketene

R'OH

H2O

NH3

RCH2COOR'

RCH2COOH

RCH2CONH2

This rearrangement can be possible either thermally or photochemically.

Thermal reaction is carried out in presence of Ag2O or colloidal Pt or Cu.

Mechanism for Thermal Reaction

C CH-

N+

NR

O

- diazoketone

- N2

Ag2O /

CH C OR

ketene

Mechanism for Photochemical Reaction

C CH-

N+

NR

O

- diazoketone

h

- N2

C CHR

O

CH C OR

ketene

With cyclic - diazoketones, the rearrangement leads to contraction of rings.

C-

O

N+

Nh

CH3OH

COOMe

O

N+

N-

Ag2O

H2O / THF

COOH

Stereochemistry:

Wolf rearrangement occurs preferentially from the S – Z conformation of -

diazoketones.

R R1

ON2

S - Z

Applications:

Wolf rearrangement is involved in an important reaction (Ardnt – Eistert) for

converting an acid into its next higher homologue.

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C

CH3

C6H5

H5C2 COOHi) SOCl2

ii) CH2N2

C

CH3

C6H5

H5C2 C

O

CH-N2

+i) Ag2O

ii) H2O

C

CH3

C6H5

H5C2 CH2COOH

2-Methyl-2-phenylbutanoic acid 3-Methyl-3-phenylpentanoic acid

9. Lossen Rearrangement

The rearrangement of acyl derivative of hydroxamic acid to isocyanate

followed by hydrolysis to the corresponding amine is known as Lossen rearrangement.

CR NH

O

OH

Hydroxamic acidCR NH

O

O C R1

O

Acyl derivative of hydroxamic acid

OH-

CR N

O

O C R1

O

CR N

O-

O C R1

O

C N RO + CR1

O

O-

H2O

NH2R+CO2

This is another variation of Hofmann rearrangement. The only difference

between Hofmann and Lossen rearrangement is that in later case the acyl derivative is

decomposed in presence of a base and the leaving group is carboxylate anion rather

than halide ion as in Hofmann rearrangement.

Lossen rearrangement has less synthetic importance due to non availability of

hydroxamic acids readily. Hydroxamic acid itself may undergo Lossen rearrangement

by the action of strong inorganic acids to primary amine.

CR NH

O

OH

Hydroxamic acid

HClCR NH

O

OH2

+- H2O

CR N+-H

O- H+

CR

O

:N:

N RCO

H2O

NH2R+CO2

Isocyanate1o amine

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Molecular Rearrangements