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.
2 1
R R

1 4
C C (if R4 = H)
R R 3 5
R R
2
R C C OH 4
3 5
R
R R 2 1
R C C R (if R has an H atom)
3 5
R R

Initially a carbocation is formed and then rearrangement takes place as per the
mechanism given below.

1 4
R R
2 + 2 1
R C C R C C R
3 5 3 5
R R R R

1 4 4
H R R R
+ 1
H C C C H2C C C R
3 5 3 5
H R R R R

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.

H3C CH3

CH3 H2C
acid
OH

Isoborneol H3C
CH3 camphene
1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol 2,2-dimethyl-3-methylidenebicyclo[2.2.1]heptane

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D. Ilangeswaran, M. Sc., M. Phil., 1

 CH3 CH3
base
H3C C. CH2 Cl H3C C. .CH CH3
CH3
Br
AlBr3
H3C CH2 CH2 Br H3C CH CH3

mechanism AlBr3
AlBr4-
+ +
H3C .CH2 CH2 + AlBr4- H3C CH CH3

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 OH

acid

R
R R R

Mechanism

O OH OH OH
+
C
H+
H
+
C R R
R R R R R R
Cyclohexadienone
Phenol

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D. Ilangeswaran, M. Sc., M. Phil., 2

 Rarely, with an electrophile phenol undergo a reverse rearrangement, i.e.,
phenol to dienone rearrangement as follows.
OH O
Br Br Br Br
+ Br Br

Br 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.

2 2
R R
1 3 4 3
R C C R + OR - 4 R O C C R
1
O Cl alkoxide O R
haloketone ester

Mechanism
-
OR4

2 4 2 4 2
R OR R OR R
1 3 1 3 1 3
R C C R R C C R -
R C C R
-
- Cl
O Cl O Cl O
2
R
4 3
R O C C R
1
O R

Cyclic - haloketones give ring contraction when subjected to this reaction

conditions.
Cl
1
2
1
+ -
OR 2 COOR
O

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D. Ilangeswaran, M. Sc., M. Phil., 3

 This reaction has also been carried out on - hydroxy ketones and on , -
epoxy ketones.
2 3 2 3
R R R R
-
1 4 OH 4
R C. C C R HOOC C C R
O
O H OH
Mechanism HOH
-
OH - OH-
2 3 2 3 2 3
R R OH R R OH R R
1 4 1 4 4
R C. C C R R C. C C R C. C C R
O - O 1 -
O O O R O

There was another mechanism proposed for this rearrangement which is given
below.
2
2
R 5 2
H R R R
- 4 5 - 3
OR R C C R
5 3 R4O-
R C C C R 6
6 3
4
R Cl - Cl - R R
6 - R OH C C
R O Cl
O O

2 5 2 5 2
5 R R R R R
R
6 - 3 6 3
R C C R R4OH R C C R
6 3
R R
- 4 H
O OR
4 4
C OR C OR
O O

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.
acid H2O
RCOOH + HN3 R-N=C=O 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.

1
HN3 1
R C R R C NH R
+
H
O O

The mechanisms for these rearrangements are described below.

1. Addition with carboxylic acids.
H+ H
HN3 - N2
+ +
R C OH R C R C N N N
- H2O
O O O

H
+ H2O
R C N: O C N R H2N R +O C O
O Isocyanate

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

+
+ 1 HN3 H N N N
1 acid R C R
R C R 1
OH R C R
O - H2O
Ketone OH

+
N N N H2O
1 + 1
acid
1 R C N R
R C R R C N R
- N2 +
OH2

1 tautomerization 1
R C N R R C NH R
OH O 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.
1 1
R R H5 C6 OOH R OR
C C C
+
O O O

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.
O
1 2 1
R R 1 O O C R R O
C R R 2
R CO3H
acid + 1 + 1
C R C R C R R O C R
O - H+
2
- R CO 2- +
-H
OH OH OH O

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.
3 3
R R
NaNH2
+ 2 2
Z - CH 2 N R Z CH N R
1 1
R R
Quaternary ammonium salt 30 amine

The following type of radical pair mechanism has been proposed for this
reaction.
3 3 3 3 3
R R R R R
+ 2 NaNH2 - + 2 - 2 2 2
Z - CH 2 N R Z CH N R Z CH N R Z CH N R Z CH N R
1 1 . . 1
R R R1 R1 R

(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.
3 3 3
R R R
- + 2 + + 2 2
Z CH N R Z C N R Z CH N R
1 1
R R1(-) R

Solvent cage

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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"Li
R - CH2 - O - R' R - CH - O-Li+ + R''H
R'
Mechanism
- 1 - - -
R CH O R R CH O R CH O R CH O
. 1 . 1 1
R R R
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.
O O
2CH2N2
- +
R C Cl R C CH N N + CH3Cl + N2
- diazoketone
O
- + Ag2O
R C CH N N R CH C O
- N2
ketene

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 R'OH
RCH2COOR'
H2O
R CH C O RCH2COOH
ketene NH3
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
O
- N2
- +
R C CH N N R CH C O
Ag2O / ketene
- diazoketone

Mechanism for Photochemical Reaction

O O
- + h
R C CH N N R C CH R CH C O
- N2 ketene
- diazoketone

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

O COOMe
+
- N N
C h

CH3OH

O
COOH
+ -
Ag2O
N N
H2O / THF

Stereochemistry:
Wolf rearrangement occurs preferentially from the S – Z conformation of -
diazoketones.
1
R R

N2
O
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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 CH3 CH3 O CH3
i) SOCl2 i) Ag2O
- +
H5C2 C COOH H5C2 C C CH N2 H5 C 2 C CH2COOH
ii) CH2N2 ii) H2O
C6 H5 C 6 H5 C6 H 5
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.
O -
O O O O O O
1 OH- 1
R C NH OH 1
R C NH O C R R C N O C R R C N O C R
Hydroxamic acid Acyl derivative of hydroxamic acid

O
H2O
1 -
CO2 +R NH2 O C N R + R C O

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.
O O O O
HCl +
- H2O - H+
+
R C NH OH R C NH OH2 R C N -H R C :N:
Hydroxamic acid

H2O
CO2 + R NH2 O C N R
1o amine Isocyanate

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