1

yMOLECULAR REARRANGEMENTS

A molecular rearrangement is a modification of the basic skeleton of a molecule that

undergoes chemical transformation. When induced and thus expected, this transformation
can be useful in synthesis. However, there are some molecular rearrangements that are
unexpected. It is therefore important to be familiar with aspects leading to
rearrangements.

1. Carbon to Carbon Rearrangements.

1.1 Pinacol Rearrangement.
The pinacol rearrangement is observed if vicinal tertiary diol is treated with acid
and affords water and a ketone of rearranged carbon skeleton. The reaction comes
from pinacol, 2,3-dimethyl-2,3-butanediol, one of the simplest diols that
undergoes the reaction.
OH OH O CH3
6N H2SO4
H3 C C C CH3 H3C C C CH3 + H2O
100oC
CH3 CH3 CH3
And in general:

OH OH O R

acid H2O
R C C R

R C C R +

R R R

Mechanism: 1,2-alkyl shift.

First, protonation of an alcohol forms a leaving group that generates a carbocation
(electron-deficient a C1). Migration of the alkyl group R from C2 to C1 transfers
the electron-deficiency to C2, where the alcohol function can stabilize it by
resonance:

OH OH OH OH2
H+ - H2O
R C C CH3 R C C CH3

R R R R
 2

H
OH O R

R C C CH3 R C C R Product

R R R

Example:
O
OH OH
H2SO4


a spiro derivative =
structure in which 2 rings
share only one carbon atom

With unsymmetrical pinacols, several points must be considered: which OH

group is removed?
- polar effects which will stabilize the cation will facilitate the release of
this OH group.

OH OH OH
C C CH3 acid
C C CH3

CH3 CH3
stabilised
by resonance
CH3 O

Ph C C CH3

Ph

- migration aptitude: which of the 2 groups will migrate when the groups
are different? In general: Ar>Alkyl>H.
Example:
OH OH

Ar1 C C Ar1 The aryl group with the greater

electron-releasing property is the
one that migrate.
Ar2 Ar2
 3

The leaving OH and the migrating group must be trans to each other:
H H
OH O

CH3 CH3 CH3

OH OH OH

cis isomer CH CH3 CH3

3
CH3 CH3

CH3
CH3
O
H
O

CH3
CH3 CH3
H
H3C
OH O

OH OH

trans isomer CH3

CH3
CH3

H3 C
O

ring contraction product

1.2 Wagner-Meerwein Rearrangement.

This rearrangement was first observed when methyl-t-butylcarbinol was heated
under acidic conditions, producing tetramethylethylene (a product of
rearrangement of the carbon skeleton). The expected product, t-butylethylene,
could only be obtained using neutral Al2O3:
CH3 CH3 OH CH3
H3C
Al2O3 H+
H3C C CH=CH2 H3C C CH CH3 C C

CH3 CH3 H3C CH3

 4

The rearrangement is well known in the hydrolysis of neopentyl derivatives:

CH3 CH3
H+ H3C C CH2
H3C C CH2OH H3C C CH2

CH3 CH3 CH3 CH3

neopentyl cation
tertiopentyl cation
(tertiary cation)
Solvolysis of neopentyl bromide affords a mixture of products arising from the
rearranged intermediate:
CH3 CH3

EtOH H3C C CH2 H3C C CH2 CH3

H3C C CH2-Br

CH3 CH3 CH3

CH2-CH3
Hof fmann less stable
elimination CH2 C
(minor) CH3
CH3
H
H3 C
Saytseff
H3C C CH2 C C more stable
CH3
H3C
CH3
OEt

H3 C C CH2-CH3

CH3

The driving force in this rearrangement is the formation of a stable carbocation.

Examples:

H+
OH
H+

camphene
isoborneol
 5

Cl
HCl

H3C
CH3
Mechanism:

H+

CH3
CH3 CH3

Cl

Cl-

H3C
H3C
Driving f orce: from 4-membered to
5-memebered ring; strain relief.

In an aromatic system, the driving force is the aromaticity of the resulting

product:

CH3 CH3 CH3

OH OH OH

H+

O O OH
H
 6

H H
O O

CH3 CH3

OH OH

O OH

H+

R R
R
R
H
O OH OH

- H+
H

R R R
R
R R
Driving f orce: the f ormation of an aromatic ring

The carbocation can be generated in different ways:

(i) from halides using Lewis acids:

CH3 CH3
AlCl3
CH3 C CH2-Cl CH3 C CH2

CH3 CH3

(ii) from alcohol under acidic conditions:

 7

CH3 CH3
H3O+
CH3 C CH2-OH CH3 C CH2

CH3 CH3

(iii) from alcohol by converting it into a good leaving group:

CH3 CH3 CH3

CH3 C CH2-OH Ts-Cl CH3 C CH2-O-Ts solvolysis CH3 C CH2

Base
CH3 CH3 CH3

(iv) from an alkene by protonation:

+
CH3 CH3
H+
CH3 C CH=CH2 CH3 C CH CH3

CH3 CH3

(v) from an amine by diazotization:

CH3 CH3 CH3
NaNO2/HCl -N2
CH3 C CH2 NH2 CH3 C CH2 N2 CH3 C CH2
0-5oC
CH3 CH3 CH3

In addition to carbon, hydrogen can also migrate in this rearrangement (proton

shift):

CH3 C CH2 CH3 C CH3

CH3 CH3

Migration aptitude: aryl groups have a higher migration aptitude as compared to

alkyl groups and hydrogen.
Aryl groups>alkyl groups>Hydrogen
decreasing migration aptitude.
Ex.: neophyl chloride undergoes solvolysis 100 times faster than neopentyl
chloride:
 8

Lewis acid
CH3 C CH2 Cl CH3 C CH2

CH3 CH3

CH3 C CH2

CH3 C CH2 CH3

The phenyl group is electron-rich and
CH3 can stabilise the cation by anchimeric
stabilised by resonance assistance; the new cation is tertiary.

Electron-donor groups have a higher migration aptitude:

pMeOPh>pMePh>Ph>pNO2Ph>Alkyl.

Wagner-Merweein rearrangement can be accompanied by ring expansion or

contraction:
Et Et H Et
CH3 CH3 CH3
C OH C O C
+
H
H
Et Et Et
strain relief
Et Et
Et
CH3 CH3 CH3
H+ Et
Et Et
 9

O
CH2NH2

HNO2
OH

NH2 OH
HNO2 CH2OH HNO2
CH2NH2

CH2

An interesting application of the Wagner-Meerwein rearrangement is the

conversion of tricyclic hydrocarbons to adamantane derivatives. All tricyclic
alkanes containing 10 carbons converted to adamantane by treatment with a
Lewis acid like AlCl3.

H2
AlCl3
catalyst

adamantane

AlCl3

AlCl3

1.3 Favorskii Rearrangement.

 10

This rearrangement is observed when α-halogenoketones are reacted with

alkoxide bases (R4O-) and forms carboxylic acids esters.

R2 R2
R1 C C R3 R 4O R4O C C R3

O X X = Cl, Br, I
O R1

If the base is OH- (or an amine), the corresponding acid (amide) is obtained.
Cyclic α-ketones give ring contraction products:

Cl
RO COOR

The reaction can also be carried out on α-hydroxyketones and α,ß-epoxyketones:

R2 R3 R2 R3

R1 HO HOOC C C R4
C C C

O R4 R1 OH
O

Mechanism:

H R2 R2

R5 R 4O R5
C C C R3 C C C R3

R5 O Cl R5 O Cl

R5 R2 R5 R2

R 4O
R6 R3 R6 R3

O OR4
O
intermediate can ring-open in 2 ways
 11

R5 R2 R5 R2

R6 C C R3 R6 C CH R3
R4OH

O C O C

OR4 OR4

This mechanism explains why the following 2 isomeric α-chloroketones lead to

the same product:

PhCH2 C CH2-Cl PhCH2CH2CO2H PhCH C CH3

O Cl O
The intermediate in both reactions is the same (phenylcyclopropane) and forms
the same opened anion, (the same):
PhCHCH2CO2R
Br H

H C C C R

Br O H H H
-dihaloketones
with an -H H H
Br R C=C
Br H R
OR' R'OOC
O unsaturated ester
H C C C R

H O Br
'-dihaloketones
with an -H
The mechanism can be proved by labeling experiments with 14C:
O *
2 * R
CO
* 1 2

* 5
Cl *
Af ter reaction, 50% of the label is f ound on the
carbonyl carbon, 25% on C2 and 25% on C5.

This result implies that the intermediate can open in 2 ways:

 12

O OR
RO2C

or
O OR
CO2R

Ketones that do not have an α-H also rearrange to give the same type of product.
This is usually called the quasi-Favorskii rearrangement.
e.g.:

Cl Ph Ph H
N CH3 HO- HCl
N CH3 N
Ph EtOH CH3
HOOC EtOOC
O Demerol
The mechanism does not involve a cyclopropanone intermediate and the
semibenzilic mechanism is in operation.

R2 R1 R2 R2
R4 O
R1 C C R3 R 4O C C R3 R4O C C R3

O Cl O Cl O R1

Another example is the ring contraction of α-halocyclobutanones which can be

catalyzed by H2O:

OH
O
O
HO
COOH

Br Br

1.4 Benzil-Benzylic Acid Rearrangement.

When treated with bases, α-diketones rearrange to give the salts of α-hydroxy
acids
 13

Ar'
HO
Ar C C Ar' Ar C COOH

O O OH

This rearrangement is so called because:

Ph

Ph C C Ph Ph C COOH

O O Benzil OH Benzilic acid

Mechanism:

Ar Ar
OH HO C C Ar'
Ar C C Ar' HO C C Ar'

O O O O O O

Ar Ar
H+ shif t H+
O C C Ar' HO C C Ar'

O OH O OH

Although generally refers to aromatic diketones, this reaction can also be applied
to α-keto aldehydes. If MeO- is used as base instead of OH-, the corresponding
ester is obtained directly. Use of RO-, (R=Et, tBu…) must be avoided as they
reduce benzyl to benzoin.
Related reactions:
Ph Ph
Ar-Mg-X +
Ph C C Ph Ph C C Ar H Ar C C Ph

O O O O O OH

1.5 Fritsch-Buttenberg-Wieckel Rearrangement.

is the transformation of 1,1-diaryl-2-haloethylenes to diarylacetylenes with strong
bases like RO-, NaNH2, and alkyl and aryllitiums.
 14

Ar H
C C OR' Ar C C Ar'
HOR
Ar' Br

Mechanism: in this process a hydrogen atom is removed from the carbon atom
with a base and the aryl group trans to the halogen migrates to form the acetylene.
The rearrangement can be stepwise or concerted:
Ar H Ar
C C base C C Ar C C Ar'
Ar' Br Ar' Br

1.6 Wolff Rearrangement

In this rearrangement, a diazoketone is transformed into a carboxylic acid
derivative via ketene:

- N2 H2O
R C CHN2 R C C O RCH2COOH

O H

The structure of the ketene is a resonance hybrid with the following important
contributing forms:

R C CH=N=N R C CH N N

O O

The Wolff rearrangement has been incorporated in a general sequence (called the
Arndt-Eistert synthesis), in which an acid is converted to its next higher homolog:

H2O/Ag2O
R C Cl CH2N2 R C CHN2 RCH2COOH
or h
O O
The first step in this reaction is the condensation of an acyl chloride with
diazomethane to form a diazoketone. The later undergoes, in a second step and
competing step, a Wolf rearrangement in the presence of silver oxide and water to
afford the acid.

- N2 Wolf f
R C CH=N=N R C CH

O O
 15

O C CH R H2O RCH2COOH
ketene
(can be isolated)

The intermediate ketene can be trapped by different nucleophiles to afford the

corresponding carboxylic acid derivatives:

EtOH
RCH2COOEt

R CH C O H2O
RCH2COOH
RNH2
RCH2CONHR

It is the best method of increasing a carbon chain by one if the carboxylic acid is
available.
CO2H COCl

SOCl2 + CH2N2
- HCl

COCHN2 CH2CO2H

1) Ag2O
2) H2O
-Naphthylacetic acid
45% overall

2 Carbon to Nitrogen Rearrangements.

2.1 Beckmann Rearrangement.
The Beckmann rearrangement is the conversion of oximes to N-substituted
amides under the influence of acids like H2SO4, SO3, PCl5, P2O5, BF3…

O O
R1
H+
C N OH C or C
R2 R1 NHR2 R2 NHR1

The main feature in this rearrangement is that in all cases, the leaving OH group
and the migrating group must be trans:
 16

OH O
R1
H+
C N C
R2 OH group trans to R2 R1 NHR2

R1 O
C N H+
C
R2 OH R2 NHR1
OH group trans to R1

Oximes are synthesized from aldehydes and ketones:

aldehydes aldoximes
Oximes
ketones ketoximes

Experiments conducted in H2O18 showed that the oxygen atom of the product
originates from the water and the product contains 50% of labeled O18. Migration
is intramolecular and occurs with retention of the migrating group configuration:

Ph O*
C N H2O*
C
Ph OH Ph NHPh
Benzophenone oxime Benzanilide

The mechanism can then be formulated as follows:

 17

Ph
C N H2O* Ph C N Ph H2 O H2O*
Ph O H

H
equal chance
O* Ph C N Ph
H H
nitrenium ion
H H H
*
O *
O O
+
Ph C N Ph - H Ph C N Ph Ph C NHPh

The synthesis of ε-caprolactam by the rearrangement of the oxime of

cyclohexanone is of commercial importance because the lactam is the
intermediate in the synthesis of a type of nylon:
OH NH
O N H2SO4
O

-caprolactam

O H
xn
catalyst C CH2CH2CH2CH2CH2-N
n
nylon-6

2.2 Hoffmann Rearrangement.

In this rearrangement an unsubstituted amide is treated with NaOBr (or a mixture
of NaOH and Br2) to give a primary amine that has one carbon less than the
starting amide:

R C NH2 NaOBr R-N=C=O

isocyanate
Hydrolysis R-NH2 CO2
 18

O O

R C NH2 Br2 R C NHBr

O
HO- O C N R
R C N Br

The isocyanate intermediate is very reactive to various nucleophiles and if HO- is

the nucleophile, a carbamate salt is obtained:

R N C O R N C O R N C O
-
HO
OH H O

O O
H+
RNH C O RNH C OH CO2 RNH2
carbamic acid amine
When an alcohol solvent is used, it acts as the nucleophile:
O
Br2/EtOH
CH3CH2 C NH2 EtN C O
Na OEt
OEt
O
EtN C O EtOH
RNH C OEt OEt
OEt Ethyl N-ethyl carbamate
80%

Sometimes, the amide as well as the amine formed in the reaction act as
nucleophiles:
O

RN C O RNH2 RNH C NHR

urea
 19

O O O

RN C O R C NH2 RNH C NH C R
Biuret (acylurea)

Imides react to afford amino acids:

NH2
NaOBr o-aminobenzoic acid
NH (or anthranilic acid)
CO2H

2.3 Curtius Rearrangement.

Curtius rearrangement involves the pyrolysis of acyl azides to yield isocyanates. It
is closely related to Hoffmann but more general and can be applied to almost any
carboxylic acid: aliphatic, aromatic, alicyclic, heterocyclic, unsaturated…

O
 R N C O N2
R C N3

Mechanism:
O O
- N2
R C N N N R C N O C N R

O O O
HNO2
R C X NaN3 R C N3 R C NHNH2

I the reaction is effected in inert solvents (benzene), isocyanates can be isolated.

e.g.:
O
Benzene CH3(CH2)10 N C O
CH3(CH2)10 C N3

81-86%

If water (or alcohol) is the solvent, the corresponding amine (carbamate) is

obtained:
H2O
R NH2
 20

O O O
R' OH
RNH C OR' or RNH C NH C R
or carbamate acyl urea
R NH2

2.4 Lossen Rearrangement.

The O-acyl derivatives of hydroxamic acids give isocyanates on heating or with
bases:
O O
OH H2 O R NH2
R C NH O-C R' R N C O

2.5 Schmidt Rearrangement.

This reaction involves addition of hydrazoic acid (HN3) to:
- carboxylic acids (most common);
- aldehydes and ketones;
- alcohols and olefins.

R C OH HN3 H2SO4 R NH2 CO2 N2

Mechanism:

O O O

R C OH H+ HN3
R C N N N
R C

H
N2 hydrolysis CO2
R N C O R NH2

The reaction with ketones is similar to the Beckmann rearrangement:

O O
H+
R C R' HN3 R C NH R'
O
(insertion of NH into the C R' bond)
Examples:
 21

O
O

HN3 NH
H+

H
N N N

R C R' H+ HN3
R C R' - H2 O
R C R'

O OH OH
H H
N N NH O
- N2 H2O
R C R' R' C N R' R' C N R'

H
O O
tautomerism
R' C N R' R' C NH R

With aldehydes, nitriles are formed:

HN3
R-CHO R-CN
H+

With alcohols and olefins, azides are formed, which upon hydrolysis lead to
imines:
R
R
R C R HN3 - N2
R3C-N3 C N R
H + 
OH R

Disadvantages of the Schmidt rearrangement: harsh conditions are required to

effect the desired conversion.
Advantages: direct conversion of carboxylic acids into amines in one step.
e.g.:
CH3(CH2)16CO2H HN3
CH3(CH2)16NH2 CO2 N2
+
Stearic acid H , H2O Heptadecylamine

Summary:
 22

O
Hof f mann
R C NH2

Curtius R C N3
RCOOH
R N C O
O H O
Lossen
R C N-O-C-R'

Schmidt HN3
H2SO4

3 Carbon to Oxygen Rearrangements.

3.1 Baeyer-Villiger Rearrangement.

Treatment of Ketones with a peroxy acid (or a peracid) gives esters by “insertion”
of oxygen.
O O O

R C R' Ph C O OH R C O R'
Perbenzoic acid

The most common reagent used in this transformation is m-chloroperbenzoic acid

(mCPBA):
Cl

OH
O
C
mCPBA
O

But other peracids or peroxy acids (like peracetic acid) can be used too. A
particular good reagent is perfluoroacetic acid.
The reaction is often applied to cyclic ketones to give lactones.
Examples:
 23

O
O

O
O
CH3C-O-OH
40oC, 6 hrs

90%

CH3C-O-OH
CHCl3, 56%
O
O O
Attack occurs at the carbonyl rather than at the C-C bond.
For unsymmetrical ketones, the approximate order of migration is:
Hydrogen>tertiary alkyl>secondary alkyl~phenyl>primary
alkyl>methyl.
Since the methyl group has a low migratory aptitude, the reaction provides a
means of cleaving a methyl ketone, R’COMe to produce an alcohol or phenol
R’OH (after hydrolysis of the ester R’OCOMe).
Diaryl ketones undergo oxidation with preferential migration of the more electron
realizing substituent, but the reaction is seldom used for preparative purposes. The
migrating ability of aryl groups is: pMeOPh->Ph->pNO2Ph-.
O O
CH3COOOH
C OMe C-O OMe

O O
C NO2 CH3COOOH O-C NO2

Enolizable ß-ketones do not react, but α-diketones lead to anhydrides:

O O O O

R C C R R C C R
O
-diketones anhydrides

With aldehydes, migration of hydrogen gives the carboxylic acids: migration of

the other group will produce the formats (rare).

Mechanism:
 24

O O O C R''

H+ R''CO3H R' C R
R' C R R' C R

OH OH

R' O
- H+ R'O C R
C R
O
OH

One important piece of evidence for this mechanism is that benzophenone-18O

gives the corresponding ester entirely labeled on the carbonyl oxygen, with no
label on the alkoxy oxygen:
O*18 O *18

Ph C Ph Ph O-C Ph

Some keones have been doubly oxidized to dialkyl carbonates by mCPBA:

O O

R C R R O C O R

3.2 Rearrangement of Hydroperoxides.

Hydroperoxides are cleaved by proton or Lewis acids in a reaction whose
principal step is a rearrangement:
R
R
+
R C O OH H
C O R OH
R
R

Migration aptitude: tertiary>secondary>propyl~hydrogen>ethyl>Me.

If aryl and alkyl groups are present, aryl migration predominates. The reaction can
take place when alcohols are heated with a mixture of H2O2 and an acid.

Mechanism:
 25

R R
H+ R C O R
R C O OH R C O OH2

R R R

OH2 R
H2 O +
R C O R C O R OH + H
R
R

e.g.:
CH3
H3C
CH
CH3
O2 H+
Ph C O OH

CH3
Cumene

CH3 O

Ph C O OH2 CH3 C CH3 Ph OH

Phenol
CH3

This is an industrial process and is more economical than:

Cl OH

NaOH
300oC, 150 atm

Chlorobenzene Phenol

3.3 McLafferty Rearrangement.

 26

Is in fact a fragmentation process affecting ketones possessing a γ-hydrogen atom;

they undergo a typical fragmentation in the mass spectrometer to produce an
alkene and a radical cation (that is observed on the mass spectrum).

CH3
H CH3
H
O C
CH3 O C
-
CH3
CH2 -e
(mass spectrometry) CH2
CH3 CH2
CH3 CH2
CH3
H H
O C CH3 CH3
CH3 O
C
CH2
CH3 CH2 CH3 CH2 CH2
m/z = 58
All arrows indicating one electron movement are half arrows (single headed)

3.4 Fries Rearrangement.

is an oxygen to carbon rearrangement that occurs when phenolic esters are heated
with Friedel-Crafts catalysts to produce acylated phenols.
O

O C OH
R

AlCl3
ortho isomer
R = alkyl, aryl

O R

Low temperatures generally favor the para position and high temperatures the
ortho product. Meta-directing substituents on the ring interfere with the reaction
as might be expected for a Friedel-Crafts process.

Mechanism: an initial complex is formed between the substrate and the catalyst so
that a catalyst to substrate molar ratio of at least 1:1 is required; then follows
intra- or intermolecular delivery of the acylium cation.
 27

ArO C R

O AlCl3

The reaction can be catalyzed by UV light and is then called photo-Fries

rearrangement. In this case, the mechanism is as follows:

*
ArO C R h ArO C R ArO C R

O O O

O OH

tautomerism
(aromatisation)

H R' R' = RCO

R'

4 Nitrogen to Carbon Rearrangements.

4.1 Stevens Rearrangement.

Quaternary ammonium salts containing an electron-withdrawing group (RCO-,
RO2C-, phenyl…) on one of the groups attached to the nitrogen react with strong
bases (such as NaOR, NaNH2…) to afford rearranged tertiary amines.

O CH3 O CH3

C6H5 C CH2 N CH3 Base

C6H5 C CH N CH3

CH2C6H5 CH2C6H5

O CH3

C6H5 C CH N CH3

CH2C6H5
The most common migrating groups are: allyl, benzyl, benzhydryl, phenacyl and
3-phenylpropargyl. When an allyl group migrates, it may involve an allylic
rearrangement within the migrating group.
 28

The Stevens rearrangement is intramolecular as shown by crossover experiments,

by 14C labeling and the retention of configuration at the migrating group.
Mechanism:
O R3 O R3

RO C CH2 N R2 Deprotonation RO C CH N R2
ylid (can be isolated)
R1 R1

O R3 O R3

RO C CH N R2 RO C CH N R2
radical pair in
R1
a solvent cage R1
O R3

RO C CH N R2

R1

The radical pair recombines rapidly to avoid racemization, and in some cases
small amounts of coupling products (R1-R1) have been isolated. If R1 is an allyl
group, the rearrangement can be concerted.

4.2 Benzidine Rearrangement.

Treatment of hydrazobenzene with acids produces about 70% of
4,4’-diaminobiphenyl (benzidine) and about 30% of 2,4’-diaminobiphenyl. This
reaction called benzidine rearrangement is general for N,N’-diarylhydrazines:
H H
H+ H2N NH2 H2N
N N

Benzidine H2N
(70%) 2,4'-diaminobiphenyl
(30%)
Three other by-products may be produced:
H
N

NH2
NH2 NH2 o/p-phenylanilines
2,2'-diaminobiphenyl (semidines)
 29

Benzidine is always the major product even if the para position is occupied. If
SO3H, CO2H, or Cl is present at para position, it may be ejected (but not R, Ar or
NR2).

Mechanism: the reacting species can be the monoprotonated intermediate

ArNH+2NHAr or the diprotonated substrate ArNH+2NH+2Ar:

H2N NH2 NH2 NH2 NH2 NH2

-2H

H H