Molecular Rearrangements

Organic Chemistry (SEM lV)

Prepared by

Dr. Kalipada Bankura

Department of Chemistry
Tamralipta Mahavidyalaya
 Molecular Rearrangements

• Rearrangment reactions are an interesting class of reactions wherein a group or

an atom migrates during the course of the reaction. While most of the
rearrangements are designed in that fashion, it can also be undesirable in some
cases. Depending on the reaction conditions, the nature of rearrangement (and
the product) could also change.

Migrating Migrating Migrating

• Rearrangement reactions involve Group Origin Terminus
the migration of a group or an
atom from one center (migration
origin) to another (migration A B
terminus) within the same
B C C A
molecule. Rearranged product
 Crossover Experiments
The purpose of crossover experiment is to determine whether the given reaction
takes place intermolecularly or intramolecularly i.e. whether reactant break apart
to form intermediates, which diffuse away into solution before they combine to
give product.
In this experiment two substrate differing in substituent are mixed together and
are reacted under the same reaction condition and the product obtained is
analyzed.
Illustration for cross-over experiments:
Consider, a simple reaction in which A-B
reacts to give C-D.
There are two possible of outcomes for the above reaction, as A, A* are
differently substituted (so are B and B*).
One in which no crossover of substituent is seen. This is possible if reaction is
intramolecular.
The other possibility is that a mixture of products are obtained in the crossover
reaction. This is possible in the case of intermolecular reaction.
Rearrangement reactions can be roughly classified on the basis of
the migration origin and migration terminus.

1. Rearrangements to Electron Deficient Carbon

2. Rearrangements to Electron Deficient Nitrogen
3. Rearrangements to Electron Deficient Oxygen
4. Sigmatropic Rearrangements
5. Other Rearrangements
Rearrangements to Electron Deficient Carbon

1. Wagner-Meerwin Rearrangement
2. Pinacol-Pinacolone Rearrangement
3. Demjanov Rearrangement(Tiffeneau- Demjanov)
4. Benzil-Benzilic acid Rearrangement
5. Wolff Rearrangement(Arndt-Eistert Synthesis)
6. Dienone-Phenol Rearrangement

N.B: All these rearrangements are discussed in classes

Rearrangements to Electron Deficient Nitrogen

1. Beckmann Rearrangement
2. Hofmann Rearrangement
3. Curtius rearrangement
4. Lossen Rearrangement
5. Schmidt Rearrangement
 Beckmann Rearrangement
The industrial formation of nylon relies upon the alkaline polymerization of a
acyclic amide known as caprolactam

Mechanism: • Follows the same pattern as pinacol

• Converts the oxime into a good leaving group
• Alkyl/ Aryl group migrates on to nitrogen as
water departs
• The product cation is then trapped by water to
give an amide
• It can also works with acyclic oximes
• PCl5, SOCl2 & other acyl or sulfonyl chlorides
can be used instead of acid
Caprolactam can be produced by the
action of sulfuric acid on the oxime of
cyclohexanone in a rearrangement
known as the Beckmann
rearrangement
In case of unsymmetrical ketone:
➢ There are two groups that could migrate
➢ There are two possible geometrical isomers of unsymmetrical oxime
➢ When the mixtures of geometrical isomer of oximes are rearranged,
mixtures of products result
➢ Interestingly, the ratio of products mirrors exactly the ratio of
geometrical isomers in the starting materials
➢ The group that has migrated, is trans to the -OH group
 Hofmann rearrangement
When an unsubstituted amide is treated with sodium hypobromite, corresponding primary
amine with one carbon less is produced. This reaction involves Hofmann rearrangement.

Reaction R in this
reaction can be
Mechanism alkyl or aryl.
In the first step, base removes a proton from amide.
The conjugate base of amide thus formed reacts with
bromine to give N-bromoamide. Acidity of proton on
nitrogen is increased by this bromine atom and its
removal becomes easy toward generating nitrene
intermediate (in which nitrogen is electron deficient).
1,2-shift of alkyl group in this nitrene intermediate
gives corresponding isocyanate. This isocyanate on
hydrolysis gives primary amine with one carbon less
than starting material.

Other Examples
When methanol is used as a
solvent instead of water,
then the corresponding
carbamate ester can be
obtained.

When optically active α-

phenylpropionamide undergoes
Hofmann degradation, α-
phenylethylamine of same
configuration and optical purity is
obtained i.e. rearrangement
proceeds with retention of
configuration.
 Curtius rearrangement:
In Curtius rearrangement, acyl azide are pyrolysed into isocynate which
can be hydrolyzed to corresponding amines. Curtius rearrangement is
catalyzed by protic or Lewis acids. Mechanism is similar to that of Hofmann
rearrangement.

However, there is no evidence

of existence of free nitrene.
These two steps may be
concerted.

In a similar reaction, alkyl azides

provide imines.
R may be alkyl, aryl or hydrogen. In the case of tertalkyl azides, there
is evidence of existence of nitrene.
 Cycloalkyl azides can yield ring expansion.

Aryl azides can also give ring expansion on

heating.

Home work: (Propose a mechanism for the

following reaction)
 Lossen rearrangement:
O-acyl derivatives of hydroxamic acids on heating with a base concerts to the
corresponding isocyanate. This reaction is known as Lossen rearrangement. The
isocyanate thus produced can be further hydrolyzed to corresponding amines.

Reaction

Mechanism

Other Examples
 Schmidt rearrangement
Reaction of carboxylic acid or aldehyde or ketone with hydrazoic acid in the
presence of mineral or Lewis acid to give corresponding primary amine or amide is
known as Schmidt rearrangement.

Cyclic ketones give lactams.

Mechanism is similar to that of Curtius
rearrangement, except that protonated azide
undergoes molecular rearrangement.

In reaction with ketone,

ketone is activated by
protonation for nucleophilic
addition of azide group to it.
In the case of alkyl aryl ketone, the aryl
group migrates preferentially except for
bulky alkyl group. Intramolecular Schmidt
reaction can be used for the preparation of
bicyclic lactams.
Example 1 Example 2 Reaction of tert-alcohol (e.g.1) or
olefin (e.g., 2) with hydrazoic acid
under acidic condition to give
substituted imines is also a form
of Schmidt rearrangement
Mechanism of the reaction is as follows. olefin
tert-alcohol
Rearrangements to Electron Deficient Oxygen

1. Baeyer Villiger Oxidation

2. Cumene hydroperoxide phenol
3. Dakin Reaction
 Baeyer Villiger Oxidation
In Baeyer-Villiger rearrangement, ketone on treatment with peracid gives ester
by oxyinsertion. Reaction is catalyzed by presence of acid catalyst. Reaction is
particularly useful for synthesis of lactones.
Reaction:
Mechanism

First step is the addition of peroxy acid to the carbonyl carbon leading to a tetrahedral
intermediate. In next step, a concerted migration of the migrating group and loss of carboxylic
acid provides the product.
The mechanism is supported by fact that oxidation of Ph2C18Oyields only PhC18OOPh (i.e. there is
no scrambling of 18O label in the product Ester.)
The loss of carboxylates and migration of R is concerted, as the reaction is known to be faster
when electron withdrawing substituents are present in the leaving group and electron donating
substituents in migrating group.
 If the migrating group is chiral then its stereochemistry is retained.
Migratory aptitude in unsymmetrical ketones is as, 30 > cyclohexyl> 20 > benzyl >
aryl > 10 > methyl. In case of aryl group, migrating ability is increased by electron
donating groups present on ring.

Migration is favored when migrating

group is antiperiplanar to the O-O bond
of leaving group. This is known as primary
stereoelectronic effect. Antiperiplanar
alignment of lone pair of electrons on
O2with migrating group is termed as
secondary stereoelectronic effect.
In the case of unsaturated ketones epoxidation is
likely to be a competitive reaction. But, Baeyer-
Villiger rearrangement is favored because ring
strain can be relieved by oxy insertion and ring
expansion.
B.V.O. of Unsaturated Ketones: It is difficult to predict the outcome
There are three possibilities & it depends on-
1) Peracids can selectively epoxidize 1) Electrophilic nature of the ketone
2) Peracids can selectively carry out B.V.O 2) Nucleophilic nature of the alkene
3) Can carry out both reactions

➢ Tertiary group migrates in preference of

the secondary Group
➢ The alkene is not as reactive as expected
because of steric crowding

Starting material configuration is

retained in the product
Small ring ketones will
readily undergo B.V.O.
 Rearrangement of hydroperoxide
Hydroperoxides can be cleaved in the presence of protic or Lewis acid.
Reaction goes through rearrangement.

Mechanism

The important steps of the mechanism (a) Protonation of

peroxide and removal of a molecule of water (b) Simultaneous
shift of the migrating alkyl group to the electron deficient
oxygen to give a rearranged carbocation (b) formation of
hemiketal by the reaction of water, which then breaks down
to give alcohol and ketone. OOH

Alkyl group must be showing some sort of CH3

anchimeric assistance and the rearrangement O2 O
H+ H+/H2O
must be going through benzonium ion in case of heat
cumene hydroperoxide-phenol rearrangement. CH3
Cumene Cumene hydroperoxide Phenol
 Dakin Reaction
Benzaldehyde or acetophenone bearing hydroxyl substituent in the ortho or para
position proceed rearrangement to give catechol or quinol, respectively known as
Dakin Reaction. The reaction is performed in the presence of alkaline hydrogen
peroxide and the mechanism is similar to that of Baeyer-Villiger reaction.

Reaction

Mechanism: Examples:
 Aromatic Rearrangement
1. Migration from oxygen to ring carbon

➢ Claisen rearrangement
➢ Fries rearrangement

2. Migration from nitrogen to ring carbon

✓ Hofmann-Martius rearrangement (N-Alkylanilines )

✓ Fisher-Hepp rearrangement (N-Alkyl-N-nitrosoanilines )
✓ Bamberger rearrangement (N-Arylhydroxylamines )
✓ Benzidine-Semidine rearrangement (Hydrazobenzenes )
✓ Orton Rearrangement (N-Haloanilides)
✓ N-azo to C-azo rearrangement
 Claisen Rearrangement [3,3]-Sigmatropic Shift
It is a [3,3]-sigmatropic rearrangement with only carbon atoms except one
oxygen involved in a six membered transition state. Claisen Rearrangement are
of two types: 1) Claisen Rearrangement of Allylvinyl Ethers:

2) Claisen Rearrangement of Allylphenyl Ethers:

Mechanism
 If ortho position is blocked, rearrangement continues to give para-product.

Other Examples

2.
1.

3.
 Fries rearrangement
Aryl esters with Lewis acid undergo rearrangement to give ortho and paraketo
substituted phenols. The complex between the ester and Lewis acid gives an
acylium ion which reacts at the ortho and para positions as in Friedel-Crafts
acylation.
Reaction
Mechanism
A mixture of aryl esters I and II
reacted to form their corresponding
keto substituted phenols along with
crossover products III and IV.
Photo Fries
 Hofmann-Martius rearrangement
(Rearrangement of N-Alkylanilines)
N-alkylanilines in presence of acid at very high temperature rearranged to ortho
and para alkylated products.
Reaction

Mechanism
 Fisher-Hepp Rearrangement
(Rearrangement of N-Alkyl-N-nitrosoanilines)
The conjugate acid of the N-Alkyl-N-nitrosoanilines supply the
nitrosonium ion which reacts mainly at the para-position in intramolecular
fashion to give the p-nitroso product.
Reaction

Mechanism
 Bamberger Rearrangement
(Rearrangement of N-Arylhydroxylamines)

N-Arylhydroxyamines with acid undergoes rearrangement to give aminophenols.

In this rearrangement, the conjugate acid of the hydroxylamine undergoes
nucleophilic attack by the solvent.
Reaction

Mechanism

When para-position is already occupied ???

Hydrolysis followed by Dienone-phenol type of rearrangement occurs.
 Benzidine-Semidine Rearrangement
(Rearrangements of Hydrazobenzenes )
Hydrazobenzene undergos [5,5]-sigmatropic rearrangement in the presence of
acid to give Benzidines, Diphenyline and Semidines.
Structure of Benzidines

Reaction
Mechanism

Other Examples

1.

2.
 Orton Rearrangement
(Rearrangements of N-Haloanilides)
Treatment of N-chloroacetanilide with hydrochloric acid affords a mixture of
ortho and para-chloracetanilides in the same proportions as in the direct
chlorination of acetanilide.
Reaction

Mechanism
 Rearrangements of N-Aryldiazoanilines
N-Aryldiazoanilines undergo rearrangement in presence of an acid to produce
p-Aryldiazenylanilines. On treatment with acid, aryldiazonium ion is formed
from the conjugate acid of amine, which migrates to the para position almost
selectively.
Reaction

N-Aryldiazoaniline p-Aryldiazenylaniline

Mechanism
Text Books:

1. R.O.C. Norman and C. M. Coxon, Principles of Organic Synthesis, CRC Press,

New York, 2009.
2. B. P. Mundy, M. G. Ellerd, F. G. Favaloro Jr, Name Reactions and Reagents in
Organic Synthesis, Wiley Interscience, New Jersey, 2005.
3. J. March, Advanced Organic Chemistry, 4th ed, Wiley Interscience, Yew
York, 1992.

Acknowledgement:

The material has been developed with the help of different text books,
journal material and web help.
 Problems
A. Predict the major products in the following reactions with mechanism.
 Explain each of the following observations.
1. Cis- and trans-1,2- dimethylcyclohexane-1,2-diol give different products on treatment with concentrated sulfuric acid.
2. In the pinacol rearrangements of PhMeC(OH)-C(OH)PhMe and Ph2C(OH)-C(OH)Me2, a phenyl group migrates in the former case but a
methyl group migrates in the latter.

3. Compound given below does not undergo Pinacol-Pinacolone rearrangement.

4. Wolff rearrangement is used to prepare higher homologue of starting acid.
5. Pinacol rearrangement is used to prepare spiroketone.
6. Aldoximes are not suitable substrates for the Beckman rearrangement.
7. Fries rearrangement of Phenyl acetate gives o-hydroxy acetophenone at high temperature and p-hydroxy acetophenone at low temperature.
8. Ortho tolyl group is having less migratory aptitude than phenyl group in Benzil-Benzillicacid rearrangement.
9. N-Methyl benzamide does not give N-Methyl aniline when treated with Br2/NaOH whereas benzamide gives aniline under similar reaction
conditions.
10. Beckman rearrangement is used prepare synthetic polymer.
11. In the Claisen rearrangement of β-phenyl allyl ether, the allyl group migrates to the 1 position and not to the 3 position.
12. In Baeyer-Villiger rearrangement, t-butyl group migrates in preference to phenyl group.
13. In the Baeyer-Villiger rearrangement of compound 1 with PhCO3H, compound 2 is obtained and not compound 3.
Provide suitable reaction pathways for following transformations and justify your answer.