Molecular rearrangement

Prof. Rakesh D. Amrutkar
Assistant Professor
10/15/2019 1
Mahatma Gandhi Vidyamandir's
Samajshri Prashantdada Hiray College of
Pharmacy, Malegaon

CONTENTS :
Molecular Rearrangement
Classification of Molecular Rearrangement
Carbonium ion /Carbon deficiency Rearrangement
Pinacole –Pinacolone Rearrangement
Wagner-meerwein rearrangement
Benzilic acid rearrangement
Wolf rearrangement
Nitrogen deficiency Rearrangement
Schmidt Rearrangement
Curtius
Hoffmann
Beckmann
Lossen
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REARRANGEMENT REACTION
The reactions which proceed by a rearrangement or
reshuffling of the atoms groups in the molecule to
produce a structural isomer of the original
substance are called Rearrangement reactions.
Most are migrations from an atom to an adjacent
one (called 1,2-shifts),but some are over longer
distances.
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Classification :
Intermolecular rearrangement :
Reactions which involve migration of group between two
molecules.
 In which the migration group gets completely detached and is later on
reattached are called intermolecular rearrangements.
Eg :Aromatic rearrangements
Intra molecular rearrangement :
Reactions which involve rearrangement with in the same molecule
Those rearrangements in which the migration group is never fully
detached from the system
Eg: Nucleophillic rearrangement
Electrophillic rearrangement
Free radical rearrangement
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C C
X
Y
C C
X
B
C
B
C
X
INTRAMOLECULAR
CYCLIC INTERMEDIATE
-Y
C C
X
Y
C C
B
C
B
C
INTER MOLECULAR
-Y
X
-X
C
B
C
X
+X-
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NUCLEOPHILLIC REARRANGAMENT :
 Migrating group migrating towards electro defficient atoms.
ELECTROPHILIC REARRANGEMENT:
migrating group migrates towards electron rich centre.
FREE-RADICAL REARRANGEMENT:
 those reactions in which migrating group moves to a free-radical centre.
AROMATIC REARRANGEMENT:
Migrating towards aromatic nucleus.
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NUCLEOPHILIC REARRANGEMENT
Migrating group migrates from a carbon atom to an adjacent electron
deficient atom which is generally C, N, O.
rearrangement to electron deficient CARBON atom(carbonium ion
rearrangement)
Eg: Pinacole-pinacolone rearrangement
rearrangement to electron deficient NITROGEN atom
E.g.: Schmidt rearrangement.
Hofmann rearrangement
rearrangement to electron deficient OXYGEN atom
E.g.: Baeyer villager reaction
Cumene hydroperoxide rearrangement
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CARBONIUM ION REARRANGEMENT:
 In this case electron deficient atom is carbon the
intermediate is known as carbonium ion rearrangement.
And the reaction of this class is known as carbonium ion
Rearrangement.
with change in c-skeleton with out change in skeleton
E.g.; Pinacole-pinacolone rearrangement E.g.: allycyclic rearrangement
Wolf rearrangement
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PINACOLE-PINACOLONE REARRANGEMENTS
 The conversion of pinacols(1,2-glycols) to ketones or aldehydes means
of acids is known as pinacol rearrangements.
MECHANISM :
The reaction involves four steps:-
 1. protonation of hydroxyl group
 2. Loss of water to form a carbocation
 3. 1,2-shift of :H, :R or : Ar to form a more stable cation
 4. Loss of H+ to form the final product
CH3
CC
OH
CH3H3C
CH3
OH
2,3-DIMETHYL-2,3-BUTANEDIOL
(PINACOL)
CH3
CC
O
CH3H3C
CH3
METHYL t-BUTYL KETONE
(PINACOLONE)
H2SO4
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Mechanism:
.
H3C
CC
OH
CH3H3C
H3C
OH
H3C
CC
OH
CH3H3C
H3C
OH2
H3C
CC
OH
CH3H3C
H3C
H3C
CC
OH
CH3H3C
CH3
H3C
CC
OH
CH3H3C
CH3
H3C
CC
O
CH3H3C
CH3
H
(1)Step
-H2O
(2)step
(3)step
-H+
(4)Step
Carbocation( 3*)
rearranged protonated ketone
Pinacol
Pinacolone
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FEATURES OF PINACOLE REARRANGEMENT:
1).Stability of carbonium ion:
 when there is a choice as which hydroxyl group will be
preferentially removed i.e.,when two oh groups are different
then that oh group will be removed which produces the more
stable cation
C6H5 C
OH
C6H5
C CH3
CH3
OH
C6H5 C
OH
C6H5
C CH3
CH3
C6H5 C
C6H5
C CH3
CH3
OH
C6H5
C6H5
C CH3
OCH3
3,3-diphenylbutan-2-one
2-methyl-1,1-diphenylpropane-1,2-diol
less stable
more stable
alkyl migration
H
-H2O
H
-H2O
-H+
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2).MIGRATORY APTITUDE:
When each of the carbon atoms of the glycol as an aryl and alkyl group, the more Nucleophilic (potentially
electron-rich) aryl group preferentially migrates.
C6H5
CC
OH
CH3H3C
C6H5
OH
CC CH3H3C
C6H5
OC6H5
migration of
phenyl group
2,3-diphenylbutane-2,3-diol 3,3-diphenylbutan-2-one
When the migratory competition is between two aryl groups, then the one
which Is better nucleophile (more powerful electron donor towards carbon)
migrates Preferentially.
TOL
CC
OH
C6H5C6H5
TOL
OH
CC
TOL
C6H5C6H5
TOL
O
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3) INTRA MOLECULAR MIGRATION:
The migrating group migrates with in the molecule, that is it
never becomes free from the rest of the molecule as it retains
its configuration in the product.
4) TRANS MIGRATION:
The migrating group migrates to the opposite side of the
leaving group which has important consequences in alicyclic
system
10/15/2019 13

CH3 - C = CH2 CH3 - C - CH2Cl CH3- C -CH2OH
CH3 - C - C =O
CH3
CH3 CH3
CH3 H
H
Cl2
Moist
Ag2O
H
Dimethyyl acetaldehyde
(Isobutaraldehyde)
Cl OH
Isobutylene
APPLICATIONS:
1.SYNTHESIS OF CARBONYL COMPOUNDS FROM ALKENES
Isobutyraldehyde may prepared on large scale from isobutylene
10/15/2019 14

O
EtONa
CH3NO2
H NaNO2+HCl
5c
-N2
O
-H
HO CH2NO2 HO CH2NH2
HO
CH2 - N N HO CH2
2.RING EXPANSION OF CYCLIC KETONES
Cylohexanone can be converted to cycloheptanone in good yield
cycloheptanone
10/15/2019 15

Ph Ph
OHOH
O Ph
Ph
-H
O
O
OH OH
H
7,8-Diphenylacenaphthene
7-Oxo-8,8-diphenylacenaphthene
Cyclopentanone
pinacol
1.Mg,ether
2.H2Oa
2
1.
3.KETONES FROM CYCLIC DIOLS
Pinacol rearrangement has been employed to prepare ketones which are otherwise
Inaccessible to synthesis
10/15/2019 16

Benzillic acid Rearrangement
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10/15/2019 R.D.Amrutkar SPH Pharmacy,Malegaon 18
1) A hydroxide anion attacks one of
the ketone groups.( nucleophilic addition ).
2) Alkyl group attack on the second carbonyl group in
a concerted step with reversion of the hydroxyl group
back to the carbonyl group.
3) This sequence resembles a nucleophilic acyl
substitution.

 The reaction is a representative of 1,2-rearrangements. These
rearrangements usually have migrating carbocations but this
reaction is unusual because it involves a migrating carbanion.
 A hydroxide anion attacks one of the ketone groups in
 1 in a nucleophilic addition to the hydroxyl anion
 2. The next step requires a bond rotation to conformer
 3 which places the migrating group R in position for attack on
the second carbonyl group in a concerted step with reversion of
the hydroxyl group back to the carbonyl group.
10/15/2019 19
 The carboxylic acid in intermediate 4 is less basic than
the hydroxyl anion and therefore proton transfer takes
place to intermediate 5 which can be protonated in
acidic workup to the final α-hydroxy–carboxylic acid 6.

Migrations to Electron-Deficient Carbons
Wagner-Meerwein Rearrangements
1,2-Shifts of migrating groups to empty orbitals in carbo-
cations or toward partially empty orbitals in developing
carbocations are the most common rearrangements of
organic molecules. Especially, migration of hydrogen atom
or alkyl or aryl groups in carbocations are called “Wagner-
Meerwein Rearrangements”

Wagner Meerwein : Tert-amyl & Neo- pentyl
comp.
alcohol, halide
Highly branched : Sub, Add, elim. i.e. Dehydration,
dehydrohalogenation
H2
CC
CH3
H3C
CH3
H+
OH C
H
CH3C
CH3
CH3
2-methylbut-2-ene
2,2-dimethylpropan-1-ol
H3C C
H
C CH3
CH3
CH3 Cl
ZnCl2
3-chloro-2,2-dimethylbutane
H3C C
H
C CH3
CH3
Cl CH3
2-chloro-2,3-dimethylbutane

Mechanism: 1) Formation of Carbonium ion by protonation
2) Rearrangement of Carbonium ion
3) Migration of Nucleophiles
4) Deprotonation

10/15/2019 23
Wolf Rearrangement

Wolff : α-diazoketones upon treatment with silver oxide and water gives carboxylic acid
C
N
N
H
O
Diazoacetophenone
Ag2O,H2O
-N2
C
OH
O
Phenyl acetic acid
C
N
N
H
O
Diazoacetophenone
C
N
N
H
O
-N2
C
H
O
-keto carbene
O
Oxirene
C
H
O
-keto carbene
C
O
H
Ketene
OH
C
O
H
OH
Mechanism

Migration to N+
N
O
R
X
- X
O C N R
Isocynate
X = Br Hoffmann
X = Curtius& Scmidt
X = OCOR Lossen
X = OH Beckmann
N N

Curtius :Acyl azide to isocynate to amine
O C N R
Isocynate
Acyl azide
O
N3R
Heat
-N2
O C N R
Isocynate
O
NR N N
O
NR N N
O
NR
+ N2
Mechanism

Hoffmann :Amide to amine with one carbon less
O
NH2R
+ NaOBr
Amide
Sodium hypobromite
NaOH + Br2
R NH2 + 2NaBr + Na2CO3 + H2O
Amine with 1C less
O C N R
Isocynate
O
NH2R Br Br
O
N
H
R
Br
NaOH
O
NR
Br
O
NR
Hydrolysis
R NH2 + CO2

Lossen: Decomposition of Hydroxamic acid
to primary amine by using base.
O
N
H
R OH
OH-
R NH2
+ CO2
Hydroxamic acid Primary amine
O
N
H
R O
Hydroxamic acid derivative
Ar
O
KOH
O
NR O Ar
O
O Ar
O
O
NR
CO N R
Isocynate
R NH2
Primary amine
H2O
Mechanism

Beckmann:Oxime to amide
R'
NR
OH
Oxime
R R'
O
H2N OH
Ketone
Hydroxyl amine
H+
R
H
N
O
R'
Amide
H2SO4, H3PO2,P2O5,SOCl2,PCl5
C
R'
N
R OH
H+
C
R'
N
R OH2
-H2O
C
R'
N
R
C N
R
R'
H2O
C N
R
R'
OH
C NH
R
R'O
-H+
Mechanism

Features: 1) Trans migration, Stereospescific
2) Acyl derivative of oxime
3) Rate of reaction depends upon ionization rate of acyl derivative
4) The migrating “C” retains configuration.
5) Breaking of C-C and Formation of C-N bond occurs synchronously
6) Not intramolecular reaction, Carbonium ion forms and then attack
of hydroxyl ion. i.e complete loss of oxime “O”
C N
Ph
Ph
OH
P
Cl
Cl
Cl Cl
Cl
Phosphoruspentachloride
C N
O
P
Cl
Cl
Cl
Cl
-OPCl4
C N
Ph
H2O
C N
HO
-H
H
C NH
O

SCHMIDT REARRANGEMENT
 Carboxylic acids react with hydrazoic acid in presence of concentrated
sulphuric acid to give amine directly, the reaction is known as Schmidt
reaction.
 RCOOH+N3H H2SO4 R-NH2 +CO2+ N2
 Schmidt reaction also occurs between ketones or
aldehydes and hydrazoic acid.

RCHO
ALDEHYDE
HN3
H2SO4
RCN
CYANIDE
RNH.CHO
N-formyl derivative of
amine
RCONHR N2
H2SO4
N3HR2COR
ketones amides
Ketones Substituted amides
Aldehydes Nitriles & N-formyl derivatives
10/15/2019 31

Mechanism:
 Mechanism involves following steps:
 1.elimination of nitrogen.
 2.formation of intermediate.
 3.intermediate undergo rearrangement to form isocyanate.
 4.hydrolysis of isocyanate to form amine & co2
Transformation occurs more rapidly with out heating
with sterically hindered acids(mesitoic acid)
10/15/2019 32

MECHANISM:
R-C
O
OH
H+
R-C
OH
OH
N3H C
OH
OHR
NH N N
H2O
R C
O
NH N N
N2
C
O
N R
ISOCYANATE
H2O
H2NR + CO2
R
C
O
N H
H+
PRIMARY AMINE10/15/2019 33

The reaction with acids i.e.benzoic acid,which require heating for the removal
of nitrogen from acid azide proceed as below
C
OH
R
O
H2SO4
H+
R C
O
OH2
R C
O
H2O
10/15/2019 34

 REACTION WITH KETONES:
R
C
R
O
H+
R R
C
HO
N3H
R C
OH
R
NH N N
H2O
R
C
R
N N N
N2
R
C
R
N
C
NR
R
H2O
H2O+
C
NR
R H+
C
O
R
NHR
KETONE
AMIDE
10/15/2019 35

 MECHANISM FOR ALDEHYDES:
H
C
O
R
H+
H
C
R
HO
N3H
H C
OH
R
NH N N
H2O
H C R
N N N
N2
IF R MOVES
H C R
N
H C
NR
H2O
H C
O
NHR
FORMYL DERIVATIVE OF PRIMARY AMINE
aldehyde
10/15/2019 36

 IF ‘H’ MOVES:
H
C
N N N
R
N2
H
C
R
N
C R
NH
R C N
CYANIDES
H+
10/15/2019 37

APPLICATIONS:
 PREPARATION OF AMINES:
 Primary amines are obtained in good yield directly from acids.
 a)
 b)
C6H5CH2COOH N3H
H2SO4
CHCL3
C6H5CH2NH2 N2 CO2
phenyl acetic acid benzyl amine
O
HO
p-toluic acid
CH3 N3H H2N
p-toluidine
H2SO4 NH2
10/15/2019 38

PREPARATION OF  AMINOACIDS:
H3C CO C
H
R
COOC2H5
alkyl aceto ester
N3H
H2SO4
CH3CO NH C
H
R
COO
acidic hydrolysis
H2N C
H
R
COOH
+ CH3COOH
ACITIC ACID
+ C2H5OH
ETHYL
ALCOHOL
C2H5
10/15/2019 39

• PREPARATION OF LACTONES:
• Cyclic ketones react to give lactones
+ N3H
H2SO4
O H
C
NH
O
Cyclohexanone caprolactam
10/15/2019 40

Rearrangements to electron deficient oxygen atom
Bayer Villager oxidation: Oxidation of ketone to ester in
presence of peracid
C
O
R'R
Ketone
+ C
O
OR
O
H
Peracid
C
O
OR
R'
Ester
C
O
C2H5H3C
Acetone
+ C
O
OH3C
O
H
Peracetic acid
C
O
OH3C
C2H5
Ethyl ethanoate
O
cyclohexanone
O
O
O
H
Perbenzoic acid
O
O
oxepan-2-one
(Caprolactone)

Oxidizing agent :
Peroxytrifluroacetic acid , Permonosulphuric acid (Caro’s acid),
Perbenzoic acid, Peracetic acid , BF3-H2O2
Mechanism
C
O
R R'
H+
C
OH
R R'O
Ph O
O
R
C
R'
OH
O
O
Ph
O
CR
OH
OR'
Carbonium
CR
OH
OR'
Oxonium
- H
O
OR
R'
Migratory aptitude:
Tert-alkyl> Sec-alkyl, aryl, benzyl> pri-alkyl> methyl

Condensed cyclic ketone, migration of lesser aptitude group
takes place and forms abnormal lactones'
H3C
CH3
O
30
10
H3C
CH3
O30
10
H3C
CH3
O
30
10
O
O
94%6%
+
Apocamphor
Lactone lactone
RCOOOH
Why?
Due to steric interaction Bulky per acid molecule
attacks carbonyl group from the side
apposite to bridge. Migration of bridge ‘C’ forms
twisted boat, if 10 ‘C’ forms Chair form

Dakin oxidation :
The replacement of aldehyde group of o/p- hydroxyl or
o-amino Benzaldehyde by hydroxyl group
in presence of alkaline hydrogen peroxide
H
OH/NH2
O
o-hydroxy/amino benzalldehyde
Alkaline
H2O2
OH
OH/NH2
Catechol/o-aminophenol
Note: This is only for aromatic Aldehyde /Ketone
having o/p –OH/NH2

H
OH/NH2
O
o-hydroxy/amino benzalldehyde
Alkaline
CH
OH/NH2
Catechol/o-aminophenol
O
O
H
O
O
O
H
- OH
C
H
OH/NH2
O
O
OH/NH2
O
- HCOOH
OH/NH2
OH
CHO
OH
OCH3
H2O2
-vanillin
OH
OH
OCH3
Pyrogallol

 Reactions & Reagents By O.P.Agarwal Published by Krishna
Prakashan Media, Pg.No. 514 to537.
 Advanced organic chemistry by Jerry march,4th Edition,
Published By John Willey & Sons Pvt.Ltd. Pg. No. 1051 to1157
 Reactions and rearrangements by S N Sanyal, 4th Edition
Published By Bharati Bhawan, Pg. No.158 to 172
 Adavanced organic chemistry by Bhal and Bhal , Published
By Chand & Company Ltd. Pg. No. 98
 Reactions and reagents By G.R.Chatwal Published by
Himalaya publishing house, Pg. No.702 to717 &731 to 732.
REFERENCES
10/15/2019 46

Molecular rearrangement

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