This document discusses various rearrangement reactions in organic chemistry, categorizing them into intramolecular and intermolecular types. Key examples include the Wagner-Meerwein, Wolff, and Beckmann rearrangements, each with specific mechanisms and applications. The document highlights the importance of these reactions in synthesizing compounds like paracetamol and other pharmaceuticals.

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REARRANGEMENT REACTIONS
Submitted by:
Nitha Naveen Dsouza
1st
M Pharm
Pharmaceutical Chemistry

2. CONTENTS
1. Wagner-Meerwein rearrangement
2. Wolff rearrangement
3. Benzil-Benzilic Acid rearrangement
4. Beckmann rearrangement
5. Lossen rearrangement
6. Claisen rearrangement

3. REARRANGEMENT REACTIONS
 Broad class of Organic reactions where the carbon skeleton of a molecule is
rearranged to give a structural isomer of the original molecule.
 Migration of an atom or group of atoms takes place from one atom to an adjacent
atom within a molecule also known as 1,2-shift or from one molecule to another
molecule
 Mainly there are 2 types of rearrangements:
1. Intermolecular Rearrangements
2. Intramolecular Rearrangements
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4. Example for Intermolecular Fries rearrangement:
Example for Intramolecular Hoffman Rearrangement:
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OCOCH3
+AlCl3
O
H3C
O
AlCl3
OAlCl3
+
O
AlCl2
Cl
H
COCH3
OH
COCH3
CH3 CO
Phenyl acetate o-Hydroxyacetophenone
Primary Amide Primary Amine
R C
O
N
H
H
Br2 /OH
R C
O
N
Br
H
OH
R C
O
N Br R C
O
N O C N R R-NH2 + CO2
H2O

5. TYPES OF REARRANGEMENTS
1. Rearrangements involving migration to Electron-Deficient Carbon
- Wagner-Meerwein rearrangement
- Pinacol-pinacolone rearrangement
- Benzil-Benzilic Acid rearrangement
-Wolff rearrangement
2. Rearrangements involving migration to Electron-Deficient Nitrogen
-Hofmann Rearrangement
-Curtius Rearrangement
-Schmidt Rearrangement
-Lossen Rearrangement
-Beckmann Rearrangement
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6. 3. Rearrangements involving migration to Electron Deficient Oxygen
-Baeyer-Villiger Oxidation
-Hydroperoxide Rearrangement
-Dakin Reaction
4. Rearrangements involving migration to Electron-Rich Carbon
-Stevens Rearrangement
-Wittig Rearrangement
-Favorskii Rearrangement
5.Rearrangements involving migration from oxygen to ring
-Fries rearrangement
-Claisen rearrangement
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7. Rearrangements involving Migration to
Electron-Deficient Carbon

8. 1. WAGNER-MEERWEIN REARRANGEMENT
▪ The Wagner-Meerwein rearrangement is an organic reaction used to convert an
alcohol to an olefin using an acid catalyst.
▪ Occurs via an intermediate carbocation and involve the migration of alkyl
group with its lone pair of electrons to an electron-deficient carbon atom.
▪ These rearrangements commonly occur in terpenoids, where it involves change
in the ring structure.
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Alcohol Olefin

9. MECHANISM
I. Protonation of the alcohol by
the acid which is then
released as water to forms a
carbocation.
II. A 1,2-shift then occurs to
form a more substituted and
stabilized carbo-cation.
III. A final deprotonation with
water produces the final
olefin product and
regenerates the acid catalyst.
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H
H
(I)
(II)
(III)

10. EXAMPLE:
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2-methylbutan-2-ol
2-methyl-but-2-ene
2-methyl-but-1-ene

11. APPLICATIONS:
1. An acid-catalysed Dehydration of the natural product Camphenilol gives
the alkene Santene (a key component of the fragrance of sandalwood oil)
Mechanism:
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12. 2. Acid-catalysed Dehydration of Isoborneol to give Camphene.
Mechanism:
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migrate C4 from C5 to C6 to create tertiary cation

13. 2.WOLFF REARRANGEMENT
▪ Wolff-rearrangement is an organic reaction in which an α-diazoketone
undergoes rearrangement with elimination of a very stable nitrogen molecule
in presence of silver oxide to form a ketene accompanied by 1,2-alkyl shift.
▪ The α-diazoketones can be prepared by the reaction of acid chlorides with
diazo compounds such as diazomethane.
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Acid chloride
diazomethane

14. MECHANISM
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▪ When this rearrangement is carried out in presence of water, alcohol or amine, the
ketene is converted into carboxylic acid, ester or amide respectively.
▪ The overall reaction known as Arndt-Eistert Synthesis proposed in 1935.

15. APPLICATIONS
1. Arndt-Eistert reaction is useful for converting an acid, RCOOH into its
next higher homologue RCH2COOH.
2.
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COOH
SOCl2
CH2N2
COCHN2
Ag2O, H2O
CH2COOH
α-Naphthoic acid α- Naphthylacetic acid
3-methyl-3-phenylbutanoic acid

16. 3. Synthesis of Mescaline
Mescaline is considered a hallucinogen or psychedelic drug, that produces euphoria
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Mescaline
3,4,5-trimethoxybenzoyl chloride
COCl
H3CO
OCH3
OCH3
CH2N2
AgNO3-NH3
CH2CONH2
H3CO
OCH3
OCH3 H3CO
OCH3
OCH3
CH2CH2NH2
Zn-Hg.HCl
[H]

17. 3. BENZIL-BENZILIC ACID REARRANGEMENT
▪ α-Diketones (Benzil) undergo a base-catalysed reaction called benzil-benzylic
acid rearrangement.
▪ Benzil on treatment with KOH, followed by acidification yields benzilic acid.
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18. MECHANISM
1. Reversible nucleophilic addition of hydroxide ion to benzil
2. Resulting hydrate anion undergoes rearrangement: 1,2-phenyl shift
3. Proton shift to obtain resonance stabilized carboxylate anion.
4. Upon acidification, benzylic acid is obtained.
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(2)
(3) (4)

19. APPLICATIONS
1. The benzil-benzylic acid rearrangement is particularly useful for the synthesis
of citric acid from ketopinic acid.
2. Benzilic acid rearrangement of furil
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Ketopinic acid Citric acid

20. ▪ Benzilic acid rearrangement of 9,10-phenanthrenequinone
▪ Benzilic acid rearrangement of cyclohexane-1,2-dione
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21. Rearrangements involving Migration to
Electron-Deficient Nitrogen

22. 4. BECKMANN REARRANGEMENT
▪ The rearrangement of oximes under the influence of a variety of acidic reagents
to N-substituted amides is known as Beckmann Rearrangement.
▪ Phosphorous pentachloride – commonly used as a catalyst
▪ Conc. Sulphuric acid, polyphosphoric acid, formic acid, thionyl chloride are also
used.
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23. MECHANISM
1. Treatment of the oxime with acid generates a good leaving group.
2. Loss of the leaving group generates an electron-deficient species accompanied
by migration of a group.
3. The resulting iminocarbocation traps water to give an amide.
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(2)
(3)
Amide

24. STEREOCHEMISTRY
▪ Chiral groups migrate with retention of configuration
▪ The rearrangement is highly stereospecific since the group "anti-" (opposite) to
the oxime hydroxyl group migrates predictably.
Example: (+)-methyl-3-heptyl ketoxime is converted by rearrangement to (+)-3-
acetamidoheptane with retention of configuration.
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(+)-methyl-3-heptyl ketoxime (+)-3-acetamidoheptane

25. APPLICATIONS:
1. The Beckmann rearrangement reaction is used for the synthesis of
paracetamol (acetaminophen), benazepril, olanzapine and other medicines.
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4-hydroxyacetophenone
oxime
Acetaminophen

26. 2. Synthetically useful application is the synthesis of caprolactam from
cyclohexanone oxime.
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Cyclohexanone oxime Caprolactam Nylon

27. 5.LOSSEN REARRANGEMENT
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▪ The rearrangement of acyl derivative of hydroxamic acid to isocyanate, followed
by hydrolysis to corresponding amine is known as Lossen rearrangement
▪ Another variation of Hoffmann rearrangement
Acyl derivative of
hydroxamic acid
Amine

28. MECHANISM
1. Acyl derivative of hydroxamic
acid is decomposed in the
presence of base.
2. Loss of the carboxylate anion
3. Hydrolysis of isocyanate to
corresponding amine
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(1)
(2)
(3)

29. ▪ Even, the hydroxamic acid itself may undergo the Lossen rearrangement, by the
action of strong inorganic acids, to primary amine.
▪ Lossen rearrangement has little synthetic importance because hydroxamic acids are
not readily available.
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30. Rearrangements involving Migration
from Oxygen to Ring

31. 6.CLAISEN REARRANGEMENT
▪ Specific to allyl aryl ethers
▪ Heating to 200-250˚C leads to an o-allylphenol
▪ Result is alkylation of the phenol in an ortho position
▪ The pericyclic conversion of an allyl phenyl ether to an o-allylphenol by heating
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ArO
(Tetrahydrofuran)

32. MECHANISM
▪ [3,3]-sigmatropic rearrangement leads to an intermediate cyclohexadiene and
proceeds via a cyclic transition state.
▪ Concerted intramolecular rearrangement.
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or
2-(2-propenyl)phenol

33. EVIDENCE FOR THE MECHANISM
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▪ Evidence for this mechanism was provided by performing the rearrangement
with allyl group with a 14
C label.
▪ The product of this reaction was shown to have the 14
C labeled carbon exclusively
bonded to the ring.
▪ Named after its discoverer, the German chemist Rainer Ludwig Claisen, who
discovered it in 1912

34. APPLICATIONS:
1. Synthesis of o-Eugenol from 2-methoxyphenol
▪ Eugenol, a volatile oil used as a desensitizer and carminative
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2-methoxyphenol
o-eugenol

35. 2. Rearrangement of chorismate to prephenate, this reaction is catalyzed by the
enzyme chorismate mutase.
▪ It’s a key step in the shikimic acid pathway responsible for the biosynthesis of
the essential amino acid's tryptophan, phenylalanine and tyrosine.
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36. REFERENCES:
▪ Organic reaction mechanisms, Fourth edition by V.K. Ahluwalia and Rakesh
Kumar Page no: 398-456
▪ Organic Chemistry,2nd
edition by Jonathan Clayden Page no: 909-910, 942-944
▪ o-EUGENOL. Org Synth 1945;25:49. https://doi.org/10.15227/orgsyn.025.0049.
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