Rearrangements

Molecular Rearrangements
Migration of one
the molecule
group from one atom to another within
Generally the migrating group never leaves the molecule

There are five types of skeletal rearrangements1. Electron deficient skeletal rearrangement
2. Electron rich skeletal rearrangement
3. Radical rearrangement
4. Rearrangements on an aromatic ring
5. Sigmatropic rearrangement
CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Electron Deficient Skeletal Rearrangement
Generally it involves migration of a group from one atom to
an adjacent atom, having six electrons in the valence shell
The molecular system may be either a cation or a neutral
molecule
Examples:
C C
C C
R
C C
R
C C
R
R
C N
R
C O
R
C N
N
R
R
C O
R
2
Wagner- Meerwin Rearrangement
Rearrangement of alcohols under acidic condition
Me
Me
OH
Me
H+
Me
H+
Me
Me
OH2
Me
Me
H
Me
Me
Alkyl migration occurs to give stable carbocation

This is the driving force for the migration of alkyl, aryl or
even hydrogen atom
Wagner- Meerwin Rearrangement
H+
HO
Isoborneol
Camphene
H+
Ring Expansion
More stable carbocation will be generated
Stability of carbocations3> 2> 1
Can we go from 3 to 2 ??
Cations can be made more stable if they become less
strained
HCl
H+
Cl
Relief in
strain from
four to five
membered
ring is driving
force
Ring Expansion
H H
Me
H H
MeLi
Me
OH
Me
Me
40% H2SO4
Me
Me
OH
Me
Me
H Me
H Me
H H
Me
Me
OH2
Me
H2O
Me
H Me
H H
Tertiary carbocation
migrated to secondary
H Me
Me
Me
Me
Me
Me
H Me
Me
6
Pinacol-Pinacolone Rearrangement
Pinacol
HO
OH
HO
H2SO4
Pinacolone
HO OH
OH2
HO
Carbocation is already tertiary

There is no ring strain
Then why should it rearrange?
Reason:
The lone pair of electrons on the oxygen is another source
to stabilize the carbocation
Pinacol-Pinacolone rearrangement can be viewed as a push and
a pull rearrangement
The carbocation formed as a result of loss of H2O, pulls the
migrating group
Lone pair on oxygen pushes the migrating group
Preparation of Spiro System:

O
HO OH
H
H
O
HO
OH2
HO
HO OH
OH
NaBH4
Epoxides :
Epoxides also undergo pinacol type rearrangement on treatment
with acid
O
Ph
MgBr
O
MgBr2
OHC
Ph
Ph
Ph
Ph
Ph
1) RMgBr
OH
2) H
With a Grignard reagent, rearrangement occurs faster than

addition to the epoxide
Migrating group preference:
It doesnt matter when we have symmetrical diols & epoxides
It doesnt matter when we have unsymmetrical epoxides & diols
HO OH2
Ph
Ph
HO
O
Ph
Ph
Ph
Ph
HO OH
Ph
Ph
H2O OH
Ph
Ph
OH
Ph
Ph
Ph
Ph
II
Only I is formed in quantitative amount because the

carbocation is stabilized by two phenyl groups
10
Semipinacol Rearrangement
They are nothing but pinacol rearrangement without choice
HO
OH
OsO4
Isonopinone
Under normal acidic conditions
H2O H
O
OH
H
O
OH
CHO
11
For the required product, the primary hydroxyl group needs
to be made as better leaving group
HO
HO
OH
CaCO3
Weak base
TsCl
Py
OTs
HO
OTs
Corey exploited a similar sequence in the synthesis of longifolene
CH3
12
O O
O O
TsCl
Py
HO
HO
O O
CaCO3
HO
TsO
CH3
Longifolene
Leaving group need not be tosylated and it can be anything

which can readily leave
AgNO3
O
OH
13
O
OMe
H+
OH
OMe
OH2
O
OMe
OH
H+
OMe
OH2
14
Diazonium salts
Tiffeneau-Demjanov Rearrangement:
HO NH2
OH
O
_N
NaNO2/HCl
N2
Selectivity :
OH
NH2
NaNO2/HCl
CHO
OH
NH2
OH
NaNO2/HCl
NaNO2/HCl
CHO
NH2
OH
NaNO2/HCl
NH2
15
Diazonium salts
Mechanism :
OH
OH
N2
CHO
N2
Alkyl group which is anti to the leaving group, will migrate

H
O
OH
N2
OH
O
N2
16
Fragmentation:
CN
CN
AcCl
N
OH
OAc
N
Stable
carbocation
Fragmentations always require electron push and electron pull
HO
OH
H2O
OH
CHO
17
An Important Method to Make Higher Cycloalkanes:
OH
H O
H
OMe
OMe
O
Me
H
O
OMe
H
OMe
H
OMe
HO
18
Base Conditions or Nucleophilic Conditions:
O
O
OH
OMs
OH
OH
OMs
Me
Me2N
OTs
Me
H3O
OHC
Antiperiplanar bond migrates

OTs
OH
OTs
Base
O
10-membered ring
19
Eschenmoser Fragmentation
O
O
NaOH/H2O2
N
TsNHNH2
NHTs
N
Base
PTSA
N Ts
Ts
N
Ts
N2#
CHO
1) NaBH4
H3O
HO
O
O3/Me2S
2) PTSA
OH
O
N
Base
Base
NHTs
O
1) NaOH/H2O2
2) TsNHNH2/PTSA
O
20
Fragmentation of Four-Membered Ring
O
O
AcOH
BF3.Et2O
OAc
Other Examples:
MsO
Base
O
HO
OH
O
Base
Aldol
condensation
O
21
Sigmatropic Rearrangements
[3,3]-Sigmatropic Rearrangement
Cope Rearrangement :
It is a [3,3]- sigmatropic rearrangement with only carbon
atoms involved in the six membered transition state
Why is it called [3,3] ?
2
1
1
2
HO
The new bond formed

has 3,3- relationship
with the old -bond
3
3
HO
22
Mechanism :
It goes via six-membered chair-like transition state
trans
trans
cis
cis
E,Z
Z,E
CH3
H3C
H3C
More stable
conformer
CH3
Less stable
conformer
E,E-isomer
Favoured
Z,Z-isomer
23
1) Cope:
2) Oxy-Cope:
HO
HO
OH
OHC
O
OH
O
24
3) Anionic-Oxy-Cope:
O
H3C
OHC
CH3
OMOM
LiO
OTBDMS
MOMO
CH3
H3C
H3C
H3C
CH3
OTBDMS
4) Claisen Rearrangement of Allylvinyl Ethers:
--unsaturated aldehyde
O
25
5) Claisen Rearrangement of Allylphenyl Ethers:

O
OH
6) Ortho-Ester Claisen Rearrangement:

RO
OR
OH
OR
_
ROH
OR
Hg(OAc)2
OEt
O
OEt
OEt
26
7) O-Allyl-O-TMS-Ketone Acetals:
OH
OTMS
OTMS
O
8) Ester-Enolate Claisen:
O
O
O
O
9) Ketene Aminals:
NR2
NR2
O
27
10) Aza-Claisen Rearrangement:

R
O
R
NH
NH
Other Examples:
K=0.25
CO2Et
H3CO
275 oC
CO2Et
OCH3
CH3
H
H
C2H5
OH
H
C2H5
H3CO
OCH3
CH3
28
Stereochemistry:
O
R
R
OTMS
OTMS
Z-silyl ether
trans
R
R
R
H
OTMS
E-silyl ether
OTMS
cis
29
[2,3]-Sigmatropic Rearrangement
Y
X
Neutral
Charged
1) Allylic Sulfoxides:
O
R
2) Allylic Sulfonium Ylides:

S
30
3) N-Oxides:
R
R N
R N
Sommelet-Hauser Rearrangement
H3C
N
H3C
CH3
CH3
CH3
H3C
CH3
CH3
H3C
CH2
CH3
NaNH2
H3C
CH3
31
Stevens Rearrangement
O
NaOH
Ph
Ph
CH2Ph
C6H5
Wittig Rearrangement
H3C
Ph
OMe
PhLi
Ph
PhLi
OH
OH
32
Ene Reaction
EWG
EWG
CO2R
OH
O
H
CO2R
33
Cheletropic Elimination
Two bonds are broken at a single atom
SO2
SO2
Ph
Ph
Ph
SO2
Ph
O
H
SO2
34
Elimination of Carbon monoxide (CO)
O
Ph
Ph
Ph
Ph
Ph
O
Ph
Ph
Ph
Ph
Ph Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
OH
Ph
Ph CHO
OEt
35
Elimination of Carbon monoxide (CO)
O
OMe
MeO
CO2Me
OMe
CO2Me
[4+2]Cycloaddition
- MeOH
Aromatization
O
- CO2
OMe
MeO2C
OMe
OMe
MeO2C
OMe
36
Dienone-Phenol Rearrangement
Me OH
H
O
Me
H2SO4
Me
Me OH
H
H
HO
Can be considered as a reversal of pinacol rearrangement

Pinacol & semipinacol rearrangements are driven by the
formation of a carbonyl group
In dienone-phenol rearrangement protonation of carbonyl
group Rearranges to a tertiary carbocation
The driving force for this reaction is the formation of
aromatic rings
37
Dienone-Phenol Rearrangement
Mechanism:
O
OH
OH
H
Me
Me
Me
Me
Me
Me
OH
OH
Me
Me
H
Me
Me
38
Beckmann Rearrangement
The industrial formation of nylon relies upon the alkaline
polymerization of a acyclic amide known as caprolactam
O
base
H
N
H
N
OH
acid
oxime
Caprolactam can be produced by the action of sulfuric acid
on the oxime of cyclohexanone in a rearrangement known as
the Beckmann rearrangement
39
Mechanism:
N
OH
OH2
OH2
N
H
N
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
40
It can also works with acyclic oximes
PCl5, SOCl2 & other acyl or sulfonyl chlorides can be used
instead of acid
N
Ph
OH
Ph
N
Ph
C
Ph
NH
NH2OH
HO
Nitrilium ion
OH
Me
Me
Ph
Migratory Aptitude:
O
Ph
OH2
Al2O3
Me
NHMe
N
Me
Me
major
minor
41
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
42
O
NH2OH
OH
HO
Me
H
N
Al2O3
Me
Me
O
H
Me
88 : 12
86 : 14
Steric effect
CH3
O
1) NH2OH
H
N
2) pTSCl
43
Baeyer Villiger Oxidation
Mechanism:
O
O
O
R
R''
C O OH
R'
O
O
H
O
R'
R'
OR
O
R''
Migratory Aptitude:
t-Bu > i-Pr = Ph > Et > Me

O
CO2H
HO
NH2
HO
L-dopa
HO
CO2H
H3C
AlCl3
AcCl
HO
CO2H
NH2
NH2
H3C
O
O
HO
H2O2
NaOH
CO2H
NH2
44
B.V.O. of Unsaturated Ketones:
There are three possibilities
1) Peracids can selectively epoxidize
2) Peracids can selectively carry out B.V.O
3) Can carry out both reactions
It is difficult to predict the outcome & it depends on1) Electrophilic nature of the ketone
2) Nucleophilic nature of the alkene
45
R'
O
H
O
R
O
R
R'
OH
BnO
mCPBA
O
BnO
O
Tertiary group migrates in preference of the secondary

group
The alkene is not as reactive as expected because of
steric crowding
46
Small ring ketones will readily undergo B.V.O.
H
O
H2O2, OH
O
O
Starting material configuration is retained in the product

O
Ph
Ph
ArCO3H
Me
Me
Me
O
Ph
Me
Me
O
O
Me
O
O
Ar
O
47
Electron-Rich (Anionic) Skeletal Rearrangements
The transition state has two more electrons
Generally initiated by basic reagents which remove a group
or an atom such as hydrogen
The residual anion then stabilizes itself by rearrangement
In the first step an acid strengthening substituent is
necessary to stabilize the ionic center
48
Stevens Rearrangement
H3C
H2 O
H3C N C C C6H5
C6H5H2C
OH
O
H3C
H
H3C N C C C6H5
CH2
H3C
H3C
C6H5
H
N C COC6H5
CH2C6H5
Proton removal is facilitated by the positive charge in the

cationic substrate and also by the enolate ion formation
Migrating groups are generally benzyl or allyl system
H2
H3C S C COC6H5
H2C C6H5
OH
H
H3C S C COC6H5
CH2
C6H5
H
H3C S C COC6H5
CH2C6H5
49
Wittig Rearrangement
It also follows a similar pathway
Only difference is substrates are much less acidic than
those encountered in Stevens rearrangement
Powerful basic reagents are required to cause the Wittig
Rearrangement
H3C
H2
O C C6H5
H2C
PhLi
H
C
C
H2
H3C
C
H2
H
C
O C C6H5
H
H
O C C6H5
H
HO C C6H5
CH3
CH3
1) PhLi
CH2
2) H3O
H2C
H
C
OH
C
H2
C
H
CH2
50
Sommelet-Hauser Rearrangement
Nucleophilic alkylation of the aromatic rings of a benzyltrimethylammonium ion
H3C
N
H3C
CH3
CH3
CH3
H3C
CH3
CH3
H3C
CH2
CH3
NaNH2
H3C
CH3
51
Rearrangements
Benzilic acid Rearrangement
O O
KOH
C6H5 C C C6H5
EtOH,
OH
C6H5 C COOH
C6H5
Mechanism:
O O
Ar
C C Ar
O O
OH
Ar
O O
C C OH
Ar
Ar
OH
Ar
C C O
Ar
C C O
Ar O
Formation of stable carboxylate salt is driving force for the

reaction
O
HO
KOH
CO2H
EtOH
Application has been limited only to aromatic -diketones

52
Rearrangements
Rearrangements on an Aromatic Ring
1. Fries Rearrangement
2. Claisen Rearrangement
3. Rearrangements of Derivative of aniline
Rearrangements of Derivatives of Aniline:
O
Cl
NHCOCH3
C CH3
Cl2
NHCOCH3
NHCOCH3
Cl
HCl
Cl
O
Cl
C CH3
HN
HCl
O
CH3
HN
Cl
Friedel
Crafts like
CH3
HN
CH3
Cl
Cl
53
Rearrangements

Rearrangements of Derivatives of Aniline:
NH2
HN N N Ph
H
p-amino diazobenzene
Diazoamino
benzene
N
N
Ph
It is still not clear whether it involves inter or intramolecular mechanism
Rearrangement of N-Methyl-N-Nitrosoamine:
Me
Me
NO
H
Me
NH
NO
Me
NH
NH
NO
NO
54
Rearrangements
Rearrangement of N-Phenylhydroxylamine:
NH2
NHOH
NH2
OH
OH
Mechanism
HO
H2O
NH
NH
NH
NH
NH
NH2
OH
OH
H+
55
Rearrangements
Rearrangements on Aromatic Ring
Rearrangement of N,N-Dimethylanilinium chloride:
NHCH3
N
CH3
275 C
H CH3
CH3
NHCH3
CH3
NHCH3
NH
HN
CH3
NH2
CH3
CH3Cl
H3C Cl
H3C
CH3
CH3
56
Rearrangements
Rearrangements on Aromatic Ring

OH
HN
HN
OH2
NH
NH
H2O
CH3
H3C
CH3
CH3
O
OH
OH
OH
H
H3O
hydrolysis
H3C
OH
H3C
H
H3C
OH
OH
OH
OH
- H+
H
H3C
OH
H3C
OH
57
Rearrangements

Rearrangement of Phenylnitramine:
NHNO2
H2N NO2
H
NH2
NH2
NH2
NO2
H
NO2
NO2
Rearrangement of Phenylsulfamic acid:

H2N SO3H
NHSO3H
H
NH2
NH2
SO3H
SO3H
These reactions involve intramolecular pathway
58
Rearrangements

Benzidine Rearrangement:
H H
N N
2H
H H
N N
H H
NH2
H2N
NH2
NH2
59
Rearrangements
Some Additional Problems
Cl
O
Cl C C
H
Cl
2CaCO3
hydrolysis of
acid derivative
O
Cl
Cl C C CN
Cl
H
NaCN
Cl
CH C
Cl
H3O
Cl
CH C
Cl
CN
Cl
CH C
Cl
OH
dichloro acetic acid
(CHCl2COO)2Ca + 2CO2 + CaCl2 + H2O
60
Rearrangements
C
O
NH3
CH3
CH3
OH
methanolic NH3
sealed tube heating
H2N
H
O
O
C
CH3
CH3
ring opening
vinylogous substitution
OH
CH3
NH2 O
CH3
61
Rearrangements
H3C
H3C
H3C
CH3
CH3
HO
CH3
HO
HO
CH3
R
HO
H
R
HO
HO
HO
CH3
R
H
CH3
HO
R
62
Rearrangements
O
OH
HO
retro Pinacol Pinacolone
Rearrangement
O
HO
Pinacol Pinacolone
Rearrangement
C
C C O
C
mCPBA
C O
C C O
C
C O
C C O
C
C O
C C O
C
H3C
CH3
O
H3C
O
H3C C
H3C CH3
63
Rearrangements
O
CH3
H3C
O
OH
Acid cat. aldol

condensation
CH3
O
CH3
H3C
O
CH3
H2O
H
OH
H3C
H3C
O H2O
OH
CH3
H3C
OH
OH
64

Rearrangements

Transféré par

Informations du document

Description originale:

Copyright

Formats disponibles

Partager ce document

Partager ou intégrer le document

Options de partage

Avez-vous trouvé ce document utile ?

Ce contenu est-il inapproprié ?

Droits d'auteur :

Formats disponibles

Rearrangements

Transféré par

Droits d'auteur :

Formats disponibles

Molecular Rearrangements

group from one atom to another within

Generally the migrating group never leaves the molecule

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

Alkyl migration occurs to give stable carbocation

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

Carbocation is already tertiary

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

Preparation of Spiro System:

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

With a Grignard reagent, rearrangement occurs faster than

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

Only I is formed in quantitative amount because the

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

Corey exploited a similar sequence in the synthesis of longifolene

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

Leaving group need not be tosylated and it can be anything

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

Alkyl group which is anti to the leaving group, will migrate

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

Antiperiplanar bond migrates

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

The new bond formed

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

4) Claisen Rearrangement of Allylvinyl Ethers:

5) Claisen Rearrangement of Allylphenyl Ethers:

6) Ortho-Ester Claisen Rearrangement:

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

10) Aza-Claisen Rearrangement:

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

2) Allylic Sulfonium Ylides:

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

Can be considered as a reversal of pinacol rearrangement

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

Follows the same pattern as pinacol

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

t-Bu > i-Pr = Ph > Et > Me

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

Tertiary group migrates in preference of the secondary

Starting material configuration is retained in the product

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

Proton removal is facilitated by the positive charge in the

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

CH-423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan