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Molecular Rearrangements
Ø  Migration of one group from one atom to another within

the molecule
Ø  Generally the migrating group never leaves the molecule
Ø  There are five types of skeletal rearrangements-
1. Electron deficient skeletal rearrangement

2. Electron rich skeletal rearrangement
3. Radical rearrangement
4. Rearrangements on an aromatic ring
5. Sigmatropic rearrangement
1
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Electron Deficient Skeletal Rearrangement
Ø  Generally it involves migration of a group from one atom to
an adjacent atom, having six electrons in the valence shell
Ø  The molecular system may be either a cation or a neutral
molecule
Examples:
C C C C
R R
C C C C
R R R
C N C N N
R R R
C O C O O
R R R
2
Wagner- Meerwin Rearrangement
Ø  Rearrangement of alcohols under acidic condition
Me Me
H+
Me
OH Me
H+
Me Me Me
H
Me Me
OH2 Me
Ø  Alkyl migration occurs to give stable carbocation

Ø  This is the driving force for the migration of alkyl, aryl or
even hydrogen atom
3
Wagner- Meerwin Rearrangement
H+
HO
Isoborneol
Camphene
H+
4
Ring Expansion
Ø  More stable carbocation will be generated
Ø  Stability of carbocations-
3°> 2°> 1°
Can we go from 3° to 2° ??
Ø  Cations can be made more stable if they become less
strained
HCl Cl
Relief in
strain from
H+ four to five
membered
ring is driving
force
5
Ring Expansion
O OH Me
H H H H Me H
40% H2SO4 Me
Me MeLi Me OH
Me Me Me
H Me H Me H
Me
OH2
H H Me
Me
H2O
Me
H Me
H H Me H Me
Me Me
Tertiary carbocation
migrated to secondary Me Me
H Me H
Me
6
Pinacol-Pinacolone Rearrangement
O
H2SO4
Pinacol Pinacolone
HO OH
HO OH2 HO H
HO OH O O
Ø  Carbocation is already tertiary

Ø  There is no ring strain
Ø  Then why should it rearrange?
Ø  Reason:
The lone pair of electrons on the oxygen is another source
to stabilize the carbocation
7
Ø  Pinacol-Pinacolone rearrangement can be viewed as a push and
a pull rearrangement
Ø  The carbocation formed as a result of loss of H2O, pulls the
migrating group
Ø  Lone pair on oxygen pushes the migrating group
Preparation of Spiro System:

O
HO OH
H
O
HO OH2 HO
8
OH
O
HO OH H NaBH4 H
Epoxides :
Epoxides also undergo pinacol type rearrangement on treatment
with acid
MgBr
O O Ph
MgBr2
OHC
Ph Ph
Ph Ph Ph
1) RMgBr OH
O
2) H R
Ø  With a Grignard reagent, rearrangement occurs faster than

addition to the epoxide
9
Ø  Migrating group preference:
It doesn’t matter when we have symmetrical diols & epoxides
It doesn’t matter when we have unsymmetrical epoxides & diols
O
HO OH2 HO
Ph Ph
Ph
Ph
Ph Ph
HO OH I
Ph
Ph
O
H2O OH OH
Ph Ph
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
OH
HO
O
OsO4
O
Isonopinone
Under normal acidic conditions

H2O H H
O O
H
OH OH
CHO
11
For the required product, the primary hydroxyl group needs
to be made as better leaving group
HO HO
TsCl OTs
OH
Py
HO
CaCO3
OTs
Weak base O
Corey exploited a similar sequence in the synthesis of longifolene
CH3
12
O O O O
O O
TsCl HO CaCO3
HO TsO O
Py
HO
CH3
Longifolene
Leaving group need not be tosylated and it can be anything
which can readily leave
I AgNO3
O
OH
13
O
OMe OMe O
H+
OH
OH2
O
OMe OMe O
OH H+ OH2
14
Diazonium salts
Tiffeneau-Demjanov Rearrangement:
O
HO NH2 OH
_N
NaNO2/HCl 2
N2 _
H
Selectivity :
OH NaNO2/HCl CHO
NH2
OH
NaNO2/HCl CHO
NH2
O
OH NaNO2/HCl
NH2
OH
NaNO2/HCl O
NH2
15
Diazonium salts
Mechanism :
OH
OH CHO
N2 N2
Alkyl group which is anti to the leaving group, will migrate
H
O
OH
N2
OH
O
N2
16
Fragmentation:
CN CN
AcCl
OH OAc
N N N
Stable
carbocation
Ø  Fragmentations always require electron push and electron pull
H
H2O OH CHO
HO OH
17
An Important Method to Make Higher Cycloalkanes:
H O OH O
O
H
OMe OMe
O O
Me
O O O
OMe OMe
O O O OMe
H H
HO
O
18
Base Conditions or Nucleophilic Conditions:
O
O O OH
OH OH
OMs OMs
Me
Me2N OTs H3O
N OHC
Me
Antiperiplanar bond migrates
OTs OTs
Base
OH O
O
10-membered ring
19
Eschenmoser Fragmentation
NHTs N Ts
O O N N
NaOH/H2O2 TsNHNH2 Base

O O O
PTSA
Ts
N
N
Ts N2#
CHO O
O O
H3O 1) NaBH4 O3/Me2S
2) PTSA
HO OH
O
Base
NHTs
N
O
Base O 1) NaOH/H2O2
2) TsNHNH2/PTSA
O
20
Fragmentation of Four-Membered Ring
O O
O O
BF3.Et2O AcOH
OAc
Other Examples:
MsO
Base
HO O
O Aldol
OH condensation
Base
O 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 3 The new σ bond formed
1
has 3,3- relationship
2
3
with the old σ-bond
α
HO HO Ο β
ω γ
δ
22
Mechanism :
It goes via six-membered chair-like transition state
trans trans cis cis
CH3
H3C
H3C
CH3
More stable
conformer Less stable
conformer
E,Z Z,E
E,E-isomer
Favoured Z,Z-isomer
23
1) Cope:
O O
2) Oxy-Cope:
HO HO
OHC
OH O
OH
O
24
3) Anionic-Oxy-Cope:
O O OHC
H3C CH3
OTBDMS
MOMO
OMOM
LiO CH3
H3C
H3C O
H3C CH3
OTBDMS
4) Claisen Rearrangement of Allylvinyl Ethers:
O α
O
β
γ-δ-unsaturated aldehyde
δ
γ
O
O
25
5) Claisen Rearrangement of Allylphenyl Ethers:

O O OH
6) Ortho-Ester Claisen Rearrangement:

OR OR
RO OR
_
O ROH O O
Hg(OAc)2
OH O
O
OEt
OEt OEt
26
7) O-Allyl-O-TMS-Ketone Acetals:
OTMS OTMS OH
O O O
8) Ester-Enolate Claisen:
O O
O O
9) Ketene Aminals:
NR2 NR2
O O
27
10) Aza-Claisen Rearrangement:
R R
O NH O NH
Other Examples:
K=0.25
CO2Et 275 oC
CO2Et
H3CO OCH3 CH3

H
H
OH C2H5
H
O
C2H5 H3CO OCH3
CH3
28
Stereochemistry:
R
R
O R O R
OTMS OTMS
Z-silyl ether trans
R R
R
R
O H O H
OTMS OTMS
E-silyl ether cis
29
[2,3]-Sigmatropic Rearrangement
Y
Y X
X
Charged Neutral
1) Allylic Sulfoxides:
O
O
S
S R
R
2) Allylic Sulfonium Ylides:
S S
30
3) N-Oxides:
R
R
R N
R N
O
O
Sommelet-Hauser Rearrangement
H3C H3C
CH3 CH3 H3C
N N CH3 H3C CH3
CH3 CH3 N N
CH2
NaNH2
H3C CH3
N
31
Stevens Rearrangement
O
O
NaOH N
N Ph Ph
C6H5 CH2Ph
Wittig Rearrangement
O Ph OMe
H3C PhLi
Ph OH
OH
O PhLi
32
Ene Reaction
H EWG EWG
CO2R
OH
O
H CO2R
33
Cheletropic Elimination
Two bonds are broken at a single atom
SO2 SO2
O Ph O
Ph
SO2
Ph O Ph O
O O
SO2 H H H
34
Elimination of Carbon monoxide (CO)
O
Ph O Ph
Ph Ph Ph
Ph Ph Ph
O
Ph
Ph Ph Ph
Ph Ph Ph Ph
Ph
Ph O O
Ph O Ph
Ph OH O
Ph CHO
H OEt
Ph O
35
Elimination of Carbon monoxide (CO)
O O Δ OMe
MeO OMe
CO2Me CO2Me
[4+2]-
Cycloaddition - MeOH
Aromatization
O
O
- CO2
OMe
OMe
MeO2C
MeO2C OMe
OMe
36
Dienone-Phenol Rearrangement
Me OH Me OH
H2SO4 Me
Me H H
H H H H
O HO
Ø  Can be considered as a reversal of pinacol rearrangement
Ø  Pinacol & semipinacol rearrangements are driven by the

formation of a carbonyl group
Ø  In dienone-phenol rearrangement protonation of carbonyl

group Rearranges to a tertiary carbocation
Ø  The driving force for this reaction is the formation of

aromatic rings
37
Dienone-Phenol Rearrangement
Mechanism:
O OH OH
Me Me Me Me Me Me
OH OH
Me
H Me
Me Me
38
Beckmann Rearrangement
The industrial formation of nylon relies upon the alkaline

polymerization of a acyclic amide known as caprolactam
OH
H N
O N O
H base acid
N
n
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:
OH OH2 OH2 H
N N
N N O
Ø  Follows the same pattern as pinacol

Ø  Converts the oxime into a good leaving group
Ø  Alkyl/ Aryl group migrates on to nitrogen as water
departs
Ø  The product cation is then trapped by water to give
an amide
40
Ø  It can also works with acyclic oximes
Ø  PCl5, SOCl2 & other acyl or sulfonyl chlorides can be used
instead of acid
Ph
OH OH2 N
N H N
C
Nitrilium ion
Ph Ph Ph Ph Ph
Migratory Aptitude:
OH
N NH
O
Me
O Me major
NH2OH Al2O3
Me
HO
N NHMe
Me O
minor
Me
41
In case of unsymmetrical ketone:
Ø  There are two groups that could migrate

Ø  There are two possible geometrical isomers of unsymmetr-
ical oxime
Ø  When the mixtures of geometrical isomer of oximes are

rearranged, mixtures of products result
Ø  Interestingly, the ratio of products mirrors exactly the ratio
of geometrical isomers in the starting materials
Ø  The group that has migrated, is trans to the -OH group
42
OH HO O
O N N H
NH2OH Al2O3 N Me H
N
Me Me Me
O
86 : 14 88 : 12
Steric effect
CH3
O
1) NH2OH H
O N
2) pTSCl
43
Baeyer Villiger Oxidation
Mechanism:
H
O
O
O R'' C O OH R R' O
O
R R' O R' OR
O
R''
Migratory Aptitude:
t-Bu > i-Pr = Ph > Et > Me
O
CO2H CO2H
AlCl3 H3C H2O2
NH2 AcCl NH2 NaOH
HO HO
HO CO2H H3C O CO2H

L-dopa NH2 O NH2
HO HO
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 on-
1) Electrophilic nature of the ketone
2) Nucleophilic nature of the alkene
45
R'
O
H O O O
O
R R R' OH
R R
BnO
BnO
mCPBA
O O O
Ø  Tertiary group migrates in preference of the secondary

group
Ø  The alkene is not as reactive as expected because of

steric crowding
46
Small ring ketones will readily undergo B.V.O.
H
O O
H2O2, OH O
Starting material configuration is retained in the product

O
Ph ArCO3H Ph O Me
Me
Me Me O
O
Me
Ph O Ar
O
Me O
47
Electron-Rich (Anionic) Skeletal Rearrangements
Ø  The transition state has two more electrons
Ø  Generally initiated by basic reagents which remove a group

or an atom such as hydrogen
Ø  The residual anion then stabilizes itself by rearrangement
Ø  In the first step an acid strengthening substituent is

necessary to stabilize the ionic center
48
Stevens Rearrangement
H3C O
H
H3C H2 O OH H3C N C C C6H5
H3C H
H3C N C C C6H5 N C COC6H5
CH2 H3C
C6H5H2C CH2C6H5
C6H5
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 H H
H3C S C COC6H5 OH H3C S C COC6H5 H3C S C COC6H5
H2C C6H5 CH2
CH2C6H5
C6H5
49
Wittig Rearrangement
Ø  It also follows a similar pathway
Ø  Only difference is substrates are much less acidic than
those encountered in Stevens rearrangement
Ø  Powerful basic reagents are required to cause the Wittig
Rearrangement
H2 O C C6H5 H H
PhLi O C C6H5 HO C C6H5
O C C6H5 H3C
H3C H CH3 CH3
H H OH
C O C 1) PhLi H
C C C CH2
H2C CH2 H2C C C
H2 H2 2) H3O H2 H
50
Sommelet-Hauser Rearrangement
Nucleophilic alkylation of the aromatic rings of a benzyl-
trimethylammonium ion
H3C H3C
CH3 CH3 H3C
N N CH3 H3C CH3
CH3 CH3 N N
CH2
NaNH2
H3C CH3
N
51
Rearrangements
Benzilic acid Rearrangement
O O OH
KOH
C6H5 C C C6H5 C6H5 C COOH
EtOH,
C6H5
Mechanism:
H OH
O O O O O O
OH
Ar C C Ar Ar C C OH Ar C C O
Ar C C O
Ar Ar O
Ar
Formation of stable carboxylate salt is driving force for the

reaction
O O
HO CO2H
KOH
EtOH
Application has been limited only to aromatic α-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
NHCOCH3 Cl C CH3 NHCOCH3 NHCOCH3
N
Cl2 Cl
HCl
Cl
O O
O O
Cl C CH3 HN CH3
N
HN CH3 HN CH3
HCl Friedel Cl
Cl
Crafts like
Cl
53
Rearrangements
Rearrangements of Derivatives of Aniline:
HN N N Ph NH2
H
p-amino diazobenzene
Diazoamino N
benzene N
Ph
It is still not clear whether it involves inter or intramolecular mechanism
Rearrangement of N-Methyl-N-Nitrosoamine:
Me
Me NO Me Me NH
N NH NH
NO
H
NO
NO
54
Rearrangements
Rearrangement of N-Phenylhydroxylamine:
NHOH NH2 NH2
OH
H
OH
Mechanism
HO H2O
NH NH NH NH NH NH2
H+
OH OH
55
Rearrangements
Rearrangements on Aromatic Ring
Rearrangement of N,N-Dimethylanilinium chloride:
NHCH3
CH3 0
N 275 C
H CH3
CH3
Δ
CH3 CH3
NHCH3 NHCH3 HN NH2
NH
CH3Cl CH3
H3C H CH3 CH3

H3C Cl
56
Rearrangements
Rearrangements on Aromatic Ring
OH OH2
HN HN NH NH
H H2O
H3C OH
CH3 CH3 CH3
O
OH OH
H3O H
hydrolysis
H
H3C OH H3C
H3C OH OH
OH
OH
- H+
H
H3C H3C
OH
OH
57
Rearrangements
Rearrangement of Phenylnitramine:
NHNO2 H2N NO2 NH2 NH2 NH2
NO2
NO2
H H
NO2
Rearrangement of Phenylsulfamic acid:

NH2
NHSO3H H2N SO3H NH2
SO3H
H
SO3H
These reactions involve intramolecular pathway
58
Rearrangements
Benzidine Rearrangement:
H H
H H 2H
N N N N
H H
NH2
H2N NH2 NH2
59
Rearrangements
Some Additional Problems
Cl O Cl O Cl O
Cl C C NaCN Cl C C CN CH C
+ 2CaCO3
Cl H Cl H Cl CN
Cl O Cl O
hydrolysis of H3O
CH C CH C
acid derivative Cl O Cl OH
dichloro acetic acid
(CHCl2COO)2Ca + 2CO2 + CaCl2 + H2O
60
Rearrangements
OH
O methanolic NH3
O C
sealed tube heating
CH3 N CH3
O H2N ring opening

O
O C
H O C vinylogous substitution
CH3
CH3
NH3
O OH
CH3
NH2 O N CH3
61
Rearrangements
R R
H3C H3C H3C CH3
R R
H
O HO HO HO
CH3 CH3
R R
HO HO
H
CH3 CH3 CH3

R
HO HO
HO H
R R
62
Rearrangements
O OH
retro Pinacol Pinacolone HO
H
Rearrangement
HO O
Pinacol Pinacolone H
Rearrangement
C C O C O
mCPBA
C C O C C O C C O
C C C
CH3
H3C
C O O
C C O H3C
C H3C C O
H3C CH3
63
Rearrangements
O
H
CH3 OH
H3C O
Acid cat. aldol
O CH3 CH3
condensation H2O
O H
CH3 H3C H3C OH
H3C
O H2O O
O
OH
CH3
H3C OH
OH
64

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Molecular Rearrangements

Ø Migration of one group from one atom to another within

Ø Generally the migrating group never leaves the molecule

Ø There are five types of skeletal rearrangements-

1. Electron deficient skeletal rearrangement

Ø Alkyl migration occurs to give stable carbocation

Ø Carbocation is already tertiary

Preparation of Spiro System:

Ø With a Grignard reagent, rearrangement occurs faster than

Under normal acidic conditions

Corey exploited a similar sequence in the synthesis of longifolene

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

Ø Fragmentations always require electron push and electron pull

Antiperiplanar bond migrates

NaOH/H2O2 TsNHNH2 Base

Why is it called [3,3] ?

4) Claisen Rearrangement of Allylvinyl Ethers:

5) Claisen Rearrangement of Allylphenyl Ethers:

6) Ortho-Ester Claisen Rearrangement:

H3CO OCH3 CH3

2) Allylic Sulfonium Ylides:

Ø Can be considered as a reversal of pinacol rearrangement

Ø Pinacol & semipinacol rearrangements are driven by the

Ø In dienone-phenol rearrangement protonation of carbonyl

Ø The driving force for this reaction is the formation of

The industrial formation of nylon relies upon the alkaline

Caprolactam can be produced by the action of sulfuric acid

Ø Follows the same pattern as pinacol

Ø There are two groups that could migrate

Ø When the mixtures of geometrical isomer of oximes are

HO CO2H H3C O CO2H

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 on-

1) Electrophilic nature of the ketone

2) Nucleophilic nature of the alkene

Ø Tertiary group migrates in preference of the secondary

Ø The alkene is not as reactive as expected because of

Starting material configuration is retained in the product

Ø The transition state has two more electrons

Ø Generally initiated by basic reagents which remove a group

Ø The residual anion then stabilizes itself by rearrangement

Ø In the first step an acid strengthening substituent is

Proton removal is facilitated by the positive charge in the

Migrating groups are generally benzyl or allyl system

Formation of stable carboxylate salt is driving force for the

Application has been limited only to aromatic α-diketones

Rearrangements of Derivatives of Aniline:

H3C H CH3 CH3

Rearrangement of Phenylsulfamic acid:

These reactions involve intramolecular pathway

H2N NH2 NH2

(CHCl2COO)2Ca + 2CO2 + CaCl2 + H2O

O H2N ring opening

CH3 CH3 CH3

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Ø  Migration of one group from one atom to another within

Ø  Generally the migrating group never leaves the molecule

Ø  There are five types of skeletal rearrangements-

Ø  Alkyl migration occurs to give stable carbocation

Ø  Carbocation is already tertiary

Ø  With a Grignard reagent, rearrangement occurs faster than

Ø  Fragmentations always require electron push and electron pull

Ø  Can be considered as a reversal of pinacol rearrangement

Ø  Pinacol & semipinacol rearrangements are driven by the

Ø  In dienone-phenol rearrangement protonation of carbonyl

Ø  The driving force for this reaction is the formation of

Ø  Follows the same pattern as pinacol

Ø  There are two groups that could migrate

Ø  When the mixtures of geometrical isomer of oximes are

Ø  Tertiary group migrates in preference of the secondary

Ø  The alkene is not as reactive as expected because of

Ø  The transition state has two more electrons

Ø  Generally initiated by basic reagents which remove a group

Ø  The residual anion then stabilizes itself by rearrangement

Ø  In the first step an acid strengthening substituent is