MOLECULAR REARRANGEMENTS

I. IntroductionRearrangement is a reaction in which a group or atom moves from

one position to other within the same molecule.

Atom A in example is called migration origin and atom B as migration

terminus.

These rearrangements can be of following types,

i.Nucleophilic or Aninotropic : in which migrating group migrates with its electron pair.

ii.Electrophilic or cationotropic : in which migrating group migrates without its electron pair.

iii.Free radical : in which migrating group migrates with only one electron.

A B

W

A B

W

Of these most commonly found are nucleophilic one.

These rearrangements can take place in two possible modes,

i.Intramolecular : In these migrating group do not completely detach from migration origin and migration of group is within the molecule only.

ii. Intermolecular : In these migrating group is completely detached from migration origin and migration of group can take place to different molecule.

A BW B WA

W A B + U A CA B W + A C U

A B U + A C W

+

II. Origin of 1,2-rearrangement

Different pathways through which 1,2-rearrngement takes place are

given below.

1.

2.

3.

C C

R

C C

R

C CO

RCO

R

CC

R

C CR

4.

5.

Reactions 1 to 3 show first reason for 1,2-rearrangement to take place

viz. formation of valence electron sextet at one of the carbon atoms of

substrate i.e. either carbocation or carbenium ion. Thermodynamic

driving force for potential 1,2-rearrangement will be significant if

rearrangement leads to structure with octets on all atoms [reaction 2 &

3] or generates some other more stable carbocation [reaction 1] i.e. if

a b y

x

a b

x

+ y

a b y

x

a b

x+ y

newly generated carbocation is stabilized electronically by its

substituents than old carbocation or angle strain is reduced due to

rearrangement in cyclic carbocation or newly generated carbocation is

captured in subsequent irreversible reaction.

Reaction 4 & 5 show second cause for occurrence of rearrangement.

In these reactions atom b is bonded to good leaving group.

Heterolysis of such a bond would give a carbocation. Departure of

leaving group is then assisted by neighboring group. This sometimes

gives a positively charged three membered ring as in reaction 5.

Rearrangement in such reactions is possible only if group x is present

at new position in product than in reactant.

III. Mechanism of nucleophilic rearrangement

Broadly these reactions consists of three steps ;

a)First step is generation of electron deficient centre in molecule. As the migrating group migrates with electron pair, the migration terminus must have an incomplete octet. This can be obtained in two ways ,

i.Through carbocation : Carbocations can be formed in various ways. The most common being dehydration of alcohol. This step is similar to that of SN1 or E1 reaction.

C

R

C OHH

C

R

C OH2 C

R

C-H2O

Rearrangement of carbocation is very important reaction in cracking of

petroleum products.

C

Me

Me

CH2BrMeSN1

C

Me

Me

CH2Me CMe

MeCH2Me

C

OH

Me

CH2MeMe + C C

Me

Me Me

H

C

Me

Me

CHMe CH2H C

Me

Me

CHMe CH3

C C

Me

Me Me

Me

C CH

Me

Me Me

Me

ii.Through nitrenes : nitrenes can be formed by decomposition of acyl azides.

b)Migrating group migrates to the previously formed electron deficient centre with its electron pair creating new electron deficient centre.

c)In third step, newly formed electron deficient centre acquires octet either by accepting a nucleophile or excluding proton.

It is observed in many cases that either two or all three steps take

place simultaneously. As seen in many cases SN1 type of first step is

very common followed by rearrangement to give more stable

carbocation. It is proved by fact that rate of reaction increases with

R C N N N

O

R C N

O

+ N2

ionizing power of solvent and it is unaffected by concentration of base.

It has been shown that rate of migration increases with degree of

electron deficiency at migration terminus.

IV. Actual nature of migrationMost of rearrangements are intramolecular. It can be shown by cross

over experiments. But, one more evidence for this fact is that, if

migrating group is chiral, its configuration is retained in the product. In

molecules where stearic nature of migration origin and terminus can

be investigated, mixed results are found i.e. either inversion or

racemisation takes place.

In this example inversion at migration terminus takes place.

But, it is not always possible for product to have two stearic

possibilities to investigate stereochemistry at migration origin or

terminus.

CPh

Ph

OH

C

H

NH2

MeHNO2

CPh

O

C

Ph

H

Me

Eg. In Beckmann rearrangement, only group anti to hydroxyl migrates.

This shows the concertedness of reaction. So, if, racemisation is

found at migration terminus, then it is probable that first step takes

place before second step, as in SN1 reaction.

And, if inversion occurs at migration terminus, then two steps might be

concerted, as in SN2.

RC

R1

NOH

R1CONHR

A B

R

X A B

R

A B

R

product

In this case, neighboring group assists departure of leaving group, as

in neighboring group nucleophilic substitution reaction. This

assistance increases rate of reaction.

In certain cases of SN1 type process, total retention of configuration of

migrating groups is seen due to conformation of carbocation.

A B

R

X A B

R

A B

R

product

V. Migratory aptitudeIn many reactions like Hofmann, Curtis, there is no question which

group migrates but in certain cases, like Beckman reaction, there

are more than one choices. But, of them, which migrates depends

upon geometry of molecule.

In Beckman reaction, only group anti to hydroxyl migrates, whereas in

case of Wagner-Meerwein and Pinnacol rearrangement, there are

many choices, as substrate contains several groups, that have equal

probability of migration. Such reactions are used for direct study of

relative migratory aptitude.

In Pinacol rearrangement, there is one more question which hydroxyl

group leaves. As it will create electron deficient centre for migration to

take place. The hydroxyl group lost will be that which generates more

stable carbocation.

In this example, hydroxyl group is lost from carbon bearing two phenyl

groups as it gives more stable carbocation. It is known that

carbocation stability is enhanced by group in order aryl > alkyl > H.

Hence, depending upon these substituents hydroxyl group is lost in

C CPh

Ph

OH

H

H

OH

C CPh

Ph H

H

OH

C CPh

Ph

H

H

O

C CPh

Ph

OH

H

H

reaction.

In order to study migratory aptitude in such reactions, substrate should

have structure R1RC(OH)C(OH)RR1 . In this case whichever hydroxyl

group leaves, it will give same carbocation and hence comparison on

migratory tendencies of R and R1 can be done.

Many factors are responsible in deciding migratory aptitude. One of

them is conformational effect. Another factor is, relative ability of group

that remains at migration origin, to stabilize positive charge.

Sometimes, if group that stabilizes positive charge is present on

migration origin, then group which actually is not having good

migratory ability, migrates. Along with this, migratory aptitude is

related to, ability of that particular group in assisting departure of

leaving group.

eg. In decomposition of tosylate, only phenyl group migrates while in

acid treatment of related alkene, competitive migration of methyl

and phenyl group is seen.

Only migration of phenyl group in first case is due to the fact that,

phenyl group assists in departure of tosyl group. Whereas, no such

possibility for second reaction.

CHCPh

Me

Me

OTsMe

reflux in benzeneC C

Me

MeMe

Ph

C CH

Ph

Me

CH2

Me

* H

C CPh Me

Me

*

Me+

C CMe Ph

Me

*

Me

All these factors costs no particular answer to migrating aptitude.

Though, in most cases, aryl migrates preferentially to alkyl group, but

it is not always true. Migratory aptitude of hydrogen is unpredictable.

Hence, mixtures are always obtained.

However, it is seen that in migration of aryl group, those having

electron donating substituents at meta or para position migrates

Preferentially, over those containing substituents on ortho position.

While, aryl group containing electron withdrawing groups show less

migratory aptitude.

VI. Reactions involving carbocationsA. Wagner-Meerwein rearrangement :

When alcohol containing more than two alkyl or aryl group on β

carbon are treated with acid, the product formed is generally a

rearranged product, rather than simple substitution or elimination

product. This reaction is called Wagner-Meerwein rearrangement.

Newly generated carbocation is stabilized generally by loss of proton

to give olefin and less often by nucleophilic substitution or loss of

some other positive group.

R2

R

R1

H

R3

OH H

R2

R1 R

R3

Mechanism of rearrangement goes through carbocation intermediate.

Wagner-Meerwein rearrangement was first found to take place in

bicyclic terpenes.

R2

R

R1

H

R3

OH H

R2

R

R1

H

R3

OH2

R2

R

R1

H

R3

R2

R1 H

R3

R

R2

R1 R

R3

OH H

Isoborneol Camphene

In these reactions, double bond is formed according to Zaitsev's rule.

Leaving group in this reaction can be hydroxyl or any other leaving

group which renders carbocationic character to carbon atom.

Direction of rearrangement is usually 30 >20 >10.

Sometimes several of rearrangement occur in one system either

simulataneously or in succession. Example of such a reaction is

C

CH3

H3C

CH3

CH2 Cl HC C

CH3

HH3C

H3C

OH

H

Camphenilol Santene

rearrangement in triterpene, 3- β-friedelanol. This compound on

treating with acid, 13(8)-oleanene is formed by seven successive 1,2

shifts.

A positive charge is generated on C-3, followed by removal of H2O,

2

34

5

10

1

6

7

8

9

11

14

13

12

15

16

17

18

19

22

21

20

H H H

HO

2

3 45

10

1

6

7

8

9

11

14

13

12

15

16

17

18

19

22

21

20

H

H

H

3-friedelanol 13(18)-oleanene

then hydride shift from 4 to 3; methyl shift from 5 to 4; hydride shift

from 10 to 5; methyl shift from 9 to 10; hydride shift from 8 to 9; methyl

shift from 14 to 8 and hydride shift from 13 to 14 takes place,

generating carbocation at C-13, which is stabilized by loss of proton

from C-18 to give olefin.

All these shifts are stereospecific.

Alkanes in presence of Lewis acid and some suitable initiator, also

undergo Wagner-Meerwein rearrangement.

Tricyclic molecules containing 10 carbon atoms on conversion give

adamantane, by successive 1,2 and 1,3 shifts of hydride and alkyl

AlCl3

group.

Tricyclic molecules containing more than 10 carbon atoms give alkyl

substituted adamantane.

Tricyclic molecules containing 14 or more carbon atoms, give

diamentane or substituted diamentane.

AlCl3

AlCl3

These reactions take place because of great thermodynamic stability

of adamantane, diamentane and similar diamond like molecules.

Some examples of Wagner-Meerwein rearrangement are given below.

AlCl3tBuBr

O

OEt

O

HO

O

OEt

O

TFA, DCM72h

76%

[ JACS, 1982, 104, 2631 ]

OH

Br

HBr, THF00C, 10 min

Ph

COOEtOH

Ph

EtOOC1 : 3 HSO3F, SO2ClF

~00C

[ Helvetica Chemica Acta, 1999, 82, 1458 ]

N

SSPh O

+

N

S S

O

H

HPh

N

S S

O

H

HPh

+BF3.Et2O-780C, 5h( 74% )

[ Helvetica Chemica Acta, 1999, 82, 1458 ]

N

Bz S O

N

S S

O

H

HBz

N

S S

O

H

HBz

++BF3 Et2O / DCM

-780C( 75% )

N

N O

O

HN

OHCOOMe

N

Br

O

NH

OMe

OMe

OMe

CH3SO3H1,2-DCE500C

N

N O

OHN

COOMe

N

Br

O

NH

OMe

OMe

OMe

86%

B.Pinacol rearrangement :

When vicinal diol is treated with acid, it rearranges to give aldehyde or

ketone. This reaction is called as Pinacol rearrangement, reaction was

originally found to take place in molecule.

The migrating group can be alkyl, aryl, hydrogen or ethoxycarbonyl

etc.

In case of symmetrical diols which hydroxyl is protonated and which

group migrates does not have much significance, but in case of

unsymmetrical diols it is important. Generally. Hydroxyl group is

protonated which gives more stable carbocation.

C

CH3

H3C

OH

C

CH3

CH3

OH

C

CH3

H3C

CH3

C

O

CH3H

Pinacol Pinacolone

In this reaction, hydroxyl group on carbon having two phenyl groups

will be protonated, as it will give more stable benzylic cation and is

formed faster.

When tri or tetra substituted glycol is used, different products

depending upon reaction condition is obtained. It also depends upon

migratory aptitude of different groups, as discussed earlier.

C

Ph

Ph

OH

C

CH3

CH3

OH

C

Ph

H3C

CH3

C

O

PhC

CH3

Ph

Ph

C

CH3

O

coldH2SO4

methylmigration

AcOH +trace ofH2SO4phenylmigration

OH OH

Ph

PhH2SO4

O

Ph

Ph

When, at least one group in glycol is hydrogen, aldehyde can be

prepared along with ketone. Aldehyde can be prepared in mild

reaction conditions such as weak acidic conditions, low temperature.

Mechanism of reaction is as follows;

C

R2

R1

OH

C

R4

R3

OH

H C

R2

R1

OH

C

R4

R3

OH2

-H2O

C

R2

R1

OH

C

R4

R3 CR1

OH

C

R2

R3

R4

-H

C

O

R1 C

R2

R3

R4

Migration of alkyl group from initially formed carbocation takes place

because, carbocation containing hydroxyl group are more stable than

that of 30 carbocation. Also, these carbocation can readily lose proton

to give corresponding carbonyl compound.

OH OH

H

O

Me2C C

OH OH

Ph

COOEt Me2C C

Ph O

COOEt

H

[ JOC, 2004, 69, 2017 ]

OHPh

OHPh

Ph

Ph

O

O PhPh

TsOH,CDCl3

+

[ Tet. Lett., 2002, 43, 6937 ]

N

SO2Ph

OH

OH

Ph

NSO2Ph

O

Ph1. MsCl, Et3N, DCM00C, 10 min

2. Et3Al, DCM-780C, 10 min

90%

Synthetically useful Pinacol rearrangement reaction is syntheses of

bridged bicyclic compound from a diol in following way.

OH OH O OH

OH2

H

H H

-H2O -H

LiAlH4

Similar type of reaction is also shown by compounds containing

different group than hydroxyl on adjacent carbon of that containing

hydroxyl group on it.

This reaction is known as Semipinacol rearrangement and involves

1,2 shift of H or alkyl from oxygenated carbon atom to neighboring C

atom i.e. carbocation to carboxonium ion rearrangement.

OHH

O

H

OBF3

BF3.Et2O -BF3

HO

OTs

O O

HO

O O

O O

O

LiClO4 inTHF,CaCO3

-H

OH

I

AgNO3

O

C.Expansion and contraction of rings :

When a positive charge is placed on alicyclic carbon, migration of

alkyl group can take place, giving ring smaller than original one. In this

transformation secondary carbocation is converted to primary

carbocation.

Similarly, when positive charge is present on carbon α to alicyclic ring,

then migration of alkyl group can give ring larger than original one.

This newly formed carbocation can then be stabilized by either

elimination or substitution.

CH2

CH2

This reaction represents special case of Wagner-Meerwein

rearrangement.

Generally, a mixture of rearranged and non rearranged products is

formed.

Reaction in which carbocation is formed by diazotization of amide is

called Demjanov reaction.

NH2

HNO2

OH

CH2OH+HNO2 CH2NH2

NH2

OH

OH

HNO2+

Mechanism is as follows.

NOHO N

OH2O

NOO

NO O

NOH -H2O

NH2N

O ON

O+

HN N O

N N OH

HNO2

N N OH2

N N

OH

H

-HNO2 H

-H2O

-N2 H2O

NH2

HNO2

OHOH

+

O

CN

LAH / Et2O00C

O

NH2

NaNO2

0.25MH2SO4 /H2O0-40C

O O

HO HO

+

[ Tetrahedron, 1993, 49, 1649 ]

O

OAc

CN

LiAlH4 / Et2O00C

O

OAc

NH2O

O

OO

+

NaNO2

0.25M H2SO4 /H2O, 0-40C

100%

12 : 1

It is found that, expansion reaction give good yields in smaller rings

where expansion gives relief from angle strain and contraction

reaction give otherwise good yields except for cyclopentyl cation.

An example of such ring expansion is; treatment of

16-methylpentaspiro[2.0.2.0.2.0.2.0.2.1]hexadecan-16-ol with

p-toluenesulfonic acid in acetone-water to give

2-methylhexacyclo[12.2.0.02,5.05,8.08,11.011,14]hexadecan-1-ol.

.

H3C OH

H

CH3OH

Reaction of certain amino alcohols give analogous reaction to

semipinacol rearrangement. This reaction is known as

Tiffeneau-Demjanov rearrangement.

HH

H

OH

40%H2SO4

H

H

OH

CH2NH2

OH

HNO2

O

These reactions carried out on four to eight membered ring, give

better results as compared to analogous Demjanov rearrangement.

[ Org. Biomol. Chem., 2004, 2, 648 ]

NH2

OH

O

NaNO2, AcOH,H2O, 00C, 1hthen reflux 1h

98%

SnBu3

CH2NH2HO

SnBu3

O

SnBu3

O

NaNO2AcOH +

64%

36%

NO

OH

CONEt2H2N

CONEt2

O

NaNO2, AcOH,H2O, 0-50C

60%

D.Acid catalyzed rearrangement of aldehyde or ketone :

Aldehyde or ketone on acid treatment give another ketone by

rearrangement.

Certain aldehyde or ketone are converted in this way to other ketones.

But, conversion of ketone to aldehyde is not seen in any case.

Mechanism of the reaction goes through protonation of carbonyl

oxygen. Two pathways are possible. One in which migration

of two groups is in opposite direction and other in which migration is

in same direction.

CR2

R3

C

R1

R4

O

H CR2

R3

C

R4

R1

O

Actual pathway is not certain. But, it is found that in certain cases only

one operates while in others both operate at same time. This can be

demonstrated by labeling carbonyl carbon. In first case, labeled

carbon is carbonyl carbon while in second case labeled carbon is

carbon α to carbonyl group.

Pathway 1:

CR2

R3

C

R1

R4

O

H CR2

R3

C

R1

R4

OH

CR2 C R1

R4

OHR3

CR2

R3

C

R4

R1

OH

-H CR2

R3

C

R4

R1

O

Pathway 2:

In case of α hydroxy aldehyde or ketone process may stop after one

migration. This is called α ketol rearrangement.

CR2

R3

C

R1

R4

O

H CR2

R3

C

R1

R4

OH

CR2 C

R3

R4

R1

O

H

CR2 C R1

R3

R4OH

CR2 C R1

R3

R4O

-H

[ J. Chem. Soc., 1956, 2483 ]

CR2

OH

C

R1

R3

O

H CR3

OH

C

R1

R2

O

OBenzene : conc.H2SO4

7 : 524h

O

85%

OBenzene : conc.H2SO4

7 : 524h

O

80%

E.Dienone-phenol rearrangement :

Cyclohexadienone containing two alkyl groups at position two or four,

on acid treatment undergoes 1,2-shift of one of these alkyl group, to

Give disubstituted phenol. Driving force of reaction is aromatization

of ring.

O

R R

H

OH

R

R

Mechanism is as follows;

O

R R

H

OH

R R

OH

R

H

R

OH

R

R

Particularly useful example is in syntheses of steroidal compound.

O

H

H

H

OH

HO

H

H

H

OH

H2SO4

1-methyloestradiol

F.Wolff rearrangement :

Wolff rearrangement is rearrangement reaction, in which a diazo

ketone is converted into ketene.

The rearrangement reaction takes place in presence of light, heat or

transition metal catalyst such as Ag2O.

The mechanism is supposed to proceed through formation of carbene

in presence of heat or light. It may also proceed through concerted

pathway in which no carbene is formed in presence of Ag2O.

R

R'

N2

O

-N2 R

R'

O

C CR

R'O

Thermally reaction is possible in range of room temperature to 7500C.

Generated ketene is highly reactive species, hence is more isolated. It

either adds nucleophile or undergoes (2+2) cycloaddition.

If the added nucleophile is water, then it forms carboxylic acid with

one carbon more. This reaction is known as Arndt-Eistert syntheses.

This reaction is of particular use in preparation of carboxylic acids with

one carbon more than starting one.

[ Org. Syn. Coll. 1988, 6, 840;1972, 52, 53]

H H

HO

O

N2

H H

HO

COOH

H

,dioxaneEt2O, H2O

h

Migratory aptitude of particular group is determined by whether

reaction is proceeding by thermal or photochemical pathway. In

photochemical pathway methyl is migrated preferentially while in

thermal pathway phenyl group migrates.

[ Org. Syn. Coll.1955, 3, 356; 1940, 20, 47 ]

PhPh

N2

O

-N2 C CPh

Ph

O

H

O

N2

O

O

O O

EtOH : dioxane1 : 1

h /

Other 1,2 migrations to carbene are also known.

C

CH3

H3C

CH3

CHN2

C

CH3

H3C

CH3

CH C CHCH3

H3C

H3Ch

+

52%

47%

N

O

N2

O

h / MeOH

N

COOMe

O

90%

G.Homologation of aldehyde or ketone :

Aldehyde or ketone can be converted to their higher analogs on

treatment with diazomethane.

Though, it appears to be an insertion reaction, it is purely

rearrangement reaction. Carbene is not formed in the reaction.

R R'

OCH2N2

RR'

O

R H

OCH2N2

R

O

Mechanism is as follows,

In case of aldehyde, hydrogen migrates preferentially which is evident

from good yields of methyl ketone.

R C R'

O

H2C N N+ C

CH2

R

O

R'

N N

C

CH2

R

O

R' R CH2C R'

O

-N2

An interesting example of this reaction is, preparation of bicyclic ring

compound using alicyclic compound containing diazo group in side

chain.

CHN2

O O O

+

H.Neighboring group participation:

Rearrangement is seen in reaction of NGP type, when the group

showing anchimeric assistance is detached at one point in substrate

and is attached to other point in final product.

CHPh CH

NR2

Br

COPh CHPh CH

N

COPh

R2

CHPh CH COPh

OH

NR2

NR2 :- N O

H2O

-H

In this reaction, due to anchimeric assistance of morpholino group,

rearrangement is seen.

CHH3C CH2

Cl

ONs CHH3C CH2

OOCCF3

Cl

ONs :- NO2RO2SO

CF3COOH

I.Migration of boron to electron deficient carbon:

On heating non terminal boron at about 100-2000C, boron moves

towards end of chain.

Boron can move past a branch.

C C

B

CC C C C

B

C CC C

B

C CCC

C CC C

CB

C CC C

C B

But, boron can not move past double branch.

If boron is present on ring, then it moves across ring and if an alkyl

side chain is present on ring, it ends on terminal carbon of side chain.

C C

B

CC C

C

C

C C CC C

C

C

B

C C CC C

C

C

B

H3C C

CH3

CH3

CH

B

CH CH3

CH3

H3C C

CH3

CH3

CH2 CH CH2

CH3

B

The reaction is useful in migration of double bond in controlled way.

B B1500

diglyme

B

B

RCH CH2

B

B

H2O2 /OH

OH

H

BH2

CH2BH2

H

H

H2O2 /OH

CH2OH

H

H

BH3, THF 1100C

J.Neber rearrangement:

Neber rearrangement is a reaction in which a ketoxime tosylate is

converted to α-amino ketone upon treatment with base.

RR'

NOTs

baseR

R'

O

NH2

RR'

NOTs

base RR'

NOTs

RR'

N

H2O

RR'

O

NH2

Base first abstracts proton α to ketoxime group. This carbanion then

displace tosylate group in nucleophilic displacement and forms azirine

which on hydrolysis gives α-aminoketone.

The reaction is sometimes assisted by Beckmann rearrangement

though it generally occurs in acidic conditions.

[ JACS, 2002, 124(26), 7640 ]

Ph

F

NOTs

1. 50% Toluene / KOH2. BzCl, Py / DCM, 6N HCl Ph

F

O

NHBz

[ JACS, 1953, 75(1), 38 ]

O2N

NO2

CH2 C

NOTs

O2N

NO2

CH C

ONH2

H2O,NaHCO3

Cl CH2 C

NOTs

ClH2O , NaHCO3

Cl CH C

O

Cl

NH2

NPh

Ph

OTsN

K2CO3

THF , rt ,18h

NPh

Ph

O

H2N

VII.Rearrangement reaction of electron deficient nitrogen

A.Hofmann rearrangement:

When an unsubstituted amide is treated with sodium hypobromite, it

gives corresponding primary amine with one carbon less. This

reaction is known as Hofmann rearrangement.

R in this reaction can be alkyl or aryl.

R C

O

NH2 + NaOBr R N C O RNH2 + CO2hydrolysis

Mechanism of reaction is as follows,

In the first step, base removes proton from amide. This conjugate

base of amide then reacts with bromine to give N-bromoamide.

R C

O

NH

H

OH R C

O

NHBr Br R C

O

NH

Br

OH

R C

O

N Br R C

O

N R N C OH2O

N

R

OH

O

H

HN

R

O

O

OH RNH2 + CO2OH

H

H

Acidity of proton on nitrogen is increased by this bromine atom and its

removal becomes easy for base to give nitrene intermediate in which

nitrogen is electron deficient. 1,2-shift of alkyl group takes place in this

nitrene to give corresponding isocynate. This isocynate on hydrolysis

gives primary amine with one carbon less than starting material.

NH2

O

NH2

Br2 /NaOH

H2O

NO2

O NH2

NaOBr / H2O

NH2

NO2

If methanol is used as solvent, in place of water then corresponding

carbamate ester is obtained.

O

NH2

O

NBS, DBU,MeOH, reflux

O

HN O

O

N

NH2

O

NBS, Hg(OAc)2,CH3OH, DMF

N

HN O

O

(H3C)3C

O

NH2

dibromotin, Hg(OAc)2,PhCH2OH, DMF

NH

O

OCH2Ph(H3C)3C

OO

C9H19

R

Bn

NH2

O

C9H19

HN OB

n

O

O

R

Bn75%

1. Pb(OAc)4,BnOH, DMF1000, 15h2. TsOH,acetone, H2O,reflux, 2.5h

R :- PhMe2Si

OH

O NH2

N

Cl Pb(OAc)4tBuOH500

OH

NH

N

ClBuO

O

t

70%

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.

O

O

HO

OH2N

OPMP OROMe

O

O

O NH

OPMP OROMe

O

NaOMe, Br2

MeOH, -780

1h, reflux

93%

CH

Ph

CONH2NaOH CH

Ph

NH2

B.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.

R N3

O

R N C O

R N

O

N N

-N2

R N

O

R N C O

In the similar reaction, alkyl azides give imines.

R may be alkyl, aryl or hydrogen. In case of tert.alkyl azides, there is

evidence of existence of nitrene.

Cycloalkyl azides give ring expansion.

R N

O

N N+ N2R N C O

NRR2CR3CN3

R

N3

HN

R

NR+

80% 20%

Aryl azides also give ring expansion on heating.

If the reaction is carried out in di-tert.butyldicarbonate, product will be

Boc protected amine.

[ Org. Lett. 2005, Vol.7, No.19, 4107 ]

N3

PhNH2N

NHPh

EtOOC

Ph

OH

O

NHBocEtOOC

Ph

Boc2O, NaN3

Bu4NBrZn(OTf)2THF, 500C

HO

H

HOH

H

HO

H

Boc2O, NaN3

Bu4NBrZn(OTf)2THF, 400C

HO

H

H

NHBoc

H

H

H

[ Bioorganic and Medicinal Chem. Lett., 9 April 1996, Vol.6,

Issue 7, 807 ]

[ Tet. Lett., 19 Feb 2007, Vol.48, Issue 8, 1403 ]

HOOC

HOOCCOOH

H2N

H2NNH2

1. Et3N, DPPABzOH

2. HBr / AcOH

cis,cis-cyclohexan-1,3,5- cis,cis-1,3,5-triamino-tricarboxylic acid cyclohexane (82%)

OH

N3

O

N3

O

tBuOHreflux

NH

O

NHBoc

O

[ JACS, 2001, 123, 12426 ]

O

O

O

HO

O

O

OTBS

HH

Hunigs baseiBuOCOCl00C, NaN3

H2O, toluene15 min,TMSCH2CH2OH3h,

O NH

O

TMS

OPMB

O

PMB

O

O

O

CHOO

SOCl2Me3SiN3reflux

N

C.Lossen rearrangement:

O-acyl derivatives of hydroxamic acids on heating with base give

isocynate, this reaction is known as Lossen rearrangement. Isocynate

can be further hydrolyzed to corresponding amines.

Mechanism is similar to that of previous reactions.

R NH

O R

O

O

OHR N C O RNH2

H2O

R NO R

O

OOH

R NO R

O

O

R N C O

H

[ Appl. and env. Microbiology, 1997, Vol.63, No.9, 3392 ]

CONHOC

H

NHR1

NHR2CNO

H

H2O

NH2

H

R1 : Et , R2 : (CH2)3NMe2

Cl

O

Br

EtOOC

HN

OCOOEt

Et3N, H2OBr

N C O

EtOH, H2O

Br

NH2

The reaction can also be carried out with hydroxamic acid.

[ J.Braz.Chem.Soc., 1995, Vol.6, No.4, 357 ]

O

OH

OH

CONHOH

O

OH

O

NH

O

Na2CO3PhOSO2Cl

COOH NH2

1. NH2OH.HClH3PO4

2. KOH

[ JACS, 1953, 75, 2014 ]

OH

O

NH21. NH2OH.HCl

H3PO42. KOH

D.Schmidt rearrangement :

Reaction of carboxylic acid or aldehyde or ketone with hydrazoic acid

in presence of mineral or Lewis acid to give corresponding primary

amine or amide respectively is known as Schmidt rearrangement.

Cyclic ketones give lactums.

RCOOH + HN3 R N C O RNH2H H2O

R R1

O

HR N

H

R1

O

+ HN3

O NH

OHN3 / H

Mechanism is similar to that of Curtius rearrangement, except that

protonated azide undergo rearrangement.

R OH

O

H-H2O

R

OH N N N

R N3

O

R

O

N N NH

R

O

N N NH

R NH

C OH

H2ORNH2 + CO2

Mechanism with ketone is,

In reaction with ketone, ketone is activated by protonation for

nucleophilic addition of azide group to it.

R R1

OH

R R1

OH HN3

H N N N

R C R1

OH

-H2O

N N N

R C R1 R1 C N RH2O

R1 C N R

OH2

-H R1 C N R

OHR1 N

H

R

Otautomerism

-N2

In case of alkyl aryl ketone, aryl group migrates preferentially except

for bulky alkyl group.

Intramolecular Schmidt reaction can be used for preparation of

bicyclic lactums.

N3

O

H

MeAlCl2 / DCM N

O

Ph

96%

MeOOCN3

ON

O

MeOOCTFA / 12h

[ JACS, 1991, 113, 896 ]

[ Org. Syn., 2007, 84, 347 ]

O

N3

N

O

1. SPh2

2. LiBF43. TiCl4

81%

O

N3N

O

TFA

[ JOC, 2007, 3, 949 ]

Reaction of tert. alcohol and olefins with hydrazoic acid in acidic

condition to give substituted imines is often termed as Schmidt

rearrangement.

MeO

MeOH3COOC

N3

ON

MeO

MeOH3COOC

OTriflic aciddry DCM-50-00C15 min

54%

OH

RRR

HN3 / H2SO4

R

R

N

R

Mechanism of the reaction is as follows.

R

R R

R

HN3 / H2SO4

R

R R

N R

OH

RRR

OH2

RRR

RRR

N

RRR

N N

CR

RN R

H -H2O HN3

-N2

R

R R

R R

R R

RH R

R R

RH

N N N

R

R N

RH

H

R

R

R N

R

R

H HN3 -N2

-H

H

[ Tet. Lett., 1988, 29, 403 ]

H3C OEt

O O

CH3

HN

OEt

O

CH3

H3C

ONaN3, CH3SO3H

CHCl3, 0.5-1 h

89%

ADA

O O

ADA

HN

O

O

O

N

ADA

NaN3, CH3SO3HDME, -300C-rt

ADA :

E.Beckmann rearrangement :

Oximes on treatment with Lewis acid or protic acid rearrange to give

substituted amides. This reaction is called as Beckmann

rearrangement.

Generally group anti to hydroxyl migrates. However this is no hard

and fast rule. R and R’ can be alkyl, aryl or hydrogen. Hydrogen does

not migrate under conditions of reaction but it migrates when reaction

is carried out with nickel acetate under neutral conditions.

R'R

NOH

PCl3

R' NH

R

O

Like Schmidt rearrangement, oximes of cyclic ketones give ring

enlargement.

Mechanism of reaction usually goes through alkyl migration with

expulsion of hydroxyl group followed by reaction similar to Schmidt

rearrangement.

NOH NH

O

Other reagents convert hydroxyl to an ester leaving group. Course of

mechanism is supported by detection of nitrillium ion by NMR and UV

spectroscopy.

R R1

NOH

R R1

NOH2

R1 C N R

R1 C N R

R1 C N R

OH2

R1 C N R

OH R1 NH

R

O

H-H2O

H2O

-HR1 C N R

[ Indian journal of chemistry, 2005, 44B, 18 ]

[ Catalysis Lett., 2005, 103, 165 ]

MeO

NOH

MeO

HN

O

H3PO4microwave

82%

NOH

HN

O

+

NH

O

MeCN, 10% Ga(OTf)3850C, 16h

[ Chemistry of natural compounds, 2009, 45, 519 ]

NHO

HN

O

SOCl2, 100C, 1%KOH

[ SynComm., 2006, 36, 321 ]

[ JOC, 2002, 67, 6272 ]

NN

OHN

NOH2SO4

microwave1800C

NOH

N

N

N

Cl

ClCl

DMF, rt, 8h

HN O

100%

[ JOC, 2007, 72, 4536 ]

I NOH

HN

O

I

12% HgCl2,MeCN , 8h

F.Stieglitz rearrangement :

Stieglitz rearrangement is a general term applied for rearrangement

reaction of trityl-N-haloamines and hydroxylamines to trityl imine.

Mechanism is as follows,

Ar3C NHOH Ar2C NArPCl5

Ar3C NHX Ar2C NArbase

NH

Ph

PhPh

OH

+ P

Cl Cl

Cl Cl

Cl

NH

Ph

PhPh

O

P

Cl Cl

Cl

Cl

Ph

PhNPh

Reaction can also be facilited by treatment with lead tetraacetate.

[ JOC, 1974, 39, 3932 ]

Ar3CNH2 Ar2C NArPb(OAc)4

C

NH2

Ph2 OCH3Pb(OAc)4 N OCH3Ph2C

+

CPh

PhN OCH3

~98%

~2%

When methanolic solution of N-chloroisoquinudine was refluxed for 2h

with AgNO3, AgCl was precipitated and 60% of

2-methoxy-1-azabicyclo[3.2.1]octane was obtained.

N

Cl

AgNO3MeOH

N

MeO

VIII. Rearrangement reactions involving electron deficient oxygen

A.Baeyer-Villiger rearrangement :

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.

R : H, OAc, OCOPh etc.

R R1

OPhCO3H

R OR1

O

R

O

H

O

R

H

O

CF3CO3H

Mechanism is as follows,

First step is addition of peroxy acid to carbonyl forming tetrahedral

intermediate. In next step concerted migration of migrating group and

loss of carboxylic acid to give product.

The mechanism is supported by fact that oxidation of Ph2C18O yields

R R1

OH

R R1

OH

C

OH

R R1

O O R2

OCRO R1

OH RO R1

O

R2CO3H

-H

only PhC18OOPh i.e. there is no scrambling of 18O label in product

ester. Loss of carboxylates and migration of R is concerted is by fact

that reaction is speeded up by electron withdrawing

substituent in leaving group and electron donating substituent in

migrating group.

Carboxylates are as such not very good leaving group. But, O-O bond

is very weak and monovalent O can not carry positive charge. So that

once peracid is added loss of carboxylate is concerted with

rearrangement driven.

Synthetic usefulness is syntheses of L-Dopa drug used to treat

Parkinson's disease.

If the migrating group is chiral then its stereochemistry is retained. By

looking at orbitals involved in reaction, this can be explained. The

sp3 orbital of migrating carbon just slips from one orbital to next with

minimum amount of structural reorganization.

HO

COOH

NH2

AlCl3,AcCl

HO

COOH

NH2

H2O2,NaOH

O

HO

COOH

NH2

OH3O

OHO

COOH

NH2

HO

L-tyrosine

L-Dopa

new sigma bond

forms on same face

of migrating group-

stereochemistry

retained.

Ph

O

ArCO3HOPh

O

O

H

Ph

PhO

O

O Ar

O

Ph

O

H

Ar

O

: orbitals of oxygen

: orbitals of carbon

Migratory aptitude in unsymmetrical ketones is as,

H>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 O2 with

migrating group is termed as secondary stereoelectronic effect.

Ph Ph

O

F

PhO Ph

Ph OPh

F

O

F OmCPBA /CHCl3NaHCO3

+

71% 29%

In case of unsaturated ketones epoxidation is likely a competitive

reaction. But, Baeyer-Villiger rearrangement is favored because ring

strain can be relieved by oxyinsertion and ring expansion.

HO

RR

OCOR'

secondary

primary

O

O

O

mCPBA

BnOBnO

Chemoselective oxidation of β-lactum aldehyde has been achieved

with mCPBA in DCM where only formates are formed in better yields.

[ Tet. Lett., 1995, 36, 3401 ]

OO

OH2O2, AcOH

H

H

H

H

O

H HC

CHO

OMe

mCPBA, DCMrt, 20h

O

H HC

OCHO

OMe

70%

Aldehyde can be oxidized to carboxylic acid due to preferential

migration of hydride. Group that can stabilize positive charge on

oxygen migrates.

Other reactions are given below.

[ JOC,1962, 27, 24 ]

Br

Cl

H

O

mCPBA, DCM

Br

Cl

OH

O

O

O

OH2O2 BF3

ether

[ JACS, 1988, 110, 6892 ]

[ JACS, 1955, 77, 2287 ]

O

O

O

O

O

cyclohexanoneoxygenase

O

O

OCF3CO3H in H2O2(CF3CO)2O in DCMNa2HPO4 in DCM

O

OBn

BnO

BnO

Cl

Cl

O

O

O

OBn

BnO

BnOCl

Cl

OmCPBANaHCO3DCM

OOHO

HO

HO

OOHO

HO

HO

OmCPBA, DCM

O OO

Caro's reagent

O O

OKHSO5, rt, 24h

[ Chem.Comm., 1996, 2333 ]

O

OKHSO5, rt, 24h

O

O

O

O

cyclopentanonemonooxygenase

98% ee

[ JOC, 2002, 67, 3651 ]

[ JOC, 2008, 73, 2633 ]

N

OH

H

H

ClCbz

mCPBA, NaHCO3DCM, rt, 30 min

N

O

O

H

H

H

Cl

Cbz

85%

H

Ph

O

COOMeCbzHN

TFPAA, 00C,DCM, >5h

H

PhO

O

COOMeCbzHN

75%

[ Tet. Lett., 2009, 50,4519 ]

MTO : Methyltrioxorhenium

[ Tet. Lett., 2001, 42, 5401 ]

O

OO

mCPBANaHCO3

DCM, 00C,30min

60%

OH3CO

OO

O

O

H3COH2O2,

supported MTO,tBuOH, 800C

[ JACS, 2010, 132, 8219 ]

[ Tet. Lett., 1992, 33, 7557 ]

H

HOH

O

O

OAcH

HOH

O

4 eq mCPBA1,2-DCE,

rt then 800C48h

65%

O

O

O

+

O

O1. Fe2O3, O2C6H5CHObenzene2. NaHCO3

97 : 3

[ JOC, 1993, 58, 4516 ]

N

PO

O

ON

PO

O

O B

Bu

Bu

N

PO O

O O

75%

Bu2BOTiPr2NEtDCM, -100C

1. PhCHO,-780C

2. 30% H2O2

[ JOC, 1994, 59, 3123 ]

N

O

O

Ph

CH2Ph

O

N

O

O

Ph

CH2Ph

mCPBA, DCM-400C, 60 min

B.Rearrangement of hydroperoxide :

Hydroperoxides can be cleaved in presence of protic or Lewis acid.

Reaction goes through rearrangement.

Mechanism is as follows.

C

R

R

OR O HH

R R

O

+ ROH

C

R

R

OR O H C

R

R

OR O H

H

C

R

ORR

C

R

ORR

OH2R R

O

+ ROH

H -H2O H2O

Acid converts peroxide to protonated peroxide which loses water

molecule. Simultaneously, shift of alkyl group to electron deficient

oxygen gives rearranged carbocation, which reacts with water to give

hemiketal which breaks down to give alcohol and ketone.

Alkyl group must be showing some sort of anchimeric assistance and

the rearrangement must be going through benzonium ion.

OOHPhAcOH

O OH

+

Benzonium ion :

OOH

OHO

+H2O / H

TS

IX. Free radical rearrangement

1,2-free radical rearrangements though less common are observed in

some cases. The mechanism is similar. First a free radical is

generated, which rearranges itself by one electron transfer. This is

followed by stabilization of newly formed radical.

As in carbocation rearrangement reactions, radical rearrangements

also show pattern as primary to secondary to tertiary.

A B

R

A B

Rproduct

Reaction of 3-methyl-3-phenylbutanal with di-tert.butylperoxide gave

product with and without rearrangement.

In this reaction no migration of methyl group is seen. Also, migration of

hydrogen is not seen (seen to lesser extent ) in free radical

C

Me

PhH2CMe CHO C

Me

Ph

CH2Me C

Me

Ph

CH3Me

C

Me

H2CMe Ph

HC

Me

H2CMe Ph

Habstraction

Habstraction

rearrangement

50%

50%

rearrangement. As phenyl group, groups like vinyl, acetoxy can also

migrate.

Also, migration for chloro group has been observed.

It is shown that migration of Cl takes place easily if migration origin is

tertiary and migration terminus is primary.

C

Cl

Cl

CHCl CH2Br C

Cl

Cl

CHCl CH2

Br

C

Cl

CH

Cl CH2

BrCl

Br2 C

Cl

CH

Cl CH2

BrClBr

Migration of chlorine and bromine might be taking place because they

can accommodate an odd electron in vacant d-orbital.

In summary, 1,2-free radical rearrangements are less common as

compared to analogous carbocation process and direction of

migration is usually towards more stable radical.

Apart from usual 1,2 shifts, 1,3 and longer distance shifts are also

known. 1,5 being most common. Transannular H shifts are also

known.

X. Migration from nitrogen to carbon

Stevens rearrangement :

In Stevens rearrangement, quaternary ammonium salt containing

electron withdrawing group on α carbon atom when treated with

strong

base rearrange to give tertiary amine.

Rearrangement is intramolecular is shown by cross over experiment.

Also, retention of configuration was seen in product.

Two mechanistic pathways are possible. One involving radical pair

trapped in solvent cage. Presence of solvent cage is important in

order to explain retention of configuration.

N

R1

R2

R3Z

N

Z

R1

R3

R2

NaNH2

Other is involving ion pair in solvent cage.

N

R1

R2

R3Z

N

R1

R2

R3Z

N

R1

R2

R3Z

N

R1

R2

R3Z

N

Z

R1

R3

R2

base

N

R1

R2

R3Z

N

R1

R2

R3Z

baseN

R1

R2

R3Z

N

Z

R1

R3

R2

Concerted reaction mechanism can also operate. But, it can not be

accounted as it requires antarafacial mode but migrating group retains

its configuration.

Reaction is used for ring enlargement.

When Z group is an aryl group, the rearrangement is known as

Sommelet-Hauser rearrangement, in which reaction of tert.alkyl

ammonium salt with NaNH2 gives N-dialkylbenzylamine with ortho

substituted aromatic ring.

NBz

N

Ph

NaNH2 / NH3

90%

Another competing reaction is Hofmann elimination, when one of the

alkyl group contains β hydrogen atom.

Sulfur yields in place of nitrogen yields also give similar reaction.

N

NaNH2 / NH3N

ZHC S

R1

R2

ZHC

R1

SR2

Some examples of Steven rearrangement are given below.

Ph

O

N PhPh

O

Ph

NNaOH

N

Et

Et

Et2NKOtBu / MeCN

N

N

PhLi

N N

tBuOK1,4-dioxane

800C

88%

N

O

COOBn

N

HC OBnOO

base

84%

[ JOC, 1974, 39, 130 ]

[ Tet. Lett., 2002, 43, 899 ]

PhHCN NN N

Ph

nBuLi inhexane

NCOOEt

Br

EtOOC

K2CO3

DMF00C-rt N COOEt

EtOOC

NCOOEtEtOOC

NN

HN

N

ONNC

base

NN

HN

N

O

NN

HN

N

O

N

NC

NC

N+

[ Tet. Lett., 2004, 45, 7525 ]

N

Ph Ph

R1

N

Ph

Ph

R1

base

N

OTfN

THF, PhLi /KHMDS-780C

XI. Migration from oxygen to carbon

Wittig rearrangement :

Ethers on reaction with alkyl lithium rearrange in similar manner to

that of Stevens rearrangement to give alkoxy lithium. This reaction is

called Wittig rearrangement.

This alkoxy lithium can then be converted to alcohol.

C

R2

H

OR3R1 R4LiC

R2

R3

OLiR1 + R4H

C

R2

R3

OLiR1 C

R2

R3

OHR1H

R may be alkyl, aryl or vinyl group.

Migratory aptitude are allylic, benzyl>ethyl>methyl>phenyl.

Mechanism follows radical pair pathway.

C

R2

H

OR3R1 R4Li C

R2

OR3R1 C

R2

OR1 C

R2

OR1

C

R2

R3

OLiR1

R3

R3

Li

i.Reaction is largely intramolecular

ii.Migratory aptitude of group is analogs to free radical mechanism.

iii.Product obtained is with retention of configuration.

Ph OPh OLi Ph OH

BuLi H

O O TMS

H

OTBDPS

OTMS

H

OTBDPS

OH

nBuLi, THF,ether, 00C

60%

O

O

O OH58%

tBuLi

MeO

O

NOMe

MeO

NOMe

OH

2eq. LDATHF, -780C

[ Tet. Lett., 1993, 34, 297 ]

tBu

O

SePh

CH2Ph

tBu

Li

OCH2Ph

NaphthyllithiumTHF, -780C, 20 min

tBu

OH

OCH2Ph

tBu

CH2Ph

OH

+

DMSO/ H2O /K2CO3

4h,

[ Tetrahedron, 2005, 61, 1095 ]

OMe

HO

O

OMe

OO tBuLi

THF-780C

When R2 is a good leaving group and electron withdrawing functional

group like CN, then this group is eliminated and ketone is formed.

C

CN

R1 OR

H

R1 R

O

+ R2H + LiCNR2Li

C

CN

R1 OR

H

R2LiC

CN

R1 O

Li

C

CN

R1 OLiR

C

CN

R1 OLi

R

R1 R

O

R

Bt : benzotriazol-1-yl

[ JACS, 1996, 118, 3317 ]

Bt

Ph O OCH3

PhOCH3

O

LDA

61%

OTBSO

TBSO OTBS

O PhO

HO

TBSO OTBS

Ph

HO

nBuLi, THF-780C-00C

[ Org. Lett., 2001, 3, 2529 ]

N

N

F3C O

O

Ph

Ph

F3C OH

OPh

Ph

N

F3COH

OPh

LiHMDSTHF / ether-780C-rt

+

[ JACS, 1962, 84, 4295 ]

[ JACS, 1966, 88, 78 ]

H2COPhH2C

MeLi H2CC

H

OH

Ph

O PhPhnBuLi Ph

OHPh

O Ph

Li

PhnBuLi Ph

Ph

OH

+Ph

OHPh

[ Tet. Lett., 2000, 11, 1003 ]

O

ON

O

N

O

29%

Et2OBuLirt, 1.3h

XII. Crossover experimentThe purpose of crossover experiment is to determine whether reaction

takes place intermolecularly or intramolecularly i.e. whether reactant

break apart to form intermediate which are released into solution

before they combine to give product.

In this experiment two substrate differing in substituent are mixed

together and are reacted in same reaction condition and the product

obtained is analyzed.

Consider, a simple reaction in which A-B reacts to give C-D.

A B C DA* B* C* D*+ +

A B C DA* B* C* D*+ + C* D C D*++

There are two possibilities of outcome of reaction.

One in which no crossover of substituent is seen. This is possible if

reaction is intramolecular.

And other possibility is that mixture of products obtained is by

crossover reaction. This is possible in case of intermolecular reaction.

Thus crossover experiment gives useful information about course of

reaction.

The experiment can be illustrated by considering Fries rearrangement.

p-Tolylbenzoate (I) on rearrangement gives

2-hydroxy-5-methylbenzophenone (II).

In the similar reaction, o-chloro-p-tolylacetate (III) give

2-hydroxy-3-chloro-5-methylacetophenone (IV).

O

O

PhAlCl3

OH

Ph

OI II

O

O

AlCl3

OH

O

ClCl

III IV

When I and II are mixed together and product is analyzed, V and VI,

along with II and IV are obtained.

This shows that the reaction proceeds intermolecularly and fragments

are formed in solution.

OH

O

OH

Ph

O

Cl

V VI