SERP course

A. Mickiewicz University,

Poznań 2012

Jan Milecki

Molecular

rearrangements

Neighboring group participation

O

Cl

Cl

Cl

S

Cl

TsO

TsO

Reacts with Nu

:

10

6

x faster than

Hydrolyses 600x faster than

Reacts with AcOH 10

11

faster than

Some reactions proceed just too easy!

What is the reason?

O

Cl

O

HO

R

O

O

R

Oxygen atom lone pair „pushes away” chloride ion, creating resonance-stabilized cation

O

O

Lone pair on the sulfur atom (strong nucleophile) expels chloride ion giving rise
to three-membered cyclic cation (strained and hence reactive)

S

Cl

S

Ph

Ph

HO

R

S

O

Ph

R

S

Cl

Cl

This mechanism is responsible for
alkylating activity (and hence toxicity) of
mustard gas!

Other examples of the lone pair assistance:

OTs

O

O

Me

O

O

Me

AcOH

OAc

OAc

OTs

OAc

=

Retention of configuration in the S

N

2 substitution indicates the neighboring group assistance!

Assisting electrons do not have to come from the lone pair –  orbital assistance

TsO

AcOH

AcO

+

Appropriate

structure

O

Ts

LUMO

HOMO

What happens, when the participating group becomes trapped and remains in the place, which was
the aim of electron attack? In this case isomeric product is formed – result of REARRANGEMENT

„Simple” substitution:

Et

2

N

Cl

Et

2

N

OH

HO

NEt

2

NaOH, H

2

O

Expected product

Real product (57% yield) .

Rearrangements

Et

2

N

Me

Cl

Good leaving group.

Secondary reaction center - slow

substitution by an external

nucleophile.

Good nucleophile,

bad leaving group

Alkyl group can migrate too

Me

I

Me

Me

Me

OH

Me

Me

AgNO

3

,

H

2

O

X

Me

I

Me

Me

Me

Me

Me

Toocrowded for S

N

2

Primary cation, too

unstable for S

N

1

Me

I

Me

Me

Me

I

Me

Me

Ag

Ag

C

Me

Me

H

H

H

+

=

Me

Me

Me

Me

Me

Me

OH

H

2

O

Transition state, rather

than intermediate

Et

2

N

Me

Cl

Et

2

N

Me

OH

HO

Me

NEt

2

Molecule rearranges to form
more stable cation

Me

Me

H

Me

H

Me

Secondary

Tertiary

Me

H

H

H

H

H

H

HOMO filled

orbital

LUMO empty

p orbital

Me

migrates

Me

H

H

H

H

H

H

Me

Me

H

H

H

HOMO

LUMO

_=

Me

Me

H

H

H

H

migrates

Carbocations rearrange easily!

How to produce a carbocation?

1. Dissociation of halogenides (promoted by silver ions)

2. Protonatiion of alcohols

3. Nitrosation of amines

(aliphatic)

RX

Ag

R

AgX

H

3

C

C

CH

3

CH

3

OH

H

3

C

C

CH

3

CH

3

OH

2

H

3

C

C

CH

3

CH

3

H

-H

2

O

H

3

C

C

CH

3

CH

3

H

2

C

NH

2

HONO

H

3

C

C

CH

3

CH

3

CH

2

+N

2

+ 2H

2

O

4. Protonation of alkenes

R

NH

2

O

N

OH

R

H

2

N

N

O

OH

R

H

N

N

O

R

N

N

OH

R + N

2

+ OH

Ar

N

N

OH

Ar

N

N

Ar

N

N

Aryl amines – dissociation only (stable salts)

H

H

How to predict the direction of rearrangement?

H

3

C

C

Ph

CH

2

C

4

H

9

H

3

C

C

CH

2

C

4

H

9

C

Ph

CH

2

C

4

H

9

CH

3

H

3

C

C

Ph

CH

2

C

4

H

9

Ph

Migration of phenyl group – very stable
intermediate (benzil and tertiary carbon atoms
in the three membered ring, charge spread over
phenyl ring). Favors this direction of migration

C

4

H

9

H

H

3

C

H





CH

3

shift

Ph shift

C

4

H

9

shift

The rearrangement was first discovered in bicyclic terpenes for example

the conversion of

isoborneol

to

camphene

The story of the rearrangement reveals that many scientists were

puzzled with this and related reactions and its close relationship to the

discovery of carbocations as intermediates

OH

OH

2

H

H

+

-H

2

O

Wagner-Meerwein rearrangement

Rearrangement of camphenilol to santene

Ring strain release can be a driving
force for rearrangement

Cl

Four-membered

ring

Five-membered

ring

HCl

Pinacol Rearrangement

 

                                                                               

In the conversion that gave its name to this reaction, the acid-
catalyzed elimination of water from pinacol gives t-butyl methyl
ketone

Mechanism of the Pinacol Rearrangement

This reaction occurs with a variety of fully substituted 1,2-diols, and can be
understood to involve the formation of a carbonium ion intermediate that
subsequently undergoes a rearrangement. The first generated intermediate, an
α-hydroxycarbonium ion, rearranges through a 1,2-alkyl shift to produce the
carbonyl compound. If two of the substituents form a ring, the Pinacol
Rearrangement can constitute a ring-expansion or ring-contraction reaction.

OH

OH

CH

3

CH

3

CH

3

O

CH

3

CH

3

O

CH

3

H

H

trans group migrates

OH

CH

3

OH

CH

3

OH

2

CH

3

O

CH

3

H

CH

3

O

CH

3

H

CH

3

O

CH

3

H

H

OH OH

OH OH

2

O

H

O

H

H

-H

2

O

Ring

expansion

OH

OH

CH

3

CH

3

OH

2

OH

CH

3

CH

3

CH

3

O

OH

2

CH

3

H

H

3

C

O

CH

3

H

H

CH

3

O

CH

3

H

Ring contraction

Baeyer-Villiger
Oxidation

                                                                                                                 
     

Mechanism of the Baeyer-Villiger
Oxidation

Order of migration R= tertiary alkyl > secondary alkyl > aryl > primary alkyl > methyl

H

R

3

N

R

R

1

R

2

R

3

N

R

R

1

R

2

B

R

3

N

R

R

1

R

2

R

3

N

R

R

1

R

2

R

3

N

R

R

1

R

2

Mechanism

Benzilic Acid Rearrangement

 

                                                                                                                                   

1,2-Diketones undergo a rearrangement in the presence of strong
base to yield α-hydroxycarboxylic acids. The best yields are obtained
when the subject diketones do not have enolizable protons.
The reaction of a cyclic diketone leads to an interesting ring
contraction:

 

                                     

Ketoaldehydes do not react in the same manner, where a hydride
shift is preferred (see Cannizzaro Reaction)

Mechanism of Benzilic Acid Rearrangement

Cannizzaro Reaction

 

                                                                                                                 

This redox disproportionation of non-enolizable aldehydes to carboxylic acids and
alcohols is conducted in concentrated base.
α-Keto aldehydes give the product of an intramolecular disproportionation in
excellent yields.

 

                             

 

                                                                                                                                                                 

Mechanism of the Cannizzaro Reaction

The Cannizzaro Reaction should be kept in mind as a source of potential
side products when aldehydes are treated under basic conditions.

Favorskii Rearrangement

O

Br

O

Br

:

O

EtO

EtO

O

OEt

O

OEt

O

OEt

Alpha-halogeno ketones

Hofmann Rearangement (Degradation)

R

1

NH

2

R

O

R

1

R

N

C

O

R

1

N

H

C

R

O

OH

R

1

NH

2

R

H

2

O

NaOH, X

2

X=Cl, Br

-CO

2

R

N

H

O

R

1

H

OH

R

N

O

R

1

H

X

O Na

R

N

X

O

R

1

R

N

X

O

R

1

H

H

2

O

R

N

X

O

R

1

H

-H

R

R

1

N

C

O

-X

R

N

H

O

R

1

H

OH

R

N

O

R

1

H

X

O Na

R

N

X

O

R

1

R

N

X

O

R

1

H

H

2

O

R

N

X

O

R

1

H

-H

R

R

1

N

C

O

-X

Mechanism

Intermediate

Nitrene

-X

R

N

O

R

1

Curtius Rearrangement

 

                                                                         

The Curtius Rearrangement is the thermal decomposition of carboxylic
azides to produce an isocyanate. These intermediates may be isolated, or
their corresponding reaction or hydrolysis products may be obtained.
The reaction sequence - including subsequent reaction with water which
leads to amines - is named the Curtius Reaction. This reaction is similar to
the Schmidt Reaction with acids, differing in that the acyl azide in the
present case is prepared from the acyl halide and an azide salt.
                                                         

Mechanism of the Curtius Rearrangement

Preparation of azides:

Decomposition:

Reaction with water to the unstable carbamic acid derivative which will undergo
spontaneous decarboxylation:

 

                                                                         

 

                                      

Isocyanates are versatile starting materials:

                                                               

Isocyanates are also of high interest as monomers for polymerization
work and in the derivatisation of biomacromolecules.

Beckmann Rearrangement

 

                                                                              

An acid-induced rearrangement of oximes to give amides.
This reaction is related to the Hofmann and Schmidt
Reactions and the Curtius Rearrangement, in that an
electropositive nitrogen is formed that initiates an alkyl
migration.

Mechanism of the Beckmann
Rearrangement

 

                                                                                 

Oximes generally have a high barrier to inversion, and accordingly this
reaction is envisioned to proceed by protonation of the oxime hydroxyl,
followed by migration of the alkyl substituent "trans" to nitrogen. The N-
O bond is simultaneously cleaved with the expulsion of water, so that
formation of a free nitrene is avoided

.

 

                                                         

 

                                                                              

Claisen Rearrangement

 

                                                         

The aliphatic Claisen Rearrangement is a [3,3]-sigmatropic
rearrangement in which an allyl vinyl ether is converted thermally to
an unsaturated carbonyl compound. The aromatic Claisen
Rearrangement is accompanied by a rearomatization:

 

                                                        

The etherification of alcohols or phenols and their subsequent Claisen
Rearrangement under thermal conditions makes possible an
extension of the carbon chain of the molecule.

Mechanism of the Claisen Rearrangement

The Claisen Rearrangement may be viewed as the oxa-variant of the Cope Rearrangement

 

                                                       

Mechanism of the Cope Rearrangement

 

                                                 

Mechanism of the Claisen Rearrangement

The aromatic Claisen Rearrangement is followed by a rearomatization:

When the ortho-position is substituted, rearomatization cannot take
place. The allyl group must first undergo a Cope Rearrangement to
the para-position before tautomerization is possible

.

                                                                             

Epoxides undergo similar rearrangement (pinacol-type)

Grignard reagents not always open epoxides in desired way!

O

Ph

Ph

Ph

Ph

O

MgBr

O

Ph

Ph

H

MgBr

2

O

RLi

RMgBr

OH

R

R

OH

O

MgBr

O

MgBr

O

H

RMgBr

R

OH

Schmidt Reaction  

   

 

                                

 

                              

 

                                  

Mechanism of the Schmidt Reaction

Reaction of carboxylic acids gives acyl azides, which rearrange to isocyanates, and
these may be hydrolyzed to carbamic acid or solvolysed to carbamates.
Decarboxylation leads to amines.

 

                                                                                                   

Alkenes are able to undergo addition of HN

3

as with any HX

reagent, and the resulting alkyl azide can rearrange to
form an imine:

 

                                                                                          

              
Tertiary alcohols give substitution by azide via a carbenium
ion, and the resulting alkyl azide can rearrange to form an
imine.