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Molecular Rearrangements

Prashant S Kharkar, PhD September 13, 2012

Organic Transformations 4 Basic Types 1. Addition: Two starting materials combine to form a product. 2. Elimination: One starting material is divided into 2 products.

3. Substitution: An atom/group of atoms is replaced by another atom


or group.

4. Rearrangement: One starting material gives one product with


a different structure

Molecular Rearrangements

The migrating group W may move a) with its electron pair Nucleophilic or anionotropic rearragements; b) without its electron pair Electrophilic or cationotropic rearragements; or c) with just one electron (free radical rearrangements) Atom A: Migration orgin Atom B: Migration terminus
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1. Nucleophilic Rearrangements [1,2]-Rearrangements


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R(H) C+
2'

R(H)
2'

1'

+ C
1'

R(H)
2'

R(H) N2'

1'

+ N

+ C
1'

(1) Wagner-Meerwein rearrangements


Wagner-Meerwein Rearrangements are [1,2]-rearrangements of H atoms or alkyl groups in carbenium ions that do not contain any heteroatoms attached to the valence-unsaturated center C-1 or to the valence-saturated center C-2.
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R(H) C+
2'

R(H)
2'

1'

+ C
1'

CH3 CH3 C CH2OH CH3


CH3 CH3 C CH2 CH3

H+

CH3 CH3 C CH2OH2 CH3


Cl-

H2O

CH3 C CH2CH3 CH3

H+

Cl CH3 C CH2CH3 CH3 CH3C=CHCH3 CH3

Pinacol-Pinacolone Rearrangement

The Pinacol rearrangement is an acid-catalyzed dehydration reaction of a vicinal(1,2) diol accompanied by a rearrangement to form an aldehyde or ketone. The pinacol rearrangement has long been used as a model for the study of the rearrangement of a carbocation.

Pinacol-Pinacolone Rearrangement Mechanism

Pinacol-Pinacolone Rearrangement Pinacol as a rearrangement with a push and a pull.

Pinacol-Pinacolone Rearrangement Choice of migrating group

In case of unsymmetrical diols, usually, the reaction leaves behind the more stable cation.

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Pinacol-Pinacolone Rearrangement Choice of migrating group

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Pinacol-Pinacolone Rearrangement Choice of migrating group Carbocation stability is enhanced by groups aryl>alkyl>H Mixtures are often produced; which group preferentially migrates may depend on the reaction conditions as well as the nature of the substrate

Migratory aptitude for groups generally is H > aryl > alkyl


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Baeyer-Villiger Rearrangement

Oxidation of ketones with peroxy acids gives esters by a novel rearrangement.


General Reaction

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Baeyer-Villiger Rearrangement Example

Oxygen insertion occurs between carbonyl carbon and larger group. Methyl ketones give acetate esters. Cyclic ketones will give lactones
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Baeyer-Villiger Rearrangement Oxygen insertion occurs between carbonyl carbon and larger group. Methyl ketones give acetate esters. Cyclic ketones will give lactones Reagents: Peroxytrifluoroacetic acid Reagent of choice Othes like m-Chloroperbenzoic acid (mCPBA), Peracetic acid, hydrogen peroxide, etc. are also used. Disodium phosphate or sodium bicarbonate is often added as a buffering agent to prevent transesterification or hydrolysis Migratory aptitude: H > tert-alkyl > cyclohexyl > secondary alkyl, aryl > primary alkyl > methyl
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Baeyer-Villiger Rearrangement

H+ :O: Me H+

Bronsted acid/base interaction: Carbonyl oxygen is protonated. This will generate a more reactive carbonyl group

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Baeyer-Villiger Rearrangement

H+ :O: Me H+

:O H Me H O R R = H, CF3, 3-Cl-Ph
:

O: O

Nucleophilic Attack of the peroxy acid on the highly reactive carbonyl unit

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Baeyer-Villiger Rearrangement

H+ :O: Me H+

:O H Me H O R
:
:

O H Me O: H O O R

O: O

Sigma bonding electron-pair migrates with the phenyl group to the electropositive oxygen centre. This in turn initiates reorganization of sigma- and pibonding electrons in the peroxy acid group. The PHENYL group migration is very reminiscent of the [1,2]-Methyl shift in carbocation rearrangements.
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Baeyer-Villiger Rearrangement

H+ :O: Me H+

:O H
:

O H Me O: H O O R

Me H O R H Me
:

O: O R = H, CF3, 3-Cl-Ph

O O

Positive charge on carbon is neutralized through the loss of the hydroxyl hydrogen as a PROTON
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Baeyer-Villiger Rearrangement

H+ :O: Me H+

:O H
:

O H Me O: H O O R

Me H O R H -H+ Me O O Me
:

O: O R = H, CF3, 3-Cl-Ph

O O

Phenyl acetate
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Baeyer-Villiger Rearrangement Reaction is regiospecific; the alkyl group migrates with retention of configuration

Aldehydes usually give acids, with the exception of electron-rich aldehydes. Migration occurs with retention of conguration.

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Baeyer-Villiger Rearrangement

Baeyer-Villiger oxidations are highly stereoselective; migration occurs with retention of conguration. Recent work also demonstrates that alkoxyalkyl groups have an extremely high migratory aptitude

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