Crossed aldol condensation

In the presence of a strong base, two different molecules of aldehyde or ketone combine to form a β-hydroxyaldehyde or a β-hydroxyketone.

This reaction is called as the aldol condensation.

Introduction

The enolate ion (carbanion) is the actual nucleophilic reagent.

The reaction breaks down to the following:The α-carbon of the donor attaches itself to the carbonyl carbon of the acceptor.

Steps in Crossed aldol condensation

Rate limiting step: Formation of alkoxide ion

CH3 C

H

O CH3 C

H

O

CH2

C

H

O

CH2

C

H

O

+ _ _

.._

acceptor

donor

The carbonyl group plays two roles in this reaction:1. It provides a site for nucleophilic attack

by the enolate ion.2. It makes the a-hydrogens sufficiently

acidic to enable the formation of reasonable concentrations of enolate ion.

NOTE: There must be a-hydrogens in order to undergo aldol condensation.Without a-hydrogens, the only possible reaction is

Cannizarro reaction

Carbonyl group in Aldol reactions

If both carbonyl compounds have α-hydrogens, then the donor and acceptor could be controlled.

If one carbonyl compound that does not have α-hydrogens is chosen, it can only act as an acceptor.

Then, but adding the donor to a dilute solution of acceptor, we can control the reaction to give only one product.

CROSSED ALDOL CONDENSATION

C H

O

+

CH3 C H

O

NaOHC CH2

OH

H

C H

O

- H2O(spontaneously)

CH CH C H

O

CINNAMALDEHYDE

Step 1: Deprotonation and formation of nucleophile.

Mechanism of Crossed Aldol condensation

CH3CHOOH-

- CH2CHO

• Step 2: Attack by nucleophile: Formation of alkoxide ion.

C

O

H

- CH2CHO

CH

CH2CHO

O-

Step 3: Hydrolysis and formation of Aldol type product

Mechanism continued…

CH

CH2CHO

O-

H-OH

CH

CH2CHO

OH

+ OH-

Step 4: Intramolecular dehydration

CH

CH2CHO

OH -H2O

CH

CH.CHO

Cinnamaldehyde

The aldol condensation is very useful in the preparation of large molecules from simple starting materials.

In biosynthesis, where large molecules are products, condensation reactions provide the only reasonable route, since all of the starting materials are small molecules containing only two or three carbons.

In synthesis of insect repellants such as 2-Ethyl-3-hydroxy hexanal

Applications of Crossed Aldol reactions

Biological synthesis of fructose

CH2 CH C H

O

OHO

P

OH

OO

CH2 C CH2 O P OH

OH

O O

O

CH2 CH C CH C CH2 O P OH

O

O

O

OH

OH

HOHO

P

OH

O O

+

Glyceraldehyde-3-phosphate

Dihydroxyacetone phosphate

Fructose-1,6-diphosphate

ALDOLCONDENSATION

enzyme

THANK U

by B.Yeswanth Prasasnna

Kumar pharmD Ist

year