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Aldol Condensation

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The aldol condensation is an important reaction that basically follows the mechanism of nucleophilic addition to a carbonyl. Aldehydes acts both as a nucleophile and a target. When acetaldehyde is treated with base an enolate ion is produced. This enolate ion, being nucleophilic can react with the carbonyl group of another acetaldehyde molecule.
Aldol condensation is an important organic reaction between an enol or enolate and a non-conjugated ketone or aldehyde.

Mechanism

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In the aldol condensation the $\alpha$-carbon atom of an aldehyde or ketone which bears a hydrogen atom adds to the carbonyl carbon atom of another aldehyde or ketone. The product is a $\beta$-hydroxy aldehyde (aldol) or ketone which can dehydrate to give aldol.

Aldol Condensation Mechanism

The aldol condensation is a very attractive route to $\alpha, \beta$-unsaturated carbonyl compounds. Aldol condensations have been performed over a temperature range between -33oC and around 100oC. The reaction times can vary from some minutes to several days. The yields of the aldol condensation reactions are enhanced by applying a large excess of the ketone.

Crossed Aldol Condensation

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When condensation is between two different carbonyl compounds, it is called crossed aldol condensation.

1. Crossed aldol condensation between two different aldehydes


If both the aldehydes are having $\alpha$ hydrogen both can produce carbanions and also can act as carbanion acceptors. Hence there occurs the formation of a mixture of four products which is of little synthetic importance. If one of the aldehydes lacks $\alpha$ hydrogen then it can act only as a carbanion acceptor. In such cases there occurs the formation of two products.

Crossed Aldol Condensation

2. Crossed aldol condensation between two different ketones


As the reactivity of ketones is quite low, a poor yield of condensation products is obtained. Therefore, it is rarely attempted.

3. Crossed aldol condensation between an aldehyde and ketone


If both an aldehyde and a ketoneare having $\alpha$-hydrogen they undergo condensation to form two products. The reason is that ketones are poor carbanion acceptors and so cannot undergo self condensation. Aldehydes which are more reactive than ketones act as carbanion acceptors and the ketones provide the carbanions.

Crossed Aldol Condensation Reaction

Mixed Aldol Condensation

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The aldol condensation is versatile in that the enolate anion of one carbonyl compound can be made to add to the carbonyl carbon to another provided that the reaction partners are carefully selected. Consider for example, the reaction between acetaldehyde and benzaldehyde when treated with base. Only acetaldehyde can form can form an enolate anion. If the enolate ion of acetaldehyde adds to the benzaldehyde carbonyl group a mixed aldol condensation occurs.

Mixed Aldol Condensation

Intramolecular Aldol Condensation

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The intramolecular aldol condensation is particularly useful. An aldol condensation takes place between two carbonyl compounds. It is obvious that if a single molecule contains two carbonyl groups than also this reaction is possible and is called an intramolecular aldol condensation. The product always contains a ring.

Intramolecular Aldol Condensation

In ring formation loss of enthalpy will prevent a 7-membered ring. On the other hand 3 or 4 membered rings are not formed due to ring strain.

Application

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Some important applications of aldol condensation where the first unambiguous synthesis of canthaxanthin, synthesis of echinenone. Aldol condensation of the monoprotected diketone with either crocetindialdehyde or 8-apo-$\beta$-caroten-8-al followed by the acid catalyzed deprotection of the ketal and an intramolecular aldol condensation gave canthaxanthin or echinenone in 9% or 13% overall yield respectively.

Another important application of aldol condensation is the last step synthesis of the important commercial product citranaxanthin where 8-apo-$\beta$-caroten-8-al is condensed with acetone under basic conditions. The yield of this condensation is high because the inexpensive keto compound acetone is used as a cosolvent.