Claisen Condensation Mechanism

What is Claisen Condensation?

The Claisen condensation reaction is an organic coupling reaction that results in the formation of a C-C bond between either a single ester and one carbonyl compound or between two esters. The reaction proceeds when a strong base is present and the product of the reaction is a beta-keto ester or a beta-diketone.

The reaction is named after its discoverer, the German chemist Rainer Ludwig Claisen. An illustration of this reaction is provided below. The mechanism of the Claisen condensation reaction proceeds with the removal of an alpha proton through the action of a strong base to result in the formation of an enolate ion.

Claisen Condensation

Claisen Condensation

  • The Claisen condensation reaction requires that a minimum of one reagent must have an alpha proton and can form an enolate anion upon deprotonation.
  • The reaction also requires the base to avoid participating in nucleophilic substitution reactions or nucleophilic addition with a carbon belonging to the carbonyl functional group.
  • An ideal base for this reaction is the sodium alkoxide which is the conjugate base of the alcohol to be formed since it is regenerated.
  • Another requirement is that the alkoxy part of the ester must behave as a good leaving group, as in the case of ethyl and methyl esters.

It can be noted that when different esters undergo a Claisen condensation reaction, a mixture of four different products is obtained. The yield of the reaction can be improved with the usage of a very strong base, such as NaOH.

Claisen Condensation Mechanism

Step 1

The strong base removes an alpha proton. This results in the generation of the enolate ion. This enolate anion is relatively stable due to the delocalization of the negative charge (electrons). Given below is the reaction which leads to the formation of the enolate anion.

Claisen Condensation Mechanism Step 1

Claisen Condensation Mechanism Step 1

Step 2

The carbonyl carbon belonging to the second ester reactant is now the target of a nucleophilic attack from the enolate anion. This leads to the elimination of the alkoxy group and the regeneration of the conjugate base of the alcohol. This alkoxide ion removes the doubly alpha proton which is formed, giving rise to a new enolate anion which is now resonance stabilized. The formation of this new enolate ion is illustrated below:

Claisen Condensation Mechanism Step 2

Claisen Condensation Mechanism Step 2

Step 3

Now, an aqueous acid (phosphoric acid or sulfuric acid, for example) is added to neutralize the negative charge on the enolate anion as well as any base which is still present. This leads to the formation of a beta-diketone or a beta-keto ester, which is immediately isolated. The leaving group is removed. The final step of the Claisen condensation mechanism can be illustrated as follows:

Claisen Condensation Mechanism Step 3

Claisen Condensation Mechanism Step 3

Thus the ester (or carbonyl compound and ester) reactants are converted into beta-keto esters or beta-diketones. The Claisen condensation reaction has been modified into several variations, which are discussed in the next subsection.

Variations

Some important variations of this organic coupling reaction are listed below.

  • The classic version of the Claisen condensation reaction involves a reaction between two molecules of an ester-containing compound where the ester is enolizable.
  • The Dieckmann condensation reaction involves the intramolecular reactions of two ester groups belonging to the same molecule. The reaction yields a beta-keto ester which has a cyclic structure.
  • When an enolizable ester/ketone is used with a non-enolizable ester, the resulting reaction is known as the crossed Claisen condensation.
  • Another modification of this reaction is the Stobbe condensation reaction, which can proceed with relatively weaker bases. It generally involves the use of a diethyl ester prepared from succinic acid.

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