The Claisen Condensation Reaction

S-hexanedione yields i-methyl-a-cyclopentenone rather than the alternative acetylcyclopropene. 

Problem 23.9 What product would you expect to obtain from base treatment of 1,6-cyclodecane-dione  

Esters, hkc aldehydes and ketones, are weakly acidic. When an ester with an x hydrogen is treated with 1 equivalent of a base such as sodium ethox-ide, a reversible condensation reaction occurs to yield a /3-keto ester. For example, ethyl acetate yields ethyl acetoacetate on treatment with base. This reaction between two ester molecules is known as the Claisen condensation reaction. (We ll use ethyl esters for consistency, but other esters will also work.) 

Ethoxide base abstracts an acidic alpha hydrogen atom from an ester molecule, yielding an ester enolate ion. 

In a nucleophilic addition, this ion adds to a second ester molecule, giving a tetrahedral intermediate. 

The selectivity observed in the intramolecular aldol reaction of hexane-2,5-dione is due to the fact that all steps in the mechanism are readily reversible, so an equilibrium is reached. Thus, the relatively strain-free cyclopentenone product is considerably more stable than the highly strained cyclopropene alternative. For similar reasons, intramolecular aldol reactions of 1,5-diketones lead only to cyclohexanone products rather than to acyl cyclohutenes. 

Treatment of a 1,3-diketone such as pentane-2,4-dione with base does not give an aldol condensation product. Explain. 

The mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule. The only difference between the aldol condensation of an aldehyde or ketone and the Claisen condensation of an ester involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is protonated to give an alcohol 

A condensation reaction between two esters using one equivalent of base is called the Claisen reaction. One ester loses an a-H atom while the other loses an alkoxide ion (RO ). The initial steps are reversible but deprotonation of the intermediate 3-keto ester (by the alkoxide ion) shifts the equilibrium to the desired product. It should be noted that deprotonation of the 3-keto ester forms an anion that can be stabilised by delocalisation over two carbonyl groups. At the end of the reaction, acid is added to reprotonate the condensation product. 

P-keto ester enoiate (anion stabiiised by resonance) 

In a condensation reaction, two molecules combine to give a product with loss of a small molecule, such as water or an alcohol 

0 0 II II The negative charge in the p-keto ester enoiate ion is stabilised by 

The alkoxide base and ester side chain should be matched. For example, the ethoxide ion (EtO ) should be used as a base for ethyl esters (R = Et in the scheme above). This ensures that if the ethoxide ion attacks the carbonyl group of an ethyl 

P-keto ester enolate (anion stabilised by resonance) 

Process to view an animation showing the mechanism of the Claisen condensation reaction. 

0 The tetrahedral intermediate expels ethoxide ion to yield a new carbonyl compound, ethyl acetoacetate. 

0 0 0 2 CHaCOCH2CHa -g liy0El ethan° CH3C—CH2COCH,CH, + CH3CH2OH 

I But ethoxide ion is a strong enough base to deprotonate ethyl acetoacetate, shifting the equilibrium and driving the overall reaction to completion. 

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Active Figure 23.5 MECHANISM Mechanism of the Claisen condensation reaction. Sign in at www. thomsonedu.com to see a simulation based on this figure and to take a short quiz. 

The Claisen condensation reaction occurs by a nucleophilic addition to an ester carboxyl group, which follows these steps ... 

Elimination of a stable molecule, often C02 or a carbonyl compound, can give an anion which usually reacts further. Examples include elimination of carbon dioxide from acetates (reaction 4.9). The reaction of iodine with acetone (propanone) in the presence of base also involves a step of this type (reaction 4.17), as does the reverse of the Claisen condensation (reaction 4.34). 

If the enolate of a carboxylic ester is formed at room temperature then selfcondensation of the ester results. This reaction is known as the Claisen condensation and gives a p-keto ester product. A variety of bases including EDA, sodium hydride or sodium alkoxides can be used and the reaction may be driven to completion by the deprotonation of the product, to give the anion of the P-keto ester (p.Sra 11). The Claisen condensation reaction works best when the two ester groups are the same, to give the self-condensation product (1.59), or when one of the ester groups is non-enoUzable. The reaction is less useful in cases where two different enolizable esters are used, as a mixture of up to four p-keto ester products is normally obtained. The product P-keto esters are useful in synthesis as they readily undergo alkylation and decarboxylation reactions (see Section 1.1.1). 

Deprotonation of the a-protons of the ketone is easily achieved by KOH to give an enolate, which is resonance stabilised, and which is a good nucleophile. Esters readily undergo nucleophilic addition-elimination with enolates in the Claisen condensation reaction. 

In the Claisen condensation reaction of a,a-disubstituted esters, ZrCU was used as a powerful promoter to produce the corresponding a,a-disubstituted P-ketoester, which is difficult to obtain under standard conditions (Equation 16) [21]. When... 

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