Carbonyl condensation reactions Claisen reaction

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

As summarized in Figure 27.7, the mevalonate pathway begins with the conversion of acetate to acetyl CoA, followed by Claisen condensation to yield acetoacety) CoA. A second carbonyl condensation reaction with a third molecule of acetyl CoA, this one an aldol-like process, then yields the six-carbon compound 3-hydroxy-3-methylglutaryl CoA, which is reduced to give mevalonate. Phosphorylation, followed by loss of C02 and phosphate ion, completes the process. 

When two molecules of ester undergo a condensation reaction, the reaction is called a Claisen condensation. Claisen condensation, like the aldol condensation, requires a strong base. However, aqueous NaOH cannot be used in Claisen condensation, because the ester can be hydrolysed by aqueous base. Therefore, most commonly used bases are nonaqueous bases, e.g. sodium ethoxide (NaOEt) in EtOH and sodium methoxide (NaOMe) in MeOH. The product of a Claisen condensation is a P-ketoester. As in the aldol condensation, one molecule of carbonyl compound is converted to an enolate anion when an a-proton is removed by a strong base, e.g. NaOEt. 

Walsh refers to the enzymes described in this section (which catalyze carbonyl condensation reactions involving one component that is not an aldehyde or ketone) as Claisen enzymes (6). I shall use that terminology here, although these reactions are not formally Claisen condensations, but they are distinguished by their mechanisms from the other adolases mentioned in Section III,A, 1. 

As the text continues to develop the chemistry of aldehydes and ketones, you will now see how the carbon adjacent to a carbonyl group can become nucleophilic. First, reactions of these new nucleophiles with common electrophiles like luiloalkiines will be covered alkylation reactions. More important arc reactions of the nucleophilic a-carbons of one carbonyl compound with electrophilic carbonyl carbons of another. They are generically termed carbonyl condensation reactions. You see them here for aldehydes and ketones the aldol condensation. (In a later chapter you will be introduced to the analogous reaction of carboxylic esters the Claisen condensation.) The products of aldol condensations are a, j3-un.saturatcd aldehydes and ketones, which contain additional sites of electrophilic and potential nucleophilic character. 

More commonly, sodium hydride is used as a base for carbonyl condensation reactions. For exarrple, Claisen condensations of ethyl acetate and ethyl isovalerate are effected by sodium hydride. Condensations of cyclohexanone with methyl benzoate and ethyl formate (eq 16) are also facile. Sodium hydride can... 

Carbanions frequently add to the carbonyl double bond. The aldol reaction, Claisen reaction, Dieckmann reaction, Michael reaction, and Knoevenagel condensation are familiar examples of carbanions (as enolates) undergoing nucleophilic addition to carbon-oxygen double bonds. 

In carbonyl condensation reactions the enolate or enol of one carbonyl compound reacts with the carbonyl group of another to join the two reactants. As part of the process, a new molecule that is derived from them condenses (forms). Often this molecule is that of an alcohol or water. The main types of condensation reactions we shall study are the Claisen condensation and the aldol condensation. Aldol condensations are preceded mechanistically by aldol additions, which we shall also study. The name aldol derives from the fact that aldehyde and alcohol functional groups are present in the products of many aldol reactions. 

Claisen condensation A carbonyl condensation reaction between two esters to give a j8-ketoester. 

Ba.se Catalyzed. Depending on the nature of the hydrocarbon groups attached to the carbonyl, ketones can either undergo self-condensation, or condense with other activated reagents, in the presence of base. Name reactions which describe these conditions include the aldol reaction, the Darzens-Claisen condensation, the Claisen-Schmidt condensation, and the Michael reaction. 

Tire 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 aldeiwde 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 product—exactly the behavior previously seen for aldehydes and ketones (Section 19.4). The tetrahedral intermediate in the Claisen reaction, however, expels an alkoxide leaving group to yield an acyl substitution product—exactly the behavior previously seen for esters (Section 21.6). The mechanism of the Claisen condensation reaction is shown in Figure 23.5. 

The Claisen reaction is a carbonyl condensation that occurs between two ester molecules and gives a /3-keto ester product. Mixed Claisen condensations... 

Claisen condensation reaction (Section 23.7) The carbonyl condensation reaction of an ester to give a /3-keto ester product. 

In the presence of a strong base, the ot carbon of a carboxylic ester can condense with the carbonyl carbon of an aldehyde or ketone to give a P-hydroxy ester, which may or may not be dehydrated to the a,P-unsaturated ester. This reaction is sometimes called the Claisen reaction,an unfortunate usage since that name is more firmly connected to 10-118. In a modem example of how the reaction is used, addition of tert-butyl acetate to LDA in hexane at -78°C gives the lithium salt of ferf-butyl acetate, " (12-21) an enolate anion. Subsequent reaction a ketone provides a simple rapid alternative to the Reformatsky reaction (16-31) as a means of preparing P-hydroxy erf-butyl esters. It is also possible for the a carbon of an aldehyde or ketone to add to the carbonyl carbon of a carboxylic ester, but this is a different reaction (10-119) involving nucleophilic substitution and not addition to a C=0 bond. It can, however, be a side reaction if the aldehyde or ketone has an a hydrogen. 

Nature builds carbon-carbon bonds essentially by aldol or Claisen-type reactions, both involving a carbonyl group as an electrophile, and an enol or enolate as a nucleophile. A less-frequent reaction bears a formal analogy to the Claisen acyloin condensation. The aldol reaction of carbohydrates always involves an aldehyde as the electrophile, and an aldehyde or ketone as the nucleophile (see Eq. 1). 

The intramolecular carbon-carbon bond-forming reactions considered in this section are based on the aldol condensation (see Section 5.18.2, p. 799), the Claisen-Schmidt reaction (see Section 6.12.2, p. 1032), the Claisen ester condensation (see Section 5.14.3, p. 736), and the Claisen reaction (see Section 6.12.2, p. 1032). Since these carbonyl addition reactions are reversible, the methods of synthesis are most successful for the formation of the thermodynamically stable five- and six-membered ring systems. The preparation of the starting materials for some of these cyclisation reactions further illustrates the utility of the Michael reaction (see Section, 5.11.6, p. 681). 

---