Claisen ester condensations

Classical /3-diketones can be obtained from the acylation of ketones by esters (Claisen condensation), in the presence of alkali-metal hydroxides, ethoxides, hydrides, or amides as condensing agents, to enhance the relatively low reactivity of the ester carbonyl group (Equation (l)).41 5 Other general synthetic methods have been described by Mehrotra.2... 

IT 26537-19-9, 4-(1,1-Dimethylethyl)benzoic acid methyl ester 150639-32-0, 4-(2-Ethoxyethoxy)benzoic acid ethyl ester (Claisen condensation of. with acetophenone)... 

CIS- s. Isomers, Rearrangement Citric acid esters s. a-Hydroxy-tricarboxylic acid esters Claisen condensation 8, 792 Cleavage (s. a. Lysis)... 

Claisen condensation Condensation of an ester with another ester, a ketone or a nitrile in the presence of sodium ethoxide, sodium or sodamidc, with the elimination of an alcohol. The result is the formation of a / -ketonic ester, ketone, or nitrile respectively, e.g. 

Clearly, the nex.t step will be to investigate the physicochemical effects, such as charge distribution and inductive and resonance effects, at the reaction center to obtain a deeper insight into the mechanisms of these biochemical reactions and the finer details of similar reactions. Here, it should be emphasized that biochemical reactions arc ruled and driven basically by the same effects as organic reactions. Figure 10.3-22 compares the Claisen condensation of acetic esters to acctoacctic esters with the analogous biochemical reaction in the human body. 

The Claisen condensation is initiated by deprotonation of an ester molecule by sodium ethanolate to give a carbanion that is stabilized, mostly by resonance, as an enolate. This carbanion makes a nucleophilic attack at the partially positively charged carbon atom of the e.ster group, leading to the formation of a C-C bond and the elimination ofan ethanolate ion, This Claisen condensation only proceeds in strongly basic conditions with a pH of about 14. 

This preparation was discovered independently by Geuther (1863) and by Frankland and Duppa (1865). The reaction was subsequently investigated in detail and so w idely extended by Claisen that it has become solely a specific example of the more general process known as the Claisen Condensation. Claisen showed that an ester under the influence of sodium ethoxide would not only condense with itself (as in the preparation of ethyl acetoacetate), but also with (i) another ester, (ii) a ketone, if of formula RCHgCOR, (iii) a nitrile, if of formula RCH CN, in each case with the elimination of alcohol. Examples of these modifications are ... 

The acetoacetic ester condensation (involving the acylation of an ester by an ester) is a special case of a more general reaction term the Claisen condensation. The latter is the condensation between a carboxylic ester and an ester (or ketone or nitrile) containing an a-hydrogen atom in the presence of a base (sodium, sodium alkoxide, sodamide, sodium triphenylmethide, etc.). If R—H is the compound containing the a- or active hydrogen atom, the Claisen condensation may be written ... 

Benzilic acid rearrangement Benzoin reaction (condensation) Blanc chloromethylation reaction Bouveault-Blanc reduction Bucherer hydantoin synthesis Bucherer reaction Cannizzaro reaction Claisen aldoi condensation Claisen condensation Claisen-Schmidt reaction. Clemmensen reduction Darzens glycidic ester condensation Diazoamino-aminoazo rearrangement Dieckmann reaction Diels-Alder reaction Doebner reaction Erlenmeyer azlactone synthesis Fischer indole synthesis Fischer-Speior esterification Friedel-Crafts reaction... 

The Claisen condensation of an aliphatic ester and a thiazolic ester gives after acidic hydrolysis a thiazolylketone (56). For example, the Claisen condensation of ethyl 4-methyl-5-thiazolecarboxylate with ethyl acetate followed by acid hydrolysis gives methyl 4-methyl-5-thiazolyl ketone in 16% yield. 

Before describing how p keto esters are used as reagents for organic synthesis we need to see how these compounds themselves are prepared The mam method for the prepa ration of p keto esters is the Claisen condensation... 

Claisen condensations involve two distinct experimental operations The first stage concludes m step 4 of Figure 21 1 where the base removes a proton from C 2 of the p keto ester Because this hydrogen is relatively acidic the position of equilibrium for step 4 lies far to the right... 

One of the following esters cannot undergo the Claisen con densation Which one Write structural formulas for the Claisen condensation products of the other two... 

Unless the p keto ester can form a stable anion by deprotonation as m step 4 of Figure 21 1 the Claisen condensation product is present m only trace amounts at equi librium Ethyl 2 methylpropanoate for example does not give any of its condensation product under the customary conditions of the Claisen condensation... 

At least two protons must be present at the a carbon for the equilibrium to favor prod uct formation Claisen condensation is possible for esters of the type RCH2CO2R but not for R2CHCO2R ... 

Mixed Claisen condensations are analogous to mixed aldol condensations and involve carbon-carbon bond formation between the a carbon atom of one ester and the carbonyl carbon of another... 

The following equation shows an example of a mixed Claisen condensation m which a benzoate ester is used as the nonenohzable component... 

Give the structure of the product obtained when ethyl phenyl acetat C6H CH2C02CH2CH3) is treated with each of the following esters under conditions of the mixed Claisen condensation... 

In a reaction related to the mixed Claisen condensation nonenolizable esters are used as acylatmg agents for ketone enolates Ketones (via their enolates) are converted to p keto esters by reaction with diethyl carbonate... 

The sequence begins with a Claisen condensation of ethyl pentanoate to give a p keto ester The ester is hydrolyzed and the resulting p keto acid decarboxylates to yield the desired ketone... 

We already know what happens when simple esters are treated with alkoxide bases— they undergo the Claisen condensation (Section 211) Simple esters have s of approximately 22 and give only a small amount of enolate when treated with alkoxide bases The small amount of enolate that is formed reacts by nucleophilic addition to the carbonyl group of the ester... 

Dieckmann cyclization (Section 21 2) An intra molecular analog of the Claisen condensation Cy die p keto esters in which the ring is five to seven membered may be formed by using this reaction... 

The following questions pertain to the esters shown and their behavior under conditions of the Claisen condensation... 

Claisen condensation (Section 21 1) Reaction in which a 3 keto ester is formed by condensation of two moles of an ester in base... 

Esters of cinnamic acid are used more extensively than the acid itself, and can be converted to the acid by standard hydrolysis protocols. The Claisen condensation between benzaldehyde and the appropriate acetate ester provides a direct, high yield route to the simple esters. 

Reaction of Enolate Anions. In the presence of certain bases, eg, sodium alkoxide, an ester having a hydrogen on the a-carbon atom undergoes a wide variety of characteristic enolate reactions. Mechanistically, the base removes a proton from the a-carbon, giving an enolate that then can react with an electrophile. Depending on the final product, the base may be consumed stoichiometricaHy or may function as a catalyst. Eor example, the sodium alkoxide used in the Claisen condensation is a catalyst ... 

Fluorinated esters have synthetic utility m Claisen condensations [24, 25] (equation 21) and Dieckmann cyclizfitions [26]. 

On treatment with alkoxide bases, esters undergo self-condensation to give a p-keto ester and an alcohol. Ethyl acetate, for exanple, undergoes a Claisen condensation on treatment with sodium ethoxide to give a p-keto ester known by its common nane ethyl ace-toacetate (also called acetoacetic ester) ... 

Esters of dicarboxylic acids undergo an intranolecular version of the Claisen condensation when a five- or six-membered ring can be fonned. 

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