The Claisen Condensation

Ludwig Claisen was a German chemist who worked during the last two decades of the nineteenth century and the first two decades of the twentieth. His name is associated with three reactions. 

The Claisen-Schmidt reaction was presented in Section 20.4, the Claisen condensation is discussed here, and the Claisen rearrangementm be introduced in Section 22.13. 

Aldol additions and condensations begin with the reaction of an enolate derived from an aldehyde or ketone with the carbonyl group of a second molecule of aldehyde or ketone. A related reaction takes place between esters and their enolates when both are present in the same solution. In ethanol containing sodium ethoxide, for example, the enolate reacts with the ester by nucleophilic acyl substitution to give a (3-keto ester in what is known as a Claisen condensation. 

The Claisen condensation is the main method for preparing P-keto esters. The simplest example is the preparation of ethyl acetoacetate from ethyl acetate. 

Ethyl acetoacetate is also called acetoacetic ester. Its systematic lUPAC name is ethyl 3-oxobutanoate, where 3-oxo signifies that C-3 is a carbonyl group. 

If we look closely at these examples, we can see that, overall, both reactions involve a condensation in which one ester loses an a hydrogen and the other loses an ethoxide ion  

We can understand how this happens if we examine the reaction mechanism in detail. In doing so, we shall see that the Claisen condensation mechanism is a classic example of acyl substitntion (nncleophilic addition-elimination at a carbonyl group). 

An alkoxide base removes an a proton from the ester, generating a nucleophilic enoiate ion. (The alkoxide base used to form the enoiate shouid have the same aikyi group as the ester, e.g., ethoxide for an ethyl ester otherwise transesterification may occur.) Although the a protons of an ester are not as acidic as those of aldehydes and ketones, the resulting enoiate is stabilized by resonance in a similar way. 

The enoiate attacks the carbonyl carbon of another ester molecule, forming a tetrahedral intermediate. The tetrahedral intermediate expels an alkoxide ion, resulting in substitution of the alkoxide by the group derived from the enoiate. The net result is nucleophilic addition-elimination at the ester carbonyl group. The overall equilibrium for the process is unfavorable thus far, however, but it is drawn toward the final product by removal of the acidic a hydrogen from the new /3-dicarbonyl system. 

Chapter 19 Condensation and Conjugate Addition Reactions of Carbonyl Compounds 

Ludwig Claisen was a German chemist who worked during the last two decades of the nineteenth century and the first two decades of the twentieth. His name is associated with three reactions. The Claisen-Schmidt reaction was presented in Section 18.10, the Claisen condensation is discussed in this section, and the Claisen rearrangement w be introduced in Section 24.13. 

Before describing how p-keto esters are used as reagents for organic synthesis, we need to see how these compounds themselves are prepared. The main method for the preparation of p-keto esters is a reaction known as the Claisen condensation  

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

The systematic lUPAC name of ethyl acetoacetate is ethyl 3-oxobutanoate. The presence of a ketone carbonyl group is indicated by the designation 0x0 along with the appropriate locant. Thus, there are four carbon atoms in the acyl group of ethyl 3-oxobutanoate, C-3 being the carbonyl carbon of the ketone function. 

Step 1 Proton abstraction from the a carbon atom of ethyl acetate to give the corresponding enolate. 

EWncipal resonance structnres of the anion of a P-keto ester 

We ll begin by describing the preparation and properties of p-keto esters, proceed to a discussion of their synthetic applications, continue to an examination of related species, and conclude by exploring some recent developments in the active field of synthetic car-banion chemistry. 

The self-aldol reaction of aldehydes and ketones gives either P-hydroxy carbonyl or a,P-unsaturated carbonyl products. When the same reaction mechanism is applied to esters, the reaction is called the Claisen condensation. Like the aldol reaction, the Claisen condensation involves the attack of an enolate (or enol) nucleophile on a carbonyl electrophile. However, subsequent elimination of the leaving group creates a P-keto ester product. If this 1,3-dicarbonyl pattern is present in a TM, it is an indication that the TM might be the product of a Claisen condensation, and a Claisen disconnection will be one option for retrosynthesis. 

Introduction to Strategies for Organic Synthesis, First Edition. Laurie S. Starkey. 2012 John Wiley Sons, Inc. Published 2012 by John Wiley Sons, Inc. 

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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 ... 

Many other examples of the Claisen Condensation will be found in textbooks of theoretical organic chemistry. 

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 ... 

This reaction must be distinguished from the Claisen condensation, which is an acylation process (see discussion before Section 111,151). 

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. 

FIGURE 21 1 The mechanism of the Claisen condensation of ethyl acetate... 

Organic chemists sometimes write equations for the Claisen condensation m a form that shows both stages explicitly... 

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... 

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... 

Ethyl benzoate cannot undergo the Claisen condensation... 

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 ... 

Ethyl ethoxalylpropionate has been prepared by the Claisen condensation of ethyl oxalate with ethyl propionate as above, and by the alkylation of ethyl ethoxalylacetate. ... 

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

Ethyl acetoacetate (acetoacetic ester), available by the Claisen condensation of ethyl acetate, has properties that make it a useful starting material for the preparation of ketones. These properties are... 

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