The Claisen Condensation of Ethyl Acetate

The Claisen Condensation of Ethyl Acetate THE OVERALL REACTION  

Step 2 Nucleophilic addition of the ester enolate to the carbonyl group of the neutral ester. The product is the anionic form of the tetrahedral intermediate. 

Ethyl 2,2,4-trimethyl-3-oxopentanoate (cannot form a stable anion formed in no more than trace amounts) 

At least two protons must be present at the a carbon of the starting ester for the equilibrium to favor product formation. Claisen condensation is possible for esters of the type RCH2CO2R, but not for RjCHCOjR.  

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

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

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... 

The Claisen condensation of ethyl acetate yields ethyl acetoacetate. This readily available compound and other P-keto esters formed by Claisen condensations are used as intermediates on the synthesis of alkyl derivatives of ketones. For example, ethyl acetoacetate is like an acetone molecule with an appended ester group. 

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. 

An important group of acylation reactions involves esters, in which case the leaving group is alkoxy or aryloxy. The self-condensation of esters is known as the Claisen condensation.216 Ethyl acetoacetate, for example, is prepared by Claisen condensation of ethyl acetate. All of the steps in the mechanism are reversible, and a full equivalent of base is needed to bring the reaction to completion. Ethyl acetoacetate is more acidic than any of the other species present and is converted to its conjugate base in the final step. The (3-ketoester product is obtained after neutralization. 

Synthesis of substituted acetic acids via acetoacetic ester Acetoacetic ester, an ester formed by the self-condensation of ethyl acetate via a Claisen condensation, has the following structure ... 

The self-condensation of ethyl acetate, with which we opened this chapter, is the most famous example of the Claisen ester condensation and it works in good yield under convenient conditions. The product (ethyl acetoacetate) is commercially available—and cheap too—so you are unlikely to want to do this particular example. 

PROBLEM 19.32 Draw the mechanism for the Claisen condensation of ethyl phenyl-acetate using the appropriate base. Include the acidification process at the end. 

Acetoacetic Ester can be prepared by the condensation of ethyl acetate, called the Acetoacetic Ester Condensation Reaction, a Claisen Condensation-. 

A crossed Claisen condensation is carried out by first adding the ester without a hydrogens to a solution of the alkoxide base. The ester with a hydrogens is slowly added to this solution, where it forms an enolate and condenses. The condensation of ethyl acetate with ethyl benzoate is an example of a crossed Claisen condensation. 

Ethyl dnnamate occurs in small amounts in storax.1 It has been prepared by the action of ethyl alcohol on cinnamic acid in the presence of dry hydrochloric or sulfuric acid 2 by the distillation of the copper salt of the monoethyl ester of benzylidene oxalacetic acid3 and by the condensation of ethyl acetate and benzaldehyde in the presence of sodium.4 The method described in the procedure is a slight modification of the one originally described by Claisen.5... 

Reduction of the carbethoxy group to the hydroxymethyl group with lithium aluminum hydride at — 35° and Claisen condensation with ethyl acetate are known to take place with pyridazinecar-boxylic acids. 6-Oxo-l,6-dihydro-2-pyridazinyl aliphatic acids, having the pyridazinonyl residue attached at the a-position of the aliphatic radical, readily undergo decarboxylative acylation with acid anhydrides in the presence of pyridine to form the corresponding 2-alkanones (107). 

A number of heterocycle-fused 1,5-diazocines have been reported. Kli-siecki and Sucharda treated an ethyl acetate solution of methyl nicotinate with sodium and obtained diazocine 126 (23RC251). In a more recent, but similar, report, Oakes and Rydon attempted a Claisen condensation of ethyl 3-aminopicolinate with ethyl acetate, but obtained instead the inter-molecular amidation product 127 (58JCS205). A similar result was reported by Brederick et al., who found that reaction of 4-amino-5-carbe-thoxypyrimidine with ethyl acetate in toluene in the presence of sodium... 

One of these important bases, diisopropylaminomagnesium bromide, was first introduced by Frostick and Hauser in 1949 as a catalyst for the Claisen condensation. However, the most generally useful base has turned out to be lithium diisopropylamide (LDA), which was first used by Hamell and Levine for the same purpose in 1950 (equation 3). After the introduction of LDA, it was more than 10 years before it was used by Wittig for the stoichiometric deprotonation of aldimines in what has come to be known as the Wittig directed aldol condensation.In a seminal paper in 1970, Rathke reported that the lithium enolate of ethyl acetate is formed by reaction of the ester with lithium hexamethyldisilazane in THF. - Rathke found that THF solutions of the lithium enolate are stable indefinitely at -78 °C, and that the enolate reacts smoothly with aldehydes and ketones to give p-hydroxy esters (equation 4). 

This anion will not be produced from a B-ketoester that has no hydrogens on the carbon between the two carbonyl groups. Such B-ketoesters would result from the Claisen condensation of an ester having only one a hydrogen. Since our problem uses ethyl acetate, the B ketoester anion is formed. This anion, like the enolate anion, is nucleophilic enough to attack the partially positively charged carbonyl carbon of an ester. Here, 0-acylation is much less thermodynamically stable than is C-acylation. Hence, the reaction of the B-ketoester anion with the ester (using ethyl acetoacetate and ethyl acetate as in our problem) is ... 

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