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What Is Acetoacetic Ester Synthesis?

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  • Written By: Aaron Lin
  • Edited By: A. Joseph
  • Last Modified Date: 25 November 2016
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Acetoacetic ester synthesis is a common synthesis reaction in organic chemistry and is used for producing an alpha substituted acetone. First, an acetoacetic ester such as ethyl acetoacetate is dissolved in alcohol — often ethanol — then deprotonated and alkylated by an electrophile such as alkyl halide. The intermediate alkylated ester is then hydrolyzed with sodium hydroxide followed by acidic aqueous solution. The workup results in decarboxylation to yield the desired alpha-substituted acetone. A wide variety of electrophiles can be used in the alkylation step, making acetoacetic ester synthesis a versatile reaction for synthesizing complex molecules.

Although a variety of alkoxy groups can be used in principle, the acetoacetic ester is often simply ethyl acetoacetate because ethanol is a cheap and commonly available solvent. Industrially, ethyl acetoacetate is prepared by treating diketene with ethanol. In the lab, however, ethyl acetoacetate also can be prepared through the Claisen condensation of ethyl acetate. Two equivalents of ethyl acetate, a cheap and common solvent, are combined in the presence of sodium ethoxide to form one equivalent of the desired ethyl acetoacetate and another equivalent of ethanol. The base and solvent must share the same ethoxy group as the ester to avoid transterification side reactions.

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The acetoacetic ester synthesis relies on the special chemistry of carbonyl compounds. In particular, the alpha carbons on carbonyl carbons are especially acidic; as a result, carbonyl compounds such as esters and ketones can easily form negatively charged enolates. This results in the resonance stabilization of the electrons on the enolate. Ethyl acetoacetate has two carbonyl groups adjacent to its alpha carbon, so it is especially acidic. Even relatively weak bases such as sodium ethoxide completely and irreversibly deprotonate ethyl acetoacetate.

After the enolate has been formed, it becomes a powerful nucleophile that is capable of being alkylated by a suitable electrophile. The most common electrophile chosen for the acetoacetic ester synthesis is a simple alkyl halide, and the resulting reaction proceeds by bimolecular nucleophilic substitution. The chemist must take care to use a primary or allylic alkyl halide to speed up the substitution reaction and to avoid competing side reactions.

More unusual electrophiles, however, can be used. For example, an alpha, beta unsaturated carbonyl compound — a Michael Acceptor — can be used in the synthesis as part of a Michael Reaction. Regardless of the electrophile, the same reaction occurs: an alkyl group is added to ethyl acetoacetate as a new carbon-carbon bond is formed.

Multiple alkylations can occur if desired. The enolate reaction can be repeated simply by adding another equivalent of base followed by another equivalent of electrophile to form the dialkylated product. The acetoacetic ester synthesis, then, is useful for synthesis of mono- and di-substituted acetones. The reaction cannot, however, be carried out a third time because there are only two protons attached to the alpha carbon in ethyl acetoacetate. As a result, at most two deprotonations, and hence two alkylations, can ever be performed.

The last two steps convert the substituted ester into the final product. The substituted acetoacetate ester is treated with sodium hydroxide to hydrolyze the ester, giving the carboxylate salt. Aqueous acid is then added, which promotes the decarboxylation of the carboxylic acid. Carbon dioxide bubbles out of the solution, leaving the substituted ketone product.

Acetoacetic ester synthesis is a versatile reaction for the synthesis of alpha-substituted ketones. It is often used in the retrosynthetic analysis of desired compounds. Whenever a desired compound is an alpha-substituted ketone, it can often be synthesized using acetoacetic ester synthesis. Chemists have recognized its utility, and it forms the basis for the manufacture of substances as diverse as perfumes, medicines and food dyes.

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