Acetoacetic ester synthesis is a versatile reaction used to produce alpha-substituted acetones. Ethyl acetoacetate is deprotonated and alkylated by an electrophile, followed by hydrolysis and decarboxylation. The reaction is based on the special chemistry of carbonyl compounds and can be performed with a variety of electrophiles. The resulting product is useful for the synthesis of complex molecules and is commonly used in the production of perfumes, medicines, and food dyes.
Acetoacetic ester synthesis is a common synthesis reaction in organic chemistry and is used to produce 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 the alkyl halide. The intermediate alkylate ester is then hydrolyzed with sodium hydroxide followed by an acidic aqueous solution. The workup leads to decarboxylation to produce 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 the synthesis of complex molecules.
While a variety of alkoxy groups can in principle be used, the acetoacetic ester is often simply ethyl acetoacetate because ethanol is a cheap and commonly available solvent. Industrially, acetoacetate of ethyl is prepared by treating diketene with ethanol. In the laboratory, however, ethyl acetoacetate can also be prepared via 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 acetate and another equivalent of ethanol. The base and solvent must share the same ethoxy group as the ester to avoid transterification side reactions.
The synthesis of acetoacetic ester is based on the special chemistry of carbonyl compounds. In particular, the alpha carbons on the carbonyls are particularly acidic; as a result, carbonyl compounds such as esters and ketones can easily form negatively charged enolates. This results in the resonance stabilization of electrons on the enolate. Ethyl acetoacetate has two carbonyl groups adjacent to its alpha carbon, so it is particularly acidic. Even relatively weak bases such as sodium ethoxide completely and irreversibly deprotonate ethyl acetoacetate.
After the enolate is formed, it becomes a powerful nucleophile which is capable of being alkylated by a suitable electrophile. The most common electrophile chosen for 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 alkyl or allyl halide to speed up the substitution reaction and avoid competing side reactions.
However, more unusual electrophiles 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.
If desired, multiple alkylations can occur. The enolate reaction can be repeated by simply adding another equivalent of base followed by another equivalent of electrophile to form the dialkylated product. The synthesis of the acetoacetic ester, therefore, is useful for the synthesis of mono- and di-substituted acetones. The reaction cannot, however, be performed a third time because there are only two protons attached to the alpha carbon in ethyl acetoacetate. Consequently, a maximum of two deprotonations, and thus two alkylations, can 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 aids in the decarboxylation of the carboxylic acid. Carbon dioxide comes out of 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 usefulness and it forms the basis for the production of different substances such as perfumes, medicines and food dyes.
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