15.27 : Esters to β-Ketoesters: Claisen Condensation Mechanism

Regular Claisen condensation involves the synthesis of β-ketoesters by combining identical ester molecules bearing two α hydrogens in the presence of an alkoxide base. The reaction commences with the deprotonation of the acidic α hydrogen by the base to form a resonance stabilized ester enolate. This nucleophilic ion then attacks the carbonyl center of another ester molecule to generate a tetrahedral alkoxide intermediate. Next, the expulsion of the alkoxide group from the intermediate restores the carbonyl center and produces an acyl-substituted ester. The alkoxide by-product subsequently abstracts the second α proton from the β-dicarbonyl compound to form a doubly-stabilized enolate ion. This step is the driving force of the reaction to completion and suggests the essential requirement of two α protons in starting ester. Finally, acidification of the enolate produces the desired β-ketoester. The utility of the Claisen condensation process is also observed in biological systems. For instance, the synthesis of acetoacetyl-CoA from the condensation of acetyl-CoA in the presence of thiolase enzyme.