15.27:
Esters to β-Ketoesters: Claisen Condensation Mechanism
Recall regular Claisen condensation as a method to obtain β-ketoesters from identical ester molecules containing two α protons in the presence of an alkoxide base.
The reaction begins with the base abstracting the acidic α hydrogen from the ester to produce a nucleophilic enolate ion stabilized by resonance.
The nucleophile attacks the carbonyl carbon of another ester molecule to produce a tetrahedral alkoxide intermediate.
The intermediate undergoes expulsion of the alkoxide group to give an acyl-substituted ester and an alkoxide by-product.
The by-product abstracts the second α hydrogen from the β-dicarbonyl compound to form a doubly-stabilized enolate, which is the driving force of the Claisen condensation.
This step emphasizes the essential requirement of two α protons in the starting esters.
Finally, the enolate is protonated by an acid to give the desired product, the β-ketoester.
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.