13.12 : Carboxylic Acids to Esters: Acid-Catalyzed (Fischer) Esterification Mechanism

Fischer esterification of a carboxylic acid is a nucleophilic acyl substitution reaction entailing the nucleophilic addition of alcohol and elimination of a water molecule as the leaving group.

The first step involves acid-catalyzed protonation of the carbonyl oxygen atom. This results in a resonance stabilized protonated acid with increased electrophilicity of the carbonyl carbon atom.

Consequently, a nucleophilic attack by the alcohol followed by deprotonation yields a tetrahedral intermediate.

The tetrahedral intermediate is unstable and immediately protonated to convert the –OH group into a better leaving group. This results in the loss of a water molecule to form a protonated ester. Finally, deprotonation yields the ester as the desired product.

The mechanism was studied via isotope labeling experiments using an ¹⁸O labeled alcohol. The yield of radioisotope-enriched esters proves that the acyl C–O bond of the acid is cleaved rather than the O–H bond.