Overview

Carboxylic acids react with alcohols to yield esters via an acid-catalyzed condensation reaction called Fischer esterification. This is a nucleophilic acyl substitution reaction that proceeds via a tetrahedral intermediate, where a water molecule is eliminated as the leaving group.

The mechanism of this reaction was confirmed by Robert and Urey (1938) through a radioisotope labeling experiment, where esterification of a carboxylic acid was carried out using ¹⁸O-labeled alcohol. The resulting ester was found to be labeled with an ¹⁸O atom, establishing the fact that the –OH group of the carboxylic acid was replaced by the –OR group from the alcohol.

Modifications of Fischer esterification use either a boron trifluoride ether complex or an organotin complex as the catalyst in an acid-free condition.

Procedure

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.