13.8: Preparation of Carboxylic Acids: Hydrolysis of Nitriles

Nitriles (R–CN) can be converted into carboxylic acids (R–COOH) upon treatment with aqueous acids, i.e., upon hydrolysis of nitriles. Under base-catalyzed conditions, carboxylate anions (R–COO⁻) are formed.

The reaction facilitates a two-step conversion of haloalkanes to carboxylic acids. Here, haloalkanes are first converted to nitriles using sodium cyanide via an S_N2 reaction. The resultant nitrile is then hydrolyzed to yield carboxylic acids bearing one more carbon than the haloalkane used. The reaction uses dimethyl sulfoxide, alcohols, or water as solvents. As the process involves the S_N2 mechanism, tertiary alkyl halides are seldom used.

Carboxylic acids can be prepared from nitriles via hydrolysis under aqueous acidic conditions. In base-catalyzed conditions, carboxylate anions are generated.

In acid-catalyzed hydrolysis, first, the nitrile nitrogen atom is protonated, rendering the cyano carbon atom more electrophilic.

This leads to an attack by the weak nucleophile—water. Next, deprotonation of the oxygen atom generates an imidic acid.

Then, the imidic acid tautomerizes to a more stable form, an amide, via two steps. The imidic nitrogen is first protonated to form a resonance stabilized protonated amide, which upon subsequent deprotonation, forms the amide.

Finally, the amide undergoes multi-step hydrolysis to generate the carboxylic acid.

Hydrolysis of nitriles is part of the two-step conversion of haloalkanes to carboxylic acids with introduction of an additional carbon to the starting haloalkane.

For example, ibuprofen—an anti-inflammatory drug—is synthesized via nitrile formation and its subsequent base hydrolysis.