Kolbe nitrile synthesis

What is Kolbe nitrile synthesis?

The Kolbe nitrile synthesis is a reaction that was discovered by Kolbe prior to 1884. It involves the synthesis of nitriles via an SN2 substitution reaction between an alkali metal cyanide and an alkyl halide, tosylate, or mesylate.

Kolbe nitrile synthesis- general reaction scheme
Kolbe nitrile synthesis

The reaction is most effective for primary alkylating agents and is typically carried out in a polar aprotic solvent such as DMSO, HMPA, or NMP. Secondary bromides may also yield moderate yields of nitriles, while tertiary halides may produce elimination products due to the cyanide’s base function.

The use of AgCN or CuCN as a nucleophile may result in the production of an isonitrile by-product, as cyanide is a bident nucleophile. The reaction has been modified to include the use of a phase-transfer catalyst and has been carried out in various ionic liquids, including [bmim][BF4], [bmim][PF6], [bmim][N(Tf)2], and [hpyr][N(Tf)2].

The Kolbe nitrile synthesis has also been applied to extend the carbon chain of carboxylic acids through the reduction of acid to alcohol, followed by the hydrolysis of a new nitrile generated through substitution of the corresponding tosylate of the reduced alcohol. It is important to note that the reaction retains the configuration of a stereocenter adjacent to the carboxy function.