Kolbe nitrile synthesis

The Kolbe nitrile synthesis is a substitution reaction commonly used for the preparation of alkyl nitriles by reaction of the corresponding alkyl halide with a metal cyanide.

A side product in the reaction is the formation of an isonitrile because the cyanide ion is an ambident nucleophile and according to Kornblum's rule is capable of reacting with either carbon or nitrogen.

General

The Kolbe nitrile reaction can be written as:

R-X + MCN → R-CN + MX

2 R-X + 2 MCN → R-CN + R-NC + 2 MX

The ratio in which both isomers form depends on the solvent and the reaction mechanism. With the application of alkali cyanides such as sodium cyanide and polar solvents the reaction type is an S_N2 reaction whereby the alkyl halide is attacked by the more nucleophilic carbon atom of the cyanide ion. Primary alkylating agents work best, while secondary bromides and chlorides react in moderate yields to give the desired nitriles. Tertiary halides mainly undergo side reactions, one of which is the E2 elimination.

According the HSAB principles, the carbon center is more basic and more nucleophilic. When protic solvents are used, the resulting greater solvation of this carbon center is thought to favor the competing reaction at the weaker nitrogen center. A similar rationale explains why the more covalent cyanide salts such as silver cyanides and cuprous cyanides also give isonitriles as main product.

Various polar aprotic solvents can be used, such as acetone and DMSO. DMSO is often used for more sterically hindered electrophilies (such as secondary and neopentyl halides) without rearrangement side-reactions.

However, due to DMSO's ability to quickly penetrate the skin and carry any dissolved compound through it, it's recommended to wear proper protection gloves when handling DMSO solutions of cyanides, as any dissolved solution that touches the bare skin will enter the bloodstream.

Procedure

• A solvent is selected, either acetone or DMSO. The solvent must be dry before use;
• In a reaction flask, the alkyl halide is added, along with the metal cyanide.
• The dry solvent is added in the flask, along with a stir bar;
• A condenser is attached to the flask, and the mixture is brought to reflux and strong stirring;
• If a small amount of sodium or potassium iodide are added in the reaction flask (unless the alkyl halide used is an alkyl iodide already), it can help the reaction. This route is called Finkelstein reaction, and can be used to increase the reactivity of the alkyl halides and improve the yield;
• Due to low solubility of the salts in acetone, the reaction may take hours or 1-2 days;
• Side products of the reaction include isonitriles. These are rapidly hydrolyzed to amines and formic acid, an extraction step with hydrochloric acid is normally sufficient in practice to remove these impurities from a desired nitrile product.

References

Relevant Scencemadness threads

• Isocyanate synthesis via halide displacement