Carboxylic Acids Derivatives

Preparation of Nitriles

Let’s discuss two strategies for preparing nitriles via substitution and dehydration reactions.

 

 

Synthesis of Nitriles via Substitution Reactions

To prepare a nitrile via a substitution reaction, we do an SN2 substitution of alkyl halides, mesylates, or tosylates with a cyanide salt such as NaCN or KCN:

 

 

Notice that from the tertiary alkyl halide, the reaction goes by SN1 mechanism even though the cyanide ion is a good nucleophile. This is because tertiary alkyl halides are too sterically hindered to undergo an SN2 substitution, and we use a polar protic solvent to facilitate the ionization of the carbon-halogen bond. The last reaction here is an example of forming diastereomeric products in SN1 reactions which happens when there is more than one chiral center in the substrate. You can read more about the stereochemistry of SN1 reactions here.

Another example of using the nucleophilicity of the cyanide ion to prepare nitriles is its reaction with aldehydes and ketones. The product of these reactions is a cyanohydrin:

 

 

Synthesis of Nitriles via Dehydration of Amides

The second approach for preparing nitriles is the dehydration of primary amides using SOCl2, POCl3, or P2O5:

 

 

There are several ways of preparing amides such as the reaction of carboxylic acids with amines using EDC or DCC coupling reagents.

 

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