Preparation of 1° Amines: Gabriel Synthesis

Direct alkylation is not a suitable method for synthesizing amines because it produces polyalkylated products. Gabriel synthesis is the most preferred method to exclusively make primary amines. The method uses phthalimide, which contains a protected form of nitrogen that participates in alkylation only once to predominantly give primary amines.

Strong bases like NaOH or KOH deprotonate the phthalimide to form the corresponding anion, which acts as a nucleophile. Further, the anion attacks an alkyl halide to give N-alkylphthalimide. This double-amide compound reacts with hydrazine under the influence of heat to produce primary amines. Alternatively, N-alkylphthalimide can also undergo hydrolysis in the presence of a base or an acid to produce primary amines.

Unhindered primary and secondary alkyl halides are the preferred substrates for Gabriel synthesis, since the reaction uses the S_N2 mechanism.

Gabriel’s method is useful for synthesizing a stimulant drug—amphetamine, used during World War II as an appetite suppressant.