Recall that direct alkylation of ammonia gives a mixture of 1°-, 2°-, and 3°-amines. To exclusively make primary amines, phthalimide—a protected form of ammonia comprising only one acidic N–H proton capable of single alkyl substitution is used.

Gabriel synthesis uses phthalimide, a base, and hydrazine to convert alkyl halides into primary amines.

In the first step, phthalimide's N–H proton is abstracted by a base, resulting in a resonance-stabilized nucleophilic anion.

The anion attacks the alkyl halide in an S_N2 fashion to give N-alkyl phthalimide, which, despite the nitrogen's lone pair, does not get alkylated due to its reduced nucleophilicity.

In the next step, hydrazine attacks one of the carbonyl groups, performing a nucleophilic acyl substitution to cleave the C–N bond.

An intramolecular N–N proton transfer, followed by another nucleophilic acyl substitution by the unreacted –NH₂ of hydrazine, forms a charged cyclic compound while simultaneously kicking off the amine with a negative charge on nitrogen.

The negative nitrogen deprotonates the positive nitrogen to give a primary amine and a stable phthalimide hydrazide.

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.

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