The Gabriel synthesis is named for the German chemist Siegmund Gabriel. Traditionally, it is a chemical reaction that transforms primary alkyl halides into primary amines using potassium phthalimide.[1][2][3][4]
The Gabriel reaction has since been generalized to include the alkylation of sulfonamides and imides, followed by deprotection, to obtain amines (see #Alternative Gabriel reagents).[5][6]
The utility of the method is based on the fact that the alkylation of ammonia is an unselective and inefficient route to amines in the laboratory (on an industrial scale, the alkylation of ammonia is, however, widely employed). The conjugate base of ammonia, sodium amide (NaNH2), is more basic than it is nucleophilic. In fact, sodium amide is used to deliberately obtain the dehydrohalogenation product.[7]
In this method, the sodium or potassium salt of phthalimide is N-alkylated with a primary alkyl halide to give the corresponding N-alkylphthalimide. The reaction fails with most secondary alkyl halides:
Upon workup by acidic hydrolysis the primary amine is liberated as the amine salt.[8] Alternatively the workup may be via the Ing-Manske procedure, involving reaction with aqueous or ethanolic hydrazine at reflux. This produces a precipitate of phthalhydrazide along with the primary amine. The first technique often produces bad yields or side products; separation of phtalhydrazide can be unpleasant. For these reasons, other methods for liberating the amine from the phthalimide exist.[9] Even with the use of the hydrazinolysis method, the Gabriel method suffers from relatively harsh conditions.
Many alternative reagents have been developed to complement the use of phthalimides. Most such reagents, e.g. the sodium salt of saccharin, are electronically similar to the phthalimide salts. In terms of their advantages, some such alternative reagents hydrolyze more readily, extend the reactivity to secondary alkyl halides, and allow the production of secondary amines.[6]