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The Gabriel synthesis is a
Upon workup by acidic
An animation of the mechanism of the Gabriel synthesis
Substitution reactions Name reactions
chemical reaction
A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and break ...
that transforms primary alkyl halide
The haloalkanes (also known as halogenoalkanes or alkyl halides) are alkanes containing one or more halogen substituents. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalkanes are widely us ...
s into primary amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent su ...
s. Traditionally, the reaction uses potassium phthalimide. The reaction is named after the German chemist Siegmund Gabriel.
The Gabriel reaction has been generalized to include the alkylation of sulfonamides and imides, followed by deprotection, to obtain amines (see Alternative Gabriel reagents).
The alkylation
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effectin ...
of ammonia
Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogeno ...
is often an unselective and inefficient route to amines. In the Gabriel method, phthalimide anion is employed as a surrogate of H2N−.
Traditional Gabriel synthesis
In this method, the sodium or potassium salt of phthalimide is ''N''-alkylated with a primaryalkyl halide
The haloalkanes (also known as halogenoalkanes or alkyl halides) are alkanes containing one or more halogen substituents. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalkanes are widely us ...
to give the corresponding ''N''-alkylphthalimide.
Upon workup by acidic hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolysis ...
the primary amine is liberated as the amine salt. Alternatively the workup may be via the Ing–Manske procedure, involving reaction with hydrazine
Hydrazine is an inorganic compound with the chemical formula . It is a simple pnictogen hydride, and is a colourless flammable liquid with an ammonia-like odour. Hydrazine is highly toxic unless handled in solution as, for example, hydrazin ...
. This method produces a precipitate of phthalhydrazide (C6H4(CO)2N2H2) along with the primary amine:
:C6H4(CO)2NR + N2H4 → C6H4(CO)2N2H2 + RNH2
Gabriel synthesis generally fails with secondary alkyl halides.
The first technique often produces low yields or side products. Separation of phthalhydrazide can be challenging. For these reasons, other methods for liberating the amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent su ...
from the phthalimide have been developed. Even with the use of the hydrazinolysis method, the Gabriel method suffers from relatively harsh conditions.
Alternative Gabriel reagents
Many alternative reagents have been developed to complement the use of phthalimides. Most such reagents (e.g. the sodium salt ofsaccharin
Saccharin (''aka'' saccharine, Sodium sacchari) is an artificial sweetener with effectively no nutritional value. It is about 550 times as sweet as sucrose but has a bitter or metallic aftertaste, especially at high concentrations. Saccharin ...
and di-tert-butyl-iminodicarboxylate) are electronically similar to the phthalimide salts, consisting of imido nucleophiles. In terms of their advantages, these reagents hydrolyze more readily, extend the reactivity to secondary alkyl halides
The haloalkanes (also known as halogenoalkanes or alkyl halides) are alkanes containing one or more halogen substituents. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalkanes are widely u ...
, and allow the production of secondary amines.
See also
* Robinson–Gabriel synthesis - also developed by Siegmund Gabriel * Delépine reaction - primary amines from benzyl or alkyl halidesReferences
{{reflist, colwidth=30emExternal links
An animation of the mechanism of the Gabriel synthesis
Substitution reactions Name reactions