The Gabriel synthesis is a

chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...

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 Hydrogen is the chemical element wi ...

s. Traditionally, the reaction uses potassium phthalimide. The reaction is named after the German chemist

Siegmund Gabriel Siegmund Gabriel (7 November 1851 – 22 March 1924) was a German chemist. Scientific career Siegmund Gabriel began studying chemistry at the University of Berlin in 1871. He continued his studies at the University of Heidelberg in 1872 wi ...

. 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 effecti ...

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 nitrogenous wa ...

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 Phthalimide is the organic compound with the formula C6H4(CO)2NH. It is the imide derivative of phthalic anhydride. It is a sublimable white solid that is slightly soluble in water but more so upon addition of base. It is used as a precursor ...

is ''N''-alkylated with a primary

to give the corresponding ''N''-alkylphthalimide. Gabriel Synthesis Scheme

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 hydrolys ...

the primary amine is liberated as the amine salt. Alternatively the workup may be via the Ing–Manske procedure, involving reaction with hydrazine. 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

from the

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 of

saccharin 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 is ...

and

di-tert-butyl-iminodicarboxylate Di-''tert''-butyl-iminodicarboxylate is an organic compound that can be described with the formula CH3)3COC(O)sub>2NH. It is a white solid that is soluble in organic solvents. The compound is used as a reagent for the preparation of primary amin ...

) 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 us ...

, and allow the production of secondary amines.

References

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External links

An animation of the mechanism of the Gabriel synthesis
Substitution reactions Name reactions

Traditional Gabriel synthesis

Alternative Gabriel reagents

See also

References

External links