The Gabriel synthesis is a

chemical reaction A chemical reaction is a process that leads to the chemistry, chemical transformation of one set of chemical substances to another. When chemical reactions occur, the atoms are rearranged and the reaction is accompanied by an Gibbs free energy, ...

that transforms primary

alkyl halide The haloalkanes (also known as halogenoalkanes or alkyl halides) are alkanes containing one or more halogen substituents of hydrogen atom. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalka ...

s into primary

amine In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

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

sulfonamide In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the Chemical structure, structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this gro ...

s and

imide In organic chemistry, an imide is a functional group consisting of two acyl groups bound to nitrogen. The compounds are structurally related to acid anhydrides, although imides are more resistant to hydrolysis. In terms of commercial applications ...

s, followed by

deprotection A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis. In man ...

, to obtain amines (see Alternative Gabriel reagents). The

alkylation Alkylation is a chemical reaction that entails transfer of an alkyl group. 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 effecting al ...

ammonia Ammonia is an inorganic chemical compound of nitrogen and hydrogen with the chemical formula, formula . A Binary compounds of hydrogen, stable binary hydride and the simplest pnictogen hydride, ammonia is a colourless gas with a distinctive pu ...

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 Sublimation (phase transition), sublimable white solid that is slightly soluble in water but more so upon addition of bas ...

is ''N''-alkylated with a primary

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

Upon workup by

acid An acid is a molecule or ion capable of either donating a proton (i.e. Hydron, hydrogen cation, H+), known as a Brønsted–Lowry acid–base theory, Brønsted–Lowry acid, or forming a covalent bond with an electron pair, known as a Lewis ...

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 reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

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 hazardous unless handled in solution as, for example, hydraz ...

. 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, also called saccharine, benzosulfimide, or E954, or used in saccharin sodium or saccharin calcium forms, is a non-nutritive artificial sweetener. Saccharin is a sultam that is about 500 times sweeter than sucrose, but has a bitter or ...

and di-tert-butyl-iminodicarboxylate) are electronically similar to the phthalimide salts, consisting of imido

nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...

s. In terms of their advantages, these reagents

hydrolyze 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 ...

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 of hydrogen atom. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalka ...

, and allow the production of secondary amines.

References

{{reflist

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