Gabriel synthesis

What is Gabriel synthesis?

In 1887, Gabriel first reported a two-step process for synthesizing primary aliphatic amines, which is now known as the Gabriel synthesis, or Gabriel primary amine synthesis, or Gabriel reaction.

In the first step, phthalimide is N-alkylated, and in the second step, the resulting N-alkyl phthalimide is hydrolyzed either under basic or acidic conditions to provide pure primary amines. The Gabriel synthesis is advantageous because it prevents over alkylation of the nitrogen atom, which would result in a mixture of primary, secondary, tertiary, and quaternary amines if ammonia directly reacted with an alkyl halide.

Síntesis de Gabriel - general reaction scheme - Gabriel primary amine synthesis - Gabriel reaction
Gabriel synthesis

Phthalimide is easily deprotonated by KOH or NaOH, resulting in a good nucleophile for N-alkylation. The hydrolysis of N-alkyl phthalimide has been found to be the rate-limiting step, with a t½ of 264 h under basic conditions and a t½ of 175 h under acidic conditions. To accelerate the hydrolysis, the Ing-Manske procedure or hydrazinolysis can be used, which involves using hydrazine to modify the hydrolysis process. Alternatively, a two-step procedure involving NaBH4/isopropanol reduction and acetic acid hydrolysis has been developed for generating primary amines.

Example

The Gabriel synthesis is a chemical reaction that produces primary amines from alkyl halides and phthalimide in the presence of a base. An example of a Gabriel synthesis is the reaction between n-butyl bromide and phthalimide in the presence of sodium hydroxide NaOH:

The alkyl halide, n-butyl bromide, is treated with a base, such as sodium hydroxide, to form an intermediate called an alkyl lithium..

The phthalimide is then added, and the nitrogen atom of the phthalimide attacks the alkyl lithium, forming an intermediate called a lithium phthalimide..

The intermediate then loses a molecule of lithium halide to form an intermediate called an imide..

The imide intermediate is then hydrolyzed by water, which causes a deprotonation to occur, forming the final product, the primary amine, n-butylamine..

The Gabriel synthesis is a useful synthetic tool for the preparation of primary amines, which are widely used in the synthesis of various organic compounds such as pharmaceuticals and agrochemicals..

Mechanism of reaction

The Gabriel synthesis is a chemical reaction that converts a primary alkyl halide and a phthalimide to a primary amine. The mechanism of the reaction is as follows:

  • Step 1: A primary alkyl halide molecule reacts with a phthalimide in the presence of a base, such as sodium hydroxide, to form a tetrahedral intermediate..
  • Step 2: The tetrahedral intermediate then collapses, releasing a molecule of halide and forming a primary amine..
  • Step 3: The base acts as a nucleophile, attacking the carbon atom of the alkyl halide, forming a tetrahedral intermediate..
  • Step 4: The intermediate then collapses, releasing the halide and forming the primary amine..

It is important to note that the Gabriel synthesis is a method for the synthesis of primary amines only, and the reactivity of the halide is crucial, as secondary and tertiary halides do not react in the same manner. Additionally, the reaction is sensitive to the presence of water and oxygen, which can hydrolyze the intermediate and prevent the formation of the primary amine..

References

Gabriel, S. (1887), Ueber eine Darstellungsweise primärer Amine aus den entsprechenden Halogenverbindungen. [On a method of representing primary amines from the corresponding halogen compounds] Ber. Dtsch. Chem. Ges., 20: 2224-2236. https://doi.org/10.1002/cber.18870200227

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