Gabriel Phthalimide Synthesis

Gabriel synthesis, named after the German scientist Siegmund Gabriel, involves the conversion of primary alkyl halides into primary amines. Potassium phthalimide is mainly used in the preparation of primary amines. This reaction generally includes alkylation of sulphonamides and imides, followed by deprotonation to obtain amines. 

The unselective and inefficient route for amines is the alkylation of ammonia.

• Theory 

The main advantage of this reaction is avoidance over alkylation. Imine, a good nucleophile, is formed by the reaction between phthalimide and potassium hydroxide. The imine follows a nucleophilic substitution reaction. It leads to the formation of an intermediate – N-alkyl phthalimide – with the help of alkyl halide. Further hydrolysis of this intermediate yields primary alkyl amine. 

Aryl amines cannot be prepared by this method because aryl halides don’t go for nucleophilic substitution.

• Mechanism

First step: An acid-base reaction occurs when potassium hydroxide is added to the phthalimide. The imide is deprotonated by the hydroxide ion. The resulting proton is more acidic than any simple amine (resonance stabilisation provided by the two neighbouring carbonyl-like groups), resulting in a strong nucleophile – the imide ion.

Second step: The alkyl halide’s electrophilic carbon is attacked by the nucleophilic imide ion. The nitrogen atom then links with the carbon itself, replacing the halogen (Fluorine, Chlorine, Bromine, or Iodine) in the alkyl halide. An N-Alkyl Phthalimide is formed as a result of this reaction.

Third step: The mechanism is very similar to base-catalysed hydrolysis of esters, but instead of oxygen, nitrogen is linked to the R group. The hydroxide ion cleaves the N-Alkyl phthalimide by attacking the carbon atom linked to the nitrogen atom. The oxygen atom is also attached to the cation in the base. When the oxygen atom replaces the nitrogen atom in the phthalimide, the hydrogens expelled from the hydroxide ion link with the nitrogen atom belonging to the R group.

The Gabriel method can be utilised to synthesise primary amines from phthalimides. Instead of utilising an aqueous base, acidic hydrolysis or hydrazinolysis can be used to follow the procedure. With secondary alkyl halides, the Gabriel technique usually fails. Another downside of this synthesis is that it produces a low yield when utilising acidic/basic hydrolysis, whereas adding hydrazine can render the synthesis conditions relatively harsh. 

The pKa of phthalimide’s NH bond is 8.3. Both the inductive and the resonance effect contribute to the increased acidity of the NH bond. The acidity of the NH bond increases by the inductive impact of two carbonyl groups. The resonance stabilisation of the conjugate base, caused by the delocalisation of nitrogen electrons with carbonyl groups, is the most important effect.

When the nitrogen atom linked to the carbon of the R group is replaced by an oxygen atom in the phthalimide, it forms a connection with the hydrogen expelled from the hydroxide ion.

Instead of utilising basic hydroxide, the reaction can be carried out using acidic hydrolysis or even hydrazine. Both, however, have drawbacks. The yield is minimal in acidic hydrolysis, and the conditions are harsh in hydrazine hydrolysis. As a result, these two are omitted.

Limitations

This reaction is used in the formation of primary alkyl amine. Secondary and tertiary amines cannot be formed by Gabriel phthalimide Synthesis. It cannot be used in the formation of aryl amine.

Things to Remember:

1. Primary amines are made via the Gabriel Phthalimide Synthesis process.
2. Primary alkyl halides are utilised to make primary amines in the Gabriel Phthalimide Synthesis method. Primary amide is also made with phthalimide.
3. The hydroxide ion dehydrogenates the imide when phthalimide and potassium hydroxide are combined. This results in the formation of a powerful nucleophile.
4. The nucleophilic imide ion attacks the electrophilic carbon in the alkyl halide.
5. The nitrogen atom replaces the halogen in the alkyl halide. The nitrogen atom forms a connection with the carbon atom, resulting in the formation of N-Alkyl Phthalimide.
6. The nitrogen atom binds to the R group, whereas the carbon atom is attacked by the potassium hydroxide hydroxide ion.

Conclusion

The Gabriel synthesis which converts alkyl halides into primary amines, involves the hydrolysis of an imide. An imide is a molecule with two acyl groups bonded to a nitrogen. Only one alkyl group can be placed on the nitrogen because there is only one hydrogen bonded to the nitrogen of phthalimide. This means that the Gabriel synthesis can be used only for the preparation of primary amines. The pKa of phthalimide’s NH bond is 8.3. Both the inductive and the resonance effect contribute to the increased acidity of the NH bond.