Gabriel Phthalimide Synthesis Mechanism

Introduction

Gabriel Phthalimide synthesis is the process of formation of primary amine only. It is a three-step process in which phthalimide reacts with a base and alkyl halide to form primary amine and salt of sodium or potassium phthalimide. German scientist Siegmund Gabriel synthesised it. In this process, we can make only primary amines not aryl amines as the aryl halides do not process nucleophilic substitution reactions. We can use any base potassium hydroxide or sodium hydroxide in this reaction.

Gabriel Phthalimide Synthesis

What is Gabriel Phthalimide?

The Gabriel Synthesis is a valuable preparation of primary amines. In this process, the phthalimide is prepared first by phthalic anhydride with aqueous ammonia and then phthalimide is reacted with an alkylating agent to form a more dipolar resonance form of phthalimide. The carbonyl group increases the acidity of the nitrogen and hydrogen bond (𝑁 − 𝐻). The negatively charged nitrogen atom displaced the halide group from the alkyl halide. Which undergoes hydrolysis reaction to form N-alkyl phthalimide and then after hydrolysis results in the formation of primary alky amine and salt of sodium or potassium phthalimide. It is a nucleophilic reaction.

Structure

The phthalimide is represented by the molecular formula $\mathrm{C_{6}H_{4}(CO_{2}N)}$. It is formed by a benzene ring attached to another ring containing five carbon and nitrogen and flanked by two carbonyl groups. It is a stable compound due to its stable resonance character.

Phthalimide

Preparation of Phthalimide

Phthalimide is a derivative of phthalic acid and is a bicyclic non-aromatic nitrogen heterocycle. It is used in activities like analgesic, preparation of amines, anti-depressant and anti-inflammatory, polymer synthesis, etc. It is prepared by heating phthalic anhydride with ammonia.

• In this reaction, the imide is formed by a nucleophilic attack of the amino group at the anhydride group of phthalic acid.

• On the ammonolysis of phthalic acid, it removes the water and forms a substrate of phthalic acid with ammonia, which on further heating forms, removed ammonia and form phthalimide.

Phthalimide Preparation from anhydride of Phthalic acid

Properties

It is an organic white to light pale yellow and is a solid compound. It is slightly acidic. It is imide derivative of phthalic anhydride. It has the following properties. Phthalimide has two carbonyl groups, that’s why it is slightly acidic.

Physical Properties:

Properties	Attributes
Colour	White solid
Chemical Formula	$\mathrm{C_{6}H_{4}(CO_{2})_{2}NH}$
Solubility	< 0.1 g/100 ml
Melting Point	238°C
Boiling Point	336°C

Chemical Properties:

• Phthalimide and its conjugate bases are obtained by the removal of a proton and are resonance stabilized. It can be written in several resonance forms leading to charge delocalization.

• Transition reaction: It reacts with an alkyl halide to form N-substituted phthalimide.

• When the mixture of phthalimide is heated with chloroacetic acid in presence of potassium hydroxide and DMF, the product formed was recrystallized by ethanol.

• When heated with hydrazine it gives phthalhydrazide and free alkyl amine.

Mechanism

The Gabriel Phthalimide synthesis is a three-step process.

Step1 − In the first step, the phthalimide is attacked by the potassium hydroxide or sodium hydroxide and the nitrogen in the phthalimide is deprotonated to form potassium phthalimide. The nitrogen in the phthalimide is highly nucleophilic.

Step 2 − In the second step the potassium phthalimide is attacked by alkyl halide on the nucleophilic imide group. The halogen of the alkyl halide is replaced by the nitrogen of the imide ion and forms N-alkyl Phthalimide.

Step3 − In the third step the N-alkyl phthalimide is attacked by the potassium or sodium hydroxide and the nitrogen detached itself from the phthalimide and forms primary amine and salt of sodium or potassium phthalimide. Nitrogen detached itself as it is more electronegative than oxygen in the phthalimide group.

Now potassium hydroxide acts as a nucleophile and attacked the nucleophilic site at the carbon-oxygen bond, then oxygen takes back its electron and tries to reconnect to carbon, in this situation nitrogen being more electronegative takes its electron back from carbon and detached from carbon and forms primary amine.

Reactions of Phthalic Anhydride

• The phthalic anhydride with primary and in presence of sulphonic acid catalyst forms, N-substituted phthalimides.

• Synthesis of 4-(1,3-dioxoisoindolin-2-yl) benzaldehyde: In a solution of 4 amino benzaldehyde drop wise phthalic anhydride is added in presence of dichloromethane and stirred at 15-20oC for 8 hours. It formed the 4-(1,3- dioxoisoindolin-2-yl) benzaldehyde which crystallizes in ether.

Phthalimide Uses

• It is used in pharmaceutical industries for the preparation of drugs like analgesics, anti-depressant, anti-inflammatory, etc. Examples are thalidomide, taltrimide, amphotalide, etc.

• It is used in the preparation of primary amines.

• In industries is used in the synthesis of polymer, dyes, saccharin, etc.

Conclusion

Gabriel Phtalalimide is a process for the synthesis of primary amines. In this reaction, phthalimide is used as the main component for the preparation of primary amine with reaction with base and alkyl halogen. With this method, we can only synthesise primary amine by the nucleophilic reaction. It does not form secondary and tertiary amine. Phthalimide is an organic white solid compound due to two carbonyl groups it is slightly acidic and a good nucleophile. It undergoes a nucleophilic substitution reaction with a base. It is used for many pharmaceuticals as well as industrial uses like in the preparation of drugs like an anti-inflammatory, antidepressant and in the synthesis of primary amines, polymers, azo dyes, etc.

FAQs

1. Why do aryl halides not undergo Gabriel Phtalaminde synthesis?

Aryl halides do not undergo nucleophilic substitution that's why they do not form amines from the Gabriel synthesis process.

2. Why secondary and tertiary amines are not formed through Gabriel Synthesis?

Secondary and tertiary amines undergo a competitive elimination reaction so, they do not form in the Gabriel synthesis reaction. one more reason is that secondary and tertiary amines do not react with an alkyl group.

3. Why is Phthalimide stable and shows different resonance forms?

Phthalimide has nitrogen connected with two carbonyl groups, they arrange in such a way that it is slightly acidic, and conjugate with base by the removal of the proton. The carbonyl group is more stable than the carboxylic group. It forms several resonance forms by the delocalization of charge.

4. In which form does phthalimide occur naturally?

Phthalimide occurs naturally in the form of kladnoite mineral analogue form. It is formed because of fires in rare coal fire sites. It is stated to be identical to phthalimide. It is found northwest of Prague, Radvanice, the Czech Republic in the Kladno coal basin.

5. Is phthalimide toxic?

Although it is less toxic it irritates the skin, respiratory tract, eyes, etc. It is combustible. It is hazardous to health, when it is heated its decomposition emits toxic fumes of nitrogen oxides. It also emits toxic gases when it reacts with azo and diazo compounds.