Gabriel Synthesis Reaction Mechanism

Introduction

• Focus on the Gabriel synthesis reaction mechanism.
• Begins with a molecule called thalamide, which contains an imide functional group (nitrogen between two carbonyl or acyl groups).

Purpose of Gabriel Synthesis

• To produce primary amines.

First Version of the Reaction

Steps:

1. Add potassium hydroxide in water.
2. Add an alkyl halide (e.g., one bromobutane).
3. Add hydrazine (H2N-NH2) or N2H4.

Product Formation

• Replace Br in the alkyl halide with NH2 to obtain the desired amine.
• Side Product: Thalamide hydrazide; the ring expands from five to six atoms, making it more stable due to decreased ring strain.

Second Version of the Reaction

Steps:

1. Use strong base (potassium hydroxide).
2. Add alkyl halide (e.g., one bromohexane).
3. Add water with hydrochloric acid in the presence of heat.
4. Add potassium hydroxide.

Product Formation

• Replace bromine with NH2, yielding a primary amine with six carbons.
• Side Product: Two carboxylic acids due to acid hydrolysis and cleavage of carbonyls.

Mechanism of the First Version

1. Addition of a base (potassium hydroxide) removes acidic hydrogen from nitrogen.
   • Stabilization of conjugate base by resonance with carbonyl groups.
2. Nucleophilic Attack: Nitrogen attacks the electrophilic alkyl halide (e.g., one bromobutane) leading to SN2 reaction.
3. Hydrazine Addition:
   • Attacks carbon; forms intermediate.
4. Formation of Thalamide Hydrazide:
   • Stability drives ring expansion from five to six atoms.
   • Reversible steps lead to final structure.

Mechanism of the Second Version

1. Water and HCl mixture activates carbonyl via protonation (H3O+ generated).
2. Nucleophilic attack by water on the activated carbonyl.
3. Formation of two hydroxyl groups as intermediates.
4. Final Step: Remove the nitrogen group to achieve the primary amine and deprotonated carboxylic acid.

Conclusion

• Both versions of Gabriel synthesis effectively yield primary amines.
• Different side products arise depending on method used (hydrazine vs. acid hydrolysis).

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