Explain the mechanism involved in the synthesis of primary amides by Gabriel synthesis

Answer 1

Gabriel synthesis is a method used to produce primary amines from alkyl halides. While it doesn't directly synthesize primary amides, the mechanism of Gabriel synthesis can be extended to illustrate how primary amines can further be converted into primary amides through a straightforward step.

Here's a breakdown of the Gabriel synthesis mechanism, followed by how the reaction can lead to primary amide synthesis indirectly:

Gabriel Synthesis Mechanism:

1. Formation of the Potassium Salt of Phthalimide: Gabriel synthesis starts with phthalimide, which is treated with a strong base (commonly potassium hydroxide or sodium hydride) to form the potassium salt of phthalimide. The base deprotonates the NH of phthalimide, making the nitrogen anionic.

   \[ \text{Phthalimide} + KOH \rightarrow \text{Potassium Phthalimide Salt} \]

2. Alkylation: The potassium salt of phthalimide is then reacted with an alkyl halide (R-X), where R is the alkyl group and X is a halogen (e.g., Cl, Br, or I). The salt acts as a nucleophile and undergoes nucleophilic substitution (S_N2) to form N-alkyl phthalimide.

   \[ \text{Potassium Phthalimide} + R-X \rightarrow \text{N-R-Phthalimide} + KX \]

3. Hydrolysis: The N-alkyl phthalimide can be hydrolyzed to liberate the primary amine. This step commonly involves the use of a strong acid or base in water to cleave the bond, producing phthalic acid and the primary amine.

   \[ \text{N-R-Phthalimide} + \text{H}_2\text{O} \rightarrow R-NH_2 + \text{Phthalic Acid} \]

Synthesis of Primary Amides:

Once the primary amine (R-NH₂) is formed from Gabriel synthesis, it can then be converted into a primary amide (R-C(O)NH₂) via a reaction with an acylating agent, such as an acid chloride or an anhydride:

1. Acylation: The primary amine can react with an acid chloride or an anhydride:

   \[ R-NH_2 + R'COCl \rightarrow R-C(O)NH_2 + HCl \]

   or

   \[ R-NH_2 + (R'CO)2O \rightarrow R-C(O)NH_2 + R'COOH \]

Overall, while the Gabriel synthesis itself produces primary amines, these products can be further transformed into primary amides through acylation. This allows for the synthesis of primary amides starting from phthalimide and an alkyl halide, illustrating the versatility of the initial synthesis steps in forming a variety of nitrogen-containing compounds.