The Hofmann rearrangement is a chemical reaction that involves the conversion of primary amides (RCO-NH2) into primary amines (RNH2) with one fewer carbon atom. It is named after the German chemist August Wilhelm von Hofmann, who first described this rearrangement.
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The general equation for the Hofmann rearrangement is as follows:
RCONH2 → R’NH2 + CO2
In this reaction, the carbonyl carbon of the primary amide is rearranged, resulting in the migration of an alkyl or aryl group (R) from the nitrogen atom to the carbonyl carbon. Simultaneously, carbon dioxide (CO2) is eliminated, and the primary amide is converted into a primary amine with one fewer carbon atom.
The Hofmann rearrangement is typically carried out by treating the primary amide with a strong oxidizing agent, such as bromine (Br2) in the presence of sodium hydroxide (NaOH) or silver oxide (Ag2O). The reaction proceeds through a reaction intermediate called an isocyanate (R-N=C=O), which is formed by the reaction of the primary amide with the oxidizing agent. The isocyanate then undergoes rearrangement to yield the primary amine and carbon dioxide.
The mechanism of the Hofmann rearrangement involves several steps:
- Formation of the isocyanate: The primary amide reacts with the oxidizing agent to form an isocyanate intermediate. This step involves the oxidation of the nitrogen atom and the elimination of a nitrogen molecule.
- Rearrangement: The isocyanate undergoes a rearrangement, leading to the migration of the alkyl or aryl group from the nitrogen to the carbonyl carbon. This rearrangement step is usually driven by the stabilization of the resultant carbocation.
- Elimination: The rearranged intermediate undergoes elimination of carbon dioxide, resulting in the formation of the primary amine.
The Hofmann rearrangement has synthetic applications in the preparation of primary amines with specific carbon chain lengths. By selecting the appropriate starting primary amide and reaction conditions, one can obtain primary amines with desired structural features. The reaction is often used in organic synthesis, especially in the preparation of pharmaceutical intermediates.
It’s important to note that the Hofmann rearrangement is regioselective, meaning that the migrating group (R) moves from the nitrogen atom to the carbonyl carbon in a way that results in the least steric hindrance. As a result, the rearranged product may not always be the thermodynamically most stable primary amine.
In summary, the Hofmann rearrangement is a chemical reaction that converts primary amides into primary amines with one fewer carbon atom. It involves the migration of an alkyl or aryl group from the nitrogen to the carbonyl carbon, accompanied by the elimination of carbon dioxide. The reaction is useful in organic synthesis for the preparation of primary amines with specific carbon chain lengths.
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