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Chapter 19: Amines Back To Chapter

19.19: Preparation of 1° Amines: Hofmann and Curtius Rearrangement Overview

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Preparation of 1° Amines: Hofmann and Curtius Rearrangement Overview

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19.20: Preparation of 1° Amines: Hofmann and Curtius Rearrangement Mechanism

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Primary amides can be converted into primary amines by Hofmann rearrangement using a halogen and an aqueous base.

The rearrangement involves an alkyl shift from the carbonyl carbon to the amine nitrogen. The reaction loses the carbonyl group in the form of CO₂.

An example of Hofmann rearrangement is the synthesis of an appetite-suppressant drug—phentermine—from an aryl amide.

Analogous to Hofmann rearrangement, Curtius rearrangement also gives primary amines, although with a different substrate—acyl azide, and under thermal conditions.

An alkyl migration to the closest nitrogen, followed by the loss of N₂ and carbon dioxide, drives the reaction forward to generate the amine.

Curtius rearrangement is used to make the antidepressant drug, Tranylcypromine.

Both rearrangements produce primary amines with the loss of one carbon, and the migrating group completely retains its configuration.

19.19: Preparation of 1° Amines: Hofmann and Curtius Rearrangement Overview

In the presence of an aqueous base and a halogen, primary amides can lose the carbonyl (as carbon dioxide) and undergo rearrangement to form primary amines. This reaction, called the Hofmann rearrangement, can produce primary amines (aryl and alkyl) in high yields without contamination by secondary and tertiary amines.

In the Curtius rearrangement, acyl azides are converted into primary amines under thermal conditions, accompanied by the loss of gaseous N₂ and CO₂. The loss of nitrogen acts as a driving force to complete the reaction.

The Hofmann and Curtius rearrangement reactions are applied in the synthesis of phentermine (an appetite-suppressant drug) and tranylcypromine (an antidepressant drug), respectively.

If the substrates are optically active, both rearrangement reactions occur with retention of configuration.

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Hofmann Rearrangement Curtius Rearrangement Primary Amides Primary Amines Aqueous Base Halogen Carbon Dioxide Aryl Amines Alkyl Amines Acyl Azides Thermal Conditions N2 CO2 Phentermine Synthesis Tranylcypromine Synthesis Optically Active Substrates

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