19.19:
Preparation of 1° Amines: Hofmann and Curtius Rearrangement Mechanism
Hofmann and Curtius rearrangements convert different carboxylic acid derivatives to primary amines.
Hofmann rearrangement begins with the base abstracting the N–H proton, followed by an α-substitution reaction with the halogen to form an N-haloamide.
Abstracting the second N–H proton provides a resonance-stabilized anion.
A further rearrangement via alkyl migration from the carbonyl carbon to the adjacent nitrogen with simultaneous loss of the halide ion produces an isocyanate intermediate.
Nucleophilic addition of water to the isocyanate forms carbamic acid, which spontaneously expels CO2, yielding an amine.
Curtius rearrangement involves a thermally induced concerted rearrangement of the azide to generate the isocyanate with the simultaneous loss of N2.
Hydration under acidic condition adds a molecule of water across the C=N bond, generating carbamic acid, which on spontaneous decarboxylation followed by neutralization gives the free amine.
Both rearrangements involve the formation of isocyanate via alkyl migration to the nitrogen atom, along with the loss of CO2 in the final step.
The leaving group, however, is different in each rearrangement.
19.19:
Preparation of 1° Amines: Hofmann and Curtius Rearrangement Mechanism
The Hofmann and Curtius rearrangement reactions can be applied to synthesize primary amines from carboxylic acid derivatives such as amides and acyl azides. In the Hofmann rearrangement, a primary amide undergoes deprotonation in the presence of a base, followed by halogenation to generate an N-haloamide. A second proton abstraction produces a stabilized anionic species, which rearranges to an isocyanate intermediate via an alkyl group migration from the carbonyl carbon to the neighboring nitrogen. The addition of water to the isocyanate yields a carbamic acid that undergoes spontaneous decarboxylation to produce a primary amine.
The Curtius rearrangement also involves an isocyanate intermediate. Here, however, acyl azides undergo a concerted rearrangement under thermal conditions to generate the isocyanate with the expulsion of a nitrogen molecule. Next, hydration, followed by the loss of CO2, yields the desired amine. The Curtius rearrangement is useful for the synthesis of carbamate esters, primary amines, and urea derivatives by the reaction of carbamic acid with alcohols, water, and amines, respectively.