Hofmann rearrangement

Hofmann rearrangement

The Hofmann rearrangement is an organic reaction used to convert a primary amide to a primary amine using a halogen, base, water, and heat. The reaction begins with deprotonation of the amide by the base to form an anion which then attacks the halogen to form a N-haloamide. A second deprotonation by the base provides an anion that rearranges to an isocyanate intermediate and releases a halide anion. The isocyanate is then attacked by water which after a series of proton transfer step results in a zwitterionic intermediate, containing an ammonium cation and a carboxylate anion. Thermal conditions result in the explosion of carbon dioxide gas and quenching of the ammonium cation to the amine product.

Mechanism

Hofmann rearrangement, also known as Hofmann degradation and not to be confused with Hofmann elimination, is the reaction of a primary amide with a halogen (chlorine or bromine) in strongly basic (sodium or potassium hydroxide) aqueous medium, which converts the amide to a primary amine.

Hoffmann bromamide reaction is one of the most important reactions in organic chemistry, included in JEE syllabus. It is one of the major reactions for the synthesis of primary amines. Some FAQs related to Hoffmann bromamide reactions are:

 

What is Hoffmann bromamide reaction?  

 

When an amide is treated with bromine in an aqueous or ethanolic solution of sodium hydroxide, degradation of amide takes place leading to the formation of primary amine. This reaction involving degradation of amide and is popularly known as Hoffmann bromamide degradation reaction. The primary amine thus formed contains one carbon less than the number of carbon atoms in that amide.

 

RCONH₂ +Br₂ + 4NaOH → R-NH₂ + Na₂CO₃ + 2NaBr + 2H₂O

 

What is the general mechanism of Hoffmann bromamide reaction?

 

The general mechanism of Hoffmann bromamide reaction includes following steps:

 

A strong base (usually an alkali) attacks the amide, this leads to deprotonation generating an anion.

 

This anion reacts with bromine to form N-bromoamide. This reaction can be seen as α-substitution reaction.

 

Deprotonation of the bromoamide molecule to generate a bromoamide anion.

 

The generated bromoamide anion undergoes rearrangement such that the R group attached to the carbonyl carbon migrates to nitrogen. The bromide ion leaves the compound simultaneously, leading to the formation of isocyanate.

 

Water molecules are added to the isocyanateto form carbamic acid. This reaction is an example of nucleophilic addition.

 

Finally, the carbamic acid loses carbon dioxide, CO₂ leading to the formation of primary amine.