31. HOFMANN REARRANGEMENT

Hofmann Rearrangement

Hofmann Rearrangement (also called Hofmann Degradation or Hofmann Bromamide Reaction) is a chemical reaction where a primary amide is converted into a primary amine using bromine and a strong base (like NaOH). The key point is that the resulting amine has one carbon atom less than the original amide.

This reaction is very useful in organic chemistry for preparing alkyl, aryl, and heterocyclic amines.

General Reaction

Primary amide → (Br2/NaOH) → Primary amine (with one carbon less)

Why This Happens

During the reaction, the amide is converted into an isocyanate intermediate. This is then broken down into a primary amine after losing carbon dioxide.

Thus, one carbon is removed in the form of CO2.

Mechanism of Hofmann Rearrangement

The mechanism occurs in several steps:

  1. Formation of N-bromoamide: The amide reacts with bromine in a basic medium to give an N-bromoamide. The N–H becomes more acidic due to both the acyl group and bromine pulling electrons.
  2. Deprotonation: The base (OH-) removes this acidic hydrogen forming an unstable nitrogen anion.
  3. Rearrangement / Migration Step: The anion loses a bromide ion, and simultaneously an alkyl or aryl group from the carbon migrates to the nitrogen. This forms an isocyanate. The migration happens with retention of stereochemistry.
  4. Hydrolysis of isocyanate: The isocyanate reacts with water to form an unstable carbamic acid, which then decomposes to give:
    • Primary amine
    • Carbon dioxide (released)

If the reaction is done in methanol instead of water, the isocyanate forms a methyl carbamate, which can later be hydrolyzed to give the amine.

Stereochemistry

The rearrangement happens with complete retention of configuration. This means optically active amides produce optically active amines without racemization.

Applications

1. Preparation of Primary Amines

Hofmann rearrangement is widely used to produce primary amines from primary amides.

  • Carboxylic acids → convert to amides → Hofmann rearrangement → amines
  • Long-chain amides may give nitriles (which can later be reduced to amines)
  • Urea gives hydrazine

2. Preparation of β-Amino Pyridine

Nicotinamide can undergo Hofmann rearrangement to give beta-aminopyridine.

3. Synthesis of Amino Acids

Useful in making amino acids where one-carbon shortening is required.

4. Preparation of Aldehydes from Hydroxyacid Amides

Hydroxyacid amides on Hofmann rearrangement give useful aldehydes (after forming intermediates like urethanes).

Important Note

Students often confuse this reaction with Hofmann Elimination, but both are different.
• Hofmann Rearrangement = primary amide → amine (one carbon less)
• Hofmann Elimination = quaternary ammonium hydroxides → alkenes

Detailed Notes:

For PDF style full-color notes, open the complete study material below:

PATH: PHARMD/PHARMD NOTES/ PHARMD FIRST YEAR NOTES/ ORGANIC CHEMISTRY/ PHARMACEUTICAL ORGANIC CHEMISTRY/ HOFMANN REARRANGEMENT.

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