Hofmann Rearrangement

Hofmann Rearrangement: Primary Amide → Primary Amine (Br₂/NaOH)

The Hofmann rearrangement (or Hofmann degradation) converts a primary amide into a primary amine with one fewer carbon using Br2/NaOH (or Cl2/NaOH). The carbonyl carbon is lost as CO2, and the R group migrates from the carbonyl carbon to nitrogen via an isocyanate intermediate.

Overall: R-C(=O)-NH2 + Br2/NaOH --> R-NH2 + CO2


Key Emphasis (Teaching Pivots)

  • One fewer carbon. The product amine has one fewer carbon than the starting amide. The carbonyl carbon is lost as CO2.
  • Primary amides only. The reaction requires a primary amide (RCONH2). N-substituted amides do not undergo this rearrangement.
  • Isocyanate intermediate. The key intermediate is an isocyanate (R-N=C=O), formed by 1,2-migration of R from carbonyl to nitrogen.
  • Migration with retention. If the migrating carbon is stereogenic, it typically retains configuration during migration.
  • Don't confuse with LiAlH4 reduction. LiAlH4 reduces amides to amines but preserves all carbons. Hofmann removes one carbon.

Quick Summary

Feature Hofmann Rearrangement
Substrate Primary amide (RCONH2)
Reagents Br2, NaOH (aq), heat
Product Primary amine (RNH2) - one fewer carbon
Key Intermediate Isocyanate (R-N=C=O)
Byproduct CO2 (carbonyl carbon lost)
Mechanism Steps 11 steps

What "moves" in the rearrangement

  • The R group migrates from the carbonyl carbon to the nitrogen (1,2-shift).
  • The migrating group keeps its configuration if it's a chiral carbon (stereoretentive migration).

Mechanism - Hofmann Rearrangement (11 Steps)

Conditions: Br2, NaOH (aq), heat

The mechanism proceeds through: (1) N-halogenation to form N-bromoamide, (2) rearrangement to an isocyanate intermediate, and (3) hydrolysis followed by decarboxylation to give the amine product.

Step 1: OH- deprotonates amide nitrogen
Step 1 - Deprotonate amide nitrogen. OH- removes an N-H proton, increasing nucleophilicity at nitrogen.
Step 2: Amide anion attacks Br2
Step 2 - N-bromination. The amide anion attacks Br2, forming an N-bromoamide and releasing Br-.
Step 3: Second deprotonation
Step 3 - Second deprotonation. OH- removes the remaining N-H proton, generating a rearrangement-ready anion.
Step 4: 1,2-rearrangement to isocyanate
Step 4 - Rearrangement to isocyanate. The R group migrates from carbonyl carbon to nitrogen as Br- leaves, forming the isocyanate (R-N=C=O).
Step 5: Water attacks isocyanate
Step 5 - Water attacks isocyanate. Water attacks the electrophilic carbon of the isocyanate, forming a tetrahedral intermediate.
Step 6: Deprotonation of oxonium
Step 6 - Deprotonate oxonium. Water abstracts a proton from the positively charged oxygen, generating H3O+ and neutralizing the intermediate.
Step 7: First N protonation
Step 7 - First N protonation. H3O+ protonates nitrogen. Nitrogen remains neutral with 3 bonds.
Step 8: Deprotonate OH to form carboxylate
Step 8 - Form carboxylate. Water abstracts the proton from OH, creating a carboxylate anion (O-) while carbonyl C=O stays intact.
Step 9: Second N protonation
Step 9 - Second N protonation. H3O+ protonates nitrogen a second time, forming an ammonium cation (N+).
Step 10: Decarboxylation
Step 10 - Decarboxylation. The carboxylate O- electrons push into C=O while the N-C bond breaks, releasing CO2 and neutralizing the ammonium.
Step 11: Final amine product
Step 11 - Final product. The primary amine (R-NH2) is formed with one fewer carbon than the starting amide.

Worked Examples

Example A - Acetamide to Methylamine. The methyl group migrates; carbonyl carbon is lost as CO2.
Example A reactant: acetamide
Reactant
Reagent: Br2, NaOH, heat
Reagent
Example A product: methylamine
Product
Example B - Benzamide to Aniline. The phenyl group migrates; carbonyl carbon is lost as CO2.
Example B reactant: benzamide
Reactant
Reagent: Br2, NaOH, heat
Reagent
Example B product: aniline
Product
Example C - Cyclohexanecarboxamide to Cyclohexylamine. The cyclohexyl group migrates; carbonyl carbon is lost as CO2.
Example C reactant: cyclohexanecarboxamide
Reactant
Reagent: Br2, NaOH, heat
Reagent
Example C product: cyclohexylamine
Product

Scope & Limitations

  • Primary amides only. Secondary and tertiary amides do not undergo this rearrangement (they lack the required N-H protons).
  • Basic/oxidizing conditions. The reaction uses strong base (NaOH) and oxidizing halogen (Br2). Acid-labile groups survive, but base-sensitive groups may react.
  • Lactams. Cyclic amides (lactams) can rearrange to give ring-contracted amines (one fewer carbon in the ring).
  • Migration stereochemistry. If the migrating carbon is a stereocenter, it typically migrates with retention of configuration.
  • Cl2/NaOH alternative. Chlorine can be used instead of bromine; the mechanism is the same.

Edge Cases & Exam Traps

1) "One fewer carbon" is the key trap

Students often draw RCONH2 --> RCH2NH2 (that's LiAlH4 reduction logic, not Hofmann). Hofmann rearrangement removes the carbonyl carbon: RCONH2 --> RNH2.

2) Migration stereochemistry

If the migrating carbon is stereogenic, the migration is typically retention (the carbon migrates as a group, not via a planar carbocation).

3) Cyclic amides (lactams) give ring contraction

A lactam can rearrange to give a ring-contracted amine (one fewer carbon in the ring). If you see a lactam + Br2/NaOH, expect a smaller ring amine.

4) Not the right reagent for N-substituted amides

If the amide is secondary or tertiary (N-substituted), expect no Hofmann product. The reaction requires two N-H protons.

5) Don't confuse with Curtius or Schmidt rearrangements

These other rearrangements also convert acyl compounds to amines via isocyanates, but use different starting materials (acyl azides for Curtius, carboxylic acids + HN3 for Schmidt).


Product Prediction Checklist

  1. Confirm primary amide: The substrate must be RCONH2.
  2. Delete the carbonyl carbon: Product skeleton is R-NH2.
  3. CO2 is the "lost carbon" (conceptually).
  4. Check for lactams: If cyclic, expect ring contraction.
  5. Check for stereocenters: Migration is typically stereoretentive.

Exam-Style Summary

  • Substrate: Primary amide (RCONH2) only
  • Reagents: Br2/NaOH (or Cl2/NaOH), heat
  • Product: Primary amine with one fewer carbon
  • Key intermediate: Isocyanate (R-N=C=O)
  • Byproduct: CO2 (the carbonyl carbon)
  • Mechanism: 11 steps via N-bromination, rearrangement to isocyanate, hydrolysis, and decarboxylation
  • Common trap: Don't confuse with LiAlH4 reduction (which preserves all carbons)

Interactive Toolbox

  • Mechanism Solver - Enter any primary amide and see the full Hofmann rearrangement mechanism.
  • Reaction Solver - Predict the amine product from any primary amide.
  • IUPAC Namer - Name your starting amides and product amines.