Reactions of Imidazole

Reactions of Imidazole include electrophilic substitution at C-4/C-5 and nucleophilic substitution at C-2.

Reactions of Imidazole

1. Tautomerism:

   • Prototropic tautomerism:
     • 1H-imidazole  ⇌  3H-imidazole
   • In practice, 1H-tautomer is more stable and dominates.

2. Electrophilic Substitution Reactions (EAS):

   1. EAS occurs readily at position-4 or 5 due to high electron density.
   2. Nitration:
      • Milder conditions than for benzene.
      • Forms 4- or 5-nitroimidazole.
   3. Halogenation:
      • Br₂ or Cl₂  →  substitution at C-5 preferentially.
   4. Acylation/Friedel-Crafts-type Reactions:
      • Possible at C-5.
      • Requires mild Lewis acid or protected N-H group.

3. Nucleophilic Substitution Reactions (NAS):

   • Occurs if EWG like NO₂ at C-4 or C-5.
   • Rare in parent imidazole due to electron richness.

4. N-Alkylation and Acylation:

   • N-1 can be alkylated easily:
   • With alkyl halides → N-alkylimidazoles
   • Acylation at N possible → amide-like derivatives.

5. Metal Coordination:

   • Strong ligand via N-3.
   • Coordinates with metals such as Cu²⁺, Fe³⁺.
   • Histidine (in proteins) uses imidazole side chain to bind metal centers.

6. Ring Opening (Harsh Conditions):

   • Possible under oxidative or nucleophilic attack with strong reagents.
   • Rare and not synthetically common.

Thank you for reading from Firsthope's notes, don't forget to check YouTube videos!