SolutionsParacetamol
Exercise 1
Why is 4-aminophenol acetylated on nitrogen and not on oxygen with acetic anhydride in water? What would be formed with excess anhydride and pyridine?
The amine nitrogen is much more nucleophilic than the phenol oxygen, whose pair is more delocalized into the ring and less basic; in water, moreover, any phenyl ester formed hydrolyses faster than the amide. With excess anhydride and pyridine both groups are acetylated and the diacetate, 4-acetamidophenyl acetate, is obtained.
Exercise 2
Propose a synthesis of paracetamol from phenol via 4-hydroxyacetophenone and a Beckmann rearrangement.
Phenol + acetic anhydride → phenyl acetate; Fries rearrangement (AlCl3 or HF) → 4-hydroxyacetophenone (major at low temperature). Hydroxylamine → oxime; Beckmann rearrangement in acid (the aryl group, anti to the OH, migrates to nitrogen) → paracetamol, the N-arylacetamide. This is the basis of the Hoechst–Celanese process.