I have seen a number of different plausible syntheses for paracetamol but they suffer from problems such poor regioselectivity of aromatic substitution (usually when nitrating phenol getting a mixture of undesired ortho and desired para). However, is the following not a plausible synthesis?
- Take aniline (I believe it's commercially available but can be synthesised from mononitration then reduction).
- React with acetic anhydride to make the amide — still ortho-, para-directing and mildly activating and the directing effects are not acid sensitive as in aniline.
- Do a Friedel–Crafts acylation with the an acyl chloride.
- React with hydrogen peroxide and sodium hydroxide to get paracetamol via a Dakin reaction.
Of course the acylation will suffer a little with regioselectivity issues but I feel like it will suffer less as the amide group is larger than a hydroxyl so favours para on steric grounds more strongly and is thus a better solution than nitration of phenol and subsequent reduction.
Nitration of phenol then reduction and reaction with acetic anhydride is the most common hit on google so I assume it's the most common method. But what's wrong with what I have suggested?
