I know that salicylic acid with acetic anhydride under acidic conditions gives acetylsalicylic acid (aspirin). But my question is, why is it that post the protonation of carbonyl oxygen of acetic anhydride as mentioned here, the nucleophilic carbonyl oxygen of the the $\ce{-COOH}$ group doesn't attack the delta postive charge on the carbonyl carbon of the protonated carbonyl group?

What makes the phenolic oxygen more nucleophilic than the carbonyl oxygen?

  • 1
    $\begingroup$ Well, probably no one got an idea to ask this - not without reason - making an anhydride from another anhydride is hardly probably when you can get an ester. $\endgroup$
    – Mithoron
    May 23 at 18:58
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    $\begingroup$ It may well do so, but the resulting anhydride will react with the phenolic oxygen. If the anhydride of acetyl salicylic acid does form it does not survive work up. The phenolic oxygen is more nucleophilic because the second oxygen attached to the carbonyl carbon is electron withdrawing $\endgroup$
    – Waylander
    May 23 at 19:26
  • $\begingroup$ Even if both groups react with acetic anhydride, the mixed anhydride will hydrolyze faster than the phenolic acetate upon aqueous workup. $\endgroup$
    – user55119
    May 23 at 23:06
  • $\begingroup$ @Mithoron I get your point. Why the ester will be favoured and anhydride won't can be backed-up with what user55119 said. Thank you! $\endgroup$ May 24 at 3:13
  • $\begingroup$ @Waylander Probably what you say is right as well. But regarding the nucleophilicity of the phenolic oxygen: isn't the lone pair of oxygen delocalized with the ring's pi cloud. While in the case of oxygen of carbonyl group, the lone pair won't get involved in any sort of resonance. Shouldn't this make oxygen of carbonyl carbon more nucleophilic? $\endgroup$ May 24 at 3:18

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