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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?

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    $\begingroup$ 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, 2021 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, 2021 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, 2021 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, 2021 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, 2021 at 3:18

2 Answers 2

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Acetic anhydride actually does react with carbonyl oxygen -- in an aldehyde. The reaction is documented in Wikipedia:

Aldehydes react with acetic anhydride in the presence of an acidic catalyst to give geminal diacetates.[1] A former industrial route to vinyl acetate involved the intermediate ethylidene diacetate, the geminal diacetate obtained from acetaldehyde and acetic anhydride:[2]

$\ce{CH3CHO + (CH3CO)2O -> (CH3CO2)2CHCH3}$

A similar reaction with the carbonyl oxygen in a carboxylic acid would yield the same product as a reaction with the hydroxyl oxygen would, so the mechanisms become hard to distinguish.

Cited References

  1. R. T. Bertz (1953). "Furfuryl Diacetate" Org. Synth., 33, 39. doi:10.15227/orgsyn.033.0039

  2. G. Roscher "Vinyl Esters" in Ullmann's Encyclopedia of Chemical Technology (2007), John Wiley & Sons: New York. doi:10.1002/14356007.a27_419

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In acidic conditions the oxygen of COOH group is not that neucleophilic as expected because it gets protonated before in acidic medium before acting as neucleophile so the best neucleophilic center in salicylic acid in acidic medium is OH which is expected to be least neucleophilic due to indulgence in resonce with ring.

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