[chiddler]

In any generic nucleophilic substitution, with an intermediate like this:



does the leaving group HAVE to be protonated? If OH(-) leaves, does it have to be converted to water? If it's methoxy, does it have to be converted to methoxide?

thank you!

[discodermolide]

In any generic nucleophilic substitution, with an intermediate like this:



does the leaving group HAVE to be protonated? If OH(-) leaves, does it have to be converted to water? If it's methoxy, does it have to be converted to methoxide?

thank you!

No it doesn't, this reaction is catalytic in base.
When you stop the reaction you will work it up with mild acid to re-protonate everything.

[azmanam]

Actually, as drawn, I'd say it'd most likely have to be catalytic in acid.  In base, you'll deprotonate the carboxylic acid.  Then your leaving group would have to be O^2-.

If it's in acid, yes the OH has to be protonated first to leave as H₂.

[discodermolide]

Actually, as drawn, I'd say it'd most likely have to be catalytic in acid.  In base, you'll deprotonate the carboxylic acid.  Then your leaving group would have to be O^2-.

If it's in acid, yes the OH has to be protonated first to leave as H₂.

As drawn I agree, but he said generic. I assumed the acid would be present as the ester.

[fledarmus]

As I understand it, the reaction as drawn doesn't occur in base - the acid is deprotonated, and nothing else happens. To run this sort of reaction you have to either use the ester as discodermolide suggested, or activate the acid as an acid halide, anhydride, or with a carbodiimide to an acyl-isourea.

[chiddler]

I meant methanol, not methoxide in my original post, but it seems you guys understood my question.

Thanks. My book (a review book. it is fallible) gave me a question that suggested it must be protonated. But I understand that it depends on the context of the reaction, be it acid or base.

Thanks very much for the helpful responses.