Anyone has a reference for the mechanism of the proton transfer on the alkoxide post-NaBH4 reduction? Lecture notes has water/methanol as source but the pKa's on that are iffy. Below is what my predecessor used. I hate the first step but the second one is much better proton transfer IMO. - ThreadSky

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racicotleanne.bsky.social • 42 days ago

Anyone has a reference for the mechanism of the proton transfer on the alkoxide post-NaBH4 reduction? Lecture notes has water/methanol as source but the pKa's on that are iffy. Below is what my predecessor used. I hate the first step but the second one is much better proton transfer IMO.

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patricklutz.bsky.social•42 days ago

I don't have a reference but I think of it more as forming the trialkylborate ester and then doing ligand exchange with solvent to release the free alcohol (though I probably wouldn't teach that in a sophomore level class).

racicotleanne.bsky.social•42 days ago

Yeah it's a tricky line to cross. Depending on the solvent and the carbonyl being reduced, you could be fine in terms of pKa (say forming hydroxide after protonating a primary alkoxide with water) but it's not by much. The lecture doesn't assess the mechanisms so they leave the protonation vague.

patricklutz.bsky.social•42 days ago

The textbook mechanism that bothers me the most is imine formation... ain't no way you're protonating a C=O with free amine still around. Lotta sloppy mechanisms that fall apart if you think about the pKas too closely.

racicotleanne.bsky.social•42 days ago

OMG don't even get me started on the imine drama. Also sometimes in the curriculum choices I would get mad. Often we teach how to make imines... then EAS... but not cover Vilsmeyer-Haack?!? That is the ONE EAS I did in research!! /rant

patricklutz.bsky.social•42 days ago

I teach imine/enamine formation as activating the C=O via hydrogen bonding, which makes me feel a little bit better. And I tell students that it's also to help prepare them for the types of proton transfers they'll see in biochem.

racicotleanne.bsky.social•42 days ago

They will complete their unlearning of proper pKas and good arrow pushing in biochem because most textbooks hurt my feelings.

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