[kriggy]

Hi, im running into some troubles with esterification of methol.

Im doing this reaction (pic): Im doing it in refluxing toluene with 1eq of catalyst (pyridine, DMAP etc) but no matter what I do I always get only about 50% conversion even when I use excess of menthol. I tried DCC+DMAP in DCM with the parent acid and got similar resuts. I tried to make metholate with NaH but didnt realy work either. I can collumn the product easily but since it is 2nd step and i need to do some 4 more AND Im gonna need more than few mg of the final product Im looking to improve the yield (usualy about 45-55% after CC).
Any ideas what might cause the lack of reactivity? Since the starting materials are fairly cheap Im kinda OK with doing it large scale and get only 50% but obviously, better yield is always better this early in synthesis

[wildfyr]

Is there a side reaction or is it only low conversion?

Try increasing the equivalences of base, and/or  using a stronger organo base such as DBU.

I know this question is borderline offensive, but are you sure everything is totally dry? Especially your bases and the menthol.

[CKabes]

I think you should try a different solvent. I think something more polar like acetonitrile might help your reaction.

[OrganicDan96]

what about doing it at lower temp maybe you are getting some thermal decomposition. toluine refluxes at quite a high temperature

[kriggy]

Is there a side reaction or is it only low conversion?

Try increasing the equivalences of base, and/or  using a stronger organo base such as DBU.

I know this question is borderline offensive, but are you sure everything is totally dry? Especially your bases and the menthol.

That is a good point. I used dry toluene dried over mol. sieves same for pyridine but I didnt realy take any real precautions. I suppose I could put sieves into the reaction.

@organicDan96: good point.
@tried it in THF and got same 50% but might give it a go again

[wildfyr]

I've always been tempted to put sieves right into a water sensitive reaction but I seldom Do. I'm worried they will catalyze some side reaction since they are complex substrates, they also have the caveat of being great but slow drying agents. For an esterification with cheap reagents I say give it a go.

Make sure your sieves are properly activated for all this drying, for individual reagents and putting in rxn, you really gotta fry them as hot as you can safely do it.

[kriggy]

Thanks, gonna try the sieves. The funny thing is that I was able to make the menthol ester of different acid  with DCC and DMAP without any particular care about drying the stuff.

[OrganicDan96]

Molecular sieves can be a bit acidic so this could cause problems

[wildfyr]

I had always heard that sieves are actually basic as received (such as here https://chemtips.wordpress.com/2014/12/01/how-to-activate-molecular-sieves/), but this fact is proving surprisingly hard to track down in a scholarly article. I would imagine they are amphoteric being aluminosilicates, so they will "remember" the pH conditions of whatever they were last exposed to.

I can't get access right now, but it might be buried in here https://onlinelibrary.wiley.com/doi/abs/10.1002/bit.10138

[kriggy]

Well I let the menthol and DMAP stirr overnight with sieves to make it dry(ish) and then run the reaction at reflux in THF but Im still having about 50% and some new minor impurities via TLC. Also, the reaction further down the road seems to not work as expected so might ditch the whole idea next week.

[rolnor]

You have a aminogroup present, could that cause problem?

[OrganicDan96]

why don't you try boc protecting that amine first?