From: Maneesh Yadav (yadavm$##$scripps.edu)
Date: Wed Mar 09 2005 - 21:43:48 EST
Dear All,
I am having a little problem with the o-alkylation of vanillin with bromomethane sulfonate and was hoping I could solicit a little practical advice.
Here is ascii, just to be clear:
(K2CO3, KOH)
Vanillin---OH + Br-CH2-SO3 Na ----> Vanillin---O-CH2-SO3
I’ve tried running high concentrations/excesses sulfonic acid in water to no avail. There is a published alkylation of a larger phenol by bromomethane sulfonate in DMF 132C, which didn’t work for me.
I am concerned about the quality of starting material which was made from CH2Br and sulfite(J Med Chem., 1987, Vol. 30, No . 12, pg. 2236), but it is a difficult thing to really test.
There is an example of using microwaves for making aryloxymethanesulfonates here (free link):
this is exactly what I need (and it should only be better using bromo vs. chloro), so far stuff tends to just smoke and char. I tried in a conventional microwave and in one where I could apply accurate powerlevel/temp/pressures…but no luck.
There is a longer route to generate the alkyl chloride on the phenol, and I think I may have some product, but it has more steps and purifications, analogous to what was done here (free link):
http://www.biochem.wisc.edu/kiessling/lab/pdfs/2002.young.AngewChemInt.pdf
I suspect what is happening in the microwave case is more of the result of a vanillin melt rather than microwaves, as described here (free link):
http://frigo.ath.cx/chemistry/me3po4.html
I did give this a try (to 150C in oil bath), but I still can’t get my hands on a mechanical stirrer, so I am having trouble with this. Gram quantities of vanillin don’t really seem to melt into a liquid, gunky solid just tends to get stuck on the side on the round bottom flask (especially with the sulfonic acid reactant and dry K2CO3/KOH) with a magnetic stirrer.
I suspect that the reaction is rate limited by the fact that you have to bring a phenolate and a sulfonic acid together, and the transition state suffers from a large amount of charge charge repulsion.
Do you have any advice at all (words of encouragement happily accepted)? I have a feeling I can get the melt to eventually work, but I need to find the right apparatus. If you have ever done something analogous or might have a little tip or insight, it would be most greatly appreciated.
Best,
Maneesh
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