ORGLIST: *seemingly* tough o-alkylation of vanillin

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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




Iíve 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 didnít 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):

http://www.rsc.org/CFCart/displayarticlefree.cfm?article=8%2D9%223%24%5=
D2%5CB%218%27%5D%5CY%28%3E%5C%23%5B4%5DP0S7%2C%3D29%23%3C%0A

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/pressuresÖbut 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.pd=
f

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 canít get my =
hands on a mechanical stirrer, so I am having trouble with this. Gram =
quantities of vanillin donít 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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