From: Jonas Nilsson (jonni$##$ifm.liu.se)
Date: Thu Nov 27 2003 - 06:36:28 EST
Hello.
I have a delicate problem that has been annoying me for some time now.
I need the N-hydroxi succinimde ester of betain (Me3N+CH2COO-Suc; Smiles:
"O=C(CC1)N(OC(C[N+](C)(C)C)=O)C1=O" ). I've tried different routes from
betain x HCl including 1)SOCl2 2)NHS and
1)diisoproylcarbodiimide/NHS/DMF/THF but the first ons seems to break down
the betain and the second one doesn't work due to solubility problems.
So I tried to work out if betain x HCl was soluble in any aprotic solvent
and found out that DMSO was the only solvent that could dissolve if to an
extent visible on nmr (about 30mM actually).
Now I tried betain x HCl in DMSO-d6 with 3 eq of N,N'-Disuccinimidyl
carbonate (DSC Smiles "O=C(CC1)N(OC(ON2C(CCC2=O)=O)=O)C1=O" ).
Nothing happens in one day. Adding diisopropylethylamine gives me some
strange by-product in a few hours. Instead I tried different amounts of
pyridine (from 0.4-16 equvalents).
The pyridine seems to do the trick! However I can observe two reactions occur.
1) Hydrolysis of DSC to form two molecules of NHS and CO2.
2) Reaction of DSC with the carboxylate to form product, NHS and CO2.
Now to some specific questions.
The hydrolysis could be explained by reaction with residual water in the
system. If this was the case however, wouldn't the rate of hydrolysis
depend on the amount of pyridine? There is no differense whatsoever of
hydrolysed DSC with 0eq or 16eq of pyridine! So could it be a constant
diffusion of water inte the system from the surroundings? But I do the
reaction in a NMR-tube, which I guess should be reasonably tight. I would
expect the rate of hydrolysis to be high in the beginning, and the when as
all water is consumed the rate would level of. And the initial rate would
be defined by the amount of pyridine.
What should be noted however is that the rate of product-formation is
hightly dependent on the amount of pyridine. With 0 eq nothing (except
hydrolysis) happens in 24 hours, but with 16eq of pyridine 55% of the
starting material is converted to product over the same period of time.
One other aspect is product stability. Workup consists of precipitation
with excess ether (15 times the volume of DMSO), and extended washing with
ether. After dissolving the precipitate in D2O however, I only see betaine
and NHS at an approximate ratio of 1:1.1. The NHS-ester should be
reasonable stable in water, shouldn't it? I know that it's not stable in
basic water but a quick pH check shows a pH of around 2 of the D2O solution.
Any ideas?
/jN
-- _______________________________Jonas Nilsson, Ph D student
IFM Organisk kemi Linköpings universitet SE-58183 Linköping
ph: +46-(0)13-282583 fax: +46-(0)13-122587 email: jonni$##$ifm.liu.se _______________________________
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