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Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: uglepik on April 05, 2011, 12:01:20 PM

Title: Odd esterification of side chain on lipo-peptide
Post by: uglepik on April 05, 2011, 12:01:20 PM

Hi guys!

I'm trying to make lipids consisting of a large lipid moiety linked to a number of amino acids, including glumatic acids. I do this on solid-phase (Rink amide MBHA resin) and consequently I cleave with tons of TFA (something like 9 mL). This also deprotects the t-butyl protecting groups on the glutamic acid side chains. In order to crash my product, I decided to try to do this in ice-cold methanol... My stuff crashed nicely BUT I got a quite prominent impurity which seems to be (according to MS and H-NMR) the METHYL-ESTER of the glutamic acid side chain... This I find quite puzzling, as I wouldn't think the combination of lots of methanol (40 mL), of course very little water, and lots of TFA would be enough to esterify the carboxylic acid. Especially giving the low temperature (0 degrees) and the relatively short time the stuff is actually in solution.

I cannot think of any other way in which this imputiry should come about.

Any thoughts?

   

Title: Re: Odd esterification of side chain on lipo-peptide
Post by: Doc Oc on April 05, 2011, 12:18:20 PM

A free acid, acid catalyst, and MeOH are perfect esterification conditions, why would you think that wasn't a good combo?  The only thing I am surprised by is the time, but TFA is a pretty powerful acid so maybe that's why.

Title: Re: Odd esterification of side chain on lipo-peptide
Post by: Honclbrif on April 05, 2011, 12:52:35 PM

Yeah, having lots of free carboxyl, lots of free alcohol, lots of acid catalyst, and very little water seems like it would favor esterification: you've loaded up one side of the equilibrium, and left the other empty. However, I'm a little surprised it happened at such a low temp.

TFA shouldn't be that hard to get rid of before the crash.

Title: Re: Odd esterification of side chain on lipo-peptide
Post by: OC pro on April 05, 2011, 02:55:42 PM

Methanol is a nice nucleophile. You are not the first observing strange (trans)esterification reactions  ;D

Title: Re: Odd esterification of side chain on lipo-peptide
Post by: uglepik on April 10, 2011, 10:21:00 AM

Thanks guys,

I've seen the same with a couple of other compounds now, so there has to be something about it. Of course the surprising factors are the low temperature and the ultra short time the stuff is dissolved - it crashes immediately and although some of it is probably in solution for esterification while the precipitate settles it is bound to be minute amounts. And this apparently leads to a prominent impurity in around 15% yield... From now on, I'm crashing in acetonitrile.