Peptide coupling reactions w/ carbodiimides - can methanol be used as solvent?
I've got to perform a peptide coupling reaction between an acid and a primary alcohol. I have used for this reaction several carbodiimides with success; EDC works OK, DIPC a little better, but DCC works the best. My procedure is standard - dissolve the acid in DCM, add DCC, and then 10 mol % acyl transfer catalyst (usually DMAP). I wait about 5 minutes and then add the amine. The only problem is, upon addition of the amine two huge clumps will form in the reaction. I'm sure that some of it is urea byproduct (DCU), but it's clear that a good chunk of it is just unreacted material. I've found that the only way to re-dissolve these big clumps of material is by addition of methanol. This dissolves everything, including the urea (DCU). I have tried other solvents and had the same problem. The only exception here is DMF, which can dissolve everything, but then I lose my product to the aqueous layer during the workup after the reaction.
This would be all be great, but my only concern is that the methanol added will act as a nucleophile and attack the activated acid, resulting in a methyl ester rather than the desired amine. Granted, mass spec of the crude doesn't reveal formation of any such methyl ester. Further, even if the methyl ester were to form, theoretically it should then be displaced by the amine starting material to deliver the desired amide product.
My real question here is - can methanol react with the activated acid during carbodiimide coupling reactions to form methyl ester? I'm inclined to believe, from my experience with this reaction, that it is a non-issue. But I would like to know for sure. Also, if anyone has had any similar experiences and could offer insight/advice, it would be much appreciated. Thanks!
Re: Peptide coupling reactions w/ carbodiimides - can methanol be used as solvent?
No, methanol can not be used as solvent for DCC mediate coupling reaction because there is always chance for formation of Ester. In presence of DMAP or basic condition you definitely get methyl ester as side product and without base you also have risk for formation of such impurities.
If you have suffer from solubility issue of DCU (Urea) use isopropyl alcohol ,As this is sterically hindered alcohol so it's reactivity is quite lower than methanol.
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