I had been trying acid amine coupling of a long carbon chain carboxylic acid with urea, I couldn't get the desired product by using EDC, DMAP and HOBt. TLC shows 2 spots, I had been isolating the lower spot considering it as my product but NMR data confirmed that it is not the product but something else. Most of the literature suggests acylation of acid followed by addition of amine. Why it is more suitable method?
Urea is an amide and not an amine! Urea will be o-acylated due to tautomerism and this is not stable to nucleophiles. You have to heat urea and carboxylic acid together for coupling. See attachment-
EDC, HOBt, HATU are the reagents which activate your acid. In other words they make OH in COOH a better leaving group. Once acid is activated, a nucleophile (for example amine) attacks and kicks off the leaving group to form a CONH bond. If the nucleophile is weak, leaving group stays with the molecule and what you get is a carboxylic acid complex with EDC, HOBt or whatever activator you are using. Urea is an example of a weak nucleophile. Possibly that is why your reactions are not working.
Try to do with T3P or HATU. while using T3P using dichloromethane solvent, in the case HAtu use DMF solvent.
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