Carboxylic acid reacts with EDC first then amine attacks to form amide. Sometimes this reaction can be carried out by mixing them all together or even EDC being added after mixing acid and amine (e.g. when reaction is not completed, more EDC is added afterwards). How does amine not react with EDC which is a carbodiimide that can form guanidine with amine?
Coupling reaction is usually carried out under basic condition, isn't amine a better nucleophile than acid under this condition?
Usually the amine carboxyl reaction is carried out at pH6, which is a compromise value taking account of the pH optimum of acid activation (~3.5) and amine reaction (~pH8). In two step reactions, you can move closer to the optimum pH for each stage.
If carboxyl is present, the favoured reaction is activation to o-acylisourea, which decays to the anhydride (and NHS ester, if NHS is present). Amines react with any of these species to give the same amide end product.
But you are right, amines can interfere at high concentrations, though it’s rarely an issue with reactions involving biomolecules. In the absence of carboxylates, then amines certainly can react with EDC. In fact use of this has been made in an assay of EDC using aniline.
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