I want to couple 2 small molecules, one is a DNA oligo with an amine group and the other one a small molecule with with a carboxyl group.
I found protocols for EDC (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide) coupling of amines and carboxylic acids, but they always refer to proteins. My molecules are stable in a wide range of pH, what buffer conditions would work best for my coupling reaction?

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    $\begingroup$ I wouldn't count DNA oligomers as small, but with biomolecules perspective is different. ;) $\endgroup$
    – Mithoron
    Jun 8, 2023 at 18:43

1 Answer 1


For this reaction the optimal buffer conditions are a pH of 4.5-5.5, which is slightly acidic. The reaction mixture should be stirred at room temperature for several hours to overnight. Common buffers used for this reaction include MES and MOPS. It is important to use an excess of EDC and the appropriate stoichiometric amount of the other reagents to ensure a high yield of the desired product.

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    $\begingroup$ What about the amines on the nucleobases? Wouldn’t they react as well, giving you an unintended product mixture? $\endgroup$
    – Karsten
    Sep 26, 2023 at 10:21
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    $\begingroup$ Good Question. I would consider using an amine-blocking reagent on the nucleobases, so it will selectively block the amine on the nucleobases while leaving the amine on the DNA oligo's end. $\endgroup$
    – Alex
    Sep 26, 2023 at 14:08

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