Science of Synthesis

Li, Y.; Fang, X.; Wang, Y., Science of Synthesis: DNA-Encoded Libraries, (2024) 1, 8.

Carbodiimides were the first coupling reagents used in the synthesis of DELs. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) is highly suitable for use in solution because the produced urea byproduct is soluble in aqueous solvents and can therefore be removed easily in the workup. Carboxylates may react with N-hydroxysuccinimide (NHS) or N-hydroxysulfosuccinimide sodium salt (s-NHS) (see ‌Scheme 3‌, Section ‌2.1.1.1.1‌) in the presence of a carbodiimide such as EDC, resulting in a semistable N-hydroxysuccinimide or N-hydroxysulfosuccinimide ester, which may then react with a primary amine to form amide crosslinks. Although the use of NHS or s-NHS is not required for carbodiimide-mediated reactions, their use greatly enhances the efficiency of the coupling reaction. Furthermore, using NHS or s-NHS makes it possible to perform a two-step reaction. Both NHS and s-NHS are soluble in aqueous and organic solvents. Activation with NHS, however, decreases the water solubility of the modified carboxylate molecule, whereas activation with s-NHS preserves or increases the water solubility of the modified molecule due to the charged sulfonate group. Therefore, the formation of amide bonds by EDC/s-NHS is a well-established and widely used method in the field of DELs.