Squaric Acid Diethylester: A Simple and Convenient Coupling Reagent

A new method for the covalent modification of poly­ mers in a two-step process is described. Squaric acid di­ ethylester reacts with primary or secondary aliphatic amines selectively to ester amides. It is shown for the first time that this class of compounds react with poly­ meric systems containing amine functionalities (e.g. g-amino groups of proteins) in aqueous solution, form­ ing stable squaric acid diamide linkages. Three different monoamides were synthesized and the reaction rates of diamide formation versus hydrolysis were determined. Detailed kinetic studies revealed that unwanted hydroly­ tic side-reactions are more than ten times slower than the formation of squaric acid diamides.