Mechanochemical and Aging-Based Amidation of Bulk and Nanowhisker Chitosan via Water-Catalyzed Carbodiimide Coupling

Despite its high potential, chitosan functionalization by amidation remains challenging, as the use of toxic or excess reagents and solvents is commonplace. Herein, we report the mechanochemical amidation of chitosan via carbodiimide coupling catalyzed by liquid-assisted grinding (LAG) with water. Carboxylic acids were covalently linked to chitosan without the need for nucleophilic catalysts or activating reagents such as 4-dimethylaminopyridine (DMAP) or N -hydroxysuccinimide (NHS) and at efficient 1:1:1 stoichiometric ratios of acid and carbodiimide to chitosan. The degree of substitution onto chitosan, which was negligible under neat grinding, was maximized under H 2 O-LAG conditions and decreased at slurry and solution volumes of water. This reaction was also efficient under mechanochemical aging, which was used to synthesize and image functionalized chitosan nanowhiskers with 3-chloropropionamide side chains. Evaluating a scope of over 30 different carboxylic acids, a trend emerged indicating that coupling efficacy was greatest when the acids were small and hydrophobic and most tolerated when the acid did not contain a nucleophilic R-group. This method highlights the catalytic potential of LAG and showcases a mechanochemical platform for the selective amidation of chitosan and chitosan nanowhiskers with carboxylic acids.