N-PEG'ylation of chitosan via “click chemistry” reactions

N-azidated chitosan was prepared by four different methods: using azidated epichlorohydrin, sodium azide plius sodium nitrite, trifluoromethane sulfonyl azide or imidazole-1-sulfonyl azide hydrochloride. Using the two last reagents, the degree of azidation (DA) of chitosan was up to 40% and 65%, respectively. N-azidated chitosans with DA at about 60% were insoluble in aqueous and common organic solvents but dissolved in 5% LiCl solution in N-methyl-2-pyrrolidone, one of the very few solvents for chitin. Chitosan-methoxy poly(ethylene glycol) derivatives containing triazolyl moiety (chitosan-N-TMPEG comb copolymers) were prepared for the first time by coupling via 1,3-dipolar cycloaddition between pendant azide and end alkyne groups of chitosan and MPEG, respectively. Comb copolymers chitosan-N-TMPEG with degree of substitution (DS) of chitosan equal to DA of chitosan were synthesized at a certain excess of MPEG alkyne reaching DS up to 40%. “Clicking” of MPEG alkyne onto azidated chitosan was successful in binary mixture of water and methylene chloride but failed in 5% LiCl solution in N-methyl-2-pyrrolidone. Significant breakdown of chitosan backbone took place under “clicking” of MPEG in the presence of Cu(II)/ascorbate catalyst resulting in graft copolymers with bimodal MWD. Chitosan-N-TMPEG copolymers contained a certain residual amount of Cu and were soluble in acetate buffer (pH 3.7). Novel comb copolymers were characterized by FT-IR and 1H NMR spectroscopy, SEC with triple detection, intrinsic viscosity, elemental and functional group analysis.