Efficient N-sulfopropylation of chitosan with 1,3-propane sultone in aqueous solutions: neutral pH as the key condition

Abstract

Conjugation of strong anionic sulfonate groups to chitosan (CS) is typically used for converting the weak cationic CS to its polyampholyte derivatives, which are of interest to different areas benefiting from both cationic and anionic groups. The content of anionic charges can be tuned by varying the level of sulfonation, which is a fundamental characteristic expressed as the degree of substitution (DS). The subject of this work is the synthesis of the representative polyampholyte of this class, N-(3-sulfopropyl)chitosan salt (SPCS), by the reaction of CS with 1,3-propane sultone (PrS) in water. According to the literature, this reaction is mostly performed under acidic conditions and should lead to SPCS with high DS values. We found that such DS values are likely overestimated due to the presence of a non-covalently bonded sulfopropyl group, originating from extensive PrS hydrolysis, in the SPCS structure. In this work, the combination of experimental and theoretical approaches resulted in selecting a neutral pH for the SPCS synthesis, which increased the efficiency of the N-sulfopropylation reaction. Quantum chemistry calculations suggest that this finding primarily corresponds with the higher reactivity of PrS to a non-protonated glucosamine unit compared to a protonated one, where the molar fraction of the non-protonated unit at neutral pH is remarkably higher than that at acidic pH. The developed purification conditions make the SPCS free from the non-covalently bonded sulfopropyl groups. We show that true DS values can be obtained by NMR regardless of the level of SPCS purity, and also by elemental analysis for completely pure SPCS. It is noticeable that while the true DS values for SPCS synthesized under acidic conditions are limited to only around 5%, these values range between 25 and 95% for SPCS synthesized under neutral conditions and can be readily controlled by the weight ratio between CS and PrS. Hence, this work provides guidelines for a simple yet feasible and highly effective sulfopropylation reaction with PrS under aqueous conditions.