Synthesis of chitooligosaccharide selenol derivatives by homogeneous dissolution in dipolar aprotic/lithium salt...

Chitooligosaccharide (COS) was derived from chitin, the second most abundant natural biopolymer after cellulose and an abundant renewable resource. Owing to its favorable biocompatibility and readily modifiable structure, COS and its derivatives were extensively investigated for biomedical and food applications. Covalent incorporation of selenium into carbohydrate frameworks represented an important route to organic selenium derivatives, among which C-Se-linked selenols attracted particular interest because of their distinctive reactivity under physiological conditions. To develop an efficient synthesis of selenized COS with selenol group, six dipolar aprotic lithium-salt solvent systems were formulated by pairing N,N-dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), or N-methyl-2-pyrrolidone (NMP) with either LiCl or LiBr and were systematically screened for COS dissolution and hydroxyl-group activation. DMAc-LiBr and DMAc-LiCl exhibited the most favorable dissolution performance. DFT calculations, molecular dynamics simulations, and structural characterization of regenerated COS indicated that the ion-dipole and hydrogen-bonding networks formed by DMAc and the lithium salts competed for polar interaction sites on COS, progressively weakened its native hydrogen-bond network, and enabled homogeneous dissolution. By employing DMAc-Li⁺ as solvents, the primary hydroxyl groups of COS were converted into bromide, chloride, or p-toluenesulfonate functionalities to afford COS-Br, COS-Cl, and COS-TsCl, respectively. Subsequent nucleophilic displacement with selenourea yielded the corresponding selenol derivatives COS_Br-SeH, COS_Cl-SeH, and COS_Ts-SeH, with the p-toluenesulfonate-mediated route affording numerically highest isolated yield. Complementary FT-IR, NMR, and XPS analyses substantiated the structural assignments of the intermediates and selenium-containing products. This study provided an effective homogeneous reaction platform for COS and a new route to C-Se-linked organic selenol derivatives.