A facile synthesis of azido-terminated heterobifunctional poly(ethylene glycol)s for “click” conjugation

Abstract

New azido-terminated heterobifunctional poly(ethylene glycol) (PEG) derivatives having primary amine and carboxyl end groups, (Azide-PEG-NH2 and Azide-PEG-COOH, respectively) were synthesized with high efficiency. An α-allyl-ω-hydroxyl PEG was prepared as the first step to Azide-PEG-X (X = NH₂ and COOH) through the ring-opening polymerization of ethylene oxide (EO) with allyl alcohol as an initiator, followed by two-step modification of the hydroxyl end to an azido group. To introduce primary amino or carboxyl functional groups, amination and carboxylation reactions of the allyl terminal ends was then conducted by a radical addition of thiol compounds. Molecular functionalities of both ends of the PEG derivatives thus prepared were characterized by ¹H, ¹³C NMR, and MALDI-TOF MS spectra, validating that the reaction proceeded quantitatively. The terminal azido functionality is available to conjugate various ligands with an alkyne group through the 1,3-dipolar cycloaddition reaction condition (“click chemistry”).