An azide-containing initiator for the cationic ring-opening-polymerization of 2-oxazolines

• 1-Azidomethyl-4-bromomethyl-benzene initiates efficiently the CROP of 2-oxazolines. • The initiator is applicable for homo and block copolymerization. • Resulting POx feature quantitative azide degree of functionalization. • The POx can easily be functionalized by SPAAC with cyclooctynes. Poly(2-oxazoline)s (POx) are a versatile class of polymers synthesized via a living cationic ring-opening polymerization (CROP). This living nature enables the precise control over molar mass, dispersity, and end-group functionality. One common method for end-capping the CROP is through termination with nucleophiles such as sodium azide, which introduces an azide end-group suitable for further click chemistry modifications. However, the functionalization of, in particular, hydrophobic POx with azide end groups for bioconjugation has posed significant synthetic challenges. Herein, we report the development of a novel initiator for the CROP of 2-oxazolines that enables the direct incorporation of an azide functionality at the α-terminus of various POx, including amphiphilic block copolymers. This approach overcomes previous limitations in quenching reactions of hydrophobic POx variants and provides consistently high end group fidelity across a spectrum of POx hydrophilicity. Polymers with an azide end group exhibited excellent reactivity in azide-alkyne cycloaddition reactions. This versatile synthetic platform expands the potential applications of POx in drug delivery systems by providing a reliable method for bioconjugation while maintaining the favorable properties that position POx as a promising PEG alternative in biomedical applications.