Unexpected Reactivity Switch in the Statistical Copolymerization of 2-Oxazolines and 2-Oxazines Enabling the One-Step Synthesis of Amphiphilic Gradient Copolymers.

Poly(2-oxazoline)s and, more recently, also poly(2-oxazine)s represent an emerging class of polymers with a broad range of applications. Surprisingly, to date, the statistical copolymerization of these two cyclic imino ether monomers has not yet been reported. Herein, we demonstrate that the statistical copolymerization of 2-oxazines with 2-oxazolines can lead to the formation of amphiphilic gradient copolymers in a single step. These gradient copolymers combine the high structural modularity of poly(2-oxazoline)s with the excellent biological properties of poly(2-oxazine)s, especially poly(2-methyl-2-oxazine). The copolymerization was found to proceed in a nonexpected way with the relative incorporation rates of the monomers being opposite to the reactivity observed for the corresponding homopolymerizations. In fact, the statistical copolymerizations lead to faster incorporation of the 2-oxazine followed by a gradual transition toward the 2-oxazoline. The self-assembly properties of the prepared amphiphilic poly[(2-methyl-2-oxazine)- grad-(2-butyl-2-oxazoline)] (PMeOzi- grad-PBuOx) as well as the thermoresponsive poly[(2-methyl-2-oxazine)- grad-(2-propyl-2-oxazoline)] (PMeOzi- grad-PPrOx) confirmed their potential as stimuli-responsive nonionic surfactants for various applications. Finally, the noncytotoxic character and cellular uptake of PMeOzi- grad-PBuOx copolymers was confirmed in vitro in SKOV3 cells.