Functional Poly(2-oxazoline)s by Direct Amidation of Methyl Ester Side Chains

Abstract

Poly(2-alkyl/aryl-2-oxazoline)s (PAOx) are biocompatible pseudopolypeptides that have received significant interest for biomedical applications in recent years. The growing popularity of PAOx in recent years is driven by its much higher chemical versatility compared with the gold standard in this field, poly(ethylene glycol) (PEG), while having similar beneficial properties, such as stealth behavior and biocompatibility. We further expand the PAOx chemical toolbox by demonstrating a novel straightforward and highly versatile postpolymerization modification platform for the introduction of side-chain functionalities. PAOx having side chain methyl ester functionalities is demonstrated to undergo facile uncatalyzed amidation reactions with a wide range of amines, yielding the corresponding PAOx with side-chain secondary amide groups containing short aliphatic linkers as well as a range of side-chain functionalities including acid, amine, alcohol, hydrazide, and propargyl groups. The PAOx with side-chain methyl ester groups can be prepared by either partial hydrolysis of a PAOx followed by the introduction of the methyl ester via modification of the secondary amine groups with methyl succinyl chloride or by the direct copolymerization of a nonfunctional 2-oxazoline monomer with a 2-methoxycarbonylethyl-2-oxazoline. Thus, this novel synthetic platform enables direct access to a wide range of side-chain functionalities from the same methyl-esterfunctionalized poly(2-oxazoline) scaffold.

Synthesis of poly(2‐oxazoline)s with side chain methyl ester functionalities: Detailed understanding of living copolymerization behavior of methyl ester containing monomers with 2‐alkyl‐2‐oxazolines

“…PAOx with methyl ester functionalized side chains are especially interesting as the methyl ester can be hydrolyzed to the carboxylic acid, a versatile functionality for conjugation of peptides and proteins. Furthermore, the methyl ester group can undergo a direct noncatalyzed amidation reaction to easily introduce a wide variety of side chain amide moieties . Very recently, we reported an increased propagation rate of the methyl ester containing monomer 2‐methoxycarbonylethyl‐2‐oxazoline (MestOx, 1 ) (Scheme ) during homopolymerization compared to 2‐methyl‐2‐oxazoline (MeOx, 3 ) or 2‐ethyl‐2‐oxazoline (EtOx, 4 ), while copolymerization surprisingly revealed slower incorporation of MestOx .…”

“…Furthermore, the methyl ester group can undergo a direct noncatalyzed amidation reaction to easily introduce a wide variety of side chain amide moieties. 31,32 Very recently, we reported an increased propagation rate of the methyl ester containing monomer 2methoxycarbonylethyl-2-oxazoline (MestOx, 1) (Scheme 2) during homopolymerization compared to 2-methyl-2oxazoline (MeOx, 3) or 2-ethyl-2-oxazoline (EtOx, 4), while copolymerization surprisingly revealed slower incorporation of MestOx. 28 Previous computational modeling suggested that the methyl ester group of the MestOx interacts with the living chain end, causing a slight increase in electrophilicity of the carbon atom C5, thereby enhancing the reactivity of the oxazolinium ring.…”

Thermal Properties of Methyl Ester-Containing Poly(2-oxazoline)s

“…Methyl esters are especially interesting, because they can undergo a direct amidation with a variety of amines to easily introduce other functional groups such as alcohols, hydrazide and amines [39][40][41][42]. Moreover, the ester can be hydrolyzed to the corresponding carboxylic acid providing a versatile handle for conjugation as well as a means to introduce pH responsiveness.…”

Acyl guanidine functional poly(2‐oxazoline)s as reactive intermediates and stimuli‐responsive materials

“…In addition, hydrolysis of the ester to the corresponding carboxylic acid can be exploited for organocatalyzed esterifications and amidations, and Ugi and Passerini multicomponent reactions . Nevertheless, the direct modification of polymers with unactivated pendant ester groups remains a challenging topic within polymer chemistry, as only recently reports have emerged of their quantitative conversion . Inspired by the guanidine‐catalyzed amidation and transesterification of polymers with pendant ester groups, we explored the use of guanidines as a reactant, rather than a catalyst, in order to synthesize the corresponding acyl guanidines.…”