Detailed Understanding of Solvent Effects for the Cationic Ring-Opening Polymerization of 2-Ethyl-2-oxazoline

Polymerization of 2-ethyl-2-oxazoline (EtOx) has often been in the spotlight for fundamental studies of poly(2-alkyl/aryl-2-oxazoline)s (PAOx) polymerization, especially initiator screening, solvent screening, and copolymerization trends. In this work, we build on previous observations of solvent effects on the cationic ring-opening polymerization (CROP) of EtOx, with additional experimental observations of previously unreported solvents to expand the explored parameter space. Our objective is to find solvents with the lowest activation energy (Ea) and higher Arrhenius preexponential factor (A), which will allow us to produce narrow molar mass distributions at higher molecular weights, in the least time. To achieve this, we examined the various single factors like Dimroth ET(30) values, the Kamlet-Abraham-Taft (KAT) linear free-energy relationship (LFER) equation(s), and the Catalan LFER equations. Only one of Catalan’s equations sufficiently disentangled dipolarity and polarizability to give a good fit due to contradictory effects. It was found that solvent nucleophilicity, electrophilicity, and polarizability affected the Ea, but not dipolarity. All four factors affected the A. This indicates that the Ea is minimized in solvents that do not solvate ions well (i.e. force ion-pairing), and A was minimized in more dipolar solvents that solvate the polymer chains well. A strongly negative activation entropy (ΔS‡) shows that the propagation reaction is associative. The Catalan LFER allows for the prediction of Ea, A, ΔH‡, and ΔS‡, and the derived kp, across a broad range of solvents

Improved synthesis of linear poly(ethylenimine) via low-temperature polymerization of 2-isopropyl-2-oxazoline in chlorobenzene

Linear poly­(ethylenimine) is a cationic polymer that is actively being progressed into clinical trials for gene therapy. The existing synthetic methodology produces a relatively broad distribution of molecular weights. We describe an improved method of polymerizing 2-alkyl-2-oxazolines as a route to linear poly­(ethylenimine). By using an apolar noninterfering solvent (chlorobenzene) at low temperature (∼42 °C), the polymerization of 2-isopropyl-2-oxazoline proceeds much more rapidly than is observed in acetonitrile, and with far fewer side reactions. ¹H NMR observations showed close ion pairing at the propagating center (vice free ions in acetonitrile) to form a propagating complex of greater reactivity than free oxazolinium ions. Our results indicate that uniform or near uniform (“monodisperse”) polymers can be synthesized with nominal deviation from the theoretically achievable Poisson distributions

Sulfolane as Common Rate Accelerating Solvent for the Cationic Ring-Opening Polymerization of 2‑Oxazolines

The search for alternative solvents for the cationic ring-opening polymerization (CROP) of 2-methyl-2-oxazoline (MeOx) is driven by the poor solubility of P­(MeOx) in polymerization solvents such as acetonitrile (CH₃CN) and chlorobenzene as well as in MeOx itself. In this study, solvent screening has revealed that especially sulfolane is a good solvent for PMeOx. Unexpectedly, an increased propagation rate constant (<i>k</i>_p) was found for the CROP of MeOx in sulfolane. Further extended kinetic studies at different temperatures (60–180 °C), revealed that the acceleration is due to an increase in frequency factor, while the activation energy (<i>E</i>_a) of the reaction is hardly affected. In order to explore the versatility of sulfolane as polymerization solvent for the CROP of 2-oxazolines in general, also the polymerization kinetics of other 2-oxazoline monomers, such as 2-ethyl-2-oxazoline (EtOx) and 2-phenyl-2-oxazoline (PhOx), have been studied, revealing a common acceleration of the CROP of 2-oxazoline monomers in sulfolane. This also enabled more controlled synthesis of PMeOx-<i>block</i>-PPhOx block copolymers that otherwise suffers from solvent incompatibility

Defined High Molar Mass Poly(2-Oxazoline)s

Poly(2-alkyl-2-oxazoline)s (PAOx) are regaining interest for biomedical applications. However, their full potential is hampered by the inability to synthesise uniform high-molar mass PAOx. In this work, we proposed alternative intrinsic chain transfer mechanisms based on 2-oxazoline and oxazolinium chain-end tautomerisation and derived improved polymerization conditions to suppress chain transfer, allowing the synthesis of highly defined poly(2-ethyl-2-oxazoline) s up to ca. 50 kDa (dispersity (D) < 1.05) and defined polymers up to at least 300 kDa (D < 1.2). The determination of the chain transfer constants for the polymerisations hinted towards the tautomerisation of the oxazolinium chain end as most plausible cause for chain transfer. Finally, the method was applied for the preparation of up to 60 kDa molar mass copolymers of 2-ethyl2- oxazoline and 2-methoxycarbonylethyl-2-oxazoline

The Label Matters: μPET Imaging of the Biodistribution of Low Molar Mass ⁸⁹Zr and ¹⁸F‑Labeled Poly(2-ethyl-2-oxazoline)

Poly­(2-alkyl-2-oxazoline)­s (PAOx) have received increasing interest for biomedical applications. Therefore, it is of fundamental importance to gain an in-depth understanding of the biodistribution profile of PAOx. We report the biodistribution of poly­(2-ethyl-2-oxazoline) (PEtOx) with a molar mass of 5 kDa radiolabeled with PET isotopes ⁸⁹Zr and ¹⁸F. ¹⁸F-labeled PEtOx is prepared by the strain-promoted azide–alkyne cycloaddition (SPAAC) of [¹⁸F]­fluoroethylazide to bicyclo[6.1.0]­non-4-yne (BCN)-functionalized PEtOx as many common labeling strategies were found to be unsuccessful for PEtOx. ⁸⁹Zr-labeled PEtOx is prepared using desferrioxamine end-groups as a chelator. Five kDa PEtOx shows a significantly faster blood clearance compared to PEtOx of higher molar mass while uptake in the liver is lower, indicating a minor contribution of the liver in excretion of the 5 kDa PEtOx. While [¹⁸F]-PEtOx displays a rapid and efficient clearance from the kidneys, 5 kDa [⁸⁹Zr]-Df-PEtOx is not efficiently cleared over the time course of the study, which is most likely caused by trapping of ⁸⁹Zr-labeled metabolites in the renal tubules and not the polymer itself, demonstrating the importance of selecting the appropriate label for biodistribution studies