Straightforward route to superhydrophilic poly(2-oxazoline)s via acylation of well-defined polyethylenimine

Herein, we describe a new method for the synthesis of superhydrophilic poly(2-alkyl-2-oxazoline)s (PAOx) from poly(2-ethyl-2-oxazoline) (PEtOx). A well-defined linear polyethylenimine was prepared from PEtOx by controlled acidic hydrolysis of its side-chains followed by reacylation with different carboxylic acids. Using this protocol, we obtained a series of new hydrophilic PAOx containing side-chain ether groups with potential in biomaterials science. The relative hydrophilicity of the polymers was assessed, revealing that poly(2-methoxymethyl-2-oxazoline) (PMeO-MeOx) is the most hydrophilic PAOx reported to date. Additionally, the amorphous poly(2-methoxy-ethoxy-ethoxymethyl-2-oxazoline) (PDEGOx) shows the lowest reported glass transition temperature (-25 degrees C) within the PAOx family to date. The biomedical potential of the prepared polymers was further fortified by an in vitro cytotoxicity study, where all polymers appeared to be noncytotoxic. The described synthetic protocol is universal and can be extremely versatile, especially for PAOx that are difficult to prepare by conventional cationic ring-opening polymerization due to the monomer interference and/or degradation

A generic platform for the visualization of all monomer sequences in individual copolymer chains

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The elusive seven-membered cyclic imino ether tetrahydrooxazepine

Cyclic imino ether heterocycles are used as ligands in transition metal catalysis, in various drugs and as reactive monomers in living cationic ring-opening polymerization (CROP). While five- and six-membered cyclic imino ethers, i.e. 2-oxazolines and 4,S-dihydro-1,3-oxazines, have extensively been studied in these areas, their seven-membered ring counterparts have remained unexplored. Herein, we report the synthesis of 2-phenyl-4,5,6,7-tetrahydro-1,3-oxazepine allowing reassignment of the earlier, incorrectly reported 4,5,6,7-tetrahydro-1,3-oxazepines as their N-acylated pyrrolidine isomers. Finally, we also report a comparison of the CROP reactivity of a homologous series of cyclic imino ethers with a 2-carbon, 3-carbon, and 4-carbon methylene bridge, revealing a remarkable ring size effect

Visualization and design of the functional group distribution during statistical copolymerization

Even though functional copolymers with a low percentage of functional comonomer units (up to 20 mol%) are widely used, for instance for the development of polymer therapeutics and hydrogels, insights in the functional group distribution over the actual chains are lacking and the average composition is conventionally used to describe the functionalization degree. Here we report the visualization of the monomer distribution over the different polymer chains by a synergetic combination of experimental and theoretical analysis aiming at the construction of functionality-chain length distributions (FUNC-CLDs). A successful design of the chemical structure of the comonomer pair, the initial functional comonomer amount (13 mol%), and the temperature (100 °C) is performed to tune the FUNC-CLD of copoly(2-oxazoline)s toward high functionalization degree for both low (100) and high (400) target degrees of polymerization. The proposed research strategy is generic and extendable to a broad range of copolymerization chemistries, including reversible deactivation radical polymerization

Chemical design of non-ionic polymer brushes as biointerfaces : poly(2-oxazine)s outperform both poly(2-oxazoline)s and PEG

The era of poly(ethylene glycol) (PEG) brushes as a universal panacea for preventing non-specific protein adsorption and providing lubrication to surfaces is coming to an end. In the functionalization of medical devices and implants, in addition to preventing non-specific protein adsorption and cell adhesion, polymer-brush formulations are often required to generate highly lubricious films. Poly(2-alkyl-2-oxazoline) (PAOXA) brushes meet these requirements, and depending on their side-group composition, they can form films that match, and in some cases surpass, the bioinert and lubricious properties of PEG analogues. Poly(2-methyl-2-oxazine) (PMOZI) provides an additional enhancement of brush hydration and main-chain flexibility, leading to complete bioinertness and a further reduction in friction. These data redefine the combination of structural parameters necessary to design polymer-brush-based biointerfaces, identifying a novel, superior polymer formulation

Cation-pi Interactions accelerate the living cationic ring-opening polymerization of unsaturated 2-alkyl-2-oxazolines

Cation-dipole interactions were previously shown to have a rate-enhancing effect on the cationic ring-opening polymerization (CROP) of 2-oxazolines bearing a side-chain ester functionality. In line with this, a similar rate enhancement-via intermolecular cation-pi interactions-was anticipated to occur when pi-bonds are introduced into the 2-oxazoline side-chains. Moreover, the incorporation of pi-bonds allows for facile postfunctionalization of the resulting poly(2-oxazoline)s with double and triple bonds in the side-chains via various click reactions. Herein, a combined molecular modeling and experimental approach was used to study the CROP reaction rates of 2-oxazolines with side-chains having varying degrees of unsaturation and side-chain length. The presence of cation-pi interactions and the influence of the degree of unsaturation were initially confirmed by means of regular molecular dynamics simulations on pentameric systems. Furthermore, a combination of enhanced molecular dynamics simulations, static calculations, and a thorough analysis of the noncovalent interactions was performed to unravel to what extent cation-pi interactions alter the reaction kinetics. Additionally, the observed trends were confirmed also in the presence of acetonitrile as solvent, in which experimentally the polymerization is performed. Most intriguingly, we found only a limited effect on the intrinsic reaction kinetics of the CROP and a preorganization effect in the reactive complex region. The latter effect was established by the unsaturated side-chains and the cationic center through a complex interplay between cation-pi, pi-pi, pi-induced dipole, and cation-dipole interactions. These findings led us to propose a two-step mechanism comprised of an equilibration step and a CROP reaction step. The influence of the degree of unsaturation, through a preorganization effect, on the equilibration step was determined with the following trend for the polymerization rates: n-ButylOx = PentynOx. The trend was experimentally confirmed by determining the polymerization rate constants

Block and gradient copoly(2-oxazoline) micelles : strikingly different on the inside

Herein, we provide a direct proof for differences in the micellar structure of amphiphilic diblock and gradient copolymers, thereby unambiguously demonstrating the influence of monomer distribution along the polymer chains on the micellization behavior. The internal structure of amphiphilic block and gradient co poly(2-oxazolines) based on the hydrophilic poly(2-methyl-2-oxazoline) (PMeOx) and the hydrophobic poly(2-phenyl-2-oxazoline) (PPhOx) was studied in water and water ethanol mixtures by small-angle X-ray scattering (SAXS), small angle neutron scattering (SANS), static and dynamic light scattering (SLS/DLS), and H-1 NMR spectroscopy. Contrast matching SANS experiments revealed that block copolymers form micelles with a uniform density profile of the core. In contrast to popular assumption, the outer part of the core of the gradient copolymer micelles has a distinctly higher density than the middle of the core. We attribute the latter finding to back-folding of chains resulting from hydrophilic hydrophobic interactions, leading to a new type of micelles that we refer to as micelles with a "bitterball-core" structure