Cleavable Polyethylene Glycol: 3,4-Epoxy-1-butene as a Comonomer to Establish Degradability at Physiologically Relevant pH.

Polyethylene glycol (PEG) has been used for decades to improve the pharmacokinetic properties of protein drugs, and several PEG-protein conjugates are approved by the FDA. However, the nondegradability of PEG restricts its use to a limiting molecular weight to permit renal excretion. In this work, we introduce a simple strategy to overcome the nondegradability of PEG by incorporating multiple pH-sensitive vinyl ether moieties into the polyether backbone. Copolymerization of 3,4-epoxy-1-butene (EPB) with ethylene oxide via anionic ring-opening polymerization (AROP) provides access to allyl moieties that can be isomerized to pH-cleavable propenyl units (isoEPB). Well-defined P(EPB-co-EG) copo…

Effect of the Substituent Position on the Anionic Copolymerization of Styrene Derivatives: Experimental Results and Density Functional Theory Calculations

In a combined synthetic, kinetic and theoretical study, the living anionic copolymerization of styrene and its ring-methylated derivatives ortho-, meta-, and para-methylstyrene (MS) was examined by real-time 1H NMR spectroscopy in the nonpolar solvents toluene-d8 and cyclohexane-d12 as well as by density functional theory calculations. Based on the NMR kinetics data, reactivity ratios for each comonomer pair were determined by the Kelen–Tudős method and numerical integration of the copolymerization equation (Contour software). The reaction pathway was modeled and followed by density functional theory (DFT) calculations to validate and predict the experimentally derived reactivity ratios. Un…

Hyperbranched Polyols via Copolymerization of 1,2-Butylene Oxide and Glycidol: Comparison of Batch Synthesis and Slow Monomer Addition

Hyperbranched poly(butylene oxide) polyols have been synthesized by multibranching anionic ring-opening copolymerization of 1,2-butylene oxide and glycidol. Systematic variation of the composition from 24 to 74% glycidol content resulted in a series of moderately distributed copolymers (Đ = 1.41–1.65, SEC), albeit with limited molecular weights in the solvent-free batch process in the range of 900–1300 g mol–1 (apparent Mn determined by SEC with PEG standards). In situ monitoring of the copolymerization kinetics by 1H NMR showed a pronounced compositional drift with respect to the monomer feed, indicating a strongly tapered microstructure caused by the higher reactivity of glycidol. In the …

Catechol Acetonide Glycidyl Ether (CAGE): A Functional Epoxide Monomer for Linear and Hyperbranched Multi-Catechol Functional Polyether Architectures

A protected catechol-containing epoxide monomer, catechol acetonide glycidyl ether (CAGE), is introduced. CAGE is conveniently obtained in three steps and enables the incorporation of surface-active catechol moieties into a broad variety of hydrophilic and biocompatible polyether architectures by copolymerization. Via acidic cleavage of the acetal protecting groups, the polymer-attached catechol functionalities are liberated and available for surface attachment or metal complexation. CAGE has been copolymerized with ethylene oxide and glycidol to obtain both linear poly(ethylene glycol) and hyperbranched polyglycerol copolymers, respectively, with multiple surface-adhesive catechol moieties…

Tapered copolymers of styrene and 4‐vinylbenzocyclobutene via carbanionic polymerization for crosslinkable polymer films

Thioether-Bearing Hyperbranched Polyether Polyols with Methionine-Like Side-Chains: A Versatile Platform for Orthogonal Functionalization

The synthesis of thioether-bearing hyperbranched polyether polyols based on an AB/AB2 type copolymerization (cyclic latent monomers) is introduced. The polymers are prepared by anionic ring-opening multibranching copolymerization of glycidol and 2-(methylthio)ethyl glycidyl ether (MTEGE), which is conveniently accessible in a single etherification step. Slow monomer addition provides control over molecular weights. Moderate dispersities (Đ = 1.48–1.85) are obtained, given the hyperbranched structure. In situ 1H NMR copolymerization kinetics reveal reactivity ratios of rG = 3.7 and rMTEGE = 0.27. Using slow monomer addition, copolymer composition can be systematically varied, allowing for th…

Capitalizing on Protecting Groups to Influence Vinyl Catechol Monomer Reactivity and Monomer Gradient in Carbanionic Copolymerization

everal vinyl catechol-based monomers with systematically varied acetal protecting groups suitable for carbanionic polymerization are introduced. All monomers are based on the 4-vinyl benzodioxole or 5-vinyl benzodioxole structure and differ in the nature of the protecting group for the catechol functionalities. Different symmetric ketones are used for the protection of the diol functionality. Polymers with average molecular weight from 2500 to 25 000 g mol−1 (Mw/Mn < 1.15) are obtained from homopolymerization of the protected monomers. All monomers are examined regarding the influence of the protecting group on the copolymerization behavior with styrene, using in situ 1H NMR kinetic studies…

Die lebende anionische Polymerisation

Zusammenfassung Vor sechzig Jahren entdeckte Michael Szwarc die lebende anionische Polymerisation. Trotz ihrer hohen synthetischen Anforderungen ist sie bis heute die praziseste Methode zur Herstellung von wohldefinierten Polymeren und inspirierte zahlreiche neue Polymerisationsmethoden. Masgeschneiderte Blockcopolymere finden sich in den verschiedensten Anwendungen von High-End-Verpackungsmaterialien uber die Elektronik bis hin zu Nanomedizin.

Poly(Ethylene Glycol) Dimethacrylates with Cleavable Ketal Sites: Precursors for Cleavable PEG-Hydrogels.

The authors introduce poly(ethylene glycol) (PEG) based macromonomers containing acid-labile ketal moieties as well as terminal methacrylate units that are amenable to radical polymerization. The synthesis of PEGs of different molecular weights (ranging from 2000 to 13 000 g mol-1 with polydispersities <1.15) with a central ketal unit (PEG-ketal-diol) and their conversion to PEG-ketal-dimethacrylates (PEG-ketal-DMA) is introduced. Degradation rates of both PEG-ketal-diols and PEG-ketal-DMA are investigated by in situ 1 H NMR kinetic studies in deuterated phosphate buffer. Hydrogels containing 0, 5, or 10 wt% of PEG-ketal-DMA and 100, 95, or 90 wt% of PEG-DMA, respectively, are synthesized a…

Oxidation-responsive and "clickable" poly(ethylene glycol) via copolymerization of 2-(methylthio)ethyl glycidyl ether

Poly(ethylene glycol) (PEG) is a widely used biocompatible polymer. We describe a novel epoxide monomer with methyl-thioether moiety, 2-(methylthio)ethyl glycidyl ether (MTEGE), which enables the synthesis of well-defined thioether-functional poly(ethylene glycol). Random and block mPEG-b-PMTEGE copolymers (Mw/Mn = 1.05-1.17) were obtained via anionic ring opening polymerization (AROP) with molecular weights ranging from 5&#8239;600 to 12&#8239;000 g·mol-1. The statistical copolymerization of MTEGE with ethylene oxide results in a random microstructure (rEO = 0.92 ± 0.02 and rMTEG E = 1.06 ± 0.02), which was confirmed by in situ 1H NMR kinetic studies. The random copolymers are thermorespon…

One-Step Block Copolymer Synthesis versus Sequential Monomer Addition: A Fundamental Study Reveals That One Methyl Group Makes a Difference

Block copolymers of polyisoprene and polystyrene are key materials for polymer nanostructures as well as for several commercially established thermoplastic elastomers. In a combined experimental and kinetic Monte Carlo simulation study, the direct (i.e., statistical) living anionic copolymerization of a mixture of isoprene (I) and 4-methylstyrene (4MS) in nonpolar media was investigated on a fundamental level. In situ 1H NMR spectroscopy enabled to directly monitor gradient formation during the copolymerization and to determine the nature of the gradient. In addition, a precise comparison with the established copolymerization of isoprene and styrene (I/S) was possible. Statistical copolymer…

Conventional Oxyanionic versus Monomer-Activated Anionic Copolymerization of Ethylene Oxide with Glycidyl Ethers: Striking Differences in Reactivity Ratios.

Detailed understanding of the monomer distribution in copolymers is essential to tailor their properties. For the first time, we have been able to utilize in situ 1H NMR spectroscopy to monitor the monomer-activated anionic ring opening copolymerization (AROP) of ethylene oxide (EO) with a glycidyl ether comonomer, namely, ethoxy ethyl glycidyl ether (EEGE). We determine reactivity ratios and draw a direct comparison to conventional oxyanionic ROP. Surprisingly, the respective monomer reactivities differ strongly between the different types of AROP. Under conventional oxyanionic conditions similar monomer reactivities of EO and EEGE are observed, leading to random structures (rEO = 1.05 ± 0…

“Clickable PEG” via anionic copolymerization of ethylene oxide and glycidyl propargyl ether

A straight forward synthesis of poly(ethylene glycol) (PEG) with multiple alkyne groups distributed along the polymer chain is introduced. Direct access to clickable PEG is achieved by the monomer-activated anionic ring-opening copolymerization (AROP) of ethylene oxide (EO) with glycidyl propargyl ether (GPgE). Notably for successful polymerization no protection of the alkyne unit is required owing to the mild reaction conditions. Defined PEG-co-PGPgE and PGPgE (co)polymers with PDIs of 1.18–1.60 and molecular weights of Mn = 3000–9500 g mol−1 were prepared. In situ1H NMR kinetic studies revealed remarkably disparate reactivity ratios of rEO = 14.8 and rGPgE = 0.076, representing a pronounc…

Copolymerization Kinetics of Glycidol and Ethylene Oxide, Propylene Oxide, and 1,2-Butylene Oxide: From Hyperbranched to Multiarm Star Topology

Copolymerization of established epoxide monomers with glycidol (G) is a key reaction to prepare branched or hyperbranched polyethers. The kinetics of the multibranching anionic ring-opening copolymerization of glycidol (a cyclic latent AB2 monomer) with ethylene oxide (EO), propylene oxide (PO), and 1,2-butylene oxide (BO; cyclic latent AB monomers), respectively, in dimethyl sulfoxide was studied. Online 1H NMR spectroscopy was employed for in situ monitoring of the individual monomer consumption during the entire course of the statistical copolymerization. Varying the counterion, both the cesium alkoxide and potassium alkoxide initiated copolymerization were studied and compared. From the…