Synthesis of Hydrophobically and Electrostatically Modified Polyacrylamides and Their Catalytic Effects on the Unimolecular Decarboxylation of 6-Nitrobenzisoxazole-3-carboxylate Anion

A series of hydrophobically and electrostatically modified polyacrylamides (Copol(AM-C12)) has been synthesized by radical-initiated copolymerization of acrylamide with n-dodecylmethyldiallylammonium bromide as the hydrophobe in aqueous solution using ammonium persulfate as the initiator. The formation of hydrophobic microdomains of the copolymers was revealed by large hypsochromic shifts of the longwavelength absorption band of the solvatochromic probe Methyl Orange, noncovalently bound to the macromolecule. It was found that the microdomains formed by these copolymers in aqueous solution are more hydrophobic than those of the cationic polysoaps poly(alkylmethyldiallylammonium halides) containing the same n-dodecyl groups as the side chains as a result of the reduced electrostatic repulsions at the periphery of the microdomains. The reduced cationic character of the copolymers Copol(AM-C12) most likely also accounts for the observation that the anionic dye Methyl Orange does not induce microdomain formation in aqueous solution. The effect of the hydrophobically and electrostatically modified polyacrylamides on the unimolecular decarboxylation of 6-nitrobenzisoxazole-3-carboxylate anion (6-NBIC) has been investigated in aqueous solutions at pH 11.3 and 30 °C. It is suggested that the relatively modest catalytic effects induced by Copol(AM-C12) should be ascribed to hydrogen-bond stabilization of the initial state by NH groups in the macromolecules. The decarboxylation rates of 6-NBIC at binding sites in hydrophobic microdomains increase with increasing n-dodecyl group content in the copolymers.

Acrylamides with hydrolytically labile carbonate ester side chains as versatile building blocks for well-defined block copolymer micelles via RAFT polymerization

En route towards improved delivery systems for targeted chemotherapy, we propose a straightforward approach for the hydrophobic modification of the acrylamide N-(2-Hydroxyethyl) acrylamide (HEAm). An ethyl or benzyl group was introduced via a hydrolytically sensitive carbonate ester yielding HEAm-EC and HEAm-BC, respectively. Block copolymers of HEAm, respectively PEG and HEAm-EC or HEAm-BC were successfully synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization, obtaining a library of well-defined block copolymers with different degrees of polymerization (DP). To further explore the versatility of our approach in terms of polymer synthesis, self-assembly, drug solubilization and in vitro cell interaction, polyethylene glycol (PEG) and polyHEAm as hydrophilic polymer blocks were compared. The block copolymers formed micellar nanoparticles (10-100 nm) in PBS and could efficiently solubilize hydrophobic dyes and anti-cancer drugs. Benzyl carbonate ester side chains increased micellar stability and drug loading capacity. Moreover, PEG as hydrophilic block showed in comparison to HEAm more promising results concerning both colloidal stability and drug loading capacity. Confocal microscopy showed that the micelles could efficiently deliver a hydrophobic dye inside the cells. Finally, we also demonstrated efficient formulation of the anti-cancer drug paclitaxel with an in vitro cancer cell killing performance comparable or even better than the two commercial PTX nano-formulations Abraxane and Genexol-PM at equal drug dose. In conclusion, modification of HEAm through carbonate linkages offers a versatile platform for the design of degradable polymers with potential for biomedical applications

pH-Degradable mannosylated nanogels for dendritic cell targeting

We report on the design of glycosylated nanogels via core-cross linking of amphiphilic non-water-soluble block copolymers composed of an acetylated glycosylated block and a pentafluorophenyl (PFP) activated ester block prepared by reversible addition fragmentation (RAFT) polymerization. Self-assembly, pH-sensitive core-cross-linking, and removal of remaining PFP esters and protecting groups are achieved in one pot and yield fully hydrated sub-100 nm nanogels. Using cell subsets that exhibit high and low expression of the mannose receptor (MR) under conditions that suppress active endocytosis, we show that mannosylated but not galactosylated nanogels can efficiently target the MR that is expressed on the cell surface of primary dendritic cells (DCs). These nanogels hold promise for immunological applications involving DCs and macrophage subsets

Rapidly self-deoxygenating controlled radical polymerization in water via in situ disproportionation of Cu(i)

Rapidly self-deoxygenating Cu-RDRP in aqueous media is investigated. The disproportionation of Cu(I)/Me6Tren in water towards Cu(II) and highly reactive Cu(0) leads to O2-free reaction environments within the first seconds of the reaction, even when the reaction takes place in the open-air. By leveraging this significantly fast O2-reducing activity of the disproportionation reaction, a range of well-defined water-soluble polymers with narrow dispersity are attained in a few minutes or less. This methodology provides the ability to prepare block copolymers via sequential monomer addition with little evidence for chain termination over the lifetime of the polymerization and allows for the synthesis of star-shaped polymers with the use of multi-functional initiators. The mechanism of self-deoxygenation is elucidated with the use of various characterization tools, and the species that participate in the rapid oxygen consumption is identified and discussed in detail

Copper mediated reversible deactivation radical polymerization in aqueous media

Key advances within the past 10 years have transformed copper mediated radical polymerization from a technique which was not very tolerant to protic media into a range of closely related processes capable of control over the polymerization of a wide range of monomers in pure water at ppm catalyst loadings; yielding water soluble macromolecules of desired molecular weight, architecture and chemical functionality, with applications ranging from drug delivery to oil field recovery. In this review we highlight and critically evaluate the synthetic methods that have been developed to control radical polymerization in water using copper complexes, identify future areas of interest and challenges still to be overcome

P450-catalyzed asymmetric cyclopropanation of electron-deficient olefins under aerobic conditions

A variant of P450 from Bacillus megaterium five mutations away from wild type is a highly active catalyst for cyclopropanation of a variety of acrylamide and acrylate olefins with ethyl diazoacetate (EDA). The very high rate of reaction enabled by histidine ligation allowed the reaction to be conducted under aerobic conditions. The promiscuity of this catalyst for a variety of substrates containing amides has enabled synthesis of a small library of precursors to levomilnacipran derivatives

Cu(0)-RDRP of methacrylates in DMSO: importance of the initiator

The controlled radical polymerization of methacrylates via Cu(0)-mediated RDRP is challenging in comparison to acrylates with most reports illustrating higher dispersities, lower monomer conversions and poorer end group fidelity relative to the acrylic analogues. Herein, we present the successful synthesis of poly(methyl methacrylate) (PMMA) in DMSO by judicious selection of optimal reaction conditions. The effect of the initiator, ligand and temperature on the rate and control of the polymerization is investigated and discussed. Under carefully optimized conditions enhanced control over the molecular weight distributions is obtained furnishing methacrylic polymers with dispersities as low as 1.10, even at very high conversions. A range of methacrylates were found to be tolerant to the optimized polymerization conditions including hydrophobic, hydrophilic and functional methacrylates including methyl and benzyl methacrylate, ethylene glycol methyl ether methacrylate and glycidyl methacrylate. The control retained during the polymerization is further highlighted by in situ chain extensions yielding well-defined block polymethacrylates

Addition-substitution reactions of 2-thio-3-chloroacrylamides with carbon, nitrogen, oxygen, sulfur and selenium nucleophiles

Synthetically versatile conjugate addition of a range of carbon, nitrogen, oxygen, sulfur and selenium nucleophiles to the highly functionalised 2-thio-3-chloroacrylamides is described. The stereochemical and synthetic features of this transformation are discussed in detail. In most instances, the nucleophile replaces the chloro substituent with retention of stereochemistry. With the oxygen nucleophiles, a second addition can occur leading to acetals, while with the nitrogen nucleophiles, E-Z isomerism occurs in the resulting enamine derivatives. The ratio of the E/Z isomers can be rationalised on the basis of the substituent and the level of oxidation

Ultra-fast aqueous polymerisation of acrylamides by high power visible light direct photoactivation RAFT polymerisation

The effect of visible LED power (λmax = 402 nm, 451 nm) on kinetics and control of direct photoactivation RAFT polymerisations of acrylamide and dimethylacrylamide are investigated. By increasing power supplied to the LEDs from 6 to 208 W, the polymerisation time required to reach >85% conversion is reduced from 12 hours to 11 minutes for acrylamide. Similar conversions are shown to be obtainable in 5 minutes for dimethylacrylamide, all without any exogenous photoinitiator or catalyst. This increase in polymerisation rate is attributed to an increase in both photon flux and a coincident increase in polymerisation temperature at higher light intensities. With both 402 nm and 451 nm LEDs exciting the same n → π* electronic transition, little difference in rate of polymerisation is seen between the two light sources. Minimal reduction in polymerisation control is observed at high irradiation intensity for acrylamide, while an increased production of low molecular weight dead chains is observed for dimethylacrylamide. This is shown to be mitigated by controlling the polymerisation temperature to 17 °C which caused both a reduction in low molecular weight tailing and an increased polymerisation time. Visible light direct photoactivation RAFT is also shown to have application in the synthesis of ultra-high molecular weight acrylamide polymers (Mn > 1 000 000 g mol−1)

Iron(III) chelating resins-IV. Crosslinked copolymer beads of 1-(B-acrylamidoethyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (AHMP) with 2-hydroxyethyl methacrylate (HEMA)

Iron(III) chelating beads have been synthesized by copolymerization of 1-(ß-acrylamidoethyl)-3-hydroxy-2-methyl-4(IH)-pyridinone (AHMP) with 2-hydroxyethyl methacrylate (HEMA), and ethyleneglycol dimethacrylate (EGDMA) as the crosslinking agent. The synthesis of the AHMP-HEMA beads was performed by suspension polymerization of AHMP, HEMA and EGDMA in benzyl alchol¿20% aqueous NaCl solution using 2,2¿-azobisisobutyronitrile (AIBN) as the initiator and polyvinylalcohol (40¿88) as a suspending agent.\ud \ud The crosslinked copolymer beads were characterized by IR, and the AHMP content was determined by elemental analysis. The AHMP-HEMA beads were not too hydrophilic, and the copolymers absorbed at equilibrium only 40¿50% water. It was found that the copolymer beads were very stable at 25°, but some degradation was observed at 121°.\ud \ud The AHMP-HEMA copolymers were able to chelate iron(III) and the chelation was dependent on the conditions such as pH and temperature. However, the capacities towards iron(III) chelation were always found to be much lower than the calculated values. The influence of the polymeric matrix on the iron(III) chelating ability was studied with iron(III) chelating resins containing various polymeric matrices. It was found that the iron(III) chelating efficiencies of the resins were strongly affected by their hydrophilicities. The low chelating efficiency of the AHMP-HEMA beads (0¿40%) is probably due to their poor swelling in water