Christopher Waldron

Aqueous copper-mediated living polymerization : exploiting rapid disproportionation of CuBr with Me6TREN

A new approach to perform single-electron transfer living radical polymerization (SET-LRP) in water is described. The key step in this process is to allow full disproportionation of CuBr/Me6TREN (TREN = tris(dimethylamino)ethyl amine to Cu(0) powder and CuBr2 in water prior to addition of both monomer and initiator. This provides an extremely powerful tool for the synthesis of functional water-soluble polymers with controlled chain length and narrow molecular weight distributions (polydispersity index approximately 1.10), including poly(N-isopropylacrylamide), N,N-dimethylacrylamide, poly(ethylene glycol) acrylate, 2-hydroxyethyl acrylate (HEA), and an acrylamido glyco monomer. The polymerizations are performed at or below ambient temperature with quantitative conversions attained in minutes. Polymers have high chain end fidelity capable of undergoing chain extensions to full conversion or multiblock copolymerization via iterative monomer addition after full conversion. Activator generated by electron transfer atom transfer radical polymerization of N-isopropylacrylamide in water was also conducted as a comparison with the SET-LRP system. This shows that the addition sequence of l-ascorbic acid is crucial in determining the onset of disproportionation, or otherwise. Finally, this robust technique was applied to polymerizations under biologically relevant conditions (PBS buffer) and a complex ethanol/water mixture (tequila).

Absolut “copper catalyzation perfected”; robust living polymerization of NIPAM: Guinness is good for SET-LRP

The controlled polymerization of N-isopropyl acrylamide (NIPAM) is reported in a range of international beers, wine, ciders and spirits utilizing Cu(0)-mediated living radical polymerization (SET-LRP). Highly active Cu(0) is first formed in situ by the rapid disproportionation of [Cu(I)(Me6-Tren)Br] in the commercial water–alcohol mixtures. Rapid, yet highly controlled, radical polymerization follows (Đ values as low as 1.05) despite the numerous chemicals of diverse functionality present in these solvents e.g. alpha acids, sugars, phenols, terpenoids, flavonoids, tannins, metallo-complexes, anethole etc. The results herein demonstrate the robust nature of the aqueous SET-LRP protocol, underlining its ability to operate efficiently in a wide range of complex chemical environments.

Copper(0)-mediated radical polymerisation in a self-generating biphasic system

Herein, we demonstrate the synthesis of well-defined poly(n-alkyl acrylate)s via copper(0)-mediated radical polymerisation in a self-generating biphasic system. During the polymerisation of n-butyl acrylate in DMSO, the polymer phase separates to yield a polymer-rich layer with very low copper content (ICP-MS analysis: 0.016 wt%). The poly(n-butyl acrylate) has been characterized by a range of techniques, including GPC, NMR and MALDI-TOF, to confirm both the controlled character of the polymerisation and the end group fidelity. Moreover, we have successfully chain extended poly(n-butyl acrylate) in this biphasic system several times with n-butyl acrylate to high conversion without intermediate purification steps. A range of other alkyl acrylates have been investigated and the control over the polymerisation is lost as the hydrophobicity of the polymer increases due to the increase in alkyl chain length indicating that it is important for the monomer to be soluble in the polar solvent.

Copper-mediated living radical polymerization (SET-LRP) of lipophilic monomers from multi-functional initiators : reducing star–star coupling at high molecular weights and high monomer conversions

The SET-LRP of lipophilic monomers (n-butyl and lauryl acrylate) from a lactose based octa-functional initiator is described. A range of highly defined lipophilic poly(acrylate) stars are prepared to relatively high molecular weights (Mn,target > 100 000 g mol−1 in some cases) and high monomer conversions (≥99%) with excellent control retained over molecular weight distributions (PDI values as low as 1.03). Phase separation of star polymers from the reaction media during polymerization is seen to occur which is advantageous in reducing star–star coupling in certain cases, without limiting the attainment of near quantitative conversions. A comparison is made between heterogeneous and homogeneous polymerization protocols to illustrate this finding.

Polymerization of long chain [meth]acrylates by Cu(0)-mediated and catalytic chain transfer polymerisation (CCTP): high fidelity end group incorporation and modification

The Cu(0)-mediated polymerization of lauryl (C12) and stearyl (C18) acrylate is reported under a range of reaction conditions. Good first order kinetics, a linear evolution of number average molecular weight (Mn) with conversion and dispersity (∼1.10) are observed. The polymerization of lauryl acrylate proceeds either homogenously or in a self-generated biphasic system, depending on the solvent employed, with little deviation in overall polymerization control. The near quantitative retention of ω-bromo end groups is exploited via nucleophilic thio-bromine substitution with thioglycerol to yield highly hydrophobic polymers with polar head groups. Modification is spectroscopically confirmed by both NMR and MALDI-TOF-MS. Highly ω-chain end functional methacrylic analogues have also been prepared by Co(II) mediated catalytic chain transfer polymerisation (CCTP). Reactive vinyl groups at the ω-chain end of poly(lauryl methacrylate) have been targeted with thioglycerol for nucleophilic thio-Michael addition with quantitative modification possible.

SET-LRP of hydrophobic and hydrophilic acrylates in tetrafluoropropanol

Efficient disproportionation of CuBr–Me6-TREN in 2,2,2-trifluoroethanol (TFE) to produce “nascent” Cu(0) and CuBr2–Me6-TREN indicates that this semifluorinated alcohol has the potential to be an excellent solvent for Cu(0) mediated single electron transfer-living radical polymerization (SET-LRP). Herein, we report the SET-LRP of a range of hydrophobic and hydrophilic acrylates, including methyl acrylate (MA), n-butyl acrylate (nBA), tert-butyl acrylate (tBA), 2-ethylhexyl acrylate (EHA) and 2-hydroxyethyl acrylate (HEA) using 2-bromopropionate (MBP) and 2-ethylbromoisopropionate (EBiB) as initiators, and Me6-TREN as ligand in TFE. Analysis of the kinetics of polymerization and of the polymer chain ends by a combination of 1H NMR, GPC, MALDI-TOF and chain-end functionalization by “thio-bromo” click reaction demonstrated the synthesis of perfect or near-perfect chain-end functional polyacrylates by SET-LRP in TFE.

SET-LRP of methacrylates in fluorinated alcohols

Activated Cu(0) wire-mediated single-electron transfer living radical polymerization (SET-LRP) of methyl methacrylate (MMA), ethyl methacrylate (EMA) and n-butyl methacrylate (BMA) was performed in two fluorinated alcohols, 2,2,2-trifluoroethanol (TFE) and 2,2,3,3-tetrafluoropropanol (TFP) using tosyl chloride (TsCl) as initiator, hydrazine-activated Cu(0) wire as catalyst, and Me6-TREN as ligand at 50 °C. The ability of these two solvents to solubilize these monomers, the resulting polymers, and mediate an efficient disproportionation of Cu(I)Br in the presence of Me6-TREN ligand to produce the “nascent” Cu(0) activator, Cu(II)Br2 deactivator and to stabilize Cu(II)Br2/Me6-TREN complex make them excellent solvents for SET-LRP of methacrylates. To the best of our knowledge, this is the first report of SET-LRP of methacrylates in fluorinated alcohols and also the first efficient SET-LRP of EMA and BMA in any solvent. The kinetic experiments and molecular weight analyses demonstrate that in all experiments a living polymerization takes place with excellent evolution of molecular weight and with narrow molecular weight distribution until almost complete monomer conversion. It was also demonstrated that the rate of polymerization conducted in TFE and TFP could be significantly enhanced by a synergistic solvent effect upon addition of a small amount of water, which mediates an even faster disproportionation of Cu(I)Br into Cu(0) activator and Cu(II)Br2 deactivator.

Effects of trehalose polycation end-group functionalization on plasmid DNA uptake and transfection.

In this study, we have synthesized six analogs of a trehalose-pentaethylenehexamine glycopolymer (Tr4) that contain (1A) adamantane, (1B) carboxy, (1C) alkynyl-oligoethyleneamine, (1D) azido trehalose, (1E) octyl, or (1F) oligoethyleneamine end groups and evaluated the effects of polymer end group chemistry on the ability of these systems to bind, compact, and deliver pDNA to cultured HeLa cells. The polymers were synthesized in one-pot azide-alkyne cycloaddition reactions with an adaptation of the Carothers equation for step-growth polymerization to produce a series of polymers with similar degrees of polymerization. An excess of end-capping monomer was added at the end of the polymerizations to maximize functionalization efficiency, which was evaluated with GPC, NMR, and MALDI-TOF. The polymers were all found to bind and compact pDNA at similarly low N/P ratios and form polyplexes with plasmid DNA. The effects of the different end group structures were most evident in the polyplex internalization and transfection assays in the presence of serum as determined by flow cytometry and luciferase gene expression, respectively. The Tr4 polymers end-capped with carboxyl groups (1B) (N/P = 7), octyne (1E) (N/P = 7), and oligoethyleneamine (1F) (N/P = 7), were taken into cells as polyplex and exhibited the highest levels of fluorescence, resulting from labeled plasmid. Similarly, the polymers end-functionalized with carboxyl groups (1E at N/P = 7), octyl groups (1E at N/P = 15), and in particular oligoethyleneamine groups (1F at N/P = 15) yielded dramatically higher reporter gene expression in the presence of serum. This study yields insight into how very subtle structural changes in polymer chemistry, such as end groups can yield very significant differences in the biological delivery efficiency and transgene expression of polymers used for pDNA delivery.

Controlled aqueous polymerization of acrylamides and acrylates and “in situ” depolymerization in the presence of dissolved CO2

Aqueous copper-mediated radical polymerization of acrylamides and acrylates in carbonated water resulted in high monomer conversions (t < 10 min) before undergoing depolymerization (60 min > t > 10 min). The regenerated monomer was characterized and repolymerized following deoxygenation of the resulting solutions to reyield polymers in high conversions that exhibit low dispersities.