Athina Anastasaki

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).

Cu(0)-Mediated Living Radical Polymerization: A Versatile Tool for Materials Synthesis

Materials Synthesis Athina Anastasaki,†,‡ Vasiliki Nikolaou,† Gabit Nurumbetov,† Paul Wilson,†,‡ Kristian Kempe,†,‡ John F. Quinn,‡ Thomas P. Davis,†,‡ Michael R. Whittaker,†,‡ and David M. Haddleton*,†,‡ †Chemistry Department, University of Warwick, Library Road, CV4 7AL, Coventry, United Kingdom ‡ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 399 Royal Parade, Parkville, Victoria 3152, Australia

Sequence-controlled multi-block glycopolymers to inhibit DC-SIGN-gp120 binding.

Glycan–protein interactions are essential for many physiological processes including cell–cell recognition, cell adhesion, cell signalling, pathogen identification, and differentiation. Dendritic cell-specific intercellular adhesion molecule3-grabbing non-integrin (DC-SIGN; CD209) is a C-type lectin (carbohydrate-binding protein) present on both macrophages and dendritic cell subpopulations and plays a critical role in many cell interactions. DC-SIGN binds to microorganisms and host molecules by recognizing surface-rich mannose-containing glycans through multivalent glycan– protein interactions and serves as a target for several viruses, such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Carbohydrate-binding proteins (CBP) have been suggested as potential microbicides for the prevention of HIV infection. However, the isolation of natural CBPs is relatively difficult because of their hydrophilic nature and low affinity for the virus. 4] Thus, synthetic lectins are of interest for carbohydrate recognition studies. Alternatively, noncarbohydrate inhibitors of mammalian lectins can be used to prevent the interaction between DC-SIGN and gp120. The structures of these multivalent ligands have a great effect on carbohydrate binding to lectins, and the use of linear polymers to effectively inhibit lectin binding has been demonstrated by several research groups. Synthetic polymer chemistry has developed rapidly in recent years. Currently, polymerization of functional monomers with the desired chain length, structure, and composition is straightforward; whereas producing polymers with monomer sequence control remains challenging, which has implications for the controlled folding of synthetic macromolecules. There are a few recent reports where sufficient control has been achieved in controlling the monomer sequence along the polymer chain. To the best of our knowledge, this is the first report where some control over the relative position of the sugars is exhibited and their binding to the human lectin DC-SIGN is demonstrated. We have used a controlled polymerization technique, single-electron transfer living radical polymerization (SET-LRP), to polymerize glycomonomers, which are prepared by copper catalyzed azide–alkyne click (CuAAC) reaction prior to polymerization. A series of glycomonomers were prepared by reaction of 3-azidopropylacrylate (APA) and alkylated mannose, glucose, and fucose using a Fischer–Helferich glycosylation. This was performed using CuSO4 and sodium ascorbate in a methanol/water mixture (see the Supporting Information). SET-LRP of the glucose monomer (GluA) was performed in dimethylsulfoxide (DMSO) using a copper(0)/copper(II) and tris[2-(dimethylamino)ethyl]amine (Me6TREN)-derived catalyst. Polymerization reached over 90 % monomer conversion in six hours whilst maintaining a narrow molecular weight distribution with increasing molecular weight. (Supporting Information, Figure S4). The obtained polymers were characterized by size exclusion chromatography (SEC) and MALDI-TOF mass spectroscopy (MS) or high-resolution electrospray ionization mass spectroscopy (HR-ESI MS), which indicated very high chain-end fidelity allowing for sequential monomer addition. We designed a polymerization reaction starting with one equivalent of initiator (I) and two equivalents of mannose glycomonomer (ManA; Figure 1a). ManA was fully consumed after 12 hours; then two equivalents of GluA in DMSO were added to the reaction mixture and GluA was consumed in 16 hours. Two equivalents of ManA in DMSO were subsequently added to the reaction mixture, and this cycle was continued until six short blocks of glycopolymers were produced (the degree of polymerization (DP) = 2 for each block, (mannose)2-(glucose)2-(mannose)2-(glucose)2(mannose)2-(glucose)2). No purification steps were required prior to addition of the subsequent monomer. The conversion of the first four blocks, as analyzed by H NMR spectroscopy, reached 100 %, shown by the complete disappearance of vinyl groups at 5.7–6.5 ppm. The glycomonomers were dissolved in purged DMSO prior to their addition and this resulted in further dilution of the reaction mixture upon each monomer addition. Traces of vinyl groups could still be detected after [*] Q. Zhang, J. Collins, A. Anastasaki, Dr. C. R. Becer, Prof. D. M. Haddleton Department of Chemistry, University of Warwick Gibbet Hill Road, Coventry, CV4 7AL (UK) E-mail: d.m.haddleton@warwick.ac.uk Homepage: http://www.warwick.ac.uk/go/polymers Dr. R. Wallis Department of Biochemistry, University of Leicester Leicester, LE1 9HN (UK) Dr. D. A. Mitchell Clinical Sciences Research Institute, Warwick Medical School, University of Warwick Coventry, CV2 2DX (UK) [**] We acknowledge financial support from the University of Warwick and the China Scholarship Council. Equipment used in this research was funded by the Innovative Uses for Advanced Materials in the Modern World (AM2) with support from AWM and ERDF. D.M.H. is a Royal Society/Wolfson Fellow and C.R.B. is a Science City Senior Research Fellow. Dr. Christopher N. Scanlan has provided the gp120. Supporting information for this article (syntheses of all materials and details of the characterization methods) is available on the WWW under http://dx.doi.org/10.1002/anie.201300068. Angewandte Chemie

Photoinduced sequence-control via one pot living radical polymerization of acrylates

The ability to regulate the activation and deactivation steps via an external stimulus has always been a challenge in polymer chemistry. In an ideal photo-mediated system, whereby high monomer conversion and excellent end group fidelity can be maintained, precise control over the polymer composition and microstructure would be a significant breakthrough. Herein, we report, a versatile, simple and inexpensive method that allows for the synthesis of sequence-controlled multiblock copolymers in a one pot polymerization reaction at ambient temperature. In the absence of a conventional photoredox catalyst and dye-sensitisers, low concentrations of CuBr2 in synergy with Me6-Tren mediate acrylic block copolymerization under UV irradiation (λmax ≈ 360 nm). Four different acrylate monomers were alternated in various combinations within the polymer composition illustrating the potential of the technique. Narrow disperse undecablock copolymers were obtained (Đ < 1.2) with quantitative conversion achieved between the iterative monomer additions. The effect of the chain length was investigated allowing for higher molecular weight multiblock copolymers to be obtained. This approach offers a versatile and inexpensive platform for the preparation of high-order multiblock functional materials with additional applications arising from the precise spatiotemporal “on/off” control and resolution when desired.

Sequence-controlled multi-block copolymerization of acrylamides via aqueous SET-LRP at 0 °C

Aqueous single electron transfer living radical polymerization (SET-LRP) has been employed to synthesize multi-block homopolymers and copolymers of a range of acrylamide monomers including N-isopropylacrylamide (NIPAM), 2-hydroxyethyl acrylamide (HEAA), N,N-dimethyl acrylamide (DMA) and N,N-diethylacrylamide (DEA). Disproportionation of Cu(I)Br in the presence of Me6TREN in water was exploited to generate reactive Cu(0) and [CuII(Me6TREN)]Br2in situ resulting in unprecedented rates of reaction whilst maintaining control over chain lengths and molecular weight distributions (Đ < 1.10). Kinetic studies enabled optimization of iterative chain extensions or block copolymerizations furnishing complex compositions in a matter of minutes/hours. In the multi-block copolymer system, the monomer sequence was successfully varied and limiting effects on the polymerization have been comprehensively examined through a series of control experiments which imply that the rate of ω-Br chain end loss is enhanced in tertiary acrylamides (DMA, DEA, N-acryloylmorpholine NAM) relative to secondary acrylamides (NIPAM, HEAA).

Sequence-controlled methacrylic multiblock copolymers via sulfur-free RAFT emulsion polymerization

Translating the precise monomer sequence control achieved in nature over macromolecular structure (for example, DNA) to whole synthetic systems has been limited due to the lack of efficient synthetic methodologies. So far, chemists have only been able to synthesize monomer sequence-controlled macromolecules by means of complex, time-consuming and iterative chemical strategies such as solid-state Merrifield-type approaches or molecularly dissolved solution-phase systems. Here, we report a rapid and quantitative synthesis of sequence-controlled multiblock polymers in discrete stable nanoscale compartments via an emulsion polymerization approach in which a vinyl-terminated macromolecule is used as an efficient chain-transfer agent. This approach is environmentally friendly, fully translatable to industry and thus represents a significant advance in the development of complex macromolecule synthesis, where a high level of molecular precision or monomer sequence control confers potential for molecular targeting, recognition and biocatalysis, as well as molecular information storage. Achieving sequence control in a synthetic polymer is more challenging and time consuming than it is for biopolymers. Now, it has been shown that the synthesis of sequence-controlled multiblock copolymers can be carried out via emulsion polymerization. This approach is environmentally friendly and yields complex multiblock materials with low dispersity and high yields.

Enlightening the Mechanism of Copper Mediated PhotoRDRP via High-Resolution Mass Spectrometry

The initiation mechanism of photochemically mediated Cu-based reversible-deactivation radical polymerization (photoRDRP) was investigated using pulsed-laser polymerization (PLP) and high-resolution mass spectrometry. The variation of the catalyst composition and ESI-MS analysis of the resulting products provided information on how initiator, ligand, copper species, and monomer are interacting upon irradiation with UV light. A discussion of the results allows for a new postulation of the mechanism of photoRDRP and-for the first time-the unambiguous identification of the initiating species and their interactions within the reaction mixture. One pathway for radical generation proceeds via UV light-induced C-Br bond scission of the initiator, giving rise to propagating radicals. The generation of copper(I) species from copper(II) can occur via several pathways, including, among others, via reduction by free amine ligand in its excited as well as from its ground state via the irradiation with UV light. The amine ligand serves as a strong reducing agent and is likely the main participant in the generation of copper(I) species.

Cu(0)-mediated living radical polymerization: recent highlights and applications; a perspective

Cu(0)-mediated living radical polymerization or single electron transfer living radical polymerization (Cu(0)-mediated LRP or SET-LRP) is a versatile polymerization technique that has attracted considerable interest during the past few years for the facile preparation of advanced materials. Importantly, the scope of Cu(0)-mediated LRP has been significantly expanded to include the polymerization of a large variety of functional monomers (e.g. acrylates, methacrylates, acrylamides, methacrylamides, styrene etc.) in several solvents e.g. with the resulting polymers possessing narrow molecular weight distributions (MWDs), fast polymerization rates and very high end-group fidelity (even at quantitative conversions) as exemplified by sequential chain extensions and block copolymerizations. These characteristics render Cu(0)-mediated LRP an ideal candidate for the facile synthesis of complex architectures that have found use in a large diversity of applications including glycopolymers, gene delivery, foldamers, polymer–protein conjugates and many others.

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.

Multiblock sequence-controlled glycopolymers via Cu(0)-LRP following efficient thiol–halogen, thiol–epoxy and CuAAC reactions

The combination of copper(0) mediated living radical polymerization (Cu(0)-LRP) with thiol–halogen, thiol–epoxy and copper catalysed alkyne azide coupling (CuAAC) click chemistry has been employed to give a new route to multiblock sequence-controlled glycopolymers. Multiblock poly(glycidyl acrylate)-co-(acrylic acid 3-trimethylsilanyl-prop-2-ynyl ester) (poly(GA)-co-(TMSPA)) were obtained by Cu(0)-LRP in DMSO at ambient temperature via iterative monomer addition whereby the sequence of the multi blocks is attained in a designed way. Thiol–halogen and thiol–epoxy reaction of poly(GA) have been exploited, which suggested a preference for the reaction of the halogen rather than the epoxide for the thiol with triethyl amine as catalyst. The obtained multiblock poly(GA)-co-(TMSPA) were then used for sequential thiol–halogen, thiol–epoxy and CuAAC reactions to build functional glycopolymers in defined sequence.