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2013 Publications


Poly(acrylates) via SET-LRP in a continuous tubular reactor, Burns, James A.; Houben, Claudia; Anastasaki, Athina; Waldron, Christopher; Lapkin, Alexei A.; Haddleton, David M., Polymer Chemistry (2013), 4(17), 4809-4813.

A simple, easy to construct, bench-top plug flow reactor consisting of PTFE tubing with a Cu(0) threaded core (wire) was used to perform SET-LRP of Me acrylate. The reaction was optimized by changing the residence time within the flow reactor. Both changing the flow reactor length and changing the flow rate was seen to control the resultant polymer mol. wt. Using a 20 cm reactor length, 95% conversion of monomer was seen at a flow rate of 0.1 mL min-1. The polymers formed had narrow mol. wt. distributions (PDI< 1.2), and very high ω-chain end fidelity, as seen by both 1H NMR and MALDI-TOF MS.

Synthesis of water soluble PEGylated (copper) phthalocyanines via Mitsunobu reaction and Cu(i)-catalysed azide-alkyne cycloaddition (CuAAC), Li, Muxiu; Khoshdel, Ezat; Haddleton, David M., Polymer Chemistry (2013), 4(16), 4405-4411.

Octa-substituted phthalocyanine (Pc) and copper phthalocyanine (CuPc) with different chain lengths of monomethyl ether polyethylene glycol (mPEG) with mol. wts. of 350, 550, 750, and up to 2000 g mol-1 were synthesized through combining a phenolic Mitsunobu reaction with Cu(i)-catalyzed azide-alkyne cycloaddn. (CuAAC) click chem. Anal. by GPC shows that narrow polydispersities (PDI ≤ 1.2) of the resultant polymeric derivs. can be achieved; photodiode array (PDA) detection confirms the formation of the desired products. The metal-free Pc polymers are clearly distinguished from polymers functionalised with CuPcs. All PEGylated (Cu)Pc polymers are highly sol. in a range of solvents and show no evidence of aggregation in common org. solvents such as chloroform, DCM, THF, etc. with a split intense Q band between 670 and 690 nm for the mPEG-Pc polymers, and a single Q band at 682 nm for the mPEG-CuPc complexes. The UV-Vis spectra of these polymers in water demonstrate that dimeric complexes are formed in all cases with a minor contribution of monomeric also found in octa-substituted mPEG-CuPc products. More remarkably, the PEGylated (Cu)Pcs with different PEG chain lengths exhibit interesting tunable thermal properties as evidenced by differential scanning calorimetry (DSC).

Polymerization of long chain [meth]acrylates by Cu(0)-mediated and catalytic chain transfer polymerisation (CCTP): high fidelity end group incorporation and modification, Anastasaki, Athina; Waldron, Christopher; Nikolaou, Vasiliki; Wilson, Paul; McHale, Ronan; Smith, Timothy; Haddleton, David M., Polymer Chemistry (2013), 4(15), 4113-4119.

The Cu(0)-mediated polymn. of lauryl (C12) and stearyl (C18) acrylate is reported under a range of reaction conditions. Good first order kinetics, a linear evolution of no. av. mol. wt. (Mn) with conversion and dispersity (∼1.10) are obsd. The polymn. of lauryl acrylate proceeds either homogenously or in a self-generated biphasic system, depending on the solvent employed, with little deviation in overall polymn. control. The near quant. 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 analogs have also been prepd. by Co(ii) mediated catalytic chain transfer polymn. (CCTP). Reactive vinyl groups at the ω-chain end of poly(lauryl methacrylate) have been targeted with thioglycerol for nucleophilic thio-Michael addn. with quant. modification possible.

Copper-mediated controlled radical polymerization under biological conditions: SET-LRP in blood serum, Zhang, Qiang; Li, Zaidong; Wilson, Paul; Haddleton, David M. Chemical Communications (Cambridge, United Kingdom) (2013), 49(59), 6608-6610.

The polymn. of hydrophilic monomers is reported utilizing Cu(0)-mediated living radical polymn., SET-LRP. Highly active Cu(0) is formed in situ as a result of rapid disproportionation of [Cu(i)(Me6-Tren)Br] in serum. Disproportionation and homogeneous controlled radical polymn. (PDI 1.09-1.25) are performed for the first time in blood (sheep) serum.

Polymer Chemistry Rooftop reactions; Haddleton, David. M., Nature Chemistry (2013), 5(5), 366-368.

A review. Designing a mol. that acts as both an initiator for a photo-controlled radical polymn. and as a reactive end-group for polymer chain crosslinking has enabled the prepn. of polymeric gels whose properties can be controlled by exposure to sunlight.

Aqueous Copper-Mediated Living Polymerization: Exploiting Rapid Disproportionation of CuBr with Me6TREN, Zhang, Qiang; Wilson, Paul; Li, Zaidong; McHale, Ronan; Godfrey, Jamie; Anastasaki, Athina; Waldron, Christopher; Haddleton, David M., Journal of the American Chemical Society (2013), 135(19), 7355-7363.

A new approach to perform single-electron transfer living radical polymn. (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 addn. of both monomer and initiator. This provides an extremely powerful tool for the synthesis of functional water-sol. polymers with controlled chain length and narrow mol. wt. distributions (polydispersity index approx. 1.10), including poly(N-isopropylacrylamide), N,N-dimethylacrylamide, poly(ethylene glycol) acrylate, 2-hydroxyethyl acrylate (HEA), and an acrylamido glyco monomer. The polymns. are performed at or below ambient temp. with quant. conversions attained in minutes. Polymers have high chain end fidelity capable of undergoing chain extensions to full conversion or multiblock copolymn. via iterative monomer addn. after full conversion. Activator generated by electron transfer atom transfer radical polymn. of N-isopropylacrylamide in water was also conducted as a comparison with the SET-LRP system. This shows that the addn. sequence of L-ascorbic acid is crucial in detg. the onset of disproportionation, or otherwise. Finally, this robust technique was applied to polymns. under biol. relevant conditions (PBS buffer) and a complex ethanol/water mixt. (tequila).


The importance of ligand reactions in Cu(0)-mediated living radical polymerization of acrylates, Anastasaki, Athina; Waldron, Christopher; Wilson, Paul; McHale, Ronan; Haddleton, David M. Polymer Chemistry (2013), 4(9), 2672-2675.

Ligand mediated termination events occur during the homo-polymn. of Me (MA) and Bu (BA) acrylate under SET-LRP (Cu(0) mediated) conditions. Careful optimization of [initiator]/[ligand] (Me6Tren) ratios is required to reduce termination in order to achieve optimum polymn

Functionalized polymer additives for novel lubricating regimes, Anastasaki, Athina A.; Waldron, Christopher; Wilson, Paul; Haddleton, David M., Abstracts of Papers, 245th ACS National Meeting & Exposition, New Orleans, LA, United States, April 7-11, 2013 (2013), POLY-471.

Homo and block copolymers have been synthesized viaSingle Electron Transfer Living Radical Polymn. (SET-LRP) and Catalytic Chain Transfer Polymn. (CCTP). Base-mediated Michael Addn. and thio-bromo 'click' reactions have also been performed for further functionization, taking advantage of the excellent end-group fidelity that both SET-LRP and CCTP can provide.

Cu(0)-mediated living radical polymerizations, Waldron, Christopher; Haddleton, David M.; Wilson, Paul; Anastasaki, Athina, Abstracts of Papers, 245th ACS National Meeting & Exposition, New Orleans, LA, United States, April 7-11, 2013 (2013), POLY-316.

Herein, recent developments in Cu(0)-mediated radical polymn. from the Haddleton group will be presented

Sequence and polymer architecture control of glycopolymers with enhanced DC-SIGN recognition, Haddleton, David M.; Anastasaki, Athina; Wilson, Paul; Zhang, Qiang; Becer, Remzi, Atracts of Papers, 245th ACS National Meeting & Exposition, New Orleans, LA, United States, April 7-11, 2013 (2013), CARB-96.

The cointrol of glycopolymer arcitecture can improve recognition to appropriate lectins. We will be presenting the use of controlled radical polymn. (SET LRP) to give sequence control of sugar epitopes in polymers with controlled aritecture. This sequence control allows for the dialing in of sugar sequences for enhanced recognition. The use of appropriate initiators enable us to make glycopolymers available for conjugation to therapeutic petpides and proteins. In particular substitued maleimides show excellent insertion into disulfide bridges thus maintaining tertiary structure. The combination of these give a very powerful method for the synthesios and use of glycopolymers. This presentation will outline our recent work in this area designed to inhibit virius recogniton.

Dual-functional materials via CCTP and selective orthogonal thiol-Michael addition/epoxide ring opening reactions, McEwan, Kayleigh A.; Slavin, Stacy; Tunnah, Edward; Haddleton, David M. Polymer Chemistry (2013), 4(8), 2608-2614.

Poly(glycidyl methacrylate) (PGMA) was synthesized by cobalt catalyzed chain transfer polymn. (CCTP) yielding, in one step, polymers with two points for post polymn. functionalization: the activated terminal vinyl bond and in chain epoxide groups. Epoxide ring-opening and a combination of thiol-Michael addn. and epoxide ring-opening was used for post-functionalization with amines and thiols to prep. a range of functional materials

Sequence-Controlled Multi-Block Glycopolymers to Inhibit DC-SIGN-gp120 Binding, Zhang, Qiang; Collins, Jennifer; Anastasaki, Athina; Wallis, Russell; Mitchell, Daniel A.; Becer, C. Remzi; Haddleton, David M., Angewandte Chemie, International Edition (2013), 52(16), 4435-4439.

A series of glycomonomers were prepd. 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 mixt. 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. Polymn. reached over 90 % monomer conversion in six hours while maintaining a narrow mol. wt. distribution with increasing mol. wt. The obtained polymers were characterized by size exclusion chromatog. (SEC) and MALDI-TOF mass spectroscopy (MS) or high-resoln. electrospray ionization mass spectroscopy (HR-ESI MS), which indicated very high chain-end fidelity allowing for sequential monomer addn.

A detailed study on understanding glycopolymer library and Con A interactions, Gou, Yanzi; Geng, Jin; Richards, Sarah-Jane; Burns, James; Remzi Becer, C.; Haddleton, D. M., Journal of Polymer Science, Part A: Polymer Chemistry (2013), 51(12), 2588-2597.

Synthetic glycopolymers are important natural oligosaccharides mimics for many biol. applications. To develop glycopolymeric drugs and therapeutic agents, factors that control the receptor-ligand interaction need to be investigated. A library of well-defined glycopolymers has been prepd. by the combination of copper mediated living radical polymn. and CuAAC click reaction via post-functionalization of alkyne-contg. precursor polymers with different sugar azides. Employing Con A as the model receptor, we explored the influence of the nature and densities of different sugars residues (mannose, galactose, and glucose) on the stoichiometry of the cluster, the rate of the cluster formation, the inhibitory potency of the glycopolymers, and the stability of the turbidity through quant. pptn. assays, turbidimetry assays, inhibitory potency assays, and reversal aggregation assays. The diversities of binding properties contributed by different clustering parameters will make it possible to define the structures of the multivalent ligands and densities of binding epitopes tailor-made for specific functions in the lectin-ligand interaction.

Conjugation-Induced Fluorescent Labeling of Proteins and Polymers Using Dithiomaleimides, Robin, Mathew P.; Wilson, Paul; Mabire, Anne B.; Kiviaho, Jenny K.; Raymond, Jeffery E.; Haddleton, David M.; O'Reilly, Rachel K., Journal of the American Chemical Society (2013), 135(8), 2875-2878.

Dithiomaleimides (DTMs) with alkyl substituents are a novel class of highly emissive fluorophores. Variable soly. and further functionalization can easily be tailored through the choice of N and S substituents. Inclusion of a DTM unit into a ROP/RAFT initiator or insertion into the disulfide bond of salmon calcitonin (sCT) demonstrates the utility for fluorescent labeling of polymers and proteins. Simultaneous PEGylation and fluorescent labeling of sCT is also demonstrated, using the DTM unit as both a linker and a fluorophore. It is anticipated that DTMs will offer an attractive alternative to commonly used bulky, planar fluorophores.

Poly(azlactone)s: versatile scaffolds for tandem post-polymerisation modification and glycopolymer synthesis., Jones, Mathew W.; Richards, Sarah-Jane; Haddleton, David M.; Gibson, Matthew I., Polymer Chemistry (2013), 4(3), 717-723.

The synthesis of polymers with latent reactivity suitable for click' type modifications in a tandem post-polymn. modification process starting with poly(azlactone) precursors is investigated. Poly(azlactones), obtained by copper(i) mediated radical polymn., were functionalized in a one-pot process with amines bearing functional groups which are incompatible with controlled radical polymn.: alkynes, alkenes, furfuryl and phenol. The reaction is quant. and 100% atom efficient presenting an efficient route to clickable scaffolds without the need for protecting group chem. Addnl., the poly(azlactones) were exploited to obtain synthetic glycopolymers. The ring opening procedure introduces a 5-atom spacer between glycan and backbone, which provides improved access to carbohydrate-binding proteins with deep binding pockets, such as the cholera toxin, for anti-adhesion applications

Copper(0)-mediated radical polymerization in a self-generating biphasic system, Boyer, Cyrille; Atme, Amir; Waldron, Christopher; Anastasaki, Athina; Wilson, Paul; Zetterlund, Per B.; Haddleton, David; Whittaker, Michael R. Polymer Chemistry (2013), 4(1), 106-112.

Herein, we demonstrate the synthesis of well-defined poly(n-alkyl acrylate)s via copper(0)-mediated radical polymn. in a self-generating biphasic system. During the polymn. of Bu acrylate in DMSO, the polymer phase separates to yield a polymer-rich layer with very low copper content (ICP-MS anal.: 0.016 wt.%). The poly(Bu acrylate) has been characterized by a range of techniques, including GPC, NMR and MALDI-TOF, to confirm both the controlled character of the polymn. and the end group fidelity. Moreover, we have successfully chain extended poly(Bu acrylate) in this biphasic system several times with Bu acrylate to high conversion without intermediate purifn. steps. A range of other alkyl acrylates have been investigated and the control over the polymn. 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 sol. in the polar solvent