Virus-glycopolymer conjugates by copper(I) catalysis of atom transfer radical polymerization and azide-alkyne cycloaddition

The Cu(I)-catalyzed ATRP and azide-alkyne cycloaddition reactions together provide a versatile method for the synthesis of end-functionalized glycopolymers and their attachment to a suitably modified viral protein scaffold.     

Identification and characterization of monoanionic tripodal tetradentate ligand complexes of copper(I) and copper(II) involved in halogen atom transfer reactions

The copper(I) complex of bis-(2-(2-pyridyl)-ethyl)-(2-(N-p-toluenesulfonamido)-ethyl)amine (PETAEA), a monoanionic, tripodal tetradentate ligand, was prepared, characterized, and shown to be an effective catalyst for atom transfer radical polymerization (ATRP). A model atom transfer reaction of Cu(PETAEA) with 1-phenylethyl bromide and TEMPO radical trapping agent was studied. The copper(II) complex formed in this reaction was identified by comparison of its spectroscopic data with that of Cu(PETAEA)Br prepared by an independent synthesis. Kinetic and spectroscopic data indicated that the reaction mechanism involved simple atom transfer from the alkyl halide to the Cu(PETAEA) to form the Cu(PETAEA)Br, and no other intermediates were involved. The solid-state structures of the copper(I) and (II) complexes appeared to be maintained in solution, so this system is an atom transfer reaction in which all of the reactive species are identified and characterized.     

Pd(DPEPhos)Cl2-catalyzed Negishi cross-couplings for the formation of biaryl and diarylmethane phloroglucinol adducts

Several functionalized biaryls and diarylmethanes containing the phloroglucinol subunit were synthesized in 55-85% yields using Negishi cross-couplings of 2,4,6-trimethoxyphenylzinc chloride with aryl and benzyl halides in the presence of catalytic quantities of Pd(DPEPhos)Cl₂. These simple to prepare couplings were generally complete in 1-24 h depending on the halide, and were applicable to aryl and benzyl halides containing both electron-donating and electron-withdrawing groups.     

Reverse atom transfer radical polymerisation (RATRP) of methacrylates using copper(I)/pyridinimine catalysts in conjunction with AIBN

N-n-Propyl-2-pyridylmethanimine, 1, N-n-octyl-2-pyridylmethanimine, 2, N-n-lauryl-2-pyridylmethanimine, 3, and N-n-octadecyl-2-pyridylmethanimine, 4 have been used in conjunction with copper(II) bromide and azo initiators for the reverse atom transfer radical polymerisation of a range of methacrylates. AIBN to Cu^IIBr₂ ratios of 0.5:1, 0.75:1 and 1:1 give PMMA with M_n 11 500 g mol⁻¹ (PDi = 1.24) (at 22% conversion), 12 500 g mol⁻¹ (PDi = 1.06) (at 83% conversion) and 10 900 g mol⁻¹ (PDi = 1.11) (at 84% conversion), respectively. A Cu^IIBr₂ complex is demonstrated to be needed at the start of the reaction for good control over molecular weight and polydispersity as reactions using Cu(I)Br as catalyst yielded PMMA of M_n 31 000 g mol⁻¹ (PDi = 2.90), reactions with no copper yield PMMA of M_n 33 000 g mol⁻¹ (PDi = 2.95). The RATRP of styrene was carried out using Cu^IIBr₂ as catalyst. AIBN to Cu^IIBr₂ ratio of 0.5:1, 0.75:1 and 1:1 gave PS with M_n = 12 400 g mol⁻¹ (PDi = 1.27) at low conversion, M_n = 15 500 g mol⁻¹ (PDi = 1.11) and 12 400 g mol⁻¹ (PDi = 1.38), respectively at ∼85% conversion. A series of block copolymers of MMA with BMA, BzMA and DMEAMA (15 600 g mol⁻¹ (PDi = 1.18), 13 300 g mol⁻¹ (PDi = 1.14) 15 300 g mol⁻¹ (PDi) = 1.16), using a PMMA macroinitiator were prepared. Emulsion polymerisation of MMA using [initiator]:[Cu^(II)Br₂] ratio = 0.5:1 with Brij surfactant gave a linear increase of M_n with respect to conversion, final M_n = 112 800 g mol⁻¹ (PDi = 1.42). Further reactions were carried out with [initiator]:[Cu^(II)Br₂] ratio = 0.75:1 and 1:1. Both giving PMMA with M_n ∼ 32 000 g mol⁻¹ (PDi ∼ 2.4). These reactions exhibit no control, this is because the azo initiator is present in excess and all of the monomer is consumed by a free radical polymerisation as opposed to a controlled reaction. Particle size analysis (DLS) showed the particle size between 160 and170 nm in all cases.     

Synthesis,characterization, and polymerization activity of [bis(4,4'-bis(neophyldimethylsilylmethyl)-2,2'-bipyridyl)copper(I)]+CuBr2- and Implications for copper(I) catalyst structures in atom transfer radical polymerization

A series of 4,4'-disilyl-substituted-2,2'-bipyridine ligands were prepared using a metathesis reaction of the dianion of 4,4'-dimethyl-2,2'-bipyridine with several trialkylsilyl chlorides: 4,4'bis(tert-butyldimethylsilylmethyl)-2,2'-bipyridine (dTBDMSbipy), 4,4'-bis(dimethylthexylsilylmethyl)-2,2'-bipyridine (dTHEXbipy), and 4,4'-bis(neophyldimethylsilylmethyl)-2-2'-bipyridine (dNEObipy). It was observed that the side chain length correlated with the ability of the ligand to form hydrocarbon soluble complexes of copper(I) bromide, with dNEObipy forming the most soluble and easily crystallized complexes. The atom transfer radical polymerization (ATRP) of styrene using dNEObipy as the ligand displayed molecular weight control equivalent to other ATRP systems in which solubilizing ligands, such as 4,4'-di-5-nonyl-2,2'-bipyridine or 4,4'-di-n-heptyl-2,2'-bipyridine, were used. The one-to-one complex of dNEObipy with CuBr was prepared and its crystal structure was determined. The resulting complex had the ionic formulation [(dNEObipy)2Cu]+[CuBr2]- and displayed similar activities in styrene ATRP as the standard 2 dNEObipy/CuBr catalyst system. These and other polymerization results in addition to NMR experiments suggest that the predominant copper(I) species formed in ATRP solutions is the 2-to-1 ligand-to-copper(I) cation, [(dNEObipy)2Cu]+, with either a dihalocuprate or halide counteranion, depending upon the conditions.     

Towards the development of highly active copper catalysts for atom transfer radical addition (ATRA) and polymerization (ATRP)

Fundamentals of copper catalyzed atom transfer radical addition (ATRA) and mechanistically similar polymerization (ATRP) were discussed. Special emphasis was placed on structural characterization and electrochemical properties of copper complexes. Recent advances in the development of highly active copper complexes for both processes were also reviewed. It was found that electron-donating groups (methoxy and methyl in the 4 and 3,5 positions, respectively) of the pyridine rings in tris(2-pyridylmethyl)amine (TPMA) ligand, significantly increase the catalytic activity in copper mediated ATRA/ATRP.     

Atom transfer radical polymerization of methyl methacrylate by copper(I)‐pyridine‐2‐carboximidate catalysts

Pyridine‐2‐carboximidates [methyl ( 1a ), ethyl ( 1b ), isopropyl ( 1c ), cyclopentyl ( 1d ), cyclohexyl ( 1e ), n‐octyl ( 1f ), and benzyl ( 1g )] were prepared from the reaction of 2‐cyanopyridine with the corresponding alcohols. Cyclopentyl‐substituted 1d was found to be a highly effective ligand for copper‐catalyzed atom transfer radical polymerization (ATRP) of methyl methacrylate (MMA). For example, the observed rate constant for a CuBr/ 1d catalytic system was found to be nearly twice as high as the cyclohexyl‐substituted CuBr/ 1e catalytic system [k_obs = (1.19 vs 0.56) × 10^?4 s^?1). The effects of the solvents, temperature, catalyst/initiator, and solvent/monomer ratio on the ATRP of MMA were studied systematically for the CuBr/ 1d catalytic system. The optimum condition for the ATRP of MMA was found to be a 1:2:1:400 [CuBr]_o/[ 1d ]_o/[ethyl 2‐bromoisobutyrate]_o/[MMA]_o ratio at 60 °C in veratrole solution, which yielded well‐defined poly(MMA) with a narrow molecular weight distribution of 1.14. The catalytically active copper complex 2d was isolated from the reaction of CuBr with 1d . Narrow molecular weight distributions as low as 1.06 were achieved for the CuBr/ 1d catalytic system by employing 10% of the deactivator CuBr₂. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 2747–2755, 2004     

Photoinitiated ambient temperature copper-catalyzed atom transfer radical addition (ATRA) and cyclization (ATRC) reactions in the presence of free-radical diazo initiator (AIBN)

The use of UV light in copper-catalyzed atom transfer radical addition (ATRA) and cyclization (ATRC) reactions of various (poly)halogenated compounds to highly active alkenes in the presence of AIBN is reported. Radicals generated from photodecomposition of AIBN efficiently regenerated the copper(I) complex at ambient temperature enabling ATRA of CCl(4) and CBr(4) with catalyst loadings as low as 0.05 mol-%. The desired monoadduct was obtained in lower yields in the ATRA of less active halogenated compounds, which was mostly due to incomplete alkene conversions. Ambient temperature ATRA of CCl(4) to various 1,6-dienes followed by sequential ATRC was also performed in the presence of UV light using [Cu(II)(TPMA)Cl][Cl] complex and AIBN. High yields of the 5-exo-trig cyclic product were obtained for all dienes with preferential formation of the cis isomer.     

Copper-catalyzed atom transfer radical addition (ATRA) and cyclization (ATRC) reactions in the presence of environmentally benign ascorbic acid as a reducing agent

In recent years, copper-catalyzed atom transfer radical addition (ATRA) has emerged as a viable organic procedure for the formation of carbon-carbon bonds starting from alkyl halides and alkenes. Studies have primarily focused on the use of free-radical initiators to regenerate the copper(I) complex or activator in situ. Although these initiators led to a significant decrease in the amount of metal catalyst, they were much less effective for highly active alkenes that readily undergo free-radical polymerization. In this study, the non-radical reducing agent ascorbic acid (commonly known as Vitamin C) was effectively employed resulting in TONs as high as 15,200 in the homogenous ATRA of polyhalogenated compounds to α-olefins, and enabling selective monoadduct formation for highly active alkenes such as acrylonitrile (TONs as high as 11,800). As low as 7-20 mol% of ascorbic acid relative to substrate was sufficient for all ATRA and ATRC reactions examined. Further, product isolations for all selected syntheses were quite facile and nearly quantitative, requiring only simple liquid-liquid extraction techniques. Reactions in the presence of ascorbic acid were also examined kinetically via (1)H NMR and UV/Vis spectroscopy. A half order rate dependence on reducing agent concentration was observed, but the first order kinetic plots became nonlinear as the concentration of ascorbic acid was increased. Finally, the use of ascorbic acid circumvented otherwise necessary purging techniques, successfully furthering the utility of these reactions in organic synthesis.     

A domino desulfitative coupling and decarboxylative coupling of 3, 4-dihydropyrimidine-2-thiones with copper(I) carboxylates

A novel and general carbon-nitrogen and carbon-carbon cross-coupling reaction between 3,4-dihydropyrimidine-2-thiones and copper(I) carboxylates were performed in the presence of palladium acetate. The copper(I) carboxylates act not only as desulfurative reagents but also as sources of carbon nucleophiles. A wide array of highly substituted and functionalized pyrimidines scaffolds were synthesized in good yields.     

Atom transfer radical addition in the presence of catalytic amounts of copper(I/II) complexes with tris(2-pyridylmethyl)amine

Highly efficient atom transfer radical addition of polyhalogenated compounds to alkenes catalyzed by copper(I/II) complexes with tris(2-pyridylmethyl)amine in the presence of a radical initiator [2,2'-azobis(2-methylpropionitrile)] was reported.     

Characterization and optimization of poly(glycidyl methacrylate-co-styrene) synthesized by atom transfer radical polymerization

Styrene (S) and glycidyl methacrylate (GMA) copolymers were synthesized by atom transfer radical polymerization (ATRP) under different conditions. The effect of initiators, ligands, solvents, and temperature to the linear first-order kinetics and polydispersity index (PDI) was investigated for bulk polymerization. First-order kinetics was observed between linearly increasing molecular weight versus conversion and low polydispersities (PDI) were achieved for ethyl 2-bromo isobutyrate (EBiB) as an initiator and N,N′,N′,N″,N″-pentamethyldiethylenetriamine (PMDETA)/CuBr as a catalyst. The copolymers with different compositions were synthesized using different in-feed ratios of monomers. Copolymers composition was calculated from ¹H NMR spectra which were further confirmed by quantitative ¹³C{¹H} NMR spectra. The monomer reactivity ratios were obtained with the help of Mayo-Lewis equation using genetic algorithm method. The values of reactivity ratios for glycidyl methacrylate and styrene monomers are r_G = 0.73 and r_S = 0.42, respectively.     

Living radical polymerization. II. Improved atom transfer radical polymerization of acrylamide in aqueous glycerol media with a novel pentamethyldiethylenetriamine‐based soluble copper(I) complex catalyst system

An improved atom transfer radical polymerization (ATRP) of acrylamide was achieved in a glycerol/water (1:1 v/v) medium with 2‐halopropionamide initiators, CuX (X = Cl or Br) as catalysts, pentamethyldiethylenetriamine (PMDETA) as a ligand, and CuX₂ (≥20 mol % CuX) and excess alkali halide (ca. 1 mol/dm³) as additives. The first‐order kinetic plots for the disappearance of the monomer at 130 °C were linear; this was a significant improvement over the results obtained earlier with the bipyridine ligand. However, even under such improved situations, about 7 mol % of the polymer chains were estimated to be formed dead. The polydispersity index was approximately 1.5. At a lower temperature (ca. 90 °C), a lower polydispersity index (1.24) was obtained for the bromide‐based initiating system. Chain‐extension experiments proved the living nature of the polymers. The presence of both extra halide ions and the monomer was necessary to take the CuX–PMDETA complex into solution. It was suggested that the soluble Cu(I) complex was formed with one PMDETA molecule acting as a monodentate ligand and with two halide ions and one acrylamide molecule occupying the other three coordination sites. Some support for the involvement of all three ligands (X^?, PMDETA, and acrylamide) in the complex formation was obtained from ultraviolet–visible spectroscopy studies. The better ATRP with the PMDETA ligand was attributed to the better stability and lesser hydrolysis of the 1:1 Cu⁺²/PMDETA complex with respect the corresponding bipyridine complex. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 2483–2494, 2004     

Synthesis of poly(2‐hydroxyethyl methacrylate) in protic media through atom transfer radical polymerization using activators generated by electron transfer

Atom transfer radical polymerization (ATRP) using activators generated by electron transfer (AGET) was investigated for the controlled polymerization of 2‐hydroxyethyl methacrylate (HEMA) in a protic solvent, a 3/2 (v/v) mixture of methyl ethyl ketone and methanol. The AGET process enabled ATRP to be started with an air‐stable Cu(II) complex that was reduced in situ by tin(II) 2‐ethylhexanoate. The reaction temperature, Cu catalysts with different ligands, and variation of the initial concentration ratio of HEMA to the initiator were examined for the synthesis of well‐controlled poly(2‐hydroxyethyl methacrylate) and a poly(methyl methacrylate)‐b‐poly(2‐hydroxyethyl methacrylate) block copolymer. The level of control in AGET ATRP was similar to that in normal ATRP in protic solvents, and this resulted in a linear increase in the molecular weight with the conversion and a narrow molecular weight distribution (weight‐average molecular weight/number‐average molecular weight < 1.3). © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 3787–3796, 2006     

Cu(i)-catalyzed atom transfer radical cyclization of trichloroacetamides tethered to electron-deficient, -neutral, and -rich alkenes: synthesis of polyfunctionalized 2-azabicyclo[3.3.1]nonanes

A novel synthetic entry to 2-azabicyclo[3.3.1]nonanes based on a copper(i)-catalyzed intramolecular coupling of amino-tethered trichloroacetamides and unsaturated nitriles, esters and alkenes, as well as enol acetates, is described. A study of the reaction conditions and the scope of the process is reported.     

Synthesis and characterization of poly(phenylene oxide) graft copolymers by atom transfer radical polymerizations

A series of comb-like poly(phenylene oxide)s (PPO) graft copolymers with controlled grafting density and length of grafts were synthesized by atom transfer radical polymerization (ATRP). The α-bromo-poly(2,6-dimethyl-1,4-phenylene oxide)s (BPPO) were used as macroinitiators to polymerize vinyl monomers and the graft copolymers carrying polystyrene (PS), poly(p-acetoxystyrene) (PAS), and poly(methyl methacrylate) (PMMA) as side chains were synthesized and characterized by NMR, FTIR, GPC, DSC and TGA. The composition-dependent glass-transition temperatures (T_g) of PPO-g-PS exhibited good correlation with theoretical curve in Couchman equations except for the cases of low PS content (<40 mol%) copolymers in which a positive deviation was observed due to enhanced molecular interactions. The increase in monomer/initiator ratio led to the increase of degree of polymerization and the decrease of polydispersity. Despite the immiscibility nature between PPO and PMMA, the PPO-g-PMMA exhibited enhanced compatibilization as apparent single T_g in a wide temperature window throughout various compositions revealing an efficient segmental mixing on a molecular scale due to grafting structure.     

Solvent-free synthesis and purification of poly[2-(dimethylamino)ethyl methacrylate] by atom transfer radical polymerization

Solvent-free synthesis of well-defined poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) (co)polymers was performed by atom transfer radical polymerization conducted under very mild conditions (in bulk at 25 degrees C). The pH-dependence and the thermo-responsive behaviour of PDMAEMA in aqueous solution were operated to isolate and purify the (co)polymers without using any organic solvent or further catalyst extraction. The viscosity in aqueous solution of so-purified PDMAEMA homopolymers and their block copolymers with poly(ethylene glycol) (PEG) was studied as a function of molar mass and concentration and a typical polyelectrolyte behaviour was observed, these catalyst-deprived polycations are able to form stable and non toxic complexes with DNA, showing good transfection efficacies in gene therapy.     

The importance of the nature of initiator and solvent in atom transfer radical polymerization of methyl methacrylate catalyzed by copper(I) N‐alkyl‐2‐pyridylmethanimine complexes

The effect of the nature of initiator and solvent in atom transfer radical polymerization of methyl methacrylate (MMA) using N‐pentyl‐2‐pyridylmethanimine as the ligand in the presence of Cu(I)Br has been investigated. Under identical concentration and temperature conditions, p‐toluenesulfonyl chloride (p‐TsCl) in diphenyl ether gives polymerization rates identical to ethyl 2‐bromoisobutyrate in xylene. However, the former system induces better control of molecular weights and lower polydispersities.     

Initiator‐free atom transfer radical polymerization of methyl methacrylate based on FeBr3(PPh3)n system

A tricomponent system, constituting monomer (methyl methacrylate, MMA), higher oxidation state transition‐metal catalyst (FeBr₃) and a ligand (triphenylphosphine, PPh₃), MMA/FeBr₃/PPh₃ system without external initiator (alkyl halide) has been studied extensively with different spectroscopic analyses. To figure out the mechanism, a series of explicit model reactions were conducted with a molar ratio of [MMA]₀/[FeBr₃]₀/[PPh₃]₀ = 200/1/n (n = 0.1–3.0) at 80 °C, and the corresponding polymerization behaviors were investigated. Combined with theoretical deduction and spectroscopic evidences, the composition of the in‐situ generated initiators was gradually confirmed, which were redox products of FeBr₃ and PPh₃. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 3842–3850