Activators Regenerated by Electron Transfer for Atom‐Transfer Radical Polymerization of (Meth)acrylates and Related Block Copolymers (2006)

Staying active: The title method allows continuous and controlled polymerization with significantly less Cu catalyst than is required for conventional atom-transfer radical polymerization (as low as 10−3 mol % vs. monomer). The CuI activator is constantly regenerated by a reducing agent, which compensates for any loss of CuI as a result of radical termination reactions (see scheme). Atom-transfer radical polymerization (ATRP) is a controlled or living radical polymerization (CRP) technique1, 2 that enables the preparation of new nanostructured materials that are not accessible by conventional free-radical polymerization (FRP). Reported herein is the ATRP of polar monomers such as (meth)acrylates and related block copolymers by means of a new initiating/catalytic method based on activators regenerated by electron transfer (ARGET) with ppm (10−4 mol % vs. monomer) amounts of Cu catalyst.3 ATRP4–7 provides a simple route to many well-defined (co)polymers with precisely controlled functionalities, topologies, and compositions.8–10 It has been very successfully applied to the preparation of many nanocomposites, hybrids, and bioconjugates.11–23 The advantages of ATRP, in comparison with other CRP processes, include the large range of available monomers and (macro)initiators, the simplicity of reaction setup, and the ability to conduct the process over a large range of temperatures, solvents, and dispersed media.6, 7, 24 ATRP (Scheme 1) is a repetitive atom-transfer process between a macromolecular alkyl halide PnX and a redox-active transition-metal complex CuIX/ligand in which Pn. radicals propagate (rate constant of propagation kp) and are reversibly formed (rate constants ka and kda). The growing radicals also terminate by coupling or disproportionation (rate constant kt). Mechanism for ATRP. An inherent feature, but also a limitation of ATRP, is the presence of a catalyst (a transition-metal complex with various ligands). The catalyst is not bound to the end of the chain, as it is in coordination polymerization, and can therefore be used in a controlled or living process with substoichiometric amounts with respect to the initiator. Nevertheless, it is typically used at concentrations ranging from 0.1 to 1 mol % with respect to the monomer and therefore needs to be removed from the final polymer. There have been several attempts to remove and recycle the catalyst efficiently by extraction, precipitation, immobilization, or by using biphasic systems.24–30 However, there is always some loss of polymerization control in biphasic systems or added cost associated with catalyst preparation. Thus, another approach to reduce the amount of ATRP catalyst, while preserving a similar reaction rate, is to enhance the rate of activation significantly (augmenting the equilibrium constant by increasing the ka/kda ratio; Scheme 1). Indeed, CuBr complexed by tetradentate ligands such as tris[2-(dimethylamino)ethyl]amine (Me6TREN) and tris(2-pyridylmethyl)amine (TPMA) is 103–105 times more active than the originally used CuBr/bipyridine complexes.31–35 However, the catalyst concentration can not simply be reduced by 103 (from a concentration equimolar with the initiator (i.e., 1 mol % vs. monomer) to 10 ppm vs. monomer) owing to the radical termination and concurrent irreversible oxidation of the catalyst (CuI to CuII). All CuI species would be converted to CuII when less than 1 % of the growing chains terminate. Furthermore, some impurities, such as oxygen or various radical inhibitors, deactivate these minute amounts of very active catalyst, and thus stringent purification methods and procedures similar to those used in ionic polymerizations are required. These limitations can be overcome by the addition of an appropriate reducing agent, such as tin(II) 2-ethylhexanoate (Sn(EH)2), which has been approved by the Food and Drug Administration (FDA), or sugars such as glucose. The Sn(EH)2 reductant can reduce the CuII species that accumulate when radicals irreversibly terminate to restore the original CuI state needed for activation (Scheme 2). In this process, the activators are continuously regenerated by electron transfer (ARGET). Mechanism for ARGET ATRP: The CuI activator is constantly regenerated by environmentally acceptable reducing agents (e.g. FDA-approved compounds, sugars etc.), which compensate for any loss of CuI as a result of radical termination. Furthermore, the process can be started with the oxidatively stable CuII species, which can be reduced in situ to the CuI state as in a previously reported AGET process (activators generated by electron transfer).36, 37 However, in AGET ATRP, the oxidatively stable CuII catalyst, present at a considerably higher concentration (>0.1 mol % vs. monomer), was reduced with nearly stoichiometric amounts of ascorbic acid or Sn(EH)2. Other reducing agents were previously used to accelerate ATRP, but the concentration of copper catalyst was always very high, essentially equal to that of the initiator.38–41 In the ARGET system, a tiny amount of Cu catalyst is used together with a sufficiently large excess of reducing agent, which not only reduces CuII to CuI but is also responsible for scavenging oxygen and radical inhibitors. The concentration of the reducing agent and related rate of reduction can greatly influence the ARGET ATRP. Herein, we report the optimized conditions for the studied system; investigations of different reducing agents and rates of reduction will be presented elsewhere. ARGET provides a real breakthrough in ATRP since the repetitive reduction cycle enables the amount of catalyst to be decreased significantly (down to single digit ppm vs. monomer). For some applications, ARGET could even allow the residual copper to be left in the final, colorless products. We have recently reported that ARGET ATRP of styrene with 10 ppm CuCl2/Me6TREN catalyst in the presence of an excess of Sn(EH)2 was well controlled and gave polymers with low polydispersities (Mw/Mn<1.2) and molecular weights that agreed excellently with theoretical values.3 Control of the molecular weight was also good even with 1 ppm Cu, but the polydispersities were higher (Mw/Mn≈1.6), which indicated that there was not enough Cu to assure fast exchange between active and dormant species. Herein, we present results of ARGET ATRP of n-butyl acrylate (nBA) and methyl methacrylate (MMA). These systems are more challenging, since the more polar acrylates coordinate more strongly to Cu42, 43 than does styrene, which could potentially affect the catalyst performance. Table 1 presents the experimental conditions and properties of poly(n-butyl acrylate) (PnBA) prepared by ARGET ATRP. The polymerization of nBA was initiated by ethyl 2-bromoisobutyrate (EtBrIB), and a final molecular weight Mn=20 000 g mol−1 was targeted. A constant amount (10 mol % vs. initiator; 0.07 mol % vs. monomer) of Sn(EH)2 and variable concentrations of the Cu-based catalyst with Me6TREN and TPMA as ligands were employed. The amount of copper was varied from 500 down to 2 ppm vs. monomer (Table 1). Entry[a] Cu[c] [ppm] t [min] Conv. [%] Mn,theo[d] [g mol−1] Mn,GPC [g mol−1] Mw/Mn 1 500 1210 97 19 400 19 600 1.18 2 50 370 91 18 100 19 400 1.26 3 10 360 90 17 900 19 100 1.40 4 2 1150 97 19 500 24 400 2.48 5[b] 50 1320 71 14 300 15 100 1.16 6[b] 10 1320 84 16 800 19 300 1.33 7[b] 2 1260 88 17 600 23 500 1.56 Figure 1 presents the evolution of the molecular weights and polydispersities with conversion for polymerization of nBA with 50 ppm CuCl2/Me6TREN catalyst. Control of the molecular weight was excellent according to theoretical values based on quantitative initiation. However, with 2 ppm Cu catalyst, the molecular weights and polydispersities were higher (Table 1, entry 4), which indicates that there was not enough Cu to assure fast exchange between active and dormant species. Molecular weights and polydispersities of poly(n-butyl acrylate) and poly(methyl methacrylate) as a function of degree of conversion of (▪) nBA and (•) MMA. Experimental conditions for nBA are given in Table 1, entry 2 and for MMA in Table 2, entry 1. Better results were obtained with the TPMA ligand, which binds more strongly to Cu than does Me6TREN44, 45 (Table 1, entries 5–7). Although TPMA forms slightly less active complexes than Me6TREN,32, 34, 46 better control over polymerization was observed. This observation can be ascribed to a higher real concentration of Cu species in the system, since TPMA binds more strongly to Cu. ARGET ATRP of nBA was also carried out in the presence of glucose (an organic reducing agent). Under conditions similar to those presented in Table 1, entry 5 (nBA/EtBrIB/CuCl2/TPMA/glucose = 160/1/0.0078/0.03/0.1; 50 ppm Cu vs. monomer; t=2640 min; T=80 °C, in 20 % v/v anisole), PnBA was formed in 48 % yield with Mn=10 500 g mol−1 and Mw/Mn=1.47 (Mn,theo=9 600 g mol−1). Table 2 presents the experimental conditions and properties of poly(methyl methacrylate) (PMMA) prepared by ARGET ATRP. Ethyl α-bromophenylacetate (EtBPA) was used as initiator and TPMA as a ligand. As in the case of nBA, MMA was polymerized by ARGET ATRP with varied amounts of Cu catalyst. The molecular weight and polydispersity of the polymer with 50 ppm Cu catalyst as a function of degree of conversion are shown in Figure 1. Figure 2 shows a kinetic plot and the evolution of the molecular-weight distribution with polymerization (2 ppm Cu catalyst). The molecular weight was well controlled; a gradual increase in the molecular-weight distribution was observed, and the final polydispersity was relatively low (Mw/Mn=1.36). a) Kinetic plot and b) evolution of GPC traces during ARGET ATRP of MMA. Experimental conditions are given in Table 2, entry 3. Entry[a] Cu[b] [ppm] t [min] Conv. [%] Mn,theo[c] [g mol−1] Mn,GPC [g mol−1] Mw/Mn 1 50 360 70 14 000 19 300 1.16 2 10 370 61 12 200 15 900 1.34 3 2 335 66 13 300 15 300 1.36 The new system was also successfully applied to the synthesis of block copolymers PnBA-b-PS and PS-b-PnBA (PS=polystyrene). Initially a PnBA block was prepared by using ARGET ATRP of nBA with 50 ppm Cu complex (Mn,GPC=19 400 g mol−1, Mn,theo=18 100 g mol−1, Mw/Mn=1.26), and then it was used as a macroinitiator. Chain extension of the PnBA macroinitiator with styrene by ARGET ATRP with 15 ppm Cu catalyst was very efficient (Mn,GPC=34 900 g mol−1, Mn,theo=37 000 g mol−1, Mw/Mn=1.18). Figure 3 presents the size-exclusion chromatography (SEC) traces recorded after each step. The reactions were well controlled, as evidenced by the monomodal gel-permeation chromatography (GPC) traces. PS macroinitiator, also prepared by ARGET ATRP with 15 ppm Cu catalyst (Mn,GPC=17 100 g mol−1, Mn,theo=15 300 g mol−1, Mw/Mn=1.18) was chain extended with nBA (50 ppm Cu catalyst) to provide a block copolymer with Mn,GPC=26 300 g mol−1 (Mn,theo=28 900 g mol−1) and Mw/Mn=1.33. GPC traces after each step of the synthesis of block copolymers PS-b-PnBA (top) and PnBA-b-PS (bottom). Experimental conditions for the polymerization of nBA: nBA/EtBrIB/CuII/Me6TREN/Sn(EH)2=160/1/0.0078/0.1/0.1; [nBA]0=5.88 M, Cu catalyst: 50 ppm vs. monomer, T=60 °C, in anisole (20 % v/v vs. monomer). Experimental conditions for polymerization of styrene: styrene/PnBA/CuCl2/Me6TREN/Sn(EH)2=200/1/0.003/0.1/0.1; [styrene]0=5.82 M, Cu catalyst: 15 ppm vs. monomer, T=110 °C, in anisole (50 % v/v vs. monomer). In summary, we report the successful polymerization of the polar monomers n-butyl acrylate and methyl methacrylate by ARGET ATRP with ppm quantities of Cu catalyst. Better control was obtained with TPMA as a ligand which binds to copper more strongly than does Me6TREN. The new ARGET system was also successfully applied to the efficient synthesis of styrene and n-butyl acrylate block copolymers. It is anticipated that ARGET ATRP will facilitate the commercial application of ATRP and simplify the preparation of many new materials, including molecular hybrids, bioconjugates, and nanocomposites. Styrene (Aldrich, 99 %), n-butyl acrylate (nBA) (Acros, 99+ %), and methyl methacrylate (MMA) (Acros, 99 %) were passed through a column filled with neutral alumina, dried over calcium hydride, and distilled under reduced pressure. Tris[2-(dimethylamino)ethyl]amine (Me6TREN),31 tris(2-pyridylmethyl)amine (TPMA)47 were synthesized following previously reported procedures. Ethyl 2-bromoisobutyrate (EtBrIB) (Acros, 98 %), ethyl α-bromophenylacetate (EtBrPA) (Aldrich, 97 %), copper(II) chloride (Acros, 99 %), tin(II) 2-ethylhexanoate (Sn(EH)2) (Aldrich), and anisole (Aldrich, 99 %) were used as received. General procedure for ARGET ATRP of nBA, (targeted number-average degree of polymerization (DPn)=160; 50 ppm Cu catalyst): Degassed nBA (5.0 mL, 35 mmol) and anisole (0.5 mL) were transferred via degassed syringes to a dry, nitrogen-purged Schlenk flask, and the Cu complex (CuCl2 0.24 mg, 0.18×10−2 mmol; Me6TREN 0.51 μL, 0.18×10−2 mmol) in degassed anisole (0.5 mL) was added. The resulting mixture was stirred for 10 minutes, and then a purged solution of Sn(EH)2 (7.29 μL, 2.2×10−2 mmol) and Me6TREN (5.8 μL, 2.2×10−2 mmol) in anisole (0.5 mL) was added. EtBrIB (32.4 μL, 22.1×10−2 mmol) was added to initiate the polymerization. An initial sample was taken, and the sealed flask was placed in an oil bath at 60 °C. Samples were taken at timed intervals and analyzed by gas chromatography (GC) and gel-permeation chromatography (GPC) to follow the progress of the reaction. The polymerization was stopped after 6.2 h (Mn,GPC=19 400, Mw/Mn=1.26, conversion=91 %) by opening the flask and exposing the catalyst to air. Synthesis of diblock copolymer PnBA-b-PS by ARGET ATRP: A PnBA macroinitiator (Mw=19 400, Mw/Mn=1.26, 2.35 g, 0.12 mmol) was dissolved in styrene monomer (2.75 mL, 24.0 mmol) in a 25-mL Schlenk flask and bubbled with nitrogen for 15 minutes. Next, a solution of Cu complex (CuCl2 4.84×10−2 mg, 0.36×10−3 mmol; Me6TREN 0.10 μL, 0.36×10−3 mmol) in degassed anisole (0.7 mL) was added. The resulting mixture was stirred for 10 minutes, and then a purged solution of Sn(EH)2 (3.9 μL, 1.2×10−2 mmol) and Me6TREN (3.2 μL, 1.2×10−2 mmol) in anisole (0.7 mL) was added. An initial sample was taken and the sealed flask was placed in an oil bath at 110 °C. Samples were taken at timed intervals and analyzed by GC and GPC. The polymerization was stopped after 30.8 h (Mn,GPC=34 900, Mw/Mn=1.18, conversion=88 %) by opening the flask and exposing the catalyst to air. Analysis: Molecular weight and polydispersity were determined by GPC (Waters 515 pump and Waters 2414 differential refractometer, PSS columns (Styrogel 105, 103, 102 Å), THF eluent, T=35 °C, flow rate=1 mL min−1). Linear polystyrene and poly(methyl methacrylate) standards were used for calibration. The conversion of the monomers was determined by using a Shimadzu GC 14-A gas chromatograph (FID detector, J&W Scientific 30 m DB WAX Megabore column, anisole internal standard). The injector and detector temperatures were kept constant at 250 °C. The analysis was carried out isothermally at 60 °C for 2 min, and then the temperature was increased to 140 °C at a rate of 40 °C min−1 and held at 140 °C for 2 min. The degree of conversion was calculated by measuring the decrease of the peak area of the monomer relative to the peak areas of the standards.