ATRP Synthesis of Amphiphilic Random, Gradient, and Block

Biomacromolecules 2003, 4, 1386-1393

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ATRP Synthesis of Amphiphilic Random, Gradient, and Block Copolymers of 2-(Dimethylamino)ethyl Methacrylate and n-Butyl Methacrylate in Aqueous Media Sang Beom Lee,†,‡ Alan J. Russell,† and Krzysztof Matyjaszewski*,‡ Department of Chemical and Petroleum Engineering & Center for Biotechnology and Bioengineering, 1249 Benedum Hall, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, and Center for Macromolecular Engineering, Department of Chemistry, 4400 Fifth Avenue, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213 Received April 25, 2003; Revised Manuscript Received May 22, 2003

Amphiphilic random, gradient, and block copolymers of 2-(dimethylamino)ethyl methacrylate (DMAEMA) and n-butyl methacrylate (BMA) were synthesized by atom transfer radical polymerization (ATRP) in water/ 2-propanol mixtures using a methoxy-poly(ethylene glycol) (MPEG) (Mn ) 2000) macroinitiator. Kinetic studies indicate that the copolymerization is well controlled with molecular weights increasing linearly with conversion. Copolymers with molecular weights up to Mn ) 34 000 and low polydispersities (Mw/Mn ) 1.11-1.47) were prepared. The reactivity ratios were calculated for the copolymerizations catalyzed by CuBr/bpy, (rDMAEMA ) 1.07, rBMA ) 1.24). The thermosensitivity and aggregation properties of the random, gradient, and block copolymers significantly depended on the architecture of the copolymers. The lower critical solution temperature of MPEG-b-PDMAEMA84 was 38 °C (5 wt % in water). Introduction Well-defined amphiphilic copolymers have interesting aqueous solution properties that may lead to many potential applications. Controlled polymerization processes such as ATRP1 allow the synthesis of various copolymers with wellcontrolled molecular weights, narrow molecular weight distribution, and defined topology. ATRP shows a tolerance to a variety of functional groups and monomers such as substituted styrenes, (meth)acrylates, (meth)acrylamides, and acrylonitrile were successfully polymerized.2 Especially, N-substituted (meth)acrylates and (meth)acrylamides polymerized by ATRP3 were of increasing interest for many application, such as biosensors, membranes, drug delivery systems, substrates for cell culture, isolation of biomolecules, and enzyme activity control, because they show specific solution properties, such as micellization, thermosensitivity, and pH sensitivity.4 Copolymers of N-isopropylacrylamide (NIPAM) and 2-(dimethylamino)ethyl methacrylate (DMAEMA) synthesized by conventional polymerization methods4a,5 show lower critical solution temperatures (LCST) around body temperature, and therefore, the exploitation of these polymers as biomaterials and polymer electrolytes was extensively investigated. However, their utility is limited because control of molecular weight, polydispersities, and copolymer topology is difficult in conventional radical polymerization. MPEG derivatives show a good solubility in most organic and aqueous media, and chemical modification of synthetic * To whom correspondence should be addressed. † University of Pittsburgh. ‡ Carnegie Mellon University.

polymers, and biomacromolecules, with MPEG was intensely studied due to the unique properties of MPEG and its general compatibility with biologic systems. The covalent attachment of MPEG to a synthetic polymer can affect both immunogenicity and antigenicity.6 Recently, several PEG derivatives were used as either macroinitiators or macromonomers in ATRP.7 MPEG-based ATRP initiators can be used for many water-insoluble systems as well as water-soluble systems. MPEG itself could be employed as one of the segments in a block copolymer if it has a sufficiently high molecular weight to induce a phase separation in solid state or solution. MPEG could be attached to modify the properties of various biomacromolecules, such as enzymes, proteins, or nucleic acids.8 It can serve as a linker between these biomacromolecules and well-defined organic polymers. At the same time, water can be used as an environmentally benign solvent for the modification of biomacromolecules with MPEG and hydrophilic/hydrophobic monomers, and several studies were reported in waterborne ATRP systems.9 In the present study, we report the synthesis and characterization of random, gradient, and block copolymers of hydrophilic DMAEMA and hydrophobic BMA containing MPEG segment using ATRP. We analyzed the kinetic behavior, evolution of molecular weight and composition in the copolymerization. The reactivity ratios of the monomers were determined. The solution properties of the polymers were investigated as a function of composition for gradient or block copolymers in aqueous solution by using NMR. The ATRP reactions were performed in water/2-propanol mixtures to find appropriate reaction conditions for the subsequent modification of enzymes. The next study will

10.1021/bm034126a CCC: $25.00 © 2003 American Chemical Society Published on Web 07/09/2003

ATRP Synthesis of DMAEMA and BMA

Biomacromolecules, Vol. 4, No. 5, 2003 1387

focus on enzyme modification and activities of the resulting hybrid materials with a thermosensitive organic “coating”. Experimental Section Materials and Methods. Materials. 2-(Dimethylamino)ethyl methacrylate (DMAEMA) and n-butyl methacrylate (BMA) were obtained from Aldrich, passed through a basic alumina column, and then distilled prior to polymerization. CuBr, CuBr2, 2,2′-bipyridine (bpy), 2-bromoisobutyric acid, 4-(dimethylamino)pyridine (4-DMAP), methoxy-poly(ethylene glycol) (MPEG, Mn ) 2000), ethyl 2-bromoisobutyrate, and all other reagents were commercial products and used without further purification. Preparation of MPEG Macroinitiator. In a 250 mL oneneck flask, MPEG (15 g, 7.5 mmol), 2-bromoisobutyric acid (2.5 g, 15 mmol), and 1,3-dicyclohexylcarbodiimide (DCC, 3.1 g, 15 mmol) were dissolved in 100 mL chloroform, and the solution was cooled to 0 °C. 4-(Dimethylamino)pyridine (4-DMAP) (0.09 g) was added, and the reaction mixture was stirred overnight at room temperature. The precipitated N,Ndicyclohexylurea was filtered off, and chloroform was then removed. The macroinitiator was then precipitated twice in cold ether, followed by drying (yield: 13.7 g, 84%). 1H NMR in D2O [δ ) 1.84 (6 H), δ ) 3.81 (182 H)] indicated that the hydroxyl end groups of the MPEG were fully esterified. Preparation of MPEG-b-(PDMAEMAx-BMAy) Random Copolymer. DMAEMA, BMA, MPEG macroinitiator, DMF (GC internal standard), deionized water, and 2-propanol were added to a 25 mL Schlenk flask with magnetic stir bar, and the reagent mixture was degassed by five freeze-pumpthaw cycles. The flask was then back-filled with nitrogen, and CuBr, CuBr2, and bpy were quickly added to the flask while the reaction mixture was frozen under liquid nitrogen. After closing the flask, it was evacuated and back-filled with nitrogen three times. The flask was then immersed in a water bath heated to 25 °C. Immediately, a sample was withdrawn for GC analysis. During the polymerization, samples were removed periodically via syringe to monitor monomer conversion by GC. After 2 h, the polymer was dissolved in a small amount of chloroform, and then passed through aluminum oxide (basic, activated) to remove Cu complexes prior to removal of solvent. Preparation of MPEG-b-(DMAEMAx-grad-BMAy) Gradient Copolymer. In the first Schlenk flask, DMAEMA, MPEG macroinitiator, DMF, deionized water, and 2-propanol were added and degassed by five freeze-pump-thaw cycles. The flask was then back-filled with nitrogen, and CuBr, CuBr2, and bpy were quickly added to the flask and followed by freezing of the reaction mixture. BMA was added to a second Schlenk flask and degassed by three freeze/pump/thaw cycles. The second reaction mixture was transferred into an airtight syringe, which was assembled to a syringe pump. The first flask was placed in a preheated water bath at 25 °C, and the initiation solution was added. Simultaneously, the continuous addition of the second reaction solution to the first one was started at a rate of 0.3 mL/h, and after 4 h, the addition of BMA was complete. The reaction was stopped after 4 h and 10 min by exposing the reaction mixture to air.

Figure 1. ATRP of DMAEMA: (a) kinetics; (b) evolution of molecular weights with conversion; and (c) evolution of SEC traces. Reaction conditions: [DMAEMA]0:[I]0:[Cu(I)]0:[Cu(II)]0:[bpy]0 ) 200:1:0.9:0.1:2 in 50 vol % 2-propanol-water (1.8:0.2 by volume) at 25 °C.

The polymer solution was diluted with chloroform and passed through an alumina column to remove the catalyst. The solvent was removed by distillation under vacuum using a rotary evaporator at 25 °C, and the polymer was dried under vacuum (10-2 mbar) for 24 h. Preparation of MPEG-b-PDMAEMAx-b-PBMAy Triblock Copolymer. DMAEMA, MPEG macroinitiator, DMF, deionized water, and 2-propanol were added to a 25 mL Schlenk flask fitted with a magnetic stir bar and the mixture was degassed by five freeze-pump-thaw cycles. The flask was then filled with nitrogen, and CuBr, CuBr2, and bpy were quickly added to the flask while the reaction mixture was frozen under liquid nitrogen. After closing the flask, it was

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Figure 2. ATRP of BMA: (a) kinetics; (b) evolution of molecular weights with conversion; and (c) evolution of SEC traces. Reaction conditions: [BMA]0:[I]0:[Cu(I)]0:[Cu(II)]0:[bpy]0 ) 200:1:0.9:0.1:2 in 50 vol % 2-propanol-water (1.8:0.2 by volume) at 25 °C.

evacuated and back-filled with nitrogen three times. The flask was then immersed in a water bath heated to 25 °C. After 1 h, the conversion reached about 40%. The reaction solution was diluted with THF, and the resulting precipitate was filtered off. The filtrate was concentrated by evaporator. The polymer was dissolved in a small amount of chloroform and the solution was then passed through aluminum oxide (basic, activated) to remove Cu complexes and concentrated to yield the MPEG-b-PDMAEMAx macroinitiator which was precipitated in hexanes followed by drying.

Lee et al.

Figure 3. Random copolymers of DMAEMA and BMA: (a) first-order kinetic plot for the copolymerization of DMAEMA and BMA at three monomer feed conditions; (b) individual monomer conversion for the copolymerization of DMAEMA and BMA, where the initial monomer feed in this copolymerization consisted of 50% (mol) BMA; (c) 95% joint confidence intervals and point estimates for the copolymerization of DMAEMA and BMA. Reaction conditions: [DMAEMA]0:[BMA]0:[I]0: [Cu(I)]0:[Cu(II)]0:[bpy]0 ) 100:100:1:0.9:0.1:2 in 50 vol % 2-propanolwater (1.8:0.2 by volume) at 25 °C.

The BMA block was then polymerized from this macroinitiator to obtain MPEG-b-PDMAEMAx-b-PBMAy structure. Characterization. The monomer conversion was measured by gas chromatography (GC). A portion of the sample was dissolved in acetone and injected directly into a Shimadzu GC-14A gas chromatograph. Conversions were obtained



Table 1. Synthesis of Amphiphilic Copolymers Containing Hydrophilic and Hydrophobic Segments DP by NMR CDCl3

a

polymera

structure

x

1 2 3 4 5 6 7 8 9

MPEG-b-PDMAEMAx MPEG-b-PBMAx MPEG-b-(PDMAEMAx-co-PBMAy) MPEG-b-(PDMAEMAx-co-PBMAy) MPEG-b-(PDMAEMAx-co-PBMAy) MPEG-b-(PDMAEMAx-grad-PBMAy) MPEG-b-(PBMAx-grad-PDMAEMAy) MPEG-b-PDMAEMAx-b-PBMAy MPEG-b-PBMAx-b-PDMAEMAy

84 183 171 110 28 118 85 92 77

D2O

y

x

43 110 146 41 31 104 93

57 0 0 0 0 42 0 45 0

SEC result

y

Mn (g/mol)

Mw/Mn

0 0 0 0 0 0 51

19 160 20 530 30 870 34 160 20 380 20 960 20 500 22 490 22 310

1.37 1.23 1.27 1.38 1.18 1.30 1.23 1.41 1.42

Samples from kinetic study.

from the ratio of the residual monomer/ DMF (internal standard) in the samples. Another portion of the samples was filtered through a 0.2 µm syringe filter, and the resulting solution was injected into SEC columns (Water 717) using 0.1% tetrabutylammonium bromide solution in DMF as the eluent. A calibration curve based on linear poly(methyl methacrylate) standards was used in conjunction with a differential refractometer to determine the molecular weight and polydispersity of each sample. ThermosensitiVity. The phase transition of the aqueous solution of a polymer (5 wt %) was detected visually in a closed glass tube while the temperature was controlled by immersion of the glass tube in an oil bath. The LCST was identified as the temperature at which the solution became turbid. Results and Discussion Polymerization. Figures 1 and 2 show the kinetic plots for monomer conversion, molecular weight evolution, and SEC traces obtained during the polymerization of MPEGb-PDMAEMAx (polymer 1 in Table 1) and MPEG-b-PBMAx (polymer 2 in Table 1), respectively. The kinetic profiles suggest fast initiation and insignificant termination (Figures 1a and 2a). This conclusion was further supported by the relatively low polydispersities of the obtained polymers. Also, the molecular weights of both copolymers increased monotonously with conversion of DMAEMA and BMA, indicating the controlled character of the polymerization (Figures 1b and 2b). Some deviations from predicted values may be due to different hydrodynamic volumes of the copolymers and the linear PMMA standards. The molecular weight distributions for all polymers are fairly narrow (Mw/Mn < 1.37). The first-order kinetic plots for the random copolymerizations carried out using the CuBr/bpy catalyst are displayed in Figure 3a. For all three of the copolymerizations, ln([M]0/ [M]) increases nearly linearly with time, indicating that the copolymerizations obey an approximately first-order dependence on total monomer concentration. Figure 3a shows that the overall rate of polymerization generally decreased as the concentration of BMA increased. On the basis of the free radical reactivity ratios of DMAEMA and BMA reported in the literature,10 it is expected that these monomers should have very similar reactivities in this copolymerization. Figure

Figure 4. Instantaneous composition of gradient copolymers: (a) MPEG-b-(DMAEMAx-grad-BMAy) and (b) MPEG-b-(BMAx-gradDMAEMAy).

3b shows individual monomer conversion using an equimolar monomer feed. After 3.5 h, approximately 88% of the original BMA had been consumed in comparison to 87% of the DMAEMA. This behavior is typical of what was seen in all copolymerizations. These results indicate that the reactivity ratios of this monomer pair follow the trends seen in conventional free radical copolymerizations. The monomer conversion data shown above were used to calculate the monomer reactivity ratios using the nonlinear regression techniques described previously.11 The joint confidence interval (JCI) and point estimate are shown in Figure 3c. The reactivity ratios are very similar (rDMAEMA ) 1.07, rBMA ) 1.24). The dependence of the overall rate of copolymer-

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Figure 5. Synthesis of the third block in triblock copolymers of DMAEMA and BMA: (a) kinetics; (b) evolution of molecular weights with conversion; and evolution of SEC traces of (c) MPEG-b-PDMAEMAx-b-PBMAy and (d) MPEG-b-PBMAx-b-PDMAEMAy. Reaction conditions: [DMAEMA]0: [BMA]0:[I]0:[Cu(I)]0:[Cu(II)]0:[bpy]0 ) 100:100:1:0.9:0.1:2 in 50 vol % 2-propanol-water (1.8:0.2 by volume) at 25 °C.

ization on monomer feed suggests either differences in equilibrium constants for each comonomer or reduction of catalyst activity in the presence of higher concentration of BMA. Similar values of reactivity ratios mean that the synthesis of gradient copolymers MPEG-b-(PDMAEMAx-grad-PBMAy) (polymer 6 in Table 1) and MPEG-b-(PBMAx-gradPDMAEMAy) (polymer 7 in Table 1) requires slow feeding of one monomer to the ATRP of the second one. The plots of the instantaneous composition vs chain length, calculated from the co-monomers conversions, are shown in Figure 4. The average, instantaneous composition in each segment decreases continuously from 100% DMAEMA, or BMA, at the beginning of the average polymer chain to around 10% at the end. This confirms the synthesis of a gradient structure. The overall compositions of MPEG-b-(DMAEMAx-gradBMAy) and MPEG-b-(BMAx-grad-PDMAEMAy) were PDMAEMA:PBMA ) 74:26 (mol %) and PBMA:PDMAEMA ) 73:27 (mol %), respectively. Table 1 lists the random, gradient, and block copolymers synthesized in this study, together with the DPs predicted from conversion data, polydispersity (SEC) and Mn values obtained from NMR and SEC, respectively. Figure 5 shows the kinetics of monomer conversion and the molecular weight evolution in the synthesis of MPEG-

b-PDMAEMAx-b-PBMAy (polymer 8 in Table 1) and MPEG-b-PBMAx-b-PDMAEMAy (polymer 9 in Table 1) triblock copolymers using a MPEG-Br macroinitiator. The formation of the third block is accompanied by nonlinear kinetics and also by a strange evolution of MW and MWD. The SEC chromatograms in Figure 5, parts c and d, indicated a continuous increase in molecular weight during the polymerization of the third segments with BMA or DMAEMA from the MPEG-b-PDMAEMAx or MPEG-b-PBMAx macroinitiators, respectively. However, there is some tailing to low molecular weight, indicating termination during the DMAEMA polymerization. The SEC traces show some bimodality, which may be due to terminated polymers connected to MPEG macroinitiator. Further purification of the triblock copolymer was achieved by washing it with excess n-hexane to remove residual BMA monomer. After drying in a vacuum oven at room temperature, the final composition of the block copolymers was calculated from the 1H NMR spectra. Thermosensitivity. The phase transition seen in thermosensitive polymers in aqueous solution is attributed to a change in the hydrophilic-hydrophobic balance of the polymers with respect to the hydrogen bonding interaction between the polymer and water molecules. Therefore, increasing the hydrophilicity of the polymer causes an



Figure 6. Concentration-dependent LCST behaviors of polymer 1 (b) and PDMAEMA initiated by ethyl 2-bromoisobutyrate (9).

increase in the LCST of the polymer in aqueous solution. Such a tendency was also observed in our systems. Homopolymers of DMAEMA initiated by MPEG and ethyl 2-bromoisobutyrate showed thermosensitivity in aqueous solution. The LCSTs of the polymers were 38 and 31 °C in 5% aqueous solution, respectively. The LCST obtained for the PDMAEMA initiated by MPEG is higher because of the presence of the hydrophilic MPEG segment. Consequently, PDMAEMA initiated by ethyl 2-bromoisobutyrate showed a lower LCST. However, LCSTs were not observed for other more hydrophobic copolymers. PDMAEMAs with LCSTs around body temperature (30-37 °C) could be good candidates for drug delivery systems. The concentration dependence of the LCST of the copolymers was determined over the range of 0.1-30-wt % of the polymers in aqueous solution. Figure 6 shows the LCST values for the two polymers over this concentration range. The LCST of the polymers was found to be almost concentration independent in the range of 5-10 wt % but increases at lower solution concentrations as reported earlier for other thermosensitive polymers.5 Aggregation Properties. Figure 7 illustrates the NMR spectra of a series of MPEG-based gradient copolymers containing DMAEMA and BMA. Protons of MPEG (3.6 ppm) were used as a reference to calibrate the integration of the other signals. To confirm the amphiphilic property of MPEG-b-(PDMAEMAx-grad-PBMAy) (polymer 6 in Table 1), the 1H NMR spectra were recorded in both CDCl3 and D2O. In CDCl3 (Figure 7a), the spectrum of the copolymer displayed the presence of peaks that could be assigned to the hydrophilic part (MPEG and PDMAEMA) and hydrophobic part (PBMA), providing integrations in accordance with the predicted copolymer composition. This suggests that all three blocks in the polymer chains were well dissolved in CDCl3. However, in D2O (Figure 7b), the significantly decreased intensity of peaks associated with PBMA segments

Figure 7. 1H NMR spectra obtained for (a) the MPEG-b-(DMAEMAxgrad-BMAy) copolymer in CDCl3; (b) in D2O; and (c) schematic representation of the plausible aggregates with a gradient PBMAcore formed in D2O.

indicated the presence of chain aggregation and formation of a supramolecular assembly. A variety of amphiphilic micelles were prepared via ATRP.12 Amphiphilic linear diblock copolymers, starlike block copolymers, and shell cross-linked micelles present the opportunity for unique micelle structure formation. Chain aggregation into polymeric

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Figure 9. 1H NMR spectra obtained for (a) the MPEG-b-PBMAx-bPDMAEMAy polymer in CDCl3; (b) in D2O; and (c) schematic representation of the plausible aggregates with a central PBMA-core formed in D2O.

Figure 8. 1H NMR spectra obtained for (a) the MPEG-b-PDMAEMAxb-PBMAy polymer in CDCl3; (b) in D2O; and (c) schematic representation of the plausible aggregates with a terminal block PBMA-core formed in D2O.

micelles leads to the formation of a semisolid internal core and, thus, to a partial suppression of the signals of PBMA or BMA surrounded by DMAEMA. However, the copolymer

with a reverse gradient structure and lower content of DMAEMA, MPEG-b-(PBMAx-grad-PDMAEMAy) (polymer 7 in Table 1) did not dissolve well in water and showed only signals due to MPEG. Figure 8 shows the NMR spectra for MPEG-b-PDMAEMAx-b-PBMAy (polymer 8 in Table 1) triblock copolymer in CDCl3 and D2O. In CDCl3, the copolymer chains are fully solvated, and all of the signals expected for each block are visible. The PBMA signals are present at the expected



intensities, indicating that this block is soluble. In D2O, the signals due to the PBMA block have completely disappeared, indicating the formation of a relatively compact, hydrophobic PBMA-core micelles, similar to the PBMA segments in MPEG-b-(PDMAEMAx-grad-PBMAy) (polymer 6 in Table 1). Interestingly, MPEG-b-PBMAx-b-PDMAEMAy (polymer 9 in Table 1) triblock copolymer showed similar NMR spectra in D2O. Both MPEG and PDMAEMA segments were soluble in D2O as shown in Figure 9b. A plausible structure for the micelle aggregates that would provide such a 1H NMR spectra from MPEG-b-PBMAx-b-PDMAEMAy (polymer 9 in Table 1) is the structure with a folded PBMA-core, as schematically presented in Figure 9c. The results of the aggregation studies in aqueous solutions are summarized in Table 1. In deuterium oxide, some portion of water-soluble PDMAEMA collapsed together with PBMA. Out of the original 92 units of PDMAEMA in MPEG-bPDMAEMAx-b-PBMAy (polymer 8 in Table 1) only 45 units were “visible” in water when 104 units of PBMA collapsed. The expected signal from the original 118 units of PDMAEMA in a gradient copolymer MPEG-b-(PDMAEMAxgrad-PBMAy) (polymer 6 in Table 1) was reduced to 42 “visible” units when 41 units of PBMA collapsed. This means that the collapse of PDMAEMA is affected by the microstructure and surrounding PBMA units. Conclusions Amphiphilic random, gradient, and block copolymers of 2-(dimethylamino)ethyl methacrylate with n-butyl methacrylate were synthesized by ATRP in aqueous media using MPEG macroinitiator. The molecular weight distributions of the resulting block copolymers were fairly narrow. The aggregation in aqueous solutions was observed by NMR spectra, and its magnitude depended strongly on composition, microstructure, and chain architecture. PDMAEMA copolymers containing a biocompatible MPEG linker is being studied as a thermosensitive outer shell for encapsulation of enzymes. Acknowledgment. This work was partially supported by the CRP Consortium at Carnegie Mellon University, the Environmental Protection Agency (R-82958001), DoD Multidisciplinary University Research Initiative (MURI) (DAAD19-01-1-0619) program administered by the Army Research Office, and the Postdoctoral Fellowship Program of Korea Science & Engineering Foundation (KOSEF). References and Notes (1) (a) Wang, J.-S.; Matyjaszewski, K. J. Am. Chem. Soc. 1995, 117, 5614. (b) Matyjaszewski, K.; Xia, J. Chem. ReV. 2001, 101, 2921. (c) Kamigaito, M.; Ando, T.; Sawamoto, M. Chem. ReV. 2001, 101,

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BM034126A

ATRP Synthesis of Amphiphilic Random, Gradient, and Block

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