Biomacromolecules 2004, 5, 1177-1180
1177
Communications Facile, Controlled, Room-Temperature RAFT Polymerization of N-Isopropylacrylamide† Anthony J. Convertine,† Neil Ayres,† Charles W. Scales,† Andrew B. Lowe,‡ and Charles L. McCormick*,†,‡ Department of Polymer Science and Department of Chemistry & Biochemistry, University of Southern Mississippi, Hattiesburg, Mississippi 39406 Received March 24, 2004; Revised Manuscript Received May 18, 2004
Poly(N-isopropyl acrylamide) is a thermoresponsive polymer that has been widely investigated for drug delivery. Herein, we report conditions facilitating the controlled, room-temperature RAFT polymerization of N-isopropylacrylamide (NIPAM). The key to success is the appropriate choice of both a suitable RAFT chain transfer agent (CTA) and initiating species. We show that the use of 2-dodecylsulfanylthiocarbonylsulfanyl-2-methyl propionic acid, a trithiocarbonate RAFT CTA, in conjunction with the room-temperature azo initiator 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile), in DMF, at 25 °C, yields conditions leading to NIPAM homopolymerizations which bear all of the characteristics of a controlled/“living” polymerization. We also demonstrate facile size exclusion chromatographic analysis of PNIPAM samples in DMF at 60 °C, directly on aliquots withdrawn during the polymerizations, which avoids the problems previously reported in the literature. During the last several years, reversible additionfragmentation chain transfer (RAFT) polymerization has proven itself to be an extremely versatile controlled/“living” free radical polymerization technique (CLRP). It has been shown to be applicable to the controlled polymerization of a wide-range of monomers, under a wide range of conditions to yield materials with predetermined molecular weights, narrow molecular weight distributions, and advanced architectures.1-6 One particularly important feature of RAFT, and a clear advantage over other CLRP techniques, is that it facilitates the controlled polymerization of (meth)acrylamido monomers. For example, we, and others, have reported the RAFT polymerization of nonionic,7-14 anionic,15-17 cationic,18,19 and zwitterionic20-22 (meth)acrylamido species under a variety of conditions employing a variety of RAFT chain transfer agents (CTAs). N-Isopropylacrylamide (NIPAM) is an extremely important nonionic acrylamido monomer and has been the subject of intensive research over the years. One of the reasons it has been so widely studied is that poly(NIPAM) (PNIPAM) possesses a readily accessible lower critical solution temperature (LCST) in water of ∼32 °C. This is close to human body temperature (37 °C) and as such has, for example, been evaluated in drug delivery applications.23-26 At present, there †
Paper number 111 in a series titled “Water-Soluble Polymers”. * To whom correspondence should be addressed. E-mail:
[email protected]. ‡ University of Southern Mississippi.
are several reports detailing the RAFT polymerization of NIPAM. For example, Ganachaud et al. reported the AIBN initiated solution polymerization of NIPAM employing both benzyl dithiobenzoate (in benzene) and cumyl dithiobenzoate (in 1,4-dioxane) at 60 °C. These authors also conducted a thorough size exclusion chromatographic (SEC) investigation of the resulting homopolymers and highlighted some of the problems associated with the analysis of PNIPAM samples using this technique.10 Subsequently, Schilli et al. disclosed the benzyl and cumyl dithiocarbamate-mediated polymerization of NIPAM, also in 1,4-dioxane at 60 °C.11 These experimental conditions led to polymers with polydispersity indices (PDIs) e 1.37. Polymer molecular weights were determined by a combination of MALDI-TOF MS and SEC. This report likewise noted the problems associated with the SEC analysis of PNIPAM, with experimentally determined molecular weights being considerably higher than predicted. More recently, Ray and co-workers demonstrated the ability to control the tacticity in RAFT polymerizations of NIPAM via the addition of a suitable Lewis acid such as Sc(OTf)3 or Y(OTf)3.27,28 Using an eluent comprised of DMF containing 0.1 M LiCl, the authors did not report any of the difficulties in analysis of the polymers by GPC previously mentioned. RAFT-prepared PNIPAM has also been employed as a thermoresponsive stabilizing layer for gold nanoparticles/clusters.29-30 The ability to conduct RAFT polymerizations at room temperature is clearly a desirable feature from both academic
10.1021/bm049825h CCC: $27.50 © 2004 American Chemical Society Published on Web 06/24/2004
1178
Biomacromolecules, Vol. 5, No. 4, 2004
Communications
Scheme 1. Synthetic Pathway for the Room Temperature RAFT Polymerization of N-Isopropylacrylamide
Table 1. Conversion, Molar Mass, and Polydispersity Data for NIPAM Homopolymerizations samplea
time (h)
conversion (%)b
[CTA]0/[I]0
Mn (theory)
Mn (expt)c
PDI
NIPAM1 NIPAM2 NIPAM3 NIPAM4 NIPAM5 NIPAM6 NIPAM7 NIPAM8 NIPAM9
6 12 24 6 12 24 6 12 24
39 58 74 52 70 86 62 77 90
20 20 20 10 10 10 5 5 5
20 400 30 600 38 600 27 500 37 000 45 000 32 600 40 700 47 000
24 000 33 000 40 000 31 000 37 000 43 000 29 200 40 000 44 500
1.04 1.05 1.05 1.03 1.06 1.03 1.07 1.06 1.06
a Polymers synthesized at 25 °C at 33 wt % monomer in DMF ([CTA] / 0 [M]0: 1/465) under a nitrogen atmosphere with 2,2-azobis(4-methoxy-2,4b dimethylvaleronitrile) as the initiator. Conversions were determined by comparing the area of the RI signal of the monomer at t0 to that at tx.c As determined by SEC (0.5 mL/min, 60 °C, Polymer Labs PL gel 5 µm mixed C column, DMF eluent).
and industrial standpoints. Room temperature RAFT polymerizations have also been previously reported. For example, Barner et al. have detailed the γ-initiated, bulk polymerization of several monomers including N,N-dimethylacrylamide and methyl methacrylate.31 Also, Quinn and co-workers reported the chemically initiated room-temperature polymerization of methyl acrylate employing 1-phenylethyl phenyldithioacetate as the RAFT CTA and AIBN as the source of primary radicals.32 Building on these reports, here we detail facile conditions that allow for the controlled, room temperature, RAFT polymerization of NIPAM, in N,Ndimethylformamide (DMF), employing a conventional azoinitiator, namely 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70) as the source of primary radicals and the commercially available, trithiocarbonate-based CTA, 2-dodecylsulfanylthiocarbonylsulfanyl-2-methyl propionic acid (DMP) (Scheme 1). All polymerizations were conducted at 25 °C under a nitrogen atmosphere at 33 wt % monomer in septasealed vials. The CTA:monomer ratios ([CTA]0/[M]0 ) 1/465) were such that the theoretical Mn at 100% conversion was 52 500. The [CTA]0/[I]0 ratios were varied between 20:1 and 5:1. Polymerization kinetics and absolute molecular weights were determined by extracting aliquots (∼0.50 mL) at predetermined time intervals using degassed syringes. The aliquots were quenched by exposure to air and the addition of a small amount of inhibitor (phenothiazine) and stored in a freezer prior to analysis. The aliquots were analyzed directly by SEC (DMF eluent, 0.5 mL/min, 60 °C, Polymer Labs PL gel 5 µm mixed C column, Viscotek-TDA (302 RI, viscosity, 7 mW 90° and 7° true low angle light scattering detectors, λ ) 670 nm)). Conversions were determined by comparing the area of the RI signal of the monomer at t0 to that at tx. The dn/dc of PNIPAM was determined to be 0.0731 at 632.8 nm in DMF at 60 °C using a Viscotek refractometer and Omnisec software.
Figure 1. (A) RI traces for PNIPAM homopolymerization at [CTA]0/ [I]0 ) 20 showing the evolution of molar mass with time. (B and C) Plots of PDI and Mn versus conversion. (D) The corresponding pseudo first-order rate plots for the NIPAM homopolymerizations as a function of variation in [CTA]0/[I]0.
The results for the homopolymerization of NIPAM, under those conditions outlined in Scheme 1, are summarized in Table 1. It is clear that the use of the trithiocarbonate DMP in conjunction with V-70 allows for the synthesis of PNIPAM in a controlled fashion. Such trithiocarbonates have been previously shown to be effective for the controlled polymerization of a variety of monomers.33-35 There is excellent agreement between the observed and theoretical molecular weights, as determined by SEC in DMF at 60 °C. Indeed, under these conditions, we encountered none of the problems previously observed in the SEC analysis of PNIPAM samples such as uncontrolled aggregation and/or the need for very careful sample preparation.10,11 An example of the quality of SEC analysis is demonstrated in Figure 1A by an overlay of the progressive RI traces from the homopolymerization of NIPAM at a [CTA]0/[I]0 ratio of 20. The traces are unimodal and symmetrical and clearly shift to lower elution
Communications
Figure 2. SEC traces for the NIPAM macroCTA (Mn ) 41 000, PDI ) 1.04) and the corresponding chain extended “block” copolymer (Mn ) 70 000, PDI ) 1.10)
times with increasing conversion, one indicator of a controlled polymerization. Moreover, the chromatograms show no evidence of higher molecular weight impurities (normally visualized as a shoulder), even at extended polymerization times, a feature which has been observed previously in RAFT polymerization including those of NIPAM.11 Also evident from Table 1, and plotted in Figure 1B, are the extremely low PDIs observed for the NIPAM homopolymers synthesized under these facile conditions. In all instances, the PDIs are e1.07. Again this is in contrast to other studies where the PDIs have been shown to increase at higher conversions. Shown in Figure 1C are the Mn versus conversion plots for three NIPAM homopolymerizations at [CTA]0/[I]0 ratios of 5, 10, and 20. The overlap and linearity of the data indicate (i) excellent molecular weight control with each of the three studied [CTA]0/[I]0 ratios and (ii) the absence of nondegenerative chain transfer events and/or other deleterious side reactions resulting in the loss of trithiocarbonate functionality. We have recently shown that such side reactions, under certain conditions, can have significant ramifications for both homopolymerization control and for subsequent block copolymer synthesis.7,36 One difference that is observed for the three different [CTA]0/[I]0 ratios manifests itself in the kinetic behavior of the polymerizations and is shown in Figure 1D. Specifically, as expected, we observed differences in the kinetic characteristics at the three different [CTA]0/[I]0 ratios. The lower the [CTA]0/[I]0 ratio the faster the polymerization. For example, at a [CTA]0/[I]0 ) 5, 90% conversion is reached after 24 h vs 74% conversion at the same time for a [CTA]0/[I]0 ) 20. All of the pseudo firstorder kinetic plots do, however, remain largely linear at lowto-moderate conversion with some curvature observed at high conversions. All of the data presented in Figure 1 indicate that the conditions reported above do indeed lead to controlled/“living” NIPAM homopolymerizations. Perhaps the ultimate, or final, test of “livingness” is the ability to quantitatively chain-extend homopolymers to yield block copolymers. As such, a PNIPAM macroCTA was synthesized and then isolated by precipitation into a large excess of petroleum ether.10 This macroCTA was subsequently chain extended with additional NIPAM monomer under experimental conditions identical to those reported above for the
Biomacromolecules, Vol. 5, No. 4, 2004 1179
homopolymerizations. Near-quantitative blocking efficiency (percent macroCTA converted to “diblock” copolymer) was confirmed by the clear shift in the SEC RI chromatograms for the macroCTA (Mn ) 41 000, PDI ) 1.04) vs the chain extended species (Mn ) 70 000, PDI ) 1.10; Figure 2). The lack of significant homopolymer impurity, as evidenced by the absence of a detectable shoulder on the RI trace of the “block” copolymer at an elution volume corresponding to the homopolymer, suggests that most of the PNIPAM macroCTA retained the trithiocarbonate functionality at the chain terminus and that it was available for subsequent reactivation. In summary, we have demonstrated the ability to conduct the RAFT polymerization of NIPAM at room temperature, in DMF, with [CTA]0/[I]0 ratios as high as 20 employing the trithiocarbonate species 2-dodecylsulfanylthiocarbonylsulfanyl-2-methyl propionic acid in conjunction with the room-temperature azo initiator 2,2′-azobis(4-methoxy-2,4dimethylvaleronitrile). Homopolymerizations remained controlled even at monomer conversions exceeding 90% and bore all of the characteristics of a controlled/“living” system. Additionally, the salt-free SEC conditions employed for the characterization of the NIPAM homo- and “block” copolymers allow excellent resolution without aggregation problems often encountered. We believe that this represents a significant advance in terms of both of the facile synthesis and characterization of NIPAM-based materials and will no doubt lead to the preparation of more structurally complex copolymers soon. Acknowledgment. The Department of Energy (DEFC26-01BC15317), Genzyme, and the MRSEC program of the National Science Foundation (DMR-0213883) are gratefully acknowledged for financial support. We would also like to thank Wako Chemicals and Noveon for their gifts of the V-70 initiator and the trithiocarbonate chain transfer agent, respectively. References and Notes (1) Rizzardo, E.; Chiefari, J.; Mayadunne, R. T. A.; Moad, G.; Thang, S. H. In Controlled/LiVing Radical Polymerization. Progress in ATRP, NMP, and RAFT; Matyjaszewski, K., Ed.; American Chemical Society: Washington, DC, 2000; Vol. 768, pp 278-296. (2) Lowe, A. B.; Sumerlin, B. S.; Donovan, M. S.; Thomas, D. B.; Hennaux, P.; McCormick, C. L. In AdVances in Controlled/LiVing Radical Polymerization; Matyjaszewski, K., Ed.; American Chemical Society: Washington, DC, 2003; Vol. 854, pp 586-602. (3) McCormick, C. L.; Lowe, A. B. Acc. Chem. Res. 2004. (4) Lowe, A. B.; McCormick, C. L. Aust. J. Chem. 2002, 55, 367-380. (5) Chiefari, J.; Mayadunne, R. T. A.; Moad, C. L.; Moad, G.; Rizzardo, E.; Postma, A.; Skidmore, M. A.; Thang, S. H. Macromolecules 2003, 36, 2273-2283. (6) Chong, Y. K.; Krstina, J.; Le, T. P. T.; Moad, G.; Postma, A.; Rizzardo, E.; Thang, S. H. Macromolecules 2003, 36, 2256-2272. (7) Thomas, D. B.; Sumerlin, B. S.; Lowe, A. B.; McCormick, C. L. Macromolecules 2003, 36, 1436-1439. (8) Donovan, M. S.; Lowe, A. B.; Sumerlin, B. S.; McCormick, C. L. Macromolecules 2002, 35, 4123-4132. (9) Donovan, M. S.; Sanford, T. A.; Lowe, A. B.; Sumerlin, B. S.; Mitsukami, Y.; McCormick, C. L. Macromolecules 2002, 35, 45704572. (10) Ganachaud, F.; Monteiro, M. J.; Gilbert, R. G.; Dourges, M.-A.; Thang, S. H.; Rizzardo, E. Macromolecules 2000, 33, 6738-6745. (11) Schilli, C.; Lanzendoerfer, M. G.; Mueller, A. H. E. Macromolecules 2002, 35, 6819-6827.
1180
Biomacromolecules, Vol. 5, No. 4, 2004
(12) D’Agosto, F.; Hughes, R.; Charreyre, M.-T.; Pichot, C.; Gilbert, R. G. Macromolecules 2003, 36, 621-629. (13) Favier, A.; Charreyre, M.-T.; Chaumont, P.; Pichot, C. Macromolecules 2002, 35, 8271-8280. (14) Sumerlin, B. S.; Lowe, A. B.; Thomas, D. B.; Convertine, A. J.; Donovan, M. S.; McCormick, C. L. J. Polym. Sci., Polym. Chem. 2004, 42, 1724-1734. (15) Sumerlin, B. S.; Donovan, M. S.; Mitsukami, Y.; Lowe, A. B.; McCormick, C. L. Macromolecules 2001, 34, 6561-6564. (16) Sumerlin, B. S.; Lowe, A. B.; Thomas, D. B.; McCormick, C. L. Macromolecules 2003, 36, 5982-5987. (17) Yusa, S.; Shimada, Y.; Mitsukami, Y.; Yamamoto, T.; Morishima, Y. Macromolecules 2003, 36, 4208-4215. (18) Vasilieva, Y. A.; Thomas, D. B.; Scales, C. W.; McCormick, C. L. Macromolecules accepted. (19) Mitsukami, Y.; Donovan, M. S.; Lowe, A. B.; McCormick, C. L. Macromolecules 2001, 34 (7), 2248-2256. (20) Donovan, M. S.; Sumerlin, B. S.; Lowe, A. B.; McCormick, C. L. Macromolecules 2002, 35, 8663-8666. (21) Donovan, M. S.; Lowe, A. B.; Sanford, T. A.; McCormick, C. L. J. Polym. Sci., Polym. Chem. 2003, 41, 1262-1281. (22) Virtanen, J.; Arotcarena, M.; Heise, B.; Ishaya, S.; Laschewsky, A.; Tenhu, K. Langmuir 2002, 18, 5360-5365. (23) Eeckman, F.; MoNs, A. J.; Amighi, K.; Int. J. Pharm. 2004, 273, 109-119. (24) Eeckman, F.; MoNs, A. J.; Amighi, K.; Eur. Polym J. 2004, 40, 873881.
Communications (25) Yamazaki, A.; Winnik, F. M.; Cornelius, R. M.; Brash, J. L. Biophys. Biochim. Acta, Membr. 1999, 1421, 103-115. (26) Dube, D.; Francis, M.; Lerous, J. C.; Winnik, F. M.; Bioconjugate Chem. 2002, 13, 685-692. (27) Ray, B.; Isobe, Y.; Morioka, K.; Habaue, S.; Okamoto, Y.; Kamigaito, M.; Sawamoto, M. Macromolecules 2003, 36, 543-545. (28) Ray, B.; Isobe, Y.; Matsumoto, K.; Habaue, S.; Okamoto, Y.; Kamigaito, M.; Sawamoto, M. Macromolecules 2004, 37, 17021710. (29) Shan, J.; Nuopponen, M.; Jiang, H.; Kauppinen, E.; Tenhu, H. Macromolecules 2003, 36, 4526-4533. (30) Raula, J.; Shan, J.; Nuopponen, M.; Niskanen, A.; Jiang, H.; Kauppinen, E. I.; Tenhu, H. Langmuir 2003, 19, 3499-3504. (31) Barner, L.; Quinn, J. F.; Barner-Kowollik, C.; Vana, P.; Davis, T. P. Eur. Polym. J. 2003, 39, 449-459. (32) Quinn, J. F.; Rizzardo, E.; Davis, T. P. Chem. Commun. 2001, 10441045. (33) Mayadunne, R., T. A.; Rizzardo, E.; Chiefari, J.; Krstina, J.; Moad, G.; Postma, A.; Thang, S., H. Macromolecules 2000, 33, 243-245. (34) Lai, J. T.; Filla, D.; Shea, D. Macromolecules 2002, 35, 6754-6756. (35) Stenzel, M. H.; Davis, T. P. J. Polym. Sci., Polym. Chem. 2002, 40, 4498-4512. (36) Thomas, D. B.; Convertine, A. J.; Hester, R. D.; Lowe, A. B.; McCormick, C. L. Macromolecules 2004, 37, 1735-1741.
BM049825H
