Synthesis of Well-Defined Poly(N-isopropylacrylamide) by the Anionic Polymerization of N-Methoxymethyl-N-isopropylacrylamide

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1 RAPID COMMUNICATION Synthesis of Well-Defined Poly(N-isopropylacrylamide) by the Anionic Polymerization of N-Methoxymethyl-N-isopropylacrylamide TAKASHI ISHIZONE, MANA ITO Department of Organic and Polymeric Materials, Graduate School of Science and Engineering, Tokyo Institute of Technology, , Ohokayama, Meguro-ku, Tokyo Japan Received 28 June 2002; accepted 13 September 2002 Published online XX Month 2002 in Wiley InterScience ( DOI: /pola Keywords: poly(n-isopropylacrylamide); anionic polymerization; N-methoxymethyl- N-isopropylacrylamide; protecting group; deprotection; lower critical solution temperature; molecular weight; molecular weight distribution Correspondence to: T. Ishizone ( polymer.titech.ac.jp) JournalofPolymerScience:PartA:PolymerChemistry,Vol.40, (2002) 2002 Wiley Periodicals, Inc. Poly(N-isopropylacrylamide) [poly(nipam)] has attracted a great deal of attention 1 on account of its potential for various applications such as hydrogels, 2 5 drug-delivery devices, 6,7 polymer-bound catalysts, 8 dendritichosts, 9 andpermeationmembranes 10 because it exhibits atypical temperature-dependent solubility in water with a lower critical solution temperature (LCST) around 32 C. 11,12 Poly(NIPAM) samples have been exclusively prepared via the free-radical polymerization of N-isopropylacrylamide (NIPAM), 1 14 and little attention has been paid to the controls on their primary chain structures, such as the molecular weight, molecular weight distribution (MWD), and stereoregularity Although the anionic polymerization of NI- PAM, an electrophilic, -unsaturated carbonyl compound, may also provide another synthetic pathway to poly(nipam), the noticeable acidity of the amide proton (pk a 25 26) 18 ofnipam prohibits its vinyl polymerization (1,2-addition mode) and alternatively induces hydrogen-transfer polymerization (1,4-addition mode) under basic conditions. 19 For such drawbacks to be overcome, the protection of functionalgroupisnecessarybeforetheanionicpolymerization of monomers containing acidic or electrophilic functionalities. In fact, we have succeeded in the anionic livingpolymerizationofstyrenes,1,3-dienes,andmethacrylates with protected functionalities, followed by the complete deprotection of the resultant polymers to give a widevarietyoffunctionalpolymerswithpredictedmolecular weights and narrow MWDs This strategy has been proven to be apowerful synthetic route for welldefinedpolymersbearingreactivefunctionalgroupssuch as OH, NH 2,SH, COOH, CHO, COCH 3,and C'CH in eachmonomerunit.however,thereissofarnosuccessful example for protecting the acidic amide moiety (OCONHO) in the monomers because the suitable protecting group for amide is rather limited in number from the viewpoints of stability and ease of deprotection, even in organic syntheses. 23 We herein report the tailored synthesis of poly(ni- PAM)bymeansoftheanionicpolymerizationofanovel protected NIPAM monomer, N-methoxymethyl-N-isopropylacrylamide (1), and the subsequent deprotection of the resultant polymer, as shown in Scheme 1. The acidic amide proton of NIPAM is purposefully masked with amethoxymethyl group to prevent termination and chain-transfer reactions during the course of the anionic polymerization. The introduced methoxymethyl group is known to be stable under basic conditions but is readily removable by amild acidic treatment. 23 The new monomer 1was synthesized in a20% yield by the reaction of NIPAM and chloromethyl methyl ether in the presence of potassium tert-butoxide in dry diethyl ether. 24 Wecarried out the anionic polymerizationof1underhighvacuumconditions(10 6 mmhg)in tetrahydrofuran (THF) at 78 C for 20 h. Diphenylm- 4328

2 RAPID COMMUNICATION 4329 Scheme 1 ethylpotassium (Ph 2 CHK) or triphenylmethylpotassium (Ph 3 CK) was used as the initiator of 1 in the absence or presence of mol equiv of Et 2 Zn versus the initiator The red color of the initiator immediately disappeared with the addition of a THF solution of 1, and this indicated that rapid initiation had occurred. After the quenching of the reaction with degassed methanol, the polymers were always obtained in quantitative yields via the precipitation of the polymerization system into hexane. The structure of the resultant polymer was characterized as poly(1) by 1 H and 13 C NMR and IR spectroscopy. 29 The methoxymethyl protecting group was found to be intact during the course of the anionic vinyl polymerization, as can be seen in Figure 1(A). The polymerization results are summarized in Table 1. The complete conversion of 1 was always achieved by the initiation with Ph 2 CHK or Ph 3 CK in the absence or presence of Et 2 Zn at 78 C within 20 h. The observed molecular weights of the poly(1)s 30 agreed with the calculated values based on the molar ratios of 1 and the organopotassium initiators, indicating the quantitative initiation efficiency. Size exclusion chromatography (SEC) showed that the resultant poly(1)s possessed unimodal MWDs. In the absence of Et 2 Zn, the polydispersity index [weight-average molecular weight/number-average molecular weight (M w /M n )] was 1.23, indicating the relatively narrow MWD. However, when the polymerization of 1 was performed in the presence of Et 2 Zn, the MWDs of the polymers were effectively narrowed. The M w /M n values were reduced to around 1.1. A typical SEC curve of poly(1) obtained with Ph 2 CHK/Et 2 Zn is shown in Figure 2(A). It is, therefore, substantiated that the anionic polymerization of a novel N,N-dialkylacrylamide (1) quantitatively proceeds in a controlled fashion in the presence of the Lewis acid Et 2 Zn, as well as our previous report concerning N,N-dimethyl-, N,N-diethyl-, and N,N-dipropylacrylamides, N-acryloyl pyrrolidine, and N-acryloyl piperidine. 28 Figure 1. 1 H NMR spectra of (A) poly(1) and (B) poly(nipam) after deprotection in CDCl 3. The peaks attributable to solvents are marked with asterisks.

3 4330 J. POLYM. SCI. PART A: POLYM. CHEM.: VOL. 40 (2002) Table 1. Anionic Polymerization of 1 in THF at 78 C for 20 h a No. 1 (mmol) Inititator 10 3 M n Type mmol Et 2 Zn (mmol) Calcd. b Obsd. c M w /M n d Ph 2 CHK Ph 2 CHK Ph 2 CHK Ph 2 CHK Ph 3 CK a The yields of isolated polymers were always quantitative. b M n (calcd.) (molecular weight of monomer) [monomer]/[initiator] molecular weight of initiator residue. c M n (obsd.) was obtained by end-group analysis with 1 H NMR spectroscopy. d M w /M n was obtained by SEC calibration with polystyrene standards in DMF containing 0.01 M LiBr. The methoxymethyl group of poly(1) was then hydrolyzed by treatment with aqueous hydrochloric acid in 1,4-dioxane or THF at room temperature for 20 h, as shown in Scheme 1. The deprotected polymer was precipitated and isolated by the reaction mixture being poured into hexane. The 1 H and 13 C NMR and IR spectra of the isolated polymer 31 were identical to those of authentic poly(nipam) obtained by the free-radical polymerization of NIPAM itself, 32 indicating that the complete removal of the methoxymethyl protecting group was attained. In the 1 H NMR spectrum of the hydrolyzed polymer, the proton signals due to CH 2 OCH 3 (3.26 ppm) and CH 2 OCH 3 (4.6 ppm) completely disappeared, as can be seen in Figure 1(B). A Figure 2. SEC curves of (A) poly(1) (M w /M n 1.07) and (B) poly(nipam) after deprotection (M w /M n 1.06), as measured in DMF containing 0.01 M LiBr. new broad signal characteristic of the amide proton can be alternatively observed at ppm. The 13 C NMR resonances at 54.6 and 75.2 ppm corresponding to the methoxymethyl groups of poly(1) thoroughly disappeared after the hydrolysis. In the IR spectra, the strong absorption at 1084 cm 1 due to the CH 3 OOOCH 2 ON linkage disappeared, whereas the new broad band of the CONH group at cm 1 appeared. Figure 2(B) clearly shows that the SEC curve of the deprotected poly(nipam) (M w /M n 1.06), measured in N,N-dimethylformamide (DMF) containing 0.01 M LiBr, maintains the unimodal and narrow shape of the original poly(1). Very interestingly, the SEC curve shifts toward a higher molecular weight region after the deprotection reaction, whereas the theoretical molecular weight of the deprotected polymer is lower than that of the protected one. 33 This is probably due to the great difference in the hydrodynamic volumes of poly(1) and the deprotected poly(nipam), which has a highly polar secondary amide functionality in a DMF solution. In fact, the degree of polymerization of deprotected poly(nipam) estimated by 1 H NMR (68) was again in good agreement with the calculated value (69). These results indicate that the deprotection of poly(1) quantitatively proceeds to give poly(nipam) with a narrow MWD and the predicted M n value without side reactions such as main-chain degradation and crosslinking. The dyad tacticity of the deprotected poly(nipam) was determined by the 1 H NMR spectrum of the methylene proton of the polymer main chain in DMSO-d 6 at 120 C. In the absence of Et 2 Zn, the tacticity of the resulting poly(nipam) is slightly isotactic-rich (m 69, r 31; Table 1, run 1). 34 However, the m contents of poly(nipam)s produced with binary initiator systems of Ph 2 CHK/Et 2 Zn (run 4) and Ph 3 CK/Et 2 Zn (run 5) decreased to 50 and 51%, respectively. These values are comparable with the tacticity of poly(nipam) (m 50) obtained by the free-radical polymerization of NIPAM with azobisisobutyronitrile (AIBN) in benzene. 32 The additive effect of Et 2 Zn is, therefore, ob-

4 RAPID COMMUNICATION 4331 served for the controls of the stereoregularity and MWD of the resulting polymers. The solubility of poly(1) certainly changed after deprotection, as expected. Before deprotection, poly(1) was soluble in benzene, diethyl ether, chloroform, 1,4- dioxane, THF, DMF, and methanol but insoluble in hexane and water. However, poly(nipam) after the deprotection showed solubility in chloroform, 1,4-dioxane, THF, DMF, methanol, and water but was insoluble in hexane, benzene, and diethyl ether. The appearance of the polar secondary amide group certainly increased the polarity of the polymer and provided poly(nipam) with poor solubility in nonpolar solvents. It should be emphasized that poly(nipam) so obtained showed the typical cloud point in aqueous media, as previously reported. 1,11,12,34 The water solution of the deprotected polymer became turbid around 32 C when the temperature increased or decreased. 35 This LCST phenomenon again supports the idea that poly(ni- PAM) is unequivocally obtained after deprotection. In summary, we have successfully synthesized water-soluble and temperature-sensitive poly(nipam) having well-defined chain structures such as predetermined M n s and narrow MWDs via the anionic polymerization of the novel protected N,N-dialkylacrylamide 1 and the subsequent deprotection of poly(1). A detailed investigation into the (co)polymerization behavior of 1 and into the relationship between the stereoregularity and solution properties of the resulting poly(nipam) is now in progress. This work was partially supported by the Shorai Foundation and the Iwatani Naoji Foundation. REFERENCES AND NOTES 1. Schild, H. G. Prog Polym Sci 1992, 17, Wu, X. S.; Hoffman, A. S.; Yager, P. J Polym Sci Part A: Polym Chem 1992, 30, Kokufuta, E.; Zhang, Y.-Q.; Tanaka, T.; Mamada, A. Macromolecules 1993, 26, Nagaoka, N.; Safranj, A.; Yoshida, M.; Omichi, H.; Kubota, H.; Katakai, R. Macromolecules 1993, 26, Liang, L.; Rieke, P. C.; Liu, J.; Fryxell, G. E.; Young, J. S.; Engelhard, M. K.; Alford, K. L. Langmuir 2000, 16, Bae, Y. H.; Okano, T.; Kim, S. W. J Polym Sci Part B: Polym Phys 1990, 28, Yoshida, R.; Sakai, K.; Okano, T.; Sakurai, Y. J Biomater Sci Polym Ed 1994, 6, Bergbreiter, D. E.; Osburn, P. L.; Wilson, A.; Sink, E. M. J Am Chem Soc 2000, 122, Kimura, M.; Kato, M.; Muto, T.; Hanabusa, K.; Shirai, H. Macromolecules 2000, 33, Park, Y. S.; Ito, Y.; Imanishi, Y. Langmuir 1998, 14, Heskins, M.; Guillet, J. E. J Macromol Sci Chem 1968, 2, Fujishige, S.; Kubota, K.; Ando, I. J Phys Chem 1989, 93, Tanahashi, T.; Kawaguchi, M.; Honda, T.; Takahashi, A. Macromolecules 1994, 27, Chen, G.; Hoffman, A. S. Nature 1995, 373, It is noteworthy that recent progress in the radical polymerization of NIPAM enables to some extent the synthesis of polymers with either a controlled molecular weight or a high isotacticity. See refs. 16 and Ganachaud, F.; Monteiro, M. J.; Gilbert, R. G.; Dourges, M.-A.; Thang, S. H.; Rizzardo, E. Macromolecules 2000, 33, Isobe, Y.; Fujioka, D.; Habaue, S.; Okamoto, Y. J Am Chem Soc 2001, 123, Bordwell, F. G. Acc Chem Res 1988, 21, The possibility of the hydrogen-transfer polymerization (1,4-addition) of NIPAM under anionic conditions has been suggested. See Kennedy, J. P.; Otsu, T. J Macromol Sci Rev Macromol Chem 1972, 6, Nakahama, S.; Hirao, A. Prog Polym Sci 1990, 15, Ishizone, T.; Okamoto, K.; Hirao, A.; Nakahama, S. Macromolecules 1999, 32, Hirao, A.; Loykulnant, S.; Ishizone, T. Prog Polym Sci 2002, 27, Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley-Interscience: New York, A colorless liquid of 1 was obtained in a 20% yield by column chromatography (silica gel, hexane/ ethyl acetate) and subsequent vacuum distillation (94 96 C at 8 mmhg). 1 H NMR (300 MHz, CDCl 3, ): 1.20 (d, J 6.7 Hz, 6H, CH 3 ), 3.32 (s, 3H, OCH 3 ), 4.60 (s, 2H, NCH 2 O), (br, 1H, CHCH 3 ), 5.71 (d, J 10.2 Hz, 1H, trans ACH 2 ), 6.36 (d, J 16.8 Hz, 1H, cis ACH 2 ), 6.58 (dd, 1H, OCHA). 13 C NMR (75 MHz, CDCl 3, ): 20.8 (CH 3 ), 45.5 (CH), 54.9 (OCH 3 ), 75.6 (NCH 2 O), (OCHA), (CH 2 A), (CAO). IR (neat): 2978, 1657, 1617, 1430, 1397, 1231, 1084 cm The striking additive effect of Et 2 Zn on the controls of molecular weights and MWDs has been reported in the anionic polymerizations of alkyl (meth)acrylates and N,N-dialkylacrylamides. See refs Ozaki, H.; Hirao, A.; Nakahama, S. Macromol Chem Phys 1995, 196, Ishizone, T.; Yoshimura, K.; Hirao, A.; Nakahama, S. Macromolecules 1998, 31, Kobayashi, M.; Okuyama, S.; Ishizone, T.; Nakahama, S. Macromolecules 1999, 32, Poly(1). 1 H NMR (300 MHz, CDCl 3, ): 1.09 (s, 6H, CH 3 ), 1.7 (2H, CH 2 CH), 2.5 (1H, CH 2 CH), 3.26 (s, 3H, OCH 3 ), (overlapped, 3H, NCH 2 O and CHCH 3 ). 13 C NMR (75 MHz, CDCl 3, ): 20.8 (CH 3 ), (CH 2 CH), 45.0 (CH), 54.6 (OCH 3 ), 75.2

5 4332 J. POLYM. SCI. PART A: POLYM. CHEM.: VOL. 40 (2002) (NCH 2 O), (CAO). IR (KBr): 2976, 1651, 1427, 1397, 1226, 1084 cm The molecular weights of the poly(1)s were estimated by end-group analysis with 1 H NMR spectroscopy. The relative signal intensities of the aromatic protons of the initiator residues were compared with those of other proton signals corresponding to the repeating units of poly(1). 31. Poly(NIPAM) after deprotection. 1 H NMR (300 MHz, CDCl 3, ): 1.16 (s, 6H, CH 3 ), (3H, CH 2 CH), 4.0 (1H, CHCH 3 ), (br, 1H, CONH). 13 C NMR (75 MHz, CDCl 3, ): 22.4 (CH 3 ), (CH 2 CH), 41.2 (CH), (CAO). IR (KBr): , 2973, 1651, 1558, 1459, 1387, 1368, 1174 cm The free-radical polymerization of NIPAM was performed with AIBN in benzene at 60 C for 17 h. A poly(nipam) (M n 36000, M w /M n 4.20) was obtained in a quantitative yield. 33. The SEC chromatogram of the deprotected poly- (NIPAM) measured in THF shifted toward the lower molecular weight region, with the narrow MWD kept narrow. 34. The poly(nipam) obtained by the deprotection of poly(1) produced with Ph 2 CHK in the absence of Et 2 Zn (Table 1, run 1) was insoluble in water. The low solubility of isotactic poly(nipam) is also reported in ref The cloud point of poly(nipam) (M n 6600, M w /M n 1.12) in water was measured by the monitoring of the transmittance of a 0.2 wt % aqueous solution at 500 nm at a heating or cooling rate of 0.2 C/min.