Design, Synthesis, and Aqueous Aggregation Behavior of Nonionic

Sep 28, 2006 - The temperature of the cloud point can be easily fine tuned by the copolymer composition. As for poly(N-isopropylacrylamide) and poly(N...
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Langmuir 2007, 23, 84-93

Design, Synthesis, and Aqueous Aggregation Behavior of Nonionic Single and Multiple Thermoresponsive Polymers† Katja Skrabania,‡ Juliane Kristen,‡ Andre´ Laschewsky,*,‡ O ¨ zgu¨r Akdemir,§ Ann Hoth,§ and § Jean-Franc¸ ois Lutz UniVersita¨t Potsdam, P.O. Box 601553, D-14415 Potsdam, Germany, and Fraunhofer Institute for Applied Polymer Research FhG-IAP, P.O. Box 600651, D-14406 Potsdam, Germany ReceiVed May 27, 2006. In Final Form: August 22, 2006 Nonionic water-soluble poly(acrylamide)s and poly(acrylate)s were synthesized by RAFT and ATRP methods. Similar to the synthesized poly(N-isopropylacrylamide) and poly(N-acryloylpyrrolidine), aqueous solutions of statistical acrylate copolymers bearing two different oligo(ethylene oxide) side chains showed a sharp clouding transition upon heating beyond characteristic temperatures. The temperature of the cloud point can be easily fine tuned by the copolymer composition. As for poly(N-isopropylacrylamide) and poly(N-acryloylpyrrolidine), the cloud-point temperatures of these statistical copolymers are rather insensitive to changes in the molar mass or the NaCl content of the solutions. Also, ternary triblock copolymers containing one permanently hydrophilic block and two different thermoresponsive blocks were synthesized, varying the block sequence systematically. Their aggregation in aqueous solution was followed by turbidimetry and dynamic light scattering. Depending on the heating process and the triblock sequence, micellar aggregates of 40 to 600 nm size were found. The thermally induced aggregation behavior depends sensitively on the block sequence but is also subject to major kinetic effects. For certain block sequences, a thermally induced two-step association is observed when heating beyond the first and second cloud points of the thermoresponsive blocks. However, the thermal-transition temperatures of the block polymers can differ from the thermal-transition temperatures of the individual homopolymers. This may be caused by end-group effects but also by mutual interactions of the different blocks in solution, as physical mixtures of the homopolymers exhibit deviations from a purely additive thermal behavior.

1. Introduction Stimuli-sensitive polymers that undergo a transition from a water-soluble to a water-insoluble state have been intensely studied in recent years within various frameworks (e.g., for hydrogels, thickeners, coatings, and associative polymers1,2). Within the latter group, block copolymers that acquire or lose amphiphilicity upon application of a stimulus have been a major focus (“surfactant on demand”).3-5 Thermoresponsive block copolymers are particularly attractive in this context because the thermally induced changes are a priori fully reversible and no reagents must be added or removed to switch the hydrophilicity or hydrophobicity. Two types of thermoresponsive behavior can be distinguished. Either polymers are water-soluble at high temperature but insoluble at low temperature (i.e., an upper critical solution temperature (UCST) exists) or polymers are water-soluble at low temperature but insoluble at high temperature (i.e., the systems exhibit a lower critical solution temperature (LCST)). Typically, the latter case predominates in aqueous solutions of nonionic polymers. In fact, a multitude of nonionic polymers † Part of the Stimuli-Responsive Materials: Polymers, Colloids, and Multicomponent Systems special issue. * Corresponding author. E-mail: [email protected]. Phone: +493319775225. Fax: +493319775036. ‡ Universita ¨ t Potsdam. § Fraunhofer Institute for Applied Polymer Research FhG-IAP.

(1) Stimuli-ResponsiVe Water Soluble and Amphiphilic Polymers; McCormick, C. L., Ed.; ACS Symposium Series 780; The American Chemical Society: Washington, DC, 2001. (2) Gil, E. S.; Hudson, S. M. Prog. Polym. Sci. 2004, 29, 1173-1222. (3) Rodrı´guez-Herna´ndez, J.; Che´cot, F.; Gnanou, Y.; Lecommandoux, S. Prog. Polym. Sci. 2005, 30, 691-724. (4) Garnier, S.; Laschewsky, J.; Storsberg, J. Tenside, Surfactants, Deterg. 2006, 43, 88-102. (5) Storsberg, J.; Garnier, S.; Mertoglu, M.; Skrabania, S.; Laschewsky, J. SO ¨ FW J. 2006, 132, 48-54.

with LCST behavior in water is known.2,6-14 Concerning amphiphilic thermoresponsive block copolymers, most investigations have focused on systems in which the hydrophilic block is converted by a thermal stimulus into a water-insoluble block.2,4,15-18 Though still a minority, double-hydrophilic block copolymers in which one of the hydrophilic blocks becomes hydrophobic in a certain temperature range and thus the copolymer becomes amphiphilic seem to behave more advantageously if a “surfactant on demand” is looked for.3,4,5,19-25 Recent efforts have aimed at increasing the complexity and flexibility of such (6) Kirsh, Yu. E. Prog. Polym. Sci. 1993, 18, 519-542. (7) Plate´, N. A.; Lebedeva, T. L.; Valuev, L. I. Polym. J. Jpn. 1999, 31, 21-27. (8) Laschewsky, A.; Rekaı¨, E. D.; Wischerhoff, E. Macromol. Chem. Phys. 2001, 202, 276-286. (9) Han, S.; Hagiwara, M.; Ishizone, T. Macromolecules 2003, 26, 83128319. (10) Sugihara, S.; Kanaoka, S.; Aoshima, S. J. Polym. Sci., Part A: Polym. Chem. 2004, 42, 2601-2611. (11) Zhang, J.-T.; Huang, S.-W.; Gao, F.-Z.; Zhuo, R.-X. Colloid Polym. Sci. 2005, 283, 461-464. (12) Sugihara, S.; Kanaoka, S.; Aoshima, S. Macromolecules 2005, 38, 19191927. (13) Seto, Y.; Aoki, T.; Kunugi, S. Colloid Polym. Sci. 2005, 283, 11371142. (14) Hua, F.; Jiang, X.; Zhao, B. Macromolecules 2006, 39, 3476-3479. (15) Yang, Z.; Pickard, S.; Deng, N.-J.; Barlow, R. J.; Attwood, D.; Booth, C. Macromolecules 1994, 27, 2371-2379. (16) Booth, C.; Attwood, D. Macromol. Rapid Commun. 2000, 21, 501-527. (17) Chen, X. R.; Ding, X. B.; Zheng, Z. H.; Peng, Y. X. Colloid Polym. Sci. 2005, 283, 452-455. (18) Garnier, S.; Laschewsky, A. Colloid Polym. Sci. 2006, 284, 1243-1254. (19) Maeda, Y.; Taniguchi, Y.; Ikeda, I. Macromol. Rapid Commun. 2001, 22, 1390-1393. (20) Robinson, K. L.; Paz-Ba´n˜ez, M. V.; Wang, X. S.; Armes, S. A. Macromolecules 2001, 34, 5799-5805. (21) Virtanen, J.; Holappa, S.; Lemmetyinnen, H.; Tenhu, H. Macromolecules 2002 35, 4763-4769. (22) Yusa, S.-i.; Shimada, Y.; Mitsukami, Y.; Yamamoto, T.; Morishima, Y. Macromolecules 2004, 37, 7507-7513. (23) Mertoglu, M.; Garnier, S.; Laschewsky, A.; Skrabania, K.; Storsberg, J. Polymer 2005, 46, 7726-7740.

10.1021/la061509w CCC: $37.00 © 2007 American Chemical Society Published on Web 09/28/2006

Nonionic ThermoresponsiVe Polymers

stimuli-sensitive polymers by designing double-sensitive polymers (i.e., such that they have two stimuli-sensitive blocks). Several scenarios are possible. If one block exhibits an UCST while the other presents a LCST at more elevated temperature, then the role of the blocks as hydrophilic and hydrophobic segments is inverted at low and high temperature; consequently, the block copolymer’s character changes with increasing temperature from amphiphilic to double-hydrophilic to amphiphilic again (“schizophrenic micelles”).26-29 Alternatively, if both blocks exhibit a LCST, a transition from a double-hydrophilic to an amphiphilic and finally to a double-hydrophobic block copolymer occurs with increasing temperature.12,14,23,30-32 The above-cited examples represent all-or-none systems with respect to amphiphilicity and associative behavior in aqueous solution. Such systems are interesting from several points of view. Still in certain cases, more gradual or more subtle changes are desirable (e.g., temperature-induced changes in the hydrophilic-hydrophobic balance (while the general amphiphilic character is preserved), with accompanying changes in micellar size or shape, surface activity, solubilization power, etc.). This may be realized by ternary ABC triblock copolymers in which a hydrophilic block and a hydrophobic block are combined with a thermoresponsive block.33-36 Three cases are possible for such ABC block copolymers, either with the permanently hydrophilic block or with the permanently hydrophobic block or with the thermoresponsive block in the middle of the polymer. However, amphiphilic block copolymers are often difficult to dissolve directly in water.4,5 Therefore, it is advantageous to use a doublethermoresponsive system in which the permanently hydrophobic block is replaced by a second thermoresponsive one with, for example, a low LCST: the polymer can be homogeneously dissolved in water at low temperatures as a triple-hydrophilic block copolymer. Then, two successive thermal transitions convert it into amphiphilic polymers of stepwise decreasing hydrophilichydrophobic balance (Figure 1). Three permutations of the position of the functional blocks are possible. Such double stimulisensitive23,37 and in particular such double thermoresponsive10,38,39 ternary triblock polymers are exceptional. This is at least partially due to the difficulty of synthesizing such polymers because typically the use of controlled polymerization methods that are compatible with all three polymer blocks is required. Though (24) Liu, B.; Perrier, S. J. Polym. Sci., Part A: Polym. Chem. 2005, 43, 36433654. (25) Convertine, A. J.; Lokitz, B. S.; Vasileva, Y.; Myrick, L. J.; Scales, C. W.; Lowe, A. B.; McCormick, C. L. Macromolecules 2006, 39, 1724-1730. (26) Liu, S. Y., Billinghma, N. C.; Armes, S. P. Angew. Chem. 2001, 113, 2390-2391. (27) Arotc¸ are´na, M.;. Heise, B.; Ishaya, S.; Laschewsky, A. J. Am. Chem. Soc. 2002, 124, 3787-3793. (28) Virtanen, J.; Arotc¸ are´na, M.; Heise, B.; Ishaya, S.; Laschewsky, A.; Tenhu, H. Langmuir 2002, 18, 5360-5365 (29) Maeda, Y.; Mochiduki, H.; Ikeda, I. Macromol. Rapid Commun. 2004, 25, 1330-1334. (30) Forder, C.; Patrickios, C. S.; Armes, S. P.; Billingham, N. C. Macromolecules 1996, 29, 8160-8169. (31) Dimitrov, P.; Rangelov, S.; Dorak, A.; Haraguchi, N.; Hirao, A.; Tsvetanov, C. B. Macromol. Symp. 2004, 215, 127-129. (32) Okabe, S.; Seno, K.-i.; Kanaoka, S.; Aoshima, S.; Shibayama, M. Macromolecules 2006, 39, 1592-1597. (33) Triftaridou, A. I.; Vamvakaki, M.; Patrickios, C. S. Polymer 2002, 43, 2921-2926. (34) Kyriacou, M. S.; Hadjiyannakou, S. C.; Vamvakaki, M.; Patrickios, C. S. Macromolecules 2004, 37, 7181-7187. (35) Zhang, W. Q.; Shi, L. Q.; Ma, R. J.; An, Y. L.; Xu, Y. L.; Wu, K. Macromolecules 2005, 38, 8850-8852. (36) Aubrecht, K. B.; Grubbs, R. B. J. Polym. Sci., Part A: Polym. Chem. 2005, 43, 5156-5167. (37) Zhu, Z.; Armes, S. P.; Liu, S. Macromolecules 2005, 38, 9803-9812. (38) Bu¨tu¨n, V.; Wang, X. S.; De Paz Ba´nez, M. V.; Robinson, K. L.; Billingham, N. C.; Armes, S. P. Macromolecules 2000, 33, 1-3. (39) Li, C.; Buurma, N. J.; Hoq, I.; Turner, C.; Armes, S. P. Langmuir 2005, 21, 11026-11033.

Langmuir, Vol. 23, No. 1, 2007 85

Figure 1. Schematic scenario of thermal transitions of double thermoresponsive ternary ABC block copolymers, adapting the hydrophilic-hydrophobic balance of polymeric amphiphiles: (i) T < LCST1 and LCST2, all blocks water soluble; (ii) LCST1 < T < LCST2, collapse of the middle block showing the lowest LCST; (iii) LCST1 < T < LCST2, collapse of the end block showing the lowest LCST; (iv) LCST1 and LCST2 < T, permanently hydrophilic end block, other blocks are collapsed; (v) LCST1 and LCST2 < T, permanently hydrophilic middle block, other blocks are collapsed.

Figure 2. Monomers used.

beautiful examples for multiple thermoresponsive polymers by living ionic polymerization were demonstrated,10,33,34 the methods of controlled free-radical polymerization40 have greatly expanded the synthetic possibilities23,39 because these methods are more tolerant toward functional hydrophilic groups. In particular, substituted acrylamides can be employed to construct the thermoresponsive blocks. Appropriate substitution of the amide nitrogen enables us to vary the LCST of poly(acrylamide)s over the full temperature scale of liquid water at ambient pressure (i.e., from 0 to 100 °C7). The most widely used monomer is N-isopropylacrylamide (M3, Figure 2) because of the weak sensitivity of its polymer’s transition temperature to changes in molar mass, concentration, and added salts.41 Moreover, aqueous solutions of poly(N-isopropylacrylamide) poly(M3) show typically a cloud-point temperature of about 32 °C, which is very convenient for many studies. Polymers other than poly(acrylamide)s, which allow broad tuning of the LCST and are suited for controlled free-radical polymerization, are acrylic and methacrylic esters of alkyl-end-capped oligo(ethylene oxide)s. 9,14,23,42

In this study, a model set of three double thermoresponsive ternary block copolymers is synthesized by controlled free-radical (40) Handbook of Radical Polymerization; Matyjaszewski, K., Davis, T. P., Eds.; Wiley-Interscience: Hoboken, NJ, 2002 (41) Schild, H. G. Prog. Polym. Sci. 1992, 17, 163-249.

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Skrabania et al.

Table 1. Polymerization Conditions Used and Samples Prepared

entry

monomer type

amount (mmol)

CTA or macroCTA (mol × 10-5)

initiator AIBN (mol × 10-5)

polym temp (°C)

solvent

polym time (h)

1 2 3 4 5 6 7 8 9 10

M1 M2 M2 M3 M3 M1 M2 M2 M2 M1

121 8 8 107 29 32 13 9 13 4

CPDTB (59.8) CDTB (8) BDTPA (3.3) CPDTB (52.9) polyM1 (14.5) polyM3 (15.7) polyM3 (6.5) poly(M1-b-M3) (4.2) poly(M3-b-M1) (6.6) poly(M3-b-M2) (2.6)

12.2 1.6 0.7 10.9 2.9 3.3 1.3 0.8 1.3 0.4

65 70 66 65 65 65 65 65 65 65

toluene (36 mL) toluene (5 mL) THF (5 mL) toluene (41 mL) toluene (35 mL) THF (11 mL) THF (8 mL) THF (9 mL) THF (8 mL) THF (8 mL)

7.5 24 2 13 12 6 6 12 12 12

Table 2. Characteristics of the Poly(acrylamide) Homo- and Block Copolymers Synthesizeda entry

sample

Mn × 10-3 (g mol-1)b

DPn of blocksb

Mvis × 10-3 (g mol-1)c,d

MSEC × 10-3 (g mol-1)f

Mw/Mn g

1 2 3 4 5 6 7 8 9 10

poly(M1) poly(M2) poly(M2) poly(M3) poly(M1-b-M3) poly(M3-b-M1) poly(M3-b-M2) poly(M1-b-M3-b-M2) poly(M3-b-M1-b-M2) poly(M3-b-M2-b-M1)

14 7 17e,f 13 20 18 21 23 26 28

139 52 133e,f 110 139-52 110-52 110-70 139-52-28 110-52-69 110-70-64

14c 7d

13 5 17 9 21 14 17 24 14 18

1.01 1.47 1.84 1.21 1.31 1.40 1.59 1.68 1.67 1.73

e

13c 35c 18c 28c h h h

a Entry numbers are the same as in Table 1. b Mn of the first block was calculated by end-group analysis of the visible band (cf. Mvis), and Mn of further blocks was calculated from the averaged compositional data according to 1H NMR, assuming that Mn of the first block is preserved in the block copolymer. c Calculated by end-group analysis of the visible band (dithiobenzoate absorbance at 499 nm,  ) 113 L mol-1 cm-1 in THF). d Calculated by end-group analysis of the visible band (dithiobenzoate absorbance at 494 nm,  ) 106 L mol-1 cm-1 in MeOH). e The visible absorbance band of the dithiophenyl acetate group (463 nm,  ) 39 L mol-1 cm-1 in butyl acetate) is too weak for a reliable determination of molar mass. f Apparent molar mass at peak maximum of SEC traces (eluent, 0.05 M LiBr/NMP; calibrated with polystyrene). g Apparent polydispersity of GPC traces (eluent, 0.05 M LiBr/NMP; calibrated with polystyrene). h The visible absorbance of the dithiobenzoate group is too weak for a reliable determination of molar mass.

polymerization and explored preliminarily with respect to their thermally induced association in water by turbidity and dynamic light scattering. The ternary block copolymers consist of a permanently hydrophilic block, a block with a relatively high LCST, and a block with a relatively low LCST. For convenience, poly(N-isopropylacrylamide) poly(M3) is chosen for the latter, and poly(N,N-dimethylacrylamide) poly(M1) is selected as the permanently hydrophilic polymer (Figure 2). The third polymer block with a relatively high LCST is chosen such that its transition temperature is expected to be about 20 °C higher than that of poly(M3) to allow sufficient resolution of the two expected thermal transitions while maintaining simple experimental conditions to study them. Because such thermoresponsive polymers have been much less studied, we compare in the first step two potential candidates, namely, poly(N-acryloylpyrrolidine) poly(M2)18,23,43 and statistical copolymers of (meth)acrylates with different oligo(ethylene oxide) chains (Figure 2, Tables 1-3)42 for this role. 2. Experimental Section 2.1. Materials. Chemicals. All reagents were purchased at the highest purity available and used as received unless otherwise stated. N,N-Dimethyl acrylamide (M1, >99%), 2-(2-ethoxyethoxy)ethyl acrylate (M4, 90%), oligo(ethylene glycol) methyl ether acrylate (M5, Mn ) 454 g‚mol-1), 2-(2-methoxyethoxy)ethyl methacrylate (M6, 95%), oligo(ethylene glycol) methyl ether methacrylate (M7, Mn ) 475 g‚mol-1), and methyl 2-bromopropionate (MBP, 98%) were purchased from Aldrich. Monomer M1 and THF were passed trough basic aluminum oxide (activity I, Merck, Germany) to remove (42) Lutz, J.-F.; Hoth, A. Macromolecules 2006, 39, 893-896. (43) Garnier, S.; Laschewsky, A. Macromolecules 2005, 38, 7580-7592.

Table 3. Properties of Acrylate Copolymers of M5 and M4 Prepared by ATRPa

1 2 3 4

[M5]0/ [M4]0

conversionb

FM5c(%)

Mnd

Mw/Mn d

cloud point (°C)

30:70 20:80 10:90 0:100

0.85 0.89 0.90 0.95

29 19 10 0

19 000 12 200 13 800 17 500

1.57 1.19 1.32 1.66

49.9e 38.5e 26.8e 9f

a Reaction conditions: ([M5]0 + [M4]0)/[MBP]0/[CuBr]0/[Bipy]0 ) 100:1:1:2; polymerization at 90 °C for 9.5 h in the bulk. a Overall monomer conversion measured by 1H NMR. b Molar fraction of M5 in the copolymer as determined by integration of 1H NMR signals. c Measured by SEC in THF. d Aqueous solutions (concentration 3 mg‚mL-1). e Measured visually.

inhibitors di-tert-butyl-p-cresol and hydroquinone monomethyl ether prior to polymerization. N-Isopropyl acrylamide (M3, 99%) was purchased from Acros and recrystallized from hexane/benzene 1:1 (vol/vol) to remove the inhibitor. 2,2′-Azobis (2-methylpropionitrile) (AIBN, 98%, Acros) was recrystallized from methanol. 2,2′ Bipyridyl (Bipy, 98%) was obtained from Fluka. Copper(I) bromide (Aldrich, 98%) and copper(I) chloride (Acros, 95%) were suspended in glacial acetic acid to remove any soluble oxidized species, filtered, washed with ethanol, and dried. N-Acryloylpyrrolidine (M2),23 cumyldithiobenzoate23 (CDTB), 4-thiobenzoylsulfanyl-4-cyanopentanoic acid23 (CPDTB), and benzyldithiophenylacetate43 (BDTPA) were prepared as described before. Atom-transfer statistical copolymerization of M6 and M7 to give poly(M6-stat-M7) is described elsewhere.42 Solvents used for synthesis and purification were all analytical grade. General Procedure for ReVersible Addition Fragmentation ChainTransfer Polymerization. Monomer, RAFT agent, and initiator AIBN were dissolved in toluene or THF. The reaction mixture was transferred to a 50 mL round-bottomed flask equipped with a magnetic stirring bar and a stopcock. Oxygen was removed from the reaction

Nonionic ThermoresponsiVe Polymers mixture by three freeze-pump-thaw cycles, followed by purging with nitrogen. The flask was immersed in a preheated oil bath and stirred for the required polymerization time. Polymerization was stopped by cooling the flask in a dry ice/acetone mixture. Polymers were purified by three precipitations into diethyl ether. Finally, the polymer samples were dissolved in water, filtered, and lyophilized. Table 1 lists the type and the amounts of monomer, initiator, and RAFT agent engaged and the solvents and the reaction temperatures for the various polymers synthesized. General Procedure for Atom-Transfer Statistical Copolymerization of M4 and M5. Copper bromide and 2,2′-bipyridyl were added to a Schlenk tube sealed with a septum. The tube was purged with dry argon for a few minutes. Then, a degassed mixture of M4 and M5 was added through the septum with a degassed syringe, and methyl 2-bromopropionate was added with a microliter syringe. The mixture was held at 90 °C for several hours and then diluted with ethanol and passed through a short silica column (60-200 mesh, Fluka) to remove the copper catalyst. The filtered solution was diluted with deionized water and dialyzed against water (Roth, ZelluTrans membrane, molecular weight cutoff 4000-6000). 2.2. Methods. Analytical NMR spectra were taken with a Bruker Avance 300 (300 MHz), and temperature-dependent NMR spectra were taken with a Bruker Avance 500 (500 MHz). UV-vis spectra were recorded with a Cary-1 (Varian) spectrophotometer equipped with a temperature controller (Julabo F-10). Quartz cuvettes (Suprasil, Hellma, Germany) with an optical path length of 10 mm were used. Number-average molar masses Mn of the homopolymers/macro RAFT agents were determined by end-group analysis using the visible absorption band of the dithioester end group (CPDTB ) 113 L‚mol-1‚cm-1 in THF, CDTB ) 106 L‚mol-1‚cm-1 in methanol), assuming that all of the polymer chains bear exactly one dithioester end group. Number-average molar masses Mn of the block copolymers were calculated from their composition according to NMR spectra, assuming that Mn of the first block is identical to the value of the macro RAFT agent employed. Size-exclusion chromatography (SEC) of the acrylamide-based polymers was run in N-methylpyrrolidone (NMP, >99%, Fluka) with 0.05 mol‚L-1 LiBr at 25 °C (flow rate 0.500 mL‚min-1) using a TSP apparatus (Thermo Separation Products from Thermo-Finnigan GmbH, Dreieich, Germany) equipped with a Shodex RI-71 refractive index detector, a TSP UV detector (270 nm), and SDV-10E3 columns (styrene divinyl benzene from MZ-Analysentechnik combined with styrene divinyl benzene from Polymer Laboratories). SEC of the statistical copolymers poly(M4-stat-M5) and poly(M6-stat-M7) was performed in tetrahydrofurane (THF) as the eluent at 25 °C using three 5 µ-MZ-SDV columns with pore sizes of 103, 105, and 106 Å (flow rate 1 mL‚min-1) and a refractive index detector (Shodex RI-71) and a UV detector (TSP UV 1000; 260 nm). All SEC systems were calibrated with polystyrene standards (PSS GmbH, Mainz, Germany). A model TP1 temperature-controlled turbidimeter (E. Tepper, Germany) was used with heating and cooling rates of 1° min-1. Transmittance of polymer solutions was set automatically to 90% at the beginning of each measurement. Dynamic light scattering was performed with a high-performance particle sizer (HPPS-ET, from Malvern Instruments) using a lightscattering apparatus equipped with a He-Ne (633 nm) laser and a thermoelectric Peltier temperature controller (temperature control range: 10-90 °C). The measurements were made at the scattering angle of θ ) 173 ° (backscattering detection). For each measurement, the optimal measurement position (i.e., the optimal distance of the focal point from the cuvette wall) and the optimal attenuator were automatically determined by the HPPS software (Dispersion Technology Software 4.0). The autocorrelation functions were analyzed with the CONTIN method. The apparent hydrodynamic diameters DH of micelles and aggregates are Z averages if not stated otherwise. They were calculated according to the Stokes-Einstein equation, DH ) kT/3πηDapp, with Dapp being the apparent diffusion coefficient and η being the viscosity of the solution. Prior to measurement, the polymer solutions were filtered using a WICOM OPTI-Flow 0.45 µm disposable filter and were placed in a quartz

Langmuir, Vol. 23, No. 1, 2007 87 glass cuvette. In the slow-heating protocol, temperature-dependent DLS experiments were run with a heating program from 25 to 65 °C in steps of 1 °C, equilibrating the samples for 10 min at each step. In the alternative rapid-heating protocol, polymer solutions were put in a cuvette at room temperature, placed in a heating bath of the desired measuring temperature, and equilibrated in the bath for 10 min before being transferred to the particle sizer that was preheated to the measuring temperature. Solutions of the block copolymers for DLS und turbidimetry measurements were prepared by dissolving the polymers at ambient temperature in deionized water, generally with a concentration of 1 g‚L-1. For the investigation of the clouding temperature as a function of added NaCl, the solutions had a polymer concentration of 3 g‚L-1.

3. Results and Discussion 3.1. Selection of the Second Thermoresponsive Block. First, a conveniently accessible (meth)acrylic polymer with a LCST of about 50-60 °C was explored, which would thus be suited as a second thermoresponsive block in copolymers containing poly(N-isopropylacrylamide) poly(M3) with its LCST of 32 °C. Out of a series of poly(acrylamide)s reviewed,7 poly(Nacryloylpyrrolidine) poly(M2) with a reported LCST of 56 °C44 seemed promising18,23,43 and was thus synthesized and investigated (Tables 1 and 2). Alternatively, one may consider polymeric acrylate and methacrylate esters of oligo(ethylene oxide)s.9,14,23,42 These monomers are well suited for controlled radical polymerization not only by the RAFT method but also by ATRP.40 However, the difference in the LCSTs of the homopolymers when adding or removing one ethylene oxide unit in the side chain is too large to provide a sensitive choice.9 To overcome this limitation, the LCST may be fine tuned by changing from homopolymers to statistical copolymers. This is a particular option for controlled free-radical polymerization because block copolymers whose blocks consist of statistical copolymers are otherwise difficult to build. Importantly, to obtain sharp phase transitions, random copolymers are needed. These are accessible by the chemical modification of precursor polymers8 or by copolymerization using chemically similar co-monomers, for instance, oligo(ethylene glycol) macromonomers of differing chain lengths (Table 3).42 For example, nearly random copolymers of M6 and M7 exhibit LCST values between 26 and 90 °C when varying the content of M6 from 100 to 0% in the copolymer.42 Alternative systems, which are more compatible with acrylamidebased blocks in block copolymer preparations of variable block sequences (vide infra) by controlled free-radical polymerization, can be based on analogous acrylate copolymers,45 using, for example, the commercial 2-(2-ethoxyethoxy)ethyl acrylate (M4) and oligo(ethylene glycol) methyl ether acrylate (M5). Whereas poly(M5) is water-soluble up to 100 °C, poly(M4) exhibits a LCST at approximately 9 °C. Cloud points of the nearly random copolymers of poly(M4-stat-M5) thus cover nearly the full thermal range of liquid water, increasing with the content of M5 in the copolymers (Table 3). For a content of approximately 30 mol % of M5, a LCST in the desired temperature range at about 50 °C is obtained. Figure 3 compares the thermal transitions of poly(M2) and of new copolymers poly(M4-stat-M5) as followed by turbidimetry. Clouding of the solutions takes place in a narrow temperature interval and with only a small hysteresis between the heating and cooling runs for all polymers. Such behavior would be expected for a homopolymer of narrow molar mass distribution (or of low molar mass dependence of the cloud point) (44) Ito, S.; Hirasa, O.; Yamauchi, A. Kobunshi Ronbunshu 1989, 46, 427. (45) Coote, M. L.; Kresnke, E. H.; Izgorodina, E. I. Macromol. Rapid Commun. 2006, 27, 473-497.

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Figure 3. Temperature-dependent transmittance at 670 nm of aqueous polymer solutions (3 mg‚mL-1). (A) poly(M2) (Table 2, entry 3); (B) poly(M4-stat-M5) (Table 3, entry 1, content of M5 ) 30 mol %). Broken lines: heating rate 1 °C‚min-1. Dotted lines: cooling rate 1 °C‚min-1.

Figure 4. Clouding temperature as a function of added NaCl for aqueous solutions of poly(M2) of different molar masses (O, benzyl end group, Mn ) 17 000 g‚mol-1 and ∆, cumyl end group, Mn ) 7000 g‚mol-1) and of copolymer poly(M6-stat-M7) (+, Mn ) 17400 g‚mol-1, content of M7 ) 10 mol %). The polymer concentration is 3 mg‚mL-1.

and corresponds to the behavior of the well-established thermoresponsive poly(M3).23 This first finding exemplifies the potential of the acrylate copolymers as attractive alternatives for poly(acrylamide) homopolymers. Concerning the transition temperatures, poly(M2) indeed meets the requirement of a cloudpoint temperature of about 20 °C higher than that of poly(M3). This requires, however, that a RAFT agent with a sufficiently polar leaving group (R group)40 be used. The benzyl moiety, which is widely employed for RAFT polymerization of acrylic monomers,23,40,43 seems to be a suitable leaving group to maintain the cloud-point temperature in the vicinity of 55 °C (Table 2). However, the considerably more hydrophobic cumyl moiety is clearly not suited to prepare poly(M2) with a cloud point reliably above 50 °C for low to moderate molar masses. Although the molar mass of the poly(M2) sample prepared with cumyldithiobenzoate as the RAFT agent is lower than of the samples prepared with benzyldithiophenylacetate as the RAFT agent (Table 2, entries 2 and 3), its cloud point is notably lowered to ca. 48 °C (Figure 4). Such end-group effects on the LCST are also known for poly(M3) with low to moderate molar masses.46 In this general context, another important parameter to know is the sensitivity of the transition temperature of thermoresponsive

Skrabania et al.

polymers to added salts. A preliminary test for added NaCl was therefore carried out for poly(M2) as well as for (meth)acrylic copolymers with oligo(ethylene oxide) side chains. Figure 4 exemplifies the evolution of the cloud points with increasing amounts of NaCl for two samples of poly(M2) and a copolymer poly(M6-stat-M7) containing ca. 10 mol % M7. A small saltingout effect of similar impact is observed for all polymers, reducing the transition temperature by about 4 °C at a concentration of 10 g‚L-1 NaCl. Accordingly, these polymers exhibit a low sensitivity to NaCl comparable to the sensitivity of the widely used poly(M3).47 Also, the sensitivity to molar mass differences of these polymers seems low. For instance, copolymers poly(M6-stat-M7) with ca. 10 mol % M7 units show cloud points of 39.5, 39.1, and 38.5 °C for number-average number molar mass of, respectively, 10 400 (Mw/Mn ) 1.2), 17 400 (Mw/Mn ) 1.2), and 29 300 g‚mol-1 (Mw/Mn ) 1.1) (copolymer concentration of 3 g‚L-1 in water). The findings demonstrate that both poly(2) and poly(M4stat-M5) with a content of ca. 30 mol % M5 in the acrylate copolymers are suitable candidates for the second thermoresponsive block in double stimuli-sensitive ternary block copolymers (cf. Figure 1) containing blocks of poly(M1) and poly(M3). The aqueous solutions of both poly(2) and poly(M4-stat-M5) undergo a thermal transition in the temperature range of interest, exhibit a sharp transition, and show low sensitivity to added NaCl. Still, for the sake of avoiding very complex molecular structures that would complicate the interpretations of the envisaged measurements, we finally preferred the homopolymer poly(M2) as a second thermoresponsive block in the following model study. Nevertheless, the choice is clearly not limited to the poly(acrylamide) family, and the new acrylate copolymers offer interesting options for the future work on thermoresponsive polymers. 3.2. Preparation of Ternary Block Copolymers. Ternary block copolymers of M1, M2, and M3 with different block sequences were prepared by successive RAFT polymerizations (Table 1). The well-established RAFT agent 4-thiobenzoylsulfanyl-4-cyanopentanoic acid CPDTB was used to prepare the first blocks of poly(M1) and poly(M3) because the leaving group of this RAFT agent is moderately hydrophilic. Thus, possible undesirable effects on the LCST by hydrophobic end groups, as discussed above, are precluded. Homopolymers poly(M1) and poly(M3) were subsequently employed as macro-RAFT agents for the polymerization of M2 and M3 or of M1, respectively. The resulting diblock copolymers poly(M1-block-M3), poly(M3-block-M2), and poly(M3-block-M1) were isolated and used on their own as macro-RAFT agents for the polymerization of the third block made of M2 or M1. The analytical data of the block copolymers are given in Table 2. Because all monomers are substituted acrylamides and thus should show similar reactivities toward dithioesters as well as similar dissociation energies for the radical-dithioester adducts,45 block copolymerizations went smoothly for any permutation of the monomer sequence. Because polymerization rates of M1, M2, and M3 differ and eventually induction periods might occur because a dithiobenzoate is used as a RAFT agent,48 whereas conversions must be kept low to allow for high blocking efficiencies and low polydispersities,40 it was not possible to prepare copolymers with exactly identical compositions. Still, the lengths of the various blocks of M1, M2, and M3 in the three copolymers are comparable (46) Furyk, S.; Zhang, Y.; Ortiz-Acosta, D.; Cremer, P. S.; Bergbreiter, D. E. J. Polym. Sci., Part A: Polym. Chem. 2006, 44, 1492-1501. (47) Freitag, R.; Garret-Flaudy, F. Langmuir 2002, 18, 3434-3440. (48) Barner-Kowollik, C.; Davis, T. P.; Heuts, J. P. A.; Stenzel, M. H.; Vana, P.; Whittaker, M. J. Polym. Sci., Part A: Polym. Chem. 2003, 41, 365-375.

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(cf. Table 2) and thus should allow meaningful comparisons. As inherent to the RAFT process, a small amount of “dead” polymer is formed in each polymerization step as well as a small amount of homopolymer,40 and the polymer products were purified by precipitation after each step. The SEC elugrams are monomodal and give no evidence of the presence of homopolymers or diblock copolymers in the final triblock copolymers, though contamination cannot be rigorously excluded. All triblock copolymers form transparent solutions in THF, CHCl3, or N-methylpyrrolidone. 3.3. Temperature-Dependent Aggregation Behavior in Aqueous Solution. All homopolymers, diblock copolymers, and ternary triblock copolymers of M1, M2, and M3 are soluble in water at ambient temperature. DLS measurements of dilute solutions did not indicate any aggregation, showing only the presence of objects with hydrodynamic diameter below 10 nm that are interpreted as isolated polymer coils. Also, 1H NMR spectra of the polymers exhibited the typical signals of all polymer blocks. However, the situation changes upon heating. Visually, the solutions become turbid when heated beyond a critical temperature. The turbidity evolves more or less with further increasing temperature for the various polymers and not always in a monotonic way. Temperature-dependent 1H NMR measurements show a gradual loss of signal intensity for the protons characteristic of fragments of M3 beyond 30 °C and of fragments of M2 beyond 60 °C, whereas the signals characteristic of fragments of M1 seem not to be affected. However, the changes in the NMR spectra do not appear as sharp transitions but evolve gradually with increasing temperature. Because a temperature-dependent visual inspection and turbidimetry indicated complex behavior for some solutions, turbidimetric measurements were combined with parallel DLS studies (Figure 5). The temperature-dependent DLS studies were all performed with the same temperature protocol because different heating and cooling rates led to different aggregate sizes. This kinetic aspect of the stimuli-driven association of thermoresponsive polymers is a matter of current research.28,49-51 Nevertheless, at first sight it becomes clear that the block sequence is a major factor influencing the thermoresponsive behavior. Also, it is evident that the temperature-induced changes are advantageously followed by both turbidimetry and by DLS because they do not necessarily detect the same events. For instance, the formation of small aggregates of poly(M1-blockM3-block-M2) upon heating is missed by turbidimetry (vide infra). An analysis of the data is best started with copolymer poly(M3-block-M2-block-M1) (Figure 5A) (i.e., the copolymer whose terminal blocks are poly(M3), which disposes of the lowest cloud point in the block copolymer system) and the permanently hydrophilic poly(M1). This molecular architecture should translate in thermal transitions from a homogeneously dissolved polymer to a linear amphiphile with a high hydrophilic-tohydrophobic balance above the LCST of poly(M3) and finally to a linear amphiphile with a low hydrophilic-to-hydrophobic balance above the LCST of the middle block of poly(M2) (cf. Figure 1, transitions (i) f (iii) f (iv)). Concerning the turbidity of the aqueous solutions, the transmittance drops indeed notably above 35 °C, which is attributed to the thermally induced collapse of the poly(M3) block. However, the cloudy solutions become more transparent and appear opaque only when heated further (49) Chen, H.; Zhang, Q.; Li, J.; Ding, Y.; Zhang, G.; Wu, C. Macromolecules 2005, 38, 8045-8050. (50) Aseyev, V.; Hietala, S.; Laukkanen, A.; Nuopponen, M.; Confortini, O.; Du Prez, F. E.; Tenhu, H. Polymer 2005, 7118-1731. (51) Kujawa, P.; Tanaka, F.; Winnik, F. M. Macromolecules 2006, 39, 30483055.

Langmuir, Vol. 23, No. 1, 2007 89

Figure 5. Temperature-dependent behavior of 0.1 wt % solutions of ternary block copolymers of M1, M2, and M3 as a function of the relative position of each block in the copolymer, as followed by DLS and turbidimetry. (A) poly(M3-block-M2-block-M1); (B) poly(M3-block-M1-block-M2); (C) poly(M1-block-M3-block-M2). Solid line: DLS curve, heating rate 1 °C‚min-1. Broken line: turbidimetric curve, heating rate 1 °C‚min-1. Dotted line: turbidimetric curve, cooling rate 1 °C‚min-1.

beyond 40 °C before they finally become milky when passing 55 °C (Figure 5A). This transition corresponds well to the LCST of the poly(M2) block. The cooling curve very closely resembles the heating curve, except for the absence of the local maximum of turbidity at about 40 °C. The perhaps surprising decrease of turbidity at intermediate temperatures upon heating has been observed occasionally before for thermoresponsive systems.14,15,23 Such a behavior was explained by different temperatures for the onset of (micro)phase separation of a polymer block, which induces clouding, and for a sufficient degree of dehydration, which is needed for the micellization of the collapsed chains.15 It is noteworthy that the intermediate minimum in the transmittance appears for this system only in the heating run, whereas a recent report observed such a reversible phenomenon.14 In agreement with the proposed explanation, DLS indicates an increase in colloid size in the solution between the cloud point and the local maximum of turbidity at 40 °C, at which a maximum colloid size of 500-600 nm is seen. Beyond this temperature, the size of the colloids decreases and stabilizes at ca. 200 nm diameter until above 54 °C, when the colloid size increases strongly again. The latter observation indicates that above the second thermal transition clustering of the primary micelles or rearrangement to larger micelles takes place for this polymer. The original micelles obviously cannot be preserved as individuals, in contrast to a different double responsive triblock copolymer

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Figure 6. Evolution of particle size distributions with temperature of 0.1 wt % aqueous solutions of block copolymers as studied by DLS and the slow-heating protocol: (A) poly(M3-block-M2-block-M1); (B) poly(M3-block-M1-block-M2); and (C) poly(M1-block-M3-blockM2).

Figure 7. Evolution of particle size distributions with temperature of 0.1 wt % aqueous solutions of block copolymers as studied by DLS and the fast-heating protocol: (A) poly(M3-block-M2-block-M1); (B) poly(M3-block-M1-block-M2); and (C) poly(M1-block-M3-blockM2).

system, for which two subsequent hydrophilic-hydrophobic transitions (induced by changes in the pH and salt concentration) changed the dimensions of individual micelles but did not induce secondary aggregation of the primary micelles.23 Otherwise, the hydrodynamic diameter would have decreased upon passing through the second thermal transition23 because the collapse of the hydrophilic shell of the core-shell-corona micelle, which is formed above the lower LCST, would reduce the size of the hydrophilic shell-corona region more than it would increase the size of the hydrophobic core. In copolymer poly(M3-block-M1-block-M2), the middle block is the permanently hydrophilic one. As discussed above, this molecular architecture should translate in the first thermal transition from a homogeneously dissolved polymer to a linear amphiphile with a high hydrophilic-to-hydrophobic balance above the LCST of poly(M3) and finally to a linear amphiphile with two hydrophobic end blocks above the LCST of poly(M2) (cf. Figure 1, transitions (i) f (iii) f (v)). Depending on the compatibility of the two collapsed blocks, mixed micelles might be formed. Alternatively, this copolymer could produce two populations of hydrophobic domains made of either poly(M3) or of poly(M2), which are tied together by the hydrophilic chains

of poly(M1). This behavior should lead to gels above a critical polymer concentration.39 Experimentally, the transparency of the aqueous solutions drops above 35 °C. The transmittance of the solution decreases markedly and continuously until ca. 45 °C and then slightly and continuously until 55 °C, above which temperature it stays virtually constant (Figure 5B). Similar to the case of poly(M3-block-M2-block-M1), DLS measurements of the solutions of poly(M3-block-M1-block-M2) exhibit an increase in colloid size in the solution between the cloud point and a local maximum of turbidity at ca. 45 °C, at which a maximum colloid size of 500 nm is found. This initial aggregation of the copolymers is again attributed to the collapse of the poly(M3) block. Upon further heating, the average size of the colloids decreases continuously toward ca. 200 nm diameter. This average size is somewhat misleading because above 45 °C the colloid size distribution becomes bimodal, comprising large (hydrodynamic diameter of about 400 nm) and small aggregates (hydrodynamic diameter of about 40 nm). The small colloid fraction increases with increasing temperature (Figure 6). This could be a consequence of a second thermal transition due to the collapse of the poly(M2) block, but it could be merely the result of a slow reorganization process (i.e., kinetic effects may play

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a role). Thus, from turbidimetry and DLS measurements, there is no clear indication of the occurrence of a second thermally induced aggregation process in this block copolymer. In the case of copolymer poly(M1-block-M3-block-M2), the middle block has the lowest LCST. This molecular architecture should result in the first thermal transition from a homogeneously dissolved polymer to a bola-shaped linear amphiphile with a high hydrophilic-to-hydrophobic balance above the LCST of poly(M3) and finally to a linear amphiphile with a low hydrophilic-to-hydrophobic balance above the LCST of the poly(M2) block (cf. Figure 1, transitions (i) f (ii) f (iv)). Experimentally, visual inspection and turbidimetry do not reveal any clouding at least until 80 °C. DLS studies, however, show the formation of small colloidal objects above 38 °C. Compared to the cloud points of the block copolymer with other block sequences, the incorporation of the poly(M3) block in the middle of the polymer obviously shifts the thermal collapse to higher temperatures. Still, as for the other block copolymers, the size of the colloids passes through a maximum upon further heating, here at ca. 45 °C, before the aggregates stabilize at a smaller size with a hydrodynamic diameter of ca. 40 nm above 50 °C. Note that also the maximum colloid size achieved temporarily of ca. 120 nm hydrodynamic diameter is much lower than for the colloids obtained for the two other block sequences for the same heating protocol. No indication of a separate, second thermally induced aggregation process is seen in the investigated temperature window of 20-70 °C. The interpretation of the temperature-dependent association studies is complicated by marked kinetic effects: The heating rate applied as well as aging may strongly influence the size of the aggregates obtained. Also, it seems that once formed, the aggregates reorganize very slowly. These phenomena are easily seen when comparing the particle size distributions of the different copolymers at a given temperature after applying a slow- (Figure 6) and fast- (Figure 7) heating protocol. Fast heating typically results in smaller aggregates, whatever the final temperature, and in narrower size distributions. In particular, the fast-heating protocol seems to reduce the extent of formation of very large aggregates (compare, for instance, Figure 6A and B with Figure 7A and B at 55 °C). Still, for polymers poly(M1-block-M2block-3) and poly(M3-block-M1-block-M2) the formation of larger aggregates at intermediate temperature (40-50 °C) and of smaller aggregates at elevated temperatures (