Water-Soluble Chiral Polyisocyanides Showing Thermoresponsive

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Water-Soluble Chiral Polyisocyanides Showing Thermoresponsive Behavior Guixia Hu, Wen Li,* Yulong Hu, Anqiu Xu, Jiatao Yan, Lianxiao Liu, Xiacong Zhang, Kun Liu, and Afang Zhang* Laboratory of Polymer Chemistry, Department of Polymer Materials, College of Materials Science and Engineering, Shanghai University, Nanchen Street 333, Materials Building Room 447, Shanghai 200444, China S Supporting Information *

ABSTRACT: To afford chiral polyisocyanides with thermoresponsiveness may open new gates to enhance their functionality and to broaden their applications. Herein, we report the synthesis of a series of novel polyisocyanides carrying oligoethylene glycols (OEGs) modified dipeptides as the pendent groups. These polyisocyanides not only show different chiroptical properties but also possess characteristic thermoresponsive behavior. The corresponding monomers carrying different OEG units in the periphery are water-soluble, thus allowing their polymerization feasible in aqueous medium with NiCl2 as the catalyst. For comparison, polyisocyanides were also prepared in organic solvents, such as dichloromethane and tetrahydrofuran. The effects of solvent and polymerization temperature as well as chemical structures of the pendants on the chiroptical properties of the resulting polymers were examined. The characteristic thermoresponsive behavior of these chiral polymers was investigated by 1H NMR spectroscopy and turbidity measurements using UV/vis spectroscopy. The thermally induced aggregation processes were also followed by dynamic light scattering. It was found that the phase transition temperatures of these polymers were significantly influenced not only by the overall hydrophilicity but also by their secondary structures.

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INTRODUCTION To mimic the helical conformations in biomacromolecules, various types of synthetic helical polymers have been developed, which are highly promising candidates for applications in optical and chiral materials.1 Polyisocyanides are one of the most intriguing helical polymers which contain an all-carbon backbone and a pendent group at each carbon atom. These specific structural characteristics lead to the limited rotation freedom of the C−C bonds and thus make these polymers relatively rigid. They were revealed to form a stable 41 helical conformation when the carbons are substituted with bulky chiral groups.2 Therefore, a number of polyisocyanides carrying chiral pendants have been reported by several groups, including Nolte,3 Takahashi,4 Veciana,5 and Yashima.6 It has been pointed out that the amide groups in the side chains can form intramolecular hydrogen bonds and thus stabilize the native helical structures of the backbone. Different synthetic methodologies have been explored for the preparation of polyisocyanides by polymerization of isocyanide monomers. This polymerization can be carried out at mild conditions, such as at rt and even in the presence of air.7 Most of the isocyanides are soluble in organic solvents, and thus, their polymerization can only be carried out in organic solvents.8 Because of their easy synthesis and unique helical structures, polyisocyanides are of great potential as scaffolds to construct functional materials. More and more attention was paid on their structural modification to enhance their functionalities. Different functional residues, such as glucose and chromo© 2013 American Chemical Society

phoric units, were introduced onto the side chains to create polyisocyanide materials with hydrophilic, magnetic, optical, and electronic properties. For example, the bioinspired sugar derived polyisocyanides were reported by Kobayashi, which exhibited little specific interactions with lectins and selforganization onto hydrophilic surfaces.9 On the basis of polyisocyanopeptides backbone, the group of Nolte and Rowan prepared perylene functionalized polymers, which were used as a synthetic antenna with a possible application as n-type material in organic photovoltaics.10 Sommerdijk used the water-stable polyisocyanides with peptide pendants as the supramolecular template for mediating the crystallization of CaCO3.11 Though plenty types of polyisocyanides with versatile side groups were reported, less attention was paid on developing the representatives with stimuli-responsive properties. One interesting work from Takahashi12 reported that polyisocyanides containing ferrocenyl groups showed electrical responsiveness. The conformation of polyisocyanides can be controlled through the oxidation and reduction of ferrocenyl units. Amabilino13 reported polyisocyanides containing tetrathiafulvalene units exhibited clearly distinguishable chiroptical properties with reversible interconversion between three univalent and two very broad mixed-valence redox states. Yashima and co-workers14 reported a series of chiral responsive Received: December 10, 2012 Revised: January 18, 2013 Published: January 31, 2013 1124

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the OEG chains for tuning the hydrophilicity of the macromolecules. Three types of polyisocyanides bearing different OEG chains were prepared via different polymerization conditions to examine the structure effects on their thermoresponsiveness. The chiral and helical structures of these polyisocyanides were checked with CD spectroscopy. Their thermoresponsive properties were investigated by 1H NMR, UV/vis spectroscopy, and dynamic light scattering measurements. The effects of polymer structures and polymer concentrations as well as the chiroptical properties on their phase transition temperatures were examined in details.

polyisocyanides via supramolecular interactions. These nonchiral polymers can adopt one-handed helical conformation through supramolecular interactions with chiral substances, and impressively, the induced helical conformation could be retained in some cases after removal of the chiral inducer. Thermoresponsive polymers are one type of the most investigated stimuli-responsive macrmolecules.15 Typically, they show an entropy-driving lower critical solution temperature (LCST) behavior once heating their aqueous solutions to the elevated temperatures. Consequently, these aqueous solutions will change from homogeneous (transparent) to heterogeneous (turbid). This entropy-driven process involves the transformation of polymer chains (partially) from hydrophilic to hydrophobic. The phase transition temperatures (Tcs) are mainly dependent on the overall hydrophilicity of the polymers.16 Recently, polymer architectures (topologies) were also found to show significant influences on their thermoresponsive behavior.17 Polymers with various chemical structures and architectures have been developed to show thermoresponsive properties and been utilized for applications ranging from surface modifications to biomaterials.18 Imparting thermoresponsive properties to chiral and helical polyisocyanides will not only afford these helical representatives with smart properties but also possibly provide a convenient way to mediate their helical conformations. In other sides, thermoresponsiveness of polyisocyanides may enrich the functionality of polyisocyanides and open a new gate for their applications as stimuli-responsive chiral materials. We recently reported a series of novel thermoresponsive dendritic macromolecules by introduction of oligo(ethylene glycol) (OEG) units to the entire, periphery, or pendent groups of the macromolecules.16d,17e,19 These macromolecules adopt unprecedented thermoresponsive behavior with fast and sharp phase transitions in the vicinity of body temperature and show excellent biocompatibilities. OEG units were selected because they cannot form strong hydrogen bondings with water. Encouraged by these, we here report for the first time on the synthesis of water-soluble polyisocyanides with thermoresponsive behavior. These polyisocyanides carry alanine and glutamic residues based dipeptide pendants and terminated with OEG chains through ester linkages (Figure 1). The alanine moiety is connected directly to the backbone to exhibit the strongest chiral induction.20 The glutamic moiety is selected as the linkage between the alanine unit and the OEG pendants in order to carry two OEG units at each repeat unit, thus affording densely packed OEG chains along the polymer backbone. Both ethoxyl- and methoxyl-terminated units were selected to cape

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EXPERIMENTAL SECTION

Materials. Triethylene glycol monoethyl ether (Et-TEG), triethylene glycol monomethyl ether (Me-TEG), and diethylene glycol monomethyl ether (Me-DEG) were purchased from TCI (Japan). HAla-OH and Boc-Glu-OH were purchased from GL (Shanghai). NiCl2·6H2O was dissolved in MeOH at concentration of 2 or 10 wt % before use. Dichloromethane (DCM) was dried over CaH2. Tetrahydrofuran (THF) was predried over sodium and then refluxed over lithium aluminum hydride (LAH) before use. Other reagents and solvents were purchased at reagent grade and used without further purification. All synthetic steps for the monomer synthesis were run under a nitrogen atmosphere. Macherey-Nagel precoated TLC plates (silica gel 60 G/UV254, 0.25 mm) were used for thin-layer chromatography (TLC) analysis. Silica gel 60 M (Macherey-Nagel, 0.04−0.063 mm, 200−300 mesh) was used as the stationary phase for column chromatography. Instrumentation and Measurements. 1H and 13C NMR spectra were recorded on a Bruker AV 500 (1H: 500 MHz, 13C: 125 MHz) spectrometer, and chemical shifts are reported as δ values (ppm) relative to internal Me4Si. High-resolution MALDI-TOF-MS analyses were performed on IonSpec Ultra instruments. Gel permeation chromatography (GPC) measurements were carried out on a Waters GPC e2695 instrument with 3 column set (Styragel HR3 + HR4 + HR5) equipped with refractive index detector (Waters 2414), and DMF (containing 1 g L−1 LiBr) as eluent at 45 °C. Multiangle light scattering detector (Wyatt Technology Corporation, Down EOS 243E) was used for some of the measurements. The calibration was performed with poly(methyl methacrylate) standards in the range of Mp = 2580−981 000 (Polymer Standards Service-USA Inc.). Circular dichroism (CD) measurements were performed on a JASCO J-815 spectropolarimeter with a thermo-controlled 1 mm quartz cell (10 accumulation, continues scanning mode, scanning speed 100 nm min−1, data pitch: 0.5 nm, response: 1 s, bandwidth: 2.0 nm). UV/vis turbidity measurements were carried out on a PE UV/vis spectrophotometer (Lambda 35) equipped with a thermo-controlled bath. Polymer aqueous solutions were placed in the spectrophotometer (path length 1 cm) and heated or cooled at a rate of 0.2 °C min−1. The absorptions of the solution at λ = 700 nm were recorded 5 s. The cloud point (Tc) is determined the one at which the transmittance at λ = 700 nm had reached 50% of its initial value. Dynamic light scattering (DLS) measurements were performed on the Dyna Pro Nanostar instrument from Wyatt Technology Corporation (He−Ne laser, λ0 = 658 nm) with a scattering angle at 90°. dn/dc of these polyisocyanides was determined to be 0.0514 with Optilab rEX (Wyatt) in the off-line mode. General Procedure for Etherification (A). Oligoethylene glycol monomethyl or ethyl ether (2.30 mmol) in dry DCM (15 mL) was added dropwise to a solution of Boc-Glu-OH (1.00 mmol), 4-N,Ndimethylaminopyridine (DMAP, 0.6 mmol), and 1-(3(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDC, 2.50 mmol) in dry DCM (80 mL) at −10 °C. The mixture was stirred for 8 h at rt. After washing successively with 10% KHSO4 and brine, the combined organic phase was dried over MgSO4. Purification by column chromatography with DCM/MeOH (40:1 then 30:1, v/v) afforded the title compounds as a colorless oil.

Figure 1. Chemical structures of polyisocyanides with different OEG pendant groups. 1125

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Compound 3f. According to general procedure B from compound 3e (3.02 g, 6.70 mmol) and TFA (6.15 g, 53.63 mmol) in DCM (10 mL), 3f was yielded as a yellow oil (3.11 g, 100%). 1H NMR (CDCl3): δ = 1.81−1.87 (m, 1H, CH2), 2.02−2.14 (m, 1H, CH2), 2.46−2.50 (m, 2H, CH2), 3.34−3.37 (m, 6H, CH3), 3.47−3.72 (m, 13H, CH + CH2), 4.18−4.33 (m, 4H, CH2). Compound 4a. According to general procedure C from DMAP (0.46 g, 3.76 mmol), 2 (1.34 g, 11.42 mmol), 3b (4.45 g, 9.52 mmol), EDC (2.75 g, 14.27 mmol), and DiPEA (2.46 g, 19.04 mmol), 4a was yielded as a colorless oil (4.31 g, 80%). 1H NMR (CDCl3): δ = 1.18− 1.22 (t, 6H, CH3), 1.39−1.41 (d, 3H, CH3), 1.99−2.50 (m, 4H, CH2), 3.49−3.71 (m, 24H, CH2), 4.17−4.33 (m, 4H, CH2), 4.56−4.63 (m, 2H, CH), 6.83−6.84 (br, 1H, NH), 7.25−7.27 (m, 4H, CH2), 8.17 (s, 1H, HCO). Compound 4b. According to general procedure D from formamide 4a (1.00 g, 1.76 mmol), TEA (1.08 g, 10.61 mmol), and triphosgene (0.37 g, 1.23 mmol), 4b was yielded as a yellow oil (0.77 g, 80%). 1H NMR (CDCl3): δ = 1.21−1.24 (t, 6H, CH3), 1.65−1.67 (d, 3H, CH3), 2.07−2.53 (m, 4H, CH2), 3.51−3.73 (m, 24H, CH2), 4.25−4.34 (m, 5H, CH + CH2), 4.59−4.64 (m, 1H, CH), 7.34−7.36 (br, 1H, NH). 13 C NMR (CDCl3): δ = 15.12, 19.65, 26.60, 30.06, 52.28, 53.01, 63.95, 64.64, 66.58, 68.71, 68.94, 69.75, 70.52, 70.63, 70.64, 76.89, 77.15, 77.40, 160.94, 166.33, 170.76, 170.80, 172.73. HRMS (ESI): m/z calcd for C25H44N2O11 [M + H]+: 549.2945. Found: 549.3027. Compound 4c. According to general procedure C from 2 (0.15 g, 1.26 mmol), 3d (0.63 g, 1.26 mmol), EDC (0.33 g, 1.71 mmol), DMAP (0.05 g, 0.46 mmol), and DiPEA (0.30 g, 2.28 mmol), 4c was yielded as a colorless oil (0.52 g, 85%). 1H NMR (CDCl3): δ = 1.37− 1.39 (d, 3H, CH3), 1.97−2.48 (m, 4H, CH2), 3.35 (s, 6H, CH3), 3.52−3.67 (m, 20H, CH2), 4.15−4,28 (m, 4H, CH2), 4.53−4.63 (m, 2H, CH), 6.87 (br, 1H, NH), 7.18−7.20 (br, 1H, NH), 8.15 (s, 1H, HCO). Compound 4d. According to general procedure D from compound 4c (0.78 g, 1.45 mmol), triphosgene (0.30 g, 1.01 mmol), and TEA (0.88 g, 8.70 mmol), 4d was yielded as a yellow oil (0.56 g, 75%). 1H NMR (CDCl3): δ = 1.66−1.67 (d, 3H, CH3), 2.041−2.58 (m, 4H, CH2), 3.38 (s, 6H, CH3), 3.54−3.72 (m, 20H, CH2), 4.22−4.48 (m, 5H, CH + CH2), 4.58−4.63 (m, 1H, CH), 7.29 (br, 1H, NH). 13C NMR (CDCl3): δ = 19.53, 26.36, 29.98, 52.08, 52.78, 58.77, 63.72, 64.45, 68.55, 68.78, 70.29, 70.29, 70.31, 70.34, 70.36, 70.37, 71.70, 71.72, 160.14, 166.43, 170.76, 172.50. HRMS (ESI): m/z calcd for C23H40N2O11 [M + H]+: 521.2632. Found: 521.2694. Compound 4e. According to general procedure B from 3f (2.64 g, 5.69 mmol), DMAP (0.21 g, 1.70 mmol), DiPEA (1.47 g, 11.36 mmol), 2 (0.75 g, 6.26 mmol), and EDC (1.64 g, 8.53 mmol), 4e was yielded as a yellow oil (2.11 g, 82%). 1H NMR (CDCl3): δ = 1.38− 1.40 (d, 3H, CH3), 1.99−2.07 (m, 1H, CH2), 2.20−2.27 (m, 1H, CH2), 2.37−2.49 (m, 2H, CH2), 3.36−3.37 (m, 6H, CH3), 3.52−3.71 (m, 12H, CH2), 4.17−4.30 (m, 4H, CH2), 4.54−4.66 (m, 2H, CH), 6.84−6.86 (br, 1H, NH), 7.14−7.16 (br, 1H, NH), 8.15 (s, 1H, HC O). Compound 4f. According to the general procedure D from 4e (0.48 g, 1.06 mmol), triphosgene (0.22 g, 0.75 mmol), and TEA (0.65 g, 6.29 mmol), 4f was yielded as a yellow oil (0.34 g, 75%). 1H NMR (CDCl3): δ = 1.66−1.67 (d, 3H, CH3), 2.07−2.16 (m, 1H, CH2), 2.25−2.32 (m, 1H, CH2), 2.42−2.55 (m, 2H, CH2), 3.38−3.39 (m, 6H, CH3), 3.54−3.57 (m, 4H, CH2), 3.63−3.67 (m, 4H, CH2), 3.71− 3.74 (m, 4H, CH2), 4.24−4.39 (m, 5H, CH + CH2), 4.59−4.63 (m, 1H, CH), 7.29 (br, 1H, NH). 13C NMR (CDCl3): δ = 19.60, 26.47, 30.06, 52.24, 52.97, 58.95, 63.83, 64.58, 68.69, 68.92, 70.34, 70.37, 71.76, 71.77, 160.78, 166.36, 170.78, 172.69. HRMS (ESI): m/z calcd for C19H32N2O9 [M + H]+: 433.2108. Found: 433.2167. Polymerization. The polymerization of the monomer was carried out in either water or organic solvent (DCM or THF) with NiCl2·6H2O as the catalyst at room or higher temperatures. A typical procedure is as follows: NiCl2·6H2O (0.32 mg, 0.0014 mmol) in MeOH (10 wt %) was added to a solution of monomer 4b (0.38 g, 0.69 mmol) in H2O (1 mL). The brown solution was stirred for 24 h at room temperature and then purified by column chromatography with DCM as the eluent to afford the polymer P1 as a yellow solid

General Procedure for Boc Deprotection (B). Trifluoroacetic acid (TFA, 7.00 mmol) was added to a solution of Boc-protected amino acid compound (1.00 mmol) in dry DCM (10 mL) at 0 °C, and the mixture was stirred over 2 h at rt. The reaction was quenched by adding an excess amount of methanol. Evaporation of solvents afforded the ammonium salt as a colorless oil. General Procedure for Amide Coupling (C). Alanine formamide (1.20 mmol), DMAP (0.40 mmol), diisopropylethylamine (DiPEA, 2.00 mmol), and the ammonium salt (1.00 mmol) were dissolved in dry DCM (100 mL) and stirred for 20 min at −15 °C. EDC (1.50 mmol) was then added in three portions, and the mixture was stirred for another 6 h. After washing successively with 10% KHSO4 and brine, the combined organic phase was dried over MgSO4. Purification by column chromatography with DCM/MeOH (40:1 and then 20:1, v/v) afforded the product as a colorless oil. General Procedure for Dehydration of Formamide with Triphosgene (D). Triphosgene (0.70 mmol) in DCM (10 mL) was added dropwise to a mixture of triethylamine (TEA, 6.00 mmol) and the formamide (1.00 mmol) in dry DCM (80 mL) over 30 min at −15 °C. The mixture was allowed to warm to 0 °C before the addition of saturated NaHCO3 aqueous solution (20 mL), and then the solution was stirred vigorously for 10 min. After washing successively with brine, the organic phase was collected and dried over MgSO4. Purification by column chromatography with DCM/MeOH (40:1, v/ v) afforded the monomer as a yellow oil, which was stored under 0 °C before use. Compound 2. The mixture of formic acid (3.57 g, 77.53 mmol) and acetic anhydride (6.88 g, 67.42 mmol) was stirred for 1.5 h at room temperature to afford compound 1, which was then added dropwise to a stirred suspension of alanine (5.00 g, 56.18 mmol) in dry ethyl acetate (50 mL) over 30 min at 0 °C. The mixture was allowed to warm to room temperature and stirred for another 1 h. The precipitate was collected by filtration with vacuum and washed with DCM. After being dried in high vacuum, compound 2 was afforded as a white solid product (5.00 g, 75%). 1H NMR (CDCl3): δ = 1.26−1.27 (d, 3H, CH3), 4.24−4.30 (q, 1H, CH), 7.80 (s, 1H, HCO), 8.39−8.40 (br, 1H, HN). Compound 3a. According to the general procedure A from triethylene glycol monoethyl ether (Et-TEG, 4.32 g, 24.2 mmol), BocGlu-OH (2.50 g, 10.40 mmol), DMAP (0.50 g, 4.09 mmol), and EDC (4.91g, 25.60 mmol), 3a was yielded as a colorless oil (5.51 g, 95%). 1 H NMR (CDCl3): δ = 1.15−1.18 (t, 6H, CH3), 1.40 (s, 9H, CH3), 1.89−2.46 (m, 4H, CH2), 3.46−3.68 (m, 24H, CH2), 4.15−4.31 (m, 5H, CH + CH2), 5.21−5.23 (br, 1H, NH). Compound 3b. According to general procedure B from 3a (5.00 g, 8.80 mmol) and TFA (7.03 g, 61.6 mmol), 3b was yielded as a colorless oil (5.12 g, 100%). 1H NMR (CDCl3): δ = 1.19−1.24 (t, 6H, CH3), 2.22−2.78 (m, 4H, CH2), 3.52−3.74 (m, 24H, CH2), 4.22− 4.44 (m, 5H, CH + CH2). Compound 3c. According to general procedure A from triethylene glycol monomethyl ether (Me-TEG, 3.21 g, 26.7 mmol), Boc-Glu-OH (3.00 g, 12.1 mmol), DMAP (0.44 g, 3.60 mmol), and EDC (5.81 g, 30.30 mmol), 3c was yielded as a colorless oil (5.96 g, 91%). 1H NMR (CDCl3): δ = 1.45 (s, 9H, CH3), 1.93−2.50 (m, 4H, CH2), 3.39 (d, 6H, CH3), 3.55−3.73 (m, 20H, CH2), 4.20−4.38 (m, 5H, CH + CH2), 5.22−5.24 (br, 1H, NH). Compound 3d. According to general procedure B from 3c (1.00 g, 1.85 mmol) and TFA (1.48 g, 12.97 mmol) in dry DCM (10 mL), 3d was yield as a yellow oil (1.02 g, 100%). 1H NMR (CDCl3): δ = 2.07− 2.15 (m, 2H, CH2), 2.45−2.52 (m, 2H, CH2), 3.22 (s, 6H, CH3), 3.39−3.61 (m, 2H, CH2), 4.04−4.22 (m, 4H, CH2), 4.25−4.31 (m, 1H, CH), 7.69−8.23 (br, 2H, NH2). Compound 3e. According to general procedure A from diethylene glycol monomethyl ether (Me-DEG, 3.21 g, 26.69 mmol), Boc-GluOH (3.00 g, 12.13 mmol), DMAP (0.45 g, 3.64 mmol), and EDC (5.81 g, 30.32 mmol), 3e was yielded as a colorless oil (5.00 g, 91%). 1 H NMR (CDCl3): δ = 1.42 (s, 9H, CH3), 1.90−1.98 (m, 1H, CH2), 2.15−2.19 (m, 1H, CH2), 2.36−2.44 (m, 4H, CH2), 3.35−3.37 (m, 6H, CH3), 3.50−3.70 (m, 12H, CH2), 4.12−4.38 (m, 5H, CH + CH2), 5.19−5.21 (br, 1H, NH). 1126

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Scheme 1. Synthesis Procedure for the Isocyanide Monomersa

Reagents and conditions: (a) formic acid, 0 °C, 2 h (100%); (b) Armour acetic anhydride, ethyl acetate, −5 °C to rt, 2 h (75%); (c) Et-TEG, MeTEG or Me-DEG, EDC, DMAP, DCM, −15 °C to rt, overnight (95%); (d) TFA, DCM, MeOH, 0 °C to rt, 4 h (100%); (e) compound 2, EDC, DMAP, DCM, −15 °C to rt, 6 h (80%); (f) TEA, triphosgene, DCM, −15 to 0 °C, 1 h (80%). Abbreviations: DCM = dichloromethane, EDC = 1(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, DMAP = 4-N,N-dimethylaminopyridine, Et-TEG = triethylene glycol monoethyl ether, Me-TEG = triethylene glycol monomethyl ether, Me-DEG = diethylene glycol monomethyl ether, TFA = trifluoroacetic acid, TEA = triethylamine. a

Table 1. Conditions for and Results from Polymerization of the Isocyanide Monomers GPC resultsa

polymerization conditions entries

polymer

[M]/[I]

[M] (mol/L)

solvent

temp (°C)

time (h)

yield (%)

Mn × 10−4

DPn

PDI

Tcb (°C)

1 2 3 4 5 6 7 8 9 10 11 12 13 14

P1(a) P1(b) P1(c) P1(d) P1(e) P1(f) P1(g) P2(a) P2(b) P2(c) P3(a) P3(b) P3(c) P3(d)

150 250 500 500 500 500 500 500 500 500 500 500 500 500

0.15 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20

H2O H2O H2O DCM DCM THF THF H2O DCM THF H2O DCM DCM THF

18 18 18 18 36 20 40 20 20 20 20 20 36 20

24 24 24 72 24 24 24 48 24 48 48 24 24 48

70 68 60 60 34 50 70 75 40 75 55 45 40 55

1.48 3.17 4.04 2.18 2.83 1.55 3.38 2.76 2.90 2.54 2.05 3.60 5.22 2.45

30 58 69 40 196 28 63 53 55 49 47 83 120 57

1.24 1.92 1.36 1.65 1.72 1.46 1.20 1.67 1.43 1.77 1.45 1.64 1.25 1.42

20.8 19.6 19.5 30.1 21.9 29.8 19.3 51.2 67.2 60.0 40.5 49.2 53.5 51.1

a Determined by GPC with DMF as eluent containing 0.1 wt % LiBr (calibrated with poly(methyl methacrylate) standards). Mn represents the number- average molecular weight. bThe apparent Tc of the polymers was determined as the temperature at 50% of the initial transmittance at λ = 700 nm.

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(0.23 g, 60%). 1H NMR (DMSO, 50 °C): δ = 1.18 (br, 6H, CH3), 1.23−1.28 (br, 3H, CH3), 1.78−2.78 (br, 2H, CH2), 2.28−2.51 (br, 2H, CH2), 33.49−3.54 (br, 24H, CH2), 4.06−4.16 (br, 5H, CH + CH2). 13C NMR (CDCl3): δ = 15.15, 55.02, 63.77, 66.56, 69.33, 69.77, 70.51, 70.62, 97.45, 97.60, 100.20, 172.71. Some signals from the backbone were not resolved. Spectroscopic Data of P2 from 4d. 1H NMR (DMSO, 50 °C): δ = 1.05−1.63 (br, 3H, CH3), 1.70−2.49 (br, 4H, CH2), 3.28 (s, 6H, CH3), 3.38−3.74 (br, 21H, CH + CH2), 3.80−4.42 (m, 5H, CH + CH2). Spectroscopic Data of P3 from 4f. 1H NMR (DMSO, 50 °C): δ = 1.16−1.52 (br, 3H, CH3), 1.52−2.43 (br, 4H, CH2), 3.28 (s, 6H, CH3), 3.45−3.60 (br, 12H, CH2), 4.12−4.41 (m, 5H, CH + CH2).

RESULTS AND DISCUSSION Monomer Synthesis and Polymerization. Three isocyanide monomers bearing the same dipeptide but carrying different oligoethylene glycol (OEG) units were synthesized. These OEG units were selected in order to afford the resulted polymers with different overall hydrophilicity. Their syntheses are summarized in Scheme 1. Starting from the reaction between formic acid and acetic anhydride, Armour acetic anhydride was afforded, which was reacted with H-Ala-OH to form the formamide 2. The esterification of commercial available triethylene glycol monoethyl ether (Et-TEG) with 1127

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Figure 2. CD and UV spectra for 0.5 mg mL−1 aqueous solutions of (a) P1(a), P1(b), P1(c) P1(d), P1(e), P1(f), and P1(g) and (b) P1(b), P2(a), and P3(a). Measured at rt. Dotted lines are guides for the eyes.

and co-workers previously,6b increasing polymerization temperature is helpful to achieve high molecular weight polymers. Chiroptical Properties of the Polyisocyanides. CD spectroscopy was applied to investigate the chiroptical properties of these aliphatic polyisocyanides in aqueous solutions. Polymerization conditions, such as solvent and temperature, show significant effects on the chirality and helical sense of resulted polymers. Figure 2a shows CD spectra of P1 polymerized from monomer 4b in different solvents and at different temperatures. The CD spectra of polymer P1 obtained from aqueous solutions at rt (entries 1−3 in Table 1) show strong Cotton effects at λ = 310 nm, which relate to the n−π* transition of the imines. This Cotton effect is characteristic for the one-handed helical sense of the polymer backbone. Differently, polymers obtained from less polar solvent DCM or THF [P1(d) and P1(f), entries 4 and 6 in Table 1] at rt show nearly no Cotton effect at λ = 310 nm, suggesting that they possess different chirality from these polymers obtained from aqueous solutions. Interestingly, polymers prepared from the same less polar solvent but at high temperature [compare P1(e) and P1(g), entries 5 and 7 in Table 1] exhibit obvious Cotton effect λ = 310 nm as P1(a), P1(b), and P1(c). This phenomenon may be caused by the different interactions of the intermolecular hydrogen bonds between the pendant amide residues of growing chain ends and the monomers during the propagation process, as suggested by Yashima and coworkers.6b In less polar solvent DCM or THF, or at low temperature, the polymerization proceeds under predominantly kinetic control, and hydrogen bonds between the pendant amide residues of the monomers and the growing chain ends play a role. While in strong polar solvents, such as H2O, or at high temperatures, hydrogen-bonding interactions will be suppressed to a certain degree, leading to the formation of a thermodynamically favorite helical conformation. Molar mass of these polymers was found to show influence on the intensities of the Cotton effects. Comparing CD spectra from P1(a), P1(b), and P1(c) in Figure 2a, it is obvious that P1(c) with the highest molar mass shows the strongest Cotton effects at λ = 310 nm. Furthermore, the influence of pendants’ chemical structures on the chiroptical properties of the polyisocyanides was investigated. Figure 2b shows the CD spectra of P1(b), P2(a), and P3(a). These polymers possess comparable molar masses and were obtained all from aqueous solutions at rt from monomers 4b, 4d, and 4f, respectively. The structures of these polymers are different only in the periphery OEG pendants, but they exhibit quite different Cotton effects. P1(b) with ethoxyl-

Boc-Glu-OH furnished 3a. Deprotection of 3a with TFA afforded quantitatively the ammonium salt 3b. Amide coupling of this salt with the compound 2 provided OEG-modified dipeptide 4a, which was dehydrated with triphosgene in the presence of TEA to give the monomer 4b in a yield of 70%. A thin-layer chromatographic method and color changing of solution were used for monitoring the dehydration. By similar procedures, other two monomers 4d and 4f with either triethylene glycol monomethyl ether (Me-TEG) or diethylene glycol monomethyl ether (Me-DEG) units, respectively, were prepared. All monomers were kept under 0 °C before use. All new compounds were characterized as analytically pure materials by 1H NMR spectroscopy, and all monomers were further characterized by 13C NMR as well as high-resolution mass spectroscopy. All monomers are liquid in yellow color at room temperature and are polymerized with an achiral catalyst NiCl2·6H2O in solutions. The detailed polymerization conditions and typical results are summarized in Table 1. It is interesting to point out that, besides the conventional organic solvents, such as DCM and THF, water is also used for the first time as polymerization solvent due to the water solubility of these monomers. Polymerization in aqueous solutions will not only benefit environment-friendly conditions but also may reduce the cost for preparing the chiral polymers. All polymerization preceded homogeneously over 24 h except 4f in H2O (entry 11). Monomer 4f cannot be dissolved well in water at rt but can still be polymerized under the aqueous condition. All polymers obtained are well soluble in water at low temperature as well as in common organic solvents, such as THF, DCM, and DMF. Their weight-average molecular weights (Mw) were determined by GPC with DMF as the eluent and are in the range (1.8−6.5) × 104 with polydispersity (PDI) less than 2.0. For comparison, molecular weights (Mw) of P1(a) (entries 1) and P1(e) (entry 5) were also determined by multiangle light scattering measurements and found to be 6.70 × 104 and 2.78 × 105, respectively. It is obvious that GPC measurements underestimate the molar mass of these rigid polymers at least by 4−6 times.21 Despite the slight uncertainty of monomer concentration during the polymerization caused by possible solvent evaporation, molecular weights of the polyisocyanides were affected mainly by the feed ratio of monomer/initiator and polymerization temperature: high molar mass polymers were obtained from high value of [M]/[I] (compare entries 1 and 2) or high polymerization temperature (compare entries 5 and 7 with entries 4 and 6, respectively). As discovered by Yashima 1128

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terminated TEG units shows the strongest Cotton effect (at 310 nm) and P2(a) with methoxyl-terminated TEG units show the intermediate intensity, while P3(a) with the shortest methoxyl-terminated DEG units exhibits the weakest Cotton effect. For comparison, the polymerization of 4f was also performed in DCM at high temperature to yield the corresponding polymer P3(c), which still shows weak Cotton effect at 310 nm (Figure S1). It is interesting to point out the minor structure deviation from ethoxyl (in P1) to methoxyl (in P2) of the terminal groups exhibits obvious influence on the Cotton effects. These results suggest that the chemical structures of the pendant units show dominate effect over the polymerization conditions on the chirality of the polymers. These big differences of the Cotton effects between polymers P1(b), P2(a), and P3(a) may mainly ascribe to the different steric hindrance caused by OEG units. The shorter DEG substituent in P3 should form less steric hindrance during the propagation than the other cases, while the longer TEG pendant in P1 would contribute the larger steric hindrance during the propagation process. This steric hindrance will not only show influence on the backbone tacticity of the polymers but also can shield the hydrogen bondings along the polymer backbone. Both can exhibit influence on the chirality of the resulted polymers. In contrast to P1 with longer pendant, P3 with the short substituent did not show significant dependence of its chirality on its molar masses (for CD spectra, see Figure S1). Thermoresponsive Behavior of the Polyisocyanides. These polymers can be dissolved well in water at low (or room) temperature but will dehydrate and collapse when their aqueous solutions are heated to elevated temperatures. At the same time, the clear faint yellow solutions will turn into turbid. These processes are fully reversible as the polymers will be dissolved again once the solutions are cooled down. It is necessary to point out that these polymers in aqueous solutions form large particles from a slightly concentrated solution (0.25 wt %), which precipitate out once heated above their phase transition temperatures and maintained for more than 10 min. This is quite different from other OEG-based thermoresponsive polymers which can form stable mesoglobules.19e,22 The thermally induced dehydration processes of these chiral polymers were then followed on microlevel by temperaturedependent 1H NMR spectroscopy. P1(d) was selected as an example, and its typical proton NMR spectra recorded from 26 to 60 °C are assembled in Figure 3. At low temperature, all proton signals from the OEG segments on P1(d) at δ = 1.38− 1.44 ppm (terminal methyl units) and δ = 3.50−3.93 ppm (CH2 groups) are broad, and the signals from peptide moieties are hardly resolved, suggesting the high rigidity of the polymer backbone. This is quite different from the OEG-based comblike or dendritic polymers which exhibit well-resolved signals due to the flexibility of both OEG pendants and the polymer backbones.17d,19d,23 When the temperature was increased to 30 °C, which is close to the phase transition temperature of the polymer,24 the signals from OEG segments became even broader and their intensity decreased. This tendency was enhanced with further increase of the solution temperature. This is caused by dehydration and aggregation of the polymers with the increase of temperature which reduces the chain mobility. The signals from OEG units are greatly decreased at 35 and 60 °C, indicating the formation of densely packed aggregates or precipitation of the polymers. The high rigidity and helical structures of the polymers together with the strong

Figure 3. Temperature-varied 1H NMR spectra of P1(d) in D2O (1.6 wt %).

hydrogen bonding between the pendant side groups may enhance the interactions between the polymer chains, thus leading to the formation of densely packed large aggregates at elevated temperatures. Turbidity measurements using UV/vis spectroscopy were further applied to investigate on the macro level the thermally induced phase transition behavior of these polyisocyanides, and their phase transition temperatures (Tcs) were determined and are shown in Table 1. Generally speaking, all polymers show relatively sharp phase transitions and small hysteresis during the heating and cooling process. This should be ascribed to the densely packing of OEG pendants along the polymer backbones, which on one side facilitate the entropy-driven dehydrations upon heating to initiate the collapse, followed with aggregations, and on the other side shield the strong hydrogen bonding interactions and enhance rehydrations upon cooling. As expected, the overall hydrophilicity of the polymers determines mainly their phase transition temperatures (Tcs). Depending on the chain length of the pendant OEG moieties and the terminal groups, the structural hydrophilicity of the three types of chiral polymers follows the order P2 > P3 > P1; therefore, their Tcs should be decreased also in the same order. For example, P2(b), P3(b), and P1(d), which were all polymerized in DCM at rt and exhibit similar Cotton effect, show Tcs of 67.2, 49.2, and 30.1 °C, respectively (Figure 4a). Tcs of polyisocyanides P2(a), P3(a), and P1(c) obtained from polymerization in water at room temperature are 51.2, 40.5, and 19.5 °C, respectively, which also follow the order of structure hydrophilicity (for turbidity curves, see Figure S2a). Polymer concentration is found to show influence on the Tc. P1(c) and P2(a) were selected as examples, and their Tcs decreased slightly from 22.9 to 19.3 °C and 57.2 to 48.8 °C, respectively, with the increase of concentration from 0.025 to 0.4 wt % (Figure 4b) (for turbidity curves, see Figure S2b,c). Besides the hydrophilicity of these polymers, interestingly, the secondary structures also contribute significant influence on their thermoresponsive behavior. These chiral polymers with the same chemical structures but obtained from different polymerization conditions show different phase transition temperatures (Table 1). The polymers with strong Cotton effects show similar Tcs, which are much lower than these from the polymers with weak Cotton effects. For example, P1(c), 1129

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Figure 4. (a) Turbidity curves for 0.25 wt % aqueous solutions of P1(d), P2(b), and P3(b), (b) dependence of cloud point (Tc) on concentrations of P1(c) and P2(a), and (c) turbidity curves for 0.25 wt % aqueous solutions of P1(c), P1(d), and P1(e). Heating and cooling rate = 0.2 °C/min.

P1(d), and P1(e) were obtained from different polymerization conditions and thus showed different chiralities. Their typical turbidity curves are shown in Figure 4c. From these curves, their corresponding Tcs are 19.5, 30.1, and 21.9 °C, respectively. These Tc values are in good agreement with the intensities of the Cotton effects of the polymers: the higher the Cotton effect, the lower the Tc. For polymers P1(c), P1(e), and P1(g) with similar strong Cotton effects, their Tcs are similar (19.5, 21.9, and 19.3 °C, respectively). While for polymers P1(d) and P1(f) with much weak Cotton effect, their Tcs are 30.1 and 29.8 °C, respectively, which are 10 deg higher than these with strong Cotton effects (Figure S3a). The above comparison is based on the fact that the molar masses of the polymers show negligible influence on their Tcs (Figure S3b). The above phenomena are also true for polymers P2 and P3. These results suggest the ordered secondary structure from the polymers facilitates the dehydration and aggregation, thus leading to the decrease of the phase transition temperatures of the corresponding polymers.25 We presume ordered arrangement of OEG pendants along polymer backbone shields the polymers from strong intermolecular hydrogen bonding interactions between the peptide units with water, which reduces the overall hydrophilicity of the polymers. In contrast, these with less ordered structures carry the scattered OEG pendants along the polymer backbone, which cannot prevent, at least partially, the strong hydrogen bonding formation between the peptide units of the polymers and water. Figure 5 is to conclusively illustrate the factors which show different influences on thermoresponsiveness of these polyisocyanides. Hydrophilicity of the polymers shows dominant effects on their Tcs. Their secondary structures also contribute significantly on

Figure 5. Illustration of factors which show different influence on the cloud points of the thermoresponsive chiral polyisocyanides.

the Tcs, but polymer concentration only shows a minor influence. Based on the evidence from 1H NMR spectroscopy and the turbidity measurements, these polyisocyanides undergo fully reversible intermolecularly aggregation and deaggregation around their Tcs. These processes were thus followed by dynamic light scattering (DLS), and the aggregate sizes were determined. The results are plotted in Figure 6 from the sample P1(c) with a dilute concentration (0.02 wt %). Below 19 °C, the apparent hydrodynamic radius (Rh) was around 11 nm, which is supposed to be the unimer’s size.26 When the temperature increased to 19 °C, which is right below the phase transition temperature of this polymer,27 Rh grew abruptly to about 102 nm, indicating the intermolecular aggregation induced by dehydration and collapse of polymer chains. Once the temperature increased over 19.5 °C, the aggregate sizes 1130

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possesses the lower transition temperature due to well shielding of strong hydrogen bondings with water through the OEG pendants. The thermally induced processes do not show an obvious influence on the chiroptical properties of these polymers, suggesting steric hindrance from the OEG-based bulky pendants, together with strong hydrogen bonding between the neighboring amide residues, provides sufficient barrier to conformation switch. These helical and thermoresponsive polymers are promising candidates for applications ranging from stimuli-responsive materials to chiral recognition and separation materials.

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ASSOCIATED CONTENT

S Supporting Information *

Figure 6. Dependence of hydrodynamic radius (Rh) of P1(c) in aqueous solutions on temperature upon heating and cooling. Concentration = 0.02 wt %; heating and cooling rate = 0.2 °C/min.

CD and UV/vis spectra, turbidity curves, and NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

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kept on increasing slowly and a plateau value is reached (about 220 nm).28 The aggregate sizes during the cooling process were also recorded. Only a small deviation exists when comparing to the heating process, which proves the fully reversible temperature-dependent aggregation behavior of this kind of polymers. Preliminary experiments show that the morphologies of the thermally induced aggregates from this kind of chiral and rigid polymers have large aspect ratios, which is quite different from the stable mesoglobules formed from flexible, thermoresponsive dendritic macromolecules decorated with similar OEG units.22 Detailed investigation, including morphology characterization with cryo-TEM measurements, is in process. The effects of thermoresponsive behavior on the helical sense of these polyisocyanides were also checked. Polymer P1(c) was selected as an example, and its CD spectra at different temperatures are shown in Figure S4a. When the polymer solution was heated from 16 (below its Tc) to 30 °C (above its Tc), only a slight change was observed from the CD spectra: the maximum absorption red-shifted from 308 to 313 nm. This suggests the hydrophilicity change and collapse of the polymer did not show much influence on its secondary structure. The same result was also obtained for the polymer P1(d) with weak Cotton effects (Figure S4b). These results suggest the OEGbased bulky substituents, together with the strong hydrogen bondings between the pendant amide residues shielded with OEG units in these polymers, provide substantial barrier to prevent their chiral conformations from switching.4a,6b,29

AUTHOR INFORMATION

Corresponding Author

*Phone +86-21-66138053; Fax +86-21-66131720; e-mail wli@ shu.edu.cn (W.L.), [email protected] (A.Z.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We cordially thank Prof. Manfred Schmidt (University of Mainz) for helpful discussions on the DLS measurements. Prof. Junpo He and Mr. Chao Zhang (both from Fudan University) are thanked for their kind support on dn/dc measurements. Dr. Hongmei Deng from the Instrumental Analysis of Research Center (Shanghai University) is thanked for her assistance in NMR measurements. This work is financially supported by National Natural Science Foundation of China (Nos. 21034004, 21104043, and 20974020) and the Science and Technology Commission of Shanghai (No. 10520500300 and 11PJ1404100).

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REFERENCES

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CONCLUSIONS We have presented the syntheses of oligoethylene glycol (OEG)-based water-soluble polyisocyanides which display thermoresponsive properties. Water solubility of the corresponding monomers makes it possible to conduct the polymerization in aqueous solutions. Polymerization conditions, including solvent polarity and temperature, as well as the structure of OEG pendants show significant influence on the chiroptical properties of the resulting polymers. Polymers with enhanced chirality were favorable from high polymerization temperature, in polar solvents, and with longer OEG units. All these polymers show characteristic thermoresponsive behavior with fast and relatively sharp phase transitions. Their phase transition temperature is dependent mainly on the structural overall hydrophilicity. Interestingly, secondary structures of the chiral polymers also show a significant influence on the transition: the polymer with higher ordered structures 1131

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