Synthesis and Thermoresponsive Behaviors of Thermo-, pH-, CO2

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Synthesis and Thermoresponsive Behaviors of Thermo‑, pH‑, CO2‑, and Oxidation-Responsive Linear and Cyclic Graft Copolymers Hongcan Zhang, Wentao Wu, Xiaoqi Zhao, and Youliang Zhao* Suzhou Key Laboratory of Macromolecular Design and Precision Synthesis, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China S Supporting Information *

ABSTRACT: Rational macromolecular design allows us to construct multiresponsive architectural polymers with a potential toward multipurpose applications. This study aims at synthesis and LCST-type thermoresponsive behaviors of multisensitive linear and cyclic graft copolymers with polyacrylamide backbone and hydrophilic PEG grafts. The cloud point could be tuned by many factors, and the effect of cyclization was confirmed by the elevated cloud point in H2O up to 12.8 °C under same conditions. The PEG-connecting Y junctions with dual amide, thioether, and tertiary amine groups allowed thermo-, solvent-, pH-, and CO2-switchable inter/intramolecular hydrogen bonding interactions and hence resulted in unusual solvent (H2O or D2O) and pH (about 6.8−8.5) dependent phase transition and irreversible CO2-responsive behavior. Meanwhile, the solution blending could lead to one or two phase transition(s) dependent on types and compositions of the blends. The meticulous introduction of multifunctional Y junctions into graft copolymers offers a versatile route to adjust multitunable thermoresponsive properties.

1. INTRODUCTION Motivated by adaptive and responsive biological systems in nature, stimuli-responsive polymers with tunable conformations, chemical structures, and physical properties have been extensively explored for many prospective multipurpose applications.1−12 Among them, thermoresponsive polymers undergo phase transition at lower (LCST) or upper (UCST) critical solution temperature due to the balance of hydrogen bonding, hydrophobic, and electrostatic interactions,5,6,13 pHsensitive polymers show variable hydrophilic/hydrophobic ratio via donating or accepting protons upon pH change,7,8 CO2responsive polymers render reversible protonation/deprotonation cycles via alternately purging with biocompatible CO2 and inert gas and have a great potential in sensors, surface adhesives, and drug delivery,14−17 and redox-sensitive polymers allow for the variation in amphiphilicity and/or the cleavage of stimuli-labile linkages in a redox environment.9,10,18,19 For instance, poly(N-isopropylacrylamide) (PNIPAM)20−23 and poly(oligo(ethylene glycol) (meth)acrylate)24,25 are popular thermoresponsive polymers, poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA),26−29 poly(N-(2-(diethylamino)ethyl) acrylamide) (PDEAEAM),30,31 and poly(N-methacryloyl-L-alanine 2-(diethylamino)ethylamide) (PMAEE)32 are typical thermo/pH/CO2-responsive polymers, and poly(ethylene glycol) (PEG)33,34 is known to possess a high affinity toward CO2 via the Lewis acid−base interactions between CO2 and ether groups (Scheme 1). In some cases, it is indispensible to develop and optimize multiresponsive systems © XXXX American Chemical Society

Scheme 1. Typical Polymers of Thermoresponsive PNIPAM, Thermo/pH/CO2-Responsive PDEAEAM and PMAEE, and the Present Thermo/pH/CO2/Oxidation-Responsive Graft Copolymer PDP and Its Analogue PDM

with the ability for sequential and predictable changes in morphology and properties so as to meet the requirements of targeted functions and applications.11,12,35,36 As a promising approach to attain this goal, postpolymerization modification allows versatile introduction of desirable moieties and functions which are incompatible with polymerization, characterization, or processing conditions.37−40 As well documented, thiolactone chemistry41−46 has afforded a robust protocol for the design of Received: January 30, 2017 Revised: April 3, 2017

A

DOI: 10.1021/acs.macromol.7b00220 Macromolecules XXXX, XXX, XXX−XXX

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Scheme 2. Synthetic Routes to Linear/Cyclic Poly(NIPAM-co-ATL) (PNA, n ≈ 101, x ≈ 0.84) and Poly(NIPAM-co-ATL)-gDEDA/PEGA (PDP)

with cyclic backbone and linear grafts are expected to exhibit more unique physicochemical properties than their corresponding linear graft copolymers. Besides the great promise as carriers for tumor-targeted drug delivery,66−68 cyclic graft copolymers have enabled us to explore the definitive effect of cyclization on temperature response.69 Although the cloud point difference between equivalent linear and cyclic polymers such as PNIPAM is usually low (ΔTc = 1−6 °C),19−21 the ΔTc value between linear and cyclic graft copolymers with a polycarbonate backbone and poly(N-acryloylmorpholine) grafts can reach up to 20 °C,69 revealing the LCST differences between linear and cyclic topological polymers may be significantly amplified as graft polymer is chosen instead of the linear one. In this context, this study aims at synthesis and solvent/ stimuli-tunable thermoresponsive properties of multiresponsive linear (l-PDP) and cyclic (c-PDP) graft copolymers poly(NIPAM-co-ATL)-g-DEDA/PEGA (where ATL, DEDA, and PEGA mean N-acryloylhomocysteine thiolactone, N,Ndiethylethylenediamine, and poly(ethylene glycol) methyl ether acrylate, respectively) comprising thermoresponsive polyacrylamide backbone, pH/CO2-sensitive diethylamino moieties and PEG grafts, and oxidation-sensitive thioether functionalities bridging the backbone and PEG segment (Scheme 2). The target graft copolymers were synthesized by combination of reversible addition−fragmentation chain transfer (RAFT) copolymerization, UV-induced Diels−Alder cycloaddition reaction,29,71 radical-induced addition−fragmentation reaction, and tandem amine−thiol−ene reactions.41−43 PDPs have some features such as doubly hydrophilic backbone and pendent chains at ambient temperature and stimuli-tunable amphiphilicity of the smart moieties surrounding the CH2CH units in the backbone at elevated temperatures, and the

tailor-made stimuli-responsive materials, by which some NIPAM-containing thermoresponsive polymers with tunable cloud point (Tc) and enhanced functions and stimuli-sensitive moieties have been synthesized by Du Prez and co-workers,44,45 and amphiphilic grafted copolymers bearing PEG grafts and polyacrylate47 or poly(amide−imide)48 backbone have been achieved via the grafting onto approach. To our surprise, the redox properties of the resultant graft copolymers comprising thioether and dual amide bearing Y junctions have not been systematically investigated. Considering the important role of redox-sensitive system in smart materials and potential stimuliswitchable inter/intramolecular hydrogen bonding interactions in the Y junctions, it is timely to extend thiolactone chemistry to synthesize multiresponsive topological polymers and explore the stimuli−property−application correlations. The function and properties of polymers are inherently related to their structures, and a wide array of applications can be targeted via control over architecture and composition.35−42,49−55 Rational design of macromolecular architecture is extremely important since it allows us to construct multiresponsive systems as well as gain deep insight into the topology effect. In comparison to the linear analogues of block copolymers, graft copolymers can exhibit distinct properties dependent on macromolecular parameters involving grafting density, segment length, and length/diameter ratio.52−55 Owing to more confined conformation,56−62 the endless cyclic polymers possess smaller hydrodynamic volumes and radii of gyration than their linear counterparts and hence show more intriguing properties including different cloud point and glass transition temperature, improved thermal stability of the selfassembled micelles,63 and increased drug or gene transfection efficiency and reduced cell toxicity.64,65 As ring and graft polymers meet together, the resultant cyclic graft copolymers B


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Figure 1. 1H NMR (400 MHz) spectra of l-PNA (A) and l-PDP (B) in CDCl3 at 25 °C.

Table 1. Results for Synthesis of Linear and Cyclic Poly(NIPAM-co-ATL) (PNA) and Poly(NIPAM-co-ATL)-g-DEDA/PEGA (PDP) Copolymersa run

sample

Mn,thb

Mn,GPCc

Mpc

ĐMc

Mn,NMRd

Tg (°C)e

Tc (°C)f

1 2 3 4

l-PNA c-PNA l-PDP c-PDP

12800 12800 22200 22300

15700 13200 24900 21300

17900 14900 28400 24000

1.18 1.19 1.15 1.18

12800 12900 22500 22600

143.9 146.1 67.0 71.6

12.3 20.8 48.8 61.6

Reaction conditions: run 1: [NIPAM]0:[ATL]0:[FBCP]0:[AIBN]0 = 100:20:1:0.1, [M]0 = 3.0 mol/L, in dioxane at 70 °C for 20 h (step i of Scheme 2); run 2: cp = 50 mg/L, UV irradiation, in acetonitrile at 25 °C for 12 h (step ii); runs 3 and 4: [ATL unit]0:[DEDA]0:[PEGA]0 = 1:2:3, [ATL unit]0 = 0.10 mol/L, in DMF at 25 °C for 48 h (steps vi and v), and the terminal RAFT moiety of l-PNA was initially removed in run 3 (step iii). b Theoretical molecular weight (g/mol) calculated by monomer conversion by 1H NMR analysis (run 1) or assuming the reaction was quantitatively performed (runs 2−4). cApparent molecular weight (Mn,GPC, g/mol), peak molecular weight (Mp, g/mol), and dispersity (ĐM) estimated by GPC using DMF eluent, RI detector, and PMMA standard samples. dMolecular weight (Mn,NMR, g/mol) determined by 1H NMR analysis. eGlass transition temperature determined by DSC. fCloud point determined by turbidity analysis (heating rate 0.5 °C/min, concentration 2.0 mg/mL, transition midpoint). a

phenoxy)propyl 4-(benzodithioyl)-4-cyanopentanoate (FBCP) mediated RAFT copolymerization of NIPAM and ATL. The copolymerization ([NIPAM]0:[ATL]0:[FBCP]0:[AIBN]0 = 100:20:1:0.1) conducted in dioxane at 70 °C for 20 h afforded l-PNA with monomer conversions of 85% (for NIPAM) and 80% (for ATL) as determined by 1H NMR analysis. In 1H NMR spectrum of l-PNA (Figure 1A), typical signals originating from the RAFT agent appeared at 10.66 (ArCHO), 7.95, 7.56, 7.38, 6.85 (PhH and ArH), 4.31 (ArCH2O), 4.15 (COOCH2), and 2.57 ppm (ArCH3), and characteristic signals in comonomer units were noted at 4.74 (CONHCH of ATL unit), 3.98 (CONHCH of NIPAM unit), 3.1−3.6 (CH2S of of ATL unit), and 1.13 ppm (CH3 of NIPAM unit); then the number of comonomer units was calculated as 85 (DPNIPAM unit = I3.98/I10.66) and 16 (DPATL unit = I4.74/I10.66). As expected from a controlled polymerization system, the molecular weight determined by 1H NMR analysis (Mn,NMR = 12 800 g/mol, Table 1) was close to the theoretical value (Mn,th = 12 400 g/mol), with relatively low dispersity (ĐM = 1.18, Figure 2). Second, cyclic poly(NIPAM-co-ATL) (c-PNA) was prepared by UV-induced ring-closure reaction. As the dilute solution of lPNA in acetonitrile (c = 0.05 mg/mL) was exposed to UV irradiation using a 120 W low pressure mercury lamp (313 nm) at 25 °C for 12 h, c-PNA was isolated in quantitative yield after evaporating the solvent. After cyclization, the characteristic

presence of dual amide linkages in the Y junctions can result in significantly enhanced inter/intramolecular hydrogen bonding interactions.70 Since multiple functions and PEG segments are integrated into the graft copolymers with dual amide, thioether, and diethylamino bearing Y junctions, the utilization of different solvents (H2O and D2O) and external stimuli can induce more interesting thermoresponsive properties. The effects of different factors such as polymer concentration (cp), deuterated solvent, additives (NaCl and urea), pH, CO2/N2 bubbling cycle, and oxidation on thermo-induced phase transition were investigated, and the influence of solution blending was also explored to reveal the cooperative or uncooperative transition.69,72 Moreover, the thermoresponsive behaviors of l-PDP and its analogues, namely, linear poly(NIPAM-co-ATL)-g-DEDA/MA (l-PDM, in which MA denoted methyl acrylate) and poly(N-(1-(2-(diethylamino)ethylamino)-1-oxo-4-(ω-methoxy-poly(ethylene glycol)carbonylethylthio)butan-2-yl)acrylamide) (l-PDMBA), were investigated to show the effect of chemical composition, and Tc differences between l-PDP and c-PDP obtained under similar conditions were compared to reveal the topology effect.

2. RESULTS AND DISCUSSION 2.1. Synthesis of Linear and Cyclic Graft Copolymers and the Comparative Samples. First, linear poly(NIPAMco-ATL) (l-PNA) was synthesized by 3-(2-formyl-3-methylC


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glycol)-carbonylethylthio)butan-2-yl)acrylamide (DMBA) unit. After modification, the original signal at 4.72 ppm (CONHCH of ATL unit, Figures 1A and 3A) completely disappeared, a new signal quantitatively appeared at 4.43 ppm (CONHCHCONH) in 1H NMR spectra (Figures 1B and 3B), and other signals were quantitatively noted at 4.24 (COOCH2CH2 connecting with PEG), 3.65 (CH2CH2O of PEG), 3.38 (terminal CH3O), 3.33 (NHCH2CH2N), 2.78 (COCH2CH2S), 2.5−2.7 (NCH 2 and CHCH 2 CH 2 S), and 1.02 ppm (CH3CH2N). 1H NMR analysis confirmed that the tandem reactions were efficiently conducted, and the Mn,NMR value was close to the expected one. In FT-IR spectra (Figure S1), characteristic absorption bands were noted at about 1734 (νCO of ester bond connecting with PEG), 1647 (νCO of amide), 1541 (δN−H of amide), 1458 (δCH2 of PEG), 1386 (δCH3), and 1103 cm−1 (νC−O−C of PEG). Meanwhile, l-PDM (Figures S2 and S3) was synthesized by modification of l-PNA using DEDA and MA, and l-PDMBA (Scheme S1, Figures S3 and S4) was generated by modification of l-PATL using procedures similar to l-PDP. Owing to the topology effect, cyclic polymer can exhibit enhanced glass transition temperature (Tg) than its linear analogue with same molecular weight.29,73−75 As determined by differential scanning calorimetry (DSC, Figure S5) analysis, T g (l-PNA) and T g (l-PDP) were 143.9 and 67.0 °C, respectively, and their cyclic products had a glass transition at 146.1 °C (for c-PNA) and 71.6 °C (for c-PDP). These results revealed that the cyclization only led to slightly increased Tg values (ΔTg = 2.2 °C for PNAs and 4.6 °C for PDPs). The potential reason lay in relatively high degree of polymerization (DP = 101), which was liable to further weaken the cyclic effect due to more similar configurational entropy between linear and cyclic graft copolymers with increasing chain length of polymer backbone.73 2.2. Thermoresponsive Behaviors of l-PDP and c-PDP Aqueous Solutions. PDP copolymers comprise thermoresponsive polyacrylamide backbone, pH/CO2-sensitive diethylamino moieties and PEG grafts, and oxidation-responsive thioether functionalities, and their macromolecular structure is more complex due to the presence of dual amide bearing Y junction. In this study, the thermosensitive behaviors of l-PDP

Figure 2. GPC traces of various copolymers (eluent: DMF).

signals corresponding to original ArCHO (10.66 ppm), PhC(S)S, and ArCH3 (2.57 ppm) moieties were absent, and new signals were observed at about 6.80 (ArH), 5.39 (ArCHOH), and 3.65 ppm (ArCH2) in the 1H NMR spectrum of c-PNA (Figure 3A). Owing to reduced hydrodynamic volume of cyclic polymer, the GPC trace of c-PNA completely shifted to lower molecular weight side as compared with l-PNA (Figure 2), with apparent molecular weight (Mn,GPC) of 13 200 g/mol. The Mn,GPC(c-PNA)/Mn,GPC(l-PNA) value of 0.84 was roughly comparable to those reported for other cyclic polymers.29,56−62,71 Last, linear and cyclic poly(NIPAM-co-ATL)-g-DEDA/ PEGA copolymers were generated by one-pot double modification of their precursors with DEDA and PEGA (Mn ≈ 480 g/mol). Considering the tandem aminolysis and Michael addition will introduce one PEG segment into the chain end of linear graft copolymer, the terminal RAFT moiety of l-PNA was initially removed by radical-induced addition−fragmentation reaction using excess AIBN, followed by thiolactone chemistry to generate the desired l-PDP. During tandem amine−thiol− ene reactions, the ATL unit was first converted into the 2acrylamido-N-(2-diethylamino)ethyl-4-mercaptobutanamide moiety, followed by Michael addition to generate N-(1-(2(diethylamino)ethylamino)-1-oxo-4-(ω-methoxy-poly(ethylene

Figure 3. 1H NMR (400 MHz) spectra of c-PNA (A) and c-PDP (B) in CDCl3 at 25 °C. D


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PDP, sample c), and 61.6 °C (c-PDP, sample d) by turbidity analysis, in which the cloud point was determined as the temperature at the half of the maximal and minimal transmittances. The cloud point of l-PDP comprising NIPAM and DMBA units was higher than that of PNIPAM (around 32 °C) and l-PDMBA (Tc = 47.0 °C, Figure S6), revealing the influence of chemical composition and topology on phase transition. Cyclic and cyclic graft copolymers exhibited higher T c than their linear analogues with similar chemical composition and molecular weight, and the ΔTc value was 8.5 °C (for PNA) and 12.8 °C (for PDP). The result was consistent with that reported by Williams et al.,69 in which the ΔTc of 20 °C for graft copolymers was significantly larger than that observed in normal nongrafted polymers. This phenomenon could be attributed to some factors such as the repulsive forces between rings or cyclic grafts, the influence of topological constraint on heat-induced dehydration and agglomeration, and distinct interactions between polymer chains and water resulting from distinct hydrodynamic volumes and/or types and strength of hydrogen bonds.20−23,29,69 2.2.2. Influence of Deuterated Solvent on Phase Transition. Temperature-dependent transmittances of PDP solutions in D2O were measured to reveal the role of deuterated solvent on phase transition. Interestingly, the change of Tc(l-PDP) and Tc(c-PDP) in H2O and D2O showed a distinct tendency, in which the copolymer solution in D2O exhibited significantly enhanced (ΔTc(l-PDP) = 15.1 °C) or reduced (ΔTc(c-PDP) = −7.6 °C) cloud point than that in H2O (Figure 4). It is worth to note that the Tc value of the linear graft copolymer in D2O could be higher than that of the cyclic graft copolymer, and this order was opposite to that

and c-PDP solutions under different conditions were investigated to reveal the effect of various factors, and the thermoresponsive properties of l-PDP, l-PDM, and l-PDMBA aqueous solutions were compared to understand the influence of grafted moieties/chains and compositions. 2.2.1. Influence of Topology on Phase Transition. As polymer concentration (cp) was fixed at 2.0 mg/mL, the temperature-dependent transmittances are plotted in Figure 4.

Figure 4. Influence of topology and solvent on transmittances and cloud points of l-PNA (a), c-PNA (b), l-PDP (c), and c-PDP (d) solutions in H2O and D2O (cp = 2.0 mg/mL).

The LCST-type soluble-to-insoluble phase transition was observed in each case, and the cloud point was determined to be 12.3 (l-PNA, sample a), 20.8 (c-PNA, sample b), 48.8 (l-

Figure 5. (A) 1H NMR spectra (400 MHz) of l-PDP and c-PDP in D2O (cp = 2.0 mg/mL) at 25 °C, in which l′, m′, n′, and o′ denoted the signals with upfield shifts. (B) 1H NMR spectra (400 MHz) of l-PDP in D2O (cp = 2.0 mg/mL) recorded at 25−80 °C. (C) Evolution of chemical shift of typical signals of l-PDP with increasing temperature. (D) Dependence of normalized integral of various protons of l-PDP on temperature. E


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around 57 °C (0.297 for signal e) and 54 °C (0.842 (c), 0.781 (b), and 0.602 (a)) and then augmented to 0.727 (e), 0.961 (c), 0.916 (b), and 0.666 (a) at 80 °C. The normalized integral of CH2N of c-PDP only fluctuated between 0.982 and 1, suggesting the intramolecular hydrogen bond was stable enough during the phase transition. The phase transition behaviors of PDP copolymers were different from normal thermosensitive polymers in that the starting temperature to reduce transmittance (T ≈ 58/46 °C) in l-PDP/c-PDP solutions was lagged behind that of desolvent (T ≈ 40/35 °C), the maximum decrease of normalized integral of NIPAM unit (about 17%) and diethylamino group (2−15%) was significantly lower than that noted in PNIPAM and PMAEE (around 87%),32 and complex hydrogen bonding donors (amide/dual amide moiety) and acceptors (diethylamino, thioether, and ethylene glycol unit) could form continuously enhanced inter/intramolecular hydrogen bonds at a critical temperature. These results indicated that the peripheral PEG segments with medium grafting density and the intramolecular hydrogen bonds within the Y junction could efficiently hinder NIPAM and diethylamino moieties from dehydration during phase transition. Moreover, dynamic light scattering (DLS) measurements at different temperatures were performed to reveal the Tc differences of PDP solutions (cp = 2.0 mg/mL) in H2O and D2O. The copolymers could form mixtures of unimolecular and conventional micelles in the solvent at 25 °C, and a dimodal distribution was noted in DLS plots (Figure S8). The lower scattered light intensities and larger hydrodynamic diameters of copolymer solutions formed in D2O suggested that the copolymers could adopt more extended conformation due to the weakened hydrogen bonds between copolymer and the solvent. As the solutions were heated above Tc, l-PDP chains simultaneously underwent intrachain contraction and interchain association/entanglement to form larger aggregates, while c-PDP chains formed smaller aggregates due to restricted interchain entanglement and penetration originating from the cyclic graft topology. With increasing temperature, the peak hydrodynamic diameters (Dpeak) exhibited a trend of rise first and then fall (in H2O) or fall first and then rise (in D2O), indicating solvent-dependent thermo-induced aggregation and desolvent behaviors. Therefore, the different transition tendency for c and d in H2O/D2O could be primarily attributed to the solventswitchable hydrogen bonding interactions in the PEGconnecting Y junctions. Dual amide groups of c and d in H2O were liable to form different types of hydrogen bonds due to the strong interactions between macromolecule and the solvent, while intramolecular hydrogen bonds could be efficiently formed within the dual amide groups (c in D2O) and N-(2-diethylamino)ethylamide moieties (d in D2O) resulting from the weakened interactions between copolymer and D2O. The significantly enhanced cloud point of c in D2O indicated that the intramolecular dual amide-based hydrogen bonds of c in D2O were more stable than inter/intramolecular interactions of c in H2O and hence required an elevated temperature to trigger the desolvent process. On the contrary, the macromolecule−solvent interactions of d in D2O were partly decreased as compared with those of d in H2O, the intramolecular hydrogen bonds formed by NHCH2CH2N further weakened the amide−solvent interactions, and thus Tc(d, H2O) was higher than Tc(d, D2O).

observed in H2O. The ΔTc values were distinctly different from those of PNIPAM (ΔTc ≈ 1 °C),79 PDEAEAM (ΔTc = −2.3 °C),31 and PMAEE (ΔTc = −11 °C),32 revealing the important role of chemical composition and topology. The presence of PEG-connecting Y junctions in graft copolymers allowed more complex interactions, and thus the addition of isotopic solvent could efficiently induce the change in interactions and result in enhanced or reduced hydrophilicity. To further understand the phase transition at LCST, the temperature-variable 1H NMR analyses of l-PDP (Figure 5) and c-PDP (Figure S7) solutions in D2O (cp = 2.0 mg/mL) were performed. In the 1H NMR spectrum of l-PDP recorded at 25 °C (a of Figures 5A), characteristic signals were noted at 4.38 (NHCHCO in Y junction), 4.33 (COOCH2CH2O-PEG), 3.93 (CHNH of NIPAM unit), 3.73 (CH2CH2O of PEG), 3.47 (CONHCH2), 3.41 (CH3O of PEG), 2.87 (COCH2CH2S), 2.78 (CH2N), 2.75 (CHCH2CH2S), 2.66 (COCH2CH2S), 1.18 (CH3 of NIPAM unit), and 1.13 ppm (CH3CH2N). Careful inspection of the 1H NMR spectrum of c-PDP at 25 °C (b of Figure 5A) revealed upfield shifts of 0.10 (CONHCH2), 0.09 (CH2N), and 0.03 ppm (CH3CH2N) than those noted in lPDP (Table S1). These results indicated the formation of more stable intramolecular hydrogen bonds within dual amide (for lPDP) and N-(2-diethylamino)ethylamide (for c-PDP) in D2O due to the weakened interactions between macromolecule and the solvent, in which the dual amide-based intramolecular hydrogen bonds could be completely inhibited in c-PDP due to the steric hindrance resulting from the cyclic graft architecture. As the temperature gradually increased from 25 to 80 °C, a downfield shift of typical protons and linear evolution of chemical shift with increasing temperature were observed in most cases (Figure 5 and Figure S7). The differences of chemical shifts at 25 and 80 °C (Δδ) of l-PDP were 0.57 (CHNH of NIPAM unit), 0.46 (CH2N of tertiary amine), 0.50/0.53 (CH2CH2O), and about 0.53 ppm (other protons, Figure 5B,C), and the Δδ values of c-PDP were 0.58 (CHNH of NIPAM unit), 0.45/0.49 (CH2CH2O), 0.47 (CHCH2CH2S), and 0.52−0.55 ppm (other protons, Figure S7B,C), in which the deviation from linear evolution started at about 58 °C (for l-PDP) and 54 °C (for c-PDP). These results confirmed the formation of enhanced inter/intramolecular hydrogen bonding interactions among amide, ethylene glycol, and diethylamino moieties at LCST, and the thioether group of c-PDP could also act as an acceptor to form hydrogen bond at high temperature. To reveal the phase transition process, six kinds of characteristic signals, namely, CH2CH2O of PEG (signal j), CHNH of NIPAM unit (signal c), CH2N of tertiary amine (signals m and n), NHCHCO in Y junction (signal e), and CH (signal b) and CH2 (signal a) in polymer backbone, were normalized by the internal standard of H2O at δ = 4.79 ppm (Figure 5D and Figure S7D). Two signals corresponding to CH2CH2O appeared as the temperature went beyond 58 °C (for l-PDP) and 54 °C (for c-PDP), and the integral of the signal with an upfield shift augmented with elevated temperature, confirming the formation of enhanced interactions between ethylene glycol and amide groups. In addition to constant integral of signal j, the normalized integral of other signals in l-PDP initially decreased as the temperature was beyond 40 °C, reached a minimum at about 58 °C (0.832 for signal c) and 61 °C (0.854 (m and n), 0.395 (e), 0.723 (b), and 0.676(a)), and then gradually recovered to 1.0 (c), 0.992 (m and n), 0.744 (e), 0.933 (b), and 0.759 (a) at 80 °C. The normalized integral of typical signals in c-PDP initially decreased to a minimum at F


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Figure 6. Influence of polymer concentration on transmittances (A) and cloud points (B) of l-PDP (c) and c-PDP (d) aqueous solutions.

Figure 7. Dependence of cloud points of copolymer aqueous solutions (cp = 2.0 mg/mL) on NaCl (A) and urea (B) concentrations.

2.2.3. Influence of Polymer Concentration on Phase Transition. As cp dropped from 5.0 to 0.5 mg/mL, Tc(l-PDP) gradually shifted from 40.8 to 72.8 °C, and Tc(c-PDP) increased from 50.7 to 77.6 °C, corresponding to the dilution effect (Figure 6). The higher cloud point of c-PDP than l-PDP (ΔTc = 4.8−12.8 °C) under same concentration could be attributed to the topology effect. The ΔTc value was roughly comparable as cp varied between 1.0 and 5.0 mg/mL, while it decreased to 4.8 °C as cp was further reduced to 0.5 mg/mL, revealing the simultaneous dilution and topology effects were correlated to polymer concentration especially in dilute solution. 2.2.4. Influence of Additives on Phase Transition. NaCl and urea were chosen as additives to reveal the thermoresponse of copolymer solution (cp = 2.0 mg/mL). As cNaCl increased from 0 to 2.0 mol/L, Tc(l-PDP) decreased from 48.8 to 33.1 °C (Figure S9A), and Tc(c-PDP) dropped from 61.6 to 38.6 °C (Figure S9C), which were similar to the normal LCST-type polymers and could be attributed to the salting-out effect.77,78 The topology effect could be confirmed by the higher Tc(cPDP) than Tc(l-PDP) under same salt concentration (Figure 7A). With increasing cNaCl, the ΔTc value gradually decreased from 12.8 to about 5.5 °C owing to the concurrent topology and salt effects. Meanwhile, the effect of urea on thermoresponse was studied to diagnose the hydrogen bond between polymer chain and the solvent. With increasing amount of urea, the cloud point of thermosensitive polymers (e.g., PNIPAM)79,80 bearing hydrogen bond with urea usually decreases, while the Tc value of polymers (e.g., PDEAEAM)31 lacking hydrogen bond with urea is liable to increase. The diethylamino

and NIPAM units are combined within PDP, and thus l-PDP and c-PDP are somehow a joint of PNIPAM and PDEAEAM. As curea increased from 0 to 1.0 mol/L, Tc(l-PDP) increased from 48.8 to 71.2 °C (Figure S9B), Tc(c-PDP) augmented from 61.6 to 77.7 °C (Figure S9D), and the tendency was similar to that noted in PDEAEAM other than PNIPAM. Although the molar ratio of NIPAM units to diethylamino moieties reached up to 5.3, the latter lying in the location which was a bit far from the polymer backbone, and the presence of PEG grafts further hindered the urea from approaching the NIPAM unit and dual amide moiety, and thus they were difficult to form the hydrogen bonds with urea. Upon addition of same amount of urea, the ΔTc value gradually dropped from 12.8 to about 6.5 °C with an increase in curea (Figure 7B). 2.2.5. Influence of pH and CO2/N2 Bubbling on Phase Transition. To our surprise, the PDP aqueous solutions (cp = 2.0 mg/mL) only exhibit LCST-type phase transition in relatively narrow pH window (pH ≈ 6.8−8.5, Figure 8A,B) although the cloud points of normal tertiary amine bearing polymers are liable to decrease with increasing basicity.28−32 As the graft copolymers were directly dissolved in deionized water (cp = 2.0 mg/mL), the pH was 7.6 (l-PDP) and 7.5 (c-PDP), respectively. With increasing pH via addition of NaOH, Tc(lPDP) shifted from 48.8 °C (pH 7.6) to 69.0 °C (pH 7.9) and 75.4 °C (pH 8.4), and Tc(c-PDP) increased from 61.6 °C (pH 7.5) to 74.4 °C (pH 7.8) and 83.1 °C (pH 8.1), in which Tc(cPDP) was higher than Tc(l-PDP) at a similar pH owing to the topology effect (Figures 8D). As the pH was further enhanced (pH ≥ 8.5), the LCST bahavior disappeared. To further gain insight into lack of phase transition at higher basicity, l-PDP G


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Figure 8. Influence of pH (A, C) and CO2/N2 bubbling cycles (B, C) on transmittances (A−C) and cloud points (D) of aqueous solutions comprising l-PDP (c, cp = 2.0 mg/mL), c-PDP (d, cp = 2.0 mg/mL), and l-PDM (e, cp = 0.5 mg/mL).

(CH3CH2N). With increasing temperature, typical signals with a downfield shift exhibited linear evolution of chemical shift with enhanced temperature, and the Δδ value at 25 and 80 °C ranged between 0.53 and 0.55 ppm (Figure S10). The normalized integrals of various signals were almost constant at different temperatures, revealing lack of obvious process for aforementioned dehydration and formation of enhanced hydrogen bonds. As NaOH was used to adjust the pH, PDP aqueous solutions showed an enhanced cloud point with increasing pH until the LCST-type phase transition vanished at higher pH, revealing that the addition of NaOH was liable to enhance the hydrophilicity of copolymer solution. For comparison, lPPEGA and l-PDM under basic conditions were investigated. Typical signals of l-PPEGA in D2O appeared at 4.26 (CH2OCO), 3.70 (CH2CH2O), and 3.38 ppm (CH3O) in the 1H NMR spectrum, and they shifted to 4.21, 3.66, and 3.34 ppm, respectively, under basic conditions (Figure S11A). The signals with an upfield shift of 0.04−0.05 ppm were noted at pH 10.4, and the normalized integrals decreased to about 80.0% (CH2OCO) and 67.4% (CH of polymer backbone) although those of PEG segment remained constant, primarily originating from the shielding effect due to the anion−dipole interactions between OH− and CH2CH2O units. The saturated aqueous solution (cp ≈ 0.8 mg/mL) comprising l-PDM without CH2CH2O unit had a cloud point of 39.8 °C, and the Tc value gradually dropped from 53.5 to 22.0 °C as the solution pH increased from 7.8 to 12.2 (cp = 0.5 mg/mL, Figure 8C and Figure S12), which was similar to those noted in normal tertiary amine bearing polymers.28−32 Careful inspection of 1H NMR spectra of l-PDP in D2O and D2O/NaOD (pH 10, Figure 9)

solution in D2O/NaOD (cp = 2.0 mg/mL, pH 10) was chosen to check 1H NMR spectroscopy during 25 and 80 °C. In the 1H NMR spectrum recorded at 25 °C (Figure 9), typical signals appeared at 3.93 (CHNH of NIPAM unit), 3.73/3.72 (CH2CH2O of PEG, in which a signal with an upfield shift of 0.01 ppm appeared), 3.41 (CH3O), 3.32 (CONHCH2), 2.79 (COCH2CH2S), 2.65 (CHCH2CH2S), 2.61 (CH2N), 2.49 (COCH2CH2S), 1.18 (CH3 of NIPAM unit), and 1.06 ppm

Figure 9. 1H NMR spectra (400 MHz) of l-PDP (cp = 2.0 mg/mL) in D2O (pH 7.7, a) and D2O/NaOD (pH 10, b) at 25 °C and the proposed chemical structure of l-PDP with dual intramolecular hydrogen bonds formed under basic conditions. H


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Figure 10. FT-IR spectra of linear and cyclic graft copolymers before and after oxidation in the range of 600−1800 cm−1 (A) and temperaturedependent transmittances of copolymer aqueous solutions (B, cp = 2.0 mg/mL).

For l-PDM solution, a similar tendency was noted, and the Tc value increased from 53.5 °C (pH 7.8) to 64.3 °C (pH 7.4) after three CO2/N2 bubbling cycles (Figure 8C) until the phase transition was invisible at pH 7.2, revealing the presence of thioether linkage could also lead to irreversible CO2-responsive behavior. The reversible Lewis acid−base interaction between CO2 and ethylene glycol unit was confirmed by 1H NMR spectra of l-PPEGA in D2O obtained during the first CO2/N2 bubbling cycle (Figure S11B). In CO2-saturated l-PPEGA solution, the signals with an upfield shift of 0.01 ppm were noted for CH (backbone), COOCH2, CH2CH2O, and terminal CH3O in the 1H NMR spectrum, in which the normalized integral of typical signals decreased to about 79.4% (COOCH2) and 76.0% (CH of polymer backbone), and the line width of the signals of CH2O and CH3O in PEG segment was broadened while the normalized integral kept constant. After further purging with N2, the chemical shift and normalized integral of various signals were completely recovered to those noted in the original solution. Furthermore, 1H NMR spectra of l-PDP in D2O obtained during CO2/N2 bubbling cycles (Figure S14) were carefully compared. In CO2-saturated solution, the signals with downfield shifts of 0.01 (CH2CH2O), 0.55 (NCH2), and 0.18 ppm (NCH2CH3) were noted, the signals of CONHCH2 and CH2CH2O overlapped with each other, while the chemical shifts of other signals remained constant. After purging with N2, the signals in the protonated moiety could not shift to those of the original tertiary amine group, and the signals with upfield shifts of 0.05 (NCH2) and 0.02 ppm (NCH2CH3) were observed in different CO2/N2 bubbling cycles. The pKa of l-PDP aqueous solution was obtained as about 7.8 based on the acid−base titration (Figure S15), and the degree of protonation of tertiary amine moieties at pH 7.6 (original), 7.4 (first N2), and 7.0 (second N2) was deduced to be around 62%, 72%, and 87%, respectively. Although the diethylamino group could be quantitatively protonated in a saturated CO2 aqueous solution, the remaining CO2 even upon purging with N2 only led to partial deprotonation due to the strong interactions with CO2. Therefore, the irreversible CO2responsive behavior could be ascribed to some factors involving the strong interaction between CO2 and diethylamino group, the Lewis acid−base interaction between CO2 and thioether/ ether groups, and the relatively high pKa of copolymer solution. Our results revealed that the Tc value could be efficiently tuned by applying CO2/N2 bubbling cycles due to the distinct degree of protonation resulting from the change in solution pH, and the ΔTc value after N2 bubbling could reach up to 23.8 °C (l-

revealed that the signals in the Y junctions shifted to the upfield under basic condition although no shift of characteristic signals in NIPAM unit (CHNH and CH3) was noted. The difference of chemical shift at pH 7.7 and 10 was 0.15 (CONHCH2), 0.08 (COCH 2 CH 2 S), 0.17 (CH 2 N), 0.10 (CHCH 2 S), 0.17 (COCH 2 CH 2 S), and 0.07 ppm (NCH 2 CH 3 ), possibly originating from the strong dual intramolecular hydrogen bonds among dual amide, tertiary amine, and thioether and/or enhanced anion−dipole interactions between OH− and polar groups in Y junction. With increasing basicity, the chemical shift of the major signal of CH2CH2O in PEG segment remained the same while a shoulder signal with an upfield shift of 0.01 ppm appeared due to the anion−dipole interactions, and the gradual deprotonation of tertiary amine moiety favored to form intramolecular hydrogen bonds within the Y junction surrounding by the hydrophilic PEG segment, leading to gradually elevated cloud points. Therefore, the abnormal thermoresponsive behaviors of l-PDP and c-PDP aqueous solutions under basic conditions could be mainly ascribed to the intramolecular hydrogen bonds within Y junction and anion−dipole interactions. To reveal the CO2 responsiveness, the copolymer solutions were subjected to a couple of CO2/N2 bubbling cycles. In each run, CO2 or N2 (10 mL/min) was purged until the solution pH kept constant. With increasing CO2/N2 bubbling cycles (Figure 8 and Figure S13), the pH of saturated CO2 aqueous solution in each cycle was stabilized at 4.7 (l-PDP), 5.2 (c-PDP), and 4.6 (l-PDM), while the pH of copolymer solution degassing with N2 was liable to decrease first and then fixed at around 6.7 (lPDP), 6.5 (c-PDP), and 7.2 (l-PDM). When PDP aqueous solution was subjected to CO2/N2 bubbling cycles and adjusted to the initial pH via addition of NaOH, its LCST behavior could be recovered (Figure S13A). These results were different from other typical CO2-switchable polymers28−32 in that the process for the protonation of tertiary amine via carbonic acid was reversible, while the physical process for the deprotonation via removing excess CO2 using N2 purging was normally irreversible. Another finding lay in the pH-sensitive LCST-type phase transition (Figure 8D). When the copolymer aqueous solution was subjected to two CO2/N2 bubbling cycles, Tc(lPDP) shifted from 48.8 °C (original, pH 7.6) to 61.3 °C (first N2, pH 7.4, cycle 1) and 72.6 °C (second N2, pH 7.0, cycle 2), Tc(c-PDP) was significantly increased from 61.6 °C (original, pH 7.5) to 72.6 °C (first N2, pH 7.3, cycle 1) and 79.8 °C (second N2, pH 6.9, cycle 2), and the phase transition vanished as more CO2/N2 bubbling cycles were adopted (Figure S13). I


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Figure 11. Influence of solution blending on transmittance of copolymer aqueous solutions (A−C, cp = 2.0 mg/mL) and dependence of cloud point on molar composition of d (rd) during c/d and a/d blending (D): (A) copolymer mixture with equimolar feed ratio (a = l-PNA, b = c-PNA, c = lPDP, and d = c-PDP); (B) c/d mixture; (C) a/d mixture.

PDP, ΔpH = 0.8), 18.2 °C (c-PDP, ΔpH = 0.9) and 10.8 °C (lPDM, ΔpH = 0.4) until the phase transition disappeared under more acidic surroundings. This phenomenon was different from that noted in tertiary amine bearing polymers such as PDMAEMA, PDEAEAM, and PMAEE,28−32 in which both transmittances and cloud points in each CO2/N2 bubbling cycle were roughly comparable even if the recycled polymer aqueous solution was higher than that of the fresh solution (ΔTc = 12 °C (for PDEAEAM) or 5.0 °C (for PMAEE)).30,32 2.2.6. Influence of Oxidation on Phase Transition. As lPDP and c-PDP were treated with H2O2 aqueous solution, the corresponding oxidation products c′ and d′ were obtained. FTIR spectra showed new absorption bands at about 1033 (νSO band), 1200, and 1367 cm−1 (symmetric and asymmetric stretching of −SO2− groups),18 suggesting the oxidation copolymers had both sulfoxide and sulfone linkages (Figure 10A). As c′ and d′ aqueous solutions (cp = 2.0 mg/mL) were subjected to turbidity analysis, only very limited decrease in transmittance was noted (Figure 10B), revealing lack of notable LCST-type phase transition. These results indicated that the PDP copolymers were sensitive to H2O2, and the oxidation could enhance the hydrophilicity and hinder the thermoresponse of graft copolymers. 2.3. Influence of Solution Blending on Thermoresponsive Properties of Copolymer Aqueous Solutions. The solution blending can act as an efficient route to tune the phase transition, in which the cloud point may be closely related to some factors such as chemical composition, molar ratio, molecular weight, and macromolecular architecture. Depending on whether there is cooperative behavior between the polymers or not, one or two transitions can be

obtained.69,72 To reveal the possibility to finely tune the Tc value of copolymer mixtures, the solution blending (cp = 2.0 mg/mL) was performed. Initial experiments were conducted using the blends comprising equimolar feed ratio of two copolymers. Except the a/d mixture with two independent transitions (Tc = 26.7 and 52.4 °C), all the other mixtures only exhibited a single cloud point (Figure 11A). The experimental Tc values of a/b, a/c, b/c, b/d, and c/d mixtures were obtained as 18.6, 21.8, 28.6, 28.8, and 56.3 °C, respectively. The preliminary results revealed that a/d mixture was liable to exhibit uncooperative behavior, while other mixtures showed cooperative behaviors, possibly originating from the variation of types and strength of mutual interactions when blended together. On this basis, dependence of phase transition on the composition of c/d mixture was studied to reveal the effect of different topology during solution blending. When blended together, c/d mixtures with molar ratio of 3:1, 1:1, and 1:3 only showed a single transition (Figure 11B), and the Tc values almost exhibited a linear evolution with increasing molar ratio of d (r d , Figure 11D), corresponding to cooperative thermoresponsive behavior. These results revealed that linear and cyclic graft copolymers with similar composition and molecular weight could efficiently interact with each other in aqueous solution, and the number of interactions between polymer chains and water was roughly close to the average value of two individual copolymers. Moreover, the influence of a/d mixtures with different ratios on the thermoresponsive behaviors was carefully investigated. Intriguingly, the a/d mixtures showed two kinds of phase transition behaviors (Figure 11C). A single transition was noted J


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Macromolecules as the molar composition of d was relatively low (rd ≤ 0.2), and two independent phase transitions appeared with increasing amount of d (Figure 11D), in which Tc1 within 21.3−38.5 °C almost exhibited a linear increase with enhanced rd (rd = 0.25− 0.95), and Tc2 initially increased from 45.2 to 56.0 °C (rd = 0.25−0.75) and then jumped to 69.5 and 70.6 °C (rd = 0.9 or 0.95). The difference in two cloud points obtained under a fixed ratio was in the range of 22.3−25.7 (rd = 0.25−0.75) and about 32 °C (rd = 0.9 or 0.95). These results suggested that a and d could moderately interact with each other; otherwise, a reduced Tc2 with increasing content of d should be observable in a system lacking mutual interaction. Tc2 obtained at a high rd (rd = 0.9 or 0.95) was about 7.9−9.0 °C higher than Tc(d), which may result from the concurrent effects of dilution and a/ d interactions. The aforementioned results indicated b/c (cyclic nongrafted + linear grafted) solution had a single cooperative phase transition whereas a/d (linear nongrafted + cyclic grafted) solution could show two transitions as rd varied between 0.25 and 0.95. To further understand the distinct phase transition behaviors, the b/c and a/d (1:1) aqueous solutions (cp = 2.0 mg/mL) were subjected to DLS measurements at different temperatures. The b/c solution showed dimodal distribution at 10 and 15 °C, the scattered light intensity continuously increased with increasing temperature (T = 10−40 °C), and the hydrodynamic diameter and particle size distribution only slightly changed during 25 and 40 °C (Figure S16A), revealing the cooperative coaggregation during phase transition due to strong interactions involving the intermolecular interactions between PEG segment and amide groups in the cyclic backbone. On the contrary, two stages of coaggregation behaviors of a/d solution were observed in temperaturedependnent DLS plots (Figure S16B), in which the scattered light intensity initially increased with enhanced temperature (T = 10−40 °C), gradually decreased (T = 40−50 °C), augmented to a maximum at about 60 °C, and then dropped, and the Dpeak values varied between 167 and 189 nm (T = 20−60 °C) and further decreased at elevated temperature. The lack of unimolecular micelles in a/d solution confirmed d had participated in the first-stage coaggregation (T = 20−40 °C) primarily corresponding to the thermo-induced loss of water bound with amide groups of a via relatively weak interactions, and the second-stage reaggregation (T = 50−60 °C) was mainly induced by dehydration of amide and diethylamino groups of d lying in the more stable microdomain constructed by the cyclic graft architecture. Therefore, the composition- and topology-dependent solution blending could be efficiently used to tune the cloud point or produce two independent transitions.

type phase transition in a narrow pH window (pH ≈ 6.8−8.5). Cyclic graft copolymer could exhibit significantly enhanced cloud point than linear graft copolymer in H2O under similar conditions, revealing the effect of cyclization. By virtue of solution blending, the mixtures could exhibit one or two phase transition(s) strongly dependent on types and molar compositions of the blends, and two independent phase transitions of linear nongrafted/cyclic grafted mixtures using suitable feed ratios could be ascribed to thermo-induced coaggregation and reaggregation resulting from temperaturedependent two stage dehydrations in different microdomains of copolymer coaggregates. The systematic design by combination of smart moieties/segments and dual amide bearing Y junction affords a versatile route to adjust thermoresponsive properties, which allows precise control over types of inter/intramolecular hydrogen bonding interactions involving single and dual intramolecular hydrogen bonds via switching the solvent and solution pH and applying CO2/N2 bubbling cycles. Our study underlies the forthcoming research on topology−property correlations of multiresponsive graft copolymers with a great potential in smart materials.

3. CONCLUSIONS We have demonstrated that rational design of graft copolymers can lead to interesting stimuli and solvent multitriggered thermoresponsive properties. The phase transition behaviors of linear and cyclic graft copolymers could be efficiently tuned by some factors involving topology, deuterated solvent, concentration, additives, pH/CO2, oxidation, and solution blending. Owing to the formation of more stable intramolecular hydrogen bonds within the dual amide groups of l-PDP and NHCH2CH2N moieties of c-PDP in D2O, they could exhibit remarkably distinct cloud points in H2O and D2O. The presence of peripheral PEG grafts and pH/CO2-switchable interactions in the Y junctions were critical to exhibit LCST-

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.7b00220. Experimental section, 1H NMR data, synthetic routes to PDMBA, FT-IR and 1H NMR spectra, DSC curves, phase transition curves, DLS plots, and titration curve (Table S1, Scheme S1, and Figures S1−S16) (PDF)

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AUTHOR INFORMATION

Corresponding Author

*(Y.Z.) E-mail [email protected]; Tel/Fax 86-51265882045. ORCID

Youliang Zhao: 0000-0002-4362-6244 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The financial support by the National Natural Science Foundation of China (No. 21474070 and 21274096) and the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions is gratefully acknowledged. The authors are grateful to Prof. Xiaohong Li at Soochow University for the kind help in 1H NMR measurement at different temperatures. REFERENCES

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