UCST or LCST? Composition-Dependent Thermoresponsive Behaviorof Poly(N‑acryloylglycinamide-co-diacetone acrylamide)Wenhui Sun,† Zesheng An,*,‡ and Peiyi Wu*,†

†The State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University,Shanghai 200433, China‡Institute of Nanochemistry and Nanobiology, College of Environmental and Chemical Engineering, Shanghai University, Shanghai200444, China

*S Supporting Information

ABSTRACT: Copolymerization has been widely used to tunethe thermoresponsive behavior of water-soluble polymers.However, the observation of both upper and lower criticalsolution temperature (UCST and LCST) from the same typeof copolymer comprising only one monomer whosehomopolymer is thermosensitive and the other monomerwhose homopolymer is nonthermosensitive has not beenreported. In this work, well-defined thermoresponsivecopolymers with tunable compositions have been synthesizedby copolymerization of N-acryloylglycinamide (NAGA) anddiacetone acrylamide (DAAM) via reversible addition−fragmentation chain transfer (RAFT) polymerization. The thermaltransitions of these copolymers are investigated using a combination of turbidimetry, dynamic light scattering (DLS), protonnuclear magnetic resonance (1H NMR), and Fourier transform infrared (FTIR) spectroscopy. The solubility of these copolymersshows a distinct dependence on the composition. While copolymers with up to 30 mol % NAGA are essentially insoluble,copolymers with 35−55 mol % NAGA or 90−100 mol % NAGA have either LCST- or UCST-type transitions respectively, andsoluble copolymers are obtained with 60−85 mol % NAGA. The LCST- and UCST-type transitions are tunable with respect tocomposition, degree of polymerization, polymer concentration, isotope effect and the presence of electrolyte. Insights fromvariable-temperature 1H NMR and FTIR spectroscopies reveal the key role of hydrogen-bonding between the NAGA andDAAM units in determining the thermal transitions.

■ INTRODUCTION

Thermoresponsive polymers play an important role in thedevelopment of advanced technologies including switchablesurfaces,1,2 drug release,3−5 catalysis,6−8 gene therapy,9,10

optical switching,11 and bioimaging.12−14 Polymers with loweror upper critical solution temperature (LCST or UCST) insolution show a miscibility gap at high or low temperatures,respectively, and phase separation into a polymer-poor andpolymer-rich phase could be observed.15 Many thermores-ponsive polymers are known to be LCST-type, such as poly(N-isopropylacrylamide) (PNIPAM),16−18 poly(N-vinylcaprolac-tam) (PVCL)19,20 and poly(oligo(ethylene glycol) (meth)-acrylate) (PPEG(M)A).21,22 However, there exist far lessUCST-type polymers. Although some zwitterionic polymersand polyelectrolytes display UCST-type response in water dueto Coulombic interactions, their thermoresponsive behavior ishighly dependent on the molar mass, type of salts, ionicstrength and valency of ions.23−27 In recent years, increasinglymore attention has been given to nonionic UCST-typepolymers with their phase transitions being dominated byhydrogen- (H-) bonding.28,29 Poly(N-acryloylglycinamide)(PNAGA) is the most studied nonionic polymer exhibitingUCST-type phase transition due to thermally controlled

reversible H-bonding.29−32 The glycinamide moiety ofPNAGA can act as both a hydrogen donor (mainly primaryamide) and acceptor (carbonyl group). Previous reportsregarding the UCST-type transition of PNAGA suggest thatthe polymer is able to form intra- and intermolecular complexesvia H-bonding between its own units.33

Copolymerization is a powerful strategy used to adjust thetransition temperatures of thermoresponsive polymers, inaddition to the manipulation of external conditions such ascounterions, redox potential, light, or pH.23,34−36 For example,we have reported that thermoresponsive copolymers of poly(2-methoxyethyl acrylate-co-poly(ethylene glycol) methyl etheracrylate) (P(MEA-co-PEGA480)) have a linear relationshipbetween the LCST and the molar ratio of MEA/PEGA,37 whileCai and co-workers have reported that gradient copolymers ofpoly(diacetone acrylamide-grad-N,N-dimethyl acrylamide) (P-(DAAM-grad-DMA)) show adjustable LCST by changing thecomonomer sequence from 16 °C to permanently water-soluble.38 In addition, poly(acrylamide-co-acrylonitrile) (poly-

Received: January 4, 2017Revised: February 2, 2017Published: March 2, 2017

Article

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© 2017 American Chemical Society 2175 DOI: 10.1021/acs.macromol.7b00020Macromolecules 2017, 50, 2175−2182

(AAm-co-AN)) is another type of nonionic UCST-typepolymer and exhibits tunable UCST on varying thecomposition of the monomers.28,39 However, the AN monomeris highly toxic, limiting its use in biomedical applications.Tuning the UCST of PNAGA by copolymerization with N-acetylacrylamide (NAcAAm) has also been reported by Agarwalet al.33 (Co)polymers of NAGA29 or other monomers27 whosehomopolymers show UCST-type transitions with monomerswhose homopolymers exhibit LCST-type behaviors have been

shown to exhibit LCST-, UCST-type, or both behaviors atprecisely tuned molar compositions.Herein, we report the development of a new class of

thermoresponsive copolymers based on copolymers of NAGAand DAAM whose homopolymer is nonthermosensitive. Aseries of statistical copolymers of poly(N-acryloylglycinamide-co-diacetone acrylamide) (P(NAGA-co-DAAM)) has beensynthesized via reversible addition−fragmentation chain trans-fer (RAFT) polymerization. Significantly, the thermoresponsivebehavior of these copolymers is highly dependent on the

Scheme 1. Synthesis of Statistical Copolymers of NAGA with DAAM

Table 1. Synthetic Conditions and Results of P(NAGA-co-DAAM) Copolymersa

polymer code composition convn (%)b Mn,thc (g/mol) Mn(GPC)

d (g/mol) Đ (GPC)d UCST/LCST (°C)f (heating/cooling)

NAGA61 P(NAGA113-co-DAAM72) 92 26700 30700 1.24 solubleNAGA30 P(NAGA58-co-DAAM138) 96 30800 33100 1.21 insoluble

U PNAGA PNAGA191 91 24500 28100e 1.23e 20/8.5C NAGA99 P(NAGA190-co-DAAM2) 91 24700 28900e 1.25e 18/7.5S NAGA95 P(NAGA177-co-DAAM9) 90 24200 28000e 1.22e 13.5/4.5T NAGA90 P(NAGA172-co-DAAM19) 92 25300 30200e 1.23e −/∼0L NAGA34 P(NAGA67-co-DAAM131) 96 30800 33400 1.22 18.5/18C NAGA41 P(NAGA80-co-DAAM116) 95 29900 32200 1.24 20/19S NAGA45 P(NAGA90-co-DAAM109) 95 30000 33500 1.20 22/21T NAGA50 P(NAGA96-co-DAAM95) 93 28400 28800 1.22 26/25

NAGA56 P(NAGA110-co-DAAM87) 92 28800 30800 1.21 41/40aTarget DP = ∼ 200. bMonomer conversion determined by 1H NMR. cTheoretical molecular weight of copolymers = (target DPNAGA × monomerconversion) × MNAGA + (target DPDAAM × monomer conversion) × MDAAM + MCTA.

dMolecular weight determined by GPC (DMF, PMMA).eMolecular weight determined by GPC (DMSO, pullulan). fThe temperature at 50% transmittance of the thermal transition was taken as the UCSTor LCST.

Figure 1. RAFT copolymerization of NAGA and DAAM in water with different molar ratios of NAGA/DAAM, [monomer]/[CTA]/[V-50] =200:1:0.08, concentration = 10%: (a) conversion vs polymerization time, (b) pseudo-first order kinetic plots, (c) NAGA50 molecular weight anddispersity vs conversion, and (d) evolution of GPC traces of NAGA50.

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composition with both UCST and LCST being observed forthe same type of copolymer. For the first time, changes in thecopolymer compositions lead to the appearance of both UCSTand LCST for the same type of copolymer. We present adetailed study of the copolymerization kinetics and the effectsof copolymer composition, concentration, deuterium isotopeand electrolytes on the thermal transitions of these well-definedcopolymers.

■ RESULTS AND DISCUSSIONPolymer Synthesis and Characterization. The P-

(NAGA-co-DAAM) copolymers were synthesized by RAFTusing 2-ethylsulfanylthiocarbonylsulfanyl-propionic acid methylester as the chain transfer agent (CTA) and 2,2′-azobis(2-methylpropionamidine) dihydrochloride (V-50) as the radicalinitiator at 70 °C in water (Scheme 1). The molar fraction ofDAAM was varied from 1 to 95 mol % to adjust thecomposition and thus the aqueous solubility of the copolymers.For all the homopolymers and copolymers, the target degree ofpolymerization (DP) was 200 and the conversion of monomerswas above 90% (Table 1). The resulting copolymers werenamed as NAGA-X, where X corresponds to the molarpercentage of NAGA in the copolymer. The composition of thecopolymers was characterized by 1H NMR (Figure S2) and themacromolecular parameters were characterized by gel per-meation chromatography (GPC). The thermal transitiontemperature of the UCST-type and LCST-type copolymers(1 wt %) was determined by turbidimetry upon cooling andheating, respectively.Figure 1 shows the polymerization kinetics for the

copolymerization of NAGA with DAAM at molar ratios of95:5, 90:10, and 50:50. In all cases, near-quantitative conversionwas achieved within 3 h (Figure 1a), and the polymerizationfollowed pseudo-first-order kinetics up to medium to highconversions (Figure 1b). Only a slight increase in thepolymerization rate on increasing DAAM from 5 to 50 mol% was observed. In addition, the two monomers in theNAGA50 copolymers had relatively close reactivities, and the

reactivity of DAAM units was slightly higher than that ofNAGA units, as confirmed by 1H NMR analysis duringcopolymerization, suggesting that the two monomers formstatistical copolymers (Figure S3). The molecular weight of theNAGA50 copolymers scaled linearly with conversion, and thedispersity (Đ) remained ∼1.2 up to near-quantitativeconversions (Figure 1c). The GPC traces exhibited a gradualshift toward high molecular weights as the conversionincreased, suggesting successful formation of well-definedcopolymers (Figure 1d). All these features indicate that theaqueous copolymerization of NAGA with DAAM was wellcontrolled by the RAFT process.

Tunable Solution Behavior. With the series of well-defined copolymers in hand (Table 1 and Table S1), theirthermoresponsive behavior was investigated using a combina-tion of turbidity, dynamic light scattering (DLS), 1H NMR, andFourier transform infrared (FTIR) spectroscopy. Copolymerswith the NAGA molar fraction varying from 5 to 30 mol %were only slightly soluble or completely insoluble in water withno cloud point being observed upon heating or cooling at acopolymer concentration of 1 wt %, which resembles theaqueous solution behavior of the PDAAM homopolymer.40

However, when the NAGA molar fraction was varied from 60to 85 mol %, the copolymers were permanently water-soluble.Interestingly, copolymers with other compositions exhibitedeither UCST- or LCST-type behavior.

UCST Properties. Copolymers with NAGA as the majorcomposition (≥95 mol %) show tunable UCST-type transitions(Figure 2). The UCST decreases from 8.5 to 4.5 °C uponcooling and from 20 to 13.5 °C upon heating (Figure 2a,b),when the DAAM molar fraction is increased from 0 to 5 mol %.PNAGA has been shown to build interpolymer complexes withpoly(acrylic acid)(PAAc)41 or PNAcAAm33 via H-bonding.Similar to PNAGA, the DAAM units also possess both ahydrogen donor (secondary amide) and an acceptor (carbonylgroup) that can form inter/intramolecular H-bonds. Thedecrease of the UCST with increasing molar fraction ofDAAM suggests that the segments formed via H-bond

Figure 2. Thermal transitions of UCST-type (co)polymers measured by turbidimetry upon cooling in water (a), dependence of UCST on DAAMmolar fraction in H2O and D2O, respectively (b), dependence of UCST of NAGA95 on the polymer concentration in water (c), and effect of salts onthe UCST of NAGA99 (d). The polymer concentration is 1 wt % except for part c.

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interactions between NAGA and DAAM may act as hydrophilicmoieties and higher molar fractions of DAAM lead to more-hydrophilic segments. The turbidity curves of these UCST-typecopolymers showed a large hysteresis (Figure S4). From athermodynamic point of view the cloud point upon cooling andheating should be identical when the solution is given sufficienttime to equilibrate. Indeed, the observed hysteresis has beensuggested to be a kinetic phenomenon.31 The molecularweights of the UCST-type copolymers with thermal transitionsabove 0 °C were in the same range from 28000 to 28900 gmol−1, thus ruling out the effect of molecular weight on theUCST or on the sharpness of the transition.33 In addition, thehighly stable H-bonds of PNAGA are relatively difficult tobreak or to form.42 Therefore, the decreased hysteresis withincreasing molar fractions of DAAM is possibly due tointermolecular H-bonds of NAGA and DAAM, which areweaker than the inter/intra-molecular H-bonds of PNAGA.As shown in Figures 2b and S5, the UCST of PNAGA (1 wt

%) in D2O is almost 10 °C higher than that in H2O during thecooling cycle. This could be explained by the fact that CO···D−N is more stabilized than CO···H−N and therefore theinteractions among the polymer chains in D2O are relativelystronger than that in H2O.

43 Moreover, it is observed that withdecreasing DAAM contents in the copolymer, the differencebetween the UCSTs of the copolymers in H2O and D2O isenhanced, suggesting that such a strong isotope effect is mainlydominated by the NAGA units. The cloud point of the UCST-type copolymers is highly dependent on the polymerconcentration, taking PNAGA95 as the example, that is, ahigher concentration leads to a higher cloud point (Figures 2cand S6). However, in dilute solution the UCST is lessconcentration dependent. This observation is similar to thephase transition behavior of PNAGA.31 In addition, electrolytessignificantly affect the UCST of NAGA99 (Figure 2d). Thecloud point decreased from 7.5 °C in pure water to 3.5 °C inthe presence of 0.5 mol L−1 of NaCl. Moreover, the cloud pointdecreased drastically in sodium thiocyanate (NaSCN) solution,which is known to be a strong hydrogen bond-construct agent,

and the copolymer became completely soluble at a NaSCNconcentration of 0.3 mol L−1. These results indicate that H-bonding is the main driving force for the phase separation attemperatures below the UCST.

LCST Properties. Interestingly, further adjusting of thecopolymer composition led to the unexpected observation ofLCST properties for the copolymers with closer molarfractions. The LCST-type copolymers with DPs ∼ 200exhibited a sharp response to temperature change and arelatively small hysteresis (Figures 3a and S7). The hysteresisfor the LCST-type copolymers is smaller than that for theUCST-type copolymers, implying a much weaker H-bondinginvolved in the LCST-type copolymers.44 Since the molarfraction of NAGA and DAAM in the copolymers is close, thereis a greater possibility for H-bonds to form between NAGA andDAAM. For these copolymers (from NAGA56 to NAGA34)the LCST of the copolymers decreased from 41 to 18.5 °Cupon heating with increasing molar fractions of the morehydrophobic DAAM (Figure 3a). As shown in Figures 3b andS8, the lower LCSTs of the copolymers in D2O than that inH2O are due to stronger polymer chain interactions in D2Othan in H2O and hence stronger inclination of aggregationduring heating. The LCST of NAGA50 was found to decreasewith concentration over the 5 wt % concentration range(Figures 3c and S9), due to the HB-driven LCST-type behaviorcaused by strong H-bonding of DAAM units.45,46 Figure 3ddisplays the LCST of the NAGA50 as a function of ionicstrength. Addition of NaCl decreased the LCST from 26 °C inwater to 21.5 °C in the presence of 0.5 mol L−1 of NaCl. Incontrast, the LCST increased from 26 to 39 °C upon increasingthe concentration of NaSCN from 0 to 0.5 mol L−1, due to theeffect of hydrogen bond-construct agent on the H-bonding ofDAAM units. Furthermore, the LCST-type transition ofNAGA50 in aqueous solution was almost unaffected by pHor phosphate-buffered saline (PBS, pH = 7.4, 0.1M) (FigureS10).To investigate the influence of the molecular weight on the

LCST-type behavior, copolymers with an equal molar ratio of

Figure 3. Thermal transitions of LCST-type copolymers measured by turbidimetry upon heating in water (a), dependence of LCST of thecopolymers on DAAM molar fraction in H2O and D2O, respectively (b), dependence of LCST of NAGA50 on the polymer concentration in water(c), and effect of salts on the LCST of NAGA50 (d). The polymer concentration is 1 wt % except for part c.

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NAGA/DAAM on varying the target DP from 50 to 500 weresynthesized (Table S2). The obtained copolymers were namedas NAGA50-x, where x corresponds to the actual DP. Kineticstudies were conducted with target DPs being 100, 200, and500. Representative sampling experiments showed that thepolymerization was very fast and >90% conversion wasachieved within 3 h of polymerization (Figure 4a). Thepolymerization followed pseudo-first-order kinetics up tomedium to high conversions. Lower target DP resulted in alower polymerization rate owing to a higher CTA concen-

tration under a fixed monomer concentration and [monomer]/[V-50] ratio (Figure 4b). The LCST was lowered from 40 °Cdown to 20.5 °C upon increasing the actual DP from 45 to 485,indicating that this LCST-type behavior was also affected byhydrophobicity, in addition to being induced by H-bonding ofDAAM units.38,47

In order to investigate the change in the aggregate structuredynamic light scattering (DLS) measurements were conducted(Figure 5). When the temperature was below the UCST ofNAGA99 or above the LCST of NAGA50, the hydrodynamic

Figure 4. RAFT copolymerization of NAGA and DAAM in water at a molar ratio of [Monomer]/[V-50] = 2500 for the synthesis of copolymers ofdifferent DPs: monomer conversion vs time (a); pseudo-first-order kinetic plots (b), thermal transitions of the copolymers measured by turbidimetry(1 wt %) in water upon heating (c) and dependence of LCST of the copolymers on DP (d).

Figure 5. Temperature-dependent DLS results of (a) NAGA99 (1 wt %) on cooling and (b) NAGA50 with various concentrations on heating inH2O and D2O.

Figure 6. (a) FTIR spectra of PDAAM, PNAGA and NAGA50, and temperature dependence of phase separation fraction p for different protons of(b) NAGA90 from 40 to 0 °C and (c) NAGA50 from 10 to 45 °C, respectively.

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diameter (Dh) of the copolymers first sharply increased, andthen gradually leveled off, indicating that the chains formedstable aggregates. The PDAAM homopolymer was insoluble inwater, while the LCST-type copolymers could form stableaggregates above the LCSTs probably due to the hydrophilicnature of PNAGA at higher temperatures which could act asstabilizing segments around the hydrophobic PDAAM seg-ments. With regard to the effect of deuterium isotopicsubstitution, we could clearly find that the size of the aggregatesin D2O (1 wt %) is larger than that in H2O after the thermaltransition, indicating that the interactions among P(NAGA-co-DAAM) chains in D2O are stronger than that in H2O,

48 whichis in agreement with the turbidimetry analysis.FTIR and 1H NMR Analysis. In order to elucidate the

significance of H-bonding between NAGA and DAAM in thecopolymers, PDAAM, PNAGA, and NAGA50 were probed byFTIR spectroscopy (Figure 6a). The Amide-I48/Amide-II49

vibrations were 1653/1551 cm−1 for PNAGA, 1666/1538 cm−1

for PDAAM, and 1659/1541 cm−1 for NAGA50, indicating thatH-bonding exists between NAGA and DAAM. It is widelyknown that lower frequency means stronger interaction in theAmide I region of the IR spectra.50 Thus, the appearance of theband at 1659 cm−1 for NAGA50, which falls between that forPNAGA and PDAAM, suggests the H-bond between NAGAand DAAM units is weaker than that in PNAGA, whichexplains the smaller hysteresis of the copolymers than that ofPNAGA.Variable-temperature 1H NMR analysis was used to follow

the interactions and the solution behavior using UCST-typecopolymer NAGA90 and LCST-type copolymer NAGA50 asthe example. The peaks attributed to NAGA90 and NAGA50both displayed an intensity reduction upon cooling or heatingrespectively, suggesting the occurrence of collapse andaggregation of the copolymers during their correspondingphase transitions (Figure S11). To quantitatively characterizethe phase transitions of the copolymers, the phase transitionfraction p was defined as p = 1 − (I/I0), where I is theintegrated intensity of the given polymer signal in the spectrumof the partly separated system, and I0 is the integrated intensityof this signal when no phase separation occurs.51,52 We take theintegrated intensities obtained for the respective D2O solutionat 40 °C for NAGA90 and 10 °C for NAGA50 as I0. The

NAGA and DAAM units in both copolymers seemed tocooperatively participate in the phase transition process (Figure6b,c), indicating that there exist H-bond interactions betweenthe NAGA and DAAM units, which is in line with the FTIRanalysis. Note that the copolymer segments connected via H-bonding between the NAGA and DAAM units are hydrophilicas confirmed by the good solubility of NAGA50 in water atlower temperatures. In addition, the pmax which appears afterthe phase transition of NAGA90 (∼1) is relatively largecompared to that of NAGA50 (∼0.6) during the phasetransitions, suggesting that the UCST-type transition has arather higher degree of phase separation. In contrast, theLCST-type transition of NAGA50 was less completepresumably because the NAGA units were hydrophilic athigher temperatures. On the basis of the analysis probed byvarious techniques, the distinct solubility properties of theP(NAGA-co-DAAM) copolymers during heating/cooling aresummarized in Scheme 2. The copolymers with NAGA as themajor component show UCST-type behavior; in contrast,LCST-type behavior for the copolymers with close molarfractions is observed. Note that the UCST-type copolymers aremore completely dehydrated after the phase transition than thatfor the LCST-type copolymers. In addition, the copolymerswith less molar fractions of NAGA were only slightly soluble orcompletely insoluble in water.

■ CONCLUSION

We have developed a novel family of thermoresponsivecopolymers of P(NAGA-co-DAAM) that have both UCST-and LCST-type thermal transitions. Well-defined copolymers oftunable compositions are effectively synthesized by RAFTaqueous copolymerization using different feeding recipe. Thecopolymer segments formed through H-bonding between theNAGA and DAAM units act as hydrophilic moieties, which isrevealed by turbidimetry, DLS, FTIR and variable-temperature1H NMR analysis. Decreased cloud point and smaller hysteresisbetween the heating and cooling cycles of the UCST-typecopolymers are observed with increasing molar fractions ofDAAM. The LCST-type behavior is believed to be associatedwith the H-bonding and hydrophobic effects of the polymerchains, and the cloud point of the LCST-type copolymersdecreases with increasing molar fractions of the more

Scheme 2. Schematic Representation of Solution Behavior of P(NAGA-co-DAAM) (Co)polymers

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hydrophobic DAAM units. Thermoresponsive profiles of thecopolymers are present over a wide range of concentration,different composition, deuterium isotopic substitution, varyingtargeting DPs and the presence of electrolytes. The appearanceof both UCST- and LCST-type thermal transitions for the sametype of copolymer at different composition regimes isunprecedented and is expected to facilitate their applicationsdue to the simplicity of the copolymerization. The copoly-merization of monomers with the ability to form different typesof H-bonds also provides a potential for discovering new typesof thermosensitive polymers.

■ ASSOCIATED CONTENT*S Supporting InformationThe Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/acs.macro-mol.7b00020.

Experimental details, data of polymer characterization,1H NMR spectra, and turbidity curves of NAGA andcopolymers (PDF)

■ AUTHOR INFORMATIONCorresponding Authors*E-mail: peiyiwu@fudan.edu.cn (P.W.).*E-mail: an.zesheng@shu.edu.cn (Z.A.).ORCIDZesheng An: 0000-0002-2064-4132Peiyi Wu: 0000-0001-7235-210XNotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSWe express thanks for the financial support from the NationalNatural Science Foundation of China (51473038 and21674025).

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