Thermo-Responsive Behavior of Amphoteric Diblock Copolymers

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Thermo-responsive Behavior of Amphoteric Diblock Copolymers Bearing Sulfonate and Quaternary Amino Pendant Groups Yuuki Kawata, Shohei Kozuka, and Shin-ichi Yusa Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b01684 • Publication Date (Web): 07 Aug 2018 Downloaded from http://pubs.acs.org on August 10, 2018

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Langmuir

A research paper for Langmuir Thermo-responsive Behavior of Amphoteric Diblock Copolymers Bearing Sulfonate and Quaternary Amino Pendant Groups

Yuuki Kawata, Shohei Kozuka, and Shin-ichi Yusa*

Department of Applied Chemistry, University of Hyogo, 2167 Shosha, Himeji, Hyogo 6712280, Japan. E-mail: [email protected]

Graphical Abstract

Abstract: Amphoteric diblock copolymers (S82An) composed of poly(2-acrylamido-2methylpropanesulfonic acid sodium salt) (PAMPS) with poly(3-(acrylamido)propyl trimethylammonium chloride) (PAPTAC) blocks were synthesized via reversible addition1 ACS Paragon Plus Environment

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fragmentation chain transfer (RAFT) radical polymerization. Three S82An were prepared with a fixed degree of polymerization (DP) for the PAMPS block (= 82) and different DP values for the PAPTAC blocks (n = 37, 83, and 183). The solubility of S82An was studied at different sodium chloride (NaCl) concentrations. S82A83 precipitated in pure water due to attractive electrostatic interactions with interpolymer chains. Conversely, S82A37 and S82A183 dissolved in pure water. In pure water S82A37 dissolved as a unimer state due to electrostatic repulsion of excess anionic charges in the polymer chain. The long anionic PAMPS block segment in S82A37 covered the short cationic PAPTAC block segment within a single polymer chain. In pure water S82A183 dispersed as polyion complex micelles due to electrostatic repulsion of the cationic PAPTAC shells. The oppositely charged PAMPS and PAPTAC blocks in S82A183 formed a core, while the excess PAPTAC block formed shells. S82An showed lower critical solution temperature (LCST) type thermo-responsive behavior at certain NaCl concentrations, and the LCST increased with the NaCl concentration. The mechanism of LCST behavior involves hydrogen bonding interactions between the pendant amide groups and water molecules.

■ INTRODUCTION Amphoteric copolymers containing pendant anionic and cationic groups such as natural proteins and synthetic copolymers have recently attracted much interest.1–4 Generally, amphoteric diblock copolymers form polyion complex (PIC) aggregates because of electrostatic interactions that cause them to precipitate in pure water.5 When a salt such as 2 ACS Paragon Plus Environment

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NaClwas added to the solution, PIC aggregates dissolved because of the screening effects of interpolymer electrostatic interactions. Liu et al.6 have reported preparation of an amphoteric block copolymer (PDEA60-b-PVBA66) composed of poly(2-(diethylamino)ethyl methacrylate) (PDEA) and poly(4-vinylbenzoic acid) (PVBA). PDEA dissolves in acidic water, while PVBA dissolves in basic water. The degrees of polymerization (DP) for the PDEA and PVBA segments were 60 and 66, respectively. When the pendant groups in acidic water are protonated, PDEA60b-PVBA66 forms polymer micelles comprising hydrophobic PVBA cores with water-soluble PDEA shells. When the pendant groups are deprotonated in basic water, the polymer forms micelles with deprotonated hydrophobic PDEA cores and hydrophilic PVBA shells. Inversion of the core and shell occurs when changing between acidic and basic aqueous solutions. Little is known about the ionization of PDEA and PVBA blocks at neutral pH to form aggregated PIC precipitates.

Figure 1. (a) Lower critical solution temperature (LCST) of poly(N-isopropylacrylamide) 3 ACS Paragon Plus Environment

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(PNIPAM),

and

(b)

upper

critical

solution

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temperature

(UCST)

of

poly(N,N’-

dimethyl(acrylamidopropyl) ammonium propane sulfonate) (PDMAAPS) in water.

Stimuli-responsive polymers exhibiting association behavior dependent on external stimuli, such as temperature, light, and pH, have attracted greatly attention and have been studied by a lot of research groups.7 For example, at low temperature thermo-responsive polymers dissolve in water but above a certain temperature become insoluble. Such a phase transition temperature is known as a lower critical solution temperature (LCST), and poly(Nisopropylacrylamide) (PNIPAM) is well-known as a LCST polymer.8 PNIPAM dissolves in water below the LCST, because PNIPAM is hydrated by hydrogen bonding with the pendant amide groups and water (Figure 1a). However, above the LCST the hydrogen bonds are broken because of increased motion of molecules, generating precipitates. Thermo-responsive polymers are intensively studied for application in drug delivery systems (DDS),9 and cell culture and recovery.10,11 Zwitterionic polymer contained both anionic and cationic charges in the same pendant such as poly(N,N’-dimethyl(acrylamidopropyl) ammonium propane sulfonate) (PDMAAPS) shows an upper critical solution temperature (UCST).12 Below the UCST PDMAAPS cannot dissolve in water to form interpolymer aggregates, since the polymer chains interact due to electrostatic interactions between them (Figure 1b). However, PDMAAPS dissolves in water

4 ACS Paragon Plus Environment

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above the UCST, since the interpolymer electrostatic interactions are broken because of an increase in motion of molecules with increasing temperature. The UCST of PDMAAPS increases with the polymer concentration.

Figure 2. (a) Chemical structures of amphoteric diblock copolymers (S82An, n = 37, 83, and 183) and (b) conceptual illustration of polyion complex (PIC) formation by S82A83, and dissociation of PIC to add sodium chloride (NaCl).

In current research, we synthesized amphoteric diblock copolymers (S82An) composed of

poly(sodium

2-acrylamido-2-methylpropanesulfonate)

(PAMPS)

and

poly(3-

(acrylamido)propyl trimethylammonium chloride) (PAPTAC) blocks via reversible additionfragmentation chain transfer (RAFT) radical polymerization (Figure 2a). The symbols “S” and “A” in S82An indicate PAMPS and PAPTAC, respectively. The subscript numbers in S82An indicate the degree of polymerization (DP) of each block. The DP of the PAMPS block was fixed at 82. S82An containing PAMPTAC blocks with three different DP values (n = 37, 83, and 183) were prepared. We studied the association behavior of S82An resulting from electrostatic


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interactions in aqueous solutions. In particular, salt effects on aqueous S82An were studied, as salts such as NaCl exhibit a screening effect on the electrostatic interactions of polymer chains (Figure 2b). Furthermore, the thermo-responsive behavior of S82An was evaluated in aqueous solutions at a certain NaCl concentration.

■ RESULTS AND DISCUSSIONTable 1. Characteristic Data for PAMPS82 and S82An; n = 37, 83, and 183 Mn(theo)b

Mn(NMR)d Mn(GPC)

Conversion sample

[M]/[CTA]/[I]

a

× 104

DP(NMR)c

× 104

× 104

(g/mol)

(g/mol)

Mw/Mn

(%) (g/mol) PAMPS82

100/1/0.4

84.7

1.78

82

1.73

1.41

1.13

S82A37

40/1/0.4

91.6

2.49

37

2.49

1.62

1.37

S82A83

100/1/0.4

86.3

3.51

83

3.45

-e

-e

S82A183

200/1/0.4

96.0

5.70

183

5.51

2.90

1.17

a

[M], [CTA], and [I] were the molar concentrations of APTAC, PAMPS82 macro-CTA, and

initiator, respectively. bCalculated from Eq. 1. cEstimated from quantitative 13C NMR in D2O containing 1.5 M NaCl. dCalculated from DP of PAPTAC. eThe sample was insoluble in the GPC eluent.


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Three amphoteric diblock copolymers (S82An; n = 37, 83, and 183) composed of PAMPS and PAPTAC blocks were prepared via RAFT. The molecular characteristics are summarized in Table 1. AMPS was initially polymerized via RAFT to obtain PAMPS82 macroCTA. APTAC was then polymerized using PAMPS82 macro-CTA to prepare S82An. To determine DP(NMR) for PAMPS82, we performed 1H NMR (Figure S1). DP(NMR) for PAMPS82, calculated from the integral intensity ratio of the pendant methylene protons at 3.4 ppm and terminal phenyl protons at around 7.5 ppm, was 82. The theoretical number-average molecular weight (Mn(theo)) and degree of polymerization (DP(theo)) were determined using following equations:

Mn (theo) = DP(theo) × MWM + MWCTA 2[M]

DP(theo) = [CTA]0 × 0

× MWM + MWCTA

(1) (2)

where MWM is monomer molecular weight, MWCTA is CTA molecular weight, [M]0 is feed monomer concentration, [CTA]0 is feed CTA concentration, and p is the percent conversion estimated from 1H NMR after polymerization. Mn(theo) for PAMPS82 was 1.78 × 104 g/mol, which was consistent with Mn(NMR) (= 1.73 × 104 g/mol) estimated from 1H NMR. The olecular weight distribution (Mw/Mn) for PAMPS82 was 1.13, which was narrow. These values indicate that RAFT polymerization of AMPS proceeded via a controlled mechanism. Therefore,


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PAMPS82 should have a terminal dithiobenzoate group, which can be used as a macro-CTA.

Figure 3. (a) 1H and (b) inverse-gated decoupling 13C NMR spectra of S82A83 in D2O containing 1.5 M NaCl.

Proton NMR measurements for S82An were recorded in D2O in the presence of 1.5 M

NaCl (Figure 3a and S2). NaCl was added to reduce the electrostatic interactions. The composition and Mn(NMR) of S82An cannot be determined from 1H NMR, as all the 1H NMR peaks attributed to PAMPS and PAMPTAC overlapped. The composition and Mn(NMR) were estimated from quantitative inverse-gated decoupling 13C NMR spectra (Figure 3b and S3).13 Mn(NMR) was estimated by comparing the integral intensity ratio of the pendant carbonyl carbon in the PAMPS block at 28 ppm to the pendant carbonyl carbon in the PAPTAC block at 52 ppm. The Mn(NMR) values were consistent with Mn(theo) calculated using Eq. 1 (Table 1).


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The values of DP(NMR) of the PAMPTAC blocks in S82An estimated from quantitative

13

C

NMR were 37, 83, and 183, respectively. We could not estimate Mn(GPC) with Mw/Mn for S82A83 from gel-permeation chromatography (GPC), because the block copolymer with similar anionic and cationic block lengths was insoluble in the GPC eluents. However, S82A37 and S82A183 dissolved in the GPC eluent, allowing estimation of molecular weight and distribution (Figure S4). The GPC elution profiles for S82A37 and S82A183 were unimodal, and the Mw/Mn values were below 1.4, indicating that the block copolymers have well-controlled structures. The apparent Mn(GPC) was smaller than Mn(NMR), presumably due to interactions between amphoteric diblock copolymers and the column.14,15 Furthermore, the polymer chain conformation of the amphoteric diblock copolymers may be different from that of the conventional random coil due to electrostatic interactions during GPC measurements, which decreases reliability of the GPC molecular weight.

Figure 4. Percent transmittance (%T) at 700 nm of aqueous S82A37 (○), S82A83 (△), and S82A183 (◇) as a function of sodium chloride concentration ([NaCl]) at a polymer concentration 9 ACS Paragon Plus Environment

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(Cp) of 10 g/L at 25°C.

To study the solubility of S82An, the percent transmittance (%T) of the aqueous solutions was measured at different NaCl concentrations ([NaCl]) (Figure 4). The polymer concentration (Cp) was fixed at 10 g/L. The %T of S82A83, which has a similar length of oppositely charged blocks, was 0–20% in aqueous solutions at 0 ≤ [NaCl] ≤ 0.9 because of attractive electrostatic interactions with oppositely charged blocks. At 1.0 ≤ [NaCl], the %T of S82A83 reached 100%, indicating complete dissolution in the aqueous solution. The electrostatic interactions of the PAMPS and PAPTAC blocks were screened by NaCl at concentrations above 1.0 M. Such solubility changes of amphoteric diblock copolymers in aqueous solutions, resulting from salt addition, have been reported previously.5 S82A37, which has the longer anionic PAMPS block, and S82A183, which has the longer cationic PAPTAC block, dissolved in pure water with %T = 100%. The %T values of both polymers decreased as [NaCl] increased. The %T values for S82A37 and S82A183 were 0% at [NaCl] = 0.2 and 0.6 M, respectively. When [NaCl] was increased further, the %T values for S82A37 and S82A183 reached 100% at [NaCl] ≥ 0.7 and 0.9 M, respectively. These unconventional behaviors are discussed in more detail later.


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Figure 5. Hydrodynamic radius (Rh) distributions of (a) S82A37 and (b) S82A183 in pure water at 25°C.

To study the association behavior of S82A37 and S82A183 in pure water, the hydrodynamic radius (Rh) and zeta potential were measured (Figure 5). The Rh distributions were unimodal. The values of Rh for S82A37 and S82A183 were 7.6 and 83.2 nm, respectively, indicating that S82A37 dissolved as a unimer state, and S82A183 formed interpolymer aggregates. The zeta potentials for S82A37 and S82A183 were −15.6 and 22.8 mV, respectively. In S82A37, the long anionic PAMPS block segment covered the short cationic PAPTAC block segment within a single polymer chain.

Interpolymer S82A183 chains aggregated to form water-soluble polyion

complex (PIC) micelles comprising a PIC core with cationic PAPTAC shells. In pure water the electrostatic repulsion of the PAPTAC shells dispersed the PIC micelles.


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Table 2. Light Scattering Data for S82A37 and S82A183 in Pure Water Sample

Mw(SLS)

Nagg

(g/mol)

Rh

(nm)

(nm)

Rg/Rh

A2

dn/dCp

(cm3 mol/g2) (mL/g)

3.46 × 104

1

-a

7.6

-a

1.12 × 10−3

0.121

S82A183 1.41 × 106

22

59.2

83.2

0.712

3.98 × 10−6

0.138

S82A37

a

Rg

The radius of gyration (Rg) was too small to determine by SLS measurements.

Table 2 summarizes the light scattering results for S82A37 and S82A183 in pure water. The weight-average molecular weight (Mw(SLS)) of S82A37, determined by SLS, was 3.46 × 104 g/mol. The Mw of a single polymer chain of S82A37 was 3.86 × 104 g/mol, estimated from Mn(NMR) (= 2.49 × 104 g/mol) and Mw/Mn (= 1.37), which is consistent with the Mw(SLS) value. Therefore, S82A37 dissolved in pure water as a unimer state, because its aggregation number (Nagg) was close to one. S82A183 formed water-soluble PIC micelles with Nagg = 22 in pure water, estimated from SLS measurements. Rg/Rh depends on the polydispersity and shape of aggregates. The theoretical Rg/Rh is higher for polydisperse and less dense structures, e.g., Rg/Rh = 0.778 for a uniform hard sphere, Rg/Rh ≈ 1 for a random coil, and Rg/Rh ≥ 2 for a rod.16– 18

Rg/Rh for S82A183 was 0.712, suggesting that this formed uniform spherical aggregates in pure

water. Rg for S82A37 was too small to estimate by SLS (Rg < 10 nm). The second virial coefficient


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(A2) represents a solubility parameter for polymers. A large A2 suggests a good solvent, while a small or negative A2 suggests a poor solvent.19,20 The value of A2 for S82A183 is less than that for S82A37. This indicates that the solubility of S82A183 in pure water was lower than that of S82A37, presumably because S82A37 dissolved as a unimer state, while S82A183 formed interpolymer aggregates. At 0.7 M ≤ [NaCl] ≤ 2.0 M the association behavior of S82An in water was studied using the Rh and light scattering intensity (LSI) (Figure S5). The values of Rh and LSI for all S82An decreased with increasing [NaCl] to constant values. For example, at [NaCl] < 0.9 M, S82A37 formed interpolymer aggregates, and at [NaCl] ≥ 0.9 M, it dissolved as a unimer state with Rh = 4.5 nm. Similarly, as [NaCl] increased, S82A83 and S82A183 dissociated to form unimer states at [NaCl] ≥ 1.3 and 1.2 M, respectively. S82An dissolved as a unimer state at high [NaCl] because of the screening effect of NaCl against electrostatic attractive interactions.


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Figure 6. Conceptual illustration of NaCl concentration dependence of association behavior of (a) S82A37 and (b) S82A183 in water at 25°C: Red and blue circles indicate anionic and cationic units, respectively.

We now discuss the solubility changes of S82A37 and S82A183 in water at different [NaCl] at 25°C (Figure 6). In pure water the Rh and zeta potential for S82A37 were 7.6 nm and −15.6 mV, respectively. S82A37 dissolves in pure water as a unimer state due to electrostatic repulsion between the surface anionic PAMPS block segments, because these covered the cationic PAMPTAC block segments within single polymer chains. When NaCl was added to the aqueous S82A37, aggregation was induced due to screening of the electrostatic repulsion until [NaCl] ≤ 0.2 M (Figure 4). When further NaCl was added to the solution to 0.9 M ≤ [NaCl], the electrostatic interactions between polymer chains were screened to induce a unimer state with Rh = 4.5 nm and zeta potential = −13.9 mV. However, S82A183 formed water-soluble PIC micelles with Nagg = 22, Rh = 83.2 nm, and zeta potential = +22.8 mV due to the electrostatic interactions in pure water. The electrostatic repulsion between the PAPTAC shells dispersed the PIC micelles in water. When NaCl was added to the aqueous S82A183, secondary aggregates of PIC micelles were induced due to screening of the electrostatic repulsion until [NaCl] ≤ 0.6 M (Figure 4). When further NaCl was added to the solution to 1.3 M ≤ [NaCl], the electrostatic interactions were completely screened to induce a unimer state with Rh = 7.0 nm and zeta


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potential = 12.7 mV. S82A183 tends to occur interpolymer association compared to S82A37, because the chain length of S82A183 was longer than that of S82A37.

Figure 7. (a) Percent transmittance（%T）at 700 nm for aqueous S82A83 at Cp = 10 g/L as a function of temperature at [NaCl] = 0.80 (〇), 0.85 (△), 0.90 (□), 0.95 (◇), 1.00 (▽), 1.05 (●), and 1.10 M (×) and (b) [NaCl] dependence on the LCST of S82A37 (○), S82A83 (△), and S82A183 (◇).

We defined the NaCl concentration at which S82An started to dissolve in the aqueous solution as the critical salt concentration. S82An showed LCST behavior around the critical salt concentration. Phase transition behaviors for S82A37, S82A83, and S82A183 were observed for NaCl concentration ranges of 0.5–0.75, 0.8–1.1, and 0.7–0.9 M, respectively. Figure 7a shows


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the temperature dependence of %T of aqueous S82A83 with varying NaCl concentrations. The phase transition temperature (Tp) for the aqueous S82An increased linearly with increasing [NaCl] (Figure 7b). Hysteresis was observed for heating and cooling for %T vs temperature. A typical example of hysteresis for S82A83 is shown in Figure S6. During heating, %T decreased with a narrow temperature range of 2°C. Precipitation from the homogeneous solution also occurred within a small temperature range. However, during cooling, the %T of the precipitated polymer increased within a broad temperature range of 18°C. The heterogeneous precipitates dissociated over a wide temperature range, because the Tp of the precipitates depends on each associate state. However, during cooling, the %T of the precipitated polymer increased within a broad temperature range of 18°C. Because the heterogeneous precipitates started to dissolve over a wide temperature range. The %T for aqueous S82A83 containing 0.9 M NaCl at Cp = 10, 5, and 1 g/L was measured as a function of temperature (Figure S7). Tp shifted to higher temperature with decreasing Cp, and as Cp decreased, the interpolymer electrostatic interactions weakened, because the distance between the polymer chains increased. As the electrostatic interactions decreased, the polymer chains became more hydrated. Tp thus shifted to higher temperature with decreasing Cp, since the energy required for dehydration increased with decreasing Cp. The strength of hydrogen bonding interactions of D2O is known to be different from that of H2O because of an isotope effect.21 The LCST of PNIPAM in D2O is about 2°C higher


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than in H2O.22 We measured %T as a function of temperature for S82A83 in H2O and D2O containing 1.0 M NaCl (Figure S8). The Tp values for S82A83 in H2O and D2O were 41°C and 43°C, respectively; therefore, the Tp value in D2O was 2°C higher than in H2O. This indicated that the thermo-responsive phase transition behavior was caused by hydrogen bonding interactions of the pendant amide groups with water molecules. The LCST of the aqueous PNIPAM decreased when urea, which inhibits hydrogen bonding, was added to the solution.23 The %T for the aqueous S82A83 with [NaCl] = 1.0 M was measured as a function of temperature with 5.0 M urea to determine Tp (Figure S8). The Tp values without and with urea were 41°C and 26°C, respectively, during heating. The LCST shifted to lower temperature when urea was added. The polymer chains were dehydrated because the hydrogen bonds of the pendant amide groups with water molecules were broken due to the presence of excess urea. These observations indicated that hydrogen bond is one of the principal driving forces for the LCST.


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Figure 8. The conceptual mechanism for LCSTlower critical solution temperature (LCST) behavior for S82A83.

The LCST mechanism of S82A83 was discussed (Figure 8). Due to the effects of both the pendant charge and hydrogen bonding interactions, S82A83 showed a LCST in water at 0.8 M ≤ [NaCl] ≤ 1.1 M. At [NaCl] < 0.8 M, S82A83 chains aggregated to form a water-insoluble PIC at 25°C, because interpolymer electrostatic interactions occurred between the PAMPS and PAPTAC blocks. When the NaCl concentration increased to around 1.0 M, the electrostatic interactions weakened due to screening effects, which occurred at the critical salt concentration at which the polymer chain could dissolve in the aqueous solution. As [NaCl] was further increased above 1.1 M, the electrostatic interactions of S82A83 were screened to form a unimer state with Rh = 6.0 nm (Figure S5). At the critical salt concentration, S82A83 dissolved in the aqueous solution at 25°C, because the amide groups generated hydrogen bonds with water to allow hydration of the polymer chains. As the temperature was raised, the hydrogen bonds cleaved due to increased molecular motion, and the polymer chains were dehydrated to show LCST behavior (Figure 8). As the NaCl concentration increased, the hydration of the S82A83 polymer chains could increase because of decreased electrostatic interactions of the pendant charge groups. The dehydration energy is higher at high salt concentrations than at low salt concentrations. Therefore, Tp shifted to higher temperature with increasing [NaCl]. The


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mechanisms of LCST behaviors for S82A37 and S82A183 were the same as for S82A83.

■ CONCLUSIONS Three amphoteric diblock copolymers (S82An, n = 37, 83, and 183) composed of anionic PAMPS and cationic PAPTAC blocks were prepared. Although in pure water S82A83 was insoluble because of attractive electrostatic interpolymer interactions, at 1.0 M ≤ [NaCl], the polymer dissolved in aqueous solutions. Light scattering data showed that S82A37 dissolved as a unimer state and S82A183 dissolved as PIC micelles with Nagg = 22 in pure water. As the NaCl concentration increased, S82A37 and S82A183 formed precipitates. With a further increase in the NaCl concentration, S82A37 and S82A183 redissolved in the aqueous solutions as unimer states due to shielding large parts of electrostatic interactions. LCST behaviors for S82An were observed at around the critical NaCl concentrations at which the polymers dissolved at 25°C. The LCST increased with the NaCl concentration. Isotope and urea effects indicated that the hydrogen bonds of the amide groups and water contributed to the LCST behavior.

■ AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. ORCID S. Yusa: 0000-0002-2838-5200 Notes 19 ACS Paragon Plus Environment

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The author declares no competing financial interest.

■ ACKNOWLEDGMENTS This work was financially supported by a Grant-in-Aid for Scientific Research (17H03071 and 16K14008) from the Japan Society for the Promotion of Science (JSPS), JSPS Bilateral Joint Research Projects, and the Cooperative Research Program of “Network Joint Research Center for Materials and Devices (20174031 and 20184035).”

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Graphical Abstract 203x70mm (72 x 72 DPI)

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Thermo-Responsive Behavior of Amphoteric Diblock Copolymers

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