Monitoring Coil-Globule Transitions of Thermo-Responsive Polymers

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Monitoring Coil-Globule Transitions of ThermoResponsive Polymers by Using NMR Solvent Relaxation Ipsita Chakraborty, Kaustuv Mukherjee, Priyadarsi De, and Rangeet Bhattacharyya J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.8b02179 • Publication Date (Web): 11 May 2018 Downloaded from http://pubs.acs.org on May 13, 2018

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The Journal of Physical Chemistry

Monitoring Coil-Globule Transitions of Thermo-Responsive Polymers by using NMR Solvent Relaxation Ipsita Chakraborty,† Kaustuv Mukherjee,† Priyadarsi De,† and Rangeet Bhattacharyya∗,‡ † Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur – 741246, India ‡ Department of Physical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur – 741246, India E-mail: [email protected]

Abstract Thermo-responsive polymers exhibit coil-globule transition in aqueous solution where the polymer undergoes from the coil-like morphology to a globular form with the change of temperature. Such transitions also reflect changes in the solvent dynamics captured by various spectroscopic methods. In this work, we construct a phenomenological model to capture the dynamics of the NMR relaxation of water molecules of an aqueous solution of thermo-responsive polymers which are known to form hydrogen bonds with the solvent water molecules. The model relies on the behavior of the polymer-solvent hydrogen bonds and the sharing of rotational kinetic energy of water molecules in the vicinity of the polymer chain and the bulk. This is shown to provide a direct estimate of the fractional change of the polymerwater hydrogen bonds across lower critical solution temperature from NMR relaxation data of

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solvent water along with a reliable estimate of the transition temperature. In addition, it also provides a measure of the dispersion of the strengths of these hydrogen bonds. We exemplify the validity of this model by successfully fitting the experimental data to show that the extracted parameters provide significant insights into the role played by the hydrogen bonds in the process. The possible extension of this model to solvents which form no hydrogen bonds with the polymers, are also discussed.

Introduction Thermo-responsive polymers are of considerable importance due to their applications in biomedical fields as drug delivery systems, as scaffolds for tissue engineering, for gene delivery and others. 1–3 These polymers are known to exhibit coil-globule transition at lower critical solution temperatures (LCST) followed by self-aggregation in aqueous solution. 4–6 Among the multitude of thermo-responsive polymers, some of the well-studied examples are N-isopropylacrylamide (NIPAM) based polymer (PNIPAM) and its derivative copolymers. LCST of PNIPAM homopolymer (∼ 32 ◦ C) is close to the body temperature, and can easily be tuned by copolymerization with other comonomers. 7–9 These polymers are soluble in aqueous solvent at temperatures lower than LCST due to having multiple number of hydrophilic groups. The coil-globule transition across LCST has been studied extensively theoretically. 10–12 Yet, to the best of our knowledge, there is no existing theoretical model which can successfully explain the behavior of NMR relaxation across LCST. The coil-globule transitions of NIPAM based thermo-responsive polymers have been observed by using solution state proton NMR by Ohta et al., 13 followed by Jiˇrí Spˇeváˇcek et al. and other groups. 14–19 It has been shown that across LCST, phase-separated globular structures of polymer in aqueous solutions affects both the shape of 1 H NMR peak and also the longitudinal and transverse relaxation times (T1 and T2 respectively) of solute protons as well as solvent protons. 13,15,17,19 An important observation of these experimental studies is that the longitudinal and the transverse relaxation times (T1 and T2 respectively) of solvent water clearly show the signature of the coil2


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globule transition. T2 (or T1 ) of solvent water rises linearly with temperature below LCST, and then drops significantly across LCST and again increases with the further increase of temperature. 13,15–17,20 Although this S-shaped nature of T2 (or T1 ) versus temperature T has been observed by these groups, yet, till date, no theoretical model exists to account for this observed behavior of the solvent T2 or T1 . On the other hand, the solvent dynamics of macromolecular solutions (considering mainly proteins 21,22 or polymers 23–26 ) have been extensively studied. It has been found by using numerical methods that water plays a critical role in self assembly of a macromolecule and its exotic structure in aqueous medium. It has been reported that the water molecules enclosed within the solvation shell present in the vicinity of a biomolecule 22 or polymers 23–26 are of mainly two types. There are slow waters present in the immediate vicinity of the macromolecules and actively participating in H-bonds which have low rotational kinetic energy; the other kind is the fast bulk water for which rotational kinetic energy is much higher. It is also known from these studies that the water molecules continually diffuse from slow to fast environments and vice versa. According to their report, the dielectric relaxation times of the slow and fast water are ∼ ns and ∼ ps respectively. So the slow water is nearly three order of magnitude slower than the fast. 21,23 It is well established that the coil-globule transitions are regulated by the hydrogen bonds (Hbonds) between the solvent water and the polymer. 23–25,27,28 At lower temperature both homopolymer and copolymers are present as random coil structure in the aqueous solution. FTIR and other spectroscopic methods have revealed that at lower temperatures compared to LCST the intermolecular H-bonds between water molecules and the hydrophilic ends (C=O and N-H) of NIPAM stabilize the coil structure; although a small number of intramolecular H-bonds between C=O and N-H are present in the solution. 29 Near LCST the breakage of a significant number of intermolecular H-bonds takes place and new intramolecular H-bonds between C=O and N-H begin to form and the polymer coil collapses to a globular structure. 24,27–30 We note that Sierra-Martín et al. 19 tried to explain the drop of T2 across LCST with the help of

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the following equation: 1 T2

mean

=

p T2 bound

+

(1 − p) T2 free

(1)

where, T2 bound and T2 free are the transverse relaxation of hydrogen bonded water molecule and free water molecule respectively, T2 mean is the average T2 which is measured and p is equal to the fraction of protons present in the bound environment. 31 Also, as Bagchi et al. and Bhattacharyya et al. mention, the values of τc i.e. the rotational correlation time for bound water are orders of magnitude larger than that of the free water. Hence, for values of p and (1 − p) nearly equal (an experimental reality), the value of T2 mean would be closer to T2 bound which is not observed. The weighted averaging of the T2 s of two different environment is applicable only if the timescale of the exchange or hopping process (τex ) is longer compared to motional time scale (τc ), which as the above studies 21,22 indicate, is not appropriate in the current context. Here, taking cues from the studies on the solvent dynamics of polymers or macromolecules, and the behavior of the polymer-water H-bonds, we construct a phenomenological model of solvent T2 as a function of temperature which, we show, accurately describes the experimentally observed S-shaped nature. The rest of this article is organized as: in the next section, we construct the phenomenological model based on previously reported experiments and simulations. Later, we show the experimental NMR relaxation data for two thermo-responsive polymers in different solvents and fit the data with our model to exemplify its validity. Finally, we discuss the usefulness of the approach and show how it can provide a direct estimation of polymer-water H-bonds at various temperature and also the strengths of those H-bonds.

Theory From the preceding discussion it is well established that the solvent dynamics of a solution of thermo-responsive polymer can be categorized into two parts, bound and free according to their mobility. 21–23 Here, we label the H-bonded water molecule broken free from the polymer chain as cold water due to their very small rotational kinetic energy compared to the bulk which is referred 4


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to as hot water. The cold molecules experience collisions with the water molecules in the bulk and eventually reach a steady state i.e. the rotational kinetic energy of the bulk water molecules is shared with the just-released molecules from the polymer to reach a steady state. Therefore, it is expected that the polymer acts as a sink, whose immediate vicinity would be populated with colder water. We note that this observation holds true when there is significant activity of H-bond formation or breakage from the polymer, i.e. close to LCST. At a temperature much lower or higher than LCST, the breaking of H-bond would be much less frequent and it is expected that the amount of cold water would be negligible. Hence at these temperature ranges, the temperature dependence of the solvent water would be dominated by the behavior of the hot water. We ignore, for simplicity, the translation-rotational coupling which also contributes to the equilibration process. We show that even with this simplified picture, a satisfactory explanation of T2 versus temperature (T ) can be obtained, provided the amount of cold water is known as a function of temperature. A pictorial depiction of the process described above is given in Figure 1.

Figure 1: The cold (water molecules with darker shade) and the hot (lighter shades) water molecules in a dilute solution of a polymer strand. Below LCST, many cold water molecules are present due to large number of polymer-water H-bond. The number of cold water reduces drastically post coil-globule transition. As the hot and cold water, having two different motional timescales get sufficient time to exchange their rotational kinetic energy and attain the steady state such that the system possesses

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a mean rotational kinetic energy, we can write: 1 1 1 [NH◦ − NH (T )] Ihω 2 icold + Nbulk Ihω 2 ihot = [NH◦ − NH (T ) + Nbulk ] Ihω 2 imean 2 2 2

(2)

where, NH◦ and NH (T ) indicate the total number of amide sites where water molecules can form H-bond with the polymer and the number of active hydrophilic sites at a given temperature, respectively. Nbulk indicates the number of water molecules in the bulk. In the last equation, I denotes the moment of inertia of the water molecules. hω 2 icold and hω 2 ihot represent the variance of the angular velocity of cold and hot water molecules respectively. hω 2 imean represents the mean variance of the angular velocity at the steady state. We note, that the averaging of rotational kinetic energy considered here is a thermal averaging process whose cause is molecular collisions. Equation (2) in the manuscript can also be rewritten in terms of the population instead of the absolute numbers. So, it can be considered as the equilibrium average taken over the Boltzmann distribution. Since, hω 2 i ∝ Dr and τc =1/6Dr (assuming isotropic rotational diffusion), where, Dr is the rotational diffusion coefficient and τc is the rotational correlation time, we can rewrite the above equation as [NH◦ − NH (T ) + Nbulk ] [NH◦ − NH (T )] Nbulk + = τccold τchot τcmean

(3)

The superscripts cold and hot denote the respective values for cold and hot water molecules. We note that [NH◦ − NH (T )] and Nbulk are of the same order of magnitude (usual experimental condition), but τccold is known to be several orders of magnitude larger than τchot (as the later is of the order of picoseconds, whereas the former denotes rotational correlation times of molecules having almost no rotational kinetic energy). 21,22 Hence, the term having the inverse of τccold in the last equation is small and can easily be ignored. Also, it is well known that in the case of liquids under the fast motional narrowing limit ωτc 1, therefore,

T2mean

1 T2

∝ τc . From this, it follows:

Nbulk T2hot = ◦ NH − NH (T ) + Nbulk

6


(4)

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We also note that T2hot has linear dependence on temperature, since T2 ∝ 1/τc ∝ Drot ∝ T , the later proportionality follows from Einstein relation. Hence we may write T2hot = aT + b, where a and b are parameters, which would be estimated from the experimental results. In recent years, many numerical calculations and simulations on the phase transition of NIPAM based molecules have been reported where the total number of H-bonds NH (T ) per polymer chain as a function of temperature have been calculated. 24–27 The reported behavior appears to be similar to an inverted tanh function, although precise form of this function has not been obtained analytically. 24–26 On the other hand, using IR spectroscopy, several groups 30,32,33 reported how the fraction of intramolecular H-bonds between carbonyl and amide groups changed as a function of temperature. Their findings show a tanh-like behavior; the intramolecular H-bonds increase across LCST. Therefore, the number of the polymer-water H-bonds must have an inverted tanhlike nature; since these hydrophilic sites either participate in polymer-water H-bonds or form intramolecular bonds. We note here, that this observation holds for a dilute or semi dilute solution of polymer in aqueous solution where there are almost no polymer cross-links and hence interstitial water. We shall proceed with the assumption of a tanh-like behavior of the number of H-bonded water molecules with the polymer as a function of temperature and examine the validity this assumption later. At temperatures much above T◦ , i.e. post coil-globule transition, the number of H-bonded water molecules is small and remains constant. 27 This number is denoted here by NH∞ . Therefore, we assume phenomenologically:

NH (T ) = NH∞ +

1 (N ◦ − NH∞ ) [1 − tanh α (T − T◦ )] 2 H

(5)

where, α is a measure of the steepness of the transition; smaller α indicates that a transition takes place over a larger change in temperature. The above equation predicts that for T T◦ , NH (T ) approaches NH◦ , and for T T◦ , NH (T ) approaches NH∞ , as expected. Across LCST, NH (T ) drops from NH◦ to NH∞ and the rate of drop depends on α.

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Thus from equations (4) and (5), we obtain:

T2mean =

where, κ = β=

◦ NH Nbulk

◦ −N ∞ NH H ◦ NH

βκ 2

aT + b [1 + tanh α (T − T◦ )] + 1.0

(6)

denotes the fractional change of H-bonded water molecules across LCST and

denotes the ratio of active intermolecular H-bond sites to the total number of bulk water

molecule. We shall use equation (6) and show that it fits the behavior of T2 versus T satisfactorily. We note that β is known since the NH◦ and Nbulk are known a priori. We note that the tanh behavior also appears in two site hopping or exchange models of T2 , but the dependence is not on temperature as shown above. 34

Experimental In this work, two aspects of coil-globule transition were studied, namely, phase transition behavior of two different NIPAM-based polymers in aqueous solutions and isotope effects on the phase transition of a single homopolymer, PNIPAM. To study the first aspect, homopolymer of NIPAM (PNIPAM) and copolymer of NIPAM with N,N-dimethylacrylamide (P(NIPAM-co-DMA)) were synthesized according to reported procedure. 35 The Characterization of the synthesized polymers, determined using NMR spectroscopy and Advanced Polymer Chromatography (APC) are given in the following table: Table 1: The characterization and composition of different thermo-responsive polymers Polymer PNIPAM P(NIPAM-co-DMA)

Mw 7661 12168

Mn 7328 11394

PDI 1.037 1.067

Monomer Composition 64/0 66/4

Synthetic procedure and characterizations are given in the supplementary information. Aqueous solutions of PNIPAM and P(NIPAM-co-DMA) were prepared in 2:1 H2 O:D2 O (v/v) with 4 g/L concentration. Also, PNIPAM has been separately dissolved in pure D2 O and pure H2 O (4 g/L), with negli8


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gible amount of D2 O added to the later for field locking. The PNIPAM solution from the study of the first aspect along-with the aforementioned two solutions of PNIPAM were used to study the solvent-isotope effect. For all solutions, the temperature run has been performed across LCST with at least 10 ◦ C of either side of estimated LCST. At each temperature sufficient time has been allowed for the solution to reach steady state. At each temperature, T2 was estimated using CPMG pulse sequence 36,37 with inter-π pulse distance 625 µs using 500 MHz Bruker Avance III spectrometer. Sufficient recycling delay (∼ 5T1 ) was used for every experiment. The power used for π/2 and π pulses was 17.8 kHz. T2 has been extracted from the single exponential fitting of the deconvoluted intensities of the water peak from the CPMG data. Unlike the T2 of deuterium reported by Kametani et. al. 38 which are in 10s of µs, the T2 of the protons of solvent water are found to be of the order of seconds. For all solutions, UV-visible spectroscopy has also been performed to cross-verify the LCST extracted from NMR. The transmittance versus temperature data from UV-visible spectroscopy are shown in the supplementary information.(Figure S1)

Results and Discussion The result of the temperature run for the first aspect are shown in the Figure 2. Both the polymers show the previously reported trend, i.e. at temperatures far away from LCST, T2 s show linear increase with the temperature and close to LCST the T2 s show a marked drop. The smooth lines represent the fitting of our experimental result with equation (6). The extracted parameters from the fitting are tabulated in Table 2. Table 2: The numerical values of five parameters obtained from the fitting of the experimental data using equation 6 for two different polymers. Polymer PNIPAM P(NIPAM-co-DMA) m n

κ 0.2 ± 0.1 0.3 ± 0.1

α (◦ C−1 ) 0.3 ± 0.1 0.3 ± 0.1

T◦ (◦ C)m 32.3 ± 0.6 35.9 ± 0.5

a (s ◦ C−1 ) 0.09 ± 0.02 0.09 ± 0.02

From the fitting of experimental data using equation (6) From UV-visible spectroscopy

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b (s) 0.7 ± 0.4 1.1 ± 0.4

T◦ (◦ C)n 32.7 35.6


4.25 4.00 3.75 3.50

T2 (s)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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3.25 3.00 2.75

T2 values : P(NIPAM co DMA) Fit : P(NIPAM co DMA) T2 values : PNIPAM Fit : PNIPAM

2.50 2.25 15

20

25

30

35

T ( C)

40

45

50

Figure 2: T2 s of protons of the solvent versus temperature for two different solute polymers along with the fit of the experimental data with equation (6). Marker-size is chosen to reflect the error in T2 data. LCST determined from UV-visible spectroscopy study are also given in the Table 2. For both the polymers, the LCST values are same (within experimental errors) as the extracted data from the fitting. Figure 2 and Table 2 show that for both the polymers, homopolymer and copolymer of NIPAM our proposed model satisfactorily fit the relaxation data and produce reliable LCST values. We note that the post-transition slope of T2 vs T (in the linear segment) is slightly smaller than that of the pre-transition value as reported earlier and as expected from our model. 17 The value of κ was obtained by dividing the first parameter by β. β was calculated from the concentration of the solution and assuming 50% of total hydrophilic sites present in the solution undergo only in the intermolecular H-bonding with water. The value of κ is slightly larger for P(NIPAM-co-DMA) than PNIPAM, possibly due to the presence of additional H-bond sites from the DMA groups.Thus the number of intra and intermolecular H-bonds varies from homopolymer to copolymer. 39 However, the values of α for the both the cases are identical within the experimental error. This suggests

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that the solvent-polymer H-bond dynamics are qualitatively same in both the cases. The values of the parameter a are identical, whereas for b the values are slightly different. The behavior of a is related to restricted diffusion as discussed later.

9 8

T2 values : D2O Fit : D2O T2 values : 2 : 1 H2O : D2O Fit : 2 : 1 H2O : D2O T2 values : H2O Fit : H2O

7

T2 (s)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


6 5 4 3 2 15

20

25

30

35

T ( C)

40

45

50

Figure 3: T2 of protons of the solvent versus temperature, for different PNIPAM solutions along with the fit of the experimental data with equation (6). Marker-size is chosen to reflect the error in T2 data. Note that the 2:1 H2 O:D2 O data and fit are repeated here from the PNIPAM solution data and fit in Figure 2.

Figure 3 shows the comparative study of relaxation behavior of three different solvents, namely, pure D2 O, 2:1 H2 O:D2 O and almost pure H2 O. All extracted parameters are given in the Table 3 along-with the confirmatory LCST values obtained from UV-visible spectroscopy. We note that the transition is flatter (happening across a greater change of temperature) with the increase of the amount of heavy water. It is known that D2 O forms stronger H-bond with the polymers. 40 This results in a stable coil structure and higher energy is required (and hence higher temperature) to complete the transition to globular form. 40 Consequently, we observe a decrease in α from the H2 O solution to D2 O. Thus, a larger spread of transition process (in terms of temperature) 11



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and consequent smaller value of α provides a measure of the dispersion of the strengths of the H-bonds. The presence of stronger H-bond with the heavy water is also reported elsewhere 41,42 which further consolidates the conclusions drawn here. Table 3: The numerical values of five parameters obtained from the fitting of the experimental data using equation 6 for three different solvents in presence of PNIPAM Solvent D2 O H2 O:D2 O (2:1)? H2 O

κ 0.4 ± 0.2 0.2 ± 0.1 0.12 ± 0.06

α (◦ C−1 ) 0.14 ± 0.04 0.3 ± 0.1 0.5 ± 0.6

T◦ (◦ C)† 33.0 ± 0.5 32.3 ± 0.6 32.3 ± 0.9

a (s ◦ C−1 ) 0.25 ± 0.09 0.09 ± 0.02 0.06 ± 0.01

b (s) 3.0 ± 2.0 0.7 ± 0.4 1.0 ± 0.3

T◦ (◦ C)‡ 33.0 32.7 32.4

†

From the fitting of experimental data using equation (6) From UV-visible spectroscopy ? Identical with the first entry in Table 2 ‡

Also, we note that κ values which indicate the fraction of H-bonds broken during the transition is higher for D2 O. We note that PNIPAM microgels in D2 O show enhanced swelling due to more extended stable chains compared to that of H2 O. 43 This evidently points to a larger number of H-bonds formed for the D2 O solutions compared to H2 O. As a result, a collapse to a globular form would accompany a bigger fractional change of H-bond for D2 O, and hence larger value of κ. The κ values in Table 3 clearly agree well with this observation. The parameter a systematically decreases from D2 O to H2 O. Since the D2 O solution exhibits extended stable chains of polymers, it is expected to have less restricted translational diffusion for the water molecule and hence a larger value of rotational diffusion. With the decrease of the amount of D2 O, consequently a value decreases. Parameter b does not show any systematic change and possibly require microscopic models to account for its behavior. It is expected that– like isotopic effects– the methodology can easily be extended to the case of mixed solvents. For example, as the reference 44 shows, if a small amount of DMSO is added to the aqueous mixture of PNIPAM, then it is observed that LCST of the system will be reduced. As the DMSO–H2 O interaction is stronger than C=O–H2 O and H2 O–N-H(PNIPAM) interactions, DMSO removes water molecules from PNIPAM. As a result, the polymer becomes relatively dehydrated and hence lower LCST exhibits. In this case, since the number of hydrogen bonds changes because of the presence of the other solvent, the change should be reflected in the behavior of the relax12


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ation time as a function of temperature. Likewise sensitivity of PNIPAM towards water/methanol, water/acetone mixture can also be studied by using our method. 45–47 Although the above discussion pertains to the cases where the solute and the solvent molecules interact via H-bonds, but it is expected that the method could be extended to the non-H-bonded solutions. For example, if a solute in a given solvents forms a well-ordered solvation shell, the solvent molecules in the shell have restricted motion and can be classified as ‘slow’ type. If this solution exhibits the phase transition then the extent of the solvation shell will change with temperature, in such cases, the application of our method is straight forward, provided the number of cold solvent molecules as a function of temperature.

Conclusions We conclude that the proposed model is capable of providing a direct quantitative estimate of the fractional change of polymer-water H-bonds and their strengths across the coil-globule transitions along with a definitive value of the LCST. The solvent-isotope effects on the coil-globule transition can also be studied from the dispersion of H-bond strengths obtained from the relative changes of the extracted parameters. The generic nature of the model ensures that it can be applied to the aqueous solutions of varieties of thermo-responsive polymers. While this model has been developed for transverse relaxation, but in the fast motional-narrowing regime, it predicts similar temperature dependence for solvent longitudinal relaxation as well. Since the experimental determination of NMR relaxation of water is one of the simplest relaxation experiment available, it is envisaged that this simple model would be a powerful tool to directly investigate the roles played by H-bonds in coil-globule transition. Moreover, this methodology is contemplated to be applicable for the mixed solvents and non-H-bonded solutions.

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Acknowledgement The authors thank Dr. Ujjal Haldar and Biswajit Saha for their assistance with the preparation and the characterization of the polymer solutions, and acknowledge NMR central facility at IISER Kolkata. IC and KM thank Council of Scientific and Industrial Research (CSIR) and University Grants Commission (UGC) India, respectively, for their research scholarships.

Supporting Information Available Brief outline of the procedure of the synthesis of the polymers used in this study are outlined along with the relevant data for the characterization of the polymers. The data from UV-visible spectroscopy are also shown here.

This material is available free of charge via the Internet at

http://pubs.acs.org/.

References (1) Guan, Y.; Zhang, Y. PNIPAM Microgels for Biomedical Applications: from Dispersed Particles to 3D Assemblies. Soft Matter. 2011, 7, 6375-6384. (2) Nagase, K.; Kobayashi, J.; Kikuchi, A,; Akiyama, Y.; Kanazawa, H.; Okano, T. Preparation of Thermoresponsive Cationic Copolymer Brush Surfaces and Application of the Surface to Separation of Biomolecules. Biomacromolecules 2008, 9, 1340-1347. (3) Kim, Y. J.; Matsunaga, Y. T. Thermo-responsive Polymers and their Application as Smart Biomaterials. J. Mater. Chem. B 2017, 5, 4307-4321. (4) Halperin, A.; Kröger, M.; F. M. Winnik Poly(N-isopropylacrylamide) Phase Diagrams: Fifty Years of Research. Angew. Chem. Int. Ed 2015, 54, 15342-15367. (5) Wang, X.; Wu, C. Light-Scattering Study of Coil-to-Globule Transition of a Poly(Nisopropylacrylamide) Chain in Deuterated Water. Macromolecules 1999, 32, 4299-4301. 14


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Monitoring Coil-Globule Transitions of Thermo-Responsive Polymers

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