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 Page 1 of 15 Polymer Chemistry
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DOI: 10.1039/C6PY01935H

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ARTICLE

Micro-dynamic mechanism of the phase transition

behavior of poly(N-isopropylacrylamide-co-2-
Cite this: DOI: 10.1039/x0xx00000x

Polymer Chemistry Accepted Manuscript

hydroxyethyl methacrylate) hydrogel revealed by two-
Published on 16 December 2016. Downloaded by Fudan University on 20/12/2016 19:20:57.

dimensional correlation spectroscopy

Received 00th January 2012,
Accepted 00th January 2012
Gehong Su,a Tao Zhou,a, * Xifei Liu,a and Yanan Maa

DOI: 10.1039/x0xx00000x
In this study, the micro-dynamic mechanism of volume phase transition behavior of poly(N-
www.rsc.org/ isopropylacrylamide-co-2-hydroxyethyl methacrylate) (PNIPAM-co-HEMA) hydrogel was investigated
by temperature-dependent FTIR spectroscopy in combination with the perturbation correlation moving
window (PCMW2D) technique and generalized two-dimensional correlation analysis. In conventional
1D FTIR spectra analysis, Boltzmann fitting curves showed that the volume phase transition temperature
and the phase transition degree of PNIPAM-co-HEMA hydrogel were lower than that of pure PNIPAM
hydrogel. It also showed that the PHEMA segments exhibit a similar “phase transition” behavior to the
PNIPAM segments, which can be ascribed to the driving effect of the phase transition of PNIPAM
segments. Furthermore, we found that the rate of water molecules being expelled out of the gel structure
during phase transition changed as an anti-S shape. PCMW2D spectra revealed that the phase transition
can be divided into two processes (named as I and II) upon heating, and further determined the
temperature regions of process I and II to be 21.8-31.4 °C and 31.4-36.5 °C, respectively. Finally,
generalized 2D correlation analysis found that both process I and II can be further divided into nine
steps. From the deduced nine steps of process I, the significant role of PHEMA for the phase transition
of PNIPAM segments was revealed. As for the deduced nine steps of process II, the driving effect of the
phase transition of PNIPAM segments for PHEMA segments was confirmed.

1. Introduction engineering,7 drug delivery,8 catalysts,9 and so on. However, the

relatively steady volume phase transition temperature (VPTT,
Poly(N-isopropyl acrylamide) (PNIPAM) is a well-known
around 32 °C) of PNIPAM hydrogel have limited its application
temperature-sensitive polymer whose aqueous solution can
scope to a certain extent. To broaden its application temperature
conventionally undergo a thermally reversible coil-to-globule phase
range, various monomers have been utilized to incorporate in
transition (hydration-to-dehydration) at around its lower critical
PNIPAM to produce a VPTT-tunable PNIPAM-based hydrogel.10-
solution temperature (LCST) of 32 °C.1, 2 Besides, by introducing 12
In general case, the incorporation of hydrophilic monomers such
an appropriate cross-linker into an aqueous reaction medium, the
as iconic acid (IA)10 and acrylic acid (AA)11 can increase the VPTT
linear PNIPAM chains will be cross-linked and generate a
of PNIPAM-based hydrogel, while the reverse is true when the
PNIPAM hydrogel,3, 4 which is the most frequently studied LCST-
hydrophobic monomers such as butyl methacrylate (BMA) and di-
type thermo-responsive hydrogels up to present. Below LCST, the
n-propyl acrylamide (DPAM) 12 are used.
PNIPAM hydrogel is hydrophilic and fully swollen in water. By
Poly(2-hydroxyethly methacrylate) (PHEMA) hydrogel is
contrast, when the temperature rise up to above LCST, PNIPAM
another extensively studied hydrogel in recent few decades, which
hydrogel will experience a discontinuous volume phase transition,
is widely used in biological and technological fields, including
resulting in that the PNIPAM hydrogel becomes hydrophobic and
contact lens,13 artificial corneas and skins,14 degradable scaffolds
exists in a collapsed states.5 Be similar to the coil-to-globule phase
for tissue engineering,15 and drug delivery,16 due to its outstanding
transition of the linear PNIPAM aqueous solution, the volume
biocompatibility and physicochemical properties. However, in
phase transition of the cross-linked PNIPAM hydrogel is also
general case, the PHEMA hydrogel is not stimuli-sensitive, making
thermal reversible.6 Due to this excellent and attractive
it incapable of responses to the external temperature change. This
temperature-responsive property, the PNIPAM hydrogel is
deficiency of PHEMA hydrogel has limited its application in some
considered to be the most promising materials in biotechnology, as
specific fields, making researchers intend to design a temperature-
well as in pharmaceutical and industrial applications, such as tissue
sensitive PHEMA-based hydrogel.17, 18

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 Polymer Chemistry
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In order to tune the VPTT of PNIPAM hydrogel and develop a
thermal responsive PHEMA-based hydrogel, many researchers
combined PNIPAM with PHEMA by copolymerization, and
developed a novel PNIPAM-co-PHEMA hydrogel.19-23 PNIPAM-
co-HEMA hydrogel not only have an excellent biocompatibility
like PHEMA hydrogel, but also possess a temperature-responsive
ability which is inherited form PNIPAM. Thus, PNIPAM-co-
HEMA hydrogel has attracted tremendous research interests since
it was synthesized. Tuncel and Cicek studied the volume phase
transition behavior of the PNIPAM-co-HEMA hydrogel and the
effective diffusion coefficient of water within the gel matrix, and
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they also discussed the factors that affect the mechanical and
thermal properties of the hydrogel.20 Furthermore, Tuncel’s groups
synthesized a series of drug immobilized PNIPAM-co-HEMA
hydrogels by redox polymerization, and they found the PNIPAM-
co-HEMA hydrogel is very suitable for being the carrier of catalase
and chymotryosin.21, 22 The swelling and the phase transition
behavior of the PNPAM-co-HEMA hydrogel were also
investigated by Lee and his coworkers. In their studies, they found
that with the increase of HEMA content, the volume phase
transition temperature and the thermo-reversibility of the hydrogel
gradually disappeared, and the swelling ratio of the gel in water
became lower.23 Most recently, the PNIPAM-co-HEMA microgel
dispersions have been synthesized and used as a new type of
injectable scaffold for three-dimensional cell culture by Zhang’s
group.24 The synthesized PNIPAM-co-HEMA microgel particles
can gelate and form a macroscopic hydrogels in the presence of
CaCl2 when heating above its VPTT around 29 °C, which is 3 °C
lower than that of the pure PNIPAM hydrogel. They considered the
lower VPTT of the PNIPAM-co-HEMA microgels can be
attributed to the hydrogen-bonding between the hydroxyl groups in
HEMA and amide I groups in NIPAM, which makes the copolymer
microgels more hydrophobic.24 Not long ago, the dynamic thermal
phase transition behavior of PNIPAM-PHEMA interpenetrating
polymer network (IPN) hydrogel was in-depth studied by mean of
IR spectroscopy by Zhang. He also found the introduction of
PHEMA decreased the volume phase transition temperature and the
volume phase transition degree of PNIPAM hydrogel, and this was
because the PHEMA acted as an “initiator” and led the volume
phase transition process of PNIPAM hydrogel to occur at a lower
temperature.25, 26
As mentioned above, much attention has been paid to the volume
phase transition behavior of PNIPAM-co-HEMA hydrogel.
However, to the best of our knowledge, a detailed study of the
micro-dynamic mechanism of the volume phase transition behavior
of the PNIPAM-co-HEMA hydrogel at the molecular level has
never been reported up to now. Whereas, a better understanding
about the micro-dynamic mechanism of phase transition behavior
of the PNIPAM-co-HEMA hydrogel is significant for scientific
investigation and its application in the biomedical field.
Generalized two-dimensional (2D) correlation infrared
spectroscopy was first proposed by Noda in 1993,27 which has
received great attentions in recent years. By using this technique,
the information which cannot be readily obtained or overlapped in
conventional 1D FTIR spectra can be easily captured due to the
significantly enhanced spectral resolution.28 Additionally, the
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DOI: 10.1039/C6PY01935H
sequential order of the intensity change can also be easily gained
according to Noda’s rule. Owing to those two advantages, 2D
correlation infrared spectroscopy has been widely used to
investigate the complex chemical or physical transition processes
of polymers.29-33 In 2006, Morita proposed a new 2D correlation
spectroscopy technique called perturbation-correlation moving-
window two-dimensional (PCMW2D) correlation spectroscopy,34
which is a further extension of generalized two-dimensional
correlation spectroscopy and MW2D method.35 By using
PCMW2D correlation spectroscopy, the spectral correlation
Polymer Chemistry Accepted Manuscript
variation along both perturbation variables (e.g., temperature in the
present study) and perturbation variables (e.g., wavenumber) axis
can be directly observed. Thus, the transition points and the
transition regions can be conveniently determined from the
correlation intensity along the perturbation variables’ direction.
In the present study, the thermal responsive PNIPAM-co-HEMA
hydrogel was synthesized at first. After that, the FTIR spectroscopy
combining with PCMW2D correlation spectroscopy and
generalized 2D correlation analysis was used to investigate the
micro-dynamic mechanism of the volume phase transition behavior
of the PNIPAM-co-HEMA hydrogel during heating. We found that
the volume phase transition of PNIPAM-co-HEMA hydrogel can
be divided into two processes, and each processes can be further
divided into nine steps. Combining with all the deduced steps in
these two processes, the micro-dynamic mechanism of the volume
phase transition of PNIPAM-co-HEMA hydrogel was successfully
revealed and elucidated.
Figure 1. Free radical copolymerization of the PNIPAM-co-HEMA hydrogel.
2. Experimental
2.1. Materials
N-isopropylacrylamide (NIPAM) and 2-hydroxyethyl
methacrylate (HEMA) were purchased from Aladdin reagent Co.
The NIPAM was recrystallized from cyclohexane, while HEMA
was purified by passing through an alkaline alumina column before
use. N,N’-methylenebisacrylamide (BIS), N,N,N’,N’-
tetramethylethylenediamine (TEMED), and ammonium persulphate
(APS) were purchased from J&K Scientific Ltd (Beijing, China)
and used without further purification. Deuterated water (D2O, D-
99.9%) was purchased from Cambridge Isotope Laboratories, Inc.
2.2. Synthesis of hydrogels
PNIPAM-co-HEMA random copolymer hydrogel was
synthesized via free radical polymerization. The NIPAM (1.5 g)
and HEMA (1 g) monomers were first dissolved in deionized water
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DOI: 10.1039/C6PY01935H

(10 g) in a beaker, and filtered to remove any possible precipitates.
Then, the solution was transferred to a three-necked round-bottom
flask, and stirred for 2 h in a nitrogen atmosphere to expel the
oxygen from the solution. After that, the cross-linker (0.005 g BIS),
the initiator (0.05 g APS) and the accelerator (0.01 g TEMED)
were separately dissolved in deionized water and added into the
solution to start the polymerization process. The reaction was
carried out at 25 °C for 48 h. The reaction and chemical structure
are shown in Fig. 1. Besides, to approve the successful
synthetization of PNIPAM-co-HEMA hydrogel, the pure PNIPAM
2D correlation FTIR spectra, the red colors were defined as
positive correlation intensity, while the blue colors were negative.
3. Results and discussion
3.1. ATR-FTIR measurement
As shown in Fig. 2, the successful synthesis of the PNIPAM-co-
HEMA hydrogel is confirmed by ATR-FTIR spectroscopy. In Fig.
2, the absorption peaks of 3275 cm-1 and 1650 cm-1 were assigned
to the stretching vibration of the amino groups (N−H) and the
amide I groups (C=O) in the side chain of PNIPAM,6 respectively.

Polymer Chemistry Accepted Manuscript

and PHEMA hydrogels were also synthesized according to the
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literature.36, 37 All the resultant three types hydrogels were dialyzed
with deionized water for one week to remove the unreacted
monomers within the network of hydrogel. The deionized water
used for dialysis was changed every two hours to ensure the
monomers were completely removed. Then, the purified hydrogels
were dried by freeze-drying to obtain dried hydrogels used in ATR-
FTIR experiments.
The band of 1734 cm-1 is attributed to the stretching vibration of
the carbonyl groups (C=O) of PHEMA.38 As seen in Fig. 2, the
ATR spectrum of PNIPAM-co-HEMA hydrogel contains both
characteristic bands of PNIPAM (3275 cm-1 and 1650 cm-1) and
PHEMA (1734 cm-1). These features approve the PNIPAM-co-
HEMA copolymer hydrogel is successfully synthesized.

2.3. ATR-FTIR experiment

Attenuated total reflection FTIR (ATR-FTIR) experiment was
used to confirm that the PNIPAM-co-HEMA hydrogel was
successful synthesized. The ATR-FTIR experiment was carried out
at room temperature by using a Nicolet iS50 Fourier transform
spectrometer equipped with a deuterated triglycine sulfate (DTGS)
detector and an ATR accessory with a ZnSe IRE-ATR crystal. All
the ATR spectra were collected at a spectral resolution of 4cm-1 by
accumulating 20 scans, and the measured wavenumber region was
3800-650 cm-1.

2.4. The in situ FTIR spectroscopy

Before the FTIR measurement, a small piece of thoroughly dried
PNIPAM-co-HEMA gel was immersed into a large amount of D2O
at 6 °C to ensure a full swelling of the hydrogel, and the D2O was
changed every day for 12 days to make sure all the H atoms of
N−H and O−H groups in hydrogel were completely replaced by the
D atoms.
The well-swelled and PNIPAM-co-HEMA hydrogel was sealed
between two small ZnSe windows and then placed into the liquid
cell (programmable heating and cooling device). After that, the
hydrogel was heated from 19 °C to 42 °C with 1 °C/min, and the Figure 2. ATR-FTIR spectra of the dried PHEMA, PNIPAM, and the PNIPAM-co-
HEMA hydrogel.
FTIR spectra within the region of 3800-1000 cm-1 were collected at
the same time. There were totally 54 FTIR spectra collected upon
In the present study, the thermal-responsibility of PNIPAM-co-
heating. Nicolet iS50 Fourier transform spectrometer equipped with
HEMA hydrogel can be directly observed by eyes. The
a DTGS detector was used for the FTIR measurement. All the
photographs of PNIPAM-co-HEMA hydrogel at different
FTIR spectrum was gathered by 20 scans with a resolution of 4 cm-
1 temperatures are shown in Fig. 3. Before taking photos, the
to obtain a good signal-to-noise ratio.
hydrogel was placed in water for 10 min to make sure the hydrogel
2.5. Two-dimensional correlation analysis was fully swollen. As shown in Fig. 3, the hydrogel is fully swollen
at room temperature. The volume of the hydrogel in Fig. 3 is large,
PCMW2D correlation FTIR spectra, as well as the generalized
and the hysteresis effect certainly exists. To ensure an obvious
2D correlation spectra, were processed, calculated, and plotted by
volume change, after the temperature gradually increases to 42 °C,
2DCS software, developed by one of the authors. To acquire a
the temperature continues to maintaining at 42 °C for 30 min.
credible result, the baseline corrections were performed in the
Subsequently, the height and the diameter of the hydrogel
regions of 3020-2850 cm-1, 2800-2140 cm-1, and 1760-1580 cm-1
obviously decrease. This clearly indicates that the network of
before analysis. The window size of MW2D spectra was chosen as
PNIPAM-co-HEMA hydrogel gradually shrinks during the volume
11 (2m+1) to generate high-quality 2D correlation spectra. In the

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 Polymer Chemistry
ARTICLE
phase transition upon heating. The volume phase transition
behavior of PNIPAM-co-HEMA hydrogel can be observed from
the macro. However, how does this behavior proceed from the
microscopic point of view? This is still a question, and aroused our
curiosity. So, a detail FTIR spectroscopic study is necessary for us
to understand its micro-dynamics mechanism.
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Figure 3. Photographs of PNIPAM-co-HEMA hydrogel at different temperatures.
The hydrogel is fully swollen at room temperature, but collapse after
preserving at 42 °C for 30 min.
3.2. Temperature-dependent FTIR spectra upon heating
Here, it is noted that D2O was used as the solvent instead of H2O
in the FTIR experiment, avoiding the overlap of the broad v(O−H)
band of H2O (around 3300 cm-1) with the v(N−H) and the v(C−H)
bands, as well as the δ(O−H) band of water around 1645 cm-1 with
the v(C=O) band of the PNIPAM-co-HEMA hydrogel. According
to the literature, the volume phase transition temperature of
PNIPAM hydrogel in D2O is only 0.7 °C higher than that in H2O.
The deuterium isotope effect does not cause an obvious change on
the magnitude of hysteresis for the transition behavior, and
therefore, D2O has little influence on the phase transition behavior
of PNIPAM-based hydrogel.39-40 Thus, it is a good choice to use
D2O as the solvent to study the phase transition behavior of
PNIPAM-co-HEMA hydrogel in our study.
The temperature-dependent FTIR spectra of PNIPAM-co-
HEMA hydrogel in D2O upon heating from 19 °C to 42 °C in the
regions of 3025-2850 cm-1, 2800-2140 cm-1, and 1800-1580 cm-1
are illustrated in Fig. 4. For clarity, not all the spectra are displayed
here. The detail assignments of the bands appearing in Fig. 4 are
listed in Table 1. It is pointed out that, except for the extensively
studied regions related to C−H and C=O groups in PNIPAM-based
systems, the stretching vibration regions of D2O (2800-2140 cm-1)
is also investigated in this study. For the phase transition behavior
of PNIPAM-based solutions and hydrogels, this region is lacked of
attentions before.
In Fig. 4(a), the region of 3020-2850 cm-1 belongs to the
stretching vibration of the alkyl groups. It can be clearly observed
that all C−H stretching bands slightly shift to a lower wavenumber
upon heating. As reported before, the bands of the hydrophobic
alkyl groups shifted to a higher wavenumber when surrounded by
water molecules; and the number of water molecules surrounding
the alkyl groups is more, the higher the wavenumber is.41
Therefore, the wavenumber changes of the C−H bands upon
heating can be explained as a gradual dehydration of hydrophobic
alkyl groups, which mainly arises from PNIPAM segments.
The bands of 2800-2140 cm-1 in Fig. 4(b) is assigned to the
stretching vibration of the hydroxyl (O−D) groups in D2O. 42 In
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Fig. 4(b), the intensity of the whole D2O region obviously
decreases during the heating. This feature reveals that D2O
molecules within the hydrogel network are expelled outside the
hydrogel network during phase transition upon heating. In the past
decades, it was widely accepted that the water molecules would be
expelled out of the hydrogel network during phase transition of
PNIPAM-based hydrogel. However, as far as we knew, it is the
first time that proven it from the perspective of FTIR spectroscopy.
Fig. 4(c) shows the stretching vibration region of carbonyl
(C=O) groups in the side chains of PNIPAM-co-HEMA hydrogel.
Polymer Chemistry Accepted Manuscript
The region of 1745-1670 cm-1 is attributed to the C=O stretching
band of HEMA moieties, and 1670-1580 cm-1 belongs to the amide
I groups of NIPAM moieties.6, 26 In the HEMA-related C=O
stretching region, the intensity changes of three bands are observed
upon heating. Specifically, the spectral intensity at 1734 cm-1
increases, while both of 1714 cm-1 and 1688 cm-1 decrease.
According to the literature, the band of 1734 cm-1 is assigned to the
stretching vibration of the “free” C=OHEMA groups, and the bands
of 1716 cm-1 and 1684 cm-1 are attributed to the C=OHEMA
stretching vibration in C=OHEMA···D−NNIPAM and C=OHEMA···D2O
hydrogen bonds, respectively.31, 38 Therefore, the intensity changes
within the HEMA-related C=O stretching region upon heating can
be considered as a transformation from the hydrogen-bonded C=O
groups of PHEMA to the “free” ones. At the same time, the amide I
groups in PNIPAM segments also show a complex spectral
intensity change upon heating. The spectral intensities of both 1652
cm-1 and 1648 cm-1 gradually enhance, while that of 1623 cm-1
decreases. In pure PNIPAM and PNIPAM-based hydrogel, the
bands of 1652 cm-1 and 1623 cm-1 are always considered to
assigned to the C=ONIPAM stretching vibrations in
C=ONIPAM···D−NNIPAM and C=ONIPAM···D2O hydrogen bonds,
respectively.6, 26, 43 However, no literature reported the assignment
of 1648 cm-1 before. It is noted that the bands of 1648cm-1 did not
appear in the amide I region of pure PNIPAM hydrogel. Therefore,
the band of 1648 cm-1 is probably attributed to C=ONIPAM groups in
C=ONIPAM···D−OHEMA hydrogen bonds structure, which is not exist
in pure PNIPAM hydrogel. Therefore, the intensity changes of
amide I groups in PNIPAM segments upon heating can be
interpreted as the hydrogen bonds transformation of C=ONIPAM
from C=ONIPAM···D2O to C=ONIPAM···D−OHEMA and
C=ONIPAM···D−ONIPAM.
To quantitatively describe the volume phase transition of
PNIPAM-co-HEMA hydrogel from the temperature-dependent
FTIR spectroscopy, the integral area changes of D2O and two kinds
of C=O groups are plotted in Fig. 5. Besides, the wavenumber
shifts of vas(−CH3) and vas(−CH2) are also illustrated in Fig. 5.
Furthermore, for an accurate determination of the transition
temperature of PNIPAM-co-HEMA hydrogel, the Boltzmann
fitting is applied for the data points. The Boltzmann equation used
is below:
A1 − A2
y= + A2 (1)
1 + e(x− x0)/∆x
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Figure 4. Temperature-dependent FTIR spectra of the PNIPAM-co-HEMA
hydrogel in D2O upon heating from 19 °C to 42 °C. (a) 3020-2850 cm-1; (b) 2800-
2140 cm-1; (c) 1800-1580 cm-1.
where A1 and A2 are the minimum and the maximum value of the
function, respectively. The x0 is the inflection of the curve on the
abscissa axis, which also equals to the transition temperature. The
∆x is the domain of this value lies.44, 45
The fitting results are all shown in Fig. 5. It can be observed that
the VPTTs are determined at 32.4 °C for −CH3 groups and 33.3 °C
for −CH2 groups. Therefore, we can infer that the dehydration of
−CH3 groups occurs earlier than that of −CH2 groups upon heating.
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Polymer Chemistry Accepted Manuscript
Figure 5. Temperature-dependent (a) wavenumber shifts of vas(−CH3) around
2980cm-1 and vas(−CH2) around 2940cm-1; (b) the integral areas in the regions of
2800-2150cm-1 (D2O), and (c) 1745-1675 cm-1 (C=OHEMA) and 1670-1580 cm-1
(C=ONIPAM). The solid lines are Boltzmann fitting curves.
Similarly, Fig. 5(c) shows that the response of HEMA-related C=O
groups is earlier than that of the NIPAM-related C=O groups. In
addition, compared with the fitting result of pure PNIPAM
hydrogel,6 it is found that the VPTTs of CH-related and amide I
groups determined from Fig. 5 are obvious lower than that of pure
PNIPAM hydrogel (above 34 °C for both CH-related and amide I
groups), which also demonstrates the incorporation of PHEMA
reduces the volume phase transition temperature of PNIPAM
hydrogel, just like the previously literatures reported.
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Polymer Chemistry Accepted Manuscript

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Figure 6. PCMW2D synchronous and asynchronous spectra of PNIPAM-co-HEMA hydrogel upon heating. The pink areas represent the positive correlation intensity,
and blue areas represent the negative.

Table 1. Band assignments of PNIPAM-co-HEMA hydrogel appearing in temperature-dependent FTIR and PCMW2D, as well as the generalized 2D
correlation spectra. 6, 26, 38, 42-44, 46-49

Wavenumber (cm-1) Assignments Wavenumber (cm-1) Assignments

2990 vas(−CH3, hydrated) 1716 v(C=OHEMA··· D−NNIPAM)

2972 vas(−CH3, dehydrated) 1706 v(C=OHEMA···D−OHEMA)

2947 vas(−CH2, hydrated) 1688 v(C=OHEMA···D2O)

2931 vas(−CH2, dehydrated) 1652 v(C=ONIPAM···D−NNIPAM)

2873 vs(−CH3, dehydrated) 1648 v(C=ONIPAM···D−OHEMA)

2850 vs(−CH2, dehydrated) 1623 v(C=ONIPAM··· D2O)

2730-2210 vs(O−D, D2O) 1618 v(C=ONIPAM···2D2O)

1734 v(C=OHEMA, free)

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As expected, in Fig. 5(a) and 5(c), both the wavenumber shifts
of vas(−CH3) and vas(−CH2), as well as the integral area change of
amide I groups (1670-1580 cm-1), show an anti-S shaped variation
curves, which is similar with pure PNIPAM hydrogel.6 But the
degree of change of these curves is weaker than that of pure
PNIPAM hydrogel. This is because PHEMA segments in polymer
chains present no temperature-responsive property under this
condition, the existence of PHEMA segments certainly slows down
the collapse of PNIPAM segments and restricts the phase transition
of PNIPAM segments during the volume phase transition.
To determine the VPTT of PNIPAM-co-HEMA hydrogel more
accurately, PCMW2D technique was employed. PCMW2D
contains the synchronous and the asynchronous correlation spectra.
For synchronous spectra, the positive correlation intensity indicates
the increase of the spectral intensity in temperature-dependent
FTIR spectra at the given wavenumber, and vice versa. The
synchronous PCMW2D is always used to determine the transition
point, which can be interpreted as the phase transition temperature
in phase transition polymers. Meanwhile, the asynchronous spectra
can be used to determine the temperature range of the transition

Polymer Chemistry Accepted Manuscript

Moreover, it is found that the integral area of C=O groups in according to the turning points in the counter map.
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HEMA moieties (1745-1675 cm-1) also shows an anti-S shaped In the present study, we focus our study on two spectral regions,
variation curve. However, this S or anti-S shaped variation curve is including the stretching vibrations related to C−H groups (3020-
a characteristic only for phase transition polymers, such as 2850 cm-1) and the C=O stretching vibrations (1745-1580 cm-1).
PNIPAM and PVCL.6, 46 Considering the PHEMA segments Fig. 6 shows the synchronous and asynchronous PCMW2D spectra
owning no temperature-responsive property, the anti-S shaped of PNIPAM-co-HEMA hydrogel in the regions of 3020-2850 cm-1,
curve of the C=O groups in HEMA moieties can be explained as 1745-1675 cm-1, and 1670-1580 cm-1 between 19 °C and 42 °C
“driven phase transition behavior”, which is contributed from the upon heating. For clarity, the results of VPTTs and temperature
driving effect of the phase transition of PNIPAM segments. It is ranges of the phase transition stemming from different bands are
noted that the variations of the integral area of C=O groups in listed in Table. 2.
HEMA moieties (decreased about 0.6 units) is much stronger than
Table 2. The VPTTs and transition ranges of different bands determined
that of PNIPAM-PHEMA IPN hydrogels (decreased about 0.05 from Fig 6.
units).26 We think this phenomenon comes from the different
structures of these two hydrogels. In PNIPAM-PHEMA IPN Wavenumber Transition point Transition region
(cm-1) (°C) (°C)
hydrogels, PNIPAM and PHEMA moieties are interconnected only
2990 33.8 21.8-35.7
by intermolecular hydrogen bonding. However, in PNIPAM-co- 2972 33.8 30.4-36.5
HEMA hydrogel, apart from the intermolecular hydrogen bonds, 2947 25.2; 31.0 21.8-30.4; 31.4-34.2
these two parts are directly linked by covalent bonds. Thus, during 2931 31.0 30.4-36.5
2875 35.6 34.2-36.5
phase transition, the driving effect of PNIPAM segments in 1734 -- 31.4-34.2
PNIPAM-co-HEMA hydrogel is stronger than that of in PNIPAM- 1716 26.3; 32.2 21.8-29.2; 31.4-34.2
PHEMA IPN hydrogel, resulting in the above phenomenon. 1688 25.6 21.8-29.2
1652 33.8 33.2-36.0
Surprisingly, in Fig. 5(b), it is found that the integral area curve 1648 33.8 31.4-36.0
of D2O also produces an approximate anti-S shape upon heating. 1623 33.0 21.8-31.4; 31.4-35.2
On one hand, it is widely known that water molecules are not As listed in Table 2, the phase transition of PNIPAM segments
thermal-sensitive. On the other hand, we know that the water in PNIPAM-co-HEMA hydrogel mainly occurs within 31.4-36.5
molecules will be expelled out of the gel structure during phase °C upon heating, which is 1.6 °C lower than that of pure PNIPAM
transition of PNIPAM-based hydrogel. Therefore, we think this hydrogel (33.0-36.5°C).6 Besides, it is noted that some correlation
anti-S shaped integral area curve of D2O implies that the rate of peaks also appear below 31.4 °C, such as 21.8-29.2 °C for 1716
water molecules being expelled out of the PNIPAM-co-HEMA cm-1 and 21.8-31.4 °C for 1623 cm-1. However, these low
hydrogel network is changed as an anti-S shape, rather than temperature correlation peaks cannot be observed in pure PNIPAM
increasing linearly with temperature enhancement. Besides, we hydrogel. These results clearly indicate that the phase transition
think this phenomenon is closely related the regular dehydration of behavior of PNIPAM-co-HEMA hydrogel upon heating is different
the hydrophobic C−H groups and the regular disassociation of from that of pure PNIPAM hydrogel, and can be divided into two
D2O-related hydrogen bonds during phase transition. It is noted that processes. Combining with the discussion before, the second
this phenomenon was also not reported before. process (at higher temperature) is certainly the phase transition of
In summary, an initial analysis of the temperature-dependent PNIPAM segments within 31.4-36.5 °C. For the first process, the
FTIR spectra helps us to get some useful information and reaches a lowest temperature detected at 21.8 °C in PCMW2D spectra is used
preliminary conclusion about the volume phase transition behavior as the onset temperature point for convenience, and the temperature
of PNIPAM-co-HEMA hydrogel upon heating. However, the key of 31.4°C which is the onset temperature of the second process can
information on the micro-dynamics mechanism interested by us is be employed as the end temperature point of the first process. Thus,
still unclear. Next, PCMW2D and the generalized 2D correlation the temperature range of the first process is defined as 21.8-31.4
analysis are resorted to reveal these key issues. °C, and that of the second process is 31.4-36.5 °C. Here, these two
processes are named as process I and II, respectively.
3.3. Perturbation-correlation moving-window (PCMW2D)
analysis

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Figure 7. Generalized synchronous and asynchronous 2D correlation spectra of PNIPAM-co-HEMA hydrogel calculated from the temperature-dependent FTIR spectra
within process I (21.8-31.4 °C). Here, the pink colors are the positive correlation intensity, and blue colors are the negative.

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3.4. Generalized 2D correlation analysis
On the basis of temperature ranges of the phase transitions
determined from PCMW2D, all the temperature-dependent FTIR
spectra within process I (21.8-31.4 °C) and process II (31.4-36.5
°C) were used to perform the generalized 2D correlation analysis.
Generalized 2D FTIR spectra also contain the synchronous and
asynchronous spectra. From the signs of correlation peaks in the
synchronous and asynchronous spectra, the sequential order of
the spectral intensity change at a given wavenumber can be
conveniently judged. The judging rule is also called as Noda’s
rule50―that is, if the correlation intensity Φ(v1, v2) in the
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synchronous spectra has the same symbol (positive or negative)
as the correlation intensity Ψ(v1, v2) in the asynchronous spectra,
the movement of band at v1 is prior to or earlier than that of band
at v2, and vice versa. In addition, if the correlation intensity in the
synchronous spectra is not zero (or blank), but zero in the
asynchronous spectra, the movements of bands at v1 and v2 are
simultaneous. Moreover, by spreading the original spectra along
a second dimension, the bands which cannot be readily
distinguished in the conventional 1D spectra can be easily
detected due to the significant enhancement of the spectra
resolution.28
3.4.1. Process I
The generalized 2D correlation spectra calculated from the
temperature-dependent FTIR spectra within process I (21.8-31.4
°C) are shown in Fig 7. It is noted that the non-visible bands at
1706 cm-1 and 1618 cm-1 in conventional 1D FTIR spectra are
detected in the asynchronous spectra of Fig. 7. The assignments
of 1706 cm-1 and 1618 cm-1 are also listed in Table 1. According
to Noda’s rule, the sequence orders among C−H, C=OHEMA, and
C=ONIPAM groups of PNIPAM-co-HEMA hydrogel in D2O upon
heating can be obtained. The detail information is summarized in
Table S1 in the Supporting Information. The sequential orders of
process I gained from Fig. 7 are as follows: 1688 cm-1 → 1716
cm-1 → 1623 cm-1 → 1618 cm-1 → 1652 cm-1 → 1648 cm-1 →
1706 cm-1 → 2990 cm-1→ 2947 cm-1. The corresponding
sequential order of the functional groups is v(C=OHEMA···D2O)
→ v(C=OHEMA···D−NNIPAM) → v(C=ONIPAM···D2O) →
v(C=ONIPAM···2D2O) → v(C=ONIPAM···D−NNIPAM) → Consequently, the next two steps (third and fourth) of process I
v(C=ONIPAM···D−OHEMA) → v(C=OHEMA···D−OHEMA) →
vas(−CH3, hydrated) → vas(−CH2, hydrated). Here, the symbol
“→” represents “before”. This result clearly shows that the
process I is composed of nine steps.
For the bands related to C=O groups, the sequential order is
1688 cm-1 → 1716 cm-1→ 1623 cm-1 → 1618 cm-1 → 1652 cm-1
→ 1648 cm-1 → 1706 cm-1. Obviously, during the heating
process, the breaking of hydrogen bonds between C=O groups of
PHEMA and D2O is at first, which is attributed to the
hydrophobic property of PHEMA and a higher mobility of
PHEMA side chains. After that, some water molecules are
expelled out of the gel structure, leading to a hydrophobic
environment in the hydrogel. In this relatively hydrophobic
environment, the disassociation of the hydrogen bonds between
C=O groups in NIPAM moieties and water molecules is
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apparently easier than the pure PNIPAM hydrogel.26 Thus, the
disassociation of the hydrogen bonds between C=O groups of
PNIPAM and water molecules (C=ONIPAM···D2O and
C=ONIPAM···2D2O) possibly occurs at a lower temperature. This
is the main reason for the decrease of VPTT of PNIPAM-co-
HEMA hydrogel compared to the pure PNIPAM hydrogel.
Furthermore, the sequential order of the bands related to C=O
groups can be summarized as C=OHEMA→C=ONIPAM, which is in
accordance with the Boltzmann fitting results in Fig. 5(c).
On the other hand, considering the movement of alkyl groups
Polymer Chemistry Accepted Manuscript
separately, the sequential order is −CH3 → −CH2. And this result
is also completely in accordance with the Boltzmann fitting
results in Fig. 5(a), showing the generalized 2D correlation
analysis is a powerful method to investigate the complex
transition of polymers. In the present study, the −CH3 groups
only exist in the side chains of molecular chains, while the −CH2
groups exist both in the side chain of PHEMA and the backbone
of PNIPAM. Thus, it can be concluded that the dehydration of
side chains takes place before that of the backbone in process I.
Overall, the whole sequential order of process I can be
summarized as: C=OHEMA → C=ONIPAM → −CH3 → −CH2. This
result reveals that the phase transition of PNIPAM segments in
PNIPAM-co-HEMA hydrogel is induced by PHEMA. Thus, the
essence of process I (21.8-31.4 °C) can be considered as the
phase transition of PNIPAM induced by PHEMA.
For an intuitive understanding of the micro-dynamic
mechanism in process I, we provide a schematic illustration in
Scheme 1, which clearly shows the deduced nine steps of process
I. As shown in Scheme 1(a), before heating, the side chain
hydrophilic groups of PNIPAM and PHEMA segments are all
hydrogen bonded with other groups or water molecules, and all
the alkyl groups are fully hydrated. After heating, it is obvious
that the first step is the disassociation of hydrogen bonds between
C=O groups of PHEMA and water molecules(C=OHEMA···D2O),
and then the second step is the breaking of the hydrogen bonds
between C=O groups of PHEMA and D−N groups of PNIPAM
(C=OHEMA···D−NNIPAM). These two steps make the environment
within hydrogel to become relative hydrophobic, resulting in the
decrease of the disassociation temperature of the hydrogen bonds
between C=O groups of PNIPAM and water molecules.
are the breaking of hydrogen bonds between C=O groups of
PNIPAM and water molecules (C=ONIPAM···D2O and
C=ONIPAM···2D2O). It is noted that these two steps are both
shown in Scheme 1(d), but the disassociation of
C=ONIPAM···D2O is slightly earlier than that of
C=ONIPAM···2D2O. The occurrence of these two steps at a lower
temperature is the main reason for the VPTT of PNIPAM-co-
HEMA hydrogel being lower than that of pure PNIPAM
hydrogel. After that, the fifth step is the hydrogen bonds
formation of C=ONIPAM···D−NNIPAM structure between the “free”
C=ONIPAM and D−N groups, and the sixth step is the generation
of the hydrogen bonds between the “free” C=ONIPAM and
D−OHEMA groups (C=ONIPAM···D−OHEMA). These “free” groups
are generated in former steps. Then, the seventh step is the
breaking
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Scheme 1. Detail steps of process I (21.8-31.4 °C) inferred from the 2D correlation analysis. D2O molecules are represented by the 3D spherical model. The red balls
are oxygen (O) atoms, and the green balls are deuterium (D) atoms. The PNIPAM segments and PHEMA segments are marked as red and black, respectively. The
hydrogen bonds of C=ONIPAM···D−NNIPAM, C=ONIPAM···D−OHEMA, C=OHEMA···D−NNIPAM and C=OHEMA···D−OHEMA are marked as red, pink, yellow, and blue, respectively.
Besides, the hydrogen bonds between carbonyl groups and D2O are all marked as black. The blue small boxes are used to highlight the structure change in each step.

of the self-associated hydrogen bonds of PHEMA moieties II can be deduced as: 2947 cm-1 → 1618 cm-1 → 1623 cm-1 →
(C=OHEMA···D−OHEMA). The eighth step is the dehydration of the 1716 cm-1 → 1706cm-1 → 2990 cm-1 → 1648 cm-1 → 1652 cm-1
hydrated side chain −CH3 groups. Then, the ninth step, namely, → 1688 cm-1. That is vas(−CH2, hydrated) →
the last step of process I is the dehydration of the hydrated –CH2 v(C=ONIPAM···2D2O) → v(C=ONIPAM···D2O) →
groups. v(C=OHEMA···D−NNIPAM) → v(C=OHEMA···D−OHEMA) →
vas(−CH3, hydrated) → v(C=ONIPAM···D−OHEMA) →
3.4.2. Process II v(C=ONIPAM···D−NNIPAM) → v(C=OHEMA···D2O). The detail
The generalized 2D correlation spectra of process II (31.4-36.5 procedure can refer to Table S2 in the Supporting Information.
°C) are illustrated in Fig. 8. Process II is the phase transition of Be similar with process I, the process II is also divided into nine
the PNIPAM segments. Similarly, the sequential order in process steps according to the obtained sequential order.

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Figure 8. Generalized synchronous and asynchronous 2D correlation spectra of PNIPAM-co-HEMA hydrogel calculated from the temperature-dependent FTIR spectra
within process II (31.4-36.5 °C).

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Scheme 2. Detail steps of process II (31.4-36.5 °C) inferred from the 2D correlation analysis. D2O molecules are represented by the 3D spherical model. The red balls
are oxygen (O) atoms, and the green balls are deuterium (D) atoms. The PNIPAM segments and PHEMA segments are marked as red and black, respectively. The
hydrogen bonds of C=ONIPAM···D−NNIPAM, C=ONIPAM···D−OHEMA, C=OHEMA···D−NNIPAM and C=OHEMA···D−OHEMA are marked as red, pink, yellow, and blue, respectively.
Besides, the hydrogen bonds between carbonyl groups and D2O are all marked as black. The blue small boxes are used to highlight the structure change in each step.

For the bands related to C−H groups, it is obvious that the
dehydration of −CH2 is earlier than that of −CH3 groups in process
II, which is opposite to that of process I. However, as mentioned
above, the −CH2 groups exist both in the side chain of PHEMA and
the backbone of PNIPAM, which cannot be clearly distinguished in
this condition. Therefore, no direct conclusion can be drawn right
now. However, on the other hand, from the synchronous and
asynchronous spectra of 3020-2850 cm-1 in Fig. 8, it is inferred that
the response of 2990 cm-1 is prior to 2875 cm-1, and 2947 cm-1 is
prior to 2850 cm-1. This indicates that the asymmetric stretching
vibration has an earlier response than the symmetric stretching
vibration for both −CH3 and −CH2 groups. According to the
literature, the direction of asymmetric stretching vibration is
parallel to the polymer chain axis, while that of symmetric
stretching vibration is vertical to the polymer chain axis.51 Thus, we
can make a conclusion that the chain collapse of PNIPAM-co-
HEMA hydrogel during phase transition is along with the
backbone.
As for the bands related to C=O groups, the sequential order can
be summarized as: C=ONIPAM → C=OHEMA. It is clear that the
movement of C=ONIPAM groups is before that of C=OHEMA groups
in process II, which is opposite to that of process I. This is because
in process II, the movement of PNIPAM segments is before that of
PHEMA segments.

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Journal Name
In summary, the sequential order of process II can be described
as: −CH2 → C=ONIPAM → C=OHEMA → −CH3. It can be inferred
that the response of C=OHEMA related groups to temperature is after
the phase transition of PNIPAM segments. This reveals that the
motion of PHEMA segments is passive, exhibiting a “driven phase
transition behavior”, which comes from the driving effect of the
phase transition of PNIPAM segments.
Be similar to process I, a schematic illustration of the obtained
nine steps of process II is provided in Scheme. 2. For process II,
the first step is the dehydration of the hydrated −CH2 groups,
indicating that the chain collapse during phase transition is along
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with the backbone. The second and the third steps are the breaking
of the hydrogen bonds between C=O groups of PNIPAM and water
molecules (C=ONIPAM···D2O and C=ONIPAM···2D2O). Also, these
two steps are both shown in Scheme 2(c). However, it is noted that
the disassociation of the C=ONIPAM···2D2O is earlier than that of
C=ONIPAM···D2O, which is opposite to that of process I. Then, the
fourth step is the breaking of the hydrogen bonds between C=O
groups of PHEMA and the D−N groups of PNIPAM
(C=OHEMA···D−NNIPAM), and the fifth step is the disassociation of
the hydrogen bonds of C=OHEMA···D−OHEMA structure. The sixth
step is the dehydration of −CH3 groups in hydrated side chains.
After that, the seventh step is the generation of the hydrogen bonds
(C=ONIPAM···D−OHEMA) between disassociated “free” C=ONIPAM
and D−OHEMA groups (in former steps), and the eighth step is the
hydrogen bond formation of C=ONIPAM···D−NNIPAM structure
between “free” C=ONIPAM and D−NNIPAM groups which are also
generated in the former steps. The last (ninth) step of process II,
also, the last step of the whole phase transition process is the
breaking of the hydrogen bonds between C=O groups of PHEMA
and water molecules (C=OHEMA···D2O). It is noted that Scheme
2(i) shows the micro-structure of PNIPAM-co-HEMA
hydrogel in D2O after phase transition upon heating.
4. Conclusions
In this paper, the temperature-dependent FTIR spectroscopy
combined with PCMW2D and generalized 2D correlation analysis
was applied to investigate the micro-dynamic mechanism of the
volume phase transition of PNIPAM-co-HEMA hydrogel in D2O
upon heating.
In the analysis of the temperature-dependent FTIR spectra,
Boltzmann fitting curves of the frequency shifts of vas(−CH3) and
vas(−CH2), as well as the integral area of amide I groups, show that
the volume phase transition temperature and the phase transition
degree of PNIPAM segments are lower than that of pure PNIPAM
hydrogel due to the incorporation of PHEMA. Moreover, we
noticed that the integral area curve of C=O groups of PHEMA
moieties also show an anti-S shaped variation, which can be
attributed to the driving effect of the phase transition of PNIPAM
segments. Besides, we specially focused on the less studied D2O
stretching vibration regions. We found that the rate of water
molecules being expelled out of the gel structure during phase
transition also show an anti-S shaped changes, rather than
increasing linearly with the temperature enhancement.
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PCMW2D spectra revealed that the phase transition behavior of
PNIPAM-co-HEMA hydrogel upon heating can be divided into
two processes (named as I and II), and further determined the phase
transition temperature regions of process I and II to be 21.8-31.4 °C
and 31.4-36.5 °C, respectively. From PCMW2D spectra, we found
that the phase transition of PNIPAM segments in PNIPAM-co-
HEMA hydrogel is about 1.6 °C lower than that of pure PNIPAM
hydrogel.
The generalized 2D correlation analysis was performed to
disclose all the sequential order of group motions during process I
Polymer Chemistry Accepted Manuscript
and II. It was found that both process I and II contain nine steps.
For process I, the deduced sequential order can be summarized as:
C=OHEMA → C=ONIPAM → −CH3 → −CH2. Based on this sequential
order, a reasonable explanation to the decrease of VPTT of
PNIPAM-co-HEMA hydrogel was given, and we confirmed that
the phase transition of PNIPAM segments in PNIPAM-co-HEMA
hydrogel is induced by PHEMA. As for process II, the sequential
order can be summarized as: −CH2 → C=ONIPAM → C=OHEMA →
−CH3. This clearly shows that the movement of PHEMA segments
is passive during heating, exhibiting a “driving phase transition
behavior”, which is due to the driving effect of the phase transition
of PNIPAM segments. Combining with the obtained sequential
orders of process I and II, an integrated micro-dynamic mechanism
of the phase transition of PNIPAM-co-HEMA hydrogel in D2O
during heating was established.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Grant No. 51473104), and State Key
Laboratory of Polymer Materials Engineering (Grant Nos.
sklpme2014-3-06, sklpme2016-3-10).
Notes and references
a
State Key Laboratory of Polymer Materials Engineering of China,
Polymer Research Institute, Sichuan University, Chengdu 610065,
China
*Corresponding author. Tel.: +86-28-85402601; Fax: +86-28-
85402465; E-mail address: zhoutaopoly@scu.edu.cn (T. Zhou)
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DOI: 10.1039/C6PY01935H

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Polymer Chemistry Accepted Manuscript

Published on 16 December 2016. Downloaded by Fudan University on 20/12/2016 19:20:57.

Micro-dynamic mechanism of the volume phase transition of PNIPAM-co-HEMA

hydrogel was established using temperature-dependent FTIR spectroscopy, PCMW2D,
and 2DCOS analysis.