Effect of molecular structure on thermoresponsive behaviors of pyrrolidone-based water-soluble polymers

Article abstract of DOI:10.1021/ma100133q

This paper describes the molecular structure dependent thermoresponsive behaviors of pyrrolidone-based water-soluble polymers. A series of well-defined poly[N-(2-methacryloyloxyethyl)pyrrolidone] (PNMEP), poly[N-(3- acryloyloxypropyl)pyrrolidone] (PNAPP), and poly[N-(3-methacryloyloxypropyl) pyrrolidone] (PNMPP) were synthesized via visible light activating RAFT polymerization at 25 °C. Kinetic studies indicate a rapid and well-controlled behavior of this polymerization. Gel permeation chromatography (GPC) and ¹H NMR analysis confirm their intact molecular structure, well-defined molecular weight, and narrow distribution. Laser light scattering and temperature-variable ¹H NMR analyses demonstrate that the cloud point of a PNMEP sample at a degree of polymerization (DP) of 96 is 1.5 °C lower than that of PNAPP at a DP = 104. Additional backbone methyl groups in PNMPP lead to a dramatic cloud point lowering, e.g., cloud point of PNMPP at a DP = 100 is 37 °C lower than that of PNAPP at a DP = 104. This is contrary to what was observed in poly(N-isopropylacrylamide) (PNIPA) and its polymethacrylamide analogues. These pyrrolidone-based polymers show a dramatic solvent isotopic effect that is different from that of PNIPA; e.g., the cloud point of PNMEP at a DP = 237 is 8.5 °C lower in D₂O than in H₂O. Increasing polymer chain length or hydrophobicity may suppress this solvent isotopic effect. This phase transition is correlated to Hofmeister series but more sensitive than PNIPA. Na₂CO₃ dramatically lowers cloud point, while NaI significantly improves cloud point, up to full dissolution in H₂O at 95 °C. The solvent isotopic effect in NaCl or Na₂CO₃ solution is the same as what observed in solution absent of salt. Upon heating D₂O solution of PNMEP, the polymer first forms the hydrated irregular colloidal aggregates near the cloud point, the phase transition occurs at the fully hydrated state at cloud point, and further heating leads to the dehydration and separation from D₂O. However, in NaCl solution, the dehydration of PNMEP occurs subsequently from apolar backbones, spacers, and finally pyrrolidone groups.

Full text of DOI:10.1021/ma100133q

Macromolecules 2010, 43, 4041–4049 4041
DOI: 10.1021/ma100133q
Effect of Molecular Structure on Thermoresponsive Behaviors of
Pyrrolidone-Based Water-Soluble Polymers
Jun Sun, Yifeng Peng, Ying Chen, Yu Liu, Junjie Deng, Lican Lu, and Yuanli Cai*
Key Laboratory of Environmentally Friendly Chemistry and Applications of Ministry of Education,
Key Laboratory of Advanced Functional Polymeric Materials of College of Hunan Province, Key Laboratory of
Polymeric Materials & Application Technology of Hunan Province, College of Chemistry, Xiangtan University,
Xiangtan, Hunan 411105, China
Received January 19, 2010; Revised Manuscript Received March 20, 2010
ABSTRACT: This paper describes the molecular structure dependent thermoresponsive behaviors of pyrro-
lidone-based water-soluble polymers. A series of well-defined poly[N-(2-methacryloyloxyethyl)pyrrolidone]
(PNMEP), poly[N-(3-acryloyloxypropyl)pyrrolidone] (PNAPP), and poly[N-(3-methacryloyloxypropyl)-
pyrrolidone] (PNMPP) were synthesized via visible light activating RAFT polymerization at 25 °C. Kinetic
studies indicate a rapid and well-controlled behavior of this polymerization. Gel permeation chromatography
1
(GPC) and H NMR analysis confirm their intact molecular structure, well-defined molecular weight, and
narrow distribution. Laser light scattering and temperature-variable 1H NMR analyses demonstrate that the
cloud point of a PNMEP sample at a degree of polymerization (DP) of 96 is 1.5 °Clower thanthat of PNAPP ata
DP = 104. Additional backbone methyl groups in PNMPP lead to a dramatic cloud point lowering, e.g., cloud
point of PNMPP at a DP = 100 is 37 °C lower than that of PNAPP at a DP = 104. This is contrary to what was
observed in poly(N-isopropylacrylamide) (PNIPA) and its polymethacrylamide analogues. These pyrrolidone-
based polymers show a dramatic solvent isotopic effect that is different from that of PNIPA; e.g., the cloud
point of PNMEP at a DP = 237 is 8.5 °C lower in D2O than in H2O. Increasing polymer chain length or hydro-
phobicity may suppress this solvent isotopic effect. This phase transition is correlated to Hofmeister series but
more sensitive than PNIPA. Na2CO3 dramatically lowers cloud point, while NaI significantly improves cloud
point, up to full dissolution in H2Oat95 °C. The solventisotopiceffectinNaCl orNa2CO3 solutionis the same as
what observed in solution absent of salt. Upon heating D2O solution of PNMEP, the polymer first forms the
hydrated irregular colloidal aggregates near the cloud point, the phasetransition occursat the fully hydrated state
at cloud point, and further heating leads to the dehydration and separation from D2O. However, in NaCl
solution, the dehydration of PNMEP occurs subsequently from apolar backbones, spacers, and finally
pyrrolidone groups.
Introduction
Another noteworthy example is the random copolymers
of 2-(2-methoxyethoxy)ethyl methacrylate and oligo(ethylene
Some water-soluble polymers may phase-separate from aqu-
eous solution on heating. The critical temperature of this phase
transition is the so-called lower critical solution temperature
(LCST). These polymers received increasing attention1 because
of their extensive bio-related applications for protein absorp-
tion,2 controlling bacterial aggregation,3 drug carriers,4,5 etc.
Thermoresponsive behaviors of these polymers depend on their
molecular structures. The structural tailorability of monomer
units may endow a variety of water-soluble polymers with
different thermoresponsive behaviors. For example, the gels of
poly(N-isopropylacrylamide) (PNIPA), poly[N-(n-propyl)acryl-
amide], or poly(N-cyclopropylacrylamide) have different LCST;6
poly(N-acryloyl-N0-propylpiperazine) has a LCST at 37 °C, but its
N0-methyl or N0-ethyl analogues are completely water-soluble;7,8
poly(N-vinylcaprolactam) has a LCST at 31 °C,9-11 but poly-
(N-vinylpyrrolidone) is completely water-soluble. This tempera-
ture-induced phase transition may be adjusted by the polymer
backbones; e.g., PNIPA has a lower LCST than poly(N-isopro-
pylmethacrylamide) (PNIPMA).12 The LCST of PNIPA is lower
than that of poly(N,N-ethylmethylacrylamide) because of the
formation of PNIPA intra- or interchain hydrogen bonding.13
glycol) methacrylate as described by Lutz and co-workers,14-16
which cannot form the inter- or intrachain hydrogen bonding.
They demonstrate that the temperature-induced phase transition
of these polymers is reversible and relatively insensitive to some
important parameters such as polymer chain length and concen-
tration and ionic strength of solutions. Moreover, because of this
molecular structure character, their aggregates could redissolve
readily upon cooling without any noticeable hysteresis.16 These
polymers are very promising for biomedical applications because
of their biocompatible oligo(ethylene glycol) segments.
As another possible alternative, pyrrolidone-based polymers may
be applied in biomedical fields. Pyrrolidone functionalities endow
polymers with some desirable properties, e.g., water solubility,
coordination capacity,17-19 and biocompatibility.20 As a typical
representative, poly(N-vinylpyrrolidone) was extensively utilized
for dispersing nanoparticles in aqueous solution,21-24 hemocom-
patible surface modification,25 controlled drug delivery,26,27 bio-
conjugation, and surface ligand immobilization.28 Considering
these excellent properties and extensive potential applications, the
exploitation of thermoresponsive behaviors of pyrrolidone-based
polymers is clearly far from enough.29-32
Early in 1998, Davis and co-workers30 described the synthesis
of pyrrolidone-based polymers via conventional radical
*Corresponding author: Ph þ86-731-58298876; Fax þ86-731-
58292251; e-mail ylcai98@xtu.edu.cn.
r 2010 American Chemical Society
Published on Web 04/07/2010
pubs.acs.org/Macromolecules

4042 Macromolecules, Vol. 43, No. 9, 2010
Sun et al.
1
to give a transparent product. Weight: 57.6 g; yield: 80.6%. H
polymerization. They demonstrated that poly[N-(2-methacryl-
oyloxyethyl)pyrrolidone] (PNMEP) had a LCST at 29-33 °C,
while poly[N-(3-methacryloyloxypropyl)pyrrolidone] (PNMPP)
could not dissolve in water at room temperature. Clearly, these
samples are ill-defined under the conventional radical polymeri-
zation. Generally, the LCST of a thermoresponsive polymer
depends on its molecular weight and distribution. Polymer
samples with intact structure, well-defined molecular weight,
and narrow distribution are essential for precise evaluation of
their thermoresponsive behaviors.
The reversible addition-fragmentation chain transfer radical
polymerization or RAFT polymerization33 is a powerful tool
extensively utilized for the synthesis of well-defined stimuli-
responsive polymers.34-44 Recently, our group developed a rapid
and well-controlled visible light activating ambient temperature
RAFT polymerization.45-49 This approach was utilized for the
synthesis of well-defined PNMEP samples.50 Our results demon-
strated that PNMEP had a cloud point covering 71.5-52.8 °C at
a Mw = 20.6-105.4 kg mol-1, which is remarkably higher than
what observed by Davis and co-workers.30 Clearly, many aspects
including structure dependence, solvent isotopic effect, and salt
effect still have to be studied for understanding the thermo-
responsive behaviors of these pyrrolidone-based polymers.
This paper describes the structure-dependent thermorespon-
sive behaviors of pyrrolidone-based polymers. For this purpose,
we synthesized a series of well-defined PNMEP and its analogues,
i.e., poly[N-(3-acryloyloxypropyl)pyrrolidone] (PNAPP) and
poly[N-(3-methacryloyloxypropyl)pyrrolidone] (PNMPP), via
the visible light activating RAFT polymerization at 25 °C. Their
cloud points were measured by laser light scattering analysis. The
solvent isotopic effect and salt effect on this temperature-induced
phase transition and dehydration were evidenced by tempera-
ture-variable 1H NMR and laser light scattering analysis.
NMR (δ, in CDCl3): 3.67 ppm (1H, CH2CH2CH2OH), 3.53 ppm
(2H, CH2CH2CH2OH), 3.40 ppm (4H, NCOCH2CH2CH2 in
pyrrolidone and CH2CH2CH2OH), 2.42 ppm (2H, NCOCH2-
CH2CH2 in pyrrolidone), 2.05 ppm (2H, NCOCH2CH2CH2 in
pyrrolidone), and 1.69 ppm (2H, CH2CH2CH2OH).
Synthesis of N-(3-Acryloyloxypropyl)pyrrolidone (NAPP)
Monomer. N-(3-Hydroxypropyl)pyrrolidone (35.75 g, 0.25 mol),
triethylamine (30.30 g, 0.30 mol), and 60.0 mL of anhydrous
chloroform were charged in a 500 mL dried round-bottom
flask. The flask was immersed in a thermostatic ice bath at 0 °C.
Acryloyl chloride (24.89 g, 0.275 mol) solution in 90.0 mL of
anhydrous chloroform was added dropwise in this flask for 2 h.
The mixture was stirred at 10 °C for 12 h. The white ammonium
salt was removed by filtration. The solution was concentrated by
rotary evaporation. The solution was extracted using subse-
quently a 5% Na2CO3 solution, a saturated NaCl solution, and
distilled water until neutralization. The solution was dried over
anhydrous MgSO4 and distilled under vacuum to give a transpar-
ent targeted monomer. Weight: 34.3 g; yield: 69%. 1H NMR (δ,
in D2O): 6.25, 6.06, and 5.83 ppm (3H, CH2dCH), 4.04 ppm
(2H, COOCH2CH2CH2), 3.22-3.34 ppm (4H, NCOCH2-
CH2CH2 in pyrrolidone and COOCH2CH2CH2), 2.26 ppm
(2H, NCOCH2CH2CH2 in pyrrolidone), 1.81-1.87 ppm (4H,
NCOCH2CH2CH2 in pyrrolidone and COOCH2CH2CH2).
The procedure for the synthesis of N-(3-methacryloyloxypro-
pyl)pyrrolidone (NMPP) was the same as above, except for
using methacrylic chloride. 1H NMR (δ, in D2O): 6.08 and 5.67
ppm (2H, CH2dCCH3), 4.14 ppm (2H, COOCH2CH2CH2),
3.35-3.47 ppm (4H, NCOCH2CH2CH2 in pyrrolidone and
COOCH2CH2CH2), 2.37 ppm (2H, NCOCH2CH2CH2 in
pyrrolidone), 1.88-2.00 ppm (7H, COOCH2CH2CH2, CH2d
CCH3, NCOCH2CH2CH2 in pyrrolidone). N-(2-Methacryl-
oyloxyethyl)pyrrolidone (NMEP) monomer was synthesized
according to our previous paper.50
Visible Light Activating RAFT Polymerization of NAPP at
25 °C. NAPP (5.91 g, 30.0 mmol), EDMAT (25.2 mg, 0.3 mmol),
TPO (5.85 mg, 0.045 mmol), and 3.00 g of anhydrous DMF were
charged in a 25 mL round-bottom flask capped with rubber
septa. The solution was deoxygenated by purging with highly
pure nitrogen gas for 40 min. The solution was irradiated with
visible light under stirring at 25 °C. Samples were collected using
deoxygenated syringes at predetermined intervals, quenched by
exposure to air and addition of traces of hydroquinone inhibi-
tor. One portion of sample was diluted in CDCl3 for 1H NMR
analysis; another portion was diluted in DMF for GPC mea-
surement. The NAPP monomer conversions were assessed by
1H NMR according to eq 1:
Experimental Section
Materials. S-1-Ethyl-S0-(R,R0-dimethyl-R00-acetic acid)trithio-
carbonate (EDMAT)51 and 2-cyanoprop-2-yl(4-fluoro)dithio-
benzoate (CPFDB)52 were synthesized according to the literature
procedures. N-Hydroxyethylpyrrolidone (95%) was purchased
from Jianhua Co. Ltd. and distilled under reduced pressure. N,N-
Dimethylformamide (DMF), triethylamine, and ethyl ether were
purchased from Shanghai Reagent Co., dried over metallic so-
dium, and distilled. Chloroform was washed with distilled water,
dried over anhydrous calcium chloride overnight, and distilled.
(2,4,6-Trimethylbenzoyl)diphenylphosphine oxide (TPO, 97%)
was purchased from Runtec Chem. Co.; 3-amino-1-propanol
and γ-butyrolactone were purchased from J&K; sodium chloride
(NaCl, >99.95%), sodium iodide (NaI, >99.95%), and sodium
carbonate (Na2CO3, >99.95%) were purchased from Shanghai
Reagent Co.; methacrylic chloride and acrylic chloride were
purchased from Aldrich; heavy water (D2O) was purchased from
Cambridge Isotope Laboratories Inc.; these reagents were used
as received. Highly pure deionized water (H2O) at resistivity over
18 MΩ cm-1 was utilized. JB400 filters were purchased from
Yaguang Sci. Edu. Equip. Co.
Visible Light Source. A mercury vapor lamp, emitting sepa-
rately at 254, 302, 313, 365, 405, 436, 545, and 577 nm, was
employed. JB400 filters were utilized to cut off the shorter wave
UV light below 400 nm and adjust the light intensity. Thus, a
mild visible light, emitting at 405, 436, 545, and 577 nm, at a mild
intensity of 250 μW cm-2 at 420 nm, was achieved for activating
the ambient temperature RAFT polymerization. Light intensity
was measured using a UV-A radiometer equipped with a 420 nm
sensor.
2
I3:88- 4:24 - I5:75- 6:48
3
conversion ¼
ꢀ 100%
ð1Þ
I3:88- 4:24
where I3.88-4.24 is the integral of proton resonance signals at δ =
3.88-4.24 ppm (COOCH2CH2CH2 of NAPP monomer and
PNAPP polymer) and I5.75-6.48 is the integral of proton reso-
nance signals at δ = 5.75-6.48 ppm (CH2dCH of NAPP
monomer).
The procedure for the visible light activating RAFT poly-
merization of NMEP or NMPP at 25 °C is the same as above,
except for using CPFDB chain transfer agent at different feed
molar ratios.
Laser Light Scattering Measurements. The light scattering
intensities were measured by laser light scattering (LLS) on a BI-
200SM Brookhaven instrument being equipped with a 100 mW
adjustable solid-state laser emitting at 532 nm, a BI-200SM
goniometer, and a BI-9000 digital correlator. The laser was
adjusted to 43 mW prior to measurements. A BI-TCD tempera-
ture controller was utilized for precisely adjusting the solution
temperature. The solutions were heated in steps and stabilized
Synthesis of N-(3-Hydroxypropyl)pyrrolidone. 3-Amino-1-
propanol (41.3 g, 0.55 mol) and γ-butyrolactone (43.0 g, 0.50 mol)
were charged in a 100 mL Teflon-lined autoclave. The solution was
heated at 230 °C for 10 h. The mixture was distilled under vacuum

Article
Macromolecules, Vol. 43, No. 9, 2010 4043
Figure 1. Molecular structures of poly[N-(2-methacryloyloxyethyl)-
pyrrolidone] (PNMEP), poly[N-(3-acryloyloxypropyl)pyrrolidone] (PN-
APP), and poly[N-(3-methacryloyloxypropyl)pyrrolidone] (PNMPP).
for 2 min before recording the data. The light scattering
intensities at an angle of 90° were recorded.
GPC measurements were performed on a PL-GPC120 setup
being equipped with a column set consisting of two PL gel 5 μm
MIXED-D columns (7.5 ꢀ 300 mm, effective molecular weight
range of 0.2-400.0 kg mol-1), using DMF as an eluent that
contained 0.01 M LiBr at 80 °C at a flow rate of 1.0 mL min-1
.
Narrow-distributed polystyrene standards in molecular weight
range of 0.5-7500.0 kg mol-1 (PSS, Mainz, Germany) were
utilized for calibration.
1H NMR analysis was performed on a 400 MHz Bruker AV-
400 NMR spectrometer equipped with a temperature controller.
Except for the temperature-variable H NMR measurements,
1
other samples were measured at 20 °C.
Results and Discussion
Davis and co-workers30 and our group50 demonstrated that
PNMEP had a LCST behavior. The pendant pyrrolidone groups
provide the water solubility via hydrogen bonding with the
adjacent water molecules. Indeed, this hydrogen bonding is the
key factor for the excellent water solubility of poly(N-vinyl-
pyrrolidone). On the other hand, the hydrophobicity of apolar
backbones and spacers of PNMEP counterbalances this dissol-
ving-favorable effect. Unlike the temperature-induced phase
transition of widely studied PNIPA, PNMEP cannot form the
inter- or intrachain hydrogen bonding. Thus, its temperature-
induced aggregates could readily redissolve upon cooling,
without any noticeable hysteresis.50 This phenomenon was
also observed in the aqueous solution of random copolymer of
2-(2-methoxyethoxy)ethyl methacrylate and oligo(ethylene
glycol) methacrylate.16
Figure 2. 1H NMR spectra of (a) N-(3-acryloyloxypropyl)pyrrolidone
(NAPP) and (b) N-(3-methacryloyloxypropyl)pyrrolidone (NMPP)
monomers in D2O.
In order to further elucidate the thermoresponsive behaviors of
polymers with this structure character, we synthesized a series of
PNMEP and its two analogues, i.e., poly[N-(3-acryloyloxypropyl)-
pyrrolidone] (PNAPP) and poly[N-(3-methacryloyloxypropyl)-
pyrrolidone] (PNMPP), via the visible light activating RAFT
polymerization at 25 °C.45-49 As shown in Figure 1, the elemental
composition of PNAPP is the same as that of PNMEP, but their
backbones and spacers are different; PNMPP and PNMEP have
the same methacrylic backbones, but PNMPP has one more
methylene in spacers.
Figure 3. Kinetic curves of the visible light activating RAFT polymeri-
zation of N-(3-acryloyloxypropyl)pyrrolidone (NAPP) using a S-1-ethyl-
S0-(R,R0-dimethyl-R00-acetic acid)trithiocarbonate (EDMAT) chain trans-
fer agent and a (2,4,6-trimethylbenzoyl)diphenylphosphine oxide (TPO)
photoinitiator at [NAPP]0:[EDMAT]0:[TPO]0 = 200:1:0.15 in 40 wt %
N,N-dimethylformamide (DMF) at 25 °C.
NAPP and NMPP monomers were synthesized via esterifying
N-(3-hydroxypropyl)pyrrolidone separately with acryloyl chlor-
ide and methacryloyl chloride. Asshown in Figure 2a, the integral
25 °C. As shown in Figure 3, at a feed molar ratio of
[NAPP]0:[EDMAT]0:[TPO]0 = 200:1:0.15, this polymeriza-
tion proceeds rapidly, 68% monomer polymerized in 21 min.
The initialization period53,54 is just 4.5 min. Moreover, the
semilogarithmic kinetic curve exhibits a linear evolution on
radiation time, suggesting a first-order kinetic character of
this RAFT polymerization. This indicates that the radical
concentration is constant and steady over the duration of this
RAFT polymerization.
0
ratio of proton signals Ia:Ib:Ia :Ic:Ieþf:Ih:Idþg equals 1:1:1:2:4:2:4.
Moreover, except for the proton signal of HOD, no other signal
of impurities is detectable. These suggest the high purity of NAPP
1
monomer. H NMR analysis also confirms the high purity of
NMPP monomer (see Figure 2b).
Synthesis of Poly[N-(3-acryloyloxypropyl)pyrrolidone]
(PNAPP). This polymer was synthesized via the visible light
activating RAFT polymerization of NAPP monomer at

4044 Macromolecules, Vol. 43, No. 9, 2010
Sun et al.
Figure 6. 1H NMR spectrum (a) and GPC trace (b) of poly[N-(3-
methylacryloyloxypropyl)pyrrolidone] (PNMPP).
Figure 4. (a) GPC trace evolution of poly[N-(3-acryloyloxypropyl)-
pyrrolidone] (PNAPP) synthesized under the same polymerizing condi-
tions as described in Figure 3. (b) Number-average molecular weight
(Mn) (solid) and polydispersity index (Mw/Mn) (hollow) of this polymer
as a function of monomer conversions.
presumably due to the calibration errors caused by using
polystyrene standards. Thus, the number-average molecular
weights of these polymers based on 1H NMR analysis were
utilized for evaluating the thermoresponsive behavior.
As shown in Figure 5, no signal at δ = 5.5-6.5 ppm
(CH2dCH of NAPP monomer) is detectable, which indi-
cates that NAPP monomer was completely removed from
the final PNAPP sample. The integral ratio of Ic:Ie:If:Ihþb
:
Iaþdþj = 2:2:2:3:6 within the analysis errors. This suggests
the intact structure of this targeted polymer. Except for the
proton signal of HOD, no proton signal of other impurities is
detectable, indicating the high purity of this polymer sample.
Moreover, as shown in the inset of Figure 5, the proton
signals at δ = 1.0-1.2 ppm (SCH2CH3 and C(CH3)2COOH
of EDMAT residues at the chain ends) are detectable; thus,
Mn may be assessed according to eq 2:
4:5Ic
Mn
¼
MNAPP þ MEDMAT
ð2Þ
Figure 5. 1H NMR spectrum of poly[N-(3-acryloyloxypropyl)pyrrolidone]
(PNAPP, GPC: Mn = 40.7 kg mol-1, Mw/Mn = 1.10) in D2O.
Ii þ k
where MNAPP and MEDMAT are the molecular weights of
NAPP monomer and EDMAT chain transfer agent. 1H
NMR analysis gives a Mn of 20.7 kg mol-1; thus, the polymer
chain length is denoted by the degree of polymerization (DP)
of 104.
Synthesis of Poly(N-(3-methacryloyloxypropyl)pyrrolidone)
(PNMPP). As shown in Figure 6a, no signal at δ = 5.5-
6.5 ppm (CH2dCCH3 of NMPP monomer) is detectable,
indicating that NMPP monomer was completely removed
As shown in Figure 4a, the GPC trace clearly shifts to
higher molecular weight side and gradually narrows down on
increasing monomer conversion. These GPC traces are
monomodal and symmetrical over 50% monomer conver-
sions. As shown in Figure 4b, the number-average molecular
weight (Mn) of PNAPP linearly increases with monomer
conversions. Moreover, the polydispersity index is reason-
ably narrow at the early stage, e.g., Mw/Mn = 1.12 at 25%
monomer conversion, which lowers down to 1.07 over 40%
monomer conversions. This suggests a well-controlled
behavior of this RAFT polymerization. Clearly, these mole-
cular weights are overestimated by GPC analysis, most
from this final PNMPP sample. The integral ratio of Ic:Ieþf
:
Ih:Iaþdþg:Ib = 2:4:2:6:3. This suggests the intact structure of
this PNMPP sample. Except for the proton signal of HOD, no
proton signal of other impurities is detectable, indicating the

Article
Macromolecules, Vol. 43, No. 9, 2010 4045
Figure 7. Light scattering intensity of a 20.0 mg mL-1 poly[N-(3-
Figure 8. Cloud point of poly[N-(2-methacryloyloxyethyl)pyrrolidone]
(PNMEP) aqueous solution as a function of the number-average
molecular weight (Mn) of this polymer. All PNMEP samples are
narrow-distributed with polydispersity indices of Mw/Mn = 1.08-1.13,
as measured by GPC analysis.
acryloyloxypropyl)pyrrolidone] (PNAPP, 1HNMR:Mn =20.7kgmol-1
;
GPC: Mn = 40.7 kg mol-1, Mw/Mn = 1.10) or poly[N-(3-methylacryl-
1
oyloxypropyl)pyrrolidone] (PNMPP, H NMR: Mn = 21.3 kg mol-1
;
GPC: Mn = 24.4 kg mol-1, Mw/Mn = 1.10) aqueous solution as a
function of solution temperature.
entropy on increasing molecular weight55,56 because the
lowering tendency clearly slows down on further increasing
Mn from 19.2 to 81.9 kg mol-1. As derived from Figure 8, at
the same Mn of 20.7 kg mol-1, PNMEP shows a cloud point
of 65.3 °C, which is 1.2 °C lower than that of its PNAPP
analogue. Generally, for PNAPP, the acrylic backbone
facilitates the chain conformational adjusting, and the addi-
tional spacer methylene enhances the hydrophobic associa-
tion. This structure effect seems to lower the cloud point. We
cannot give a reasonable explanation at present.
high purity of this polymer sample. As shown in the inset
of Figure 6, the proton signals at δ = 7.0-8.5 ppm (4H in
4-fluorobenzene of CPFDB residues at the polymer chain ends)
are detectable; thus, Mn may be assessed according to eq 3:
2Ic
Mn
¼
MNMPP þ MCPFDB
ð3Þ
Ii þ j
where MNMPP and MCPFDB are the molecular weights of NMPP
monomer and CPFDB chain transfer agent. 1H NMR analysis
gives a Mn of 21.3 kg mol-1, or DP = 100, which is comparable
to that of its corresponding PNAPP analogue as mentioned
above. Moreover, as shown in Figure 6b, the GPC trace of this
polymer is reasonably symmetrical and gives a narrow distribu-
tion of Mw/Mn = 1.10.
Solvent Isotopic Effect on Thermoresponsive Behaviors. As
shown in Figure 9, in light water (H2O), PNMEP at DP =
237 exhibits a cloud point of 58.3 °C. This cloud point
linearly lowers down to 49.8 °C in D2O on increasing molar
fraction of heavy water (D2O) (see Supporting Information
Figure S1), 8.5 °C lower than in H2O. Cremer and co-
workers59 also observed a lowering LCST of elastin-like
polypeptides in D2O than in H2O. However, this lowering
tendency is contrary to what was observed in PNIPA, whose
LCST is ∼1 °C higher in D2O than in H2O.60,61
Effect of Molecular Structure on Temperature-Induced
Phase Transition. As shown in Figure 7, PNMPP was fully
dissolved in water at solution temperature below 25 °C. On
heating up to 29.5 °C, the light intensity dramatically in-
creased, suggesting the occurrence of phase transition. This
critical temperature was the so-called cloud point. The
transparent solution changed to milky, and the polymer
settled down at the bottom of vial on further heating to
32 °C and kept for 2 h. However, as described by Iskander
et al.,30 the PNMPP sample synthesized via conventional
radical polymerization is water-insoluble at room tempera-
ture. This implies that the molecular weight of their PNMPP
In D2O solution at 48 °C, ca. 2 °C below the cloud point of
49.8 °C, the light scattering analysis revealed a strong
angular dependence of hydrodynamic diameters (Dh) of
aggregates roughly at 53-238 nm over a measuring angle
range of 45°-120°. However, as kept the solution at 48 °C for
2 h, the intensity was essentially constant at 2.5 kcps (see
Figure 10), and Dh at roughly 200-260 nm, as measured at a
fixed angle of 90°. These indicate the formation of irregular
1
sample is at least higher than 21.3 kg mol-1
.
colloidal aggregates. Based on H NMR analysis, the inte-
gral ratio of PNMEP proton signals at 48 °C is essentially the
same as that at 20 °C, suggesting the fully hydrated state of
these aggregates.
In contrast, at a DP = 104, PNAPP exhibits a cloud point
of 66.5 °C, which is 37 °C higher than that of the above-
mentioned PNMPP (DP = 100). This difference is contrary
to what was observed in PNIPA and its poly(N-isopro-
pylmethacrylamide) (PNIPMA) analogue; the LCST of
PNIPA is 13 °C lower than that of PNIPMA due to the
restrained intrachain collapse and interchain association by
the additional backbone methyl groups in PNIPMA.12 Un-
like PNIPA or PNIPMA, PNAPP or PNMPP cannot form
the intra- or interchain hydrogen bonding; thus, the tem-
perature-induced phase transition attributes to the enhanced
effect of hydrophobic association.
As shown in Figure 10, in D2O solution at 52 °C, ca. 2 °C
over the cloud point of 49.8 °C, this solution became turbid
immediately, and the intensity increased at the beginning; it
rapidly lowered down after 15 min. Further keeping this
solution at 52 °C for 5 h, the polymer settled down at the
bottom of vial as an oily consistency. This suggests the
macrophase separation rather than the formation of colloi-
dal aggregates.
On the basis of the results of Cremer and co-workers,59
hydrogen bonding rather than hydrophobicity is the key
factor in the stabilization of the collapsed state of elastin-like
polypeptides in D2O. However, the hydrogen bonding of
PNIPA amides with the adjacent D2O molecules is ∼5%
As shown in Figure 8, over a relatively low molecular
weight range of Mn = 16.2-19.2 kg mol-1, the cloud point
dramatically lowers down on increasing molecular weight.
This dramatic decrease attributes to the reduced mixing

4046 Macromolecules, Vol. 43, No. 9, 2010
Sun et al.
Figure 9. Cloud point of a 20.0 mg mL-1 poly[N-(2-methacryloyloxyethyl)-
pyrrolidone] (PNMEP, 1H NMR: Mn = 47.0 kg mol-1; GPC: Mn =
39.0 kg mol-1, Mw/Mn = 1.09) in the mixed solvent of D2O and H2O as
a function of molar percentage of D2O.
Figure 11. (a) Light scattering intensity of a 16 mg mL-1 poly[N-(2-
methacryloyloxyethyl)pyrrolidone] (PNMEP, 1H NMR: Mn = 81.9 kg
mol-1; GPC: Mn = 85.0 kg mol-1, Mw/Mn = 1.11) in H2O or D2O as a
function of solution temperature. (b) The integral ratios of each
Figure 10. Light scattering intensity of a 20.0 mg mL-1 poly[N-(2-metha-
PNMEP proton to that of D2O (I/ID O) as a function of solution
2
cryloyloxyethyl)pyrrolidone] (PNMEP, 1H NMR: Mn = 47.0 kg mol-1
;
temperature.
GPC: Mn = 39.0 kg mol-1, Mw/Mn = 1.09) solution in D2O, separately at
48 or 52 °C, as a function of time for keeping this temperature.
As shown in Figure 11b, on heating the solution from 22 to
46 °C, the integral ratios of protons in either pyrrolidone
rings or COOCH2CH2 keep essentially constant within the
analysis errors. This indicates the full hydration of this
polymer. The integral ratio relative to the backbone methyl
protons was slightly attenuated on elevating solution tem-
perature. These integral ratios dramatically decrease on
further heating the solution up to 51.9 °C. Thereafter, this
decrease tendency slows down up to 60 °C.
It should be noted that we were previously misled and
drew a wrong conclusion, simply based on these tempera-
ture-variable 1H NMR results.50 Actually, according to the
light scattering results as shown in Figure 11a, in D2O
solution, the cloud point of this polymer is at 44.6 °C, which
is 1.4 °C lower than the critical temperature of 46 °C, where
the integral ratios dramatically decrease. This suggests that
the dehydration temperature is higher than the cloud point,
rather than below this cloud point as described in our
previous paper.50
As shown in Figure 12, the cloud point of PNMPP at a
DP = 100 is 2.8 °C lower in D2O than in H2O, much less
pronounced than the LCST difference of above-mentioned
PNMEP samples. This suggests that the enhanced spacer
hydrophobicity suppresses this solvent isotopic effect.
Salt Effect on Thermoresponsive Behaviors. Na2CO3 signi-
ficantly lowers the cloud point of PNMEP from 58.3 °C in
deionized H2O down to 36.7 °C in 0.101 mol L-1 Na2CO3
stronger than that with H2O molecules;62 thus, breaking
these hydrogen bonds is more enthalpically costly in D2O.63
This leads to a more extended conformation64 or higher
LCST60 of PNIPA in D2O than in H2O. Nevertheless, there
is no strong hydrogen bond donor in PNMEP but weaker
van der Waals interaction, including hydrophobic associa-
tion of apolar backbones and spacers. Thus, this significant
LCST lowering attributes to this structure character. Clearly,
further intensive studies are necessary to clarify this pheno-
menon.
In order to elucidate this solvent isotopic effect, a PNMEP
at a long chain length of DP = 415 was utilized for laser light
scattering analysis and temperature-variable 1H NMR mea-
surements. As shown in Figure 11a, its cloud point is 8.0 °C
lower in D2O than in H2O. This ΔT is 0.5 °C smaller than that
of the above-mentioned shorter one. This suggests that the
increase of chain length may suppress this solvent isotopic
effect.
The temperature-induced dehydration was quantitatively
assessed by temperature-variable H NMR analysis, using
1
the proton signal of HOD in D2O solvent as an external
standard. Considering the constant concentration of HOD
in this solution at 22-60 °C, the temperature-induced dehy-
dration may be detected based on the attenuation of PNMEP
protons as compared with the proton signal of HOD.

Article
Macromolecules, Vol. 43, No. 9, 2010 4047
Figure 12. Light scattering intensity of a 20 mg mL-1 poly[N-(3-
methacryloyloxypropyl)pyrrolidone] (PNMPP, 1H NMR: Mn = 21.3
kg mol-1; GPC: Mn = 24.4 kg mol-1, Mw/Mn = 1.10) in H2O or D2O
as a function of solution temperature.
aqueous solution (see Supporting Information Figure S2).
As derived from Figure 13a, this cloud point linearly lowers
down at a slope (ΔT/ΔCNa CO ) of -218 °C/mol L-1, which
3
is remarkably more pron2ounced than what observed in
PNIPA (-27 °C/mol L-1).57 This suggests that the addition
of Na2CO3 significantly enhances the hydrophobic associa-
tion. In addition, ΔT/ΔCNa CO in D2O is the same as that in
2
H2O, suggesting the same solve3nt isotopic effect, in either the
absence or presence of NaCO3.
The addition of NaCl also lowers the cloud point from
58.3 °C in deionized H2O down to 38.9 °C in 0.999 mol L-1
NaCl aqueous solution (see Supporting Information Figure
S3). As derived from Figure 13b, the cloud point linearly
lowers down with NaCl concentration at a slope (ΔT/
ΔCNaCl) of -19 °C/mol L-1, but less pronounced than the
above-mentioned ΔT/ΔCNa CO . However, it is somewhat
2
3
higher than that of PNIPA (-10 °C/mol L-1).58 In addition,
ΔT/ΔCNaCl in D2O is the same as that in H2O, suggesting the
same solvent isotopic effect, in either the absence or presence
of NaCl.
However, as shown in Figure 13c, the cloud point sig-
nificantly improves on the addition of NaI, e.g., from 58.3 °C
in deionized H2O up to 79 °C in 0.0995 mol L-1 NaI aqueous
solution (see Supporting Information Figure S4). Further
increasing the concentration of NaI up to 1.0 mol L-1 leads
to the full dissolution of this polymer up to 95 °C. This
phenomenon is different from what observed in PNIPA.58
In summary, similar to the widely studied effect of Hof-
meister anions on LCST of PNIPA65,66,57 or elastin-like
polypeptides,59 the phase transition of PNMEP is also
Figure 13. Cloud point evolution of a 20.0 mg mL-1 poly[N-(2-metha-
cryloyloxyethyl)pyrrolidone] (PNMEP, 1H NMR: Mn = 47.0 kg mol-1
;
GPC: Mn = 39.0 kg mol-1, Mw/Mn = 1.09) solution in D2O or H2O, as a
function of concentration of (a) Na2CO3, (b) NaCl, or (c) NaI.
2-
correlated to Hofmeister series.67-70 CO3 or Cl- anions
methylene protons d and e, neighboring the amide nitrogen,
becomes sharp and narrow. This suggests that iodide anions
bind directly to the nitrogen of amide,57 leading to the
significant hydration of its neighboring methylenes.
As shown in Figure 15a, in NaCl solution, the integrals
of PNMEP proton signals keep essentially constant below
30 °C. On further elevating the solution temperature, the
signal of backbone methyl protons gradually attenuates,
followed by the attenuation of signal of spacer methylene
protons. The signals of methylene protons neighboring the
amide nitrogen of pyrrolidone groups slightly attenuate
around the cloud point of 37.7 °C, as assessed by light
scattering analysis. This indicates that this temperature-
induced dehydration occurs subsequently from polymer
backbones, hydrophobic spacers, and finally pyrrolidone
groups in NaCl solution.
polarize their adjacent water molecules, which are in turn
involved in hydrogen bonding with pyrrolidones, thus modu-
lating the hydrophobic hydration, leading to a salting-out
effect or lowering the cloud point. However, I- anions may
bind directly to the amides of pendant pyrridone groups,57
leading to a salting-in effect, up to fully dissolving this
polymer at 95 °C.
As shown in Figure 14, the integral ratio of PNMEP
proton signals equals the hydrogen ratio of this polymer,
suggesting that this polymer was fully dissolved in D2O at
20 °C. On the other hand, in NaCl solution, these proton
signals shift to low magnetic field. This suggests that NaCl
disturbs the chemical environment of polymer protons. This
disturbance is more pronounced in NaI solution, leading to
the signals shift to much lower magnetic field. The signal of

4048 Macromolecules, Vol. 43, No. 9, 2010
Sun et al.
(see Figure 10b). This suggests that the dehydration temp-
erature is higher than the cloud point in solution absent
of salt.
Conclusion
A series of pyrrolidone-based water-soluble polymers, poly-
[N-(2-methacryloyloxyethyl)pyrrolidone] (PNMEP), poly[N-(3-
acryloyloxypropyl)pyrrolidone] (PNAPP), and poly[N-(3-metha-
cryloyloxypropyl)pyrrolidone] (PNMPP), were synthesized via
visible light activating RAFT polymerization at 25 °C. Kinetic
studies indicate a rapid and well-controlled behavior of this RAFT
polymerization. Moreover, GPC and 1H NMR analysis confirmed
the intact molecular structure, well-defined molecular weight, and
narrow molecular weight distribution (Mw/Mn = 1.08-1.13) of
these polymers.
Laser light scattering measurements demonstrate that the
cloud points of these polymers strongly depend on the molecular
structure of monomer units. For example, the monomer units of
PNMEP and PNAPP have the same elemental composition,
but the cloud point of PNMEP at a DP = 96 is 1.5 °C lower
than that of PNAPP at the same DP = 104. The additional
backbone methyl in PNMPP leads to a dramatic cloud point
lowering; e.g., PNAPP at a DP=104 exhibits a cloud point
of 66.5 °C, while PNMPP at a DP = 100 exhibits a cloud
point of 29.5 °C in H2O. This dramatic cloud point lowering is
totally contrary to what was observed in PNIPA or PNIP-
MA.12 This dramatic cloud point lowering also led Davis and
co-workers drawing a conclusion that this polymer was water-
insoluble.50
Figure 14. 1H NMR spectra of a 20 mg mL-1 poly[N-(2-metha-
cryloyloxyethyl)pyrrolidone] (PNMEP, 1H NMR: Mn=47.0 kg mol-1
;
GPC: Mn = 39.0 kg mol-1, Mw/Mn = 1.09) solution in D2O at 20 °C;
separately in D2O absent of salt, 0.8 mol L-1 NaCl solution, or 0.8 mol
L
-1 NaI solution.
This structure character also leads to a dramatic solvent
isotopic effect that is contrary to what observed in PNIPA.60,61
For example, the cloud point of PNMEP at a DP = 237 is 8.5 °C
lower in D2O than in H2O. Increasing the chain length to DP =
415 leads to a -8.0 °C cloud point difference between in D2O and
in H2O. Increasing the hydrophobicity may suppress this solvent
isotopic effect; e.g., for PNMPP at a DP = 100, the cloud point is
2.8 °C lower in D2O than in H2O.
The cloud points of these pyrrolidone-based polymers are
correlated to Hofmeister series. The addition of Na2CO3 or NaCl
leads to the salting-out effect, thereby lowering the cloud point.
These salt effect is more pronounced in Na2CO3 solution, leading
to a dramatic decrease of cloud point. However, because I-
anions bind directly to the amide nitrogen of pyrrolidone groups,
the addition of NaI leads to a salting-in effect, thereby signifi-
cantly improving the cloud point, up to fully dissolving of
PNMEP at 95 °C. The solvent isotopic effect in NaCl or Na2CO3
solution is the same as in solution absent of salt. On the basis of
the results of temperature-variable 1H NMR and light scattering
analysis, upon heating D2O solution, PNMEP first forms the
fully hydrated irregular colloidal aggregates near cloud point,
the phase transition occurs at the fully hydrated state at cloud
point, and further heating leads to the dehydration and macro-
phase separation of this polymer from D2O. However, in
NaCl solution, the dehydration occurs subsequently from poly-
mer backbones, hydrophobic spacers, and finally pyrrolidone
groups.
Figure 15. Integral ratios of each proton in poly[N-(2-methacryl-
1
oyloxyethyl)pyrrolidone] (PNMEP, H NMR: Mn = 47.0 kg mol-1
;
GPC: Mn = 39.0 kg mol-1, Mw/Mn = 1.09) to that of D2O (I/ID O) as a
2
function of solution temperature; (a) in 0.8 mol L-1 NaCl solution, (b)
in solution absent of salt.
Acknowledgment. We thank the National Natural Science
Foundation of China (20674064, 20874081) and the Research
Fund for Doctoral Program of Higher Education of China
(200805300004) for financial support of this research.
In contrast, as shown in Figure 15b, in the solution
absent of salt, the proton signals of PNMEP do not attenuate
around its cloud point of 49.8 °C. These results demon-
strate that NaCl enhances the hydrophobic association
and thus lowers down the cloud point of this polymer. On
the other hand, this integral ratio variation is essen-
tially the same as what observed in a long-chain PNMEP
Supporting Information Available: Figures for D2O/H2O
ratio or salt concentration dependence of light scattering in-
tensity of a 20.0 mg mL-1 PNMEP solution. This material is
available free of charge via the Internet at http://pubs.acs.org.

Article
Macromolecules, Vol. 43, No. 9, 2010 4049
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