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displaying a lower critical solution temperature (LCST) in the
physiological range (30e40 ꢀC). Its hydrolysis does not produce
small toxic amine compounds as in the case of poly(N-iso-
propylacrylamide) (PNIPAM) which is the most widely studied
thermoresponsive polymer. These characteristics, in addition to
noncytotoxicity and biocompatibility, suggested that PNVCL is of
particular interest for the development in the biomedical field
[33e35]. Moreover, the LCST behavior of PNVCL is sensitive to
changes of both the polymer chain length and concentration.
Thus, the LCST value of PNVCL can easily be modified by con-
trolling the polymer molecular weight with no requirement of
using a comonomer [36,37]. Although many linear NVCL-based
polymers have been synthesized, little attention has been paid
to cyclic PNVCL. Herein, we reported our study on the synthesis of
2.3. Synthesis of propargyl 2-chloropropionate (PCP)
The ATRP initiator, propargyl 2-chloropropionate (PCP) was
synthesized by the reaction of propargyl alcohol with
2-chloropropionyl chloride. A mixture of propargyl alcohol (2.0 mL,
33.7 mmol) and TEA (5.6 mL, 37.1 mmol) in dry dichloromethane
(DCM) was stirred and cooled to 0 ꢀC in an ice-water bath.
2-chloropropionyl chloride (3.4 mL, 33.8 mmol) in dry DCM was
added dropwise to the mixture. The reaction mixture was stirred at
0 ꢀC for another 30 min and then at room temperature for 12 h. The
resulting triethylammonium salts were filtrated out, and the filtrate
was washed with saturated NaHCO3 solution and dried over
MgSO4. After the solvent had evaporated, the remaining product
was purified by silica gel column chromatography (petroleum
ethereEtOAc, 50: 1) to yielded a yellow oil (4.18 g, yield: 85%). 1H
NMR (CDCl3): dH 1.74 (d, J ¼ 2.3 Hz, 3H, CH3), 2.55 (s, 1H, C^CH),
4.46 (m, 1H, CHCl), 4.79 (m, 2H, OCH2).
well-defined cyclic PNVCL from a-alkyne-u-azide linear precursor
at a relatively high concentration (10 mg/mL) via a combination of
supramolecular self-assembly and “selective click” cyclization. To
the best of our knowledge, this is the first report of cyclic PNVCL.
The thermoresponsive and micellar behaviors of cyclic PNVCL and
its linear precursor were also investigated and compared.
2.4. Synthesis of l-PNVCL-Cl
l-PNVCL-Cl was prepared by ATRP of NVCL. NVCL (610.3 mg,
4.38 mmol), CuCl (3.9 mg, 0.04 mmol), CuCl2 (0.6 mg, 0.004 mmol),
Me6Cyclam (12.5 mg, 0.044 mmol), a mixture of 1,4-dioxane and
isopropanol were added to a Schlenk flask that was fitted with a
rubber septum and pump-filled with nitrogen three times. And
then, PCP (6 mg, 0.044 mmol) were added to the flask under ni-
trogen. The solution was stirred at 30 ꢀC for 2 h. The crude product
was dissolved in deionized (DI) water and then transferred to a
dialysis bag (MWCO ¼ 3500) and dialyzed against deionized water
for 6 days. The final product was dried under vacuum for 24 h,
yielding a white solid (overall yield: 58%).
2. Experimental
2.1. Materials
N-vinylcaprolactam (98%, Aldrich) was distilled under reduced
pressure and then stored at 4 ꢀC. CuCl (97%, Sinopharm Chemical
Reagent Co. Ltd., China) was purified by stirring in acetic acid,
washed with methanol, and then dried in vacuum. 1,4-Dioxane was
distilled over sodium. Dichloromethane (DCM) was distilled from
anhydrous calcium chloride for drying. Me6Cyclam was synthesized
according to the method described in the literature [38]. Triethyl-
amine (TEA, Sinopharm Chemical Reagent, China) was stirred over
Na and distilled under reduced pressure. Propargyl alcohol (99%)
and CuCl2 (99.999%) were purchased from Aldrich and used
without further purification. 2-Chloropropionyl chloride (99%),
sodium azide (NaN3, 99%), sodium ascorbate, copper sulfate
(CuSO4) and other reagents were obtained from Sinopharm
Chemical Reagent Co. Ltd. without further purification.
2.5. Synthesis of l-PNVCL-N3
l-PNVCL-N3 was synthesized by the nucleophilic substitution
reaction of l-PNVCL-Cl with NaN3. 8.5 g of l-PNVCL-Cl was dissolved
in 30 mL of DMF. NaN3 (325 mg, 5 mmol) was then added and the
reaction mixture was stirred at 45 ꢀC for 48 h. After removing DMF
under reduced pressure, the remaining product was dissolved
in THF and passed through a neutral alumina column to remove
residual sodium salts. The resulting product was dried under
vacuum for 24 h, yielding a white solid (7.3 g, yield: 93%).
2.2. Characterizations
2.6. Synthesis of c-PNVCL in micellar media
1H NMR spectra were determined on a Bruker DRX-500 spec-
trometer in CDCl3. Tetramethylsilicone (TMS) was used as internal
standards. Chemical shifts are reported in parts per million (ppm)
relative to CDCl3 (7.26 ppm). FT-IR spectra were taken on a Nicolet
AVATAR 360 FT-IR spectrometer. Molecular weight and poly-
dispersity of polymers were measured by gel permeation
chromatography/multi-angle laser light scattering (GPC/MALLS).
The GPC-MALLS system consisted of a Waters 2690D separations
module and a Waters 2414 refractive index detector (RI), and a
Wyatt DAWN EOS MALLS detector. Styragel HR1 and HR4 columns
(Waters) were used at 40 ꢀC with polystyrene as standards and THF
as a mobile phase at a flow rate of 0.3 mL minꢁ1. TEM images were
obtained using a Hitachi H-600 instrument operating at an accel-
eration voltage of 80 kV. DLS measurements were performed with a
Zetasizer ZEN 3600 instrument (Malvern, UK) operating at
20e50 ꢀC using a light scattering apparatus equipped with a HeeNe
laser. The scattering angle was kept at 173ꢀ (backscattering) and the
wave length in the vacuum was set as 633 nm during the whole
experiment. Malvern DTS 6.20 software was used to analyze the
data. Each reported measurement was the average of three runs.
c-PNVCL was synthesized via “selective” click reaction in
aqueous micellar media. A round bottom flask was charged with
l-PNVCL-N3 (400 mg) and water (40 mL). After dissolving at room
temperature, the flask was placed in an oil bath thermostated at
30 ꢀC. Sodium ascorbate (50 mg, 0.25 mmol) and CuSO4 (25 mg,
0.15 mmol) were then added. The reaction mixture was stirred at
30 ꢀC for 24 h before it was removed the solvent and then the
remaining product was dissolved in THF and passed through a
neutral alumina column to remove residual sodium salts. The
product was further purified by precipitation into anhydrous ethyl
ether and dried under vacuum for 24 h, yielding a light yellow-
colored solid (0.34 g, yield: 85%).
2.7. Transmittance measurements
The optical transmittance of aqueous solution of linear or cyclic
PNVCL at various temperatures was measured at 500 nm with a
UV-vis spectrometer (CARY UV-50, VARIAN) equipped with a
water-circulation heating stage. The heating rate was 1 ꢀC/5 min.