Dual stimuli-responsive polyamines derived from modified N-vinylpyrrolidones through CuAAC click chemistry

Article abstract of DOI:10.1002/pola.27949

The synthesis via copper(I)-catalyzed azide alkyne cycloaddition (CuAAC) of three new monomer derivatives of N-vinyl-2-pyrrolidone (VP) carrying cyclic pyrrolidine, piperidine, and piperazine groups and the corresponding copolymers with unmodified VP is s

Full text of DOI:10.1002/pola.27949

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Dual Stimuli-Responsive Polyamines Derived from Modified
N-Vinylpyrrolidones Through CuAAC Click Chemistry
1
1
2
1
1
Anselmo del Prado, Rodrigo Navarro, Pavel Levkin, Alberto Gallardo, Carlos Elvira,
1
Helmut Reinecke
1
Instituto De Ciencia Y Tecnolog ꢀı a De Pol ꢀı meros, ICTP-CSIC, Juan De La Cierva 3, Madrid 28006, Spain
2
Institute of Toxicology and Genetic, Karlsruhe Institute of Technology, Karlsruhe 76344, Germany
Correspondence to: A. del Prado (E-mail: anseldollan@gmail.com)
Received 14 August 2015; accepted 30 September 2015; published online 22 October 2015
DOI: 10.1002/pola.27949
ABSTRACT: The synthesis via copper(I)-catalyzed azide alkyne
cycloaddition (CuAAC) of three new monomer derivatives of N-
vinyl-2-pyrrolidone (VP) carrying cyclic pyrrolidine, piperidine,
and piperazine groups and the corresponding copolymers with
unmodified VP is shown. The systems bearing pyrrolidine and
piperidine displayed both thermo- and pH-response, which has
not been reported previously for a polymer with polyvinylpyr-
rolidone (PVP) backbone. A broad modulation of the LCST with
the copolymer composition and pH was observed in a temper-
ature range 0–100 8C. The polymers carrying piperazine exhib-
ited broad buffering regions and no thermosensitivity. V
2015
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Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem.
2016, 54, 1098–1108
KEYWORDS: functionalization of polymers; polyamines; radical
polymerization; stimuli-sensitive polymers; synthesis; thermal
properties
INTRODUCTION Polyvinylpyrrolidone (PVP) is one of the
most frequently used polymers due to its native properties
Among these functional groups like ester and amide
1
0
11
12
groups, alcohols and thiols, alkyl groups, and even
1
3
cyclodextrins can be pointed out. Recently, PVPs carrying
primary amines were synthesized in our group and used as
precursor for other derivatizations due to the high reactivity
(
non-toxic, neutral, biocompatible, good solubility in water
as well as in many organic solvents) that make it suitable for
use in many biomedical and technical fields, either as coat-
1
4
1
2,3
of the amine group.
ing, surfactant, stabilizer (E1201), as clarifying agent in
drinks and support in tablets (it has been approved as food
One interesting feature that may be accomplished by incor-
porating appropriate structures to polymeric VP-derivatives
is the stimuli-responsiveness in aqueous media, that is, the
preparation of smart PVP polymers. “Smart polymers,” which
have received much attention in recent years, are polymers
that respond with dramatic property changes to variations of
the environment triggering changes in their structural orga-
nization and morphology. When temperature is the stimulus,
a water-soluble polymer (such as the well-known poly(N-iso-
propylacrylamide) PNIPAAm) undergoes a phase transition
as a response to a temperature change. The most common
thermosensitivity is the lower critical solution temperature
phenomenon (LCST), which is the case when the inter and
intramolecular interactions between soluble polymer chains
increase above a critical temperature, leading to the non-
4
–6
additive by the FDA), as antifouling material,
and so forth.
Modification of PVP has been pursued for the purpose of
adding functional groups to its conventional form, trying to
maintain its excellent properties. A commonly reported strat-
egy for its functionalization is the copolymerization of the
VP monomer with other monomers carrying a functional
7
,8
groups, obtaining a functionalized copolymer of VP. How-
ever, VP belongs to a group of “less-activated” monomers,
whose reactivity in radical polymerization is lower than that
of typical commercial monomers such as acrylates, metha-
crylates, and styrenes. Therefore, besides losing the PVP
backbone in the copolymers of VP with those monomeric
9
families, materials which are structurally heterogeneous are
obtained what inevitably interferes in the final properties.
Lately, numerous studies have been focused on the function-
alization of PVP maintaining its backbone, using VP mono-
mer modified with functional groups in the lactam ring.
15
solubility of the polymer and its subsequent precipitation.
A particular and very interesting type of aqueous thermosen-
sitivity is the case where the system is additionally sensitive
Additional Supporting Information may be found in the online version of this article.
2015 Wiley Periodicals, Inc.
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to pH, that is, a scenario of double responsiveness where
temperature and/or pH changes induce a change in the poly-
mer microstructure. Although this may be obtained by
copolymerization of thermosensitive units (like NIPAAm) and
ionizable units (such as acrylic, methacrylic acids, or amine
some THF was added before removing the diethylether under
reduced pressure. Assuming a 100% yield, a 0.7 M THF solu-
tion was prepared for the next reaction (see Scheme 1)
2
1
N -pl. FTIR (cm ): 2964, 2876, 2789, 2095, 1459, 1442,
3
1
6–21
1349, 1278, 1150, 1056, 955, 861.
derivatives),
there is a type of structure that provides
simultaneously both types of sensitivity: pendant aliphatic
2
1
N -pp. FTIR (cm ): 2936, 2856, 2801, 2094, 1469, 1456,
3
ionizable tertiary amines such as those included in poly(N,N-
2
2
1442, 1377, 1351, 1302, 1277, 1157, 1123, 1040, 931, 862,
758.
diethylaminoethyl methacrylate), poly-DEAEM,
poly(N,N-
2
3
dimethylaminoethyl methacrylate), poly-DMAEM, or poly(e-
2
4
thylpyrrolidine methacrylate), poly-EPyM. As an example,
Poly-DEAEM has LCST values around 40 8C at pH 7.
Tert-Butyl 4-(2-Hydroxyethyl)piperazine-1-Carboxylate
2
2–26
(HO-pz-Boc) (3)
Di-tert-butyldicarbonate (10.9 mL, 46.09 mmol) was dis-
Polymeric VP-derivatives showing LCST have been actually
prepared by copolymerization of VP with thermosensitive
solved in 35 mL of CH Cl and added dropwise to a solution
2
2
2
7–29
of 5 g of 1-(2-hydroxyethyl)piperazine (5 g, 38.40 mmol) in
dichloromethane (50 mL). During the addition, the reaction
mixture was maintained at 0 8C and, then, was allowed to
units.
In addition, and pursuing the desire of maintain-
ing the PVP backbone as mentioned above, some PVP sys-
tems with thermosensitive properties have been synthesized
from native VP monomer and different alkylated VP mono-
warm up to room temperature. After 2 h, saturated NH Cl
4
solution was used to quench the reaction (30 mL). The
organic layer was separated and the aqueous one was
extracted with CH Cl (2 3 40 mL). The organic layers were
3
0,31
mers.
However, and to the best of our knowledge, no
smart PVP polymers showing dual stimuli-response in aque-
ous media, to temperature and pH, has yet been reported. In
this work, N-vinylpyrrolidone monomers modified with sev-
eral cyclic aliphatic amines (pyrrolidine, piperidine, and
piperazine) have been synthesized and copolymerized with
pure VP, obtaining different aminated polymers—some of
them showing dual sensitivity—with a true PVP backbone.
VP monomers with amine groups were synthesized by cop-
per(I)-catalyzed azide alkyne cycloaddition (CuAAC). Homo-
polymers and copolymers with unmodified VP have been
prepared by conventional free radical polymerization. The
sensitivity of these new polymers to pH and temperature
has been studied.
2
2
combined and dried over anhydrous sodium sulfate. The sol-
vent was removed under reduced pressure. The white resi-
due was purified by column chromatography using silica gel
as stationary phase and hexane/ethyl acetate (3:1) as eluent
to yield a white solid. Yield: 100%.
1
H NMR (CDCl , 400 MHz): d 5 3.60 (t, 2H, HO-CH , J 5 5.6
3
2
Hz), 3.40 (t, 4H, CH -CH -NCOOtBu-CH -CH , J 5 5.2 Hz),
2
2
2
2
2.83 (s, 1H, -OH), 2.51 (t, 2H, HO-CH -CH , J 5 5.6 Hz), (t,
2
2
4H, CH -NCOOtBu-CH , J 5 5.2 Hz), 1.24, (s, 9H, NCOOtBu).
2
2
1
3
C RMN (CDCl , 100 MHz): d 5 154.76 (NCOOtBu), 79.78
3
(HO-CH ), 77.36 (NCOOC(CH ) ), 59.56 (CH -CH -NCOOtBu-
2
3 3
2
2
CH -CH ), 57.86 (HO-CH -CH ), 52.82 (CH -NCOOtBu-CH ),
2
2
2
2
2
2
2
1
EXPERIMENTAL
3 3
28.48 (NCOOC(CH ) ). FTIR (cm ): 3437, 2975, 2933, 2864,
2
1
811, 1692, 1457, 1419, 1365, 1290, 1244, 1167, 1126,
077, 1054, 1003, 926, 865, 768.
Materials
1-Vinyl-2-pyrrolidone (Sigma–Aldrich) was distilled under
0
reduced pressure before use. 2,2 -Azobis(isobutyronitrile)
Tert-Butyl 4-(2-((Tosyloxy)ethyl)piperazine-
-Carboxylate (TsO-pz-Boc) (4)
(
AIBN) 98% (Sigma–Aldrich) was used after recrystallization
1
in methanol. Di-tert-butyldicarbonate 97% (Aefa Aesar) and
Copper(II) sulfate pentahydrate 98.5% (Quimicen) were
used as received. All other chemicals were purchased in
Sigma–Aldrich and used as received.
HO-pz-Boc (3.3 g, 14.33 mmol) was dissolved in 30 mL of
CH Cl and cooled using an ice bath. A solution of p-toluene-
2
2
sulfonyl chloride (2.79 g, 14.33 mmol) in 20 mL of CH Cl2
2
was slowly added and the mixture was allowed to warm up
to 35 8C under magnetic stirring. After 4 h, the reaction mix-
ture was diluted with 10 mL CH Cl and washed with 10 mL
Synthesis of VP Derivatives
2
2
1
1
-(2-Azidoethyl)pyrrolidine (N -Pl) (1) and
3
of a saturated aqueous solution of NaHCO3 (three times).
The organic layers were collected and dried over anhydrous
sodium sulfate. The solid was removed by filtration and the
solvent was evaporated under reduced pressure to yield a
pale yellow solid. Yield: 95%.
-(2-Azidoethyl)piperidine (N -Pp) (2)
3
Five grams of the hydrochloride salt (1 equiv.) was dissolved
in deionized water (140 mL). Then, sodium azide (2 equiv.)
was added and the solution was warmed up to 70 8C under
magnetic stirring. After 5 h, the solution was cooled down
using an ice bath and KOH (1.1 equiv.) was slowly added to
the mixture. Finally, 150 mL of diethylether was added to the
reaction mixture and the aqueous layer was extract twice
with diethylether (2 3 100 mL). The organic layers were
combined and dried over anhydrous sodium sulfate. For secu-
rity reasons, the products were never completely dried but
1
H NMR (CDCl , 400 MHz): d 5 7.95 (d, 2H, Ar-H, J 5 8.4 Hz),
3
7.40 (d, 2H, Ar-H, J 5 8.40 Hz), 3.66 (t, 2H, O-CH , J 5 5.2
2
Hz), 3.47 (t, 4H, CH -CH -NCOOtBu-CH -CH , J 5 4.8 Hz),
2
2
2
2
2.62 (t, 2H, O-CH -CH , J 5 5.2 Hz), 2.53 (t, 4H, CH -
2
2
2
NCOOtBu-CH , J 5 4.8 Hz), 2.48 (s, 3H, CH -Ar), 1.45 (s, 9H,
2
1
3
3
NCOOtBu).
C
RMN (CDCl3, 100 MHz): d 5 154.79
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SCHEME 1 Synthesis of aminated azido compounds (above) and its vinylpyrrolidone derivatives using CuAAC chemistry (below).
(
7
5
NCOOtBu), 147.01, 141.85, 130.44, 127.25, 80.15 (HO-CH2),
7.45 (NCOOC(CH ) ), 59.69 (CH -CH -NCOOtBu-CH -CH ),
3-Propargyl-N-vinyl-2-Pyrrolidone (VP-Gyl) (6)
Diisopropylamine (7 mL, 50 mmol) was added at 278 8C to
a solution of butyllithium (17.3 mL, 43 mmol) in 80 mL of
anhydrous THF. The mixture was warmed up to 0 8C under
stirring for 10 min and was cooled back to 278 8C. VP
(5 mL, 43 mmol) was dropwise added to this solution and
was kept at 278 8C for 1 h. Then, propargyl bromide
3
3
2
2
2
2
7.71 (HO-CH -CH ), 52.96 (CH -NCOOtBu-CH ), 28.60
2 2 2 2
21
(NCOOC(CH ) ), 22.04 (CH ). FTIR (cm ): 3415, 2978,
3 3 3
2
1
8
933, 2869, 2815, 1690, 1594, 1457, 1419, 1366, 1290,
245, 1189, 1172, 1127, 1081, 1055, 1034, 1004, 926, 865,
13, 769, 699, 653.
(
4.8 mL, 43 mmol) was added to the solution, and the mix-
ture was slowly warmed up to 0 8C and stirred during 5 h.
Finally, the resulting yellow solution was quenched with
water (40 mL). Dichloromethane (30 mL) was added and
the organic layer was separated. The aqueous layer was then
extracted three times with dichloromethane (30 mL). The
organic layers were combined and dried over anhydrous
sodium sulfate. The solid was removed by simple filtration
and the solvent was evaporated under reduced pressure. The
yellow residue was purified by column chromatography
using silica gel as stationary phase and hexane/ethyl acetate
(5:1) as eluent to yield colorless oil. Yield: 62%.
Tert-Butyl 4-(2-Azidoethyl)piperazine-1-Carboxylate
-pz-Boc) (5)
TsO-pz-Boc (3.7 g, 9.73 mmol) was dissolved in 50 mL of
DMF. Then, sodium azide (1.26 g, 19.46 mmol) was dis-
(N
3
solved in 10 mL of H O and added to the reaction mixture,
2
that was warmed up to 70 8C under magnetic stirring.
After 72 h, the solution was cooled down with an ice bath,
and KOH (1.20 g, 20 mmol) dissolved in 20 mL of water
was slowly added to the mixture. Finally, the reaction mix-
ture was added to 100 mL of CH Cl and the aqueous
2
2
2 2
layer was extracted with CH Cl (2 3 100 mL). The
1
H NMR (CDCl , 500 MHz): d 5 7.08 (dd, 1H, N-CH5CH ,
3
2
organic layers were combined and dried over anhydrous
sodium sulfate. The same security protocol as in the prep-
aration of N pl and N pp was used. Assuming 100% yield,
J 5 16.0 and 9.0 Hz), 4.46 (d, 1H, cis N-CH5CHH, J 5 9.0 Hz),
.42 (d, 1H, trans N-CH5CHH, J 5 16.0 Hz), 3.56 (td, 1H, CO-
4
3
3
N-CHH, J 5 10.0 and 3.0 Hz), 3.41 (dt, 1H, CO-N-CHH,
J 5 10.0 and 8.0 Hz), 2.77–2.71 (m, 1H, CH-CO), 2.66 (ddd,
1
CH, J 5 17.0, 4.5, and 2.5 Hz), 2.41–2.34 (m, 1H, CO-CH-
CHH), 2.08–2.00 (m, 1H, CO-CH-CHH), 1.97 (t, 1H, C-CH,
a 0.1 g/mL THF solution was prepared for the next
reaction.
H, CHH-C-CH, J 5 17.0, 4.5 and 2.5), 2.48 (ddd, 1H, CHH-C-
2
1
FTIR (cm ): 2978, 2933, 2814, 2099, 1692, 1457, 1416,
365, 1281, 1241, 1167, 1126, 1004, 931, 866, 769.
1
1
100
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1
3
J 5 2.5 Hz). C RMN (CDCl , 125 MHz): d 5 172.96 (NCO),
54.48 (N-CH -(CH ) -CH ), 47.75 (CH-N-CH -CH ), 42.79 (CO-
2 2 3 2 2 2
3
1
7
29.39 (N-CH5CH ), 94.70 (N-CH5CH ), 80.93 (CꢀCH),
N-CH ), 42.64 (CO-CH), 26.47 (CO-CH-CH ), 25.97 (N-CH -
2 2 2
2
2
0.00 (CꢀCH), 42.81 (CO-N-CH ), 41.36 (CO-CH), 23.40 (N-
CH -CH -CH ), 24.12 (N-(CH ) -CH -(CH ) ), 23.41 (N-CH -
2 2 2 2 2 2 2 2 2
2
2
1
21
CH -CH ), 20.21 (CH -CꢀCH). FTIR (cm ): 3293, 3252,
CH ). FTIR (cm ): 2933, 2851, 2781, 1697, 1631, 1551,
2
2
2
2
2
8
1
886, 2117, 1694, 1629, 1427, 1389, 1328, 1315, 1268, 980,
51. HRMS (ESI, m/z): [M 1 H] calculated for C
50.0913, found 150.0914.
1428, 1390, 1327, 1269, 1045, 982, 851. HRMS (ESI, m/z):
1
1
9
H
11NO
[M 1 H]
calculated for C H N O 304.2137, found
16 25 5
304.2132.
Aminated N-Vinyl-2-Pyrrolidone Compounds
VP-gyl (2.00 g, 13.4 mmol) and sodium L-(1)-ascorbate
0.53 g, 2.68 mmol) were added to THF (10 mL). Separately,
Tert-Butyl 4-(2-(4-((1-Vinyl-2-pyrrolidon-3-yl)methyl)-
H-1,2,3-Triazol-1-yl)ethyl) Piperazine-1-Carboxylate
VPcpz-Boc) (9)
1
(
(
copper(II) sulfate pentahydrate (1.02g, 4.02 mmol) was dis-
solved in deionized water (6 mL). These two solutions were
added at the same time to 20 mL of the azido tertiary amine
compound solution (N -pl, N -pp, or N -pz-Boc) in THF pre-
1
(
Yield: 80%) H NMR (CDCl , 500 MHz): d 5 7.48 (s, 1H, C-
3
CH-N), 7.05 (dd, 1H, N-CH5CH , J 5 16.0 and 9.0 Hz), 4.44–
2
4
.35 (m, 4H, CH-N-CH2 and N-CH5CH ), 3.40–3.33 (m, 6H,
2
3
3
3
CH -NCOOtBu-CH2 and CO-N-CH ), 3.17 (dd, 1H, CHH-C,
2
2
viously prepared (13.4 mmol of azocompound) under stir-
ring at 30 8C. After 24 h, the reaction was quenched adding
J 5 10 and 4.5 Hz), 3.00 (dd, 1H, CHH-C, J 5 15.0 and 7.5
Hz), 2.95–2.89 (m, 1H, CH-CO), 2.79 (t, 2H, CH-N-CH -CH
J 5 6.0 Hz), 2.41–2.38 (m, 4H, CH -CH -NCOOtBu-CH -CH ),
2
2
,
5
mL of MeOH and left stirring for 10 min. Then, 50 mL of
2
2
2
2
an aqueous solution Na CO3 0.1 M was added, followed by
2
2
.33–2.27 (m, 1H, CO-CH-CHH), 2.00–2.92 (m, 1H, CO-CH-
50 mL of chloroform. The aqueous layer was then extracted
13
CHH), 1.47–1.43 (m, 9H, NCOOtBu). C RMN (CDCl , 125
3
twice with chloroform (30 mL). The organic layers were
combined and dried over anhydrous sodium sulfate. The sol-
vent was evaporated under reduced pressure and purified
by column chromatography using aluminum oxide as station-
ary phase and hexane/ethyl acetate/triethylamine (4:4:1) as
eluent.
MHz): d 5 174.03 (NCO), 154.62 (NCOOtBu), 144.49 (C-CH-
N), 129.27 (N-CH5CH2), 122.63 (C-CH-N), 94.63 (N-
CH5CH ), 79.74 (NCOOC(CH ), 57.50 (CH-N-CH -CH ), 52.83
2
3
2
2
(
(
CH
CH
2
-CH
-CH
2
2
-NCOOtBu-CH
-NCOOtBu-CH
2
-CH
-CH
2
2
), 47.55 (CH-N-CH
2
-CH
), 42.58 (CO-
2
), 45.66
2
2
), 42.77 (CO-N-CH
2
CH), 28.38 (NCOOC(CH ) ), 26.35 (CO-CH-CH ), 23.35 (N-
3
3
2
2
1
CH -CH ). FTIR (cm ): 2933, 2859, 2818, 1690, 1633,
3
-((1-(2-(Pyrrolidin-1-yl)ethyl)21H-1,2,3-triazol-4-
2
2
1
551, 1458, 1424, 1391, 1365, 1328, 1276, 1249, 1170,
yl)methyl)21-Vinyl-2-Pyrrolidone (VPcpl) (7)
1
1
1130, 1048, 1005, 865, 770. HRMS (ESI, m/z): [M 1 H] cal-
(
Yield: 90%) H NMR (CDCl
3
, 500 MHz): d 5 7.47 (s, 1H, C-
culated for C H N O 405.2609, found 405.2609.
CH-N), 7.06 (dd, 1H, N-CH5CH , J 5 16.0 and 9.0 Hz), 4.43–
20 32
6 3
2
4
.35 (m, 4H, CH-N-CH and N-CH5CH ), 3.34 (dd, 2H, CO-N-
2 2
Polymerization Reactions
CH , J 5 9.0 and 5.5 Hz), 3.18 (dd, 1H, CHH-C, J 5 14.5 and 4
2
All polymers were synthesized using a conventional free rad-
ical polymerization procedure: monomers and initiator
Hz), 3.00–2.90 (m, 4H, CHH-C, CH-CO, and CH-N-CH -CH ),
2
2
2
.53–2.50 (m, 4H, N-CH -(CH ) -CH ), 2.33–2.27 (m, 1H, CO-
2 2 2 2
(
1
AIBN) were dissolved in 1,4-dioxane at concentrations of
CH-CHH), 2.00–1.93 (m, 1H, CO-CH-CHH), 1.78–1.75 (m, 4H,
2
2
1
3
.0 mol/L and 1.5 3 10
mol/L, respectively. Gaseous N2
N-CH
2
-(CH
2
)
2
).
3
C RMN (CDCl , 125 MHz): d 5 174.10
was flushed through the solutions for 20 min. The polymer-
ization reactions were performed at 60 8C during 24 h to
attain total conversion. Copolymers of VP and the modified
VPs were prepared using four different molar monomer feed
ratios FVPcpx of 0.2, 0.4, 0.6, and 0.8, being VPcpx VPcpl,
VPcpp, or VPcpz-Boc (see Scheme 2). The obtained copoly-
mers have been labeled as poly (VP-co-VPcpx)-Z, being Z the
nominal molar percentage of the aminated unit (i.e., 20, 40,
(
NCO), 144.50 (C-CH-N), 129.30 (N-CH5CH ), 122.48 (C-CH-
2
N), 94.56 (N-CH5CH ), 55.51 (CH-N-CH -CH ), 54.06 (N-CH -
2
2
2
2
(CH ) -CH ), 49.33 (CH-N-CH -CH ), 42.79 (CO-N-CH ), 42.60
2 2 2 2 2 2
(CO-CH), 26.49 (CO-CH-CH2), 23.55 (N-CH -(CH ) -CH ),
2 2 2 2
2
1
2
1
3.42 (N-CH -CH ). FTIR (cm ): 2957, 2879, 2798, 1698,
2 2
632, 1550, 1428, 1389, 1327, 1270, 1048, 981, 851. HRMS
1
(
ESI, m/z): [M 1 H] calculated for C H N O 290.1979,
15 23 5
found 290.1975.
6
0, or 80). Homopolymers were also synthesized. The molar
3
-((1-(2-(Piperidin-1-yl)ethyl)21H-1,2,3-Triazol-4-
fractions of VPcpl, VPcpp, and VPcpz-Boc (fVPcpx) in the
copolymers were determined by H NMR in CDCl . These
compositions were calculated comparing the area of the CH-
2
N-CH band (corresponding to the k band in Fig. 2) with
that of the group of signals between 2.50 and 4.30 ppm,
using the following equations:
yl)methyl)21-Vinyl-2-Pyrrolidone (VPcpp) (8)
1
3
1
(Yield: 82%) H NMR (CDCl
3
, 500 MHz): d 5 7.50 (s, 1H, C-
CH-N), 7.06 (dd, 1H, N-CH5CH , J 5 16.0 and 9.0 Hz), 4.44–
2
4.35 (m, 4H, CH-N-CH2 and N-CH5CH ), 3.37–3.31 (m, 2H,
2
CO-N-CH ), 3.18 (dd, 1H, CHH-C, J 5 14 and 3.5 Hz), 3.00–
2
2.89 (m, 2H, CHH-C and CH-CO), 2.44–2.38 (m, 4H, N-CH2-
A4:5-4:75 2HVPcpx
55HVP112HVPcpl
(1)
(2)
(
1
1
CH ) -CH ), 2.26–2.33 (m, 1H, CO-CH-CHH), 2.03–1.92 (m,
2
3
2
H, CO-CH-CHH), 1.60–1.53 (m, 4H, N-CH
2 2 2 2
-CH -CH -CH ),
1
3
A
2:50-4:30
.44–1.40 (m, 2H, N-(CH ) -CH . C RMN (CDCl , 125 MHz):
2
2
2
3
d 5 174.09 (NCO), 144.40 (C-CH-N), 129.33 (N-CH5CH2),
1
22.61 (C-CH-N), 94.53 (N-CH5CH ), 58.29 (CH-N-CH -CH ),
2:50-4:30
A 55HVP18HVPcpp
(3)
2
2
2
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A2:50-4:3055HVP112HVPcpz-Boc
HVPcpx
(4)
(5)
fVPcpx5
100
HVPcpx1 HVP
A schematic representation of the polymerization is shown
in Scheme 2.
Homopolymers and copolymers from VPcpl and VPcpp were
isolated and purified by dialysis in water using membranes
of cut-off 1000 Da, followed by freeze drying.
Homopolymer and copolymers from VPcpz-Boc were isolated
and purified by several precipitation–solution–precipitation
cycles in diethylether–chloroform–diethylether. Deprotected
poly-VPcpz and poly(VP-co-VPcpz) were prepared from the cor-
responding VPcpz-Boc polymers by reaction with an excess of
trifluoroacetic acid (CF COOH/VPcpz 4:1 molar ratio) in CH Cl
3
2
2
at room temperature. After 15 h, the solvent was removed at
low pressure and the residue obtained was dissolved in 5 mL
of water, the pH adjusted to 7 with 1 M NaOH and the poly-
mers were isolated and purified by dialysis in water using
membranes of cut-off 1000 Da, followed by freeze drying.
SCHEME 2 Synthesis of poly vinylpyrrolidones carrying pyrrol-
idine (VPcpl), piperidine (VPcpp), or piperazine (VPcpz-Boc and
VPcpz) groups.
Methods and Characterization
Thin layer chromatography (TLC) was performed on alumi-
num sheets 60 F254 Merck silica gel and compounds were
visualized by irradiation with UV light and/or by treatment
with a solution of Ninhydrin in n-BuOH/EtOH or H
5%) in EtOH followed by heating. Flash chromatography
was performed using thick walled columns, using silica gel
2 4
SO
(
1
FIGURE 1 H NMR spectra of the modified vinylpyrrolidone monomers in CDCl
3
.
1
102
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TABLE 1 Characterization of the Synthesized Polymers
Poly(VP-co-VPcpl)
trometer. Fourier Transform Infrared (FTIR) spectra were
recorded on a Perkin Elmer RX-1 instrument with a Univer-
sal Attenuated Total Reflectance (ATR) device using dia-
mond/ZnSe as internal reflection elements.
M
n
Buffering
T
g
a
b
b
c
d
F
VPcpl
f
VPcpl
(kDa)
DI
Region
(8C)
Raman spectra were recorded on a Renishaw InVia Reflex
Raman system. An optical microscope is coupled to the sys-
tem. The Raman scattering is excited using a diode laser at a
wavelength of 785 nm. The laser beam is focused on the
sample with a 0.75 503 microscope objective. The laser
power, exposure time, and number of accumulations corre-
spond to 320 mW, 10 s, and 5, respectively.
0
0
0
0
1
.2
.4
.6
.8
.0
0.18
0.43
0.54
0.78
1.00
46.2
46.4
44.0
41.9
33.4
1.54
1.65
1.75
1.78
1.72
8.8–8.9
8.3–9.2
7.7–9.2
7.5–9.1
7.0–9.0
125
105
89
83
72
Poly(VP-co-VPcpp)
The number-average molecular weight (M ) and polydisper-
n
M
n
Buffering
T
g
sity index (DI) of the polymers were measured by gel perme-
a
b
b
c
d
F
VPcpp
f
VPcpp
(kDa)
DI
Region
(8C)
ation chromatography (GPC) with
chromatographic system equipped with a Waters model
414 refractive index detector, using Styragel (300 3
.8 mm, 5 lm nominal particle size) HR3 and HR5 water
a
Perkin Elmer
0
0
0
0
1
.20
.40
.60
.80
.00
0.17
0.44
0.60
0.83
1.00
42.9
39.2
36.7
28.2
23.2
1.46
1.44
1.49
1.52
1.51
8.7–8.8
8.0–8.8
8.0–8.7
7.7–8.5
7.5–8.5
126
109
102
91
2
7
columns. DMF with 1 wt % LiBr was used as eluent. Meas-
urements were performed at 70 8C at a flow rate of 0.7 mL/
min using a polymer concentration of 4 mg/mL. The calibra-
tion was performed with monodispersed polystyrene stand-
ards in the range of 2.0 and 9000.0 kDa.
77
Poly(VP-co-VPcpz-Boc)
M
n
Buffering
c,e
T
g
g
The glass transition temperature (T ) of the polymers was
a
b
b
d,e
F
VPcpz-Boc
f
VPcpz-Boc
(kDa)
DI
Region
(8C)
determined by Differential Scanning Calorimetry (DSC) using a
Perkin-Elmer DSC-7 calorimeter. Thermal transition temperature
measurements were conducted by heating the samples from 30
0
0
0
0
1
.20
.40
.60
.80
.00
0.19
0.36
0.58
0.78
1.00
41.9
42.3
45.7
48.3
63.3
2.10
2.15
1.94
1.82
1.49
>9.0
>8.0
>8.0
>8.0
>8.0
157
145
125
112
105
to 180 8C at 20 8C/min. T was estimated form the inflexion
g
point of the second run. Typical sample weights were 8–10 mg.
The dissociation constant (pK ) values of the polymers were
a
determined by acid–base titration of 5 mg of polymer in
5 mL aqueous 0.15 M NaCl. An aqueous solution of NaOH
a
b
c
1
Calculated by H NMR analysis.
Determined by GPC in DMF with LiBr 1%.
Determined by acid–base titration with NaOH 0.1 M.
(
0.1 M) was used to carry out the titration using small
d
e
amounts (20 lL) to avoid the modification of the ionic
strength. Initially, a small volume of HCl (1 M) was added to
ensure the ionization of the amine groups (around pH 3.0).
Determined by DSC (T
Experiment performed on the deprotected polymers P(VP-co-VPcpz).
g
PVP: 170 8C).
V
R
(
(
Merck 60) or deactivated aluminum oxide, Brockmann II
Aldrich).
The changes of pH were measured with a SCHOTT Instru-
ments handylab pH11 pH-meter.
1
13
Monomers H NMR and C NMR spectra were recorded on a
The LCST of the aqueous polymer solutions was determined
measuring the optical transmittance at 600 nm wavelength in
several buffer solutions at different pH (7, 7.4, 8, and 9 per-
formed in phosphate buffer solution, while the pH 10 measure-
ment was performed in ammonia buffer solution). The
measurements were accomplished using a polymer concentra-
tion of 2 mg/mL. The analysis was performed in a UV–visible
spectrometer Cary 3 BIO-Varian. The temperature was gradually
increased from 5 to 85 8C at a heating rate of 1 8C/min. The
LSCT was estimated as the temperature at 50% transmittance.
1
VARIAN NMR system (400 and 500 MHz for H, and 100 and
25 MHz for C, respectively) using CDCl as solvent at room
temperature and trimethylsilane (TMS) as the internal stand-
ard. Chemical shift values (d) are reported in parts per million
ppm) relative to TMS. Coupling constants (J values) are
reported in Hertz (Hz), and spin multiplicities are indicated
by the following symbols: s (singlet), d (doublet), t (triplet), q
quartet), dd (doublet of doublets), dt (doublet of triplets),
ddd (doublet of doublet of doublets), td (triplet of doublets),
and m (multiplet or unresolved). The H NMR spectra of the
polymers were measured on an Inova 300 spectrometer (300
MHz) using CDCl3 or D O as solvents at room temperature
and trimethylsilane (TMS) as the internal standard.
1
3
1
3
(
(
1
The compositional variation of the copolymerization reac-
tions versus the conversion has been described theoretically
2
3
2
using the software Copol, assuming that the copolymeriza-
tion is governed by the terminal model, and using the reac-
3
3
Mass spectrometry (MS) analyses were performed as high
resolution ESI measurements on a VG AutoSpec mass spec-
tivity ratios from a similar reaction of literature.
The
terminal model considers the reactivity of the growing chain
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1
FIGURE 2 H NMR spectra of the functionalized polyvinylpyrrolidone copolymers with FVPcpx 5 0.4.
to depend on the nature of the terminal unit, and in the case
of binary copolymerizations needs two parameters—namely,
the reactivity ratios—to describe the reaction. These reactiv-
ity ratios are given by eqs 6 and 7,
sized products are reported in supporting information (Sup-
porting Information Figs. 1.1–3), where an intense band
21
appears around 2100 cm
corresponding to the azide
groups. Then, using CuAAC click reactions under mild condi-
tions (30 8C and 24 h), the aminated vinylpyrrolidones were
obtained in high yields (always higher than 80%).
k11
r15
r25
(6)
(7)
k12
k22
1
Figure 1 shows the H NMR spectra of the synthesized vinyl-
pyrrolidone derivatives, using a VP spectrum at the bottom
as a reference. VP-gyl, VP modified with a propargyl group,
was obtained in a 62% yield and its proton spectrum is
characterized by a C-CH proton at 1.97 ppm and the splitting
of the protons in the lactame cycle due to the mono-
alkylation. After the click reaction with the different azides, a
singlet at 7.50–7.45 ppm appears indicating clearly the 1,2,3-
triazole ring formed in each case. Comparing the spectra of
VPcpl, VPcpp, and VPcpz-Boc, the peaks corresponding to the
lactame cycle are maintained, as well as the vinyl group nec-
essary for its subsequent polymerization. Figure 1 shows the
assignments of the different protons.
k21
where k (i, j 5 1, 2) is the rate constant for the addition of a
ij
monomer M to a propagating chain end ꢁM . A reactivity
j
i
ratio value r
1
higher or lower than 1, means that a growing
chain end ꢁM
1
is more reactive towards monomer 1 or 2,
respectively. This terminal model can be used for the
description of these systems having in mind that it is an
3
4
approximation to the reality.
RESULTS AND DISCUSSION
Three new aminated monomers based on N-vinylpyrrolidone
have been synthesized using CuAAC click chemistry. On one
hand, VP monomer functionalized with an alkyne group (VP-
1
Figure 2 shows the H NMR spectra of the three copolymers
synthesized with
a
nominal feed molar fraction of
1
3
gyl), whose synthesis have been previously reported
Scheme 1), was used as alkyne precursor. On the other
FVPcpx 5 0.4, selected as example. A spectrum of pure PVP is
shown at the bottom as a reference. One band at 7.70–7.40
ppm indicated the presence of the triazole in the polymers,
as well as a band at 4.60–4.40 corresponding to the methyl-
ene group next to the triazole (k) moiety. In addition, the
rest of the highlighted signals in the figure show the success-
ful synthesis of the polymers with the corresponding amine
in the side chain of each PVP. The copolymer composition,
(
hand, azido compounds carrying pyrrolidine (N -pl), piperi-
3
dine (N -pp), and a protected piperazine (N -pz-Boc) group
3
3
were obtained by substitution of a leaving group (chloride
or tosylate group). For security reasons, these intermediates
were not isolated due to the high reactivity of these low
molecular weight azido compounds. IR spectra of the synthe-
1
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the copolymers than for their respective homopolymers,
except for VPcpz-Boc polymers. Polydispersity indexes
between 1.4 and 2.0 were obtained, typical of the conven-
tional free radical polymerization used in this work.
The T s of the prepared polymers are included in Table 1.
g
The T s of statistical copolymers and miscible polymers are
g
normally predicted using the Fox equation:
1
w1
w2
5
1
(8)
Tg Tg1 Tg2
where T 1 and T 2 are the T of the corresponding homopol-
g
g
g
ymers, and w and w are the weight fractions of the compo-
1
2
nents. Polymer DSC analysis was performed comparing the
s with theoretical T values calculated using the Fox equa-
tion considering VP as component 1 (which T is 170 8C)
T
g
g
g
and the aminated VP as component 2 (whose T s are 72, 77,
g
and 101 8C for the homopolymers poly-VPcpl, poly-VPcpp,
and poly-VPcpp-Boc, respectively).
The obtained Tg for all copolymers in each aminated VP
series decreases linearly when increasing the amount of the
modified component in the copolymer. This behavior is con-
sistent with the Fox equation. However, theoretical Tgs
obtained by the Fox equation mismatched with the obtained
Tgs in poly(VP-co-VPcpz) polymers, approaching the theoreti-
cal values when increasing the functionalized composition,
(
see Supporting Information Fig. S3). This behavior could be
FIGURE 3 LCST values of pyrrolidine (poly(VP-co-VPcpl),
above) and piperidine (poly(VP-co-VPcpp), below) polymers
versus amine composition in the polymer under different pH
values. LCST values were determined at 50% transmittance.
due to the possible formation of intra and intermolecular
hydrogen bonding between secondary amines.
Thermo- and pH-Responsive Behavior
[
Color figure can be viewed in the online issue, which is avail-
The aminated PVPs display pH sensitivity due to the presence
of secondary and tertiary amines in their structure, exhibiting
buffering regions of 8.0–9.2 for VPcpl polymers, 7.8–8.8 for
VPcpp polymers, and higher than 8.0 for VPcpz polymers (see
Supporting Information Fig. S4). The range of the polymers
buffering region depends on the nature of the amine groups,
able at wileyonlinelibrary.com.]
calculated as indicated in the experimental section, agrees
well with the nominal feed composition indicating that both
units are properly incorporated to the polymeric chains (see
Table 1). The copolymers synthesized from VP and VPcpz-
Boc were treated with CF COOH in CH Cl to deprotect the
3
5,36
on the so-called polyelectrolytic effect
and on the copoly-
mer composition (amine content). The higher the amine
3
2
2
piperazine rings in the polymer, disappearing completely the
bands from the protecting group (p protons) at 1.80–1.40
ppm. The spectra of the deprotected VPcpz polymers are
included in supporting information (Supporting Information
Fig. S2).
The polymers were also characterized using Infrared and
Raman spectroscopy, where a characteristic band around
21
1
550 cm demonstrates the presence of the triazole group.
Its intensity is more sensitive in Raman than in Infrared
spectroscopy. Infrared and Raman characterization of these
homopolymers and copolymers are included in supporting
information (Supporting Information Fig. S2).
The molecular weights of the polymers and the molecular
weight distributions were obtained from the GPC measure-
ment using DMF with LiBr (1 wt %) as the eluent. The
FIGURE 4 Theoretical instantaneous copolymer molar fraction
results are listed in Table 1 showing a higher average M for
of VPcpx versus the conversion.
n
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FIGURE 5 Thermal response of the VPcpl (right) and VPcpp (left) polymers at pH 8 (above), and thermal response of poly(VP-co-
VPcpl)280 copolymer (left) and poly(VP-co-VPcpp)280 copolymer (right) at different pH values (below). [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
content, the broader the buffering region. Polymers carrying
piperazine groups showed wider pKa ranges than polymers
modified with pyrrolidine and piperidine groups, due to the
presence of a secondary amine in its structure in addition to
the tertiary amine. This large buffering region may be of inter-
est in gene therapy applications of these polymers as non-
viral vectors, by participating in the so-called “proton sponge
occurs. For each copolymer system, the thermosensitivity
clearly depends on the composition and pH (see Fig. 3).
On one hand and for a given pH, the higher is the content of
unmodified VP (which is more hydrophilic than the modified
aminated units), the higher is the LCST. Similar composi-
tional dependencies have been described for other systems
in which thermosensitive units had been copolymerized with
3
7
effect.” The polymers bearing pendant pyrrolidine or piperi-
dine groups also exhibit a cloud point during the titration
1
6–21
hydrophilic units.
It has to be noted that this depend-
ence is not linear. The higher the amine content, the less
pronounced the variation of the LCST. This behavior may be
related, to some extent, to the compositional heterogeneity
of the chains as it has been described for similar couples
(
performed at room temperature), which has been related to
a temperature-induced phase transition of the polymers (LCST
phenomenon). Therefore, a complete study of the thermosen-
sitivity was performed by turbidimetric measurements in pH
buffer solutions as described in Experimental section. Figure
(
VP/VP modified in 3 position with CH -R groups) that
2
3
3
unmodified VP is slightly more reactive. Assuming that the
reaction can be compositionally described by the terminal
model and using the reactivity ratios from ref. 15, which
have also been determined in dioxane, the Copol software
can theoretically describe the reaction in terms of instanta-
3
collects all LCST values.
PVP with pendant piperazine groups did not displayed any
observable thermosensitivity in any buffer conditions. This
behavior may be related to the presence of an additional sec-
ondary amine moiety that shifts the hydrophilic/hydrophobic
balance to a scenario of total aqueous solubility in the
observable region.
3
2
neous copolymer composition versus the conversion.
Figure 4 shows that the higher the initial feed FVPcpx, the
higher the compositional heterogeneity. This tendency may
explain—to some extent—the non-lineal shape of the graphs
in Figure 3. If a heterogeneous collection of chains exists, the
turbidimetry may mainly be related to the chains with
higher amine content (because these chains suffer the
Copolymers and homopolymers of VPcpl and VPcpp did
show LCST at pH 7 or higher. Below this critical temperature,
the polymers are soluble. Above the LCST, inter- and/or
intra-molecular interactions dominate and phase separation
1
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transition at lower temperatures than the rest of the chains).
The shape of the curves would then be related to the higher
deviation of the curves from the nominal values at increasing
cyclic structure and the composition. The thermosensitivity
exhibited by the copolymer with only a 20 mol % of piperi-
dine is remarkable, and may indicate a participation of VP
units in the LCST phenomenon.
FVPcpx
.
On the other hand and for a given composition, the higher
the pH, the lower is the LCST. This behavior has also been
3
8
found in similar alkylated tertiary amines and is related to
the protonation, which increases the hydrophilia and hinders
the polymer–polymer interactions responsible for the phase
separation. Selected turbidimetric graphs have been depicted
in Figure 5 showing these dependences on composition and
pH: the upper graphs show the turbidimetric studies of
copolymers with different compositions for a selected pH
ACKNOWLEDGMENTS
The authors gratefully acknowledge support from the grants
ref. MAT-2010-20001 and MAT2013-42957-R. A. del Prado
acknowledges the Ministry of Economy and Competitiveness,
Spain, for the FPI grant. R. Navarro gratefully acknowledges
funding from the Spanish Research Council (CSIC) and Euro-
pean Social Fund (ESF) through the JAE-doc program.
(
8), while the lower graphs show the influence of the pH for
a selected composition (FVPcpx 5 0.8). The abrupt transition
observed for most of the systems has to be noted.
REFERENCES AND NOTES
When comparing both copolymeric systems, remarkable dif-
ferences have been found. The copolymers carrying piperi-
dine moieties (the VPcpp system) exhibited for each pH
lower LCST values than the system bearing pyrrolidine moi-
eties (the VPcpl system). This is in agreement with the
higher hydrophobicity of the piperidine cycle which has one
more methylene group in its structure. In addition, the LCST
values of the VPcpp system did not change when pH
increased from 9 to 10, which may indicate that the piperi-
dine system is totally deprotonated at pH 9, having the same
interactions at both pHs. Moreover, it has to be noted that
the poly(VP-co-VPcpp)220 copolymer exhibited thermosensi-
tivity despite of the very low content of sensitive units,
whereas poly(VP-co-VPcpl)220 which is homologous in com-
position did not show a LCST at any condition. This behavior
of the VPcpp system may suggest a participation of the
amphiphilic VP structure in the polymer–polymer interac-
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