Facile synthesis of temperature- and pH-responsive dendritic-linear-dendritic copolymer

Article abstract of DOI:10.1246/cl.160215

Dendritic-linear-dendritic triblock copolymers have attracted much attention due to their unique topology and special features. However, facile methods are still necessary to synthesize uniform dendritic-linear-dendritic copolymers. Here, we report an eff

Full text of DOI:10.1246/cl.160215

Received: March 1, 2016 | Accepted: March 25, 2016 | Web Released: June 5, 2016
CL-160215
Facile Synthesis of Temperature- and pH-responsive Dendritic­Linear­Dendritic Copolymer
Xiao-Man Xu, Ze Zhang, and Ye-Zi You*
Key Lab of Soft Matter Chemistry, Chinese Academy of Sciences, Department of Polymer Science and Engineering,
University of Science and Technology of China, Hefei 230026, Anhui, P. R. China
(
E-mail: yzyou@ustc.edu.cn)
Dendritic­linear­dendritic triblock copolymers have attracted
much attention due to their unique topology and special features.
However, facile methods are still necessary to synthesize uniform
dendritic­linear­dendritic copolymers. Here, we report an
effective strategy for the synthesis of a temperature- and pH-
responsive dendritic­linear­dendritic poly(amido amine)-poly(N-
isopropylacrylamide)-poly(amido amine) (PAMAM-PNIPAM-
PAMAM), and evaluate the temperature- and pH-responsive
properties of PAMAM-PNIPAM-PAMAM.
S
S
NIPAM, AIBN
S O NH
NH
O
S
S
S
S
S
10
10
S
S
n
nS
S
1
0
10
(
1). n-Butylamine
2). Methyl acrylate
(
O
S
NH
n
NH
O
O
O
O
NH
n
NH O
H2N
NH2
O
O
N
S
N
n
O
S
H
H
S
O
n
G 0
A,B
A: Methyl acrylate, 35 °C
B: Ethanediamine, 35 °C
A,B
H2NH2N NH2
H2N
A,B
H2N NH2NH2
NH2
G 1.0
H2N
A,B
NH2
NH2
Keywords: Dendrimer
|
Dendritic–linear–dendritic copolymers |
H2N
H2N
G 2.0
N
N
A,B
N
N
G 3.0
NH2
Temperature and pH responsivity
N
N
H2N
H2N
H2N
H2N
H2N
N
G 4.0
N
NH2
N
N
NH2
NH2
N
N
N
N
N
N
NH2
NH2
NH
N
N
Discovering novel and facile methods to prepare polymers
with different topologies has become one of the focus areas of
polymer chemistry due to the fact that topology has a significant
N
N
H2N
H2N
N
N
2
N
N
NH2
N
O
S
NH
N
NH O
H2N
H2N
N
N
N
O
O
NH2
N
N
N
N
N
NH2
NH2
NH2
N
n
S
N
H2N
N
N
H
n
H
N
N
1
H2N
N
N
influence on polymer properties. Owing to their compact
H2
N
N
N
N
N
N
N
NH2
H2N
N
N
NH2
H2N
H2N
H2N
N
N
NH
NH
structure and numerous functional groups, dendrimers have wide
2
N
N
2
2­4
NH2
potential applications in many fields. Various dendrimer-like
H2N
N
N
NH
H2N
H2N
H2
N
N
NH
2
2
5
­8
N
N
NH2
NH2
NH2
NH2
polymers have been synthesized to mimic dendrimers.
N
H2N
N
N
N
N
H2N
Compared with dendrimers, dendritic­linear­dendritic copoly-
mers have some special properties because the linear block can
endow them with some unique features, leading to numerous
H2N
H2N
NH
NH
2
NH2
NH2
2
G 5.0
9
­12
applications in gene and drug delivery.
Figure 1. Synthetic route of PAMAM-PNIPAM-PAMAM G 5.0.
Based on these reported dendritic­linear­dendritic copoly-
mers, synthetic strategies can be generally divided into three
categories. (1) Coupling method, linear polymer chain reacts
with a reactive dendron, which requires strict reaction conditions,
and the uniform dendritic­linear­dendritic copolymer cannot
formed PNIPAM with two thiol ends (HS-PNIPAM-SH).23,24
Then, the thiol was ready to react with methyl acrylate in very
high efficiency via the Michael addition reaction,
2
5,26
forming
be obtained because some unreacted dendrons remain in the
PNIPAM with two methyl ester ends (MA-PNIPAM-MA).
Amine-capped PNIPAM (NH2-PNIPAM-NH2) was obtained by
the amidation of MA-PNIPAM-MA with ethanediamine. At last,
PAMAM-PNIPAM-PAMAM G 5.0 was synthesized using NH2-
PNIPAM-NH2 as the linear block through iterative multistep
reactions of Michael addition with methyl acrylate followed by
amidation with ethanediamine. Using this method, well-defined
dendritic­linear­dendritic polymers can be easily synthesized.
Because each step has very high efficiency, the resulting
PAMAM-PNIPAM-PAMAM is uniform.
product.1
3­15
(2) Macro reagent method, two dendrons are
connected by a small molecular initiator or chain transfer reagent
to form macro reagents, and the macro reagents were used in
controlled radical polymerizations to form dendritic­linear­
dendritic copolymers. However, the formation of a uniform
macro reagent is very difficult because it is very hard to remove
1
6,17
unreacted dendrons.
(3) Divergent method, the linear
polymer block with dendritic blocks at both ends is prepared
9­12,18­22
through iterative multistep reactions.
The popularity of
the divergent method is limited due to the lack of a convenient
way to introduce more functional polymers as the linear block.
Here, we combined reversible addition­fragmentation chain
transfer (RAFT) polymerization and the divergent method for
the synthesis of temperature- and pH-responsive dendritic­
linear­dendritic PAMAM-PNIPAM-PAMAM, as shown in
Figure 1. 1,2-Phenylenebis(methylene) didodecyl dicarbonotri-
thioate with two trithiocarbonate units was first used as the RAFT
agent in the polymerization of N-isopropylacrylamide (NIPAM),
producing poly(N-isopropylacrylamide) (PNIPAM) with two
trithiocarbonate units at both ends. Subsequently, treating the
PNIPAM with two trithiocarbonate ends using n-butylamine
RAFT polymerization of NIPAM using 1,2-phenylene-
bis(methylene) didodecyl dicarbonotrithioate as the chain transfer
agent was carried out at 70 °C, producing PNIPAM with two
trithiocarbonate ends (Figure 2A). Two PNIPAMs were synthe-
sized, and the degrees of polymerization (DPs) of the PNIPAMs
were 60 and 90 respectively, which were calculated based on
1
H NMR (Figure 2B) by comparing the protons integral values of
the CH2 neighbored S atom at 3.4 ppm to the pendent methine
of the PNIPAM at 3.9­4.1 ppm. According to the GPC curves
shown in Figure 3, the number-average molecular weight values
(7900 and 11900) were in agreement with the DPs based on
1
H NMR analyses, and the polydispersity indexes (PDIs) of the
Chem. Lett. 2016, 45, 679–681 | doi:10.1246/cl.160215
© 2016 The Chemical Society of Japan | 679

reaction of thiol with methyl acrylate was at such a high rate that
the oxidative coupling reaction of thiols may have been sup-
pressed. According to the GPC curves of the MA-PNIPAM-MA
shown in Figure 3, no shoulder peak appeared at the higher
molecular weight position, indicating that there was no combi-
S
S
c
h
j
S
S
S
S
h
1
0
i
10
b
c
a
1
j
nation of two thiols via oxidate coupling. In its H NMR
A
B
spectrum shown in Figure 2C, it is clear that the peak
corresponding to dodecyl units disappeared while a new peak
corresponding to methyl ester appeared, suggesting that methyl
acrylate terminals have been linked onto the PNIPAM. The
conversion of the thiol-Michael addition reaction, calculated by
comparing the protons integral values of the CH3 unit of methyl
acrylate to the pendent methine proton of NIPAM at 3.9­4.1 ppm,
was ca. 100%, indicating that almost all of the thiols had reacted
with methyl acrylate. Subsequently, NH2-PNIPAM-NH2 was
obtained by the amidation of MA-PNIPAM-MA with ethanedi-
a,b
g
acetone
i
g
f
O
S
NH
n
NH O
S
S
c
h
j
10S
e n
S
S
i 10
d
f
b
d
a
f
M
e
a,b
h
g
6
0.12
O
4.00
g
O
S
NH
n
NH
d
O
1
O
amine. In the H NMR spectrum, the peak of the CH3 unit
c
k
O
e n
S
f
O
corresponding to the methyl ester at 3.7 ppm disappeared
(Figure 2D), suggesting that all of the methyl ester groups had
reacted with ethanediamine. With these two reactions in one-pot,
all of the PNIPAM with two trithiocarbonate ends had been
converted into NH2-PNIPAM-NH2.
b
d
a
C
k
e
a,b
6
f
0.12 5.99
g
g
O
NH
n
NH
d
O
The dendritic­linear­dendritic PAMAM-PNIPAM-PAMAM
was synthesized using NH2-PNIPAM-NH2 as the linear block.
This route consists of two steps alternately repeated to achieve
higher generations as follows the divergent synthesis technique.
In the first step, Michael addition of methyl acrylate with the
primary amine terminal groups results in a tertiary amine branch
point with a methyl ester terminal. In the second step, the methyl
ester terminal group undergoes amidation by ethanediamine to
regenerate the primary terminal groups. Each step was monitored
O
O
c
H
2
N
NH
2
D
N
H
S
e n
S
N
H
b
f
d
a
e
a,b
7
6
5
4
3
2
1
Chemical shift/ppm
Figure 2. 1H NMR spectra of 1,2-phenylenebis(methylene) dido-
decyl dicarbonotrithioate (A), PNIPAM60 (B), MA-PNIPAM60-MA
C), and NH2-PNIPAM60-NH2 (D) in CDCl3.
1
by H NMR and GPC. We measured the molecular weights of
(
PAMAM-PNIPAM-PAMAM G 3.5 and G 4.5 instead of G 4.0
and G 5.0 because PAMAM-PNIPAM-PAMAM G 4.0 and G 5.0
were insoluble in DMF. According to the GPC curves shown
in Figure S12, no new peak appeared and all the PDIs of the
PAMAM-PNIPAM-PAMAM polymers were lower than 1.22,
indicating that all of the products were uniform dendritic­linear­
dendritic polymers.
PNIPAM60 Mw = 7900 PDI = 1.16
PNIPAM90 Mw = 11900 PDI = 1.16
AM-PNIPAM90-MA Mw=10200 PDI =1.18
AM-PNIPAM60-MA Mw = 7100 PDI = 1.21
A
B
In this study, the temperature-responsive behavior of
PAMAM-PNIPAM-PAMAM G 5.0 was determined from the
temperature dependence of the scattering intensity measured at a
1
2
14
16
12
14
16
9
0° scattering angle. This approach permits sensitive determi-
Elusion time/min
Elution time/min
nation of the transition temperature even in polymer solutions of
low concentrations exhibiting low levels of molecular associa-
tion, which may be difficult to capture with the traditional
Figure 3. GPC curves of PNIPAM60 and MA-PNIPAM60-MA (A),
PNIPAM90 and MA-PNIPAM90-MA (B) in DMF.
2
9
method. However, the tertiary amines inside the dendron were
2
,30
not protonated until the pH dropped to 5. Measurements about
the pH-responsive behaviors of PAMAM-PNIPAM-PAMAM G
PNIPAMs were 1.16, suggesting that the polymerization of
NIPAM was well-controlled.
¹
1
5.0 aqueous solution (1 mg mL ) were conducted at 25 °C, as
shown in Figure 4. The tertiary amines inside the dendrons
became nonprotonated when the pH of the solution increased to 8
from 5, and PAMAM dendrons became hydrophobic; therefore,
PAMAM dendrons aggregated into nanoparticles with PNIPAM
stabilizing the particles. We also investigated their temperature-
responsive behaviors at pH 5 and 8, as shown in Figure 5. At
pH 5, the scattering intensity increased with the increase in
temperature, which resulted from that PNIPAM became hydro-
phobic and aggregated, the aggregated nanoparticles were
stabilized by PAMAM dendrons. At pH 8, the tertiary amines
The trithiocarbonate ends can be easily converted into thiol
ends by the aminolysis of the trithiocarbonate units using n-
butylamine, as shown in Figure 1. Subsequently, the thiols
reacted with methyl acrylate affords the desired MA-PNIPAM-
MA.2 Because the aminolysis of the trithiocarbonate functions
and the thiol-Michael addition reaction were both much faster
than the addition of n-butylamine to methyl acrylate, these two
steps can be conducted via a one-pot protocol. In order to avoid
the oxidation of thiols by oxygen, the reaction mixture was
stirred under an argon atmosphere. The thiol-Michael addition
7,28
680 | Chem. Lett. 2016, 45, 679–681 | doi:10.1246/cl.160215
© 2016 The Chemical Society of Japan

A
B
The authors gratefully acknowledge support from the Na-
tional Science Foundation of China (Nos. 51273187, 21374107,
and 21474097) and the Fundamental Research Funds of the
Central Universities (No. WK2060200012).
80
60
40
20
0
8
6
4
0
0
0
20
0
Supporting Information is available on http://dx.doi.org/
1
0.1246/cl.160215.
3
4
5
6
7
8
3
4
5
6
7
8
pH
pH
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PAMAM-PNIPAM-PAMAM G 5.0, indicating that the gener-
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In this study, we have shown a facile method to synthesize
well-defined dendritic­linear­dendritic polymers via RAFT
polymerization, aminolysis of the trithiocarbonate, thiol-Michael
addition reaction, and amidation, followed by continuous
Michael addition and amidation reaction. Also, the temperature-
and pH-responsive behaviors of these polymers were investi-
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Chem. Lett. 2016, 45, 679–681 | doi:10.1246/cl.160215
© 2016 The Chemical Society of Japan | 681