Arm-cleavable microgel star polymers: A versatile strategy for direct core analysis and functionalization

Article abstract of DOI:10.1021/ja505646p

Arm-cleavable microgel star polymers were developed, where the arm chains can readily be cleaved by acidolysis after the synthesis, allowing isolation of the core, direct analysis of its structure, and also the creation of functional nanometer-sized microgels. The key is to employ a macroinitiator (PEG-acetal-Cl) that carries an acetal linkage between a poly(ethylene glycol) arm chain and a chloride initiating site. From this, star polymers were synthesized via the linking reaction with a divinyl monomer and a ruthenium catalyst in living radical polymerization. The arms were subsequently cleaved by acidolysis of the acetal linker to give soluble microgels (cores free from arms). Full characterization revealed that the microgel cores are spherical, nano-sized (<20 nm), and of relatively low density. Amphiphilic, water-soluble, and thermosensitive arm-free microgels can be obtained by additionally employing functional methacrylate upon arm linking.

Full text of DOI:10.1021/ja505646p

Communication
pubs.acs.org/JACS
Arm-Cleavable Microgel Star Polymers: A Versatile Strategy for
Direct Core Analysis and Functionalization
Takaya Terashima,* Saki Nishioka, Yuta Koda, Mikihito Takenaka, and Mitsuo Sawamoto*
Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
S
* Supporting Information
Scheme 1. Arm-Cleavable Microgel Star Polymers for Core
Isolation and Functional Microgel Formation
ABSTRACT: Arm-cleavable microgel star polymers were
developed, where the arm chains can readily be cleaved by
acidolysis after the synthesis, allowing isolation of the core,
direct analysis of its structure, and also the creation of
functional nanometer-sized microgels. The key is to
employ a macroinitiator (PEG−acetal−Cl) that carries
an acetal linkage between a poly(ethylene glycol) arm
chain and a chloride initiating site. From this, star
polymers were synthesized via the linking reaction with a
divinyl monomer and a ruthenium catalyst in living radical
polymerization. The arms were subsequently cleaved by
acidolysis of the acetal linker to give soluble microgels
(cores free from arms). Full characterization revealed that
the microgel cores are spherical, nano-sized (<20 nm), and
of relatively low density. Amphiphilic, water-soluble, and
thermosensitive arm-free microgels can be obtained by
additionally employing functional methacrylate upon arm
linking.
icrogel-core star polymers1−16 are core−shell-type micro-
Mgels in which a core is covered by 10−100 linear polymers
(arms) and thus is isolated from the outer environment and
solubilized, despite a cross-linked network therein. After the first
discovery in living anionic polymerization in the 1960−70s,5−7
microgel star polymers have been synthesized by the arm-linking
method, in which living linear polymers or macroinitiators (or
macromonomers) are locally cross-linked with multifunctional
linking agents (e.g., divinylbenzene) to form microgel cores.
More recently, microgel star polymers10−15 have been revisited
in living radical polymerization17,18 to create functional compart-
ments for efficient and selective molecular recognition11−13,15
and unique catalysis for organic synthesis and polymer-
ization.10,13,14
involves arm chains, prepared and isolated in advance, that carry
a readily cleavable unit in addition to an initiating site (an alkyl
halide) for metal-catalyzed living radical polymerization or the
arm-linking step for star polymer synthesis in the presence of a
bifunctional linking agent. The cleavable unit herein is an
acetal,19,20 which is readily cleaved after the core formation by
acidolysis without affecting the arm chains and their pendant
groups (esters for methacrylates).
Beyond our anticipation and previous consideration, it has
turned out that the microgel cores separated from their arms are
fully soluble in common organic solvents and water, which allows
detailed characterization in regard to the molecular weight, size,
density, and viscosity as with soluble non-cross-linked polymers,
for the first time to our best knowledge.
These results are important in that, despite the cross-linked
network structure, microgel cores have a void spacious enough
for the diffusion and/or encapsulation of substrates, guest
molecules, and polymers. Rather surprisingly, however, direct
characterization of the microgels in terms of structure, size,
density, and solubility has hardly been examined over 40 years
after the first discovery,16 except for some examples of star
polymer characterization with scattering techniques.1,9 This is
primarily because the cores always have arms and are difficult to
separate for detailed characterization.
The arm-cleavable microgel star polymers were further
applicable as versatile templates to create well-defined and
functionalized soluble microgels with nanometer size (<20 nm),
whereas the synthesis of such microgels by other means is
generally difficult, as direct polymerization of divinyl monomers
often induces gelation even under dilute conditions and/or
provides microgels with a broad molecular weight distribution.21
As illustrated in Scheme 1, we first designed an “acid-cleavable”
macroinitiator (PEG−acetal−Cl) that carries an acetal linkage
between poly(ethylene glycol) methyl ether (PEG−OH) (Mn ≈
In this work, we designed “arm-cleavable” microgel star
polymers via living radical polymerization to isolate and directly
analyze the microgel cores (Scheme 1). The new approach
Received: June 9, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja505646p | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
5000) for arm chains and a chlorine-based initiating group for
microgelation. The acetal unit is stable under the relatively basic
conditions for star polymer synthesis via ruthenium-catalyzed
polymerization, while it should be easily cleaved under acidic
conditions. The macroinitiator was prepared in high yield (93%)
by the treatment of PEG−OH with 2-(vinyloxy)ethyl 2-chloro-2-
phenylacetate in the presence of pyridinium p-toluenesulfonate
in CH2Cl2 at 0 °C. The quantitative introduction of a chlorine-
based initiating group was confirmed by 1H NMR spectroscopy
(Figure S1 in the Supporting Information), where PEG−acetal−
Cl shows the methyne (4.7 ppm) and methyl (1.2 ppm) protons
of the acetal unit, and also by matrix-assisted laser desorption/
ionization time-of-flight mass spectrometry (Figure S2).
Microgel star polymers were then synthesized by the linking
reaction of PEG−acetal−Cl (Mn = 4600; Mw/Mn = 1.04) with
ethylene glycol dimethacrylate (EGDMA) and a ruthenium
catalytic system [Ru(Ind)Cl(PPh3)2/n-Bu3N] in toluene 80 °C
([PEG−acetal−Cl]0 = 20 mM, r = [EGDMA]0/[PEG−acetal−
Cl]0 = 10/1) (Figure 1a). EGDMA was smoothly consumed up
scattering SEC (SEC-MALLS) and found to have an absolute
weight-average molecular weight (Mw) of 340 000, an arm
number (Narm) of 51, and a radius of gyration (Rg) of 10 nm
(Table 1, entry 1). 1H NMR analysis supported the formation of
EGDMA microgels by the broad signals originating from
unreacted pendant olefin (5.6 and 6.1 ppm) and methacrylate
backbones (0.8−2.2 ppm) (Figure S3). Importantly, the in-arm
acetal units remained intact during the core formation, as the
methyne (4.6 ppm) and methyl (1.2 ppm) protons were
observed.
The arms were cleaved with trifluoroacetic acid, and the free
PEG chains were separated by washing the reaction mixture with
water and/or by preparative SEC to give microgel core C1. The
quantitative cleavage of the acetal linkage of S1 was confirmed by
1H NMR analysis (Figure S3). The isolated core was soluble in
common organic solvents (DMF, THF, CH2Cl2, etc.) even
without linear arms, which allowed its full characterization by
analytical techniques generally employed for soluble polymers
such as star polymer S1.
The overall molecular weight of C1 by SEC was smaller than
that of S1 (Figure 1b), and importantly, the absolute Mw was 96
000 by SEC-MALLS (Table 1, entry 2), in reasonable agreement
with the calculated value of 120 000 [Mw,calcd = Fw × r × (conv./
100) × Narm × Mw/Mn, where Fw is the formula weight of
EGDMA, r = [EGDMA]0/[PEG−acetal−Cl]0 (10/1), conv. is
the conversion of EGDMA, Narm = 51, and Mw/Mn is the
dispersity ratio as determined by SEC (1.4)].
The concentration of unreacted pendent olefins in the in-core
1
EGDMA units of C1 was 13 mol %, as estimated by H NMR
analysis (in CD2Cl2 at 25 °C) on the basis of the olefin (5.6 and
6.1 ppm) to aromatic (7.1−7.4 ppm) signal intensity ratio
(Figure S3); a similar olefin content was found in S1, from which
C1 was obtained. Despite their same origin, the methacrylate
signals of the isolated core appeared stronger than in the star,
indicating that in S1 the arm chains somehow reduce the
mobility of the cross-linking chains but not the pendant olefins,
which rather freely dangle at the end of the spacer.
Figure 1. SEC curves of (a) arm-cleavable microgel star polymer S1
prepared by the linking reaction of PEG−acetal−Cl with EGDMA and
(b) EGDMA microgel C1 obtained by arm cleavage of S1 with
trifluoroacetic acid.
With 10 EGDMA fed per arm, a 94% EGDMA conversion
upon linking, and 51 arms per molecule (Table 1, entries 1 and
2), the microgel core of S1 and C1 obtained therefrom contain
an average of ∼480 EGDMA units (=10 × 0.94 × 51), among
which at least 50 units (or ∼10%) were employed for
intermolecular linking (i.e., one unit for attaching an additional
arm). With 13% of the pendant olefins remaining unreacted in
to 94% in 49 h, giving star polymer S1 with a high molecular
weight and a narrow molecular weight distribution in high yield
[88% by size-exclusion chromatography (SEC)].
After the removal of the residue of unreacted arms and
intermediates (two peaks in the low-molecular-weight region),
S1 was characterized by SEC coupled with multiangle laser light
a
Table 1. Characterization of Arm-Cleavable Microgel Star Polymers and Microgels
[Arm]0
(mM)
conv.
b
time
(h)
olefin
c
Mw
(SEC)
Mw/Mn
d
Mw
(MALLS) Narm
Mw
(calcd)
Rg
[η]
e
d
e
f
g
e
h
entry code core monomer (r)
(%)
(%)
(SEC)
(nm) (mL/g)
a
1
2
3
4
5
S1
C1
S2
C2
S3
EGDMA (10)
20
−
40
94
−
89
49
−
20
13
13
16
17
7
84900
23500
170000
39000
49000
1.22
1.40
1.58
1.69
1.46
340000
96000
51
−
116
−
10
21
8.5
23
6.0
22
0.27
0.56
0.30
0.44
0.27
i
−
120000
n.d.
18
EGDMA (10)
765000
309000
200000
−
−
−
20
−
92
−
146
−
19
345000
−
8.4
9.7
EGDMA/PEGMA
(10/10)
i
6
7
8
C3
S4
−
−
20
−
−
82
−
−
34
−
7
8
8
31700
87100
47000
1.37
1.66
1.38
136000
410000
240000
−
45
−
150000
−
280000
n.d.
17
7.5
0.52
0.28
0.41
PEGDMA (10)
30
14
C4
−
11
a
Conditions: In toluene at 80 °C. [(P)EGDMA]0/[PEGMA]0/[PEG−acetal−Cl]0/[Ru(Ind)Cl(PPh3)2]0/[n-Bu3N]0 (mM): S1 and S4, 200/0/20/
b
c
2.0/20; S2, 400/0/40/2.0/20; S3, 200/200/20/2.0/20. Monomer(s) conversion by 1H NMR analysis. Olefin content per core EGDMA unit by1H
NMR analysis. By SEC in DMF (10 mM LiBr) with a PEO calibration. By SEC-MALLS viscometry in DMF (10 mM LiBr). Number of arms per
d
e
f
g
star: Narm = (weight fraction of arms) × Mw (MALLS)/Mw,arm Molecular weight of microgels calculated as Mw (calcd) = Fw (core monomers) ×
h
i
conv. × Narm × r × Mw/Mn (SEC). Obtained from the Mark−Houwink−Sakurada equation ([η] = KMa). Not determined because of the size limit.
B
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Journal of the American Chemical Society
Communication
the core, this means that ∼77% of the pendant olefins (=100 −
10 − 13) were consumed by the intramolecular cross-linking
and/or ladderlike polymerization in the core region upon core
formation. It should be noted that such a detailed analysis of the
core’s chemical structure was made possible by the core
separation and isolation in this work.
The arm cleavage also enabled for the first time the
characterization of the physical properties of the core compared
with its parent star polymer. Generally, globular macromolecules
show solution viscosities smaller than those of their linear
counterparts.22,23 Analysis by SEC-MALLS with a viscosity
detector (Figure 2 and Table 1, entries 1 and 2) showed that S1
From these results, the microgel core is of a swelled and spherical
network structure with a relatively low density. The Rg data for
C1 also revealed that the arm chain density over the core surface
of S1 was 0.21 chain/nm2, indicating a high-density polymer
brush.24
The primary structure and the physical properties of the arm-
cleaved microgels could be tuned by changing the synthetic
conditions of their parent star polymers (Table 1 and Figure S4).
For example, increasing the initial concentration of PEG−
acetal−Cl from 20 to 40 mM while applying the same feed ratio
of EGDMA (r = 10) led to star polymer S2 and arm-free microgel
C2 (∼1030 EGDMA units) with an increased molecular weight
[Mw (MALLS)] and a larger size (Rg) (Table 1, entries 3 and 4)
relative to S1 and C1, respectively. The enhanced core formation
is most likely due to a more efficient intermolecular arm linking.
In spite of the larger Mw, both the viscosity [η] and shape index a
of C2 were smaller than those of C1 (Figure 2), indicating a
higher network density in the former.
As illustrated in Chart 1, an amphiphilic and thermosensitive
microgel, C3 (Mw = 136 000 with 175 short pendent PEG
Chart 1. Amphiphilic and Thermosensitive PEG Microgels
Figure 2. Molecular weight dependence of the intrinsic viscosity for S1
(Mw = 340 000), C1 (Mw = 96 000), C2 (Mw = 309 000), PEO (Mw =
187 000), and PMMA (Mw = 146 000) in DMF.
chains), was obtained from star polymer S3, for which PEG
methyl ether methacrylate (PEGMA) (Mn = 475) was
additionally employed with EGDMA on arm linking. A similar
microgel, C4 (Mw = 240 000 with 370 short PEG spacers) was
also obtained from star polymer S4 with PEG dimethacrylate
(PEGDMA) (Mn = 550) as a linking agent in place of EGDMA
(Table 1 and Figures S4 and S5). While S4 and S1 carried nearly
the same numbers of arms, Mw and Rg of the former were larger as
expected from a longer spacer in the linking agent. As a result, C4
had a larger Mw than C1.
C3 and C4 were amphiphilic and soluble not only in organic
solvents but also in alcohols and water. With either pendant or
spacer PEG units, these microgels were thermosensitive with
lower critical solution temperature-type phase separation in
water25,26 at 60 °C (C3) and 40 °C (C4) (Figure S8). In spite of
the smaller hydrophobic contents [hydrophobic methacrylate/
hydrophilic PEG = 3/1 (C3), 2/1 (C4)], C4 had a cloud point
lower than that for C3. This would be due to the restricted
mobility and conformation of the PEG spacers bridging the
methacrylate units, promoting dehydration of PEG units.
In conclusion, we successfully isolated and directly analyzed
microgel cores in star polymers with an acid-cleavable macro-
initiator (PEG−acetal−Cl). To our knowledge, the structures
and some physical properties of microgel cores were precisely
characterized for the first time in over 40 years since the initial
synthesis of microgel-core star polymers. Despite the absence of
surrounding arm layers, the isolated cores are soluble in various
solvents, in contrast to a previous premise that microgel cores are
solubilized by their linear arms. The cores are spherical, have a
nanoscale network structure (<20 nm) with a relatively large void
space (∼50%), and can be amphiphilic and thermosensitive with
designed linking agents. As a result of their tunable properties
and precise characterization, arm-cleavable microgel star
and C1 actually had intrinsic viscosities ([η]) smaller than those
of their linear counterparts poly(ethylene oxide) (PEO) (Mw =
187 000) and poly(methyl methacrylate) (PMMA) (Mw = 146
000), respectively, with similar molecular weights ([η] = 21, 8.5,
160, and 33 mL/g for S1, C1, PEO, and PMMA, respectively, in
DMF at room temperature).
The double logarithmic plots of [η] versus molar mass (Mw by
MALLS) were fitted using the Mark−Houwink−Sakurada
equation ([η] = KMa), where the index a (the slope) depends
on the polymer conformation (a < 0.5, spherical; 0.5 < a < 1.0,
random coil of a linear chain) (Figure 2). For S1, the slope a over
the SEC peak molecular weight (Mp ≈ 230 000) was 0.27,
indicating that it is globular and different from the linear
polymers (PEO, a = 0.72; PMMA, a = 0.69). In addition, [η]
slightly decreased with increasing Mw to reach a minimum
around Mp (Figure S6). This suggests that the conformation of
the star gradually changes from branched to globular with
increasing Mw or arm number, and this conformational shift, in
turn, offsets an increase in [η] expected for star polymers with
more arms.
For C1, a was 0.56, close to the upper limit of 0.5 for a spherical
shape but small for a random coil. The fact that the shape index
was clearly larger than that of the star suggests that the core
would be a swelled, nearly spherical gel and more flexible in shape
than the parent star polymer surrounded by linear arms.
The core−shell structure of S1 and the nearly spherical
structure of C1 were further supported by small-angle X-ray
scattering (SAXS) analysis in DMF (Figure S7). The radii of
gyration (Rg) as determined by the Guinier plot were 7.1 nm for
S1 and 4.4 nm for C1. With the assumption of a spherical shape,
the EGDMA density in the core microgel was thus 0.44 g/mL,
meaning that C1 is occupied by solvent about 55% in volume.
C
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Journal of the American Chemical Society
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(24) Tsujii, Y.; Ohno, K.; Yamamoto, S.; Goto, A.; Fukuda, T. Adv.
Polym. Sci. 2006, 197, 1.
(25) Lutz, J.-F. J. Polym. Sci., Part A: Polym. Chem. 2008, 46, 3459.
(26) Terashima, T.; Kawabe, M.; Miyabara, Y.; Yoda, H.; Sawamoto,
M. Nat. Commun. 2013, 4, 2321.
polymers and the resulting isolated microgels would lead to
tailor-made functional microgels (nanogels), capsules, and
delivery vessels, among others.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental details, SEC curves, H NMR spectra, Mark−
Houwink−Sakurada plots, and SAXS profiles. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
terashima@living.polym.kyoto-u.ac.jp
sawamoto@star.polym.kyoto-u.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Ministry of Education,
Science, Sports and Culture through Grants-in-Aid for Scientific
Research (A: 24245026) and Young Scientist (B: 24750104).
We also thank Mr. Eiichi Tsuruta and Ms. Tomomi Miyata
(Shoko Scientific Co., Ltd.) for viscosity measurements and Prof.
Daichi Ida (Department of Polymer Chemistry, Kyoto
University) for helpful discussion about the viscosity results.
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