Synthesis and single-chain folding of amphiphilic random copolymers in water

Article abstract of DOI:10.1021/ma402355v

Amphiphilic random methacrylate copolymers, consisting of poly(ethylene glycol) (PEG) and alkyl pendent groups, undergo reversible single-chain self-folding in water via intramolecular hydrophobic interaction, to generate a dynamic unimolecular hydrophobic nanospace, similar in shape but structurally different relative to micelles and microgel star polymers. These copolymers were prepared by the ruthenium-catalyzed living radical copolymerization of a PEG methacrylate (PEGMA) and an alkyl methacrylate (RMA; R, -C_nH _2n+1, n = 1-18), where copolymer composition, degree of polymerization, and hydrophobic R moiety were varied. Detailed structural and chain-folding characterization has revealed: single-chain folding is favored with the RMA content 20-40 mol % per chain; the hydrophobic inner compartment (or the self-folded structure) is stable even at a high polymer concentration (up to ～6 wt %); and folded-unfolded transition occurs on addition of methanol or by elevating solution temperature, finally to phase-separation above a lower critical solution temperature.

Full text of DOI:10.1021/ma402355v

Article
pubs.acs.org/Macromolecules
Synthesis and Single-Chain Folding of Amphiphilic Random
Copolymers in Water
Takaya Terashima,* Takanori Sugita, Kaoru Fukae, and Mitsuo Sawamoto*
Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
*
S Supporting Information
ABSTRACT: Amphiphilic random methacrylate copolymers,
consisting of poly(ethylene glycol) (PEG) and alkyl pendent
groups, undergo reversible single-chain self-folding in water via
intramolecular hydrophobic interaction, to generate a dynamic
unimolecular hydrophobic nanospace, similar in shape but
structurally different relative to micelles and microgel star
polymers. These copolymers were prepared by the ruthenium-
catalyzed living radical copolymerization of a PEG meth-
acrylate (PEGMA) and an alkyl methacrylate (RMA; R,
−
C H , n = 1−18), where copolymer composition, degree
n
2n+1
of polymerization, and hydrophobic R moiety were varied.
Detailed structural and chain-folding characterization has
revealed: single-chain folding is favored with the RMA content 20−40 mol % per chain; the hydrophobic inner compartment
(
or the self-folded structure) is stable even at a high polymer concentration (up to ∼6 wt %); and folded−unfolded transition
occurs on addition of methanol or by elevating solution temperature, finally to phase-separation above a lower critical solution
temperature.
2
−4
INTRODUCTION
controllability, living radical polymerization
is effective in
■
designing functional polymers with precision primary structures
on demand. Such designed linear polymers (random, block,
gradient, etc.) may further be chemically cross-linked, patched,
or physically associated, to be transformed into the following
globular materials: (a) microgel-core star polymers via the
chemical cross-linking of multiple linear polymer arm chains
Protein, enzyme, and related natural polymers involve self-
folding of a single linear chain in water to form a globular
1
tertiary structure comprising a precision nano cavity. With the
specific compartments thus generated within the self-folded
form, coupled with precision sequence and chain length, natural
polymers, as autonomous single chains, develop and express
efficient, selective, and unique functions (recognition and
catalysis, among many others) in water. Self-folding is often
triggered by a site-specific association of functional groups in
polymer chains of a precisely controlled primary structure
5
−16
with multifunctional monomers;
(b) micelles, vesicles, and
polymersomes via the physical self-assembly of multiple
amphiphilic block copolymers in poor solvents for one of the
17−20
segments;
and (c) unimer micelles and single-chain
polymeric nanoparticles (SCPNs) via the self-folding of
functional random copolymers with intramolecular interaction
(
molecular weight, tacticity, monomer sequence, etc.) and
resulting secondary structures. Intramolecular hydrophobic
interaction is one of the most important factors to stabilize
such a self-folding conformation in water; i.e., hydrophobic
groups and segments avoid contacting water, to be placed
within the interior of a self-folded structure and thereby to
effectively create hydrophobic nano compartment(s).
(
single-chain physical association) and/or intramolecular
21−37
chemical cross-linking.
2
3−26
Among these strategies, unimer micelles
and
are structurally regarded as artificial mimics of
proteins and enzymes and thus are expected to generate
27−37
SCPNs
36
intriguing compartments that express unique functions. Most
of SCPNs have been fabricated by the self-folding of
hydrophobic, functionalized random copolymers with intra-
In contrast, common synthetic linear polymers, or non-
functionalized flexible chains including polystyrene and poly-
(
(
methyl methacrylate), may exist as an isolated molecule
single chain) in good solvents but usually in a random-coil
27−30
molecular hydrogen-bonding
or covalent-bond cross-
in organic solvents under diluted conditions (but
not in water), whereas amphiphilic and thermosensitive
31−35
linking
conformation without a specific inner space, because of the lack
of specific interaction among inter- and/or intramolecular
chains. To produce three-dimensional nano compartments
from synthetic linear polymers, functionalization (e.g.,
amphiphilic property) and precision control of primary
structures (molecular weight, monomer sequence, etc.) are
thus essential. Thanks to high functionality tolerance and
23−26,36
random copolymers or homopolymers
in water tend
Received: November 13, 2013
Revised: December 21, 2013
Published: January 15, 2014
©
2014 American Chemical Society
589
dx.doi.org/10.1021/ma402355v | Macromolecules 2014, 47, 589−600

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Scheme 1. Synthesis of PEGMA/RMA Amphiphilic Random Copolymers via Ruthenium-Catalyzed Living Radical
Polymerization and Single Chain Folding of Amphiphilic Copolymers in Water
to collapse into unimer micelles via a single-chain intra-
molecular hydrophobic interaction, as with natural polymers.
Recently, it was found that amphiphilic random copolymers of
single-chain folding in water and (2) the characterization of the
resulting unimer micelles and the inner hydrophobic compart-
ments in terms of size, compactness, mobility, hydrophobicity,
and thermosensitive solubility in water. Systematic and
fundamental researches would be a key to design PEGMA/
RMA random copolymers as scaffolds for single-chain folding
functional compartments.
For this, we have synthesized a variety of PEGMA/RMA
random copolymers by our ruthenium-catalyzed living radical
polymerization, where the feed ratio (composition) of the two
monomers [PEGMA/RMA (m/n) = 200/0−80/120 and 80/
20], the degree of polymerization (DP = 200 or 100), and
1
0,38−42
hydrophilic PEGMA
and hydrophobic and hydrogen-
bonding (BTAMA), prepared by living radical polymerization,
were efficiently and reversibly self-folded by the intramolecular
hydrogen-bonding self-assembly of the pendant BTA units in
water, where PEGMA: poly(ethylene glycol) methyl ether
methacrylate [CH C(CH )CO (CH CH O) CH ; n = 8.5
2
3
2
2
2
n
3
or 23]; BTAMA, benzene-1,3,5-tricarboxamide-bearing meth-
3
6
acrylate. Characterization of the copolymers by light or
neutron scattering and circular dichloism spectroscopy revealed
that the precision control of PEGMA/BTAMA composition
hydrophilic RMA alkyl groups (R, −C H2n+1; n = 1−18) were
n
(
hydrophilic/hydrophobic balance) is essential for the selective
systematically varied (Scheme 1). The resulting copolymers
were analyzed by size-exclusion chromatography (SEC),
multiangle laser light scattering (MALLS), dynamic light
36a,c
single-chain folding in water.
Living radical polymerization
further allows the direct and/or position-selective incorporation
1
of catalytically active groups (phosphine ligand and rutheniu-
scattering (DLS), proton nuclear magnetic resonance ( H
3
6a
36d
NMR) spectroscopy, and ultraviolet/visible (UV−vis) spec-
troscopy. All of PEGMA/RMA random copolymers with RMA
content of 10 to 40 mol % were efficiently and reversibly folded
via a single chain in water to give dynamic, compact, and
hydrophobic compartments. The compartments were unfolded
by addition of methanol and more mobile up on temperature,
and the hydrophobicity increased with increasing the content
m, L-proline ) into PEGMA/BTAMA-based copolymers.
These copolymers in fact induced efficient catalysis in water via
self-folded hydrophobic compartment around the catalytic sites,
reminiscent of enzymatic catalysis.
It should be noted that single chain-based compartments
involve the direct reflection of the molecular design of linear
polymer precursors (monomer sequence, composition, degree
29c,36
and/or pendant length (R, −C H2n+1) of RMA. These
of polymerization, functionalization, etc.)
more precisely tunable than multi chain-based counterparts
micelles, vesicles, and microgel-core star polymers). For
to be much
n
PEGMA/RMA random copolymers further showed sharp and
reversible lower critical solution temperature (LCST) and
(
38−42
phase separation in water.
The cloud point temperature
example, the number of functional groups in self-folded
polymers in principle corresponds to that in the linear
precursors, which can be conveniently controlled by the
molar feed ratio of monomers in copolymerization.
uniquely changed, dependent on the content and/or pendant
structure of RMA.
EXPERIMENTAL SECTION
Herein we report on the single-chain folding of amphiphilic
random copolymers of PEGMA and a hydrophobic alkyl
methacrylate (RMA) in water via intramolecular hydrophobic
interaction (Scheme 1). This system is one of the simplest
models in self-folding polymers just triggered by hydrophobic
physical association without any additional interaction (hydro-
gen-bonding etc.) and/or chemical linking (polymerization,
dimerization, click reaction etc.). The objectives of this work
include: (1) the establishment of molecular design of
amphiphilic random copolymer precursors to selectively induce
■
Materials. Monomer Synthesis. Methacryloyl chloride (TCI,
purity >80.0%) and triethylamine (TCI, purity >99.0%) were purified
by distillation before use. 1-Octanol (Wako, purity >98%), 1-
adamantaneethanol (Wako, purity >97.0%), cyclododecanemethanol
(
Aldrich, purity >95.0%), 1-octadecanol (Wako, purity >80.0%), dry
THF (Wako, dehydrated), and dry diethyl ether (Wako, dehydrated)
were used without further purification.
Polymerization. Methyl methacrylate (MMA: TCI; purity >99.8%),
n-butyl methacrylate (nBMA: TCI; purity >99%), tert-butyl meth-
acrylate (tBMA: TCI; purity >98%), and tetralin (1,2,3,4-tetrahy-
5
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dx.doi.org/10.1021/ma402355v | Macromolecules 2014, 47, 589−600

Macromolecules
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dronaphthalene: Kishida Chemical; purity >98%; an internal standard
for H NMR analysis) were dried overnight over calcium chloride and
distilled from calcium hydride under reduced pressure before use.
25 °C, δ = 0 TMS]: δ = 6.08 (dd, 1 H, J = 1.7, 1.1), 5.54 (q, 1 H, J =
1.5), 4.12 (dt, 2 H, J = 6.7, 1.5), 1.93 (q, 3 H, J = 1.4), 1.65 (dq, 2 H, J
1
13
= 20.8, 4.8), 1.39−1.20 (m, 10 H), 0.89 (t, 3 H). C NMR [125 MHz,
Poly(ethylene glycol) methyl ether methacrylate [PEGMA; CH 
CDCl , 25 °C, δ = 77.0 CDCl ]: δ = 167.4, 136.5, 125.2, 64.8, 31.8,
2
3
3
+
CMeCO (CH CH O) Me: M = 475; n = 8.5 on average] (Aldrich)
29.2, 28.6, 26.0, 22.6, 18.3, 14.0. ESI−MS m/z ([M + Na] ): calcd for
2
2
2
n
n
and dodecyl methacrylate (DMA) (Wako, purity >95%) were purified
by an inhibitor removal column (Aldrich) and were degassed by triple
vacuum-argon purge cycles before use. n-Octyl methacrylate (OcMA),
C H O Na, 221.2; found, 221.4.
12
22
2
AdMA. In a 100 mL round-bottomed flask filled with argon,
methacryloyl chloride (11.37 mmol, 1.1 mL) was added to a solution
of 1-adamantaneethanol (13.87 mmol, 2.5 g) and triethylamine (13.63
mmol, 1.9 mL) in dry diethyl ether (25 mL) at 0 °C. The reaction
mixture was stirred at 25 °C for 18 h and was poured into distilled
water (50 mL). The aqueous phase was separated and extracted by
diethyl ether (25 mL), and the ether extracts were combined with the
organic layer. The combined organic phase was washed with water
three times, ammonia−water, and brine and was dried over anhydrous
Na SO overnight. After the ether was removed in vacuo, the crude
1-adamantylethyl methacrylate (AdMA), cyclododecylmethyl meth-
acrylate (CDMA), and octadecyl methacrylate (OMA) were
synthesized as shown below. Ethyl 2-chloro-2-phenylacetate (ECPA:
Aldrich; purity >97%) was distilled under reduced pressure before use.
Ru(Ind)Cl(PPh ) (Aldrich) were used as received and handled in a
3
2
glovebox under moisture- and oxygen-free argon (H O < 1 ppm; O <
2
2
1
ppm). n-Bu N (TCI, purity >99%) were degassed before use.
3
Toluene (solvent) was purified before use; passing it through a
purification column (Glass Contour Solvent Systems: SG Water USA).
Characterization. Molecular weight distribution (MWD) curves,
2
4
product was purified by silica gel column chromatography with
hexane/ethyl acetate (99/1, v/v) to give AdMA as a colorless liquid
1
number-average molecular weight (M ), peak top molecular weight
(2.6 g, 92% yield). H NMR [500 MHz, CDCl , 25 °C. δ = 0 TMS] δ
n
3
(
M ), and M /M ratio of polymers were measured by SEC in DMF
= 6.08 (dd, 1 H, J = 1.6, 1.0), 5.54 (m, 1 H), 4.20 (t, 2 H, J = 7.3), 1.95
(m, 3 H), 1.94 (t, 3H, J = 1.1), 1.72−1.62 (m, 6 H), 1.56−1.53 (m,
p
w
n
containing 10 mM LiBr at 40 °C (flow rate: 1 mL/min) on three
linear-type polystyrene gel columns (Shodex KF-805L: exclusion limit
6H), 1.47 (t, 2 H, J = 7.3). 13C NMR [125 MHz, CDCl , 25 °C, δ =
3
6
=
4 × 10 ; particle size =10 μm; pore size =5000 Å; 0.8 cm i.d. × 30
77.0 CDCl ] δ = 167.7, 136.7, 125.2, 61.3, 42.7, 42.6, 37.2, 32.0, 28.7,
3
+
cm) that were connected to a Jasco PU-2080 precision pump, a Jasco
RI-2031 refractive index detector, and a Jasco UV-2075 UV/vis
detector set at 270 nm. The columns were calibrated against 10
18.5. ESI-MS m/z ([M + Na] ) calcd. for C H O Na 271.4, found
16
25
2
271.3.
CDMA. In 100 mL round-bottomed flask filled with argon,
methacryloyl chloride (11.37 mmol, 1.1 mL) was added to a solution
of cyclododecylmethanol (12.51 mmol, 2.9 g) and triethylamine
(13.63 mmol, 1.9 mL) in dry diethyl ether (25 mL) at 0 °C. The
reaction mixture was stirred at 25 °C for 18 h and was poured into
distilled water (50 mL). The aqueous phase was separated and
extracted by diethyl ether (25 mL), and the ether extracts were
combined with the organic layer. The combined organic phase was
washed with water three times, ammonia−water, and brine, and was
dried over anhydrous Na SO overnight. After the ether was removed
standard poly(MMA) samples (Polymer Laboratories: M = 1000−
n
1
200000; M /M = 1.06−1.22) or 10 standard poly(ethylene oxide)
w
n
samples (Polymer Laboratories: M = 1460−737000; M /M = 1.03−
1
n
w
n
.07). MWD curves and M of polymers were measured by SEC in
p
H O at 30 °C (flow rate: 1 mL/min) on a silica gel column (TOSOH
2
6
G4000SW : exclusion limit = 7 × 10 ; particle size = 8 μm; 0.8 cm
XL
i.d. × 30 cm) that was connected to the same pump and detectors as
those in DMF. The column was calibrated against 10 standard
poly(ethylene oxide) samples (Polymer Laboratories: M = 1460−
n
2
4
1
7
37000; M /M = 1.03−1.07). H NMR spectra were recorded in
CDCl , CD Cl , CD OD, and D O on a JEOL JNM-ECA500
in vacuo, the crude product was purified by silica gel column
w
n
chromatography with hexane/ethyl acetate (99/1, v/v) to give CDMA
3
2
2
3
2
1
spectrometer operating at 500.16 MHz. Electorospray ionization
as a colorless liquid (1.7 g, 56% yield). H NMR [500 MHz, CDCl ,
3
mass spectrometry (ESI−MS) was performed on Waters Quattro
25 °C, δ = 0 TMS]: δ = 6.09 (dd, 1 H, J = 1.7, 0.9), 5.54 (m, 1 H),
4.00 (d, 2 H, J = 6.6), 1.95 (m, 3 H), 1.87 (m, 1 H), 1.44−1.29 (m, 22
H). 13C NMR [125 MHz, CDCl , 25 °C, δ = 77.0 CDCl ]: δ = 167.7,
micro API. Absolute weight-average molecular weight (M ) of
w
polymers in DMF or H O was determined by multiangle laser light
2
3
3
scattering (MALLS) equipped with SEC on a Dawn E instrument
136.7, 125.2, 68.7, 33.5, 26.7, 24.4, 23.8, 23.7, 22.2, 18.5. ESI−MS m/z
+
(
Wyatt Technology: Ga−As laser; λ = 690 nm). The SEC was
([M + Na] ): calcd for C H O Na, 289.4; found, 289.3.
17
30
2
performed in DMF containing 10 mM LiBr at 40 °C (flow rate: 1 mL/
min) on three linear-type polystyrene gel columns (Shodex KF-805L)
ODMA. In 100 mL round-bottomed flask filled with argon,
methacryloyl chloride (8.27 mmol, 0.8 mL) was added to a solution
of 1-octadecanol (9.25 mmol, 2.5 g) and triethylamine (8.61 mmol, 1.2
mL) in dry THF (25 mL) at 0 °C. The reaction mixture was stirred at
25 °C for 18 h. After the evaporation of the reaction solution, diethyl
ether (25 mL) and distilled water (50 mL) were poured into the flask.
The aqueous phase was separated and extracted by diethyl ether (25
mL), and the ether extracts were combined with the organic layer. The
combined organic phase was washed with water three times,
ammonia−water, and brine and was dried over anhydrous Na SO
or in H O at 30 °C (flow rate: 1 mL/min) on a silica gel column
2
(
TOSOH G4000SW ), that were connected to a Jasco PU-2080
XL
precision pump, a Jasco RI-1530 refractive index detector, and a Jasco
UV-1570 UV/vis detector set at 270 nm. Refractive index increment
(
dn/dc) was measured in DMF at 40 °C on an Optilab DSP
refractometer (Wyatt Technology: λ = 690 nm, c < 2.5 mg/mL).
Dynamic light scattering (DLS) was measured on Otsuka Photal
ELSZ-0 equipped with a semiconductor laser (wavelength: 658 nm) at
2
4
2
5 °C. The measuring angle was 165° and the data was analyzed by
overnight. After the ether was removed in vacuo, the crude product
was purified by silica gel column chromatography with hexane/ethyl
CONTIN fitting method. Ultraviolet−visible (UV/vis) spectra were
obtained from Shimadzu MultiSpec 1500 or UV-1800 in H O, H O/
acetate (99/1, v/v) to give ODMA as a colorless liquid (1.1 g, 39%
2
2
1
acetone (19/1), and acetone at 25 °C (optical path length =1.0 cm).
Synthesis of Monomers. OcMA. In 100 mL round-bottomed
flask filled with argon, methacryloyl chloride (7.56 mmol, 0.7 mL) was
added to a solution of 1-octanol (5.04 mmol, 0.8 g) and triethylamine
yield). H NMR [500 MHz, CDCl , 25 °C, δ = 0 TMS]: δ = 6.09 (dd,
3
1 H, J = 1.7, 0.9), 5.54 (m, 1 H), 4.13 (t, 2 H, J = 6.7), 1.94 (t, 3 H, J =
1.1), 1.67 (m, 2 H), 1.26 (m, 30 H), 0.88 (t, 3 H, J = 6.9). C NMR
[125 MHz, CDCl , 25 °C, δ = 77.0 CDCl ]: δ =167.6, 136.7, 125.2,
1
3
3
3
(
5.04 mmol, 1.1 mL) in dry diethyl ether (25 mL) at 0 °C. The
65.0, 32.1, 29.9, 29.7, 29.5, 29.4, 28.8, 26.2, 22.9, 18.5, 14.3. ESI−MS
+
reaction mixture was stirred at 25 °C for 18 h and was poured into
distilled water (50 mL). The aqueous phase was separated and
extracted by diethyl ether (25 mL), and the ether extracts were
combined with the organic layer. The combined organic phase was
washed with water three times, ammonia−water, and brine, and was
dried over anhydrous Na SO overnight. After the ether was removed
m/z ([M + Na] ): calcd for C H O Na, 361.6; found, 361.4.
22
42
2
Synthesis of Amphiphilic Copolymers. The synthesis of
PEGMA/RMA amphiphilic copolymers (1−15) was carried out by
syringe technique under argon in baked glass tubes equipped with a
three-way stopcock via ruthenium-catalyzed living radical polymer-
1
ization. A typical procedure for 3 and peak assignments for H NMR
2
4
in vacuo, the crude product was purified by silica gel column
spectra of 9, 10, 11, 12, 13, and 14 were given:
PEGMA/DMA (160/40) Random Copolymer (3). In a 30 mL glass
chromatography with hexane/ethyl acetate (99/1, v/v) to give OcMA
1
as a colorless liquid (0.7 g, 67% yield). H NMR [500 MHz, CDCl ,
tube was placed Ru(Ind)Cl(PPh ) (0.0096 mmol, 7.5 mg). Then,
3
3 2
5
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a
Table 1. PEGMA/RMA Amphiphilic Copolymers Prepared by Ruthenium-Catalyzed Living Radical Polymerization
c
Mw,H2O
PEGMA/RMA time
convn (%)
Mn
(SEC)
M /Mn
m/nobsd
Mn
Mw,DMF
f
w
a
b
d
d
1
e
1
e
g
h
i
code
RMA
(m/n)
(h)
PEGMA/RMA
(SEC)
( H NMR) ( H NMR) (MALLS) ADMF (MALLS)
AH2O
1
2
3
4
5
6
7
8
9
−
200/0
34
59
48
48
52
52
47
48
63
69
46
70
75
70
12
81/−
52 400
41 000
41 100
43 900
43 300
44 000
36 100
49 400
54 400
49 500
50 500
42 100
42 000
40 100
55 600
1.24
1.42
1.28
1.23
1.21
1.20
1.17
1.31
1.25
1.27
1.24
1.44
1.37
1.38
1.53
205/0
97 400
84 400
89 800
77 700
67 900
73 900
42 400
79 600
76 900
77 300
83 700
85 100
84 200
88 200
92 800
143 800
110 200
119 300
91 400
89 100
104 300
70 300
91 400
100 300
87 500
94 800
123 900
114 700
110 200
−
1.19
0.92
1.04
0.96
1.08
1.18
1.42
0.88
1.13
0.89
0.91
1.01
0.99
0.90
124 900
114 300
135 500
107 900
183 900
491 600
75 000
87 300
83 800
71 200
89 800
122 500
121 900
136 900
−
0.87
1.04
1.14
1.18
2.06
4.71
1.07
0.96
0.81
0.83
0.95
0.99
1.06
1.24
DMA
DMA
DMA
DMA
DMA
DMA
180/20
160/40
120/80
100/100
80/120
80/20
80/81
86/83
79/81
82/81
83/84
92/90
86/81
82/85
82/82
82/81
80/81
88/88
83/76
−/14
167/19
164/46
116/88
95/89
92/118
79/19
MMA
nBMA
tBMA
OcMA
AdMA
160/40
160/40
160/40
160/40
160/40
156/53
149/42
151/38
160/38
156/44
155/38
155/37
164/56
1
1
1
1
1
1
0
1
2
3
4
5
CDMA 160/40
ODMA 160/40
DMA
160/40 (block)
−
−
a
[
PEGMA] + [RMA] /[ECPA] /[Ru(Ind)Cl(PPh ) ] /[n-Bu N] = 500/2.1/1.0/10 mM (entries 1−6, 8−14), 400 + 100/4.2/2.0/20 mM (entry
0
0
0
3
2
0
3
0
7
) in toluene at 80 °C. [DMA] /[PPEGMA−Cl] /[Ru(Ind)Cl(PPh ) ] /[n-Bu N] = 500/1.5/1.0/10 mM in toluene at 80 °C (entry 15):
0
0
3
2
0
3
0
PPEGMA−Cl (M = 53,800, M /M = 1.31). RMA: dodecyl methacrylate (DMA); methyl methacrylate (MMA); n-butyl methacrylate (nBMA); t-
butyl methacrylate (tBMA); n-octyl methacrylate (OcMA); 1-(adamantane)ethyl methacrylate (AdMA); cyclododecylmethyl methacrylate
n
w
n
b
(
CDMA); octadecyl methacrylate (ODMA). Calculated degree of polymerization (DP) of PEGMA and RMA at 84% conversion: m =
c d
1
0 0 0 0 n
0
.84[PEGMA] /[ECPA] ; n = 0.84[RMA] /[ECPA] . Monomer conversion: determined by H NMR. Number-average molecular weight (M )
and molecular weight distribution (M /M ): determined by size-exclusion chromatography (SEC) in DMF (10 mM LiBr) with PMMA standard
w
n
e
1
f
calibration. Observed DP of PEGMA (m) and RMA (n) in copolymers and M : determined by H NMR. Absolute weight-average molecular
weight (M ): determined by multiangle laser light scattering (MALLS) coupled with SEC in DMF (10 mM LiBr). Association number in DMF:
ADMF = Mw, DMF(MALLS)/[M (NMR) × M /M (SEC)]. Absolute weight-average molecular weight (M ): determined by multiangle laser light
scattering (MALLS) coupled with SEC in H O. Association number in H O: A
n
g
w
h
n
w
n
i
w
= Mw, H2O(MALLS)/Mw, DMF(MALLS).
2
2
H
2
O
toluene (5.7 mL), tetralin (0.2 mL), a toluene solution of n-Bu N (400
(−COOCH CH CH −), 3.85−3.43 (−OCH CH O−), 3.38−3.29
3
2
2
2
2
2
mM, 0.4 mL, n-Bu N = 0.16 mmol), PEGMA (3.2 mmol, 1.4 mL),
(−OCH ), 2. 20−1. 77 (-CH C(CH )−), 1. 77−1. 63
3
3
2
3
DMA (0.8 mmol, 0.23 mL), and ECPA (0.0166 mmol, 0.03 mL) were
added sequentially in that order into the tube at 25 °C under argon.
The total volume of the reaction mixture was thus 8 mL. The glass
tube was placed in an oil bath kept at 80 °C. At predetermined
intervals, the mixture was sampled with a syringe under dry argon, and
( − C O O C H C H 2 ( C H 2
)
C H 3 ) , 1 . 6 3 − 1 . 2 5 ,
2
5
(−COOCH CH (CH ) CH ), 1.25−0.80 (−COO(CH ) CH ,
2
2
2
5
3
2
7
3
−CH C(CH )−).
2
3
1
PEGMA/AdMA (160/40) Random Copolymer (12). H NMR [500
MHz, acetone-d , 25 °C, δ = 2.05 CH COCH ]: δ 7.38−7.25
6
3
3
the reaction was terminated by cooling the solution to −78 °C. The
(aromatic), 4.25−3.95 (−COOCH −), 3.85−3.43 (−OCH CH O−),
2
2
2
1
monomer conversion was determined by H NMR in CDCl with
3.38−3.29 (−OCH ), 2.20−1.43 (−CH C(CH )−, 1-adamantylethyl
3
3
2
3
tetralin as an internal standard. The quenched reaction solutions were
evaporated to dryness. The crude product was purified by silica gel
column chromatography with toluene as an eluent, and precipitated
pendants), 1.24−0.80 (−CH C(CH )−).
2
3
1
PEGMA/CDMA (160/40) Random Copolymer (13). H NMR [500
MHz, acetone-d , 25 °C, δ = 2.05 CH COCH ]: δ 7.38−7.24
6
3
3
into hexane, to give 3. SEC (DMF, PMMA std.): M = 41 100 g/mol;
(aromatic), 4.25−4.05 (−COOCH −), 3.82−3.43 (−OCH CH O−),
n
2
2
2
M /M = 1.28. dn/dc (DMF) = 0.040. SEC-MALLS (DMF, 0.01 M
3.38−3.29 (−OCH ), 2.20−1.76 (−CH C(CH )−, -CH(CH ) ),
w
n
3
2
3
2 2
1
LiBr): M = 119 000 g/mol. H NMR [500 MHz, acetone-d , 25 °C, δ
1.65−1.25 (cyclododecylmethyl pendants: −CH −), 1.25−0.80
w
6
2
=
(
3
(
(
−
2.05 CH COCH ]: δ 7.38−7.25 (aromatic), 4.25−4.08
(−CH C(CH )−).
3
3
2
3
1
−COOCH CH O−), 4.08−3.92 (−COOCH CH CH −), 3.85−
PEGMA/ODMA (160/40) Random Copolymer (14). H NMR [500
MHz, acetone-d , 25 °C, δ = 2.05 CH COCH ]: δ 7.40−7.25
2
2
2
2
2
.43 (−OCH CH O−), 3.38−3.29 (−OCH ), 2.20−1.78 (-CH C-
2
2
3
2
6
3
3
CH )−), 1.75−1.65 (−COOCH CH (CH ) CH ), 1.65−1.25
(aromatic), 4.25−4.07 (−COOCH CH O−), 4.07−3.92
3
2
2
2
9
3
2
2
−COOCH CH (CH ) CH ), 1.25−0.80 (−COO(CH ) CH ,
(−COOCH CH CH −), 3.85−3.43 (−OCH CH O−), 3.38−3.29
2
2
2
9
3
2
11
3
2
2
2
2
2
CH C(CH )−).
(−OCH ), 2. 20−1. 78 (-CH C(CH )−), 1. 75−1. 64
2
3
3
2
3
1
PEGMA/nBMA (160/40) Random Copolymer (9). H NMR [500
( − C O O C H C H 2 ( C H 2
)
C H 3 ) , 1 . 6 2 − 1 . 2 5
2
1 5
MHz, acetone-d , 25 °C, δ = 2.05 CH COCH ]: δ 7.38−7.23
(−COOCH CH (CH ) CH ), 1.25−0.80 (−COO(CH ) CH ,
6
3
3
2
2
2
15
3
2
17
3
(
(
(
(
1
aromatic), 4.25−4.08 (−COOCH CH O−), 4.08−3.92
−CH C(CH )−).
2
2
2
3
−COOCH CH CH −), 3.85−3.43 (−OCH CH O−), 3.38−3.29
PEGMA/DMA (160/40) Block Copolymer (15). 15 was synthesized
by ruthenium-catalyzed living radical polymerization of DMA with a
PPEGMA−Cl macroinitiator. For PPEGMA−Cl (DP = 160),
Ru(Ind)Cl(PPh ) (0.0096 mmol, 7.5 mg) was placed in a 30 mL
2
2
2
2
2
−OCH ), 2.20−1.77 (−CH C(CH )−), 1.77−1.60
3
2
3
−COOCH CH CH CH ), 1.60−1.38, (−COOCH CH CH CH ),
2
2
2
3
2
2
2
3
.25−0.80 (−COO(CH ) CH , −CH C(CH )−).
2
3
3
2
3
3 2
1
PEGMA/tBMA (160/40) Random Copolymer (10). H NMR [500
glass tube. Then, toluene (5.6 mL), tetralin (0.2 mL), a toluene
MHz, acetone-d , 25 °C, δ = 2.05 CH COCH ]: δ 7.38−7.23
solution of n-Bu N (400 mM, 0.4 mL, n-Bu N = 0.16 mmol), PEGMA
6
3
3
3
3
(
(
(
(
aromatic), 4.25−4.00 (−COOCH CH O−), 3.85−3.43
(4.0 mmol, 1.7 mL), and ECPA (0.0166 mmol, 0.03 mL) were added
sequentially in that order into the tube at 25 °C under argon. The total
volume of the reaction mixture was thus 8 mL. The glass tube was
placed in an oil bath kept at 80 °C. After 34 h, the reaction was
terminated by cooling the solution to −78 °C (78% conversion:
2
2
−OCH CH O−), 3.37−3.29 (−OCH ), 2.20−1.77 (−CH C-
2
2
3
2
CH )−), 1.63−1.51 (−COOC(CH ) ), 1.30−0.80 (−COO-
3
3 3
CH ) CH , −CH C(CH )−).
2
7
3
2
3
1
PEGMA/OcMA (160/40) Random Copolymer (11). H NMR [500
1
MHz, acetone-d , 25 °C, δ = 2.05 CH COCH ]: δ 7.38−7.23
determined by H NMR). The quenched solutions were evaporated to
6
3
3
(
aromatic), 4.25−4.08 (−COOCH CH O−), 4.08−3.92
dryness. The crude product was purified by silica gel column
2
2
5
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Figure 1. (a) Time−conversion curve and (b) SEC curves of samples at 12 h (dash), 23 h (gray), and 48 h (black), obtained from Ru-catalyzed
living radical copolymerization of PEGMA and DMA for a PEGMA/DMA (160/40) copolymer (3): [PEGMA] /[DMA] /[ECPA] /
0
0
0
[
Ru(Ind)Cl(PPh ) ] /[n-Bu N] = 400/100/2.1/1.0/10 mM in toluene at 80 °C. (c) DMA content (100n/m+n) in PEGMA/DMA (m/n)
3 2 0 3 0
copolymers (2−6) as a function of calculated DMA content.
1
Figure 2. H NMR spectra of PEGMA/RMA (160/40) random copolymers (3, 9−14) in acetone-d at 25 °C. RMA: (a) nBMA (9); (b) tBMA
6
(
10); (c) OcMA (11); (d) DMA (3); (e) AdMA (12); (f) CDMA (13); (g) ODMA (14).
chromatography with toluene as an eluent, and precipitated into
Then, toluene (1.4 mL), tetralin (0.1 mL), a toluene solution of n-
Bu N (400 mM, 0.15 mL, n-Bu N = 0.06 mmol), DMA (3.0 mmol,
0.88 mL), and a toluene solution of PPEGMA−Cl (2.56 mM, 3.5 mL,
PPEGMA−Cl = 0.0090 mmol) were added sequentially in that order
into the tube at 25 °C under argon. The total volume of the reaction
hexane, to give PPEGMA−Cl. SEC (DMF, PMMA std.): M = 53 800
n
3
3
1
g/mol; M /M = 1.31. H NMR (CD Cl ): M = 78100 g/mol.
w
n
2
2
n
For block copolymerization of DMA from PPEGMA-Cl, Ru(Ind)-
Cl(PPh ) (0.0060 mmol, 4.7 mg) was placed in a 30 mL glass tube.
3
2
5
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Figure 3. (a) Effects of DMA content of PEGMA/RMA copolymers (1-6: PEGMA/DMA = 200/0−80/120) on R in CH Cl (black open square),
h
2
2
DMF (red open triangle), and H O (blue open circles), and AH in H O (filled circles). DLS for R : [polymer] = 10 mg/mL at 25 °C. (b) Effects of
2
2
O
2
h
total polymer concentration of PEGMA/RMA (160/40: red; 120/80: blue) copolymers on R in H O: [polymer] = 1−60 mg/mL at 25 °C. (c)
h
2
Effects of RMA pendant carbon number (R: −C H , n = 1−18) of PEGMA/RMA (160/40) copolymers (3, 8, 9, 11, 14) on the ratio of SEC
n
2n+1
peak-top molecular weight in H O and that in DMF [M (H O)/M (DMF)].
2
p
2
p
mixture was thus 6 mL. The glass tube was placed in an oil bath kept at
0 °C. After 12 h, the reaction was terminated by cooling the solution
to −78 °C (14% conversion: determined by H NMR). The quenched
reaction solutions were evaporated to dryness. The crude product was
ratio and targeted DP (m/n) (Figure 1b, Table 1). It should be
noted that the synchronized consumption of two monomers
supports the random incorporation of both hydrophilic and
hydrophobic units into a polymer chain without any biased
8
1
fractionated by preparative SEC to give 15. SEC (DMF, PMMA std.):
43
1
sequence distribution such as gradient copolymers.
Analyzed by proton nuclear magnetic resonance ( H NMR),
M = 55 600 g/mol; M /M = 1.53. H NMR [500 MHz, CDCl , 25
n
w
n
3
1
°
(
3
C, δ = 7.26 CHCl ]: δ 7.30−7.15 (aromatic), 4.18−3.98
3
all of the copolymers exhibited proton signals corresponding
RMA alkyl pendants (4.0−3.9, 1.8−1.0 ppm), oligo-
(oxyethylene) units of PEGMA (4.2−4.0, 3.9−3.3 ppm), and
a phenyl group of ECPA (7.4−7.2 ppm), in addition to their
methacrylate backbones (methylene: 2.2−1.8 ppm, methyl:
−COOCH CH O−), 3.98−3.82 (−COOCH CH CH −), 3.75−
2
2
2
2
2
.44 (−OCH CH O−), 3.42−3.32 (−OCH ), 2.12−1.67 (−CH C-
2
2
3
2
(
CH )−), 1.67−1.52 (−COOCH CH (CH ) CH ), 1.52−1.12
−COOCH CH (CH ) CH ), 1.12−0.70 (−COO(CH ) CH ,
3
2
2
2
9
3
(
−
2
2
2
9
3
2
11
3
CH C(CH )−).
2
3
1
.3−0.8 ppm) (Figure 2). DPs of PEGMA and RMA in
RESULTS AND DISCUSSION
copolymers (m/n ), estimated from the area ratio of their
■
obsd
pendant units to the initiator phenyl group, were well
consistent with DPs calculated from the feed ratio of their
monomers to ECPA and the conversion. The number-average
Synthesis of PEGMA/RMA Amphiphilic Copolymers.
To establish molecular design suitable for single-chain folding
of polymers via intramolecular hydrophobic interaction in
water, a series of methacrylate-based amphiphilic copolymers
was synthesized by ruthenium-catalyzed living radical polymer-
ization (Scheme 1). PEGMA (Mn = 475, an average
oxyethylene unit of 8.5) and alkyl methacrylates (RMA) were
employed as hydrophilic and hydrophobic units, respectively. In
particular, alkyl groups of RMA were systematically investigated
with respect to carbon numbers (hydrophobicity) and
bulkiness: methyl methacrylate (MMA); n-butyl methacrylate
molecular weight (M ) was determined as 42 400−97 400 by
n
1
H NMR. DMA content in copolymers increased in proportion
to the feed ratio of DMA in monomers (Figure 1c, Table 1),
demonstrating that monomer feed ratio is directly reflected to
monomer composition in copolymers (2−14). A PEGMA/
DMA (160/40) block copolymer [15, M
M = 1.56, M
n n
(SEC) = 55 600; M
( H NMR) = 92,800], a block version of 3, was
also prepared by Ru(Ind)Cl(PPh -catalyzed polymerization
of DMA with a PPEGMA−Cl macroinitiator (DP = 160, M
53 800; M /M = 1.31). Owing to hydrophilic PEGMA units,
all of the copolymers (1−15) are soluble in water.
/
n
w
1
)
3 2
(
(
nBMA); tert-butyl methacrylate (tBMA); n-octyl methacrylate
OcMA); dodecyl methacrylate (DMA); 1-adamantylethyl
=
n
w
n
methacrylate (AdMA); cyclododecylmethyl methacrylate
(
CDMA); octadecyl methacrylate (ODMA).
Random copolymerization of PEGMA and RMA was
Single-Chain Folding in Water. Folding and/or aggrega-
tion properties of amphiphilic copolymers (1−15) in water
were investigated with multiangle laser light scattering coupled
with SEC (SEC−MALLS) and dynamic light scattering (DLS).
If their copolymers fold via a single chain with intramolecular
hydrophobic interaction in water to form compact unimer
micelles, the molecular weight in water is identical to the value
estimated as a single chain, while the size in water would be
smaller than that in good organic solvents.
conducted with a ruthenium catalytic system [Ru(Ind)Cl-
35
a
(
PPh ) /n-Bu N] and a chloride initiator (ECPA) in toluene
3 2 3
at 80 °C (Table 1). The total degree of polymerization (DP)
for copolymers [DP = ([PEGMA] + [RMA] )/[ECPA] ] was
0
0
0
set as 240 or 120, and the molar ratio of PEGMA and RMA was
changed from 10/0 to 4/6. The targeted DP for their respective
monomers at 84% conversion (m = 0.84[PEGMA] /[ECPA] ,
0
0
n = 0.84[RMA] /[ECPA] ) was thus given: m/n = 200/0−80/
Unimer vs Multi-Chain Aggregation. Absolute weight-
0
0
1
20, 80/20. PEGMA and RMA were simultaneously and
average molecular weight [M (MALLS)] for a PEGMA
w
smoothly consumed up to 80−90% (Figure 1a and S1,
Supporting Information) to give well-controlled random
copolymers (1−14) with narrow molecular weight distribution
homopolymer (1) and PEGMA/RMA random copolymers
(2−14) was determined by multiangle laser light scattering
coupled with SEC (SEC−MALLS) in DMF and H O (Table
2
(
M /M ) [size-exclusion chromatography (SEC) calibrated
1). In DMF, 1−14 had M
(MALLS) ranging from 70,300
w
n
w,DMF
against PMMA standards: M = 36 100−54 400; M /M =
to 143,800, which were respectively close to the values
n
w
n
1
1.2−1.4], independent of RMA species, the monomer feed
calculated from their corresponding M by H NMR and
n
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1
M /M by SEC [M
= M ( H NMR) × M /M (SEC)].
nm, Figure 3b) and at high temperature ([3] = 10 mg/mL: Rh
= 6.0−7.0 nm from 25 to 80 °C, Figure S2). This is because the
steric repulsion by multiple hydrophilic PEG chains and the
intramolecular hydrophobic interaction from RMA pendants
successfully isolate a single main chain in water to prevent
intermolecular aggregation.
w
n
w,calcd
n
w
n
Thus, the association number of 1−14 in DMF (ADMF), defined
as A = M (MALLS)/M , is almost 1, indicating that
DMF
w,DMF
w,calcd
amphiphilic (co)polymers (1−14) exist as unimer in DMF.
In contrast, their copolymers had Mw,H2O(MALLS) widely
ranging from 71,200 to 491,600 in H O. The association
2
PEGMA/RMA (160/40) random copolymers (3, 8−14)
with different RMAs (RMA: 20 mol %) were further analyzed
number (AH2O), defined as AH2O = Mw,H2O(MALLS)/
Mw,DMF(MALLS), depended on the hydrophobic RMA content
to approximately range from 1 to 5 (Figure 3a and Table1);
copolymers with less than 40 mol % DMA (1−4, 7: m/n =
by DLS and SEC. All of the copolymers had R in water smaller
h
than that in CH Cl and that for a PEGMA hompolymer (1) in
2
2
water (Table 2). The SEC peak-top molecular weight (M ) of
p
2
00/0−120/80, 80/20) existed as unimer in water (AH2O
=
∼
1), while those with over 50 mol % DMA (5, 6: m/n = 100/
Table 2. Hydrodynamic Radius of PEGMA/RMA
Copolymers
a
1
00, 80/120) in turn formed multichain aggregates (AH2O
=
>
2). In the case of 20 mol % RMA, all copolymers (3, 7−14)
b
b
entry
code
RMA
R (CH Cl )
R (H O)
h
2
2
h
2
were unimer in water, independent of hydrophobic pendant
structures (R) and degree of polymerization. These results
suggest that the local concentration of RMA per a chain is
critical to control the intra- or intermolecular association of
their copolymers in water.
1
2
3
4
5
6
7
8
9
1
−
DMA
8.0
7.7
5.8
4.6
5.7
7.8
7.6
7.7
6.0
6.3
6.6
3
9.0
7
DMA
6.0
8
MMA
nBMA
tBMA
OcMA
AdMA
CDMA
ODMA
DMA
6.8
9
11.6
10.9
9.7
Compact Structure via Single-Chain Folding. Hydro-
10
11
12
13
14
15
dynamic radius (R ) for a PEGMA homopolymer (1) and
PEGMA/DMA random copolymers (2−6) was then deter-
mined by dynamic light scattering (DLS) in various solvents
h
8.2
7.2
(CH Cl , DMF, H O) at 25 °C ([polymer] = 10 mg/mL)
(Figures 3, 4, S2, Table S1). In H O, all of the copolymers
2 2 2
1
1
0
1
8.0
2
13.3
110
a
Entry 1: a PEGMA homopolymer (1). Entries 2, 4−10: PEGMA/
RMA (160/40) random copolymers (3, 8-14). Entry 3: a PEGMA/
DMA (80/20) random copolymer (7). Entry 11: a PEGMA/DMA
b
(
160/40) block copolymer (15). Determined by DLS in H O or
2
CH Cl at 25 °C: [polymer] = 10 mg/mL.
2
2
copolymers (3, 8, 9, 11, 14) in H O was then compared with
2
that in DMF [M (H O)/M (DMF)] (Figure 3c), where both
p
2
p
of the SECs are calibrated against poly(ethylene oxide)
standards. Noted that the ratio [M (H O)/M (DMF)] means
p
2
p
the compactness of their folding structures in water, normalized
by the structure in DMF. As shown in Figure 3c, M (H O)/
p
2
M (DMF) gradually decreased with increasing the carbon
p
number of RMA [R: −CH (8); −C H (9); −C H (11);
3
4
9
8
17
−
C H (3); −C H (14)], where the most hydrophobic 14
12
25
18 37
gave a minimum value of 0.50. Thus, the folding structure of
copolymers gradually becomes compact with increasing the
pendant hydrophobicity. Additionally, shorter DP of copoly-
mers [DP = 100 (7), 200 (3)] gave smaller R in water [R =
Figure 4. DLS intensity distributions of (a) a PEGMA/DMA (160/
0) random copolymer (3) and (b) a PEGMA/DMA (160/40) block
copolymer (15) in CH Cl2 (black) and H O (blue) at 25 °C:
4
h
h
2
2
4
.6 nm (7), 5.8 nm (3)] (Table S1).
In sharp contrast to the random counterpart (3), a PEGMA/
[
polymer] = 10 mg/mL.
DMA (160/40) block copolymer (15) formed large
showed single modal DLS intensity distribution, typically
intermolecular aggregates in water, in which R in water (110
h
shown in Figure 4a. R gradually decreased with increasing
h
nm) was much larger than that in CH Cl (13.3 nm, Figure 4b,
2
2
RMA content up to 40 mol % [R (nm) = 7.7 (1), 7.6 (2), 5.8
h
Table 2). Thus, efficient single-chain folding of polymers into
compact unimer micelles involves random sequence distribu-
tion of PEG pendants and alkyl counterparts (R) with 20−40
mol % RMA content.
(
3), 5.0 (4)] and in turn increased over 50 mol % RMA [R =
h
7
.9 (5), 11.1 (6)]. Considering AH2O, their copolymers
gradually fold in H O to be compact structures with increasing
2
RMA up to 40 mol % and in turn form large intermolecular
Mobility of Hydrophobic Compartments in Water.
Single-chain folding of PEGMA/RMA random copolymers in
water may give dynamic and reversible hydrophobic compart-
ments within unimer micelles. Thus, the local mobility was first
aggregates over 50 mol % RMA. In contrast, R for 1−6 was
h
almost constant in CH Cl (∼9 nm) and DMF (∼7 nm)
2
2
(
Figure 3a), suggesting that the conformation of the (co)-
1
polymers is independent of the monomer composition in such
good organic solvents. Importantly, the compact structure of
copolymers (3 and 4) in water was maintained even at high
evaluated by H NMR measurements of a PEGMA/DMA
(160/40) copolymer (3) in CD OD/D O mixed solvents (10/
3
2
0−0/10, v/v) at 25 °C (Figure 5 and S3). In CD OD alone, 3
3
polymer concentration ([3 or 4] = 1−60 mg/mL: R = 5.0−6.0
clearly exhibited proton signals assignable to PEG pendants [c
h
5
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(
methylene): 2.1−1.7 ppm; a (methyl): 1.2−0.8 ppm], where
the area ratio is consistent with that calculated in acetone-d
6
(
Figure 5a and 2d), indicating that all segments are fully soluble
and mobile without any aggregation. In contrast, the hydro-
phobic dodecyl pendants and methacrylate backbones were
evidently broadened in D O (Figure 5d).
2
To clarify effects of water on the mobility of hydrophobic
segments, half width of proton signals (Hz) for PEG units (c, d,
e) and dodecyl pendants (h) was plotted as a function of
CD OD volume fraction in CD OD/D O (10/0−0/10, v/v)
3
3
2
44
(
Figure 6a). The half width for the dodecyl group (h) and the
PEG methylene protons adjacent to a methacrylate backbone
c) was gradually broader as D O fraction increased. In
(
2
contrast, the width for PEG middle (d) and tip (e) segments
was constant. These results demonstrate that hydrophobic
dodecyl pendants and a methacrylate backbone and PEG root
segments intramolecularly aggregate to be thermodynamically
restricted as D O increased, whereas PEG chains are fully
2
1
mobile, independent of solvent composition. Similarly, the
mobility of other long and/or large hydrophobic alkyl pendants
(adamantylethyl, 12; cyclododecylmethyl, 13; octadecyl, 14)
was also reduced in water. Thus, single-chain folding of
amphiphilic copolymers gives a dynamically aggregating
hydrophobic space of alkyl pendants and a methacrylate main
chain, that is covered by multiple and mobile PEG chains. The
self-folding copolymers can be thereby regarded as single-chain
star polymers carrying a hydrophobic dynamic core and short
PEG arms.
Figure 5. H NMR spectra of a PEGMA/DMA (160/40) copolymer
(
3) in (a) CD OD or (b) CD OD/D O (1/1, v/v) at 25 °C, and in
D O at (c) 5, (d) 25, and (e) 80 °C. Peak assignments: corresponding
to those in Figure 2d.
3 3 2
2
(
−COOCH CH −), 4.1−4.0 ppm; d (−OCH CH O−), 3.8−
2
2
2
2
3
.4 ppm; e (−OCH ), 3.3 ppm], dodecyl counterparts [f
3
(
−COOCH CH −), 3.9−3.8 ppm; g (−COOCH CH −),
2
2
2
2
1
.7−1.6 ppm; h (−COOCH CH (CH ) CH ), i
2
2
2
9
3
(
−(CH ) CH ): 1.3 ppm], and methacrylate backbones [b
2
11
3
1
Figure 6. (a) Effects of CD OD on half width of H NMR signals (c, d, e, h: see Figure 5) of a PEGMA/DMA (160/40) copolymer (3) in CD OD/
3
3
1
D O (10/0−0/10, v/v) at 25 °C. (b) Effects of temperature on half width of H NMR signals (c, d, e, h) of 3 in D O at 5−80 °C. Effects of
hydrophobic monomers [RMA: non (1), DMA (3), ODMA (14)] on (c) peak c (methylene protons of PEG adjacent to a methacrylate backbone)
2
2
and (d) peak d (methylene protons of middle PEG segments) in D O at 5−80 °C.
2
5
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Figure 7. (a) UV−vis spectra of Reichardt’s dye (RD) (black), RD with a PEGMA/DMA (160/40) copolymer (3, red) or a PEGMA homopolymer
1, blue) in H O/acetone (19/1, v/v) and RD in acetone (dash) at 25 °C: [polymer] /[RD] = 0.045/0.45 mM. (b) Effects of polymer
(
2
0
0
concentration and species (1: black; 3: red; 7: red dash; 8: green; 14: blue) on λmax of RD: [polymer] /[RD] = 0.0045/0.45−0.090/0.45 mM in
0
0
H O/acetone (19/1, v/v) at 25 °C. Effects of (c) DMA content in copolymers (1-6) and (d) the carbon number (n) of R [−(CH ) −(H)] in
2
2 n
PEGMA/RMA (160/40) random copolymers [n = 0 (1), 1 (8), 4 (9, 10), 8 (11), 12 (3, 12), 13(13), 18 (14)] on λ of RD: [polymer] /[RD] =
max
0
0
0
.090/0.45 mM in H O/acetone (19/1, v/v) at 25 °C.
2
1
Next, temperature-dependent H NMR measurements of 3
hydrophobic microdomains (e.g., an inner space of micelles) in
water to exhibit UV−vis absorptions directly reflecting the
polarity of the local environments.
As shown in Figure 7a, RD in fact shows negative
solvatochromic shift for the intramolecular charge transfer
band, dependent on solvents: λmax (maximum wavelength) =
were conducted in D O between 5 and 80 °C (Figure 5c-5e
2
and S4). The proton signals for the methacrylate (a, b), the
dodecyl pendants (f, g, h, i), and the PEG root methylene (c)
became gradually broader by cooling temperature from 80 °C
and peaks b, f, g finally disappeared at 5 °C in spite of sharp
signals for PEG units (d, e). Similarly confirmed by their half
width plots in Figure 6b, the local mobility around methacrylate
backbones and alkyl pendants is selectively reduced in water by
cooling temperature.
455 nm in H O/acetone (19/1, v/v), 675 nm in acetone.
2
Though a small amount of acetone was used as a cosolvent for
the better solubility of RD, the λmax in H O/acetone (19/1, v/
2
v) was quite close to that in H O (λ = 453 nm) previously
2
max
45
A longer alkyl (n-C H )-bearing copolymer (PEGMA/
reported. Thus, hydrophobicity of self-folded PEGMA/RMA
1
8
37
ODMA copolymer 14) also showed tendency similar to 3 with
n-C H pendants (Figure S5). Judging from their PEG root
random copolymers was examined through UV−vis measure-
ments of RD with their polymers in H O/acetone (19/1, v/v)
12
25
2
methylene units (peak c), the mobility of methacrylate
backbones is almost identical among 14 and 3 and much
smaller than that for a PEGMA homopolymer (1) (Figure 6c
and S5−S7). In contrast, the mobility of PEG units (d, e) is
independent of hydrophobic monomers (DMA or ODMA)
at 25 °C (Figure 7).
In the presence of a PEGMA/DMA (160/40) copolymer
(3), λmax of RD red-shifted to 544 nm ([3] /[RD] = 0.045/
0
0
0.45 mM), suggesting that the dye is enclosed within the self-
folded compartment to reflect the microdomain hydrophobicity
on UV−vis absorption. The efficient encapsulation of RD into
(
Figure 6d: constant half width for d) because PEG chains
1
emanate from an intramolecularly collapsed hydrophobic core
3 was confirmed by H NMR analysis; the proton signals of RD
to outer environment to be free from any restriction.
with 3 turned broad in D O (Figure S8). Additionally, the
2
Hydrophobicity of Self-Folded Compartments. Sol-
vatochromism is a powerful tool to evaluate the polarity of
solvents and microheterogenous media such as solutions of
solvatochromic red shift of RD with 3 was larger than that with
a PEGMA homopolymer (1) (Figure 7a), indicating that
dodecyl pendants effectively provide hydrophobic spaces.
We further systematically investigated effects of the total
concentration of polymers to dye ([polymer] /[RD] ), the
3
6e,45−47
surfactants, polymers, micelles and so on.
A pyridinium
4
5
N-phenolate betaine dye, so-called Reichardt’s dye (RD), is a
0
0
typical solvatochromic compound that induces hypsochromic
local concentration of a hydrophobic DMA per a chain (100n/
(m + n)), and the structures of RMA on hydrophobic
compartments (Figure 7b−d and Figure S9). Figure 7b plots
(
blue) shift of UV−vis absorption derived from the intra-
molecular charge transfer via increasing solvent polarity. Owing
to the low solubility in water, RD is often encapsulated into
λ
of RD in the presence of PEGMA/RMA copolymers (3, 8,
max
5
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4) or 1 as a function of the molar ratio of polymers to RD
Article
1
(
[polymer] /[RD] ). Here, polymer concentration ([poly-
0 0
mer] ) was changed from 0.0045 mM to 0.09 mM with
0
constant RD concentration (0.45 mM) in H O/acetone (19/1,
2
v/v). Typically with 3, λmax increased with increasing polymer
concentration ([3]) up to 0.045 mM and turned constant (545
nm) over 0.045 mM ([polymer] /[RD] = 0.1, Figure 7b),
0
0
demonstrating that hydrophobic dyes were gradually enclosed
into the self-folded hydrophobic compartments of 3 with
increasing polymer concentration. Judging from a starting point
of the plateau in this titration curve, 3 can presumably carry 10
dyes per a chain in water. In contrast, the red shift of RD with 1
was never saturated even at high polymer concentration (0.09
mM). This indicates that a PEGMA homopolymer (1) is
hydrophilic fail to capture RD stably.
λmax depends not only on total polymer concentration
(
[polymer] ) but also on the local concentration of hydro-
0
phobic pendants (100n/(m + n)). For PEGMA/DMA (m/n)
copolymers with different DMA content (1−6: m/n = 0/200−
1
20/80, [polymer] = 0.09 mM), λ increased with increasing
0 max
n from 0 to 100 and was finally constant over 100 (50 mol % of
DMA) (Figure 7c). Interestingly, the hydrophobicity for the
self-folded compartment of 4 with 40 mol % DMA was almost
identical to that for the multichain aggregates of 5 or 6 with
over 50 mol % DMA.
A PEGMA/DMA (80/20) copolymer (7: DP = 100), a
shorter DP version of 3 (DP = 200), also induced red shift for
RD. The trend is the following: Δλ [λmax − 453 nm (RD
max
alone)] with 7 was almost half of that with 3 at low total
polymer concentration ([polymer] = <0.009 mM; [polymer] /
0
0
[
RD] = <0.02); the saturated λ with 7 was identical to that
0 max
with 3 at high polymer concentration ([polymer] = 0.09 mM)
0
(
Figure 7b). These results indicate that hydrophobicity of self-
folded compartments relies on the local density (m/n ratio)
and pendant structures (R) of hydrophobic monomers. In fact,
the hydrophobicity for PEGMA/RMA (160/40) copolymers
increased with increasing the pendant carbon numbers of RMA
Figure 8. Transmittance of aqueous solutions of (a) a PEGMA/DMA
copolymer (3) and (b) PEGMA/RMA copolymers [RMA: nBMA (9);
OcMA (10); DMA (3); ODMA (14)] as a function of temperature
(heating/cooling rate and range: 1 °C/min from 40 to 95 °C):
[
RMA: MMA (8) < nBMA (9) < OcMA (11) < DMA (3),
[
polymer] = 4 mg/mL.
AdMA (12) < CDMA (13) < ODMA (14)] (Figures 7d and
S9). As an exception, a tBMA-carrying copolymer (10) showed
the same λmax as a MMA counterpart (8); i.e., 10 was less
hydrophobic than a nBMA counterpart (9, nonbranched
pendant), probably because the tertiary butyl groups attach
adjacently onto a methacrylate backbone fail to effectively
create hydrophobic compartments.
The hydrophobicity of a PEGMA/DMA (160/40) copoly-
mer (3) also increased with temperature, where λmax of RD
gradually shifted from 545 to 555 nm upon temperature from
structures of amphiphilic copolymers are gradually mobile upon
temperature to be unfolded, followed by the intermolecular
aggregation over LCST. Cp for copolymers was lower than that
for a PEGMA homopolymer (1, Cp = 92 °C). For PEGMA/
DMA copolymers (2−6: m/n = 180/20−80/120), Cp linearly
decreased with increasing a hydrophobic DMA content (n)
from 0 to 40 mol % and further steeply decreased over 40 mol
% DMA content (Figure 9a). Such a unique composition-
dependence on Cp would be derived from the conformation
difference of copolymers between single-chain folding and
multichain aggregate.
PEGMA/RMA (160/40) random copolymers further
showed unique phase separation properties dependent on
hydrophobic RMA species. Cp decreased with increasing the
carbon numbers (n) of R from 1 to 4 [n = 1 (MMA, 8), 4
(nBMA, 9; tBMA, 10)] and in turn gradually increased with
increasing n from 4 to 18 [n = 4 (nBMA, 9; tBMA, 10), 8
(OcMA, 11), 12 (DMA, 3; AdMA, 12), 13 (CDMA, 13), 18
(ODMA, 14)] (Figure 9b). It should be noted that Cp of the
most hydrophobic ODMA-based copolymer (14: 89 °C) is
close to that of PEGMA homopolymer (1). This result strongly
suggests that ODMA pendants comprise a hydrophobic core
2
5 to 80 °C (Figure S9). The increasing hydrophobicity would
effectively contribute to the selective single-chain folding in
water even at high temperature.
Thermosensitivity in Water. PEG-based polymers often
show lower critical solution temperature (LCST)-type phase
38−41
separation in water.
aqueous solutions of PEGMA/RMA random copolymers (DP
200: 2−6, 8−14) was determined by temperature-dependent
Thus, the cloud point (Cp) of the
=
UV−vis measurements ([polymer] = 4 mg/mL, heating/
cooling speed = 1 °C/min) monitored at λ = 660 nm. Here, Cp
was defined as the temperature in 50% transmittance for their
aqueous solutions that were heated from 40 to 95 °C.
All of their copolymers sharply and reversibly exhibited
LCST-type phase separation in water without any hysteresis
(Figures 8 and S10; Table S2). In water, single-chain folding
5
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Article
Figure 9. (a) Effects of DMA content (n) on cloud point (Cp: °C) for the aqueous solutions of PEGMA/DMA (m/n) copolymers (1−6). (b)
Effects of carbon numbers (n) of R [(CH ) H] on Cp (°C) for the aqueous solutions of PEGMA/RMA (160/40) copolymers [n = 0 (1), 1 (8), 4
2
n
(
9), 8 (11), 12 (3), 13(13), 18 (14)]. Condition: [polymer] = 4 mg/mL; heating speed = 1 °C/min.
0
spatially segregated from PEG units to hardly promote
dehydration of PEGMA units for LCST-type phase separation.
Notes
The authors declare no competing financial interest.
CONCLUSIONS
■
ACKNOWLEDGMENTS
■
Amphiphilic methacrylate random copolymers bearing hydro-
philic PEG and hydrophobic alkyl pendants were efficiently
obtained from ruthenium-catalyzed living radical copolymeriza-
tion of PEGMA and alkyl methacrylates (RMA). The
copolymers successfully undergo single-chain folding in water
with intramolecular hydrophobic interaction to lead to compact
unimer micelles comprising hydrophobic compartments.
Selective single-chain folding involves random incorporation
of hydrophilic and hydrophobic monomers into a chain with
This research was supported by the Ministry of Education,
Science, Sports and Culture through a Grant-in-Aid for
Scientific Research (A: 24245026) and Young Scientist (B:
2
4750104), for which T.T. is grateful.
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AUTHOR INFORMATION
Corresponding Authors
(T.T.) Telephone: +81-75-383-2600. Fax: +81-75-383-2601
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(M.S.) E-mail: sawamoto@star.polym.kyoto-u.ac.jp.
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dx.doi.org/10.1021/ma402355v | Macromolecules 2014, 47, 589−600