Efficient synthesis of amine-functional diblock copolymer nanoparticles via RAFT dispersion polymerization of benzyl methacrylate in alcoholic media

Article abstract of DOI:10.1021/ma300898e

Benzyl methacrylate (BzMA) is polymerized via reversible addition-fragmentation chain transfer (RAFT) chemistry under alcoholic dispersion polymerization conditions in ethanol using a poly(2-(dimethylamino) ethyl methacrylate) (PDMA) chain transfer agent

Full text of DOI:10.1021/ma300898e

Article
pubs.acs.org/Macromolecules
Efficient Synthesis of Amine-Functional Diblock Copolymer
Nanoparticles via RAFT Dispersion Polymerization of Benzyl
Methacrylate in Alcoholic Media
Elizabeth R. Jones, Mona Semsarilar, Adam Blanazs, and Steven P. Armes*
Dainton Building, Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, South Yorkshire S3 7HF, U.K.
S
* Supporting Information
ABSTRACT: Benzyl methacrylate (BzMA) is polymerized via
reversible addition−fragmentation chain transfer (RAFT) chemistry
under alcoholic dispersion polymerization conditions in ethanol using
a poly(2-(dimethylamino)ethyl methacrylate) (PDMA) chain transfer
agent (CTA) at 70 °C. In principle, polymerization-induced self-
assembly can lead to the formation of either spherical micelles, worm-
like micelles, or vesicles, with the preferred morphology being
dictated by the hydrophilic−hydrophobic balance of the PDMA−
PBzMA diblock copolymer chains. Very high monomer conversions
1
(>99%) are routinely obtained within 24 h as judged by H NMR
studies. Moreover, THF GPC analyses confirmed that relatively low polydispersities (Mw/Mn < 1.30) are achieved, indicating
reasonably good pseudoliving character. A detailed phase diagram was constructed using a PDMA31 macro-CTA by
systematically varying both the target degree of polymerization of the PBzMA block and the total solids concentration of the
reaction solution. This phase diagram can be used to reliably predict the synthesis conditions required to produce pure phases,
rather than merely mixed phases (e.g., spheres plus worms or worms plus vesicles). Finally, these PDMA−PBzMA diblock
copolymer nanoparticles remain colloidally stable when transferred from ethanol into water; aqueous electrophoresis studies
confirmed that the particles acquire appreciable cationic character below pH 7 due to protonation of the PDMA stabilizer chains.
achieved.20−22 Alternatively, we have shown that RAFT
aqueous dispersion polymerization formulations based on 2-
hydroxypropyl methacrylate (HPMA) appear to have consid-
erable commercial potential, since this approach allows efficient
INTRODUCTION
■
Over the past decade or so, reversible addition−fragmentation
chain transfer (RAFT) polymerization1 has been utilized by
many research groups to prepare a wide range of diblock
copolymers with relatively low polydispersities. Amphiphilic
syntheses of pure block copolymer phases comprising spheres,
worms, or vesicles.4,23,24 Moreover, a predictive phase diagram
diblock copolymers are of particular interest since they can self-
for one particular formulation has been recently published,23
while careful sampling of the reaction solution of a second
formulation has shed new light on our understanding of the
mechanism of the worm-to-vesicle transition during the in situ
evolution of diblock copolymer morphologies.24 Finally, Pan
and co-workers reported that various copolymer morphologies
can be obtained by RAFT alcoholic dispersion polymerization
using polystyrene as the core-forming (i.e., structure-directing)
block.25−27 However, in this case monomer conversions are
typically substantially incomplete (ranging from 30 to 70%)28,29
due to the relatively slow polymerization of styrene. This
disadvantage almost certainly makes such formulations
unsuitable for industrial applications, since the cost of removing
the unreacted styrene monomer would be prohibitive.
assemble in aqueous solution to form various morphologies.2−6
They are already widely used as polymeric surfactants (e.g.,
Pluronics) and have many other potential applications, such as
drug delivery,7−9 MRI imaging,10 water purification mem-
branes,11 nanoreactors,12,13 and inorganic templates for
photonics.14
Traditionally, amphiphilic block copolymers were synthe-
sized and isolated, with a subsequent processing step being
used to induce self-assembly. Typical processing techniques
include a solvent switch, a pH switch, or thin film
rehydration.15−17 However, such self-assembly is usually only
achievable at relatively low copolymer concentration, which
makes the scaled-up production of diblock copolymer-based
“nano-objects” rather problematic. Recently, a polymerization-
induced self-assembly approach has been investigated, which
enables bespoke organic nanoparticles to be prepared directly
at much higher concentrations.18,19 For example, Charleux et al.
have optimized various RAFT aqueous emulsion formulations
in order to prepare various “nano-objects” based on water-
immiscible commodity monomers such as styrene or n-butyl
acrylate, with relatively high monomer conversions being
For surfactant amphiphiles, Israelachvili and co-workers30
have demonstrated that the final morphology depends on the
dimensionless “packing parameter”, p, as defined by eq 1.31
Received: May 3, 2012
Revised: May 30, 2012
Published: June 13, 2012
© 2012 American Chemical Society
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Scheme 1. Chain Extension of a Poly(2-(dimethylamino)ethyl methacrylate) (PDMA) Macro-CTA with Benzyl Methacrylate
(BzMA) by RAFT Alcoholic Dispersion Polymerization at 70 °C To Produce Sterically Stabilized PDMA−PBzMA Diblock
a
Copolymer Nanoparticles via Polymerization-Induced Self-Assembly
a
Here only a spherical morphology is depicted, but systematic variation of the reaction conditions allows either PDMA−PBzMA worms or vesicles
to be targeted (see main text).
v
a0lc
aqueous solution at an appropriate solution pH allows the
PDMA stabilizer chains to acquire polyelectrolytic character.
p =
(1)
Here v, a0, and lc represent the volume of the hydrophobic
chains, the optimal area of the headgroup, and the length of the
hydrophobic tail, respectively. If p ≤ 0.33, the self-assembly of
amphiphiles in aqueous solution produces spherical micelles,
whereas anisotropic worm-like micelles are obtained when 0.33
≤ p ≤ 0.50 and vesicles are formed when p > 0.50.31 It is
generally believed that this geometric argument also holds for
amphiphilic diblock copolymers as well as conventional
surfactants.30−33
EXPERIMENTAL SECTION
■
Materials. All reagents were purchased from Sigma-Aldrich (UK)
and used as received unless otherwise noted. 4,4′-Azobis(4-
cyanovaleric acid) (ACVA)) or 2,2′-azobis(isobutyronitrile) (AIBN)
was used as an initiator. Benzyl methacrylate (96%) was passed
through a column of inhibitor remover (also purchased from Sigma)
prior to use.
Synthesis of 4-Cyano-4-(2-phenylethanesulfanyl-
thiocarbonyl)sulfanylpentanoic Acid (PETTC). 2-Phenylethane-
thiol (10.5 g, 76 mmol) was gradually added over 10 min to a stirred
suspension of sodium hydride (60% in oil) (3.15 g, 79 mmol) in
diethyl ether (150 mL) at between 5 and 10 °C. Vigorous evolution of
hydrogen gas was observed, and the grayish suspension was slowly
transformed into a white viscous slurry of sodium phenylethanethio-
late over 30 min. The reaction mixture was cooled to 0 °C, and carbon
disulfide (6.0 g, 79 mmol) was gradually added to produce a thick
yellow precipitate of sodium 2-phenylethanetrithiocarbonate, which
was collected by filtration after 30 min and subsequently used in the
next step without further purification. Solid iodine (6.3 g, 0.025 mol)
was gradually added to a suspension of sodium 2-phenylethane-
trithiocarbonate (11.6 g, 0.049 mol) in diethyl ether (100 mL). This
reaction mixture was then stirred at room temperature for 1 h, and the
insoluble white precipitate of sodium iodide was removed by filtration.
The yellow−brown filtrate was washed with an aqueous solution of
sodium thiosulfate to remove excess iodine, dried over sodium sulfate,
and then evaporated to yield bis(2-phenylethanesulfanylthiocarbonyl)
disulfide (∼100% yield). A solution of 4,4′-azobis(4-cyanopentanoic
acid) (ACVA) (2.10 g, 0.0075 mol) and bis(2-phenylethane
sulfanylthiocarbonyl) disulfide (2.13 g, 0.005 mol) in ethyl acetate
(50 mL) was degassed by nitrogen bubbling and heated at reflux under
a dry nitrogen atmosphere for 18 h. After removal of the volatiles
under vacuum, the crude product was washed with water (five 100 mL
portions). The organic phase was concentrated and purified by silica
chromatography using a mixed eluent (petroleum ether:ethyl acetate =
7:3, gradually increasing to 4:6) to afford 4-cyano-4-(2-
phenylethanesulfanylthiocarbonyl)sulfanylpentanoic acid as a yellow
Recently, Charleux and co-workers have reported18,22 that
the polymerization-induced self-assembly of diblock copoly-
mers via RAFT aqueous emulsion polymerization is much more
difficult to achieve if the stabilizer chain has polyelectrolyte
character. This is because strong lateral electrostatic repulsive
forces prevent the efficient packing of highly charged chains
within a coronal layer. In principle, this problem can be avoided
by addition of salt to screen the electrostatics or by diluting the
stabilizer charge density by copolymerizing the ionic monomer
with a nonionic monomer.22 We have also recently explored a
third possibility in the context of RAFT aqueous dispersion
polymerization, which is the judicious use of binary mixtures of
polyelectrolyte and nonionic macro-CTAs in order to modulate
the charge density within the coronal layer via an entropic
mixing mechanism.34
Herein we report the polymerization-induced self-assembly
of an all-methacrylic diblock copolymer via RAFT alcoholic
dispersion polymerization. Unlike the styrene-based formula-
tions reported by Pan and co-workers,26,27 we show that this
new formulation enables very high monomer conversions to be
achieved within 24 h at 70 °C. A poly(2-(dimethylamino)ethyl
methacrylate) (PDMA) macro-CTA with a fixed mean degree
of polymerization (DP, or x) is chain-extended using benzyl
methacrylate (BzMA) so as to systematically vary the packing
parameter, p, and hence the morphology of the diblock
copolymer nanoparticles (see Scheme 1). A detailed phase
diagram for this formulation is constructed by varying the total
solids concentration of the reaction solution, using the
approach described by Sugihara et al.23 One motivation for
this study was the realization that the polyelectrolytic block
copolymer self-assembly problem described above for aqueous
formulations might be addressed by such an alcoholic
formulation. More specifically, the synthesis of a weak
polyelectrolyte-based diblock copolymer via RAFT dispersion
polymerization in alcohol ensures that the polyelectrolyte
chains remain uncharged during their self-assembly, while the
subsequent transfer of these neutral “nano-objects” into
1
oil. H NMR (400.13 MHz, CD2Cl2, 298 K): δ (ppm) = 1.89 (3H,
−CH3), 2.34−2.62 (m, 2H, −CH2), 2.7 (t, 2H, −CH2), 3.0 (t, 2H,
−CH2), 3.6 (t, 2H, −CH2), 7.2−7.4 (m, 5H, aromatic). 13C NMR
(400.13 MHz, CD2Cl2, 298 K): δ (ppm) = 24.2 (CH3), 29.6
(CH2CH2COOH), 30.1 (CH2Ph), 33.1 (CH2CH2COOH), 39.9
(SCH2CH2Ph), 45.7 (SCCH2), 118.6 (CN), 127.4, 128.8, 129.2,
144.3 (Ph), 177.4 (CO), 222.2 (CS).
Synthesis of Poly(2-(dimethylamino)ethyl methacrylate)
(PDMA) Macro-CTA Agent. A round-bottomed flask was charged
with 2-(dimethylamino)ethyl methacrylate (DMA; 10.0 g, 63 mmol),
PETTC (0.432 g, 1.27 mmol), ACVA (36 mg, 0.127 mmol), and THF
(10.0 g) (target DP = 50). The sealed reaction vessel was purged with
nitrogen and placed in a preheated oil bath at 70 °C for 6 h. The
resulting polymer (monomer conversion = 67%; Mn = 5500 g mol−1,
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Mw/Mn = 1.22) was purified by precipitation into excess petroleum
ether. The mean degree of polymerization (DP) of this PDMA macro-
CTA was calculated to be 31 using 1H NMR spectroscopy by
comparing the integrated signals corresponding to the aromatic
protons at 7.2−7.4 ppm with those due to the methacrylic polymer
backbone at 0.4−2.5 ppm. This was repeated with an increased
amount of DMA to synthesize a longer PDMA macro-CTA; in this
case the amounts of reagents used were DMA (30.0 g, 190 mmol),
PETTC (0.648 g, 1.9 mmol), ACVA (54.0 g, 0.19 mmol), and THF
(30 g) (target DP = 100). Again, these were sealed in a reaction vessel,
purged with nitrogen, and then placed in an oil bath at 70 °C for 8 h
10 min. The resulting polymer (monomer conversion = 68%; Mn = 11
300 g mol−1, Mw/Mn = 1.19) was purified by precipitation into excess
petroleum ether. The mean DP of this PDMA macro-CTA was
excess solution. To stain the deposited nanoparticles, a 0.75% w/w
aqueous solution of uranyl formate (10 μL) was placed via micropipet
on the sample-loaded grid for 20 s and then carefully blotted to
remove excess stain. Each grid was then carefully dried using a vacuum
hose.
RESULTS AND DISCUSSION
■
In a recent communication, we reported that simply replacing
styrene with BzMA as the core-forming monomer in RAFT
1
calculated to be 74 using H NMR spectroscopy by comparing the
integrated signals corresponding to the aromatic protons at 7.2−7.4
ppm with those due to the methacrylic polymer backbone at 0.4−2.5
ppm.
Synthesis of Poly(2-(dimethylamino)ethyl methacrylate)−
Poly(benzyl methacrylate) (PDMA−PBzMA) Diblock Copoly-
mer Particles via Dispersion Polymerization in Ethanol. In a
typical RAFT dispersion polymerization synthesis conducted at 17%
w/w total solids, BzMA (2.50 g, 14.2 mmol), AIBN (0.90 mg, 0.006
mmol), and PDMA31 macro-CTA (144 mg, 0.028 mmol) were
dissolved in ethanol (13.23 g). The reaction mixture was sealed in a
round-bottomed flask, purged with nitrogen gas for 15 min, and then
placed in a preheated oil bath at 70 °C for 24 h. The final monomer
1
1
Figure 1. Kinetic data derived from H NMR spectroscopy studies of
conversion was determined by H NMR analysis by integrating the
the RAFT dispersion polymerization of benzyl methacrylate at 70 °C
in ethanol using a PDMA31 macro-CTA and AIBN initiator at a total
solids concentration of 17%. Target diblock composition was
PDMA31-PBzMA500; [macro-CTA]/[AIBN] = 5.0.
PBzMA peak (CH2) at 4.9 ppm to BzMA monomer vinyl peaks (CH2)
at 5.2 and 5.4 ppm.
In further PDMA−PBzMA diblock copolymer syntheses, the mean
DP of the PBzMA block was systematically varied by adjusting the
amount of BzMA monomer. Finally, syntheses were also conducted at
varying total solids concentrations (either 10, 13, 20, 25, or 29% w/w)
simply by adjusting the amount of ethanol added to the formulation.
Copolymer Characterization. Diblock copolymer molecular
weight distributions were assessed using gel permeation chromatog-
raphy (GPC). The GPC setup comprised two 5 μm (30 cm) “Mixed
C” columns and a WellChrom K-2301 refractive index detector
operating at 950
30 nm. THF eluent contained 2.0% v/v
triethylamine and 0.05% w/v butylhydroxytoluene (BHT) was used
at a flow rate of 1.0 mL min−1. A series of ten near-monodisperse
linear poly(methyl methacrylate) standards (Mp ranging from 1280 to
330 000 g mol−1) were purchased from Polymer Laboratories (Church
Stretton, UK) and employed for calibration using the above refractive
index detector.
1H NMR spectra were acquired on a Bruker 400 MHz spectrometer
in either CDCl3 or CD2Cl2. All chemical shifts are reported in ppm
(δ). TEM studies were conducted using a Philips CM 100 instrument
operating at 100 kV. To prepare TEM samples, 5.0 μL of a dilute
aqueous copolymer solution was placed onto a carbon-coated copper
grid, stained with uranyl formate, and dried under ambient conditions.
DLS measurements were conducted using a Malvern Instruments
Zetasizer Nano series instrument equipped with a 4 mW He−Ne laser
operating at 633 nm, an avalanche photodiode detector with high
quantum efficiency, and an ALV/LSE-5003 multiple tau digital
correlator electronics system. Aqueous electrophoresis measurements
were performed on 0.01% w/v aqueous copolymer solutions in 0.01 M
NaCl using the same Malvern Instruments Zetasizer Nano series
instrument. The solution pH was adjusted by the addition of 0.01 M
HCl or 0.01 M KOH using an autotitrator.
Transmission electron microscopy (TEM) imaging was performed
at 100 kV on a Phillips CM100 instrument equipped with a Gatan 1 k
CCD camera. Aggregate solutions were diluted with ethanol at 20 °C
to generate 0.20% w/w dispersions. Copper/palladium TEM grids
(Agar Scientific, UK) were surface-coated in-house to yield a thin film
of amorphous carbon. The grids were then plasma glow-discharged for
30 s to create a hydrophilic surface. Each aqueous diblock copolymer
dispersion (0.20% w/w, 10 μL) was placed onto a freshly glow-
discharged grid for 1 min and then blotted with filter paper to remove
Figure 2. Evolution of the number-average molecular weight and
polydispersity (Mw/Mn) with conversion for the RAFT dispersion
polymerization of benzyl methacrylate at 70 °C in ethanol using a
PDMA31 macro-CTA and AIBN initiator at a total solids
concentration of 17%. The target diblock composition was
PDMA31−PBzMA500, and the [macro-CTA]/[AIBN] molar ratio
was 5.0.
alcoholic dispersion polymerization syntheses leads to much
higher monomer conversions being attained in each case when
using four different methacrylate-based RAFT macro-CTAs.35
Such all-methacrylic formulations represent a potentially
important breakthrough, since they are much more amenable
to industrial scale-up. Previously, the use of a weak polyacid
macro-CTA was emphasized.35 In the present study, we focus
on a complementary weak polybase macro-CTA, as exemplified
by PDMA. Thus, a PDMA macro-CTA was synthesized by
solution polymerization in THF at 70 °C (see Scheme 1).
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Figure 3. Gel permeation chromatography traces obtained for the
RAFT dispersion polymerization of BzMA in ethanol at 70 °C using a
PDMA31 macro-CTA and AIBN initiator at a total solids
concentration of 17%. The target composition was PDMA31−
PBzMA500, and the [macro-CTA]/[AIBN] molar ratio was 5.0.
Figure 5. TEM images obtained for PDMA31−PBzMAx diblock
copolymer particles synthesized at a total solids concentration of 17%
via RAFT dispersion polymerization in ethanol at 70 °C using a
PDMA31 macro-CTA, AIBN initiator, and a [macro-CTA]/[AIBN]
molar ratio of 5.0. Systematic variation of the target degree of
polymerization, x, of the core-forming PBzMA block enables the
particle morphology to be adjusted from (a) spheres (x = 60) to (b)
worms (x = 80) to (c) a worm/vesicle mixed phase (x = 90) to (d)
pure vesicles (x = 100).
was obtained after 12 h, with essentially full conversion being
achieved after 24 h. After just 2 h, there is a discernible increase
in the rate of polymerization, which is consistent with
previously reported observations for a RAFT aqueous
dispersion polymerization formulation.24 This time period
corresponds to the onset of micellar nucleation, since visual
inspection confirms a concomitant increase in the turbidity of
the reaction solution. This suggests that the enhanced rate of
polymerization is due to the solubilization of unreacted BzMA
monomer within the growing PBzMA nanoparticles. We
believe that such monomer partitioning leads to a relatively
high local monomer concentration and that the nascent
growing nanoparticles effectively act as “nanoreactors”.
However, this hypothesis is rather difficult to confirm
experimentally. Nevertheless, analysis of the kinetic data
shown in Figure 1 suggests that micellar nucleation leads to
an apparent rate enhancement by at least a factor of 4.5, which
compares quite well with that recently reported by Blanazs et al.
for the RAFT aqueous dispersion polymerization of HPMA.
For the RAFT synthesis of a PBzMA homopolymer in ethanol,
macroscopic precipitation is observed when targeting a mean
DP as low as 20. However, the enhanced rate of polymerization
observed after 2 h in Figure 1 occurs at a monomer conversion
of around 10%, which corresponds to a PBzMA block DP of
∼50 (since the final target DP is 500). Visual inspection
confirms that this rate enhancement coincides with the onset of
nucleation, since the reaction solution becomes distinctly turbid
at around 2 h. This critical DP is significantly higher than that
required for precipitation of PBzMA homopolymer because the
solvent mixture is not pure ethanol, but a mixture of ethanol
and BzMA monomer. The unreacted monomer acts as a
cosolvent for the PBzMA chains and hence delays the onset of
nucleation. It is also likely that conjugation of the solvatophobic
PBzMA chains to the solvatophilic PDMA stabilizer chains
Figure 4. Phase diagram constructed for the PDMA31−PBzMAx RAFT
dispersion polymerization formulation by systematic variation of the
mean target degree of polymerization of PBzMA (x) and the total
solids concentration using a fixed mean degree of polymerization of 31
for the PDMA macro-CTA. The mean DP of the PBzMA block in
each case was determined by 1H NMR spectroscopy (in either CD2Cl2
or CDCl3), by comparing the integrated benzyl protons at 4.9 ppm
with the methylene vinyl protons due to the BzMA monomer at 5.2
and 5.4 ppm.
After purification by precipitation into excess petroleum
1
ether, its mean DP was determined to be 31 as judged by H
NMR spectroscopy, while THF GPC analysis indicated a final
polydispersity of 1.22. This PDMA31 macro-CTA was then
chain-extended with BzMA via RAFT dispersion polymer-
ization in ethanol at 70 °C to produce a series of PDMA31−
PBzMAx diblock copolymers. Since the PBzMA chains are
insoluble in ethanol, a range of copolymer morphologies can be
generated via in situ self-assembly by varying the DP of the
PBzMA chains and hence adjusting v and lc for a fixed a0
according to eq 1. In each case the alcohol-soluble PDMA
chains act as an effective steric stabilizer for the diblock
copolymer “nano-object”.
A kinetic study of the BzMA polymerization was conducted
when targeting a DP of 500 for the core-forming block (Figure
1). 1H NMR analysis indicated that a BzMA conversion of 89%
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Table 1. Monomer Conversions, Intensity-Average Particle Diameters, and GPC Molecular Weights and Polydispersities
Obtained for PDMA31−PBzMAx Diblock Copolymer Particle Syntheses Conducted at a Total Solids Concentration of 10−29%
w/w by RAFT Alcoholic Dispersion Polymerization in Ethanol at 70 °C
a
GPC
DLS
diameter
TEM
solids (%)
10
target composition
BzMA % conv
actual BzMA DP
Mn
Mw/Mn
PDI
morphology
PDMA31-PBzMA40
PDMA31-PBzMA60
PDMA31-PBzMA70
PDMA31-PBzMA80
PDMA31-PBzMA90
PDMA31-PBzMA100
PDMA31-PBzMA120
PDMA31-PBzMA60
PDMA31-PBzMA70
PDMA31-PBzMA500
PDMA31-PBzMA500
PDMA31-PBzMA65
PDMA31-PBzMA500
PDMA31-PBzMA500
PDMA31-PBzMA65
PDMA31-PBzMA70
PDMA31-PBzMA80
PDMA31-PBzMA90
PDMA31-PBzMA100
PDMA31-PBzMA70
PDMA31-PBzMA90
PDMA31-PBzMA40
PDMA31-PBzMA60
PDMA31-PBzMA80
PDMA31-PBzMA85
PDMA31-PBzMA100
PDMA31-PBzMA120
PDMA31-PBzMA500
PDMA31-PBzMA500
PDMA31-PBzMA80
PDMA31-PBzMA90
PDMA31-PBzMA100
PDMA31-PBzMA110
92
97
37
58
64
71
76
91
102
60
67
30
60
62
30
60
62
70
80
90
98
68
88
39
60
78
85
98
118
35
75
80
90
100
110
10 300
12 500
15 000
15 100
16 500
17 300
22 000
14 000
17 000
12 500
15 000
16 100
12 500
15 000
16 100
15 000
16 300
22 000
22 300
16 400
19 300
11 250
14 800
16 300
17 900
19 150
24 800
14 000
20 000
18 800
19 700
20 000
22 900
1.31
1.36
1.25
1.31
1.24
1.33
1.25
1.27
1.19
1.28
1.27
1.19
1.28
1.27
1.19
1.30
1.29
1.19
1.22
1.22
1.21
1.24
1.21
1.28
1.25
1.31
1.18
1.23
1.22
1.21
1.24
1.30
1.23
65
96
0.29
0.13
0.29
0.39
0.63
0.25
0.21
0.21
0.81
0.2
spheres
spheres + worms
spheres + worms
worms
92
179
330
979
450
411
75
89
84
worms + vesicles
vesicles + worms
vesicles
91
85
13
17
100
95
worms + spheres
worms + spheres
spheres
334
58
b
6
b
12
73
0.07
0.34
0.20
0.07
0.34
0.32
0.89
0.81
0.3
spheres
95
154
58
worms + spheres
spheres
b
6
b
12
73
spheres
95
100
100
100
98
154
310
1274
1056
642
333
693
48
worms + spheres
worms
worms
worms + vesicles
vesicles
20
23
97
0.85
0.89
0.14
0.28
0.56
0.52
0.2
worms + spheres
worms + vesicles
spheres
98
97
100
97
301
541
631
563
529
30
worms
worms
100
98
worms
worms + vesicles
vesicles
98
0.26
0.21
0.13
0.76
0.61
0.26
0.41
b
7
spheres
b
14
57
spheres
29
100
100
100
100
510
542
256
490
spheres + worms
worms
worms + vesicles
vesicles
a
Intensity-average diameter. PDI is the polydispersity calculated using cumulants analysis software provided by the instrument manufacturer
b
(Malvern). Indicates data obtained from the analysis of multiple samples extracted from an in situ polymerization in which higher values were
targeted for the final DP of the PBzMA block.
dispersion polymerization of BzMA conducted in various
ethanol/water mixtures.36 In this case, the addition of water
worsens the solvency for the growing PBzMA chains, which
leads to much faster rates of polymerization (∼100%
conversion within 2 h at 80 °C). In contrast, herein we focus
on a purely alcoholic formulation to ensure that the PDMA
stabilizer chains (pKa ∼ 7.0−7.5) remain nonprotonated.
The evolution of molecular weight with conversion was also
monitored to assess the character of the BzMA polymerization
(see Figure 2). The observed linear relationship indicates a
well-controlled pseudoliving RAFT polymerization. Polydisper-
sities remained between 1.20 and 1.30 throughout the reaction,
with the final PDMA31−PBzMA500 diblock copolymer having
an Mw/Mn of 1.25. GPC traces were invariably unimodal with
Figure 6. Zeta potential vs pH curves obtained for PDMA31−
little or no tailing, which indicated a relatively high blocking
efficiency and suggested that relatively few polymer chains were
terminated prematurely (see Figure 3).
■
○
PBzMA40 spheres ( ), PDMA31−PBzMA80 worms ( ), and
▲
PDMA31−PBzMA190 vesicles ( ).
The PDMA31 macro-CTA was prepared on a relatively large
scale so that a detailed phase diagram could be constructed
using a single batch of macro-CTA. This is an important point,
delays precipitation of the former block. Very recently, similar
kinetic data have been reported by Charleux et al. for RAFT
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targeting a PDMA31−PBzMA100 diblock composition is
polydisperse vesicles. The same general behavior is observed
at each of the concentrations investigated. It is interesting to
compare this phase diagram with that recently published by our
group for a related RAFT aqueous dispersion polymerization
formulation using poly(2-hydroxypropyl methacrylate)
(PHPMA) as the core-forming block.23 In both cases, the
worm phase space is relatively narrow. However, there are
important qualitative differences: diblock copolymer vesicles
could only be generated in aqueous solution by targeting a high
DP for the core-forming block and also by performing the
polymerization of 2-hydroxypropyl methacrylate at relatively
high solids (22.5−25%). In contrast, the present alcoholic
formulation allows vesicles to be generated at just 10% solids,
which suggests that the copolymer concentration has a much
weaker influence on particle morphology in this case. In this
sense the data shown in Figures 4 and 5 are consistent with the
observations made by Blanazs and co-workers, who also found
that spheres, worms, or vesicles could be obtained at 10% solids
using an alternative RAFT aqueous dispersion polymerization
formulation.24
Hence it seems likely that both the precise chemical nature
and mean DP of the stabilizer chains may also play an
important role in determining the final copolymer morphology.
In addition, differences in the interaction of the core-forming
block with the continuous phase may be important. PHPMA is
only weakly hydrophobic in the presence of water: although
this homopolymer is water-insoluble, it is known to exhibit
thermoresponsive behavior when conjugated to a more
hydrophilic block if its DP is relatively low.37 In contrast,
ethanol is a strong non-solvent even for relatively short PBzMA
chains (DP ∼ 20).
All of the experimental results (including DLS particle
diameters and THF GPC data) associated with the phase
diagram shown in Figure 4 are summarized in Table 1. TEM
studies confirm that the spherical diblock copolymer nano-
particles can exhibit relatively narrow size distributions (see
Figure 5a), whereas worms or vesicles (or mixed phases)
invariably possess significantly higher polydispersities. How-
ever, the Stokes−Einstein equation only reports a “sphere-
equivalent” diameter, so the DLS technique should be treated
with some caution when characterizing the worm phase. The
relatively high vesicle polydispersities indicated by DLS studies
are consistent with the corresponding TEM images obtained
for these dispersions. Regardless of the final copolymer
morphology, the diblock copolymer chains had relatively low
polydispersities (Mw/Mn = 1.18−1.36; vs poly(methyl meth-
acrylate) calibration standards) as judged by THF GPC, which
suggests reasonably good control. Perhaps more importantly,
Figure 7. TEM images obtained for (top row) PDMA31−PBzMA40
spheres, (middle row) PDMA31−PBzMA80 worms, and (bottom row)
PDMA31−PBzMA120 vesicles. The continuous phase in which these
nano-objects were dispersed prior to TEM grid preparation was either
ethanol (a−c), an acidic aqueous solution at pH 3 (d−f), or an alkaline
aqueous solution at pH 10 (g−i).
because it is not trivial to precisely target a particular mean DP
for a macro-CTA, and ideally this parameter should be held
constant. The phase diagram shown in Figure 4 was generated
by systematic variation of the total solids concentration for the
BzMA polymerization from 10 to 29% w/w and the mean DP
of the core-forming PBzMA block. For a given DP of the
macro-CTA, the latter parameter dictates the molecular
curvature (or packing parameter p) of the diblock copolymer
chains, which in turn determines the final copolymer
morphology (as judged by post mortem TEM studies).
For a given total solids content, there is a gradual evolution
from spheres to worms to vesicles as the target DP of the
PBzMA chains is increased, with mixed phases always being
observed between the three pure phases. This important
observation is illustrated in Figure 5, which depicts a series of
TEM images recorded for BzMA polymerizations conducted at
17% w/w solids. Well-defined spheres are obtained at a mean
PBzMA DP of 60, whereas a pure worm phase is identified for a
DP of 80. A “worm plus vesicle” mixed phase is observed at a
mean PBzMA DP of 90, while the sole phase produced when
Table 2. Monomer Conversions, GPC Molecular Weights and Polydispersities, Intensity-Average Particle Diameters and
Morphologies Obtained for PDMA74−PBzMAx Diblock Copolymer Particles Prepared at 10% Solids by RAFT Alcoholic
Dispersion Polymerization of Benzyl Methacrylate in Ethanol at 70 °C
a
GPC
DLS
TEM
target composition
BzMA % conv
actual DP of PBzMA
Mn
Mw/Mn
diameter
PDI
morphology
PDMA74-PBzMA100
PDMA74-PBzMA250
PDMA74-PBzMA500
PDMA74-PBzMA800
PDMA74-PBzMA1000
88
92
96
97
93
88
230
480
776
930
19 200
40 400
1.40
1.22
1.25
1.23
1.34
36
50
0.06
0.04
0.05
0.01
0.04
spheres
spheres
spheres
spheres
spheres
68 800
73
104 000
116 000
95
108
a
Intensity-average diameter. PDI is the polydispersity calculated using cumulants analysis software provided by the manufacturer (Malvern).
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Figure 8. TEM images obtained for PDMA74−PBzMAx diblock copolymer particles synthesized at a total solids concentration of 10% using RAFT
dispersion polymerization in ethanol at 70 °C with a PDMA74 macro-CTA, AIBN initiator and using a [macro-CTA]/[AIBN] molar ratio of 5.0. (a−
e) Systematic variation of the target degree of polymerization, x, of the core-forming PBzMA block enables the particle diameter to be adjusted from
36 to 108 nm (as judged by DLS in ethanol). (f) Intensity-average diameter distributions for the same five samples of PDMA74−PBzMAx spherical
nanoparticles in ethanol.
1H NMR studies indicated that most BzMA conversions ranged
copolymer curvature conferred by this longer PDMA74 macro-
CTA, it was anticipated that solely spherical nanoparticles would
be produced over a relatively wide size range. Thus the target
DP for the core-forming PBzMA block was systematically
varied between 100 and 1000 (see Table 2). Although the final
BzMA conversions for this series are slightly lower than
previously observed (88−97%), the intensity-average particle
diameter increased monotonically as longer PBzMA chains
were targeted, while size distributions remained relatively
narrow in all cases (DLS polydispersities were below 0.07 in
each case). TEM images and DLS size distributions for each of
these alcoholic dispersions are shown in Figure 8. Recent work
by Zhang et al.38 on diblock copolymer nanoparticles prepared
via RAFT aqueous emulsion polymerization of styrene suggests
that some chains may be buried within the particle cores; it has
not been determined whether this is also true in the present
study.
from 90 to 100%, which is significantly higher than those
reported by Pan and co-workers for polystyrene core-forming
chains via RAFT dispersion polymerizations in alcohol.26,28
THF GPC data for all copolymers gave monomodal curves
with little or no tailing, indicating good blocking efficiency and
a fairly well controlled reaction with little evidence of
premature termination.
Diluting these ethanol-dispersed “nano-objects” 1000-fold
with water leads to protonation of the PDMA stabilizer chains
(pKa 7.0−7.5); hence the particles acquire cationic character.
Aqueous electrophoresis studies were conducted on each of the
three “pure phase” copolymer morphologies (i.e., spheres,
worms, and vesicles) in order to assess their surface charge
(zeta potential) and relative colloidal stabilities (see Figure 6).
At low pH these dispersions each possess positive zeta
potentials ranging from +34 to +47 mV, confirming
protonation of the weakly polybasic PDMA chains. Isoelectric
points were observed at around pH 7.6, pH 8.8, and pH 9.3 for
the vesicles, spheres, and worms, respectively. The physical
explanation for these subtle variations in isoelectric point is not
clear and will be the subject of future work.
Dilute aqueous dispersions of spheres, worms and vesicles
were prepared in turn at both pH 3 and pH 10 and
subsequently analyzed to investigate whether their transfer
from ethanol to water had any effect on copolymer morphology
(see Figure 7). TEM studies indicated that the sphere and
vesicle particle morphologies are not dramatically altered at
either low or high pH. In the case of the worm-like
morphology, some vesicles are generated at pH 10. This is
believed to be due to the minimal cationic charge on the
PDMA chains since this pH significantly exceeds their pKa.
However, pH-dependent DLS studies using an autotitrator
indicate a significant increase in apparent size above pH 7 for all
three copolymer morphologies. This is interpreted as evidence
for flocculation at around the isoelectric point, rather than due
to a significant change in the particle dimensions.
CONCLUSIONS
■
In summary, RAFT dispersion polymerization of benzyl
methacrylate (BzMA) using a poly(2-(dimethylamino)ethyl
methacrylate) (PDMA) macro-CTA in ethanol at 70 °C leads
to the efficient production of near-monodisperse diblock
copolymers, which self-assemble in situ to form spheres,
worms, or vesicles depending on the precise reaction
conditions. Near-monodisperse sterically stabilized spherical
nanoparticles can be reproducibly synthesized with mean
diameters that can be readily adjusted from 36 to 108 nm
simply by varying the degree of polymerization of the core-
forming PBzMA block. A diblock copolymer worm phase can
also be accessed; such worms are relatively polydisperse in
terms of their lengths but have well-defined widths (∼10−20
nm). Relatively polydisperse vesicles with intensity-average
diameters ranging from 411 to 642 nm can also be obtained.
For a fixed PDMA stabilizer DP of 31, a detailed phase diagram
has been constructed. The observed particle morphology is very
sensitive to the target degree of polymerization of the core-
forming PBzMA block but is somewhat less sensitive to the
total solids concentration of the reaction solution, which ranged
A second PDMA macro-CTA with a somewhat higher mean
DP of 74 (Mw/Mn = 1.19) was also evaluated. Given the higher
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ASSOCIATED CONTENT
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(26) Wan, W.-M.; Pan, C.-Y. Polym. Chem. 2010, 1, 1475.
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* Supporting Information
Zeta potential and hydrodynamic diameter data as a function of
solution pH. This material is available free of charge via the
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: s.p.armes@sheffield.ac.uk.
Academic Press: London, 1991.
(32) Antonietti, M.; Forster, S. Adv. Mater. 2003, 15, 1323.
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Notes
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The authors declare no competing financial interest.
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Biomacromolecules 2009, 10, 1875.
ACKNOWLEDGMENTS
■
S.P.A. thanks EPSRC for postdoctoral support of M.S. (EP/
G007950/1) and A.B. (EP/E012949/1). The University of
Sheffield is thanked for a summer vacation undergraduate grant
to support E.R.J.
(38) Zhang, W. J.; D’Agosto, F.; Boyron, O.; Rieger, J.; Charleux, B.
Macromolecules 2011, 44, 7584.
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