From a water-immiscible monomer to block copolymer nano-objects via a one-pot RAFT aqueous dispersion polymerization formulation

Article abstract of DOI:10.1021/ma301909w

We describe the facile atom-efficient synthesis of diblock copolymer nano-objects via a one-pot RAFT aqueous dispersion polymerization protocol starting from a water-immiscible methacrylic monomer. More specifically, an aqueous emulsion of glycidyl methacrylate (GlyMA) is quantitatively converted into a 10% w/w aqueous solution of glycerol monomethacrylate (GMA) at 80 C in air within 9 h in deionized water. ¹H NMR spectroscopy studies indicate no evidence for either methacrylic ester hydrolysis or polymerization during this ring-opening reaction. Kinetic analysis indicates that a significant rate acceleration occurs as the reaction mixture switches from a two-phase emulsion to a single aqueous phase. This observation is fully consistent with the GlyMA-GMA-water ternary phase diagram determined at 80 C. The 10% w/w aqueous solution of GMA can be polymerized using RAFT chemistry to produce a near-monodisperse PGMA macromolecular chain-transfer agent (macro-CTA), which indicates that relatively little dimethacrylate impurity is produced during the conversion of GlyMA into GMA. This PGMA macro-CTA can be subsequently chain-extended using 2-hydroxypropyl methacrylate (HPMA) via a RAFT aqueous dispersion polymerization formulation. The resulting PGMA-PHPMA diblock copolymers can form well-defined spheres, worms, or vesicles depending on the relative block compositions, since this dictates the copolymer curvature and hence the self-assembly behavior. Bearing in mind that GMA is a relatively expensive specialty monomer and GlyMA is a commodity monomer, this appears to be a highly cost-effective, purely aqueous one-pot route to diblock copolymer nano-objects.

Full text of DOI:10.1021/ma301909w

Article
pubs.acs.org/Macromolecules
From a Water-Immiscible Monomer to Block Copolymer Nano-
Objects via a One-Pot RAFT Aqueous Dispersion Polymerization
Formulation
L. P. D. Ratcliffe, A. J. Ryan, and S. P. Armes*
Dainton Building, Department of Chemistry, The University of Sheffield, Brook Hill, Sheffield, South Yorkshire S3 7HF, U.K.
S
* Supporting Information
ABSTRACT: We describe the facile atom-efficient synthesis
of diblock copolymer nano-objects via a one-pot RAFT
aqueous dispersion polymerization protocol starting from a
water-immiscible methacrylic monomer. More specifically, an
aqueous emulsion of glycidyl methacrylate (GlyMA) is
quantitatively converted into a 10% w/w aqueous solution of
glycerol monomethacrylate (GMA) at 80 °C in air within 9 h
1
in deionized water. H NMR spectroscopy studies indicate no
evidence for either methacrylic ester hydrolysis or polymer-
ization during this ring-opening reaction. Kinetic analysis indicates that a significant rate acceleration occurs as the reaction
mixture switches from a two-phase emulsion to a single aqueous phase. This observation is fully consistent with the GlyMA−
GMA−water ternary phase diagram determined at 80 °C. The 10% w/w aqueous solution of GMA can be polymerized using
RAFT chemistry to produce a near-monodisperse PGMA macromolecular chain-transfer agent (macro-CTA), which indicates
that relatively little dimethacrylate impurity is produced during the conversion of GlyMA into GMA. This PGMA macro-CTA
can be subsequently chain-extended using 2-hydroxypropyl methacrylate (HPMA) via a RAFT aqueous dispersion
polymerization formulation. The resulting PGMA−PHPMA diblock copolymers can form well-defined spheres, worms, or
vesicles depending on the relative block compositions, since this dictates the copolymer curvature and hence the self-assembly
behavior. Bearing in mind that GMA is a relatively expensive specialty monomer and GlyMA is a commodity monomer, this
appears to be a highly cost-effective, purely aqueous one-pot route to diblock copolymer nano-objects.
In 2010, Li and Armes20 reported the synthesis of
amphiphilic diblock copolymers based on GMA and 2-
hydroxypropyl methacrylate (HPMA) using reversible addi-
methacrylic monomer that is used commercially for the
INTRODUCTION
■
Glycerol monomethacrylate (GMA) is a hydrophilic nonionic
manufacture of soft contact lenses.1 In academic studies it
has also been utilized as a comonomer to prepare highly
biocompatible cross-linked hydrogels.1−4 GMA is usually
synthesized from glycerol, using acetone to protect two of its
three hydroxyl groups, prior to transesterification of the third
hydroxyl group with methyl methacrylate and finally selective
removal of the acetyl protecting group. This multistep route
makes GMA a relatively expensive specialty monomer and also
leads to a mixture of 1,3- and 2,3-hydroxy isomers.5
In principle, well-defined PGMA-based block copolymers can
be prepared using anionic polymerization. However, protecting
group chemistry is required for the hydroxyl groups, which
necessitates a three-step synthesis.6,7 More recently, a range of
controlled-structure GMA-based copolymers, including homo-
polymers,5 diblock and triblock copolymers,8−11 and macro-
monomers,12 have been synthesized directly using living radical
polymerization. For example, atom transfer radical polymer-
ization (ATRP)13−16 has been used to prepare well-defined
sterically stabilized latex particles that (i) adsorb reversibly onto
cellulose fibers via phenylboronic acid-mediated binding,17 (ii)
act as model Pickering emulsifiers,18 and (iii) can be covalently
stabilized to produce colloidosomes.19
tion−fragmentation chain transfer (RAFT) polymeriza-
tion.21−23 First, GMA was homopolymerized to produce a
water-soluble macromolecular chain transfer agent (macro-
CTA). Then chain extension was conducted using HPMA
under aqueous dispersion polymerization conditions (HPMA is
water-miscible up to 10% w/w at 70 °C but forms a water-
insoluble homopolymer). Using a fixed mean degree of
polymerization of the macro-CTA and working at an overall
concentration of 10% solids, a series of near-monodisperse
sterically stabilized PGMA−PHPMA diblock copolymer nano-
particles of controllable size in the 26−105 nm range were
produced simply by varying the target DP of the core-forming
PHPMA block. Moreover, a polydisperse vesicular morphology
was produced at 20% solids, and a one-pot protocol was briefly
explored. However, block copolymer polydispersities were
relatively high (Mw/Mn > 3.5) when targeting longer DP values
for the core-forming block due to the presence of a
dimethacrylate impurity in the HPMA monomer, which
Received: September 12, 2012
Revised: January 4, 2013
Published: January 17, 2013
© 2013 American Chemical Society
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Scheme 1. Conversion of Glycidyl Methacrylate (GlyMA) to Glycerol Monomethacrylate (GMA) in Water at 80 °C, Followed
by the in Situ Preparation of a near-Monodisperse PGMA Macro-CTA via RAFT Aqueous Solution Polymerization, Followed by
a
the Synthesis of a Well-Defined PGMA−PHPMA Diblock Copolymer via RAFT Aqueous Dispersion Polymerization
a
Systematic variation of the mean degree of polymerization of the core-forming hydrophobic PHPMA block enables either spheres, worms, or
vesicles to be obtained using this atom-efficient one-pot aqueous formulation.
Figure 1. 1H NMR spectra (CD3OD) of glycerol monomethacrylate (GMA) monomer prepared via hydrolysis of glycidyl methacrylate (GlyMA) at
10% w/w (upper spectrum), commercial GMA monomer donated by Cognis (middle spectrum), and commercial glycidyl methacrylate monomer
(lower spectrum).
inevitably led to branching. Moreover, blocking efficiencies
were relatively poor: GPC analyses typically revealed the
presence of significant levels (10−20%) of PGMA macro-CTA
as a contaminant.
(and hence degelation) being observed on cooling.26,27 This
unusual behavior allows facile sterilization via cold ultra-
filtration, with the original gel being reformed at ambient
temperature.
This prototype RAFT aqueous dispersion polymerization
formulation was subsequently optimized by Blanazs et al.24
Very high HPMA conversions were achieved within 2 h at 70
°C, with good blocking efficiencies and relatively low final
polydispersities (Mw/Mn < 1.20). In particular, detailed phase
diagrams were constructed that enable three distinct diblock
copolymer morphologies (spheres, worms, or vesicles) to be
reliably targeted.25 Moreover, the worm phase forms free-
standing aqueous gels due to inter-worm contacts.26 Such
worm gels are soft, shear-thinning, highly biocompatible, and
thermo-responsive, with a reversible worm-to-sphere transition
Herein we describe the synthesis of well-defined PGMA−
PHPMA diblock copolymers starting from glycidyl methacry-
late (GlyMA). In principle, this commodity monomer is an
ideal starting material, since literature precedent suggests that it
should react with 1 equiv of water to produce GMA with no
side products.28−30 In practice, GlyMA is water-immiscible, and
the only literature reports of such an approach involves the use
of glacial acetic acid or H2SO4 as a catalyst.31 However, we
show that a 10% w/w aqueous emulsion of GlyMA is
quantitatively converted into a 10% w/w aqueous solution of
GMA simply on heating at 80 °C for 8−9 h in the absence of
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copolymers of varying PHPMA DPs at a fixed PGMA DP. Finally, the
reaction was quenched by cooling to 0 °C and exposure to air.
Construction of Ternary Phase Diagram. An aqueous solution
of GMA and an aqueous emulsion of GlyMA were prepared at the
same monomer concentration (10.0% w/w) at 21 °C. The GMA
solution was gradually added to the GlyMA emulsion (3.00 g) in
known proportions (determined gravimetrically using a four-figure
balance) and shaken vigorously until the GMA−GlyMA aqueous
mixture became homogeneous, as judged by visual inspection. This
protocol was repeated several times and at various GMA and GlyMA
concentrations to obtain a ternary phase diagram. This phase diagram
protocol was repeated at 80 °C using a temperature-controlled oil
bath.
any catalyst (see Scheme 1 and Figure 1). Once formed, GMA
is directly polymerized in situ via RAFT aqueous solution
polymerization to produce a PGMA macro-CTA, which can be
subsequently chain-extended with HPMA to generate a range
of diblock copolymer nano-objects with controllable morphol-
ogies via a highly convenient and atom-efficient one-pot
protocol.
EXPERIMENTAL SECTION
■
Materials. Glycidyl methacrylate (GlyMA; 97%), 2-hydroxypropyl
methacrylate (HPMA; 97%), and 4,4′-azobis(4-cyanopentanoic acid)
(ACVA; V-501; 99%). HPLC analysis of the HPMA monomer24
indicated a dimethacrylate impurity of around 0.10 mol %. Glycerol
monomethacrylate (GMA; 99.8%) was kindly donated by Cognis
Performance Chemicals (Hythe, UK) and used without further
purification. Deuterated methanol (CD3OD) was purchased from
Goss Scientific (Nantwich, UK). Sodium hydrogen carbonate
(Laboratory Reagent grade) was purchased from Fisher Scientific
(Loughborough, UK). All solvents were of HPLC quality and were
purchased from Fisher Scientific (Loughborough, UK). Deionized
water (pH 6.3 at 21 °C) was used for all aqueous polymerizations.
Synthesis of Glycerol Monomethacrylate (GMA) from
Glycidyl Methacrylate (GlyMA). In a typical experiment, glycidyl
methacrylate (4.96 g, 35 mmol) was added to water (44.78 g, 2.49
mol, 10% w/w solution) in a round-bottomed flask fitted with a
condenser. The initial emulsion was stirred for 9 h at 80 °C and
eventually became a homogeneous aqueous solution, with 99%
1
Copolymer Characterization. H NMR Spectroscopy. All NMR
spectra were recorded using a 400 MHz Bruker Avance-400
spectrometer in CD3OD. At least 64 scans were recorded per
spectrum in each case.
Gel Permeation Chromatography (GPC). Polymer molecular
weights and polydispersities were determined using a DMF GPC
instrument operating at 60 °C that comprised two Polymer
Laboratories PL gel 5 μm Mixed C columns and one PL polar gel 5
μm guard column connected in series to a Varian 390 LC
multidetector suite (only the refractive index detector was utilized)
and a Varian 290-LC pump injection module. The GPC eluent was
HPLC grade DMF containing 10 mM LiBr and was filtered prior to
use. The flow rate was 1.0 mL min−1, and DMSO was used as a flow-
rate marker. Calibration was conducted using a series of 10 near-
monodisperse poly(methyl methacrylate) standards (Mn = 625−618
000 g mol−1, K = 2.094 × 10−3, α = 0.642). Chromatograms were
analyzed using Varian Cirrus GPC software.
Transmission Electron Microscopy (TEM). Copper 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
40 s to create a hydrophilic surface. Each aqueous diblock copolymer
dispersion (0.20% w/w, 11 μL) was placed onto a freshly glow-
discharged grid for 1 min and then blotted with filter paper to remove
excess solution. To stain the deposited nanoparticles, a 0.75% w/w
aqueous solution of uranyl formate (9 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. Imaging was performed at 100 kV using a Phillips CM100
instrument equipped with a Gatan 1k CCD camera.
1
1
conversion to glycerol monomethacrylate as judged by H NMR. H
NMR (400.13 MHz, CD3OD, 298 K): δ 1.97 (s, 3H, −CH3), 3.55−
3.65 (m, 2H, −CH2), 3.68−3.78 (m, 2H, −CH2), 3.86−3.92 (m, 1H,
−CH), 4.12−4.28 (m, 2H, −CH2), 4.93−5.0 (m, 1H, −CH), 5.63−
5.69 (m, 1H, =CH2), 6.14−6.2 (m, 1H, =CH2).
PGMAx Macro-CTA Synthesis Starting from GlyMA. A typical
protocol for the synthesis of PGMA56 is as follows. To a round-
bottomed flask containing 4-cyano-4-(2-phenylethane
sulfanylthiocarbonyl)sulfanylpentanoic acid (PETTC) RAFT agent
(0.222 mmol, 0.075 g, synthesized using the method described by
Semsarilar et al.32), an aqueous solution of GMA monomer (10 mmol,
1.60 g in 14.42 mL, prepared as described above) was added to target a
mean degree of polymerization (DP) of 45, assuming a CTA efficiency
of 100%. Further water (0.79 g, to afford a 10% w/w solution), ACVA
initiator (0.044 mmol, 12.5 mg, CTA/ACVA molar ratio = 5.0), and
NaHCO3 (0.225 mmol, 18.9 mg) were then added to this solution,
which was stirred until all of the PETTC had dissolved. The resulting
yellow solution was degassed via a nitrogen sparge for 30 min, before
the sealed flask was immersed into an oil bath set at 70 °C. After 4.5 h
Dynamic Light Scattering (DLS). Intensity-average diameters were
calculated via the Stokes−Einstein equation for dilute aqueous
dispersions of diblock copolymer nano-objects at 25 °C using a
Malvern Zetasizer NanoZS instrument at a scattering angle of 173°.
1
(final GMA conversion exceeded 99%, as judged by H NMR), the
RESULTS AND DISCUSSION
■
RAFT polymerization was quenched by immersion in ice and the
reaction solution was exposed to air. A small aliquot was removed,
freeze-dried, and then dissolved in methanol before precipitation into a
10-fold excess of chloroform. The precipitated PGMA macro-CTA was
washed three times with chloroform before being dried in a vacuum
A wide range of stimulus-responsive block copolymers can be
prepared using RAFT polymerization.33−41 In particular,
bespoke diblock copolymer nano-objects can be readily
prepared by polymerization-induced self-assembly (PISA)
using this chemistry.25,42−49 In addition to the examples
discussed in the Introduction, well-known literature reports
include the polymerization of N-isopropylacrylamide using a
poly(N,N′-dimethylacrylamide) macro-CTA via RAFT aqueous
dispersion polymerization50 and the polymerization of either
styrene51,52 or benzyl methacrylate45,46,53 or cholesteryl-based
monomers47 in either alcohol or alcohol/water mixtures via
RAFT dispersion polymerization. Similarly, An et al.54−56 have
reported a successful aqueous RAFT formulation for the
polymerization of acrylic monomers such as 2-methoxyethyl
acrylate.
1
oven overnight at 40 °C. H NMR analysis indicated a DP of 56 for
this PGMA macro-CTA as judged by end-group analysis. This
indicates a CTA efficiency of ∼80%. DMF GPC (refractive index
detector, using a series of near-monodisperse poly(methyl meth-
acrylate) calibration standards) indicated an Mn of 17 600 g mol−1 and
an Mw/Mn of 1.10.
RAFT Aqueous Dispersion Polymerization of a PGMA56−
PHPMA373 Diblock Copolymer. A typical protocol for the synthesis
of a PGMA56−PHPMA373 diblock copolymer is as follows: HPMA
monomer (3.90 g, 27.05 mmol; target DP = 373) and water (35.15 g,
to produce 10% w/w solids) were added in turn to a solution of
PGMA56 macro-CTA (0.65 g, 4.06 mmol dissolved in 5.85 g water) in
a 100 mL round-bottomed flask. ACVA was then added (6.04 mg,
0.022 mmol, CTA/ACVA molar ratio = 4.0), and the solution was
degassed via a nitrogen sparge for 30 min. The reaction flask was then
sealed and immersed in an oil bath set at 70 °C. The reaction solution
was then sampled at various time intervals to obtain a series of diblock
Recently, we reported the elucidation of detailed phase
diagrams for PGMA−PHPMA diblock copolymer nano-objects
prepared via RAFT aqueous dispersion polymerization.24 We
regard this formulation as a convenient prototypical model to
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develop our understanding of such systems. Moreover, in view
of the well-documented biocompatibility of both PGMA and
PHPMA,3,26,57,58 such formulations are expected to have
potential biomedical applications. Important goals of the
present study were (i) to address the relatively high cost of
using GMA and (ii) to develop a convenient one-pot aqueous
protocol that was sufficiently robust to allow access to each of
the three known morphologies (spheres, worms, and
vesicles).24,25
According to Shaw and co-workers, GlyMA can be converted
into GMA via forced hydrolysis in aqueous solution in the
presence of acetic acid at 80 °C.31a However, there is some
literature precedent to suggest that an acid catalyst may not be
required. For example, Wang et al.28 reported that epoxy ring-
opening reactions can be achieved for a wide range of water-
immiscible compounds (e.g., styrene oxide or cyclohexene
oxide) with good selectivity simply by heating an aqueous
suspension of the starting material to either 60 or 100 °C in the
absence of any other reagents. Since the dissociation constant
of water increases at elevated temperatures,59 Wang et al.28
suggested that water acted as both a reagent and a (very) mild
acid catalyst. However, epoxy-based vinyl monomers such as
GlyMA were not examined in this earlier study. Similarly,
Greenwood and co-workers60 have shown that the forced
hydrolysis of 3-glycidoxypropyltrimethoxysilane in dilute
aqueous solution at 60 °C allows the in situ synthesis of
glycerol-functionalized silica sols.29
Despite the above literature reports, it is not at all obvious
that such an approach would work well for epoxy-based
methacrylic monomers such as GlyMA. This is because
prolonged heating in water at high temperature is likely to
cause ester hydrolysis and perhaps also background polymer-
ization as well as the desired ring-opening of the epoxide group.
Moreover, at intermediate conversions it is also feasible that the
hydroxyl groups of the initially generated GMA might react
with the epoxide ring of the remaining GlyMA, which would
lead to the unwanted production of dimethacrylate impurities.
Nevertheless, we decided to explore the feasibility of converting
GlyMA into GMA in deionized water at 80 °C in the absence
of any catalyst (see Scheme 1). Since oxygen is a well-known
inhibitor, this reaction was conducted in air in order to prevent
in situ polymerization using an initial GlyMA concentration of
5, 10, or 15% w/w. The solubility of GlyMA in water was
estimated by visual inspection to be 1.4−1.5% w/w at 21 °C
and 2.4−2.5% w/w at 80 °C. Thus, each initial reaction mixture
was a two-phase GlyMA-in-water emulsion, rather than a
homogeneous aqueous solution. Conversion of GlyMA into
GMA was monitored by 1H NMR spectroscopy: the two epoxy
proton signals (5, see Figure 1) at 2.68 and 2.85 ppm due to
GlyMA gradually disappeared (see Figure S1 in the Supporting
Information), while new GMA signals assigned to the two
protons of the 2,3-hydroxy isomer (e) and the four protons of
the 1,3-hydroxy isomer (e′) appeared at 3.6 and 3.75 ppm,
respectively. This approach generated the representative kinetic
data shown in Figure 2 (see Figure S2 for the corresponding
conversion vs time curves).
Figure 2. Rate of hydrolysis of glycidyl methacrylate (GlyMA) to form
glycerol monomethacrylate (GMA) in water at 80 °C in the presence
of air at three different GlyMA concentrations, as judged by 1H NMR
spectroscopy. A significant rate enhancement is observed in each case,
the onset of which corresponds to the point in the reaction at which
sufficient GMA is generated to transform the initial two-phase
emulsion into a homogeneous aqueous solution (see inset).
of conditions, there will be a critical concentration of GMA
product that solubilizes all of the remaining water-immiscible
starting material to produce a single-phase reaction mixture,
which contains a higher GlyMA concentration than the limiting
aqueous solubility of this reactant. This hypothesis is supported
by visual inspection of the reaction solution, which changes
from a turbid emulsion to a transparent solution (see inset
digital photographs in Figure 2) at approximately the same
characteristic time at which the onset of the rate acceleration is
observed. This phase change occurs at approximately 1, 4, or 5
h for initial GlyMA concentrations of 5.0, 10.0, or 15.0% w/w,
respectively (see Figure 2 and Table 1).
Second, it is clear that the overall rate of conversion of
GlyMA into GMA is actually faster at a lower initial GlyMA
concentration (see Table 1). At first sight, this observation
appears to be counterintuitive: water is always present in large
excess (∼50 M for a 10% w/w formulation) in each
experiment, so the rate of reaction might be expected to be
simply pseudo-first-order with respect to the GlyMA
concentration. This classical assumption is valid for many
reactions conducted in homogeneous solution but requires
modification due to the heterogeneous (two-phase) nature of
the initial reaction mixture. Essentially, two pseudo-first-order
rate constants are required to describe the overall kinetics: a
relatively low rate constant is observed for the initial hydrolysis
conducted under heterogeneous conditions, whereas a
significantly higher value is obtained once the reaction solution
becomes homogeneous. Thus, the conversion of GlyMA into
GMA at 5.0% w/w is significantly faster than at 10.0% w/w (or
15.0% w/w) because rather less GMA is required to solubilize the
remaining GlyMA if the latter is present at a lower concentration.
As a result, the characteristic time period required for the
initially heterogeneous reaction mixture to become homoge-
neous is minimized, which leads to a faster overall rate of reaction
at a lower reagent concentration. This may also explain why the
acetic acid-catalyzed transformation of GlyMA into GMA was
conducted under relatively dilute conditions (∼7% w/w) by
Shaw et al.31a
There are several features of interest. First, the rate of
hydrolysis of GlyMA for the initial emulsion is relatively slow
due to the limited aqueous solubility of this monomer.
However, this rate clearly increases dramatically after a certain
characteristic time period. This corresponds to the point at
which the initial two-phase aqueous emulsion becomes a
homogeneous aqueous solution. This is because, for a given set
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Table 1. Heterogeneous and Homogeneous Rate Constants for the Conversion of Glycidyl Methacrylate (GlyMA) into Glycerol
Monomethacrylate (GMA) in Water at 80 °C in the Presence of Air at Three Different GlyMA Concentrations, As Judged by 1H
a
NMR Spectroscopy
initial
[GlyMA],
% w/w
estd time required for a
single phase reaction
soln, h
[GlyMA] at point of
[GMA] at point of
formation of single phase,
% w/w
two-phase rate one-phase rate
react time for conv of formation of single phase,
const, ×104 s−1 const, ×104 s−1
GlyMA into GMA
% w/w
5.0
10.0
15.0
1.02
0.58
0.46
1.33
1.37
1.02
1
4
5
8 h (96%)
9 h (99%)
14 h (99%)
2.5
4
2.5
6
6
9
a
1
The actual GlyMA and GMA concentrations at the point of formation of a homogeneous reaction solution are also estimated from the H NMR
data.
In view of this unusual situation, a GlyMA−GMA−water
primarily occur at the droplet surface during the initial two-
phase regime. Otherwise, a faster rate of hydrolysis would be
expected at higher GlyMA concentrations which is inconsistent
with the kinetic data shown in Figure 2. Instead, it is believed
that hydrolysis primarily occurs in the aqueous solution phase
at a rate that depends on the relatively low concentration of
dissolved GlyMA monomer (2.4 to 2.5% w/w), with the
emulsion droplets simply acting as GlyMA reservoirs.
ternary phase diagram was constructed at both ambient
temperature (21 °C) and also at the reaction temperature
used for the conversion of GlyMA to GMA (80 °C). This
tenary phase diagram is shown in Figure 3. The phase space for
In principle, at least three side reactions may occur during
the transformation of GlyMA into GMA. First, ester hydrolysis
of either GlyMA or GMA to produce methacrylic acid (and the
corresponding alcohol) might be expected. Second, polymer-
ization of either monomer could occur, although this is less
likely if the reaction is conducted in air because oxygen acts as
an effective inhibitor. Third, epoxy groups can be ring-opened
with primary or secondary alcohols; thus, GlyMA could react
with GMA to produce a dimethacrylate impurity. In practice,
1
the H NMR spectrum recorded for an aqueous solution of
GMA monomer produced after heating a 10.0% w/w aqueous
emulsion of GlyMA for 9 h at 80 °C is remarkably clean, with
no evidence for any of these side reactions (see Figure 1). In
1
fact, the main difference between this H NMR spectrum and
that of commercial GMA synthesized via the acetone protecting
group strategy (kindly donated by Cognis) is simply the relative
proportions of the major and minor isomers, which are 2,3-
dihydroxypropyl methacrylate and 1,3-dihydroxypropyl meth-
acrylate, respectively (see inset chemical structures in Figure 1).
The commercial route to GMA produces a 92:8 isomeric ratio,
whereas the GlyMA route to GMA utilized in the present work
generates an 87:13 isomeric ratio. As a comparison, Shaw et al.
obtained a 75:25 isomeric ratio for the synthesis of GMA from
GlyMA using an acetic acid catalyst; these workers also
suggested a mechanism to account for the formation of the
minor isomer.31 Despite this subtle variation in isomeric
composition, the GMA produced by forced hydrolysis of
GlyMA in the present study appears to behave identically to the
GMA provided by Cognis monomer when used for the in situ
synthesis of PGMA−PHPMA diblock copolymer nanoparticles
(see below).
The 10% w/w aqueous GMA solution obtained after the
hydrolysis of GlyMA at 80 °C for 9 h is a convenient starting
point for the one-pot synthesis of a PGMA macro-CTA via
RAFT chemistry. Thus, the aqueous GMA solution was cooled
to 20 °C and deoxygenated using a nitrogen sparge, and the
RAFT CTA (PETTC), free radical initiator (ACVA;
[PETTC]/[ACVA] molar ratio = 5.0), and NaHCO3 were
added prior to conducting the RAFT polymerization of GMA
at 70 °C, as shown in Scheme 1. A trithiocarbonate was
preferred for this aqueous solution polymerization since such
CTAs are known to be less susceptible to hydrolysis than
dithiobenzoates.22 NaHCO3 was utilized to ensure water
Figure 3. Ternary phase diagram obtained for various mass fractions of
glycidyl methacrylate, glycerol monomethacrylate, and water obtained
at 21 °C (black squares) and 80 °C (red circles). The blue triangles
represent the three critical ternary compositions corresponding to the
observed phase change from an initial aqueous emulsion to a
homogeneous aqueous solution for glycidyl methacrylate concen-
trations of 5.0, 10.0, or 15.0% w/w, as judged by 1H NMR
spectroscopy (see Figure 2).
the homogeneous (single phase) aqueous solution is clearly
larger at 80 °C than at 21 °C. This is consistent with the higher
water solubility observed for GlyMA at 80 °C but may also
indicate that the cosolvency effect of the GMA is greater at this
temperature. As anticipated, the critical compositions required
for the formation of a homogeneous GlyMA−GMA−water
solution indicated by this phase diagram correspond closely to
those estimated from the intermediate GlyMA conversions
1
(calculated from the H NMR data; see blue triangles) at the
characteristic times required for an upturn in the reaction rate
(see Table 1). This indicates that a self-consistent set of
physicochemical data has been obtained for this GlyMA-to-
GMA transformation. The initial GlyMA-in-water emulsions
were also characterized by optical microscopy at 21 °C.
Relatively unstable and rather polydisperse droplets of
approximately 5−200 μm were observed (see Figure S3),
with laser diffraction studies suggesting volume-average
diameters of 10−20 μm, regardless of the GlyMA concentration
(see Figure S4). This suggests that hydrolysis does not
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Figure 4. Kinetic data obtained for the synthesis of PGMA macro-CTA. A DP of 45 was targeted and a CTA/initiator molar ratio of 5.0 was utilized
at 70 °C in aqueous solution: (a) conversion vs time curve (black squares) and the corresponding semi-logarithmic plot (red circles); (b) DMF GPC
1
curves obtained with corresponding conversions, as judged by H NMR spectroscopy.
solubility of the PETTC in its anionic carboxylate form. The
mean degree of polymerization (DP) of the PGMA chains was
targeted to be 45, since we have recently shown that such DP
values enable a range of diblock copolymer morphologies to be
accessed when conducting RAFT syntheses under such
conditions.20,24,25 After a brief induction period of around 20
min (a common feature of RAFT polymerizations according to
the literature61−64), essentially full conversion (>99%) was
achieved within 4 h (see Figure 4a). DMF GPC chromatograms
were unimodal, and the evolution of molecular weight with
conversion was linear (see Figure 4b), which is characteristic of
such pseudo-living polymerizations. The near-monodisperse
nature of the PGMA chains (Mw/Mn = 1.10 at full conversion)
suggests that the dimethacrylate content of the GMA monomer
is relatively low, since this impurity would inevitably lead to
extensive branching if present at an appreciable concentra-
tion.65,66 However, it is perhaps noteworthy that such
branching can be difficult to detect when relatively low DP
values are targeted (see Figure S5 in the Supporting
Information and accompanying text for RAFT syntheses of
PGMA conducted in homogeneous solution when targeting a
higher DP of 200). After 4.5 h, a small sample of the PGMA
macro-CTA was extracted, freeze-dried from water, and
The reaction conditions used for the RAFT aqueous
dispersion polymerization of HPMA at 10.0% w/w solids are
indicated in Scheme 1. A diblock composition of PGMA56−
PHPMA373 was targeted, since our previous studies indicated
that such a formulation leads to the in situ evolution of
copolymer morphology.24,25 The polymerizing solution was
periodically sampled at various time intervals in order to
monitor both the monomer conversion and any change in
copolymer morphology. More than 99% conversion was
achieved within 1.5 h, as judged by 1H NMR studies.24 Diblock
copolymers with relatively low final polydispersities (Mw/Mn <
1.33) were produced that contained only modest levels of
macro-CTA contamination and the theoretical Mn values were
comparable to those given by the GPC data (see Figure 5).
Moreover, polydispersities increased with conversion, which
suggests some degree of branching due to low levels of
dimethacrylate impurity, as described elsewhere.20,24,67
1
precipitated into excess chloroform for H NMR and GPC
studies. The mean DP was estimated to be 56, which suggests a
CTA efficiency of around 80%. GPC analysis (vs poly(methyl
methacrylate) standards) indicated an Mn of 17 600 and an
Mw/Mn of 1.10.
Two different protocols were explored for the chain
extension of this PGMA56 macro-CTA. First, a deoxygenated
aqueous solution of HPMA and ACVA was added to the
aqueous PGMA56 solution while still under a nitrogen
atmosphere at 70 °C, thus allowing in situ polymerization of
HPMA to produce PGMA−PHPMA diblock copolymer nano-
objects. Alternatively, the PGMA56 aqueous solution was
exposed to air, cooled to 20 °C, and stored at 5 °C prior to
subsequent use. Such aqueous macro-CTA solutions could be
efficiently chain-extended with HPMA under RAFT aqueous
dispersion polymerization conditions up to 3 weeks after their
original synthesis to produce comparable results to those
achieved with the macro-CTA used immediately for in situ
PGMA−PHPMA diblock copolymer syntheses.
Figure 5. DMF GPC curves obtained for a series of PGMA56−
PHPMAy diblock copolymers (where y varies from 194 to 298) and
the corresponding PGMA56 macro-CTA.
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Figure 6. Representative TEM images obtained at various reaction times for the RAFT aqueous dispersion polymerization of HPMA at 70 °C using
a PGMA56 macro-CTA when targeting a final diblock copolymer composition of PGMA56−PHPMA373 at 10% w/w solids. (a) PGMA56−PHPMA194
spheres (at 52% HPMA conversion) (b) PGMA56−PHPMA272 sphere/worm mixed phase (at 73% HPMA conversion), (c) PGMA56−PHPMA280
worms (at 75% HPMA conversion), (d) PGMA56−PHPMA298 worm/vesicle mixed phase (at 80% HPMA conversion), and (e) PGMA56−
PHPMA336 vesicles (at 90% HPMA conversion).
The samples were subsequently analyzed by TEM to assess
HPMA concentration within the growing PHPMA-core
micelles.24
their copolymer morphology, as shown in Figure 6. The first
1
sample had an HPMA conversion of 53% as judged by H
NMR. This corresponds to a mean block composition of
PGMA56−PHPMA194 which is a predominantly spherical phase.
The second sample (PGMA56−PHPMA272) exhibited a mixed
sphere/short worm phase, while a pure worm phase is observed
at 75% conversion (PGMA56−PHPMA280). A predominantly
vesicular phase was obtained at 90% conversion (PGMA56−
PHPMA336), with pure vesicles being observed for all samples
taken after this point. In general, the observed evolution in
diblock copolymer morphology is consistent with that
previously reported by Blanazs et al.24,25 DLS analysis of the
diluted reaction solutions corroborated these TEM studies.
Thus, the spheres observed in Figure 6a had an intensity-
average diameter of 32 nm and a relatively low polydispersity
(0.085). The pure worm phase (Figure 6c) had a sphere-
equivalent intensity-average diameter of 52 nm and a rather
higher polydispersity of 0.133, while the vesicular phase shown
in Figure 6e had an intensity-average diameter of 316 nm and a
relatively broad size distribution (polydispersity = 0.215).
Similar DLS observations have been previously reported by
Blanazs and co-workers.24,26
Finally, it is perhaps worth emphasizing the complex phase
behavior exemplified by this facile one-pot formulation. During
the initial in situ hydrolysis of GlyMA, its rate of conversion
into GMA is significantly enhanced by the switch from a two-
phase emulsion to the formation of a single phase, since this
increases the GlyMA concentration in the aqueous continuous
phase. The GMA monomer is then polymerized in
homogeneous aqueous solution to produce a water-soluble
macro-CTA. During the subsequent RAFT polymerization of
HPMA using this PGMA macro-CTA, the rate of polymer-
ization of the hydrophobic monomer is enhanced by phase
separation, since nucleation leads to a relatively high local
CONCLUSIONS
■
A highly convenient atom-efficient one-pot synthesis of well-
defined PGMA−PHPMA diblock copolymer nano-objects
starting from glycidyl methacrylate (GlyMA) using RAFT
aqueous dispersion polymerization is described. This water-
immiscible commodity monomer is readily converted into
glycerol monomethacrylate simply by heating a 10% w/w
aqueous emulsion of GlyMA droplets at 80 °C in air for 9 h in
the absence of any catalyst. Remarkably, 1H NMR spectroscopy
indicates that this transformation is highly selective, with no
background evidence for either ester hydrolysis or polymer-
ization and only a relatively low level of dimethacrylate impurity
is produced. The kinetics of GlyMA hydrolysis is complex: a
significant rate enhancement is observed when the initial two-
phase aqueous emulsion eventually becomes a homogeneous
aqueous solution. Since GMA acts as a cosolvent for GlyMA,
this transformation occurs at a critical intermediate conversion
that depends on both the initial GlyMA concentration and the
reaction temperature. This leads to an unusual observation: the
rate of hydrolysis is actually faster when conducted in more
dilute solution. Construction of a GlyMA−GMA−water ternary
phase diagram sheds useful light on this system. Once formed,
the GMA is directly polymerized in situ via RAFT aqueous
solution polymerization to produce a PGMA macro-CTA,
which can be subsequently chain-extended with HPMA under
aqueous dispersion polymerization conditions to generate a
range of diblock copolymer nano-objects with well-defined
morphologies (e.g., spheres, worms, or vesicles). This new
approach augurs well for potential applications of these nano-
objects, since it significantly reduces their overall cost by
replacing the relatively expensive GMA monomer with a much
cheaper feedstock (GlyMA). It also offers a potentially cost-
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effective solution for compliance with new legislation regarding
the registration of chemicals in Europe (REACH).
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ASSOCIATED CONTENT
■
5274−5276.
S
* Supporting Information
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1
Typical intermediate H NMR spectra and conversion vs time
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microscopy images and laser diffraction droplet size distribu-
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obtained for PGMA200 homopolymers. This material is
available. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
*E-mail s.p.armes@shef.ac.uk.
Notes
The authors declare the following competing financial
interest(s): We have filed a process patent application to
protect the IP associated with this work.
ACKNOWLEDGMENTS
■
We thank the Scott Bader company (Wollaston, Northants,
UK) for part-funding this EPSRC PhD studentship and also for
permission to publish this work. Cognis (now GEO) is
acknowledged for its generous supply of GMA and HPMA
monomers. We thank Prof. N. C. Billingham of the University
of Sussex, UK for useful comments on an early draft of this
manuscript.
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