European Polymer Journal xxx (2015) xxx–xxx

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European Polymer Journal

journal homepage: www.elsevier.com/locate/europolj

Schizophrenic thermoresponsive block copolymer micelles

based on LCST and UCST behavior in ethanol–water mixtures
Aydin Can a,b,c,d,1, Qilu Zhang e,2, Tobias Rudolph c,d,1, Felix H. Schacher c,d,1,
Jean-François Gohy f, Ulrich S. Schubert a,b,c,d,⇑,1, Richard Hoogenboom e,⇑,2
a
Laboratory of Macromolecular Chemistry and Nanoscience, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands
b
Dutch Polymer Institute (DPI), John F. Kennedylaan 2, 5612 AB Eindhoven, The Netherlands
c
Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich-Schiller-University Jena, Humboldtstrasse 10, 07743 Jena, Germany
d
Jena Center of Soft Mater (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany
e
Supramolecular Chemistry Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 S4, 9000 Ghent, Belgium
f
Bio and Soft Matter (BSMA), Institute of Condensed Matter and Nanoscience (IMCN), Université catholique de Louvain, Place L. Pasteur 1, 1348
Louvain-la-Neuve, Belgium

a r t i c l e i n f o a b s t r a c t

Article history: The development of responsive and multiresponsive polymers is gaining interest as they
Received 1 January 2015 enable the development of more and more complex responsive materials. In this contribu-
Received in revised form 1 April 2015 tion, the synthesis and solubility behavior of well-defined poly(methyl acrylate) (PMA) and
Accepted 6 April 2015
poly(diethylene glycol ethyl ether acrylate) (PDEGEA) homopolymers as well as PMA-
Available online xxxx
block-PDEGEA block copolymers is reported. At first, a solubility screening of the
homopolymers in ethanol–water solvent mixtures was performed in a high-throughput
Keywords:
experimentation (HTE) manner using parallel turbidimetry, which revealed that in
Micellization
Thermoresponsive polymers
35 wt% ethanol PMA undergoes an upper critical solution temperature (UCST) phase tran-
UCST behavior sition while PDEGEA undergoes a lower critical solution temperature phase transition in
LCST behavior this solvent mixture. Moreover, the thermoresponsive self-assembly of PMA-b-PDEGEA
Self-assembly block copolymers in water and ethanol were investigated by turbidimetry and DLS reveal-
Ethanol–water mixtures ing UCST-induced disassembly of the micelles in ethanol and LCST-induced clustering of
the micelles in water. Finally schizophrenic behavior of the PMA-b-PDEGEA block copoly-
mers in 35 wt% ethanol is demonstrated.
Ó 2015 Elsevier Ltd. All rights reserved.

1. Introduction homogeneous catalysis, biomimetic materials, and cosmet-

ics. Polymeric micelles are mostly prepared via self-assem-
Thermoresponsive polymers have attracted significant bly of amphiphilic block copolymers and the incorporation
interest due to their potential applications in drug delivery, of thermoresponsive polymer blocks leads to responsive
micelles [1–8]. The preparation of such well-defined
⇑ Corresponding authors at: Laboratory of Organic and Macromolecular amphiphilic block copolymers is strongly facilitated by
Chemistry (IOMC), Friedrich-Schiller-University Jena, Humboldtstrasse
the important advances that have been made in living
10, 07743 Jena, Germany. Fax: +49 (0)3641 948202 (U.S. Schubert);
Supramolecular Chemistry Group, Department of Organic and Macro- and controlled polymerization techniques in the last few
molecular Chemistry, Ghent University, Krijgslaan 281 S4, 9000 Ghent, decades [9–14]. These polymerization techniques, includ-
Belgium. Fax: +32 (0)9 264 4998 (R. Hoogenboom). ing anionic, controlled radical, group transfer, and
E-mail addresses: [email protected] (U.S. Schubert), metathesis polymerization, have all been successfully used
[email protected] (R. Hoogenboom).
1 to prepare well-defined block copolymers.
Fax: +49 (0)3641 948202.
2
Fax: +32 (0)9 264 4998.

http://dx.doi.org/10.1016/j.eurpolymj.2015.04.008
0014-3057/Ó 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Can A et al. Schizophrenic thermoresponsive block copolymer micelles based on LCST and UCST behavior
in ethanol–water mixtures. Eur. Polym. J. (2015), http://dx.doi.org/10.1016/j.eurpolymj.2015.04.008
2 A. Can et al. / European Polymer Journal xxx (2015) xxx–xxx

Thermoresponsive polymer solubility transitions can be poly(vinyl alcohol) copolymers [39], proline based systems
basically divided in two types; lower critical solution tem- [40] and homopolymers of N-acryloylasparaginamide [34].
perature (LCST) behavior and upper critical solution tem- UCST behavior in water–alcohol solvent mixtures has been
perature (UCST) behavior. From the literature reported for, e.g., poly(2-oxazoline)s [41–43], poly(methyl
perspective, LCST is most commonly studied since all methacrylate) [44–46], poly(methyl acrylate) [47],
water-soluble polymers with intermediate hydrophilicity poly(oligoethyleneglycol (meth)acrylate) [46] and a
exhibit a LCST transition, including a wide range of polyampholyte [48]. Furthermore, polymer UCST behavior
homopolymers and almost unlimited number of different has been observed in water–DMSO mixtures [49] or in
copolymers [15–21]. The LCST phase transition has also ionic liquids [50] too. From the application perspective,
been exploited for a wide range of applications often in there are only few examples involving UCST polymers uti-
the biomedical field [17,22], including drug delivery lization for nanoparticles [51], nanocomposites [52] and
[15,23], switchable surfaces for cell growth [24,25] and nanogels [53].
actuators for microfluidic devices [26,27], whereby the The occurrence of LCST and UCST behavior in different
transition temperature can be easily tuned by copolymer- polymer systems prompted scientists to combine both
ization or by adding additives like salts or buffers [28– within a single material. In case of block copolymers, such
31]. In contrast to the vast amount of literature on LCST dual responsive systems that can form micelles or reversed
polymers, much less studies are reported involving UCST micelles at different conditions are known as ‘schizophre-
polymers since a UCST phase transition is not commonly nic’ block copolymers [54]. Combining both LCST and
observed in aqueous polymer solutions. From a thermody- UCST thermoresponsive behavior into one block copolymer
namic perspective, temperature induced solubility phase enables inversion of core and corona by simply changing
transitions are related to both polymer–polymer and poly- the temperature and has mostly been achieved with poly-
mer–solvent interactions. In water the polymer–solvent betaines [55–58] or polysulfobetaine [59–61] as UCST
interactions mainly depend on hydrogen bonding between polymer [62–65]. For example, a non-ionic LCST polymer
water and the polymer as well as polymer–polymer inter- based on N-isopropylacrylamide (NIPA) and a polybetaine
actions. Heating an aqueous polymer solution will UCST polymer based on 3-[N-(3-methacrylamidopropyl)-
decrease the attractive hydrogen bonding polymer–water N,N-dimethyl]ammoniopropane sulfonate was reported
interactions while the loss of entropy due to fixation of to yield schizophrenic block copolymers after fine tuning
water molecules increases. Eventually, this leads to of the block length [66]. Only very recently, we reported
entropy driven dehydration of the polymer chains upon a schizophrenic block copolymer that could be switched
heating, i.e. LCST behavior. Since UCST behavior is the between three states based on the combined UCST and
reverse phenomenon, it rarely occurs in water and specific LCST behavior of poly(dimethylaminoethyl methacrylate)
polymers need to be designed with strong attractive forces in presence of hexacyanocobalt(III) trivalent anions [67–
at low temperature while being strongly hydrophilic to 69].
avoid the occurrence of LCST behavior upon heating too, In the current contribution, we aimed to introduce both
or at least make sure the LCST phase transition occurs at LCST and UCST behavior within a non-ionic amphiphilic
higher temperatures than the UCST phase transition [32– block copolymer leading to both thermoresponsive as well
35]. Alternatively, the solvent can be changed from water as schizophrenic micelles, depending on the utilized sol-
to alcohol/water mixtures that show non-ideal mixing vent mixture. Poly(methyl acrylate) (PMA) was chosen as
behavior, accompanied with significant decrease in solvent UCST block based on our recent report that it shows
polarity upon heating also leading to a UCST type phase UCST behavior in ethanol–water solvent mixtures [47].
behavior [36,37]. There are several polymer classes that Poly(diethylene glycol ethyl ether acrylate) (PDEGEA)
are studied for their UCST behavior in water like poly(vinyl was chosen as LCST segment since it shows LCST behavior
methyl ether)s [38], N-acryloylglycinamide (NAGA) in water and expectedly also in ethanol–water solvent
homopolymer and copolymers from NAGA and N-acety- mixtures with low ethanol content [70]. At first, the LCST
lacrylamide (NAcAAm) [32,35], poly(p-dioxanone)-grafted and UCST behaviors of PMA and PDEGEA homopolymers

Scheme 1. Schematic representation of the synthesis of PMA macroinitiators and PMA-b-PDEGEA block copolymers via ATRP.

Please cite this article in press as: Can A et al. Schizophrenic thermoresponsive block copolymer micelles based on LCST and UCST behavior
in ethanol–water mixtures. Eur. Polym. J. (2015), http://dx.doi.org/10.1016/j.eurpolymj.2015.04.008
 A. Can et al. / European Polymer Journal xxx (2015) xxx–xxx 3

in ethanol–water solvent mixtures will be discussed. acrylate (DEGEA). The resulting PMA-b-PDEGEA block
Furthermore, thermoresponsive micellization of PMA-b- copolymers have dispersities below 1.30 as determined
PDEGEA block copolymers will be evaluated in ethanol- by SEC (Fig. 1) indicative of the formation of defined block
rich and aqueous solutions. Finally, the ethanol–water sol- copolymers and a systematical variation in block length
vent ratio will be fine-tuned in search for combined LCST– and composition was successfully achieved allowing the
UCST schizophrenic micellization behavior. evaluation of structure–property relationships in the tem-
perature responsive solubility and micellization behavior.
It should be noted that all SEC traces reveal the presence
2. Results and discussion of a small high molar mass shoulder ascribed to coupling
due to termination, unavoidable during the radical poly-
2.1. Polymer synthesis merization of acrylates. MALDI-TOF MS also revealed the
formation of well-defined block copolymers, even allowing
In the current study, the aim was to prepare thermore- the calculation of their molar mass (Fig. 1, Table 1). The
sponsive and schizophrenic micelles from poly(methyl presence of a relatively large homopolymer fraction in
acrylate)-block-poly(diethylene glycol ethyl ether acrylate) the MALDI TOF mass spectra is opposing the SEC results
(PMA-b-PDEGEA) block copolymers in ethanol–water sol- and may be ascribed to the significantly easier desorption
vent mixtures. The block copolymers were synthesized and ionization of the homopolymers in comparison to the
via ATRP in a two-step approach as depicted in block copolymers. Therefore, 1H NMR spectroscopy was
Scheme 1. All the synthesized PMA homopolymers used to accurately determine the monomer ratio of the
revealed a narrow molar mass distribution by SEC as was block copolymers based on the integrals of the signals cor-
also confirmed by MALDI-TOF-MS (Table 1). The PMA responding to the side chains of PMA and PDEGEA that are
homopolymers were subsequently used as macroinitiators indicated in Fig. 2. The combination of MALDI-TOF MS and
1
for the polymerization of diethyleneglycol ethyl ether H NMR spectroscopy was then used to calculate the DP of

Table 1
Number average molar mass (Mn) and dispersity (Ð) of the synthesized PMA macro-initiators and PMA-PDEGEA block copolymers.

Entry Polymer structurea Mn,theob (g/mol) Mn,SEC (g/mol) Mn,MALDI (g/mol) Ð (SEC) fPMAc (wt%)
PMA1 PMA64 4000 5800 5200 1.06
PDEGEA1 PDEGEA30 6000 6250 5600 1.13
PDEGEA2 PDEGEA94 15,200 18,800 17,600 1.14
Macro1 PMA102 7100 9700 8600 1.06
Macro2 PMA54 3800 5400 4700 1.06
Macro3 PMA40 4600 3700 4000 1.07
P1 PMA102-b-PDEGEA16 10,100 13,000 11,500 1.09 74
P2 PMA102-b-PDEGEA66 19,500 22,500 22,000 1.14 41
P3 PMA54-b-PDEGEA102 23,000 24,000 24,000 1.20 20
P4 PMA40-b-PDEGEA200 42,200 28,000 41,000 1.30 8
a
Calculated from MALDI-TOF MS for the homopolymers and a combination of MALDI-TOF MS and 1H NMR spectroscopy for the block copolymers.
b
Calculated from GC conversion.
c
Calculated from 1H NMR spectroscopy.

Fig. 1. Comparison of SEC traces (A) and MALDI-TOF mass spectra (B) of P1 (yellow trace), P2 (green trace), P3 (red trace), P4 (blue trace). (For interpretation
of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Please cite this article in press as: Can A et al. Schizophrenic thermoresponsive block copolymer micelles based on LCST and UCST behavior
in ethanol–water mixtures. Eur. Polym. J. (2015), http://dx.doi.org/10.1016/j.eurpolymj.2015.04.008
4 A. Can et al. / European Polymer Journal xxx (2015) xxx–xxx

Fig. 2. Comparison of 1H NMR spectra of P1 (yellow trace), P2 (green trace), P3 (red trace), P4 (blue trace) as well as the structural assignment of the signals.
(For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

both blocks, which is required to correlate the block Upon addition of ethanol to an aqueous solution of
copolymer structure with the solubility behavior. PDEGEA, the solubility is initially lowered, i.e. the Tcp
decreases, which can be ascribed to the cononsolvency
2.2. Homopolymer solubility behavior in ethanol–water effect [71–74], whereby the addition of a good solvent
mixtures leads to lower solubility. Adding more ethanol to the sol-
vent mixture eventually also leads to increased solubility
The thermoresponsive solubility of the PMA and as ethanol is a better solvent for PDEGEA than water. The
PDEGEA homopolymers was investigated by turbidimetry PDEGEA with higher DP shows very similar solubility with
in ethanol–water solvent mixtures with varying composi- 0–20 wt% ethanol while a slight decrease in solubility in
tion as basis for further evaluation of the thermorespon- solutions with 25–35 wt% ethanol is observed.
sive and schizophrenic micellization behavior of the These solubility studies on the PMA and PDEGEA
PMA-b-PDEGEA block copolymers (Fig. 3). The PMA homopolymers reveal an interesting intermediate solvent
homopolymers revealed an UCST behavior with only small composition regime, where PMA exhibits a UCST transition
hysteresis between heating and cooling in ethanol rich and PDEGEA exhibits a LCST transition, namely with 30–
solutions ranging from 35 to 100 wt% ethanol with a solu- 40 wt% ethanol in water. Thus, it may be anticipated that
bility maximum around 70–80 wt%. The enhanced solubil- PMA-b-PDEGEA block copolymers could reveal both LCST
ity of PMA upon adding the non-solvent water to ethanol, and UCST behavior in this solvent mixture range poten-
as revealed by a decrease in the UCST transition tempera- tially leading to schizophrenic micelles.
ture, can be ascribed to the non-ideal mixing behavior of
water and ethanol. The maximum polymer solubility in 2.3. Thermoresponsive micellization of PMA-b-PDEGEA block
70–80 wt% of ethanol in water can be ascribed to water copolymers in ethanol–water mixtures
being mostly present as individual molecules leading to
efficient hydration of PMA. As a result PMA becomes more The complex thermoresponsive micellization of the
soluble as water acts as a solubilizing hydration layer as PMA-b-PDEGEA block copolymers was investigated in
previously also demonstrated for PMMA [44]. Further three different solvent regimes, namely ethanol, water
increasing the water content, i.e. lowering the ethanol con- and in 30–40 wt% ethanol–water mixtures. Based on the
tent below 70 wt%, leads to higher solvent polarity and the study of homopolymer solubility behavior, vide supra, it
presence of water clusters leading to a decrease in PMA is expected that the block copolymers can be switched
solubility, eventually leading to insolubility of PMA between micelles at lower temperatures and individually
domains in solvent mixtures with less than 35 wt% etha- dissolved polymer chains in ethanol, making use of the
nol. By roughly doubling the DP of the PMA homopolymer PMA UCST transition. In water, micelles are expected to
from 64 to 102, the UCST transition phase diagram is be formed at lower temperatures where PMA is insoluble
shifted to lower cloud point temperatures (Tcp) indicating and PDEGEA is soluble. Upon heating above the LCST tran-
decreased solubility as was previously also reported for sition temperature the PDEGEA will collapse and the
PMMA in ethanol–water solvent mixtures [45]. micelles will agglomerate, while the PMA stabilizes the
Subsequently, the solubility of the PDEGEA homopoly- core in solution. In the intermediate solvent composition
mers was studied revealing that PDEGEA exhibits LCST regime where both PMA and PDEGEA are thermorespon-
behavior in solvent mixtures with low ethanol content sive, it is expected that PMA-core micelles are present at
and it is fully soluble above a 40 wt% ethanol content. low temperatures, followed by aggregation upon heating

Please cite this article in press as: Can A et al. Schizophrenic thermoresponsive block copolymer micelles based on LCST and UCST behavior
in ethanol–water mixtures. Eur. Polym. J. (2015), http://dx.doi.org/10.1016/j.eurpolymj.2015.04.008
 A. Can et al. / European Polymer Journal xxx (2015) xxx–xxx 5

100

90

80

70

Temperature ( C)
60
PMA64 heating
o
50 PMA64 cooling
40 PMA102 heating
30 PMA102 cooling
PDEGEA30 heating
20
PDEGEA30 cooling
10
PDEGEA94 heating
0 PDEGEA94 cooling
-10

0 10 20 30 40 50 60 70 80 90 100
Ethanol content (wt%)

Fig. 3. Cloud point temperatures (Tcp) of PMA and PDEGEA homopolymers as function of the ethanol content in the ethanol–water solvent mixture (PMA
shows UCST behavior, PDEGEA shows LCST behavior, all measured at 5 mg/mL).

above the LCST transition of PDEGEA and further heating After establishing the UCST controlled thermorespon-
leads to solubilization of PMA, potentially leading to sive aggregation behavior for PMA-b-PDEGEA block
reversed micelles. All these thermoresponsive micelliza- copolymers, we focused our attention to the LCST con-
tion scenarios are schematically depicted in Scheme 2. trolled thermoresponsive micellization behavior in water
At first, the thermoresponsive micellization behavior as depicted in Scheme 2. The expected transition from
of the PMA-b-PDEGEA block copolymers was investigated micelles or aggregates at low temperature and larger
in ethanol-rich solvent mixtures, where PDEGEA is fully agglomerates when heating above the LCST phase transi-
soluble and PMA is only soluble above the UCST phase tion temperature of PDEGEA complicates the analysis as
transition temperature. In order to investigate this behav- the agglomerated state was found to be unstable leading
ior, solubility studies of the block copolymers were per- to macroscopic precipitation. Macroscopic observations
formed by turbidimetry in ethanol. The transmittance and turbidimetry revealed that both P1 and P4 are fully
versus temperature plots show that the polymers P2 and insoluble in water, P1 due to a too large PMA fraction
P3 form turbid solutions below 5 °C and upon heating and P4 due to the rather long PDEGEA block that appar-
the solutions become clear (Fig. 4). This behavior is ently has a LCST phase transition temperature below 0 °C
indicative for a transition from polymer aggregates to sol- (Fig. 6). For P2 and P3 it was possible to obtain stable solu-
uble polymer chains due to the UCST transition of PMA tions at low temperatures and upon heating the transmit-
upon heating. In contrast, P1 shows scattered transmit- tance decreased due to agglomeration of the formed
tance due to poor solubility of the polymer while P4 aggregates. Unfortunately, DLS did not provide useful
was found to be to fully soluble and did not show a tran- information as at low temperatures very high polydispersi-
sition in turbidimetry. ties were obtained for the aggregates and at elevated tem-
In order to better understand the thermoresponsive peratures the formed agglomerates were too large. In
behavior of the PMA-b-PDEGEA block copolymers in etha- conclusion, we can only qualitatively report that PMA-b-
nol, temperature controlled dynamic light scattering (DLS) PDEGEA undergoes aggregation in water as well as further
was performed for block copolymer P3 in ethanol. At low agglomeration of the aggregates upon heating beyond the
temperatures, large aggregates with particle size with a LCST phase transition temperature of the PDEGEA
hydrodynamic size of around 860 and 660 nm were segment.
observed at 2 and 10 °C, respectively (Fig. 5). Further heat- Finally, the schizophrenic micellization of the PMA-b-
ing to 20 °C led to a decrease in particle size to 2–3 nm PDEGEA block copolymers was investigated in solvent
indicative of individual polymer chains resulting from the mixtures with 30, 35 and 40 wt% ethanol. P1 and P2 were
UCST phase transition of the PMA block from hydrophobic found to be insoluble within the temperature range that
to hydrophilic. Repeating the measurement as well as we studied (0–80 °C) indicating that the hydrophobic
using intensity distribution and volume distribution also PMA block is too large.
confirmed the validity and reproducibility of the results. For P3 the UCST transition of PMA was observed around
Importantly, the gradual decrease in particle size when 8 to 8 °C depending on the ethanol content of the solvent
heating from 2 to 10 °C may be a direct result of the enthal- mixture (30 wt%, 35 wt% and 40 wt% ethanol; Fig. 7). The
pic nature of the UCST phase transition, in contrast to the LCST transition of PDEGEA could not be observed, indicat-
sharp entropic LCST phase transition [75]. ing that the PDEGEA block is too short and remains soluble

Please cite this article in press as: Can A et al. Schizophrenic thermoresponsive block copolymer micelles based on LCST and UCST behavior
in ethanol–water mixtures. Eur. Polym. J. (2015), http://dx.doi.org/10.1016/j.eurpolymj.2015.04.008
6 A. Can et al. / European Polymer Journal xxx (2015) xxx–xxx

Scheme 2. Schematic representation of the expected thermoresponsive micellization behavior of the PMA-b-PDEGEA block copolymers.

Fig. 4. Transmittance versus temperature plots for the block copolymers

Fig. 5. Hydrodynamic diameter of the objects in solution resulting from
P1 (yellow curve), P2 (green curve) and P3 (red curve) in pure
dynamic light scattering as function of temperature for block copolymer
ethanol.(For interpretation of the references to colour in this figure
P3 in ethanol.
legend, the reader is referred to the web version of this article.)

in the investigated temperature range. As such it may be distribution (note that intensity distributions are plotted)
speculated that P3 undergoes a temperature transition of larger aggregates is also observed, most likely represent-
from micelles at low temperatures to individual polymer ing loose polymer aggregates. From the angle dependent
chains when passing the UCST phase transition tempera- measurements it can be concluded that smaller objects
ture of PMA. are spherical due to the approximately constant shape of
DLS investigations were performed to verify this the curve with an increase in the scattering angle. Albeit
hypothesis that unimers are present above the UCST tran- the presence of small objects confirms the hypothesis that
sition at 25 °C (Fig. 8). All three solvent mixtures revealed PDEGEA is soluble at 25 °C, the observed size of 15 nm in
the presence of mainly small objects with a size that 30 wt% ethanol is rather large and may indicate selective
decreases from 15 to 5 nm when improving the solvent solvation of the PMA by ethanol molecules leading to a lar-
quality from 30 to 40 wt% ethanol. A second minor ger hydrodynamic size.

Please cite this article in press as: Can A et al. Schizophrenic thermoresponsive block copolymer micelles based on LCST and UCST behavior
in ethanol–water mixtures. Eur. Polym. J. (2015), http://dx.doi.org/10.1016/j.eurpolymj.2015.04.008
 A. Can et al. / European Polymer Journal xxx (2015) xxx–xxx 7

Fig. 6. Transmittance versus temperature plots for the block copolymers

P1 (yellow curve), P2 (green curve) and P3 (red curve) in pure water.(For
interpretation of the references to colour in this figure legend, the reader
is referred to the web version of this article.)

Fig. 7. Transmittance versus temperature plots for the block copolymer

P3 in ethanol–water mixtures: 30 wt% (black curve), 35 wt% (red curve),
and 40 wt% (blue curve) ethanol. (For interpretation of the references to
colour in this figure legend, the reader is referred to the web version of
this article.)

Despite that P3 revealed UCST responsive micellization,

the length of the PDEGEA was still too short to observe its
LCST transition. Therefore, the thermoresponsive micel- Fig. 8. Representative intensity size distributions obtained by DLS at
lization behavior of P4, which has a DP of 40 for PMA 25 °C (CONTIN analysis for scattering at 75° (black curve), 90° (red curve)
and a DP of 200 for PDEGEA, was studied. During the tur- and 105° (blue curve)) for PMA54-b-PDEGEA102 (P3) 30% (top), 35%
bidimetry measurements (Fig. 9) it was observed that the (middle) and 40% (bottom) ethanol–water mixtures. (For interpretation of
the references to colour in this figure legend, the reader is referred to the
block copolymer in a solvent mixture with 40 wt% ethanol web version of this article.)
revealed two different phase transitions around 18 and
63 °C, respectively. The appearance of the solution at dif-
ferent temperatures was visually inspected (photographs phase transition resulting in its aggregation while PMA
are included in Fig. 9) revealing that the solution of remains soluble, leading to an increase in turbidity. As
PMA40-b-PDEGEA200 (P4) first undergoes a transition from such, the turbidimetry and visual inspection confirm the
a turbid solution into a clear solution upon heating from 0 anticipated schizophrenic thermoresponsive aggregation
to 30 °C, which can be ascribed to the UCST transition of behavior of PMA-b-PDEGEA, although not following the
PMA at 18 °C. Then, the block copolymer solution remains order of events as proposed in Scheme 2. Instead, upon
clear within the 18–63 °C temperature range. Upon further heating from 0 to 80 °C the UCST transition of PMA occurs
heating above 63 °C PDEGEA collapses due to its LCST first followed by the LCST transition of PDEGEA. This

Please cite this article in press as: Can A et al. Schizophrenic thermoresponsive block copolymer micelles based on LCST and UCST behavior
in ethanol–water mixtures. Eur. Polym. J. (2015), http://dx.doi.org/10.1016/j.eurpolymj.2015.04.008
8 A. Can et al. / European Polymer Journal xxx (2015) xxx–xxx

100
Second heating
Second cooling
80

Transmittance (%) 60

40

20

0 10 20 30 40 50 60 70 80 90 100
Temperature (°C)

Fig. 9. Transmittance versus temperature plots for the block copolymer P3 in an ethanol–water mixture with 40 wt% ethanol: heating (red curve) and
cooling (blue curve). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

change in the order of events is due to the influence of one is the solvophobic block. Heating the solution leads to a
block onto the phase transition temperature of the other clear solution at intermediate temperatures when heating
block. The presence of the soluble PDEGEA block lowers above the UCST transition of PMA and to aggregates with
the UCST transition temperature of PMA while the soluble PDEGEA as solvophobic block at further elevated tempera-
PMA, above its UCST transition, also increases the LCST tures above the LCST phase transition temperature of the
transition temperature of the PDEGEA. PDEGEA block. An important observation is that the UCST
and LCST transition temperatures in the block copolymer
are reversed in comparison to the homopolymers, which
3. Conclusions
we ascribe to the cross-influence of the attached blocks
to the phase transition temperatures of the other blocks,
Defined PMA and PDEGEA homopolymers as well as
i.e. the UCST of PMA is lowered due to attaching a more
PMA-b-PDEGEA block copolymers were successfully syn-
soluble block while the LCST of PDEGEA is increased due
thesized by ATRP. All block copolymers with a molar mass
attaching the soluble, above its UCST, PMA block.
up to 40 kDa could be analyzed by MALDI-TOF MS, SEC and
1
H NMR spectroscopy, although a significant amount of
homopolymer impurity was observed in MALDI-TOF MS, 4. Experimental part
presumably due to easier ionization. The thermorespon-
sive solubility behavior of the homopolymers was first 4.1. Materials
studied in ethanol–water mixtures, revealing that PMA
undergoes a UCST phase transition in ethanol rich solu- Ethyl-2-bromoisobutyrate (EBIB) (Aldrich, >98%), cop-
tions and PDEGEA undergoes a LCST phase transition in per (I) bromide (CuBr) (Aldrich, 99.999%), and
water-rich solvent mixtures. Interestingly, at intermediate N,N,Nl,N,Nlll-pentamethyldiethylenetriamine (PMDETA)
ethanol content of 35–40 wt% ethanol, both homopoly- (Aldrich, 99%) were used as received. The solvents, dichlor-
mers show an opposite thermoresponsive behavior. omethane, hexane, ethanol and methanol were obtained
Furthermore, it was found that both PMA and PDEGEA from Biosolve and used as received. Anisole (Aldrich,
have molar mass dependent cloud point temperatures that 99%), di ethylene glycol ethoxy acrylate (Aldrich, 99%)
decrease with increasing molar mass. Moreover, the PMA- and methyl acrylate (Aldrich, 99%) were purified by pass-
b-PDEGEA block copolymer is demonstrated to undergo ing over a short silica column. Demineralized water was
UCST-controlled self-assembly in ethanol, whereby used in all experiments.
micelles are formed at low temperatures that dissolve into
unimers upon heating above the PMA UCST phase transi-
tion. In water, the block copolymer self-assembles at lower 4.2. Instrumentation
temperatures and the formed aggregates further agglomer-
1
ate when heating above the PDEGEA LCST phase transition H NMR spectra were recorded on a Varian AM-400
temperature. Finally, block copolymer P4 is shown to spectrometer using deuterated chloroform (CDCl3) as sol-
undergo temperature induced schizophrenic self-assem- vent. Chemical shifts are reported in ppm relative to TMS
bly. At low temperatures it forms aggregates where PMA or residual solvent signals.

Please cite this article in press as: Can A et al. Schizophrenic thermoresponsive block copolymer micelles based on LCST and UCST behavior
in ethanol–water mixtures. Eur. Polym. J. (2015), http://dx.doi.org/10.1016/j.eurpolymj.2015.04.008
 A. Can et al. / European Polymer Journal xxx (2015) xxx–xxx 9

Size exclusion chromatography (SEC) was measured on purged with argon gas during cooling to ambient temper-
a Shimadzu system equipped with a SCL-A10 system con- ature before use. The polymerization was conducted in a
troller, a LC-10AD pump, a RID-10A refractive index detec- microwave vial using anisole as solvent. The catalyst
tor, a SPD-10A UVdetector at 254 nm, and a PLgel 5 lm (CuBr) was weighed into the flask. The reaction flask with
Mixed-D column at 50 °C utilizing a chloroform:triethy- a stirring bar was sealed with rubber septa and purged
lamine:2-propanol (94:4:2) mixture as eluent at a flow with argon for 15 min. Subsequently, the monomer (MA
rate of 1 mL/min. The molar masses and the molar mass or DEGEA) and the ligand (PMDETA) were dissolved in ani-
distribution of the prepared polymers were calculated sole and transferred into the reaction flask by syringe. The
using poly(styrene) and poly(methyl methacrylate) solution was stirred and bubbled with argon for 15 min
standards. before the solution was immersed into a preheated oil
MALDI-TOF MS measurements were performed with an bath. The initiator was introduced into the reaction flask
Ultraflex III TOF/TOF (Bruker Daltonics, Bremen, Germany) by a syringe. When using macroinitiators, the polymer
mass spectrometer equipped with a Nd:YAG laser and a was dissolved in anisole before adding to the polymeriza-
collision cell. All spectra were measured in the positive tion mixture. Polymerizations were carried out under
ion mode. The instrument was calibrated prior to each argon at 90 °C. The solution was initially light green and
measurement with an external PMMA standard turned from light purple to dark purple in time. During
H(CH2CCH3COOCH3)nH + Na+(measured with sodium the polymerization, samples were taken and directly ana-
iodide) from PSS in the required measurement range. MS lyzed by GC and SEC. The polymerizations were stopped
data were processed using the software FlexAnalysis, if the desired conversion or molar mass was obtained.
PolyTools 1.0 and an isotope pattern calculator from The final polymers were dissolved in dichloromethane,
Bruker Daltonics and Data Explorer software. precipitated into ice-cold methanol for macroinitiators
For the sample preparation, all polymers (10 mg/mL) in and hexane for block copolymers and dried in a vacuum
THF, DCTB in chloroform (20 mg/mL) were used, and NaI oven overnight.
was used as the doping salt in analysis. The dried-droplet To remove the catalyst, the polymers were dissolved in
spotting technique (matrix and analyte previously mixed dichloromethane and passed through a basic aluminum
together) was applied. For each sample 1 lL of the mixture oxide column prepared with the same solvent. The poly-
was spotted onto the target plate. mer that eluted over the column was reprecipitated into
GC measurements were performed on an Interscience ice-cold methanol or hexane and dried in a vacuum oven
Trace GC with a Trace Column RTX-5 connected to a PAL overnight. The pure polymers were dissolved in chloro-
autosampler. For direct injection of the polymerization form and analyzed by SEC, 1H NMR spectroscopy and
mixtures, a special Interscience liner with additional glass MALDI-TOF MS.
wool was used.
The turbidity measurements were performed using a 4.4. ATRP of MA and DEGEA
Crystal 16Ò turbidimeter from Avantium Technologies.
The transmittance was measured during two controlled PMA64: 15 mL anisole, 12.09 g (0.15 mol) of methyl
heating/cooling cycles from 20 to 100 °C with a heating acrylate, 143 mg (1 mmol) of CuBr, 209 lL (1 mmol) of
rate of 1.0 °C per minute. The second cycle was used to PMDETA and 147 lL (1 mmol) of ethyl-2-bromoisobu-
determine the transition temperatures at 50% transmit- tyrate (EBIB) were introduced to the vial for polymeriza-
tance. Samples were prepared by weighing 5.0 mg or tion according to the general procedure. The
1.0 mg of the polymer into a HPLC vial covered with a polymerization was carried out at 90 °C for 4 h. The result-
screw cap containing a hole and a septum. Subsequently, ing polymer was dissolved in 10 mL dichloromethane, pre-
1.0 mL of the desired ethanol–water solvent mixture was cipitated into 200 mL ice-cold methanol and dried in a
added. vacuum oven overnight resulting in 4.2 g polymer (94%
DLS measurements were performed on a Malvern CGS- yield) which has a 44% conversion, number average molar
3 apparatus equipped with a He–Ne laser with a wave- mass of 5800 g/mol and a polydispersity of 1.06.
length k of 632.8 nm. The temperature was controlled, PDEGEA30: 10 mL anisole, 9.4 g (0.05 mol) of DEGEA,
and the measurements were conducted at three angles 143 mg (1 mmol) of CuBr, 209 lL (1 mmol) of PMDETA
(50°, 90° and 130°). The experimental autocorrelation and 147 lL (1 mmol) of EBIB were introduced to the vial
function was analyzed using the Cumulant and CONTIN for polymerization according to the general procedure.
methods. All measurements were conducted at a concen- The polymerization was carried out at 90 °C for 3 h. The
tration of 5 mg/mL leading to the determination of appar- resulting polymer was dissolved in 10 mL dichloro-
ent hydrodynamic diameters. The linear evolution of C methane, precipitated into 200 mL ice-cold methanol and
versus q2 was systematically verified at three different scat- dried in a vacuum oven overnight resulting in 5.2 g poly-
tering angles by extrapolation to 0° scattering angle, con- mer (92% yield) which has a 62% conversion, number aver-
firming the formation of spherical micelles. age molar mass of 6250 g/mol and a polydispersity of 1.13.
PDEGEA94: 20 mL anisole, 18.8 g (0.1 mol) of DEGEA,
4.3. General procedure for the solution ATRP for the synthesis 143 mg (1 mmol) of CuBr, 209 lL (1 mmol) of PMDETA
of homo and block (co)polymers and 147 lL (1 mmol) of EBIB were introduced to the vial
for polymerization according to the general procedure.
The used glassware and other tools like needles or stir- The polymerization was carried out at 90 °C for 16 h. The
ring bars were dried overnight in an oven at 120 °C and resulting polymer was dissolved in 10 mL

Please cite this article in press as: Can A et al. Schizophrenic thermoresponsive block copolymer micelles based on LCST and UCST behavior
in ethanol–water mixtures. Eur. Polym. J. (2015), http://dx.doi.org/10.1016/j.eurpolymj.2015.04.008
10 A. Can et al. / European Polymer Journal xxx (2015) xxx–xxx

dichloromethane, precipitated into 200 mL ice-cold 23% conversion, number average molar mass of
methanol and dried in a vacuum oven overnight resulting 22,500 g/mol and a polydispersity of 1.14.
in 8.2 g polymer (91% yield) which has a 40% conversion, PMA54-b-PDEGEA: 10 mL anisole, 7.53 g (0.04 mol) of
number average molar mass of 18,800 g/mol and a polydis- DEGEA, 29 mg (0.2 mmol) of CuBr, 42 lL (0.2 mmol) of
persity of 1.14. PMDETA and 1.0 g (0.2 mmol) of poly(methyl acrylate)
PMA102: 13 mL anisole, 13.00 g (0.15 mol) of methyl (PMA54) as macroinitiator were introduced to the vial for
acrylate, 72 mg (0.75 mmol) of CuBr, 157 lL (0.75 mmol) polymerization according to the general procedure. The
of PMDETA and 110 lL (0.75 mmol) of EBIB were intro- polymerization was carried out at 90 °C for 10 h. The
duced to the vial for polymerization according to the gen- resulting polymer was dissolved in 5 mL dichloromethane,
eral procedure. The polymerization was carried out at precipitated into hexane and dried in a vacuum oven over-
90 °C for 6 h. The resulting polymer was dissolved in night resulting in 3.4 g polymer (89% yield) which has a
10 mL dichloromethane, precipitated into 250 mL ice-cold 37% conversion, weight average molar mass of
methanol and dried in a vacuum oven overnight resulting 24,000 g/mol and a polydispersity of 1.20.
in 4.8 g polymer (92% yield) which has a 40% conversion, PMA40-b-PDEGEA: 10 mL anisole, 7.53 g (0.04 mol) of
number average molar mass of 9700 g/mol and a polydis- DEGEA, 29 mg (1 mmol) of CuBr, 42 lL (1 mmol) of
persity of 1.06. PMDETA and 1.0 g (0.2 mmol) of poly(methyl acrylate)
PMA54: 10 mL anisole, 10.07 g (0.117 mol) of methyl (PMA40) as macroinitiator were introduced to the vial for
acrylate, 168 mg (1.17 mmol) of CuBr, 244 lL (1.17 mmol) polymerization according to the general procedure. The
of PMDETA and 167 lL (1.17 mmol) of EBIB were intro- polymerization was carried out at 90 °C for 16 h. The
duced to the vial for polymerization according to the gen- resulting polymer was dissolved in 5 mL dichloromethane,
eral procedure. The polymerization was carried out at precipitated into hexane and dried in a vacuum oven over-
90 °C for 3 h. The resulting polymer was dissolved in night resulting in 3.9 g polymer (94% yield) which has a
10 mL dichloromethane, precipitated into 200 mL ice-cold 42% conversion, number average molar mass of
methanol and dried in a vacuum oven overnight resulting 28,000 g/mol and a polydispersity of 1.30.
in 3.9 g polymer (93% yield) which has a 42% conversion,
number average molar mass of 5400 g/mol and a polydis-
4.6. Micellization procedure
persity of 1.06.
PMA40: 10 mL anisole, 8.6 g (0.1 mol) of methyl acrylate,
The polymer sample was weighed into a HPLC vial cov-
143 mg (1 mmol) of CuBr, 209 lL (1 mmol) of PMDETA and
ered with a screw cap containing a hole and a septum and
147 lL (1 mmol) of EBIB were introduced to the vial for
required amount of ethanol, water or ethanol–water (30/
polymerization according to the general procedure. The
70 wt%, 35/65 wt% or 40/60 wt%) solvent mixture was
polymerization was carried out at 90 °C for 1 h. The result-
added resulting in 5 mg/mL concentration. Subsequently,
ing polymer was dissolved in 5 mL dichloromethane, pre-
this mixture of very viscous polymer and solvent was
cipitated into 100 mL ice-cold methanol and dried in a
heated till 60 °C via constant heat of 1 °C/min in a system-
vacuum oven overnight resulting in 4.1 g polymer (93%
atic way. The micellar solution was obtained by cooling to
yield) which has a 51% conversion, number average molar
ambient temperature.
mass of 4000 g/mol and a polydispersity of 1.07.
Caution: It is important to use high quality HPLC vials
covered with a screw cap with a hole and a septum, which
acts as pressure valve, upon heating beyond the boiling
4.5. ATRP of DEGEA with PMA macroinitiators
point of the solvents for the preparation of the micelles
to prevent too high overpressures potentially leading to
PMA102-b-PDEGEA: 5 mL anisole, 2.82 g (0.015 mol) of
explosion of the vial.
DEGEA, 36 mg (0.25 mmol) of CuBr, 52 lL (0.25 mmol) of
PMDETA and 2.5 g (0.2 mmol) of poly(methyl acrylate)
(PMA102) as macroinitiator were introduced to the vial Acknowledgements
for polymerization according to the general procedure.
The polymerization was carried out at 90 °C for 10 h. The The Dutch Polymer Institute (DPI; project #604) is
resulting polymer was dissolved in 5 mL dichloromethane, acknowledged for financial support. QZ thanks China
precipitated into hexane and dried in a vacuum oven over- Scholarship Council (2010629042) and Ghent University
night resulting in 2.8 g polymer (94% yield) which has a (BOF11/CHN/009)) for financial support for his PhD pro-
17% conversion, number average molar mass of gram. JFG and RH acknowledge the Belgian Program on
13,000 g/mol and a polydispersity of 1.09. Interuniversity Attraction Poles initiated by the Belgian
PMA102-b-PDEGEA: 10 mL anisole, 8.09 g (0.043 mol) of State, the Prime Minister’s office (P7/05). TR acknowledges
DEGEA, 31 mg (0.215 mmol) of CuBr, 45 lL (0.215 mmol) the Carl-Zeiss foundation for a PhD-scholarship.
of PMDETA and 2.043 g (0.215 mmol) of poly(methyl acry-
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in ethanol–water mixtures. Eur. Polym. J. (2015), http://dx.doi.org/10.1016/j.eurpolymj.2015.04.008
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Please cite this article in press as: Can A et al. Schizophrenic thermoresponsive block copolymer micelles based on LCST and UCST behavior
in ethanol–water mixtures. Eur. Polym. J. (2015), http://dx.doi.org/10.1016/j.eurpolymj.2015.04.008