Lower critical solution temperature behaviors of aromatic compounds with oligo(ethylene glycol) chains

Article abstract of DOI:10.1246/cl.150596

Amphiphilic small molecules comprising aromatic units and amphiphilic oligo(ethylene glycol) side chains were synthesized. These compounds exhibit lower critical solution temperatures (LCST) in aqueous solutions. Control of the LCST has been achieved by changing the solute concentration and adding salts or organic solvents.

Full text of DOI:10.1246/cl.150596

CL-150596
Received: June 23, 2015 | Accepted: July 24, 2015 | Web Released: October 5, 2015
Lower Critical Solution Temperature Behaviors of Aromatic Compounds
with Oligo(ethylene glycol) Chains
Masato Arai and Kazuaki Ito*
Department of Chemistry and Chemical Engineering, Graduate School of Science and Engineering,
Yamagata University, 4-3-16 Jyonan, Yonezawa, Yamagata 992-8510
(E-mail: itokazu@yz.yamagata-u.ac.jp)
Amphiphilic small molecules comprising aromatic units and
tosylate and the resulting product 6 was further treated with
hydrazine to give the corresponding hydrazide derivative 76 in
87% yield. The hydrazide derivative 7 was reacted with benzoyl
chloride in the presence of sodium carbonate to give 1 in 73%
yield. Similar reactions using 1-naphthalenecarboxylic acid
chloride, 9-anthracenecarboxylic acid chloride, and 1-pyrene-
carboxylic acid chloride instead of benzoyl chloride gave the
corresponding compounds 2, 3, and 4, in 87%, 84%, and 62%
yields, respectively.
amphiphilic oligo(ethylene glycol) side chains were synthesized.
These compounds exhibit lower critical solution temperatures
(LCST) in aqueous solutions. Control of the LCST has been
achieved by changing the solute concentration and adding salts
or organic solvents.
The self-assembly of molecules into supramolecular struc-
tures is an interesting approach for the development of new
nanomaterials.1 One example of a unique self-assembly phe-
nomenon is lower critical solution temperature (LCST) behavior,
wherein a material exhibits a phase transition from a soluble
state to an insoluble state when the temperature exceeds the
LCST. Recently, such temperature-responsive materials have
attracted considerable attention because of their promising
applications in many fields such as biomedicine, sensors,
catalysts, and molecule isolation.2 Although materials exhibiting
the LCST phenomena have been extensively studied in
water-soluble polymers such as poly(N-isopropylacrylamide),
poly(methyl vinyl ether), and poly(ethylene glycol),3 few studies
have been published on small molecules that exhibit LCST.4
Thus, we have investigated small molecules with LCST, that can
be easily modified to control the aggregation behavior and
introduce functional groups. It is generally accepted that an
appropriate ratio of hydrophilic-hydrophobic moieties in the
molecules is required for LCST behavior to occur.5 Therefore,
we designed hydrophobic aromatic compounds 1-4 bearing
amphiphilic oligo(ethylene glycol) moieties as materials that are
potentially responsive to changes in temperature (Figure 1). In
this study, we report the syntheses and solution properties of
these novel amphiphilic compounds.
Compounds 1, 2, and 4 were readily soluble in pure water at
room temperature, whereas 3 was not soluble in pure water even
under heating.7 In the aqueous solutions, compounds 1, 2, and 4
show similar thermal behaviors in response to heat. The aqueous
solutions were transparent at room temperature and became
turbid on warming, indicating that these compounds exhibited
LCST phenomena. This behavior of these compounds 1, 2, and
4 was reversible in cycles of warming and cooling and might
be caused by entropically favorable dehydration because of the
oligo(ethylene glycol) chains.8
To determine the transition temperature (Tt) for the LCST
phenomena, the transmittance values at 800 nm for the aqueous
solutions (concentration: 50 mM) were measured while heating
in the temperature range of 10-90 °C. The solutions were clear
at low temperature. Upon warming, the transmittance values at
800 nm remained at 100% until a certain temperature and then
suddenly decreased, indicating that the solution became turbid.
The whole process was thermally reversible and did not show
hysteresis (Figure S1). The temperature dependences of trans-
mittance at 800 nm for the different solutions are shown in
Figure 2. From the plots of transmittance at 800 nm versus
temperature, the values of Tt for 1, 2, and 4 were found to be 86,
Amphiphilic aromatic compounds 1-4 were synthesized as
shown in Scheme S1. Methyl gallic acid (5) was prepared in
75% yield via the reaction of gallic acid and dry methanol in the
presence of concentrated H2SO4 as catalyst. Methyl gallic acid
(5) was reacted with 2-[2-(2-methoxyethoxy)ethoxy]ethoxyl
Figure 2. Temperature dependence of light transmittance for
50 mM aqueous solutions of 1 (red line), 2 (blue line), 4 (black
line), and 7 (green line).
Figure 1. Amphiphilic aromatic compounds bearing oligo(ethyl-
ene glycol) chains 1-4.
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© 2015 The Chemical Society of Japan

Figure 3. Temperature dependence of light transmittance for
pure water, 5 wt % NaCl aqueous solution, and 3 wt % sodium
benzoate aqueous solution of 2 (c = 10 mM).
Figure 4. Concentration (c)-composition (ºH O) phase diagram
2
for 4 in ethanol/water mixture (open circles: non LCST behavior,
filled circles: LCST behavior).
43, and 52 °C, respectively. In contrast, the hydazide derivative
7, which lack an aromatic unit, did not exhibit any LCST
behavior.
To investigate the solute concentration dependence of Tt, the
transmittance at 800 nm was also measured at different solution
concentrations. The transmittance at 800 nm versus temperature
plots at various concentrations for 1, 2, and 4 are shown in
Figure S2. The Tt values for these three compounds shifted to
higher temperature with decreasing concentration (1: 86 °C at
50 mM, 80 °C at 100 mM; 2: 50 °C at 10 mM, 43 °C at 50 mM; 4:
55 °C at 1 mM, 52 °C at 3-50 mM). The critical concentrations
of LCST behavior of 1, 2, and 4 shift to lower values with
increasing hydrophobicity of the aromatic unit (1: 50 mM, 2:
10 mM, 4: 1 mM) as shown in Figure S2, indicating that the
hydrophobic components play an important role in the LCST
phenomena.
To investigate the effect of added salt on the LCST
behavior, sodium chloride or sodium benzoate was added to
the aqueous solutions of 1, 2, and 4. The addition of sodium
chloride decreased the Tt values of all three compounds.
Conversely, the addition of sodium benzoate increased the Tt
values (Figures 3 and S3). Furthermore, these salt effects were
enhanced by increasing the salt concentration. These behaviors
indicate that sodium chloride has a salting-out effect, whereas
sodium benzoate has a salting-in effect.9,10
The aqueous solution of 4 exhibits LCST behavior even in
the presence of organic solvents. Therefore, we investigated the
LCST behavior of 4 in mixed water/organic solvents with a
wide range of concentrations (1-100 mM) and mixed solvent
Figure 5. Size distributions in DLS in aqueous solutions of (a) 2
at 25 °C (red line: 10 mM, black line: 50 mM), red dotted line
(60 °C, 10 mM), black dotted line (50 °C, 50 mM); (b) 4 at 25 °C
(green line: 5 mM, red line: 10 mM, black line: 50 mM) and at
60 °C (green dotted line: 5 mM, red dotted line: 10 mM, black
dotted line: 50 mM).
the boundary line toward higher proportion of water (Figure S4).
These obtained results indicated that increasing the hydro-
phobicity of the organic cosolvent depresses LCST behavior.
To examine the size distributions of the aggregates of
compounds 2 and 4, dynamic light scattering (DLS) measure-
ments were carried out below and above Tt (Figure 5). Below Tt,
scattering peaks of 2 and 4 were observed for sizes of less than
10 nm, whereas above Tt, the observed peaks corresponded to
size larger than 1000 nm. The obtained hydrodynamic diameter
(Dh) values below and above Tt were significantly different,
indicating that the molecules predominantly existed as large
assemblies above Tt. Similar behavior was observed in the
compositions (ºH O (proportion of H2O in solvent mixture): 0-
2
100%). These solutions were examined at both low and high
temperature allowing the observation of two types of behavior:
transparent solution and opaque state. The LCST phenomena
were observed as the proportion of H2O in the solvent mixture
increased. When ethanol was used as the organic solvent,
a clearly demarcated boundary region emerged between the
transparent solution and the opaque state, as shown in Figure 4.
When methanol was used as organic cosolvent, the boundary
line shifted toward a lower proportion of water compared to
when ethanol was used: in contrast, the use of 1-propanol shifted
Chem. Lett. 2015, 44, 1416–1418 | doi:10.1246/cl.150596
© 2015 The Chemical Society of Japan | 1417

presence of salts (sodium chloride and sodium benzoate) as
shown in Figure S5.
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Variable-temperature (VT) 1H NMR measurements were
carried out on 50 mM solution of 1 in D2O. In the spectrum of 1
below Tt (30 °C), all signals were sharp and no peak broadening
was observed. In contrast, all the proton signals became broader
above Tt (70 °C). This observation supports the idea that the
phase separation of 1 occurs along with the suppression of the
molecule movements.11 Similar signal changes were observed
for the analogous compounds 2 and 4 at elevated temperature
(Figure S6).
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3
4
The gelation abilities of compounds 1-4 were also
examined in thirty organic solvents. Gel formation was
determined using the “stable to inversion of the test-tube”
method.12 Compounds 1-4 did not form organogels in any of the
tested organic solvents (Table S1). We also investigated the
gelation abilities using water/organic solvent mixtures: com-
pound 3 formed a gel when methanol or ethanol was used as the
organic cosolvent (Table S2). The results led us to conduct a
detailed examination of the gelation behavior of 3 in water/
ethanol mixtures with different compositions. Compound 3
could be dissolved in solvent mixtures containing 0%-60% (by
volume) water, however, gelation was not observed. Conversely,
compound 3 formed a gel in solvent mixtures containing 70%-
80% water, and yielded suspensions or remained insoluble
in mixtures containing more than 90% water. As shown in
Figure S7, the solutions of 3 in mixed water/ethanol solvents
containing 0%-60% water were slightly fluorescent under UV
light, whereas the gel states in solvents containing 70%-80%
water were highly fluorescent. The fluorescence spectra of 3 in
solution and gel states were collected in water/ethanol solvent
mixtures (Figure S8). Gelation-induced fluorescence enhance-
ment was observed for 3 in water/ethanol mixture containing
70%-80% water.13 The self-assembled gel structure of the
xerogel of 3 was examined by scanning electron microscopy
(SEM). The SEM image of the gel formed in the mixture
containing 80% water indicated that the gel had sheet-like
aggregates with thicknesses of approximately several hundred
nm (Figure S9).
In summary, we have prepared amphiphilic aromatic
compounds 1-4 with tri(ethylene glycol) side chains and
examined their LCST behaviors in aqueous solutions. Com-
pounds 1, 2, and 4 exhibited LCST behavior in pure water (and
in water/organic solvent mixture for 4), and the values of Tt
increased with a decreasing solution concentration. Compounds
1, 2, and 4 also exhibited decreased or increased Tt values in the
presence of added salts, indicating salting-out and salting-in
effects. The temperature-dependent aggregation behaviors were
also supported by DLS and VT 1H NMR measurements.
Compound 3 formed a gel in 70-80% water/ethanol mixtures
and exhibited gelation-induced fluorescence enhancement.
These amphiphilic aromatic compounds 1-4 show thermosensi-
tive properties making them potential temperature-responsive
materials.
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1418 | Chem. Lett. 2015, 44, 1416–1418 | doi:10.1246/cl.150596
© 2015 The Chemical Society of Japan