Synthesis of fluorinated oxadiazoles with gelation and oxygen storage ability

Article abstract of DOI:10.1039/c2ob07024c

A new family of fluorinated low molecular weight (LMW) gelators has been synthesized through SNAr substitution of 5-polyfluoroaryl-3-perfluoroheptyl-1,2, 4-oxadiazoles with glycine ester. The obtained compounds give thermal and pH-sensitive hydrogels or thermo-reversible organogels in DMSO. Oxygen solubility studies showed the ability to maintain high oxygen levels in solution and in gel blend with plate counter agar (PCA). The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob07024c

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PAPER
Synthesis of fluorinated oxadiazoles with gelation and oxygen storage ability†
Antonio Palumbo Piccionello,*a Annalisa Guarcello,a Alessandro Calabrese,a,b Ivana Pibiri,a Andrea Pacea
and Silvestre Buscemia
Received 2nd December 2011, Accepted 15th February 2012
DOI: 10.1039/c2ob07024c
A new family of fluorinated low molecular weight (LMW) gelators has been synthesized through SNAr
substitution of 5-polyfluoroaryl-3-perfluoroheptyl-1,2,4-oxadiazoles with glycine ester. The obtained
compounds give thermal and pH-sensitive hydrogels or thermo-reversible organogels in DMSO. Oxygen
solubility studies showed the ability to maintain high oxygen levels in solution and in gel blend with plate
counter agar (PCA).
pentafluorophenyl-1,2,4-oxadiazole as arylating agent.6 Interest-
ingly, the obtained fluorinated polymers formed association col-
Introduction
Gel formation represents an attractive research area due to the
unique properties of this type of soft material which presents
many applications in the biomedical field.1 Hydrogels represent
the most interesting class of gels due to their current and pro-
spective pharmacological uses.1 Compared to the most common
polymeric gelators, which predominantly form chemical gels,
low molecular weight gelators (LMWGs) essentially form phys-
ical gels in which the molecules are self-assembled into three-
dimensional structures, held together by non-covalent inter-
actions.2 Because of the typical supramolecular interaction, these
molecules are arranged as well ordered assemblies and the
formed gels are stable, thermally reversible and exhibit a high
tolerance towards additives.2 Moreover, low minimal gelation
concentrations (MGC) are often found for LMWGs.2e–g In this
context, the introduction of fluorinated moieties into amphiphilic
molecules has been widely studied due to their peculiar proper-
ties such as chemical inertness, thermal stability, very high
surface activity, high gas solubility and low critical micelle con-
centrations (CMC).3,4 Moreover, fluorinated colloidal systems
allow the obtainment of highly organized structures such as
micelles, bilayers, vesicles and tubules, whose formation is
enhanced by the aggregation of fluorous moieties.4 This ten-
dency to self-assemble has been also used in order to promote
hydrogel formation from various fluorinated polymers.5
Recently, we reported the introduction of fluorinated moieties
into polyaspartamide copolymers using 3-perfluoroheptyl-5-
loids consisting of macromolecular units where the hydrophobic
fluorinated oxadiazole blocks were aggregated within the core of
the micelle.6 Indeed, 1,2,4-oxadiazoles present many biological
activities7 and their perfluoroalkylated derivatives possess a pro-
nounced tendency to self-assemble.8 Based on these consider-
ations, we decided to design new fluorinated amphiphilic
oxadiazoles, with potential self-assembly and hydrogelation
ability. In fact, while fluorinated LMW organogelators are
common,9 only a few examples of fluorinated LMW hydrogela-
tors have been reported.10 Additionally, the presence of func-
tional groups able to respond to different acidic conditions has
been considered due to the importance of pH-sensitive hydro-
gels.11 According to the general structural architecture reported
for low molecular weight hydrogelators,12 our designed com-
pounds contain a seven-carbon perfluoroalkyl chain as hydro-
phobic portion,
a
polyfluorophenyl-1,2,4-oxadiazole rigid
spacer, and the aminoacidic moiety of glycine as a pH-sensitive
polar head group (Fig. 1).
Results and discussion
Considering that 5-polyfluorophenyl-1,2,4-oxadiazoles can
easily undergo nucleophilic aromatic substitution of the 4′-fluoro
moiety under mild experimental conditions,13 we decided to
aDipartimento di Scienze e Tecnologie Molecolari e Biomolecolari –
Sez. Chimica Organica “E. Paternò”, Università degli Studi di
Palermo, Viale delle Scienze – Parco d’Orleans II, Ed. 17, I-90128
Palermo, Italy. E-mail: antonio.palumbopiccionello@unipa.it; Fax:
+39091596825; Tel: +3909123897544
bENEA UTTRI-RIF, Ufficio di Palermo, via Catania 2, 90141 Palermo,
Italy
†Electronic supplementary information (ESI) available: NMR spectra of
compounds 4–9. See DOI: 10.1039/c2ob07024c
Fig. 1 General structure for designed fluorinated amphiphilic
oxadiazoles.
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introduce the aminoacidic moiety of glycine on the already
formed oxadiazoles 4 during the late steps of the synthetic route
(Scheme 1). In turn, 1,2,4-oxadiazoles 4 were obtained following
the conventional amidoxime route7 through initial acylation of
perfluoroheptylamidoxime 114 and subsequent solvent-free cycli-
zation of the corresponding O-acyl-amidoxime 3 (Scheme 1).
Glycine ethyl ester was then introduced through SNAr, in DMF
at rt, producing compounds 5, which were finally converted into
the corresponding acids 6 (Scheme 1).
Compounds 6a–c, which differ in the fluorine content of the
rigid spacer, resulted insoluble in water even after prolonged
reflux. Nevertheless, complete dissolution of 6a–c in water was
reached by adding an equimolar amount of an inorganic base
MOH (M+ = Li+, Na+, K+). Interestingly, gelation was observed
after heating and subsequently cooling the obtained solutions,
with formation of semi-transparent hydrogels from all com-
pounds 6. On the other hand, any attempt to obtain organogels
from compounds 6 in common organic solvents failed due to
formation of solutions (in DMF, DMSO, EtOH, MeOH, or THF)
or precipitate (in DCM, CHCl3, or PhCH3). Minimal gelation
concentrations (MGC, mg mL−1) in water were determined by
performing the tube inversion test on lithium, sodium and pot-
assium salts of oxadiazoles 6a–c (Table 1).
It is noteworthy that the fluorine content of the arylic spacer
has a dramatic effect on the MGC which decreases by about
20–35% for each added fluorine atom and indicates the deproto-
nated form of 6c as the most effective gelator in all cases. Con-
sidering the effect of cations on the gelation ability of
compounds 6, it’s noteworthy that the MGC increased as the
radius of the alkaline metal ion decreased. In this case K+, which
compared with Li+ and Na+ has been recently shown to be the
least effective in stabilizing spherical micelles of amphiphilic
polycarboxylates,15 was the most efficient cation in enhancing
water gelation ability of deprotonated 6c. A likely explanation
considers the ability of the potassium cation in stabilizing aggre-
gates with low curvature such as bilayers of cylindrical
micelles.15,16
The self-assembling properties of the potassium salt of com-
pound 6c were further characterized by determining the critical
aggregation concentration (CAC). By using pyrene as fluorescent
probe, a CAC of 1.91 0.02 × 10−4 M was found, a value which
is about two orders of magnitude lower than that of other fluori-
nated anionic surfactants,10d and than MGC. This result suggests
the hierarchical self-assembly of aggregates toward the formation
of physical gels. The pyrene emission I1/I3 ratio decreases as the
concentration of 6c− increases, reaching its lowest value of 1.36
(Fig. 2) which is similar to that found for other fluorinated sur-
factants.17 This indicates that pyrene is presumably positioned at
the interface of the hydrated aggregate palisade layer.17
All obtained gels from 6a–c were stable at room temperature
for more than two months and were responsive to pH and temp-
erature changes. Addition of 1 equivalent of HCl to the gel
phase caused precipitation of the oxadiazole compound while
gel formation was again observed by addition of a base (Fig. 3).
In particular, for the potassium salts of oxadiazole 6c, a tran-
sition pH value of pHsol–gel = 6.6 was determined for the gel dis-
assembling process.
This reversible pH-dependent gelation behavior can be
obviously ascribed to the presence of the glycine moiety.18 Simi-
larly, liquid and gel phases were reversibly observed upon
heating and cooling, respectively (Fig. 3). The gel–sol transition
Table 1 Minimal gelation concentration (MGC) in water for the anions
of compounds 6a–c with different cations
Compound
Cation
MGC (mg mL−1
)
6a
6a
6a
6b
6b
6b
6c
6c
6c
K+
25
30
37.5
20
22.5
30
12.5
15
20
Na+
Li+
K+
Na+
Li+
K+
Na+
Li+
Scheme 1 Synthesis of compounds 5 and 6. (i) K2CO3, acetone, rt; (ii)
180 °C/solvent-free (70–74% over two steps); (iii) glycine ethyl ester,
K2CO3, DMF, rt (65–86%); (iv) KOH, H2O–THF, rt (77–95%).
Fig. 2 Variations of the I1/I3 ratio of the pyrene vibronic fluorescence
spectrum as a function of K+6c− concentration in water.
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Fig. 3 Reversible sol–gel phase transition for the gel of 6c triggered
by pH and temperature.
Table 2 Gel–sol transition temperature (Tgs) for the anion of
compound 6c with different cations
Compound
Cation
Tgs (°C)
Fig. 5 POM image for gel obtained from compound 6c as potassium
salt.
6c
6c
6c
K+
26.7 0.2
26.5 0.2
27.6 0.2
Na+
Li+
Fig. 6 SEM images for the xerogel obtained from compound 6c as
potassium salt (left) and as sodium salt (right).
Table 3 MGC and Tgs in DMSO for compounds 5a–c
Fig. 4 Dependence of Tgs on the concentration of K+6c− hydrogel.
Compound
MGC (mg mL−1
)
Tgs (°C)
temperatures (Tgs) of gels, at the MGC, obtained from compound
6c with different cations are reported in Table 2. No significant
variation of Tgs was observed by varying the alkaline metal.19
The gel–sol transition temperature (Tgs) of representative potass-
ium salt of compound 6c was also studied as a function of the
gelator concentration, by using the dropping ball method
(Fig. 4).
The Tgs increased by about 2.0 °C by increasing the concen-
tration of the gelator from 12.5 to 70 mg mL−1, without further
significant changes at higher concentrations. Such a narrow Tgs
variation indicates that the gel phase consists of an homogeneous
micro-structured network.20 Unfortunately, such a narrow vari-
ation and the lack of melting temperature of the potassium salt of
6c, did not allow us to apply Schrader’s equation21 to estimate
the transition enthalpy.
POM images, obtained for the hydrogel of the potassium salt
of 6c, revealed the formation of a lamellar morphology (Fig. 5).
The morphology of xerogels obtained from compound 6c was
also studied by scanning electronic microscopy (SEM) as a func-
tion of the cations. A lamellar microstructure with the fluorinated
amphiphile forming oriented porous planar sheet aggregates of
10–20 μm length was observed with potassium as the cation.
Less ordered planar sheet aggregates a few micrometers in
length were observed with sodium (Fig. 6).22 Such molecular
arrangement could be interpreted as the initial formation of
5a
5b
5c
15
—
10.5
67.3 0.2
—
30.6 0.2
supramolecular aggregates with low curvature (for example a
bilayer) and subsequent hierarchical self-assembly into lamellae.
This hypothesis is in agreement with the ability of potassium ion
to stabilize such supramolecular aggregates.15,16
Additionally, the potential organogelation ability of esters 5a–
c was investigated in different solvents. Any attempt to obtain
organogels from compounds 5 in common organic solvents
failed due to formation of solutions (in DMF, EtOH, MeOH,
THF, DCM, CHCl3, PhCH3). On the other hand, oxadiazoles 5a,
c form stable and semi-transparent organogels in DMSO, while
compound 5b results insoluble in the same solvent. This could
be ascribed to the strongest lateral dipole moment induced by the
asymmetric distribution of fluorine atoms on the phenyl-ring in
5b with respect to 5a,c.23 Minimal gelation concentrations
(MGC, mg mL−1) in DMSO were determined by performing the
tube inversion test (Table 3). Also in this case, the fluorine
content on the phenyl-ring is crucial on the MGC values, reveal-
ing compound 5c, with the highest fluorine content, as the most
effective organogelators. Obtained organogels are stable for
more than one month an exhibit a thermal responsive behavior.
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Fig. 7 Dependence of Tgs on the concentration of 5c organogel in
DMSO.
Fig. 8 Plot of the natural logarithm of 5c concentration (ln C) versus
the reciprocal absolute temperature of gel–sol transition (1000/Tgs).
In fact, liquid and gel phases were reversibly observed upon
heating and cooling, respectively. The gel–sol transition tempera-
ture (Tgs) of gels, at the MGC, obtained from compounds 5a and
5c were determined by using the dropping ball method and are
reported in Table 3.
The gel–sol transition temperature (Tgs) of representative com-
pound 5c was also studied as a function of the gelator concen-
tration (Fig. 7). Also in this case, a narrow increase of the Tgs
(5 °C) was observed by increasing the concentration of the
gelator from 10.5 to 25 mg mL−1, without further significant
changes at higher concentrations.
The gel–sol phase transition can be considered as a dissolution
process of microcrystals and is described by eqn (1) derived
from Schrader’s relation:21
ln C ¼ ꢀΔHgs=RTgs þ ΔHgs=RTm
ð1Þ
where C is the molar gel concentration, ΔHgs is the gel–sol tran-
sition enthalpy, R is the gas constant, Tgs is the transition temp-
erature and Tm is the melting temperature of the pure compound.
Therefore, an estimate of ΔHgs for the organogel 5c in DMSO
was determined from the linear fitting of ln C for 5c versus
1000/Tgs (Fig. 8).
Fig. 9 POM image of organogel of compound 5c in DMSO; image of
the organogel (inset).
Data analysis showed a good agreement between the value of
ΔHgs obtained from the slope (ΔHgs = 77.5 0.8 kJ mol−1) and
that obtained from intercept (ΔHgs = 81 3 kJ mol−1) of the
fitting equation.
POM images, obtained for the organogel in DMSO of 5c,
revealed the formation of a fibrillar network (Fig. 9). In this case
such supramolecular architecture could be ascribed to the initial
formation of cylindrical aggregates as previously observed for
non-ionic fluorinated gelators.9,10
For comparison, we also synthesized compounds 8 and 9 con-
taining a longer C–H hydrophobic chain. These compounds
were obtained, adapting the above described synthetic method,
starting from 5-pentafluorophenyl-3-undecyl-1,2,4-oxadiazole 7
(Scheme 2).
Scheme 2 Synthesis of compounds 8 and 9. (i) glycine ethyl ester,
K2CO3, DMF, rt (85%); (ii) KOH, H2O–THF, rt (91%).
Interestingly, the replacement of the perfluorocarbon moiety
with a hydrocarbon chain strongly affected the aggregation be-
haviour. In fact, no gel formation was observed either for com-
pound 8 in DMSO or for the potassium salt of compound 9 in
H2O, up to a 50 mg ml−1 concentration. This suggests a crucial
role of the perfluoroalkyl-chain for the supramolecular aggrega-
tion of these type of LMWGs.
An interesting application of these fluorinated LMWGs can be
envisaged by considering the oxygen affinity of perfluorocarbon
moieties.4 Therefore, we decided to investigate if the occurrence
of micellar aggregates formation, for representative compound
6c, could exploit its potential as oxygen delivery system. In
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order to obtain some information about the behavior as O2 car-
riers, oxygen release kinetics from solutions of potassium salts
of 6c were performed, by means of a previously reported satur-
ation method,6 at 25 °C and at different concentrations of K+6c−
(10−4 and 10−3 M). Oxygen release studies in solutions, were
also performed by using potassium perfluorooctanoate (KPO) as
reference. KPO is a fluorinated anionic surfactant, which forms
micelles at a concentration two orders of magnitude higher than
K+6c− (∼10−2 M), but does not form gels. Oxygen solubility
was determined after saturation of the solutions (pO2 = 1 atm)
and monitored, as a function of time, at atmospheric pressure
(pO2 = 0.21 atm). According to reported in vivo kinetics exper-
iments,24 the obtained desaturation curves were approximated by
a single exponential function (eqn (2))
The oxygen release curves were recorded at 37 °C as a func-
tion of time for both a plate counter agar (PCA) 1% (w/v) gel,
used as model cell culture medium, and a PCA 1% (w/v) gel
containing a 0.1% (w/v) of compound 6c as additive (Fig. 11).
Interestingly, the addition of oxadiazole 6c results in an
improvement of the oxygen profile with respect to PCA gel.
Conclusions
In summary, new 1,2,4-oxadiazoles containing fluorinated
hydrophobic chains and rigid spacers linked to an aminoacidic
polar group, were synthesized and characterized as hydrogela-
tors. They form thermally reversible and pH-sensitive gels with
low MGC, if compared to similar fluorinated gelators.10 The
½O2ꢁ ¼ ½O2ꢁ0 þ ½O2ꢁload ꢂ eꢀKt
ð2Þ
where [O2]0 (mg l−1) is the oxygen solubility after saturation of
the medium at t0, [O2]∞ (mg l−1) is the oxygen solubility at t∞,
[O2]load = [O2]0 − [O2]∞ represents the amount of oxygen
loaded by the aggregate, and K (min−1) is the clearance constant,
i.e. the inverse of the rate of oxygen release from the medium.
The obtained data are reported in Table 4 and in Fig. 10.
At 10−4 M concentration, a value below the CAC of both
KPO and K+6c−, the latter was able to dissolve more oxygen at
saturation (Δ[O2]0 = 4.61 ppm) and maintaining it in solution for
a longer time than KPO. Moreover, O2 solubility at saturation
for K+6c− was also higher than in water (Δ[O2]0 = 2.21 ppm)
despite the low concentration of K+6c−. Oxygen solubility at
atmospheric pressure ([O2]∞) was slightly higher than in pure
water for both KPO and K+6c−, with an higher value for KPO.
At 10−3 M, where only compound K+6c− is above its CAC,
K+6c− is able to dissolve more oxygen at atmospheric pressure
than KPO and release it more than four times slower. The sig-
nificant difference between K values of K+6c− and KPO at 10−3
M concentration, can be explained in terms of formation of
micellar aggregates that allow K+6c− to create an oxygen reser-
voir, as previously observed for fluorinated polymeric
amphiphiles.6b
In this context, application of fluorinated compounds to dis-
solve respiratory gases has attracted significant interest focused
primarily on their use to enhance oxygen supply to cells and
tissues.26 Therefore, the ability of salt K+6c− to maintain high
oxygen level in solution prompted us to investigate the potential
use of compound 6c as oxygen transporter in cell culture
systems.
Fig. 10 Oxygen release curves from aqueous solutions of 6c (blue)
and PO (red) at 10−4 M (upper) and 10−3 M (lower).
Table 4 Parameters of eqn (2) determined for desaturation curves as a
function of time of oxygen saturated aqueous solutions of 6c and POa
Compound
10−4
M
10−3
M
6c
[O2]0 = 40.66 ppm
[O2]∞ = 8.55 ppm
K = 1.23 × 10−2 min−1
[O2]0 = 36.05 ppm
[O2]∞ = 8.83 ppm
K = 1.64 × 10−2 min−1
[O2]0 = 37.38 ppm
[O2]∞ = 9.53 ppm
K = 5.85 × 10−3 min−1
[O2]0 = 41.27 ppm
[O2]∞ = 9.35 ppm
K = 2.56 × 10−2 min−1
KPO
a For pure water [O2]0 = 38.45 ppm;6b [O2]∞ = 8.37 ppm.25
Fig. 11 Oxygen release curves from gels of PCA 1% (red) and PCA
1%+ 6c 0.1% (blue).
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1
2
trend of the minimal gelation concentration, as a function of the
structure of deprotonated 6a–c, showed that the fluorine content
of the aromatic portion is crucial for the gelation process high-
lighting the role of the fluoroaryl group in non-covalent inter-
actions. The gelator 6c forms, in water, ordered lamellar
structures due to layered supramolecular assembly. The variation
on MGC values could be interpreted in terms of the enhanced
aggregation ability with potassium salts due to the formation of
highly ordered structures in comparison with sodium salts as evi-
denced by SEM experiments. The obtained compounds may rep-
resent a new family of fluorinated LMWGs. The low clearance
constant value for compound 6c suggests the potential use as
oxygen carrier. Further investigation on factors affecting the
aggregation mode and on biomedical perspective applications
are currently under way.
Ar), 147.1 (dd, JC–F = 263 Hz, JC–F = 11 Hz, C–F Ar), 148.5
(dd, 1JC–F = 241 Hz, 2JC–F = 9 Hz, C–F Ar), 162.3 (t, 2JC–F = 28
Hz, Het C3) and 172.9 (Het C5); m/z: 586 (M+,100%).
5-(2,3,4,5,6-Pentafluorophenyl)-3-undecyl-1,2,4-oxadiazole 7.
(0.71 g, 78%) oil (Found: C, 58.55; H, 5.95; N, 7.30.
C19H23F5N2O requires C, 58.46; H, 5.94; N, 7.18%); νmax(Nu-
jol)/cm−1 1657; δH(250 MHz; CDCl3) 0.86 (t, 3H, JH–H = 6.6
3
Hz, CH3), 1.25–1.42 (m, 16H, overlapped signals), 1.74–1.86
(m, 2H, CH2) and 2.82 (t, 2H, JH–H = 7.6 Hz, Het–CH2);
δC(62.5 MHz; CDCl3) 14.0 (CH3), 22.6 (CH2), 26.0 (CH2), 26.9
(CH2), 29.1 (CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (CH2), 29.6 (2
3
1
× CH2), 31.9 (CH2), 101.5 (C–Het Ar), 138.1 (d, JC–F = 255
Hz, C–F Ar), 143.7 (d, 1JC–F = 260 Hz, C–F Ar), 145.5 (d, 1JC–F
= 272 Hz, C–F Ar), 165.7 (Het C3) and 171.6 (Het C5); m/z:
390 (M+,100%).
Experimental section
General procedure for preparation of oxadiazoles 5a–c and 8
Instrumentation and chemicals
t-BuOK (0.448 g, 4 mmol) and, after 30 minutes, oxadiazole 4
or 7 (2 mmol) were added to a solution of glycine ethyl ester
hydrochloride (0.558 g, 4 mmol) in DMF (3 mL). The reaction
mixture was stirred at room temperature, until complete conver-
sion of the starting material occurred (TLC). The mixture was
then treated with water (50 mL) and extracted with EtOAc. The
combined organic layers were dried over Na2SO4, filtered and
the solvent removed under reduced pressure. The residue was
chromatographed giving compound 5a–c and 8.
Melting points were determined on a hot-stage apparatus. FT-IR
spectra were registered in Nujol mull. H-NMR and 13C-NMR
1
spectra were recorded at indicated frequencies, residual solvent
peak was used as reference. Flash chromatography was per-
formed by using silica gel (0.040–0.063 mm) and mixtures of
ethyl acetate and petroleum ether (fraction boiling in the range
of 40–60 °C) in various ratios. Compounds 1,14 3c,14 4c14 and
undecyl amidoxime27 were obtained according to previously
reported method.
Ethyl 2-(2,6-difluoro-4-(3-perfluoroheptyl-1,2,4-oxadiazol-5-
yl)phenylamino)acetate 5a. (0.85 g, 65%) mp 132–133 °C
(from petroleum ether) (Found: C, 35.00; H, 1.50; N, 6.40.
C19H10F17N3O3 requires C, 35.04; H, 1.55; N, 6.45%); νmax(Nu-
jol)/cm−1 3393, 1736 and 1624; δH(300 MHz; CDCl3) 1.38 (t,
General procedure for the synthesis of oxadiazoles 4a–b and 7
1.2 eq. of benzoyl chloride 2 (2.8 mmol) and K2CO3 (0.386 g,
2.8 mmol) were added to a solution of 1 or undecyl amidox-
ime27 (2.33 mol) in acetone (50 mL). The mixture was stirred at
room temperature for 1 h. The solvent was then removed under
vacuum, the residue treated with water and a white solid was iso-
lated by filtration. Obtained powder was heated at 180 °C in a
tube until complete consumption of the starting material (TLC).
The obtained residue was chromatographed producing oxadia-
zoles 4a–b and 7.
3JH–H = 6.6 Hz, 3H, CH3), 4.31–4.39 (m, 4H, CH2O + CH2N),
3
4.95 (bs, 1H, exch. with D2O, NH) and 7.74 (dd, 2H, JH–F
=
5
7.8 Hz, JH–F′ = 2.4 Hz, Ar); δC(62.5 MHz; CDCl3) 14.1 (CH3),
46.4 (CH2N), 61.8 (CH2O), 104–124 (overlapped signals, C7F15
+ Ar), 132.5 (t, JC–F = 13 Hz, C–N Ar), 151.5 (d, JC–F = 241
2
1
2
Hz, C–F Ar), 162.3 (t, JC–F = 25 Hz, Het C3), 170.2 (CO) and
175.3 (Het C5); m/z: 651 (M+,100%).
Ethyl 2-(2,3,6-trifluoro-4-(3-perfluoroheptyl-1,2,4-oxadiazol-5-
yl)phenylamino)acetate 5b. (1.03 g, 77%) mp 105–106 °C
(from petroleum ether) (Found: C, 34.15; H, 1.30; N, 6.25.
C19H9F18N3O3 requires C, 34.10; H, 1.36; N, 6.28%); νmax(Nu-
jol)/cm−1 3377, 1732 and 1637; δH(300 MHz; CDCl3) 1.33 (t,
3JH–H = 6.9 Hz, 3H, CH3), 4.27–4.34 (m, 4H, CH2O + CH2N),
5.01 (bs, 1H, exch. with D2O, NH) and 7.60–7.67 (m, 1H, Ar);
δC(62.5 MHz; CDCl3) 14.2 (CH3), 46.2 (CH2N), 62.0 (CH2O),
96.2 (C–Het Ar), 106–120 (overlapped signals, C7F15 + Ar),
131.9 (C–N Ar), 140.7 (dd, 1JC–F = 259 Hz, 2JC–F = 13 Hz, C–F
5-(3,4,5-Trifluorophenyl)-3-perfluoroheptyl-1,2,4-oxadiazole 4a.
(0.98 g, 74%) mp 36–37 °C (from petroleum ether) (Found: C,
31.70; H, 0.30; N, 4.90. C15H2F18N2O requires C, 31.71; H,
0.35; N, 4.93%); νmax(Nujol)/cm−1 1632; δH(300 MHz; CDCl3)
7.78–7.83 (m, 2H, Ar); δC(62.5 MHz; CDCl3) 105–124 (over-
1
2
lapped signals, C7F15 + Ar), 143.6 (dt, JC–F = 261 Hz, JC–F
=
1
2
15 Hz, C–F Ar), 151.8 (dd, JC–F = 253 Hz, JC–F = 8 Hz, C–F
2
Ar), 162.5 (t, JC–F = 28 Hz, Het C3) and 175.3 (Het C5); m/z:
568 (M+,100%).
1
1
Ar), 147.1 (d, JC–F = 243 Hz, C–F Ar), 147.8 (dd, JC–F = 259
2
2
5-(2,3,4,5-Tetrafluorophenyl)-3-perfluoroheptyl-1,2,4-oxadiazole
4b. (0.95 g, 70%) mp 28–29 °C (from petroleum ether) (Found:
C, 30.70; H, 0.15; N, 4.80. C15HF19N2O requires C, 30.74; H,
0.17; N, 4.78%); νmax(Nujol)/cm−1 1637; δH(300 MHz; CDCl3)
7.86–7.89 (m, 1H, Ar); δC(62.5 MHz; CDCl3) 104–120 (over-
Hz, JC–F = 13 Hz, C–F Ar), 161.8 (t, JC–F = 27 Hz, Het C3),
170.1 (CO) and 174.2 (Het C5); m/z: 669 (M+,100%).
Ethyl 2-(2,3,5,6-tetrafluoro-4-(3-perfluoroheptyl-1,2,4-oxadia-
zol-5-yl)phenylamino)acetate 5c. (1.18 g, 86%) mp 94–96 °C
(from petroleum ether) (Found: C, 33.20; H, 1.10; N, 6.15.
C19H8F19N3O3 requires C, 33.21; H, 1.17; N, 6.11%);
1
2
lapped signals, C7F15 + Ar), 141.8 (dt, JC–F = 255 Hz, JC–F
=
1
2
13 Hz, C–F Ar), 144.6 (dt, JC–F = 264 Hz, JC–F = 13 Hz, C–F
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νmax(Nujol)/cm−1 3364, 1732 and 1649; δH(300 MHz, CDCl3):
δ = 1.40 (t, 3H, 3JH–H = 6.3 Hz, CH3), 4.34–4.41 (m, 4H, CH2O
2-(2,3,5,6-Tetrafluoro-4-(3-(perfluoroheptyl)-1,2,4-oxadiazol-5-
yl)phenylamino)acetic acid 6c. (1.25 g, 95%) mp 127–130 °C
(from H2O) (Found: C, 30.90; H, 0.60; N, 6.35. C17H4F19N3O3
requires C, 30.97; H, 0.61; N, 6.37%); νmax(Nujol)/cm−1 3394,
1722 and 1661; δH(300 MHz; DMSO-d6) 4.16 (bs, 2H, CH2N),
7.60 (bs, 1H, exch. with D2O, NH) and 12.95 (bs, 1H, exch.
with D2O, OH); δC(62.5 MHz; DMSO-d6) 46.0 (CH2N), 88.2
(C–Het Ar), 103–120 (overlapped signals, C7F15), 133.9 (C–N
+ CH2N) and 5.21 (bs, 1H, exch. with D2O, NH); δC(62.5 MHz;
2
CDCl3) 13.9 (CH3), 46.0 (CH2N), 62.1 (CH2O), 91.1 (t, JC–F
=
13 Hz, C–Het Ar), 104–124 (overlapped signals, C7F15), 132.2
1
2
(C–N Ar), 136.9 (dd, JC–F = 240 Hz, JC–F = 13 Hz, C–F Ar),
1
2
146.2 (dd, JC–F = 261 Hz, JC–F = 9 Hz, C–F Ar), 161.9 (t,
2JC–F = 28 Hz, Het C3), 169.7 (CO) and 170.6 (Het C5); m/z:
687 (M+,100%).
1
1
Ar), 136.2 (d, JC–F = 246 Hz, C–F Ar), 145.8 (d, JC–F = 248
2
Hz, C–F Ar), 160.9 (t, JC–F = 28 Hz, Het C3), 171.1 (Het C5)
and 171.9 (CO); m/z: 659 (M+,100%).
Ethyl 2-(2,3,5,6-tetrafluoro-4-(3-undecyl-1,2,4-oxadiazol-5-yl)
phenylamino)acetate 8. (0.80 g, 85%) mp 83–85 °C (from pet-
roleum ether) (Found: C, 58.40; H, 6.55; N, 8.90.
C23H31F4N3O3 requires C, 58.34; H, 6.60; N, 8.87%); νmax(Nu-
jol)/cm−1 3372, 1726 and 1656; δH(300 MHz; CDCl3) 0.89 (t,
2-(2,3,5,6-Tetrafluoro-4-(3-(undecyl)-1,2,4-oxadiazol-5-yl)phe-
nylamino)acetic acid 9. (0.81 g, 91%) mp 110–112 °C (from
H2O) (Found: C, 56.60; H, 6.20; N, 9.30. C21H27F4N3O3
requires C, 56.62; H, 6.11; N, 9.43%); νmax(Nujol)/cm−1 3354,
3
3H, JH–H = 6.7 Hz, CH3), 1.27–1.35 (m, 19H, overlapped
3
3
1734 and 1653; δH(300 MHz; CDCl3) 0.88 (t, 3H, JH–H = 6.0
signals), 1.76–1.86 (m, 2H, CH2), 2.83 (t, 2H, JH–H = 7.6 Hz,
Hz, CH3), 1.26–1.37 (m, 16H, overlapped signals), 1.78–1.83
(m, 2H, CH2), 2.84 (t, 2H, JH–H = 7.8 Hz, Het–CH2), 4.37 (bs,
Het–CH2), 4.26–4.33 (m, 4H, CH2O + CH2N) and 4.96 (bs, 1H,
exch. with D2O, NH); δC(75 MHz; CDCl3) 14.5 (2 × CH3), 23.1
(CH2), 26.5 (CH2), 27.4 (CH2), 29.5 (CH2), 29.6 (CH2), 29.7
(CH2), 29.9 (CH2), 30.0 (2 × CH2), 32.3 (CH2), 46.6 (CH2N),
3
2H, CH2N) and 4.94 (bs, 1H, exch. with D2O, NH); δC(75 MHz;
CDCl3) 12.8 (CH3), 21.4 (CH2), 24.7 (CH2), 25.7 (CH2), 27.8
(CH2), 27.9 (CH2), 28.0 (CH2), 28.1 (CH2), 28.3 (2 × CH2),
30.6 (CH2), 44.5 (CH2N), 91.7 (m, C–Het Ar), 129.4 (m, C–N
Ar), 135.6 (bd, 1JC–F = 230 Hz, C–F Ar), 144.5 (bd, 1JC–F = 256
Hz, C–F Ar), 166.3 (Het C3), 169.7 (Het C5) and 172.6 (CO);
m/z: 445 (M+,100%).
2
62.4 (CH2O), 93.3 (t, JC–F = 14.1 Hz, C–Het Ar), 130.9–131.2
1
2
(m, C–N Ar), 137.3 (dd, JC–F = 238 Hz, JC–F = 14 Hz, C–F
1
Ar), 146.1 (bd, JC–F = 252 Hz, C–F Ar), 167.9 (Het C3), 170.2
(CO) and 171.5 (Het C5); m/z: 473 (M+,100%).
General procedure for preparation of compounds 6a–c
Gel formation and MGC determination
A solution of compound 5 or 8 (2 mmol) in THF (10 mL) and
KOH 10 m (1 mL) was stirred at room temperature for 2 h. The
reaction mixture was concentrated under reduced pressure, the
residue was treated with water (25 mL) and the resulting mixture
was acidified with HCl 1 m. The formed precipitate of com-
pound 6a–c or 9 was collected by filtration.
A weighed amount of gelator and solvent were placed in a vial.
An equimolar amount of the inorganic base (KOH, NaOH or
LiOH) was added for determinations with compounds 6a–c in
water. The mixture was heated at 50 °C until a clear solution was
obtained. The vials were allowed to cool down to room tempera-
ture. The state of the solution was evaluated by inverting the
vial. MGC was the minimal concentration which gave no liquid
flow.
2-(2,6-Difluoro-4-(3-perfluoroheptyl-1,2,4-oxadiazol-5-yl)phe-
nylamino)acetic acid 6a. (0.96 g, 77%) mp 139–140 °C (from
H2O) (Found: C, 32.70; H, 0.90; N, 6.70. C17H6F17N3O3
requires C, 32.76; H, 0.97; N, 6.74%); νmax(Nujol)/cm−1 3410,
1732 and 1626; δH(300 MHz; DMSO-d6) 4.17 (s, 2H, CH2N),
6.89 (bs, 1H, exch. with D2O, NH), 7.76 (bs, 2H, Ar) and 12.81
(bs, 1H, exch. with D2O, OH); δC(62.5 MHz; DMSO-d6) 45.5
(CH2N), 105–120 (overlapped signals, C7F15 + Ar), 131.8 (t,
Fluorescence measurements
Fluorescence emission spectra were registered in water. Emission
spectra were recorded in the range 350–500 nm using an exci-
tation wavelength of 333 nm. The widths of the slits were set at
1.5 and 1.0 nm for excitation and emission, respectively. The
mixtures for the measurements were prepared as following.
Known amounts of a solution of pyrene in acetone were care-
fully added to dark flasks. After solvent evaporation, the sample
solutions were added and equilibrated at room temperature for 2
days. For all of the mixtures, the final concentration of pyrene
was 5 × 10−7 M (i.e., its solubility in water).
1
2JC–F = 13 Hz, C–N Ar), 150.8 (d, JC–F = 240 Hz, C–F Ar),
2
161.0 (t, JC–F = 28 Hz, Het C3), 171.9 (CO) and 176.7 (Het
C5); m/z: 623 (M+,100%).
2-(2,3,6-Trifluoro-4-(3-perfluoroheptyl-1,2,4-oxadiazol-5-yl)phe-
nylamino)acetic acid 6b. (1.06 g, 83%) mp 128–129 °C (from
H2O) (Found: C, 31.80; H, 0.80; N, 6.50. C17H5F18N3O3
requires C, 31.84; H, 0.79; N, 6.55%); νmax(Nujol)/cm−1 3452,
1724 and 1639; δH(300 MHz; DMSO-d6) 4.17 (bs, 2H, CH2N),
7.18 (bs, 1H, exch. with D2O, NH), 7.57–7.63 (m, 1H, Ar) and
12.90 (bs, 1H, exch. with D2O, OH); δC(62.5 MHz; DMSO-d6)
45.3 (CH2N), 96.1 (C–Het Ar), 105–120 (overlapped signals,
Determination of pHsol–gel
A gel of compound 6c, above MGC concentration (15 mg
mL−1) was prepared in 10 mL of water, according to the general
procedure described above. An initial pH = 9.8 was measured by
submerging a pH-meter electrode within the gel phase. Equal
amounts (11 μL, 0.05 eq.) of HCl 1 m were subsequently added
1
C7F15 + Ar), 133.4 (C–N Ar), 139.4 (d, JC–F = 232 Hz, C–F
1
1
Ar), 146.6 (d, JC–F = 236 Hz, C–F Ar), 147.3 (d, JC–F = 255
2
Hz, C–F Ar), 160.8 (t, JC–F = 28 Hz, Het C3), 171.7 (CO) and
174.1 (Het C5); m/z: 641 (M+,100%).
3050 | Org. Biomol. Chem., 2012, 10, 3044–3052
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G. Pitarresi, G. Cavallaro, F. S. Palumbo and G. Giammona, Macromol.
Biosci., 2009, 9, 393; (f) G. Tripodo, G. Pitarresi, F. S. Palumbo, E.
F. Craparo and G. Giammona, Macromol. Biosci., 2005, 5, 1074.
2 (a) P. Terech and R. G. Weiss, Chem. Rev., 1997, 97, 3133; (b) L.
A. Estroff and A. D. Hamilton, Chem. Rev., 2004, 104, 1201; (c) M. de
Loos, B. L. Feringa and J. H. van Esch, Eur. J. Org. Chem., 2005, 3615;
(d) N. M. Sangeetha and U. Maitra, Chem. Soc. Rev., 2005, 34, 821. As
examples of gelators (supergelators) which gelate at very low concen-
tration see: (e) H. Kobayashi, A. Friggeri, K. Koumoto, M. Amaike,
S. Shinkai and D. N. Reinhoudt, Org. Lett., 2002, 4, 1423;
(f) A. Srivastava, S. Ghorai, A. Bhattacharjya and S. Bhattacharya, J.
Org. Chem., 2005, 70, 6574; (g) Y. Qiao, Y. Lin, Z. Yang, H. Chen,
S. Zhang, Y. Yan and J. Huang, J. Phys. Chem. B, 2010, 114, 11725.
3 (a) R. Filler, Y. Kobayashi and L. M. Yagupolskii, Organofluorine Com-
pounds in Medicinal Chemistry and Biomedical Applications, Elsevier,
Amsterdam, 1993; (b) Chemistry of Organic Fluorine Compounds II. A
Critical Review, ed. M. Hudlicky and A. E. Pavlath, ACS Monograph
187, American Chemical Society, Washington, DC, 1995.
to the gel phase, which was heated and cooled after each acid
addition observing solubilization (upon heating) and gel for-
mation (upon cooling). A final pH = 6.6 was determined when
the gel formation was no more occurring, after a total addition of
0.5 eq. of HCl.
Determination of Tgs
Tgswere determined through the dropping ball method. A steel
ball (160 mg) was gently placed on the top of the gel (2 g) in a
glass vial. The closed vial was placed firmly in a water bath,
which was heated progressively at a rate of 0.1 °C per minute.
The sample temperature was determined by a sensor dipped in a
separate vial, next to the heating gel, which was filled with the
same solvent. The Tgswas defined as the temperature at which
the ball touched the bottom of the vial. The experiment was
repeated three times to produce consistent results.
4 See for example: (a) J. G. Riess, Tetrahedron, 2002, 58, 4113; (b) M.
P. Krafft, Curr. Opin. Colloid Interface Sci., 2003, 8, 213; (c) M.
P. Krafft, J. Polym. Sci., Part A: Polym. Chem., 2006, 44, 4251.
5 See for example: (a) J. Roovers, Macromolecules, 1986, 18, 1361;
(b) A. Matsuda, T. Kaneko, J. Gong and Y. Osada, Macromolecules,
2000, 33, 2535; (c) K. Matsumoto, R. Nishimura, H. Mazaki,
H. Matsuoka and H. Yamaoka, J. Polym. Sci., Part A: Polym. Chem.,
2001, 39, 3751; (d) G. Tae, J. A. Kornfield, J. A. Hubbell,
D. Johannsmann and T. E. Hogen-Esch, Macromolecules, 2001, 34,
6409; (e) K. Kuroda, K. Fujimoto, J. Sunamoto and K. Akiyoshi, Lang-
muir, 2002, 18, 3780; (f) A. F. M. Kilbinger and R. H. Grubbs, Angew.
Chem., Int. Ed., 2002, 41, 1563; (g) W. F. Lee and T. M. Liu, J. Appl.
Polym. Sci., 2006, 100, 4661.
6 (a) D. Mandracchia, A. Palumbo Piccionello, G. Pitarresi, A. Pace,
S. Buscemi and G. Giammona, Macromol. Biosci., 2007, 7, 836;
(b) G. Pitarresi, A. Palumbo Piccionello, R. Calabrese, A. Pace,
S. Buscemi and G. Giammona, J. Fluorine Chem., 2008, 129, 1096.
7 For a recent review on 1,2,4-oxadiazoles see: A. Pace and P. Pierro, Org.
Biomol. Chem., 2009, 7, 4337–4348.
Scanning electron microscopy (SEM)
The morphology and the size of the aggregates obtained in
aqueous phase have been observed by scanning electron
microscopy (SEM). The samples have been prepared by putting
the gels in a carbon stub and letting them dry at room tempera-
ture overnight before electron microscope analysis.
Oxygen solubility measurements
Oxygen solubility measurements were performed, as previously
reported,6 by using a digital oxymeter, with a Schott Gerade
120 mm probe having a membrane with an exterior Teflon layer.
Measures were recorded by placing the electrode tip into the
bulk phase at 80 mm distance from the air–liquid (or air–gel)
interface. Data from oxygen saturated aqueous solutions (20 ml)
containing K+6c− or KPO at different concentrations, were
taken at atmospheric pressure. In particular, each solution
was initially stirred with a magnetic stir bar while pure oxygen
was continuously bubbled. The temperature of each solution was
adjusted to 25 °C by using a thermostated oil bath. Once the sol-
ution reached a stable maximum oxygen concentration (saturated
solution), bubbling was stopped and the release of dissolved
oxygen was determined by evaluating the change in the oxygen
solubility (desaturation) as a function of time. Similarly,
measurements on PCA and 6c@PCA gels were performed at
37 °C, without stirring.
8 F. Lo Celso, I. Pibiri, A. Triolo, R. Triolo, A. Pace, S. Buscemi and
N. Vivona, J. Mater. Chem., 2007, 17, 1201.
9 See for example: (a) J. Loiseau, M. Lescanne, A. Colin, F. Fages, J.-
B. Verlhac and J.-M. Vincent, Tetrahedron, 2002, 58, 4049;
(b) G. Mathew, S. L. Snyder, P. Terech, C. J. Glinka and R. G. Weiss, J.
Am. Chem. Soc., 2003, 125, 10275; (c) M. George, S. L. Snyder,
P. Terech and R. G. Weiss, Langmuir, 2005, 21, 9970; (d) A. R. Borges,
M. Hyacinth, M. Lum, C. M. Dingle, P. L. Hamilton, M. Chruszcz,
L. Pu, M. Sabat and K. L. Caran, Langmuir, 2008, 24, 7421; (e) S.
S. Babu, V. K. Praveen, S. Prasanthkumar and A. Ajayaghosh, Chem.–
Eur. J., 2008, 14, 9577; (f) A. Raghavanpil, S. Reinartz and K.
W. Hutchenson, J. Fluorine Chem., 2009, 130, 410.
10 (a) T. Imae, K. Funayama, M. P. Krafft, F. Giulieri, T. Tada and
T. Matsumoto, J. Colloid Interface Sci., 1999, 212, 330; (b) S. F. Pang
and D. B. Zhu, Chem. Phys. Lett., 2002, 358, 479; (c) A. Palumbo Pic-
cionello, A. Pace, S. Buscemi, N. Vivona and G. Giorgi, Tetrahedron
Lett., 2009, 50, 1472; (d) S. Buscemi, G. Lazzara, S. Milioto and
A. Palumbo Piccionello, Langmuir, 2009, 25, 13368; (e) D. M. Ryan, S.
B. Anderson, F. Timur Senguen, R. E. Youngman and B. L. Nilsson, Soft
Matter, 2010, 6, 475; (f) G. Godeau, C. Brun, H. Arnion, C. Staedel and
P. Barthélémy, Tetrahedron Lett., 2010, 51, 1012.
11 (a) G. Giammona, G. Pitarresi, G. Cavallaro, B. Carlisi, E. F. Craparo and
D. Mandracchia, J. Drug Delivery Sci. Technol., 2006, 16, 77; (b) M.
A. Casadei, G. Pitarresi, R. Calabrese, P. Paolicelli and G. Giammona,
Biomacromolecules, 2008, 9, 43.
Acknowledgements
12 T. Kunitake, Y. Okahata, M. Shimomura, S. Yasunami and K. Takarabe,
J. Am. Chem. Soc., 1981, 103, 5401.
The authors are grateful to Dr Maria Luisa Bondì (ISMN-CNR,
Division of Palermo) for SEM measurements. Financial support
from the University of Palermo is gratefully acknowledged.
13 (a) S. Buscemi, A. Pace, R. Calabrese, N. Vivona and P. Metrangolo, Tet-
rahedron, 2001, 57, 5865; (b) A. Pace, I. Pibiri, S. Buscemi, N. Vivona
and L. Malpezzi, J. Org. Chem., 2004, 69, 4108; (c) S. Buscemi,
A. Pace, I. Pibiri, N. Vivona and T. Caronna, J. Fluorine Chem., 2004,
125, 165; (d) S. Buscemi, A. Pace, A. Palumbo Piccionello, I. Pibiri and
N. Vivona, Heterocycles, 2005, 65, 387; (e) A. Palumbo Piccionello,
A. Pace, I. Pibiri, S. Buscemi and N. Vivona, Tetrahedron, 2006, 62,
8792; (f) S. Buscemi, A. Pace, A. Palumbo Piccionello, S. Pappalardo,
D. Garozzo, T. Pilati, G. Gattuso, A. Pappalardo, I. Pisagatti and M.
F. Parisi, Tetrahedron Lett., 2006, 47, 9049; (g) A. Palumbo Piccionello,
A. Pace, P. Pierro, I. Pibiri, S. Buscemi and N. Vivona, Tetrahedron,
Notes and references
1 (a) Hydrogels in Medicine and Pharmacy, ed. N. A. Peppas, CRC Press,
Boca Raton, 1987, vol. 3; (b) K. Y. Lee and J. D. Mooney, Chem. Rev.,
2001, 101, 1869; (c) J. Jagur-Grodzinski, Polym. Adv. Technol., 2010, 21,
27; (d) G. Pitarresi, G. Tripodo, R. Calabrese, E. F. Craparo, M. Licciardi
and G. Giammona, Macromol. Biosci., 2008, 8, 891; (e) G. Tripodo,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3044–3052 | 3051

View Online
2009, 65, 119; (h) I. Pibiri, A. Palumbo Piccionello, A. Calabrese,
S. Buscemi, N. Vivona and A. Pace, Eur. J. Org. Chem., 2010, 4549.
14 S. Buscemi, A. Pace, A. Palumbo Piccionello and N. Vivona, J. Fluorine
Chem., 2006, 127, 1601.
20 J. Kowalczuk, S. Jarosz and J. Tritt-Goc, Tetrahedron, 2009, 65, 9801.
21 K. Murata, K. Aoki, T. Suzuki, T. Hanada, H. Kawabata, T. Komori,
F. Oseto, K. Ueda and S. Shinkai, J. Am. Chem. Soc., 1994, 116, 6664
and references cited therein.
15 K. Rosenlehner, B. Schade, C. Böttcher, C. M. Jäger, T. Clark, F.
W. Heinemann and A. Hirsch, Chem.–Eur. J., 2010, 16, 9544.
16 C. M. Jäger, A. Hirsch, B. Schade, C. Böttcher and T. Clark, Chem.–Eur.
J., 2009, 15, 8586.
22 As examples on the ions influence on the gel properties see: (a) H. Basit,
A. Pal, S. Sen and S. Bhattacharya, Chem.–Eur. J., 2008, 14, 6534;
(b) A. Pal, H. Basit, S. Sen, V. K. Aswal and S. Bhattacharya, J. Mater.
Chem., 2009, 19, 4325.
17 K. C. Hoang and S. Mecozzi, Langmuir, 2004, 20, 7347.
18 pKa values could not be determined due to insolubility in water at pH <
pHsol–gel, see: A. Bryson, N. R. Davies and E. P. Serjeant, J. Am. Chem.
Soc., 1963, 85, 1933.
19 As example of negligible effects of salts on Tgssee: S. Kumar Kundu,
M. Yoshida and M. Shibayama, J. Phys. Chem. B, 2010, 114, 1541 and
references cited therein.
23 M. Hird, Chem. Soc. Rev., 2007, 36, 2070.
24 B. A. Berkowitz, C. A. Wilson and D. L. Hatchell, Invest. Opthalmol.
Vis. Sci., 1991, 32, 2382.
25 P. C. Rooney and D. D. Daniels, Pet. Technol. Q., 1998, 3, 97.
26 K. C. Lowe, J. Fluorine Chem., 2002, 118, 19.
27 K. P. Flora, B. van’t Riet and G. L. Wampler, Cancer Res., 1978, 38,
1291.
3052 | Org. Biomol. Chem., 2012, 10, 3044–3052
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