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Selective catechol-triggered supramolecular gel disassemblyw

Published on 24 September 2010. Downloaded by The University of British Columbia Library on 30/10/2014 00:46:13.

Jose A. Saez, Beatriu Escuder* and Juan F. Miravet*

Received 12th July 2010, Accepted 7th September 2010
DOI: 10.1039/c0cc02510k
Supramolecular gels formed by an isonicotinic acid derivative in
toluene are selectively disassembled in the presence of catechol.
The results represent a unique example of molecular recognition
associated to gel rupture which is of interest, for example, in
controlled drug release applications.
The preparation of smart, stimuli responsive materials is of
great interest in a variety of areas, being of special relevance
for biomedical applications. For these purposes mostly polymeric
materials have been used which respond to a variety of stimuli
such as temperature, or chemical species.1 Supramolecular gels
represent a new type of soft materials which are formed
from low molecular weight compounds and whose study has
blossomed in recent decades.2 Supramolecular gelators form
elongated supramolecular aggregates that further evolve to
nanobrilar networks which entrap the solvent to yield a gel.
The self-assembly process is driven by specic non-covalent
intermolecular interactions and can aord functional materials
which are of interest in areas such as tissue engineering,
electronic and photonic materials and catalysis.3 A very
relevant point of interest is the stimuli responsiveness associated
with supramolecular gels. Aside from their characteristic
temperature and concentration dependence, gel formation
can be controlled by stimuli such as for example light,4 or
ultrasound.5 Of special interest is their response to chemical
species such as enzymes,6 red-ox7 or acidbase reagents.8 Aiming
to practical applications such as drug release, it is desirable to
promote gel disassembly in response to determined chemicals.
In this respect, several examples of gel disruption associated to
anions and metal cations have been reported.9 For example,
anion-triggered gel disassembly can arise from partial dissolution
of the gelator or transformation of the gel into a crystalline
solid.9b,d However, the use of neutral organic substrates for
this purpose has been scarcely reported.10
Following the studies of the interaction of hydroxyl containing
aromatic compounds with gels of 1 (Scheme 1) in acetonitrile,11a
we have carried studies in toluene. Here we describe how the gels
formed in toluene by the isonicotinic acid derived compound 1
can be selectively taken apart in the presence of catechol.
Noticeably, we have found that the disassembly process is highly
selective to the catechol structural motif.
In this work gels were formed in toluene by cooling a 12 mM
hot solution of 1 to room temperature. These gels were
described to be stable at least up to 95 1C and to present a
microbrillar crystalline network.11b When gels were formed

Departament de Qumica Inorga`nica i Orga`nica, Universitat Jaume I,

Avda., Sos Baynat s/n, 12071 Castello, Spain. E-mail: [email protected],
[email protected]
w Electronic supplementary information (ESI) available: Experimental
procedures. See DOI: 10.1039/c0cc02510k

7996

Chem. Commun., 2010, 46, 79967998

Scheme 1

in the presence of a 24 mM solution of dierent hydroxyl

containing aromatic compounds, remarkably after 1 h, gel
rupture was observed only when catechol (11) was present,
yielding a material composed of gelatinous particles that was
no longer self-supported (see Fig. 1). All the other gel samples
were stable for more than 24 h. Similar results were obtained
when solutions of the phenolic compounds were deposited
over the gels.
The results show that gel disassembly is very sensitive to
the structure of the hydroxyaromatic compounds. The gel
inertness towards resorcinol (6) and hydroquinone (10) indicates
that the 1,2-dihydroxy pattern is very important in the observed
activity. On the other hand, the fact that the gel is stable in the
presence of the rather acidic compound 4-nitrophenol (9)
reveals that the driving force of the gel rupture is not associated
to an acidbase reaction between phenolic and pyridine
moieties. It can be noted that the gel stability towards
1,2-dimethoxybenzene (veratrole, 8) shows that the hydroxy
groups play a key role in the observed behaviour. As a matter
of fact, gel destruction processes were also observed when
substituted catechols such as 3-methylcatechol or 3-cyanocatechol were present (not shown).

Fig. 1 Images of gels formed by compound 1 (12 mM) from

24 mM solutions in toluene of compounds 411 (from left to right).
Top: freshly formed gels. Bottom: 1 h later.

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Fig. 3 Wireframe and space-lling energy minimized model for the

interaction of 2 and cathecol. (B3LYP/6-31G* level in toluene through
PCM method, see references and further data in ESIw). Dotted lines
indicate hydrogen bonding.

Fig. 2 1H NMR spectra obtained in the study of the interaction of

compound 2 (12 mM) and catechol (24 mM) in toluene-d8: (a) catechol
aromatic signals; (b) pyridine signals.

A similar study was carried out for gels formed by compound 3, an analogue of 1 obtained by the replacement of the
pyridine moieties by phenyl subunits.12 In this case all the gels
were stable for more than 96 h, highlighting that the pyridine
unit plays a key role in the gel destruction process.
To gain insight into the interaction that gives rise to the
observed process, NMR studies were carried out with compound 2 which is a toluene soluble analogue of 1.
As can be observed in Fig. 2, when the interaction of
catechol and compound 2 was studied by 1H NMR in
toluene-d8 the aromatic signals from both molecules showed
signicant changes. In both cases chemical shift and multiplicity variation were observed. This result can be ascribed to
the formation of a complex species which would present pp
interactions with the closely positioned aromatic groups,
giving rise to the NMR shielding and deshielding eects
observed. The presence of pp interactions between electronrich and -poor aromatic units is well described.13 The complex
species most likely shows reduced conformational mobility for
the pyridine moiety which results in the transformation of
the doublet-type signals of 2 into the observed multiplets.
Additionally, the amide NH units of compound 2 also show a
remarkable change in chemical shift. For example, the broad
NH signal observed at ca. 7.7 ppm in the spectrum of the
mixture 2 + catechol from Fig. 2 is shifted ca. 0.4 ppm
downeld upon comparison to its signal in free compound 2.
The NMR signal shifts described above were not detected
when acetonitrile, a hydrogen-bonding acceptor, was used as
solvent, suggesting that hydrogen-bonding interactions are
important in the studied case. This observation agrees with
the stability of the gels of 1 in acetonitrile in the presence of
catechol.6a
Computational studies for the complex between 2 and
catechol agree with these considerations. An energy minimized
model can be built which shows hydrogen bonding between
the catechol hydroxy groups and the amide NHs (Fig. 3). The
calculated model shows that intramolecular hydrogen bonding
between hydroxy groups of catechol is broken to allow for the
two-point interaction with the two amide units of the gelator.
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This is in agreement with the observed NMR shifts for both

amide signals upon interaction with catechol. In this model the
aromatic units are close enough to each other to produce the
perturbations of the chemical shift values upon complex
formation, as observed experimentally.
When the disassembly process of gel 1 (12 mM) in toluene
was monitored by NMR it was observed that after 12 h
the gelator molecules remained insoluble (NMR-silent)
after gel disassembly and that the concentration of free
(NMR-observable) catechol signicantly diminished from
24 mM to 5 mM (see ESIw). These data indicate the formation
of insoluble complexes between 1 and catechol with a ratio of
pyridine moieties/catechol close to 1, which can be ascribed to
the interaction of each gelator molecule with two catechol
molecules through the pyridine end groups. The formation of
these species is schematized in Fig. 4 and would lead to a
disruption of the columnar hydrogen-bonded arrays responsible of gelation, giving rise to insoluble aggregates. The
driving force for such a process, as suggested by the NMR
studies with compound 2 described above, would be hydrogen
bonding and pp interactions.
The model proposed for the interaction of catechol and
1 is capable to explain the selectivity observed in the gel
disassembly. For example, gelator 3 is capable of forming
similar hydrogen-bonding complexes as 1 but lacks the presence
of the electron-poor pyridine aromatic ring. 1,2-Dihydroxynaphthalene (4) and veratrole (8) could in principle interact

Fig. 4 Schematic representation of the proposed interaction of the gel

bres formed by 1 with catechol. Hashed lines indicate hydrogen
bonding and the dashed line indicates pp interaction.

Chem. Commun., 2010, 46, 79967998

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with the valine derivatives in a similar way as catechol,

behaving as hydrogen bond acceptors, but these compounds
do not alter the stability of the gel formed by 1 probably due to
steric eects associated to the presence, respectively, of the
extended aromatic unit and the methyl groups. Alternatively,
it can be hypothesized that the initial stage of gel disassembly
could involve the adsorption of catechol on the gel bers
through hydrogen bonding interactions of hydroxy groups
of catechol with the nitrogen atoms of the pyridine unit. This
initial step would be blocked for veratrole due the lack of
donor hydrogen bonding atoms.
Finally, the application of these results to stimuli responsive
controlled release was tested. For this purpose two gels formed
in the presence of tetraphenylporphyrin (a strongly coloured
compound) were charged with solutions of resorcinol and
catechol, respectively. After 30 min the amount of porphyrin
liberated into solution as determined by UV-VIS spectroscopy
was signicantly larger in the case of the sample containing
catechol, which showed gel destruction (see ESIw). The
amount of porphyrin liberated in the sample with resorcinol
was the same as that obtained for control experiments without
additives and reects the self-diusion of the porphyrin from
the gel to the overlying solution.
In summary, it can be stated that an intriguing case of
molecular recognition which is translated macroscopically to
gel destruction is reported. The results can be rationalized on
the basis of the complementary nature of the isonicotinic acid
derivatives and catechol which interact with each other
through hydrogen bonding and pp interactions. The case
described can be considered as a proof of concept of the use
of organic molecules to trigger selective gel disassembly.
Potential uses of this approach in medicinal chemistry are
envisaged considering the results described up to date on the
use of supramolecular gels in controlled release.14,15 In this
particular case it has to be noted that toluene presents a similar
polarity to media used commonly in pharmacy and that the
catechol structural moiety is common in metabolites such as
catecholamines. Finally, it can be recalled that the design of
molecules capable of disruption of brillar aggregates is of
interest in the search of new drugs for protein aggregation
diseases.16
The authors thank the Spanish Ministry of Science and
Innovation (Grants CTQ2006-14984 and CTQ2009-13961)
and Universitat Jaume I (Grants P1-1B2009-42 and
P1-1B2007-11) for funding.

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