Stimuli-responsive supramolecular gelation in ferrocene-peptide conjugates

Article abstract of DOI:10.1002/chem.201302450

Teaching an old dog new tricks: Ferrocene-dipeptide conjugates capable of forming gels in response to various external signals including sound, thermal, redox, and mechanical stress are reported (see figure). Interesting examples of how ferrocene-peptide conjugates can be exploited for the construction of organometallic gelators are demonstrated.

Full text of DOI:10.1002/chem.201302450

DOI: 10.1002/chem.201302450
Stimuli-Responsive Supramolecular Gelation in Ferrocene–Peptide
Conjugates
Rouzbeh Afrasiabi and Heinz-Bernhard Kraatz*[a]
Smart and functional materials have attracted a lot of at-
tures, we have coupled this dipeptide, and its analogue Boc-
l-Lys(Z)-l-Phe-OMe, to ferrocene monocarboxylic acid to
induce gel formation in the respective ferrocene–peptide
conjugates (see Scheme 1).[7]
tention in the last three decades because of their potential
applications in the development of new molecular devices.[1]
In this regard, organogels represent an important medium
for the preparation of stimuli-responsive materials.[2] The
concept of supramolecular devices is still in its infancy and
much research is required to develop systems that possess
the same responsive behavior that is present in nature. Pep-
tides and proteins are capable of demonstrating multistimuli
responsive behavior, and naturally occurring amino acids
can be attractive building blocks to extend the same stimuli-
responsive features to the development of functional materi-
als.[3] Owing to its redox-active properties, ferrocene has
been found to be useful in a plethora of applications includ-
ing sensing, catalysis, and in responsive materials.[4] Impor-
tantly, ferrocene–peptide conjugates have attracted tremen-
dous attention in designing secondary-structure mimics of
peptides because these conjugates have the ability to form
hierarchical assemblies driven by weak non-covalent interac-
tions.[5] Despite these interesting features, the application of
ferrocene–peptide foldamers in forming supramolecular gels
has not yet been explored. Herein, we report two novel fer-
rocene–dipeptide organogelators that are capable of forming
gels in various solvents. The prepared gels demonstrate re-
versible responses to various external signals including ther-
mal, sound, redox, and mechanical stress. Considering the
fact that serendipity is one of the main pathways to discov-
ery in organogel research, organometallic-based gelators are
not abundant; the ferrocene–dipeptide conjugates reported
here are intriguing organometallic gelators.[6] We have previ-
ously reported Boc-l-Phe-l-Lys(Z)-OMe to have a robust
self-organization property that can lead to hierarchical self-
assembly and gel formation. Owing to these attractive fea-
The studies were focused on synthesizing ferrocene mono-
carboxylic acid derivatives because of their higher propensi-
ty to form intermolecular hydrogen bonds compared with
ferrocene–dicarboxylic acid conjugates, which are well-docu-
mented to form intramolecular–interchain hydrogen
bonds.[8] Initially, the peptides were directly coupled to fer-
rocene monocarboxylic acid to form conjugates 1 and 2. In-
vestigation of the self-assembly of these compounds in dif-
ferent solvents showed the low tendency of the molecules to
undergo extensive self-organization. In response to heating
and cooling or application of sonication,[9] solutions of 1 and
2 in toluene exhibited an increase in viscosity, accompanied
by a change in the opacity of the mixture that could indicate
limited organization into a fibrous network, which collapses
upon formation.[10] The inability of the molecules to proper-
ly self-assemble and induce gel formation can be attributed
to restricted inter- and intramolecular interactions that pre-
vent the formation of an extended hydrogen-bonded net-
work. This outcome is in agreement with previous knowl-
edge that monosubstituted ferrocene derivatives are incapa-
ble of directing self-assembly and that the formation of
supramolecular structures in these ferrocene–peptide conju-
gates is serendipitous; most of the previously reported sys-
tems exhibit no induced chirality for the ferrocene moiety in
solution (identified by the lack of circular dichroism (CD)
signals in the 400–600 nm region).[8d,11] However, it was as-
sumed that, at least in case of 1 and 2, this restriction in
self-assembly was chiefly a response to the steric hindrance
between the dipeptide and the ferrocene moiety. To investi-
gate this hypothesis we synthesized derivatives 3 and 4, in
which the dipeptide is connected to ferrocene monocarbox-
ylic acid through a linker (see the Supporting Information
for the synthetic procedure).
[a] R. Afrasiabi, Prof. H.-B. Kraatz
Department of Physical and Environmental Sciences
University of Toronto at Scarborough
1265 Military Trail, Toronto, M1C 1A4 (Canada)
and
Although the direct attachment of the dipeptides to ferro-
cene monocarboxylic acid did not result in proper self-as-
sembly, incorporation of the linker allowed 3 and 4 to in-
stantly form strong gels in aromatic solvents (see the Sup-
porting Information). Instant gel formation was observed
upon cooling, or sonication of, a hot solution of 3 or 4 in tol-
uene, o-xylene, p-xylene, m-xylene, 1,2-dichlorobenzene,
chlororobenzene, and mesitylene with some of the minimum
gelation concentration (mgc) values falling below 0.1 wt%.
Department of Chemistry
University of Toronto
80 St. George Street, Toronto,
Ontario M5S 3H6 (Canada)
Fax : (+1)416-287-7279
E-mail: bernie.kraatz@utoronto.ca
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302450.
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Chem. Eur. J. 2013, 19, 17296 – 17300

COMMUNICATION
crease for the peak at
1620 cmÀ1 upon gelation. These
differences
can
indicate
a change in inter- and intramo-
lecular hydrogen-bonding pat-
terns after gel formation. Cyclic
voltammograms of 3 in mix-
tures of dichloromethane and
toluene in varying ratios (Fig-
ure 2D) show a quasireversible
oxidation and reduction wave
that gradually shifts upon in-
creasing the amount of toluene.
The observed changes in the
peak potentials are speculated
to partially arise from the grad-
ual self-assembly of the mole-
cules; this gradual self-assembly
shields the ferrocene moiety
from the solution. Nevertheless,
the contribution of the change
in solvent composition to the
Scheme 1. Structure of the ferrocene–peptide derivatives synthesized in this study.
observed shift cannot be ruled
out, and is thought to be the
Additionally, gelation in acetone, nitrobenzene, chloroform,
dichloromethane, and cyclohexane was observed, but gela-
tion was only possible after extensive sonication (3–10 min),
and with higher concentrations of the gelators.
reason behind the necessity of using small amounts of
a second solvent with a higher diffusion coefficient than tol-
uene (for example acetone, dichloromethane, or acetoni-
trile). This second solvent allows the redox process to take
place with chemical control of the sol–gel transition.
Both of the gelators, 3 and 4, are redox responsive and
sol–gel transition cycles can be carried out using chemical
agents (Figure 1E and F). Figure 1E shows the UV/Vis
spectra observed upon sol–gel transitions for a gel of com-
pound 3 in acetone (acetone–toluene mixtures demonstrate
faster gelation in response to heating and cooling, but show
a slower response when chemical agents are used in compar-
ison with gels of 3 in pure acetone). Photographs of the sol–
gel transitions (Figure 1F) show how different external stim-
uli affect a 1 wt% gel of 3 in acetone. Depositing a small
To gain better insight into the self-assembly of the ferro-
cene conjugates in aromatic solvents, thermal-denaturation
experiments were carried out. The toluene gel of 3 was se-
lected to represent the two ferrocene–peptide organogels
during the denaturation experiments. Temperature-depen-
dent UV/Vis spectra of 3 in toluene (Figure 1A), showed an
increase in absorption intensity (hyperchromic effect) after
the hot solution of 3 at 808C transitioned to gel state at
258C. This observation can be attributed to the formation of
aggregates, which are induced by the self-assembly of the
molecules, to generate a supramolecular structure that gives
rise to a high ratio of light scattering upon gelation. To elu-
cidate the chiral arrangement of molecules in the gel state,
circular dichroism (CD) experiments were performed. CD
signals recorded for the toluene gel of 3 (Figure 1B) exhibit-
ed a prominent negative Cotton effect at 500 nm that gradu-
ally reduced to zero following slow heating to 808C. Thus,
the CD studies indicate the existence of supramolecular
chirality that is determined by the molecular chirality of the
gelator. The CD signal observed at 400–600 nm is indicative
of chiral organization of the ferrocene moiety; to the best of
our knowledge, this chiral organization has not been ob-
served or investigated in previously reported peptide conju-
gates of ferrocene monocarboxylic acid.[8a,d,11c] The thermally
induced decrease in CD signals originates from the disas-
sembly of the chiral supramolecular structure, and is a conse-
quence of diminishing non-covalent interactions. The FTIR
spectrum of 3 (Figure 1C) shows an increase in the intensity
of the peaks at 1643 cmÀ1 and 1690 cmÀ1, in addition to a de-
amount of Fe
transition of the gel to a solution state (an FeACHTUNGTRENNUNG
ACHTUNGTRENNUNG
tion with less than equimolar amounts of the oxidizing
agent, with respect to gelator 3, must be used). The solution
formed after the gel transition contains the oxidized form of
the gelator (Sol+), the presence of which is supported by
the green color of the mixture, attributed to the oxidation of
ferrocene to a ferrocenium cation. This color change is also
in agreement with the appearance of a peak at 650 nm in
the UV/Vis spectrum (Figure 1E middle spectrum). Intro-
ducing a reducing agent such as ascorbic acid (in solid or so-
lution form) to the mixture, accompanied by sonication
allows reversal of the changes induced by Fe
pected, chemically induced redox sol–gel transitions, by
using solutions of Fe(ClO4)3 as the oxidizing agent and
ascorbic acid as the reducing agent, cannot be performed in
ACHTUNGTRNEN(UNG ClO4)3. As ex-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
multiple cycles. This behavior is due to the fact that the oxi-
dizing and reducing agents can act as impurities and thus ad-
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H.-B. Kraatz and R. Afrasiabi
Figure 1. A) Temperature-dependent UV/Vis spectra for the toluene gel
of compound 3. B) Variable-temperature CD spectra for the toluene gel
of 3. C) FTIR spectra of the toluene gel of compound 3 (solid line) and
gelator 3 before gelation (dotted line). D) Cyclic voltammograms of 3 in
mixtures of dichloromethane/toluene (0:1 solid line, 1:1 dotted line).
E) UV/Vis spectra of 3 in acetone under different conditions: Sonication-
induced gel state (top), oxidized solution 10 min after addition of the oxi-
dizing agent (middle), solution formed after addition of the reducing
agent (bottom). F) Photographs of sol–gel transitions for 3 in acetone.
Figure 2. A) 1H NMR spectra of 3 in [D6]acetone showing the changes
observed in response to different stimuli (+ and X denote peaks assigned
to the ferrocene moiety). B) Temperature-dependent 1H NMR spectra of
3 (+ and X denote peaks assigned to the ferrocene moiety, other symbols
are assigned to amide protons). C) Thermal stability of the toluene gel of
3 as a function of gelator concentration. D) Frequency-sweep experiment
of a 0.5 wt% toluene gel of 3 at a constant strain of 1%. E) Strain-sweep
experiment performed on a 0.5 wt% toluene gel of 3 at a constant fre-
quency of 1 Hz. F) Thixotropic behavior of the toluene gel of 3.
versely affect gelation time and gel strength. This point is
further supported by the field-emission scanning electron
microscopy (FESEM) images of the recovered gel after one
cycle of oxidation and reduction (see below).
dized solution, the sonication -induced gelation is accompa-
nied by an upfield shift of both the amide protons and pro-
tons related to the aromatic region. Comparison of these re-
sults with those of the original solution of 3 in [D6]acetone,
indicates that p–p stacking might be the main factor behind
gel formation in response to sonication. Temperature-depen-
1H NMR studies on the [D6]acetone gel of 3 demonstrate
the changes observed in response to redox induced sol–gel
transition by chemical agents (Figure 2A). Acetone was se-
lected for these experiments because of the delay in gel for-
mation in response to sonication, and faster oxidation and
reduction of the species in this solvent. As shown in Fig-
ure 2A, introduction of an oxidizing agent results in the oxi-
dation of the ferrocene unit to a paramagnetic ferrocenium
cation, which is evident by the broadening and disappear-
ance of peaks from the ferrocene moiety. Solution-to-gel
transition can be performed by the addition of a reducing
agent followed by sonication. In comparison with the oxi-
1
dent H NMR studies of 3 in [D8]toluene provide more in-
sight into the non-covalent interactions responsible for gel
formation and provide the reasons behind more effective ge-
lation in aromatic solvents (Figure 2B). In solution state
and at temperatures higher than Tgel–sol, the observed spectra
can be attributed to the unorganized molecules in solution.
As the temperature is decreased below 608C an upfield shift
of the aromatic proton resonances is observed, indicative of
aggregation by p–p stacking. After decreasing the tempera-
ture to 208C, the recorded signals correspond to the solvent
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Gelation in Ferrocene–Peptide Conjugates
COMMUNICATION
molecules that are not captured inside the gel structure. Un-
fortunately, the changes observed in the amide proton sig-
nals for toluene gel 3 do not conclusively show the exact
contribution of hydrogen bonding in gel formation. Howev-
er, the noticeable changes in the intensity of the signals aris-
ing from the ferrocene unit demonstrate the fast exclusion
of this moiety from the environment. These changes are in
accordance with the hypothesis that the ferrocene moiety is
transferred inside the supramolecular structure upon gel for-
mation (Figure 2B). The thermal stability of the gels was
also studied by tube-inversion experiments at various con-
centrations (Figure 2C shows the results for toluene gel 3).
Gels of 3 and 4 in toluene showed only minor differences in
thermal stability; at a concentration of 5 mm the Tgel value
was 788C for both 3 and 4. However, at lower concentra-
tions the gel of 3 in toluene was found to be thermally more
stable than the toluene gel of 4. Moreover, the minimum ge-
lation concentration (mgc) value for 3 was lower than that
for 4; gelator 3 was able to act as a super-gelator for toluene
(mgc=0.098 wt%) and exhibited extensive self-assembly,
even in much lower concentrations. Notably, because of the
dependence of yield stress on the size of the vial and on the
mass of the gel, tube-inversion tests can lead to the false
identification of a material as gel. Accordingly, rheological
studies were carried out to further investigate the gels and
determine the linear viscoelastic regime. Operating in the
linear regime allows the study of the mechanical behavior of
the gels without disrupting the underlying forces that sup-
port the supramolecular structure. Dynamic oscillatory
measurements at a constant strain of 1%, and as a function
of increasing angular frequency, demonstrate the changes of
storage and loss modulus for 3 (Figure 2D). G’ and G’’
(G’=elastic modulus and G’’=viscous modulus) were found
to be independent of applied frequency below 15 Hz and G’
values in this range were always greater than G’’, indicative
of predominant elastic character. In strain-sweep experi-
ments performed at a constant frequency of 1 Hz, the G’
values for a 0.5 wt% toluene gel of 3 displayed minor
changes in response to increasing strain up to 2% (Fig-
ure 2E). Beyond this limit the G’ value gradually decreases
and eventually becomes equal to that of G’’. Surprisingly,
the gels of both 3 and 4 in toluene demonstrate recovery of
their mechanical properties soon after mechanical stress is
removed. Gelator 3 exhibits superior thixotropic behavior
compared with 4 and was thus selected for further study.
Figure 2F demonstrates one cycle of breaking and recovery
for the toluene gel of 3. The gel was initially subjected to
a non-destructive shear rate of 0.01 1 sÀ1, which resulted in
no change in the viscosity of the sample. Following this, a de-
structive shear rate was applied that induced structure
breakdown. Upon removing or reducing the shear rate the
gel recovers its mechanical properties, supported by the in-
crease in viscosity after standing for 4 min. The morphology
of the toluene xerogels of ferrocene conjugates 3 and 4 were
analyzed by FESEM. Figure 3 shows the formation of
a highly entangled network that is predominated by nanofi-
Figure 3. FESEM micrographs: A) Xerogel of 3 obtained from toluene
gel. B) Xerogel of 4 obtained from toluene gel. C) Xerogel of 3 obtained
from acetone gel before addition of the oxidizing agent. D) Xerogel of 3
obtained from acetone gel after addition of the oxidizing agent. Scale
bars denote 1 mm.
FESEM experiments also showed that the xerogel of 3 in
acetone (Figure 3C) contained larger nanofibers compared
with the xerogel of 3 in toluene. Figure 3D shows the initial
changes in the morphology after adding an oxidizing agent
to the acetone gel of 3. FESEM micrographs of the xerogel
of 3 after one cycle of oxidation and reduction (see the Sup-
porting Information), show a decrease in the size of the
fibers; this decrease could be responsible for the previously
mentioned reduction in gel strength for the chemically re-
constituted gel.
In summary, we have successfully synthesized and charac-
terized two novel ferrocene–dipeptide conjugates that are
capable of forming gels in response to various external sig-
nals including sound, thermal, redox and mechanical stress.
The gelators exhibit excellent gelation properties and can
act as super-gelators for selective aromatic solvents at ambi-
ent temperature. Importantly, gelation is not limited to
liquid aromatic hydrocarbons (typically observed in other
peptide conjugates of ferrocene), and is possible in other
solvents, allowing redox induced sol–gel transitions in ace-
tone.[12] The current report demonstrates interesting exam-
ples of how ferrocene–peptide conjugates can be exploited
for the construction of organometallic gelators. We believe
that the results presented here can lead to the design of new
ferrocene–peptide nanomaterials that can find applications
in a variety of fields. Our current studies are aimed at using
similar systems in the development of organogels and hydro-
gels for potential applications in sensing, and as platforms
for supramolecular logic-gate operations.
Acknowledgements
Financial support from NSERC and the University of Toronto is grateful-
ly acknowledged. We thank Tony Adamo for help with data collection
ACHTUNGTRENNUNGber morphology in the case of 3 and nanotapes for 4.
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H.-B. Kraatz and R. Afrasiabi
and acknowledge the Nanofabrication facility at Western University
Canada for SEM imaging.
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Keywords: ferrocene · gels · peptides · self-healing · stimuli
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Received: June 25, 2013
Published online: November 8, 2013
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Chem. Eur. J. 2013, 19, 17296 – 17300