A gemini guest triggers the self-assembly of a calixarene capsule in water at neutral pH

Article abstract of DOI:10.1039/c1cc11211b

A gemini guest having both aromatic units and negative charges induces the self-assembling of a homodimeric capsule when interacting with a positively charged calixarene at pH 7.

Full text of DOI:10.1039/c1cc11211b

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COMMUNICATION
A gemini guest triggers the self-assembly of a calixarene capsule in water
at neutral pHwz
Carmela Bonaccorso,a Carmelo Sgarlata,a Giulia Grasso,b Valeria Zito,b Domenico Sciotto*a
and Giuseppe Arena*a
Received 28th February 2011, Accepted 28th March 2011
DOI: 10.1039/c1cc11211b
A gemini guest having both aromatic units and negative charges
induces the self-assembling of a homodimeric capsule when
interacting with a positively charged calixarene at pH 7.
We have reported on the inclusion of some aromatic anions
at two different pH values and showed that the degree of
protonation of the host affects their inclusion.5 pH may also
limit the host and/or the host–guest assembly solubility. Only
two examples of water-soluble self-assembling capsules, that
are not based on metal–ligand interactions, have been reported
so far and both these systems reach an adequate solubility
at pH 9.2,6 We have recently reported on a capsule that
self-assembles in neutral aqueous solution;7 the interaction
capacity of the aromatic ends and the negative charges of the
guest BS1 with both the cavity walls and the upper rim of
the host TAC4, respectively, triggered the capsule formation. The
thermodynamic parameters (DH o 0 and DS > 0), though,
emphasized that the guest–host direct mutual interaction in
this system is an important contribution to the total, yet it is
not the only relevant one, as also stressed by Schmidtchen in a
recent review article.8 Building on this previous study, we
asked ourselves whether and to what extent a shorter spacer
would still permit capsule templation.9 Thus, we synthesized
the guest depicted in Scheme 1 and screened its interaction
One of the main targets of supramolecular chemistry is to
develop simple yet comprehensive and reliable methods to
effectively hold together separate parts of complex archi-
tectures, exclusively through cooperative non-covalent inter-
actions. Self-assembled molecular capsules have attracted
considerable interest over the last couple of decades not just
for their often appealing complex structures but also because
they can be used to perform reactions that are problematic in
aqueous solution.1,2 Indeed, confined spaces offer a unique
opportunity to examine and manipulate the properties of
encapsulated small molecules and reactive intermediates. By
way of example, Gibb and Simin have shown that capsules
may be used as nanoscale reaction chambers and are also
capable of promoting the formation of products not observed
in solution.2 Ramamurthy et al. have demonstrated the
possibility of trapping a high-energy conformer of a piperidine
derivative within a supramolecular assembly in water at
pH 8.5.2 Raymond et al. have demonstrated that the highly
reactive iminium ion may be managed in water when
encapsulated within a self-assembled metal cluster cavity.2 In
water one has to deal with problems that are not encountered
in organic solvents. In this solvent complex organic archi-
tectures often have limited solubility, the host–guest binding
constant drops and pH becomes crucial.2,3 If, as it is often the
case, the host has proton binding sites, protonation may
modify both the binding ability of a receptor and the overall
charge. Bowman-James et al. reported pH-dependent solution
studies of the interaction of protonable cryptands with
fluoride, showing that fluoride ions were included in the highly
protonated form of the macrocycle.4
1
with TAC4 (Scheme 1). H NMR, DOSY, ROESY, ESI-MS
and preliminary nano-ITC results provide converging evidence
that BS2 leads to the formation of a capsule in neutral
aqueous solution. Knowing that TAC4 forms a 2 : 1 complex
with BS1, we initially examined the 1H NMR spectra of
solutions with different TAC4/BS2 ratios (D2O, phosphate
buffer, pD = 7.1). NMR guest signals are considerably upfield
a
`
Dipartimento di Scienze Chimiche, Universita degli Studi di Catania,
Viale Andrea Doria 6, 95125 Catania, Italy.
E-mail: garena@unict.it, dsciotto@unict.it
b IBB, CNR, c/o Dipartimento di Scienze Chimiche, Universita` degli
Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy
w This article is part of a ChemComm ‘Supramolecular Chemistry’
web-based themed issue marking the International Year of Chemistry
2011.
z Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c1cc11211b
Scheme 1 Host and guests investigated.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 6117–6119 6117

Fig. 2 Positive-ion ESI-MS/MS spectrum of the TAC4/BS2 mixture
(host/guest ratio 4; R = NC2H7) at m/z 1925.2 ion.
presence of several adducts and a wide range of fragmented
ions in the first-order mass spectra, as typically observed
for solutions containing such adducts.7,10 However, the
combination of positive-ion and tandem mass spectrometric
experiments (Fig. 2) has revealed the peaks attributable to the
1 : 1 and 2 : 1 host–guest complexes and their adducts with
Fig.
1
1H NMR titration spectra for the TAC4/BS2 system
(D2O, phosphate buffer, pD 7.1).
ꢁ
H2PO4 as well as with Na+.
shifted, as compared to the uncomplexed guest, upon addition
of up to 8 equiv. of TAC4, owing to the ring current effect of
the four aromatic nuclei of the host cavity. Guest signals are
observed as averaged single resonances due to the fast
exchange between the free and the complexed species on the
NMR time scale. Fig. 1 shows that the methyl groups of BS2
experience the larger upfield shift (up to 1.8 ppm) upon
complexation followed by the H1 and H2 aromatic protons
whereas the H3 signals and the methylene protons of the alkyl
linker undergo only a negligible change. This clearly indicates
that the double-headed guest binds by inserting its aromatic
moieties into the lipophilic pocket provided by the host while
leaving the polar sulfonate groups at the upper rim of the
calixarene.
The thermodynamics of the binding reaction was also
investigated by isothermal titration calorimetry (ITC). The
ITC titration curve for the interaction of TAC4 with BS2
markedly differs from the analogous curve recorded for BS1
(Fig. 3 and Fig. S3 (ESIz)). Due to the procedure employed for
the ITC titrations (the guest is increasingly added to the host),
the equilibrium between the 2 : 1 and 1 : 1 complexes is shifted
in favor of the capsule in the presence of excess host, i.e., in the
first points only (Fig. S4, ESIz). This implies that a relatively
large number of titrations have to be performed to obtain an
accurate fitting of the first portion of the curve.11 The
preliminary data for the present system corroborate the
speciation and the magnitude of the binding constants
obtained via 1H NMR: both techniques indicate that the
1 : 1 and the 2 : 1 species coexist in solution at neutral pH.
The log K21 for the formation of the 2 : 1 species reproduces
the one determined via 1H NMR (log K21 are 3.0 and 3.3,
respectively) and both techniques indicate that the overall
log b21 for the formation of the capsule is of the same order
of magnitude (log b21 E 7.2). Since the interaction of TAC4
with BS2 on the whole liberates more heat than the analogous
interaction with BS1 (Fig. 3) the formation of the assembly
The large complexation induced shift (CIS, Fig. S1, ESIz)
observed for the methyl groups of BS2 suggests that such
groups are deeply included into each host cavity whilst the
short spacer which tethers the two aromatic units of the guest
shares the equatorial region between the two ‘‘facing’’ calix-
arenes thus crafting a well packed capsule-like architecture.
The positively charged upper rims of the two calixarenes
facing each other are ‘‘shielded’’ by the sulfonate groups of
the (encapsulated) ends of the guest.
NMR titration data (Fig. S2, ESIz) allowed for the
determination of the association constants: the fit of the
chemical shifts using the 1 : 1 and 2 : 1 host–guest binding
model yielded log K values of 4.5 ꢀ 0.1 and 3.3 ꢀ 0.1,
respectively. The overall binding constant for the formation
of the capsule (log b21 = 7.8) is slightly larger than the value
previously reported for the system assembled using a longer
spacer (logb21 = 7.40). Likely, the shorter and more rigid linker
of BS2 enables a tighter connection between the two calixarenes
and promotes the formation of the capsule maximizing both the
electrostatic and the hydrophobic interactions.
Fig. 3 Net heats for the addition of BS1 (blue circles) and BS2
(purple circles) to aqueous solutions of TAC4 (pH = 6.8, phosphate
buffer).
The ESI-MS spectra of aqueous solutions containing TAC4
and BS2 show a complex fragmentation pattern, due to the
c
6118 Chem. Commun., 2011, 47, 6117–6119
This journal is The Royal Society of Chemistry 2011

with BS2 is driven by enthalpic and entropic contributions
that are different from those determined for the guest with the
longer spacer.
provided further insight on the structure of the capsule (Fig. 5
and S6, ESIz). Cross peaks between the Hc signals of the host
and the H1, H2 (Fig. 5 inset) and CH3 (Fig. S7, ESIz) protons
of the guest suggest that the two aromatic ends of BS2 are
deeply inserted into the calixarene cavities. As expected, only a
weak cross-peak was detected between the methylene protons
of the alkyl chain of the guest and the methyl groups of the
host. The correlation observed between the Ha and Hb signals
of the host and the H1, H2 and H3 signals of the guest further
confirms the spatial proximity of the components of the
capsule (Fig. 5). Interestingly, most of these NOESY correla-
tions can no longer be detected at H/G ratios lower than 3,
that is when the 1 : 1 complex is the main species in solution
(Fig. S5, ESIz).
The data so far collected indicate that whilst the formation
of the 1 : 1 species with BS2 is more exothermic than the
analogous species with BS1 by ca 10 kJ molꢁ1, the formation
of the capsule has a smaller enthalpic and a larger entropic
contribution; perhaps the closer proximity of the two hemi-
spheres is the main reason for the differences observed.
To further corroborate the speciation obtained through the
chemical shift values, we also resorted to diffusion NMR
spectroscopy (DOSY) since this technique has been found to
be an invaluable tool for the characterization of bulky supra-
molecular structures and highly symmetric non-covalent
aggregates in solution.12 DOSY experiments carried out at
different host/guest ratios (Fig. 4) show that, as increasing
amounts of the host are added, the self-diffusion coefficient of
the free guest dramatically drops as a consequence of its larger
size resulting in complex formation. Attempts to fit the
diffusion data by considering the HG model only proved to
be unsuccessful (Fig. 4). The ‘‘extrapolated’’ diffusion
coefficient for the HG species (3.3 ꢀ 0.1 ꢂ 10ꢁ10 m2 sꢁ1) is
smaller than that of free BS2 (4.4 ꢀ 0.1 ꢂ 10ꢁ10 m2 sꢁ1) but
significantly larger than the value found for the H2G species
(2.6 ꢀ 0.1 ꢂ 10ꢁ10 m2 sꢁ1) thus confirming the existence of a
bulkier complex in solution.13 Furthermore, ROESY NMR
spectra recorded at different TAC4/BS2 ratios markedly
display NOE interactions between host and guest signals and
We have shown that a gemini guest with a shorter spacer
(BS2 vs. BS1) still triggers the self-assembling of a more
compact homodimeric capsule (percentage of formation
>70%, Fig. S5, ESIz). The electrostatic interactions between
the opposite charges residing on the guest and the host and the
use of p–p interactions to give effective binding in water
confirm the surprising features of the system and suggest a
new strategy towards anion templated capsules in highly
competitive media like water. The successful trapping of BS1
and BS2 in water at neutral pH, albeit not a general example,
is suggestive of the possibility of yet to be discovered examples.
We are currently investigating gemini guests covering a range
of lengths of the spacer to examine their ability to act as
templating agents and thus trigger capsule formation.
We are grateful to MIUR (PRIN 2008F5A3AF_005) and
University of Catania for funding.
Notes and references
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2 S. Liu and B. C. Gibb, Chem. Commun., 2008, 3709; V. M. Dong,
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S. Raghothama and V. Ramamurthy, Org. Lett., 2010, 12, 4544;
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M. D. Pluth, B. E. F. Tiedemann, V. Zito, G. Arena and
K. N. Raymond, J. Am. Chem. Soc., 2010, 132, 1005.
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T. Clifford, A. Danby, J. M. Llinares, S. Mason, E. Garcia-Espana
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5 C. Sgarlata, C. Bonaccorso, F. G. Gulino, V. Zito, G. Arena and
D. Sciotto, New J. Chem., 2009, 33, 991.
Fig. 4 BS2 self-diffusion coefficients. Black full circles, experimental
data points; red broken line, HG model; blue solid line, HG + H2G model.
6 F. Corbellini, L. D. Costanzo, M. Crego-Calama, S. Geremia
and D. N. Reinhoudt, J. Am. Chem. Soc., 2003, 125, 9946.
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11 Additional experiments are currently underway to improve the
accuracy of the ITC data.
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44, 520.
13 A satisfactory fit of the experimental data was obtained when using
the HG + H2G model only and gave log K values of 4.7 ꢀ 0.1 and
3.0 ꢀ 0.1 that nicely agree with those obtained through 1H NMR.
Fig. 5 2D ROESY (D2O, phosphate buffer, pD 7.1, H/G = 5);
off-diagonal peaks of interest are encircled.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 6117–6119 6119