Allosterically driven self-assemblies of interlocked calix[6]arene receptors

Article abstract of DOI:10.1039/c0ob01020k

The construction of self-assembled receptors based on flexible concave subunits is a challenging task and constitutes an interesting approach to mimic binding processes occurring in biological systems. The receptors studied herein are based on flexible calix[6]arene skeletons bearing three (or more) acid-base functionalities at their narrow rim. When complementary, they self-assemble in a tail-to-tail manner to give a diabolo-like complex, provided that each calixarene subunit hosts a guest. The allosterically-driven multi-recognition pattern is highly selective and leads to stable quaternary adducts. In order to evaluate the scope of this system, various polyamino and polyacidic calix[6]arenes have been studied. It is shown that modifications of the nature of the wide rim substituents do not alter the efficiency of the quaternary self-assembling process, even with the more flexible macrocycles that lack tBu substituents. On the contrary, the replacement of the latter by smaller groups led to receptors with broader scope, as larger guests such as tryptamine and dopamine derivatives were stabilized in the cavities. Implementation of extra-functionalities at the narrow rim were revealed also to be of high interest. Indeed, it is shown that secondary interactions take place between the two calix-subunits when they present additional and complementary functions such as carboxylate and ureido moieties. The ureido arms are also capable of binding the counter anion Cl^- of the ammonium guest, thus leading to a quinternary neutral complex. Such remarkable behavior is due to the versatility of the calix[6]arene platform, which allows the implementation of a high number of functions, leading to multiple non-covalent attractive interactions, whereas the macrocycle remains flexible, thus allowing induced-fit processes to occur.

Full text of DOI:10.1039/c0ob01020k

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PAPER
Allosterically driven self-assemblies of interlocked calix[6]arene receptors†
Ste´phane Le Gac,*a Jean-Franc¸ois Picron,b Olivia Reinaudc and Ivan Jabin*b
Received 11th November 2010, Accepted 22nd December 2010
DOI: 10.1039/c0ob01020k
The construction of self-assembled receptors based on flexible concave subunits is a challenging task
and constitutes an interesting approach to mimic binding processes occurring in biological systems. The
receptors studied herein are based on flexible calix[6]arene skeletons bearing three (or more) acid–base
functionalities at their narrow rim. When complementary, they self-assemble in a tail-to-tail manner to
give a diabolo-like complex, provided that each calixarene subunit hosts a guest. The
allosterically-driven multi-recognition pattern is highly selective and leads to stable quaternary adducts.
In order to evaluate the scope of this system, various polyamino and polyacidic calix[6]arenes have been
studied. It is shown that modifications of the nature of the wide rim substituents do not alter the
efficiency of the quaternary self-assembling process, even with the more flexible macrocycles that lack
tBu substituents. On the contrary, the replacement of the latter by smaller groups led to receptors with
broader scope, as larger guests such as tryptamine and dopamine derivatives were stabilized in the
cavities. Implementation of extra-functionalities at the narrow rim were revealed also to be of high
interest. Indeed, it is shown that secondary interactions take place between the two calix-subunits when
they present additional and complementary functions such as carboxylate and ureido moieties. The
ureido arms are also capable of binding the counter anion Cl- of the ammonium guest, thus leading to
a quinternary neutral complex. Such remarkable behavior is due to the versatility of the calix[6]arene
platform, which allows the implementation of a high number of functions, leading to multiple
non-covalent attractive interactions, whereas the macrocycle remains flexible, thus allowing induced-fit
processes to occur.
Self-assembly4 of molecular receptors present clear advantages
over covalent synthesis: (i) it avoids tedious multistep synthesis
Synthetic self-assembled receptors are a particular class of host
thanks to error correcting processes; (ii) it enhances rates of guest
Introduction
exchange through partial dissociation of the host.5 The use of rigid
skeletons that can provide reversible interactions with a high direc-
tionality has become a widespread strategy to drive and direct the
assembly process into discrete structures with a precise positioning
of the subunits. Planar poly-aryl or aromatic molecules (e.g. tris(4-
pyridyl)triazines or porphyrins), curved shape molecules (e.g.
glycoluril derivatives) or bowl shape molecules (e.g. calix[4]arenes
or resorcinarene cavitands) are among the most popular subunits
and their assembly has been achieved mainly via H-bonding
interactions6 or coordinative bonds.7 Such a strategy for elab-
orating self-assembled receptors strongly differs from what is
encountered in natural systems. Indeed, most of the biological
receptors are based on rather flexible structures (e.g., protein scaf-
folds), and nanomolar affinity is commonly achieved in aqueous
media, several orders of magnitude better than what synthetic-
rigid-receptors can do.8 Recent insights into molecular recognition
by proteins have highlighted that the binding of the ligand can
induce a reinforcement of intra-protein interactions through a
reduction of the receptor dynamics.9 This reinforced molecular
recognition strategy, that is the use of secondary intra-receptor
interactions to strengthen ligand binding, can likely explain the
molecules that are built through the non-covalent assembly of
several (identical or not) subunits.1 Over the last two decades,
particular attention has been directed toward the design of
self-assembled receptors that display capsule-like, tubular-like
or cage-like shapes. The confined, generally hydrophobic, nano-
environment defined by these three-dimensional structures allows
selection of guest molecules and their separation from the bulk.
Such isolated molecules can display unique physical properties and
chemical reactivities.2 This field of research is now at a stage where
applications such as molecular flasks are becoming realistic.3
aSciences Chimiques de Rennes, Universite´ de Rennes1, UMR CNRS 6226,
263 avenue du Ge´ne´ral Leclerc, CS 74205, 35042, Rennes Cedex, France.
E-mail: stephane.legac@univ-rennes1.fr
bLaboratoire de Chimie Organique, Universite´ Libre de Bruxelles (U.L.B.),
avenue F.D. Roosevelt 50, CP160/06, B-1050, Brussels, Belgium.
E-mail: ijabin@ulb.ac.be
cLaboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques,
UMR CNRS 8601, Universite´ Paris Descartes, 45 rue des Saints Pe`res,
75006, Paris, France
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c0ob01020k
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Fig. 1 The use of calix[6]tris-amine 1 and calix[6]tris-acid 2 for the elaboration of self-assembled receptors.
high affinities observed with natural systems. Transposed into
synthetic systems, such a strategy represents an emergent approach
contrasting with the design of rigid receptors focused exclusively
on the direct host–guest interactions.10 Thus, even if synthetic self-
assembled receptors based on flexible macrocyclic scaffolds are
still scarcely studied,11 there is a considerable interest in developing
such receptors since secondary intra-receptor interactions could
arise from conformational rearrangement triggered by guest
binding.
In the field of molecular recognition, calix[6]arenes are less
studied than the smaller tetramers.12 This is mainly due to
the difficulty of constraining the calix[6]arene structure into a
particular conformation since, in contrast to calix[4]arenes, the
narrow rim is wide enough to allow rotation of the bulky p-
tBu groups of the phenolic units through the annulus. Thus, to
behave as a molecular host, the flexible calix[6]arene skeleton needs
to be rigidified into the cone conformation, this conformation
providing a well defined cavity ideally suited for guest inclusion.
For that purpose, several strategies involving covalent bridging,13
metal ion coordination14 or anion binding15 have been devel-
oped. The resulting conformationally constrained but still flexible
calix[6]arene hosts have exhibited unique host–guest properties
and, in many cases, the flexibility of the host was turned into an
advantage since induced fit processes were observed.16 However,
despite an appealing potential in molecular recognition, the design
of self-assembled calix[6]arene edifices remains a challenging task.
Indeed, only a few examples of such supramolecular hosts have
been described, most of them being homo-dimers connected
through the wide rim via H-bonding interactions.17
As part of our research on biomimetic host–guest systems,
we were interested in the design of multi-cavities self-assembled
receptors, as such receptors could provide a means to achieve
allosteric control of guest binding.18,19 Thus, we recently turned
our attention to the narrow rim self-assembly of calix[6]arenes
through ionic interactions (Fig. 1). We first found that the flexible
calix[6]tris-amine 1 can be frozen into its cone conformation upon
protonation, the rigidification arising from the formation of an
ion paired cap and a network of H-bonding interactions between
the ammonium arms and their counter anions.20 As a result,
the positively charged calixarene presents a polarized cavity that
hosts efficiently polar neutral molecules through charge–dipole,
CH-p and H-bonding interactions. The supramolecular capping
strategy has then been used to associate a rigid concave cavity
such as a cyclotriveratrylene bearing three carboxylic groups to
the tris-amino calix[6]arene (Fig. 1).21 The resulting self-assembled
heteroditopic receptor was shown to encapsulate a polar neutral
guest into each cavity with, however, a different recognition mode
and thus different affinities.
Conversely, the calix[6]tris-acid 2 was shown to be efficiently
constrained into a cone through an acid–base reaction with
three equivalents of amine. The resulting self-assembled structure
is shaped by two ammonium ions capping the narrow rim of
the calixarene in an exo position through ion pairing with the
carboxylate arms, and by a third one in an endo position (Fig. 1).22
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Indeed, the resulting tris-carboxylate polarized host was found to
display a high affinity for ammonium ions as guests thanks to a
combination of weak interactions (charge–dipole, H-bonding and
CH-p) in a way that is very similar to the above described case of
calix[6]tris-amine 1.
Results
∑ Synthesis of the calixarene subunits 3, 4, 5 and 8
The calixarene subunits 3, 4, 5 and 8 were chosen for the
elaboration of the new self-assembled receptors (Scheme 1).
The synthesis of calix[6]-1,3,5-trisamine-2,4,6-trisurea 3 was
previously reported25 via a strategy involving a selective tris-
protection reaction.26 For the poly-acidic subunits, we focused
on calix[6]hexa-acid derivatives for the following reasons: (i)
they are more accessible than the corresponding 1,3,5-trisacids
(such as 2); (ii) they provide additional carboxylic groups that
could participate in the ion-pairing assembly; (iii) they can be
readily derivatized at the wide rim. Hence, calix[6]hexa-acid 4 was
prepared as described in the literature.27 This compound however,
suffers from the presence of the bulky tBu groups on the wide rim
that restrict the size of the cavity. The related calix[6]hexa-acids 5
and 8, which present an open cavity in the cone conformation, were
thus also synthesized. In contrast to 5, compound 8 was expected
to be highly soluble in organic media. Calix[6]hexa-acid 5 was
prepared by following a literature procedure28 while 8 was readily
obtained in two steps from the known calix[6]arene 6 (Scheme 1).29
Finally, the complementary calix[6]tris-amine 1 and calix[6]tris-
acid 2 subunits were self-assembled into a diabolo-like hetero-
dimer displaying divergent cavities,23 at the very condition however
that the cavities were shaped by their respective guest molecules.24
Hence, the selective formation of a rare [1+1+1+1] quaternary
complex through an allosterically coupled, double induced fit
process was demonstrated. Such a system is characterized by the
triple ammonium-carboxylate ion-pairing that drives the assembly
process and polarizes the cavities, while the specific host–guest
interactions direct the process into a discrete and highly ordered
structure. This last result clearly highlighted that a structure with
controlled flexibility can be a valuable alternative to rigid subunits
for the construction of sophisticated self-assembled receptors.
We thus became interested in exploring this further and possibly
expanding the scope of these self-assembled bis-calix[6]arene-
based receptors. On the one hand, in view of practical applications,
more accessible calix[6]arene subunits that can endo-complex
large guests were desirable. On the other hand, we thought of
implementing additional recognition motifs on the calixarene
subunits. Here, we present the results obtained with calix[6]arenes
bearing various functionalities at the narrow rim and various
substituents at the wide rim (Scheme 1).
∑ NMR studies of the host–guest properties of the calixarene
subunits 3, 4, 5 and 8
In a first set of experiments, the host–guest properties of the
calixarene subunits 3, 4, 5 and 8 were evaluated by 1H NMR spec-
troscopy and compared to those of the parent tris-functionalized
receptors (i.e. 3 vs. 1 and 4, 5, 8 vs. 2). Hence, upon protonation
by trifluoroacetic acid (TFA), 3 was found to endo-complex
quantitatively one equivalent of the neutral 2-imidazolidinone
(IMI) (Scheme 2, top left). The resulting host–guest complex
3H+,3TFA-
IMI
3
displays a C3v symmetrical NMR pattern with a high-
field singlet corresponding to the included IMI (dCH2IMIin = 0.36
ppm),30 the in and out guest exchange being slow on the NMR
time scale. It is noteworthy that the complexation induced shift
(CIS) of the included IMI is similar to the one observed with
1I3MH+I ,3TFA- (DdCH2 ª - 3.2 ppm). The addition of an excess of PrNH2
to a CDCl3 solution of calix[6]hexa-acid 4 led to the formation of
-6H+,5PrNH3+
PrNH3+
the host–guest complex 4
(Scheme 2, top right).31 A 1H
NMR titration experiment revealed that, similarly to the parent
receptor 2, only two exo-complexed ammonium ions are necessary
to achieve the supramolecular capping of the host.30 Complex
-6H+,5PrNH3+
PrNH3+
4
displays a C6v symmetrical 1H NMR pattern at room
temperature that likely corresponds to an average spectrum of the
two identical C3v symmetrical flattened cone conformations in fast
inter-conversion on the NMR time scale.30,32 Again, a slow host–
guest exchange occurs at the NMR time scale and the CISs of
the propylammonium guest are similar to those observed with the
-3H+,2PrNH3+
PrNH3+
parent endo-complex 2
(DdCH3 ª - 2.6 ppm).22 Despite an
extremely low solubility in CDCl3, the calix[6]hexa-acid 5 was fully
extracted upon addition of an excess of octylamine (> 6 equiv)
and the quantitative endo-complexation of the octylammonium
ion was observed. The CISs indicate that the protons in the b
position relative to the charged nitrogen atom are located in the
heart of the cavity, while the chain extremity is protruding outside
of the cavity (Scheme 2, bottom, and Fig. 2a). Calix[6]arene 8
was fully soluble in organic media thanks to the hexa-allylic
groups, and the ammonium salts of the biologically relevant
Scheme 1 Structures of the calix[6]arene subunits 3, 4, 5 and 8. i)
BrCH2COOEt, K2CO3, acetone, reflux, 62%; ii) NMe4OH, THF, reflux,
97%.
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Fig. 2 1H NMR spectra at 298 K of host–guest complexes (a) 5OctNH3+
-6H+,5OctNH3+ (CDCl3) and (b) 8-6H+,5DopaMe2NH3+ (2 : 1 CD3OD : CDCl3 solution). ᭢: OctNH3
+
DopaMe2NH3+
in or DopaMe2 in; D: OctNH2 free or DopaMe2 free; S: solvent; w: water; *: residual grease.
O-methylated derivatives of 6-hydroxytryptamine and dopamine
were fully endo-complexed, even in a polar protic media (i.e. in a
2 : 1 CD3OD : CDCl3 solution) (Fig. 2b).30 Again, the CISs attest
to the presence of these large guests in the heart of the hydrophobic
cavity (Scheme 2, bottom). This result highlights the efficiency of
ionic interactions combined to a polarized hydrophobic cavity for
the building of stable host–guest adducts in polar protic media.
All these NMR data show that the hexa-functionalized
calix[6]arenes (i.e. 3, 4, 5 and 8) display similar host–guest proper-
ties compared with the parent tris-functionalized compounds (i.e.
1 and 2):
∑ they are rigidified in the same flattened cone conformation
upon ionization (protonation to yield poly-ammonium hosts
or deprotonation to yield poly-carboxylate hosts) thanks to
supramolecular capping by the counter ions;33
∑ their polarized cavity readily accommodates polar guests
(neutral, dipolar in the case of ammonium hosts and ammonium
ions in the case of carboxylic acid hosts);
compounds were observed (see Fig. 3a). These ill-defined NMR
spectra were found to be insensitive to the temperature and, thus,
should correspond to mixtures of non-discrete assemblies. This
absence of selectivity in the recognition processes is attributable to
the high conformational flexibility of the calix[6]arene partners;
ii) however, upon addition of a polar neutral molecule (e.g. 3 to 5
equiv. of IMI) and of an amine or an ammonium ion (1 equiv.),34
a spectacular sharpening of the spectra together with high-field
signals attributed to the included guest molecules were observed
(Fig. 3b–d).35 These well resolved NMR spectra are characteristic
of the [1+1+1+1]36 self-assembly of the calixarene subunits into
tail-to-tail bis-calix[6]arenes, each calixarene including its specific
guest in the heart of the cavity. Two sets of doublets were observed
for the ArCH2 protons of the calixarene cores, showing that
both partners are rigidified in the cone conformation upon guest
inclusion. A broad signal around 8.5–9 ppm, corresponding to the
+
NH3 protons, attested to the proton exchange between the two
calixarene partners;
∑ the host–guest complexes are remarkably resistant in H-
bonding competitive media.
Finally, the replacement of the tBu groups by smaller sub-
stituents (H or allyl) led to the “opening” of the calixarene cavity,
thus allowing the inclusion of large ammonium guests in spite of
the high flexibility of the calix[6]arene skeleton.
iii) the in and out guest exchanges were slow on the NMR
time scale and the CISs are similar to those observed for the
related monomeric endo-complexes, which shows an analogous
mode of recognition. The small differences, however, reveal a close
proximity between the complementary self-assembled hosts;
iv) overall association constants for the whole assembly process
were estimated to be > 1011 M-3 (Scheme 3 entries 2, 3, 6–9).
In each case, the formation of such self-assembled quaternary
complexes relies on a highly selective process since no other
species were observed. This selectivity is remarkable taking into
account the high flexibility of the hosts and the chemical diversity
of the four partners (i.e. a tris-amine or trisureido-trisamine,
a tris- or hexa-carboxylic acid, a cyclic urea and a primary
alkyl ammonium ion). The assembly processes proceed through
induced-fit processes that are allosterically coupled, the key step
being the shaping of both calixarene cores by their respective
guests. In other words, the success of this process is due to the
high degree of complementarity between the four partners.
∑ NMR studies of the self-assembly process between the calixarene
subunits 3, 4, 5 and 8 into [1+1+1+1] complexes
The receptor ability of the calixarene subunits 3, 4, 5 and 8 being
checked, their self-assembly in tail-to-tail bis-calix[6]arenes was
investigated by 1H NMR spectroscopy in CDCl3 (Scheme 3, entries
2 to 9). Common features were observed for the self-assembly
processes:
i) when calix[6]tris-amines 1 or 3 were combined with the com-
plementary calix[6]hexa-acids 4, 5 or 8 (1 : 1 ratio), broad 1H NMR
spectra that differ from the NMR signatures of the separated
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Scheme 2 Host–guest properties of the calix[6]arene subunits 3, 4, 5 and 8. i): TFA, IMI (3 equiv.), CDCl3; ii): PrNH2 (> 6 equiv.), CDCl3; iii): R’NH2,
(> 6 equiv.), CDCl3 or 2 : 1 CD3OD : CDCl3.
All these NMR considerations are similar to what was observed
in the case of the [1+1+1+1] self-assembly of the parent receptors
(Scheme 3, entry 1) and thus show that the strategy can be
extended to more functionalized and/or flexible calix[6]arene
subunits.24 However, in comparison to the parent receptors and
as shown below, the self-assemblies made of hexa-functionalized
calix[6]arene subunits can display additional features and, notably,
lead to secondary intra-assembly interactions.
guest. For instance, in the case of the subunits 1 and 4 (entry 3),
the addition of 1 equiv. of PrNH2 to a mixture of 1, 4 and IMI
(1 : 1 : 3 ratio) led to the tetra-deprotonated species of 4 (i.e. 4-4H+
)
3H+
IMI
-4H+
PrNH3+
and to the selective formation of the assembly 1 ·4
that is
now a neutral entity (Fig. 3c).37,38 Thus, the hexa-carboxylic acid
4 plays a triple role: it behaves as a cap for 13H+, as a receptor
for the ammonium ion, but also as a proton source for the in situ
generation of its own guest.
∑ Assemblies with calix[6]hexa-acid subunits: evidence for
versatility
∑ Assemblies with subunits possessing an enlarged cavity:
encapsulation of large bio-relevant guests
Whereas with calix[6]tris-acid 2, formation of the quaternary
adduct requires the addition of its guest in the form of an
ammonium ion, with the calix[6]hexa-acids, the guest could be
introduced in the form of its free base as well (Scheme 3, entries
3–5 and 9). Indeed, upon the triple proton exchange between the
calix[6]tris-amine and the calix[6]hexa-acid, three carboxylic acid
groups remain available for the in situ generation of the ammonium
With calix[6]hexa-acids 5 and 8, it was possible to obtain
the [1+1+1+1] self-assemblies with larger ammonium guests
(Scheme 3, entries 4 and 5).39 For instance, 5 could be self-
assembled with 1 in the presence of IMI and ammonium ions de-
rived either from propylamine, phenylethylamine or O-methylated
dopamine.30 The assembly of 8 with 3 in the presence of IMI and
the O-methylated dopamine was also successful (Fig. 3d). In all
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Scheme 3 Formation of tail-to-tail self-assemblies triggered by guest inclusion.
cases, the CISs values attest to the deep inclusion of the aromatic
ring of the guests into the cavities, with a slow in and out guest
exchange process on the NMR time scale, even at high temperature
(330 K).30
to the presence of the three anion binding ureido groups in
alternate positions at the narrow rim. Hence, the NMR spectra
of the quaternary assemblies obtained by mixing calix[6]tris-
amine 3, calix[6]hexa-acid 4 and IMI (1 : 1 : 3 ratio) with 1 equiv.
of PrNH3 Pic- or 1 equiv. of PrNH2 (Scheme 3, entries 8 and
+
9) differ by the chemical shift of the PhNHCO protons. Indeed,
∑ Assemblies with the calix[6]trisamine-trisurea 3: evidence for
secondary interactions
3H+
the PhNHCO protons of 3 experienced a significant downfield
IMI
shift (DdPhNHCO = 0.37 ppm) when assembled with the tetra-
-4H+
-3H+
The calix[6]tris-amine-trisurea 3 was well adapted for the estab-
lishment of secondary interactions within the assemblies thanks
deprotonated subunit 4
vs. the tris-deprotonated one 4
PrNH3+
PrNH3+
(Scheme 4, left).30 This downfield shift is in agreement with the
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Fig. 3 1H NMR spectra (CDCl3, 298 K) of a 1 : 1 mixture of 1 and 4 before (a) and after (b) the addition of IMI and PrNH3+Pic- (1 equiv.), leading to
the discrete assembly of Pic-; (c) related assembly obtained upon addition of IMI and PrNH2 (1 equiv.) to a 1 : 1 mixture of 1 and 4; (d) assembly. S =
solvent, w = water.
3H+
IMI
implication of the ureido groups in H-bonding interactions and
ureido groups of 3 . In this case, the binding of the ammo-
nium salt PrNH3 Cl- corresponds to an ion-pair recognition
+
thus indicates the presence of intra-assembly interactions between
3H+
IMI
process,40 where the ammonium ion and the chloride anion are
simultaneously recognized by separated binding sites. In other
words, the resulting supramolecular structure corresponds to a
the ureido groups of 3
and the fourth carboxylate group of
4-4H+ (see the structure displayed in Scheme 4). The compari-
son of the NMR spectra corresponding to the self-assemblies
3H+
IMI
-3H+
3
·2
,X- (with X- = Pic- or Cl-) was also instructive
quinternary [1+1+1+1+1] self-assembly, namely 3 ·Cl-·2
3H+
-3H+
PrNH3+
PrNH3+
IMI
(Scheme 3, entries 6 and 7) (Scheme 4, right). Again, a sig-
nificant downfield shift of the signal of the PhNHCO protons
was observed when a chloride counter ion was used instead
of a picrate one (DdPhNHCO = 0.30 ppm, Scheme 4 inset). The
chemical shift of the CH2 protons of the included IMI was also
influenced by the nature of the counter anion (0.34 ppm in the
case of the chloride vs. 0.44 ppm in the case of the picrate).
These data indicate the binding of the chloride anion by the
(see the structure depicted in Scheme 4). This corresponds to
a very rare case of a discrete assembly involving five different
partners, where a neutral molecule, an ammonium ion and an
anion are simultaneously bound to a receptor. All in all, the
alternate trisamino-trisureido functionalization at the narrow rim
of 3 can be viewed as a dual recognition site since both ammonium
and ureido arms are involved in the recognition process with the
second calixarene partner.
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1
Scheme 4 Self assembled complexes obtained with calix[6]trisamine-trisurea 3 and calix[6]hexa-acid 4 or calix[6]tris-acid 2. Inset: H NMR spectra
(CDCl3, 298 K), selected areas; O: CONHPh protons.
∑ Replacement of the bulkytBu groups at the wide rim by smaller
substituents (a hydrogen atom or an allyl group) does not alter the
formation of the self-assemblies in spite of the increased flexibility
of the macrocycles. On the contrary, this allowed the inclusion of
larger guests such as the bio-relevant tryptamine and dopamine
derivatives. Indeed, these calix-cavities can largely open to include
the aromatic moieties of these guests.
∑ Introduction of extra functionalities at the narrow rim does
not disrupt the self-assembly processes. Indeed, it is shown that
extra acid functions can participate in the host–guest process
by providing the necessary equivalent of acid to protonate the
amine into the guest ammonium, thus expanding the versatility of
the system. With ureido groups, secondary interactions between
both calixarene units have been demonstrated in the quaternary
[1+1+1+1] self-assemblies. This shows a possible strategy to
reinforce the stability of such adducts.
Conclusion
The introduction of three or more acid–base functionalities at
the narrow rim of calix[6]arenes was revealed to be a successful
strategy for obtaining a supramolecular system that responds to a
variety of stimuli in a very specific way. Upon ionization of three
acidic functions or three amino-functions, the calix[6]arene core
becomes self-assembled into a cone, provided a guest molecule
shapes its cavity. The efficiency of the induced-fit process relies
on the polarization of the hydrophobic cavity that becomes a
good host, providing there is at one extremity, a charged site
with hydrogen-bond acceptors and/or donors, and at the other
extremity, aromatic walls that can widely open to allow guest
inclusion. Combining two complementary calixarenes, one acidic,
the other basic, led to a remarkable self-assembled heteroditopic
receptor that responds specifically to two different guests. In that
case, formation of the quaternary [1+1+1+1] adducts is under
double allosteric control.
The goal of this study was to evaluate the scope of these
remarkable spontaneous recognition processes, and see whether
changes or introduction of additional functions at the calixarene
core can lead to new features, thus opening the route to more
sophisticated but also more versatile systems. Therefore, the study
of the self-assembly process via triple ion pairing of calix[6]arenes
bearing acid–base functionalities at the narrow rim has been
extended to subunits displaying various substitution patterns at
the narrow rim and at the wide rim. The formation of host–guest
adducts through ionization and capping with counter anions, as
well as of the bis-calixarene self-assemblies, has been explored and
has shown interesting new features.
∑ Finally, the same ureido groups have been shown to be
capable of interacting with an anion such as a chloride, within
the self-assembly, thus leading to a formally neutral [1+1+1+1+1]
complex.
In conclusion, this work shows that a sophisticated molec-
ular recognition pattern can be constructed to create ad-
ditional host–host (urea–carboxylate) and host–guest (urea–
counteranion) interactions. These intra-receptor interactions may
be viewed as reminiscent of protein–protein recognition and
enzyme–substrate interaction, both being interlocked, and under
allosteric control. Their achievement is possible because of the
versatility of the calix[6]arene functionalization together with
the flexibility of its skeleton. Further research in our labo-
ratory will be directed toward the study of the self-assembly
2394 | Org. Biomol. Chem., 2011, 9, 2387–2396
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3H+
IMI
-3H+
,Pic-
processes in water with calixarene subunits bearing hydrophilic
groups.
Representative procedure of a self-assembly: 1 ·4
PrNH3
The spectrum displayed in Fig. 3a was recorded at 298 K after
dissolving 1 (3.0 mg, 2.6 mmol) and 4 (3.5 mg, 2.6 mmol) in
CDCl3 (0.6 mL, neutralized with basic alumina). The subsequent
addition of IMI (4 equiv.) and PrNH3 Pic- (1 equiv.) led to the
Experimental
+
General procedures
spectrum displayed in Fig. 3b, which corresponds to the formation
, Pic- as a unique species. H NMR (CDCl3, 300
3H+
of 1 ·4
IMI
-3H+
1
All reactions were performed under an inert atmosphere. Silica gel
(230–400 mesh) was used for flash chromatography purifications.
1H NMR spectra were recorded at 300 MHz or 400 MHz and
13C NMR spectra were recorded at 100 MHz. Chemical shifts are
expressed in ppm. Traces of residual solvent were used as internal
PrNH3+
MHz) d -1.66 (t, 3H, J = 7.5 Hz, H3N+CH2CH2CH3in), -0.79 (m,
2H, J = 7.8 Hz, H3N+CH2CH2CH3in), 0.34 (s, 4H, CH2 IMIin),
0.58 (m, 2H, J = 7.8 Hz, H3N+CH2CH2CH3in), 0.77 (s, 27 H,
tBu), 1.21 (s, 54 H, tBu), 1.41 (s, 27H, tBu), 3.40 (d, 6H, J =
15 Hz, ArCH2), 3.50 (d, 6H, J = 15 Hz, ArCH2), 3.62 (sb, 6H,
NCH2CH2O), 3.89 (s, 9H, OMe), 4.25 (s, 2H, NH IMIin) 4.31(sb,
6H, NCH2CH2O), 4.45 (d, 6H, J = 15 Hz, ArCH2), 4.52 (s, 12H,
OCH2COO), 4.56 (d, 6H, J = 15 Hz, ArCH2), 6.64 (s, 6H, ArH),
7.03 (s, 12H, ArH), 7.33 (s, 6H, ArH), 8.77 (s, 2H, ArH Pic-).
1
standard in the case of H and 13C NMR spectra. In all cases,
CDCl3 was filtered over a short column of basic alumina in order
to remove traces of HCl. Most of the 1H NMR spectra signals were
attributed through 2D NMR analyses (COSY, HSQC, HMQC,
HMBC).
Estimation of the overall association constants for the whole
assembly process in CDCl3
Calix[6]hexaallyl-hexaester 7
In a sealed reactor, calix[6]arene 6 (500 mg, 0.57 mmol) was
dissolved in acetone (8 mL) and K2CO3 (1.42 g, 10.3 mmol) and a
solution of ethyl bromoacetate (1.9 mL, 17.0 mmol) in acetone (7
mL) were successively added. The mixture was refluxed for 5 days
and the solvent was removed under reduced pressure. The residue
was dissolved in dichloromethane (50 mL) and washed with water
(25 mL). The aqueous layer was extracted with dichloromethane
(2 ¥ 15 mL). The combined organic layers were concentrated
under reduced pressure and the residue was subjected to flash
chromatography (CH2Cl2–AcOEt; 98 : 2), yiel◦ding compound 7 as
a white solid (490 mg, 62%). m.p.: 138–141 C (dec); IR (KBr):
n = 2979, 1756, 1637, 1559, 1472 cm-1; 1H NMR (CDCl3, 328 K,
400 MHz) d 1.28 (t, 18H, J = 7.0 Hz, COOCH2CH3), 2.68 (s,
12H, ArCH2CHCH2), 4.07 (s, 12H, ArCH2), 4.23 (q, 12H, J =
7.0 Hz, COOCH2CH3), 4.55 (s, 12H, OCH2COO), 4.83 (m, 12H,
ArCH2CHCH2), 5.66 (d, 6H, J = 6.1 Hz, ArCH2CHCH2), 6.55
(s, 12H, ArH); 13C NMR (CDCl3, 328 K, 100 MHz) d 14.4, 31.1,
39.1, 61.0, 71.1, 114.9, 129.5, 133.5, 136.5, 138.3, 153.4, 169.5;
HRMS (ESI-TOF) calcd for C84H97O18 (M+H+) 1393.6675, found
1393.6650.
Accurate determination of the overall association constants for the
formation of the quaternary complexes is not possible as “free”
calixarenes are aggregated. However, the values were estimated
based on the NMR spectra (CDCl3) obtained with PrNH3 Pic-
+
and IMI according to the following procedure: suitable aliquots
of a solution of IMI were added to a 1 : 1 : 1 solution of both
calix subunits and PrNH3 Pic- (2.5 10-3 M) in such a way that the
+
1
corresponding H NMR spectra recorded at 298 K revealed the
quantitative formation of the [1+1+1+1] self-assembly. The con-
centration of the undetectable species (i.e. both free calix subunits
+
and free PrNH3 ) and the concentration of the [1+1+1+1] complex
were estimated to be 5% and 95%, respectively, of the starting host
concentration. The overall association constant was estimated
according to the following equation: K > [complex]/{[first calix
subunit]x[second calix subunit]x[PrNH3 Pic-]x[IMI]}.
+
Acknowledgements
This research was supported by the Fonds pour la formation a` la
Recherche dans l’Industrie et dans l’Agriculture (F.R.I.A.) and by
the Universite´ Libre de Bruxelles (U.L.B.).
Calix[6]hexaallyl-hexaacid 8
In a sealed reactor, calix[6]arene 7 (120 mg, 0.086 mmol) was
dissolved in THF (4 mL) and a 10% (v/v) aqueous solution of
NMe4OH (6 mL, 6.25 mmol) was added. The mixture was refluxed
for 22 h and, upon cooling to 0 ◦C, a concentrated aqueous
solution of HCl was added dropwise under stirring until acidic pH
(~1). The THF was then removed under reduced pressure, leading
to the apparition of a white precipitate in the aqueous phase. The
solid was isolated by suction filtration on a glass filter and extensive
washing with water (pH ~ 5). Compound 8 was obtained as a
white solid without further purification (102 mg, 97%). m.p.: 160–
165 ◦C (dec); IR (KBr): n 3550 to 2700, 1745, 1639 cm-1; 1H NMR
(DMSO-d6, 373 K, 400 MHz) d 2.66 (s, 12H, ArCH2CHCH2),
4.02 (sb, 12H, ArCH2), 4.44 (s, 12H, OCH2COOH), 4.82 (m,
12H, ArCH2CHCH2), 5.65 (m, 6H, ArCH2CHCH2), 6.54 (s, 12H,
ArH); 13C NMR (DMSO-d6, 373 K, 100 MHz) d 30.1, 37.8, 69.9,
114.0, 128.3, 132.6, 134.8, 137.5, 152.5, 169.6; HRMS (ESI-TOF)
calcd for C72H72NaO18 (M+Na+) 1247.4616, found 1247.4589.
Notes and References
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©

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23 For rare examples of tubular tail-to-tail bis-calix[6]arenes featuring a
triple covalent linkage, see: (a) S. Le Gac, X. Zeng, O. Reinaud and
I. Jabin, J. Org. Chem., 2005, 70, 1204–1210; (b) S. Moerkerke, M.
Me´nand and I. Jabin, Chem.–Eur. J., 2010, 16, 11712–11719.
24 S. Le Gac, J. Marrot, O. Reinaud and I. Jabin, Angew. Chem., Int. Ed.,
2006, 45, 3123–3126.
25 S. Le Gac, M. Me´nand and I. Jabin, Org. Lett., 2008, 10, 5195–5198.
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27 S.-K. Chang and I. Cho, J. Chem. Soc., Perkin Trans. 1, 1986, 211–214.
28 I. Alam and C. D. Gutsche, J. Org. Chem., 1990, 55, 4487–4489.
29 J. Wang and C. D. Gutsche, J. Am. Chem. Soc., 1998, 120, 12226–12231.
30 See the Supporting Information†.
31 The signal of the OCH2 protons was highfield shifted as compared to
4, attesting to the deprotonation of the COOH groups. The addition
+
of an excess of PrNH3 picrate salt to a CDCl3 solution of 4 led, after
sonication, to the extraction of 3 equiv. of the ammonium ion and to
the quantitative formation of the endo-complex 4PrNH3+
2PrNH3+. In that case,
the chemical shift of the CH2O protons was not affected by the addition
of the ammonium ion.
32 A C3v symmetrical pattern is observed below 243 K.
33 It is noteworthy that such a supramolecular control of the conformation
of calix[6]arenes that lack the p-tBu groups is extremely rare. See: J. C.
Iglesias-Sanchez, B. Souto, C. J. Pastor, J. de Mendoza and P. Prados,
J. Org. Chem., 2005, 70, 10400–10407.
34 The addition of more than one equiv. of the ammonium guest disrupted
the quaternary assemblies while a large excess of IMI (> 20 equiv.) was
tolerated.
35 In all cases, all the signals of these NMR spectra were assigned thanks
to 2D NMR spectra (see the Supporting Information†).
36 This ratio is deduced from the integration of the high-field signals of
the guests.
14 (a) S. Blanchard, L. Le Clainche, M.-N. Rager, B. Chansou, J.-P.
Tuchagues, A. F. Duprat, Y. Le Mest and O. Reinaud, Angew. Chem.,
Int. Ed., 1998, 37, 2732–2735; (b) O. Se´ne`que, M.-N. Rager, M. Giorgi
and O. Reinaud, J. Am. Chem. Soc., 2000, 122, 6183–6189; (c) O.
Reinaud, Y. Le Mest, I. Jabin inCalixarenes in the Nanoworld, ed.
J. Vicens and J. Harrowfield, Springer-Verlag, The Netherlands, 2006,
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Jabin and O. Reinaud, Org. Biomol. Chem., 2009, 7, 2485–2500 and
references therein.
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Chem. Int. Ed., 2000, 39, 3453–3456; (b) A. Arduini, F. Calzavacca, A.
Pochini and A. Secchi, Chem.–Eur. J., 2003, 9, 793–799; (c) M. Hamon,
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2008, 73, 7067–7071.
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Reinaud, Org. Biomol. Chem., 2008, 6, 3930–3934. See also ref. 13f.
17 (a) A. Arduini, L. Domiano, L. Ogliosi, A. Pochini, A. Secchi and
R. Ungaro, J. Org. Chem., 1997, 62, 7866–7868; (b) J. J. Gonzalez, R.
Ferdani, E. Albertini, J. M. Blasco, A. Arduini, A. Pochini, P. Prados
and J. de Mendoza, Chem.–Eur. J., 2000, 6, 73–80; (c) A. M. Rincon,
P. Prados and J. de Mendoza, Eur. J. Org. Chem., 2002, 640–644; (d) R.
37 The average chemical shift of the OCH2 protons of 4 was high-
3H+
field shifted in the case of 1 ·4
IMI
-4H+
compared to the assembly
PrNH3+
3H+
IMI
-3H+
PrNH3+
1
·4
,Pic- (dOCH2 = 4.49 vs. 4.52 ppm, respectively). This is in
agreement with the deprotonation of an additional carboxylic acid
group.
38 The addition of an excess of PrNH2 (3 equiv.) disrupted the quaternary
-nH+
assembly and led to the complex 4
as the major species. Also, the
PrNH3+
use of a calix[6]hexa-amine as the partner for the calix[6]hexa-acid 4
did not lead to a discrete assembly.
39 Although not soluble in chloroform, calix[6]hexa-acid 5 was fully
extracted in the presence of calix[6]tris-amine 1.
40 For a recent review on ion-pair receptors, see: S. K. Kim and J. L.
Sessler, Chem. Soc. Rev., 2010, 39, 3784–3809.
2396 | Org. Biomol. Chem., 2011, 9, 2387–2396
This journal is
The Royal Society of Chemistry 2011
©