Acid-base modulation of a versatile heteroditopic calix[6]arene based receptor

Article abstract of DOI:10.1039/c1ob05759f

A new calix[6]crypturea (3) has been efficiently synthesized through a domino Staudinger/aza-Wittig reaction followed by a [1 + 1] macrocyclization step. In comparison to the previously reported tren-based calix[6]crypturea, this heteroditopic receptor 3

Full text of DOI:10.1039/c1ob05759f

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 6373
www.rsc.org/obc
PAPER
Acid–base modulation of a versatile heteroditopic calix[6]arene based
receptor†
Damien Cornut,a Je´roˆme Marrot,b Johan Woutersc and Ivan Jabin*a
Received 13th May 2011, Accepted 16th June 2011
DOI: 10.1039/c1ob05759f
A new calix[6]crypturea (3) has been efficiently synthesized through a domino Staudinger/aza-Wittig
reaction followed by a [1 + 1] macrocyclization step. In comparison to the previously reported
tren-based calix[6]crypturea, this heteroditopic receptor 3 displays a more flexible and larger tris-ureido
cap. Due to this structural alteration, 3 exhibits unique host–guest properties: (i) the protonation of its
basic cap leads to a rigidification of the whole structure and, thus, allosteric control of the binding
properties and selective guest switching processes are possible, (ii) its versatility is unprecedented in the
literature since it can bind either neutral molecules, anions, primary/secondary ammonium ions,
quaternary ammonium ions or contact ion pairs according to different modes of recognition and with a
remarkable selectivity within each family of guest, (iii) cascade complexes even stable in a protic
environment can be obtained. These remarkable features are nicely illustrated by the fact that,
according to the nature of its counterion, an ammonium ion R1R2NH2 can be accommodated into the
+
cavity either as an independent guest, as a contact ion-pair or as a cascade complex. All these results
are reminiscent of biological receptors and validate the strategy that consists of designing receptors
presenting a high flexibility that can be controlled by an external stimulus.
have been reported.7,10 A possible explanation lies in their high
1
Introduction
conformational rigidity, indeed rigid receptors are usually more
selective but less versatile. As a consequence, using rather flexible
macrocyclic structures for the building of versatile receptors
appears as an appealing strategy, the challenge being, however,
to control their flexibility in order to reach high selectivity. In this
regard, different families of bio-inspired receptors that combine
a donor or acceptor polyaza-binding site in close proximity to
a hydrophobic cavity have been built from the highly flexible
calix[6]arene skeleton.11 It was shown that the flexibility of their
calix[6]arene subunit can be restricted either through coordination
to a metal ion,12 an anion13 or even through ion-pairing14 and
covalent capping.15 All these calix[6]arenes based-systems are
constrained in the cone conformation and thus present a concave
cavity suitable to include an organic guest. Moreover, flexibility
of the calix[6]arene core turned out to be an advantage as the
cavity size can adapt to the guest.16 Such induced-fit phenomena
(i.e. shaping the cone through guest binding) have been notably
exploited for the elaboration of allosterically coupled multi-
receptors.14b,e One of these families of receptors, i.e. the calix[6]tris-
ureas (Fig. 1),13,17 has been found to strongly bind either anions
or organic contact-ion pairs in a cooperative way.18,19 Indeed,
the converging three ureido groups allow strong binding to
anions, which, in turn, allows strong binding of an ion-paired
ammonium accommodated into the calixarene cavity. Recently, an
even more versatile and sophisticated heteroditopic receptor has
been obtained through the grafting of a covalent tren-based tris-
ureido cap on the narrow rim of the calix[6]arene cavity (Fig. 1).20
The design of efficient molecular receptors for charged or neutral
species is a major objective in supramolecular chemistry.1 Indeed,
such receptors can find many applications in various areas, such
as sensing, catalysis, nanoscience, biomimicry, drug delivery and
separation science. A classical strategy for the elaboration of
artificial hosts consists of using concave macrocyclic structures dis-
playing a hydrophobic cavity such as cyclodextrins2 or cavitands3
(e.g. resorcinarenes,4 cyclotriveratrylenes,5 or calixarenes6). In this
context, versatile receptors, i.e. receptors capable of recognizing
different families of guests, are particularly attractive since the
control of their binding properties by an external stimulus can
be notably exploited for the construction of unique switchable
systems.7 However, most receptors described so far are highly
specific for a particular guest or family of guests (i.e. metal or
ammonium ions,1c anions,8 ion pairs9 or neutral molecules4a).
Thus, only few examples of versatile cavity-based receptors
aLaboratoire de Chimie Organique, Universite´ Libre de Bruxelles
(U.L.B.), Av. F. D. Roosevelt 50, CP160/06, B-1050 Brussels, Belgium.
E-mail: ijabin@ulb.ac.be; Fax: (+) 32-2-650-27-98; Tel: (+) 32-2-650-35-
37
bInstitut Lavoisier, UMR CNRS 8180, Universite´ de Versailles St-Quentin
en Yvelines, 45 av. des Etats-Unis, 78035 Versailles cedex, France
cDe´partement de Chimie, Universite´ de Namur (FUNDP), Rue de Bruxelles
61, B5-5000 Namur, Belgium
† Electronic supplementary information (ESI) available. CCDC reference
number 820544. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1ob05759f
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6373–6384 | 6373
©

View Article Online
2
Results and discussion
2.1 Synthesis and characterization by NMR spectroscopy and
XRD analysis of calix[6]crypturea 3
Calix[6]crypturea 3 was obtained from the known20 calix[6]tris-
azide 2 and the commercially available tris(3-aminopropyl)amine
through a domino Staudinger/aza-Wittig reaction followed by
a [1 + 1] macrocyclization step. More precisely, the reaction
of calix[6]tris-azide 2 with PPh3/CO2 led in situ to the reac-
tive intermediate calix[6]tris-isocyanate which was immediately
reacted with the tris-amine under high dilution conditions. Flash
chromatography purification of the crude mixture led to the
desired calix[6]crypturea 3 in an overall 50% yield from 2
(Scheme 1).
Fig. 1 Structures of the calix[6]tris-ureas, calix[6]crypturea 1.
Calix[6]crypturea 3 was characterized by 1H NMR spectroscopy
at 298 K and all the signals were assigned through 2D NMR
analyses.25 Thus, the 1H NMR spectra recorded in either CDCl3,
CD3CN/CDCl3 (7 : 3) or CD3OD/CDCl3 (7 : 3) show very similar
C3v symmetrical patterns characteristic of averaged cone confor-
mations (see Fig. 2a for the spectrum in CDCl3).25 In contrast
to the parent receptor 1, the NMR spectrum of 3 in an apolar
solvent such as CDCl3 was weakly sensitive to the addition of
water or to the temperature (from 258 K to 328 K).25 In all
solvents, the downfield chemical shift of the three methoxy groups
may result from a fast self-inclusion of one of these groups that
averages three dissymmetrical but equivalent conformations (2.88
ppm < dOMe < 3.24 ppm).26 Such an hypothesis was confirmed
by an X-ray structure† obtained by slow diffusion of Et2O into
a cold (4 ◦C) CHCl3/CH3CN solution of calix[6]crypturea 3
(Fig. 3, left). Indeed, the calixarene core stands in a pinched cone
conformation with one methoxy group deeply included into the
cavity. In addition, the flexible tris-ureido cap displays a distorted
conformation with one introverted ureido arm that establishes
strong hydrogen bonding interactions with the two NH of a
This calix[6]crypturea (1) exhibits unique host–guest properties
toward polar neutral molecules, anions, or contact organic ion
pairs and it has been shown that these versatile host properties can
be controlled by protonation of the apical nitrogen of the capping
tren moiety. Indeed, due to a steric repulsion with the introverted
NH+ proton, anion release was observed upon protonation of the
basic cap of 1.21,22 Thus, sophisticated three-way supramolecular
switches based on the interconversion of host–guest systems
have been reported with this receptor.23 Moreover, thanks to the
flexibility of the calixarene framework, the intra-cavity binding of
large biologically relevant ammonium salts was evidenced through
induced fit processes that involve the spreading of the anisole
units.
In the course of designing readily available calixarene based
receptors whose host properties can be controlled by external stim-
uli, a related calix[6]crypturea bearing an additional methylene
group that moves the proton sensitive site away from the tris-
ureido binding site has been envisaged. Indeed, with this receptor,
the complexation of an anion sandwiched between the positively
charged NH+ of the cap and a co-bound ammonium ion into the
cavity was expected. Examples of such cascade complexes made
of organic cations are extremely rare in the literature.24 Besides, we
wanted to see if the higher flexibility of this new receptor could be
controlled through protonation and, thus, if allosteric regulation
and molecular switches could be achieved.
˚
second ureido group [d(N ◊ ◊ ◊ O) = 2.748 and 2.843 A]. Additional
intermolecular hydrogen bonding interactions that involve these
two ureido groups are also observable in the lattice, leading to a
linear H-bonding network (Fig. 3, right).
The protonated derivative 3·H+ was obtained quantitatively
after the addition of 1 equiv. of picric acid (PicH) to a solution of 3
in either CDCl3, CD3CN/CDCl3 (7 : 3) or CD3OD/CDCl3 (7 : 3).25
In all cases, a notable downfield shift of the NCH2CH2 protons
clearly indicated the protonation of the bridging tertiary amine
(DdNCH2 >0.74 ppm and DdNCH2CH2 >0.29 ppm).27 It is noteworthy
Here, we report the synthesis of this new calix[6]crypturea
(3) and its remarkably versatile binding properties toward either
neutral or charged species, with major differences being observed
in comparison with what was reported for the parent receptor 1.
Scheme 1 Synthesis of calix[6]crypturea 3.
This journal is
6374 | Org. Biomol. Chem., 2011, 9, 6373–6384
The Royal Society of Chemistry 2011
©

View Article Online
Fig. 2 1H NMR spectra (300 MHz, 298 K) of a) 3 in CDCl3; b) 3·H+…Imi in CDCl3; —: free Imi; W: water; S: residual solvent; *: residual grease.
2.2 Neutral molecule recognition
The host properties of calix[6]crypturea 3 toward polar neutral
guests (G) were first investigated at 298 K by NMR spectroscopy
in CDCl3. Thus, the addition of an excess of imidazolidin-2-
one (Imi), tetrahydropyrimidin-2(1H)-one (Thp), pyrrolidin-2-
one (Pyro) or DMSO did not affect the NMR spectrum of 3.
The reluctance of 3 for such neutral guests differs from what
was observed with the parent receptor 1 and can be rationalized
by the higher flexibility and thus the weaker preorganization of
the tris-ureido binding site of 3. However, while the binding of
small alcohols, DMF or propionamide could not be evidenced
with the protonated derivative 3·H+, the selective inclusion of Imi,
Thp and Pyro was detected (Scheme 2). The resulting complexes
Fig. 3 Left: X-ray structure of calix[6]crypturea 3. Selected distances:
d(N ◊ ◊ ◊ O) = 2.748 and 2.843 A. Right: X-ray structures of 3 displaying the
inter- and intramolecular H-bond interactions within the unit cell.
˚
that, in CDCl3 and CD3CN/CDCl3 (7 : 3), the NH+ proton is
clearly apparent at 10.73 and 10.07 ppm respectively.
Scheme 2 Host–guest properties of calix[6]crypturea 3·H+ toward neutral guests and reversible base-triggered release of these guests. Left inset: CISs of
the neutral guests. Right inset: high-field region of the 1H NMR spectra (CDCl3, 300 MHz, 298 K) of a) 3·H+; b) +IMI (8 equiv.); c) +DBU (2 equiv.); d)
+PicH (7 equiv.). nd: not determined because of signal overlapping.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6373–6384 | 6375
©

View Article Online
Table 1 Relative affinities (KG/Pyro) and association constant (Ka) of the neutral guests (G) in the case of 3·H+…G
a
Entry
Guest
KG/Pyro in CDCl3
Ka (M-1)b in CD3OD/CDCl3 (1 : 2)
1
2
3
Imi
Thp
Pyro
17
2
1
18
—
—
a Relative affinity determined at 298 K and defined as ([Gin]¥[Pyrofree])/([Gfree]¥[Pyroin]) where the subscript “in” stands for “included”. Errors estimated
10%; b Ka was determined at 298 K by integration of the different species in equilibrium. Ka is defined as: Ka = [3·H+…G]/([3·H+]¥[G]). Error estimated
10%.
3·H+…G display well defined NMR spectra characteristic of C3v
symmetrical flattened cone conformation with the OMe groups
expelled from the cavity (dOMe >3.78 ppm) (Fig. 2b). In all cases,
the host–guest exchanges between 3·H+ and 3·H+…G were found
to be slow on the NMR time scale and integration of the high-field
signals belonging to the included guest indicate a 1 : 1 host–guest
stoichiometry. The complexation induced shifts (CISs) clearly
indicate a positioning of the guests in the heart of the cavity (left
inset, Scheme 2). These CISs are similar to those reported for the
protonated 1·H+, suggesting a comparable mode of recognition,
i.e. hydrogen bonding interactions between the NH ureido groups
of the cap and the carbonyl oxygen atom of the guests as well as
between the NH(s) group(s) of the guests and the phenoxy oxygen
atom(s) of the calixarene core. In addition, a 1H NMR competitive
+
Fig. 4 Energy minimized structures of 3·H+…Imi (left) and 3·H+…PrNH3
(right). With the exception of the NH, all the hydrogen atoms
are omitted for clarity. Selected distances (A) for 3·H+…Imi:
˚
binding experiment showed that the relative affinity of Imi toward
host 3·H+ is one order of magnitude higher than that of Thp and
Pyro (Table 1, entry 1 vs. entries 2 and 3).28 Such a selectivity
for ureido guests has been already described with closely related
calix[6]arene based systems and has been rationalized thanks to
an X-ray structure which revealed a four H bonding recognition
process.14b Compared with 3, the better recognition ability of
3·H+ could be due to an additional charge–dipole interaction
between the protonated cap and the polar guests. In addition,
a rigidification of the protonated cap could arise from a strong
hydrogen bonding interaction between the NH+ and an introverted
ureido group (dNH+ = ca. 10.55 ppm in all cases) (see structure of
3·H+…G displayed in Scheme 2).29 In such a case, the proton acts
as an effector that favours the binding of neutral guests through
a deep conformational reorganization of the tris-ureido binding
site. All these considerations were corroborated with an optimized
structure of 3·H+…Imi obtained through computer modelling
(Fig. 4, left).30 Indeed, the position of the guest, the mode of
recognition and the conformation of receptor 3·H+ obtained after
energy minimization are highly compatible with what was deduced
from the NMR data. Notably, a complementary DAAD-ADDA31
quadruple H-bonding array between the ureido guest and 3·H+
as well as the presence of an introverted ureido arm can be
observed. All in all, the optimized host–guest edifice is stabilized
through seven H-bonding interactions. In a protic environment,
i.e. CD3OD/CDCl3 (1 : 2), it was still possible to observe the com-
plexation of Imi but with a weak association constant (Table 1).25,32
Finally, taking advantage of the reluctance of 3 for neutral guests,
a highly selective switching process between 3 and 3·H+…Imi was
achieved (right inset, Scheme 2). Indeed, the progressive addition
of a base, i.e. diaza(1,3)bicyclo[5.4.0]undecene (DBU) to the host–
guest complex 3·H+…Imi led solely to the formation of 3, while the
further addition of PicH restored cleanly the complex 3·H+…Imi.
This switching process clearly illustrates that the complexation of
N(host)–O(Imi): 2.77 and 3.04; N(Imi)–O(host): 2.68 and 2.79;
N+–O(ureido): 2.44; N(ureido)–O(ureido): 2.82; N(ureido)–O(methoxy):
3.15. For 3·H+…PrNH3+: N+(guest)–O(host): 2.76; N+(host)–O(ureido):
2.84; N(ureido)–O(ureido): 2.91; N(ureido)–O(methoxy): 3.07 and 3.13.
neutral guests by host 3 can be controlled by an external stimulus,
i.e. the addition of acids or bases to the medium.
2.3 Anion recognition
The binding of various anions (Xn-, with n = 1 or 2) by
calix[6]crypturea 3 was investigated by NMR spectroscopy in
CD3CN/CDCl3 (7 : 3) through the progressive addition of the
corresponding tetra-n-butylammonium salts (nTBA+Xn-). In all
cases, only one set of signals was apparent over the course of
the titration, showing fast host–guest exchanges on the NMR
-
-
time scale. The complexation of Cl-, Br-, AcO-, NO3 , H2PO4
2-
and SO4 through hydrogen bonding interactions was clearly
evidenced by the significant downfield shift of the ureido protons.33
A concomitant downfield shift of the CH2O protons as well as an
upfield shift of the OMe signal were observed. Moreover, the whole
calixarene framework experiences a dramatic conformational
change upon complexation of the anion since the tBuin and tBuout
as well as the ArHin and ArHout interchange their positions (Fig. 5
for 3…SO42-). Thus, similarly to 1, receptor 3 recognizes the anions
at the level of the crypturea cap through an induced fit process that
involves the highly favourable filling of the cavity by the methoxy
groups and the spreading of the ureido arms (Scheme 3).
The association constants Ka were estimated by monitoring
the CISs of appropriate signals of calix[6]crypturea 3, i.e. signals
displaying significant shift upon complexation and no overlapping
region (i.e. CH2O or ArH protons).25 The data obtained for
receptor 3 as well as those reported for the parent compound
2-
1 (in CD3CN) are given in Table 2. First, the affinity of SO4
toward host 3 is ca. two to three orders of magnitude higher
6376 | Org. Biomol. Chem., 2011, 9, 6373–6384
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Table 2 Comparison of the association constants Ka of calix[6]cryptureas 1 and 3 toward anions Xn- (with n = 1 or 2)
Ka (M-1)b
Entry
Anion Xn-a
Geometry of Xn-
1 (in CD3CN)
3 [in CD3CN/CDCl3 (7 : 3)]
1
2
3
4
5
6
Cl-c
Br-
spherical
spherical
V-shaped
trigonal
tetrahedral
tetrahedral
48 300d
1930d
160d
98
58
22
300
48
300
16 300
AcO-
-
NO3
H2PO4
SO4
-
—
nde
2-
a TBA+ counterion was used in all cases; b Ka determined at 298 K and defined as: Ka = [1…X-]/([1]¥[X-]). Initial host concentration [1]i = 10-3 to 4.10-3
M
and [3]i = 10-3 M. Errors estimated 10%; c hydrate salt; d determined at 243 K; e not determined because a weak complexation and an abnormal looking
titration curve were observed. This latter could result from an exo-complexation of the anion.
words, host 1 possesses a preorganized tris-ureido recognition site
of reduced size that can ensure a strong and selective binding
of small anions even in a protic solvent while 3 shows a strong
affinity for the bicharged sulfate anion but the higher flexibility
of its binding site weakens its complexation ability in protic
solvents. Finally, when the titration experiment was conducted
with (TBA+)2SO4 and 3·H+ (obtained from 3 and 1 equiv. of
2-
PicH), a deprotonation of the receptor by the sulfate anion was
observed over the course of the titration.25 Thus, similarly to what
was observed with 1·H+ which was reluctant to bind anions, this
result seems to indicate that the binding ability of 3 toward anions
is not reinforced through its protonation.
2.4 Ammonium ion recognition
Fig. 5 a–l) 1H NMR spectra (300 MHz, 298 K) in CD3CN/CDCl3
Upon the progressive addition of picrate salts of primary or
(7 : 3) obtained upon the progressive addition of (TBA+)2SO4 (from 0
2-
secondary ammonium ions R1R2NH2 Pic- (with R1 = alkyl and
+
to 9.5 equiv) to calix[6]crypturea 3. S: residual solvent.
R2 = H or alkyl, Scheme 4) to a solution of calix[6]crypturea 3
in CDCl3, increasing sharp signals corresponding to a new C3v
symmetrical calixarene species were apparent.25,34 In all cases,
the new species display a flattened cone conformation with
the OMe groups expelled from the cavity (dOMe >3.84 ppm),
down-field NH ureido signals and high-field signals (<0 ppm)
corresponding to the inclusion of 1 equiv. of the ammonium
ion into the cavity (Fig. 6a). The CISs of the alkyl chain of the
ammonium ions indicate a positioning of these guests in the heart
of the cavity (top inset, Scheme 4). Moreover, in all cases, the
presence of a down-field NH+ signal (dNH+ >at 10 ppm) as well
as a significant down-field shift of the NCH2CH2 protons attest
to the protonation of the bridging tertiary amine. Addition of
PicH to these host–guest complexes did not affect their NMR
spectrum and superimposable NMR patterns were obtained upon
the addition of the ammonium salts to 3·H+.25 All these NMR
data clearly indicate the selective formation of the dicationic host–
Scheme 3 Host–guest properties of calix[6]crypturea 3 toward anions in
CD3CN/CDCl3 (7 : 3).
than those obtained with the other anions (Table 2, entry 6 vs.
entries 1–5). This high selectivity for the sulfate anion strongly
differs from what was observed with 1. Indeed, in the case of the
more rigid receptor 1, the smallness of the pocket delimited by
the tris-ureido cap and the introverted methoxy groups led to a
binding discrimination which was mostly based on the size of the
anions and thus a high selectivity was observed for the smaller
chloride anion (Table 2, entry 1). In contrast, Cl- is only poorly
recognized by 3 as compared either to the more basic acetate or to
the tetrahedral anions (Table 2, entries 1 vs. 3, 5 and 6). Moreover,
if the binding of Cl- by 1 was evidenced in a protic solvent (i.e.
in CD3OD), the NMR spectrum of 3 remained unchanged upon
guest complexes 3·H+…R1R2NH2 (Scheme 4).35 Interestingly, no
+
endo-complex other than this dicationic complex was observable
upon the progressive addition of even an excess of the free amine
R1R2NH2 to 3·H+. Thus, while parent receptors 1 or 1·H+ were
insensitive to ammonium picrate salts, calix[6]crypturea 3 can
accommodate ammonium ions but the prior protonation of the
cap is mandatory (Scheme 4). The energy minimized structure of
3·H+…PrNH3 shows that the NH+ proton is hydrogen bonded
+
with an introverted ureido arm of the cap (Fig. 4, right), the
ammonium ion sitting in the cavity and being stabilized through
2-
the addition of (TBA+)2SO4 in CD3OD/CDCl3 (7 : 3). In other
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6373–6384 | 6377
©

View Article Online
Scheme 4 Host–guest properties of calix[6]cryptureas 3 and 3·H+ toward ammonium ions. Insets: CISs of the ammonium ions and selected regions of
the 1H NMR spectra [CD3OD/CDCl3 (7 : 3), 300 MHz, 298 K] of a) 3…TMA+; b) +PicH (1.5 equiv.); c) +DBU (1.5 equiv.); d) +PicH (3.5 equiv.). nd:
not determined because of signal overlapping. S: residual solvent; *: DBU. CH2(a) and CH2(b) stand respectively for NCH2 and NCH2CH2.
+
2-
Fig. 6 1H NMR spectra (300 MHz, 298 K) of a) 3·H+…PrNH3 in CDCl3; b) 3…PrNH3+Cl- in CDCl3; c) 3·H+…PrNH3+SO4 in CDCl3; d)
3·H+…PrNH3+SO4 in CD3OD/CDCl3 (1 : 3); —: free PrNH3+; ᭢: PrNH3 included; : TBA+; W: water; S: residual solvent.
2-
+
᭹
a H-bonding interaction with a phenoxy oxygen atom of the
calixarene framework.30 Additional intramolecular H-bonding
interactions between the tris-ureido cap and the calixarene can
be observed on the optimized structure. Since the ammonium ion
and the NH+ proton are on distinct binding sites, in this case,
the NH+ proton can be considered as an heterotropic allosteric
activator that triggers the binding of the ammonium ions through
a rigidification of the tris-ureido cap and, as a consequence, of
the whole receptor. To our knowledge, these results constitute a
rare case of endo-complexation of ammonium ions by a cationic
receptor. Besides, no inclusion of the larger ammonium salt
HexNH3 Pic- could be detected, showing that the calixarene cavity
+
6378 | Org. Biomol. Chem., 2011, 9, 6373–6384
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
controls the size of the guest. In CD3OD/CDCl3 (7 : 3), no binding
of various primary, secondary or tertiary ammonium ions was
observed even after a subsequent addition of PicH. However, to
our delight, the endo-complexation of the tetramethylammonium
ion (TMA+) was clearly apparent in this protic environment (Ka =
28 M-1) (Scheme 4). Moreover, in strong contrast with what was
observed with primary or secondary ammonium ions, addition of
PicH to the host–guest complex 3…TMA+ led to the release of
the TMA+ ion and to the formation of 3·H+.25 These observations
show that quaternary ammonium ions are bound according to
a different mode of recognition, and in this case, an inactive
form of the receptor results from the protonation of the cap.
These acid–base controllable properties of the receptor were again
exemplified by a selective host–guest switching process between
3·H+ and 3…TMA+ through the alternating addition of PicH and
DBU (right bottom inset, Scheme 4).25
strong differences between the two host–guest complexes show
the crucial role played by the anion. Indeed, in analogy with the
parent receptor 1, these observations denote that PrNH3 Cl- is
+
recognized as a contact ion pair thanks to the close proximity
between the two binding sites of 3 (i.e. the calixarene cavity and
the three facing ureido groups). Due to the strong electrostatic
interaction between the two partners of the associated ion-pair,
the complexation of each partner is greatly reinforced when
the other is simultaneously recognized and this mutual positive
cooperativity increases the stability of the ternary complex in a
protic environment. In CDCl3, the cumulative formation constant
+
b2 for the simultaneous complexation of PrNH3 and Cl- was
estimated to be >7.2 ¥ 109 M-2, while in CD3OD/CDCl3 (1 : 9),
a much lower constant was found (Table 3, entry 1). A weaker
binding of the bulkier pyrrolidinium chloride (PyrNH2 Cl-) was
+
also observed (Scheme 5, Table 3). Despite the extremely poor
solubility of TMA+Cl- in CDCl3, host 3 was able to extract a
significant amount of this salt,25 and the absence of free TMA+Cl-
suggested a strong binding of the ion-pair (Table 3, entry 3). How-
ever, when the spectrum was recorded in CD3OD/CDCl3 (7 : 3),
a NMR pattern superimposable to that obtained with TMA+Pic-
was observed, indicating the selective formation of the host–guest
complex 3…TMA+ (Scheme 4). Interestingly, drastically different
CISs were observed for the methyl groups of the TMA+Cl- salt
in CDCl3 and CD3OD/CDCl3 (7 : 3) (-2.57 ppm and -1.21 ppm
respectively), attesting to a completely different binding mode for
the cationic guest.25 Such NMR data provides additional support
for the co-binding of the chloride anion in pure CDCl3. Finally,
to our delight, the binding of the neurotransmitter acetylcholine
chloride (Ach+Cl-) was also clearly detected (Scheme 5) (Table 3,
entry 4).25
2.5 Ion-pair recognition
The simultaneous complexation of an ammonium ion into the
cavity and an anion at the level of the tris-ureido cap was
then investigated by NMR spectroscopy in CDCl3. Thus, the
progressive addition of PrNH3 Cl- to 3 led to the selective
+
formation of a new C3v symmetrical NMR pattern characteristic
of the ternary complex 3…PrNH3 Cl- (Scheme 5).36 Indeed, this
+
complex displays a flattened cone conformation with the OMe
groups ejected from the cavity (dOMe = 4.06 ppm) and high-field
signals belonging to the included propylammonium (Fig. 6b). In
comparison with 3·H+…PrNH3 , the upfield chemical shift of the
+
NCH2CH2 protons and the absence of signal above 7.5 ppm attest
that the bridging tertiary amine is not protonated (Fig. 6a vs.
6b). Interestingly, while the protonated complex 3·H+…PrNH3
+
Compared with the former receptor 1, major improvements
in the ion-pairs’ binding properties were observed with host
3. Indeed, while the protonation of the ternary complex
was the only observable species upon the addition of PrNH3 Pic-
+
even in sub-stoichiometric quantity (vide supra), the addition
1…PrNH3 Cl- led to the exclusive formation of 1·H+, the addition
+
of an excess of PrNH3 Cl- (i.e. 2 equiv.) did not lead to the
+
+
of PicH to 3…PrNH3 Cl- in CDCl3 afforded the cascade complex
protonation of 3…PrNH3 Cl- whose NMR spectrum remained
+
3·H+…PrNH3 Cl- (i.e. high-field signals below 0 ppm belonging
+
unaffected. Moreover, in contrast to 3·H+…PrNH3 , the neutral
+
to the included ammonium ion and the presence of a NH+ signal)
complex 3…PrNH3 Cl- was still visible in the presence of a small
+
with a cumulative formation constant b2 of 2.2 ¥ 105 M-2 (Table 4,
amount of a protic solvent, i.e. CD3OD/CDCl3 (1 : 9).25 These
Scheme 5 Host–guest properties of calix[6]cryptureas 3 and 3·H+ toward ion-pairs. Insets: CISs of the ammonium ions. nd: not determined because of
signal overlapping.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6373–6384 | 6379
©

View Article Online
of 3·H+…PrNH3 SO4
.
Moreover, addition of (PrNH3 )2SO4
+
2- 25
+
2-
Table 3 Cumulative formation constants b2 of the ion-pairs in the case
of 3
(2 equiv.) to 3 led to the formation of 3·H+…PrNH3 SO42- showing
that the propylammonium ion can act as the proton source
for the elaboration of the cascade complex.25 All these results
indicate a highly cooperative and selective host–guest process.
Indeed, there are two requirements that must be met for the endo-
complexation of ammonium ions in this protic environment: (i)
the receptor needs to be activated through protonation and (ii) a
sandwiched bicharged anion that can equilibrate the charges and
stabilize the cationic guest has to be present. Along these lines,
the remarkable versatility of the receptor 3 was also illustrated
+
b2 (M-2)a
Entry
Guest
in CDCl3
in CD3OD/CDCl3 (1 : 9)
1
2
3
4
PrNH3+Cl-
PyrNH2+Cl-
TMA+Cl-
Ach+Cl-
>7.2 ¥ 109
2860
1.2 ¥ 104
—
—
—
>9.2 ¥ 106
140
a
b2 determined at 298 K by integration of the different species in
equilibrium. b2 is defined as [3…R1R2NH2+Cl-]/([3] ¥ [R1R2NH2+] ¥ [Cl-]).
Initial host concentration [3]i = 0.7 10-3 to 4.7 10-3 M. Error estimated
10%.
+
2-
by the formation of the cascade complex 3·H+…PrNH3 SO4
upon the addition of (TBA+)2SO4 to a CDCl3 solution of a
2-
mixture of 3…PrNH3 Cl- and 1 equiv. of free PrNH3 Cl-. Thus,
the addition of a basic species, i.e. (TBA+)2SO42-, can induce the
protonation of the receptor, the driving force being the formation
of the favourable neutral cascade complex.25 Finally, the binding
+
+
Table 4 Cumulative formation constants b2 of the ion-pairs in the case
of 3·H+
b2 (M-2)b
+
2-
of PyrNH2 SO4 was also achieved in CD3OD/CDCl3 (1 : 3)
(Scheme 5).25 The cumulative formation constants b2 for the
simultaneous complexation of the ammonium ions and either the
chloride or the sulfate anion by 3·H+ are summarized in Table 4.
These data indicate a binding discrimination in favour of the
Entry
Guesta
in CDCl3
in CD3OD/CDCl3 (1 : 3)
1
2
3
PrNH3+Cl-
PrNH3+SO4
2.2 ¥ 105
>8.6 ¥ 108
—
—
2-
2-
1.0 ¥ 106
6.5 ¥ 105
PyrNH2+SO4
2-
smaller propylammonium ion associated to the bicharged SO4
anion (Table 4, entry 2 vs. entries 1 and 3).
a TBA+ counterion was used in the case of the sulfate anion; b b2 determined
at 298 K by integration of the different species in equilibrium. b2 is
defined as [3·H+…R1R2NH2+Xn-]/([3·H+] ¥ [R1R2NH2+] ¥ [Xn-]). Initial
host concentration [3·H+]i = 2.4 10-3 to 3 10-3 M. Error estimated 10%.
3
Conclusion
entry 1). This finding prompted us to investigate the use of the
sulfate anion, since such a bicharged anion would lead to more
favourable neutral cascade complexes. Thus, the addition of a
The synthesis of a new calix[6]crypturea (3) was efficiently achieved
through a domino Staudinger/aza-Wittig reaction followed by a
[1 + 1] macrocyclization step. As far as we know, the versatility of
this heteroditopic receptor is unique since it can either recognize
neutral molecules, anions, ammonium ions and contact ion pairs
with a remarkable selectivity within each family of guest. Similarly
to what was observed with the former calix[6]crypturea 1, the
present work also underscores the remarkable ability of 3 to
strongly bind contact organic ion-pairs, the closeness of the two
binding sites being crucial in the recognition process since it avoids
the unfavourable separation of the co-bound ions. However, in
comparison with 1, the tripodal cap of 3 includes an additional
methylene group that moves the proton sensitive site away from
the tris-ureido binding site. This small structural alteration leads
to drastic differences between the host–guest properties of these
two receptors:
∑ 3 possesses a more flexible and larger tris-ureido cap and, thus,
(i) is unable to bind neutral guests unless protonated, (ii) exhibits
weaker recognition ability toward anions, (iii) displays a selectivity
toward bigger anions such as SO42-, (iv) is more versatile than 1.
∑ the protonation of 3 leads to the rigidification of the tripodal
cap probably thanks to the establishment of H bond interactions
with an introverted ureido arm. This rigidification is transmitted to
the whole calixarene cavity and, as a result, the more preorganized
protonated form 3·H+ can now host neutral guests and, very
surprisingly, primary or secondary ammonium ions. In this latter
case, the NH+ proton can be considered as an allosteric effector
that permits the binding of ammonium ions into the cavity through
a deep conformational alteration of the tris-ureido cap. This result
constitutes a rare case of endo-complexation of ammonium ions
by a cationic receptor. It is noteworthy that 1 or 1·H+ are unable
to recognize ammonium ions.
few equivalents of PicH/PrNH3 TBA+SO4 to 3 in CDCl3 led
+
2-
selectively to the formation of the complex 3·H+…PrNH3 SO4
+
2-
(Scheme 5) with a remarkably high b2 (Table 4, entry 2). In
strong contrast, it was not possible to obtain the cascade complex
1·H+…PrNH3 SO42- under similar conditions, the only observable
+
species being 1·H+ with this receptor. As shown in Fig. 6c,
the NMR pattern of the cascade complex 3·H+…PrNH3 SO4
+
2-
differs from those of the host–guest complexes 3·H+…PrNH3 ,
+
3…PrNH3 Cl-, and 3·H+…PrNH3 Cl-.37 In particular, larger
+
+
down-field shifts are observed for the NH+ proton of the cap
+
+
(if compared with 3·H+…PrNH3 and 3·H+…PrNH3 Cl-) and for
the ureido protons (if compared with 3·H+…PrNH3 Cl-), in good
+
agreement with stronger H-bonding interactions with the co-
bound bicharged sulfate anion. Moreover, the chemical shifts of
the included ammonium ion of 3·H+…PrNH3 SO4 are slightly
+
2-
different from those of 3·H+…PrNH3 Cl- and 3…PrNH3 Cl-,
indicating a close proximity between the cationic guest and
its counterion (Fig. 6b vs. 6c). Very interestingly, the cascade
+
+
+
2-
complex 3·H+…PrNH3 SO4 proved to be remarkably resistant
in a markedly protic solvent since its NMR spectrum in CDCl3
was not affected by the addition of one third of CD3OD (Table 4,
entry 2).25
The role of the different partners of this unique cascade complex
was evaluated through a series of NMR binding studies in
CD3OD/CDCl3 (1 : 3). In this mixture of solvents, no inclusion of
+
the ammonium ion was detected upon the addition of PrNH3 Pic-
(1 equiv.) or PrNH3 Cl- (2 equiv.)/PicH (1 equiv.). However,
+
the subsequent addition of respectively TBA+HSO4 (1 equiv.)
-
2-
or (TBA+)2SO4 (2 equiv.) afforded the quantitative formation
6380 | Org. Biomol. Chem., 2011, 9, 6373–6384
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
∑ the greater distance between the proton sensitive site and
the tris-ureido binding site of 3 allows the formation of cascade
5 min and the reaction mixture was stirred at room temperature
under CO2 atmosphere overnight. Subsequently, the reaction
medium was drained with argon, placed in a syringe and the
volume was adjusted to 10 mL with anhydrous THF. After-
wards, a second 10 mL syringe containing a solution of tris(3-
aminopropyl)amine (65 mL, 328 mmol) in anhydrous THF (10 mL)
was prepared. Then, the two solutions were simultaneously intro-
duced at room temperature via a syringe pump (4.8 mL h-1) into a
stirred solution of anhydrous THF (140 mL) under argon atmo-
sphere and the resulting solution was stirred one additional hour.
The reaction mixture was evaporated to dryness and the crude
solid was purified over silica gel (CH2Cl2/MeOH/25% aqueous
NH4OH; 88 : 12 : 0.6) to give the corresponding calix[6]crypturea
3 (230 mg, 50%) as a white solid. M.p. 262 ◦C (dec); IR (KBr)
nmax 3350, 2960, 1652, 1558, 1481 cm-1; 1H NMR (300 MHz,
CDCl3/CD3CN (3 : 7), 298 K) d (ppm) 1.00 (s, 27H, tBu), 1.12
(s, 27H, tBu), 1.65 (sb, 6H, NCH2CH2), 2.38 (sb, 6H, NCH2), 3.15
(m, 15H, OCH3, NHCH2), 3.30–3.49 (m, 12H, J = 15 Hz, CHeq,
NHCH2), 3.61 (sb, 6H, OCH2), 4.43 (d, J = 15 Hz, 6H, CHax), 5.83
(sb, 3H, CH2CH2CH2NH), 5.91 (sb, 3H, OCH2CH2NH), 6.90 (s,
6H, ArH), 7.05 (s, 6H, ArH); 13C NMR (75 MHz, CDCl3/CD3CN
(3 : 7), 298 K) d (ppm) 28.0 (NCH2CH2CH2NH),38 30.6 (ArCH2),
32.1 (CH3tBu), 35.0 (CqtBu), 35.1 (CqtBu), 39.7 (NCH2CH2CH2NH),
41.5 (OCH2CH2NH), 52.7 (NCH2CH2CH2NH), 61.6 (CH3O),
73.7 (OCH2CH2NH), 126.9 (CHAr), 127.0 (CHAr), 134.0 (CAr-
CH2), 134.44 (CAr-CH2), 146.6 (CAr-tBu), 147.0 (CAr-tBu), 153.2
(CAr-O), 154.7 (CAr-O), 160.1 (CO). HRMS calc. for C87H124N7O9:
1410.9461, found: 1410.9468.
complexes 3·H+…R1R2NH2 Xn- with an anion bound between
+
the convergent ureido groups and sandwiched between the NH+
proton and an ammonium ion accommodated into the cavity.
Remarkably, with a bicharged anion such as SO42-, these cascade
complexes are even stable in a protic environment. As a reminder,
when protonated, 1 was inert toward anions or ion pairs because
of the too short distance between the capping tertiary nitrogen
and the ureido groups.
All in all, when an ammonium ion R1R2NH2 is added to the
+
calix[6]crypturea 3, three different types of host–guest system
can be selectively obtained depending on the nature of the
counterion. With a poorly coordinating anion such as Pic-,
the dicationic complex 3·H+…R1R2NH2 is observed, while with
+
coordinating monocharged X- (e.g. Cl-) and bicharged anions
X2- (e.g. SO42-), neutral complexes 3…R1R2NH2 X- and cascade
+
complexes 3·H+…R1R2NH2 X2- are respectively formed. This
+
strong dependence of the protonation state of the receptor on
the nature of the anion present in solution nicely illustrates the
unique and sophisticated host properties displayed by 3.
All these results validate the strategy that consists of designing
receptors presenting a high flexibility that can be controlled by
an external stimulus. Indeed, as illustrated in the present work,
allosteric control and selective guest switching processes can be
achieved with such receptors. It is noteworthy that most of the
biological receptors are based on rather flexible systems (e.g. pro-
tein scaffolds) and the function of some is allosterically regulated
or pH dependent. Thus, besides its structure that reminds us of
biological receptors, i.e. a tunable recognition site protected by a
hydrophobic corridor that can adapt its conformation to the size
of the guest, receptor 3 is highly reminiscent of what is encountered
in natural systems. Current efforts are now being directed toward
the synthesis and study of water-soluble related receptors.
Determination of the relative affinities of the neutral molecules
KG/Pyro in the case of 3·H+ through 1H NMR competitive binding
studies in CDCl3
To a CDCl3 solution containing 3·H+ (4 ¥ 10-3 to 5 ¥ 10-3 M)
were successively added Pyro (>1 equiv.) and a second guest G
1
(>1 equiv.) in such a ratio that a H NMR spectrum recorded
at 298 K showed the resonances of both complexes 3·H+…Pyro
and 3·H+…G besides the signals corresponding to the free guests
(Pyro and G). Integration of the signals of the included guests,
Experimental section
General procedures
All reactions were performed under an inert atmosphere.
Anhydrous THF was obtained through distillation over
Na/benzophenone. Silica gel (230–400 mesh) was used for flash
chromatography purifications. 1H NMR spectra were recorded at
600, 400 or 300 MHz and 13C NMR spectra were recorded at
75 MHz. Chemical shifts are expressed in ppm. Traces of residual
solvent were used as internal standard and CDCl3 was filtered
over a short column of basic alumina to remove traces of DCl.
i.e. Pyroin and Gin, and of the free guests, i.e. Pyrofree and Gfree
allowed us to calculate the relative affinity KG/Pyro, defined as
([Gin] ¥ [Pyrofree])/([Gfree] ¥ [Pyroin]).
,
Determination of the association constant Ka of 3·H+ toward Imi
in CD3OD/CDCl3 (1 : 2)
To a 1 : 2 CD3OD/CDCl3 solution containing 3·H+ (2.3 ¥ 10-3 M)
was added Imi in such a ratio that a 1H NMR spectrum recorded
at 298 K showed the resonances of both calixarene species 3·H+
and 3·H+…Imi besides the signals corresponding to the free guest
(Imi). Integration of the signals of the calixarene species 3·H+ and
3·H+…Imi and of the free guest (Imi) allowed us to calculate the
association constant Ka according to the following equation: Ka =
[3·H+…Imi]/([3·H+] ¥ [Imi]).
1
Most of the H NMR spectra signals were attributed through
2D NMR analyses (COSY, HSQC, HMBC). Mass spectra were
recorded on an ESI-MS apparatus equipped with an ion-trap
using the following settings: flow rate: 10 mL min-1, spray voltage:
5 kV, capillary temperature: 160 ◦C, capillary voltage: -15V, tube
lens offset voltage: -30V. The calix[6]tris-azide 2 was prepared as
previously described.20
Determination of the association constant Ka of 3 toward TMA+ in
Calix[6]crypturea 3
CD3OD/CDCl3 (7 : 3)
To a solution of calix[6]tris-azide 2 (401 mg, 328 mmol) in
anhydrous THF (10 mL) was added triphenylphosphine (518 mg,
1.975 mmol). Then, CO2 was bubbled through the solution for
To a 7 : 3 CD3OD/CDCl3 solution containing 3 (3.3 ¥ 10-3 M)
was added TMA+Pic- in such a ratio that a H NMR spectrum
1
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6373–6384 | 6381
©

View Article Online
+
recorded at 298 K showed the resonances of both calixarene species
3 and 3…TMA+ besides the signals corresponding to the free guest
(TMA+). Integration of the signals of the calixarene species 3 and
3…TMA+ and of the free guest (TMA+) allowed us to calculate the
association constant Ka according to the following equation: Ka =
[3…TMA+]/([3] ¥ [TMA+]).
3 and 3…Ach+Cl- or 3…PyrNH2 Cl- and of the free salts allowed
us to calculate the cumulative formation constants b2 according
to the following equation: b2 = [3…Ach+Cl-]/([3] ¥ [Ach+] ¥ [Cl-])
or b2 = [3…PyrNH2 Cl-]/([3] ¥ [PyrNH2 ] ¥ [Cl-]).
+
+
Determination of the cumulative formation constants b2 of 3·H+
+
toward PrNH3 Cl in CDCl3
Determination of the association constants Ka of 3 toward anions
To a CDCl3 solution containing 3·H+ (2.4 ¥ 10-3 M) was added
Xn- in CD3CN/CDCl3 (7 : 3)
PrNH3 Cl- in such a ratio that a 1H NMR spectrum recorded at
+
The association constants Ka were determined according to the
following procedure: a solution of calix[6]crypturea 3 (1 ¥ 10-3 to
3 ¥ 10-3 M) in CD3CN/CDCl3 (7 : 3) was prepared. This solution
was divided in two solutions (i.e. A and B) and the anion salt
(nTBA+Xn-) was added to the solution A. Suitable aliquots of
solution A were added to solution B. The corresponding 1H
NMR spectra recorded at 298 K revealed one set of signals for
the complex 3…Xn- and for the free receptor 3 in fast exchange
on the NMR time scale. Thus, the association constants Ka were
determined by nonlinear least-square-fitting of 1 : 1 binding profile
to the chemical shift of either the OCH2 or the ArH protons. The
error on the association constant was estimated as the standard
deviation of the association constant values provided by the fitting
(10%).
298 K showed the resonances of both calixarene species 3·H+ and
3·H+…PrNH3 Cl- besides the signals corresponding to the free
+
salt. Integration of the signals of the calixarene species 3·H+ and
3·H+…PrNH3 Cl- and of the free salts allowed us to calculate the
+
overall binding constant b2 according to the following equation:
b2 = [3·H+…PrNH3 Cl-]/([3·H+] ¥ [PrNH3 ] ¥ [Cl-]).
+
+
Estimation of the cumulative formation constants b2 of 3·H+
+
2-
toward PrNH3 SO4 in CDCl3
Cumulative formation constants b2 were estimated according to
+
2-
the following procedure: the ammonium salt (PrNH3 TBA+) SO4
were added to a solution of receptor 3·H+ (ca 3 ¥ 10-3 M) in
1
such a way that the corresponding H NMR spectra recorded
at 298 K revealed the total disappearance of the free receptor
3·H+. The concentration of the undetectable species (i.e. 3·H+)
and the concentration of the ternary complex were estimated to
be respectively 5% and 95% of the starting host concentration.
Cumulative formation constants b2 were estimated according
Estimation of the cumulative formation constant b2 of 3 toward
PrNH3 Cl- in CDCl3.
+
Cumulative formation constant b2 was estimated according to the
+
+
following procedure: suitable aliquots of a solution of PrNH3 Cl-
to the following equation: b2 > [3·H+…PrNH3 SO42-]/([3·H+] ¥
were added to a solution of receptor 3 (0.7 ¥ 10-3 M) in such
[PrNH3 ] ¥ [SO42-]).
+
1
a way that the corresponding H NMR spectrum recorded at
Determination of the cumulative formation constants b2 of 3·H+
298 K revealed the total disappearance of the free receptor
3. The concentration of the undetectable species (i.e. 3) and
the concentration of the ternary complex were estimated to be
respectively 5% and 95% of the starting host concentration.
Cumulative formation constant b2 was estimated according to the
+
2-
+
2-
toward PrNH3 SO4 and PyrNH2 SO4 in CD3OD/CDCl3
(1 : 3)
To a CD3OD/CDCl3 (1 : 3) solution containing 3 (2.9 ¥ 10-3 M)
was added PrNH3+ Pic- or PyrNH2+ Pic-and TBA+ HSO4- in such
a ratio that a 1H NMR spectrum recorded at 298 K showed the res-
following equation: b2 > [3…PrNH3 Cl-]/([3] ¥ [PrNH3 ] ¥ [Cl-]).
+
+
onances of both calixarene species 3·H+ and 3·H+…PrNH3 SO4
+
2-
Estimation of the cumulative formation constant b2 of 3 toward
+
2-
or 3·H+…PyrNH2 SO4 besides the signals corresponding to the
TMA+Cl- in CDCl3
free salts. Integration of the signals of the calixarene species 3·H+
+
-
+
2-
Cumulative formation constant b2 was estimated according to the
following procedure: suitable aliquots of a solution of TMA+Cl-
were added to a solution of receptor 3 (4.7 ¥ 10-3 M) in such a
and 3·H+…PrNH3 SO4 or 3·H+…PyrNH2 SO4 and of the free
salts allowed us to calculate the overall binding constant b2 accord-
ing to the following equation: b2 = [3·H+…PrNH3 SO42-]/([3·H+] ¥
+
[PrNH3 ] ¥ [SO42-]) or b2 = [3·H+…PyrNH2 SO42-]/([3·H+] ¥
1
+
+
ratio that a H NMR spectrum recorded at 298 K showed the
resonances of both calixarene species 3 and 3…TMA+Cl-. The
concentration of the undetectable species (i.e. free TMA+Cl-) was
estimated to be 5% of the starting host concentration. Cumulative
formation constant b2 was estimated according to the following
equation: b2 > [3…TMA+Cl-]/([3] ¥ [TMA+] ¥ [Cl-]).
[PyrNH2 ] ¥ [SO42-]).
+
Crystal data of calix[6]crypturea 3
Crystal data: C87H123N7O9, Mw = 1410.92, monoclinic, space group
˚
˚
P21/c; dimensions: a = 16.1331(14) A, b = 37.634(3) A, c =
◦
3
˚
˚
17.1581(15) A, b = 98.715(2) , V = 10297.4(15) A ; Z = 4; m =
0.059 mm-1; 123747 reflections measured at 100 K; independent
reflections: 18406 [8840 Fo >4s (Fo)]; data were collected up to
a 2qmax value of 50.42◦ (99.1% coverage). Number of variables:
925; R1 = 0.0822, wR2 = 0.2253, S = 1.048; highest residual electron
Determination of the cumulative formation constants b2 of 3
toward either Ach+Cl- or PyrNH2 Cl- in CDCl3
+
To a CDCl3 solution containing 3 (ca. 4 ¥ 10-3 M) was added the
ammonium salt in such a ratio that a 1H NMR spectrum recorded
at 298 K showed the resonances of both calixarene species 3 and
-3
˚
density 0.738 e.A (all data R1 = 0.1499, wR2 = 0.2463). Several
3…Ach+Cl- or 3…PyrNH2 Cl- besides the signals corresponding
disordered solvent molecules were initially modelled as discrete
+
to the free salts. Integration of the signals of the calixarene species
acetonitrile molecules but they were ultimately removed from the
6382 | Org. Biomol. Chem., 2011, 9, 6373–6384
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
structure. The data set was corrected for a disordered solvent with
the program PLATON/SQUEEZE.39 CCDC 820544 contains the
supplementary crystallographic data for this paper.†
4879–4884; (c) X. Zeng, N. Hucher, O. Reinaud and I. Jabin, J. Org.
Chem., 2004, 69, 6886–6889; (d) S. Le Gac, X. Zeng, O. Reinaud and I.
Jabin, J. Org. Chem., 2005, 70, 1204–1210; (e) X. Zeng, D. Coquie`re, A.
Alenda, E. Garrier, T. Prange´, Y. Li, O. Reinaud and I. Jabin, Chem.–
Eur. J., 2006, 12, 6393–6402; (f) S. Le Gac, X. Zeng, C. Girardot and I.
Jabin, J. Org. Chem., 2006, 71, 9233–9236.
Acknowledgements
16 D. Coquie`re, J. Marrot and O. Reinaud, Org. Biomol. Chem., 2008, 6,
3930–3934.
17 For another example of calix[6]arenes bearing three (thio)ureido arms
on the narrow rim but with a binding site for anions far away from the
cavity, see: J. Scheerder, J. F. J. Engbersen, A. Casnati, R. Ungaro and
D. N. Reinhoudt, J. Org. Chem., 1995, 60, 6448–6454.
This research was supported by the Universite´ Libre de Bruxelles
(U.L.B.) (PhD grant of DC).
18 Examples of metal-free complexation of contact ion pairs are still rare,
see: (a) S. Kubik, J. Am. Chem. Soc., 1999, 121, 5846–5855; (b) J. M.
Mahoney, J. P. Davis, A. M. Beatty and B. D. Smith, J. Org. Chem., 2003,
68, 9819–9820; (c) M. D. Lankshear, I. M. Dudley, K.-M. Chan, A. R.
Cowley, S. M. Santos, V. Felix and P. D. Beer, Chem.–Eur. J., 2008, 14,
2248–2263; (d) J. L. Atwood and A. Szumna, Chem. Commun., 2003,
940–941; (e) S. Le Gac and I. Jabin, Chem.–Eur. J., 2008, 14, 548–
557.
19 For recent examples of calixarene based receptors for separated organic
ion pairs: (a) A. Arduini, R. Ferdani, A. Pochini, A. Secchi and
F. Ugozzoli, Angew. Chem., Int. Ed., 2000, 39, 3453–3456; (b) A.
Arduini, E. Brindani, G. Giorgi, A. Pochini and A. Secchi, J. Org.
Chem., 2002, 67, 6188–6194; (c) D. Garozzo, G. Gattuso, A. Notti,
A. Pappalardo, S. Pappalardo, M. F. Parisi, M. Perez and I. Pisagatti,
Angew. Chem., Int. Ed., 2005, 44, 4892–4896; (d) M. D. Lankshear,
N. H. Evans, S. R. Bayly and P. D. Beer, Chem.–Eur. J., 2007, 13,
3861–3870; (e) S. Le Gac, M. Me´nand and I. Jabin, Org. Lett., 2008,
10, 5195–5198; (f) C. Gargiulli, G. Gattuso, C. Liotta, A. Notti, M. F.
Parisi, I. Pisagatti and S. Pappalardo, J. Org. Chem., 2009, 74, 4350–
4353.
Notes and References
1 (a) J.-M. Lehn, in Supramolecular Chemistry, Wiley-VCH, Weinheim,
1995; (b) J. W. Steed, D. R. Turner and K. J. Wallace, in Core
Concepts in Supramolecular Chemistry and Nanochemistry, Wiley-
VCH, Chippenham, 2007; (c) J. H. Hartley, T. D. James and C. J.
Ward, J. Chem. Soc., Perkin Trans. 1, 2000, 3155–3184.
2 Special issue on cyclodextrins: Chem. Rev., 1998, 98, pp. 1741–2076.
3 (a) D. J. Cram and J. M. Cram, in Container Molecules and their Guests,
Vol. 4: Monographs in Supramolecular Chemistry (Ed., J. F. Stoddart),
The Royal Society of Chemistry, Cambridge, 1994; (b) F. Hof, S. L.
Craig, C. Nuckolls and J. Rebek, Jr., Angew. Chem., Int. Ed., 2002, 41,
1488–1508; (c) R. Warmuth and J. Yoon, Acc. Chem. Res., 2001, 34, 95–
105; (d) I. Higler, P. Timmerman, W. Verboom and D. N. Reinhoudt,
Eur. J. Org. Chem., 1998, 12, 2689–2702.
4 (a) B. W. Purse and J. Rebek, Jr., Proc. Natl. Acad. Sci. U. S. A., 2005,
102, 10777–10782; (b) A. Jasat and J. C. Sherman, Chem. Rev., 1999,
99, 931–967.
5 (a) T. Brotin and J.-P. Dutasta, Chem. Rev., 2009, 109, 88–130; (b) A.
Collet, Tetrahedron, 1987, 43, 5725–5759.
20 M. Me´nand and I. Jabin, Org. Lett., 2009, 11, 673–676.
21 M. Me´nand and I. Jabin, Chem.–Eur. J., 2010, 16, 2159–2169.
22 For other examples of acid–base controllable systems based on
calixarenes, see: (a) S. Pappalardo, V. Villari, S. Slovak, Y. Cohen, G.
Gattuso, A. Notti, A. Pappalardo, I. Pisagatti and M. F. Parisi, Chem.–
Eur. J., 2007, 13, 8164–8173; (b) S. Silvi, A. Arduini, A. Pochini, A.
Secchi, M. Tomasulo, F. M. Raymo, M. Baroncini and A. Credi, J. Am.
Chem. Soc., 2007, 129, 13378–13379.
6 C. D. Gutsche, in Calixarenes Revisited, Monographs in Supramolecular
Chemistry (Ed., J. F. Stoddart), The Royal Society of Chemistry,
Cambridge, 1998.
7 (a) T. Tuntulani, P. Thavornyutikarn, S. Poompradub, N. Jaiboon, V.
Ruangpornvisuti, N. Chaichit, Z. Asfari and J. Vicens, Tetrahedron,
2002, 58, 10277–10285; (b) U. Darbost, O. Se´ne`que, Y. Li, G. Bertho,
J. Marrot, M.-N. Rager, O. Reinaud and I. Jabin, Chem.–Eur. J., 2007,
13, 2078–2088.
23 For leading examples of other three-way supramolecular switches, see:
(a) P. R. Ashton, V. Balzani, J. Becher, A. Credi, M. C. T. Fyfe, G.
Mattersteig, S. Menzer, M. B. Nielsen, F. M. Raymo, J. F. Stoddart, M.
Venturi and D. J. Williams, J. Am. Chem. Soc., 1999, 121, 3951–3957;
(b) D. A. Leigh, J. K. Y. Wong, F. Dehez and F. Zerbetto, Nature, 2003,
424, 174–179; (c) I. Hwang, A. Y. Ziganshina, Y. H. Ko, G. Yun and
K. Kim, Chem. Commun., 2009, 416–418.
8 (a) J. L. Sessler, P. A. Gale and W.-S. Cho, in Anion Receptor Chemistry,
The Royal Society of Chemistry, Cambridge, 2006; (b) P. D. Beer
and P. A. Gale, Angew. Chem., Int. Ed., 2001, 40, 486–516; (c) P. A.
Gale, Coord. Chem. Rev., 2003, 240, 191–221; (d) S. O. Kang, R. A.
Begum and K. Bowman-James, Angew. Chem., Int. Ed., 2006, 45, 7882–
7894.
9 S. K. Kim and J. L. Sessler, Chem. Soc. Rev., 2010, 39, 3784–3809.
10 (a) M. J. Deetz, M. Shang and B. D. Smith, J. Am. Chem. Soc., 2000,
122, 6201–6207; (b) O. Se´ne`que, M.-N. Rager, M. Giorgi, T. Prange´, A.
Tomas and O. Reinaud, J. Am. Chem. Soc., 2005, 127, 14833–14840;
(c) U. Darbost, M.-N. Rager, S. Petit, I. Jabin and O. Reinaud, J. Am.
Chem. Soc., 2005, 127, 8517–8525; (d) G. Ambrosi, P. Dapporto, M.
Formica, V. Fusi, L. Giorgi, A. Guerri, M. Micheloni, P. Paoli, R.
Pontellini and P. Rossi, Inorg. Chem., 2006, 45, 304–314.
11 (a) O. Reinaud, Y. Le Mest and I. Jabin, in Calixarenes in the Nanoworld,
ed. J. Vicens and J. Harrowfield, Springer-Verlag, Netherlands, 2006,
ch. 13, pp. 259–285; (b) D. Coquie`re, S. Le Gac, U. Darbost, O. Se´ne`que,
I. Jabin and O. Reinaud, Org. Biomol. Chem., 2009, 7, 2485–2500.
12 (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) Y.
Rondelez, M.-N. Rager, A. Duprat and O. Reinaud, J. Am. Chem.
Soc., 2002, 124, 1334–1340.
24 (a) S. Moerkerke, M. Me´nand and I. Jabin, Chem.–Eur. J., 2010, 16,
11712–11719; (b) I. Ravikumar, P. S. Lakshminarayanan, E. Suresh and
P. Ghosh, Inorg. Chem., 2008, 47, 7992–7999.
25 See the Electronic Supporting Information (ESI†).
26 When the three OMe groups are directed outside of the cavity, a
chemical shift of ca. 3.9 ppm is observed. Conversely, a chemical shift
of ca. 2.1 ppm usually corresponds to a self-inclusion of these three
groups.
27 In pure CDCl3, 3·H+ displayed a broad NMR spectrum and the
protonation process was slow on the NMR scale. In contrast, in
CD3CN/CDCl3 (7 : 3) and CD3OD/CDCl3 (7 : 3), well defined spectra
and fast proton transfers were observed. Surprisingly, in these polar
solvents, two conformations differing by the chemical shift of the
OMe groups were visible (see the ESI†). In both cases, one of
the conformations is very close to that observed in the case of 3
and the other one corresponds to a C3v symmetrical flattened cone
conformation with the three OMe groups included into the cavity (dOMe
<2.18 ppm).
13 M. Hamon, M. Me´nand, S. Le Gac, M. Luhmer, V. Dalla and I. Jabin,
J. Org. Chem., 2008, 73, 7067–7071.
28 Addition of 1.5 equiv. of Imi to 3·H+ led to a mixture of 3·H+…Imi
and 3·H+ in slow exchange on the NMR timescale (see the ESI†).
However, accurate determination of the association constant, Ka (Ka =
[3·H+…Imi]/([3·H+] ¥ [Imi]) from the integrations of the different species
was not possible because of the weak competitive binding of water.
This competitive binding was checked by NMR spectroscopy through
the addition of aliquots of water to the above mixture of 3·H+…Imi
and 3·H+ (see the ESI†). For a reference on the effects of water on
hydrogen-bonding-based hosts in chloroform, see: J. C. Adrian, Jr. and
C. S. Wilcox, J. Am. Chem. Soc., 1991, 113, 678–680.
14 (a) U. Darbost, X. Zeng, M. Giorgi and I. Jabin, J. Org. Chem., 2005,
70, 10552–10560; (b) S. Le Gac, J. Marrot, O. Reinaud and I. Jabin,
Angew. Chem., Int. Ed., 2006, 45, 3123–3126; (c) S. Le Gac, M. Luhmer,
O. Reinaud and I. Jabin, Tetrahedron, 2007, 63, 10721–10730; (d) S. Le
Gac, M. Giorgi and I. Jabin, Supramol. Chem., 2007, 19, 185–197; (e) S.
Le Gac, J.-F. Picron, O. Reinaud and I. Jabin, Org. Biomol. Chem., 2011,
9, 2387–2396.
15 (a) I. Jabin and O. Reinaud, J. Org. Chem., 2003, 68, 3416–3419; (b) U.
Darbost, M. Giorgi, O. Reinaud and I. Jabin, J. Org. Chem., 2004, 69,
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6373–6384 | 6383
©

View Article Online
29 Such an intramolecular H-bonded ring between the apical NH+
and an introverted C O has already been evidenced on a related
calix[6]trenamido receptor, see: A. Lascaux, S. Le Gac, J. Wouters,
M. Luhmer and I. Jabin, Org. Biomol. Chem., 2010, 8, 4607–4616.
30 Starting geometries were constructed via the Builder module of
InsightII (Accelrys) and optimized using the PM6 hamiltonian (J. J.
P. Stewart, J. Mol. Model., 2007, 13, 1173–1213) via the semi-empirical
MOPAC2009 software (Stewart Computational Chemistry). In order
to achieve convergence of the geometry optimization to chemically
reasonable structures, H atoms of the ureido groups were constrained.
Similarly, position of the H+ was forced to bind the nitrogen of the
tripodal cap of the receptor.
33 In the case of the titration with (TBA+)2SO42-, the NH ureido signals
became extremely broad over the course of the titration (see Fig. 5) and,
thus, it was not possible to determine precisely their chemical shift.
34 The complexation of the tetramethylammonium salt TMA+Pic- was
also evaluated in CDCl3. However, host 3 was not able to extract this
insoluble quaternary ammonium salt.
35 Note that in all cases, a minor species that does not display high-field
signals below 0 ppm was observed. Given the broadness of its NMR
signals, it was not possible to conclude whether the cap is protonated
or not. Since the proportion of this species did not change upon the
addition of a large excess of ammonium salts, this minor compound
could result from an exo-complexation of the ammonium ion.
36 Note that the host–guest exchange is slow on the NMR timescale.
31 D and A stand for hydrogen-bond donors and acceptors respec-
tively.
37 See the ESI† for the comparison between 3·H+…PrNH3+SO4 and
2-
32 In the case of calixcrypturea 1·H+, the protic solvent (i.e. CD3OD) was
a significant competitor for the calixarene cavity. However, despite this
competitive process with the solvent, an apparent association constant
of ca. 10 M-1 was determined for Imi.
3·H+…PrNH3+Cl-.
38 This signal was determined by HMQC analysis.
39 P. Van der Sluis and A. L. Spek, Acta Crystallogr., Sect. A: Found.
Crystallogr., 1990, A46, 194–201.
6384 | Org. Biomol. Chem., 2011, 9, 6373–6384
This journal is
The Royal Society of Chemistry 2011
©