Ditopic receptors based on lower- and upper-rim substituted hexahomotrioxacalix[3]arenes: Cation-controlled hydrogen bonding of anion

Article abstract of DOI:10.1002/asia.201100926

Heteroditopic hexahomotrioxacalix[3]arene receptors that are capable of binding an anion and a cation simultaneously in a cooperative fashion were synthesized. The structure of one of the triamide derivatives was confirmed by single-crystal X-ray diffract

Full text of DOI:10.1002/asia.201100926

DOI: 10.1002/asia.201100926
Ditopic Receptors based on Lower- and Upper-Rim Substituted
Hexahomotrioxacalix[3]arenes: Cation-Controlled Hydrogen Bonding of
Anion
Xin-Long Ni,[a, b] Jun Tahara,[a] Shofiur Rahman,[a] Xi Zeng,[b] David L. Hughes,[c]
Carl Redshaw,[c] and Takehiko Yamato*[a]
Abstract: Heteroditopic hexahomo-
trioxacalix[3]arene receptors that are
capable of binding an anion and a
cation simultaneously in a cooperative
fashion were synthesized. The structure
of one of the triamide derivatives was
confirmed by single-crystal X-ray dif-
fraction. The binding of alkali metals
at the lower rim, and the binding of
anions (chloride, bromide) at the upper
rim, has been investigated by using
1H NMR titration experiments. Alkali
metal binding at the lower rim controls
the calix cavity. Li+-ion binding to the
lower rim can improve the binding
ability of anions at the upper rim
amide moiety by a factor of 15, thus
suggesting a strong positive allosteric
effect for anion recognition. However,
when a Na+ cation is bound to the
ionophoric site on the lower rim, the
calix cavity is changed from a “flat-
tened cone” to a more-upright form,
which is favored for intramolecular hy-
drogen bonding between the neighbor-
ing NH and C=O groups; this change
can block the inclusion of anions onto
the amide moiety at the upper rim,
which strongly suggests a negative allo-
steric effect of Na+-ion binding, which
controls the cooperative recognition
system.
Keywords: anions
· calixarenes ·
cations · hydrogen bonds · recep-
tors
Introduction
traction, and membrane transport.[2] However, the design of
convergent heteroditopic receptors is quite a challenge be-
cause the ion-binding sites have to be incorporated into a
suitably preorganized scaffold that holds them in close prox-
imity, but not so close that the sites interact. One of the first
successful examples of a ditopic salt receptor for the associa-
tion of ion pairs was reported by Reetz et al.[3a] The Lewis-
acidic boron atom can form a reversible dative bond with
the FÀ anion, which promotes simultaneous coordination of
a K+ cation by the oxygen atoms in the surrounding crown
ether.
Calixarenes and their derivatives are attractive compounds
for host–guest and supramolecular chemistry. Facile func-
tionalization at their upper and lower rims makes them suit-
able as binding sites for guest encapsulation and molecular
assembly.[1] The design and application of new heteroditopic
receptor systems that are capable of the simultaneous coor-
dination of both anionic and cationic guest species has re-
cently attracted a great deal of interest, as these systems
have the potential to act as agents for salt solubilization, ex-
On the other hand, a growing research topic in supra-
molecular chemistry is controlled self-assembly;[3] for exam-
ple, a number of groups have shown how salts can be used
to template the dimerization of receptors in water-saturated
CDCl3, with water acting as a stabilizing agent.[3b] In some
cases, the assembled aggregate is large enough to act as a
capsule and completely encapsulate both ions of the salt.[3c]
A related design is the so-called “venus fly trap” capsule, an
example of which was reported by Atwood and Szumna,
who showed that an extended, deep-cavity resorcinarene de-
[a] Dr. X.-L. Ni, J. Tahara, Dr. S. Rahman, Prof. T. Yamato
Department of Applied Chemistry
Faculty of Science and Engineering
Saga University
1 Honjo-machi 1, Saga-shi, Saga 840-8502 (Japan)
Fax : (+81)952-28-8548
E-mail: yamatot@cc.saga-u.ac.jp
[b] Dr. X.-L. Ni, Prof. X. Zeng
Department Key Laboratory of Macrocyclic and Supramolecular
Chemistry of Guizhou Province
+
rivative can completely encapsulate an NMe4 cation with a
ClÀ anion held by hydrogen-bonding interactions at the cap-
sule entrance.[3d] Furthermore, Beer and co-workers report-
ed that a heteroditopic calix[4]diquinone receptor,[4a] which
was capable of binding an anion and cation simultaneously
in a cooperative fashion, could only recognize halide anions
in the presence of a suitable co-bound cationic guest spe-
cies; this receptor also displayed affinity for certain ion pairs
Guizhou University
Guiyang, Guizhou, 550025 (China)
[c] Dr. D. L. Hughes, Dr. C. Redshaw
School of Chemistry
University of East Anglia
Norwich, NR4 7 JT (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100926.
Chem. Asian J. 2012, 7, 519 – 527
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519

FULL PAPERS
when no affinity for either of the free ions was observed. By
incorporating aza-crown moieties into amide-based rutheni-
um–bipyridyl anion receptors, chloride binding was en-
hanced by the presence of potassium bound in close proxim-
ity within the crowns.[4b] In a similar approach, Reinhoudt
and co-workers[5] took advantage of the ease of derivatiza-
tion of calix[4]arenes to build new salt-binders. By function-
alizing the metacyclophane on its lower-rim with cation-
binding features, and on its upper-rim with hydrogen-bond
donors (ureas), they obtained several heterotropic systems
(which contain binding sites for different substrates) that
had cooperative binding properties. They demonstrated that
prior sodium binding induces a large rearrangement in the
conformations of the ligand, which preorganizes the hydro-
gen-bond groups for efficient anion complexation. By tar-
geting phosphoryl–choline derivatives, which form a family
of biologically relevant Zwitterions, de Mendoza and co-
workers[6] prepared an efficient calix[6]arene-based receptor
that binds both cationic and anionic parts of the target and
offers a synthetic alternative to the very costly catalytic anti-
body technology. Consequently, a number of heteroditopic
receptors for the recognition of ion-pairs have been recently
reported by several groups.[7,8] Interest in a contact ion-pair
binding approach, wherein the anion and cation are bound
essentially as one moiety, is particularly noteworthy as this
avoids the energetically unfavorable separation of the two
ions.[9] Importantly, the geometry of the ditopic receptor
must be optimized so that the anion and cation binding sites
are located in an appropriate proximity to one another so as
to enhance this interaction; incorrect orientation could lead
to the ion pair associating outside of the receptor, or to sol-
vent-separated ion binding. Cooperative and allosteric
metal-salt-complexation behavior, whereby the binding of
the charged metal-cation guest can enhance the subsequent
coordination of the paired anion through electrostatic and
conformational effects, has been demonstrated in a number
of ditopic amide-based receptor systems.[10]
enes, that were capable of recognizing anions and primary
ammonium ions.[14]
Moving from our interest in the synthesis of heteroditopic
receptors that function not only as anion binders but also as
cation binders, we introduced amide groups onto the upper
rim, and diethylacetamides onto the lower rim of the hexa-
homotrioxacalix[3]arene. Herein, we report the synthesis
and complexation studies of cone-hexahomotrioxacalix[3]ar-
ene-triamide derivatives that demonstrated a dramatic en-
hancement of anion binding at the upper rim when a Li+ ion
was bound onto the lower rim. The recognition behavior to-
1
wards cations and anions was investigated by H NMR ex-
periments in CDCl3/CD3CN solution.
Results and Discussion
The preparation of cone-7,15,23-triethoxycarbonyl-25,26,27-
tris(N,N-diethylaminocarbonylmethoxy)-2,4,10,12,18,20-hex-
ahomo-3,11,19-trioxacalix[3]arene (cone-4) is shown in
Scheme 1. Thus, bis(hydroxymethylation) of ethyl-4-hydrox-
ybenzoate (1) with formaldehyde in aqueous NaOH for one
week afforded ethyl-3,5-bis(hydroxymethyl)-4-hydroxyben-
zoate (2)[15] in 41% yield. Heating compound 2 to reflux in
p-xylene for 24 hours afforded hexahomotrioxacalix[3]arene
3.[11a] The O-alkylation of compound 3 with N,N-diethyl-
chloroacetamide in the presence of NaI/NaH in refluxing
tetrahydrofuran gave cone-tris(N,N-diethylaminocarbonyl-
methoxy)hexahomo-trioxacalix[3]arene cone-4[11a] in 52%
yield. Hydrolysis of the O-alkylated compound, cone-4, was
carried out with NaOH in a mixture of ethanol/water (4:1)
at 508C for 2 hours to yield the cone-hexahomotrioxaca-
lix[3]arene tricarboxylic acid (cone-5[11a]; Scheme 2).
Derivatives of cone-Hexahomotrioxacalix[3]arene tria-
mide (cone-7a–7d) were prepared by the condensation of
cone-5 with 4-substituted anilines 6a–6d in the presence of
dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotria-
zole (HOBt) at room temperature for 20 hours in dichloro-
methane. These triamides (7a–7d), which were immobilized
Homooxacalixarenes are hosts that have larger cavities
and possess more conformational flexibility than classical
calixarenes.[11,12] This flexibility
is useful for inducing supra-
molecular responses to stimuli.
For example, Shinkai and co-
workers reported that hexaho-
motrioxacalix[3]arenes
were
capable of encapsulating and
releasing C60 depending on the
size of the alkali-metal cat-
ions.[11]
Hexahomotrioxaca-
lix[3]arene derivatives with C3
symmetry can selectively bind
ammonium ions, which play
important roles in both chemis-
try and biology.[13] Recently, we
reported C3-symmetric ditopic
receptors, based on functional-
ized hexahomotrioxacalix[3]ar-
Scheme 1. Synthesis of calixarene cone-4.
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Ditopic Receptors Based on Substituted Hexahomotrioxacalix[3]arenes
Scheme 2. Synthesis of calixarene cone-7.
in a “flattened-cone” conformation (in which the phenolic
rings were tilted to open up the calixarene cavity) were ob-
tained in moderate yields. Conformational assignments for
compounds 7a–7d were firmly established by the presence
of the bridging methylene protons with DdH separations in
1H NMR spectra (CDCl3) between Hax and Heq of 0.49, 0.51,
0.41, and 0.34 ppm, respectively. For the calix[4]arenes, the
DdH values of the ArCH2Ar protons were correlated to the
orientation of their adjacent aromatic rings.[13,16] The same
findings were observed in homotrioxacalix[3]arenes.[14] In
addition, singlet peaks were observed for the NH protons at
d=7.96, 7.73, 8.07, and 8.16 ppm for compounds 7a–7d, re-
spectively, thereby confirming the adoption of the flattened-
Figure 1. a) X-ray structure of cone-7c. Hydrogen atoms have been omit-
ted for clarity. Thermal ellipsoids are drawn at the 50% probability level.
b) View of the calixarene ring showing the groups on the upper rim of
cone-7c, projected on to the plane of C11, C21, and C31; the orientations
of the phenol rings and the distortion from C3 symmetry are shown. Hy-
drogen atoms and the atoms of the lower rim groups have been omitted
for clarity. Ok
were no intramolecular hydrogen bonding interactions ob-
served, but two of the amide NH groups formed intermolec-
ular hydrogen bonds.
The anion-coordination properties of cone-7a–7d were in-
vestigated by 1H NMR titration experiments with various
tetrabutylammonium (TBA) anions, such as chloride, bro-
mide, acetate, and benzoate in CDCl3/CD3CN=10:1 (v/v).
All of the titration experiments were performed at a con-
stant concentration of receptor (ca. 3ꢁ10À3 m), with an in-
creasing number of equivalents of the anion solution (0–9
equiv TBA salts). Substantial downfield shifts of the amide
NH signal were observed when tetrabutylammonium chlo-
ride and -bromide salts were added, thereby indicating that
anion binding was taking place in the vicinity of the amide
NH group (Figure 2 and Figure 3). Figure 2 shows the
1H NMR spectra of cone-7c in the presence of lithium and
chloride ions.
1
cone conformation in these products. Because the H NMR
spectra were almost unaffected by changes in the polarity of
the solvent (CDCl3, CDCl3/CD3CN (10:1), [D6]DMSO), we
concluded that possible intra-/intermolecular hydrogen
bonds were either very weak or absent under the measuring
conditions.
Recrystallization from methanol and chloroform pro-
duced X-ray-quality colorless crystals of cone-7c. An
ORTEP of cone-7c is shown in Figure 1a. In the solid state,
cone-7c adopts quite a different, deformed-cone conforma-
tion; two of the phenol rings are tilted outwards (as in a
normal cone), but the third, C21–C26, tilts inwards so that
the fluorophenyl group (of F246) lies between the other two
fluorophenyl groups (Figure 1b). The whole molecule is dis-
torted considerably from a C3-symmetric cone shape. There
When 1 equivalent of LiClO4 was added to solutions of
cone-7, the DdH values for Hax and Heq for the ArCH2O
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521

T. Yamato et al.
FULL PAPERS
carbonylmethoxy groups, and that the phenol groups in the
cone-7cꢀLi+ complex adopt the more-upright C3-symmetric
form. Similar findings were observed for the cone-7bꢀLi+
complex (DdH =0.25 ppm) compared to the free cone-7b
(DdH =0.51 ppm). Therefore, the conformations of the hosts
cone-7b and cone-7c have been rearranged by the Li+-ion
binding to afford conformations that are more appealing for
anion inclusion. Further addition of lithium ions did not
change the spectra, thereby indicating that 1:1 complexes of
Li+-ions/cone-7 were formed.
Controlled titration experiment of cone-3 and cone-4 with
Li+ and Na+ ions suggested that both alkali-metal cations
could not be complexed by the lower rim functionalization
moiety (N,N-diethylmethoxycarbonylmethoxy) rather than
the upper rim moiety of the series of hexahomotrioxaca-
lix[3]arene derivatives[11a,d] (see the Supporting Information,
Figures S1 and S2). In addition, an investigation of the
downfield shift observed for the amide protons of receptor
cone-7c upon complexation with alkali metals demonstrated
that this shift is caused by the formation of intramolecular
hydrogen bonds following a conformational change in the
receptor (cone-7c) and not by the effect of the counterions
(see the Supporting Information, Figures S3 and S4).
1
Figure 2. Partial H NMR titration of cone-7c/guest complex (H/G=1:1);
a) free cone-7c; b) cone-7cꢀLiClO4; c) Bu4NClꢁ[cone-7cꢀLi+]; d) cone-
7cꢀBu4NCl. Solvent: CDCl3/CD3CN (10:1, v/v).ok
To investigate the enhanced anion binding in the presence
of alkali metals, Bu4NCl (1 equiv) was added to solutions of
compounds 7a–7d (3ꢁ10À3 m) in the presence of LiClO4 in
CDCl3/CD3CN (10:1, v/v). This addition resulted in, for ex-
ample, a further downfield shift of the NH protons (d=8.74
to 8.93 ppm) when chloride ions were added to the solution
of [cone-7cꢀLiClO4] (Figure 2c). On the other hand, when
only chloride ions were added (in the absence of LiClO4),
the large downfield shift of the NH protons was not ob-
served (Figure 2d). The other receptors exhibited similar
trends to cone-7c in their affinity towards spherical anions,
such as ClÀ and BrÀ. With increasing size/decreasing basicity
of the halides, the association constants (calculated from the
changes in chemical shifts of the amide protons; summar-
ized in Table 1) were generally diminished for hosts cone-7;
in the presence of Li+ ions, the corresponding association
constants were greatly increased.
1
Figure 3. Changes in the H NMR spectra of cone-7c/Bu4NX (X=Cl and
Br) in the presence and absence of LiClO4. Solvent: CDCl3/CD3CN
(10:1, v/v).ok
methylene protons changed and the signals for the N,N-di-
ethylmethoxycarbonylmethoxy protons (ArOCH2CONEt2)
were shifted downfield (d=3.49 and 3.51 ppm for cone-7b
and cone-7c, respectively). It is known that the introduction
of bulky substituents onto the OH groups forces the phenol
units to stand upright from the calixarene ring plane.[1] This
inclination is reflected by the chemical-shift difference
(DdH) between the axial and equatorial ArCH2 protons.
Shinkai and co-workers demonstrated that metal cations
that appropriately preorganize the hexahomotrioxacalix[3]-
calixarene ester derivatives into their cone conformation
can make these calixarenes excellent [60]fullerene receptors
in solution through an allosteric effect.[11a,d] Interestingly, the
DdH value (from peaks around 4.5–5.1 ppm) for the cone-
7cꢀLi+ complex (0.26 ppm) was smaller than that of the
free cone-7c (0.49 ppm; Figure 2). This result implies that
lithium ions form complexes with the N,N-diethylmethoxy-
Table 1. Association constants[a] of hosts cone-7a–7d with chloride and
bromide ions.[b]
Association constant Ka [mÀ1
ClÀ+Li+ BrÀ BrÀ+Li+
]
Host
R
ClÀ
31(Æ6)
cone-7a
cone-7b
cone-7c
cone-7d
H
Me
F
1557
1082
2234
5123
A
50(Æ6)
1241
134
1449
3289
ACHTUNGTRENNUNG
50(Æ7)
E
24(Æ5)
ACHTUNGTRENNUNG
150
396
N
N
95
A
ACHTUNGTRENNUNG
CF3
E
G
168
A
ACHTUNGTRENNUNG
[a] Measured in CDCl3/CD3CN (10:1, v/v) at 278C by the 1H NMR titra-
tion method using the chemical-shift change of the NH proton; host con-
centration was 3ꢁ10À3 m. [b] Guests used: LiClO4, tetrabutylammonium
chloride, and bromide.ok
Thus, a significant increase, more than 15-fold, in the
strength of the anion binding was observed when lithium
ions were complexed. This positive cooperative binding of
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Ditopic Receptors Based on Substituted Hexahomotrioxacalix[3]arenes
the halide in the presence of lithium ion could be attributed
to the allosteric and electrostatic effects of the complexed
lithium ions.
Figure 3 shows that further addition of Bu4NX (X=Cl,
Br) to the solution of cone-7c in CDCl3/CD3CN (10:1, v/v),
in the presence and absence of LiClO4 resulted in clear
1
downfield shifts of the H NMR signals of the NH proton,
thus indicating that complexation of the halide guests is
through hydrogen-bonding interactions (also see the Sup-
porting Information, Figures S5 and S6).
Figure 4. Partial 1H NMR spectra of cone-7c/guest (H/G=1:1); a) free
cone-7c; b) cone-7cꢀNaClO4; c) Bu4NClꢁ[cone-7cꢀNa+]. Solvent:
CDCl3/CD3CN (10:1, v/v).ok
We note that the complexation constants also depended
on the substituents on the upper rim. In the presence of
more-electronegative atoms, such as F and CF3 (cone-7c and
cone-7d, respectively), the association constants were great-
er than for the unsubstituted receptor (cone-7a). By con-
trast, in the case of cone-7b, with the electron-donating Me
group, there was a general decrease in the Ka value for the
complexation with halides. Therefore, the introduction of
electron-withdrawing groups onto the upper rim appears to
increase the acidity of the amide protons, and hence en-
hance the anion-binding ability through hydrogen-bonding
interactions.
proximity of the amide moieties around the cavity means
that the anion binding site would be blocked and controlled
by intramolecular hydrogen-bonding interactions and con-
formational allosteric effects. Similar findings were also ob-
served for cone-7a, cone-7b, and cone-7d in the absence
and in the presence of Na+ ions. Thus, a plausible halide
anion binding mode of the ditopic receptors cone-7, con-
trolled by Li+ and Na+ cations (see the Supporting Informa-
tion, Figures S7–S10) is shown in Scheme 3.
Receptors cone-7a–d showed a preference for complexa-
tion of ClÀ over BrÀ (Table 1). This preference suggests that
the cavity formed by the three amide moieties might be
more complementary to the size of the ClÀ ions than to that
of the BrÀ ions, as well as the higher electronegativity of the
Thus, the binding of alkali-metal cations at the lower rim
appears to control the conformation of the calix cavity. Li+-
ion binding at the lower rim can improve the binding ability
of anions to the amide moiety on the upper rim and the
anion-complexation ability increases 15-fold, thus suggesting
a strong positive allosteric effect. However, when a Na+
cation is bound to the ionophoric lower rim, a more-upright
mode may be adopted; this narrow cavity might be smaller
and favor intramolecular hydrogen bonding between neigh-
boring NH and C=O groups and would thus block the inclu-
sion of halide anions binding onto the amide moiety on the
upper rim; this result strongly suggests that a negative allo-
steric effect exists in the case of Na+-ion binding and con-
trols the cooperative-recognition system.
ClÀ anion versus the BrÀ anion. In the case of tris
ACTHNUTRGNEU(GN urea)-
functionalized calix[6]arene, the preferred anion complexa-
tion is of BrÀ ions because the calix cavity is large and the
three functionalized moieties at the 1, 3, and 5 positions of
the calix[6]arene[17] are more complementary for the size of
the BrÀ ions than for the ClÀ ions. Calix[5]arene derivatives
have been reported to form complexes with alkylammonium
ions and are known to display an enzyme-like selectivity[18]
towards biologically important ammonium substrates. Be-
cause hexahomotrioxacalix[3]arenes and their derivatives
also have a potentially C3-symmetric conformation, they
might also bind to primary ammonium ions, thereby having
a potential application not only in chemical but also in bio-
logical systems.
Receptor cone-7 was able to bind all of the anions tested,
irrespective of their shape. The association constants for the
complexation of the cone-7a–7d receptors with other tetra-
butylammonium (TBA) anions, such as fluoride, acetate,
and benzoate (see the Supporting Information, Figures S11
Interestingly, no complexa-
tion of halide anions by the re-
ceptors cone-7 was observed in
the presence of NaClO4. The
DdH value for the cone-
7cꢀNa+ complex (0.11 ppm,
Figure 4b) was smaller than
that of cone-7cꢀLi+ (0.28 ppm,
Figure 2b). This result indi-
cates that the phenol groups in
cone-7ꢀNa+ are positioned in
a more-upright orientation[11d]
from the interaction of the
N,N-diethylmethoxycarbonyl-
methoxy groups with Na+ ions.
Scheme 3. Plausible binding mode of cone-7 complex with Bu4NX (X=Cl and Br) in the presence of LiClO4
Presumably, the much closer
and NaClO4 in CDCl3/CD3CN (10:1, v/v).
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523

T. Yamato et al.
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and S12), were also calculated from chemical-shift changes
for the amide protons (Table 2); these results shows that the
complexation constants were strongly affected by the size
Experimental Section
General
All melting points (Yanagimoto MP-S1) are uncorrected. 1H NMR spec-
tra (300 MHz) were recorded on a Nippon Denshi JEOL FT-300 NMR
spectrometer with SiMe4 as an internal reference: J-values are given in
Hz. IR spectra were measured for samples as KBr pellets in a Nippon
Denshi JIR-AQ2OM spectrophotometer. Elemental analyses were per-
formed on a Yanaco MT-5.
Table 2. Association constants[a] of hosts cone-7a–7d with various
anions.[b]
Association constant Ka [mÀ1
]
Host
R
H
FÀ ClÀ
BrÀ
50(Æ6)
24(Æ5)
95
(Æ10)
(Æ36) 168(Æ23) 1085
MeCOOÀ
PhCOOÀ
Synthesis of Ethyl-3,5-bis(hydroxymethyl)-4-hydroxybenzoate (2)[15]
[c]
cone-7a
–
–
–
–
31(Æ6)
57(Æ8)
56(Æ7)
83(Æ8)
60(Æ7)
cone-7b Me
cone-7c
cone-7d CF3
50(Æ7)
Ethyl-4-hydroxybenzoate (1; 20 g, 0.12 mol) was dissolved in cold aque-
ous NaOH (6 g in 50 mL H2O) and condensed with aqueous formalde-
hyde (30 mL, 37% solution). After 2 days, additional aqueous formalde-
hyde solution (2ꢁ30 mL) was added and the solution was heated to
reflux for 1 week. After cooling to RT, the solution was stirred vigorously
and neutralized with HCl solution (4m, 25 mL), thereby resulting in the
formation of a yellow oil. The oil was extracted with CHCl3 (3ꢁ50 mL)
and the organic layer was dried with MgSO4. The solution was filtered
and the volatile compounds were removed under reduced pressure to
yield a pale-yellow tar. The tar was dissolved in (CHCl3/CH3OH, 1:5),
cooled to 08C for 12 h, and filtered to give a pale-yellow solid (11.2 g,
yield 41%). Recrystallization from (CHCl3/CH3OH, 3:1) gave ethyl-3,5-
bis(hydroxymethyl)-4-hydroxybenzoate (2) as a white solid. M.p. 122–
F
150
396
(Æ20)
G
553
(Æ58)
1107
(Æ110)
E
E
[a] Measured in CDCl3/CD3CN (10:1, v/v) at 278C by the 1H NMR titra-
tion method using the chemical-shift change of the NH proton; host con-
centration was 3ꢁ10À3 m. [b] Guest used: tetrabutyammonium anions.
[c] No change in the chemical shift of NH proton was observed under the
conditions used.ok
and/or shape of the guest anions. Interestingly, the associa-
tion constants (Ka) for acetate and benzoate were much
larger than those for ClÀ and BrÀ ions. These findings might
be attributable to the trigonal shapes of acetate and ben-
zoate which could lead to favorable intermolecular hydro-
1
1238C; H NMR (300 MHz, [D6]DMSO): dH =1.28 (t, 3H; CH3), 4.25 (q,
2H; OCH2), 4.55 (s, 4H; ArCH2O), 7.82 (s, 2H; ArH), 9.36 ppm (s, 1H;
ArOH).
À
gen-bonding interactions with the amide protons; C H···p
Synthesis of 7,15,23-Triethoxycarbonyl-25,26,27-trihydroxy-2,4,10,12,18,20-
interactions or stacking interactions between the planar ace-
tate group or the benzoate arene ring and the phenyl rings
of the amide groups may also be contributing factors, and
hexahomo-3,11,19-trioxacalix[3]arene (3)[11a]
Ethyl-3,5-bis(hydroxymethyl)-4-hydroxybenzoate (2; 2.5 g, 0.011 mol)
was heated to reflux at 145–1508C for 24 h in p-xylene (100 mL); the
water produced was removed at intervals. The solvent was removed
under reduced pressure. The residue was extracted with CHCl3 and the
solvent was again removed under reduced pressure. The residue was dis-
solved in a minimum amount of CH2Cl2 and then MeOH was added until
the solution became cloudy. On cooling the solution to 08C for 12 h,
product 3 precipitated as a white solid (435 mg; yield 19%). M.p. 225–
2268C; 1H NMR (300 MHz, CDCl3): dH =1.37 (t, 9H; OCH2CH3), 4.34
(q, 6H; OCH2), 4.76 (s, 12H; ArCH2O), 7.87 (s, 6H; ArH), 9.19 ppm (s,
3H; ArOH).
1
may be responsible for the disappearance of the H NMR
signal of the NH proton in the presence of alkali metals (see
the Supporting Information, Figures S13 and S14).
Conclusions
Heteroditopic hexahomotrioxacalix[3]arene receptors are
capable of binding an anion and cation simultaneously in a
cooperative fashion. cone-Hexahomotrioxacalix[3]arenes
bearing N,N-diethylacetamide and substituted-triamide
chains on their lower and upper rims, respectively, were syn-
thesized in a stepwise fashion from triol 3. The binding of
the alkali metals and anions (chloride, bromide) at the
lower and upper rims, respectively, was investigated by using
1H NMR titration experiments. Cation binding of the alkali
metals at the lower rim controls the cavity size and shape of
the calixarene; for example, Li+-ion binding to the lower
rim can improve the binding ability of anions to the amide
moiety on the upper rim by a factor of 15. However, when a
Na+ cation was bound to the ionophoric lower rim, the calix
cavity changed from a flattened cone shape to a more-up-
right form that may favor intramolecular hydrogen bonding
between neighboring NH and C=O groups and thus block
the binding site for anions at the upper rim.
Synthesis of 7,15,23-Triethoxycarbonyl-25,26,27-tris(N,N-
diethylaminocarbonylmethoxy)-3,11,19-trioxacalix[3]arene (cone-4)[11a]
NaH (172 mg) and NaI (719 mg) were added to a solution of hexahomo-
trioxacalix[3]arene 3 (300 mg, 0.48 mmol) in dry THF/DMF (25 mL, 5:1,
v/v), and stirring was continued at RT for 1 h. N,N-diethylchloroaceta-
mide (719 mg, 4.8 mmol) was added to the stirring solution and the mix-
ture was heated to reflux at 608C for 48 h under an Ar atmosphere.
After cooling to RT, the mixture was poured onto ice and acidified with
1m HCl. The solution was extracted with EtOAc (2ꢁ50 mL), and washed
with water (2ꢁ50 mL) and brine (50 mL). After drying with MgSO4, the
solvent was removed under reduced pressure. The residue was recrystal-
lized from MeOH to afford cone-4 (240 mg, yield 52%). M.p. 190–1918C;
1H NMR (300 MHz, CDCl3): dH =1.19–1.26 (m, 18H; NCH2CH3), 1.32–
1.36 (t, J=7.8 Hz, 9H; OCH2CH3), 3.25 (q, J=6.5 Hz, 6H; NCH2CH3),
3.47 (q, J=6.5 Hz, 6H; NCH2CH3), 4.27–4.35(m, 6H; OCH2CH3), 4.78(s,
12H; ArCH2O), 4.81 (s, 6H; ArOCH2), 7.92 ppm (s, 6H; ArH).
Synthesis of 7,15,23-Trihydroxycarbonyl-25,26,27-tris(N,N-
diethylaminocarbonylmethoxy)-3,11,19-trioxacalix[3]arene triacid (cone-
5)[11a]
Hexahomotrioxacalix[3]arene cone-4 (200 mg, 0.20 mmol) was added to a
solution of 300 mg NaOH (EtOH/water, 4:1, 25 mL) and heated under
refluxing conditions at 508C for 2 h. After being cooled to RT, the reac-
tion mixture was neutralized with 1m HCl solution and extracted with
CH2Cl2 (2ꢁ50 mL), and washed with water (2ꢁ50 mL) and brine
(50 mL). After drying with MgSO4, the solvent was removed under re-
Further studies on the synthesis of ion-controlled ditopic
receptors based on hexahomotrioxacalix[3]arenes are under-
way in our laboratory.
524
www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 519 – 527

Ditopic Receptors Based on Substituted Hexahomotrioxacalix[3]arenes
duced pressure. The residue was recrystallized from CH2Cl2/n-hexane
(1:3, v/v) to afford cone-5 (139 mg, yield 79%). M.p. 126–1278C,
1H NMR (300 MHz, CDCl3): dH =1.16–1.24 (m, 18H; NCH2CH3), 3.32
(q, J=6.0 Hz, 6H; NCH2CH3), 3.43 (q, J=6.0 Hz, 6H; NCH2CH3), 4.55
(s, 6H; ArOCH2), 4.70 (d, J=13.8 Hz; ArCH2(eq)O), 4.82 (d, J=13.8 Hz;
ArCH2(ax)O), 7.95 ppm (s, 6H; ArH).
PhHb), 8.16 ppm (3H, s, NH); 13C NMR(75 MHz, CDCl3): d=12.94,
14.05, 40.08, 40.88, 68.82, 72.17, 115.01, 115.30, 122.69, 122.79, 129.03,
130.90, 132.41, 134.07, 158.60, 166.05, 166.88 ppm; FAB-MS: m/z 1309.46
[M]+; elemental analysis calcd. (%) for C66H69O12N6F9 (1309.27): C 60.55,
H 5.31, N 6.42; found: C 60.25, H 5.36, N 6.28.
Determination of the Association Constants
The association constants were determined by using 1H NMR titration
experiments in a constant concentration of host receptor (3ꢁ10À3 m) and
varying the guest concentration (0–10ꢁ10À3 m). The 1H NMR chemical
shift of the amide protons (NH) signal was used as a probe. The associa-
tion constant (Ka) for the complexes of cone-7 were calculated by non-
linear curve-fitting analysis of the observed chemical shifts of the NH
protons according to the literature procedure.[19]
Synthesis of 7,15,23–Tris(4-methylphenylaminocarbonyl)-25,26,27-tris-
(N,N-diethylaminocarbonylmethoxy)-2,4,10,12,18,20-hexahomo-3,11,19-
trioxacalix[3]arene (cone-7b)
A solution of dicyclohexylcarbodiimide (DCC; 190 mg, 0.92 mmol) in
CH2Cl2 (5 mL) was added dropwise at 08C to a solution of cone-5
(100 mg, 0.11 mmol), p-toluidine (6b; 130 mg, 1.17 mmol) and 1-hydroxy-
benzotriazole (HOBt; 26 mg, 0.17 mmol) in CH2Cl2 (12 mL). The reac-
tion mixture was stirred for 15 h at RT, then condensed under reduced
pressure. The residue was extracted with EtOAc (2ꢁ30 mL); the com-
bined extracts were washed with 10% citric acid (2ꢁ20 mL), 5% sodium
bicarbonate (20 mL), water (20 mL), and saturated brine (20 mL); the so-
lution was dried (Na2SO4) and condensed under reduced pressure. The
residue was recrystallized from MeOH to give cone-7b (64 mg, 49%) as
colorless prisms. M.p. 186–1888C; IR (KBr): n˜ =2977, 2929, 1644, 1519,
1H NMR Titration Experiments
A solution of Bu4NX (X=Cl, Br) in CDCl3/CD3CN (10:1, v/v, 0–9ꢁ
10À3 m) in the presence or absence of LiClO4 and NaClO4 was added to a
CDCl3/CD3CN (10:1, v/v, 3ꢁ10À3 m) solution of cone-7 in an NMR tube.
1H NMR spectra were recorded after addition of the reactants and the
1
temperature of the NMR probe was kept constant at 278C. The H NMR
1477, 1456, 1323, 1190, 1093, 1072, 1054, 904, 823, 667, 513 cmÀ1
.
data of the most-representative complexes are given below:
1H NMR (300 MHz, CDCl3): dH =1.12–1.23 (m, 18H; NCH2CH3), 2.25
(9H, s; PhCH3), 3.31 (q, J=7.14 Hz, 6H; NCH2CH3), 3.38 (q, J=
7.14 Hz, 6H; NCH2CH3), 4.55 (d, J=12.6 Hz; ArCH2(eq)O), 4.67 (s, 6H;
ArOCH2), 5.06 (d, J=12.6 Hz; ArCH2(ax)O), 7.03 (d, J=8.25 Hz, 6H;
PhHa), 7.25 (d, J=11.9 Hz, 6H; PhHb), 7.27 (s, 6H; ArH), 7.73 ppm (3H,
s, NH). 13C NMR (75 MHz, CDCl3): d=12.73, 14.00, 20.65, 40.06, 40.08,
68.98, 72.03, 120.99, 129.04, 129.12, 131.04, 132.20, 133.84, 135.12, 158.58,
166.04, 167.05 ppm. FAB-MS: m/z 1147.53 [M]+; elemental analysis calcd.
(%) for C66H78O12N6 (1147.36): C 69.09, H 6.85, N 7.32; found: C 68.79,
H 7.00, N 7.45.
cone-7bꢀLi+: (CDCl3/CD3CN, 10:1, v/v): dH =1.15–1.24 (m, 18H;
NCH3), 2.26 (9H, s; PhCH3), 3.17 (q, 6H; NCH2), 3.49 (q, 6H; NCH2),
4.55 (d, 6H; ArCH2(eq)O), 4.69 (s, 6H; ArOCH2), 4.80 (d, 6H;
ArCH2(ax)O), 6.89(d, 6H; PhHa), 7.36 (d, 6H; PhHb), 7.61(s, 6H; ArH),
8.74 ppm (3H, s, NH).
ClÀꢁ[cone-7bꢀLi+]: (CDCl3/CD3CN, 10:1, v/v): dH =1.12–1.23 (m, 18H;
NCH3), 2.25 (9H, s; PhCH3), 3.18 (q, 6H; NCH2), 3.49 (q, 6H; NCH2),
4.57 (d, 6H; ArCH2(eq)O), 4.68 (s, 6H; ArOCH2), 4.79 (d, 6H;
ArCH2(ax)O), 6.87 (d, 6H; PhHa), 7.37 (d, 6H; PhHb), 7.62 (s, 6H; ArH),
8.97 ppm (3H, s; NH).
BrÀꢁ[cone-7bꢀLi+]: (CDCl3/CD3CN, 10:1, v/v): dH =1.12–1.23 (m, 18H;
NCH3), 2.25 (9H, s; PhCH3), 3.18 (q, J=7.1 Hz; NCH2), 3.48 (q, 6H;
NCH2), 4.56 (d, 6H; ArCH2(eq)O), 4.68 (s, 6H; ArOCH2), 4.77 (d, 6H;
ArCH2(ax)O), 6.88 (d, 6H; PhHa), 7.41 (d, 6H; PhHb), 7.73 (s, 6H; ArH),
8.87 ppm (3H, s; NH).
cone-7cꢀLi+: (CDCl3/CD3CN, 10:1, v/v): dH =1.17–1.24 (m, 18H; NCH3),
3.20 (q, 6H; NCH2), 3.51 (q, 6H; NCH2), 4.52 (d, 6H, ArCH2(eq)O), 4.69
(s, 6H, ArOCH2), 4.80 (d, 6H; ArCH2(ax)O), 6.88 (t, 6H; PhHa), 7.37(d,
6H; PhHb), 7.62(s, 6H; ArH), 8.74 ppm (3H, s; NH).
cone-7cꢀNa+: (CDCl3/CD3CN, 10:1, v/v): dH =1.17–1.24 (m, 18H;
NCH3), 3.23 (q, 6H; NCH2), 3.54 (q, 6H; NCH2), 4.64 (d, 6H; Ar-
CH2(eq)O), 4.69 (s, 6H; ArOCH2), 4.75 (d, 6H; ArCH2(ax)O), 6.93 (t, 6H;
PhHa), 7.31 (d, 6H; PhHb), 7.47 (s, 6H; ArH), 8.98 ppm (3H, s; NH).
ClÀꢁ[cone-7cꢀLi+]: (CDCl3/CD3CN, 10:1, v/v): dH =1.17–1.25 (m, 18H;
NCH3), 3.20 (q, 6H; NCH2), 3.51 (q, 6H; NCH2), 4.58 (d, 6H; Ar-
CH2(eq)O), 4.67 (s, 6H; ArOCH2), 4.74 (d, 6H; ArCH2(ax)O), 6.70 (t, 6H;
PhHa), 7.41 (d, 6H; PhHb), 7.57 (s, 6H; ArH), 8.93 ppm (3H, s; NH).
cone-7cꢀClÀ: (CDCl3/CD3CN, 10:1, v/v): dH =1.17–1.23 (m, 18H;
NCH3), 3.27 (q, 6H; NCH2), 3.40 (q, 6H; NCH2), 4.57 (d, 6H; Ar-
CH2(eq)O), 4.70 (s, 6H; ArOCH2), 5.04 (d, 6H; ArCH2(ax)O), 6.83 (t, 6H;
PhHa), 7.44 (d, 6H; PhHb), 7.43 (s, 6H; ArH), 8.01 ppm (3H, s; NH).
BrÀꢁ[cone-7cꢀLi+]: (CDCl3/CD3CN, 10:1, v/v): dH =1.17–1.23 (m, 18H;
NCH3), 3.19 (q, 6H; NCH2), 3.50 (q, 6H; NCH2), 4.61 (d, 6H; Ar-
CH2(eq)O), 4.69 (s, 6H; ArOCH2), 4.76 (d, 6H; ArCH2(ax)O), 6.75 (t, 6H;
PhHa), 7.58 (d, 6H; PhHb), 7.80 (s, 6H; ArH), 8.57 ppm (3H, s; NH).
cone-7cꢀBrÀ: (CDCl3/CD3CN, 10:1, v/v): dH =1.17–1.24 (m, 18H;
NCH3), 3.29 (q, 6H; NCH2), 3.42 (q, 6H; NCH2), 4.57 (d, 6H; Ar-
CH2(eq)O), 4.70 (s, 6H; ArOCH2), 5.06 (d, 6H; ArCH2(ax)O), 6.95 (t, 6H;
PhHa), 7.24 (d, 6H; PhHb), 7.32 (s, 6H; ArH) and 7.96 ppm (3H, s; NH).
Similarly, compounds cone-7a, cone-7c, and cone-7d were synthesized as
described above in 52, 57, and 62% yields, respectively.
7,15,23-Tris(phenylaminocarbonyl)-25,26,27-tris(N,N-diethylaminocarbo-
nylmethoxy)-2,4,10,12,18,20-hexahomo-3,11,19-trioxacalix[3]arene (cone-
7a) was obtained as colorless prisms. M.p. 204–2058C; IR (KBr): n˜ =
2931, 1650, 1560, 1540, 1504, 1452, 1052, 809, 667 cmÀ1
;
1H NMR
(300 MHz, CDCl3): dH =1.13–1.23 (m, 18H; NCH2CH3), 3.31–3.44 (m,
12H; NCH2), 4.54 (d, J=12.6 Hz, 6H; ArCH2(eq)O), 4.68 (s, 6H;
ArOCH2), 5.03 (d, J=13.2 Hz, 6H; ArCH2(ax)O), 7.04–7.40 (m, 15H;
ArH), 7.32 (s, 6H; ArH), 7.96 ppm (3H, s; NH); 13C NMR(75 MHz,
CDCl3): d=12.97, 14.30, 40.16, 41.00, 69.28, 72.11, 120.92, 124.43, 128.78,
129.16, 131.19, 132.57, 137.86, 158.84, 166.09, 166.89 ppm; FAB-MS: m/z
1105.53 [M]+; elemental analysis calcd. (%) for C63H72O12N6 (1105.28):
C 68.46, H 6.57, N 7.60; found: C 68.18, H 6.28, N 7.66.
7,15,23-Tris(4-fluorophenylaminocarbonyl)-25,26,27-tris-(N,N-diethylami-
nocarbonylmethoxy)-2,4,10,12,18,20-hexahomo-3,11,19-trioxacalix[3]ar-
ene (cone-7c) was obtained as colorless prisms. M.p. 237–2388C; IR
(KBr): n˜ =2959, 2863, 1689, 1602, 1537, 1483, 1445, 1363, 1311, 1198,
1068, 879, 754, 693, 503 cmÀ1; 1H NMR (300 MHz, CDCl3): dH =1.17–1.22
(m, 18H; NCH3), 3.29 (q, J=7.14 Hz, 6H; NCH2), 3.40 (q, J=7.14 Hz,
6H; NCH2), 4.58 (d, J=13.0 Hz; ArCH2(eq)O), 4.67 (s, 6H; ArOCH2),
4.99 (d, J=13.0 Hz; ArCH2(ax)O), 6.88 (t, J=8.82 Hz, 6H; PhHa), 7.33 (t,
J=6.9 Hz, 6H; PhHb), 7.35 (s, 6H; ArH), 8.07 ppm (3H, s; NH);
13C NMR (75 MHz, CDCl3): d=12.94, 14.28, 40.16, 41.00, 69.42, 72.19,
108.25, 114.10, 119.87, 124.50, 128.49, 132.66, 133.44, 143.14, 161.53,
161.83, 166.45 ppm. FAB-MS: m/z 1159.45 [M]+; elemental analysis calcd.
(%) for C63H69O12N6F3 (1159.25): C 65.27, H 6.00, N 7.25; found: C 65.55,
H 6.28, N 7.28.
7,15,23-Tris(4-trifluoromethylphenylaminocarbonyl)-25,26,27-tris-(N,N-di-
ethylaminocarbonylmethoxy)-2,4,10,12,18,20-hexahomo-3,11,19-trioxaca-
lix[3]arene (cone-7d) was obtained as colorless prisms. M.p. 273–2748C;
IR (KBr): n˜ =2974, 2931, 1789, 1652, 1477, 1458, 1439, 1309, 1161, 1092,
Crystallographic Analysis of cone-7c
1074, 742 cmÀ1 1H NMR (300 MHz, CDCl3): dH =1.14–1.25 (m, 18H;
.
Crystal data: C63H69F3N6O12; Mr =1159.2; monoclinic; space group: P21/n
(equiv to no. 14); a=20.9753(3), b=12.9216(2), c=22.2116(3) ꢂ; b=
NCH2CH3), 3.37 (q, 12H, J=7.8 Hz; NCH2), 4.63 (d, J=13.2 Hz, 6H;
ArCH2(eq)O), 4.67 (s, 6H; ArOCH2), 4.97 (d, J=13.2 Hz; ArCH2(ax)O),
7.38 (d, J=8.4 Hz, 6H; PhHa), 7.43 (s, 6H; ArH), 7.49 (d, J=8.4 Hz, 6H;
Chem. Asian J. 2012, 7, 519 – 527
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
525

T. Yamato et al.
FULL PAPERS
91.4868(14)8; V=6018.08(15) ꢂ3; Z=4; 1cald =1.279 gcmÀ3
;
F
G
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2448; T=140(1) K; mACHTUNGTRENNUNG ACHTUNGTRENN(UNG MoKa)=0.71069 ꢂ.
(MoKa)=1.0 cmÀ1; l
Crystals were colorless blocks. One, crystal size 0.35ꢁ0.27ꢁ0.12 mm, was
mounted in oil on a glass fiber and fixed in a stream of cold nitrogen on
an Oxford Diffraction Xcalibur-3 CCD diffractometer equipped with
MoKa radiation and a graphite monochromator. Intensity data were mea-
sured by thin-slice w- and f-scans. 81209 reflections measured, 7854
unique reflections (Rint =0.100) to qmax =22.58; 5904 observed with I>
2s(I).
The data were processed using the CrysAlisPro-CCD and -RED[20] pro-
grams. The structure was determined by direct methods using the
SHELXS program[21] and refined by the full-matrix least-squares method,
on F2s, in SHELXL.[21] The non-hydrogen atoms were refined with aniso-
tropic thermal parameters. Hydrogen atoms were included in idealized
positions and their Uiso values were set to ride on the Ueq values of the
parent carbon or nitrogen atoms. At the conclusion of the refinement,
wR2 =0.109 and R1 =0.110[21] for all 7854 reflections weighted w=[s2-
2
2
N
ACHTUNGTRENNUNG
(0.0463P)2]À1 with P=(Fo +2Fc2)/3; for the “observed” data only,
ACHTUNGTRENNUNG
Scattering factors for neutral atoms were taken from reference [22].
Computer programs used in this analysis have been noted above, and
were run through WinGX[23] on a Dell Precision 370 PC at the University
of East Anglia. CCDC 826164 (cone-7c) contains the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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Acknowledgements
We would like to thank the OTEC at Saga University and the Interna-
tional Collaborative Project Fund of Guizhou province at Guizhou Uni-
versity for financial support. We also would like to thank the EPSRC
(overseas travel grant to C.R.) and the The Royal Society for financial
support.
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Received: November 11, 2011
Published online: January 13, 2012
Chem. Asian J. 2012, 7, 519 – 527
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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