Ditopic receptors of hexaamide derivatives derived from hexahomotrioxacalix[3]arene triacetic acid

Article abstract of DOI:10.1139/v05-260

The lower rim functionalized hexahomotrioxacalix[3]arene hexaamide 7 having an amino acid moiety with cone conformation was synthesized from triol 1 by a stepwise reaction. The different extractability for alkali metal ions, transition metal ions, and alk

Full text of DOI:10.1139/v05-260

58
Ditopic receptors of hexaamide derivatives
derived from hexahomotrioxacalix[3]arene
triacetic acid
Takehiko Yamato, Shofiur Rahman, Zeng Xi, Fumika Kitajima, and Jeong Tae Gil
Abstract: The lower rim functionalized hexahomotrioxacalix[3]arene hexaamide 7 having an amino acid moiety with
cone conformation was synthesized from triol 1 by a stepwise reaction. The different extractability for alkali metal
ions, transition metal ions, and alkylammonium ions from water into dichloromethane was discussed. Owing to the
strong intramolecular hydrogen bond between the neighboring NH and CO groups in hexaamide 7, its affinity to metal
+
cations was weakened. Hexaamide 7 shows a single selectivity to n-BuNH3 . The anion complexation of hexaamide 7
1
was also studied by H NMR titration experiments. Hexaamide 7 binds halides through the intermolecular hydrogen
bond among the NH hydrogens of the amide in a 1:1 fashion in CDCl3. Thus, hexaamide 7 serves as a heteroditopic
receptor that can complex with halides (Cl–, Br–) and n-BuNH3 at the same time. The association constants calculated
+
from the chemical shift changes of the amide protons are Ka = 536 32 (mol/L)–1 for Cl– and Ka = 230 17 (mol/L)–1
for Br–.
Key words: hexahomotrioxacalix[3]arenes, ionophores, molecular recognition, ammonium ion, ditopic receptor.
Résumé : Utilisant le triol 1 comme produit de départ, on a réalisé la synthèse par étape de l’hexahomotrioxacalix[3]arène
hexaamide 7 dont la ceinture inférieure fonctionnalisée porte une portion d’acide aminé avec conformation en cône. On
discute des possibilités de l’extraire de solutions aqueuses vers du dichlorométhane à l’aide de divers ions métalliques
alcalins ou métalliques et avec des ions alkylammonium. En raison de la forte liaison hydrogène intramoléculaire entre
les groupes voisins NH et CO dans l’hexaamide 7, son affinité pour les cations métalliques est réduite. L’hexaamide 7
+
présente une sélectivité particulière pour le n-BuNH3 . La complexation anionique de l’hexaamide 7 a aussi été étudiée
1
par des expériences de titrage par RMN du H. Dans le CDCl3, l’hexaamide 7 se lie aux halogénures par le biais d’une
liaison hydrogène intermoléculaire 1 : 1 avec les atomes d’hydrogène NH de l’amide. L’hexaamide 7 peut donc servir
de récepteur hétéroditopique qui peut complexer en même temps les halogénures (Cl–, Br–) et le n-BuNH3 . Les cons-
+
tantes d’association obtenues à partir des changements du déplacement chimique des protons de l’amide sont
Ka = 536 32 (mol/L)–1 pour Cl– et Ka = 230 17 (mol/L)–1 pour Br–.
Mots clés : hexahomotrioxacalix[3]arène, ionophores, reconnaissance moléculaire, ion ammonium, récepteur ditopique.
[Traduit par la Rédaction] Yamato et al. 64
Introduction
symmetry can selectively bind ammonium ions, which play
important roles in both chemistry and biology (3). Thus,
Takeshita and Shinkai (2b) reported the construction of C3
symmetry pyrene-functionalized hexahomotrioxacalix[3]arenes,
which selectively recognize primary ammonium ions.
Calixarene and related macrocycles have received consid-
erable attention for their host–guest chemistry as ionophoric
receptors and potential enzyme mimics in biology. Chemical
modification of calixarene represents a simple though effec-
tive and versatile way of producing receptors with highly se-
lective cation-binding properties (1). Shinkai and co-workers
(2) reported the complexation of alkali metals to hexahomo-
trioxacalix[3]arene derivatives with alkylated phenolic
oxygens. Hexahomotrioxacalix[3]arene derivatives with C3
On the other hand, the hydrogen bond plays an important
role in the self-assembly of molecular recognition and has
been investigated in calixarene systems. An intermolecular
hydrogen-bonded duplex was formed through the interaction
between a calix[4]arene with four carboxyl groups, and a
calix[4]arene with stilbazole moieties was reported (4).
Arduini et al. (5) also described the formation of a hydrogen-
bonded dimer in CDCl3 based on the self-complementarity
of carboxylic acid. The intramolecular hydrogen bonding also
formed among opposing urea groups, which can bind an-
ionic species, in calix[4]arene (6). Thus, the design of new
ditopic ligands (7) for the simultaneous complexation of an-
ionic and cationic guest species is a new exciting area of co-
ordination chemistry of significant relevance to the selective
extraction and (or) transportation of metal salts across
lipophilic membranes. Rare examples of receptors contain-
Received 16 September 2005. Published on the NRC
Research Press Web site at http://canjchem.nrc.ca on
25 February 2006.
T. Yamato,1 S. Rahman, Z. Xi, F. Kitajima, and J.T. Gil.
Department of Applied Chemistry, Faculty of Science and
Engineering, Saga University, Honjo-machi 1, Saga-shi, Saga
840-8502, Japan.
1Corresponding author (e-mail: yamatot@cc.saga-u.ac.jp).
Can. J. Chem. 84: 58–64 (2006)
doi:10.1139/V05-260
© 2006 NRC Canada

Yamato et al.
59
Scheme 1.
OMe
C O
CH2
NH
C O
CH2
H2NCH2COOMe (4a)
DCC/HOBt, CH2Cl2
O
Dioxane/ NaOH (aq)
CH2
CH2
cone-2b
O
room temp. for 1 h
(79%)
room temp. for 15 h
(71%)
3
Me
cone-5
OH
C O
CH2
NH
NHb
C O
CH2
NHa
C O
C O
CH2
O
CH2
O
p-toluidine (4b)
DCC/HOBt, CH2Cl2
CH2
CH2
CH2
CH2
O
O
room temp. for 15 h
(85%)
3
3
cone-7
cone-6
monium ions and halides (12a). On the other hand, the intro-
duction of multiple binding sites for cations and anions is
important for the construction of the allosteric host–guest in-
clusion systems. In the present paper, we describe the syn-
thesis, conformations, and metal and ammonium ion
complexation properties of the additional amino acid linked
cone p-methylphenyl amide derivative having two hydro-
gen-bonding systems and C3-symmetric ionophoric cavities.
Chart 1.
Me
NH
Me
Me
7
O
23
27
HN
NH
O
25 OR
OR
O
O
O
O
OR
O
O
26
O
O
O
O
Results and discussion
15
cone-Hexahomotrioxacalix[3]arene tricarboxylic acid
(cone-2b) was prepared by hydrolysis of cone-[(N,N-diethyl-
aminocarbonyl)methoxy]hexahomotrioxacalix[3]arene (cone-
2a) with aq. KOH in a mixture of dioxane and water, which
was prepared by O-alkylation of 1 with N,N-diethylchloro-
acetoamide in the presence of NaH according to the reported
procedures (2d, 12). cone-Hexahomotrioxacalix[3]arene tri-
amide (cone-5) was prepared by a condensation reaction of
cone-2b with glycine methyl ester (4a) in the presence of
dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotri-
azole (HOBt) at room temperature for 15 h in CH2Cl2. cone-
5 was converted to triacid cone-6 by hydrolysis with aq.
NaOH in a mixture of dioxane and water at room tempera-
ture. cone-6 was treated with p-toluidine (4b) in the pres-
ence of DCC and HOBt similar to that of cone-5 to afford
1; R= H
cone-2a; R = CH2CONEt2
cone-2b; R = CH2COOH
cone-3
ing appropriate covalently linked binding sites for anions
and cations include Lewis acidic boron (8), uranyl (9), poly-
ammonium (10) centers combined with crown ether moi-
eties, and crown ether or urea-functionalized calix[4]arene
ionophores (11), which are capable of solubilizing alkali
metal salts into organic media (Chart 1).
Recently, we reported a ditopic receptor (cone-3) incorpo-
rating these two types of recognition sites by introducing
three amide groups to the phenolic oxygens of homotri-
oxacalix[3]arene, which can simultaneously bind alkyl am-
© 2006 NRC Canada

60
Can. J. Chem. Vol. 84, 2006
Fig. 1. Binding mode of host cone-7 and n-BuNH3X.
Me
Me
Me
Me
Me
Me
X-
NH
HN
O
HN
O
NH
HN
HN
O
O
O
O
HN
O
HN
O
HN
O
NH
+
HN
X-
NH
n-Bu
NH3
O
O
O
O
O
O
H
H
H
O
O
O
O
+
N
O
O
O
O
O
cone-7
CH3CH2CH2CH2–
X = Cl-, Br-
the desired compound cone-hexahomotrioxacalix[3]arene
hexaamide (cone-7) in 85% yield (Scheme 1).
compound cone-7 was broken, and the new intermolecular
hydrogen bonding was formed.
From the singlet peaks of tert-butyl protons and calix ben-
zene protons for cone-7, it could be seen that the conforma-
tion remained in the desired compound with the cone
conformation. To investigate the intramolecular hydrogen
bond between the neighboring NH and CO groups of cone-7
in detail, a reference compound 9c was synthesized from 4-
tert-butyl-2,6-dimethylphenoxyacetic acid (8) following a
method similar to that used in the preparation of cone-7.
Interestingly, hexaamide cone-7 shows low efficiency for
metal cations compared with cone-2a (2d). The ionophoric
activity of cone-7 was almost absent. Hexaamide cone-7
shows a single affinity only to n-butylammonium ion owing
to the C3-symmetric structure. However, no extractability for
isobutyl- or tert-butyl-ammonium ion was observed under
the conditions used. The ionophores usually form loose ion
pairs with metal picrates, which produced the maximum ab-
sorption peak at 377 nm (14, 15). Interestingly, the hexa-
Conformation assignment for the new hexahomotrioxa-
calix[3]arene hexaamide (cone-7) is firmly established by
the presence of AB quartets for the bridging methylene pro-
tons with a ∆δ separation between Hax and Heq of 0.45 ppm
+
amide cone-7 also forms a contact ion pair with n-BuNH3
and shows the maximum absorption peak at 365 nm. In
comparison with cone-7, N,N-diethylamide derivative cone-
2a has a higher affinity to alkali metal ions (Na+ (93.0% ex-
traction) and K+ (71.6%)), transition metal ions (Ag+ (90.4%)
and Cu2+ (27.5%)), and typical metal ion (Al3+ (19.1%)).
Higher extractabilities of the cone-N,N-diethylamide deriva-
tive for n-butyl- (97.8%), isobutyl- (48.1%), and tert-butyl-
ammonium ion (35.4%) were observed and are attributable
to the higher electron density of the oxygen of the carbonyl
group by the electron donation ability of the amide group
through conjugation N–C=O ↔ N+=C–O– (2d, 12a, 12b).
These findings clearly indicate that because of the strong hy-
drogen-bonding formation between NH and neighboring CO
groups in hexaamide cone-7, there is no affinity shown for
either hard or soft metal cations.
1
in its H NMR spectrum (CDCl3). In the calix[4]arenes, the
∆δ values of the ArCH2Ar protons have been correlated to
the orientation of adjacent aromatic rings, i.e., ∆δ > 1 ppm
with cone conformation or syn orientation, ∆δ of approxi-
mately 0.5 ppm with flattened cone or out orientation,
and ∆δ of 0 ppm with 1,3-alternate or anti orientation (13).
The same findings were observed in hexahomotrioxa-
calix[3]arenes (2a). Thus, we can deduce that cone-7 prefers
a flattened cone conformation in which hydrogen bonding
can form. The intramolecular hydrogen bond was formed be-
tween neighboring NH and C=O groups, which induced a
large downfield shift for the NHa proton (δ 8.45 ppm, ∆δ =
+0.69 ppm) and NHb proton (δ 9.21 ppm, ∆δ = +0.85 ppm)
in cone-7 compared with compound 9c (NHa proton,
δ 7.76 ppm; NHb proton, δ 8.36 ppm). When the concentra-
tion of cone-7 in CDCl3 was diluted about 40 times, there
was no change in the chemical shifts for both NHa and NHb
protons, which is attributed to the concentration-independent
intramolecular hydrogen bonds formed in this compound.
Interestingly, the chemical shift of the NHb protons in cone-
7 was shifted to a lower magnetic field to δ 9.91 ppm in
DMSO-d6 than in CDCl3 (δ 9.21 ppm, ∆δ = +0.70 ppm).
This phenomenon was attributed to the intermolecular
hydrogen bonding formed between the NHb proton and
DMSO-d6. The intramolecular hydrogen bonding formed in
The present binding mode can be demonstrated more clearly
1
by using H NMR spectroscopy. There are two modes for
cone-7 to bind with n-butylammonium ion (Fig. 1), i.e.,
from the lower rim through substituent moieties or from the
upper rim through the π cavity formed by three aromatic
rings. As shown in Fig. 2, the chemical shifts of cone-7 are
different in the absence or presence of n-butylammonium
ion. After adding an equivalent of n-BuNH3Cl to a solution
of cone-7 (5 × 10–3 (mol/L)–1) in CDCl3 at 27 °C, methylene
protons of ArCH2OCH2Ar and Ar′OCH2CONHCH2CON-
HC6H4CH3 were dramatically shifted to a lower magnetic
field, indicating that the binding mode is occurring through
© 2006 NRC Canada

Yamato et al.
61
Fig. 2. Chemical shift changes (∆δ) of cone-5 and cone-7 (5 ×
10–3 mol/L) induced in the presence of n-BuNH3Cl (5 ×
10–3 mol/L) in CDCl3 at 27 °C. A plus sign (+) denotes a shift
to lower magnetic field, whereas a minus sign (–) denotes a shift
to higher magnetic field.
Table 1. Association constants (Ka, (mol/L)–1) and free energies
of association (∆G, kJ mol–1) of hosts cone-3, cone-5, and cone-
7 with halide anions.
Cl–
Br–
Hosts
Ka
–∆G°
Ka
–∆G°
-0.06
Me
cone-3
cone-5
cone-7
8520 510
1060 60
536 32
22.6
17.4
15.7
1731 122
220 16
230 17
18.6
13.4
13.6
-0.10
-0.08
+0.05
OMe
C O
NHb +0.30
Note: In CDCl3 at 27 °C; host concentration was 5 mmol/L.
C O
CH2 -0.05
-0.04
the π cavity, the conformation was changed and intramole-
cular hydrogen bonding was broken. Thus, the complexation
of the anionic guest Cl– through hydrogen bonding is possi-
ble (16). Upon the addition of n-Bu4NI and PhMe3NCl to a
solution of cone-7 in CDCl3 (5 × 10–3 (mol/L)–1), no
complexation of halide anions was observed. This is due to
the strong intramolecular hydrogen bonding, which breaks
the anion binding site.
CH2
+1.11
NH
NHa
-0.09
C O
C O
CH2 +0.86
+0.80
CH2
O
+0.69
+0.63
O
CH2
CH2
CH2
-0.08
CH2
+0.03
O
O
Based on this observation, we investigated the complex-
ation of cone-7 with n-butylammonium halide counterions.
With the addition of ammonium halide counterions, the pro-
ton peaks in cone-7 were separated into complex and
uncomplex. The downfield shift of NHb might be attributed
to the presence of the anionic guest close to the NHb group
by the intramolecular hydrogen bonding. The chloride anion
induces a larger downfield shift for the amide hydrogen of
cone-7 than the bromide anion does. For example, signifi-
cant downfield shifts of ∆δ = +0.60 ppm for the NHb proton
in the case of Cl– and ∆δ = +0.40 ppm in the case of Br–
were observed. As the electronegativity of the halogen atom
decreased with the series of Cl, Br, and I atoms, the intensity
of hydrogen bonding formed between their anions and NH
protons should be decreased following the same order. In
+0.26
+0.07
+0.28
+0.12
3
3
cone-5
cone-7
the π cavity formed by the three aromatic rings. This bind-
ing is attributed to the π effect of aromatic rings on the C-H
protons of the alkyl group because both the host and guest
molecules have a C3-symmetric conformation. With an ex-
cess of n-BuNH3Cl, the free guest molecule and the encap-
1
sulated guest molecule were clearly observed by H NMR
spectroscopy in which the encapsulated one was shifted up-
field: CH3 (δ 0.95–0.26 ppm, ∆δ = –0.69 ppm), CH3CH2 (δ
1.45–0.30 ppm, ∆δ = –1.05 ppm), CH3CH2CH2 (δ 1.77 to
−0.25 ppm, ∆δ = –2.02 ppm), and CH2N (δ 3.00–0.30 ppm,
∆δ = –2.70 ppm). The NHb proton in cone-7 was shifted to a
lower magnetic field (δ 9.21–9.51 ppm, ∆δ = +0.30 ppm)
while NHa was shifted to an upper field (δ 8.45–8.36 ppm,
∆δ = –0.09 ppm). This observation indicates that the
complexation of the anionic guest Cl– occurred at the p-
methylphenyl amide moiety but not at the glycine amide
moiety. This is different from the observation that NH of the
glycine amide in cone-5 was shifted strongly to a lower
magnetic field (δ 8.03–9.14 ppm, ∆δ = +1.11 ppm).
1
fact, in H NMR spectrum of a mixture of cone-7 and n-
+
BuNH3 X–, a larger downfield chemical shift in the complex
of NHb with Cl– was observed as compared with Br– and I–.
The association constants calculated from these changes in
chemical shifts of the amide protons are Ka = 536
32 (mol/L)–1 (∆G° = 15.7 kJ mol–1) for Cl– and Ka = 230
17 (mol/L)–1 (–∆G° = 13.6 kJ mol–1) for Br–. The smaller Ka
values for the halide anions than for those of cone-3 and
cone-5 might be attributable to the reduced electrostatic at-
tractive interaction between n-butylammonium ion and the
halide anions arising from the longer distance (Table 1).
Similar to triamide cone-3, hexaamide cone-7 shows a
preference for Cl– over Br– complexation (Fig. 3). This find-
ing suggests that the cavity formed by the threefold amide
moieties is more complementary to the size of the Cl– than
to that of Br–, as well as the higher electronegativity of Cl–
than that of Br–. In the case of tri(urea)-functionalized
calix[6]arene, the anion complexation is prefered for Br– be-
cause it has a large calix cavity and the three functionalized
moieties in the 1, 3, and 5 positions of calix[6]arene are
more complementary to the size of Br– than to that of Cl–
(16b). Calix[5]arene derivatives were reported to complex
with alkylammonium ions and to display an enzymelike se-
lectivity (17) towards biologically important ammonium
substrates. Since hexahomotrioxacalix[3]arenes and their de-
As mentioned above, ∆δ between Hax and Heq of the
ArCH2Ar methylene protons in calix[4]arene serves as a
measure of the “flattening”. The ∆δ value increases from
+
0.37 to 0.92 ppm in cone-7 upon the binding of n-BuNH3 .
These findings imply that cone-7 stands up when the guest is
+
included because n-BuNH3 enters into the π cavity formed
by the three aromatic rings and Cl– complexes with NHb by
hydrogen-bonding interaction. Similar findings were ob-
served in the case of cone-5 and n-BuNH3Cl (the ∆δ value
increases from 0.40 to 1.15 ppm).
Intramolecular hydrogen bonding in cone-7 weakens the
affinity of cone-7 to metal ions, which were encapsulated
through the lower rim of the homotrioxacalix[3]arene deriva-
+
tive. When cone-7 was complexed with n-BuNH3 through
© 2006 NRC Canada

62
Can. J. Chem. Vol. 84, 2006
Fig. 3. Dependence of halide anion on chemical shift values of
proton NHb in cone-7.
Materials
cone-Hexahomotrioxacalix[3]arene triacetic acid (cone-2b)
and (4-tert-butyl-2,6-dimethyl)phenoxyacetic acid (8) were
prepared according to the previously reported procedures
(2d, 12a, 12b).
Preparation of cone-7,15,23-tri-tert-butyl-25,26,27-
tris[(methoxyacetylaminocarbonyl)methoxy]-2,3,10,11,
18,19-hexahomo-3,11,19-trioxacalix[3]arene (cone-5)
To
a
solution of cone-hexahomotrioxacalix[3]arene
triacetic acid (cone-2b) (400 mg, 0.532 mmol) and glycine
methyl ester (4a) (427 mg, 4.80 mmol) in CH2Cl2 (30 mL)
was added 1-hydroxybenzotriazole (HOBt) (94 mg,
0.697 mmol). To the mixture was added a solution of
dicyclohexylcarbodiimide (DCC) (684 mg) in CH2Cl2
(10 mL) dropwise at 0 °C. Then the solution was stirred for
15 h at room temperature. After reaction, the solvent was re-
moved; then the residue was dissolved with AcOEt and fil-
tered; the filtrate was washed with 10% citric acid, water,
5% sodium bicarbonate, water, and brine, dried with
Na2SO4, and condensed under reduced pressure. The residue
was chromatographed over silica gel (Wako, C-300; 100 g)
with AcOEt as the eluent to give a colorless solid. The solid
was recrystallized from methanol to give cone-5 (365 mg,
[X–] / [cone-7] (mol)
rivatives have the C3-symmetric conformation, they can bind
with primary ammonium ions, having a potential function
not only in chemical but also in biological systems (3).
70.5%) as colorless prisms, mp 90–92 °C. IR (KBr) νmax
:
1
3350, 2958, 2871, 1752, 1678, 1540, 1484, 1200, 1076. H
NMR (CDCl3) δ: 1.13 (27H, s, t-Bu), 3.78 (9H, s, CH3),
4.15 (6H, d, J = 5.86 Hz, N-CH2), 4.38 (6H, d, J = 12.7 Hz,
ArCH2O), 4.78 (6H, d, J = 12.7 Hz, ArCH2O), 4.23 (6H, s,
ArOCH2), 6.95 (6H, s, Ar-H), 8.03 (3H, s, NH). m/z: 964
([M]+). Anal. calcd. for C51H69O15N3 (964.12): C 63.54, H
7.21, N 4.36; found: C 63.75, H 7.35, N 4.26.
Conclusions
We have demonstrated that the relationship between the
properties of ionophore hosts and their intramolecular hy-
drogen bonding was taken into account in C3-symmetric
conformation. Owing to the intramolecular hydrogen bond-
ing, the affinities of ionophore cone-7 to metal ions were
weakened; cone-7 does not bind alkali metal ions because
the binding site was blocked. However, hexaamide cone-7
can bind n-butylammonium ion through the π cavity formed
by three aryl rings, which can provide functional moieties in
biological systems with good affinity and high selectivity.
Interestingly, hexaamide cone-7 binds a halide through the
intermolecular hydrogen bonding among the NHb hydrogens
of p-methyphenyl amide in a 1:1 fashion in CDCl3 in spite
of the reduced electrostatic attractive interaction between n-
butylammonium ions and the halide anions arising from the
longer distance. Thus, hexaamide cone-7 serves as a hetero-
Preparation of cone-7,15,23-tri-tert-butyl-25,26,27-
tris[(hydroxyacetylaminocarbonyl)methoxy]-2,3,10,
11,18,19-hexahomo-3,11,19-trioxacalix[3]arene (cone-6)
To a mixture of cone-5 (225 mg, 0.23 mmol) in dioxane
(35 mL) was added an aqueous 1 mol/L NaOH solution
(25 mL), the mixture was stirred at room temperature for
1 h, then the solvent was removed under reduced pressure.
The residue was acidified to neutral pH. The dispersion was
extracted with ethyl acetate (30 mL × 2). The combined ex-
tracts were washed with 10% citric acid (20 mL × 2), 5% so-
dium bicarbonate (20 mL), water (20 mL), and saturated
brine (20 mL), dried with Na2SO4, and condensed under re-
duced pressure. The residue was washed with hexane to give
cone-6 (170 mg, 79%) as a colorless solid, mp 215–217 °C.
IR (KBr) νmax: 3500–3250, 2958, 2867, 1736, 1661, 1540,
1457, 1363, 1231, 1197, 1093. 1H NMR (CDCl3–
MeOH[D4], 3:1 v/v) δ: 1.13 (27H, s, t-Bu), 4.13 (6H, s,
ArOCH2), 4.20 (6H, d, J = 5.86 Hz, N-CH2), 4.42 (6H, d,
J = 12.7 Hz, ArCH2O), 4.80 (6H, d, J = 12.7 Hz, ArCH2O),
6.97 (6H, s, Ar-H), 8.18 (3H, t, J = 5.86 Hz, NH). m/z: 922
([M]+). Anal. calcd. for C48H63O15N3 (922.05): C 62.53, H
6.89, N 4.56; found: C 62.72, H 6.73, N 4.40.
+
ditopic receptor that can complex with Cl– and n-BuNH3 at
the same time. These results give some insight into the mo-
lecular design of new synthetic receptors for use in anion-
controlled biomimetic systems.
Experimental
All melting points (Yanagimoto MP-S1) were uncor-
rected. H NMR spectra were recorded on a Nippon Denshi
1
JEOL FT-270 spectrometer. Chemical shifts are reported as δ
values (ppm) relative to internal Me4Si. Mass spectra were
obtained on a Nippon Denshi JMS-01SG-2 mass spectrome-
ter at an ionization energy of 70 eV using a direct inlet sys-
tem through GLC; m/z values reported include the parent ion
peak. IR spectra were obtained on a Nippon Denshi JIR-
AQ2OM spectrophotometer as KBr disks. Elemental analy-
ses were performed using a Yanaco MT-5. UV spectra were
measured by a Hitachi 220A spectrophotometer.
Preparation of the hexaamide derivative of homo-
oxacalix[3]arene (cone-7)
To a solution of cone triacid homocalix[3]arene (cone-6)
(491 mg, 0.532 mmol) and p-toluidine (4b) (514 mg,
4.80 mmol) in CH2Cl2 (30 mL) was added HOBt (94 mg,
© 2006 NRC Canada

Yamato et al.
63
Scheme 2. Reagents and conditions: (i) H2NCH2COOMe (4a),
DCC–HOBt, CH2Cl2, room temp. for 15 h; (ii) Dioxane–
NaOH(aq), room temp. for 1 h; (iii) p-toluidine (4b), DCC–
HOBt, CH2Cl2, room temp. for 15 h.
0.697 mmol). To the mixture was added a solution of DCC
(684 mg) in CH2Cl2 (10 mL) dropwise at 0 °C. Then the so-
lution was stirred for 15 h at room temperature. After reac-
tion, the solvent was removed; then the residue was
dissolved with AcOEt and filtered; the filtrate was washed
with 10% citric acid, water, 5% sodium bicarbonate, water,
and brine, dried with Na2SO4, and condensed under reduced
pressure. The residue was chromatographed over silica gel
(Wako, C-300; 100 g) with AcOEt as the eluent to give a
colorless solid. The solid was recrystallized from methanol
to give cone-7 (538 mg, 85%) as colorless prisms, mp 147–
149 °C. IR (KBr) νmax: 3476, 3410, 3312, 2958, 2867, 1664,
OCH2CONHaR
Me
OCH2COOH
Me
Me
Me
i
9
8
1
a; R = CH2COOMe (66%)
b; R = CH2COOH (59%)
c; R = CH2CONHb
1609, 1541, 1516, 1482, 1197, 818. H NMR (CDCl3) δ:
ii
1.11 (27H, s, t-Bu), 2.29 (9H, s, Ar′-CH3), 4.09 (6H, s,
ArOCH2), 4.20 (6H, d, J = 5.86 Hz, N-CH2), 4.34 (6H, d,
J = 12.7 Hz, ArCH2O), 4.79 (6H, d, J = 12.7 Hz, ArCH2O),
6.95 (6H, s, Ar-H), 7.08 (6H, d, J = 8.8 Hz, Ar′-Ha), 7.43
(6H, d, J = 8.8 Hz, Ar′-Hb), 8.45 (3H, t, J = 5.86 Hz, NHa),
9.21 (3H, s, NHb); (DMSO-d6) δ: 1.23 (27H, s, t-Bu), 2.23
(9H, s, Ar′-CH3), 4.01 (6H, d, J = 5.86 Hz, N-CH2), 4.19
(6H, s, ArOCH2), 4.47 (6H, d, J = 12.7 Hz, ArCH2O), 4.77
(6H, d, J = 12.7 Hz, ArCH2O), 6.94 (6H, s, Ar-H), 7.06 (6H,
d, J = 8.8 Hz, Ar′-Ha), 7.39 (6H, d, J = 8.8 Hz, Ar′-Hb),
8.25 (3H, t, J = 5.86 Hz, NHa), 9.91 (3H, s, NHb). 13C NMR
(CDCl3) δ: 20.89, 31.44, 34.28, 43.98, 70.28, 73.26, 120.20,
127.79, 129.52, 129.52, 131.05, 134.18, 135.16, 147.39,
153.51, 167.74, 170.99. m/z: 1189 ([M]+). Anal. calcd. for
C69H84O12N6 (1189.47): C 69.68, H 7.12, N 7.07; found: C
69.51, H 7.23, N 7.14.
iii
(61%)
Me
bined extracts were washed orderly with water (20 mL) and
saturated brine (20 mL), dried with Na2SO4, and condensed
under reduced pressure. The residue was washed with hex-
ane to give 9b (Scheme 2) (81 mg, 59%) as a colorless solid,
mp 193–195 °C. IR (KBr) νmax: 3383, 2963, 2925, 2867,
1730, 1635, 1540, 1436, 1245, 1229, 1124. 1H NMR
(CDCl3) δ: 1.29 (9H, s, t-Bu), 2.27 (6H, s, CH3), 3.10 (1H,
broad, COOH), 4.25 (2H, d, J = 5.37 Hz, N-CH2), 4.35
(2H, s, ArOCH2), 7.03 (2H, s, Ar-H), 7.46 (1H, t, J =
5.37 Hz, NH). m/z: 293 ([M]+). Anal. calcd. for C16H23O4N
(293.37): C 65.51, H 7.9, N 4.77; found: C 65.63, H 7.87, N
4.64.
Preparation of 4-tert-butyl-2,6-dimethyl[(methoxyacetyl-
aminocarbonyl)methoxy]benzene (9a)
To a solution of (4-tert-butyl-2,6-dimethyl)phenoxyacetic
acid (8) (100 mg, 0.43 mmol), glycine methyl ester (4a)
(114 mg, 1.28 mmol), and HOBt (75 mg, 0.17 mmol) in
CH2Cl2 (12 mL) was added a solution of DCC (560 mg) in
CH2Cl2 (5 mL) dropwise at 0 °C. After the mixture was
stirred for 7 h at room temperature, it was condensed under
reduced pressure. The residue was extracted with ethyl ace-
tate (30 mL × 2). The combined extracts were washed with
10% citric acid (20 mL × 2), 5% sodium bicarbonate
(20 mL), water (20 mL), and saturated brine (20 mL), dried
with Na2SO4, and condensed under reduced pressure. The
residue was recrystallized from methanol to give the title
compound 9a (Scheme 2) (87 mg, 66%) as colorless prisms,
mp 101 to 102 °C. IR (KBr) νmax: 3337, 3320, 2968, 2865,
Preparation of 4-tert-butyl-2,6-dimethyl[(4-
methylphenylaminocarbonyl)methoxy]benzene (9c)
To a solution of 9b (50 mg, 0.17 mmol), p-toluidine (4b)
(55 mg, 0.51 mmol), and HOBt (23 mg, 0.17 mmol) in
CH2Cl2 (12 mL) was added a solution of DCC (171 mg) in
CH2Cl2 (5 mL) dropwise at 0 °C. After the mixture was
stirred for 15 h at room temperature, it was condensed under
reduced pressure. The residue was extracted with ethyl ace-
tate (30 mL × 2). The combined extracts were washed with
10% citric acid (20 cm3 × 2), 5% sodium bicarbonate
(20 mL), water (20 mL), and saturated brine (20 mL), dried
with Na2SO4, and condensed under reduced pressure. The
residue was recrystallized from hexane–CH2Cl2 (3:1) to give
9c (Scheme 3) (83 mg, 61.2%) as colorless prisms, mp 233
to 234 °C. IR (KBr) νmax: 3383, 3320, 3289, 2962, 2948,
1
1755, 1734, 1667, 1534, 1488, 1277, 1197, 1182, 1056. H
1
NMR (CDCl3) δ: 1.29 (9H, s, t-Bu), 2.27 (6H, s, CH3), 3.80
(3H, s, OCH3), 4.20 (2H, d, J = 5.37 Hz, N-CH2), 4.33
(2H, s, ArOCH2), 7.03 (2H, s, Ar-H), 7.46 (1H, t, J = 5.37 Hz,
NH). m/z: 307 ([M]+). Anal. calcd. for C17H25O4N (307.39):
C 66.43, H 8.2, N 4.56; found: C 66.23, H 8.35, N 4.68.
2851, 1699, 1609, 1526, 1312, 1195. H NMR (CDCl3) δ:
1.29 (9H, s, t-Bu), 2.27 (6H, s, CH3), 2.31 (3H, s, ArCH3),
4.25 (2H, d, J = 5.37 Hz, N-CH2), 4.36 (2H, s, ArOCH2),
7.02 (2H, s, Ar-H), 7.13, 7.42 (each 2H, d, J = 8.8 Hz, Ar-
Ha, Ar-Hb), 7.76 (1H, t, J = 5.37 Hz, NHa), 8.36 (1H, s,
NHb). m/z: 382 ([M]+). Anal. calcd. for C23H30O3N2
(382.51): C 72.22, H 7.91, N 7.32; found: C 72.45, H 7.73,
N 7.48.
Preparation of 4-tert-butyl-2,6-dimethyl[(hydroxyacetyl-
aminocarbonyl)methoxy]benzene (9b)
To a solution of 9a (150 mg) in dioxane (30 mL) was
added an aqueous 1 mol/L NaOH solution (30 mL) at room
temperature. After the mixture was stirred at room tempera-
ture for 1 h, it was condensed under reduced pressure. The
residue was then acidified to neutral condition. The precipi-
tate was extracted with ethyl acetate (30 mL × 2). The com-
Picrate extraction measurements
Alkali metal picrates (2.5 × 10–4 mol/L) were prepared in
situ by dissolving 0.1 mol/L of alkali metal hydroxide in
2.5 × 10–4 mol/L of picric acid; triply distilled water was
used for all aqueous solutions. Similarly, metallic picrates
© 2006 NRC Canada

64
Can. J. Chem. Vol. 84, 2006
5. A. Arduini, M. Fabbi, M. Mantovani, L. Mirone, A. Pochini,
A. Secchi, and R. Ungaro. J. Org. Chem. 60, 1454 (1995).
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were prepared in situ by dissolving 0.1 mol/L of metallic ni-
trate (AgNO3, Cu(NO3)2·3H2O, Al(NO3)3·9H2O) in 2.5 ×
10–4 mol/L of picric acid. Alkyl ammonium picrates were
prepared by mixing an equimolar amount of alkylamine and
picric acid in methanol.
Two-phase solvent extraction was carried out between wa-
ter (5 mL, [alkali picrate] = 2.5 × 10–4 mol/L) and CH2Cl2
(5 mL, [ionophore] = 2.5 × 10–4 mol/L). The two-phase mix-
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confirmed that this period is sufficient to attain the distribu-
tion equilibrium. This was repeated 3 times, and the solu-
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1
The measurements were performed by H NMR titration
experiments in
a varying guest concentration of 0–
50 mmol/L and a constant concentration of host receptors
(5 mmol/L). As a probe, the chemical shift of the amide pro-
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values were calculated by the integral intensity of NH pro-
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© 2006 NRC Canada