Heteroditopic receptors tris(2-pyridylamide) derivatives derived from hexahomotrioxacalix[3]arene triacetic acid

Article abstract of DOI:10.1007/s10847-010-9863-8

The lower rim functionalized cone-hexahomotrioxacalix[3]arene tris(2-pyridylamide) derivatives cone- 3 and cone-7 having the hydrogen bonding groups and 2-pyridyl groups were synthesized from triol 1 by a stepwise reaction. Extraction data for alkali meta

Full text of DOI:10.1007/s10847-010-9863-8

J Incl Phenom Macrocycl Chem (2011) 70:69–80
DOI 10.1007/s10847-010-9863-8
ORIGINAL ARTICLE
Heteroditopic receptors tris(2-pyridylamide) derivatives derived
from hexahomotrioxacalix[3]arene triacetic acid
•
Masashi Takimoto Xin-Long Ni Shofuir Rahman
•
•
•
Zeng Xi Takehiko Yamato
Received: 29 August 2009 / Accepted: 9 September 2010 / Published online: 26 September 2010
Ó Springer Science+Business Media B.V. 2010
Abstract The lower rim functionalized cone-hexahomo-
trioxacalix[3]arene tris(2-pyridylamide) derivatives cone-3
and cone-7 having the hydrogen bonding groups and 2-
pyridyl groups were synthesized from triol 1 by a stepwise
reaction. Extraction data for alkali metal ions, transition
metal ions, and alkyl ammonium ions from water into
dichloromethane are discussed. Due to the strong intra-
molecular hydrogen bonding between the neighboring NH
and CO groups, their affinities to metal cations were
weakened. The complexation modes of cone-3 and cone-7
with n-BuNH3Cl and AgSO3CF3 were also demonstrated
by 1H NMR titration in CDCl3. Tris(2-pyridylamide)
derivatives cone-3 and cone-7 can complex with n-butyl
ammonium ion and silver cation at the same time to form
the heteroditopic complexation.
ionophoric receptors and potential enzyme mimics in
biology. Chemical modification of calixarene represents a
simple though effective and versatile way of producing
receptors with high selective cation binding properties
[1–4]. Shinkai and co-workers have reported the com-
plexation of alkali metals to hexahomotrioxacalix[3]arene
derivatives with alkylated phenolic oxygens [5–10]. Hexa-
homotrioxacalix[3]arene derivatives with C3-symmetry can
selectively bind ammonium ions which play important roles
in both chemistry and biology [11, 12]. Thus, Shinkai et al.
reported the construction of C3-symmmetry pyrene func-
tionalized hexahomotrioxacalix[3]arenes, which selectively
recognize primary ammonium ions [6].
On the other hand, hydrogen bond plays an important
role in the self-assembly of molecular recognition and has
been aroused investigation 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 moi-
eties was reported [13]. Arduini et al. also described the
formation of a hydrogen-bonded dimer in CDCl3 based on
the self-complementarity of carboxylic acid [14]. The
intramolecular hydrogen-bonding was also formed among
opposing urea groups, which can bind anionic species, in
calix[4]arene [15–17]. Thus, the design of new ditopic
ligands [18] for the simultaneous complexation of anionic
and cationic guest species is a new exciting area of
coordination chemistry of significant relevance to the
selective extraction and/or transportation of metal salts
across lipophilic membranes. Rare examples of receptors
containing appropriate covalently linked binding sites for
anions and cations include Lewis-acidic boron [19], uranyl
[20], polyammonium [21] centers combined with crown
ether moieties and crown ether or urea functionalized
calix[4]arene ionophores [15, 22] which are capable of
Keywords Macrocycles ꢀ Hexahomotrioxacalix[3]arenes
ꢀ Ionophores ꢀ Molecular recognition ꢀ Ammonium ion ꢀ
Ditopic receptors
Introduction
Calixarene and related macrocycles have received consid-
erable attention for their host–guest chemistry as
M. Takimoto ꢀ X.-L. Ni ꢀ S. Rahman ꢀ T. Yamato (&)
Department of Applied Chemistry, Faculty of Science and
Engineering, Saga University, Honjo-machi 1, Saga-shi, Saga
840-8502, Japan
e-mail: yamatot@cc.saga-u.ac.jp
Z. Xi
Key Laboratory of Macrocyclic and Supramolecular Chemistry
of Guizhou Province, Guizhou University, Guiyang 550025,
Guizhou, China
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J Incl Phenom Macrocycl Chem (2011) 70:69–80
solubilizing alkali metal salts into organic media
(Chart 1).
Results and discussion
Incorporating these two types of recognition sites by
introduction of three amide groups on the phenolic oxygens
of homotrioxacalix[3]arene will create potential heterodi-
topic receptors capable of binding cations and anions,
especially ammonium ions and halides. On the other hand,
we have reported the synthesis, conformational studies
and inclusion properties of tris[(2-pyridylaminocarbon-
yl)methoxy]hexahomotrioxacalix[3]arene cone-3 derived
from hexahomotrioxacalix[3]arene 1 [23–26], which show
strong Ag? ion affinity. Therefore, 2-pyridylamide deriv-
atives having the hydrogen-binding groups might show
interesting complexation behavior for Ag? as well as
anions and ammonium ions.
cone-Hexahomotrioxacalix[3]arene tricarboxylic acid
cone-2b was prepared by hydrolysis of cone-[(N,N-dieth-
ylaminocarbonyl)methoxy]hexahomotrioxacalix[3]arene
cone-2a with KOH aq. in a mixture of dioxane and water,
which was prepared by O-alkylation of 1 with N,N-dieth-
ylchloroacetoamide in the presence of NaH according to
the reported procedures [6, 23]. cone-Hexahomotrioxaca-
lix[3]arene triamide cone-5 was prepared by condensation
reaction of cone-2b with glycine methyl easter (4a) in the
presence of DCC (dicyclohexylcarbodiimide) and HOBt
(1-hydroxybenzotriazole) at room temperature for 15 h in
CH2Cl2. cone-5 was converted to triacid cone-6 by
hydrolysis with NaOH aq. in the mixture of dioxane and
water at room temperature. cone-6 was reacted again with
2-aminopyridine (4b) in the presence of DCC and HOBt
similar to that of cone-5 to afford the desired compound
Hexahomooxacalix[3]arene is flexible compared to
calix[4]arene due to its ethereal linkages, and has a C3-
symmetrical structure which is expected to be particularly
useful in receptors of primary ammonium cations. Modified
homooxacalix[3]arene with functional groups will have the
potential as a flexible ditopic receptor. Thus, the introduction
of multiple binding sites of cations and anions is important
for the construction of the allosteric host–guest inclusion
systems. Having the pyridyl groups on its alkylated moieties,
compounds can complex with n-BuNH3? and silver cation,
respectively. Thus, the potential of them as the ditopic
receptor to complex with n-BuNH3? and silver cation will be
great interesting in the coordination chemistry.
cone-hexahomotrioxacalix[3]arene tris(2-pyridylamide)
derivative cone-7 in 85% yield (Scheme 1).
From the singlet peaks for cone-7, the conformation was
remained in the desired compound with cone-conforma-
tion. In order to investigate the conformation of cone-7 in
detail, a reference compound 9c was synthesized from 4-
tert-butyl-2,6-dimethylphenoxyacetic acid 8 following the
similar method in the preparation of cone-7 (Scheme 2).
Conformation assignment for the new cone-hexahomo-
trioxacalix[3]arene tris(2-pyridylamide) derivative cone-7
is firmly established by the presence of AB quartets for the
bridging methylene protons with a Dd separation between
Hax and Heq of d 0.55 ppm in its 1H NMR spectrum
(CDCl3). In the calix[4]arenes, the Dd values of the
ArCH2Ar protons have been correlated to the orientation of
adjacent aromatic rings, i.e. Dd [ 1 ppm with cone con-
formation or syn orientation, Dd of about 0.5 with flattened
cone or out orientation, Dd of 0 ppm with 1,3-alternate or
anti orientation [27]. The same findings were observed in
hexahomotrioxacalix[3]arenes [5]. Thus, we can deduce
that cone-7 prefers a flattened cone conformation, in which
hydrogen bonding can form. The intramolecular hydrogen
bond was formed between neighboring NH and C=O
groups which induced a large downfield shift for NHa
proton (d 8.45 ppm, Dd = ?0.69 ppm) and NHb proton
(d 9.21 ppm, Dd = ?0.85 ppm) in cone-7 compared to
compound 9c (NHa proton, d 7.76 ppm; NHb proton, d
8.36 ppm). When the concentration of cone-7 in CDCl3
was diluted about 40 times, there is no change of the
chemical shifts in both NHa and NHb protons, which was
attributed to the concentration-independent intramolecular
hydrogen bonding formed in this compound. Interestingly,
the chemical shift of the NHb protons in cone-7 was shifted
to lower field to d 9.91 ppm in DMSO-d6 than that in
CDCl3 (d 9.21 ppm, Dd = ?0.70 ppm). This phenomenon
In the present paper, we describe the synthesis, confor-
mations, and metal and ammonium ion complexation
properties of the cone tris(2-pyridylamide) derivatives
cone-3 and cone-7 having the hydrogen-binding groups
derived from hexahomotrioxacalix[3]arene tricarboxylic
acid, which are supposed to have C3-symmetric ionophoric
cavities.
7
O
23
27
25OR
O
OR
OR
O
OR
RO
OR
26
15
1; R= H
cone-2a; R= CH2CONEt2
cone-2b; R= CH2COOH
cone-3; R= CH2CONH
N
Chart 1 Synthesis of tris[(2-pyridylaminocarbonyl)methoxy]hexa-
homotrioxacalix[3]arene cone-3
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J Incl Phenom Macrocycl Chem (2011) 70:69–80
71
Scheme 1 Synthesis of cone-
hexahomotrioxacalix[3]arene
tris(2-pyridylamide) derivative
cone-7
OMe
C O
CH2
NH
C O
CH2
O
H2NCH2COOMe (4a)
DCC/HOBt, CH2Cl2
Dioxane/ NaOHaq.
CH2
CH2
cone-2b
O
room temp. for 1 h
(79%)
room temp. for 15 h
(71%)
3
cone-5
N
OH
NHb
C O
CH2
NHa
C O
C O
CH2
NH
C O
CH2
O
CH2
O
2-aminopyridine (4b)
DCC/HOBt, CH2Cl2
CH2
CH2
CH2
CH2
O
O
room temp. for 15 h
(85%)
3
3
cone-7
cone-6
OCH2COOH
Me
OCH2CONHaR
[28, 29]. We have deduced that compounds cone-5–cone-7
prefer to the flatten-cone conformation for the intramolec-
ular hydrogen bonding in CDCl3. The difference of chem-
ical shift between the proton Hax and Heq in the bridge
methylene in compounds cone-5–cone-7 was smaller in
DMSO-d6 (from d 0.2 to 0.4 ppm) than that in CDCl3 (from
d 0.4 to 0.6 ppm). The ethereal linkage in homooxaca-
lix[3]arene is more flexible than the methylene group in
calix[4]arene, when the NH proton was solvated by solvent
in DMSO-d6, the wobbling intensity of the calix benzene
ring becomes much stronger than that in CDCl3, and make
the conformation more flatten. The CPK model was also
proven that compounds cone-5–cone-7 prefer to the flatten-
cone conformation in order to reduce the steric energy.
The alkyloxy calixarene can bind cations, neutral mol-
ecules or anions to form complexes, which had been
investigated by several groups through different types of
calixarenes [1–4, 30, 31]. The two phase solvent extraction
is an efficient and available method to investigate the host
molecules bind metal cations [5–12]. Extraction studies
were conducted by the standard two phase procedure
whereby dilute solutions of each calixarene derivatives in
dichloromethane were shaken with neutral aqueous metal
Me
Me
Me
i
9
8
a; R = CH2COOMe
b; R = CH2COOH
c; R = CH2CONHb
(66%)
ii
(95%)
iii
(89%)
N
Reagents and conditions: i) H2NCH2COOMe (4a), DCC/HOBt, CH2Cl2,
room temp. for 15 h; ii) Dioxane/NaOHaq, room temp. for 1 h; iii)
2-aminopyridine (4b), DCC/HOBt, CH2Cl2, room temp. for 15 h.
Scheme 2 Synthesis of reference compound 9c
was attributed to the intermolecular hydrogen bonding
formed between the NHb proton and solvent DMSO-d6.
The intramolecular hydrogen bonding formed in compound
cone-7 was broken and the new intermolecular hydrogen
bonding was formed.
In the calix[n]arene series, the (d values of the ArCH2Ar
protons have been correlated to the orientation of adjacent
aromatic rings and it is applicable to homooxacalix[3]arene
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Table 1 Extraction (%) of metal and ammonium picrates in CH2Cl2
Na?
K?
Ag?
Cu2?
Al3?
n-BuNH3
i-BuNH3
t-BuNH3
?
?
?
Ionophore
cone-3
cone-7
cone-5
cone-2a
0
0
76.9
53.3
0
16.6
8.9
0
11.5
14.7
0
38.1
13.2
9.2
1.9
1.2
0.8
1.2
0
0
0
0
\0
48.1
\0
35.4
93.0
71.6
90.4
27.5
19.2
97.8
Extraction (%) of metal and ammonium picrates by ionophores in CH2Cl2. Extraction conditions; 2.5 9 10-4 M of ionophore in CH2Cl2;
2.5 9 10-4 M of picric acid in 0.1 M of alkali hydroxide or metallic nitrate at 25 °C. Ionophore solution (5.0 mL) was shaken for 24 h with
picrate solution (5.0 mL) and % extraction was measured by the absorbance of picrate in CH2Cl2. Experimental error was 2%
picrate solutions, following which the equilibrium distri-
bution of the picrate was measured spectrophotometrically.
Interestingly, tris(2-pyridylamide) derivatives cone-3
and cone-7 show low efficiency for alkali metal ions and
alkyl ammonium ions compared to N,N-diethylamide
derivative cone-2a [8, 23, 24]. The ionophoric activity of
compound cone-5 was almost absent, but cone-5 shows a
single affinity to n-butyl ammonium ion. The ionophores
usually form a loose ion pairs with metal picrates, which
produced the maximum absorption peak at 377 nm [32–
34]. As to Cu2? and Al3?, they form a contact ion pairs
with cone-3 and cone-7, which showed the maximum
absorption peak at 365 nm. Interestingly, the tris(2-pyri-
dylamide) derivative cone-7 also forms a contact ion pair
1:1 and a 2:1 metal complexation of cone-7 might be
possible.
As shown in Fig. 1, the percent extractions reach max-
imum at 0.5 mol fraction for this cation. The fact clearly
indicates that Ag? forms 1:1 complex with cone-7. It was
also found that the corresponding cone-5 hardly extracted
Ag? cation in this experimental conditions (extraction %:
less than 1%). Thus, Ag? should be completely bound by
soft pyridine cavity of cone-7 and homotrioxacalix[3]arene
cavity does not participate in the complexation. In order to
explore the binding mode of three lower-rim side chains
having pyridyl groups, we examined the 1H NMR chemical
shift differences between those before and after the addi-
tion of an equimolar AgSO3CF3, and composition of the
ion–ionophore complex.
?
with n-BuNH3 and shows the maximum absorption peak
at 365 nm. In comparison with cone-7, N,N-diethylamide
derivative cone-2a has higher affinity to alkali metal ions,
Na?, K?, transition metal ions, Ag? and Cu2? and typical
metal ion Al3? [35–38]. Higher extractabilities of cone-
N,N-diethylamide derivative cone-2a for n-butyl (97.8%),
i-butyl (48.1%) and t-butyl ammonium ion (35.4%) are
also observed and are attributable to the higher electron
density of oxygen of carbonyl group by electron-donationg
ability of the amide group through conjugation N–
C=O $ N?=C–O- [8, 23, 24]. These findings clearly
indicate that due to the strong hydrogen bonding formation
between NH and neighboring CO groups in hexaamide
cone-7, it shows no affinity for alkali metal ions. In con-
trast, cone-3 and cone-7 has high affinity to transition metal
ions, Ag? and Cu2? and typical metal ion Al3?. These
findings clearly indicate that the lower-rim side chains
having pyridyl groups play a significant role on the com-
plexation with soft transition metal ions. Thus, the cations
might be encapsulated into the cavity formed by pyridine
rings (Table 1).
After titration with an equivalent of AgSO3CF3, the
protons in pyridine rings in cone-7 were shifted to lower
magnetic field except H3 shifted to upper field (Dd =
-0.20 ppm). This indicates that the nitrogen atoms turned
to inside the cavity and interact with Ag?, which makes
great downfield shift for H4, H5 and H6 induced by the
1
0.8
0.6
0.4
0.2
0
Shinkai et al. reported that the 1,3-alternate conformer
of calix[4]arene tetraester can form both a 1:1 and a 2:1
metal/calixarene complex and the two metal-binding sites
1
0
0.2
0.4
0.6
0.8
1
display negative allostericity by H NMR titration experi-
Mole fraction of [Guest] / ([Host]+[Guest])
[Host]+[Guest] = 1.5 10-4M
ment [39]. In the present system, due to the existence of
three metal-binding sites of pyridine moiety there are
several possibilities for metal complexation mode. Thus, a
Fig. 1 Job plots of the extractions of Ag? with host cone-7
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J Incl Phenom Macrocycl Chem (2011) 70:69–80
73
inductive effect arising for the N–Ag? interaction present
in this cavity. Almost no change was observed for other
protons in cone-7 after complexation. After complexation
with Ag?, cone-7 still remains the C3-symmetrical con-
formation and NHa proton is also shifted to lower field
(Dd = ?0.03 ppm) due to the increased intramolecular
hydrogen bonding formed with the neighboring C=O group
(Fig. 2).
pyridine rings. The pyridine rings rotated around the NHb–
C(pyridyl) linkage to make the coordination while little
conformation was changed for the whole structure.
The present ammonium ions binding mode can be also
demonstrated more clearly by using 1H NMR spectroscopy.
There are two modes for cone-7 to bind with n-butyl
ammonium ions, i.e. from the lower rim through substitu-
ents moieties or from the upper rim through the p-cavity
formed by three aromatic rings. The chemical shift dif-
ferences in the absence and presence of n-butyl ammonium
ion are shown in Fig. 3. After adding an equivalent of n-
BuNH3Cl to solution of cone-7 (5 9 10-3 M) in CDCl3 at
27 °C, protons on aromatic rings, ArCH2O, ArOCH2 were
dramatically shifted to lower magnetic field, which indicate
that the binding mode is occurred through the p-cavity
formed by three aromatic rings. This binding is attributed
to the p-effect of aromatic rings because both the host and
the guest molecules have a C3-symmetric conformation.
With excess of n-BuNH3Cl, the free guest molecules and
the encapsulated molecules were clearly observed by the
Similar phenomena were also observed in the case of
complex of cone-3 with Ag?. The protons in pyridyl rings
were shifted to lower magnetic field except H3 to upper
field (Dd: -0.01 ppm). Thus, silver cation was complex
with three pyridine groups through the N–Ag? interaction
and affected the pyridyl protons shifted to lower magnetic
field. In comparison with cone-7, the larger chemical shift
changes for other protons in cone-3 after complexation
were observed. For example, in the case of cone-3, the tert-
butyl proton and the calix benzene proton, located on the
upper rim of the structure, were changed very little with
?0.03 and -0.05 ppm, respectively.
1
Same protons in cone-7, having the longer distance
between pyridine rings and calix benzene rings, were only
?0.01 and -0.01 ppm. This is attributable to the longer
alkylated chain in cone-7 between the pyridyl moieties and
phenolic oxygens than that in cone-3. When complex was
formed by the pyridine rings and silver cation, the complex
position was located only into the cavity of N atom in
proton H NMR spectroscopy, in which the encapsulated
one was shifted to upfield, CH3 (0.95–0.26, Dd =
-0.69 ppm), CH3CH2 (1.45–0.30, Dd = -1.05 ppm),
CH3CH2CH2 (1.77 to -0.25, Dd = -2.02 ppm) and CH2N
(3.00–0.30, Dd = -2.70 ppm). The chemical shift of
NH protons in cone-7 was shifted to lower magnetic
field (d 8.32–9.07 ppm; Dd = ?0.75 ppm for NHa
Fig. 2 Chemical shift changes
of cone-3 and cone-7 induced in
the presence of AgSO3CF3; (?)
denotes the down-field and (-)
denotes the up-field shift
(300 MHz, CDCl3:CD3CN,
30:1 v/v, 27 °C)
+0.11
5
+0.03
+0.10
-0.20
6
4
3
N
+0.30
NHb
+0.27
5
C
O
+0.13
+0.37
-0.01
6
4
3
+0.16
+0.03
CH2
NHa
N
NH
C
+0.40
O
C
O
CH2
O
CH2
O
-0.08
+0.07
-0.07 (ax)
+0.03 (ax)
CH2
CH2
CH2
CH2
-0.08 (eq)
-0.01
O
O
-0.20 (eq)
-0.05
+0.03
+0.01
3
3
cone-3
cone-7
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J Incl Phenom Macrocycl Chem (2011) 70:69–80
Fig. 3 Chemical shift changes
of cone-3 and cone-7 induced in
the presence of n-BuNH3Cl; (?)
denotes the down-field and (-)
denotes the up-field shift
(300 MHz, CDCl3:CD3CN,
30:1 v/v, 27 °C)
-0.03
5
0.00
-0.01
-0.20
6
4
3
N
NHb
-0.02
5
+0.06
+0.02
6
C
O
-0.02
0.00
4
3
N
CH2 +0.01
NHa
+0.75
NH
C
+0.81
O
C
O
+0.74
CH2
O
CH2
+0.89
+0.19 (ax)
CH2
O
-0.05 (ax)
CH2
CH2
CH2
O
O
+0.71 (eq)
+0.27
+0.55 (eq)
+0.24
+0.08
+0.01
3
3
cone-7
cone-3
(d 9.41–9.47 ppm; Dd = ?0.06 ppm for NHb) while NH
in n-BuNH3Cl was shifted to upper field (d 8.30–5.93;
Dd = -2.37 ppm). As mentioned above, intramolecular
hydrogen bonding in cone-7 weakens the affinity of cone-7
to metal ions which were encapsulated through the lower
rim of homotrioxacalix[3]arene derivatives. When cone-7
Modified homooxacalix[3]arene with functional groups
will have the potential as a flexible ditopic receptor.
Compounds cone-3 and cone-7 have been proven to com-
plex with alkylammonium ion and silver cation simulta-
neously. Thus, the potential of them as the ditopic receptor
?
to complex with n-BuNH3 and silver cation will be great
interesting in the coordination chemistry.
?
was complexed with n-BuNH3 through p-cavity, the
conformation of cone-7 was changed and intramolecular
hydrogen bonding was impossible in this conformation. As
a result, the NHa proton in cone-7 was shifted to lower
magnetic field to indicate complexation of the anionic
guest Cl- through hydrogen bonging. Similar phenomena
were also observed in the case of complex of cone-3 with
n-BuNH3Cl. It was also found that addition of n-Bu4NI and
PhMe3NCl to a solution of cone-3 and cone-7 in CDCl3
(5 9 10-3 M), no complexation of halide anions was
observed. Due to the strong intramolecular hydrogen
bonding, the anion binding site is blocked.
Compounds cone-3 and cone-7 were determined with
1
silver cation and n-butyl ammonium ion through H NMR
titration to investigate the possibility as the ditopicrecep-
tors. At first, with adding two equivalents of silver cation,
the chemical shift of protons peaks was changed as
described above. The further investigation was continued
by adding two equivalent of n-butyl ammonium picrate to
the solution of compounds cone-3 and cone-7 in the pres-
ence of silver cation. The results were shown in Table 2.
The induced chemical shift to upper field of n-butyl
ammonium protons strongly suggested the complexation of
cone-7 . Ag? with n-butyl ammonium ion. Furthermore,
the conformation of the host was changed too. Both tert-
butyl protons and calix benzene protons were shifted to the
lower field under the complexation with n-butyl ammo-
nium ions. The chemical shift difference between the axial
proton and equatorial proton in bridge methylene was
increased upper to d 0.93 ppm under the presence of both
n-butyl ammonium ion and silver cation, which was mostly
contributed by the complexation with n-butyl ammonium
ion. Furthermore, the chemical shift of protons on pyridine
As mentioned previously, Dd between Hax and Heq of
the ArCH2Ar methylene protons in calix[4]arene serves as
a measure of the ‘flattening’. Dd increases from d 0.43 to d
?
1.17 ppm in cone-3 upon the binding of n-BuNH3 and
from d 0.58 to d 1.08 ppm in cone-7 upon the binding of
n-BuNH3?, respectively. These findings imply that both
cone-3 and cone-7 stands up when the guest is included
?
because n-BuNH3 enters into the p-cavity formed by
three aromatic rings. On the other hand, Ag? was encap-
sulated into the cavity formed by pyridine rings.
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J Incl Phenom Macrocycl Chem (2011) 70:69–80
75
Table 2 Selected proton chemical shifts (d, ppm) (300 MHz, CDCl3:CD3CN, 30:1 v/v, 27 °C) of cone-3 and cone-7 complexed with Ag? and
n-BuNH3
?
tBu
Ar-H
ArOCH2 (NCH2)
ArCH2O
Py-H
H3
H4
H5
H6
cone-3
?Ag?
Ag? ? n-BuNH3
1.15
1.18
1.24
1.11
1.12
1.21
6.99
6.94
7.28
6.96
6.95
7.26
4.49
4.95, 4.53
4.97, 4.33
5.32, 4.35
4.92, 4.37
4.85, 4.29
5.26, 4.33
7.89
7.88
7.91
8.20
8.00
7.96
7.49
7.86
7.62
7.69
7.79
7.73
6.90
7.20
7.05
7.04
7.15
7.10
8.17
8.30
8.21
8.30
8.33
8.23
4.41
?
?
5.01
cone-7
?Ag?
Ag? ? n-BuNH3
4.11 (4.21)
4.18 (4.37)
4.82 (4.22)
When cone-7 . Ag? complexed with n-BuNH3
through p-cavity, intramolecular hydrogen bonding broken
and the conformations of cone-7 . Ag? changed into a
symmetrical cone conformation. Thus, the complexation of
the anionic guest Cl- through hydrogen bonding is possible
[33, 34]. Upon addition of Bu4NCl or Bu4NBr to a
5 9 10-3 M solution of cone-7 . Ag? CDCl3/CD3CN, no
complexations of halide anions were observed. Owing to
intramolecular hydrogen bonding between NHa proton and
neighboring CO moieties of cone-7 . Ag?, the anion-
binding site is blocked. Base on this observation, we inves-
tigated the complexation of cone-7 . Ag? with n-butyl-
ammonium halide counterions. After adding an equivalent of
n-BuNH3Cl to a solution of cone-7 . Ag? (5 9 10-3 M) in
CDCl3/CD3CN (10:1 v/v) at 27 °C, the protons on aromatic
rings, ArCH2O, ArOCH2 were dramatically shifted to lower
magnetic field, which indicate that the binding mode are
occurred through the p-cavity formed by three aromatic
?
rings showed small changes (0.04–0.10 ppm) proving that
the complex with silver cation was remained after cone-
7 . Ag? complex with n-butyl ammonium ion. The
chemical shift of protons in pyridine in the complex of
cone-3 . Ag? has also a little change after it complex
with n-butyl ammonium ion. Compared to the values of
chemical shift on the complex of cone-7 . Ag? with
n-butyl ammonium ion, the similar tendency as that of
cone-3 . Ag? gave the same result as that of cone-
7 . Ag?. Thus, compounds cone-3 and cone-7 can com-
plex with n-butyl ammonium ions and silver cation at the
same time to form the heteroditopic complexation (Fig. 4).
The anion complexation of cone-7 . Ag? as a ditopic
receptor was studied by 1H NMR titration experiments [33,
34, 40–42]. However, we have not yet succeeded to get an
evidence for cone-7 . Ag? binding halide through the
intermolecular hydrogen bonding among the NHa hydro-
gens of amide in a 1:1 fashion in CDCl3.
Fig. 4 Binding mode of cone-
hexahomotrioxacalix[3]arene
tris(2-pyridylamide) derivative
cone-7 with Ag? and
n-BuNH3Cl
N
N
N
N
Ag+
N
N
HN
HN
HN
NHb
NH
HbN
O
O
O
O
O
O
Ag+
H2C
HN
H2C
NH
CH2
NHa
H2C
CH2
H2C
HN
NH
NHa
Cl-
O
O
O
O
O
O
O
H
O
N
H
H
O
O
O
O
O
O
O
O
+
Cl-
n-Bu
NH3
O
O
cone-7
Ditopic receptor
CH3CH2CH2CH2–
123

76
J Incl Phenom Macrocycl Chem (2011) 70:69–80
rings. Intramolecular hydrogen bonding between NHa pro-
tons and CO moieties were impossible in this conformation
due to the rigidification of the hexahomotrioxacalix[3]arene
skeleton. This is evident from the large downfield shift of the
1H NMR signal for the aromatic hydrogens from d = 6.96 to
d = 7.26 ppm. Additionally, larger downfield shift of the
NHa protons from d = 8.32 to d = 9.07 ppm (Dd =
?0.75 ppm) to indicating complexation with the anionic
guest through hydrogen bonding. Similar finding were also
observed for the complexation of cone-7 . Ag? with
n-BuNH3Br. As the electronegativity of the halogen atom
decreased with the series of Cl and Br atoms, the intensity of
hydrogen bonding formed between their anions and NHa
protons should be decreased following the same order. In
fact, in 1H NMR spectrum of a mixture of cone-7 . Ag? and
n-BuNH3?X-, a larger downfield of chemical shift in the
complex of NHa with Cl- was observed as compared with
Br-. The association constants of cone-3 and cone-7 with n-
BuNH3? ions in the absence and presence of Ag? calculated
from the chemical shift changes of ArCH2O are summarized
in Table 3.
n-BuNH3? complexation induces a structural change that is
prerequisite for anion complexation. This process resembles
a heterotopic allosteric effect [43].
Conclusion
For the first time, the relationship between properties of
ionophore hosts and their intramolecular hydrogen bonding
was taken into account in C3-symmetric conformation. Due
to the intramolecular hydrogen bonding, the affinities of
ionophores cone-3 and cone-7 to metal ions were weak-
ened, it does not bind alkali metal ions because the binding
site was blocked. Both cone-3 and cone-7 can bind n-butyl
ammonium ions through the p-cavity formed by three aryl
rings, which can provide functional moieties in biologic
systems with good affinity and high selectivity. As C3-
symmetrical pyridyl-substituted calixarene, ionophores
cone-3 and cone-7 can bind Ag? ion and the complexation
mode was elucidated clearly in this paper. Thus, iono-
phores cone-3 and cone-7 serve as a heteroditopic receptor
which can complex with Ag? and n-BuNH3 at the same
?
Interestingly, the association constant Ka for the com-
plexation of cone-7 with n-BuNH3Cl (Ka = 2570 250) is
much larger than that with n-BuNH3pic (Ka = 2250 130).
Similar finding was observed in the complexation of cone-3
(Ka = 3690 310 for n-BuNH3Cl and Ka = 2675 155
for n-BuNH3pic). Thus, in the presence of chloride ion the
complexation of n-butylammonium ion increases compared
to picrate counterions, due to strong electrostatic interaction
between n-butylammonium and Cl- ions included in the
cavity of cone-7. In contrast, in the presence of Ag? the
complexation of cone-7 with n-butylammonium chloride
decreases compared to n-butylammonium picrate due to
strong electrostatic interaction between Ag? and Cl- ions.
These results show that cone-7 can simultaneously complex
time. The nitrogen atom in pyridine ring turned from out-
ward against the cavity to inside the cavity to interact with
Ag?. After complexation of tris(2-pyridylamide) derivative
cone-7 with Ag?, the original C3-symmetry has been
remained for cone-7. Although we have not yet succeeded
to get an evidence for cone-7 binding halide through the
intermolecular hydrogen bonding among the NHa hydro-
gens of amide, cone-7 can simultaneously complex with
Ag?, n-BuNH3? and Cl- ion from the consideration of the
association constants Ka in the presence of different
counteranions. To the best of our knowledge the present
result is the first example of heterogeneous dinuclear
complex in the hexahomooxacalix[3]arene family. These
results give some insight into the molecular design of new
synthetic receptors for use in anion controlled of biomi-
metic systems.
with Ag?, n-BuNH3 and Cl- or Br- ions and that
?
Table 3 Association constants (Ka, M-1) of cone-3 and cone-7 with
?
n-BuNH3 ions in CDCl3:CD3CN = 10:1 (v/v) at 27 °C
Experimental
Guest
Association constant Ka (M-1
)
cone-3
cone-7
All mps (Yanagimoto MP-S1) are uncorrected. NMR
spectra were determined at 270 MHz with a Nippon Denshi
JEOL FT-270 NMR spectrometer with SiMe4 as an internal
reference: J-values are given in Hz. IR spectra were mea-
sured for samples as KBr pellets or a liquid film on NaCl
plates in a Nipon Denshi JIR-AQ2OM spectrophotometer.
UV spectra were measured by Shimadzu 240 spectropho-
tometer. Mass spectra were obtained on a Nippon Denshi
JMS-01SA-2 spectrometer at 75 eV using a direct-inlet
system through GLC. Elemental analysis: Yanaco MT-5.
n-BuNH3pic
Ag? ? n-BuNH3pic
2675 155
1075 65
3690 310
570 40
2250 130
1355 65
2570 250
985 50
n-BuNH3Cl
Ag? ? n-BuNH3Cl
Measured in CDCl3:CD3CN = 10:1 (v/v) at 27 °C by the 1H NMR
titration method of the chemical shift change of the NH proton
and ArCH2O, host concentration was 5 9 10-3 M. Guest were
used as AgSO3CF3, n-butylammonium picrate and n-butylammonium
chloride
123

J Incl Phenom Macrocycl Chem (2011) 70:69–80
Materials
77
brine (20 mL), dried (Na2SO4) and condensed under
reduce pressure. The residue was washed with hexane to
give cone-6 (170 mg, 79%) as colorless solid. Mp
215–217 °C. IR mmax (KBr)/cm-1 3500–3250, 2958, 2867,
1736, 1661, 1540, 1457, 1363, 1231, 1197, 1093. 1H NMR
d (CDCl3-MeOH[D4], 3:1, v/v) 1.13 (27H, s, tBu), 4.13
(6H, s, ArOCH2), 4.20 (6H, d, J 5.86, N-CH2), 4.42 (6H, d,
J 12.7, ArCH2O), 4.80 (6H, d, J 12.7, ArCH2O), 6.97 (6H,
s, Ar-H), 8.18 (3H, t, NH). MS 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%.
cone-Hexahomotrioxacalix[3]arene triacetic acid (cone-
2b), cone-7,15,23-tri-tert-butyl-25,26,27-tris[(2-pyridyla-
minocarbonyl)methoxy]-2,4,10,12,18,20-hexahomo-3,11,
19-trioxacalix[3]arene (cone-3) and (4-tert-butyl-2,6-
dimethyl)phenoxyacetic acid (8) were prepared according
to the previously reported procedures [8, 23, 24].
Synthesis
Synthesis of cone conformation of 7,15,23-tri-tert-butyl-
25,26,27-tris[(methoxyacetyl)amino]carbonylmethoxy]-
2,4,10,12,18,20-hexahomo-3,11,19-trioxacalix[3]arene
(cone-5)
Synthesis of tris(2-pyridylamide) derivative
of homooxacalix[3]arene (cone-7)
To a solution of cone triacid homocalix[3]arene (cone-6)
(491 mg, 0.532 mmol) in CH2Cl2 (30 mL) with 2-amino-
pyridine (514 mg, 4.80 mmol) was added HOBt (94 mg,
0.697 mmol), then the mixture solution was stirred at 0 °C
while adding a solution of DCC (684 mg) in CH2Cl2 (10 mL)
by dropwise. Then the solution was stirred for 15 h at room
temperature. After reaction, remove solvent, then the residue
was dissolved with AcOEt and filtered, the filtrate was
washed orderly with 10% citric acid, water, 5% sodium
bicarbonate, water and brine. Dried with Na2SO4 then
removed solvent under reduced pressure. The residue was
chromatographed over silica gel (Wako, C-300; 100 g) with
AcOEt as eluent to give a colorless solid. The solid was re-
crystallized from methanol to give cone-7 (538 mg, 85%) as
colorless prisms. Mp 152–154 °C. IR mmax (KBr)/cm-1 3476,
3410, 3312, 2958, 2867, 1664, 1609, 1541, 1516, 1482, 1197,
To a solution of cone triacid homocalix[3]arene (cone-2b)
(400 mg, 0.532 mmol) in CH2Cl2 (30 mL) with glycine
methyl ester (4a) (427 mg, 4.80 mmol) was added HOBt
(94 mg, 0.697 mmol), then the mixture solution was stirred
at 0 °C while adding a solution of DCC (684 mg) in
CH2Cl2 (10 mL) by dropwise. Then the solution was stir-
red for 15 h at room temperature. After reaction, remove
solvent, then the residue was dissolved with AcOEt and
filtered, the filtrate was washed orderly with 10% citric
acid, water, 5% sodium bicarbonate, water and brine. Dried
with Na2SO4 then removed solvent under reduced pressure.
The residue was chromatographed over silica gel (Wako,
C-300; 100 g) with AcOEt as eluent to give a colorless
solid. The solid was recrystallized from methanol to give
cone-5 (365 mg, 70.5%) as colorless prisms. Mp 90–92 °C.
IR mmax (KBr)/cm-1 3350, 2958, 2871, 1752, 1678, 1540,
1
818. H NMR d (CDCl3) 1.12 (27H, s, tBu), 4.13 (6H, s,
1
1484, 1200, 1076. H NMR d (CDCl3) 1.13 (27H, s, tBu),
ArOCH2), 4.23 (6H, d, J 5.86, N-CH2), 4.35 (6H, d, J 12.7,
ArCH2O), 4.90 (6H, d, J 12.7, ArCH2O), 6.96 (6H, s, Ar-H),
7.04 (3H, m, pyridine-H5), 7.69 (m, 3H, pyridine-H4), 8.20
(3H, d, J 8.30, pyridine-H3), 8.30 (3H, dd, J 3.90, 2.44, pyr-
idine-H6), 8.45 (3H, t, NHa), 9.21 (3H, s, NHb). MS m/z 1150
(M?). Anal. Calcd. for C63H75O12N9 (1150.35): C, 65.76; H,
6.57; N, 10.96. Found: C, 65.61; H, 6.38; N, 10.04%.
3.78 (9H, s, CH3), 4.15 (6H, d, J 5.86, N-CH2), 4.38 (6H, d,
J 12.7, ArCH2O), 4.78 (6H, d, J 12.7, ArCH2O), 4.23 (6H,
s, ArOCH2), 6.95 (6H, s, Ar-H), 8.03 (3H, s, NH). MS 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%.
Synthesis of cone conformation of 7,15,23-tri-tert-butyl-
25,26,27-tris[(hydroxyacetyl)amino]carbonylmethoxy]-
2,4,10,12,18,20-hexahomo-3,11,19-trioxacalix[3]arene
(cone-6)
Preparation of 4-tert-butyl-2,6-
dimethyl[(methoxyacetylaminocarbonyl)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 dropwise a solution of DCC
(560 mg) in CH2Cl2 (5 mL) 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
acetate (30 mL 9 2). The combined extracts were washed
with 10% citric acid (20 mL 9 2), 5% sodium bicarbonate
To a mixture of cone-5 (225 mg) in dioxane (35 mL) was
added 1 M NaOH aqueous solution (25 mL), the mixture
was stirred at room temperature for 1 h, then the solution
was removed dioxane under reduced pressure. The residue
was acidified to neutral condition. The dispersion was
extracted with ethyl acetate (2 9 30 mL). The combined
extracts were washed with 10% citric acid (2 9 20 mL),
5% sodium bicarbonate (20 mL), water (20 mL), saturated
123

78
J Incl Phenom Macrocycl Chem (2011) 70:69–80
(20 mL), water (20 mL), saturated brine (20 mL), dried
(Na2SO4) and condensed under reduce pressure. The resi-
due was recrystallized from methanol to give the title
compound 9a (87 mg, 66%) as colorless prisms. Mp
101–102 °C. IR mmax (KBr)/cm-1 3337, 3320, 2968, 2865,
1755, 1734, 1667, 1534, 1488, 1277, 1197, 1182, 1056. 1H
NMR d (CDCl3) 1.29 (9H, s, tBu), 2.27 (6H, s, CH3), 3.80
(3H, s, OCH3), 4.20 (2H, d, J 5.37, N-CH2), 4.33 (2H, s,
ArOCH2), 7.03 (2H, s, Ar-H), 7.46 (1H, t, NH). MS 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%.
ArOCH2), 7.03 (2H, s, Ar-H), 7.09 (1H, m, pyridine-H5),
7.75 (1H, m, pyridine-H4), 8.21 (1H, d, J 8.30, pyridine-
H3), 8.30 (1H, dd, J 3.90, 2.44, pyridine-H6), 7.76 (1H, t,
NHa), 8.36 (1H, s, NHb). MS m/z 369 (M?). Anal. Calcd.
for C21H27O3N3 (369.46): C, 68.27; H, 7.37; N, 11.37.
Found: C, 68.45; H, 7.53; N, 11.48%.
Picrate extraction measurements
Alkali metal picrates (2.5 9 10-4 M) were prepared in situ
by dissolving 0.1 M of alkali metal hydroxide in 2.5 9 10-4
M of picric acid; triply distilled water was used for all
aqueous solutions. Similarly, metallic picrates were pre-
pared in situ by dissolving 0.1 M of metallic nitrate [AgNO3,
Cu(NO3)2ꢀ3H2O, Al(NO3)3ꢀ9H2O] in 2.5 9 10-4 M of pic-
ric acid. Alkyl ammonium picrates were prepared by mixing
an equimolar of alkylamine and picric acid in methanol.
Two-phase solvent extraction was carried out between
water (5 mL, [alkali picrate] = 2.5 9 10-4 M) and CH2Cl2
(5 mL, [ionophore] = 2.5 9 10-4 M). The two-phase
mixture was shaken in a stoppered flask for 24 h at 25 °C.
We confirmed that this period is sufficient to attain the dis-
tribution equilibrium. This was repeated three times, and the
solutions were left standing until phase separation was
complete. The extractability was determined spectrophoto-
chemically from the decrease in the absorbance of the pic-
rate ion in the aqueous phase as described by Pedersen [44].
Preparation of 4-tert-butyl-2,6-dimethyl
[(hydroxyacetylaminocarbonyl)methoxy]benzene (9b)
To a solution of 9a (150 mg, 0.49 mmol) in dioxane
(30 mL) was added 1 M NaOH aqueous solution (30 mL),
at room temperature. After the mixture was stirred at room
temperature for 1 h, it was condensed under reduced pres-
sure. The residue was then acidified to neutral condition.
The precipitate was extracted with ethyl acetate
(30 mL 9 2). The combined extracts were washed with
water (20 mL), saturated brine (20 mL), dried (Na2SO4)
and condensed under reduce pressure. The residue was
washed with hexane to give 9b (136 mg, 95%) as a color-
less solid. Mp 193–195 °C. IR mmax (KBr)/cm-1 3383,
2963, 2925, 2867, 1730, 1635, 1540, 1436, 1245, 1229,
1
1124. H NMR d (CDCl3) 1.29 (9H, s, tBu), 2.27(6H, s,
CH3), 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).
MS 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%.
1H NMR complexation experiment
To a CDCl3 solution (5 9 10-3 M) of cone-3 and cone-7 in
the NMR tube was added an equivalent of n-BuNH3X. The
spectrum was registered after addition and the temperature
of NMR probe kept constant at 27 °C.
Preparation of 4-tert-butyl-2,6-dimethyl[(2-
pyridylaminocarbonyl)methoxy]benzene (9c)
Determination of association constants
To a solution of 9b (50 mg, 0.17 mmol), 2-aminopyridine
(55 mg, 0.51 mmol) and 1-hydroxybenzotriazole (HOBt)
(23 mg, 0.17 mmol) in CH2Cl2 (12 mL) was added drop-
wise a solution of dicyclohexylcarbodiimide (DCC)
(171 mg) in CH2Cl2 (5 mL) 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 acetate (2 9 30 mL). The combined extracts were
washed with 10% citric acid (2 9 20 mL), 5% sodium
bicarbonate (20 mL), water (20 mL), saturated brine
(20 mL), dried (Na2SO4) and condensed under reduce
pressure. The residue was recrystallized from hexane-
CH2Cl2 (3:1) gave 9c (56 mg, 89%) as colorless prisms.
Mp 217–219 °C; IR mmax (KBr)/cm-1 3407, 3268, 2960,
2950, 2867, 1699, 1665, 1577, 1541, 1518, 1432, 1300,
1
The measurements were performed by H NMR titration
experiments in a varying guest concentration of 0–50 mM
and a constant concentration of host receptors with 5 mM. As
a probe the chemical shift of the amide protons [C(O)NHb]
signal was used. The association constant values were cal-
culated by the integral intensity of NH protons in the complex
and free host molecules according to the literature [45].
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