Synthesis and heteronuclear inclusion properties of a novel thiacalix[4]arene-based hard-soft receptor with 1,3-alternate conformation

Article abstract of DOI:10.1007/s10847-010-9740-5

A novel thiacalix[4]arene ditopic receptor with 1,3-alternate conformation and possessing two complexation sites for hard and soft cations, 5,11,17,23-tetra-tert-butyl-25,27-bis[(N,N-diethylaminocarbonyl)methoxy]-26,28-bis[(pyridylmethyl)oxy]-2,8,14,20-tetrathiacalix[4]arene is prepared. Regioselective synthesis of distal-bis[(N,N-diethylaminocarbonyl)methoxy]thiacalix[4]arene is accomplished by a protection-deprotection method using benzyl groups as a protecting group. The deprotection of benzyl group was succeeded in the presence of solid superacid (Nafion-H) under refluxing benzene. Its complexation behavior is examined by ¹H-NMR titration experiments. The formation of 1:2 homo- and heteronuclear complexes demonstrates that the preorganization, subtle conformational changes and affinity have a pronounced effect on the complexation of the receptor.

Full text of DOI:10.1007/s10847-010-9740-5

J Incl Phenom Macrocycl Chem (2010) 68:99–108
DOI 10.1007/s10847-010-9740-5
ORIGINAL ARTICLE
Synthesis and heteronuclear inclusion properties of a novel
thiacalix[4]arene-based hard-soft receptor with 1,3-alternate
conformation
•
Xin-long Ni Hirotsugu Tomiyasu Tomoe Shimizu
•
•
•
Carol Perez-Casas Zeng Xi Takehiko Yamato
•
´
Received: 14 September 2009 / Accepted: 14 January 2010 / Published online: 5 February 2010
Ó Springer Science+Business Media B.V. 2010
Abstract A novel thiacalix[4]arene ditopic receptor with
1,3-alternate conformation and possessing two complexation
sites for hard and soft cations, 5,11,17,23-tetra-tert-butyl-25,
27-bis[(N,N-diethylaminocarbonyl)methoxy]-26,28-bis[(pyr-
idylmethyl)oxy]-2,8,14,20-tetrathiacalix[4]arene is prepared.
Regioselective synthesis of distal-bis[(N,N-diethylaminocar-
bonyl)methoxy]thiacalix[4]arene is accomplished by a
protection-deprotection method using benzyl groups as a
protecting group. The deprotection of benzyl group was suc-
ceeded in the presence of solid superacid (Nafion-H) under
refluxing benzene. Its complexation behavior is examined by
1H-NMR titration experiments. The formation of 1:2 homo-
and heteronuclear complexes demonstrates that the preorga-
nization, subtle conformational changes and affinity have a
pronounced effect on the complexation of the receptor.
known that the conformation of the calix plays a very
important role in the complexation process [4, 5]. In par-
ticular, the so-called calix[4]arene 1,3-alternate confor-
mation, which has D2h-symmetry, tube-shape can, be well
adapted for the formation of 1:1 as well as 1:2 complexes
owing to its symmetrical ditopic arrangement [6–8].
Papparlardo et al. [9] reported the synthesis of
calix[4]arenes bearing pendant pyridine groups at the lower
rim as potential ligands for transition metals [9–11].
We reported the synthesis, conformation studies and
inclusion properties of tetrakis[(2-pyridylmethyl)oxy]tet-
rathiacalix[4]arenes with cone and 1,2-alternate confor-
mation, which show strong Ag? affinity [12]. Furthermore,
recently we reported similar studies of tetrakis[(N,N-dieth-
ylaminocarbonyl)methoxyl]tetrathiacalix[4]arene [13] with
cone and 1,3-alternate conformation, which show the
ability to form 1:2 complexes. Di- or polytopic receptors are
those constructed with two or more binding subunits within
the same macrocyclic structure [14].
Keywords Thiacalix[4]arene ꢀ O-alkylation ꢀ
Conformation ꢀ Ionophores ꢀ Metal complexation ꢀ
Hard-soft receptors
With this in mind we have designed the novel receptors
with 1,3-alternate conformation, having two different
sidearms and showing affinity not only toward alkali metal
cations but also toward soft heavy metal cations. Thus,
there is substantial interest in its synthesis and complexa-
tion behavior towards K? and Ag? ions. Multi-recognition
of K? and Ag? owing to the presence of two amide moi-
eties at one edge of the thiacalix[4]arene cavity and two
2-pyridylmethyl moieties at the other edge, is expected.
Based on the fact that amide groups [15] show high affinity
for Ag?, a strong simultaneous and cooperative effect
between the amide moiety and 2-pyridylmethyl groups
during the binding with Ag? could be considered.
Introduction
Recently, thiacalix[4]arenes [1–3] have been used as
potential platforms due to their novel features. It is well
´
X. Ni ꢀ H. Tomiyasu ꢀ T. Shimizu ꢀ C. Perez-Casas ꢀ 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
In this paper we report on the synthesis and inclusion
properties of 1,3-alternate-5,11,17,23-tetra-tert-butyl-
25,27-bis[(N,N-diethylaminocarbonyl)methoxy]-26,28-bis
Key Laboratory of Macrocyclic and Supramolecular Chemistry
of Guizhou Province, Guizhou University, 550025 Guiyang,
Guizhou, China
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J Incl Phenom Macrocycl Chem (2010) 68:99–108
[(pyridylmethyl)oxy]-2,8,14,20-tetrathiacalix[4]arene from
methoxyl]tetrathiacalix[4]arene with 2-(chloromethyl)
pyridine.
Debenzylation of 1,3-alternate-3 in the presence of Nafion-
H (100 wt%) as a catalyst, was carried out in boiling
benzene for 24 h to afford the desired bis[(N,N-diethyla-
minocarbonyl)methoxy] derivative distal-4 in 50% yield
along with the recovery of the starting compound and
diphenylmethane. Depending on the amount of Nafion-H
and an acceptor for benzyl group, i.e. benzene or toluene,
selective debenzylation was found to be possible. Thus, the
maximum yield (85%) and the reduced reaction time to
12 h was achieved in the presence of 200 wt% equivalents
of Nafion-H in the toluene as an acceptor for benzyl group
(Scheme 1). The ring cleavage of the S–C bond in the
thiacalixarene moiety as well as trans-tert-butylation was
not also observed under the conditions used. The presently
developed procedure provides excellent yield, easy isola-
tion of the products, and ready regeneration of the catalyst
without the loss of activity [26, 27].
The 1H-NMR spectra of 3 show two singlets for the tert-
butyl protons at d 0.83 and d 1.30 ppm, in which the former
peak can be observed at a higher field due to the ring
current effect arising from the two benzyl benzenes intro-
duced. The singlet signals of the methylene protons
(OCH2Ph and OCH2CONEt2) in 3 were also observed at
higher field (d 4.70 and 4.95 ppm) than that for the
methylene protons (OCH2Ph) in distal-2 (d 5.49 ppm) due
to the ring current effect arising from the two inverted calix
benzene rings. These observations strongly suggest 3
adopts 1,3-alternate conformation [13].
Results and discussion
Synthesis
Attempted regioselective O-alkylation of hydroxy groups in
calixarene 1 with N,N-diethylchloroacetamide to afford
distal-bis[(N,N-diethylaminocarbonyl)methoxy]thiacalix[4]
arene distal-4 as following the reported procedure [15]
failed. Although the desired bis-O-alkylation product distal-
4 was obtained along with the tetra-O-alkylation product, the
isolation of distal-4 in pure was quite difficult. On the other
hand, recently, we have reported that regioselective syn-
thesis of distal-di-O-alkoxythiacalix[4]arenes is accom-
plished by a protection-deprotection method using benzyl
groups as a protecting group [16]. In fact, O-benzylation of
tetrathiacalix[4]arene 1 carried out with 10 equiv. of benzyl
bromide in the presence of Na2CO3 according to the reported
procedure furnished exclusively the formation of the
disubstituted product distal-2 in spite of the use of a large
excess of benzyl bromide. The reaction of bisbenzylated
compound distal-2 with N,N-diethylchloroacetamide in
acetone in the presence of Cs2CO3 as base under reflux for
17 h yielded 1,3-alternate-3 in 90% yield.
Attempted removal of the benzyl group in 1,3-alternate-
3 with Me3SiBr [17–23] in CHCl3 at room temperature for
3 h or hydrogenation in the presence of Pd–C [24, 25] at
room temperature for 3 h to afford the desired bis[(N,N-
diethylaminocarbonyl)methoxy] derivative distal-4 was
unsuccessful. Only the recovery of the starting compound
was obtained which is different from the results affording
the debenzylated products in quantitative yield in the case
of calix[4]arenes [17–22]. It is possible that the sulfur
atoms in the thiacalix[4]arene might deactivate the cata-
lytic activity of Pd–C. Finally, we have succeeded the
debenzylation of 1,3-alternate-3 in the presence of AlCl3 in
toluene at room temperature for 5 h to afford the desired
diol distal-4 in 72%. The maximum yield was obtained in
the presence of 5 equivalents of AlCl3. The ring cleavage
of the S–C bond in the thiacalixarene moiety as well as
trans-tert-butylation was not observed under the conditions
used. This result indicates that the protection-deprotection
method is recommended as a useful strategy for the syn-
thesis of distal-4.
The calixarenes show concentration-independent hydro-
xyl stretching bands in the 3,200 cm-1 region of the infrared
spectrum and a signal at d 9–10 ppm in the 1H-NMR spec-
trum, indicative of very strong intramolecular hydrogen
bonding and the cyclic nature of calixarenes [4, 5]. The IR
(KBr) spectrum of distal-4 shows the absorption for the
hydroxyl stretching vibration around 3363 cm-1. The
1H-NMR signal for hydroxyl group was observed at d
8.54 ppm. Furthermore, the previously noted upfield shift for
the methylene protons in the alkoxy groups in the 1H-NMR
spectra of 1,3-alternate-3 has not been observed. Therefore,
distal-bis[(N,N-diethylaminocarbonyl)methoxy]thiacalix[4]
arene (distal-4) might adopt the cone-conformation due to
the intramolecular hydrogen bonding between two hydroxy
groups and alkoxy groups. Thus hydroxy groups and alkoxy
groups of dialkoxytetrathiacalix[4]arenes have a tendency to
orientate in the same direction and therefore favoured the
adoption of the ‘‘cone’’ conformation.
Consequently, we have demonstrated for the first time
that the regioselective synthesis of distal-bis[(N,N-dieth-
ylaminocarbonyl)methoxy]thiacalix[4]arene (distal-4) is
accomplished by a protection-deprotection method using
benzyl groups as a protecting group. Solid superacid
(Nafion-H) was found to be a good catalyst for the present
deprotection of benzyl group.
On the other hand, recently, we have found that the
Nafion-H catalyst, a perfluorinated sulfonic acid resin [26,
27], is effective in a wide range of liquid and gas phase
reactions, including electrophilic substitutions on aromatic
nuclei, transalkylations, condensations and so on [28–33].
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J Incl Phenom Macrocycl Chem (2010) 68:99–108
101
Scheme 1
OH
S
S
S
S
OBzl
OH
OH
OH HO
OH
OBzl
BzlBr, Na2CO3
acetone
reflux for 17 h
(93%)
distal-2
OH
OH
HO
Bzl= CH2
OH
1
OR
BzlO
OH
Nafion-H
(200 wt%)
OBzl
OH
RCl, Cs2CO3
OR
distal-2
RO
acetone
reflux for 17 h
toluene
reflux for 12 h
(85%)
distal-4
RO
1,3-alternate-3
(90%)
R = CH2CONEt2
R = CH2CONEt2
Compound 5 is obtained in 87% yield by the stereose-
lective O-alkylation of the amide distal-4 with 2-(chloro-
methyl)pyridine in dry THF-DMF in the presence of
Cs2CO3 (Scheme 2). Similar yield was obtained by
O-alkylation in the presence of K2CO3. However, use of
Na2CO3 as a base resulted in the recovery of the starting
compound.
The magnitude of this shielding, calculated as the
difference between pertinent the reference compound 7,
which was prepared by O-alkylation of 4-tert-butyl-2,6-
dimethylphenol 6 with 2-(chloromethyl)pyridine in the
presence of NaH in 63% yield (Scheme 3).
Interestingly, the hetero aromatic protons of the pyridine
rings of 1,3-alternate-5 are exposed to the ring current
shielding effect [38–41] operating in facing pyridine ring
and the diaryl thiaether linkage, and resonate at higher
fields with respect to those of pyridine protons of 1,3-
alternate-5 and reference compound 7, increases signifi-
cantly for the H3 and H4 protons. The remarkable shielding
effects experienced by the H4 (d -0.36 ppm) and H3 (d -
1.02 ppm) (Table 1) protons of the pyridine rings suggest
that these protons are located much closer to the opposing
pyridine ring than are the H5 and H6 protons and folded
1
The H-NMR spectrum of 5 shows two singlets for the
tert-butyl protons at d 0.83 and 1.30 ppm, in which the
former peak can be observed at a higher field due to the
ring current effect arising from the two pyridine rings
introduced. Similarly, the OCH2Py and OCH2CO protons
resonances appear at d 5.15 and 4.65 ppm, respectively.
These chemical shift values together with the examples
reported in the literature [12, 13, 34–37] strongly suggest
that the 5 adopts a ‘‘1,3-alternate conformation’’.
Scheme 2
Et2N
NEt2
O
O
O
O
NEt2
S
O
O
Et2N
O
OH
O
OH
S
S
S
S
2-PicCl, Cs2CO3
S
S
S
O
THF-DMF
reflux for 17 h
O
(87%)
N
N
distal-4
1,3-alternate-5
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J Incl Phenom Macrocycl Chem (2010) 68:99–108
5
6
4
3
N
CH2
O
OH
Me
Me
Me
Me
2-PicCl, NaH
THF/ DMF
reflux for 17 h
(63%)
7
6
Scheme 3
Table 1 Chemical shift of pyridine protons in 1,3-alternate-5 and
reference 7a,b
Compd.
Chemical shift, d pm
H6 H5
7.20c
Fig. 2 Job Plot of the extraction of K? with 1,3-alternate-5
H4
7.74c
7.38c
H3
7.74c
7
8.58
Stoichiometry
1,3-alternate-5
8.50
7.13
6.72
Dd
-0.08
-0.07
-0.36
-1.02
The stoichiometry of the 1,3-alternate-5 complexes with
Na?, K? and Ag? is determined by a two phase-extraction
experiment (H2O/CH2Cl2), using the continuous variation
method. The percent extractions for Na? and K? complex
(Job plots) support the exclusive formation of the 1:1
complex (Fig. 2). In the case of Ag? the percent extraction
reaches maximum at 0.7 mol when change the 5 and silver
cation systematically, which indicates that 1,3-alternate-5
a
Dd Values are the difference of the chemcial shift between 1,3-
alternate-5 and reference 7 in CDCl3 at 27 °C
b
A minus sign (–) denotes a shift to higher magnetic field
c
The midpoint values of multiplet are indicated
into the p-cavity [12, 13] formed by two thiacalix benzene
rings and are thus shifted stronger upfield. This is doubtless
due to the electron repulsion between the nitrogen atoms in
the pyridine rings and the diaryl thiaether linkages. Thus,
nitrogens inboth pyridine rings were orientated outwards
with respect to the thiacalixarene cavity. The preoganiza-
tion of 1,3-alternate-5 might provide the possibility to act
as ditopic receptor, Fig. 1.
1
forms 1:2 complex with Ag?, fact also confirmed by H-
NMR (Fig. 3).
1H-NMR titration experiments with KSO3CF3, NaClO4
and AgSO3CF3 are carried out. 1H-NMR titration
= OCH2CONEt2
OCH2COOEt
R
R
O
O
Binding
Site 2
O O
S
S
S
S
O
O
Binding
Site 1
N
N
1,3-alternate-5; R= NEt2
1,3-alternate-8; R= OEt
H4
H5
H3
N
= OCH2
H6
Fig. 1 Structures of ditopic receptors based on thiacalix[4]arenes
Fig. 3 Job Plot of the extraction of Ag? with 1,3-alternate-5
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J Incl Phenom Macrocycl Chem (2010) 68:99–108
103
experiments of 1,3-alternate-5 with KSO3CF3 two distinct
signals for free 1,3-alternate-5 and 1:1 1,3-alternate-
5 . K1 complex are observed when up to 1 equiv. of
KSO3CF3 is titrated, which implies ligand exchange is slow
on the NMR time scale (Fig. 4). Only the 1:11,3-alternate-
5 . K1 [Fig. 4c] are formed even with a large excess of
KSO3CF3. The addition of an equiv. of KSO3CF3 to
1,3-alternate-5 causes immediate complexation as dem-
onstrated by the downfield shift of the both methylene
protons (OCH2CONEt2, Dd = ?0.12 ppm; OCH2Py, Dd
= ?0.09 ppm), whereas the pyridine protons were scarcely
affected (H3, Dd = -0.02 ppm). Titration with NaClO4
afforded similar results (OCH2CONEt2, Dd = ?0.10 ppm;
OCH2Py, Dd = ?0.10 ppm). The results confirm that the
two amides compose an ionophoric cavity stronger for K?
and Na? than the two 2-pyridine moieties [6, 34].
Similarly, titration with 1 equiv. of AgSO3CF3 to 1,3-
alternate-5 also causes immediate complexation as dem-
onstrated by the downfield shift of the amide protons
(OCH2CONEt2, Dd = ?0.12 ppm) and the OCH2Py pro-
tons (OCH2Py, Dd = ?0.10 ppm, Table 2), whereas the
Py protons were scarcely affected. These findings together
with the slow ligand exchange process observed could
suggest that Ag? is bound in the cavity delineated by the
amide moiety (1:1 1,3-alternate-5 . Ag1 complex).
Interestingly, additional peaks appeared in the 1,3-alter-
nate-5 . Ag1 complex spectrum which prove the forma-
tion of the dinuclear complex Ag1,1,3-alternate-
5 . Ag1. The OCH2Py and H3 protons appear as broad
signals at d 5.15 and 6.53 ppm, respectively.
We have already reported [13] that in the case of the
corresponding ester derivative, 5,11,17,23-tetra-tert-butyl-
25,27-bis[(ethoxycarbonyl)methoxy]-26,28-bis[(pyridyl-
methyl)oxy]-2,8,14,20-tetrathiacalix[4]arene only the 1:1
complexe 1,3-alternate-8 . K? was formed even with a
large excess of KSO3CF3. The results confirm that the two
ester moieties of 1,3-alternate-8 compose an ionophoric
cavity stronger for K? and Na? than the two pyridyl
moieties. On the other hand, titration with 1 equiv. of
AgSO3CF3 to 1,3-alternate-8 causes a dramatic upfield
shift for the methylene protons of OCH2Py in 1,3-alter-
nate-8 (Dd = -0.48 ppm) while the Py protons display a
downfield shift, strongly suggesting that Ag? is bound to
the nitrogen atoms of pyridine and phenolic oxygens which
affects the H6, H5, H4, H3 protons in pyridine rings (1:1
Ag?,1,3-alternate-8 complex). Spectral changes of the
1:1 Ag?,1,3-alternate-8 complex in the presence of an
excess of AgSO3CF3 were not detectable, which supports
the exclusive formation of the 1:1 Ag?,1,3-alternate-8
complex. The exclusive formation of mononuclear com-
plexes of 1,3-alternate-8 with Na?, K? and Ag? was
observed even through the formation of the heterogeneous
dinuclear complexes was expected.
Fig. 4 Partial 1H-NMR of 1,3-alternate-5 (4 9 10-3 M) at 300 MHz
in CDCl3:CD3CN 2:1 v/v. a Free ligand, b Addition of 1 equiv. of
KSO3CF3 after 5 min. c after 3 h. D denotes solvent signal
Table 2 1H-NMR chemical shift (Dd) of pyridine protons and methylene protons of OCH2Py of 1:1 complexesa,c,d
Proton
1,3-alternate-5
Dd (ppm)b in the presence of metal
1,3-alternate-8
Dd (ppm)b in the presence of metal
Na?
K?
Ag?
Na?
K?
Ag?
H6
?0.05
-0.25
?0.10
?0.09
-0.02
?0.09
?0.04
-0.26
?0.10
?0.02
-0.24
?0.06
?0.04
-0.26
?0.08
?0.47
?0.75
-0.48
H3
OCH2Py
a
300 MHz, in CDCl3:CD3CN 2:1, 26 °C
Dd = d (metal)–d (free ligand)
b
c
d
(–) denotes a shift to up field. (?) denotes a shift to down field
The signals of H4 and H5 overlap with other signals
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J Incl Phenom Macrocycl Chem (2010) 68:99–108
Complexation of 1,3-alternate-5 with both alkali metals
is very similar to that of 1,3-alternate-8, but the D d of H3
with K? significantly decreases. Noticeable differences are
observed in 1,3-alternate-5 . Ag1 complex. The up field
of the protons H3 and the down field shift of the OCH2Py
are the most remarkable difference when compare with
Ag1,1,3-alternate-8 complex; thus, the hypothesis that
Ag? complexes with the amide moieties is confirmed.
Allosteric studies
The presence of allosteric effect in 1,3-alternate-5 is
studied by three sets of 1H-NMR titration. In the first set of
experiments, 5 equiv. AgSO3CF3 were added into the
solution containing 1,3-alternate-5 . Na1 and 1,3-alter-
1
nate-5 . K1. The H-NMR resonance significantly dif-
fered from that of the 1:1 1,3-alternate-5 . Na1 and 1,3-
alternate-5 . K1 complexes. Thus, new peaks are
observed in 1,3-alternate-5 . K1 and 1,3-alternate-
5 . Na1 assignable to the 1:2 Ag1,1,3-alternate-
Fig. 5 Partial 1H-NMR of 1,3-alternate-5 (4 9 10-3 M) at 300 MHz
in CDCl3:CD3CN 2:1 v/v. a Free ligand, b in the presence of 1 equiv.
of AgSO3CF3, c in the presence of 5 equiv. of AgSO3CF3, d Addition
of KSO3CF3 into c solution, e After 3 h Ag?,1,3-alternate-5 . K?
complex, D denotes solvent signal
5 . K1
complex
(Kass = 2.88 9 103 M-1
)
and
Ag1,1,3-alternate-5 . Na1 (Kass = 2.75 9 103 M-1).
The association constant values for the complexation of
Ag? by the pyridine moiety remain virtually unchanged
which proves the existence of strong positive cooperativity.
The 1H-NMR spectra of 1,3-alternate-5 complexes are
repeatedly scanned at various time intervals (1 h to 5 h).
After 3 h, only the signals for 1:2 Ag1,1,3-alternate-
5 . K1 and Ag1,1,3-alternate-5 . Na1 complexes
could be observed, indicating that the equilibrium was
reached. Table 3 shows the essential chemical shift of
pyridine protons of 1:2 complexes of 1,3-alternate-5.
The complexation of 1,3-alternate-5 with the first ion
(K?, Na? or Ag?), does not affect the induced-fit recog-
nition of a second ion which implies a positive coopera-
tivity between the two sides which favors the formation
of the 1:2 Ag1,1,3-alternate-5 . K1, and Ag1,1,3-
alternate-5 . Na1 complexes. The chemical shift of
OCH2Py protons as well as that of H3 and H6 protons of
pyridine ring shift to up field, being the most remarkable
shift in those of Ag1,1,3-alternate-5 . K1 complex.
These results indicated that the Ag? complexes through the
metal–oxygen electrostatic interactions and metal-nitrogen
interaction.
In contrast, the 1H-NMR resonance upon titration of 1:1
1,3-alternate-5 . Ag1 with K?, once the equilibrium was
reached, is very similar to that observed in the reverse
titration, already described. Interestingly, the 1H-NMR
pattern of the 1:2 Ag1,1,3-alternate-5 . Ag1 upon
addition of an excess of K? and after a short time (30 min)
turn out to be that of the 1:2 Ag1,1,3-alternate-5 . K?,
Fig. 5e. The released of Ag? in Ag1,1,3-alternate-
5 . Ag1 and the captured of K? instead (Ag1,1,3-
alternate-5 . K?) can be ascribed to the preorganization
of 1,3-alternate-5. The affinity of amide moiety to K?
Table 3 1H-NMR chemical shift (Dd) of pyridine protons and
methylene protons of OCH2Py of 1:2 complexes of 1,3-alternate-
5a,c,d
Complex
Dd (ppm)b in of 1:2 complexes
(Kass = 3.12 9 104 M-1
)
is higher than to Ag?
OCH2Py
H3
H6
(Kass = 2.08 9 104 M-1), which is uncommon, Sche-
me 4B; thus the formation of Ag1,1,3-alternate-5 . K1
is realized, presumably, through two steps Scheme 4A.
Finally, the addition of 5 equiv. of NaClO4 into the
solution of 1,3-alternate-5 . Ag1 separately, does not
cause any change in the spectra, only the signals for 1:1
complex are presented. Contrary to what is observed in the
previous titration, the 1:2 complex of Ag1,1,3-alternate-
Ag1, 1,3-alternate-5.Ag1
Ag1, 1,3-alternate-5.K1
Ag1, 1,3-alternate-5.Na1
a
-0.09
-0.13
-0.07
?0.07
-0.20
?0.08
?0.08
-0.25
?0.06
300 MHz, in CDCl3:CD3CN 2:1, 26 °C
Dd = d (metal)–d (free ligand)
b
c
d
(–) denotes a shift to up field. (?) denotes a shift to down field
The signals of H4 and H5 overlap with other signals
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J Incl Phenom Macrocycl Chem (2010) 68:99–108
105
Experimental
1
All mps (Yanagimoto MP-S1) are uncorrected. H-NMR
spectra were determined 300 MHz with a Nippon Denshi
JEOL FT-300 NMR spectrometer with SiMe4 as an internal
reference: J-values are given in Hz. IR were measured for
samples as KBr pellets in a Nippon Denshi JIR-AQ2OM
spectrophotometer. Mass spectra were obtained on a Nip-
pon Denshi JMS-01SA-2 spectrometer at 75 eV using a
direct-inlet system through GLC. UV spectra were mea-
sured by Shimadzu 240 spectrophotometer. Elemental
analysis: Yanaco MT-5.
1,3-alternate-5
(A)
1,3-alternate-5⊃K+
Ag+⊂1,3-alternate-5⊃K+
Materials
1,3-alternate-5⊃Ag+
Ag+⊂1,3-alternate-5⊃K+
(B)
I
5,11,17,23-Tetra-tert-butyl-2,8,14,20-tetrathiacalix[4]arene-
25,26,27,28-tetraol 1 was prepared according to the
reported procedure [1].
II
= Ag+
= K+
Ag+⊂1,3-alternate-5⊃Ag+
Scheme 4 Complexation process in 1,3-alternate-5:
effect. b I. Positive allosteric effect, II. Affinity effect
a
Affinity
Synthesis
Benzylation of 1 with benzyl bromide in the presence
of Na2CO3
5 . Na? is not formed. Comparison among the Kass of
Na? (Kass = 1.9 9 104 M-1), K?, and Ag? could explain
why the Ag1,1,3-alternate-5 . Na? is formed only in
one path: 1,3-alternate-5 . Na1 ? Ag1 ? Ag1,1,3-
alternate-5 . Na?. The presence of Na? does not cause
the realized of Ag? from the amide moiety, so the inter-
change of metals Ag?? Na? does not occur.
A mixture of 1 (200 mg, 0.276 mmol) and Na2CO3
(293 mg, 2.8 mmol) in acetone (15 mL) was heated at
reflux for 1 h. Benzyl bromide (0.34 mL, 2.8 mmol) was
then added and the mixture heated at reflux for 20 h. After
cooling the reaction mixture to room temperature, it was
filtered. The filtrate was concentrated and the residue was
extracted with CH2Cl2 (100 mL 9 2) and washed with
water (50 mL 9 2), and dried (Na2SO4). The filtrate was
concentrated to give a yellow oil, which was then distilled
under reduced pressure to remove the excess unreacted
benzyl bromide using a Kugelrohr apparatus. The residue
was washed with methanol to give the crude distal-2
(230 mg, 93%) as a colorless solid. Recrystallization from
MeOH:CHCl3 (3:1) gave 25,27-bis(benzyloxy)-26,28-
dihydroxy-5,11,17,23-tetratert-butyl-2,8,14,20-tetrathiaca-
lix[4]arene, distal-2 as colourless prisms. Mp 250–252 °C.
IR m (KBr)/cm-1 3383 (OH), 2962, 2867, 1478, 1448,
1437, 1363, 1260, 1244, 886 and 756. 1H-NMR d (CDCl3)
0.79 (18H, s, tBu), 1.34 (18H, s, tBu), 5.49 (4H, s,
OCH2Ph), 6.96 (4H, s, Ar–H), 7.24–7.36 (6H, m, Ph-H),
7.61–7.64 (4H, m, Ph-H), 7.68 (4H, s, Ar–H) and 7.98 (2H,
s, OH). MS m/z 901 (M?). Anal. Calcd. For C54H60O4S4
(901.34) C, 71.97; H, 6.72. Found: C, 72.08; H, 6.86.
Conclusion
The compound 1,3-alternate-5 presents high affinity for K?
and Ag? ions due to the 1,3-alternate conformation, as
expected, but showed a remarkable opposite cooperative
behavior which is ascribed to the presence of allosteric
effect which is strongly impacted by preorganization,
complexation mode and functional affinity. But, most
importantly, a cooperative behavior between the two edges
of the thiacalix[4]arene cavity favors the 1:2 Ag1,1,3-
alternate-5 . Ag1 and Ag1,1,3-alternate-5 . K1 com-
plexes formation. The unexpected high affinity of the amide
groups to K? ion is an important example of how the pre-
organization impacts the complexation behavior. To the
best of our knowledge the formation of 1:2 complex
Ag1,1,3-alternate-5 . K1 is the first example of heter-
ogeneous dinuclear complex in the thiacalix[4]arene fam-
ily. These results give some insight into the molecular
design of new synthetic receptors for use in metal controlled
of biomimetic systems.
O-Alkylation of distal-2 with N,N-diethylchloroacetamide
in the presence of Cs2CO3
A mixture of distal-2 (680 mg, 0.754 mmol) and Cs2CO3
(2.46 g, 7.54 mmol) in dry acetone (30 mL) was heated at
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J Incl Phenom Macrocycl Chem (2010) 68:99–108
reflux for 1 h under N2. A solution of N,N-diethylchloro-
acetamide (1.13 g, 7.54 mmol) was then added and the
mixture heated at reflux for an additional 17 h. After
cooling the reaction mixture to room temperature, it was
acidified with 1 M HCl (10 mL) and extracted with
CH2Cl2 (100 mL 9 2). The combined extracts were
washed with water (50 mL 9 2), and dried (Na2SO4) and
condensed under reduced pressure to give a yellow oil. The
residue was washed with methanol to give 1,3-alternate-3
(510 mg, 60%) as a colorless solid. Recrystallization from
MeOH:CHCl3 (3:1) gave 1,3-alternate-25,27-bis(benzyl-
oxy)-26,28-bis[(N,N-diethylaminocarbonyl)methoxy]-5,11,
17,23-tetra- tert-butyl-2,8,14,20-tetrathiacalix[4]arene, 1,3-
alternate-3 as a colourless prisms. Mp 255–256 °C. IR m
(KBr)/cm-1 1664 (C = O). 1H-NMR d (CDCl3) 0.83 (18H,
s, tBu), 0.89–1.00 (6H, m, CH2CH3), 1.10–1.20 (6H, m,
CH2CH3), 1.30 (18H, s, tBu), 3.12–3.19 (4H, m,
CONCH2), 3.35–3.42 (4H, m, CONCH2), 4.70 (4H, s,
CH2CON), 4.95 (4H, s, CH2Ph), 7.18 (4H, s, Ar–H),
7.17–7.23 (10H, m, Ph-H) and 7.62 (4H, s, Ar–H). MS m/z
1127.5 (M?). Anal. Calcd. For C66H82N2O6S4 (1127.64) C,
70.3; H, 7.33; N, 2.48. Found: C, 70.25; H, 7.28; N, 2.44.
give a yellow oil, which was washed with hexane to give
distal-4 (142 mg, 85%) as a colorless solid.
Synthesis of 5,11,17,23-tetra-tert-butyl-25,27-bis[(N,N-
diethylaminocarbonyl)methoxy]-26,28-bis[(pyridylmethyl)
oxy]-2,8,14,20-tetrathiacalix[4]arene (1,3-alternate-5)
A mixture of amide distal-4 (370 mg, 0.390 mmol),
Cs2CO3 (1.26 g, 3.90 mmol) in dry THF (6 mL) was
heated at reflux for 1 h under nitrogen. Then a solution of
2-(chloromethyl)pyridine [prepared by neutralization of
2-(chloromethyl)pyridine hydrochloride (639 mg, 3.90
mmol) in DMF (8 mL) with a solution of triethylamine
(0.53 mL, 3.90 mmol) in THF (8 mL) at room tempera-
ture]was added and the mixture heated for 17 h. After
cooling the reaction mixture to room temperature, it was
acidified with 1 M HCl (15 mL) and extracted with
CH2Cl2 (50 mL 9 2). The combined extracts were washed
with water (50 mL 9 2), dried (Mg2SO4) and condense
under reduced pressure to give 1,3-alternate-5 (250 mg,
57%) as a colorless solid. Recrystallization from CHCl3–
MeOH afforded 5,11,17,23-tetra-tert-butyl-25,27-bis[(N,N-
diethylaminocarbonyl)methoxy]-26,28-bis[(pyridyl-methy-
l)oxy]-2,8,14,20-tetrathiacalix[4]arene, 1,3-alternate-5 as
colorless prisms. Mp 246–251 °C. IR m (KBr)/cm-1: 1674
(C = O); 1H-NMR d (CDCl3) 0.83 (18H, s, tBu), 1.2 (12H,
t, J = 7.4, CH2CH3), 1.30 (18H, s, tBu), 3.08 (4H, q,
J = 7.4 Hz, CH2CH3), 3.33 (4H, q, J = 7.4 Hz, CH2CH3),
4.65 (4H, s, OCH2CO), 5.15 (4H, s, OCH2Py), 6.72 (2H, d,
J = 7.3 Hz, PyH3), 7.11 (4H, s, ArH), 7.13 (2H, m, PyH5),
7.38 (2H, m, PyH4), 7.49 (4H, s, ArH) and 8.50 (2H, d,
J = 4.4 Hz, PyH6). MS m/z: 1129.4 (M?). Anal. Calcd. for
C64H80O6S4N4 (1129,61): C, 68.05; H, 7.14; N, 4.96.
Found: C, 68.04; H, 7.13; N, 4.92.
AlCl3 catalyzed debenzylation of 1,3-alternate-3 in toluene
A mixture of AlCl3 (246 mg, 1.85 mmol) in dry CH2Cl2
(1.5 mL) was stirred at room temperature for 30 min and
then 1,3-alternate-3 (350 mg, 0.31 mmol) dissolved in
toluene (10 mL) was added. The reaction was vigorously
stirred at room temperature for 5 h and then quenched with
1 N HCl, extracted with CH2Cl2. The organic layer was
separated, washed twice with brine, dried with MgSO4 and
evaporated to dryness to obtain 5,11,17,23-tetra-tert-butyl-
25,27-bis-[(N,N-diethylaminocarbonyl)methoxy]-26,28-
dihydroxy-2,8,14,20-tetrathiacalix[4]arene, distal-4 (211 mg,
72%) as colorless solid. Recrystallization from CHCl3–
MeOH afforded dital-4 as colorless prisms. Mp 259–
264 °C. IR m (KBr)/cm-1 3363, 1666; 1H-NMR d (CDCl3)
0.82 (18H, s, tBu), 1.24 (12H, t, J = 7.4 Hz, CH2CH3),
1.35 (18H, s, tBu), 3.38 (4H, q, J = 7.4 Hz, CH2CH3), 3.55
(4H, q, J = 7.4 Hz, CH2CH3), 5.37 (4H, s, OCH2CO),
6.88 (4H, s, ArH), 7.63 (4H, s, ArH), 8.54 (2H, s, OH). MS
m/z: 947.5 (M?). Anal. Calcd. for C52H70O6S4N2 (947.39):
C, 65.93; H, 7.45; N, 2.96. Found: C, 65.67; H, 7.41; N,
2.96.
Synthesis of 4-tert-butyl-2,6-dimethyl[(2-pyridylmethyl)
oxy]benzene 7
A mixture of 4-tert-butyl-2,6-dimethylphenol 6 (400 mg,
2.25 mmol) and NaH (580 mg, 14.5 mmol, 60%) in dry
THF (20 mL) was heated at reflux for 1 h under N2. Then a
solution of 2-(chloromethyl)pyridine (14.5 mmol) [pre-
pared by neutralization of 2-(chloromethyl)pyridine
hydrochloride (2.38 g, 14.5 mmol) in DMF (15 mL) with a
solution of triethylamine (2.02 mL, 14.52 mmol) in THF
(25 mL) at room temperature] was added and the mixture
heated at reflux for an additional 17 h. After cooling the
reaction mixture to room temperature, it was acidified
with 1 M HCl (10 mL) and extracted with CH2Cl2
(100 mL 9 2). The combined extracts were washed with
water (50 mL 9 2), dried (Na2SO4) and condensed under
reduced pressure to give a yellow oil. The residue was
chromatographed on silica gel with methanol as an eluent
Nafion-H catalyzed debenzylation of 1,3-alternate-3
in toluene
A mixture of 1,3-alternate-3 (200 mg, 0.177 mmol) and
Nafion-H (400 mg) in toluene (6 mL) was heated at 100 °C
for 12 h. After cooling the reaction mixture to room tem-
perature, it was filtered. The filtrate was concentrated to
123

J Incl Phenom Macrocycl Chem (2010) 68:99–108
107
to give the title compound 7 (380 mg, 63%) as a colorless
oil. IR m (NaCl)/cm-1: 2963, 2870, 1605, 1473, 1456,
1436, 1413, 1270, 804, 797; 1H-NMR d (CDCl3) 1.30 (9H,
s, tBu), 2.31 (6H, s, CH3), 4.95 (2H, s, CH2Py), 7.05 (2H, s,
Ar–H), 7.20 (1H, m, Py-H5), 7.74 (2H, m, Py-H3 and Py-
H4), 8.58 (1H, dd, J = 0.9, 4.9, Py-H6). MS m/z: 269 (M?).
Anal. Calcd. for C18H23NO (269.39): C, 80.26; H, 8.61; N,
5.2. Found: C, 80.55; H, 8.49; N, 4.98.
OCH2Py protons, maintaining the concentration of 1:1
complex constant (4.0 mM in CDCl3-CD3CN) and adding
aliquots of cation (AgSO3CF3 and/or KSO3CF3) from
0–50 mM in the same solvent mixture.
1H-NMR complexation experiments
To a CDCl3 solution (4 9 10-3 M) of the receptor 1,3-
alternate-5 in the NMR tube was added a CD3CN solution
(4 9 10-3 M) of AgSO3CF3, KSO3CF3 and NaClO4. The
spectrum was registered after addition and the temperature
of NMR probe kept constant at 27 °C.
Stoichiometry of metal complexation
The method of continuous variation was employed to
determine the stoichiometry of 1,3-alternate-5. Two-phase
solvent extraction was carried out between aqueous pi-
crates (5 mL, [metal picrate] = 2 9 10-4 M, AgNO3,
0.1 M, NaOH or KOH) and 1,3-alternate-5 (5 mL, [1,3-
alternate-5] = 2 9 10-4 M in CH2Cl2). The molar ratios
of the both 1,3-alternate-5 and metal picrate were varied
from 0 to 1, while the total concentration was kept at
several constant levels. The two-phase mixture in a glass
tube immersed in a thermostated water bath at 25 °C was
shaken at 300 strokes per min for 1 h and then kept, at the
same temperature, for 2 h, allowing the complete separa-
tion of the two phases. The absorbance of each solution
was determined by UV spectroscopy (k = 290 nm). Job
plots were generated by plotting the extracted [Ag?] versus
the mole fraction of metal.
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