A specific and ratiometric chemosensor for Hg2+ based on triazole coupled ortho-methoxyphenylazocalix[4arene

Article abstract of DOI:10.1016/j.tet.2011.08.052

Calix[4arene 3, which contains two distal triazole groups on the lower rim and two distal o-methoxyphenylazo groups on the upper rim, was synthesized and found to be a specific and ratiometric sensor for Hg²⁺ in a polar protic solvent. A series

Full text of DOI:10.1016/j.tet.2011.08.052

Tetrahedron 67 (2011) 8131e8139
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A specific and ratiometric chemosensor for Hg2þ based on triazole coupled
ortho-methoxyphenylazocalix[4]arene
*
*
Nae-Jen Wang, Chung-Ming Sun , Wen-Sheng Chung
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 30050, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 April 2011
Received in revised form 3 July 2011
Accepted 19 August 2011
Available online 25 August 2011
Calix[4]arene 3, which contains two distal triazole groups on the lower rim and two distal o-methox-
yphenylazo groups on the upper rim, was synthesized and found to be a specific and ratiometric sensor
for Hg2þ in a polar protic solvent. A series of o-methoxyphenylazo derivatives (3, 4, 5, 7, and 9) were
synthesized, which proved that the lower-rim triazoles and the hydroxyl azophenol(s) were the major
ligands for metal ion binding. Though analogues 4 and 10 showed some sensitivity for Hg2þ, compound 3
was the only ratiometric chemosensor for Hg2þ among the series of azocalix[4]arenes synthesized in this
work. The formation of 3$Hg2þ complex was supported by UV/vis and NMR titration studies and Mass
spectrometry. Based on the symmetrical features of NMR spectra of 3$Hg2þ, the complex is believed to be
symmetrical with respect to the calix[4]arene cavity. Furthermore, the complex was determined to be
1:1 binding stoichiometry by Job’s plot, and the association constant was determined to be 4.02ꢀ103 Mꢁ1
using BenesieHildebrand plot.
Keywords:
Azocalix[4]arene
Click reaction
Triazole
Chemosensor
Mercury ion
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
functioned as a chromophore; occasionally, they also functioned as
a metal-chelating ligand. When the upper-rim arylazo groups in
Mercury is one of the toxic heavy transition-metal ions and as
reported by US Environmental Protection Agency (EPA), the annual
total global mercury emissions from all sources, both natural and
human-generated, reached nearly 7500 tons in 2005.1 When in-
haled by human body, mercury can trigger several serious disor-
ders, including sensory, motor, and neurological;2 therefore, many
sophisticated analytical tools have been developed to detect mer-
cury ions. To design a useful chemosensor for metal ions,3 two main
issues should be considered: (1) high selectivity, and (2) the
effective conversion of recognition event into optical or electro-
chemical signals. In this aspect, we have been interested in de-
veloping naked eye sensors for metal ions due to its simplicity and
convenience.
a calix[4]arene only play the role as a chromophore, the lower-rim
modification of the azocalixarenes, by ester, carboxylic acid, het-
erocyclic ring, or crown ether groups,5 is usually required to endow
it with metal-chelating ability. We were one of the first to introduce
triazoles as the metal ion binding ligands of the chromogenic
azocalix[4]arenes, for example, para-methoxyphenylazocalix[4]
arene 10 (Scheme 1) was reported5a to be a chromogenic sensor for
Ca2þ and Pb2þ, while the para-nitrophenylazocalix[4]arene ana-
logue of 10 was found to be a dual sensor for Ca2þ and Fꢁ.5c
Upper-rim arylazo functionalized calix[4]arenes, which play not
only as a chromophore but also as a metal ion binding site, were also
intensively explored.6 The main working principle for the chromo-
genic sensing of these upper-rim arylazo functionalized calix[4]
arenes toward metal ions is that metal ion enhances the tautomeri-
zation of the azophenols to quinoneehydrazones.7 Nomura and co-
workers reported the first example of using the upper-rim azophe-
nol substituted calix[6]arene as both chromophores and metal ion
chelating ligands, which showed high selectivity toward Agþ, Hgþ,
Azo compounds are widely used in chromoionophores because
they could exhibit substantial color changes observable by the
€
naked eyes upon complexation with guest molecules or ions. Vogtle
and co-workers were one of the pioneers in coupling the 4-(4-
nitrophenyl)azo group with a crown ether and found that it
showed a large hypsochromic shift when bonded with Ba2þ 4
.
The
and Hg2þ 6f
. We reported that 5,17-bisallyl-11,23-bis-(p-methox-
binding ability of azocalixarenes for metal ions was intensively
yphenyl)azocalix-[4]arene, without lower-rim modification, was
a highly sensitive chromogenic sensor for Hg2þ, in which both the
upper-rim p-allyl- and p-methoxyphenylazo groups were involved
investigated in recent years,5,6 in which the azo groups mostly
in the recognition of Hg2þ 6g,h
reported that
.
Recently, Kim and co-workers also
5,11,17,23-tetra[(2-ethylacetoethoxyphenyl)azo-
* Corresponding authors. Tel.: þ886 3 513 1517; fax: þ886 3 572 3764. (W.-S.C);
tel.: þ886 3 513 1511; fax: þ886 3 513 1511 (C.-M.S.); e-mail addresses: cmsun@
mail.nctu.edu.tw (C.-M. Sun), wschung@cc.nctu.edu.tw (W.-S. Chung).
phenyl]calix[4]arene exhibited selectivity toward transition-metal
ions over alkali and alkaline earth metal ions.6c,d
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.052

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N.-J. Wang et al. / Tetrahedron 67 (2011) 8131e8139
H3CO
H3CO
OCH3
OCH3
OCH3
N
N
N
N
N
N
N
N
O
N
N
O
O
O
O
OH
OH
OH
OH
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
5
3
4
OCH3
OCH3
N
N
N
H3CO
OCH3
N
N
N
N
N
N
N
OH
OCH3
O
OH
OH
O
O
OH
OH
O
N
N
N
N
9
N
N
7
10
Scheme 1. The structures of target azo compounds.
Initially we intended to design an allosteric calix[4]arene 3 by
combining the lower-rim two distal triazole units as one metal ion
binding site and the upper-rim two distal ortho-methoxyphenylazo
units as the other; the idea came from the report that ortho-
substituted-phenylazo groups might help to bind metal ions.6i
However, in the end we found that 3 did not function as an allo-
steric sensor; it only exhibited a high selectivity toward Hg2þ in
MeOH. To assess the relative binding abilities of the upper-rim or-
tho-methoxy-phenylazophenol and the lower-rim triazoles of 3, we
also synthesized compounds 4, 5, 7, and 9 (Scheme 1) for com-
parison. UV/vis, NMR, MASS spectrometry, and molecular modeling
(DMol3)14 were used to identify the possible binding modes of 3
cycloaddition reactions of 2a and 2b with 1-(azidomethyl)benzene
under the Click condition8 afforded the azocalix[4]arenes 3 and 4 in
71% and 73% yield, respectively. Further etherification of 3 with 1-
iodopropane in the presence of K2CO3 was unsuccessful pre-
sumably due to the steric hindrance of the flanking triazole groups
next to the hydroxyl phenols. When stronger base, such as sodium
hydride, was used to react 3 with 1-iodopropane in DMF at 80 ꢂC, it
gave 5 only in 10% yield even after 18 h of reaction time and 87% of 3
was recovered. In contrast, 1,3-dipropylation of calix[4]arene was
readily carried out with an excess of 1-iodopropane and K2CO3 in
refluxing CH3CN to afford 6 in 78% yield.10 Control compounds 7
and 9, using 6 and 2,6-dimethylphenol 8, respectively, as the
starting materials, were synthesized by the azo-coupling reaction
similar to that used in the preparation of 2a and 2b and the yields
were 39% and 83%, respectively (see Scheme 2). The lower yield for
the azotization of 6 compared to that of 1 was due to the recovery of
50% of starting material. The structures of all azo-coupled calix[4]
arenes were fully characterized by NMR (1H and 13C), MS, and
HRMS (see Experimental section). In 1H NMR spectra, the methy-
lene bridge protons of these azocalix[4]arenes 3e5 and 7 exhibit
with Hg2þ
.
2. Results and discussion
Five new o-methoxyphenylazo-coupled chemosensors (3e5, 7,
and 9) were synthesized and their structures and synthetic path-
ways are shown in Schemes 1 and 2. Chemosensor 3 and its ana-
logue 4 were obtained via azo-coupling reaction of 1 followed by
click reaction.8 The azotization of 25,27-bis(O-propargyl)calix[4]
arene 15a,9 using o-anisidine in concd HCl and NaNO2 in acetone
and pyridine gave the upper-rim distal bis-azo-coupled calix[4]
arene 2a and mono-azo-coupled calix[4]arene 2b in 36% and 42%
yield, respectively. The ratio of 2a/2b increased with the reaction
time and their structures can be distinguished by 1H NMR spectra.
Both 2a and 2b exhibited similar singlet peaks for the methoxy
one set of doublet signals around d 4.4e4.1 ppm and d 3.6e3.0 ppm,
implying that they are more stable in cone conformations. 13C NMR
of the methylene bridge carbons of these azocalix[4]arenes 3e5
and 7 exhibited signals around
d 32 ppm further support that they
were in cone conformations.11
The absorption maxima (lmax) and molar extinction coefficients
of the five target azo-coupled calix[4]arenes synthesized in this
work are summarized in Table 1. As can be seen, the absorption
maxima (lmax) of 3, 4, 7, and 9 with azophenol form are above
369 nm. Azocalix[4]arene 5, whose two distal hydroxyl groups of
azophenol were converted to propoxy groups, had a shorter lmax
(364 nm). Besides, the lmax of 3, which contains two azophenol
units was almost the same as that of 4 with mono-azophenol.
Furthermore, azo-coupled calix[4]arenes 3 and 7, which contain
protons around
showed different splitting patterns. The methylene bridge protons
of 2a exhibited two doublet peaks at 4.2 and 3.4 ppm; whereas
those of 2b exhibited four doublet peaks around 4.2 and 3.3 ppm.
d 4.0 ppm, but their methylene bridge protons
d
d
After building mono- and bis-azo groups on the upper rim of
calix[4]arene, the lower-rim two distal triazoles groups were
obtained by 1,3-dipolar cycloaddition reactions. 1,3-Dipolar

N.-J. Wang et al. / Tetrahedron 67 (2011) 8131e8139
8133
H3CO
OCH3
OCH3
N
N
N
N
N
N
i
O
OH
OH
O
+
O
O
OH
OH
OH
OH
O
O
1
2a 36%
2b 42%
ii
ii
4 73%
3 71%
iii
5 10%
iv
v
i
7 39%
O
OH
OH
O
HO
OH
OH
OH
6 78%
9 83%
OH
8
Scheme 2. Synthetic pathways for chromoionophores 3e5, 7, and 9. Reagents and conditions: (i) o-anisidine/acetone, NaNO2/concd HCl, pyridine, 0 ꢂC, 3 days; (ii) 1-(azidomethyl)-
benzene, CuI, THF/H2O, 50 ꢂC, 18 h; (iii) 1-iodopropane, NaH/DMF, 80 ꢂC, 18 h; (iv) 1-iodopropane, K2CO3/CH3CN, reflux 1 day; (v) o-anisidine/acetone, NaNO2/concd HCl, pyridine,
0
ꢂC, 12 h.
Table 1
these ligands in the titration experiments were around 10e20 mM
lmax and corresponding extinction coefficients of azo-coupled compounds 3e5, 7,
and 9 in methanolechloroform (v/v, 98:2) cosolvent at 25 ꢂC
depending on their molar extinction coefficients. The results are
shown in Figs. 1 and 2. The UV/vis spectra of the upper-rim distal o-
methoxyphenylazo-coupled calix[4]arenes 3, 5, and 7 with and
without 15 metal perchlorates were studied (Fig. 1a,c, and d). Li-
gand 7, a control compound of 3 whose lower-rim distal triazole
units were replaced by two propoxy groups, did not show any shift
in its lmax after adding 15 different metal perchlorates (Fig. 1d). The
results imply that the triazole units are the major binding ligands
for Hg2þ. Ligand 5, another control compound of 3, in which the
lower-rim two triazoles units were intact but the two azophenol
groups were protected by propoxy groups, exhibited much smaller
affinities toward Hg2þ, Agþ, and Cu2þ ions with some hypsochromic
shifts (Fig. 1c). Compound 9, o-methoxy-phenylazophenol, did not
show any affinity toward the 15 metal ions (Fig. 1e), implying that
not only the azophenol groups but also the triazole groups are
Compound
lmax (nm)
3 )
(Mꢁ1 cmꢁ1
3
4
5
7
9
373
372
364
371
369
43,500 (ꢃ2500)
23,000 (ꢃ1000)
23,500 (ꢃ1500)
32,500 (ꢃ1500)
24,500 (ꢃ2500)
bis-o-methoxyphenly-azophenol groups had the larger molar ex-
tinction coefficients compared to those of 4 and 9, which contain
only mono-azophenol. Note that the molar extinction coefficient of
bis-arylazo-coupled calix[4]arene 3 was almost twice as big as that
of its mono-arylazo-coupled analogue 4. Smaller extinction co-
efficient and lmax of 7 versus that of 3 implies that there may be
hydrogen bonding interaction between the lower-rim triazole and
the hydroxyl groups of the azophenols in 3, which slightly favors
the tautomerization of the azophenol to quinoneehydrazones.6g,h
The binding properties of ligands 3e5, 7, and 9 were assessed by
necessary components for the chromogenic sensing of Hg2þ
.
To further explore the relationship between the binding ability
and the number of the azophenol units, UV/vis spectra of ligands 3
(with distal bis-azophenol units) and 4 (with mono-azophenol
unit) were screened with various metal ions. Ligands 3 and 4
exhibited a specific selectivity toward Hg2þ ion over all other metal
ions (Fig. 1a and b) but with different binding affinities. When
the addition of 10 equiv of metal perchlorates (Liþ, Naþ, Kþ, Mg2þ
Ca2þ, Ba2þ, Agþ, Cu2þ, Ni2þ, Cd2þ, Hg2þ, Zn2þ, Mn2þ, Pb2þ, and Cr3þ
in a MeOH/CHCl3 (v/v, 98:2) cosolvent and the concentration of
,
)

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N.-J. Wang et al. / Tetrahedron 67 (2011) 8131e8139
Fig. 1. UV/vis spectra of various ligands in the presence and absence of 10 equiv of 15 different metal perchlorate salts (Liþ, Naþ, Kþ, Mg2þ, Ca2þ, Ba2þ, Agþ, Cu2þ, Ni2þ, Cd2þ, Hg2þ
Zn2þ, Mn2þ, Pb2þ, and Cr3þ) in MeOH/CHCl3 (v/v, 98:2): (a) ligand 3, 10
M; (b) ligand 4, 15 M; (c) ligand 5, 10 M; (d) ligand 7, 10 M; (e) ligand 9, 20 M, and (f) ligand 10, 10 M.
,
m
m
m
m
m
m
contains two upper-rim arylazo phenols, is a better sensor for Hg2þ
than compound 4, which contains only ‘one’ upper-rim arylazo-
phenol unit.
In order to evaluate the role of the position of the methoxy
substituent on the arylazo group, the UV/vis spectra of ligand 3 and
its structural isomer 105a were screened over 15 metal ions (Fig. 1a
and f). The only difference between 3 and 10 is the position of the
methoxy substituent on the upper-rim arylazo units (Scheme 1)
where 3 contains two distal ortho-methoxy-phenylazophenol units
while 10 contains two distal para-methoxypenylazophenol units. It
is important to note that ligand 10 was previously reported5a to be
a chromogenic sensor for Ca2þ and Pb2þ in acetonitrile. In this
work, ligand 10 also showed some UV/vis response toward Hg2þ in
MeOH/CHCl3 (v/v, 98:2) protic cosolvent and its spectra changes are
similar to those of 4 (cf. Fig. 1b and f) but to a much less extent
compared to that of ligand 3. Upon adding Hg2þ, ligand 3 showed
a more distinct bathochromic shift (Dlmax¼78 nm) compared to
that of 10 in MeOH/CHCl3 (v/v, 98:2) cosolvent (cf. Fig. 1a and f). The
results indicated that 3, which contained two ortho-
Fig. 2. Colors of ligand 3 (10 mM) in the absence and presence of 10 equiv of 15 dif-
ferent metal perchlorate salts in MeOH/CHCl3 (v/v, 98:2). From left to right: free ligand
3, and ligand 3 with 10 equiv of Liþ, Naþ, Kþ, Mg2þ, Ca2þ, Ba2þ, Hg2þ, Agþ, Cr3þ, Mn2þ
,
Ni2þ, Zn2þ, Cd2þ, Pb2þ, Cu2þ, respectively.
complexed with Hg2þ, the lmax of 3 showed not only a bath-
ochromic shift (Dlmax¼78 nm) but also a hyperchromic effect (in-
crease in intensity). It was showing a much less effect on lmax and
absorption intensity when ligand 4 was treated with Hg2þ. There-
fore, the color of solution 3 changed from pale yellow to beige upon
adding Hg2þ, which can be easily observed by the naked eyes,
whereas, the color of solution 4 did not show any discernable
change upon adding Hg2þ (Fig. 1b). Thus, compound 3, which

N.-J. Wang et al. / Tetrahedron 67 (2011) 8131e8139
8135
methoxyphenyl-azophenol groups, was a more effective chromo-
(a)
genic sensor for Hg2þ than 10 that contained two para-methox-
yphenyl-azophenol groups.
Upon adding Hg(ClO4)2 to the solution of 3 in MeOH/CHCl3 (v/v,
98:2) cosolvent, it exhibited a marked bathochromic shift in its lmax
as shown in Fig. 3. The intensity of the absorption maximum at
373 nm gradually decreased with the formation of a new absorp-
tion band at 451 nm (Dlmax¼78 nm). Two isosbestic points at 311
and 420 nm were observed in the titration spectra of 3 with
Hg(ClO4)2 and the spectral feature was consistent with a 1:1
binding ratio between 3 and Hg2þ. Further support of the 1:1
binding ratio came from Job plot experiments,12 where absorption
of the complex at 451 nm was plotted against the molar fraction of
3 under the condition of an invariant total concentration. As a re-
sult, the concentration of the complex 3$Hg2þ approached a maxi-
mum when the molar fraction of [3]/([3]þ[Hg2þ]) was about 0.5
(Fig. 4a).12 The 1:1 association constant of the bis-o-methox-
yphenylazocalix[4]arene 3 with Hg2þ in MeOH/CHCl3 cosolvent
was determined to be 4.02ꢀ103 Mꢁ1 on the basis of Bene-
sieHildebrand plot (Fig. 4b).13 The UV/vis spectral change between
3 and complex 3$Hg2þ was fully reversible, namely, the addition of
H2O to the solution of 3$Hg2þ reversed its color to free ligand 3
(Fig. S19, Supplementary data).
(b)
Fig. 4. (a) Job’s plot of a 1:1 complex of 3 and Hg2þ, where the absorption of complex
at 451 nm was plotted against the mole fraction of 3 at an invariant total concentration
of 10 mM; (b) BenesieHildebrand plot of 3 with Hg(ClO4)2.
the addition of 0e0.8 equiv Hg2þ, the peak of the proton Hf on the
azophenol unit of 3 remained singlet until it disappeared (Figs. 5
and S4, Supplementary data).These spectral features imply that
the two distal hydroxyl azophenol units of ligand 3 formed a weak
but symmetrical complex with Hg2þ. Protons Hh and Hi on the calix
[4]arene skeleton of ligand 3 were downfield shifted by only
0.04 ppm in the presence of 1 equiv of Hg2þ, whereas the methy-
lene bridge protons Hj had more noticeable changes in chemical
shifts. When 1 equiv of Hg2þ was added to 3, one set of the
methylene bridge protons, Hj1, was downfield shifted by about
0.13 ppm and then partly merged into the peak of MeOH; the other
set of methylene bridge protons, Hj2, was upfield shifted by about
0.04 ppm and the peaks eventually merged partly into the methoxy
group protons (Ha).
The chemical shift difference (Dd), between the two sets of
methylene bridge protons, was about 0.85 ppm in free ligand 3
(Fig. 5a) but was reduced to 0.68 ppm in the presence of 1 equiv of
Hg2þ (Fig. 5d), which implied that the complex 3$Hg2þ was in
a flattened cone conformation.5b,11c The protons Hk, Hm, and the
nearby phenyl group were little influenced when the concentration
of Hg2þ increased, but the triazole proton Hl was downfield shifted
by 0.16 ppm in the presence of 1 equiv of Hg2þ, which showed the
most significant shift among all the protons of ligand 3. Accord-
ingly, we proposed that Hg2þ was bonded to the two nitrogen
atoms of the lower-rim distal triazole units of ligand 3 and formed
a symmetrical flattened cone conformation, in which the two distal
hydroxyl azophenol also assisted in the binding of Hg2þ by elec-
trostatic interaction (Chart 1). The upper-rim two distal arylazo
units only functioned as the signal transduction units in ligand 3. It
should be noted that the symmetrical complexation of Hg2þ in the
protic cosolvent system used in this work is quite different from
those reported in other azo-coupled calix[4]arenes studied in
Fig. 3. UV/vis spectra of 3 (10
mM) upon adding various amounts of Hg(ClO4)2 in
MeOH/CHCl3 (v/v, 98:2) cosolvent at 25 ꢂC.
A similar Job plot experiment on compound 4 with Hg2þ was
carried out, which showed a 1:1 binding ratio of 4$Hg2þ (Fig. S1,
Supplementary data). Note that the absorption change of the
complex 4$Hg2þ was too small to allow an accurate estimation of
the binding constant (Fig. S2, Supplementary data). An electrospray
mass spectrometry of complex 3$Hg2þ showed a peak at m/
z¼1235.4 corresponding to the mass of [3eHþHg]þ (Fig. S3,
Supplementary data).
In order to gain insight into the structure of complex 3$Hg2þ, we
carried out 1H NMR titration experiments on 3 with different
amounts of Hg2þ. 1H NMR spectra of 3 (2.5 mM) in the presence of
different equivalent of Hg(ClO4)2 were measured in a methanol-d4/
CDCl3 (v/v, 1:1) cosolvent (Fig. 5). When 1.5 mM (0.6 equiv) of Hg2þ
was added to 3, solid precipitates started to occur, which gradually
caused the signal to decrease as the concentration of Hg2þ in-
creased (Fig. 5b). Upon the complexation of 3 with Hg2þ, the
chemical shifts of protons HaeHf on the azophenol units of ligand 3
were little influenced. Proton Hf initially moved downfield by
0.03 ppm in the presence of 0.6 equiv of Hg2þ (Fig. 5b), however, it
moved back to its original location (at
d 8.03 ppm) in the presence
of 2 mM (0.8 equiv) of Hg2þ (Fig. 5c), and then buried under the
chloroform peak in the presence of 1 equiv of Hg2þ (Fig. 5d), the
signal became weaker because more precipitates formed. During

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N.-J. Wang et al. / Tetrahedron 67 (2011) 8131e8139
Fig. 5. 1H NMR spectra of 3 (2.5 mM) in a methanol-d4/CDCl3 (v/v, 1:1) cosolvent in the presence of different amount of Hg(ClO4)2: (a) 0 mM; (b) 1.5 mM (0.6 equiv); (c) 2 mM
(0.8 equiv), and (d) 2.5 mM (1 equiv), where * denotes signals from solvents MeOH and CHCl3, : denotes an external standard CHCl3, and V denotes the sweeping noise from the
instrument.
acetonitrile,5a,b in which the metal complexation was mostly un-
symmetrical with respect to the calix[4]arene skeleton.
Finally, the optimized geometries of 3 and 10 were calculated by
the molecular modeling DMol314 and simulated in MeOH envi-
ronment (Fig. 6 and Tables S1e4, Supplementary data). The DMol3
method from Material Studio 5.0 is developed by Accelrys Inc. in
which the wavefunctions are expanded in terms of accurate nu-
merical basis set. We used a double-numeric quality basis set with
polarization functions (DNP). The size of the DNP basis set is
comparable to Gaussian 6-31G**, but DNP is more accurate than
a Gaussian basis set of the same size.15a During geometry optimi-
zation, displacements were set at 10ꢁ3 Bohr radius (0.529177 A),
ꢀ
gradient at 10ꢁ3 Hartree/Bohr radius, and energy at 10ꢁ5 Hartree.15b
In general, the calculated optimized geometries of 3 and 10 posses
the cone formation in MeOH, where the two distal phenoxy groups
of the triazolylmethoxy benzenes are almost parallel to each other
while the other two distal azophenol groups are oriented outward
to give a ‘pinched cone’ (or so-called ‘flattered cone’) conformation.
Fig. 6. Optimized geometries for ligands (a)
calculation.
3 and (b) 10 in MeOH by DMol3
Chart 1. A possible binding mode of 3$Hg2þ
.

N.-J. Wang et al. / Tetrahedron 67 (2011) 8131e8139
8137
Scrutiny of the optimized geometries of 3 and 10 in MeOH
(Fig. 6) showed some important features: (1) the C2eC4 distance
between two distal phenolic ethers is 5.480 A in 3 but is 4.708 A in
10; (2) the C1eC3 distance between two distal upper-rim azo-
by column chromatography with ethyl acetate/hexane as an eluent
and gave the corresponding products in 20e83% yield.
ꢀ
ꢀ
4.2.1. Data for 5,17-bis(o-methoxyphenyl)azo-25,27-dipropargyloxy-
26,28-dihydroxycalix[4]arene (2a). The solid was eluted with ethyl
acetate/hexane (v/v, 1:1) and gave 0.17 g (36%) of an orange pow-
der; mp 213e214 ꢂC; Rf¼0.65 (EtOAc/hexane, 1:1); 1H NMR (CDCl3,
ꢀ
ꢀ
phenyl groups is 10.179 A in 3 but is 10.323 A in 10; (3) in particular,
the N1eN2 distance of the lower-rim two distal triazole units is
ꢀ
ꢀ
7.751 A in 3 but is 10.323 A in 10. The features indicate that in order
to decrease the repulsion between ortho-methoxyphenylazo units
and its neighboring phenolic units, the two distal phenolic units on
the calix[4]arene 3 were more flattened than that of 10 and thus
resulted in the closer distance between the two distal triazole units
on the lower rim of 3. We speculate that the smaller lower-rim
cavity of ligand 3 compared to that of 10, might have some effect
300 MHz)
d
7.77 (4H, s, PheH), 7.63 (2H, s, OH), 7.60 (2H, dd, J¼8.0,
1.6 Hz, PheH), 7.43e7.37 (2H, m, PheH), 7.09e6.94 (8H, m, PheH),
6.76 (2H, t, J¼7.5 Hz, PheH), 4.83 (4H, d, J¼2.4 Hz, OCH2), 4.44 (4H,
d, J¼13.2 Hz, PheCH2ePh), 4.03 (6H, s, OCH3), 3.58 (4H, d,
J¼13.2 Hz, PheCH2ePh), 2.63 (2H, t, J¼2.4 Hz, OCH2CCH); 13C NMR
(CDCl3, 75.4 MHz)
d 156.7 (Cq), 156.6 (Cq), 151.7 (Cq), 146.7 (Cq),
on its more effective complexation with Hg2þ
.
143.1 (Cq), 133.0 (Cq), 131.8 (CH), 129.9 (Cq), 129.6 (CH), 128.9 (Cq),
126.3 (CH), 124.4 (CH), 121.3 (CH), 117.6 (CH), 112.8 (CH), 78.4 (Cq),
77.6 (CH), 64.0 (CH2), 56.7 (CH3), 32.1 (CH2); MS (FAB, m/z) 769
[MþHþ]; HRMS m/z calcd for C48H41N4O6 769.3026, found
769.3028.
3. Conclusions
A series of ortho-methoxyphenylazocalix[4]arenes (3, 4, 5, and
7) with different lower-rim substituents or different number of the
upper-rim azo unit were synthesized to probe the ion sensing
abilities of the triazole groups and the o-methoxy-phenyl-
azophenol units. Ligand 3, which has two distal ortho-methox-
yphenylazo groups on the upper-rim and bis-benzyl-1,2,3-
triazolylmethoxy groups at the lower rim, was proven to be
a ratiometric and specific chromogenic sensor for Hg2þ in polar
protic solvent MeOH/CHCl3 (v/v, 98:2). All other analogues syn-
thesized (4, 5, and 7) and compound 105a reported previously were
not as good as that of 3 even though their skeletons and attached
functional groups were quite similar. The complex 3$Hg2þ in protic
solvent studied here has a flattened cone conformation and is
symmetrical with respect to the calix[4]arene skeleton. Our studies
in the past5a,c,6g,h and this work showed that solvent effect plays
a crucial role in determining the selectivity and sensitivity of
chromogenic sensors for metal ions based on upper-rim arylazo-
coupled calix[4]arenes.
4.2.2. Data for 5-(o-methoxyphenyl)azo-25,27-dipropargyloxy-26,28-
dihydroxycalix[4]arene (2b). The solid was eluted with ethyl ace-
tate/hexane (v/v, 1:2) and gave 0.16 g (42%) of an orange powder;
mp 207e209 ꢂC; Rf¼0.73 (EtOAc/hexane, 1:1); 1H NMR (CDCl3,
300 MHz)
d 7.76 (2H, s, PheH), 7.63 (1H, s, OH), 7.62e7.58 (1H, m,
OH), 7.42e7.37 (1H, m, PheH), 7.11e6.99 (5H, m, PheH), 6.93 (2H,
dd, J¼7.5,1.5 Hz, PheH), 6.86 (2H, dd, J¼7.7, 1.3 Hz, PheH), 6.76e6.69
(3H, m, PheH), 4.81 (4H, d, J¼2.4 Hz, OCH2), 4.44 (2H, d, J¼13.2 Hz,
PheCH2ePh), 4.41 (2H, d, J¼13.2 Hz, PheCH2ePh), 4.03 (3H, s,
OCH3), 3.56 (2H, d, J¼13.2 Hz, PheCH2ePh), 3.43 (2H, d, J¼13.2 Hz,
PheCH2ePh), 2.60 (2H, t, J¼2.4 Hz, OCH2CCH); 13C NMR (CDCl3,
75.4 MHz)
d 156.8(Cq), 156.6 (Cq), 153.4 (Cq), 151.7 (Cq), 146.6 (Cq),
143.1 (Cq), 133.7 (Cq), 133.1 (Cq), 131.7 (CH), 129.7 (CH), 129.6 (Cq),
129.0 (CH), 128.9 (CH), 128.7 (Cq), 126.2 (CH), 124.4 (CH), 121.3 (CH),
119.6 (CH), 117.6 (CH), 112.8 (CH), 78.6 (Cq), 77.6 (CH), 63.9 (CH2),
56.7 (CH3), 32.2 (CH2), 32.1 (CH2); MS (FAB, m/z) 635 [MþHþ]; HRMS
m/z calcd for C41H35N2O5 635.2546, found 635.2532.
4. Experimental section
4.1. general
4.2.3. 5,17-Bis(o-methoxyphenyl)azo-25,27-bis(1-benzyl-1H-1,2,3-
triazolylmethyloxy)-26,28-dihydroxycalix[4]arene (3). To a mixture
of 2a 0.20 g (0.26 mmol) and 1-(azidomethyl)benzene 0.12 g
(0.92 mmol) in THF/H2O 30 mL (v/v, 6:1) was added CuI 2.50 mg
(0.01 mmol) and then reflux for 18 h. After evaporation of solvent,
the residue was dissolved in CH2Cl2 and washed thrice with H2O.
The organic layer was dried over MgSO4 and the filtrate was con-
centrated under reduce pressure. The crude product was purified
by column chromatography with ethyl acetate/hexane (v/v, 3:1) to
afford pure compound 3 0.19 g (71%); mp 256e257 ꢂC; Rf¼0.18
All reported yields were isolated yields. Flash column chroma-
tography was performed using silica gel (70e230 mesh). 1H NMR
spectra were recorded in a 300 MHz NMR spectrometer, using the
CDCl3 solvent peak as an internal standard. 13C NMR spectra were
recorded at 75.4 MHz. The following abbreviations are used: singlet
(s), doublet (d), triplet (t), quartet (q), and multiplet (m). High
resolution Mass spectra were measured at FAB mode or Electron
Impact by JMS-700 HRMS. Melting points were measured with
a Yanaco MP500D apparatus and were uncorrected. UV/vis spectra
were measured with an HP-8453 spectrophotometer and solvents
were of HPLC grades.
(EtOAc/hexane, 1:1); 1H NMR (CDCl3, 300 MHz)
d 8.08 (2H, s, OH),
7.78 (2H, s, CCHN), 7.70 (4H, s, PheH), 7.60 (2H, dd, J¼8.0, 1.62 Hz,
PheH), 7.43e7.25 (12H, m, PheH), 7.09e6.99 (4H, m, PheH), 6.94
(4H, d, J¼7.6 Hz, PheH), 6.75 (2H, t, J¼7.6 Hz, PheH), 5.62 (4H, s,
NCH2Ph), 5.21 (4H, s, OCH2), 4.17 (4H, d, J¼13.2 Hz, PhCH2Ph), 4.14
(6H, s, OCH3), 3.37 (4H, d, J¼13.2 Hz, PhCH2Ph); 13C NMR (CDCl3,
25,27-Bis(O-propargyl)calix[4]arene 15a,8 and 25,27-bis(O-pro-
pyl)calix[4]arene 610 were synthesized according to the literature
procedures.
75.4 MHz) d 156.8 (Cq), 156.6 (Cq), 151.7 (Cq), 133.0 (Cq), 131.8 (CH),
130.0 (Cq), 129.5 (CH), 129.3 (CH), 128.6 (Cq), 128.5 (CH), 126.3
(CH), 124.4 (CH), 124.0 (CH), 121.3 (CH), 117.6 (CH), 112.8 (CH), 70.0
(CH2), 56.7 (CH3), 54.8 (CH2), 31.8 (CH2); MS (FAB, m/z) 1036
[MþHþ]; HRMS m/z calcd for C62H54N10O6 1034.4228, found
1034.4235.
4.2. General procedures for the synthesis of 2a, 2b, 7, and 9
To an ice cold solution of o-anisidine 0.18 g (1.50 mmol) in 4 N
HCl (4 mL) and acetone (5 mL) was added a solution of NaNO2
(0.20 g, 3.00 mmol) in H2O (5 mL), and the mixture was stirred for
3 h in ice-water bath. The combined solution was added, re-
spectively to another ice cold solution of 1, 6, or 8 (0.60 mmol) in
pyridine (10 mL) to produce a colored solution. The reaction mix-
ture was stirred for 1e3 days at 0 ꢂC and then treated with 4 N HCl
(50 mL) to give a colored precipitate. The solid residue was purified
4.2.4. 5-(o-Methoxyphenyl)azo-25,27-bis(1-benzyl-1H-1,2,3-
triazolylmethyloxy)-26,28-dihydroxycalix[4]arene (4). To a mixture
of 2b 0.20 g (0.32 mmol) and 1-(azidomethyl)benzene 0.15 g
(1.10 mmol) in THF/H2O 30 mL (v/v, 6:1) was added CuI 6.00 mg
(0.03 mmol) and then reflux for 18 h. After evaporation of solvent,
the residue was dissolved in CH2Cl2 and washed thrice with H2O.

8138
N.-J. Wang et al. / Tetrahedron 67 (2011) 8131e8139
The organic layer was dried over MgSO4 and the filtrate was con-
centrated under reduce pressure. The crude product was purified
by column chromatography with ethyl acetate/hexane (v/v, 3:1) to
afford pure compound 4 0.21 g (73%); mp 146e147 ꢂC; Rf¼0.25
(CH2Cl2/hexane,1:1); 1H NMR (CDCl3, 300 MHz)
PheH), 7.40e7.35 (1H, m, PheH), 7.08e6.98 (2H, m, PheH), 4.01
(3H, s, OCH3), 2.31 (6H, s, 2CH3); 13C NMR (CDCl3, 75.4 MHz)
156.2
(Cq), 146.4 (Cq), 142.0 (Cq), 131.4 (CH), 124.9 (CH), 124.5 (CH), 121.3
(CH), 117.2 (CH), 112.7 (CH), 56.7 (CH3), 16.4 (CH3); MS (EI, m/z) 256
[Mþ]; HRMS m/z calcd for C15H16N2O2 256.1212, found 256.1207.
d 7.65e7.61 (3H, m,
d
(EtOAc/hexane, 1:1); 1H NMR (CDCl3, 300 MHz)
d 8.16 (1H, s, OH),
7.77 (2H, s, CCHN), 7.68 (2H, s, PheH), 7.60 (1H, dd, J¼8.0, 1.7 Hz,
PheH), 7.55 (1H, s, OH), 7.41e7.26 (10H, m, PheH), 7.09e6.98 (4H,
m, PheH), 6.91 (2H, dd, J¼7.5, 1.4 Hz, PheH), 6.84 (2H, dd, J¼7.7,
1.5 Hz, PheH), 6.73e6.64 (3H, m, PheH), 5.58 (4H, s, NCH2Ph), 5.17
(4H, s, OCH2C), 4.17 (2H, d, J¼13.1 Hz, PhCH2Ph), 4.16 (2H, d,
J¼13.2 Hz, PhCH2Ph), 4.03 (3H, s, OCH3), 3.35 (2H, d, J¼13.2 Hz,
PhCH2Ph), 3.26 (2H, d, J¼13.1 Hz, PhCH2Ph); 13C NMR (CDCl3,
Acknowledgements
We thank the National Science Council (NSC), Taiwan and the
Ministry of Education (MOE) Approaching Top University (ATU)
Program of the Ministry of Education, Taiwan, Republic of China for
financial support.
75.4 MHz) d 156.8 (Cq), 156.6 (Cq), 153.4 (Cq), 151.8 (Cq), 146.6 (Cq),
144.3 (Cq), 143.1 (Cq), 135.3 (Cq), 133.6 (Cq), 133.0 (Cq), 131.7 (CH),
129.7 (CH), 129.6 (CH), 129.5 (CH), 129.1 (Cq),128.9 (CH),128.7 (CH),
128.4 (CH),128.2 (CH),126.2 (CH),124.3 (CH),123.9 (CH),121.3 (CH),
119.6 (CH), 117.5 (CH), 112.8 (CH), 70.2 (CH2), 56.7 (CH3), 54.6 (CH2),
31.8 (CH2), 31.7 (CH2); MS (FAB, m/z) 901 [MþHþ]; HRMS m/z calcd
for C55H48N8O5 900.3748, found 900.3737.
Supplementary data
UV/vis titration spectra and Job’s plot of 4 with Hg(ClO4)2; the
mass spectrum of complex 3$Hg2þ and the part expansion of 1H
NMR titration spectra of 3 with Hg(ClO4)2; 1H and 13C spectra of
new compounds 2aeb, 3e5, 7 and 9. Data calculated by molecular
modeling DMol3 for the optimized geometries of 3 and 10. Sup-
plementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tet.2011.08.052. These data include
MOL files and InChIKeys of the most important compounds de-
scribed in this article.
4.2.5. 5,17-Bis(o-methoxyphenyl)azo-25,27-bis(1-benzyl-1H-1,2,3-
triazolylmethyloxy)-26,28-dipropyloxycalix[4]arene (5). To a well
stirred solution of 3 0.20 g (0.19 mmol) and NaH 0.14 g (5.78 mmol)
in dry DMF (20 mL) was added 1-iodopropane 0.66 g (3.86 mmol)
and then stirred at 80 ꢂC for 18 h. After quenching the NaH by
adding MeOH in an ice-water bath, the reaction solution was
extracted thrice with CH2Cl2 (20 mL). The organic layer was dried
over MgSO4 and the filtrate was evaporated to give the crude
product. The crude product was purified by column chromatog-
raphy with acetone/hexane (v/v, 1:1) to afford pure compound 5
0.03 g (14%); mp 82e84 ꢂC; Rf¼0.28 (EtOAc/hexane, 1:1); 1H NMR
References and notes
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(CDCl3, 300 MHz)
d 7.57e7.55 (2H, m, PheH), 7.51 (4H, s, C]
CHN), 7.42e7.36 (10H, m, Ph), 7.30e7.28 (3H, m, PheH), 7.07 (3H,
d, J¼8.2 Hz, PheH), 6.96 (2H, t, J¼15.2 Hz, PheH), 6.32 (6H, d,
J¼7.6 Hz, PheH), 5.52 (4H, s, NCH2Ph), 5.01 (4H, s, OCH2), 4.29
(4H, d, J¼13.2 Hz, PhCH2Ph), 4.01 (6H, s, OCH3), 3.85 (4H, t,
J¼7.9 Hz, OCH2CH2CH3), 3.00 (4H, d, J¼13.5 Hz, PhCH2Ph),
1.75e1.67 (4H, m, OCH2CH2CH3), 0.69 (6H, t, J¼7.41 Hz,
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d 161.0 (Cq), 156.9
(Cq), 154.3 (Cq), 148.6 (Cq), 144.9 (Cq), 143.0(Cq), 137.2 (Cq), 135.1
(Cq), 133.8 (Cq), 132.0 (CH), 129.7 (CH), 129.6 (CH), 129.5 (CH),
129.4 (CH), 128.5 (CH), 128.4 (CH), 124.0 (CH), 123.4 (CH), 123.3
(CH), 121.3 (CH), 117.4 (CH), 113.0(CH), 77.2 (CH2), 67.7 (CH2), 56.8
(CH3), 54.6 (CH2), 31.5 (CH2), 23.4 (CH2), 10.4 (CH3); MS (FAB, m/z)
1121 [MþHþ]; HRMS m/z calcd for C68H66N10O6 1118.5167, found
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4.2.6. Data for 5,17-bis(o-methoxyphenyl)azo-25,27-dipropyloxy-
26,28-dihydroxycalix[4]arene (7). The solid was eluted with ethyl
acetate/hexane (v/v, 1:3) and gave 0.09 g (20%) of an orange pow-
der; mp 332e334 ꢂC; Rf¼0.9 (EtOAc/hexane, 1:1); 1H NMR (CDCl3,
300 MHz)
d
8.84 (2H, s, OH), 7.75 (4H, s, PheH), 7.59 (2H, dd, J¼8.0,
1.68 Hz, PheH), 7.41e7.36 (2H, m, PheH), 7.08e6.98 (8H, m, PheH),
6.78 (2H, t, J¼7.5 Hz, PheH), 4.34 (4H, d, J¼13.1 Hz, PhCH2Ph),
4.05e4.01 (10H, m, 2OCH3 and 2OCH2CH2CH3), 3.55 (4H, d,
J¼13.1 Hz, PhCH2Ph), 2.13e2.07 (4H, m, OCH2CH2CH3), 1.35 (6H, t,
J¼7.4 Hz, OCH2CH2CH3); 13C NMR (CDCl3, 75.4 MHz)
d
157.3 (Cq),
ꢁ
€
156.6 (Cq), 152.2 (Cq), 146.5 (Cq), 143.2 (Cq), 133.1 (Cq), 131.7 (CH),
129.8 (CH), 128.7 (Cq), 125.8 (CH), 124.4 (CH), 121.7 (CH), 117.6 (CH),
(CH), 78.8 (CH2), 56.7 (CH3), 31.7 (CH2), 32.9 (CH2), 11.3 (CH3); MS
(FAB, m/z) 778 [MþHþ]; HRMS m/z calcd for C48H48N4O6 776.3574,
found 776.3576.
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(9). The solid was eluted with ethyl acetate/hexane (v/v, 1:1) and
gave 0.52 g (83%) of an orange powder, mp 47e48 ꢂC; Rf¼0.15

N.-J. Wang et al. / Tetrahedron 67 (2011) 8131e8139
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