Tetrazoles and para-substituted phenylazo-coupled calix[4]arenes as highly sensitive chromogenic sensors for Ca2+

Article abstract of DOI:10.1002/ejoc.200900603

Calix[4]arenes 3a (R = OMe) and 3b (R = NO₂) with 5,17bis[4-(4-substituted-phenyl)azo] and 25,27-bisoxymethyltetrazole groups were synthesized by 1,3-dipolar cycloaddition of oxyacetonitrile azocalix[4]arenes 2a and 2b activated with trimethyls

Full text of DOI:10.1002/ejoc.200900603

FULL PAPER
DOI: 10.1002/ejoc.200900603
Tetrazoles and para-Substituted Phenylazo-Coupled Calix[4]arenes as Highly
Sensitive Chromogenic Sensors for Ca2+
Yu-Jen Chen[a] and Wen-Sheng Chung*[a]
Keywords: Cycloaddition / Inclusion compounds / Nitrogen heterocycles / Calixarenes / Ionophores
Calix[4]arenes 3a (R = OMe) and 3b (R = NO2) with 5,17-
bis[4-(4-substituted-phenyl)azo] and 25,27-bisoxymethyl-
tetrazole groups were synthesized by 1,3-dipolar cycload-
dition of oxyacetonitrile azocalix[4]arenes 2a and 2b acti-
vated with trimethylsilyl azide. UV/Vis screening of 3a and
revealed 1:1 binding stoichiometry for each of the complexes.
The association constants for 3a·Ca2+, 3b·Ca2+, 3b·Ba2+, and
3b·Pb2+ were determined by Benesi–Hildebrand plots. On
1
the basis of H NMR titration results, Ca2+ was bound to the
two partially deprotonated hydroxy azophenol groups and
3b with 14 metal ions showed that 3a (with p-methoxyphen- one of the two tetrazole groups of 3a and 3b.
ylazo substituent) was a highly chromogenic sensor to Ca2+
,
whereas 3b (with p-nitrophenylazo substituent) showed color
changes toward Ca2+, Ba2+, and Pb2+. Job plot experiments
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
gradation, they have been frequently used as robust linkers
to construct 2D and 3D coordination polymers[5] and C-
glycoclusters on a calix[4]arene scaffold.[6a,6b] Despite the
high potential of tetrazoles and its derivatives in metal ion
coordination, their use in conjunction with a calix[4]arene
scaffold in metal-ion sensing is still scarce. One such rare
application[6c] was the synthesis of calix[4]arenes bearing
two or four tetrazole ligating groups at the upper rim, which
formed a strong 2:2 complex with palladium dichloride.
The efficient and high-yielding synthesis of tetrazoles by
Huisgen 1,3-dipolar cycloaddition reactions of nitriles with
organic azides has become very popular and useful after
the tremendous efforts by Sharpless and co-workers;[7] for
instance, they have explored various possible electron-with-
drawing cyanides or by adding ZnBr2 in water to improve
the overall yields of the reactions. Yamamoto and co-
workers[8] have also reported a palladium-catalyzed three-
component coupling reaction to synthesize tetrazoles with
good to excellent yields. Accordingly, tetrazole groups can
be readily synthesized by the reaction of nitrile with acti-
vated azide through the addition of either strong Lewis ac-
ids,[9] amine salts,[9b,9c] or dialkyltin oxides.[10,11] These re-
ports prompted us to explore the syntheses of calix[4]arenes
with bistetrazoles at the lower rim and para-substituted
phenylazo moieties at the upper rim and their application
Introduction
In the design of artificial receptors for cations and
anions, para-substituted phenyl azophenol groups are fre-
quently used as the chromogenic units, because they give
rise to intense color changes upon complexation with cer-
tain metal ions or anions.[1,2] Recently, we reported the syn-
theses of a series of upper-rim 4-allyl- and 4-methoxyphen-
ylazo-coupled calix[4]arenes that were found to be sensitive
chromogenic sensors for Hg2+ by azophenol to quinone–
hydrazone tautomerism.[1a,1b] It was also found that upper-
rim arylazo-coupled calix[4]arenes with lower-rim triazole
groups showed selective color changes toward Ca2+ and
Pb2+ [1c]
Besides cation sensing, these mono- or bisarylazo
.
substituted calix[4]arenes were also found to be useful in
anion sensing as reported by the research groups of
Hong,[2a] Kim,[2b] and Chen.[2c] Using calix[4]arenes with
and without a 4-(4-nitrophenyl)azo group, Kim and co-
workers[2i] successfully demonstrated that cyclic voltamme-
try is a useful complement to UV/Vis absorption spec-
troscopy in the detection of Ca2+ ions.
Tetrazoles are heterocyclic compounds having similar
pKa values with those of carboxylic acids, and they are fre-
quently swapped with carboxylic acids during the develop-
ment of pharmaceuticals.[3,4] The cationic binding abilities
of tetrazoles in their anionic and neutral forms have been
independently studied by Hof[4a,4b] and Kraft.[4c–4e] Because
tetrazoles are quite resistant to chemical and enzymatic de-
in chromogenic sensing of metal ions, especially Ca2+
.
Results and Discussion
[a] Department of Applied Chemistry, National Chiao Tung
University, Hsinchu,
The synthetic pathways for the syntheses of azocalix[4]-
arenes with two distal oxyacetonitrile groups 2a and 2b, two
distal oxymethyltetrazole groups 3a and 3b, and control
compounds 4 and 6 are depicted in Scheme 1. 5,17-Bis[4-
30050 Taiwan, Republic of China
E-mail: wschung@cc.nctu.edu.tw
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900603.
4770
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Highly Sensitive Chromogenic Sensors for Ca2+
Scheme 1. Synthesis of chromogenic calix[4]arenes 2, 3, and control compounds 4 and 6. Reagents and conditions: (i) para-substituted
aniline/acetone, NaNO2/4  HCl, pyridine, 0 °C, 4 h; (ii) TMSN3, Bu2SnO, toluene, 100 °C, 16–36 h; (iii) TMSN3, TBAF, 120 °C, 22 h.
(4-substituted-phenyl)azo]-25,27-dioxyacetonitrilecalix[4]-
the presence of a Lewis acid in tetrahydrofuran.[9] Com-
arenes 2a (R = OMe) and 2b (R = NO2) were synthesized pound 6 has the characteristic downfield and broad signal
starting from 25,27-dioxyacetonitrilecalix[4]arene 1[12] by a of the tetrazole proton at 14.2 ppm in CDCl3 (Supporting
diazo coupling reaction with the use of para-substituted Information, Figure S11). The proton signals of the tetra-
aniline[1] in 87 and 63% yield, respectively. The di-n-butyltin zole units in calix[4]arenes 3a, 3b, and 4 were not observed
oxide mediated addition of trimethylsilyl azide (TMSN3) in CD3CN, perhaps as a result of its participation in intra-
with oxyacetonitrile calix[4]arenes 2a and 2b in toluene af- molecular hydrogen bonding.[4b,4f]
forded the very polar 5,17-bis[4-(4-substituted-phenyl)azo]-
The UV/Vis absorption maxima (λmax) and molar extinc-
25,27-bis[(oxymethyl)-2H-tetrazole]calix[4]arenes 3a and 3b tion coefficients of the chromogenic calix[4]arenes 2a, 2b,
in 89 and 67% yield, respectively. This method of forming 3a, and 3b, and control compounds 4 and 6 are summarized
tetrazole rings is adapted from the work of Lukyanov;[10] in Table 1. In acetonitrile solutions, the molar extinction
however, traditional heating instead of microwave irradia- coefficients of 4 and 6 are smaller than those of 2a, 2b, 3a,
tion was used instead.
and 3b as a result of their lack of conjugated arylazo groups
The formation of calix[4]arene 3a, with lower-rim oxyme- in the skeleton. The 4-(4-methoxyphenyl)azocalix[4]arenes
thyltetrazoles, from 2a can be monitored by variation of 2a and 3a have shorter λmax values (ca. 362 nm) than those
the 1H NMR signal of the lower-rim oxymethylene protons, of 4-(4-nitrophenyl)azocalix[4]arenes 2b and 3b (ca.
which are downfield shifted from ca. 4.9 ppm in 2a to 385 nm).
6.3 ppm in 3a (Supporting Information); furthermore, the
signals of the carbon atoms of the corresponding oxyme-
thylenes are also downfield shifted from ca. 62 ppm in oxya-
cetonitrile 2a to ca. 67 ppm in oxymethyltetrazole 3a. Fur-
ther support of the tetrazole-modified azocalix[4]arenes 3a
and 3b came from their HRMS spectra. Control compound
4, without the azo substituents, was synthesized in 87%
yield from compound 1 by using similar reaction conditions
to those used in the syntheses of 3a and 3b. Calix[4]arenes
2a, 2b, 3a, 3b, and 4 are all in cone conformation, as could
be recognized from their respective methylene bridge signals
appearing around 31 ppm in the 13C NMR spectra.[13] Con-
trol compound 6 can be prepared by using tetrabutylammo-
Table 1. The absorption maxima (λmax) and corresponding extinc-
tion coefficients of arylazocalix[4]arenes 2 and 3 and control com-
pounds 4 and 6 in CH3CN at 298 K.
Compound
λmax (nm)
ε (–1 cm–1)
2a
2b
3a
3b
4
362
385
363
386
277
262
88000
73000
86000
95000
6700
6
290
The affinities of these 4-(4-substituted-phenyl)azocalix-
nium fluoride (TBAF) and trimethylsilyl azide under neat [4]arenes for metal ions with or without lower-rim oxy-
conditions,[14] or by treating 5 with sodium azide (NaN3) in methyltetrazole groups were investigated next. The UV/Vis
Eur. J. Org. Chem. 2009, 4770–4776
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Y.-J. Chen, W.-S. Chung
FULL PAPER
Figure 1. UV/Vis spectra of host 3a (10 µ) in the absence and presence of 14 different metal perchlorates (10 equiv.) in (a) CH3CN and
(b) CH3CN/MeOH (9:1) at 298 K.
spectra of 3a (10 µ) in the presence of perchlorate salts of Table 2. Association constants Ka (–1) and bathochromic shifts for
1:1 complexes of azocalix[4]arenes 2a, 2b, 3a, and 3b with metal
Li+, Na+, K+, Mg2+, Ca2+, Ba2+, Pb2+, Cr3+, Mn2+, Ni2+
,
perchlorates in CH3CN at 298 K.
Zn2+, Ag+, Cd2+, and Hg2+ (10 equiv.) in CH3CN are
shown in Figure 1a. Tetrazole–azophenol host 3a exhibited
a remarkable bathochromic shift (from 363 to 533 nm) and
hyperchromic effect toward Ca2+. Medium responses to
Cr3+ and Pb2+ were also found for 3a; however, no change
in UV/Vis was found for the rest of the metal ions exam-
ined. In contrast, control compound 7, without a calix[4]-
arene scaffold, showed only a small bathochromic shift to-
Compound
Metal ion
λmax, ∆λ (nm)[a]
Ka (–1)[b]
[c]
2a
2a
2b
2b
3a
3a
3a
3b
3b
3b
Ca2+
Cr3+
Ca2+
Ba2+
Ca2+
Cr3+
Pb2+
Ca2+
Ba2+
Pb2+
531, 169
510, 148
503, 118
492, 107
533, 170
512, 149
544, 181
500, 114
487, 101
501, 115
–
8.1ϫ104
4.2ϫ104
3.1ϫ104
9.1ϫ104
1.1ϫ104
8.4ϫ103
3.1ϫ105
1.1ϫ105
1.6ϫ105
ward Cr3+ [1c]
When a mixed solvent of CH3CN/MeOH
.
(9:1) was used, compound 3a showed a chromogenic re-
sponse toward Ca2+ only, although with a smaller extinc-
tion coefficient. We did not use the mix solvent system for
metal-ion screening because of its lower sensitivity relative
to that in CH3CN.
[a] ∆λmax = λcomplex – λhost. [b] Calculated by Benesi–Hildebrand
plots. [c] Ka was not determined, because the absorbance difference
at low metal ion concentration was too small to be evaluated.
The results from UV/Vis titration of 3a with metal ions
in CH3CN support that oxymethyltetrazole moieties are 115 nm but was about 101 nm for 3b·Ba2+. By increasing
strong ligands for metal-ion complexation; furthermore, the the amounts of Ca2+, the color of 3a changed from color-
electrostatic interactions between the phenols and metal less to magenta; thus, 3a can be used as a naked-eye sensor
cations bring about the bathochromic shift of 3a. Although for Ca2+ (Figure 3).
2a also showed apparent bathochromic shifts toward Cr3+
The Job plot of 3a with Ca2+ revealed a 1:1 stoichiome-
and Ca2+ (Supporting Information, Figure S13), its associa- try for the complex (Figure 4).[15] The association constant
tion constant was too small to be measured for Ca2+ or of 3a·Ca2+ in CH3CN was determined to be
smaller than that with 3a. Accordingly, the oxymethyltetra- 9.1ϫ104 –1 by Benesi–Hildebrand plot[16] (Figure 5). The
zole units on 3a are superior ligands than the oxyacetonitr- association constants of hosts 2a, 2b, 3a, and 3b with metal
ile units on 2a in chelating Ca2+ ions. In contrast, the ions that showed color changes are summarized in Table 2.
screening of 4-(4-nitrophenyl)azo analogues 3b and 2b to- The binding affinities of 3b toward Ca2+, Ba2+, and Pb2+
ward metal ions showed strong bathochromic shifts toward were 10–30 times larger than those of 3a with correspond-
Ca2+, Pb2+, and Ba2+ (with decreasing Ka values; Support- ing metal ions; nevertheless, 3b showed a poorer selectivity
ing Information, Figures S14 and S15; Table 2). Calix[4]ar- compared to that of 3a (which is selective to Ca2+).
enes 3b and 2b, using the more-popular 4-(4-nitrophenyl)- Furthermore, the affinities of 2b toward Ca2+, Ba2+, and
azo groups, showed poorer metal-ion selectivity relative to Pb2+ ions are in general smaller than those of 3b, implying
that of their 4-(4-methoxyphenyl)azo analogues, 3a and 2a. that the oxymethyltetrazoles are superior to oxyacetonitriles
The UV/Vis spectra of 3a upon titration with various as metal coordination ligands in the lower rim of the bisary-
concentrations of Ca2+ in CH3CN are show in Figure 2. As lazocalix[4]arenes. We also noted that tetrazole receptor 3a,
the concentration of Ca2+ increased, the absorption maxi- like its triazole analogue 8,[1c] had a very similar binding
mum of free host 3a at 363 nm gradually decreased in inten- behavior and association constants toward Ca2+ and Pb2+
.
sity with a concomitant increase in the absorption band at The Ka of 8·Ca2+ and 8·Pb2+ in CH3CN was reported to
533 nm with three isosbestic points at 268, 299, and 420 nm. be 7.06ϫ104 and 8.57ϫ103 –1, respectively.[1c] For com-
The bathochromic shift of 3b·Ca2+ and 3b·Pb2+ was about parison, the Ka of 3·Ca2+ and 3·Pb2+ was 9.1ϫ104 and
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Highly Sensitive Chromogenic Sensors for Ca2+
Figure 5. Benesi–Hildebrand plot of 3a with Ca(ClO4)2 in CH3CN
at 298 K.
Figure 2. UV/Vis spectra of 3a (10 µ) upon titration with various
equivalents of Ca(ClO4)2 in CH3CN at 298 K.
In order to gain insight into the complexation modes of
1
3a with Ca2+ ion, we took a series of H NMR spectra of
3a (1.25 m in CD3CN) in the presence of different
amounts of Ca2+. Upon complexation of 3a with Ca2+, the
signal of the methoxy protons (Ha) was upfield shifted by
about 0.04 ppm, whereas the hydroxy azophenol proton He
was downfield shifted to 11.9 ppm (with integration of 2
H). Protons on the 4-methoxyphenylazo groups (Hb and
Hc) exhibited significant upfield shifts by ca. 0.11–
0.28 ppm. Furthermore, the singlet peak on the azophenol
Hd was split into two peaks: one was downfield shifted by
0.20 ppm and the other upfield shifted by 0.08 ppm. More-
over, the two doublets of the methylene bridge protons Hh
were also upfield shifted by ca. 0.19–0.33 ppm. Note that
the H NMR signals from 3a and complex 3a·Ca2+ coex-
1
Figure 3. (a) The color of host 3a (10 µ in acetonitrile) and (b) in
the presence of Ca2+ (50 µ). Solutions that did not show color
changes are omitted.
isted under the experimental conditions (Figure 6). Similar
chemical shift changes were found in the titrations of 3b
with Ca2+, Ba2+, and Pb2+ ions (Supporting Information,
Figures S34–S36), indicating that the metal-ion binding
modes of 3a and 3b were similar. The chemical shift differ-
ences (∆δ) between the two methylene bridge protons of
receptors 2a,b and 3a,b fall in the range of
0.635Ϯ0.015 ppm in CD3CN, which implies that they are
8.4ϫ103 –1, respectively. The only noticeable difference
between the two receptors may be on their association con-
stant Ka toward Cr3+, as it is two orders of magnitude
stronger in tetrazole receptor 3a than in triazole analogue
8.
of flattened cone conformation. In the presence of Ca2+
,
the phenylazo groups of ligand 3a converged to facilitate
the cation binding by the OH groups; therefore, the ∆δ be-
tween the two methylene bridge protons became 0.77 ppm.
The move toward cone conformation upon complexation
with metal ion is corroborated with the upfield shift of the
aromatic protons Hb and Hc (vide supra), which experience
a mutual diamagnetic shielding from the opposite aryl
ring.[17a] Accordingly, we propose that Ca2+ was bound to
the 4-(4-substituted-phenyl)azocalix[4]arenes 3a and 3b by
the two hydroxy azophenol groups and one of the two oxy-
methyltetrazole groups to form an asymmetric complex (see
structure in Figure 6).
All proton signals were downfield shifted when 2a or 3a
was titrated with Cr3+; however, with no change in any of
the splitting patterns (Supporting Information, Figures S31
and S33). The results imply that 2a or 3a formed a symmet-
rical complex with Cr3+ [17b]
On the basis of UV/Vis ti-
.
Figure 4. Job plot of a 1:1 complex of 3a with Ca2+, where the
absorbance at 533 nm was plotted against the molar fraction of 3a
at an invariant total concentration of 10 µ in CH3CN at 298 K.
tration results, 2a (Ka = 8.1ϫ104 –1) has a larger binding
affinity than 3a (Ka = 1.1ϫ104 –1) toward Cr3+. Com-
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Y.-J. Chen, W.-S. Chung
FULL PAPER
using 1,3-dipolar cycloaddition of oxyacetonitrile azoca-
lix[4]arenes 2a and 2b activated with trimethylsilyl azide.
UV/Vis screening showed that calix[4]arene 3a (R = OMe)
showed a large bathochromic shift toward Ca2+ with good
selectivity, whereas 3b (R = NO2) showed color changes
toward Ca2+, Ba2+, and Pb2+. Calix[4]arenes 3a and 3b with
two p-substituted phenylazo groups at the upper rim and
two oxymethyltetrazole groups at the lower rim showed
very similar chromogenic sensing abilities toward metal
ions; furthermore, they showed stronger association con-
stants toward Ca2+ than did 2a, 2b, or bistriazole analogue
1
8[1c] reported previously. On the basis of H NMR titration
results, Ca2+ was bound to the two partially deprotonated
hydroxy azophenol groups and one of the two tetrazole
groups of 3a and 3b.
1
Figure 6. (a) H NMR spectra of 3a (1.25 m) in CD3CN and (b)
in the presence of 1.25 m (1.00 equiv.) of Ca(ClO4)2, where * de-
notes an external standard CHCl3 and o denotes a sweeping noise
from instrument.
Experimental Section
pound 2b with lower-rim oxyacetonitrile groups, showed
relatively smaller change in chemical shifts when compared
to the lower-rim oxymethyltetrazole 3b in complexation
with Ca2+, Ba2+, or Pb2+ ions (Supporting Information,
Figure S32).[18] Surprisingly, lower-rim bisoxymethyltetra-
zole-modified calix[4]arene 4 and control compound 6 did
not show any complexation-induced chemical shift change
with Ca2+ (Supporting Information, Figures S37 and S38).
The results suggest that both azophenols and oxymethylte-
trazoles/or oxyacetonitrile groups are required in the chro-
mogenic sensing with metal ions. Furthermore, it is interest-
ing to note that calix[4]arenes 3a and 3b, with two p-substi-
tuted phenylazo groups at the upper rim and two oxyme-
thyltetrazole groups at the lower rim, showed very similar
chromogenic sensing abilities toward metal ions compared
to their lower-rim bisoxymethyltriazole analogue 8[1c] re-
ported previously.
All reported yields were isolated yields. Flash column chromatog-
raphy was performed by using silica gel (70–230 mesh). Melting
points were determined with a Yanaco MP500D apparatus and are
uncorrected. 1H NMR spectra were recorded at 300 MHz with the
solvent peak (usually CDCl3) as an internal standard, and 13C
NMR spectra were recorded at 75.4 MHz or 125 MHz. Mass spec-
tra were recorded at electron ionization, Q-TOF LC–MS–MS or at
FAB mode using m-nitrobenzyl alcohol (NBA) as the matrix. UV/
Vis spectra were recorded with an HP-8453 spectrophotometer and
solvents were of HPLC grade. 25,27-Dioxyacetonitrile-26,28-dihy-
droxycalix[4]arene (1) was synthesized according to a literature pro-
cedure.[12]
General Procedure for the Synthesis of 2a and 2b: To an ice-cold
solution of NaNO2 (7.50 mmol) in 4  HCl (6.00 mL) was added
a solution of para-substituted aniline (4.00 mmol) in acetone
(8.00 mL), and the mixture was stirred for 1 min. The combined
solution was added dropwise to another ice-cold solution of 25,27-
dioxyacetonitrile-26,28-dihydroxycalix[4]arene (1; 1.00 mmol) in
pyridine (12.00 mL) to produce an ox-blood-red solution. The reac-
tion mixture was stirred at 0 °C for 4 h and treated with 4  HCl
(60 mL) to give a colored precipitate. The separated precipitate was
dissolved in CH2Cl2 (20 mL) and added H2O (40 mL) then ex-
tracted with CH2Cl2 (2ϫ10 mL). The organic layers were com-
bined and concentrated, and the residue was recrystallized with
CH2Cl2/MeOH to give the corresponding products 2a (2.68 g,
Summary and Conclusions
We report here the synthesis of calix[4]arenes 3a (R =
OMe) and 3b (R = NO2) with two distal tetrazole groups
at the lower rim and two 4-R-phenylazo groups at the upper
rim for metal-ion sensing studies. The bisoxymethyltetra-
zole-modified calix[4]arenes 3a and 3b were synthesized by 87%) and 2b (2.02 g, 63%).
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Highly Sensitive Chromogenic Sensors for Ca2+
5,17-Bis[4-(4-methoxyphenyl)azo]-25,27-dioxyacetonitrile-26,28-di- General Procedure for the Synthesis of 25,27-Bis[(oxymethyl)-2H-
hydroxycalix[4]arene (2a): Yellow solid. M.p. 217–219 °C. Rf = 0.42
tetrazole]-26,28-dihydroxycalix[4]arene (4): To a solution of 1
(0.45 g, 0.90 mmol) in anhydrous toluene (20 mL) was added dibu-
tyltin oxide (0.09 g, 0.36 mmol) and trimethylsilyl azide (0.52 g,
1
(hexane/ethyl acetate, 3:1). H NMR (300 MHz, CDCl3): δ = 3.67
(d, J = 13.8 Hz, 4 H, Hh), 3.90 (s, 6 H, Ha), 4.32 (d, J = 13.8 Hz,
4 H, Hh), 4.91 (s, 4 H, Hi), 6.57 (s, 2 H, He), 6.81 (t, J = 7.5 Hz, 2 4.50 mmol). The reaction mixture was stirred at 100 °C for 16 h
H, Hf), 6.96 (d, J = 7.5 Hz, 4 H, Hg), 7.02 (d, J = 9.0 Hz, 4 H, and then cooled to room temperature. The solvent was removed,
Hb), 7.76 (s, 4 H, Hd), 7.89 (d, J = 9.0 Hz, 4 H, Hc) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 31.8 (CH2), 56.5 (CH3), 61.6
and the residue was then treated with 10% aqueous HCl (30 mL)
and CH2Cl2 (3ϫ10 mL). The extract was dried with Na2SO4 and
(CH2), 115.5 (CH), 117.4 (Cq), 124.3 (CH), 124.9 (CH), 127.1 concentrated under reduced pressure. The residue was subjected to
(CH), 129.5 (CH), 130.6 (Cq), 133.7 (Cq), 146.2 (Cq), 147.4 (Cq), flash chromatography (hexane/ethyl acetate, 2:1; then ethyl acetate/
152.4 (Cq), 156.3 (Cq), 162.2 (Cq) ppm. MS (FAB): m/z = 771 [M
+ H+]. HRMS (FAB): calcd. for C46H39N6O6 [M + H+] 771.2926;
found 771.2927.
methanol, 1:0–5:1 gradient) to give 4 (0.46 g, 87%) as a white solid.
M.p. 239–241 °C. Rf = 0.20 (ethyl acetate/methanol, 5:1). 1H NMR
(300 MHz, CD3CN): δ = 3.50 (d, J = 13.5 Hz, 4 H, Hf), 4.21 (d, J
= 13.5 Hz, 4 H, Hf), 5.48 (s, 4 H, Hg), 6.75 (t, J = 7.5 Hz, 2 H,
Ha), 6.91 (t, J = 7.5 Hz, 2 H, Hd), 7.07 (d, J = 7.5 Hz, 4 H, Hb),
7.19 (d, J = 7.5 Hz, 4 H, He) ppm. 13C NMR (75 MHz, CD3CN):
δ = 32.2 (CH2), 68.6 (CH2), 121.8 (CH), 127.8 (CH), 129.2 (Cq),
130.4 (CH), 130.8 (CH), 135.2 (Cq), 152.7 (Cq), 153.5 (Cq), 155.4
(Cq) ppm. MS (FAB): m/z = 889 [M + H+]. HRMS (FAB): calcd.
for C32H28N8O4 [M+] 588.2234; found 588.2238.
5,17-Bis[4-(4-nitrophenyl)azo]-25,27-dioxyacetonitrile-26,28-dihy-
droxycalix[4]arene (2b): Red solid. M.p. 218–219 °C. Rf = 0.51
1
(CH2Cl2). H NMR (300 MHz, CDCl3): δ = 3.73 (d, J = 13.5 Hz,
4 H, Hg), 4.36 (d, J = 13.5 Hz, 4 H, Hg), 4.96 (s, 4 H, Hh), 6.89 (t,
J = 7.5 Hz, 2 H, He), 7.01 (d, J = 7.5 Hz, 6 H, Hd + Hf), 7.89 (s,
4 H, Hc), 8.02 (d, J = 8.9 Hz, 4 H, Hb), 8.40 (d, J = 8.9 Hz, 4 H,
Ha) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 31.8 (CH2), 61.4
(CH2), 117.5 (Cq), 123.9 (CH), 125.6 (CH), 126.0 (CH), 127.0
(CH), 130.0 (Cq), 130.7 (CH), 133.6 (Cq), 146.3 (Cq), 148.7 (Cq),
152.7 (Cq), 156.6 (Cq), 158.4 (Cq) ppm. MS (ESI): m/z = 801.4 [M
+ H+]. HRMS (FAB): calcd. for C44H33N8O8 [M + H+] 801.2416;
found 801.2417.
General Procedure for the Synthesis of 5-[(2,6-Dimethylphenoxy)-
methyl]-2H-tetrazole (6): A mixture of 2-(2,6-dimethylphenoxy)ace-
tonitrile (5; 0.65 g, 4.04 mmol), tetrabutylammonium fluoride
(0.50 g, 2.02 mmol), and trimethylsilyl azide (0.70 g, 6.06 mmol)
was stirred at 120 °C for 22 h and then cooled to room temperature.
The crude products were treated with 10% aqueous HCl (30 mL)
and CH2Cl2 (3ϫ10 mL). The extract was dried with Na2SO4 and
concentrated under reduced pressure. The residue subjected to col-
umn chromatography (CH2Cl2/ethyl acetate, gradient) to give 6
(0.72 g, 87%) as a white solid. M.p. 107–109 °C. Rf = 0.31 (hexane/
General Procedure for the Synthesis of 3a and 3b: Dibutyltin oxide
(0.18 mmol) and trimethylsilyl azide (3.68 mmol) were added to a
solution of 2a or 2b (0.92 mmol) in anhydrous toluene (15 mL).
The reaction mixture was stirred at 100 °C for 36 h and then cooled
to room temperature. The solvent was removed, and the residue
was then treated with 10 % aqueous HCl (30 mL) and CH2Cl2
(3ϫ10 mL). The extract was dried with Na2SO4 and concentrated
under reduced pressure. The residue was subjected to flash
chromatography (CH2Cl2/ethyl acetate, 2:1; then ethyl acetate/
methanol, 1:0–1:1 gradient) to give the corresponding products 3a
(0.70 g, 89%) and 3b (0.55 g, 67%).
1
ethyl acetate, 1:1). H NMR (300 MHz, CDCl3): δ = 2.21 (s, 6 H,
Hc), 5.24 (s, 2 H, Hd), 6.90–7.03 (m, 3 H, ArH), 14.21 (s, 1 H, He)
ppm. 13C NMR (75 MHz, CDCl3): δ = 16.1 (CH3), 63.5 (CH2),
125.2 (CH), 129.2 (CH), 130.5 (Cq), 154.3 (Cq) ppm. MS (EI): m/z
(%) = 122 (100), 121 (92), 204 (55) [M+], 77 (54), 91 (53). HRMS
(EI): calcd. for C10H12N4O [M+] 204.1011; found 204.1013.
Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR spectra of compounds 2–6; UV/Vis titration spectra;
Job plots; Benesi–Hildebrand plots of 2a, 2b, and 3b; 1H NMR
spectra of 2–6 with metal perchlorate salts.
5,17-Bis[4-(4-methoxyphenyl)azo]-25,27-bis[(oxymethyl)-2H-tetra-
zole]-26,28-dihydroxycalix[4]arene (3a): Yellow solid. M.p. 237–
239 °C. Rf = 0.34 (ethyl acetate/methanol, 1:1). 1H NMR
(300 MHz, CD3CN): δ = 4.47 (d, J = 13.4 Hz, 4 H, Hh), 4.72 (s, 6
H, Ha), 5.10 (d, J = 13.4 Hz, 4 H, Hh), 6.34 (s, 4 H, Hi), 7.77 (t, J
= 7.6 Hz, 2 H, Hf), 7.92 (d, J = 9.0 Hz, 4 H, Hb), 7.97 (d, J =
7.6 Hz, 4 H, Hg), 8.62 (s, 4 H, Hd), 8.69 (d, J = 9.0 Hz, 4 H, Hc)
ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 31.4 (CH2), 56.7
(CH3), 67.0 (CH2), 115.6 (CH), 124.4 (CH), 125.1 (CH), 126.9
(CH), 129.5 (Cq), 130.5 (CH), 130.7 (Cq), 146.2 (Cq), 147.4 (Cq),
152.8 (Cq), 154.4 (Cq), 156.5 (Cq), 162.3 (Cq) ppm. MS (FAB): m/z
= 857 [M + H+]. HRMS (FAB): calcd. for C46H41N12O6 [M + H+]
857.3267; found 857.3276.
Acknowledgments
We thank the National Science Council (NSC) and the MOE ATU
Program of the Ministry of Education, Taiwan, Republic of China,
for financial support.
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Rf = 0.33 (ethyl acetate/methanol, 1:1). 1H NMR (300 MHz,
CD3CN): δ = 4.50 (d, J = 13.5 Hz, 4 H, Hg), 5.12 (d, J = 13.5 Hz,
4 H, Hg), 6.35 (s, 4 H, Hh), 7.78 (t, J = 7.5 Hz, 2 H, He), 7.98 (d,
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Eur. J. Org. Chem. 2009, 4770–4776
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4775

Y.-J. Chen, W.-S. Chung
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1
fluorescence spectroscopy (in THF) and by H NMR titration
(in [D6]DMSO) was reported by Fang, (ii) the Ka was two or-
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Received: June 1, 2009
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Published Online: August 17, 2009
4776
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4770–4776