Phenyl-calix[4]arene-based fluorescent sensors: Cooperative binding for carboxylates

Article abstract of DOI:10.1021/jo062258z

Tetrakis-(4-carbamoylphenyl)-substituted and tetrakis-(4-amidophenyl)- substituted calix[4]arenes as well as the monomeric biphenylcarbamate have been synthesized as fluorescent receptors for anion sensing. Their binding properties with various anions inc

Full text of DOI:10.1021/jo062258z

Phenyl-calix[4]arene-Based Fluorescent Sensors: Cooperative
Binding for Carboxylates
Xiao Hua Sun,† Wenye Li,†,‡ Ping Fang Xia,† Hai-Bin Luo,†,§ Yingli Wei,†,‡
Man Shing Wong,†,* Yuen-Kit Cheng,†,* and Shaomin Shuang‡,*
Department of Chemistry, Hong Kong Baptist UniVersity, Kowloon Tong, Hong Kong SAR, China, School
of Chemistry and Chemical Engineering, Institute of AdVanced Chemistry, Shanxi UniVersity, Taiyuan
030006, China, and School of Pharmaceutical Sciences, Sun Yat-Sen UniVersity,
Guangzhou 510080, China
mswong@hkbu.edu.hk
ReceiVed October 31, 2006
Tetrakis-(4-carbamoylphenyl)-substituted and tetrakis-(4-amidophenyl)-substituted calix[4]arenes as well
as the monomeric biphenylcarbamate have been synthesized as fluorescent receptors for anion sensing.
-
Their binding properties with various anions including F-, CH3COO-, Ph-COO-, and H2PO4 were
1
investigated by fluorescence titrations, Job plot experiments, H NMR spectroscopies, and ESI-MS
measurements. Importantly, we have found that calix[4]arene-based sensors exhibit greatly enhanced
binding affinity and selectivity toward carboxylates. The binding associations of tetrakis-(4-carbam-
oylphenyl)-substituted calix[4]arene for carboxylates are 1-2 orders of magnitude greater than those of
the monomeric biphenylcarbamate sensor. Such an enhancement in the binding affinity and selectivity is
attributed to the cooperative binding of the multiple ligating groups as revealed from the ab inito DFT
calculations. Although tetrakis-(4-amidophenyl)-substituted calix[4]arene exhibited relatively weaker
binding affinity toward anions, its superior binding selectivity for acetate ion over fluoride ion is evident.
Our results also suggest that carbamate functionality is a useful H-bond donor for hydrogen-bonding
interactions in molecular recognition and supramolecular chemistry.
Introduction
complementary structural components that show good recogni-
tion properties requires building in relatively strong and
directional adhesive forces. Among various noncovalent interac-
tions, hydrogen-bonding interactions are particularly useful and
There are currently considerable efforts on exploring efficient
artificial receptors for targeted anion recognition and sensing
as anions are ubiquitous and play important roles in biological,
medical, environmental, and chemical sciences.1 Despite the
tremendous progress in developing metal ion sensing in recent
years,2 design and synthesis of an artificial receptor/sensor that
exhibits high binding affinity and selectivity to a targeted anion
still remain a great challenge to the scientific community as
anions exhibit a wide range of geometries and selective anionic
receptors are difficult to design and synthesize.1 The design of
(1) (a) Haugland, R. P. The Handbook. A Guide to Fluorescent Probes
and Labeling Technologies, 10th ed.; Molecular Probes Inc.: Eugene, OR,
2005. (b) Anion sensing; Stibor, I., Ed.; Springer-Verlag: Berlin 2005. (c)
Martinez-Manez, R.; Sancenon, F. Chem. ReV. 2003, 103, 4419-4476. (d)
Beer, P. D.; Gale, P. A. Angew. Chem., Int. Ed. 2001, 40, 486-516. (e)
Haryley, J. H.; James, T. D.; Ward, C. J. J. Chem. Soc. Parkin Trans. 2000,
1, 3155-3184. (f) de Silva, A. P.; Nimal Gunaratne, H. Q.; Gunnlaugsson,
T.; Huxley, A. J. M.; Mccoy, C. P.; Rademacher, J. T.; Rice, T. E. Chem.
ReV. 1997, 97, 1515-1566. (g) Fluorescent Chemosensors for Ion and
Molecule Recognition; Czarnik, A. W., Ed.; American Chemical Society
Books: Washington, DC, 1993. (h) Lhota´k, P. Top. Curr. Chem. 2005,
255, 65-95. (i) Matthews, S. E.; Beer, P. D. Supramol. Chem. 2005, 17,
411-435.
† Hong Kong Baptist University.
‡ Shanxi University.
§ Sun Yat-Sen University.
10.1021/jo062258z CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/08/2007
J. Org. Chem. 2007, 72, 2419-2426
2419

Sun et al.
SCHEME 1. Syntheses of Aryl-Substituted Calix[4]arenes 3 and 5
effective in this regard. Receptors bearing functional groups such
as amides,3 ureas,4 thioureas,5 and positively charged groups6
have been widely used to recognize anions via hydrogen-
bonding interactions; on the other hand, carbamate functionality
is rarely used for this purpose.7 Strong binding affinity offers
potential for high sensitivity at low analyte concentration. To
achieve high binding affinity and good selectivity, a rigid and
preorganized receptor site that is complementary to the targeted
guest is of paramount importance. In addition, receptors/sensors
bearing multiple ligating groups have been shown to be useful
to promote cooperative binding, which would result in enhanced
binding affinity.8
Calix[4]arene is greatly used as a molecular scaffold in the
design of artificial receptors9 because of its tunable and unique
three-dimensional structure together with the ease of function-
alization. On the other hand, there are few examples taking
advantage of an extended preorganized rigid platform of calix-
[4]arene for construction of supramolecular systems.10 The
expanded or extended cavity could be beneficial to the
encapsulation and recognition properties. Furthermore, the
extended calix[4]arene skeleton with π-conjugated units could
act as a chromophore or fluorophore. Upon binding with a guest,
the change of the spectral properties would give rise to a sensing
mechanism. Anion sensors developed from a change in fluo-
rescence properties upon binding are considered particularly
attractive because they offer promise for high sensitivity at low
analyte concentration.1f
(2) For recent references, see: (a) Desvergne, J. P.; Czarnik, A. W.
Chemosensors of Ion and Molecule Recognition; Kluwer: Dordrecht, 1997.
(b) Fluorescent Chemosensors for Ion and Molecule Recognition; Czarnik,
A. W., Ed.; American Chemical Society: Washington, DC, 1992. (c) Kim,
S. K.; Lee, J. K.; Lee, S. H.; Lim, M. S. Lee, S. W.; Sim, W.; Kim, J. S.
J. Org. Chem. 2004, 69, 2877-2880. (d) Budka, J.; Lhota´k, P.; Stibor, I.;
Michlova´, V.; Sykroa, J.; Cisarova´, I. Tetrahedron Lett. 2002, 43, 2857-
2861. (e) Metivier, R.; Leray, I. Valeur, B. Chem. Eur. J. 2004, 10, 4480-
4490. (f) Kim, J. H.; Hwang, A. R.; Chang, S. K. Tetrahedron Lett. 2004,
45, 7557-7561. (g) Choi, M. J.; Kim, M. Y.; Chang, S. K. Chem. Commun.
2001, 1664-1665. (h) Hanaoka, K.; Kikuchi, K.; Kojima, H.; Urano, Y.;
Nagano, T. J. Am. Chem. Soc. 2004, 126, 12470-12476. (i) Chen, P.;
Greenberg, B.; Taghavi, S.; Romano, C.; vander Lelie, D.; He, C. Angew.
Chem., Int. Ed. 2005, 44, 2715-2719.
(3) (a) Tomapatanaget, B.; Tuntulani, T.; Chailapakul, O. Org. Lett. 2003,
5, 1539-1542. (b) Kim, S. K.; Bok, J. H.; Bartsch, R. A.; Lee, J. Y.; Kim,
J. S. Org. Lett. 2005, 7, 4839-4842.
(4) (a) Massimo, B.; Boca, D. L.; Go´mez, D. E.; Fabbrizzi, L.; Licchelli,
M.; Monzani, E. J. Am. Chem. Soc. 2004, 126, 16507-16514. (b) Dudic,
M.; Lhota´k, P.; Stibor, I.; Lang, K.; Proskova´. P. Org. Lett. 2003, 5, 149-
152.
It has been shown that the cone-conformed calix[4]arene
derivatives bearing four urea functionalities tend to self-assemble
into the dimeric capsules via intermolecular hydrogen bonds.10,11
However, by taking advantage of the structural preorganization
of extended cone-conformed phenyl-substituted calix[4]arene
(5) (a) Pfeffer, F. M.; Gunnlaugsson, T.; Jensen, P.; Kruger, P. E. Org.
Lett. 2005, 7, 5357-5360. (b) Liu, S. Y.; Fang, L.; He, Y. B.; Chan, W.
H.; Yeung, K. T.; Cheng, Y. K.; Yang, R. H. Org. Lett. 2005, 7, 5825-
5828.
(6) (a) Metzer, A.; Gloe, K. Stephan, H.; Schmidtchen, F. P. J. Org.
Chem. 1996, 61, 2051-2055. (b) Breccia, P.; Van Gool, M.; Pe´rez-
Ferna´nedz, R.; Mart´ın-Santamaria, S.; Gago, F.; Prados, P.; de Mendoza,
J. J. Am. Chem. Soc., 2003, 125, 8270-8284. (c) Amendola, V.; Boiocchi,
M.; Fabbarizzi, L.; Palchetti, A. Chem. Eur. J. 2005, 11, 120-127.
(7) Fang, L.; Chan, W. H.; He, Y. B.; Kwong, D. W. J.; Lee, A. W. M.
J. Org. Chem. 2005, 70, 7640-7646.
(8) (a) Wright, A. T.; Anslyn, E. V. Org. Lett. 2004, 6, 1341-1344. (b)
Wong, M. S.; Xia, P. F.; Zhang, X. L.; Lo, P. K.; Cheng, Y.-K.; Yeung,
K.-T.; Guo, X.; Shuang, S. M. J. Org. Chem. 2005, 70, 2816-2819.
(9) For recent reviews, see: (a) Calixarenes 2001; Asfari, Z., Bohmer,
V., Harrowfield, J., Vicens, J., Eds.; Kluwer: Dordrecht, 2001. (b) Ikeda,
A.; Shinkai, S. Chem. ReV. 1997, 97, 1713-1734. (c) Danil de Mamor, A.
F.; Cleverley, R. M.; Zapata-Ormachea, M. L. Chem. ReV. 1998, 98, 2495-
2525.
(10) Cho, Y. L.; Rudkevich, D. M.; Rebek, Jr., J. J. Am. Chem. Soc.
2000, 122, 9868-9869.
(11) Rebek, J., Jr. Chem. Commun. 2000, 637-643.
2420 J. Org. Chem., Vol. 72, No. 7, 2007

Phenyl-calix[4]arene-Based Fluorescent Sensors
TABLE 1. Stoichiometric Ratio (R) and Association Constant (K) of Tetrakis-(4-carbamoyl-phenyl)-Substituted Calix[4]arene 3,
Tetrakis-(4-amidophenyl)-Substituted Calix[4]arene 5, and Monomeric Biphenylcarbamate 7 with Anions
-
F-
CH3COO-
H2PO4
PhCOO-
receptor
Ra
log K
K
Ra
K
Ra
log K
K
Ra
K
3
1:1
1:4
1:1
3.87b
21.2b
1:1
1:4
3.16b
18.3b
1:1
1:1
4.6 × 105 c
4.4 × 104 c
4490c
1:1
3.9 × 104 c
5
7
8866c
9582c
-
-
3.73b
2.57b
-
1:1
-
1:1
1:1
1:1
3490c
1000c
a Determined by the Job plot. b Determined from the static quenching equation, log(Io - I)/I ) log K + n log [A]. c Calculated from nonlinear curve
fitting analysis of fluorescent titration data.
together with co-operatively reinforced hydrogen-bonding in-
teractions of appended ligating groups such as carbamate and
amide functionalities at the upper (or wide) rim, binding- and
selectivity-enhanced phenyl-substituted calixarene-based fluo-
rescent anion sensors have been developed. We herein report
the synthesis and investigation of anion binding/sensing studies
of novel tetrakis-(4-carbamoylphenyl)-substituted calix[4]arene
3, tetrakis-(4-amidophenyl)-substituted calix[4]arene 5, and the
monomeric biphenylcarbamate 7. We have found that the
multiple carbamate-ligated calix[4]arene sensor exhibits superior
binding affinity toward carboxylates as compared to the
monomeric biphenylcarbamate counterpart.
Results and Discussion
The syntheses of tetrakis-(4-carbamoylphenyl)-substituted
calix[4]arene 3 and tetrakis-(4-amidophenyl)-substituted calix-
[4]arene 5 are shown in Scheme 1. Palladium-catalyzed Kumada
coupling of tetrakisbromocalix[4]arene 112 and (4-(trimethyl-
silyloxy)-phenyl)magnesium bromide, which was freshly gener-
ated by 1-bromo-4-(trimethylsilyloxy)benzene and magnesium
turnings, followed by hydrolysis afforded tetrakis(4-hydroxy-
phenyl)-substituted calix[4]arene 2 in 71% yield. Refluxing of
2 and phenyl isocyanate in the presence of Et3N in CH3CN for
24 h afforded tetrakis(4-carbamoylphenyl)-substituted calix[4]-
arene 3 in 86% isolated yield. One the other hand, palladium-
catalyzed Suzuki coupling of 1 with 4-formylbenzeneboronic
acid using Pd(OAc)2/P(o-tol)3 as a catalyst gave tetrakis(4-
formylphenyl)calix[4]arene 413 in a moderate yield. Oxidation
of 4 using sodium chlorite in the presence of sulfamic acid14
yielded the corresponding acid in a quantitative yield. Amidation
of carboxyphenylcalix[4]arene via the acid chloride with aniline
FIGURE 1. (a) Fluorescence spectra of 3 upon addition of various
[F-] in CH3CN. The inset shows the Job plot of 3 and [F-]. (b)
Fluorescence spectra of 3 upon addition of various [Ph-COO-] in CH3-
CN. The inset shows the Job plot of 3 and [Ph-COO-].
afforded the desired tetrakis-(4-amidophenyl)-substituted calix-
[4]arene 5 in 75% isolated yield. The monomeric biphenylcar-
bamate sensor 7 was also prepared accordingly using the same
synthetic approach for comparison (see Supporting Information).
All the newly synthesized receptors were fully characterized
1
with H NMR, 13C NMR, high-resolution MALDI-TOF, and
elemental analyses and found to be in good agreement with the
structures.
The binding and sensing properties of 3, 5, and 7 with various
anions were initially investigated by fluorescence titration. Upon
titration of 3 in acetonitrile with various anions (Bu4N+X-)
including F-, CH3COO-, H2PO4-, and Ph-COO-, the fluores-
cence intensity of 3 peaked at 350 nm and progressively
decreased together with a slight shift of emission maximum
(Figure 1). In some cases, there was also a weak emission band
(12) (a) Wong, M. S.; Zhang, X. L.; Chen, D. Z.; Cheung, W. H. Chem.
Commun. 2003, 138-139. (b) Wong, M. S.; Xia, P. F.; Lo, P. K.; Sun, X.
H.; Wong, W. Y.; Shuang, S. M. J. Org. Chem. 2006, 71, 940-946. (c)
Lo, P. K.; Chen, D. Z.; Meng, Q. W.; Wong, M. S. Chem. Mater. 2006,
18, 3924-3930.
(13) Wong, M. S.; Nicoud, J.-F. Tetrahedron Lett. 1993, 34, 8237-8239.
(14) Arduini, A.; Fabbi.; Mantovani, M.; Mirone, L.; Pochini, A.; Secchi,
A.; Ungaro, R. J. Org. Chem. 1995, 60, 1454-1457.
J. Org. Chem, Vol. 72, No. 7, 2007 2421

Sun et al.
1
FIGURE 2. Spectra of H NMR titration of (a) 3 (1.85 mM) and (b) 7 (10 mM) with n-Bu4N+CH3COO- in CD3CN.
that slowly emerged at 425-430 nm when an anion was added
in a large excess. Interestingly, upon an addition of aqueous
acid, the fluorescence intensity was restored and the weak band
disappeared. These observations are consistent with the fact that
the anion interacts with the N-H protons of the carbamate-
appended calix[4]arene through hydrogen bonds. On the other
hand, there were no significant spectral changes upon titration
Ph-COO- (Figure 1), implying the presence of two binding
stages/modes. Job plot analyses showed that 3 first formed 1:1
stoichiometric complexes with F- and H2PO4- and became 1:4
complexes when F- and H2PO4 was added in a large excess,
-
respectively. The formation of 1:1 and 1:4 complexes were
further confirmed by the ESI-MS measurements showing a base
peak or peak at m/z 1456.6, 378.3, 1534.6, and 456.2 corre-
sponding to 3‚F-, 3‚4F-, 3‚H2PO4-, and 3‚4H2PO4-, respec-
tively. (See Supporting Information.)
-
of 3 with Cl-, Br-, I-, and HSO4 anions, signifying that 3
showed insignificant binding affinity toward these anions. (See
Supporting Information.)
Analyzing the titration data using the static quenching
equation15 consistently supported the existence of two binding
In view of the fluorescence titration spectra of 3, there was
a greater extent of intensity quenching after addition of more
-
than 6 equiv of F- or H2PO4 in contrast to the sequential
(15) Pang, Y. H.; Yang, L. L.; Shuang, S. M.; Dong, C.; Thompson, M.
J. Photochem. Photobiol., B 2005, 80, 139-144.
decrease in fluorescence intensity induced by CH3COO- and
2422 J. Org. Chem., Vol. 72, No. 7, 2007

Phenyl-calix[4]arene-Based Fluorescent Sensors
FIGURE 3. 1H NMR spectra of the aromatic region of (a) 3 and (b) 7 and their corresponding hydrogen-bonded complexes upon addition of
excess of anions in CD3CN.
stoichiometries and also provided the estimated binding as-
sociations of the two complexes in which the carbamate-
appended receptor 3 bound stronger with F- (log K1 ) 3.87,
log K4 ) 21.2) than H2PO4- (log K1 ) 3.16, log K4 ) 18.3) in
both stoichiometric complexes agreeable to the decreasing
basicity of the anions as shown in Table 1. In sharp contrast,
the calix[4]arene-based receptor 3 only gave rise to a 1:1 binding
with CH3COO- and Ph-COO- according to the Job plot. The
binding associations of 3‚CH3COO- and 3‚Ph-COO- as deter-
mined by nonlinear curve fitting analysis16 are 4.6 × 105 M-1
and 3.9 × 104 M-1, respectively. The ESI-MS analyses further
confirmed a 1:1 stoichiometric complex formation of 3‚CH3COO-
and 3‚Ph-COO- with a peak or base peak at m/z 1496.8 and
1558.8, respectively. The fluorescent quenching was also
observed upon titration of the monomeric biphenylcarbamate
sensor 7 with various anions; however, the binding affinities
of 7 toward those anions are significantly weaker as compared
to those of 3, particularly for carboxylates. The order of anion
affinity of 7 in 1:1 stoichiometries as determined by the Job
plot analyses is F- (K ) 9.6 × 103 M-1) > CH3COO- (K )
4.5 × 103 M-1) > H2PO4- (K ) 3.5 × 103 M-1) > Ph-COO-
(K ) 1.0 × 103 M-1) which is also consistent to the decreasing
basicity of the anions.
On the other hand, upon titration of amidophenyl-substituted
calix[4]arene 5 with various anions, only F- and CH3COO-
could give rise to significantly progressive fluorescent quenching
peaked at 400 nm. The ESI-MS analyses suggested a 1:1
stoichiometric complex formation of 5‚F- and 5‚CH3COO- with
a peak at m/z 1392.1 and 1432.5, respectively. The binding
associations for F- and CH3COO- in a 1:1 binding stoichiom-
etry, which were further confirmed by the Job plot, are 8.9 ×
103 M-1 and 4.3 × 104 M-1, respectively, as estimated by
nonlinear curve fitting analysis of titration data. These results
suggested that sensor 5 exhibited higher selectivity for CH3COO-
than for F-. The binding associations of 3 and 5 for carboxylates
are comparable to those of the best calix[4]arene-based anion
receptors; on the other hand, these receptors exhibit much higher
selectivity toward acetate over benzoate (for 3, Kacetate/benzoate
12; for 5, Kacetate/benzoate > 104).1h,1i
∼
The interactions of the receptor 3, 5, and 7 with anions were
1
further investigated by H NMR spectroscopy. Complexation
of monomeric biphenyl-carbamate receptor 7 with anions was
(16) Macomber, R. S. J. Chem. Educ. 1992, 69, 375-378.
further supported by the growth of a new set of upfield-shifted
J. Org. Chem, Vol. 72, No. 7, 2007 2423

Sun et al.
FIGURE 4. Optimized structures of (a) 3‚CH3COÃ- and (b) 3‚Ph-COÃ- complexes obtained by B3LYP 6-31G DFT calculations (see the Supporting
Information for details). In panel a, the methyl group of acetate is represented as a single black ball for clarity. The pertinent hydrogren bonds are
highlighted as green dotted lines delimited by bond lengths (in Å) given by the precursor oxygen (red) and nitrogen (blue) atoms. The calix[4]-
arenes are simply rendered as pink sticks.
aromatic protons corresponding to the hydrogen-bonded com-
plex due to a slow exchange in NMR time scale (Figure 2). In
particular, large upfield shifts of aromatic protons of 7 upon
complexation with F-, CH3COO-, and Ph-COO- came from
N-substituted phenyl ring (i.e., ∆δ for o-Ar-H and p-Ar-H )
0.89 and 0.50 ppm, respectively, in CD3CN) (Figure 3). The
peak broadening together with diminished intensity of the N-H
resonance as well as the upfield shift of aromatic protons of 7
due to the increase in the electron density of the phenyl ring
upon an addition of anions consistently supported the formation
of the hydrogen bond between the N-H proton of the carbamate
moiety and anions. On the other hand, the receptor 7 showed
remarkably different in the shifting pattern of proton resonances
upon complexation with H2PO4-, in which the upfield shifts of
the aromatic protons of the carbamate-substituted phenyl ring
(∆δ ) 0.25-0.27 ppm) are greater than those of N-substituted
phenyl ring (∆δ ) 0.02-0.12 ppm). There was also a new broad
proton resonance growing around 10.5 ppm while the N-H
resonance peak decreased progressively (Figure 3). These
findings suggest that the hydrogen-bonding interaction formed
between the carbonyl of the carbamate moiety and the H-O of
being greater than those of the N-substituted phenyl ring (∆δ
for o-Ar-H ) 0.002-0.08 ppm).
1H NMR titrations of 5 with F- and CH3COO- were carried
out in CD3COCD3 due to insufficient solubility in CD3CN. In
contrast to 3 and 7, binding of 5 with anions is kinetically fast
on the NMR time scale; nevertheless, anion-induced shifts of
the proton resonances of 5 were apparent. (See Supporting
Information.) The downfield shift and peak broadening of the
proton of the N-H moiety as well as the significantly large
downfield shift of aromatic protons that are ortho to the
N-substituent (∆δ ) 0.2-0.37 ppm) and to the carbonyl
substituent (∆δ ) 0.28-0.75 ppm) upon addition of anions
suggest the formation of hydrogen-bonded complex.
The very large binding constants obtained for 3‚4F- and
3‚4H2PO4- hydrogen-bonded complexes are due to the additive
effect of the four carbamoyl binding sites of 3 interacting
-
separately with four F- and four H2PO4 anions, respectively.
On the other hand, the greatly enhanced binding of the calix-
[4]arene-based receptor 3 toward carboxylates in a 1:1 binding
stoichiometry is attributed to the cooperative binding of multiple
carbamate ligating groups. As carboxylates are Y-shaped anions,
it would be more favorable to have the hydrogen bonds formed
between carboxylate and the two opposite -NH groups of
carbamoyl moieties flanked from the extended calix[4]arene
skeleton. Such a cooperative (or bidentate) binding mode was
revealed in both of the optimized structures of 3‚CH3COO- and
3‚Ph-COO- complexes, as shown in Figure 4 according to ab
inito B3LYP 6-31G DFT calculations using Gaussian 03.17 To
achieve the bidentate binding mode, the carbamoylphenyl-calix-
[4]arene receptor adopts a pinched cone conformation with a
diminished cavity for encapsulation which is more pronounced
in the benzoate case. This also leads to the methyl group of
acetate or the phenyl group of benzoate swayed sideways from
the receptor in the complexes. In view of the 1H NMR titration
spectra, both of the methyl proton resonances of acetates and
aromatic proton resonances of benzoates exhibit no significant
upfield shift upon binding with receptor 3 as compared to those
of the monomeric receptor 7 (Figures S4 and S8), consistently
suggesting that these anions possess no close van der Waal
-
H2PO4 is significant.
In view of the spectra of 1H NMR titrations of carbamoylphe-
nyl-substituted calix[4]arene 3 with anions, the evolution of the
chemical shifts was very complex due to slow equilibration of
mixtures of receptor and receptor-anion complex (Figure 2a).
However, the peak broadening and downfield shift of the N-H
peaks as well as the overall trend of the upfield shift of the
aromatic protons of 3 were evident and were very similar to
those of the corresponding monomeric receptor 7, suggesting
that the same binding site/mode is used for the formation of
the hydrogen-bonded receptor-anion complex (Figures 2 and
3). The large upfield shifts of aromatic protons of 3 upon
complexation with F-, CH3COO-, and Ph-COO- also originated
from N-substituted phenyl rings (i.e., ∆δ for o-Ar-H ) 0.78
and p-Ar-H 0.42 ppm in CD3CN). Consistent with the mono-
meric receptor 7, receptor 3 used a slightly different binding
-
mode with H2PO4 in which the interaction between the
-
carbonyl of the carbamate moiety and H-O of H2PO4 is
significantly contributed as shown by the upfield shifts of the
aromatic protons of the biphenyl ring (∆δ ) 0.18-0.22 ppm)
2424 J. Org. Chem., Vol. 72, No. 7, 2007

Phenyl-calix[4]arene-Based Fluorescent Sensors
Hz, 4H), 3.96 (t, J ) 7.3 Hz, 8H), 3.32 (d, J ) 12.7 Hz, 4H),
2.02-2.10 (m, 8H), 1.07 (t, J ) 7.3 Hz, 12H). 13C NMR (67.5
MHz, CD3COCD3, δ) 156.8, 156.1, 135.7, 135.5, 133.4, 128.2,
127.1, 115.9, 77.6, 31.8, 24.0, 10.7. IR (KBr) νmax 3426, 3026,
1612, 1517, 1227. MS (FAB) m/z 960.8 [M+]. HRMS (MALDI-
TOF) Calcd for C64H64NaO8, 983.4498. Found: 983.4465 [M +
Na]+.
contact with the receptor. Nevertheless, the binding affinities
of carbamoylphenyl-substituted calix[4]arene 3 toward carboxy-
lates are 1-2 orders of magnitudes larger than those of the
monomeric biphenylcarbamate sensor 7 (Table 1). Furthermore,
such a cooperative binding mode could play a key role in
enhancing the binding and selectivity of amidophenyl-substituted
calix[4]arene 5 toward CH3COO- over F-.
5,11,17,23-Tetrakis(4-(N-phenylcarbamoyl)phenyl)-25,26,27,-
28-tetrapropoxycalix[4]arene 3. To a 100 mL flask containing 2
(0.50 g, 0.52 mmol) in 30 mL of CH3CN were added freshly
distilled phenyl isocyanate (0.50 g, 4.2 mmol) and Et3N (53 mg,
0.52 mmol). The solution mixture was refluxed for 24 h. After the
reaction mixture cooled to room temperature, 20 mL of water was
added, and the organic phase was extracted with chloroform (20
× 3 mL). The combined organic phase was washed with brine and
dried over anhydrous Na2SO4. After evaporating the solvents, the
residue was washed with MeOH and then purified by silica gel
chromatography using gradient elution method with petroleum ether
Conclusions
In conclusion, novel fluorescent anion sensors tetrakis-(4-
carbamoylphenyl)-substituted calix[4]arene, tetrakis-(4-ami-
dophenyl)-substituted calix[4]arene, and the monomeric biphe-
nylcarbamate have been designed, synthesized, and investigated
1
by fluorescent titration, H NMR spectroscopic, and ESI-MS
studies. Importantly, we have demonstrated that tetrakis-(4-
carbamoylphenyl)-substituted calix[4]arene sensor shows greatly
enhanced binding affinity and selectivity toward these anions
as compared to the monomeric biphenylcarbamate counterparts,
particularly for carboxylates. Despite a relatively weaker binding
affinity toward anions, tetrakis-(4-amidophenyl)-substituted
calix[4]arene also exhibits superior binding selectivity for acetate
ion over fluoride ion. The binding and selectivity enhancement
of phenylcalix[4]arene-based sensors are attributed to the
cooperative binding of the multiple carbamoyl ligating groups
as revealed from ab inito quantum mechanical calculations. This
approach provides an alternative means to design and synthesize
binding- and selectivity-enhanced receptors and sensors for
carboxylates. Our results also show that carbamate functionality
is a useful H-bond donor for hydrogen-bonding interactions in
molecular recognition and supramolecular chemistry.
1
and chloroform affording a white solid (0.64 g, 86% yield). H
NMR (400 MHz, CD3COCD3, δ) 9.00 (b, 4H), 7.54 (d, J ) 8.0
Hz, 8H), 7.27 (t, J ) 7.6 Hz, 8H), 7.22 (d, J ) 8.4 Hz, 8H), 7.11
(s, 8H), 7.02 (t, J ) 7.6 Hz, 4H), 6.99 (d, J ) 8.8 Hz, 8H), 4.64
(d, J ) 13.2 Hz, 4H), 4.02 (t, J ) 7.6 Hz, 8H), 3.42 (d, J ) 13.2
Hz, 4H), 2.06-2.08 (m, 8H), 1.11 (t, J ) 7.2 Hz, 12H). 13C NMR
(100 MHz, CD3COCD3, δ) 157.2, 152.6, 150.7, 139.8, 139.3, 136.1,
135.2, 129.7, 128.1, 127.9, 123.9, 122.7, 119.4, 77.9, 31.9, 24.2,
10.8. IR (KBr) νmax 3405, 3054, 1745, 1731, 1601, 1506, 1204.
HRMS (MALDI-TOF) Calcd for C92H84N4NaO12, 1460.6016.
Found: 1460.6064 [M + Na]+. Anal. Calcd for C92H84N4O12: C,
76.86; H, 5.89; N, 3.90. Found: C, 76.60; H, 5.93; N, 3.85.
5,11,17,23-Tetrakis(4-formylphenyl)-25,26,27,28-tetra-
propoxycalix[4]arene 4. To a 100 mL flask containing 1 (0.23 g,
0.25 mmol) and commercially available 4-formylphenylboronic
acid (0.23 g, 1.53 mmol) in 50 mL of toluene were added Pd-
(OAc)2 (11 mg, 5 mol %), P(o-tol)3 (30 mg, 10 mol %), 2 mL of
methanol, and 2 mL of 2 M K2CO3. The mixture was stirred
at 75 °C overnight under N2. After the mixture was cooled to room
temperature, 20 mL of water was added. The reaction mixture was
acidified to pH 3-4 using 6 M HCl and then extracted with ethyl
acetate (20 × 3 mL). The combined organic phase was dried over
anhydrous Na2SO4 and evaporated to dryness. The residue obtained
was further purified by silica gel flash column chromatography
using gradient elution method with petroleum ether and ethyl acetate
Experimental Section
5,11,17,23-Tetrakis(4-hydroxyphenyl)-25,26,27,28-tetra-
propoxycalix[4]arene 2. To a 250 mL two-necked flask contain-
ing 1 (0.50 g, 0.55 mmol) in 50 mL of anhydrous THF were
added PdCl2(dppf) (24 mg, 5 mol %) and excess freshly prepared
4-trimethylsilyloxyphenylmagnesium bromide.18 The mixture was
heated to reflux in N2 atmosphere for 3 h. After the solution mixture
cooled to room temperature, 20 mL of water was carefully added,
and the mixture was then acidified to pH 3-4 using 6 M HCl.
After extracting with ethyl acetate (20 × 3 mL), the organic phase
was combined and dried over anhydrous Na2SO4 and evaporated
to dryness. The residue was purified by silica gel flash chroma-
tography using gradient elution method with petroleum ether and
ethyl acetate as eluent affording a white solid (0.37 g, 71% yield).
1H NMR (270 MHz, CD3COCD3, δ) 8.10 (s, 4H), 7.03 (d, J ) 8.6
Hz, 8H), 6.96 (s, 8H), 6.62 (d, J ) 8.6 Hz, 8H), 4.57 (d, J ) 12.7
1
as eluent affording a white solid (0.18 g, 64% yield). H NMR
(400 MHz, CDCl3, δ) 9.85 (s, 4H), 7.56 (d, J ) 8 Hz, 8H), 7.22
(d, J ) 8 Hz, 8H), 6.98 (s, 8H), 4.60 (d, J ) 13.2 Hz, 4H), 3.97 (t,
J ) 7.2 Hz, 8H), 3.33 (d, J ) 13.2 Hz, 4H), 1.96-2.04 (m, 8H),
1.06 (t, J ) 7.2 Hz, 12H). 13C NMR (100 MHz, CDCl3, δ) 191.7,
157.3, 146.7, 135.5, 134.4, 133.5, 129.9, 127.2, 126.7, 77.1, 31.3,
23.3, 10.3. IR (KBr) νmax 3052, 1698, 1603, 1464, 1170. MS (FAB)
m/z 1008.1 [M+].
5,11,17,23-Tetrakis(4-carboxyphenyl)-25,26,27,28-tetra-
propoxycalix[4]arene. To a 100 mL flask containing 4 (0.19 g,
0.19 mmol) in 10 mL of CHCl3 and 30 mL of acetone were added
1 mL aqueous sulfamic acid (0.30 g, 3.1 mmol) and 1 mL aqueous
sodium chlorite (0.28 g, 3.1 mmol). The mixture was stirred at room
temperature for 1 h and then evaporated to dryness. The solid
obtained was washed with water and acetone, affording a quantita-
tive yield of the corresponding acid as a white solid. 1H NMR (270
MHz, DMSO-d6, δ) 12.4 (b, 4H), 7.65 (d, J ) 8.1 Hz, 8H), 7.23
(d, J ) 8.1 Hz, 8H), 7.06 (s, 8H), 4.44 (d, J ) 13.2 Hz, 4H), 3.90
(t, J ) 7.0 Hz, 8H), 3.40 (d, J ) 13.2 Hz, 4H), 1.93-1.95 (m,
8H), 1.02 (t, J ) 7.3 Hz, 12H). 13C NMR (67.5 MHz, DMSO-d6,
δ) 166.6, 156.3, 144.2, 134.8, 132.8, 129.3, 128.4, 126.6, 125.8,
76.4, 30.4, 22.9, 10.3. IR (KBr) υmax 3434, 3054, 1693, 1608, 1180.
MS (FAB) m/z 1072.8 [M+]. HRMS (ESI-TOF) Calcd for
C68H63O12, 1071.4320. Found: 1071.4285 [M - H]-.
(17) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03, ReVision C.02; Gaussian, Inc.: Wallingford, CT; 2004.
5,11,17,23-Tetrakis(4-(N-phenylformamido)phenyl)-25,26,27,-
28-tetrapropoxycalix[4]arene 5. To a 100 mL two-necked round
(18) Xiang, S.; Zhang, Y. L.; Xin, Q.; Li. C. J. Org. Chem. 2002, 67,
2686.
J. Org. Chem, Vol. 72, No. 7, 2007 2425

Sun et al.
bottle flask containing 5,11,17,23-tetrakis(4-carboxyphenyl)-25,-
26,27,28-tetrapropoxycalix[4]arene (0.15 g, 0.14 mmol) in 30 mL
of dry chloroform was added thionyl chloride (0.5 mL, 6.88 mmol)
while stirring at room temperature under N2. The solution mixture
was refluxed for 4 h. After removal of the solvent, a white solid
was obtained. To the while solid were added 50 mL of dry DCM
and 0.2 mL of freshly distilled aniline. The mixture was refluxed
overnight. After cooling to room temperature, the reaction mixture
was filtered. The residue was first dissolved in 5 mL of DMF and
then precipitated by 20 mL of methanol. The precipitate was washed
with 10 mL of water, 10 mL of methanol, and 20 mL of diethyl
ether affording a white solid 5 (0.147 g, 75% yield). 1H NMR (400
MHz, CD3COCD3, δ) 9.39 (s, 4H,), 7.79 (d, J ) 8.8 Hz, 8H), 7.76
(d, J ) 8.8 Hz, 8H), 7.36 (d, J ) 8.0 Hz, 8H), 7.24 (t, J ) 7.6 Hz,
8H), 7.20 (s, 8H), 7.05 (t, J ) 7.6 Hz, 4H), 4.66 (d, J ) 13.2 Hz,
4H), 4.05 (t, J ) 7.6 Hz, 8H), 3.47 (d, J ) 13.2 Hz, 4H), 2.08-
2.13 (m, 8H), 1.12 (t, J ) 7.6 Hz, 12H). 13C NMR (100 MHz,
CDCl3, δ) 166.1, 157.8, 144.9, 140.3, 136.4, 134.7, 134.1, 129.4,
128.7, 128.0, 127.1, 124.4, 121.3, 77.9, 30.8, 24.2, 10.8. IR (KBr)
ν
max 3422, 3055, 1653, 1600, 1532, 1440, 1319. HRMS (MALDI-
TOF) Calcd for C92H84N4NaO8, 1396.6214. Found: 1396.6226 [M
+ Na]+. Anal. Calcd for C92H84N2O8: C, 80.44; H, 6.16; N, 4.08.
Found: C, 80.08; H, 6.32; N, 3.98.
Acknowledgment. This work was supported by a Faculty
Research Grant (FRG/05-06/II-49), Hong Kong Baptist Uni-
versity, and an Earmarked Research Grant (HKBU2019/02P)
from Research Grants Council, Hong Kong SAR, China.
Supporting Information Available: General experimental
details. 1H NMR, 13C NMR, and MS data of 7. Results of
1
fluorescence titration, H NMR titration, Job plots, and ESI-MS
for 3, 5, and 7 with anions, and 1H NMR and 13C NMR spectra of
3 and 5. Results of calculations. This information is available free
of charge via the Internet at http://pubs.acs.org.
JO062258Z
2426 J. Org. Chem., Vol. 72, No. 7, 2007