Novel 2,2′-bipyridine-modified calix[4]arenes: Ratiometric fluorescent chemosensors for Zn2+ ion

Article abstract of DOI:10.1016/j.tetlet.2010.04.135

Two calix[4]arene derivatives with modified bipyridine as binding sites have been designed and synthesized. Compounds 1 and 2 are the first 2,2′-bipyridine-modified calix[4]arene-based sensors that can detect Zn²⁺ selectively with respect to ratiometric fluorescent changes and red shift. A binuclear complex structure has been demonstrated in the binding modes of 1-Zn²⁺ and 2-Zn²⁺ complexes.

Full text of DOI:10.1016/j.tetlet.2010.04.135

Tetrahedron Letters 51 (2010) 3719–3723
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel 2,20-bipyridine-modified calix[4]arenes: ratiometric fluorescent
chemosensors for Zn2+ ion
Jun Feng Zhang a, Sankarprasad Bhuniya a, Young Hoon Lee a, Changwan Bae a, Joung Hae Lee b,
,
*
Jong Seung Kim a,
*
a Department of Chemistry, Korea University, Seoul 130-701, Republic of Korea
b Korea Research Institute of Standards and Science, Daejon 305-600, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Two calix[4]arene derivatives with modified bipyridine as binding sites have been designed and synthe-
sized. Compounds 1 and 2 are the first 2,20-bipyridine-modified calix[4]arene-based sensors that can
detect Zn2+ selectively with respect to ratiometric fluorescent changes and red shift. A binuclear complex
structure has been demonstrated in the binding modes of 1-Zn2+ and 2-Zn2+ complexes.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 5 April 2010
Revised 23 April 2010
Accepted 30 April 2010
Available online 9 May 2010
Keywords:
Chemosensor
Zinc
Bipyridine
Calixarenes
Ratiometric
Recently, chemosensors based on the ion-induced fluorescence
changes are becoming increasingly popular due to their simplicity,
high sensitivity, and selectivity.1 In particular, the development of
a high selective fluorescent probe for zinc ion in the presence of a
variety of other metal ions has received great attention.2 Zinc ion is
one of the most abundant transition-metal ions in mammals and
plays crucial roles in many important biological processes such
as protein synthesis, neural signal transduction, enzyme regula-
tion, and gene expression.3 The zinc deficiency could cause unbal-
anced metabolism, which is responsible for many severe diseases
such as low blood sugar, Alzheimer’s disease, epilepsy, ischemic
stroke, and infantile diarrhea.4 On the other hand, pancreatic islets
containing relatively high concentrations of zinc ion could play
critical roles in insulin biosynthesis, storage, and secretion.5 More-
over, zinc is an agricultural and food waste product in the environ-
ment, excessive concentration of zinc may reduce the soil
microbial activity, resulting in phytotoxic effect and other prob-
lems.6 Therefore, the exploration of simple, quick, and efficient
Zn2+-selective fluorescent chemosensor is necessary not only for
the fundamental research but also for biological application in liv-
ing systems.
duction of fluorophore. Modifications of calixarenes have given rise
to a great number of derivatives with tunable binding properties
and a variety of fluorescent properties.7 Some of them have been
reported in our previous works and proved to be effective fluores-
cent sensors for Cu2+, Ca2+, Ag+, In3+, and some other metal ions.8 In
the present work, the calix[4]arenes in conjunction with binding
groups would facilitate the recognition of metal ions.
Bipyridine ligand is well known and has been extensively used
as a metal-chelating ligand due to its robust redox stability and
ease of functionalization.9,10 A distinguishing feature of this ligand
working as a sensor is the sensitive response toward zinc ions with
a significant red shift in emission,11 which provides the potential to
form a ratiometric fluorescent sensor that exhibits a spectral shift
upon binding to the analytes of interest. Compared to multitudi-
nous of zinc sensors functioning as cation-responsive optical
switches that translate the binding event into either an increase
or decrease of the emission intensity, only a few ratiometric fluo-
rescent sensors for zinc have been reported.11–13 Therefore, to de-
velop a high selective and ratiometric fluorescent Zn2+ sensor by
rationally modifying the calix[4]arenes structure and introducing
of modified bipyridine as binding ligand attracts our attention. As
the crown ether can act as a fluorescent ionophore and amide
group could increase the solubility, for comparison, crown ether
and amide group were introduced in 2.
Calixarenes are well known for basic molecular scaffolds with
structural rigidity, special molecular appearance, and facile intro-
Herein, we report two novel fluorescent chemosensors, 25,27-di
[methoxy(4-phenyl)-(60-phenyl-20,200-bipyridine)]-26,28-dihydroxy-
calix[4]arene (1) and 25,27-bis[N-(4-phenylmethyl-(60-phenyl-
* Corresponding authors.
E-mail addresses: ecljh@kriss.re.kr (J.H. Lee), jongskim@korea.ac.kr (J.S. Kim).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.135

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J. F. Zhang et al. / Tetrahedron Letters 51 (2010) 3719–3723
20,200-bipyridine))aminocarbonyl-methoxy]calix[4]-crown-5
(2),
which displayed a selective fluorescent change with Zn2+ in compar-
ison with various metal ions examined in CH3CN. Results showed
that upon addition of Zn2+ to the solution of 1 and 2, the fluorescence
bands at 363 nm and 356 nm are decreased gradually and concom-
itantly the bands centered at 408 nm (for 1) and 414 nm (for 2) are
increased, respectively. A red shift of approximately 45 nm and
58 nm was observed in 1 and 2, respectively. To the best of our
knowledge, 1 and 2 are the first example of 2,20-bipyridine-modified
calix[4]arene-based compounds used as Zn2+ fluorescent chemo-
sensors with ratiometric fluorescent changes and red shift.
Fluorescent sensors 1 and 2 were prepared as outlined in
Scheme 1. Compound 1 was synthesized by a typical Williamson
ether synthesis. When compound 8 was reacted with 2 equiv of 6
in the presence of K2CO3 in CH3CN, 1 was obtained in a moderate
yield of 56%. Reaction of 3 and 4 with DMAP and EDCI in DMF at
room temperature afforded fluorescent chemosensors 2 in 52%
yields.14
Figure 1. UV–vis spectra (a) and fluorescence spectra (b) of 1 (solid and dash lines)
and 2 (dot and dash dot line) in the absence and in the presence of 5 equiv of
Zn(ClO4)2 in dry CH3CN.
Studies on the UV–vis absorption and fluorescent emission pro-
cesses revealed that 1 and 2 showed sensitivity toward Zn2+ in
CH3CN. As shown in Figure 1a, in the absence of Zn2+, 1 and 2
showed similar absorption band at 260 nm with small shoulder
band at 314 nm. Upon addition of Zn2+ up to 5 equiv to the
solution, a major absorption band at 282 nm with shoulder band
at 320 nm and a major absorption band at 281 nm with shoulder
Scheme 1. Synthetic route of 1 and 2. (i) K2CO3, CH3CN reflux. (56%); (ii) NBS and small amount of BPO, CCl4 reflux, (72%); (iii) NaN3, DMF, 90 °C (83%); (iv) PPh3 and ammonia
water, pyridine rt (67%); (v) DMAP, EDCI, DMF rt (52%).

J. F. Zhang et al. / Tetrahedron Letters 51 (2010) 3719–3723
3721
band at 319 nm were observed for 1 and 2, respectively. In the
fluorescent spectra, coordination of Zn2+ caused red shift from
363 nm to 408 nm for 1 and red shift from 356 nm to 414 nm for
2 (Fig. 1b).
To understand the binding mode of 1 and Zn2+, UV–vis titration
experiments were performed (Fig. 2). With gradual addition of Zn2+
to the solution of 1, the UV–vis absorption band at 257 nm de-
creased sharply, whereas at 281 nm and 320 nm increased signifi-
cantly, with an isosbestic point at 257 nm observed. Upon addition
of 2 equiv of Zn2+ (Fig. 2 inset), the peaks at 257 nm and 281 nm
reached their maxima, which could be assumed to the bipyri-
dine-bounded zinc complex formation in 1. Similar changes were
observed upon addition of Zn2+ solution to the solution of 2
(Fig. 3) as well, indicating that 2 follows the same binding mode
with Zn2+ as that of 1, and the crown ethers and amides groups
of 2 were not involved in the coordination.
To further investigate the sensing properties of 1, we performed
fluorescence titration of 1 (10 l
M) with Zn2+ ion in CH3CN solution.
Figure 4. Changes in fluorescence spectra of 1 (10
(0–30
I363 as a function of Zn2+ concentration.
l
M) upon addition of Zn(ClO4)2
l
M) in acetonitrile (kex = 320 nm). Inset: ratiometric calibration curve I408/
Figure 4 shows the gradual changes of the fluorescence spectra of 1
upon addition of Zn2+. When the concentration of Zn2+ ion was in-
creased, the fluorescence intensity at 363 nm was decreased with a
new red shifted emission band centered at 408 nm. The red shift of
emission band can be explained by stabilization of the intramolec-
ular charge transfer (ICT) excited state of 1 and the formation of
1-Zn2+ complexes.13 After addition of 2 equiv of Zn2+, the peak at
363 nm was evanesced (Fig. 4 inset) and the red shift reached its
maximum. Similar fluorescent changes were noticed in aqueous
solution upon successive addition of Zn2+ ion to 1 as shown in
Figure S1. In another observation, we noticed that by changing of
perchlorate counter ions with sulfate, acetate, or chloride there
was no considerable change on optical properties of 1, which
implied that the optical properties of 1 were independent of coun-
ter anions (Fig. S2).
To know the insight of binding mode of ligand with zinc ion, we
performed the Job plot experiment (Fig. S3). A maximum fluores-
cence change was observed when the molar fraction of the Zn2+
perchlorate versus ligand 1 was about 0.67, which implied a 1:2
complex (1-2Zn2+) formation. Similarly, upon addition of Zn2+ to
the solution of 2, the fluorescence intensity at 356 nm decreased
with the concomitant formation of a new red shifted emission
band centered at 414 nm (Fig. 5), suggesting a binuclear complex
(2-2Zn2+) formation. From the fluorescence titration profiles, the
dissociation constants (Kd) of 1-Zn2+ and 2-Zn2+ in CH3CN solution
Figure 2. UV titrations of
1 (10 l lM) in
M) upon addition of Zn2+ (0–30
acetonitrile. Inset: titration of the change in the absorption of 1 measured at 257
and 320 nm versus the concentration of added Zn2+ ions.
Figure 3. UV titrations of
2
(10
l
M) upon addition of Zn2+ (0–30
l
M) in
Figure 5. Changes in fluorescence spectra of 2 (10
(0–30 M) in acetonitrile (kex = 320 nm). Inset: ratiometric calibration curve I414
I356 as a function of Zn2+ concentration.
lM) upon addition of Zn(ClO4)2
acetonitrile. Inset: titration of the change in the absorption of 2 measured at 260
l
/
and 319 nm versus the concentration of added Zn2+ ions.

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J. F. Zhang et al. / Tetrahedron Letters 51 (2010) 3719–3723
Figure 6. Perspective drawing (30% thermal ellipsoids) of the complex 1-ZnCl2 with the hydrogen atoms removed for clarity. Selected bonds length, (Å): Zn(1)–N(1) 2.072,
Zn(1)–N(2) 2.084, Zn(1)–Cl(1) 2.192, Zn(1)–Cl(2) 2.201.
were calculated to be Kd = 4.58 ꢀ 10ꢁ3 and Kd = 2.03 ꢀ 10ꢁ3 for 1
and 2, respectively.
was added, the proton signals of bipyridiyl moieties were consider-
ably changed and broadened due to coordination of the zinc ion.
The selectivity of the fluorescence response of 1 to zinc ions
over other competitive metal ions was then examined. Figure 7
showed the fluorescence response of 1 to various metal ions in
CH3CN solution. Pb2+, Al3+, alkali (Li+, Na+, K+, Rb+, Cs+), and alkaline
earth (Mg2+, Ca2+, Sr2+, Ba2+) metal perchlorates did not show much
change to the emission properties of 1. However, some heavy and
As shown in Figure 6, further evidence for the binding mode
was provided by 1-ZnCl2 single crystals structure. When 1 reacted
with ZnCl2 in a 1:1 molar ratio in acetonitrile solution at room tem-
perature, the mononuclear 1-ZnCl2 complex with one bipyridine
N,N-chelation coordinated to the Zn center was obtained. Unfortu-
nately, attempts to prepare a crystal of the binuclear 1-2Zn2+ com-
plex through the reaction of 1 and ZnCl2 in a 1:2 molar ratio in
organic solution were unsuccessful. However, depending on the
1-ZnCl2 crystal structure, it could be deduced that the coordination
process of the two bipyridine groups in 1 with zinc ion was inde-
pendent, that is, one bipyridine group in 1 could coordinate to
one zinc ion independently, while the other bipyridine group did
not involve in the coordination. We assumed that in the presence
of more zinc ions, the free bipyridine group could coordinate to an-
other zinc ion with the same coordination mode as that of the first
bipyridine group. As a consequence, one molecular 1 can bind two
molecular zinc ions, that well corresponds to the results of Job’s
plot. To get further insight on the characteristic of zinc complexa-
tion, the cation recognition was evaluated by 1H NMR titration in
DMSO-d6. A partial 1H NMR spectrum of 1, upon addition of zinc
cation, is shown in Figure S4. Notably, when 2 equiv of zinc cation
transition-metals, such as Ag+, Co2+, Cu2+, Fe2+, Fe3+, Cd2+, and Hg2+
,
showed significant quenching in the emission band at 363 nm.
Most importantly, only the titration of Zn2+ showed a strong red
shift to 408 nm which inferred that Zn2+ could be easily distin-
guished from other various metal ions (Fig. 6 inset) as tested. Sim-
ilarly, 2 also showed high selective fluorescence response to zinc
among various metal ions in CH3CN solution. Titration of alkali
and alkaline earth metal perchlorates did not show much change
to the optical properties of 2 (Fig. S5).
Acknowledgment
This work was supported by the Creative Research Initiative
program (No. 2010-0000728) of Korea Research Foundation.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.04.135.
References and notes
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Figure 7. Fluorescence spectra of 1 (10
metal cation perchlorates (each concentration was 50
wavelength of 320 nm. Inset: plot of fluorescence intensity of 1 (10 lM) monitored
at 408 nm with different metal ions.
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3723
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temperature. The solvent was removed in vacuo. MC (100 mL) and H2O
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MeOH = 95:5 as eluent gave 0.62 g (67%) of 4 as a white solid. 1H NMR
(300 MHz): d 2.34 (s, 2H, –NH2), 3.40 (s, 2H, –CH2), 7.32–7.36 (m, 1H), 7.46–
7.57 (m, 5H), 7.78–7.89 (m, 3H), 7.98 (s, 1H), 8.21 (d, 2H, J = 6.9 Hz), 8.63–8.73
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Preparation of 25,27-di[methoxy(4-phenyl)-(60-phenyl-20,200-bipyridine)]-26,28-
dihydroxycalix[4]arene (1): To a solution of 5 (0.5 g, 1.2 mmol) in 100 mL
acetonitrile and toluene (V/V = 1:1) were added 6 (1 g, 2.5 mmol) and K2CO3
(350 mg, 2.5 mmol) as a base. The reaction mixture was refluxed for 48 h and
cooled down to room temperature. The solvent was removed in vacuo. CH2Cl2
(100 mL) and H2O (100 mL) were added and the organic layer was washed
three times with water, dried over MgSO4, and evaporated under vacuo.
Column chromatography of the crude product by silica gel with hexane/
EtOAc = 4:1 as eluent gave 0.7 g (56%) of 1 as a white solid. 1H NMR (300 MHz):
d 3.44 (d, 4H, J = 13 Hz), 4.43 (d, 4H, J = 13 Hz), 5.22 (s, 4H), 6.69 (t, 2H,
J = 7.4 Hz), 6.82 (t, 2H, J = 7.1 Hz), 6.98 (d, 4H, J = 7.6 Hz), 7.10 (d, 4H, J = 7.5 Hz),
7.20–7.24 (m, 2H), 7.35–7.37 (m, 6H), 7.59–7.67 (m, 4H), 7.72 (d, 4H,
J = 8.3 Hz), 7.86–7.93 (m, 8H), 8.29 (s, 2H), 8.11 (s, 2H), 8.33 (d, 2H,
J = 7.9 Hz), 8.58 (d, 2H, J = 4.8 Hz). 13C NMR (100 MHz): 31.54, 77.84, 117.04,
117.75, 119.11, 121.65, 123.56, 125.71, 126.87, 127.43, 127.71, 127.87, 128.40,
128.58, 128.79, 129.20, 133.29, 137.77, 137.92, 138.91, 148.06, 148.69, 151.78,
153.37, 156.46 ppm. FAB-MS (1064.43): 1065.12 [M+H+].
9. Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000, 100, 3553.
10. Goodall, W.; Williams, J. A. G. Chem. Commun. 2001, 2514.
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Sreejith, S.; Divya, K. P.; Ajayaghosh, A. Chem. Commun. 2008, 2903.
12. Carol, P.; Sreejith, S.; Ajayaghosh, A. Chem. Asian J. 2007, 2, 338.
13. Kozhevnikov, D. N.; Shabunina, O. V.; Kopchuk, D. S.; Slepukhina, P. A.;
Kozhevnikova, V. N. Tetrahedron Lett. 2006, 47, 7025.
14. General: compounds 4-(tolyl)-6-phenyl-2,20-bipyridine (7),15 4-(bromometh-
ylphenyl)-6-phenyl-2,20-bipyridine (6),15 calix[4]arene (8),8a and 25,27-bis-
(hydroxycarbonylmethoxy) calix[4]crown-5 (3)8a were synthesized according
to the literature process. All reagents and solvents for synthesis were
commercial and used without further purification. All the reactions have
been performed under high pure nitrogen or argon atmosphere. Synthesized
products have been purified by column chromatography on silica gel (100–
200 mesh). All fluorescence and UV–vis absorption spectra were recorded in
RF-5301PC and S-3100 spectrophotometer, respectively. NMR and mass
spectra were recorded at Varian instrument (300 MHz) and FAB-MS mass
spectra. X-ray crystal structure determination was performed with a Bruker
Preparation of 25,27-Bis[N-(4-phenylmethyl-(60-phenyl-20,200-bipyridine))amino-
carbonyl-methoxy]calix[4]-crown-5 (2). To a solution of 3 (100 mg, 0.14 mmol)
in DMF (10 ml) were added 4 (100 mg, 0.3 mmol), 1-(3-dimethylaminopropyl)-
3-ethylcarbodiimide hydrochloride (EDCI) (60 mg, 0.3 mmol), and 4-
dimethylaminopyridine (DMAP) (40 mg, 0.3 mmol). The reaction mixture
was stirred at room temperature for 24 h. H2O (100 mL) was added and
extracted with ethyl acetate (100 mL ꢀ 3), dried over MgSO4, and evaporated
under vacuo. Column chromatography of the crude product by silica gel with
MC/MeOH = 30:1 as eluent gave 99 mg (52%) of 1 as a white solid. 1H NMR
(300 MHz): d 3.37 (t, 4H, J = 5.9 Hz), 3.54 (s, 4H), 3.60–3.67 (m, 12H), 3.78 (d,
4H, J = 15.9 Hz), 3.86 (d, 4H, J = 15.8 Hz), 4.37 (d, 4H, J = 6.1 Hz), 6.61 (t, 2H,
J = 7.5 Hz), 6.94 (t, 8H, J = 7.3 Hz), 7.19 (d, 4H, J = 7.5 Hz), 7.27–7.30 (m, 2H),
7.42–7.51 (m, 10H), 7.78–7.84 (m, 6H), 7.91 (s, 2H), 8.14 (d, 4H, J = 6.8 Hz),
8.64–8.66 (m, 6H). 13C NMR (100 MHz): 37.27, 42.41, 57.64, 59.70, 68.79,
69.68, 69.99, 70.31, 72.30, 116.71, 118.22, 121.25, 123.22, 124.70, 127.22,
127.36, 128.68, 129.11, 129.54, 129.97, 134.09, 134.40, 136.41, 137.70, 138.97,
141.10, 149.62, 155.48, 155.61, 156.03, 156.34, 156.77, 168.98 ppm. ESI-MS
(1336.56): 1337.5 [M+H+].
SMART APEX CCD X-ray diffractometer, using graphite monochromated MoK
radiation (k = 0.71073 Å, and scans). The data were reduced using
SAINTPLUS and multiscan absorption correction using SADABS was
a
u
x
a
performed. The structure was solved using SHELXS-97, and full matrix least
squares refinement against F2 was carried out using SHELXL-97 in anisotropic
approximation for non-hydrogen atoms. All hydrogen atoms were assigned on
the basis of geometrical considerations and were allowed to ride upon the
respective carbon atoms.
Preparation of 4-azidemethylphenyl-60-phenyl-20,200-bipyridine (5): Under
nitrogen, 6 (2.00 g, 5.0 mmol) and NaN3 (0.4 g, 6.0 mmol) in 10 mL of DMF
were stirred at 90 °C for 4 h and cooled to room temperature. EtOAc (100 mL)
and H2O (100 mL) were added and the water layer was extracted three times
with EtOAc, the organic layers were dried over MgSO4 and evaporated under
vacuo. Column chromatography of the crude product by silica gel with hexane/
Single crystal data for 1-ZnCl2: C74H56Cl2N4O4ZnꢂCH3CN, Mw = 1239.32,
colorless crystal, size: 0.15 ꢀ0 0.10 ꢀ 0.08 mm3, triclinic, space group P ꢁ 1,
0
0
a = 11.151(2) ÅA, b = 15.235(3) ÅA, 0c = 20.065(4) ÅA,
a = 96.35(3) °, b = 102.95(3) °,
c
= 95.27(3) °, V = 3277.6(1) ÅA3, T = 170(2) K, Z = 2, D = 1.283 mg/m3,
EtOAc = 6:1 as eluent gave 1.51 g (83%) of
5
as
a
white solid. 1H NMR
q
= 0.190 mmꢁ1, F(000) = 1316; 11795 reflections measured, of which 7869
(300 MHz): d 4.38 (s, 2H, –CH2), 7.30–7.35 (m, 1H), 7.42–7.57 (m, 5H), 7.79–
7.88 (m, 3H), 7.95 (s, 1H), 8.21 (d, 2H, J = 6.9 Hz), 8.64–8.74 (m, 3H).
were unique (Rint = 0.0322). 806 refined parameters, final R1 = 0.0640 for
reflections with I > 2
r (I), wR2 = 0.1780 (all data), GOF = 0.778. Final largest
0
Preparation of 4-aminomethylphenyl-60-phenyl-20,200-bipyridine (4): Under
nitrogen, 5 (1.00 g, 2.75 mmol) and PPh3 (2.20 g, 8.40 mmol) in 20 mL of
pyridine were stirred at room temperature for 5 h, then 5 mL ammonia water
diffraction peak and hole: 1.356 and ꢁ0.467 e ÅAꢁ3
.
15. Ding, J.; Pan, D.; Tung, C.-H.; Wu, L.-Z. Inorg. Chem. 2008, 47, 5099.