Ratiometric fluorescent determination of Zn(II): A new class of tripodal receptor using mixed imine and amide linkages

Article abstract of DOI:10.1016/j.tet.2010.08.024

We synthesized a novel receptor with a unique combination of sp² nitrogen (-CH=N-) and carbonyl groups from amide linkages. These two moieties are judiciously incorporated into the receptor design such that these sites simultaneous binding a metal ion may generate a stable five-member ring. The receptor has been used to selectively detect Zn²⁺ through changes in the fluorescence spectra. Upon Zn²⁺ binding with the receptor, the fluorescence band shifted to enhance fluorescence intensity, allowing ratiometric determination of Zn²⁺ concentration.

Full text of DOI:10.1016/j.tet.2010.08.024

Tetrahedron 66 (2010) 7965e7969
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Tetrahedron
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Ratiometric fluorescent determination of Zn(II): a new class of tripodal receptor
using mixed imine and amide linkages
,
Doo Youn Lee a, Narinder Singh b, Min Joung Kim a, Doo Ok Jang a
*
a Department of Chemistry, Yonsei University, Wonju, Gangwon 220-710, Republic of Korea
b Department of Chemistry, Indian Institute of Technology Ropar, Rupnagar, Punjab 140001, India
a r t i c l e i n f o
a b s t r a c t
We synthesized a novel receptor with a unique combination of sp2 nitrogen (eCH]Ne) and carbonyl
groups from amide linkages. These two moieties are judiciously incorporated into the receptor design
such that these sites simultaneous binding a metal ion may generate a stable five-member ring. The
receptor has been used to selectively detect Zn2þ through changes in the fluorescence spectra. Upon Zn2þ
binding with the receptor, the fluorescence band shifted to enhance fluorescence intensity, allowing
ratiometric determination of Zn2þ concentration.
Article history:
Received 18 June 2010
Received in revised form 10 August 2010
Accepted 10 August 2010
Available online 14 August 2010
Keywords:
Zn2þ
Ó 2010 Elsevier Ltd. All rights reserved.
Sensor
Fluorescent
Ratiometric detection
Tripodal
1. Introduction
3d104s0 configuration.10 Many of these qualities have been addressed
in several reported Zn2þ chemosensors. However, most of these
Transition metal ions are an interesting paradox in life.1 They
can be both integral enzyme components necessary for biological
activity,2 and toxic to human life, flora, and fauna. Zinc is one of
many transition metal ions necessary for life, and is the second
most abundant transition metal ion, after Fe2þ or Fe3þ, in humans
and other mammals.3 Zn2þ plays vital roles in cellular metabolism,
neurotransmission, signal transduction and gene expression.4
Misregulated Zn2þ concentrations have been associated with
physical growth retardation and neurological disorders, such as
cerebral ischemia and Alzheimer’s disease.5
sensors have limited selectivity, and many change intensities at
a single wavelength.11 Measuring at a single wavelength suffers from
further errors due to receptor concentration, photobleaching and
environmental effects. Alternatively, using the ratio of fluorescence
intensity at two wavelengths, or ratiometric fluorescent de-
termination, eliminates these errors, but can only offered by sensors
that show shift emission bands upon binding with analytes.
The present investigation aimed to develop a highly sensitive
and selective ratiometric chemosensor that works across a wide
range of Zn2þ concentrations, including low concentrations.
Although many Zn2þ selective receptors have been reported, few
ratiometrically determine Zn2þ concentrations.12 Due to poor de-
sign, several of these sensors, mainly di-2-picolylamine (DPA),
polyamines, iminodiacetic acid, bipyridine, quinoline, or Schiff-
bases, suffer from interference from first row transition metal ions,
such as Fe2þ, Co2þ, Cu2þ, etc.13 These binding sites have similar
binding affinities for multiple transition metal ions. The binding
sites in this study are based upon X-ray crystallographic analysis of
many zinc enzymes.14 These structures can be used to map out the
preferred coordination sphere of Zn2þ. The resulting coordination
spheres can be broadly categorized as catalytic, cocatalytic, and
structural. These categories are sufficient to draw conclusions on
the structural identities of zinc binding sites. Imidazole nitrogens,
carboxylate oxygens, and cysteine thiols predominate as ligands in
catalytic, cocatalytic, and structural sites, respectively.15 Thus, we
Developing a chemosensor to estimate Zn2þ concentration is
important. Fluorescent chemosensors are particularly interesting
because of their sensitivity.6 The design of a Zn2þ chemosensor must
fulfill some basic criteria: (i) The sensor must have a linear re-
lationship between fluorescence intensity and Zn2þ concentration
across a broad range of Zn2þ concentrations.7 (ii) The sensor should
be selective for Zn2þ, not responding to other biological metal ions,
and should not be perturbed by the environment.8 (iii) The sensor
should respond quickly, i.e., Zn2þ should complex with the co-
ordination sphere quickly and stably.6c,9 The sensor design is crucial
because Zn2þ is spectroscopically and magnetically silent due to its
* Corresponding author. Tel.: þ82 337602261; fax: þ82 337602182; e-mail
address: dojang@yonsei.ac.kr (D.O. Jang).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.024

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D.Y. Lee et al. / Tetrahedron 66 (2010) 7965e7969
incorporated a unique combination of sp2 nitrogens (eCH]Ne)
and carbonyl groups from amide linkages into our receptor design.
Upon these two sites simultaneous binding Zn2þ metal ions, a sta-
ble five-membered chelate ring forms.16 Additionally, Zn2þ is
a border line case in HSAB principle.17 sp2 nitrogen is relatively soft,
while the carbonyl group is harder binding site. Thus, this unique
combination of imine and amide linkages in eCH]NeNHeC(O)e
framework could serve our purposes.
900
800
700
600
500
400
300
200
100
0
Host
Ag(I)
Co(II)
Fe(III)
Ni(II)
Ca(II)
Cu(II)
Mg(II)
Zn(II)
2. Results and discussion
340
390
440
490
540
590
Wavelength (nm)
Tripodal receptor 5 was synthesized as shown in Scheme 1.
Tripodal aldehyde 3 was synthesized as described in the litera-
ture.18 The required receptor 5 was prepared in 98% yield by the
condensation of tripodal aldehyde 3 with benzoic hydrazide 4. The
formation of imine linkages was determined from the singlet signal
at 8.81 ppm in the 1H NMR spectrum of compound 5. To establish
the role of tripodal framework to recognize Zn2þ, compound 7 was
designed and synthesized. The compound 7 has the same type of
binding sites as the tripodal receptor 5.
Figure 1. Changes in fluorescence intensity of receptor
5 (10 mM) upon adding
particular metal ions (40
m
M) in CH3CN/DMSO¼99:1 (lex¼323 nm).
This enhanced fluorescence intensity in the new band seems
to be due to combination of structural rigidity of the metal
complex and metal binding close to the fluorophore. These fac-
tors might also cooperate to induce the emission band shift. The
O
N
O
O
Cl
OH
N
O
+
NaOH
EtOH
Cl
O
Cl
O
O
1
2
3
PhC(O)NHNH2
O
N
4
O
O
N
N
NH
HN
NH
O
N
O
O
5
4
N NH
CHO
O
6
7
Scheme 1.
The photophysical properties of 5 were investigated in CH3CN/
DMSO (99:1, v/v). Receptor 5 displayed a characteristic UVevis
spectrum with three bands at lmax¼284, 298, and 323 nm (Fig. S2).
The band at lmax¼323 nm was designated as an intraligand charge
transfer transition in the molecule due to imine linkages. Upon
imine linked free sensor may undergo cisetrans isomerism,
giving weak fluorescence intensity due to the non-radiative de-
cay of the excited state.19bef Metal binding with the sp2 nitrogen
donor (eCH]Ne) hinders this freedom, and consequently blocks
the route of non-radiative decay, resulting in enhanced fluores-
cence. The metal binding close to the fluorophore changes the ICT
band.20a Receptor 5 binding with Zn2þ showed a change in its
UVevis spectrum (Fig. S2) demonstrating the binding of Zn2þ in
the ground state of the receptor, which also authenticates the
shift in CT band.20b Thus, the red-shift along with enhanced
fluorescence results from two operations. The metal binding
modulates fluorescence intensity at two bands. Therefore, re-
ceptor 5 can be used for ratiometric fluorescent determination of
Zn2þ. The ratiometric response of receptor 5 toward the surveyed
metal ions is displayed in Figure 2. The results show a highly
selective response to Zn2þ ions.
excitation of receptor 5 (10 mM in CH3CN/DMSO (99:1, v/v)) at
lmax¼323 nm, the fluorescence spectrum of receptor gives emis-
sion at lmax¼370 nm.19a The binding properties of receptor 5 were
evaluated toward various metal ions, such as Ca2þ, Mg2þ, Fe3þ
,
Co2þ, Ni2þ, Cu2þ, Zn2þ, and Agþ (Fig. 1). Upon adding 40
m
M Zn2þ
solution to 10 receptor 5, the emission intensity at
mM
lmax¼370 nm decreased and a new red-shifted emission band at
lmax¼432 nm appeared, which increased by more than 40-fold.
This is reasonably good brightness to consider this receptor a Zn2þ
sensor. The other metal ions (as nitrate salts) revealed no such shift
in the emission band under the same conditions.

D.Y. Lee et al. / Tetrahedron 66 (2010) 7965e7969
7967
0.006
0.005
0.004
0.003
0.002
0.001
35
30
25
20
15
10
5
y = 0.0078x + 0.0015
R² = 0.9902
K= 1.9( 0.2)× 104M-1
0
0
0.1
0.2
0.3
0.4
0.5
0.6
0
1 / [G]
Ag(I)
Ca(II) Co(II) Cu(II) Fe(III) Mg(II) Ni(II)
Zn(II)
M) upon
Figure 4. BenesieHildebrand plot to determine the stability constant of Zn2þ with
receptor 5.
Figure 2. Ratiometric fluorescence (I432/I370) response of receptor 5 (10
adding a particular metal salt (40
M) in CH3CN/DMSO¼99:1.
m
m
To determine the binding pattern of receptor 5 with Zn2þ we
began with the stoichiometry of the complex. Continuous variation
methods were used to determine the stoichiometric ratios of re-
To evaluate the role of an array of binding sites available in
tripodal receptor 5, receptor 7 was designed and synthesized.
Receptor 7 resembles a single pod of receptor 5. Similar to re-
ceptor 5, receptor 7 displayed a fluorescence emission band at
ceptor 5 and Zn2þ 23
Figure 5 shows Job’s plot of the fluorescence
.
intensity of free receptor 5 and the intensity of the system with the
molar fraction of the host {[H]/([H]þ[G])} for a series of solutions in
which the total host and Zn2þ concentrations were constant and the
molar fraction of host continuously varied. The results illustrate that
the plot approaches a maximum when the molar fraction of host is
about 0.5, meaning that Zn2þ forms a 1:1 complex with receptor 5.
lmax¼350 nm at 30
mM in CH3CN/DMSO (99:1, v/v) upon excita-
tion at lmax¼292 nm. For these experiments, we used 30
m
m
M
M
receptor 7 to have approximately equal binding sites as 10
receptor 5. The binding properties of receptor 7 were evaluated
toward various metal ions. As expected, adding 40
M Zn2þ ions to
30 M receptor 7 neither shifted any emission band nor enhanced
m
m
0.5
0.4
0.3
0.2
0.1
0
fluorescent intensity. These experiments clearly authenticate the
role of judicial binding in a tripodal framework. In other words,
the binding sites in receptor 5 not only provide appropriate
binding but also structural rigidity or organization in the
pseudocavity.
To gain additional insight into applications for receptor 5 as
a Zn2þ sensor, a titration was performed as shown in Figure 3.
Figure 3 shows the changes in the fluorescence spectrum pattern
of receptor 5 upon continuously adding Zn2þ ions. The titration
shows that continuously adding Zn2þ ions to 10
mM receptor 5,
0
0.2
0.4
0.6
0.8
1
[H] / ([H]+[G])
decreased the emission band intensity at lmax¼370 nm, while the
intensity at lmax¼432 nm gradually increased. The titration
showed another point at which the fluorescence intensity in-
creased at low Zn2þ concentrations and reached a plateau at
Figure 5. Job’s plot between receptor 5 and Zn2þ. The [HG] concentration was calcu-
lated by the equation [HG]¼OI/Ioꢁ[H].
40 m mM
M Zn2þ. Thus, receptor 5 is very sensitive, and even 2.0
The exact binding mode was established by 1H NMR while ti-
trating receptor 5 with Zn2þ ions (Fig. 6). Upon adding 0.5 equiv of
Zn2þ ions to receptor 5, the 1H NMR signals of eCH]Ne and
eNHeC(O)e showed downfield and upfield shifts, respectively. The
methylene (eCH2e) signals shifted downfield and split in two.
Similarly, all signals corresponding to aromatic protons shifted.
Adding the next equivalent also shifted the signals except for
eCH]Ne. At the end of the titration, the NH signal of eNHeC(O)e
shifted by Dd¼0.34 ppm and eCH]Ne signals by Dd¼0.04 ppm.
The synchronized shifts in CH signal of eCH]Ne and NH signal of
eNHeC(O)e reveal that these binding sites are participate for co-
ordinating to Zn2þ in the receptor pseudocavity.
Zn2þ modulates fluorescence intensity. Moreover, complex for-
mation does not take much time, as all these spectra were recor-
ded immediately after mixing Zn2þ
. Figure S1 shows the
ratiometric response of receptor 5 for Zn2þ. The linearity of this
graph indicates that the sensor can be used along a specific range
of Zn2þ concentrations with detection limit as low as 0.9
mM
Zn .
2þ 21 Based on the BenesieHildebrand plot, the Ka of receptor 5
for Zn2þ was (1.9ꢀ0.2)ꢁ104 Mꢂ1 (Fig. 4).22
Host
2 μM
6 μM
900
800
700
600
500
400
300
200
100
0
4 μM
8 μM
10 μM
14 μM
18 μM
22 μM
26 μM
30 μM
34 μM
38 μM
12 μM
16 μM
20 μM
24 μM
28 μM
32 μM
36 μM
40 μM
340
390
440
490
540
590
Wavelength (nm)
Figure 3. Fluorescence spectra changes of receptor 5 (10
CH3CN/DMSO¼99:1 (lex¼323 nm).
mM) upon adding Zn(NO3)2 in
Figure 6. Family of 1H NMR spectra of receptor 5 upon adding Zn2þ ions in DMSO-d6.

7968
D.Y. Lee et al. / Tetrahedron 66 (2010) 7965e7969
Every attempt failed to obtain a single crystal of the complex;
4. Experimental section
4.1. General information
this limited us to comment on the exact structure of the complex
and the conformation of amide moiety. We performed MacroModel
calculations for the binding mode of receptor 5 with Zn2þ (Fig. 7).24
The calculated structures support our hypothesis that the imine
and amide linkages are responsible for Zn2þ coordination as dem-
onstrated by NMR studies and these binding sites are projected
toward the metal ion in the energy minimized Zn2þ complex of
receptor 5. The energy minimized calculations also reveal that the
C]N bonds exist in E configuration and the rotamers with respect
to the carbonenitrogen hydrazide bond are in Z conformation in
the complex formed.25
All solvents were dried by standard methods. Unless otherwise
specified, chemicals were purchased from commercial suppliers,
and used without further purification. TLC was performed on glass
sheets pre-coated with silica gel (Kieselgel 60 F254, Merck). The 1H
and 13C NMR spectrum were performed in DMSO-d6 with TMS as an
internal reference on a Bruker 400 NMR spectrometer, which op-
erated at 400 MHz for 1H and 100 MHz for 13C nuclei. The chemical
shifts were reported as
d values (ppm) relative to TMS. The CHN
Figure 7. Energy minimized structure of Zn2þ complex with receptor 5 as obtained by MacroModel calculation (two views of the same metal complex).
Finally, we analyzed the utility of receptor 5 as a Zn2þ sensor in
a competitive medium, a medium that contains other metal ions
(Fig. 8). In these experiments, fluorescence intensity was measured
in a series of solutions containing receptor 5, with different
amounts of Zn2þ and other metal ions all at the same concentration.
The fluorescence intensity was almost identical to that in the ab-
sence of other metal ions. Therefore, receptor 5 is highly selective
analyses were obtained on a CE Instrument EA1110. The fluores-
cence measurements were performed on a PerkineElmer LS55
Luminescence Spectrometer.
4.2. Synthesis of compound 5
A solution of 2,20,200-((nitrilotris(ethane-2,1-diyl))tris(oxy))tri-
benzaldehyde (100 mg, 0.22 mmol) in THF (10 mL) was added to
benzoic hydrazide (103 mg, 0.76 mmol) and a catalytic amount of
Zn(ClO4)2 in MeOH (10 mL) under argon at room temperature. After
stirring for 3 h at room temperature, a precipitated solid was fil-
tered and washed with THF and MeOH, yielding 176 mg (98%) of
compound 5: White solid; mp: 254w257 ꢃC, 1H NMR (400 MHz,
for, and can be used to recognize Zn2þ
.
900
800
700
600
500
400
300
200
100
0
Zn(II)
Zn(II)+Ag(I)
Zn(II)+Ca(II)
Zn(II)+Co(II)
Zn(II)+Cu(II)
Zn(II)+Fe(III)
Zn(II)+Mg(II)
Zn(II)+Ni(II)
DMSO-d6):
d
3.15 (t, 6H, J¼5.2 Hz, CH2), 4.20 (t, 6H, J¼5.2 Hz, CH2),
6.95e6.98 (m, 3H, Ar), 7.07e7.10 (m, 3H, Ar), 7.27e7.31 (m, 3H, Ar),
7.47e7.50 (m, 6H, Ar), 7.55e7.59 (m, 3H, Ar), 7.83e7.87 (m, 9H, Ar),
8.81 (s, 3H, CH]N),11.82 (br, 3H, eNH); 13C NMR (100 MHz, DMSO-
d6):
d 53.8, 67.1, 112.9, 120.8, 122.7, 125.7, 127.6, 128.4, 131.4, 131.7,
133.5, 143.5, 157.0, 163.1. Anal. Calcd for C48H45N7O6: C, 70.66; H,
5.56; N, 12.02. Found C, 70.68; H, 5.57; N, 11.99.
0
6
12
18
24
30
36
42
Concentration of Cation (μM)
4.3. Metal binding studies
Figure 8. Estimating Zn2þ ions with receptor 5 (10
mM) in the presence of equimolar
metal ions in CH3CN/DMSO (99:1, v/v) at 432 nm.
Metal binding ability of receptor 5 was performed using 10
of receptor 5 in CH3CN/DMSO (99:1, v/v). Measuring flasks each
contained 10 M of receptor 5 along with varied amounts of a par-
mM
3. Conclusions
m
ticular salt in CH3CN/DMSO (99:1, v/v). The solutions were kept at
25ꢀ1 ꢃC for 3 h, and were shaken occasionally. Fluorescence spectra
were recorded with excitation at 323 nm.
A novel receptor has been synthesized to determine Zn2þ con-
centrations. The receptor has the unique combination of sp2
nitrogen (eCH]Ne) and carbonyl groups from amide linkages that
provide perfect binding sites for Zn2þ. Upon Zn2þ binding with
receptor 5, the fluorescence band shifted and increased in intensity.
Therefore, receptor 5 can be used to ratiometrically determine Zn2þ
concentration. The receptor is selective for Zn2þ even in competi-
tion with other metal ions.
4.4. Stability constant determination
The stability constant of receptor 5 with zinc was determined by
preparing solutions containing 10 mM of receptor 5 and varying

D.Y. Lee et al. / Tetrahedron 66 (2010) 7965e7969
7969
8. (a) Hayashita, T.; Takagi, M. In Comprehensive Supramolecular Chemistry;
Atwood, J. L., Davies, J. E. D., MacNicol, D. D., Vogtle, F., Suslick, K. S., Eds.;
Pergamon: Oxford, 1996; pp 635e669; (b) Gutsche, C. D. Calix[4]arenes re-
visited; The Royal Society of Chemistry: Cambridge, 1998, pp 164e165.
9. Lakowicz, J. R. Topics in Fluorescence Spectroscopy, Probe Design and Chemical
Sensing; Academic: New York, NY, 1994; p 4.
amounts (0e40 mM) of zinc salt in CH3CN/DMSO (99:1, v/v). The
emission was measured at 432 nm.
€
4.5. Stoichiometry determination
10. Burdette, S. C.; Frederickson, C. J.; Bu, W.; Lippard, S. J. J. Am. Chem. Soc. 2003,
125, 1778e1787.
Mixtures of receptorezinc salt were prepared at 1:9, 2:8, 3:7,
4:6, 5:5, 6:4, 7:3, 8:2, 9:1. These solutions were kept at 25ꢀ1 ꢃC
before recording their spectra. The plot of [HG] versus [H]/[H]þ[G]
was used to determine the stoichiometry of the complex. [HG] was
calculated by the equation [HG]¼OI/Ioꢁ[H].
11. (a) Que, E. L.; Domaille, D. W.; Chang, C. J. Chem. Rev. 2008, 108, 1517e1549; (b)
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Banthia, S.; Samanta, A. J. Phys. Chem. B 2006, 110, 6437e6440; (e) Grynkiewicz,
G.; Poenie, M.; Tsien, R. Y. J. Biol. Chem. 1985, 260, 3440e3450.
12. (a) Xu, Z.; Baek, K.-H.; Kim, H. N.; Cui, J.; Qian, X.; Spring, D. R.; Shin, I.; Yoon, J.
J. Am. Chem. Soc. 2010, 132, 601e610; (b) Zhang, X.; Lovejoy, K. S.; Jasanoff, A.;
Lippard, S. J. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 10780e10785; (c) Qian, F.;
Zhang, C.; Zhang, Y.; He, W.; Gao, X.; Hu, P.; Guo, Z. J. Am. Chem. Soc. 2009, 131,
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4.6. Competitive Zn2D binding
Solutions were prepared containing receptor 5 (10
equimolar interfering metal ions and Zn2þ ions (6,12,18, 24, 30, and
36 M). The fluorescence intensity of each solution was recorded at
mM) and
m
432 nm.
Acknowledgements
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This work was supported by the National Research Foundation
(NRF) grant funded by the Korea government (MEST) through the
Center for Bioactive Molecular Hybrids (No. R11-2003-019-00000-0).
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.08.024. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
14. Vallee, B. L.; Auld, D. S. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 2715e2718.
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