Ratiometric and simultaneous estimation of Fe3+ and Cu 2+ ions: 1,3,5-substituted triethylbenzene derivatives coupled with benzimidazole

Article abstract of DOI:10.1016/j.tetlet.2011.05.078

We synthesized a novel 1,3,5-substituted triethylbenzene derivative with a benzimidazole moiety as a binding and signalling subunit. The triethylbenzene platform was judiciously incorporated into the receptor design such that all the fluorophores are in c

Full text of DOI:10.1016/j.tetlet.2011.05.078

Tetrahedron Letters 52 (2011) 3886–3890
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Ratiometric and simultaneous estimation of Fe3+ and Cu2+ ions:
1,3,5-substituted triethylbenzene derivatives coupled with benzimidazole
Doo Youn Lee a, Narinder Singh b, Doo Ok Jang a,
⇑
a Department of Chemistry, Yonsei University, Wonju 220-710, Republic of Korea
b Department of Chemistry, Indian Institute of Technology Ropar, Rupnagar, Punjab 140 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We synthesized a novel 1,3,5-substituted triethylbenzene derivative with a benzimidazole moiety as a
binding and signalling subunit. The triethylbenzene platform was judiciously incorporated into the
receptor design such that all the fluorophores are in close proximity to each other in order to facilitate
stacking. The advantage of this approach lies in the fact that the receptor will offer a dual channel emis-
sion for the multiple ratiometric determination of metal ions. The sensor was tested in a CH3CN/H2O (7:3,
v/v, pH 7.1) HEPES buffered solution and successfully developed for the ratiometric and simultaneous
estimation of Fe3+ and Cu2+ ions in aqueous samples.
Received 22 April 2011
Revised 13 May 2011
Accepted 16 May 2011
Available online 24 May 2011
Keywords:
Ratiometric
Simultaneous estimation
Sensor
Ó 2011 Elsevier Ltd. All rights reserved.
Fluorescent
Multifunctional receptor
Transition metal ions have biological importance as micronutri-
ents in most organs and are essential to sustain all forms of life.
However, unregulated amounts may cause or exacerbate damage
to vital organs, resulting in progression in disease state or cell
apoptosis.1 Hence, detecting these transition metal ions has be-
come an increasing concern due to their effects on human health
and the environment.2 Most studies have focused on selective
chemosensors for a particular analyte that can be a single cation,
anion, or biomolecule.3 However, on the basis of semi-selective
sensor design, interesting alternatives for seminal concepts to-
wards the simultaneous estimation of multiple analytes, such as
more than one transition metal ion, can be developed.4 Ratiometric
estimation is advantageous in that it is a method, that is, free from
errors due to phototransformation, receptor concentrations, and
environmental effect.5 The aim of the present study was to develop
a receptor for ratiometric and simultaneous estimation of multiple
analytes.
According to Schmidtchen, the selectiveness of some sensors is
due to serendipitous discoveries of the selective interaction of a par-
ticular receptor with the analyte.6 However, it is quite possible to
rationally design a molecular sensor for a particular task. In our sys-
tematic approach with benzimidazole-based receptors, we have ad-
dressed several solutions by using photoinduced electron transfer
(PET), internal charge transfer (ICT), molecular rigidity, and a combi-
nation of more than one mechanism.7 In our previously reported
examples, we noticed only a single band in the emission spectrum
of pure benzimidazole-based receptors. Reported examples of
simultaneous estimation of two analytes are based on two mecha-
nisms, that is, one analyte exhibits an ‘ON–OFF’ behaviour, and the
other demonstrates a shift in band due to ICT.8 Thus, ratiometric
determination for the latter is possible, while no such ratiometric
estimation is possible for the former. To the best of our knowledge,
no benzimidazole-based receptor has shown the fluorophore stack-
ing that induces excimer formation. As the excimers generally emit
at higher wavelengths,9 a clear-cut multiple ratiometric estimation
of multiple analytes is possible. The dearth of excimer formation in
any benzimidazole-based receptor is due to the lack of suitable flex-
ibility and/or steric factors of the receptor, as these may retard stack-
ing. To counter this problem, we designed a new receptor based
upon the findings of Anslyn.10 1,3,5-Substituted trimethylbenzene
derivatives can adopt two types of conformations, that is, all podes
on one side (Fig. 1A) or podes on two different sides (Fig. 1B) depend-
ing upon the length of the side arm and other steric factors. In 1,3,5-
substituted triethylbenzene derivatives (Fig. 1C), due to steric gear-
ing, all three functional substituents are disposed on the same side of
the benzene plane. The metal binding moieties in these ligands at-
tached at the 2,4,6-position are forced to position on the same side
of the benzene ring and spacer since this particular configuration
is the most thermodynamically stable due to the steric repulsion
between the neighbouring substituents.10 Thus, the incorporation
of a triethylbenzene derivative in the design of our receptor may
bring all the benzimidazole moieties to one side, resulting in stack-
ing of the fluorophores and thereby creating two emission bands.
⇑
Corresponding author. Tel.: +82 337602261; fax: +82 337602182.
E-mail address: dojang@yonsei.ac.kr (D.O. Jang).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.078

D. Y. Lee et al. / Tetrahedron Letters 52 (2011) 3886–3890
3887
A
B
C
All podes on
one side
All podes on
one side
Podes on
different side
Figure 1. Possible conformations of a 1,3,5-substituted trimethylbenzene derivative (A and B) and the most stable conformation of the 1,3,5-substituted triethylbenzene
derivative (C).
A typical receptor was synthesized by a series of steps shown in
Scheme 1. Compound 1 was prepared by using methods reported
in the literature.11 Compound 2 was synthesized by a reaction of
salicyaldehyde with tribromide 1 in the presence of KOH.12 A con-
densation reaction of trialdehyde 2 with 2-(1H-benzo[d]imidazol-
2-yl)aniline (3) afforded the Schiff base. The imine linkages of this
crude product were reduced with NaBH4 to obtain the final prod-
uct 4, which was purified with silica gel chromatography.13
The photophysical properties of receptor 4 were investigated in
a CH3CN/H2O (7:3, v/v, pH 7.1) HEPES buffered solution. In this
typical solvent combination, receptor 4 (10 lM) displayed a num-
ber of bands in its UV-Vis spectrum, including a well-defined band
at kmax = 361 nm. The fluorescent spectrum of receptor 4 exhibited
a well-defined maximum at 418 nm that was recorded at 10 lM
Figure 2. Changes in the fluorescent intensity of receptor 4 (10
lM) upon addition
concentration in a CH3CN/H2O (7:3, v/v, pH 7.1) HEPES buffered
solution when excited at 361 nm. As per our expectations, in addi-
tion to the emission band at 418 nm, another emission band was
observed at 580 nm, most probably due to the stacking of fluoro-
phores in the pure host at this concentration (Fig. 2). To investigate
the properties of receptor 4 as a sensor for metal ions, the solutions
were prepared in CH3CN/H2O (7:3, v/v, pH 7.1) HEPES buffered
of a particular metal (40 M) nitrate salt in a HEPES buffered CH3CN/H2O (7:3, v/v,
l
pH 7.1) solution (kex = 361 nm).
solution each with a fixed concentration (10 lM) of receptor 4
along with a fixed concentration (40 lM) of a unique metal ion.
The results are shown in Figures 2 and 3. It is evident that the bind-
O
O
Br
O
KOH
PrOH, 64%
OH
Br
+
O
O
O
Br
O
1
2
1) 3, Zn(ClO4)2, MeOH/THF
2) NaBH4, THF, 52 %
NH
Z
HN
Z
H
N
O
O
Z
H
N
O
N
H2N
3
H
N
4
Z:
N
Scheme 1.

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D. Y. Lee et al. / Tetrahedron Letters 52 (2011) 3886–3890
Figure 3. Changes in fluorescent emission of receptor 4 (10 lM) upon addition of a
particular cation (40 lM) in a CH3CN/H2O (7:3, v/v, pH 7.1) HEPES buffered solution
irradiated at 365 nm using a hand-held UV lamp.
ing of Fe3+ and Cu2+ caused significant changes in the fluorescence
bands of receptor 4, showing the selective and unique binding of
two metal ions. Notably, no change in fluorescent spectrum was
observed with the addition of anions, indicating a lack of anion
binding ( Fig. S1). The binding of Fe3+ with receptor 4 resulted in
the quenching of fluorescent intensity both at 418 and 610 nm
with the emergence of a new band at 462 nm, indicating that
Fe3+ binds very closely to the fluorophore and affects the CT band.
14 On the other hand, the binding of Cu2+ with receptor 4 quenched
fluorescent intensity at 580 nm and showed enhancement at
418 nm. The enhancement in the fluorescence band is a common
indicator of Cu2+ binding because the metal ion blocks the PET
channel.15 Metal binding may also cause rigidity of a highly flexible
receptor such as tripodal receptor 4, making nonradiative decay
less probable. In such a situation, an enhancement in intensity is
observed.16 The effect of metal binding on receptor 4 was also
monitored with UV-Vis spectroscopy (Fig. S2). Interestingly, the
selective and unique binding of Fe3+ and Cu2+ was observed. Anions
had no effect on the UV–Vis spectrum of receptor 4 ( Fig. S3).
To gain more insight with respect to the properties of receptor 4
as a sensor for the estimation of Fe3+ and Cu2+ in HEPES buffered
CH3CN/H2O (7:3, v/v, pH 7.1), fluorescence titrations were carried
out. Figure 4 illustrates the emission response of receptor 4 with
an increase in the concentration of Fe3+ ions in a HEPES buffered
CH3CN/H2O (7:3, v/v, pH 7.1) solution. Upon addition of Fe3+ ions
into the solution containing receptor 4, the fluorescent intensity
Figure 5. Changes in UV–Vis spectrum of receptor 4 (10
lM) upon addition of
Fe(NO)3 (0–100 M) in a CH3CN/H2O (7:3, v/v, pH 7.1) HEPES buffered solution.
l
of the continuous addition of Fe3+ on the UV–Vis spectrum of
receptor 4 is shown inFigure 5. On the basis of these data, the asso-
ciation constant, Ka, of receptor 4 for Fe3+ was found to be the same
as that obtained by the fluorescence titration
( Fig. S6,
Ka = 1.1 0.1 Â 103 MÀ1).
Similarly, Figure 6 demonstrates the changes in the fluorescent
spectrum of receptor 4 with an increase in Cu2+ concentration in a
HEPES buffered CH3CN/H2O (7:3, v/v, pH 7.1) solution. The succes-
sive addition of Cu2+ into the solution containing receptor 4 caused
the gradual quenching in fluorescent intensity at 580 nm and a
prominent enhancement at 418 nm. Therefore, receptor 4 can be
used for selective estimation of Cu2+ within a concentration range
of 0–100.0
lM. The ratiometric calibration curve is shown in the
inset of Fig. 6, and the minimum detection limit was found to be
of a 10 lM solution of receptor 4 was quenched at both 418 and
580 nm. A new band appeared at 462 nm and developed consis-
tently with clear isoemissive points. Receptor 4 exhibited a high
sensitivity to Fe3+, with quenching at two wavelengths and
enhancement at one wavelength. Using this data, ratiometric esti-
mation is possible within a concentration range of 0–110 lM, as
shown in the inset of Figure 4. The minimum detection limit was
calculated to be 1.19 Â 10À5 M.17 The association constant, Ka, of
receptor 4 for Fe3+ was calculated on the basis of the Benesi–Hilde-
brand plot ( Fig. S4),18 and it was found to be 1.1 0.1 Â 103 MÀ1
.
Figure 6. Changes in the fluorescent spectra of receptor 4 (10
l
M) upon addition of
The stoichiometry of the complex that formed was determined
Cu(NO3)2 (0–100
lM) in a HEPES buffered CH3CN/H2O (7:3, v/v, pH 7.1) solution
by the Job’s plot ( Fig. S5), and was found to be 1:1.19 The effect
(kex = 361 nm).
Figure 4. Changes in the fluorescent spectra of receptor 4 (10
l
M) upon addition of
Fe(NO3)3 (0–110
lM) in a HEPES buffered CH3CN/H2O (7:3, v/v, pH 7.1) solution
Figure 7. Changes in UV–Vis spectrum of receptor 4 (10
(0–50 M) salt in a CH3CN/H2O (7:3, v/v, pH 7.1) HEPES buffered solution.
l
M) upon addition of Cu2+
(kex = 361 nm).
l

D. Y. Lee et al. / Tetrahedron Letters 52 (2011) 3886–3890
3889
Figure 8. Plot of the fluorescent intensity of receptor 4 as a function of metal ion concentrations recorded in a HEPES buffered CH3CN/H2O (7:3, v/v, pH 7.1) solution
(kex = 361 nm). The estimation of Fe3+ at kmax = 462 nm (plot A: 4 + Fe3+ ); 4 + Fe3+ + Cu2+ )) and the estimation of Cu2+ at kmax = 418 nm (plot B: 4 + Cu2+
);
4 + Fe3+ + Cu2+
)).
(
(
(
(
1.86 Â 10À5 M.17 The association constant, Ka, of receptor 4 for Cu2+
in a HEPES buffered CH3CN/H2O (7:3, v/v, pH 7.1) solution was cal-
culated on the basis of the Benesi–Hildebrand plot ( Fig. S7), and it
was found to be 1.0 0.1 Â 103 MÀ1. The stoichiometry of the com-
plex that was formed was determined by the Job’s plot ( Fig. S8),
and it was found to be 1:1.19 A titration with UV–Vis spectroscopy
was also performed (Fig. 7). On the basis of these data, the associ-
ation constant, Ka, of receptor 4 for Cu2+ was calculated to be the
same as that obtained by fluorescence spectroscopy ( Fig. S9,
Ka = 1.0 0.1 Â 103 MÀ1).
References and notes
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The metal binding test shown in Figure 2 revealed that receptor
4 can be developed for the simultaneous estimation of Fe3+ and
Cu2+. A series of competitive titrations were performed to deter-
mine the limit at which Fe3+ and Cu2+ could be measured in the
presence of each other as competing ions. As already shown, Cu2+
was the only ion among those tested that was likely to cause po-
tential interference in the measurement of Fe3+ by receptor 4 and
vice versa. Therefore, we tested the ability of receptor 4 to operate
in solutions containing equimolar concentrations of Fe3+ and Cu2+
.
Figure 8A shows the plot for solutions containing receptor 4 + Fe3+
and those containing receptor 4 + Fe3+ + equimolar Cu2+; the two
sets of data appear to be in good agreement. This suggests that
Fe3+ binding induced changes in the fluorescence signals of recep-
tor 4, which are independent of the presence of Cu2+. The same
studies were repeated using Cu2+ as the analyte and Fe3+ as the
interfering ion (Fig. 8B). It was found that similar to Fe3+ estima-
tion, the changes induced by Cu2+ in the fluorescence signals of
5. (a) Tomat, E.; Lippard, S. J. Inorg. Chem. 2010, 49, 9113–9115; (b) Dong, M.;
Wang, Y.-W.; Peng, Y. Org. Lett. 2010, 12, 5310–5313; (c) Qu, Y.; Hua, J.; Tian, H.
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8. Lee, D. Y.; Singh, N.; Jang, D. O. Tetrahedron Lett. 2010, 51, 1103–1106.
9. Lee, H. N.; Singh, N. J.; Kim, S. K.; Kwon, J. Y.; Kim, Y. Y.; Kim, K. S.; Yoon, J.
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Wiskur, S. L.; Anslyn, E. V. Org. Lett. 2004, 6, 2499–2501; (d) Wisbur, S. L.;
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Anslyn, E. V. Acc. Chem. Res. 2001, 34, 963–972.
receptor 4 were independent of the presence of Fe3+
.
In conclusion, we have prepared a 1,3,5-substituted triethyl-
benzene-based tripodal receptor with a benzimidazole moiety as
a binding and signalling subunit. The receptor was tested for a
number of metal ions and found to exhibit binding affinity for
Fe3+ and Cu2+. The response for both of these metal ions was un-
ique, and was independent of any tested metal ion. The receptor
was shown to be feasible for use in the simultaneous, selective,
and ratiometric determination of both metal ions.
Acknowledgement
11. Vacca, A.; Nativi, C.; Cacciarini, M.; Pergoli, R.; Roelens, S. J. Am. Chem. Soc.
2004, 126, 16456–16465.
12. Synthesis of compound 2: A solution of salicylaldehyde (111 mg, 0.91 mmol)
and KOH (59 mg, 1.02 mmol) in nPrOH (20 mL) was stirred vigorously at room
temperature. After 30 min 1,3,5-tris(bromomethyl)-2,4,6-triethylbenzene
(100 mg, 0.23 mmol) was added. The reaction mixture was heated to reflux
for 11 h. After evaporation of the solvent, the residue was dissolved in CH2Cl2
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).
and then washed with water. Adding MeOH to the solution yielded
precipitated solid in 64% yield (83 mg): light brown solid; mp: 190–192 °C;
IR
max: 3477, 2967, 2873, 1687, 1598, 1484, 1228 cmÀ1 1H NMR (400 MHz,
a
Supplementary data
m
;
CDCl3): d 1.23 (t, 9H, –CH3, J = 7.6 Hz), 2.85 (q, 6H, –CH2, J = 7.6 Hz), 5.21 (s, 6H,
–CH2), 7.07–7.10 (m, 3H, Ar), 7.22–7.24 (m, 3H, Ar), 7.60–7.65 (m, 3H, Ar),
7.86–7.88 (m, 3H, Ar), 10.40 (s, 3H, –CHO); 13C NMR (100 MHz, CDCl3): d 16.8,
23.3, 65.0, 112.6, 121.4, 125.3, 128.7, 130.5, 136.3, 147.1, 161.3, 189.8; MS (ESI)
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.078.

3890
D. Y. Lee et al. / Tetrahedron Letters 52 (2011) 3886–3890
m/z (%): 564 (M+, 100). Anal. Calcd for C36H36O6: C, 76.57; H, 6.43. Found: C,
76.48; H, 6.52.
13. Synthesis of compound 4: A solution of compound 2 (45 mg, 0.08 mmol) in THF
8.92 (br, 3H, –NH), 9.46 (br, 3H, –NH); 13C NMR (100 MHz, DMSO-d6): d 16.3,
22.5, 40.9, 64.5, 110.7, 110.8, 111.0, 111.7, 114.7, 118.2, 120.6, 121.4, 122.5,
127.2, 127.5, 127.6, 128.2, 130.7, 130.8, 133.4, 142.6, 146.0, 147.4, 152.4,
156.3; MS (ESI) m/z (%): 1144 (M+, 100), 889 (60), 573 (6), 427 (4). Anal. Calcd
for C75H69N9O3: C, 78.71; H, 6.08; N, 11.02. Found: C, 78.68; H, 6.14; N, 10.98.
14. de Silva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson, T.; Huxley, A. J. M.; McCoy, C.
P.; Rademacher, J. T.; Rice, T. E. Chem. Rev. 1997, 97, 1515–1566.
15. Fabbrizzi, L.; Poggi, A. Chem. Soc. Rev. 1995, 24, 197–202.
(20 mL) was added to
a solution of 2-(2-aminophenyl)-1H-benzimidazole
(67 mg, 0.32 mmol) and a catalytic amount of Zn(ClO4)2 in MeOH (10 mL)
under argon. After stirring for 6 h at room temperature, the solvent was
removed. The residue was dissolved in CH2Cl2 (20 mL), and NaBH4 (30 mg,
0.8 mmol) was added. The solution was heated to reflux for 13 h. After cooling
to room temperature, water was added to produce a precipitate. The solid was
washed with ether, yielding a light yellow solid in 52% yield (48 mg): light
16. (a) Kondo, S.-I.; Sato, M. Tetrahedron 2006, 62, 4844–4850; (b) Kondo, S.-I.;
Kinjo, T.; Yano, Y. Tetrahedron Lett. 2005, 46, 3183–3186; (c) McFarland, S. A.;
Finney, N. S. J. Am. Chem. Soc. 2002, 124, 1178–1179.
yellow solid; mp: 169–172 °C; IR m ;
max: 3393, 3270, 3061, 2969 cmÀ1 1H NMR
(400 MHz, CDCl3): d 1.19 (t, 9H, –CH3, J = 7.2 Hz), 2.79 (q, 6H, –CH2, J = 7.2 Hz),
4.33 (s, 6H, –CH2), 5.08 (s, 6H, –CH2), 6.49–6.55 (m, 6H, Ar), 6.90–6.93 (m, 3H,
Ar), 7.01–7.05 (m, 3H, Ar), 7.09–7.11 (m, 3H, Ar), 7.18–7.20 (m, 6H, Ar), 7.26–
7.30 (m, 4H, Ar), 7.34–7.36 (m, 5H, Ar), 7.41–7.43 (m, 3H, Ar), 7.64 (br, 3H, Ar),
17. Shortreed, M.; Kopelman, R.; Kuhn, M.; Hoyland, B. Anal. Chem. 1996, 68, 1414–
1418.
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