Benzimidazole-based imine-linked chemosensor: Chromogenic sensor for Mg2+ and fluorescent sensor for Cr3+

Article abstract of DOI:10.1016/j.tet.2012.01.047

We synthesized an imine-linked, benzimidazole-based chemosensor that can be used for chromogenic recognition of Mg²⁺ and fluorescent recognition of Cr³⁺. The chemosensor shows sensitive, selective, and ratiometric recognition of Cr

Full text of DOI:10.1016/j.tet.2012.01.047

Tetrahedron 68 (2012) 2289e2293
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Benzimidazole-based imine-linked chemosensor: chromogenic sensor for Mg2þ
and fluorescent sensor for Cr3þ
,
c,
*
Preeti Saluja a, Hemant Sharma a, Navneet Kaur b, Narinder Singh a , Doo Ok Jang
*
a Department of Chemistry, Indian Institute of Technology Ropar, Rupnagar, Punjab 140001, India
b Centre for Nanoscience & Nanotechnology, Punjab University, Chandigarh, Punjab 160014, India
c Department of Chemistry, Yonsei University, Wonju, Gangwon 220-710, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
We synthesized an imine-linked, benzimidazole-based chemosensor that can be used for chromogenic
recognition of Mg2þ and fluorescent recognition of Cr3þ. The chemosensor shows sensitive, selective, and
ratiometric recognition of Cr3þ through concurrent quenching at one wavelength and enhancement of
fluorescence intensity at another wavelength. It can also be used to detect Mg2þ via UVevis absorption
spectroscopy. DFT calculations support these phenomena. The sensor can be used to strain microbe cells
without breakage.
Received 16 December 2011
Received in revised form 16 January 2012
Accepted 17 January 2012
Available online 24 January 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Multifunctional sensor
Benzimidazole
Chemosensor
Mg(II)
Cr(III)
1. Introduction
of our ongoing research for the development of multifunctional
sensors,9 here we report a sensor comprised of two dyes that was
Sugar-laden food, high calorie intake, and a sedentary lifestyle
increase the risk of diabetes. Recent studies have shown that de-
ficiency in two trace minerals, i.e., magnesium and chromium, is
also responsible for type 2 diabetes.1 Chromium improves insulin
sensitivity and acts as a glucose tolerance factor through the me-
tabolism of carbohydrates, fats, and protein.2 Magnesium is a co-
factor in the phosphorylation of glucose during carbohydrate
metabolism.3 In addition, Mg2þ is also required for the proper
functioning of the nerves and the immune system and for muscle
and bone health.4 Mg2þ and Cr3þ represent an interesting paradox
in the human body as a trace amount of both is required for normal
physiological functions. However, unregulated amounts of both
may cause serious problems.5 Magnesium may lead to hyper-
magnesia6 and chromium interacts with some medications such as
beta-blockers and NSAIDs.7 Hence, measuring Mg2þ and Cr3þ in the
blood serum is a necessary component of epidemiologic studies,8
and the estimation of these minerals in food stuffs may help to
formulate guidelines for determining the dietary requirements of
diabetic patients.
fabricated in such a way that one dye has hard binding sites for
Mg2þ and the other dye contains borderline binding sites for Cr3þ
.
These two dyes respond differently when probed by two different
spectroscopic techniques. Such multifunctional sensors have many
advantages: (a) the sensor is devised for two metal ions, and if the
concentration of these metal ions is estimated through two dif-
ferent techniques, then this will avoid interference in estimation;
(b) this strategy is useful where a large amount of sample is not
available for individual estimation of both analytes; (c) this method
is less time consuming as the analyst has to prepare only a single
sample for analysis of both metal ions.
2. Results and Discussion
We synthesized sensor 1 by a simple condensation reaction
between 2-(2-aminophenyl)-1H-benzimidazole (fluorescent moi-
ety) and 2-hydroxy-5-nitrobenzaldehyde (chromogenic moiety).
Sensor 1 is designed based upon recognition studies of sensors 2
and 3, which were synthesized via a condensation reaction
(Scheme 1).10 Sensor 2 was found to be a fluorescent sensor for Cr3þ
and this binding event led to quenching in intensity at 425 nm and
a small enhancement at 480 nm in a HEPES buffered CH3CN/H2O
(8:2, v/v, pH¼7.0) solvent system (Figs. S4A and S5). However,
sensor 2 was not selective for Cr3þ and also showed some affinity
These facts encouraged us to develop a sensor for the estimation
of both Mg2þ and Cr3þ under biological conditions. In continuation
* Corresponding authors. E-mail addresses: nsingh@iitrpr.ac.in (N. Singh),
dojang@yonsei.ac.kr (D.O. Jang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.047

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P. Saluja et al. / Tetrahedron 68 (2012) 2289e2293
Scheme 1.
for other metal ions. Similarly, sensor 2 was not selective for any
particular metal ion when the metal binding affinity of 2 was tested
with UVevis absorption spectroscopy (Fig. S4B). Sensor 3 had some
affinity for Mg2þ as evident from the changes in the UVevis spectra
of 3 when recorded in a HEPES buffered CH3CN/H2O (8:2, v/v,
pH¼7.0) solvent system (Fig. S6A). The successive addition of Mg2þ
to a solution of 3 resulted in an increase in absorbance at 355 nm
and a decrease in absorbance at 395 nm with two isosbestic points
at 385 and 450 nm (Fig. S7). However, sensor 3 is limited by the fact
that further addition of Mg2þ led to some precipitation. The fluo-
rescence spectra of 3 were not shifted selectively for any particular
metal ion (Fig. S6B). Binding sites of sensors 2 and 3 provided
a sufficient background for sensor design, which can be used for the
intensity of 1 at 415 nm and enhancement at 475 nm (Fig. 2B). Such
changes at two wavelengths offer an interesting opportunity for
ratiometric fluorescence determination of analytes (Fig. S14).
Ratiometric determinations have advantages over conventional
monitoring at a single wavelength because the system is free from
errors, which cause sensor concentrations, photo-bleaching, and so
on.13 The stoichiometry of the complex was determined with mass
spectra, showing the formation of a 2:1 host/guest complex based
on the presence of a peak at m/z¼768 (Fig. S10). The Job plot
analysis for the complex formed between 1 and Cr3þ was at max-
imum at a molar fraction of Cr3þ at 0.66, also confirming the for-
mation of a 2:1 host/guest complex for Cr3þ (Fig. S13). The
association constant for 1$Cr3þ was calculated by fluorescence ti-
tration, and was found to be 1.6 (ꢀ0.1)ꢁ104 Mꢂ2. The detection
simultaneous estimation of Mg2þ and Cr3þ
.
The UVevis spectrum of sensor 1 was recorded in a HEPES
buffered CH3CN/H2O (8:2, v/v, pH¼7.0) solvent system. The ab-
sorption spectrum of sensor 1 displayed well-defined bands at 300,
350, and 400 nm. The role of pH on the photophysical properties of
sensor 1 was evaluated by varying the pH of the solution from 1.3 to
13.1. The acidic pH range drastically affected the photophysical
properties of sensor 1 as evident in Fig. S8. Therefore, to preclude
the influence of pH, all the studies were carried out in a HEPES
buffered solution (pH¼7.0ꢀ0.1). The cation binding affinity of
sensor 1 toward different alkali, alkaline earth, and transition metal
ions was investigated with fluorescence and UVevis absorption
spectroscopy. Upon addition of Mg2þ to a solution of sensor 1 in
HEPES buffered CH3CN/H2O (8:2, v/v, pH¼7.0), the observed ab-
sorption band of sensor 1 at 400 nm decreased in absorbance and
the other two bands showed an increase in absorbance (Fig. 1A).
However, no such significant changes in sensor 1 were observed
with any other tested cations. To gain more insight into the pho-
range was turned out to be 79.4e340 mM.
The complementary relationship between host and guest was
further confirmed with density functional theory (DFT) calculations
using Becke’s three parameterized LeeeYangeParr (B3LYP) ex-
change functional with 6-31G
*
basis sets on Gaussian 09
1
A
Host
Na(I)
K(I)
Mn(II)
Sr(II)
Ba(II)
Ca(II)
Cr(III)
Co(II)
Cu(II)
Pb(II)
Hg(II)
0.8
0.6
0.4
0.2
0
Mg(II)
Fe(III)
Ni(II)
Zn(II)
Ag(I)
Cd(II)
tophysical properties of sensor 1 as a chromogenic sensor for Mg2þ
,
a titration was performed (Fig. 1B). Successive additions of Mg2þ to
a solution of sensor 1 in HEPES buffered CH3CN/H2O (8:2, v/v,
pH¼7.0) led to a stepwise decrease in absorbance at 400 nm and an
increase in absorbance at 350 nm with a clear isosbestic point at
385 nm. The preferential binding of Mg2þ in the pseudocavity of
sensor 1 reveals that the sensor binding sites are complementary to
Mg2þ in terms of size and hardehard interactions. The detection
225 245 265 285 305 325 345 365 385 405 425 445 465 485 505
Wave le ngth (nm)
B
0.5
0.4
0.3
0.2
0.1
0
range was turned out to be 3.2e100 mM.
The stoichiometry of the 1$Mg2þ complex was determined by
mass spectrometry and the Job plot method.11 The mass spectrum
of 1$Mg2þ revealed a 1:1 stoichiometry of the complex based on
the presence of a peak at m/z¼382 (Fig. S9). The Job plot analysis
indicated the formation of a 1:1 host/guest complex (Fig. S12). A Ka
value of 1$Mg2þ was calculated based on the UVevis absorption
titration12 and was found to be 3.2(ꢀ0.1)ꢁ102 Mꢂ2
.
Cr3þ binding with sensor 1 led to a change in the fluorescent
spectra of 1 with quenching at 415 nm and enhancement at
475 nm. No such significant and unique changes were observed
upon binding of any of the other metal ions (Fig. 2A). To evaluate
sensor 1 as a fluorescent sensor for Cr3þ, titrations were performed
with successive additions of Cr3þ to a solution of 1 in HEPES buff-
ered CH3CN/H2O (8:2, v/v, pH¼7.0), which led to the same type of
profile as observed in Fig. 2A, i.e., quenching in the fluorescence
246 266 286 306 326 346 366 386 406 426 446
Wavelength (nm)
Fig. 1. (A) Changes in the UVevis absorption spectra of sensor 1 (1.5
mM) in the
presence of metal nitrate salts in HEPES buffered CH3CN/H2O (8:2, v/v, pH¼7.0). (B)
Changes in UVevis absorption spectra of sensor 1 (1.5 mM) with increasing concen-
trations of Mg2þ in HEPES buffered CH3CN/H2O (8:2, v/v, pH¼7.0).

P. Saluja et al. / Tetrahedron 68 (2012) 2289e2293
2291
programs.14 The optimized structure of the enol form of sensor 1
and its Mg2þ complex are shown in Fig. 3A and B. The enol form of 1
has symmetry with three different planes that intersect each other,
shown by dihedral angles in Table S1. However, a Mg2þ complex
with the enol form of 1 results in marked changes in the geometry
of 1 upon coordination with Mg2þ. A comparison of the optimized
structures of 1 and the 1$Mg2þ complex reveals that the face of the
benzimidazole moiety rotates to provide a binding site for Mg2þ
,
i.e., N11 and N12 exchange their positions during formation of the
complex. This event leads to the destruction of intramolecular hy-
drogen bonding in the complex, which prevails in 1. However, the
metal complex is more stable than the enol form of 1 as evident
from the comparison of total energy of the enol form of 1 and its
Mg2þ complex (Table S2).
The modulation of the fluorescence spectrum of 1 with the
addition of Cr3þ is due to the formation of a more stable Cr3þ
complex with the keto form of 1, which occurs due to the excited
state intramolecular proton transfer (ESIPT) from the enol form of
1 through ketoeenol tautomerism. In the absence of Cr3þ, the
enol form is in equilibrium with its keto tautomer in the excited
state. As Cr3þ binds to the keto form, the keto form is removed
from equilibrium, which is maintained via the production of
more keto tautomer. Thus, the intensity due to the enol tautomer
decreases while that from the Cr3þ-bound keto tautomer
increases.
The DFT calculations for keto and enol forms are shown in
Fig. 3A and C. C1 symmetry of the enol form of 1 having aromatic
moieties in three different planes approaches planarity in the
keto form of 1, as supported by the dihedral angles shown in
Table S1. This concept of more planarity in the keto form is fur-
ther strengthened by comparison of the bond distance between
ꢀ
O36/H13 in both forms of 1, i.e., this bond distance is 3.05 A in
ꢀ
the enol form and that of the keto form is 1.91 A. Due to flipping
of the 2-hydroxy-5-nitro benzene moiety, O36 in the keto form
comes close to N12 and N25 and forms a pseudocavity with two
intramolecular hydrogen bonds as compared to the enol form,
which has only one due to the non-planarity in the structure. In
the keto form, the hydrogen bonding distances between
ꢀ
ꢀ
O36/H13 and O36/H40 are found to be 1.91 A and 1.95 A,
respectively.
The DFT calculated structure of the Cr3þ complex (host/
guest¼2:1) with the keto form of 1 has a multifaceted structure
with two intramolecular hydrogen bonds, N37/H77 and
O36/H10 with lengths of 1.99 A and 1.42 A, respectively. The
optimized energy data indicates that the keto form of 1 with Cr3þ
forms a more stable complex as compared to the enol complex
formed with Mg2þ, shown in Table S2. The calculated molecular
orbital diagrams from the optimization data support the shifts in
ꢀ
ꢀ
Fig. 2. (A) Changes in the fluorescence spectrum of 1 (0.5 mM) upon addition of metal
nitrate salts in HEPES buffered CH3CN/H2O (8:2, v/v, pH¼7.0) with excitation at
300 nm. (B) A bar diagram showing fluorescence intensity in the presence of different
metals at 475 nm. (C) Changes in the fluorescence spectrum of sensor 1 (0.5 mM) with
increasing concentrations of Cr3þ in HEPES buffered CH3CN/H2O (8:2, v/v, pH¼7.0).
Fig. 3. Optimized structure of (A) the enol form of 1, (B) the Mg2þ complex with the enol form of 1, (C) the keto form of 1, and (D) the Cr3þ complex with the keto form of 1. Red, blue
and gray spheres correspond to O, N, and C atoms, respectively, while yellow and sky-blue spheres are Mg2þ and Cr3þ, respectively. The labeling of each atom is shown in Fig. S15.
DFT calculations were performed with the B3LYP exchange functional with a 6-31G* base set using a suite of Gaussian 09 programs.

2292
P. Saluja et al. / Tetrahedron 68 (2012) 2289e2293
Fig. 4. Microscopic images of (A) blank yeast cells, (B) yeast cells cultured in medium enriched with Cr3þ, (C) blank yeast cells treated with sensor 1, and (D) yeast cells cultured in
medium enriched with Cr3þ and then treated with sensor 1 (before performing microscopy, the cells were washed with a CH3CN/H2O (8:2, v/v, pH¼7.0) solvent mixture).
fluorescence bands. The energy gaps between the HOMOeLUMO
of the enol and keto forms of 1 and the Cr3þ complex with the
keto form of 1 were calculated in the absence of any solvent. The
energy gaps were found to be 269.9, 173.7, and 70.6 kJ/mol, re-
spectively. These calculated values are consistent with the ex-
perimental data obtained in HEPES buffered CH3CN/H2O (8:2, v/v,
pH¼7.0). That is, fluorescence emissions of the enol and keto
forms of 1 and the Cr3þ complex with the keto form of 1 are at
415, 470, and 475 nm, respectively. Frontier molecular orbital
diagrams clarify that the HOMO has high electron density in the
pseudocavity region of both forms of 1, which results in cati-
onedipole interactions between the metal cation and ligand
(Table S3). These cationedipole interactions give rise to stability
in the 1$Cr3þ complex. The same coordination sphere of 1 for
both of Mg2þ and Cr3þ was also confirmed with IR spectra and
mass spectrometry. The IR band of 1 at 1640 cmꢂ1 is assigned to
eCH]Ne and is shifted to higher wave numbers in both com-
plexes. Similarly, a broad IR band of 1 up to 3740 cmꢂ1 due to
eOH is also shifted to 3690 and 3680 cmꢂ1 for the Mg2þ and Cr3þ
complexes, respectively.
To evaluate the application of sensor 1 in biological systems,15
we cultured Saccharomyces cerevisiae (yeast) in normal broth and
under experimental media containing Mg2þ/Cr3þ. The cells cul-
tured in normal media and media containing Cr3þ ions were treated
with sensor 1 (dissolved in a HEPES buffered CH3CN/H2O (8:2, v/v,
pH¼7.0) solvent mixture). Before performing microscopy, the cells
were washed with a CH3CN/H2O (8:2, v/v, pH¼7.0) solvent mixture.
The microscopic investigations revealed that sensor 1 is capable of
binding Cr3þ in a cellular medium (Fig. 4). Similarly, cells were
cultured to investigate the role of sensor 1 for Mg2þ. However, color
changes due to the binding of Mg2þ were not so distinct under
optical microscopy, although the changes in absorbance were
measurable with diffuse reflectance under UVevis absorption
spectroscopy.
The microscopic image (Fig. 4D) clearly shows that sensor 1
passes through the yeast cell membrane and stains the cytoplasm
enriched with Cr3þ. To confirm that sensor 1 does not lead to the
destruction of the microbe, SEM images of the cells cultured with
Cr3þ and then treated with sensor
1 were obtained. The
smoothness of the microbe surface in both cases confirms that
sensor 1 does not cause any breakage to the surface of the microbe
(Fig. 5).
To test the practical applicability of sensor 1 as a chromogenic
sensor for Mg2þ as well as a fluorescence sensor for Cr3þ, com-
petitive experiments were carried out. In the first set of experi-
ments, a solution of Mg2þ and Cr3þ was added to a solution of 1. A
mass spectrum of the resulting complex showed the existence of
a 1:1 complex for Mg2þ and a 2:1 complex for Cr3þ (Fig. S11). From
this evidence, we conclude that the formation of complexes with
both metal ions is independent of the presence of another metal
ion. Further, there is no expected influence from the estimation of
another metal ion (Fig. S17). Practically, a comparison of the fluo-
rescence intensity of 1 in the presence of 1 equiv of Cr3þ and sec-
ondly in the presence of 1 equiv of each of Cr3þ and Mg2þ showed
3. Conclusion
In conclusion, an imine-linked, benzimidazole-based chemo-
sensor was synthesized for chromogenic recognition of Mg2þ and
fluorescent recognition of Cr3þ. The chemosensor was found to
provide sensitive, selective, and ratiometric recognition of Cr3þ
through concurrent quenching at one wavelength and enhance-
ment of fluorescence intensity at the other wavelength. The same
sensor can be used to detect Mg2þ using UVevis absorption spec-
troscopy. The results are supported with DFT calculations. The
sensor is applicable for straining microbial cells without any
breakage.
that estimation of Cr3þ was independent of the presence of Mg2þ
.
Similarly, an independent experiment also showed that the esti-
mation of Mg2þ with sensor 1 using UVevis absorption was not
affected by the presence of Cr3þ
.
Acknowledgements
This work was supported by the IndiaeKorea Joint Program of
Cooperation in Science & Technology (2011-0027710) and the CSIR
project (01(2417)/10/EMR-II). P.S. is thankful to UGC India for a re-
search fellowship. We thank Mr. S. Soni of CSIO Chandigarh for
fluorescence microscopy assistance.
Supplementary data
Supplementary data related to this article can be found in the
online version, at doi:10.1016/j.tet.2012.01.047.
References and notes
Fig. 5. SEM images showing the surface morphology of (A) normal yeast cells and (B)
yeast cells cultured with Cr3þ and then treated with sensor 1 (before performing
microscopy, the cells were washed with a CH3CN/H2O (8:2, v/v, pH¼7.0) solvent
mixture).
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