Synthesis, crystal structure, and DNA-binding studies of a cadmium(II) complex with bis(N-benzylbenzimidazol-2-ylmethyl)aniline

Article abstract of DOI:10.1080/15533174.2013.862819

A complex of cadmium (II) picrate (pic) with Bis(N-benzylbenzimidazol-2-ylmethyl)aniline (Bebba), with composition [Cd(Bebba)₂](pic)₂, was synthesized and characterized by elemental analysis, electrical conductivity and IR and UV/Vis

Full text of DOI:10.1080/15533174.2013.862819

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Synthesis, Crystal Structure and DNA-Binding
Studies of a Cadmium(II) Complex with the Bis(N-
benzylbenzimidazol-2-ylmethyl)aniline
Huilu Wua, Yanhui Zhanga, Yuchen Baia, Xiaoli Wanga, Jin Konga & Furong Shia
a School of Chemical and Biological Engineering, Lanzhou Jiaotong University, Lanzhou
730070, P. R. China
Accepted author version posted online: 24 Nov 2014.
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To cite this article: Huilu Wu, Yanhui Zhang, Yuchen Bai, Xiaoli Wang, Jin Kong & Furong Shi (2014): Synthesis, Crystal
Structure and DNA-Binding Studies of a Cadmium(II) Complex with the Bis(N-benzylbenzimidazol-2-ylmethyl)aniline, Synthesis
and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, DOI: 10.1080/15533174.2013.862819
To link to this article: http://dx.doi.org/10.1080/15533174.2013.862819
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Synthesis, Crystal Structure and DNA-Binding Studies of a Cadmium(II) Complex with
the Bis(N-benzylbenzimidazol-2-ylmethyl)aniline
Huilu Wu, Yanhui Zhang, Yuchen Bai, Xiaoli Wang, Jin Kong, Furong Shi
School of Chemical and Biological Engineering, Lanzhou Jiaotong University, Lanzhou 730070,
P. R. China
ABSTRACT
A complex of cadmium (II) picrate (pic) with Bis(N-benzylbenzimidazol-2-ylmethyl)aniline
(Bebba), with composition [Cd(Bebba)2](pic)2, was synthesized and characterized by elemental
analysis, electrical conductivity and IR and UV/Vis spectral measurements. The crystal structure
of the cadmium(II) complex has been determined by single-crystal X-ray diffraction. The
cadmium(II) cation is bonded to two Bebba ligands through four benzimidazole nitrogen,
resulting in a distorted octahedron geometry. The DNA-binding properties of the cadmium(II)
complex were investigated by electronic absorption, fluorescence spectra and viscosity
measurements. The experimental results suggest that the cadmium(II) complex binds to DNA in
an intercalation mode.
Keywords: Bis(N-benzylbenzimidazol-2-ylmethyl)aniline; Cadmium(II) complex; Crystal
structure; DNA binding property.
 Correspondence author. E-mail : wuhuilu@163.com
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INSTRODUCTION
Since the benzimidazole unit is the key building block for a variety of compounds which have
crucial roles in the functions of biologically important molecules, there is a constant and growing
interest over the past few years for the synthesis and biological studies of benzimidazole
derivatives [1-3]. Benzimidazole compounds are environmentally friendly compounds with two
high active nitrogen atoms in 1, 3-sites [4-6]. Benzimidazoles and their derivatives have a wide
range of well-known biological activities such as anticancer [7-10], antimicrobial [11-12],
antifungal [13], antiviral [14], etc. An interesting concept for finding a complex with distinct
biological and pharmaceutical features, the bis(N-methylbenzimidazol-2-ylmethyl)aniline
(Bebba) was selected as a ligand to chelate cadmium(II), which may enhance the interaction of
the metal center(s) with DNA [15].
In this paper, we report the synthesis, crystal structure, and DNA-binding properties of the
Cd(II) picrate complex with Bebba.
EXPERIMENTAL
Materials
All chemicals and solvents were reagent grade and used without further purification.
Elemental analyses were determined using a Carlo Erba 1106 elemental analyzer. The IR spectra
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were recorded on a BRUKER FT-IR VERTEX 70 spectrometer in the range of 4000-400 cm-1
1
using KBr pellets. H-NMR spectra were obtained with a Mercury plus 400MHz NMR
spectrometer with TMS as internal standard and DMSO-d6 as solvent. Electronic spectra were
taken on a LabTech UV Bluestar spectrophotometer. Fluorescence measurements were
performed on a LS-45 spectrofluorophotometer. Electrolytic conductance measurements were
made with a DDS-307 type conductivity bridge using 10-3 mol·L-1 solution in DMF at room
temperature.
Calf thymus (CT-DNA) and ethidium bromide (EB) were obtained from Sigma-Aldrich
Chemicals Co. (USA). Tris-HCl buffer solution containing 5 mM Tris-HCl / 50 mM NaCl (pH =
7.2) in double-distilled water was used to prepare all stock solutions for DNA binding studies.
The stock solution of DNA (2.5×10-3 M) was prepared in Tris-HCl/NaCl buffer (pH = 7.2, stored
at 4 °C and used when not more than 4 days). The solution of CT-DNA gave a ratio of UV
absorbance at 260 nm and 280 nm, A260/A280, of 1.8-1.9, indicating that the DNA was
sufficiently free of proteins [16]. The concentration of CT-DNA was determined from its
absorption intensity at 260 nm with a molar extinction coefficient of 6600 M-1cm-1 [17]. The
absorption spectra of complex binding of DNA was performed by increasing amounts of DNA to
complex in 5 mM Tris-HCl/50 mM NaCl buffer (pH = 7.2). The stock solution of ligand and
complex was dissolved in DMF at the concentration 3×10-3 M.
By the fluorescence spectral method, the relative binding of complex to CT-DNA was studied
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with an EB-DNA complex solution in 5 mM Tris-HCl/50 mM NaCl buffer (pH = 7.2).
Fluorescence intensities (520 nm excitation) were measured at different complex concentrations.
The experiment was carried out by titrating complex into EB-DNA complex solution ([EB] = 2.2
× 10-3M, [CT-DNA] = 2.5× 10-3 M).
Viscosity experiments were carried out using an Ubbelodhe viscometer maintained at a
constant temperature at 25.0 ± 0.1 ºC in a thermostatic water-bath. Flow time was measured with
a digital stopwatch, and each sample was measured three times, and an average flow time was
calculated. Titrations were performed for the complex (3-30 μM) and complex was introduced
into the CT-DNA solution (50 μM) present in the viscometer. Data were presented as (η / η0)1/3
versus the ratio of the concentration of the compound to CT-DNA, where η is the viscosity of
CT-DNA in the presence of the complex, and η0 is the viscosity of CT-DNA alone. Viscosity
values were calculated from the observed flow time of CT-DNA containing solutions corrected
for the flow time of the buffer alone (t0) with the equation η = (t − t0) / t0 [18].
Preparation of bis(benzimidazol-2-ylmethyl)aniline(bba)
A mixture of phenylimiodiacetic acid (54.25 g, 0.25 mol) and o-phenylenediamine (54.00 g, 0.50
mol) in ethylene glycol (250 mL) was refluxed for 24 h. The yellow precipitate was filtered and
washed with distill water. Yield 82.05 g (75.8 %). Anal. Calcd for C22H19N5 (%): C, 74.77; H,
5.42; N, 19.82. Found (%): C, 74.79; H, 5.41; N, 19.83. Selected IR data (KBr ν/cm-1): 1600m
(C=C), 1445m (C=N), 1272m (C-N), 743m(O-Ar). 1H NMR (400 MHz, DMSO-d6, δ /
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ppm): 7.2-7.68(m, 10H, benzimidazole), 6.55-7.10(m, 5H, Ph), 5.14(s, 4H, CH2). ΛM. (DMF, 297
K): 3 S·cm2·mol-1.
Preparation of bis(N-benzylbenzimidazol-2-ylmethyl)aniline (Bebba)
The synthesis of the ligand Bebba is displayed as scheme 1. 5.3 g (0.015mol)
bis(benzimidazol-2-ylmethylene)aniline with 1.17 g (0.03mol) potassium in 150mL evaporated
tetrahydrofuran was followed by adding 5.13 g (0.03mol) benzyl bromide. The resulting solution
was concentrated and recrystallized from methanol which was given pale yellow block crystals
of Bebba. Yield 6.14 g (75.8%). Anal. Calcd for C34H31N5 (%): C, 80.13; H, 6.13; N, 13.74.
Found (%): C, 80.27; H, 6.07 ; N, 13.66. Selected IR data (KBr ν/cm-1): 1600m (C=C), 1454m
(C=N), 1291m (C-N)，744m(O-Ar). 1H NMR (400 MHz, DMSO-d6, δ / ppm): 7.13-7.60(m,
8H, benzimidazole), 7.09-6.64(m, 5H, Ph), 5.019(s, 4H, CH2), 3.78-3.21(s, 14H, benzyl).
UV/Vis (DMF): λ = 282, 287 nm. ΛM. (DMF, 297 K): 7 S·cm2·mol-1.
Preparation of [Cd(Bebba)2](pic)2
To a stirred solution of Bebba (0.267 g, 0.5 mmol) in hot MeOH (10 mL) was added Cd(pic)2
(0.143 g, 0.25 mmol) in MeOH (5 mL). A pale-yellow crystalline product formed rapidly. The
precipitate was filtered off, washed with MeOH and absolute Et2O, and dried in vacuo. The dried
precipitate was dissolved in DMF to form a yellow solution into which Et2O was allowed to
diffuse in at r. t. Paleyellow crystals of [Cd(Bebba)2](pic)2 suitable for X-ray diffraction were
obtained after five days. Anal. Calcd for C84H66CdN16O14 (%): C, 61.98; H, 3.59; N, 13.77.
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Found: C, 61.83; H, 3.79; N, 13.61. Selected IR data (KBr ν/cm-1): 1633m  (C=C), 1495m
(C=N), 1312m (C-N)，742m (O-Ar). ΛM. (DMF, 297 K): 130 S·cm2·mol-1.
X-Ray crystal structure determination
All data were obtained using a Bruker Smart CCD diffractometer with graphite
Monochromated Mo-Ka radiation ( λ = 0.71073 Å ) at 296 K. Date reduction and cell refinement
were performed using SAINT programs [19]. The absorption corrections were carried out by the
empirical method. The structure was solved by Direct Methods and refined by full-matrix
least-squares against F2 of data using SHELXTL software [20].
The non-H atoms in the structure were subjected to anisotropic refinement. Hydrogen were
located geometrically and treated with the riding model. Basic crystal data, description of the
diffraction experiment, and details of the structure refinement are given in Table 1. Selected
bond distances and angles are presented in Table 2.
RESULTS AND DISCUSSION
The synthetic route for the ligand Bebba is shown in Scheme 1. The Cd(II) complex
[Cd(Bebba)2](pic)2 was prepared by reaction of Bebba with Cd(pic)2 in methanol. It is soluble in
polar aprotic solvents such as DMF, DMSO and MeCN, slightly soluble in ethanol, methanol,
ethyl acetate, and chloroform, and insoluble in water, Et2O and petroleum ether. The elemental
analysis shows that its composition is [Cd(Bebba)2](pic)2 which was confirmed by the crystal
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structure analysis.
Crystal structure of [Cd(Bebba)2](pic)2
The central Cd(II) is six-coordinate, by virtue of six nitrogen atoms from two tridentate
Bebba(Fig. 1). The coordination geometry of Cd(II) is that of a distorted octahedron with (N1,
N3, N4, and N1A) providing the equatorial plane. In the equatorial plane, the lengths of the
bonds connected with Cd(II) range from 2.2285 to 3.031 Å , The ligand–metal–ligand angles
vary from 62.82(6)° to 127.02(15)°, while the bond lengths between Cd(II) and the apical
nitrogen atoms (N3A, N4A) are almost equal, average 2.255 Å . The bond angle of N3A–Cd–
N4A in axial positions is 126.45(7)°. Therefore, compared with a regular octahedron, it reflects a
relatively distorted coordination octahedron around Cd(II) [21－23] . Besides, In the crystal
structure a parallel arrangement between the benzene rings is realized indicating π - π stacking of
them with a distance between them of around 4.012Å (Fig. 2).
IR and UV spctra
The IR spectral data for the free ligand and the Cd(II) complex with their relative assignments
have been studied to characterize their structures. The IR spectrum of the free ligand Bebba
shows characteristic absorption bands of the benzimidazole group at 1600, 1447, and 1280 cm−1
assigned to  (C=C),  (C=N) and  (C-N), respectively [24 – 25]. The bands are shifted by
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around 30 cm−1 in the complex, which implies direct coordination of the metal ion to four
benzimidazole nitrogen atoms and two nitrogen atoms, which are the preferred atoms for
coordination as found for other metal complexes with benzimidazoles. Information regarding the
possible bonding modes of the picrate and benzimidazole rings may also be obtained from the
bands at 708, 1177, 1312, and 1633 cm−1. The results agree with those determined by X-ray
diffraction.
DMF solutions of the ligand Bebba and its cadmium(II) complex show, as expected, almost
identical UV spectra. The UV bands of Bebba (287 nm) are only marginally blue-shifted (2 nm)
in the complex, which is a clear evidence of C=N coordination to cadmium(II). The absorption
band is assigned to π→π* (benzimidazole) transitions.
DNA banding mode and affinity
Electronic absorption titration
Electronic absorption spectroscopy is universally employed to determine the binding
characteristics of metal complexes with DNA. The absorption spectra of the ligand Bebba and
the Cd(II) complex in the absence and presence of CT-DNA are given in Figs. 3 (a), (b)
respectively. As for the ligand Bebba with two well-resolved bands at 276 and 282 nm (Fig. 3(a)),
in Fig. 3(b) there are also two well-resolved bands at about 282, 287 nm for the complex (Fig.
3(c)), in Fig. 3(d). With increasing DNA concentrations, the hypochromism are 16.34 % at 287
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nm for the ligand Bebba, and 24.25 % at 287nm for the Cd(II) complex. These spectral
characteristics suggest that the Cd(II) complex interacts with DNA, most likely through a mode
that involves a stacking interaction between the aromatic chromophore and the base pairs .
The binding constant Kb for the complex has been determined from the plot of [DNA] / (εa−εf)
vs. [DNA] and found to be 6.26 ×104 M−1. Kb for the ligand (1.41 ×105 M−1) is larger than for the
complex. Compared with those of a so-called DNA-intercalative ruthenium complexes , the
binding constants (Kb) of Bebba and the Cd(II) complex suggest that the two compounds most
probably bind to DNA in an intercalation mode. With the above intrinsic binding constant values,
the binding affinity of the Cd(II) complex is stronger than that of Bebba.
However, the affinity for DNA is more strong in case of Cd(II) complex when compared with
the ligand. For this difference, we attributed to three possible reasons. (i) By comparison of the
molecular structure of the ligand and Cd(II) complex, we find the greater number of coplanar
aromatic rings may lead to higher affinity for DNA [26]. (ii) The charge transfer of coordinated
Bebba ligands caused by the coordination of the central Cd(II) atom, lead to the reduce of the
charge density of the plane conjugate system, which is conducive to insert. (iii) This difference in
their DNA binding ability also could be attributed to the presence of an electron deficient center
in the charged Cd(II) complex where an additional interaction between the complex and
phosphate rich DNA back bone may occur .
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Competitive binding with EB
Ethidium bromide (EB) is one of the most sensitive fluorescent probes which can bind to
DNA through intercalation [27, 28]. Competitive binding to DNA of the drugs with EB could
provide rich information with regard to the DNA-binding affinity. As shown in Fig.4, the
fluorescence intensity decrease obviously with the increasing concentration of the ligand Bebba
and the Cd(II) complexes. The Ksv values for ligand are 7.31×103 M−1 and the Cd(II) complex is
3.23×103 M−1, respectively. The quenching plots illustrate that the quenching of EB bound to
DNA by the compounds are in good agreement with the linear Sterne-Volmer equation and the
binding ability of two compounds follows the order Cd(II) complexes > Bebba. Furthermore,
such quenching constants of the ligand and the Cd(II) complexes suggest that the interaction of
all the compounds with DNA should be of intercalation.
Viscosity studies
Optical photophysical probes generally provide necessary, but not sufficient clues to support a
binding model. Measurements of DNA viscosity that is sensitive to DNA length are regarded as
the least ambiguous and the most critical tests of binding in solution in the absence of
crystallographic structural data [29]. Intercalating agents are expected to elongate the double
helix to accommodate the ligands in between the bases leading to an increase in the viscosity of
DNA. In contrast, compounds that bind exclusively in the DNA grooves by partial and/or
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non-classical intercalation under the same conditions, typically cause less pronounced (positive
or negative) or no change in DNA solution viscosity [30]. The values of (η / η0)1/3 were plotted
against [compound] / [DNA] (Fig. 5). Upon addition of the ligand, the Cd(II) complex the
viscosity of rod-like CT-DNA increased significantly, which suggests that the ligand Bebba, the
Cd(II) complex can bind to DNA by intercalation [31].
CONCLUSION
In summary, a complex [Cd(Bebba)2](pic)2 has been synthesized and characterized by
elemental analysis, molar conductivity, IR spectra and UV–Vis spectra. DNA binding properties
of the free ligand Bebba and its complex were investigated by ultraviolet absorption
spectroscopy, fluorescence spectroscopy and viscosity measurements. The results support the
fact that two compounds can bind to DNA via intercalation mode.
SUPPLEMENTARY MATERIALS
Supplemental data is for this article is available at the publisher’s website. Crystallographic
data (excluding structure factors) for the structure in this article have been deposited with the
Cambridge Crystallographic Data Center as supplementary publication CCDC 837721. Copies of
the data can be obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK.
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ACKNOWLEDGEMENTS
The present research was supported by the Fundamental Research Funds for the Gansu
Province Universities (212086), National Natural Science Foundation of Gansu Province (Grant
No. 1212RJZA037), and ‘Qing Lan’ Talent Engineering Funds for Lanzhou Jiaotong University.
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2-Oxopropane .Synth React Inorg Met Org Nano Met Chem. 2009, 39, 614-617.
[31]Satyanarayana, S.; Dabrowiak, J.C.; Chaires, J.B. Tris(phenanthroline)ruthenium(II)
enantiomer interactions with DNA: Mode and specificity of binding. Biochem. 1993, 32,
2573–2584.
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Scheme.1. The synthesis of the ligand Bebba .
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TABLE 1 Crystal data and structure refinement for [Cd(Bebba)2](pic)2
formula
C84 H66 Cd N16 O14
M
Temperature (K)
system
space group
a(Å)
1635.93
293(2)
Monoclinic
P2/c
11.8100(10)
b(Å)
13.7340(12)
c(Å)
22.809(2)
a/(°)
90
95.2900(10)
/(°)
90
/(°)
V/Å3
3683.8(6)
Z
2
1.475
1684

caled g/cm3
F(000)
Limiting indices
Crystal size mm
-14<=h<=14, -16<=k<=16, -27<=l<=22
0.40 x 0.38 x 0.30
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q range for data collection, deg
Final R indices [I>2sigma(I)]
R indices (all data)
1.73 < θ < 25.50
R1 = 0.0365, wR2 = 0.0955
R1 = 0.0425, wR2 = 0.1000
0.893 and 0.860
Δρ(max) and Δρ(min)
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TABLE 2 Selected bond lengths (Å) and angles (°) for [Cd(Bebba)2](pic)2
Bond lengths Cd(1)-N(3)#1
Cd(1)-N(4)#1
2.2285(18)
2.2799(19)
3.031(2)
Cd(1)-N(3)
Cd(1)-N(4)
Cd(1)-N(1)#1
2.2285(18)
2.2799(19)
3.031(2)
Cd(1)-N(1)
Bond angles
N(3)#1-Cd(1)-N(3) 110.92(10)
N(3)-Cd(1)-N(4)#1 101.50(7)
N(3)#1-Cd(1)-N(4)#1 126.45(7)
N(3)#1-Cd(1)-N(4)
N(4)#1-Cd(1)-N(4)
C(36)-N(4)-Cd(1)
C(21)-N(3)-Cd(1)
N(3)-Cd(1)-N(1)
N(4)#1-Cd(1)-N(1)
101.50(7)
91.21(10)
126.27(15)
126.07(15)
63.79(6)
N(3)-Cd(1)-N(4)
C(23)-N(4)-Cd(1)
C(8)-N(3)-Cd(1)
126.45(7)
123.50(15)
127.02(15)
N(3)#1-Cd(1)-N(1) 123.73(6)
N(4)-Cd(1)-N(1) 62.82(6)
108.45(6)
Symmetry transformations used to generate equivalent atoms: #1 -x,y,-z+1/2
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Fig. 1. Molecular structure and atom-numberings of [Cd(Bebba)2]2+ with hydrogen atoms
omitted for clarity.
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Fig.2. The structure of the Cd(II)complex linked via π - π stacking interaction
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Fig. 3. Electronic spectra of the free ligand Bebba (a) and complex the Cd(II) complex (c) in
Tris–HCl buffer upon addition of CT-DNA. [DNA] = 1×10−5 - 9×10−5 M. The arrow shows the
emission intensity changes upon increasing DNA concentration. [DNA] / ( εa−εf) versus. [DNA]
for the titration of the free ligand Bebba (b) and the Cd(II) complex (d) with CT-DNA
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Fig. 4. Emission spectra of EB bound to CT-DNA in the presence of the free Bebba (a) and the
Cd(II)complex (c), λex = 520 nm., [Compound] = 0.6×10−5 – 6×10−5 M. The arrows show the
intensity changes upon increasing con- centrations of the complexes. Fluorescence quenching
curves of EB bound to CT-DNA by the free Bebba (b) and the Cd(II)complex (d). (Plots of I0 / I
versus. [Compound].)
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Fig. 5. Effect of increasing amounts of the compounds on the relative viscosity at 25.0 ± 0.1C
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