Novel Pd(II) and Pt(II) complexes of N,N-donor benzimidazole ligand: Synthesis, spectral, electrochemical, DFT studies and evaluation of biological activity

Article abstract of DOI:10.1016/j.ica.2011.04.036

(1H-benzimidazol-2-ylmethyl)-(4-nitro-phenyl)-amine (L) and its Pd(II) and Pt(II) complexes have been synthesized as potential anticancer compounds and their structures were elucidated using a variety of physico-chemical techniques. The activation thermod

Full text of DOI:10.1016/j.ica.2011.04.036

Inorganica Chimica Acta 373 (2011) 249–258
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Novel Pd(II) and Pt(II) complexes of N,N-donor benzimidazole ligand: Synthesis,
spectral, electrochemical, DFT studies and evaluation of biological activity
⇑
Nour T. Abdel Ghani, Ahmed M. Mansour
Chemistry Department, Faculty of Science, Cairo University, Gamaa Street, Giza 12613, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
(1H-benzimidazol-2-ylmethyl)-(4-nitro-phenyl)-amine (L) and its Pd(II) and Pt(II) complexes have been
synthesized as potential anticancer compounds and their structures were elucidated using a variety of
physico-chemical techniques. The activation thermodynamic parameters were calculated using non-iso-
thermal methods. Theoretical calculations invoking geometry optimization, charge distribution and
molecular orbital description HOMO and LUMO were done using density functional theory. Natural bond
orbital analysis (NBO) was performed for the investigation of major stabilizing orbital interactions. The
experimental results, and the calculated molecular parameters, bond distances and angles, revealed a
square-planar geometry around the metallic center through the pyridine-type nitrogen of the benzimid-
azole ring (Npy) and secondary amino group (NHsec) and two chlorine atoms. Electrochemical investiga-
tion of the complexes showed some irreversible, reversible, and quasi-reversible redox reactions. The
synthesized ligand, in comparison to its metal complexes was screened for its antibacterial activity.
The cytotoxicity assay of the complexes against three-cell lines breast cancer (MCF7), colon Carcinoma
(HCT) and human heptacellular Carcinoma (Hep-G2) was studied.
Received 3 November 2010
Received in revised form 7 March 2011
Accepted 20 April 2011
Available online 27 April 2011
Keywords:
Benzimidazole
Platinum complex
DFT
NBO
Antitumor
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
lating ligands incorporating benzimidazole groups have been
extensively studied in the context of modeling biological systems
Despite the widespread use of cis-diaminedichloroplatinum(II)
(cis-platin) as an anticancer drug there is still scope for improve-
ment, with respect to reduced toxicity [1], increased clinical effec-
tiveness, broader spectrum of action, elimination of side effects
(e.g. nausea, hearing loss, vomiting, etc.), increased solubility, and
the ability to use it in combination with other drugs. Many deriv-
atives of cis-platin also inhibit growth, and these compounds have
at least one N–H group [2] (one of the reasons for choosing the li-
gand under study), which is responsible for important hydrogen-
bond donor properties, either in the approach of the biological tar-
get or the final structure. Recently, interest was carried out in the
developing cis-platin analogs, which have heterocyclic amine li-
gands coordinated to the cyctotoxic platinum(II) moiety. Several
platinum complexes with N-heterocyclic ligands such as imidaz-
ole, thiazole, benzimidazole, benzothiazole, and benzoxazole were
reported [3]. The benzimidazole scaffold is a useful structural motif
for displaying chemical functionality in biologically active mole-
cules. Some of its derivatives have potent biological activities as
antitumor [4], anti-HIV [5], anti-Parkinson [6], and antimicrobial
[7] agents. At the same time, because of the coordination chemistry
of azoles acting as ligands in transition metal compounds, the che-
in recent years [8]. Our aim was to take into account all the previ-
ously mentioned properties of anticancer drugs and synthesize
new platinum(II) and palladium(II) complexes of new N,N donor
benzimidazole derivatived cis-platin analogs that could prove to
be potent antitumor agents through characterization and elucida-
tion of their structures using different spectroscopic, thermal and
conductance measurements. Density functional theory (DFT) cal-
culations were done in order to correlate between the theoretical
and experimental results.
2. Experimental
2.1. Synthesis of ligand (L) and its complexes
The benzimidazole L (Fig. 1) was prepared by condensation of
equimolar quantities of 2-chloromethylbenzimidazole [9] with
4-nitroaniline. The reaction mixture was refluxed in ethanol in
the presence of sodium iodide for about 18–24 h. Then, the reac-
tion mixture was neutralized and the solid was separated by dilu-
tion with de-ionized water, and recrystallized from ethanol.
One millimole K2PdCl4 was prepared by dissolving 0.177 g PdCl2
in 0.149 g/50 ml aqueous potassium chloride solution. The solid
metal complexes of the benzimidazole compound (L) with Pd(II),
and Pt(II) metal ions were prepared by adding a hot ethanolic
⇑
Corresponding author. Fax: +20 2 35728843.
E-mail address: inorganic_am@yahoo.com (A.M. Mansour).
0020-1693/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2011.04.036

250
N.T. Abdel Ghani, A.M. Mansour / Inorganica Chimica Acta 373 (2011) 249–258
pic were referenced to TMS, which was calculated at the same level
of theory (dTMS = 31.88). The optimized structures, vibrational fre-
quencies, 1H chemical shifts, and the natural bond (NBO) analysis
of the metal complexes were obtained at B3LYP/LANL2DZ level of
theory.
2.4. Biological activity
2.4.1. Antimicrobial activity
The antimicrobial activities of the test samples were deter-
mined using a modified Kirby–Bauer disc diffusion method [16]
under standard conditions using Mueller–Hinton agar medium, as
described by NCCLS [17]. The antimicrobial activities were carried
out using culture of Bacillus subtilis, Staphylococcus aureus, Strepto-
coccus faecalis as Gram-positive bacteria and Escherichia coli,
Pseudomonas aeruginosa, Neisseria gonorrhoeae as Gram-negative
Fig. 1. The optimized structure of benzimidazole L.
solution (60 °C) of the ligand (1 mmol) to a hot aqueous solution
(60 °C) of the metal ions (1 mmol; K2PdCl4, or K2PtCl4). The result-
ing mixtures were stirred under reflux for about 1–2 h, whereupon
the complexes precipitated.
bacteria. Briefly, 100
of fresh media until they reached a count of approximately 108
cells/ml. 100 l of microbial suspension was spread onto agar
ll of the test bacteria were grown in 10 ml
l
plates corresponding to the broth in which they were maintained.
DMSO (0.1 ml) alone was used as control under the same condi-
tions for each microorganism, subtracting the diameter of inhibi-
tion zone resulting with DMSO, from that obtained in each case.
The results were compared with a similar run of Tetracycline as
an antibacterial. The antimicrobial activities could be calculated
as a mean of three replicates.
2.2. Instruments
Infrared spectra of the ligand and its complexes were recorded
in potassium bromide discs using FTIR-460 plus, JASCO, Japan, in
4000–200 cmÀ1 region. The 1H NMR spectra were run at
300 MHz using dimethylsulfoxide (DMSO-d6) as a solvent and tet-
ramethylsilane (TMS) as a reference using Varian-Oxford Mercury
VX-300 NMR. Deuterium oxide (D2O) was used to confirm the pres-
ence of ionizable protons. The mass spectra measurements were
recorded with the aid of a SHIMADZU QP-2010 plus mass spectrom-
eter at 70 eV. The thermogravimetric analysis (TGA) and differen-
tial thermal analysis (DTA) were carried out in dynamic nitrogen
atmosphere (20 ml minÀ1) with a heating rate of 10 °C minÀ1 using
DTG-60H SIMULTANEOUS DTA-TG APPARATUS-SHIMADZU. Digital
Jenway 4330 Conductivity-pH meter with (1.02) cell constant was
used for pH and molar conductance measurements. Spectrophoto-
metric measurements were carried out using automated spectro-
photometer UV–Vis. SHIMADZU Lambda 4B using 1 cm matched
quartz cells. Cyclic voltammetry measurements were performed
using a three-electrode configuration cell connected to an EG and
G scanning potentiostat model 372. A Pt disc was used as working
electrode and a Pt wire as auxiliary electrode. The reference elec-
trode was Ag/AgCl electrode adjusted to 0.00 V versus SCE. Sample
solutions (50 ml) of 10À3 M concentration in DMF with 0.1 M
NaClO4ÁH2O as supporting electrolyte were used for the measure-
ments. A potential range of +2000 to À2000 mV, with a scan rate
of 100 mV sÀ1 was used.
2.4.2. Cell culture and cytotoxicity determination
Three human cancer cell lines were used for in vitro screening
experiments; breast cancer (MCF7), colon Carcinoma (HCT) and hu-
man heptacellular Carcinoma (Hep-G2). They were obtained frozen
in liquid nitrogen (À180 °C) from the American Type Culture Col-
lection. The tumor cell lines were maintained in the National Can-
cer Institute, Cairo, Egypt, by serial sub-culturing. Cell culture
cytotoxicity assays were carried out as described previously [18].
RPMI-1640 medium was used for culturing and maintenance of
the human tumor cell lines [18]. Cells were seeded in 96-well
plates at a concentration of 5 Â 104–105 cell/well in a fresh med-
ium and left to attach to the plates for 24 h. Growth inhibition of
cells was calculated spectrophotometrically using a standard
method with the protein-binding dye sulforhodamine B (SRB)
[19]. The results were compared with a similar run of cis-platin
as an antitumor compound.
3. Result and discussion
3.1. IR spectral studies
The theoretical IR spectra of the benzimidazole L were obtained
at DFT/B3LYP level of theory using 6-311G(d,p) and LANL2DZ basis
sets. At this level of theory, the calculated harmonic force constants
and frequencies are higher than the experimental values, due to
basis set truncation and neglecting of electron correlation and
mechanical anharmonicity [20]. To compensate these shortcom-
ings, scale factors were introduced and an explanation of this ap-
proach was discussed [21]. Two different methods were applied:
(i) uniform scaling [21], the scaling factors are 0.963 for 6-
311G(d,p) and 0.970 for LANL2DZ basis sets; (ii) linear regression
method [22], in this method, the plot of the calculated frequencies
versus their experimental values resulted in a straight line, whose
2.3. Theoretical calculations
The molecular structure of the benzimidazole L in the ground
state was optimized by a DFT method using B3LYP functional
[10,11] combined with 6-311G(d,p) and LANL2DZ basis sets. Calcu-
lations were carried out using GAUSSIAN 03 [12]. The vibrational fre-
quencies of the benzimidazole (L) and the corresponding normal
modes were evaluated at the optimized geometry [13] using the
same basis sets. Vibrational modes were analyzed using GAUSSVIEW
software [14]. The main reason for choosing the LANL2DZ basis
set is its inclusion of relativistic effect that is essential for heavy
elements, e.g. Pd(II) and Pt(II), in order to compare between the
optimized structures of the ligand and its complexes. The 1H
NMR chemical shifts of the benzimidazole (L) were computed at
the B3LYP/6-311+G(2d,p) level of theory in the gaseous state by
applying the (GIAO) approach [15] and the values for the 1H-isotro-
equation was used to correct the calculated frequencies (mcalc).
The benzimidazole L has a strong intermolecular hydrogen
bond [3] N16–HÁ Á ÁN15 [23], which makes the IR spectrum shows
strong and broad absorption band in the region 3500–2200 cmÀ1
.
However, the band located at 3360 cmÀ1 is assigned to the

N.T. Abdel Ghani, A.M. Mansour / Inorganica Chimica Acta 373 (2011) 249–258
251
benzimidazolic NH (NHBz), while its theoretical value is observed
at 3497 cmÀ1 as calculated by 6-311G(d,p). This discrepancy may
be justified on the basis that the calculation was performed on a
single molecule in the gaseous state contrary to the experimental
values that were recorded in presence of intermolecular interac-
smaller than the calculated ones. However, the experimental
chemical shift of the NHBz proton is shifted towards higher mag-
netic field than the calculated one by 4.29 ppm, as previously re-
ported [31]. This may be due to neglect of the non-specific
solute–solvent interactions (in the gas phase), and the intermolec-
ular hydrogen bond in our calculations as compared with the
experimental chemical shifts that are obtained from the DMSO
solutions (hydrogen-bonded solvent).
tions. In complexes, the m
(NHBz) is observed at 3356 cmÀ1 (Pd-L)
and 3355 cmÀ1 (Pt-L). This confirms that the NHBz group remains
intact in the complexes [3,24].
The sharp band at 3479 cmÀ1 in the benzimidazole L is assigned
to
m(NHsec) that is in a good agreement with the theoretical value
3.3. Mass spectrometry
(Supplementary material, Table S1). This band is still observed in
its complexes, but it is shifted to lower frequencies and becomes
broad at 3386 cmÀ1 (Pd-L) and 3418 cmÀ1 (Pt-L) indicating its
involvement in the coordination sphere [25]. The band at
The electron impact mass spectra of the ligand L and its com-
plexes were recorded at 70 eV. The benzimidazole L has a strong
molecular ion peak at m/z 268, and decomposes to offer a peak
at m/z 131, which is assigned to 2-methylene benzimidazole. The
fragment at m/z 118 is recognized to the benzimidazole ring, while
that at m/z 93 is known to the aniline moiety. The mass spectrum
of Pd-L complex has M+ at m/z 481 corresponding to
[PdLCl2Á2H2O]+ with three fragmentation routes as shown in
Scheme 1.
1631 cmÀ1 is assigned to
m(C@N), which deviates from the un-
scaled vibration mode (1665 cmÀ1) and the previously reported
data [26] owing to the presence of intermolecular hydrogen bond.
It was found that the scaling is not necessary in the latter range as
previously reported [27]. In complexes, the
lower frequencies as compared with the free group resulting in
its overlapping with (C@C) in the same region and thus it is diffi-
m(C@N) is shifted to
m
The Pt-L complex has a strong M+ at m/z 534 owing to [PtLCl2]+
with three fragmentation routes. The first route is traced by a peak
at m/z 450 owing to elimination of NO2, Cl, and ionizable protons
from M+ followed by the removal of imidazolic NH group and
2C2H2 molecules from the benzimidazole ring to give a fragment
at m/z 350. Thus, the participation of C@Npy in the chelation intro-
duces a weakness point through which the benzimidazole ring
decomposes to imidazole moiety. The second route involves the
loss of 2Cl and oxygen gas to provide a peak at m/z 431. The third
route engages the loss of C2H2 from the benzimidazole ring to give
a fragment at m/z 509.
cult to assign this vibration mode experimentally.
Unfortunately, the metal–nitrogen stretching bands could not
be distinguished from other ring skeleton vibrations present in this
region [3]. The far-IR spectrum of Pd-L complex shows two med-
ium bands at 368 and 362 cmÀ1 due to
m(Pd–Cl) in a cis-square pla-
nar structure [24]. Similarly, the platinum complex shows these
modes at 372 and 360 cmÀ1. The band at 850 cmÀ1 in the spectrum
of the palladium complex is assigned to the rocking mode of the
water of hydration [28]. Other vibration modes of the benzimid-
azole L are assigned (Supplementary material, Table S1). Finally,
IR study reveals that the ligand coordinated to the metal ions via
the pyridine-type nitrogen (Npy) of the benzimidazole ring and sec-
ondary amino group (NHsec).
3.4. Electronic absorption
3.4.1. Electronic absorption spectra in organic solvents
3.2. 1H NMR studies
The electronic spectrum of L displayed five absorption bands
in ethanol. The first and second bands at 206 and 230 nm may
The NHBz signal appears at 12.39 ppm [29] in the benzimidazole
L and moves downfield in its complexes; 13.36 ppm for Pd-L and
13.61 ppm for Pt-L complex. This shift is related to the charge den-
sity change in the benzimidazole ring, which supports the fact that
the coordination occurs via the pyridine-type nitrogen. The triplet
signal at 6.69 ppm in the free ligand is due to the NHsec group that
is obscured by the aromatic signals, whereas the doublet signal at
4.64 ppm is assigned to the CH2 group. In complexes, both signals
move downfield owing to the participation of the NHsec group in
the chelation (Supplementary material, Fig. S1). The methylene
group appears as a pair of quartet at 5.14 and 5.52 ppm for Pd-L
and 4.81 and 4.94 ppm for Pt-L, as the CH2 protons are no longer
isochronous, where the equatorial proton points away from the
metal ion than the axial one does.
be assigned to the medium and low energy p–
p⁄ transitions with-
in the phenyl rings of the aniline and benzimidazole moieties,
respectively [32]. The shoulder at 240 nm and the bands at 273
and 280 nm may be assigned to
ized -electron system and in the heteroatomic groups inside
p–
p⁄ transitions in the delocal-
p
the benzimidazole molecule [33] as the n–p⁄ transition is not ob-
served in the benzimidazole compounds [34,35]. The bands at
273 and 280 nm appear doublet due to probable existence of a
tautomeric structure [36] as supported by comparing our spec-
trum with that of 1-methyl-2-phenyl-benzimidazole [34], where
this fine structure is lost. The longer wavelength band at
370 nm can be assigned to an intramolecular charge transfer
interaction from the aromatic nucleus to the neighboring nitro
acceptor center [32].
The protons of the aniline ring give rise to four-line pattern at
6.59, 6.75 ppm for the two protons in the ortho-position with re-
spect to NHsec and 7.93, 8.03 ppm with respect to the nitro group.
However, the signals of the benzimidazole protons are much
broader [30] and are shown at 7.14, 7.15, 7.49, and 7.55 ppm. In
complexes, the aromatic protons nearest the coordination centers
are found to suffer maximum downfield shifts compared with
the other aromatic protons.
The calculated chemical shifts of the methylene (4.69 ppm) and
the NHsec (6.52 ppm) groups in the benzimidazole (L), are in agree-
ment with the experimental values. The theoretical chemical shifts
at 8.03, 7.93, 6.75, and 6.59 ppm in the benzimidazole L are as-
signed to the aromatic protons of the aniline moiety, while the sig-
nals at 7.55, 7.49, 7.15, and 7.14 ppm are attributed to the
benzimidazolic protons. Thus, the experimental values are slightly
The absorption spectrum of L was observed in solvents of differ-
ent polarity and of hydrogen bond formation tendency. The two
bands at 274 and 280 nm in the cylcohexane (reference solvent)
are slightly blue shifted in ethanol and 2-propanol (hydrogen-
bonding solvents) suggests that the benzimidazole L is acting as
a proton acceptor [37] at the pyridine-type nitrogen. However,
the latter bands are red-shifted in DMF and DMSO (hydrogen bond
acceptor solvents) due to an almost proton transfer from the solute
molecules to these solvents. On the other hand, the CT band
(370 nm) displayed a red shifted with increasing the solvent polar-
ity, except for acetonitrile and dioxane, owing to a higher solvent
stabilization of the excited state as the solvent polarity increases
[32]. The values of the observed transition energies (Eobs) and oscil-
lator strengths (fobs) of all the bands in the electronic spectra of the
benzimidazole L in different solvents were calculated [32] and

252
N.T. Abdel Ghani, A.M. Mansour / Inorganica Chimica Acta 373 (2011) 249–258
Cl
Cl
Pd
B
O
A
N
N
N
2H2O
A
O
N
H
A
H
B
m/z = 481 (12%)
A
Cl
Cl
Cl
Cl
Cl
Cl
Pd
NH2
N
Pd
Pd
O
N
N
N
N
H2C
N
CH2
O
H
N
m/z = 397 (10%)
m/z = 342 (8%)
m/z = 307 (19%)
N
O2N
Cl
Pd
H2C
m/z = 138 (28%)
Pd
N
N
N
N
NH
O
H
CH2
N
H
N
m/z = 255 (10%)
m/z = 131(8%)
m/z = 362 (10%)
Pd
N
N
H2C
m/z = 92 (80%)
H
N
H
m/z = 226 (9%)
m/z = 118 (8%)
Scheme 1. Fragmentation pattern of Pd-L complex.
Table 1
Maximum wavelength (kmax, nm), wavenumber (cmÀ1), molar absorptivity (
e
max, L molÀ1 cmÀ1),
p
–
p⁄ transition energy (Eobs), and oscillator strength (fobs), of benzimidazole L in
different solvents.
mmax  104 (cmÀ1
)
emax  104
Eobs (eV)
fobs
Solvent
kmax (nm)
mmax  104 (cmÀ1
)
emax  104
Eobs (eV)
fobs
ꢀ
ꢀ
Solvent
kmax (nm)
Cyclohexane
248
274
280
368
275
282
387
4.03
3.65
3.57
2.72
3.64
3.55
2.58
0.96
0.81
0.80
1.61
0.14
0.14
1.94
5.01
4.53
4.43
3.37
4.52
4.40
3.21
0.09
0.02
0.01
0.38
0.01
0.01
0.35
Acetonitrile
232
274
280
368
235
274
281
362
235
273
280
370
4.31
3.65
3.57
2.72
4.26
3.65
3.56
2.76
4.26
3.66
3.57
2.70
1.07
0.57
0.61
1.78
1.57
0.68
0.71
1.83
0.67
0.46
0.52
1.73
5.35
4.53
4.43
3.37
5.28
4.53
4.42
3.43
5.28
4.55
4.43
3.36
0.23
0.01
0.01
0.43
0.28
0.01
0.01
0.43
0.11
0.01
0.01
0.41
DMSO
DMF
Dioxane
263
274
281
382
206
230
273
280
370
3.80
3.65
3.56
2.62
4.85
4.35
3.66
3.57
2.70
1.04
0.50
0.43
1.96
1.27
2.05
1.12
1.18
3.17
4.72
4.53
4.42
3.25
6.03
5.40
4.55
4.43
3.36
0.03
0.01
0.01
0.37
0.25
0.53
0.02
0.02
0.79
2-Propanol
Ethanol
tabulated in Table 1. Application of dielectric relation [32] to the
band at 370 nm did not give a linear relation indicating that the
spectral shifts are not governed solely by the dielectric effect of
the solvents. However, the effects of solvent dipolarity/
polarizability and hydrogen bonding on this band are interpreted
by means of a linear solvation energy relationship [38], which
indicates that the solvatochromism is mainly due to solvent
dipolarity/polarizability.
3.4.2. Electronic absorption spectra in solutions of varying pH
The absorption spectra of 3 Â 10À5 M solutions of compound L
in 20% (v/v) ethanolic solutions of varying pH values were scanned
in the UV–Vis. range. The CT band at 370 nm in ethanol is red
shifted over the entire pH range from 376 nm (pH 2–4) to
386 nm at pH 12. This may be due to the lower percentage of eth-
anol in the buffering medium and the presence of water as the
highly polar solvent. This is confirmed by observing the position

N.T. Abdel Ghani, A.M. Mansour / Inorganica Chimica Acta 373 (2011) 249–258
253
of this band at 387 nm in DMSO as previously discussed. With
increasing [H+], a shoulder appears at 219 nm (pH 2) and vanishes
with rising pH, corresponding to the deprotonation of pyridine-
type nitrogen. The bands located at 273 and 280 nm in ethanol
are blue shifted to 269 and 275 nm in the pH 2–4 (as found in eth-
anol and 2-propanol) owing to the protonation of Npy and NHsec
and these bands retain their positions between pH 6–12. The pH-
absorbance changes [39] were utilized to calculate the acid disso-
ciation constants. Four pKa values were reported. The first one is
2.40 0.02 corresponding to deprotonation of the protonated
NHsec. The pKa value 5.21 0.12 may be attributed to the ionization
of the protonated Npy [35]. The third pKa 7.52 0.03 is accounted
for the ionization of the NHsec group, while the fourth pKa
11.57 0.02 is attributed to deprotonation of the NHBz group.
63.36%). Desorption of these water molecules at relatively high
temperature indicates the involvement of these molecules in
hydrogen bond as confirmed from its mass spectrum, where a frag-
ment at m/z 481 corresponding to [PdLCl2]Á2H2O was found. The fi-
nal stage (620–1200 °C) brings the total mass loss up to 80.70% of
the parent complex (80.19%) with a Pd as a final residue.
Discussing the simultaneous TGA/DTA curves constructed for
Pt-L complex, one can observe two endothermic mass loss stages
at 250 and 397 °C. The first stage is assigned to the exclusion of
one chlorine atom with a mass loss 6.75% (calcd. 6.55%). The
second step brings the total mass loss up to 60.06% of the parent
complex (calcd. 61.24 %) with a Pt + C as a final residue [42].
Coats–Redfern [43] and Horowitz–Metzger methods [44] are used
to calculate the thermodynamic parameters from TGA curves. It is
found that the E⁄ and
mal stage to another for a given complex, indicating that the rate of
decomposition decreases in the same order. The positive
H⁄ val-
ues mean endothermic processes, while the negative
S⁄ values
D
G⁄ values increase on going from one ther-
3.4.3. Electronic absorption spectra of complexes
D
The electronic spectra of 10À4 M of the studied complexes were
scanned in DMF. The two bands between 270 and 280 nm (35 714–
37 000 cmÀ1) in the complexes are assigned to internal ligand tran-
D
indicate that the complexes are formed spontaneously and are
highly ordered in their activated states.
sitions (p–
p⁄ in the benzimidazole ring). It is possible to calculate
the value of D1 from the first spin allowed d–d transition [40].
3.6. Theoretical calculations
The first low energy spin allowed bands at 20 408 cmÀ1
(
D1 = 22 508 cmÀ1, log
e
max = 4.12) and 21 231 cmÀ1
(
D1 = 23 331
max = 4.06) in Pd-L and Pt-L complexes, respectively,
have been assigned to the transition 1A1g ? 1A2g
1). While, the
band near 26,041 cmÀ1 in Pd-L (log
max = 3.40) is assigned to
1A1g ? 1B1g 2). The band at 27 027 cmÀ1 (log
max = 3.45) in Pt-L
complex is assigned to a combination of MLCT and 1A1g ? 1Eg band
3) [41]. Thus, the electronic spectra of these complexes are indic-
3.6.1. Geometry optimization
cmÀ1, log
e
Full geometry optimizations were performed at the DFT level of
theory [13]. The optimized bond lengths of C@N and C–NH in the
benzimidazole ring of compound L are 1.308 and 1.380 Å for
B3LYP/6-311G (Supplementary material, Table S2). This discrep-
ancy between C@N and C–NH, confirms that the hydrogen atom
is fixed at one of the two nitrogen atoms through intermolecular
hydrogen bond. These values coincide with those found from the
optimization of 2-methylbenzimidazole and benzimidazole [45]
under the same level of theory. The bicycle system of 2-methyl-
benzimidazole is planar [46] and the methyl group deviates from
the planarity by 0.054°. Substitution of one hydrogen atom by 4-
nitroaniline moiety shows essentially non-planar structure with
dihedral angle N15–C7–C8–N17 = 126.6° between the benzimidazole
and aniline moieties. In addition, these latter bonds have a shorter
distance than any amine compound, which is due to the participa-
tion of the lone electron pair of nitrogen atom in the resonance of
the benzimidazole ring. The benzimidazole L shows accumulation
of the negative charge density on the pyridine-type nitrogen,
which is a very important structural feature related directly to
the ability to bind the metal ions. Several calculated thermody-
namic parameters are reported as (Supplementary material,
Table S2).
(m
e
(m
e
(m
ative of square planar geometry [41].
On the other hand, the benzimidazole L is considered to be
excellent selective chromphoretic reagent for Pd(II) metal ion, this
is indicated by the large difference in kmax between the free ligand
and the Pd-L complex (Fig. 2). It was found that, there is a differ-
ence of about 30 nm between the maximum wavelengths in the
acidic and basic medium, and this may be due to conversion of di-
chloro palladium complex into dihydroxo one with increasing of
pH.
3.5. Thermal analyses and kinetics studies
The TGA/DTA curves of Pd-L complex represent four decompo-
sition steps. The first two endothermic stages at 72 and 240 °C are
responsible for desorption of 3H2O hydrated molecules. The third
endothermic peak at 366 °C is assigned to elimination of 2H2O, Cl
and one L molecule with a mass loss amounting to 63.20% (calcd.
The fully optimized geometries of cis-PdLCl2 and cis-PtLCl2 and
numbering of atoms are shown in Fig. 3 and their selected geo-
metric parameters are listed in Table 2. The coordination sphere
around the metallic center in cis-PdLCl2 and cis-PtLCl2 complexes
is made up of Npy, NHsec and 2Cl completing the square planar
geometry. The four donor atoms are coplanar, while the phenyl
ring is bent out of the coordination plane by angle 88.861° and
157.428° for cis-PdLCl2 and cis-PtLCl2 complexes, respectively.
It was found that the Pd–NHsec bond length is about 5.31% long-
er than the Pd–Npy bond distance [47]. It is seen that the optimized
Pd–NHsec and Pd–Npy bond lengths in cis-PdLCl2 complex are
slightly longer than the Pt–NH3 bond distance in cis-platin by
0.17 and 0.06 Å, respectively, while the Pd–Cl bond lengths are
longer than Pt–Cl by 0.05 and 0.03 Å for M–Cl22 and M–Cl23,
respectively, owing to the trans-effect. Finally, the Pd–Npy
(2.07 Å) and Pd–NHsec (2.186 Å) bond lengths are in good agree-
ment with that observed in some benzimidazole complexes [48].
The C13N11 and C14N21 bond lengths in cis-PdLCl2 were in-
creased upon the coordination of Npy, and NHsec to the metal center
as shown in Table 2. On the other hand, the Pt–NHsec and Pt–Npy
pH = 5
2
pH = 6
pH = 7
pH = 8
pH = 9
pH = 10
pH = 11
pH = 12
1.5
1
0.5
0
425
475
525
575
625
Wavelength, nm
Fig. 2. Electronic absorption spectra of Pd-L complex in buffer solutions of varying
pH.

254
N.T. Abdel Ghani, A.M. Mansour / Inorganica Chimica Acta 373 (2011) 249–258
Fig. 3. Optimized structures of (a) cis-PdLCl2 and (b) cis-PtLCl2 complexes.
Table 2
Selected bond lengths (Å), angles (°) and charge for cis-PdLCl2 and cis-PtLCl2 complexes.
cis-PdLCl2
cis-PtLCl2
Bond lengths (Å)
Bond angles (°)
Charge
Bond lengths (Å)
Bond angles (°)
Charge
C1C2
C2C3
C3C4
C4C5
1.425
C1C2C3
C2C3C4
C3C4C5
C4C5C6
C5C6C1
C6C1C2
121.005
116.969
121.751
121.668
116.458
122.148
107.566
107.675
111.179
108.629
117.706
118.266
119.960
119.041
121.739
118.989
120.005
120.259
80.555
C1 = 0.151
C2 = 0.149
C1C2
C2C3
C3C4
C4C5
1.425
C1C2C3
C2C3C4
C3C4C5
C4C5C6
C5C6C1
C6C1C2
120.752
117.058
121.854
121.511
116.497
122.326
107.346
107.678
111.350
108.594
111.854
119.476
119.859
118.518
122.173
118.784
119.652
120.995
81.0082
90.7672
123.908
C1 = 0.154
C2 = 0.149
1.406
1.402
1.422
1.404
1.409
1.411
1.337
1.378
1.505
1.502
1.455
1.413
1.398
1.407
1.404
1.401
1.411
2.070
2.186
2.384
2.360
1.474
1.279
1.281
1.407
1.402
1.421
1.403
1.415
1.409
1.338
1.376
1.497
1.522
1.471
1.405
1.403
1.403
1.407
1.399
1.407
2.052
2.155
2.400
2.390
C3 = À0.187
C4 = À0.210
C5 = À0.195
C6 = À0.249
N11 = À0.561
N12 = À0.602
C13 = 0.468
C3 = À0.186
C4 = À0.211
C5 = À0.195
C6 = À0.250
N11 = À0.561
N12 = À0.597
C13 = 0.469
C14 = À0.242
C15 = 0.197
C16 = À0.226
C17 = À0.169
C18 = 0.079
C19 = À0.166
C20 = À0.217
N21 = À0.699
Cl22 = À0.514
Cl23 = À0.481
Pt = 0.618
C5C6
C5C6
C2N11
C1N12
C13N11
C13N12
C13C14
C14N21
C15N21
C15C16
C16C17
C17C18
C18C19
C19C20
C15C20
N11Pd
N21Pd
Cl22Pd
Cl23Pd
N33C18
N33O34
N33O35
C2N11
C1N12
C13N11
C13N12
C13C14
C14N21
C15N21
C15C16
C16C17
C17C18
C18C19
C19C20
C15C20
N11Pt
C2N11C13
C1N12C13
N11C13N12
C13C14N21
C14N21C15
N21C15C16
C15C16C17
C16C17C18
C17C18C19
C18C19C20
C19C20C15
C20C15C16
N11PdN21
Cl22PdCl23
O34N33O35
C2N11C13
C1N12C13
N11C13N12
C13C14N21
C14N21C15
N21C15C16
C15C16C17
C16C17C18
C17C18C19
C18C19C20
C19C20C15
C20C15C16
N11PtN21
Cl22PtCl23
O34N33O35
C14 = À0.252
C15 = 0.193
C16 = À0.214
C17 = À0.167
C18 = 0.071
C19 = À0.169
C20 = À0.252
N21 = À0.693
Cl22 = À0.542
Cl23 = À0.485
Pd = 0.685
94.889
123.828
N21Pt
Cl22Pt
Cl23Pt
N33 = 0.44352
O34 = À0.36389
O35 = À0.37392
N33 = 0.445
O34 = À0.367
O35 = À0.363
E (a.u.)
À1066.689
À1059.102
Zero-point E (kcal molÀ1
)
159.305
159.28091
Rotational constants (GHz)
0.242, 0.125, 0.096
0.394, 0.093, 0.080
Entropy (cal molÀ1 KÀ1
Translational
Rotational
)
44.161
35.954
75.323
14.904
44.706
35.944
77.816
16.887
Vibrational
Total dipole moment (D)
bond lengths in cis-PtLCl2 complex are shorter than the corre-
sponding ones in the palladium complex by 0.02 and 0.03 Å,
respectively.
The optimized N11–Pd–N21 (80.555°) is smaller than that
found in cis-platin (NH3–Pt–NH3) by 6.445° and this can be inter-
preted in terms of CH2 group, which connects the two coordination
sites and prevent opening of this angle. The calculated Cl22–
Pd–Cl23 (94.889°) angle is larger than the experimental one in
cis-platin molecule by 2.989° [49], since the intramolecular hydro-
gen bonding N21–H27Á Á ÁCl22 (2.731 Å) opens up this angle. The
optimized N11PtN21 is close to that found in cis-PdLCl2 complex,
while the Cl18PtC19 is slightly different from that exists in cis-pla-
tin by 2.99°. This indicates that there is a weak or almost no intra-
molecular hydrogen bonding as found in the cis-PdLCl2 and this
may be attributed to the significant difference in the bending angle
of aniline ring as previously mentioned.

N.T. Abdel Ghani, A.M. Mansour / Inorganica Chimica Acta 373 (2011) 249–258
255
3.6.2. Natural bond orbital (NBO) analysis
The strength of this interaction can be estimated by the second or-
der perturbation theory.
The natural bond orbital (NBO) analysis of cis-PdLCl2 complex
was performed and could be used to estimate the delocalization
of electron density between occupied Lewis-type orbitals and for-
mally unoccupied non-Lewis NBOs (antibonding or Rydberg),
which corresponds to a stabilizing donor–acceptor interaction
[50]. Table 2 collects the natural charges on atoms. The largest neg-
ative charges are located on the two nitrogen atoms, Npy (À0.561e)
and NHsec (À0.693e). Thus, the bond lengths of PdNpy and PdNHsec
are different. According to the NBO, the electron configuration of
Pd is: [core]5s0.354d8.945p0.025d0.016p0.01. Thus, 36 core electrons,
9.29 valence electrons (on 5s and 4d atomic orbitals) and 0.036
Rydberg electrons (mainly on 5p, 5d and 6p orbitals) give the
45.315 electrons. This is consistent with the calculated natural
charge on Pd atom (+0.685) in the palladium complex, which cor-
responds to the difference between 45.315e and the total number
of electrons in the isolated Pd atom (46e). In addition, the two chlo-
rine atoms (Cl22 and Cl23) have larger negative charge À0.542e
and À0.485e, respectively. Thus, the positive atomic charge upon
the Pd(II) was substantially reduced as a consequence of electron
Table 4 lists the selected values of the calculated second order
interaction energy (E2) between donor–acceptor orbitals in cis-
PdLCl2 complex. The strongest interactions are the electron dona-
tions from LP(1)N11 to the antibonding acceptor r⁄(Pd–Cl22) orbi-
tals, e.g. LP(1)N11 ? r⁄(Pd–Cl22). As shown in Table 3, the
LP(1)N11 orbital has 69.39% p-character and is occupied by 1.728
electrons (this is consistent with a delocalization of electron den-
sity from the idealized occupancy of 2.0e). The donation of electron
density from the coordination sites in the ligand to the Pd molec-
ular orbitals has a clear correspondence to a chemical picture of
the coordination bonds.
3.6.3. Frontier molecular orbitals
The frontier molecular orbitals play also an important role in
the electric and optical properties, as well as in UV–Vis. spectra
and chemical reactions [51]. Fig. 4 shows the distributions and en-
ergy levels of the HOMOÀ1, HOMO, LUMO and LUMO+1 orbitals
computed at the B3LYP/LANL2DZ level for cis-PdLCl2 complex.
The values of the energy separation between the HOMO and LUMO
are 3.02 and 3.32 eV for cis-PdLCl2 and benzimidazole L,
respectively.
density donation from 2Cl, Npy and NHsec
.
Table 3 lists the calculated occupancies of natural orbitals.
Three classes of NBOs are included, the Lewis-type (s and p bond-
ing or lone pair) orbitals, the valence non-Lewis (acceptors, for-
mally unfilled) orbitals and the Rydberg NBOs, which originate
from orbitals outside the atomic valence shell. The calculated nat-
ural hybrids on atoms are also given in this Table 3. According to
calculations, the palladium atom forms two sigma bonds with
two chlorine atoms, while the two bonds between palladium and
the nitrogen atoms can be described as donation of electron den-
sity from a lone pair (LP) orbital on each nitrogen atom to palla-
3.7. Electrochemical studies
The redox behavior of the benzimidazole L and its Pd-L and Pt-
L complexes were studied by cyclic voltammetry (CV) in DMF.
The cyclic voltammogram of L displayed two reversible and qua-
si-reversible reduction peaks at E1/2 = À1.42 and À1.05 V. The first
peak could be assigned to a four-electron reduction of nitro group
generating the hydroxylamine derivative according to [52]: R-
NO2 + 4eÀ + 4H+ ? R-NHOH + H2O. The second cathodic peak as-
signed to the further reduction of the hydroxylamine to p-amino
derivative. On the other hand, the irreversible anodic peak at
0.08 V is attributed to oxidization of the secondary amino group.
In addition, the CV of the palladium complex exhibited two
reversible reduction peaks (ipa/ipc is unity) at À1.10 and À0.60 V
dium molecular orbitals. As follows from Table 3, the
r(Pd–Cl22)
bond is formed from an sp0.01d1.09 hybrid on palladium atom
(which is the mixture of 47.53% s, 0.47% p and 52.00% d atomic
orbitals) and sp13.62 hybrid on the chlorine atom (93.16% p contri-
bution). The results from NBO analysis show that the
r(Pd–Cl22)
bond is strongly polarized towards the chlorine atom, with about
78.90% of electron density concentrated on the chlorine atom.
Table 3
Occupancy of natural orbitals (NBOs) and hybrids calculated for cis-PdLCl2 (selected).
Donora Lewis-type NBOs (A–B)
Occupancy
1.977
Hybridb
AO (%)c
Acceptord nonLewis NBOs
NBOs
0.033
r(C2–N11)
r(C13–N11)
p(C13–N11)
r(C14–N21)
r(C15–N21)
r(Pd–Cl22)
r(Pd–Cl23)
r(N21–H27)
sp1.93 (N11)
sp2.57 (C2)
sp1.84 (N11)
sp2.12 (C13)
sp (N11)
s(34.18)p(65.82)
s(27.97)p(72.03)
s(35.24)p(64.76)
s(32.10)p(67.90)
s(0.01)p(99.99)
r⁄(C2–N11)
1.978
1.899
1.980
1.985
1.935
1.928
r⁄(C13–N11)
p⁄(C13–N11)
r⁄(Cl4–N21)
r⁄(C15–N21)
r⁄(Pd–Cl22)
r⁄(Pd–Cl23)
0.023
0.429
0.022
0.038
0.324
0.268
sp99.99 (C13)
sp2.52 (N21)
sp3.43(C14)
Sp1.95 (N21)
sp2.75 (C15)
sp0.01d1.09 (Pd)
sp13.62 (C122)
sp0.01d1.03 (Pd)
sp15.68 (C123)
sp2.94 (N21)
sp2.27
s(0.01)p(99.99)
s(28.41)p(71.59)
s(22.56)p(77.44)
s(33.12)p(66.88)
s(33.78)p(66.13)
s(47.53)p(0.47)d(52.00)
s(6.84)p(93.16)
s(48.91)p(0.52)d(50.57)
s(6.00)p(94.00)
1.980
1.728
1.713
1.991
1.989
1.995
1.991
1.988
s(25.39)p(74.61)
s(30.61)p(69.39)
s(12.31)p(87.69)
s(79.52)p(20.48)
s(64.92)p(35.08)
s(0.30)p(0.07)d(99.63)
s(0.68)p(0.06)d(99.26)
s(1.53)p(0.05)d(98.42)
LP(1)N11
LP(1)N21
LP(1)Cl22
LP(1)Cl23
LP(1)Pd
RY⁄(1)N11
RY⁄(1)N21
RY⁄(1)Cl22
RY⁄(1)Cl23
RY⁄(1)Pd
0.008
0.007
0.0003
0.0004
0.017
0.003
0.002
sp7.12
sp0.26
sp0.54
sp0.21d99.99
sp0.08d99.99
sp0.03d64.23
LP(2)Pd
LP(3)Pd
RY⁄(2)Pd
RY⁄(3)Pd
a
b
c
LP(n)A is a valence lone pair orbital (n) on A atom.
Hybrid on A atom in the A–B bond or otherwise, as indicated.
Percentage contribution of atomic orbitals in NBO hybrid.
d
Starred label (*) denotes antibonding, and Ry corresponds to the Rydberg NBO orbital.

256
N.T. Abdel Ghani, A.M. Mansour / Inorganica Chimica Acta 373 (2011) 249–258
Table 4
6.0e-5
Second-order interaction energy (E2, kcal/mol) between donor and acceptor orbitals
4.0e-5
2.0e-5
0.0
in cis-PdLCl2 complex calculated at B3LYP/LANL2DZ level of theory (selected).
Donor ? acceptor
E2
Donor ? acceptor
E2
LP(1)N11 ? r⁄(Pd–Cl22)
66.85
45.85
14.09
r
r
r
(N11–C13) ? r⁄(Pd–Cl22)
(N21–H27) ? r⁄(Pd–Cl23)
(N21–C14) ? r⁄(Pd–Cl23)
3.56
3.02
1.72
LP(1)N21 ? r⁄(Pd–Cl23)
-2.0e-5
-4.0e-5
-6.0e-5
-8.0e-5
-1.0e-4
-1.2e-4
-1.4e-4
r
(Pd–Cl23) ? r⁄(Pd–Cl22)
corresponding to reduction of nitro group as shown in Fig. 5. The
reduction process is shifted towards lower potential revealed an
enhancement of the reduction process in the presence of palla-
dium. The disappearance of anodic process indicated the partici-
pation of the secondary amino group in the complex formation.
On the other hand, the platinum complex showed the first reduc-
tion process at À1.12 V.
-1.5
-1.0
-0.5
0.0
0.5
Potential, V
It might be tempting now to correlate the values Ered derived
from CV with HOMO–LUMO energy differences obtained from
DFT calculations. The UV–Vis. absorption of a molecule corresponds
indeed to excitation of an electron from the HOMO into the LUMO,
whereas electro-oxidation corresponds only to the removal of an
electron from the HOMO. A correlation might be possible if reduc-
tion of this molecule (i.e. donation of an electron into the LUMO)
may be possible; in this case, the potential difference between oxi-
dation and reduction potentials may be correlated with the HOMO–
LUMO energy gap [53]. The potential difference between the reduc-
tion peaks (R-NO2 ? R-NHOH) in the benzimidazole and that of its
Pd-L complex is 0.32 V, which is in a good agreement with the shift
associated the HOMO–LUMO gaps on going from the benzimidazole
L to its palladium complex (0.30 eV). The DFT data have assigned
that the LUMO of the Pd-L complex is constituted mainly by the ni-
tro group of the ligand and thus the reduction is considered as elec-
tron accommodation at nitro dominated orbitals.
Fig. 5. Cyclic voltammogram of Pd-L complex.
In the present study, the molar conductance values of 10À3
for Pd-L and Pt-L in DMF revealed low conductance values 14.16
and 20.81
À1 cm2 moleÀ1, respectively, this may be taken as an
evidence for the presence of chlorine atoms inside the coordination
sphere of these complexes, indicating the non-electrolytic nature
of these complexes.
M
X
3.8. Biological activity studies
3.8.1. Antimicrobial activity
The data showed that the ligand L and its complexes have the
capacity of inhibiting the metabolic growth of the investigated
Fig. 4. Molecular orbital surfaces and energy levels of cis-PdLCl2 complex.

N.T. Abdel Ghani, A.M. Mansour / Inorganica Chimica Acta 373 (2011) 249–258
257
bacteria, B. subtilis, S. aureus and S. faecalis as Gram-positive bacte-
ria and P. aeruginosa, E. coli and N. gonorrhoeae as Gram-negative
bacteria, to different extents. The size of the inhibition zone de-
pends upon the culture medium, incubation conditions, rate of dif-
fusion and the concentration of the antibacterial agent (the activity
increases as the concentration increases). In the present study, the
benzimidazole L and its Pt-L complex are active against both types
of the bacteria, which may indicate broad-spectrum properties.
The remarkable activity of these compounds may be arising from
the benzimidazole ring, which may play an important role in the
antibacterial activity. The mode of action may involve the forma-
tion of a hydrogen bond through the tertiary nitrogen of the imid-
azole ring with the active centers of the cell constituents, resulting
in interference with the normal cell process.
The Pd-L complex is only toxic against E. coli and N. gonorrhoeae
as Gram-negative bacteria. The inhibitory activity of this complex
is related to the cell wall structure of the bacteria. This is possible
because the cell wall is essential to the survival of bacteria and
some antibiotics are able to kill bacteria by inhibiting a step in
the synthesis of peptidoglycan [54]. A possible explanation for
the poor activity of these complexes with respect to their ligand
may be attributed to their inability to chelate metals essential for
the metabolism of microorganisms and/or to form hydrogen bonds
with the active centers of cell structures, resulting in an interfer-
ence with the normal cell cycle. Furthermore, the low activity of
these complexes may be also due to their low lipophilicity, because
of which penetration of the complex through the lipid membrane
was decreased and hence, they could neither block nor inhibit
the growth of the microorganism. Therefore, we confirm that the
toxicity of the complexes can be related to the strengths of the
M–L bond, in addition to other factors such as size of the cation,
and receptor sites.
veals that the strong coordination bonds result from donation of
electron density from a lone pair orbital on the nitrogen atoms to
the acceptor metal molecular orbitals, e.g. (LP(1)N11 ? r⁄(Pd–
Cl22)) and (LP(1)N21 ? r⁄(Pd–Cl23)). It was found that the studied
compounds have the capacity of inhibiting the metabolic growth of
the investigated bacteria to different extents. In addition, the com-
plexes are toxic against three cell lines of different origin and rep-
resent an interesting class of new compounds from the viewpoint
of their physicochemical and structural properties. Based on the re-
sults obtained from the physico-chemical techniques and theoret-
ical calculations of the metal complexes, one can conclude that the
studied ligand behaves as a neutral bidentate ligand coordinated to
the metal ions via the pyridine-type nitrogen of the benzimidazole
ring and secondary amino group. Thus, square planar geometry is
suggested for the studied complexes, [PtLCl2] and [PdLCl2]Á5H2O.
Acknowledgments
We would like to extend our grateful thanks to Prof. Rifaat Hilal,
Chemistry Department, Faculty of Science, Cairo University for
allowing us to use his version of the GUASSIAN98W package of
programs.
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.ica.2011.04.036.
References
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3.8.2. Antitumor activity
To evaluate the potential usefulness of palladium and platinum
complexes synthesized as antitumor agents, three cell lines of dif-
ferent origin, breast cancer (MCF-7), colon Carcinoma (HCT) and hu-
man heptacellular Carcinoma (Hep-G2) were treated. All the studied
compounds showed activity against all the studied cell lines. On
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the studied cells at 100 lM. This happens because the ligand-ex-
change behavior of platinum compounds is quite slow, which gives
them a high kinetic stability and results in ligand-exchange reac-
tions of minutes to days, rather than microseconds to seconds for
many other coordination compounds. In addition, another unusual
phenomenon deals with the preferred ligands for platinum ions is
that Pt(II) has a strong thermodynamic preference for binding to S-
donor ligands and for this reason, one would predict that platinum
compounds would perhaps never reach DNA, with many cellular
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