Synthesis, crystal structure, spectral and electrochemical characterization, DNA binding and free radical scavenging studies of ferrocene-based thioureas

Article abstract of DOI:10.1080/00958972.2019.1651846

Thioureas are important building blocks in medicinal chemistry; ferrocenes as highly hydrophobic moieties induce very interesting qualities in medicinal compounds. In this article, we have synthesized four ferrocene incorporated N,N′-disubstituted benzoyl

Full text of DOI:10.1080/00958972.2019.1651846

Journal of Coordination Chemistry
ISSN: 0095-8972 (Print) 1029-0389 (Online) Journal homepage: https://www.tandfonline.com/loi/gcoo20
Synthesis, crystal structure, spectral and
electrochemical characterization, DNA binding and
free radical scavenging studies of ferrocene-based
thioureas
Bhajan Lal, Ammarah Kanwal, Ataf Ali Altaf, Amin Badshah, Faiza Asghar,
Sadia Akhter, Shafiqullah Marwat, Syed Ishtiaq Khan & Muhammad Nawaz
Tahir
To cite this article: Bhajan Lal, Ammarah Kanwal, Ataf Ali Altaf, Amin Badshah, Faiza Asghar,
Sadia Akhter, Shafiqullah Marwat, Syed Ishtiaq Khan & Muhammad Nawaz Tahir (2019):
Synthesis, crystal structure, spectral and electrochemical characterization, DNA binding and free
radical scavenging studies of ferrocene-based thioureas, Journal of Coordination Chemistry, DOI:
10.1080/00958972.2019.1651846
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JOURNAL OF COORDINATION CHEMISTRY
https://doi.org/10.1080/00958972.2019.1651846
Synthesis, crystal structure, spectral and electrochemical
characterization, DNA binding and free radical
scavenging studies of ferrocene-based thioureas
a
b
c
d
e
Bhajan Lal , Ammarah Kanwal , Ataf Ali Altaf , Amin Badshah , Faiza Asghar ,
c
c
c
Sadia Akhter , Shafiqullah Marwat , Syed Ishtiaq Khan and
Muhammad Nawaz Tahir
f
a
b
Institute of Chemistry, Shah Abdul Latif University, Khairpur, Pakistan; Cast Metals and Foundry
c
Technology Centre (CM and FT) PCSIR, Daska, District Sialkot, Pakistan; Department of Chemistry,
University of Gujrat, Hafiz Hayat Campus, Gujrat, Pakistan; Department of Chemistry, Quaid-i-Azam
d
e
University, Islamabad, Pakistan; Department of Chemistry, University of Wah, Wah, Pakistan;
f
Department of Physics, University of Sargodha, Sargodha, Pakistan
ABSTRACT
ARTICLE HISTORY
Thioureas are important building blocks in medicinal chemistry;
ferrocenes as highly hydrophobic moieties induce very interesting
qualities in medicinal compounds. In this article, we have synthe-
Received 22 February 2019
Accepted 19 July 2019
0
KEYWORDS
sized four ferrocene incorporated N,N -disubstituted benzoyl thio-
Ferrocene-based thioureas;
crystal structure; redox
nature; DFT calculations;
DNA binding; free
5 5 5 4 6 4
ureas (3a–3d) with general formula C H -Fe-C H C H Cl-NH-CS-
NH-CO-C H (H/CH ). Molecular structures of these compounds
6
4
3
were characterized in solid and solution phases. In solution
1
13
molecular structures were established by H and C NMR and
cyclic voltammetry. In the solid state their structures were charac-
terized by elemental analyses and FTIR spectroscopy. Two of the
compounds (3a and 3d) had also been structurally determined by
single crystal X-ray diffraction analysis. The electrochemical char-
acterization showed a reversible process with one electron trans-
fer from Fe(II) to Fe(III). The single crystal analysis showed strong
intermolecular non-covalent interactions in these compounds.
Molecular structures of these compounds were also studied by
density functional theory (DFT) calculation . DFT studies showed
good correlation between calculated parameters and experimen-
tal results of solution phase and solid state characterizations.
Compounds 3a–3d were evaluated for DNA interaction and anti-
oxidant activity. These compounds interact with DNA via electro-
static forces and liberate significant binding constants and
energies. Antioxidant potential –CSNH and –CONH groups induce
same level of free radical scavenging ability in these compounds.
radical scavenging
CONTACT Amin Badshah
aminbadshah@yahoo.com; Ataf Ali Altaf
atafali_altaf@yahoo.com
Supplemental data for this article is available online at https://doi.org/10.1080/00958972.2019.1651846.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group

2
B. LAL ET AL.
1. Introduction
For more than 50% of the treatments in the clinic to kill cancerous cells, platinum-
based drugs like cisplatin, carboplatin and oxaliplatin are used [1]. Despite their tre-
mendous success, their use has also been limited due to inherent and acquired resist-
ance and the presence of a number of dose-limiting side effects [2]. The cytotoxicity
of Pt-based anticancer drugs is related to their interaction with deoxyribosenucleic
acid (DNA) that ultimately inhibits the transcription and replication resulting in cell
death [3]. As a consequence of its particular chemical structure, cisplatin offers little
possibility for rational improvements to increase its tumor specificity and thereby
reduce undesired side effects. Organometallic compounds have recently been found
to be promising anticancer drug candidates [4]. Organometallic compounds have great
structural variety, far more diverse stereochemistry than organic compounds (for an octa-
hedral complex with six different ligands, 30 stereoisomers exist), and by rational ligand
design, provide control over key kinetic properties (such as hydrolysis rate of ligands) [5].
Furthermore, they are kinetically stable, usually uncharged, and lipophilic and their metal
is in a low oxidation state [6]. Typical classes of organometallic complexes such as metal-
locenes, half-sandwich, carbene-, CO-, or p-ligands, which have been widely used for
catalysis or bio-sensing purposes, have now also found application in medicinal chemistry
[7]. Among metallocenes, ferrocene and its derivatives have been studied as potential che-
motherapeutics [8, 9]. Thioureas are an important class of medicinal compounds [10–14].
Incorporation of ferrocenyl moiety in the structure of tamoxifen resulted in increased anti-
cancer activity [15]. The anticancer activity of ferrocene derivatives is dependent on the
oxidation state of iron in the ferrocene moiety with some results, indicating that the Fe(II)
ferrocenyl compound is more active than Fe(III) ones [16]. Electron transfer reactions
involving ferrocenium ion may generate reactive oxygen species (ROS) such as hydroxyl

JOURNAL OF COORDINATION CHEMISTRY
3
0
Scheme 1. The reaction scheme for synthesis of ferrocene incorporated N,N -disubstituted thioureas.
.
radicals ( OH). ROS can cause damage to DNA [17] and may also be responsible for anti-
cancer activity through the formation of radical metabolites that bring about biological
damage in cancer cells [18]. Some ferrocene-based thioureas bearing significant activity
have been published [19–22]. Herein we present the systematic synthesis, structural char-
acterization, redox behavior, extent of DNA binding and free radical scavenging potency
of some new ferrocene incorporated benzoylthioureas.
2. Results and discussion
2.1. Synthesis
0
The pathway adopted for synthesis of six new ferrocene incorporated N,N -disubsti-
tuted thioureas is sketched in Scheme 1. Compounds 3a–3d are synthesized by react-
ing 4-ferrocenyl-3-chloroaniline with freshly prepared isothiocyanates under N in dry
2
acetone [13, 19]. The compounds were structurally characterized by using different
analytical techniques.
2.2. Solution phase characterization
1
13
In the solution phase, all products were characterized by H and C NMR, and electro-
chemical characterizations were made by cyclic voltammetry.

4
B. LAL ET AL.
Figure 1. Cyclic voltammograms of 2 mM DMSO solution of 3d (representative compound) at dif-
ferent scan rates (50–250 mV/s), obtained on a three electrode system: platinum disc working elec-
trode, secondary calomel as reference electrode and platinum wire counter electrode.
1
13
The H and C NMR spectra of 3a–3d were taken in DMSO as reported in
1
Section 4. The H NMR data showed that unsubstituted Cp-ring of ferrocene dis-
played singlet for five protons at 4.22–4.17 ppm; however, the substituted Cp-ring
of ferrocene split into two signals in the region of 4.84–4.38 ppm. The methyl pro-
tons (attached to phenyl ring for 3b–3d) are at 2.58–1.28 ppm as singlets with inte-
gral value of three. The substituted aromatic ring gave signals at 7.91–7.56 ppm
[
19–22]. The –CSNH and –CONH protons are downfield at 12.74–8.84 ppm. The
multiplicity and intensity of signals were used to identify nonequivalent protons.
The integration curve revealed that protons present in the molecule and the area
under the curve were in agreement.
1
3
The C NMR spectral data of 3a–3d revealed that unsubstituted Cp-ring of ferro-
cene showed a singlet for five carbons at 69.86–69.73 ppm whereas the substituted
Cp-ring of ferrocene split into three signals, the ipso carbon (attached to phenyl ring)
at 83.68–83.49 ppm. The other two signals were at 68.87–67.94 ppm. The methyl car-
bon (attached to phenyl ring for 3b–3d) is at 21.79–20.23 ppm. Compounds 3a–3d
exhibited signals for aromatic carbons at 145.10–121.80 ppm. The two most downfield
signals are attributed to carbon of thiocarbonyl and carbonyl as weak signals at
1
13
1
78.01–166.92 ppm and 169.57–153.55 ppm, respectively [19–22]. The H and C NMR
data for 3a–3d are in agreement with the data for other similar compounds [19–22].
The cyclic voltammograms of 3a–3d were scanned using a three electrode system
2
in DMSO. Platinum disc working electrode, with surface area 0.071 cm , was used
along with a secondary calomel reference electrode and platinum wire was kept as
counter electrode. In cyclic voltammograms of 3d (Figure 1) obtained at 100 mV/s
scan rate, two signals were observed, one in forward scan at anodic potential (E ) of
pa
2
85 mV with anodic peak current (I ) of 2.6 mA and the other one in reverse scan at
pa
cathodic potential (E ) 223 mV with cathodic peak current (I ) of ꢀ2.4 mA. The change
pc
pc

JOURNAL OF COORDINATION CHEMISTRY
5
Figure 2. Cyclic voltammograms of 2 mM DMSO solution of 3a, 3c and 3d at 250 mV/s scan rates
voltammogram for 3b was recorded on 100 mV/s).
(
of scan rate on the voltammogram was studied by stepwise increments of 50 mV up
to the scan rate 250 mV/s (Figure 1). No significant change was observed in the
anodic/cathodic peak position by the variation of scan rate; increase in the magnitude
of current was observed upon increasing the scan rate, indicating the reversibility of
the electrochemical redox process [23]. The reversibility of the process was further
confirmed from magnitude of the ratio of cathodic to anodic peak current (Ipc/Ipa
¼
0
.92 ꢁ 1) that is almost equal to one [24]. The potential difference (DE ) between the
p
two peak potentials was DE ¼ E ꢀE ¼ 62 mV. This indicates that the number of
p
pc
pa
electrons involved in the electrochemical process is 58/62 ¼ 0.93 ꢁ 1 [25]. Hence, these
observations confirmed that the electrochemical reaction on the surface of platinum
disc working electrode is a one electron reversible redox process [25]. Different ferro-
cene compounds give Epa and Epc values of 200–820 mV and 140–780 mV, respectively,
þ
for reversible redox of ferrocene (Fc) to ferrocenium (Fc ) [20, 22, 26–28]. Therefore,
the electrochemical reaction can be associated with the reversible redox process of Fc
þ
þ
to Fc and Fc to Fc transformations in 3d on the surface of working electrode.
Compounds 3a–3c behave in a similar manner but are not discussed here. Figure 2
presents the voltammograms for these compounds. The diffusion of 3a–3d on the sur-
face of the electrode was calculated in terms of diffusion coefficient (D ) by using
o
Randles-Sevcik Equation (1) [25],
Ipa ¼ 2:69 ꢂ 10 n AC D t1=2
5
3=2
ꢃ
1=2
(1)
o
o
ꢀ
1
where Ipa is the anodic peak current in ampere, V is the scan rate in V s , Cₒ
⃰
is the
ꢀ
3
2
concentration in mol cm , A is the cross-sectional area of electrode in cm , n is the
number of electrons involved in the reaction and Dₒ is the diffusion coefficient in
2
ꢀ1
cm s . The data obtained are reported in Table 1 and the experimental data are pro-
vided in the Supplementary Material.

6
B. LAL ET AL.
Table 1. The electrochemical data (experimental electrode potentials compared with calculated
energies of HOMO and LUMO levels), diffusion coefficient (Dₒ) of free compound, compound-DNA
adduct, binding constant and binding energy of 3a, 3b, 3c and 3d.
Dₒ of free
Dₒ of compound-DNA
Binding
Binding
energy
(kJ mol )
E
pa, Epc
E
HOMO
E
LUMO
compound
adduct
constant
2
ꢀ1
2 ꢀ1
ꢀ1
ꢀ1
Compound
(mV)
(eV)
(eV)
(cm s
)
(cm s
)
(M
)
1.7 ꢂ 10ꢀ
7
7
7
7
2.9 ꢂ 10
3.6 ꢂ 10
6.8 ꢂ 10
8.8 ꢂ 10
ꢀ8
ꢀ8
ꢀ7
ꢀ8
3.1 ꢂ 10
2.4 ꢂ 10
2.8 ꢂ 10
4.1 ꢂ 10
3
3
3
3
19.92
19.28
19.66
20.61
3
3
3
3
a
b
c
718, 652
642, 578
518, 453
285, 223
ꢀ5.2455
ꢀ5.2461
ꢀ5.2300
ꢀ5.2268
ꢀ2.0637
ꢀ1.9579
ꢀ2.0109
ꢀ1.9886
ꢀ
2.0 ꢂ 10
ꢀ
2.0 ꢂ 10
d
2.4 ꢂ 10ꢀ
2.3. In-silico characterization by density functional theory (DFT)
Computational calculations were undertaken for these electro-active compounds in
order to complement the experimental results of cyclic voltammetry. The oxidation-
reduction potentials of the synthesized ferrocenyl thioureas measured from cyclic vol-
tammetry indicated parallel trend to that anticipated from the density functional the-
ory (DFT) work.
The ease of reduction of the complexes varies as 3a > 3b >3c > 3d. An analogous
trend was attained from the ELUMO values, i.e. the highest reduction potential and
most negative ELUMO value of 3a correspond to easiest reduction [29–31]. A more
negative ELUMO favors addition of electrons as the energies of the orbitals are lowered.
Figures 3 and 4 display the representative graphical demonstration of the HOMO and
LUMO orbitals of 3a and 3d, respectively. The HOMO orbitals are localized on the
ferrocene moiety (Fe metal), whereas the LUMO orbitals are extended over the thio-
urea functionality (containing electron-withdrawing N and O) and the terminal phenyl
ring. The HOMO-LUMO energy gaps were in close agreement with the electrochemical
band gaps computed from the difference between the oxidation and reduction poten-
tial of the species (Table 1) [32]. The EHOMO values acquired from DFT were compared
with the oxidation potentials achieved from the electrochemical measurements. The
oxidation potentials observed experimentally for 3a–3d fluctuate as 3d >3c > 3b >
3
a. This observation is supported from the DFT study by comparing the EHOMO values,
which are less negative for 3d, signifying its ease of oxidation as compared to other
compounds (Table 1).
DFT measurements also established the Mulliken charges on these molecular struc-
tures to determine the sites which are susceptible to electrophilic or nucleophilic
attack (Figure 5) [33]. The explored molecules 3a–3d have numerous probable sites
for electrophilic (denoted by red color) and nucleophilic attack (symbolized by green
color), as depicted in Figure 5(b,d) for 3a and 3d, respectively.
2
.4. Solid phase characterization
In the solid state, the products were characterized by Fourier Transformation Infrared
FTIR) spectroscopy, and 3a and 3d were also characterized by single crystal X-ray
diffraction.
The FTIR data are reported in Section 4. The data indicate that highest energy
vibrations for these compounds (thiourea’s N–H stretching bands) were observed at
(
ꢀ
1
ꢀ1
3247–3422 cm [12, 31]. A sharp signal at 1661–1673 cm was observed for amide

JOURNAL OF COORDINATION CHEMISTRY
7
Figure 3. Graphical demonstration of HOMO and LUMO energy levels of 3b.
based C ¼ O, in agreement with literature data [34–36]. A broad signal for 3a–3d was
ꢀ
1
observed from 1036 to 1275 cm
that originated from the thiourea C ¼ S [37].
However, the characteristic peak of the Fe-Cp stretching band appeared at
79–486 cm [35, 36] and other C ¼ C and C-H (sp and sp ) bands were observed in
ꢀ
1
3
2
4
their usual regions [38].
2.5. Single crystal X-ray studies
Careful crystallization of 3a and 3d in toluene by slow evaporation yielded orange
crystals suitable for single crystal X-ray diffraction analysis. Data pertaining to the data
collection and structure refinement show that 3a crystallized in the triclinic crystal sys-
ꢀ
tem with Pi space group. A multi-scan absorption correction method was used. The
other crystal parameters calculated at 296 K using Mo K (k ¼ 0.71073) radiation were
a
empirical formula C H FeN OSCl, unit cell dimensions a ¼ 7.6045(18) Å, b ¼ 11.712(3)
24
19
2
ꢄ
ꢄ
3
ꢄ
Å, c ¼ 11.841(3) Å, a ¼ 86.297(8) , b ¼ 86.760(8) , c ¼ 81.079(9) , M ¼ 474.77, volume ¼
3
1
038.5(4) Å , Z ¼ 2, Density ¼ 1.518 g/cm , F(000) ¼ 588.0, Crystal size ¼
3
0
.27 ꢂ 0.16 ꢂ 0.14 mm , index ranges (h, k, l)
¼ (9, 14, 14), (h, k, l)
¼ (ꢀ9, ꢀ14,
max
min

8
B. LAL ET AL.
Figure 4. Graphical demonstration of HOMO and LUMO energy levels of 3d.
Figure 5. Mulliken charge distribution on the optimized 3b designated by color change on the
atoms with color scheme and scale (red for negative charge and green for positive charge). The
numerical values of Mulliken charges for this molecule and all the other molecules calculated by
DFT can be seen in the electronic supplementary data (Table S1).

JOURNAL OF COORDINATION CHEMISTRY
9
Figure 6. Molecular structures (50% probability ORTEP) of 3a and 3d with numbering schemes.
ꢄ
ꢀ
14), total reflections ¼ 4087, Mu ¼ 0.974 mmꢀ1, hmax ¼ 26.00 , S ¼ 0.995, R ¼ 0.0662
and wR2 ¼ 0.1843.
ꢀ
Compound 3d crystallized in the triclinic crystal system with Pi space group. A
multi-scan absorption correction method was used. The other crystal parameters calcu-
lated at 296 K using Mo Ka (k ¼ 0.71073) radiation were empirical formula
C H FeN OSCl, unit cell dimensions a ¼ 7.7009(4) Å, b ¼ 11.7399(6) Å, c ¼ 11.9509(6)
2
5
21
2
ꢄ
ꢄ
ꢄ
3
Å, a ¼ 89.752(3) , b ¼ 88.039(2) , c ¼ 86.517(3) , M ¼ 488.80, volume ¼ 1077.83(10) Å ,
3
3
Z ¼ 2, density ¼ 1.506 g/cm , F(000) ¼ 504.0, crystal size ¼ 0.32 ꢂ 0.25 ꢂ 0.23 mm ,
index ranges (h, k, l)
¼ (9, 14, 14), (h, k, l)
¼ (ꢀ9, ꢀ14, ꢀ14), total reflections ¼
max
ꢀ
min
1
ꢄ
4250, Mu ¼ 0.941 mm , h
¼ 26.00 , S ¼ 1.027, R ¼ 0.0510 and wR2 ¼ 0.0859.
max
Interatomic distances, bond angles and torsion angles can be seen in the crystallo-
graphic information files provided as supplementary material of the article. Figure 6
represents the molecular structures with numbering scheme for 3a and 3d. The intra-
molecular hydrogen bonding and intermolecular interactions present in these com-
pounds are summarized in Table 2 and Figure 7.
The rings A (C6-C10), B (C11-C16), C (H , N1, C17, N2, C18, O) and D (C19-C24) in
N1
3
a and 3d are planar. In 3a, the root mean square (r.m.s) deviations of the rings A–D
from planarity are 0.0008, 0.0077, 0.0448 and 0.0044 Å, respectively; in 3d the r.m.s
deviations of the rings A–D from planarity are 0.0019, 0.0091, 0.0535 and 0.0083 Å,
respectively. Intramolecular hydrogen bonding in these structures exists as mentioned
in Figure 7 and Table 2. This intramolecular hydrogen bonding (NH—O type) is
responsible for the planarity of six atoms forming ring C in both compounds. This
intramolecular hydrogen bonding is well known for aroyl or acoyl substituted organic

1
0
B. LAL ET AL.
Table 2. The intramolecular and intermolecular hydrogen bond interactions in 3a and 3d.
ꢄ
H-bonding
X
H
Y
d(X–H) (Å)
d(H–Y) (Å)
d(X–Y) (Å)
<(XHY) ( )
3
a
Intramolecular
Intermolecular
Intermolecular
N1
N2
C24
H1a
H2a
H24
O
S
S
0.860
0.860
0.930
1.929
2.817
2.689
2.646
3.636
3.376
139.87
159.22
131.36
3
d
Intramolecular
Intermolecular
N1
N2
H1a
H2a
O
S
0.860
0.860
1.595
2.710
2.657
3.540
137.49
162.80
Figure 7. Dimeric structures of 3a and 3d mediated by hydrogen bonding interactions.
thioureas as we found in the ferrocene analogs [39–41]. This planarity normally spread
the p-electronic cloud over the conjugated system and compels rings A–D to be on a
sole surface, as reported for similar compounds [41, 42]. The presence of chloride on
ring B destroys the co-planarity of all the rings as indicated by the inter planar angles.
ꢄ
ꢄ
The inter planar angles between the planes in 3a and 3d are A/B ¼ 32.49 , 29.84 ; A/
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
C ¼ 7.07 , 5.59 ; A/D ¼ 7.21 , 16.35 ; B/C ¼ 25.46 , 27.38 ; B/D ¼ 38.87 , 45.6 and C/
ꢄ
ꢄ
D ¼ 13.94 , 18.31 , respectively. In 3d, the presence of methyl group (electron donor)
also disturbs the unidirectional charge flow and increases the inter planar angle
between rings C and D in comparison to that in 3a. However, the bond distances
between A and B rings 1.482(5) (for 3a), (C10–C11 ¼ 1.474(3) (for 3d), are less than the
normal C–C single bond distance 1.54 Å), indicating double bond character due to res-
onance over these rings.

JOURNAL OF COORDINATION CHEMISTRY
11
ꢀ
1
Figure 8. Cyclic voltammograms of 2 mM 3d at 150 mVs scan rate in the absence and presence
of 30–120 mM DNA, obtained on a three electrode system: platinum disc working electrode, sec-
ondary calomel as reference electrode and platinum wire counter electrode. (Inset) Plot of log (I/Io-
I) vs. log (1/[DNA]) for determination of binding constant.
The two independent molecules exist in an asymmetric unit which is connected
alternately to each other by the intermolecular hydrogen bonding of type NH—S,
CH—O and secondary non-covalent interactions (CH—S) to produce a dimeric struc-
ture as shown in Figure 7. These intermolecular non-bonding secondary interactions
are important for different properties [34, 43]. Literature studies demonstrate that
compounds with stronger nonbonding interactions have more ability to bind with bio-
logical macromolecules like proteins and DNA [34, 43]. Thus, we expect good bio-
logical activity and binding of these compounds with DNA.
2.6. DNA binding studies using cyclic voltammetry
The cyclic voltammograms of 3a–3d were utilized for probing reaction between DNA
and 3a–3d. Sample solutions in DMSO were prepared by fixing concentrations of test
compounds and varying concentrations of DNA. The freshly prepared solutions were
deaerated and placed for equilibration. These solutions were scanned for electrochem-
ical response under the same conditions as discussed in the previous section (solution
phase characterization by cyclic voltammetry). The cyclic voltammetry response thus
obtained is useful to elaborate the reaction between the test compounds and DNA.
For 3d (a representative example), the voltammogram obtained is presented in Figure
8
; there is decrease in the peak current values upon the addition of DNA to solution
of 3d. There is about 40% decrease in the peak current after the addition of 120 mM
DNA, suggesting formation of an adduct of 3d with DNA, which lowers the mobility
of 3d molecules and hence cause the decrease in current [25]. The peak potentials

1
2
B. LAL ET AL.
Figure 9. Variation in absorbance of DPPH spectrum with the increase in concentration of 3b in
65 mM DPPH solution in ethanol.
1
also change and shift to lower values; lowering of redox potentials indicate that DNA
facilitates the redox process of 3d by providing electronic charge density from its
phosphate backbone [22]. This provides evidence for electrostatic mode of interaction
between DNA and 3d [41]. Hence, the mode of interaction of 3d with DNA was elec-
trostatic as one can see cathodic shift and decrease in peak current on addition of
increasing concentrations of DNA [20].
Figure 8 further shows that continuous addition of DNA to the solution of 3d
changes the electrochemical behavior of 3d on the surface of the working electrode.
This change in electrochemical profile has been quantified in terms of binding con-
stant (K) and diffusion coefficient of 3d on electrode surface. The values of binding
constants (K) were calculated by the following equation [44]:
Log ð1=½DNAꢅÞ ¼ log K þ log ðI=I – IÞ
(2)
o
where I is the peak current of free 3d and I is the peak current of 3d-DNA adduct.
o
The obtained value of binding constant was utilized to calculate the change in Gibb’s
free energy (DG) of the reaction between 3d and DNA [44], according to the equation
(
DG ¼ ꢀRT lnK), and the calculated value is reported in Table 1 along with other data.
The moderate value of DG signifies spontaneity of the 3d-DNA interaction. The diffu-
sion coefficients (Dₒ) of free compounds and compound-DNA adducts were calculated
from Randles-Sevcik Equation (3) [25],
Ipa ¼ 2:69 ꢂ 10 n AC D t1=2
5
3=2
ꢃ
1=2
(3)
o
o
ꢀ
1
where Ipa is the anodic peak current in amperes, v is the scan rate in V s , Cₒ
⃰
is the
ꢀ
3
2
concentration in mol cm , A is the cross-sectional area of electrode in cm and n is
the number of electrons involved in the reaction. The compound-DNA adduct forma-
tion can be justified as free molecules (with low molecular weight) easily diffuse and
show more peak current, whereas when interacting with DNA, the quantity of free
molecules became less, as a result decrease in current was observed and hence the
lower value of Dₒ. The other compounds 3a–3c responded similarly when studied for
DNA interaction. Their interaction results and data obtained are reported in Table 1
and also compared with similar examples from the literature. The electrostatic mode

JOURNAL OF COORDINATION CHEMISTRY
13
of interaction is the same for all screened compounds. The mechanism of interaction
þ2
with DNA can be suggested as the involvement of Fe which may bind with the
þ2
þ3
DNA, followed by oxidation; the other possibility is Fe first oxidizes to Fe and this
oxidized form then interacts with the negatively charged phosphate of the DNA helix
structure, in accord with literature reports [8, 41].
2.7. Free radical scavenging screening
The DPPH method was utilized to estimate the free radical scavenging (antioxidant)
potentials of 3a–3d in ethanol [45]. Figure 9 presents the spectral profile of DPPH in
the presence of 3b. The reason behind this is free DPPH molecules are scavenged by
3
b molecules, decreasing concentration of DPPH decreasing absorbance. The decrease
in absorbance at 519 nm was used to estimate the percent inhibition of the test com-
pound by using the procedure given in Section 4. The percent inhibitions were uti-
lized to calculate the IC50 value; all the compounds have similar spectral profiles of
DPPH with different values for percent inhibition and hence the IC50 values. IC50 values
for 3a, 3b, 3c and 3d are 25.27 mg/mL, 10.17 mg/mL, 28.02 mg/mL and 17.90 mg/mL,
respectively.
Biological disorders, cancers and other diseases are associated with higher levels of
reactive oxidant (RO) species (free radicals) in the body [46, 47]. Under normal physio-
logical conditions these free radicals are tightly controlled by biological antioxidants.
When biological antioxidants fail, these harmful free radicals increase in concentration,
and, on increasing, these radicals injure cells by damaging lipids, proteins, DNA and
sugars and initiate many degenerative diseases like cancer. Compounds 3a–3d
showed significant free radical scavenging behavior. The suggested mechanism of
scavenging DPPH free radical may be donation of hydrogen from the compound to
1
the DPPH free radical, so DPPH is no longer a free radical [48]. H NMR values for
–
CSNH and –CONH are very downfield, which showed that these protons are labile
and acidic and can easily be liberated. It is plausible that these protons are responsible
for the free radical scavenging activity.
3. Conclusion
0
Four newly synthesized ferrocene incorporated N,N -disubstituted thioureas (3a–3d)
have been prepared and characterized. Compounds 3a and 3d were characterized by
X-ray crystallography. In the solid state, these compounds have good nonbonding
(van der Waals and hydrogen bonding) interactions. These compounds have signifi-
cant DNA binding and free radical scavenging activity. All the synthesized compounds
2
þ
exhibited electrostatic mode of interaction with DNA and it is assumed that the Fe
/
3
þ
Fe interacts with phosphates of double helical structure. DFT calculations were per-
formed for the molecular structures of these compounds. The calculated electrochem-
ical band gaps were in good correlation with experimental results of Fe /Fe redox
reaction on the electrode surface. The lower IC50 values of these compounds suggest
their potential as a new class of metal-based antioxidants.
2
þ
3þ

1
4
B. LAL ET AL.
4. Experimental
4
.1. Materials and methods
Ferrocene, 3-chloro-4-nitroaniline, potassium thiocyanate, sodium nitrite, benzoyl chloride,
-methylbenzoyl chloride, 3-methylbenzoyl chloride, 4-methylbenzoyl chloride, tetrabuty-
lammonium perchlorate (TBAP), hydrochloric acid and 2,2-diphenyl-1-picrylhydrazyl
DPPH) were purchased from Sigma Aldrich (St. Louis, MO. USA) and used as received.
2
(
Solvents such as ethanol, methanol, acetone, diethyl ether and petroleum ether were
purified by using standard procedures [49]. Sodium salt of DNA (purchased from Acros,
Geel – Belgium) was used as received. Ten millimolar stock solution of DNA was pre-
pared in 20% aqueous DMSO. The system was buffered at pH 7 by phosphate buffer
(
0.1 M NaH PO þ 0.1 M NaOH) to avoid the decomposition of ferrocenium in a basic
2
4
solution and protonation of the ferrocenyl group in strongly acidic conditions.
Tetrabutylammoniumperchlorate (TBAP) (Fluka - Shanghai, China, 99% purity) was further
purified by re-crystallization using methanol. The nucleotide to protein (N/P) ratio of 1.85
was obtained from the ratio of absorbance at 260 and 280 nm (A260/A280 ¼ 1.85), evi-
denced for protein-free DNA [34]. All other reagents were of analytical grade. Doubly dis-
tilled water and absolute ethanol were used for all sample solutions. The molar
ꢀ
1
ꢀ1
absorption coefficient for DNA has been used as 6600 M cm
.
1
13
H and C NMR spectra were obtained using a BRUKER AVANCE 300 MHz NMR
spectrometer with deuterated solvents and tetramethylsilane as an internal reference.
Chemical shift values are given in ppm, coupling constants in Hz. FTIR spectra were
ꢀ
1
recorded with a Thermo Scientific Nicolet-6700 FTIR spectrometer (400–4000 cm ). X-
ray measurements were collected on a Bruker kappa APEXII CCD diffractometer
equipped with graphite-monochromated Mo-Ka radiation (k ¼ 0.71073 Å) source. Cyclic
voltammetry measurements were performed using an Eco Chemie Auto lab PGSTAT
1
2 potentiostat/galvanostat (Utrecht, The Netherlands) with the electrochemical soft-
ware package GPES 4.9. A Pharma Spac UV-1800 UV-Visible Spectrophotometer
SHIMADZU, Kyoto, Japan) was used to record UV-visible spectral measurements.
(
4.2. Synthesis of 1-benzoyl-3-(4-ferrocenyl-3-chlorophenyl) thiourea (3a)
To solution of benzoyl chloride (0.41 mL, 3.6 mmol) in dried acetone (100 mL), potas-
sium thiocyanate (0.35 g, 3.6 mmol) was added under N . 3-Chloro-4-ferrocenylaniline
2
(1.125 g, 3.6 mmol) was added to the resulting reaction mixture and kept stirring for
4
h. The reaction mixture was then poured into ice cooled water and stirred vigor-
ously. The solid product was filtered off and washed with deionized water. 3a was
dried in air and re-crystallized from ethyl acetate. Yield (1.3 g, 76%), Elemental analysis
Cal. (%) for C H FeN OSCl: C, 60.71; H, 4.03; N, 5.90; S, 6.75. Found (%): C, 60.68; H,
2
4
19
2
ꢀ
ꢀ1
1
ꢀ1
ꢀ1
4
(
(
.09; N, 5.87; S, 6.72. FTIR (t cm ): Fe-cp (481 cm ), NH (3422 cm ), C ¼ O
ꢀ
1
ꢀ1
2
1661 cm ), C ¼ S (1137–1256 cm ), C ¼ C Ar (1455–1592 cm ), sp
CH
ꢀ
1
1
3029.5 cm ). H NMR (300 MHz, DMSO-d ): d 12.70 (s, 1 H, CSNH), 9.15 (s, 1 H, CONH),
6
7
.91–7.65 (m, 7 H, C H -C H ), 4.78 (s, 2 H, C H ), 4.38 (s, 2 H, C H ), 4.17 (s, 5 H, C H )
6 3 6 5 5 4 5 4 5 5
1
3
ppm. C NMR (75 MHz, DMSO-d ): d 177.91, 167.04, 135.98, 135.88, 133.93, 132.20,
6
131.47, 131.30, 129.31, 127.55, 125.22, 121.80, 83.47, 69.73, 68.73, 67.94 ppm.

JOURNAL OF COORDINATION CHEMISTRY
15
4.3. 1-(2-Methylbenzoyl)-3-(3-chloro-4-ferrocenylphenyl) thiourea (3 b)
Compound 3b was prepared using the same method as for 3a except using 2-methyl-
benzoyl chloride in place of benzoyl chloride in equimolar ratio. Yield (1.27 g, 72%),
Elemental analysis Cal. (%) for C H FeN OSCl: C, 61.43; H, 4.33; N, 5.73; S, 6.56.
2
5
21
2
ꢀ
1
ꢀ1
Found (%): C, 61.40; H, 4.29; N, 5.75; S, 6.59. FTIR (t cm ): Fe-cp (486 cm ), NH
ꢀ
1
ꢀ1
ꢀ1
ꢀ1
(
3403 cm ), C ¼ O (1673 cm ), C ¼ S (1106–1165 cm ), C ¼ C Ar (1519–1574 cm ),
3
ꢀ1
2
ꢀ1
1
sp CH (3032 cm ), sp CH (3159 cm ). H NMR (300 MHz, DMSO-d ): d 12.59 (s, 1 H,
6
CSNH), 8.84 (s, 1 H, CONH), 7.57 (m, 7 H, C H -C H ), 4.77 (s, 2 H, C H ), 4.38 (s, 2 H,
6
4
6
3
5 4
13
C H ), 4.18 (s, 5 H, C H ), 2.58 (s, 3 H, CH ) ppm. C NMR (75 MHz, DMSO-d ): d 178.01,
5
4
5
5
3
6
1
1
69.57, 137.83, 135.93, 135.87, 132.57, 132.28, 132.19, 132.03, 131.29, 127.01, 126.39,
25.22, 121.81, 83.52, 69.79, 68.78, 68.23, 20.23 ppm.
4.4. 1-(3-Methylbenzoyl)-3-(3-chloro-4-ferrocenylphenyl) thiourea (3c)
Compound 3c was prepared using the same method as for 3a except using 3-methyl-
benzoyl chloride in place of benzoyl chloride in equimolar ratio. Yield (1.28 g, 73%),
Elemental analysis Cal. (%) for C H FeN OSCl: C, 61.43; H, 4.33; N, 5.73; S, 6.56.
2
5
21
2
ꢀ
1
ꢀ1
Found (%): C, 61.44; H, 4.36; N, 5.72; S, 6.53. FTIR (t cm ): Fe-cp (485 cm ), NH
ꢀ
1
ꢀ1
ꢀ1
ꢀ1
(
3299 cm ), C ¼ O (1673 cm ), C ¼ S (1139–1275 cm ), C ¼ C Ar (1519–1566 cm ),
3
ꢀ1
2
ꢀ1
1
sp CH (3085 cm ), sp CH (3113 cm ). H NMR (300 MHz, DMSO-d ): d 12.71 (s, 1 H,
6
CSNH), 9.09 (s, 1 H, CONH), 7.87–7.51 (m, 7 H, C6H4, C H ), 4.78 (s, 2 H, C H ), 4.38 (s,
6
3
5 4
13
2
1
1
H, C H ), 4.18 (s, 5 H, C H ), 2.48 (s, 3 H, CH ) ppm. C NMR (75 MHz, DMSO-d ): d
5 4 5 5 3 6
77.84, 167.26, 139.40, 136.00, 135.86, 134.74, 132.19, 131.28, 129.19, 128.88, 128.10,
25.39, 125.23, 124.64, 121.81, 83.68, 69.86, 68.87, 21.41 ppm.
4.5. 1-(4-Methylbenzoyl)-3-(3-chloro-4-ferrocenylphenyl) thiourea (3d)
Compound 3d was prepared using the same method as for 3a except using 4-methylben-
zoyl chloride in place of benzoyl chloride in equimolar ratio. Yield (1.35 g, 77%), Elemental
analysis Cal. (%) for C H FeN OSCl: C, 61.43; H, 4.33; N, 5.73; S, 6.56. Found (%): C, 61.46;
2
5
21
2
ꢀ
1
ꢀ1
ꢀ1
ꢀ1
H, 4.36; N, 5.71; S, 6.54. FTIR (t cm ): Fe-cp (479 cm ), NH (3247 cm ), C ¼ O
ꢀ
1
ꢀ1
3
ꢀ1
2
(
1663 cm ), C ¼ S (1032–1105 cm ), C ¼ C Ar (1524–1568 cm ), sp CH (3019 cm ), sp
ꢀ1 1
CH (3157 cm ). H NMR (300 MHz, DMSO-d ): d 12.74 (s, 1 H, CSNH), 9.08 (s, 1 H, CONH),
6
7
.56 (m, 7 H, C H -C H ), 4.84 (s, 2 H, C H ), 4.43 (s, 2 H, C H ), 4.22 (s, 5 H, C H ), 1.28 (s, 3 H,
6 4 6 3 5 4 5 4 5 5
13
CH ) ppm. C NMR (75 MHz, DMSO-d ): d 166.92, 153.53, 145.10, 136.02, 135.81, 133.98,
3
6
132.20, 131.30, 130.02, 127.58, 125.22, 121.82, 83.49, 69.73, 68.71, 67.95, 21.79 ppm.
4.6. Single crystal X-ray diffraction analysis
X-ray measurements were made on a Bruker Kappa APEXII CCD diffractometer equipped
with graphite-monochromated Mo-Ka radiation (k ¼ 0.71073 Å) source. The data collection
used x scans, and a multi-scan absorption correction was applied. The structure was solved
by using a SHELXS97 (Sheldrick, 273 2008) program and it was refined by full-matrix least-
squares using SHELXL-97 [50]. Different software like Mercury and ENCIFER were used to
draw the structures of the analyzed compounds.

1
6
B. LAL ET AL.
4.7. Free radical scavenging screening
The antioxidant activities of 3a–3d were determined by using the DPPH method [48].
The sample solutions were prepared by keeping constant concentration of DPPH
(
165 mM) with increasing concentration of compounds (3.125, 6.25, 12.5, 25, 50, 100 mg
ꢀ
1
mL ) in ethanol and buffered at pH 6 (0.1 M NaH PO þ 0.1 M NaOH). All these mix-
2
4
ture were kept in the dark for 30 min and absorbance was measured at 517 nm in dim
light using a Shimadzu 1800 UV-Vis spectrophotometer. From the mean value of three
readings, % inhibition was calculated by using the equation [% inhibition ¼ 100 (1 –
A /A )], where A and A are the absorbance of DPPH solution (at 517 nm) in the
s
o
o
s
absence and presence of test samples, respectively [45, 48].
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
The authors are thankful to the Higher Education Commission (HEC) Pakistan and Pakistan
Academy of Science (PAS), Islamabad, Pakistan, for their financial support.
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