Synthesis, characterization and DNA binding studies of penta- and hexa-coordinated diorganotin(IV) 4-(4-nitrophenyl)piperazine-1-carbodithioates

Article abstract of DOI:10.1016/j.jorganchem.2009.01.047

Two chlorodiorganotin(IV) complexes with general formula R₂SnClL (R = n-C₄H₉ (1) and C₂H₅ (2) and a diphenyltin(IV) derivative with general formula Ph₂SnL₂ (3), where L = 4-(4-ni

Full text of DOI:10.1016/j.jorganchem.2009.01.047

Journal of Organometallic Chemistry 694 (2009) 1998–2004
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Synthesis, characterization and DNA binding studies of penta- and hexa-coordinated
diorganotin(IV) 4-(4-nitrophenyl)piperazine-1-carbodithioates
a
b
Zia-ur-Rehman a, Afzal Shah a, Niaz Muhammad a, Saqib Ali a, , Rumana Qureshi , Ian Sydney Butler
*
a Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan
b Department of Chemistry, McGill University, 801 Sherbrook St. West, Montreal, Quebec, Canada H3A2K6
a r t i c l e i n f o
a b s t r a c t
Article history:
Two chlorodiorganotin(IV) complexes with general formula R2SnClL (R = n-C4H9 (1) and C2H5 (2) and a
diphenyltin(IV) derivative with general formula Ph2SnL2 (3), where L = 4-(4-nitrophenyl)piperazine-1-
carbodithioate ligand, were prepared and characterized by elemental analysis, Raman, FT-IR, multinu-
clear NMR (1H, 13C and 119Sn) and mass spectrometry. On the basis of spectroscopic data the effective
coordination number of Sn atom was found five (1 and 2) and six (3) both in solution and solid state. Elec-
trochemical, kinetic and thermodynamic parameters of complexes 1–3, interacting with DNA were eval-
uated by cyclic voltammetry. The linearity of the plots between the peak current (I) and the square root of
Received 28 November 2008
Received in revised form 15 January 2009
Accepted 27 January 2009
Available online 5 February 2009
Keywords:
Dithiocarboxylate
Diorganotin(IV) complexes
Spectroscopy
the scan rate (
ficients of the free (Df) and DNA bound forms (Db), standard rate constants (ks) and charge transfer coef-
ficients ( ) were determined by the application of Randle–Sevcik, Nicholson and Kochi equations. The
m
1/2) indicated the electrochemical processes to be diffusion controlled. The diffusion coef-
a
Complex–DNA interaction
values of binding constant and binding site size were evaluated from voltammetric data. The results
revealed the following increasing order of binding strength: 1 (5.4 ꢀ 103) < 3 (8.4 ꢀ 103) < 2 (1.24 ꢀ
104) Mꢁ1. The UV–Vis spectroscopic data also indicated the same order of binding strength. Furthermore,
the binding mode was suggested on the base of shift in peak potential (CV) and absorption maxima (UV–
Vis spectroscopy).
Ó 2009 Elsevier B.V. All rights reserved.
1. Introduction
Deoxyribonucleic acid (DNA) plays an essential role in biologi-
cal processes since it is the storehouse of genetic information.
Cancer is a leading cause of premature death in the world. It can
be cured by preventing the rapid proliferation of cancer cells for
which the replication of DNA is to be arrested. Such an objective
can be achieved either by (i) ionizing radiation via reactive oxygen
species or (ii) chemotherapy using chemical substances that di-
rectly interact with DNA. Metallocomplexes of platinium(II) like
cisplatin, oxalylplatin, nedaplatin and carboplatin achieved clinical
status as a result of intensive research focused on anti-cancer coor-
dination compounds. However, in spite of their high activity, the
applications of cisplatin and similar compounds are limited by
serious disadvantages like: (a) poor water solubility (b) toxicity
and (c) tolerance by the tumor. In the search for effective alterna-
tives, Organotin(IV) dithiocarboxylates received utmost attention
on account of their potential apoptotic inducing character. More-
over, these complexes have limited side effects with high thera-
peutic index as compared to the clinically used cisplatin and
carboplatin [1].
Various mutagens can damage its replication machinery which
may lead to programmed cell death. The proliferation of cancer
cells can be prevented by the interaction of DNA binding molecules
which may dysfunction it either by strand scission or chain cutting
or local unwinding of its double helical structure, leading to vari-
ous pathological changes in living organisms.
The investigation of drug–DNA interaction is important for
understanding the molecular mechanism of drug action and
designing [2]. Such interactions are studied by a variety of tech-
niques like cyclic voltammetry, UV–Vis, fluorescence, Raman and
NMR spectroscopy [3]. The interaction of some metal chelates of
Co(III), Ru(II) and Os(II) with DNA were studied by cyclic voltam-
metry [4–7] but their lower affinity to DNA prompted the research-
ers to concentrate their efforts on other potential metal complexes.
In the quest for exploring effective DNA binders and as per our
interest in organotin(IV) dithiocarboxylates [8–10], we synthesized
three potential anti-cancer tin based chelates of 4-(4-nitro-
phenyl)piperazine-1-carbodithioate, characterized and investi-
gated their interaction with DNA by cyclic voltammetry and
UV–Vis spectroscopy. The structure of ligand-salt and organic
groups attached to Sn atom along with numbering scheme is
presented in Scheme 1.
* Corresponding author.
E-mail address: drsa54@yahoo.com (S. Ali).
0022-328X/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2009.01.047

Zia-ur-Rehman et al. / Journal of Organometallic Chemistry 694 (2009) 1998–2004
1999
1210
m
(C@S), 1507
m
(C–N). IR (cmꢁ1): 1030
m
(C–S), 1478
m
(C–N).
6
5
5'
β
3
2
a
b
1H NMR (ppm): 8.1, 8.0 (d, H6,6 ,6a,6 a
,
3JH–H = 9.6 Hz), 7.1, 6.9 (d,
S
1
3a
N
6a
5a
2a
0
0
3
O2N
N
N
S-H N
NO2
0
0
0
0
H5,5 ,5a,5 a JH–H = 9.6 Hz). 4.42–4.39, 3.69–3.65 (m, H3,3 ,3a,3 a).
+
2
4
7
3.50–3.47, 3.27–3.24 (m, H2,2 ,2a,2 a). 13C NMR (ppm): 213.5 (C-1),
154.9, 154.7, 138.4, 137.1, 131.3, 126.3, 114.0, 112.6 (Ar-C). 49.0,
46.3 (C-3, 30, 3a, 30a), 43.1, 40.9 (C-2, 20). EI-MS, m/z (%):
[C10H14N3O2]Å+ 208 (4.7), [C10H13N3O2]Å+ 207 (38.7), [C8H9N2O2]+
165 (100), [C8H9 N2O]+ 149 (4), [C8H9N]Å+ 119 (19.8), [C6H5]+ 76
(24.4).
4a
7a
6'a
0
0
6'
3' 2'
2'a 3'a
5'a
γ
β
δ
β
α
CH3
α
,
α
H2C CH3
R =
,
δ
γ
Scheme 1.
2.2.2. Synthesis of chlorodibutylstannyl 4-(4-nitrophenyl)piperazine-
1-carbodithioate (1)
Bu2SnCl2 (0.53 g, 1.76 mmol) and L-salt (0.862 g, 1.76 mmol)
was mixed together in methanol (90 mL) and the mixture was re-
fluxed for 6 h with constant stirring, the yellowish product thus
obtained was filtered and recrystallized from chloroform–ethanol
(Yield: 0.74 g, 77%). M.p. 115–117 °C. Elemental Anal. Calc. for
C19H30N3O2S2SnCl: C, 41.43; H, 5.49; N, 7.63; S, 11.64. Found: C,
2. Experimental
2.1. Materials and methods
Reagents, n-Bu2SnCl2, Et2SnCl2 Ph2SnCl2 and 4-(4-nitrophenyl)
piperazine were obtained from Aldrich, dimethylsulphoxide
(DMSO) with 99.5% purity and CS2 from Riedal-de-Haën; methanol
from E. Merck was dried before use by the reported method [11].
DNA was extracted from human blood by Falcon method [12].
The purity of DNA was checked from the ratio of absorbance at
260 and 280 nm (A260/A280 = 1.85). The concentration of the stock
solution of DNA (2.5 mM in nucleotide phosphate, NP) was deter-
mined by monitoring the absorbance at 260 nm, using the molar
41.38; H, 5.45; N, 7.57; S, 11.55%. Raman (cmꢁ1): 614
m
(C–S),
(Sn–
(Sn–C). EI-
1202
m
(C@S), 1507
m
(C–N), 517
m
(Sn–C), 346
m
(Sn–S), 263
m
Cl). IR (cmꢁ1): 1125, 1006
m(CS2), 1487
m
(C–N), 502
m
MS, m/z (%): [C15H21N3O2S2SnCl]+ 494 (2), [C4H9S2SnCl]Å+ 276 (6),
[C4H9S2Sn]+ 241 (21), [S2SnCl]+ 219 (30), [S2Sn]Å+ 184 (9), [C4H9Sn]Å+
177 (6), [SnCl]Å+ 155 (43). 1H NMR (ppm): 8.08 (d, H6,6
,
3JH–H
=
0
3
0
0
9.3 Hz), 6.77 (d, H5,5
,
JH–H = 9.3 Hz), 4.29–4.19 (m, H3,3 ), 3.64–
0
3.57 (m, H2,2 ), 2.08–1.35 (m, CH2, SnBu2), 0.92 (t, CH3, SnBu2,
3J = 7.2 Hz). 13C NMR (ppm): 198.5 (C-1), 154.0, 138.9, 126.2,
extinction coefficient (e
) of 6600 Mꢁ1 cmꢁ1. Electrochemical grade
112.6 (C-Ar), 50.7 (C-2, 20), 46.0 (C-3, 30), 29.6 (C-b), 28.0 (C-
c),
tetrabutylammonium fluoroborate (TBAFB) purchased from Fluka
was used as supporting electrolyte. Nitrogen saturated solutions
were obtained by bubbling high purity N2 for at least 10 min in
the solution and keeping the environment of the pure gas over
the solution during the voltammetric experiments.
26.5 (C-
a
), 13.9 (C-d). 119Sn NMR: d = ꢁ185 ppm.
2.2.3. Synthesis of chlorodiethylstannyl 4-(4-nitrophenyl)piperazine-
1-carbodithioate (2)
Compound 2 was prepared in the same way as 1, using the same
molar amounts, to give yellow crystals. (Yield: 0.63 g, 72%). M.p.
156–157 °C. Elemental Anal. Calc. for C15H22N3O2S2SnCl: C, 36.42;
H, 4.48; N 8.49; S, 12.96. Found: C, 36.38; H, 5.46; N, 8.43; S,
Microanalysis was done using a Leco CHNS 932 apparatus. Ra-
man spectra ( cmꢁ1) were measured with an InVia Renishaw spec-
trometer, using argon-ion (514.5 nm) and near-infrared diode
(785 nm) lasers. WIRE 2.0 software was used for the data acquisition
and spectra manipulations. IR spectra in the range 4000–400 cmꢁ1
were obtained on bio-Rad FT-IR spectrophotometer with samples
investigated as KBr discs or thin film on NaCl cell. NMR spectra
(d6-DMSO) were obtained using Hg-300 and a Varian Unity 500-
MHZ instruments. Electron impact (70 eV) mass spectra were re-
corded on a Kratos MS25RFA instrument. Electrochemical experi-
ments were carried out using an Autolab PGSTAT 302 running
with GPES (General Purpose Electrochemical System) version 4.9,
software (Eco-Chemie, Utrecht, The Netherlands). Voltammograms
were recorded at room temperature using a three-electrode sys-
tem; a glassy carbon-electrode of 0.071 cm2 area as working elec-
trode, a saturated calomel electrode (SCE) as a reference and
platinum wire as counter electrode. Prior to every electrochemical
12.87%. Raman (cmꢁ1): 615
513 (Sn–C), 350 (Sn–S), 268
(CS2), 1490 (C–N), 503
m
(C–S), 1202
m
m(C@S), 1511 m(C–N),
m
m
(Sn–Cl). IR (cmꢁ1): 1124, 1002
m
m
m(Sn-C). EI-MS, m/z (%):
[C13H17N3O2S2SnCl]+ 466 (2), [C2H5S2SnCl]Å+ 248 (9), [S2SnCl]+
219 (47), [C2H5S2Sn]+ 213 (21), [S2Sn]Å+ 184 (11), [SnCl]+ 155
(51), [C2H5Sn]+ 149 (6), [Sn]Å+ 120 (10). 1H NMR (ppm): 8.12 (d,
3
H6,6
,
JH–H = 9.0), 6.81 (d, H5,5
,
3JH–H = 9.0 Hz), 4.20–4.17 (m,
0
0
3
0
0
H3,3 ), 3.65–4.12 (m, H2,2 ), 1.84 (q, CH2, SnEt2, JH–H = 6.0 Hz),
1.47 (t, CH3, SnEt2, JH–H = 6.0). 13C NMR (ppm): 197.0 (C-1),
3
153.7, 139.0, 126.2, 112.6 (C-Ar), 50.7 (C-2, 20), 46.0 (C-3, 30),
21.6 [(C-
a
),
J
1 119Sn–13C = 530], 10.5 (C-b). 119Sn NMR: d = ꢁ177.
2.2.4. Synthesis of diphenylstannyl bis[4-(4-nitrophenyl)piperazine-1-
carbodithioate] (3)
assay, the working electrode was used to polish with 0.25-lm dia-
mond paste on a nylon buffing pad, followed by washing with
water. All the experiments were carried out at room temperature
(ca. 25 1 °C).
Compound 3 was prepared in the same way as 1, using the li-
gand-salt to Ph2SnCl2 ratio 2:1, to give yellow solid. (Yield:
1.08 g, 73%). M.p. 224–226 °C. Elemental Anal. Calc. for
C34H34N6O4S4Sn: C, 48.75; H, 4.09; N, 10.03; S, 15.31. Found: C,
48.67; H, 3.95; N, 9.97; S, 15.25%. Raman (cmꢁ1): 653
m
(C–S),
2.2. Synthesis
1196
1112, 988
m(C@S), 1305 m(C–N), 269 m(Sn–C), 365 m
(Sn–S), IR (cmꢁ1):
m
(CS2), 1488 m
(C–N). EI-MS, m/z (%): [C34H34N6O4S4Sn]Å+
2.2.1. Synthesis of 4-(4-nitrophenyl)piperazinium 4-(4-
nitrophenyl)piperazine-1-carbodithioate (L-salt)
838 (0.4), [C22H26N4OS4Sn]+ 610 (1.7), [C16H21N4OS4Sn]Å+ 533 (12),
[C16H21N4 OS3 Sn]+ 501 (8), [C12H13N2OS3Sn]Å+ 417 (3), [C6H5Sn]+
Dropwise addition of CS2 (in excess) in methanol (50 mL) to 4-
(4-nitrophenyl) piperazine (5 g, 24.15 mmol) in methanol (50 mL)
followed by stirring for 4 h at 0 °C gave the yellowish product.
The yellow product was filtered off and was washed with diethyl
ether (Yield: 4.91 g, 83%). M.p. 180–182 °C. Elemental Anal. Calc.
for C21H26N6O4S2: C, 51.41; H, 5.34; N, 17.13; S, 13.07. Found: C,
197 (39), [Sn]Å+ 120 (19). 1H NMR (ppm): 8.06 (d, H6,6
9.3 Hz), 6.91 (d, H5,5
,
3JH–H
=
0
3
0
0
,
JH–H = 9.3), 4.13–4.06 (m, H3,3 ), 3.72–3.69
(m, H2,2 ), 7.94 (bs, Ho, SnPh2), 7.46 (bs, Hm,p, SnPh2). 13C NMR
(ppm): 197.5 (C-1), 154.2, 137.7, 126.4, 112.8 (C-Ar), 51.8 (C-2,
0
20), 45.1 (C-3, 30), 135.7 (C-
a), 131.3 (C-b), 130.1 (C-c), 129.5
51.37; H, 5.30; N, 17. 11; S, 13.01%. Raman (cmꢁ1): 664
m(C–S),
(C-d). 119Sn NMR: d = ꢁ333.

2000
Zia-ur-Rehman et al. / Journal of Organometallic Chemistry 694 (2009) 1998–2004
1125–1112 cmꢁ1 have been attributed to the asymmetric absorp-
3. Results and discussion
tion of
metric
m
m
(CS2)as and the 998–1006 cmꢁ1 can be assigned to the sym-
(CS2)s absorption frequencies. According to the literature
(CS2)as and (CS2)s are
3.1. Proposed mechanism of ligand and complexes 1–3 synthesis
[13], for complexes 1–3, the difference of
m
m
119–124 cmꢁ1, indicating that 1,1-dithioate moiety of the ligand
is linked to the central tin in a bidentate fashion. The stretching
vibration peaks of the C–N, were located at ꢂ1490 cmꢁ1 and are
intermediate between the values for C–N single bond (1250–
1360 cmꢁ1) and C@N double bond (1640–1690 cmꢁ1). Partial dou-
ble bond character for the C–N bond would result in some partial
double bond character for the C–S bonds. The appearance of new
peaks at ꢂ502 cmꢁ1, in compounds 1 and 2, were assigned to
Sn–C. The analyses are in agreement with X-ray single crystal dif-
fraction results, recently reported by our group [14,15], for com-
plexes 1 and 2.
The nucleophilic attack of 4-(4-nitrophenyl)piperazine on car-
bon disulfide gave as 4-(4-nitrophenyl)piperazine-1-carbodithioic
acid as intermediate which undergoes acid–base reaction with
unreacted 4-(4-nitrophenyl)piperazine to gave 4-(4-nitrophenyl)
piperazinium 4-(4-nitrophenyl)piperazine-1-carbodithioate (L-salt).
The reaction of the equimolar ligand-salt with R2SnCl2 (R = Bu,
Et) gave R2SnLCl and 4-(4-nitrophenyl)piperazinium chloride
while refluxing Ph2SnCl2 with ligand-salt in the ratio of 1:2 gave
Ph2SnL2 and the same by-product as shown in Scheme 2. This
mechanism has been proposed on the basis of multinuclear NMR
(1H and 13C) study of ligand.
3.3. NMR spectra
3.2. Vibration spectra
In the 1H NMR spectra of the complexes, the integral ratio of
the signals resulting from protons of the ligand to those from pro-
tons of the organic groups on the Sn provides a reliable measure
of the metal to ligand ratio in the synthesized complexes. The dis-
appearance of duplication peak pattern due to 4-(4-nitro-
phenyl)piperazinium ion and appearance of proton signals for
the organic groups attached to Sn confirmed the formation of
complexes 1–3. The protons of piperazine moiety of the ligand
showed two multiplet in the aliphatic region while aromatic part
of the ligand gave two doublets due to two non-equivalent sets of
protons in all three complexes. Dibutyl, diethyl and diphenyl
groups of the organotin moiety display signals in their expected
regions.
The assignment of Raman bands of the three complexes has
been made by comparison with the Raman spectra of their related
precursors. A new absorption band at 346–365 cmꢁ1 for 1–3,
which is absent from the spectra of the free ligand, can be assigned
to the Sn–S stretching mode of vibration. Very sharp Sn–C peak
was observed at 517 cmꢁ1 in first two complexes, whereas in
diphenyltin(IV) derivative a weak vibration mode at 269 cmꢁ1
was assigned to Sn–C. In addition, Raman spectra of complex 1
and 2 display peaks associated with m(Sn–Cl).
In IR spectra of organotin(IV) dithiocarboxylates, out of all the
vibration modes C–N, CS2 stretching frequencies are of particular
interest in term of coordination mode of 1,1-dithioate moiety. In
the IR spectra of complexes 1–3, the strong peaks that appear at
S
4 h stirring
+
O2N
N
NH
CS2
O2N
N
N
SH
N
273 K
Dry MeOH
O2N
NH
..
S
O2N
N
N
S-H N
N
NO2
+
2
0.5
R2SnCl2 /
6 h reflux
Ph2SnCl2
Dry MeOH
R
S
NH Cl-
O2N
N
N
Cl
Sn
O2N
N
+
+
2
S
R
OR
Ph
Sn
Ph
S
S
O2N
N
N
N
N
NO2
S
S
(3)
R = Bu (1) and Et (2)
Scheme 2.

Zia-ur-Rehman et al. / Journal of Organometallic Chemistry 694 (2009) 1998–2004
2001
In 13C NMR spectra, the duplicate peak pattern due to 4-(4-
-50
-40
-30
-20
-10
0
a
nitrophenyl)piperazinium ion disappeared due to detachment of
this group from the ligand upon its complexation to Sn. A small
shift in the position of C(1) was noted which resulted from deshiel-
ding of this particular carbon due to disconnection of cationic part
of ligand and coordination of CS2 moiety through both sulfur atoms
to Sn. Moreover, the 1J[119Sn,13C] coupling constant observed for
complex 2, 530 Hz, was the same as that reported for analogous
5-coordinate derivatives [16,17].
b
1119Sn NMR spectroscopy has been found to be very useful for
the elucidation of the nature of coordination in the organotin(IV)
dithiocarboxylates. Even though for each complex with the same
coordination number, some wide range of d(119Sn) values are ob-
served depending on the different organic and dithiocarboxylate
groups attached to the Sn atom, there is an approximate linear
relationship between the 119Sn values and the coordination num-
bers of the complexes. Thus, for the known organotin(IV) dithio-
carboxylates [18], d(119Sn) have been found to lie between ꢁ150
to ꢁ250 ppm in penta-coordinate, while a range ꢁ300 to ꢁ500
ppm have been observed for hexa-coordinate Sn atom. Based on
d(119Sn) value, complexes 1 and 2 showed penta-coordinate geom-
etry while the Sn atom is six coordinate (ꢁ333 ppm) in complex 3.
10
20
30
-0.6
-0.8
-1
-1.2
-1.4
-1.6
-1.8
-2
E/ V vs SCE
Fig. 1. CV behavior of 3 mM 1 at clean GC electrode in the absence (a) and presence
of 60 lM DNA (b) in 10% aqueous DMSO using 0.1 M TBAFB as supporting
electrolyte at 0.1 V sꢁ1 scan rate.
the interaction of 1 with DNA. The negative shift (107 mV) in po-
tential is ascribes electrostatic interaction of 1 with the anionic
phosphate of DNA [20]. Such an interaction can be explained by
the probable labile nature of dithiocarboxylate ligand due to the
steric repulsion of bulky butyl groups.
3.4. Mass spectra
Mass-spectral data for 1–3 showed rich ion distributions but
our interest lies in Sn containing ions. These ions were quantita-
tively identified by inspection from the characteristic isotopic peak
pattern for Sn [19]. The mass spectral data reported here are re-
lated to the principal isotope 120Sn. Complexes 1–3 showed no
molecular ion (MÅ+) as is generally the case for main group organo-
metallic compounds, however, for compounds 1–3, the different
fragments observed are consistent with structures proposed on
the basis of other spectroscopic techniques.
The CV behavior of 3 mM 2 at 100 mV sꢁ1 scan rate (Fig. 2)
shows reduction at Epc = ꢁ1.191 V and oxidation of the reduced
product at Epa = ꢁ1.083 V. In the presence of 60
lM DNA, the
cathodic peak is displaced in the positive direction accompanied
with the decrease in peak current. The same trend was also ob-
served for 3. Such peculiar CV characteristics are suggestive of
intercalation of 2 and 3 into the double stranded DNA [21]. The
electrochemical parameters (as obtained from CV) of complexes
1–3, in the absence and presence of 60 lM DNA are listed in Table
1. The electron-donating groups disfavor reduction by shifting the
formal potential (E°) in the more negative direction while the elec-
tron-withdrawing groups facilitate reduction by shifting the E° to
less negative values. The results reveal that the formal potential
varies in the sequence: 1 > 3 > 2, symptomatic of easy reduction
of 2 due to the lower electron-donating ability of ethyl than butyl
and phenyl groups. The shift of formal potentials of complexes 2
and 3 to less negative values by the addition of DNA can be attrib-
uted to their intercalation into the stacked base pairs domain of
DNA. Whereas the cathodic shift of E° (in case of 1) indicates elec-
trostatic interaction of 1 with the negatively charged oxygen of
phosphate backbone of DNA.
3.5. Cyclic voltammetry
The redox behavior of complexes 1–3 on clean glassy carbon-
electrode was investigated in the absence and presence of DNA,
using 10% aqueous DMSO at 25 °C. The CV of all the complexes
(with and without DNA) showed a pair of redox waves with elec-
trochemical parameters reported in Table 1. Typical CV behavior
of 1, in the absence and presence of DNA is shown in Fig. 1. The vol-
tammogram of the free complex 1 shows cathodic peak at
Epc = ꢁ1.308 V, due to the reduction of 1. On scanning in the posi-
tive direction, an oxidation peak is observed at Epa = ꢁ1.174 V. This
peak is presumably due to the oxidation of the reduction product
of 1. The difference of anodic and cathodic peak potential of about
134 mV and the ratio of their currents Ipc/Ipa > 1 designate the elec-
trochemical process to be quasi-reversible. In the presence of
-50
-40
-30
-20
-10
0
a
60 lM DNA, the 21.5% drop in cathodic peak current (Ipc) signifies
b
Table 1
CV data of compounds 1–3a,b,c
.
Compound
CV data
Epa (V)
Epc (V)
D
Ep (mV)
E° (V)
Ipc/Ipa
10
1
ꢁ1.174
ꢁ1.274
ꢁ1.083
ꢁ0.947
ꢁ1.169
ꢁ1.096
ꢁ1.308
ꢁ1.415
ꢁ1.191
ꢁ1.073
ꢁ1.271
ꢁ1.201
134
141
108
126
102
105
ꢁ1.241
ꢁ1.344
ꢁ1.137
ꢁ1.01
1.76
2.10
2.32
1.80
1.29
1.37
1-DNA
2
2-DNA
3
20
30
-0.6
-0.8
-1
-1.2
-1.4
-1.6
ꢁ1.22
E/ V vs. SCE
3-DNA
ꢁ1.148
aAll potentials were measured versus SCE in 10% aqueous DMSO at 0.1 V sꢁ1
.
Fig. 2. CV behavior of 3 mM 2 at clean GC electrode in the absence (a) and presence
of 60 DNA (b) in 10% aqueous DMSO using 0.1 M TBAFB as supporting
electrolyte at 0.1 V sꢁ1 scan rate.
bDEp = (Epa ꢁ Epc).
lM
cE° = (Epa + Epc)/2.

2002
Zia-ur-Rehman et al. / Journal of Organometallic Chemistry 694 (2009) 1998–2004
The diffusion coefficients of the free and DNA bound forms of
complexes 1–3 were determined by the application of Randle–Sev-
cik expression [22,23]
the absence of chloro group which can interact strongly with the
solvent, thus causing lowering of the diffusion coefficient in case
of 1 and 2. The higher Df value of 2 as compared 1 may be due to
more hydrophobic butyl than ethyl groups. The variation of molec-
ular weights in the same order in which the Df varies disprove the
idea that a heavy molecule diffuses slowly to the electrode surface.
The results reveal that the nature of the groups attached to the cen-
tral metal ion plays a dominant role in deciding the order in which
the values of Df change. The Db values of the DNA bound com-
plexes, summarized in Table 2, are an order of magnitude smaller
than the Df values of the free complexes. The reason could be the
slow mobility of the heavy complex–DNA adducts.
I ¼ 2:69 ꢀ 105n3=2ACoDo1=2m1=2
ð1Þ
where I is the peak current (A), A is the surface area of the electrode
(cm2), Co is the bulk concentration (mol cmꢁ3) of the electroactive
species, Do is the diffusion coefficient (cm2 sꢁ1),
m is the scan rate
(V sꢁ1) and n is the number of electrons involved in the electron
transfer reaction.
The linearity of I versus m1/2 plots (Fig. 3a and b) demonstrates,
that the main mass transport of these complexes (in the absence
and presence of DNA) to the electrode surface is diffusion con-
trolled. The values of the diffusion coefficient (Df) listed in Table
2 vary in the order: 3 > 1 > 2, indicating greater Df of 3, due to
The values of standard rate constant (ks) of the electron transfer
reaction of these complexes at the electrode surface were obtained
from Nicholson equation [24]
ks
w ¼
ð2Þ
h
i
1=2
nf
RT
t
p
Do
a
90
80
70
60
where
ration,
w
is a dimensionless parameter (depending upon peak sepa-
Ep) and all other parameters have their usual significance.
D
An examination of Table 2 reflects that the ks values of DNA
bound complexes are lower as compared to the free complexes.
The magnitude of ks with an order of 10ꢁ4 corresponds to the quasi-
reversible nature of the redox processes with slow electron trans-
fer kinetics. The sequence (3 > 2 > 1) of the ks values without DNA,
is pinpointing the fact, that the fast diffusing 3 with no chloro
group is more favorable for electron transfer than complexes 1
and 2. The slow electron transfer of 1 than 2 may be due to its
greater molecular weight. For getting further evidences about the
nature of the electrochemical processes of the free and DNA bound
50
2
1
40
30
20
10
0
3
0.2
0.3
0.4
0.5
0.6
0.7
0.8
complexes 1–3, the charge transfer coefficients (
mined by the application of Kochi formula [25]
a
) were deter-
1/2(Vs-1 )1/2
υ
"
#
ðE1=2 ꢁ Ec Þ
b
2
50
40
30
20
10
p
a
a
¼
ð3Þ
ðEap ꢁ EcpÞ
1
3
with values of more than 0.5 (Table 2) for all the complexes (with
and without DNA) unambiguously symbolize the quasi-reversibility
of the electrochemical processes.
The sequential drop in the peak current of the complexes by the
addition of increasing concentration of DNA, ranging from 20 to
60 lM, can be used to quantify the binding constant by using the
equation [26] given below
logð1=½DNAꢃÞ ¼ log K þ logðIHꢁG=ðIG ꢁ IHꢁGÞÞ
ð4Þ
where K is the binding constant, IG and IH–G are the peak currents of
the free guest (G) and the complex (H–G), respectively.
The intercept of log (1/[DNA]) versus log(IH–G/(IG ꢁ IH–G)) plots
(Fig. 4) yielded the binding constant K, varying in the sequence:
2-DNA > 3-DNA > 1-DNA. The binding of these complexes with
DNA will damage the genetic machinery resulting in the failure
of the cancerous cells to replicate.
0.3
0.4
0.5
0.6
0.7
0.8
υ1/2
(
)
-1 1/2
Vs
Fig. 3. (a) Plots of I vs.
m
1/2, for the determination of the diffusion coefficients of
1/2, for the
3 mM 1–3. Scan rates: 0.1, 0.2, 0.3, 0.4 and 0.5 V sꢁ1. (b) Plots of I vs.
m
determination of the diffusion coefficients of 3 mM 1–3 in the presence of 60 lM
DNA. Scan rates: 0.1, 0.2, 0.3, 0.4 and 0.5 V sꢁ1
.
Table 2
Summary of kinetic and binding parameters of compounds 1–3, as obtained from electrochemical measurements.
Compound
Kinetic parameters
Binding parameters
Df ꢀ 107 (cm2/s)
Db ꢀ 108 (cm2/s)
a
ks ꢀ 104 (cm/s)
s(bp)
K ꢀ 10ꢁ4 (Mꢁ1
)
D
G (kJ molꢁ1
)
1
2.98
ꢀ
ꢀ
0.69
0.67
0.74
0.69
0.68
0.57
2.31
0.82
3.59
1.51
6.09
1.13
ꢀ
ꢀ
1-DNA
2
2-DNA
3
4.57
ꢀ
0.42
0.5
0.54
ꢀ
ꢁ21.29
ꢀ
2.61
ꢀ
9.28
ꢀ
1.24
ꢀ
ꢁ23.35
ꢀ
5.25
ꢀ
3-DNA
2.12
0.45
0.84
ꢁ22.39

Zia-ur-Rehman et al. / Journal of Organometallic Chemistry 694 (2009) 1998–2004
2003
5
4.8
4.6
4.4
4.2
the slopes of Cb/Cf versus [DNA] plots. (Fig. 5) The values of ‘s’ de-
crease in the order: 2 > 3 > 1. The small binding site size of 1 may
be due to its electrostatic interaction with DNA. The results dem-
onstrate that two molecules of complexes 2 and 3 cover one base
pair when intercalate into DNA.
1
2
3
3.6. UV–Vis spectroscopy
The interaction of complexes 1–3 with DNA was also examined
by UV–Vis absorption titration for getting further clues about the
mode of interaction and binding strength. The effect of varying
1
A
0.15
0.65
1.15
1.65
log((IH-G)/(IG-IH-G))
0.8
a
Fig. 4. Plots of log (IH–G/(IG ꢁ IH–G)) vs. log(1/[DNA]) used to calculate the binding
constants of complexes 1–3 with DNA.
0.6
0.4
The greater K of these Sn complexes than those observed for
similar DNA-intercalating Cr and Ru complexes; [CrCl2(dicnq)2]+
and [Ru((dicnq)3]+2, with K reported as 1.20 ꢀ 103 and 9.70 ꢀ
103 Mꢁ1 [27–29], suggests their potential candidature as chemo-
therapeutic agents. The negative values of standard Gibbs free en-
h
0.2
0
300
400
500
600
ergy (D
G = ꢁRTlnK) indicate the spontaneity of their binding
Wavelength/nm
interaction with DNA.
1
0.8
0.6
0.4
0.2
0
For the determination of binding site size the following simple
binding model was used [5]:
B
a
Cb=Cf ¼ Kf½free base pairsꢃ=sg
ð5Þ
where ‘s’ is the binding site size in terms of base pairs. Measuring
the concentration of DNA in terms of [NP], the concentration of base
pairs can be expressed as [DNA]/2. So Eq. (5) can be written as
Cb=Cf ¼ Kf½DNAꢃ=2sg
ð6Þ
h
Cf and Cb denote the concentrations of free and DNA bound species,
respectively.
The Cb/Cf ratio was determined by the equation given below
[30]
300
400
500
600
Cb=Cf ¼ ðI ꢁ IDNAÞ=IDNA
where IDNA and I represent the peak current of the drug with and
without DNA.
Putting the values of K as calculated according to Eq. (4), the
values of binding site size as listed in Table 2 were obtained from
ð7Þ
Wavelength/nm
1
0.8
0.6
0.4
0.2
0
C
a
0.7
2
0.6
3
0.5
g
0.4
1
0.3
0.2
0.1
0
290
390
490
590
Wavelength/nm
Fig. 6. (A) Absorption spectra of 30
(b) 30 M, (c) 40 M, (d) 50 M, (e), 60
aqueous DMSO at 25 °C. (B) Absorption spectra of 30
presence of 20 M, (b) 30 M, (c) 40 M, (d) 50 M, (e), 60
80 M DNA (h) in 10% aqueous DMSO at 25 °C. (C) Absorption spectra of 30
the absence (a) and presence of 20 M, (b) 30 M, (c) 40 M, (d) 50 M, (e), 60
(f), and 80 M DNA (g) in 10% aqueous DMSO at 25 °C.
l
M 1 in the absence (a) and presence of 20
M (f), 70 M (g) and 80 M DNA (h) in 10%
M 2 in the absence (a) and
M (f), 70 M (g) and
M 3 in
lM,
l
l
l
l
l
l
l
10
20
30
40
50
60
70
l
l
l
l
l
l
[DNA]/μM
l
l
l
l
l
l
lM
Fig. 5. I ꢁ IDNA/IDNA vs. [DNA] for the determination of binding site size.
l

2004
Zia-ur-Rehman et al. / Journal of Organometallic Chemistry 694 (2009) 1998–2004
concentration of DNA (20–80
spectra of 30 lM 1–3 is shown in Fig. 6A–C. The maximum absorp-
tion of complex 1 (Fig. 6A) at kmax = 397 nm, exhibited blue shift of
6 nm, indicating electrostatic interaction of 1 with DNA. Fig. 6B
l
M) on the electronic absorption
ks values of the DNA bound complexes as compared to free com-
plexes indicated slower electron transfer kinetics. The charge
transfer coefficient ( > 0.5), ratio of peak currents (Ipc/Ipa > 1)
and peak potential difference ( Ep > 60 < 212) indicated the qua-
a
D
shows that the peak position of 30
ly from kmax = 396 to 403 nm by the addition of 80
l
M 2 is shifted bathochromical-
si-reversibility of the redox processes. The binding constant, bind-
ing site size and the Gibbs free energy varied in the sequence:
2 > 3 > 1.
lM DNA,
accompanied with hypochromic shift from 0.796 to 0.307. These
remarkable spectral characteristics suggest intercalation of 2 into
the stacked base pairs domain of DNA [31–33]. The hypochromic
effect is caused by the overlapping of the electronic states of the
intercalating chromophore of the complex 2 with the DNA bases
Acknowledgment
The authors are grateful to Higher Education Commission of
Pakistan (HEC) for financial support.
[34] and the bathochromic shift is caused by the lowering in
p–
p
* transition energy of the complex due to its ordered stacking be-
tween the DNA base pairs after intercalation [35]. By the addition
of DNA, a slight red shift of peak at 410 nm and pronounce hypo-
chromic effect suggestive of intercalative mode of interaction of
3 (Fig. 6C). In short, UV–Vis results are quite consistent with the
CV results.
References
[1] E.R.T. Tiekink, Appl. Organomet. Chem. 22 (2008) 533.
[2] R.K. Gilpin, Anal. Chem. 69 (1997) 145R.
[3] Y.G. Jun, X.J. Juan, C.H. Yuan, L.Z. Zhou, Chin. J. Chem. 22 (2004) 1325.
[4] M.T. Carter, A.J. Bard, J. Am. Chem. Soc. 109 (1987) 7528.
[5] M.T. Carter, M. Rodriguez, A.J. Bard, J. Am. Chem. 111 (1989) 8901.
[6] T.C. Richards, A.J. Bard, Anal. Chem. 67 (1995) 3140.
[7] M. Rodriguez, A.J. Bard, Anal. Chem. 62 (1990) 2658.
[8] Z. Rehman, S. Shahzadi, S. Ali, G.X. Jin, Turk. J. Chem. 31 (2007) 435.
[9] Z. Rehman, M.M. Barsan, I. Wharf, N. Muhammad, S. Ali, A. Meetsma, Inorg.
Chim. Acta 361 (2008) 3322.
The binding constants were calculated according to the follow-
ing Eq. (8) [36–37]:
A0
eG
ꢁ
eG
eG eHꢁG
1
¼
þ
ð8Þ
A ꢁ A0 eHꢁG
ꢁ
eG K½DNAꢃ
[10] Z. Rehman, S. Shahzadi, S. Ali, A. Badshah, J. Iranian Chem. Soc. 3 (2006) 157.
[11] W.F.L. Armarego, C. Chai, Purification of Laboratory Chemicals, 5th ed.,
Butterworth, Oxford, 2003.
[12] J. Sambrook, E.F. Fritsch, T. Maniatis, Molecular Cloning: A Laboratory Manual,
2nd ed., Cold Spring Harbour Laboratory Press, New York, 1989.
[13] H.D. Yin, S.C. Xue, Appl. Organometal. Chem. 20 (2006) 283.
[14] Z. Rahman, S. Ali, N. Muhammed, A. Meetsma, Acta Crystallogr., Sect. E E63
(2007) m89.
[15] Z. Rahman, S. Ali, N. Muhammad, A. Meetsma, Acta Crystallogr., Sect. E E62
(2006) m3560.
[16] B. Wrackmeyer, Annu. Rep. NMR Spectrosc. 16 (1985) 73.
[17] B. Wrackmeyer, Annu. Rep. NMR Spectrosc. 38 (1999) 203.
[18] A. Tarassoli, T. Sedaghat, B. Neumüller, M. Ghassemzadeh, Inorg. Chim. Acta
318 (2001) 15.
where K is the binding constant, A0 and A are absorbance of the free
drug and the apparent one, eG and eH–G are their absorption coeffi-
cients, respectively.
The slope to intercept ratio of the plot between A0/(A ꢁ A0) ver-
sus 1/[DNA] yielded the binding constant, K = 1.32 ꢀ 103,
7.21 ꢀ 103 and 6.22 ꢀ 103 Mꢁ1 for 1–3, respectively. The K ob-
tained here follows the same order as was obtained from CV data.
The slight difference in the values of UV–Vis and CV binding con-
stant may be due to the use of supporting electrolyte in CV
measurements.
[19] P.G. Harrison, in: P.G. Harrison (Ed.), Chemistry of Tin, 1st ed., Blackie
Academic and Professional, London, 1989, p. 105.
4. Conclusions
[20] X. Jiang, X. Lin, Bioelectrochemistry 68 (2006) 206.
[21] A. Shah, A.M. Khan, R. Qureshi, F.L. Ansari, M.F. Nazar, S.S. Shah, Int. J. Mol. Sci.
9 (2008) 1424.
In summary, new complexes 1–3 of 4-(4-nitrophenyl)pipera-
zine-1-carbodithioate ligand were synthesized and characterized.
Spectroscopic exploration confirmed penta-coordinate geometry
for 1 and 2, while hexa-coordinate environment was found around
Sn in 3. The anisobidentate nature of the ligand proposed from the
IR spectroscopy concurs well with the reported crystal structures
for 1 and 2. The decrease in peak currents of complexes 1–3, by
the addition of DNA evidenced their interaction with DNA. The po-
sitive shift of peak potential in case of 2 and 3 by the addition of
DNA, signified the intercalation mode, in which the molecules in-
sert into the base pair domain of DNA, due to which the diffusion
coefficients of the bound complexes are lowered as was observed.
In general, the diffusion coefficients of the compounds decrease
with the increase in molecular weight but the results of our exper-
iments showed opposite trend indicating the dominant role of the
ligands in deciding the order in which the Df values vary. The lower
[22] J.E.B. Randles, Trans. Faraday Soc. 44 (1948) 327.
[23] A. Sevcik, Collect. Czech., Chem. Commun. 13 (1948) 349.
[24] E. Niranjana, R.R. Naik, B.E.K. Swamy, Y.D. Bodke, B.S. Sherigara, H.
Jayadevappa, B.V. Badami, Int. J. Electrochem. Sci. 3 (2008) 980.
[25] R.J. Klinger, J.K. Kochi, J. Phys. Chem. 85 (1981) 12.
[26] Q. Feng, N.Q. Li, Y.Y. Jiang, Anal. Chim. Acta 344 (1997) 97.
[27] Q. Lie, P. Yang, H. Wang, M. Guo, J. Inorg. Biochem. 64 (1996) 181.
[28] J. Rusanova, S. Decurtins, E. Rosanov, H.S. Evans, S. Delahaye, A. Hauser, J.
Chem. Soc., Dalton. Trans. (2002) 4318.
[29] A. Ambroise, B.G. Maiya, Inorg. Chem. 39 (2000) 4264.
[30] M. Aslanoglu, C.J. Isaac, A. Houlton, B.R. Horrocks, Analyst 125 (2000) 1791.
[31] E.C. Long, J.K. Barton, Acc. Chem. Res. 23 (1990) 273.
[32] G.J. Yang, J.J. Xu, H.Y. Chen, Z.Z. Leng, Chin. J. Chem. 22 (2004) 1325.
[33] L.Z. Zhang, G.Q. Tang, J. Photochem. Photobiol. B: Biol. 74 (2004) 119.
[34] R. Fukuda, S. Takenaka, M. Takagi, J. Chem. Soc., Chem. Commun. 15 (1990)
1028.
[35] X.J. Dang, J. Tong, H.L. Li, J. Inclusion Phenom. 24 (1996) 275.
[36] M.Y. Ni, Y. Wang, H.L. Li, Pol. J. Chem. 71 (1997) 816.
[37] J.B. Lepecq, C. Paoletti, J. Mol. Biol. 27 (1967) 87.