Synthetic, structural and kinetic studies on the binding of cyclohexane-1,2-bis(4-methyl-3-thiosemicarbazone) to divalent metal ions (Co, Ni, Cu, Zn or Cd)

Article abstract of DOI:10.1039/b814852j

The reactions of cyclohexane-1,2-bis(4-methyl-3-thiosemicarbazone) (CHMTSC) with MCl₂ (M = Co, Ni, Cu or Zn) and Cd(NO₃)₂ have been shown to produce complexes in which the thiosemicarbazone has been doubly deprotonated {[M

Full text of DOI:10.1039/b814852j

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/dalton | Dalton Transactions
Synthetic, structural and kinetic studies on the binding of
cyclohexane-1,2-bis(4-methyl-3-thiosemicarbazone) to divalent
metal ions (Co, Ni, Cu, Zn or Cd)†
a
b
b
b
Ahmed Jasim M. Al-Karawi,* William Clegg, Ross W. Harrington and Richard A. Henderson*
Received 26th August 2008, Accepted 29th September 2008
First published as an Advance Article on the web 12th November 2008
DOI: 10.1039/b814852j
The reactions of cyclohexane-1,2-bis(4-methyl-3-thiosemicarbazone) (CHMTSC) with MCl
Ni, Cu or Zn) and Cd(NO have been shown to produce complexes in which the thiosemicarbazone
has been doubly deprotonated {[M(CHMTSC - 2H )] (M = Co, Ni or Ni)}, analogous to those
reported earlier with other Schiff base thiosemicarbazones. However, with ZnCl and Cd(NO , the
complexes isolated are [ZnCl(CHMTSC)]Cl and [Cd(NO )(CHMTSC)]NO , containing the protonated
2
(M = Co,
)
3 2
+
2
)
3 2
3
3
forms of the ligand, which have been characterised by X-ray crystallography, as has free CHMTSC. The
kinetics of the reactions between CHMTSC and all the various metal salts have been determined by
stopped-flow spectrophotometry. In all cases, the reactions are complete on the seconds timescale. The
reactions exhibit a first-order dependence on the concentration of metal salt and a first-order
dependence on the concentration of CHMTSC. The thermodynamic and kinetic factors influencing the
protonation state of the coordinated thiosemicarbazone are discussed.
Introduction
quantitative determination of a variety of metal ions, and in
organic analysis for identification of aldehydes and ketones.
The presence of amide, imine and C=S groups in thiosemi-
22,23
Thiosemicarbazides and their metal complexes find applications
in areas as diverse as nuclear medicine, pharmacology and
analytical chemistry. In particular, Cu(II) Schiff base com-
plexes of thiosemicarbazones have been investigated as anticancer
carbazides make them potentially polydentate ligands with
1–6
24–26
a variety of different donor atoms possible.
Numerous
complexes of thiosemicarbazones have been prepared and
7
chemotherapeutic agents and radical scavengers. In addition, it is
27–31
characterized.
In this paper, we report the synthesis, charac-
their use as agents capable of delivering radioactive copper in new
copper-based radiopharmaceuticals, together with the hypoxic
selectivity of certain copper thiosemicarbazone complexes, that
terization and X-ray crystal structure of cyclohexane-1,2-bis(4-
methyl-3-thiosemicarbazone) (CHMTSC) (Fig. 1). This molecule
2+
coordinates to a variety of divalent metal ions M (M = Co, Ni,
6–8
has created much recent interest. Furthermore, there has been
an increased interest in thiosemicarbazones, particularly in the
last few years, related to their range of biological properties,
Cu, Zn or Cd), and two types of complexes are obtained, which
differ in the protonation state of the CHMTSC ligand. With Zn
or Cd, X-ray crystallography shows that the isolated products
9
–16
for example as antiviral, antibacterial and anticancer agents,
2+
contain the {M(CHMTSC)} core in which CHTMSC acts as a
17
18
antifungal and antitumour properties as well as being suggested
19,20
as pesticides.
These biological activities are often attributed to
thiosemicarbazones chelating with metal ions. The present level
of interest in metal complexes of thiosemicarbazones stems from
the fact that the biological activity of the organic compound is
21
enhanced by coordination to a transition metal.
In the laboratory, the interest in thiosemicarbazone complexes
relates to their applications in chemical analysis. In inorganic
analysis, thiosemicarbazones have been used as reagents for the
a
Al-Mustansiriya University, College of Sciences, Department of Chem-
istry, P.O. Box 46010, Baghdad, Iraq. E-mail: a_jasim2006@yahoo.com;
Tel: +964 7901 333 232
b
School of Chemistry, Newcastle University, Newcastle upon Tyne, UK NE1
7
0
†
RU. E-mail: r.a.henderson@ncl.ac.uk; Fax: +44 0191 222 6929; Tel: +44
191 222 6636
Electronic supplementary information (ESI) available: Kinetic data for
Fig. 1 The structure of CHTMSC. Selected bond lengths ( A˚ ) and angles
( ): C(3)–N(3) 1.2979(17), C(2)–S(1) 1.6829(4), N(3)–N(2) 1.3585(16),
2+
the reactions between M (M = Zn, Cd, Co, Ni or Cu) and CHMTSC
◦
◦
in MeCN at 25 C. CCDC reference numbers 699874–699876. For ESI
and crystallographic data in CIF or other electronic format see DOI:
1
C(2)–N(1) 1.3248(19), N(2)–C(2)
120.44(12), N(2)–C(2)–S(1) 118.90(11), N(2)–C(2)–N(1) 115.49(12).
=
1.3693(18); C(3)–N(3)–N(2)
0.1039/b814852j
5
64 | Dalton Trans., 2009, 564–570
This journal is © The Royal Society of Chemistry 2009

View Article Online
+
Table 1 Characterization of [M(CHMTSC - 2H )] (M = Co, Ni or Cu)
a
IR spectrum/cm-1
Elemental Analysis (calcd)
UV-vis spectrum
max/dm mol cm-1 Mass spectrum (M ) m/BM
3
-1
+
M
Colour
Yield (%)
C
N
H
l
max/nm
e
u
NH
u
CN
Co Dark red
Ni Green
72
62
35.1 (35.0) 24.3 (24.5) 4.8 (4.7) 512
70
35.3 (35.0) 24.1 (24.5) 4.9 (4.7) 635
220
750
160
320
240
900
342
343
1.75
—
3183
3130
1581
1587
3
4
4
05
93
Cu Dark green 73
34.2 (34.5) 24.4 (24.2) 4.5 (4.6) 367
347
1.65
3196
1573
a
Calculated values based on formulation [M(C10
16 6 2
H N S
)].
+
planar quadridentate ligand. The remainder of the coordination
sphere comprises anionic ligands derived from the parent metal
salt. In contrast, with Co, Ni or Cu, the isolated products are
Preparation of [M(CHMTSC - 2H )] (M = Co, Ni or Cu)
The preparation of all these complexes is essentially the same
and so a generic description of their synthesis will be presented.
To a solution of the metal nitrate salt in acetonitrile was added
the stoichiometric amount of CHMTSC. The solution was not
stirred and a microcrystalline solid was formed immediately. The
+
the neutral [M(CHMTSC - 2H )], in which the CHMTSC ligand
has been deprotonated at the two hydrazide nitrogen sites. Similar
32,33
complexes of Zn, Ni and Cu have been described before.
Kinetic
studies on the formation of all these complexes, together with
2
+
solid was removed by filtration, washed with CH CN, then diethyl
3
consideration of how coordination to M would affect N–H
acidity, suggests the factors that lead to formation of the two
types of products.
ether and finally dried in vacuo. All attempts to recrystallize
the samples, or to grow crystals from the reaction mixture,
suitable for X-ray crystallography, were unsuccessful. Elemental
analysis data, colour and yield for the complexes are given in
Table 1.
Experimental
Elemental analyses (C, H and N) were carried out on a Carlo
Erba 1108 analyzer. Electronic spectra were measured in the
region 200–1100 nm for solutions in DMF at room temperature
using a Shimadzu 160 UV–vis spectrophotometer. Infrared spectra
were recorded by using a Thermo Electron Corporation Nicolet
Preparation [Zn(CHMTSC)Cl]Cl·CH
3
CN
To a solution of anhydrous ZnCl in CH CN was added the
2
3
stoichiometric amount of CHMTSC. The solution was not stirred,
and after leaving undisturbed for 2–3 d, yellow crystals were
deposited. The crystals were removed by filtration, washed with
a small amount of MeCN and dried in vacuo. Yield = 66%.
1
13
Avatar 370 spectrometer. H and C NMR spectra were recorded
in DMSO–d using a Bruker 300 MHz spectrometer. Mass
6
1
H NMR spectrum d/ppm: 1.68–2.87 (cyclohexane protons,
spectra were obtained using an EI (+) micro mass autospec high-
resolution magnetic sector mass spectrometer.
m, 8H); 2.08 (CH
3
CN, s, 3H); 2.98 (CH , s, 6H); 8.87 (N(1)H
3
1
3
1
and N(6)H, s, 2H); 10.63 (N(2)H and N(5)H, s, 2H). C{ H}
All reagents were commercially available (Aldrich Chemical
Co.) and were used without further purification. All manipulations
in the synthesis of CHMTSC and the complexes were performed
in air. Solvents used in the syntheses were distilled from the
appropriate drying agent immediately prior to use.
NMR spectrum d/ppm: 20.14–29.90 (cyclohexane carbons); 30.13
(
(
CH
C=S).
3
); 32.52 (CH
3
CN); 137.82 (CH
C∫N); 146.15 (N=C); 178.67
3
Preparation [Cd(CHMTSC)(NO
3
)]NO
3
·CH
3
CN
This complex was prepared by a method analogous to that
Preparation of CHMTSC
described above for [Zn(CHMTSC)Cl]Cl·CH
3
CN, except that
1
To cyclohexane-1,2-dione (1.2 g, 10.7 mmol) dissolved in methanol
Cd(NO
3
)
2
·4H
2
O was employed. Yield = 68%. H NMR spectrum
3
(
50 cm ) was added 4-methyl-3-thiosemicarbazide (2.25 g,
d/ppm: 1.75–2.87 (cyclohexane protons, m, 8H); 3.09 (CH
3
, s,
3
2
1.4 mmol) in methanol (20 cm ). The mixture was heated under
6H); 8.85 (N(1)H and N(6)H, s, 2H); 11.36 (N(2)H and N(5)H, s,
1
3
1
reflux for 3 h. The clear solution was allowed to stand and
then was left to cool to 0 C. Yellow crystals formed after
2H). C{ H} NMR spectrum: 19.16–29.63 (cyclohexane carbons);
C); 178.53 (C=S).
◦
30.22 (CH ); 145.22 (N
=
3
4
8 h, and these were removed by filtration, washed with ice-cold
methanol and dried under vacuum. Yield = 50%, m.p = 188–
X-Ray crystal structures of CHMTSC, [Zn(CHMTSC)Cl]Cl·
CH CN and [Cd(CHMTSC)NO ]NO CN
·CH
◦
1
90 C. Elemental analysis (calculated value in parentheses): C
3
3
3
3
1
4
1.69 (41.96), H 6.42 (6.29), N 29.08 (29.37). H NMR spectrum
˚
d/ppm: 1.7–2.4 (cyclohexane protons, m, 8H); 3.0 (CH
(1)H and N(6)H, s, 2H); 10.6 (N(2)H and N(5)H, s, 2H). C{ H}
NMR spectrum d/ppm: 21.64–27.53 (cyclohexane carbons); 33.94
CH
); 138.32 (N=C); 179.53 (C=S).
3
, s, 6H); 8.6
Data were collected with MoKa radiation (l = 0.71073 A) at
1
3
1
34
(
N
150 K on a Bruker SMART 1K diffractometer. Semi-empirical
absorption corrections were applied, based on repeated and
symmetry-equivalent reflections. Non-merohedral twinning for
(
3
This journal is © The Royal Society of Chemistry 2009
Dalton Trans., 2009, 564–570 | 565

View Article Online
Table 2 Crystal and refinement data for the structures of CHMTSC, [ZnCl(CHMTSC)]Cl·MeCN and [Cd(NO
3
)(CHMTSC)]NO
[Cd(NO
3
·MeCN
Compound
CHMTSC
[ZnCl(CHMTSC)]Cl·CH
3
CN
3
)(CHMTSC)]NO
3
·CH
3
CN
Formula
C
10
H
18
N
6
S
2
C
12
H
21Cl
2
N
7
S
2
Zn
12 9 6 2
C H21CdN O S
-
1
M
r
/g mol
286.4
Monoclinic
P2 /n
10.1389(7)
8.7161(6)
15.9291(11)
99.967(1)
1386.44(17)
4
1.372
0.38
0.870, 0.895
11 948
3358, 0.0173
235
463.8
Monoclinic
P2 /n
11.9205(11)
7.8966(7)
20.2112(18)
100.084(2)
1873.1(3)
4
1.644
1.83
0.678, 0.982
28 236
563.9
Monoclinic
P2 /n
Crystal system
Space group
a/A˚
1
1
1
10.0365(11)
8.8416(9)
24.652(3)
101.2411(17)
2145.6(4)
4
1.746
1.261
0.700, 0.905
18 450
5196, 0.0287
290
b/A˚
c/A˚
◦
b/
V/A˚
3
Z
D
-
3
calc/g cm
m/mm
-1
Max., min. transmission
Reflections measured
Unique reflections, Rint
Refined parameters
237
2
R (F, F > 2s)
0.0350
0.0925
1.084
0.39, -0.24
0.0537
0.1130
1.061
0.0258
0.0621
1.096
0.86, -1.03
2
R
w
(F , all data)
2
Goodness of fit on F
Max., min. electron density/e A˚ -
3
0.75, -0.65
the Zn complex prevents the merging of equivalent reflections be-
fore refinement. The structures were solved by direct methods, and
refined on all F values. H atoms were refined freely for CHMTSC
Results and discussion
2
Type of complex formed
and on heteroatoms of the complexes, and were constrained with
a riding model otherwise. Crystal and refinement data are given
in Table 2.
Cyclohexane-1,2-bis(4-methyl-3-thiosemicarbazone) (CHMTSC)
was prepared by the condensation of cyclohexane-1,2-dione and
35
4
-methyl-3-thiosemicarbazide. The compound was characterized
1
13
by elemental analysis, IR, H, C NMR spectroscopy and mass
spectrometry (see Experimental), as well as X-ray crystallography
Kinetic studies
(
Fig. 1). The UV-vis spectrum of CHMTSC exhibited two
In the kinetic studies, the hydrated nitrate salts of Zn, Cd, Co, Ni
absorption peaks at 307 and 358 nm, tentatively attributable to
the (p–p*) and (n–p*) transitions, respectively. The X-ray crystal
structure reveals no unusual structural features and the bond
lengths and angles are very similar to those of other Schiff bases
and Cu were used. Acetonitrile (the solvent) was dried over CaH
2
and distilled under an atmosphere of dinitrogen immediately prior
to use.
32,33
All kinetic studies were performed using an Applied Photo-
physics SX.18MV stopped-flow spectrophotometer modified to
handle air-sensitive and non-aqueous solutions. The spectropho-
tometer was controlled via a RISC pc. The temperature was
derived from diones and thiosemicarbazides.
Consideration of the composition of CHMTSC indicates that
any of the six nitrogen atoms or two sulfur atoms could coordinate
to a metal ion. Studies on the reactions of CHMTSC with a
variety of divalent metal ions (M = Co, Ni, Cu, Zn or Cd), in
a 1 : 1 stoichiometric ratio, showed that two types of complexes
are formed. For M = Zn or Cd, well-formed crystalline salts
are produced slowly from solution and the structures have been
determined by X-ray crystallography. The structures clearly show
that in both the Zn and Cd complexes CHMTSC acts as a
quadridentate ligand with the two imine nitrogen atoms and two
sulfur atoms coordinating to the metals. In both complexes, the
CHMTSC ligand is effectively planar, presumably because of the
inflexibility in this ligand due to the extensive multiple bonding.
Furthermore, the bond lengths and angles within the ligand are
essentially the same for both the Cd and Zn complexes and are
◦
maintained at 25.0 ± 0.1 C using a Grant LTD 6G thermostat tank
with combined recirculating pump. The reactant solutions of metal
salt and CHMTSC were prepared in CH CN under an atmosphere
3
of dinitrogen and transferred to the spectrophotometer via gas-
tight, all-glass syringes. The solutions of all reagents were prepared
by dilution from freshly made stock solutions and used within 1 h
of preparation.
The absorbance-time traces were fitted to exponential curves
using the Applied Photophysics software. The observed rate
constants (kobs) presented in Fig. 6 are the average of at least three
experiments. The error bars presented in the figures show a 10%
reproducibility. All experiments were performed under pseudo-
first-order conditions with the concentration of CHMTSC in an
very similar to those reported for other Schiff base ligands derived
36
31–33
excess over the concentration of the metal ion. The dependence
on the concentration of CHMTSC was determined from plots of
from diones and thiosemicarbazides.
The remainder of the Zn
and Cd coordination is the anion of the metal salt used in the
preparation.
kobs versus [CHMTSC], as illustrated in Fig. 6. The straight line
plots were analysed by least-square fits, constrained to go through
the origin.
In [ZnCl(CHMTSC)]Cl (Fig. 2), Zn is five-coordinate. The
overall geometry is best described as square-based pyramidal,
5
66 | Dalton Trans., 2009, 564–570
This journal is © The Royal Society of Chemistry 2009

View Article Online
Fig. 4 The polymeric cation of [Cd(NO
3
)(CHMTSC)]NO
3
·CH
3
CN,
Fig. 2 Structure of [ZnCl(CHMTSC)]Cl·CH
3
CN. Selected bond lengths
showing the interconnection via bridging nitrates between adjacent
◦
+
˚
(
A˚ ) and bond angles ( ) are shown in Table 3.
[Cd(NO
(
3
)(CHMTSC)] units. Selected bond lengths (A) and bond angles
◦
) are shown in Table 3. Symmetry operator: (A) 3/2 - x, 1/2 + y,
1
/2 - z.
with the two imine nitrogen atoms and the two sulfur atoms of
the CHMTSC ligand occupying the basal positions, and a chloro
ligand occupying the apical site. The other chloride ion is not
coordinated. The angles between the donor atoms of the Schiff
angles between the donor atoms of the Schiff base ligand and the
O(3) oxygen atom are all 90 ± 8 .
◦
◦
In both [ZnCl(CHMTSC)]Cl and [Cd(NO
3
)(CHMTSC)]NO ,
3
base ligand and the coordinated Cl are all greater than 100 ,
a CH CN molecule, which was indicated by the elemental analysis
3
˚
showing that Zn sits slightly (0.40 A) above the mean plane of
and spectroscopy of the complex, is evident in the crystal structure.
A comparison of the various bond lengths and angles within
the CHMTSC ligands in the Zn and Cd complexes (Table 3)
shows that they are very similar, and also very similar to
those of uncoordinated CHMTSC (Fig. 1). Previous studies on
other Schiff base thiosemicarbazone complexes have reported the
the quadridentate ligand.
In [Cd(NO
3
)(CHMTSC)]NO (Fig. 3 and 4), Cd is seven-
3
coordinate. The repeating monomeric unit comprises Cd coor-
dinated by the planar CHTMSC ligand, and a nitrate group
32
acting as a bidentate ligand, as shown in Fig 3. Each of
+
these [Cd(NO
3
)(CHMTSC)] units is connected to its neighbour
+
X-ray crystal structures of [M(thiosemicarbazone - 2H )] (M =
through one of the coordinated oxygen atoms of the bidentate
nitrate. Thus, the coordination environment of each Cd atom
comprises a central CHMTSC quadridentate ligand and two trans
nitrate groups; one nitrate is a bidentate ligand to Cd whilst the
other is a monodentate ligand bonded through an oxygen atom,
which is also bonded to the adjacent Cd atom. The result is that
the coordination sphere of the Cd is probably best described as
a distorted octahedron with the CHMTSC ligand defining an
equatorial plane. In contrast to the Zn complex, the Cd atom
in this complex sits in the plane of the Schiff base ligand. The
Zn, Ni or Cu) in which the Schiff base thiosemicarbazone ligand
is deprotonated at the hydrazide atoms. Thus, in the structure of
[
Zn(ATSE)(MeOH)] (where ATSE has the structure shown below)
˚
the average of the two C–N (hydrazide) bond lengths is 1.325 A
and the average C–S bond length is 1.758 A. A comparison with
the analogous bond lengths for [ZnCl(CHMTSC)] presented in
˚
+
Table 3 shows that the C–S distance in the CHMTSC complex is
significantly shorter than in the (deprotonated) ATSE complex.
Similarly, the C–N (hydrazide) bond length in the CHMTSC
complex is appreciably longer than in the ATSE complex. These
observations indicate that, whilst there is delocalisation in the
ATSE ligand, and both the C–N and C–S bonds have partial
double bond character, in the CHMTSC ligand, the C–S bond
has more double bond character and the C–N (hydrazide) bond
more single bond character.
In contrast to the type of complex obtained in the reactions
between the Zn and Cd salts and CHMTSC, with the salts
of Co, Ni or Cu elemental analysis and mass spectra of these
materials indicate that they are neutral complexes with the
+
formulation, [M(CHMTSC - 2H )], analogous to those such as
Fig. 3 Structure of the asymmetric unit of [Cd(NO
3
)(CHMTSC)]Cl·
◦
CH
Table 3.
3
CN. Selected bond lengths ( A˚ ) and bond angles ( ) are shown in
the ATSE complex described above. These complexes are formed
by dissociation of protons from the two hydrazide nitrogen atoms
This journal is © The Royal Society of Chemistry 2009
Dalton Trans., 2009, 564–570 | 567

View Article Online
◦
Table 3 Comparison of selected bond lengths ( A˚ ) and angles ( )
in the structures of [ZnCl(CHMTSC)]Cl·CH CN and [Cd(NO )-
CHMTSC)]NO CN
·CH
The poor solubility of the Ni complex precluded measuring the
H NMR spectrum.
1
3
3
(
3
3
Kinetics and mechanism of complex formation
Zn complex
Cd complex
We have investigated the kinetics of the reactions of CHMTSC
Ligand dimensions
2
+
with M (M = Co, Ni, Cu, Zn and Cd) in CH
3
CN, using stopped-
flow spectrophotometry to see if there is a difference in the kinetics
for the formation of the complexes where CHMTSC is coordinated
C(2)–N(2)
N(2)–N(3)
N(3)–C(3)
S(1)–C(2)
C(3)–N(3)–N(2)
N(3)–N(2)–C(2)
N(2)–C(2)–S(1)
N(2)–C(2)–N(1)
1.370(2)
1.352(2)
1.296(2)
1.359(3)
1.364(3)
1.287(3)
1.692(2)
119.27(19)
120.4(2)
(
M = Zn or Cd) or where the deprotonated ligand, CHMTSC -
1.709(2)
+
122.99(16)
117.10(16)
122.61(14)
115.36(18)
2H is coordinated (M = Co, Ni or Cu).
The reactions were studied under pseudo-first-order condi-
124.06(18)
115.2(2)
2+
tions with [CHMTSC] ≥ 10[M ]. In all cases, the stopped-
flow absorbance-time traces can be fitted to a single exponential
curve (Fig. 6), indicating that the reaction exhibits a first-order
Coordination
geometry
M = Zn
M = Cd
2
+
dependence on the concentration of M . This conclusion is
2
+
confirmed in studies where the concentration of M was varied in
-
3
-3
Zn–Cl(1)
Cd–O(1)
Cd–O(3)
Cd–O(1A)
M–S(1)
M–S(2)
M–N(3)
M–N(4)
S(1)–Zn–Cl(1)
S(2)–Zn–Cl(1)
N(3)–Zn–Cl(1)
N(4)–Zn–Cl(1)
S(1)–Cd–O(3)
S(2)–Cd–O(3)
N(3)–Cd–O(3)
N(4)–Cd–O(3)
S(1)–Cd–O(1)
S(2)–Cd–O(1)
N(3)–Cd–O(1)
N(4)–Cd–O(1)
S(1)–M–N(3)
S(1)–M–S(2)
N(3)–M–N(4)
S(2)–M–N(4)
2.2908(5)
—
—
—
the range 0.2–1.0 mmol dm with [CHMTSC] = 10 mmol dm ,
but the values of the observed rate constants (kobs) for each reaction
did not change (see ESI†).
2.4387(16)
2.5797(18)
2.3715(16)
2.5918(6)
2.5954(7)
2.3954(18)
2.4039(17)
—
—
2.3698(5)
2.3915(6)
2.1539(16)
2.1516(15)
111.06(2)
108.24(2)
100.70(4)
100.81(4)
—
—
—
—
—
—
—
—
80.37(4)
109.23(2)
71.55(6)
80.42(4)
—
—
—
97.73(4)
94.55(4)
83.09(6)
83.59(6)
81.96(4)
81.01(4)
124.03(6)
125.51(5)
74.15(5)
145.25(2)
65.79(6)
74.09(5)
of CHMTSC (Fig. 5). There are two sources of ionizable protons
in CHMTSC: N–H on the hydrazide residue and N–H on the
NHMe group. Despite numerous attempts, we have been unable
to produce crystals of suitable quality for X-ray structural analysis.
2+
Fig. 6 Typical kinetic data for the reactions of M with CHMTSC
◦
2+
in MeCN at 25 C. The example shown is for the reaction with Co .
2+
Top shows a typical stopped-flow absorbance-time curve when [Co ] =
3
-3
0
.2 mmol dm- and [CHMTSC] = 2 mmol dm . The solid black curve
is the experimental data and the grey dashed curve is the fit. The fit is
-1.9t
defined by the equation A
dependence of kobs on the concentration of CHMTSC. Error bars show
t
= 0.359–0.335e . Bottom shows the first-order
1
0% reproducibility. Straight line fit to the data is that defined by the
3
equation kobs = 1.3 ¥ 10 [CHMTSC].
For each different metal ion, the dependence of kobs on the con-
centration of CHMTSC was the same, with all reactions exhibiting
a first-order dependence on the concentration of CHMTSC, as
Fig. 5 Product types formed in the reactions of MX
68 | Dalton Trans., 2009, 564–570
2
salts with CHMTSC.
5
This journal is © The Royal Society of Chemistry 2009

View Article Online
typified by the plot shown in Fig. 6 and the corresponding rate
law in eqn (1). The reactions could only be studied up to a
Table 4 Summary of rate constants for the reactions of CHMTSC
with M (M = Co, Ni, Cu, Zn or Cd) in MeCN at 25.0 C
2+
◦
-
3
maximum concentration of [CHMTSC] = 10 mmol dm because
2+
M
/dm mol s-1
3
-1
Metal ion M
k
a
of the limited solubility of the thiosemicarbazone in CH CN. A
3
3
mechanism consistent with the observed kinetics is shown in
Fig. 7.
Co
Ni
Cu
Zn
Cd
1.3 ± 0.1 ¥ 102
6.0 ± 0.5 ¥ 10
3
2.0 ± 0.2 ¥ 10
2
6.4 ± 0.5 ¥ 10
6.2 ± 0.5 ¥ 10
2
+
-
d ÈM
˘
2
Î
˚
M
2+
(
1)
=
ka
[
CHMTSC
]
ÈM
˘
˚
Î
dt
2
+
M
M
2+
2+
-
d ÈM
˘
k1 k2
[
CHMTSC
]
ÈM
˘
[M(NCMe) ] and reflects the relative dissociative lability of these
6
38
Î
˚
Î
˚
= k
(2)
(3)
M
metal ions.
dt
[
CH CN
]
+ k M
[
CHMTSC
]
-
1
3
2
2
+
The rates of the reactions between [M(NCMe)
Ni or Cu) and CHMTSC are 10–1000 times slower than the
rates of solvent exchange of the cations in acetonitrile. This
observation is consistent with the Eigen–Wilkins mechanism in
n
]
(M = Co,
2
+
M
M
2+
-
d ÈM
˘
k1 k2
[
CHMTSC
]
ÈM
˘
Î
˚
Î
˚
38
=
M
dt
k-
[
CH CN
]
39
1
3
2
+
n
which outer-sphere association of CHMTSC with [M(NCMe) ]
precedes rate-limiting dissociation of a coordinated solvent, but
the CHMTSC does not always bind to the vacant site on the metal
complex. Most of the time another solvent molecule will bind
to the coordinatively-unsaturated intermediate. Consequently, the
rate of solvent exchange is faster than the rate of substitution.
Conclusions
In this paper, we have described two types of complexes formed
in the reactions between CHMTSC and divalent metal ions; the
difference in the two types of complex is that with M = Zn or Cd
2
+
the isolated products contain the {M(CHMTSC)} core whilst
with M = Co, Ni or Cu the products contain {M(CHMTSC -
+
2
H )} in which the CHMTSC ligand has been deprotonated,
presumably at both hydrazide nitrogen atoms. It is clearly of
importance to understand the factors that control which type of
complex is formed: kinetic or thermodynamic.
Fig. 7 Proposed mechanism for the formation of complexes containing
2+
+
the {M(CHMTSC)} and {M(CHMTSC - 2H )} cores in the reactions
of M with CHMTSC in MeCN.
2
+
2+
Our kinetic studies on the reactions between M and CHMTSC
show that for all systems, both the rate laws and values of the
rate constants are very similar. There is no obvious difference
in the kinetics between formation of products containing a
37
In line with other studies on chelate formation, we propose
that the rate-limiting step of the chelate formation is the initial
2
+
+
{M(CHMTSC)} or a {M(CHMTSC - 2H )} core. This observa-
tion indicates that the protonation state of the ligand is controlled
by factors, which occur after the steps monitored in the kinetic
studies. It seems likely, therefore, that the protonation state of
the CHMTSC ligand is controlled principally by thermodynamic
factors defined by the metal site (metal and its co-ligands).
It would be anticipated that coordination of a hard Lewis
2
+
binding of CHMTSC to [M(NCMe)
the coordinated CH CN molecules. The usual intimate mechanism
for such a reaction is dissociative and involves initial dissoci-
n
] by replacement of one of
3
2
+
ation of a coordinated solvent from [M(NCMe)
[
n
] , generating
2
+
M(NCMe)(n-1)] containing a vacant site at which CHMTSC can
bind (we suggest initially through a sulfur) as shown in Fig. 7.
The full rate law for this mechanism is shown in eqn (2) and
indicates that, over a large concentration range of CHMTSC, the
kinetics would exhibit a non-linear dependence on concentration
of CHMTSC. However, when the concentration of CHMTSC is
2
+
acid (M ) to the Schiff base thiosemicarbazide will make the
N–H groups on CHMTSC more acidic through the electron-
withdrawing ability of the metal ion. However, the electron-
withdrawing capability of the metal ion would be expected to
be tempered by the coordination of an anion to the metal site.
This proposal rationalizes why we isolate complexes containing
M
M
small, k-1 [MeCN] > k
2
[CHMTSC] the rate law would simplify
to that shown in eqn (3), which is of the same form as observed
experimentally in eqn (1). For each of the reactions studied, the
the protonated CHMTSC ligands at Zn–Cl and Cd–NO . If
3
M
M
M
M
values of k
a
= k
1
k
2
/k-1 [MeCN] are presented in Table 4.
such an argument is valid, then the protonation state of the
thiosemicarbazide quadridentate ligand is coupled to, and can
Inspection of the rate constants in Table 4 reveals some
interesting trends. In particular, the values of k
insensitive to the nature of M . Interestingly though, k
M
-
a
are rather
increases
be controlled by, the coordination of anions (X ) to the metal, as
2
+
M
a
illustrated in eqn (4). Whilst this is an attractive, and reasonable
proposition, it is difficult to test because of the poor solubility of
with the metal in the sequence Cu > Co > Ni, which is the
same order as the solvent exchange rates of the corresponding
+
[M(CHMTSC - 2H )], which complicates any analysis.
This journal is © The Royal Society of Chemistry 2009
Dalton Trans., 2009, 564–570 | 569

View Article Online
1
1
1
2 J. R. Dimmock, R. N. Puthucode, J. M. Smith, M. Hetherington, J. W.
Quail, U. Pugazhenthi, T. Lechler and J. P. Stables, J. Med. Chem.,
(
4)
1
996, 39, 3984.
3 J. R. Dimmock, S. Pandeya, J. W. Quail, U. Pugazhenthi, T. M. Allen,
G. Y. Kao, J. Balzarini and E. DeClercq, Eur. J. Med. Chem., 1995, 30,
3
03.
However, all of the divalent metal ions studied in this paper are
labile centres and it would be anticipated that all of them would
be capable of binding anions present in solution, presumably
with the anions having similar residence times on the metal. It
would be anticipated therefore that all the systems reported in this
4 J. R. Dimmock, K. Sidhu, S. Tumber, S. K. Basram, M. Chen, J. W.
Quail, J. W. Yang, I. Rozas and D. F. Weaver, Eur. J. Med. Chem., 1995,
30, 287.
1
1
5 G. Ibrahim, G. Bouet, I. H. Hall and M. A. Khan, J. Inorg. Biochem.,
2
000, 81, 29.
6 N. Buu-Hoi, T. Loc and N. Xuong, Bull. Soc. Chim. Fr., 1955,
694.
+
paper could produce complexes of the type [MX(CHMTSC)] and
+
17 M. A. Ali and S. E. Livingston, Coord. Chem. Rev., 1974, 13,
[
M(CHMTSC - 2H )]. The observation that when M = Co, Ni or
+
101.
Cu we only isolate complexes of the type [M(CHMTSC - 2H )]
1
8 H. G. Petering, H. H. Buskik and G. E. Underwood, Cancer Res., 1964,
indicates what controls the type of product isolated is the relative
solubilities of [MX(CHMTSC)] and [M(CHMTSC - 2H )]. The
6
4, 367.
+
+
19 J. R. Dilworth, J. Lewis, J. Miller and Y. Zheng, J. Chem. Soc., Dalton
Trans., 1995, 1357.
2
+
very poor solubility of [M(CHMTSC - 2H )] (M = Co, Ni or
0 D. X. West, S. Padhye and P. B. Sonawane, Struct. Bonding, 1991, 76,
Cu) results in these species being the only products isolated in
the reactions. Attempts to protonate these complexes with strong
1
.
21 M. J. Cambell, Coord. Chem. Rev., 1975, 15, 279.
2
2
2
2
2 S. Ghazy, M. Kabil, A. El-Asmy and Y. E. Sherif, Afinidad, 1995, 52,
28.
3 M. Kabil, S. Ghazy, A. El-Asmy and Y. E. Sherif, Anal. Sci., 1996, 12,
31.
4 S. B. Novakovic, Z. D. Tomic, V. Jevtovic and V. M. Leovac, Acta
Crystallogr., Sect. C: Cryst. Struct. Commun., 2002, 58, m358.
5 O. Mikhailov, M. Kazymova, T. Shumilora and S. Solovieva, Transition
Met. Chem., 2003, 28, 665.
acids (HCl or HNO ) did not produce any tractable product, only
decomposition of the complex.
3
1
4
Acknowledgements
We thank the Iraqi Ministry of Higher Education and Scientific
Research for funding. Baghdad University and Al-Mustansiriya
University (to A. J. M. Al-K.).
26 A. A. Abou-Hussen, N. M. El-Metwally, E. M. Saad and A. A. El-
Asmy, J. Coord. Chem., 2005, 58, 1735.
2
2
7 M. Campbell, Coord. Chem. Rev., 1975, 15, 279.
8 S. Padhye and G. B. Kauffman, Coord. Chem. Rev., 1985, 63,
1
27.
Notes and references
2
9 J. S. Casas, M. S. Garcia-Tasende and J. Sordo, Coord. Chem. Rev.,
1
Y. Kang, N. Yang, S. Kang, J. Ko, C.-H. Lee and Y.-H. Lee,
Organometallics, 1997, 16, 5522.
D. X. West, J. K. Swearingen, J. Valdes-Martinez, S. Hernandez-Ortega,
A. K. El-Sawaf, F. van Meurs, A. Castineras, I. Garcia and E. Bermejo,
Polyhedron, 1999, 18, 2919.
P. Tarasconi, S. Capacchi, G. Pelosi, M. Cornia, R. Albertini, A. Bonati,
P. Dall Aglio, P. Lunghi and S. Pinelli, Bioorg. Med. Chem., 2000, 8,
2000, 209, 197.
30 V. Arion, M. Revenco, J. Gradinaru, Y. Simonov, V. Kravtsov, N.
Gerbeleu, E. Saint-Aman and F. Adams, Rev. Inorg. Chem., 2001,
21, 1.
31 C. Clarke, A. R. Cowley, J. R. Dilworth and P. S. Donnelly, Dalton
Trans., 2004, 2402.
32 J. P. Holland, F. I. Aigbirhio, H. M. Betts, P. D. Bonnitcha, P. Burke,
M. Christlieb, G. C. Churchill, A. R. Cowley, J. R. Dilworth, P. S.
Donnelly, J. C. Green, J. M. Peach, S. R. Vasudevan and J. E. Warren,
Inorg. Chem., 2007, 46, 465, and references therein.
33 A. R. Cowley, J. R. Dilworth, P. S. Donnelly, J. M. Heslop and S. R.
Ratcliffe, Dalton Trans., 2007, 209, and references therein.
34 SMART and SAINT software, Bruker AXS Inc., Madison, Wisconsin,
USA, 2001; CELL_NOW, G. M. Sheldrick, University of G o¨ ttingen,
Germany, 2007.
2
3
1
57.
A. Kumar and S. Chandra, Synth. React. Inorg. Met.-Org. Chem., 1993,
3, 671.
S. E. Ghazy, M. A. Kabil, A. A. El-Asmy and Y. A. Sherief, Anal. Lett.,
996, 29, 1215.
4
5
6
7
8
9
2
1
J. R. Dilworth, A. H. Cowley, P. S. Donnelly, A. D. Gee and J. M.
Heslop, Dalton Trans., 2004, 2404.
K. Wada, Y. Fujibayashi and A. Yokoyama, Arch. Biochem. and
Biophys., 1994, 310, 1.
Y. Fujibayashi, H. Taniuchi, Y. Yonekura, H. Ohtani, J. Konishi and
A. Yokohawa, J. Nucl. Med., 1993, 38, 1155.
Z. Xiao, P. S. Donnelly, M. Zimmermann and A. G. Wedd, Inorg.
Chem., 2008, 47, 4338, and references therein.
35 G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr., 2008,
64, 112.
36 R. G. Wilkins, Kinetics and Mechanism of Reactions of Transition Metal
Complexes, VCH, Weinheim, 1991, 2nd edn, ch. 1.
37 M. L. Tobe and J. Burgess, Inorganic Reaction Mechanisms, Longman,
1
1
0 N. Z. Knezevic, V. M. Leovac, V. Jevtovic, S. Grguric-Spika and T. J.
Sabo, Inorg. Chem. Commun., 2003, 6, 561.
1 P. Yogeeswari, D. Sriram, V. Veena, R. Kavya, K. Rakhra, J. V.
Ragavendran, S. Mehta, S. Thirumuruga and J. P. Stables, Biomed.
Pharmacother., 2005, 59, 51.
Harlow, 1999, ch. 7, and references therein.
38 (a) F. A. Dunand, L. Helm and A. E. Merbach, Adv. Inorg. Chem., 2003,
54, 1, and references therein; (b) J. Burgess, Metal Ions in Solution, Ellis-
Horwood, Chichester, 1978, ch. 11.
39 D. T. Richens, Chem. Rev., 2005, 105, 1961, and references therein.
5
70 | Dalton Trans., 2009, 564–570
This journal is © The Royal Society of Chemistry 2009