Synthesis, characterization, and X-ray crystal structures of copper(II) and nickel(II) complexes with two bis(thiosemicarbazone) ligands and investigation of their electrochemical behavior

Article abstract of DOI:10.1007/s11243-015-9997-z

Two new bis(thiosemicarbazone) ligands having a halogen substituent on the non-coordinating phenyl rings, namely 2-[1-(2-{3-[2-({2-[(4-bromoanilino)carbothioyl]hydrazono} methyl)phenoxy]propoxy}phenyl)methylidene]-N1-(4-bromophenyl)-1-hydrazinecarbothiami

Full text of DOI:10.1007/s11243-015-9997-z

Transition Met Chem
DOI 10.1007/s11243-015-9997-z
Synthesis, characterization, and X-ray crystal structures
of copper(II) and nickel(II) complexes with two
bis(thiosemicarbazone) ligands and investigation of their
electrochemical behavior
Seyed Abolfazl Hosseini-Yazdi1 Sara Hosseinpour1 Ali Akbar Khandar1
Jonathan White2
•
•
•
Received: 8 August 2015 / Accepted: 29 October 2015
Ó Springer International Publishing Switzerland 2015
Abstract Two new bis(thiosemicarbazone) ligands having
a halogen substituent on the non-coordinating phenyl rings,
namely 2-[1-(2-{3-[2-({2-[(4-bromoanilino)carbothioyl]
hydrazono} methyl)phenoxy]propoxy}phenyl)methylidene]-
N1-(4-bromophenyl)-1-hydrazinecarbothiamide (H2L3) and
2-[1-(2-{3-[2-({2-[(4-bromoanilino)carbothioyl]hydrazono}
methyl)phenoxy]-2-hydroxypropoxy}phenyl) methylidene]-
Introduction
Thiosemicarbazone (TSC) ligands, derived from the con-
densation of a thiosemicarbazide with an aldehyde or
ketone, are useful for obtaining coordination spheres with
mixed N/S donors. Transition metal-based thiosemicar-
bazone complexes can show a wide range of biological
activities including antibacterial, antifungal, antiviral,
antimalarial, and antitumor activities, which have been
investigated intensively over five decades [1, 2].
N1-(4-bromophenyl)-1-hydrazinecarbothiamide
(H3L4),
were used in thesynthesis of a series of CuII andNiII complexes
[Cu(L3)]ÁMeOH, [Cu(HL4)], [Ni(L3)], and [Ni(HL4)]Á
MeOH. The complexes were characterized by physico-
chemical and spectroscopic methods. Single-crystal X-ray
structures of [Cu(L3)]ÁMeOH, [Cu(HL4)], and [Ni(L3)]
showed that the metal centers are coordinated by two imine
nitrogen atoms and two sulfur atoms in a distorted square-
planar coordination geometry. Electrochemical investiga-
tions showed that all of these CuII and NiII complexes were
reversibly reducible. Although the bromine substituent on
the phenyl ring and the hydroxyl group are far from the metal
centers, they have an effect on the redox potentials of the NiII/I
and CuII/I couples.
Structure–activity relationships are important for the
design of thiosemicarbazone complexes [3, 4]. Recently, a
series of Cu(II) complexes of substituted bis(thiosemicar-
bazone) ligands has been reported, in which substitution of
the ligand has a significant effect on their electrochemical
behavior [1, 5, 6] and biological activity [7, 8]. Indeed, a
close relationship between the electrochemical behavior
and biological activity has been noted [4, 9–11]. The redox
potential of the accessible CuII/CuI couple varies dramati-
cally depending on the ligand environment, specifically the
donor set, geometry, substituent electronic and steric
effects, and chelation [12]. The factors controlling the
stabilization/destabilization of Cu(I) and Ni(I) species in
various coordination environments are of interest not only
for inorganic chemists, but also for biochemists. Unusual
oxidation states of nickel involved in the active sites of
certain hydrogenases and dehydrogenases [13] and com-
plexes which stabilize the CuI oxidation state have been
used as anticancer chemotherapeutic agents [14] and as
superoxide dismutase-like radical scavengers [15].
Electronic supplementary material The online version of this
article (doi:10.1007/s11243-015-9997-z) contains supplementary
material, which is available to authorized users.
& Seyed Abolfazl Hosseini-Yazdi
hosseiniyazdi@yahoo.com
We have been previously reported nickel(II) and cop-
per(II) complexes of two bis(thiosemicarbazone) ligands,
H2L1 and H3L2 (Scheme 1), which showed a marked
ability to stabilize low oxidation states of CuI and NiI [16].
In an extension of these studies, here we report the synthesis
1
Department of Inorganic Chemistry, Faculty of Chemistry,
University of Tabriz, Tabriz 51666-14766, Iran
2
School of Chemistry and Bio-21 Institute, University of
Melbourne, Parkville, VIC, Australia
123

Transition Met Chem
Scheme 1 Ligands and
corresponding complexes
of two bromine-substituted bis(thiosemicarbazone) ligands,
H2L3 and H3L4 (Scheme 1). The effects of halogen groups
at positions R2 and R3 and a hydroxyl group at R1 on the
structure and electrochemical behavior of the copper(II) and
nickel(II) complexes have been investigated.
found to be shifted to lower frequencies in the range of
1301–1303 cm-1. This is consistent with thiolate formation
and coordination via the thiolate sulfur atom [19, 20].
Based on the above spectral evidence, we deduce that
the ligands H2L3 and H3L4 are coordinated via the
azomethine nitrogen and thiolate sulfur. These observa-
tions have also been confirmed by X-ray single-crystal
structure determinations.
Results and discussion
Synthesis and characterization
UV–Vis spectroscopy
Condensation of two equivalents 4-bromophenyl thiosemi-
carbazide and one equivalent of 2-[3-(2-formylphenoxy)
propoxy]benzaldehyde (1) and 2-[3-(2-formylphenoxy)-2-
hydroxypropoxy]benzaldehyde (2) as dialdehydes gave
bis(thiosemicarbazones) H2L3 and H3L4, respectively, in
The UV–Vis spectra of all these compounds were recorded
in CH2Cl2 (as a non-coordinating solvent) and are shown in
Figs. 1 and 2, while the spectral data are tabulated in
Table 1. The spectra of H2L3 and H3L4 exhibit similar
patterns in the 230–700 nm region, being dominated by
intra-ligand bands around 312 and 340 nm for H2L3 and
313 and 336 nm for H3L4 associated with the phenyl rings,
1
high yields. The H NMR spectra of H2L3 and H3L4 in
DMSO-d6 exhibited singlets at 8.63 and 8.62 ppm, respec-
tively, assigned to the HC=N protons. Also singlets at d
10.12 and 10.10 ppm assigned to the BrPhNH protons and
at d 11.91 and 11.88 ppm assigned to the =N–NH protons
were observed for H2L3 and H3L4, respectively. Usually
the SH resonance for the thiol form of a thiosemicarbazone
appears as a broad signal at d = 4.0 0.2 ppm; no such
signal was observed in these spectra, indicating that both
ligands exist in the thione form in solution [17]. Further-
more, the FTIR spectra of H2L3 and H3L4 did not display
any SH vibration in the region 2500–2600 cm-1, indicating
that in the solid state both compounds are in the thione
form [18].
The nickel(II) and copper(II) complexes were prepared
by the reactions of the respective acetates with the ligands
under reflux. If we consider the strongest peak at 1542
cm-1 for H2L3 and at 1551 cm-1 for H3L4 corresponding
to the imine bond, these peaks are shifted to lower wave
numbers upon coordination (1487, 1486, 1506, and
1497 cm-1, respectively, for [CuL3]ÁMeOH, [Cu(HL4)],
[NiL3], and [Ni(HL4)]ÁMeOH). In the free ligands, a band
at 1321 cm-1 for H2L3 and at 1336 cm-1 for H3L4 is
assigned to m(C=S), whereas in the complexes, this band is
Fig. 1 UV–Vis absorption spectra of 3 9 10-5 M [CuL3]ÁMeOH,
4 9 10-5 M [Cu(HL4)], 5 9 10-4 M [H3L4] and 3 9 10-4
[H2L3]
M
123

Transition Met Chem
of the compound with toluene. Selected bond lengths and
angles of the three complexes are given in Table 2. Crystal
structures of the complexes are shown in Figs. 3, 4 and 5.
The crystal structures of the copper complexes confirm the
geometry predicted from spectroscopic data, and the
ligands act as tetradentate in a distorted square-planar
arrangement according to the geometrical parameters s4,
defined as [360 - (a ? b)]/141, where a and b are the two
largest coordination angles [22]. The s4 values are zero and
unity for perfect square-planar and tetrahedral geometries,
respectively. The calculated s4 indexes are 0.36 and 0.44
for [Cu(L3)]ÁMeOH and [Cu(HL4)], respectively. Distor-
tion from square-planar is therefore greater for [Cu(HL4)]
than for [Cu(L3)]ÁMeOH. Both ligands are dianionic, and
the copper centers are coordinated by two imine nitrogen
atoms and two sulfur atoms giving an overall CuN2S2
coordination environment.
Fig. 2 UV–Vis absorption spectra of 4 9 10-5 M [NiL3], 3 9 10-5
M [Ni(HL4)]ÁMeOH, 5 9 10-4 M [H3L4] and 3 9 10-4 M [H2L3]
Both complexes have Cu–S bonds that are longer than
the Cu–N bonds; the bond lengths are in the ranges
observed for similar complexes [16, 23], with Cu–Nimine
Table 1 Electronic spectral data of the compounds in CH2Cl2
Compound
k, nm (e, M-1cm-1
)
˚
bond lengths [1.9922(18) and 1.9945(19) A] and Cu–S
˚
bond lengths [2.2299(6) and 2.2385(6) A] for
H2L3
312 (35631) sh, 340 (42199)
313 (22157) sh, 336 (27396)
[Cu(L3)]ÁMeOH and Cu–Nimine bond lengths (1.992 (3)
H3L4
˚
and 2.008(3) A) and Cu–S bond lengths [2.2269(9) and
[Cu(L3)]ÁMeOH
246 (41170), 332 (47875), 443
(2508) sh, 593 (1308)
˚
2.2211(10) A] for [Cu(HL4)].
Comparison of the bond lengths to copper in the two
[Cu(HL4)]
246 (18315), 333 (22100), 443
(2600) sh, 587 (993)
complexes reveals only small differences. The bond
˚
lengths of N2–C7 and N5–C25 at 1.301(3) and 1.303(3) A,
[Ni(L3)]
271 (34098), 337 (26101), 520 (233)
270 (52014), 337 (32761), 526 (434)
respectively, in [Cu(L3)]ÁMeOH and 1.314(4) and 1.307(4)
[Ni(HL4)]ÁMeOH
˚
A, respectively, in [Cu(HL4)] are consistent with C=N
double bonds and close to the lengths of the C=N double
imines, and thione fragments of the ligands. Upon com-
plexation, H2L3 gives new and broad bands centered at
332 and 337 nm in [Cu(L3)]ÁMeOH and [Ni(L3)],
respectively. Similarly, complexes of H3L4 show new and
broad bands centered at 333 and 337 nm in [Cu(HL4)] and
[Ni(HL4)]ÁMeOH, respectively. Also new bands were
observed at 246 nm for the copper(II) complexes and at
270 and 271 nm for the nickel(II) complexes. According to
the literature [21], these new absorption bands arise from
transitions of electrons from the sulfur lone pairs to the
carbon backbone. In addition, upon coordination new
bands (two bands for the copper(II) complexes and one
band for the nickel(II) complexes) above 400 nm are
assigned to d–d transitions, corresponding to square-planar
geometries around both metals [16].
bonds N3–C8 and N4–C24 which are 1.289(3) and
˚
1.286(3) A, respectively, in [Cu(L3)]ÁMeOH and 1.294(4)
˚
and 1.289(34) A, respectively, in [Cu(HL4)]. The N–N
˚
bond lengths are shorter than the value of 1.44 A, accepted
as a typical N–N single bond, and agree well with those of
similar reported thiosemicarbazones [24]. The C–S bonds
˚
lengths are intermediate between a single bond (1.82 A)
˚
and double bond (1.56 A) but are closer to single-bond
character, thus showing the partial double-bond character
implied by the corresponding structures usually considered
for thiosemicarbazones [24]. This suggests electron delo-
calization in both ligands upon coordination to the metal,
together with deprotonation of the NH groups.
The structure of [Ni(L3)] confirms the N2S2 coordina-
tion mode with a slight distortion from square-planar
geometry (s4 = 0.22). The N2–C7 and N5–C25 bond
˚
Crystal structures of the complexes
lengths are 1.287(6) and 1.299(7) A, respectively, both
corresponding to a double bond. The S1–C7 and S2–C25
˚
bond lengths are 1.766(5) and 1.760(5) A, respectively,
[Cu(L3)]ÁMeOH and [Cu(HL4)] were crystalized by slow
evaporation from chloroform/methanol and chloroform/
ethanol solvent mixtures, respectively. Crystals of [Ni(L3)]
were obtained by diffusing a chloroform/ethanol solution
corresponding to a single-bond character. This suggests
that in all these complexes, the ligands lose their hydrazine
hydrogens and the electrons are delocalized. The bond
123

Transition Met Chem
Table 2 Selected bond lengths
˚
Bond lengths
[Cu(L3)]ÁMeOH
[Cu(HL4)]
Bond lengths
[Ni(L3)]
(A) and angles (°) for
[Cu(L3)]ÁMeOH, [Cu(HL4)],
and [Ni(L3)]
Cu1–S1
Cu1–S2
Cu1–N3
Cu1–N4
S1–C7
2.2299(6)
2.2393(6)
1.9964(19)
1.9923(18)
1.759(2)
1.750(2)
1.301(3)
1.364(3)
1.303(3)
1.303(3)
1.396(2)
1.393(2)
1.286(3)
1.289(3)
2.2276(9)
2.2212(9)
1.994(2)
2.005(3)
1.754(3)
1.750(4)
1.314(4)
1.360(4)
1.307(4)
1.371(4)
1.397(3)
1.398(3)
1.289(4)
1.294(4)
Ni1–S1
Ni1–S2
Ni1–N3
Ni1–N4
S1–C7
2.1689(14)
2.1614(15)
1.89 6(4)
1.903(4)
1.766(5)
1.760(5)
1.287(6)
1.299(7)
1.354(7)
1.370(6)
1.421(5)
1.396(6)
1.304(7)
1.295(6)
S2–C25
N2–C7
N1–C7
N5–C25
N6–C25
N3–N2
N4–N5
N4–C24
N3–C8
S2–C25
N2–C7
N5–C25
N6–C25
N1–C7
N2–N3
N4–N5
N4–C24
N3–C8
Bond angles
[Cu(L3)]ÁMeOH
[Cu(HL4)]
Bond angles
[Ni(L3)]
N3–Cu1–N4
N3–Cu1–S2
N4–Cu1–S2
N3–Cu1–S1
N4–Cu1–S1
S2–Cu1–S1
98.51(7)
152.77(6)
86.25(5)
85.24(5)
156.10(6)
101.22(2)
100.64(10)
149.59(8)
86.11(8)
N3–Ni1–N4
N3–Ni1–S2
N4–Ni1–S2
N3–Ni1–S1
N4–Ni1–S1
S2–Ni1–S1
96.61(17)
162.28(14)
86.31(13)
85.75(12)
166.55(14)
95.47(5)
85.60(7)
147.73(8)
104.47(4)
Fig. 3 Thermal ellipsoid plot
drawn at the 30 % probability
level for [Cu(L3)]ÁMeOH. For
clarity, the minor disordered site
(5 %) (i.e., C26a, C27a, C28a,
C29a, C30a, C31a, and Br2a),
methanol, and some hydrogens
have been omitted
lengths and angles are in good agreement with the reported
data for related Ni(II) thiosemicarbazone complexes [18,
24].
Intermolecular hydrogen bonds in [Cu(L3)]ÁMeOH and
[Ni(L3)] are also similar (Fig S1). In both cases, two
complex units make contact via C3–H3ÁÁÁS1 and N1–
˚
The intramolecular hydrogen bonds patterns in all of
these complexes are very similar; the uncoordinated imine
nitrogen atoms (N2 and N5) are involved in hydrogen
bonds with the hydrogen atoms of the 4-bromo phenyl ring
(see Table 3; Fig. 6).
H1ÁÁÁS1 interactions, with distances C3ÁÁÁS1 = 3.665(2) A
˚
and N1ÁÁÁS1 = 3.514(2) A for [Cu(L3)]ÁMeOH, and C3–
H3ÁÁÁS1 and C3–H3ÁÁÁS2 interactions with C3ÁÁÁS1 =
˚
˚
3.753(5) A and C3ÁÁÁS2 = 3.721(5) A for [Ni(L3)] (Fig
S1). Additional hydrogen bonds, C30–H30ÁÁÁBr1 and
123

Transition Met Chem
Fig. 4 Thermal ellipsoid plot
drawn at the 30 % probability
level for [Cu(HL4)]. For clarity,
the disordered site (50 %) (i.e.,
C26a, C27a, C28a, C29a, C30a,
C31a, and Br2a) and some
hydrogen atoms have been
omitted
Fig. 5 Thermal ellipsoid plot
drawn at the 30 % probability
level for [Ni(L3)]. For clarity,
the minor disordered site (17 %)
(i.e., C26a, C27a, C28a, C29a,
C30a, C31a, and Br2a) and
some hydrogen atoms have been
omitted
C30A–H30AÁÁÁBr1 in [Cu(L3)]ÁMeOH and C28–H28ÁÁÁBr1
and C28A–H28AÁÁÁBr1 in [Ni(L3)], connect the molecules
in the other direction. In [Cu(L3)]ÁMeOH, solvent metha-
nol molecules are involved in hydrogen bonds, acting as
hydrogen acceptors from N6–H6A and C31–H31 with
hydrogen bond network. It acts as a hydrogen acceptor
˚
from N1–H1 with distance N1ÁÁÁO1 = 2.880(4) A to give a
1D hydrogen bond network (Fig S2a). In addition, the OH
group acts as a hydrogen donor to N2 with distance
˚
O1ÁÁÁN2 = 2.896(4) A. Therefore, by means of N1–
˚
distances N6ÁÁÁO3 = 3.005(4) A and C31ÁÁÁO3 = 3.310(3)
H1ÁÁÁO1 and O1–HÁÁÁN2 hydrogen bonds, 1D double-chain
hydrogen bonds are formed (Fig S2b). These chains are
held together by N6–H6AÁÁÁBr1 hydrogen bonds and
S2ÁÁÁBr1 short contacts (Fig S2c).
˚
A (Fig S1a).
The pattern of hydrogen bonds in [Cu(HL4)] is differ-
ent. The OH group in H3L4 is very effective in forming a
123

Transition Met Chem
˚
Table 3 Inter- and intra-molecular hydrogen bond geometries (A, deg) for [Cu(L3)]ÁMeOH, [Cu(HL4)], and [Ni(L3)]
Hydrogen bonds
Compound
D–H_A
d(D–H)
d(H_A)
d(D_A)
\(D–H_A)
[Cu(L3)]ÁMeOH
N1–H1A_S1i
0.75(3)
0.93
2.82(3)
2.88
3.514(2)
3.665(2)
3.005(4)
3.310(3)
3.427(8)
3.856(3)
3.8959(17)
3.93(3)
156(3)
142
C3–H3_S1i
N6–H6A_O3
0.81(4)
0.93
2.21(4)
2.51
168(3)
145
C31–H31_O3
C16–H16A_Br2Aii
C17–H17B_S1iii
C30–H30_Br1iv
C30A–H30A_Br1iv
C5–H5_N2(intra)
C27–H27_N5(intra)
C27A–H27A_N5(intra)
0.97
2.59
145
0.97
2.94
158
0.93
3.09
146
0.93
3.04
160
0.93
2.27
2.875(3)
2.799(2)
2.99(3)
122
0.93
2.18
123
0.93
2.50
113
Symmetry codes: (i) –x ? 1, -y - 1, -z ? 1; (ii) -x ? 2, y ? 1/2, -z ? 1/2; (iii) x, -y - 1/2, z - 1/2; (iv) x ? 1, y - 1, z
[Cu(HL4)]
N1–H1_O1i
0.86
2.04
2.880(4)
2.896(4)
3.524(4)
3.667(4)
3.860(4)
3.568(4)
2.970(5)
2.927(4)
164
O1–H_N2v
0.82(3)
0.86
2.21(3)
2.86
158(3)
136
N6–H6A_Br1ii
C30–H30_S2iii
C27A–H27A_Br1iv
O1–H_N3v
0.93
2.95
135
0.93
3.05
147
0.82(1)
0.93
2.96(3)
2.4
133(4)
120
C27–H27_N5(intra)
C3–H3_N2(intra)
0.93
2.53
106
Symmetry codes: (i) x, y ? 1, z; (ii) -x ? 3/2, -y ? 1, z ? 1/2; (iii) -x ? 1, -y ? 1, -z ? 1; (iv) x - 1/2, y, -z ? 1/2; (v) -x ? 3/2,
y - 1/2, z
[Ni(L3)]
C3–H3_S1i
0.93
0.93
0.97
0.97
0.93
0.93
0.93
0.93
0.93
2.98
3.01
2.61
2.95
3.08
3.08
2.24
2.23
2.19
3.753(5)
3.721(5)
3.465(9)
3.852(6)
3.839(5)
3.92(2)
142
135
147
156
140
150
122
122
121
C3–H3_S2i
C16–H16B_Br2Aii
C17–H17B_S1iii
C28–H28_Br1iv
C28A–H28A_Br1iv
C5–H5_N2(intra)
C31–H31_N5(intra)
C31A–H31A_N5(intra)
2.840(7)
2.826(6)
2.791(18)
Symmetry codes: (i) -x ? 1, -y, -z ? 1; (ii) -x, y ? 1/2, -z ? 3/2; (iii) x, -y ? 1/2, z ? 1/2; (iv) x - 1, y - 1, z
Cyclic voltammetry studies
The aim of this study was to find a relationship between
the substituents R2 and R3 and the redox potentials. We
therefore chose substituent groups with similar chemical and
physical properties to ensure that the frontier orbitals would
be similar. We expected the redox potentials of the bromine-
substituted complexes would shift to more negative poten-
tials relative to their chlorine-substituted counterparts, as
would be expected from the electron-withdrawing and
inductive effects of chlorine compared with bromine.
However in some cases it was found that changes in the
redox potential are not consistent with the changes expected
on the basis of substituent inductive effects.
The cyclic voltammograms for all the complexes were
recorded in DMF using the same cell setup. The fer-
rocene/ferrocenium couple (Fc/Fc?, E1/2 = 0.505 V,
DEp = 130 mV)wasusedasa standard. Allofthecomplexes
exhibited single-electron metal-centered redox responses in
DMF solution. We have previously reported the electro-
chemistry of the nickel(II) and copper(II) complexes of the
analogous H2L1 and H3L2 [16], and these data are included
here for comparison. Figures 7 and 8 show the cyclic
voltammograms of the copper(II) and nickel(II) complexes,
illustrating the variations in redox potentials. These results
are summarized in Table 4.
The [CuL3] and [Cu(HL4)] complexes exhibit a rever-
sible one-electron metal-centered CuII/CuI redox couple at
123

Transition Met Chem
Fig. 7 CVs of [Cu(L3)], [Cu(HL4)], [Cu(L1)], and [Cu(HL2)] in
DMF solution at 100 mVs-1 scan rate
Fig. 6 Intramolecular hydrogen bonds in
b [Ni(L3)], c [Cu(HL4)]
a
[Cu(L3)]ÁMeOH,
E1/2 = -0.163 and 0.128 V, respectively, versus an Ag/
AgCl reference electrode in DMF. The reduction potential
of [Cu(HL4)] is anodically shifted by 291 mV relative to
[CuL3] comparing the redox couple potentials of the
chorine-substituted [CuL1] complex with the bromine-
substituted [Cu(L3)] complex, and the potential of
[Cu(L1)] is anodically shifted by 186 mV relative to
[Cu(L3)]. This behavior can be assigned to the electron-
withdrawing properties of chlorine relative to bromine.
However, [Cu(HL4)] incorporating the NHPhBr moiety
has the highest redox potential (E1/2 = 0.128 V) which
cannot be explained by inductive effects alone.
Fig. 8 CVs of [Ni(L3)], [Ni(HL4)], [Ni(L1)], and [Ni(HL2)] in
DMF solution at 100 mVs-1 scan rate
changes the reversibility of the reductive response. The
electrochemical behavior of [Ni(L3)] and [Ni(HL4)] is
compared with their chlorine-containing analogs in Fig. 8.
The reductive potential of [Ni(L3)] was anodically shifted
by 91 mV relative to its chlorine-substituted analog
[Ni(L1)]. A similar trend was observed between [Ni(HL4)]
and [Ni(HL2)], with redox couples at -0.706 and
-0.871 V, respectively. Therefore, data for these nickel
complexes are in contrast to the expected inductive effect
of the substituent.
The CV of [Ni(L3)] displays a reversible response at
E1/2 = -0.706 versus Ag/AgCl (Epc = -0.762 V, Epa
=
-0.651 V and DEp = 111 mV). The [Ni(HL4)] complex
exhibits a quasi-reversible reductive response at the same
redox
potential
E1/2 = -0.706 V
(Epc = -0.772,
Epa = -0.641 V) but with a greater DEp value (131 mV)
than [Ni(L3)]. Therefore, the OH substituent on H3L4
123

Transition Met Chem
observed at more negative potentials; in fact, it is located in
a range that is accessible to cellular oxidants and reduc-
tants. Since hypoxic cells are known to be mildly acidic,
the measurements were repeated after addition of acetic
acid to the sample solution. The resultant voltammograms
showed loss of reversibility of the CuII/CuI couple (Fig. 9).
This suggests that in the acidic environment of hypoxic
cells reduction is likely to be coupled to protonation, as has
been suggested for copper diacetyl-bis(N4-methylth-
iosemicarbazone ([Cu(ATSM)]) [26].
Table 4 Cyclic voltammetry data for complexes in DMF solution at
100 mVs-1 scan rate
Complex
Epc (V) Epa (V) DEp (mV) E1/2 (V) |ipc|/|ipa|
[Cu(L3)]
[Cu(HL4)]
[Cu(L1)]
-0.214 -0.113 101
-0.163
0.128
1.16
1.21
1
0.088
0.168
0.058
80
70
71
-0.013
0.023
[Cu(HL2)] -0.134 -0.063
-0.099
-0.706
-0.706
-0.797
-0.871
0.88
1.09
1.27
1.08
1.29
[Ni(L3)]
-0.762 -0.651 111
-0.772 -0.641 131
[Ni(HL4)]
[Ni(L1)]
-0.832 -0.761
71
[Ni(HL2)]
-0.921 -0.821 100
Conclusion
Cu(II) and Ni(II) complexes of N(4)-substituted
bis(thiosemicarbazone) ligands were prepared in good
yields. Both ligands lose hydrazinic hydrogen atoms upon
coordination to act as dianions and coordinating to the
metal center by two imine nitrogen atoms and two sulfur
atoms in a distorted square-planar coordination geometry.
Bromine substitution on the phenyl ring far from the metal
site perturbs the electrochemical behavior of these copper
and nickel complexes. Hydroxyl and halogen substituents
on the phenyl ring at the terminal nitrogen atom changed
the redox potentials by 227 mV for the copper complexes
and 165 mV for the nickel complexes.
Experimental section
Materials and methods
2-[3-(2-formylphenoxy)propoxy]benzaldehyde (1) and 2-
[3-(2-formylphenoxy)-2-hydroxypropoxy]benzaldehyde (2)
were prepared according to the literature methods [27–29].
Other reagents and solvents were obtained from Alfa Aesar
and Merck and were used as received.
Fig. 9 CV of [Cu(L3)] at different concentrations of acetic acid
The bromine-substituted complexes, [CuL3] and
[Cu(HL4)], exhibit the lowest and highest redox potentials,
respectively, but the chlorine-substituted nickel complexes
have more negative redox potentials and bromine-substi-
tuted nickel complexes have more positive redox poten-
tials, in contrast to the expected inductive effects. This
work shows that the link between redox potential and
inductive effect is complicated, and several factors
including the energy of the LUMO, the energy of the
reduced MI species, the solvation free energy, and other
enthalpy and entropy contributions are in play [4, 25].
The mechanism of hypoxic selectivity of CuII com-
plexes has been discussed in terms of the redox potentials
for reduction of CuII complexes to CuI, the most selective
complexes being those that are difficult to reduce. Among
the present complexes, the redox potential of [Cu(L3)] is
1H NMR spectra were recorded on a Bruker Avance 400
spectrometer in DMSO-d6, and chemical shifts are given
relative to residual solvent protons as internal standard at
room temperature. Elemental analyses were obtained on an
Elementar Vario EL III instrument. FTIR spectra were
recorded on an FTIR Spectrometer Bruker Tensor 27 in the
region 4000–400 cm-1 using KBr pellets. UV–Vis spectra
were recorded with an Analytik Jena Specord 250 spec-
trophotometer in the region 230–1100 nm in CH2Cl2.
Melting points were obtained with an Electrothermal 9100
instrument and are uncorrected. Cyclic voltammograms
were measured using a glassy carbon working electrode, a
platinum wire auxiliary electrode, and an Ag/AgCl refer-
ence electrode. All potentials are referenced to the Ag/
AgCl reference electrode. All scans were recorded in
123

Transition Met Chem
deoxygenated DMF containing 10-3 M of the complex and
0.1 M LiClO4 as supporting electrolyte.
filtered. The yellow precipitate was washed with methanol
and then diethyl ether. Yield 0.69 g (92 %). m. p. 220 °C.
FTIR (KBr disk, cm-1): t(OH) 3505 m, t(NH) 3265 w,
3160 m, tas(CH2) 2991 m, t(C=C) 1594 s, t(C=N) 1551 s,
t(C=C) 1513 s, t(C=C) 1485 s, 1451 m, 1400 m, t(C=S)
Synthesis of 4-bromophenyl thiosemicarbazide
4-bromophenyl thiosemicarbazide was prepared in two
steps. The intermediate dithiocarbamate salt was produced
according to the method previously reported [30]. CS2
(8 mL) was added to a mixture of 4-bromoaniline (6.9 g,
0.04 mol) and KOH (5 g, 0.09 mol) in ethanol (100 mL).
The mixture was stirred at room temperature for 2 h. An
additional 3 mL of CS2 was then added, and the mixture
was heated to reflux for 2 h. The mixture was then cooled,
poured into water (100 mL) and stirred at room tempera-
ture overnight. The precipitate was filtered off to obtain the
intermediate potassium phenylcarbamodithioate with a
yield of 9.2 g (80 %). This intermediate was further treated
with a 30-fold excess of 99 % NH2NH2ÁH2O in methanol.
The mixture was heated to reflux for about 10 h, and the
progress of the reaction was monitored by TLC, which
showed that the reaction reached equilibrium to give the
potassium dithiocarbamate salt. The solvent volume was
concentrated by rotary evaporation to about 3–4 mL; on
cooling the solution to room temperature, colorless cubic
crystals were formed. These were collected by filtration
and washed with cold methanol to give 4-bromophenyl
thiosemicarbazide with a yield of 4.3 g (55 %).
1336 m, 1296 m, tas(C–O–C) 1256 s, 1199 m, 1113 w,
1
755 s. H
ts(C–O–C) 1065 m, 819 m, d(=C–Haromatic o.o.p
)
NMR (400 MHz, DMSO-d6): d 4.23–4.29 (m, 5H, CH2-
CH(OH)CH2), 5.38 (s, 1H, OH), 6.99 (t, 2H, ArH), 7.14 (d,
2H. ArH), 7.41 (t, 2H, ArH), 7.53–7.60 (m, 8H, ArH), 8.23
(d, 2H, ArH), 8.62 (s, 2H, ArCHN), 10.10 (s, 2H, NHAr),
11.88 (s, 2H, NH) ppm.
General procedure for synthesis of the complexes
The required ligand (0.5 mmol) was dissolved in a
dichloromethane/methanol mixture (10:1) under reflux. To
this refluxing solution was added a solution of the metal
acetate (Cu2? or Ni2?, 1 mmol) in methanol, and refluxing
was continued for a further 4 h. The solvent was concen-
trated, and the resulting precipitates were filtered off and
washed with methanol and then with diethyl ether. The
complexes are air stable and soluble in chloroform and
DMF but slightly soluble in ethanol and methanol.
[Cu(L3)]ÁMeOH
Dark green crystals. Yield 0.42 g (75 %). m.p. 210 °C
(dec.). Anal. Calc. (%) for C31H26Br2CuN6O2S2.CH3OH
(formula weight = 834.105): C 46.1, H 3.6, N 10.1; found
(%): C 45.8, H 3.6, N 9.8. FTIR (KBr disk, cm-1): t(OH)
3399 m, t(NH) 3324 m, tas(CH2) 2954 w, ts(CH2) 2883
w, t(C=C) 1593 s, t(C=N) 1486 s, 1388 s, 1348 m,
t(C=S) 1302 s, tas(C–O–C) 1246 s, 1162 m, 1112 m,
Synthesis of H2L3
To a refluxing solution of 4-bromophenyl thiosemicar-
bazide (0.5 g, 2 mmol) in methanol (20 mL), a solution of
dialdehyde 1 (0.28 g, 1 mmol) in methanol (40 mL) was
added. A yellow precipitate formed immediately. This was
filtered off, washed with methanol and then diethyl ether.
Yield 0.68 g (92 %). m. p. 215 °C (dec.). FTIR (KBr disk,
cm-1): t(NH) 3288 m, t(NH) 3141 m, tas(CH2) 2972 m,
t(C=C) 1590 s, t(C=N) 1542 s, t(C=C) 1491 s, 1394 m,
ts(C–O–C) 1063 s, 821 s, d(=C–Haromatic o.o.p
)
751 s.
[Cu(HL4)]
t(C=S) 1321 m, 1293 m, tas(C–O–C) 1254 s, 1194 s,
Dark green crystals. Yield 0.41 g (77 %). m.p. 220 °C
(dec.). Anal. Calc. (%) for C31H26Br2CuN6O3S2 (formula
weight = 818.063): C calc. 45.5, H 3.2, N 10.3; found (%):
C 45.3, H 3.1, N 10.2. FTIR (KBr disk, cm-1): t(OH, NH)
3473 s, 3416 s, tas(CH2) 2961 w, t(C=C) 1598 m, t(C=N)
1487 s, 1388 m, t(C=S) 1301 m, tas(C–O–C) 1249 m,
1106 m, ts(C–O–C) 1063 m, 1026 m, 811 m, d(=C–Haro-
1
754 m. H
ts(C–O–C) 1066 m, 822 w, d(=C–Haromatic o.o.p
)
NMR (400 MHz, DMSO-d6): d 2.28 (quintet, 2H, CH2-
CH2CH2), 4.30 (t, 4H, CH2CH2CH2), 6.99 (t, 2H, ArH),
7.13 (d, 2H. ArH), 7.41 (t, 2H, ArH), 7.53–7.59 (m, 8H,
ArH), 8.25 (d, 2H, ArH), 8.63 (s, 2H, ArCHN), 10.12 (s,
2H, NHAr), 11.91 (s, 2H, NH) ppm.
)
matic o.o.p
749 m.
Synthesis of H3L4
[Ni(L3)]
H3L4 was prepared by a similar procedure to that used for
H2L3 except that dialdehyde 2 (1 mmol, 0.3 g) was used
instead of 1 and the precipitation was not immediate. After
30-min refluxing, the precipitation began to form. Reflux-
ing was followed for 10 h, and then, the mixture was
Yellow brown crystals. Yield 0.40 g (82 %). m.p. 240 °C
(dec.). Anal. Calc. (%) for C31H26Br2N6NiO2S2 (formula
weight = 797.211): C 46.7, H 3.3, N 10.5; found (%): C
46.5, H 3.2, N 10.5. FTIR (KBr disk, cm-1): t(OH, NH)
123

Transition Met Chem
3431 m, 3365 m, 3081 w, tas(CH2) 2948 w, ts(CH2) 2892
w, t(C=C) 1594 s, t(C=C) 1544 s, t(C=N) 1506 s, 1392 s,
1355 m, t(C=S) 1303 s, tas(C–O–C) 1253 s, 1161 m,
t(C=N) 1497 s, 1389 s, t(C=S) 1302 s, tas(C–O–C)
1244 s, 1110 m, ts(C–O–C) 1037 m, 820 m, d(=C–Haro-
)
matic o.o.p
750 m.
1113 m, ts(C–O–C) 1048 m, 822 m, d(=C–Haromatic o.o.p
)
753 m.
X-ray crystallography
[Ni(HL4)]ÁMeOH
Intensity data were collected with an Oxford Diffraction
SuperNova CCD diffractometer using either Mo–Ka or
Cu–Ka radiation. The temperature during data collection
was maintained at 130.0(1) K using an Oxford Cryosys-
tems cooling device. The structures were solved by direct
methods and difference Fourier synthesis [31]. The aniso-
tropic atomic displacement parameters (ADPs) were
Light brown crystals. Yield 0.41 g (82 %). m.p. 220 °C
(dec.). Anal. Calc. (%) for C31H26Br2N6NiO3S2.CH3OH
(formula weight = 845.252): C 45.5, H 3.6, N 9.9; found
(%): C 45.4, H 3.5, N 9.9. FTIR (KBr disk, cm-1): t(OH,
NH) 3429 s, 3411 s, tas(CH2) 2925 w, t(C=C) 1594 s,
Table 5 Crystal data and structure refinement parameters for [Cu(L3)]ÁMeOH, [Cu(HL4)], and [Ni(L3)]
[Cu(L3)]ÁMeOH
[Cu(HL4)]
[Ni(L3)]
Empirical formula
Formula weight
Temperature
C32H30Br2CuN6O3S2
834.1
C31H26Br2CuN6O3S2
818.06
C31H26Br2N6NiO2S2
797.23
130 K
130 K
130 K
Radiation type
Wavelength
Cu Ka
˚
1.54184 A
Mo Ka
˚
0.71073 A
Cu Ka
˚
1.54184 A
Crystal system
Space group
Monoclinic
P21/c
Orthorhombic
Pbca
Monoclinic
P21/c
˚
a = 19.2142(3) A
˚
a = 20.4110(7) A
˚
a = 18.9633(8) A
Unit cell dimensions
˚
b = 9.1029(1) A
˚
b = 11.5451(4) A
˚
b = 9.2399(3) A
˚
c = 19.9113(3) A
˚
c = 27.6605(8) A
˚
c = 19.7923(8) A
b = 107.238(2) °
3326.15(9) A
a = b = c = 90°
6518.1(4) A
b = 106.981(5)°
3316.8(2) A
3
˚
3
˚
3
˚
Volume
Z
4
8
4
Density (calculated)
Absorption coefficient
F(000)
1.666 Mg m-3
5.27 mm-1
1676
1.667 Mg m-3
3.29 mm-1
3272
1.597 Mg m-3
5.16 mm-1
1600
Crystal size (mm)
0.24 9 0.15 9 0.03
0.23 9 0.20 9 0.06
0.41 9 0.11 9 0.03
hmax, hmin
77.1°, 4.7°
25.0°, 3.5°
67.5°, 4.6°
Index ranges
-20 B h B 24,
-10 B k B 11,
-25 B l B 17
23690
-23 B h B 24,
-9 B k B 13,
-32 B l B 32
36278
-22 B h B 22,
-11 B k B 8,
-23 B l B 23
17899
Reflections collected
Independent reflections
Absorption correction
6960 [Rint = 0.032]
Gaussian
5724 [Rint = 0.055]
Multi-scan
5965[Rint = 0.073]
Gaussian
-1
)
˚
(sin h/k)max (A
0.632
0.595
0.599
T
min, Tmax
0.234, 0.784
Least-squares matrix full on F2
6960/463
0.755, 1.000
Least-squares matrix full on F2
5724/460
0.218, 0.827
Least-squares matrix full on F2
5965/445
Refinement method
Data/parameters
Restraints
43
19
43
R[F2 [ 2r(F2)], wR(F2)
0.034, 0.093
1.04, 0.007
0.76 and -0.71
0.038, 0.091
1.06, 0.001
0.77 and -0.70
0.056, 0.163
1.00, 0.001
1.22 and -0.79
S, (D/r)max
-3
˚
Dqmax, Dqmin (e A
)
w = 1/[r2(Fo2) ? (0.0494P)2 ? 2.5409P], where P = (Fo2 ? 2F2c)/3 for [Cu(L3)]ÁMeOH
w = 1/[r2(Fo2) ? (0.0372P)2 ? 4.9592P], where P = (Fo2 ? 2F2c)/3 for [Cu(HL4)]
w = 1/[r2(Fo2) ? (0.0781P)2], where P = (Fo2 ? 2F2c)/3 for [Ni(L3)]
123

Transition Met Chem
6. Dearling JLJ, Lewis JS, Mullen GED, Welch MJ, Blower PJ
(2002) J Biol Inorg Chem 7:249–259
refined for all non-hydrogen atoms. The hydrogen atoms
were placed in calculated positions and refined by appli-
cation of a riding model. Hydrogen atoms of the hydroxyl
and N–H groups were located in the difference Fourier
map. They were restrained according to their idealized
geometrical positions and refined. In all three complexes,
the difference Fourier map showed residual electron den-
sity near the atoms of the Br-substituted phenyl ring (C26–
C31), and hence, the positions of those atoms were split in
two. The ADPs of each site were constrained to those of the
second site, and sum of occupancies of each splitted atoms
was constrained to one. The refinement of occupancies for
the twofold disordered substituted phenyl rings was
[Cu(L3)]ÁMeOH, 95/5 %, [Cu(HL4)], 50/50 %, and
[Ni(L3)], 83/17 %. Refining the structures with disordered
phenyl rings improved the structural models. Thermal
ellipsoid plots were generated using the program ORTEP-3
[32] integrated within the WINGX [33, 34] suite of pro-
grams. Crystal data for [Cu(L3)]ÁMeOH, [Cu(HL4)] and
[Ni(L3)] are given in Table 5.
7. Zeglis BM, Divilov V, Lewis JS (2011)
54:2391–2398
J Med Chem
8. Hall MD, Brimacombe KR, Varonka MS, Pluchino KM, Monda
JK, Li J, Walsh MJ, Boxer MB, Warren TH, Fales HM,
Gottesman MM (2011) J Med Chem 54:5878–5889
9. Stefani C, Punnia-Moorthy G, Lovejoy DB, Jansson PJ, Kali-
nowski DS, Sharpe PC, Bernhardt PV, Richardson DR (2011) J
Med Chem 54:6936–6948
10. Palanimuthu D, Shinde SV, Somasundaram K, Samuelson AG
(2013) J Med Chem 56:722–734
11. Cowley AR, Dilworth JR, Donnelly PS, Gee AD, Heslop JM
(2004) Dalton Trans pp 2404–2412
12. Santini C, Pellei M, Gandin V, Porchia M, Tisato F, Marzano C
(2014) Chem Rev 114:815–862
13. Hall LH, Miller MC, West DX (1997) Met-Based Drugs 4:89–95
14. Price KA, Crouch PJ, Volitakis I, Paterson BM, Lim SC, Don-
nelly PS, White AR (2011) Inorg Chem 50:9594–9605
15. Urackova ZD, Mendiola MA, Sevilla MT, Valent A (1999)
Bioelectrochem Bioenerg 48:109–116
16. Hosseini-Yazdi SA, Hosseinpour S, Khandar AA, Kassel WS,
Piro NA (2015) Inorg Chim Acta 427:124–130
17. Gattegno D, Giuliani AM (1974) Tetrahedron 30:701–704
18. Mohan M, Agarawal A, Jha NK (1988) J Inorg Biochem
34:41–54
19. Sreekanth A, Fun H-K, Kurup MRP (2005) J Mol Struct
737:61–67
Appendix A: Supplementary material
20. Latheef L, Kurup MRP (2008) Polyhedron 27:35–43
21. Holland JP, Aigbirhio FI, Betts HM, Bonnitcha PD, Burke P,
Christlieb M, Churchill GC, Cowley AR, Dilworth JR, Donnelly
PS, Green JC, Peach JM, Vasudevan SR, Warren JE (2007) Inorg
Chem 46:465–485
22. Yang L, Powell DR, Houser RP (2007) Dalton Trans 955–964
23. Alsop L, Cowley AR, Dilworth JR, Donnelly PS, Peach JM,
Rider JT (2005) Inorg Chim Acta 358:2770–2780
24. Lopez-Torres E, Mendiola M, Pastor CJ, Perez BS (2004) Inorg
Chem 43:5222–5230
CCDC 1052408, 1052409, and 1052410 contain the sup-
plementary crystallographic data for Cu(L3)]ÁMeOH,
[Cu(HL4)], and [Ni(L3)] complexes, respectively. These
data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
25. Reynolds CA, King PM, Richards WG (1988) Nature 334:80–82
26. Cowley AR, Dilworth JR, Donnelly PS, Labisbal E, Sousa A
(2002) J Am Chem Soc 124:5270–5271
Acknowledgments We would like to thank University of Tabriz for
supporting this work.
27. Khandar AA, Hosseini-Yazdi SA (2003) Polyhedron
22:1481–1487
28. Hosseini-Yazdi SA, Mirzaahmadi A, Samadzadeh-Aghdam P,
Khandar AA, Mahmoudi G, Kassel WS, Dougherty WG (2014)
Inorg Chim Acta 414:115–120
References
29. Hosseini-Yazdi SA, Samadzadeh-Aghdam P, Mirzaahmadi A,
Khandar AA, Mahmoudi G, Ruck M, Doert T, Balula SS, Cunha-
Silva L (2014) Polyhedron 80:41–46
30. Lukmantara AY, Kalinowski DS, Kumar N, Richardson DR
(2013) Org Biomol Chem 11:6414–6425
31. Sheldrick GM (2008) Acta Cryst A64:112–122
32. Farrugia LJ (1997) J Appl Cryst 30:565
33. Farrugia LJ (1999) J Appl Cryst 32:837–838
34. Van Der Sluis P, Spek AL (1990) Acta Cryst A46:194–201
1. West DX, Liberta AE (1993) Coord Chem Rev 123:49–71
2. Lobana TS, Sharma R, Bawa G, Khanna S (2009) Coord Chem
Rev 253:977–1055
3. Fatondji HR, Kpoviessi S, Gbaguidi F, Bero J, Hannaert V,
Quetin-Leclercq J, Poupaert J, Moudachirou M, Accrombessi GC
(2013) Med Chem Res 22:2151–2162
4. Maurer RI, Blower PJ, Dilworth JR, Reynolds CA, Zheng Y,
Mullen GED (2002) J Med Chem 45:1420–1431
5. Beckford FA, Thessing J, Stott A, Holder AA, Poluektov OG, Li
L, Seeram NP (2012) Inorg Chem Commun 15:225–229
123