Synthesis, characterization, molecular modeling and biological activity of mixed ligand complexes of Cu(II), Ni(II) and Co(II) based on 1,10-phenanthroline and novel thiosemicarbazone

Article abstract of DOI:10.1016/j.ica.2013.06.040

A combined experimental and computational study of novel mixed ligand Cu(II), Ni(II) and Co(II) complexes of 2-(1-(2-phenyl-hydrazono)-propan-2- ylidene)hydrazine-carbothioamide (TPHP) and 1,10-phenanthroline (1,10-Phen) have been synthesized. The complexes have been characterized by elemental analyses, IR, solid reflectance, magnetic moment, ¹HNMR and molar conductance. Spectral data showed that the 1,10-phenanthroline acts as neutral bidentate ligand coordinating to the metal ion through two nitrogen donor atoms and thiosemicarbazone acts as monobasic tridentate coordinating through two imine-N and thiolate sulphur groups. The geometry of the studied M(II) complexes has been fully optimized using parameterized PM3 semiempirical method. It was observed that the M-S bond length is longer than that of M-Cl in the isolated complexes and the M-N bond length is shorter than that of M-Cl. Also, valuable information is obtained from calculations of molecular parameters for all complexes including net dipole moment of the metal complexes, values of binding energy, which proved that the complexes are more stable than the free ligand. The metal chelates have been screened for their antimicrobial activities using the disc diffusion method against different selected types of bacteria (G ⁺: Bacillus subtillis RCMB 010067, Staphylococcus aureus RCMB 010028); G^-: Pseudomonas aeuroginosa RCMB 010043, Escherichia coli RCMB 010052)) and fungi (Aspergillus flavus RCMB 02568, Pencicillium italicum RCMB 03924, Candida albicans RCMB 05031, Geotricum candidum RCMB 05097). Finally, structure-activity relationship studies were investigated with the aim to correlate physico-chemical properties that may be related to the antimicrobial action of the studied compounds. Protonation constant of (TPHP) ligand and stability constants of its M(II) complexes were determined by potentiometric titration method in 70%:30% DMSO-water mixture at 0.1 mol dm ^-3 NaCl.

Full text of DOI:10.1016/j.ica.2013.06.040

Inorganica Chimica Acta 407 (2013) 58–68
Contents lists available at SciVerse ScienceDirect
Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Synthesis, characterization, molecular modeling and biological activity
of mixed ligand complexes of Cu(II), Ni(II) and Co(II) based on
1,10-phenanthroline and novel thiosemicarbazone q
M. Aljahdali a, Ahmed A. EL-Sherif b,c,
⇑
a Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
b Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
c Department of Chemistry, Faculty of Arts and Science, Northern Borders University, Rafha-156, KSA
a r t i c l e i n f o
a b s t r a c t
Article history:
A combined experimental and computational study of novel mixed ligand Cu(II), Ni(II) and Co(II)
ccomplexes of 2-(1-(2-phenyl-hydrazono)-propan-2-ylidene)hydrazine-carbothioamide (TPHP) and
1,10-phenanthroline (1,10-Phen) have been synthesized. The complexes have been characterized by ele-
mental analyses, IR, solid reflectance, magnetic moment, 1HNMR and molar conductance. Spectral data
showed that the 1,10-phenanthroline acts as neutral bidentate ligand coordinating to the metal ion
through two nitrogen donor atoms and thiosemicarbazone acts as monobasic tridentate coordinating
through two imine-N and thiolate sulphur groups. The geometry of the studied M(II) complexes has been
fully optimized using parameterized PM3 semiempirical method. It was observed that the M–S bond
length is longer than that of M–Cl in the isolated complexes and the M–N bond length is shorter than that
of M–Cl. Also, valuable information is obtained from calculations of molecular parameters for all com-
plexes including net dipole moment of the metal complexes, values of binding energy, which proved that
the complexes are more stable than the free ligand. The metal chelates have been screened for their anti-
microbial activities using the disc diffusion method against different selected types of bacteria (G+: Bacil-
lus subtillis RCMB 010067, Staphylococcus aureus RCMB 010028); Gꢀ: Pseudomonas aeuroginosa RCMB
010043, Escherichia coli RCMB 010052)) and fungi (Aspergillus flavus RCMB 02568, Pencicillium italicum
RCMB 03924, Candida albicans RCMB 05031, Geotricum candidum RCMB 05097). Finally, structure–activ-
ity relationship studies were investigated with the aim to correlate physico-chemical properties that may
be related to the antimicrobial action of the studied compounds. Protonation constant of (TPHP) ligand
and stability constants of its M(II) complexes were determined by potentiometric titration method in
70%:30% DMSO–water mixture at 0.1 mol dmꢀ3 NaCl.
Received 16 March 2013
Received in revised form 20 June 2013
Accepted 24 June 2013
Available online 16 July 2013
Keywords:
Thiosemicarbazone
1,10-Phenanthroline
Transition metals
Quantum calculations
Biological activity
Ó 2013 The Authors. Published by Elsevier B.V. All rights reserved.
1. Introduction
Antibiotics provide the main basis for the therapy of microbial
(bacterial and fungal) infections. However, overuse of antibiotics
In recent years, the number of life-threatening infections dis-
eases caused by multi-drug resistant Gram-positive and Gram-
negative pathogen bacteria has reached an alarming level in many
countries around the world [1]. More than 50 million people
worldwide are infected and up to 110,000 of these die every year.
has become the major factor for the emergence and dissemination
of multi-drug resistant strains of several groups of microorganisms
[2]. Furthermore, the pharmacological drugs available are either
too expensive or have undesirable side effects [3]. Thus, in light
of the evidence of rapid global spread of resistant clinical isolates,
the need to find new antimicrobial agents is of paramount impor-
tance. Considerable attention has been focused on thiosemicarba-
zone compounds due to their wide biological activities [4,5].
Thiosemicarbazones and their complexes have been extensively
studied because they have a wide range of actual or potential med-
ical applications [6–10] which include notably antiparasital [11],
antibacterial [12] antitumor activities [13], antiviral [14],
fungicidal [15] and antineoplastic [16]. In general, thiosemicarba-
zones are obtained by condensation of the corresponding
Abbreviations: PHP, 1-(phenyl-hydrazono)-propan-2-one; TPHP, 2-(1-(2-phe-
nyl-hydrazono)-propan-2-ylidene) hydrazine-carbothioamide; QM, quantum
calculations.
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-No Derivative Works License, which per-
mits non-commercial use, distribution, and reproduction in any medium, provided
the original author and source are credited.
⇑
Corresponding author. Mobile: +20 1060160168.
E-mail address: aelsherif72@yahoo.com (A.A. EL-Sherif).
0020-1693/$ - see front matter Ó 2013 The Authors. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ica.2013.06.040

M. Aljahdali, A.A. EL-Sherif / Inorganica Chimica Acta 407 (2013) 58–68
59
thiosemicarbazide with aldehydes or ketones. Thiosemicarbazones
(TSCNs) exist in the tautomeric thione (A) and thiol (B) forms
(Scheme 1). It is well known that some drugs exhibit increased
activity when administered as metal complexes [17,18] and sev-
eral metal chelates have been shown to inhibit tumor growth
[19]. 1,10-Phenanthroline (Scheme 2) is the parent of an important
class of chelating agents. The choice of phenanthroline is mainly
due to two factors. This heteroaromatic moiety can provide a
further binding site for metal cations. It is rigid, and provides
two aromatic nitrogens whose unshared electron pairs can act
N
N
1,10-Phenanthroline
(1,10-Phen)
Scheme 2. Structural formula of 1,10-phenanthroline.
co-operatively in binding cations [20]. The
makes phenanthroline an excellent
p
-electron deficiency
p
-acceptor. Moreover,
concentrated HCl in 150 ml of ice water is added slowly with stir-
ring. The diazonium salt solution is then added over a period of
20 min, and the mixture is made basic by the addition of 82 g of so-
dium acetate dissolved in 300 ml of water. The temperature of the
reaction mixture is raised slowly to 50 °C and maintained at this
temperature for 2 h; the separated solid is collected on a filter
and dried. The yield of crude product is 77 g (95%). Purification
can be effected by recrystallization from 200 ml of toluene.
The purified product weighs 66 g (82%); m.p. 148–150 °C.
Chemical equations for preparation are shown in Scheme 3.
1,10-phenanthroline, the ligand moiety of the ternary complexes
presented in this work is of considerable interest also according
to the biological or pharmacological properties (antifungal, anti-
mycoplasma and antiviral) of some of its metal complexes [21].
In view of the above facts and in continuation of our interest in
studying the ligating behavior of such bio-relevant compounds
[22–31], herein we carry out synthesis, spectral characterization
and biological studies of mixed-ligand complexes involving some
transition metal ions, 1,10-phen and TPHP. Also, the structure–
activity relationship studies were investigated with the aim to cor-
relate chemical properties and biological activities of studied
compounds.
2.2.2. Synthesis of TPHP-thiosemicarbazone
The general route of synthesis (Scheme 4) is shown in the fol-
lowing. Equimolar amounts of (PHP) (0.1620 g, 1 mmol) in 25 ml
ethanol with an ethanolic solution (25 ml) of thiosemicarbazide
(0.0911 g, 1 mmol) were mixed and then refluxed on a hot plate
for 4–5 h. The obtained precipitate was separated out, filtered off,
washed with diethyl ether and dried overnight under silica gel.
2. Experimental
2.1. Materials
All chemicals used were of analytical reagent grade (AR), and of
the highest purity available. They included CuCl2.2H2O (Sigma),
CoCl2ꢁ6H2O and NiCl2ꢁ6H2O (BDH), C2H5OH (Sigma), DMSO
(BDH), HCl, KOH (BDH) thiosemicarbazide (Merck); 1,10-phenan-
throline (1,10-phen), aniline, ethyl acetoacetate, sodium acetate
trihydrate and sodium nitrite (Sigma). Bi-distilled water was used.
2.2.2.1. 2-(1-(2-Phenyl-hydrazono)-propan-2-ylidene)hydrazine-car-
bothioamide (TPHP). Yield, 72%. Colour, Yellow. Anal. Calc. for
C
10H13N5S: C, 51.02; H, 5.53; N, 29.78; S, 13.62. Found: C, 50.98;
H, 5.40; N, 29.70; S, 13.60%. IR (KBr, cmꢀ1): 3265, 3384 (NH2),
1500, 1247, 1095, 750 (Thioamide bands, I, II, III and IV respec-
tively), 3151 (N2H), 1068 (N–N), 1595 (C@N). 1H NMR (DMSO):
11.32 (s, 1H, N2H), 10.31 (s, 2H, NH2), 2.02 (s, 3H, –CH3), 7.61 (m,
5H, –Ar).
2.2. Synthesis
2.2.1. Synthesis of 1-(phenyl-hydrazono)-propan-2-one (PHP)
It is prepared as reported in the literature [32,33] as follows: in
a 4-l beaker equipped with a mechanical stirrer, 65 g (64 ml,
0.5 mol) of ethyl acetoacetate was added to 35 g (0.53 mol) of
85% potassium hydroxide in 1120 ml of water. The mixture is al-
lowed to stand at room temperature for 24 h. Forty-seven grams
(48 ml, 0.5 mol) of aniline is dissolved in 200 ml of aqueous HCl
(prepared from equal volumes of concentrated acid and water) in
a 2-l beaker. The beaker is equipped with a mechanical stirrer
and immersed in an ice-salt bath. After the solution has cooled to
0–5 °C, 36 g. (0.52 mol) of sodium nitrite dissolved in 1 l of water
is added slowly, with stirring, from a separatory funnel. The tip
of the stem of the separatory funnel dipped well below the surface
of the liquid. The rate of addition is adjusted to maintain the tem-
perature between 0 and 5 °C. A drop of the reaction mixture is
tested from time to time with starch-iodide paper until nitrous
acid persists in the solution during a 5-min interval. The solution
of potassium acetoacetate is cooled to °C, and 45 ml of
2.2.3. Synthesis of complexes
To a solution of TPHP (0.235 g, 1 mmol) in hot ethanol (25 mL)
was added sodium acetate trihydrate (0.136 g, 1 mmol) followed
by 1,10-phenanthroline (0.180 g, 1 mmol) and finally metal salt
(0.170 g, CuCl2ꢁ2H2O, 0.2379 g CoCl2ꢁ6H2O, 0.2376 g NiCl2ꢁ6H2O,
1 mmol). The mixture was heated under reflux for 5–6 h at 80 °C.
The precipitated complexes were then filtered off, washed with
petroleum ether and dried overnight in a vacuum desiccator.
2.2.3.1. [Cu(1,10-phen)(TPHP)Cl] (1). Yield, 78%. Anal. Calc. for C22-
H20N7SCuCl (Mwt, 513.51): C, 51.46; H, 3.93; N, 19.09; S, 6.24;
Cl, 6.90. Found: C, 51.39; H, 3.91; N, 19.05; S, 6.20; Cl, 6.86%. IR
(KBr, cmꢀ1): 1502, 1249, 1090, 733 (Thioamide bands, I, II, III and
IV respectively), 1084 (N–N), 1574 (C@N), 410 (M–N), 330 (M–S),
275 (M–Cl), 1548 (C@N, phen).
H
N
S
R 1
R 2
S H
R 1
R 2
N
N H R3
N
N
N H R3
(A)
(B)
Scheme 1. Thione-thiol tautomers of thiosemicarbazones.

60
M. Aljahdali, A.A. EL-Sherif / Inorganica Chimica Acta 407 (2013) 58–68
Scheme 3. Chemical reactions involved in the preparation of the PHP ligand.
H
H
N
EtOH
CH3
CH3
N
N
+ NH2NHCSNH2
N
H
N
N
O
S
NH2
Scheme 4. Preparation of TPHP-thiosemicarbazone ligand.
2.2.3.2. [Ni(1,10-phen)(TPHP)Cl] (2). Yield, 75%. Anal. Calc. for C22-
H20N7SNiCl (Mwt, 508.65): C, 51.95; H, 3.96; N, 19.28; S, 6.30; Cl,
6.97. Found: C, 51.87; H, 3.90; N, 19.23; S, 6.28; Cl, 6.90%. IR
(KBr, cmꢀ1): 1496, 1248, 1089, 729 (Thioamide bands, I, II, III and
IV respectively), 1081 (N–N), 1571 (C@N), 403 (M–N), 328 (M–S),
270 (M–Cl), 1552 (C@N, phen).
2.5. Instruments
Elemental analyses were carried out at the Department of
Chemistry, Faculty of Science, King Abdul-Aziz University, Jed-
dah21589, KSA. The analyses were performed twice to check the
accuracy of the analyses data. Infrared spectra were recorded on
an 8001-PC FTIR Shimadzu spectrophotometer using KBr pellets.
The solid reflectance spectra were measured on a Schimadzu
3101 pc spectrophotometer. The molar conductance of the com-
2.2.3.3. [Co(1,10-phen)(TPHP)Cl]ꢁH2O (3). Yield, 80%. Anal. Calc. for
C22H22N7OSCoCl (Mwt, 526.92): C, 50.15; H, 4.21; N, 18.61; S,
6.07; Cl, 6.73. Found: C, 50.11; H, 4.17; N, 18.56; S, 6.01; Cl,
6.69%. IR (KBr, cmꢀ1): 3573 (OH), 1493, 1251, 1088, 721 (Thioam-
ide bands, I, II, III and IV respectively), 1079 (N–N), 1570 (C@N),
401 (M–N), 328 (M–S), 267 (M–Cl), 1555 (C@N, phen).
plexes was measured for 1.00 ꢂ 10ꢀ3
M DMSO solutions at
25 1 °C using a systronic conductivity bridge type 305. The room
temperature magnetic susceptibility measurements for the com-
plexes were determined by the Gouy balance using Hg[Co(SCN)4]
as a calibrant. The 1H NMR spectra were recorded using a Bruker
ARX-300 instrument. Chemical shifts are reported in parts per mil-
lion (ppm) relative to tetramethylsilane using deuterated DMSO as
solvent. EPR signals were recorded at room temperature by using a
Bruker EMX spectrometer (X-band) product of Bruker, Germany.
The operating conditions are, microwave power = 0.201 mW, mod-
ulation amplitude = 4.00 Gauss, modulation frequency = 100 kHz,
sweep width = 200 Gauss, microwave frequency = 9.775 GHz, time
constant = 81.92 ms and sweep time = 20.97 s. The detection limits
of EPR technique depends on the type of sample, sample size,
detector sensitivity, frequency of the incident microwave
radiation.
2.3. Molecular modeling
An attempt to gain a better insight on the molecular structure of
the synthesized thiosemicarbazone complexes, geometric optimi-
zation and conformation analysis has performed using semiempir-
ical parameterized PM3 method as implemented in HyperChem
7.5 [34]. A gradient of 1 ꢂ 10ꢀ2 cal A°ꢀ1 molꢀ1 was set as a conver-
gence criterion in all the molecular mechanics and quantum
calculations
2.4. Biological activity
The antimicrobial bioassay was performed according to proto-
cols described previously using a modified Kirby-Bauer disc diffu-
sion method [35–41]. The antimicrobial activities of metal
complexes were studied against Gram (+) bacteria as Bacillus sub-
tillis RCMB 010067, Staphylococcus aureus RCMB 010028); Gram
(ꢀ) bacteria as (Pseudomonas aeuroginosa RCMB 010043, Esche-
richia coli RCMB 010052) and fungi as Aspergillus flavus RCMB
02568, Pencicillium italicum RCMB 03924, Candida albicans RCMB
05031, Geotricum candidum RCMB 05097. Standard discs of Genta-
micin and Ampicillin (antibacterial agents), Amphotericin B (anti-
fungal agent) served as positive controls for antimicrobial
2.6. Potentiometric titrations
The potentiometric cell was calibrated before each experiment
to convert the pH meter readings into hydrogen ion concentration
as reported in literature [42]. The ionic products (Kw = [H+][OHꢀ])
were calculated at a constant ionic strength of 0.10 mol-dmꢀ3 with
NaCl in 70% aqueous DMSO solutions based on measurements of
[OHꢀ] and pH in several series of experiments. We calculated the
reproducible values of pKw for the examined 70% aqueous dimethyl
sulfoxide solution. The pKw value obtained is 15.75 0.2 in this
medium [43]. Potentiometric titrations were carried out at con-
stant temperature and in an inert atmosphere of nitrogen with
activity but filter discs impregnated with 10
were used as a negative control.
ll of solvent (DMSO)
CO2-free standardized 0.05 mol-dmꢀ3 NaOH as titrant in
a
The antibacterial results of the compounds were compared with
the standard and % activity index for the complexes was calculated
by using the formula as given below:
40.0 ml solution at constant ionic strength 0.1 mol dmꢀ3, (adjusted
with NaCl). The proton association constants of the ligands (TPHP)
were determined potentiometrically by titrating (1.25 ꢂ 10ꢀ3
-
mol dmꢀ3) of the ligand solution (40 cm3). The stability constants
of the M(II) complexes were determined using potentiometric data
Zone of inhibition by test compoundðdiameterÞ
%Activity index ¼
Zone of inhibition by standardðdiameterÞ
obtained from (40 cm3) mixture containing M(II) (1.25 ꢂ 10ꢀ3
-
ꢂ 100
mol dmꢀ3) + (TPHP) (1.25 ꢂ 10ꢀ3 mol dmꢀ3).

M. Aljahdali, A.A. EL-Sherif / Inorganica Chimica Acta 407 (2013) 58–68
61
All titrations were performed in a purified N2 atmosphere at
I = 0.1 mol dmꢀ3 NaCl and T = 25 °C. The potentiometric cell was
calibrated before each experiment so as to measure the hydrogen
ion concentration rather than its activity. The pH-meter readings
(B) recorded in DMSO–water solutions were converted to hydro-
gen ion concentration [H+] by using the widely used relation given
by Van Uitert and Hass Eq. (1) [44] as shown below.
coordination. In the ligands spectra, the strong band observed at
1595 cmꢀ1 is assigned to
(C@N) stretching vibration [49]. In the
spectra of complexes, this band was not observed at the same fre-
quencies and the same intensities. They shifted after coordination
to lower energies by ca. 21–25 cmꢀ1, indicating coordination via
m
azomethine nitrogen [50]. The m(N–N) of the thiosemicarbazone li-
gand is found at 1068 cmꢀ1. The increase in frequency of this band
in the spectra of complexes is an evidence for the enethiolization of
the ligand and the coordination via the azomethine nitrogen. A
band which appeared at 3151 cmꢀ1 due to N–H in the TPHP-ligand
disappeared on complexation which acts as further evidence for
ꢀ log½Hþꢃ ¼ B þ log UH
ð1Þ
where log UH is the correction factor for the solvent composition
and ionic strength for which B is read.
the enethiolization of the ligand. Also, the possibility of a-nitrogen
(N2H) coordination is ruled out because of considerable strain [51].
The IR spectrum of the free 1,10-phen ligand shows a very stronger
bands at ꢄ1570 cmꢀ1 due to stretching frequency of C@N present
in 1,10-phenanthroline moiety. This band was shifted to lower fre-
quencies in the complexes ꢄ15–22 cmꢀ1, which clearly indicate
that the coordination of the two nitrogen atoms of the neutral
1,10-phen ligand to M(II) ion upon complexation. The bands ob-
2.7. Data processing
The calculations were obtained from ca. 100 data points in each
titration using the computer program MINIQUAD-75 [45]. The proton-
ation constants of the isolated compounds were determined at 70%
DMSO-30% H2O by trying various possible composition models.
The model selected gave the best statistical fit and was chemically
consistent with the titration data without giving any systematic
drifts in the magnitudes of various residuals, as described else-
where [45]. The fitted model was tested by comparing the experi-
mental titration data points and the theoretical curve calculated
from the values of the acid dissociation constant of the compounds.
The species distribution diagrams were obtained using the pro-
gram SPECIES [46] under the experimental conditions employed.
served at 3573–3566 cmꢀ1 are due to
m(O–H). As reported in liter-
ature, coordinated water should exhibit frequencies at 825, 575
and 500 cmꢀ1 [22,52,53]. The absence of spectral bands in these re-
gions in the spectra of complexes indicates that the water mole-
cules in these complexes are not coordinated but are present as
lattice water. The coordination positions of the thiosemicarbazones
in the M(II) complexes are confirmed by assigning the strong bands
observed in the far IR spectra of the complexes. The bands ob-
served at (410–401) and (330–328) cmꢀ1 are assigned to
[54] and (M–S) [55] respectively. The values of (M–N) and
(M–S) follow the order Cu > Ni > Co in parallel with the crystal
m(M–N)
3. Results and discussion
m
m
m
3.1. Elemental analysis
field stabilization energies [55,56]. In the literature, the bands
appearing between 160 and 300 cmꢀ1 are allotted to the vibration
of the M–X bonds where M = metal and X@Cl or Br [50,56]. In our
The analytical data of the complexes show the formation of
1:1:1 [M:1,10-phen:TPHP] ratio, where M represents Cu(II), Ni(II)
and Co(II) ions, TPHP, represents the deprotonated thiosemicarba-
zone while 1,10-phen represents the neutral bidentate 1,10-phe-
nanthroline. The isolated solid complexes are stable in air and
are insoluble in water and common organic solvents but soluble
in DMF and DMSO. The molar conductance indicates that all the
complexes are nonelectrolytic in nature. Elemental analyses data
were in a good agreement with the suggested formula of the iso-
lated metal chelates. Attempts to obtain single crystal suitable
for X-ray determination were unsuccessful, thus molecular model-
ing for these complexes were investigated.
case the
m
(M–Cl) frequencies appearing between 275–267 cmꢀ1
are in good agreement with the reported values in the literature.
Based on the above spectral evidences, it is confirmed that the li-
gand is coordinated to the M(II) ion as a tridentate anion, coordi-
nating via the two azomethine nitrogen atoms and the thiolate
sulfur atom after deprotonation.
3.3. 1H NMR spectra
The 1H NMR spectra of the TPHP-thiosemicarbazone compound
in DMSO-d6 don’t show any resonance at ca. 4.0 ppm attributable
to –SH proton resonance, while the appearance of a peak at
11.32 ppm (field of appearance of the signal of NH group next to
C@S) confirms that even in a polar solvent such as DMSO they re-
main in the thione form. The methyl protons appear at 2.02 ppm
region. The multiplet at 7.61 ppm has been assigned to the aro-
matic ring protons of the thiosemicarbazone ligand. The spectra
of TPHP compound showed signals at d 10.31 ppm assigned to
the NH2 protons.
3.2. IR Spectra and mode of bonding
As known, the TPHP ligand has different potential coordinating
sites. In the absence of more powerful techniques such as X-ray,
the IR has proven to be, in this particular case, a suitable technique
to give enough information to elucidate the way of bonding of
TPHP. Thus a detailed interpretation of IR spectra of TPHP and
the effect of binding of Cu(II), Ni(II) and Co(II) ions on the vibration
frequencies of the free TPHP ligand is discussed in this paper. The
IR spectra of the free ligand and its metal complexes are carried out
in the 4000–200 cmꢀ1 range. All of the thiomamide bands in the
free TPHP ligand are shifted to some degree upon complexation
but the most significant change is that observed in the thioamide
3.4. Magnetic moment and electronic spectra
The electronic spectral data along with magnetic susceptibility
measurements gave adequate support in establishing the geometry
of the metal complexes. The solid reflectance spectra of metal com-
plexes show different bands at different wavelengths, each one is
corresponding to certain transition which suggests the geometry
of the complex compounds. The magnetic moments of the com-
plexes were measured at room temperature. These data along with
the tentative assignments of spectral bands and the magnetic mo-
ment values are presented in Table 1.
IV band, which contain the largest proportion of
i.e. the C@S on coordination gains C–S character. The negative shift
of the (C@S) band in the complexes confirm the coordination via
m(CS) activity,
m
the thiolate sulfur [47-49]. The spectra of the free (TPHP) show two
bands at 3265 and 3384 cmꢀ1, due to msym and masym of the NH2
group. These absorptions remain unaltered in the metal complexes
confirming the non-involvement of this terminal NH2 group upon

62
M. Aljahdali, A.A. EL-Sherif / Inorganica Chimica Acta 407 (2013) 58–68
Table 1
Molar conductance, magnetic moment, electronic spectral data and ESR parameters of the complexes.
a
Compounds
KM
leff (B.M.)
kmax (cmꢀ1
)
Assignment
Geometry
g||
g\
gavg
G
[Cu(1,10-phen)(TPHP)Cl] (1)
[Ni(1,10-phen)(TPHP)Cl] (2)
11.5
10.2
1.89
2.88
16286
10100
16900
23800
9950
2B1g
3A2g
3A2g
3A2g
4T1g
4T1g
4T1g
?
?
?
?
?
?
?
2B2g
Octahedral
Octahedral
2.131
–
2.030
–
2.097
–
4.64
–
3T2g(F)
3T1g(F)
3T1g(P)
4T2g(F)
4A2g(F)
4T1g(P)
[Co(1,10-phen)(TPHP)Cl]ꢁH2O (3)
9.6
5.02
Octahedral
–
–
–
–
17400
19800
a
Molar conductance measured for 10ꢀ3 M DMSO solution,
X .
ꢀ1 cm2 molꢀ1
3.4.1. Magnetic moment
the secular equations given by König [61] (Table 2). The value of b
lies in the range 0.673–0.782. These values indicate that the appre-
ciable covalent character of metal ligand bond.
The magnetic susceptibility measurements in the solid state
show that the present complexes are paramagnetic at room tem-
perature. For the [Cu(1,10-phen)(TPHP)Cl] complex; the magnetic
moment is equal to 1.89 B.M. (Table 1) which assigned to octahe-
3.6. ESR spectrum of [Cu(1,10-phen)(TPHP)Cl] complex
dral geometry. Ni(II) complex gave
a magnetic moment of
2.88 B.M and hence assigned as octahedral, because of the square
planar complexes of Ni(II) are a diamagnetic while tetrahedral
complexes have magnetic moments in the range 3.20–4.10 B.M.
[57]. The Co(II) octahedral complexes generally show magnetic
ESR spectroscopy is a direct measurement of electron spin when
there are unpaired electrons within a chemical structure and thus
provides a way to investigate the electronic spin state and oxida-
tion state of the coordinated metal ion. Also, the ESR spectra of
the complexes provide information about hyperfine and superhy-
perfine structures that are important in studying the metal ion
environment in the complexes, such as geometry, nature of ligation
sites from the ligand to the metal, and the degree of covalence of
the metal–ligand bonds. To obtain further information about the
stereochemistry and the site of the metal ligand bonding and to
determine the magnetic interaction in the metal complexes, ESR
spectra of the complexes were recorded in the solid state. The
room temperature powder ESR spectrum of [Cu(1,10-
moments (leff) between 4.7 and 5.2 B.M. because of the orbital
contribution [57]. Since the orbital contribution of tetrahedral
Co(II) complexes have generally lower magnetic moments
(ꢄ3.87 B.M.), as compared to that of octahedral complexes
(ꢄ4.7–5.2 B.M.) [58]. Co(II) complex showed a magnetic moment
of 5.02 B.M. at room temperature suggesting consistency with its
octahedral environment.
3.4.2. Electronic spectra
Electronic spectra of six coordinate copper(II) complexes have
either D4h or C4v symmetry, and the eg and t2g levels of the 2D free
ion term will split into B1g, A1g, B2g and Eg levels, respectively. Thus
the three spin allowed transitions are expected in the visible and
near IR regions. These bands may be assigned to following transi-
phen)(TPHP)Cl] exhibits an axial signal with two g values
(g|| = 2.131, g\ = 2.030). In axially elongated octahedral and square
2
planar complexes, the unpaired electron occupies the dx 2 orbital
ꢀy
2
with B1g ground state resulting in g|| > g\. However, in a com-
pressed octahedron the unpaired electron occupies the dz2 orbital
tions: 2B1g ? 2A1g (dx 2 ? dz2), 2B1g ? 2B2g (dx 2 ? dxy) and
with 2A1g ground state having g\ > g||. The observed ‘‘g’’ values sug-
2
2
ꢀy
ꢀy
2
2
2
2B1g ? 2Eg (dx 2 ? dxz, dyz) in order of increasing energy. The en-
gest that the unpaired electron lies predominantly in the dx
ꢀy
ꢀy
ergy level sequence will depend on the amount of distortion due to
ligand field and Jahn–Teller effect [59]. But only few complexes are
known in which such bands are resolved either by Gaussian anal-
ysis or single crystal polarization studies. The electronic spectra of
copper (II) complex showed one band at 16286 cmꢀ1 (614 nm) cor-
responding to 2B1g ? 2B2g transition (Fig. 1) and this is consistent
with an octahedral configuration [60]. The solid reflectance spec-
trum of the Ni(II) complex shows three bands in the near IR–visible
orbital. Therefore the trend g|| > g\ > ge (2.0023) observed for this
2
2
complex indicating that dx
is the ground state with the d9
ꢀy
[Cu2+] octahedral geometry around the copper(II) ion [62] in the
complex. Kivelson and Neiman [63] have reported that g|| < 2.3
and g|| > 2.3 is characteristic for covalent and ionic characters,
respectively. By applying this criterion, the Cu(II)-complex under
study has mainly covalent metal–ligand bonding. In axial symme-
try, the g-values are related by the expression, G = (g|| ꢀ 2)/(g
g\ ꢀ 2), where G is the exchange interaction parameter and,
according to Hathaway [62], if the value of G is greater than 4,
the exchange interaction between copper(II) centers in the solid
state is negligible, whereas when G is less than 4, a considerable
exchange interaction is indicated in the solid complex. For
[Cu(1,10-phen)(TPHP)Cl], the calculated G value for Cu(II)-complex
is 4.64, suggesting that the local tetragonal axes are only slightly
misaligned and the exchange interactions between Cu(II) ions are
negligible [64].
region
m
at
m
1 = 10100 cmꢀ1
(990 nm)
[3A2g ? 3T2g(F)],
m
3 = 23800 cmꢀ1
2 = 16900 cmꢀ1 (592 nm) [3A2g ? 3T1g(F)] and
(420 nm) [3A2g ? 3T1g(P)] (Table 1). These frequencies are well
within the range expected for octahedral Ni(II) complexes
[59,60]. The Co(II) complexes generally give rise to three absorp-
tion bands in the visible region under the influence of the octahe-
dral field by the excitation of the electron from the ground state
4
4
4
4T1g (F) to the excited states T2g(F), A2g(F) and T1g(P). In the
[Co(1,10-phen)(TPHP)Cl]ꢁH2O complex, three bands are observed
at 9950 cmꢀ1 (1005 nm) [4T1g (F) ? 4T2g (F)] (ˆ1), 17400 cmꢀ1
(575 nm) [4T1g (F) ? 4A2g (F)] (ˆ2) and 20200 cmꢀ1 (495 nm) [4T1g
(F) ? 4T1g (P)] (ˆ3) as reported in many octahedral cobalt(II)
complexes.
3.7. Conductivity measurements
The chelates were dissolved in DMSO and the molar conductiv-
ities of 10ꢀ3 M of their solutions at 25 1 °C were measured. As
seen from Table 1, the molar conductivity values for M(II)-chelates
3.5. Ligand field parameters
are 9.6–11.5
X
ꢀ1 cm2 molꢀ1 indicating nonelectrolytic nature of
The ligand field splitting energy (10 Dq), interelectronic repul-
the complexes. On the other hand, copper(II) complexes are more
conductive than cobalt(II) and nickel(II) complexes. These results
may be due to from higher stability constants of the copper(II)
sion parameter (B), ratio m2
/m1 and covalency factor (nephelauxetic
ratio) (b) for the Co(II) and Ni(II) complexes were calculated using

M. Aljahdali, A.A. EL-Sherif / Inorganica Chimica Acta 407 (2013) 58–68
63
Fig. 1. Antibacterial activity of mixed-ligand complexes (The antibacterial standard agents used were Gentamicin for Gꢀ and Ampicillin for G+).
Table 2
Electronic parameters of the Co(II) and Ni(II) complexes.a
Complex
Observed bands/cmꢀ1
m2/
m1
B
b
bo
10 Dq
m1
m2
m3
[Ni(1,10-phen)(TPHP)Cl] (2)
[Co(1,10-phen)(TPHP)Cl]ꢁH2O (3)
10100
9950
16900
17400
23800
20200
1.67
1.74
693
762
0.673
0.785
32.68
21.44
10100
11141
a
The ligand field splitting energy (10 Dq), interelectronic repulsion parameter (B) and covalency factor nephelauxetic ratio) (b) for the Co(II) and Ni(II) complexes were
calculated using the secular equations given by König [63].
complexes than both the nickel(II) and cobalt(II) complexes [65].
Hence, the conductivity measurements of the metal(II)-chelates
confirm the proposed general formulae of those chelates as sug-
gested depending upon the results of elemental analyses, UV–Vis,
ESR and IR spectra.
compounds against the selected types of bacteria (Fig. 2) indicates
that CuII > NiII > CoII [74]. The synthesized thiosemicarbazone
compound and its complexes are inactive against Candida (Table 4).
Cu(II), Ni(II) and Co(II) complexes have high antifungal activity
against Geotricum candidum (RCMB 05097), the inhibitions zones
are 24.7, 21.3 and 20.9 mm, respectively. The highest activity index
for Cu(II)-complex is 98.6 vs. E. coli (RCMB 010052) and 91.9 vs. A.
flavus (RCMB 02568). The increased activity of the metal chelate
can be explained on the basis of chelation theory. It is known that
chelation tends to make the ligand act as more powerful and po-
tent bactericidal agent, killing more of the bacteria than the ligand.
It is observed that in a complex, the positive charge of the metal is
partially shared with the donor atoms present in the ligands and
3.8. Antimicrobial activity
The question about the involvement of the metal complexes in
medical treatment is of special interest, as it is known that the bac-
teria can achieve resistance to antibiotics through biochemical and
morphological modifications [66]. Therefore, researching new
compounds of antimicrobial activity is of paramount importance
[67–70]. It seems therefore to be of considerable interest to assess
the biological potential of the novel thiosemicarbazone ligand its
mixed-ligand complexes against different species of bacteria. The
organisms used in the present investigations included two Gram
positive (S. pyogones and B. subtillis) and two Gram negative (P.
aereuguinosa and E. coli). The diffusion agar technique was used
to evaluate the antibacterial activity of the synthesized mixed li-
gand complexes [66–73]. The medium used for growing the culture
was nutrient agar. The results of antimicrobial assessment, Table 3,
exhibit that TPHP has a high antibacterial activity against B. subtillis
(RCMB 010067) with 19.4 mm inhibition zone. The TPHP ligand
and its complexes did not exhibit antibacterial activity against P.
euroginosa (RCMB 010043) except Cu(II)-complex has a compara-
ble zone of inhibition (15.4 mm) to the standard antibacterial
agent (17.3 mm). Cu(II), Ni(II) and Co(II) complexes have high anti-
microbial activity against S. aureus (RCMB 010028), the inhibitions
zones are 27.5, 24.9 and 23.7 mm, respectively. It is worth noting
that the comparison of antibacterial activity (Table 3) of the
there may be
p-electron delocalization over the whole chelation.
This increases the lipophilic character of the metal chelate and fa-
vors its permeation through the lipoid layer of the bacterial
membranes.
3.9. Molecular modeling
In the absence of a crystal structure, to obtain the molecular
conformation of a compound, energy minimization studies were
carried out on the basis of the semi-empirical PM3 level provided
by HyperChem 7.5 software. The calculated dipole moment, total
energy, binding energy, HOMO, and LUMO energies after geomet-
rical optimization of the structures of complexes were given in
Table 5.
3.9.1. Bond length and bond angle calculations
The bond lengths and bond angles of [Ni(1,10-phen)(TPHP)Cl]
complex as a representative example of M(II) compounds are given

64
M. Aljahdali, A.A. EL-Sherif / Inorganica Chimica Acta 407 (2013) 58–68
Table 3
Antibacterial activity of M(II) complexes.
Compounds
Diameter of inhibition zone (in mm)a
(Gꢀ)
(G+)
Pseudomonas euroginosa (RCMB 010043) Escherichia coli (RCMB 010052) Bacillus subtillis (RCMB 010067) Staphylococcus aureus (RCMB 010028)
Conc. (mg/ml) 1 mg/ml
Activity index
–
89.01
–
–
1 mg/ml
Activity index
62.78
96.86
82.95
81.61
1 mg/ml
Activity index
70.80
95.98
84.30
81.75
1 mg/ml
Activity index
55.86
84.87
76.85
73.14
TPHP
(1)
(2)
NA
15.4 0.29
NA
14.0 0.64
21.6 0.29
19.5 0.37
18.2 0.24
22.3 0.18
19.4 0.64
26.3 0.41
23.1 0.39
22.4 0.26
27.4 0.18
18.1 0.35
27.5 0.25
24.9 0.37
23.7 0.41
32.4 0.10
(3)
NA
17.3 0.15
Standardb
a
Mean zone of inhibition in mm standard deviation beyond well diameter (6 mm) produced on a range of environmental and clinically pathogenic microorganisms using
(1 mg/ml) concentration of tested samples.
b
The standard antibacterial agents used are Gentamicin for G- and Ampicillin for G+.
Fig. 2. Octahedral structure of Co(II) complex and numbering system adopted in the present work.
Table 4
Antifungal activity of M(II) complexes.
Compounds
Diameter of inhibition zone (in mm)a
Aspergillus flavus (RCMB 02568) Pencicillium italicum (RCMB 03924)
Candida albicans (RCMB 05031)
Geotricum candidum (RCMB 05097)
Conc. (mg nml)
1 mgnml
Activity index
65.82
91.98
75.55
72.15
1 mg nml
Activity index
67.12
89.4 9
74.88
72.60
1 mg nml
NA
NA
NA
NA
Activity index
1 mg nml
Activity index
65.15
86.06
74.21
72.82
TPHP
15.6 0.58
21.8 0.47
17.9 0.51
17.1 0.28
23.7 0.10
14.7 0.44
19.6 0.44
16.8 0.57
15.9 0.62
21.9 0.12
–
–
–
–
18.7 0.64
24.7 0.15
21.3 0.23
20.9 0.19
28.7 0.22
(1)
(2)
(3)
Amphotericin (B)
19.8 0.20
a
Mean zone of inhibition in mm standard deviation beyond well diameter (6 mm) produced on a range of environmental and clinically pathogenic microorganisms using
(1 mg/ml) concentration of tested samples.
in Supplementary data. A drawing of Co(II) and Ni(II) complexes
with the atomic numbering scheme is shown in Figs. 2 and 3 while
selected bond lengths and angles for M(II) complexes are given in
Supplementary data. The coordination results in the changes of
bond lengths and angles of the thiosemicarbazone moiety, as ex-
pected, thus when the bond lengths in the coordinated thiosemi-
carbazone ligand are compared with those in the free
thiosemicarbazone ligand, it is seen that coordination elongates
the thiosemicarbazone moiety’s C–S bond from 1.631 Å to 1.750–
1.77 Å and contracts adjacent N–C(S) bond from 1.437 Å to
1.314–1.397 Å in , which is consistent with the C–S acquiring a par-
tial single bond and N–C(S) a partial double bond character. These
changes in bond lengths are attributable to stabilization of the
iminothiolate form of the thiosemicarbazone ligand upon

M. Aljahdali, A.A. EL-Sherif / Inorganica Chimica Acta 407 (2013) 58–68
65
(typical bond lengths being C(sp2)–S 1.706 Å in (MeS)2C@C(SMe)2
and C@S 1.630 Å in naphthylphenylthioketone) [76,77]. This also
confirms the IR and spectral data which assumed that the C@S
on coordination gains C–S character. Similar structural features
are known for other metal complexes of such ligands that have
the same coordination sites [75,78]. The other bond lengths and
angles also suffer some changes, but not significantly. Moreover,
the bond length data shows that the M–N and M–S distances are
comparable with those reported for other thiosemicarbazone cop-
per (II) complex (e.g. Cu–Niminic = 1.98 and Cu–S = 2.26 Å in 3-eth-
oxy-2-oxo butyraldehyde bis(thiosemicarbazonato) copper(II),
[79]. In general, the M–S bond length is longer than that of M–Cl
for the all M(II) complexes and the M–N bond length is shorter
than M–Cl bond length showing that the bond length obeyed this
Table 5
Some energetic properties of the M(II) complexes calculated by PM3 method.
Complex Total
energy
(kcal/mol)
Binding
energy
(kcal/
Electronic
energy (kcal/ moment
mol)
Dipole
HOMO LUMO
mol)
(1)
(2)
(3)
ꢀ132306.25 ꢀ5695.23 ꢀ1158161.10 8.16
ꢀ129041.72 ꢀ5840.45 ꢀ1190387.68 10.03
ꢀ123331.73 ꢀ5995.91 ꢀ1150944.83 10.12
ꢀ4.01 ꢀ1.37
ꢀ7.03 ꢀ1.90
ꢀ3.65 ꢀ1.85
complexation via loss of the hydrazinic proton [75]. This means
that, C–S distances which are in the range of single bond character
being some of the largest found for thiosemicarbazone complexes
Fig. 3. Octahedral structure of Ni(II) complex and numbering system adopted in the present work.
Fig. 4. Calculated bond lengths before and after complexation for TPHP and M(II) complexes.

66
M. Aljahdali, A.A. EL-Sherif / Inorganica Chimica Acta 407 (2013) 58–68
order M–S > M–Cl > M–N (Fig. 4). The bond angles around the M(II)
center (ꢄ90) prove that the geometric is octahedral as proposed by
the different tools of analysis mentioned previously. Finally, from
the interpretation of elemental and thermal analyses, spectral data
(infrared, electronic, 1H NMR and ESR) as well as magnetic suscep-
tibility measurements at room temperature, conductivity mea-
surements and QM calculations, it is possible to draw up the
tentative octahedral structures of the metal complexes.
nature of the compound increases, which favors its permeation
more efficiently through the lipid layer of the microorganism
[87], thus destroying them more aggressively. From the data given
in Table 5, [Cu(1,10-phen)(TPHP)Cl] has a lower dipole moment
(l = 8.16), thus, it is suggested that, its lipophilic nature is large
in comparison to the other complexes which in turn deactivates
enzymes responsible for respiration processes of the tested mi-
cro-organisms more than the other complexes i.e. the formation
of a lipophilic complex could enhance its penetration through the
cytoplasmic membrane, and consequently increase the cellular up-
take of metal ions by bacterial cells. The same finding was obtained
for tin complexes with thiosemicarbazones [88]. Consequently, the
biological activity of the tested complexes obeyed this order Cu > -
Ni ꢅ Co. The dipole moment of both Ni(II) and Co(II) complexes are
approximately the same and hence a little difference in the biolog-
ical activity of both complexes was observed.
3.9.2. Molecular parameters
Quantum chemical parameters of organic compounds are ob-
tained from calculations, such as the energy of the highest occu-
pied molecular orbital, EHOMO, energy of the lowest unoccupied
molecular orbital, ELUMO. Additional parameters, such as separation
energies (
(Pi), absolute hardness (
licity ( ) [79–83], global softness (S) and additional electronic
charge ( Nmax) have been calculated according to the given equa-
tions in literature [84]. The concepts of the parameters and Pi are
related to each other. The inverse of the global hardness is desig-
D
E), absolute electronegativities (
v), chemical potentials
g
), absolute softness (
r), global electrophi-
x
D
3.11. Structure of the complexes
v
Single crystals of the complexes could not be isolated; thus, no
definitive structure can be described. However, it is concluded that
from elemental analysis, IR, ESR and 1H NMR spectra, the thiosem-
icarbazone ligand (TPHP) behaves as a monobasic tridentate ligand
coordinated to the metal ions Cu(II), Ni(II) and Co(II) through the
thiolate group and the azomethine-N atoms (NNS) while 1,10-
phen acts as a neutral bidentate ligand coordinated through the
pyridine nitrogen atoms. On the basis of the elemental analysis
and spectral data octahedral geometry is suggested for all investi-
gated complexes.
nated as the softness
can deduced that:
r [85]. From the obtained data (Table 6) we
(a) The highest occupied molecular orbital (HOMO) and lowest
unoccupied molecular orbital (LUMO) are very popular
quantum chemical parameters. These molecular orbitals
are also called the frontier molecular orbitals (FMOs) and
determine the way of interaction for the molecule with
other species. The FMOs are important in molecular reactiv-
ity. The HOMO is the orbital that could act as an electron
donor, since it is the highest energy orbital containing elec-
trons. The LUMO is the orbital that could act as the electron
accepter, since it is the lowest energy orbital that can accept
electrons. The energies of the HOMO (ꢀ8.66) and LUMO
(ꢀ1.05) are negative, which indicate the title molecule is sta-
ble [86].
(b) Lower HOMO energy values show that the molecule donat-
ing electron ability is weaker. On contrary, a higher HOMO
energy implies that the molecule is a good electron donor.
The LUMO energy presents the ability of a molecule receiv-
ing an electron.
(c) From the calculations of the binding energy we notice that
there is an increase of the value of the calculated binding
energy of complexes compared to that of the ligand which
indicates that the stability of the formed metal complexes
is higher than that of TPHP-ligand (ꢀ2900.72 kcal/mol).
3.12. Equilibrium studies
The study of complex formation equilibria for the investigated
ligands cannot be carried out in aqueous solution because of the
nature of the compounds involved. These compounds are insoluble
in water. This solvent has been widely used for potentiometric
determination of protonation and formation equilibria. The mix-
ture DMSO–water 70%:30% was the chosen solvent for our study.
In such a medium, the studied thiosemicarbazones are soluble giv-
ing stable solutions. The use of this mixed solvent has some advan-
tages over pure DMSO. Thus, pure DMSO is very hygroscopic and
controlling its water content is difficult [43,89]. This fact would af-
fect reproducibility of our experiment. However, DMSO–water
70%:30% mixture has only small hygroscopic character. A further
advantage is its compatibility with the standard glass electrode,
so that the pH measurements may be carried out in a similar
way to that employed in a purely aqueous solution. In contrast,
the use of pure DMSO is not recommended for potentiometry. An-
other advantage of the DMSO–water 70:30% mixture is its large
acidity range (pKw = 15.75 0.2) [43] which allows the investiga-
tion of deprotonation equilibria of weak acids which could be
hardly studied in water [43,89]. Trials were carried out for study-
ing the complex-formation equilibria for both binary and mixed-li-
gand complexes. Binary complex formation equilibria was only
studied due to the precipitation occurs by addition of 1,10-phen
does not permit the determination of their formation constants
of the corresponding complexes.
3.10. Molecular modeling and biological activity
Theoretical calculations were performed in order to investigate
physico-chemical properties that may be related to the antimicro-
bial action of the studied compounds. A property of interest in this
study was the dipole moments, which may give some insight on
the degree of hydrophobicity/hydrophilicity of the compounds.
SAR studies suggested that there is an inverse correlation between
the dipole moment and the activity of the isolated M(II)-complexes
towards the studied bacterial and fungal species. As dipole mo-
ment decreases the polarity decreases and in turn the lipophilic
It is known that, protonation constants are important in pre-
parative chemistry. Therefore, if the protonation constants of a cer-
tain substance are known, it is possible to isolate it with a
maximum yield by finding the pH range where the compounds
show minimum ionization. Also, the data related to the proton-
ation constants of bio-relevant compounds will be valuable in fur-
ther understanding of their chemistry in biological systems.
Additionally, analytical chemists are supposed to know the related
constants of the species present in the medium to determine the
Table 6
The calculated quantum chemical parameters of the ligand and its metal complexes.
Compound
v
g
r
Pi
D
E
x
DNmax
Cu(II)
Ni(II)
Co(II)
2.69
4.47
2.55
1.32
2.57
1.10
0.76
0.39
0.91
ꢀ2.69
ꢀ4.47
ꢀ2.55
2.64
5.13
2.20
2.74
3.89
2.96
2.04
1.74
2.32

M. Aljahdali, A.A. EL-Sherif / Inorganica Chimica Acta 407 (2013) 58–68
67
accuracy and most suitable medium for their analysis. The major
reasons for the determination of protonation constants can be
summarized as follows:
This value is in fair agreement with pKa of SH group (7.36) tak-
ing into consideration the acidification upon complexation i.e. the
lower pKa values 6.35 and 7.08 for Cu-TPHP and Ni-TPHP com-
plexes respectively than that of free TPHP ligand (7.36) indicates
acidification upon coordination to M(II) ion.
The stability constants listed in Table 7 clearly show that the sta-
bility order of the M(II)–TPHP binary systems in terms of metal ions
is Cu(II) > Ni(II) > Co(II) and copper(II) has the highest stability of all
the studied complexes. This behavior is in line with stability order
of the binary complexes and Irving–Williams order [93]. In general,
it is noted that the stability constant of the Cu2+ complex is quite
large compared to the other metals (logK[Cu(TPHP)] = 11.95 >
logK[Ni(TPHP)] = 10.69 > logK[Co(TPHP)] = 10.22). The sharp maximum
of the Cu(II) complex is due to the Jahn–Teller which will give CuII
extra stabilization due to tetragonal distortion of the octahedral
symmetry [94,95].
(1) One can calculate the pH and the ratio of different forms of a
certain substance by the use of its protonation constants.
(2) Protonation of a newly synthesized compound can also give
supportive information about its structure. If theoretically
calculated protonation constants are in good accordance
with the experimental values, it is possible that the pro-
posed structure could be correct.
(3) Due to the fact that different forms of different substances
have different UV spectra, by choosing a suitable pH value
one can carry out spectrophotometric quantitative analyses.
The choice of the pH values requires knowledge of proton-
ation constants.
(4) It is necessary that the protonation constants be known in
order to prepare buffer solutions at different pH values [90].
(5) In addition, for the calculations of stability constants of the
complex formation of bio-active compounds with metal
ions, their protonation constants are used [43,91].
4. Conclusions
(6) Knowledge of the equilibrium constants of some compounds
is necessary for the calculation of the concentration of each
ionized species at any pH, which is important for the com-
plete understanding of the physiochemical behavior of such
molecules [43,91]. Therefore, this study was therefore deter-
mining the protonation constants of the newly synthesized
compounds.
The present paper reports on the synthesis, characterization
and biological activity of [M(1,10-phen)(TPHP)Cl].nH2O complexes.
The synthetic procedure in this work resulted in the formation of
complexes in the molar ratio (1:1:1) (M:1,10-phen : TPHP) respec-
tively. From the molar conductance data, it was found that all the
M(II) chelates are considered as nonelectrolytes. On the basis of the
analytical, conductivity, magnetic data, infrared, molecular model-
ing and electronic spectral data octahedral geometry is suggested
for all investigated complexes. In the absence of X-ray single crys-
tal data of the current synthesized complexes and based on the
physicochemical studies and geometrical optimization, a tentative
structure could be proposed as shown for Co(II) and Ni(II) com-
plexes in Figs. 2 and 3. Geometry optimization and conformational
analysis have been performed and the perfect agreement with the
spectral studies allow for suggesting the exact structures of all the
studied complexes. The antimicrobial study reveals that some of
the synthesized complexes show better activity or comparable
activity to the standard drug antibiotic. The metal complexes were
more active against Gram-positive than Gram-negative bacteria. It
may be concluded that antibacterial activity of the compounds is
related to cell wall structure of the bacteria. It is possible because
the cell wall is essential to the survival of many bacteria and some
antibiotics are able to kill bacteria by inhibiting a step in the syn-
thesis of peptidoglycan. SAR studies suggested that there is an in-
verse correlation between the dipole moment and the activity of
the complexes against the studied bacterial and fungal species. In
summary, compounds discussed in this article, represent a good
model for comparison to establish a good correlation of structure
and activity. The relationship between structural and biological
properties has been explored which could be helpful in designing
more potent antibacterial agents.
The overall stability constants (bpqr) of the studied complexes
can be defined by Eqs. (2) and (3):
pM þ qL þ rH $ MpLqHr
ð2Þ
ð3Þ
½MpLqHrꢃ
bpqr
¼
p
q
r
½Mꢃ ½Lꢃ ½Hꢃ
where M denotes the metal ion, L the thiosemicarbazone ligand, H
the proton and p, q and r are the respective stoichiometric coeffi-
cients. The stoichiometric stability constants of M(II) complexes of
the investigated TPHP-thiosemicarbazone ligand were determined
in 70% DMSO–water mixture at 25 °C and these constants are tabu-
lated in Table 7. The data also show the formation of the binary
complexes with stoichiometric coefficients 110 and 111 for both
Cu(II) and Ni(II) complexes and 110 species for Co(II) complex.
The pKa of the protonated complex can be calculated using Eq. (4)
[92].
pKa ¼ logb111 ꢀ logb110
ð4Þ
Table 7
Logarithms of the protonation of TPHP-thiosemicarbazone ligand and stability
constants of M(II)–TPHP complexes of in 70% DMSO–water mixture (I = 0.1 mol dmꢀ3
NaCl, T = 25.0 0.01 °C).
Compound
TPHP
p
q
ra
logbb
Sc
Appendix A. Supplementary material
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
2
0
1
0
1
0
11.25 0.03
18.72 0.05
11.95 0.07
18.30 0.08
10.89 0.06
17.97 0.08
10.22 0.03
3.2E-8
The antifungal activity curve of the isolated chelates against the
selected types of fungi and the visible electronic spectra of
[Cu(TPHP)(1,10-Phen)Cl] complex were given in supplementary
data. Additionally Tables of bond distances (Å) and angles (°) or
[Ni(1,10-phen)(TPHP)Cl] complex and Comparison of Bond length
(Å) and angles (°) for free TPHP-thiosemicarbazone ligand and its
M(II)-complexes were also given in supplementary data.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.ica.2013.06.040.
Cu-TTPHP
Ni-TTPHP
Co-TTPHP
1.2E-7
5.7E-7
6.3E-7
p, q, r are the stoichiometric coefficient corresponding to M(II), TPHP and H+
respectively.
a
b
Standard deviations.
Sum of squares of residuals.
c

68
M. Aljahdali, A.A. EL-Sherif / Inorganica Chimica Acta 407 (2013) 58–68
[47] D.X. West, Y.-H. Yang, T.L. Goldberg, A.E. Liberta, J. Valdes-Matines, S.
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