Synthesis, characterization and biological properties of mixed ligand complexes of cobalt(II/III) valproate with 2,9-dimethyl-1,10-phenanthroline and 1,10-phenanthroline

Article abstract of DOI:10.1002/aoc.3904

The synthesis of mononuclear cobalt(II/III) complexes with two different ligands (complex 2: [Co(valp)₂(2,9-dmp)] and complex 3: [Co(valp)₂(H₂O)(1,10-phen)]) was investigated and the characterization of both complexes was

Full text of DOI:10.1002/aoc.3904

Received: 26 January 2017
DOI: 10.1002/aoc.3904
Revised: 29 March 2017
Accepted: 29 April 2017
F U L L PA P E R
Synthesis, characterization and biological properties of mixed
ligand complexes of cobalt(II/III) valproate with 2,9‐dimethyl‐
1
,10‐phenanthroline and 1,10‐phenanthroline
Amani Abu Shamma* | Hijazi Abu Ali*
| Shayma Kamel
Department of Chemistry, Birzeit University,
West Bank, Palestine
The synthesis of mononuclear cobalt(II/III) complexes with two different ligands
complex 2: [Co(valp) (2,9‐dmp)] and complex 3: [Co(valp) (H O)(1,10‐phen)])
(
2
2
2
Correspondence
was investigated and the characterization of both complexes was achieved using
IR, UV–Vis, and single crystal X‐ray diffraction. Using single crystal X‐ray diffrac-
tion, the crystal structure of each of the complexes was determined. Additionally, the
biological activity of these complexes was studied in five gram‐positive and four
gram‐negative bacterial strains. Whereas in all gram‐negative bacteria tested, cobalt
valproate complexes did not show any anti‐bacterial activity, both complexes had
effects on gram positive bacteria. Complex 2 demonstrated good anti‐bacterial activ-
ity against all gram‐positive bacteria with inhibition zone diameter (IZD) ranging
between 15–28 mm. Complex 3 exhibited low inhibition activity against all gram‐
positive bacteria except E. faecalis with IZD ranging between 11.3–13.7 mm. More-
over, as an indication of its uses as industrial catalyst, the rate of bis(p‐nitrophenyl)
phosphate (BNPP) hydrolysis when catalyzed by these complexes was measured at
different temperatures, concentrations and pH. Complex 2 proved to be a better
catalyst to induce the hydrolysis of BNPP.
Hijazi Abu Ali, Department of Chemistry,
Birzeit University, P.O. Box 14, West
Bank, Palestine.
Email: habuali@birzeit.edu;
habuali1@yahoo.com
KEYWORDS
anti‐bacterial activity, carboxylate coordination modes, cobalt complexes, nitrogen donor ligands, phosphate
hydrolysis, valproate
1
| INTRODUCTION
as a catalyst in industrial applications such as nitrile
hydratase and methionine aminopeptidase.
[
3,6,7]
Co(III) ion is found in different biological systems such as
vitamin B12 (cobalamin) which is a key molecule for the for-
mation of blood cell and the normal functioning of the
Nitrogen based ligands are used in the synthesis and
design of compounds for biological, chemotherapeutic and
pharmacological applications such as anti‐rheumatics and
[1–5]
[8,9]
nervous system and the brain.
In addition to its uses in
anti‐histamines.
1,10‐Phenanthroline is an efficient che-
bioinorganic chemistry, cobalt can be used in biotechnology
lating nitrogen donor ligand which produces stable com-
plexes in a solution with transition and post transition metal
ions. 1,10‐Phenanthroline complexes possess additional
properties because it contains heteroaromatic and aromatic
groups. It has been shown that 1,10‐phenanthroline copper
complex has an antitumor activity and inhibits both RNA
*
These authors have contributed equally to this work
Abbreviations: 1,10‐phen, 1,10‐phenanthroline; 2,9‐dmp, 2,9‐dimethy‐
1
,10‐phenanthroline;
BNPP,
Bis(p‐nitrophenyl)
phosphate;
E,
[
9,10]
Erythromycin; G, Gentamycin; valp, valproate
and DNA polymerase activities.
Appl Organometal Chem. 2017;e3904.
wileyonlinelibrary.com/journal/aoc
Copyright © 2017 John Wiley & Sons, Ltd.
1 of 12
https://doi.org/10.1002/aoc.3904

2
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ABU SHAMMA ET AL.
Biological activities of metal complexes depend both on
structure of the catalyst and the pH value are factors affecting
+
n
[29,30]
the type of the metal ion (M ) and the nature of the
the hydrolysis of phosphodiester bond.
We determined
[
11,12]
ligand.
Cobalt(II) complexes with N‐ and O‐ donor
the efficiency of these compounds as catalysts using the
hydrolysis of BNPP as a readout.
ligands have been studied in a wide range of biological
applications because they have diverse properties such as
anti‐microbial and antitumor activities. The activity of
transition metal complexes can be improved by using differ-
ent N‐heterocyclic ligands such as 1,10‐phenanthroline, 2‐
2
2
| EXPERIMENTAL
[8]
aminopyridine and 2‐methylamino pyridine.
Carboxylic acids are important precursors used in the syn-
.1 | Chemicals, materials and biological
species
[
13]
thesis of many in inorganic organometallic complexes. Dif-
ferent carboxylic acids and their derivatives such as cinnamic
acid, valproic acid and ibuprofen are used in various medicinal
All reagents, chemicals and solvents were purchased from
commercial sources and used without any further purification.
Escherichia coli, Staphylococcus aureus, Micrococcus luteus,
Bacillus subtilis, Klebsiella pneumonia, Proteus mirabilis,
Enterococcus faecalis, Pseudomonas aeruginosa and Staphy-
lococcus epidermidis were obtained from the department of
Biology and Biochemistry at Birzeit University.
[14,15]
and pharmaceutical applications.
In recent studies,
researchers prepared carboxylate groups with transition metals
such as Zn, Co and Cu to increase their biological efficiency in
[16]
biological and pharmaceutical applications.
Valproic acid is a pharmacologically active compound
that is rapidly metabolized in the liver. In addition, due to
its unique short chain fatty acid moiety it is easily delivered
into cells and organisms leading to an increased
[
17,18]
2.2 | Physical measurements
bioavailability.
Moreover, it has been shown that valproic acid has a wide
range of clinical uses, for instance, it is used as antibiotic drugs
for the treatment of many diseases such as migraines, epilepsy,
Melting points were measured by using Electrothermal melt-
ing point apparatus. IR spectra of cobalt complexes were taken
on a Bruker Tensor II using KBr pellets in the region 200–
[18–20]
and bipolar disorder.
However, valproic acid causes
−1
4
000 cm . UV–Vis spectra in MeOH solvent were deter-
many side effects in humans such as hair loss and weight gain.
Hence, complexing valproate with metal may reduce these
mined in the region 200–800 nm using Agilent 8453 photodi-
ode array (PDA) spectrophotometer. The magnetic
susceptibility measurements of powdered complexes were
[18,20,21]
side effects and enhance the biological activity.
Metal based drugs have been extensively utilized in inor-
ganic, pharmaceutical and medicinal chemistry to produce
new drugs which depend on metal ions and organic
determined by magnetic susceptibility, HgCo(NSC) complex
4
(mercury cobalt‐thiocyanate) was used as standard complex.
[
10]
ligands.
complexes are widely used in biological systems and indus-
trial applications. For example, dirhenium(III)
dichlorotetraisobutyrate inhibits cancer cell growth and
Transition metals coordinated with carboxylate
2
.3 | Synthesis and characterization of cobalt
valproate complexes
[22]
dirhodium(II) tetraacetate is used as catalyst.
All cobalt valproate complexes were prepared at room tem-
perature (RT).
There are many examples of metal valproate complexes
such as copper, cadmium(II), cobalt(II), zinc(II) and
[
23–26]
manganese(II).
cadmium(II), cobalt(II) and manganese(II) valproate with
,10‐phenanthroline and imidazole. The complexes were
tested for their biological activities such as anti‐bacterial
Tabrizi and McArdle have studied
1
2
.3.1 | Synthesis of cobalt valproate
[
Co (valp) ] (1)
[26]
2
4
and anti‐cancer activities.
In this paper, we report the synthesis and characterization
of two mononuclear cobalt(II/III) complexes with two differ-
ent ligands. The complexes' biological activities and their
ability to be used as catalysts in industrial applications are
measured. The hydrolysis of BNPP is very important in envi-
Sodium valproate (2.00 g, 12.1 mmol) in water was slowly
added to a stirred aqueous solution of CoCl .6H O (1.42 g,
2
2
6.0 mmol), then the formed purple solid was filtered from
aqueous solution, washed with cold water and air dried.
The complex was characterized by using IR‐spectroscopy,
UV‐spectroscopy.
[27,28]
ronmental, industrial and biological applications.
The
−1
hydrolytic cleavage of phosphodiester bond is very difficult
to take place, but it may be enhanced by using an artificial
catalyst which may be organic or inorganic. The temperature,
Yield = 86.50%; m.p = 58 °C; IR (KBr, cm ): 2959,
2872, 1556, 1450, 1419, 1330, 753, 469; UV–Vis (MeOH,
λ (nm) (є/Lmol− cm )): 270 (7576.5), 492 (43.6).
1
−1

ABU SHAMMA ET AL.
3 of 12
2
.3.2 | Synthesis of cobalt valproate 2,9‐
dimethyl‐1,10‐phenanthroline complex
co(valp) (2,9‐dmp)] (2)
2.3.3 | Synthesis of cobalt valproate 1,10‐
phenanthroline complex [co(valp) (H O)(1,10‐
2
2
[
phen)] (3)
2
2
,9‐dmp (0.14 g, 0.66 mmol) was dissolved in 10 ml
1,10‐phen (0.44 g, 2.2 mmol) was dissolved in 10 ml
MeOH, then the solution was added to a stirred MeOH
solution of complex 1 (0.78 g, 2.2 mmol), then the solution
was stirred for 5.5 h, the solvent was evaporated and a
brown precipitate was obtained. The complex was character-
ized using IR‐spectroscopy, UV‐spectroscopy, magnetic
moment and single crystal X‐ray diffraction. Recrystalliza-
tion from MeOH produced suitable crystals for X‐ray struc-
ture determination.
MeOH, then the solution was added to a stirred MeOH
solution of complex 1 (0.12 g, 0.33 mmol), then the solution
was stirred for 3 h, the solvent was evaporated and a
purple precipitate was obtained. The complex was
characterized using IR‐spectroscopy, UV‐spectroscopy,
magnetic moment and single crystal X‐ray diffraction.
Recrystallization from MeOH produced suitable crystals
for X‐ray structure determination.
−1
Yield = 82.57%; m.p = 125‐126 °C; IR (KBr, cm−1):
3100, 2958, 2930, 2869, 1587, 1514, 1445, 1422, 1420,
1400, 1219, 1160, 1141, 848, 758, 727, 645, 552, 490;
Yield = 87.81%; m.p = 134‐139 °C; IR (KBr, cm ):
090, 3050, 2954, 2930, 2850, 1544, 1495, 1480, 1410,
400, 1220, 1111, 1033, 864, 762, 760, 654, 549, 474;UV–
3
1
−1
−1
−1
−1
Vis (MeOH, λ (nm) (є/Lmol cm )): 230 (33601), 270
27432), 329 (1183.9), 502 (12.8), 521 (12.5); μeff = 4.33 BM.
UV–Vis (MeOH, λ (nm) (є/Lmol cm )): 270 (61829),
228 (36510), 525 (33.9); μeff = 4.50 BM.
(
TABLE 1 Crystallographic data and structure refinements for complexes 2 and 3.
Complex 2
Complex 3
40CoN
543.55
295(1) K
Empirical formula
Formula weight
Temperature
C
30
H
42CoN
553.59
295(1) K
2
O
4
C
28
H
2 5
O
Wavelength
0.71073 Å
Monoclinic
P2(1)/c
0.71073 Å
Monoclinic
C2/c
Crystal system
Space group
Unit cell dimensions
a = 14.138(2) Å α = 90°.
b = 22.216(3) Å β = 94.974(2)°
c = 9.865(1) Å γ = 90°
a = 19.561(4) Å α = 90°
b = 18.810(4) Å β = 106.223(4)°
c = 16.177(4) Å γ = 90°
3
3
Volume
3086.7(7) Å
5715(2) Å
Z
4
8
3
3
Density (calculated)
Absorption coefficient
F(000)
1.191 Mg/m
0.590 mm−
1.263 Mg/m
0.638 mm−1
1
1180
2312
3
3
Crystal size
0.51 × 0.15 × 0.14 mm
0.26 × 0.18 × 0.13 mm
Theta range for data collection
Index ranges
2.59 to 27.00°.
2.17 to 27.00°.
−18 < =h < =18, −28 < =k < =28,
−24 < =h < =24, −24 < =k < =24,
−20 < =l < =20
−
12 < =l < =12
Reflections collected
32838
30976
6224 [R(int) = 0.0689]
99.7%
Independent reflections
Completeness to theta = 26.00°
Absorption correction
6698 [R(int) = 0.0805]
99.5%
Semi‐empirical from equivalents
0.9220 and 0.7530
Semi‐empirical from equivalents
0.9216 and 0.8516
Max. and min. transmission
Refinement method
2
2
Full‐matrix least‐squares on F
Full‐matrix least‐squares on F
Data/restraints /parameters
Goodness‐of‐fit on F2
6698 / 10 / 276
1.334
6224 / 0 / 329
1.438
Final R indices [I > 2sigma(I)]
R1 = 0.1972, wR2 = 0.3880
R1 = 0.2363, wR2 = 0.4106
0.817 and −0.784 e.Å−
2 2 1/2
R1 = 0.1605, wR2 = 0.2873
R1 = 0.1695, wR2 = 0.2913
0.685 and −1.329 e.Å−3
a
R indices (all data)
3
Largest diff. peak and hole
a
2
2 2
R1 = ∑|| Fo| –| Fc|| / ∑| Fo and wR2 = ∑[w(F0 – Fc ) ]/ ∑[w(Fo ) ]

4
of 12
ABU SHAMMA ET AL.
2
.4 | X‐ray crystallography
50 μM HEPES buffer solution then the pH of the solution
was adjusted with HCl or NaOH after that BNPP was dis-
solved in buffer solution and the volume of the solution
Single crystal X‐ray analysis of complexes 2 and 3 were car-
ried out by attaching single crystal to a glass fiber with epoxy
glue, and then it was transferred to X‐ray diffractometer
system (Bruker SMART APEX CCD) which is controlled
by using Pentium‐based PC running the SMART software
[37,38]
was adjusted to 100 ml in the volumetric flask.
Different concentrations of the cobalt complexes were
prepared in MeOH solution in order to be used as
catalysts in the BNPP hydrolysis process. The rate of p‐
nitrophenol formation was measured at λ = 400 nm
[
31–33]
package.
The diffracted graphite‐monochromated (Kα
radiation λ = 0.71073 Å) was detected on a phosphor screen
at ‐44 °C and it held at 6.0 cm from the crystal. A detector
−1
−1
(
ter.
ɛ = 13400 L.mol .cm ) using UV–vis spectrophotome-
[38–40]
array of 512 X 512 pixels (a pixel size
̴
120 μm) was used
Crystal data and structure refinements are
summarized in Table 1.
The kinetic experiments were carried out in triplicates
[
31]
to collect data.
by adding 1.5 ml of the cobalt complex into 1.5 ml of
BNPP solution in a quartz cell at constant temperature,
then the solution was mixed immediately and the kinetic
[
38,39]
measurement was performed.
was calculated from the slope of the linear plot of p‐nitro-
phenol concentration against time; [(rate) = (dc/dt)0
The initial rate (Vo)
2
.5 | Anti‐bacterial activity
The anti‐bacterial activities for cobalt complexes were inves-
tigated against five gram‐positive (Staphylococcus aureus,
Micrococcus luteus, Bacillus subtilis, Enterococcus faecalis
and Staphylococcus epidermidis) and four gram‐negative
bacteria (Escherichia coli, Klebsiella pneumonia, Proteus
mirabilis and Pseudomonas aeruginosa).
=
0
[
27]
(
dA/dt) /ɛ].
0
2.7 | Synthesis of cobalt complexes
Cobalt valproate complex [Co (valp) ] (1) was prepared at
2
4
In‐vitro, anti‐bacterial test was carried out by using Agar
diffusion method. The sterile saline solution was prepared by
dissolving 0.5 g of NaCl in 500 ml of water then the solution
was autoclaved. Single bacterial colonies were dissolved in
the sterile saline until the turbidity of the suspended cells
reached the McFarland 0.5 Standard then the bacterial inocu-
late were spread on the surface of the Muller Hinton nutrient
agar by using a sterile cotton swab. After that, the wells
RT by adding 2 equivalent of sodium valproate to 1 equiva-
lent of CoCl as shown in Scheme 1. The purple solid prod-
2
uct was formed with a yield of 86.50%.
The novel two different ligands cobalt complexes were
synthesized by adding N‐donor ligands to complex 1 as
shown in Scheme 2. The physical properties of complexes 2
and 3 are listed in Table 2.
(
6 mm in diameter) in the agar plate were made by using a
[
34,35]
sterile glass borer.
2
2
.8 | Crystallographic study
Cobalt complexes were dissolved in DMSO (6 mg/ml).
5 μl of the test samples were added into the respective
wells in plates and the plates were incubated at 37 °C for
.8.1 | Crystal structure of complex 2
2
[
co(valp) (2,9‐dmp)]
2
12–24 h. Gentamycin (G) and Erythromycin (E) were used
The crystal structure of complex 2 is shown in Figure 1. The
as positive control while DMSO was used as negative con-
trol. The activities of the complexes were determined by
measuring IZD (inhibition zone diameter) in mm
mononuclear [Co(valp) (2,9‐dmp)] complex crystallizes in
2
monoclinic crystal system and P2(1)/c space group. For the
four molecules per unit cell, the asymmetric unit (one
molecule) consists of one Co(II), two bidentate chelating
valp groups and one bidentate 2,9‐dmp molecule forming
(millimetre). The results from this part were determined by
calculating the average of three trials and are stated as aver-
[23,25,36]
o
age ± standard error.
distorted octahedral geometry; N(2)‐Co(1)‐N(1) = 78.5(3) ,
2
.6 | Kinetic measurements of BNPP
hydrolysis
Kinetic experiments were performed at different temperatures
(
7
1
25 °C, 37 °C and 40 °C), different pH values (7.04, 7.48 and
−3
.91) and different catalytic concentrations from 1 × 10 to
−
6
× 10 M.
HEPES buffer, (4‐(2‐hydroxyethyl)‐1‐piperazineethane-
sulfonic acid) was used to maintain a constant pH value.
A minimum amount of deionized water was added to a
2 4
SCHEME 1 Synthesis of [Co (valp) ] (1)

ABU SHAMMA ET AL.
5 of 12
FIGURE 1 X‐ray structure of co(valp) (2,9‐dmp) (2)
2
o
o
O(3)‐Co(1)‐O(2) = 92.2(3) , O(1)‐Co(1)‐N(1) = 86.8(2) ,
o
O(1 W)‐Co(1)‐N(1) = 88.7(2) and O(1 W)‐Co(1)‐N(2) =
09.0(2) . The two asymmetric units are bounded to each
o
1
other by two water molecules through hydrogen bonding
which further stabilized the structure. Selected bond dis-
tances and bond angles for complex 3 are listed in
Table 4.
The average bond distance of Co‐N in complex 3
2.159 Å) is longer than those found in [Co(1,10‐phen)(4‐
(
SCHEME 2 Synthesis of complexes 2 and 3
OMe‐3,6‐DBSQ) (1.956 Å) where 4‐OMe‐3,6‐DBSQ is 4‐
methoxy‐3,6‐ di‐tert‐butyl‐benzoquinone‐1,2.
2
o
o
[43]
O(3)‐Co(1)‐N(1) = 110.7(3) , O(3)‐Co(1)‐O(4) = 58.5(4) ,
o
o
O(2)‐Co(1)‐O(4) = 94.4(5) , O(2)‐Co(1)‐O(1) = 59.6(3)
The values of C‐O bond distances in carboxylate group
depend on the bonding geometry for metal carboxylate
group. In monodentate carboxylate group, the bond distances
are 1.235 (2) Å and 1.305 (2) Å while in bidentate carboxyl-
o
and N(2)‐Co(1)‐O(1) = 101.1(3) . Selected bond distances
and bond angles for complex 2 are listed in Table 3.
The average bond distances of Co‐O (2.134 Å) and Co‐N
[
42]
(
2.128 Å) are similar to the reported values in cobalt‐2,9‐
ate groups it is 1.267 (2) Å.
The covalent and non‐cova-
dimethyl‐1,10‐phenanthroline complexes (2.135 Å and
lent bonds of C‐O in monodentate valproate in complex 3
are 1.246(9) Å and 1.231(10) Å, respectively which are close
to bond distances in monodentate carboxylate groups. On the
other hand, the average values of C‐O bidentate bonds in
complex 3 is 1.254 Å which is close to the bond distance
[41]
2.136 Å, respectively).
In addition, the bond distances of
Co‐O in complex 2 are in agreement with related Co‐O bonds
in cobalt carboxylate complexes which are in the 2.0406 (12)
[42]
to 2.2460 (12) Å range.
[
42]
found in bidentate carboxylate groups.
The hydrogen bonds for complex 3 are summarized in
Table 5 which shows only one intermolecular hydrogen
bonding O(1 W)‐H(1 W1)...O(4)#1 (1.94 Ǻ). This bond
2
.8.2 | Crystal structure of complex 3
[
co(valp) (H O)(1,10‐phen)]
2
2
[
36]
The crystal structure of complex 3 is shown in Figure 2. The
mononuclear [Co(valp) (H O)(1,10‐phen)] complex was
affects the geometry and stability of the complex.
2
2
crystallized in monoclinic crystal system and C2/c space
group. For the eight molecules per unit cell, the asymmetric
unit (one molecule) consists of one Co(III), one monodentate
valproate, one bidentate valproate, one 1,10‐phen and one
water molecule revealing distorted octahedral arrangement;
2
.9 | IR spectroscopy
The IR spectral data for complexes 2 and 3 are listed inTable 6.
For complex 2, the ν (COO ) at 1544 cm and ν (COO ) at
1410 cm have been observed. The Δν value for complex 2
−
−1
−
as
s
o
o
−1
O(3)‐Co(1)‐N(2) = 89.6(2) , O(1)‐Co(1)‐O(2) = 59.9(2) ,
TABLE 2 Physical properties and % yields of complexes 1–3
Complex
Co (valp)
m.p (°C)
58
% yield
86.50
87.81
82.57
Solubility
2
4
(1)
(2,9‐dmp) (2)
(H O)(1,10‐phen) (3)
CH
CH
CH
3
3
3
OH, ether, petroleum ether
OH, C OH, (CH CO, CH
3 2
OH, CH Cl , CHCl , C OH, (CH )
Co(valp)
Co(valp)
2
2
134–139
125–126
2
H
5
3
)
2
3
CN, CH
2 2 3
Cl , CHCl
2
2
2
3
2
H
5
CO

6
of 12
ABU SHAMMA ET AL.
o
TABLE 3 Selected bond distances (Å) and bond angles ( ) for com-
plex 2
calculated number of unpaired electrons. Table 8 shows the
magnetic properties of complexes 2 and 3.
Angle (o)
The bands between 228–270 nm for complexes 2 and 3
are assigned to the intra‐ligand transition bands in addition
to charge transfer bands. The results also showed similarities
between the cobalt complexes and their parent ligands with
very small shifts caused by Co coordination. Complex 2
showed an additional band at 329 nm which may be assigned
as charge transfer band.
Bond
Distance (Å)
2.137(8)
Bonds
Co(1)‐N(1)
Co(1)‐N(2)
Co(1)‐O(1)
Co(1)‐O(2)
Co(1)‐O(3)
Co(1)‐O(4)
C(1)‐N(1)
C(9)‐N(1)
C(6)‐N(2)
C(12)‐N(2)
C(15)‐O(1)
C(15)‐O(2)
C(23)‐O(3)
C(23)‐O(4)
N(2)‐Co(1)‐N(1)
O(3)‐Co(1)‐N(1)
O(3)‐Co(1)‐O(4)
O(2)‐Co(1)‐O(4)
O(2)‐Co(1)‐O(1)
N(2)‐Co(1)‐O(1)
C(1)‐N(1)‐Co(1)
C(6)‐N(2)‐Co(1)
C(15)‐O(1)‐Co(1)
C(15)‐O(2)‐Co(1)
C(23)‐O(3)‐Co(1)
C(23)‐O(4)‐Co(1)
O(3)‐C(23)‐O(4)
O(2)‐C(15)‐O(1)
78.5(3)
110.7(3)
58.5(4)
2.119(8)
2.126(7)
2.125(7)
94.4(5)
2.124(8)
59.6(3)
2.161(11)
1.366(12)
1.295(15)
1.366(10)
1.304(13)
1.240(12)
1.217(12)
1.207(16)
1.229(15)
101.1(3)
111.8(6)
113.1(6)
90.5(6)
The magnetic moment of complex 2 is 4.33 BM. This
value is consistent with the presence of three unpaired elec-
7
trons which indicates a high spin d octahedral geometry.
The electronic spectra for complex 2 exhibits two d‐d transi-
91.2(6)
−1
−1
tion bands at 502 nm (12.8 Lmol cm ) and 521 nm (12.5
92.6(8)
−1
−1
4
4
Lmol cm ) for complex 2 as a result of T ! T (F)
1g
2g
90.2(10)
118.7(13)
118.6(10)
4
4
and T ! T (P) electronic transition bands. The third
1
4
g
1g
4
band ( T1g ! A (F)) is embedded in the charge transfer
2g
bands and intra‐ligand transition bands. The UV–Vis spectral
data of complex 2 is similar to those observed for [Co(2‐
[
8,44]
ampy) (dca) ].
2
2
The magnetic moment for complex 3 is 4.83 BM. This
value indicates the presence of four unpaired electrons
6
supporting a high spin d octahedral geometry. The elec-
tronic spectra of this complex exhibits one d‐d transition
band for (525 nm). Moreover, high spin Co(III) octahedral
complex 3 was obtained because water and 1,10‐phen
ligands behaved as weak field ligands in the present
[
45]
case.
2.11 | Anti‐bacterial activity
Before measurement of their biological activity, the solution
stability of the complexes was tested and checked periodically
2 2
FIGURE 2 X‐ray structure of co(valp) (H O) (1,10‐phen) (3)
1
13
by H and C NMR in chloroform and DMSO solvents and
always gave the same data. In addition, the complexes were
crystallized by slow solvent evaporation at room temperature
that took several days and gave the same physical properties
of the compounds. The in‐vitro anti‐bacterial activity for com-
plexes 2 and 3 were tested against gram‐positive and gram‐
negative bacteria by using agar diffusion method. The results
are summarized in Table 9 and Table 10 for gram‐negative
and gram‐positive bacteria, respectively.
−
1
−1 [23]
(
134 cm ) is less than Δν of Na (137 cm ) which indi-
valp
cates bidentate chelating coordination mode.
−
−1
Complex 3 showed two ν (COO ) bands at 1587 cm
as
−1
−
−1
and 1514 cm and two ν (COO ) bands at 1445 cm and
s
−
1
1
1
9
422 cm , respectively. The Δν values of complex 5 are
−
1
42 cm which is larger than Δν of the free salt and
−
1
2 cm which is smaller than Δν of Na(valp). These results
indicate that this complex contains monodentate and
bidentate chelating coordination modes.
Complexes 2 and 3 didn't show anti‐bacterial activity
against the tested gram‐negative bacteria because the
gram‐negative bacteria contain more layers than gram‐pos-
itive bacteria in their cell wall. This outer membrane
which consists of lipopolysaccharides, resists the antibiotic
and it contains porin proteins which is permeable for small
2
.10 | Magnetic moments and UV–Vis
spectral data for cobalt complexes
[
46]
The electronic spectra of cobalt complexes were recorded in
MeOH solution. The electronic transition data for complexes
and 3 and their parent ligands are summarized in Table 7.
molecules such as glucose.
In addition, complex 3
did not exhibit any anti‐bacterial activity against gram‐pos-
itive bacteria.
2
The magnetic moments of the prepared complexes have
been determined using the spin only formula and the
Complex 2 showed good anti‐bacterial activity against all
tested microorganisms with IZD ranging between 15–28 mm

ABU SHAMMA ET AL.
7 of 12
o
TABLE 4 Selected bond distances (Ǻ) and bond angles ( ) for complex 3
o
Bond
Distance (Å)
2.158(6)
2.214(7)
2.017(5)
2.177(6)
2.141(6)
2.067(5)
1.264(11)
1.243(11)
1.246(9)
1.231(10)
1.540(12)
0.8741
Bonds
O(3)‐Co(1)‐N(2)
O(1)‐Co(1)‐O(2)
O(3)‐Co(1)‐O(2)
O(1)‐Co(1)‐N(1)
O(1 W)‐Co(1)‐N(1)
O(1 W)‐Co(1)‐N(2)
C(21)‐O(3)‐Co(1)
C(5)‐N(1)‐Co(1)
C(6)‐N(2)‐Co(1)
C(13)‐O(1)‐Co(1)
C(13)‐O(2)‐Co(1)
Co(1)‐O(1 W)‐H(1 W1)
H(1 W1)‐O(1 W)‐H(2 W1)
O(2)‐C(13)‐O(1)
O(4)‐C(21)‐O(3)
N(2)‐C(6)‐C(5)
Angle ( )
Co(1)‐O(1)
Co(1)‐O(2)
Co(1)‐O(3)
Co(1)‐N(1)
Co(1)‐N(2)
Co(1)‐O(1 W)
C(13)‐O(1)
C(13)‐O(2)
C(21)‐O(3)
C(21)‐O(4)
C(21)‐C(22)
O(1 W)‐H(1 W1)
O(1 W)‐H(2 W1)
C(1)‐N(1)
89.6(2)
59.9(2)
92.2(3)
86.8(2)
88.7(2)
109.0(2)
137.7(6)
113.4(5)
115.3(5)
90.5(5)
88.5(5)
111.3
0.8234
128.5
1.319(10)
1.354(10)
1.351(9)
1.312(9)
121.1(8)
127.3(8)
116.9(7)
117.9(6)
C(5)‐N(1)
C(6)‐N(2)
C(10)‐N(2)
N(1)‐C(5)‐C(6)
TABLE 5 Hydrogen bond for complex 3
TABLE 8 Magnetic properties for complexes 2 and 3
d(D‐H) d(H...A) d(D...A) <(DHA)
Magnetic moments
# of unpaired
electrons (n)
o
D‐H...A (Ǻ)
O(1 W)‐H(1 W1)...O(4)#1
(Ǻ)
(Ǻ)
(Ǻ)
( )
Complex
Co(valp)
2)
Co(valp)
phen) (3)
(μeff) (BM)
0.87
1.94
2.611(8)
132.0
2
(2,9‐dmp)
4.33
3
(
2
(H
2
O)(1,10‐
4. 83
4
TABLE 6 Assignment of IR bands and wave numbers for complexes
and 3
2
Complex 4 (cm−1
Complex 5 (cm−1
TABLE 9 In‐vitro anti‐bacterial activity results for complexes 2 and
against gram‐negative bacteria
Assignments
)
)
3
ν
ν
as(COO−)
1587, 1514
1445, 1422
142, 92
1544
1410
134
(COO−)
K.
P.
P.
s
−
Compounds
E. coli
pneumoniae mirabilis aeruginosa
Δν(COO )
a
Diameter of zones complete inhibition of growth (mm)
G
25.3 ± 0.9 34.7 ± 3.4 27.0 ± 1.0 20.0 ± 1.8
24.0 ± 1.6 21.5 ± 0.5 17.3 ± 0.9 21.7 ± 3.3
TABLE 7 The electronic data for complexes 2 and 3 and their
parent ligands
E
CoCl
2
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
‐
−
−
λ
(nm)
max ε (L.mol
Pure
ligands (nm)
λmax ε (L.mol
Valp
1
−1
1
−1
Complex
Co(valp)
2)
.cm
)
.cm
58280
272 184090
)
DMSO
2
(2,9‐dmp)
230
33601
27432
1183.9
12.8
2,9‐
dmp
231
Complex 2
2
3
5
5
70
29
02
21
(
2
,9‐dmp
Complex 3
,10‐phen
12.5
1
31.0 ± 0.6 32.0 ± 1.0 33.0 ± 0.6
Co(valp)
2
(H
2
O)(1,10‐ 270
61829
36510
33.9
1,10‐ 266
phen 225
45919
45488
2
5
28
25
phen) (3)
‐
a
Dashes indicated zero inhibition; all microorganisms were resistant to DMSO.
The data stated as average ± standard deviation (N = 3), the concentration was
6
mg/mL in DMSO.
but the parent ligand 2,9‐dmp showed higher anti‐bacterial
activity compared to complex 2 except M. luteus and M.
subtilis which showed slightly higher anti‐bacterial activity
than its parent ligand. On the other hand, complex 2 showed
anti‐bacterial activity against E. faecalis whereas its parent
ligand did not show any anti‐bacterial activity.
Complex 3 showed low inhibition activity against all
gram‐positive bacteria except E. faecalis with IZD between

8
of 12
ABU SHAMMA ET AL.
TABLE 10 In‐vitro anti‐bacterial activity results for complexes 2 and 3 against gram positive bacteria
Compounds
S. aureus
M. Luteus
B. subtilis
E. faecalis
S. epidemidis
Diameter of zones complete inhibition of growth (mm)a
G
29.3 ± 3.2
41.3 ± 1.4
12.0 ± 3.0
‐
34.7 ± 3.4
40.0 ± 0.1
‐
29.3 ± 4.4
36.0 ± 2.1
‐
16.3 ± 0.9
34.7 ± 1.4
45.0 ± 0.7
‐
E
‐
‐
‐
CoCl
2
Valp
‐
‐
‐
DMSO
‐
‐
‐
‐
‐
Complex 2
20.0 ± 0.6
23.3 ± 0.9
13.0 ± 1.9
16.8 ± 0.3
19.5 ± 0.5
19.3 ± 0.4
11.3 ± 0.3
35.7 ± 0.3
16.5 ± 2.5
16.3 ± 0.7
11.5 ± 1.5
32.7 ± 1.2
15.5 ± 2.5
28.0 ± 2.0
31.0 ± 0.6
13.7 ± 1.9
16.3 ± 0.8
2
,9‐dmp
Complex 3
,10‐phen
‐
‐
1
19.0 ± 0.8
‐
a
Dashes indicated zero inhibition; all microorganisms were resistant to DMSO.
The data stated as average ± standard deviation (N = 3), the concentration was 6 mg/ml in DMSO.
1
1.3–13.7 mm. However, these values are lower than those
oxidative stress in the bacteria, which ultimately leads to
[
51]
for its parent ligand 1,10‐phen.
bacterial death.
It was suggested that zinc exhibits the
Valproate and CoCl did not show any anti‐bacterial
activity against gram‐positive and gram‐negative bacteria
antibacterial effect by binding to the bacterial membrane,
thus increasing the lag phase and the generation time of
the organism, which prolongs cell division resulting in cell
2
except CoCl which showed low inhibition activity against
2
[
55]
S. aureus with IZD of 12 mm. The complexation of cobalt
valproate with nitrogen donor ligands showed low inhibition
activity against gram‐positive bacteria compared to the posi-
tive controls (E and G).
death.
Intriguingly, the zinc oxide (ZnO) nanoparticles
have a broad spectrum antibacterial activity against both
Gram‐negative and Gram‐positive bacteria including major
foodborne pathogens like Escherichia coli O157:H7, Salmo-
nella, Listeria monocytogenes, Staphylococcus aureus, and
Previously, we published the synthesis of similar Zn(II)
[
52,53]
valproate complexes with considerable anti‐bacterial activity
Campylobacter jejuni.
The antibacterial activity of
[23,25]
compared to the valproate drug.
ZnO has been attributed to the disruption of the cell mem-
brane and the increase in the expression of oxidative stress
response genes such as katA and ahpC) and a general stress
In general, the anti‐bacterial activity was dependent on the
concentration of the complex; this was obvious by the propor-
tionality found between the concentration and the IZD value.
Compounds are considered significantly active when IZD is
larger than 15 mm, moderately active when IZD is between
[
53]
response gene (dnaK).
Gram‐positive bacteria has a plasma membrane and a
thick cell wall while the Gram‐negative bacteria has plasma
membrane, cell wall and an outer membrane which adds
another layer of complexity in terms of interaction and pen-
etration of these complexes into the bacteria.
[
47]
7
and 14 mm and weakly active for IZD less than 7 mm.
Although it is not clear why some compounds exhibit dif-
ferent bacterial activity with Gram‐positive and Gram‐nega-
tive bacteria, it may be ascribed to the difference in the
overall structure of their cell walls.
It is not known why complexes 2 and 3 did not show anti-
bacterial activity against the tested Gram‐negative and Gram‐
positive bacteria. These complexes harbor the zinc ion, the
carboxylate group and the nitrogen base. It is plausible that
the structural differences in the nitrogen bases of these com-
plexes hindered their binding to the membrane or DNA of the
tested bacteria.
[48]
Metal ions are essential for the survival of microbes in
the environment or the host. Therefore, the microbes should
ensure uptake of metal ions according to their physiological
needs as the imbalance in metals homeostasis could be del-
eterious to the microbe. Host defense against bacterial infec-
tion consists of either sequestering ions resulting in bacterial
starvation, or increased release of these metals, which
results in toxicity. Zinc is required for optimal bacterial
The site of action of the non‐steroidal anti‐inflammatory
drugs (NSAIDs) in human body is determined by inhibiting
the synthesis of prostaglandin through effect on cyclooxygen-
−
5
−7
[49]
[54]
growth at a concentration of 10 to 10 M,
however
ase enzyme.
This mechanism is not available in microor-
high concentration of zinc ions exhibit antibacterial proper-
ganisms due to lack of the presence of cyclooxygenase.
Otherwise, killing activity of ibuprofen in Candida cells
[
50]
ties.
The toxicity of high concentration of Zn has been
shown with infections associated with Streptococcus pneu-
was found through direct damage in their cytoplasmic mem-
[
51]
[55]
monia,
where excess zinc competes with manganese
brane.
Intriguingly, it has been shown that Ibuprofen
resulting in manganese starvation, and initiation of the
exhibit antibacterial activity against six periodontal

ABU SHAMMA ET AL.
9 of 12
BNPP hydrolysis was obtained by changing one of the above
factors while maintaining the other two constant. The results
showed that complexes 2 and 3 may be used as catalyst for
the BNPP hydrolysis.
One possible mechanism of the BNPP catalytic
cleavage is shown in Figure 3. First, water molecule
coordinates with metal complex to produce complex A.
During the second step, the metal complex is coordinated
to oxygen atom on the P = O of BNPP in aqueous
solution, forming complex B. Third, intramolecular metal
hydroxide in complex B attacks the P atom in BNPP
molecule to release p‐nitrophenol and this step is (the key
step of hydrolysis. Do you mean the rate determining step
since you are talking about mechanism? If so, then replace
the (key step of hydrolysis with the rate determining step).
Fourth, water molecule quickly coordinates again with
complex to produce D where p‐nitrophenol and phosphoric
acid are quickly released. Finally, water molecule is bonded
again to the metal complex and thus the catalytic cycle is
FIGURE 3 The possible mechanism of the BNPP catalytic cleavage
[
56]
microorganisms.
The exact mechanism of antibacterial
activity of NSAIDs is unclear. However, studies have pro-
[
27,29,30,58]
[57]
completed.
posed inhibition of bacterial DNA synthesis
ment of membrane activity.
or impair-
[56]
2
.12.1 | Effect of pH on BNPP catalytic
hydrolysis
2
.12 | BNPP catalytic hydrolysis
Figure 4 shows the absorbance versus time relationship for
complex 2 at different pH values and constant temperature
and concentration of both BNPP and complex. The initial
The rate of BNPP hydrolysis was studied at different temper-
atures, pH and concentrations. The optimum condition for
FIGURE 4 BNPP hydrolysis by complex
2
in MeOH /HEPEs buffer solution with
different pH values under the selected
conditions (T = 25 °C, [complex
] = 2 × 10 M and [BNPP] = 1 × 10−4 M)
−
3
2
FIGURE 5 BNPP hydrolysis by complex
in MeOH /HEPEs buffer solution with
2
different temp values under the selected
conditions (pH = 7.04, [complex
] = 2 × 10 M and [BNPP] = 1 × 10−4 M)
−
4
2

1
0 of 12
ABU SHAMMA ET AL.
TABLE 11 Kinetic parameters of the phosphate diester group hydrolysis for complex 2 and 3 at different BNPP concentrations
Concentration
M)
2‐order
(
rate
a
b
V
o
V
max
K
(mol/l)
3.5 × 10−4
m
K
cat
K
BNPP
Complexes
BNPP
(mol/l.S)
5.5 × 10−8
3.1 × 10−8
2.0 × 10−8
6.0 × 10−8
3.2 × 10−8
2.0 × 10−8
(mol/l.S)
1 × 10−7
(S−1)
5 × 10−4
(l.mol−1.S‐1)
(2 × 10−
(2 × 10−
(2 × 10−
(2 × 10−
(2 × 10−
(2 × 10−
4
4
4
4
4
4
)
)
)
)
)
)
1 × 10−3
2 × 10−4
1 × 10−4
1 × 10−3
2 × 10−4
1 × 10−4
0.143 × 10
1
2
2
2
3
3
3
1 × 10−7
3.7 × 10−4
5 × 10−4
0.135 × 10
1
a
K
cat = Vmax/[complex],
b
K
BNPP = Kcat/K
m
rate (V ) of BNPP hydrolysis was calculated by measuring
cation, one monodentate valporate, one bidentate valporate,
one 1,10‐phen and water molecules revealing distorted octa-
hedral arrangement.
Cobalt valproate complexes showed anti‐bacterial
activity against gram‐positive bacteria but did not exhibit
any anti‐bacterial activity against gram‐negative bacteria.
In general, the complexation of cobalt valproate with
nitrogen donor ligands showed low inhibition activity
against gram‐positive bacteria compared to the positive
controls (E and G).
o
the absorbance of p‐nitrophenol against time at
[
38,39]
−8
4
4
00 nm.
The V values (mol/l.S) are 3 × 10 ,
o
× 10 and 2 × 10−8 at pH = 7.91, 7.48 and 7.02 for com-
−
9
plex 2. The maximum V was obtained at pH = 7.91 for
o
complex 2.
2
.12.2 | Effect of temperature on the BNPP
catalytic hydrolysis
The rate of BNPP hydrolysis was studied in order
to determine the effect of cobalt complexes on the
phosphate ester hydrolysis. The results showed that the
hydrolysis rate of BNPP decreased in the following order:
Figure 5 shows the absorbance versus time relationship for
complex 2 at different temp values and constant pH and con-
centration of both BNPP and complex. The V values (mol/L.
o
−
8
−8
−9
S) are 2 × 10 , 1 × 10 and 3 × 10 at 25 °C, 37 °C and
0 °C for complex 2. The maximum V was obtained at 25 °C
2
> 3 and their values are higher than other synthetic
4
o
chemical models.
for complex 2.
The Kinetic parameters of BNPP hydrolysis are shown in
Table 11. The results indicate that the rate of BNPP hydroly-
sis by the prepared complexes is greater for complex 2 and
their values are higher than other synthetic chemical models
ACKNOWLEDGEMENT
The authors thank the office of Vice President for Academic
Affairs at Birzeit University for their financial support.
−5
−1 −1
(
K /K = 1.3–43 × 10
M
s
at 35 °C and pH 7.3–
cat
m
[59]
10.5 for Zn complexes).
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ABU SHAMMA ET AL.
SUPPORTING INFORMATION
How to cite this article: Abu Shamma A, Abu Ali H,
Kamel S. Synthesis, characterization and biological
properties of mixed ligand complexes of cobalt(II/III)
valproate with 2,9‐dimethyl‐1,10‐phenanthroline and
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CCDC 1488001 and 1488003 contains the supplementary
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,10‐phenanthroline. Appl Organometal Chem. 2017;
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