Synthesis, characterization and X-ray crystal structure of potentially N6O2 coordinating macroacyclic Schiff base ligands and their Mn(II), Zn(II) and Cd(II) complexes; cytotoxic, antibacterial properties and competitive 7Li NMR studies

Article abstract of DOI:10.1016/j.poly.2018.12.052

In this work, two new symmetrical, potentially N₆O₂ coordinating, macroacyclic Schiff base ligands (H₂L¹ and H₂L²) were derived from the condensation of a newly synthesized polyamine, 2,2′-(ethane-1,2-diylbis(piperazine-4,1-diyl))bis(ethan-1-amine) (A), with 2-hydroxybenzaldehyde and 2-hydroxy-3-methoxybenzaldhyde respectively. Six macroacylic Schiff base complexes were prepared by direct reaction of H₂L¹ or H₂L² with Mn(II), Zn(II) or Cd(II) metal ions in equimolar ratios. The products were characterized by several physicochemical measurements. As well, the crystal structure of H₂L¹ was confirmed by a single crystal X-ray structural analysis. Competitive ⁷Li NMR experiments were used to probe the complexation of Mn²⁺, Zn²⁺ and Cd²⁺ ions with (H₂L¹) and (H₂L²) in both acetonitrile and methanol. The stabilities of the final complexes were found to be in the order M–(H₂L¹) > M–(H₂L²) and Cd²⁺ > Zn²⁺ > Mn²⁺. The cytotoxic and antibacterial properties of these complexes were also investigated.

Full text of DOI:10.1016/j.poly.2018.12.052

Accepted Manuscript
Synthesis, characterization and X-ray crystal structure of potentially N O co-
6
2
ordinating macroacyclic Schiff base ligands and their Mn(II), Zn(II) and Cd(II)
7
complexes; cytotoxic, antibacterial properties and competitive Li NMR studies
Fatemeh Forouzandeh, Hassan Keypour, Mohammad Hasan Zebarjadian,
Masoumeh Mahmoudabadi, Leila Hosseinzadeh, Roya Karamian, Masoumeh
Ahmadi Khoei, Robert William Gable
PII:
S0277-5387(19)30004-X
https://doi.org/10.1016/j.poly.2018.12.052
POLY 13670
DOI:
Reference:
To appear in:
Polyhedron
Received Date:
Revised Date:
Accepted Date:
28 October 2018
26 December 2018
29 December 2018
Please cite this article as: F. Forouzandeh, H. Keypour, M.H. Zebarjadian, M. Mahmoudabadi, L. Hosseinzadeh, R.
Karamian, M.A. Khoei, R.W. Gable, Synthesis, characterization and X-ray crystal structure of potentially N O
6
2
coordinating macroacyclic Schiff base ligands and their Mn(II), Zn(II) and Cd(II) complexes; cytotoxic, antibacterial
7
properties and competitive Li NMR studies, Polyhedron (2019), doi: https://doi.org/10.1016/j.poly.2018.12.052
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Synthesis, characterization and X-ray crystal structure of potentially N
6
O
2
coordinating macroacyclic Schiff base ligands and their Mn(II), Zn(II) and
7
Cd(II) complexes; cytotoxic, antibacterial properties and competitive Li
NMR studies
a
a,
b
Fatemeh Forouzandeh , Hassan Keypour *, Mohammad Hasan Zebarjadian , Masoumeh
a
c
d
d
Mahmoudabadi , Leila Hosseinzadeh , Roya Karamian , Masoumeh Ahmadi Khoei , Robert
William Gablee
a
Faculty of Chemistry, Bu-Ali Sina University, Hamedan 65174, Iran
b
Farhangian University, Hamedan 6513666157, Iran
c
Pharmaceutical Sciences Research Center, karmanshah University of Medical Sciences,
Kermanshah, Iran
d
Department of Biology, Bu-Ali Sina University, Hamedan 65175/4661, Iran
e
School of Chemistry, University of Melbourne, Victoria 3010, Australia
*
Corresponding authors. Tel.+98 (81) 38242044; fax:+98 (81) 38272404.
E-mail addresses: haskey1@yahoo.com (H. Keypour).
1

Abstract
In this work, two new symmetrical, potentially N
6
2
O coordinating, macroacyclic Schiff base
ligands (H
2
L1 and H
2
L2) were derived from the condensation of a newly synthesized polyamine,
2
,2'-(ethane-1,2-diylbis(piperazine-4,1-diyl))bis(ethan-1-amine)(A),with 2-Hydroxybenzaldehyde
and 2-hydroxy-3-methoxybenzaldhyde respectively. Six macroacylic Schiff base complexes were
L1 or H L2 with Mn(II), Zn(II) or Cd(II) metal ions in equimolar
prepared by direct reaction of H
2
2
ratios. The products were characterized by several physicochemical measurements. As well, the
crystal structure of H
L1 was confirmed by a single crystal X-ray structural analysis. Competitive
2
7
2+
2+
2+
Li NMR experiments were used to probe the complexation of Mn , Zn and Cd ions with
L1) and (H L2) in both acetonitrile and methanol. The stabilities of the final complexes were
(H
2
2
L1) > M-(H
L ) and Cd > Zn > Mn . The cytotoxic and
2
2+
2+
2+
found to be in the order M-(H
2
2
antibacterial properties of these complexes were also investigated.
Keywords: Macroacyclic Schiff base, Piperazine, Stoichiometry and stability of complexes,
Cytotoxic, Antibacterial
2

1
. Introduction
Schiff base complexes have remained the most important stereo chemical models in main group
and transition metal coordination chemistry because of their structural variety and simplicity in
their synthesis [1, 2]. They have an important role in many areas of coordination chemistry,
from classic synthetic chemistry to modern biochemical and physicochemical studies of metal
complexes [3-8]. Piperazine is one of the most extensively used and studied heterocyclic
compounds. The piperazine moiety is a structural part of many analgesics, psychotropic and
antitumor drugs [9-11]. It is a useful component in the design of both macroacyclic and
macrocyclic compounds due to a number of structural properties, such as having a bifunctional
scaffold for the linkers, acting as a good hydrogen-bond acceptor, having the ability to complex
with a variety of metal ions and the capability of undergoing nucleophilic substitution reactions
with different types of halide compounds [12]. As well, piperazine compounds have good
potential for the development of new bioactive agents [13]. Accordingly, we have focused on the
design and synthesis of new Schiff base ligands containing the piperazine moiety for several
years. During last decade, we have reported a number of macrocyclic and macroacyclic Schiff
base complexes containing one piperazine moiety with Zn(II), Mn(II) and Cd(II) metal ions [14-
2
0]. In this work, we report the synthesis of Schiff base ligands bearing two piperazine moieties
and their Zn(II), Mn(II) and Cd(II) complexes. These complexes were characterized by several
L1, an X-ray structural analysis. Their cytotoxic
physicochemical techniques and, in case of H
2
and antibacterial properties have also been investigated.
3

2
2
1
. Experimental
.1. Materials
,2-dibromoethane, 1-(2-aminoethyl)piperazine, phthalic anhydride, 2-Hydroxybenzaldehyde, 2-
Hydroxy-3-methoxybenzaldehyde and the manganese, zinc and cadmium perchlorates were
commercial products (from Merck, Aldrich and Fluka), and were used without further
purification. Solvents were of reagent grade and were purified by the usual methods.
Caution! Perchlorate salts are potentially explosive. Only a small amount of material should be
prepared and handled with great care.
2
.2. Instrumentation
CHN analyses were carried out using a Perkin–Elmer, CHNS/O elemental analyzer model 2400
series 2. Infrared spectra were measured using KBr pellets on a BIO-RADFTS-40A
-1
1
13
spectrophotometer (4000–400 cm ). H and C NMR spectra were measured in DMSO-d
6
and
CDCl -d on a Bruker Avance 400 MHz spectrometer using Si(CH as an internal standard.
3
)
3 4
Mass spectra were recorded on an Agilent technologies (HP) 5973 mass spectrometer operating
at an ionization potential of 70 eV.
4

2
.3. X-ray crystallography
Light yellow single crystals of H
2
L1 [C28
H
40
N
6
2
O ] were crystallized by slow evaporation from
methanol. Data collection was carried out on a Rigaku Oxford Diffraction SuperNova
diffractometer using mirror monochromated Cu Kα radiation (λ = 1.54184 Å) at 130 K. Using
Olex2 [21], the structure was solved with the ShelXT [22] structure solution program using
Intrinsic Phasing and refined with the ShelXL [23] refinement package using Least Squares
2
minimization on F , using all data. Gaussian absorption corrections were applied to the data. All
non‐hydrogen atoms were refined with anisotropic displacement parameters, while all hydrogen
atoms were refined with isotropic displacement parameters. Crystallographic data for the ligand
H
2
L1 is listed in Table 1.
<Please insert Table 1>
7
2
.4. Li NMR spectroscopy study
All NMR measurements were made using a Jeol 90Q FX-FT NMR spectrometer with a field
strength of 2.113 Tesla. The temperature of the probe was fixed to ± 0.1°C using the temperature
controller in the spectrometer. The lithium-7 NMR spectra of the solutions were recorded at
2
5.0(1) ºC. Under these conditions, lithium-7 resonates at 33.742 MHz. A 4.0 molar aqueous
LiCl solution was used as external reference and the recorded lithium-7 chemical shifts refer to
this solution; the upfield shift from the reference defined as negative. Stock solutions of the
Schiff bases were prepared with concentrations of 0.1 M, in both methanol and acetonitrile,
while solutions of the metal perchlorates, in both methanol and acetonitrile, were prepared at
concentrations of 0.01 M. The solutions of the metal salts, in both solvents, were titrated against
5

the solutions of both Schiff bases, up to a ligand:metal mole ratio of 4. Using a micro syringe, an
aliquot of the Schiff base ligand was added to the solution of the metal and the resulting solution
put in an ultrasonic stirrer for 10 minutes after which the solution was thermostated at 25 °C for
1
2
2
0 min to achieve temperature equilibrium.
.5. Synthesis
.5.1. Synthesis of 2,2'-(ethane-1,2-diylbis(piperazine-4,1-diyl))bis(ethan-1-amine) (A)
ᵒ
Phthalic anhydride (1.48 g, 10 mmol) was melted in a beaker at 180 C followed by the addition
1
-(2-Aminoethyl)piperazine (1.29 g, 10 mmol) to the beaker and mixture stirred for 15 min, after
which the mixture was then allowed to cool. The resulting solid was washed with hot ethanol and
then dissolved in hot acetonitrile followed by the drop wise addition of 1,2-dibromoethane (0.94
g, 5 mmol) after which the solution refluxed for 48 hours. The solid product was then filtered off,
extracted with chloroform and then refluxed with 25% aqueous HCl (300 ml) for 12 h. After
cooling, the phthalic acid produced was filtered off and the solution evaporated to a small
volume after which and the hexamine salt was precipitated by the addition of absolute ethanol
and the solid washed with a small amount of diethyl ether. To a suspension of the amine salt (1
mmol) in ethanol (10 ml) was added a solution of NaOH (6 mmol) in ethanol (10 ml). The
resulted mixture was stirred for 30 minutes at room temperature. The precipitate was filtered off
and the filtrate evaporated to dryness. The resulting white powder was characterized as the pure
-1
compound (scheme 1). Yield: 0.85 g (60%). EI-MS (m/z): 284. IR (KBr, cm ): 3293–3443, 1628
1
ѵ(NH
2
). H NMR (D
2
O, ppm) δ
H
=2.33-2.35 (t, 2H
e
), 2.37-2.43 (m, 8Hc,d), 2.73-2.77 (t, 2H ),
b
6

1
3
3
.02-3.05 (t, 2H
a
) . C NMR (D
2
O, ppm) δ
C
=36.69 (C
a
), 38.03.4 (C
e
), 52.01-53.89 (C , ), 57.52
c
d
(C
b
).
<Please insert scheme 1>
L1 and H
L )
2
2
.5.2. Synthesis of the ligands (H
2
2
A solution of the prepared amine (0.5 mmol) in absolute ethanol (10 ml) was added drop wise to
a solution of either 2-Hydroxybenzaldehyde or 2-hydroxy-3-methoxybenzaldehyde (1 mmol) in
absolute ethanol (20 ml). After refluxing the solution for 12 h the resultant yellow powder was
filtered off, washed with diethyl ether and dried under vacuum (scheme 2).
1
-1
1
H
2
L : Yield: 0.19 g (75%). EI-MS (m/z): 492. IR (KBr, cm ): 3428 ѵ(OH), 1637 ѵ(C=N). H
NMR (CDCl , ppm) δ = 2.54–2.57 (broad, 20Hj-l), 2.69–2.73 (m, 4H ), 3.72-3.76 (m, 4H ), 6.86-
.33 (m, 8Ha-f), 8.36 (s, 2H , ppm) δ = 53.66(Cj,k), 55.91
), 57.07 (C ), 58.69 (C ), 131.21 (C ), 132.22 (C ),
), 165.59 (C ).
3
H
i
h
1
3
7
g
), 13.45 (s, 2H(OH)). C NMR (CDCl
3
c
(C
h
l
i
), 117.04 (C ), 118.51 (C ), 118.79 (C
b
d
f
c
e
1
61.19 (C
a
g
2
-1
1
H
2
L : Yield: 0.19 g (75%). EI-MS (m/z): 552. IR (KBr, cm ): 3446 ѵ(OH), 1635 ѵ(C=N). H
NMR (CDCl
3
, ppm) δ
H
= 2.54–2.65 (broad, 20Hj-l), 2.69–2.72 (t, 4H
i
), 3.72-3.76 (t, 4H ), 3.91 (s,
h
1
3
6
5
1
H
methoxy), 6.78-6.93 (m, 6Ha-f), 8.33 (s, 2H
3.29-53.62 (Cj-k), 55.82 (C ), 56.03 (COCH3), 56.55 (C
18.41 (C ), 122.81 (C ), 148.55 (C ), 152.3 (C ), 165.56 (C
g
), 13.89 (s, 2H(OH)). C NMR (CDCl
), 58.57 (C ), 113.71 (C ), 117.69 (C
).
3
, ppm) δ
c
=
h
l
i
c
d
),
f
e
b
a
g
<Please insert scheme 2>
7

2
.5.3. Synthesis of the metal complexes– general procedure
To an ethanol solution of (H
2
L1 or H L2) (0.5 mmol) was added either manganese perchlorate,
2
zinc perchlorate or cadmium perchlorate (0.5 mmol) dissolved in absolute methanol and the
solution was refluxed for 12 h. The resulting powder was filtered off and dried under vacuum.
2
.5.3.1. [Mn(H
Brown powder. Yield: 0.21 g (77%). Anal. Calc. for C28
H, 5.40; N, 11.26. Found: C, 44.49; H, 5.20; N, 11.06%. EI-MS (m/z): 648. IR (KBr, cm ): 3434
2
L1)(ClO
4
)](ClO
4
)
H40Cl
2
MnN O10 (MW: 746.5): C, 45.05;
6
-1
ѵ(OH), 1615 ѵ(C=N), 1197, 623 ѵ (ClO -
L1)(ClO
), 428 ѵ(M-N). Λ
(CH CN)=176 Ω cm mol .
-1
2
-1
4
m
3
2
.5.3.2. [Zn(H
2
4
)](ClO )
4
Yellow powder. Yield: 0.21 g (74%). Anal. Calc. for C28
H40Cl
2
ZnN
6
O10 (MW: 756.03): C,
4
4.43; H, 5.33; N, 11.10. Found: C, 43.72; H, 5.53; N, 10.73%. EI-MS (m/z): 557. IR (KBr, cm-
1)
: 3443 ѵ(OH), 1623 ѵ(C=N), 1191, 624 ѵ (ClO -
-1
2
-
4
), 468 ѵ(M-N). Λ
m
(CH
3
CN)=169 Ω cm mol
), 3.72-3.83 (t, 4H ),
), 13.88 (s, 2H(OH)). C NMR (DMSO-d , ppm)
=29.3-31.5 (Ch,q), 51.7-52.1 (Cl,m), 52.5-54.4 (Cn,o), 54.7-55.7 (Cj,k), 57.9 (C ), 59.4 (C ), 110-
63.7 (Ca-f, s-x), 166.3 (C ), 168.8 (C ).
)](ClO
1. 1
H NMR (DMSO-d , ppm) δ =2.37-2.57 (m, 20Hj-o), 2.65-2.73(m, 4H
6
H
h
i
1
3
6
.42-7 (m, Hb-e, t-w), 8.45 (s, H
g
), 8.58 (s, H
r
6
δ
1
2
c
i
p
g
r
.5.3.3 [Cd(H
2
L1)(ClO
4
4
)
Yellow powder. Yield: 0.23 g (66%). Anal. Calc. for C28
H40Cl
2
CdN
6
O10 (MW: 804): C, 41.83;
-1
H, 5.02; N, 10.45. Found: C, 41.07; H, 5.36; N, 9.93%. EI-MS (m/z): 603. IR (KBr, cm ): 3431
ѵ(OH), 1633 ѵ(C=N), 1108, 625 ѵ (ClO -
NMR (DMSO-d , ppm) δ =2.32-2.51 (m, 20Hj-o), 2.51-2.58(t, 4H
), 8.51 (s, H
), 402 ѵ(M-N). Λ
(CH
), 3.65-3.75 (t, 4H
), 13.81 (s, 2H(OH)). C NMR (DMSO-d , ppm) δ
CN)=168 Ω cm mol . H
), 6.42-6.99
=29.3-
-1
2
-1 1
4
m
3
6
H
h
i
1
3
(
m, Hb-e, t-w), 8.38 (s, H
g
r
6
c
8

3
1.5 (Ch,q), 50-51.7 (Cl,m), 52-54.2 (Cn,o), 54.5-55.8 (Cj,k), 57 (C
i
), 57.7 (C ), 112.20-153.43 (Ca-f,
p
s-x), 166.32 (C
g
), 171.56 (C
r
).
2
.5.3.4. [Mn(H
2
L2)(ClO
4
)](ClO )
4
Brown powder. Yield: 0.22 g (73%). Anal. Calc. for C30
H44Cl
2
MnN
6
O12 (MW: 806): C, 44.68;
-1
H, 5.50; N, 10.42. Found: C, 44.51; H, 5.22; N, 10.21%. EI-MS (m/z): 704. IR (KBr, cm ): 3456
ѵ(OH), 1614 ѵ(C=N), 1083, 624 ѵ (ClO -
L2)(ClO
), 462 ѵ(M-N). Λ
(CH CN)=172 Ω cm mol .
-1
2
-1
4
m
3
2
.5.3.5. [Zn(H
2
4
)](ClO )
4
Yellow powder. Yield: 0.18 g (60%). Anal. Calc. for C30
H44Cl
2
ZnN
6
O12 (MW: 816.99): C,
-1
4
4.10; H, 5.43; N, 10.29. Found: C, 44.51; H, 5.23; N, 9.87%. EI-MS (m/z): 620. IR (KBr, cm ):
-1
2
-1
3
447 ѵ(OH), 1630 ѵ(C=N), 1108, 625 ѵ (ClO -
, ppm) δ =2.15-2.73 (m, 20Hj-o), 2.73-2.84 (m, 4Hi,p), 3.63-3.73(m, 2H
.74-3.82 (s, 6H(OCH3)), 3.84-3.9 (m, 2H
4
), 431 ѵ(M-N). Λ
m
(CH CN)=193 Ω cm mol .
3
1H NMR (DMSO-d
),
6
H
q
3
1
5
h
), 6.45-7.13 (m, 6Hc-e, t-v), 8.47 (s, H
g
), 8.61 (s, H
r
),
1
3
3.91 (s, 2H(OH)). C NMR (DMSO-d
4.9-55.7 (Cn,o), 56.6 (C ), 57.8 (C
).
.5.3.6. [Cd(H
6
, ppm) δ
c
=53.1-53-3 (Cl,m), 56.1-56.3(Cj,k), 56.6(C(OCH3)),
), 114.9-153.6 (Ca-f, s-x), 166.8 (C
i
h
), 58.5 (C
p
), 59.9 (C
q
g
), 168.7
(C
r
2
2
L2)(ClO
4
)](ClO )
4
Yellow powder. Yield: 0.23 g (69%). Anal. Calc. for C30
H44Cl
2
CdN
6
O12 (MW: 864): C, 41.7; H,
-1
5
.13; N, 9.73. Found: C, 41.03; H, 5.21; N, 9.24%. EI-MS (m/z): 764. IR (KBr, cm ): 3462
ѵ(OH), 1630 ѵ(C=N), 1189, 625 ѵ (ClO -
NMR (DMSO-d , ppm) δ =2.03-2.65 (m, 20Hj-o), 2.65-2.83 (m, 4Hi,p), 3.59-3.64(m, 2H
.75 (s, 6H(OCH3)), 3.76-3.8 (m, 2H ) 6.26-6.99 (m, 6Hc-e, t-v), 8.27 (s, H ), 8.50 (s, H ), 13.82 (s,
=51.52 (Cl,m), 51.8-53.2(Cj,k), 54.4 (C(OCH3)), 55.6-54.8
), 440 ѵ(M-N). Λ
(CH
CN)=182 Ω cm mol . H
-1
2
-1 1
4
m
3
6
H
q
), 3.65-
3
2
h
g
r
1
3
H
(OH)). C NMR (DMSO-d
6
, ppm) δ
c
(C
n,o), 55.7 (C ), 57.9 (C ), 69.2 (C
i
h
p
), 60.0 (C
q
), 110-153.6 (Ca-f, s-x), 163.6 (C
g
), 166.3 (C ).
r
9

2
.6. Cytotoxic assays
MTT assays were carried out to examine the cytotoxicity of the prepared complexes toward
normal cells, and to investigate whether these complexes are able to exert antiproliferative
effects against two cancer cell lines (A2780 and PC3) and a normal cell line (Fibroblast); these
cell lines were supplied from Pasteur Institute of Iran. Cells were seeded and grown in DMEM
3
medium (15-20×10 cells in each well) containing fetal bovine serum (10% v/v) and 1%
penicillin/streptomycin (100 U/mL:100 U/mL). Culture plates were placed in a humidified
º
incubator containing 5% CO
2
at 37 C. These cells were then exposed to different concentrations
of the complexes in DMSO (12.5-100 µg/ml) and the samples incubated for 24 h. At appropriate
time intervals, the medium was replenished with 0.5 mg/mL and then cells were incubated for
°
further 3 h at 37 C. Thereafter, to enable the solubilizing of the formazan crystals, 100 µl DMSO
was added to the culture medium. The controls and treated cells were subjected to an Eliza micro
plate reader (Bio Tek Instruments, USA) to measure their absorbance at 570 nm. Cell viability
percentage of each sample was calculated by dividing the absorbance at 570 nm, corresponding
to each treatment group, to that of control group. The IC50 value (the concentration in which 50%
of cells were killed) was calculated by preparing a logarithmic plot the viability percentage of
cells versus the concentration of samples. All the MTT assays were carried out in triplicate.
2
.7. Antibacterial assays
1
0

The antimicrobial activity of all synthesized compounds was assessed against four Gram positive
and negative bacteria, namely Staphylococcus aureus (Wild), Bacillus cereus (PTCC 1247),
Pseadomonasaeroginesa (PTCC 15442) and Escherichia coli (Wild) by the disc diffusion
method [24]. All compounds were dissolved in DMSO to final concentrations of 50 and 100
8
mg/L. All tests were carried out using 10 mL of suspension cultures containing 1.5×10 bacteria
-1
mL , spread on nutrient agar medium. Negative controls were applied by using DMSO solution.
Nitrofurantion and Neomycin and were used as positive standard references. A statistical
analysis of the variance was performed using the Student’s t-test, using the SPSS program, where
a P value ≤ 0.05 was regarded as significant.
3
. Result and discussion
A new polyamine (A) containing two piperazine moieties was synthesized and, using this amine,
L1 and
L2) were prepared from the reaction with 2-Hydroxybenzaldehyde and 2-hydroxy-3-
two new symmetrical, potentially N
6
O
2
coordinating macroacyclic Schiff base ligands (H
2
H
2
methoxybenzaldehyde, respectively. Six new macroacyclic Schiff base complexes were prepared
L1 and H L2) with Mn(II), Zn(II) and
from direct reaction of the two new Schiff base ligands (H
2
2
Cd(II) metal ions. Elemental analysis confirm the synthesis of all compounds. The mass spectra
L1)ClO
]+, [Zn(H
L )] ,
1
2+
show peaks at 648, 557, 603, 704, 620 and 764 for complexes [Mn(H
2
4
2
1
2+
L2)ClO
]+, [Zn(H
2
2+
L2)ClO
]+ respectively.
[
Cd(H
2
L )] , [Mn(H
2
4
2
L )] and [Cd(H
2
4
3
.1. IR spectra
1
1

-1
IR spectrum of polyamine (A) exhibits a (NH ) vibration in 3293-3443 cm . IR spectra of both
2
-1
-1
ligands exhibit a ѵ(C=N) vibration in 1637 cm and 1635 cm and do not show any bands
expected for the free carbonyls or primary amines, indicating that complete condensation has
occurred. In the IR spectra of the metal complexes, the ѵ(C=N) band is shifted to lower
-1
frequency (1614–1633 cm ), compared to that found the free ligands, confirming the
coordination of the metal to the ligand. Absorption bands at approximately 1100 and 620 cm-1
arising from the perchlorate anions were found to be split, indicating that the perchlorate anions
-1
were coordinated to metal ions. A broad band at approximately 3400 cm is due to the OH group
of the ligand, indicating that that deprotonation does not occur in the metal complexes.
-1
Furthermore, new weak bands in the range of 402-468 cm are attributed to the M-N bonds.
3
.2. NMR spectra
1
3
The C NMR spectrum of polyamine (A) shows four main peaks (36.6-57.5 ppm), while in the
1H NMR spectrum a broad signal for the amine protons appears at 2.4 ppm due to proton
1
L1 and H L2 the signal for the imine
exchange in D
2
O solvent. In the H NMR spectra of H
2
2
proton appears at 8.3 ppm, while the signal for the hydroxyl protons appear at 13.4 and 13.8 ppm
respectively. There were no signals due to amine protons, confirming the complete synthesis of
1
3
L1 and H L2, the number of peaks and their
the Schiff base ligands. In C NMR spectrum of H
2
2
chemical shifts are also consistent with the ligand structures. Using the DEPT 135 technique the
L1 shows 10 peaks including 5 positive and 5 negative peaks which are related to
spectrum of H
2
CH groups and CH
2
groups respectively, while 2 peaks (161.1 and 118.7 ppm) related to C
a
and
C
f
are no longer present. The spectrum of H
2
L2 shows 10 peaks including 5 positive and 5
negative peaks which are related to CH, CH
3
(56 ppm) groups and CH groups respectively,
2
1
2

1
while 3 peaks (152.3, 148.5and 118.4 ppm) related to C
a
, C
b
and C are no longer present. The H
f
NMR spectra of the complexes showed two peaks indicating two non-equivalence imine groups
1
2+
in the zinc and cadmium complexes: 8.4 and 8.5 ppm [Zn(H L )] , 8.4 and 8.6 ppm
2
2
2+
1
2+
2
2+
[
Zn(H
the corresponding signal in the free ligand. The signal of the hydroxyl protons appears at 13.8-
4.00 ppm, indicating that two phenolic OH groups are not deprotonated. Slight frequency shifts
2
L )] , 8.3 and 8.5 ppm [Cd(H
2
L )] and 8.2 and 8.5 ppm [Cd(H
2
L )] , shifted respect to
1
1
3
are also observed for the aromatic protons when compared with the free ligands. The C NMR
spectra of the complexes show two peaks corresponding to the imine carbon atoms showing that
two imine carbon atoms are not identical. These peaks were appeared at 168.8 and 166.3 ppm in
1
2+
2
2+
1
2+
[
Zn(H
2
L )] , 168.7 and 166.8 ppm in [Zn(H
2
L )] , 171.5 and 166.3 ppm in [Cd(H
2
L )] , 166.3
2
2+
and 163.6 ppm in [Cd(H
2
L )] The symmetry of metal complexes is reduced, so the number of
1
3
peaks appearing in the C NMR spectra of the metal complexes were more than was found for
the free ligands. There should be 28 and 29 main peaks in the 13C NMR spectra of the
1
2+
1
2+
2
2+
2
2+
(
[Zn(H
2
L )] , [Cd(H
2
L )] ) complexes and ([Zn(H
2
L )] , [Cd(H L )] ) complexes,
2
respectively, however overlapping of peaks would be expected due to the similarity of several of
the carbon atoms, and the low resolution of instrument.
3
.3. Molar conductivity
The molar conductance values can be predicted by the electrolytic nature of the mononuclear
metal complexes. Herein, the molar conductivity values for all mononuclear complexes in MeCN
2
-1
-
are in or slightly above the literature range for a 1:1 electrolyte in MeCN (120-160 cm Ω mol
1,
but values as high as 199 cm Ω mol have been used to characterize 1:1 electrolytes in
2
-1
-1
1
3

MeCN) [25]. All of these values are consistent with existence the perchlorate group as counter
anion in the complexes.
3
.4. X-ray structure
Light yellow single crystals of H
2
L1 were crystallized by slow evaporation from methanol.
Crystallographic data and structure refinement parameters are given in Table 1 and selected bond
lengths and angles are given in Table 2.
The molecule is situated around a center of symmetry and adopts an extended, almost linear
arrangement (Figure 1). The phenol hydrogen is involved in an intramolecular hydrogen bond
with the imine nitrogen. The atoms of the imine group are coplanar with the phenol group, the
maximum deviation from the plane being 0.0475(9) Å. The piperazine ring is in a chair
conformation, the dihedral angle between the four carbon atoms of the ring and the phenol ring
being 14.77(7)°. There are no significant intermolecular contacts.
<Please insert Fig. 1>
<Please insert Table 2>
3
.5. Stoichiometry and stability constant
7
The Li chemical shifts were monitored as a function of the mole ratio of metal to the
macroacyclic Schiff base ligands H
2
L1 and H
2
L2 in both acetonitrile and methanol. In all cases,
7
+
the presence of only a single Li resonance reveals that the exchange rate of Li ion between the
1
4

7
bulk solution and the complexed sites is fast on the NMR time scale (Fig. 2). All the resulting Li
1
n+
chemical shifts as a function of the [H
2
L ]/[M ] mole ratio are illustrated in Figure 3. As can
+
L1 in Fig. 2A), addition of H L1 or
be seen, in the absence of other metal ions (Li curves with H
2
2
H
L2 Schiff base ligand to the lithium ion solution causes an almost linear paramagnetic shift in
2
7
the observed Li chemical shift, δobs, which is due to the population-averaged combination of the
+
+
chemical shifts of Li ion in the bulk solvent, δLi, with that of the Li ion complexed with ligand,
LiH2L, values that are quite different due to differences in the electron densities surrounding the
probe nucleus in the two sites, δobs = PLi
titration of metal ion with the ligand). The variations of Li chemical shift with the H
δ
δLi+ PLiH2L δLiH2L (where, PLi + PLiH2L = 1 in the course of
7
+
2
L/Li mole
ratio were used to calculate the formation constants of Li+ complexes with Schiff base ligands.
Assuming that the fast-exchange kinetics prevail, it has been shown that in solutions containing
+
fixed concentration of Li by varying amount of ligand, CH2L, the observed chemical shift of the
metal ion is given by [26]:

2
2
2
2
2
Li
obs  [(K C  K C 1)  (K C  K C  2K CH2LCLi

Li Li
Li H2L
Li H2L
Li Li

1
/ 2

2K C  2K C 1) ]( LiH2L )/ 2K C


Eq. 1
Li H2L
Li Li
H L
Li Li
LiH L
2
2
+
Where δLi and δLi-H2L are the respective chemical shifts of the free and complexed Li ion. The
nonlinear least-squares curve fitting program KINFIT [27] was used to evaluate KLi and δLi-H2L
2
+
2+
values. In this paper, we were interested in investigating the complexation of Cd , Zn and
Mn2+ ions with H L1 and H L2 in methanol and acetonitrile solutions. These cations have
2
2
unsuitable NMR properties, such as high quadrupole moment, low receptivity, insensitive
1
5

7
chemical shifts, etc. [28]. Therefore, in this paper, we employed Li NMR as a more sensitive
2
+
2+
2+
probe [29-32] to study the formation of the resulting complexes of Mn , Zn and Cd ions with
L1 and H
L in solutions. Solutions containing Li and each of the M ions with the
2
+
2+
H
2
2
concentration of both metals being 0.01 M, were titrated with each of the Schiff base ligands
L1 and H
L ), while monitoring the chemical shift changes of the Li nucleus in solution [33-
2
7
(H
2
2
7
2+
3
6]. The plots of the Li chemical shift in the presence of equimolar concentrations of M ions
+
n+
and Li (0.01 M) as a function of H L/M mole ratio in acetonitrile and methanol solutions are
2
shown in figure 3. As it is obvious from Figures 2 and 3, the change in chemical shift with the
n+
H L/M mole ratio is quite linear at mole ratio less than 1, the mole ratio plots in the presence of
2
2
+
+
n+
other used M ions show a small change in chemical shift of the Li ion at H L/ M mole ratios
2
between 0 and 1, followed by a sharp linear increase in δobs, which begins to level off at mole
ratios bigger than 2. The resulting mole ratio plots show that, due to the higher stability of the
2
+
+
2+
M -H
2
L complexes over the Li -H
2
L complex, most of the ligand complexes with the M ion at
n+
+
H
2
L/ M mole ratios less than 1 so that most of the Li ions remain free in solution and, thus, the
7Li chemical shift changes only slightly. However, at mole ratios larger than 1, where the amount
2
+
+
of free M ions in solution very small, the Li ions are able begin to form 1:1 complexes with
the added ligand and, thus, the δobs-mole ratio behavior at mole ratios larger than 1 shows a trend
+
similar to that observed in the case of titration of Li ion alone with the ligand (see Figs. 2B and
3
), indicating the quantitative formation of 1:1 complexes of the ligands with all three studied
2
+
M ions.
1
6

<
Please insert Fig. 2>
Please insert Fig. 3>
<
The competitive complexation equilibria for the case of 1:1 complexation between Schiff base
+
2+
ligands and Li and the M ions can be written as:




Li  H L  Li H L
K  [Li H L]/[Li ][H L]
Eq. 2
Eq. 3
2
2
Li
2
2
2

2
2
2
M
 H L  M H L
K  [M H L]/[M ][H L]
2
2
M
2
2
The free Schiff base ligand concentration is then obtained from Eq. 4 [37].
3
2
K K [H L] {K K (C C C )  K  K }[H L]
Li
M
2
Li
M
H2L
Li
M
Li
M
2

{K (C C ) K (C C ) 1}[H L 1][H L]C  0
Eq. 4
Li
H2L
Li
M
H2L
M
2
2
H2L
+
2+
Where CH2L, CLi, and C
M
are the analytical concentrations of the ligand, Li and M ion,
7
respectively and KLi calculated by Eq. 1. In this case, the observed [ Li] NMR chemical shift is
obtained from Eq. 5 [30].
obs  P   P

Eq. 5
Li Li
LiH2L LiH2L
1
7

Where PLi and PLiH2L are the mole fractions of the free and complexed lithium ion, respectively.
+
+
By substitution from Eq. 2 and the mass balance equation CLi=[Li ] + [Li H
2
L], Eq. 5 can be
written as:
obs {


LiL[H L]K }/{1 K [H L]}
Eq. 6
Li
2
Li
Li
2
The K
and fitting the chemical shift-mole ratio data to Eq. 6 by using the KINFIT program [38]. A
computer fit of the data is displayed in Figure 4 and the resulting log K values are collected in
M
values were evaluated by obtaining the free Schiff base ligand concentration from Eq. 4
f
2
+
Table 3. Our assumption that the 1:1 stoichiometry for both M -H L complexes seems
2
reasonable in the light of a reasonable agreement between the observed and calculated chemical
shifts.
<Please insert Fig. 4>
<Please insert Table 3>
The observed stability constants of the in situ generated complexes are significantly affected by
two main factors, the nature of counter anions and the concentrations of the salts used. Ion pair
formation, between the metal ions and their counter anions, may also have an effect. Thus, in
this work, we used the same salt concentration of 0.01 M with the same counter anions, to ensure
the constant effect of concentration and counter anion on stability constants of all the complexes.
The results in Table 3 confirmed that, in both solvents and all three studied metal ions, the
1
8

resulting complexes of two ligands vary in the order of MH
2
L1> MH L2. This is due to the fact
2
that two Schiff base ligands (H
2
L1 and H L2) differ in the substituted groups (Scheme 2).
2
The information in Table 3 clearly indicate that, the stability of the resulted complexes changes
2
+
2+
2+
in the order of Mn <Zn <Cd in both solvents. The stability of the complexes are controlled
by several factors comprising:(i) the scope of interaction between donor atoms (nitrogen and
oxygen) of Schiff base ligands with the cations, (ii) the adaption between the size of metal ions
and the steric size of the formed Schiff base ligands distortion, (iii) soft-hard acid-base concept
of the metal ion and the donor atoms of the nitrogen and oxygen, (iv) desolvation of cation and
the donors and solvation of the macroacycle. The factors (iii) and (iv) depend significantly on the
nature of the solvents employed. On the NMR time scale, the stability of the Mn2+ and Zn2+
2
+
2+
complexes with both Schiff base ligands was changed in the order of Zn >Mn , most probably
because of its ionic solvation in the solvents used [39]. The results display the highest stability
2
+
2+
for Cd complexes with both Schiff base ligands between all three employed M ions. This is
2
+
most likely due to the larger size of the Cd ion at soft nature, which could coordinate better
with the donor atoms of the relatively large and flexible Schiff base ligands [40-42]. Based on
given data in Table 3, the stability of the formed complexes depended on the solvent
combination. In all cases, the resulting complexes are more stable in acetonitrile than in
methanol. It should be noted that, while acetonitrile and methanol have about the same dielectric
constants (i.e., D=33.0 for methanol and D=36.1 for acetonitrile), their solvating abilities, as
expressed by the Gutmann donor number [43], are different (i.e., DN =79.0 kj/mol for methanol
and DN = 59.0 kj/mol for acetonitrile). Thus, methanol, which has a higher solvating ability
compared to acetonitrile, can compete more strongly with the Schiff base ligands for the metal
1
9

ions than can acetonitrile. Consequently, formation of the weaker complexes is more likely to
occur in methanol than in acetonitrile.
3
.6. Cytotoxicity activities
In order to examine whether the prepared complexes can inhibit the proliferation of ovarian and
prostate cancer cells, the viability of these cells before and after exposure of complexes were
compared. As well, the toxicity of these newly synthesized complexes toward normal fibroblast
cells were also examined to ensure the non-toxic nature of these products (Figure 5(a)). As can
be seen the figure obviously indicated that all the six complexes were non-toxic for normal cells
(viability percentage >60% even at the highest concentration) and none of the curves reached
IC50 value, whereas these samples all significantly decreased the viability of A2780 ovarian
cancer cells in a dose-dependent manner, they all were potent in killing more than 50% of cells.
The IC50 value of four samples ([Zn(H
2
L2)(ClO
4
)](ClO
4
), [Cd(H
2
L2)(ClO
4
)](ClO ),
4
[
Mn(H
2
L1)(ClO L1)(ClO
4
)](ClO
4
), and [Cd(H
2
4
)](ClO ) were the same (about 12.5 μg/ml),
4
however the [Mn(H
2
L1)(ClO
4
)](ClO ) complex possessed a less toxic effect toward A2780 (IC50
4
value of 25 μg/ml). The least toxic effect on ovarian cancer cells could be attributed to the
L1)(ClO
)](ClO ), which killed 50% of cells at concentration about 100 μg/ml.
complex [Zn(H
2
4
4
The antiproliferative effect of these compounds would be necessarily compared with the metal-
based cytotoxic compounds that are commonly used for the treatment of cancer, such as
cisplatin. There are several studies reporting the toxicity of cisplatin toward different cancer
cells. Cisplatin, as a standard anticancer drug, possessed significant effect against A2780 and
PC3 cells. The IC50 concentration has been found to be almost 0.73-2.8 μM (0.219-0.842 μg/ml)
2
0

in previous studies [44, 45]. The comparison between the present compounds and cisplatin
reveals that although these compounds have less potent anticancer activity, in comparison to
cisplatin, their toxic concentrations are in an acceptable range. These results confirmed that the
synthesized complexes in the present study could be promising candidates for preparing novel
chemotherapeutics against ovarian carcinoma, especially as the results also show that these
compounds exert no toxicity toward normal fibroblast cells. The other similar study on
macrocyclic complexes containing piperazine have shown to be great agents against A2780 cells
[
20, 46]. Herein, the results also indicated that all the samples, were not able to affect PC3
L2)(ClO
)](ClO ) complex which was reached
prostate cancer cells significantly except [Cd(H
2
4
4
the IC50 value at the used concentration (100 μg/ml), while the IC50 value of cisplatin has been
reported to be 2.3 μM(0.690 μg/ml) toward PC3 cells [45]. These results could be used as
starting point for our research program to introduce the potent compounds as novel anticancer
agents. Further studies on the effect of these compounds against other types of normal cells, and
also in experimental animals, would be beneficial to provide a definite conclusion, and to
unequivocally ensure the safety of these compounds as anticancer agents. Furthermore,
investigations on the mechanism of action of these compounds against ovarian cancer cells
would be of a great importance.
<Please insert Fig. 5>
2
1

3
.7. Antibacterial activities
The antibacterial activity of all compounds were studied against four types of Gram positive and
negative bacteria, compared with the antibacterial activity of two antibiotics. All compounds
were dissolved in 2 different concentrations of DMSO. Also, DMSO (used as the solvent) was
screened against all bacteria included in this work and no activity was found. The antibacterial
activities of all compounds were increased with an increase in the concentration of the samples
(Table 4). It was found that metal complexes have higher activities than the free ligands against
all bacterial strains tested. Generally, the metal complexes [Zn(H
2
L1)(ClO
4
)](ClO ),
4
[
Cd(H
2
L1)(ClO L1)(ClO
4
)](ClO
4
) and then [Mn(H
2
4
)](ClO ) showed more antibacterial activity
4
against all bacterial species than other samples, which were even greater than the standard
L1 and H L2 represented
antibiotics of neomycin and nitrofurantion. In contrast, the samples H
2
2
the weakest activity against the bacterial tested, except for B. cereus. The other samples gave
different activities against the studied bacteria.
<Please insert Table 4>
Description of the proposed structures of the complexes
Starting from a metal:ligand mole ratio of 1, where M=Zn (II), Mn (II), Cd (II), mononuclear
complexes have been obtained. Unfortunately, our attempt to get suitable single crystals for X-
ray structural analyses were unsuccessful. Accordingly, all the complexes were characterized by
a number of physicochemical techniques. In the IR spectra of complexes, the shift of (C=N) to
lower frequency, the splitting of the perchlorate bands, the existence the broad bands in the
2
2

-1
range 3431-3462 cm related to OH groups and the appearance of new weak bands in the range
-1
1
of 402-468 cm , attributed to the M-N bonds, are important features of spectra. In the H NMR
spectra of the complexes, two signals related to the imine protons are shifted with respect to the
corresponding signal in the free ligand, indicating that the two imino groups are non-equivalent.
1
As well, the presence of hydroxyl proton signals in the H NMR spectra confirms that the two
1
3
phenolic OH moieties did not deprotonate upon complex formation. Furthermore, the C NMR
spectra of the complexes show two peaks corresponding to the imine carbon atoms, indicating
that the symmetry of ligands was reduced in the complexes. An increase in the number of peaks
in the 13C NMR spectra of the complexes, compared to the free ligands, confirm the
unsymmetrical structure of complexes. The molar conductivity data indicates that all complexes
are electrolytes due to the presence of one counter ion in their structures. Stoichiometry and
2
+
stability constant data clearly indicate that the 1:1 M -H
2
L complexes are formed in non-
L)(ClO )](ClO ) has a
aqueous solvents. Based on this information we propose that [M(H
2
4
4
distorted pentagonal bipyramidal geometry with the azomethine nitrogen and the nitrogen atoms
of piperazine rings coordinating to the metal in the equatorial plan, with the azomethine
nitrogen and perchlorate anion coordinating in the axial positions. Mass spectra and elemental
analysis are consistent with the proposed structure.
4
. Conclusion
In summary, this paper describes the synthesis and spectroscopic characterization of a series of
manganese (II), cadmium (II) and zinc (II) complexes with two new Schiff base ligands derived
from piperazine. The molecular structure of ligand H
2
L1 has been determined by a single crystal
X-ray structural analysis. The complexes have been characterized by a number of
2
3

physiochemical techniques. It is proposed that these complexes have a distorted pentagonal
bipyramidal geometry with the metal coordinated by the six donor atoms of the ligand and one
perchlorate. The Nuclear Magnetic Resonance stoichiometry study clearly indicates that the 1:1
2
+
M -H
2
L complexes are formed in non-aqueous solvents. All of the synthesized complexes have
L1)(ClO
)](ClO ) and
been investigated for antibacterial activities. The metal complexes [Zn(H
2
4
4
[
Cd(H
2
L1)(ClO L1)(ClO
4
)](ClO
4
) and then [Mn(H
2
4
)](ClO ) showed more antibacterial activity
4
against all bacterial species than other samples; their activity was even greater than the
standard antibiotics of neomycin and nitrofurantion. We studied the cytotoxic activity of all
complexes on ovarian and prostate cancer cells. All synthesized samples significantly decreased
the viability of A2780 ovarian cancer cells however none of the samples, except for
[
Cd(H
2
L2)(ClO
4
)](ClO ), were able to affect PC3 prostate cancer cells.
4
5
. Supplementary data
CCDC 1861798 contains the supplementary crystallographic data for [H
2
L1] compound. This
data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from
the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
(+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.
Acknowledgements
We are grateful to the Faculty of Chemistry of Bu Ali Sina University, for financial supports.
2
4

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2
8

Table 1.
1
2
Crystal data and structure refinement for H L .
Crystal data
rwg2018_18Gau
Identification code
Empirical formula
C
28
H
40
N
6
O
2
Formula weight
Temperature/K
492.66
130.00(10)
Crystal system
Space group
monoclinic
I2/a
a/Å
b/Å
c/Å
α/°
β/°
γ/°
Volume/Å
Z
9.4074(3)
5.7404(2)
49.0645(14)
90
90.442(3)
90
2649.51(16)
4
1.235
3
3
ρ
calcg/cm
μ/mm-
1
0.632
F(000)
1064.0
0.448 × 0.125 × 0.12
CuKα (λ = 1.54184)
Crystal size/mm3
Radiation
2Θ range for data collection/° 7.206 to 154.384
Index ranges
-11 ≤ h ≤ 11, -7 ≤ k ≤ 7, -61 ≤ l ≤ 52
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
Final R indexes [I>=2σ (I)]
Final R indexes [all data]
12671
2788 [Rint = 0.0263, Rsigma = 0.0167]
2788/0/244
1.059
R
R
1
= 0.0363, wR
= 0.0387, wR
2
= 0.0964
= 0.0990
1
2
Largest diff. peak/hole / e Å-3 0.22/-0.16
2
9