Structural studies and anticancer activity of a novel (N6O 4) macrocyclic ligand and its Cu(II) complexes

Article abstract of DOI:10.1016/j.saa.2010.10.021

A novel (N₆O₄) macrocyclic ligand (L) and its Cu(II) complexes have been prepared and characterized by elemental analysis, spectral, thermal (TG/DTG), magnetic, and conductivity measurements. Quantum chemical calculations have also been carried out at B3LYP/6-31+G(d,p) to study the structure of the ligand and one of its complexes. The results show a novel macrocyclic ligand with potential amide oxygen atom, amide and amine nitrogen atoms available for coordination. Distorted square pyramidal ([Cu(L)Cl]Cl·2.5H₂O (1), [Cu(L)NO₃]NO ₃·3.5H₂O (2), and [Cu(L)Br]Br·3H ₂O (4) and octahedral ([Cu(L)(OAc)₂]·5H ₂O (3)) geometries were proposed. The EPR data of 1, 2, and 4 indicate d¹ x² _-y² ground state of Cu(II) ion with a considerable exchange interaction. The measured cytotoxicity for L and its complexes (1, 2) against three tumor cell lines showed that coordination improves the antitumor activity of the ligand; IC₅₀ for breast cancer cells are ≈8.5, 3, and 4 μg/mL for L and complexes (1) and (2), respectively.

Full text of DOI:10.1016/j.saa.2010.10.021

Spectrochimica Acta Part A 78 (2011) 360–370
Contents lists available at ScienceDirect
Spectrochimica Acta Part A: Molecular and
Biomolecular Spectroscopy
journal homepage: www.elsevier.com/locate/saa
Structural studies and anticancer activity of a novel (N6O4) macrocyclic ligand
and its Cu(II) complexes
Hanaa A. El-Boraey, Sanaa M. Emam, Dina A. Tolan, Ahmed M. El-Nahas∗
Department of Chemistry, Faculty of Science, El-Menoufia University, Shebin El-Kom, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel (N6O4) macrocyclic ligand (L) and its Cu(II) complexes have been prepared and characterized
by elemental analysis, spectral, thermal (TG/DTG), magnetic, and conductivity measurements. Quan-
tum chemical calculations have also been carried out at B3LYP/6-31+G(d,p) to study the structure
of the ligand and one of its complexes. The results show a novel macrocyclic ligand with potential
amide oxygen atom, amide and amine nitrogen atoms available for coordination. Distorted square
pyramidal ([Cu(L)Cl]Cl·2.5H2O (1), [Cu(L)NO3]NO3·3.5H2O (2), and [Cu(L)Br]Br·3H2O (4) and octahedral
Received 4 August 2010
Received in revised form
29 September 2010
Accepted 18 October 2010
Keywords:
([Cu(L)(OAc)2]·5H2O (3)) geometries were proposed. The EPR data of 1, 2, and 4 indicate d1 x2 2 ground
−y
Macrocyclic ligand
Copper(II) complexes
Spectral studies
Thermal analysis (TG/DTG)
Antitumor activity
DFT calculations
state of Cu(II) ion with a considerable exchange interaction. The measured cytotoxicity for L and its
complexes (1, 2) against three tumor cell lines showed that coordination improves the antitumor activ-
ity of the ligand; IC50 for breast cancer cells are ≈8.5, 3, and 4 ␮g/mL for L and complexes (1) and (2),
respectively.
© 2010 Elsevier B.V. All rights reserved.
1. Introduction
Copper(II) ion is known to be involved in many biological
processes [16,17] and its role in increasing antitumor efficacy of
Design of new macrocyclic compounds of different sizes, struc-
tures and properties represents an active area of research due to
their widespread applications in chemistry and biology [1–13].
These rings can accommodate a variety of metal ions depend-
ing on the cavity size, metal ion, and ring structure [10,12,13].
The coordination chemistry of several macrocyclic ligands has
been the subject of many studies [2–11]. The most common
route for preparation of Polyaza macrocycles is the condensa-
tion of primary diamines with dialdehydes, diketones or diesters
[1,12–14]. One class of these macrocycles is those incorporating
amide groups [1,3–6,8–10,12,13]. Due to the presence of proton
donor (N–H) and proton acceptor (C O), hydrogen bond forma-
tion is common in these macrocycles and affects their structures
[1,6]. Hydrogen bonding is crucial for functionality of biological sys-
tems such as RNA, DNA, proteins, and enzymes. Therefore, many
efforts have been devoted to design new molecules with poten-
tial hydrogen bonding to interact with these biological systems
[1,3–6,8–10,12–15]. Macrocyclic compounds containing oxalamide
moiety have been synthesized and showed a variety of catalytic and
biological activities [1,8–10,12,13]. The amide groups can bind with
different metal ions via nitrogen and/or oxygen atoms. Compounds
incorporating metal atoms are known as antitumor drugs such as
cisplatin [16].
organic molecules was established [7,18–24]. However, to the best
of our knowledge, the synthesis of a macrocyclic compound derived
from the interaction of dipropylenetriamine with diethyloxalate
has not been done so far. Therefore, this work reports the synthesis
and characterization of the aforementioned compound and some of
its Cu(II) complexes. This ligand represents a 22-membered (N6O4)
macrocyclic molecule viz 1,4,8,12,15,19-hexaazacyclo-docosane-
2,3,13,14 tetraone (L), Scheme 1. The structures of the targeted
ligand and complexes were characterized by elemental analysis,
spectral (IR, UV–Vis (MS, 1H NMR for the ligand) and EPR) studies
and thermal techniques, molar conductance and magnetic suscep-
tibility measurements. Anticancer activity of L and its complexes (1,
2) was also estimated. Quantum chemical calculations have been
carried out to support and interpret experimental findings.
2. Experimental
2.1. Materials and methods
All chemicals and solvents were of analytical grade and were
used as received.
2.1.1. Synthesis of the macrocyclic ligand
The (N6O4) ligand has been synthesized as described elsewhere
for similar compounds [8,9,12,13]. A solution of diethyloxalate
((2 mL, 2.19 g, 15 mmol) in ethanol (60 mL) was added dropwise
to a solution of dipropylenetriamine (2 mL, 2.21 g, 16.92 mmol)
∗
Corresponding author. Tel.: +20 16 4607974; fax: +20 48 2235689.
E-mail address: amelnahas@hotmail.com (A.M. El-Nahas).
1386-1425/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.saa.2010.10.021

H.A. El-Boraey et al. / Spectrochimica Acta Part A 78 (2011) 360–370
361
N
H
HN
O
NH
O
O
O
N
+
r.t.
C H OH
2 5
4
OC2H5
H
O
C2H5O
2
2
+
NH
HN
Ethanol
NH2
H2N
O
H
N
L
Scheme 1. Route of formation and suggested structure of the macrocyclic ligand (L).
in ethanol (70 mL) at room temperature and stirred vigorously
overnight. The white precipitate formed (2.1 g, 50%) was filtered off
and washed several times with cold EtOH and CH3CN and vacuuo
dried over P4O10 (m.p. 190 ◦C).
cell to the wall of the plate. Different concentrations of the com-
pounds under test (0, 1, 2.5, 5 and 10 ␮g/mL) were added to the
cell monolayer triplicate wells which were prepared for individ-
ual dose. Monolayer cells were incubated with the compounds for
48 h at 37 ◦C and in 5% CO2 atmosphere. After 48 h, the cells were
fixed, washed and stained with Sulfo-Rhodamine-B stain. Excess
stain was washed with acetic acid and attached stain was recov-
ered with Tris EDTA buffer. Color intensity was measured in an
ELISA reader. The relation between the surviving fraction and the
tested compound’s concentration was plotted to get the survival
curve of each tumor cell line for the specified compound.
2.1.2. Synthesis of the macrocyclic complexes
To a suspension of the macrocyclic ligand (0.5 g, 1.35 mmol)
in 50 mL ethanol, a solution of hydrated copper(II) salt (chloride,
nitrate, acetate or bromide for complexes 1, 2, 3 and 4, respec-
tively) in 50 mL ethanol was added gradually, in molar ratio 1:1
(ligand: metal). The reaction mixture was heated under reflux for
8 h. The formed solid product was removed by filtration washed
several times with ethanol and vacuuo dried over P4O10
.
2.4. Quantum chemical calculations
All electronic structure calculations were performed using the
Gaussian03 suite of programs [26]. Geometry optimizations for
the macrocyclic ligand and its complex (1) have been conducted
without constraints using Density Functional Theory (DFT) at the
B3LYP [27–29] functionals in conjunction with the 3-21G(d) basis
set. Vibrational frequency calculations have been carried out at
the same level of theory to characterize the optimized structures
as minima or transition states and to correct energies for zero-
point energy and thermal contribution. The vibrational modes were
examined by using the ChemCraft program [30]. The calculated
vibrational frequencies were scaled by 0.962 to account for the
anharmonicity of the experimental frequencies. The calculations
indicated that the ligand and complex (1) are minima (all eigen-
values of the force constant matrix are positive). Partial charge
distributions were calculated using the natural population anal-
ysis (NPA) method [31]. Energies of all species were further refined
at the B3LYP/6-31+G(d,p). Solvation effect has been modeled in
ethanol using the polarized continuum model (PCM) of Tomasi and
coworkers [32–35] at the B3LYP/6-31+G(d,p) level.
2.2. Physical measurements
The elemental analyses (C, H, N) were performed at Micro Ana-
lytical Center, Cairo University Giza, Egypt. Copper(II) content in the
complexes was determined via iodometric method, while halide
ions were determined by Volhard’s method. Mass spectra (MS)
were performed at the National Centre Institute, Egypt by the
Thermo Electron Corporation. The Fourier Transform Infrared (FT-
IR) measurements were performed (4000–400 cm−1) in KBr discs
using Nenexeus-Nicolidite-640-MSA FT-IR, Thermo-Electronics Co.
The UV–visible absorption spectra were measured in Nujol mull
using 4802 UV/vis double beam spectrophotometer. The 1H NMR
spectrum was recorded in DMSO d6 using Varian Gemini 200
NMR spectrophotometer at 300 MHz. The electron paramagnetic
resonance (EPR) spectra were recorded using a Varian E-109C
model X-band spectrometer. The magnetic field modulation fre-
quency was 100 kHz and the microwave power was around 10 mW.
Molar conductivities were measured in DMSO solution of the com-
plexes (10−3 M) using a CON 6000 conductivity meter, Cyberscan,
Eutech instruments. Magnetic susceptibilities of the complexes
were measured by the modified Gouy method at room tempera-
ture using Magnetic Susceptibility Johnson Matthey Balance. The
effective magnetic moments were calculated using the relation
ꢀeff = 2.828(ꢁmT)1/2 B.M., where ꢁm is the molar magnetic suscep-
tibility corrected for diamagnetism of all atoms in the compounds
using Selwood and Pascal’s constants. Thermal analysis (TG/DTG)
were obtained out by using a Shimadzu DTA/TG-50 Thermal ana-
lyzer with a heating rate of 10 ◦C /min in nitrogen atmosphere with
a following rate 20 mL/min in the temperature range 30–800 ◦C
using platinum crucibles.
3. Results and discussion
The physical properties and analytical data of the ligand and
its Cu(II) complexes were given in Table 1. The condensation of
diethyloxalate with dipropylenetriamine gives the expected [2 + 2]
tetraamide macrocyclic compound (L) (Scheme 1). The reaction
of the macrocyclic ligand with the hydrated copper(II) chloride,
nitrate, acetate or bromide in 1:1 molar ratio yielded the Cu(II) com-
plexes (Scheme 2). The new compounds have been characterized
by elemental analyses, spectral (IR, UV–Vis, EPR (MS, 1H NMR for
the ligand)), thermal analysis (TG/DTG) techniques, magnetic and
conductivity measurements. The elemental analyses data are con-
sistent with the proposed molecular formulas that show 1:1 metal
to ligand ratio in these complexes. The novel green or blue cop-
per(II) compounds are stable in air. The crystals were unsuitable
for single-crystal X-ray structure determination and are insolu-
ble in most common solvents, including ethanol, methanol, ethyl
acetate, and acetonitrile. Complexes (1, 2) are soluble in dimethyl-
2.3. Biological tests
Potential cytotoxicity of the ligand (L) and its complexes (1, 2)
was measured at the National Cancer Institute, Cairo University
Egypt by SRB assay using the method of Skehan et al. [25]. Cells
were plated in 96-multiwell plate (104 cells/well) for 24 h before
the treatment with the target compounds to allow attachment of

362
H.A. El-Boraey et al. / Spectrochimica Acta Part A 78 (2011) 360–370
X
X
HN
HN
NH
HN
HN
NH
O
O
O
Cu
X
Cu
O
HN
X. nH2O
. nH2O
HN
O
O
O
NH
HN
O
NH
HN
(1)
(2)
(3)
X = Cl, n = 2.5
X = NO3, n = 3.5
X = Br, n = 3
(4)
X = OAc, n = 5
Scheme 2. Suggested structures of the complexes (1–4).
observed at 3500 cm−1, while on complexation a broad band at
ca. 3459–3407 cm−1 was found indicating the presence of crystal-
lized water molecules. Additionally, bands at ca. 3407–3300 cm−1
recorded for the complexes, were attributed to the overlap of
free and coordinated ꢃ(N–H) of secondary amido/amino groups of
the ligand [13]. The stretching frequencies of the amide-I ꢃ(C O)
groups in the complexes appear in two separate regions. The first
region was observed at 1628–1602 cm−1 which is lower than the
ꢃ(C O) of the free ligand (1652 cm−1). This low shift, may be
ascribed to the coordination of the C O group to the metal ion.
The second region located at 1660–1658 cm−1 is nearly at the same
stretching frequency of the free ligand (1652 cm−1). This indicates
the presence of uncoordinated C O groups.
sulfoxide (DMSO) without change in color. Molar conductivity
measurements of complexes (1, 2) in 10−3 M DMSO solution are
in the 58–72 ꢂ−1 cm2 mol−1 range, correspond to 1:1 electrolyte
[36]. With the exception of DMSO, the solubility of the macro-
cyclic ligand in other organic solvents is very limited. Intra- and/or
intermolecular hydrogen bonds network is probably the key factor
behind such limited solubility. It has been reported that hydrogen
bond network could be a driving force in the formation of the [2 + 2]
product [12].
3.1. Spectral studies
3.1.1. Mass spectra and 1H NMR
It is noticed that the IR absorptions of complexes show a high
frequency shift for coordinated ꢃ(N–H) and a low shift for coor-
dinated ꢃ(C O) compared to the ligand (Table 2). This behavior
reveals that the electronic density of nitrogen is more delocal-
ized with the carbonyl group in the complexes than in the ligand
[1]. The IR spectra of the complexes also show that the amide II
ı(N–H) recorded at 1525 cm−1 in the free ligand, is shifted to a lower
frequency (1520–1510 cm−1) and that amide III, ꢃ(C–N) occurs at
1215 cm−1 in the free macrocycle ligand is shifted to higher fre-
quency (1226–1225 cm−1) supporting coordination through the
The electrospray ionization (ESI) mass spectrum of the free
ligand (L) in DMSO solution of approximately 10−4 M confirms
the [2 + 2] macrocyclic form by observing a molecular ion peak at
m/z 371 amu [MH+] corresponds molecular formula of C16H30N6O4
(calculated M = 370). The mass spectrum of the free ligand also
shows structurally important fragment ions at m/z 56 [C3H6N]+,
m/z 70 [C3H7N2]+, m/z 129 [C6H15N3]+, m/z 186 [C8H15N3O2]+,
m/z 299 [C14H29N5O2]+, m/z 328 [C15H30N6O3]+ and m/z 343 amu
[C15H30N6O3]+. The 1H NMR spectrum of the free macrocyclic lig-
and shows a signal at ı 8.84 ppm attributed to amide (4H (br),
CO–NH) and at ı 3.48 ppm (–CO–NH–CH2). The signals appeared
at ı 2.533 ppm and ı 1.633 ppm could be assigned to secondary
amine (–CH2–NH–CH2–) and methylene protons, respectively.
C
O group. A further evidence for these coordination modes is
the appearance of new two peaks at 530–508 and 483–425 cm−1
due to ꢃ(Cu–O) and ꢃ(Cu–N) stretching vibrations, respectively.
The IR spectrum of complex (2) displays an absorption band at
1385 cm−1 characterizing the free nature of the nitrate ion; the
presence of ionic nitrate is also supported by conductance measure-
ments [13,36–41]. Complex (2) exhibits also bands around 1430,
1340, and 1040 cm−1 corresponding to monodentate nitrate group
[36–41]. The acetato complex (3) displays two bands at 1575 and
1380 cm−1 assignable to ꢃas(COO−) and ꢃs(COO−). This difference
of 195 cm−1 confirms the monodentate nature of the coordinated
acetate [42]. Therefore, and according to the IR spectra, it is con-
cluded that the current macrocyclic ligand behaves as a neutral
tetradentate ligand binds to the metal ion via two amide nitrogens,
one secondary nitrogen atom, and one amide oxygen atom.
3.1.2. Infrared spectra
Selected IR spectral bands for the ligand and its complexes are
given in Table 2. The IR spectrum of the free ligand is character-
ized mainly by the strong bands at 3292, 1652, 1215, 1525, and
766 cm−1, which are attributed to the stretching frequencies of
NH (secondary amino group), amide-I ꢃ(C O), amide-III ꢃ(C–N),
and bending frequencies of amide-II ı(N–H), and amide-IV ı(C O)
bands, respectively [8,9]. This supports the macrocyclic nature of
the ligand. There is another broad band at 3500 cm−1 due to the
presence of lattice water molecules. The alkyl CH2 group shows
characteristic stretching absorption bands in the region 2943 cm−1
deformation band at 1442 cm−1 and rocking modes at 677 cm−1
,
,
respectively. The bonding of the ligand to copper(II) has been
judged by a careful comparison of the infrared spectra of the com-
plexes with that of the free ligand. In general, the IR spectra of
the complexes exhibit merged and broadened bands compared to
the sharp bands of free ligand. The ꢃ(O–H) band of free ligand was
3.1.3. Electronic spectra and magnetic moment
The tentative assignments of the significant electronic spectral
bands of complexes are presented in Table 3. The electronic spec-
trum of L in Nujoll mulls as well as in DMSO show absorption
bands at 230, 330–290 nm, are due to n–␲* electronic transitions

Table 1
Analytical and physical data for the macrocyclic ligand and its Cu(II) complexes.
No.
Compound
Color
Empirical formula
Yield (%)
Decomp. Temp (◦C)
Analysis Calc. (F) (%)
ꢄm ꢂ−1 cm2 mol−1
C
H
N
M
Halogen
Ligand (L·2H2O)
White
Green
Green
Dark blue
Green
C16H34N6O6
50
195
200
200
193
200
47.29 (48.41)
34.9 (35.1)
30.94 (30.91)
37.14 (37.77)
29.90 (29.00)
8.3 (8.49)
6.3 (6.06)
5.96 (5.84)
7.22 (7.65)
5.4 (5.64)
20.6 (20.52)
15.2 (15.04)
18.3 (17.82)
14.41 (14.77)
12.96 (12.58)
–
–
–
58.3
72.27
Insoluble
Insoluble
1
2
3
4
[Cu(L)Cl]Cl·2.5H2O
[Cu(L)NO3] NO3·3.5H2O
[Cu(L)(OAc)2] 5H2O
[Cu(L) Br]Br·3H2O
C16H35N6O6.5Cu
C16H37N8O13.5Cu
C20H46N6O13Cu
C16H36N6O7Cu
75.3
92.3
75
11.56 (11.7)
10.2 (10.00)
9.90 (9.90)
9.80 (10.20)
12.9 (12.42)
–
–
90
24.66 (24.1)
Table 2
Important IR spectral bands (cm−1) of the macrocyclic ligand and its copper(II) complexes.
No.
Compound
ꢃ(O–H)
ꢃ(N–H)
ꢃ(C O)
ꢃ(C O) amide I
ı(N–H)
ꢃ(C–N)
ı(C O)
ꢃ(M–O)
ꢃ(M–N)
Anion (NO3−, OAc−
)
amide I free
coord.
amide II
amide III
amide-IV
L·2H2O
3500
3412
3428
3292
3304
3300
1652
1658
1660
–
1602
1602
1525
1517
1520
1215
1226
1225
766
762
754
–
510
508
–
462
425
–
–
1
2
[Cu(L)Cl]Cl·2.5H2O
[Cu(L)NO3]NO3·3.5H2O
(1385, 820)a
(1430, 1340)b
(1575, 1380)c
–
3
4
[Cu(L)(OAc)2]·5H2O
[Cu(L)(Br)]Br·3H2O
3459
3407
3415
3300
1660
1660
1628
1602
1510
1516
1225
1225
755
739
520
530
450
483
a
Ionic nitrate.
Monodentate nitrate.
Monodentate acetate.
b
c

364
H.A. El-Boraey et al. / Spectrochimica Acta Part A 78 (2011) 360–370
Table 3
EPR, bonding parameters, electronic spectral bands and magnetic moments of Cu(II) complexes.
Parameter
Complex
1
2
3
4
g//
2.21
2.06
2.11
–
3.631
0.47
2.22
2.07
2.12
–
3.236
0.51
–
–
–
2.09
–
2.210
2.06
2.11
–
3.134
0.49
g
⊥
a
gav
giso
G
K/2/
–
K⊥2
0.82
0.70
15,197
24,691
0.90
0.77
15,384
22,222
88.0
–
–
–
–
0.90
0.76
15,384
22,222
118
K2
ꢅE2 (cm−1
ꢆE3 (cm−1
A// (gauss)
)
)
–
–
A
⊥
(gauss)
–
52.0
–
60
Aav (gauss)
f (cm)
˛
ˇ2
ꢇ2
–
–
–
–
63.4
248
0.53
0.96
–
–
–
–
79.3
182
0.61
0.80
2
–
1.68
–
1.47
d–d transitions (nm)
Other transitions (nm)
658(br), 405
380(s) 335, 250
650(br), 450
370–350(s), 290
800(s), 475
370(s), 260(s)
650(br), 450
380–370(s), 230
ꢀ
ꢁ
ꢀeff (B.M.)
1. 57
1.58
1.80
1.32
gav = 2g + g///3, 3K2 = 2K⊥2 + K2
.
a
⊥
//
3.1.4. EPR spectra
[2]. The geometry of the copper(II) complexes has been deduced
from the electronic and EPR spectra and further supported by quan-
tum chemical calculations. The electronic spectra of complexes (1,
2, 4) display bands around 658–650 and 450–405 nm which are
indicative of distorted square pyramidal geometries, These bands
EPR spectra of Cu(II) complexes provide information about the
coordination environment around copper(II) ion [43,45]. The solid
state EPR spectra of the copper(II) complexes (1–4) were recorded
at room temperature on the X-band frequency 9.71 GHz. The EPR
parameters observed for the powdered complexes are listed in
Table 3. With the exception of complex (3), the EPR spectra of other
Cu(II) complexes on the high field side are more intense than the
low field side, indicating a dx2−y2 ground state for the copper(II)
ion. Analysis of the spectra gives g// = 2.22–2.12 and g = 2.07–2.06
(Table 3). The trend g// > g > 2.0023, observed for the complexes
under investigation also suggests dx2−y2 ground state for the Cu(II)
ion [46–48]. The greater value of g// compared to g proposes a dis-
may be assigned to the transitions 2B1g → A1g and 2B1g → Eg [42].
The electronic spectra of complexes (1, 2) in DMSO also show
the same absorption spectra indicating that the structure is not
affected by solvent. The acetato complex (3) exhibits band around
800 and near 475 nm corresponding to distorted octahedral geom-
2
2
⊥
2
2
2
2
⊥
etry. These bands may be assigned to B1g → B2g and B1g → Eg
transitions, respectively [3]. Additional peaks observed at higher
energy were assigned to intra-ligand transitions. The room tem-
perature magnetic moments measurements of the complexes are
given in Table 3. The expected range for magnetically diluted Cu(II)
complexes extended between 1.7 and 2.2 B.M. Complexes with the
magnetic moments below this range indicate antiferromagnetic
coupling [43]. Although complex (4) has a mononuclear structure,
it shows subnormal value (1.32 B.M.) which may be attributed to
intermolecular copper–copper interaction [43–45].
⊥
torted square pyramidal structure and rules out the possibility of a
triagonal bipyramidal structure which is expected to have g > g
⊥
//
[49,50]. Also, the observed g// values of less than 2.3 provide evi-
dence for the covalent character of bonding between Cu(II) ion and
the ligand [51]. The exchange interaction between the copper cen-
ters in polycrystalline sample is explained by Hathaway expression
G = g// − 2.0023/g⊥ − 2.0023 [52]. The exchange interaction is neg-
4000
6000
4000
2
2000
3
2000
0
-2000
-4000
0
-2000
-4000
-6000
-6000
-8000
2400 2600 2800 3000 3200 3400 3600 3800 4000 4200
2400 2600 2800 3000 3200 3400 3600 3800 4000 4200
G
G
Fig. 1. EPR spectra of complexes (2, 3) as polycrystalline sample at RT.

H.A. El-Boraey et al. / Spectrochimica Acta Part A 78 (2011) 360–370
365
Table 4
Thermal data of the investigated compounds.
No
Compound
Temperature range (◦C)
DTG
Mass loss%
Calc.
Reaction
Leaving species
TG
(F.)
Ligand (L·2H2O)
[Cu(L)Cl]Cl·2.5H2O
163, 190
339, 557
30–195
195–625
8.80
91.2
(8.8)
(91.2)
(i)a
–2H2O
Decomposition
(ii)b
1
2
55
298, 569
30–100
200–700
at 700
8.16
67.3
24.48
(8.18)
(i)a
–2.5H2O
–ligand(C16H30N6O4)
CuCl2
(67.3)
(ii)b
(24.52)c
[Cu(L)NO3] NO3·3.5H2O
50
178
260, 426
30–130
154–200
200–501
at 501
7.2
2.9
74.9
14.7
(6.7)
(2.9)
(i)a
(i)
–2.5H2O
–H2O
Gradual decomposition
CuO1.5
(74.5)
(ii)b
(14.8)c
3
[Cu(L)(OAc)2]·5H2O
[Cu(L) Br]Br·3H2O
50
268, 530
30–190
193–613
at 613
14.0
66.8
19.19
(14.0)
(67.0)
(19.0)c
(i)a
–5H2O
Gradual decomposition
Cu(OAc)
(ii)b
4
50
30–101
200–724
at 724
8.33
81.87
9.81
(8.00)
(82.4)
(9.60)c
(i)a
–3H2O
Loss of C16H30N6O4Br2
Cu
301, 376, 694
(ii)b
a
Dehydration.
Decomposition.
Final product percent.
b
c
˛2 = 0.53–0.61 indicating high covalency in these complexes. On
the other hand, the values of ˇ2 (0.96–0.80) reflect the presence
of in-plane ␲-bonding. The ꢇ2 values of 1.47–1.68 show an ionic
character of the out-of-plane-␲-bonding [58]. Complex (3) exhibits
isotropic EPR spectrum with intense broad signal without hyperfine
structure, Fig. 1. This is attributed to exchange interaction which
would be mainly dipolar in character between the copper ions of
the neighboring molecules and unresolved hyperfine interaction in
the solid state [59].
ligible if G > 4, whereas a considerable interaction occurs for G < 4.
As shown in Table 3, the calculated G values for copper(II) com-
plexes (1, 2, 4) are less than 4 suggesting some interaction between
Cu(II) ions in the solid state, which is further confirmed by their
subnormal magnetic moments values.
Complexes (2) (Fig. 1) and (4) show hyperfine anisotropy EPR
spectra with well-defined hyperfine structure on the low field
region due to the interaction between the unpaired electron of
Cu(II) ion with its nucleus This allows accurate calculations of
g// and A// values that are used to determine the empirical fac-
tor f = g///A//, which is used as an index for tetragonal distortion
[53–55]. The value of f from 105 to 135 cm indicates square-planar
structures whereas larger values reveal tetragonally distorted com-
plexes [53]. The f values for the investigated complexes given in
Table 3 indicate distorted square pyramidal geometry. The EPR
3.2. Thermal analysis
The thermal properties of the current macrocyclic ligand and
its copper(II) complexes were investigated by thermogravimet-
ric analysis (TGA) and differential thermogravimetry (DTG), under
nitrogen atmosphere from 30 to 800 ◦C; important data are sum-
marized in Table 4.
parameters g , g , gav, A (Cu) and A (Cu) and the energies of
⊥
⊥
//
//
d–d transitions were used to evaluate the bonding parameters ˛2,
ˇ2 and ꢇ2 which are used as measures of covalency of in-plane ꢈ
bonding, in-plane and out-of- plane ␲-bonding, respectively. The
parameter ˛2 is calculated from the following relation [51,56]:
3.2.1. Ligand
For the macrocyclic ligand, the TGA curve shows weight loss
of 8.8% (theoretical. 8.8%); in the temperature range of 30–195 ◦C.
The two weak endothermic DTG peaks recorded at 163 and 190 ◦C
reflect the loss of two water molecules per ligand molecule. These
results agree well with the composition of the ligand determined
from elemental analysis and IR spectrum. The TG curve indicates
a thermal stability till 195 ◦C which coincides with the melting
point of the ligand (190 ◦C). The TG curve also shows two decom-
position steps (Fig. 2) in the temperature range 190–625 ◦C, with
total weight loss of 100.0% (found 100.0%), for the first and second
steps. These weight losses may be ascribed to the successive loss
of C16H30N6O4 molecule as gases at the given temperature range,
coincide with DTG curve which shows peaks maximum at 339 and
557 ◦C.
A//
3
7
2
˛
=
+ (g// − 2.0023) + (g⊥ − 2.0023) + 0.04
0.036
The orbital reduction factors (K/2/ = ˛2ˇ2 and K⊥2 = ˛2ꢇ2) which
are the parallel and perpendicular components of orbital reduc-
tion factor also, give significant information about the nature of the
bonding in copper complexes, they can be calculated using these
expressions,
(g// − 2.0023)ꢆE2
K/2/
=
8ꢉo
(g⊥ − 2.0023)ꢆE3
=
2ꢉo
K⊥2
where ꢉo is the spin-orbit coupling constant (ꢉo = −828 cm−1 for
3.2.2. Complexes
2
free Cu(II) ion) and ꢆE2 = 2B1g → A1g, ꢆE3
=
2B1g
→
2Eg.
Fig. 2 represents TG/DTG curves of the complexes (1–4). The
corresponding data are summarized in Table 4. The thermal behav-
ior of all complexes is almost similar. For complexes (1, 2, 4), The
TG curves show weight loss in the temperature range 30–190 ◦C,
associated with one endothermic DTG peak at 50–55 ◦C. This was
assigned to loss of water of crystallization in one step (Table 4),
the lower onset of dehydration processes (30 ◦C) together with
its extended range of temperatures indicate physical bonding for
Complexes with K// < K imply a considerable in-plane ␲-
⊥
bonding, while those with K// > K indicate an out-of-plane ␲
⊥
bonding [57]. In complexes (2, 4), K// < K and K < 1 indicates the
⊥
presence of significant in-plane ␲ bonding and greater covalent
character for M–L bonding. However, the bond between Cu(II) ion
and the ligand in-plane ␴ bond is purely ionic if ˛2 = 1 and entirely
covalent if ˛2 = 0.5 [58]. The complexes under investigation give

366
H.A. El-Boraey et al. / Spectrochimica Acta Part A 78 (2011) 360–370
Fig. 2. TG/DTG curves of the macrocyclic ligand and its copper(II) complexes (1–4).
water of crystallization [60–64]. For Complex (2), the TG curve
shows also weight loss of 2.9% (theoretical.2.9%), in the range of
154–200 ◦C, associated with endothermic DTG peak at 178 ◦C. This
was assigned to loss of the last water molecule. As seen on hot
stage microscope, the complex decomposes at 200 ◦C; the rela-
tively high value of the temperature of the second dehydration step
for complex (2) indicates strong water-lattice interaction. For com-
plex (3), The TG curve shows weight loss in the temperature range
30–190 ◦C, associated with one endothermic DTG peak at 55 ◦C that
was assigned to loss of five molecules of water of crystallization
in one step (Table 4). As the temperature is increased; complexes
degrade only in two steps. This degradation is due to pyrolysis of
the organic ligand molecule. On the basis of elemental analysis,
molar conductance measurements, magnetic susceptibilities, dif-
ferent spectra, thermal data, and the discussion given above, the
suggested structures for the complexes (1–4) are given in Scheme 2.
complex (1). The optimized structures of the ligand and complex
(1) are displayed in Fig. 3.
The complex (1) adopts a square pyramidal structure with the
Cu(II) ion coordinated to two amide nitrogen atoms, one amine
nitrogen atom, and one oxygen atom. These four atoms form a dis-
torted plane with the Cl atom located at the z-axis. The angular
structural parameter ␶ [65,66] defined as the difference between
the O1CuN6 (159.6◦) and N4CuN5 (133.3◦) angles divided by 60◦
equals 0.44 compared to 1 for equilateral bipyramid and 0 for
square pyramid. Moreover, the sum of bond angles around Cu atom
is 344◦ which implies a pyramidalization degree of 16◦. Starting the
optimization process with an octahedral configuration for complex
(1) leads gradually to the distorted square pyramidal structure with
one of the Cl anions leaving the first coordination sphere to attach
with one of the O–H of water and N4–H via hydrogen bonds in
the second shell. All these observations support the experimen-
tal assignment of the distorted square pyramidal structure of the
complex (1).
3.3. DFT calculations
As depicted in Fig. 3, the optimized lengths for Cu–N5, Cu–N6,
Cu–N4, Cu–O1, and Cu–Clcoord are 1.989, 1.925, 2.055, 1.996, and
Because of our unsuccessful trails to get crystalline samples for
X-ray crystallography, DFT calculations have been conducted for
betterunderstandingof thestructures ofthemacrocyclicligandand
˚
2.322 A, respectively. The second Cl atom is located outside the
first coordination sphere with the Cu–Cluncoord bond distance of

H.A. El-Boraey et al. / Spectrochimica Acta Part A 78 (2011) 360–370
367
Fig. 3. Optimized structures of the ligand and complex (1) at B3LYP/3-21G(d).
˚
on amine nitrogen is more than on the amide nitrogen because the
electrons on the latter are resonating with the adjacent carbonyl
group. This gives rise to a shorter Cu–Namine bond compared to
3.495 A. This Cl forms two hydrogen bonds with amide N4–H and
˚
water O–H bonds of 2.019 and 2.030 A, respectively. A compa-
rable geometrical parameters were reported previously for other
complexes where Cu(II) is coordinated to nitrogen and oxygen
atoms at B3LYP/6-31G, B3LYP/LanL2DZ, and B3PW91/ LanL2DZ lev-
els [67,68].
˚
Cu–Namide.(1.925 vs. 1.989 or 2.055 A, respectively). From the sec-
ond order perturbation NBO energy analysis, it has been shown
that the strength of interaction of the Cu(II) ions with donor atoms
decreases in the order Cl > Namine > Namide > Namide > O; 39, 24, 20,
17, and 15 kcal/mol, respectively.
The charge on the Cu(II) ion in the complex (1) of 1.515 e is
lower than its value in the free ion of +2e. This indicates a charge
transfer from the ligands (L, Cl−) to the central ion. The nitrogen
and oxygen atoms acquired more negative in the complex while the
positive charges on amine and amide hydrogen atoms are increased
upon complexation. The increase of the positive charges on these
hydrogen atoms might help in forming strong hydrogen bonds with
biological molecules.
In order to shed light into the electronic structures of the lig-
and and its complex (1), natural bond orbital (NBO) analysis was
carried out. Charges on all atoms were calculated from natural
population analysis (NPA). NPA charges over nitrogen and oxygen
atoms in the ligand and its copper(II) complex and the electron
configuration of Cu(II) ion are listed in Table 5. The negative charge
on nitrogen atoms are larger than on oxygen atoms. Therefore, it
is expected that copper(II) ion will bind preferably with nitrogen
atoms than with oxygen atoms unless the formers are hindered
from coordination for steric reasons. In general, the negative charge

368
H.A. El-Boraey et al. / Spectrochimica Acta Part A 78 (2011) 360–370
Table 5
Table 9
Electron population and NPA charges at B3LYP/3-21G(d).
Lethal concentration (IC50) of the macrocyclic ligand and its copper(II) complexes
on different cell lines.
AO
Electron population
Atoma
NPA charges
Complex (1)
1.515
No.
Compound
IC50 (␮g/mL)
Free Cu(II) Complex (1)
L
HCF7
HEPG2
HCT 116
1s
2s
3s
4s
2
2
2
0
2
2
2
2
2
2
0
0
0
2
2
2
2
1
2
Cu
N5
N6
N4
O1
Clcoord
Cluncoord
1.99999
1.99928
0.39037
1.99998
1.99998
1.99998
1.99925
1.99928
1.99943
0.03146
0.03881
0.03974
1.63644
1.9201
1.79722
1.78832
1.82461
27.46424
8.96669
1.5
−0.634 −0.831
−0.690 −0.844
−0.642 −0.826
−0.590 −0.661
−0.833
(L·2 H2O)
8.46
2.82
3.89
13.9
3.28
3.43
17.3
3.74
4.19
1
2
[Cu(L)Cl]Cl 2.5H2O
[Cu(L)NO3]NO3 3.5H2O
2px
2py
2pz
3px
3py
3pz
4px
4py
4pz
3dxy
3dxz
3dyz
3dx2−y2
3dz2
−0.757
values at 3292 cm−1 and 1652 cm−1. In the complex (1), the stretch-
ing N–H and C O modes are shifted to higher and lower values,
respectively. Theoretically, the coordinated N–H and C O bonds are
shifted toward lower frequencies compared to the uncoordinated
ones on the other side of the ligand.
The frontier molecular orbital energies of the ligand and com-
plex (1) are listed in Table 7. The highest occupied molecular orbital
(HOMO) and the lowest unoccupied molecular orbital (LUMO)
represent a means of measuring electron donating or accepting
ability of a given molecular system, respectively. The LUMO in
complex (1) is strongly stabilized and, therefore, the energy gap
(ꢆE = ELUMO − EHOMO) is relatively lower than in the ligand suggest-
ing a strong activity of the former [69].
No. electrons 27
3dtotal
NPA Charge
9
2
a
Atoms numbering system is given in Fig. 3.
The calculated binding energies of the complex (1) in the gas
phase and ethanolic solution at different levels of theory are given
in Table 8. It is clear that the calculations in ethanol decrease the
binding energy by 3–4 times due to the high electrostatic stabi-
lization of the free Cu(II) ion in ethanol solution compared to the
complex itself.
Table 6
Selected vibrational modes and IR of ligand and its copper(II) complex (1).
Mode
Ligand
Complex (1)
Calcd.
Calcd.
Exp.
Exp.
ꢃ(N–H)
3120–3390
3292(br)a
3361–3129
3127b
3304(br)a
3.4. Biological activity
ꢃ(C O)
1614–1652
1652(br)a
1661–1691
1658
1633b
1602b
ꢃ(Cu–O) + ꢃ(Cu–N)
535–370
510–462
The biological activities of the macrocyclic ligand and its com-
plexes (1, 2) (tested at the National centre Institute, Cairo University
Egypt) were detected by SRB assay. The results of these experiments
are collected in Table 9 and plotted in Fig. 4 The pharmacological
testing has proved that the ligand and its copper (II) complexes (1,
2) show excellent anticancer activity toward breast cells (HCF7),
human hepatocarcinoma HEPG2 cells and colon carcinoma cells
(HCT116). The measured cytotoxicity for the macrocyclic ligand
and its complexes (1, 2) against three tumor cell lines shows that
coordination improves the antitumor activity of the new ligand.
For breast cancer cells, the IC50 values are ∼8.5, 3, and 4 ␮g/mL for
the ligand, complexes (1) and (2), respectively. The other two can-
cer cells give similar or slightly less activity. The enhanced activity
of the investigated complexes agree with the documented activ-
ity of copper(II) complexes as antitumor agents [7,19,20,18,21–24].
Our reported values for complexes (1) and (2) for breast cancer
a
Broad band centered at this position.
Groups coordinated with copper.
b
Table 7
Energies (eV) of frontier molecular orbitals (HOMO, LUMO) of the ligand and com-
plex (1).
Compound
HOMO
LUMO
ꢆE
Ligand (L)
Complex (1)
−4.87
−5.03
−0.64
−2.19
4.23
2.84
The calculated and experimental vibrational frequencies are
collected in Table 6. The computed N–H and
C O stretch-
ing vibrational modes of the ligand of 3120–3390 cm−1 and
1614–1652 cm−1 match well with the corresponding experimental
Table 8
Energies (X) of Cu(II), H2O, Cl−, ligand, and complex (1) in the gas phas and ethanolic solution at B3LYP/basis sets.
X/Level
Ligand (au)
Cl− (au)
H2O (au)
Cu(II) (au)
Complex (1) (au)
ꢆXa (kcal/mol)
E0/3-21G(d)
E298/3-21G(d)
H298/3-21G(d)
G298/3-21G(d)
E0/6-31+G(d,p)
E298/6-31+G(d,p)
H298/6-31+G(d,p)
G298/6-31+G(d,p)
E0/6-31+G(d,p) (in Ethanol)
E298/6-31+G(d,p) (in Ethanol)
H298/6-31+G(d,p) (in Ethanol)
G2988/6-31+G(d,p) (in Ethanol)
−1249.85612
−1249.83008
−1249.82914
−1249.91184
−1256.81514
−1256.78910
−1256.78816
−1256.87086
−1256.85648
−1256.83044
−1256.82950
−1256.91220
−458.16037
−458.15896
−458.15801
−458.17539
−460.27473
−460.27331
−460.27237
−460.28975
−460.38550
−460.38408
−460.38314
−460.40052
−75.95421
−75.95137
−75.95043
−75.97195
−76.41261
−76.40978
−76.40883
−76.43036
−76.42512
−76.42228
−76.42134
−76.44286
−1631.51161
−1631.51020
−1631.51020
−1631.49576
−1639.25153
−1639.25011
−1639.25011
−1639.23567
−1639.73609
−1639.73467
−1639.73467
−1639.72023
−3950.83063
−3950.79543
−3950.79449
−3950.89653
−3970.46602
−3970.43082
−3970.42987
−3970.53192
−3970.51787
−3970.48266
−3970.48172
−3970.583767
−774.19
−774.66
−777.03
−749.40
−643.00
−643.47
−645.84
−618.21
−190.89 (−494.87)b
−191.27 (−495.34)b
−193.64 (−497.71)b
−166.01 (−470.08)b
a
X = E0, E298
, H298, G298 (total energy corrected for zero-point energy, total energy at 298 K, enthalpy at 298 K, and free energy at 298 K), ꢆX (binding
energy) = (Xcomplex − XL − 2XH2O − 2XCl−).
b
Calculated using unsolvated Cu(II) ion.

H.A. El-Boraey et al. / Spectrochimica Acta Part A 78 (2011) 360–370
369
Fig. 4. Dose response curves of HCT116 (ꢀ), MCF7 (ꢀ), HEPG2 (᭹) cells after treatment with the ligand (L) and complexes (1, 2).
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given by Cu(II) Schiff mono-base complexes with 2-thiophene-
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the complex and ligand, respectively. Second is the high stability
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4. Conclusions
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analytical and physicochemical analysis confirmed the composi-
tion and the structure of the newly obtained compounds. The
results obtained can be summarized as follows:
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tate ligand when reacts with different Cu(II) salts.
2. Mononuclear complexes are formed. They adopt distorted
square pyramidal configurations with the chloride, bromide, and
nitrate. However, the acetato complex prefers a distorted octa-
hedral geometry.
3. Quantum chemical calculations support the experimental char-
acterization of the structures of the ligand and complexes.
4. The pharmacological results suggest that the novel ligand and
its copper(II) complexes are potent anticancer agents. Besides,
the cytotoxicity of copper complexes is higher than that of the
ligand, which implies an increase in the antitumor activity with
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Acknowledgments
We would like to thank Professor Kimihiko Hirao (Riken, Wako,
Japan) and Professor Tetsuya Taketsugu (Hokkaido University, Sap-
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