New 15-membered tetraaza (N4) macrocyclic ligand and its transition metal complexes: Spectral, magnetic, thermal and anticancer activity

Article abstract of DOI:10.1016/j.saa.2014.11.015

Novel tetraamidemacrocyclic 15-membered ligand [L] i.e. naphthyl-dibenzo[1,5,9,12]tetraazacyclopentadecine-6,10,11,15-tetraoneand its transition metal complexes with Fe(II), Co(II), Ni(II), Cu(II), Ru(III) and Pd(II) have been synthesized and characterized by elemental analysis, spectral, thermal as well as magnetic and molar conductivity measurements. On the basis of analytical, spectral (IR, MS, UV-Vis, ¹H NMR and EPR) and thermal studies distorted octahedral or square planar geometry has been proposed for the complexes. The antitumor activity of the synthesized ligand and some complexes against human breast cancer cell lines (MCF-7) and human hepatocarcinoma cell lines (HepG2) has been studied. The complexes (IC₅₀ = 2.27-2.7, 8.33-31.1 μg/mL, respectively) showed potent antitumor activity, towards the former cell lines comparable with their ligand (IC₅₀ = 13, 26 μg/mL, respectively). The results show that the activity of the ligand towards breast cancer cell line becomes more pronounced and significant when coordinated to the metal ion.

Full text of DOI:10.1016/j.saa.2014.11.015

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 138 (2015) 553–562
Contents lists available at ScienceDirect
Spectrochimica Acta Part A: Molecular and
Biomolecular Spectroscopy
journal homepage: www.elsevier.com/locate/saa
New 15-membered tetraaza (N4) macrocyclic ligand and its transition
metal complexes: Spectral, magnetic, thermal and anticancer activity
⇑
Hanaa A. El-Boraey , Ohyla A. EL-Gammal
Department of Chemistry, Faculty of Science, El-Menoufia University, Shebin El-Kom, Egypt
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
ꢀ
ꢀ
ꢀ
Novel metal complexes of (N4)
macrocyclic ligand have been
synthesized and characterized.
Analytical, spectral and thermal data
confirm the structure of the
compounds.
In vitro antitumor activity shows that
the obtained compounds are potent
anticancer agents.
O
reflux
8hr
O
O
O
O
NH
C
H
HN
C
5C2O
HN
NH
C
C
C
C
+
2
H
H
C2 5O
+
O
H5
OC2
NH2
NH
O
HN
H2N
O
A
L
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 August 2014
Received in revised form 29 October 2014
Accepted 5 November 2014
Available online 26 November 2014
Novel tetraamidemacrocyclic 15-membered ligand [L] i.e. naphthyl-dibenzo[1,5,9,12]tetraazacyclopen-
tadecine-6,10,11,15-tetraoneand its transition metal complexes with Fe(II), Co(II), Ni(II), Cu(II), Ru(III)
and Pd(II) have been synthesized and characterized by elemental analysis, spectral, thermal as well as
magnetic and molar conductivity measurements. On the basis of analytical, spectral (IR, MS, UV–Vis,
1H NMR and EPR) and thermal studies distorted octahedral or square planar geometry has been proposed
for the complexes. The antitumor activity of the synthesized ligand and some complexes against human
breast cancer cell lines (MCF-7) and human hepatocarcinoma cell lines (HepG2) has been studied. The
Keywords:
Tetraazamacrocyclic
Macrocyclic metal complexes
Spectral studies
Antitumor activity
IC50
complexes (IC50 = 2.27–2.7, 8.33–31.1
the former cell lines comparable with their ligand (IC50 = 13, 26
l
g/mL, respectively) showed potent antitumor activity, towards
g/mL, respectively). The results show
l
that the activity of the ligand towards breast cancer cell line becomes more pronounced and significant
when coordinated to the metal ion.
Ó 2014 Elsevier B.V. All rights reserved.
Introduction
of crystal-field effects play also an important role [15,16]. The inter-
est in macrocyclic complexes especially those with polydentate
The design and synthesis of macrocycles and their metal com-
plexes represent an active area of research due to their widespread
applications in biology, supra-molecular chemistry, new materials
[1–14], etc. These rings can accommodate a variety of metal ions
depending on the cavity size, metal ion, and ring structure, for
transition metal ions, features such as the nature and magnitude
ligands stems from the chemical properties that the macrocyclic
ligands bring to the complexes as well as the variety of geometrical
forms available and the possible encapsulation of the metal ion
[17,18]. Complexes with polyazamacrocyclic ligands have remained
a focus of scientific attention and have potential applications in dif-
ferent areas [7,10,19,20]. One class of these macrocycles is those
incorporating amide groups. The amide groups can bind with differ-
ent metal ions via nitrogen and/or oxygen atoms [1,2,21–24]. These
compounds not only can act as hydrogen-bonding host molecules
⇑
Corresponding author. Tel.: +20 111 7532777; fax: +20 48 2235689.
E-mail address: helboraey@yahoomail.com (H.A. El-Boraey).
http://dx.doi.org/10.1016/j.saa.2014.11.015
1386-1425/Ó 2014 Elsevier B.V. All rights reserved.

554
H.A. El-Boraey, O.A. EL-Gammal / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 138 (2015) 553–562
Scheme 1. Synthetic route for the preparation of macrocyclic ligand (L).
but also can form macrocyclic rotors [25]. Also, Macrocyclic amides
are ubiquitous in biochemistry, because they provide the linkages
that held together two of the most important types of biopolymers,
nucleic acids and proteins [22,26]. Moreover, macrocyclic amides
have potential applications in electrophosphorescence devices
(EL) and homogenous catalysis [27]. Very recently we have synthe-
sized and characterized a new macrocyclic ligand and its transition
metal complexes [8]. This ligand represents a 15-membered (N5)
ligand i.e. 1,5,8,12- tetetraaza -3,4: 9,10-dibenzo-6- ethyl-7-
methyl-1,12-(2,6-pyrido)cyclopentadecan-5,7 diene-2,11-dione.
The ligand and its transition metal complexes show an important
biological activity as anticancer agents. As a continuation to our
work we report herein the synthesis, spectroscopic characterization
and anticancer activity of Fe(II), Co(II), Ni(II), Cu(II), Ru(III), Pd(II)
complexes with new tetraamidemacrocyclic 15-membered (N4)
ligand i.e. naphthyldibenzo[1,5,9,12]tetraazacyclopentadecine-
6,10,11,15-tetraone. These complexes have been characterized with
the help of various physicochemical techniques. Further the antitu-
mor activity against human breast cancer cell line MCF-7, and
human hepatocarcinoma cell HepG2 in vitro were detected.
for 8 h. The brown solid precipitate formed was collected by filtra-
tion and washed several times with cold ethanol and dried under
vacuum.
Synthesis of the metal complexes
All the metal complexes (Scheme 2) were prepared as follows:
0.5 g of the ligand was dissolved in 50 mL acetone. To this solution
20 mL ethanolic solution of different metal salt was added drop-
wise in molar ratio 1:1(metal:ligand). The reaction mixture was
stirred under reflux whereupon the complexes precipitated. The
precipitated solid complex was separated from the solution by fil-
tration, purified by washing several times with ethanol and then
dried under vacuum at room temperature.
Physical measurements
The elemental analyses (C,H,N) were performed at Microanalyt-
ical Center, Cairo University Giza, Egypt using CHNS-932 (LECO)
Vario Elemental Analyzer.
Metals and halide analyses were estimated using standard meth-
ods [29,30]. Electrospray mass spectra (ESI) for the complexes were
performed at the National Research Center, Egypt by the Thermo
Electron Corporation. The electron impact mass spectrum (EI) for
the ligand was run on Shimadzu-QP 2010 plus Mass Spectrometer,
Microanalytical Laboratory, Faculty of Science, Cairo University,
Egypt. The Fourier Transform Infrared (FTIR) measurements were
performed (4000–400 cmꢂ1) in KBr discs using Nenexeus-Nicoli-
dite-640-MSA FT-IR, Thermo-Electronics Co. The UV–visible
absorption spectra were measured in DMF using 4802 UV/vis dou-
ble 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 frequency was 100 kHz and the micro-
wave power was around 10 mW. Molar conductivities were mea-
sured in DMF solution of the complexes (10ꢂ3 M) using a CON
6000 conductivity meter, Cyberscan, Eutech Instruments. Magnetic
susceptibilities of the complexes were measured by the modified
Gouy method at room temperature using Magnetic Susceptibility
Experimental
Materials and methods
All chemicals used in the synthesis were of reagent grade and
used as submitted from Aldrich without further purification. Isatoic
anhydride, 1,8-diaminonaphthalene and diethyloxalate were pur-
chased from Sigma Aldrich Chemical Company and used as received.
Synthesis of the starting material
The starting material (A) has been synthesized as previously
reported for similar compounds [1,8,28]. A mixture of 1H-benzo[d]
[1,3]oxazine-2,4-dione(1 g, 6 mmol) with 1,8-diaminonaphalene
(0.48 g, 3 mmol) (2:1 M ratio) in hot distilled water was stirred
at 60 °C for about 1 h. Heating on water bath was continued till
the effervescence of CO2 gas ceased. The reaction mixture was
allowed to stand overnight. The brown solid precipitate was col-
lected by filtration, washed with hot water and dried in vacuum.
Recrystallization from ethanol gave brown crystals of 2-amino-N-
[2-(2-amino-benzoylamino)-naphthyl]-benzamide (A) (Scheme 1).
Color: brown, yield: 1.00 g (100%), m.p:120 °C. Anal. Calc.% for
Johnson Matthey Balance. The effective magnetic moments were
½
calculated using the relation
l
eff = 2.828(
v
mT) B.M., where vm is
the molar magnetic susceptibility corrected for diamagnetism of
all atoms in the compounds using Selwood and Pascal’s constants.
Thermal analysis (TG/DTG) was obtained out by using a Shimadzu
DTA/TG-50 Thermal analyzer with a heating rate of 10 °C/min in
nitrogen atmosphere with a following rate 20 mL/min in the tem-
perature range 30–800 °C using platinum crucibles.
C
24H20N4O2ꢁ1½H2O (MW: 423): C 68.08, H 5.4,N 13.24. Found:%
C 67.83, H 5.33, N 12.51. Selected IR data (KBr, cmꢂ1): 3466
(OH), 3371 (NH2), 1630 (C@O)), 1503 (CAN) + d(NAH)],
1240 (CAN), 752
(C@O).1H NMR (DMSO-d6d, ppm) d = 6.603–
m
m
m
m[t
m
u
8.64(Ar, H), d = 6.577–6.579 (Ar–NH2), d = 12.065 (NH- amide).
Mass spectrum (EI, m/z):Calc. M = 396, Found: 395(MAH)+.
Biological tests
Synthesis of ligand (L)
The cytotoxicity of the compounds was tested at the National
Cancer Institute, Cairo University Egypt by SRB assay using the
method of Skehan et al. [31]. Cells were plated in 96-multiwell
0.5 g (1 mmol) of compound (A) in acetone was refluxed with
0.22 g (0.2 ml) of diethyloxalate in ethanol in molar ratio (1:1)

H.A. El-Boraey, O.A. EL-Gammal / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 138 (2015) 553–562
555
48 h, cells were fixed, washed and stained with Sulfo-Rhoda-
mine-B stain. Excess stain was washed with acetic acid and
attached stain was recovered with Tris EDTA buffer. Color intensity
was measured in an ELISA reader. The relation between surviving
fraction and drug concentration is plotted to get the survival curve
of each tumor cell line after the specified compound.
O
O
C
H
HN
C
C
NH
X
M
Y
.n
N
N
H
Results and discussion
C
O
O
The reaction of (A) with diethyloxalate gives the expected
tetraamidemacrocyclic compound, L. This ligand represents a
15-membered (N4) macrocyclic molecule (Scheme 1). The macro-
cyclic ligand and its metal complexes are air stable at room tem-
perature, non-hygroscopic. The elemental, spectral, magnetic and
thermal analysis data (Tables 1–5) are consistent with their pro-
posed molecular formulae. The elemental analyses show that all
complexes are formed in 1 M:1 L molar ratio. It should be noted
that many attempts have failed to crystallize suitable single crys-
tals for X-ray analysis for any of complexes, due to their partial sol-
ubility in common organic or mixed solvents. However, they are
soluble in polar solvents such as DMF/DMSO. The conductance
measurements, recorded for 10ꢂ3 M solution of the metal com-
plexes in DMF, are listed in Table 1. All complexes are non-
conducting and the measured molar conductance ranged from 27
No
M
X
Y
n
(1)
(2)
(3)
Fe(III)
Co(II) OAc
Ni(II)
Ni(II)
Ni(II)
Cl
OH
H2O
2H2O
EtOH
OAc
Cl
OH
(4)
(5)
NO3
OAc
NO3
OAc
½EtOH
3H2O
(7)
(8)
Cu(II)
Cu(II)
Br
NO3
OH
OH
EtOH
EtOH
to 3
X
ꢂ1 cm2 molꢂ1 indicating their neutrality [32,33].
O
NH
NH
O
FT-IR
C
C
H
X
Y
.n
M
The preliminary identification regarding formation of the com-
plexes, were obtained from IR spectral findings (Table 2). In general,
the IR spectrum of the free ligand shows strong bands at 3376, 1625,
1514, 1296, and 754 cmꢂ1, which are attributedto the stretching fre-
N
O
N
H
C
C
O
quencies of NH, amide-I
t
(C@O), amide-II[
t(CAN) + d(NAH)],
amide-III (CAN) and amide-IV
t
u
(C@O) bands, respectively [1,34–
36], which support to macrocyclic nature of the ligand. The IR
spectrum also shows two peaks at 2930, 2869 cmꢂ1, attributed to
Intra- and/or intermolecular hydrogen bonds. On complexation,
No
M
Cu(II)
Cu(II)
X
Y
n
(6)
Cl
Cl
H2O.½EtOH
2H2O
(9)
OAc
ClO4
Cl
OAc
OH
Cl
the lowering of amide-I
m(C@O) frequency value in complexes
(10) Cu(II)
(12) Pd(II)
3H2O
1½ H2O
(1–5,7,8) (1623–1603 cmꢂ1) indicating the coordination of the four
amide nitrogen. However, the stretching frequency of the amide-I
m(C@O) group in the complexes (6,9,10–12) was observed in two
separate regions. The former region was observed at (1616–
1606 cmꢂ1) which is lower than the amide-I of the free ligand
(1625 cmꢂ1). The latter region was observed at 1652–1642 cmꢂ1
which is higher than the stretching frequency of the free ligand.
The latter region may be due to the presence of uncoordinated
amide-I
modes is the appearance of new band at 470–408 cmꢂ1 due to
(MAN) stretching vibrations [2,11]. The IR spectra of the com-
m(C@O) group. A further evidence for these coordination
O
C
NH
C
NH
O
C
Cl
Cl
Cl
t
.EtOH
Ru
plexes also show that the amide II and amide III occur at 1514,
1296 cmꢂ1 in the free ligand, are slightly shifted to lower or higher
frequency (Table 2) supporting coordination through the amide
nitrogen atoms [1]. Aquo and hydroxo complexes exhibit a strong
N
N
OH2
H
H
C
O
O
as well as broad band at 3460–3246 cmꢂ1 due to
t(OH) vibration.
This observation has been further confirmed by the appearance of
(11)
new medium intensity band in the 501–571 cmꢂ1 region, assignable
Scheme 2. Suggested structure of the compounds (1–12).
to
bands due to coordinated anions. The nitrato complexes (4,8) show
the bands at 1383 cmꢂ1 5), 1295–1296 cmꢂ1
1), 1048–
1051 cmꢂ1 2) and 823–832 cmꢂ1
3). The value of 1), i.e.,
t(MAO) [37]. Further, the IR spectra of the complexes show the
(m
(m
plate (104 cells/well) for 24 h before treatment with the com-
pounds to allow attachment of cell to the wall of the plate. Differ-
ent concentrations of the compound under test (0, 2.5, 5, 10, 20 lg/
mL) added to the cell monolayer triplicate wells were prepared for
each individual dose. Monolayer cells were incubated with the
compounds for 48 h at 37 °C and in atmosphere of 5% CO2. After
(
m
(
m
D
(
m5 m
ꢂ
88–87 cmꢂ1 suggests the monodentate coordination of NOꢂ3 ions
[38]. The presence of coordinated nitrate is also supported by con-
ductance measurements (Table 1). The IR spectra of acetato com-
plexes (2,5,9) display two bandsꢂat 1585 andꢂ1367–1388 cmꢂ1
.
The energy separation between ma) sym(COO and ms)ym(COO is found to

556
H.A. El-Boraey, O.A. EL-Gammal / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 138 (2015) 553–562
Table 1
Analytical and physical data for the macrocyclic ligand and its complexes.
a
No
Compound
Color
Yield (%)
M. Wt
D.T/°C
Analysis: calc. (found) (%)
(Km)
C
H
N
M
X
L = C26H18N4O4.H2O
[FeLCl(OH)]ꢁH2O
Brown
Black
Brown
Black
Brown
Brown
Black
Dark-brown
Black
35
60
108
83
40
94
80
100
88
100
90
468
200
150
147
225
190
190
220
250
135
230
-
66.66 (66.95)
54.14 (54.21)
54.31 (53.35)
55.33 (56.35)
49.41 (50.1)
52.88 (52.55)
51.75 (50.91)
51.18 (51.66)
52.62 (52.92)
53.93 (54.08)
45.61 (45.3)
46.56 (46.95)
47.67 (48.54)
4.27 (3.95)
3.64 (3.45)
4. 22 (4.3)
4.11 (3.97)
3.20 (3.09)
4.41 (4.3)
3.67 (3.11)
3.80 (2.82)
3.91 (3.47)
4.19 (3.79)
3.07 (3.37)
3.6 (3.31)
3.2 (3.5)
11.96 (12.49)
9.72 (9.98)
8.44 (8.9)
9.22 (9.96)
12.81 (12.34)
8.23 (8.71)
8.95 (8.92)
8. 53 (9.25)
10.96 (11.53)
8.38 (9. 3)
–
–
–
26
3
27
20
7
1
2
3
4
5
6
7
8
577.3
662.9
607.2
655.7
680.7
626
656.5
638.5
667.5
684
9.67 (9.3)
8.88 (9.42)
9.67 (9.7)
8.95 (9.39)
8.62 (8.81)
10.14 (9.52)
9.67 (10.58)
9.95 (10.16)
9.51 (9.50)
9.28 (8.89)
13.9 (13.46)
16.49 (16.73)
6.15 (5.9)
–
5.85 (5.9)
–
[CoL(OAc)2]ꢁ2H2O
[NiLCl(OH)]ꢁEtOH
[NiL(NO3)2]ꢁ½EtOH
[NiL(OAc)2]ꢁ3H2O
[CuLCl2]ꢁH2Oꢁ½EtOH
[CuLBr(OH)]ꢁEtOH
[CuL(NO3)(OH)]ꢁEtOH
[CuL(OAc)2]ꢁ2H2O
[CuLClO4(OH)]ꢁ3H2O
[RuLCl3(H2O)]ꢁEtOH
[PdLCl2]ꢁ1½H2O
–
11.34 (11.53)
12.18 (12.33)
–
7
9
26
14
22
15
14
9
Dark- brown
Dark-brown
Black
–
10
11
12
8.18 (7.54)
7.76 (7.51)
8.56 (8.65)
14.55 (13.93)
14.76 (14.2)
10.8 (10.8)
100
98
721.5
654
260
230
Gray
a
X
ꢂ1 cm2 molꢂ1 DMF solutions (10ꢂ3 M), X: Halogen.
Table 2
a
Important IR spectral bands (cmꢂ1
) of the macrocyclic ligand and its complexes.
No
Compound
m
OH/NH
Amide bands
I
m
(M-O)
m
(M-N)
(NOꢂ3 , OAcꢂ, ClOꢂ4
)
II
III
(IV)
L = C26H18N4O4ꢁH2O
[FeLCl(OH)]ꢁH2O
3376(b)
3417(b)
3383(s)
3318(b)
3422(b)
3393(b)
3431(s)
3422(vb)
3426(b)
3443(b)
3421(vb)
3426(b)
3426(m)
1625(b)
1623(b)
1618(m)
1608(w)
1616(b)
1618(b)
1651(m), 1609(m)
1608(w)
1614(b)
1514(m)
1512(m)
1510(m)
1524(s)
1519(s)
1506(s)
1520(s)
1515(s)
1516(m)
1511(s)
1515(s)
1523(m)
1524(vs)
1296(m)
1263(vb)
1316(w)
1296(m)
1295(w)
1298(m)
1296(m)
1296(m)
1296(w)
1296(m)
1298(m)
1293(b)
1297(m)
754(s)
756(s)
756(s)
754(s)
756(s)
754(s)
756(s)
754(s)
754(m)
755(s)
755(s)
754(s)
756(vs)
–
–
–
–
1
2
3
4
5
6
7
8
476(s)
409(s)
[CoL(OAc)2]ꢁ2H2O
[NiLCl(OH)]ꢁEtOH
[NiL(NO3)2]ꢁ½EtOH
[NiL(OAc)2]ꢁ3H2O
[CuLCl2]ꢁH2Oꢁ½EtOH
[CuLBr(OH)]ꢁEtOH
[CuL(NO3)(OH)]ꢁEtOH
[CuL(OAc)2]ꢁ2H2O
[CuLClO4ꢁ(OH)]ꢁ3H2O
[RuLCl3(H2O)]ꢁEtOH
[PdLCl2]ꢁ1½H2O
502(br)
519(w)
525(w)
519(w)
501(s)
522(w)
543(w)
505(m)
503(s)
421(m)
447(m)
430(w)
441(w)
409(m)
451(w)
437(m)
436(m)
431(w)
470(m)
448(w)
1585(m), 1388(w), 824(m)
–
1383(s), 1295(w), 823(m)
1585(m), 1382(w), 823(m)
–
–
1383(s), 1296(w), 832(m)
1584(m), 1367(s), 823(m)
1107(w), 627(m)
–
–
9
1652(m), 1616(w)
1646(vb), 1610(vb)
1606(vb)
10
11
12
571(w)
593(w)
1642(m), 1604(s)
a
vb, very broad; s, strong; m, medium; w, weak; b, broad; m, stretching.
bidentate one with the electron pair of two amide nitrogen atoms
only.
Table 3
Electronic spectral data (nm) and magnetic moment (B.M.) of the metal complexes.
No
Compound
kmax (nm)
leff (B.M.)
Mass and 1H NMR spectral studies
1
2
3
4
5
6
7
8
[FeLCl(OH)]ꢁH2O
530a, 350c, 260d
4.76
4.9
2.13
2.8
2.8
2.005
2.1
2.08
2.06
2.01
1.88
dia
[CoL(OAc)2]ꢁ2H2O
[NiLCl(OH)]ꢁEtOH
[NiL(NO3)2]ꢁ½EtOH
[NiL(OAc)2]ꢁH2O
520a, 350c, 260d
The electron impact (EI) mass spectrum of the ligand (Fig. 1)
gives a molecular ion peak at m/z = 450 amu (Calc. m/z = 450).
The spectrum also shows important fragment ions at: m/z 74 for
[C6H5 A3H]+, 103 for [C7H5O + 2H]+, 118 for [C7H5NOAH]+, 156
for [C10H8N2]+, 277 for [C17H17N3O + 2H]+, 395 for [C24H18N4O2
AH]+. The 1H NMR spectrum of the ligand (Fig. 1S) was recorded
in DMSO-d6 solution. The spectrum displayed signal at d (6.59–
8.61 ppm) assigned to aromatic ring protons and signal at ca. d
(12.50 ppm) assigned to amide protons. Also 1H NMR spectrum
of [PdLCl2]ꢁ1½H2O complex (12) (Fig. 2S) was recorded in DMSO-
d6. The spectrum showed similar signals as for the ligand, but the
position of the amide proton signal in the complex is downfield
(11.88 ppm) in comparison with the free ligand (12.50 ppm), indi-
cating the involvement of the amide group in chelation [8]. Thus,
the 1H NMR results support the assigned geometry.
520a, 340c, 260d
530a, 340c, 270d
540a, 340c, 260d
[CuLCl2]ꢁH2Oꢁ½EtOH
[CuLBr(OH)]ꢁEtOH
[CuL(NO3)(OH)].EtOH
[CuL(OAc)2]ꢁ2H2O
[CuLClO4(OH)]ꢁ3H2O
[RuLCl3(H2O)]ꢁEtOH
[PdLCl2]ꢁ1½H2O
700a, 530a, 320c, 250d
520a, 370c, 250d
530a, 375c, 250d
9
700a, 500a, 360c, 266d
700a, 530a, 490b, 320c, 260d
550a, 333c, 278d
10
11
12
600a, 450b, 345c, 266d
a
b
c
d–d transition.
LMCT.
n ? p*
.
d
p
? .
p*
be >144 cmꢂ1, and this indicates the monodentate nature of the
acetate ion [18,37]. In complex (10), the peak around 1107 cmꢂ1 is
splited, which clearly explains the presence of coordinated perchlo-
rate ion [39]. Therefore, and according to the IR spectra, it is concluded
that the macrocyclic ligand behaves as a neutral quatridentate one,
with the lone electron pair of four amide nitrogen atoms in complexes
(1–5,7,8),while in complexes (6,9,10–12) the ligand behaves as a
Mass spectra of complexes
Mass spectra provide additional structural information about
the analyzed species. The ESI-MS of complexes (6,12) (Fig. 2)
show molecular ion peak at m/z = 626, 656 amu corresponding
to [CuLCl2]H2Oꢁ½EtOH (6), [PdLCl21½H2O + 2H] (12) (calculated

H.A. El-Boraey, O.A. EL-Gammal / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 138 (2015) 553–562
557
Table 4
EPR spectral data of Cu(II) complexes.
No Complex
g
g\
gav
G
A
Eꢂ4 cmꢂ1 A\ Eꢂ4 cmꢂ1 a2
b2
c2
K
k
K\
K
f (cm)
k
k
6
7
8
9
[CuLCl2]H2Oꢁ½EtOH
[CuLBr(OH)]ꢁEtOH
2.195
2.195
2.0335 2.0873 5.8
2.0425 2.0933 4.58
163
–
–
161
171
47.46
–
–
43
37.86
0.6986
–
–
0.9218 0.8345 128.5
0.644
–
–
0.583
–
–
0.36516
–
–
–
–
–
–
–
–
[CuL(NO3)(OH)]ꢁEtOH 2.167
2.039
2.0816 4.28
[CuL(OAc)2]ꢁ2H2O
2.110
2.0335 2.0758 4.8
0.67166 0.8635 0.9138 127.65 0.5800 0.6138 0.602
0.7278 0.977 0.8453 116.94 0.7114 0.6144 0.4203
10
[CuLClO4(OH)]ꢁ3H2O
2.2237 2.0335 2.095
6.6
2K2? þK2k
2g?þg
ga
¼
k ; K2
¼
.
v
3
3
Table 5
Thermal data of the complexes.
No
Compound
Temp/oC
DTG
Wt. loss calc. (found)%
Reaction
Leaving species
TG
L = C26H18N4O4ꢁH2O
[FeLCl(OH)]ꢁH2O
52
30–100
200–650
30–77
150–477
at 477
30–147
147–190
at 400
30–92
200–559
at 559
30–85
190–556
at 556
30–148
190–445
at 445
30–78
220–550
at 550
30–132
250–577
at 577
30–90
135–660
at 660
4.00(4.15)
96.00(95.85)
3.12(3.06)
87.22 (87.35)
9.69(9.65)c
5.43(5.35)
82.93(82.17)
12.5 (12.44)
7.57(7.66)
(i)a
AH2O
Decomp.
AH2O
Decomp.
„½Fe2O3
A2H2O
Decomp.
„Co2O3
AEtOH
Decomp.
„Ni
A½EtOH
Decomp.
„Ni
A3H2O
Decomp.
„NiO
A(H2O + ½EtOH)
Decomp.
„Cu
AEtOH
Decomp.
„Cu
AEtOH
Decomp.
„Cu
202,335,586
42
162,354,386
(ii)d
(i)a
1
2
3
4
5
6
7
8
9
(ii)d
[CoL(OAc)2]ꢁ2H2O
[NiLCl(OH)]ꢁEtOH
[NiL(NO3)2]ꢁ½EtOH
[NiL(OAc)2].3H2O
[CuLCl2]ꢁH2Oꢁ½EtOH
[CuLBr(OH)]ꢁEtOH
[CuL(NO3)(OH)]ꢁEtOH
[CuL(OAc)2]ꢁ2H2O
49
(i)a
156,268,299
(ii)d
53
(i)b
306,374,529
82.74(82.74)
(ii)d
9.66(9.6)c
61
410,562
3.51(3.2)
(i)b
87.54 (87.67)
8.95 (7.2)c
7.9(7.43)
81.38(81.13)
10.97(11.29)c
6.55(6.24)
83.9(84.06)
10.22(10.5)c
7.01(6.88)
(ii)d
57
(i)a
204,339,380
(ii)d
46
285,490
(i)a+b
(ii)d
56
(i)b
274,405,560
83.32(83.52)
(ii)d
9.65(9.6)c
52
7.4(7.41)
(i)b
132,195,319,398
82.38(83.88)
(ii)d
9.5(8.8)c
38,57
294,329
30–85
5.39(5.18)
(i)a
A2H2O
230–295
295–400
at 400
30–125
260–435
at 435
30–102
230–353
353–483
at 483
17.67(17.76)
65.04(65.35)
11.9(12.71)c
8.86(8.32)
73.82 (74.32)
17.32(17.36)c
4.12(4.7)
19.35(19.25)
57.13(55.85)
19.4 (20.2)c
(ii)d
(ii)d
A2(OAc)
Completion of decomp.
„CuO
A(EtOH + H2O)
Decomp.
„½Ru2O3
A1½H2O
A(Cl2 +(2CO))
Completion of decomp.
„PdO
11
12
[RuLCl3(H2O)]ꢁEtOH
[PdLCl2]ꢁ1½H2O
52
345,435
(i)a+b
(ii)d
48
(i)a
271, 362,464
(ii)d
(ii)d
a
b
c
dehydration.
desolvation.
final product percent.
decomposition.
d
Fig. 1. The EI mass spectrum of ligand, L.

558
H.A. El-Boraey, O.A. EL-Gammal / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 138 (2015) 553–562
Fig. 2. The ESI mass spectrum of Pd(II)complex (12).
2
m/z = 625.5, 654). The mass spectra of the complexes also
show important fragment ions at m/z 63[Cu], 92[Cu(CN)]+,
167[Cu(C7H4N)]+, 194[Cu(C8H4ONH)]+, 285[Cu(C14H8ON2 + H)]+,
band indicates that the three transitions 2B1g ? 2A1g
(t1); B1g ?
2B2g 2), and 2B1g ? 2Eg(
(t
t
3), which are of similar energy, give rise
to only one broad absorption band. The broadness of the band
may be due to dynamic Jahn–Teller distortion [45,47–49]. The
electronic spectra of the copper(II) complexes (6,9,10) show inten-
sive bands at 700 and 530–500 nm, could be assigned to
319[Cu(C14H8O3N2 + H)]+,
475[Cu(C24H18O3N4 + H)]+,
490[Cu
(C24H18O4N4)]+, 532[Cu(C26H20O5N4)]+, 626[CuLCl2]H2O + ½EtOH
for complex (6), m/z at 78[C6H4 + H]+, 200[Pd(C6H4O)]+,
304[Pd(C12H10N2O) + 2H]+, 519[Pd(C24H18N4O3) + H]+,656[PdLCl2]
1½H2O for complex (12), respectively.
2B1g ? 2B2g, and 2 1g ? 2Eg transitions, respectively. This indicates
B
the possibility of square planar geometry of copper(II) complexes
[50,51]. The geometry of the Cu(II) complexes is further supported
by the magnetic moment values (2.05–2.1 B.M., Table 3). These
values correspond to one unpaired electron and indicate that these
complexes are monomeric in nature and metal–metal interaction
is absent [44].
Electronic spectra and magnetic measurements
The electronic spectra of the complexes were recorded in DMF
solution. The absorption bands displayed by the complexes as well
as the room temperature effective magnetic moment values
(leff B.M.) are listed in Table 3. The complexes exhibit the high
Ruthenium(III) complex
energy bands in the range 450–490 nm which are attributed to
the LMCT.
The electronic absorption spectrum of Ru(III) complex (11)
exhibits band at 550 nm. This band is assigned to 2T2g ? 4T1g tran-
sition [52–54]. The position of the absorption band as well as the
magnetic susceptibility measurements (1.88 B.M.) indicate the
Iron(II) and cobalt(II) complexes
presence of one unpaired electron and confirm
octahedral configuration [52].
a low-spin
The electronic absorption spectrum of Fe(II) complex (1) exhib-
its a broad peak at 530 nm, that is assigned to 5T2g ? 5Eg transition,
suggesting distorted octahedral geometry around Fe(II) ion
[40–42]. This finding was further emphasized by the measured
magnetic moment (4.76 B.M.), indicating octahedral geometry
[40,43]. The electronic absorption spectrum of Co(II) complex (2)
exhibits a broad band at 520 nm corresponding to 4T1g(F) ? 4A2g(F)
transition, which is compatible well with octahedral geometry
[44,45]. The magnetic moment value of the Co(II) complex (2)
measured at room temperature is found to be 4.99 B.M., which
lie in the range (4.80–5.20 B.M.), showing that it has three
unpaired electrons and high-spin octahedral configuration [7,44].
Palladium(II) complex
The electronic spectrum of Pd(II) complex (12) displays two
d–d- bands at 600 and 440 nm which may be assigned to Alg
1
?
lA2g and 1A1g ? 1Blg transitions, respectively. The coordination of
the chloride to the square-planar bivalent palladium center is
confirmed by its non-electrolytic nature in DMF solution. The
electronic spectrum indicates square-planar geometry around the
palladium(II) ion [34,50,55] which is further confirmed by its
diamagnetic nature.
Nickel(II) complexes
EPR spectroscopic studies
The electronic absorption spectra of Ni(II) complexes (3–5)
display band in the range 540–520 nm which is assigned to
3A2g(F) ? 3T1g(P) transition indicating octahedral geometry
[45,46]. The magnetic moment of the nickel complexes at room
temperature lie in the range 2.1–2.8 B.M. These values agree with
the presence of Ni(II) ion in octahedral geometry [45].
The solid state EPR spectra of the copper(II) complexes (6–10)
(Figs. 3a and 3b) were recorded at room temperature on the
X-band frequency 9.719 GHz. The EPR parameters are listed in
Table 4. All complexes give axial spectra, analysis of spectra gives
g = 2.16–2.23 and g\ = 2.02–2.04. The trend g > g\ > 2.0023 sug-
k
k
gests dx2
ground state for the Cu(II) ion [8,44,45]. Complexes
ꢂy2
Copper(II) complexes
(6,9,10) show hyperfine spectral lines at the lower field, the g ,
k
g\, A , A\ values have been estimated. The g values of all
k
k
The electronic spectra of the Cu(II) complexes (7,8) exhibit a
complexes are found to be less than 2.3 indicating a considerable
strong broad band centered at 530–520 nm. The broadness of the
covalence character in copper-ligand bond [56]. In addition, the

H.A. El-Boraey, O.A. EL-Gammal / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 138 (2015) 553–562
559
where k0 represents the one electron spin–orbit coupling constant
for the free ion and equal to ꢂ828 cmꢂ1
,
D2 ¼ 2B1g ! B2g
;
2
D3
¼
2B1g
!
2Eg. For pure
r
-bonding, K ꢃ K\ ꢃ 0.77, for in-plane
k
p
-bonding K < K\ and for out-of-plane p-bonding K > K\. For com-
k
k
plex (9) K < K\ indicating in-plane p-bonding, the observed K and
k
k
K\ values for the complexes (6,10) are in agreement with the relation
K > K\ which is in agreement with the presence of out of plane
k
p
-bonding [61,62]. The low values of K (0.365–0.602) indicate the
covalent nature of the complexes. Also the values of bonding param-
eters -bonding and in-plane bonding.
2, b2, 2 indicate in-plane
a
c
p
r
Thermal studies
In order to give more insight into the structure and thermal sta-
bilities of the ligand and its complexes, the thermal behavior has
been carried out using thermogravimetry (TG/DTG) technique.
The thermogravimetric studies have been made in the temperature
range RT–800 °C. The nature of proposed chemical change with
temperature and the percent of metal oxide obtained are given
in Table 5. The results obtained from thermogravimetric analysis
[63–67] were in agreement with the suggested theoretical formu-
lae from the elemental analyses. The thermal behavior of perchlo-
rate complex (10) has not been investigated, due to its explosive
nature.
Fig. 3a. EPR spectra of complexes (6–8) as polycrystalline sample at RT.
Ligand
The TGA curve of the ligand shows weight loss of 4.13% (Calc.
4.00%) in the temperature range of 30–100 °C. The DTG peak
recorded at 52 °C reflects the loss of one water molecule per ligand
molecule. Also the TG curve shows one decomposition step in the
temperature range 200–650 °C.
Complexes
Iron(II) and cobalt(II) complexes
The TG curves of Fe(II) and Co(II) complexes (1,2) (Fig. 4) show
weight loss in the temperature range 30–150 °C (Calc./Found%
3.12/3.06; 5.43/5.35) associated with one DTG peak at 42,49 °C
that was assigned to loss of one or two molecules of water of
crystallization for complexes (1,2), respectively. The TG/DTG
curves exhibit gradual decomposition at a temperature range
147–150 °C, leaving Fe2O3, Co2O3 as final residue.
Fig. 3b. EPR spectra of complexes (9,10) as polycrystalline sample at RT.
exchange coupling interaction between two copper centers
is explained by Hathaway expression [57], G = g ꢂ 2.0023/
k
g\ ꢂ 2.0023. The values of G (6.6–4.28) in these complexes are
>4.0 and therefore, the local tetragonal axes are aligned parallel
or only slightly misaligned and there is no exchange interaction
between copper centers in the polycrystalline compound.
Nickel (II) complexes
For Ni(II) complexes (3–5), the TG curves show weight loss in
the temperature range 30–148 °C (Calc./Found% 7.57/7.66; 3.51/
3.2; 7.9/7.43) associated with one DTG peak at 53–61 °C. That
was assigned to loss of solvent of crystallization in one step
(Table 5). On further heating the thermograms register a plateau
region, corresponding to Ni for complexes (3,4), NiO for complex
(5), respectively.
The empirical factor f = g /A , is an index of tetragonal distortion
k
k
and its value depends on the nature of the coordinated atom. The
value of f from 105 to 135 cm indicates square-planar structures
whereas larger values reveal tetragonally distorted complexes [58].
The calculated f values for complexes (6,9,10) (Table 4) fall in the
range 116.9–128.5 cm, indicating square planar structure. The EPR
parameters and the energies of d–d transitions were used to calculate
the bonding parameters
sured of the covalence of the in-plane
plane bonds, respectively [59]. The in-plane
2, was calculated using the following equations [56,60]:
a
2, b2 and
c
2 which may be regarded as mea-
bonds, in-plane and out-of-
bonding parameter
2 = A /
r
Copper(II) complexes
p
r
The TG/DTG curves of Cu(II) complexes (6–9) (Fig. 4) show
weight loss from room temperature up to 132 °C, associated with
one DTG peak, that was attributed to loss of solvent of crystalliza-
tion on one step (Table 5). On further heating the complexes
decomposed at 135–250 °C. The thermogram of complex (9) shows
two steps of decomposition. The first one (230–295 °C) is due to
the loss of 2(OAc) (Calc./Found%; 17.67/17.76), the second one
(295–400 °C) involves the completion of the decomposition pro-
cess. The thermograms register a plateau region, corresponding
to Cu for complexes (6–8), CuO for complex (9), respectively.
a
a
k
0.036 + (g ꢂ 2.0023) + 3/7(g\ ꢂ 2.0023) + 0.04. The observed values
k
of a2 (0.67–0.73) are less than unity, which indicate that the MAL
bonds in complexes are partially ionic and partially covalent in
nature. Significant information about the nature of bonding in the
copper(II) complexes can also be derived from the magnitude of
K = a2b2 and K\ a2b2 whicharetheparallel andperpendicularcom-
=
k
ponents of orbital reduction factor, and were estimated from the
expression, K2k ¼ ðgk ꢂ 2:0023Þ
D
2=8k0; K2 ¼ ðg? ꢂ 2:0023Þ
D3=2k0,
?

560
H.A. El-Boraey, O.A. EL-Gammal / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 138 (2015) 553–562
* weight of sample (mg)
Fig. 4. TG/DTG curves of the complexes (1,6,11,12).
Table 6
Kinetic and thermodynamic data of complexes (6,7,9,11,12).
No
Complex
D.T. (K)
A (Sꢂ1
)
S* (J molꢂ 1Kꢂ1
)
E* (kJ molꢂ1
)
H*
G*
Cs
aR2
6
7
9
11
12
[CuLCl2]ꢁH2Oꢁ½EtOH
[CuLBr(OH)]ꢁEtOH
[CuL(OAc)2]ꢁ2H2O
[RuLCl3(H2O)]ꢁEtOH
[PdLCl2]ꢁ1½H2O
493–823
523–850
503–673
533–708
503–756
8.094E5
5.373E6
1.069E6
2.317E5
4.927E4
ꢂ16.558
ꢂ14.839
ꢂ16.305
ꢂ17.547
ꢂ19.4348
22.820
47.902
44.6
13.853
9.178
17.844
41.978
39.49
8.608
3.8032
27.74
0.34
0.38
0.37
0.39
0.28
0.98
0.98
0.97
0.97
0.98
52.543
49.501
19.66
16.358
a
R2: Correlation coefficient.
Ruthenium(III) and palladium(II) complexes
Kinetic and thermodynamic parameters for complexes (6,7,9,11,12)
The kinetic and thermodynamic parameters of the decomposi-
tion stages of the desolvated complexes (6,7,9,11,12) were deter-
mined from TGA thermogram using the Coats–Redfern equation
[68]. The Horowitz and Metzger [69] equation Cs = (n)1/1ꢂn was
The TG curves of Ru(III) and Pd(II) complexes (11,12) (Fig. 4)
show weight loss in the temperature range 30–125 °C, (Calc./
Found% 8.86/8.32; 4.12/4.7) associated with one DTG peak at 52,
48 °C, that was assigned to loss of solvent of crystallization
(Table 5), the TG/DTG curve of complex (11) exhibits gradual
decomposition at 260 °C, remaining Ru2O3 as final residue. Com-
plex (12) shows two decomposition stages. The first one, in the
temperature range 230–353 °C is due to loss of chlorine molecule
together with two molecules of carbon monoxide (weight loss;
Calc./Found%; 19.35/19.25). The second one involves the comple-
tion of the decomposition process, remaining PdO as final residue
[1,66].
used for the determination of the value of the reaction order, and
msꢂm
given by Cs ¼
1 , where Cs is the weight fraction of the sub-
m0ꢂm
1
stance present at DTG peak temperature Ts, ms is the remaining
weight at Ts, m0 and m1 are the initial and final weights of the sub-
stance, respectively. The estimated values of Cs for the thermal
decomposition of the desolvated complexes were found in the
range of 0.28–0.39 (Table 6). This indicates that the decomposition
follows first order kinetic [70]. So, the values of the activation

H.A. El-Boraey, O.A. EL-Gammal / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 138 (2015) 553–562
561
Table 7
similar metal complexes as antitumor agents [2,61,73–75]. The
enhanced activity may be attributed to the increase in conjugation
in the ligand moiety on complexation [76]. The type of metal ions
may be another reason for their different anticancer activity. These
compounds seem to be promising as an anticancer agent towards
human breast cancer cell lines because of their high cytotoxic
activity. The active sequence of the ligand and its complexes
follows the trend:
Lethal concentration (IC50) of the ligand and some of its metal complexes on MCF-7
and HepG2.
No
Compound
IC50 (l
g/mL)a
MCF-7
HepG2
L = C26H18N4O4ꢁH2O
[FeLCl(OH)]ꢁH2O
13
2.5
2.7
2.3
2.39
2.27
26
1
3
6
11
12
8.33
(Na)b
24.5
30.5
31.1
[NiLCl(OH)]ꢁEtOH
[CuLCl2]ꢁH2Oꢁ½EtOH
[RuLCl3(H2O)]ꢁEtOH
[PdLCl2]ꢁ1½H2O
PdðIIÞ > CuðIIÞ > RuðIIIÞ > FeðIIÞ > NiðIIÞ > L for MCF-7cells;
FeðIIÞ > CuðIIÞ > L > RuðIIIÞ > PdðIIÞfor HepG2 cells
a
IC50 is the concentration of compound (in
lg/mL) that inhibits a proliferation
rate of the tumor cells by 50% as compared to control untreated cells.
b
Na = has no activity.
Conclusions
energy E⁄, Arrhenius constant A, the activation entropy S⁄, the
activation enthalpy H⁄ and the free energy of activation G⁄ are
calculated by applying Coats–Redfern equation for n = 1:
We have presented the synthesis and characterization of a
novel tetraamide (N4) macrocyclic ligand and some of its transition
metal complexes (1–12). The physicochemical and spectroscopic
data confirmed the composition and the structure of the newly
obtained compounds. Spectral, magnetic, thermal studies lead to
the conclusions that:
ꢀ
ꢁ
ꢀ
ꢁ
ꢂ logð1 ꢂ xÞ
AR
2RT
Eꢄ
log
¼ log
1 ꢂ
ꢂ
ð1Þ
hEꢄ
Eꢄ
2:303RT
T2
where x is the fraction decomposed, R: is the gas constant and h is
the heating rate. Since (1–2RT/E⁄) ’ 1, a plot of the left-hand side of
Eq. (1) against 1/T gives a straight line from its slope and intercept,
E⁄ and A were calculated. The entropy of activation S⁄, enthalpy of
activation H⁄ and the free energy change of activation G⁄ were
calculated using the following equations. S⁄ = R[ ln (Ah/kT)], H⁄ =
E⁄ ꢂ RT and G⁄ = H⁄ ꢂ TS⁄. The calculated kinetic and thermody-
namic values are summarized in Table 6. The high values of E⁄
reveal high stability of the chelates. Since H⁄ > 0 the reactions are
endothermic. The reaction for which G⁄ is positive and S⁄ is negative
considered as non-spontaneous reactions. The entropy of activation
was found to have negative values in the complexes, indicating that
the activated complex has a more ordered structure than the corre-
sponding reactant [71]. The correlation coefficients of the Arrhenius
plots of the thermal decomposition steps were found to lie in the
range 0.98–0.97 showing a good fit with linear function.
1. The ligand behaves as neutral quatridentate or neutral biden-
tate one.
2. The metal complexes exhibited octahedral or square planar
geometry.
3. EPR studies indicate the covalent nature of the complexes.
4. The results of the in vitro anticancer activity against breast can-
cer cell line (MCF7), hepatocarcinoma cancer cells (HepG2)
showed that the ligand as well as its complexes is potent anti-
cancer agents, which have potential to develop as anticancer
drugs. Besides, the cytotoxicity of the complexes is higher than
that of the ligand, which implies an increase in the antitumor
activity with coordination.
Acknowledgements
On the basis of elemental analyses, molar conductance mea-
surements, magnetic susceptibilities, different spectra and thermal
data the suggested structures for the complexes (1–12) are given in
Scheme 2.
The authors would like to thank Dr. Mahmoud Moawad,
Pathology Department, National Cancer Institute, Cairo University,
Cairo, Egypt, for his help with the in vitro anticancer activity.
Biological activity
Appendix A. Supplementary material
The results of the in vitro cytotoxic activity were expressed as
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.saa.2014.11.015.
IC50 (the concentration of the compound in
lg/mL that inhibits
proliferation of the cells by 50% as compared to the untreated con-
trol cells) are given in Table 7. The ligand shows IC50 value of 13,
26 lg/mL towards human breast cancer cell lines (MCF-7) and
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