Template synthesis and physicochemical studies of 14-membered functionalized pendant arm schiff-base macrocyclic complexes of Co(II), Ni(II), Cu(II), and Zn(II): DNA binding studies on a Cu(II) complex

Article abstract of DOI:10.1080/15533174.2011.591345

A series of functional pendant armed 14-membered Schiff-base macrocyclic complexes [ML(NO₃)2], where M = Co(II), Ni(II), Cu(II), and Zn(II), has been synthesized by template condensation of 3,3′-diaminobenzidene and acetylacetone. The complexes have been characterized by elemental analyses, molar conductance measurements, magnetic susceptibility measurements, and electrospray ionization (ESI) mass, 1H-nuclear magnetic resonance (NMR), infrared (IR), electronic, and electron paramagnetic resonance (EPR) spectral studies. The results of elemental analyses, ESI mass spectroscopy, and conductivity measurements confirmed the stoichiometry of the complexes, while the characteristic absorption bands and resonance peaks in IR and NMR spectra confirmed the formation of frameworks of complexes. The molar conductance measurements of the complexes in dimethyl sulfoxide (DMSO) correspond to being non-electrolyte in nature. However, the overall geometry of the complexes has been assigned on the positions of bands in electronic spectra and magnetic moment data. The distortion in Cu(II) complexes has been deduced on the basis of EPR data. Absorption and fluorescence studies on the Cu(II) complex show a significant binding to CT DNA. Copyright Taylor & Francis Group, LLC.

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Template Synthesis and Physicochemical Studies of
14-Membered Functionalized Pendant Arm Schiff-
Base Macrocyclic Complexes of Co(II), Ni(II), Cu(II),
and Zn(II): DNA Binding Studies on a Cu(II) Complex
Mohammad Shakir a , Mohammad Azam a , Sultana Naseem a & Asad U. Khan b
a Department of Chemistry , Aligarh Muslim University , Aligarh, India
b Interdisciplinary Biotechnology Unit , Aligarh Muslim University , Aligarh, India
Published online: 04 Oct 2011.
To cite this article: Mohammad Shakir , Mohammad Azam , Sultana Naseem & Asad U. Khan (2011) Template Synthesis
and Physicochemical Studies of 14-Membered Functionalized Pendant Arm Schiff-Base Macrocyclic Complexes of Co(II),
Ni(II), Cu(II), and Zn(II): DNA Binding Studies on a Cu(II) Complex, Synthesis and Reactivity in Inorganic, Metal-Organic,
and Nano-Metal Chemistry, 41:8, 1056-1062, DOI: 10.1080/15533174.2011.591345
To link to this article: http://dx.doi.org/10.1080/15533174.2011.591345
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Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 41:1056–1062, 2011
Copyright ꢀ Taylor & Francis Group, LLC
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ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2011.591345
Template Synthesis and Physicochemical Studies of
14-Membered Functionalized Pendant Arm Schiff-Base
Macrocyclic Complexes of Co(II), Ni(II), Cu(II), and Zn(II):
DNA Binding Studies on a Cu(II) Complex
Mohammad Shakir,1 Mohammad Azam,1 Sultana Naseem,1 and Asad U. Khan2
1Department of Chemistry, Aligarh Muslim University, Aligarh, India
2Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India
Such compounds usually behave as model ligands for metal en-
zymes, as metal ion-selective ligands, and as metal-chelating
agents for medical purposes and are also significant for the de-
velopment of new methodologies.[3] Schiff bases have been of
great importance in the macrocyclic area of chemistry due to
their selective chelation to certain metal ions depending on the
number, type, and position of their donor atoms, the ionic ra-
dius of the metal center, coordinating properties of counterions,
and rational synthetic routes involving metal ion as template,
which orient the reacting groups of linear substrates in the de-
sired conformation prior to ring closure.[4,5] Much effort has now
been focused on pendant arm macrocyclic complexes due to the
fact that the ligating group attached to the macrocyclic skeleton
can offer additional donor groups to maintain the coordination
sphere of metals in the macrocycles.[6] These molecules play
an important role in the processes of molecular recognition of
organic compounds.[7,8] Complexes of modified aza-crowns are
useful as agents for the selective binding of actinides.[9] Pendant
arms can enhance the selectivity of the ligand for a given ion and
may allow for fine-tuning of the properties of the complexes.[10]
These ligands have the ability to stabilize complexes with un-
usual oxidation states and mixed valence states. Their complexes
exhibit antitumor or anti-HIV activity, act as probes and model
molecules for biochemical processes, and also have the ability to
cleave DNA.[11–13] Further, bimetallic complexes have a possi-
bility of magnetic interactions between two metal ions, leading
to the design of molecular magnetic materials.[14] Functional-
ized pendant arm macrocyclic complexes have been designed
and prepared to mimic the structure and properties of certain
metalloenzymes and metalloproteins.[15] Currently, the chem-
istry of tetraaza macrocyclic ligands bearing a functionalized
pendant arm continues to develop intensively, because of their
applications in various areas such as medical, environmental sci-
ences, biomimetic chemistry, catalysis, and molecular electron-
ics.[10,16–20] Such ligands show enhanced thermodynamic and
kinetic stabilities due to their modified complexation properties
relative to the corresponding simple macrocycle precursor.[21]
A series of functional pendant armed 14-membered Schiff-base
macrocyclic complexes [ML(NO3)2], where M = Co(II), Ni(II),
Cu(II), and Zn(II), has been synthesized by template condensa-
tion of 3,3ꢀ-diaminobenzidene and acetylacetone. The complexes
have been characterized by elemental analyses, molar conduc-
tance measurements, magnetic susceptibility measurements, and
electrospray ionization (ESI) mass, 1H-nuclear magnetic resonance
(NMR), infrared (IR), electronic, and electron paramagnetic res-
onance (EPR) spectral studies. The results of elemental analyses,
ESI mass spectroscopy, and conductivity measurements confirmed
the stoichiometry of the complexes, while the characteristic ab-
sorption bands and resonance peaks in IR and NMR spectra
confirmed the formation of frameworks of complexes. The mo-
lar conductance measurements of the complexes in dimethyl sul-
foxide (DMSO) correspond to being non-electrolyte in nature.
However, the overall geometry of the complexes has been as-
signed on the positions of bands in electronic spectra and mag-
netic moment data. The distortion in Cu(II) complexes has been
deduced on the basis of EPR data. Absorption and fluorescence
studies on the Cu(II) complex show a significant binding to CT
DNA.
Keywords DNA binding studies, functional pendant arm, Schiff
base macrocyclic complexes, spectral studies, template
synthesis
INTRODUCTION
The design and study of well-arranged metal-containing
macrocycles have gained an accelerated research interest in
recent years and have been the subject of numerous reports
because of the compounds’ unique coordination chemistry.[1,2]
Received 11 March 2011; accepted 28 March 2011.
Address correspondence to Mohammad Shakir, Department of
Chemistry, Aligarh Muslim University, Aligarh 202002, India. E-mail:
shakir078@yahoo.com
1056

DNA BINDING STUDIES ON A Cu(II) COMPLEX
1057
These properties stimulate researchers to further exploit their
derivatives.[22]
Keeping these facts in mind, we have synthesized and char-
acterized 14-membered functionalized pendant arm Schiff base
macrocyclic complexes by the template condensation reaction
of 3,3ꢁ-diaminobenzidene and acetylacetone.
EXPERIMENTAL
Materials and Methods
Metal salts (all from Merck) were commercially available
pure samples. The chemicals 3,3ꢁ-diaminobenzidene (Acros)
and acetylacetone (Fluka) were used as received. All the solvents
used were of standard analytical grade. Highly polymerized calf-
thymus DNA sodium salt (7% Na content) was purchased from
Sigma Chemical Co. Other chemicals were of reagent grade and
used without further purification.
Preparation of Stock Solutions
FIG. 1. Stern–Volmer plot for binding of Cu(II) complex with DNA at 298 K.
Calf thymus DNA was dissolved to 0.5% w/w, (12.5 mM
DNA/phosphate) in 0.1 M sodium phosphate buffer (pH 7.40)
at 310 K for 24 h with occasional stirring to ensure forma-
tion of homogeneous solution. The purity of the DNA solution
was checked from the absorbance ratio A260/A280. Since the
absorption ratio lies in the range 1.8 < A260/A280 < 1.9, no fur-
ther deproteinization of DNA was needed. A stock solution of
[CuL(NO3)2] complex at 5 mg/mL concentration was also pre-
pared.
complexes were recorded on a Micromass Quattro II triple-
quadruple mass spectrometer. Electron paramagnetic resonance
(EPR) spectra were recorded at room temperature on a Varian
E-4 X-band spectrometer using TCNE as the g-marker. The ul-
traviolet (UV)–visible spectrophotometric studies of the freshly
prepared 10−3 M dimethyl sulfoxide (DMSO) solutions of the
complexes in the range 200–1100 nm were conducted using
a Cintra 5 GBC Scientific Spectrophotometer at room temper-
ature. Magnetic susceptibility measurements were carried out
using a Faraday balance at 25◦C. The electrical conductivities
(10−3 M solution in DMSO) were obtained on a Systronic type
302 conductivity bridge thermostated at 25.00 0.05◦C. Fluo-
rescence measurements were performed on a spectrofluorimeter
model RF-5301PC (Shimadzu, Japan) equipped with a 150-W
xenon lamp and a slit width of 5 nm. A 1.00-cm quartz cell was
Synthesis of the Complexes
Dinitrato[2,3:9,10-biphenyldiamine-5,7,12,14-tetramethyl-
1,4,8,11-tetraazacycloteradecane-4,7,11,14-tetraene]
Metal(II), [MLNO3] [M = Co(II), Ni(II), Cu(II), and Zn(II)
To a solution of 3,3ꢁ-diaminobenzidine (0.002 mol, 0.428 g)
in 20 mL of acetonitrile and distilled water (1:1 ratio) placed
in a round-bottom flask was slowly added a solution of acety-
lacetone (0.002 mol, 0.20 mL) taken in 20 mL acetonitrile and
the mixture was stirred for about 2–3 h. This was followed by
addition of metal nitrate (0.001 mL) solution in 20 mL ace-
tonitrile. The reaction mixture was stirred for 12 h, leading to
the isolation of a solid product. The solid product thus formed
was filtered, washed with methanol, and dried in vacuum.
Physical Measurements
The elemental analyses were obtained from the micro-
analytical laboratory of the Central Drug Research Institute
(CDRI), Lucknow, India. The infrared (IR) spectra (4000–200
cm−1) were recorded as KBr/CsI discs on the Perkin-Elmer 2400
spectrometer. Metals were determined volumetrically.[23] 1H-
Nuclear magnetic resonance (NMR) spectra were recorded in
DMSO-d6 using a Bruker Avance II 400 NMR spectrometer
with Me4Si as an internal standard from SAIF, Punjab Uni-
versity, Chandigarh, India. Electrospray mass spectra of the
FIG. 2. Plotoflog(F0 –F)/Fversuslog[Q] fordetermining thebindingconstant
and number of binding sides of Cu(II) complex on DNA.

1058
M. SHAKIR ET AL.
used for measurements. For the determination of binding param- plot of combined quenching (both static and dynamic) has an
eters, 30 µM of complex solution was placed in a quartz cell and upward curvature. When ligand molecules bind independently
increasing amounts of ctDNA solution were titrated. Fluores- to a set of equivalent sites on a macromolecule, the equilibrium
cence spectra were recorded at temperature 310 K in the range between free and bound molecules is given by Eq. 2[25]
:
of 300–400 nm upon excitation at 365 nm (λex was 365 nm).
The UV measurements of calf thymus DNA were recorded on a
Shimadzu double-beam spectrophotometer model UV1700 us-
ing a cuvette of 1 cm path length. Absorbance value of DNA in
the absence and presence of the complex was made in the range
of 220–300 nm. DNA concentration was fixed at 0.1 µM, while
the complex concentration was varied from 5 to 20 µM.
log[(F0−F)/F] = log K + n log[Q]
[2]
where K and n are the binding constant and the number of
binding sites, respectively. Thus, a plot of log(F0 – F)/F versus
log[Q] can be used to determine K as well as n (Figure 2). The
values of K and n were found to be (1.11 1.13) × 104 M−1
and 1.01, respectively.
Binding Equilibrium
To further elaborate the fluorescence quenching mechanism
the Stern–Volmer equation (Eq. 1) was used for data analysis[24]
:
RESULTS AND DISCUSSION
The template condensation reaction between 3,3ꢁ-
diaminobenzidene and acetylacetone (1:2:2 molar ratio) re-
sulted in the formation of a novel series of Schiff-base
F0/F = 1 + KSV[Q]
[1]
where F0 and F are the steady-state fluorescence intensities in pendant armed macrocyclic complexes, [ML(NO3)2] [M =
the absence and presence of quencher, respectively. KSV is the Co(II), Ni(II), Cu(II), and Zn(II)] (Scheme 1). The progress
Stern–Volmer quenching constant and [Q] is the concentration of the reaction was monitored by running thin-layer chro-
of quencher (DNA). The Ksv for the [CuL(NO3)2] complex was matography (TLC) on silica gel-coated plates. The com-
found to be of the order of 104 (1.39 × 104 Lmol−1). The lin- plexes formed are solids at room temperature and soluble in
earity of the F0/F versus [Q] (Stern–Volmer) plots for the DNA- DMSO.
[CuL(NO3)2] complex (Figure 1) depicts that the quenching
The formation of complexes was ascertained on the basis of
may be static or dynamic, since the characteristic Stern–Volmer results of elemental analyses, electrospray ionization (ESI) mass
H2N
H2N
NH2
NH2
H3C
2
CH3
2
+
O
O
MX2.nH2O
H3C
CH3
H2N
H2N
N
N
NO3 N
M
NH2
NH2
NO3 N
H3C
CH3
SCH. 1. Suggested structure of Schiff base macrocyclic complexes. M = Co(II), Ni(II), Cu(II), and Zn(II).

DNA BINDING STUDIES ON A Cu(II) COMPLEX
1059
TABLE 1
Elemental analyses, m/z values, colors, yields, molar conductance, and melting points of complexes
Found (calc.)%
Molar conductivity
(ohm−1 cm2 mol−1)/
m.p. (◦C)
m/z Found
Complexes
(calc.)
Color
Black
Yield (%)
55
M
C
H
N
[CoL(NO3)2]
C34H36N10CoO6
[NiL(NO3)2]
C34H36N10NiO6
[CuL(NO3)2]
C34H36N10CuO6
[ZnL(NO3)2]
738.79
(739.65)
738.32
(739.41)
743.15
7.56
(7.96)
7.40
(7.94)
8.33
55.83
(55.21)
55.65
(55.23)
54.45
4.42
(4.91)
4.15
(4.91)
4.35
18.53
(18.94)
18.25
(18.94)
18.70
22/282
21/272
23/265
24/263
Brown
Black
Gray
58
62
56
(744.27)
738.32
(8.54)
8.15
(54.87)
54.94
(4.87)
4.58
(18.82)
18.33
C34H36N10ZnO6
(746.10)
(8.76)
(54.73)
(4.86)
(18.77)
plexes.[29] The IR spectra of these complexes show additional
bands in the 1230–1270, 1040–1070, and 860–890 cm−1 re-
gion, which are consistent with monodentate coordination of
the nitrato group.[29]
spectra (Table 1), Fourier-transform infrared (FT-IR) (Table 2),
and H-NMR spectra. The overall geometry of the complexes
was inferred from the observed values of magnetic moments
and electronic spectra (Table 3). The molar conductance mea-
surements of all the complexes in DMSO suggest their non
electrolytic nature.[26]
1
1H-NMR Spectra
1
The H-NMR spectra of the Zn(II) complex show a sharp
IR Spectra
signal at 2.47 ppm corresponding to imine methyl (CH3C N;
12H) protons, while a singlet at 2.13 ppm may be as-
signed to central methylene (C-CH2-C; 4H) protons of the
2,4-pentanedione.[30] However, a singlet at 4.29 ppm may
be attributed to the primary amino protons (C6H3-NH2, 8H)
of benzidine. A broad multiplet observed in the 6.95–7.21
ppm region may be assigned to the aromatic ring pro-
tons.[31]
Preliminary identification of the synthesized pendant-armed
Schiff-base macrocyclic complexes has been obtained from IR
spectra (Table 2). The absence of bands characteristic of the
carbonyl group of acetyl acetone and the appearance of the
υ(C N) bands in the 1590–1620 cm−1 region strongly sug-
gests that the macrocyclic framework has been formed.[27]
This is further supported by the appearance of a new band
in the region 480–500 cm−1 assignable to υ(M−N) vibra-
tion.[28] However, the appearance of a doublet in the region
3380–3350 cm−1 in all macrocyclic complexes may be due to
EPR Spectra
The EPR spectrum of the powdered solid copper(II) complex
the N–H stretching frequency of the primary amino groups of was recorded on X-band at frequency 9.1 GHz under a magnetic
the benzidine moiety. A weak absorption band in the region field strength of 3000 G and scan rate 2000, recorded at room
2920–2925 cm−1 may be assigned to the CH3 stretching vi- temperature. The g and g values were computed from the
ꢂꢂ
⊥
bration.[29] All the complexes show sharp bands corresponding spectrum using TCNE free radical as g marker, which gives g =
ꢂ
to υ(C−H), δ(C−H), and phenyl ring vibrations, which ap- 2.13 and g = 2.05. The observed g value is less than 2.3, which
⊥
ꢂ
pear at their expected positions (Table 2). The coordination of is in agreement with the covalent character of the metal–ligand
nitrato groups has been ascertained by appearance of bands bond. The observed trend g > g > 2.0023 suggests that the
ꢂ
⊥
in the 230–240 cm−1 regions, which may reasonably be as- unpaired electron is localized in the dX2-dy2 orbital of the Cu(II)
signed to υ(M−O) of the O–NO2 group in [M(L)(NO3)2] com- ion.
TABLE 2
IR spectral data of the complexes (cm−1
)
Complexes
υ(C N)
υ(C–H)
δ(C–H)
υ(M–N)
υ(M–O)
Ring vibrations
[CoL(NO3)2]
[NiL(NO3)2]
[CuL(NO3)2]
[ZnL(NO3)2]
1590 s
1605 s
1620 s
1600 s
2925 s
2895 s
2882 s
2905 s
1450 s
1442 s
1450 s
1468 s
480 s
500 s
485 s
490 s
240 m
237 m
235 m
230 m
1460 s, 1070 s, 785 s
1455s, 1095 s, 775 s
1480 s, 1080 s, 770 s
1470 s, 1090 s, 790 s

1060
M. SHAKIR ET AL.
TABLE 3
served magnetic moment value of 4.59 B.M. corresponding to a
high-spin state further supports the octahedral geometry around
the Co(II) ion.[33,34]
Magnetic moments and electronic spectral bands with their
assignments of the complexes
The proposed octahedral geometry around the Ni(II) ion in
[NiL(NO3)2] has been inferred from the observed band posi-
tions at 10,030, 15,650, and 24,360 cm−1 attributed to 3A2g(F)
→ T2g(F), A2g(F) → T1g(F), and A2g(F) → T1g(P) tran-
sitions, respectively, similar to those reported earlier.[35] The
observed magnetic moment of 2.92 B.M. further corroborates
an octahedral environment around the Ni(II) ion in the high-spin
configuration.[36]
µeff.
(BM)
Band position
(cm−1
Complexes
)
Assignments
3
3
3
3
3
4
[CoL(NO3)2]
4.59
2.92
1.86
9185
16,850
21,200
10,030
15,650
24,360
11,425
18,750
27,355
4T1g(F) → T2g(F)
4
4T1g(F) → A2g(F)
4
4T1g(F) → T1g(P)
3
[NiL(NO3)2]
[CuL(NO3)2]
3A2g(F) → T2g(F),
3
3A2g(F) → T1g(F)
3
3A2g(F) → T1g(P)
The absorption spectrum of the six-coordinate Cu(II) com-
plex shows three bands at 11,425, 18,750, and 27,355 cm−1
,
2
2B1g → A1g
2
2
corresponding to the transitions 2B1g → A1g, 2B1g → B2, and
2
2B1g → B2g
2
2B1g→ Eg, respectively. Therefore, it may be concluded that the
2
2B1g → Eg
complex possesses tetragonally distorted octahedral geometry.
It has been further confirmed by the magnetic moment value of
1.82 B.M. for this complex.[37]
G = (g − 2)/(g − 2), which measures the exchange inter-
ꢂ
⊥
Fluorescence Measurements: Binding Property of the
[CuL(NO3)2] Complex with DNA
The fluorescence spectroscopy provides insight into the
changes taking place in the microenvironment of the
DNA–[CuL(NO3)2] complex. The interaction of [CuL(NO3)2]
action between the metal centers in polycrystalline solid, was
calculated and it has been found to be less than 4, suggesting
considerable exchange interaction in the solid complexes.[32]
Electronic Spectra and Magnetic Moments
The electronic spectrum of the [CoL(NO3)2] complex complex with calf thymus DNA was studied by monitor-
showed three absorption bands at 9185, 16,850, and 21,200 ing the changes in the intrinsic fluorescence of [CuL(NO3)2]
4
4
cm−1 assignable to the 4T1g(F) → T2g(F), 4T1g(F) → A2g(F), complex at varying DNA concentration. Figure 3 shows the
and 4T1g(F) → T1g(P) transitions, respectively, corresponding representative fluorescence emission spectra of the synthesized
4
to the octahedral geometry around the cobalt(II) ion. The ob- compound upon excitation at 280 nm. The addition of DNA
FIG. 3. Fluorescence emission spectra of Cu(II) complex in the absence and presence of increasing amount of DNA from (a) to (j); pH 7.4; T = 298 K (color
figure available online).

DNA BINDING STUDIES ON A Cu(II) COMPLEX
1061
caused a gradual decrease in the fluorescence emission inten- the π–π∗ orbital of the bound ligand can couple with the π
sity of the complex with a conspicuous change in the emission orbital of the base pairs, due to decreased π–π∗ transition en-
spectra. It can be seen that a higher excess of DNA led to ergy, which results in bathochromic shift. The prominent shift
more effective quenching of the fluorophore molecule fluores- in the spectra also suggests the tight complexation of synthe-
cence. The quenching of the compound fluorescence clearly in- sized molecule with DNA, which resulted in the change in the
dicated that the binding of the DNA to the[CuL(NO3)2] complex absorption maxima of the DNA. The changes just described are
has changed the microenvironment of the fluorophore residue. indicative of the conformational alteration of DNA on Cu(II)
The reduction in the intrinsic fluorescence of the synthesized complex binding.
molecule upon interaction with DNA could be due to masking
or burial of [CuL(NO3)2] complex fluorophore upon interac-
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Absorption Spectroscopy
UV-Vis absorption studies were performed to further ascer-
tain the DNA–[CuL(NO3)2] complex interaction. The UV ab-
sorbance showed an increase with the increase in drug concen-
tration (Figure 4). Since [CuL(NO3)2] complex does not show
any peak in this region (Figure 4), the rise in the DNA ab-
sorbance is indicative of the complex formation between DNA
and [CuL(NO3)2]. The [CuL(NO3)2] complex at 260 nm exhib-
ited hyperchromism of 30% at 1:1 molar ratio. Hypochromism
and hyperchromism are both spectral features of DNA concern-
ing its double-helix structure. Hypochromism means the DNA
binding mode of the complex is electrostatic effect or intercala-
tion, which can stabilize the DNA duplex, and hyperchromism
means the breakage of the secondary structure of DNA.[38,39] So
we primarily speculate that complex is interacting with the sec-
ondary structure with calf thymus DNA, resulting in its breakage
and perturbation. After interaction with the base pairs of DNA,
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