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Synthesis, characterization and applications of copper(II) complexes with N– and O–donor ligands
ISLAMABAD
A Thesis Submitted to the Department of Chemistry,
Quaid-i-Azam University, Islamabad, in partial fulfillment of the
requirements for the degree of
Doctor of Philosophy
in
Inorganic/Analytical Chemistry
by
Muhammad Iqbal
Department of Chemistry
Quaid-i-Azam University
Islamabad, Pakistan
(2013)
Dedicated
to
Humanity
CONTENTS
Acknowledgements i
Abstract iii
List of Tables v
List of Figures vi
List of Schemes ix
List of abbreviations x
Chapter 1 Introduction 1-54
1.1 Copper(II) carboxylates 4
1.2 Structural diversity of Cu(II) carboxylates 5
1.2.1 Tetra-coordinated geometry 6
1.2.2 Penta-coordinated geometry 7
1.2.3 Hexa-coordinated geometry 9
1.2.4 Di- and polynuclear copper(II) carboxylates 10
1.3 Geometry around copper(II) ion in paddlewheel structures 13
1.4 Supra-molecular structures of copper(II) carboxylates 14
1.5 Polypyridyl ligands 16
1.6 General account of DNA activity 17
1.7 Effect of ligands on structure and properties 19
1.8 Effect of metal ion 21
References 24-54
Chapter 2 Experimental 55-71
2.1 Materials and methods 55
2.2 Single crystal X–ray crystallographic studies 55
2.2.1 Complexes 1b, 2a, 2b, 4a, 5a, 6b and 7a 55
2.2.2 Complexes 1a, 3a, 4b and 5b 56
2.2.3 Complexes 1, 1c, 2, 2c, 3b, 5c, 6, 6a, 6c, 7b, 8a, 8b, and 8c 56
2.3 DNA interaction study by cyclic voltammetry 56
2.4 DNA interaction study by absorption spectroscopy 57
2.5 Antibacterial studies 57
2.6 Antifungal studies 58
2.7 General procedures for the synthesis of complexes 59
2.7.1 Polynuclear complexes, 1–8 59
2.7.2 Dinuclear complexes 59
2.7.2.1 Paddlewheel complexes, 1a–8a 59
2.7.2.2 O–bridged complexes, 1b–8b 64
2.7.3 Mononuclear complexes, 1c–8c 64
References 70
Chapter 3 Results and Discussion 72-148
3.1 FT–IR data 72
3.2 Powder XRD Study 78
3.3 Crystal structure description of the complexes 79
3.3.1 Polynuclear complexes 79
3.3.2 Dinuclear complexes 85
3.3.2.1 Dinuclear paddlewheel complexes 85
3.3.2.2 96
3.3.3 Mononuclear complexes 104
3.4 DNA binding study through cyclic voltammetry 110
3.4.1 Predominant electrostatic mode of interaction 110
3.4.2 Predominant intercalative mode 113
3.4.3 Mixed binding mode 113
3.5 Absorption spectroscopy 122
3.6 DNA study through absorption spectroscopy 123
3.6.1 Classical intercalation 123
3.6.2 Mixed binding mode: Electrostatic with groove
binding mode
123
3.6.3 Mixed binding mode: Partial intercalation with groove
binding mode
125
3.7 Biological studies 130
3.7.1 Antibacterial study 130
3.7.2 Antifungal studies 134
References 137
Conclusions 149
Publications 151
i
ACKNOWLEDGEMENTS
I owe my profound thanks and deepest sense of gratitude to Almighty ALLAH, Who
blessed me with fortitude, potential and capability to complete my Ph.D work.
I wish to express fervent sense of thankfulness to my affectionate supervisor, Prof. Dr.
Saqib Ali (PoP), Department of Chemistry, Quaid-i-Azam University, Islamabad, for his
wholehearted interest and dedicated supervision. His inspiring guidance, valuable suggestions,
energizing encouragement, generous help, good manners and friendly behavior enabled me to
accomplish this tough task.
I am highly grateful to Prof. Dr. Amin Badshah (T.I), Chairman, Department of
Chemistry, Quaid-i-Azam University, Islamabad, for providing lab. facilities during research
work. His friendly behavior, cheering attitude and fruitful discussion will always be
acknowledged.
I express my heartfelt gratitude to Dr. Niaz Muhammad and Dr. Zia-ur-Rehman for
their continuous guidance, valuable suggestions and proper steering at every step of my research
work. Their encouragement and advice proved a hill of support during my stay in the
department.
I am highly indebted to Dr. Paul W. Davies, Department of Chemistry, University of
Birmingham, U.K, for his supervision, mammoth help and cooperation and for accommodating
me in his lab. for a span of six months. I also acknowledge Dr. Paul W. Anderson of the same
department for the valuable discussion regarding my research.
Many thanks to Mr. Naseer Ali Shah, Department of Biochemistry, Quaid i Azam
University, Islamabad, for the biological studies and interpretation of the data. His timely and
enthusiastic cooperation will always be remembered.
Many thanks to crystallographers, Prof. Dr. M. Nawaz Tahir, University of Sargodha
and Dr. Manzar Sohail, University of the Sunshine Coast, Sippy Downs, QLD, Australia, for
single crystal analysis (data collection, structure solution and structure analysis) and fruitful
collaboration.
A special word of gratitude is due to Prof. Dr. Syed Ahmad Timizi, Dr. Safeer Ahmed,
Dr. Afzal Shah and Dr. Arif Nadeem for their assistance, valuable suggestions and data
ii
interpretation in, XRD, CV and DNA interaction study. The timely help of Mr. Iqbal Ahmad in
electrochemical studies will always be remembered.
I would like to express my deepest appreciation to all colleagues, lab.-fellows whom in
one way or the other assisted me, mentioning them individually by name is rather impossible.
I am greatly honored to mention the nice cooperation of all employees and para-teaching
staff of the department, especially Mr. M. Sharif Chohan and Mr. Rana Tahir Shabbir. The
timely cooperation and help of Mr. Rana Matloob Ahmad and Mr. Tariq Aziz (CNC) in
providing softwares for various techniques is highly acknowledged.
Last but not the least, no words to portray my feelings of admiration about my
affectionate parents and all my family members, the prayers of whom enabled me to achieve this
target.
Many thanks to the Higher Education Commission of Pakistan for providing me the
indigenous Ph.D. scholarship during my study within the country as well as abroad (IRSIP).
Muhammad Iqbal
iii
ABSTRACT
In the present study, four series of copper(II) carboxylates mixed with N-donor ligands have
been synthesized by treating copper sulfate with a carboxylate moiety followed by reacting it
with an N-donor compound in an aqueous medium. The carboxylate ligands used were
substituted phenyl acetic acids [4–methyl (1, 1a, 1b, 1c), 4–H (2, 2a, 2b, 2c), 4–methoxy (3, 3a,
3b, 3c), 4–bromo (4, 4a, 4b, 4c), 4–chloro (5, 5a, 5b, 5c), 4–floro (6, 6a, 6b, 6c), 4–nitro (7, 7a,
7b, 7c) and 2–nitro (8, 8a, 8b, 8c)] while the N-donor ligands were pyridine (a), –bipyridine
(b) and 1,10–phenanthroline (c). The coordination modes of ligands and the structure and
geometry assignments of the complexes were determined using different analytical techniques
such as FT-IR, UV-Visible spectroscopy, powder and single crystal XRD. Based on the results,
the ligand was found to coordinate to the Cu(II) ion through the COO moiety in bridging
bidentate (1-8, 1a-8a), monodentate (1b-6b and 8b) and chelating bidentate fashions (1c, 3c-8c
and 7b). Complex 2c was found to be unique because it had OH bridges and the carboxylate
ligand is lying uncoordinated in the crystal lattice while the 5th
coordination site around each
copper(II) ion of the dinuclear complex is occupied by a water molecule. The geometry and
structure of the complexes, as confirmed through single crystal X-ray analyses was found to be
square pyramidal and polynuclear (1-8, without N-donor ligand), square pyramidal and dinuclear
(with pyridine, 1a-8a and –bipyridine, 1b-6b, 8b) and distorted octahedral and mono-nuclear
(1c, 3c-8c, with 1,10-phenanthroline and 7b with –bipyridine). The bulk property such as the
purity of the complexes was confirmed through powder XRD of the crystalline samples where
the simulated and experimental spectra were in complete agreement with each other.
The DNA binding ability of all the synthesized complexes was studied by cyclic voltammetry
(CV) and UV-Visible spectroscopy. The diffusion coefficient of the free and DNA bound
complexes were determined by the Randles-Sevcik equation. The positive peak potential shift in
iv
CV and the hypochromic effect in spectroscopy observed for complexes 4-8, 3a, 5a-8a, 1b, 5b,
and 3c-7c evidenced the intercalative mode of interaction of these complexes with DNA while
the negative potential shift observed for 3b, 4b, 8b, 1c, 2c, and 8c indicated electrostatic
interactions. A mixed binding mode (electrostatic with intercalation) was observed for the rest of
the complexes 1, 2, 3, 1a, 2a, 4a, 2b, 6b and 7b. The CV results revealed the highest binding
strengths for 2, 3, 6, 5a, 6a, 1b, 3b-6b, 3c-6c and 7c (Kb range = 3.166 × 104 to 2.13 × 10
5). The
UV-Vis spectroscopic data also indicated the same pattern of binding strength. Moreover, the
λmax ε v w t UV-Vis spectroscopy. The peak ranges in
spectroscopy show that the geometry around copper(II) in case of 1-8 and 1a-8a is square
pyramidal while 1b-8b and 1c-8c exhibit an octahedral geometry in DMSO solution.
Biological screening of the complexes against medically important bacterial and fungal strains
has exhibited a significant antibacterial and antifungal activity for 1c, 2c, 6c and 7c and 1, 1b, 2,
2c, 3c, 5a, and 7c, respectively while 4a, 4b, 5, 5c, and 8c were found to have moderate
antifungal activity. The potent DNA binding ability supported by biocidal activity indicated that
these complexes can have a potential for the anti-cancer activity as well.
v
List of Tables
Table Title Page
3.1 Physical data of the complexes 75
3.2 IR data (cm−1
) of the complexes 76
3.3 Structure refinement parameters of complexes 1, 2 and 6. 81
3.4 Selected bond lengths and angles of complexes 1, 2 and 6 83
3.5 Structure refinement parameters of complexes 1a-8a 88,89
3.6 Selected Bond lengths and angles of dinuclear paddlewheel
complexes, 1a-8a
90
3.7 Comparison of Cu–ligand bond lengths (Å) of 1a-8a with
structurally related copper(II) complexes
91
3.8 Structure refinement parameters of O-bridged dinuclear
complexes
98,99
3.9 Selected bond lengths and angles of O-bridged dinuclear
complexes
100
3.10 Structure refinement parameters of mononuclear complexes 107
3.11 Selected bond lenths and angles of mononuclear complexes 108
3.12 Shift in peak potential of the complexes on DNA addition 112
3.13 Decrease in peak current of the complexes on DNA addition 119
3.14 Do (cm2s−1
) and Kb (M−1
) values of the complexes obtained from
CV
121
3.15 Kb, ε and shift λmax with DNA addition in UV 124
3.16 Antibacterial data of complexes: Average Zone of inhibition
(mm)
132
3.17 Antibacterial data of complexes: Minimum Inhibitory
Concentration (MIC) (mg/mL)
133
3.18 Antifungal data of complexes: Mean value of percent growth
inhibition (%) along with their standard deviation values
135
vi
List of Figures
Figure Title Page
1.1 Examples of distorted tetrahedral copper(II) ions 7
1.2 Examples of square planar copper(II) ions 7
1.3 Examples of trigonal bipyramidal geometry around Cu(II) ions 8
1.4 Examples of square pyramidal geometry around copper(II) ions 9
1.5 Examples of octahedral geometry around copper(II) ions 10
3.1 FT-IR spectrum of complex 7a 73
3.2 FT-IR spectrum of complex 7b 74
3.3 Experimental and simulated spectra of complexes 1, 3a, 3b and
8c belonging to polynuclear, dinuclear paddlewheel, dinuclear O-
bridged and mononuclear series of the synthesized complexes,
respectively.
78
3.4 Polymeric chain of complex 2, representing the general pattern of
the inter-linked paddlewheel units in the polymeric complexes.
Hydrogen atoms have been removed for clarity.
79
3.5 ORTEP drawings of complexes 1 (a), 2 (b) and 6 (c) 80
3.6 Packing diagrams of complexes 1 (a), 2 (b) and 6 (c) showing the
relative abundance of secondary interactions in three complexes
where each molecule represents a polymeric chain.
Intermolecular interactions are shown by dotted lines.
84
3.7 ORTEP drawings of complexes 1a (a), 2a (b), 3a (c), 4a (d), 5a
(e), 6a (f), 7a (g) and 8a (h). 87
3.8 Packing diagrams of complexes 1a (a), 2a (b), 3a (c), 4a (d), 5a
(e), 6a (f), 7a (g) and 8a (h). Hydrogen atoms have been
removed from the diagrams of 2a and 6a for clarity. Inter-
molecular interactions have been shown by dotted lines.
95
3.9 ORTEP drawings of the complexes 1b (a), 2b (b), 3b (c), 4b (d),
5b (e), 6b (f), 8b (g) and 2c (h). Hydrogen atoms have been
removed from 3b for clarity
101
vii
3.10 Packing diagrams of complexes 1b (a), 2b (b), 3b (c), 4b (d), 5b
(e), 6b (f), 8b (g) and 2c (h). H-bonding and other inter-
molecular interactions in 2c have been shown by dotted lines
103
3.11 ORTEP drawings of mono-nuclear complexes 1c (a), 5c (b), 6c
(c), 8c (d) and 7b (e). 105
3.12 Packing diagrams of the mono-nuclear complexes 1c (a), 5c (b),
6c (c), 8c (d) and 7b (e). 109
3.13 Cyclic voltammograms of 1c, 2c, 3b, 4b, 8b and 8c in the
absence and presence of 10-70 μM DNA. In each case the peak
current decreases and the peak potential is shifted to the left hand
side on successive DNA addition
111
3.14 Cyclic voltammograms of 4-8, 3a, 5a-8a, 1b, 5b, and 3c-7c in
the absence and presence of 10-90 μM NA. I h th
peak current decreases and the peak potential is shifted to the
right hand side on successive addition of DNA.
114,
115
3.15 Cyclic voltammograms of 1, 2, 2a, 2b, 3, 4a and 6b in the
absence and presence of 10-90 μM DNA. In each case the peak
current decreases and the peak potential is shifted to right hand
side with respect to the shift with the first addition of DNA.
117
3.16 Cyclic voltammograms of 1a and 7b in the absence and presence
of 10-90 μM DNA. In each case the peak current decreases and
peak potential is shifted to the left hand side with respect to the
shift with the first addition of DNA.
118
3.17 Plots of log 1/[DNA] vs. log ip/(io-ip) for the calculation of the
binding constants of complexes 1-8 (a), 1a-8a (b), 1b-8b (c) and
1c-8c (d).
120
3.18
3.19
Absorption spectra of 1a, 2, 2a, 6, 7a in the absence (a) and
presence of 10-80 μM NA ( -i). These complexes exhibited
hypochromism with a pronounced red shift with successive DNA
addition.
Absorption spectra of 2b, 2c, 4c, 5c, 7 and 8c in the absence (a)
126
127
viii
and presence of 10-90 μM NA ( -j). These complexes
exhibited hypochromism with a blue shift on successive DNA
addition.
3.20 Absorption spectra of 1, 1b, 1c, 3-5, 3a-6a, 8a, 3b-8b, 3c, 6c and
7c in the absence (a) and presence of 10-90 μM NA ( -j).
These complexes exhibited hypochromism with a small red shift
on successive DNA addition.
128,
129
3.21 Plots of Ao/(A-Ao) vs. 1/[DNA] for the calculation of the binding
constants of the complexes 1-8 (a), 1a-8a (b), 1b-8b (c) and 1c-
8c (d).
130
3.22 Graphical representation of the antifungal activity of the
complexes with respect to that of Terbinafine. 136
ix
List of Schemes
Scheme Title Page
1.1 General structures of polynuclear paddlewheel copper(II)
carboxylates
11
1.2 Common types of polypyridyl ligands 12
2.1 Synthetic procedure for polynuclear complexes, where R = 4–
CH3 (1), H (2), 4–CH3–O (3), 4–Br (4), 4–Cl (5), 4–F (6), 4–NO2
(7) and 2–NO2 (8)
60
2.2 Synthetic procedure for dinuclear paddlewheel complexes, where
R= 4–CH3 (1a), H (2a), 4–CH3–O (3a), 4–Br (4a), 4–Cl (5a), 4–
F (6a), 4–NO2 (7a) and 2–NO2 (8a)
61
2.3 Synthetic procedure for dinuclear O–bridged complexes, where
R= 4–CH3 (1b), H (2b), 4–CH3–O (3b), 4–Br (4b), 4–Cl (5b), 4–
F (6b) and 2–NO2 (8b)
62
2.4 Synthetic procedure for mononuclear complexes, where R= 4–
CH3 (1c), 4–CH3–O (3c), 4–Br (4c), 4–Cl (5c), 4–F (6c), 4–NO2
(7c) and 2–NO2 (8c)
63
x
List of Abbreviations
CV Cyclic voltammetry
DNA Deoxyribonucleic acid
SSDNA Salmon sperm deoxyribonucleic acid
XRD X-ray diffraction
DMSO Dimethyl sulfoxide
UV Ultraviolet
CSD Cambridge structural database
SBU Secondary building unit
FT-IR Fourier transform infra-red
ATR Attenuated total reflectance
XDS X-ray detector software
GCE Glassy carbon electrode
CFU Colony forming units
SDA Sabouraud dextrose agar
MP Melting point
MIC Minimum inhibitory concentration
1
Chapter 1
Introduction
Owing to the ever increasing demand for commercially available bioactive metal based
drugs, their synthesis and study is the focal point of coordination chemistry research groups [1-
3]. The superiority of metal-based over organic-based drugs arises from the flexibility of the
former in their geometry, coordination number and redox properties. The pharmacological
properties of the latter group of drugs (serving as ligands in the former category) have been
found to enhance tremendously on attachment to a metal ion and depending upon the nature of
ligand and metal ion, the resulting complex can be steered to a variety of the desired applications
[4-7]. Since there is a wide variation in the intrinsic properties of transition metal ions, most of
their complexes find cost effective applications in various areas such as drug delivery, bioactive
agents and catalysis [8-10]. Obviously, a shortlisting is necessary for a sufficiently in-depth
exploration of coordination chemistry of the metal ion under study and applications of the
resulting complexes. The foremost criterion for selection would be the efficiency for the desired
applications. However, availability, cost effective synthesis, compatibility and benignity to the
non-targeted areas of the biological systems and the status and impact of their remnants on the
environment after use [11,12], have to be considered as well.
The developmental history of drugs has shown that sufficiently potent drugs have lost their
popularity owing to their non-conformity to one or more of the aforementioned criteria [12-17].
The toxic effects of the resulting drug could be potentially reduced by avoiding toxic metals and
selecting one or more metals from the list of the essential metals (Mn, Fe, Co, Cu, Zn, Mo)
which are non-toxic up to a certain limit. Studying the coordination chemistry and therapeutic
2
applications of the complexes derived from these metals [18-26], it has been found that being
close akin of platinum, copper-based complexes exhibit similar or improved therapeutic
properties with relatively reduced side effects [27-31]. In this regard, several copper-based drugs
have been studied and patented. Among these, a class of N and O-donor copper(II) complexes
called Casiopeinas possess superior in vivo as well as in vitro superoxide dismutase and
antineoplastic potency as compared to that of cisplatin [32-34]. Moreover, the danger of intra-
chromosomal recombination leading to the instability of the genome is considerably smaller with
copper complexes [35]. This discovery has helped to shortlist copper and encouraged the
exploration of some new copper complexes for improved properties. However, similar to
cisplatin, some copper complexes have been found to exert oxidative disturbances mainly due to
the generation of reactive oxygen species through the Haber–Weiss and Fenton-like reactions
[36] affecting the function of mitochondria and neurons [14, 37]. So the aim was to prepare
complexes of similar therapeutic properties but with reduced toxic effects on the normal tissues.
The desired modification was thought to be accomplished either by changing the coordination
sphere of the central metal core or attached ligands to it as compared to the already studied and
reported copper(II) complexes [38-40]. In order to achieve a useful structural modification, one
or more of the structural parameters such as geometry, nuclearity and electrostatic redox
properties of the central copper(II) ion of the desired complexes, have to be varied. These
structural parameters have a prominent impact on the permeability through biological
membranes as well as DNA binding ability of the metal based drug [12,18, 41-43].
Arriving at the desired structural diversity was also facilitated via a judicious selection of the
ligands having suitable ligator atoms, symmetry and flexible coordinating ability to copper(II)
ion. Knowing that the carboxylate moiety can open up new structural avenues through its
3
variable coordinating modes to metal ions, some planar, C2-symmetric N-donor ligands of
similar coordinating power have been coupled with it. Thus, the geometry and planarity of the
resulting complexes have been controlled by N and O-donor ligands while the redox properties
have been found to be affected more with the former ligand. Moreover, the carboxylate moiety
favors the solubility of the resulting complexes in aqueous media which enables us to tune the
pH of the reaction mixture for changing the reactivity and selectivity of the ligands as well as
metal ion. The improved water solubility is a property of immense significance to the complexes
destined for biological applications, green homogeneous metal catalysis and electrochemical
solution studies [44-46].
The complexes reported here have been synthesized easily in aqueous medium and are
sufficiently stable to allow their further studies in a wide range of solvent systems. These
comprise of four series of O and N-donor copper(II) carboxylates, where O and N come from
substituted phenyl acetate and a simple aromatic heterocycle such as -bipyridine or
1,10-phenanthroline, respectively. The series differ in nuclearity, geometry around copper(II)
and the ligator atoms while the relatively distant para-substitutent of carboxylate ligand has been
changed in each series. The complexes have been structurally confirmed through single crystal
XRD. A detailed electrochemical study of the complexes has been carried out before and after
DNA addition to the solution of the complex, in a water/DMSO (1:4) mixed solvent system. The
DNA-binding ability of the complexes has been confirmed through UV-visible
spectrophotometry as well. The crystal structure diversity is clearly manifested in their redox
properties and interaction with DNA and the resulting voltammetric behavior of the complexes
has been successfully correlated to the geometry, coordination environment and stability of the
redox active metal center.
4
1.1 Copper(II) carboxylates:
Copper(II) carboxylates play a vital role in biological processes as well as artificial
functional materials [47-49]. These exercise some desirable features over other metal
carboxylates such as robust, thermally stable and neutral supra-molecular structures with
relatively larger pore size (in case of polymeric carboxylates) [50-52]. Moreover, while
synthesizing mixed N- and O-donor complexes, their original carboxylate central metal core
undergoes relatively smaller change on the introduction of sterically less demanding N-donor
ligands (compare the dimeric pyridine containing complexes with polymeric ones) [53]. It has
been observed that Cu(II) ion has moderate affinity for the carboxylate moiety and the resulting
copper-carboxylate central core is easily reorganized with the incorporation of an N-donor
ligand.
The above mentioned findings have been proved true and the selected N-donor aromatic
ligands have replaced the Cu(II)-bonded carboxylate moiety partially, favoring mixed ligand
complexes whether monomeric or dimeric. Additionally, their versatility to coordinate in
bridging, non-chelating and chelating modes was expected to exhibit more structurally diverse
mixed ligand complexes with the selected mono and bidentate N-donor ligands. In this way, we
were able to study the effect of N-donor ligands of varying coordination power on these copper
carboxylates in aqueous medium. Polymeric mixed ligand copper(II) complexes involving
similar ligands and those with same ligator atoms throughout have been synthesized and studied
[54-62], h w v t v t th N- - h
-bipyridine and 1,10-phenanthroline on the structure and properties of discrete
(monomeric and dimeric) copper(II) carboxylates has been presented here. Moreover, the redox
activity of the synthesized complexes is purely metal based so the effect of ligands and geometry
5
around the central metal ion is clearly manifested in terms of variation in electrochemical
behavior. The introduction of N-donor ligands in the structural motif of the homolyptic
complexes (polymeric) has been successfully followed with the consequent change in the redox
properties of the latter, since the independent voltammetic response of the former is either un-
noticed (pyridine containing complexes) or lying in a far away region (as in bipyridine and
phenanthroline derivatives) compared to that of the latter. In this way the electrochemical signal
of the copper(II) ion has been unambiguously described in all the complexes and correlated
mutually as well as with literature.
The structural variation was manifested in the DNA binding ability of the complexes as well
which is critically affected by the nature of the metal ion, its geometry and the ligands attached
to it. Extensive work is being done on the DNA binding ability of copper(II) complexes in the
hope to design and develop a suitable substitute for platinum based drugs [8, 63-68]. Structurally
variant carboxylates have exhibited variable DNA binding abilities which have been correlated
to nuclearity, planarity and geometry of the DNA-binding species.
1.2 Structural diversity of Cu(II) carboxylates:
The copper(II) ion (a Lewis acid of intermediate strength) has a remarkable ability to form
stable complexes in tetra-, penta- and hexa-valent states with ligands (Lewis bases) of varying
electron donor capacity [69-71]. Owing to the flexible nature of electron pair acceptance,
copper(II) carboxylates exhibit a variety of structural motifs ranging from mono-, di-, tri-, tetra-
and penta- to polynuclear. Moreover, the chelating ability of the multi-donor ligands confers
further stability and versatility upon these complexes [72,73]. Thus, both the nature of the metal
ion as well as the ligand are responsible for this versatility of structure. The synthesized
6
complexes are mono-, di- and polynuclear type, however a brief overview of the most common
structural types already reported is also presented here.
1.2.1 Tetra-coordinated geometry: The two most common types of four-coordinated geometry
are tetrahedral and square planar, out of which the former type is very rare for homolyptic
copper(II) carboxylates. This is due to the oxophilic nature [74] of copper(II), its tendency to
form dimeric or polymeric complexes and expand its coordination sphere up to five or six
ligands. However, tetrahedral and square planar geometry has been found for other ligands
attached to copper(II) ion. These complexes seem to have been stabilized by other structural
factors such as intermolecular interactions, bridging and the presence of stabilizing groups in
molecular structure or crystal lattice [58,72, 75-82]. Figure 1.1-A h w th ‘ ’ formed by
π-stacking of the pyridyl moieties. This is an adduct of CuBr2 and 2,3-dihydro-1-(2-
pyridylmethyl)-imidazo[1,2-f]phenanthridinium bromide adopting a tetrahedral geometry with a
CuNBr3 coordination motif [76]. Similarly, the square planar geometry shown in Fig. 1.2-A
seems to be stabilized by the steric crowding of the attached ligands preventing other groups
from approaching closer to the central metal ion as well as by the secondary interactions of the
lattice counter ions [73]. Figure 1.2-B shows another example of square planar coordination
geometry around copper(II) ion. Since four coordinated copper is more stable in square planar
than tetrahedral structures, the former geometry is more widespread compared to the latter one
[75,83]. Moreover, the tetrahedral geometry is preferred for copper(I) due to sp3 hybridization of
Cu(I) as compared to copper(II) with a dsp2 hybridization as indicated by the mixed valence
structure shown in Fig. 1.1-B, where the square planar Cu1 is in +2 oxidation state while the
tetrahedral Cu2, Cu3 and Cu4 are more typical of copper(I) ions [84].
7
A B
Figure 1.1: Examples of distorted tetrahedral copper(II) ions. A, adduct of CuBr2 and 2,3-
dihydro-1-(2-pyridyl-methyl)-imidazo[1,2-f]phenanthridinium bromide and B,
Asymmetric unit of [Cu3ICu
IIBr3(3,5-Dmpip-dtc)2]n (hydrogen atoms are omitted for
clarity) where 3,5-Dmpip-dtc– = 3,5-dimethylpiperidine dithiocarbamate.
A B
Figure 1.2: Examples of square planar copper(II) ions. A, [CuSal]+SbF
6-, excluding
hydrogen atoms, where Sal=N N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexane-
(1R,2R)-diamine and B, [Cu(qui)(phen)]NO3·H2O where Hqui=2-phenyl-3-hydroxy-
4(1H)-quinolinone, and phen=1,10-phenanthroline
1.2.2 Penta-coordinated Geometry: The geometry of copper(II) ion varies from trigonal
bipyramidal to square pyramidal when coordinated by five ligands. The Addison parameter, τ
used to decide about the geometry around metal ions in five coordinated complexes [85]. The
A t τ = (α–β)/60 wh α is the largest β is the second largest
8
coordination angle around the metal ion. H th v τ is 1 for a trigonal bipyramidal and
0 for a square pyramidal geometry. Electron paramagnetic studies on such five coordinated
Cu(II)-complexes have shown that with gradual decrease in temperature from 295 to 103 K, the
trigonal bipyramidal geometry is converted to square pyramidal and this is accompanied by
shifting of the unpaired electron on copper(II) ion from the dz2 to the dx
2-y
2 orbital [86]. Thus,
although, affected by the nature of attached ligands, these two geometries have their
characteristic structural repercussions. Trigonal bipyramidal geometry is exemplified in Figs.
1.3-A and B [18,61,76,86].
A B
Figure 1.3: Examples of trigonal bipyramidal geometry around copper(II) ions. A,
[Cu2(μ-F)(μ-Lm*)2](BF4)3 where Lm* = m-bis[bis(3,5-dimethyl-1-pyrazolyl)-
methyl]benzene and B, [CuII(bpy)2(CN)-Cu
II(bpy)2]2(BF4)6·(H2O)3
The other most commonly encountered five coordinated geometry is square pyramidal
which is exemplified in mono- as well as di-nuclear structures as shown in Figs. 1.4-A
[87,88] and B, C and D [89,90], respectively, whereas Figs. 1.4-B and C represent oxygen
bridged square pyramidal structures of this work.
The structure shown in Fig. 1.4 D belongs to a very important class of copper
carboxylates having paddlewheel structures. The square base of the square pyramid around
9
each copper(II) ion is formed of four oxygen atoms with copper(II) ion slightly bulging out
of the plane towards the apical position. The dx2–y
2 orbital of the copper(II) ion containing the
unpaired electron is lying in the plane of the four Cu–O bonds of the square base. This
electron is coupled with that of the other copper(II) ion of the dinuclear complex due to a
super exchange interaction through carboxylate bridges and gives rise to a detectable
cumulative magnetic moment as a result of the intra-dimer coupling in case of paddlewheel
complexes [91,92].
A B
C D
Figure 1.4: Examples of square pyramidal geometry around copper(II) ions. A,
[Cu(isophthalate)(1,10-phenanthroline)2], B, [Cu2(1,10-phenanthroline)2(OH)2(H2O)2], C,
[Cu2( -bipyridine)2(4-florophenylacetate)4] and D, [Cu2(pyridine)2(4-florophenylacetate)4].
10
1.2.3 Hexa-coordinated Geometry: This type of geometry is exemplified by octahedral
structures, most frequently encountered in mono-nuclear copper(II) carboxylates as shown in
Fig. 1.5-A [74,93]. Figures 1.5-B and C show the unpublished structures of this work, having a
distorted octahedral geometry.
A B C
Figure 1.5: Examples of octahedral geometries around copper(II) ion. A, [Cu(fen)2(im)2]
where Hfen = Fenoprofen and im = imidazole, B, ( -bipyridine)(4-nitrophenylacetate)2]
and C, [Cu(1,10-phenanthroline)(2-nitrophenylacetate)2]
1.2.4 Di- and polynuclear copper(II) carboxylates
Mono-nuclear copper(II) carboxylates can be linked via spacer ligands as well as bridging
groups to result in dinuclear or polynuclear complexes. The bridging groups can be mono- or
polyatomic. The former category is exemplified by halogen [94], oxygen [95] etc., while the
latter by hydroxo-, aqua-[96], nitrato- [97] or carboxylate bridges [89,90].
The paddlewheel structure is the most frequent and familiar motif present in dinuclear
carboxylates and, accordingly, has been widely used for the illustration of the supra-molecular
structure of such complexes as well as polymeric ones [98,99]. The majority of the reported
complexes involves carboxylate derivatives resulting in paddlewheel cage-shaped dinuclear
[(OOCR)4M2] unit although other bridging ligands, for example N-heterocycles, may also be
11
employed [100]. Such dinuclear copper(II) carboxylate derivatives are found in some tissues of
mammals including blood plasma which regulate the specificity of copper(II) to amino acids
[101]. As revealed by the Cambridge Structural Database (CSD) data, more than 11% cases of
8328 crystal structures of copper(II) carboxylates are represented by a [(OOCR)4M2] type of
dimeric motif. Of structural importance is the reliability, symmetry and stability of this dimeric
secondary building unit (SBU) which facilitates the design and construction of structurally
diverse dimeric as well as polymeric copper(II) carboxylate systems having applications in
magnetism, catalysis, pharmaceuticals and absorbents [47, 102-104]. The general structures of
polynuclear copper(II) carboxylates involving paddlewheel SBUs are depicted in scheme 1.1.
Among these, type-I grows without additional ligands and an oxygen atom of the carboxylate
moiety acts as a tridentate bridging ligand [105]; in type-II, trans coordinating ligands serve as
bridges between copper(II) ions of the consecutive SBUs [60, 106] while in type-III, the
individual SBUs are linked via bridging ligands between Cu and O [107].
Cu
Cu
O
O
CRO
O
CR
O
O
C RO
O
CR
Cu
Cu
O
O
CRO
O
CR
O
O
C RO
O
CR
Cu
Cu
O
O
CRO
O
CR
O
O
C RO
O
CR
Cu
Cu
O
O
CRO
O
CR
O
O
C RO
O
CR
L
Cu
Cu
O
O
CRO
O
CR
O
O
C RO
O
CR
Cu
Cu
O
O
CRO
O
CR
O
O
C RO
O
CR
L L
I II III
Scheme 1.1: General structures of polynuclear paddlewheel copper(II) carboxylates. I, grown
without additional ligands, II, ligands bridging between two Cu and III, ligands bridging between
Cu and O.
The other frequently encountered dinuclear structure is oxygen bridged copper(II)
carboxylate. In such structures, the carboxylate moiety acts as monodentate, chelating bidentate
12
μ2-O bridging type. This results by introducing N-donor ligands of suitable coordinating
ability to the reaction mixture having paddlewheel structure. Most commonly employed N-donor
ligands t t t t h t h -
bipyridine, 1,10-phenanthroline and their substituted derivatives (shown in scheme 1.2).
Employing pyridine does not disturb the stable paddlewheel structure in solution but the
bidentate ligands convert the paddlewheel structure into oxygen bridged structure resulting in
N N N N
1,10-phenanthroline (phen)
N N
dipyrido-[3,2-d:2;3-f]-quinoxaline (dpq)
2,2-bipyridine (bpy)
N N
3,4,7,8-tetramethyl-1,10-phenanthroline (tmp)
Scheme 1.2: Common types of polypyridyl ligands.
a symmetric square pyramidal geometry around each copper(II) ion. Moreover, the bridging
oxygen and the planar organic moiety open up avenues to applications such as magnetism and
DNA binding ability, respectively. The relatively high biological activity is attributed to the
planar structure as well as the un-coordinated oxygen atom of the carboxylate moiety [108].
13
The synthesized complexes contain pyridine, -bipyridine and 1,10-phenanthroline as N-
donor ligands. There is a considerable variation in the structure and properties of the complexes
with the introduction of N-donor ligands. In the absence of any N-donor ligand, the structure is
polymeric where the dinuclear SBUs are linked via an oxygen atom of the carboxylate moiety
(type-I in scheme 1.1). Since there is no suitable apical ligand for the paddlewheel, the oxygen of
the neighboring paddlewheel serves as the apical ligand, resulting in an infinite array of the inter-
connected SBUs. However, with the addition of pyridine, this relatively weaker, inter-dinuclear
─ k th v th . Th wh t t
intact and the resulting structure consists of discrete dinulear molecules. The μ- -carboxylate
bridging is converted to a carboxylato-μ2- t t t t
t -bipyridine as an N-donor ligand. Now the structure is still dinuclear but quite
different than the paddlewheel; here the two copper(II) ions of the dinuclear molecule are
bridged by the oxygen atoms of carboxylate moieties. Introducing 1,10-phenanthroline to the
reaction mixture, the final product consists of mono-nuclear octahedral copper(II) units with two
chelating carboxylate moieties along with a 1,10-phenanthroline molecule. These results have
been discussed and correlated to the reaction conditions and reactants used. The effect of
synthetic procedure on structural parameters has been discussed and compared with some
already reported complexes.
1.3 Geometry around copper(II) ion in paddlewheel structures:
Copper(II) carboxylate dimers like this are common; there are hundreds of examples on the
Cambridge Crystallographic Database. The Cu···Cu distance is always short in these compounds
at 2.6-2.7 Å, because the geometry of the carboxylate ligands forces the Cu ions to be close.
14
H w v t th t th ─ th . Th t h
usually draws a bond between two copper ions because the Cu···Cu distance is short, but it is
meaningless.
Th ─ bond in such dinuclear complexes can't exist because the unpaired electron on
the copper(II) ions is in the dx2─
2 orbital that is not oriented the right way for a Cu···Cu bond,
th t t w th th (II) t w th ─ ds. The dz2
orbitals on both copper ions are pointing the right way for a Cu···Cu bond, but they are fully
t w th t h. S ─ th t
t . Th th ─ ─N ( . . ─ l ligand) bonds are real so the Cu ions
are square pyramidal, in such complexes [62,92, 109-112].
I th th z wh th ─ th q
the square pyramidal geometry around each copper while the apical ligand is pyridine and the
oxygen atom of the neighboring paddlewheel in case of dinuclear and polynuclear complexes,
respectively. Keeping in view the above discussion, such complexes have been drawn without
─ th t h n in paddlewheel complexes has been
described as square pyramidal in line with other authors [104,106].
1.4 Supra-molecular structures of copper(II) carboxylates:
In the modern era, supra-molecular chemistry and molecular recognition are determined by
non-covalent interactions. As opposed to covalent interactions which lead to the formation of
classical molecules, these non-covalent forces result in the formation of molecular clusters and
this latter process has a considerable impact on the overall chemistry of the subunits i.e., classical
molecules. Non-covalent interactions (called van der Waals interactions also) were recognized
15
for the first time by van der Waals in the 19th
century which helped to understand the non-ideal
h v . Th t h π···π t k t ···π ···π
interactions which form the basis of supra-molecular chemistry. These forces are accompanied
by halogen–halogen and C–H···X (X= O, N, F, Cl or Br etc.) contacts as well which serve as
additional forces taking part in the supra-molecular architecture [113-115]. Hydrogen bonding as
w π···π t t a central role in the chemistry, structure and function of biological
t 116 117]. t ···π t t t th t v t
t h 118 119] ···π t t h v h t t th h t
and future prospects of using anion receptors in molecular recognition [120-123]. These
interactions have been taken into account in crystal engineering for the design and synthesis of
new functional materials [124].
In case of metal complexes having organic ligands, the most common molecular
functionalities such as hydroxyl, floro, amino and carboxylate are involved in the spatial
arrangement of molecules that lead to repetitive van der Waals patterns [116]. The crystal
packing of such metal-organic complexes contains classical as well as non-classical hydrogen
bonds accompanied by stacking interactions and the desired properties and robustness in the
solid state structure is provided by the joint action of all these forces [125,126].
The synthesized copper(II) carboxylates in this work have carboxylate as dominant
molecular functionality accompanied by nitro, floro, chloro, bromo and methoxy groups. Since
the carboxylates are completely deprotonated, there is no sufficiently polar hydrogen left for a
true H-bonding interactions. The majority of the supra-molecular synthons arise as a result of
weak C–H···X (X= O, N, F, Cl and Br) interactions. However, some of the crystals contain
lattice water molecules which serve to keep the complex molecules together via extensive H-
16
bonding. Such complexes have relatively compact structure as indicated by the higher density of
their crystals. The effects of the aforementioned functionalities on the inter-molecular
arrangement in the crystal lattice have been studied and useful correlations have been made
which can help in crystal engineering of the related complexes.
1.5 Polypyridyl ligands:
Since a judicious selection of the ligands is necessary for the preparation of less toxic, target-
specific and preferably noncovalently binding metal based drugs [127,128], it has been found
that transition metal polypyridyl complexes fulfill almost all of these criteria due to their unusual
electronic properties, planar structure and diverse chemical reactivity resulting in noncovalent
interactions with DNA [129-133]. Common types of polypyridyl ligands have been shown in
Scheme 1.2. The first chemical nuclease [Cu(phen)2]+ that can successfully cleave DNA was
developed by Sigman and co-workers [134-139]. It has also been shown to exhibit potent
antiviral activity leading to the blockage of pro-viral DNA synthesis [140]. A number of simple
as well as substituted, homoliptic as well as mixed ligand polypryridyl copper(II) complexes, viz,
[Cu(tdp)(tmp)]-(ClO4)] [28] (where H(tdp) = 2-[(2-(2-hydroxy-ethylamino)ethylimino)methyl]-
phenol), [Cu(dpq)2(H2O)]2+
[141], [Cu-(L)Cl2]2+
(where L = - th - -
t 1 ] - -1- th - -bipyridyl cation) [143] and [Cu(imda)L] [144-146]
(where imda = iminodi- acetic acid and L = 1,10-phenanthroline and 5,6-dimethyl-1,10-
phenanthroline) have been reported to hydrolyze the nucleic acid phosphate back bone. Recently,
Reedjik and co-workers have synthesized structurally similar copper(II) complexes [147,148].
They have screened the synthesized complexes for their self-activated DNA cleavage and
cytotoxic effects on L1210 murine leukemia and A 2780 human ovarian carcinoma cell lines and
17
proved successful. Similarly, hydrolytic cleavage of plasmid DNA at pysiological pH as well as
efficient cytotoxicity to a human carcinoma cell line has been reported for a dimeric copper(II)
complex derived from the unsymmetric ligand, N-(2-hydroxybenzyl)- -tris(2-
pyridylmethyl)-1,3-diaminopropan-2-ol [71].
Prompted by the biological potency of these complexes, we have synthesized various
carboxylate derivatives of pyridine as well as simple polypyridyl ligands. The phenyl ring of the
carboxylate ligand combined with the planar polypyridyl ring systems was expected to bind to
DNA non-covalently with a major contribution of intercalative mode of interaction between the
DNA base pairs. These complexes have been screened for electrochemical redox as well as DNA
binding ability through cyclic voltammetry and UV-visible spectrophotometry. Consistent with
their structure, the synthesized complexes exhibited a mixed intercalative as well as electrostatic
mode of interaction with DNA. Moreover, the redox properties of the central copper(II) ion have
been influenced in accordance to the electronic properties of the attached ligands.
1.6 General Account of DNA Activity:
Metallopharmaceuticals are introduced to the body in an inactive form called pro-drug which
is metabolized in vivo to the active species. In the pro-drug form, there is no risk of drug
deactivation by the cellular components before reaching its target and ideally its activation
occurs in the tissue of interest [8,13]. Pro-drug activation can be triggered by light, pH or redox
environment [149,150]. The infected areas of the biological systems such as tumors are
characterized by an insufficient supply of fresh blood, low oxygen level and higher concentration
of cellular reducing agents like glutathione, resulting in a more reducing environment than the
surrounding normal tissues. This hypoxic condition of the cancerous tissues has been exploited
18
for the therapeutic selectivity where metal based drugs are selectively activated under such
reducing environment. Having biologically accessible redox potential is the clear advantage of
metal based drugs over the organic drugs. In this regard, N and O-donor Cu(II) complexes have
already been synthesized and tested for their biological activities under aerobic and hypoxic
conditions [151-155] and have been found to exhibit significantly higher activities under hypoxic
as compared to aerobic conditions. Accordingly, the most successful way of activating the pro-
drug is the redox activation via exposure to the reducing cellular environment [13,155,156-158].
It has been confirmed as a result of numerous biological experiments that the primary
intracellular target of these anti-cancer drugs is DNA, resulting in blocking of cell division and
cell death [159-164]; the interaction of the complexes with DNA forms the basis of their
therapeutic index as well as DNA probing.
Several bio-analytical and bio-physical techniques are available to study the DNA binding
properties of metal complexes. However, owing to its low cost, easy operation and high
sensitivity, electrochemical techniques are being used extensively to study and investigate the
interaction and binding properties of electro-active substances such as anticancer drugs [165-
168] and metal complexes [169-172] to DNA. Owing to the well-documented and useful electro-
activity of copper(II) complexes, the synthesized complexes were subjected to electrochemical
solution study before and after DNA addition. The DNA binding ability has been confirmed
through UV-Visible spectrophotometry as well. The mode of interaction of the synthesized
complexes with DNA has been judged from the peak shift in cyclic voltammetry and UV-Visible
spectroscopy. The results of both the techniques are in agreement and support each other. A
mixed electrostatic as well as intercalative mode of interaction was observed for the complexes.
The former mode of interaction has been attributed to the copper(II) ion while the latter to the
19
presence of enough planar groups in the molecular structure of each complex. These complexes
were aimed to bind to DNA non-covalently and this has been born out through these
experimental techniques. The results of the present work have been correlated mutually as well
as with already reported complexes present in literature.
1.7 Effect of ligands on structure and properties:
Ligand plays crucial role in governing the arrangement of metal ions and nuclearity of the
resulting complex. Applying this strategy, synthetic chemists have successfully synthesized
various multi-functional compounds (ligands) and their metal complexes of desired structure and
properties [73,173-178]. The supra-molecular architecture as well as the distance and nature of
interaction between secondary building units are a function of the groups attached to the ligands.
The length of different spacer groups, conformational preferences and ability to transmit
magnetic exchanges in a polymeric complex is affected significantly by the organic ligands that
bind the metal ions in various ways [179-187]. The properties of the resulting complex are
modified to a great extent by the nature of the attached ligands. For example an important
property of the transition metal complexes is the sensitivity of the redox property of the central
metal core to the nature of the attached ligands so that its redox potential can be altered
according to that of the biological system under consideration. This is accomplished by varying
the electronic properties of the attached ligands which in turn affect the electrostatic properties
and the electron transfer efficiency of the central metal ion. There is a proportionate change in
the redox properties of metal centered copper(II) carboxylates with the number of N-donor
ligator atoms [37, 54, 73, 188-191], allowing its unambiguous comparative study. Similarly,
thermodynamic and kinetic stability, cytotoxicity and lipophilicity of the copper(II) carboxylate
20
complexes have been shown to be significantly influenced by the alkyl substituents of the ligands
attached to the central metal ion. It was also shown that bulky alkyl groups can enhance the
lipophilicity of the complex but, at the same time, hamper the approach of sulfhydryl reductants
through steric hindrance [192-195]. Moreover, non-steroidal anti-inflammatory drugs have been
shown to exhibit significantly higher anti-inflammatory activity on complexation to copper(II) as
compared to the un-complexed parent drug [196,197].
Since the solubility of a drug is crucial for its in vivo action, coordination of a water soluble
ligand to the otherwise insoluble complex has been shown to enhance its activity through
enhanced solubility [63,198,199]. The role of ligand in taking the metal based drug to its target
tissue [200,201] and a tenfold increase in the cellular uptake of the drug as a result of the
attachment of a ligand having high 1-octanol/H2O partition coefficient (log P ≈ 3.4) has been
observed [202,203].
Pyridine derivatives have long been recognized to act as diverse bio-active, physiological as
well as medicinal agents [28,127,204]. In the present work, the required stability to these
complexes has been provided with special ligator properties such as polarized covalent bond
(which is more stable than an ordinary covalent bond) of carboxylate group. Thus the complexes,
beset with planar moieties, were expected to interact with DNA in a non-covalent manner. As
expected, all of the synthesized complexes have been found to interact with DNA through a
mixed intercalative as well as electrostatic mode of interaction. The significant contribution of
intercalation is in accordance to the presence of planar aromatic rings both homo- as well as
hetero-cyclic. The variation in redox properties as well as DNA binding potency of the
synthesized copper(II) carboxylates has been successfully correlated with ligand and metal based
21
structural features and the corresponding values compared with some already reported
structurally related complexes.
1.8 Effect of metal ion:
The role of metal ion in governing the properties of the metal based complexes and steering
those to the desired applications is of prime importance. The multiple role of the metal ion is
manifested in determining the geometry of the resulting complex [93,205-207], controlling the
spatial arrangement of the coordinated species [42,208] and enhancing the biological activity as
well as assembling two or more of the bio-active ligands [209-211]. Poly-nuclear complexes
have been found to be more efficient than the corresponding mono-nuclear analogues and the
enhancement in the biological potency has been attributed to the cumulative effect of the metal
ions [30,197,212,213]. Of particular importance is the variable redox activity of copper(II) ion
which is the basis for its crucial role in the catalytic activity of oxido-reductases. Moreover, the
copper(II) ion acts as an electron relay through easily accessible redox states (CuI/II and
CuII/III) (e.g., plastocyanin in photosynthesis) and this property is enhanced in the dinuclear
complexes [27,214-217]. The relatively high nucleobase affinity and efficient DNA-binding
activity of copper(II) carboxylates stem from the relatively strong Lewis acidity of Cu2+
ion,
compared to other less acidic transition metal ions. However, due to the weak nature of the
electrostatic interaction of the complexes with negatively charged DNA, the design and
development of complexes binding with DNA through intercalative and groove binding modes is
of prime importance. This is also important owing to the side effects of the covalently bonding
platinum based complexes with DNA [218-220]
22
As mentioned in section 1.6, extensive research is underway to design target specific self
activatable metal based drugs for the infected tissues, where the most challenging issue is the
activation of the pro-drug on reaching its target tissue. The use of oxidizing agents (as trigger)
for the activation has been debated for its harmful side products formed so the self-induced
redox-activation of the drug via exposing to the hypoxic environment of the target tissue is
considered the most desirable and found successful for redox active metal based drugs
[13,161,162,221-224]. The ability to undergo structural change or electron transfer reactions
leading to the activation of the metal based drugs under accessible biological potential-drop are
critically dependent on the central metal ion of the drug molecule [151,152]. Copper complexes
have long been recognized to have different reactivity and properties in different oxidation states
[225-229]. Moreov th t ‘h ’ the copper(II) ion allows the attached ligands
to modify its redox ability and structural properties, easily [71,176,230].
The aim of the study was to fulfill both of the above mentioned requirements, i.e., design and
synthesis of self-activatable electro-active complexes and their non-covalent interaction with
DNA. The former property has been checked via cyclic voltammetry while the latter by DNA
binding studies. The synthesized complexes undergo self-induced redox activity (Cu(I)/ Cu(II)
and Cu(II)/ Cu(III)) in mixed water/DMSO solvent system under a potential drop accessible in
biological systems. The facile inter-conversion of these redox states and the re-shuffling of the
redox potential through the attached ligands herald their potential use as self-activatable drugs.
The DNA binding activity through cyclic voltammetry and UV-visible spectrophotometry has
shown a mixed electrostatic as well as intercalative mode of interaction with salmon sperm
DNA. Thus the objectives of the study have been achieved at least partially which show the
worth of the research work undertaken. This has also become evident that the synthesized
23
complexes could find interesting applications in various biological as well as material science
research areas. The implications of the present study have been discussed and correlated with
already reported complexes.
24
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55
Chapter 2
Experimental
2.1 Materials and methods
Anhydrous CuSO4, 4–methyl–, 4–methoxy–, 4–bromo–, 4–chloro–, 4–floro–, 4–nitro–, and 2–
t h t h t –bipyridine, 1,10–phenanthroline,
NaHCO3, KCl and sodium salt of the salmon sperm DNA were obtained from Fluka,
Switzerland. Solvents like methanol, chloroform and dimethyl sulfoxide were obtained from
Merck, Germany and used as such without drying and further purification. Water used was
singly distilled. The melting points were obtained in a capillary tube using a Gallenkamp, serial
number C040281, U.K, electro–thermal melting point apparatus. FT–IR spectra were recorded
on a Nicolet–6700 FT–IR spectrophotometer, Thermo Scientific, USA, in the range from 4000 to
400 cm−1
using attenuated total reflectance (ATR) sampling technique.
2.2 Single crystal X–ray crystallographic studies
2.2.1 Complexes 1b, 2a, 2b, 4a, 5a, 6b and 7a
Diffraction data for these complexes were collected at 100(2) K on beamline MX1 at the
A t S h t (λ = 0.708 7 Å) 1]. Th t t t
pattern was performed by XDS software [2]. The crystal structures were solved by a direct
method followed by refinement against F2 with full–matrix least–squares using the program
SHELXL–97 [3]. All non–hydrogen atoms were refined with anisotropic displacement
parameters.
56
2.2.2 Complexes 1a, 3a, 4b and 5b
Crystallographic data for these complexes were collected at 298 K using an Oxford Diffraction
Gemini S Ultra CCD diffractometer using graphite-monochromated Mo– α t (λ =
0.71073 Å). Data reduction and empirical absorption corrections were accomplished using
CrysAlis Pro (Oxford, Diffraction, version 171.33.66). Structures were solved by direct method
with SHELXS–86 and refined by full–matrix least–squares analysis against F2 with SHELXL–97
[4] within the WinGX package [5]. The drawings of the complexes were produced using
ORTEP3 [6].
2.2.3 Complexes 1, 1c, 2, 2c, 3b, 5c, 6, 6a, 6c, 7b, 8a, 8b, and 8c
X–ray single crystal analyses of these complexes were performed at 296 K on a Bruker Kappa
APEX–II CCD diffractometer using graphite-monochromated Mo– α t (λ = 0.71073 Å).
The crystal structures were solved by direct method followed by final refinement carried on F2
with full–matrix least–squares using the program SHELXL–97 [3].
2.3 DNA interaction study by cyclic voltammetry
Voltammetric experiments were performed using an SP–300 potentiostate, serial number 0134,
BioLogic Scientific Instruments, France. Measurements were carried out in aqueous DMSO
(1:4) solution containing 0.01 M KCl, under an N2 saturated environment in a conventional
three-electrode cell with saturated silver/silver chloride electrode (Ag/AgCl) as reference, a thin
platinum wire as counter and a bare glassy carbon electrode (GCE) with a surface area of 0.196
cm2 as the working electrode. Prior to experiment the GCE was polished with alumina (Al2O3)
on a nylon buffing pad followed by washing with acetone and finally with distilled water.
Electrochemical measurements were carried out at room temperature (25 ± 0.5 o
C).
57
An appropriate amount of the sodium salt of the salmon sperm DNA (SSDNA) was dissolved in
distilled water and stirred overnight. The nucleotide to protein (N/P) ratio of ∼1.9 was obtained
from the ratio of absorbance at 260 and 280 nm (A260/A280 = 1.9), indicating that the SSDNA is
sufficiently free from protein [7]. The SSDNA concentration was determined via absorption
spectroscopy using the molar absorption coefficient of 6600 M−1
cm−1
(260 nm) for SSDNA [8].
Voltammograms of 3 mM solution of all the complexes prepared in aqueous DMSO (1:4) were
t k th 10 0 30 0 0 60 70 80 μM NA. M v
order to calculate various redox parameters, cyclic voltamograms were also recorded on 50, 75,
100, 125, 150, 175, 200, 400, 600, 900, 1200 and 1400 mV s−1
, before and after adding DNA to
the solutions of the complexes.
2.4 DNA interaction study by absorption spectroscopy
Solutions of the complexes for UV–Visible spectrophotometric analysis were prepared in
aqueous DMSO (1:4) at a concentration of 6 mM. The UV absorption titrations were performed
by keeping the concentration of the complexes fixed while varying the SSDNA concentration.
Equivalent solutions of SSDNA were added to each of the complex and reference solutions to
eliminate the absorbance of SSDNA itself. Complex–SSDNA solutions were allowed to incubate
for 30 minutes at room temperature and the spectra were recorded at room temperature (25 ± 1
oC) using cuvettes of 1 cm path length.
2.5 Antibacterial studies
All the synthesized complexes were tested for their bactericidal potential against four bacterial
strains; three Gram-positive (Micrococcus luteus, Staphylococcus aureus and Bacillus subtilis)
and one Gram-negative (Escherichia coli). Antibacterial activity was ascertained by using the
agar well-diffusion method [9,10]. Broth culture (0.75 mL) containing ca. 106 colony forming
58
units (CFU) per mL of the test strain was added to 75 mL of agar medium serving as nutrient, at
45 oC. The mixture was mixed well and then poured into a sterile petri plate of 14 cm diameter.
After solidification, 8 mm wells were dug into the medium with the help of a sterile metallic
. Th 100 μL MS t (1 /L) the test complexes were added to the respective
labeled wells. Here the standard antibacterial drug Cefixime (1 mg mL) was used as positive
control while the DMSO served as negative control. The plates for each bacterial strain were
prepared in triplicate followed by their aerobic incubation at 37 oC for 24 h. The diameter of the
zone around each well, showing complete inhibition (mm) was measured to determine the
antibacterial activity of the complexes.
2.6 Antifungal studies
Selective complexes were screened for their antifungal activity against three fungal strains
(Mucor piriformis, Aspergillus Niger, Helminthosporium solani) using the agar tube dilution
method [10,11]. Test tubes containing 4 mL Sabouraud dextrose agar (SDA) medium were screw
caped and autoclaved at 121 oC for 15 min. The tubes were subsequently allowed to cool at 50
o w th t 66.6 μL th t k t t t t h th
tubes having non-solidified SDA. The concentration of the stock solutions of the complexes was
1 / L MS wh th t th t w 00 μ / L.
These tubes were then placed in a slanting position and allowed to solidify at room temperature.
A 4 mm diameter piece of inoculum was used to inoculate each of these tubes from a fungal
culture prepared seven days earlier. DMSO and Turbinafine (200 mg/mL) present in the media
served as negative and positive control, respectively. The linear growth (mm) was measured to
determine the growth of each fungal strain after incubating the tubes at 28 oC for 7 days. Growth
59
inhibition by the complex was calculated with the help of the following equation (equation 2.1)
using the growth in vehicle control as a reference:
)
) ) (2.1)
2.7 General procedures for the synthesis of complexes
2.7.1 Polynuclear complexes, 1–8
Sodium bicarbonate (0.504 g, 6 mmol) was reacted with an equimolar quantity (6 mmol each) of
substituted phenyl acetic acid [4–methyl (0.90 g), 4–H (0.817 g), 4–methoxy (0.997 g), 4–bromo
(1.290 g), 4–chloro (1.03 g), 4–floro (0.925 g), 4–nitro (1.086 g) and 2–nitro (1.086 g)] for
complexes 1–8 at 60 oC in distilled water. After complete neutralization of the acid with base, the
aqueous solution of copper sulphate (0.240 g, 3 mmol) was added drop wise. The reaction
mixture was stirred for 4 h at 60 oC as depicted in scheme 2.1 which is termed as step–I for all
further discussions. The final product was filtered, washed thoroughly with distilled water and
air dried. The solid was recrystallized from a mixture of chloroform and methanol (1:1) and
characterized using FT–IR and X–ray single crystal analysis.
2.7.2 Dinuclear complexes
2.7.2.1 Paddlewheel complexes, 1a–8a
For complexes 1a–8a, step–I was followed and after the completion of the reaction, methanolic
solution of pyridine (0.24 ml, 3 mmol) was added to each of these reaction mixtures. Stirring was
continued for further 3 h under the reaction conditions as depicted in scheme 2.2. The final
product of all the complexes was filtered, washed thoroughly with distilled water and air dried.
60
H2C ONa
O
H2C OH
O
NaHCO360° C
CuSO4 60° C
Cu
Cu
O
O
CO
O
C O
O
CO
O
C
Cu
Cu
O
O
C O
O
CO
O
CO
O
C
R
R
R
RR
R
R
R
R
R
Scheme 2.1: Synthetic procedure for polynuclear complexes, where R = 4–CH3 (1), H (2), 4–
CH3–O (3), 4–Br (4), 4–Cl (5), 4–F (6), 4–NO2 (7) and 2–NO2 (8)
61
Cu
Cu
O
O
C O
OC O
O
CO
O
C
Cu
Cu
O
O
C O
OC
O
O
CO
O
C
R
R
R
RR
R
R
pyridine
N Cu Cu
O O
C
O OC
OO
C
OO
C
N
RR
R
R
R
60° C
Scheme 2.2: Synthetic procedure for dinuclear paddlewheel complexes, where R= 4–CH3 (1a), H
(2a), 4–CH3–O (3a), 4–Br (4a), 4–Cl (5a), 4–F (6a), 4–NO2 (7a) and 2–NO2 (8a)
62
Cu
Cu
O
O
C O
OC O
O
CO
O
C
Cu
Cu
O
O
C O
OC
O
O
CO
O
C
R
R
R
R
R
R
R
2,2-bipyridine
CuCu
N
NN
N
O
O
O
O
O
O
OO
R
R
R
R
R
60° C
Scheme 2.3: Synthetic procedure for dinuclear O–bridged complexes, where R= 4–CH3 (1b), H
(2b), 4–CH3–O (3b), 4–Br (4b), 4–Cl (5b), 4–F (6b) and 2–NO2 (8b)
63
Cu
Cu
O
O
C O
OC O
O
CO
O
C
Cu
Cu
O
O
C O
OC
O
O
CO
O
C
R
R
R
R
R
R
R
1,10phenanthroline
Cu
N
NO
O
O
O
R
R
R
60° C
Scheme 2.4: Synthetic procedure for mononuclear complexes, where R= 4–CH3 (1c), 4–CH3–O
(3c), 4–Br (4c), 4–Cl (5c), 4–F (6c), 4–NO2 (7c) and 2–NO2 (8c)
64
The solid was recrystallized from a mixture of chloroform and methanol (1:1) and characterized
by using FT–IR and X–ray single crystal analysis.
2.7.2.2 O–bridged Complexes, 1b–8b
For complexes 1b–8b, step–I w w t th t th t –
bipyridine (0.468 g, 3 mmol) was added to each of these reaction mixtures with constant stirring
which was continued for 3 h with reaction conditions as depicted in scheme 2.3. The final
product of all the complexes was filtered, washed thoroughly with distilled water and air dried.
The solid was recrystallized from a mixture of chloroform and methanol (1:1) and characterized
using FT–IR and X–ray single crystal analysis. All the complexes (except 7b) were dinuclear
whereas 7b was found mononuclear.
2.7.3 Mononuclear complexes, 1c–8c
For complexes 1c–8c step–I was followed and after the completion of the reaction, solid 1,10–
phenanthroline (0.540 g, 3 mmol) was added to each of these reaction mixtures with constant
stirring which was continued for further 3 h under reaction conditions as depicted in scheme 2.4.
The final product was filtered, washed thoroughly with distilled water and air dried. The solid
obtained was recrystallized from a mixture of chloroform and methanol (1:1) and characterized
using FT–IR and X–ray single crystal analysis. All the complexes (except 2c) were mononuclear
while 2c was found dinuclear.
Complex 1: Blue crystals; m.p. 208–209 oC; yield (60%). FT–IR (cm
−1): 1612 ν(OCO)asym, 1382
ν(OCO)sym ∆ν = 30 2880 νCH3, 2960 νCH2, 3030 ν(Ar–H), 1580, 1445 νAr(C=C), 422 ν(Cu–
O).
Complex 2: Light blue crystals; m.p. 228–230 oC; yield (70%). FT–IR (cm
−1): 1590 ν(OCO)asym,
1394 ν(OCO)sym ∆ν = 196 2968 νCH2, 3050 ν(Ar–H), 1575, 1435 νAr(C=C), 418 ν(Cu–O).
65
Complex 3: Light blue crystals; m.p. 248–249 oC; yield (70%). FT–IR (cm
−1): 1610 ν(OCO)asym,
1415 ν(OCO)sym ∆ν = 19 2855 νCH3, 2929 νCH2, 1040 ν(CH3–O), 3008 ν(Ar–H), 1243 ν(Ar–
O), 1586, 1438 νAr(C=C), 416 ν(Cu–O).
Complex 4: Blue crystals; m.p. 200–201 oC; yield (78%). FT–IR (cm
−1): 1588 ν(OCO)asym, 1388
ν(OCO)sym ∆ν = 200, 2920 νCH2, 3020 ν(Ar–H), 1600, 1450 νAr(C=C), 986 ν(Ar–Br), 414
ν(Cu–O).
Complex 5: Blue crystals; m.p. 190–192 oC; yield (70%). FT–IR (cm
−1): 1598 ν(OCO)asym, 1409
ν(OCO)sym ∆ν = 189, 2940 νCH2, 3047 ν(Ar–H), 1026 ν(Ar–Cl), 1585, 1434 νAr(C=C), 423
ν(Cu–O).
Complex 6: Blue crystals; m.p. 218–220 oC; yield (60%). FT-IR (cm
−1): 1592 ν(OCO)asym, 1395
ν(OCO)sym ∆ν = 197 2948 νCH2, 3020 ν(Ar–H), 1505 νAr(C=C), 1211 ν(Ar–F), 420 ν(Cu–O).
Complex 7: Light blue crystals; m.p. 190–191 oC; yield (65%). FT–IR (cm
−1): 1615 ν(OCO)asym,
1436 ν(OCO)sym ∆ν = 179, 2920 νCH2, 3052 ν(Ar–H), 1580, 1437 νAr(C=C), 1431, 1341
ν(NO2), 414 ν(Cu–O).
Complex 8: Light blue crystals; m.p. 210–211 oC; yield (70%). FT–IR (cm
−1): 1620 ν(OCO)asym,
1422 ν(OCO)sym ∆ν = 198, 2935 νCH2, 3059 ν(Ar–H), 1570, 1484 νAr(C=C), 1435, 1332
ν(NO2), 418 ν(Cu–O).
Complex 1a: Light blue crystals; m.p. 185–186 oC; yield (80%). FT–IR (cm
−1): 1625
ν(OCO)asym, 1418 ν(OCO)sym ∆ν = 07 2860 νCH3, 2967 νCH2, 3071 ν(Ar–H), 1605, 1500
νAr(C=C), 416 ν(Cu–O), 480 ν(Cu–N).
Complex 2a: Light blue crystals; m.p. 185–187 oC; yield (80%). FT–IR (cm
−1): 1624
ν(OCO)asym, 1446 ν(OCO)sym ∆ν = 178 2921 νCH2, 3032 ν(Ar–H), 1588, 1427 νAr(C=C), 422
ν(Cu–O), 478 ν(Cu–N).
66
Complex 3a: Blue crystals; m.p. 145–147 oC; yield (80%). FT–IR (cm
−1): 1580 ν(OCO)asym,
1398 ν(OCO)sym ∆ν = 182, 2835 νCH3, 2929 νCH2, 1029 ν(CH3–O), 3008 ν(Ar–H), 1243 ν(Ar–
O), 1613, 1464 νAr(C=C), 418 ν(Cu–O), 478 ν(Cu–N).
Complex 4a: Light blue crystals; m.p. 175–176 oC; yield (78%). FT–IR (cm
−1): 1620
ν(OCO)asym, 1430 ν(OCO)sym ∆ν = 190, 2920 νCH2, 3020 ν(Ar–H), 1610, 1460 νAr(C=C), 986
ν(Ar–Br), 414 ν(Cu–O), 468 ν(Cu–N).
Complex 5a: Blue crystals; m.p. 189–190 oC; yield (70%). FT–IR (cm
−1): 1692 ν(OCO)asym,
1492 ν(OCO)sym ∆ν = 200, 2926 νCH2, 3037 ν(Ar–H), 1096 ν(Ar–Cl), 1585, 1434 νAr(C=C),
417 ν(Cu–O), 470 ν(Cu–N).
Complex 6a: Light blue crystals; m.p. 182–183 oC; yield (70%). FT–IR (cm
−1): 1650
ν(OCO)asym, 1442 ν(OCO)sym ∆ν = 208, 2920 νCH2, 3031 ν(Ar–H), 1162 ν(Ar–F), 1586, 1438
νAr(C=C), 422 ν(Cu–O), 475 ν(Cu–N).
Complex 7a: Blue crystals; m.p. 150–152 oC; yield (70%). FT–IR (cm
−1): 1624 ν(OCO)asym,
1417 ν(OCO)sym ∆ν = 207, 2950 νCH2, 3032 ν(Ar–H), 1598, 1417 νAr(C=C), 1431, 1341
ν(NO2), 423 ν(Cu–O), 481 ν(Cu–N).
Complex 8a: Light blue crystals; m.p. 160–161 oC; yield (70%). FT–IR (cm
−1): 1582
ν(OCO)asym, 1390 ν(OCO)sym ∆ν = 192, 2955 νCH2, 3039 ν(Ar–H), 1570, 1484 νAr(C=C), 1439,
1330 ν(NO2), 422 ν(Cu–O), 480 ν(Cu–N).
Complex 1b: Light blue crystals; m.p. 150–151 oC; yield (70%). FT–IR (cm
−1): 1614
ν(OCO)asym, 1362 ν(OCO)sym ∆ν = 252, 2970 νCH2, 2919 νCH3, 3020 ν(Ar–H), 1582, 1425
νAr(C=C), 416 ν(Cu–O), 480 ν(Cu–N).
67
Complex 2b: Light blue crystals; m.p. 185–186 oC; yield (80%). FT–IR (cm
−1): 1599
ν(OCO)asym, 1366 ν(OCO)sym ∆ν = 33 2931 νCH2, 3032 ν(Ar–H), 1580, 1427 νAr(C=C), 422
ν(Cu–O), 478 ν(Cu–N).
Complex 3b: Blue crystals; m.p. 165–166 oC; yield (80%). FT–IR (cm
−1): 1626 ν(OCO)asym,
1368 ν(OCO)sym ∆ν = 258, 2865 νCH3, 2949 νCH2, 1029 ν(CH3–O), 3008 ν(Ar–H), 1243 ν(Ar–
O), 1603, 1464 νAr(C=C), 418 ν(Cu–O), 478 ν(Cu–N).
Complex 4b: Light blue crystals; m.p. 160–162 oC; yield (78%). FT–IR (cm
−1): 1607
ν(OCO)asym, 1360 ν(OCO)sym ∆ν = 247, 2960 νCH2, 3042 ν(Ar–H), 1600, 1440 νAr(C=C), 982
ν(Ar–Br), 414 ν(Cu–O), 468 ν(Cu–N).
Complex 5b: Blue crystals; m.p. 145–146 oC; yield (80%). FT–IR (cm
−1): 1615 ν(OCO)asym,
1380 ν(OCO)sym ∆ν = 235, 2980 νCH2, 3084 ν(Ar–H), 1597, 1473 νAr(C=C), 1008 ν(Ar–Cl),
417 ν(Cu–O), 470 ν(Cu–N).
Complex 6b: Light blue crystals; m.p. 150–152 oC; yield (70%). FT–IR (cm
−1): 1614
ν(OCO)asym, 1388 ν(OCO)sym ∆ν = 226, 2975 νCH2, 3084 ν(Ar–H), 1598, 1473 νAr(C=C), 1217
ν(Ar–F), 422 ν(Cu–O), 475 ν(Cu–N).
Complex 7b: Blue crystals; m.p. 175–176 oC; yield (70%). FT–IR (cm
−1): 1568 ν(OCO)asym,
1438 ν(OCO)sym ∆ν = 130, 2950 νCH2, 3032 ν(Ar–H), 1595, 1447 νAr(C=C), 1431, 1341
ν(NO2), 422 ν(Cu–O), 481 ν(Cu–N).
Complex 8b: Light blue crystals; m.p. 160–162 oC; yield (70%). FT–IR (cm
−1): 1617
ν(OCO)asym, 1362 ν(OCO)sym ∆ν = 255, 2970 νCH2, 3052 ν(Ar–H), 1570, 1484 νAr(C=C), 1441,
1328 ν(NO2), 422 ν(Cu–O), 480 ν(Cu–N).
68
Complex 1c: Blue crystals; m.p. 220–221 oC; yield (70%). FT–IR (cm
−1): 1541 ν(OCO)asym,
1427 ν(OCO)sym ∆ν = 114, 2965 νCH2, 2935 νCH3, 3055 ν(Ar–H), 1582, 1425 νAr(C=C), 416
ν(Cu–O), 480 ν(Cu–N).
Complex 2c: Light blue crystals; m.p. 185–186 oC; yield (65%). FT–IR (cm
−1): 1643
ν(OCO)asym, 1388 ν(OCO)sym ∆ν = 2931 νCH2, 3032 ν(Ar–H), 1580, 1427 νAr(C=C), 423
ν(Cu–O), 481 ν(Cu–N).
Complex 3c: Blue crystals; m.p. 165–167 oC; yield (60%). FT–IR (cm
−1): 1611 ν(OCO)asym,
1473 ν(OCO)sym ∆ν = 138, 2835 νCH3, 2962 νCH2, 1029 ν(CH3–O), 3018 ν(Ar–H), 1240 ν(Ar–
O), 1600, 1464 νAr(C=C), 422 ν(Cu–O), 468 ν(Cu–N).
Complex 4c: Light blue crystals; m.p. 205–206 oC; yield (68%). FT–IR (cm
−1): 1595
ν(OCO)asym, 1466 ν(OCO)sym ∆ν = 129, 2966 νCH2, 3048 ν(Ar–H), 1590, 1440 νAr(C=C), 991
ν(Ar–Br), 423 ν(Cu–O), 470 ν(Cu–N).
Complex 5c: Blue crystals; m.p. 215–216 oC; yield (60%). FT–IR (cm
−1): 1606 ν(OCO)asym,
1486 ν(OCO)sym ∆ν = 120, 2946 νCH2, 3062 ν(Ar–H), 1590, 1473 νAr(C=C), 1018 ν(Ar–Cl),
418 ν(Cu–O), 478 ν(Cu–N).
Complex 6c: Blue crystals; m.p. 178–180 oC; yield (65%). FT–IR (cm
−1): 1580 ν(OCO)asym,
1444 ν(OCO)sym ∆ν = 136, 2962 νCH2, 3084 ν(Ar–H), 1595, 1473 νAr(C=C), 1206 ν(Ar–F), 414
ν(Cu–O), 468 ν(Cu–N).
Complex 7c: Blue crystals; m.p. 175–176 oC; yield (60%). FT–IR (cm
−1): 1585 ν(OCO)asym,
1445 ν(OCO)sym ∆ν = 140, 2948 νCH2, 3062 ν(Ar–H), 1575, 1497 νAr(C=C), 1431, 1341
ν(NO2), 413 ν(Cu–O), 475 ν(Cu–N).
69
Complex 8c: Blue crystals; m.p. 182–185 oC; yield (65%). FT–IR (cm
−1): 1582 ν(OCO)asym,
1440 ν(OCO)sym ∆ν = 142, 2962 νCH2, 3052 ν(Ar–H), 1572, 1464 νAr(C=C), 1432, 1331
ν(NO2), 417 ν(Cu–O), 470 ν(Cu–N).
70
References
[1] T. M. McPhillips, S. E. McPhillips, H. J. Chiu, A. E. Cohen, A. M. Deacon, P. J. Ellis, E.
Garman, A. Gonzale, N. K. Sauter, R. P. Phizackerley, S. M. Soltis, P. Kuhn, Blu-Ice and
the Distributed Control System: Software for data acquisition and instrument control at
macromolecular crystallography beamlines, J. Synchrotron Rad., 9 (2002) 401–406.
[2] W. Kabsch, XDS, Acta Cryst., D 66 (2010) 125–132.
[3] G. M. Sheldrick, A short history of SHELX, Acta Cryst., A 64 (2008) 112–122.
[4] G. M. Sheldrick, SHELXL-97, Program for the refinement of crystal structure;
University of Göttingen: Germany, 1997.
[5] L. J. Farrugia, WinGX suite for small-molecule single-crystal crystallography, J. Appl.
Crystallogr., 32 (1999) 837–838.
[6] L. J. Farrugia, XRDIFF: Simulation of X-ray diffraction patterns, J. Appl. Crystallogr.,
30 (1997) 565–566.
[7] S. Dey, S. Sarkar, H. Paul, E. Zangrando, P. Chattopadhyay, Copper(II) complex with
tridentate N-donor ligand: Synthesis, crystal structure, reactivity and DNA binding study,
Polyhedron, 29 (2010) 1583–1587.
[8] C. V. Sastri, D. Eswaramoorthy, L. Giribabu, B. G. Maiya, DNA interactions of new
mixed-ligand complexes of cobalt(III) and nickel(II) that incorporate modified
phenanthroline ligands, J. Inorg. Biochem., 94 (2003) 138–145.
[9] M. Sirajuddin, S. Ali, N.A. Shah, M.R. Khan, M. N. Tahir, Synthesis, characterization,
biological screenings and interaction with calf thymus DNA of a novel azomethine
71
3-((3,5-dimethylphenylimino)methyl)benzene-1,2-diol, Spectrochim. Acta Part A, 94
(2012) 134–142.
[10] A. Rehman, M. I. Choudhary, W. J. Thomsen, Bioassay Techniques for Drug
Development, Harwood Academic Press, Amsterdam, The Netherlands, (2001) pp. 14-
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[11] B. N. Mayer, N. R. Ferrigni, J. E. Putnam, L. B. Jacobson, D. E. Nichols, J. L.
Mclaughlin, Brine Shrimp: A convenient general bioassay for active plant constituents,
Planta Med., 45 (1982) 31–34.
72
Chapter 3
Results and Discussion
Copper(II) complexes with substituted phenyl acetates and N-donor aromatic
heterocyclic rings have been synthesized by following schemes 2.1-2.4. The yields are in the
range of 65 - 75 %. There are four series, each comprising of eight complexes owing to eight
different substituted phenyl acetates used. Thus there are 32 newly synthesized crystalline
complexes having sharp melting points out of which 24 have been characterized using single
crystal XRD. They are air stable and soluble in common organic solvents. These complexes have
been characterized by various analytical techniques such as infra red and UV-Visible
spectroscopy as well as powder and single crystal X-ray diffraction while the purity level of the
complexes was confirmed by powder XRD pattern. DNA binding parameters for all the
complexes were evaluated, using cyclic voltammetry and UV-Visible spectrophotometry. The
complexes have been screened for antibacterial and antifungal activity as well. The physical data
of the complexes has been summarized in Table 3.1.
3.1 FT–IR data
FT-IR spectra of the complexes revealed all the characteristic bands which helped to
deduce their structures. FT-IR spectra of representative complexes (7a and 7b) have been shown
in Figs. 3.1 and 3.2, respectively. The bonding mode of the carboxylate moiety was different in
each series of the complexes as indicated by its characteristic stretching frequency. For the series
of polymeric complexes (1-8) the carboxylate moiety showed two bands in 1590–1620 and
1334–1422 cm−1
regions corresponding to the asymmetric and symmetric OCO stretching
vibrations, respectively. The same functionality showed bands in 1580–1692 and 1390–1492
cm−1
regions corresponding to the asymmetric and symmetric OCO stretching vibrations of
73
Figure 3.1: FT-IR spectrum of complex 7a
74
Figure 3.2: FT-IR spectrum of complex 7b
75
Table 3.1: Physical data of the complexes
Complex Yield (%) Melting point (oC) Color of crystals
1 60 208–209 Blue
2 70 228–230 Light blue
3 70 248–249 Light blue
4 78 200–201 Blue
5 70 190–192 Blue
6 60 218–220 Blue
7 65 190–191 Light blue
8 70 210–211 Light blue
1a 80 185–186 Light blue
2a 80 185–187 Light blue
3a 80 145–147 Blue
4a 78 175–176 Light blue
5a 70 189–190 Blue
6a 70 182–183 Light blue
7a 70 150–152 Blue
8a 70 160–161 Light blue
1b 70 150–151 Light blue
2b 80 185–186 Light blue
3b 80 165–166 Blue
4b 78 160–162 Light blue
5b 80 145–146 Blue
6b 70 150–152 Light blue
7b 70 175–176 Blue
8b 70 160–162 Light blue
1c 70 220–221 Blue
2c 65 185–186 Light blue
3c 60 165–167 Blue
4c 68 205–206 Light blue
5c 60 215–216 Blue
6c 65 178–180 Blue
7c 60 175–176 Blue
8c 65 182–185 Blue
the dinuclear paddlewheel complexes (1a-8a), respectively. Similarly, absorption bands were
observed in the respective regions for OCO groups of the dinuclear O-bridged (1b-6b, 8b, and
2c) and mono-nuclear (7b, 1c, 3c-8c) complexes as well, as listed in Table 3.2. This was further
supported by the appearance of a Cu–O absorption band in 414–423 cm−1
range which confirmed
the coordination of the carboxylate ligands through oxygen. The values ∆ν = {νasym( ) −
76
Table 3.2: IR data (cm−1
) of the complexes
Complex v(OCO)asym v(OCO)sym Δv v(Cu–N) v(Cu–O)
Polynuclear complexes
1 1612 1382 202 --- 422
2 1590 1394 204 --- 418
3 1610 1415 195 --- 416
4 1588 1388 200 --- 414
5 1598 1409 189 --- 423
6 1592 1395 197 --- 420
7 1615 1334 179 --- 414
8 1620 1422 198 --- 418
Dinuclear paddlewheel complexes
1a 1625 1418 207 480 416 2a 1624 1446 178 478 422 3a 1580 1398 182 478 418 4a 1620 1430 190 468 414
5a 1692 1492 200 470 417 6a 1650 1442 208 475 422
7a 1624 1417 207 481 423 8a 1582 1390 192 480 422
Dinuclear O-bridged complexes
1b 1614 1362 252 480 416 2b 1599 1366 233 478 422 3b 1626 1338 258 478 418 4b 1607 1360 247 468 414
5b 1615 1380 235 470 417 6b 1614 1388 226 475 422
8b 1617 1362 255 480 422
2c 1648 1388 260 481 423 Mono-nuclear complexes
1c 1541 1427 114 480 416 3c 1611 1473 138 468 422
4c 1592 1466 126 470 423 5c 1606 1486 120 478 418 6c 1580 1444 136 468 414
7c 1585 1445 140 475 413
8c 1582 1440 142 470 417 7b 1568 1438 130 481 422
νsym(OCO)} calculated for the complexes confirmed the bonding modes of the carboxylate
moiety to copper(II) ion and were found typical of brigding bidentate, monodentate and chelate
bidentate coordination modes for the series of polymeric and paddlewheel, O-bridged and
77
mononuclear complexes, respectively [1]. The higher ∆ν value observed for 2c (260) was
indicative of the uncoordinated carboxylate moiety in the crystal lattice. In addition, the
appearance of C=N stretching band of the complexes at a frequency below 1600 cm−1
(1586–
1600) instead of its normally observed characteristic region (1610–1625 cm−1
) [2,3] indicated the
involvement of the nitrogen atom of pyridine in bonding with copper(II) ion [4]. This was further
supported by the appearance of a new medium intensity band for each of the complexes in the
region 468–481 cm−1
, attributable to a Cu–N vibration [5]. The aromatic C=C and C–H
stretching vibrations were observed in the regions 1558–1497 and 3008–3071 cm−1
, respectively.
The presence of the nitro group in 7, 7a, 7b, 7c, 8, 8a, 8b and 8c was confirmed from two intense
bands observed in the region 1328–1441 cm−1
. The methylene C–H stretching frequencies of the
complexes were observed in the range of 2917–2970 cm−1
which were supported by the presence
of bands at 692–722 and 1398–1418 cm−1
corresponding to its rocking and bending
deformations, respectively. Methyl C–H stretching frequencies gave rise to absorption bands at
2890–2921 cm−1
in complexes 1, 1a, 1b and 1c, supported by the band at 1440–1452 cm−1
assignable to the bending vibration of this functionality.
According to the t t -bipyridine and 1,10-phenanthroline give rise to absorption
bands at 3337, 1434, 1274, 1138, 1090, 851 and 756 cm−1
[6]. Keeping in view these absorption
values, the bands appearing at 1270, 1128, 1070 and 759 cm−1 h v t th
t -bipyridine and 1,10-phenanthroline molecules in the series of dinuclear O-
bridged and mono-nuclear complexes. The broad absorption band observed at 3200–3600 cm−1
is assigned to the O–H stretching of the lattice water molecules present in complexes 1b-6b, 1c,
2c and 6c.
78
3.2 Powder XRD study
Powder X-ray diffraction spectra of the synthesized complexes have been obtained and
compared with the respective simulated spectra of each complex by superimposing the spectra.
Figure 3.3 shows spectra of representative complexes from each of the four series. The simulated
and experimental powder XRD patterns are in complete agreement with each other for the
complexes, showing that the complexes have been synthesized and crystallized in completely
pure form.
5 10 15 20 25 30 35 40
0
60
120
180
240
300
360
420
1
2 Theta
Inte
nsity
simulated
experimental
6 9 12 15 18 21 24 27 30
0
40
80
120
160
200
240
Inte
nsity
2 Theta
3a
simulated
experimental
6 9 12 15 18 21 24 27 30
0
40
80
120
160
200
240
280
3b
2 Theta
Inte
nsity
experimental
simulated
6 9 12 15 18 21 24 27 30
0
70
140
210
280
350
420
490
8c
2 Theta
Inte
nsity
simulated
experimental
Figure 3.3: Experimental and simulated spectra of complexes 1, 3a, 3b and 8c belonging to
polynuclear, dinuclear paddlewheel, dinuclear O-bridged and mononuclear series of the
synthesized complexes, respectively.
79
3.3 Crystal structure description of the complexes
3.3.1 Polynuclear complexes
This series consists of eight polymeric complexes arising as a result of the interlinking of the
dinuclear paddlewheel units: a typical feature of copper(II) carboxylates as depicted in Fig. 3.4
through the structure of complex 2. The dinuclear units are interlinked via copper and oxygen
atoms resulting in polymeric structure. In an individual dinuclear unit, the two copper(II) ions are
linked by four carboxylate ligands in bridging bidentate fashion. The carboxylate ligands are 4-
methyl (1), 4-methoxy (3), 4-bromo (4), 4-chloro (5), 4-floro (6), 4-nitro (7) and 2-nitrophenyl
acetate (8) and phenyl acetate (2).
As shown by the single crystal XRD analysis of 1, 2 and 6, for which the ORTEP
diagrams, structure refinement parameters and bond length and angles are shown in Fig. 3.5 and
Tables 3.3 and 3.4, respectively, each copper is penta-coordinated with square pyramidal
geometry where the square base of the {CuO5} chromophore is formed by oxygen atoms of the
Figure 3.4: Polymeric chain of complex 2, representing the general pattern of the inter-linked
paddlewheel units in the polymeric complexes. Hydrogen atoms have been removed for clarity.
80
a.
b.
c.
Figure 3.5: ORTEP drawings of complexes 1 (a), 2 (b) and 6 (c)
bridging carboxylate groups of the dinuclear unit while the apical position is occupied by an
oxygen atom of the neighboring paddlewheel unit. The inter-dinuclear Cu–Oaverage bond distances
(2.225(2) Å) are somewhat longer than the rest of the Cu–O distances (1.952(2) Å) and are
similar to those found in structurally related complexes having two [7] and four [8] paddlewheel
81
Table 3.3: Structure refinement parameters of complexes 1, 2 and 6.
Complex 1 2 6
Empirical formula C36 H36 Cu2 O8 C32 H28 Cu2 O8 C32 H24 F4 Cu2 O8
Formula weight (g mol−1
) 723.72 667.64 739.59
Temperature (K) 296(2) 296(2) 296(2)
Wavelength (Å) 0.71073 0.71073 0.71073
Crystal system Monoclinic Monoclinic Monoclinic
Space group P 21/n P 21/c C 2/c
Unit cell dimensions
a (Å) 17.2182(19) 5.2034(3) 26.1472(19)
b (Å) 5.2503(4) 26.4615(13) 5.1647(3)
c (Å) 17.8257(18) 10.3265(4) 22.2109(14)
α (°) 90 90 90.00
β (°) 98.101(4) 98.204(2) 98.892(4)
γ (°) 90 90 90.00
Volume (Å3) 1595.4(3) 1407.30(12) 2963.4(3)
Z 4 4 4
ρ ( t ) (M / 3) 1.507 1.576 1.658
Absorption coeff. (mm-1) 1.386 1.564 1.513
F(000) 748 684 1496
Crystal size (mm3) 0.24 × 0.16 × 0.15 0.28 × 0.16 × 0.15 0.25 × 0.20 × 0.18
θ (°) 1.539 to 27.985 2.14 to 25.25 2.24 to 25.25
Index ranges
- ≤ h ≤
- ≤ k ≤ 6
- 3 ≤ ≤ 3
-6 ≤ h ≤
-31 ≤ k ≤ 31
-11 ≤ ≤ 1
-30 ≤ h ≤ 30
-6 ≤ k ≤ 6
- 6 ≤ ≤ 6
Reflections collected 3839 10824 10610
Independent reflections 2118 2548 2673
t t θ = 7.1 ° 99.8 % 99.9 % 99.9 %
Refinement method Full-matrix LS on
F2
Full-matrix LS on
F2
Full-matrix LS on
F2
Data / restraints /
parameters 2118 / 0 / 204 2548 / 0 / 190 2673 / 24 / 242
Goodness-of-fit on F2 0.960 0.949 0.981
Final R I > σ (I)] R1 = 0.1111,
wR2 = 0.0483
R1 = 0.0815,
wR2 = 0.0369
R1 = 0.0957,
wR2 = 0.0502
R indices (all data) R1 = 0.1184,
wR2 = 0.0907
R1 = 0.0857,
wR2 = 0.0518
R1 = 0.1170,
wR2 = 0.1039
82
units. This shows the relatively stable nature of the paddlewheel subunits and that the inter-
paddlewheel Cu–O bond has been formed to complete the coordination sphere of the copper(II)
ion. The relative weak nature of this bond is confirmed from its facile breaking on addition of
pyridine to the reaction mixture where the polymer is converted to dinuclear paddlewheel
structure (complexes 1a-8a) and the apical position gets occupied by pyridine ligand. As typical
of other square pyramidal Cu(II) complexes, the elongation of the apical bond is also caused by
the repulsive effect of the filled dz2 orbital lying along this axis [9]. This type of stepped
polymeric structure where a lone pair on the coordinated oxygen atom of carboxylate ligand of
one paddlewheel is coordinated to the copper(II) ion of the other paddlewheel unit represents the
relatively rarely encountered class of copper(II) complexes [8-11]. The average Cu···Cu distance
within a paddlewheel secondary building unit (SBU) of the polymeric complexes is 2.5841(5) Å
as compared to that of the dinuclear pyridine containing complexes (1a-8a) 2.6545(5) Å. This
slight change in Cu···Cu distance is in accordance to the decrease in Cu–O bond iconicity
happening during a shift from polynuclear to dinuclear complexes having N-donor ligands
(compare Cu–O and Cu–N bond lengths given in Table 3.7) [12,13].
Supramolecular structures:
Supra-molecular structures of 1, 2 and 6 are shown in Figs. 3.6 a-c. The packing diagram of 6
(Fig. 3.6 c) shows that the polymeric molecular chains grow along b-axis and are held together
by inte ∙∙∙H t t between the carboxylate oxygen atoms of one molecular layer
and phenyl ring hydrogen atoms of the other. Similarly, F atoms of one molecular layer are in a
suitable position to interact with methylene hydrogen atoms of the side layer molecules. As
compared to 6, there are relatively fewer inter–layer interactions in the packing structure of 2 and
the polymeric chains grow along a-axis. This change may be due to the replacement of hydrogen
83
Table 3.4: Selected bond lengths and angles of complexes 1, 2 and 6.
for florine in 2. The fewer interactions among the molecular layers result in lower density of the
unit cell (Table 3.3) as well as relatively higher solubility of 2 in organic solvents. The supra-
molecular structure of 1 is not much different from that of 2. Here the polymeric molecular
chains of infinite length are formed along b- wh th v h k
H∙∙∙ t t tw th h t th h .
Th t - h ∙∙∙H t t w .
Complex
Bond
1 2 6
Distances, Å
Cu(1)-O(1) 2.007(2) 1.940(2) 1.957(3)
Cu(1)-O(2) 1.968(2) 1.949(2) 2.015(3)
Cu(1)-O(3) 1.941(3) 2.210(2) 1.935(4)
Cu(1)-O(3) --- 2.013(2) ---
Cu(1)-O(1) 2.239(2) --- ---
Cu(1)-O(2) --- --- 2.211(3)
Cu(1)-O(4) 1.941(3) 1.952(2) 1.942(4)
Cu(1)-Cu(1) 2.5962(8) 2.5841(5) 2.5743(10)
Angles, °
O(4)-Cu(1)-O(1) 88.15(11) 90.27(9) 90.19(15)
O(2)-Cu(1)-O(3) 88.17(11) 90.88(9) 91.81(15)
O(1)-Cu(1)-O(2) 169.28(9) 169.76(9) 169.68(12)
O(4)-Cu(1)-O(3) 169.45(10) 169.58(9) ---
O(1)-Cu(1)-O(3) 91.20(11) 88.66(9) 88.21(16)
O(4)-Cu(1)-O(2) 90.51(11) 88.35(9) 87.92(14)
O(1)-Cu(1)-O(3) 95.46(10) 95.26(8) ---
O(3)-Cu(1)-O(3) --- 80.28(8) ---
O(4)-Cu(1)-O(1) 94.72(10) --- ---
O(3)-Cu(1)-O(4) --- 110.14(8) 169.51(15)
O(2)-Cu(1)-O(3) --- 94.75(8) 96.05(15)
O(4)-Cu(1)-O(2) --- --- 94.26(14)
O(1)-Cu(1)-O(2) 112.33(9) --- 109.62(12)
O(2)-Cu(1)-O(2) --- --- 80.64(13)
O(1)-Cu(1)-O(1) 78.39(10) --- ---
84
a.
b.
c.
Figure 3.6: Packing diagrams of complexes 1 (a), 2 (b) and 6 (c) showing the relative abundance
of secondary interactions in three complexes where each molecule represents a polymeric chain.
Intermolecular interactions are shown by dotted lines.
85
3.3.2 Dinuclear complexes
3.3.2.1 Dinuclear paddlewheel complexes.
This series consists of eight dinuclear complexes represented by the general formula,
pyCu(RCOO)4Cupy where py is pyridine and RCOO is 4-methyl (1a), 4-methoxy (3a), 4-Bromo
(4a), 4-chloro (5a), 4-floro (6a), 4-nitro (7a) and 2-nitrophenyl acetate (8a) and phenyl acetate
(2a). Single crystal analyses afforded the structures and relevant information of the complexes
presented in Figs. 3.7 (a-h) and Tables 3.5 and 3.6, respectively.
Complexes in this category display the classical paddlewheel structures having four
carboxylate ligands bonded in a syn–syn configuration, bridging the two copper(II) ions, while
the two pyridine molecules occupy the axial coordination sites resulting in a distorted square
pyramidal coordination geometry for each Cu(II) ion. The Cu···Cu and Cu–O distances are in
the ranges 2.6411(8) – 2.6631(13) and 1.952(4) – 1.981(2) A˚, respectively which show that
these are close to each other as well as to those observed for the structurally related dimer of
Cu(II) ions with trifloroacetate ligands already reported [Cu2(CF3CO2)4(CH3CN)2] (Cu···Cu =
2.766(1) and Cu–O = 1.969(5) A˚) [12,14]. The difference in Cu···Cu distances of the complexes
1a-8a from that of the above cited complex is attributable to the relatively higher basic strength
of the N-donor ligands in the former complexes, resulting in slight decrease in their Cu–O bond
ionic character, compared to that in the latter complex [12]. The Cu–N distances (2.1448(16) –
2.174(4) A˚) are comparable to those found for the apical N-donor acetonitrile ligand (2.114(2)
A˚) [14] but longer than those found for imidazole N-donor ligand (1.9815(15) A˚) in mono-
nuclear octahedral carboxylate complex [15]. This is attributed to the elongation of the apical
Cu–ligand bond distance as a consequence of the repulsion exerted by the doubly occupied dz2
orbital along this axis [9]. However, the Cu–N bond length has been found to vary with the basic
86
strength of the lone pair on the nitrogen atom of the N-donor moiety. Varying the substituents on
the pyridine ring, the Cu–N bond length has been found to increase in the following order: 4-
NMe2 < H < 3-NH2 < 2-NH2 < (NH2)2 < NH2, CH3 [16-18].
A comparison of the Cu···Cu, Cu–O and Cu–N distances of the synthesized complexes
with other related complexes is given in Table 3.7.
The coordination environment around each copper atom of all the complexes is a {CuNO4}
square pyramid. The matching structural parameters (bond lengths and angles) of the complexes
is reflective of the similar coordination environment around copper(II) ions in the synthesized
complexes of this series. The cis angles ( O–Cu–O) of the square base, consisting of four O
atoms in complexes 1a-8a range from 87.15(7) to 91.88(12)o while the respective trans angles
around copper are 167.26(11) – 167.98(8)
o. M v th ···Cu bond angles in
complexes 1a-8a range from 79.29(4) to 88.49(4)o wh th N th
range 91.88(6) – 97.76(8)o, respectively. These angle values (and also the corresponding bond
lengths) are similar to those found for copper(II) complex where the N-atom comes from the
long tethering bis(4-pyridylmethyl)piperazine and the carboxylate oxygen atoms from 1,3-
phenylenediacetate [19]. However, noteworthy is the striking difference in the O–Cu–N angle
value of this complex compared to those of 1a-8a, although all the complexes have typical
paddlewheel central cores. The wider range of O–Cu–N angles {105.87(6) – 86.77(6)o} of the
cited complex, compared to those of 1a-8a {91.88(6) – 97.76(8)o} is attributed to the
compromise between the two cross-linking O and N–donor ligands to allow the polymeric
structure of the former complex. That is, the polymeric structure is made possible at the expense
of O–Cu–N angle deviation from the value possessed by a typical paddlewheel central core. Here
both the O and N–donor ligands are trans-bidentate and the overall structure is a 3-D network
87
a. b. c.
d. e.
f. g. h.
Figure 3.7: ORTEP drawings of complexes 1a (a), 2a (b), 3a (c), 4a (d), 5a (e), 6a (f), 7a (g) and 8a (h).
88
Table 3.5: Structure refinement parameters of the complexes 1a-8a.
Complex 1a 2a 3a 4a
Chemical formula C46 H46 Cu2 N2 O8 C42 H38 Cu2 N2 O8 C46 H46 Cu2 N2 O12 C42 H34 Br4 Cu2 N2 O8
Formula mass (g mol−1
) 1005.85 825.86 945.93 1141.41
Temperature (K) 298(2) 100(2) 298(2) 100(2)
Wavelength (Å) 0.71073 0.71073 1.54180 0.71073
Crystal system Triclinic Triclinic Triclinic Monoclinic
Space group P-1 P -1 P -1 P 21/n 1 1
a (Å) 8.1242(6) 11.0320(15) 10.4217(11) 7.9320(7)
b (Å) 9.9550(6) 16.619(2) 10.6386(10) 16.6630(6)
c (Å) 13.8752(7) 20.340(2) 12.0191(12) 17.3660(7)
α (°) 85.367(5) 92.747(2) 76.618(8) 68.504(3)
β (°) 74.121(5) 89.982(6) 72.086(9) 90.008(3)
γ (°) 76.464(6) 93.035(3) 63.440(10) 90.008(3)
Volume (Å3) 1049.21(11) 3719.6(8) 1127.2(2) 2135.6(2)
Z 1 4 1 2
ρ ( t ) ( −3
) 1.592 1.475 1.393 1.775
Absorption coeff. (mm−1
) 1.096 1.201 1.694 4.791
F(000) 514 1704 490 1124
Crystal size (mm) 0.4 × 0.4 × 0.3 0.27 × 0.22 × 0.19 0.1 × 0.1 × 0.05 0.27 × 0.19 × 0.14
θ (°) 3.01 to 25.00 1.23 to 25 3.89 to 60.70 1.45 to 27.17
Index ranges
-9 ≤ h ≤ 9
-8 ≤ k ≤ 11
-16 ≤ ≤ 16
-13 ≤ h ≤13
-19 ≤ k ≤18
- 1 ≤ ≤
-11 ≤ h ≤ 11
-1 ≤ k ≤ 10
-13 ≤ ≤13
-10 ≤ h ≤ 10
- 1 ≤ k ≤ 1
- ≤ ≤
Reflections collected 6529 23108 7323 33624
Independent reflections 3454 12187 3363 4730
Refinement method Full-matrix LS on F2 Full-matrix LS on F2 Full-matrix LS on F2 Full-matrix LS on F2
Data/restraints/parameters 3454 / 18 / 354 12187 / 7 / 1278 3363 / 0 / 280 4730 / 0 / 283
Goodness-of-fit on F2 0.882 1.087 1.060 1.029
F R I > σ (I)] R1 =0.0360, wR2 =0.0632 R1 =0.0383, wR2 =0.0944 R1 =0.0575, wR2 =0.1543 R1 =0.0866, wR2 =0.2455
R indices (all data) R1 =0.0539, wR2 =0.0659 R1 =0.0537, wR2 =0.1009 R1 =0.0669, wR =0.1677 R1 =0.1054, wR2 =0.2676
89
Table 3.5 (continued)
Complex 5a 6a 7a 8a
Chemical formula C42 H34 Cl4 Cu2 N2 O8 C42 H34 F4 Cu2 N2 O8 C42 H34 Cu2 N6 O16 C42 H34 Cu2 N6 O16
Formula mass (g mol−1
) 963.59 897.79 881.93 1005.83
Temperature (K) 100(2) 296(2) 100(2) 296(2)
Wavelength (Å) 0.708457 0.71073 0.71073 0.71073
Crystal system Monoclinic Triclinic Triclinic Monoclinic
Space group P 21/n P -1 P-1 C 2/c
a (Å) 16.6830(19) 12.0582(3) 10.3480(12) 17.4542(6)
b (Å) 7.9380(7) 12.9571(4) 10.9390(5) 17.1802(6)
c (Å) 16.7760(12) 14.6191(4) 11.3790(4) 15.2065(5)
α (°) 90 78.873(2) 78.681(4) 90
β (°) 110.813(2) 74.229(3) 69.070(4) 107.411(1)
γ (°) 90 69.542(2) 61.996(5) 90
Volume (Å3) 2076.7(3) 2047.26(11) 1061.58(14) 4351.0(3)
Z 2 2 1 4
ρ ( t ) ( −3
) 1.541 1.456 1.380 1.535
Absorption coeff. (mm−1
) 1.336 1.111 1.057 1.057
F(000) 980 916 458 2056
Crystal size (mm) 0.4 × 0.3 × 0.3 0.30 × 0.16 × 0.15 0.27 × 0.24 × 0.21 0.30 × 0.25 × 0.23
θ (°) 2.60 to 28.69 2.35 to 25.25 2.37 to 25.00 1.70 to 27.88
Index ranges
-19 ≤ h ≤ 19
-9 ≤ k ≤ 9
- 0 ≤ ≤ 0
-1 ≤ h ≤ 1
-1 ≤ k ≤ 1
-17 ≤ ≤ 17
-1 ≤ h ≤ 11
-13 ≤ k ≤ 13
-13 ≤ ≤ 13
-18 ≤ h ≤
- ≤ k ≤ 1
-19 ≤ ≤ 19
Reflections collected 26055 30120 6865 5166
Independent reflections 3712 7330 3687 3776
t t θ (%) 99.80 98.6 92.3 99.7
Refinement method Full-matrix LS on F2 Full-matrix LS on F2 Full-matrix LS on F2 Full-matrix LS on F2
Data/restraints/parameters 3712 / 1 / 331 7330 / 8 / 531 3687 / 0 / 298 5166 / 0 / 298
Goodness-of-fit on F2 0.97 0.988 1.048 1.022
Final R indices [I > σ(I)] R1 =0.0322, wR2 =0.0976 R1 =0.0834, wR2 =0.0482 R1 =0.036, wR2 =0.0632 R1 =0.0367, wR2 =0.0853
R indices (all data) R1 =0.0347, wR2 =0.1001 R1 =0.1355, wR2 =0.1103 R1 =0.0539, wR2 =0.0659 R1 =0.0594, wR2 =0.0944
90
Table 3.6: Selected Bond lengths and angles of dinuclear paddlewheel complexes, 1a-8a.
Complex
Bond
1a 2a 3a 4a 5a 6a 7a 8a
Distances, Å
Cu(1)-O(1) 1.9666(17) 1.975(2) 1.971(2) 1.967(4) 1.9682(14) 1.958(4) 1.9691(16) 1.971(4)
Cu(1)-O(2) 1.9751(18) 1.976(2) 1.975(3) 1.964(5) 1.9768(14) 1.952(4) 1.9689(16) 1.967(4)
Cu(1)-O(3) 1.9768(18) 1.981(2) 1.980(2) 1.980(4) 1.9661(13) 1.961(4) 1.9784(16) 1.964(5)
Cu(1)-O(4) 1.9661(19) 1.971(2) 1.970(3) 1.971(4) 1.9722(14) 1.953(4) 1.9773(16) 1.980(4)
Cu(1)-N(1) 2.157(2) 2.153(2) 2.165(3) 2.149(5) 2.1448(16) 2.174(4) 2.1455(18) 2.149(5)
Cu(1)-Cu(1) 2.6502(7) 2.6451(5) 2.6595(10) 2.6631(13) 2.6555(5) 2.6411(8) 2.6563(6) 2.6631(13)
Angles, °
O(4)-Cu(1)-O(1) 90.10(8) 90.51(9) 90.19(12) 91.7(2) 87.15(7) 87.90(16) 90.80(7) 87.3(2)
O(2)-Cu(1)-O(3) 88.95(8) 88.65(9) 91.88(12) 90.0(2) 87.88(7) 89.48(16) 91.41(7) 88.3(2)
O(1)-Cu(1)-O(2) 89.41(8) 89.06(9) 86.98(11) 88.3(2) 91.07(7) 97.04(16) 87.46(7) 90.0(2)
O(4)-Cu(1)-O(3) 88.84(8) 89.11(9) 88.19(12) 87.3(2) 91.27(7) 90.92(16) 87.73(7) 91.7(2)
O(1)-Cu(1)-O(3) 167.54(7) 167.47(8) 167.26(11) 167.32(19) 167.65(6) 167.76(15) 167.80(6) 167.12(18)
O(4)-Cu(1)-O(2) 167.52(7) 167.70(8) 167.49(11) 167.12(18) 167.75(6) 168.15(12) 167.74(6) 167.32(19)
O(4)-Cu(1)-N(1) 96.12(8) 98.50(9) 96.85(12) 102.25(19) 101.35(6) 100.03(16) 95.90(7) 102.25(19)
O(1)-Cu(1)-N(1) 96.35(8) 93.77(9) 96.81(11) 90.37(19) 100.44(6) 92.15(13) 96.35(7) 90.37(19)
O(2)-Cu(1)-N(1) 94.68(8) 98.26(8) 95.59(11) 92.15(18) 90.90(6) 89.19(16) 94.68(7) 92.15(18)
O(3)-Cu(1)-N(1) 97.76(8) 94.19(8) 95.93(11) 100.74(18) 91.88(6) 94.78(16) 97.51(7) 100.74(18)
O(4)-Cu(1)-Cu(1) 81.84(6) 85.39(6) 83.48(9) 86.60(14) 88.49(4) 82.5(1) 82.24(5) 86.60(14)
O(1)-Cu(1)-Cu(1) 81.84(6) 82.31(6) 84.12(8) 80.72(13) 86.32(4) 84.7(1) 85.69(6) 80.72(13)
O(2)-Cu(1)-Cu(1) 84.38(6) 84.72(6) 84.11(8) 79.52(13) 79.29(4) 83.5(1) 85.57(5) 79.52(13)
O(3)-Cu(1)-Cu(1) 83.22(6) 82.77(6) 83.14(8) 87.75(13) 81.39(4) 85.4(1) 83.21(5) 87.75(13)
N(1)-Cu(1)-Cu(1) 177.75(6) 175.05(6) 179.01(8) 167.92(14) 168.25(4) 174.4(1) 176.82(5) 167.92(14)
91
Table 3.7. Comparison of Cu–ligand bond lengths (Å) of 1a-8a with structurally related copper(II) complexes.
Complex Cu···Cu Cu–N Cu–O Reference
1a-8a (range) 2.6411(8) - 2.6631(13) 2.1448(16) - 2.174(4) 1.952(4) -1.981(2) this work
((2-NH2)C5H4N)2Cu2(μ-OOCCMe3)4 2.6307(9) 2.163(5) 1.942(5)-1.990(5) [15]
((3-NH2)C5H4N)2Cu2(μ-OOCCMe3)4 2.6360(18) 2.155(10) 1.937(8)-1.989(8) [15]
(η2-OOCCMe3)2((4-NMe2)C5H4N)2 -- 2.00(2) 1.965(16) [15]
((4-NMe2)C5H4N)2Cu2(μ-OOCCMe3)4 2.664(3) 2.138(10) 1.961(10)-1.999(9) [15]
(C9H7N)2Cu2(μ-OOCCMe3)4 2.6543(9) 2.223(3) 1.956(3)-1.985(2) [15,17]
((2-NH2)(6-CH3)C5H3N)2Cu2(μ-OOCCMe3)4 2.730(1) 2.296(3) 1.963(2)-1.974(2 [15,16]
((NH2)2C5H3N)2Cu2(μ-OOCCMe3)4.C6H6 2.762(1) 2.243(3) 1.922(6)-2.019(5) [15,16]
92
coordination polymer but the central paddlewheel units have the same structural characteristics
as those of the dimers 1a-8a and other reported dimeric complexes [12,20].
The most important feature responsible for the paddlewheel structure in such complexes
comes out t th t t th Cu···Cu angles and th t t
N angle from the ideal value of 90o. The result is the deviation of the {CuO4} square base
from ideal planarity and a substantial disparity from a perfect square pyramidal geometry around
pentacoordinated Cu(II) ion. Th N ···Cu bond angles range from 168.25(4) to 179.01(8)o in
complexes 1a-8a. Each molecule possesses a center of symmetry located at the midpoint of the
two copper(II) ions and the geometry around each Cu(II) in all the complexes is distorted square
pyramidal.
Supra-molecular structures:
The complexes 1a-3a, 6a and 7a crystallize in the triclinic crystal system with P-1, and
4a, 5a and 8a in monoclinic crystal system with (P 21/n 1 1), (P 21/n) and (C 2/c) space groups,
respectively. The crystal packing is formed by a large number of inter-molecular associations in
which oxygen, nitrogen and hydrogen atoms take part. However, all the complexes have
different packing arrangement of the dimeric units as shown in Figs. 3.8 a-h.
1a: In case of 1a, an oxygen atom and a methylene hydrogen of the same carboxylate group of
one molecule associates with methylene hydrogen and oxygen atom, respectively of the adjacent
molecule. In this way both ligands of the trans-lying carboxylate pairs of one molecule are H-
bonded with the adjacent carboxylate group of the neighboring molecule, while the other pair of
trans-carboxylate ligands is unable to do so, resulting in a 1D chain along the a-axis. The crystal
packing consists of an infinite number of such chains lying side by side forming 2D sheet as
shown in Fig. 3.8 a.
93
2a: In the packing of 2a, there is no contribution of H-bonding owing to the absence of hydrogen
capable to be involved in H-bonding. However the hydrogen atoms of the phenyl ring are closer
enough to the carboxylate oxygen atoms of the neighboring molecule to establish a mutual
weaker interaction resulting in the intermolecular arrangement along the c-axis as shown in Fig.
3.8 b.
3a: Looking at the packing diagram of complex 3a shown in Fig. 3.8 c, it is seen that there is a
higher number of inter-molecular interactions per dinuclear unit. There is no hydrogen suitable
for hydrogen bonding but the oxygen atom of methoxy group is closer enough with a hydrogen
atom of the phenyl group of another molecule. Similarly, an oxygen atom of the carboxylate
moiety of one molecule is associated with hydrogen atom at the para-position to the nitrogen of
pyridine of the neighboring molecules.
4a: Owing to the absence of sufficiently polar H-atoms, the crystal packing (Fig. 3.8 d) is formed
as a result of O···H H··· B ···H interactions among the molecules. The
carboxylate oxygen atoms of the two trans-lying ligands of one molecule are lying closer with
hydrogen atoms at position 3 of the pyridine ligands of the neighboring molecules. Similarly,
two bromine atoms of one m t w th th h h t
th h . H···C type of interaction is present between the methylene
hydrogen atom of one molecule with carboxylate carbon of the side-lying molecule.
5a: Crystal packing (Fig. 3.8 e) is formed by the interaction of an oxygen atom of each of the
two trans lying carboxylate moieties of a molecule with the hydrogen atom at meta meta position
of the pyridine molecule of the neighboring molecule. There are relatively fewer intermolecular
interactions in this complex compared to other pyridine derivatives.
94
6a: The crystal packing of 6a (Fig. 3.8 f) is quite different from that of 5a, although one might
think that there is mere replacement of F for Cl. It may be due to the presence of two
crystallographically different molecules in the unit cell of the former. Another factor is the
replacement of florine for chlorine in the former complex. Every F atom is close to a hydrogen
atom of pyridine or phenyl ring of the neighboring molecules. Similarly, oxygen atoms of all the
carboxylate ligands are involved in O···H t t t . Th th h h
intermolecular interactions in 6a compared to 5a.
7a: In the supra-molecular structure of complex 7a (Fig. 3.8 g), an oxygen atom of a carboxylate
group is closer enough to the hydrogen at the para position to the nitrogen of the pyridine of the
neighboring molecule. Thus each molecule has two suitably oriented oxygen atoms capable of
interaction with the trans H-atoms of the pyridine group of the neighboring molecule. This
arrangement is repeated indefinitely, resulting in a 1D chain along the a-axis. These chains
constitute 2D sheets in oac-plane.
8a: Its crystal packing (Fig. 3.8 h) arises as a result of O···H C type interactions between
carboxylate oxygen atoms and phenyl ring hydrogen atoms of the neighboring molecules.
Similarly, oxygen of the nitro group interacts with hydrogen atom of pyridine through an O···H
C type interaction. The ortho-nitro group of 8a cannot participate in secondary interactions with
the neighboring molecules as effectively as the para-nitro group of 7a. This gives rise to the
difference in the packing arrangement of the molecules of the two complexes.
In short, the difference in supra-molecular structures of the complexes 1a-8a comes partly from
the differences in the cis and trans angles around the Cu(II) ions (Table 3.6) and partly from the
different substituents at the para-position of the phenyl ring of the carboxylate ligands. The
former factor has rendered it difficult for the oxygen of the carboxylate moiety to come closer
95
a. b. c.
d. e.
f. g. h.
Figure 3.8: Packing diagrams of complexes 1a (a), 2a (b), 3a (c), 4a (d), 5a (e), 6a (f), 7a (g) and 8a (h). Hydrogen atoms have
been removed from the diagrams of 2a and 6a for clarity. Inter-molecular interactions have been shown by dotted lines.
96
and interact with the methylene hydrogen atoms of the neighboring dimer in 7a, 3a and 5a while
the latter factor provides additional sites for the inter-dimer interactions between two
neighboring 1D chains affecting the resulting 2D sheet. The relatively higher number of
intermolecular interactions combined with the shorter chain length of alkyl groups in 1a-8a
compared to that of the structurally related tetra-nuclear complex [{Cu2(OOCC5H11)4(urea)}2]
has been proposed to be responsible for the dimeric nature of the complexes. Such complexes
prefer an isolated dimeric structure rather than a tetra-nuclear or polymeric structure [7]. It seems
that longer alkyl chains probably enable additional stabilization of the tetra-nuclear structure
causing its precipitation in preference to the isolated di-nuclear molecules.
3.3.2.2 Dinuclear O bridged complexes
The ORTEP diagrams with the atomic numbering scheme of the complexes in this series
are shown in Figs. 3.9 a-h, while the crystal data and structure refinement parameters are given
in Tables 3.8 and 3.9.
This series consists of eight dinuclear complexes where the two copper(II) ions are
t tw μ-1,1-O atoms belonging to carboxylate ligands and hydroxyl moieties in case
of complexes 1b-6b and 8b and 2c t v . h (II) th t
t tw th t t t -bipyridine molecule in
bidentate manner. (The carboxylate ligands are 4-methyl (1b), 4-methoxy (3b), 4-bromo (4b), 4-
chloro (5b), 4-floro (6b) and 2-nitrophenyl acetate (8b) and phenyl acetate (2b,2c)). However, in
2c, each copper(II) ion is coordinated by a water molecule and 1,10-phenanthroline, where the
phenylacetate ion lies un-coordinated in the crystal lattice. Thus each copper(II) ion is penta-
coordinated with square pyramidal geometry. The complexes are centrosymmetric in which the
metal centers are bridged by μ-1,1-O with the center of symmetry at the center of the Cu2O2
97
parallelogram core. Constituting the axial position of one square pyramid, each of the bridging
oxygen atoms is part of the square plane of the other square pyramid in all the complexes except
in 2c where both bridging oxygen atoms are shared by the square bases of both square pyramids
and the axial position is occupied by the coordinated water molecule. Each pair of the copper
centers forms a four cornered planar Cu2O2 core where the two bipyridine or 1,10-phenanthroline
molecules are trans oriented with respect to the Cu2O2 core forming five-membered chelate rings
with Cu. The range of the distortion factor τ (=β-α/60о wh β α th t
largest angles around the penta-coordinated metal ion, respectively) calculated for all complexes
is 0.059-0.060 except 2c whose τ valve was found to be 0.04, indicating a slightly distorted
square pyramidal geometry around each copper(II) [21]. The bulky carboxylate ligands cause
slightly higher deviation from the ideal square pyramidal geometry around the copper(II) ion
compared to the coordinated water and hydroxyl groups in 2c. Another difference is that the
bridging oxygen atoms are more symmetrically bonded to copper(II) ions in 2c compared to
other complexes. An outstanding feature of complex 2c is the short intermetallic distance
(2.912(10) Å). This value is among the shortest (II)∙∙∙ (II) t t
hydroxo bridged complexes [22]. The Cu–Nbipy,phen bond distances are in the range of
1.9999(18)– 2.0216(19) Å and are similar to those found in previously reported dinuclear
copper-bipyridine complexes [23-25]. As mentioned earlier, the Cu–O distances of the
bipyridine derivatives (1b-6b, 8b) are quite asymmetrical compared to those of 2c. The Cu–O
bond distances in the equatorial plane are in the range of 1.9352(15) – 1.9818(14) Å, typical of
the Cu–O equatorial distances of the previously reported dimeric [26] and polymeric [27,28]
complexes. The axial Cu–O distances range from 2.3305(14) to 2.3863(16) Å indicating
relatively weaker interaction with copper. Since square pyramidal complexes of copper(II) ion
98
Table 3.8: Structure refinement parameters of O-bridged dinuclear complexes
Complex 1b 2b 3b 4b
Empirical formula C56 H56 Cu2 N4 O10 C52 H48 Cu2 N4 O10 C56 H52 Cu2 N4 O12 C52 H44 Br4 Cu2 N4 O10
Formula weight (g mol−1
) 1072.13 1016.04 1100.12 1331.63
Temperature (K) 100(2) 100(2) 296(2) 100(2)
Wavelength (Å) 0.71073 0.71073 0.71073 0.71073
Crystal system Monoclinic Monoclinic Triclinic Monoclinic
Space group P 2 1/n P 1 1 21/n P -1 P 21/n
a (Å) 10.0250(15) 10.138(2) 10.1789(2) 10.0090(16)
b (Å) 15.3790(9) 14.4270(18) 15.0362(4) 15.2930(10)
c (Å) 16.0700(11) 15.8970(12) 16.5426(4) 16.5740(17)
α (°) 90 90 87.8940(10) 90
β (°) 99.443(4) 90 82.736(2) 100.518(4)
γ (°) 90 79.650(12) 84.9510(10) 90
Volume (Å3) 2444.0(4) 2287.3(6) 2500.97(10) 2494.3(5)
Z 2 2 2 2
ρ (calculated) (Mg/m3) 1.457 1.475 1.461 1.773
Absorption coeff. (mm-1) 0.936 0.996 0.920 4.120
F(000) 1116 1052 1140 1324
Crystal size (mm3) 0.3 × 0.2 × 0.18 0.31 × 0.26 × 0.14 0.35 × 0.28 × 0.25 0.31 × 0.24 × 0.15
θ t t (°) 1.28 to 28.76 1.28 to 28.75 1.24 to 26.00 1.83 to 27.14
Index ranges
-13 ≤ h ≤13
- 0 ≤ k ≤ 0
- 1 ≤ ≤ 1
-1 ≤ h ≤ 1
-17 ≤ k ≤ 17
-18 ≤ ≤ 18
-1 ≤ h ≤ 1
-18 ≤ k ≤ 17
- 0 ≤ ≤ 0
-1 ≤ h ≤ 1
-19 ≤ k ≤ 19
- 1 ≤ ≤ 1
Reflections collected 6357 28021 31576 39625
Independent reflections 5875 3893 9784 5177
t t θ = 7.1 ° 96.10 % 96.80 % 99.4 % 93.6 %
Refinement method Full-matrix LS on F2 Full-matrix LS on F2 Full-matrix LS on F2 Full-matrix LS on F2
Data / restraints / parameters 5875/ 0 / 327 3893 / 5 / 404 9784 / 0 / 671 5177 / 9 / 413
Goodness-of-fit on F2 1.117 1.086 0.981 1.094
F R I > σ (I)] R1= 0.0361, wR = 0.0885 R1= 0.0384, wR = 0.1011 R1= 0.0957, wR = 0.0387 R1= 0.0424, wR1= 0.1039
R indices (all data) R1= 0.0392, wR = 0.0986 R1= 0.0398, wR = 0.1023 R1= 0.1029, wR = 0.0533 R1= 0.0497, wR2 = 0.1118
99
Table 3.8 (continued)
Complex 5b 6b 8b 2c
Empirical formula C52 H44 Cl4 Cu2 N4 O10 C52 H44 F4 Cu2 N4 O10 C52H40Cu2N8O16 C40 H48 Cu2 N4 O14
Formula weight (g mol−1
) 1153.79 1088.01 1160.00 935.92
Temperature (K) 298(2) 100(2) 296(2) 296(2)
Wavelength (Å) 0.71073 0.71073 0.71073 0.71073
Crystal system Monoclinic Monoclinic Triclinic Triclinic
Space group P21/n P21/n P -1 P -1
Unit cell dimensions
a (Å) 10.0887(3) 9.948(2) 10.0311(6) 9.3345(5)
b (Å) 15.4702(5) 15.335(3) 10.4118(8) 10.1079(5)
c (Å) 16.2429(4) 15.460(3) 13.3815(14) 11.5827(7)
α (°) 90 90 109.694(4) 73.232(3)
β (°) 100.627(2) 101.58(3) 106.636(3) 76.426(2)
γ (°) 90 90 97.439(2) 82.616(3)
Volume (Å3) 2491.62(13) 2310.5(8) 1220.57(18) 1014.99(10)
Z 2 2 2 1
ρ ( t ) (M / 3) 1.538 1.564 1.578 1.531
Absorption coeff. (mm-1) 1.132 1.004 0.955 1.122
F(000) 1180 1116 594 486
Crystal size (mm3) 0.5 × 0.2 × 0.2 0.35 × 0.24 × 0.21 0.25 × 0.22 × 0.15 0.2 × 0.22 × 0.18
θ (°) 2.92 to 24.99 2.25 to 28.69 1.728 to 26.000 1.88 to 26.000
Index ranges
-11 ≤ h ≤11 -11 ≤ h ≤11 -1 ≤ h ≤1 -11 ≤ h ≤11
-18 ≤ k≤ 18 -18 ≤ k ≤18 -1 ≤ k ≤1 -1 ≤ k ≤1
-19 ≤ ≤19 -18 ≤ k ≤18 -16 ≤ k ≤16 -1 ≤ k ≤1
Reflections collected 11264 14039 17735 14963
Independent reflections 4381 4035 4794 3951
t t θ = 7.1 ° 99.80 % 99.30 % 99.90 % 99.90 %
Refinement method Full-matrix LS on F2 Full-matrix LS on F2 Full-matrix LS on F2 Full-matrix LS on F2
Data / restraints / parameters 4381 / 0 / 325 4035 / 0 / 405 4794 / 0 / 352 3951 / 0 / 298
Goodness-of-fit on F2 0.837 1.077 1.037 1.050
F R I > σ (I)] R1= 0.0325, wR2 = 0.0580 R1= 0.0335, wR2 = 0.086 R1= 0.0291, wR2 = 0.0712 R1= 0.0277, R2 = 0.0667
R indices (all data) R1 = 0.0588, wR2 =0.0610 R1= 0.0375, R2 =0.0883 R1=0.0356, wR2 =0.0743 R1=0.0335, wR2 =0.0692
100
Table 3.9: Selected bond lengths and angles of O-bridged dinuclear complexes
Complex
Bond
1b 2b 3b 4b 5b 6b 8b 2c
Distances, Å
N(1)-Cu(1) 2.0062(15) 2.0168(16) 2.002(2) 2.005(3) 2.0216(19) 1.9999(18) 2.0100(15) 2.0348(16)
N(2)-Cu(1) 2.0148(16) 2.0054(18) 2.014(2) 2.017(3) 2.0049(18) 2.0189(18) 2.0084(15) 2.0147(17)
O(1)-Cu(1) 1.9359(13) 1.9485(15) 1.9503(18) 1.930(2) 1.9352(15) 1.9441(16) 1.9417(13) 1.9428(15)
O(3)-Cu(1) 1.9767(13) 1.9818(14) 1.9675(17) 1.972(2) 1.9746(15) 1.9800(15) 1.9728(12) ---
Cu(1)-O(3) 2.3594(14) 2.3305(14) 2.3048(17) 2.357(2) 2.3863(16) 2.3535(15) 2.3766(13) ---
Cu(1)-O(2) --- --- --- --- --- --- --- 2.2621(18)
Cu(1)-O(1) --- --- --- --- --- --- --- 1.9522(14)
Cu(1)-Cu(1) 2.912(10)
Angles, °
O(1)-Cu(1)-O(3) 91.11(6) 90.79(6) 89.58(8) 90.86(10) 91.74(7) 91.69(7) 92.18(5) ---
O(1)-Cu(1)-N(2) 172.29(6) 171.89(6) 169.52(8) 172.46(12) 171.87(7) 172.31(7) 171.75(6) 165.85(6)
O(3)-Cu(1)-N(2) 95.94(6) 95.40(6) 98.37(8) 95.60(10) 95.43(7) 95.51(7) 97.95(6) ---
O(1)-Cu(1)-N(1) 92.01(6) 92.81(6) 91.40(9) 92.55(11) 91.89(7) 91.89(7) 92.88(6) 171.25(6)
O(3)-Cu(1)-N(1) 173.59(6) 174.03(6) 175.83(8) 174.42(10) 174.52(7) 174.48(6) 173.35(6) ---
N(2)-Cu(1)-N(1) 80.68(6) 80.60(7) 80.20(9) 80.72(11) 80.69(8) 80.74(7) 80.48(6) 81.66(7)
O(1)-Cu(1)-O(3) 89.15(5) 89.08(6) 89.42(7) 88.59(9) 90.18(6) 90.41(6) 88.67(5) ---
O(3)-Cu(1)-O(3) 77.34(5) 77.44(6) 79.68(7) 78.54(9) 77.97(7) 77.84(6) 78.18(5) ---
N(2)-Cu(1)-O(3) 95.44(6) 97.37(6) 98.68(7) 96.47(10) 95.04(6) 93.76(6) 96.07(5) ---
N(1)-Cu(1)-O(3) 108.30(5) 107.37(6) 104.38(8) 105.95(10) 106.13(6) 106.33(6) 102.01(5) ---
N(1)-Cu(1)-O(2) --- --- --- --- --- --- --- 96.77(6)
O(1)-Cu(1)-O(1) --- --- --- --- --- --- --- 83.23(7)
101
a. b.
c. d.
e. f.
g. h.
Figure 3.9: ORTEP drawings of the complexes 1b (a), 2b (b), 3b (c), 4b (d), 5b (e), 6b (f),
8b (g) and 2c (h). Hydrogen atoms have been removed from 3b for clarity.
102
are Jahn-Teller inactive, the lengthening of the apical Cu–O bonds is owing to the double
electron occupancy of the antibonding a1 (dz2) leading to increased electron density of the filled
antibonding orbital along the apical Cu–O bond axis [9]. The b1 (dx2–y
2) orbital is singly
occupied and is unable to offer that much repulsion to the four ligands (two Cu–O and two Cu–N
bonds) present in the basal plane. The elongation of the apical bond length in these complexes is
of comparable magnitude to that observed in the previously reported complexes [29]. This
significant difference in the Cu–O bond distance involving the bridging oxygen, results in a
greater separation between the two copper ions of the dimer and the nearly square pyramidal
geometry around each copper ion. The Cu–O–Cu asymmetric bridging behavior is also typical of
other 5-coordinate copper(II) complexes [24,26,29].
The N–Cu–N angle is 81.66(8)о and between 80.60(7) – 80.74(7)
о for 2c and the rest of
the complexes, respectively representing the smallest angle around Cu being formed by the
copper ion and two N atoms of 1,10-phenanthroline or bipyridine molecule as found in similar
complexes of copper(II) with ligands having N and O donor atoms [30-32].
Packing arrangement:
The packing diagrams of the complexes are shown in Figs. 3.10 a-h, where the
uncoordinated oxygen atom of the carboxylate moiety is involved in weaker interactions with the
hydrogen atoms of the bipyridine ligand of the neighboring dimer and those of the lattice water
molecule. Additionally, the water molecule present in the crystal lattice is responsible for strong
intermolecular interactions: its oxygen and hydrogen atoms are oriented to the methylene
hydrogen and the uncoordinated oxygen atoms of the carboxylate ligands of the two neighboring
dinuclear complexes, respectively, thus completing the packing.
Similarly, one out of two florine atoms of each of the two asymmetric units of the
103
a. b.
c. d.
e. f.
g. h.
Figure 3.10: Packing diagrams of complexes 1b (a), 2b (b), 3b (c), 4b (d), 5b (e), 6b (f),
(g) and 2c (h). H-bonding and other inter-molecular interactions in 2c have been shown
by dotted lines.
104
dimeric molecules of complex 6b is closer enough to attract methylene hydrogen atoms of a
ligand in the next dimer. In addition, all the bromine atoms in 4b are v v B ∙∙∙H
interactions with methylene and phenyl ring hydrogen atoms of the neighboring complexes.
Compared to other oxygen bridged complexes, reported here, there is no water
molecule in 3b and 8b. This causes relatively fewer intermolecular interactions in these
complexes. Moreover, there are two crystallographically different molecules in the unit cell of
complex 3b. These differences cause a variation in the intermolecular interactions and thus give
rise to differences in the supra-molecular structure of 3b and 8b compared to other analogues.
An interesting packing arrangement exhibited by 2c is shown in Fig. 3.10 h. Here the
t h t t h t th h ∙∙∙H ∙∙∙H
∙∙∙H t t wh th tt w t . Th t v
hydrogen bonding makes 2c a compact structure as indicated by the small volume of the unit cell
compared to other analogues of the series (Table 3.8).
3.3.3 Mononuclear complexes
This series includes mononuclear complexes where one bidentate N-donor and two
carboxylate ligands are bonded to the copper(II) ion. The carboxylate ligands are 4-methyl (1c),
4-methoxy (3c), 4-bromo (4c), 4-chloro (5c), 4-floro (6c), 4-nitro (7b,7c) and 2-nitrophenyl
acetate (8c) wh th N- -bipyridine and 1,10-phenanthroline in case of 7b and
the rest of the members of the series, respectively. X-ray single crystal analysis of 1c, 5c, 6c, 8c
and 7b shows that the copper(II) ion is hexa-coordinated where each of the three ligands
coordinates in bidentate fashion except in 6c where one carboxylate ligand is monodentate and
the sixth coordination site is occupied by a water molecule. Thus the copper(II) ion is located at
the center of a distorted octahedron consisting of four oxygen atoms (O1,O2,O3,O4) from the
105
a. b.
c. d.
e.
Figure 3.11: ORTEP drawings of mono-nuclear complexes 1c (a), 5c (b), 6c (c), 8c (d)
and 7b (e).
two chelating carboxylate ligands and two nitrogen atoms from 2, -bipyridine or 1,10-
phenanthroline, except 6c. Two oxygen and two nitrogen atoms occupy the corners of the square
base and the remaining two oxygen atoms occupy the axial positions of the octahedron. The axial
Cu–O distances are much longer than the equatorial ones owing to the Jahn-Teller effect [9]. The
Cu–N bond lengths are typical of those of structurally related copper(II) complexes with 1,10-
106
phenanthroline [33]. The trans bond angles O–Cu–N and O–Cu–O range from 156.14(10) (6c) to
174.60(10)° (6c) and 141.41(7) (1c) to 150.45(10)° (8c), respectively. These values show marked
deviation from the ideal value of 180° indicating that the coordination geometry around copper is
distorted octahedral. The least deviation from an octahedral geometry is shown by 6c where one
of the carboxylate ligands is monodentate and the sixth coordination site is occupied by a water
molecule. The strain caused by the chelating nature of the carboxylate moiety is thus partly
released and the O–Cu–N angle value (174.60(10)°) is closer to the ideal value (180°). ORTEP
representations of the structures including the atom numbering scheme are given in Fig. 3.11 and
the structure refinement parameters and the selected bond lengths and angles are given in Tables
3.10 and 3.11, respectively.
Supra-molecular structures:
Supra-molecular structures of the mono-nuclear complexes are shown in Fig. 3.12.
1c: Crystal packing (Fig. 3.12 ) ∙∙∙H t t tw the phenanthroline
hydrogen atoms and carboxylate oxygen atoms. The lattice water molecule plays an important
role in connecting two molecules: its hydrogen and oxygen atoms are oriented towards
carboxylate oxygen atoms of the neighboring molecules and methylene, methyl and
phenanthroline hydrogen atoms of three molecules lying around it, respectively. Thus, owing to
the lattice water molecules in 1c, its supra-molecular structure is quite different than that of 5c.
5c: The crystal packing is formed by O∙∙∙H nteractions as shown in Fig. 3.12 b. The hydrogen
atoms at positions 4, 5 and 6, 7 of the phenanthroline ring of one molecule have weak
interactions with the carboxylate oxygen atom of the neighboring molecules lying on both sides
of it. Moreover, the carboxylate oxygen atom of one molecule is also involved in the same type
of interaction with the hydrogen atom at position 2 of the phenyl ring of the neighboring
molecule.
107
Table 3.10: Structure refinement parameters of mononuclear complexes
Complex 1c 5c 6c 8c 7b
Empirical formula C30 H28 Cu N2 O5 C28 H20 Cl2 Cu N2 O4 C28 H22 Cu F2 N2 O5 C28 H20 Cu N4 O8 C26 H20 Cu N4 O8
Formula weight (g mol−1
) 560.08 582.90 568.01 604.02 580.00
Temperature (K) 296(2) 296(2) 296(2) 296(2) 296(2)
Wavelength (Å) 0.71073 0.71073 0.71073 0.71073 0.71073
Crystal system Monoclinic Triclinic Monoclinic Triclinic Monolinic
Space group C 2/c P -1 P 21/n P -1 P 21/c
a (Å) 21.0475(6) 7.4203(5) 13.0522(10) 8.9106(10) 7.8143(4)
b (Å) 12.7750(6) 12.1512(8) 12.0762(11) 11.5323(13) 20.480(1)
c (Å) 20.8195(7) 15.5325(10) 16.4526(13) 14.0898(16) 15.6345(7)
α (°) 90 109.849(2) 90 66.905(5) 90
β (°) 108.353(2) 102.602(1) 101.533(5) 72.695(4) 94.990(2)
γ (°) 90 94.963(2) 90 86.387(5) 90
Volume (Å3) 5313.2(3) 1265.73(15) 2540.9(4) 1269.2(3) 2492.6(2)
Z 8 2 4 2 4
ρ ( t ) (M / 3) 1.400 1.529 1.485 1.581 1.546
Absorption coeff. (mm-1) 0.865 1.112 0.916 0.922 0.936
F(000) 2328 594 1164 618 1188
Crystal size (mm3) 0.24 × 0.20 × 0.18 0.25 × 0.22 × 0.16 0.30 × 0.24 × 0.23 0.25 × 0.22 × 0.18 0.28 × 0.25 × 0.22
θ (°) 2.00 to 25.50 1.64 to 26.00 1.824 to 26.000 1.645 to 26.000 1.64 to 26.00
Index ranges
- ≤ h ≤ 1
-1 ≤ k ≤ 1
- ≤ ≤
-9 ≤ h ≤ 8
-1 ≤ k ≤ 1
-18 ≤ ≤ 19
-16 ≤ h ≤ 16
-1 ≤ k ≤ 1
-6 ≤ ≤ 0
-10 ≤ h ≤ 10
-1 ≤ k ≤ 1
-1 ≤ ≤ 17
-9 ≤ h ≤ 9
- ≤ k ≤ 1
-19 ≤ ≤ 19
Reflections collected 21160 19535 19689 18472 19535
Independent reflections 4948 4931 4985 4968 4899
t t θ = 7.1 ° 99.90 % 99.40 % 99.90 % 99.60 % 99.9 %
Refinement method Full-matrix LS on F2 Full-matrix LS on F2 Full-matrix LS on F2 Full-matrix LS on F2 Full-matrix LS on F2
Data / restraints /parameters 4948 / 0 / 351 4931 / 0 / 334 4985 / 0 / 350 4968 / 0 / 370 4899 / 0 / 359
Goodness-of-fit on F2 1.014 1.038 1.016 1.023 1.026
F R I > σ (I)] R1 = 0.0881,
wR2 = 0.0397
R1 = 0.0887,
wR2 = 0.0353
R1 = 0.0422,
wR2 = 0.0859
R1 = 0.0465,
wR2 = 0.1001
R1 = 0.0829,
wR2 = 0.0331
R indices (all data) R1 = 0.0996,
wR2 = 0.0707
R1 = 0.0952,
wR2 = 0.0464
R1 = 0.0745,
wR2 = 0.0985
R1 = 0.0781,
wR2 = 0.1143
R1 = 0.0932,
wR2 = 0.0548
108
Table 3.11: Selected bond lenths and angles of mononuclear complexes
6c: It - h t t ∙∙∙H t t t
t h t th h th h ∙∙∙H
interactions as well. Intermolecular interactions in 6c are relatively fewer owing probably to the
least involvement of F atoms as shown in Fig. 3.12 c.
8c: It - t t t ∙∙∙H t t tw th
carboxylate oxygen and methylene hydrogen atom of the neighboring molecules. Similarly,
Complex
Bond
1c 5c 6c 8c 7b
Distances, Å
Cu(1)-O(1) 1.9374(18) 1.9258(19) 2.147(3) 1.966(2) 1.9598(16)
Cu(1)-O(2) 2.679(2) 2.774(2) 2.429(3) 2.414(2) 2.504(15)
Cu(1)-O(3) 1.9555(18) 1.9331(18) 1.937(2) --- ---
Cu(1)-O(4) 2.518(2) 2.777(2) --- --- ---
Cu(1)-O(5) --- --- 2.085(3) 1.946(2) 1.9515(18)
Cu(1)-O(6) --- --- --- 2.658(2) 2.63(3)
Cu(1)-N(1) 2.017(2) 2.033(2) 2.123(3) 1.994(3) 1.9949(16)
Cu(1)-N(2) 2.022(2) 2.036(2) 2.006(2) 2.008(3) 1.9975(18)
Angles, °
O(1)-Cu(1)-O(2) 54.01(8) 52.34(8) 93.40(9) 59.18(8) 57.7(3)
O(1)-Cu(1)-O(3) 95.96(8) 93.77(8) 91.71(10) --- ---
O(1)-Cu(1)-N(2) 166.92(9) 172.77(9) 87.64(10) 93.38(10) 95.26(7)
O(3)-Cu(1)-N(2) 93.21(8) 92.80(8) 174.60(10) --- ---
O(1)-Cu(1)-N(1) 90.71(8) 92.81(8) 101.38(10) 160.21(10) 171.72(7)
O(3)-Cu(1)-N(1) 170.76(8) 172.97(9) 95.16(10) --- ---
N(2)-Cu(1)-N(1) 81.32(8) 80.78(8) 79.74(10) 81.61(10) 81.02(7)
O(1)-Cu(1)-O(4) 103.93(8) 95.58(7) --- --- ---
O(3)-Cu(1)-O(4) 57.08(7) 52.16(8) --- --- ---
O(2)-Cu(1)-O(4) 141.41(7) 135.42(7) --- --- ---
O(2)-Cu(1)-O(3) 91.15(7) 95.18(7) 93.40(9) --- ---
O(5)-Cu(1)-O(3) --- --- 94.11(10) --- ---
O(5)-Cu(1)-N(2) --- --- 88.82(10) 166.14(10) 166.03(7)
O(5)-Cu(1)-N(1) --- --- 103.61(10) 93.31(10) 92.75(7)
O(5)-Cu(1)-O(1) --- --- 153.69(11) 95.54(9) 92.44(7)
O(5)-Cu(1)-O(2) --- --- 97.93(10) 103.10(10) 97.1(5)
O(2)-Cu(1)-N(1) --- --- 156.14(10) --- ---
O(6)-Cu(1)-N(2) --- --- --- 112.5(2) 114.3(6)
O(6)-Cu(1)-O(2) --- --- --- 150.45(10) 142.15(6)
109
a. b.
c. d.
e.
Figure 3.12: Packing diagrams of mono-nuclear complexes
1c (a), 5c (b), 6c (c), 8c (d) and 7b (e).
th h t v v ∙∙∙H t t w th the phenyl ring of the
side lying molecule. Here, only one oxygen atom of the ortho-nitro group is involved in
secondary interactions with neighboring molecules, therefore, the intermolecular interactions are
110
fewer compared to those of 7b (compare Figs. 3.12 d and e).
7b: Owing to the suitably oriented para- t th t k t t
∙∙∙H t t tw t th th
oppositely lying neighboring molecules. The packing is aided by th ∙∙∙H t t t
between carboxylate moiety and phenyl ring as well. The intermolecular interactions are
relatively higher (Fig. 3.12 e) compared to other members of the series owing to the suitably
oriented para-nitro groups.
3.4 DNA binding study through cyclic voltammetry
Cyclic voltammetry was employed to explore the DNA binding ability of the complexes
at various scan rates. The shift in peak potential was used to interpret the mode of DNA binding
activity of the complexes. A negative shift in the potential i.e., to the less positive region (or to
more negative region in case of reduction signal) on addition of DNA indicates electrostatic
mode of interaction with complex [34,35], while a positive shift in the potential i.e., to more
positive region (or to less negative region in case of reduction signal) exhibits an intercalative
mode. However, pure electrostatic or intercalative modes of interaction are seldom encountered
and, more often, a mixed behavior is usually observed in practice. Based on the above criteria,
the following types of DNA binding modes have been observed for the synthesized complexes.
3.4.1 Predominant electrostatic mode of interaction
A shift of 52, 104, 30, 141, 20 and 20 mV in the potential to the less positive region (or to
more negative region in case of reduction signal) was observed on addition of DNA to 1c, 2c, 3b,
4b, 8b and 8c, respectively, as shown in Fig. 3.13, exhibiting an electrostatic mode of DNA
interaction with complexes [34]. The shift to the less positive potential side was retained on
successive addition of DNA as well. Owing to the continuous shift in the same direction with
111
-0.4 -0.2 0.0 0.2 0.4-0.012
-0.009
-0.006
-0.003
0.000
0.003
0.006I
/ m
A
E / V
1cDNA addition
-0.36 -0.18 0.00 0.18 0.36 0.54
-0.010
-0.005
0.000
0.005
0.010
I /
mA
E / V
2cDNA addition
-0.50 -0.25 0.00 0.25 0.50
-0.09
-0.06
-0.03
0.00
0.03
I /
mA
E / V
3bDNA addition
-0.6 -0.4 -0.2 0.0 0.2 0.4-0.015
-0.010
-0.005
0.000
0.005
0.010
I /
mA
E / V
4b DNA addition
-0.4 -0.2 0.0 0.2 0.4 0.6
-0.024
-0.016
-0.008
0.000
0.008
0.016
I /
mA
E / V
8bDNA addition
-0.6 -0.4 -0.2 0.0 0.2 0.4 0.6
-0.03
-0.02
-0.01
0.00
0.01
I /
mA
E / V
8cDNA addition
Figure 3.13: Cyclic voltammograms of 1c, 2c, 3b, 4b, 8b and 8c in the absence and presence of
10-70 μM DNA. In each case the peak current decreases and peak potential is shifted to left hand
side on successive DNA addition.
112
Table 3.12: Shift in peak potential of the complexes on DNA addition
Complex
Peak potential
(mV) before
DNA addition
Peak potential
(mV) after
DNA addition
Peak shift (mV)
w th 10 μM
DNA (1st addition)
Peak shift (mV)
during (10-80
μM) NA t
Predominant electrostatic mode
1c -28 -80 52 10
2c 72 -32 104 47
3b 174 154 30 10
4b 113 -28 141 20
8b 283 273 10 10
8c -230 -240 10 10
Predominant intercalative mode
4 123 165 42 60
5 94 110 16 54
6 23 33 10 97
7 204 214 10 Minor shift
8 133 153 20 41
3a 152 164 12 40
5a 98 184 86 11
6a 165 203 38 19
7a 425 455 30 61
8a 100 118 18 05
1b 92 93 1 Minor shift
5b 183 203 20 51
3c 153 195 42 39
4c 153 183 30 71
5c 91 92 1 1
6c 224 294 70 20
7c 271 254 17 86
Mixed binding mode
1 13 -17 30 13
2 40 -40 80 55
2a 185 15 170 10
2b 154 128 26 39
3 14 40 36 30
4a -8 -99 91 30
6b -237 -277 40 30
1a 30 73 43 21
7b 281 284 02 12
113
successive DNA addition, the mode of binding has been termed as predominantly electrostatic.
The largest shift was observed for 4b (141 mV) which is attributed to the presence of para-
chlorine atoms that are able to interact easily with DNA. The next higher value is observed for 2c
(104 mV) which can be attributed to the presence of coordinated water as well as bridging
hydroxyl groups both of which increase electrostatic interaction with DNA.
3.4.2 Predominant intercalative mode
Complexes 4-8, 3a, 5a-8a, 1b, 5b, and 3c-7c experienced shifts to more positive region
(or to less negative region in the case of reduction peaks) with addition of DNA as listed in Table
3.12. On successive DNA addition, there is a further shifting of the peak potential to the more
positive potential region as shown in Fig. 3.14. The predominant intercalative ability of these
complexes is ascribed to the presence of planar aromatic rings. The high intercalative ability of
the complexes 4, 4c, 5a, 6c, 7a and 7c shows that the para-nitro (7a and 7c), bromo (4 and 4c),
chloro (5a) and floro (6c) groups have prominent impact on the DNA binding ability of these
complexes. Since these groups are more efficient electrostatic binders, there must be a significant
contribution of electrostatic interaction in these complexes along with intercalation between
DNA base pairs.
3.4.3 Mixed binding mode
A shift of 30, 80, 170, 26, 36, 91 and 40 mV in the potential to the less positive region (or to
more negative region in case of reduction signal) was observed on addition of DNA to 1, 2, 2a,
2b, 3, 4a and 6b as shown in Fig. 3.15, exhibiting an electrostatic mode of interaction with the
complex [34]. However, after successive addition of SSDNA, there was an observable shift to
the right hand side indicating a concomitant intercalative mode of interaction with SSDNA as
well. The intercalative ability of the complexes is attributed to the homo- as well as heterocyclic
114
-0.6 -0.4 -0.2 0.0 0.2 0.4
-0.04
-0.03
-0.02
-0.01
0.00
0.01
0.02
0.03
I /
mA
E / V
4DNA addition
-0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6
-0.04
-0.02
0.00
0.02
0.04
I /
mA
E / V
DNA addition5
-0.6 -0.4 -0.2 0.0 0.2 0.4
-0.024
-0.016
-0.008
0.000
0.008
0.016
I /
mA
E / V
6DNA addition
-0.6 -0.4 -0.2 0.0 0.2 0.4 0.6-0.06
-0.04
-0.02
0.00
0.02
0.04
0.06
I /
mA
E / V
7 DNA addition
-0.6 -0.4 -0.2 0.0 0.2 0.4 0.6
-0.02
-0.01
0.00
0.01
0.02
I /
mA
E / V
8DNA addition
-0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6
-0.08
-0.04
0.00
0.04
0.08
I /
mA
E / V
3aDNA addition
-0.6 -0.4 -0.2 0.0 0.2 0.4
-0.036
-0.024
-0.012
0.000
0.012
0.024
0.036
I /
mA
E / V
5aDNA addition
-0.4 -0.2 0.0 0.2 0.4
-0.010
-0.005
0.000
0.005
0.010
I /
mA
E / V
6aDNA addition
-0.6 -0.4 -0.2 0.0 0.2 0.4 0.6
-0.02
-0.01
0.00
0.01
0.02
0.03
I /
mA
E / V
DNA addition7a
(Figure continued, caption on next page)
115
-0.6 -0.4 -0.2 0.0 0.2 0.4 0.6
-0.02
-0.01
0.00
0.01
0.02
I /
mA
E / V
8DNA addition
-0.6 -0.4 -0.2 0.0 0.2 0.4 0.6
-0.04
-0.03
-0.02
-0.01
0.00
0.01
0.02
I /
mA
E / V
1bDNA addition
-0.6 -0.4 -0.2 0.0 0.2 0.4 0.6
-0.06
-0.04
-0.02
0.00
0.02
I /
mA
E / V
DNA addition
5b
-0.6 -0.4 -0.2 0.0 0.2 0.4-0.04
-0.03
-0.02
-0.01
0.00
0.01
0.02
I /
mA
E / V
3cDNA addition
-0.6 -0.4 -0.2 0.0 0.2 0.4 0.6
-0.03
-0.02
-0.01
0.00
0.01
0.02
I /
mA
E / V
4cDNA addition
-0.4 -0.2 0.0 0.2 0.4
-0.020
-0.015
-0.010
-0.005
0.000
0.005
0.010
I /
mA
E / V
5cDNA addition
-0.4 -0.2 0.0 0.2 0.4
-0.020
-0.015
-0.010
-0.005
0.000
0.005
0.010
I / m
A
E / V
6cDNA addition
-0.4 -0.2 0.0 0.2 0.4 0.6 0.8
-0.051
-0.034
-0.017
0.000
0.017
0.034
I /
mA
E / V
7cDNA addition
Figure 3.14: Cyclic voltammograms of 4-8, 3a, 5a-8a, 1b, 5b, and 3c-7c in the absence and presence of 10-90 μM DNA. In each
case the peak current decreases and the peak potential is shifted to right hand side on successive addition of DNA.
116
aromatic rings in the molecular structures of these complexes while the concomitant electrostatic
mode is owing to the presence of halogen as well as polar methoxy groups at the para-positions
of the phenyl ring which are able to establish electrostatic interaction with DNA base pairs. Since
the shift in peak potential towards less positive region is far more compared to the shift towards
more positive region, the major mode of binding will be electrostatic.
Similarly, the peak potential of the two complexes 1a and 7b experienced a shift to more
positive region (or less negative region in case of reduction peak) with the addition of DNA.
However, with successive DNA addition, the peak potential was continuously shifted to the
reverse direction, i.e., towards less positive potential region as shown in Fig. 3.16. This behavior
might be due to a mixed binding mode (intercalative and electrostatic) of complexes 1a and 7b
with DNA. This type of mixed binding is different from that discussed in the start of this section,
as evident from the shift in the peak potential with DNA addition. Here, a pronounced shift
towards more positive potential is followed by a relatively small shift towards the opposite
direction with each successive DNA addition. Owing to this, intercalation seems to be more
dominant as compared to the electrostatic mode of interaction as seen from the voltammogram of
1a (Fig. 3.16).
In conclusion, the complexes possess DNA-binding ability which has been found to be
sufficiently high for some of the complexes such as 1, 2, 2a, 3, 4a, 4c, 5a, 6, 6a, 6c and 7c. The
diversity in the structure (the presence of polar as well as planar groups) gives rise to a mixed
DNA binding mode for these complexes.
In addition to the peak shift, the peak current experienced a diminution on the addition of
DNA to the complex solution as listed in Table 3.13. This decrease in the peak current is
attributed to the decrease in concentration of the unbound electro-active complex as a
117
-0.3 -0.2 -0.1 0.0 0.1 0.2 0.3
-0.015
-0.010
-0.005
0.000
0.005
0.010
0.015
I /
mA
E / V
1DNA addition
-0.4 -0.3 -0.2 -0.1 0.0 0.1 0.2 0.3
-0.03
-0.02
-0.01
0.00
0.01
0.02
0.03
I /
mA
E / V
2 DNA addition
-0.1 0.0 0.1 0.20.0195
0.0210
0.0225
0.0240
0.0255
0.0270
-1.5 -1.0 -0.5 0.0 0.5
-0.030
-0.015
0.000
0.015
0.030
E / V
I / m
A
complex
DNA2a
I /
mA
E / V
DNA addition
-0.6 -0.4 -0.2 0.0 0.2 0.4 0.6-0.08
-0.06
-0.04
-0.02
0.00
0.02
I /
mA
E / V
2bDNA addition
-0.3 -0.2 -0.1 0.0 0.1 0.2 0.3 0.4
-0.03
-0.02
-0.01
0.00
0.01
0.02
0.03
0.04
I /
mA
E / V
3
DNA addition
-0.4 -0.2 0.0 0.2 0.4
-0.03
-0.02
-0.01
0.00
0.01
0.02
0.03
0.04
E / V
I /
mA
4aDNA addition
-0.92 -0.69 -0.46 -0.23 0.00 0.23 0.46 0.69
-0.054
-0.036
-0.018
0.000
0.018
0.036
I /
mA
E / V
6bDNA addition
Figure 3.15: Cyclic voltammograms of 1, 2, 2a, 2b, 3, 4a and 6b in the absence and presence of
10-90 μM DNA. In each case the peak current decreases and the peak potential is shifted to the
right hand side with respect to the shift with the first addition of DNA.
118
-0.6 -0.4 -0.2 0.0 0.2 0.4
-0.02
-0.01
0.00
0.01
0.02
I /
mA
E / V
1aDNA addition
-0.4 -0.2 0.0 0.2 0.4 0.6
-0.024
-0.016
-0.008
0.000
0.008
0.016
I /
mA
E / V
DNA addition
7b
Figure 3.16: Cyclic voltammograms of 1a and 7b in the absence and presence of 10-90 μM
DNA. In each case the peak current decreases and the peak potential is shifted to the left hand
side with respect to the shift with the first addition of DNA.
consequence of the complex-DNA adducts formation following the DNA addition. The decrease
in the peak current and the shift in the potential is far more than those observed for other dimeric
Cu(II) and Ni(II) complexes [36,37], indicating more efficient and facile interaction of the
complex with DNA. The slope value of ip vs. v1/2
plot is reduced on addition of DNA indicating
the binding of DNA with complexes [38,39].
On the basis of the decrease in peak current of the unbound complex by the addition of
t t t (10 t 90 μM) SS NA th t t w t . Th plot
of log 1/[DNA] vs. log I/(Io-I) gave rise to a straight line (Fig. 3.17), whose intercept was used to
calculate the binding constant using the following equation (equation 3.1) [40]:
log (1/[DNA]) = log Kb + log I/(Io-I) (3.1)
where Kb is the binding constant, Io and I are the peak currents of the complex in the absence and
presence of DNA, respectively. The values of Kb calculated for the complexes are listed in Table
3.14. The higher values of Kb are those of 2, 4c, 5a, 5b, 5c and 6 which may be due to the
presence of the para-nitro (2), bromo (4c), chloro (5a, 5b, 5c) and floro (6) groups, enhancing
the interaction of the complexes with DNA. These Kb values are comparable to other structurally
119
Table 3.13: Decrease in the peak current of the complexes on DNA addition
Complex
Peak current
(μA)
DNA addition
Peak current
(μA) t
DNA addition
Reduction in Peak
t w th 10 μM
DNA (1st addition)
Predominant electrostatic mode
1c 7 6 1
2c 10 9 1
3b 50 44 6
4b 40 24 16
8b 17 16 1
8c 17 16 1
Predominant intercalative mode
4 35 28 7
5 39 33 6
6 20 13 07
7 57 47 10
8 25 23 2
3a 76 73 3
5a 40 21 19
6a 12 7 5
7a 31 30 1
8a 31 24 7
1b 19 18 1
5b 29 28 1
3c 25 20 5
4c 23 18 5
5c 13 12 1
6c 15 10 5
7c 42 30 12
Mixed binding mode
1 19 12 7
2 38 18 20
2a 28 22 6
2b 34 32 2
3 40 14 26
4a 10 8 2
6b 36 35 1
1a 27 18 9
7b 16 14 2
120
related copper(II) [41,42] and Rh(II) [37] complexes.
The DNA binding of the complexes was also confirmed by calculating the diffusion
coefficient of the complexes before and after the DNA addition. This was accomplished by
measuring the voltammograms at different scan rates before and after the DNA addition and
putting the relevant parameters in the Randles-Sevcik equation [43] (equation 3.2):
ip = (2.99×105) n(αn)
1/2AC
* Do
1/2 v
1/2 (3.2)
where ip, α, n, Do, C*, A and v denote the peak current in ampere, charge transfer coefficient, the
number of electrons involved in the electron transfer process, diffusion coefficient in cm2s–1
,
-0.2 0.0 0.2 0.4 0.6
4.4
4.6
4.8
5.0
5.2
5.4
log (I/(Io-I))
log (
1/[
DN
A]
(M))
1
2
3
4
5
6
7
8
a
-0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.24.4
4.6
4.8
5.0
5.2
5.4
log (I/(Io-I))
log (
1/[
DN
A]
(M))
1a
2a
3a
4a
5a
6a
7a
8a
b
-1.0 -0.5 0.0 0.5 1.0 1.5 2.0
4.4
4.6
4.8
5.0
5.2
log (I/(Io-I))
log (
1/[
DN
A]
(M))
1b
2b
3b
4b
5b
6b
7b
8b
c
-0.5 0.0 0.5 1.0 1.5 2.0
4.4
4.6
4.8
5.0
5.2
log (
1/[
DN
A]
(M))
log (I/(Io-I))
1c
2c
3c
4c
5c
6c
7c
8c
d
Figure 3.17: Plots of log 1/[DNA] vs. log I/(Io-I) for the calculation of the binding constants of
complexes 1-8 (a), 1a-8a (b), 1b-8b (c) and 1c-8c (d).
121
Table 3.14: Do (cm2s–1
) and Kb (M–1
) values of the complexes obtained from CV
S # Complex Do before DNA
addition × 10–8
Do after DNA
addition × 10–8
Kb × 104
1 1 3.032 1.177 0.334
2 2 16.280 4.889 8.845
3 3 16.781 3.309 3.161
4 4 77.382 19.752 1.626
5 5 42.765 17.105 1.187
6 6 23.170 0.891 7.547
7 7 121.101 36.192 2.457
8 8 5.781 4.664 2.108
9 1a 34.309 4.034 1.445
10 2a 73.570 53.105 0.307
11 3a 199.821 162.852 1.007
12 4a 27.702 13.722 0.771
13 5a 64.410 6.407 21.383
14 6a 7.912 0.305 3.695
15 7a 16.421 3.703 2.371
16 8a 41.552 10.661 0.067
17 1b 2.180 2.041 3.325
18 2b 13.783 5.936 2.426
19 3b 28.861 5.401 5.542
20 4b 0.854 0.798 4.451
21 5b 69.812 0.311 8.585
22 6b 28.255 8.413 3.667
23 7b 1.807 1.337 1.820
24 8b 2.736 1.645 1.631
25 1c 0.789 0.161 0.581
26 2c 4.149 2.861 2.426
27 3c 7.085 0.992 4.781
28 4c 16.960 0.425 8.176
29 5c 0.972 0.719 6.390
30 6c 5.778 0.022 3.667
31 7c 32.725 2.214 4.053
32 8c 10.323 6.625 0.378
122
bulk concentration of the complex in mol cm–3
, surface area of the working electrode in cm2
and
potential scan rate in V s–1
, respectively.
The slope values for Do calculation were obtained making use of the respective ip vs. v1/2
plots for oxidation and reduction and αn was calculated using Bard and Faulkner relation [44]
(equation 3.3).
α = 47.7/[Ep–Ep/2] mV (3.3)
where Ep is the peak potential and Ep/2 is the peak potential at half of the maximum peak current
value. The values of Do thus calculated for the complexes before and after DNA addition are
given in Table 3.14. The lower values of diffusion coefficients of DNA-bound complexes
compared to those of the unbound complexes show a reduction in the mobility of the former
[45,46]. The reduction in mobility of the complexes with the DNA addition shows the adduct
formation between the two.
3.5 Absorption spectroscopy
All the complexes show a broad band in the visible region of the electromagnetic
spectrum corresponding to d-d transitions of Cu2+
[29,32]. These peaks have been found typical
of geometrically similar copper(II) complexes and helped to confirm the structure of the
complexes in solution. The complexes 1-8 and 1a-8a h w t w th λmax
ranging from 723-744 and 720-737 nm, respectively, which are typical of distorted square
pyramidal geometry in solution and has been found typical of some already reported copper(II)
complexes of similar structures [47-49]. This shows the retention of the square pyramidal
geometry and the stable nature of the paddlewheel structures of the two series. In the polymeric
complexes 1-8, there is the possibility of breaking off the relatively weaker inter- ‒
bond in solution. However, the vacant coordination site produced in this way seems to be re-
123
occupied by the highly coordinating DMSO molecule and the square pyramidal geometry is re-
established around copper(II). The complexes 1b-8b and 1c-8c show broad absorption bands
w th λmax ranging from 658-689 and 678-695 nm, respectively, which is typical of a distorted
octahedral geometry in solution. This shows the retention of the octahedral geometry of the
mononuclear complexes 1c and 3c-8c and the attachment of a DMSO molecule opposite to the
axial site of the square pyramidal complexes 1b-8b and 2c. According to the literature, other
copper(II) complexes of octahedral geometry have been found to show absorbances in the same
wave length region [50-53]. These w t t λmax ε th wh h
listed in Table 3.15. Th ε v t th t t t (II) mplexes
already reported [29,50].
3.6 DNA study through absorption spectroscopy
The variation of λmax and the absorbance as a consequence of the interaction with DNA
can be followed spectrophotometrically and used to determine binding parameters such as
binding constant if the complex interacts with DNA. The mode of interaction of the complexes
w th NA j th h t λmax: a blue shift (shift towards shorter wavelength)
indicates electrostatic while red shift (shift towards longer wavelengths) is manifested by
intercalative mode of interaction [37,54-56]. However, when the red shift is very small, groove
binding is the major mode of DNA-interaction. Usually, the shift of λmax is accompanied by very
pronounced hypochromism (decrease in absorbance) as well. All of the synthesized complexes
exhibited a pronounced hypochromism with successive addition of SSDNA (10-90 μM).
However, based on the shift of λmax (Table 3.15), the complexes have been categorized in the
following three groups with respect to their DNA binding modes:
124
Table 3.15: Kb, ε and shift λmax with DNA addition in UV
S # Complex λmax (nm)
before DNA
addition
λmax (nm)
after DNA
addition
ε
(L mol–1
cm–1
)
Kb
(M–1
)
× 104
1 1 723 734 150 0.690
2 2 724 758 156 1.384
3 3 723 732 159 1.144
4 4 730 734 162 1.098
5 5 731 735 160 1.509
6 6 725 754 163 1.094
7 7 744 735 152 1.342
8 8 734 --- 155 ---
9 1a 720 753 136 1.141
10 2a 723 756 130 0.529
11 3a 723 728 132 1.143
12 4a 732 735 135 0.587
13 5a 731 734 133 1.003
14 6a 737 741 141 3.430
15 7a 735 760 142 2.029
16 8a 732 735 137 0.077
17 1b 665 673 182 1.187
18 2b 676 660 184 1.361
19 3b 676 679 189 1.922
20 4b 689 693 190 1.106
21 5b 671 675 182 2.895
22 6b 680 684 193 1.438
23 7b 658 670 198 1.351
24 8b 677 681 184 1.356
25 1c 688 692 201 0.540
26 2c 687 677 205 1.399
27 3c 678 685 208 1.540
28 4c 680 672 211 1.726
29 5c 689 673 205 1.577
30 6c 691 695 209 1.411
31 7c 686 690 205 1.134
32 8c 695 673 208 1.871
125
3.6.1 Classical intercalation
Complexes 1a, 2, 2a, 6, 7a exhibited hypochromism (reduction in absorbance) with a
large red shift (25-34 nm) as shown in Fig. 3.18 and this was attributed to the intercalation of a
planar phenyl ring as well as pyridine moieties into the base pairs of SSDNA.
3.6.2 Mixed binding mode: Electrostatic with groove binding mode
Th λmax of the complexes 2b, 2c, 4c, 5c, 7 and 8c exhibited blue shift (8-22 nm)
accompanied by hypochromism as shown in Fig. 3.19. This behavior is typical of electrostatic
interaction with concomitant groove binding. The highest blue shift was observed for 8c (22 nm)
which is attributed to the presence of a suitably oriented ortho-nitro group attached to the
aromatic ring which enhances the electrostatic interaction with the SSDNA.
3.6.3 Mixed binding mode: Partial intercalation with groove binding mode
The extensive hypochromism of these complexes is accompanied by a small red shift of
4-12 nm. These are 1, 1b, 1c, 3-5, 3a-6a, 8a, 3b-8b, 3c, 6c and 7c and their spectra are shown in
Fig. 3.20.
The quantitative affinity of copper(II) complexes for SSDNA was judged from the
intrinsic binding constant of the two, calculated by monitoring the variation in the absorbance
with an incremental addition of SSDNA. The spectrophotometric evaluation of the binding
constant for the DNA-binding species is performed by making use of the famous Benesi-
Hildebrand equation [57] (equation 3.4):
where A0 and A are the absorbance of the complexes in the absence and presence of DNA while
εG εH is their absorption coefficients, respectively. The binding constant, K is evaluated
from the slope to intercept ratio of the plot between the terms on the left-hand side of equation
126
500 600 700 800 900 1000 1100
0.00
0.15
0.30
0.45
0.60
0.75
0.90
Wavelength (nm)
Absorb
ance
1a a
h
500 600 700 800 900 1000 11000.00
0.18
0.36
0.54
0.72
Wavelength (nm)
Ab
sorb
an
ce
2 a
i
500 600 700 800 900 1000 1100
0.0
0.2
0.4
0.6
0.8
Wavelength (nm)
Ab
sorb
an
ce
2aa
i
500 600 700 800 900 1000 11000.0
0.2
0.4
0.6
0.8
1.0
Wavelength (nm)
Absorb
ance
6 a
h
500 600 700 800 900 1000 11000.0
0.2
0.4
0.6
0.8
1.0
1.2
Wavelength (nm)
Ab
sorb
an
ce
7a a
i
Figure 3.18: Absorption spectra of 1a, 2, 2a, 6, 7a in the absence (a) and presence of 10-80 μM
DNA (b-i).
127
500 600 700 800 900 1000 1100
0.0
0.2
0.4
0.6
0.8
Wavelength (nm)
Ab
sorb
an
ce
2b a
i
500 600 700 800 900 1000 1100-0.2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Wavelength (nm)
Absorb
ance
a
j
2c
500 600 700 800 900 1000 1100
0.0
0.2
0.4
0.6
0.8
1.0
Wavelength (nm)
Ab
sorb
an
ce
4c a
i
500 600 700 800 900 1000 1100
0.0
0.1
0.2
0.3
0.4
0.5
0.6
Wavelength (nm)
Absorb
ance
5ca
h
500 600 700 800 900 1000 1100-0.2
0.0
0.2
0.4
0.6
0.8
Wavelength (nm)
Ab
sorb
an
ce
7a
i
500 600 700 800 900 1000 1100
0.00
0.05
0.10
0.15
0.20
0.25
0.30
Wavelength (nm)
Absorb
ance
8c a
i
Figure 3.19: Absorption spectra of 2b, 2c, 4c, 5c, 7 and 8c in the absence (a) and presence of 10-
90 μM NA ( -j).
128
500 600 700 800 900 1000 1100
0.0
0.2
0.4
0.6
0.8
1.0
Wavelength (nm)
Ab
sorb
an
ce
1
i
a
500 600 700 800 900 1000 1100
0.15
0.30
0.45
0.60
0.75
0.90
Wavelength (nm)
Ab
sorb
an
ce
1b a
g
500 600 700 800 900 1000 1100
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Wavelength (nm)
Absorb
ance
1ca
h
500 600 700 800 900 1000 1100
0.0
0.2
0.4
0.6
0.8
Ab
sorb
an
ve
Wavelength (nm)
3a
j
600 700 800 900 1000 1100
0.0
0.2
0.4
0.6
0.8
Wavelength (nm)
Ab
sorb
an
ce
4a
i
500 600 700 800 900 1000 1100
0.0
0.2
0.4
0.6
0.8
1.0
Wavelength (nm)
Absorb
ance
a
h
5
500 600 700 800 900 1000 1100
0.0
0.2
0.4
0.6
0.8
1.0
Wavelength (nm)
Ab
sorb
an
ce
3a a
j
600 700 800 900 1000 1100
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Wavelength (nm)
Absorb
ance
4aa
i
500 600 700 800 900 1000 1100
0.0
0.2
0.4
0.6
0.8
1.0
Wavelength (nm)
Ab
sorb
an
ce
5aa
j
500 600 700 800 900 1000 1100
0.0
0.2
0.4
0.6
0.8
1.0
Wavelength (nm)
Ab
sorb
an
ce
6a a
i
500 600 700 800 900 1000 1100
0.00
0.05
0.10
0.15
0.20
0.25
0.30
Wavelength (nm)
Ab
sorb
an
ce
8aa
h
500 600 700 800 900 1000 1100
0.0
0.2
0.4
0.6
0.8
Ab
sorb
an
ce
Wavelength (nm)
3b a
i
(Figure continued, caption on next page)
129
500 600 700 800 900 1000 1100
0.00
0.07
0.14
0.21
0.28
0.35
0.42
Wavelength (nm)
Absorb
ance
4b a
i
500 600 700 800 900 1000 1100
-0.05
0.00
0.05
0.10
0.15
0.20
0.25
0.30
Wavelength (nm)
Ab
sorb
an
ce
5ba
j
500 600 700 800 900 1000 1100
0.2
0.4
0.6
0.8
1.0
Wavelength (nm)
Absorb
ance
a
j
6b
500 600 700 800 900 1000 1100
0.0
0.2
0.4
0.6
0.8
Wavelength (nm)
Absorb
ance
7b a
i
500 600 700 800 900 1000 1100
0.0
0.2
0.4
0.6
0.8
Wavelength (nm)
Absorb
ance
8b a
i
500 600 700 800 900 1000 1100
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Wavelength (nm)
Absorb
ance
3c a
g
500 600 700 800 900 1000 1100
-0.2
0.0
0.2
0.4
0.6
0.8
Wavelength (nm)
Ab
sorb
an
ce
6c a
j
500 600 700 800 900 1000 1100
0.0
0.2
0.4
0.6
0.8
1.0
Wavelength (nm)
Ab
sorb
an
ce
7c a
i
Figure 3.20: Absorption spectra of 1, 1b, 1c, 3-5, 3a-6a, 8a, 3b-8b, 3c, 6c and 7c in the absence (a) and presence of 10-90 μM NA
(b-j).
130
3.4 against 1/[DNA] as shown in Fig. 3.21.
The binding constants thus calculated for the complexes are listed in Table 3.15. The
values of binding constants match well with those calculated through cyclic voltammetry.
Moreover, the highest DNA-binding ability of 3b, 4c, 5, 5b, 5c, 6b, 6a, 7a and 8c as indicated by
the high values of their Kb can be attributed to the para-substituent on the phenyl ring in these
complexes. These substituents are para-methoxy (3b), bromo (4c), chloro (5, 5b, 5c), floro (6b,
0 20000 40000 60000 80000 100000
-9
-8
-7
-6
-5
-4
-3
-2
-1
1 / [DNA] (M)-1
Ao /
A-A
o
1
2
3
4
5
6
7
a
20000 40000 60000 80000 100000-12
-10
-8
-6
-4
-2
1 / [DNA] (M)-1
Ao /
A-A
o
1a
2a
3a
4a
5a
6a
7a
8a
b
20000 40000 60000 80000 100000-9
-8
-7
-6
-5
-4
-3
-2
-1
1 / [DNA] (M)-1
Ao /
A-A
o
1b
2b
3b
4b
5b
6b
7b
8b
c
20000 40000 60000 80000 100000-9
-8
-7
-6
-5
-4
-3
-2
-1
1 / [DNA] (M)-1
Ao /
A-A
o
1c
2c
3c
4c
5c
6c
7c
8c
d
Figure 3.21: Plots of Ao/(A-Ao) vs. 1/[DNA] for the calculation of the binding constants of the
complexes 1-8 (a), 1a-8a (b), 1b-8b (c) and 1c-8c (d).
131
6a) and nitro (7a) and ortho-nitro (8c) groups. The spectrophotometrically determined Kb values
are comparable to those determined through the same technique for structurally similar
copper(II) complexes present in the literature [58-61]. Thus the complexes exhibiting a high
DNA-binding ability in cyclic voltammetry have been confirmed by UV-visible spectroscopy as
well.
3.7 Biological Studies
3.7.1 Antibacterial study
All the complexes were screened for their in vitro antibacterial activity against three
Gram-Positive (Micrococcus luteus, Staphylococcus aureus and Bacillus subtilis) and one Gram-
negative bacterial strains (Escherichia coli). The results for the complexes showing
antibacterial activity are summarized in Tables 3.16 and 3.17. The activity was determined by
measuring the area of zone of inhibition (mm) and was classified according to the standard
procedure commonly followed, where the activity is considered significant, good, low or
non-significant corresponding to the area of inhibited zone ≥ 20, 18-20, 15-17 or 11-14 mm,
respectively [62]. The results in Table 3.16 demonstrate that complexes 1c (Escherichia coli and
Staphylococcus aureus), 2c (Micrococcus luteus, Bacillus subtilis and Escherichia coli), 6c
(Bacillus subtilis and Escherichia coli) and 7c (Escherichia coli) showed a significant activity
against the respective bacterial strains while 1c, 3c and 6c and 7c exhibited good activity against
Micrococcus luteus, and Bacillus subtilis, respectively. Moreover, 6c also showed a good activity
against Staphylococcus aureus. 1a, 2a, 5a, 5c showed low and 3a showed non-significant
antibacterial activity against some of the tested bacterial strains as shown in Table 3.16. The
significant activity of the complexes belonging to the series of mono-nuclear complexes can be
attributed to their high permeability through the cell membrane of the bacterial cell. Once inside
132
Table 3.16: Antibacterial data of complexes: Average zone of inhibition (mm)
Compound Micrococcus
luteus
Bacillus
subtilis
Escherichia
coli
Staphylococcus
aureus
1 NA NA NA NA
2 NA NA NA NA
3 NA NA NA NA
4 NA NA NA NA
5 ND ND ND ND
6 NA NA NA NA
7 NA NA NA NA
8 ND ND ND ND
1a NA 17 NA 14
2a 16 NA NA NA
3a 14 NA NA NA
4a NA NA NA NA
5a NA 15 NA NA
6a NA NA NA NA
7a ND ND ND ND
8a NA NA NA NA
1b NA NA NA NA
2b NA NA NA NA
3b NA NA NA NA
4b NA NA NA NA
5b ND ND ND ND
6b NA NA NA NA
7b NA NA NA NA
8b NA NA NA NA
1c 19 16 20 23
2c 22 21 24 NA
3c 18 NA NA NA
4c NA NA NA NA
5c NA NA 14 NA
6c 18 23 26 18
7c 14 18 23 14
8c NA NA NA NA
cefixime 33 29 30 35
Concentration: 1 mg/mL in DMSO. Reference drug, Cefixime: 1 mg/mL.
ND means activity not determined. NA means not active
133
Table 3.17: Antibacterial data of complexes: Minimum Inhibitory Concentration (MIC) (mg/mL)
Compound Micrococcus
luteus
Bacillus
subtilis
Escherichia
coli
Staphylococcus
aureus
1 NA NA NA NA
2 NA NA NA NA
3 NA NA NA NA
4 NA NA NA NA
5 ND ND ND ND
6 NA NA NA NA
7 NA NA NA NA
8 ND ND ND ND
1a NA 1 NA 1
2a 0.5 NA NA NA
3a 0.5 NA NA NA
4a NA NA NA NA
5a NA 1 NA NA
6a NA NA NA NA
7a ND ND ND ND
8a NA NA NA NA
1b NA NA NA NA
2b NA NA NA NA
3b NA NA NA NA
4b NA NA NA NA
5b ND ND ND ND
6b NA NA NA NA
7b NA NA NA NA
8b NA NA NA NA
1c 0.25 0.25 0.25 0.25
2c 0.5 0.5 0.25 NA
3c 0.5 NA NA NA
4c NA NA NA NA
5c NA NA 1 NA
6c 0.25 0.25 0.25 0.5
7c 1 0.5 0.25 1
8c NA NA NA NA
Maximum Concentration: 1 mg/mL in DMSO. Reference drug, Cefixime: 1 mg/mL.
ND means activity not determined. NA means not active.
134
the cell, the complexes have enough polar side groups (Cl (5c), F (6c) and nitro (7c)) as well as
planar phenyl and phenanthroline rings through which the complexes interact with the DNA as
well as various other molecules of the bacterial cells, blocking its normal functioning and
growth. The minimum inhibitory concentration (MIC) of the complexes is lower than some other
copper(II) complexes already reported [63,64]. None of the complexes showed activity
comparable to or higher than the standard drug which may be due to the saturated and stable
geometry and structures of the complexes. The hampered diffusibility may be the dominant
factor for the low activity of the relatively bulky dinuclear complexes in DMSO.
According to the literature, the mechanism of killing the microbes may be due to one or
th t h z h t Tw ’ h t
hampering the formation of normal cell walls in microorganisms [65]. Various metabolic
pathways are blocked by de-activating cellular enzymes that drive these metabolic pathways of
the microorganisms. Similarly, the permeability of a complex is enhanced by increasing the
lipophilic character of the central metal ion by chelating groups which reduce the polarity of
the metal ion by partial sharing its positive charge. Moreover, the ionic character of the metal
ion is also reduced by delocalizing the electronic density towards the metal by various
aromatic rings in its vicinity [66,67]. All these factors enhance the permeability of the
complexes through the lipid bilayer of the biological membranes.
3.7.2 Antifungal studies
Some selective complexes (shown in Table 3.18) were screened for antifungal activity
against three fungal strains (Mucor piriformis, Aspergillus niger and Helminthosporium solani)
by using agar tube dilution method. The results are shown in Table 3.18 and Fig. 3.22.
Terbinafine was used as standard drug in this study. The activity was determined by measuring
135
the percent growth inhibition where more than 70 % growth inhibition means significant, 60–
70 % good, 50–60 % moderate and below 50% non-significant activity [62].
The results showed that complexes 1, 1b and 2c (Mucor piriformis), 3c and 7c
(Aspergillus Niger) and 2 and 5a (Helminthosporium solani) exhibited significant while 5, 5a, 4b
and 3c (Mucor piriformis), 8c (Aspergillus Niger) and 4a, 3c and 5c (Helminthosporium solani)
moderate antifungal activity against the respective fungal strains. The antifungal activity of the
rest of the test complexes is either moderate or non-significant as listed in Table 3.18. In
agreement with the bactericidal activity, the series of mononuclear complexes (3c, 5c, 7c and 8c)
Table 3.18: Antifungal data of complexes: Mean Value of Percent Growth Inhibition (%) along
with their standard deviation values.
Compound Mucor piriformis Aspergillus Niger Helminthosporium solani
1 75 ± 4 50 ± 3 0
2 42.5 ± 1.5 22.5 ± 1.2 75 ± 2.5
5 60 ± 3 15 ± 1.2 52.5 ± 3.1
8 32.5 ± 1.5 27.5 ± 2.3 0
1a 45 ± 2 52.5 ± 3.5 57.5 ± 3.5
4a 55 ± 2.5 0 62.5 ± 4.1
5a 60 ± 3.5 0 72.5 ± 5
8a 30 ± 2 32.5 ± 1.8 50 ± 2.3
1b 82.5 ± 4.8 47.5 ± 3.2 47.5 ± 3.2
2b 57.5 ± 2.5 55 ± 2.8 40 ± 3.1
3b 22.5 ± 1.7 45 ± 3.2 50 ± 3.5
4b 65 ± 3.6 42.5 ± 3.1 55 ± 3.6
7b 35 ± 1.8 0 0
8b 57.5 ± 3.5 45 ± 2.5 52.5 ± 3.5
2c 75 ± 4.2 42.5 ± 3.6 55 ± 3.5
3c 70 ± 4.5 72.5 ± 4.2 65 ± 3.6
4c 22.5 ± 1.2 0 40 ± 2.5
5c 25 ± 1.8 20 ± 1 70 ± 4.5
7c 35 ± 2.6 72.5 ± 3.2 45 ± 3.1
8c 52.5 ± 3.5 62.5 ± 2.1 55 ± 2.5
Turbinafine 100 100 100
In vitro agar tube dilution method, concentration: 200 µg/mL in DMSO.
% inhibition of fungal growth = 100 – Gt/Gc × 100. Gt = linear
growth in test tube (mm) and Gc = linear growth in vehicle control (mm).
136
has been found to possess higher fungicidal activity as well which can be attributed to the facile
access of these complexes to their biological target. The higher activity of 5, 5a and 5c is
attributable to facile electrostatic interaction of the para-chloro group of these complexes with
DNA, protein or enzymes of the target biological systems hampering their normal metabolysis
and growth. The behavior of the complexes against the fungal strains is typical of the other
copper(II) complexes already reported where the complexes show antifungal activity against
some of the strains but totally inactive against others [68,69]. The series wise activity of the
complexes has been graphically depicted in Fig. 3.22 with respect to that of the standard drug
terbinafine. Complexes 1, 2 and 5 and 1b and 4b belong to the polynuclear and dinuclear O-
bridged series which showed better antifungal activity but no antibacterial activity.
0
20
40
60
80
100
Gro
wth
inhib
itio
n (
%)
Mucor piriformis
Aspergillus niger
Helminthosporium solani
Terbinafine1 2 5 8 1a 4a 5a 8a 1b 2b 3b 4b 7b 8b 2c 3c 4c 5c 7c 8c
Complexes
Figure 3.22: Graphical representation of the antifungal activity of the complexes with respect to
that of Terbinafine
137
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149
CONCLUSIONS
• Mixed N and O-donor ligand copper(II) carboxylates have been synthesized, isolated and
purified in quantitative yield.
• Their characterization has been confirmed through single crystal XRD while the purity
level was evaluated by superimposing the simulated and experimental XRD plots which
were found in complete agreement showing that the crystalline samples are composed of
the single crystalline phase without any other impurity.
• Crystal structures have shown that the geometry around copper(II) ion is square
pyramidal in all the complexes except in the mononuclear ones where the geometry was
found octahedral. The bridging oxygen atom is bonded asymmetrically to two copper(II)
ions of the dinuclear molecules.
• The DNA binding ability of the complexes was judged from CV and UV-Visible
spectroscopy by calculating the intrinsic binding constant of the complexes with DNA
from both techniques. Both techniques resulted in comparable values of Kb which was
found of the order of 104 –10
5 M
–1.
• Moreover, the reduction of the diffusion co-efficient of the complexes on addition of
DNA further supported the DNA binding ability of the complexes.
• The nature of the DNA binding process was found to be electrostatic, intercalative as
well as a mixed type as indicated by the shift of the k t t λmax.
• Th ε v of the complexes ranged from 130-209 (L mol–1
cm–1
) while the
characteristic broad absorption peaks indicated square pyramidal and octahedral
geometries for polynuclear and dinuclear paddlewheel and O-bridged dinuclear and
mononuclear complexes, respectively in DMSO solution.
150
• Significant antibacterial activities were observed for 1c, 2c, 6c and 7c against Gram-
posetive as well as Gram-negative bacterial strains. Some of the complexes exhibited
moderate activities as well.
• The results of antifungal activities were more encouraging where significant and
moderate activities were exhibited by 1, 1b, 2, 2c, 3c, 5a, and 7c, and 4a, 4b, 5, 5c, and
8c, respectively.
151
PUBLICATIONS
Muhammad Iqbal, Iqbal Ahmad, Saqib Ali, Niaz Muhammad, Safeer Ahmed, Manzar
S h ‘‘ -wh ’’ t (II): S th t t t
and electrochemical studies, Polyhedron, 50 (2013) 524–531.
Muhammad Iqbal, Saqib Ali, Niaz Muhammad, Manzar Sohail, Synthesis, crystal
structures and electrochemical characterization of dinuclear paddlewheel copper(II)
carboxylates, Polyhedron, 57 (2013) 83–93.
Muhammad Iqbal, Saqib Ali, Zia-ur-Rehman, Niaz Muhammad, Manzar Sohail,
Vedapriya Pandarinathan, Synthesis, crystal structure description, electrochemical and
NA t ‘ wh ’ (II) t . Accepted manuscript.
