1

CHAPTER 1

1. Introduction

Coordination chemistry has become an interesting field of research rather than a closed

body of knowledge. Nowadays a large number of articles on coordination compounds are being

published. New synthetic techniques allow the identification of a huge number of fascinating

complexes and in the laboratory they continue to pose synthetic challenges. Metal complexes

play an important and diversified roles in biological systems. The role of chlorophyll,

haemoglobin, carbonic anhydrase, vitamin B12, xanthine oxidase and haemocyanin shows the

intimate linkage between inorganic chemistry and biology. Studies of these types of metal

complexes are now a part of the highly demanding field, bio-inorganic chemistry.

Metal complexes find attractive applications in the field of biology. Metal complexes are

used as diagnostic and therapeutic agents. Studies on metal based anticancer drugs and

antiarthritic agents are some of the currently active topics of investigation in bio-inorganic

chemistry. Many metal complexes, especially those of Schiff bases, have been studied from the

point of view of using them as antibacterial, antifungal and anticancer drugs. In this chapter, a

review of Schiff bases, their metal complexes and their general applications is presented.

1.1. Schiff base ligands

Schiff bases are an important class of ligands due to their synthetic flexibility, selectivity

and sensitivity towards the central metal atom and structural similarities with natural biological

substances. Schiff base ligands considered as ‘privileged ligands’1 contain the azomethine group

(-CH=N-) and they are prepared by the condensation of a primary amine and a carbonyl

compound. The azomethine group is particularly suited for binding to metal ions via the lone pair
 2

on nitrogen. When the Schiff bases contain one or more donor atoms in addition to -C=N- group,

they act as polydentate chetating ligands or macrocycles. Because of the versatility of the Schiff

bases, a large number of complexes with interesting structures are synthesized even now. Schiff

bases derived from aliphatic aldehydes are unstable and are readily polymerizable2 while those

derived from aromatic aldehydes are more stable. The common Schiff bases are crystalline and

feebly basic in nature. In general, aldehydes react faster than ketones in condensation reactions,

leading to the formation of Schiff bases as the reaction centre of an aldehyde is sterically less

hindered than that of a ketone. Furthermore, the extra carbon of ketone donates electron density

to the azomethine carbon and thus makes the ketone less electrophilic compared to aldehyde3.

Schiff bases can act as bidentate, tridentate, tetradentate or polydentate ligands depending

upon the other functional groups present and they are capable of forming very stable complexes

with transition metals. If they bear a functional group, usually the hydroxyl, sufficiently near the

site of condensation in such a way that a five or six membered ring can be formed when reacting

with a metal ion (Figure. 1.1).

Schiff bases derived from aromatic amines and aromatic aldehydes have a wide variety of

applications in many fields, such as biological, inorganic and analytical chemistry4,5.

 3

OH
C
R N
OH
NR12
C N
R R1

Bidentate Tridentate

CH3

OH HO R R
C C
C N N C N OH N
R R
OH HO

Tetradentate Pentadentate

Figure 1.1. Some types of Schiff base ligands

Generally Schiff bases are prepared under acid or base catalysis or with heat. When two

equivalents of salicylaldehyde are condensed with a diamine, a particular type of chelating Schiff

base is produced, the so-called Salen ligands, with four coordinating sites and two axial sites

open to ancillary ligands, are very much like porphyrins, but can be more easily prepared. The

term Salen was used only to describe the tetradentate Schiff bases derived from ethylenediamine

(Figure. 1.2).

R
H
N OH
N OH
N OH 4R=H
N OH H 5 R = tBu
R

R
Salen Chiran salen

Figure 1.2. Different Salen ligands

 4

Schiff bases of ethylenediamine/triethylenetetramine (salen) with benzaldehyde/cinnamic

aldehyde/salicylaldehyde as corrosion inhibitors of zinc in sulphuric acid have been reported by

Desai et al6. Recent report says, some Schiff bases (Figure 1.3) are also employed as fluorescent

indicators in spectrofluorometric monitoring of small changes in pH7.

N N

N N

NaO3S
(I) (II)

NO2 NO2

N N

NaO3S
(III) (IV)

Cl Cl

N N

NaO3S
(V) (VI)

Figure 1.3. Structure of fluorescent Schiff bases

1.2. Schiff base metal complexes

Schiff base metal complexes are generally prepared by treating metal halides with

Schiff base ligands under suitable experimental conditions. In special cases metal alkoxides,

metal amides, metal alkyls or metal acetates have been used for the synthesis. There are

numerous literature reviews on the synthesis and characterization of Schiff base metal

complexes8-10.

Generally transition metal ions are used to prepare coordination complexes, as there is

possibility of synthesizing a variety of complexes with variable oxidation states, different

 5

coordination geometries and interesting physicochemical properties. A large number of tridentate

and tetradentate Schiff base ligands are reported in literature11-13. The –OH or –SH groups when

present ortho to the azomethine moiety in the Schiff base can induce tautomerism in the

compound and give rise to different structures.

The transition metals, especially first row transition metal ions, are well known for their

ability to form wide range of coordination complexes in which octahedral, tetrahedral, and

square planar geometries predominate. Copper(II) is a typical transition metal ion to form

complexes, but less typical in its reluctance to take up a regular octahedral (or) tetrahedral

geometry. The magnitude of the splitting of the electronic energy levels in copper(II) complexes

tend to be larger than other first row transition metals due to the presence of large Jahn-Teller

distortion. Copper is one of the essential trace elements present in living organisms. A number of

important redox enzymes like hemocyanins, superoxide dismutase, blue copper proteins, etc.,

contains copper atoms bound to protein molecules.

Copper(II) complexes with amino acids are cited as having potent anti-inflammatory and

anti- ulcer activity14. Copper ions are found to be present in the active sites of many number of

metalloproteins, which are involved in important biological electron transfer reactions as well as

in molecular oxygen redox reactions15-16. There has been a substantial interest in the rational

design of novel transition metal complexes, which bind and cleave duplex DNA with high

sequence or structure selectivity. The characterization of DNA recognition by small transition-

metal complexes has been substantially aided by the DNA cleavage chemistry that is associated

with redox-active or photoactivated metal complexes.

 6

Non-covalent interactions between positively charged metallointercalators and the base-

pair stack of DNA has been an area of interest for some time. It is clear that a number of factors

affect both the sequence selectivity of intercalators binding to DNA and the resulting twist angle,

and therefore it is necessary to understand the structural features of intercalators that control the

specificity of their binding. This, inturn should lead to the design of more specifically targeted

intercalators. The synthesis and investigation of synthetic reversible dioxygen carriers have

attracted substantial interest in recent years and their physico-chemical properties are sufficiently

favourable for application in industries and medicine17-18. Synthetic oxygen carriers have been

studied extensively over several decades for two main reasons viz (i) to understand the

mechanism of oxygen binding proteins and (ii) to design complexes suitable for practical

applications. Co(II) complexes of porphyrins, Schiff bases and tetraaza systems (Figure 1.4 (A-

C) are usually studied as models for oxygen carriers. Schiff bases used for the studies of oxygen

carrying properties are generally tetradentate, of which at least two of the ligating atoms should

be nitrogen, with the others being nitrogen, oxygen, sulphur (or) combination of the three.

Tian et al19 reported the nuclease activity (DNA cleavage) of Cobalt(II) complexes with

pBR322 DNA in the absence of any external agents.

OH HO
N N
C Co C
H N N H

A
 7

Figure 1.4. (A-C) Co(II) complexes of porphyrins, Schiff bases and tetraaza systems

The intercalative DNA-Binding studies of a Nickel(II) coordination compound

Ni(bpy)2dppz2+ have been reported20.

1.3. 4-Aminoantipyrine based Schiff bases and their metal complexes

As early as 1884, Knorr discovered the antipyretic (temperature reducing) action of a

pyrazole derivative in humans and due to its antipyretic property he named the compound

"Antipyrine". Transition metal complexes of pyrazolone derivatives are of huge interest due to

their biological activities, especially pyrazolone Schiff-base derivatives. Among the pyrazolone

derivatives, 4-aminoantipyrine forms a variety of Schiff bases with aldehydes/ketones, and they

are reported to be finer reagents in biological, pharmacological, clinical and analytical

 8

applications21. 4-Aminoantipyrine has an N-phenyl group and a –CH group on either side of a

polar carbonyl group, thus resembling N-substituted amides. Coordination chemists, medicinal

chemists and analytical chemists have extensively studied 4-aminoantipyrine. The carbonyl

group in 4-aminoantipyrine is a potential donor due to the large dipole moment (5.48 D) and

strong basic character.

Three modes of coordination must be considered for the system, unidentate with bonding

through either oxygen or the amino nitrogen or chelation utilizing both these donors. The

majority of the Schiff bases of 4-aminoantipyrine derivatives are obtained in good yield by

condensation of aqueous or alcoholic solution22-23. Depending upon the form (neutral,

protonated) of the ligand precursor, it is possible to get either neutral or protonated forms of the

ligands. Since 4-aminoantipyrine has an additional possible coordination site in the amino

nitrogen, it was considered really valuable to study the complexes of this ligand.

1.3.1. Metal Complexes derived from 4-aminoantipyrine

Guru and Rao24 prepared zinc complexes of 4-aminoantipyrine. Gopalakrishnan and

Patel25 carried out the physico-chemical studies on antipyrine complexes of CoCl2, CoBr2,

CuCl2, and CuBr2 of the type MX2.2AAP. Both electrical conductance and cryoscopic

determination of molecular weight in nitrobenzene showed them to be monomeric non-

electrolytes.

Bose and Patel26 prepared the Cu(II) nitrate and bromide complexes of 4-

dimethylaminoantipyrine and characterized them by spectral studies. Prabhakaran and Patel27

 9

prepared antipyrine complexes of Fe(III) chloride and thiocyanate. The decrease in value of the

C=O stretch in IR spectra predict coordination through the carbonyl oxygen to Fe(III).

Agarwal et al synthesized mixed ligand complexes of thorium(IV) derived from 4[N-(2-

hydroxy-1-naphthalidene)amino]antipyrinesemicarbazone (HNAAPS) and 4-[N-

(cinnamalidene)-amino]antipyrinesemicarbazone (CAAPS) as primary ligand and diphenyl

sulfoxide (DPSO) as secondary ligand with the general composition ThX4.n(L).DPSO

(n=1,X=Cl, Br, NCS or NO3; n=2,X=I or ClO4, L=HNAAPS or CAAPS) and characterized

through elemental analysis, molar conductance, IR and thermogravimetric analysis28(Figure

1.5).

N N
OH H
H O O
N N
N N N
N N N
NH2 NH2

HNAAPS CAAPS

Figure 1.5. Schiff bases derived from semicarbazone

1.3.2. Reaction of 4-aminoantipyrine amino group

Kuncheria et al29 synthesized ten new complexes of thorium(IV) nitrate with Schiff bases

derived from 4-aminoantipyrine (4AAP) and carbonyl compounds such as benzaldehyde, 2-

nitrobenzaldehyde, 3-nitrobenzaldehyde, 4-methylbenzaldehyde, 4-N,N-

dimethylaminobenzaldehyde, 2-hydroxybenzaldehyde, 2-hydroxyacetophenone, acetylacetone,

benzoylacetone and 2-hydroxy-1-naphthaldehyde. These complexes have been characterized by

elemental analysis, molecular weight determination, conduction and spectral studies. Mn(II),
 10

Co(II) and Ni(II) complexes with tridentate Schiff bases derived from 4-aminoantipyrine and

different aldehydes (2-hydroxy-1-naphthaldehyde and 2,4-dihydroxybenzaldehyde) were

prepared. For all complexes, spectroscopic results suggested an octahedral geometry30. Savant

and Ramamurthy31 studied antipyrine complexes of Ti(II), Zr(II), Th(IV) and U(IV) perchlorates.

They are stable at room temperature and decomposed exothermally at 300°C. Spectral studies

indicated the bonding of metal to ligand through carbonyl oxygen. Nair et al synthesized new

lanthanide nitrate complexes of the Schiff base derived from 4-aminoantipyrine and 2-

hydroxybenzaldehyde32, 33
viz. 4-[N-(2-hydroxybenzylidene)amino]antipyrine. Gadre et al34

reported isolation and structure elucidation of complexes of the Schiff-base ligands, salicylidene-

4-aminoantipyrine and acetylaceto-4-aminoantipyrine with UO22+ and Ln3+, respectively. In

1986, Agarwal et al35 synthesized a new Schiff base by condensing 4-[N-

(benzylidene)amino]antipyrine with semicarbazide. The semicarbazide forms an azomethine

group with the cyclic carbonyl present in the 4-aminoantipyrine36. Ismail et al37 synthesized

copper complexes derived by condensation of 4-aminoantipyrine with furfuraldehyde and the

corresponding thiophenealdehyde, 4-furfurylidene-aminoantipyrine and 4[N(2-

thienylmethylidene) amino]antipyrine. Mohamed et al38 synthesized Fe(III) and Cu(II)

complexes derived from catecholamine and 4-aminoantipyrine. These were characterized by IR,

UV-Vis, magnetic and thermal studies which indicated that Fe(III) forms 1 : 2 (M :

catecholamines) chelates while Cu(II) forms 1 : 1 chelates. Magnetic moment measurements

reveal the presence of Fe(III) chelates in octahedral geometry while the Cu(II) chelates are

square-planar; the structures of the complexes are given in Figure 1.6.

 11

N N O N
O N O N
N

HN NH HN
NC
R OH O R O OH2
R
Fe Cu
O HO O
OH2 OH2

Figure 1.6. Octahedral and square-planar geometry of the complexes

Agarwal et al39 studied some high coordinated complexes of thorium(IV) and

dioxouranium(VI) derived from 4-[N-(2-hydroxy-1-naphthalidene)amino]antipyrine and

thiosemicarbazone. The compounds were characterized by analytical, molar mass, molar

conductance and infrared studies. Thermal stabilities of these complexes were investigated by

thermogravimetric analysis. Issaadi et al40 synthesized an tetradentate N2O3 type Schiff base and

its complexes with Cu(II), Co(II), Zn(II) and Cd(II) which were characterized by spectroscopic

determinations and cyclic voltammetry. The spectral techniques indicated that Cu(II) and Cd(II)

complexes are mononuclear while Co(II) and Zn(II) complexes appeared to be binuclear.

Iron(III) complexes of 4-[N-(antipyrylmethylidene)amino]antipyrine with counter ions

such as perchlorate, nitrate, thiocyanate, chloride and bromide have been prepared by Linert et

al41 and were characterized by elemental analyses, electrical conductance in non-aqueous

solvents, IR, electronic spectra, magnetic susceptibility measurements and thermogravimetric

analysis. Kinetic parameters like activation energy, pre-exponential factor and entropy of

activation were also computed (Figure 1.7).

 12

H
C N
N N
N O O N

Figure 1.7. 4-[N-(4-antipyrylmethylidene)amino]antipyrine

Issa et al42 synthesized five Schiff bases derived from 4-amino antipyrine and
1
benzaldehyde derivatives; their UV–Vis, IR, H NMR and fluorescence spectra were

investigated and supported by MO calculations using an atom superposition and electron

delocalization molecular orbital theory. The square planar and octahedral geometry of the 4-

aminoantipyrine derived metal complexes are given in Figure 1.8.

O H
NH2
OH
N CH O
N O
N . nH2O
N Cu
N O X
Copper salt

O H Square planar geometry

metal salt Cl

Cl

N Cl N
M
N O Cl
N
N

Octahedral geometry

Figure 1.8. Octahedral and square-planar complexes

 13

Donia and Ebeid43 synthesized Ni(II) complexes using ligands such as 4-[N-(2-hydroxy-

1-naphthylidene)amino]antipyrine and 4-[N-(salicylidene)amino]antipyrine. These complexes

were studied using differential thermal analysis, electronic and IR spectroscopy, X-ray powder

diffraction and electrical conductivity. Thermochromism in these complexes has been attributed

to dehydration.

Liang et al44 synthesized Cu(II) complexes of the Schiff base derived from

picolinaldehyde N-oxide and 4-aminoantipyridine. These were characterized by elemental

analysis, IR, 1H NMR and single crystal XRD studies. Alaudeen et al45 carried out transition

metal chelates of Mn(II), Cr(II), Fe(III), Co(III), Zn(II) and Cd(II) with 4-aminoantipyrine,

thiosemicarbazide and 2-aminobenzothiazole. Ravindran46 reported iron(III) complexes derived

from 4-aminoantipyrine and acetylacetone and characterized by elemental analyses, conductance

measurements, IR, UV-Vis., and Mossbauer spectral studies, which suggested an octahedral

geometry around iron(III).

Agarwal et al47 synthesized lanthanide(III) complexes derived from 4-aminoantipyrine, 4-

methoxybenzaldehyde and thiosemicarbazone. These were characterized by magnetic, spectral

and thermal techniques. Agarwal et al48 synthesized copper(II) complexes of thiosemicarbazones

of Schiff bases derived from 4-aminoantipyrine and some aromatic aldehydes, which were

characterized through elemental analysis, molecular weight, electrical conductance, infrared,

electronic spectra and magnetic susceptibilities and were also screened for antibacterial and

antifungal properties.

Sinha et al49 synthesized Pd(II) and Ag(II) complexes derived from 4-aminoantipyrine

and imidazole. These complexes were characterized by UV-Vis, IR and 1H-NMR spectral

studies. Rosu et al50 synthesized Cu(II) complexes derived from 4-aminoantipyrine and
 14

salicylaldehyde, which were characterized by 1H NMR, UV-Vis, IR and ESR spectroscopy.

Determinations of the antimicrobial activity of the ligands and the complexes were carried out

against some bacteria. Complexes of uranyl(VI) nitrate with functional Schiff bases derived from

acetylacetone, salicylaldehyde and 2-hydroxy-1-napthaldehyde with 4-aminoantipyrine were

synthesized from neutral or alkaline media and their spectra-structure correlation obtained. The

ligands behave differently at different pH of the reaction solution51.

Three oxovanadium(IV) Schiff-base complexes having the formula VO(Phen)(L)]SO4

(where L=4[(benzylidene)amino]antipyrine, [(cinnamalidene)amino]antipyrine and 4[(2-

chlorobenzylidene)amino]antipyrine) were designed using benzaldehyde/cinnamaldehyde/2-

chlorobenzaldehyde with 4-aminoantipyrine, 1,10-phenanthroline, and vanadyl sulphate in the 1

: 1 : 1 molar ratio. Microanalytical and spectral techniques were used to confirm the structures.

Electronic spectral studies suggest square pyramidal geometry around vanadium52.

Nair and Thomas53 reported oxovanadium complexes derived from 4-aminoantipyrine

and p-chlorophenol by diazotization and coupling which were characterized by spectral

techniques. All the complexes were monomeric and neutral with square pyramidal geometry.

Nair and Mathew54,55 reported mercury(II)/dioxotungston chelates of azo dyes derived from 4-

aminoantipyrine and p-cresol/p-chlorophenol/ p-nitrophenol. These complexes were screened

against some bacteria for antibacterial activity. Nair et al56 synthesized Cu(II) complexes derived

from 4-aminoantipyrine and p-cresol/p-chlorophenol by diazotization and coupling. All the

complexes have square-planar geometry. West et al.57 synthesized iron(III), cobalt(II/III),

nickel(II), copper(II) and zinc(II) complexes derived from 2-formylpyridine, N-antipyrinyl and

thiosemicarbazone. Ligand field parameters were calculated and the proposed stereochemistry is
 15

based on various physical and spectral methods. Bhattacharaya et al58 prepared adducts of some

aryltinhalides with antipyrine. The IR data of this adduct indicated coordination through the

carbonyl oxygen of the ligand. Bailey and Peterson59 observed that 4-aminoantipyrine was a

monodentate ligand bonding through nitrogen in complexes of Cu(II), Co(II) and Ni(II) only

when bromide anion was coordinated to the metal. This may be due to the greater ability of

bromide to accept electrons from the metal ion via back bonding, thereby reducing the electron

density on the metal. This effect could be counteracted by donation from nitrogen rather than

oxygen. A large number of compounds of antipyrine have been shown to be unidentate; oxygen

coordination is confirmed from IR spectral studies60-62.

V. K. Revankar et al63 reported Co(II), Ni(II), Cu(II) and Zn(II) complexes derived from

2-hydroxy-3-formylquinoline and isatin with 4-aminoantipyrine and characterized by spectral

techniques. All the complexes were monomeric and neutral with octahedral geometry (Figure

1.9).

O NH2 N OH
N N
O O
N N O N N
N N N
N H H O HO
OO N Reflux in ethanol
Reflux in ethanol
H for 3 h for 3 h

metal salt
metal salt

N N
N
N O
N O N
O NH N
N M . 2H2O
O N O
. H2O O N
Cl M
Cl H2O N

Figure 1.9. Octahedral complexes derived from 2-hydroxy-3-formylquinoline

 16

Prakash et al reported64 Cr(III), Mn(II), Co(III), Ni(II), Cu(II), Zn(II) and Cd(II) chelates

of Schiffs base derived from vanillin and 4-aminoantipyrine. All the complexes are shown to be

monomeric and octahedral geometry.

The chelates of VO(II), Cr(III), Mn(II), Fe(III), Co(II), Ni(II), Cu(II) and Zn(II) with 4-

formyloxime-1,3-diphenyl-2-pyrazolin-5-one (FDPPZ) derived from 4-formyl-1,3-diphenyl-2-

pyrazolin-5-one and hydroxylamine65 were characterized by elemental analysis, conductivity,

magnetic measurements and spectral studies. The ligand field parameters for VO(IV), Cr(III),

Co(II) and Ni(II) chelates were calculated. Infrared spectra of 4AAP and its duplexes are quite

complex due to the existence of numerous functional groups in the molecule66.

1.3.3. Reaction of 4-aminoantipyrine carbonyl group

The carbonyl group of 4-aminoantipyrine was also condensed by primary amino groups.

Chakaraborti67 synthesized ten new nickel(II) coordination compounds of 4-[N-(2-hydroxy-1-

naphthalidene)aminoantipyrine thiosemicarbazone and 4-[N-(cinnamalidene)aminoantipyrine

thiosemicarbazone of general formula NiX2.L.H2O (X=Cl-, NO3-, NCS- or CH3COO-) or

Ni(ClO4)2.2L. The complexes were characterized on the basis of elemental analyses, molecular

weight, conductivity, magnetic moment, IR and electronic spectral data. The coordination

number of Ni2+ in these complexes is presumed to be six with octahedral geometry. In all the

complexes both thiosemicarbazones were neutral tridentate (N, N, S) ligands.

Thermogravimetric data of the Nickel complex indicated that the complex is stable to ca 140°C,

indicating the complex to be non-hygroscopic. Reaction of Cu(II) salts with 4-[N-(2-hydroxy-1-

naphthalidene)aminoantipyrine thiosemicarbazone (HNAAPT) resulted in formation of

CuX2(HNAAPT).H2O (X=Cl-, Br-,NO3-, NCS- or CH3COO-). Characterization of these

 17

complexes were made on the basis of elemental analysis, molecular weight, magnetic moment,

conductivity measurements, IR and UV-Visible spectra. Thermal properties of these complexes

were also investigated68. M.M. Omar et al69-70 synthesized complexes of Schiff base derived

from 4-aminoantipyrine with 2-aminophenol/2-aminobenzoic acid.

Chandra et al reported71 Co(III), Ni(II) and Cu(II) complexes of Schiff base derived from

3,3’-thiodipropionic acid, 4-aminoantipyrine and ethylamine (Figure 1.10) and were

characterized by spectral methods. The nickel(II) complexes were found to have octahedral

geometry, whereas cobalt(II) and copper(II) complexes were of tetragonal geometry.

O O
S
NH HN

N N
N N N
H2C CH CH2
3 H3 C

Figure 1.10. Schiff base adopted from Ref 71

Neutral tetradentate complexes of Cu(II), Ni(II), Co(II), Mn(II), Zn(II) and VO(IV) were

synthesized72-73 using Schiff bases derived from 2-aminophenol/2-aminothiophenol with 1-

phenyl-2,3-dimethyl-4(4-iminopentan-2-one)-pyrazol-5-one and acetoacetanilido-4-

aminoantipyrine in ethanol and characterized by microanalytical data, IR, UV-Vis, 1H-NMR and

ESR spectra. The IR and UV-vis spectra suggest that all the complexes have square-planar

geometry except vanadyl and manganese complexes which show square-pyramidal and

octahedral geometries, respectively. The redox behavior of copper and vanadyl complexes has

been studied by CV and ESR spectra of copper and vanadyl complexes were also discussed.

Antimicrobial activity of the Schiff base and complexes have been extensively studied on some

microorganisms. The general structure of Schiff base metal complexes is shown in Figure 1.11.
 18

H
R CH3

N O R = CH3 and Ph-NH

M M = Cu, Co, Ni and Zn

N
N N X X = O and S

Figure 1.11. Tetradentate ligand complexes

Joseph et al74 reported copper complexes derived from 5-hydroxyflavone with 4-

aminoantipyrine, o-aminophenol, o-aminobenzoic acid, o-aminothiazole, thiosemicarbazide, 4-

aminoantipyrine-o-aminophenol, 4-aminoantipyrine-o-aminobenzoic acid, 4-aminoantipyrine-o-

aminothiazole and 4-aminoantipyrine-thiosemicarbazide. The spectral and magnetic results of

the Cu(II) complexes suggest square planar geometry. The DNA binding properties of copper

complexes were studied by using electronic absorption spectra, viscosity and thermal

denaturation experiments.

Raman et al75 synthesized neutral tetradentate complexes of Cu(II), Ni(II), Co(II), Mn(II),

VO(IV) and Zn(II) using Schiff bases derived from Salicylaldehyde with 4-aminoantipyrine and

2-aminophenol/2-aminothiophenol in ethanol. The spectral data suggest that the complexes

exhibit square-planar geometry except the Mn(II) and VO(IV) complexes. The Mn(II) chelates

show an octahedral environment and the VO(IV) chelates exhibit square pyramidal geometry.

Neutral complexes Cu(II), Ni(II) and Zn(II) derived from salicylaldehyde/o-vanillin with

4-aminoantipyrine and 2-aminobenzoic acid. Their structural features and other properties were

deduced from elemental analysis, magnetic susceptibility and molar conductivity as well as from

mass, IR, UV–vis, 1H NMR and EPR spectral studies. All the complexes have square planar

geometry. DNA binding and cleavage studies are also reported76. Raman et al77 synthesized

aminoacid based Cu(II), Ni(II) and Zn(II) complexes of tetradentate Schiff base ligand derived
 19

from salicylaldehyde with 4-aminoantipyrine and alanine/valine. All the complexes have square

planar. Antibacterial, antifungal, DNA binding and cleavage studies were also made. Raman et al

reported78 tridentate Schiff base derived from 3,4-dimethoxybenzaldehyde with 4-

aminoantipyrine and 2-aminobenzoic acid. Cu(II), Co(II), Ni(II) and Zn(II) complexes are

octahedral geometry (Figure 1.12) and the DNA studies were carried out by absorption spectra,

cyclic voltammetric, and viscosity measurement.

N R
N O N O
N M
N
M
N O N
N
O
O
R
O
R = H and OCH3 R = CH3 and (CH3)2
M = Cu(II), Ni(II) and Zn(II) M = Cu(II), Ni(II) and Zn(II)

Figure 1.12. Schiff base metal complexes derived from 2-aminobenzoic acid/aminoacid

Cu(II) complexes have been synthesized from the Schiff base derived from salicylidene-

4-aminoantipyrine and aniline/p-chloroaniline, p-methylaniline/p-nitroaniline (Figure 1.13). The

structural features have been determined from microanalysis and spectra, which show that all the

complexes were square planar. The antimicrobial activity and powder XRD pattern of all the

complexes were also reported21. Joseph et al79 synthesized copper complexes of Schiff base

derived from furfurlyidene-4-aminoantipyrine and aniline/p-nitroaniline, p-hydroxyaniline.

Spectral results showed that all complexes are square planar. The antimicrobial activity and

powder XRD pattern of all the complexes were also discussed.

 20

N O
Cu
N N Cl
N

X
X = H, Cl, CH3 and NO2

Figure 1.13. Schiff base derived from salicylidene-4-aminoantipyrine

and aniline derivatives

Schiff base synthesized from benzaldehyde, salicylaldehyde, 3-hydroxy-4-

nitrobenzaldehyde with 4-aminoantipyrine and o-phenylenediamine was a tetradentate ligand

forming cationic complexes with Cu(II), Ni(II), Co(II) and Zn(II) salts in ethanol. All the

synthesized complexes were characterized by spectral techniques. The IR and UV-vis spectra

suggested that all complexes were square planar80-82. The Schiff base derived from the

condensation of 3,4-dimethoxybenzaldehyde with 4-aminoantipyrine and o-phenylenediamine

was a tetradentate ligand and all the complexes are square planar except cobalt complex which

has octahedral geometry83. Prakash et al84 reported Mn(II), Co(II), Ni(II), Cu(II) and Zn(II)

complexes Schiff base derived from furfuraldehyde, with 4-aminoantipyrine and o-

phenylenediamine. The data of the complexes suggested square planar geometry for the metals

with primary valency two. They also reported Mn(II), Co(II), Ni(II) and Cu(II) complexes of

Schiff base from vanillin with 4-aminoantipyrine and o-phenylenediamine85. Spectra results

showed that all complexes have square planar geometry (Figure 1.14).
 21

R R

CH CH
N N
M
N N
N N N N

R = H, 2-OH and 3-OH-4-NO2

M = Cu, Co, Ni and Zn

Figure 1.14. Schiff base derived from o-phenylenediamine with different aldehydes

Reaction of CoX2 (X=Cl-, NO3-, NCS- or CH3COO- or ClO4-) with 4-[N-

(benzalidene)aminoantipyrine thiosemicarbazone and 4-[N-(2-hydroxybenzalidene)

aminoantipyrine thiosemicarbazone yielded complexes of general formula CoX2(L)H2O or

Co(ClO4)2.2L. All the complexes were six coordinated according to magnetic and electronic

spectral measurements. The IR data of the complexes indicated that both thiosemicarbazones

were neutral tridentate (N, N, S) ligands86. Raman et al87 reported Cu(II) and Zn(II) complexes

derived from 3,4-dimethoxybenzaldehyde and 4-aminoantipyrine with

semicarbazide/thiosemicarbazide. All the complexes were characterized by elemental analysis,

1
molar conductivity, IR, H NMR, UV–vis, ESI-Mass, magnetic susceptibility, cyclic

voltammetric measurements and EPR spectral studies. All the complexes were monomeric and

were exhibiting distorted octahedral geometry.

1.4. Applications of Schiff base metal complexes

Versatility of Schiff base ligands and biological, analytical and industrial applications of

their complexes make further investigations in this area highly desirable. The applications of

Schiff base complexes are discussed briefly.

 22

Schiff base complexes88-89 of various transition metals have been investigated for their

applications in various fields. Oxygen and nitrogen donor Schiff bases (salen type) are of

particular interest because of their ability to form transition metal complexes with unusual

configurations, structural ability and sensitivity to molecular environments90-91. Schiff base

complexes have proven effective in constructing supramolecular architectures such as

coordination polymers and helical assemblies92-94. They have been found to be associated with

biological activities, such as antibacterial, antiviral, anticunvalsant63 and antimalarial action95-97.

1.4.1. Antimicrobial activity

Co(II), Ni(II), Cu(II) and Zn(II) complexes of the Schiff base derived from vanillin and

DL-α-aminobutyric acid found to exhibit higher antibacterial activity compared to the Schiff

base98. Copper, nickel, iron and zinc complexes of the Schiff base derived from salicylaldehyde

with 2-aminobenzoic acid show good antibacterial activity against several pathogenic bacteria

such as Pseudomonas aeruginosa, Proteus vulgaris, Proteus mirabilis, Klebsiella pneumonia

and Staphylococcus aureus99. Metal complexes of Schiff bases derived from 2-

furancarboxaldehyde and o-phenylenediamine and 2-thiophenecarboxaldehyde and 2-

aminothiophenol were screened for antibacterial activities against Escherichia coli,

Pseudomonas aeruginosa, and Staphylococcus Pyogones and fungal activity against candida

albicans100. N-5-chloro-salicylidiene tauriene Schiff bases and its copper and nickel complexes

show antibacterial activity against Colibacillus and Pseudomonas aeruginosa101.

Copper, cobalt and nickel complexes of Schiff base from diacetyl with ethylenediamine

and benzoic acid showed antibacterial activity against Bacillus subtilis and Escherichia coli and

antifungal activity against Aspirgillus niger and Aspirgillus flavus102. Mn(II), Co(II), Ni(II) and
 23

Cu(II) complexes of Schiff base derived from Pyrrole-2-aldehyde and ethylenediamine exhibit

antibacterial activity against Escherichia coli and Staphylococcus aureus103 (Figure 1.15).

C N N C
N H H N
H H

Figure 1.15. Schiff base derived from Pyrrole-2-aldehyde and ethylenediamine

1.4.2. Biological applications of 4-aminoantipyrine based Schiff bases and their metal

complexes

Complexes derived from 4-aminoantipyrine exhibit greater biological activity than

pyrazole derivatives. 4-Aminoantipyrine derived complexes show antimicrobial, anti-malarial

and anti-tumorous activities. The antimicrobial activity of 4-aminoantipyrine derivatives was

tested against Staphylococcus aureus, Klebsilla pneumoniae, Salmonella typhi, Pseudomonas

aeruginosa and Bacillus subtilis. The complexes showed higher inhibitory activity than the

ligands and have higher activity than ampicillin, except for Klebsilla pneumoniae and

Pseudomonas aeruginosa21.

Rosu et al. reported biological activity of certain ligands and their copper complexes50 on

samples of E. coli, K. pneumoniae, A. boumanii, S. aureus, P. aeruginosa and Candida sp. The

Schiff-base ligand and its copper complex exhibited high bactericidal activity towards E. coli and

A. boumanii, good activity against S. aureus and E. coli, exhibiting their potential usefulness as

broad spectrum antimicrobial agents. The biocidal activity studies of the oxovanadyl complexes

and the free ligands towards three gram-positive bacteria: B. subtilis, Sarcina lutea and S.

aphylococcus; seven gram negative bacteria viz E. coli, K. pneumoniae, P. aeruginosa, S. typhi,

Serratia marcescens, Shigella sonnie and Proteus mirabilis; three fungal species: Aspergillus
 24

flarus, Penicillium chrysogenum and candida albicans, have been made by Ismail et al37; the

activity is related to the nature and structure of the complexes. The copper complex was the most

promising broad spectrum antimicrobial agent due to the presence of coordinated anion and

bridged –OH- with higher antimicrobial activity than the other complexes. It is found to be

superior to all other complexes against all the test organisms except P. aeruginosa.

Some of the isolated metal-4-aminoantipyrine derivatives were tested against a variety of

microorganisms, and some other biotests have also been performed. In most tests, the activity of

the complexes is comparable to free 4-aminoantipyrine derivatives. In certain examples, the

activity increased but there is no evidence of further clinical tests. The efficacy of metal-based

therapeutic agents changes considerably by making small changes in the Schiff-base ligand

attached to the metal104. The in vitro antimicrobial activity of ML73 (L=acetoacetanilido-4-

aminoantipyrine and 2-aminophenol/2-aminothiophenol, where M=Cu(II), Ni(II), Co(II), Zn(II)

and VO(II) and MnL.2H2O was tested against bacteria such as S. typhi, S. aureus, K.

pneumoniae, B. subtilis, S. flexneri and P. aeruginosa and the fungi A. niger and R. bataicola.

From the data the inhibition zone of the metal chelates is found to be higher than that of the

ligand. Such increased activity of the metal chelates is due to the lipophilic nature of the metal

ion in complexes. Furthermore, the mode of action of the compounds may involve the formation

of a hydrogen bond through the azomethine nitrogen atom with the active centers of all the

constituents, resulting in interference with normal cell process. The minimum inhibitory

concentration (MIC) values of copper(II) complexes derived from salicylidene-4-

aminoantipyrine and aniline derivatives were determined for five bacteria viz. S. aureus, K.

pneumoniae, S. typhi, P. aeruginosa and B. subtilis by serial dilution. A comparative study of the

ligands and their copper complexes indicates that the copper complexes exhibit slightly higher
 25

antibacterial activity than the free ligands and ampicillin21. Such increased activity of the

complexes can be explained on the basis of Overtone’s concept and Tweedy’s concept. Raman et

al105 synthesized a tetraaza macrocyclic Schiff base and its metal complexes derived from 1,2-

(diimino-4-antipyrinyl)-1,2-diphenylethane and o-phenylenediamine in ethanol and its metal

complexes and studied their biological activity.

1.4.3. DNA study of Schiff base metal complexes

1.4.3.1.Structure of DNA

DNA is Deoxyribonucleic acid, the chemistry of life. This nucleic acid is made of long

chain of nucleotides, which are complex molecules present in the nucleus of all cellular forms of

life and many viruses and in the cytoplasm of single celled bacteria which do not have a nucleus.

DNA carrier have a nucleus. DNA carriers along its length has a series of coded chemicals

called genes, which give instructions for passing hereditary characteristics, such as leaf shape,

claw length, hair or eye colour as well as susceptibility to some diseases.

Each nucleotide consists of 1) a sugar with five carbon atoms, either (a) Deoxyribose,

present in DNA or (b) Ribose, present in RNA. 2) One of the three phosphates with four oxygen

atoms, two of which are negatively charged attached to the 5’ carbon atom of the deoxyribose

sugar and covalently to the 3’ of the next. (One electron from each atom joins two together). 3) A

base: One of four kinds of nucleobases (a base). A base is a ring structure containing nitrogen

and is attached to the 1’ carbon atom of the deoxyribose sugar. The four bases in DNA are

Adenine (A) and Guanine (G) which are purines; Thymine (T) and Cytosine (C) which are

pyrimidines. The most widely accepted model for the structure of DNA molecule was proposed

by Watson and Crick in 1953 for which they were awarded the Nobel Prize for Medicine in

1962. According to the model DNA molecule is a double helix (Figure 1.16). The molecule is
 26

formed by two antiparallel polynucleotide strands which are spirally coiled round each other in a

right-handed helix. The two strands are held together by hydrogen bonds. The double stranded

helical structure has alternated major and minor grooves. Each strand is a long polynucleotide of

deoxyribonucleotides. The two strands are complementary to each other with regards to the

arrangement of the bases in the two strands. Thus, in the double helix, purines and pyrimidines

exist in base pairs, i.e., (A and T) and (G and C). As a result, if the base sequence of one strand

of DNA is known, the base sequence of its complementary strand can be easily deduced. The

backbone of the strand is formed by alternately arranged deoxyribose sugar and phosphate

molecules which are joined by the phosphodiester linkages.

Figure 1.16. Structure of DNA

The DNA molecule that Watson and Crick described was in B form. However, DNA can

exist in other form also. A and B forms have right handed helix while Z form has left handed

helix. B is the major form that is found in the cell. The following table summarises the features

of the different forms of DNA and Figure 1.17 shows different forms of DNA.
 27

Figure 1.17. Different forms of DNA

Geometry attribute A-form B-form Z-form

Helix sense right-handed right-handed left-handed
Repeating unit 1bp 1bp 2 bp
bp/turn 11 10.5 12
Pitch/turn of helix 28.2 Å (2.82 nm) 33.2 Å (3.32 nm) 45.6 Å (4.56 nm)
Diameter 23 Å (2.3 nm) 20 Å (2.0 nm) 18 Å (1.8 nm)

1.4.3.2. DNA binding modes

The interaction of small molecules like metal complexes with DNA has been an active

area of research at the interface of chemistry and biology106-111. These small molecules are

stabilized in binding to DNA through a series of weak interactions, such as the p-stacking

interactions associated with intercalation of a planar aromatic group between the base pairs,

hydrogen-bonding and van der Waals interactions of functionalities bound along the groove of

the DNA helix112 and the electrostatic interaction of the cation with phosphate group of DNA113.

Small molecules (metal complexes) bind to DNA double helix by three distinguished

binding modes114-115. They are,

 28

 Intercalative binding / Intercalation

 Groove binding

 Electrostatic binding / External binding

Intercalative binding results when small molecules or the drug intercalate into the

nonpolar interior of the DNA helix. Aromatic group is stacked between the base pairs in this type

of binding and this happens when ligands of an appropriate size and chemical nature fit

themselves in between base pairs of DNA. The ligands suitable for intercalation are mostly

polycyclic, aromatic and polar and therefore often make good nucleic acid stains. There is a

current interest in designing and synthesizing DNA strand, as these molecules might function as

chemotherapeutic agents (Figure 1.18).

Figure 1.18. Intercalative binding

Groove binding interactions involve direct interactions of the bound molecule with edges

of base pairs in either of the major (G-C) or minor (A-T) grooves of the nucleic acids. The

antibiotic netropsin is a model groove binder in which methyl group prevents intercalation116.

Binding within the major groove of the double helix is rare for small molecules (Figure 1.19).
 29

Figure 1.19. Groove binding

Electrostatic interaction (Figure 1.20) happens in the case of positively charged

molecules. They electrostatically interact with the negatively charged phosphate backbone of

DNA chain. Electrostatic attraction is generally weak under physiological conditions. Cations

such as Mg2+ usually interact in this way117.

Figure 1.20. External binding

Varying the substitutive group or substituent position in the intercalative ligand can

create some interesting differences in the space configuration and the electron density

distribution of transition metal complexes, which will result in some differences in spectral

properties and the DNA binding behavior of the complexes and will be helpful to clearly

understand the binding mechanism of transition metal complexes to DNA118, 119.

 30

1.4.3.3. DNA Cleavage by Schiff base metal complexes

DNA cleavage by metal complexes generally proceeds via two major pathways:

oxidative pathway and hydrolytic pathway. The DNA cleavage activity of metal complexes can

be targeted towards different constituents of DNA: the heterocyclic bases, deoxyribose sugar

moiety and phosphodiester linkage. Oxidative cleavage of DNA takes place in the presence of

additives or photo-induced DNA cleavage. Photo-cleavers require the presence of a photo-

sensitizer that can be activated on irradiation with UV or visible light.

Many metal complexes have been studied to understand their capability in the hydrolytic

cleavage of DNA which involves hydrolysis of phosphodiester bond. Nucleophilic activation is

required for hydrolytic cleavage of phosphodiester bond due to unusual stability of the diester

bond in DNA. Among several types of DNA cleavage reactions, those occurring under

photoactivation are of particular importance in highly targeted chemotherapeutic applications.

The reagents showing photo induced DNA cleavage have major advantage over chemical

nucleases, as the latter requires a reducing agent or H2O2 for its activity. The reagents cleaving

DNA on photoactivation generally show localized effect as they are otherwise non toxic and

such compounds should be useful in the photodynamic therapy (PDT), which has emerged as a

promising tool against cancer. The Food & Drug Administration (FDA) approved PDT drug

photophrin, which is a mixture of hematoporphyrin derivatives and is currently used for the

treatment of lung and oesophageal cancer.

The design of molecules that exhibit strong binding affinity to DNA is a challenging area

of research. Such molecules can act as excellent chemotherapeutic reagents that exert their

biological activity through interactions with DNA120-125. Interactions with DNA are not the only
 31

factors that determine the biological activity of these molecules, but their reactivity and

selectivity are often correlated with their mode of binding with DNA. Therefore, a better

understanding of the factors that govern the interactions of small molecules with DNA is an

important in the rational design of various DNA-targeted chemotherapeutic agents and molecular

probes for DNA. Of these small molecules, the bifunctional derivatives that can undergo photo

induced electron-transfer processes have attracted much attention in recent years for their use in

DNA detection, analysis and cleavage126-131. Stable and inert complexes containing active metal

centres are extremely valuable as probes of biological systems.

Gupta et al reported DNA binding properties of a series of transition metal complexes

having potential NNO-tridentate donor Schiff bases derived from the condensation of 2,6-

dibenzoyl-4-methylphenol with diamines132-137. Saif and coworkers reported mixed ligand

complexes prepared from 2-(hydroxybenzylidine)thiosemicarbazone using glycine, 2-

aminopyridine and 1,10-phenanthroline. Cu(II) complexes of this Schiff base interact with native

calf thymus DNA by groove or intercalating binding mode138. Binuclear copper(II) complexes

having the Schiff base ligand, N,N’-bis(3,5-tert-butylsalicylidene-2-hydroxy)-1,3-

propanediamine, are found to be effective in the cleavage of plasmid DNA in the presence of

H2O2 at pH = 7.2 and 37°C. Cu(II) Schiff base complexes derived from diethylenetriamine and

2-thiophene-carboxaldehyde/2-furaldehyde/pyrrole-2-carboxaldehyde are reported to interact

with DNA through a simple mode of coordination139. Copper (II) complex of Schiff bases

prepared from salicylaldehyde, 2,4-dihydroxy-benzaldehyde and glycine possess Antitumour

activity140. Complete cleavage of double stranded pUC19 DNA by the Cu(II) complex.

[Cu(dpq)2(H2O)] (ClO4)2 (where dpq = dipyridoquinoxaline) was reported by Shanta Dhar et

al141 (Figure 1.21).

 32

2+

N N H2O N N
Cu
N N N N

Figure 1.21. Copper complex for the cleavage of pUC19 DNA

Various metal complexes of dppz, [Co(phen)(qdppz)]3+ and [Ni(phen)(qdppz)]3+ were

found to be intercalators of DNA due to the extensively π-conjugated and planar structure of this

novel ligand142. The Co(II) and Ni(II) complexes of salicylaldehyde-2-phenylquinoline-4-

carbohydrazone interact with calf-thymus DNA through groove binding143. Metal complexes of

copper, cobalt, nickel and zinc are used now-a-days to study the metal complex-DNA

interactions.

Nair et al studied DNA cleavage with Schiff base derived from indole-3-carboxaldehyde

and m-amino benzoic acid/glycylglycine144,145. They reported metal complexes of Schiff base

derived from 4-isopropylbenzaldehyde and 1,2-diaminoethane. Interestingly, when reaction with

Cu(II) ion this ligand undergoes hydrolytic cleavage to form ethylenediamine copper(II)

complex and the corresponding aldehyde146.

1.4.3.4. DNA cleavage studies of 4-aminoantipyrine Schiff base metal complexes

A knowledge of interaction of DNA with small molecules are basic in the design of new

types of pharmaceutical products. Some metal complexes interact with DNA and induce

breakage of DNA strands. Thus, to cancer genes, after DNA strand cleaves, the DNA double

strands break. The replication ability of the cancer gene is destroyed. Many complexes including

the platinum group have been synthesized and tested in a number of biological systems after the

discovery of cis-platin. A number of metal complexes of 4-aminoantipyrine derived ligands have

 33

been studied in view of their possibility to lead to advanced functional materials, tuning the

redox potentials, affinity towards DNA, and specificity for the DNA base sequence recognition.

DNA cleavage was conducted using CT DNA by gel electrophoresis with the corresponding

metal complexes in the presence of H2O2 as oxidant. Raman et al carried out CT DNA cleavage

studies of 4-aminoantipyrine derived Schiff bases and their complexes82. Cu(II), Ni(II) and

Co(II) complexes cleave DNA as compared to control DNA, while Mn(II), Zn(II), VO(IV),

Hg(II) and Cd(II) complexes do not cleave DNA in the presence of H2O2. System comprising,

DNA-H2O2-Cu(II) complex, DNA-H2O2-Co(II) complex, DNA-H2O2-Ni(II) complex and DNA-

H2O2-Zn(II) complex were studied under the same conditions using electrophoresis and the result

reveals that cleavage of DNA in Cu(II) system is more efficient than other systems. All the other

systems showed the same electrophoretic behavior and less cleavage activity against CT DNA147.

Similar investigations were made with three oxovanadium(IV) Schiff-base complexes52 viz:

[VO(Phen)(L)]SO4 where L=[(benzylidene)amino]antipyrine (1a),

4[(cinnamalidene)amino]antipyrine (1b) and 4[(2-chlorobenzylidene)amino]Antipyrine (1c)

along with reference DNA. DNA-H2O2-1a complex, DNA-H2O2-1b complex and DNA-H2O2-1c

complex were prepared under the same conditions. Damage of DNA in 1a was attributed to the

cleavage of DNA. The 1b and 1c systems showed the same electrophoretic behavior and less

cleavage activity against CT DNA. The available literature reveals that the cleavage efficiency of

the complexes compared to controls is due to their efficient DNA–binding ability. The metal

complexes are able to convert super coiled DNA into open circular DNA. General oxidative

mechanisms proposed for DNA cleavage by hydroxyl radicals via abstraction of a hydrogen

from sugar units predict the release of specific residues arising from transformed sugars,

depending on the position from which the hydrogen is removed148. The cleavage is inhibited by
 34

free radical scavengers implying that hydroxyl radical or peroxy derivatives mediate the

cleavage149. The reaction is modulated by a metallocomplex bound hydroxyl radical or a peroxo

species generated from the co-reactant H2O2. Raman et al reported plasmid pUC19 super coiled

(SC) DNA cleavage studies of metal complexes derived from 3,4-dimethoxybenzaldehyde with

4-aminoantipyrine and 2-aminobenzoic acid/o-phenylenediamine and tyramine78, 83, 150 .

Jayabalakrishnan et al151 reported the synthesis and DNA cleavage studies of three hexa-

coordinated ruthenium(II) Schiff base complexes of the type [RuCl(CO)(B)L] (B =

PPh3/AsPh3/py and L = monobasic tridentate Schiff base ligand derived by the condensation of

salicylaldehyde with 4-aminoantipyrine.

 35

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