1

CHAPTER-I

Introduction

Literature Survey

Aim and Significance of the present study

2

“THE EVER INCREASING APPLICATIONS OF METAL

COMPLEXES IN VARIOUS FIELDS OF SCIENCE IS THE DRIVING

FORCE FOR THE RESEARCH AND DEVELOPMENT IN

COORDINATION CHEMISTRY”

Coordination compounds are the inorganic salts formed by the

combination of two or more simple compounds in stoichiometric ratio. The

first theory regarding coordination compounds was proposed in 1893 by Alfred

Werner who is the Father of Coordination Chemistry. He received Noble

prize for his work on coordination chemistry in 1913. Coordination compounds

containing at least one complex ion in which a central metal ion is surrounded

by certain number of ions or molecules through coordinate bonds, study of

these types of compounds are called as coordination chemistry.

Today coordination chemistry comprises a large body of inorganic

chemistry research. It is mainly the chemistry of metal complexes and has

fascinated and inspired the chemists all over the world. There is an ever

increasing academic, commercial and biochemical interest on the metal

complexes of organic chelating ligands. This has resulted in the emergence of

allied fields like organometallic chemistry, homogenous catalysis and

bioinorganic chemistry. Among the chelating ligands, Schiff bases have

attraction the chemists due to ease preparation and complexation. Although

there has been a welcome renaissance in inorganic chemistry after Werner’s

time [1], the base tenants of this theory has not been discarded but has been

refined and extended greatly. Realisation of the involvement metal complexes

in biological systems has also helped to sustain a live interest in metal

complexes of multidentate ligands. Multidentate ligand systems such as Schiff

bases, azo compounds, hydrazones, etc., form unique class of compounds.

Among these compounds, Schiff bases and their metal complexes occupy an

outstanding role in the development of coordination chemistry, because of the

synthetic proclivity, structural diversion and varied applications in different

fields. Hence, it is quite fascinating to discuss the salient features of this class

of compounds, which form the part of this investigation.

3

The list of noble prizes on Coordination chemistry is significant and

shows the manifestation of Coordination chemistry into various fields of

science.

Nobel Prizes on Coordination Chemistry

Year Name Worked on

1912 Victor Grignard Grignard's reagents.

1913 Alfred Werner The area on the nature of bonds of atoms in molecules in inorganic chemistry.

1915

1918

Rihard Vilshtetter

Fritz Haber

The area of pigments in plant world especially chlorophyll.

The synthesis of ammonia.

1930 Hans Fisher Investigation of construction of hemine and chlorophyll.

1963 Karl Ziegler Giulio Natta Discovery of isotactic polypropylene.

1964 Doroti Meri Kroufut Hodzkin Determination of structures of biologically active substances by X-Rays.

1973 Ernst Otto Fischer &

Geoffrey Wilkinson

Organometallic chemistry.

1987 Donald James Cram, Jean-Marie Lehn and Charles J. Pedersen

Elaboration and applications of molecules having structurally-specified interactions of high selectivity.

2001 William S. Knowles, Ryoji Noyori and K. Barry Sharpless

Research in pharmaceutical industry: creation of chiral catalysts for redox-reactions.

2005 Yves Chauvin, Robert H. Grubbs, Richard R. Schrock

The development of the metathesis method in organic synthesis.

4

A new era has started in coordination chemistry since 1869 after Schiff’s

elegant synthesis of azomethane complexes of copper (II) from preformed

metal, salicylaldeyde and primary amine. Schiff base is formed as a

condensation product of primary amine with carbonyl compounds. This was

first reported by Schiff [2], which contain the >C=N- group which is also

called azomethane, imine or anil. The >C=N- group in combination with more

such groups or others like phenolic –OH or amino groups can effectively form

metal complexes. The Schiff base ligands and their complexes have significant

importance in chemistry and every year a number of reports are published on

the preparation of these compounds and their application in chemical reactions

[3]. Schiff bases of aliphatic aldehydes are relatively unstable and readily

polymerizable, while those of aromatic aldehydes having effective conjugation

are stable. In general, aldehydes react faster than ketones in condensation

reactions, leading to the formation of Schiff bases as the reaction centre of

aldehyde are sterically less hindered than that of ketone. Furthermore, the extra

carbon of ketone donates electron density to the azomethine carbon and thus

makes the ketone less electrophilic compared to aldehyde.

The Schiff base compounds and their complexes are widely applied in

enantioselective cyclopropanation of styrenes [4],asymmetric addition of

cyanide to aldehydes [5], asymmetric aziridination of olefins [6],

enantioselective epoxidation [6,7], regio- selective ring opening of epoxides [8]

and as a membrane in ion selective electrode [9–13]. The metal complexes of

Schiff bases also finds applications in versatile catalytic reactions for organic

synthesis [14-17], degradation of organic substances [18], in

radiopharmaceuticals [19], their ability to reversibly bind oxygen [20] and

photo chromic properties [21]. Schiff base metal complexes have also found

greater applications in biological field.

Schiff bases have been reported to exhibit a variety of biological actions

by virtue of the azomethine linkage, which is responsible for various

antibacterial, antifungal, herbicidal, clinical and analytical activities [22–25].

Recently, there has been tremendous interest in studies related to the interaction

5

of transition metal ions with nucleic acid. because of their relevance in the

development of new reagents for biotechnology and medicine [26]. There has

also been substantial interest in the rational design of novel transition metal

complexes, which bind and cleave duplex DNA with high sequence and

structure selectivity [27-29].Various studies have shown that, the presence of

lone pair of electron on trigonally hybridised nitrogen atom of the azomethane

group >C=N- is of fundamental chemical and biological importance

[30].Biological significance of Schiff base complexes have been reported

widely in literature [31]. Many Schiff bases have been used as analytical

reagents, corrosion inhibitors, flocculants, medicines and therapeutic agents

[32-33].Many Schiff Base complexes of metals possess antitoxic, cytotoxic,

antimicrobial and antibacterial activity [34-35]. Some Schiff base complexes

have been reported to be active against leukemia and also exhibit antitumor

activity [36].

Some Schiff base complexes have been reported to possess therapeutic

activities [37-40] and found to possess anti-inflammatory, antipyretic,

analgesic, cardioscopic and diuretic action. The use of Schiff base complexes

in nuclear medicine also has been reported recently [41]. Some Schiff bases

show retardation in root development in detached cabbage leaves [42]. Copper

azomethane complexes find application as pigments. There is suggestive

evidence that, the visual pigment rhodospin contains azomethane linkages [43].

Schiff bases have been reported to exhibit a variety of biological actions

by virtue of the azomethine linkage, which is responsible for various

antibacterial, antifungal, herbicidal, clinical and analytical activities [44–47]. It

is known that, chelation of metal ions with organic ligands acts synergistically

to increase their biological activities [48]. Recently, there has been tremendous

interest in studies related to the interaction of transition metal ions with nucleic

acid because of their relevance in the development of new reagents for

biotechnology and medicine [49]. There has also been substantial interest in the

6

rational design of novel transition metal complexes, which bind and cleave

duplex DNA with high sequence and structure selectivity [50-52].

Coumarin

Coumarin (2H-chromen-2-one, 2H-1-benzopyran-2-one) is structurally

the least complex member of a large class of compounds known as

benzopyrones and also coumarins are among the best known oxygen

heterocyclics with a d-lactone ring which comprise a very large class of

compounds found throughout the plant kingdom [53-55]. The biological

activities of coumarin derivatives are multiple and include antithrombotic [56],

antimicrobial [57], antiallergic [58], anti-inflammatory [59], antitumor [60] and

anticoagulants [61]. Derivatives of coumarin are known to possess significant

antifungal as well as antibacterial properties. Many of the coumarins present in

plants and also their synthetic analogues, have been reported to be good

antifungal and antibacterial agents [62-69]. Preliminary structure– activity

relationship studies have shown that, the presence of hydroxyl or carboxylic

groups on the coumarin nucleus is necessary for antimicrobial activities [70].

The presence of coumarin nucleus in the antibiotics, such as novobiocin,

clorobiocin and coumermycin A1 were identified over forty years ago. But, the

use of these antibiotics has been limited due to their poor water solubility, low

activity against Gram-negative bacteria and the rapid emergence of resistance

[71-47].

Coumarins are nowadays an important group of organic compounds that

are used as additives to food and cosmetics, optical brightening agents and

dispersed putrescent and laser dyes [72-74]. The derivatives of coumarin

usually occur as secondary metabolites present in seeds, roots and leaves of

many plant species. Their function is far from clear, though suggestions include

waste products, plant growth regulators, fungi stats and bacterio stats. It is

therefore of utmost importance that, the synthesis of coumarin and its

derivatives should be achieved by a simple and effective method. The synthesis

of this heterocyclic nucleus is of current interest. Coumarins have been

7

synthesized by several methods including Von Pechman, Knovenagel and

Reformatsky reactions.

However, renewed interest in these antibiotics has arisen following the

discovery that, they are potent catalytic inhibitors of DNA gyrase.

Additionally, these antibiotics have been shown to be active against Gram-

positive bacteria, especially against Methicillin-resistant Staphylococcus

aureus (MRSA) [75]. Further, derivatisation of novobiocin, clorobiocin, and

coumermycin A1 has allowed for the production of novel coumarin antibiotics

displaying excellent inhibition of DNA supercoiling by DNA gyrase B and

good antibacterial activity against vancomycin, teicoplanin and novobiocin

resistant Enterococci species [76-78].

A part from the biological significance, Schiff bases and their metal

complexes find applications in various other fields. Some aromatic Schiff bases

have been used as stabilizers [79] for a wide variety of compounds which

include jet fuels, fuel oils, lubricating oils etc., Schiff bases have been

incorporated in several polymers [80] to produce certain desirable

characteristics in the final products. This includes superconducting property,

resistance towards heat, light and oxidation, hardness and vulcanisation.

Certain Schiff base complexes of metals have been used for the catalytic

oxidation of ascorbic acid and cysteine. Some Schiff base complexes have been

used in the catalytic decomposition of hydrogen peroxide [81]. Aromatic Schiff

bases and their metal complexes are found to have strong catalytic influence

[82] on reactions like oxidation, decomposition and polymerisation. Many

Schiff base complexes find use as dyes and as electrographic materials. In

view of such a fascinating structural and biological features of coumarins, in

the present study hydroxy substituted formyl coumarins have been utilized for

the synthesis of various Schiff bases.

Isatin

Isatin (1H-indole-2,3-dione) was first obtained by Erdman and Laurent

in 1841 as a product from the oxidation of indigo by nitric and chromic acids.

8

Isatin and its derivatives have been extensively used as versatile reagents in

organic synthesis: to obtain heterocyclic compounds and as raw material for

drugs [83-84], some synthetic oxindole based compounds have been developed

as anticancer, anti-HIV or antimicrobial agents [85]. The synthetic versatility of

isatin has stemmed from the interest in the biological and pharmacological

properties of its derivatives. In recent years, there has been enhanced interest in

the synthesis and characterization of transition metal complexes containing

Schiff bases as ligands, due to their importance as catalysts for many reactions

[86-87]. Tetradentate Schiff base complexes of isatin are also very important

for various biological applications, [88-89] namely antibacterial, antiviral,

antimalarial, antitumour, [90-91] etc., In addition, anti-inflammatory activity

has also been reported for these complexes [92-93]. The complexes of

transition metals with Schiff bases show better biological activity than the free

ligands [94]. Although there is a wealth of information concerning transition

metal complexes with isatin Schiff bases [95-97] it is largely confined to the

first row metals, such as copper, iron, cobalt and nickel [98-99].

Triazole

Substituted 1,2,4-triazoles are among the large number of heterocyclic

compounds that have received the most attention during the last two decades as

potential antimicrobial agents. They are associated with diverse biological

activities such as fungicidal, antimicrobial, antiviral activities etc. [100-104].

The 1,2,4-triazole nucleus has been incorporated into a wide variety of

therapeutically interesting drugs, including H1/H2 histamine receptor blockers,

Cholinesterase- active agents, CNS stimulants, antianxiety agents and sedatives

[105]. Mercapto derivatives of substituted 4-amino-l,2,4-triazoles are

particularly interesting as complexing agents due to the presence of four

potential donor atoms (three nitrogen and one sulphur), consequently many

metal derivatives of ligands of this type have been prepared [106-110]. Schiff

bases of o-phenylenediamine and its complexes have a variety of applications

9

including biological [111], clinical [112] and analytical [113]. Earlier work has

shown that, some drugs exhibited increased activity when administered as

metal chelates rather than as organic compounds [114-115] and that the

coordinating possibility of o-phenylenediamine has been improved by

condensing with a variety of carbonyl compounds. Also the primary amines are

known as better condensing agents.

Survey of the Previous Work

S. U. Rehman et al., have synthesized the Schiff bases derived from 3-

formyl-4-chlorocoumarin and heteroaromatic amines/hydrazides [116]. The

Co(II), Ni(II), Cu(II) and Zn(II) complexes of these Schiff bases have been

synthesized, stpectroscopically characterized and screened for their in-vitro

antibacterial activity against E. coli, K. pneumoniae, P. mirabilis, P.

aeruginosa, S. typhi, S. dysenteriae, B. cereus, C. diphtheriae, S. aureus and S.

pyogenes bacterial strains and for in -vitro antifungal activity against T.

longifusus, C. albicans, A. flavus, M. canis, F. solani and C. glaberata.

From our laboratory, G.B.Bagihalli et al., have studied the Co(II),

Ni(II),Cu(II) and Zn(II) complexes with Schiff bases derived from 3-

substituted-4-amino-5-mercapto-1,2,4-triazole and 8-formyl-7-hydroxy-4-

methylcoumarin [117] have been reported. These complexes have been

characterized on the basis of elemental analyses, spectral, magnetic and thermal

studies.

N

NN

S

N

N

N N

R S

N

CHO

O

OCH3OH2

OH2

R

MCH

OO

CH3

OM

OH2

OH2

O

n

R=H, CH3, C2H5 and C3H7

10

G.B.Bagihalli et al., have reported the complexes Co(II), Ni(II) and

Cu(II) with Schiff bases derived from 3-substituted-4-amino-5-hydrazino-

1,2,4-triazole and 8-formyl-7-hydroxy-4-methylcoumarin [118]. These

complexes have been characterized on the basis of elemental analyses, spectral,

magnetic and thermal studies.

N

NN

NH

CHOO

OCH3

CH

O

CH3

ON

O

R

N

M

OH2

OH2

Very recently, series of metal complexes of Co(II), Ni(II) and Cu(II)

have been synthesized with the Schiff base derived from thiocarbohydrazide

and 8-formyl-7-hydroxy-4-methylcoumarin [120]. From our laboratory, the

structures of these complexes have been proposed by elemental analyses, molar

conductance, spectral (IR, UV–Vis, ESR and FAB-mass), magnetic, thermal

and electrochemical studies. These complexes are soluble in DMF and DMSO

and molar conductance values indicate that they are non-electrolytes.

The series of metal complexes of Co(II), Ni(II) and Cu(II) have been

synthesized with the Schiff base derived from Ortho-Phthalaldehyde and Bis-

(4-Amino-5- Mercapto-1,2,4-Triazole-3-yl)Alkanes [121]. The structures of the

complexes have been proposed by elemental analyses, molar conductance,

spectral (IR, UV–Vis, ESR and FAB-mass), magnetic, thermal and

electrochemical studies. These complexes are soluble in DMF and DMSO and

molar conductance values indicate that, they are non-electrolytes.

11

N N

N

N

NN

SH N

NN

S H

N

N N

SH N

N N

S H

N

( C H2)

( C H 2)

MO H2 O H2 .

n

n

o o

o o

N

N

o

o

( H 2 O)3

Karaliota et al., reported the binuclear molecules [Cu2(L)4(H2O)2], in

which the two copper atoms are bridged in pairs by four carboxylic groups of

the coumarin-3-carboxylate ligand, and are also bonded to two water molecules

[122]. Thus, each copper atom is coordinated by four oxygen atoms lying on its

basal plane and the water oxygen atom on its apex. The coordination sphere

may be completed with the Cu�Cu contact to form a distorted octahedron.

Finally, two additional water molecules complete the molecular formu

[Cu2(L)4(H2O)2]·2H2O. These two lattice water molecules per dimmer stabilize

the structure, most probably via hydrogen-bonds. An extensive hydrogen-

bonded network could account well for the insolubility of the complex.

B. S. Creaven et al., have reported the Cu(II) complexes of bidentate

coumarin Schiff bases [123]. The Schiff bases have been synthesized via

condensation of 7-amino-4-methylcoumarin with a number of substituted

12

salicylaldehydes and are characterized by IR, 1H & 13C NMR, UV-vis., and

elemental analyses. Subsequently, these ligands are reacted with copper(II)

acetate to form Cu(II) complexes. These Cu(II) complexes were characterized

by IR, UV-vis., molar conductance, magnetic properties and crystal analysis

data. The Schiff bases and their Cu(II) complexes were studied for their anti-

candida activities.

Junna Yao et al., have reported the coumarin-based podand-type ligand

and its five complexes [Ln(NO3)3L] (Ln = Pr, Eu, Gd, Tb and Er] were

synthesized. The Ln(III) ion is coordinated with ten oxygen atoms, four of

which belong to the tetradentate ligand ‘L’ and the remaining six belong to

three bidentate nitrate groups. The four ‘O’ atoms assume a half-ring shape,

and form a pentacyclic-ring-like coordination structure together with one ‘O’

atom of the nitrate. The two chelate chains are flexible and their distance and

separation angle decrease with the smallness of coordinated metal ions.

The synthetic route for the ligand ‘L’ and the lanthanide complexes

13

The pentacyclic-ring-like structure in the coordination polyhedron

Aim and Significance of the Present Research Work

In recent years, there has been lot of interest shown in the synthesis and

physico-chemical properties of transition metal complexes with substituted 1,

2, 4-triazoles. Triazoles and their derivatives have been proved to be effective

bactericides [65], pesticides [124], fungicides [125, 126] and insecticides [127,

128]. Many Schiff bases derived from either heterocyclic amines or aldehydes

have been studied for their ability to form complexes with the transition metals

[129-130].

In biological front, Coumarins have long been recognized to possess

anti-inflammatory [131], antioxidant [132], antithrombtic [133], antiallergic

[134], hepatoprotective [135], antiviral [136] and anticarcinogenic [137]

activities. The hydroxycoumarins are typical phenolic compounds and

therefore, used as potent metal chelators and free redical scavengers. They are

powerful chain-breaking antioxidants [138]. The coumarins display a

remarkable array of biochemical and pharmacological actions [139], the

antitumor effects of coumarin and its major metabolite, 7-hydroxycoumarin,

were tested in several human tumor cell lines [140]. Furthermore, cytotoxic

effects of complexes of coumarin derivatives were examined on several

neuronal cell lines [141].

14

It is in this context that, the author undertook a comprehensive research

work on the synthesis of some transition metal complexes of various bidentate,

tridentate and tetradentate Schiff bases. Thus, the aim of present research work

is to synthesize some Schiff bases derived from coumarin, triazole and isatin

etc., and to stitch them with various transition metal ions to form metal

complexes.

The Schiff bases and their metal complexes were characterized by

extensive spectroscopic and analytical methods. The structural properties of

Schiff bases have been studied by FT-IR, UV-vis., FAB-Mass, NMR (1H and 13C) and elemental analyses. Owing to the fluorescence properties of

precursors, some of the Schiff bases and their metal complexes have been

evaluated for their fluorescence properties.

X-ray crystallographic study is the most definite source of information

regarding the structure of a complex. But, due to the difficulty in obtaining the

crystals of metal complexes suitable for X-ray crystallographic study, has

rendered this method less suitable for these complexes. In such cases, a variety

of other techniques can be used with good effect and have been done in this

investigation. The structural diversities of metal complexes have been

undoubtedly proposed in the light of FT-IR, UV-vis., FAB-Mass, NMR and

ESR spectral data wherever possible or applicable, elemental analyses,

conductance measurements, magnetic measurements and thermogravimetric

analyses studies. Electrochemical behaviour of some metal complexes has been

studied by the Cyclic Voltametry. From the study, electron transfer

mechanisms were proposed. Thermal decomposition studies of some metal

complexes resulted some valuable information regarding the thermal stabilities

of the metal complexes. The fluorescence properties of some metal complexes

have also been investigated. With respect to the significant applications of

Schiff bases and their metal complexes in medicinal field, appropriately termed

as “Medicinal Inorganic Chemistry”; Schiff bases and their metal complexes

have been evaluated for their antibacterial and antifungal activities. Also, some

of the metal complexes have been tested for their DNA cleavage properties on

isolated genomic DNA of various human pathogens.

15

The main purpose of this research work has been to synthesize some new

Schiff bases to utilize as ligands and to study the ligands and their metal

complexes from a structural point of view. These ligands with a variety of

bonding interactions, tautomeric phenomena, potential variety of bonding

modes and hydrogen bonding interactions, were expected to provide

stimulating results. This expectation became fruitful. Metal chelates of Schiff

bases hold exciting possibilities for the future concerning to their wide

applications viz. in designing new catalytic systems, in formulating new

synthetic route, in developing new analytical reagents and in metal based

antimicrobial agents etc., Hopefully, the results of this investigation would

attract increased interest in this field.

Schiff Bases Synthesized in the Present Investigation

The following series of new Schiff bases have been synthesized in the

present research investigation.

1. Synthesis of Schiff bases derived from 8-formyl-7-hydroxy-4

methylcoumarin/5-formyl-6-hydroxycoumarin and 4, 4’-

diaminodiphenyl sulfone (Dapsone) (Figure-I).

2. Synthesis of Schiff base derived from novel macrocyclic Schiff bases

derived from bis-(4-amino-5-mercapto-1,2,4-triazole-3-yl)alkanes and

1, 6- bis(2-formylphenyl)hexane (Figure-II).

3. Synthesis of Schiff bases derived from 4-Aminoantipyrine and 8-

formyl-7-hydroxy-4-methylcoumarin / 5-formyl-6-hydroxy coumarin

(Figure-III). 4. Synthesis of Schiff bases derived from Isatin monohydrazone and P-

Dimethylamino benzaldeyde (Figure -IV).

5. Synthesis of Schiff bases derived from o-substituted thiosemicarbazides

and 8-formyl-7-hydroxy-4-methylcoumarin (Figure -V).

6. Synthesis of Schiff bases derived from Substituted 1,2,4-triazoles

and Isatin (Figure - VI).

N N

SO2

OO

CH3

CH

OH OOH

CH

O

CH3

N N

SO2

O

CH

OH

O O O

CH

OH

Schiff base-I Schiff base-II

n=1, 2, 3 & 4

NO

NN CH3

O

CH3

CH

OOH

CH3

N CH3

N

O N

CH

O O

OH

CH3

Schiff base-I Schiff base-II

(Figure-I)

���������

���������

17

N O

N-N= NCH3

CH3

CH

Schiff baseH

R

R = H, CH3, Cl

NH C N

HN

S

HC

O

O

OH

CH3

�

N O

N NN

N

R

SH

H

R = H,CH3,C2H5,C3H7 �

����������

����������

����������

18

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