Chapter-1 - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/54390/7/08_chapter 1.pdf · (antiprotozoa and anticonvulsant) and thiosemicarbazone (antibacterial, antifungal, antitumoral,

Chapter-1 SEMICARBAZONE AND THIOSEMICARBAZONE A BRIEF INTRODUCTION------------------------------------------1-30 1.1 Introduction--------------------------------------------------------------1-4 1.2 Semicarbazone and thiosemicarbazone in the biological filed

A survey-------------------------------------------------------------------4-81.3 Stereochemistry, bonding and nature of coordination of

Semicarbazone and thiosemicarbazones----------------------------8-16 1.4 Objective and scope of present work--------------------------------16-171.5 Introduction to the relevant analytical techniques---------------18-23 1.6 Conclusion-------------------------------------------------------------------241.7 References----------------------------------------------------------------25-30

1

CHAPTER-1

SEMICARBAZONE AND THIOSEMICARBAZONE A BRIEF INTRODUCTION

1.1 INTRODUCTION

Coordination compounds have been a challenge to the inorganic chemist since

they were identified in the nineteenth century. After the profound studies done

by Alfred Werner, inorganic chemistry witnessed a great outflow of

coordination compounds, with unique structural characteristics and diverse

applications. The stereochemistry of coordination compounds is one of major

interests of the coordination chemist. The development of instrumental

techniques provides methods of investigating thermal, spectral and magnetic

properties of metal complexes. Coordination compounds can have a wide

variety of structures depending on the metal ion, coordination number and

denticity of the ligands used. The presence of more electronegative nitrogen,

oxygen or sulfur atoms on the ligand structure is established to enhance the

coordination possibilities of ligands.

Thiosemicarbazone are very versatile ligands. They can coordinate to

metal as neutral molecules or after deprotonation as anionic ligands and can

Chapter 1

2

adopt a variety of different coordination modes. Thiosemicarbazones and

semicarbazones act as ligands because;

1. They have better co-ordination tendency.

2. They form more stable complexes.

3. They have better selectivity.

4. They may form macrocyclic ligands

5. They have the ability to produce some new and unique complexes

with enhanced biological and analytical properties1. Certain

thiosemicarbazones are relatively specific inhibitors of ribonucleotide

reductase, which is an important metabolic target for the development

of chemotherapeutic agents against cancer2 .

Thiosemicarbazone usually act as chelating ligands with transition metal ion

bonding through the sulphur and hydrazine nitrogen atom. Thiosemicarbazone

and their complexes have received considerable attention because of their

pharmacological activities.

Semicarbazone are the schiff bases, usually obtained by condensation of

semicarbazide with suitable aldehydes and ketones Fig(1.1).

R1

R2

+ NH

O

NHH N 22

H+

H2O-

R1

R2

O N

NH

NH2

O

Fig.1.1: Method of synthesis of Semicarbazone

Semicarbazone and Thiosemicarbazone- A Brief Iintroduction

3

An interesting artibute of semicarbazone is that in solid state, they

predominately exist in the keto form, whereas in solution state, they exhibit a

keto-enol tautomerism. Keto form act as neutral bidentate ligand and the enol

form can deprotonate and serve as mono –anionic bidentate ligand in metal

complexes. Thus semicarbazone are versatile ligands in both neutral and anionic

forms fig (1.2) keto-enol tautomerism of semicarbazones.

Both tautomeric forms have an efficient electron delocalization along the

semicarbazone moiety. Aromatic substituent on semicarbazone skeleton can

furher enhance the delocalization of electron charge density. These classes of

compounds usually react with metallic cations giving complexes in which the

semicarbazone behave as chelating ligands upon coordination to a metal centre,

the delocalization is further increased through the metal chelate rings. The

coordination possibilities are further increased if the substituent has additional

donor atoms.

Chapter 1

4

The semicarbazone and thiosemicarbazone usually behave as chelating

ligands and usually react with metallic cations giving complexes.They are

versatile ligands in both neutral and anionic forms. Metal complexes of

semicarbazone and thio-semicarbazone have gained special attention due to

their importance in medicine and biological system3.taaaa

1.2 SEMICARBAZONE AND THIOSEMICARBAZONE IN THE

BIOLOGICAL FILED A SURVEY

Semicarbazones present a wide range of bioactivities, and their chemistry and

pharmacological applications have been extensively investigated. The biological

properties of semicarbazones are often related to metal ion coordination. Firstly,

lipophilicity, which controls the rate of entry into the cell, is modified by

coordination4. Also, the metal complex can be more active than the free ligand.

The mechanism of action can involve binding to a metal in vivo or the metal

complex may be a vehicle for activation of the ligand as the cytotoxic agent.

Moreover, coordination may lead to significant reduction of drug-resistance5.

The semicarbazone and thiosemicarbazone usually behave as chelating ligands

and usually react with metallic cations giving complexes. Copper (II)

complexes with semicarbazides and thiosemicarbazides have received much

attention due to their wide range of applications with as an antibacterial6-9,

antifungal10-13, In addition, they also have been used in the treatment of a

number of tumors, including Hodgkin,s disease.


5

In addition thio- and semicarbazone possess a wide range of bioactivities

and their chemistry and pharmacological applications have been extensively

investigated the more significant bioactivities of a variety of semicarbazone

(antiprotozoa and anticonvulsant) and thiosemicarbazone (antibacterial,

antifungal, antitumoral, antiviral) and their metal complexes have been

reviewed together with the proposed mechanism of action and structure

reactivity relationship14-15.

A variety of 5-nitrofuryl semicarbazone derivatives have been developed

for the therapy of Chagas disease, a major problem in the Central and the South

America16. 4-Bromo benzaldehyde semicarbazone has been used as

anticonvulsant. Recently, a review reported on the anticonvulsant activity of

thiosemicarbazones, semicarbazones and hydrazones derived from aromatic and

unsaturated carbonyl compounds as well as from other precursors17. In contrast

to thiosemicarbazones, literature records fewer examples of semicarbazones

presenting significant anticancer and cytotoxic activity but some nitroso,

naphtopyran, and fluorine derivatives showed anti-leukemia effect in mice18.

Coordination chemistry of PLSC- based complex (pyridoxal-

semicarbazone) proved to be very interesting as this ligands can exist in

neutral, mono and dianionic form depending on PH , while in most predominant

tridentate coordination mode achieved through hydragenic nitrogen , phenolic

and carbonyl oxygen atom, allows it to be an excellent chelating ligand19.

Chapter 1

6

The ligands based on semicarbazone and pyridoxal moieties (forms found

in vitamin B6) has an enormous potential as a biologically active reagents as it

has been demonstrated that transition metal complexes incorporating

semicarbazone show biological activity, in particular, with regard to biological

importance, nickel (II) complex with semicarbazone ligands show antibacterial

activity20 and copper(II) complexes containing semicarbazones have also

displayed biological properties21-23.Additionally, several nickel (II) complexes

with octadiensemicarbazone exhibit strong inhibitory activity against

staphylococcus aureus and E. coli24. In vitro anticancer studied of several

nickel(II) complexes with napthoqinone semicarbazone and thiosemicarbazone

on MCF-7 human breast cancer cells reveal that semicarbazone derivative with

nickel(II) complexes is more actively inhibiting cell proliferation than

thiosemicarbazone 25.

A number of authors have been interested in investigating the biological

and medicinal properties of transition metal complexes of semicarbazones and

thiosemicarbazones in recent years. New square planer complexes of general

formula [M(NNS)Cl] [M=Pd(II), Pt(II), NNS=anionic forms of 6 methyl-2-

formyl pyridine Schiff bases of S-benzyl dithiocarbazates have been prepared.

Both Schiff bases exhibit strong cytotoxicity against the human ovarium cancer

(Caov-3) cell lines, the S-methyl derivative being two times more active than

the S-benzyl derivative26. Palladium(II) and platinum (II) complexes


7

carbothioamide have been prepared and screened for their antimicrobial activity

against the fungi Macrophomina phaseolina and fusarium oxysporium by agar

plate technique.The results prove that the compounds exhibit and it is important

to note that the metal chelates show more inhibitory effects than the parent

ligands. The increased lipophilic character of these complexes seems to be

responsible for their enhanced biological potency27.Novel metal benzoic

semicarbazone complexes have been synthesized from substituted

benzoisemicarbazones. These compounds for their antimicrobial activities

against four test organism E.coli, S.aureus, Ps. aeruginosa, B. subtilis at a

against their organism were determined by serial dilution method28. A good

deal of work has been reported on the preparation and structural investigation of

semicarbazone and their complexes29-30.

The square planar platinum(II) and palladium (II) complexes M(HL)Cl2

and M(L)Cl type with thiosemicarbazone ligands derived from

phenylacetaldehyde and 2-formylpyridine showed high cytotoxicity in vitro

against HL60 Leukemia and P388 mouse leukemia cell lines31. While

platinum(II) and palladium (II) binuclear complexes with p-isopropyl

benzaldehyde thiosemicarbazone ligands exhibit strong cytotoxic activities on

mouse tumor cell inhibition32-33.

Chapter 1

8

Schiff bases are regarded as “privileged ligands” due to their capability to form

complexes with a wide range of transition metal ions yielding stable and

intensely colored metal complexes. Some of them have been shown to exhibit

interesting physical and chemical properties and potential biological34-39

activities. Metal complexes of Ni(II) are found to as a sensor40 and also

nanoparticle act as a sensor41. Semicarbazone are frequently used in the

qualitative organic analysis of carbonyl compounds42.

1.3 Stereochemistry, bonding and nature of coordination of semicarbazones

A review of semicarbazone and thiosemicarbazone43 showed that in free

unsubstituted semicarbazones in the solid state, the C=N-NH-CO-NH2 backbone

is usually planar, with O atom trans to azomethine N atom.(Fig.1.3)

Fig. 1.3 Structure of semicarbazone

Few semicarbazone are exception to this rule. Although there are several

electronic and steric factors that may contribute to the adoption of this

rearrangement, the most is probably that the trans arrangement places the amine


9

and azomethine nitrogen atoms in relative position suitable for

intramolecular hydrogen bonding44.

Interestingly, semicarbazone show a variety of coordination modes with

transition metals, the coordination mode is influenced by the number and type

of substituent. This is because the active donor sites of ligand vary depending

upon the substituent. According to the reports the coordination mode of

semicarbazone is very sensitive towards minor variation in the experimental

conditions. The nature of substituent on the carbonyl compound and metal

salts45.

In most of the complexes we synthesized semicarbazone act as tridentate

ligand and in some cases semicarbazone exhibit as potential quadridentate when

the second pyridyl nitrogen involved in coordination process. The coordination

mode of N4- substituted46 fig.(1.4) is given below.

Fig. 1.4 Coordination mode ONO - tricoordination

Chapter 1

10

The different coordination modes of substituted benzaldehyde semicarbazone

given below47 fig(1.5);

Fig. 1.5 (a)

Fig.1.5 (b)

Fig. 1.5 (c)

Fig. 1.5 (a,b,c) Different Coordination Modes


11

Owing the availability of NH-C=S group, thiosemicarbazone exhibit thione –

thiol tautomerism. In solid they exist in thione form but in solution they exist as

an equilibrium mixture of thione and thiol form as shown in the fig.1.6.

Fig. 1.6 Equillibrium mixture of thione and thiol

Presence of N=C, made them to exist as E and Z stereo isomers. Considering

the thermodynamic, E isomer will predominate in the mixture48.The existence

of two forms of E isomer viz EI and EII is reported the EI isomer has more

intermolecular hydrogen bonding49 than EII. The isomer are represented in the

fig.1.7

Chapter 1

12

Fig.1.7 Structure of E and Z stereoisomer, E1 and E11 isomer

The E and Z isomer of 2- formylpyridine thiosemicarbazone as well as those of

the other hetro cyclic thiosemicarbazone has been separated and characterized50.

The stable difference in stereochemistry between isomer was based upon the

degree of shielding obserbed for the 2N proton of the z isomer.

However in most complexes thiosemicarbazone coordinate as bidentate

ligand via the azomethine nitrogen and thione thiol sulphur. When additional

coordination functionality is present. The proximity of the donating centre, the


13

ligand will coordinate in a tridentate manner. This can be accomplished

by the neutral molecule or the monobasic anion upon loss of hydrogen.

Besides the denticity variation, consideration of the charge distribution is

complicated in the semicarbazone due to the existence of thione thiol tautomers.

Although the thione form predominates in the solid state, solution of

thiosemicarbazone molecules show a mixture of both tautomers. As a result

depending upon the preparative condition, the metal complexes can be cationic,

neutral or anionic. Most of the earlier investigation of metal thiosemicarbazone

complexes have involved ligands in the uncharged thione form, but a number of

recent reports have featured complexes in which the 2N- hydrogen is lost, and

thiosemicarbazone coordinate in the thiol form51. Furthermore, it is possible to

isolate complexes containing both the neutral and anionic forms of the ligand

bonded to the same metal ion. Ablov and gerbeleu suggested that formation of

these mixed “tautomer” complexes is promoted by trivalent central metal ion

like Cr(III), Fe(III) and Co(III).

Recently we have reported the crystal structure of pyridine 2-

carbaldehyde 4N Phenethyl thiosemicarbazone in which the thiosemicarbazone

group adopts an EE configuration, i.e., trans configuration are obserbed about

both the azomethine and hydrazinic bonds52. Although there are several

electronic and steric factors that may contribute to the adoption of this

arrangement, the most important is probably that the trans arrangement places

Chapter 1

14

the amine and azomethine nitrogen atoms in relative position are

suitable for intramolecular hydrogen bonding53. In fact, the complete

substitution of amine hydrogen result in crystallization with S atom cis with

azomethine nitrogen giving z configuration fig(1.8).

Presence of NH-C=S group in thiosemicarbazone can bring about thione- thiol

tautomerism. In solution thiosemicarbazonees exist as an equilibrium mixture of

thione(III) and thiol (I ) forms fig(1.9).


15

Enolization into the thiol form results in an effective conjugation along the

thiosemicarbazone skeleton thus enhancing electron delocalization along the

moiety. In the case of heteroaromatic thiosemicarbazone, delocalization of

electron cloud is extended along with the generation of new potential sites for

coordination to a metal centre, the delocalization is further increased through

the metal chelate rings. This is one of the reason for choosing pyridine-2-

carbaldehyde as the carbonyl base of our ligands. Through thiosemicarbazone

can coordinate to metals in the neutral thione form, usually chelation takes place

through the anion formed by deprotonation of hydrazinic NH groups, via

enolization to the thiol form. The stereochemistry adopted by the

thiosemicarbazone ligand with transition metal ion depends essentially on the

Chapter 1

16

presence of additional coordination sites in the ligand moiety and the charge on

the ligand which in turn is influenced by thione - thiole equilibrium, and pH of

the medium used for reaction. Studies have revealed that steric effects of the

various substituent in the thiosemicarbazone moiety considerably affect the

stereochemistry54.

Thiosemicarbazone can adopt a variety of different coordination modes.

In most of the series, thiosemicarbazone coordinate as bidentate ligands via

azomethine nitrogen and thione/thiolato sulphur. When additional coordination

functionality is present in the proximity of donating centres, the ligands will

coordinate in a tridentate manner. This can be accomplished either by neutral

molecule or by the monobasic anion upon loss of hydrogen. Although the thione

form predominates in the solid state, solution of thiosemicarbazone molecule

show a mixture of both tautomers. As a result, depending upon the preparative

conditions, the metal complexes can be cationic, neutral or anionic.

1.4 Objective and Scope of the present work

The significance of semicarbazone and thiosemicarbazone and their metal

complexes, apart from their diverse chemical and structural characteristics,

stems from not only their potential but also their proved application as

biologically active molecules. The wide application and structural diversity of

metal complexes of semicarbazone prompted us to synthesize the tridentate

NNO- donor semicarbazones and their metal complexes. Due to good chelating


17

ability, the present work is mainly concerned with the studies on

complexes of salicylaldehyde, m-hydroxy benzaldehyde and p- hydroxy

benzaldehyde semicarbazones and thiosemicarbazones. By emphasizing this

point the objectives of the present work are as follows:

The Salicylaldehyde semicarbazone/thiosemicarbazone (L1/L2=SSC/

STSC) m-hydroxy benzaldehyde semicarbazone/thiosemicarbazone (L3/L4=m-

HBSC/m-HBTSC), p- hydroxy benzaldehyde semicarbazone\

thiosemicarbazone (L5,L6= p-HBSC/p-HBTSC). The composition of ligand

were determined by the CHN analysis. For the characterization of these

compounds by 1HNMR and IR spectral studies. The metal complexes of Ni2+,

Cu2+, Mn2+ and Co2+ were characterized by 1HNMR, IR and UV spectral

studies. These complexes were characterized various spectroscopic techniques,

magnetic and conductivity studies.This thesis is divided into six chapters. All

the ligands of semicarbazone and thiosemicarbazone, L1, L2, L3, L4, L5, L6 and

the Complexes of [Mn(L4)2Cl2, [Mn(L6)2Cl2], [Ni(L4)2)Cl2], [Ni(L6)2)Cl2],

[Co(L2)2Cl2], [Co(L4)2Br2], [Cu(L2)2Br2] [Cu(L4)2Br2] [Ni(L3)2Br2] have been

screened against Bacteria (a) gram positive Staphylococcus aureus(S aureus),

(b) gram negative Ecoli and fungi Aspergillus niger and Candida albicans by

agar disc diffusion method at conc.-

Chapter 1

18

1.5 Introduction to the relevant analytical techniques

Several methods, conventional and modern are available for elucidating the

structure of ligands and their coordination compounds. The complexes are

characterized by elemental analysis, molar conductance, magnetic susceptibility

measurement and spectral (electronic, IR, EPR, 1HNMR). Studies some of the

physical chemical methods adopted during the present investigation are

discussed below.

1.5.1 Elemental analysis

The C,H and N were analyzed on Carlo-Erba 1106 elemental analyzer. The

nitrogen content of the complexes was determined using kjeldahl, method at

Indian Institute of Technolgy.

1.5.2 Magnetic Susceptibility measurement

The magnetic susceptibility and the magnetic moment are often used to describe

the magnetic behaviour of substance. A magnetic dipole is a macroscopic or

microscopic magnetic system in which the north and south poles are separated

by a short but definte distance. In the presence of a magnetic field, magnetic

dipoles within a material experience a turning effect and become partially

oriented. The magnetic moment refers to the turning effect produced when a

magnetic is placed in a magnetic field. The fundamental unit of magnetic


19

moment is the bohr magneton. For isotropic the magnetic susceptibility ( ) is

defined by,

= M/H

Where M is the magnetic moment per unit volume (magnetization) and H

is the strength of magnetic field. The molar susceptibility M is simply defined

as the susceptibility per gram mole .Hence,

M = × molecular weight

The magnetic susceptibility value calculated from magnetic measurement

is the sum of paramagnetic and diamagnetic susceptibility. To calculate the

exact eff), the value of diamagnetic susceptibility

is substracted from the susceptibility calculated from observed results. When

the structural formula of the complexes is correctly known, diamagnetic

correction can be calculated from pascal,s constant.

The magnetic susceptibility measurement were carried out in the

polycrystalline state on a vibrating sample magnetometer (VSM) at 5.0 khz field

strength at room temperature at Indian institute of Technology, Roorkee.

1.5.3 Infrared spectroscopy

The vibrational states of a molecule can be probed in a variety of ways . The

most direct way is infra-red spectroscopy because of vibrational transition

Chapter 1

20

typically require an amount of energy that corresponds to infrared region of the

spectrum 4000 and 400 cm-1 (wavenumber). Radiation in this region can be

utilized in structure determination in coordination chemistry by making use of

the fact that interatomic bonds in ligand absorb it.

Infrared spectra (KBr) were recorded on FTIR spectrum BX-11

spectrophotometer at Sophisticated Instrumentation Facility, Indian Institute of

Technology (IIT), Delhi.

1.5.4 Electronic spectroscopic

Electronic spectroscopy is the measurement of the wavelength and intensity of

absorption of near ultra violet and visible light by a sample. UV- vis

spectroscopy is usually applied to organic molecule and inorganic ions or

complexes. The absorption of UV or visible radiation corresponds to the

excitation of outer electrons.

There are three types of electronic transition that can be considered for

coordination compounds. Possible transitions of , and n electrons are

shown in fig 1.4. Most absorption spectroscopy of ligands is based on n

and transition. Many inorganic species show ligand to metal. Charge

transfer (LMCT) transition and metal to ligand charge transfer (MLCT)

transition(not as common as (LMCT). Transition probability in ligand field


21

transition (d-d transition) is determined by the spin selection rule and the

orbital (Laporte) selection rule.

Electronic spectra were recorded on a carry 5ooo, version 1.09 UV- Vis-

NIR Spectrophotometer from solution of compounds in chloroform/DMF at

Inderprastha Engineering Institute, Sahibabad.

1.5.5 NMR Spectroscopy

1H NMR spectra were recorded using Bruker AMX 400 FT-NMR spectrometer

using TMS as the internal standard at Sophisticated Instrumentation Facility,

Indian Institute Technology (IIT), Delhi.

1.5.6 EPR Spectroscopy

Electron paramagnetic resonance is based upon the spllitting of magnetic energy

levels produced by the action of a magnetic field on an unpaired electron

contained in an ion, a molecule or complexes. The free electron behave as a

spinning negatively charged particle with a resulting magnetic moment. By

virtue of its charge and spin an electron act as a bar magnet and can interact

with an external magnetic field. The magnetism of an electron can be expressed

by saying tha

The magnetic moment of an electron is nearly 1000 times greater than

that of a proton and is given by

- g s

Chapter 1

22

Where g is called the spectroscopic splitting factor or gyromagnetic ratio when

electrons are placed in a magnetic field, they will have their energy changed by

a certain number of ergs, given by

= ±

Where H is the strength of magnetic field.

EPR measurement require that an odd or unpaired electron occurs in the

substance. The effect of magnetic moments of nuclei on ESR spectrum is

known as hyperfine interactions and responsible for splitting of ESR line, giving

rise to hyperfine structure. Energy states separated by hyperfine coupling

constant A.

Number of hyperfine lines is given by (2NI+1) .Where n is the number of

equivalent nuclei with spin I. further splitting of states by nearby nuclei, such as

14N is reffered to as superfine coupling . Symmetry can also have an effect on

EPR spectra. If the spectra are obtained from frozen solution from a powder,

Where anisotropy is not averaged from by motion of the molecule, a complex

pattern can emerge, when gx= gy=gz in a perfectly cubic crystal, such a g value

is the isotropic one. In axial environment the g factor are anisotropic (gz = gll

and gx, gy = g ). For a rhombic molecular environment, three g factors are

observed.


23

1.5.7 Conductivity measurement

The molar conductivities of the complexes in dimethyl formamide (DMF)

solution (10-3 M) at room temperature were measured using a direct reading on

the ELICO (CM82T) conductivity bridge.

Chapter 1

24

1.6 Conclusion

This chapter has dealt with an extensive literature study relating semicarbazone

and thiosemicarbazone and their transition metal complex. Many authors have

reported anticancer, antibacterial, antifungal, antimalarial, antiviral, antifilarial

and anti –HIV activities of these compounds. They have been against small pox,

leprosy, psoriasis, rheumatism, trypanosomiasis and coccidiosis. The transition

metal complexes are far more biologically active than uncoordinated

semicarbazone and thiosemicarbazone and their enhanced biological activity

has been an active area of investigation among medicinal researchers.

Thiosemicarbazone exist as E and Z isomer and they exhibit thione- thiol

tautomerism.The present work is mainly concerned with the studies on

complexes of salicylaldehyde, m-hydroxy benzaldehyde and p- hydroxy

benzaldehyde semicarbazones and thiosemicarbazones. The composition of

ligand were determined by the CHN analysis. For the characterization of these

compounds by 1HNMR and IR spectral studies. The metal complexes of Ni2+,

Cu2+, Mn2+ and Co2+ were characterized by 1HNMR, IR and UV spectral

studies. These compounds have been screened against Bacteria (a) gram

positive Staphylococcus aureus(S aureus), (b) gram negative Ecoli and fungi

Aspergillus niger and Candida albicans by agar disc diffusion method at conc.-


25

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Chapter 1

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Chapter-1 - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/54390/7/08_chapter 1.pdf · (antiprotozoa and anticonvulsant) and thiosemicarbazone (antibacterial, antifungal, antitumoral,

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