ABSTRACT
Two novel acylpyrazolone ligands; (1-(5- hydroxy-3-methyl-1-phenyl-1-H-pyrazol-4-yl) pentan-1-one (HMPPp) and 1-(5-hydroxy-3-methyl-1-phenyl-1-H-pyrazol-4-yl) nonadecan-1-one (HMPPn) were synthesized by reacting pentanoyl chloride with 3-methyl-1-phenylpyrazol-5-one and nonadecanoyl chloride with 3-methyl-1-phenylpyrazol-5-one respectively. Fe(III), Mn(II), and Ti(III) metal complexes of both ligands were also synthesized. The ligands and complexes were characterized based on elemental analysis, IR, 1HNMR and 13CNMR spectroscopy. Physical properties such as colour, melting points and solubility profile were also determined for both the ligands and the complexes. The ligandscomplexed through its C=O and deprotonated hydroxyl group. The CO-M and O-M bond stretching frequencies of the metal complexes were compared with that of the ligand. The result showed that, increase in electron density; caused the bond length to increase and consequently the vibrational frequencies were shifted upfield. The ligand and its metal complexes studied are not ionic in nature. The solubility data showed that the complexes are soluble in organic solvents. Furthermore the result on the antimicrobial of the ligand as well as the metal complexes against three gram positive bacteria (Staphylococcus aureus, Bacillus subtillsand Streptococcus aureus), three gram negative bacteria (Escherichia coli, Klebsiella pneumonia and Pseudomonas aeruginosa), and threefungals which include Aspergilusniger, candida albicansandSacharomycescerevisiae showed that they are biologically active and there activity has been attributed to the presence of anazomethane and hydroxyl group in the pyrazolone ring. The study on the minimum inhibitory concentration (MIC) of both ligands (HMPPp and HMPPn) and their complexes showed that there were growths of inhibition in all the microbes inoculated at 0.1 and 0.025 μg/ml.From the studies, it was observed that the metal ions under investigation can be sequestrated using these ligands. However, the zones of inhibition of the complexes were observed to be remarkably higher than those of the ligands. The result on the solvent extraction showed that pH level values of 3 – 4.5 favoured the extraction of the metal by the ligands, and remained valid up to pH levels of 4.5. Also the average logarithms of the equilibrium constant (Kex) values for the metals at the different extractant concentrations at a constant pH of 4 showed that the ligands are more efficient in the recovery of Mn(II) > Fe(III) > Ti(III) from their aqueous solutions.
TABLE
OF CONTENTS
Title Page i
Declaration ii
Certification iii
Dedication iv
Acknowledgements v
Table of Content vi
List of Tables xi
List of Figures xviii
List of Schemes xxiv
List of Acronyms xxv
Abstract xxix
CHAPTER
1: INTRODUCTION 1
1.1 Background
of the Study 1
1.2 Statement
of the Problem 5
1.3 Aim
and Objectives of the Study 5
1.4 Justification 6
1.5 Scope
of the Study 7
CHAPTER
2: LITERATURE REVIEW 8
2.1 Conceptual
Frame Work 8
2.1.1 Chemistry
of pyrazolone 8
2.1.2 Solvent
extraction 12
2.1.3 Ligands 14
2.1.4 Importance
of coordination compounds 15
2.1.5 Chemistry
of transition metals 16
2.2.1 Bonding
in Coordination Compounds 18
2.2.2 Chelation
theory 18
2.2.3 Effective
atomic number rule 19
2.2.4 Valence
bond theory 20
2.2.5 Crystal
field theory 20
2.2.6 Molecular
orbital theory 22
2.3 Applications
of Pyrazolones 22
CHAPTER
3: MATERIAL AND METHODS 59
3.1 Chemical
and Solvent 62
3.2 Methods
of Characterization 60
3.3 Methods
of Synthesis 62
3.3.1 Synthesis
of the ligand 62
3.3.2 Synthesis
of the metal complexes of the ligands 64
3.4 Solvent
Extraction Procedures 64
3.4.1 Dependence
of solvent extraction on the pH of the aqueous solutions 65
3.4.2 Effect
of time on solvent extraction process 66
3.5 Biological
activities of both Ligands and their Complexes 67
3.5.1 Antimicrobial
activity: Preparation of test Organism 67
CHAPTER
4: RESULTS AND DISCUSSION 69
4.1 Physical
and Analytical Data 69
4.1.1 Micro
analytical Measurement 69
4.1.2 Conductivity
measurement 69
4.1.3 Melting
point determination 71
4.1.4 Solubility
data 71
4.1.5 Color 71
4.2 Spectrophotometric
Measurement 72
4.2.1 Infra
– red spectra 72
4.2.2 Nuclear
magnetic resonance (NMR) spectra 86
4.2.2.1 The
proton (1H) NMR 86
4.2.2.2 Carbon
– 13 (13C) NMR 96
4.3 Proposed Structures of the Ligands and
their Metal Complexes 107
4.4 Data on the Solvent Extraction
Processes. 114
4.4.1 Solvent extraction equilibrium 114
4.4.2 Dependence of solvent extraction on the
concentrations of the ligands 114
4.4.3 Dependence of solvent extraction on the
pH of the aqueous solutions
of the metal ions. 122
4.4.4 Separation factor (Sf). 131
4.5. Kinetics or Rate of Recovery of the
Metals 134
4.6 Mechanism of the Solvent Extraction
Reaction 149
4.7 Results of Antimicrobial Activity of
HMPPp, HMPPn Ligands and their 151
Complexes
4.7.1 Zone diameter of inhibition (ZDI) of the
ligands and their metal complexes. 151
CHAPTER 5: CONCLUSION AND
RECOMMENDATIONS 158
5.1 Conclusion 158
5.2 Recommendation 161
REFERENCES 161
APPENDICES
LIST
OF TABLES
2.1: Pyrazolone derivatives with antitumor properties 38
2.2: Cytotoxicity (IC50) of three
pyrazolone compounds against
four types of human tumor cells 40
3.1: List of materials and chemicals 59
4.1: Physical
and microanalytical data for the ligand and the metal
complexes 71
4.2: Solubility data of the ligands and their
metal complexes in various
solvents 74
4.3: Selected IR bands of
the Ligand 73
4.4: Selected IR band for
the Fe(HMPPp)3.2H2O complex 74
4.5: Selected IR band for
the Mn(HMPPp)2.2H2O complex 75
4.6: Selected IR band for
the Ti(HMPPp)3.2H2O] complex 76
4.7: Summary of the IR peaks; a comparism of the
ligand and
the complexes 77
4.8: Selected IR band for
the HMPPn Ligand 80
4.9: Selected IR bands of
the Fe(MPPn)3.2H2O 81
4.10: Selected IR band for
the [Mn(HMPPO).H2O] complex 82
4.11: Selected IR band for
the [Ti(HMPPn)3.2H2O] complex 83
4.12: Summary of the IR peaks; a comparism of the
ligand and
the complexes 84
4.13: Important Chemical Shifts for 1H
NMR Spectrum of
HMPPp (ligand) 87
4.14: Important Chemical Shifts (δ) for 1H
NMR Spectrum of
HMPPn (ligand) 88
4.15: Important Chemical Shifts for 1H
NMR Spectrum of
Fe(MPPp)3.2H2O 89
4.16 Important Chemical Shifts for 1H
NMR Spectrum of
Mn(MPPp)2.2H2O 90
4.17 Important Chemical Shifts for 1H
NMR Spectrum of
Ti(MPPp)3.2H2O 91
4.18 Important Chemical Shifts for 1H
NMR Spectrum of
Fe(MPPn)3.2H2O 92
4.19 Important Chemical Shifts for 1H
NMR Spectrum of
Ti(MPPn)3.2H2O 93
4.20 Important Chemical Shifts for 1H
NMR Spectrum of
Mn(MPPn)2.2H2O 94
4.21: 1H NMR Spectral Data showing the
chemical shifts of the
free ligands and the metal complexes
in DMSO solvent, at a
frequency of 600 MHz 95
4.22 Important Chemical Shifts (δ) for 13C
NMR Spectrum of 97
HMPPp (Ligand)
4.23 Important Chemical Shifts (δ) for 13C
NMR Spectrum of
HMPPn (Ligand) 98
4.24 Important Chemical Shifts (δ) for 13C
NMR Spectrum of
Fe(MPPn)3.2H2O 99
4.25 Important Chemical Shifts (δ) for 13C
NMR Spectrum of
Mn(MPPn)2.2H2O 100
4.26 Important Chemical Shifts (δ) for 13C
NMR Spectrum of
Ti(MPPp)3.2H2O 101
4.27 Important Chemical Shifts (δ) for 13C
NMR Spectrum of
Fe(MPPn)3.2H2O 102
4.28 Important Chemical Shifts (δ) for 13C
NMR Spectrum of
Mn(MPPn)2.2H2O 103
4.29 Important Chemical Shifts (δ) for 13C
NMR Spectrum of
Ti(MPPn)3.2H2O 104
4.22: 13C NMR Spectral Data for the free
ligands and the metal
complexes in DMSO solvent at a
frequency of 600 MHz 105
4.31a: Data on the solvent extraction of the metal
ions from their
aqueous solutions, at various
concentrations of HMPPp ligand
at pH 4, initial metal ion
concentration of 0.5g/l for
Mn(MPPp)2.2H2O 113
4.31
(b): Data on the solvent extraction of the
metal ions from their a
queous solutions, at various
concentrations of HMPPp ligand
at pH 4, initial metal ion
concentration of 0.5g/l for
Fe(MPPp)3.2H2O 114
4.31
(c): Data on the solvent extraction of the
metal ions from their a
queous solutions, at various
concentrations of HMPPp ligand
at pH 4, initial metal ion
concentration of 0.5g/l for
Ti(MPPp)3.2H2O 115
4.32
(a): Data on the solvent extraction of the
metal ions from their a
queous solutions, at various
concentrations of HMPPp ligand
at pH 4, initial metal ion
concentration of 0.5g/l for
Mn(MPPn)2.2H2O 116
4.32
(b): Data on the solvent extraction of the
metal ions from their a
queous solutions, at various
concentrations of HMPPp ligand
at pH 4, initial metal ion
concentration of 0.5g/l for
Fe(MPPn)3.2H2O 117
4.32
(c): Data on the solvent extraction of the
metal ions from their a
queous solutions, at various
concentrations of HMPPp ligand
at pH 4, initial metal ion
concentration of 0.5g/l for
Ti(MPPn)3.2H2O 118
4.33
(a): Data on the solvent extraction of the metal ions at different pH
values of their aqueous
solutions using 0.2 M HMPPp ligand, initial
metal
ion concentration of 0.5g/l for Mn(MPPp)2.2H2O 123
4.33
(b): Data on the solvent
extraction of the metal ions at different pH
values of
their aqueous solutions using 0.2 M HMPPp ligand, initial
metal
ion concentration of 0.5g/l for Fe(MPPp)3.2H2O 124
4.33
(c): Data
on the solvent extraction of the metal ions at different pH
values
of their aqueous solutions using 0.2 M HMPPp ligand, initial
metal
ion concentration of 0.5g/l for Ti(MPPp)3.2H2O 125
4.34
(a): Data on the solvent extraction of
the metal ions at different pH
values
of their aqueous solutions using 0.2 M HMPPn ligand, initial
metal
ion concentration of 0.5g/l for Mn(MPPp)2.2H2O 126
4.34
(b): Data on the solvent
extraction of the metal ions at different pH
values
of their aqueous solutions using 0.2 M HMPPn ligand, initial
metal
ion concentration of 0.5g/l for Fe(MPPp)3.2H2O 127
4.34
(c): Data on the solvent extraction of
the metal ions at different pH
values
of their aqueous solutions using 0.2 M HMPPn ligand, initial
metal
ion concentration of 0.5g/l for Ti(MPPp)3.2H2O 128
4.35: Separation Factor (Sf)
amongst Mn2+, Fe3+, and Ti3+, ions with the
HMPPp
and HMPPn ligands at the various concentrations of the
ligands
at constant pH 4 133
4.36: Data on the extent of
extraction of the metal ions for one hour at
intervals
of 10 minutes using HMPPp ligand, at an initial concentration
ofMn+
= 0.50 g/l. 136
4.37: Data
on the extent of extraction of the metal ions for one hour at
intervals
of 10 minutes using HMPPn ligand, at an initial concentration
ofMn+
= 0.50 g/l. 136
4.38: Rate of extraction of the metal
ions at different concentrations of the
HMPPpligand
at pH 4 for 30 minutes, at an initial concentration of
Mn+
= 0.50 g/l; obtained from Tables 4.31 (a – c) . 140
4.39: Rate
of extraction of the metal ions at different concentrations of the
HMPPn
ligand at pH 4 for 30 minutes, at an initial concentration of
Mn+
= 0.50 g/l; obtained from Tables 4.32 (a - c) 141
Table
4.40: Rate of solvent extraction
of the metal ions (Mn, Fe and Ti) at
different
pH of the aqueous solutions of the metal ions at 0.2 M of
HMPPp
ligand for 30 minutes, at an initial concentration of
Mn+
= 0.50 g/l; from Table 4.33 (a-c). 144
Table
4.41: Rate of solvent extraction
of the metal ions at different pH of the
aqueous
solutions of the metal ions at 0.2 M of HMPPn ligand for
30
minutes, at an initial concentration of Mn+ = 0.50 g/l; from
Table
4.34 (a - c). 145
Table
4.42: Antibacteria activity HMPPp
ligand and their metal complexes a
gainstgrampositive
bacteria
Table
4.43: Antibacteria activity of
synthesized pyrazolone ligand and their
metalcomplexes
against gram negative bacteria
Table
4.44: Antifungal activity of
synthesized pyrazolone ligand and their metal
complexes against
selected fungals
Table 4.45: The minimum inhibitory concentrations
(MIC) of the ligands and their
metal complexes
against some selected gram positive and gram
negativebacteria
Table
4.46: The minimum inhibitory
concentrations (MIC) of the ligands and their
metal complexes
against some selected fungals
LIST OF FIGURE
1.1: Structure of Pyrazol ‘a’ and Pyrazol-5-one
‘b’ 2
2.1:
Structures of pyrazole and
pyrazol-5-one 8
2.2
Crystal field splitting 21
2.3
Selected pyrazolone with
pharmaceutical properties ‘a’ 23
2.4
Selected pyrazolone with
pharmaceutical propperties ‘b’ 24
2.5
Pyrazolonededrivatives by Ismalet al., 2018 34
2.6
Pyrazolonededrivatives by Ismal et al
2018 35
2.7: Prazolone
derivatives with antitumor properties 39
2.8: Cyclic azole substituted diphenyl 40
2.9: Anilino – 3 - (4 – hydroxyl – 3 –
methylphenyl) – 5 –
(2,
6- dichloro phenyl)-4, 5-dihydro- 1H- 1-pyrazolyl methanethione 41
2.10: 1,
3, 5-trisubstituted pyrazolines bearing benzofuran 42
2.11: 1-acetyl-3,5-
diphenyl-4,5-dihydro-(1H)-pyrazole derivative 42
2.12:
1, 3, 4-Oxadiazole and pyrazoline
containing 1, 8-Naphthyridine 43
2.13:
3,5-diaryl-1-phenyl/
isonicotinoyl-2-pyrazolines 43
2.14:
Substituted 1, 2- Pyrazolines derived
from nalidixic acid 44
2.15: New 3-(5- aryl-
4,5-dihydro-1H-pyrazol-3-yl)-4-hydroxy-2
Hchromene-2-one 44
2.16: 1-(4-Aryl-2-
thiazolyl)-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives 45
2.17: 3-(benzofuran-2-yl)-4,5-dihydro-5-aryl-1-[4-
(aryl)-1,3-thiazol-2-yl]
-1H-pyrazoles 45
2.18: 3-(4-Biphenyl)- 5-substituted
phenyl-2-pyrazolines and 1-Benzoyl-3-
(4-biphenyl)-5-substituted
phenyl-2- pyrazolin 46
2.19: Bis (3 – aryl – 4, 5 – dihydro – 1H – pyrazole
– 1 – carboxamides)
and
their thio – analogues 47
2.20: 1-[(4,5-dihydro5-phenyl-3-(phenyl amino)
pyrazol-1yl)] ethanone
Derivative 49
2.21:
3-(3-Acetoamino) phenyl-1, 5-substituted
phenyl-2-pyrazolines 49
2.22: methyl 4-chloro-1-(2,5-difluorophenyl)-5-
(4-flurophenyl)- 50
pyrazole-3-carboxylate
2.23:
Pyrazole-Pyrazolone Derivatives 54
2.24: Structures
of (a) pyrazolones compounds 1 – 3 and (b) new compounds
containingpyrazolones
(IIIa-c, IV a-c and Va-c) 56
4.1: IR spectrum of 1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)
pentan-1-one
(HMPPp). 73
4.2:
IR spectrum of Fe(MPPp)3.2H2O 74
4.3:
IR spectrum of Mn(MPPp)2.2H2O 75
4.4:
IR spectrum of Ti(MPPp)3.2H2O 76
4.5: IR spectrum of 1-(5-hydroxy-3-methyl-1-phenyl-1H-
pyrazol-4-yl) nonadecan-1-one,
(HMPPn) 80
4.6:
IR spectrum of Fe(MPPn)3.2H2O 81
4.7:
IR spectrum of Mn(MPPn)2.2H2O 82
4.8:
IR spectrum of Ti(MPPn)3.2H2O. 83
4.9: 1H NMR Spectrum of HMPPp
(ligand). 87
4.10:
1H NMR Spectrum of HMPPn
(ligand 88
4.11:
1H NMR Spectrum of Fe(MPPp)3.2H2O 89
4.12:
1H NMR Spectrum of Mn(MPPp)2.2H2O 90
4.13:
1H NMR Spectrum of Ti(MPPp)3.2H2O 91
4.14:
1H NMR Spectrum of Fe(MPPn)3.2H2O 92
4.15:
1H NMR Spectrum of Ti(MPPn)3.2H2O 93
4.16:
1H NMR Spectrum of Mn(MPPn)2.2H2O 94
4.17:
13C NMR Spectrum of HMPPp
(Ligand). 97
4.18:
13C NMR Spectrum of HMPPn
(Ligand) 98
4.19:
13C NMR Spectrum of Fe(MPPp)3.2H2O 99
4.20:
13C NMR Spectrum of Mn(MPPn)2.2H2O 100
4.21:
13C NMR Spectrum of Ti(MPPp)3.2H2O 101
4.22:
13C NMR Spectrum of Fe(MPPn)3.2H2O 102
4.23:
13C NMR Spectrum of Mn(MPPn)2.2H2O 103
4.24:
13C NMR Spectrum of Ti(MPPn)3.2H2O 104
4.25 Proposed structure of 1-(5-hydroxy-3-methyl-1-phenyl-
1H-pyrazol-4-yl) pentan-1-one (HMPPp) ligand 107
4.26 Proposed structure of 1-(5-hydroxy-3-methyl-1-phenyl
-1H-pyrazol-4-yl) nonadecan-1-one (HMPPn) Ligands 107
4.27 Proposed structure of the Fe(III) complexe of
1-(5-hydroxy-3
-methyl-1-phenyl-1H-pyrazol-4-yl) pentan-1-one
(HMPPp) 108
4.28 Proposed structure of the Mn(II) complexe of 1-(5-hydroxy-3
-methyl-1-phenyl-1H-pyrazol-4-yl) pentan-1-one
(HMPPp) 108
4.29 Proposed structure of the Ti(III) complexe of
1-(5-hydroxy-3-
methyl-1-phenyl-1H-pyrazol-4-yl) pentan-1-one
(HMPPp) 109
4.30 Proposed structure of the Fe(III) complexe of
1-(5-hydroxy-3-
methyl-1-phenyl-1H-pyrazol-4-yl) nonadecan-1-one
(HMPPn) 109
4.31 Proposed structure of the Mn(II) complexe of 1-(5-hydroxy-3-
methyl-1-phenyl-1H-pyrazol-4-yl) nonadecan-1-one
(HMPPn) 110
4.32 Proposed structure of the Ti(III) complexe of
1-(5-hydroxy-3-
methyl-1-phenyl-1H-pyrazol-4-yl) nonadecan-1-one
(HMPPn) 110
4.33: Plot of log of distribution ratio, D of the
metallic ions versus log
[HMPPp]
atpH 4 119
4.34: Plot of log of distribution ratio, D of the
metallic ions versus
log[HMPPn]
at pH 4. 120
4.35: Plots of log of distribution ratio, D of the
Mn(II), Fe(III) and
Ti(III)
ions versus pH at 0.2 M of HMPPp concentrations 129
4.36: Plots of log of distribution ratio, D of the
Mn(II), Fe(III) and
Ti(III) ions versus pH at 0.2 M of HMPPn
concentrations 130
4.37: Plot of data on the extent of extraction of the
metal ions for one
houratintervals of 10
minutes using the HMPPp ligand, at an
initial concentration of Mn+
= 0.50 g/l 137
4.38: Plot of data on the extent of extraction of the
metal ions for one
houratintervals of 10
minutes using the HMPPn ligand, at an
initial concentration of Mn+
= 0.50 g/l 138
4.39: Plot of data on the rate of solvent extraction
of the metal ions at
differentHMPPpligand
concentrations, at an initial concentration
of
Mn+ = 0.50 mg 142
4.40: Plot of data on the rate of solvent extraction
of the metal ions at
differentHMPPnligand
concentrations, at an initial concentration
of
Mn+ = 0.50 mg. 143
4.41: Plots of data on the rate of solvent extraction
of Mn2+, Fe3+ andTi3+
ions at different pH values
and 0.2 M HMPPp ligand concentration,
at
an initialconcentration of Mn+ = 0.50 mg. 146
4.42: Plots of data on the rate of solvent extraction
of Mn2+, Fe3+ and
Ti3+ions at
different pH values and0.2 M HMPPn ligand
concentration, at an
Initialconcentration of Mn+ = 0.50 mg. 147
SCHEMES
2.1 Synthesis of Pyrazole from dicarbonyl
compounds 9
2.2:
Synthesis of Pyrazole from acrylic aldehyde 9
2.3: Synthesis of Pyrazole from ethyl
ethoxymethleno acetate 10
2.4:
Synthesis of Pyrazole from α, β –
ethylene carbonyl compounds 10
2.5:
Synthesis of Pyrazole from 1.3 –
dipolar addition 10
2.6:
Synthesis of dihydropyrazole 11
2.7:
Synthesis of 5 – aminopyrazole 11
2.8:
Synthesis of unsubstitutedpyrazolones 11
2.9;
solvent free synthesis of pyrazolone 12
2.10 Synthesis of Bmpp-Ph 28
2.11: Synthesis
of 4-acyl-5-methyl-2-phenyl-pyrazol-3-one-phenylhydrazones 57
2.12: Synthesis
of 4-acyl-3-methyl-1-phenyl-2-pyrazolin-5-one-sulfanilamide. 58
3.1: Synthesis of HMPPp 63
3.2: Synthesis of HMPPn 63
USED ABBREVIATIONS
13C
NMR Carbon-13 Nuclear magnetic
resonance
1HNMR Proton Nuclear magnetic resonance
Ampp-Dh
: acetyldinitrophenylhydrazone,
Ampp-Ph
: 4-Acetyl-3-methyl-1-phenyl-2-pyrazoline-5-one
phenylhydrazone.
Bmpp-Dh
: benzoyldinitrophenylhydrazone
Bmpp-Ph
: benzoylphenylhydrazone
CAI : cholesterol
absorption and inhibiting
CFT: Crystal Field Theory
CN: Coordination
Number
CNS Central Nervous System
CT-DNA Cirdulating
tumor DNA
DMSO
: Dimethylsulphoxide
DNA Deoxyribonucleic
acid
DPPH
: 1,1-diphenyl-2-picryl-hydrazil
EAN: Effective Atomic
Number
EDTA
Ethylenediaminetetraacetic
acid
FTIR Fourier – transform infrared
spectroscopy
GABA Gamma
aminobutyric acid
H37Rv
M. tuberculosis strain
HAPPy
: 4-butanoyl-3-methyl-1-phenylpyrazol-5-one
HBUP
: 1-phenyl-3-methyl-4-butyryl-pyrazolone-5
HCT116 Colorectal
Carcinima cell line
HDDPA: 1-hydroxydodecylidene-1,1-diphosphonic
acid
HepG2
liver heptacellular cells,
HepG2 Hepatoma
G2 cell line
HHDPA
: 1-hydroxyhexadecylidene-1,1-diphosphonic
acid
HMPPn : 1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)
nonadecan-1-one )
HMPPp : 1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)
pentan-1-one)
HPMAD,
4-acetyl-1-phenyl-3-methyl-pyrazol-5-ones
HPMBP 4-benzoyl-1-phenyl-3-methyl-pyrazol-5-ones
HPMBUP 4-butyryl-1-phenyl-3-methyl-pyrazol-5-ones
HPMCP 4-capyrol-1-phenyl-3-methyl-pyrazol-5-ones
HPMNP
: 1-phenyl-3-methyl-4-(p-nitrobenzoyl)pyrazolone
HPMPP)
4-propionyl-1-phenyl-3-methyl-pyrazol-5-ones
HPP 4-Pamitoyl-1-phenyl-3-methylpyrazolone
HTTA
chelating agents
in vitro latins word for “within the
glass”
in vivo Latin word for “within the
living”
IR Infrared
IUPAC International
Union of Pure and Applied Chemistry
KBv200
Cell xenografts
LCAO
: linear Combination of Atomic
Orbitals
MCF-7 Breast
carcinoma cell line
MCF-7 Michigan
Cancer Foundation -7.
MDR
KBv200KB Multidrug resistance cell
line
MIBK
: Methyl isobutylketone
MIC
: Minimum Inhibitory
Concentration
NSAID Nonsteroidal
anti-inflammatory drugs
OVCAR3
Ovarian carcinoma cell line),
PGE2
Postaglandin E2
pH Potential of hydrogen
PTZ Pentylenetetrazole ( induced seizures)
SEM Scanning
Electron Microscopy
TBP
Tributylphosphate
TGA
: Thermogravimetric
analysis
THF
Tetrahydrofuran
THF
: Tetrahydrofuran ,
TOPO Chelating agent
UV Ultraviolet
XRD X
– Ray Diffraction
CHAPTER
1
INTRODUCTION
1.1
BACKGROUND
OF THE STUDY
Coordination Chemistry refers to the
chemistry of compounds or complexes formed by Lewis acids (usually metals)
bonded to Lewis bases (usually inorganic ions or molecules, or organic
molecules, or their ions) through the donation of lone pair electrons, (Geoffrey,
2010). These coordination compounds or complexes are ionic or neutral in
nature, containing central metal ions/atoms closely surrounded by electron
donor groups called ligands or coordinating agents (Geoffrey, 2010). In this
regards, the coordinating agents (or complexing agents) must have at least an
available free electron pair on a single or more donor atoms, while the orbital
system of the central metal atom (M), must be of the right energy and capable
of accepting the pair of electron from the ligand to form coordinate covalent
bond between itself and the ligand (L). A complex metal ion of the type, [M(H2O)6]n+,
is an example of a coordination compound
because M is bonded to water molecules by coordinate covalent bond. The ligand
(H2O) provides the electron pairs that are shared between it and the
central metal atom (M). The term, complex, is
used not only for the common ions such as [Co(H2O)6]3+,
[Ag (NH3)2]+, [Cd (CN)4]2-,
[PbI4]2- and uncharged species like Pt(NH3)2Cl2,
but also for other types of coordination compounds and species such as the
ions, BF4-, PO43-, ClO4-,
etc. Each metal atom (or ion) has a characteristic maximum number of coordinate
bonds it can form directly with the donor atoms under normal conditions. This
number is called the Coordination Number (CN). Coordination number therefore,
is the maximum number of donor atoms that coordinate or bond directly to the
central metal ion (Mn+) at any point in time. Coordination numbers
of 2, 4, 5, 6 and 8 are the most common and useful.
Coordination compounds have been seen to play
crucial role in medical cum biological processes. According to Wagnet and Nadia
(2017), many organic compounds used in medicine do not have a purely organic mode
of action, some are trigered or biologically-activated by metal ion metabolism.
Inorganic compounds of pyrazolone and its derivatives have so far been proven
to be highly active against microbial activities.(Wagnat
& Nadia, 2017)
Pyrazolone (C3H4N2O)
is a five-membered ring lactam derivative of pyrazole (C3H4N2)
that has a keto (C=O) group.
Fig
1.1: Structure of Pyrazol ‘a’ and Pyrazol-5-one ‘b’
|
That
is, when any of the 3, 4, 5 positions of carbon in pyrazole has double bonded
oxygen atom attached, pyrazolone is obtained, hence, pyrazol-3-one,
pyrazol-4-one and pyrazol-5-one respectively.
Pyrazolones
are versatile reagents and can become potent drugs in pharmaceutical practice. They
have strong anti-fungal, antihistamic and analgesic properties (Wagnat &
Nadia, 2017). They are also applied in hydrometallurgy and water treatment (Ehirim,
2018).Substituted pyrazolones, such as substituted 2-pyrazolin-5–ones, have
been shown to play essential roles as substructures in a wide range of
medicines, agrochemicals, dyes, pigments, and chelating agents. According to Ekekweet al., (2012), a number of substituted
pyrazolones have been used as reagents in inorganic analysis. Uzoukwu (1995),
in Ehirim (2019), asserts that antipyrine (1–phenyl–2,3–dimethyl–pyrazolone-5),
4–isopropyl-antipyrine and 1–phenyl–3–methyl–pyrazolone–5 (acylpyrazolone) have
been widely mentioned in literature for the detection and determination of
various cations.
Many
reactions involved in processing minerals in aqueous solution lead to metal
complex formation. In most of these processes, complex formation has been found
to improve reaction kinetics and metal recovery (Halil et al., 2015). Formation of coordination complexes in
hydrometallurgical processes has been very common among other processes, such
as leaching, solvent extraction, ion exchange, flotation and electroplating (Baba
and Adekola, 2011). It has been suggested that in electroplating, electrolyte
baths having complex ions in solution provide the most effective and efficient
plating characteristics and good quality deposits of uniform thickness. In some
operations, such as solvent extraction and ion exchange, complex formation is
just a pre-requisite (Wail, 2013).
In
this regard, acylpyrazolone ligands have been used as metal extractors or
chelating reagents in the spectroscopic determination of metals in traces
(Al-Zoubi et al., 2016); and numerous
studies on its syntheses, characterization, metal complexation, and various
applications have appeared in the literature. Due to a number of valuable
properties of these complexes, such as high extracting ability, intense color
of the complex extracts, and low solubility of the complexes in some solvents,
these reactions are widely used in analytical chemistry for the determination
and isolation of almost all metal ions. Furthermore, formation of complexes with
acylpyrazolones is applied in the separation of elements with simillar
properties, i.e. lanthanides, coinage metals, actinides, early transition
metals, etc, (Teng et al., 2012). A
study by Ehirim et al., 2014 revealed
that 4-acylpyrazol-5-ones, as modified β-diketones, are able to extract metal
ions at lower pH values than open-chain β–diketones. They therefore offer the
possibility of avoiding the pH region where hydrolysis of the metal ions takes
place (Chang et al., 2011). Uzoukwu and
Adiukwu studied the extraction of chromium (VI) metal ion from aqueous
solutions of 1-phenyl-3-methyl-4-butyrylpyrazolone-5 (HBuP), theirstudies
revealed that a solution of HBuP in chloroform-butanol is a more efficient
organic extractant than solutions of the ligand in methyl isobutylketone (MIBK)
or chloroform.
According to Wagnat
& Nadia, (2017), acylpyrazolone
have been described as prominent analytical reagents and potent drugs or
pharmaceutical agents; having strong anti-fungal, antihistamic and analgesic
properties. AlsoBurham et al., (2019) accounts that
acylpyrazolone can be applied as both NMR shift reagents and FESER materials, they
are also applied in hydrometallurgy, water treatment,and used in metal extraction and construction of
ion-exchange resins for metal ions,
Akinremi (2012), opined that the presence of a
metal increases the biological activitits of many drugsand ligands. So far,
acylpyrazolones has shown to axhibit or possess many chemical properties. To
this end, it has become important to generate an acypyrazolone based compounds
and its corresponding metal complex to study its biological activities and
solvent extraction.
1.2 STATEMENT OF THE
PROBLEM
Although pyrazolones have received remarkable
attention in the area of pharmacautical chemistry (Vasilii, 2021). Research has shown that many pyrazoline
derivatives were previously associated with side effects such as
agranulocytosis, bodyrashes and blood dyskaryosis (Mojzych, 2021). As a result progress was haultedfor sometime. But
due to the importance of pyrazolones, newer and novel pyrazolone derivative
with less tocity are on high demand.
Alsoan environmental problem such as heavy
metal contaminations has become a pertinent issue that needs attention. Due to
their toxicity to soil, plants aquatic life and human health at high
concentration metal axtraction has becom the center of attraction to
researchers.
Hence the need to synthesize newer and novel
pyrazolone derivative with less tocity is required.
1.3 AIM AND OBJECTIVES OF
THE STUDY
The aim of this work
is to investigate the synthesis, characterization, antimicrobial and
solvent extraction activities, of two novel pyrazolone ligands;1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) pentan-1-one (HMPPp)
and 1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) nonadecan-1-one (HMPPn) ligands and their Mn(II),
Fe(III) and Ti(III) metal complexes.
The aim was achieved
through the following specific objectives
1.
Synthesis of two novel pyrazolone ligands; (1-(5-
hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) pentan-1-one (HMPPp) and
1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl) nonadecan-1-one (HMPPn) ligands
2.
Synthesis of Mn(II), Fe(III) and
Ti(III) metal complexes of the pyrazolones
3.
Investigation of the metal- ligand mode of interaction and bonding, and
the type of complexes formed, using elemental or microanalysis, UV-visible, IR,
and NMR.
4.
Investigation of the solvent
extraction strength of the ligands under very low concentrations of metal ions
5.
Prediction of possible mechanism of
the solvent extraction of the ligands
6.
Investigation of antimicrobial activity of the synthesized ligand as
well as their metal complexes against various Gram-positive, Gram-negative bacteria
and Fungi.
1.4 JUSTIFICATION
OF THE STUDY
Pyrazolone, has become the center of
attraction as they exhibit cholesterol absorption and inhibiting (CAI)
activity.They also possess antiviral, antibacteria properties and have been
described as prominent analytical reagents and potent drugs or pharmaceutical
agents; having strong anti-fungal, antihistamic and analgesic properties
(Hassan et al., 2015). They are used
as NMR shift reagents and FESER materials, applied in hydrometallurgy, water
treatment (Burham et al., 2019), used
in metal extraction and construction of ion-exchange resins for metal ions,
etc.
However,
these and many other works gave only selected data on the antibacteria
activities, the structure, coordination numbers of the metal complexes, the
formation constants and solvent extraction strength under very low
concentrations of metal ions, and without any indication on the mechanisms of
the solvent extraction process of these pyrazolones.
1.5 SCOPE
OF THE STUDY
This work is limited
to the synthesis of the two pyrazolone ligands and theirMn(II), Fe(III) and
Ti(III) metal complexes. The full characterization of each of the synthesized
ligands and their metal complexes, propose structures for the complexes, solvent
extraction activities and determination of their anti-microbial activity has
been studied.
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