ABSTRACT
The oxidation of hydrazine, hydrazinium ion,1,2-diphenylhydrazine, L-tyrosine, D-ascorbic acid and D-fructose, by molecular iodine was studied using semi-empirical and density functional theory (DFT) methods, respectively. The computational method used for calculating geometries in this work is termed a ―cascade method‖ because of its use of molecular mechanics to remove strain energies followed by semi-empirical methods as precursors for more accurate DFT methods.The semi-empirical studies were carried out at either themodified neglect of diatomic overlap(MNDO) or parameterization method 3 (PM3) levels while all the DFT studies were carried out using 6-311+G** basis set of the density functional theory (DFT) method at the Becke 3 term, Lee Yang, Par (B3LYP) level of computation. For each system studied, molecular information such as net charges, values of frontier orbital energies, composition, proportions and bonding contribution were determined and analysed. Thus, through these means, possible reactive sites of molecules or reacting species were searched and obtained. Postulated transition states, intermediates and products were also searched and computed using the PM3 and DFT methods. Based on the results of the computation for the different systems studied, different possible reaction mechanisms for the various systems were proposed. For the 1,2-diphenylhydrazine – iodine reaction system, two possible reaction mechanisms were proposed, for the L-tyrosine – iodine reaction system, previously published reaction mechanism was modified based on the most favourable energetics of the transition states, for the L-ascorbic acid– iodine reaction system, two possible reaction mechanisms were proposed, for the D-fructose – iodine reaction system, one reaction mechanism was proposed, while for the hydrazine / hydrazinium ion– iodine reaction system, four reaction mechanisms were proposed. For each system investigated, out of the various plausible mechanisms postulated, comparisons of the enthalpies of reactions of the various pathways as well as the activation barriers of the respective rate determining steps were made. The computed enthalpies of the oxidation reactions
viii
were carried out at standard conditions of 298.15K and 1 atmosphere for the PM3 and DFT calculations. For each system, the pathway with the least activation barriers and enthalpy of reactions were chosen as the most probable mechanism of reaction for the system. Other thermodynamic parameters such as ΔGo andΔSo for reacting species, especially transition states and intermediates which were used to support the validity of the postulated mechanisms were also computed. The activation parameters for the most energetically favourable pathway for the respective reaction systems were calculated and given. The data obtained for the limiting step of the 1,2-diphenylhydrazine – iodine reaction system are: Δ‡G = -7.11 x103 kJ/mol, Δ‡S = 2.71 x101 kJ/mol andEa = 44.40kJ/mol. For theL-tyrosine – iodine reaction system, Δ‡G = -1.10 x105kJ/mol,Δ‡S = 1.28 x105 kJ/mol and Ea = 3.52 x103kJ/mol.For the limiting step for the D-ascorbic acid – iodine reaction system, Δ‡G = -2.93x104kJ/mol, Δ‡S = 1.28 x105kJ/mol and Ea = 3.14 x103kJ/mol.For the limiting step for the D- fructose – iodine reaction system, Δ‡G = -6.78 x104kJ/mol, Δ‡S = 6.74 x104kJ/mol and Ea = 3.82 x103kJ/mol. While for the hydrazine / hydrazinium ion – iodine reaction system, activation parameters for the limiting step of the most energetically favourable pathway were determined as, Δ‡G = -8.01 x104 kJ/mol, Δ‡S = -1.24 x106 kJ/mol and Ea = 6.86 x103kJ/mol.
TABLE OF CONTENTS
Cover page
i
Title page
ii
Declaration
iii
Certification
iv
Dedication
v
Acknowledgements
vi
Abstract
vii
Table of Contents
ix
List of Tables
xvii
List of Figures
xix
List of Schemes
xxii
Appendices
xxiii
List of Abbreviations
xxiv
CHAPTER ONE
1
1.0
INTRODUCTION
1
1.1
Iodine
1
1.2
Hydrazine and Its Derivatives
3
1.3
L-Tyrosine
5
1.4
L-Ascorbic Acid
6
1.5
Reducing Sugars
8
1.6
Statement of the Research Problem
10
1.7
Justification of the Research
11
1.8
The Research Questions
13
x
1.9
The Research Hypotheses
14
1.10
Conceptual Framework
14
1.11
Theoretical Framework
16
1.12
Aim and Objectives
17
CHAPTER TWO
18
2.0
LITERATURE REVIEW
18
2.1
Computational Approaches for Investigation of the Reaction Mechanisms
18
2.2
Computational Chemistry
24
2.3
Ab initio (Quantum Mechanics)
25
2.3.1
The Born-Oppenheimer approximation
28
2.3.2
Potential energy surface
29
2.3.2.1
Hessian index
31
2.3.3
Geometry optimization
31
2.3.4
Hartree-Fock self-consistent field method
32
2.3.5
Post-Hartree-Fock methods
32
2.4
Semi-Empirical Calculations
34
2.4.1
Modified neglect of diatomic overlap
35
2.4.2
Austin model 1
35
2.4.3
Parameterization method 3
36
2.4.4
Partial retention of diatomic differential overlap
37
2.4.5
Parameterization method 3 with extension for transition metals
38
2.5
Density Functional (Theory) Calculations
38
2.5.1
Basis sets
39
2.5.1.1
Basis set superposition error
44
xi
2.5.1.2
Temperature
45
2.5.1.3
Performance
45
2.6
Molecular Mechanics
46
2.6.1
Force field parameterization
48
2.6.2
Atomic charges
49
2.6.3
Polarizable force fields
51
2.7
Simulations
52
2.7.1
Free energy perturbations
55
2.8
Molecular dynamics calculations
57
2.9
Computational Chemistry and Experiment
57
CHAPTER THREE
58
3.0
MATERIALS AND METHODS
58
3.1
Materials
58
3.2
Methodology
59
3.3
Details of the Computation Procedures
60
3.3.1
Geometry optimization of reactants, activated complexes, intermediates and products using semi-empirical methods
61
3.3.1.1
Geometry optimization of reactants, activated complexes, intermediates and products using dft methods
62
3.3.2
Calculation of HOMO and LUMO of optimized molecules
63
3.3.3
Determination of chemical reactivity of optimized molecules: mapping of HOMO and LUMO densities of optimized molecules
63
3.3.4
Calculation of thermodynamics, molecular and other physicochemical properties of reacting species and products
64
3.3.5
Construction of potential energy surface diagrams
64
3.3.6
Enthalpy of reaction and rate constant calculations
65
3.4
Post Computation Processing
67
xii
CHAPTER FOUR
68
4.0
RESULTS
68
4.1
Structure Optimization of Reactants, Transition States, Intermediates and Products
68
4.1.1
Optimized geometries of 1,2-diphenylhydrazine – iodine reaction system
68
4.1.2
Optimized geometries of l-tyrosine – iodine reaction system
70
4.1.3
Optimized geometries of l-ascorbic acid – iodine reaction system
71
4.1.4
Optimized geometries of d-fructose – iodine reaction system
72
4.1.5
Optimized geometries of hydrazine/hydrazinium ion – iodine reaction system
73
4.1.6
Mapping and calculation of HOMO and LUMO of reactants
74
4.3
Searches for Transition States and Intermediates
80
4.3.1
Transition states and intermediates for 1,2-diphenylhydrazine – iodine reaction system
80
4.3.2
Transition states and intermediates for L-tyrosine – iodine reaction system
81
4.3.3
Transition states and intermediates for L-ascorbic acid – iodine reaction system
82
4.3.4
Transition states and intermediates for D-fructose– iodine reaction system
83
4.3.5
Transition states and intermediates for hydrazine/hydrazinium ion – iodine reaction system
84
4.4
Calculation of Thermodynamics, Molecular and other Physicochemical Properties of Reacting Species and Products
85
4.4.1
Computation of heat of formation, total electronic energy and other thermodynamic parameters of reacting species and products for 1,2-diphenylhydrazine – iodine reaction system
85
4.4.1.1
Charge distribution and exposed surface study of 1,2-diphenylhydrazine
85
4.4.2
Computation of heat of formation, total electronic energy and other activation parameters of reacting species and products for L-tyrosine – iodine reaction system
85
4.4.2.1
Charge distribution and exposed surface study of L-tyrosine
86
4.4.3
Computation of heat of formation, total electronic energy and other activation parameters of reacting species and products for L-ascorbic – iodine reaction
xiii
system
86
4.4.3.1
Charge distribution and exposed surface study of L-ascorbic acid
87
4.4.4
Computation of heat of formation, total electronic energy and other activation parameters of reacting species and products for D-fructose – iodine reaction system
87
4.4.4.1
Charge Distribution and Exposed Surface Study of D-Fructose
88
4.4.5
Computation of heat of formation, total electronic energy and other thermodynamic parameters of reacting species and products for hydrazine / hydrazinium ion – iodine reaction system
88
4.4.5.1
Charge distribution and exposed surface study of hydrazine / hydrazinium ion
89
4.5
Construction of Potential Energy Surface Diagrams
89
4.5.1
Potential energy surface diagrams of reaction of 1,2-diphenylhydrazine – iodine reaction system according to the chain multi-step and cyclic mechanism
89
4.5.2
Potential energy surface diagrams of reactions of l-tyrosine – iodine reaction system according to the PM3 and DFT methods, respectively
125
4.5.3
Potential energy surface diagrams of reaction of L ascorbic acid -iodine reaction system according to the DFT and PM3 studies
125
4.5.4
Potential energy surface diagrams of reaction of D-fructose – iodinereaction system for the respective DFT and PM3 studies
125
4.5.5
Potential energy surface diagrams of reactions of hydrazine / hydrazinium ion – iodine reaction system according to the DFT methods for routes i-iv, respectively
126
4.6
Proposal of More Plausible Mechanisms for the Biomolecules – Iodine Reaction Systems
144
4.6.1
More plausible mechanisms for reaction of 1,2 diphenylhydrazine – iodine reaction system according to the chain multi step and cyclic mechanism
144
4.6.2
More plausible mechanisms for reactions of L-tyrosine – iodine reaction system
146
4.6.3
More plausible mechanisms for reaction of L-ascorbic acid – iodine reaction system
147
4.6.4
More plausible mechanisms for reaction of d-fructose – iodine reaction system
149
4.6.5
More plausible mechanisms for reactions of hydrazine / hydrazinium ion – iodine reaction system according to the dft methods for routes i – iv,
xiv
respectively
150
CHAPTER FIVE
154
5.0
DISCUSSION
154
5.1
Geometry Optimization of Reactants, Activated Complexes, Intermediates and Products
154
5.2
Mapped and Calculated HOMO and LUMO of Reactants
154
5.3
Searched Transition States and Intermediates
158
5.3.1
Transition states and intermediates for 1,2-diphenylhydrazine – iodine reaction system
159
5.3.2
Transition states and intermediates for L-Tyrosine – iodine reaction system
159
5.3.3
Transition states and intermediates for L-ascorbic acid – iodine reaction system
160
5.3.4
Transition states and intermediates for D-fructose– iodine reaction system
161
5.3.5
Transition states and intermediates for hydrazine/hydrazinium ion – iodine reaction system
161
5.4
Calculation of Thermodynamics, Molecular and other Physicochemical
Properties of Reacting Species and Products
162
5.4.1
1,2-diphenylhydrazine – iodine system
162
5.4.1.1
Charge distribution, bond length and exposed surface area of 1,2-diphenylhydrazine
163
5.4.2
L-tyrosine – iodine system
164
5.4.2.1
Charge distribution, bond length and exposed surface area of L-tyrosine
165
5.4.3
L-ascorbic acid – iodine system
166
5.4.3.1
Charge distribution, bond length and exposed surface area of L-ascorbic acid
166
5.4.4
D-fructose – iodine system
167
5.4.4.1
Charge distribution, bond length and exposed surface area of D-fructose
167
5.4.5
Hydrazine/hydrazinium ion – iodine system
168
5.4.5.1
Charge distribution, bond length and exposed surface area of hydrazine / hydrazinium ion
169
5.5
Construction of Potential Energy Surface Diagrams
170
xv
5.6
Proposal of More Plausible Mechanisms for the Biomolecules -Iodine Reaction Systems
172
5.6.1
1,2-diphenylhydrazine – iodine reaction system
175
5.6.2
L-tyrosine – iodine reaction system
177
5.6.3
L-ascorbic acid – iodine reaction system
179
5.6.3.1
Route I
180
5.6.3.2
Route II
180
5.6.3.3
DFT studies
181
5.6.3.4
Semi-empirical PM3 studies
181
5.6.4
D-fructose – iodine reaction system
182
5.6.4.1
Step 1
183
5.6.4.2
Step 2
183
5.6.4.3
Step 3
183
5.6.5
Hydrazine / hydrazinium ion – iodine reaction system
184
5.6.5.1
Route I
185
5.6.5.2
Route II
185
5.6.5.3
Route III
186
5.6.5.4
Route IV
186
5.7
Enthalpy of Reaction and Rate Constant Calculations for the Biomolecules – Iodine Reaction Systems
187
5.7.1
1,2-diphenylhydrazine – iodine reaction system
189
5.7.2
L-tyrosine – iodine reaction system
191
5.7.3
L-ascorbic acid – iodine reaction system
191
5.7.4
D-fructose – iodine reaction system
193
5.7.5
Hydrazine / hydrazinium ion – iodine reaction system
194
5.8
Rate Laws for the Proposed Mechanisms of Reactions
195
xvi
5.8.1
Rate laws for 1,2-diphenylhydrazine – iodine reaction system
195
5.8.1.1
The chain multi-step mechanism
195
5.8.1.2
The one-step cyclic activated complex mechanism
196
5.8.2
L-tyrosine – iodine reaction system
196
5.8.3
L-ascorbic acid – iodine reaction system
197
5.8.3.1
The one-step cyclic activated complex mechanism
197
5.8.3.2
The two-steps mechanism
198
5.8.4
D-fructose – iodine reaction system
198
5.8.5
Hydrazine / hydrazinium ion – iodine reaction system
200
5.8.5.1
Route I
200
5.8.5.2
Route II
201
5.8.5.3
Route III
202
5.8.5.4
Route IV
202
5.9
Comparison of Rate Constants
203
CHAPTER SIX
206
6.0
SUMMARY, CONCLUSION AND RECCOMMENDATION
206
6.1
Summary
206
6.2
Conclusion
207
6.2
Recommendation
208
REFERENCES
210
xvii
CHAPTER ONE
1.0 INTRODUCTION
1.1 Iodine
Iodine is an essential micronutrient for mammals including humans and appears to be the heaviest required element in a diet. Iodine compounds are useful in medicine and lack of it in the diet is a cause of goiter (Pearceet al., 2013;Olvera-Caltzontzin et al.,2013; Doggui and El Atia, 2015). Iodine is absolutely necessary for a healthy thyroid as well as ovaries, breasts and prostate (Arroyo-Helguera et al., 2006; Zimmermann,2013; Doggui and El Atia, 2015). Iodine deficiency, though easily treated, continues to be a problem for approximately a fifth of the world population.Goitre, or enlargement of the thyroid, has been recognized for many years assymptoms of iodine deficiency. These pathological conditions are normally grouped under the common name of Iodine Deficiency Disorders (IDD) (Hetzel et al.,1990; Koniget al., 2011; Doggui and El Atia, 2015). Iodine deficiency is the largest preventable cause of mental retardation worldwide (Cao et al.,1994; Pearceet al., 2013). In severe cases, it can result in cretinism, a form of mental retardation. Mshelia et al (2010) reported in their studies that volatization from oceans and precipitation of ocean water is the origin of most iodine content of diet (Miller and Heyland, 2013) and is considered critical to compensate for metabolic losses. Goitre surveys conducted so far are limited to clinical symptoms, urinary iodine output and, to some extent, plasma thyroid hormone levels (Doggui and El Atia, 2015; Aceves et al., 2013; Bizhanova and Kopp, 2009; Langer et al., 2003).
The thyroid gland needs iodine to make hormones. If the thyroid doesn‘t have enough iodine to do its job, feedback systems in the body cause the thyroid to work harder. This can cause an enlarged thyroid gland (goiter), which becomes evident as a swollen neck. Other
2
consequences of not having enough iodine (iodine deficiency) are also serious. Iodine deficiency and the resulting low levels of thyroid hormone can cause women to stop ovulating, leading to infertility (Cao et al., 1994). Iodine deficiency can also lead to an autoimmune disease of the thyroid and may increase the risk of getting thyroid cancer (Cao et al., 1994).
Iodine is used to prevent iodine deficiency and its consequences, including goiter. It is also used for treating a skin disease caused by a fungus (Cutaneous sporotrichosis), treating fibrocystic breast disease; preventing breast cancer, eye disease, diabetes, and heart disease and stroke, and as an expectorant(Agarwalet al., 2008;Bonifaz et al., 2007;Aroraet al., 2003; Cabezaset al.,1996).Iodine is applied to the skin to kill germs, prevent soreness inside the mouth (mucositis) caused by chemotherapy, and treat diabetic ulcers(Mahajanet al., 2010; Patrick, 2008). It is also reported that iodine has very specific protective effects against several common poisons like fluoride and bromide and, to a lesser extent, helps eliminate lead and mercury from the body (Apelqvist and Ragnarson, 1996). A number of compounds of pharmaceutical importance from a variety of chemical families, including thiocyanates, isothiocyanates, thiourea and derivatives, imidazoles, and various amines and proteins, were found to form charge transfer complexes with iodine(Yusubova and Zhdankinb, 2015; Raby et al., 2013; Cunningham and Nuenke, 1959;Thomasand Aune, 1977). All the studies cited showed that iodine acted as the oxidant or the electron acceptor.
These are just a few of the reasons to become interested in iodine, and truly, the study of the mechanism of oxidation of substrates by iodine has been the subject of several studies, but among which no complete agreement is found (Mshelia et al., 2010; Funai and Blesa,1984;Hasty,1975;King et al., 1978;Palmer and Lietzke, 1982;Smith and Martell, 1976;
3
Chernov‘yantset al. 2013). The mechanisms of the oxidation of substances by iodine is not only as varied as the number of authors who have published such works, but also as the number of internationally recognized peer reviewed journals in which such works were published (Klebanoff, 1967; Hasty, 1975; Smith and Martell, 1976; King et al., 1978;Palmer and Lietzke, 1982;Funai and Blesa, 1984; Cao Xue et al, 1994; Aghaie et al., 2008, Mshelia et al., 2010; Zhu et al., 2013; Tang et al., 2013; Chernov‘yantset al. 2013).A further investigation seemed desirable (Bhatnagaret al.,1990;Goyal et al., 1989), because all these previously cited studies showed that iodine reactions with the hydrazines and various biomolecules are of physiological importance. This study was, therefore, undertaken to provide better mechanisms of the reactions of iodine with the hydrazinesand biomolecules discussed in the subsequent sub-sections (1.2 – 1.5).
1.2 Hydrazine and Its Derivatives
It is well known that hydrazine and its derivatives play important role in biological activity studies. A number of hydrazide-hydrazones are claimed to possess interesting antibacterial and antifungal (Loncleet al., 2004), anticonvulsant (Sridhar et al., 2002), anti-inflammatory (Gaston et al., 1996) antimalarial (Gaston et al., 1996) and anti- tuberculosis activities (Maccariet al., 2005). It is also well known that iodine quantitatively oxidizes substances containing the -NH-NH, group. This reaction is the basis of one of the standard analytical procedures to titrate hydrazine and related substances, in particular isonicotinoyl-hydrazide which is widely used in the pharmaceutical industry because of its bacteriostatic properties against Mycobacterium tuberculosis (Laidler, 1978;Funai and Blesa,1984;Sultanet al., 1985;Rao and Dalvi, 1990; Cao-Xue et al., 1994;Mshelia et al, 2010).
4
1,2-Diphenylhydrazine, a derivative of hydrazine and also known as hydrazobenzene, is used as an antisludging additive to motor oil, a desuckering agent for tobacco plants, a reductant in the reclamation of rubber, a component of experimental organometallic polymers, an ingredient in photo-chromic resin compositions, and a component in polymerization reactions. It is also used in the manufacture of hydrogen peroxide(Mondal and Banerjee, 2009;Bhatnagar et al., 1990;Kellyetal., 1994;IPCS, 1993). Some 1,2-diphenylhydrazine derivatives are used as flame retarding agents (Ohnishiet al., 2000). Several aryl hydrazine interactions in small molecule complexes were studied to see how they might react with iron and other substances (Zdilla et al., 2008). The study found that a 3mM solution of benzene completely disproportionate 6 equivalents of 1,2-diphenylhydrazine into aniline and azobenzene. Their effort to shift the chemistry in a different direction was only partially successful. Several others (Globig and Freundt, 1996; Globigetal.,1996; Assi etal., 1996;Khalil et al., 1999;Homer et al., 1985) have also reported that the reactions of 1, 2-diphenylhydrazine and its derivatives are pH dependent and will yield different products depending on the pH of the reaction medium. These studies (Zdillaet al., 2008;Globig and Freundt, 1996; Globiget al., 1996; Assietal., 1996; Khalilet a.l, 1999; Homeret al., 1985) concluded that 1,2-diarylhydrazines and their derivatives enjoy complicated chemistries that include structural rearrangement and disproportionation and that their interactions with metal ions are complex and incompletely understood. Although 1,2-diphenylhydrazine is known to be oxidized readily by many oxidants (Ayuband Mahmood, 2013; May and Halpern, 1961; Whalley et al., 1956; Blackmoreet al., 2008; Zarkesh et al., 2008; Luu et al., 2007), only in a few other cases have the reaction mechanisms been examined, especially its reaction mechanisms with iodine(Ayub and Mahmood, 2013; Shallangwa et al., 2014a). It is alsonoteworthy to state that the various mechanisms proposed were not conclusive and needed to be revisited.
5
1.3 L-Tyrosine
The study of the oxidation of proteins and amino acids is of interest because of their biological significance and selectivity towards oxidant to yield different products (Laloo and Mahanti, 1990; Giulivi and Davies, 2001). Amino acids act not only as the building block in protein synthesis but also play a significant role in metabolism, nutrition, fortification of seeds, biochemical research and have been oxidized by a variety of oxidizing agents (Malika et al., 2010; Hung and Stanbury, 2005; Faller et al., 2002).
L-tyrosine (L-Tyr) is a nonessential or a semi-essential amino acid the body makes from another amino acid called phenylalanine (Xiashi and Suqin, 2010; Poustie and Wildgoose, 2010; Hoffman et al., 2010). It is a building block for several important brain chemicals called neurotransmitters, including epinephrine, norepinephrine and dopamine(Webster and Wildgoose, 2013; Mahoneyet al., 2007). Tyrosine is used for the treatment of tuberculosis, myelitis, encephalitis, thyroid bacterial infections and as a nutritional supplement. Parkinson‘s disease, albinism, depression, and other mood disorders were generally found when L-tyrosine levels are abnormal (Gelenberget al., 1982;Meyers, 2000;Parry, 2001). Tyrosine also helps produce melanin, the pigment responsible for hair and skin colour. It helps in the function of organs responsible for making and regulating hormones, including the adrenal, thyroid, and pituitary glands. It is involved in the structure of almost every protein in the body (Marquez and Dunford, 1995;vanSpronsen et al., 2001; Tumiltyet al., 2011;Bergès et al., 2011; Azoriet al., 2011).
It has been reported (Klebanoff, 1967;Aghaie et al., 2008;Doggui and El Atia, 2015) that free iodine reacts with the protein of bacteria (presumably by iodinating tyrosine residues)
6
and thus kills the bacteria. At pH = 6.8, iodine reacts with tyrosine as well as with cysteine(Klebanoff, 1967; Aghaie et al., 2008). Iodine deficiency is currently the most preventable cause of the world‘s cretinism, brain damage and thyroid disorders as well as those of ovaries, breasts and prostate(Aghaie et al., 2008; Cao Xue et al., 1994). These are just a few of the reasons why the study of iodine is interesting. Biologically, iodine is most essential in the synthesis of thyroid hormones, which serve in the differentiation, growth, metabolism and physiological function of virtually all tissues (Yen, 2001). In the thyroids colloid, iodide is collected and concentrated. After concentration, iodide is oxidized to I+ by the enzyme thyroid peroxidase (TPO) in the presence of H2O2 (Aghaie et al., 2008). The oxidized iodine is then bound to tyrosine residues of the protein thyroglobulin to produce monoiodothyrosine (MIT) and diiodothyrosine (DIT). Thyroglobulin (Tg) acts as the substrate for thyroid hormone (T3, T4) biosynthesis (Malletet al., 1995). Aghaei et al(2008) proposed four different possible transition states for the oxidation of L-tyrosine by iodine but could not decide which of the four possible transition state would be the most favoured one. In one of the published papers from this work, Shallangwa et al(2014c) revisited this reaction computationally and the authors were able to determined, energetically, the most favourable transition state.
1.4 L-Ascorbic Acid
Ascorbic acid is water soluble sugar acid with antioxidant properties or with strong reducing action and it is an important co-enzyme for internal hydroxylation reaction (Rahmanet al., 2007). The L-isomer of ascorbic acid is commonly known as vitamin C and is foundnaturally in fruits and vegetables (Kennedy et al., 1989; Rahman Khanet al., 2006; Dioha et al., 2011; Okieiet al., 2008). Vitamin C (ascorbic acid) is an important component of human diet. Some of its functional roles include its use as a nutrition food additive, antioxidant, reducing agent,
7
stabilizer, modifier andcolour stabilizer (Kapuret al., 2012). Its absence in human leads to scurvy, a deficiency disease (Eitenmilleret al., 2008), where the protein, collagen, cannot form fibres properly and this results in skin lesions and blood vessel fragility (Kuninori and Nishiyama, 1993;Ryley and Kajda, 1994; Cheema and Pant, 2011).
Ascorbic acid is susceptible to oxidation in acidic, basic or neutral media. The oxidation of ascorbic acid is a very important redox reaction, as it has interesting biological properties and is also a powerful reductant. Ascorbic acid is a lactone with a 2,3-endiol group (Khan and Sarwar, 2001; Mateiet al., 2008). It is very effective as a reducing agent and is quantitatively reversibly oxidized in aqueous solution by different oxidizing agents. The products of the oxidation depend largely on the pH of the reaction; however, its oxidation by various oxidizing agents in acid solution produces dehydroascorbic acid, a lactone whose ring can be easily hydrolyzed to give the free carboxylic group Linda (Khan and Sarwar, 2001; Matei et al., 2008; Linda,2001).
A number of articles have been written on the oxidation of ascorbic acid in acidic and basic media with various inorganic (Rajannaet al., 1996; Palet al., 1994;Perolav and Pedersen, 1994; Kagayamaet al., 1994; Lealet al., 1993; Martinez et al., 1992) and organic substrates (Vermaet al., 1996; Rao, et al., 1987;Helleret al., 2001). However, the reduction of iodine with ascorbic acid though severally reported, were somewhat limited in kinetic and mechanistic details (Khan and Sarwar, 2001; Sitti and Bunbun, 2009). Given the importance of the vitamin in human health and its widespread use as an antioxidant inprocessed foods, study of its degradation products by iodine is worthy of investigation (Khan and Sarwar, 2001).
8
1.5 Reducing Sugars
The study of sugars or carbohydrates in general is one of the most exciting fields of biochemistry (Tao and Raffel, 2009; Bare et al., 2007) and organic chemistry (Mahmoodet al.,2009; Finar, 1978;Olusanya and Odebunmi, 2013) and has been the subject of extensive research in recent years. Sugars serve as the major fuel for biological systems, supplying living cells with the required energy for daily functioning and, therefore, the understanding of the oxidation of sugars is of immense importance. Sugars serveas the body’s primary source of energy. Abundant energy is primarily stored in the complex molecular structure of the sugars or carbohydrates (Kim et al., 2002; Bond and Lovley, 2003). Carbohydrates must be burned or oxidized if energy is to be released. When complex compounds are metabolized, the atoms rearrange themselves into simpler compounds and, in the process, release thestoredenergy for use.
A vast amount of literature (Martin et al., 2002; Hao et al., 2003; OdebunmiandOwalude, 2005;Odebunmi and Owalude, 2007;Pigman and Anet, 1972; Jin et al., 2014, Hietanen et al., 2012; Marzorati et al., 2005,) is available on the kinetics of oxidation of carbohydrates by various organic and inorganic oxidants. The oxidations of some reducing sugars by diperiodatoargentate (III), diperiodate Arsenate (III) and osmium tetraoxide in alkaline medium have been reported (Raoetal., 1995; Venkate and Jaya, 1995; Singh et al., 1991). Oxidation of maltose and lactose by copper (II) ion and hexacyanoferrate (III) ion, have been also studied in alkaline medium(OlusanyaandOdebunmi, 2011), whileOkeolaet al (2010) investigatedthe kinetics of catalyzed oxidation of glucose and galactose by hexacyanoferrate (III) ion and copper sulphate in alkaline medium. Oxidation of D-glucose, D-fructose and D-mannose by 12-tungstocobaltate(III) has been investigated by several others(Banerjee et al., 1988;Babasahebet al., 2012)too.
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The catalyzed and non-catalyzed oxidation of sugars has been investigated in detail using organic oxidants such as N-halo compounds (Singh et al., 2002;Singh et al., 2004a;Singh et al., 2006a; Singh et al., 2006b;Lyengaret al.,1990; Gowdaetal., 2005; Rangappa et al., 1998a;Rangappa et al., 1998b). Inorganic oxidants such as Cu(II), ammonical Ag(I) and Nessler’s reagent have been used in the non-catalyzed oxidation of sugars in an aqueous alkaline medium (Singh et al., 1975; Singh et al., 1978; Singh et al., 1980). The mechanism for the oxidation of some aldoses by Cr(VI), V(V) and Ce(IV) investigated in acidic media has also been reported (SenGuptaet al., 1998).The oxidations of sugars have been carried out in both acidic and alkaline media using such oxidants as transition metal ions, inorganic acids, organometallic complexes and enzymes.
The use of periodate in the non-catalyzed oxidation of carbohydrates and Ru(III) and the ruthenate ion-catalyzed oxidation of reducing sugars in an alkaline medium are also available(Tizianiet al., 2003; Singhet al., 2004b).The oxidation of sugars especially the mono and disaccharides occurs under different conditions of pH, temperature and ionic strength giving products that depend on the oxidants used. The results showed that the mechanism may depend on the nature of the substrates; in some cases, it involves the formation of intermediate complex, free radical or transition states. The mechanism of oxidation of reducing sugars, especially the mono and disaccharides, by different oxidants has been the subject of several studies, but despite the vast studies on the oxidation sugars those involving iodine are scarce. An investigation of oxidation of sugar with iodine is, therefore, desirable.
1.6 Statement of the Research Problem
Iodine as an element has many uses in different areas as highlighted in the preceding sections. Iodine reduces thyroid hormone and can kill fungus, bacteria, and other microorganisms such
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as amoebae. Iodine, in the form ofpotassium iodide, is also used to treat (but not prevent) the effects of a radioactive accident (WHO, 2002; Majidnia and Idris, 2015). It is well known that iodine quantitatively oxidizes substances such as hydrazine, hydrazine derivatives, amino acids like tyrosine, ascorbic acid, reducing sugars as highlighted in sections 1.2 – 1.5. The substrates mentioned above are, in their own rights, quite interesting molecules and deserved to be studied. But more than that, their reactions with iodine, another very interesting substance, is not well studied, and if studied the mechanisms were not well understood, or the mechanisms proposed by the various researchers were always at variance with others who studied similar or same reactions(Mshelia et al, 2010; Funai and Blesa, 1984).
The seemed to be a gap in knowledge related to the reaction mechanisms of iodine, a very important molecule with great physiological and biological activities and the molecules studied. May and Halpern (1961) studied the reaction of iodine with 1,2-diphenylhydrazine and gave a mechanism that was not consistent with their stoichiometry of reaction. Funai and Blesa (1984), Sultan et al (1985), Mshelia et al(2010) also investigated the reaction mechanisms of iodine with hydrazine and its derivative, and proposed dissimilar mechanisms of the same reactions. Aghaie et al (2008)investigated the reaction mechanismof iodine withL-tyrosine and gave a mechanism in which they proposed four different like transition states, but could not determine which of the transition states could be the most favourable one. Several groups (Morelli, 1976; Rao et al.,1987; Sitti and Bunbun, 2009; Canterbury, 2014) studied and gave dissimilar mechanisms for the oxidation of L-ascorbic acid by iodine. The studies of Odebunmi and Owalude (2008), Mahmood et al (2009), Olusanya and Odebunmi (2013) also showed that reported mechanisms of reducing sugars are varied. The dissimilar mechanisms reported are as results of the inability of the researchers to deduce the correct nature of the transition states involved in the reactions. It is documented that that
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transition states of reactions have not been isolated and characterized experimentally in the laboratory.
1.7Justification of the Research
In writing a reaction mechanism, a step-by-step account of the bond (electron) reorganizations that take place in the course of a reaction is given. These mechanisms do not have any objective existence, as more often, they cannot be proven; they are merely the Chemist‘s attempt to represent what is going on in a reaction. Although experiments can suggest that some mechanisms are reasonable and others are not, for many reactions, there is no evidence regarding the mechanism, and the authors are free to write whatever mechanism they choose as accepted mechanistic patterns, subject only to the constraint that they have not contravened any established chemical law (Miller and Solomon, 1999; Moore and Pearson, 1980).
Reaction mechanisms offer the practicing Chemists insights into how molecules react, enable them to manipulate the course of known reactions, aid them in predicting the course of known reactions using new substrates, and help them to develop new reactions and reagents. In order to understand and write reaction mechanisms, it is essential to have a detailed knowledge of the structures of the molecules involved and to be able to notate these structures unambiguously (Miller and Solomon, 1999; Atkin and de Paula, 2006; Koch and Holthausen, 2000). But it is often difficult to predict what will actually happen in the course of a reaction, especially with regard to the intermediates and transition states, as more often the transition states cannot be isolated and characterized. This explained why there could be different mechanism for the same reaction when the mechanism is written on the basis of experiments. But modern computational methods have now been developed that could search
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for the transient species, such as intermediates and transition states, and really confirm, by vibrational analysis, whether they are true transition states or not. The methods also take the further step of providing the reaction energetics for various proposed reaction pathways. This allows for the selection between mechanisms on the basis of the predicted lowest energy pathway (Jordan, 2007; Levine, 1988; Becke, 1988; Lee et al., 1988; Wanno and Ruangpornvisuti, 2006).
It is these advantages that the computational methods have over the experimental that makes it possible to re-investigate the various ambiguously published reaction mechanisms of the oxidation ofthe following substrates: hydrazinium ion, hydrazine molecule, 1,2-diphenylhydrazine, L-tyrosine, L-ascorbic acid and D-fructose by molecular iodine. The investigation would specifically address and:
i. resolve all the conflicts (dissimilar mechanisms for same reaction) associated with the reactions of iodine with substrates listed above and proposed new mechanisms for each of them;
ii. establish all possible reaction pathways and the most favourable one for each reaction;
iii. identify and characterize all the transient species which are not accessible experimentally for all the reaction pathways;
iv. calculate thermodynamic and some physico-chemical parameters of all reactive species and products of reactions
v. derive rate-law for each of the pathways that are consistent with the mechanisms proposed.
vi. calculate and compare the rate constants of the reactions based on the proposed logical reaction mechanism.
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1.8The Research Questions
The computational chemistry modelling experiment reported in this study is exploratory. Both semi-empirical and DFT methods would be used to optimize the structures of reactants, intermediates, transition states and products of each reaction. Semi-empirical and DFT methods would be used to search for intermediates and transition state and, to calculate the thermochemical and other physicochemical properties of the optimized reactants, intermediates, transition states and products of each reaction. Logical reaction mechanisms based on the information gathered from the use of the computation tools highlighted above would be explored and derived.
To achieve the purpose of the study, the followingresearch questions were asked and addressed. They include:
i. What doesthisresearch want to find out or know abouttheoptimized structures of reactants, intermediates, transition states and products of each reaction?Usually, the total energies, thermodynamic, activation and other physicochemical parameters would be sufficient.
ii. What level of accuracyis expected from the calculations on the optimized structures of reactants, intermediates, transition states and products of each reaction to be? Semi-empirical methods use more severe approximations and/or empirical data to increase the speed of calculations, but give less accurate results, while the DFT methods are more exact but more time consuming (Springborg, 1997;Jensen, 1999; Cramer, 2002).
iii. How much time is available for the research to be completed? The semi-empirical calculations are fast and can be completed in hours, but the DFT
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calculations can take days, weeks or even months to complete depending on how large the molecules are and also depending on how big the basis set chosen.Ab initiomethods take even longer time than the DFT methods to complete a single calculation(Parr and Yang, 1989; Ochterski, 2000).
iv. What approximations would be made or would be acceptable? Whereas semi-empirical methods, use more severe approximations to increase the speed of
calculations, the DFT methods, which are more exact in their approximations, areconsidered to be fairly robust (Lewars, 2003; Gao, 1996;Hehre et al., 1986).
1.9The Research Hypotheses
The study was guided by the following null and alternative hypotheses:
i. Null hypothesis: All the published reaction mechanisms of the oxidation of substrates by iodine are correct;
ii. Alternative hypothesis: Some or all of the published reaction mechanisms of the oxidation of substrates by iodine needed to be modified.
1.10Conceptual Framework
The conceptual framework of the research work is as given in Figure 1.1showing the various tasks that are expected to be carried out on the reaction of iodine with the hydrazines and biomolecules.
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Figure 1.1: The research conceptual framework
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1.11 Theoretical Framework
The past 35 years have seen rapid developments in the field of computer science and these developments have in turn brought about a rapid development of the relatively, new area of computational chemistry (Clementi, 1980; Ostlund et al., 1982; Hopfinger, 1984; Leszczynski, 2000; Dykstra et al.,2011; Crammer, 2013; Floudas and Pardalos, 2013).Armed by the contemporary computational power, the computational chemists are able to formulate high level theoretical models describing the real interactions between reacting species. Various methods are available for simulations of the interactions and possible behaviour. Opposed to chemical experimental procedures, computational methods are relatively fast and, combined with optimization methods, quite reliable (Jensen, 1999; Leszczynski, 2000; Cramer, 2002;Al-Hashimi and Hussein, 2010; Kortagere et al., 2010; Dykstra et al.,2011; Crammer, 2013; Floudas and Pardalos, 2013). As for the investigation of the reaction mechanisms of the redox reactions of some bio-substrates with molecular iodine, the best solution seems to be molecular modeling.
The primary characteristic of any mutual interaction betweentwo molecules is the energy. Computational chemistry is capable of calculating theoretical values of such interaction at different levels of simplification (Al-Hashimi and Hussein, 2010). Like the most applications in computational chemistry, the important task is to find a proper level of simplification that allows the computations to be relatively fast, yet providing satisfactory results with regard to the real, experimentally determined behavior of the system.
For investigating interactions between a large molecule and a small molecule that binds to the larger one, there are several possibilities of addressing this problem. Probably the best-explored, and nowadays basics, are the semi-empirical and density functional theory
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(DFT)methods (Motaet al., 2010). This aim is realized by carrying out the tasks enumerated in the aim and objectivesof this study.
1.12Aim and Objectives
The researchwas aimed to computationally investigate the reaction mechanisms of the oxidation of some hydrazines(hydrazinium ion, hydrazine, 1,2-diphenylhydrazine) and biomolecules(L-tyrosine, L-ascorbic acid, D-fructose) by moleculariodine. The aim would be achieved through the following objectives:To
i. use both semi empirical and density functional theory (DFT) methods to optimize the structures of reactants, intermediates, transition states and products of each reaction.
ii. use both semi empirical and DFT methods to search for intermediates and transition states.
iii. calculate the thermochemical and other physico-chemical properties of the optimized reactants, intermediates, transition states and products of each reaction.
iv. plotthe potential energy surface diagrams of the various elementary steps of the reactions
v. write a logical reaction mechanism based the information gathered from (i) – (iv) above.
vi. calculate the kinetic data of the reactions based on the proposed logical reaction mechanism.
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