Sodium Periodate as a Selective Oxidant for Diclofenac Sodium in Alkaline Medium: A Quantum Chemical Approach

Diclofenac sodium is a well known anti-inflammatory drug. It has also been proclaimed to exhibit adverse effects on aquatic animals through sewage and waste water treatment plants. Kinetic and mechanistic studies of the novel oxidation of diclofenac sodium (DFS) by sodium periodate were discussed with an emphasis on structure and reactivity by using kinetic and computational approach. The proposed work had been studied in alkaline medium at 303 K and at a constant ionic strength of 0.60 mol.dm−3. Formation of [2-(2,6-dicloro-phynylamino)-phenyl]-methanol as the oxidation product of DFS is confirmed with the help of structure elucidation. The active species of catalyst, oxidant and oxidation products were recognized by UV and IR spectral studies. Proton inventory studies in H2O−D2O mixtures had been shown the involvement of a single exchangeable proton of OH− ion in the transition state. All quantum chemical calculations were executed at level of density functional theory (DFT) with B3LYP function using 6-31G (d,p) basis atomic set for the validation of structure, reaction and mechanism. Molecular orbital energies, nonlinear optical properties, bond length, bond angles, reactivity, electrophilic and nucleophilic regions were delineated. Influence of various reactants on rate of chemical reaction were also ascertained and elucidated spectro-photometrically. Activation parameters have been assessed using Arrhenius-Eyring plots. A suitable mechanism consistent with observed kinetic results had been implicated and rate law deduced. Copyright © 2020 BCREC Group. All rights reserved


Introduction
In a chemical reaction, if all reagents along with catalyst are in similar phase then reaction is regarded as homogenous. In such cases, catalysts are deliberated as solute in liquid reactants. Practically homogenous catalysis is more viewed [3][4]. Sodium periodate, an inorganic salt comprises a periodate anion and sodium cation, which can also be referred as sodium salt of periodic acid. During oxidation it reduces to periodite as stable product [5][6]. When our investigation had been done without mercuric acetate then reaction mixtures approach to pale yellow color. This yellow color manifested the formation of molecule due to interaction of iodide ion in oxidant. Because of this parallel reaction, there is hindrance in main oxidation reaction. Hence, iodide ion has to be discharged to obstruct the formation of iodine molecule. Here, mercuric acetate is utilized as scavenger or trapping agent for iodide ion. When Icomes in contact of mercuric acetate, it forms a complex [Hg(I)4] 2-and Iget trapped in this complex. In this way parallel reaction gets discontinued with the help of mercuric acetate.
Diclofenac sodium (DFS), i.e. [o-[(2,6dichlorophenyl) amino]phenyl] sodium acetate, pertains with the non-steroidal antiinflammatory drugs. There is a necessity to proliferate a simple and economical method for the probation of DFS in pharmaceutical preparations. This drug belongs to non-steroidal anti-inflammatory drugs (NSAIDs). It has several applications in medical field like analgesic, antipyretic and anti-inflammatory [7]. Although it has been acknowledged for its efficient role relieving pain of inflammation and primary dysmenorrhea, anti-inflammatory action and inhibits prostaglandin synthesis, but its mode of action is still not known clearly. It has also been employed in treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis [8]. Because of its least solubility, commercially it exists in form its sodium salt.
On the basis of above results obtained after completion of reaction, we analyzed that pH value plays paramount role for reaction. The rate constants for slowest step and other equilibrium constants are helpful for elucidation of reaction mechanism. The mechanism elaborated is a consequence of all experimental data, spectral, kinetic and mechanistic studies. The negligible effect of ionic strength and dielectric constant shows that there is a reaction between neutral and charged species. The values of ∆H and ∆S favors given reactions. In all cases the negative value of ∆S shows that intermediate is more ordered then reactants [9]. For theoretical study all quantum chemical calculations were executed at level of density functional theory (DFT) with B3LYP function using 6-31G (d,p) basis atomic set for the validation of structure, reaction and mechanism. Polarizability and hyper-polarizabilities values have been calculated along with NLO and NBO computations of the product [10]. Global reactivity descriptors, like ionization potential, electron affinity, electronegativity, electrophilicity index and chemical potential, have been computed to predict the reactivity of the molecule. These DFT calculations also help in the interpretation of complex formed during experimental conditions [11][12][13][14][15].
So far, there was no report on the kinetics of DFS oxidation by alkaline sodium periodate in presence of Os(VIII) catalyst. Due to pharmaceutical importance of DFS and complexity of proposed reaction, a detailed study of this reaction becomes important. This study aims to check the reactivity of DFS towards sodium periodate in Os(VIII) catalyzed reaction and also elucidate the active species of catalyst and oxidant. With the help of kinetic and spectral results, we arrive at a suitable mechanism and also compute thermodynamic quantities for various steps. All the quantities and facts are further verified by using computational approach towards reaction. Hence we could compare theoretical and experimental data. The elucidation of mechanism allows chemistry to be interpreted, understood and predicted.

Kinetic Measurements
The progression of reaction was pursued iodometrically and also confirmed spectrophotometrically at various temperatures. It was authenticated that there was no significant interference from other species present in the reaction mixture at this condition. The reaction was observed to more than 85% completion of the reaction. The orders for various species were elucidated from the slopes of plots of log reaction rate versus log of respective concentrations of species. The rate constants were reproducible within ±5%. Regression analysis of experimental data to procure regression coefficient 'r' and the standard deviation 'S', of points from the regression line, was performed with the Origin 6.0 professional.

Computational Quantum-Chemical Methods
All calculations were performed using Gauss-View 5.0.8 software [16]. The geometries of the ground state were fully optimized using the most popular B3LYP method [17], applying 6-31-G (d,p) [18] of basis sets without symmetry constraints and using default convergence criteria. The optimized structure ob-

Stoichiometry and Product Analysis
The results indicated 1:2 stoichiometry between substrate and oxidant. The oxidation product of DFS oxidation was extracted with ether and recrystallised with aqueous alcohol. Only one product, i.e. [2-(2,6-dichlorophenylamino)-phenyl]-methanol, was isolated with the help of preparative TLC and other separation technique and characterized by UV and FT-IR spectral studies. The product was further confirmed by its characteristic IR spectrum ( Figure 1). The absence of a sharp band (peak) at 1695 cm −1 (due to the acidic carbonyl in DFS) confirms the nature of the product. Further, the secondary amine (-NH) group observed around 3387 cm −1 in DFS is retained in the product. All these observations proved the formation of [2-(2,6-dicloro-phynylamino)phenyl]-methanol as the major product. For the confirmation of product, spectrophotometer is calibrated by using distilled water as solvent and then formation of [2-(2,6-dicloro-phynylamino)-phenyl]-methanol as the oxidation product of DFS was confirmed by the peak around 262 nm ultraviolet spectrum which was recorded in the region 200-900 nm on UVvisible Double-Beam Spectrophotometer (systronic-2203) instrument with methanol as a solvent. The reaction products do not undergo further oxidation under the existing kinetic conditions (Scheme 1).

Scheme 1.
Catalytic oxidation of diclofenac sodium

Reactivity of sodium periodate in alkaline medium
For determination of order of reaction with respect to sodium periodate at 35 °C in presence of Os(VIII) to oxidize diclofenac sodium by sodium periodate in alkaline medium various experiments were performed and the results are tabulated in Table 1. The concentration of [NaIO4] varies from 0.83 ×10 -3 to 5.00 × 10 -3 M at constant concentration of other reactants. At fixed time (5 min.) rate of reaction for each kinetic run was determined by the slope of tangent. This Table 1 represents that rate of reaction is directly proportional to concentration of NaIO4 which means increase in concentration of NaIO4 also increases the rate of reaction. This first order kinetics is confirmed by linearity of the plot of log [NaIO4] vs. log (-dc/dt) (r ≥  0.99, S ≤ 0.062) up to 85% completion of reaction ( Figure 2). The first order kinetics is also supported by constant value of k1 given in Table 1 and it was further confirmed by least square method (Figure 3).   determine the dependence of reaction concentration with respect to Os(VIII). The concentration of Os(VIII) ranges from 1.31×10 -6 M to 7.88×10 -6 M. The linear relationship between log [Os(VIII)] and log (-dc/dt) (r ≥ 0.99, S ≤ 0.0021) up to 85% completion of reaction ( Figure 4). Figure 4 also shows that order of reaction is unity with respect to Os(VIII) throughout the reaction. These results are also confirmed by least square method ( Figure 5).

Effect of alkaline medium
In case of oxidation of DFS, the reaction order with respect to [OH -] is evaluated by various reaction experiments performed at 35 °C keeping all other reactants constant. The results of reaction are given in Table 1, in which sodium hydroxide concentration ranges from 0.83×10 −3 M to 5.00×10 −3 M, keeping constant concentration of other reactants. These results may conclude that as the concentration of sodium hydroxide increases reaction rate decreases. Therefore reaction has negative effect with respect to hydroxide ion which is ascertained by the plot of log [NaOH] vs. log (−dc/dt) up to 90% completion of reaction ( Figure 6). The results of experiments are summarized no effect of heavy water on rate of reaction. So in order to justify current reaction mechanism we can say that there is no involvement of protonated reducing pharmaceutical drugs.

Effect
The ionic strength of any reaction provides the importance of Debye-Huckel limiting law and if the rate of reaction is proportional to concentration of activated complex then its validity is justified. Debye-Huckel gave the following equation to represent the relationship between activity coefficient and ionic strength-     The calculated and experimental structure ( Figure 8) of diclofenac sodium has longest distance between O29−Na30 is established to be 2.18 Å, due to interaction of carboxylate and sodium metal. The distance between C2−Cl22 and C4−C23 are 1.76 Å and 1.77 Å, respectively, because of interaction between lone pair of halogens and carbon atoms.
Due to the delocalization of nonbonding electrons from N10 to both phenyl rings the bond length between N10−H11 becomes shortest one, i.e. 1.01 Å. All C−C and C−H bond distances of rings are in the range 1.50-1.54 Å and 1.09-1.11 Å, respectively ( Table 2). The sym-metry of the molecule, with chloride substituent and N-substituted phenyl ring with a carboxylate ion, yields distortion in ring angles than 120°. The delocalization of non-bonding electrons of N10 results increase in bond angle (129.29°) than customary 120° while the C−O−Na has least bond angle, i.e. 87.24°.
Product was obtained as needle shaped crystal by slow evaporation of water solvent at room temperature and crystallized in triclinic system with space group C1, with unit cell parameters a = 0.269287, b = 0.272785 and c = 0.443140. In product the computational calculated and experimental longest distance between C8−Cl14 and C12−Cl15 are 1.75 Å and 1.76 Å, respectively. Meanwhile, other C−C have bond length analogous to the experimental value (1.54 Å), and this was exactly similar for all C−C bonds and the smallest bond lengths are in between H28−O17, i.e. 0.9666 Å. Some bond angles C−N−C are above 120° due lone pair electrons of nitrogen atom. Other C−C−C are not much distorted from customary 120°. The resemblance between the optimized and experimental crystal structure is good enough displaying that the optimized structure is almost similar to the experimental structure. The existence of lone pair of electrons, electronegativity of the oxygen, nitrogen and chlorine atom causes distortion in bond angle and bond length.

Electronic absorption
Formation of [2-(2,6-dichlorophenylamino)phenyl]-methanol as the oxidation product of diclofenac sodium was assured by the peak  around 262 nm ultraviolet spectrum which was recorded in the region 200-900 nm on UVvisible Double-Beam Spectrophotometer (systronic-2203) instrument with water as a solvent. The UV-Visible spectrum of reactant and compound have been studied by TD-DFT method using B3LYP and 6-31-G (d,p) basis sets. The UV data with excitation energies, oscillator strength (f), percentage contribution of probable transitions and resultant absorption wavelengths have been analyzed with experimental results. The theoretical UV spectrum of DFS (ƒ=0.0404) in water has an intense electronic transition at 224 nm and 272 nm while   , 15 (2), 2020,   product (ƒ=0.0111) has electronic transition at 286 nm, which complies with the measured experimental data of DFS ( exp. = 262 nm and 288 nm) and product ( exp. = 262nm and 318 nm), respectively ( Figure 9). These data corresponds to the transition from HOMO to LUMO with 64%, H to L+1 with 63% and H to L+2 transition with 63% contribution due to л → л* transition in diclofenac sodium . Product corresponds to the transition from HOMO to LUMO with 70%, H to L+1 with 69% and H to L+2 with 66% contribution due to л → л* transition ( Figure 10). The given HO-MO-LUMO of molecules represents the reactivity and kinetic sustainability their interaction. Since the energy gap between HOMO-LUMO least, so electron can be easily promoted from HOMO to LUMO. The molecular orbital diagram ( Figure 10) shows that diclofenac sodium has more reactivity for proposed oxidation reaction.

Molecular electrostatic potential
The MEP value of diclofenac sodium around O7 is −1.419 and MEP values of [2-(2,6dichlo ro phe ny l am ino ) -p he ny l] -me thano l around −7.866 respectively. In oxidation product, C7, C12, and C11 is slightly electron rich in nature. The molecular electrostatic potential contour surface of diclofenac sodium and its oxidation product (Figure 11) shows that the negative regions are electrophilic regions, these are mainly over the oxygen atoms (O28), while O29 is slightly electron deficient as MEP figure of diclofenac sodium depicted and O18 are slightly electron deficient in its oxidation product, the positive regions are the nucleophilic regions and these are over the carbon atoms connected with oxygen atom and over the hydrogen atoms of both the molecule. In both, the compounds chlorine atoms are neutral in nature while nitrogen atoms are electron deficient in nature.

Non-bond orbital analysis
NBO analysis has been performed on the molecule at the DFT/B3LYP/6-31G+ (d,p) level in order to elucidate the intramolecular and delocalization of electron density within the molecule, which are presented in Table 3. For oxidation product, C7−C12 of the NBO conjugated with л* (C8-C9) leads to an enormous stabilization of 319.50 kJ/mol. This strong stabilization denotes the larger delocalization. As the interaction around the ring increases the biological activity in the compound also enhanced. Second-order perturbation theory analysis of the Fock matrix in NBO basis for product is given in Table 3 and the correlation between donor (i), acceptor (j) and stabilization energy E(2) is given as: (2) where qi = donor orbital occupancy, Ei and Ej = diagonal elements, and Fij = off diagonal NBO fock matrix element. The NBO analysis represents the intramolecular charge transfer in product as:
tively (Table 4). The values for both diclofenac sodium and its oxidation product were found to be greater than those of urea (the o of urea 0.3728×10 −30 esu). Thus, both are good NLO material.

Thermodynamic analysis
Due to the various chemical and physical phenomena thermodynamic analysis play consequential role in elucidation of reaction mechanism. In present analysis, we calculate zero point vibrational energy, rotational constants and various energies, using DFt-B3LYP/6-31G (d,p) method ( Table 5). All the thermodynamic calculations are conducted in gas phase and not in solution.

Global reactivity descriptors
The global reactivity descriptors define the type of interaction, bonding and active centre of molecule which helps in elucidation of mechanism. The nature of molecular orbital defines its most reactive position while the HOMO-LUMO energy gap defines biological activity of that compound. Least energy gap indicates higher polarizability of molecule and less kinetic stability. Ionization potential (IP), electron affinity (EA), electronegativity (χ), chemical potential (μ), global hardness (η), global softness (S), and electrophilicity index (ω) were listed in Table 6. As the HOMO-LUMO energy gap increases, the molecule becomes harder, which resist the deformation of electron cloud. The higher the value of the electrophilicity index (ω), the better is the electrophilic character. Hence, DFS is less electrophilic than its oxidation product.

Thermodynamic Analysis
A vant Hoff's plot was inclined for the variation of k with temperature [i.e. log k versus 1/T] ( Figure 12) and the values of the enthalpy of reaction ∆H, entropy of reaction ∆S, and free energy of reaction ∆G were calculated. Moderate ∆H* and ∆E* values are favourable for electron transfer reaction. Entropy of activation plays vital role in the chemical reaction between ions or between an ion and a neutral molecule or a neutral molecule forming ions. When reaction takes place between two ions of opposite charges, their union will results in a lowering of net charge, and due this some frozen solvent molecules will released with an increase of entropy. But on the other hand, when reaction takes place between two similarly charged species, the transition state will be a more highly charged ion, and due to this, more solvent molecules will be required for separate the ions, leading to a decrease in entropy. High positive value of free energy change of activation (∆G*) indicated that the transition state was highly solvated, while negative value of entropy of activation (∆S*) suggested the formation of an activated complex with reduction in degree of freedom. Deviation in the rate within the reaction series may be caused by change in the enthalpy or entropy of activation. A negative value of ΔS* suggests that the two ionic species combine in rate determining step to give a single intermediate complex which is more ordered than the reactants [16−18].  Table 7. Thermodynamic activation parameters for the oxidation of DFS by sodium periodate catalysed by Osmium(VIII) in alkaline medium.

Figure 12.
Arrhenius plot between log k vs. 1/T for oxidation of pharmaceutical drugs (acetylsalicylic acid, acetaminophen and diclofenac sodium).

Theory and Discussion of Results
Ionic strength determination accurately defines pH of solutions by estimating concentration of all ions in the solution. Similarly in any ionic reaction the interaction between ions play vital role because ions act like conducting spheres for solvent with constant dielectric constant (). According to Bohr model for ion in solutions, the force acting between ions, The negative sign is used because x decreases by dx when ion moves together by a distance dx. The work executed for moving ions from its initial state to final dAB is therefore, If ions have same sign then work is positive otherwise vice versa. By using Gibbs free energy equation, Equation (4) may be written as, The slope of the line obtained by plotting ln k a g a in s t 1 /  g iv e s the v a lue o f ZAZBe 2 /40dABkBT. Hence, we can calculate dAB from experimental slope. For elaborating the effect of dielectric constant, we use various ratios of Acetic acid and water percentage which alters the dielectric constant of the medium (D). The D values were deliberated from the equation, (6) where DW and DA are the dielectric constants of pure water and acetic acid respectively and VA and VB are the volume of fractions of components, water and acetic acid, respectively in total mixture. Different reactions were performed with various concentration of acetic acid keeping concentration of all other reactants constant at 35 °C. The concentration of acetic acid varies from 5% to 20% (v/v). The results emphasize that there was no significant effect of dielectric constant under the experimental conditions. The low value of rate constant for slow step of the mechanism confirms that the oxidation apparently occurs through an inner-sphere mechanism. This conclusion was supported by previous literature [19−20]. The catalyst Os(VIII) forms the complex with organic substrates, which enhances the reducing ability of the substrate than that with no catalyst. Further, the catalyst Os(VIII) modifies the reaction pathway by lowering the energy of activation. The Os(VIII) catalyzed reaction, however, is logically fast in view of speediness of Os(VIII) to act across the -COO bond. The reaction product does not manipulate the rate in alkaline media since it has been observed that it is not involved in the pre-equilibrium process. All of the observations also confirm the proposed mechanism. On the basis of kinetic results, active species of Os(VIII) oxide and sodium periodate and other kinetic properties with respect to [Substrate], [OH − ], [Hg(II)] and ionic strength of medium, the following mechanistic steps are proposed.

Reaction Mechanism
The negative effect of [OH-] indicates that in above reaction equilibrium shifted towards right (Scheme 2). Therefore, the [OsO4(OH)2]is the active species of osmium(VIII) oxide in alkaline medium.

Scheme 2:
Hydrolysis of hydrated osmium tetra oxide  The Lineweaver-Burk plot proved the complex formation between Os(VIII) and drug, which explains fractional order in [drug]. The rate law for Scheme 1 is derived as, The rate law (9) can be rearranged to Equation (10), which is suitable for verification. Equation

Conclusion
The oxidation of DFS by NaIO4 experienced a slow reaction rate in alkaline media, but increased in rate in the existence of the Os(VIII) catalyst. The observed results were explained by plausible mechanisms and the related rate laws were deduced which were further justified by the application of computational approach. The catalyst Os(VIII) forms complex with DFS, which shows a great reducing property than DFS itself. In the absence of catalyst oxidation of DFS by NaIO4 is very lethargic, but it becomes superficial in the presence of Os(VIII) catalyst. The reactive species of NaIO4 is IO4not NaIO4 itself. Oxidation products were recognized and activation parameters were evaluated. The observed results have been explained by a reasonable mechanism and the related rate law. The observed results have been explained by mechanism and related law has been deduced. Since the HOMO-LUMO energy gap of product is lower than DFS, so that the product is less stable. On basis of NLO calculations value of βo for both DFS and product were higher than urea so both have good optical property. Therefore, we can conclude that both plays vital role in pharmaceutical industry and have NLO applications.