PRODUCTION RATE OF HETEROCYCLIC COMPOUNDS IODINATED N-(

. Iodinated heterocyclic molecules are crucial structural components of many natural products, including hormones, vitamins, and medicines. The pharmaceutical survey is very interested in the investigation of the kinetics of the iodination of N-( p -chlorophenyl)-3,5-dimethyl-1,1-dioxo-1,2-thiazine. The rate of iodination is directly dependent on the concentration of both 1,2-thiazine and iodine under different molar ratios (1:10), (10:1) adopted on the isolation method, the observed rate of iodination, the pseudo-first-order and the second order using (1:1) molar ratio in the overall reaction using spectrophotometric techniques. Thermodynamic activation parameters activation energy E a , enthalpy change ΔH # , entropy change ΔS # , and Gibbs free energy ΔG # of activation were calculated from the rate constant at temperatures 273


INTRODUCTION
Sulfonamides have been used as antibacterial (antibiotic) agents and have been recognized as therapeutic agents for a long time [1][2][3][4]. Cyclic counterparts have attracted a lot of attention because they are also known to inhibit a number of enzymes, including cysteine protease, human immunodeficiency virus (HIV) protease carbonic anhydrase, and cyclooxygenase [5]. Due to the spacious applicability of sulfonamides, it is eligible to find general and novel methods for their synthesis.
Chantarasriwong et al. reported a general method used for aromatic sulfonic acids and can be applied to aliphatic and heterocyclic sulfonyl acid (Scheme 1), R -may be aromatic, aliphatic and heteroaromatic [6]. Scheme 1. Sulfonamide formation from sulfonic acids.

Kinetic experimental techniques
Several experimental methods are employed in kinetics investigations to carry out these measurements. UV-Vis spectroscopy is the method utilized in kinetic investigations that is most useful. The reactor would be submerged in the thermostat liquid bath because the experiment should be conducted in isothermal conditions. A Spectroscan 80D instrument spectrophotometer with serial no.: 18-1884-01-0113, with UV-spectroscan software, using 1 cm matched quartz cells with a home-made cell jacket, made from a thin copper sheet, which was painted by a black dye to minimize the light reflection, connected a thermostatic digital circulating bath.
The instrument records the absorbance curve systematically for the product and automatically at a fixed cycle time (in second), between (190-1100) nm. Taking continuous readings until the absorbance remains constant for two hours, and this value represents (A∞), for six different temperatures (273, 283, 293, 298, 303, 318) K.
Kinetic experiment of the N-(p-Chlorophenyl)-3,5-dimethyl-1,1-dioxo-1,2-thiazine: I2 molar ratio 1:10 The kinetic study was carried out under pseudo-first order condition [1,2-thiazine] ≪ [I2] with a 1:10 molar ratio, and the rate studies were carried out at a constant temperature. Using a 25 mL conical flask, 0.235 g (0.001 mol) of N-(p-chlorophenyl)-3,5-dimethyl-1,1-dioxo-1,2-thiazine and 5 mL of ethanol were added using the micro burette; the flask was placed inside the automatic liquid bath at 298 K for thermal equilibration for 30 min before the experiment. In the other flask, mercuric oxide (HgO) 2.16 g (0.016 mol) was dissolved in 10 mL acetic acid, and the two above solutions were mixed. Then the iodinating agent, (I2) 2.53 g (0.01 mol) was dissolved in 5 mL ethanol, then added to the sample solution and quickly mixed to the cuvette and capped; the cuvette was inserted into the UV-Visible system. Then taking the baseline spectrum at full range of wave length (190-1100) nm for all the solution mixture to auto zero all the peaks of the reactant solutions, the "start" button was pressed, and the instrument records the absorbance curve systematically for the product, taking continuous readings automatically at fixed cycle time every 300 seconds until the absorbance remains constant for two hours which represents (A∞). All the experiments were repeated at six different temperatures (273, 283, 293, 298, 303, 318) K.
The rate constant k for the iodination of 1,2-thiazine by I2 with molar ratio 1:10 at different temperatures is followed by the pseudo-first-order kinetic according to the equation (1) [16,17]: where At is the absorbance of the product at each time interval t, A∞: absorbance of the product at an infinite time t∞, equivalent to the initial concentration of reactant (a), t: time in sec, k1: firstorder rate constant of reaction in 1/sec, (A∞-At): concentration of product at any time, equivalent to the remaining concentration of reactant a-x. The value of k1 for each temperature was evaluated from the slope of the linear plots of ln(A∞-At) against t, the data plots are shown in Figure 2 and the summary of findings of k1, t1/2, and R 2 are given in the Table 1, where t1/2 is the half-life of the reaction. R 2 is the correlation coefficient.

Determination of thermodynamic activation parameters
Interpreting the Arrhenius equation's parameters is crucial to the development of the concept that when the reactants are transformed into a product: From the obtained results of the activation energy Ea in Figure (3), the enthalpy of activation ΔH # , entropy ΔS # and Gibbs free energy of activation ΔG # can be obtained using equations [18,19]: where kb = 1.3806*10 -23 J /K, h = 6.626*10 -34 J sec. The Arrhenius parameters, activated enthalpies and entropies obtained from the plotted graphs are tabulated in Table 2.

Iodination of N-(p-chlorophenyl)-3,5-dimethyl-1,1-dioxo-1,2-thiazine by I2 10:1 molar ratio
From the physical properties of the product, H 1 -and C 13 -NMR, IR, and UV-data are all very close to that of the reactant unsubstituted (by iodine); the reaction achieved between 1 mmol of I2 and 10 mmol N-(p-chlorophenyl)-3,5-dimethyl-1,1-dioxo-1,2-thiazine but the product disappeared between the large quantities of 1,2-thiazine reactant, in addition to that the product is more soluble in solvents than reactant itself during recrystallization and this is one of the reasons that the product is undetectable even by IR, H 1 -NMR and C 13 -NMR and so it was not possible to do kinetic work for this reaction.

Iodination of N-(p-chlorophenyl)-3,5-dimethyl-1,1-dioxo-1,2-thiazine by I2 1:1 molar ratio
Iodination using the same molar ratio of each reactant, the two and three-dimensional absorption spectra, Figure 4 shows the variation of absorbance of the peaks at max 410 nm with time shows the absorbance of the product increase with time indicating that the reactions are clean forward processes since no equilibrium was observed during kinetic runs.
These reactions were determined as second order equation; first-order with respect to each reactant and can be described by equation (9) [17,18]: The plot of At/A∞(A∞-At) with the time t has a slope k2 which is the second order rate constant, the plots show excellent fit to the second order equation as shown in Figure 5 and the data are tabulated in the Table 3.   Table 3. Observed rate constants, for the iodination of 1,2-thiazine with ICl with 1:1 molar ratio. Direct iodination of N-(p-chlorophenyl)-3,5-dimethyl-1,1-dioxo-1,2-thiazine with iodine undergo electrophilic attack depending on the molar ratio as [I2] ≫ [1,2-thiazine] as shown in Scheme 3 obtaining 4,6-diiodo N-(p-chlorophenyl)-3,5-dimethyl-1,1-dioxo-1,2-thiazine (4) obtaining pseudo first order condition and plotting ln(A∞-At) against time t as shown in the figure 2 the small k1 values table 1 indicates a slow reaction which depends on the nucleophilicity of the amine (N) group and the substituted chlorine (p-Cl) of the aromatic ring is electron withdrawing that is reduces electron density at the reaction center.
The large activation energy values Ea = 33.177 kJ/mol shown in Table 2, which increase the rate of the reaction as the temperature increase, explain that the slowness of the reaction and the reactants need high energy for the transition state to reach the product. The enthalpy of activation (ΔH # ) is also large and positive, which is the energy to affect the stretching or breaking of bonds that consumes more energy as the temperature decrease. The entropy of activation (ΔS # ), which measures the change in the degree of organization or order of both the reacting molecules themselves and the distribution energy as shown in Table 2, are negative values indicating the rigid configure with less degree of freedom for the activated complex than the reactant molecule.
Pseudo-second order plots showed good linearity as in Figure 5; the rate constants obtained from the reaction mixture prepared with different temperatures are observed in the Table 3 which R 2 value indicates a very good fitness. Results of Table 3 indicate slower reaction rate of iodine monochloride with N-(p-chlorophenyl)-3,5-dimethyl-1,1-dioxo-1,2-thiazine, due to electronic withdrawing group on the phenyl ring that effects on the electrophilic substitution reaction. From Arrhenius plots for iodination of 1,2-thiazine at six different ranged 273-318 K as presented in Figure 6, from the Table 4 Ea value 46.23 kJ/mol and A-values 4.610 5 mol/s. dm 3 are obtained, Ea value for 1,2-thiazine is high because of p-substituted chlorine is electron withdrawing group which decrease the electrophilicity of 1,2-thiazine to attack the iodine for electrophilic aromatic substitution which makes the reaction complex easier and faster for the reaction. The analogous interpretation of the A-factor is that it is a measure of the rate at which collisions occurred, irrespective of their energy. Hence the product of A-factor gives the rate of successful collisions [20]. The entropy of activation gives a measure of the inherent probability of the transition state, apart from energetic considerations, if ΔS # is large and negative, the formation of the transition state requires the reacting molecules to adopt precise conformations and approach one another at a precise angle. As molecules vary widely in their conformational stability, in their rigidity, and in their complexity, one might expect the values of ΔS # to vary widely between different reactions [20]. Table 4. Arrhenius and thermodynamic parameters for the iodination reaction of 1,2-thiazine using 1:1 molar ratio.
Iodination of electron-rich heteroaromatic 1,2-thiazine compounds is relatively easy. It can be carried out under mild reaction conditions, and a variety of halogenation reagents have been developed by chemists all over the world.

CONCLUSION
This research has mainly focused to demonstrate the rate of production of highly valuable heterocyclic compounds of iodine electrophilic substitution of (1,2-thiazine) and to demonstrates the ability to utilize a modern in situ spectroscopic method (UV-Vis spectroscopy), making the study quite simple and free from strict experimental conditions and is characterized by wide linear dynamic ranges and high sensitivity to investigate these reaction kinetics under different temperature range and determining thermodynamic activation parameters. The rate of iodinated 1,2-thiazine production is second order directly proportional to the concentrations of both I2 and 1,2-thiazine according to kinetics, and according to the change of the thermodynamic parameters ΔH # , ΔS # , and ΔG # , the reaction requires more energy to break bonds due to the rigid configuration and nonspontaneous transition state complex.