1. INTRODUCTION:

2, 3-Disubstituted l, 4-benzothiazines have attracted our interest due to their broad biological activities. This heterocyclic system possesses wide range of pharmacological activities such as antifungal, immune stimulating, anti-aldosoreductase, anti-rheumatic anti-allergic, vasorelaxant, anti-arrhythmic, antihypertensive, neuroprotetive, cytotoxic and anti-inflammatory, potassium channel opener, antidepressant, anti-HIV activites,^1-6 antidiabetic,⁷ antihypertensive,⁸ antimicrobial,^9-11 antifungal¹²and anticancer¹³. 1,4-Benzothiazines are known for their utility as dyestuffs,¹⁴ photographic developers,¹⁵ultraviolet light absorbers and antioxidants.¹⁶

Recently Reddy’s Lab has reported the use of 1,4-benzothiazines to reduce obesity.¹⁷ Attempts are made to synthesize 1,4-benzothiazines as herbicidal agents.¹⁸ The synthetic, biological, chemical, physical and spectral aspects of 1, 4-benzothiazines are well reviewed¹⁹.These multifarious applications of 2, 3-disubstituted 1,4- benzothiazines have prompted to develop an efficient synthetic route or to modify the existing route used for their preparation.

To develop or to modify exciting synthetic protocols, kinetics plays vital role as it provides in site into reaction paths. Kinetics of various types of transformations has been reported for getting the respective products rapidly and cost effectively. The kinetics and mechanism of reactions of thioacids and pyridinium bromochromate (PBC, as a mild and selective oxidizing agent in synthetic organic chemistry) have been reported by Banerji et al.²⁰ and the rate of reactions were measured by spectrophotometer. Kumbhat et al.^21-22havereported spectrophotometric kinetic measurements of oxidation of aliphatic aldehydes by 2-2’bipyridinium chlorochromate in dimethyl sulphoxide, carried for obtaining corresponding carboxylic acids in different organic solvents. Khorassani et al.²³have performed kinetic study of the reaction between triphenylphosphine and dialkyl acetylene dicarboxylate in the presence of NH acid and measurements were recorded using UV spectrophotometer. In last decayed our collaborators have reported kinetics of condensations and cyclocondensation for optimising the formation of acylated hydroxamic acids, thiazoles and unsymmetrical thioureas. Burungale et al.²⁴ have reported the kinetics of O-acylation of hydroxamic acids using acetic anhydride in non aqueous medium acetonitrile/dioxane. The thermodynamic parameters, mechanism and rate expressions have also been studied. The kinetics of condensation of aryl isothiocyanates with aryl amines in non-aqueous medium has been investigated by Pathrikar, et al^25-27. The condensation reaction is first order with amines and isothiocyanates, the effect of substituents on the rate of condensation and the thermodynamic parameters are evaluated and the kinetic measurements have been carried using spectrophotometer technique. The second order rate constants for the condensation of chloroacetone with thiourea and p-substituted phenyl thioureas have been evaluated by Zaware et al.^28-32The effect of the substituents on the rates of the condensation has also been studied.

Considering the need of alternative efficient synthetic route or to modify the existing route used for their preparation and better protocol for value added 1, 4-benzothiazines here we consider that, the kinetics of commonly used cyclocondensation protocol for obtaining 2, 3 disubstituted 1, 4-benzothiazines be carried. In view of that in present investigation we attempted kinetics of cyclocondensation of bisanilino disulphide and l, 3-dicarbonyts/diketones in DMSO.

2. KINETIC MEASURMENTS:

In the present work we have measured the rates of the cyclocondensation of bisanilino disulphide and l-3 dicarbonyls/diketones using spectrophotometric method, UV-1601 Shimadzu spectrophotometer was used for determining the concentrations of products, 1, 4-benzothiazines after certain time intervals. A high precision thermostatic oil bath was used to carry the cyclocondensation. The accuracy of the reaction temperature was about ±0.1^oC.

The solutions of bisanilino disulphides and l-3 dicarbonyls (acetyl acetone) of the desired molarities were prepared in different solvents. From their stock 20 ml of the disulphide solution and 20ml of the dicarbonyls/diketones were taken out separate flasks and then warmed, in the thermostatic oil bath at (70⁰C -120⁰C) till to attend the required temperature. Then the contents of the flask having dicarbonyls/diketones solution was completely transferred to the two necked round bottom flask bearing the bisanilino disulphide solution. The obtained reaction mass was thoroughly stirred and incubated in thermostatic oil both at the required temperature. At definite time intervals a fixed volume (0.5ml) of aliquot was removed from the reaction mass and diluted with ethanol to make the desired/measurable concentrations. The optical density of the diluted solution was measured at their appropriate λ max (i.e. 433, 465, 344, 416nm) using spectrophotometer. From this optical density the concentration (x) of 2, 3-disubstituted 1, 4-benzothiazines generated at particular time was determined with the help of standard/reference plot of respective 2, 3 -disubstituted 1, 4-benzothiazines (3a-d).

Similarly the kinetic measurements of the cyclocondensation leading to 1,4-benzothiazines by separately varying 1, 3-dicarbonyls/diketones, solvents and temperature have been carried using stoichiometric DMSO as an oxidant. This method was found to be convenient and gave reproducible results.

3. MATERIAL AND METHODS:

2, 3 Disubstituted 1, 4-benzothiazines have been synthesized using reported procedure i.e.by carrying oxidative cyclocondensation of equimolar amount of 2- amino-benzenethiol with 1, 3-dicarbonyls/diketones using DMSO as solvent and an oxidant. This synthesis is one pot and has two successive steps in first step 2-aminobenzenethiol oxidised to the respective bisanilino disulphides and in the second successive step cyclocondensation of the intermediate, bisanilino disulphides and l, 3-dicarbonyts/diketones has occurred leading towards the corresponding 2,3-disubstituted 1, 4-benzothiazines.

The dicarbonyls used in the work were acetyl acetone (3a), benzoyl acetone (3b), dibenzoyl methane (3c) and ethyl acetoacetate (3d). Solvents used were acetonitrile, ethanol and dimethyl sulphoxide (DMSO). All these reagents were obtained from S.D Fine chemicals of HPLC/AR grade and purified by literature procedure.^33-35 The products obtained were crystallized from ethanol and 2,3-disubstituted 1, 4-benzothiazines 3a,3b,3c and 3d were found to melt at 197⁰C, 189⁰ C, 92⁰C and 142⁰C, respectively. The melting points of these 2,3-disubstituted 1, 4-benzothiazines were in good agreement with those reported in the literature³³. Oxidised to the respective bisanilino disulphides and in the second successive step cyclocondensation of the intermediate, bisanilino disulphides and l, 3-dicarbonyts/diketones has occurred leading towards the corresponding 2,3-disubstituted 1, 4-benzothiazines.

4. RESULT AND DISCUSSION:

The term oxidative cyclocondensation was purposely used. When the above cyclocondensation was carried in the absence of oxidants the products obtained were accompanying with unreacted l, 3-dicarbonyls, bisanilino disulphide and the product yields were less than 50%. To avoid formation of the by products and impurities we have attempted this cyclocondensation in the presence of oxidant, DMSO which gives high yield in relatively short duration without unreacted reactants and by-products. This would have been caused due to rapid quantitative oxidation of the 2-aminothiophenol, generated in-situ in the cyclocondensation of the 1, 3-dicarbonyls and bisanilino disulphide

The stoichiometric study indicates that when one mole of bisanilino disulphide and one mole 1, 3-dicarbonyls allowed to react gave 1 mol of product, 2, 3-disubstituted 1, 4-benzothiazines. Kinetic measurements of oxidative cyclocondensation have been carried out separately in solvents DMSO, acetonitrile, alcohol and result is recorded. The reaction rates were determined by varying concentrations of bisanilino disulphide and keeping concentration of l, 3-dicarbonyls constant Table 1 at 348K. Similarly the rates were determined by varying concentrations l, 3-dicarbonyls by keeping concentration of bisanilino disulphide constant at Table 2. The rate constants were calculated using second order rate law and the rate constants were found to be fairly constant. Kinetic measurements were carried using equal concentration of reactants at five different temperatures in organic solvent in presence of and oxidant DMSO Table 3. The rates of the formation of 2, 3 disubstituted l, 4-benzothiazines have been increased with increase in temperature. The observed rate constants of the condensation carried separately in different solvents i.e. DMSO, acetonitrile and ethanol are recorded in Table 4. The determined thermodynamic parameters indicates that there are overall negative values of entropy of activation, the low magnitude of enthalpy of activation, consistency of free energy of activation and values of frequency factor. All these parameter are presented in Table 5.

Table 1: Rate constants [k × l0^-3] for a reaction of 0.1 M 1,3-dicarbonyls varying with concentration of bisanilino disulphide in DMSO/acetonitrile/ethanol at 348K 3a (acetyl acetone),3b (benzoyl acetone),3c (dibenzoyl methane) and 4d (ethyl acetoacetate)

1,3-Dicarb onyls	0.1M Bis anilino disulphide			0.08M Bis anilino disulphide				0.06M Bis anilino disulphide			0.04M Bis anilino disulphide
1,3-Dicarb onyls	DM SO	Etha nol	Aceto nitrile	DM SO	Etha nol	Aceto nitrile		DM SO	Etha nol	Aceto nitrile	DM SO	Etha nol	Aceto nitrile
3a	0.426	0180	0.246	0.386	0.168	0.236		0.354	0.156	0.226	0.340	0.141	0.207
3b	0.211	0.064	0.125	0.201	0.063	0.115		0.185	0.058	0.102	0.179	0.055	0.092
3c	0.150	0.062	0.117	0.149	0.061		0.107	0.137	0.056	0.098	0.125	0.052	0.094
3d	0.619	0.387	0.409	0.593	0.386		0.393	0.585	0.349	0.374	0.557	0.328	0.355

Table 2: Rate constants [k × l0^-3] for a reaction of 0.1 M bis-anilino disulphide varying with concentration of 1,3-dicarbonyls in DMSO/actonitrile/ethanol at 348K

1,3-Dicarb onyls	0.1M Bis anilino disulphide			0.08M Bis anilino disulphide				0.06M Bis anilino disulphide			0.04M Bis anilino disulphide
1,3-Dicarb onyls	DM SO	Etha nol	Aceto nitrile	DM SO	Etha nol	Aceto nitrile		DM SO	Etha nol	Aceto nitrile	DM SO	Etha nol	Aceto nitrile
3a	0.426	0182	0.245	0.373	0.175	0.236		0.353	0.162	0.226	0.336	0.155	0.195
3b	0.210	0.064	0.125	0.206	0.063	0.064		0.195	0.060	0.108	0.191	0.059	0.098
3c	0.150	0.062	0.116	0.143	0.061		0.058	0.137	0.057	0.096	0.124	0.051	0.093
3d	0.618	0.387	0.409	0.593	0.368		0.374	0.585	0.352	0.368	0.560	0.337	0.359

Table 3: Rate constants at different temperature of 1,3-dicarbonyls and bisanilino disulphide using DMSO.

Name of diketones	k×10 ^-3 at 398K dm^-3 mol^-1sec^-1Ethanol	k×10 ^-3 at 388K dm^-3 mol^-1sec^-1Acetonitrile	k×10 ^-3 at 378K dm^-3 mol^-1sec^-1DMSO
3a	0.18	0.246	0.426
3b	0.064	0.125	0.211
3c	0.062	0.117	0.150
3d	0.392	0.409	0.649

Table 4: Rate constants at different temperature of 1,3-dicarbonyls and bisanilino disulphides using DMSO.

Name of diketones	k×10 ^-3 at 398K dm^-3 mol^-1sec^-1	k×10 ^-3 at 388K dm^-3 mol^-1sec^-1	k×10 ^-3 at 378K dm^-3 mol^-1sec^-1	k×10 ^-3 at 368K dm^-3 mol^-1sec^-1	k×10 ^-3 at 348K dm^-3 mol^-1sec^-1
3a	19.562	8.825	4.652	2.563	0.426
3b	2.914	2.097	1.158	0.678	0.211
3c	2.914	1.03	0.750	0.470	0.150
3d	6.04	4.50	2.490	1.480	0.610

The plot of l/a-x Vs. time of kinetic measurements carried using equal concentration of acetyl acetone (0.1M) and bisanilino disulphide (0.1M) in DMSO as an oxidant and solvent as a representative case. The slope of straight line of the plot gives the rate constant.

The graph of log dx/dt against log X was plotted. The slope of the plot was found to be nearly one, which indicates that the reaction is first order with respect to bisanilino disulphide.

The negative values of entropy of activation (ΔS#) indicate that activated complex is less probable and the rate of reaction is slow. The values of (ΔH#) and (ΔS#) are consistent which indicate that the reaction proceeds through organized transition state. The bond breaking and bond formation are of almost equal magnitude. The consistency of (ΔG#) values suggest that similar mechanism is operative in all the cyclocondensation leading to 2, 3-disubstituted l, 4-benzothiazines. Frequency factor values are far below l0 ^l3 which shows that the reaction is initially between neutral molecules.

The order of reaction of cyclocondensation at identical temperature using similar Oxidants performed in different solvents was found to be DMSO > acetonitrile > ethanol This indicates that protic solvents might be reducing nucleophilic behaviour of bisanilino disulphide due to intermolecular hydrogen bonding. The rates of cyclocondensation, carried separately under similar reaction conditions by varying 1, 3-dicarbonyls in different solvents in the presence of DMSO as an oxidant was found to be Ethyl acetoacetate > acetyl acetone > benzoyl acetone > dibenzoyl methane

The oxidative cyclocondensation was performed separately by varying concentrations of bisanilino disulphide and keeping the concentrations of l, 3-dicarbonyls constant and vice versa in solvents DMSO/ethanol/acetonitrile at 348 K using an oxidant DMSO. The rate constants have been calculated and also obtained graphically which was found to be first order with respect to l,3- dicarbonyls and also first order with bisanilino disulphide clearly indicating that overall order of the reaction is two.

It was found that the rates of the reaction have been found to be increased with increase in concentrations of bisanilino disulphide and 1,3-dicarbonyls. In this cyclocondensation the substrates l, 3-dicarbonyls are not having compositional similarities and therefore linear free energy relationship [Hammatte relationship] has not been determined/ established. The rate of cyclocondensation was found to be enhanced with increase in temperature which has helped to optimize the reaction conditions.

Rate expression:

1. Generation of bisanilino disulphide.

2. Cyclocondensation of disulphide with 1, 3-dicarbonyls/diketone.

A+D k₁ In₁-------------------------------------------------- (1)

In ₁k₂In ₂----------------------------------------------------(2)

In ₂ k₃ product + o-aminobenzenethiol + H₂O----------(3)

The cyclocondenced product 2, 3-disubstituted l, 4-benzothizines is formed in Step-3.

Hence the rate of the cyclocondensation is directly proportional concentration of In ₂.

[In₂]

i.e.= k₃[ In₂] -------------------------------------------(4)

To determine the concentration of the intermediate, In₂is quite difficult. However it should be expressed in terms of measurable quantities. Hence applying steady state condensation to In₂which is formed in Step-2 and removed in Step-3

Rate of formation of In₂= Rate of removal of In₂

k₂[In₁] = k₃[In₂]

[In₂] =

Substituting the value of In₂ in equation 4

=k₃

= k₂[ In₁] ---------------------------------------------(5)

Even concentration of In₁ is also not measurable and can be determined by applying steady state condensation

i.e. Rate of formation of In₁=Rate of remove of In₁

k₁ [A] [D] = k₂[In₁]

[In₂] =

Substituting the value of In₁ in equation 5

= k ₂

= k₁[A] [D]

k₁ is constant, Thus,

[A] [D]

Total order of reaction=1 +1=2

This indicates that the cyclocondensation is first order with respect to bisanilino disulphide [A] and also with respect to 1, 3-dicarbonyls [D] Thus over all order of condensation is second.

Hence theoretically derived rate law expression on the basis of proposed mechanism is in good agreement with the experimental results. Where the rate constants are calculated using second order rate equation.

Abbreviations used in mechanism and rate expression are

Bisanilino disulphide = A

1, 3-Dicarbonyls = D

2, 3-Disubstituted 1, 4-benzothiazines = P

Intermediates = In₁, In₂

Rate Constants = k₁, k₂, k₃.

5. CONCLUSION:

First time kinetics of cyclocondensation of bisanilino disulphide and 1,3-dicarbonyls has been carried for optimising reaction conditions for getting biodynamic 2,3-disubstituted 1,4-benzothiazines rapidly and cost effectively. From the kinetic study it is observed that an effective convenient general protocol for generating 2,3-disubstituted 1,4-benzothiazines by performing one pot cyclocondensation of bisanilino disulphide and 1,3-dicarbonyls in the presence of stiochiometric DMSO as an oxidant and solvent at 110⁰ c. These optimised conditions are found to give the reaction products with quantitative yields within 90 minutes.

6. CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

7. ACKNOWLEDGEMENT:

Authors are thankful to the managements of Mahyco Research foundation Trust’s, Jalna for encouragement of this research work and for providing necessary laboratory facilities.

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Received on 05.06.2021 Modified on 08.07.2021

Asian J. Research Chem. 2021; 14(5):339-344.

DOI: 10.52711/0974-4150.2021.00058

Name of diketones	Frequency Factor (A) Sec^-1	Energy of activation (Ea)^#KJmol ^-1	Enthaply of activation (ΔH)^#KJmol ^-1	Entropy of activation (ΔS)^#KJmol ^-1	Free energy (ΔG)^# KJmol ^-1
3a	3.945	5751.8014	2609.11	-284.7	110.2155
3b	7.031	4114.7208	972.029	-300.6	114.592
3c	24.04	3502.0122	359.32	-305.9	115.9721
3d	5.984	3572.8566	430.165	-295.7	112.1893