Mechanism of Oxidation of ( p-Substituted Phenylthio ) acetic Acids with N-Chlorosaccharin

The kinetics of oxidation of (phenylthio)acetic acid (PTAA) with N-chlorosaccharin (NCSA) have been studied potentiometrically in 80:20 (v/v) acetonitrile-water medium at 298 K. The reaction is first-order each with respect to PTAA and NCSA and shows a negative dependence on [H]. NCSA itself is shown to be the active oxidizing species. Effects of ionic strength variation, added saccharin, added acrylonitrile, added NaCl and solvent composition variation have been studied. Effect of substituents on the reaction rate has been analysed by employing various (p-sustituted phenylthio)acetic acids. The electron-releasing substituent in the phenyl ring of PTAA accelerates the reaction rate while the electron-withdrawing substituent retards the rate. The excellently linear Hammett plot yields a large negative ρ value, supporting the involvement a chlorosulphonium ion intermediate in the rate-determining step.


Introduction
N-halo compounds find increasingly vast usage 1 as oxidant for the synthesis of a variety of organic compounds as they are the sources of positive halogen and the mechanism of these reactions depends on the nature of active oxidising species, which in turn depends on the nature of halogen atom, the groups attached to the nitrogen atom and the reaction conditions.The list of N-halo compounds being extensively used for kinetic studies includes N-chloroand N-bromo-benzenesulphonamide 2,3 , N-bromo-and N-chloroacetamide 4 , N-chloroand N-bromosuccinimide [5][6][7][8] , N-chloronicotinamide 9 , N-chloro-and N-bromo-benzamide 10 , N-chloro-and N-bromosaccharin 11,12 , chloramines-T 13 , etc. Investigations on kinetics of oxidation of hydroxy acids 11a , alcohols 11b , aldehydes 12a , amino acids 7b , thiosemicarbazides 7c , alcohols 8a and sulphides 8b with N-halo compounds are a bound in literature.However, no study involving (phenylthio)acetic acids and N-chlorosaccharin has been reported so far.Keeping these points in mind, we thought it fit to study the kinetics and mechanism of oxidation of (p-substituted phenylthio)acetic acids (p-X-C 6 H 4 SCH 2 COOH; X = H, OCH 3 , CH 3 , F, Cl and NO 2 ) with NCSA.Hereunder, the results obtained in the present study are presented.

Experimental
The (phenylthio)acetic acids were prepared by known methods 14 and were purified by repeated recrystallisation from aqueous ethanol.Doubly distilled water was used throughout the experiment, the second distillation being from permanganate.AR grade N-chlorosaccharin (Aldrich), perchloric acid (E.Merck) and GR grade sodium perchlorate were used as received.Acetonitrile was purified 15 by refluxing with P 2 O 5 .

Kinetic measurements
The kinetic runs were carried out in 80% acetonitrile -20% water (v/v) solvent mixture in acid medium, the acid strength being maintained by the addition of HClO 4 and the ionic strength by NaClO 4 .The kinetics were followed potentiometrically in a manner as described earlier 16 .The emf of the cell was measured periodically using an Equip-Tronics potentiometer while the reaction mixture was magnetically stirred continuously.The temperature of the reaction mixture was maintained at the desired value to an accuracy of ± 0.1 o C by circulating thermostated water in the reaction vessel.The pseudo first-order rate constants (k obs ) were calculated from the slopes of ln(E t -E ∞ ) versus time plots (r > 0.990) and the results were reproducible to an accuracy of ± 5%.The second-order rate constants (k 2 ) were obtained as k obs /[PTAA].

Product analysis
In a typical experiment, the reaction mixture containing 50 fold excess of PTAA over NCSA was kept overnight under stirring.The solvent was removed by distillation.The residue was then extracted with ether.The extract was dried over anhydrous sodium sulphate and the solvent evaporated.The residue was subjected to TLC analysis on a silica gel plate developed in a solvent system of n-butanol-acetic acid-water (40-10-50%, upper layer was used).The residue gave two spots, which were made visible by exposure to iodine; one corresponding to (phenylthio)acetic acid (R f = 0.84) and the other to phenylsulphinylacetic acid (R f = 0.45).Further, the IR spectra of the residue showed an intense absorption band at 1050 cm -1 characteristic of SO stretching frequency.The formation of corresponding phenylsulphinylacetic acid as the product was also confirmed with other (p-substituted phenylthio)acetic acids also.

Stoichiometry
In a typical experiment, a reaction mixture containing 10 times excess of NCSA over PTAA was prepared and allowed to react overnight.Then the unreacted NCSA was estimated, which established a 1:1 stoichiometry between NCSA and PTAA, as represented in Scheme 1.

Results and Discussion
The kinetics of oxidation of PTAA by NCSA was carried out potentiometrically in 80:20 (v/v) acetonitrile-water mixture at 298 K in the presence of perchloric acid at constant ionic strength under pseudo first-order conditions ([PTAA] >> [NCSA]).The ionic strength of the medium  The k obs values measured at different initial concentrations of H + for the oxidation of PTAA (Table 1) reveal that the reaction rate decreases slightly with increase in the concentration of H + .The plot of k 2 versus [H + ] is linear (r = 0.996) with a negative slope (Figure 2), establishing the inhibitory role of H + .The result obtained in the present study can be rationalized if NCSA itself is considered to be the oxidizing species.A similar conclusion has been arrived at in the oxidation of alkyl phenyl and diphenyl sulphides with NCS 6 .

Figure 2. Effect of [H + ] in the oxidation of PTAA with NCSA.
The rate of the reaction is not significantly affected by the change in the ionic strength (I) of the medium (Table 2) brought about by the addition of sodium perchlorate, pointing out the participation of a neutral species as a reactant in the ratedetermining step.The addition of saccharin has no effect on the rate of oxidation (Table 2), suggesting that the step in which saccharin is formed as one of the products is not reversible.The involvement of free-radical intermediates during the reaction can be excluded as the rate constant is not affected by the addition of acrylonitrile (Table 3).The added NaCl has no effect on the rate of oxidation (Table 3), establishing that the course of the oxidation does not involve chloronium ion or molecular chlorine as active species.An increase in the water content of acetonitrile-water solvent system causes an increase in the rate of oxidation (Table 3).A plot of log k obs versus 1/ε is linear (Figure 3; r = 0.996) with a negative slope indicating that the transition state is more polarized than the two reactants together in the initial state.The pseudo first-order and second-order rate constants for the oxidation of these (p-substituted phenylthio)acetic acids with NCSA at 298 K are collected Table 4. Electronreleasing substituents in the phenyl ring accelerate the rate, while electron-donating substituents produce the opposite effect.The log k 2 values show excellent correlation with σ p values (Figure 4; slope = -3.12± 0.08, r = 0.998).The negative value of ρ indicates an accumulation of positive charge at the reaction sulphur centre, while the magnitude of ρ value indicates the extent of charge development on the sulphur atom in the transition state of rate-determining step.

Mechanism
In earlier studies with N-halo compounds in aqueous acid medium, X + , X 2 , HOX, H 2 O + X and >NXH + are discussed 18 to be the probable reactive species.The observation that the reaction rate is not affected by added saccharin excludes the possibility of HOCl or H 2 O + Cl being the reactive species 19,22 .The reaction rate is independent of the added NaCl concentration, which indicates that neither chloronium ion nor molecular chlorine is involved in the rate-determining step of the reaction 9,23 .Also, the previous studies illustrate that a first-order dependence of rate of oxidation on [H + ] is attributed to the involvement of H 2 O + X active species 19 , a zero-order dependence to the involvement of the HOX active species 20 and a fractional-order dependence to the involvement of the >NXH + active species 6,21 .In the present investigation, therefore, the negative fractional-order dependence on [H + ] establishes the involvement of NCSA itself as reactive species.Based on these kinetic observations, the following mechanism (Scheme 2) has been proposed. (2) The mechanism in Scheme 2 accounts for the decrease in rate of oxidation with increasing [H + ].When the concentration of H + in the reaction solution is increased, more and more NCSA becomes inactive in the form of NCSAH + species (eq.1), thereby causing a decrease in the rate of reaction.Similar conclusion has been arrived at in the studies of oxidation of acetophenone 24 , aspirin 25 and α-hydroxy acids 26 by NBP, amino acids by NBS 27 , secondary amines by CAT 27 and L-tyrosine by BAB 28 , where the N-halo reagent itself has been proposed as reactive oxidizing species.
The rate law can be expressed as The high ρ value (-3.12) obtained in the present study provides support for the chlorosulphonium ion intermediate, (CH 2 COOH)PhS + Cl in the reaction.This conclusion is further supported by the fact that the present ρ value is analogous to those reported for the oxidations of organic sulphides with NCS 6 (-3.33),NBA 29 (-2.37),NBB 30 (-3.18), CAT 31 (-4.25) and Br 2 18b (-3.2),where the intermediacy of such halosulphonium ions has been proposed.

Conclusion
The NCSA oxidation of (p-substituted phenylthio)acetic acids follows a S N 2 type mechanism, in which NCSA itself is the oxidizing species.The proposed mechanism has been well substantiated by substituent effect studies.

3 . 9 aFigure 3 .
Figure 3. Plot of log k obs versus 1/ε for the oxidation of PTAA with NCSA The effect of substituents at the 4-position of the phenyl ring of PTAA was also studied.The pseudo first-order and second-order rate constants for the oxidation of these (p-substituted phenylthio)acetic acids with NCSA at 298 K are collected Table4.Electronreleasing substituents in the phenyl ring accelerate the rate, while electron-donating substituents produce the opposite effect.The log k 2 values show excellent correlation with σ p values (Figure4; slope = -3.12± 0.08, r = 0.998).The negative value of ρ indicates an accumulation of positive charge at the reaction sulphur centre, while the magnitude of ρ value indicates the extent of charge development on the sulphur atom in the transition state of rate-determining step.

Figure 4 .
Figure 4. Hammett plot for the oxidation of (p-substituted phenylthio)acetic acids by NCSA at 298 K Scheme 1Scheme 2

Table 1 .
Mechanism of Oxidation of (p-Substituted Phenylthio)acetic Acids was maintained by the addition of NaClO 4 .The pseudo first-order rate constants, k obs and the second-order rate constants, k 2 at different initial concentrations of NCSA, PTAA and H + are presented in Table1.At constant initial concentration of PTAA, k obs values remain almost constant upon varying the initial concentration of NCSA; this coupled with the observation of linear ln(E t -E ∞ ) versus time plots ensures that the order of the reaction in NCSA is one.Also, the rate data in Table1point out that k obs value increases linearly in a first-order fashion with increase in the initial concentration of PTAA.Similar trend is observed in the k obs and k 2 values for the oxidation of other (p-substituted phenylthio)acetic acids.The constancy of k 2 at varying initial concentrations of PTAA (Table1) and the excellent linearity of the plot of log k obs versus log [PTAA] with unit slope (slope = 1.013 ± 0.003, r = 0.999) point out that the reaction follows first-order kinetics with respect to[PTAA].Also, the plot of 1/k obs versus 1/[PTAA] is linear passing through origin (Figure1; r = 0.999), thus excluding a Michaelis-Menten type of mechanism.Pseudo-first-order and second-order rate constants for the oxidation of PTAA by NCSA in aqueous acetonitrile at 298 Ka,b PhSOCH2COOH PhSCH2COOH 1/Kobs, S 1/ [PTAA]o, M -1

Table 2 .
Influence of ionic strength and saccharin on reaction rate for the oxidation of PTAA with NCSA a

Table 4 .
Pseudo-first-order and second-order rate constants for the oxidation of thioacids, X-C 6 H 5 SCH 2 COOH by NCSA a