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

The kinetics of oxidation of (phenylthio)acetic acid (PTAA) by N-Bromophthalimide (NBP) in acetonitrile-water solvent mixture at 298 K in the presence of perchloric acid has been followed potentiometrically. The reaction is first-order each in NBP and PTAA and inverse fractional-order in H. Also, it has been found that the reaction rate is not affected by changes in ionic strength of the reaction medium or by the addition of chemicals such as phthalimide, acrylonitrile and potassium bromide. However, an increase in the water content of the solvent mixture causes an increase in the rate of reaction. These observations have been well analyzed in favour of a SN2-type mechanism, involving NBP itself as the reactive species. 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 bromosulphonium ion intermediate in the rate-determining step.


Experimental
The (phenylthio)acetic acids were prepared by known methods 20 and were purified by repeated recrystallisations from aqueous ethanol.Doubly distilled water was used throughout the experiment, the second distillation being from permanganate.AR grade N-bromophthalimide (Aldrich), perchloric acid (E.Merck) and GR grade sodium perchlorate were used as received.Acetonitrile was purified 21 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 22 .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 NBP 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 NBP over PTAA was prepared and allowed to react overnight.Then the unreacted NBP was estimated, which established a 1:1 stoichiometry between NBP and PTAA, as represented in the Scheme 1.

Results and Discussion
The kinetics of oxidation of PTAA by NBP 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] >> [NBP]).The ionic strength of the medium was maintained by the addition of NaClO Also, the plot of 1/k obs versus 1/[PTAA] is linear passing through origin (Figure 1), thus excluding a Michaelis-Menten type of mechanism.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 = 0.989) with a negative slope (Figure 2), establishing the inhibitory role of H + .The result obtained in the present study can be rationalized if NBP 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 24 .

Figure 2. Effect of [H + ] in the oxidation of PTAA with NBP
The rate of the reaction is not significantly affected by the change in the ionic strength 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 rate-determining 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.Mechanism of Oxidation of (p-Substituted Phenylthio)acetic Acids 5 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 KBr has no effect on the rate of oxidation (Table 3), establishing that the course of the oxidation does not involve Br + ion or Br 2 as active species.An increase in the water content of acetonitrilewater 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 NBP at 298 K are collected Table 4. Electron-releasing 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 = -3.22±0.05,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 25 to be the probable reactive species.The observation that the reaction rate is not affected by added phthalimide excludes the possibility of HOBr or H 2 O + Br being the reactive species 26 .The reaction rate is independent of the added KBr concentration, which indicates that neither bromonium ion nor molecular bromine is involved in the rate-determining step of the reaction 27 .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 26a , a zero-order dependence to the involvement of the HOX active species 28 and a fractional-order dependence to the involvement of the >NXH+ active species 24,29 .In the present investigation, therefore, the negative fractional-order dependence on [H + ] establishes the involvement of NBP itself as reactive species.Based on these kinetic observations, the following mechanism (Scheme 2) has been proposed. (3) slow (3) 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 NBP becomes inactive in the form of NBPH + 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 30 , aspirin 18 and α-hydroxy acids 31 by NBP, amino acids by NBS 32 , secondary amines by CAT 32 and L-tyrosine by BAB 33 , where the N-halo reagent itself has been proposed as reactive oxidizing species.
The rate law can be expressed as The high ρ value (-3.22) obtained in the present study provides support for the chlorosulphonium ion intermediate, (CH 2 COOH)PhS + Br 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 24 (-3.33),NBA 34 (-2.37),NBB 13 (-3.18),CAT 35 (-4.25) and Br 2 36 (-3.2),where the intermediacy of such halosulphonium ions has been proposed.

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

Figure 1 .
Figure 1.Double reciprocal plot for the oxidation of PTAA with NBP The k obs values measured at different initial concentrations of H + for the oxidation of PTAA (Table1) reveal that the reaction rate decreases slightly with increase in the concentration of H + .The plot of k 2 versus [H + ] is linear (r = 0.989) with a negative slope (Figure2), establishing the inhibitory role of H + .The result obtained in the present study can be rationalized if NBP 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 NCS24 .

aFigure 3 .
Figure 3. Plot of log k obs versus 1/ε for the oxidation of PTAA with NBP 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 NBP at 298 K are collected Table 4. Electron-releasing 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 = -3.22±0.05,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.Table 4. Pseudo first-order and second-order rate constants for the oxidation of thioacids, X-C 6 H 5 SCH 2 COOH by NBP at 298 K a X 10 4 k obs , s -1 10 2 k 2 , M -1 s -1 OMe 78.0 ± 6.9 390 ± 35 Me 33.9 ± 3.0 170 ± 15 H 8.48 ± 0.68 42.3 ± 3.5 F 5.65 ± 0.43 28.3 ± 2.2 Cl 1.73 ± 0.14 8.65 ± 0.70 NO 2 0.03 ± 0.00 0.15 ± 0.00 .I. ALHAJI et al.

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

Table 1 .
Pseudo-first-order and second-order rate constants for the oxidation of PTAA by NBP in aqueous acetonitrile at 298 K a,b 4. The pseudo-firstorder rate constants, k obs and the second-order rate constants, k 2 at different initial concentrations of NBP, 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 NBP; this coupled with the observation of linear ln(E t -E ∞ ) versus time plots ensures that the order of the reaction in NBP 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 = 1.02 ± 0.04, r = 0.997) indicate that the reaction follows first-order kinetics with respect to [PTAA].c Estimated from pseudo-first-order plots over 60% reaction.d Individual k 2 values estimated as k obs /[PTAA] o

Table 3 .
Influence of added acrylonitrile (AN), KBr and solvent composition on reaction rate for the oxidation of PTAA with NCSA at 298 K 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 NBP at 298 K a