Kinetics and Mechanism of Permanganate Oxidation of Clopidogrel

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Kinetics and Mechanism of Permanganate Oxidation of Clopidogrel Hydrogen Sulfate: An Antiplatelet Drug in Acid Perchlorate Solutions Kirthi S. Byadagi, Rajeshwari V. Hosahalli, Sharanappa T. Nandibewoor, and Shivamurti A. Chimatadar* P. G. Department of Studies in Chemistry, Karnatak University, Pavate Nagar, Dharwad 580003, India ABSTRACT: The oxidation of clopidogrel hydrogen sulfate, commercially known as Plavix, by permanganate ion in aqueous perchloric acid medium at a constant ionic strength (I = 0.06 mol dm3) has been investigated spectrophotometrically at 526 nm. The reaction between clopidogrel hydrogen sulfate and permanganate in acid medium exhibits a 5:4 stoichiometry. The identified oxidation products, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, (2-chlorophenyl)oxoacetic acid, and formaldehyde as a byproduct, are different from those obtained by biological metabolism. The reaction is first-order in MnO4 and less than first-order in both the clopidogrel hydrogen sulfate and H+ ion concentrations. The active species of permanganate was found to be HMnO4. The oxidation reaction in acid medium was found to proceed through a permanganateclopidogrel complex that decomposes slowly in a rate-determining step followed by other fast steps to give the products. The main products were identified by spot test and IR and GC-MS spectral studies. The reaction constants involved in different steps of the mechanism were calculated at different temperatures. The activation parameters with respect to the slow step of the mechanism were computed, and thermodynamic quantities were also determined.

1. INTRODUCTION Potassium permanganate is widely used as an oxidizing agent in both synthetic and analytical chemistry and also as a disinfectant.1 Among the six oxidation states of manganese from 2+ to 7+, permanganate, Mn(VII), is the most potent oxidation state in both acidic and alkaline media.1 Oxidation by permanganate ion finds extensive application in organic synthesis.2 In general, the reduction1 of permanganate in slightly basic or neutral solution and in acid media goes through Mn(IV) and Mn(II), with reduction potentials3 of 1.695 V for Mn(VII)/Mn(IV) and 1.51 V for Mn(VII)/Mn(II). In acid medium, permanganate exists in different forms, namely, HMnO4 and H2MnO4+, and depending on the nature of the reductant, the oxidant has been assigned both inner-sphere and outer-sphere mechanism pathways in their redox reactions.1,4,5 Clopidogrel hydrogen sulfate {D-methyl(2-chlorophenyl)-5(4,5,6,7-tetrahydrothieno)[3,2-c]pyridinyl acetate hydrogen sulfate} (CHS) is a thienopyridine prodrug used clinically to inhibit ADP-induced platelet aggregation. Clopidogrel is inactive in vitro and requires in vivo oxidation by hepatic/intestinal cytochrome P450 isoenzymes. The majority of clopidogrel6 is hydrolyzed by esterases to an inactive carboxylic acid derivative that accounts for 85% of the clopidogrel-related compounds circulating in plasma. P450 catalyzes the oxidation of the thiophene ring of clopidogrel to 2-oxoclopidogrel. The 2-oxo intermediate is then oxidized further by P450. The second oxidation results in opening of the thiophene ring to form both a carboxyl group and a thiol group. The thiol group forms a disulfide bond with the P2Y12 ADP receptor on platelets.6 The biological metabolism7 of clopidogrel is depicted in Scheme 1. Clopidogrel hydrogen sulfate is freely soluble in water, but its solubility is strongly pH-dependent. The site of absorption of such drugs is restricted to the acidic environment of the stomach, and the bioavailability varies according to the actual pH of the gastrointestinal tract. The aqueous solution of clopidogrel hydrogen r 2011 American Chemical Society

sulfate (100 mg/mL) is strongly acidic. Adjustment of the pH toward a physiologically acceptable value sharply decreases the solubility of the salt; above pH 5, the base form of the drug, which has a gummy consistency, is precipitated. The base form of the drug is practically insoluble in water, with a solubility8 of less than 0.02 mg/mL. A literature survey reveals that there are no reports on the oxidation of clopidogrel by any oxidant in either acidic or alkaline medium. In view of the potential pharmaceutical importance of clopidogrel and the lack of reported kinetic and mechanistic data on the oxidation of this drug by oxidants other than those involved in biological metabolism,7 a detailed oxidation study might elucidate the mechanism of conversion of such compounds. The present investigation is aimed at checking the reactivity of clopidogrel toward permanganate in acid medium, determining the redox chemistry of Mn(VII) in such media, and establishing a plausible mechanism.

2. EXPERIMENTAL SECTION 2.1. Materials and Reagents. All chemicals were of analytical reagent grade, and doubly distilled water was used throughout this work. An aqueous solution of clopidogrel hydrogen sulfate (CHS) (Viva Drugs Pvt. Ltd.) was prepared by maintaining the pH lower than 1.0. The purity of the drug was checked by comparing its IR spectrum and melting point with the literature data (mp 177 °C, lit. 178 °C). Permanganate stock solution was obtained by dissolving potassium permanganate (Glaxo, Analar) in water and standardized by titrating against oxalic acid.9 Freshly prepared and standardized permanganate solutions were always used in the kinetics experiments. Manganese(II) solution was Received: January 24, 2011 Accepted: August 20, 2011 Revised: July 23, 2011 Published: August 21, 2011 10962

dx.doi.org/10.1021/ie200164g | Ind. Eng. Chem. Res. 2011, 50, 10962–10971

Industrial & Engineering Chemistry Research

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Scheme 1. Biological Metabolism of Clopidogrel Hydrogen Sulfate

Figure 1. First-order plots of oxidation of clopidogrel hydrogen sulfate by permanganate at 25 °C. Conditions: [CHS] = 1.0 103; [HClO4] = 1.0 102; I = 0.06; [MnO4] = (1) 0.5, (2) 1.0, (3) 2.0, (4) 3.0, and (5) 4.0 104 mol dm3.

prepared by dissolving manganese sulfate (AR) in water. Perchloric acid (Glaxo, Excelar) and sodium perchlorate were used to provide the required acidity and ionic strength, respectively. 2.2. Instruments Used. For kinetic measurements, a Peltier accessory (temperature-controlled) attached to a varian CARY 50 Bio UVvis spectrophotometer (Varian, Victoria, Australia) was used. For product analysis, a Shimadzu 17A gas chromatograph with a Shimadzu QP-5050A mass spectrometer using the electron impact (EI) ionization technique, a Nicolet 5700 FT-IR spectrometer (Thermo Electron Corporation, Madison, WI), and an Elico model LI120 pH meter were used. 2.3. Kinetic Measurements. All kinetics was followed under pseudo-first-order conditions, where the concentration of clopidogrel was much greater than that of permanganate at 25 ( 0.1 °C (unless otherwise specified) and at a constant ionic strength of 0.06 mol dm3. The reaction was initiated by mixing thermally equilibriated (25 ( 0.1 °C) solutions of permanganate and clopidogrel that also contained the required concentrations of HClO4 and NaClO4. The progress of the reaction was followed spectrophotometrically at 526 nm as a function of time by monitoring the decrease in the absorbance of permanganate in a 1-cm cell placed in the thermostatted compartment of a Varian CARY 50 Bio UVvisible spectrophotometer. The application of Beer’s law under the reaction conditions was previously verified in the permanganate concentration range of (0.505.0) 104 mol dm3 at 526 nm in 1.0 102 mol dm3 perchloric

acid. The molar absorptivity index of permanganate at 526 nm was found to be ε = 2200 ( 50 dm3 mol1 cm1. The kinetics was followed to more than 85% completion of the reaction, and good first-order kinetics was observed. The pseudofirst-order rate constants, kobs, were calculated from the slopes of plots of the logarithm of absorbance versus time (Figure 1). The pseudo-first-order plots were linear to over 80% completion of the reaction. The kobs values were reproducible within (5% and are the averages of at least three independent kinetic runs (Table 1). The spectral changes during the oxidation reaction are shown in Figure 2.

3. RESULTS 3.1. Stoichiometry and Product Analysis. Different sets of reaction mixtures containing excess permanganate with respect to clopidogrel in the presence of constant concentrations of HClO4 and NaClO4 were kept in closed containers under a nitrogen atmosphere at 25 °C. After 2 h, the unreacted permanganate concentration was assayed spectrophotometrically by measuring the absorbance at 526 nm. The results indicated that 5 mol of clopidogrel hydrogen sulfate consumed 4 mol of permanganate according to the Scheme 2. The oxidation products were isolated using the thin-layer chromatography (TLC) separation technique and characterized by physicochemical spectral studies. The reaction products were identified as Mn2+, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (A), (2-chlorophenyl)oxoacetic acid (B), and formaldehyde as a byproduct. Mn2+ was confirmed by UVvis spectra and spot test.9 Products A and B were confirmed by IR (KBr) spectra. The IR spectrum of A showed an amide stretching band at 3381.6 cm1

Scheme 2. Stoichiometry of Oxidation of Clopidogrel by Acidic Permanganate

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Table 1. Effects of Variations in the MnO4, CHS, and HClO4 Concentrations on the Oxidation of Clopidogrel Hydrogen Sulfate by Permanganate in Perchlorate Solutions at 25 °C and I = 0.06 mol dm3 kobs (103 s1) [MnO4] (104 mol dm3)

[CHS] (103 mol dm3)

[H+] (mol dm3)

found

calculated

0.5

3.0

1.0

2.17

2.24

1.0

3.0

1.0

2.12

2.24

2.0 3.0

3.0 3.0

1.0 1.0

2.22 2.12

2.24 2.24

4.0

3.0

1.0

2.20

2.24

5.0

3.0

1.0

2.11

2.24

1.0

0.5

1.0

1.21

1.20

1.0

0.8

1.0

1.79

1.84

1.0

1.0

1.0

2.22

2.24

1.0

2.0

1.0

3.86

3.91

1.0 1.0

3.0 4.0

1.0 1.0

5.08 6.02

5.21 6.26

1.0

5.0

1.0

8.00

7.11

1.0

1.0

0.5

1.43

1.39

1.0

1.0

0.8

1.84

1.94

1.0

1.0

1.0

2.22

2.24

1.0

1.0

2.0

2.93

3.22

1.0

1.0

3.0

3.92

3.77

1.0 1.0

1.0 1.0

4.0 5.0

4.28 4.79

4.12 4.36

Figure 2. Spectral changes during the oxidation of clopidogrel hydrogen sulfate by permanganate in perchlorate solutions at 25 °C. Conditions: [MnO4] = 1.0 104, [CHS] = 1.0 103, [HClO4] = 1.0 102, and I = 0.06 mol dm3 (scanning time interval is 1 min).

(Figure 3a), and that of B showed two CdO stretching bands at 1667.5 and 1744.9 cm1 and an OH stretch at 3409.0 cm1 (Figure 3b). The presence of A and B was also confirmed by gas chromatography mass spectrometry (GC-MS) analysis. GC-MS data were obtained on a Shimadzu 17A gas chromatograph with a Shimadzu QP-5050A mass spectrometer using the EI ionization technique. The mass spectrum of product A showed a molecular

ion and base peak at 139 amu (Figure 4a), and that of product B showed a molecular ion peak at 184 amu (Figure 4b). All other peaks observed in the GC-MS spectra can be interpreted in accordance with the structures of products A and B. The byproduct formaldehyde was identified by spot test.10 The identified products were different from those obtained by biological metabolism. In the case of biological metabolism, the obtained products 10964



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were 85% clopidogrel inactive metabolite and 15% clopidogrel active metabolite. 3.2. Reaction Orders. The reaction orders were determined from the slopes of log kobs versus log(concentration) plots constructed by varying the concentrations of clopidogrel and perchloric acid in turn, keeping all other concentrations and conditions constant. 3.3. Dependence of Rate on the Concentration of Permanganate. The oxidant permanganate concentration was varied in the range of (0.55.0) 104 mol dm3, keeping all other conditions constant. At different permanganate concentrations, fairly constant kobs values were obtained, indicating a first-order dependence with respect to the permanganate concentration (Table 1). This was also confirmed by the linearity of the plots of log(absorbance) versus time up to 80% completion of the reaction (Figure 1). 3.4. Dependence of Rate on the Concentration of Clopidogrel Hydrogen Sulfate. The effect of clopidogrel hydrogen sulfate (CHS) on the rate of reaction was studied at constant concentrations of permanganate and HClO4 at a constant ionic strength of 0.06 mol dm3 at 25 °C. The substrate was varied in the range of (0.55.0) 103 mol dm3. The kobs values increased with increasing concentration of clopidogrel (Table 1). From the value of the slope of the plot of log kobs versus log [CHS], the reaction order with respect to the concentration of CHS was found to be less than unity (0.79). 3.5. Dependence of Rate on the Concentration of Perchloric Acid. The effect of an increase in the concentration of acid on the reaction was studied at constant concentrations of permanganate and clopidogrel at a constant ionic strength of 0.06 mol dm3 at 25 °C. The acid concentration was varied in the range of (0.55.0) 102 mol dm3. The rate constants were found to increase with increasing perchloric acid concentration (Table 1). From the value of the slope of the plot of log kobs versus log [HClO4] the reaction order with respect to the concentration of HClO4 and was found to be less than unity (0.52). Based on these experimental results, the rate law can be written as rate ¼ kobs ½MnO4 ½CHS0:79 ½Hþ 0:52

Table 2. Effects of Temperature on the Oxidation of Clopidogrel Hydrogen Sulfate by Permanganate in Aqueous Perchlorate Solutions (a) Rate Constant with Respect to the Slow Step of Scheme 3 temperature (°C)

k (102 s1)

15

0.64

25

1.56

35

3.40

45

7.23 (b) Activation Parameters

parameter Ea (kJ mol

1

value 61 ( 3

)

ΔH‡ (kJ mol 1)

59 ( 3

ΔS‡ (J K1 mol1)

81 ( 2

ΔG‡ (kJ mol 1) log A

83 ( 2 9 ( 0.1 (c) Effects of Temperature on the First and Second Equilibrium Steps of Scheme 3 K2 (102 dm3

temperature 1

K1 (10

(°C)

3

1

dm mol )

mol1)

15

4.24

4.19

25

4.05

5.78

35

3.94

5.95

45

3.75

6.28

(d) Thermodynamic Quantities with Respect to First and Second

ð1Þ

Steps of Scheme 3 thermodynamic

3.6. Dependence of Rate on Ionic Strength (I) and Dielectric Constant (D). The ionic strength was varied between

0.06 and 0.22 mol dm3 by varying concentration of NaClO4. The addition of NaClO4 at constant concentrations of reactants and other conditions showed that increasing ionic strength had a negligible effect on the rate of reaction. The effect of dielectric constant was studied by varying the acetic acid/water (v/v) content in the reaction mixture from 0% to 40%, with all other conditions being maintained constant. It was found that the rate decreased with decreasing dielectric constant of the reaction medium (Figure 5). 3.7. Effect of Initially Added Products. Because Mn(II) is one of the oxidation products, its effect on the rate of reaction was investigated in the range of (0.503.0) 104 mol dm3, keeping the reactant concentrations and other conditions constant. It was found that Mn(II) had no significant effect on the rate of reaction. 3.8. Polymerization Study. The intervention of free radicals was examined as follows: A known quantity of acrylonitrile scavenger was added to the reaction mixture, which was then kept under an inert atmosphere for 2 h at room temperature. Upon dilution of the

quantity

value from K1

value from K2

ΔH (kJ mol 1)

3 ( 0.08

ΔS (J K1 mol1)

21 ( 0.6

84 ( 3

ΔG (kJ mol 1)

9 ( 0.04

16 ( 0.8

10 ( 0.3

reaction mixture with methanol, no precipitate was formed, which indicates the absence of intervention of free radicals in the reaction. 3.9. Effect of Temperature. The rate of reaction was measured at different temperatures, namely, 15, 25, 35, and 45 °C, with varying concentrations of acid and clopidogrel hydrogen sulfate, keeping other conditions constant. The rate of reaction was found to increase with increasing temperature. The rate constant of the slow step (k), the formation constant of HMnO4 (K1), and the formation constant of complex (K2) in Scheme 3 were obtained from the intercepts and slopes of the plots of 1/kobs versus 1/[H+] (Figure 6a) and 1/kobs versus 1/[CHS] (Figure 6b) at four different temperatures. The energy of activation, Ea, was evaluated from the slope of an Arrhenius plot of 10965



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Figure 3. FT-IR spectra of (a) 4,5,6,7-tetrahydrothieno[3,2-c]pyridine and (b) (2-chlorophenyl)oxoacetic acid, the oxidation products of clopidogrel hydrogen sulfate by permanganate.

log k versus 1/T (Table 2). The enthalpy of activation ΔH‡, the entropy of activation ΔS‡ and the free energy of activation ΔG‡ were obtained by using the Eyring equation11 (Table 2). The van’t Hoff plot (log K1 versus 1/T) was drawn, and the thermodynamic quantities were calculated (Table 2).

4. DISCUSSION Permanganate ion, MnO4, is a powerful oxidizing agent in acid medium. The stable oxidation product of MnO4 in acid medium is Mn(II). The spectral changes during the reaction are shown in Figure 2. A literature survey indicated that Mn(IV) ions 10966



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Figure 4. GC-MS spectra of (a) 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, showing the molecular ion peak and base peak at m/z 139 amu, and (b) (2-chlorophenyl)oxoacetic acid, showing the molecular ion peak at m/z 184 amu.

absorb in the range of 400600 nm.12 Figure 2 shows a lack of spectral changes in this wavelength range, which means that MnO2 is not a reaction product. Furthermore, because no rise and fall in the absorption was observed at 418 nm, it is concluded that Mn(IV) does not intervene as a possible oxidizing agent since it is short-lived.12 The reaction between clopidogrel and MnO4 has a stoichiometry 5:4 with a first-order dependence on the MnO4 concentration and less-than-unity orders in both the CHS and HClO4 concentrations. The fact that Mn(II) is the reduced product of Mn(VII) in the reaction might indicate that clopidogrel hydrogen sulfate shows a strong reducing character in HClO4 medium. In view of the presence of perchloric acid in the reaction mixture, the oxidation of CHS by perchloric acid was checked, and it was found to be negligible compared to the oxidation of CHS by permanganate. The active species of permanganate in aqueous acid medium can be deduced from the dependence of the rate on the H+ concentration in the reaction medium. The apparent order less than unity in HClO4 concentration might be an indication of

permanganate species as permanganic acid. In acid medium, permanganic acid (HMnO4) is a more efficient oxidant species of manganese(VII) than permanganate ion.1,13 In addition, it was observed that the reaction rate increased with increasing HClO4 concentration and tended toward a limiting value at high acidities (Figure 7). The plot of kobs versus HClO4 is a curve of decreasing slope (convex to the rate axis) (Figure 7), from which it can be inferred14 that rapid equilibrium with the protonated form is involved. At higher acidities [in the acid concentration range of (0.55.0) 102 mol dm3], protonation is almost complete, leading to the limiting rate; this indicates that only the protonated form is active. The negligible effect of ionic strength on the rate of reaction also confirms that HMnO4 is the active species of MnO4. Thus, in acid medium, MnO4 exists as HMnO4 K1

MnO4 þ Hþ h HMnO4 ½MnðVIIÞ

ð2Þ

where K1 is the formation constant of HMnO4. 10967



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Figure 5. Effects of dielectric constant on the reaction.

Scheme 3. Proposed Mechanism for the Oxidation of Clopidogrel Hydrogen Sulfate by Permanganate in Acid Perchlorate Solution

Figure 6. Verification of rate law (eq 3) in the form of an equation (eq 5) for the oxidation of clopidogrel hydrogen sulfate by permanganate in perchlorate solutions. Plots of 1/kobs versus (a) 1/[H+] and (b) 1/[CHS] at different temperatures. (Conditions as in Table 1.)

In view of these aspects and the experimental observations, a reasonable reaction mechanism can be proposed in which all of the observed orders with respect to the concentrations of constituents, namely, MnO4, CHS, and H+, can be well accommodated. The results suggest that the protonated form of permanganate is the active species of MnO4 in prior equilibrium, which reacts with 1 mol of clopidogrel bisulfate in the second equilibrium step to form a complex that then decomposes in a slow step to give

one of the products, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, the intermediate (2-chlorophenyl)oxoacetic acid methyl ester, and Mn(V). The intermediate undergoes hydrolysis in a further fast step to give the other final product, (2-chlorophenyl)oxoacetic acid, and a second intermediate, methyl alcohol. The formed methyl alcohol reacts with 2 mol of Mn(V) in a fast step to give 2 mol of Mn(IV) and formaldehyde as a byproduct. The formed Mn(IV) reacts with 2 mol of Mn(V) in a fast step to give 2 mol of Mn(II) and Mn(VII), thus satisfying the stoichiometric observations. Although Mn(VI) and Mn(IV) are the final reduced species of MnO4 in alkaline and neutral media, it was observed that Mn(II) was the only reduced species of MnO4 in acid medum (vide infra). The evidence for intermediates such as Mn(V) and Mn(IV) is as presented in the literature.17a,19 A reasonable mechanism is proposed in Scheme 3. Scheme 3 is only one of the possible mechanisms for the reaction. The results indicate the formation of a complex between clopidogrel hydrogen sulfate and HMnO4. The spectral evidence for a complex between the substrate and oxidant was obtained from UVvis spectra of clopidogrel hydrogen sulfate and clopidogrel hydrogen sulfateMnO4 mixtures in which a hypsochromic shift of 5 nm (from 311 to 306 nm) was observed (Figure 8). Complex formation was also confirmed kinetically 10968



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with a MichaelisMenten plot (Figure 6b). The probable structure of the complex C is

Such complex formation between substrate and oxidant has also been reported in the literature.15,16 Substituting eqs 8, 11, and 13 into eq 6 and omitting the subscripts, we have

entropy of activation observed in the decomposition of the intermediate complex is in accordance with the propositions suggested for oxidation reactions of an inner-sphere nature.15

d½MnO4 rate ¼ dt ¼

kK1 K2 ½MnO4 ½Hþ ½CHS 1 þ K1 ½Hþ þ K1 K2 ½Hþ ½CHS

ð3Þ

or rate ¼ kobs ½MnO4 ¼

kK1 K2 ½Hþ ½CHS 1 þ K1 ½Hþ þ K1 K2 ½Hþ ½CHS

ð4Þ

The rate law in eq 6 can be rearranged to the form 1 kobs

1 1 1 þ þ ¼ þ kK1 K2 ½H ½CHS kK2 ½CHS k

Figure 7. Plot of kobs versus [HClO4], a curve of decreasing slope (convex to the rate axis). (Conditions as in Table 1.)

5. CONCLUSIONS The oxidant MnO4 exists in acid medium as HMnO4, which takes part in the chemical reaction. The oxidation of clopidogrel hydrogen sulfate by permanganate is pH-dependent and has a stoichiometry of 5:4. The oxidation products were identified as Mn2+, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, (2-chlorophenyl)oxoacetic acid, and formaldehyde. The oxidation products are different from those obtained from biological metabolism. The proposed mechanism is consistent with all of the experimental results. ’ APPENDIX Derivation of the Rate Equation. According to Scheme 2

ð5Þ

which is suitable for verification. According to eq 5, plots of 1/kobs versus 1/[H+] and 1/kobs versus 1/[CHS] should be linear, and this was found to be the case (Figure 6a,b). From the slopes and intercepts of these plots, the values of k, K1, and K2 at 25 °C were obtained as 1.56 102 dm3 mol1 s1, 4.05 101 dm3 mol1, and 5.78 102 dm3 mol1, respectively. The value of K1 is in good agreement with earlier work.17 The negligible effect of ionic strength is consistent with reaction between two neutral molecules, as in Scheme 3. The effect of solvent on the rate of reaction has been described in the literature.18 An increase in the content of acetic acid in the reaction mixture leads to a decrease in the rate of reaction, which is contrary (Figure 5) to the result expected for a reaction between two neutral molecules in a medium of lower dielectric constant. Perhaps, this effect is countered substantially by the formation of active reactant species to a greater extent in a low-dielectric-constant medium, leading to a net decrease in the rate. The modest activation energy and sizable entropy of activation support a complex transition state in the reaction. The values of ΔH‡ and ΔS‡ are both favorable for electrontransfer processes.19 The negative value of ΔS‡ indicates that the complex is more ordered than the reactants. The high negative

rate ¼

d½MnO4 ¼ k½complex¼ kK2 ½HMnO4 ½CHS dt

¼ kK1 K2 ½MnO4 f ½Hþ f ½CHS

ð6Þ

However, the total permanganate concentration can be written as ½MnO4 t ¼ ½MnO4 f þ ½HMnO4 þ ½complex ¼ ½MnO4 f þ K1 ½MnO4 f ½Hþ þ K2 ½CHS½HMnO4 ¼ ½MnO4 f þ K1 ½MnO4 f ½Hþ þ K1 K2 ½MnO4 f ½Hþ ½CHS ¼ ½MnO4 f ð1 þ K1 ½Hþ þ K1 K2 ½Hþ ½CHSÞ

ð7Þ

Therefore ½MnO4 f ¼

1 þ K1

½MnO4 t þ K1 K2 ½Hþ ½CHS

½Hþ

ð8Þ

where the subscripts t and f stands for total and free MnO4 concentrations, respectively. Similarly ½CHSt ¼ ½CHSf þ ½complex ¼ ½CHSf þ K2 ½CHSf ½HMnO4 10969



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k = rate constant with respect to the slow step of the reaction mechanism (s1) K1, K2 = equilibrium constants (dm3 mol1) kobs = pseudo-first-order rate constant for the reaction (s1) T = absolute temperature (K) ΔG = change in free energy of reaction (k J mol1) ΔG‡ = free energy of activation (k J mol 1) ΔH = change in enthalpy of reaction (k J mol1) ΔH‡ = enthalpy of activation (k J mol 1) ΔS = change in entropy of reaction (J K1 mol1) ΔS‡ = entropy of activation (J K1 mol1) ε = molar absorption coefficient (dm3 mol1 cm1)

’ REFERENCES Figure 8. Spectroscopic evidence for complex formation between permanganate and clopidogrel hydrogen sulfate: UVvis spectra of (a) clopidogrel hydrogen sulfate, (b) permanganate, and (c) a mixture of permanganate and clopidogrel. Conditions: [CHS] = 1.0 103, [MnO4-] = 1.0 104 mol dm3.

¼ ½CHSf ð1 þ K2 ½CHSf ½HMnO4 Þ

ð9Þ

Therefore ½CHSf ¼

½CHSt 1 þ K2 ½CHS½HMnO4

CHSf ¼ CHSt

ð10Þ ð11Þ

because K2[CHS][HMnO4] , 1, on account of the low MnO4 concentration used in the experiments and ½Hþ t ¼ ½Hþ f þ ½HMnO4 ¼ ½Hþ f þ K1 ½MnO4 ½Hþ f ¼ ½Hþ f ð1 þ K1 ½MnO4 Þ

ð12Þ

Therefore ½Hþ t ¼ ½Hþ f

ð13Þ

Substituting eqs 8, 11, and 13 into eq 6 and omitting the subscripts, we obtain

rate ¼

d½MnO4 kK1 K2 ½MnO4 ½Hþ ½CHS ¼ dt 1 þ K1 ½Hþ þ K1 K2 ½Hþ ½CHS

ð14Þ

’ AUTHOR INFORMATION Corresponding Author

*Tel.: 0836-2215286. Fax: 0836-2747884. E-mail: schimatadar@ gmail.com.

’ ACKNOWLEDGMENT One of the authors (Kirthi S. Byadagi) thanks UGC, New Delhi for the award of Research Fellowship in Science for Meritorious Students (RFSMS). ’ NOMENCLATURE D = dielectric constant of the medium I = ionic strength of the medium (mol dm3)

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Kinetics and Mechanism of Permanganate Oxidation of Clopidogrel

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