Kinetic and Mechanistic Investigations of Oxidation of Pentoxifylline

Jul 2, 2009 - P.G. Department of Studies in Chemistry, Karnatak UniVersity, Dharwad-580 003, India. The kinetics of oxidation of a hemorheologic drug,...
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Ind. Eng. Chem. Res. 2009, 48, 7025–7031

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Kinetic and Mechanistic Investigations of Oxidation of Pentoxifylline Drug by Alkaline Permanganate Rajesh N. Hegde, Nagaraj P. Shetti, and Sharanappa T. Nandibewoor* P.G. Department of Studies in Chemistry, Karnatak UniVersity, Dharwad-580 003, India

The kinetics of oxidation of a hemorheologic drug, pentoxifylline by permanganate in alkaline medium at a constant ionic strength of 0.10 mol dm-3 was studied spectrophotometrically using a rapid kinetic HI-TECH SFA-12 accessory. The reaction between permanganate and pentoxifylline in alkaline medium exhibits 1:2 stoichiometry (pentoxifylline/permanganate). The reaction is of first order in [permanganate ion] and less than unit order dependence each in [PTX] and [OH-]. However, the orders in [PTX] and [OH-] changes from first order to zero order as their concentrations increase. A decrease in the dielectric constant of the medium increases the rate of the reaction. The effect of added products and ionic strength of the reaction medium have been investigated. The oxidation reaction in alkaline medium has been shown to proceed via a permanganate-pentoxifylline complex, which decomposes slowly in a rate-determining step followed by a fast step to give the products. A suitable mechanism is proposed. The main products were identified by TLC and spectral studies including LC-MS. The reaction constants involved in the different steps of the mechanism are calculated. The activation parameters with respect to slow step of the mechanism are computed and discussed and thermodynamic quantities are also determined. 1. Introduction Potassium permanganate is widely used as an oxidizing agent as well as in analytical chemistry and also as disinfectant. These reactions are governed by the pH of the medium. Among six oxidation states of manganese from +2 to +7, permanganate, Mn(VII), is the most potent oxidation state in acid as well as in alkaline media. The oxidation by permanganate ion finds extensive application in organic synthesis.1,2 During oxidation by permanganate, it is evident that permanganate is reduced to various oxidation states in acidic, alkaline, and neutral media. The manganese chemistry involved in these multistep redox reactions is an important source of information as the manganese intermediates are relatively easy to identify when they have sufficiently long lifetime, and oxidation states of the intermediates permit useful conclusions as to the possible reaction mechanisms including the nature of intermediates. In a strongly alkaline medium, the stable reduction product3,4 of permanganate ion is magnate ion, MnO42-. The process can be divided into a number of partial steps and examined separately. The MnO2 appears only after a long time, that is, after the complete consumption of MnO4-. No mechanistic information is available to distinguish between a direct one-electron reduction to Mn(VI) and a mechanism in which a hypomanganate Mn(V) is formed in a two-electron reduction followed by a rapid reaction.5 Pentoxifylline(3,7-dimethyl-1-(5-oxo-hexyl)-3,7-dihydro-purine-2,6-dione) (PTX), a trisubstituted purine and xanthine derivative, is a hemorheologic agent used for the treatement of peripheral arterial disease6 and intermittent claudication. PTX improves blood flow through the peripheral circulation by decreasing blood viscosity, inhibiting platelet aggregation, enhancing eruthrocyte flexibility, and diminishing fibrinogen concentration.7 Apart from these well-known hemorheological properties, it has been found to exert a wide range of immunological activities. It has been reported that PTX disturbs polarization and migration of human leukocytes.8 Oxypurines xanthine, hypoxanthine, and uric acid are products of metabo* To whom correspondence should be addressed. Tel.:+91-8362770524. Fax: +91-836-2747884. E-mail: [email protected].

lism of nucleotides.9 Pentoxifylline also diminishes leukocyteendothelium interaction and may have a therapeutic role in preventing ischemia repefusion injury in microsurgical operations,10 prevents atherosclerosis in diabetes mellitus11 and is a nonselective phosphodiesterase inhibitor that decreases the tumor necrosis factor (TNF) gene transcription.12 In view of the medicinal value and potential pharmaceutical importance of PTX and lack of literature on the oxidation mechanism of this drug by permanganate, there was a need for understanding the oxidation mechanism of this bioactive compound. Thus the study could throw some light on the fate of the compound in biological systems. We have undertaken a careful study of oxidation of PTX by permanganate in aqueous alkaline medium. The aims of the present work are (1) to establish a rate law through kinetic measurements, (2) to propose a suitable reaction mechanism, (3) to identify the reactive species of permanganate ion, and (4) to identify the oxidation products of PTX. 2. Experimental Section 2.1. Chemicals and Solutions. All chemicals used were of reagent grade and double distilled water was used throughout the work. Stock solution of PTX (M/s. S.S. Antibiotics Pvt. Ltd., Aurangabad, India) was prepared by dissolving the appropriate amount of sample in double distilled water. The PTX was used as received without any treatment. The required concentration of PTX was used from its aqueous stock solution. The solution of potassium permanganate (BDH) was prepared and standardized against oxalic acid.13 Potassium manganate solution was prepared as described by Carrington and Symons14 as follows: an aqueous solution of potassium permanganate was heated to boiling (∼100 °C) in 8.0 mol dm-3 KOH solution until it turned green. The solid potassium manganate, which formed on cooling, was recrystallized from the KOH solution. Using the required amount of recrystallized sample, a stock solution of potassium manganate was then prepared in aqueous KOH. The solution was standardized by measuring the absorbance at 608 nm (ε ) 1530 ( 20 dm3 mol-1 cm -1). All other

10.1021/ie9004145 CCC: $40.75  2009 American Chemical Society Published on Web 07/02/2009

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reagents were of analytical grade and their solutions were prepared by dissolving the requisite amounts of the samples in doubly distilled water. NaOH and NaClO4 were used to provide the required alkalinity and to maintain the ionic strength, respectively. The effect of alkali on the stability of pentoxifylline in the absence of permanganate was tested. It was found that alkali had no effect on the stability of pentoxifylline at the experimental conditions employed in this study. 2.2. Instruments Used. For kinetic measurements, a Peltier Accessory (temperature control) attached Varian CARY 50 Bio UV-vis spectrophotometer (Varian, Victoria-3170, Australia) connected to a rapid kinetic accessory (HI-TECH SFA-12) was used. For product analysis, a Nicolet Impact-410 FTIR (Thermo, U.S.A.), 300 MHz 1H NMR spectrometer (Bruker, Switzerland), and LC-MS (Agilent 1100 series-API 2000) mass spectrometer using the EI ionization technique were used. For pH measurements the Elico pH meter model LI120) was used. 2.3. Kinetic Studies. Since the initial rate was fast, the kinetic measurements were performed on a Hitachi 150-20 UV-visible spectrophotometer attached to a rapid kinetic accessory (HITECH SFA-12). All kinetic measurements were followed under pseudo-first-order conditions where the PTX used was in excess over [permanganate] at a constant ionic strength of 0.10 mol dm-3. The reaction was initiated by mixing previously thermostatted solutions of permanganate and PTX, which also contained required quantities of NaOH and NaClO4 to maintain required alkalinity and ionic strength, respectively. The temperature was maintained at 25 ( 0.1 °C. The course of the reaction was followed by monitoring the decrease in the absorbance of permanganate, in a 1 cm quartz cell at its absorption maximum 526 nm. The application of Beer’s law to permanganate at 526 nm has also been verified, giving ε ) 2083 ( 50 dm3 mol-1 cm-1 (lit. ε ) 2200 dm3 mol-1 cm-1). The first-order rate constants kobs were evaluated by the plots of log (At - A∞) versus time by fitting the data to the expression At ) A∞ + (A0 - A∞) e-kobst, where At, A0, and A∞ are absorbances of permanganate at time t, 0, and ∞, respectively. The plots in almost all cases were linear up to 85% completion of the reaction, and kobs values were reproducible within (5%. In the course of measurements, the solution changed from violet to blue and then to green. The spectrum of the green solution was identical to that of MnO42-. It is probable that the blue color originated from the violet of permanganate and the green from the manganate, excluding the accumulation of hypomanganate {Mn(V)}. The formation of Mn(VI) was also evidenced by a decreasing absorbance of Mn(VII) at 526 nm and an increasing absorbance of Mn(VI) at 608 nm during the course of the reaction. 3. Results 3.1. Stoichiometry and Product Analysis. Different sets of reaction mixtures containing varying ratios of permanganate to PTX in the presence of constant amounts of OH- and NaClO4 were kept for 1 h in a closed vessel under nitrogen atmosphere. The remaining concentration of permanganate was estimated spectrophotometrically at 526 nm. The results indicated a 1:2 stoichiometry as given in eq 1. The limiting logarithmic method was also used to determine the stoichiometry of the reaction. In this method,15 two sets of experiments were carried out. The first set of experiments was carried out using increasing permanganate concentrations (2.0 × 10-5 to 2.0 × 10-4 M) at fixed PTX concentration (1.0 × 10-3 M). The second set of experiments was carried out using increasing PTX concentrations (6.0 × 10-4 to 6.0 × 10-3 M)

Figure 1. Limiting logarithmic plot for stoichiometric ratio between PTX and permanganate: (a) log absorbance vs log [PTX] and (b) log absorbance vs log [MnO4-].

at fixed permanganate concentration (1.0 × 10-4 M). The logarithms of the obtained absorbances were plotted as a function of the logarithms of the permanganate and PTX concentration in the first and second sets of experiments, respectively. The slopes of the fitting lines in both sets of experiments were calculated. The values of the slopes were 1.2445 and 0.5911, respectively (Figure 1). Hence, it is concluded that the molar reactivity of the reaction is 1.2445/ 0.5911, that is, the reaction proceeds in the ratio of 2:1; pointing out that one molecule of the drug reacts with two molecules of permanganate (Figure 1) as shown: The main reaction product of pentoxifylline, 1-(4-hydroxybutyl)-3,7-dimethyl-3,7-dihydro-purine-2,6-dione, was isolated with the help of TLC and other separation techniques and characterized by LC-MS, FT-IR and 1H NMR spectral studies. The product was confirmed by its IR spectrum which showed the absence of aliphatic CdO stretching at 1719 cm-1 which was present for the parent molecule, and showed the band at 3431 cm-1 indicating the presence of alcoholic OH group. The product was also characterized by the NMR spectra (CDCl3, δ ppm) chemical shift at 1.82 (s, 1H), which disappeared on D2O exchange. Further, the product was subjected to LC-mass spectral analysis. LC-MS data was obtained on an Agilent 1100 seriesAPI 2000 mass spectrometer using the EI ionization technique. The analysis was carried out using a reverse phase highperformance liquid chromatography (HPLC) system with a phenomenes C-18 column, HP 1100 series diode array UV/ visible detector, and HP 1100 MSD series mass analyzer. A 10 µl portion of acidified reaction mixture was injected. The mobile phase consisted of acetonitrile and methanol (containing 0.1% CH3COOH) at a flow rate of 1 mL/min. Gradient elution was run to separate substrate and reaction products. UV detection was at 270 nm. LC-MS analysis of the reaction mixture indicated the presence of product, 1-(4-hydroxy-butyl)-3,7dimethyl-3,7-dihydro-purine-2,6-dione, with molecular ion peak (M + 1) of m/z 253.1 amu (Figure 2b). Sodium acetate was confirmed by spot test.16 It was observed that 1-(4-hydroxy-butyl)-3,7-dimethyl-3,7-dihydro-purine-2,6dione did not undergo further oxidation under the present kinetic conditions. 3.2. Reaction Orders. The reaction orders were determined from the slope of log kobs versus log (concentration) plots by varying the concentrations of PTX and alkali in turn while keeping all other concentrations and conditions constant.

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3.3. Effect of Concentration of Manganese(VII). At constant concentration of PTX, 1.0 × 10-3 mol dm-3, and alkali, 4.0 × 10-2 mol dm-3, and at constant ionic strength, 0.10 mol dm-3, the oxidant permanganate concentration was varied in the range of 2.0 × 10-5 to 2.0 × 10-4 mol dm-3, and the fairly constant kobs values indicate that the order with respect to [permanganate] was one (Table 1). This was also confirmed by linearity of the plots of log[At - A∞] versus time (r g 0.986) up to 85% completion of the reaction (Figure 3). 3.4. Effect of Concentration of PTX. The substrate, PTX concentration was varied in the range of 6.0 × 10-4 to 6.0 × 10-3 mol dm-3 at 25 °C keeping all other reactants concentration and conditions constant. The kobs values increased with increase in concentration of PTX. (Table 1). The apparent order in [PTX] was found to be less than unity under the experimental concentrations. However, at lower concentrations of PTX the reaction was first order in [PTX] and at high concentration of PTX, the reaction was independent of [PTX]. The order in [PTX] changes from first order to zero order as [PTX] varies. 3.5. Effect of Concentration of Alkali. The effect of increasing concentration of alkali was studied on the reaction rate at constant concentration of PTX and permanganate at constant ionic strength of 0.10 mol dm-3 at 25 °C. The rate constants increased with the increase in alkali concentration (Table 1) and the order in [OH-] was found to be less than unity. Similar to as in the case of PTX, the order in alkali changes from first order to zero order as [OH -] increases.

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3.6. Effect of Ionic Strength and Dielectric Constant. The effect of ionic strength was studied by varying the sodium perchlorate concentration. The ionic strength of the reaction medium was varied from 0.1 to 0.5 mol dm-3 at constant concentrations of permanganate, PTX, and alkali. It was found that the rate constant decreases with increasing concentration of NaClO4. The plot of log kobs versus I was found to be linear with negative slope. Dielectric constant of the medium, “D” was varied by varying the tert-butyl alcohol and water percentage. The D values were calculated from the equation D ) DwVw + DBVB, where Dw and DB are dielectric constants of pure water and tert-butyl alcohol, respectively, and Vw and VB are the volume fractions of components water and tert-butyl alcohol respectively in the total mixture. On decreasing the dielectric constant of the reaction medium, a decrease in the rate was observed, and the plot of log kobs versus 1/D was linear with negative slope (Figure 4). 3.7. Effect of Initially Added Product. The initially added product, such as manganese(VI), did not have any significant effect on the rate of reaction. Kinetic runs were also carried out in nitrogen atmosphere in order to understand the effect of dissolved oxygen on the rate of reaction. No significant difference in the results was obtained under a nitrogen atmosphere and in the presence of air. In view of the ubiquitous contamination of carbonate in the basic medium, the effect of carbonate was also studied. Added carbonate had no effect on the reaction rates.

Figure 2. (a) Liquid chromatogram, (b) LC-MS spectra of product of oxidation of pentoxifylline by MnO4-, and (c) LC-MS spectra of pentoxifylline.

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Table 1. Effect of Variation of [Permanganate], [Pentoxifylline], and [Alkali] on the Permanganate Oxidation of Pentoxifylline in Alkaline Medium at 25 0C and I ) 0.1 mol dm-3 [MnO4-] × 104 (mol dm-3)

[PTX] × 103 (mol dm-3)

[OH-] × 102 (mol dm-3)

kobs × 102 (s-1)

kcal × 102 (s-1)

0.2 0.4 0.6 0.8 1.0 2.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0

1.0 1.0 1.0 1.0 1.0 1.0 0.6 0.8 1.0 2.0 4.0 6.0 1.0 1.0 1.0 1.0 1.0 1.0

4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 1.0 2.0 4.0 6.0 8.0 10.0

5.0 4.9 4.8 4.8 4.8 5.1 3.2 4.1 4.8 8.9 15.3 19.8 1.6 2.8 4.8 6.3 8.1 9.1

4.9 4.9 4.9 4.9 4.9 4.9 3.1 4.0 4.9 8.8 14.7 18.9 1.6 2.8 4.9 6.4 7.6 8.6

From the above experimental results the rate law is written as -

rate )

-d[MnO4 ] ) kobs[MnO4-][PTX]0.78[OH-]0.75 dt

Figure 4. Effect of ionic strength and dielectric constant of the medium on oxidation of pentoxifylline by permanganate at 25 °C.

3.8. Polymerization Study. The intervention of free radicals in the reaction was examined as follows. The reaction mixture, to which a known quantity of acrylonitrile monomer was initially added, was kept for 2 h in an inert atmosphere. On diluting the reaction mixture with methanol, a white precipitate was formed, indicating the intervention of free radicals in the reaction. The blank experiments of either permanganate or PTX alone with acrylonitrile did not induce any polymerization under the same condition as those induced for the reaction mixture. Initially added acrylonitrile decreased the rate of reaction indicating free radical intervention, which is the case in earlier work.17 3.9. Effect of Temperature. The kinetics was studied at four different temperatures under constant concentrations of permanganate, PTX, alkali and sodium perchlorate. The rate

Figure 5. Effect of [OH- ] on permanganate: 1.0 × 10-4 mol dm-3 permanganate with (1) 0, (2) 1.0 × 10-2, (3) 2.0 × 10-2, (4) 4.0 × 10-2, (5) 6.0 × 10-2, and (6) 8.0 × 10-2 mol dm-3 [OH- ].

constants, k, of the slow step of Scheme 1 were obtained from the intercept of 1/kobs versus 1/[PTX] (r g 0.9983) at four different temperatures. The energy of activation was calculated from the Arrhenius plot of log k versus 1/T, from which the activation parameters were calculated and are listed in Table 3. 4. Discussion

Figure 3. First-order plots for the oxidation of pentoxifylline by permanganate in aqueous alkaline medium at 25 °C. [MnO4-] × 104 (mol dm-3): (1) 0.2, (2) 0.4, (3) 0.6, (4) 1.0, and (5) 2.0 ([PTX] × 103 ) 1.0, [OH-] ) 0.04 and I ) 0.10 mol dm-3).

The permanganate ion is a powerful oxidant in aqueous alkaline medium. Under the present experimental conditions (pH > 12) the reduction product of Mn(VII) that is, Mn(VI), is stable, and further reduction is not to be expected.14 Diode array rapid scan spectrophotometric studies have shown that at pH > 12, Mn(VII) is reduced to Mn(VI), and no further reduction has been observed. The reaction between PTX and permanganate in alkaline medium has a stoichiometry of 1:2 with an order of

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less than unity both in PTX and alkali concentrations and a first order dependence on [permanganate]. No effect of the products was observed. Based on the experimental results, the following mechanism has been proposed for the oxidation of PTX, which explains all the observed orders as shown in Scheme 1. The results indicate that first the OH- combines with permanganate to give an alkaline permanganate species [MnO4.OH]2- in a prior equilibrium step, which is the case in earlier work.18,19 The permanganate species then reacts with substrate to give a complex (C), which decomposes in a slow step to give a free radical of pentoxifylline, MnO4- and acetate ion which is further followed by a subsequent fast step to yield the reaction products as shown in Scheme 1. Spectroscopic evidence for the complex formation between oxidant and substrate was obtained from UV-vis spectra of PTX (1.0 × 10-3), permanganate (1.0 × 10-4, [OH-] ) 0.04 mol dm-3), and a mixture of both. A bathochromic shift of about 4 nm from 294 to 298 nm in the spectra of PTX to mixture of permanganate and PTX was observed. Such type of complex between a substrate and an oxidant has been observed in other studies.20 With increasing the alkali concentration of the medium, the rate of the reaction increases rapidly, which might be due to the formation of [MnO4.OH]2- species.19 This species might be evidenced by the increasing absorbance with increase in the concentration of OH- at constant concentration of permanganate (Figure 5). Since Scheme 1 is in accordance with the generally wellaccepted principle of noncomplementary oxidations taking place in sequence of one-electron steps, the reaction between the substrate and oxidant would afford a radical intermediate. The existence of transient free radical intermediate was indicated by the positive test involving polymerization of olefinic monomers. This type of radical intermediate has also been observed in earlier work20 on alkaline permanganate oxidations of various organic substrates. According to Scheme 1 rate )

d[MnO4-] ) k[C] dt -

) kK1K2[PTX]f[MnO4 ]f[OH ]f

-

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[MnO4 ]T ) [MnO4 ]f + [MnO4 · OH] + [C] ) [MnO4-]f{1 + K1[OH-] + K1K2[PTX][OH-]} 2-

(4)

where [MnO4-]T and [MnO4-]f refer to total and free MnO4concentrations, respectively. Therefore, free [MnO4-] is given by [MnO4-]f )

[MnO4-]T

(5)

1 + K1[OH-] + K1K2[PTX][OH-]

Similarly [OH- ]f was calculated as [OH-]f )

[OH-]T 1 + k1[MnO4-] + k1k2[PTX][MnO4-]

In view of low concentrations of MnO4- and PTX used, the denominator of the above equation approximates to unity. Therefore,

Similarly,

[OH-]f ) [OH-]T

(6)

[PTX]f ) [PTX]T

(7)

Substituting eqs 5, 6, and 7 in eq 3 and omitting T and f, we get rate )

kK1K2[PTX][MnO4-][OH-]

(8)

1 + K1[OH-] + K1K2[PTX][OH-]

or kK1K2[PTX][OH-] rate ) k ) obs [MnO4-] 1 + K1[OH-] + K1K2[PTX][OH-] (9) Further, eq 9 can be rearranged to eq 10, which is suitable for verification of the rate law.

(2) -

The total [MnO4 -] can be written as

-

1 1 1 1 + + ) kobs kK2[PTX] k kK1K2[PTX][OH-]

(3)

(10)

According to the eq 10, the plots of 1/kobs versus 1/[PTX] (r g 0.9983) and 1/kobs versus 1/[OH-] (r g 0.9987) were linear with

Scheme 1. Mechanism for the Oxidation of PTX by Alkaline Manganese(VII)

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Ind. Eng. Chem. Res., Vol. 48, No. 15, 2009 Table 3. Activation Parameters and Thermodynamic Quantities for the Oxidation of Pentoxifylline by Permanganate in Aqueous Alkaline Medium (a) Activation Parameters Ea (kJ mol )

∆H # (kJ mol-1)

∆S # (J K-1mol-1)

∆G # (kJ mol-1)

log10 A

56.6 ( 2

54 ( 2

-70 ( 1

75 ( 1

9.5 ( 0.2

-1

(b) Thermodynamic Quantities ∆H (kJ mol-1) ∆S (JK-1 mol-1) ∆G298 (kJ mol-1) Figure 6. Verification of rate law (9) in the form of eq 10 for the oxidation of pentoxifylline by permanganate (conditions as given in Table 1). Table 2. Effect of Temperature on K1, K2, and k for the Oxidation of Pentoxifylline by Permanganate in Aqueous Alkaline Medium temp (K)

K1 (dm3 mol-1)

K2 × 10-3 (dm3 mol-1)

k (s-1)

288 293 298 303

3.02 4.54 5.96 7.04

1.41 1.02 0.65 0.58

0.19 0.25 0.44 0.58

an intercept supporting the [MnO4 · OH]2- -pentoxifylline complex, and which is verified in Figure 6. From the slopes and intercepts of such plots, the values of K1, K2, and k at 25 °C were calculated as 5.96 dm3 mol-1, 6.47 × 102 dm3 mol-1, and 4.41 × 10-1 s-1, respectively. The value of K1 is in agreement with earlier data.21 Using these values, the rate constants under different experimental conditions were calculated by eq 9 and compared with experimental data. There is a good agreement between them (Table 1), which fortifies Scheme 1. The decrease in the rate, with increasing ionic strength, is contrary to a reaction between neutral and charged species of reactants, as presented in Scheme 1. This might be due to the presence of different ions and use of high ionic strength in the reaction medium. The effect of solvent on the reaction rate has been described in detail in the literature.22 For the limiting case of a zero angle approach between two dipoles or anion-dipole system, Amis22 has shown that a plot of log kobs versus 1/D gives a straight line, with a negative slope for a reaction between a negative ion and a dipole or two dipoles, and with a positive slope for positive ion and dipole interaction. In the present study, the plot observed had a negative slope as shown in Figure 4, which supports the involvement of negative ions as given in Scheme 1. The thermodynamic quantities for the first equilibrium step in Scheme 1 can be evaluated as follows. The hydroxyl ion concentration and substrate ion concentration (as in Table 1) was varied at four different temperatures. From the slopes and intercepts of the plots of 1/kobs versus 1/[PTX] (r g 0.9983) and 1/kobs versus 1/[OH-] (r g 0.9987) the values of K1 and K2 were calculated at different temperatures and are tabulated in Table 2. The van’t Hoff’s plot was drawn for the variation of K1 with temperature (i.e., log K1 versus 1/T (r g 0.9698)), and the values of the enthalpy of reaction, ∆H, entropy of reaction, ∆S, and free energy of reaction, ∆G, were calculated (Table 3). A comparison of the latter values with those obtained for the slow step of the reaction shows that these values mainly refer to the rate limiting step, supporting the fact that the reactions preceding the rate determining step are fairly fast and involve little activation energy.23 In the same manner, K2 values were calculated at different temperatures and the corresponding

values from K1

values from K2

40.9 ( 2 152 ( 2 -4.8 ( 0.3

-45.1 ( 0.9 -96 ( 3 -16.9 ( 1

values of thermodynamic quantities are given in Table 3. The negative value of ∆S # suggests that the intermediate complex is more ordered than the reactants.20 The moderate ∆H # and ∆S # values are favorable for electron transfer reaction. The value of ∆H # was due to energy of solution changes in the transition state. 5. Conclusion It is interesting that the oxidant species MnO4- requires a pH > 12, below which the system becomes disturbed and the reaction proceeds further to give a reduced product of the oxidant as Mn(IV). Hence, it becomes apparent that the role pH in the reaction medium is crucial. It is also noteworthy that under the conditions studied, the reaction occurs in successive one electron reduction in a single step. The active species of MnO4- is understood to be [MnO4 · OH]2-. The description of the mechanism is consistent with all the experimental evidence including kinetic, spectral, and product studies. Nomenclature and Abbreviations Mn(VII)) ) manganese(VII) PTX ) pentoxifylline ε ) molar absorption coefficient kobs ) observed rate constant k ) rate constant with respect to slow step of the mechanism K1 and K2 ) equilibrium constants ∆H ) change in enthalpy of reaction ∆S ) change in entropy of reaction ∆G ) change in free energy of reaction ∆H # ) enthalpy of activation ∆S # ) entropy of activation ∆G # ) free energy of activation D ) dielectric constant of the medium I ) ionic strength of the medium FT-IR ) Fourier transform infrared spectra 1 H NMR ) proton nuclear magnetic resonance UV ) ultraviolet spectra TLC ) thin layer chromatography LC-MS ) liquid chromatography mass spectrometry

Literature Cited (1) Shaabani, A.; Tavasoli-Rad, F.; Lee, D. G. Potassium Permanganate Oxidation of Organic Compound. Synth. Commun. 2005, 35, 571–580. (2) Caron, P.; Dugger, R. W.; Ruggeri, S. G.; Ragan, J. A.; Brown Ripin, D. H. Large-Scale Oxidations in the Pharmaceutical Industry. Chem. ReV. 2006, 106, 2943–2989. (3) Simandi, L. I.; Jaky, M.; Savage, C. R.; Schelly, Z. A. Kinetics and Mechanism of the Permanganate Oxidation of Sulfite in Alkaline Solutions. The Nature of Short Lived Intermediates. J. Am. Chem. Soc. 1985, 107, 4220–4229.

Ind. Eng. Chem. Res., Vol. 48, No. 15, 2009 (4) (a) Timmanagoudar, P. L.; Hiremath, G. A.; Nandibewoor, S. T. Permanganate Oxidation of Chromium(III) in Aqueous Alkaline Medium: A Kinetic Study by the Stopped-Flow Technique. Transition. Met. Chem. 1997, 22, 193–196. (b) Nadimpalli, S.; Rallabandi, R. A.; Dikshitulu, L. S. A. Kinetic and Mechanism of the Oxidation of Selenium(IV) by Permanganate. Transition Met. Chem. 1993, 18, 510–514. (5) (a) Panari, R. G.; Chougale, R. B.; Nandibewoor, S. T. Kinetic and Mechanism of the Oxidation of L-phenylalanine by Alkaline Permanganate. Pol. J. Chem. 1998, 72, 99–107. (b) Bohm, A.; Adam, M.; Mauermann, H.; Stein, S.; Mullen, K. Solid State Photoreactivity of Ortho-distyrylaromatic Compounds. Tetrahedron Lett. 1992, 33, 2795–2798. (6) Dettelbach, H. R.; Aviado, D. M. Clinical Pharmacology of Pentoxifylline with Special Reference to Its Hemorheologic Effect for the Treatement of Intermittent Claudication. J. Clin. Pharmacol. 1985, 25, 8– 26. (7) Baker, D. E.; Campbell, R. K. Pentoxifylline: A New Agent for Intermittent Claudication. Drug Intell. Clin. Pharm. 1985, 19, 345–348. (8) Dominguez-Jimenez, C.; Sancho, D.; Nieto, M.; Montoya, M. C.; Barreiro, O.; Sanchez-Madrid, F.; Gonazalez-Amaro, R. Effect of Pentoxifylline on Polarization and Migration of Human Leukocytes. J. Leukoc. Biol. 2002, 71, 588–596. (9) Murray, A. W. The Biological Significance of Purine Salvage. Annu. ReV. Biochem. 1971, 40, 811–826. (10) Unal, C.; Sen, C.; Iscen, D.; Dalcik, H. In Vivo Observation of Leukocyte-endothelium Interaction in Ischemia Reperfusion Injury with the Dorsal Window Chamber and the Effects of Pentoxifylline on Reperfusion Injury. J. Surg. Res. 2007, 138, 259–266. (11) Rituparna, M.; Agrawal, N. K.; Dash, D.; Pandey, B. L. Effect of Pentoxifylline on Inflammatory Burden, Oxidative Stress and Platelet Aggregability in Hypertensive Type 2 Diabetes Mellitus Patients. Vascul. Pharmacol. 2007, 47, 118–124. (12) Umaprasanna, S. K.; Reddy, R. K. A Toast to Pentoxifylline. Am. J. Gastroenterol. 2001, 96, 1635–1637. (13) Jeffery, G. H.; Bassett, J.; Mendham, J.; Denny, R. C. Vogel’s Text Book of QuantitatiVe Chemical Analysis, 5th ed.; ELBS Longman: Essex, U.K, 1996; p 370.

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(14) Carrington, A.; Symons, M. C. R. Structure and Reactivity of Oxyanions of Transition Metals. Part I. The Manganese Oxy-anions. J. Chem. Soc. 1956, 3373–3376. (15) Rose, J. AdVanced Physicochemical Experiments; Pitman: London, U.K., 1964. (16) Fiegl, F. Spot Tests in Organic Analysis; Elsevier: New York, 1975, p 455. (17) Farokhi, S. A.; Kini, A. K.; Nandibewoor, S. T. Oxidation of l-Hydroxyproline by Aqueous Alkaline PermanganatesA Kinetic Study. Inorg. React. Mech. 2002, 4, 67–76. (18) Thabaj, K. A.; Kulkarni, S. D.; Chimatadar, S. A.; Nandibewoor, S. T. Oxidative Transformation of Ciprofloxacine by Alkaline PermanganatesA kinetic and Mechanistic Study. Polyhedron 2007, 26, 4877–4885. (19) (a) Panari, R. G.; Chougale, R. B.; Nandibewoor, S. T. Oxidation of Mandelic Acid by Alkaline Potassium Permanganate; A Kinetic Study. J. Phys. Org. Chem. 1998, 11, 1–7. (b) Baes, C. F., Mesmer, R. E. The Hydrolysis of Cations; John Wiley and Sons: New York, 1976; p 224. (20) Seregar, V. C.; Hiremath, C. V.; Nandibewoor, S. T. Palladium(II) Catalysed Oxidation of L-proline by Heptavalent Manganese in Aqueous Alkaline Medium: A Free Radical Intervention and Decarboxylation. Transition Met. Chem. 2006, 31, 541–548. (21) Farokhi, S. A.; Nandibewoor, S. T. Kinetics and Mechanism of Oxidative Decarboxylation of Benzilic Acid by Alkaline Permanganate Using the Stopped-Flow Technique. J. Chem. Res. (s) 2003, 8, 451–453. (22) (a) Moelwyn-Hughes, E. A. Physical Chemistry, 2nd ed.; Pergamon Press: New York, 1961. (b) Amis, E. S. SolVent Effects on Reaction Rates and Mechanisms; Academic Press: New York, 1966; p 183. (23) Rangappa, K. S.; Raghavendra, M. P.; Mahadevappa, D. S.; Channegowda, D. Sodium N-Chlorobenzenesulfonamide as a Selective Oxidant for Hexosamines in Alkaline Medium: A Kinetic and Mechanistic Study. J. Org. Chem. 1998, 63, 531.

ReceiVed for reView March 13, 2009 ReVised manuscript receiVed May 27, 2009 Accepted June 14, 2009 IE9004145