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Conclusive evidence for autocatalytic behaviour of manganese(II) ions in the oxidative degradation of ondansetron by permanganate in aqueous sulfuric acid medium – a kinetic and mechanistic approach
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JECE 616 1–10 Journal of Environmental Chemical Engineering xxx (2015) xxx–xxx
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Conclusive evidence for autocatalytic behaviour of manganese(II) ions in the oxidative degradation of ondansetron by permanganate in aqueous sulfuric acid medium – a kinetic and mechanistic approach
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Mallavva B. Bolattin, Sharanappa T. Nandibewoor, Shivamurti A. Chimatadar *
5
P. G. Department of Studies in Chemistry, Karnatak University, Pavate Nagar, Dharwad, Karnataka 580 003, India
A R T I C L E I N F O
A B S T R A C T
Article history: Received 19 February 2015 Accepted 1 April 2015
The oxidation of ondansetron by permanganate in aqueous sulfuric acid medium has been investigated spectrophotometrically under the pseudo-first order condition at 25 C and at constant ionic strength, I = 0.60 mol dm3. The reaction between ondansetron and permanganate in acid medium exhibits 2:1 stoichiometry. The products are identified and characterised by IR and GC–MS spectral studies. The identified oxidation products are 1-methyl-2-((E)-4-(2-methyl-1H-imidazol-1-yl)but-3-enyl)-1Hindole-3-carboxylic acid and Mn(II), which are different from those obtained by hepatic metabolism. The reaction is autocatalysed due to one of the product, Mn(II). The reaction is first order with respect to MnO4 and less than unit order with respect to ondansetron, acid and Mn(II) concentrations. The oxidation reaction in acid medium proceeds through a permanganate–ondansetron complex that decomposes slowly in a rate-determining step followed by other fast steps to give the products. The reaction constants involved in different steps of the mechanism are calculated at different temperatures. The activation parameters with respect to the slow step of the mechanism are computed, and thermodynamic quantities are also determined. ã 2015 Published by Elsevier Ltd.
Keywords: Autocatalysis Ondansetron Permanganate Oxidation Mechanism Thermodynamic parameters
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Introduction Ondansetron (1,2,3,9-tetrahydro-9-methyl-3-(2-methyl-1Himidazol-1-ylmethyl)-4H-carbazol-4-one hydrochloride dehydrate) (OSH), is a newly approved potent antiemetic drug and selective 5-HT3-receptor antagonist, which has demonstrated antiemetic activity and good tolerability in the prevention of chemotherapy or radiotherapy-induced and postoperative induced nausea and vomiting [1]. The pharmacologic and therapeutic use of ondansetron have been the subject of several previous reviews focusing primarily on the use of the drug for prevention of chemotherapy induced nausea and vomiting in adult patients [1–5]. Ondansetron hydrochloride is well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. The major route of clearance of ondansetron in man is by hepatic metabolism (95%). Ondansetron is metabolised by hydroxylation at the indole moiety to 7- and 8-hydroxy ondansetron followed by glucuronide or sulfate conjugation [6,7].
* Corresponding author. Tel.: +91 836 2770524; fax: +91 836 274788. E-mail address: [email protected] (S.A. Chimatadar).
The chemoreceptor trigger zone and the gastrointestinal tract have been identified as sources for chemo- or radio-therapy induced nausea and vomiting [8]. It is possible that the chemotherapy and radiation cause the release of serotonin (5-hydroxytryptamine) in the gastrointestinal tract, particularly in the small intestine. By selective binding and competitive 5-HT3 receptor, ondansetron blocks the activation of both central and peripheral reflex and inhibits the effect of emetogenic chemotherapy and radiotherapy. Potassium permanganate is widely used as an oxidising agent, disinfectant and also as an analytical reagent. It is strong and vividly coloured oxidant and its reactions are governed by the pH of the medium. Among six oxidation states of manganese from +2 to +7, permanganate is the most potent oxidation state in acid with reduction potential, 1.69 V of Mn(VII)/Mn(VI) couple and 1.51 V of Mn(VII)/Mn(II) couple [9]. The oxidation by permanganate ion finds extensive applications in organic syntheses [10]. The mechanism by which the multivalent oxidant oxidises a substrate depends not only on the substrate but also on the medium [11] used for the study. In acidic medium it exists in different forms as HMnO4, H2MnO4+, HMnO3, Mn2O7 and depending on the nature of the reductant, the oxidant has been assigned both inner sphere and outer sphere pathway in their redox reactions [12,13]. There is
http://dx.doi.org/10.1016/j.jece.2015.04.003 2213-3437/ ã 2015 Published by Elsevier Ltd.
Please cite this article in press as: M.B. Bolattin, et al., Conclusive evidence for autocatalytic behaviour of manganese(II) ions in the oxidative degradation of ondansetron by permanganate in aqueous sulfuric acid medium – a kinetic and mechanistic approach, J. Environ. Chem. Eng. (2015), http://dx.doi.org/10.1016/j.jece.2015.04.003
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considerable evidence that, with many reactions of permanganate in acid media, some oxidation reactions are performed by ions derived from the tri- and tetra-valent states of manganese. These ions are formed by reaction between di- and hepta-valent ions. Divalent ions are always present in solutions of permanganate, albeit in minute concentration, as a result of the below equilibrium [14]. 4MnO4 þ 12Hþ Ð 4Mn2þ þ 5O2 þ 6H2 O
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The oxidation of various organic compounds with potassium permanganate is known to be autocatalytic (the rate of the reaction is influenced by the concentration of reaction intermediates or products) which are rare in literature [15,16]. In the present study, the oxidation of ondansetron by permanganate shows autocatalytic pathway in which Mn(II) ions have been determined, which are responsible for this effect. Literature survey reveals that there are no reports on the oxidation of ondansetron by any oxidant in either acidic or alkaline medium. The aim of the study is to understand the mechanistic profile of ondansetron in redox reactions and provide an insight into the interaction of metal ions with the substrate and its mode of action in biological systems and also to know the active species of KMnO4. In view of the potential pharmaceutical importance of ondansetron and lack of reported kinetic and mechanistic data on the oxidation of this drug by any oxidant other than those involved in the hepatic metabolism (Scheme 1) [6], a detailed oxidation study is undertaken.
Experimental
71
Materials and reagents
72
All chemicals were of analytical reagent grade and doubly distilled water was used throughout this work. An aqueous solution of ondansetron hydrochloride (Himedia) was prepared and 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) [17]. Permanganate stock solution was obtained by dissolving potassium permanganate (Glaxo, Analar) in water and standardised by titrating against oxalic acid [18]. Manganese(II) solution was prepared by dissolving manganese sulfate (AR) in water. Sulfuric acid (Glaxo, Excelar) and sodium sulfate (s.d. Fine Chem-Ltd.) were used to provide the required acidity and ionic strength, respectively.
73
Instruments used
85
For kinetic measurements, a Peltier accessory (temperaturecontrolled) attached to a varian Cary 50 Bio UV–vis 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.
86
O N N
other routes N
N-Demethylation
Hydroxylation O
O
N
N
N
N
OH
N
N
H desmethyl ondansetron
8 hydroxy 6 hydroxy 7 hydroxy ondansetron ondansetron ondansetron
Hydroxy desmethyl ondansetron
Conjugation
glucuronide
sulphate
glucuronide
sulphate
Scheme 1. Metabolism of ondansetron.
Please cite this article in press as: M.B. Bolattin, et al., Conclusive evidence for autocatalytic behaviour of manganese(II) ions in the oxidative degradation of ondansetron by permanganate in aqueous sulfuric acid medium – a kinetic and mechanistic approach, J. Environ. Chem. Eng. (2015), http://dx.doi.org/10.1016/j.jece.2015.04.003
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Kinetic measurements
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The oxidation of ondansetron by KMnO4 was followed under pseudo-first-order conditions, where [ondansetron] [MnO4] in autocatalysis reaction at 25.0 0.1 C, and at a constant ionic strength of 0.60 mol dm3. The reaction was initiated by mixing thermally equilibrated (25 C) solutions of permanganate and ondansetron that also contained the required concentrations of H2SO4 and Na2SO4. 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 thermostated compartment of a varian Cary 50 Bio UV–vis spectrophotometer. The application of Beer’s law under the reaction conditions was previously verified in the permanganate concentration range of 1.0 104– 8.0 104 mol dm3 at 526 nm in 0.01 mol dm3 sulfuric acid. The molar absorptivity index of permanganate at 526 nm was found to be e = 2200 50 dm3 mol1 cm1. In the present study one of the product Mn(II), autocatalyses the reaction (Fig. 1). Hence the initial rates were determined. The choice of initial rates was made according to the autocatalytic nature of the reaction and failure of the data to fit good first order kinetics in [MnO4]. The initial rates were obtained from the slopes of [MnO4] versus time plots by plane mirror method [19]. The initial rates 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 Fig. 2.
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Table 1 Effect of variation of MnO4, ondansetron and sulfuric acid concentrations on the autocatalysed oxidative degradation of ondansetron by permanganate in sulfuric acid medium at 25 C and I = 0.60 mol dm3. [MnO4] 104 (mol dm3)
[OSH] 103 (mol dm3)
[H2SO4] 102 (mol dm3)
0.1 0.2 0.5 1 2 2 2 2 2 2 2 2 2 2 2 2
1 1 1 1 1 1 2 3 4 5 1 1 1 1 1 1
1 1 1 1 1 1 1 1 1 1 0.5 1 2 3 4 5
Rate 105 (mol dm3 s1) Calc.
0.28 0.5 1.2 2.3 4.4 4.4 7.8 9.7 11.7 13 2.2 4.4 6.8 9.7 11.2 12.6
0.22 0.48 1.1 2.2 4.5 4.5 7.4 9.5 11.1 12.4 2.48 4.5 7.1 9.25 10.6 12
HO
O 2
Exptl.
O
N N
+ Mn(VII) + 2H2O
2
N
N N
N
120
Results
121
Stoichiometry and product analysis
122
Stoichiometry of the reaction was determined by analytical method. In this method, different sets of reaction mixtures containing excess permanganate with respect to ondansetron at constant concentrations of H2SO4 and Na2SO4 were kept in closed containers under a nitrogen atmosphere at 25 oC. After 2 h, the unreacted permanganate concentration was assayed spectrophotometrically by measuring the absorbance at 526 nm. The results indicated that 2 mol of ondansetron consumes 1 mol of permanganate according to the Eq. (1).
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Fig. 1. First order plots; [MnO4] 104 mol dm3 = (1) 0.50, (2) 1.0 and (3) 2.0; [OSH] = 1.0 103, [H2SO4] = 0.01 and I = 0.60 mol dm3; inset: plot of rate versus product of reactant concentrations.
+ Mn(III) + 4H+ 2Mn(III)
2MnðIIIÞ ! MnðIVÞ þ MnðIIÞ
Mn(IV) + Mn(II)
(1)
Eq. (1): stoichiometry of oxidative degradation of ondansetron by permanganate. The reaction products were eluted with ether as solvent; the reaction products were identified as Mn(II) and 1-methyl-2-((E)-4(2-methyl-1H-imidazol-1-yl)but-3-enyl)-1H-indole-3-carboxylic acid. The main product 1-methyl-2-((E)-4-(2-methyl-1Himidazol-1-yl)but-3-enyl)-1H-indole-3-carboxylic acid is a heterocyclic compound, which contains both indole and imidazole rings. This main product was isolated with the help of TLC and other separation techniques and characterised by GC–MS, FT-IR spectral studies and Mn2+ was identified by UV–vis spectra and spot test [17]. GC–MS analysis of the reaction products indicates presence of 1-methyl-2-((E)-4-(2-methyl-1H-imidazol-1-yl)but3-enyl)-1H-indole-3-carboxylic acid oxidation product with
Fig. 2. UV–vis spectral changes at 25 C; [MnO4] = 2.0 104, [OSH] = 1.0 103, [H2SO4] = 0.01 and I = 0.60 mol dm3; scanning interval time of: 1.0–10.0 min.
Please cite this article in press as: M.B. Bolattin, et al., Conclusive evidence for autocatalytic behaviour of manganese(II) ions in the oxidative degradation of ondansetron by permanganate in aqueous sulfuric acid medium – a kinetic and mechanistic approach, J. Environ. Chem. Eng. (2015), http://dx.doi.org/10.1016/j.jece.2015.04.003
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Fig. 3. GC–MS of reaction product with molecular ion peak at 309 amu.
5.0 103–5.0 102 mol dm3. It was observed that, the increase in the acid concentration increases the rate of oxidation of ondansetron (Table 1). From the slope of the plot of log (initial rate) versus log [H2SO4] the reaction order with respect to the concentration of H2SO4 was found to be less than unity (0.75).
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molecular ion at m/z 309 (Fig. 3). The IR spectrum of the product shows an intense sharp peak at 1653 cm1 due to acidic C¼O stretching; the peak due to carboxylic OH stretching appear at 3392 cm1; A C O stretching observed at 1279 cm1 and OH bending observed at 1427 and 912 cm1 (Fig. S1).
151
Reaction orders
Dependence of rate on ionic strength (I) and dielectric constant (D)
184
152
The permanganate oxidation of ondansetron in aqueous sulfuric acid medium proceeds with a measurable rate in the autocatalysed path. The reaction orders have been determined from the slopes of log (initial rate) versus log (concentration) plots by varying the concentrations of MnO4, ondansetron, and H2SO4 in turn while keeping others constant.
The ionic strength was varied between 0.60 and 2.20 mol dm3 by varying concentration of Na2SO4. It was observed that, at constant concentrations of reactants, addition of Na2SO4 did not have any significant 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 initial rates of the reaction increased with decreasing the dielectric constant of the medium and the plot of log (initial rate) versus 1/D was linear with positive slope. Dielectric constant of the medium was computed from the values of pure liquids [20]. No reaction of the solvent with the oxidant occurred under the experimental conditions employed.
185
Effect of initially added products
198
The addition of the product 1-methyl-2-((E)-4-(2-methyl-1Himidazol-1-yl)but-3-enyl)-1H-indole-3-carboxylic acid did not show any significant effect. However, addition of the product, Mn(II), in the range of 0.50 104–5.0 104 mol dm3, keeping
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153 154 155 156 157 158 159 160 161 162 163 164
Dependence of rate on the concentration of permanganate The oxidant permanganate concentration was varied in the range of 0.10 104–2.0 104 mol dm3, keeping all other conditions constant. As the permanganate concentration increases the rate of the reaction also increases (Table 1). From the slope of the plot of log (initial rate) versus log [MnO4] confirms that order with respect to [MnO4] was unity (0.93).
165
Dependence of rate on the concentration of ondansetron
166
173
The effect of ondansetron on the rate of reaction was studied at constant concentrations of permanganate, H2SO4 and at a constant ionic strength and temperature. The substrate was varied in the range of 1.0 103–5.0 103 mol dm3. The initial rate increases with increasing concentration of ondansetron (Table 1). From the value of the slope of the plot of log (initial rate) versus log [ondansetron], the reaction order with respect to the ondansetron concentration was found to be less than unity (0.67).
174
Dependence of rate on the concentration of sulfuric acid
175
The effect of an increase in the concentration of sulfuric acid on the reaction was studied at constant concentrations of permanganate and ondansetron at a constant ionic strength and temperature. The acid concentration was varied in the range of
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Table 2 Effect of manganese(II) concentration on the autocatalysed oxidative degradation of ondansetron by permanganate in sulfuric acid medium at 25 C. [Mn(II)] 104 (mol dm3)
Rate 105 (mol dm3 s1)
0.5 1.0 2.0 3.0 4.0 5.0
4.40 6.80 9.62 11.6 13.0 14.2
Please cite this article in press as: M.B. Bolattin, et al., Conclusive evidence for autocatalytic behaviour of manganese(II) ions in the oxidative degradation of ondansetron by permanganate in aqueous sulfuric acid medium – a kinetic and mechanistic approach, J. Environ. Chem. Eng. (2015), http://dx.doi.org/10.1016/j.jece.2015.04.003
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other conditions constant appreciably increases the reaction rate (Table 2). As the initial concentration of Mn(II) was increased, the rate progressively increased. This illustrates the autocatalytic nature of the product Mn(II). The order with respect to [Mn(II)] was found to be less than unity (0.50). Rates of reaction with 22 different sets of concentrations of permanganate, ondansetron, sulfuric acid and manganese(II) at constant ionic strength were found to obey the rate Eq. (2) as shown in Fig. 1 (inset).
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rate a ½MnO4 ½OSH0:67 ½H2 SO4 0:75 ½MnðIIÞ0:50
(2)
212
Effect of added halides and metal ions
213
233
Effect of halide ions on the rate of reaction were studied by adding KCl and KBr (1.0 102–9.0 102 mol dm3) to the reaction mixture. However, the effect of iodide has not been studied due to the intervention of black coloured (iodine) precipitate in the reaction mixture. The rate of the reaction increases with increase in the concentration of Cl and Br indicating that halide ions have catalytic effect on the rate of reaction. The order of the catalytic activity increases in the order Br > Cl. According to bridge theory [21], the electron transfer or effectiveness of the bridge decreases in the order of I > Br > Cl. The difference in the rates of halogen transfer is expected; as the most polarizable ligand must transfer most easily this type of behaviour is already known [22,23]. Effect of different salts with cations (K+, Na+, Ca2+, Mg2+ and Al3+) are studied by adding K2SO4, NaCl, CaCl2, MgSO4 and Al2(SO4)3 to the reaction mixture. As the metal ion concentration increases the rate of the reaction was also increases and it can be observed that the rate of the reaction is enhanced more by the monovalent ions K+ and Na+, than by divalent Ca2+ and Mg2+ ions, as reported in literature [24–26]. Addition of Al3+ did not show any significant effect on the rate of reaction (Fig. 4).
234
Polymerization study
235
The generation of free radicals during the course of the oxidation was confirmed by using acrylonitrile monomer. In this, 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 reaction mixture
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5
with methanol, precipitate was formed, which indicates the intervention of free radicals in the reaction.
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Effect of temperature
242
The kinetics was studied at four different temperatures 15, 25, 35 and 45 C under varying concentrations of ondansetron, acid and potassium permanganate, keeping other conditions constant. A decrease in rate was observed with increase in temperature, this is contrary to the expected. The rate constant of the slow step (k), the formation constant of HMnO4 (K1), and the formation constant of complex (K2) in Scheme 2 were obtained from the intercepts and slopes of the plots of [MnO4]/rate versus 1/[H+] and [MnO4]/rate versus 1/[OSH] (Fig. 5) at four different temperatures. The enthalpy of activation, DH# and the entropy of activation, DS# were obtained Q3 by the Eyring equation [27].
243
241
244 245 246 247 248 249 250 251 252 253 255 254
k¼
kB T ðDG Þ kB T ðDH þT DS Þ e RT ¼ e RT h h
(3)
where k is the rate constant with respect to slow step of Scheme 2, kB is the Boltzmann’s constant, R is the gas constant, T is the absolute temperature and DG# is the free energy of activation. The linear form of Eq. (3) is k DH DS kB þ þ ln ln ¼ T RT R h
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(4) 263
The slope of the plot of log k/T versus 1/T gives the value of enthalpy of activation. By using the value DH#, and the rate constant at a particular temperature T, the value of DS# was obtained by simple rearrangement of Eq. (4). Using these values of DH# and DS#, the free energy of activation, DG#298 can be obtained (Table 3a). The thermodynamic quantities of the first and the second step of Scheme 2 were evaluated from the van’t Hoff plots (log K1 versus 1/T and log K2 versus 1/T) at four different temperatures. The values of K1 and K2 at four different temperatures and the values of thermodynamic quantities are given in Table 3c.
264
Discussion
275
Oxidation of organic substrates by potassium permanganate in the acidic medium is usually a multi-stage process due to the ability of manganese to exist in a multitude of oxidation states [28]. The degradation of organic molecules proceeds via the breakage of discreet covalent bonds while manganese undergoes reduction to lower valence states via a number of electron transitions. With certain reductants in strongly acidic solutions, an overall five electron change may occur which is represented by:
276
MnO4 þ 8Hþ þ 5e Ð Mn2þ þ 4H2 O
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277 278 279 280 281 282 283
(5) 284
Q6
Fig. 4. Effect of added salts (1) KBr, (2) NaCl, (3) CaCl2, (4) MgSO4, (5) K2SO4, (6) KCl and (7) Al2(SO4)3 at 25 C.
In the present study the reaction between ondansetron and potassium permanganate had a stoichiometry 2:1 with unit order dependence on [MnO4] and less than unit order with respect to substrate, acid and Mn(II) concentration. Based on the experimental results, a mechanism is proposed for which all the observed orders in each constituent, such as [oxidant], [reductant] and [H+], are well accommodated. The active species of permanganate in aqueous acid solution may be deduced from the dependence of the rate on [H+] in the reaction medium. It has been observed that, as the [H+] increases
Please cite this article in press as: M.B. Bolattin, et al., Conclusive evidence for autocatalytic behaviour of manganese(II) ions in the oxidative degradation of ondansetron by permanganate in aqueous sulfuric acid medium – a kinetic and mechanistic approach, J. Environ. Chem. Eng. (2015), http://dx.doi.org/10.1016/j.jece.2015.04.003
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O N N
K2
+ HMnO4
Complex(C1)
N
HO
Complex(C1)
k1
OH
N
+ MnO42- + 2H+
N
slow H2O
. HO C N
.
C
N
{Mn(VI)}
O H
O
HO + MnO42-
N
fast
N
N
N
N + MnO43- + H+ {Mn(V)}
HO
O N + MnO43- + H2O
N
fast N
O
N N
N + MnO45- + 2H+ {Mn(III)}
2Mn(III)
Mn(IV) + Mn(II)
Scheme 2. Proposed mechanism for the autocatalysed oxidation of ondansetron by permanganate in aqueous sulfuric acid medium.
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the rate of the reaction also increases. The noticeable order of the reaction in [H+] is significantly less than unity, which may be an indication of the formation of permanganic acid from permanganate ion. In fact, permanganic acid is a more efficient oxidant species of manganese(VII) than permanganate ion [29]. At higher acidities protonation is almost complete, leading to the limiting rate, which indicates that only the protonated form is active thus, the acid–permanganate equilibrium. MnO4 þ Hþ Ð HMnO4
(6)
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The results suggest that, the protonated form of permanganate, the active species are formed in prior equilibrium step, which combines with 1 mol of ondansetron in the second equilibrium step to form a complex. The complex undergoes hydrolysis in the rate determining step to give a free radical derived from ondansetron and an intermediate Mn(VI) species. In the next fast step the intermediate Mn(VI) reacts with a free radical derived from ondansetron, producing 1-methyl-2-((E)-4-(2-methyl-1Himidazol-1-yl)but-3-enyl)-1H-indole-3-carboxylic acid and an intermediate Mn(V) species. In further fast step the intermediate
Fig. 5. Verification plot for Eq. (15) at 25 C.
Please cite this article in press as: M.B. Bolattin, et al., Conclusive evidence for autocatalytic behaviour of manganese(II) ions in the oxidative degradation of ondansetron by permanganate in aqueous sulfuric acid medium – a kinetic and mechanistic approach, J. Environ. Chem. Eng. (2015), http://dx.doi.org/10.1016/j.jece.2015.04.003
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Mn(V), being very active and unstable in acid medium, reacts with another molecule of substrate to form the same oxidation product and an intermediate Mn(III) species. This step is further followed by fast step in which two Mn(III) species decomposes to give Mn (IV) and Mn(II) species as reported in the literature [30], which satisfy the observed stoichiometry. From all these experimental results, the following mechanism is proposed in the form of Scheme 2. Since none of the intermediate species could be detected, Scheme 2 is only one of several possible mechanisms for the reaction in the presence of free radicals. Attempts were made spectroscopically to detect the proposed intermediate Mn(V) and Mn(III) species as the reaction proceeded. Unfortunately, the low concentrations of Mn(III) and Mn(V) intermediates obtained under our experimental conditions made the attempted detection unsuccessful. However, there are reports in the literature for the existence of Mn(III) and Mn(V) [31]. The evidence for the complex (C1) formation was obtained from UV–vis spectrum of ondansetron and mixture of ondansetron and permanganate, which indicates the hypsochromic shift of 5 nm from 314 to 309 nm (Fig. S2). The presence of the isosbestic point in the UV–vis spectrum supports the formation of complex in the reaction (Fig. 2) and complex formation was also confirmed kinetically with a Michaelis–Menten plot (Fig. 5). The probable structure of the complex (C1) is given below. Such complex formation between substrate and oxidant was also reported in the literature [32].
7
Table 3 Effect of temperature on the autocatalysed oxidative degradation of ondansetron by permanganate in sulfuric acid medium. (a) Rate constant with respect to slow step of Scheme 1 and activation parameters. Temperature (K)
k1 (dm3 mol1 s1)
Activation parameters
Values
288 298 308 318
2.10 1.12 0.98 0.76
DH# (kJ mol1) DS# (J K1 mol1) DG#298 (kJ mol1)
27 1.1 334 14 72 3 5 0.2
log A
(b) Effect of temperature on first and second equilibrium step of Scheme 1. Temperature ( C)
K1 (dm3 mol1)
K2 104 (dm3 mol1)
288 298 308 318
4.10 3.72 2.80 1.90
0.25 0.76 1.43 2.80
(c) Thermodynamic quantities with respect to first and second equilibrium step of Scheme 1. Thermodynamic quantities
Values from K1
Values from K2
DH (kJ mol1) DS (J K1 mol1) DG (kJ mol1)
19.6 55.6 2.80
60.2 274.9 23.2
341 342
O
344 345
O
346
O
rate ¼
Mn
d½MnO4 ¼ k1 K 1 K 2 ½MnO4 ½Hþ ½OSH dt
364
½MnO4 t
¼ ¼ ¼
N
349
366
N
351
½MnO4 f ¼
353
357
Permanganate ions are primarily responsible for the oxidation of substrate ondansetron. The intermediate complex subsequently undergoes decomposition to give the reaction products. From Scheme 2 the rate law can be derived as follows: rate ¼
d½MnO4 ¼ k1 ½ComplexðC1 Þ dt
(7)
½MnO4 t f1 þ K 1 ½Hþ þ K 1 K 2 ½Hþ ½OSHg
(11)
where the subscripts ‘t’ and ‘f’ stands for total and free MnO4 concentrations respectively. Similarly: ½OSHf
358 359
367
Therefore,
352
356
½MnO4 f þ ½HMnO4 þ ½ComplexðC1 Þ ½MnO4 f þ K 1 ½MnO4 f ½Hþ þ K 1 K 2 ½MnO4 f ½Hþ ½OSH ½MnO4 f f1 þ K 1 ½Hþ þ K 1 K 2 ½Hþ ½OSHg
N
350
355
365
The total permanganate concentration can be written as:
347
354
(10)
O O
348
363
Substituting Eqs. (8) and (9) in Eq. (7) we get,
H
343
¼ ¼ ¼
368 369
½OSHf þ ½ComplexðC1 Þ ½OSHf þ K 2 ½OSH½HMnO4 ½OSH f f1 þ K 2 ½HMnO4 g
From the second step of Scheme 2 we have, K2 ¼
½ComplexðC1 Þ ½OSH½HMnO4
½OSHf ¼
½OSHt f1 þ K 2 ½HMnO4 g 370
½ComplexðC1 Þ ¼ K 2 ½OSH½HMnO4
(8)
360 361
Because K2[HMnO4] 1, on account of the low concentration used in the experiments ½OSHf ¼ ½OSHt
From the first step of Scheme 2 we have,
MnO4
372
(12) 374 373
and
½HMnO4 K1 ¼ ½MnO4 ½Hþ
½Ht ¼ ½Hf
371
(13) 375
½HMnO4 ¼ K 1 ½MnO4 ½Hþ
(9)
Substituting Eqs. (11)–(13) in Eq. (10) and omitting the subscripts, we obtain
362
Please cite this article in press as: M.B. Bolattin, et al., Conclusive evidence for autocatalytic behaviour of manganese(II) ions in the oxidative degradation of ondansetron by permanganate in aqueous sulfuric acid medium – a kinetic and mechanistic approach, J. Environ. Chem. Eng. (2015), http://dx.doi.org/10.1016/j.jece.2015.04.003
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rate ¼
378
d½MnO4 k1 K 1 K 2 ½MnO4 ½Hþ ½OSH ¼ dt 1 þ K 1 ½Hþ þ K 1 K 2 ½Hþ ½OSH
(14)
Eq. (14) can be rearranged into Eq. (15), which is suitable for verification ½MnO4 1 1 1 ¼ þ þ rate k1 K 1 K 2 ½OSH½Hþ k1 K 2 ½OSH k1
(15)
383
According to Eq. (15) the plots of [MnO4]/rate versus 1/[H+] and [MnO4]/rate versus 1/[OSH] are expected to be linear and are found to be so. From the slopes and intercepts of these plots, the values of K1, K2 and k1 are calculated and are found to be 3.72 dm3 mol1, 0.76 104 dm3 mol1 and 1.12 dm3 mol1 s1, respectively.
384
Autocatalysis by Mn(II) in acidic medium
385
In alkaline or weakly acidic solution, permanganate changes to Mn(IV), while in a strongly acidic medium, permanganate is further reduced, forming Mn(II). In the case where permanganate serves as an oxidising agent in an acid medium, the possible intermediate species are Mn(VI), Mn(V), Mn(III) and Mn(IV). On the other hand, Mn(II), the ultimate reaction product, acts as an autocatalyst. Therefore, the MnO4 oxidations provide chemical kinetics with a challenging mechanism, due to the ability of manganese to exist in a multitude of oxidation states [33]. In the present case Mn(II) was found to autocatalyse the rate of oxidation of ondansetron by permanganate. In all the experiments performed, curves were obtained with a sigmoid profile. This characteristic suggests an autocatalytic phenomenon. In order to demonstrate the effect of Mn(II) species which are responsible for the autocatalytic effect, kinetic runs were carried out in the presence of Mn(II). The catalytic effect of Mn(II) on the rate of reaction was studied in the range 0.50 104–5.0 104 mol dm3, while maintaining the other conditions constant. As the concentration of Mn2+ ions increased, the rate of the reaction increases considerably (Table 2). Although there is a possibility to inhibit the catalytic effect of Mn(II) ions, by carrying the same reaction in the presence of pyrophosphate and fluoride ions [34] as they are good complexing agents for Mn(III) and Mn(IV) ions. The catalytic effect of Mn(II) can be interpreted in either of two ways; (a) Mn(II) may form a complex with the substrate which is then oxidised by HMnO4 or (b) Mn(II) first reacts with Mn(VII) to produce Mn(III) which accelerates the rate of reaction. The less than unit order (0.21) in Mn(II) ions may be attributed to the complex formation between ondansetron and Mn(II). The complex (C2) is then subsequently involved in the interaction with MnO4. These steps in Scheme 3 are a part of Scheme 2. According to Scheme 3:
379 380 381 382
386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416
K3 ¼
½ComplexðC2 Þ ½MnðIIÞ½OSH
½ComplexðC2 Þ ¼ K 3 ½MnðIIÞ½OSH 419 420
On substituting the values, Eq. (16) becomes rate ¼ k2 K 3 ½MnðIIÞf ½OSHf
(17) 421 422
The total concentration of Mn(II) is given by, ¼ ¼ ¼
½MnðIIÞt
rate ¼ k2 ½ComplexðC2 Þ
418
From the first step of Scheme 3 we have:
½MnðIIÞf ¼
½MnðIIÞf þ ½ComplexðC2 Þ ½MnðIIÞf þ K 3 ½MnðIIÞf ½OSH ½MnðIIÞf f1 þ K 3 ½OSHg
MnðIIÞt f1 þ K 3 ½OSHg
(18) 423 424
Similarly, ¼ ¼ ¼
½OSHt
½OSHf ¼
½OSHf þ ½ComplexðC2 Þ ½OSHf þ K 3 ½OSH½MnðIIÞ ½OSHf f1 þ K 3 ½MnðIIÞg
½OSHt f1 þ K 3 ½MnðIIÞg
(19) 425 426
Substituting Eqs. (18) and (19) in Eq. (17) gives rateautocat ¼
k2 K 3 ½MnðIIÞ½OSH f1 þ K 3 ½OSHgf1 þ K 3 ½MnðIIÞg 427
Thus, when Mn(II) is initially present, a composite scheme involving all of the steps of Schemes 2 and 3 operates and rate law becomes:
rateautocat ¼
k2 K 3 ½MnðIIÞ½OSH 1 þ K 3 ½OSH þ K 3 ½MnðIIÞ þ K 23 ½OSH½MnðIIÞ
431
O K3
Complex(C2)
N
Complex(C2)
k2
Products
slow
Scheme 3. Proposed mechanism for autocatalysis by Mn(II).
430
(20)
417
Mn(II) + N
429
rategross ¼ rate þ rateautocat
(16)
N
428
Fig. 6. Verification plot for Eq. (21) for autocatalysis at 25 C.
Please cite this article in press as: M.B. Bolattin, et al., Conclusive evidence for autocatalytic behaviour of manganese(II) ions in the oxidative degradation of ondansetron by permanganate in aqueous sulfuric acid medium – a kinetic and mechanistic approach, J. Environ. Chem. Eng. (2015), http://dx.doi.org/10.1016/j.jece.2015.04.003
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In view of the low concentrations of [OSH] and [Mn(II)] used, the term K32[OSH] [Mn(II)] in the denominator is less than unity and can be neglected. The rate law (Eq. (20)) may be verified by rearranging it into the form: ½OSH 1 1 1 þ þ ¼ rateautocat k2 ½MnðIIÞ k2 K 3 ½MnðIIÞ k2
(21)
458
According to Eq. (21), the plot of [OSH]/rateautocat versus 1/[Mn(II)] is expected to be linear and is found to be so (Fig. 6). The slope and intercept of such plots lead to the values of K3 and k2 and are 3.3 101 dm3 mol1 and 0.174 dm3 mol1 s1 respectively at 25 C. The ionic strength has no effect on the rate of the reaction which is in agreement with the observed results. The effect of solvent on the reaction rate has been described in detail in the literature [35–37]. The increase in the acetic acid content in the reaction medium leads to an increase in the rate of reaction. This effect is encountered substantially by the formation of active reactant species to a greater extent in low relative permittivity media, leading to the net increase in the reaction rate [19]. The values of enthalpy of reaction DH, entropy of reaction DS and free energy of reaction DG were calculated for the first and second equilibrium steps of Scheme 2. These values are given in Table 3c. The negative temperature dependence of rate constant of slow step (k1) and negative value of enthalpy of activation (DH# = 27 kJ mol1) obtained indicate that the reaction embodies a prior equilibrium (Scheme 2). Such situations have been reported in the literature [38–41]. The high negative value of entropy of activation (DS# = 334 J K1 mol1) indicates that the complex is more ordered than the reactants [42–44]. The positive value of free energy of activation (DG# = 72 kJ mol1) indicate that the transition state is highly solvated [45].
459
Conclusion
460
474
The oxidation of ondansetron by permanganate in aqueous sulfuric acid medium exhibits autocatalysis phenomena by one of the products, Mn(II). The characteristic sigmoid profile observed for the variation of permanganate concentration (absorption) versus time at 526 nm supports the autocatalytic behaviour of Mn(II). Thus, we report the first conclusive evidence for an autocatalytic oxidation process of ondansetron by permanganate in aqueous sulfuric acid medium. The reaction between ondansetron and permanganate in acid medium exhibits a 2:1 stoichiometry with reductant to oxidant. The active species of permanganate was found to be HMnO4. The identified oxidation products are 1-methyl-2-((E)-4-(2-methyl-1Himidazol-1-yl)but-3-enyl)-1H-indole-3-carboxylic acid and Mn(II), which are different from those obtained by hepatic metabolism. The proposed mechanism is consistent with all of the experimental results.
475
Acknowledgement
476
479
One of the authors, Mallavva B. Bolattin gratefully acknowledges the University Grants Commission (UGC), New Delhi for the award of “Research Fellowship in Science for Meritorious Students” (Award Letter No: KU/Sch/RFSMS/2012-13/672).
480
Appendix A. Supplementary data
481 482
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jece.2015.04.003.
483
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1 2 3
Conclusive evidence for autocatalytic behaviour of manganese(II) ions in the oxidative degradation of ondansetron by permanganate in aqueous sulfuric acid medium – a kinetic and mechanistic approach
4 Q1
Mallavva B. Bolattin, Sharanappa T. Nandibewoor, Shivamurti A. Chimatadar *
5
P. G. Department of Studies in Chemistry, Karnatak University, Pavate Nagar, Dharwad, Karnataka 580 003, India
A R T I C L E I N F O
A B S T R A C T
Article history: Received 19 February 2015 Accepted 1 April 2015
The oxidation of ondansetron by permanganate in aqueous sulfuric acid medium has been investigated spectrophotometrically under the pseudo-first order condition at 25 C and at constant ionic strength, I = 0.60 mol dm3. The reaction between ondansetron and permanganate in acid medium exhibits 2:1 stoichiometry. The products are identified and characterised by IR and GC–MS spectral studies. The identified oxidation products are 1-methyl-2-((E)-4-(2-methyl-1H-imidazol-1-yl)but-3-enyl)-1Hindole-3-carboxylic acid and Mn(II), which are different from those obtained by hepatic metabolism. The reaction is autocatalysed due to one of the product, Mn(II). The reaction is first order with respect to MnO4 and less than unit order with respect to ondansetron, acid and Mn(II) concentrations. The oxidation reaction in acid medium proceeds through a permanganate–ondansetron complex that decomposes slowly in a rate-determining step followed by other fast steps to give the products. The reaction constants involved in different steps of the mechanism are calculated at different temperatures. The activation parameters with respect to the slow step of the mechanism are computed, and thermodynamic quantities are also determined. ã 2015 Published by Elsevier Ltd.
Keywords: Autocatalysis Ondansetron Permanganate Oxidation Mechanism Thermodynamic parameters
6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Introduction Ondansetron (1,2,3,9-tetrahydro-9-methyl-3-(2-methyl-1Himidazol-1-ylmethyl)-4H-carbazol-4-one hydrochloride dehydrate) (OSH), is a newly approved potent antiemetic drug and selective 5-HT3-receptor antagonist, which has demonstrated antiemetic activity and good tolerability in the prevention of chemotherapy or radiotherapy-induced and postoperative induced nausea and vomiting [1]. The pharmacologic and therapeutic use of ondansetron have been the subject of several previous reviews focusing primarily on the use of the drug for prevention of chemotherapy induced nausea and vomiting in adult patients [1–5]. Ondansetron hydrochloride is well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. The major route of clearance of ondansetron in man is by hepatic metabolism (95%). Ondansetron is metabolised by hydroxylation at the indole moiety to 7- and 8-hydroxy ondansetron followed by glucuronide or sulfate conjugation [6,7].
* Corresponding author. Tel.: +91 836 2770524; fax: +91 836 274788. E-mail address: [email protected] (S.A. Chimatadar).
The chemoreceptor trigger zone and the gastrointestinal tract have been identified as sources for chemo- or radio-therapy induced nausea and vomiting [8]. It is possible that the chemotherapy and radiation cause the release of serotonin (5-hydroxytryptamine) in the gastrointestinal tract, particularly in the small intestine. By selective binding and competitive 5-HT3 receptor, ondansetron blocks the activation of both central and peripheral reflex and inhibits the effect of emetogenic chemotherapy and radiotherapy. Potassium permanganate is widely used as an oxidising agent, disinfectant and also as an analytical reagent. It is strong and vividly coloured oxidant and its reactions are governed by the pH of the medium. Among six oxidation states of manganese from +2 to +7, permanganate is the most potent oxidation state in acid with reduction potential, 1.69 V of Mn(VII)/Mn(VI) couple and 1.51 V of Mn(VII)/Mn(II) couple [9]. The oxidation by permanganate ion finds extensive applications in organic syntheses [10]. The mechanism by which the multivalent oxidant oxidises a substrate depends not only on the substrate but also on the medium [11] used for the study. In acidic medium it exists in different forms as HMnO4, H2MnO4+, HMnO3, Mn2O7 and depending on the nature of the reductant, the oxidant has been assigned both inner sphere and outer sphere pathway in their redox reactions [12,13]. There is
http://dx.doi.org/10.1016/j.jece.2015.04.003 2213-3437/ ã 2015 Published by Elsevier Ltd.
Please cite this article in press as: M.B. Bolattin, et al., Conclusive evidence for autocatalytic behaviour of manganese(II) ions in the oxidative degradation of ondansetron by permanganate in aqueous sulfuric acid medium – a kinetic and mechanistic approach, J. Environ. Chem. Eng. (2015), http://dx.doi.org/10.1016/j.jece.2015.04.003
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considerable evidence that, with many reactions of permanganate in acid media, some oxidation reactions are performed by ions derived from the tri- and tetra-valent states of manganese. These ions are formed by reaction between di- and hepta-valent ions. Divalent ions are always present in solutions of permanganate, albeit in minute concentration, as a result of the below equilibrium [14]. 4MnO4 þ 12Hþ Ð 4Mn2þ þ 5O2 þ 6H2 O
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The oxidation of various organic compounds with potassium permanganate is known to be autocatalytic (the rate of the reaction is influenced by the concentration of reaction intermediates or products) which are rare in literature [15,16]. In the present study, the oxidation of ondansetron by permanganate shows autocatalytic pathway in which Mn(II) ions have been determined, which are responsible for this effect. Literature survey reveals that there are no reports on the oxidation of ondansetron by any oxidant in either acidic or alkaline medium. The aim of the study is to understand the mechanistic profile of ondansetron in redox reactions and provide an insight into the interaction of metal ions with the substrate and its mode of action in biological systems and also to know the active species of KMnO4. In view of the potential pharmaceutical importance of ondansetron and lack of reported kinetic and mechanistic data on the oxidation of this drug by any oxidant other than those involved in the hepatic metabolism (Scheme 1) [6], a detailed oxidation study is undertaken.
Experimental
71
Materials and reagents
72
All chemicals were of analytical reagent grade and doubly distilled water was used throughout this work. An aqueous solution of ondansetron hydrochloride (Himedia) was prepared and 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) [17]. Permanganate stock solution was obtained by dissolving potassium permanganate (Glaxo, Analar) in water and standardised by titrating against oxalic acid [18]. Manganese(II) solution was prepared by dissolving manganese sulfate (AR) in water. Sulfuric acid (Glaxo, Excelar) and sodium sulfate (s.d. Fine Chem-Ltd.) were used to provide the required acidity and ionic strength, respectively.
73
Instruments used
85
For kinetic measurements, a Peltier accessory (temperaturecontrolled) attached to a varian Cary 50 Bio UV–vis 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.
86
O N N
other routes N
N-Demethylation
Hydroxylation O
O
N
N
N
N
OH
N
N
H desmethyl ondansetron
8 hydroxy 6 hydroxy 7 hydroxy ondansetron ondansetron ondansetron
Hydroxy desmethyl ondansetron
Conjugation
glucuronide
sulphate
glucuronide
sulphate
Scheme 1. Metabolism of ondansetron.
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Kinetic measurements
95
The oxidation of ondansetron by KMnO4 was followed under pseudo-first-order conditions, where [ondansetron] [MnO4] in autocatalysis reaction at 25.0 0.1 C, and at a constant ionic strength of 0.60 mol dm3. The reaction was initiated by mixing thermally equilibrated (25 C) solutions of permanganate and ondansetron that also contained the required concentrations of H2SO4 and Na2SO4. 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 thermostated compartment of a varian Cary 50 Bio UV–vis spectrophotometer. The application of Beer’s law under the reaction conditions was previously verified in the permanganate concentration range of 1.0 104– 8.0 104 mol dm3 at 526 nm in 0.01 mol dm3 sulfuric acid. The molar absorptivity index of permanganate at 526 nm was found to be e = 2200 50 dm3 mol1 cm1. In the present study one of the product Mn(II), autocatalyses the reaction (Fig. 1). Hence the initial rates were determined. The choice of initial rates was made according to the autocatalytic nature of the reaction and failure of the data to fit good first order kinetics in [MnO4]. The initial rates were obtained from the slopes of [MnO4] versus time plots by plane mirror method [19]. The initial rates 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 Fig. 2.
96 Q2 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119
3
Table 1 Effect of variation of MnO4, ondansetron and sulfuric acid concentrations on the autocatalysed oxidative degradation of ondansetron by permanganate in sulfuric acid medium at 25 C and I = 0.60 mol dm3. [MnO4] 104 (mol dm3)
[OSH] 103 (mol dm3)
[H2SO4] 102 (mol dm3)
0.1 0.2 0.5 1 2 2 2 2 2 2 2 2 2 2 2 2
1 1 1 1 1 1 2 3 4 5 1 1 1 1 1 1
1 1 1 1 1 1 1 1 1 1 0.5 1 2 3 4 5
Rate 105 (mol dm3 s1) Calc.
0.28 0.5 1.2 2.3 4.4 4.4 7.8 9.7 11.7 13 2.2 4.4 6.8 9.7 11.2 12.6
0.22 0.48 1.1 2.2 4.5 4.5 7.4 9.5 11.1 12.4 2.48 4.5 7.1 9.25 10.6 12
HO
O 2
Exptl.
O
N N
+ Mn(VII) + 2H2O
2
N
N N
N
120
Results
121
Stoichiometry and product analysis
122
Stoichiometry of the reaction was determined by analytical method. In this method, different sets of reaction mixtures containing excess permanganate with respect to ondansetron at constant concentrations of H2SO4 and Na2SO4 were kept in closed containers under a nitrogen atmosphere at 25 oC. After 2 h, the unreacted permanganate concentration was assayed spectrophotometrically by measuring the absorbance at 526 nm. The results indicated that 2 mol of ondansetron consumes 1 mol of permanganate according to the Eq. (1).
123 124 125 126 127 128 129 130
Fig. 1. First order plots; [MnO4] 104 mol dm3 = (1) 0.50, (2) 1.0 and (3) 2.0; [OSH] = 1.0 103, [H2SO4] = 0.01 and I = 0.60 mol dm3; inset: plot of rate versus product of reactant concentrations.
+ Mn(III) + 4H+ 2Mn(III)
2MnðIIIÞ ! MnðIVÞ þ MnðIIÞ
Mn(IV) + Mn(II)
(1)
Eq. (1): stoichiometry of oxidative degradation of ondansetron by permanganate. The reaction products were eluted with ether as solvent; the reaction products were identified as Mn(II) and 1-methyl-2-((E)-4(2-methyl-1H-imidazol-1-yl)but-3-enyl)-1H-indole-3-carboxylic acid. The main product 1-methyl-2-((E)-4-(2-methyl-1Himidazol-1-yl)but-3-enyl)-1H-indole-3-carboxylic acid is a heterocyclic compound, which contains both indole and imidazole rings. This main product was isolated with the help of TLC and other separation techniques and characterised by GC–MS, FT-IR spectral studies and Mn2+ was identified by UV–vis spectra and spot test [17]. GC–MS analysis of the reaction products indicates presence of 1-methyl-2-((E)-4-(2-methyl-1H-imidazol-1-yl)but3-enyl)-1H-indole-3-carboxylic acid oxidation product with
Fig. 2. UV–vis spectral changes at 25 C; [MnO4] = 2.0 104, [OSH] = 1.0 103, [H2SO4] = 0.01 and I = 0.60 mol dm3; scanning interval time of: 1.0–10.0 min.
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Fig. 3. GC–MS of reaction product with molecular ion peak at 309 amu.
5.0 103–5.0 102 mol dm3. It was observed that, the increase in the acid concentration increases the rate of oxidation of ondansetron (Table 1). From the slope of the plot of log (initial rate) versus log [H2SO4] the reaction order with respect to the concentration of H2SO4 was found to be less than unity (0.75).
179
150
molecular ion at m/z 309 (Fig. 3). The IR spectrum of the product shows an intense sharp peak at 1653 cm1 due to acidic C¼O stretching; the peak due to carboxylic OH stretching appear at 3392 cm1; A C O stretching observed at 1279 cm1 and OH bending observed at 1427 and 912 cm1 (Fig. S1).
151
Reaction orders
Dependence of rate on ionic strength (I) and dielectric constant (D)
184
152
The permanganate oxidation of ondansetron in aqueous sulfuric acid medium proceeds with a measurable rate in the autocatalysed path. The reaction orders have been determined from the slopes of log (initial rate) versus log (concentration) plots by varying the concentrations of MnO4, ondansetron, and H2SO4 in turn while keeping others constant.
The ionic strength was varied between 0.60 and 2.20 mol dm3 by varying concentration of Na2SO4. It was observed that, at constant concentrations of reactants, addition of Na2SO4 did not have any significant 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 initial rates of the reaction increased with decreasing the dielectric constant of the medium and the plot of log (initial rate) versus 1/D was linear with positive slope. Dielectric constant of the medium was computed from the values of pure liquids [20]. No reaction of the solvent with the oxidant occurred under the experimental conditions employed.
185
Effect of initially added products
198
The addition of the product 1-methyl-2-((E)-4-(2-methyl-1Himidazol-1-yl)but-3-enyl)-1H-indole-3-carboxylic acid did not show any significant effect. However, addition of the product, Mn(II), in the range of 0.50 104–5.0 104 mol dm3, keeping
199
146 147 148 149
153 154 155 156 157 158 159 160 161 162 163 164
Dependence of rate on the concentration of permanganate The oxidant permanganate concentration was varied in the range of 0.10 104–2.0 104 mol dm3, keeping all other conditions constant. As the permanganate concentration increases the rate of the reaction also increases (Table 1). From the slope of the plot of log (initial rate) versus log [MnO4] confirms that order with respect to [MnO4] was unity (0.93).
165
Dependence of rate on the concentration of ondansetron
166
173
The effect of ondansetron on the rate of reaction was studied at constant concentrations of permanganate, H2SO4 and at a constant ionic strength and temperature. The substrate was varied in the range of 1.0 103–5.0 103 mol dm3. The initial rate increases with increasing concentration of ondansetron (Table 1). From the value of the slope of the plot of log (initial rate) versus log [ondansetron], the reaction order with respect to the ondansetron concentration was found to be less than unity (0.67).
174
Dependence of rate on the concentration of sulfuric acid
175
The effect of an increase in the concentration of sulfuric acid on the reaction was studied at constant concentrations of permanganate and ondansetron at a constant ionic strength and temperature. The acid concentration was varied in the range of
167 168 169 170 171 172
176 177 178
Table 2 Effect of manganese(II) concentration on the autocatalysed oxidative degradation of ondansetron by permanganate in sulfuric acid medium at 25 C. [Mn(II)] 104 (mol dm3)
Rate 105 (mol dm3 s1)
0.5 1.0 2.0 3.0 4.0 5.0
4.40 6.80 9.62 11.6 13.0 14.2
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186 187 188 189 190 191 192 193 194 195 196 197
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other conditions constant appreciably increases the reaction rate (Table 2). As the initial concentration of Mn(II) was increased, the rate progressively increased. This illustrates the autocatalytic nature of the product Mn(II). The order with respect to [Mn(II)] was found to be less than unity (0.50). Rates of reaction with 22 different sets of concentrations of permanganate, ondansetron, sulfuric acid and manganese(II) at constant ionic strength were found to obey the rate Eq. (2) as shown in Fig. 1 (inset).
204 205 206 207 208 209 210 211
rate a ½MnO4 ½OSH0:67 ½H2 SO4 0:75 ½MnðIIÞ0:50
(2)
212
Effect of added halides and metal ions
213
233
Effect of halide ions on the rate of reaction were studied by adding KCl and KBr (1.0 102–9.0 102 mol dm3) to the reaction mixture. However, the effect of iodide has not been studied due to the intervention of black coloured (iodine) precipitate in the reaction mixture. The rate of the reaction increases with increase in the concentration of Cl and Br indicating that halide ions have catalytic effect on the rate of reaction. The order of the catalytic activity increases in the order Br > Cl. According to bridge theory [21], the electron transfer or effectiveness of the bridge decreases in the order of I > Br > Cl. The difference in the rates of halogen transfer is expected; as the most polarizable ligand must transfer most easily this type of behaviour is already known [22,23]. Effect of different salts with cations (K+, Na+, Ca2+, Mg2+ and Al3+) are studied by adding K2SO4, NaCl, CaCl2, MgSO4 and Al2(SO4)3 to the reaction mixture. As the metal ion concentration increases the rate of the reaction was also increases and it can be observed that the rate of the reaction is enhanced more by the monovalent ions K+ and Na+, than by divalent Ca2+ and Mg2+ ions, as reported in literature [24–26]. Addition of Al3+ did not show any significant effect on the rate of reaction (Fig. 4).
234
Polymerization study
235
The generation of free radicals during the course of the oxidation was confirmed by using acrylonitrile monomer. In this, 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 reaction mixture
214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232
236 237 238 239
5
with methanol, precipitate was formed, which indicates the intervention of free radicals in the reaction.
240
Effect of temperature
242
The kinetics was studied at four different temperatures 15, 25, 35 and 45 C under varying concentrations of ondansetron, acid and potassium permanganate, keeping other conditions constant. A decrease in rate was observed with increase in temperature, this is contrary to the expected. The rate constant of the slow step (k), the formation constant of HMnO4 (K1), and the formation constant of complex (K2) in Scheme 2 were obtained from the intercepts and slopes of the plots of [MnO4]/rate versus 1/[H+] and [MnO4]/rate versus 1/[OSH] (Fig. 5) at four different temperatures. The enthalpy of activation, DH# and the entropy of activation, DS# were obtained Q3 by the Eyring equation [27].
243
241
244 245 246 247 248 249 250 251 252 253 255 254
k¼
kB T ðDG Þ kB T ðDH þT DS Þ e RT ¼ e RT h h
(3)
where k is the rate constant with respect to slow step of Scheme 2, kB is the Boltzmann’s constant, R is the gas constant, T is the absolute temperature and DG# is the free energy of activation. The linear form of Eq. (3) is k DH DS kB þ þ ln ln ¼ T RT R h
257 256 258 259 260 261 262
(4) 263
The slope of the plot of log k/T versus 1/T gives the value of enthalpy of activation. By using the value DH#, and the rate constant at a particular temperature T, the value of DS# was obtained by simple rearrangement of Eq. (4). Using these values of DH# and DS#, the free energy of activation, DG#298 can be obtained (Table 3a). The thermodynamic quantities of the first and the second step of Scheme 2 were evaluated from the van’t Hoff plots (log K1 versus 1/T and log K2 versus 1/T) at four different temperatures. The values of K1 and K2 at four different temperatures and the values of thermodynamic quantities are given in Table 3c.
264
Discussion
275
Oxidation of organic substrates by potassium permanganate in the acidic medium is usually a multi-stage process due to the ability of manganese to exist in a multitude of oxidation states [28]. The degradation of organic molecules proceeds via the breakage of discreet covalent bonds while manganese undergoes reduction to lower valence states via a number of electron transitions. With certain reductants in strongly acidic solutions, an overall five electron change may occur which is represented by:
276
MnO4 þ 8Hþ þ 5e Ð Mn2þ þ 4H2 O
265 266 267 268 269 270 271 272 273 274
277 278 279 280 281 282 283
(5) 284
Q6
Fig. 4. Effect of added salts (1) KBr, (2) NaCl, (3) CaCl2, (4) MgSO4, (5) K2SO4, (6) KCl and (7) Al2(SO4)3 at 25 C.
In the present study the reaction between ondansetron and potassium permanganate had a stoichiometry 2:1 with unit order dependence on [MnO4] and less than unit order with respect to substrate, acid and Mn(II) concentration. Based on the experimental results, a mechanism is proposed for which all the observed orders in each constituent, such as [oxidant], [reductant] and [H+], are well accommodated. The active species of permanganate in aqueous acid solution may be deduced from the dependence of the rate on [H+] in the reaction medium. It has been observed that, as the [H+] increases
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O N N
K2
+ HMnO4
Complex(C1)
N
HO
Complex(C1)
k1
OH
N
+ MnO42- + 2H+
N
slow H2O
. HO C N
.
C
N
{Mn(VI)}
O H
O
HO + MnO42-
N
fast
N
N
N
N + MnO43- + H+ {Mn(V)}
HO
O N + MnO43- + H2O
N
fast N
O
N N
N + MnO45- + 2H+ {Mn(III)}
2Mn(III)
Mn(IV) + Mn(II)
Scheme 2. Proposed mechanism for the autocatalysed oxidation of ondansetron by permanganate in aqueous sulfuric acid medium.
295 296 297 298 299 300 301 302
the rate of the reaction also increases. The noticeable order of the reaction in [H+] is significantly less than unity, which may be an indication of the formation of permanganic acid from permanganate ion. In fact, permanganic acid is a more efficient oxidant species of manganese(VII) than permanganate ion [29]. At higher acidities protonation is almost complete, leading to the limiting rate, which indicates that only the protonated form is active thus, the acid–permanganate equilibrium. MnO4 þ Hþ Ð HMnO4
(6)
303 304 305 306 307 308 309 310 311 312 313
The results suggest that, the protonated form of permanganate, the active species are formed in prior equilibrium step, which combines with 1 mol of ondansetron in the second equilibrium step to form a complex. The complex undergoes hydrolysis in the rate determining step to give a free radical derived from ondansetron and an intermediate Mn(VI) species. In the next fast step the intermediate Mn(VI) reacts with a free radical derived from ondansetron, producing 1-methyl-2-((E)-4-(2-methyl-1Himidazol-1-yl)but-3-enyl)-1H-indole-3-carboxylic acid and an intermediate Mn(V) species. In further fast step the intermediate
Fig. 5. Verification plot for Eq. (15) at 25 C.
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Mn(V), being very active and unstable in acid medium, reacts with another molecule of substrate to form the same oxidation product and an intermediate Mn(III) species. This step is further followed by fast step in which two Mn(III) species decomposes to give Mn (IV) and Mn(II) species as reported in the literature [30], which satisfy the observed stoichiometry. From all these experimental results, the following mechanism is proposed in the form of Scheme 2. Since none of the intermediate species could be detected, Scheme 2 is only one of several possible mechanisms for the reaction in the presence of free radicals. Attempts were made spectroscopically to detect the proposed intermediate Mn(V) and Mn(III) species as the reaction proceeded. Unfortunately, the low concentrations of Mn(III) and Mn(V) intermediates obtained under our experimental conditions made the attempted detection unsuccessful. However, there are reports in the literature for the existence of Mn(III) and Mn(V) [31]. The evidence for the complex (C1) formation was obtained from UV–vis spectrum of ondansetron and mixture of ondansetron and permanganate, which indicates the hypsochromic shift of 5 nm from 314 to 309 nm (Fig. S2). The presence of the isosbestic point in the UV–vis spectrum supports the formation of complex in the reaction (Fig. 2) and complex formation was also confirmed kinetically with a Michaelis–Menten plot (Fig. 5). The probable structure of the complex (C1) is given below. Such complex formation between substrate and oxidant was also reported in the literature [32].
7
Table 3 Effect of temperature on the autocatalysed oxidative degradation of ondansetron by permanganate in sulfuric acid medium. (a) Rate constant with respect to slow step of Scheme 1 and activation parameters. Temperature (K)
k1 (dm3 mol1 s1)
Activation parameters
Values
288 298 308 318
2.10 1.12 0.98 0.76
DH# (kJ mol1) DS# (J K1 mol1) DG#298 (kJ mol1)
27 1.1 334 14 72 3 5 0.2
log A
(b) Effect of temperature on first and second equilibrium step of Scheme 1. Temperature ( C)
K1 (dm3 mol1)
K2 104 (dm3 mol1)
288 298 308 318
4.10 3.72 2.80 1.90
0.25 0.76 1.43 2.80
(c) Thermodynamic quantities with respect to first and second equilibrium step of Scheme 1. Thermodynamic quantities
Values from K1
Values from K2
DH (kJ mol1) DS (J K1 mol1) DG (kJ mol1)
19.6 55.6 2.80
60.2 274.9 23.2
341 342
O
344 345
O
346
O
rate ¼
Mn
d½MnO4 ¼ k1 K 1 K 2 ½MnO4 ½Hþ ½OSH dt
364
½MnO4 t
¼ ¼ ¼
N
349
366
N
351
½MnO4 f ¼
353
357
Permanganate ions are primarily responsible for the oxidation of substrate ondansetron. The intermediate complex subsequently undergoes decomposition to give the reaction products. From Scheme 2 the rate law can be derived as follows: rate ¼
d½MnO4 ¼ k1 ½ComplexðC1 Þ dt
(7)
½MnO4 t f1 þ K 1 ½Hþ þ K 1 K 2 ½Hþ ½OSHg
(11)
where the subscripts ‘t’ and ‘f’ stands for total and free MnO4 concentrations respectively. Similarly: ½OSHf
358 359
367
Therefore,
352
356
½MnO4 f þ ½HMnO4 þ ½ComplexðC1 Þ ½MnO4 f þ K 1 ½MnO4 f ½Hþ þ K 1 K 2 ½MnO4 f ½Hþ ½OSH ½MnO4 f f1 þ K 1 ½Hþ þ K 1 K 2 ½Hþ ½OSHg
N
350
355
365
The total permanganate concentration can be written as:
347
354
(10)
O O
348
363
Substituting Eqs. (8) and (9) in Eq. (7) we get,
H
343
¼ ¼ ¼
368 369
½OSHf þ ½ComplexðC1 Þ ½OSHf þ K 2 ½OSH½HMnO4 ½OSH f f1 þ K 2 ½HMnO4 g
From the second step of Scheme 2 we have, K2 ¼
½ComplexðC1 Þ ½OSH½HMnO4
½OSHf ¼
½OSHt f1 þ K 2 ½HMnO4 g 370
½ComplexðC1 Þ ¼ K 2 ½OSH½HMnO4
(8)
360 361
Because K2[HMnO4] 1, on account of the low concentration used in the experiments ½OSHf ¼ ½OSHt
From the first step of Scheme 2 we have,
MnO4
372
(12) 374 373
and
½HMnO4 K1 ¼ ½MnO4 ½Hþ
½Ht ¼ ½Hf
371
(13) 375
½HMnO4 ¼ K 1 ½MnO4 ½Hþ
(9)
Substituting Eqs. (11)–(13) in Eq. (10) and omitting the subscripts, we obtain
362
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rate ¼
378
d½MnO4 k1 K 1 K 2 ½MnO4 ½Hþ ½OSH ¼ dt 1 þ K 1 ½Hþ þ K 1 K 2 ½Hþ ½OSH
(14)
Eq. (14) can be rearranged into Eq. (15), which is suitable for verification ½MnO4 1 1 1 ¼ þ þ rate k1 K 1 K 2 ½OSH½Hþ k1 K 2 ½OSH k1
(15)
383
According to Eq. (15) the plots of [MnO4]/rate versus 1/[H+] and [MnO4]/rate versus 1/[OSH] are expected to be linear and are found to be so. From the slopes and intercepts of these plots, the values of K1, K2 and k1 are calculated and are found to be 3.72 dm3 mol1, 0.76 104 dm3 mol1 and 1.12 dm3 mol1 s1, respectively.
384
Autocatalysis by Mn(II) in acidic medium
385
In alkaline or weakly acidic solution, permanganate changes to Mn(IV), while in a strongly acidic medium, permanganate is further reduced, forming Mn(II). In the case where permanganate serves as an oxidising agent in an acid medium, the possible intermediate species are Mn(VI), Mn(V), Mn(III) and Mn(IV). On the other hand, Mn(II), the ultimate reaction product, acts as an autocatalyst. Therefore, the MnO4 oxidations provide chemical kinetics with a challenging mechanism, due to the ability of manganese to exist in a multitude of oxidation states [33]. In the present case Mn(II) was found to autocatalyse the rate of oxidation of ondansetron by permanganate. In all the experiments performed, curves were obtained with a sigmoid profile. This characteristic suggests an autocatalytic phenomenon. In order to demonstrate the effect of Mn(II) species which are responsible for the autocatalytic effect, kinetic runs were carried out in the presence of Mn(II). The catalytic effect of Mn(II) on the rate of reaction was studied in the range 0.50 104–5.0 104 mol dm3, while maintaining the other conditions constant. As the concentration of Mn2+ ions increased, the rate of the reaction increases considerably (Table 2). Although there is a possibility to inhibit the catalytic effect of Mn(II) ions, by carrying the same reaction in the presence of pyrophosphate and fluoride ions [34] as they are good complexing agents for Mn(III) and Mn(IV) ions. The catalytic effect of Mn(II) can be interpreted in either of two ways; (a) Mn(II) may form a complex with the substrate which is then oxidised by HMnO4 or (b) Mn(II) first reacts with Mn(VII) to produce Mn(III) which accelerates the rate of reaction. The less than unit order (0.21) in Mn(II) ions may be attributed to the complex formation between ondansetron and Mn(II). The complex (C2) is then subsequently involved in the interaction with MnO4. These steps in Scheme 3 are a part of Scheme 2. According to Scheme 3:
379 380 381 382
386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416
K3 ¼
½ComplexðC2 Þ ½MnðIIÞ½OSH
½ComplexðC2 Þ ¼ K 3 ½MnðIIÞ½OSH 419 420
On substituting the values, Eq. (16) becomes rate ¼ k2 K 3 ½MnðIIÞf ½OSHf
(17) 421 422
The total concentration of Mn(II) is given by, ¼ ¼ ¼
½MnðIIÞt
rate ¼ k2 ½ComplexðC2 Þ
418
From the first step of Scheme 3 we have:
½MnðIIÞf ¼
½MnðIIÞf þ ½ComplexðC2 Þ ½MnðIIÞf þ K 3 ½MnðIIÞf ½OSH ½MnðIIÞf f1 þ K 3 ½OSHg
MnðIIÞt f1 þ K 3 ½OSHg
(18) 423 424
Similarly, ¼ ¼ ¼
½OSHt
½OSHf ¼
½OSHf þ ½ComplexðC2 Þ ½OSHf þ K 3 ½OSH½MnðIIÞ ½OSHf f1 þ K 3 ½MnðIIÞg
½OSHt f1 þ K 3 ½MnðIIÞg
(19) 425 426
Substituting Eqs. (18) and (19) in Eq. (17) gives rateautocat ¼
k2 K 3 ½MnðIIÞ½OSH f1 þ K 3 ½OSHgf1 þ K 3 ½MnðIIÞg 427
Thus, when Mn(II) is initially present, a composite scheme involving all of the steps of Schemes 2 and 3 operates and rate law becomes:
rateautocat ¼
k2 K 3 ½MnðIIÞ½OSH 1 þ K 3 ½OSH þ K 3 ½MnðIIÞ þ K 23 ½OSH½MnðIIÞ
431
O K3
Complex(C2)
N
Complex(C2)
k2
Products
slow
Scheme 3. Proposed mechanism for autocatalysis by Mn(II).
430
(20)
417
Mn(II) + N
429
rategross ¼ rate þ rateautocat
(16)
N
428
Fig. 6. Verification plot for Eq. (21) for autocatalysis at 25 C.
Please cite this article in press as: M.B. Bolattin, et al., Conclusive evidence for autocatalytic behaviour of manganese(II) ions in the oxidative degradation of ondansetron by permanganate in aqueous sulfuric acid medium – a kinetic and mechanistic approach, J. Environ. Chem. Eng. (2015), http://dx.doi.org/10.1016/j.jece.2015.04.003
G Model
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In view of the low concentrations of [OSH] and [Mn(II)] used, the term K32[OSH] [Mn(II)] in the denominator is less than unity and can be neglected. The rate law (Eq. (20)) may be verified by rearranging it into the form: ½OSH 1 1 1 þ þ ¼ rateautocat k2 ½MnðIIÞ k2 K 3 ½MnðIIÞ k2
(21)
458
According to Eq. (21), the plot of [OSH]/rateautocat versus 1/[Mn(II)] is expected to be linear and is found to be so (Fig. 6). The slope and intercept of such plots lead to the values of K3 and k2 and are 3.3 101 dm3 mol1 and 0.174 dm3 mol1 s1 respectively at 25 C. The ionic strength has no effect on the rate of the reaction which is in agreement with the observed results. The effect of solvent on the reaction rate has been described in detail in the literature [35–37]. The increase in the acetic acid content in the reaction medium leads to an increase in the rate of reaction. This effect is encountered substantially by the formation of active reactant species to a greater extent in low relative permittivity media, leading to the net increase in the reaction rate [19]. The values of enthalpy of reaction DH, entropy of reaction DS and free energy of reaction DG were calculated for the first and second equilibrium steps of Scheme 2. These values are given in Table 3c. The negative temperature dependence of rate constant of slow step (k1) and negative value of enthalpy of activation (DH# = 27 kJ mol1) obtained indicate that the reaction embodies a prior equilibrium (Scheme 2). Such situations have been reported in the literature [38–41]. The high negative value of entropy of activation (DS# = 334 J K1 mol1) indicates that the complex is more ordered than the reactants [42–44]. The positive value of free energy of activation (DG# = 72 kJ mol1) indicate that the transition state is highly solvated [45].
459
Conclusion
460
474
The oxidation of ondansetron by permanganate in aqueous sulfuric acid medium exhibits autocatalysis phenomena by one of the products, Mn(II). The characteristic sigmoid profile observed for the variation of permanganate concentration (absorption) versus time at 526 nm supports the autocatalytic behaviour of Mn(II). Thus, we report the first conclusive evidence for an autocatalytic oxidation process of ondansetron by permanganate in aqueous sulfuric acid medium. The reaction between ondansetron and permanganate in acid medium exhibits a 2:1 stoichiometry with reductant to oxidant. The active species of permanganate was found to be HMnO4. The identified oxidation products are 1-methyl-2-((E)-4-(2-methyl-1Himidazol-1-yl)but-3-enyl)-1H-indole-3-carboxylic acid and Mn(II), which are different from those obtained by hepatic metabolism. The proposed mechanism is consistent with all of the experimental results.
475
Acknowledgement
476
479
One of the authors, Mallavva B. Bolattin gratefully acknowledges the University Grants Commission (UGC), New Delhi for the award of “Research Fellowship in Science for Meritorious Students” (Award Letter No: KU/Sch/RFSMS/2012-13/672).
480
Appendix A. Supplementary data
481 482
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jece.2015.04.003.
483
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