Oxidative Cleavage of Acetaminophen by Cetyltrimethylammonium

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Oxidative Cleavage of Acetaminophen by Cetyltrimethylammonium Dichromate: A Mechanistic Study Sarita Garnayak and Sabita Patel* Department of Chemistry, National Institute of TechnologyRourkela, Rourkela769 008, India S Supporting Information *

ABSTRACT: In this contribution, we report the oxidation of a potential analgesic and anti-inflammatory drug acetaminophen by lipopathic oxidant, cetyltrimethylammonium dichromate (CTADC), in a nonpolar medium and in the presence of surfactants. Acetaminophen is oxidized to p-benzoquinone and acetamide by CTADC in the presence of acetic acid. Michaelis−Menten-type kinetics are observed with respect to the substrate. The chemical nature of the intermediate, transition state, and reaction mechanism are proposed on the basis of (i) the observed rate constant dependencies on the [reactants], (ii) the high negative entropy of activation, and (iii) the effect of solvent polarity on rate constant values. The deuterium kinetic isotope effect and solvent kinetic isotope effect are also determined and provide further support for the proposed mechanism. The decrease in rate with the addition of different ionic and nonionic surfactants confirms the formation of a reverse micellar aggregate, which controls the reaction because of the charge on the interface and also because of the partition of the oxidant and the substrate in two different domains.

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(CTAP),11 cerate (CTACN),12 and dichromate (CTADC)13−20 toward various organic substrates. These are inorganic anionic oxidants attached to an amphipathic cationic organic carrier, cetyltrimethylammonium (CTA+) ion, to carry the oxidants into the organic phase. These oxidants are hydrophobic and exist as tight ion pairs of the cationic carrier CTA+ and the anionic oxidant counterions in nonpolar medium. CTADC acts as a mild, chemoselective, and biomimetic oxidant.16−20 It oxidizes aromatic amines and thiols to the corresponding coupled dehydrogenated product,17 aldoximes to the nitriles,18 and cholesterol to 7-dehydrocholesterol19 selectively. It forms a reverse micellar aggregate in a nonpolar medium and forms mixed aggregated structures in the presence of various surfactants due to the presence of the cationic carrier CTA+.20 Akin to the biological oxidant (enzyme), it provides a suitable active site for reaction and, thus, mimics a biological system.19 Herein, we have made an attempt to investigate the oxidative metabolism of the analgesic and antipyretic drug acetaminophen by Cr(VI) oxidant in a biomimetic environment. Further, kinetic and spectrophotometric determinations of acetaminophen in pharmaceutical formulations have been the subject of interest to many investigators due to their sensitivity, selectivity, simplicity, and accuracy.21 In these methods, the drug (acetaminophen) is oxidized using the metal ion oxidant, and thus, the amount of drug has been estimated. However, in most of the methods, a high concentration of strong acid, high temperature, and longer reaction time are required for the process.22 In most of the cases, it does not require any acid for the oxidation, whereas in some cases it requires a very low

INTRODUCTION Acetaminophen, or paracetamol, is a well-known drug that finds extensive application for its potent analgesic and antipyretic action. It is generally regarded as a nonsteroidal antiinflammatory drug (NSAID), though it possesses little antiinflammatory activity and also lacks the other typical actions of NSAIDs, such as antiplatelet activity and gastrotoxicity.1,2 In spite of acetaminophen’s wide use and popularity, its mechanism of action at a molecular level has not yet been completely elucidated. Andersson et al.3 found that the electrophilic metabolites N-acetyl-p-benzoquinone imine (NAPQI) and p-benzoquinone, but not acetaminophen itself, activate mouse and human TRPA1 and, as a consequence, reduce voltage-gated calcium and sodium currents in primary sensory neurons responsible for the decrease in pain and fever. Acetaminophen is metabolized predominantly in the liver into nontoxic products primarily through three metabolic pathways (Scheme 1).4,5 Glucuronidation and sulfation account for more than 80% of the metabolism of the drug to form glucuronide and sulfate conjugates respectively.4,5 A minor fraction (less than 15%) of the drug is oxidized by cytochrome P4506 to form N-acetyl-p-benzoquinone imine (NAPQI)7,8 and 3-hydroxy-acetaminophen (3-OH-APAP).9 These oxidized reactive metabolites are inactivated with reduced glutathione to form cysteine and mercapturic acid conjugates. Thus, all three metabolic pathways yield final products that are inactive and nontoxic and are eventually excreted by the kidneys. In the third pathway, however, the intermediate oxidized product NAPQI is toxic. Overdoses of acetaminophen cause liver and renal toxicity as a result of depletion of glutathione and of covalent binding of the excess reactive metabolite to vital cell constituents.10 In our efforts in exploring some lipophilic oxidants to oxidize organic substrates in organic solvents, we have reported the oxidation behavior of cetyltrimethylammonium permanganate © 2013 American Chemical Society

Received: Revised: Accepted: Published: 13645

July 16, 2013 August 23, 2013 August 27, 2013 August 27, 2013 dx.doi.org/10.1021/ie402272b | Ind. Eng. Chem. Res. 2013, 52, 13645−13653

Industrial & Engineering Chemistry Research

Article

Scheme 1. Metabolic Pathways of Acetaminophen

phen (Figure S2, Supporting Information), about 70% conversion of N−H to N−D was confirmed. Kinetic Measurements. The oxidation kinetics of acetaminophen by CTADC in the presence of acetic acid was investigated using a UV−vis spectroscopic method by monitoring the decrease in the optical density (OD) of CTADC at an analytical wavelength of 350 nm. The reactions were performed under pseudo-first-order conditions by keeping a large excess (10 times or more) of the acetaminophen with respect to CTADC, and the observed rate constant (kobs) was calculated from the linear plot (r = 0.99) of log[CTADC] versus time for up to 75% completion of the reaction. The temperature in the reaction cell was controlled by circulating water using a Lauda thermostat with a temperature fluctuation of 0.05 °C. The effects of the variation of [CTADC], [acetaminophen], [acid], and [surfactant] on the rate constant were investigated by varying the concentration of the desired constituent in the reaction mixture. All experiments were repeated at least three times, and the rates of reactions were obtained with an error of ±4%. Some of the kinetics were run under a nitrogen atmosphere, and the data were found to be similar (within an error of 2%) to those in normal atmospheric conditions. Hence, most of the reactions were carried out without a nitrogen environment. The solvent isotope effect was investigated using 3:7 mixtures of H2O/acetic acid and D2O/ acetic acid instead of acetonitrile−acetic acid during kinetic studies. Acetic acid was equilibrated with water and D2O separately for 3 h before its use in the reaction process. Product Analysis. The reaction mixture containing acetaminophen and CTADC in 3:1 ratio in acetonitrile medium was stirred and refluxed for 3 h in the presence of acetic acid. The mixture turned reddish-green, indicating the formation of reduced Cr(III). The completion of the reaction was monitored using TLC. Then the product was separated by preparative TLC, taking chloroform and methanol as the solvent, and characterized by IR, NMR, and CHN analysis. Mp = 115 °C. IR (KBr, νmax/cm−1): There is an intense peak at 1642 cm−1 due to (CO) stretching, 1317 (Ar CH bending). 1H NMR (400 MHz, CDCl3): δ/ppm 6.806 (4H, s). 13 C NMR (100 MHz, CDCl3): δ/ppm 136.54 and 187.18. Anal. Calcd for C8H9NO2: C, 63.56; H, 6.00; N, 9.27. Found:

concentration of acid (around 5−10% of acetic acid) compared to that of conventional Cr(VI) oxidants. Owing to the selectivity, sensitivity, accuracy of kinetic methods, and the mildness of the oxidant, the oxidation kinetics of acetaminophen by CTADC can be a better alternative to the available methods for the determination of acetaminophen in drug formulations. To achieve the objectives, the oxidation products were isolated and characterized. Kinetics were run in organic media with varied polarities and in microheterogeneous systems generated from the presence of various surfactants. The resultant data were analyzed using an appropriate kinetic model. By varying [substrate], [acid], and [CTADC] and from the thermodynamics of the reaction, a suitable mechanism for the reaction was proposed. The solvent kinetic isotope effect and deuterium kinetic isotope effect was also determined to have better insight into the reaction mechanism.

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EXPERIMENTAL DETAILS Materials. Cetyltrimethylammonium dichromate (CTADC) was prepared by the method reported earlier,17 and its purity was checked by estimating Cr(VI) iodometrically.23 Acetaminophen was purchased from Sigma-Aldrich, India, and used without further purification. The organic solvents were purified by standard methods.24 The surfactants cetyltrimethylammonium bromide (CTAB) and sodium dodecylsulfate (SDS) were purified by recrystallization from aqueous ethanol, and their purity was checked with physical constants. TritonX-100 (TX-100) was purchased from Merck, India, and used without further purification. Acetic acid (Merck) was used as source of hydrogen ions and was also used as such. The D2O (Sigma-Aldrich) was of NMR grade with 99.8% D. Synthesis of Deuterated Acetaminophen. Acetaminophen (500 mg) was added to 2 mL of D2O. To this mixture, acetonitrile was added dropwise until a clear solution was obtained. It was stirred for 1 h and was kept at room temperature for 3−4 h. A white crystalline solid was obtained that was isolated by filtration. Comparing the 1H NMR spectrum of D2O-treated acetaminophen (Figure S1, Supporting Information) with the 1H NMR spectrum of acetamino13646

dx.doi.org/10.1021/ie402272b | Ind. Eng. Chem. Res. 2013, 52, 13645−13653


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Figure 1. (A) Plot of 104 × kobs versus 102 × [acetaminophen]. (B) Plot of 10−4 × kobs versus 10−2 × [acetaminophen] in the oxidation reaction of CTADC with acetaminophen at 298 K.

(Table S1, Supporting Information). The rate constant was found to increase exponentially with an increase in the [acetic acid] with almost no reaction in the absence of acid. The logarithmic plot of kobs vs [acetic acid] shows a second-order dependency with respect to acetic acid. The exponential increase in oxidation rate with an increase in [acetic acid] indicates the involvement of protonation of dichromate in the oxidation process. The protonation may be a result of exchange of CTA+ with H+ in the acetonitrile/acetic acid medium. With respect to [acetaminophen], a Michaelis−Menten-type curve was obtained with a fractional order dependency (Figure 1A). Further, the Lineweaver−Burk double reciprocal plot was found to be a straight line with an intercept in the y-axis (Figure 1B). Accordingly, a mechanism is proposed in which a complex is formed between the oxidant and the substrate prior to the rate determining step, akin to an enzyme substrate complex. In the rate determining step, the complex subsequently decomposes to afford the products (Scheme 2).

C, 61.32; H, 4.71; N, 8.89. The presence of acetamide in the product mixture was verified by a spot test and also by comparing it with the standard sample.25 Stoichiometry. The stoichiometry of the reaction was determined by performing the experiment at 298 K under the condition [CTADC] ≈ [acetaminophen] at varying acetaminophen concentrations. The disappearance of Cr(VI) was followed until the absorbance values became constant. The [CTADC] after 48 h was estimated. A stoichiometry ratio of [CTADC]/ [acetaminophen] ≈ 0.35 was observed, which confirmed a 1:3 CTADC: acetaminophen relationship.

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RESULTS AND DISCUSSION Oxidative metabolism of acetaminophen by different oxidizing systems is a subject of interest for many investigators to determine the amount of drug in pharmaceutical formulations or for degradation of anthropogenic compounds for treatment of waste and drinking water. Hiremath et al.26 oxidized acetaminophen to quinineoxime by diperiodatoargentate (III) in alkaline medium. Kissinger et al.27,28 and Sánchez-Obrero et al.29 have investigated the electrochemical oxidation of acetaminophen using different electrodes and proved that the first reaction step is an electrochemical oxidation that involves two electrons and two protons to generate N-acetyl-pbenzoquinone imine, which further decomposes to stable products by subsequent nonelectrochemical steps. Tabassum et al.30,31 have proposed free radical pathways for oxidative degradation of acetaminophen to benzoquinone by acidified dichromate and neutral permanganate. Oxidation of acetaminophen by CTADC in a 3:1 ratio in an acetonitrile−acetic acid mixture afforded benzoquinone and acetamide with other products. From the stoichiometric analysis, it has been found that 1 mol equiv of CTADC reacts with 3 mol equiv of acetaminophen, and therefore the ratio of Cr(VI)/acetaminophen is found to be 1:1.5. Cr(VI) is reduced to Cr(IV) during the reaction process, which is further disproportionate to the final reduced state of chromium (i.e., Cr(III)). The existence of Cr(III) in the product mixture was established from the absorption maximum at 580 nm.32 The proposal of one electron oxidation giving rise to free radicals may be ruled out for the present reaction due the following two factors: (i) oxidation of acetaminophen, in an atmosphere of nitrogen, failed to induce polymerization of acrylonitrile33 and (ii) the addition of acrylonitrile did not affect the rate of oxidation reaction.34 The observed rate constant of reaction was calculated by monitoring the depletion of chromium(VI) peaks at 350 nm

Scheme 2. Mechanism for the Oxidation of Acetaminophen by CTADC

Using a steady state approximation, equation S1 and S2 (Supporting Information) were derived, and the following rate expression can be written.35 1 1 1 = + kobs k 2K[Acetaminophen] k2 (1) From the plot of kobs against [acetaminophen] (Figure 1A), the Michaelis−Menten constant, Km = (k−1 + k2)/k+1) is found to be 0.5 × 10−2 M. While investigating the oxidation of acetaminophen by human cytochrome P450 2E1 and 2A6, Chen et al. obtained Km values in the range of 0.13 × 10−2 M to 0.46 × 10−2 M.36 By using the Lineweaver−Burk type double reciprocal equation (eq 1), the binding constant K = k+1/k−1 and k2 are found to be 232 L mol−1 and 3.67 × 10−4 s−1, respectively. From K, Km, and k2 values, the k+1 and k−1 were calculated to be 0.13 s−1 and 5.56 × 10−4 s−1, respectively. The closeness in the k2 and kobs values also suggests that the decomposition of the complex is the rate-limiting process. The linear plot (R2 = 0.98) of observed versus predicted rate constant (Figure S3, Supporting Information) by using k2 and K with varying [acetaminophen] supports the kinetic model. 13647



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With an increase in [CTADC], the rate constant decreases with a fractional order dependency (Figure 2). The decrease in

Figure 2. Plot of 104 × kobs versus 104 × [CTADC] in the oxidation reaction of acetaminophen by CTADC at 298 K.

Figure 3. Effect of [surfactant] on the observed rate constants in the oxidation reaction of acetaminophen by CTADC at 298 K.

the rate constant with an increase in [CTADC] is well established in the oxidation of organic substrates by CTADC in organic medium.13−15,19,20 In aqueous media, a linear decrease in rate constant with an increase in the concentration of Cr(VI) was observed by Menakshisundaram and Vinothini.37 They explained the fact through the lesser formation of acid chromate, which is the reactive species in the reaction medium. A similar decrease is also observed by other authors.38 The decrease in rate constant in the present study is attributed to the aggregation of CTADC in organic solvents. Due to the reverse micellar-type aggregation of CTADC in organic solvents, the dichromate ion is enveloped by the CTA+, and the acetaminophen is partitioned into different phases: (i) inner polar core, (ii) cationic reverse micellar interface, and (iii) nonpolar bulk solvent. Therefore, the effective concentration of the substrate in the proximity of the dichromate decreases which leads to the decrease in the rate constant. Further, [AcOH] versus the rate constant profile predicts an acidcatalyzed reaction. But in the cationic interface of CTADC reversed micelle, a proton may not be available for the dichromate, and therefore, a rate decrease is expected. With increasing [CTADC], there may be an increase in aggregation, and thus, a negative trend is inevitable. To supplement the above propositions, the effect of various surfactants, namely CTAB (a cationic surfactant), TX-100 (a nonionic surfactant), and SDS (an anionic surfactant), were analyzed. All these surfactants can form reverse micelles in organic solvents,39−42 mixed micelles with various ionic and nonionic surfactants,43−47 and aggregated structures with CTADC.19,20 When CTAB was added to the reaction mixture, the rate constant was found to decrease sharply with increasing [CTAB] (Figure 3). Above a concentration of 7.2 × 10−3 M of CTAB, the rate constant almost levels off around 0.5 × 10−4 s−1. This observation also corroborates the earlier argument of reverse micellar-type aggregation and of the partition of the oxidant and substrate in different subphases. Assuming the rate decrease is only due to the partition effect, for complete entrapment of a dichromate (2.18 × 10−4 M) by CTA+ (7.2 × 10−3 M), it requires a composition of 1:33 of CTADC/CTAB. Though to a lesser extent, addition of the nonionic surfactant TX-100 shows similar type of decreasing trend and requires 20 molecules of TX-100 for complete entrapment of 1 molecule of CTADC. If the rate decrease is only due to the partition effect, a substantial decrease in the rate constant with an increase in [SDS] is also expected. On the other hand, if the rate change is

only due to the availability of a proton on the reverse micellar interface, micellar catalysis by anionic interface is expected. However, addition of SDS has no remarkable effect on the rate of the reaction. This may be attributed to the charge neutralization of the reverse micellar interface in the presence of dodecylsulfate anion of SDS and provide a suitable residing site for H+, a dichromate ion, and acetaminophen. Thus, the decrease in rate constant due to partitioning of oxidant and substrate may be counterbalanced by an increase in the rate due to formation of a suitable environment for the possible interaction of oxidant, substrate, and acetic acid. These two propositions are described schematically in Figure 4. Figure4A,B represent the repulsion of H+ from the reverse micellar cationic interface of CTA+. The extent of repulsion is less in the TX-100 reverse micelle, where the positive charge on the interface is only due to the CTA+ from CTADC. Figure 4C shows the interaction between cationic CTA+ and anionic DS− (dodecylsulfate), resulting in charge neutralization on the interface. From all the above observations, a mechanism is proposed (Scheme 3), where CTADC first equilibrates with acetic acid to form protonated dichromate, which then forms a chromate ester complex with acetaminophen. The complex then decomposes to the products, namely benzoquinone and acetamide. Effect of Solvent Polarity. Investigation of the effects of solvent on reactivity always plays a crucial role in determining the nature of the transition state and the mechanism of the reaction. The change in the reaction rates due to changes in solvent properties is mainly due to differential solvation of the starting material and transition state by the solvents. When the reactant molecules proceed to the transition state, the solvent molecules orient themselves to stabilize the transition state. If the transition state is stabilized to a greater extent than the starting material, the reaction proceeds faster. If the starting material is stabilized to a greater extent than the transition state, the reaction proceeds slower. In the present investigation, to observe the effect of environment, the rate of the reaction was measured with the change in solvent polarity. The oxidation of acetaminophen by CTADC was studied in solutions containing varying proportions of acetonitrile:acetone and acetonitrile:ethyl acetate in the presence of acetic acid. The observed rate constants (Table S2 and S3, Supporting Information) are correlated with different solvent parameters such as π* (solvent polarity),48,49 β (hydrogen bond acceptor basicity),48,49 A 13648



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(anion solvating power of the solvent),50 B (cation solvating power of the solvent),50 and A + B (solvent polarity),50 log P (logarithm of the partition coefficient between octanol and water; referred to as solvent hydrophobicity),51 dielectric constant (ε), dipole moment (μ), viscosity (η), density (ρ), and surface tension (γ). The polarity parameters for the solvent mixtures have been estimated approximately from the polarity parameters of the pure solvents. An increase in the polarity and decrease in the hydrophobicity of the medium increased the rate of the reaction. This fact illustrates the formation of a more polar transition state than the reactants in the rate determining step. Further, the increase in rate constant with an increase in ion solvating power (A + B) of the solvent depicts an ionic transition state for the oxidation reaction. However, a similar increasing trend with an increase in both A and B proposes the involvement of both cation and anion in the transition state. On the basis of these observations, it may be proposed that in the rate determining step, the complex (C) decomposes to the products through an ionic transition state as represented in Scheme 4. The nonideal decrease in the rate with a decrease in solvent polarity (figure 56) is ascribed to the preferential solvation of the transition state and the positively charged intermediate by acetonitrile.52 Due to the presence of nonbonding electrons, acetonitrile acts as a good cation solvator.53 The positive charge in the zwitterionic transition state is localized on the NH+ moiety, whereas the negative charge is delocalized through the benzene ring and chromate moiety. Accordingly, the transition state (1) might behave more as a cation than anion and could be strongly solvated in acetonitrile through ion−dipole interactions, leading to stabilization of the transition state.54 Further, an analysis of the rate constant values with respect to polarity parameters exhibits some interesting results. From the bilinear plots of kobs against polarity parameters (figure 5-6), an ordination between two classes of solvent compositions was experienced. The dissimilar trends in these two groups of solvent compositions suggest a complex mechanism with varied contributions of these solvents toward the reaction mechanism. The variation of the rate constant with changes in different parameters (such as the concentration of reactants involved, the addition of surfactants, and a change in polarity of the medium) shows the importance of two factors toward the mechanism:

Figure 4. Schematic representation of the surfactant effect on the oxidation reaction of acetaminophen by CTADC in presence of acetic acid. (A) Effect of CTAB. (B) Effect of TX-100. (C) Effect of SDS.

1. Stability of the transition state. Scheme 3. Proposed Mechanism for the Oxidation of Acetaminophen by CTADC

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Scheme 4. Proposed Structure of the Ionic Transition State

Figure 5. Plots of 104 × kobs vs dielectric constant of the medium (ε) in the oxidation of acetaminophen in (A) acetonitrile:ethyl acetate and (B) acetonitrile:acetone binary mixture of solvents.

Figure 6. Plots of 104 × kobs vs log P (solvent hydrophobicity) in the oxidation of acetaminophen in (A) acetonitrile:ethyl acetate and (B) acetonitrile:acetone binary mixture of solvents.

increase in the nonpolarity of the solvents, reverse micellization increases, which results in a higher partition of oxidant and substrate into two different phases, imparting a rate decrease. To get further support for the proposed mechanism and transition state, the kinetic isotope effect (kH/kD), the solvent kinetic isotope effect (k(H2O)/k(D2O)), and the effect of temperature have been investigated. Determination of Deuterium Kinetic Isotope Effect. Kinetic isotope effect (KIE) has frequently been used to study organic reaction mechanisms and to get information on the structure of the transition state.57 To study the deuterium kinetic isotope effect, acetaminophen was treated with D2O to obtain deuterated acetaminophen. The 1H NMR spectrum of the D2O treated acetaminophen (Supporting Information Figure S1) suggested approximately 70% exchange of N−H proton to form deuteroacetaminophen (1). Using 1, the

2. Partition of CTADC, acetaminophen, and acetic acid in different microheterogeneous phases due to the formation of reverse micelle. In the acetonitrile−ethyl acetate mixture, with the decrease in dielectric constant of the medium from 31 to 27, a slow decrease in rate constant is observed (slope = 0.02). In the lower side of the plot from dielectric constant values 25 to 10, a sharp decrease is experienced, with a slope of 0.13. Thus, the decrease in rate constant with the decrease in dielectric constant is six times faster on the lower side compared to that of the higher side. If the change in rate constant with a change in solvent composition is only due to the stability of polar transition state, linear plots of kobs vs polarity parameters are expected. In the mixture of acetonitrile and acetone, a similar decrease in rate constant is observed in lower dielectric constant (from 28 to 22) region, with a slope of 0.29. However, in the higher side, the rate constant remains constant. The sharp decrease in rate constant in the low polar region is explained through the combining effect of the lesser stability of transition state and the higher ease of formation of reverse micellar aggregation of CTADC in nonpolar solvents. Quaternary ammonium and phosphonium salts exist as ion pairs or an aggregation of ion pairs in nonaqueous medium.55 The degree of aggregation of these salts in a nonpolar solvent is inversely proportional to the polarity of the medium.56 With an

deuterium kinetic isotope effect was determined and found to be 1. If the rate determining step involves the breaking of an N−H bond, a large deuterium isotope effect is to be expected. 13650



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Scheme 5. Proposed Reaction Path for the Formation of Benzoquinone

Because no isotope effect is found in the present reaction, it is concluded that the rate determining step does not involve the breaking of an N−H bond. Therefore, it may be assumed that the complex(C) decomposes to the N-acetyl-p-benzoquinone iminium ion in the rate determining step, which on deprotonation furnished NAPQI in a fast process. NAPQI is further hydrolyzed to form benzoquinone and acetamide in the acidic medium (Scheme 5). Determination of Solvent Kinetic Isotope Effect. Isotopic labeling on solvents may influence the rate of the reaction and sometimes gives useful information for the elucidation of reaction mechanism. To obtain the solvent kinetic isotope effect (k(H2O)/k(D2O)), the reaction was carried out in a 3:7 mixture of H2O−acetic acid and D2O− acetic acid. The solvent kinetic isotope effect, k(H2O)/k(D2O), was found to be (1.57 × 10−3)/(1.29 × 10−3) = 1.22. The magnitude of the isotope effect in this case is similar to that of a secondary isotope effect and it may be explained through the differential solute−solvent interaction due to isotopic substitution.58 On isotopic substitution, the physical characteristics of the solvents change; consequently, the strength of hydrogen bonds also change. The hydrogen bond strength is higher in D2O compared to water.59 The hydrogen bonding energy in D2O is 929 J mol−1 more negative than in H2O at 298.15K.60,61 Both the reactant and the transition state formed stronger hydrogen bonds with D2O than water and thus stabilized more, leading to higher drop in free energy in D2O. However, as proposed in Scheme 4 and 5, there is charge induction in the transition state; thus, the difference in free energy of the transition states in D2O and in water is predicted to be less compared to the free energy difference of the reactants in both the solvents (Figure 7). Calculating the thermodynamic parameters in both the cases (Table 1), this difference is found to be 0.4 kJ mol−1. Consequently, the solvent kinetic isotope effect is greater than one, though considerably smaller. Effect of Temperature. With an increase in temperature, the rate constant was found to increase linearly (Table 1). The thermodynamic parameters like Ea, ΔH⧧, ΔS⧧, and ΔG⧧ were calculated and found to be 48.7 kJ/mol, 46.2 kJ/mol, −160 J mol−1 K−1, and 93.7 kJ/mol, respectively, in acetonitrile. The proposed mechanism is also supported by the values of thermodynamic parameters. The lower energy of activation and high free energy of activation support the formation of a highly solvated transition state. The high negative entropy of

Figure 7. Free energy diagram (Solid line: D2O solvated reactant and TS. Dotted line: H2O solvated reactant and TS) depicting a drop in the free energy of the reactant and transition state due to solvation in D2O. The difference in the free energy of reactants, ΔG(RD2O−RH2O), is greater than the difference in the free energy of the transition states, ΔG(TSD2O−TSH2O), due to difference in the strength of hydrogen bonds.

activation is also indicative of a more extensively solvated activated complex than the reactants.62,63 The formation of ions from neutral molecules passes through a polar transition state, implying a drop in entropy due to extensive solvation, and ΔS⧧ assumes a larger negative value. Further, with a decrease in the solvent polarity, the value of ΔS⧧ became a larger negative, showing an appreciable increase in ordering in less polar solvents (Table 1). All these experiments support the formation of an ionic polar transition state.

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CONCLUSION In conclusion, the oxidant (CTADC) oxidizes acetaminophen to p-benzoquinone following Michaelis−Menten kinetics, thus mimicking enzyme activity. The first step involves a very fast formation of the association complex between acetaminophen and CTADC and is followed by a second rate-determining dissociation of the complex proceeding via a polar transition state to form N-acetyl-p-benzoquinone iminium ion intermediate, which on subsequent deprotonation and hydrolysis forms the product. CTADC assembles to form reverse micelles in nonpolar solvents and mixed reverse micelles with other 13651



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Table 1. Activation Parameters Determined in Different Solvents for the Oxidation of Acetaminophen by CTADC 104 × kobs (s−1) Solvent

293 K

298 K

303 K

308 K

313 K

ΔH⧧ kJ/mol

ΔG⧧ kJ/mol

ΔS⧧ J mol−1 K−1

Acetonitrile Ethyl acetate Dioxane H2O−Acetic acid (3:7) D2O−Acetic acid (3:7)

1.59 1.08 0.47 10.40 9.40

2.42 1.46 0.64 15.74 12.86

3.44 2.03 0.84 19.65 17.96

4.45 2.65 1.11 27.11 23.41

5.77

46.22 42.87 40.35 44.01 43.61

93.74 94.89 96.97 89.14 89.49

−159.47 −174.44 −189.90 −151.41 −153.90

(7) Dahlin, D. C.; Miwa, G. T.; Lu, A. Y.; Nelson, S. D. N-Acetyl-pbenzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc. Natl. Acad. Sci. U. S. A. 1984, 81, 1327. (8) Corcoran, G. B.; Mitchell, J. R.; Vaishnav, Y. N.; Horning, E. C. Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate, N-acetyl-p-benzoquinoneimine. Mol. Pharmacol. 1980, 18, 536. (9) Hinson, J. A.; Pohl, L. R.; Monks, T. J.; Gillette, J. R.; Guengerich, F. P. 3-Hydroxyacetaminophen: A microsomal metabolite of acetaminophen. Evidence against an epoxide as the reactive metabolite of acetaminophen. Drug Metab. Dispos. 1980, 8, 289. (10) Parmar, D.; Kandakar, M. Mitochondrial ATPase: A target for paracetamol induced hepatotoxicity. Eur. J. Pharmacol. 1995, 293, 225. (11) Dash, S.; Patel, S.; Mishra, B. K. Oxidation by permanganate: Synthetic and mechanistic aspects. Tetrahedron 2009, 65, 707. (12) Nayak, B. B.; Sahoo, S.; Patel, S.; Dash, S.; Mishra, B. K. Ce(IV) oxidation of alcohols using cetyltrimethylammonium ceric nitrate. Indian J. Chem. 2008, 47A, 1486. (13) Sahoo, P. R.; Patel, S.; Mishra, B. K. Oxidation kinetics of simvastatin using cetyltrimethylammonium dichromate. Int. J. Chem. Kinet. 2013, 45, 236. (14) Sahu, S.; Sahoo, P.; Patel, S.; Mishra, B. K. Oxidation of arylthiourea by cetyltrimethylammonium dichromate. Synth. Commun. 2010, 40, 3268. (15) Patel, S.; Sung, D. D.; Mishra, B. K. Oxidation of diols by cetyltrimethylammonium dichromate. Indian J. Chem. 2008, 47A, 1218. (16) Patel, S.; Mishra, B. K. Chromium (VI) Oxidants having quaternary ammonium ions: studies on synthetic applications and oxidation kinetics. Tetrahedron 2007, 63, 4367. (17) Patel, S.; Mishra, B. K. Cetyltrimethylammonium dichromate: a mild oxidant for coupling amines and thiols. Tetrahedron Lett. 2004, 45, 1371. (18) Sahu, S.; Patel, S.; Mishra, B. K. Selective oxidation of arylaldoximes by cetyltrimethyl ammonium dichromate to arylaldehydes and arylnitriles. Synth. Commun. 2005, 35, 3123. (19) Patel, S.; Mishra, B. K. Oxidation of cholesterol by a biomimmetic oxidant, cetyltrimethylammonium dichromate. J. Org. Chem. 2006, 71, 3522. (20) Patel, S.; Mishra, B. K. Oxidation of alcohol by lipopathic Cr(VI): A mechanistic study. J. Org. Chem. 2006, 71, 6759. (21) Shrestha, S. R.; Pradhananga, R. R. Spectrophotometric method for the determination of paracetamol. J. Nepal Chem. Soc. 2009, 24, 39. (22) Sultan, S. M. Spectrophotometric determination of paracetamol in drug formulations by oxidation with potassium dichromate. Talanta 1987, 30, 605. (23) Vogel, A. I. A Textbook of Quantitative Inorganic Analysis, 3rd ed.; Longmans: London, 1961. (24) Riddick, J. A.; Bunger, W. B. Organic Solvents −Physical Properties and Methods of Purification, 3rd ed.; Techniques of Chemistry, Vol. II, Wiley-Interscience: New York, 1970. (25) Vogel, A. I.Furnis, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Longman, London, 1989; pg 1230. (26) Hiremath, D. C.; Hiremath, C. V.; Nandibewoor, S. T. Oxidation of paracetamol drug by a new oxidant diperiodatoargentate (III) in aqueous alkaline medium. Eur. J. Chem. 2006, 3, 13.

surfactants and provides different residing sides for reactants. The substrate and oxidant are thus partitioned into two different types of environments; accordingly, the reaction is controlled. The outcome from the solvent effect illustrates the contribution of reverse micellization and the stability of the transition state toward the rate of the reaction. The proposed mechanism also gets support from the solvent isotope effect, the deuterium kinetic isotope effect, and the effect of temperature on the reaction rate.

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ASSOCIATED CONTENT

S Supporting Information *

1

H NMR spectrum of deuterated acetaminophen and acetaminophen; plots of predicted vs observed rate constant; kobs data with change in reactants concentrations; kobs data with change in solvent polarity along with solvent polarity parameter. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*S. Patel. E-mail: [email protected]; [email protected]. in. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Department of Science and Technology (DST), New Delhi, India, for financial support through SERC FAST Track research project (SR/FT/CS-023/2009) and the FIST programme.

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REFERENCES

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Oxidative Cleavage of Acetaminophen by Cetyltrimethylammonium

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