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Oxidation of Epinephrine to Adrenochrome by Cetyltrimethylammonium Dichromate: A Mechanistic Study Sarita Garnayak and Sabita Patel* Department of Chemistry, National Institute of Technology-Rourkela, Rourkela, Odisha India 769 008 S Supporting Information *

ABSTRACT: The present study reports the oxidation of epinephrine (adrenaline), a neurotransmitter by a lipid compatible lipophilic Cr (VI) oxidant, cetyltrimethylammonium dichromate (CTADC). The kinetics of the reaction is studied in organic media in the presence of acetic acid by UV−vis spectroscopic method. The rate of the reaction is measured by monitoring adrenochrome, the oxidized product of epinephrine at 455 nm. The reaction is fractional order with respect to CTADC and epinephrine. Acetic acid is found to retard the rate of the reaction. A suitable ionic mechanism is proposed based on the experimental findings where epinephrine is converted to adrenochrome through the intermediate, leucochrome. The proposed reaction mechanism is also supported by the effect of solvent, effect of temperature, and effect of surfactants on the rate of the reaction. The decrease in rate constant due to increase in polarity and hydrogen bond acceptor ability of the solvent indicates the existence of a less polar transition state and stabilization of the reactants through strong intermolecular hydrogen bonding. The addition of surfactants (cationic, anionic, and nonionic) decreased the rate of reaction, and the retardation is explained through the partition of oxidant and substrate in different microheterogeneous media.



INTRODUCTION Epinephrine, commonly known as adrenaline, is a hormone and neurotransmitter belonging to the catecholamine family.1 It liberates glucose in to the bloodstream through a variety of enzymatic reaction and finally stimulates the body to make a spontaneous decision to fight or flight.2−4 The role of epinephrine as a neurotransmitter highly depends upon its oxidation mechanism. Inside the body adrenaline is oxidized by an enzyme known as amine oxidase, and in that case adrenaline molecule is oxidized in the side chain.5 At an intermediate pH (6−8), epinephrine in aqueous buffer is oxidized to red colored substances known as adrenochrome.6 Autoxidation of epinephrine produces hematin, methemoglobin, and adrenochrome.7−10 The literature reports a good deal of examples for the oxidation of epinephrine to various colored organic products and intermediates by different homogeneous and heterogeneous oxidizing systems.11−23 It is proposed that organic radicals are involved in these oxidations of epinephrine. Fenton’s reagent at pH 4.5 oxidizes adrenaline to adrenochrome by a free-radical mechanism.11 In the catalytic oxidation of epinephrine to adrenochrome by mesoporous silica nanoparticles (MSN) as heterogeneous catalyst, it is reported that large surface area, characteristic mesoporosity, and surface structures facilitate the deposit of reactants inside MSN particles, and catalyze the oxidation process.18 Szigyarto et al.19 have studied the Mn(II) complex catalyzed oxidation of epinephrine to adrenochrome at room temperature. They proposed that the catalytic effect is mainly due to the binding of the catalyst to dioxygen and the substrate and formation of a ternary complex among the catalyst−dioxygen−substrate as active intermediate. Lupano et al.20,21 have used a hydrogelbased Co(II) catalyst complex for H2O2 activation for the oxidation of epinephrine to adrenochrome. With the use of a © 2014 American Chemical Society

Co(II)−poly(EGDE-DA) complex, about 77% of conversion was achieved in 30 min, while with the use of Co(II)− Poly(EGDE-MAA-2MI) about 80% conversion of epinephrine to adrenochrome was achieved in less than 6 min, following a pseudo-first-order kinetic model. In continuation of our efforts in exploring some biomimetic oxidants to oxidize organic substrates in organic solvents, we have reported the oxidation behavior of cetyltrimethylammonium dichromate (CTADC)24−30 toward various organic substrates. It is an inorganic oxidant with an amphipathic organic carrier, cetyltrimethylammonium (CTA+) ion, to carry the oxidants into the organic media. CTADC is hydrophobic and thus supports the existence of a tight ion pair of the cationic carrier and the anionic oxidant counterion in nonpolar medium. Because of the presence of the CTA+ counterion, it forms a reverse micellar-type aggregate in nonpolar solvents, provides different residing sides for the reactants, and controls the reaction, giving rise to product selectivity. The main objective of the present report aims to investigate the selective oxidation of epinephrine by CTADC. The oxidation product was characterized, and kinetics were run in media with varied polarities and also in microheterogeneous systems generated from the presence of cationic surfactant, CTAB (cetyltrimethylammonium bromide), anionic surfactant, SDS (sodium dodecyl sulfate), and nonionic surfactant, Triton X-100 (isooctylphenoxypolyoxyethanol), at different concentrations. The resultant data were analyzed using a suitable kinetic model. By varying [substrate], [acid], and [CTADC] in the reaction process, a suitable mechanism for the reaction was Received: Revised: Accepted: Published: 12249

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followed spectrophotometrically by monitoring the appearance of the product adrenochrome at an analytical wavelength of 455 nm (Figure 1). Though the reaction is possible in the absence

proposed. The thermodynamics of the reaction was also analyzed by running the kinetics at various temperatures. Further, the kinetic and spectrophotometric determinations of drugs in pharmaceutical formulations have been the subject of interest for many years because of the sensitivity, selectivity, simplicity, and accuracy of these measurements.31−36 In these methods the drug is oxidized and the amount is estimated. CTADC is a lipophilic and mild oxidant and, in most of the cases, it does not require any acid for the oxidation, while in some cases it requires a very low concentration of acid (around 5−10% of acetic acid) as compared to conventional Cr(VI) oxidants.24−30 Owing to the selectivity, sensitivity, and accuracy of kinetic methods and because of the mildness of the oxidant, the oxidation kinetics of epinephrine by CTADC can be used for the detection and estimation of epinephrine in drug formulations. Again, as CTADC is insoluble in aqueous medium, this oxidant can be used as a heterogeneous catalyst for decomposition of various pharmaceutical pollutants such as epinephrine in wastewater treatment.

Figure 1. UV−vis spectra of reaction mixture for the reaction of CTADC and epinephrine in the presence of acetic acid in acetonitrile showing the product formation at different time interval.



EXPERIMENTAL DETAILS Materials. Cetyltrimethylammonium dichromate (CTADC) was prepared by the method reported earlier.24 Its purity was checked from the NMR spectra and by estimating Cr(VI) iodometrically.37 Epinephrine was purchased from Sigma-Aldrich, India and used without further purification. Glacial acetic acid was used without further purification. The organic solvents used were purified by standard methods.38 The surfactant cetyltrimethylammonium bromide (CTAB) and sodium dodecylsulfate (SDS) were purified by recrystallization from aqueous ethanol, and its purity was checked by measuring the conductance in aqueous medium. The nonionic surfactant TX-100 was purchased from Sigma-Aldrich, India, and used as such. Kinetic Measurements. The rate of oxidation of epinephrine by CTADC in the presence of acetic acid was investigated using Shimadzu UV-1800 UV−vis spectrophotometer fitted with thermostatic cell holders. The temperature in the reaction cell was controlled by circulating water by using a Lauda thermostat within a temperature fluctuation of 0.05 °C. All reactions were carried out under pseudo-first-order conditions, that is, in excess CTADC. The reaction was followed by monitoring the appearance of the product adrenochrome at an analytical wavelength of 455 nm. The effect of variation of [CTADC], [epinephrine], [acid], and [surfactant] on the rate constant was 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 within the error of ±6%.

of acetic acid, epinephrine is sparingly soluble in acetonitrile in the absence of acetic acid. Hence kinetics was studied in the presence of a fixed amount of acetic acid in the medium. The rate constants were measured under pseudo-first-order conditions with the concentration of CTADC maintained in more than 10-fold excess relative to the substrate concentration. All reactions obeyed first-order kinetics. Pseudo-firstorder rate constants (kobs) were calculated from the linear plots of ln (A∞ − At) vs t. From the kobs values corresponding rates were calculated by multiplication of the kobs values with the [substrate]. The kobs and rate values at different reaction conditions are summarized in Table 1. Table 1. Effect of [Epinephrine] and [CTADC] on the Oxidation of Epinephrine by CTADC in Acetonitrile at 298 K rate × 108 (M s−1)



RESULTS AND DISCUSSION Under reflux conditions, the solution of CTADC and epinephrine in acetonitrile yielded a red colored product, which was identified as adrenochrome from the occurrence of a broad absorption peak at 455 nm in the UV−vis absorption spectrum of the reaction mixture.18,19,23,39,40 Extraction of a dirty green residue from the reaction mixture illustrates the reduction of Cr(VI) to Cr(III) in the reaction process. A limiting logarithmic method is used to determine the stoichiometry of the reaction, which was found to be 3:2 epinephrine to CTADC, respectively.41,42 The reaction kinetics of epinephrine with CTADC in the presence of acetic acid was

a

[CTADC] × 104 (M)

[Epinephrine] × 104 (M)

kobs × 104 (s−1)

observed

calculateda

5.8 5.8 5.8 5.8 5.8 5.8 5.8 4.65 9.31 11.64 13.96 17.45

0.06 0.12 0.18 0.3 0.5 0.6 0.9 0.6 0.6 0.6 0.6 0.6

17.2 25 31.8 37.9 42.2 43.1 44.5 44.5 39.8 38.5 38.2 38.2

1.03 3.00 5.72 11.37 21.10 25.86 40.05 26.70 23.88 23.10 22.92 22.92

1.17 2.97 5.12 10.20 20.32 25.98 44.88 26.78 24.35 23.61 23.03 22.34

Calculated using eq 1

From the linear logarithm plot of rate versus [substrate], the order of reaction with respect to epinephrine is found to be 1.35. Using multiple regression analysis, log (rate) values obtained at different conditions were correlated with the parameters of the reaction condition, that is, [substrate] and [oxidant], to obtain a relationship between the rates of reaction with the parameters of the reaction condition. The regression model, thus obtained, has been given in eq 1. Accordingly the 12250

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rate expression can be written as in eq 2. The constant term (i.e., −1.337) in the regression model demonstrates that when the reactant concentration tends to 1 the rate constant and hence the rate tends to 4.6 × 10−2 s−1.

Scheme 1. Proposed Mechanism for the Oxidation of Epinephrine to Adrenochrome by CTADC

log(rate) = −1.337( ±0.186) − 0.138(± 0.059) log[CTADC] + 1.349(± 0.03) log[epinephrine]

R2 = 0.996,

F = 1071,

(1)

n = 12

rate = 0.046[CTADC]−0.14 [epinephrine]1.35

(2)

Using the regression model, the log (rate) values were predicted and plotted against the observed values (Figure 2). A linear plot without any outlier supports the regression model.

Figure 2. Plot of predicted versus observed log (rate) for the oxidation reaction of epinephrine with CTADC in acetonitrile at 298 K.

Oxidation of hydroxylic and phenolic substrates by CTADC goes through a multistep reaction process, where the first step is the formation of a 1:1 association complex between the oxidant and the substrate.26−30 The complex subsequently decomposes to the products through rate determining hydrogen abstraction by the chromate oxygen. In the present study the fractional orders with respect to the oxidant and the substrate (eq 2) indicate the occurrence of a complex reaction mechanism, which may be proposed as in Scheme 1. Epinephrine first forms a complex (C1) with CTADC which then decomposes to form epinephrine quinone (P1). Intramolecular cyclization through a nucleophilic attack by the nitrogen on the quinone ring of P1 followed by aromatization through proton transfer afforded leucochrome (P2). As reported earlier, the half-life of the primary oxidation product (P1) was only 0.06 s; that is, this open chain quinone exists only as a very transient intermediate between epinephrine and adrenochrome.43 In the presence of Cr(VI), leucochrome further oxidizes to the product adrenochrome (P3) through the rate determining decomposition of complex (C2). The proposed mechanism gets support from the retarding effect of acetic acid. With an increase in the concentration of acetic acid, the rate of the reaction was found to decrease linearly (eq 3 and Figure 3). As per eq 3, in the absence of acetic acid, the rate of the reaction will be 32.67 × 10−8 M s−1. In acidic medium epinephrine exists in the cationic form (1) and is oxidized to the cationic quinone (2).43 The protonation at nitrogen prevents the nucleophilic attack for possible intramolecular cyclization to form the P2. With a decrease in acidity the increase in formation of free base leads to cyclization, and as a result, the rate of the reaction increases.

Figure 3. Plot of rate of the reaction versus [acetic acid] for the oxidation of epinephrine with CTADC in acetonitrile at 298 K.

If step 2 would have been the rate-determining step, there would not be any rate retardation with increase in [acetic acid], rather a rate increase would have been observed because of an increase in the formation of protonated dichromate and fast formation of complexes C1 and C2. Thus, step-5 may be proposed to be the rate-determining step. With an increase in acidity, [P2] decreases, affecting the [C2] and thus affecting the rate of the reaction. rate = − 2.1458[acetic acid] + 32.67

R2 = 0.997

(3)

After the removal of the organic products, the presence of green colored residue in the reaction mixture supports the reduction of Cr(VI) to Cr(III).44 The possibility of a free 12251

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aggregate of CTADC with the added surfactant and partition of reactants in different subphases. In presence of SDS, a significantly higher decrease is observed as compared to the CTAB and TX-100. SDS forms a reverse micelle with negative charge at the interface and thus provides a favorable residing site for H+. In our earlier work, in the acetic acid catalyzed oxidation of various organic substrates by CTADC, we observed the opposite trend with respect to [SDS].26−29 The results were explained through the stabilization of protonated dichromate in the anionic interface of SDS reverse micelle. In the present study, the protonated dichromate is also stabilized in the SDS reverse micellar interface (Scheme 3), which may increase the concentration of C1 leading to the enhancement in the formation of P1. On the other hand, it may decrease the concentration of P2 (which is supposed to be the reactant for the second oxidative process), due to stabilization of protonated epinephrine quinone (2) resulting in a decrease in the rate. The thermodynamic parameters such as activation energy (Ea), enthalpy of activation (ΔH⧧), free energy of activation (ΔG‡), and entropy of activation (ΔS‡) were calculated using the Arrhenius and Eyring equation, and the results are presented in Table 2. The high-negative values of ΔS‡ are indicative of involvement of a highly ordered transition state rather than the reactants.63,64 It supports the existence of a cyclic or a forced transition state during the abstraction of the ohydroxyl proton of complex C2 to form adrenochrome in the rate-determining step.65 The proposed mechanism especially formation of forced nonpolar transition state is further supported by the effect of solvent polarity on the reaction rate. The oxidation reaction was carried out in solutions containing varying proportions of acetonitrile/dimethyl sulfoxide (DMSO) in the presence of acetic acid. The observed rate constants (Table 3) were correlated with different solvent parameters such as dielectric constant (ε), π* (solvent polarity),66,67 β (hydrogen bond acceptor basicity),66,67 A (anion solvating power of the solvent),68 B (cation solvating power of the solvent),68 and log P (logarithm of partition coefficient between octanol and water referred as solvent hydrophobicity).69 The polarity parameters for the solvent mixtures have been estimated approximately from the polarity parameters of the pure solvents. With an increase in polarity of the medium the rate constant is found to decrease, delineating a less polar transition state than reactants (Table 3). Figures 5 and 6 show the change in kobs with change in the composition of DMSO and change in hydrogen-bond acceptor (HBA) basicity β of the solvent in acetonitrile/DMSO mixture, respectively. On increasing the mole fraction of DMSO from 0 to 0.2 in the acetonitrile/ DMSO mixture, a sharp decrease in rate constant is observed (from 43 × 10−4 to 9 × 10−4 s−1). On the other hand, at a higher mole fraction of DMSO (>0.2), the rate constant is virtually independent of the composition. This observation demonstrates preferential solvation of the reactants and/or transition state in DMSO. The validity of isokinetic relationship with an isokinetic temperature of 366 K confirms that the bilinear decreasing trend is not due to a change in mechanism.70−72 A brief discussion on the calculation of isokinetic temperature is presented in the Supporting Information. Further, as DMSO contains nucleophilic oxygen, the decrease in rate may also be attributed to nucleophilic role of

radical mechanism was ruled out because of the following: (i) no precipitate was observed by addition of acrylonitrile to the reaction mixture;45−47 (ii) there is no signal in the EPR spectrum; (iii) the addition of acrylonitrile does not have any effect on the rate of reaction. Thus, during the oxidation process, Cr(VI) was reduced to Cr(IV). The reduced Cr(IV) by a disproportionation reaction in a sequential manner further changed to Cr(III) (Scheme 2). Scheme 2. Sequential Conversion of Cr(VI) to Cr(III) in the Oxidation Reaction of Epinephrine by CTADC

The existence of Cr(IV) as the reduced state in oxidation of various organic substrates by different chromium oxidants including onium chromates and dichromates is well established.48,49 A nonlinear decrease in rate with increase in [CTADC] is observed (Table 1). Similar observations have been made for oxidation reactions of various organic substrates in organic solvents by lipophilic oxidants namely CTADC26−29 and CTAP.50−53 These oxidants, in nonpolar solvents form reverse micellar-type aggregates because of the presence of a CTA+ counterion. As a result, the dichromate ions remain enveloped by the CTA+ and the epinephrine is partitioned into different phases, namely inner polar core, cationic reverse micellar interface, and 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. To supplement the above proposition, the effect of various surfactants such as CTAB (cetyltrimethylammonium bromide) a cationic surfactant, TX-100 (Triton X-100) a nonionic surfactant, and SDS (sodium dodecylsulfate) an anionic surfactant on the rate of the reaction was analyzed. All these surfactants can form reverse micelles in organic solvents54−57 and mixed micelles with various ionic and nonionic surfactants.58−62 Thus, formation of mixed aggregated structures with CTADC in nonpolar medium is expected. Asymptotic decreasing profiles in the rates are observed with increase in surfactant concentrations (Figure 4). This may provide evidence for the formation of mixed reverse micellar

Figure 4. Effect of [surfactants] in the rates of the reaction in the oxidation of epinephrine by CTADC at 298 K. 12252

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Scheme 3. Schematic Representation of the Effect of SDS on the Oxidation Reaction of Epinephrine by CTADC in the Presence of Acetic Acid; Stabilization of Protonated Epinephrine Quinone on the Interface

Table 2. Activation Parameters for the Oxidation of Epinephrine by CTADC in the Presence of Acetic Acid (kobs Values Obtained at the Given Temperatures (K)) 104 kobs (s−1) solvent

288

293

298

303

308

313

318

acetonitrile acetonitrile/ DMSO (1:1) DMSO

23.5

32.8 4.8

43.1 6.3 0.4

56.4 8.6 0.6

67.0 12.9 1.1

20.0 1.8

25.6 3.0

Ea

ΔH⧧

ΔG⧧

ΔS⧧

323

kJ/mol

kJ/mol

kJ/mol

J mol−1 K−1

5.1

39.0 54.0 82.5

36.5 51.5 79.9

82.6 90.6 98.1

−168 −133 −62

Table 3. Observed Rate Constants in the Oxidation of Epinephrine by CTADC at 298 K in Acetonitrile/DMSO Solvent Mixture mole fraction (CH3CN)

mole fraction (DMSO)

π*

β

log P

ε

104 kobs (S−1)

0.83 0.82 0.76 0.71 0.68 0.60 0.51 0.42 0.18 0.00

0 0.01 0.07 0.11 0.14 0.22 0.30 0.39 0.61 0.78

0.707 0.708 0.713 0.718 0.721 0.728 0.736 0.745 0.767 0.784

0.308 0.313 0.333 0.349 0.360 0.388 0.418 0.450 0.533 0.595

−0.283 −0.296 −0.352 −0.395 −0.424 −0.500 −0.581 −0.665 −0.89 −1.06

31.174 31.265 31.638 31.928 32.127 32.641 33.183 33.750 35.27 36.40

43.1 30.20 15.23 12.17 10.20 8.82 7.7 6.3 2.40 0.40

Figure 5. Change in kobs with change in the composition of DMSO in an acetonitrile/DMSO mixture in the oxidation of epinephrine by CTADC at 298 K.

oxygen of DMSO instead of nitrogen in step 3 of the proposed mechanism (Scheme 1). To investigate the matter, the effect of composition of nonpolar solvents such as chloroform on the rate constant was also investigated. A similar type of increase in rate constant with decrease in polarity was observed when the reaction was carried out in an acetonitrile/chloroform mixture (Table SI-1, Figure SI-1 Supporting Information). Thus, it may be proposed that the change in rate constant with change in solvent polarity is primarily due to the preferential solvation of reactants in polar solvents. The decrease in rate constant with an increase in DMSO composition may be attributed to the following reasons. If the reactants are solvated more efficiently in DMSO than

Figure 6. Change in kobs with change in hydrogen bond acceptor (HBA) basicity β of the solvent in an acetonitrile/DMSO mixture in the oxidation of epinephrine by CTADC at 298 K.

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Scheme 4. Intramolecular and Intermolecular Hydrogen Bonding of the Oxidant−Substrate Complex in Different Solvents

acetonitrile with respect to the activated complex, then Ea will increase. Consequently, kobs will decrease and the reaction will be slower. Second, if the activated complex is solvated less efficiently in DMSO than acetonitrile compared to the reactants, then Ea will also increase in value leading to a slower rate of the reaction. Though both DMSO and acetonitrile are dipolar aprotic solvents with minor difference in the polarity (ε of DMSO = 46.45; ε of acetonitrile = 37.5), there is a large difference in the HBA basicity (β of DMSO = 0.76; β of acetonitrile = 0.31). Thus, the preferential solvation of the reactants (the oxidant− substrate complex (C2) in the rate-determining step) is supposed to be due to specific solute−solvent interaction, that is, hydrogen bonding. This proposal also gets support from a similar decrease of rate constant with respect to β (Figure 4B). In the oxidant-substrate complex (C2), two types of hydrogen bonding leading to a difference in rate are expected: (i) intramolecular H-bonding in low polar and low HBA solvents, (ii) intermolecular H-bonding with higher HBA solvents (Scheme 4). From Scheme 4 it is obvious that stronger intramolecular H-bonding leads to a higher rate of hydrogen abstraction from the o-hydroxy group, and thus the rate of the reaction is higher. High polar solvents having higher β values preferentially solvate the complex and also stabilize the complex through intermolecular H-bonding, leading to lesser rate of decomposition of the complex. The higher energy of activation and slower rate of formation of adrenochrome with an increase in DMSO composition (Table 2) is thus attributed to the stronger intermolecular hydrogen bonding providing additional stabilization to the oxidant−substrate complex. The further high polar nature of DMSO may destabilize the nonpolar transition state compared to acetonitrile. This phenomenon is presented graphically in Scheme 5. The lower the temperature is, the stronger is the preferential solvation of the probe molecules by the molecules of solvent.73 An increase in temperature results in increased kinetic energy of molecules, and thereby the interaction between molecules connected with preferential solvation becomes weaker. The hydrogen bonding between the reactants and solvents also weakens, resulting in an increase in the rate of reaction. The proposition of the formation of a nonpolar transition state compared to that of the reactant is also supported from the numerical values of entropy of activation. The entropy of activation (ΔS⧧) in acetonitrile is −168 J mol−1 K−1 while in DMSO it is found to be −62 J mol−1 K−1. The values of ΔS⧧ are generally influenced by the degree of solvation and solvent polarity. If the transition state is more extensively solvated than the reactants, ΔS⧧ assumes a larger negative value due to appreciable increase in ordering in the solvation shell.72 Thus,

Scheme 5. Qualitative Representation of the Solvent Effect on Activation Energies in Acetonitrile/DMSO Mixture in the Oxidation of Epinephrine by CTADC

the higher negative value of ΔS⧧ in acetonitrile as compared to DMSO may be attributed to the greater solvation of the nonpolar transition state in the less polar solvent.



CONCLUSION The oxidant (CTADC) oxidizes epinephrine to adrenochrome selectively without affecting the secondary hydroxyl group present in the side chain of the epinephrine. The reaction proceeds through a multistep ionic mechanism. From the experimental data a mechanism was proposed where epinephrine is first converted to epinephrine quinone. Intramolecular cyclization followed by aromatization through proton transfer affords leucochrome which further oxidizes to the product adrenochrome through the rate determining decomposition of complex (C2) via a less polar transition state. The proposed mechanism gets support from the rate retarding effect in the presence of acetic acid and surfactant. CTADC assembles to form reverse micelles in nonpolar solvents with cations at the interface providing different residing sides for the reactants thus mimicking enzyme activity. The substrate and oxidant are partitioned into two different types of environments, and accordingly the reaction is controlled. The outcome from solvent effect illustrates that in the rate-determining step the oxidant−substrate complex decomposes via a cyclic nonpolar transition state. Polar solvents with higher HBA ability stabilize the reactants and destabilize the transition state leading to an increase in energy of activation and lesser rate of reaction.



ASSOCIATED CONTENT

S Supporting Information *

Observed rate constant (kobs) data at various compositions of chloroform; the plot of kobs versus mole fraction of chloroform; calculation of isokinetic temperature. This material is available free of charge via the Internet at http://pubs.acs.org. 12254

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AUTHOR INFORMATION

Corresponding Author

*Email: [email protected]; [email protected]. Notes

The authors declare no competing financial interest.



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



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