Mechanism of Oxidation of the Antituberculosis Drug Isoniazid by

Article pubs.acs.org/IECR

Mechanism of Oxidation of the Antituberculosis Drug Isoniazid by Bromate in Aqueous Hydrochloric Acid Medium Ramesh S. Yalgudre and Gavisiddappa S. Gokavi* Kinetics and Catalysis Laboratory, Department of Chemistry, Shivaji University, Kolhapur 416004, Maharashtra State, India ABSTRACT: The oxidation of isoniazid by bromate was investigated kinetically under pseudo-first-order conditions in acid medium. The reaction was accelerated by the hydrogen ion due to the various protonation equilibria of both the reactants. The mechanism involves diprotonated isoniazid as the active species which forms two complexes with the diprotonated and unprotonated oxidant. The complex formed between the diprotonated oxidant and the protonated −NH2 group of hydrazide moiety of isoniazid decomposes into isonicotinic acid. Formation of another stable ion pair complex decreases the rate of reaction. The UV−vis examination of the solutions support the formation of both protonated isoniazid and the complexes. A probable mechanism on the basis of kinetic results involving formation of an acyl diimide of the isoniazid was proposed.

1. INTRODUCTION Isoniazid is one of the main drugs used for treatment of tuberculosis which is a disease caused by Mycobacterium tuberculosis. In its complex mode of action, isoniazid is oxidized to produce activated species.1 The acyl radical is predicted to be the intermediate produced during isoniazid oxidation which combines with NAD+ to produce1 the actual inhibitor of the Mycobacterium. Another role of isoniazid is its inhibiting effect on the activity of the myeloperoxidase enzyme. This myeloperoxidase enzyme2 is stored in primary granules and kills the invading pathogens. The digestion of pathogens and their oxidative reaction with myeloperoxidase results in the production of various reactive intermediates including superoxide2 and hydrogen peroxide. Further, the reaction between hydrogen peroxide and chloride ion leads to the generation of hypochlorous acid which likely damages tissue at the sites of inflammation. Inhibitors are essential to reduce the myeloperoxidase-dependent inflammatory tissue damage. Substituted benzoic acid hydrazides are promising inhibitors1 of the myeloperoxidase activity. These hydrazides react with the intermediate generated by the reaction between myeloperoxidase and hydrogen peroxide. In the absence of an inhibitor like hydrazide, such an intermediate2 reacts with chloride to generate hypochlorous acid. Thus, isoniazid in both of its roles, a drug and an inhibitor, undergoes oxidative transformation in the presence of an enzyme as well as an oxidant. Therefore, the nature and mechanistic aspects of the oxidation of isoniazid by oxidants like bromate will be of help in understanding the metabolic activity and assessment of its oxidative stress as well as its analytical3 assay.

concentration HCl (BDH) was used. Acetic acid (SD fine) and acrylonitrile (SD fine) were used directly as received to study the effect of solvent polarity on the reaction medium and free radical formation, respectively. 2.2. Kinetic Measurement. The reaction was studied under pseudo-first-order conditions keeping the hydrazide concentration at a large excess over that of oxidant, KBrO3, at a constant temperature of 26.0 ± 0.1 °C. The reaction was initiated by mixing the previously thermostatted solutions of the oxidant and substrate, which also contained the required amount of hydrochloric acid, sodium perchlorate, and distilled water. The reaction was followed by titrating the reaction mixture for unreacted oxidant iodometrically, and the rate constants were determined from the pseudo-first-order plots of the log[oxidant] against time. The pseudo-first-order plots were linear for more than 90% of the reaction, and rate constants were reproducible within ±6%.

3. RESULTS 3.1. Stoichiometry and Product Analysis. The stoichiometry of bromate oxidations predicts either Br2 or HOBr as the product of reaction but the hydrazides can be very easily oxidized by both of them in acidic solutions due to the oxidation potential4 of HOBr or Br2 of 1.34 and 1.07 V, respectively. The test for formation of bromide ion was carried out in sulfuric acid solution instead of hydrochloric acid by adding 0.1 mL of 0.01 mol dm−3 silver nitrate solution to the reaction mixture after completion of the reaction. The precipitation of silver bromide confirmed the formation of bromide as one of the product of the reaction. Therefore, the product of the reaction under the present experimental conditions is the bromide ion. It is also noticed during the kinetic studies and the stoichiometric analysis that no bromine was evolved further confirming the bromide ion as the only product.

2. EXPERIMENTAL SECTION 2.1. Materials. Double distilled water was used throughout the work. All the chemicals used for experiments were of reagent grade. The stock solution of KBrO3 was prepared by dissolving KBrO3 (BDH) in water and standardizing iodometrically. The solution of isoniazid (SD fine) was prepared by dissolving the requisite amount in water. The ionic strength was maintained using sodium perchlorate, and to vary hydrogen ion © 2012 American Chemical Society

Received: Revised: Accepted: Published: 5135

December 29, 2011 February 2, 2012 March 17, 2012 March 18, 2012 dx.doi.org/10.1021/ie203058s | Ind. Eng. Chem. Res. 2012, 51, 5135−5140

Industrial & Engineering Chemistry Research

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Further, in 10 mL of 0.6 mol dm−3 hydrochloric acid 10 mmol isoniazid (1.371 g) was dissolved. To the resulting solution, 5 mmol (0.835 g) of KBrO3 was added. The reaction mixture was stirred at 26 °C for a day. The respective isonicotinic acid (≈0.350 g, 95% yield) precipitated and was filtered, washed with water to remove soluble impurities, and recrystallized from methanol. The GC analysis of the solution of the product in methanol shows (Figure 1) a peak at m/z 123,

Table 1. Effect of Reactants and [HCl] on the Reaction at 299 Ka

a

102[isoniazid] mol dm−3

103[bromate] mol dm−3

104 kobs s−1

0.4 0.6 0.8 1.0 2.0 3.0 4.0 6.0 8.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0

2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 0.5 0.8 1.0 2.0 3.0 4.0 5.0

2.2 2.2 2.1 2.1 2.0 1.9 1.8 1.7 1.6 2.0 2.0 2.1 2.1 2.0 2.0 2.1

[HCl] = 0.1 mol dm−3 and I = 0.5 mol dm−3.

of reactant species present in the solution. The [H+] was varied between 5.0 × 10−2 and 0.4 mol dm−3 (Table 2). Increasing Table 2. Effect of [H+] on the Rate Constants and the Various Protonated Species of Reactants at 299 Ka

Figure 1. GC−MS spectra of reaction product, isonicotinic acid, showing both base peak and molecular ion peak at m/z 123.

BrO3−

and the melting point of the recrystallized product was found to be 308 °C (lit mp = 310 °C5). The GC−MS of the isonicotinic acid was carried out with Shimadzu GC-2010 and MS-QP-2010 instruments on a Rtx-5 ms-60 m column with 0.25 mm internal diameter. The overall run time was 21 min and the conditions were 80 °C for the first min, 80−280 oC for the next 20 min at the rate of 10 oC per min. The carrier gas was helium at the flow rate of 1 mL per min, the ionization source temperature was 250 °C, and the scan range was 40−350 amu. From the GC−MS analysis and the mp, determination of the product of the reaction is confirmed to be isonicotinic acid. Therefore, the stoichiometry of the reaction was found to be two moles of oxidant per three moles of the hydrazide as shown in eq 1.

+

10[H ] mol dm−3

104 kobs s−1

0.5 0.8 1.0 2.0 2.5 3.0 4.0

0.52 1.2 2.0 5.0 8.0 11.0 18.0

10 mol dm 1.72 1.59 1.52 1.22 1.11 1.02 0.87

4

10 [HBrO3] mol dm−3

106[H2BrO3+] mol dm−3

2.71 4.02 4.80 7.71 8.77 9.67 11.0

0.90 2.13 3.19 10.2 14.4 19.3 29.2

a 3 10 [BrO3−] = 2.0 mol dm−3, 102 [isoniazid] = 2.0 mol dm−3, I = 0.5 mol dm−3.

[H+] accelerates the rate of the reaction and the order in [H+] is found to be 1.8 as determined from the plot of log kobs against log [H+]. 3.4. Effect of Ionic Strength. The effects of ionic strength and temperature were studied keeping [isoniazid], [KBrO3], and [HCl] constant at 2.0 × 10−2 mol dm−3, 2.0 × 10−3 mol dm−3, and 0.1 mol dm−3, respectively. Sodium perchlorate was used to vary the ionic strength. The rate of the reaction increases with increasing ionic strength (from 0.1 to 0.5 mol dm−3). 3.5. Effect of Solvent Polarity. The effect of solvent polarity on the reaction was studied by varying percentage of acetic acid from 2 to 40% v/v keeping isoniazid and bromate concentration constant at 2.0 × 10−2 mol dm−3 and 2.0 × 10−3 mol dm−3, respectively. The dielectric constants of the reaction mixture were calculated by using the values for pure solvents. It was found that the decrease in the dielectric constant increases the rate of the reaction. The plot of log kobs against (1/D), where D is the dielectric constant, was found to be linear with negative slope. 3.6. Effect of Temperature. The effect of temperature on the reaction was studied at 20, 26, 30, and 40 °C. The activation parameters ΔH⧧, ΔG⧧ and −ΔS⧧ were found to be

2BrO− 3 + 3RCONHNH2 → 2Br− + 3RCOOH + 3H2O + 3N2

[BrO3−] −3

3

(1)

where R = C5H5N. 3.2. Effect of Reactant Concentration. The reaction was carried out under pseudo-first-order conditions keeping the concentration of isoniazid at a large excess at a constant concentration of HCl at 0.1 mol dm−3 and at a constant ionic strength of 0.5 mol dm−3 (Table 1). The pseudo-first-order plots were found to be linear upon varying the concentration of oxidant between 0.5 × 10−3 and 5.0 × 10−3 mol dm−3 and keeping the concentration of isoniazid constant at 2.0 × 10−2 mol dm−3, respectively (Table 1), indicating the order in oxidant concentration is unity. The effect of isoniazid was studied by varying the concentration of isoniazid between 0.4 × 10−2 and 8.0 × 10−2 mol dm−3 keeping all other concentrations constant (Table 1). The pseudo-first-order rate constants, kobs, were found to decrease as the concentration of isoniazid increases (Table 1). 3.3. Effect of Hydrogen Ion Concentration. The effect of hydrogen ion was studied in order to understand the nature 5136

dx.doi.org/10.1021/ie203058s | Ind. Eng. Chem. Res. 2012, 51, 5135−5140


Article

72.1 ± 0.5 kJ mol−1, 94.8 ± 0.5 kJ mol−1, and 75.8 ± 4 JK−1 mol−1 as determined from the linear plots of log kobs and log (kobs/T) against 1/T, respectively. 3.7. Test for Free Radical Intervention. To understand the intervention of free radicals,6,7 in the reaction, the reaction was studied in the presence of added acrylonitrile. There was no induced polymerization of the acrylonitrile as there was no formation of the precipitate, and also it did not affect the rate of the reaction.

4. DISCUSSION

Figure 2. Effect of [HCl] on the UV−vis spectra of isoniazid: (1) isoniazid; (2) isoniazid + HCl; 104[isoniazid] = 2.0 mol dm−3., [HCl] = 0.1 mol dm−3, I = 0.5 mol dm−3.

The bromate oxidations of one-electron oxidants were also found to involve the induction period8 due to initial hydrogenion-dependent reduction of bromate according to the equilibrium shown in eq 2. But in the present investigation there was no such induction period which was also not observed by R. C. Thompson9 during oxovanadium(IV) oxidation Red + BrO3− + 3H + → Ox + HBrO2 + H2O

3.16 dm3 mol−1 and 6.6 × 10−2 dm3 mol−1, respectively, for formation K3

BrO3− + H + HooI HBrO3 K4

HBrO3 + H + HooI H2BrO3+

(2)

(6) (7)

of HBrO 3 and H 2 BrO 3 + . Using these constants the concentration of HBrO3 and H2BrO3+ were calculated for each [H+] of the reaction medium (Table 2). From Table 2 it can be seen that there is an increase in the [HBrO3] and [H2BrO3+] as [H+] is varied from 0.05 to 0.4 mol dm−3 while that of [BrO3−] decreases. The data of Table 2 was also used to plot kobs and [H2BrO3+] as a function of [H+] (Figure 3).

by bromate. Therefore, the hydrogen ion dependence of the reaction is not due to reaction 2. The order in [H+] was found to be 1.8 indicating two prior protonation equilibria. There are two possible protonation sites in isoniazid,10 the pyridine nitrogen and the −NH2 group of the isoniazid. The pK of the pyridine nitrogen is reported10 to be 1.8 and that of the −NH2 group of isoniazid is 3.5. The protonation equilibria of both sites can be represented as in eqs 3 and 4, respectively. Further, the π → π* and n → π* transitions of the hydrazide are observed11

Figure 3. Plot of kobs and [H2BrO3+] as a function of [H+]; 103[BrO3−] = 2.0 mol dm−3, 102[isoniazid] = 2.0 mol dm−3, I = 0.5 mol dm−3.

between 225 and 260 nm and 270−290 nm, respectively, and both these transitions are sensitive to the pH of the solution. Therefore, to get further information regarding protonation, the UV−vis spectra of isoniazid was examined in the presence of HCl. The spectrum of aqueous solution of isoniazid shows a peak at 264 nm but in the presence of 0.1 mol dm−3 HCl the peak shifts to 268 nm with increase in intensity (Figure 2) indicating the protonation of isoniazid. Since the reaction is carried out in acidic medium the hydrazide moiety will be completely in its protonated form due to its very low pK values.10 Therefore, within the range of [H+] used in the present study (0.05−0.4 mol dm −3 ), the isoniazid is completely transformed into the diprotonated form, IH22+. Simillaraly protonation of bromate had been considered12,13 in some of the reports with stepwise protonation constants of

The variation of kobs as the [H+] varies was found to parallel that of [H2BrO3+] (Figure 3). Therefore, [H2BrO3+] is considered as the active oxidant species of the reaction. Further, the values of kobs were found to decrease as [isoniazid] increases (Table 1). Such a decrease would be due to formation of two complexes between the reactants, one of them does not decompose while the other decomposes to give products. In acidic medium the active species of the isoniazid is IH22+ as shown in equilibrium 3, which contains protonated pyridine nitrogen as well as a protonated −NH2 group of the hydrazide moiety. The complex between the protonated −NH2 group leads to the further reaction, while that with protonated pyridine nitrogen does not undergo 5137



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if the positive charge is transferred to carboxylic oxygen through tautomerism. Therefore, the rapid tautomerism of the hydrazide is considered as the first step of Scheme 1. According to Scheme 1 the tautomeric form of the hydrazide forms complex I in the second step, which undergoes decomposition to give a diimide intermediate. Such diimide intermediates18−20 are proposed during the oxidation of hydrazides. Further, the nucleophilic attack of water molecules on the carbonyl carbon of acyl diimide intermediate gives isonicotinic acid and another intermediate NHNH. The fast oxidation of NHNH by the HOBr will complete the observed stoichiometry of the reaction. The decrease in the kobs values as the concentration of isoniazid increases is due to the formation of an inert ion-pair complex between the protonated pyridine nitrogen and the bromate ion. The reaction of Scheme 1 involves formation of two complexes, and complex I decomposes in a two-electron transfer slow step generating acyl diimide as intermediate, while ion-pair complex II does not undergo any reaction thus reducing the concentrations of both the reactant spe cies. The rate law according to Scheme 1 can be derived as follows. The rate of reaction is given by eq 15. The [Complex I] can be obtained from eq 9 of Scheme 1 and its substitution in 15 results into eq 16. Then from eqs 6 to 10 total bromate ion concentration,[BrO3−]t, can be obtained as in eq 17. Expressing concentrations of all bromate species in terms of free bromate ion, [BrO3−]f, we get eq 18 which can be simplified to eq 19 to obtain free bromate ion concentration. Then from eq 19 and equilibria 6 and 7, [H2BrO3+] can be obtained as in eq 20. Substituting for [H2BrO3+] from 20 in the rate eq 16 and also considering all hydrazide in the diprotonated form, [IH22+] we get eq 21 and corresponding pseudo-first-order rate constant by eq 22. Since, the K3K4 is very small, eq 22 can be simplified to 23 by neglecting the terms cotaining the product K3K4[H+]2 in the denominator. At constant [H+] and at varying concentration of isoniazid, inverting the expression 23 we get equation 24. While at constant concentration of isoniazid rearranging and inverting eq 23 we get eq 26.

further reaction. Such stable tetraalkylammonium salts of bromate14−16 have been prepared and used for various synthetic applications. Therefore, the complex between the pyridinium ion of isoniazid and BrO3− in the present study is quite stable and does not undergo any oxidative transformation thus converting the oxidant into an inactive form. To understand the interaction between the reactants, the UV−vis spectra of isoniazid in the presence of bormate in acidic medium was investigated. It was observed that the intensity of the absorbance between 200 and 300 nm increases as the bromate ion concentration increases (Figure 4)

Figure 4. Effect of [BrO3−] on the UV−vis spectra of isoniazid: 104[isoniazid] = 2.0 mol dm−3., [HCl] = 0.1 mol dm−3, I = 0.5 mol dm−3; 103 [BrO3−] = 0.4, 1.0, 2.0, 3.0, 4.0 mol dm−3.

indicating the complex formation between the two. Therefore, the mechanism of reaction, by considering the IH22+ and H2BrO3+ as the active species of the isoniazid and bromate, respectively, can be represented as in Scheme 1. Hydrazides Scheme 1. Mechanism of Oxidation of Isoniazid by Bromate

rate = k1[Complex I]

(15)

rate = k1K5[IH2 2 +][H2BrO3+]

(16)

[BrO3−]t = [BrO3−]f + [HBrO3] + [H2BrO3+] + [Complex I] + [Complex II]

(17)

[BrO3−]t = [BrO3−]f + K3[H+][BrO3−]f + K3K 4[H+]2 × [BrO3−]f + K3K 4K5[H+]2 [IH2 2 +] × [BrO3−]f + K 6[IH2 2 +][BrO3−]f

(18)

[BrO3−]f = [BrO3−]t /(1 + K3[H+] + K3K 4[H+]2 + K3K 4K5[H+]2 [IH2 2 +] + K 6[IH2 2 +]) (19)

[H2BrO3+] = (K3K 4[H+]2 [BrO3−]t ) /(1 + K3[H+] + K3K 4[H+]2

are known to undergo tautomerism which is rapid in aqueous solutions.17 Since, both the reactive species are cations, H2BrO3+ and IH22+, the electrophilic attack of oxidant on nucleophilic nitrogen of hydrazide moiety would be facilitated

+ K3K 4K5[H+]2 [IH2 2 +] + K 6[IH2 2 +]) (20) 5138



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Rate = (k1K3K 4K5[H+]2 [IH2 2 +][BrO3−]t )

both are linear thus verifying the derived expression for kobs. The increase in relative permittivity of the reaction medium with acetic acid increases the rate of reaction and the plot of log kobs against (1/D), where D is the dielectric constant of the medium, is linear with a negative slope. The charge separation in the transition state formed, and its larger size increases its stability21 in the medium of higher relative permittivity thus increasing the rate of reaction with an increase in acetic acid content. The negative value of ΔS⧧can be ascribed to the nature of electron pairing and unpairing processes and to the lesser degrees of freedom formerly available to the reactants and moderate value of enthalpy of activation is due to the electron transfer process.

/(1 + K3[H+] + K3K 4[H+]2 + K3K 4K5[H+]2 × [IH2 2 +] + K 6[IH2 2 +])

(21)

kobs = (k1K3K 4K5[H+]2 )/(1 + K3[H+] + K3K 4[H+]2 + K3K 4K5[H+]2 [IH2 2 2 +] + K 6[IH2 2 2 +]) k1K3K 4K5[H+]2

kobs =

1 kobs

+2

[H ]

(1 + K3[H+] + K 6[IH2 2 2 +])

=

kobs

(22)

(1 + K3[H+])

K 6[IH2 2 +] + k1K3K 4K5[H+]2 k1K3K 4K5[H+]2

=

■

(23)

Corresponding Author

(24)

*E-mail: [email protected]. Tel.: 91-231-2609167. Fax: 91-231-2692333.

k1K3K 4K5 (1 + K3[H+] + K 6[IH2 2 +])

K3[H+] (1 + K 6[IH2 2 +]) [H+]2 = + kobs k1K3K 4K5 k1K3K 4K5

AUTHOR INFORMATION

Notes (25)

The authors declare no competing financial interest.

(26)

ACKNOWLEDGMENTS R.S.Y. gratefully acknowledges UGC, New Delhi, for the award of Teacher fellowship under the FIP- UGC-XI plan.

■ ■

Equations 24 and 26 can be verified by plotting (1/kobs) against [IH22+] and ([H+]2/kobs) against [H+], respectively. The figures of such plots are shown in Figure 5 and Figure 6, respectively, and

REFERENCES

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Figure 5. Plot of ([H+]2/kobs) against [H+]: 103[BrO3−] = 2.0 mol dm−3, 102[isoniazid] = 2.0 mol dm−3, I = 0.5 mol dm−3.

Figure 6. Plot of (1/kobs) against [IH22+]: 103[BrO3−] = 2.0 mol dm−3, 10[HCl] = 1.0 mol dm−3, I = 0.5 mol dm−3. 5139



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(14) Grancicova, O. The effect of tetrabutylammonium ion on the uncatalyzed bromate oscillator. React. Kinet. Catal. Lett. 2008, 94, 99. (15) Nath, U.; Das, S. S.; Deb, D.; Das, P. J. Tetra-n-alkylammonium bromatesNew and efficient reagents for deoximation. New J. Chem. 2004, 28, 1423. (16) Das, S. S.; Nath, U.; Deb, D.; Das, P. J. A convenient method for the oxidation of aromatic amines to nitro compounds using tetra-nalkylammonium bromates. Synth. Commun. 2004, 34, 2359. (17) Tavakol, H. Kinetic and thermodynamic study of inter- and intramolecular proton transfer in N′-acetyl formahydrazide tautomers. Int. J. Quantum Chem. 2011, 111, 3717. (18) Kulkarni, P. P.; Kadam, A. J.; Desai, U. V.; Mane, R. B.; Wadgaonkar, P. P. A simple and efficient oxidation of hydrazides to N,N′-diacylhydrazines using oxone in an aqueous medium. J. Chem. Res.(S) 2000, 184−185. (19) Jadhav, V. K.; Wadgaonkar, P. P.; Salunkhe, M. M. Oxidation of hydrazides using sodium perborate: formation of N,N′-diacylhydrazines. J. Chin. Chem. Soc. 1998, 45, 831. (20) Kadam, S. D.; Supale, A. R.; Gokavi, G. S. Kinetics and mechanism of oxidation of benzoic acid hydrazide by bromate catalyzed by anderson type hexamolybdochromate(III) in aqueous acidic medium. Z. Phys. Chem. 2008, 222, 635. (21) Amis, E. S. Solvent Effects on the Reaction and Mechanism; Academic Press: New York, 1966; p 183.

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Mechanism of Oxidation of the Antituberculosis Drug Isoniazid by

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