Oxidation of Antitubercular Drug Isoniazid by a Lipopathic Oxidant, Cetyltrimethylammonium Dichromate: A Mechanistic Study

Article abstract of DOI:10.1002/kin.20968

The oxidation of an antitubercular drug isoniazid by a lipopathic oxidant cetyltrimethylammonium dichromate (CTADC) in a nonpolar medium generates isonicotinic acid both in the presence and the absence of acetic acid. The conventional UV–vis spectrophotometric method is used to study the reaction kinetics. The occurrence of the Michaelis–Menten–type kinetics with respect to isoniazid confirms the binding of oxidant and substrate to form a complex before the rate-determining step. The existence of the inverse solvent kinetic isotope effect, k(H₂O)/ k(D₂O) = 0.7, in an acid-catalyzed reaction proposes a multistep reaction mechanism. A decrease in the rate constant with an increase in [CTADC] reveals the formation of reverse micellar–type aggregates of CTADC in nonpolar solvents. In the presence of different ionic and nonionic surfactants, CTADC forms mixed aggregates and controls the reaction due to the charge on the interface and also due to partition of oxidant and substrate in two different domains. High negative entropy of activation (ΔS^? = –145 and –159 J K^?1 mol^?1 in the absence and presence of acetic acid) proposes a more ordered and highly solvated transition state than the reactants. Furthermore, the solvent polarity-reactivity relationship reveals (i) the presence of less polar and less ionic transition state compared to the reactants during the oxidation, (ii) differential contribution from nonpolar and dipolar aprotic solvents toward the reaction process, and (iii) the existence of polarity/hydrophobic switch at log P = 0.73. A suitable mechanism has been proposed on the basis of experimental results. These results may provide insight into the mechanism of isoniazid oxidation in hydrophobic environment and may assist in understanding the drug resistance in different location.

Full text of DOI:10.1002/kin.20968

Oxidation of Antitubercular
Drug Isoniazid by a
Lipopathic Oxidant,
Cetyltrimethylammonium
Dichromate: A Mechanistic
Study
SARITA GARNAYAK, SABITA PATEL
Department of Chemistry, National Institute of Technology Rourkela, Rourkela 769 008, India
Received 12 March 2015; revised 17 October 2015; accepted 17 October 2015
DOI 10.1002/kin.20968
Published online 25 November 2015 in Wiley Online Library (wileyonlinelibrary.com).
ABSTRACT: The oxidation of an antitubercular drug isoniazid by a lipopathic oxidant
cetyltrimethylammonium dichromate (CTADC) in a nonpolar medium generates isonicotinic
acid both in the presence and the absence of acetic acid. The conventional UV–vis spectropho-
tometric method is used to study the reaction kinetics. The occurrence of the Michaelis–
Menten–type kinetics with respect to isoniazid confirms the binding of oxidant and substrate
to form a complex before the rate-determining step. The existence of the inverse solvent ki-
netic isotope effect, k(H2O)/ k(D2O) = 0.7, in an acid-catalyzed reaction proposes a multistep
reaction mechanism. A decrease in the rate constant with an increase in [CTADC] reveals the
formation of reverse micellar–type aggregates of CTADC in nonpolar solvents. In the presence
of different ionic and nonionic surfactants, CTADC forms mixed aggregates and controls the
reaction due to the charge on the interface and also due to partition of oxidant and substrate in
‡
−1
−1
two different domains. High negative entropy of activation (ꢀS = –145 and –159 J K mol
in the absence and presence of acetic acid) proposes a more ordered and highly solvated tran-
sition state than the reactants. Furthermore, the solvent polarity-reactivity relationship reveals
(i) the presence of less polar and less ionic transition state compared to the reactants during
the oxidation, (ii) differential contribution from nonpolar and dipolar aprotic solvents toward
the reaction process, and (iii) the existence of polarity/hydrophobic switch at log P = 0.73. A
suitable mechanism has been proposed on the basis of experimental results. These results may
Correspondence to: Sabita Patel; e-mail: sabita patel@yahoo.
com; sabitap@nitrkl.ac.in.
Supporting Information is available in the online issue at
www.wileyonlinelibrary.com.
Dedicated to prof. Bijay Kumar Mishra on his 61st birth
anniversary.
ꢀC
2015 Wiley Periodicals, Inc.

OXIDATION OF ANTITUBERCULAR DRUG ISONIAZID BY CETYLTRIMETHYLAMMONIUM DICHROMATE
33
provide insight into the mechanism of isoniazid oxidation in hydrophobic environment and
may assist in understanding the drug resistance in different location. ꢀC 2015 Wiley Periodicals,
Inc. Int J Chem Kinet 48: 32–44, 2016
INTRODUCTION
their antimycobacterial properties, none of these an-
timycobacterial properties are suitable and approved
for tuberculosis treatment till today [15–20]. Thus a
brief idea about isoniazid oxidative metabolism in di-
verse environment is desirable to get invaluable in-
formation on the mechanistic pathway, cause, and the
condition for oxidative instability, which will help to
understand drug resistance.
In this regard, the present study aims at revealing the
mechanism of oxidation of antitubercular drug isoni-
azid by Cr(VI) in a surfactant-generated hydrophobic
and biomimetic environment. To achieve the objec-
tive of the present investigation, (i) the oxidation prod-
ucts in the presence and in the absence of acid were
characterized; (ii) kinetics was studied using the UV–
vis spectrophotometric method in different media with
varied polarities and also in microheterogeneous sys-
tems generated due to the presence of cationic surfac-
tant, CTAB (cetyltrimethylammonium bromide), an-
ionic surfactant, SDS (sodium dodecylsulfate), and
nonionic surfactant, Triton X-100 (isooctylphenoxy-
polyoxyethanol, TX-100), at different concentrations;
(iii) the effect of reactant concentrations and solvent
kinetic isotope effect were measured; (iv) the ther-
modynamics of the reaction was analyzed by running
the kinetics at various temperatures; and (v) a suitable
mechanism for the reaction was proposed.
An analysis of the trend of oxidation reaction due to
various oxidants in organic solvents has led to engi-
neer many novel oxidants among which phase trans-
ferring oxidants are gaining wide interest [1,2]. These
reagents have amphipathic cations (mostly quaternary
ammonium ions) as the carriers of the anionic oxi-
dant unit (such as dichromate, permanganate) to sol-
ubilize it in organic solvents and are thus termed as
lipopathic oxidants. Owing to amphipathic character-
istics of these onium ions and resultant ion pair char-
acteristics with the anionic counterpart, the solubility,
reactivity, and redox potentials of the oxidants vary
significantly. These reagents are found to be mild,
chemoselective, and regioselective.
With an objective to develop a new efficient, selec-
tive, and mild oxidation protocol, the oxidizing abil-
ity of a lipopathic oxidant namely cetyltrimethylam-
monium dichromate (CTADC), has been explored by
our research group using the cetyltrimethylammonium
(CTA) ion as the onium counterion for anionic dichro-
mate [3–9]. The mildness of CTADC is well docu-
mented. In the oxidation of aromatic amines to di-
azo [7], ayrlaldoximes to nitriles [8], and cholesterol
to 7-dehydrocholesterol [9], it acts as a mild dehy-
drogenating oxidant. Furthermore, due to the presence
of the organic counter ion having the hydrophobic C16
alkyl tail and trimethylammonium head group, it shows
biomimetic characteristics providing microheteroge-
neous environment with different solubilization pock-
ets for the substrates as in the case of micelles, re-
versed micelles, microemulsions, vesicles for artificial
systems, and proteins and lipid membranes in living
systems.
Isoniazid is selected as one of the most effective in-
hibitors of bacteria Mycobacterium smegmatis and M.
tuberculosis and widely used as a first line drug along
with rifampicin and streptomycin for the chemother-
apy of tuberculosis since 1952 [10,11]. Soon after the
reemergence of tuberculosis in the mid-1980s coupled
with increasing numbers of isoniazid-resistant bacte-
rial strains [12–14], several research groups through-
out the world are engaged in developing novel, highly
effective, fast acting antituberculosis drugs with low
toxicity profiles and performing activity against both
drug-sensitive and drug-resistant Mycobacterium tu-
berculosis (Mtb). Although several probable tubercu-
losis drug candidates are synthesized and screened for
EXPERIMENTAL
Materials
CTADC was prepared by the method reported ear-
lier [7], and its purity was checked by estimating
Cr(VI) iodometrically [21]. Isoniazid was purified by
recrystallization from ethanol. Glacial acetic acid was
used without further purification. The organic solvents
were purified by the standard methods [22]. Surfactants
CTAB and SDS were purified by recrystallization from
aqueous ethanol, and their purity was checked from
physical constants. TX-100 was used without further
purification.
Product Analysis
The reaction mixture containing CTADC (1.72 g,
2 M) and isoniazid (0.15 g, 1 M) in chloroform in the
presence of 10% acetic acid was stirred and refluxed
International Journal of Chemical Kinetics DOI 10.1002/kin.20968

3
4
GARNAYAK AND PATEL
at 50°C for 3 h. The mixture was turned to green, indi-
cating the formation of Cr(III). The completion of the
reaction was monitored by thin-layer chromatography
tions of [CTADC] ꢀ [isoniazid] ([CTADC] = 1.75
4
−
−4
× 10 to 8.73 × 10 and [isoniazid] = 4.36 ×
−
5
−4
10 to 1.1 × 10 ) at various isoniazid concen-
trations. The disappearance of Cr(VI) was followed
until the absorbance values became constant. The
[CTADC] was estimated after 48 h. A stoichiometry
ratio, ꢀ[CTADC]/ꢀ[isoniazid] = 0.7, was observed,
which confirmed a 1:1.5 CTADC/isoniazid relation-
ship.
(TLC). The solvent was evaporated, and the reaction
mixture was subjected to column chromatography. The
column chromatographic separation was done in a clas-
sical glass column using silica gel (100–200 mesh) as
an adsorbent and a chloroform:methanol (9:1) mixture
as an eluent. A white-colored solid product thus ob-
tained (86 mg, yield 64%, melting point 305°C (sub-
limes)) was characterized from IR, NMR, and C, H,
The stoichiometry of the reaction was also deter-
mined by the limiting logarithmic method [23]. In this
method, two different sets of experiments were done.
In the first set of experiment, the CTADC concentra-
−
1
N analysis. IR (KBr, ν
O–H), 1712 (C=O) 1415 (C=N). H NMR (400 MHz,
DMSO-d6): δ/ppm 3.47 (bs), 8.76 (2H, d, J = 3.6 Hz),
̅
max/cm ): 2924 (C–H), 2407
1
(
−
4
−4
tion was varied (1.3 × 10 M to 3.9 × 10 M) at
13
−3
7
.8 (2H, d, J = 3.6 Hz) C NMR (100 MHz, DMSO-
a fixed isoniazid concentration (1.1 × 10 M), and
d6): δ/ppm 166.96, 150.18, 140.1, 129.3. Anal. Calcd
for C6H5N1O2: C, 58.54; H, 4.06; N, 11.38. Found:
C, 58.12; H, 4.04; N, 11.34. The IR, NMR, and CHN
spectral analyses of the product agreed well with that
of isonicotinic acid. In the absence of acetic acid, the
oxidation reaction was completed at about 6 h. The
product in this case was also found to be isonicotinic
acid.
in the second set of experiment the isoniazid concen-
−
4
−3
4
tration was varied (2.2 × 10 M to 2.2 × 10 M)
−
at a fixed CTADC concentration (0.44 × 10 M).
The absorbances of Cr(VI) at 450 nm were recorded
after 15 min of addition of reactants. The logarithms
of the obtained absorbances were plotted against log
[CTADC] and log [isoniazid] in the first and the sec-
ond set of experiments, respectively. The slopes of the
fitting lines in both sets of experiments were calculated
and found to be 1.1 and 1.58, respectively. Thus, the
molar reactivity of the reaction is found to be 1.1/1.58,
i.e. the reaction proceeds in the ratio of around 0.7 with
respect to CTADC and isoniazid.
Kinetic Measurements
The oxidation of isoniazid by CTADC was studied in
different solvents and surfactant systems. The temper-
ature in the reaction cell was controlled by circulating
water by using a Lauda thermostat within a temper-
ature fluctuation of 0.05°C. The reactions were per-
formed under pseudo–first-order conditions by keep-
ing excess of the isoniazid with respect to CTADC.
The rate of disappearance of the Cr(VI) species was
followed spectrophotometrically by monitoring the ab-
sorption band at 380 nm in the absence of acid and
RESULTS AND DISCUSSION
The reaction mixture consisting of CTADC and iso-
niazid in nonpolar solvents like chloroform becomes
green after 6 h under the reflux condition. The ox-
idation product was isolated using chromatographic
separation techniques. From the CHN, IR, and NMR
spectral analysis, the product was found to be isoni-
cotinic acid. In the presence of 10% acetic acid, the
oxidation reaction is completed at about 3 h, giving
rise to the same product.
4
50 nm in the presence of acetic acid. The first-order
rate constant, kobs, was obtained from the linear plot of
log [CTADC] against time for up to 75% completion
of the reaction. The values reported are the average
of at least triplicate runs and were reproducible within
6
% error. Some of the kinetics were run under nitrogen
Stoichiometric analysis reveals the reaction of
atmosphere, and the data were found to be almost the
same (within an error of 2%) as those under normal
atmospheric conditions. Hence, most of the reactions
were carried out without nitrogen environment. The
solvent kinetic isotope effect was investigated using
1
mole equivalent of CTADC with 1.5 mole equiva-
lent of isoniazid, and thus the ratio of CTADC/ isoni-
azid to be 1:1.5. The green coloration of the product
mixtures due to the absorption maxima around 550–
580 nm supports the formation of reduced Cr(III) [24].
1
:1 mixtures of H2O/acetonitrile, and in a 1:1 mix-
The possibility of one-electron oxidation giving rise to
free radicals may be ruled out for the present reaction
due the following factors: (i) oxidation of isoniazid,
in an atmosphere of nitrogen, failed to induce poly-
merization of acrylonitrile [25]; (ii) the addition of
acrylonitrile did not affect the rate of oxidation reac-
tion [23]; and (iii) the absence of signal in the EPR
ture of D2O/acetonitrile instead of chloroform in the
presence of 2% acetic acid.
Stoichiometry
The stoichiometry of the reaction was determined by
performing the experiment at 298 K, under the condi-
International Journal of Chemical Kinetics DOI 10.1002/kin.20968

OXIDATION OF ANTITUBERCULAR DRUG ISONIAZID BY CETYLTRIMETHYLAMMONIUM DICHROMATE
35
spectrum. Furthermore, if the reaction wound have
gone through free radical intermediates, formation of
acyloxyamine addition product would be expected in
the presence of the radical trapper TEMPO (2,2,6,6-
tetramethylpiperidinyloxy, a stable nitroxyl radical).
The absence of any acyloxyamine addition product in
the reaction mixture in the presence of TEMPO may
confirm the absence of the isonicotinoyl radical in the
reaction process [26].
Thus during the oxidation process, Cr(VI) is re-
duced to Cr(IV), which further changes to Cr(III) by a
disproportionation reaction in a sequential manner. The
existence of Cr(IV) as the reduced state in oxidation
of various organic substrates by different chromium
oxidants including onium chromates and dichromates
are well established [27–29]. Using the result, the sto-
ichiometric equation may be formulated as in Eq. (1).
Table I Effect of [Isoniazid], [CTADC], and [Acetic
Acid] on the Oxidation of Isoniazid by CTADC in
Chloroform at 298 K
[
CTADC]
[Isoniazid]
(×10 M)
[Acetic Acid]
(M)
kobs
(×10 s
4
4
3
−1
)
(×10 M)
0
0
1
2
2
3.05
0.44
0.88
1
2
2
3
0
0
.44
.88
.31
.18
.64
11
11
11
11
11
11
11
11
11
–
–
–
–
–
–
0.79
0.79
0.79
0.79
0.79
0.79
–
–
–
–
–
1.81 ± 0.05
2.06 ± 0.06
2.28 ± 0.07
2.69 ± 0.07
2.48 ± 0.08
2.26 ± 0.08
6.62 ± 0.27
6.02 ± 0.24
5.55 ± 0.22
4.82 ± 0.17
4.66 ± 0.17
4.51 ± 0.16
1.09 ± 0.03
1.43 ± 0.04
1.50 ± 0.03
1.56 ± 0.04
1.62 ± 0.05
1.65 ± 0.06
1.68 ± 0.06
1.72 ± 0.05
1.78 ± 0.07
1.81 ± 0.05
4.37 ± 0.16
4.69 ± 0.17
5.02 ± 0.20
5.31 ± 0.21
5.54 ± 0.21
5.73 ± 0.23
5.92 ± 0.23
6.40 ± 0.24
6.62 ± 0.26
4.82 ± 0.17
3.34 ± 0.12
3.90 ± 0.13
4.38 ± 0.15
4.82 ± 0.17
5.12 ± 0.20
5.34 ± 0.20
5.76 ± 0.23
6.25 ± 0.25
6.52 ± 0.25
6.83 ± 0.27
7.55 ± 0.28
.31
.18
.64
.05
.44
.44
11
11
11
1.1
2.2
2.73
3.27
3.82
4.36
4.91
5.45
8.18
11.0
2.2
2.73
3.27
3.82
4.36
4.91
5.45
8.18
11.0
11
+
−
+
2
(CTA )2Cr2O + 3 Isoniazid + 4H
7
0.44
0
0
.44
.44
→
+
3 Isonicotinic acid + 3N2 + 5H2O
4CTA + 4Cr(III)
+
(1)
0.44
.44
0.44
–
–
–
–
0
For the mechanistic analysis of the oxidation re-
action of isoniazid by CTADC, the reaction kinetics
was investigated using the UV–vis spectroscopic tech-
nique. The rates of reactions are monitored by observ-
ing the rate of depletion of Cr(VI) absorption peak. The
observed rate constants, kobs, at varying concentrations
of the substrates involved are calculated by maintain-
ing the pseudo–first-order condition and are presented
in Table I.
0.44
0.44
0.44
0.44
0.44
0.44
0.44
0.44
0.44
0.44
0.44
2.18
2.18
2.18
2.18
2.18
2.18
2.18
2.18
2.18
2.18
2.18
–
0.79
0.79
0.79
0.79
0.79
0.79
0.79
0.79
0.79
0.79
0.32
0.48
0.64
0.79
0.95
1.11
1.27
1.43
1.59
1.75
1.91
Effect of [Acetic Acid]
11
11
11
11
11
11
11
11
The observed rate constant of the reaction increases
linearly with an increase in the concentration of acetic
acid, indicating protonation of dichromate as well as
protonation of isoniazid during the reaction process.
The plot of the log rate versus log [acetic acid] depicts
a fractional order (i.e., 0.5) dependency with respect
to acid. The kobs obeys the following relationship with
[acetic acid]:
11
11
11
kobs= k0 + kcat[Acetic Acid]
2.18
where kcat refers to the rate constant for the acid-
catalyzed oxidation of isoniazid and k0 refers to the un-
Effect of [Isoniazid]
−
3
−1
catalyzed rate constant and found to be 2.7 × 10
s ,
indicating an appreciable oxidation of isoniazid with
CTADC in the absence of acid. Thus to have more
insight into the reaction mechanism, the reaction was
studied both in the absence and in the presence of acetic
acid.
The observed rate constants determined in the absence
of acetic acid increase asymptotically with increas-
ing concentration of isoniazid, approaching its max-
−
3
−1
(Fig. 1A). Thus a
imum value of 1.8 × 10
s
Michaelis–Menten–type kinetics is proposed, i.e. the
International Journal of Chemical Kinetics DOI 10.1002/kin.20968

3
6
GARNAYAK AND PATEL
Table II Km Values for the Oxidation of Organic
Substrates by CTADC
Km (Without
Km (Acid
Substrate
Acid) (M) Catalyzed) (M) Reference
−
4
Cholesterol
Benzyl alcohol
Cyclohexanol
Isoniazid
–
–
–
2.4 × 10
[9]
[31]
[32]
Present
study
0.1
0.2
−
4
−4
0.9 × 10
1.7 × 10
The steady-state dissociation constant of the
oxidant–substrate complex known as the Michaelis–
Menten constant, Km ( = (k–1 + k2)/k+1), was calcu-
−
4
lated to be 0.9 × 10 M. Km is the substrate concen-
tration at which the reaction rate falls to half maximum
and is an inverse measure of the substrate’s affinity for
the catalyst (enzyme). Smaller the Km, higher is the
affinity of the catalyst toward the substrate. Km values
for the oxidation reaction of CTADC with different al-
coholic substrates are compared with that of isoniazid
(Table II). Although in each of the three alcoholic sub-
strates, a chromate ester intermediate is formed with
the bonding of a hard donor –OH with a hard accep-
3
4
Figure 1 (A) Plot of 10 kobs versus 10 [isoniazid] and (B)
3
4
plot of 1/10 kobs versus 1/10 [isoniazid] in the oxidation
reaction of isoniazid with CTADC in chloroform at 298 K.
tor Cr(VI); K for cholesterol is much lower than that
m
of cyclohexanol and benzylalcohol. The lower Km and
higher affinity for cholesterol may be attributed to the
hydrophobic interaction with the nonpolar tail of the
lipophilic oxidant [9]. Although isoniazid has less hy-
drophobicity and softer bonding (–NH2) site, the lower
Km values compared to the above alcoholic substrates
show higher affinity of CTADC toward isoniazid. This
may be explained through the proximity of carbonyl
oxygen and chromium in the oxidant substrate com-
plex, which provides additional stabilization.
reaction involves the binding of oxidant to the substrate
to form a complex prior to the rate-determining step.
The complex subsequently decomposes to the products
(Eqs. (2) and (3)):
k+1
Isoniazid + CTADC ꢀ [Complex]
(2)
(3)
k−1
k2
From the Lineweaver–Burk double reciprocal plot
[
Complex] → Product
(
1
Fig. 1B), k2 and K (= k+1/k–1) were calculated to be
−
3
−1 −1
3
.99 × 10
s
and 11181 dm mol , respectively.
By applying the steady-state approximation, the fol-
lowing rate expression is obtained (Eq. (4)) [30]:
Using Km, k2, and K values, k+1 and k–1 were found
3
3
−1 −1
−1 −1
s ,
to be 3.5 × 10 dm mol
s
and 3.15 × 10
ꢀ
ꢁ
respectively. In the oxidation of isoniazid to isonico-
tinic acid by the enzyme catalase-peroxidase from M.
tuberculosis, Johnsson and Schultz [33] have reported
d Complex
Rate = −
= kobs [CTADC]
dt
−2
−1
s and
a similar order of kcat and Km, i.e., 4.5 × 10
−
4
Kk2 [Isoniazid] [CTADC]
1.98 × 10 M, respectively.
=
The acid-catalyzed process also follows the same
trend with a change in [substrate]. The corresponding
1
+ K [Isoniazid]
−
4
ꢀ
ꢁ
Km, k2, K, k+1, and k–1 are found to be 1.7 × 10 M,
7.69 × 10 , 5909 dm mol , 10,000 dm mol
d Complex
1
Kk [Isoniazid]
−3 −1
− −1
3
−1
3
−1
2
s
−
×
= kobs =
1
dt
[CTADC]
1 + K [Isoniazid]
s , and 1.69 s , respectively. Lower binding affin-
ity of oxidant and substrate in the acid-catalyzed pro-
cess may be attributed to the (i) higher polarity of the
medium where solvation of isoniazid will be higher,
1
1
1
=
+
(4)
kobs
k2K [Isoniazid]
k2
International Journal of Chemical Kinetics DOI 10.1002/kin.20968

OXIDATION OF ANTITUBERCULAR DRUG ISONIAZID BY CETYLTRIMETHYLAMMONIUM DICHROMATE
37
Scheme 1 Proposed mechanism for the oxidation of isoniazid by CTADC in the absence of acetic acid.
leading to a decrease in the interaction of isoniazid and
CTADC; or (ii) protonation of isoniazid, which reduces
the interaction of protonated isoniazid with CTADC.
As the actual oxidant is anionic, higher binding affinity
of oxidant and protonated isoniazid is expected. How-
ever, the presence of contact ion pair between dichro-
rate of decomposition of the complex (C). A higher
rate of reaction in the presence of acid is, thus, due to
a higher rate of decomposition of the complex though
the binding affinity of oxidant and substrate is higher
in the absence of acid. In the presence of acid, the
carbonyl carbon acquires a partial positive charge due
to the polarization of the carbonyl bond owing to the
protonation of the carbonyl oxygen. The higher rate
of decomposition is thus attributed to the higher elec-
trophilicity of the carbonyl carbon due to which the
reactivity of hydroxyl oxygen toward carbonyl carbon
increases, increasing the overall rate of the reaction.
To get further support for the proposed mechanism,
the effect of temperature and solvent kinetic isotope
effect (k(H2O)/k(D2O)) have been investigated.
+
mate and CTA in a nonpolar medium decreases the
binding affinity due to repulsion between protonated
+
isoniazid and CTA .
Consistent with the above observations, the reaction
mechanisms for oxidation of isoniazid with CTADC
without acid (Scheme 1) and in the presence of acetic
acid (Scheme 2) have been proposed where the dichro-
mate ion forms an N-substituted acid hydrazide inter-
mediate complex with isoniazid. The complex subse-
quently decomposes into products, namely isonicotinic
acid, diazene, and Cr(IV) by a slow rate-determining
process, where chromate oxygen attacks to the car-
bonyl carbon through the formation of a cyclic five-
membered transition state. Diazene further oxidizes
to dinitrogen and water with another mole of Cr(VI).
Yalgudre and Gokavi [34], while investigating the oxi-
dation of isoniazid by bromate in aqueous hydrochloric
acid medium, demonstrated the formation dinitrogen
and water from diazene intermediate. The formation of
unstable diazene intermediate in the oxidation of iso-
niazid has also been reported by Bodiguel et al. [35].
Karimi et al. [36] have described the formation of dini-
trogen in the electrocatalytic dehydrogenative oxida-
tion of isoniazid to isonicotinic acid via an acyl diazene
intermediate.
Effect of Temperature
The observed rate constants increase linearly with an
increase in temperature. The thermodynamic parame-
‡
‡
‡
ters such as ꢀH , ꢀS , and ꢀG were calculated from
the plot of ln(k/T) versus 1/T using Eyring equations
(Eqs. (5) and (6)) and are presented in Table III. The
high negative entropy of activations is indicative of
the formation of a forced, more ordered ,and exten-
sively solvated transition state than the reactants in the
rate-determining step in both the cases [37,38]:
ꢂ
ꢃ
ꢂ
ꢃ
‡
‡
kBT
h
ꢀS
R
ꢀH
RT
k =
exp
exp −
(5)
(6)
Comparing kobs, k2, and K values of both without
acid and acid-catalyzed oxidation processes, it is found
that the rate of the reaction is dependent mostly on the
ꢂ
ꢃ
ꢂ
ꢃ
‡
‡
k
T
kB
h
ꢀS
ꢀH
ln
= ln
+
−
RT
R
International Journal of Chemical Kinetics DOI 10.1002/kin.20968

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8
GARNAYAK AND PATEL
Scheme 2 Proposed mechanism for the oxidation of isoniazid by CTADC in the presence of acetic acid.
Table III Observed Rate Constants and Activation Parameters for the Oxidation of Isoniazid by CTADC in the Absence
of Acid and in the Presence of Acetic Acid
1
03 kobs (s
−1
)
‡
‡
‡
ꢀG
ꢀ
H
ꢀS
(kJ mol 1)
−
(J K mol
−1
−1
)
−1
(kJ mol )
[Acetic Acid]
293 K
298 K
303 K
308 K
–
0
1.82 (± 0.04) 2.69 (± 0.07) 3.7 (± 0.15) 4.65 (± 0.19)
4.26 (± 0.15) 4.82 (± 0.17) 5.56 (± 0.21) 6.1 (± 0.23)
44.6
15.8
−145
−159
87.7
63.2
.79 M
Conditions: [Isoniazid] = 1.1 × 10− M and [CTADC] = 2.18 × 10 M.
3
−4
Determination of the Solvent Kinetic
Isotope Effect
rate-determining step and thus supports the forma-
tion of complex “C” in the reaction process. Owing
to immiscibility of the chloroform–water binary mix-
ture and improper solubility of reactants in aqueous
medium, the solvent kinetic isotope effect is measured
in a different solvent medium other than chloroform.
Thus it may be anticipated that the reaction mechanism
in both the cases differ. The validity of isokinetic re-
lationship (Eq. (7)) for a series of solvents including
chloroform and acetonitrile-water mixture was veri-
fied from the linear plot of ꢀH versus ꢀS (Fig. SI1
†ESI in the Supporting Information) and demonstrated
same mechanism for the whole solvent series [42].
The isokinetic temperature, β for the present oxidation
process in the presence of acetic acid is found to be
To obtain the solvent kinetic isotope effect
(k(H2O)/k(D2O)), the reaction was carried out in a 1:1
mixture of H2O–acetonitrile and in a 1:1 mixture of
D2O–acetonitrile in the presence of 2% acetic acid.
Acetic acid was equilibrated with H2O and D2O for
3
h before its use in the reaction process. The solvent
isotope effect k(H2O)/k(D2O) was found to be ((3.3
−
3
−3
‡
‡
×
10 )/(4.84 × 10 )) = 0.68. The acid-catalyzed
rate is faster in D2O than in H2O, when a preequi-
librium protonation is involved [39–41]. The inverse
solvent kinetic isotope effect, i.e., k(D2O) >k(H2O),
indicates that the NH2 group is not involved in the
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OXIDATION OF ANTITUBERCULAR DRUG ISONIAZID BY CETYLTRIMETHYLAMMONIUM DICHROMATE
39
3
4
Figure 2 Plot of 10 kobs versus 10 [CTADC] in the oxidation reaction of isoniazid with CTADC in chloroform at 298 K:
(
−
3
A) without acid (B) in the presence of 0.79 M acetic acid. [Isoniazid] = 1.1 × 10 M.
3
14 K, where the rate of every member of the series is
• the rate of depletion of complex (C1 or C2) by
the forward reaction, k2,
same.
•
•
stability of transition state, and
‡
‡
ꢀ
H = βꢀS +c
(7)
the partition of the oxidant and substrate in two
microheterogeneous domains due to the forma-
tion of reversed micelle.
Effect of [CTADC]
To obtain a clear picture on these aspects, the effect
of different surfactants (with varied charge) and various
solvents (with varied hydrophobicity and polarity) on
the reactivity was investigated.
With an increase in [CTADC] in the absence of acid,
the rate constants are found to increase up to [CTADC]
−4
=
2.18 × 10 M and then decreases (Fig. 2A). How-
ever, in the presence of acetic acid, a direct decrease
in the rate constant is observed with an increase in
[
CTADC] (Fig. 2B). In the oxidation of various alco-
Effect of Surfactants
holic compounds by CTADC, Mishra and co-workers
found similar decreasing trends in the rate constants
at the higher CTADC concentration and have pro-
posed the formation of reverse micellar–type aggre-
gates [9,31,32]. In the present study, the decrease in
the rate constant at high oxidant concentration is also
ascribed to the formation of reverse micellar aggre-
gates of CTADC where dichromate anions are encap-
To study the effect of surfactant on the reaction rate,
three different surfactants such as CTAB (a cationic
surfactant), SDS (an anionic surfactant), and TX-100
(a nonionic surfactant) were used. All the three surfac-
tants can form reverse micelle in a nonpolar medium
[44–47] and also form mixed micelle with various ionic
and nonionic surfactants [48–52]. All these surfactants
can form mixed aggregates with CTADC. If the rate
change is only because of the partition of oxidant and
substrate in two different microheterogeneous media,
consequently a more or less decrease in rate would
have been expected in all the cases.
In the absence of acid, a sharp decrease in the
rate constant was observed on addition of CTAB and
SDS, which support the formation of reverse micellar
aggregates (Fig. 3). However, on addition of TX-100
the rate constant initially increased up to a concen-
+
sulated by the CTA aggregates and thus the effective
concentration of substrates in the vicinity of the dichro-
mate decreases due to the partition of substrates in two
different microheterogeneous phases, i.e., reverse mi-
cellar core and the bulk solution. The concentration
of CTADC at which the decrease in the rate constant
begins differs in the two processes: with acid it starts
−5
before 4.4 × 10 M, whereas without acid it is ap-
-4
proximately 2.18 × 10 M. The presence of acetic
acid starts the aggregation at a lower concentration.
Amphiphilic molecules form reversed micelle in the
nonpolar solvents either in the presence of water or in
the presence of nonaqueous polar solvents [43]. The
presence of acetic acid triggers the formation of re-
verse micellar aggregates of CTADC in chloroform,
and thus the aggregation starts at lower concentration.
Based on the above results, it is proposed that the
mechanism of oxidation of isoniazid by CTADC de-
pends on the following:
−
2
tration of 1.16 × 10 M and then decreased sharply
-2
(Fig. 4). Above 3.5 × 10 M of TX-100, the rate con-
-3
−1
stant almost became stable around 1.2 × 10 s . The
increase is explained through a greater attractive inter-
action of oxyethylene units of TX-100 with the cationic
head group of CTADC and repulsive interaction with
that of anionic oxygen of the complex, increasing the
rate of decomposition of the complex. At high concen-
tration of TX-100, the partition factor becomes more
International Journal of Chemical Kinetics DOI 10.1002/kin.20968

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GARNAYAK AND PATEL
Figure 3 Effect of CTAB and SDS in the oxidation of
isoniazid by CTADC in chloroform at 398 K. [Isoniazid] =
−3
−4
1
.1 × 10 M and [CTADC] = 2.18 × 10 M.
Figure 5 Effect of surfactants on the oxidation of isoniazid
by CTADC in the presence of acetic acid in chloroform at
−
3
3
1
98 K. [Isoniazid] = 1.1 × 10 M, [CTADC] = 2.18 ×
−
4
0
M, and [acetic acid] = 0.79 M.
cationic interface. In contrast to CTAB, the increase in
the rate constant in the presence of the anionic surfac-
tant SDS is explained through the (i) increase in the
+
effective concentration of H on the anionic interface
of SDS, (ii) rapid formation of the active-protonated
dichromate, and (iii) an increase in the protonation of
the carbonyl group thus increasing the electrophilic-
ity of the carbonyl carbon on the anionic interface of
SDS reverse micelle. In case of TX-100, the increase
Figure 4 Effect of TX-100 in the oxidation of isoniazid by
+
in the rate constant due to accumulation of H on the
−
3
CTADC in chloroform at 398 K. [Isoniazid] = 1.1 × 10
polar oxyethylene interface is compensated by the de-
crease in the rate constant due to partition of reactants
in different phases.
M and [CTADC] = 2.18 × 10− M.
4
important than the electronic factor in the reverse mi-
cellar aggregates of the nonionic surfactant. Assuming
the rate decrease at high [surfactant] is due only to the
partition effect, for complete entrapment of a CTADC
it requires a composition of 1:160 of CTADC/TX-100
and 1:16 of CTADC/SDS in the reaction mixture.
In the presence of acetic acid, the three surfactants
influence the rate differently. When CTAB was added
to the reaction medium, a decrease in the rate constant
was observed whereas addition of SDS increased it
Effect of Solvents
Investigation of solvent effects on reactivity always
plays a crucial role in determining nature of the tran-
sition state and the mechanism of a reaction [53]. In
essence, the reaction rates are influenced by 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 them-
selves to stabilize the transition state. If the transition
state is stabilized to a greater extent than the starting
material, then the reaction proceeds faster. If the start-
ing material is stabilized to a greater extent than the
transition state, then the reaction proceeds slowly.
In the present investigation, 12 different solvents
were used having nonpolar and dipolar aprotic charac-
teristics. The solvent effect was investigated only in the
presence of acid due to poor solubility of reactants in
most of the solvents. The observed rate constant shows
significant solvent sensitivity (Table SI1, †ESI in the
Supporting Information). We have made an attempt
(Fig. 5). Furthermore, the addition of nonionic surfac-
tant TX-100 has no significant effect on the reaction
rate in acidic medium. CTAB forms reverse micelle
with a cationic interface and thus in the presence of
acetic acid, apart from the partition factor the decrease
in rate constant is attributed to the following factors:
+
(
i) a decrease in the effective concentration of H on
a cationic interface of CTAB, (ii) slow formation of
the active protonated dichromate, and (iii) a decrease
in the electrophilicity of the carbonyl carbon by re-
ducing the protonation of the carbonyl oxygen on the
International Journal of Chemical Kinetics DOI 10.1002/kin.20968

OXIDATION OF ANTITUBERCULAR DRUG ISONIAZID BY CETYLTRIMETHYLAMMONIUM DICHROMATE
41
to correlate the solvent-induced change in reactivity
termed as “solvatoreactivity” with the solvent param-
eters such as π* (solvent polarity) [54,55], β (hydro-
gen bond acceptor basicity) [54,55], A (anion-solvating
power of the solvent) [56], B (cation-solvating power
of the solvent) [56], and A + B (solvent polarity) [56],
log P (solvent hydrophobicity) [57], dielectric constant
(ε), dipole moment (μ), viscosity (η), density (ρ), and
surface tension (γ ). The plots of kobs with various po-
larity parameters exhibit some interesting results.
The plot of kobs versus polarity parameter π* ex-
hibits (Fig. SI2, †ESI in the Supporting Information)
a negative slope (with benzene, toluene, chloroform,
and dioxane as outliers), indicating a rate retardation
due to the increase in the polarity of the solvents.
Furthermore, the plot of dielectric constant (ε) val-
ues with kobs (Fig. SI3, †ESI in the Supporting In-
formation) shows a sharp rate increase in the lower
side (ε: 0–9) followed by a significant rate decrease
in the higher side (ε: 6–47). The increase in the rate
is due to the solvents such as benzene, toluene, chlo-
roform, and dioxane, whereas the rate decrease is due
to the solvents such as dimethyl sulfoxide (DMSO),
N,N-dimethylformamide (DMF), acetone, acetonitrile
and nitrobenzene with ethyl acetate, tetrahydrofuran
3
Figure 6 Plot of 10 kobs versus log P of the solvents in the
oxidation reaction of isoniazid with CTADC at 298 K.
transition state where the charge is more dispersed. Fur-
thermore, if the change in rate constants with change in
solvent polarity is only due to the stability of reactants
or transition state, then the rate constant should also
increase with a decrease in polarity for the nonpolar
and less polar solvents. However, the opposite trend
in this case proposes the existence of reverse micellar
aggregation of CTADC in nonpolar solvents. Quater-
nary ammonium and phosphonium salts exist as ion
pairs or an aggregation of ion pairs in a nonaqueous
medium [58]. The degree of aggregation of these salts
in a nonpolar solvent is inversely proportional to the
polarity of the medium [59]. With an increase in non-
polarity of the solvents, reverse micellization increases
which results in higher partition of oxidant and sub-
strate into two different phases, imparting a decrease
in the rate.
The above analysis may lead to the following propo-
sition: (i) For the polar group of solvents, polarity (or
hydrophilicity) is prominent due to solvation of reac-
tants and transition state through polar–polar specific
and nonspecific solute solvent interactions; and (ii) for
the second group of solvents, nonpolarity or hydropho-
bicity is predominant due to formation of reverse mi-
cellar aggregates.
To confirm this proposition of differential contribu-
tion, the reactivity was correlated with log P. log P, the
logarithm of the partition coefficient of the substrate
between octanol and water, has the inherent charac-
teristics of both hydrophilicity (partition from or to
water) and hydrophobicity (partition from or to oc-
tanol) [60]. The bilinear plot of kobs versus log P of
the solvents (Fig. 6) indicates a balanced contribution
from both the factors. A maximum at ethyl acetate
(log P = 0.73) in the plot indicates a hydrophobic
switch, which balances the polarity and hydrophobic
contributions of the solvents. In the lower side of log
P values (<0.82), increasing hydrophobicity has a rate
(THF), and dichloromethane being common in both
the cases. The plot of kobs versus dipole moment (μ)
demonstrates similar increasing and decreasing trends
(
Fig. SI4, †ESI in the Supporting Information) in the
lower and higher sides, respectively.
The above results clearly envisage the division of
these solvents into two groups: the first group for high
polar solvents whereas the second group for apolar
solvents. Low polar solvents such as ethyl acetate and
THF are common for both the groups. For the former
polar group, the rate of the reaction decreases with
an increase in polarity, whereas for the later nonpo-
lar and low polar solvent group rate acceleration with
polarity is observed. The opposite trends in these two
groups of solvents suggest a complex mechanism with
varied contribution of these solvents toward the re-
action mechanism through the above-mentioned three
factors.
The negative contribution of polarity toward the re-
action rate for the polar solvents suggests a relatively
less polar transition state than the reactants. The degree
of solvation of polar reactants and the complex (C1 and
C2) is more in the polar solvents compared to the tran-
sition state. Thus the rate of association of reactants
to form complex and also the rate of decomposition of
complex (k2) decreases, leading to an overall rate retar-
dation. This proposition of a less polar transition state
in the reaction mechanism is also supported by high
negative entropy of activation, which suggests a cyclic
International Journal of Chemical Kinetics DOI 10.1002/kin.20968

4
2
GARNAYAK AND PATEL
Scheme 3 Probable pathway for the formation of isonicotinic acid.
acceleration, whereas with higher log P values (>0.73)
retardation of the rate is observed. Solvents with log
P values less than 0.73 solvate the reactants and the
transition state through polar interactions only (hy-
drophilicity), and the solvents with log P values more
than 0.82 solvate through apolar interactions only (hy-
drophobicity), whereas the common solvents ethyl ac-
etate and THF solvate through both polar and apolar
interactions. This type of polarity switch (at log P =
noyl cation, diazene, and Cr(VI). An increase in the
rate of reaction in anionic SDS reverse micelle and a
decrease in cationic CTAB reverse micelle may sup-
port this path. However, the results from the effect of
solvents and the effect of temperature on rate constants
precluded Route 2. Thus, it may be proposed that in
nonpolar environment, the breaking of the C–N bond to
form the isonicotinoyl cation and attaching of the chro-
mate hydroxyl group to the electrophilic isonicotinoyl
cation are simultaneously lead to a nonpolar cyclic
transition state, solvated and stabilized by a nonpolar
medium (Route 3). Any change in the functionality
of the oxidant–substrate complex, which increases the
nucleophilicity of the hydroxyl group, electrophilicity
of acyl carbon, and hydrophobicity of the reaction cen-
ter, leads to an increase in the rate of nucleophilic acyl
substitution through Route 3.
0.88) has also been reported in the literature in the study
of solvationof p-nitroaniline in alcohol–dioxane binary
solvent mixtures and attributed to the differential con-
tribution of hydrophilic and hydrophobic parts of the
solvents, leading to preferential salvation [61]. Pani-
grahi et al. [62] have reported similar reversal in sol-
vatochromism of some hydrophobic styrylpyridinium
dyes and explained the fact through structural transi-
tion of the solvation shell with a change in nature and
polarity of the solvents.
Furthermore, for the polar group, an increase in both
anion-solvating power (A) and cation-solvating power
CONCLUSIONS
(
B) (Fig. SI5, †ESI in the Supporting Information) of
In conclusion, the oxidant (CTADC) oxidizes iso-
niazid to isonicotinic acid following the Michaelis–
Menten kinetics, thus mimicking enzyme activity. The
first step is a very fast formation of association com-
plex between isoniazid and CTADC, followed by a
second rate-determining dissociation of the complex
proceeding via a less ionic and less polar transition
state. CTADC assembles to form reverse micelle in
nonpolar solvents with cations at the interface, pro-
viding different residing sides for the reactants, thus
mimicking enzyme activity. The substrate and oxi-
dant are partitioned into two different types of envi-
ronments, and, accordingly, the reaction is controlled.
The outcome from the solvent effect illustrates the
presence of reversal in “solvatoreactivity” with a po-
larity/hydrophobic switch at log P = 0.73, due to
the solvents have adverse effect on the rate constant, de-
lineating less ionic and nonpolar transition state. These
results also support the formation of cyclic transition
state in the rate-determining step. With an increase in
A and B, solvation of the complex increases through
specific solvation of the respective ionic part by the
solvents and thus the reactivity decreases.
Similar to the mechanism described by Amos
et. al. [63] for the oxidation of isoniazid, other mech-
anisms may also be proposed as shown in Scheme 3.
Possibility of Route 1 leading to the isonicotinoyl radi-
cal is ruled out due to the absence of EPR signal and the
absence of O-acyl hydroxyl amine adduct in the pres-
ence of TEMPO as mentioned earlier. Route 2 shows
the cleavage of the C–N bond to form a free isonicoti-
International Journal of Chemical Kinetics DOI 10.1002/kin.20968

OXIDATION OF ANTITUBERCULAR DRUG ISONIAZID BY CETYLTRIMETHYLAMMONIUM DICHROMATE
43
differential contribution from nonpolar and polar sol-
vents. Nonpolar solvents contribute more to the reverse
micellization, whereas polar solvents contribute to the
stability of reactants and transition state. CTADC pro-
vides Cr(VI) for oxidation of substrate as well as it
provides reverse micellar aggregates resembling that
of lipid cell membrane. In this hydrophobic environ-
ment, isoniazid is oxidized to isonicotinic acid.
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International Journal of Chemical Kinetics DOI 10.1002/kin.20968