Oxidation of isoniazid by N-haloarenesulfonamidates in alkaline medium: A kinetic and mechanistic study

Article abstract of DOI:10.1002/(SICI)1097-4601(2000)32:4<221::AID-KIN4>3.0.CO;2-1

The kinetics of oxidation of Isoniazid (INH) by sodium N-haloarenesulfonamidates, chloramine-T (CAT), bromamine-T (BAT), chloramine-B (CAB), and bromamine-B (BAB), has been studied in alkaline medium at 303 K. The oxidation reaction follows identical kinetics with a first-order dependence on each [oxidant] and [INH] and an inverse fractional-order on [OH^-]. Addition of the reaction product (p-toluenesulfonamide or benzenesulfonamide) had no significant effect on the reaction rate. Variation of ionic strength and addition of halide ions have no influence on the rate. There is a negative effect of dielectric constant of the solvent. Studies of solvent isotope effects using D₂O showed a retardation of rate in the heavier medium. The reaction was studied at different temperatures, and activation parameters have been computed from the Arrhenius and Eyring plots. Isonicotinic acid was identified as the oxidation product by GC-MS. A two-pathway mechanism is proposed in which RNHX and the anion RNX^- interact with the substrate in the rate-limiting steps. The mechanism proposed and the derived rate laws are consistent with the observed kinetics. The rate of oxidation of INH increases in the order: BAT>BAB>CAT>CAB. This effect is mainly due to electronic factors.

Full text of DOI:10.1002/(SICI)1097-4601(2000)32:4<221::AID-KIN4>3.0.CO;2-1

Oxidation of Isoniazid by N-
Haloarenesulfonamidates
in Alkaline Medium:
A Kinetic and Mechanistic
Study
PUTTASWAMY,1 T. M. ANURADHA,1 R. RAMACHANDRAPPA,1 N. M. MADE GOWDA2
1Department of Post-Graduate Studies in Chemistry, Central College, Bangalore University, Bangalore - 560 001, India
2Department of Chemistry, Western Illinois University, 1 University Circle, Macomb, IL 61455, USA
Received 12 March 1999; accepted 30 December 1999
ABSTRACT: The kinetics of oxidation of Isoniazid (INH) by sodium N-haloarenesulfonamidates,
chloramine-T (CAT), bromamine-T (BAT), chloramine-B (CAB), and bromamine-B (BAB), has
been studied in alkaline medium at 303 K. The oxidation reaction follows identical kinetics
with a first-order dependence on each [oxidant] and [INH] and an inverse fractional-order
on [OHϪ]. Addition of the reaction product (p-toluenesulfonamide or benzenesulfonamide)
had no significant effect on the reaction rate. Variation of ionic strength and addition of
halide ions have no influence on the rate. There is a negative effect of dielectric con-
stant of the solvent. Studies of solvent isotope effects using D2O showed a retardation of
rate in the heavier medium. The reaction was studied at different temperatures, and acti-
vation parameters have been computed from the Arrhenius and Eyring plots. Isonicotinic
acid was identified as the oxidation product by GC-MS. A two-pathway mechanism is pro-
posed in which RNHX and the anion RNXϪ interact with the substrate in the rate-limiting
steps. The mechanism proposed and the derived rate laws are consistent with the observed
kinetics. The rate of oxidation of INH increases in the order: BAT Ͼ BAB Ͼ CAT Ͼ CAB. This
effect is mainly due to electronic factors. ᭧ 2000 John Wiley & Sons, Inc. Int J Chem Kinet 32: 221–
230, 2000
INTRODUCTION
[2], and Bremner [3]. The prominent members of this
class of compounds are chloramine-T (p-Me-C6H4-
SO2NClNa · 3H2O or CAT), Chloramine-B (C6H5-
SO2NClNa · 1.5 H2O or CAB) and the corresponding
bromine analogues bromamine-T (p-Me-C6H4-
SO2NBrNa · 3H2O or BAT) and bromamine-B (C6H5-
SO2NBrNa · 1.5 H2O or BAB). Since these oxidants
react with a wide variety of functional groups, they are
used as reagents for analytical and kinetic investiga-
tions [4–7]. Although the oxidation of organicsub-
Considerable attention has centered around the chem-
istry of N-haloarenesulfonamidates because of their
diverse properties to act as halonium cations, hypo-
halites, and N-anions, which behave both as electro-
philes and nucleophiles. The subject has been re-
viewed by Campbell and Johnson [1], Banerji et al.
Correspondence to: N. M. Made Gowda or Puttaswamy
᭧ 2000 John Wiley & Sons, Inc.

222
PUTTASWAMY ET AL.
strates with N-haloarenesulfonamidates has been ex-
tensively studied, little information is available on the
oxidation kinetics of pharmaceuticals by N-haloare-
nesulfonamidates.
elucidating the mechanism of oxidation of the drug in
solution and also to assessing the relative rates of ox-
idation of INH by N-haloarenesulfonamidates.
Although aliphaticazo ocmpounds of the type
R9N"N9H appear to be unstable, derivatives of
the type R9N"N9R are much more stable. Iso-
niazid, an azene derivative (INH, pyridine-4-carbox-
ylic acid hydrazide), is an antitubercular drug that is
now widely used along with ribampicin and strepto-
myin in the chemotherapy of tuberculosis. Because of
its importance, several analytical procedures are re-
ported in the literature [8–10] for the assay of this
drug. There seems to be a little information available
on the oxidation kinetics of INH or azo compounds in
general by haloamines. Liu and Margerum [11] have
studied the kinetics of oxidation of hydrazine by aque-
ous iodine over a wide range of acidity from pH 0.35
to 8.00, using stopped-flow and pulsed-accelerated-
flow methods. A multistep mechanism is proposed
where iodine reacts rapidly with N2H4 to form the ad-
duct I2N2H4, which undergoes general base-assisted
deprotonation with loss of IϪ ion in the rate-limiting
step. At high pH, hydrazine acts as a general base as
well as the initial nucleophile. Electrochemical oxi-
dation of niazid and isoniazid at mercury electrodes in
the pH range 6–13 was studied by Mellado et al. [12].
Intermediates were identified using controlled poten-
tial electrolysis. Between pH 6.0 and 7.5, Py9
CO9NH"NH and Py9CO9NH"NϪ species
were observed, whereas at higher pH, the intermedi-
EXPERIMENTAL
Chloramine-T (Loba Chemie) was purified by the
method of Morris et al. [15] while CAB, BAT, and
BAB were prepared by the known procedures [16–
18]. The purity of these oxidants was checked through
their spectroscopic data and iodometric assay of the
active halogen content. Aqueous solutions of the oxi-
dants were standardized by the iodometricmethod and
preserved in brown bottles to prevent photochemical
deterioration. Analar-grade isoniazid (BDH, Poole,
UK) was recrystallized before use and the purity of the
compound was checked by standard methods. All
other reagents used were of analytical grade. Solvent
isotope studies were performed with D2O (99.2%)
supplied by the Bhabha AtomicResearhc Centre,
Mumbai, India. The ionicstrength of the reaction mix-
ture was kept at a high value (0.5 M) with a concen-
trated solution of sodium perchlorate. Triply distilled
water was used for preparing all aqueous solutions.
Kinetic Measurements
Kineticruns were performed under pseudo first-order
conditions with tenfold excess of the INH over the
oxidant at 303 K. The reaction was carried out in stop-
pered Pyrex glass tubes whose outer surfaces were
coated black to eliminate photochemical effects. For
each run, requisite amounts of solutions of INH,
NaOH, NaClO4, and water (to maintain a constant total
volume) were mixed in the tube, which was kept in a
waterbath at 303 K for thermal equilibrium. A mea-
sured amount of the oxidant solution, also kept at the
same temperature, was rapidly added to the mixture in
the boiling tube with stirring. The progress of the re-
action was monitored by iodometric determination of
the unreacted oxidant in measured aliquots of the re-
action mixture withdrawn at different intervals of time.
The course of the reaction was studied for at least two
half-lives. The pseudo first-order rate constants, kЈ,
calculated from the linear plots of log [oxidant] vs.
time were reproducible within Ϯ3%.
Ϫ
Ϫ
ates were Py9CO9N2H2 and Py9CO9N2 .
The final products in both cases were nicotinic and
isonicotinic acids. In the oxidation of INH by catalase
peroxidase from Mycobacterium tuberculosis [13], the
acyl diimide Py9CO9N"NH and Py9CO9
N2ϩ were found to be the intermediates. There is also
the formation of a dibenzyl radical, which leads to the
corresponding acyl radical Py"CO . The mecha-
ؒ
nism proposed provides a number of possibilities for
the mode of action of INH, one possibility being that
the drug is converted in vivo into a number of highly
reactive species capable of either oxidizing or acylat-
ing the groups in proteins [13]. Mechanistic aspects of
the action of INH and ethionamide in the chemother-
apy of tuberculosis have been studied by Johnsson et
al. [14]. It is noted that despite the importance of the
above drugs, relatively less information is known
about their mode of action at the molecular level.
In the background of the available information on
the mechanism of oxidation of INH, it is of immense
interest to follow the oxidation kinetics of INH with
halogen ϩ1 oxidants. Hence, the present article re-
ports the kinetics of oxidation of INH by CAT, CAB,
BAT, and BAB in alkaline medium with a view to
Stoichiometry and Product Analysis
Varying ratios of the oxidant and INH under condi-
tions [oxidant] ϾϾ [INH] in the presence of 0.02 M
NaOH were kept at 303 K for 24 h. The unchanged
oxidant in the reaction mixture was determined by io-
dometrictitrations. The analysis showed that one mole

OXIDATION OF ISONIAZID BY N-HALOARENESULFONAMIDATES IN ALKALINE MEDIUM
223
Figure 1 Mass spectrum of isonicotinic acid with its parent molecular ion peak at mass/charge
122.05.
of INH reacted with two moles of the oxidant. The
observed stoichiometry is shown in Eq. (1):
obtained on a 17A Shimadzu gas chromatograph with
a QP-5000 Shimadzu mass spectrometer. The GC had
a capillary column with 250ЊC oven temperature,
200ЊC interface temperature, and approximately
150ЊC column temperature. The mass data were ob-
tained using the electron impact method. The mass
spectrum showing an Mϩ parent ion peak at 122.05
amu clearly confirms the identity of isonicotinic acid.
C5H4NCONHNH2 ϩ 2RNXNa ϩ H2O !:
C5H4NCOOH ϩ N2 ϩ 2RNH2 ϩ 2NaX (1)
where R ϭ p Ϫ Me-C6H4SO2 for CAT and BAT,
C6H5SO2 for CAB and BAB, and X ϭ Cl or Br.
The reaction products of the oxidants, p-toluesul-
fonamide (PTS) and benzenesulfonamide (BSA), were
recrystallized from a mixture of dichloromethane-
petroleum ether (7 : 3 v/v) and detected by TLC with
petroleum ether : chloroform : l-butanol (2 : 2 : 1 v/v) as
the solvent system and iodine as the developing re-
agent. The determined Rf values of 0.84 and 0.88, re-
spectively, were consistent with the literature values
[7]. The oxidation product, isonicotinic acid, in the
reaction mixture was detected by the color reaction
with sodium pentacyanoamine ferrate [19] and also
identified by its melting point of 313–314ЊC (lit.m.p.
310–315ЊC). Its identity was further confirmed by
mass spectral analysis (Fig. 1). The GC-MS data were
Test for Free Radicals. Addition of the reaction mix-
ture to the acrylamide monomer in the dark did not
initiate polymerization, indicating the absence of free
radicals. Control experiments performed with solu-
tions containing all the components of the reaction
mixture except the oxidant and with the individual ox-
idant solutions were also negative.
RESULTS
The kinetics of oxidation of INH by CAT, CAB, BAT,
and BAB was investigated at several initial concentra-

224
PUTTASWAMY ET AL.
Table I Effect of Varying Oxidant Concentration on the Reaction Ratea
Ϫ
1
kЈ ϫ 103/s
104 [Oxidant]/ M
BAT
BAB
CAT
CAB
4.00
6.00
8.00
10.0
12.0
14.0
16.0
2.15
2.08
2.10
2.02
2.18
2.22
2.16
1.30
1.46
1.42
1.49
1.36
1.32
1.40
0.900
0.920
0.910
0.890
0.900
0.920
0.910
0.630
0.660
0.650
0.640
0.670
0.630
0.650
a [INH]0 ϭ 6.00 ϫ 10Ϫ3 M; [NaOH] ϭ 2.00 ϫ 10Ϫ2 M, I ϭ 0.50 M; Temp. ϭ 303 K.
tions of the reactants in NaOH medium. The same ox-
idation behavior is observed for all the four oxidants
(OX).
Effect of PTS and BSA Concentrations on
the Rate
Addition of the reaction product, p-toluenesulfonam-
ide or benzenesulfonamide (0.50 ϫ 10Ϫ3 Ϫ 3.0 ϫ 10Ϫ
3
Effect of Reactants on the Rate
M), to the reaction mixture did not affect the rate sig-
nificantly.
Under pseudo first-order conditions of [INH]0 ϾϾ
[OX]0 at constant [OHϪ] and temperature, plots of log
[OX]0 vs. time were linear, showing a first-order de-
pendence of the reaction rate on [OX]. The values of
pseudo first-order rate constants, kЈ, are given in Table
I. Furthermore, the rate constant did not change with
the change in [OX]o , confirming the first-order depen-
dence on [OX]. The rate increased with increasing
[INH]0 (Table II), and plots of log kЈ vs. log [INH]
were linear (Fig. 2) with unit slope. Further, plots of
kЈ vs. [INH] gave straight lines passing through the
origin, confirming the first-order dependence on [INH]
(plots are not shown).
Effects of Halide Ions and Ionic Strength
on the Rate
Addition of the halide ions, ClϪ or BrϪ, in the form of
their sodium salts (0.50 ϫ 10Ϫ3 Ϫ 3.0 ϫ 10Ϫ3 M) had
no effect on the rate. Also, the ionic strength (I) of the
reaction medium varied by adding NaClO4 (0.20–
0.80 M) did not influence the rate.
Effect of Varying Dielectric Constant on the
Rate
Rate studies were made in water-MeOH mixtures of
different compositions representing varying dielectric
constant (D) of the solvent medium. The rate de-
creased with increase in MeOH content and plots of
log kЈ vs. 1/D were linear (Fig. 4) with negative slopes
supporting a rate-limiting step with charge dispersal
(where D values were obtained from the literature
Effect of NaOH Concentration on the Rate
At constant [OX], [INH], and temperature, the reaction
rate decreased with increase in [NaOH] (Table III).
Plots of log kЈ vs. log [NaOH] were linear (Fig. 3)
with negative fractional slopes indicating a negative
fractional order (0.5–0.7) dependence on [OHϪ].
Table II Effect of Varying Isoniazid Concentration on the Reaction Ratea
Ϫ
1
kЈ ϫ 103/s
103 [INH]/ M
BAT
BAB
CAT
CAB
2.00
4.00
6.00
0.730
1.50
2.10
2.74
3.45
4.28
5.05
0.510
0.970
1.42
1.90
2.42
2.95
3.65
0.310
0.540
0.910
1.15
1.46
1.79
0.210
0.390
0.650
0.820
1.06
8.00
10.00
12.00
14.00
1.28
1.43
2.10
a [Oxidant]0 ϭ 8.00 ϫ 10Ϫ4 M; [NaOH] ϭ 2.00 ϫ 10Ϫ2 M, I ϭ 0.50 M; Temp. ϭ 303 K.

OXIDATION OF ISONIAZID BY N-HALOARENESULFONAMIDATES IN ALKALINE MEDIUM
225
stant. Activation parameters calculated from the linear
Arrhenius and Eyring plots of ln kЈ vs. 1/T, and ln
(kЈ/T) vs. 1/T, respectively, are given in Table IV.
DISCUSSION
Investigations of Pryde and Soper [21], Higuchi et al.
[22], Bishop and Jennings [23], and Hardy and John-
ston [24] on sodium-N-haloarenesulfonamidates have
shown that similar equilibria exist in acid and alkaline
solutions. The possible equilibria in aqueous haloam-
ine solutions are
RNXNa EF RNXϪ ϩ Naϩ
RNXϪ ϩ Hϩ EF RNHX
(2)
(3)
(4)
(5)
(6)
(7)
Figure 2 Plots of log kЈ vs. log [INH]. Experimental con-
ditions are as in Table II.
2RNHX EF RNX2 ϩ RNH2
RNHX ϩ H2O EF RNH2 ϩ HOX
RNX2 ϩ H2O EF RNHX ϩ HOX
HOX EF Hϩ ϩ OXϪ
[20]). Blank experiments performed showed that
MeOH was not oxidized significantly by the oxidants
under the present experimental conditions.
Solvent Isotope Studies
As the rate was dependent on [OHϪ], solvent isotope
studies were made using D2O as the solvent medium.
Therefore, the possible oxidizing species in acid me-
dium are RNHX, RNX2, HOX, and probably H2OXϩ,
and in alkaline solutions RNHX, HOX, RNXϪ, and
OXϪ. The oxidation potential of haloamine-sulfona-
mide system is pH dependent and decreases with in-
crease in pH of the medium [25]. In alkaline solutions
of haloamine, dihaloamine does not exist, and the pos-
sible species are the anions RNXϪ, and OXϪ which
could be transformed into the more reactive oxidizing
species RNHX and HOX in the course of reaction in
alkaline medium. A retarding influence of OHϪ ions
on the reaction rate noticed in several haloaminometric
reactions [24–28] has been attributed to the formation
3
1
The values of kЈ(H2O) are 0.910 ϫ 10Ϫ sϪ and
2.10 ϫ 10Ϫ sϪ , and those of kЈ(D2O) are 0.720 ϫ
3
1
3
3
10Ϫ sϪ1 and 1.68 ϫ 10Ϫ sϪ1 leading to solvent isotope
effects, kЈ(H2O)/kЈ(D2O), of 1.26 and 1.25 for CAT
and BAT, respectively.
Effect of Temperature on the Rate
The effect of temperature on the rate was studied by
performing the kinetics at various temperatures (298 K
–313 K) keeping other experimental conditions con-
Table III Effect of Varying Sodium Hydroxide Concentration on the Reaction Ratea
Ϫ
1
kЈ ϫ 103/s
102 [NaOH]/ M
BAT
BAB
CAT
CAB
0.50
1.00
2.00
4.00
6.00
8.00
10.00
4.42
3.13
2.10
1.51
1.13
0.970
0.850
2.98
2.04
1.42
1.03
0.790
0.650
0.580
2.42
1.54
1.25
0.980
0.650
0.420
0.300
0.260
0.230
0.910
0.560
0.410
0.330
0.280
a [Oxidant]0 ϭ 8.00 ϫ 10Ϫ4 M; [INH]0 ϭ 6.00 ϫ 10Ϫ3 M, I ϭ 0.50 M; Temp. ϭ 303 K.

226
PUTTASWAMY ET AL.
Figure 3 Plots of log kЈ vs. log [NaOH]. Experimental conditions are as in Table III.
of the conjugate acid RNHX from RNXϪ in a base
retarding step.
An inverse fractional-order dependence of the rate
on [OHϪ] observed in the oxidation of INH by hal-
oamine indicates that a fraction of the overall reaction
proceeds via an alternative path without the OHϪ ion
but involving the anion RNXϪ. Schemes I and II have
been proposed to account for the observed kinetics for
the oxidation of INH by N-haloamines in alkaline so-
lutions.
k1
RNXϪ ϩ H2O E
(OX)
R
F RNHX ϩ OHϪ
kϪ
1
fast (i)
k2
XЈ
RNHX ϩ INH 9
9
:
ϩ RNH2
(complex I)
slow & rds (ii)
k3
XЈ ϩ RNHX 9
9: Products fast (iii)
Scheme I
Scheme I leads to the following rate law [eq. (8)]:
Ϫd[OX] K1k2 [OX][INH]
ϭ
(8)
dt
[OHϪ]
k4
9:
RNXϪ ϩ INH 9
XЉ
ϩ RNHϪ
(OX)
(complex II)
slow & rds (i)
k5
XЉ ϩ RNXϪ 9
9: Products fast (ii)
Ϫ
4
Figure 4 Plots of log kЈ vs. 1/D. [Oxidant]0 ϭ 8.00 ϫ 10
k6
9
RNHϪ ϩ H2O 9
: RNH2 ϩ OHϪ fast (iii)
Ϫ
3
Ϫ2
M; [INH]0 ϭ 6.00 ϫ 10 M; [NaOH] ϭ 2.00 ϫ 10 M;
I ϭ 0.50 M; Temp. ϭ 303 K.
Scheme II

OXIDATION OF ISONIAZID BY N-HALOARENESULFONAMIDATES IN ALKALINE MEDIUM
227
Table IV Activation Parameters for the Oxidation of Isoniazid by CAT, CAB, BAT and BABa
Ea
(kJ mol
⌬H‡
(kJ mol
⌬S‡
⌬G‡
(kJ mol )
Ϫ
1
Ϫ
1
Ϫ
Ϫ
1
Ϫ1
Oxidant
)
)
(JK 1 mol
)
BAT
BAB
CAT
CAB
29.7
33.5
38.3
43.4
27.2
31.0
35.8
40.9
Ϫ198.5
Ϫ197.5
Ϫ185.3
Ϫ171.3
89.8
90.8
91.9
92.8
a [Oxidant]0 ϭ 8.00 ϫ 10Ϫ4 M; [INH]0 ϭ 6.00 ϫ 10Ϫ3 M, [NaOH] ϭ 2.00 ϫ 10Ϫ2 M; I ϭ 0.50 M.
Scheme II leads to the rate law [eq. (9)]
the first-order dependence on [OX] and [INH] and in-
verse first-order on [OHϪ], while scheme II and rate
law [eq. (9)] show the rate to be independent of [OHϪ].
The net outcome of the two pathways results in the
combined rate law [eq. (10)] from which the inverse-
fractional-dependence of the rate on [OHϪ] can be in-
ferred.
Ϫd[OX]
ϭ k4 [OX][INH]
dt
(9)
Here, complexes XЈ and XЉ are as defined in Schemes
III and IV. Scheme I and the rate law [eq. (8)] support
Scheme III

228
PUTTASWAMY ET AL.
Scheme IV
Ϫd[OX] K1k2 [OX][INH]
with another mole of oxidant to give a dihalo com-
Rate ϭ
ϭ
[OHϪ]
pound, which on hydrolysis yields isonicotinic acid.
For a reaction involving a fast equilibrium Hϩ or
OHϪ ion transfer, the rate increases in D2O medium
since D3Oϩ and ODϪ are a stronger acid and a stronger
base, respectively, than Hϩ and OHϪ ions [29]. In the
present case, the observed solvent isotope effect of kЈ
(H2O)/kЈ (D2O) Ͼ 1 is due to the greater basicity of
ODϪ compared to OHϪ. However, the magnitude of
retardation in D2O is small (expected value is ϳ2–3
times greater [25]) due to the hydrolysis step,
which tends to make the normal kinetic isotope effect
kH/kD Ͼ 1 for the slow step of Scheme I, and also
fractional negative order dependence on [OHϪ].
Hence, this observation supports the proposed mech-
anism.
dt
ϩ k4[OX][INH] (10)
Detailed mechanisms involving electron transfers
during the oxidation of isoniazid by RNHX and RNXϪ
are shown in Schemes III and IV, respectively. In gen-
eral, the azo compounds, R9N"N9R, have the
primary tendency to decompose into organic free rad-
icals and liberate nitrogen as follows: R9N"N9
и
R : 2R ϩ N2. However, the absence of free radicals
in the present work indicates that the azo link is intact,
and the electrophilic attack of the oxidant at the lone
pairs of electrons on N atoms is more probable. In the
initial step, the electrophile Xϩ from the oxidant binds
with the electron-rich nitrogen atom of the substrate
to form the intermediate complex, which further reacts
The reduction product (PTS or BSA) does not in-
fluence the rate, indicating its non-involvement in a

OXIDATION OF ISONIAZID BY N-HALOARENESULFONAMIDATES IN ALKALINE MEDIUM
229
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pre-equilibrium. The change in the ionic strength of
the medium does not alter the rate, indicating that non-
ionicspecies are involved in the rate-limiting steps.
The effect of solvent in the reaction kinetics has been
described in detail in the monographs of Moelwyn-
Hughes [30], Laidler et al. [31–33], Benson [34],
Frost and Pearson [35], Amis [36], and Entelis and
Tiger [37]. For the limiting case of a zero angle of
approach between two dipoles or an ion-dipole sys-
tem, Amis [36] has shown that a plot of log kЈ vs.
1/D gives a straight line, with a negative slope for a
negative ion-dipole or a dipole-dipole interaction,
while a positive slope results for a positive ion-dipole
interaction. The negative dielectric effect in the
present studies supports the interaction between a neg-
ative ion and a dipole in the rate-limiting steps.
The moderate Ea values support the proposed
mechanism. While the low values of ⌬S‡ indicate the
formation of rigid associative transition states, the
nearly constant ⌬G‡ values suggest that the oxidation
of INH by N-haloamines occurs by a similar mecha-
nism. Under comparable conditions, it was observed
that the rates are found to be higher with BAT and
BAB than the chlorine analogues (Table I) and follow
the sequence BAT Ͼ BAB Ͼ CAT Ͼ CAB. This
could be attributed to the difference in elecrophilicities
of the halogen cations Brϩ and Clϩ involved in the
oxidation process and is related to the ease with which
these species can be formed in reactions. A similar
behavior has been noted in the oxidation of indigo-
carmine [6], indoles [7], dialkylsulfides [38], and con-
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One of the authors (TMA) thanks the Bangalore University,
Bangalore, for the award of an M. Phil. fellowship. RR is
grateful to the Principal and Management, Jyothi Nivas Col-
lege, Bangalore, for permitting him to pursue research in the
Department of Postgraduate Studies in Chemistry, Central
College, Bangalore. We thank Prof. D S. Mahadevappa, Pro-
fessor Emeritus, Department of Studies in Chemistry, Uni-
versity of Mysore, Mysore, India, for helpful discussions.
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