Kinetics and mechanism of oxidation of captopril by diperiodatocuprate(III) in aqueous alkaline medium

Article abstract of DOI:10.1007/s00706-014-1329-z

Captopril is a sulfur containing drug which inhibits angiotensin-converting enzyme. Its kinetics of oxidation were studied spectrophotometrically using diperiodatocuprate(III) in aqueous alkali. Major oxidative product of captopril was identified as captopril disulfide along with trace amount of the hydrolyzed product, l-proline. Kinetics of oxidation was found to be first order each in [oxidant] and [reductant]. Rate of reaction was decreased by increasing [OH^-], whereas added periodate retarded the rate. Other kinetic parameters viz., ionic strength, dielectric constant, temperature effect, and intervention of free radical were also studied. Activation parameters like E_A, ΔH^#, ΔS^#, ΔG ^#, and log A were calculated. A suitable mechanism was proposed. Rate law for proposed mechanism was derived and verified. Reaction constants involved in various steps of mechanism were evaluated and used to regenerate first-order experimental rate constants at various experimental conditions.

Full text of DOI:10.1007/s00706-014-1329-z

Monatsh Chem (2015) 146:219–229
DOI 10.1007/s00706-014-1329-z
ORIGINAL PAPER
Kinetics and mechanism of oxidation of captopril
by diperiodatocuprate(III) in aqueous alkaline medium
•
Mahantesh A. Angadi Suresh M. Tuwar
Received: 14 August 2014 / Accepted: 29 September 2014 / Published online: 17 December 2014
Ó Springer-Verlag Wien 2014
Abstract Captopril is a sulfur containing drug which
inhibits angiotensin-converting enzyme. Its kinetics of
oxidation were studied spectrophotometrically using dipe-
riodatocuprate(III) in aqueous alkali. Major oxidative
product of captopril was identified as captopril disulfide
along with trace amount of the hydrolyzed product,
L-proline. Kinetics of oxidation was found to be first order
each in [oxidant] and [reductant]. Rate of reaction was
decreased by increasing [OH-], whereas added periodate
retarded the rate. Other kinetic parameters viz., ionic
strength, dielectric constant, temperature effect, and inter-
vention of free radical were also studied. Activation
parameters like EA, DH#, DS#, DG#, and log A were cal-
culated. A suitable mechanism was proposed. Rate law for
proposed mechanism was derived and verified. Reaction
constants involved in various steps of mechanism were
evaluated and used to regenerate first-order experimental
rate constants at various experimental conditions.
tighten the blood vessels, so blood flows more smoothly
and heart can pump blood more efficiently [4]. Chemically,
captopril is 1-[(2S)-3-mercapto-2-methylpropionyl]-L-pro-
line. Its sulfhydryl group may contribute to its
pharmacological action and account for some adverse
reactions that occur at higher doses. Its therapeutic appli-
cations for treatment of cancer had also been investigated
[5]. Although stability of captopril in presence of air has
been studied in detail [6–9], chemistry of formation of its
disulfide had not been investigated in detail. However,
reports are available on its interaction with other thiols
[10].
Diperiodatocuprate(III) [DPC] was chosen as an oxi-
dizing agent for oxidation of captopril because it is a single
equivalent oxidant, and usually oxidizes many organic
compounds via free radical formation. As a part of this
study, a dimer formed due to captopril oxidation is char-
acterized by its FT–IR and GC–MS studies. Hence, we
report herein the results of oxidation which may be first of
its kind where it gives a detailed mechanistic study of
oxidation path of captopril and characterization of its
products.
Keywords Diperiodatocuprate(III) ꢀ Captopril ꢀ
Oxidation ꢀ Kinetics ꢀ Periodate ꢀ DPC
Recently, kinetics of oxidation of various organic
compounds have been studied using transition metals in
their highest oxidation states [11, 12]. Transition metals in
their highest oxidation state are stabilized by chelating with
suitable polydentate ligands like periodate, tellurate, eth-
ylenebis(biguanide), etc. These ligands are mainly used to
stabilize Ni(IV) [13], Ag(III) [14–17], and Cu(III) [18, 19].
Such metal complexes are found to be potent oxidizing
agents in aqueous alkali, and they are mainly used [20–22]
as oxidizing agents in the analytical system. Hence, their
relative stability is exploited for kinetic study of oxidation
of many inorganic [23] and organic [11, 24] substrates,
particularly amino acids [19]. Among Ni(IV), Ag(III), and
Introduction
Captopril (Capt) is an orally active inhibitor of angiotensin-
converting enzyme. It is widely used to treat high blood
pressure (hypertension), congestive heart failure, and var-
ious renal syndromes such as diabetic nephropathy and
scleroderma [1–3]. It decreases certain chemicals that
M. A. Angadi ꢀ S. M. Tuwar (&)
Department of Chemistry, Karnatak Science College,
Dharwad 580 001, Karnataka, India
e-mail: sm.tuwar@gmail.com
123

220
M. A. Angadi, S. M. Tuwar
Cu(III) complexes, Cu(III) is a single equivalent oxidant
and relatively stable with periodate ligand rather than tel-
lurate. Apart from this and the fact that copper(III)
periodate exists in alkali in various forms like diperioda-
tocuprate(III), deprotonated diperiodatocuprate(III), and
monoperiodatocuprate(III). Among these, normally only
one will be very reactive. Hence, the title reaction is
undertaken to identify the reactive species of copper(III)
periodate, detailed oxidation path of captopril, and char-
acterization of captopril disulfide.
2 mol of captopril to give captopril disulfide as shown in
Scheme 1.
Oxidative products were identified as follows: the above
solution of reaction mixture was acidified and subjected to
TLC for separation of constituents. An iodine spray
showed two spots and they were compared with Rf values
of known standards. The compounds were identified as
captopril disulfide and a small quantity of L-proline which
might be formed due to hydrolysis of captopril. These
products were subjected to FT–IR and GC–MS indepen-
dently for analysis. They were analyzed as follows:
1. In IR scanning, the disappearance of S–H peak at
2,565 cm-1 due to S–H vibration and appearance of
new peak at 486 cm-1 for S–S stretching clearly
indicates [25, 26] the formation of captopril disulfide
(Fig. 1). In IR spectra of other compound, appearance
of a broad band at 3,420 cm-1 due to N–H vibration
and disappearance of amide band at 1,491 cm-1
support the presence of L-proline [27] due to hydro-
lysis at amide moiety of captopril (Fig. 2).
Results and discussion
Stoichiometry and product analysis
Different sets of reaction mixtures containing varying
ratios of DPC to captopril in presence of constant amount
of OH-, IO4-, and KNO3 were kept for 6 h at 30 °C in a
closed vessel under inert atmosphere for completion of
reaction. When [DPC] [ [Capt], unreacted DPC concen-
tration was estimated spectrophotometrically at 416 nm.
Results indicated that 2 mol of DPC were consumed by
2. In GC–MS study, molecular ion peak m/z was found to
be 433 which is expected for captopril disulfide
(Fig. 3) and that of L-proline was 115 (Fig. 4).
However, main product was estimated to be captopril
disulfide.
Scheme 1
COO
OOC
COO
S
Reaction orders
N
N
N
2
O
S
O
O
SH
Reaction order and order with respect to each reactant was
determined by varying the concentrations of reductant, per-
iodate, and alkali in turn, while keeping the others constant.
+ 2 [Cu(H2IO6)2]3- + 2 OH-
+ 2 Cu2+ + 4 H2IO63- + 2 H2O
Fig. 1 FT–IR spectrum of the
captopril disulfide formed due
to the oxidation of captopril by
diperiodatocuprate(III) in
aqueous alkaline medium at
30 °C
95
85
75
65
55
45
3900
3400
2900
2400
1900
1400
900
400
Wavenumber /cm-1
123

Kinetics and mechanism of oxidation of captopril
221
Fig. 2 FT–IR spectrum of the L-proline formed due to hydrolysis of captopril while oxidation by diperiodatocuprate(III) in aqueous alkaline
medium at 30 °C
Effect of diperiodatocuprate(III) concentration
Effect of added periodate concentration
Concentration of DPC was varied in the range 1.0 9 10-5
–
Effect of initially added periodate on rate of reaction was
studied by varying the concentration of metaperiodate from
3.0 9 10-4 to 5.0 9 10-3 mol dm-3 at constant concen-
trations of DPC, captopril, alkali, and ionic strength. Rate
constants were decreased with increase in [IO4-] (Table 1)
and the order was found to be -0.6.
2.0 9 10-4 mol dm-3 at fixed [Capt], [OH-], [IO4-], and
ionic strength. Non-variation in pseudo-first-order rate
constants at various concentrations of DPC indicates the
order in [DPC] as unity (Table 1). This was also confirmed
from linearity of plots of log [DPC] vs. time.
Effect of initially added products
Effect of captopril concentration
Effect of initially added products viz., Cu(II), captopril
disulfide and L-proline was studied in the concentration
range 4.0 9 10-5–4.0 9 10-4 mol dm-3 when all other
reactants concentrations were kept constant. It was noticed
that rate of reaction was unaltered on addition of these
products. However, rapid decrease in optical density at the
initial stage was reduced with increase in concentration of
Cu(II) and first-order plots were totally linear at the opti-
Substrate [Capt] was varied in the range of 5.0 9 10-4
–
5.0 9 10-3 mol dm-3 at 30 °C keeping all other reactants
concentration constant. kobs values were increased with
increasing the concentrations of captopril (Table 1). From
the plot of log kobs vs. log [Capt], order in [Capt] was
calculated to be unity.
mum [Cu(II)] of 1.0 9 10-4 mol dm-3
.
Effect of alkali concentration
At a fixed ionic strength of 0.2 mol dm-3 and other
conditions remaining constant, [OH-] was varied from
0.01 to 0.2 mol dm-3. It was noticed that increase in
[OH-] increases the rate of reaction with an order of 0.5
(Table 1).
Effect of ionic strength and solvent polarity
Effect of ionic strength was studied by varying the [KNO3] in
reaction medium. Ionic strength of reaction medium was var-
ied from 0.05 to 0.5 mol dm-3 at constant concentrations of
123

222
M. A. Angadi, S. M. Tuwar
Fig. 3 GC–MS spectrum of captopril disulfide formed by the oxidation of captopril by diperiodatocuprate(III) in aqueous alkaline medium at
30 °C
Fig. 4 GC–MS spectrum of L-proline formed due to hydrolysis of captopril during oxidation by diperiodatocuprate(III) in aqueous alkaline
medium at 30 °C
123

Kinetics and mechanism of oxidation of captopril
223
Table 1 Effect of variation of [DPC], [Capt], [OH-], and [IO4-] on oxidation of captopril by diperiodatocuprate(III) in aqueous alkaline
medium at 30 °C
104 9 [DPC]/mol dm-3
103 9 [Capt]/mol dm-3
[OH-]/mol dm-3
103 9 [IO4-]/mol dm-3
103 9 kobs/s-1,a
103 9 kcal/s-1,b
0.1
0.2
0.4
0.7
1.0
1.5
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.7
1.0
2.0
4.0
5.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.01
0.02
0.03
0.05
0.08
0.10
0.20
0.05
0.05
0.05
0.05
0.05
0.05
0.05
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.3
0.5
0.7
1.0
2.0
3.0
5.0
0.68
0.69
0.68
0.68
0.67
0.67
0.69
0.31
0.42
0.68
1.61
3.02
4.06
0.25
0.40
0.52
0.68
0.84
0.90
1.12
1.10
0.94
0.80
0.68
0.59
0.35
0.23
–
–
–
–
–
–
–
0.36
0.49
0.71
1.42
2.85
3.56
0.24
0.41
0.54
0.71
0.87
0.94
1.12
1.34
1.07
0.89
0.71
0.43
0.31
0.20
I = 0.2 mol dm-3
a
Experimental
The kcal are calculated using k = 3.16 dm3 mol-1 s-1, K1 = 11.66 dm3 mol-1, and K2 = 9.2 9 10-4 mol dm-3 in Eq. 5
b
DPC, captopril, IO4-, and alkali. It was observed that as ionic
strength increases rate of reaction also increased (Table 2).
Plot of log kobs vs. HI was linear with a unit positive slope.
Relative permittivity of the medium was varied by
varying t-butyl alcohol/water percentage (v/v). Since
dielectric constant D for various percentage compositions
were not available in literature, they were computed using
their D in pure state [28]. Variation of D of the medium did
not influence the rate of reaction. Earlier, it had also been
confirmed that there was no reaction between solvent and
oxidant under experimental conditions used.
In view of this, acrylonitrile was used as a free radical
scavenger and tested in the reaction mixture as follows: the
reaction mixture was mixed with acrylonitrile monomer
and kept for 24 h under inert atmosphere. On dilution with
methanol, a white copies precipitate of polymer was
formed, indicating the intervention of free radicals in
reaction. The experiment of either DPC or captopril with
acrylonitrile alone did not induce polymerization under
similar condition as those induced with reaction mixture.
Initially added acrylonitrile also decreased the rate, indi-
cating a free radical intervention [29].
Polymerization study
Effect of temperature
DPC is a single equivalent oxidant. Hence, intervention of
free radical generated from organic compound is expected.
Kinetics were also studied at 30, 35, 40, 45, and 50 °C with
[DPC] = 1.0 9 10-4, [Capt] = 1.0 9 10-3, [OH-] = 0.05,
123

224
M. A. Angadi, S. M. Tuwar
an aqueous alkaline medium of high pH range employed in
the study, periodate is unlikely to exist as HIO6- as is evident
from its involvement in multiple equilibria [30] (Eqs. 1, 2, 3).
Table 2 Effect of variation of ionic strength (I) and dielectric
constant of the medium on oxidation of captopril by diperiodato-
cuprate(III) in aqueous alkaline medium at 30 °C
Ionic strength (I)
D = 78.5
Dielectric constant (D)
I = 0.1 mol dm-3
KI
H5IO6 ꢀ H4IO6ꢁ þ Hþ KI ¼ 5:1 ꢂ 10ꢁ14
ð1Þ
ð2Þ
ð3Þ
KII
H4IO6 ꢀ H3IO62ꢁ þ Hþ KII ¼ 4:9 ꢂ 10ꢁ9
ꢁ
I/mol HI
103 9 kobs/s-1 % of t-butyl
alcohol in
water (v/v)
D
103 9 kobs/s-1
dm-3
KIII
2ꢁ
H3IO6 ꢀ H2IO63ꢁ þ Hþ KIII ¼ 2:5 ꢂ 10ꢁ12
0.05
0.08
0.10
0.15
0.20
0.30
0.50
0.224 0.44
0
5
78.5 0.67
75.1 0.68
71.7 0.68
68.4 0.69
65.0 0.70
62.5 0.68
The periodic acid exists in the form of H5IO6 and
2-
-
H4IO6 in acid and H3IO6
3-
0.283 0.49
0.316 0.52
0.387 0.65
0.447 0.67
0.548 0.80
0.707 1.20
and H2IO6
in alkaline
10
15
20
25
–
media. Hence, under alkaline conditions as employed in
2-
this study, the main species are expected to be as H3IO6
3-
or H2IO6 or both. Thus, under the pH employed in this
study, a soluble copper(III) periodate complex might exist
as [Cu(H3IO6)2]- or [Cu(H2IO6)2]3-. Similar forms of
complexes have also been reported for nickel(IV) periodate
[12, 19, 31, 32] and silver(III) periodate complexes [14,
15]. In the present study, the observations that reaction is
first order each in [DPC] and [Capt], fractional order in
[OH-] and retarding effect of added periodate can be
accommodated in the following mechanism (Scheme 2).
In step (1), DPC undergoes deprotonation to give
deprotonated diperiodatocuprate(III) complex which
explains fractional order in [OH-]. In step (2), monoperio-
datocuprate(III) (MPC) is formed by exchanging periodate
ligand with water in the inner coordination sphere of Cu(III).
This explains the retarding effect of periodate. In step
(3), MPC oxidizes captopril to captopril free radical by
absorbing H atom from S–H moiety which supports the
–
–
[DPC] = 1.0 9 10-4
[IO4-] = 1.0 9 10-3 mol dm-3
,
[Capt] = 4.0 9 10-3
,
[OH-] = 0.05,
[IO4-] = 1.0 9 10-3, I = 0.2/mol dm-3. Rate was found
to be increased with increase in temperature. First-order
rate constants kobs 9 103 s-1 were obtained as 0.67, 1.03,
1.80, 2.56, and 4.46 at 30, 35, 40, 45, and 50 °C, respec-
tively. From the Arrhenius plot log kobs vs. 1/T, activation
energy EA (76.0 2 kJ mol-1) and other activation
parameters DH= (74.0 2 kJ mol-1), DS= (-123
3 J K-1 mol-1), DG= (11.0 0.2 kJ mol-1), and log
A (10.0 0.4) are calculated.
Water soluble Cu(III) periodate complex is reported [11]
to be [Cu(HIO6)2(OH)2]7- or Na7KHCu(IO6)2. However, in
Scheme 2
K1
[Cu(H3IO6)2]- + OH-
[Cu(H3IO6) (H2IO6)]2- + H2O
(i)
K2
[Cu(H3IO6) (H2IO6)]2- + 2 H2O
[Cu(H3IO6) (H2O)2]+ + H2IO6
3-
(ii)
2-
+ Cu2+ + H3IO6
+ 2 H2O + H+
COO
COO
N
k
N
[Cu(H3IO6) (H2O)2]+
+
(iii)
slow
O
O
S
SH
COO
S
N
fast
COO
O
COO
S
2
N
N
(iv)
(v)
O
O
S
fast
H+ + OH-
H2O
123

Kinetics and mechanism of oxidation of captopril
225
Scheme 3
O
I
H2O
COO
COO
SH
O
O
OH
OH
N
N
Cu
+
H
O
I
-H2O
O
O
OH
OH
O
O
S
H2O
OH
Cu
H2O
OH
COO
N
COO
S
N
H
2-
+ Cu2+ + H3IO6 + H+ + H2O
O
I
O
O
OH
OH
O
S
O
Cu
H2O
OH
COO
COO
N
COO
COO
N
N
N
O
O
O
S
S
O
S
S
1.80
1.75
1.70
1.65
1.60
1.55
Scheme 4
HS
HS
N
N
O
O
O
O
O
O
2+
Cu
Cu
H2O
OH2
H2O
OH2
0
200
400
600
800
1000
1200
Time /s
Fig. 5 Log (absorbance) vs. time plot of oxidation of captopril by
diperiodatocuprate(III) in aqueous alkaline medium at 30 °C,
[DPC] = 1.0 9 10-4, [Capt] = 1.0 9 10-3, [OH-] = 0.05, [IO4-] =
1.0 9 10-3, I = 0.2 mol dm-3
intervention free radical as observed in the polymerization
study. In the subsequent step, free radicals generated from
captopril undergo dimerisation to form captopril disulfide
(Scheme 3). It is well characterized by IR and GCMS
studies. However, in the experimental part, it was observed
that reaction was very fast for few seconds at the beginning
of the reaction (Fig. 5).
123

226
M. A. Angadi, S. M. Tuwar
70
60
50
40
30
20
10
0
547.4
when [Cu(II)] is equal to [DPC]. Once they are equal, first-
order plots were found to be linear from the start of reac-
tion. This behavior of interaction of Cu(II) with captopril is
not incorporated in Scheme 2.
Nevertheless, when reaction proceeds Cu(II) formed
from DPC interacts with captopril to give Cu(II)-captopril
complex (Scheme 4). When this is oxidized by DPC, its
dimer (Scheme 5) is formed which is evidenced by its ESI–
MS spectral studies (Fig. 6) for the molecular ion mass of
547.4. Similar metal ion—captopril disulfide with sil-
ver(I) is reported [33].
549.4
509.5
471.5
531.6
Increase in rate with increasing ionic strength can be
explained on the basis of interaction between positively
charged MPC with positively charged Cu(II)-captopril
complex (Scheme 4) involved in slow step. Both the spe-
cies carry a single positive charge on one each. Hence,
expected slope to be unity in the graph of log kobs vs.
HI and found to be so in present investigation which
supports a slow step of Scheme 2.
364.2
95.0
0
100
200
300
400
500
600
m/z
Fig. 6 ESI-MS spectrum of Cu(II)—captopril disulfide complex
with its molecular ion peak at 547.4
[OH-]-1 / dm3 mol-1
Scheme 2 leads to the following rate law, given by Eq. 4
(vide ‘‘Appendix’’):
0
20
40
60
80
100
120
4.0
3.0
2.0
1.0
0.0
4.5
3.0
1.5
0.0
rate / ½Captꢃ½CuðH3IO6ÞðH2OÞ ꢃþ
2
kK1K2½Captꢃf½OHꢁꢃ
kobs
¼
½H2IO63ꢁꢃ þ K1½H2IO63ꢁꢃ½OHꢁꢃ þ K1K2½OHꢁꢃ
ð4Þ
Rate law (4) in the form of (5) is verified by omitting ‘f’
and ‘T’ in the plots of [Capt]/kobs vs. [H2IO63-] and
1/[OH-], all of which should be linear and found to be so
(Fig. 7).
1
½H2IO63ꢁꢃ
½H2IO63ꢁꢃ
1
¼
þ
þ
ð5Þ
kobs kK1K2½Captꢃ½OHꢁꢃ kK2½Captꢃ k½Captꢃ
or
0.0
2.0
4.0
6.0
½Captꢃ
½H2IO63ꢁꢃ
½H2IO63ꢁꢃ
1
[IO4 ]×103/ mol dm-3
¼
þ
þ
-
kobs
kK1K2½OHꢁꢃ
kK2
k
Fig. 7 Verification of rate law (5) on oxidation of captopril by
diperiodatocuprate(III) in aqueous alkaline medium at 30 °C
From the slopes and intercepts of such plots, values of
constants, k = 3.16 dm3 mol-1 s-1, K1 = 11.66 dm3
mol-1, and K2 = 9.2 9 10-4 mol dm-3 for 30 °C are
obtained. Further, these values are used in rate law (4) at
different experimental conditions (Table 1) to regenerate
It was evidenced by a rapid decrease in optical density
of DPC at the earlier stage of reaction. This might be due to
a rapid oxidation of captopril by DPC. Nevertheless, rate of
this rapid fall is suppressed when the reduction product of
DPC, the Cu(II) was added initially. Initial addition of
Cu(II) might have been involved in the formation of
complex with captopril in its trans-isomeric form with
respect to amide bond (Scheme 4) of captopril.
k
obs. These regenerated values are found to be in close
agreement with those of experimentally observed values
(Table 1). This fortifies the mechanism of oxidation as
shown in Scheme 2 and also rate law (4).
Since order with respect to oxidant and reductant is one
each, it is expected that oxidation path follows an outer
sphere mechanism. It is evidenced by a large value of EA
(76.0 kJ mol-1) and frequency factor, log A (10.0).
Negative value of DS= (-123 J K-1 mol-1) indicates
that two species, either two polar or polar and ionic species
This complex would be less reactive compared to the
un-complexed captopril. The similar observations have
been made in earlier reports [7]. However, it was observed
that the rapid fall of reaction at initial stage was controlled
123

Kinetics and mechanism of oxidation of captopril
227
combine in the rate determining step to give an activated
complex, i.e., more ordered than the reactants [34, 35].
Value of DS# is within the range for radical reaction that
has been ascribed [36] to the nature of electron pairing and
un-pairing processes, and to loss of degrees of freedom
(formerly available to the reactants) on formation of a
rigid transition state. Small positive value of DG#
(11.0 kJ mol-1) and small value of second-order rate
constant (3.16 dm3 mol-1 s-1) of slow step envisage the
electron transfer through an outer sphere mechanism.
in presence of a little excess of periodate in the solution for
several months. The complex was characterized by its UV–
Vis spectrum, which exhibits two strong broad absorption
bands at 416 and 265 nm. Aqueous solution of copper(III)
was standardized by both iodometric and gravimetric [38]
methods.
Periodate solution was prepared by dissolving a known
amount of potassium metaperiodate in hot water, and kept
it for 24 h. Its concentration was ascertained iodometri-
cally [39] at neutral pH maintained by a phosphate buffer.
Since periodate is present in excess over DPC, the pos-
sibility of oxidation of captopril by periodate in alkaline
medium at 30 °C was tested by following the reaction
iodometrically. It was found that there was no significant
reaction between periodate and captopril under the
experimental conditions employed compared to the DPC
oxidation of captopril. Aqueous solutions of KOH and
KNO3 were employed in reaction solutions to maintain
required alkalinity and ionic strength, respectively. Cop-
per(II) solution was prepared by dissolving required
quantity of CuSO4ꢀ5H2O in distilled water. The reports
reveal [6–9] that captopril undergoes aerial oxidation and
also with dissolved O2 in condensed phase at high pres-
sure. Hence, kinetic runs were also carried out in N2
atmosphere to understand the effect of dissolved oxygen
on rate of reaction. No significant difference in the results
was obtained under N2 atmosphere and in presence of air
at normal pressure and temperature. In view of ubiquitous
contamination of carbonate in basic medium, effect of
carbonate was also studied and found that added carbonate
did not alter the reaction rate.
Conclusion
Kinetics of oxidation of anti-hypertensive drug captopril is
studied using DPC as metal ion. It may be a first of its kind
as no metal ions are used to oxidize captopril so far.
Oxidative product of captopril as captopril disulfide is well
characterized by different spectroscopic methods. In the
present study, the oxidative product of captopril in its
complex form with Cu(II) is well characterized. Oxidation
was ascribed to be outer sphere mechanism which is evi-
denced by the magnitudes of DS#, log A, DH#, and first-
order dependency on each of oxidant and reductant. An
abnormal rapid reaction at initial stage is explained with
the support of experimental results of retarding effect of
added product Cu(II).
Experimental
Used chemicals captopril, KOH, KIO4, KIO3, K2S2O8,
NaOH, KNO3, and acrylonitrile were of analytical grade.
Purity of captopril was checked by its melting point. Their
reaction solutions were prepared in double distilled water
free from dissolved oxygen and carbon dioxide. Acrylo-
nitrile and K2S2O8 were purified by distillation and re-
crystallization, respectively, to remove any traces of
impurities.
Kinetic studies
Kinetics of oxidation of captopril by DPC were followed
under pseudo-first-order conditions where [Capt] was in
excess over [DPC] at 30 0.1 °C. Reaction was initiated
by mixing required quantities of a previously thermostated
solution of DPC and captopril which also contained defi-
-
nite quantities of KOH, KNO3, and IO4 to maintain the
Preparation of DPC
required concentration of alkali, ionic strength, and perio-
date. In a reaction mixture, the total concentration of
hydroxide ion was calculated by considering KOH in DPC
as well as KOH added additionally. Similarly, total me-
taperiodate concentration was calculated by considering
metaperiodate present in solution of DPC and additionally
added. Kinetics of reaction were monitored by following
decrease in absorption of DPC in a 1 cm quartz cell of a
thermostatted compartment of a Hitachi-U3310 spectro-
photometer at its kmax of 416 nm as a function of time.
None of the other species depicted any absorption at this
wavelength. Obedience of absorbance by DPC to Beer’s
law at its kmax of 416 nm was verified earlier and molar
Diperiodatocuprate(III) was prepared [37] by oxidizing
CuSO4ꢀ5H2O in aqueous alkaline medium as follows:
3.54 g copper sulfate, 6.8 g potassium metaperiodate, 2.2 g
potassium persulfate, and 9.0 g potassium hydroxide were
added to 250 cm3 of water. The mixture was heated to
boiling on a hot plate with constant stirring until it turns
dark red, and boiling was continued for another 20 min to
ensure the completion of reaction. The mixture was then
cooled and filtered through a sintered glass crucible (G-4).
This filtrate was diluted to 250 cm3 with distilled water.
The solution obtained was fairly stable at room temperature
123

228
M. A. Angadi, S. M. Tuwar
absorbency index e was found to be 6,250 50 dm3 mol-1
cm-1 (lit. value: e = 6,500 50 dm3 mol-1 cm-1 [39]).
First-order rate constants, kobs were obtained from the
slopes of plots of log (a–x) vs. time, where a and x being
initial and change in concentration of DPC at time t,
respectively. Plots were linear except at the beginning of
reaction for few seconds. Initially, reaction was found to
be very fast due to the rapid formation of a complex
between DPC and captopril or orientation of the mole-
cules (discussed elsewhere). However, kobs were
calculated from the linear portion of first-order plots for
all the variations of different species of reaction. Non-
linearity of plot of log absorbance vs. time at the start of
reaction is shown in Fig. 5. Rate constants were repro-
ducible within 5 %.
On substituting Eq. (8) in (7), Eq. (9) results
kK1K2½Captꢃ ½CuðIIIÞꢃ ½OHꢁꢃ
d½DPCꢃ
dt
f
T
ꢁ
¼
[H2IO63ꢁꢃþK1[H2IO63ꢁ][OHꢁ] + K1K2[OHꢁ]
ð9Þ
or
kK1K2½Captꢃ ½OHꢁꢃ
f
kobs
¼
3ꢁ
½H2IO63ꢁ þ K1½H2IO6 ꢃ½OHꢁꢃ þ K1K2½OHꢁꢃ
ð10Þ
Rate law (10) in the form of (11) and (12) is verified by
3-
omitting ‘f’ and ‘T’ in plots of [Capt]/kobs vs. [H2IO6
and 1/[OH-], all of which should be linear.
]
1
½H2IO63ꢁꢃ
½H2IO63ꢁꢃ
1
¼
þ
þ
ð11Þ
kobs kK1K2½Captꢃ½OHꢁꢃ kK2½Captꢃ k½Captꢃ
Acknowledgments The authors are grateful to the Principal, Kar-
natak Science College, Dharwad, Karnataka, India for providing the
necessary facilities to carry out this work. They also thank the
Raptakos Brett and Co., Microlabs Ltd. KLAB, Mumbai, India for
providing the free sample of captopril.
or
½Captꢃ
½H2IO63ꢁꢃ
½H2IO63ꢁꢃ
1
¼
þ
þ
:
ð12Þ
kobs
kK1K2½OHꢁꢃ
kK2
k
Appendix A
References
Derivation for rate law of mechanism of oxidation
of captopril by diperiodatocuprate(III) in aqueous
alkaline medium
1. Ondetti MA, Rubin B, Cushman DW (1977) Science 196:441
2. Cushman DW, Cheung HS, Sabo EF, Ondetti MA (1977) Bio-
chemistry 16:5484
3. Cushman DW, Cheung HS, Sabo EF, Ondetti MA (1978) Prog
Cardiovasc Dis 21:176
4. Wu PC, Hung YB, Chang JJF, Chang JS, Tsai YH (2000) Int J
Pharm 209:87
5. Attoub S, Gaben AM, Al-Salam SNY (2008) Ann Acad Sci 1138:65
6. Lee TY, Notari RE (1987) Pharm Res 4:98
7. Lin B, Zhan XC, Li LL, Li CR, Qi HJ, Tao JL (2008) Yakugaku
Zasshi 128:617
8. Timminis P, Jackson IM, Wang YJ (1982) Int J Pharm 11:329
9. Kaden H (1982) Captopril. In: Analytical profiles of drug sub-
stances, vol 11. American Pharmaceutical Association, Washington,
DC, pp 79
The rate law for Scheme 2 can derived as
rate / ½Captꢃ½CuðH3IO6ÞðH2OÞ ꢃþ
ð6Þ
ð7Þ
2
2ꢁ
d½DPCꢃ kK2½Captꢃf½CuðH3IO6ÞðH2IO6Þꢃf
ꢁ
¼
¼
½H2IO63ꢁꢃf
dt
ꢁ
kK1K2½Captꢃf½CuðH3IO6Þ2ꢃf ½OHꢁꢃ
½H2IO63ꢁꢃ
However,
[Cu(III)]T
¼ ½CuðH3IO6Þ ꢃ ꢁ þ ½CuðH3IO6ÞðH2IO6Þꢃ
10. Rabenstein DL, Theriault YA (1985) Can J Chem 63:33
11. Movius WG (1973) Inorg Chem 12:31
12. Angadi MA, Tuwar SM (2010) J Solut Chem 39:165
13. Tuwar SM, Nandibewoor ST, Raju JR (1992) J Indian Chem Soc
69:651
14. Jose TP, Angadi MA, Salunke MS, Tuwar SM (2008) Main
Group Chem 7:109
15. Kumar A, Kumar PJ, Ramamurthy P (1999) Polyhedron 18:773
16. Kumar A, Kumar PJ (1999) Phys Org Chem 12:79
17. Kumar A, Vaishali P, Ramamurthy P (2000) Int J Chem Kinet
32:286
18. Bal Reddy K, Sethuram B, Navaneeth Rao T (1981) Indian J
Chem 20A:395
19. Jose TP, Tuwar SM (2007) J Mol Str 827:137
20. Patil ST, Angadi MA, Harihar AL (2008) J Solut Chem 37:1795
21. Angadi MA, Tuwar SM (2012) E J Chem 9:203
22. Angadi MA, Tuwar SM (2012) Global J Phys Chem 3:1
2ꢁ
2 f
f
þ
ꢁ
þ ½CuðH3IO6ÞðH2OÞ2ꢃf ¼ ½CuðH3IO6Þ2ꢃf
ꢁ
þ K1½CuðH3IO6Þ2ꢃf ½OHꢁꢃ
2ꢁ
K2½CuðH3IO6ÞðH2IO6Þꢃ
ꢁ
þ
¼ ½CuðH3IO6Þ2ꢃf
½H2IO63ꢁꢃ
ꢁ
K1K2½CuðH3IO6Þ2ꢃf ½OHꢁꢃ
ꢁ
þ K1½CuðH3IO6Þ2ꢃf ½OHꢁꢃ þ
½H2IO63ꢁꢃ
ꢁ
ꢀ
K1K2½OHꢁꢃ
ꢁ
¼ ½CuðH3IO6Þ2ꢃf 1 þ K1½OHꢁ þ
½H2IO36ꢁꢃ
½CuðIIIÞꢃT ½H2IO36ꢁꢃ
ꢁ
½CuðH3IO6Þ2Þꢃf
¼
½H2IO36ꢁꢃ þ K1½H2IO36ꢁꢃ½OHꢁꢃ þ K1K2½OHꢁꢃ
ð8Þ
123

Kinetics and mechanism of oxidation of captopril
229
23. Simandi LI, Jaky M, Savage CR, Schelly ZA (1985) J Am Chem
Soc 107:4220
31. Lide DR (1992) CRC hand book of chemistry and physics, 73rd
edn. CRC Press, London, p 8
24. Szamuuer J, Jaky M, Germasimov QV (1992) Int J Chem Kinet
24:145
32. Kolthoff IM, Meehan EJ, Carr EM (1953) J Am Chem Soc
75:1439
25. Jaiswal PK, Yadava KL (1973) Indian J Chem 11:837
26. Mendham J, Denney RC, Barnes JD, Thomas MJK (2003) Vo-
gel’s text book of quantitative analysis, 6th edn. Pearson
Education, Delhi, p 466
27. Sharanabasamma K, Salunke MS, Tuwar SM (2008) J Solut
Chem 37:1217
28. Badi SS, Tuwar SM (2013) J Solut Chem 42:1518
29. Hampton C, Demoin D Vibrational spectroscopy tutorial: sulfur
and phosphorus, NIST chemistry web book. http://webbook.nist.
gov
33. Bailar JC, Emeleus HJ, Nyholm SR, Trotman-Dikenson AF
(1975) Comprehensive inorganic chemistry, vol 2. Pergamon
Press, Oxford, p 1456
34. Bhattacharya SB, Saha B, Datta SA, Banerjee P (1998) Coord
Chem Rev 170:47
35. Haines RI, McAuley A (1981) Coord Chem Rev 39:77
36. Cavalu S, Pinzaru SC, Chis V (2007) Romanian J Biophys 17:195
37. Puttaswamy TM, Anuradha TM (2001) Indian J Chem 40:514
38. Rangappa KS, Anita N, Made Gowda NM (2001) Synth React
Inorg Met Org Chem 31:1499
30. Sheena Mary Y, Ushakumari L, Harikumar B, Tresa Varghese H,
Yohannan Panicker C (2009) J Iran Chem Soc 6:138
39. Walling C (1957) Free radicals in solution. Wiley, New York
123