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86 CHAPTER III
1. INTRODUCTION
Hexacyanoferrate (III) (HCF) is [1] an efficient one- electron oxidant and has
been observed to be “substitution inert - transition metal complex” [2].
Mechanism of oxidation by HCF should be through an outer sphere process,
the transfer of an electron occurring from substrates to metal ion through a
cyano ligand. The chemistry of HCF, in alkaline medium is well understood
[3-10], particularly by its oxidative capacity in oxidation of inorganic and
organic compounds. Its usefulness may be due to its unequivocal stability,
solubility, single equivalent change and its moderate reduction potential,
[Fe(CN)6]3-
/ [Fe(CN)6]4-
of +0.41 V in basic medium. Studies involving HCF
as an oxidant in acid media [11] are limited by the fact that its reduction
potential is small (+ 0.36 V) in such media [12]. Although, HCF is a poor
oxidant in acid media, it is a selective outer sphere reactant applicable to most
easily oxidizable substrates, and is used as an interceptor of free radical; this
feature turns the species into efficient one electron particularly, interesting in
the comparative study of octahedral complexes. Generally, oxidizing ability is
enhanced in acidic solvents, hence, only few contributions have been published
in such media. However, in the present study an adverse effect of acid
concentration on rate of reaction is observed.
Captopril, 1-[2(s)-3-mercapto-2-methyl-1-oxopropyl]-L-proline, is the
first angiotensin converting enzyme. It is used in the management of
hypertension, heart failure, nephropathy [13], various renal syndromes such as
diabetic nephropathy, scleroderma [14-16] and inhibiting the progression of
87 CHAPTER III
atherosclerosis [17]. It decreases certain chemicals that tighten the blood
vessels, so blood flows more smoothly and heart can pump blood more
efficiently [18]. Its sulfhydryl group may contribute to its pharmacological
action and account for some adverse reactions that occur at higher doses. Its
therapeutic applications for the treatment of cancer had also been investigated
[19].
Captopril inhibits the active sites of zinc-glycoproteins like other proline
containing peptides. It normally has an equilibrium conformation between
cis and trans isomers with respect to conformation across the peptide bond.
The trans(I): cis(II) ratio for captopril at room temperature is 6:1 in aqueous
solutions but the active form of captopril is the trans isomer when bound to the
enzyme [20]. Characteristic of thiols, captopril reportedly undergoes oxidation
to form the dimer, captopril disulfide [21, 22].
(I) (II)
CH2
N
CHCO2H
C
H2
CH2
O
C
CH3
N
CH
2
C
H2
CH2
HO2CCH
O
CCH
3
HSCH2CH HSCH2CH
A literature survey reveals that analysis of captopril was carried out by
using various methods. In conventional method, it is analyzed using oxidants
like dissolved oxygen, hexacyanoferrate(III) [23], chloramine–T [24],
potassium iodate [25, 26], palladium(II) chloride [27] etc. Although, the
kinetics of oxidation of captopril was studied by using HCF in aqueous alkali
88 CHAPTER III
[28], the results obtained in acidic medium are found to be substantially
different from those in alkali, particularly in stoichiometry, oxidative product,
order in reactants and the effect of pH. Hence, the title reaction was studied to
establish the reaction path in acidic medium.
2. EXPERIMENTAL SECTION
2.1. Materials and Reagents
All chemicals used were of reagent grade. Doubly distilled water was used
throughout the study. The stock solution of captopril was prepared by
dissolving a known amount of captopril in distilled water, its purity have been
checked by its m.p and TLC for a single spot. A solution of HCF was prepared
by dissolving K3[Fe(CN)6] (BDH) in water and this was standardized
iodometrically [29]. It is known that it undergoes reduction when exposed to
sunlight for a long time and its yellow color becomes dark, thereby its ‘ε’ value
varies with ageing. Hence, a fresh solution of HCF was used for all kinetic
measurements. To study the product effect on the rate of reaction, a stock
solution of [Fe(CN)6]4-
was prepared by dissolving a sample of K4[Fe(CN)6]
(S.D. fine) crystals in distilled water. During kinetic experiments, HClO4 and
NaClO4 were employed to maintain the required acidity and ionic strength,
respectively, in the reaction medium.
2.2. Kinetic Measurements
The reaction was initiated by mixing a HCF solution with captopril, which also
contained the required amounts of HClO4 and NaClO4. The reaction was
studied at 300 ± 1 K under pseudo first order conditions where [Capt] was in
89 CHAPTER III
excess over [HCF]. The kinetics was monitored by following the decrease in
absorption of HCF in a 1 cm quartz cell of a thermostated compartment of a
Hitachi-U3310 spectrophotometer at its λmax = 420 nm as a function of time.
None of the other substrates showed any absorption at this wavelength (Figure
III (a), p. 90). Applicability of the Beer - Lamberts law for HCF at 420 nm
(Figure III (b), p. 90) under the reaction condition had earlier been verified
giving ‘ε’ = 1060 (±20) dm3
mol-1
cm-1
. Pseudo first order rate constants, kobs,
were calculated from slopes of log[HCF] versus time plots. The plots were
linear up to 50% completion of the reaction (Table III (a), p. 91 and Figure III
(c), p. 92), the non-linearity beyond that is due to the retarding effect of one of
the reaction products, [Fe(CN)6]4-
(discussed elsewhere). The order with
respect to each reactant was determined from the slopes of plots of log kobs
versus log (conc.) except in [HCF].
3. RESULTS
3.1. Stoichiometry and Product Analysis
More than ten sets of reaction mixtures containing varying ratios of HCF to
captopril, in 0.01 mol dm-3
HClO4 at a constant ionic strength of 0.05 mol dm-3
,
were kept for over 24 hrs. at 300K in a closed vessel for completion of reaction
(Table III (b), p. 94). When [HCF] > [Capt], unreacted [HCF] was analyzed by
measuring its absorption at 420 nm, spectrophotometrically, and also
iodometrically using starch as an indicator, in the presence of zinc sulphate
to avoid the reverse reaction. The results indicated that 2 mol of HCF are
90 CHAPTER III
0.0
0.2
0.4
0.6
0.8
1.0
230 280 330 380 430 480
0.0
0.2
0.4
0.6
0.8
1.0
0.0 2.0 4.0 6.0 8.0 10.0
Figure III (a)
Spectrum of hexacyanoferrate(III) in aqueous acidic medium at 300K.
[HCF] = 4.0 x 10-4
; [H+] = 1.0 x 10
-2;
I=0.05 / mol dm-3
.
Figure III (b)
Verification of Beer’s law at 420 nm for freshly prepared hexacyanoferrate(III)
in aqueous acidic medium at 300K.
[H+] = 0.01; I = 0.05 / mol dm
-3
Ab
sorb
ance
[HCF] x 104 (mol dm
-3)
262
304
420
λ (nm)
Ab
sorb
ance
91 CHAPTER III
Table III (a)
Example run for the oxidation of captopril by hexacyanoferrate(III) in aqueous
acidic medium at 300K.
[HCF] = 4.0x 10-4
; [Capt]= 8.0 x 10-3
;
[H+] = 0.01 ; I=0.05 / mol dm
-3.
Time Absorbance 104
x [HCF]
(min) (420 nm) (mol dm
-3)
0.00 0.421 4.000
2.50 0.364 3.434
5.00 0.335 3.160
7.50 0.316 2.981
10.0 0.301 2.840
12.5 0.290 2.734
15.0 0.281 2.651
17.5 0.274 2.585
20.0 0.267 2.519
22.5 0.262 2.472
25.0 0.258 2.434
27.5 0.254 2.396
30.0 0.251 2.368
92 CHAPTER III
Ab
sorb
ance
Time (min)
0.22
0.27
0.32
0.37
0.42
0.47
0.0 5.0 10.0 15.0 20.0 25.0 30.0
Figure III (c)
Example run at 420 nm for the oxidation of captopril by hexacyanoferrate(III)
in aqueous acidic medium at 300K.
(Conditions as in Table III (a), p. 91)
93 CHAPTER III
Table III (b)
Stoichiometry for the oxidation of captopril by hexacyanoferrate(III) in
aqueous acidic medium at 300K.
[H+] = 0.01; I = 0.05 / mol dm
-3
Taken Unreacted Reacted
104 x [HCF]
(mol dm-3
)
104 x [Capt]
(mol dm-3
)
104 x [HCF]
(mol dm-3
)
104 x [HCF]
(mol dm-3
)
1.0 1.0 0.00 1.00
2.0 1.0 1.11 0.89
3.0 1.0 2.16 0.84
4.0 1.0 3.11 0.89
6.0 1.0 5.05 0.95
8.0 3.0 5.01 2.98
10 5.0 5.36 4.64
12 5.0 7.35 4.65
4.0
40
0.00
4.00
94 CHAPTER III
consumed by 2 mol of captopril to give captopril disulfide as shown in
eqn. (1).
N NN
2[Fe(CN)6]3- +
HOOC
CH3
CH2CH SC
O
S CH2CH
CH3
C
O
COOH
2
CH3
CH2CH SHCO
HOOC
+ 2H++ 2[Fe(CN)6]4-
The oxidation product of captopril was characterized as follows: the
above solution of reaction mixture was subjected to TLC for separation of
constituents. Iodine spray showed a single spot, indicating only one oxidation
product is resulted. This was identified as captopril disulfide by FT-IR and GC-
MS analysis. In IR-scanning the disappearance of S-H vibration peak at 2565
cm-1
and the appearance of a new peak at 486 cm-1
for S-S stretching clearly
indicating the formation of captopril disulfide (Figure III (d), p. 95). In the GC-
MS study, the molecular ion peak, m/z was found to be 432 (m/z = 432 ±1)
which was expected for captopril disulfide (Figure III (e), p. 96).
3.2. Reaction Order
The orders with respect to [Capt] and [acid] were determined by log kobs versus
log [conc] plots; these orders were obtained by varying concentration of
reductant and acid in turn while keeping the others constant. Since, first order
plots were linear up only to 50%, due to the retarding effect of product, the
initial rate method was used to determine the order of reaction. It was found
that both methods gave identical results. Hence, first order plots were used for
determination of reaction order for various reactants.
(1)
95 CHAPTER III
Figure III (d)
FT-IR spectrum of captopril disulfide formed due to oxidation of captopril by
hexacyanoferrate(III) in aqueous acidic medium.
% t
ran
smit
tan
ce
Wave numbers (cm-1
)
27
48
.1
10
76
.1
17
31
.8
16
35
.4
12
88
.2
14
05
.9
11
28
.2
10
08
.6
62
2.9 4
86
.0
28
63
.8
29
62
.2
34
21
.2
29
31
.3
70
5.8
75
2.1
83
3.1
45
55
65
75
85
95
400900140019002400290034003900
N N
C
O
CHCH2S
HOOC
C
O
CH CH2S
COOH
CH3CH3
96 CHAPTER III
Figure III (e)
GC-MS spectrum of captopril disulfide formed due to oxidation of captopril by
hexacyanoferrate(III) in aqueous acidic medium.
m/z
Rel
ativ
e A
bu
nd
ance
N N
C
O
CHCH2S
HOOC
C
O
CH CH2S
COOH
CH3CH3
Mol. Mass = 433
97 CHAPTER III
3.2.1. Effect of [HCF]
The effect of [HCF] on rate of reaction was studied by varying its
concentration in the concentration range, 8.0 x10-5
to 8.0x10-4
mol dm-3
at fixed
[Capt], [H+] and ionic strength. The order in [HCF] was found to be unity, as
plots of log [HCF] versus time were linear (Figure III (f), p. 99) with no
variation in slope for different [HCF] (Table III (c), p. 98).
3.2.2. Effect of [Capt]
The substrate, [Capt], was varied in the concentration range of 4.0 x 10-3
to 3.0
x 10-2
mol dm-3
at 300K, keeping all other reactants concentrations constant to
understand the effect of [Capt]. kobs values increase with increasing
concentration of captopril (Table III (c), p. 98). From the plot of log kobs versus
log[Capt], the order in [Capt] was calculated to be unity (Figure III (g), p. 100).
3.2.3. Effect of [H+]
At a fixed ionic strength of 0.05 mol dm-3
and other conditions remaining
constant, [HClO4] was varied from 5.0 x 10-3
to 5.0 x 10-2
mol dm-3
. It was
noticed that as [H+] increases the rate of reaction decreases (Table III (c), p. 98)
with an order -0.7 (Figure III (g), p. 100). This decrease in rate with increase in
[H+] is due to involvement of an acid - base equilibria.
The pK1 value was reported [30] to be -0.6. Using this value, the
concentrations of H[Fe(CN)6]2-
and [Fe(CN)6]3-
were calculated (Table III (d),
p. 101) under various [H+] to arrive at the amount of active form of HCF in
H[Fe(CN)6]2-
K1 [Fe(CN)6]3- + H+ (2)
98 CHAPTER III
Table III(c)
Effect of variation of [HCF] , [Capt] and [H
+] on oxidation of captopril by
hexacyanoferrate(III) in aqueous acid medium at 300K.
I=0.05 mol dm-3
.
104
x [HCF]
102 x [Capt] 10
2 x [H
+] 10
3 x kobs (s
-1)
( mol dm-3
) ( mol dm-3
) ( mol dm-3
) Exptl.a Calc.
b
0.8
1.0
2.0
3.0
4.0
6.0
8.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.4
0.6
0.8
1.0
1.5
3.0
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
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
1.5
2.0
3.0
4.0
5.0
1.62
1.93
1.34
1.23
1.06
1.07
0.74
0.43
0.74
1.06
1.34
2.04
4.71
1.58
1.26
1.06
0.72
0.59
0.43
0.33
0.28
--
--
--
--
--
--
--
0.50
0.75
1.00
1.25
1.88
3.76
1.49
1.25
1.00
0.75
0.61
0.43
0.34
0.28
a. Experimental value
b. Calculated values; kcal are calculated from the constants, k1 = 0.36 dm3
mol-1
s-1
and K1 = 5.3 x 10-3
mol dm-3
in eqn. (10)
99 CHAPTER III
Figure III (f)
First order plots of various concentrations of HCF on oxidation of captopril by
hexacyanoferrate(III) in aqueous acid medium at 300K.
[HCF] = (1) 2.0 x 104 (2) 3.0 x 10
4 (3) 4.0 x 10
4 (4) 6.0 x 10
4
(5) 8.0 x 104 / mol dm
-3.
(Conditions as in Table III (c), p. 98)
Time (min)
2+
lo
g A
bso
rban
ce
0.8
1.0
1.2
1.4
1.6
1.8
2.0
0 5 10 15 20 25 30
(1)
(2)
(3)
(4)
(5)
100 CHAPTER III
0.4
0.7
1.0
1.3
1.6
1.9
0.5 0.7 0.9 1.1 1.3 1.5 1.7
0.2
0.5
0.8
1.1
1.4
1.7
0.5 0.7 0.9 1.1 1.3 1.5 1.7
3.94
3.95
3.96
3.97
3.98
3.99
4.00
0.00 0.01 0.02 0.03 0.04 0.05
0
4
8
12
16
20
Figure III (g)
Order plot of [Capt] and [H+] on the oxidation of captopril by
hexacyanoferrate(III) in aqueous acid medium at 300K.
(Conditions as in Table III (c), p. 98)
Figure III (h)
Variation of concentration of HCF species at various [H+] along with kobs
values in the of captopril by hexacyanoferrate(III) in aqueous acid medium at
300K. (Conditions as in Table III (d), p. 101)
3 + log [H+]
4 +
log
ko
bs
3+ log [Capt]
4 +
log k
ob
s
[H+] mol dm
-3
[Fe(
CN
) 6]3
- x 1
04 m
ol
dm
-3
ko
bs x
10
4 s-1
101 CHAPTER III
Table III (d)
Effect of [H+] on HCF(III) species and kobs of oxidation of captopril by
hexacyanoferrate(III) in aqueous acid medium at 300K.
[HCF] = 4.0x 10-4
; [Capt]= 8.0 x 10-3
;
I=0.05 / mol dm-3
.
kcal are calculated from the constants, k1 = 0.36 dm3
mol-1
s-1
and K1 = 5.3 x
10-3
mol dm-3
in eqn. (10)
[H+]
x 102
(mol dm-3
)
[Fe(CN)6]3-
f
x 104
(mol dm-3
)
H[Fe(CN)6]2-
x 106
(mol dm-3
)
H2[Fe(CN)6]-
x 1011
(mol dm-3
)
H3[Fe(CN)6]
x 1020
(mol dm-3
)
kobs
x 103
(s-1
)
kcal
x 103
(s-1
)
0.5
0.7
1.0
1.5
2.0
3.0
4.0
5.0
3.995
3.993
3.990
3.985
3.980
3.970
3.960
3.950
0.502
0.702
1.002
1.502
2.000
2.992
3.980
4.963
0.148
0.289
0.590
1.327
2.355
5.286
9.375
14.61
0.415
1.139
3.320
11.19
26.49
89.18
210.9
410.8
1.58
1.25
1.06
0.72
0.59
0.43
0.33
0.28
1.49
1.25
1.00
0.75
0.61
0.43
0.34
0.28
102 CHAPTER III
acid medium. It was found that [Fe(CN)6]3-
varied linearly with [H+] (Figure III
(h), p. 100).
3.2.4. Effect of Initially Added Product
The effect of added product, [Fe(CN)6]4-
, was studied in the concentration
range, 8.0 x 10-5
to 8.0 x 10-4
mol dm-3
, at a constant ionic strength and all other
conditions being constant. The rate of reaction decreased on addition of product
with an order -0.5 (Table III (e), p. 103 and Figure III (i), p. 103). Another
product, captopril disulfide, did not influence the rate of reaction.
3.2.5 Effect of Ionic Strength and Dielectric Constant of the medium
The effect of ionic strength was studied by varying [NaClO4] in the reaction
medium. Ionic strength of the reaction medium was varied from 0.01 to
0.2 mol dm-3
at constant concentrations of HCF, captopril and acid. It was
observed that variation of ionic strength did not affect the rate of reaction
(Table III (f), p. 104).
The effect of change in dielectric constant (D) of the medium on
reaction rate was studied by using different compositions (v/v) of acetic acid
and water. The kobs values were found to increase with increasing dielectric
constant of the medium (Table III (f), p. 104). Dielectric constants of their
different compositions were calculated from the values of the pure substances
as;
D = D1V1 + D2V2 (3)
where V1 and V2 are volume fractions and D1 and D2 are dielectric constants of
water and acetic acid as 78.5 and 6.15 at 300K respectively. Earlier, it was
103 CHAPTER III
0.2
0.4
0.6
0.8
1.8 2.0 2.2 2.4 2.6 2.8 3.0
Table III(e)
Effect of variation of concentration of product, [Fe(CN)6]4-
on the oxidation of
captopril by hexacyanoferrate(III) in aqueous acid medium at 300K.
[HCF] = 4.0x 10-4
; [Capt]= 8.0 x 10-3
;
[H+] = 0.01 ; I=0.05 / mol dm
-3.
104 x [Fe(CN)6]
4-
( mol dm-3
)
104
x kobs (s-1
)
Exptl.a Calc.
b
0.8 4.57 4.20
1.0 4.40 4.03
2.0 3.31 3.37
3.0 2.83 2.90
4.0 2.53 2.54
6.0 2.05 2.02
8.0 1.79 1.71 aExperimental value
bCalculated values; kcal are calculated from the constants, k1 = 0.36 dm
3 mol
-1
s-1
, k2 = 0.52 dm3
mol-1
s-1
, k3 = 2.11x 10-4
s-1
and K1 = 5.3 x 10-3
mol dm-3
in
eqn. (17).
Figure III (i)
Order plot of [Fe(CN)6]4-
on the oxidation of captopril by
hexacyanoferrate(III) in aqueous acid medium at 300K.
(Conditions as in Table III (e) p. 103)
6 + log [Fe(CN)6]4-
4 +
log k
ob
s
104 CHAPTER III
Table III(f)
Effect of Ionic strength (I) and Dielectric constant (D) of the medium on
oxidation of captopril by hexacyanoferrate(III) in aqueous acid medium at
300K.
[HCF] = 4.0x 10-4
; [Capt]= 8.0 x 10-3
;
[H+] = 0.01/ mol dm
-3
Ionic strength (I) Dielectric constant (D)
(D = 78.5) (I = 0.05 mol dm-3
)
I
(mol dm-3
) √I
103 x
kobs
(s-1
)
% of acetic
acid in water
(v/v)
D
103 x
kobs
(s-1
)
0.01 0.10 1.06 00 78.5 1.06
0.02 0.14 1.06 05 74.9 1.02
0.03 0.17 1.06 10 71.3 0.96
0.05 0.22 1.05 15 67.6 0.90
0.07 0.26 1.06 20 64.0 0.84
0.10 0.32 1.06 25 60.4 0.79
0.20 0.45 1.05 --- --- ---
105 CHAPTER III
verified that there was no reaction of the solvent with oxidant under
experimental conditions.
3.2.6. Effect of Temperature
Temperature dependency of the rate of reaction was studied by varying the
temperature from 300 to 320K at constant concentrations of HCF, Capt, H+ and
ionic strength. It was noticed that increase in temperature, influences the rate
only marginally. Hence, the activation energy, Ea, was not calculated.
3.2.7. Polymerization Study
Since HCF is known to a generator of free radicals, due to its single equivalent
change in redox reactions, the involvement of free radical species in organic
substrate, captopril, was assayed by a polymerization test: few drops of pure
acrylonitrile were added initially to a reaction mixture containing 3.0 cm3 of
HCF (0.004 mol dm-3
), 3.0 cm3
of captopril (0.004 mol dm-3
) and 2.0 cm3 of
HClO4 (0.01 mol dm-3
) in an inert atmosphere, with the result of progressive
formation of a white precipitate in the whole reaction mixture, indicating the
presence of free radicals during oxidation of captopril. When the experiment
was repeated in the absence of captopril under similar condition, the test was
negative. This indicates that the reaction was routed through a free radical path.
4. DISCUSSION
Hexacyanoferrate(III) is known [30] to exist in several protonated forms in acid
medium as
HFe(CN)6
2- H+ + Fe(CN)63-
K1(4)
106 CHAPTER III
With the ionization constant pK1 = - 0.6, pK2 = - 3.33 and pK3 = - 6.25.
Acid concentrations employed in the present study clearly reveals that
[Fe(CN)6]3-
existed either as H[Fe(CN)6]2-
or un-protonated ferricyanide.
The existence of higher protonated complexes is ruled out as they exist at
relatively higher [H+] [30]. Thus, a single protonated ferricyanide,
H[Fe(CN)6]2-
, or un-protonated ferricyanide may be the reactive species in the
present investigation. Nevertheless, a retarding effect of added [H+] rules out
the possibility of involvement of H[Fe(CN)6]2-
as a reactive species. Thus,
[Fe(CN)6]3-
appears to be the reactive form in the present study. The rate
determining step of hexacyanoferrate(III) (HCF) oxidation of many organic
substrates that follow first order kinetics in both oxidant and reductant is
transfer of the first electron from reductant to the oxidant [31-33]. The rate
determining step should be irreversible as is generally the case for one electron
oxidants [33]; the oxidation takes place through generation of a free radical, as
HCF is a single equivalent oxidant. The polymerization study also shows the
formation of free radicals. For the reduction of HCF by captopril in acid
medium, a mechanism is proposed which involves the attack of HCF on neutral
captopril in a rate determining step to lead a free radical, which is followed by
a fast step in which free radicals generated combine to yield a captopril
disulfide. Hence, a proposed mechanism includes following steps.
H2Fe(CN)6- H+ + HFe(CN)6
2-
K2
K3H3Fe(CN)6 H+ + H2Fe(CN)6
-
(5)
(6)
107 CHAPTER III
H[Fe(CN)6]
2- K1
[Fe(CN)6]3- + H+
Although a study of kinetics of oxidation of captopril by
hexcaynoferrate(III) was reported by Khan, et al. [28] in aqueous alkaline
medium, the results of the present investigations in acid medium are
substantially different. In the former study, the order in captopril was found to
be less than unity (0.25), whereas in the present case there is a unit order in
[Capt]. Hence, in former study, the mechanism proposed for oxidation of
captopril was through formation of a complex between oxidant and substrate in
a slow step followed by decomposition in subsequent steps, leading to free
radical, dimerization of free radicals / oxidation of free radical to sulphoxide
etc., which is supported by 3:1 stoichiometry of [HCF] : [Capt]. However, such
compounds were not isolated and characterized. Moreover, in the reported [28]
study, stoichiometry reveals that, sulphoxide was the only oxidative product
whereas the mechanism indicates captopril disulfide as a final product. This is
(i)
NN N
Scheme 1
CH3
CH2CH SC
O
S CH2CH
CH3
C
O
COOH
2
OCH3
CH2CHC
HOOC HOOC
.S
Fast
(iii)
(ii)
NHOOC
[Fe(CN)6]3- +
CH3
CH2CH SHC
O
N
Slow
k1 [Fe(CN)6]4- +
O
CH3
CH2CHC
HOOC
.S
108 CHAPTER III
α Rate [HCF] [Capt]
an ambiguity in that study. A literature survey in the analysis of captopril by
various oxidizing agents reported that captopril disulfide is the only product
[23, 28, 34, 35]. Apart from this is the fact that the kobs values increased hardly
by 10% for a 10 fold rise of [OH-]. Hence, the role of [OH
-] was negligible in
that study [28]. Thus, the mechanism proposed in alkaline medium is
contradictory to expectations. However, in the present investigation a
mechanism is proposed in accordance with unit order dependency each in
oxidant and substrate, free radical intervention supported by polymerization
study and active species of HCF as [Fe(CN)6]3-
from the negative dependency
in [H+].
The rate law for the above mechanism can be derived as follows.
[Fe(CN)6]
3-f + [H Fe(CN)6]
2-[HCF]T=
[Fe(CN)6]3- [H+]
K1
[Fe(CN)6]3-
f +[HCF]T= f f
[Fe(CN)6]3-
f = K1 [HCF]T
K1 + [H+]
Substituting eqn. (8) in eqn. (7) yields eqn. (9):
Rate = k1 [ Fe(CN)6 ]3- [Capt] (7)
(8)
1 +[H+]f
K1
[HCF]T = [Fe(CN)6]3-
f
= [Fe(CN)6]3-
f
K1 + [H+]f
K1
109 CHAPTER III
Rate = - d[Fe(CN)6]
3-
dt=
K1 [HCF]T [ Capt]
K1 + [H+]
k1
K1 [ Capt]
K1 + [H+]
k1=kobs
Inversion and rearrangement of eqn. (10) gives eqn. (11):
k1 [Capt] K1
k1 [Capt] K1
= 1
kobs
+ K1 [H+]
K1
k1
[H+]1
k1
+=[Capt]
kobs
Mechanism and rate law are verified in the form of eqn. (11), by plotting
a graph of [Capt]/kobs versus [H+]. It should be linear and found so in Figure III
(j), (p. 110). From the slope and intercept of the plot, the values of k1 and K1
are calculated as 0.36 ± 0.01 dm3
mol-1
s-1
and 5.33(± 0.01) x 10-3
mol dm-3
respectively, at 300K. Further, these values are used in rate law (10) at different
experimental conditions as in Table III (c), (p. 98) to regenerate kobs. The
regenerated values are found to be in close agreement with those of
experimentally observed values. This fortifies the mechanism and rate law (10).
[H+] employed in the present investigation envisages that the oxidant
species occurs in two different forms, [Fe(CN)6]3-
and H[Fe(CN)6]2-
, and they
are in equilibrium. The variation of concentrations of these two species with
[H+] was calculated using the pk1
as
- 0.6. It was found that [Fe(CN)6]
3- varied
linearly with kobs. Hence, it appears to be the active form of HCF. Involvement
(9)
(10)
(11)
110 CHAPTER III
Figure III (j)
Verification of rate law (10) on oxidation of captopril by hexacyanoferrate(III)
in aqueous acid medium at 300K.
(Conditions as in Table III (c), p. 98).
[H+] (mol dm
-3)
[Cap
t]/
k ob
s (m
ol
dm
-3s)
0
5
10
15
20
25
30
35
0 0.01 0.02 0.03 0.04 0.05 0.06
111 CHAPTER III
NN N
.
Scheme 2
CH3
CH2CH SC
O
S CH2CH
CH3
C
O
COOH
OCH3
CH2CHC
HOOC HOOC
S
Slow
(Capt. free radical) (Capt. dimer)
1
2
k3
of this species with neutral captopril in a slow step of oxidation of captopril
supports the non-influence of added salt on the rate of reaction.
Retardation of rate due to added product, [Fe(CN)6]4-
, is not shown in
scheme 1. Retardation may be due to a secondary salt effect or because it
readily forms a complex with the substrate compared to hexacyanoferrate(III).
Such a complex may be less reactive than the free substrate.
This feature is supported by the marginal decrease in kobs with increase
in [HCF] where the concentration of [Fe(CN)6]4-
steadily increases with
increase in [HCF] (Table III (c), p. 98).
Alternatively, the following mechanism can be proposed to explain the
retarding effect of initially added product, [Fe(CN)6]4-
, with an order -0.5.
H[Fe(CN)6]
2- K1
[Fe(CN)6]3- + H+
NN
.
(Capt) (Capt. Free radical)
[Fe(CN)6]4- +
O
CH3
CH2CHC
HOOC
S[Fe(CN)6]3- +
CH3
CH2CH SHC
O
k1
k2
HOOC
Fe(CN)64- + Capt Complex (12)
(iv)
(v)
(vi)
112 CHAPTER III
k1[Fe(CN)6]3-
[Capt] = k2 [Capt. free radical] [Fe(CN)6]4-
+ k3[Capt. free radical]
The rate law for this mechanism can be derived as follows.
Applying Bodenstein’s steady state principle to free radical gives:
Hence, eqn. (13) becomes
From eqn. (8), eqn. (15) for [Fe(CN)6]3-
can be written as
( k2
[Fe(CN)6]4- )k3+
[HCF]K1 [Capt]k1k3rate =
+ [H+]K1
)+ [H+]( K1 k2
[Fe(CN)6]4- k3+( )
K1 [Capt]k1k3kobs =
At the beginning of reaction [Fe(CN)6]4-
= 0. Therefore, eqn. (17) reduces to
eqn. (18) which is similar to eqn. (10) in which reaction is operating as per
scheme 1.
However, in the presence of [Fe(CN)6]4-
that may be added initially or forms
during the reaction, eqn. (17) will be the rate law for mechanism of scheme 2.
Eqn. (17) also reveals that when k2[Fe(CN)6]4-
is less than k3, scheme 1
Rate = k3 [Capt. Radical]
k1 [Fe(CN)6]3-
k2[Fe(CN)6]4- + k3
[Capt. free radical] =
[Capt] [Fe(CN)6]3-k1k3
k3+k2 [Fe(CN)6]4-
rate =
(13)
(14)
(15)
(16)
(17)
(18)
)+ [H+]
K1 [Capt]k1kobs =
( K1
113 CHAPTER III
operates where there will be a little effect of [Fe(CN)6]4-
on the rate of reaction.
When k2[Fe(CN)6]4-
≥ k3, scheme 2 operates where there will be a measurable
effect of [Fe(CN)6]4-
on retardation of the rate of reaction. This supports the
non linearity of first order plots above 50% of the reaction.
eqn. (17) can be rearranged into eqn. (19) to evaluate the k2 and k3:
K1k1 [Capt]
(K1 + [H+] ) kobs
[Fe(CN)6]4-
k3
1
k2
= +
According, to eqn. (19), the plot of L.H.S versus [Fe(CN)6]4-
should be
linear and found so in Figure III (k), (p. 114). From the slope and intercept of
the plot, the values of k2 and k3 are calculated as 0.52 dm3
mol-1
s-1
and 2.11x
10-4
s-1
, respectively, at 300K. Further, these values along with K1 and k1
obtained in Figure III (j), (p. 110) are used in the rate law (17) at different
experimental conditions as in Table III (e), (p. 103) to regenerate kobs. The
regenerated values are found to be in close agreement with those of the
experimentally observed values. This fortifies the mechanism of scheme 2 and
the rate law (17).
The non- influence of temperature on the rate of reaction may also due
to dominance of the concentration of a less reactive hexacyanoferrate(II) -
substrate complex with temperature. Retardation of rate due to such complex is
counter balanced by an increase in the rate of oxidation of captopril by HCF in
a normal course of reaction.
The activated complex may be highly solvated in higher dielectric
constant media than the lower one. Thus, there should be an increase in rate
(19)
114 CHAPTER III
0.0
2.0
4.0
6.0
8.0
0.0 2.0 4.0 6.0 8.0 10.0
0.85
0.90
0.95
1.00
1.05
1.25 1.35 1.45 1.55 1.65
Figure III (k)
Verification of rate law (17) on oxidation of captopril by hexacyanoferrate(III)
in aqueous acid medium at 300K.
(Conditions as in Table III (e), p. 103).
Figure III (l)
Effect of dielectric constant of the medium on oxidation of captopril by
hexacyanoferrate(III) in aqueous acid medium at 300K.
(Conditions as in Table III (f), p. 104)
[Fe(CN)6]4-
x 104 (mol dm
-3)
K1
k1
[C
apt]
/ (
K1 +
[H
+])
ko
bs
1/D x 102
4 +
log
ko
bs
115 CHAPTER III
with increase in dielectric constant of the medium, supported by a negative
slope in the plot of log kobs versus 1/D (Figure III (l), p. 114).
5. CONCLUSION
A free radical mechanism for oxidation of captopril by HCF in moderately
acidic medium was proposed to give captopril disulfide. Captopril disulfide
was characterized by FT-IR and mass spectra. The reactive form of HCF in
acid medium was proposed to be [Fe(CN)6]3-
. The mechanism proposed in the
present investigation at lower pH is substantially different from that at higher
pH medium already reported. The non- influence of temperature on rate of
reaction is due to involvement of a less reactive hexacyanoferrate(II) - substrate
complex.
116 CHAPTER III
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Recommended