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

6. REFERENCE

[1] Sharanabasamma, K., Angadi, M.A., Salunke, M.S., Tuwar, S. M., Ind.

Eng. Chem. Res., 48, 1038, 2009.

[2] Wiberg, K. B., Maltz, H., Okano, M., Inorg. Chem., 7, 830, 1968.

[3] Kelson, E. P., Phengsy, P. P., Int. J. Chem. Kinet., 32, 760, 2000.

[4] Vovk, A. I., Muraveva, I. V., Kukhar, V. P., Baklan, V. F., Russ. J. Gen.

Chem., 70, 1108, 2000.

[5] Speakman, P. T., Waters, W. A., J. Chem. Soc., 40, 1955.

[6] Jose, T. P., Nandibewoor, S. T., Tuwar, S. M., J. Sol. Chem., 35, 51,

2006.

[7] Singh, V. N., Singh, M. P., Saxena, B. B. L., Indian. J. Chem. 8, 529,

1970.

[8] Leal, J. M., Garcia, B., Domingo, P. L., Coord. Chem. Rev., 173, 79,

1998.

[9] Tuwar, S. M., Nandibewoor, S. T., Raju, J. R., Trans. Met. Chem., 16,

335, 1991.

[10] Jose, T. P., Angadi, M. A., Salunke, M. S., Tuwar, S. M., J. Mol. Struct.,

892, 121, 2008.

[11] Charles W. J. S., Wilkins, R. G., Inorg. Chem., 19, 3244, 1980.

[12] Day, M. C., Selbin, J., Theoretical Inorganic Chemistry, Reinhold

Publishing Corporation, New York, pp.226, 1964.

[13] Martindale, The Extra Pharmacopoeia, 29th

ed., The Pharmaceutical press,

London, pp.468, 1989.

117 CHAPTER III

[14] Ondetti, M. A., Rubin, B., Cushman, D. W., Science, 196, 441, 1977.

[15] Cushman, D. W., Cheung, E. F., Sabo, E. F., Ondetti, M. A.,

Biochemistry, 16, 5484, 1977.

[16] Cushman, D. W., Cheung, E. F., Sabo, E. F., Ondetti, M. A., Prog.

Cardiovasc. Dis., 21, 176, 1978.

[17] Aberg, G., Ferrer, P., J. Cardiovasc. Pharmacol., 15, S65, 1990.

[18] Nora, Y. K., Chew, Hak-Kim Chan., Int. J. Pharma., 209, 87, 2000.

[19] Attoub, S., Gaben, A. M., Al-Salam, S. Ann. N. Y., Acad. Sci. 1138, 65,

2008.

[20] Gree, D. S. S., Hilter, I. H., Morris, G. A., Whalley, L., Magnet. Reson.

Chem., 28, 820, 1990.

[21] Ferguson, R. K., Brunner, H. R., Turini, G. A., Gavras, H., McKinstry, D.

N., Lancet, 775, 1977.

[22] Timmins, P., Jackson, I. M., Wang, Y. J., Int. J. Pharm., 11, 329, 1982.

[23] Rahman, N., Anwar, N., Kashif, M., Hoda, N., Acta. Phar., 56, 347,

2006.

[24] Basavaiah, K., Nagegowda, P., Oxid. Commun., 27, 186, 2004.

[25] Basavaiah, K., Chandrashekhar, U., Swamy, J. M., Charan, V. S.,

Prameela, H. C., Oxid. Commun., 26, 432, 2003.

[26] Basavaiah, K., Chandrashekhar, U., Swamy, J. M., Prameela, H. C.,

Charan, V. S., Nagegowda, P., Bulg. Chem. Commun., 35, 54, 2003.

[27] Jovanovic, T., Stankovic, B., Koricanac, Z., J. Pharm. Biomed. Anal., 13,

213, 1995.

118 CHAPTER III

[28] Khan, A. A. P., Mohd, A., Bano, S., Siddiqi, K. S., Journal of sulfur

Chemistry, 32, 427, 2011.

[29] Jeffery, G. H., Bassett, J., Mendham, J., Denney, R. C., Vogel’s text book

of quantitative chemical analysis, 5th

edn. ELBS Longman, Essex, UK, (a)

pp. 181 (b) pp. 320, 1991.

[30] Garcia, B., Ruiz, R., Leal, J. M., J. Phys. Chem., 112, 4921, 2008.

[31] Friedrich, W.: Vitamins, Walter de Gruyter, Berlin, XII, 1058 S., geb.,

DM 380.00. – ISBN 3-11-010244-7/0-89925-273-7, 1988.

[32] Abe, Y., Dohmaru, T., Horii, H., Tanguchi, S., Can. J. Chem., 63, 1005,

1984.

[33] Leal, J. M., Domingo, P. L., Garcla, B., Ibeas, S., J. Chem. Soc. Faraday

Trans., 89, 3571, 1993.

[34] Rabenstein, D. L., Theriault, Y., Can. J. Chem., 63, 33, 1985.

[35] Chandru, H., Sharada, A. C., E- journal Chem., 4, 216, 2007.