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Article history: This study investigated on kinetics of oxidation of captopril by QDC was studied spectrophotometrically in acidic
Received 23 November 2014 medium along with its mechanistic pathway. Such studies are greatly helpful in gaining an insight into the inter-
Received in revised form 7 December 2014 action of metal ions through the study of the mechanistic pathway of CPL in redox reactions. The oxidative prod-
Accepted 11 December 2014
uct of captopril was found to be captopril disulfide was separated, and identified by FT-IR. A suitable free radical
Available online 23 December 2014
mechanism was proposed. The reaction exhibited first-order kinetics with respect to [oxidant] and fractional
Keywords:
order in CPL. Consequently, the interaction between the complex species and CPL is supported kinetic orders
CPL of reaction by spectrophotometric verification, positive entropy of activation and the first-order rate constant in-
Kinetics creased with the increase in the dielectric constant and increase ionic strength of the medium. The reaction con-
Mechanism stants involved in the mechanism were computed and the overall activation parameters were evaluated which
Polymerization lend support to the proposed mechanism.
Ionic strength © 2014 Elsevier B.V. All rights reserved.
Rate constant
Activation parameters
1. Introduction CPL has three different potential donor groups (Sthiol, Oacid, and
Oamide) which may bind with metal ions to form 1:1 stoichiometric
Captopril-(2S)-3-mercapto-2-methyl propionyl-L-proline (CPL) is a ratio in acidic medium and 1:2 stoichiometric ratio in nearly basic me-
well-known drug applied therapeutically as an antihypertensive agent dium [5].
[1], it is also prescribed for the treatment of congestive heart failure [2]. The sulfhydryl group is also the key functional group in the metabo-
A chemical synthesis of captopril (Fig. 1) has been reported elsewhere lism of CPL. CPL is oxidized after dissolution in water to form its disulfide
[3]. and mixed disulfides with thiol-containing amino acids, peptides, and
It inhibits the active sites of a zinc glycoprotein, the angiotensin proteins [6,7].
converting enzyme (ACE), blocking the conversion of Angiotensin(I) to The chemistry of the reduction of Cr(VI) to Cr(III) with a selec-
Angiotensin(II), the level of which is elevated in patients with hyperten- tion of organic and inorganic reductants be able to occur by a multi-
sions. Captopril exists in solution as an equilibrium mixture of trans and plicity of mechanisms which depend on the nature of the reducing
cis isomers with respect to the conformation across the amide bond [4]. agent [8]. The continuation of different species of Cr (VI) in acid so-
lutions, unstable oxidation states [Cr (IV) and Cr (V)] and the incli-
nation of Cr (III) to form a range of complexes, all merge to provide
systems of significant complexity [9]. Attempts have been done to con-
firm the intermediacy of Cr (IV) and Cr (V) by utilization of competitive
experiments [10,11].
The oxidation capacity completely depends on their redox potential.
The reported reduction potential of the Cr(VI)/Cr(III) couple is 1.33 V
[12]. It is widely known that the redox potential depends upon the pH
dependent. Thus, this potent oxidant is used mainly as an electron
abstracting/proton abstracting agent, or in free radical generation dur-
ing the oxidation of numerous organic compounds. The reagent,
⁎ Corresponding author at: Chemistry Department, King Abdulaziz University, Jeddah
21589, Saudi Arabia. quinolinium dichromate (QDC) is an adaptable oxidant so as to deserve
E-mail address: draapk@gmail.com (A.A.P. Khan). further study, which has been used extensively as a suitable oxidant for
http://dx.doi.org/10.1016/j.molliq.2014.12.017
0167-7322/© 2014 Elsevier B.V. All rights reserved.
2 A.M. Asiri et al. / Journal of Molecular Liquids 203 (2015) 1–6
(Fig. 2). The pseudo-first-order rate constants, kobs, calculated from the
slopes of plots were reproducible within ±4% error.
1/kobs x 10 s
-2
1/kobs x 10 s
4
-2
3.5
3
2.5
2
1 1.5
0 0.5
2.3 1.9 1.5 1.1 0.7 0.3
Fig. 3. Acidic effects observed upon the oxidation of CPL by QDC at room temperature.
-2 3 -1
1/[CPL] x 10 dm mol
under pseudo-first-order conditions of [substrate] N N [QDC] by vary-
ing the concentration of QDC at constant substrate and [H +] at 25 °C Fig. 4. Effects of [H+] and [CPL] on the reaction rate at 25 °C.
3.4. Influence of temperature and ionic strength 3.6. Influence of solvent composition or dielectric constant
The effect of temperature was examined in the range of 15–40 °C. The effect of dielectric constant (D) on the rate was studied by vary-
The reaction was also studied at higher temperatures but it was found ing the composition of the CH3CN–water mixture in the solvent. The
that the complex undergoes degradation. The reaction rate is increased rate increased with increasing proportion of CH3CN–water. Plots of
with increasing temperature that means the reaction followed the Ar- kobs vs. 1/D were linear (Fig. 5) with a positive slope suggesting that
rhenius equation. The reaction rate proceeds at 25 °C. Therefore, room the relatively less polar transition state as compared to the ground
temperature was recommended as the optimum temperature, for the state is stabilized with decreasing solvent polarity [31].
reaction system. The effect of ionic strength (I) on the reaction was
also studied, in 0.01–0.3 mol L − 1 range, using KNO3. Then ionic 4. Influence of acrylonitrile study for the free radicals
strength of the reaction medium 0.05 mol L − 1 was selected for further
study as it provided suitable change in absorbance value. Free radical measurements were performed by monitoring precipi-
tation on reaction mixtures taking CPL, QDC and HClO4 in a round bot-
3.5. Influence of the rate on Cr(III) and added salts tom with screw cap and rubber liner test tube and the acrylonitrile
solution in another test tube. After equilibrated the system, the solu-
The effect of varying concentrations of Cr(III) (which is the reduction tions were mixed and the reaction mixture was kept for 2 h in dark in
product of the oxidant) on the rate was investigated at constant [oxi- an inert N2 atmosphere at room temperature. A white precipitate of
dant], [substrate], and ionic strength. The reaction rate was not affected the CPL product formed clearly indicating the in situ formation of free
by the presence of Cr(III) indicating that it was not involved in a pre- radicals in the reaction was routed. It is also ascertained by the decrease
in rate with initial addition of monomer.
Table 1
Effects of varying concentrations of QDC, CPL, and perchloric acid on the rate in acid solu- 4.1. Stoichiometric studies
tions at 25 °C and at I = 2.50 mol dm−3 (Scheme. 2).
[QDC] × 104 [CPL] × 102 [HClO4] Kexp × 103 kcal × 103 The stoichiometry of the reaction was studied by taking number of
(mol dm−3) (mol dm−3) (mol dm−3) (s−1) (s−1) reaction mixtures containing large excess of QDC over CPL. The reaction
Variation of [QDC] mixtures were allowed to stand in the presence of HClO4 at 25 °C for
2.0 0.8 3.00 4.28 8.14 completion. After completion of the reaction, the concentration of the
4.0 0.8 3.00 6.25 8.14
5.0 0.8 3.00 8.12 8.15
1/D x 103
8.0 0.8 3.00 8.43 8.14
10.0 0.8 3.00 8.56 8.14 22 20 18 16 14 12 10
12.0 0.8 3.00 8.74 8.15 1.8 2
Variation of [CPL] 1.6 1.8
5.0 0.4 3.00 4.40 4.42 1.6
1.4
5.0 0.6 3.00 7.23 7.25 1.4
4+ log kobs
4+ logkobs
tion of the intermediates chromium species like (V), (IV) [32] and
½Q DCt ¼ ½Q DC f þ ½H2CrO4 þ ½Complex
their slowly decompose to (III). The electronic spectrum of Cr(III)- h i 2 h i 2
þ þ
species lies in the range of 320–600 nm. Here QDC in the presence ½Q DCt ¼ ½Q DC f þ K 2 ½Q DC f H þ K 1 K 2 ½CPL f ½Q DC f H
h i 2 f
h i 2 f
of two moles of acid to give species H2CrO4. There have been reports þ þ ð2Þ
½Q DCt ¼ ½Q DC f þ 1 þ K 2 H þ K 1 K 2 ½CPL f H
of the involvement of species in aqueous acid solution chromium f f
(VI) exists in the form of H2CrO4 [33,34]. ½Q DCt
½Q DC f ¼
The stoichiometry of the oxidation of QDC with CPL is found to be 1 þ K 2 ½Hþ f 2 þ K 1 K 2 ½CPL f ½Hþ f 2
2:1. As the acid concentration is increases, the rate of reaction also
increased (Table 1). No effects of initially added Cr(III) and quinoline ½CPLt ¼ ½CPL f þ ½Complex
h i 2
to the reaction mixture of the QDC and the substrate on the rate of the ½CPLt ¼ ½CPL f þ K 1 K 2 ½CPL f ½Q DC f H
þ
reaction was observed and this rules out the presence of the pre-equi- h i 2f
librium before the rate determining step in the mechanism, and the ½CPLt ¼ ½CPL f þ 1 þ K 1 K 2 ½CPL f H
þ ð3Þ
f
oxidant reacts only after protonation of QDC. In Scheme 2, the results
½CPL f
suggest that H2CrO4 combines with a molecule of CPL to form a com- ½CPLt ¼
1 þ K 1 K 2 ½CPL f ½Hþ f 2
plex. Further, which decomposes in the rate determining step to give
an intermediate chromium(IV) species and a free radical generated
½CPLt ¼ ½CPL f ð4Þ
from the substrate as a result of oxidation by H2CrO4 at a slow step.
The free radical formation is detected by the polymerization test h i
h i 22
þ þ
where copious precipitation was observed in the reaction mixture, to H ¼ H þ ½H2CrO4 þ ½Complex
which a known quantity of acrylonitrile has been added initially, was h 2
it
h if2 h i 2 h i 2
þ þ þ þ
H ¼ H þ K 2 ½Q DC f H þ K 1 K 2 ½CPL f ½Q DC f H
kept in an inert atmosphere at room temperature for 4 h. Upon diluting h i2 h i 2
t f f f
þ þ ð5Þ
the reaction mixture with methanol, a white precipitate resulted H ¼ H þ 1K 2 ½Q DC f þ K 1 K 2 ½CPL f ½Q DC f
suggesting that was participation of free radicals in the reaction system. h i 2
t f þ
þ H t2
In the next step another molecule of acid chromate combine with H ¼
f 1 þ K 2 ½Q DC f þ K 1 K 2 ½CPL f ½Q DC f
one molecule of CPL producing another molecule of an intermediate,
chromium(III) and product of CPL. In a further fast step, two mole- h i 2 h i 2
þ þ
cules of free radical generated in Scheme 2 are combining to give H ¼ H ð6Þ
t f
CPL disulfide. Further, it is supported by FTIR spectra that, the disap-
pearance of SH vibration peak at 2565 cm− 1 and appearance of new þ 2
−d½Q DC kK 1 K 2 ½CPL½Q DC H
peak at 620 cm− 1 for S\S stretching, clearly indicates the formation Rate ¼ ¼ ð7Þ
dt 1 þ K 2 ½Hþ 2 þ K 1 K 2 ½CPL½Hþ 2
of disulfide.
The rate law is in agreement with the observed experimental results 2
showed a first order with respect to each concentration of acidity, oxi- Rate kK 1 K 2 ½CPL Hþ
¼ K obs ¼ ð8Þ
dant and substrate. ½Q DCt 1 þ K 2 ½Hþ 2 þ K 1 K 2 ½CPL f ½Hþ 2
1 1 1 1 conditions and compared with experimental kobs values. They are found
¼ þ þ : ð9Þ
K obs kK 1 K 2 ½CPL½Hþ 2 K 1 K 2 ½CPL k to be in reasonably agreeing with each other which fortifies the mecha-
nism as in Scheme 2. The thermodynamic quantities for the first and
second equilibrium steps of Scheme 2 can be evaluated.
(i) From the plot of 1/kobs versus 1/[CPL] The reactions were studied at different temperatures to obtain vari-
(Intercept)1 = 1/k ous values of activation parameters (Table 2). From the Arrhenius plots
Therefore, k = 1/(Intercept)1 = 2.123 × 10−2 s−1 of log k versus 1/T, activation energy, and other thermodynamic
(Slope)1 = 1/kK1K2[H+]2 + 1/k.
(ii) From the plot of 1/kobs versus 1/[H+]2 Table 2
Effect of temperature on the reaction rate for the oxidation of CPL by QDC in acid solutions
(Intercept)2 = 98.21 = 1/kK1K2[CPL] + 1/k.
[CPL]0 = 4.00 × 10−3 M, [QDC] = 5.00 × 10−4 M, and [H+] = 3.00 M.
From (Intercept)1, the value of k = 2.123 × 10−2 s−1.
Temperature (K) k × 102 (s−1) log k 1/T × 103
Hence,
(a) Effect of temperature with respect to slow step of Scheme 1
98.21 = 1/2.123 × 10−2 × K2 × 4.0 10−3 + 1/1.328 × 10−2
293 7.42 0.870 3.413
1 + K2(4.0 × 10−3) = 98.21 × 2.123 × 10−2 K2 × 4.0 × 10−3 298 8.34 0.921 3.356
1 + .004 K2 = .008399932 K2 303 10.12 1.005 3.300
308 12.22 1.087 3.246
1 = .008399932 K2 − 004 K2
1 = K2(.008399932 − .004) Parameters Values
1 = K2(.004399932)
(b) Activation parameters
K2 = 230.41 dm3 mol−1
Ea (kJ mol−1) 68.5
(Slope)2 = 608.5 = 1/kK1K2[CPL] ΔH± (kJ mol−1) 45.8
608.5 = 1/2.123 × 10−2 × 230.41 dm3 mol−1 × 4.0 · 10−3 × K1 ΔS±(J K−1 mol−1) −76.4
K1 = 8.34 × 10−2 dm6 mol−2 ΔG± (kJ mol−1) 52.5
At 25 °C: (c) Temp. (K) K1 × 102 dm6 mol−2 K2 × 10−2 dm3 mol−1
K1 = 8.34 × 10− dm6 mol−2
293 5.52 1.52
K2 = 230.41 dm3 mol−1 298 6.34 2.10
k = 2.123 × 10−2 s−1. 303 7.22 1.18
308 8.34 2.30
parameters for the oxidation of CPL by QDC have been calculated. The [2] N.E. Enany, F. Belal, M. Rizk, Int. J. Biomed. Sci. 2 (2008) 4.
[3] M. Shimazaki, J. Hasegawa, K. Kan, K. Nomura, Y. Nose, H. Kondo, T. Ohashi, K.
values of negative ΔS# and positive ΔH# suggest the formation of Watanabe, Chem. Pharm. Bull. 30 (1982) 3139.
more ordered activated complexes and the transition state is highly sol- [4] D.L. Rabenstein, A.A. Isab, Anal. Chem. 54 (1982) 526.
vated [35]. [5] M.A. Hughes, G.L. Smith, D.R. Williams, Inorg. Chim. Acta 107 (1985) 247.
[6] O.H. Drummer, P.J. Worland, B. Jarrott, Biochem. Pharmacol. 32 (1983) 1563.
A comparison of these values with those obtained for the slow step [7] I.H.K. Yeung, A.M. Breekenridge, B.M. Park, Biochem. Pharmacol. 32 (1983) 2467.
of the reaction shows that they mainly refer to the rate-limiting step, [8] M. Mitewa, P.R. Bontchev, Coord. Chem. Rev. 61 (1985) 241.
supporting the fact that the reaction before the rate determining step [9] J.K. Beattie, G.P. Haight Jr., Prog. Inorg. Chem. 17 (1972) 93.
[10] K.B. Wiberg, W.H. Richardson, J. Am. Chem. Soc. 84 (1962) 2800.
is fairly fast and the value of energy of activation shows that the reaction [11] G.P. Haight Jr., T.J. Huang, B.Z. Shakhashiri, J. Inorg. Nucl. Chem. 33 (1971) 2169.
is slow and enthalpy is controlled [36]. An increase in the volume of [12] J.F. Perez-Benito, C. Arias, Can. J. Chem. 71 (1993) 649.
acetic acid leads to an increase in the reaction rate. A plot of logkobs ver- [13] S.A. Chimatadar, T. Basavaraj, S.T. Nandibewoor, Polyhedron 25 (2006) 2976.
[14] S. Meenakshisundaram, M. Amutha, Bull. Pol. Acad. Sci. Chem. 49 (2001) 165.
sus 1/D was linear with positive slope which is contrary to the conven-
[15] S. Kabilan, R. Girija, R.J.C. Reis, A.P.M. Seguradom, J. Chem. Soc. Perkin Trans. 6
tion. Perhaps the effect is countered substantially by the formation of (2002) 1151.
active species to a greater extent in a low dielectric constant medium [16] S. Das, G.S. Chaubey, M.K. Mahanti, Kinet. Catal. 43 (2002) 794.
leading to the net increase in the rate [37]. The observed modest enthal- [17] G.S. Chaubey, S. Das, M.K. Mahanti, Can. J. Chem./Rev. Can. Chim. 81 (2003) 204.
[18] G.S. Chaubey, S. Das, M.K. Mahanti, Bull. Chem. Soc. Jpn. 75 (2002) 2215.
py of activation and a higher rate constant for the slow step indicate that [19] A.S. Chimatadar, S.B. Koujalagi, S.T. Nandibewoor, Trans. Met. Chem. 27 (2002) 704.
the oxidation presumably occurs via an inner-sphere mechanism. This [20] A.A.P. Khan, A. Mohd, S. Bano, K.S. Siddiqi, Ind. Eng. Chem. Res. 17 (2011) 9883.
conclusion is supported by observations made earlier. [21] N. Rahman, N. Anwar, M. Kashif, N. Hoda, Acta Pharma. 56 (2006) 347.
[22] K. Basavaiah, P. Nagegowda, Oxid. Commun. 27 (2004) 186.
[23] K. Basavaiah, U. Chandrashekhar, J.M. Swamy, V.S. Charan, H.C. Prameela, Oxid.
5. Conclusion Commun. 26 (2003) 432.
[24] K. Basavaiah, U. Chandrashekhar, J.M. Swamy, H.C. Prameela, V.S. Charan, P.
Nagegowda, 35 (2003) 54.
In summary, the oxidation of captopril by QDC was found to proceed [25] K. Siddiqi, S. Bano, A. Mohd, A.A.P. Khan, Chin. J. Chem. 27 (2009) 1755.
by the formation of free radical generated from captopril followed by [26] A.A.P. Khan, A. Mohd, S. Bano, K.S. Siddiqi, J. Sulfur Chem. 32 (2011) 427.
dimerization of the free radicals. The product of captopril was found [27] G.P. Kapungu, G. Rukweza, T. Tran, W. Mbiya, R. Adigun, P. Ndungu, B. Martincigh,
R.H. Simoyi, J. Phys. Chem. A 117 (2013) 2704.
to be captopril disulfide which was characterized by TLC and FT-IR. [28] S. Badi, S.M. Tuwar, J. Solution Chem. 42 (2013) 1518.
The rate constant of slow step and other equilibrium constants involved [29] K. Balasubramanian, V. Prathiba, Indian J. Chem. 25B (1986) 326.
in the mechanism are evaluated and activation parameters with respect [30] P. Timmins, I.M. Jackson, Y.I. Wang, Int. J. Pharm. 11 (1982) 329.
[31] E.S. Amis, Solvent Effects on Reaction Rates and Mechanisms, Academic Press, New
to slow step of reaction were computed. The overall mechanistic
York, 1966.
sequence described here, is consistent with the products formed. [32] J.Y. Tong, E.L. King, J. Am. Chem. Soc. 75 (1953) 6180.
[33] V. Daier, S. Siganorella, M. Rizzotto, M.I. Frascaroli, C. Palopolic, C. Broudino, J.M.
Acknowledgments Salas-peregrin, L.F. Sala, Can. J. Chem. 77 (1999) 57.
[34] M. Rahaman, J. Rocek, J. Am. Chem. Soc. 93 (1971) 5462.
[35] A.A.P. Khan, A.M. Asiri, N. Azum, M.A. Rub, A. Khan, A.O. Al-Youbi, Ind. Eng. Chem.
This paper was funded by the Deanship of Scientific Research (DSR), Res. 51 (2012) 4819.
King Abdulaziz University, under grant No. (D-004/431). The authors, [36] A.A.P. Khan, A. Khan, A.M. Asiri, M.A. Rub, J. Taiwan Inst. Chem. Eng. 1 (2014) 127.
[37] A.A.P. Khan, A.M. Asiri, A. Khan, N. Azum, M.A. Rub, M.M. Rahman, S.B. Khan, K.S.
therefore, acknowledge technical and financial support of KAU. Siddiqi, K.A. Alamry, J. Ind. Eng. Chem. 19 (2013) 595.
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