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Spectroscopic and kinetic studies on the interaction of ketoconazole and povidone drugs with DDQ
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Spectrochimica Acta Part A 69 (2008) 1082–1088
Spectroscopic and kinetic studies on the interaction of ketoconazole and povidone drugs with DDQ M. Pandeeswaran, K.P. Elango ∗ Department of Chemistry, Gandhigram Rural University, Gandhigram 624302, India Received 28 March 2007; received in revised form 6 June 2007; accepted 8 June 2007
Abstract The kinetics and mechanism of the interaction between 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and ketoconazole and povidone drugs has been investigated spectroscopically. In the presence of large excess of donor, the 1:1 CT complex is transformed into a final product, which has been isolated and characterized by FT-IR and GC–MS techniques. The rate of formation of product has been measured as a function of time in different solvents at three temperatures. The thermodynamic parameters, viz. activation energy, enthalpy, entropy and free energy of activation were computed from temperature dependence of rate constants. Based on the spectro-kinetic results a plausible mechanism for the formation of the complex and its transformation into final product is presented and discussed. © 2007 Published by Elsevier B.V. Keywords: Charge transfer; Drugs; DDQ; Kinetics
1. Introduction
2. Experimental
Review of the literature reveals that a fairly extensive study has been carried out on the possible role of charge-transfer (CT) and inner () complexes as reaction intermediates in the reaction of organic and inorganic molecules with electron acceptors, particularly quinones [1–10]. However, to the best of our knowledge, such systematic kinetic studies involving drug molecules is seldom in the literature. Quinones are one of the well-known electron acceptors [11–16] that give rise to spectacular chargetransfer complexes with variety of donors. The study of quinones for their CT-interactions stems from their possible role in biological reactions. Quinones are known to be important in many biological fields [17]. Thus, the mechanism of interaction of quinones with drugs, in general, is a research topic of significant interest and hence the present study. The primary objective, therefore, of the present article is to study the kinetics and mechanism of the interaction between the electron acceptor 2,3dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and two drugs, viz. ketoconazole and povidone.
The electron acceptor 2,3-dichloro-5,6-dicyano-1,4benzoquinone (DDQ) (Aldrich, India) was recrystallized from dry methylene chloride. Spectroscopy grade solvents (Merck, India) were used without further purification. The selection of the solvents is based on the solubility of the components and so as to have a wide range of (ca. 30 units) relative permittivity. The electron donor drugs ketoconazole (antifungal) and povidone (hypoalbuminemia) were obtained as gift samples from locally available pharmaceutical company and were used as received. The structures of the donor drugs are shown below.
∗
Corresponding author. E-mail address: [email protected] (K.P. Elango).
1386-1425/$ – see front matter © 2007 Published by Elsevier B.V. doi:10.1016/j.saa.2007.06.007
Solutions for the spectroscopic measurements were prepared by dissolving accurately weighed amounts of donor (D) and acceptor (A) in the appropriate volume of solvent immediately before running the spectra. The electronic absorption spectra
M. Pandeeswaran, K.P. Elango / Spectrochimica Acta Part A 69 (2008) 1082–1088
are recorded on a Shimadzu (UV 240, Graphicord) double beam spectrophotometer using 1 cm matched quartz cells. The temperature of the cell holder was controlled with a water flow. FT-IR spectra were recorded in a JASCO FT-IR 460 Plus spectrometer. The GC–MS spectra of the reaction product were obtained from CSIR Lab, Bhavanagar, India. The molecular orbital package, MOPAC 2000 version 1.11 (PM3 method) was used for the theoretical calculation of the ionization potential of the donor drugs [18]. The conductance of the solutions was measured on an Elico, India Conductivity Bridge. Equimolar stock solutions of D and A were thermostated to a constant temperature and were mixed in the conductivity cell by varying the mole fraction of A. The solutions were stirred after each addition and a constant time interval was permitted to record the conductance. The reaction kinetics for the formation of final product was followed at three different temperatures (298–313 K) in various solvents, keeping [D] [A]. The increase in absorbance of the reaction product at 298–350 nm (depending on the donor and solvents) was followed as a function of time. The pseudofirst-order rate constants (k) were calculated from the gradients of log (A∞ − At ) against time plots, where A∞ and At represent the absorbances at infinity and time t, respectively. The second-order rate constants were calculated by dividing k by [drug].
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The increase in conductivity observed upon CT complex formation is explained by the possibility that the CT complex formed between D and A may undergo dissociation into ionic intermediate in solvents of sufficiently high relative permittivity giving rise to appreciable conductivity according to the following general scheme [19]: D + A DA +
−
DA [D A ]
(1) (2)
The value of the conductivity above a base line connecting the conductivities of pure D and A solutions is a measure of the excess conductivity caused by the formation and subsequent ionization of the CT complex. As has been suggested, the inner complex thus formed may then act as an intermediate in the formation of final product [20]. 3.2. Electronic spectral studies
In the present study the resulting drug–DDQ solutions in tertbutyl alcohol exhibit appreciable conductivities which may be due to the formation of CT complex. In both the cases studied, the conductivity–mole fraction plots yielded a maximum at an drug:DDQ molar ratio of 1:1 as evidenced from Fig. 1.
In order to obtain information about the kinetics and mechanism of the interaction of DDQ with the drugs, the electronic spectra of the DDQ (1.32 × 10−4 M) in the presence of a large excess of the donors (i.e. [drug]/[DDQ] > 200) were obtained as a function of time in different solvents. Representative spectra are given in Figs. 2 and 3. Other systems studied show a similar spectral behavior with time. As seen, either the drugs or DDQ show any considerable absorption in the 400–600 nm range, addition of the drugs to the DDQ solution results in some absorption bands in this spectral region, presumably due to the formation of a charge-transfer complex which causes the appearance of a deep red colour in solution. Obviously, the spectra recorded for the CT complex between the drugs and DDQ are time dependent. With increase in time the deep colour solution begins to disappear and the intensity of the absorption bands in the 400–600 nm region decreases whereas the intensity of the
Fig. 1. Conductivity vs. mole fraction of DDQ plots. for the drugs–DDQ systems in tert-butyl alcohol.
Fig. 2. Absorption spectra of ketoconazole with DDQ in tert-butyl alcohol at 298 K; [donor] = 5.010 × 10−3 M and [DDQ] = 6.934 × 10−5 M.
3. Results and discussion 3.1. Conductivity studies
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sity on the carbonyl and cyano groups of the substituted DDQ molecule. In both the cases product analysis was carried out by employing GC–MS technique. The mass spectrum of the product of povidone–DDQ system displayed molecular ion peaks at m/z (%) at 301 (100), 217 (24) and 70 (15) suggesting the molecular weight of the assigned product. The following fragments observed in the mass spectrum of the compound confirm the structure of the reaction product.
Fig. 3. Absorption spectra of povidone with DDQ in acetonitrile at 298 K; [donor] = 3.95 × 10−2 M and [DDQ] = 1.322 × 10−4 M.
298–350 nm (depending on solvent) continues to increase until the end of the reaction. The absorption spectra of the povidone–DDQ system studied reveals that the spectra are characterized by maximum absorptions at the wavelengths 588, 542, 458 and 348 nm. Such spectral features are in agreement with those reported for the DDQ•− radical ion [21]. Similar spectral features were observed for the other system also [10,22]. The observed enhanced absorption band intensities, immediately after mixing D and A, supports the fact that the CT complex formed is of the dative-type structure which consequently converts to an ionic intermediate possessing the spectral characteristics of radical ion. However, the observed gradual decrease in the intensity of the CT bands in the 400–600 nm spectral regions could be due to the consumption of the ionic intermediate through an irreversible chemical reaction, while the continuous increase of the 298–350 nm bands with elapse of time is indicative of the formation of the final reaction product. Further, in the case of ketoconazole–DDQ system, a shoulder appearing around 380 nm in the spectrum of the mixture of DDQ and drugs reveals that the quinone chromophore is probably not disturbed by the reaction of DDQ with the drugs [10]. 3.3. Characterization of the reaction product The reaction product was obtained by allowing the reactants to react for 24 h under kinetic conditions and subjected to MPLC (Buchi, Switzerland) separation. In FT-IR studies, the (C O) and (C N) stretching vibrations in the DDQ species appeared at 1678 and 2226 cm−1 , respectively [23]. In the FTIR spectra of the isolated reaction products the two stretching vibrations occurred at 1645 and 2068 cm−1 (for ketoconazole) and 1662 and 2209 cm−1 (for povidone), respectively. Such a bathochromic shift could be indicative of a higher charge den-
However, due to the large size of the ketoconazole molecule the mass spectrum of the reaction product of this compound is very much complicated as a result of large number of fragments and hence no attempt was made to study it. 3.4. Characteristics of the CT complex The absorbance of the new low energy band were measured using constant acceptor concentration (in a given solvent) and varying concentrations of a donor depending on the solvent, but always [D] [A]. The formation constants (K) and molar extinction coefficients (ε) of the CT-complexes were determined spectrophotometrically in the temperature range 298–313 K using the Scott equation [24]: [D][A] [D] 1 = + d ε Kε
(3)
where [D] and [A] are the initial molar concentration of the donor and acceptor, respectively and d is the absorbance. The values of K and ε are determined from the gradient and intercept of the linear plot of [D][A]/d against [D]. A representative plot is shown in Fig. 4. The results (Table 1) reveal that the observed high value of K suggests that the formed CT-complexes are of a strong type [25]. The stoichiometry of the CT-complexes of the electron donors with the acceptor was determined by applying Job’s method of continuous variation [26] which provides symmetrical curves with maxima at a mole fraction of 0.5, in both the cases, confirming a 1:1 stoichiometric ratio (figure not shown). The linearity of the plots of the Scott equation further supports this result. The values of oscillator strength (f) which is a measure of integrated intensity of the CT-band and transition dipole moment (μ), were calculated by using the approximate equations [27] given in Eqs. (4) and (5), where εmax is the molar extinction coefficient of the CT-complex at the wavelength of maximum
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Table 2 Effect of concentration of D and A on the rate of product formation [D] (×102 M)
[A] (×104 M)
k1 (×104 s−1 )
k2 (×102 )
Ketoconazole–DDQ 0.65 0.82 0.98 1.14 1.14 1.14 1.14 1.14
1.06 1.06 1.06 1.06 0.61 0.76 0.91 1.06
2.81 3.50 4.25 4.94 4.89 4.91 4.87 4.94
4.32 4.27 4.33 4.33
Povidone–DDQ 2.62 2.83 3.39 3.96 3.96 3.96 3.96 3.96
1.32 1.32 1.32 1.32 0.76 0.94 1.13 1.32
1.59 2.06 2.70 3.09 3.05 3.14 2.96 3.09
0.61 0.72 0.79 0.78
Fig. 4. Scott linear plot for ketoconazole and povidone with DDQ at 298 K.
absorption and ν1/2 is the half band-width in wave number units. The values of f and μ thus obtained are given in Table 1: f = 4.32 × 10−9 [εmax ν1/2 ] εmax ν1/2 1/2 μ = 0.0958 ν¯ max
(4) (5)
The values of f are rather relatively large indicating a strong interaction between the donor–acceptor pairs with relative high probabilities of CT-transitions [25]. Out of the many applications of CT-complexes, one important application is to calculate the ionization potential of the donor. The ionization potential (Ip ) of the highest filled molecular orbital of the donor was estimated from CT energies of its complexes with the acceptor making use of the empirical equations reported in the literature [28]. The calculated Ip values for molecular orbital participating in CT-interaction of the drugs are listed in Table 1. In the present study, the theoretical (MOPAC PM3 method) and experimental ionization potential values are in good agreement with each other. This fact supports the interpretation that the low energy band can be regarded as the CT band.
Further evidence for the nature of CT-interaction in the present systems is the calculation of the dissociation energy (W) of the charge-transfer excited state of the complex. Hence, the dissociation energies of the complex were calculated from their CT-energy, hνCT , the ionization potential of the donor, Ip and electron affinity, EA , of the acceptor using the empirical relation [29] given in the following equation: hνCT = Ip − EA − W
(6)
The calculated values of W (Table 1) suggest that the investigated complex is reasonably strong and stable under the studied conditions with higher resonance stabilization energy [25]. 3.5. Kinetic results The pseudo-first-order rate constants for the formation of the product are independent of initial concentrations of DDQ (Table 2) indicating first-order dependence in [DDQ]. The plot of log k versus log [drug] is linear with a slope of unity, in both the cases (for ketoconazole, r 0.999; slope 1.01 ± 0.02 and for povidone, r 0.997; slope 1.21 ± 0.07) indicating unit order dependence in [drug]. The experimental rate law for the
Table 1 Spectral properties of the CT complex formed between the drugs and DDQ in acetonitrile solvent at 298 K Property
Ketoconazole
Povidone
λmax (nm) hνCT (eV) νmax (×1014 s−1 ) Formation constant, K (dm3 mol−1 ) Extinction coefficient, ε (dm3 mol−1 cm−1 ) Oscillator strength, f Dipole moment, μ Ionization potential (eV) Dissociation energy (eV)
585 2.12 5.13 143.7 2261 0.014 1.33 8.36 (8.38)a 4.33
588 2.11 5.10 67.4 2986 0.020 1.68 8.35 (9.00)a 4.33
a
Calculated by MOPAC (PM3) method.
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Table 3 Kinetic and thermodynamic data on the reaction of DDQ with ketoconazole Solvent
Chloroform4.90 Chlorobenzene Dichloromethane 1,2-Dichloroethane Tert-butyl alcohol Iso-propyl alcohol DMF
λ (nm)
εr
374 5.62 8.93 10.36 12.47 17.93 36.71
1.02 372 378 384 360 360 435
k (×104 s−1 ) 298 K
305 K
31 K
1.18 0.67 2.85 4.94 7.01 11.27 52.97
1.69 1.00 3.92 8.64 9.09 15.04 88.84
23.7 1.81 4.49 10.42 10.60 19.47 149.69
H# (kJ mol−1 )
−S# (J K−1 mol−1 )
G# (kJ mol−1 )
Ea (kJ mol−1 )
ka (×104 s−1 )
242 48.6 20.8 35.8 18.8 20.7 41.2
95.8 162 243 188 242 233 153
26.2 96.9 93.2 91.8 90.9 90.1 86.8
0.98 51.1 23.4 38.3 21.3 28.2 53.7
0.57 2.28 4.91 6.88 10.92 48.23
εr : relative permittivity of the medium. a λ 585 nm and 298 K.
formation of the product may be given as d[product] = k[DDQ][drug] dt The pseudo-first-order rate constants, k, were evaluated by employing the increase in absorbance of 290–350 nm band at different temperatures and solvents. The results are shown in Tables 3 and 4. The rates are sensitive to solvent, k values, in both the drugs, increases with an increase in relative permittivity of the medium. This solvent dependence of k values suggests that there may be some charge separation in the transformation of CT complex to the final product. Formation of such a more polar transition state is well supported by the large negative entropies of activation, S◦ . Further, in both the cases, there exist a linear correlation (Fig. 5, r > 0.96) between H◦ and S◦ indicating the operation of a common mechanism in all the solvents studied. Attempts have also been made to evaluate the rate constants for the disappearance of the CT complex by employing the decrease in absorbance of the low energy CT band. However, it is not possible to do so especially at high temperatures and in the solvents with higher relative permittivity. This may be due to the fact that under such conditions the rate of conversion of the CT complex to -complex and consequently the formation of the final product may be very high. This observation is parallel to the results of the dependence of k on the solvent and temperature and also with the electronic spectral data as described earlier in this section. The estimated rate constants for the disappearance
Fig. 5. Relation between enthalpy and entropy of activation for the interaction of drugs with DDQ.
of the CT complex are also collected in Tables 3 and 4. The results indicate that the rate of disappearance of the CT complex is slightly slower than that of the formation of the product suggesting that this conversion involves an intermediate stage and this may be the ionic intermediate suggested in spectral and conductance studies.
Table 4 Kinetic and thermodynamic data on the reaction of DDQ with povidone Solvent
Chloroform Dichloromethane 1,2-Dichloroethane Tert-butyl alcohol Iso-propyl alcohol Acetonitrile
εr
4.90 8.93 10.36 12.47 17.93 37.50
λnm
350 303 350 298 297 348
εr : relative permittivity of the medium. a Decrease in absorbance. b At 298 K.
k (×104 s−1 ) 298 K
305 K
313 K
0.75 1.90 1.56 2.07 2.60 5.39
0.95 2.53 3.05 3.33 4.33 7.10
1.15 3.07 3.96 4.27 5.53 8.50
H# (kJ mol−1 )
−S# (J K−1 mol−1 )
G# (kJ mol−1 )
Ea (kJ mol−1 )
a (nm)
kb (×104 s−1 )
19.5 22.1 45.3 34.7 36.3 20.9
258 242 165 199 192 237
96.4 94.3 94.5 94.0 93.5 91.6
22.1 24.7 47.8 37.2 38.8 23.5
460 588 460 462 462 460
0.72 1.72 1.01 2.01 2.41 5.02
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3.6. Solvent effect
3.7. Mechanism
It seems reasonable to assume that anion radicals are formed from electron donor–acceptor interaction via a CT complex, as depicted in Eqs. (1) and (2). Increase in polarity of the solvent would tend to stabilize the radical ion state, with respect to other states of the system, due to ion–solvent interaction. It is possible that the solvent interaction could also influence the first step (Eq. (1)), perhaps accompanied by an alteration of charge in the complex. Hereto, increase in polarity of the solvent could enhance the contribution of dative state and hence lead to a stronger charge transfer [29]. Results in Tables 3 and 4 indicate that the rate of product formation increase with increase in relative permittivity of the medium. A plot of log k versus εr is linear with positive slope (Fig. 6). It is evident from the figure that, there is deviation from linearity especially at higher relative permittivity values. This may be due to the fact that with increase in polarity of the medium solvent–solvent interaction becomes increasingly significant in addition to solute–solvent interactions. Thus, the satisfactory correlation, with correlation coefficient around 0.92, in all likelihood may be as a result of specific solute–solvent–solvent interactions. In the case of ketoconazole–DDQ interaction, the solvent change from chloroform to DMF causes 50-fold rate acceleration for the reaction which corresponds to a decrease in G◦ of nearly10 kJ mol−1 . Parallel to this observation, in the case of povidone–DDQ system, there is sevenfold increase in rate from chloroform to acetonitrile corresponds to 5 kJ mol−1 decrease in G◦ . This is due to the fact increase in relative permittivity of the medium would assist the formation of dative state (Eq. (1)) and as a result the formation of radical anion (Eq. (2)) and consequently enhances the rate of the reaction. This is well supported by the results of spectroscopic, spectrokinetic and thermodynamic studies explained earlier in this section.
Substitution on the quinone ring by drugs is certainly possible particularly when the aromatic ring contains activating electron withdrawing chlorine atoms. Based on the characteristics of the CT complex and foregoing spectro-kinetic results the mechanism of the interaction between DDQ and the drugs can be represented as K1
DDQ + drugCT complex (fast), K2
CT complexinner complex (fast), k
inner complexproduct
(slow)
The above mechanism leads to the following rate law. d[product] = k [inner complex] dt d[product] or = k[DDQ][drug] dt where k = k K1 K2 . The above rate law is in agreement with the observed kinetic results, i.e. the rate of formation of the product is first each with respect to DDQ and the drug. In general in such donor–acceptor interactions whether or not the various intermediates proposed are seen in the electronic absorption spectra depend on the experimental conditions like temperature and especially the kind of solvents used. 4. Conclusions Spectro-kinetic studies reveal that the interaction of 2,3dichloro-5,6-dicyano-1,4-benzoquinone and ketoconazole and povidone drugs was found to be proceed through three steps, out of these, the formation of outer complex and its conversion to inner complex are extremely fast, whereas the formation of the final product is the rate determining slow step. The 1:1 CT complex formed was characterized spectroscopically. The pseudo-first-order rate constants for the formation of the product increase with increase in relative permittivity of the medium. The activation parameters support the proposed mechanism. The mechanism of the interaction of these drugs studied may be useful in understanding the binding of drug molecule in real pharmacokinetic study. References
Fig. 6. Plot of log k vs. relative permittivity of the medium.
[1] T. Nogami, K. Yoshihara, H. Hosoya, S. Nagakura, J. Phys. Chem. 73 (1969) 2670. [2] W.J. Lautenberger, J.G. Miller, J. Phys. Chem. 74 (1970) 2722. [3] P.C. Dwivedi, A.K. Banga, J. Phys. Chem. 85 (1981) 1768. [4] U. Muralikrishna, Y.V.S.K. Seshasayi, M. Krishnamurthy, React. Kinet. Catal. Lett. 24 (1984) 193. [5] M. Krishnamurthy, K. Surendrababu, U. Muralikrishna, Indian J. Chem. A 27 (1988) 669. [6] A.A. Hassan, N.K. Mohamed, E.H. El-Tamany, B.A. Ali, A.E. Mourad, Monatshefte fur Chemie 126 (1995) 653.
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[7] N.S. Nudelman, M. Savini, C.E.S. Alvaro, V. Nicotra, J. Yankelevich, J. Chem. Soc., Perkin Trans. 2 (1999) 1627. [8] T. Roy, K. Datta, M.K. Nayek, A.K. Mukherjee, M. Banerjee, B.K. Seal, J. Chem. Soc., Perkin Trans. 2 (1999) 2219. [9] D.A. Durfey, R.U. Kirss, C. Frommen, W.M. Reiff, Inorg. Chim. Acta 357 (2004) 311. [10] M. Hasani, M. Shamsipur, Spectrochim. Acta A 61 (2005) 815. [11] R. Foster, Organic Charge Transfer Complexes, Academic Press, London, 1969. [12] M. Arslan, H. Duymus, Spectrochim. Acta A 67 (2007) 573. [13] H. Duymus, M. Arslan, M. Kucukaslamoglu, M. Zengin, Spectrochim. Acta A 65 (2006) 1120. [14] H.M.A. Salman, M.M. Abu-Krisha, H.S. El-Sheshtawy, Can. J. Anal. Sci. Spect. 49 (2004) 282. [15] M.S. Refat, A.M. El-Didamony, Spectrochim. Acta 65A (2006) 732. [16] G.G. Mohamed, F.A.N. El-Dien, E.U. Farag, Spectrochim. Acta A 65 (2006) 11.
[17] A.M. Slifkin, Charge Transfer Interactions of Biomolecules, Academic Press, New York, 1971. [18] J.J.P. Stewart, J. Comput. Chem. 10 (1989) 209. [19] P.C. Dwivedi, A.K. Banga, A. Gupta, Electrochim. Acta 28 (1983) 801. [20] G. Neelgund, M.L. Budni, Spectrochim. Acta A 61 (2005) 1729. [21] J.S. Miller, J.P. Krusic, D.A. Dixon, M.W. Reiff, H.J. Zhang, C.E. Anderson, J.A. Epstein, J. Am. Chem. Soc. 108 (1986) 4459. [22] M. Hasani, M. Shamsipur, J. Chem. Soc., Perkin Trans. 2 (1998) 1277. [23] Y. Fu, G. Fu, A.B.P. Lever, Inorg. Chem. 33 (1994) 1038. [24] R.L. Scott, Recl. Trav. Chim. Pays-Bas Belg. 75 (1956) 787. [25] M. Pandeeswaran, K.P. Elango, Spectrochim. Acta A 65 (2006) 1148. [26] P. Job, Ann. Chim. Phys. 9 (1928) 113. [27] R. Rathone, S.V. Lindeman, J.K. Kochi, J. Am. Chem. Soc. 119 (1997) 9393. [28] G.G. Aloisi, Pignataro, J. Chem. Soc., Faraday Trans. 69 (1973) 534. [29] I. Isenberg, S.L. Baird Jr., J. Am. Chem. Soc. 84 (1962) 3803.
Spectrochimica Acta Part A 69 (2008) 1082–1088
Spectroscopic and kinetic studies on the interaction of ketoconazole and povidone drugs with DDQ M. Pandeeswaran, K.P. Elango ∗ Department of Chemistry, Gandhigram Rural University, Gandhigram 624302, India Received 28 March 2007; received in revised form 6 June 2007; accepted 8 June 2007
Abstract The kinetics and mechanism of the interaction between 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and ketoconazole and povidone drugs has been investigated spectroscopically. In the presence of large excess of donor, the 1:1 CT complex is transformed into a final product, which has been isolated and characterized by FT-IR and GC–MS techniques. The rate of formation of product has been measured as a function of time in different solvents at three temperatures. The thermodynamic parameters, viz. activation energy, enthalpy, entropy and free energy of activation were computed from temperature dependence of rate constants. Based on the spectro-kinetic results a plausible mechanism for the formation of the complex and its transformation into final product is presented and discussed. © 2007 Published by Elsevier B.V. Keywords: Charge transfer; Drugs; DDQ; Kinetics
1. Introduction
2. Experimental
Review of the literature reveals that a fairly extensive study has been carried out on the possible role of charge-transfer (CT) and inner () complexes as reaction intermediates in the reaction of organic and inorganic molecules with electron acceptors, particularly quinones [1–10]. However, to the best of our knowledge, such systematic kinetic studies involving drug molecules is seldom in the literature. Quinones are one of the well-known electron acceptors [11–16] that give rise to spectacular chargetransfer complexes with variety of donors. The study of quinones for their CT-interactions stems from their possible role in biological reactions. Quinones are known to be important in many biological fields [17]. Thus, the mechanism of interaction of quinones with drugs, in general, is a research topic of significant interest and hence the present study. The primary objective, therefore, of the present article is to study the kinetics and mechanism of the interaction between the electron acceptor 2,3dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and two drugs, viz. ketoconazole and povidone.
The electron acceptor 2,3-dichloro-5,6-dicyano-1,4benzoquinone (DDQ) (Aldrich, India) was recrystallized from dry methylene chloride. Spectroscopy grade solvents (Merck, India) were used without further purification. The selection of the solvents is based on the solubility of the components and so as to have a wide range of (ca. 30 units) relative permittivity. The electron donor drugs ketoconazole (antifungal) and povidone (hypoalbuminemia) were obtained as gift samples from locally available pharmaceutical company and were used as received. The structures of the donor drugs are shown below.
∗
Corresponding author. E-mail address: [email protected] (K.P. Elango).
1386-1425/$ – see front matter © 2007 Published by Elsevier B.V. doi:10.1016/j.saa.2007.06.007
Solutions for the spectroscopic measurements were prepared by dissolving accurately weighed amounts of donor (D) and acceptor (A) in the appropriate volume of solvent immediately before running the spectra. The electronic absorption spectra
M. Pandeeswaran, K.P. Elango / Spectrochimica Acta Part A 69 (2008) 1082–1088
are recorded on a Shimadzu (UV 240, Graphicord) double beam spectrophotometer using 1 cm matched quartz cells. The temperature of the cell holder was controlled with a water flow. FT-IR spectra were recorded in a JASCO FT-IR 460 Plus spectrometer. The GC–MS spectra of the reaction product were obtained from CSIR Lab, Bhavanagar, India. The molecular orbital package, MOPAC 2000 version 1.11 (PM3 method) was used for the theoretical calculation of the ionization potential of the donor drugs [18]. The conductance of the solutions was measured on an Elico, India Conductivity Bridge. Equimolar stock solutions of D and A were thermostated to a constant temperature and were mixed in the conductivity cell by varying the mole fraction of A. The solutions were stirred after each addition and a constant time interval was permitted to record the conductance. The reaction kinetics for the formation of final product was followed at three different temperatures (298–313 K) in various solvents, keeping [D] [A]. The increase in absorbance of the reaction product at 298–350 nm (depending on the donor and solvents) was followed as a function of time. The pseudofirst-order rate constants (k) were calculated from the gradients of log (A∞ − At ) against time plots, where A∞ and At represent the absorbances at infinity and time t, respectively. The second-order rate constants were calculated by dividing k by [drug].
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The increase in conductivity observed upon CT complex formation is explained by the possibility that the CT complex formed between D and A may undergo dissociation into ionic intermediate in solvents of sufficiently high relative permittivity giving rise to appreciable conductivity according to the following general scheme [19]: D + A DA +
−
DA [D A ]
(1) (2)
The value of the conductivity above a base line connecting the conductivities of pure D and A solutions is a measure of the excess conductivity caused by the formation and subsequent ionization of the CT complex. As has been suggested, the inner complex thus formed may then act as an intermediate in the formation of final product [20]. 3.2. Electronic spectral studies
In the present study the resulting drug–DDQ solutions in tertbutyl alcohol exhibit appreciable conductivities which may be due to the formation of CT complex. In both the cases studied, the conductivity–mole fraction plots yielded a maximum at an drug:DDQ molar ratio of 1:1 as evidenced from Fig. 1.
In order to obtain information about the kinetics and mechanism of the interaction of DDQ with the drugs, the electronic spectra of the DDQ (1.32 × 10−4 M) in the presence of a large excess of the donors (i.e. [drug]/[DDQ] > 200) were obtained as a function of time in different solvents. Representative spectra are given in Figs. 2 and 3. Other systems studied show a similar spectral behavior with time. As seen, either the drugs or DDQ show any considerable absorption in the 400–600 nm range, addition of the drugs to the DDQ solution results in some absorption bands in this spectral region, presumably due to the formation of a charge-transfer complex which causes the appearance of a deep red colour in solution. Obviously, the spectra recorded for the CT complex between the drugs and DDQ are time dependent. With increase in time the deep colour solution begins to disappear and the intensity of the absorption bands in the 400–600 nm region decreases whereas the intensity of the
Fig. 1. Conductivity vs. mole fraction of DDQ plots. for the drugs–DDQ systems in tert-butyl alcohol.
Fig. 2. Absorption spectra of ketoconazole with DDQ in tert-butyl alcohol at 298 K; [donor] = 5.010 × 10−3 M and [DDQ] = 6.934 × 10−5 M.
3. Results and discussion 3.1. Conductivity studies
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sity on the carbonyl and cyano groups of the substituted DDQ molecule. In both the cases product analysis was carried out by employing GC–MS technique. The mass spectrum of the product of povidone–DDQ system displayed molecular ion peaks at m/z (%) at 301 (100), 217 (24) and 70 (15) suggesting the molecular weight of the assigned product. The following fragments observed in the mass spectrum of the compound confirm the structure of the reaction product.
Fig. 3. Absorption spectra of povidone with DDQ in acetonitrile at 298 K; [donor] = 3.95 × 10−2 M and [DDQ] = 1.322 × 10−4 M.
298–350 nm (depending on solvent) continues to increase until the end of the reaction. The absorption spectra of the povidone–DDQ system studied reveals that the spectra are characterized by maximum absorptions at the wavelengths 588, 542, 458 and 348 nm. Such spectral features are in agreement with those reported for the DDQ•− radical ion [21]. Similar spectral features were observed for the other system also [10,22]. The observed enhanced absorption band intensities, immediately after mixing D and A, supports the fact that the CT complex formed is of the dative-type structure which consequently converts to an ionic intermediate possessing the spectral characteristics of radical ion. However, the observed gradual decrease in the intensity of the CT bands in the 400–600 nm spectral regions could be due to the consumption of the ionic intermediate through an irreversible chemical reaction, while the continuous increase of the 298–350 nm bands with elapse of time is indicative of the formation of the final reaction product. Further, in the case of ketoconazole–DDQ system, a shoulder appearing around 380 nm in the spectrum of the mixture of DDQ and drugs reveals that the quinone chromophore is probably not disturbed by the reaction of DDQ with the drugs [10]. 3.3. Characterization of the reaction product The reaction product was obtained by allowing the reactants to react for 24 h under kinetic conditions and subjected to MPLC (Buchi, Switzerland) separation. In FT-IR studies, the (C O) and (C N) stretching vibrations in the DDQ species appeared at 1678 and 2226 cm−1 , respectively [23]. In the FTIR spectra of the isolated reaction products the two stretching vibrations occurred at 1645 and 2068 cm−1 (for ketoconazole) and 1662 and 2209 cm−1 (for povidone), respectively. Such a bathochromic shift could be indicative of a higher charge den-
However, due to the large size of the ketoconazole molecule the mass spectrum of the reaction product of this compound is very much complicated as a result of large number of fragments and hence no attempt was made to study it. 3.4. Characteristics of the CT complex The absorbance of the new low energy band were measured using constant acceptor concentration (in a given solvent) and varying concentrations of a donor depending on the solvent, but always [D] [A]. The formation constants (K) and molar extinction coefficients (ε) of the CT-complexes were determined spectrophotometrically in the temperature range 298–313 K using the Scott equation [24]: [D][A] [D] 1 = + d ε Kε
(3)
where [D] and [A] are the initial molar concentration of the donor and acceptor, respectively and d is the absorbance. The values of K and ε are determined from the gradient and intercept of the linear plot of [D][A]/d against [D]. A representative plot is shown in Fig. 4. The results (Table 1) reveal that the observed high value of K suggests that the formed CT-complexes are of a strong type [25]. The stoichiometry of the CT-complexes of the electron donors with the acceptor was determined by applying Job’s method of continuous variation [26] which provides symmetrical curves with maxima at a mole fraction of 0.5, in both the cases, confirming a 1:1 stoichiometric ratio (figure not shown). The linearity of the plots of the Scott equation further supports this result. The values of oscillator strength (f) which is a measure of integrated intensity of the CT-band and transition dipole moment (μ), were calculated by using the approximate equations [27] given in Eqs. (4) and (5), where εmax is the molar extinction coefficient of the CT-complex at the wavelength of maximum
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Table 2 Effect of concentration of D and A on the rate of product formation [D] (×102 M)
[A] (×104 M)
k1 (×104 s−1 )
k2 (×102 )
Ketoconazole–DDQ 0.65 0.82 0.98 1.14 1.14 1.14 1.14 1.14
1.06 1.06 1.06 1.06 0.61 0.76 0.91 1.06
2.81 3.50 4.25 4.94 4.89 4.91 4.87 4.94
4.32 4.27 4.33 4.33
Povidone–DDQ 2.62 2.83 3.39 3.96 3.96 3.96 3.96 3.96
1.32 1.32 1.32 1.32 0.76 0.94 1.13 1.32
1.59 2.06 2.70 3.09 3.05 3.14 2.96 3.09
0.61 0.72 0.79 0.78
Fig. 4. Scott linear plot for ketoconazole and povidone with DDQ at 298 K.
absorption and ν1/2 is the half band-width in wave number units. The values of f and μ thus obtained are given in Table 1: f = 4.32 × 10−9 [εmax ν1/2 ] εmax ν1/2 1/2 μ = 0.0958 ν¯ max
(4) (5)
The values of f are rather relatively large indicating a strong interaction between the donor–acceptor pairs with relative high probabilities of CT-transitions [25]. Out of the many applications of CT-complexes, one important application is to calculate the ionization potential of the donor. The ionization potential (Ip ) of the highest filled molecular orbital of the donor was estimated from CT energies of its complexes with the acceptor making use of the empirical equations reported in the literature [28]. The calculated Ip values for molecular orbital participating in CT-interaction of the drugs are listed in Table 1. In the present study, the theoretical (MOPAC PM3 method) and experimental ionization potential values are in good agreement with each other. This fact supports the interpretation that the low energy band can be regarded as the CT band.
Further evidence for the nature of CT-interaction in the present systems is the calculation of the dissociation energy (W) of the charge-transfer excited state of the complex. Hence, the dissociation energies of the complex were calculated from their CT-energy, hνCT , the ionization potential of the donor, Ip and electron affinity, EA , of the acceptor using the empirical relation [29] given in the following equation: hνCT = Ip − EA − W
(6)
The calculated values of W (Table 1) suggest that the investigated complex is reasonably strong and stable under the studied conditions with higher resonance stabilization energy [25]. 3.5. Kinetic results The pseudo-first-order rate constants for the formation of the product are independent of initial concentrations of DDQ (Table 2) indicating first-order dependence in [DDQ]. The plot of log k versus log [drug] is linear with a slope of unity, in both the cases (for ketoconazole, r 0.999; slope 1.01 ± 0.02 and for povidone, r 0.997; slope 1.21 ± 0.07) indicating unit order dependence in [drug]. The experimental rate law for the
Table 1 Spectral properties of the CT complex formed between the drugs and DDQ in acetonitrile solvent at 298 K Property
Ketoconazole
Povidone
λmax (nm) hνCT (eV) νmax (×1014 s−1 ) Formation constant, K (dm3 mol−1 ) Extinction coefficient, ε (dm3 mol−1 cm−1 ) Oscillator strength, f Dipole moment, μ Ionization potential (eV) Dissociation energy (eV)
585 2.12 5.13 143.7 2261 0.014 1.33 8.36 (8.38)a 4.33
588 2.11 5.10 67.4 2986 0.020 1.68 8.35 (9.00)a 4.33
a
Calculated by MOPAC (PM3) method.
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Table 3 Kinetic and thermodynamic data on the reaction of DDQ with ketoconazole Solvent
Chloroform4.90 Chlorobenzene Dichloromethane 1,2-Dichloroethane Tert-butyl alcohol Iso-propyl alcohol DMF
λ (nm)
εr
374 5.62 8.93 10.36 12.47 17.93 36.71
1.02 372 378 384 360 360 435
k (×104 s−1 ) 298 K
305 K
31 K
1.18 0.67 2.85 4.94 7.01 11.27 52.97
1.69 1.00 3.92 8.64 9.09 15.04 88.84
23.7 1.81 4.49 10.42 10.60 19.47 149.69
H# (kJ mol−1 )
−S# (J K−1 mol−1 )
G# (kJ mol−1 )
Ea (kJ mol−1 )
ka (×104 s−1 )
242 48.6 20.8 35.8 18.8 20.7 41.2
95.8 162 243 188 242 233 153
26.2 96.9 93.2 91.8 90.9 90.1 86.8
0.98 51.1 23.4 38.3 21.3 28.2 53.7
0.57 2.28 4.91 6.88 10.92 48.23
εr : relative permittivity of the medium. a λ 585 nm and 298 K.
formation of the product may be given as d[product] = k[DDQ][drug] dt The pseudo-first-order rate constants, k, were evaluated by employing the increase in absorbance of 290–350 nm band at different temperatures and solvents. The results are shown in Tables 3 and 4. The rates are sensitive to solvent, k values, in both the drugs, increases with an increase in relative permittivity of the medium. This solvent dependence of k values suggests that there may be some charge separation in the transformation of CT complex to the final product. Formation of such a more polar transition state is well supported by the large negative entropies of activation, S◦ . Further, in both the cases, there exist a linear correlation (Fig. 5, r > 0.96) between H◦ and S◦ indicating the operation of a common mechanism in all the solvents studied. Attempts have also been made to evaluate the rate constants for the disappearance of the CT complex by employing the decrease in absorbance of the low energy CT band. However, it is not possible to do so especially at high temperatures and in the solvents with higher relative permittivity. This may be due to the fact that under such conditions the rate of conversion of the CT complex to -complex and consequently the formation of the final product may be very high. This observation is parallel to the results of the dependence of k on the solvent and temperature and also with the electronic spectral data as described earlier in this section. The estimated rate constants for the disappearance
Fig. 5. Relation between enthalpy and entropy of activation for the interaction of drugs with DDQ.
of the CT complex are also collected in Tables 3 and 4. The results indicate that the rate of disappearance of the CT complex is slightly slower than that of the formation of the product suggesting that this conversion involves an intermediate stage and this may be the ionic intermediate suggested in spectral and conductance studies.
Table 4 Kinetic and thermodynamic data on the reaction of DDQ with povidone Solvent
Chloroform Dichloromethane 1,2-Dichloroethane Tert-butyl alcohol Iso-propyl alcohol Acetonitrile
εr
4.90 8.93 10.36 12.47 17.93 37.50
λnm
350 303 350 298 297 348
εr : relative permittivity of the medium. a Decrease in absorbance. b At 298 K.
k (×104 s−1 ) 298 K
305 K
313 K
0.75 1.90 1.56 2.07 2.60 5.39
0.95 2.53 3.05 3.33 4.33 7.10
1.15 3.07 3.96 4.27 5.53 8.50
H# (kJ mol−1 )
−S# (J K−1 mol−1 )
G# (kJ mol−1 )
Ea (kJ mol−1 )
a (nm)
kb (×104 s−1 )
19.5 22.1 45.3 34.7 36.3 20.9
258 242 165 199 192 237
96.4 94.3 94.5 94.0 93.5 91.6
22.1 24.7 47.8 37.2 38.8 23.5
460 588 460 462 462 460
0.72 1.72 1.01 2.01 2.41 5.02
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3.6. Solvent effect
3.7. Mechanism
It seems reasonable to assume that anion radicals are formed from electron donor–acceptor interaction via a CT complex, as depicted in Eqs. (1) and (2). Increase in polarity of the solvent would tend to stabilize the radical ion state, with respect to other states of the system, due to ion–solvent interaction. It is possible that the solvent interaction could also influence the first step (Eq. (1)), perhaps accompanied by an alteration of charge in the complex. Hereto, increase in polarity of the solvent could enhance the contribution of dative state and hence lead to a stronger charge transfer [29]. Results in Tables 3 and 4 indicate that the rate of product formation increase with increase in relative permittivity of the medium. A plot of log k versus εr is linear with positive slope (Fig. 6). It is evident from the figure that, there is deviation from linearity especially at higher relative permittivity values. This may be due to the fact that with increase in polarity of the medium solvent–solvent interaction becomes increasingly significant in addition to solute–solvent interactions. Thus, the satisfactory correlation, with correlation coefficient around 0.92, in all likelihood may be as a result of specific solute–solvent–solvent interactions. In the case of ketoconazole–DDQ interaction, the solvent change from chloroform to DMF causes 50-fold rate acceleration for the reaction which corresponds to a decrease in G◦ of nearly10 kJ mol−1 . Parallel to this observation, in the case of povidone–DDQ system, there is sevenfold increase in rate from chloroform to acetonitrile corresponds to 5 kJ mol−1 decrease in G◦ . This is due to the fact increase in relative permittivity of the medium would assist the formation of dative state (Eq. (1)) and as a result the formation of radical anion (Eq. (2)) and consequently enhances the rate of the reaction. This is well supported by the results of spectroscopic, spectrokinetic and thermodynamic studies explained earlier in this section.
Substitution on the quinone ring by drugs is certainly possible particularly when the aromatic ring contains activating electron withdrawing chlorine atoms. Based on the characteristics of the CT complex and foregoing spectro-kinetic results the mechanism of the interaction between DDQ and the drugs can be represented as K1
DDQ + drugCT complex (fast), K2
CT complexinner complex (fast), k
inner complexproduct
(slow)
The above mechanism leads to the following rate law. d[product] = k [inner complex] dt d[product] or = k[DDQ][drug] dt where k = k K1 K2 . The above rate law is in agreement with the observed kinetic results, i.e. the rate of formation of the product is first each with respect to DDQ and the drug. In general in such donor–acceptor interactions whether or not the various intermediates proposed are seen in the electronic absorption spectra depend on the experimental conditions like temperature and especially the kind of solvents used. 4. Conclusions Spectro-kinetic studies reveal that the interaction of 2,3dichloro-5,6-dicyano-1,4-benzoquinone and ketoconazole and povidone drugs was found to be proceed through three steps, out of these, the formation of outer complex and its conversion to inner complex are extremely fast, whereas the formation of the final product is the rate determining slow step. The 1:1 CT complex formed was characterized spectroscopically. The pseudo-first-order rate constants for the formation of the product increase with increase in relative permittivity of the medium. The activation parameters support the proposed mechanism. The mechanism of the interaction of these drugs studied may be useful in understanding the binding of drug molecule in real pharmacokinetic study. References
Fig. 6. Plot of log k vs. relative permittivity of the medium.
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