Physical Chemistry Communications, Volume 3 Issue 2, October 2016 www.bacpl.org/j/pcc
Mechanism of Oxidation of Theophylline by Silver (III) Periodate Complex in Aqueous Alkaline Medium Arunkumar T. Buddanavar and Sharanappa T. Nandibewoor* P. G. Department of studies in Chemistry, Karnatak University, Dharwad – 580 003, India Email address: stnandibewoor@yahoo.com Tel: +918362215286; Fax: +918362747884 Abstract The kinetics of oxidation of theophylline (TP) by diperiodatoargentate (III) (DPA) in aqueous alkaline medium at a constant ionic strength of 0.31 mol dm−3 was studied spectrophotometrically. The reaction between TP and DPA in alkaline medium exhibits 1:2 stoichiometry. The reaction is of the first order with respect to [DPA] and has a zero order in [TP] and unit order in [alkali]. The main oxidation product was identified as 3‐methyl‐2,6‐dioxo‐2,3dihydro‐6H‐purine‐1(7H)‐carbaldehyde by spot test, FT‐IR and LC‐MS spectral studies. A probable mechanism was proposed; the activation parameters were computed and discussed. Keywords Oxidation, Diperiodatoargentate, Theophylline and Spectroscopy
Introduction Theophylline, also known as 1,3‐dimethylxanthine, (TP) is a methylxanthine drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma and infant apnea. It blocks the action of adenosine, an inhibitor neurotransmitter that induces sleep, contracts the smooth muscles and relaxes the cardiac muscle, strengthens right heart function and diaphragm movement. It is one of the most commonly used bronchodilators and respiratory stimulants for the treatment of asthma and lung diseases of adults [1, 2]. It has been shown that theophylline may reverse the clinical observations of steroid insensitivity in patients with COPD and asthmatics that are active smokers via a distinctly separate mechanism. Like other methylated xanthine derivatives, TP is both a competitive nonselective phosphodiesterase inhibitor [1] and nonselective adenosine receptor antagonist [2]. The presence and accumulation of theophylline in aquatic environments, at low concentrations, may pose threats to the ecosystem and human health. The silver (III) periodate complex (DPA) is a powerful oxidizing agent in an alkaline medium with a reduction potential [3] of 1.74 V. It is widely used as a volumetric reagent for the determination of various organic and inorganic species [4, 5]. To study the kinetics of oxidation of various organic substrates, DPA was used as an oxidizing agent [6‐8]. They generally found that order with respect to both the oxidant and substrate was unity and [OHˉ] was found to enhance the rate of reaction. It was also observed that they did not arrive the possible active species of DPA in alkali and therefore, they proposed mechanisms by generalizing the DPA as [Ag(HL)L](X+1) −. However, Kumar et al. [9‐11] made an effort to give evidence for the reactive form of DPA at an alkaline pH. In the present investigation, different observations were observed and we have obtained evidence for the reactive species for DPA in an alkaline medium. A literature survey reveals that there are no reports on the mechanism of oxidation of theophylline by DPA in an alkaline medium. In view of the pharmaceutical importance of TP and in order to understand the active species of the oxidant and to identify a suitable mechanism, the title reaction was investigated. Such studies are of much significance in understanding the mechanistic profile of theophylline in redox reactions and provide an insight into the interaction of metal ions with the substrate and its mode of action in biological systems. Hence, the present investigation is aimed at checking the reactivity of TP towards DPA and to arrive at the plausible mechanism. An understanding of the mechanism allows the chemistry to be interpreted, understood and predicted.
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Experimental Materials and Methods All the chemicals used were of analytical grade and the Millipore water was used throughout the experiments. Theophylline was purchased from sigma aldrich and a stock solution of TP was prepared by dissolving an appropriate amount of drug in millipore water. The required concentration of TP solution was prepared daily from its stock solution. A standard solution of periodate (IO4ˉ) was prepared by dissolving known weight of potassium periodate (KIO4ˉ) in hot water, and used after keeping solution for 24 hours to attain the equilibrium. The concentration of (IO4ˉ) was ascertained by iodometrically [12] at neutral pH maintained using phosphate buffer. KNO3 and KOH were used to maintain ionic strength and alkalinity of the reaction. Aqueous solution of AgNO3 was used to study the product effect and t‐Butyl alcohol was used to study the dielectric constant of the reaction medium. The reaction temperature was maintained within 25 ± 0.1 ⁰C. Preparation of DPA DPA was prepared by oxidizing Ag(I) in the presence of KIO4 as described elsewhere [13]. The mixture of 28 gm of KOH and 23 gm of KIO4 in 100 cm3 of water along with 8.5 gm AgNO3 was heated just to boiling and 20 gm of K2S2O8 was added in several lots with constant stirring and then allowed solution to cool. 40 g of NaOH was added slowly to the filtrate, after the addition of voluminous orange precipitate agglomerates. The precipitate was filtered in medium porosity fritted glass filter and washed three to four times with ice cold water. The pure crystals were dissolved in 50 cm3 Millipore water and warmed to 80 ⁰C with constant stirring thereby some solid was dissolved to give a red solution. The resulting hot solution was filtered and on cooling at room temperature, the orange crystals separated out and were recrystallised from Millipore water. The complex was characterized from its UV spectrum, which exhibited three peaks at 208, 252 and 361 nm (Figure. 1). These spectral features were identical to those reported earlier for DPA [12]. The magnetic moment study revealed that the complex was diamagnetic. The compound prepared was analyzed for silver and periodate by acidifying a solution of the material with HCl, recovering and weighing the AgCl for Ag and titrating the iodine liberated when excess of KI was added to the filtrate for IO4ˉ. The stock solution of DPA was used for the required concentration of DPA solution in the reaction mixture.
FIGURE 1. SPECTRUM OF DIPERIODATOARGENTATE (III) IN AQUEOUS SOLUTION AT 25 0C AT ([DPA] = 105 mol dm‐3)
Instrumentation All kinetic measurements were performed on a Varian CARY 50 Bio UV‐ Visible Spectrophotometer (Varian, Victoria‐3170, and Australia) and a Peltier Accessory (temperature control) attached. For pH measurements ELICO pH meter model LI 120 was used. The product analysis was carried out by QP‐2010S Shimadzu gas chromatograph mass spectrometer and Nicolet 5700‐FT‐IR spectrometer. Kinetic Measurements The reaction was carried under the pseudo‐first order condition at a constant ionic strength of 0.31mol/dm3, where concentration of TP was greater than the oxidant (DPA) at 25± 0.1⁰C, unless otherwise specified. The reaction was initiated by mixing DPA with TP solution, which also contained the required concentrations of KIO4, KNO3 and
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KOH and the progress of the reaction was monitored spectrophotometrically at 361 nm which is the maximum absorption wavelength of DPA with the decrease in absorbance due to DPA with the molar absorbency index, ‘ɛ’ to be 13900 ± 100 dm3mol‐1cm‐1. The rate constants were determined from the log (absorbance) vs time plots and the rate constants obtained were average of triplicate runs. The plots were linear up to 80% completion of reaction under the range of [OHˉ] used. During the kinetics a constant concentration, viz. 1.0 x 10‐6 mol dm‐3 of KIO4 was used throughout the study unless otherwise stated. Since periodate is present in the excess in DPA, the possibility of oxidation of TP by periodate in alkaline medium at 298 K was tested.
FIGURE 2. UV‐VIS SPECTROSCOPIC CHANGES OCCURRING IN THE OXIDATION OF THEOPHYLLINE BY ALKALINE DIPERIODATOARGENTATE (III) AT 298 K AT [TP]= (1×104 MOL DM‐3), [DPA] = (1×105 mol dm‐3), [OHˉ]= (3.0 mol dm‐3) AND I = 0.31 mol dm‐ 3, WITH A SCANNING TIME OF (1) 0.30 min, (2) 1.0 min, (3) 1.30 min, (4) 2.0 min AND (5) 2.30 min.
The progress of the reaction was followed iodometrically. However, it was found that there was no significant reaction under the experimental conditions employed compared with the DPA oxidation of TP. The total concentrations of periodate and alkali were calculated by considering the amount present in the DPA solution and that additionally added. Dissolved O2, CO2 and surface of reaction vessel had no effect on the reaction rate. Fresh solutions were used for carrying out each kinetic study. In view of the modest concentrations of alkali used in the reaction media, attention was also given to the effect of the surface of the reaction vessels on the kinetics. Use of polythene/acrylic equipment and quartz or polyacrylate cell gave the same results as with the glass vessels and cells. In view of the ubiquitous contamination of carbonate in the basic medium, the effect of carbonate was also studied. Added carbonate had no effect on the reaction rates. The spectroscopic changes during the reaction are shown in Fig. 2. It is evident from the figure that the concentration of DPA decreases at 361 nm. Results Stoichiometry and Product Analysis Different sets of reaction mixtures containing varying ratios of DPA to TP, in the presence of a constant amount of OHˉ, KIO4 and KNO3, were kept for 3 hours in a closed vessel under a nitrogen atmosphere. The remaining concentration of DPA was assayed by measuring the absorbance at 362 nm. The results indicated a 1: 2 stoichiometry (TP:DPA) as given in Scheme 1
O
O
H3C O
H N
N
C
+ 2[Ag(H3IO6)(H2IO6)]2¯+ H2O N CH3
N
H O
O N
H N 2 3 + + 2Ag + 4H+ + 2H3IO6 ¯+ 2H2IO6 ¯
N N CH3
3-methyl-2,6-dioxo-2,3-dihydro-6H-purine-1(7H)-carbaldehyde
SCHEME 1. STOCHIOMETRY OF TP AND DPA
The main product was identified as 3‐methyl‐2, 6‐dioxo‐2, 3dihydro‐6H‐purine‐1(7H)‐carbaldehyde by spot test [14]. The product was extracted with ether and recrystallized from aqueous alcohol and was characterized by infrared (IR) and LC–MS spectral studies. The nature of the product was evidenced by the IR spectrum, which has
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shown a carbonyl (>C=O) stretch at 1623 cm‐1, –NH stretching at 3412 cm‐1and characteristic aldehyde –CH overtone bands at 2928 and 2854 cm‐1 (Fig. 3).
FIGURE 3. FT‐IR SPECTRUM OF 3‐METHYL‐2,6‐DIOXO‐2,3DIHYDRO‐6H‐PURINE‐1(7H)‐CARBALDEHYDE
FIGURE. 4 LC‐MASS SPECTRUM OF 23‐METHYL‐2,6‐DIOXO‐2,3DIHYDRO‐6H‐PURINE‐1(7H)‐CARBALDEHYDE WITH ITS MOLECULAR ION PEAK AT 194.12 m/z.
The product was also confirmed by LC–MS analysis data. The mass spectrum showed molecular ion peak at 194.12amu (Fig. 3), which corresponds to the product, and another peak at 181.07, which corresponds to the protonated TP (TP–H+). The yield obtained via LC–MS was 90%. Another product, the formation of free Ag(I) in solution was detected by adding a KCl solution to the reaction mixture, which produced white turbidity due to the formation of AgCl. The reaction products did not undergo further oxidation under the present kinetic conditions. Reaction Order The reaction orders with respect to reactive species were determined from the slopes of log kobs versus log(Conc.) plots, or kobs versus [reactant] plots by varying concentrations of the reductant, alkali and periodate, in turn while keeping others constant. Effect of [Diperiodatoargentate(III)] The DPA concentration varied from 0.2 x10‐5 to 2.0x10‐5 mol dm‐3. The linearity and almost parallel plots of log (absorbance) versus time, indicates that reaction is the first order with respect to DPA. This was also confirmed by varying the concentration of DPA, which did not show any changes in rate constants, (Table 1).
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Effect of Theophylline The effect of theophylline was studied in the range of 0.2 x10‐4 to 2.0 x10‐4 mol dm‐3 at 25 0C while keeping the other reactant concentrations and conditions constant. The rate constants remained almost the same. The order of reaction was found to be independent on [TP]. Hence, its order is zero (Table 1). Effect of [Alkali] The effect of the alkali on the reaction was studied in the range of 0.5 x10‐1 to 3.0 x10‐1 mol dm‐3 at constant concentrations of TP, DPA and [IO4ˉ] at a constant ionic strength. The rate constants increased with an increase in [alkali] and the order was found to be a unity (Table 1). TABLE. 1 EFFECT OF VARIATION OF [DPA], [TP], [OHˉ] AND [IO4ˉ] ON THE DPA OXIDATION OF TP IN ALKALINE MEDIUM AT 250C AND I = 0.31 mol dm‐3
DPA×105 mol dm‐3
[TP] ×104 mol dm‐3
[OH] ×101 mol dm‐3
[IO4] ×106 mol dm‐3
kobs×103 (S-1)
0.2
1.0
3.0
1.0
3.53
0.5
1.0
3.0
1.0
3.19
0.8
1.0
3.0
1.0
3.32
1.0
1.0
3.0
1.0
2.90
1.5
1.0
3.0
1.0
3.11
2.0
1.0
3.0
1.0
3.13
1.0
0.2
3.0
1.0
2.74
1.0
0.5
3.0
1.0
3.00
1.0
0.8
3.0
1.0
3.03
1.0
1.0
3.0
1.0
2.90
1.0
1.5
3.0
1.0
2.96
1.0
2.0
3.0
1.0
2.81
1.0
1.0
0.5
1.0
0.48
1.0
1.0
1.0
1.0
0.69
1.0
1.0
1.5
1.0
0.99
1.0
1.0
2.0
1.0
1.15
1.0
1.0
2.5
1.0
1.47
1.0
1.0
3.0
1.0
2.90
1.0
1.0
3.0
0.2
2.24
1.0
1.0
3.0
0.5
2.39
1.0
1.0
3.0
0.8
2.35
1.0
1.0
3.0
1.0
2.90
1.0
1.0
3.0
1.5
2.46
1.0
1.0
3.0
2.0
2.49
Effect of [Periodate] The effect of periodate was observed by varying the concentration from 0.2 x10‐6 to 2.0 x10‐6 mol dm‐3 while keeping all other reactants concentrations constant. It was observed that the rate constants were almost constant by increasing [IO4ˉ] (Table 1). Effect of Initially Added Products The initially added products, Ag (I) and 3‐methyl‐2, 6‐dioxo‐2, 3dihydro‐6H‐purine‐1(7H)‐carbaldehyde, did not have any significant effect on the rate of the reaction.
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Effect of the Ionic Strength and Dielectric Constant of the Medium The effect of varying [KNO3] at constant [DPA], [TP], [OH] and [IO4ˉ] was found that an increase in the ionic strength had no significant effect on the rate of the reaction. The dielectric constant (t‐butyl alcohol‐water %) of the medium had no significant effect on the rate of reaction. Test for Free Radicals (Polymerization Study) The intervention of free radicals was examined as follows. The reaction mixture, to which a known quantity of acrylonitrile monomer had been added initially, was kept in an inert atmosphere for 2 hours. On diluting the reaction mixture with methanol, a white precipitate was formed indicating the intervention of free radicals in the reaction. The blank experiments of either DPA or TP alone with acrylonitrile did not induce any polymerization under the same condition as those induced for reaction mixture. Initially added acrylonitrile decreases the rate of reaction indicating free radical intervention, which is the case in earlier work [15]. Effect of Temperature The rate of reaction was measured at four different temperatures 15, 25, 35 and 45 0C under the standard conditions. The rate was found to increase with increase in temperature. The energy of activation corresponding to these constants was evaluated from the Arrhenius plot of log kobs vs 1/T, from which the thermodynamic parameters were calculated and are listed in Table 2. TABLE. 2
(A). EFFECT OF TEMPERATURE ON THE OXIDATION OF THEOPHYLLINE BY DIPERIODATOARGENTATE(III) IN AN AQUEOUS ALKALINE MEDIUM AT [TP]= 1×10‐ 4 mol dm‐3, [DPA] = 1×10‐5 mol dm‐3, [OHˉ]=3.0 mol dm‐3 AND I = 0.31mol dm‐3, Temperature (K)
kobs × 103 (S‐1)
288
1.12
298
2.90
308
3.73
318
4.89
(B). THERMODYNAMIC ACTIVATION PARAMETERS FOR THE OXIDATION OF TP BY DPA IN AQUEOUS ALKALINE MEDIUM, TP = 1×10‐4 mol dm‐3, DPA=1×10‐5 mol dm‐3 AND [OHˉ] = 3.0 mol dm‐3. ACTIVATION PARAMETERS Parameters
Values
Ea ( kJmol‐1)
34 ± 2
ΔH≠ ( kJmol‐1)
32 ± 2
ΔS≠ (JK‐1mol‐1)
‐111± 4
ΔG ( kJmol )
77 ± 4
log A
5 ±0.2
≠
‐1
Discussion In the later period of 20th century, the kinetic of oxidation of some organic and inorganic substrates have been studied by Ag (III) species which may be due to its strong versatile nature of two electrons oxidant. Among the various species of Ag(III), (Ag(OH)4ˉ), diperiodatoargentate (III) and ethylenebis (biguanide) silver (III) (EBS) are of maximum attention to the researchers due to their relative stability [16]. The stability of (Ag(OH)4ˉ) is very sensitive towards traces of dissolved oxygen and other impurities in the reaction medium whereupon it had not drawn much attention. However, the other two forms of Ag(III) [6,9] are considerably stable, where the DPA is used in highly alkaline medium and EBS is used in highly acidic medium. The literature survey [17] reveals that the water soluble diperiodatoargentate(III) (DPA) has a formula [Ag(IO6)2]7− with dsp2 configuration of square planar structure, similar to diperiodatocopper (III) complex with two bidentate ligands, periodate to form a planar molecule. When the same molecule is used in alkaline medium, it is unlikely to exist as [Ag(IO6)2]7− as periodate is known to be in various protonated forms [18,19] depending on pH of the solution as given in following multiple equilibria (1) –(3).
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H5IO6
H4IO6¯ + H +
(1)
H4IO6¯
H3IO62¯ + H +
(2)
2
3
H3IO6 ¯
H2IO6 ¯ + H
+
(3)
Periodic acid (H5IO6) exists in acid medium and also as H4IO6ˉat pH 7. Thus, under the present alkaline conditions, the main species are expected to be H3IO62ˉand H2IO63ˉ. At higher concentrations, periodate also tends to dimerise. On the contrary, in the literature the DPA is proposed as [Ag(HL)2]x‐ in which L is a periodate with an uncertain number of protons and “HL” is a protonated periodate of uncertain number of protons. This can be ruled out by considering the alternative form [19] of IO4ˉ at pH > 7 which is in the form H3IO62‐ or H2IO63ˉ. Hence, DPA could exist as [Ag(H3IO6)2]ˉ or [Ag(H2IO6)2]3‐ in alkaline medium. Therefore, under the present condition, diperiodatoargentate (III) may be depicted as [Ag(H3IO6)2]ˉ. The similar speciation of periodate in alkali was proposed for diperiodatonickelate (IV). The added products did not have any significant effect on the rate of reaction. Mechanism for Reaction The reaction between DPA and TP in an alkaline medium has a 1: 2 stoichiometry (TP: DPA) with a first order dependence on [DPA] and a zero order on [substrate], a unit order on [alkali] and zero order on [periodate]. No effect from the added products was observed. Based on the order with respect to the reactants, such as [DPA], [OHˉ], [IO4ˉ], and [TP], the following mechanism has been proposed by considering TP in its neutral form, which explains all the other experimental observations as in Scheme 2. [Ag(H3IO6)2]¯ + OH ¯
slow
[Ag(H3IO6)(H2IO6)]2¯+ H2O
O H3C
O H N
N
O
H 2C 2
+ [Ag(H3IO6)(H2IO6)] ¯ N
N
O
CH3
OH
O H N
N
H2C + Ag
N
O
2+
N
fast
O
+
H2O
O H N
C
H N + [Ag(H2IO6)(H3IO6)]2¯ N
H+
CH3
O N
Ag+ +
N
N
O
O
OH
O
H N
N
CH3
H2C
2+ + Ag + H2IO63¯+ H3IO62¯+ H+
N
N
CH3
H2C
H N
N
fast
fast
N
H
N
O
N
N
CH3
CH3 +
+ Ag + 2H+ + H3IO62¯ + H2IO63¯ 4H+ +
4OH ¯
fast
4H2O
SCHEME 2. DETAILED MECHANISM OF THE OXIDATION OF THEOPHYLLINE BY ALKALINE DIPERIODATOARGENTATE(III)
It is interesting to note that in most of the reports of DPA oxidation, [OHˉ] had an increasing effect on rate of reaction, periodate retarded the rate and MPA was considered as active species of DPA. However, in the present kinetic study, different results have been obtained. In this study, the order in each concentration of alkali and DPA was unity, however the order in [TP] was found to be zero. Such type of zero order in [sub] is rare in literature [20‐ 22]. In the first pre‐equilibrium step, DPA reacts with [OHˉ] in a rate determining step to give the deprotonated
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form of DPA. In the second step, TP reacts with deprotonated DPA in a fast step to give a free radical derived from TP along with other byproducts. Further, this free radical undergoes reaction in further fast steps to give final products. Thus, all these results indicate a mechanism of the type shown in Scheme 2 Scheme 2 leads to rate law and the rate expression is written as - d [DPA] dt
= rate = k obs [Ag(H3IO6)2]¯ [OH¯]
The negligible effect of ionic strength and dielectric constant on the rate of reaction explains qualitatively the reaction between neutral molecule and charged species, as seen in Scheme 2. The effect of solvent on reaction rate has been described in detail in the literature [23]. The negative value of ∆S# suggests that the intermediate species are more ordered than the reactants and small value of log A supports the mechanism. Conclusion The oxidation of theophylline by DPA was studied and zero order dependent on theophylline was observed which is rare in literature. Among the various species of DPA in aqueous, alkaline medium [Ag(H3IO6) (H2IO6)]2− was considered to be the active species for the title reaction. The results indicated that the role of pH in the reaction medium is crucial. Temperature effect and activation parameters were evaluated. The overall mechanistic sequence described here is consistent with all the experimental evidences including the product, spectral, mechanistic and kinetic studies. REFERENCES
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