Oxidation of a anticholinergic drug atropine sulfate monohydrate by alkaline copper(III) periodate complex: A kinetic and mechanistic study

Article abstract of DOI:10.1524/zpch.2012.0201

The oxidation of a anticholinergic drug, Atropine sulfate monohydrate (ASM) by diperiodatocuprate( III) (DPC) has been investigated spectrophotometrically in aqueous alkaline medium at a constant ionic strength of 0.50mol dm ^-3. The reaction between diperiodatocuprate(III) and atropine sulfate exhibits 1 : 2 stoichiometry (atropine sulfate : diperiodatocuprate(III)). The main oxidation products were identified and confirmed by spectral studies including IR, ¹H NMR and GC-MS. A suitable mechanism is proposed. The order with respect to diperiodatocuprate(III) concentration was unity, while the order with respect to atropine sulfate concentration was less than unity over the concentration range studied. The rates increased with an increase in alkali concentration and decreased with an increase in periodate concentration. The activation parameters with respect to slow step of the mechanism were calculated and the thermodynamic quantities were also determined. Kinetic experiments suggest that [Cu(OH)₂(H₃IO₆)]- is the reactive species of copper(III). by Oldenbourg Wissenschaftsverlag, Muenchen.

Full text of DOI:10.1524/zpch.2012.0201

Z. Phys. Chem. 226 (2012) 233–249 / DOI 10.1524/zpch.2012.0201
© by Oldenbourg Wissenschaftsverlag, München
Oxidation of a Anticholinergic Drug Atropine
Sulfate Monohydrate by Alkaline Copper(III)
Periodate Complex: A Kinetic and Mechanistic
Study
By Kirthi S. Byadagi, Rajeshwari V. Hosahalli, Sharanappa T. Nandibewoor, and
∗
Shivamurti A. Chimatadar
P.G. Department of Studies in Chemistry, Karnatak University, Dharwad – 580003, India
(Received October 28, 2011; accepted in revised form February 2, 2012)
Atropine Sulfate / Diperiodatocuprate(III) / Oxidation / Kinetics / Mechanism
The oxidation of a anticholinergic drug, Atropine sulfate monohydrate (ASM) by diperioda-
tocuprate(III) (DPC) has been investigated spectrophotometrically in aqueous alkaline medium
at a constant ionic strength of 0.50 mol dm−3. The reaction between diperiodatocuprate(III) and
atropine sulfate exhibits 1 : 2 stoichiometry (atropine sulfate: diperiodatocuprate(III)). The main
oxidation products were identified and confirmed by spectral studies including IR, 1H NMR and
GC-MS. A suitable mechanism is proposed. The order with respect to diperiodatocuprate(III)
concentration was unity, while the order with respect to atropine sulfate concentration was less
than unity over the concentration range studied. The rates increased with an increase in alkali
concentration and decreased with an increase in periodate concentration. The activation parameters
with respect to slow step of the mechanism were calculated and the thermodynamic quantities
were also determined. Kinetic experiments suggest that [Cu(OH)2(H3IO6)]− is the reactive species
of copper(III).
1. Introduction
Atropine, one of the solenaceous alkaloids, contains two cyclic structures, the alicyclic
nitrogen-containing alcohol tropine and the aromatic tropic acid, joined by an ester link-
age [1]. The most common atropine compound used in medicine is atropine sulfate
•
•
monohydrate (ASM) (C17H23NO3)2 H2SO4 H2O, the full chemical name is 1αH,5αH-
Tropan-3-α-ol( )-tropate(ester), sulfate monohydrate. The structure is shown below.
Atropine is found in many members of the Solanaceae family. The most commonly
found sources are Atropa belladonna, Datura inoxia, D. metel, and D. stramonium. It
is a secondary metabolite of these plants and serves as a drug with a wide variety of
effects. It is a competitive antagonist for the muscarinic acetylcholine receptor. It is
* Corresponding author. E-mail: schimatadar@gmail.com
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234
K. S. Byadagi et al.
Scheme 1.
classified as an anticholinergic drug. Atropine is a core medicine in the World Health
Organization’s “Essential Drugs List”, which is a list of minimum medical needs for
a basic health care system [2]. Although atropine earlier enjoyed widespread use in the
treatment of peptic ulcer, today it is mostly used in resuscitation [3], anaesthesia [4],
and ophthalmology, usually as the more soluble sulfate salt. It is a specific antidote
for the treatment of poisoning with organophosphorus and carbamate insecticides and
organophosphorus nerve agents. Its degradation by microorganisms has been reported
by several groups [5,6] and, in cases for which the mechanism has been studied, hy-
drolysis of the ester linkage to give the two separate cyclic components is the initial
step.
In recent years the study of oxidation states of transition metals has intrigued
many researchers. Transition metals in their higher oxidation states can generally be
stabilized by chelation with suitable polydentate ligands. Metal chelates such as diperi-
odatocuprate(III) [7], diperiodatoargentate(III) [8] and diperiodatonickelate(IV) [9] are
good oxidants in a medium with an appropriate pH value. Diperiodatocuprate(III) is
a versatile one-electron oxidant and the oxidation study of DPC is scanty in view of its
limited solubility and stability in aqueous medium. Its use as an analytical reagent is
now well recognized [10]. The kinetics of self-decomposition of these complexes was
studied in detail. Copper(III) is shown to be an intermediate in the copper(II) catalysed
oxidation of aminoacids by peroxodisulfate. The oxidation reaction usually involves
the copper(II)–copper(I) couple and such aspects are dealt in different reviews [11,12].
Copper complexes have a major role in oxidation chemistry due to their abundance
and relevance in biological chemistry [11]. Copper(III) is involved in many biologi-
cal electron transfer reactions [13]. When copper(III) periodate complex is the oxidant
and multiple equilibria between different copper(III) species are involved, it would be
interesting to know which of the species is the active oxidant.
Literature survey revealed that no attention has been paid towards the oxidation of
atropine sulfate monohydrate (ASM) with any oxidant from the kinetic and mechanistic
point of view. Such studies are of much significance in understanding the mechanistic
profile of atropine sulfate in redox reactions and provide an insight into the interaction
of metal ions with the substrate and its mode of action in biological systems. As part of
continuation of our work in our laboratory [11] and also to know the active species of
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Oxidation of a Anticholinergic Drug Atropine Sulfate Monohydrate
235
Cu(III) and the complexity of the reaction, a detailed study of the title reaction becomes
important. Hence, the present investigation is aimed at checking the reactivity of ASM
towards DPC and to arrive at the plausible mechanisms.
2. Experimental
2.1 Materials and methods
All reagents were of analytical grade and millipore water was used throughout the work.
A solution of atropine sulfate (SD Fine Chem Ltd) was prepared by dissolving an ap-
propriate amount in millipore water. The purity of ASM was checked by comparing its
IR spectrum and with its m.p. 192 ◦C (Literature: 190–194 ◦C). The required concen-
tration of ASM was obtained from its stock solution. The copper(III) periodate complex
was prepared [14] and standardized by a standard procedure [15]. The UV-Vis spectrum
with maximum absorption at 415 nm verified the existence of copper(III) complex. The
ionic strength was maintained by adding KNO3 (BDH) solution and the pH value was
regulated with KOH (Fisher scientific) solution. A stock solution of IO4− was prepared
by dissolving a known weight of KIO4 (Himedia) in hot water and used after keeping
for 24 h to attain the equilibrium. Its concentration was ascertained iodometrically [16]
at neutral pH maintained using phosphate buffer. Solutions of ASM and DPC were
always freshly prepared before use.
2.2 Instruments used
(i) For kinetics measurements: A CARY 50 Bio UV-Vis Spectrophotometer (Varian,
Victoria-3170, Australia) was used.
(ii) For product analysis: A QP-2010S Shimadzu gas chromatograph mass spec-
trometer, Nicolet 5700-FT-IR spectrometer (Thermo, U.S.A.), 300 MHz 1H NMR spec-
trophotometer (Bruker, Switzerland) and for pH measurements (Elico pH meter model
LI120) were used.
2.3 Kinetic measurements
The oxidation of ASM by DPC was followed under pseudo first-order condition where
[ASM] > [DPC] at 25 0.1 ◦C, unless otherwise specified. The reaction was initiated
by mixing DPC with the ASM solution which also contained required concentrations of
KNO3, KOH and KIO4. The progress of the reaction was monitored spectrophotomet-
rically at 415 nm i.e., decrease in absorbance of DPC with the molar absorbancy index,
ε = 6231 100 dm3 mol−1 cm−1. The spectral changes during the chemical reaction for
the standard condition at 25 ◦C are shown in Fig. 1. It is evident from the figure that
the concentration of DPC decreases at 415 nm. It was verified that there was almost no
interference from other species in the reaction mixture at this wavelength.
The pseudo–first order rate constants, kobs were determined from slopes of plots of
log(absorbance) vs. time plots (Fig. 2). The plots were linear up to 80% completion of
the reaction. The rate constants were reproducible to within 5% and are the average of
three independent kinetic runs (Table 1). During kinetics a constant concentration viz.
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236
K. S. Byadagi et al.
Fig. 1. UV-Vis spectral changes during the oxidation of atropine sulfate by alkaline diperiodato-cuprate(III)
at 25 ◦C; [DPC] = 5.0×10−5, [ASM]= 3.0×10−3, [OH−] = 0.30 (pH = 13.4) and I = 0.50 mol dm−3 with
scanning interval time of: (1) 1.0, (2) 2.0, (3) 3.0, (4) 4.0, (5) 5.0 and (6) 6.0 min.
Fig. 2. First order plots of oxidation of atropine sulfate by alkaline diperiodatocuprate(III) at 298 K;
[ASM]= 3.0×10−3
,
[OH−] = 0.30 (pH = 13.4), I = 0.50 mol dm−3
,
[DPC] × 105 mol dm−3 = (1) 1.0,
(2) 3.0, (3) 5.0, (4) 7.0, (5) 10.0.
1.0×10−5 mol dm−3 of KIO4 was used throughout the study unless otherwise stated.
Since excess of periodate is present in DPC, the possibility of oxidation of ASM by pe-
riodate in alkaline medium at 298 K was verified and found that there was no significant
reaction DPC and IO4 under experimental conditions. The total concentrations of peri-
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Oxidation of a Anticholinergic Drug Atropine Sulfate Monohydrate
237
−
Table 1. Effect of variation of DPC, ASM, OH− and IO4 concentrations on the oxidation of atropine sul-
fate by alkaline copper(III) periodate complex at 298 K and I = 0.50 mol dm−3
.
[DPC] × 105
[ASM]× 103
[OH−]
[IO4−] × 105
kobs × 103 (s−1
)
(mol dm−3
)
(mol dm−3
)
(mol dm−3
)
(mol dm−3
)
Found
Calculated
1.0
3.0
5.0
7.0
10.0
3.0
3.0
3.0
3.0
3.0
0.3
0.3
0.3
0.3
0.3
1.0
1.0
1.0
1.0
1.0
2.22
2.32
2.21
2.30
2.34
2.35
2.35
2.35
2.35
2.35
5.0
5.0
5.0
5.0
5.0
0.5
0.7
1.0
3.0
5.0
0.3
0.3
0.3
0.3
0.3
1.0
1.0
1.0
1.0
1.0
0.53
0.72
1.09
2.21
3.47
0.51
0.69
0.96
2.35
3.32
5.0
5.0
5.0
5.0
5.0
3.0
3.0
3.0
3.0
3.0
0.05
0.07
0.1
0.3
0.5
1.0
1.0
1.0
1.0
1.0
0.80
1.00
1.37
2.21
2.94
0.79
1.02
1.31
2.35
2.79
5.0
5.0
5.0
5.0
5.0
3.0
3.0
3.0
3.0
3.0
0.3
0.3
0.3
0.3
0.3
1.0
3.0
5.0
7.0
10.0
2.21
1.07
0.72
0.51
0.37
2.35
1.06
0.68
0.51
0.36
odate and OH− was calculated by considering the amount present in DPC solution and
that additionally added. Kinetic runs were also carried out in N2 atmosphere in order to
understand the effect of dissolved oxygen on the rate of the reaction. No significant dif-
ference in the results was obtained in presence and absence of nitrogen. 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.
Regression analysis of experimental data to obtain regression coefficient r and the
standard deviation S, of points from the regression line, was performed with the Mi-
crosoft office excel 2003 program.
3. Results
3.1 Stoichiometry and product analysis
Different sets of reaction mixture containing varying ratios of DPC to ASM in pres-
ence of constant amount of OH−, KIO4, and KNO3 were kept for 5 h in a closed vessel
under nitrogen atmosphere. The remaining concentration of DPC was assayed by meas-
uring the absorbance at 415 nm. The results indicated 1 : 2 stoichiometry i.e., one mole
of ASM required two moles of DPC as shown in Eq. (1).
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238
K. S. Byadagi et al.
Scheme 2.
Fig. 3. GC-MS spectra of tropine showed molecular ion peak at m/z 141 amu and base peak at m/z
124 amu.
After completion of reaction, the reaction mixture was acidified, concentrated and
extracted with ether. The ethereal layer was subjected to column chromatography using
hexane and ethyl acetate in 8 : 2 (v/v) and the fractions were subjected to spectral inves-
tigations. The main reaction products were identified as tropine and benzaldehyde. The
1
products were characterized and confirmed by FT-IR, GC-MS and H NMR spectral
studies.
The IR spectrum of tropine showed a broad band at 3245 cm−1 assigned to –OH
stretching. The GC-MS mass spectrum of tropine showed the base peak at 124 amu
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Oxidation of a Anticholinergic Drug Atropine Sulfate Monohydrate
239
Fig. 4. 1H NMR spectrum of tropine, the oxidation product of atropine sulfate by alkaline diperioda-
tocuprate(III).
and molecular ion peak at 141 amu (Fig. 3). The 1H NMR spectral analysis of tropine
showed a broad singlet for –OH at δ 12.36 ppm (D2O exchangeable), singlet for proton
adjacent to –OH group at δ 3.89 ppm, multiplets for the protons of –CH2 are observed
in the range δ 2.50–3.57 ppm. Methyl protons attached to nitrogen appear at δ 3.64 ppm
and a singlet for the proton on the carbon attached to –OH group appeared at δ 3.92 ppm
(Fig. 4) thus confirming the product tropine. Another product benzaldehyde was con-
firmed by its GC-MS spectrum which showed a molecular ion peak at 106 amu and also
confirmed by its hydrazone derivative [17].
The byproducts were identified as methyl alcohol, which was confirmed by
sodium test [17] and CO2 was qualitatively detected by bubbling nitrogen gas through
the acidified reaction mixture and passing the liberated gas through tube contain-
ing limewater. The presence of Cu(OH)2 was confirmed by UV-Vis spectroscopic
analysis.
3.2 Reaction orders
The reaction orders were determined from the slope of log kobs vs. log(concentration)
plots by varying the concentrations of atropine sulfate, alkali, periodate in turn while
keeping all other concentrations constant.
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240
K. S. Byadagi et al.
Fig. 5. Effect of atropine sulfate concentration on the oxidation of atropine sulfate by alkaline diperi-
odatocuprate(III) at 25 ◦C; [DPC] = 5.0×10−5, [ASM]= 3.0×10−3, [OH−] = 0.30 (pH = 13.4) and I =
0.50 mol dm−3
.
3.3 Effect of [diperiodatocuprate(III)]
The oxidant diperiodatocuprate(III) (DPC) concentration was varied in the range of
1.0×10−5–1.0×10−4 mol dm−3 at constant concentrations of ASM, OH− and IO4 .
−
The fairly constant kobs values indicate that order with respect to DPC concentration was
unity (Table 1). This was also confirmed by the linearity of the plots of log (absorbance)
vs. time plots (Fig. 2) upto 80% completion of reaction (r ≥ 0.9988, S ≤ 0.008).
3.4 Effect of [atropine sulfate]
The effect of ASM was studied in the range of 5.0×10−4–5.0×10−3 mol dm−3 at con-
stant concentrations of DPC, OH− and IO4− at constant ionic strength of 0.50 mol dm−3
at 25 ◦C. The rate constants increased with increase in the concentration of ASM
(Table 1). The order with respect to ASM concentration was obtained from the plot of
logkobs vs. log[ASM] (Fig. 5) and was found to be less than unity (0.79) (r ≥ 0.9916,
S ≤ 0.002).
3.5 Effect of [alkali]
The effect of alkali concentration was studied in the range of 0.050–0.50 mol dm−3 (pH
−
range from 12.6 to 13.6) at constant concentrations of DPC, ASM, IO4 and at con-
stant ionic strength. The rate constants increased with increase in alkali concentration
(Table 1). The order with respect to OH− concentration was found to be less than unity
(0.55) (r ≥ 0.9875, S ≤ 0.019).
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Oxidation of a Anticholinergic Drug Atropine Sulfate Monohydrate
241
3.6 Effect of [periodate]
The effect of periodate concentration was studied in the range of 1.0×10−5–
1.0×10−4 mol dm−3 at constant concentrations of DPC, ASM, OH− and at constant
ionic strength. The experimental results indicated that the added periodate had a retard-
ing effect on the rate of reaction (Table 1). The order with respect to IO4− concentration
was found to be negative fractional (−0.77) (r ≥ 0.9903, S ≤ 0.001).
3.7 Effect of ionic strength (I) and dielectric constant (D)
The effect of ionic strength (I) was studied by varying KNO3 concentration. Ionic
strength was varied in the range of 0.3–1.0 mol dm−3 at constant concentration of reac-
tants. Dielectric constant of the medium (D) was studied by varying t-butyl alcohol and
water percentage. It was experimentally observed that, both ionic strength and dielectric
constant of the medium did not have any significant effect on the rate of reaction.
3.8 Effect of initially added products
The added products, copper(II) (CuSO4), tropine and benzaldehyde did not have any
significant effect on the rate of reaction.
Thus, from the observed results, the experimental rate law for the reaction is
1.0
0.79
0.55
−
Rate = kobs[DPC] [ASM] [OH−] [IO4 ]−0.77
(1)
3.9 Polymerization study
The intervention of free radicals was detected as follows: the reaction mixture, to which
a known quantity of acrylonitrile (scavenger) had been added initially, was kept for 2 h
in an inert atmosphere. On diluting the reaction mixture with methanol, a white precip-
itate was formed, indicating the intervention of free radicals in the reaction. The blank
experiments of either DPC or ASM alone with acrylonitrile did not induce any poly-
merization under the same condition as those induced for the reaction mixture. Initially
added acrylonitrile decreases the rate of reaction indicating free radical intervention in
the reaction [18].
3.10 Effect of temperature
The kinetics was studied at four different temperatures under varying concentrations of
atropine sulfate, alkali and periodate, keeping other conditions constant. The rate of re-
action increased with increase in temperature. The rate constants (k) of the slow step
of Scheme 1 were obtained from the slopes and the intercepts of the plots of 1/kobs vs.
1/[ASM], 1/kobs vs. 1/[OH−] and 1/kobs vs. [H3IO62−] at four different temperatures.
The energy of activation is obtained from Arrhenius plot, log k vs. 1/T. The enthalpy of
activation, ΔH# and entropy of activation ΔS#, were obtained by Eyring equation [19]
kBT
h
kBT
h
#
#
#
/RT)
+TΔS )/RT
k =
e(−ΔG
=
e−(ΔH
(2)
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242
K. S. Byadagi et al.
Table 2. Effect of temperature on the oxidation of atropine sulfate by alkaline copper(III) periodate com-
plex.
(a) Rate constants with respect to slow step of Scheme 1
Temperature (K)
k × 102 (s−1
)
288
298
308
318
0.39
0.87
1.82
4.01
(b) Activation parameters
Parameters
Value
Ea
58 3 (k J mol−1
56 2 (k J mol−1
)
)
ΔH#
ΔS#
−96 5 (J K−1 mol−1
)
ΔG#
log A
84 4 (k J mol−1
8.2 0.3
)
(c) Effect of temperature on first, second and third equilibrium step of Scheme 1
Temperature
(K)
K1
K2 × 105
K3 × 10−2
(dm3 mol−1
)
(dm3 mol−1
)
(dm3 mol−1
)
288
298
308
318
2.10
1.77
1.49
1.10
0.25
0.58
1.50
2.29
9.34
7.31
5.27
3.34
(d) Thermodynamic quantities with respect to first, second and third step of Scheme 1
Thermodynamic
quantities
Values from
Values from
Values from
K1
K2
K3
ΔH (k J mol−1
ΔS (J K−1 mol−1
ΔG298 (k J mol−1
)
−16.02
−49.16
−1.42
57.44
92.75
29.84
−25.81
−33.2
)
)
−16.34
where k is the rate constant, kB is the Boltzmann’s constant, h is the Planck’s constant,
R is the gas constant, T is the absolute temperature and ΔG# is the free energy of
activation. The linear form of Eq. (2) is
k
ΔH# ΔS#
kB
h
ln = −
+
+ln
R
t
RT
The slope of the plot of log k/T vs. 1/T gives the value of enthalpy of activation, ΔH#.
By using this value of ΔH#, and the rate constant at a particular temperature T, the
value of entropy of activation, ΔS# was obtained by simple rearrangement of Eq. (2).
Using these values of ΔH# and ΔS#, the free energy of activation, ΔG# was obtained
(Table 2).
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Oxidation of a Anticholinergic Drug Atropine Sulfate Monohydrate
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4. Discussion
The water soluble copper(III) periodate complex is reported [20] to be
[Cu(HIO6)2(OH)2]7−. However, in an aqueous alkaline medium and at a high pH range
4−
(pH = 12.6–13.6) as employed in this study, periodate is unlikely to exist as HIO6
(as present in the complex) as is evident from its involvement in the multiple equilib-
ria [11,21] Eqs. (3)–(5) depending on the pH of the solution.
H5IO6 ꢀ H4IO6− +H+
H4IO6− ꢀ H3IO62− +H+
H3IO62− ꢀ H2IO63− +H+
(3)
(4)
(5)
−
Periodic acid exists as H5IO6 in an acid medium and as H4IO6 around pH 7. Thus,
under the conditions employed in alkaline medium, the main species are expected to be
H3IO62− and H2IO63−. At higher concentrations, periodate also tends to dimerise [7,22].
However, formation of this dimer species, H2I2O104− is negligible under conditions em-
ployed for kinetic study. Hence, at the pH = 13.4, employed in this study, the soluble
copper(III) periodate complex exists as diperiodatocuprate(III), [Cu(OH)2(H3IO6)2]3−,
a conclusion also supported by literature [23].
The reaction between DPC and ASM in alkaline medium presents [DPC]/[ASM] =
2 : 1 stoichiometry with first order dependency in [DPC] and fractional order in [ASM]
and [OH−], added periodate retarded the rate and no effect of added products were ob-
served. On the basis of experimental results, a plausible reaction mechanism has been
proposed for which all the observed orders in each constituent may be well accom-
modated. Lister [24] proposed the copper(III) periodate in alkaline medium into three
forms as diperiodatocuprate(III) (DPC), monoperiodatocuprate(III) (MPC) and tetrahy-
droxocuprate(III). The latter is ruled out as its equilibrium constant is 8.0×10−11 at
40 ◦C. Hence, in the present study, in view of the negative less than unit order in perio-
date concentration on rate of reaction, monoperiodatocuprate(III) MPC is considered to
be the active species of copper(III) periodate complex. The structures of DPC and MPC
are as given below.
The results of increase in the rate with increase in alkali concentration and decrease
in the rate with increase in periodate concentration suggest that equilibria of different
copper(III) periodate complexes are possible as in Eqs. (6) and (7).
[Cu(OH)2(H3IO6)2]3− +OH− ꢀ [[Cu(OH)2(H3IO6)(H2IO6)]4− +H2O
(6)
(7)
3−
[Cu(OH)2(H3IO6)(H2IO6)]4− ꢀ [Cu(OH)2(H3IO6)]− +[H2IO6]
−
The inverse fractional order in [IO4 ] might also be due to this reason. Less than unit
order in [ASM] presumably results from formation of a complex (C) between the ox-
idant and atropine sulfate prior to the formation of the products. K3 is the composite
equilibrium constant comprising the equilibrium to bind ASM to MPC species to form
a complex (C). Then this complex (C) decomposes in a slow step to form an intermedi-
ate free radical species and one of the final product tropine derived from atropine sulfate
and byproduct CO2. This intermediate free radical species further reacts with another
mole of MPC species in a fast step to form the final products such as benzaldehyde,
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244
K. S. Byadagi et al.
Scheme 3.
Scheme 4. Detailed Scheme for the oxidation of atropine sulfate by alkaline diperidatocuprate(III).
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Oxidation of a Anticholinergic Drug Atropine Sulfate Monohydrate
245
Scheme 5.
methyl alcohol, Cu(II) and periodate. All these results may be interpreted in a detailed
mechanistic Scheme 1 as shown below.
Since Scheme 1 is in accordance with the generally well accepted principle of non-
complementary oxidations taking place in sequence of one-electron steps, the reaction
between the substrate and oxidant would afford a radical intermediate. A free radical
scavenging experiment revealed such a possibility. This type of radical intermediate has
also been observed in literature [25].
Spectroscopic evidence for the complex formation between oxidant and sub-
strate was obtained from UV-Vis spectra of DPC (5.0×10−5 mol dm−3), ASM
(3.0×10−3 mol dm−3), [OH−] (0.3 mol dm−3) and a mixture of both. A bathochromic
shift of about 4 nm from 253 to 257 nm in the spectra of DPC to mixture of DPC
and ASM was observed. The Michaelis–Menten plot (Fig. 6) proved the complex for-
mation between oxidant and substrate, which explains less than unit order in [ASM].
Such a complex between an oxidant and substrate was also been observed in other
studies [25]. The probable structure of complex is given below.
Scheme 1 leads to the rate law Eq. (8),
−d[DPC]
Rate =
dt
kK1 K2 K3[ASM][OH−][DPC]
=
−
−
−
3−
3−
[H2IO6 ]+ K1[OH ][H2IO6 ]+ K1 K2[OH ]+ K1 K2 K3[ASM][OH ]
Rate
kobs
=
=
(8)
[DPC]
kK1 K2 K3[ASM][OH−]
−
−
−
3−
3−
[H2IO6 ]+ K1[OH ][H2IO6 ]+ K1 K2[OH ]+ K1 K2 K3[ASM][OH ]
which explains all the observed kinetic orders of different species. The rate law Eq. (8)
can be rearranged into the following form, which is suitable for verification.
3−
3−
1
[H2IO6
]
[H2IO6
]
1
1
=
+
+
+
(9)
kobs
kK1 K2 K3[ASM][OH−] kK2 K3[ASM] kK3[ASM]
k
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246
K. S. Byadagi et al.
Fig. 6. Verification of rate law Eq. (8) for the oxidation of atropine sulfate by diperiodatocuprate(III). Plots:
a): 1/kobs vs. 1/[ASM], b): 1/kobs vs. 1/[OH−], c): 1/kobs vs. [H3IO62−] at four different temperatures (con-
ditions as in Table 1).
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Oxidation of a Anticholinergic Drug Atropine Sulfate Monohydrate
247
According to Eq. (9), other conditions being constant, plots of 1/kobs vs. 1/[ASM],
1/kobs vs. 1/[OH−] and 1/kobs vs. [H3IO62−] should be linear and are found to be so
(Fig. 6a–c). The slopes and intercepts of such plots lead to the values of K1, K2,
K3 and k (Table 2). Using these constants, the rate constants were calculated over
different experimental conditions, and there is a reasonable agreement between the cal-
culated and the experimental values (Table 1), which fortifies the proposed mechanism
(Scheme 1).
The equilibrium constant K1 is far greater than K2 which may be attributed to the
greater tendency of DPC to undergo hydrolysis compared to the dissociation of hy-
drolyzed species in alkaline medium.
The negligible effect of ionic strength and dielectric constant of medium on the rate
explains qualitatively the reaction between neutral and negatively charged ion, as seen
in Scheme 1.
The thermodynamic quantities for the different equilibrium steps, in Scheme 1 can
be evaluated as follows. The van’t Hoff plots were made for the variation of K1, K2 and
K3 with temperature (log K1 vs. 1/T, log K2 vs. 1/Tand log K3 vs. 1/T). The values of
enthalpy of reaction ΔH, entropy of reaction ΔS and free energy of reaction ΔG, were
calculated for the first, second and third equilibrium steps. These values are given in
Table 2. A comparison of the thermodynamic quantities of first step of Scheme 1 with
those obtained for slow step of the reaction shows that these values mainly refer to the
rate limiting step, supporting the fact that the reaction before rate determining step is
fairly fast and involves low activation energy. The value of ΔS# is within the range for
a radical reaction and has been ascribed to the nature of electron pairing and unpairing
processes and to the loss of degrees of freedom formerly available to the reactants upon
the formation of rigid transition state [26]. The negative value of ΔS# indicates that the
intermediate complex (C) is more ordered than the reactants [27]. The observed modest
enthalpy of activation and a relatively low value of the entropy of activation, as well as
higher rate constant of the slow step, indicate that the oxidation presumably occurs via
inner-sphere mechanism [28].
5. Conclusion
Among various species of DPC in alkaline medium, monoperiodatocuptrate(III),
(MPC) [Cu(OH)2(H3IO6)]− is considered as active species for the title reaction. The re-
sults indicate that, the role of pH in the reaction medium is crucial. Rate constant of
slow step and other equilibrium constants involved in the mechanism are evaluated and
activation parameters with respect to slow step of reaction were computed. The over-
all mechanistic sequence described here is consistent with product studies, mechanistic
and kinetic studies.
Acknowledgement
One of the authors (Kirthi S. Byadagi) thanks UGC, New Delhi for the award of Re-
search Fellowship in Science for Meritorious Students (RFSMS).
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248
K. S. Byadagi et al.
Appendix
According to Scheme 1,
3−
−d[DPC]
kK1 K2 K3[ASM][OH−][Cu(OH)2(H3IO6)2]
Rate =
= k[C] =
(10)
3−
dt
[H2IO6 ]
4−
[DPC]T = [DPC]f +[Cu(OH)2(H3IO6)(H2IO6)] +[Cu(OH)2(H3IO6)]−+Complex (C)
ꢀ
ꢁ
[H2IO6 ]+ K1[H2IO6 ][OH−]+ K1 K2[OH−]+ K1 K2 K3[OH−][ASM]
3−
3−
= [DPC]f
3−
[H2IO6
]
(11)
Where [DPC]T and [DPC]f refer to total and free DPC concentrations respectively. The
free [DPC] is given by
3−
[DPC]T[H2IO6
]
[DPC]f =
−
−
−
3−
3−
[H2IO6 ]+ K1[H2IO6 ][OH ]+ K1 K2[OH ]+ K1 K2 K3[OH ][ASM]
(12)
Similarly,
[ASM]T = [ASM]f +[C]
3−
[ASM]T[H2IO6
]
[ASM]f =
−
3−
3−
[H2IO6 ]+ K1 K2 K3[OH ][Cu(OH)2(H3IO6)2]
In view of low concentration of DPC used, the term K1 K2 K3 [OH−] [Cu(OH)2
(H3IO6)2]3− compared to [H2IO6]3− can be neglected.
Hence,
[ASM]f = [ASM]T
Similarly,
(13)
[OH−]f = [OH−]
(14)
Substituting Eqs. (12)–(14) in Eq. (10), we get rate law Eq. (15), on omitting the sub-
scripts ‘T’ and ‘f’
kK1 K2 K3[ASM][OH−][DPC]
Rate =
−
−
−
3−
3−
[H2IO6 ]+ K1[H2IO6 ][OH ]+ K1 K2[OH ]+ K1 K2 K3[OH ][ASM]
OR
(15)
Rate
kK1 K2 K3[ASM][OH−]
= kobs
=
−
−
−
3−
3−
[DPC]
[H2IO6 ]+K1[H2IO6 ][OH ]+K1 K2[OH ]+K1 K2 K3[OH ][ASM]
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Oxidation of a Anticholinergic Drug Atropine Sulfate Monohydrate
249
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