Oxidation of 1,3,7-trimethylxanthine by hypochlorite ion

Article abstract of DOI:10.1134/S0036024411080152

The kinetics of the oxidative conversion of 1,3,7-trimethylxanthine upon treatment with hypochlorite ions (OCl^-) in aqueous medium at 283-298 K and pH 8.2 was studied. The reaction order with respect to each component was determined and proved to be 1. It was established that the temperature dependence of the reaction rate follows the Arrhenius equation. The activation parameters of the reaction were measured: E _a = 33.58 kJ/mol, ΔH ^≠ = 31.12 kJ/mol, ΔS ^≠ = -170.02 J/(K mol), ΔG ^≠ = 81.45 kJ/mol. The stoichiometry of the reaction was studied, and the chemistry of the oxidative conversion of caffeine treated with OCl^- is discussed.

Full text of DOI:10.1134/S0036024411080152

ISSN 0036ꢀ0244, Russian Journal of Physical Chemistry A, 2011, Vol. 85, No. 8, pp. 1358–1362. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © V.P. Kheidorov, Yu.A. Ershov, G.Yu. Chalyi, O.V. Titorovich, 2011, published in Zhurnal Fizicheskoi Khimii, 2011, Vol. 85, No. 8, pp. 1472–1476.
CHEMICAL KINETICS
AND CATALYSIS
Oxidation of 1,3,7ꢀTrimethylxanthine by Hypochlorite Ion
V. P. Kheidorova, Yu. A. Ershovb, G. Yu. Chalyia, and O. V. Titorovichb
a Vitebsk State Medical University, Vitebsk, 210023 Belarus
b Bauman State Technical University, Moscow, 105005 Russia
eꢀmail: heidorov@mail.ru
Received December 22, 2010
Abstract—The kinetics of the oxidative conversion of 1,3,7ꢀtrimethylxanthine upon treatment with
hypochlorite ions (OCl–) in aqueous medium at 283–298 K and pH 8.2 was studied. The reaction order with
respect to each component was determined and proved to be 1. It was established that the temperature depenꢀ
dence of the reaction rate follows the Arrhenius equation. The activation parameters of the reaction were
≠
≠
≠
measured: Ea = 33.58 kJ/mol,
Δ
H
= 31.12 kJ/mol,
Δ
S
=
⎯
170.02 J/(K mol), G = 81.45 kJ/mol. The stoꢀ
Δ
ichiometry of the reaction was studied, and the chemistry of the oxidative conversion of caffeine treated with
OCl– is discussed.
Keywords: kinetics, the Arrhenius equation, stoichiometry of reaction, oxidation, caffeine, hypochlorite ions.
DOI: 10.1134/S0036024411080152
INTRODUCTION
In [12], the oxidation of CF and related methylxꢀ
anthines by a free radical in Fe3+
EDTA/H2O2/ascorꢀ
bate ion systems and the Fe3+
EDTA/H2O2/a mixꢀ
ture of polyphenols was discussed. It was pointed out
that oxidation begins with the C8 position in the
purine structure to form a hydroxy group. Further oxiꢀ
⎯
⎯
This work continues our series of studies on the
chemical transformations of biologically active subꢀ
stances treated with oxidating agents containing the
highly active hypochlorite group [1–8].
Caffeine (CF, 1,3,7ꢀtrimethylxanthine) is a natural dation of CF produces N1ꢀ, N3ꢀ, and N7ꢀdemethyꢀ
dihydroxypurine alkaloid (a derivative of purine) conꢀ lated xanthines and small amounts of 6ꢀaminoꢀ5ꢀ(Nꢀ
tained in many popular and widely consumed beverꢀ formylmethylamino)ꢀ1,3ꢀdimethyluracil.
ages such as coffee, tea, and various energy drinks.
The oxidation of CF in the systems UV/H2O2,
Due to the huge popularity of caffeineꢀcontaining
TiO2/UV and in Fenton’s system was studied in [13].
drinks and drugs, caffeine and its derivatives are the
It was noted that CF is initially oxidized to N,N'ꢀdimꢀ
objects of numerous investigations. In [9], it was
ethylparabanic acid, presumably via the addition of an
proved that caffeine effectively traps oxygen’s free radꢀ
OHꢀgroup to the C5=C6 double bond, the second
icals; in [10], its antioxidative activity was detected in
intermediate being di(Nꢀhydroxymethyl)parabanic
situ in instant and real coffee. At the same time, cafꢀ
acid.
feine and its related compounds, which have been used
in medicine to treat various pathologies for more than
100 years, are of interest to researchers due to a recent
study by British biochemists [11] who reported these
alkaloids form a putative basis for the development of
new pharmaceuticals against cancer, cardiovascular
and inflammatory diseases.
CF transformations during ozonation were
reported in [14]. The ozonation of CF in water was
performed at different pH values, including acidic
conditions. Most products resulted from the imidazole
ring opening upon a break of the N9=C8 double bond.
The photooxidation of CF upon treatment with
peroxydiphosphate anions was studied in [15]. The
major oxidation product was 1,3,7ꢀtrimethyluric acid.
Of particular interest in this context is the study of
oxidative transformations of purine derivatives in
order to understand and model the metabolism of this
group of biologically active substances in vitro and
Jayaram and Mayanna investigated the oxidation
in vivo, and the development of methods for analyzing of CF on treatment with chloramineꢀB in HCl
these compounds in different objects, medical and medium at 303–323 K [17] and upon treatment with
biological included. Research in this direction has chloramineꢀT in HCl and NaOH solutions. By studyꢀ
been conducted for several decades, but the reported ing the oxidation of CF, the authors hoped to underꢀ
data on the oxidative conversion of CF were obtained stand the metabolism processes and to find an analogy
under differing experimental conditions [12–21] and to the processes that occurring in an organism, but this
the available results are inconsistent.
analogy was not clearly indicated in the paper. It was
1358

OXIDATION OF 1,3,7ꢀTRIMETHYLXANTHINE BY THE HYPOCHLORITE ION
1359
reported that CF in both cases was oxidized to dimeꢀ
thylalloxan and methylurea.
A
1
0.4
We earlier investigated the reactivity of purine
derivatives toward the oxidative effect of chloramineꢀ
B in a hydrochloric acid medium. It was established
that unlike theophylline, CF yielded no colored prodꢀ
uct with chloramineꢀB under analogous conditions.
The kinetics and thermodynamics of the oxidative
reaction of chloramineꢀB [1, 2] with theophylline
were examined, resulting in the development of highly
sensitive and straightforward methods for the analytiꢀ
cal control of theophylline in medications and body
fluids that were later patented [19–21].
0.2
0
2
30
60
90
120
, min
t
An analysis of recent scientific works shows that the
issues of the oxidative conversions of purine derivatives
including CF and theophylline are complex and
ambiguous rather than simple, and the corresponding
outcomes depend on the nature of the substrate (its
structural analogue), and on the oxidants and experiꢀ
mental conditions.
It is of practical and scientific interest to study the
kinetics of the oxidative transformation of CF comꢀ
pared to theophylline in connection with their metabꢀ
olism and the developments of methods for determiꢀ
nation of the abovementioned compounds and their
structural analogs in various objects, including pharꢀ
maceuticals and biological materials.
The present work investigated the kinetics of the
interaction of CF with the hypochlorite ions (OCl–).
The results of this investigation can be employed for
further examination of the kinetic behavior of other
structural analogs, purinic bases, nucleosides and
nucleotides, and for the optimization of the correꢀ
sponding analytical reactions and methods.
Fig. 1. Accumulation of products of the oxidation of CF
) and theophylline ( ) in one reaction medium at 296 K,
(
1
2
–
–2
–5
pH 8.2, [OCl ] = 1.35
×
10 M,
c
= 10.0 × 10 M,
CF
–5
c
= 5.0 × 10 M.
theophylline
solution, and water (in order to maintain a constant
total volume for all the experiments) were placed in a
reaction vessel and thermostated. The temperature
was maintained with an accuracy of 0.1 K. A meaꢀ
sured amount of the oxidant solution, thermostated at
the same temperature, was quickly added to the reacꢀ
tion mixture. The reaction was conducted with an
excess of hypochlorite ions, and an excess of phenol
immediately stopped the reaction. The absorbance of
the reaction product was measured using an SFꢀ60
spectrophotometer at
λ
= 630 nm. The reaction stoꢀ
ichiometry was calculated from the composition of
reaction mixtures containing different initial concenꢀ
–
trations of CF and
24 h after the onset of the
OCl
reaction at ≈296 K.
RESULTS AND DISCUSSION
EXPERIMENTAL
The obtained results from our comparative experiꢀ
ments showed that in same system (mixture) the oxiꢀ
dation rate of theophylline is several orders of magniꢀ
tude higher than that of CF treated with HC, though
they are very close in terms of structural analogs and
differ only in one group, a methyl radical (–CH3) in
the position N7.
The reagents used in this work were all of chemiꢀ
cally pure grade. Solutions were prepared from bidisꢀ
tilled water. Sodium hypochlorite (HC), prepared by
passing gaseous chlorine through an aqueous solution
of NaOH at 273 K, was used as the oxidative reactant.
The solution was stored in a lightꢀshielded flask in
order to prevent its photochemical decomposition.
The prepared solution was then standardized iodoꢀ
metrically using a standard solution of sodium thiosulꢀ
fate as the titrant and starch as the indicator. Under
these conditions, the HC concentration remained
constant for some time. CF (99%) was obtained from
Sigma. The 0.001 M CF standard solution was preꢀ
pared by dissolving an accurately weighed CF sample
in bidistilled water. Its concentration was determined
O
O
CH3
H
H3C
O
H3C
O
N
N
4
4
N
N
3
2
3
5
6
5
6
7
7
8
8
2
9
N
9
N
1
N
1
N
CH3
caffeine
CH3
theophylline
by UV spectroscopy at
= 273 nm (A11 = 650) [22].
λ
Such an experimental finding in chemical kinetics
(as in the given example for the oxidation of CF and
theophylline by HC) proved unexpected and interestꢀ
ing (Fig. 1).
The medium pH 8.2 was maintained by a borate
buffer solution. The pH was measured by an Iꢀ160 ion
meter equipped with an ESLꢀ43ꢀ07SR glass electrode
and a silver chloride reference electrode. Required
The results were processed on the basis of the
amounts of 1,3,7ꢀtrimethylxanthine solution, buffer kinetic measurements. The oxidation of CF upon
RUSSIAN JOURNAL OF PHYSICAL CHEMISTRY A
Vol. 85
No. 8 2011

1360
KHEIDOROV et al.
of the reaction with respect to the substrate and the
oxidant.
Data on the dependence of the reaction of the conꢀ
5 + logcCF
1.0
0.6
0.6
0.8
1.2
0.1
0.3
0.5
0.7
centration of CF at pH 8.2, 296 K,
[
–] = 1.35
×
OCl
10–2 M is provided below.
1
5
c
×
10 , М
8
2.0 4.0 6.0 8.0 10.0 12.0 14.0
0.48 1.25 2.13 2.86 3.56 4.44 4.95
CF
W
×
10 , mol/(l s)
0.4
0.2
0
This dependence is virtually linear in the logarithꢀ
mic coordinates of steadyꢀstate rate–CF concentraꢀ
tion (Fig. 2, curve ).
1
Data on the dependence of the reaction rate on
[OCl–] at cCF
sented below.
= 10.0 ×
10–5 M, pH 8.2, 296 K is preꢀ
2
–
3
[OCl ]
×
10 , М 2.7 4.1 5.4 6.8 8.1 9.5 10.8 12.2 13.5 14.9
0.72 1.08 1.43 1.79 2.15 2.51 2.87 3.23 3.58 3.96
8
W
×
10 ,
0.6
0.8
1.0
3 + log[OCl−]
1.2
mol/(l s)
This dependence is also linear in logarithmic coorꢀ
dinates (Fig. 2, curve ). The line slopes for CF and the
hypochlorite ion are equal to 1 within the error limits;
hence, the kinetic order in CF and
– is 1.
Fig. 2. Dependence of the logarithm of the rate of reaction
2
product accumulation on the logarithm of reactant conꢀ
centrations: (
1)
c
, (2) cOCl– at 296 K, pH 8.2.
CF
OCl
From the above data, it follows that the kinetics
OCl–
of the reaction of CF with
the law
is described by
treatment with HC under experimental conditions
proceeded in such a way that kinetic curves for subꢀ
strate consumption and product accumulation can
be divided into two parts with different rate laws
(Fig. 1). The experimental character of the kinetic
curves at different CF and HC concentrations at an
initial temporal segment (until 30 min) when a sigꢀ
nificant amount of CF (>70%) is converted to reacꢀ
tion products is linear.
dc/dt = kсCF[OCl−],
(1)
where cCF, [OCl–] represent the concentrations of CF
and [OCl–], respectively.
The rate constant values calculated by Eq. (1)
remain satisfactorily constant within the experimental
error over the studied range of reactant concentraꢀ
tions. At 296 K, k = 2.64 0.15 ×
10–2 l/(mol s).
From an analysis of the kinetic curves obtained for
an excess of oxidant it follows that it seemingly attacks
not only CF but also the formed reaction product,
since a pronounced maximum of product accumulaꢀ
tion was observed in the experiments. The product
concentration began to fall after a period of some time
The temperature dependence of the reaction rate
in the interval 283 to 298 K (Fig. 3) is described by the
Arrhenius equation
k
= 2.21
= 2.21
104 l/(mol s); activation energy Ea
33.58 kJ/mol. Parameters of the activation state are as
×
104exp(–33.58/RT),
where
A
×
=
(Fig. 1, curve
2).
≠
follow: activation enthalpy
Δ
H
= 31.12 kJ/mol; actiꢀ
= –170.02 J/(mol K); Gibbs
energy G = 81.45 kJ/mol.
The temperature dependence of the reaction rate
≠
vation entropy
Δ
S
was studied in the range of 283 298 K. The experiꢀ
⎯
≠
Δ
mental results are well described within the Arrhenius
equation.
Negative entropy and a low preꢀexponential facꢀ
tor are characteristic of many oxidations, complex
ion–molecular processes, and the formation of
intermediate complexes. The high positive values of
A change in the ionic strength in the reaction
medium upon the addition of varied amounts of 0.1 M
NaCl solution had virtually no effect on the oxidation
rate. The addition of cobalt salts resulted in an
increase in the reaction rate and in an increase in
product yield.
≠
≠
Δ
H
and
Δ
G suggest that the transition state is highly
solvated.
Experiments on determining the reaction stoichiꢀ
ometry demonstrated that the ratio of the consumed
amount of
– to the amount of oxidized CF ranges
OCl
The dependence of the oxidation rate on the
concentration of CF and hypochlorite ions was
from 1 to 5 mol when the initial molar concentration
ratio [OCl–]/cCF is increased from 0.1 to 10. Oxidaꢀ
investigated in order to determine the kinetic order tion stops at intermediate steps if an excess of CF is
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OXIDATION OF 1,3,7ꢀTRIMETHYLXANTHINE BY THE HYPOCHLORITE ION
1361
–
present. Conversely, if an excess of
is present, thus required for the deep oxidation of 1 mol CF:
OCl
the process proceeds to such highly oxidized end
products as symmetric N,N'ꢀdimethylurea, methyꢀ
lurea, and so on.
−
+
−
.
(I)
4OCl +8e +8H = 4Cl + 4H2O
Reduction of the hypochlorite ion to the chloride
ion requires the addition of two electrons and two proꢀ
The oxidation of CF upon treatment with
– is
OCl
–
tons. According to our experiments, 4 mol
is accordingly described by the equation:
OCl
H
N
H
N
O
CH3
N
H3C
H3C
CH3
H3C
O
O
N
+ 4OCl– + 2HOH
+ 3CO2 + 4Cl–.
(II)
H
N
N
O
N
NH2
CH3
Given the experimental results and our analysis of
Aqueous solutions in the reaction system under
literature data on the conversions of purinic bases investigation contain an excess of hydroxide ions
–
resulting from the hydrolysis of
:
and xanthine derivatives [23], the mechanism of
reaction (II) can be represented as follows: The priꢀ
mary product of the reaction of HC with CF in a
OCl
HOCl + OH–.
The thermodynamic equilibrium constant of the
reaction
– + HOH
↔
(IV)
OCl
weakly alkaline aqueous medium is 8ꢀoxocaffeine,
–
which undergoes further oxidation by
to proꢀ
OCl
duce a series of products of the cleavage of the hetꢀ
erocyclic purine system [24].
NH2Cl + OH–
↔
NH2OH + Cl–
(V)
in an alkaline medium is determined by the ratio
Saturation of the conjugated electron system at
π
the C5=C6 double bond leads to the rapid disapꢀ
pearance of the characteristic ultraviolet absorꢀ
bance at λmax = 273 nm. After the formation of 5,6ꢀ
,
)
(2)
K = aNH OHaCl− /(aNH Cla
OH−
2
2
where
,
,
,
2
are the activities of the
aNH OH aCl− aNH Cl aOH−
dioxocaffeine, a hydrolytic cleavage at the C5
⎯
C6
2
corresponding particles.
bond occurs to form methylparabanic acid. Upon
further oxidation, this is decarboxylated to yield
methylurea, which is in turn oxidized to release
chloramine:
8 + log
0.55
W
H
N
NH2
O
+ OCl–
H3C
O
H
(III)
0.45
0.35
+ NH2Cl.
H3C N
O−
The formation of chloramine was detected photoꢀ
metrically at λmax = 244 nm.
Chloramine is unstable thermodynamically, and
its accumulation, chemical equilibrium, and
0.25
3.35
3.45
3.55
hydrolysis can be characterized by curves
1 and 2
1
103/ , K−
T
(Fig. 1). Figure 1 shows that there is an initial
increase in the product concentration. An equilibꢀ
rium plateau is then observed, after which the conꢀ
centration of the reaction product begins to graduꢀ
ally decline.
Fig. 3. Dependence of the reaction rate logarithm on the
–2
inverse temperature at cOCl– = 1.35
–5
×
10 M,
с
=
CF
10.0
× 10 M, pH 8.2.
RUSSIAN JOURNAL OF PHYSICAL CHEMISTRY A
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1362
KHEIDOROV et al.
9. X. Shi, N. S. Dalai, and A. C. Jain, Food Chem. Toxiꢀ
CONCLUSIONS
col. 29, 1 (1991).
We established that the oxidative transformation of
CF upon treatment with HC occurs slowly at 283–
298 K in several steps. The formation and composition
of intermediate and final products depend on the subꢀ
strate/oxidant molar ratio, their nature, and the reacꢀ
tion conditions. It would be interesting to continue
this study by investigating the kinetics and mechanism
of the oxidative conversion of other purine derivatives,
including nucleosides and nucleotides.
10. R. H. Stadler and L. B. Fay, J. Agricult. Food Chem. 43
,
1332 (1995).
11. L. C. Foukas, J. Jensen, P. R. Shepherd, et al., J. Biol.
Chem. 271, 37124 (2002).
12. R. H. Stadler, J. Richoz, R. J. Turesky, et al., Free Rad.
Res. 24, 225 (1996).
13. I. Dalmazio, L. S. Santos, R. P. Lopes, et al., Environ.
Sci. Technol. 39, 5982 (2005).
A method for determining CF in medicoꢀpharmaꢀ
ceutical objects has been developed on the basis of
these investigations into the kinetics of the CF oxidaꢀ
tion. This material has been submitted to the Belarus
National Center for Intellectual Property.
14. R. Rosal, A. Rodriguez, J. A. PerdigonꢀMelon, et al.,
Chemosphere 74, 825 (2009).
15. M. R. Kumar and M. Andinarayana, Proc. Ind. Acad.
Sci. (Chem. Sci.) 112, 551 (2000).
16. K. A. Regal, K. L. Kunze, R. M. Peter, and S. D. Nelꢀ
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