Kinetics and mechanistic approach to the oxidative behavior of biological anticancer platinum(IV) complex toward L-asparagine in acid medium and the effect of copper(II) catalyst

Article abstract of DOI:10.1002/kin.20886

The catalytic effect of copper(II) ions toward the oxidation of L-asparagine (Asn) by an anticancer platinum(IV) complex in the form of hexachloroplatinate(IV) (HCP) has been investigated in aqueous acid medium at the constant ionic strength and temperature. The progress of both uncatalyzed and copper(II)-catalyzed oxidation reactions has been monitored spectrophotometrically. The stoichiometry in both cases is [Asn]/[HCP] = 1:1. The kinetics of both redox reactions is first order with respect to [oxidant] and less than the unit order in [acid]. The order with respect to [Asn]_T decreases from unity in the uncatalyzed path to less than unity in the catalyzed one. The catalyzed path is first order in [Cu^II]_T. Increasing ionic strength and dielectric constant decreases the oxidation rates. The final oxidation products of L-asparagine are identified as the corresponding aldehyde (α-formyl acetamide), ammonium ion, and carbon dioxide. Tentative mechanisms of both reactions have been suggested. The appropriate rate laws are deduced. The activation parameters of the uncatalyzed reaction have been evaluated and discussed.

Full text of DOI:10.1002/kin.20886

Kinetics and Mechanistic
Approach to the Oxidative
Behavior of Biological
Anticancer Platinum(IV)
Complex toward
L-Asparagine in Acid
Medium and the Effect of
Copper(II) Catalyst
AHMED FAWZY1,2
1Chemistry Department, Faculty of Science, Assiut University, Assiut, 71516, Egypt
2Chemistry Department, Faculty of Applied Sciences, Umm Al-Qura University, Makkah Al-Mukarramah, 13401, Saudi
Arabia Kingdom
Received 25 April 2014; revised 4 October 2014; accepted 4 October 2014
DOI 10.1002/kin.20886
Published online 5 November 2014 in Wiley Online Library (wileyonlinelibrary.com).
ABSTRACT: The catalytic effect of copper(II) ions toward the oxidation of L-asparagine (Asn)
by an anticancer platinum(IV) complex in the form of hexachloroplatinate(IV) (HCP) has been
investigated in aqueous acid medium at the constant ionic strength and temperature. The
progress of both uncatalyzed and copper(II)-catalyzed oxidation reactions has been monitored
spectrophotometrically. The stoichiometry in both cases is [Asn]/[HCP] = 1:1. The kinetics of
both redox reactions is first order with respect to [oxidant] and less than the unit order in
[acid]. The order with respect to [Asn]T decreases from unity in the uncatalyzed path to less
than unity in the catalyzed one. The catalyzed path is first order in [CuII]T. Increasing ionic
strength and dielectric constant decreases the oxidation rates. The final oxidation products of
L-asparagine are identified as the corresponding aldehyde (α-formyl acetamide), ammonium
ion, and carbon dioxide. Tentative mechanisms of both reactions have been suggested. The
Correspondence to: A. Fawzy; e-mail: afsaad13@yahoo.com.
C
ꢀ
2014 Wiley Periodicals, Inc.

2
FAWZY
appropriate rate laws are deduced. The activation parameters of the uncatalyzed reaction have
ꢀC
been evaluated and discussed. 2014 Wiley Periodicals, Inc. Int J Chem Kinet 47: 1–12, 2015
likely to be due to effective PtIV transport into the
cell, followed by reduction to the more reactive plat-
inum(II) compounds. Studies of oxidation of inor-
ganic and organic substrates using platinum(IV) com-
plexes in the form of hexachloroplatinate(IV) (HCP),
[PtCl6]2−, as an oxidant are scarce and limited to a
few cases [12–19], in which [PtCl6]2− may behave as
one- or two-electron oxidant, depending on the sub-
strate and experimental conditions. The knowledge of
the reactivity of platinum(IV) compounds toward their
reduction by a potential bioreductant like L-asparagine
may be important for understanding the mechanism of
where antitumor activity as well as for designing new
compounds with the least side effect. Chois et al. [19]
reported that there is a correlation between a rate of
reduction and anticancer activity in a series of homol-
ogous platinum(IV) complexes without going into the
details of the reaction mechanism.
Transition metal ions have been widely employed
as homogeneous catalysts for oxidation of organic and
inorganic substrates by one of different paths such as
formation of complexes with the reactants, oxidation
of substrate itself, or through the formation of free rad-
icals [20]. Studies of the oxidation reactions of amino
acids catalyzed by metal ions are an important field
of chemistry due to the role played by metals in bio-
logical systems. Copper(II) complexes of amino acids
present important pharmacological interest as several
of them show a wide spectrum of effects, including
anti-inflammatory, antiulcer, anticonvulsant, and even
antitumoral activity [21,22]. In the pharmacological
activity of certain copper complexes when compared
with that of the free ligands, the complexes are usually
more active than the parent ligands. Some copper(II)
complexes with L-asparagine have been reported in
earlier studies [23–25].
INTRODUCTION
Oxidation reactions are of fundamental importance in
nature and are regarded as key transformations in or-
ganic synthesis. Kinetic investigations on the homoge-
neous catalyzed oxidation of organic compounds in a
liquid phase are considerably limited, and, therefore,
the mechanistic exposition of such reactions has valu-
able contribution to the knowledge of chemistry.
The study of amino acids is one of the most exciting
fields of organic chemistry. They play a significant role
in a number of metabolic reactions such as biosynthe-
sis of polypeptide, protein, and nucleotides. Thus the
mechanism of analogous nonenzymatic chemical pro-
cesses in the oxidation of amino acids is a potential
area for intensive investigation [1] to understand some
aspects of enzyme kinetics. The oxidation of α-amino
acids is of great importance both from chemical point
of view and its bearing on the mechanism of amino
acids metabolism. They have been oxidized by a va-
riety of reagents under different experimental condi-
tions, and they often undergo oxidative decarboxyla-
tion and deamination [2–8].
L-Asparagine is one of the amino acids that oc-
cur in relatively high concentrations in plant tissues.
Its role in the metabolism is crucial. It finds exten-
sive applications in the production of pharmaceuticals
and medicine, and as a reducing agent in chemical
and biochemical systems. The rate of reduction by L-
asparagine depends on the oxidant nature and pH of
the medium. The oxidation of L-asparagine has been
previously studied by few reagents such as sodium N-
chloro-p-toluene sulfonamide catalyzed by CuII in al-
kaline media [4], alkaline diperiodatonickelate(IV) [5],
peroxydisulfate in acid medium [6], and permanganate
in acid [7] and alkaline [8] media. In most cases, the
final oxidation products of L-asparagine were α-formyl
acetamide, ammonia, and carbon dioxide.
An extensive literature survey revealed no report on
the mechanistic studies of oxidation of L-asparagine
by hexachloroplatinate(IV) in acid medium. Hence, we
felt it would be worthwhile to investigate the oxidative
behavior of hexachloroplatinate(IV) with L-asparagine
in the absence and presence of copper(II) catalyst to ex-
plore the kinetic and mechanistic aspects of such redox
reactions in strong acid medium. This study will en-
able to understand the complicated biological reaction
in living systems and will also help to understand the
catalyticactivityof CuII along withtheoxidative capac-
ity of hexachloroplatinate(IV). In view of the above-
mentioned arguments and the dearth of literature on
Many metal ions in their complex form act as good
oxidants in acidic, basic, and neutral media. How-
ever, oxidation capacity depends on their redox po-
tential, and the latter depends on pH of the medium.
There has been significant interest in the chemistry of
biologically active platinum(IV) complexes for their
remarkable anticancer properties [9–11]. Octahedral
platinum(IV) complexes appeared attractive because
they are usually substitution inert and require reduc-
tion to PtII species to act as potential anticancer drugs.
The anticancer activity of platinum(IV) complexes is
International Journal of Chemical Kinetics DOI 10.1002/kin.20886

OXIDATIVE BEHAVIOR OF BIOLOGICAL ANTICANCER PLATINUM(IV) COMPLEX
3
the oxidation of this amino acid, I have carried out a
detailed study of the title reaction.
alyzed paths. Thus, the total rate constant (kT) is equal
to the sum of the rate constants of the catalyzed (kC)
and uncatalyzed (kU) reactions, so kC = kT – kU. The
pseudo–first-order rate constants (kU and kC) were de-
termined from the slopes of the initial linear portions
of ln(absorbance) versus time plots. The rate constants
were the average of at least three independent kinetic
runs and were reproducible to within 4%.
EXPERIMENTAL
Materials and Methods
Materials. All chemicals employed in the present
work were of reagent grade, and their solutions were
prepared by dissolving the requisite amounts of the
samples in doubly distilled water. A stock solution
of L-asparagine (Asn; E. Merck, Germany) was pre-
pared afresh by dissolving the amino acid sample in
bidistilled water. Chloroplatinic acid solution (Johnson
Matthey, USA) was used without further purification.
Required solution of the reagent was freshly prepared
before each experiment by proper dilution of its origi-
nal solution, which was standardized spectrophotomet-
rically [26]. The solution was stored in a dark bottle to
keep away from light and restandardized periodically.
The ionic strength, I, of the reaction mixtures was ad-
justed to 2.0 mol dm−3 using Na2SO4. The reactions
temperature (25°C) was controlled within 0.1°C.
Kinetic Measurements. The kinetic runs were fol-
lowed under pseudo–first-order conditions with L-
asparagine in at least a ten-fold excess over that of
hexachloroplatinate(IV) at 25°C unless stated oth-
erwise. The reactions were initiated by mixing the
previously thermostated solutions of hexachloroplati-
nate(IV) and L-asparagine that also contained the cal-
culated amount of H2SO4 and Na2SO4 to maintain the
required acidity and ionic strength, respectively, and a
copper(II) catalyst in the case of a catalyzed reaction.
The courses of the reactions were followed by record-
ing the decrease in absorbance, as a function of time,
of hexachloroplatinate(IV) at its absorption maximum
(262 nm), where hexachloroplatinate(IV) absorbs to a
considerably greater extent than any of the other re-
actants and products, in a thermostated quartz cell on
a Shimadzu UV-1800 PC automatic scanning double-
beam spectrophotometer. The applicability of Beer’s
law was verified at 262 nm under the reaction condi-
tions that the molar extinction coefficient, ε, was deter-
mined (ε = 1.32 0.03 × 104 dm3 mol−1 cm−1) and
was found to be in a good agreement with that reported
previously [26]. Also, there was no interference from
other reagents at this wavelength.
The effect of dissolved oxygen on the reaction rates
was checked by preparing the reaction mixtures and
following the reactions under a nitrogen atmosphere.
There are no significant changes in the results obtained
in the presence of nitrogen from those in the presence
of air.
RESULTS
Spectral Scans
The UV–vis spectral scans during the courses of the
reactions between L-asparagine and hexachloroplati-
nate(IV) in the absence and presence of the copper(II)
catalyst are shown in Figs. 1a and 1b, respectively.
The spectrum of [PtCl6]2− ions exhibits one absorp-
tion band with a maximum at λmax = 262 nm. A grad-
ual decrease in [PtCl6]2− absorbance at its absorption
maximum with time was observed without formation
of new absorption bands, isosbestic points, or shifting
λmax
.
Stoichiometry and Product Analysis
Different sets of reaction mixtures containing various
amounts of hexachloroplatinate(IV) and L-asparagine
at fixed acidity, ionic strength, and temperature were
allowed to react for 24 h in an inert atmosphere. Af-
ter completion of the reactions, the unreacted [PtCl62−
]
was assayed spectrophotometrically by measuring the
absorbance at 262 nm, showing that 1 mol of [PtCl6]2−
consumed 1 mol of L-asparagine. The reaction stoi-
chiometry may thus be represented as follows:
H2N(CO)CH2 − CH(NH2)COOH + [PtCl6]2− + H2O
= H2N(CO)CH2 − CHO + NH+4 + CO2
+ [PtCl4]2−+ 2Cl−+ H+
(1)
The reactions were followed for more than three
half-lives. As the reduction of hexachloroplatinate(IV)
by L-asparagine in acid medium proceeds with a mea-
surable rate in the absence of copper(II) ions, the cat-
alyzed reaction is understood to occur in parallel paths,
with contributions from both the catalyzed and uncat-
The above stoichiometric equation is consistent
with the results of products analysis. The products were
identified as the corresponding aldehyde (α-formyl ac-
etamide) by the spot test [27], the ammonium ion by
International Journal of Chemical Kinetics DOI 10.1002/kin.20886

4
FAWZY
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
Pt IV
PtIV
(a)
(b)
Asn
Asn
CuII
0.0
200
200
225
250
275
300
325
350
225
250
275
300
325
350
Wavelength, nm
Wavelength, nm
Figure 1 Spectral scans for (a) uncatalyzed and (b) copper(II)-catalyzed oxidation of L-asparagine by hexachloroplatinate(IV)
in sulfuric acid medium. [Asn] = 6 × 10−2, [PtCl62−] = 7.6 × 10−5, [H+] = 1.0 and I = 2.0 mol dm−3 at 25°C. Scanning time
intervals = 2 min. [CuII] = 5 × 10−4 mol dm−3
.
Table I Influence of [PtCl62−], [Asn], [H+], and Ionic
Strength, I, on the Pseudo–First-Order Rate Constant
Values in the Uncatalyzed Oxidation of l-Asparagine by
Hexachloroplatinate(IV) in Sulfuric Acid Medium at
25°C.
Nessler’s reagent [28], and carbon dioxide by lime-
water. The product α-formyl acetamide was also esti-
mated quantitatively as its 2,4-Dinitrophenylhydrazine
derivative [28]. It was further observed that the alde-
hyde does not undergo further oxidation under the
present experimental conditions, where a test for the
corresponding carboxylic acid was negative. Similar
oxidation products with different experimental condi-
tions have also been reported earlier [4–8]. On the other
hand, the formation of [PtCl4]2− was confirmed [29] by
the observed black precipitate of platinum(II) hydrox-
ide on the addition of alkali to the reaction mixture,
according to the following reaction:
×105
×105
[PtCl62−
]
×102 [Asn]
[H+]
I
kU
(mol dm−3) (mol dm−3) (mol dm−3) (mol dm−3) (s−1
)
4.0
6.0
7.6
10.0
12.0
6.0
6.0
6.0
6.0
6.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
2.0
27.3
27.8
28.0
29.1
28.2
7.6
7.6
7.6
7.6
7.6
2.0
4.0
6.0
8.0
10.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
2.0
10.2
18.1
28.0
34.4
43.0
[PtCl4]2−+ 2OH−= Pt(OH)2 + 4Cl−
Furthermore, a similar product was reported by oth-
ers [29,30] for the reaction between [PtCl6]2– and dif-
ferent reductants.
7.6
7.6
7.6
7.6
7.6
6.0
6.0
6.0
6.0
6.0
0.2
0.5
1.0
1.5
2.0
2.0
2.0
2.0
2.0
2.0
9.8
17.1
28.0
42.9
55.7
Reaction Order
The reaction orders (n) with respect to the reactants for
both uncatalyzed and catalyzed reactions were deter-
mined from the slopes of the log kU and log kC versus
log (concentration) plots using the relationship (log k =
n log C + constant) by varying the concentrations (C)
of substrate, acid, and catalyst, in turn, while keeping
other conditions constant.
7.6
7.6
7.6
7.6
7.6
6.0
6.0
6.0
6.0
6.0
1.0
1.0
1.0
1.0
1.0
2.0
2.5
3.0
3.5
4.0
28.0
25.2
22.5
20.3
19.5
Experimental error 3%.
The oxidant, hexachloroplatinate(IV), was varied in
the range from 4 × 10−5 to 12 × 10−5 mol dm−3 while
keeping other conditions constant. It has been observed
that the increase in the oxidant concentration does not
alter the oxidation rate of L-asparagine (Table I). This
indicates that the rate of oxidation is independent of
the oxidant concentration and the order of reaction
with respect to the oxidant is confirmed to be one.
The observed pseudo–first-order rate constants
(kU and kC) were determined at different initial
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OXIDATIVE BEHAVIOR OF BIOLOGICAL ANTICANCER PLATINUM(IV) COMPLEX
5
These results show that the pseudo–first-order rate con-
stants (kU and kC) decrease with an increase in the ionic
strength of the medium, and the Debye-Hu¨ckel plots
were linear with negative slopes (Fig. 3).
120
90
60
30
0
Uncatalyzed reaction
Catalyzed reaction
Effect of the Dielectric Constant
The dielectric constant or the relative permittivity (D)
effect was studied by varying the t-butyl alcohol–water
content in the reaction mixtures at 25°C. The rate con-
stants increase with the decrease in the dielectric con-
stant of the solvent mixture. The plots of log kU and log
kC versus 1/D were linear with positive slopes (figure
not shown).
0.0
0.5
1.0
1.5
2.0
[H+], mol dm-3
Effect of the [CuII] Catalyst
Figure 2 Plots of pseudo–first-order rate constants kU and
kC versus [H+] in the uncatalyzed and copper(II)-catalyzed
oxidation of L-asparagine by hexachloroplatinate(IV) in sul-
furic acid medium. [Asn] = 6 × 10−2, [PtCl62−] = 7.6 ×
10−5, and I = 2.0 mol dm−3 at 25°C. [CuII] = 5 ×
The reaction rate was measured with various [CuII],
(3–8) ×10−4 mol dm−3, while other variables re-
main constant. The reaction rate enhances with the
increase in [CuII] (Table II). A plot of kC versus [CuII]
(Fig. 4) yielded a good linear plot passing through ori-
gin, suggesting that the order with respect to [CuII] is
one as also confirmed from the plot of log kC versus
log[CuII] (slope ࣈ 1).
10−4 mol dm−3
.
concentrations of the reductant L-asparagine, whereas
other variables such as the concentration of the oxidant,
copper(II) catalyst, and sodium sulfate were kept con-
stant. The pH and temperature were also kept constant.
Plots of the observed rate constants versus [Asn]T at the
constant pH are linear, passing through origin for the
uncatalyzed reaction and with a positive intercept for
the catalyzed one. These observations confirm the first-
order and fractional first-order (n = 0.91) dependences
with respect to the amino acid for the uncatalyzed and
catalyzed reactions, respectively.
Effect of Temperature
The influence of temperature on the rate of uncatalyzed
reaction was studied at 20, 25, 30, and 35°C by keeping
other variables constant. The observed rate constant kU
increases with raising of the temperature.
Polymerization Study
To study the possible presence of free radicals during
the uncatalyzed and catalyzed reactions, the reaction
mixtures to which a known amount of an acrylonitrile
scavenger was initially added and was kept for 6 h
in an inert atmosphere. On diluting the mixtures with
methanol, no white precipitate was formed thus con-
firming the absence of free radical intervention in these
reactions.
Although the second-order rate constants were de-
termined only at [H+] = 1 mol dm−3, the influence of
pH was tested by measuring pseudo–first-order reac-
tion rate coefficients at constant [Asn], [PtCl62−], [CuII]
(for the catalyzed reaction), ionic strength and tem-
perature but with various [H+] (0.2–2.0 mol dm−3).
The pseudo–first-order rate constants were found to
increase with an increase in [H+]. Plots of kU and
kC versus [H+] were linear with positive intercepts as
shown in Fig. 2, confirming fractional first-order de-
pendences with respect to [H+].
DISCUSSION
Nature of L-Asparagine in Acid Medium
Effect of Ionic Strength
Generally, amino acids are known [31] to exist in zwit-
terionic forms in equilibrium with anionic and cationic
forms depending upon the pH of the solution according
to the following equilibria:
To investigate the effect of the ionic strength on both
catalyzed and uncatalyzed reactions, the reactions were
studied at several initial concentrations of sodium sul-
fate but at constant concentrations of L-asparagine,
[PtCl6]2–, and CuII, and at constant pH and temper-
ature. The results are presented in Tables I and II.
International Journal of Chemical Kinetics DOI 10.1002/kin.20886

6
FAWZY
Table II Influence of [PtCl62−], [Asn], [H+], [CuII], and Ionic Strength, I, on the Pseudo–First-Order Rate Constant in
the Copper-Catalyzed Oxidation of l-Asparagine by Hexachloroplatinate(IV) in Sulfuric Acid Medium at 25°C.
×105 [PtCl62−
]
×102 [Asn]
[H+]
×104 [CuII]
I
×105 kC
(mol dm−3
)
(mol dm−3
)
(mol dm−3
)
(mol dm−3
)
(mol dm−3
)
(s−1
)
4.0
6.0
7.6
10.0
12.0
6.0
6.0
6.0
6.0
6.0
1.0
1.0
1.0
1.0
1.0
5.0
5.0
5.0
5.0
5.0
2.0
2.0
2.0
2.0
2.0
65.2
68.3
66.7
63.6
69.8
7.6
7.6
7.6
7.6
7.6
2.0
4.0
6.0
8.0
10.0
1.0
1.0
1.0
1.0
1.0
5.0
5.0
5.0
5.0
5.0
2.0
2.0
2.0
2.0
2.0
27.7
46.5
66.7
83.3
101.3
7.6
7.6
7.6
7.6
7.6
6.0
6.0
6.0
6.0
6.0
0.2
0.5
1.0
1.5
2.0
5.0
5.0
5.0
5.0
5.0
2.0
2.0
2.0
2.0
2.0
24.8
40.9
66.7
86.1
104.7
7.6
7.6
7.6
7.6
7.6
6.0
6.0
6.0
6.0
6.0
1.0
1.0
1.0
1.0
1.0
3.0
4.0
5.0
6.0
8.0
2.0
2.0
2.0
2.0
2.0
40.2
55.4
66.7
89.9
110.2
7.6
7.6
7.6
7.6
7.6
6.0
6.0
6.0
6.0
6.0
1.0
1.0
1.0
1.0
1.0
5.0
5.0
5.0
5.0
5.0
2.0
2.5
3.0
3.5
4.0
66.7
58.9
55.5
52.1
46.8
Experimental error 4%.
where R is H2N(CO)CH2 and K1 is the stepwise pro-
tonation constant of L-asparagine.
-7.2
-7.6
-8.0
Because of the concentration of the hydrogen ion
employed in the present reactions is sufficiently high
as well as the observed enhancement of the reaction
rates on increasing acid concentration, with a fractional
first-order dependence on [H+], the protonated form of
L-asparagine (Asn+) may be the reactive species in the
rate-determining step, which plays the main role in the
reaction kinetics.
Uncatalyzed reaction
Catalyzed reaction
-8.4
0.52
0.56
0.60
0.64
0.68
Nature of Hexachloroplatinate(IV) Species
I1/2 / (1+I1/2)
In acid medium, Kramer and Koch [32] reported that
platinum(IV) species is present as [PtCl6]2−, which
is assumed to be the principal reactive oxidant. The
reduction of [PtCl6]2− generally proceeds as follows:
Figure 3 Debye–Hu¨ckel plots in the uncatalyzed and
copper(II)-catalyzed oxidation of L-asparagine by hex-
achloroplatinate(IV) in sulfuric acid medium. [Asn] = 6 ×
10−2, [PtCl62−] = 7.6 × 10−5, and [H+] = 1.0 mol dm−3 at
25°C. [CuII] = 5 × 10−4 mol dm−3
.
[PtCl6]2−+ 2e−= [PtCl4]2−+ 2Cl−
In this redox process, octahedral PtIV is reduced to
square planar PtII with release of two Cl− ions. There-
fore, this reaction is better classified as a reductive-
elimination reaction [33]. The reduction potential of
PtIV/PtII couple has been measured [34] as 0.68 V.
International Journal of Chemical Kinetics DOI 10.1002/kin.20886

OXIDATIVE BEHAVIOR OF BIOLOGICAL ANTICANCER PLATINUM(IV) COMPLEX
7
a one-step two-electron mechanism or by a two suc-
cessive one electron transfer mechanism.
120
90
60
30
0
Mechanism of Uncatalyzed Oxidation
Reaction
The experimental data show that the pseudo–first-order
rate constant for reduction of [PtCl6]2− increases with
decreasing pH with a fractional first-order dependence
on [H+], suggesting that the amino acid substrate is
first subjected to protonation (Eq. (2)).
The reaction between L-asparagine and [PtCl6]2-
has a stoichiometry of 1:1 with the first-order depen-
dence on both [PtCl6]2− and L-asparagine. The rate
of reaction decreases on increasing the ionic strength
and dielectric constant of the medium, suggesting that
the reaction occurs between two ions with opposite
charge [39,40].
0
2
4
6
8
104 [CuII], mol dm-3
Figure 4 Plot of kC versus [CuII] in the copper(II)-
catalyzed oxidation of L-asparagine by hexachloroplati-
nate(IV) in sulfuric acid medium. [Asn] = 6×10−2, [PtCl62−
]
Initial complex formation between [PtCl6]2− and L-
asparagine can be excluded because of the substitution
inertness of [PtCl6]2−. This is also confirmed by the
absence of any spectroscopic evidence for the forma-
tion of such a complex in the UV–vis spectra as shown
in Fig. 1a. Furthermore, the independence of [Asn]
to the well–known Michaelis–Menten [41] kinetics,
1/kU versus 1/[Asn], for enzyme-substrate reactions is
considered as a kinetic evidence against intermediate
formation.
A plausible mechanism for the redox process in-
volves protonation of L-asparagine followed by an at-
tack of the protonated amino acid on [PtCl6]2− to give
rise to the oxidation products as depicted by the fol-
lowing equations:
= 7.6 × 10−5, [H+] = 1.0 and I = 2.0 mol dm−3 at
25°C.
Reaction Mechanism
Since platinum(IV) complexes are generally substitu-
tion inert [35], initial complex formation prior to elec-
tron transfer does not normally take place in reductive-
elimination reactions [36] and electron transfer by a
substitution controlled inner sphere mechanism is un-
likely [35]. Halide-mediated reductive-elimination re-
actions of platinum(IV) complexes involving various
inorganic [36] and biological [19,30] reductants have
been suggested to take place via a nucleophilic attack
by the reductant on a coordinated halide to a good leav-
ing center, PtIV [30]. Reductive-elimination reactions
of platinum(IV) compounds via a halide-bridged ac-
tivated complex are formally equivalent to a transfer
of Cl+ from the oxidizing PtIV center to the reducing
nucleophile, followed by loss of the trans ligand [37].
Two alternative reaction mechanisms for the oxida-
tion of L-asparagine by hexachloroplatinate(IV) may
be considered. The first mechanism involves a simul-
taneous two-electron transfer in a single step. The sec-
ond one involves two successive one-electron transfer
steps. If the transition states of reductant and/or oxi-
dant are unstable, a simultaneous two-electron transfer
mechanism may be suggested such as that in the oxi-
dation of uranium(IV) by [PtCl6]2- [38]. In the present
study, addition of an acrylonitrile monomer to the re-
action mixture failed to give polymerized products. It
may be that the free radical like PtIII species is too
short-lived to interact with acrylonitrile to give the
polymerized product under our experimental condi-
tions. Consequently, the reaction can proceed either by
K1
Asn + H+ ꢀ Asn+
(2)
(3)
k1
Asn++ [PtCl6]2− −→ Products
slow
Within the protolytic L-asparagine system, there are
carboxylate and amine groups, which may act as nu-
cleophiles toward coordinated chloride, depending on
pH of the medium [42]. The protolytic group with the
highest basicity interacts with the platinum(IV) com-
plex in the rate–determining step. Thus, at low pH,
where the amine group is protonated, the carboxy-
late group should be able to attack [PtCl6]2−. When
the carboxylate group approaches a chloride ligand
in [PtCl6]2−, it forms a short–lived chloride–bridged
transition state within which the electron density of the
PtIV–chloride bond is displaced toward the platinum
center, making the chloride ligand more prone to ac-
cept electrons from the incoming reductant nucleophile
International Journal of Chemical Kinetics DOI 10.1002/kin.20886

8
FAWZY
O
O
Cl
2-
Cl
k1
slow
H2N
H2N
[PtCl6]2-
..... ...... ......
OH
+
Cl
O
H
Cl
Pt
O
Cl
O
NH3
NH3
Cl
+
+
Asn+
Transition state
fast
H2N
H
H
H2N
H2O
fast
O
O
O
NH2
+
Iminium cation
Aldehyde
+
+
NH4
+
-
[PtCl4]2- + 2Cl + 2H+ + CO2
Scheme 1 Mechanism of uncatalyzed oxidation of L-asparagine by hexachloroplatinate(IV) in sulfuric acid medium.
(L-asparagine) and transfer them to the platinum cen-
ter rapidly (see Scheme 1). This facilitates the rapid
reductive-elimination reaction. Therefore, such a reac-
tion might be visualized as a nucleophilic substitution
on the halogen with the platinum moiety as the leav-
ing group. As already pointed out by Taube [43], no
sharp distinction is visible between a two-electron re-
dox change involving atom transfer and such a nucle-
ophilic substitution. A concerted two-electron transfer
from L-asparagine to the PtIV center leading to the re-
lease of two halide ions and formation of the reaction
products is observed.
where [Asn] is the equilibrium concentration of L-
asparagine according to Eq. (2).
Thus the rate law expression becomes
k1K1[H+]
1 + K1[H+]
kU =
[Asn]T = kꢁ[Asn]T
(7)
where [Asn]T is the total or stoichiometric concentra-
tion of L-asparagine ([Asn]T = [Asn] + [Asn+]) and kꢁ
is an empirical constant, which equals:
According to Eqs. (2) and (3), the redox reaction
follows the second-order rate law as given by the fol-
lowing equation:
k1K1[H+]
1 + K1[H+]
kꢁ =
(8)
−d[PtCl26−
]
Rate =
= k1[Asn+][PtCl26−
= k1K1[Asn][H+][PtCl62−
]
Assuming that K1[H+] >> 1 [44,45], hence, Eq.
(7) may be simplified to Eq. (9)
dt
]
(4)
kU = k1[Asn]T
(9)
Under the pseudo–first-order condition, the rate law
can be expressed by the following equation (5)
According to Eq. (9), plots of kU against [Asn]T at
constant [H+] should be linear passing through origin
as was experimentally observed at four temperatures
(Fig. 5). The second-order rate constant obtained as
slopes of such plots, along with its activation enthalpy
and entropy, which are calculated from the Eyring plot
(Fig. 6, are listed in Table III. The rate coefficient k1
is expected to be dependent on pH because of the
displacement of the protolytic equilibrium involving
−d[PtCl26−
]
Rate =
= kU[PtCl26−
]
(5)
dt
Comparing Eqs. (4) and (5), the following relation-
ship is obtained:
kU = k1K1[Asn][H+]
(6)
International Journal of Chemical Kinetics DOI 10.1002/kin.20886

OXIDATIVE BEHAVIOR OF BIOLOGICAL ANTICANCER PLATINUM(IV) COMPLEX
9
the cationic species of the amino acid (cf. Eq. (2)). The
observed large negative value of ꢀS suggests that
100
80
60
40
20
0
ࣔ
the reactants form the transition state, which is more
ordered than the reactants, due to loss of degrees of
293 K
298 K
303 K
308 K
ࣔ
ࣔ
freedom. The experimental values of ꢀH and ꢀS
were both favorable for electron transfer processes.
Mechanism of Copper(II)-Catalyzed
Reaction
The reaction between [PtCl6]2− and L-asparagine in
acid medium in the presence of small amounts of the
copper(II) catalyst is similar to the uncatalyzed re-
action with respect to stoichiometry, influence of the
ionic strength and dielectric constant, and reaction or-
ders, except for the order with respect to L-asparagine
where addition of the CuII catalyst changed the or-
der in [Asn] from unity to fractional. In addition, the
reaction is first order with respect to the copper(II)
catalyst.
0
2
4
6
8
10
12
102 [Asn], mol dm-3
Figure 5 Plots of kU versus [Asn] in the uncatalyzed oxi-
dation of L-asparagine by hexachloroplatinate(IV) in sulfuric
acid medium at different temperatures. [PtCl62−] = 7.6 ×
10−5, [H+] = 1.0, and I = 2.0 mol dm−3
.
The observed less than unit order in [Asn] presum-
ably results from a complex formation between the
catalyst copper(II) and substrate prior to the reaction
with the oxidant. The formation of the complex was
also proved kinetically by a nonzero intercept of the
plot of [CuII]/kC versus 1/[Asn] (figure not shown).
Such complexes between L-asparagine and copper(II)
catalyst have been reported in earlier studies [25–27].
In view of the above-mentioned aspects, proto-
nated L-asparagine is suggested to combine with CuII
species, [Cu(H2O)6]2+, to form an intermediate com-
plex, [Asn–Cu]3+, which then reacts in a slow step
with 1 mol of [PtCl6]2− to give rise to the prod-
ucts with regenerating the catalyst CuII (Scheme 2).
The results are accommodated in the following
sequence:
35.4
35.1
34.8
34.5
34.2
3.20
3.25
3.30
3.35
3.40
3.45
103 (1/T), K-1
Figure 6 Eyring plot of the second-order rate constant in
the uncatalyzed oxidation of L-asparagine by hexachloro-
platinate(IV) in sulfuric acid medium. [Asn] = 6 × 10−2
,
K1
[PtCl62−] = 7.6 × 10−5, [H+] = 1.0, and I = 2.0 mol dm−3
Asn + H+ ꢀ Asn+
(2)
(10)
(11)
at 25°C.
K2
Asn++ Cu2+ ꢀ [Asn − Cu]3+(C)
Table III Activation Parameters of the Second-Order
Rate Constant (k1) in the Uncatalyzed Oxidation of
l-Asparagine by Hexachloroplatinate(IV) in Sulfuric Acid
Mediuma
k2
C + [PtCl6]2− −→ Products + Cu2+
slow
Temperature (K)
According to the proposed mechanism, the rate
of disappearance of [PtCl6]2− or formation of the
products can be expressed by the following rate-law
equation:
Parameter
293
3.12
298
4.21
303
5.83
–152.81
43.36
308
8.40
103k1 (dm3 mol−1 s−1
)
ࣔ
ꢀS (J mol−1K−1
)
ࣔ
ꢀH (kJ mol−1
)
a[Asn] = 6 × 10−2, [PtCl26−] = 7.6 × 10−5, [H+] = 1.0, and
−d[PtCl26−
]
I = 2.0 mol dm−3
.
Rate =
= k2[C][PtCl26−
]
(12)
Experimental errors 4%.
dt
International Journal of Chemical Kinetics DOI 10.1002/kin.20886

10
FAWZY
According to Eq. (13), at constant [H+], the plot
of [CuII]/kC against 1/[Asn] was found be linear with
a positive intercept (figure not shown), supporting the
CuII–asparagine complex. From the intercept of such
plot, the value of the rate constant of the slow step (k2)
O
O
O
H
OH2
++
+
OH
+
O
[Cu(H2O)6]2+
H3N
H3N
OH2
OH2
Cu
K
2
NH2
- 2H2O
N
H2
OH2
is calculated to be 0.33 dm3 mol−1 s−1
.
O
Asn+
Intermediate complex (C)
APPENDIX: DESCRIPTION
k2
[PtCl6]2-
slow
According to the suggested mechanism for copper(II)–
catalyzed oxidation reaction,
+
H2N
O
H
−d[PtCl26−
]
H
O
Rate(C)
=
= k2[C][PtCl26−
]
(A1)
H2O
fast
dt
NH2
NH2
From Eq. (2)
O
Iminium cation
Aldehyde
[Asn+]
[Asn][H+]
+
K1 =
(A2)
(A3)
+
+
[Cu(H2O)4]2+
[PtCl ]2-
NH4
+
4
-
+
+
2Cl + 2H + CO2
Therefore,
Scheme 2 Mechanism of copper(II)-catalyzed oxidation
of L-asparagine by hexachloroplatinate(IV) in sulfuric acid
medium.
[Asn+] =K1[Asn][H+]
From reaction (10) and Eq. (A3)
The relationship between the rate of complex for-
mation and the substrate, hydrogen ion, catalyst,
and oxidant concentrations can be deduced (see the
Appendix) to give the following rate-law equation:
[C]
[C]
K1[Asn][H+][CuII]
K2 =
=
(A4)
[Asn+][CuII]
k2K1K2[Asn][H+][CuII][PtCl26−
1 + K1[H+] + K1K2[Asn][H+] + K1K2[H+][CuII]
]
Therefore, [C] =K1K2[Asn][H+][CuII] (A5)
Rate =
(13)
Substituting Eq. (A5) into Eq. (A1) yields
In view of low concentration of [CuII] used, the term
K1K2[H+][CuII] in the denominator can be neglected.
Therefore, Eq. (13) becomes
Rate(C) = k2K1K2[Asn][H+][CuII][PtCl62−
]
(A6)
The total concentration of L-asparagine is given by
k2K1K2[Asn][H+][CuII][PtCl26−
1 + K1[H+] + K1K2[Asn][H+]
]
Rate =
(14)
[Asn]T= [Asn]F + [Asn+] + [C]
(A7)
Under the pseudo–first-order condition,
where [Asn]T and [Asn]F stand for total and free con-
centrations of L-asparagine.
Substituting Eqs. (A3) and (A5) into Eq. (A7)
gives
−d[PtCl26−
]
Rate =
=kC[PtCl26−
]
(15)
dt
[Asn]T = [Asn]F + K1[Asn]F[H+] + K1K2[Asn]F[H+][CuII]
Comparing Eqs. (14) and (15) and rearrangement,
Eq. (16) is obtained:
(A8)
[Asn]T = [Asn]F(1 + K1[H+] + K1K2[H+][CuII])
(A9)
ꢀ
ꢁ
[CuII]
kC
1 + K1[H+]
1
1
=
+
(16)
k2K1K2[H+] [Asn] k2
International Journal of Chemical Kinetics DOI 10.1002/kin.20886

OXIDATIVE BEHAVIOR OF BIOLOGICAL ANTICANCER PLATINUM(IV) COMPLEX
11
and with rearrangement, it becomes
Therefore,
ꢀ
ꢁ
[Asn]T
1 + K1[H+] + K1K2[H+][CuII]
[CuII]
kC
1 + K1[H+]
1
1
[Asn]F =
(A10)
(A11)
=
+
(A19)
k2K1K2[H+] [Asn] k2
Similarly,
[CuII]T = [CuII]F + [C]
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International Journal of Chemical Kinetics DOI 10.1002/kin.20886