Kinetics and mechanism for reduction of halo- and haloam(m)ine platinum(IV) complexes by L-ascorbate

Article abstract of DOI:10.1016/S0020-1693(01)00762-9

Reduction of the model platinum(IV) complexes cis-[PtCl₄(NH₃)₂] (1), trans-[PtCl₄(NH₃)₂] (2), trans-[PtCl₂(en)₂]²⁺ (3), trans-[PtBr₂(NH₃)₄]²⁺ (4), [PtCl₆]^2- (5), and [PtBr₆]^2- (6) with L-ascorbic acid (H₂Asc) in 1.0 M aqueous medium at 25°C in the region 1.75≤pH≤7.20 has been investigated using stopped-flow spectrophotometry. The redox reactions follow the rate law: -d[Pt(IV]/dt=k[H₂Asc]_tot[Pt(IV)] where k is a pH-dependent second-order rate constant and [H₂Asc]_tot, the total concentration of ascorbic acid. The pH-dependence of k is attributed to parallel reduction of Pt(IV) by the protolytic species HAsc^- and Asc^2-. Analysis of the kinetics data reveals that the ascorbate anion Asc^2- is up to seven orders of magnitude more reactive than HAsc^- while H₂Asc is unreactive. Electron transfer from HAsc^-/Asc^2- to the Pt(IV) compounds is suggested to take place by a mechanism involving a reductive attack on any one of the mutually trans-halide ligands by Asc^2- and/or HAsc^- forming a halide-bridged activated complex. The rapid reduction of these complexes supports the assumption that ascorbate Asc^2- might be an important reductant at physiological conditions for anticancer active Pt(IV) pro-drugs capable of undergoing reductive trans elimination. The parameters ΔH^≠ and ΔS^≠ for reduction of Pt(IV) with Asc^2- have been determined from the study of the temperature dependence of k.

Full text of DOI:10.1016/S0020-1693(01)00762-9

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Inorganica Chimica Acta 331 (2002) 98–108
Kinetics and mechanism for reduction of halo- and haloam(m)ine
platinum(IV) complexes by
L-ascorbate
a,c
b
c
a,
Kelemu Lemma , Donald A. House , Negussie Retta , Lars I. Elding *
a
Inorganic Chemistry, Chemical Center, Lund Uni6ersity, P.O. Box 124, SE-221 00 Lund, Sweden
b
Chemistry Department, Uni6ersity of Canterbury, Pri6ate Bag 4800, Christchurch, New Zealand
c
Department of Chemistry, Addis Ababa Uni6ersity, P.O. Box 1176, Addis Ababa, Ethiopia
Received 17 July 2001; accepted 19 October 2001
Dedicated to Professor A.G. Sykes at the occasion of his retirement
Abstract
2
+
Reduction of the model platinum(IV) complexes cis-[PtCl (NH ) ] (1), trans-[PtCl (NH ) ] (2), trans-[PtCl (en) ]
(3),
4
3 2
4
3 2
2
2
2
+
2−
2−
trans-[PtBr (NH ) ]
(4), [PtCl6]
the region 1.755pH57.20 has been investigated using stopped-flow spectrophotometry. The redox reactions follow the rate law:
d[Pt(IV]/dt=k[H Asc]tot[Pt(IV)] where k is a pH-dependent second-order rate constant and [H Asc] , the total concentration
(5), and [PtBr6]
(6) with L-ascorbic acid (H Asc) in 1.0 M aqueous medium at 25 °C in
2
3 4
2
−
2
2
tot
−
2−
of ascorbic acid. The pH-dependence of k is attributed to parallel reduction of Pt(IV) by the protolytic species HAsc and Asc
.
2
−
−
Analysis of the kinetics data reveals that the ascorbate anion Asc
is up to seven orders of magnitude more reactive than HAsc
to the Pt(IV) compounds is suggested to take place by a
−
2−
while H Asc is unreactive. Electron transfer from HAsc /Asc
2
2
−
−
mechanism involving a reductive attack on any one of the mutually trans-halide ligands by Asc
halide-bridged activated complex. The rapid reduction of these complexes supports the assumption that ascorbate Asc
be an important reductant at physiological conditions for anticancer active Pt(IV) pro-drugs capable of undergoing reductive trans
and/or HAsc forming a
2
−
might
"
"
2−
elimination. The parameters DH and DS for reduction of Pt(IV) with Asc
temperature dependence of k. © 2002 Elsevier Science B.V. All rights reserved.
have been determined from the study of the
Keywords: Kinetics and mechanism; Reduction; Platinum(IV) complexes; L-Ascorbic acid
1
. Introduction
and biological systems [10–16]. Rates of reduction by
ascorbic acid/ascorbate are dependent on the nature of
the oxidant and the acidity of the reaction medium,
Electron transfer reactions between Pt(IV) com-
pounds and biological reductants are of current inter-
est because of their relevance to the understanding of
the biological action of antitumor active Pt(IV) drugs.
It is generally assumed that the Pt(IV) compounds are
reduced in vivo to their Pt(II) analogues by reductants
since the unprotolysed acid (H Asc), hydrogen ascor-
2
−
2−
bate (HAsc ), and ascorbate (Asc ) may act as re-
ductants. Different mechanisms have been proposed
for the reactions between ascorbic acid and metal com-
plexes [14–22], and different mechanisms should be
expected due to differences in, for instance, the nature
of the substrate complexes used. Thus, the reactions
have been classified as: (1) outer-sphere; (2) inner-
sphere; as well as (3) bridged electron transfers. In the
latter case ascorbate is bound to a co-ordinated ligand
prior to electron transfer [18]. When the redox process
involves a decrease in co-ordination number, as in the
case of Pt(IV) to Pt(II) transformations, the reactions
might be better classified as (4) reductive eliminations
[7].
such as thiols, ascorbic acid (H Asc), and methionine
2
[
1–8]. For example, cis-[PtCl (c-C H NH )(NH )]
2 6 11 2 3
(
JM118) has been identified as the major metabolite in
samples taken from patients treated with cis,trans,cis-
PtCl (OCOCH ) (c-C H NH )(NH )] (JM216) [9].
[
2
3 2
6
11
2
3
Ascorbic acid is a well characterised two-electron
reductant widely used as a reducing agent in chemical
*
Corresponding author. Fax: +46-46-222 4439.
E-mail address: larsi.elding@inorg.lu.se (L.I. Elding).
0020-1693/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved.
PII: S0020-1693(01)00762-9

K. Lemma et al. / Inorganica Chimica Acta 331 (2002) 98–108
99
Table S2
However, the literature is discordant. Bose and
Weaver [23] recently concluded that reduction of a
series of Pt(IV) anticancer active drugs by ascorbate is
catalysed by Pt(II) which is in disagreement with Evans
and Green’s [24] earlier report that ascorbic acid reduc-
tion of cis,trans,cis-[PtCl (OH) (i-propylamine) ] (ipro-
pH Dependence of observed pseudo-first-order rate constants for
ascorbate reduction of trans-[PtCl (NH ) ] (2) at 25 °C and I=1.0
4
3 2
a
M
kobsd (s−1
)
pH
[H Asc] (mM)
2
tot
2
2
2
−
−
2
2
5
.08
2.5
5
(2.4090.01)×10
(4.5290.06)×10
0.08890.002
0.14190.001
0.21090.002
Table S1
pH Dependence of observed pseudo-first-order rate constants for
1
1
0
7
a
ascorbate reduction of cis-PtCl (NH ) ] (1) at 25 °C and I=1.0 M
4
3 2
25
−2
pH
.03
[H Asc] (mM)
kobsd (s−1)
5.47
2.5
(4.8890.03)×10
(9.4490.02)×10
0.18990.001
0.31090.002
0.46690.002
2
tot
−
2
5
10
17
25
−
−
−
2
2
2
5
5
5
6
6
6
6
7
7
2.5
(2.4090.01)×10
(4.6090.01)×10
(8.8090.01)×10
0.14590.001
5
0
7
5
.0
1
1
2
−
2
5
6
.75
.01
2
4
8
3
0
(7.7590.09)×10
0.15190.001
0.29790.002
0.46890.003
0.73990.004
0.21890.002
−
2
.47
.76
.01
.28
.66
.90
.01
.16
2
4
8
3
0
(4.1290.07)×10
0.79890.007
0.15290.001
0.24290.001
0.37890.003
1
2
1
2
1.5
3
6
0
5
0.09690.002
0.19290.002
0.37690.002
0.61590.004
0.92190.007
−
2
2
4
8
3
0
(8.0690.06)×10
0.15390.001
0.29590.003
0.48890.002
0.74390.007
1
1
1
2
6.27
1.5
3
6
0
5
0.16790.003
0.33090.004
0.65590.003
1.06490.015
1.63490.013
−
2
1.5
3
6
(9.690.1)×10
0.18890.002
0.36290.003
0.60790.003
0.9090.01
1
1
1
1
0
5
6.51
6.66
6.87
7.01
7.16
1.5
3
6
10
15
0.27390.002
0.54490.004
1.10090.005
1.82090.011
2.7090.03
2
4
8
3
0
0.23490.002
0.45590.004
0.89990.004
1.45190.006
2.2490.02
1
2
1.5
3
6
10
15
0.39590.003
0.77790.004
1.5290.01
2.5490.02
3.8890.04
1.5
3
6
0.39190.002
0.79890.007
1.56090.007
2.5890.03
1
1
0
5
3.9590.04
1.5
0.60690.004
1.23090.005
2.3990.02
3.9890.03
5.8590.12
2
4
8
3
0
0.88690.005
1.7090.01
3.3690.01
5.3790.05
8.3290.03
3
6
0
5
1
1
1
2
1.5
3
6
0
5
0.83690.007
1.6590.01
3.1890.03
5.2990.06
7.8390.09
1.5
3
6
0.82790.008
1.62090.007
3.180920
5.2290.05
7.7490.14
1
1
1
1
0
5
1.5
3
6
1.1590.01
2.2390.01
4.2790.04
5.2490.05
9.6890.11
1.5
3
6
1.17090.016
2.3090.03
4.4490.02
6.9790.08
10.3590.09
7
5
.5
1
1
0
5
1
a
−
a
−
[
Cl ]=0.7 M; u=320 nm. Errors are given as one standard
[Cl ]=0.7 M; u=320 nm. Errors are given as one standard
deviation.
deviation.

100
K. Lemma et al. / Inorganica Chimica Acta 331 (2002) 98–108
Table S4
platin) is reversible with no catalysis by Pt(II). On the
other hand, Mehrotra et al. have reported that reduc-
pH Dependence of observed pseudo-first-order rate constants for
2
+
ascorbate reduction of trans-[PtBr (NH ) ] (4) at 25 °C and I=1.0
2
3 4
2
−
tion of [PtCl6] by ascorbic acid in an aqueous hydro-
chloric acid medium proceeds by an outer-sphere
mechanism involving a five co-ordinate Pt(III) interme-
diate [25]. Choi et al. [26] reported recently that there is
a correlation between the rate of reduction and the
anticancer activity in a series of homologous Pt(IV)
complexes, without going into details about the reac-
tion mechanisms, however. The present study was un-
dertaken with the aim of extending the knowledge of
the kinetic and thermodynamic parameters that charac-
terise reduction of Pt(IV) complexes by ascorbic acid/
ascorbate and clarifying the mechanistic details, using
the following series of model complexes: cis-
a
M
pH
[H Asc] (mM)
kobsd (s−1)
2
tot
−
2
2
2
.02
5
0
(4.1090.04)×10
(7.990.1)×10
−2
1
−
15
(11.3490.05)×10
−
2
2
5
(18.390.2)×10
−
2
2.25
2
4
0
0
(3.1490.11)×10
(6.490.2)×10
−
2
2
2
−
1
2
(14.790.4)×10
(28.590.5)×10
−
−
2
2
.50
2
4
0
(6.5690.11)×10
(12.490.3)×10
−
2
−2
1
(29.390.3)×10
(57.691.9)×10
−
2
[
[
(
PtCl (NH ) ] (1), trans-[PtCl (NH ) ] (2), trans-
20
4
3 2
2
4
3 2
2+
+
2−
PtCl (en) ]
(3), trans-[PtBr (NH ) ]
(4), [PtCl6]
2
2
2
3 4
2.75
2
4
0.10090.003
0.2090.01
0.4690.01
0.9290.02
2
−
5), and [PtBr6]
(6).
1
2
0
0
Table S3
pH Dependence of observed pseudo-first-order rate constants for
3
.00
.25
2
4
0
0
0.17490.005
0.3490.01
0.7890.02
1.5090.01
2
+
ascorbate reduction of trans-[PtCl (en) ]
M
(3) at 25 °C and I=1.0
2
2
a
1
2
pH
[H Asc] (mM)
kobsd (s−1)
2
tot
3
0.5
1.0
2.5
5.0
0.6790.002
0.13690.003
0.32490.012
0.60390.021
−
−
2
2
4.27
10.0
(2.0290.03)×10
(3.4690.02)×10
(5.090.1)×10
1
7.5
5.0
−
2
2
−
−
2
2
3.50
3.96
0.5
1.0
2.5
5.0
0.10590.002
0.20090.003
0.44290.022
0.86690.005
4
.52
.78
.96
.25
.45
.75
5.0
0.0
7.5
5.0
(1.6890.09)×10
(3.4790.06)×10
(6.290.1)×10
1
1
2
−
2
2
−
(8.990.1)×10
−
2
2
0.5
1.0
2.5
0.17590.005
0.3590.01
0.8890.06
1.7590.08
4
4
5
5
5
6
5.0
0.0
7.5
5.0
(3.1790.05)×10
(6.490.1)×10
−
2
2
1
1
2
−
(11.490.6)×10
0.1690.01
5
.0
−
5.0
0.0
7.5
5.0
(4.6790.06)×10
(9.790.1)×10
0.16890.003
a
−
[
Br ]=0–50 mM, u=318 nm. Errors are given as one standard
−
2
1
1
2
deviation.
0.25990.003
2
. Experimental
5.0
0.0
7.5
5.0
0.08990.003
0.19190.004
0.3290.01
1
1
2
2.1. Chemicals and solutions
0.4890.01
Compounds 1 and 2 (Strem Chemicals), 5 and 6
5.0
0.0
7.5
5.0
0.14590.004
0.28390.001
0.5090.03
(
Alfa Products), L-H Asc (Merck), and sodium hydro-
1
1
2
2
gen ascorbate (ICN Biochemicals Inc.) were used as
received. Compounds 3 and 4 were prepared according
to literature methods by oxidising [Pt(en)
Chemicals) with 30% H O in a conc. HCl medium and
0.7490.01
5.0
0.0
7.5
5.0
0.31590.017
0.62590.037
1.0690.02
]Cl (Strem
2 2
1
1
2
2
2
2+
[Pt(NH ) ]
with Br in 1.0 M HBr medium, respec-
2
3
4
1.4990.05
tively [27,28]. All other chemicals used were of analyti-
cal grade.
Water doubly distilled from quartz, boiled and
flushed with Ar for at least 30 min was used for
solution preparations. Acetate and phosphate buffers
.00
5.0
0.0
7.5
0.5190.01
1.0090.02
1.7690.06
1
1
a
−
[
Cl ]=0.7 M; u=320 nm. Errors are given as one standard
−
3
deviation.
containing 3×10 M Na H (edta) were used to main-
2 2

K. Lemma et al. / Inorganica Chimica Acta 331 (2002) 98–108
101
Table S6
tain constant pH. No observable influence of the
buffers used was observed except for compound 4,
pH Dependence of observed pseudo-first-order rate constants for
ascorbate reduction of [PtBr6]
2
−
a
(6) at 25 °C and I=1.0 M
which was studied in an HClO –NaClO4 medium.
4
pH [H Asc]tot (mM)
k
obsd (s−1)
Na H (edta) was added in order to sequester trace
2
2
2
concentrations of transition metals that could otherwise
catalyse the autoxidation of ascorbic acid (vide infra)
−
2
3
.70
3.5
7
1
7.5
5
(2.2690.02)×10
(4.4190.02)×10
(6.7090.02)×10
0.10690.001
−2
−2
[29–31]. Fresh solutions of ascorbic acid (0.4–50 mM)
1
1
2
0.15390.001
Table S5
pH Dependence of observed pseudo-first-order rate constants for
−2
4
.10
2.5
5
(3.090.1)×10
(5.7390.03)×10
(8.690.2)×10
0.14290.001
2
−
a
−2
ascorbate reduction of [PtCl6]
(5) at 25 °C and I=1.0 M
−
2
7
.5
pH
[H Asc] (mM)
kobsd (s−1)
12.5
2
tot
2
5
0.28190.002
−
−
−
−
2
2
2
2
5
5
5
5
.14
2.5
5
(1.5590.01)×10
(2.9390.02)×10
(4.1390.02)×10
(6.5290.05)×10
0.12990.001
4.35
2.5
5.0
0.03590.001
0.07390.003
0.18490.004
0.35890.009
7
.5
12.5
2
1
2
2.5
5
5
−
−
2
2
4.57
4.85
5.23
5.74
6.25
6.49
2
4
8
3
0
(4.8490.01)×10
(9.3990.05)×10
0.18790.001
0.30690.002
0.47890.001
−
−
−
2
2
2
.47
.74
.97
2.5
5
(2.5090.02)×10
(4.8090.05)×10
(9.3090.07)×10
0.14890.002
1
1
2
0
6
5
1
2
0.23990.002
−
2
2
4
3
0
0
(7.2390.02)×10
0.14790.004
0.49390.002
0.77090.003
1.9490.01
−
−
−
2
2
2
1
2
4
(1.8590.03)×10
(3.5090.07)×10
(6.7390.04)×10
0.12290.001
1
2
5
7
.5
1
1
5
0.24590.002
−
2
1
2
4
8
5
(7.990.1)×10
0.16590.001
0.32890.003
0.63890.003
1.16990.009
−
−
2
2
1
2
4
6
0
(3.1290.04)×10
(5.8490.05)×10
0.11390.002
.5
0.17990.002
0.27490.002
1
0.5
1
2
4
7
0.10490.001
0.21490.002
0.42490.002
0.83390.003
1.57090.008
6
.28
.51
7.5
0.32090.005
0.32590.005
b
7
.5
−
2
6
1
2
4
6
0
(8.790.1)×10
0.17590.002
0.34790.008
0.54990.003
0.85290.007
.5
0.5
1
2
4
7
0.26790.001
0.52290.001
1.05090.003
2.08090.003
3.99090.005
.5
1
6
6
.68
.90
1
2
4
7
0
0.13490.003
0.26790.002
0.52190.005
0.9690.01
.5
0.4
0.37390.002
0.72690.002
1.4290.01
2.21090.004
3.6390.03
.5
.5
0
1
2
4
.8
.6
.5
1
1.2890.01
1
2
4
6
0
5
0.22290.002
0.43490.002
0.83290.008
1.34090.005
2.0690.01
6.87
7.20
0.2
0.4
0.8
1.5
0.39090.002
0.79290.007
1.5390.01
2.8290.01
4.5990.03
1
1
3.0390.03
2
.5
7.15
1
2
4
6
0
0.38590.002
0.74490.003
1.4390.01
2.2690.02
3.4590.06
0.2
0.4
0.8
1.25
0.89090.007
1.7590.01
3.4590.02
5.1090.02
8.7590.04
.5
1
2
.0
a
−
[
Cl ]=0.7 M; u=320 nm. Errors are given as one standard
a
−
deviation.
[Br ]=0.7 M; u=370–400 nm. Errors are given as one standard
b
Measured in the presence of [PtCl ]2− (tenfold excess).
deviation.
4

1
02
K. Lemma et al. / Inorganica Chimica Acta 331 (2002) 98–108
−3
−
5
and the Pt(IV) compounds (4×10 –1×10
M)
were prepared in buffer and flushed with Ar immedi-
ately prior to kinetic measurements. All measuring
solutions were protected from excessive exposure to
daylight.
2.2. Kinetic measurements
The pH of buffer solutions was measured with a
Metrohm 632 digital pH meter equipped with a combi-
nation glass electrode and activities of oxonium ions
−
pH
aH=10
were calculated directly from pH meter
readings. Standard buffers of pH 2.0, 4.0, and 7.0
obtained from Merck were used to calibrate the pH
meter. Spectra were recorded on a Milton Roy 3000
diode array spectrophotometer using 1.0 cm quartz
Fig. 3. Effect of addition of Cu2+ on the observed pseudo-first-order
2
−
rate constant kobsd for reduction of [PtCl ]
(5) at pH 5.79 and
M, [Pt(IV)]=1×
6
2
+
−5
2
5 °C. Reaction conditions: [Cu ]=1×10
−
4
−3
1
0
M (", ꢀ); [Na H (edta)]=3×10
M, anaerobic (ꢀ); No
2
2
Na H (edta), aerobic (").
2
2
Suprasil cells. Kinetic measurements were performed at
5 °C in 1.0 M aq. chloride or bromide medium using
2
an Applied Photophysics Bio-Sequential SX-17MX
Stopped-Flow ASVD Spectrophotometer. Reduction of
the Pt(IV) complexes was investigated in the regions
1
7
.755pH53.96 (4), 4.05pH56.0 (3), 2.255pH5
.20 (6), and 4.05pH57.20 (1, 2, 5).
The redox reactions were investigated under pseudo-
first-order conditions with at least tenfold excess of
ascorbic acid by monitoring the absorbance decrease at
3
18 (4), 320 (1, 2), 330 (3, 5), and 370–430 nm (6).
Reactions were followed for at least four half-lives with
four to six independent kinetic runs. Pseudo-first-order
rate constants were obtained as average values from
repetitive measurements. The total ionic strength was
adjusted to 1.0 M with either NaCl or NaBr as appro-
priate to suppress hydrolysis of the Pt(IV) complexes.
Addition of chloride or bromide has no observable
effect on the pseudo-first-order rate constants. Temper-
ature dependence of the second-order overall rate con-
stants k was investigated at pH 5.74. All primary data
are summarised in the supplementary material Tables
S1, S2, S3, S4, S5 and S6.
Fig. 1. Stoichiometric plot for the reaction between L-ascorbate and
2
−
−4
[
[
PtBr ]
(6). Reaction conditions: [Pt(IV)]=2×10
M, pH 6.49,
6
−
−3
Br ]=0.7 M, [Na H (edta)]=3×10
M, I=1.0 M.
2
2
3
. Results and discussion
3.1. Stoichiometry
The stoichiometry for reduction of 6 by ascorbate
was determined by a spectrophotometric titration of a
fixed concentration of the complex with sodium hydro-
gen ascorbate. The break in the plot of absorbance
versus [H Asc] /[Pt(IV)] occurred at the expected ratio
Fig. 2. Plots of kobsd vs. [H Asc] for compounds 2 (ꢁ, x=3), 3 (ꢂ,
2
tot
x=1), 5 (ꢀ, x=2), and 6 (", x=1) at constant pH 5.74 and I=1.0
−
4
−4
M. Experimental conditions: [Pt(IV)]=1.0×10
(ꢀ), 2.0×10
−
5
−4
−
(
ꢁ), 5×10
M ("), and 5×10
M (ꢂ); [Cl ]=0.7 M (ꢂ, ꢀ,
2
tot
−
−3
ꢁ
), [Br ]=0.7 M ("); [Na H (edta)]=3×10
M in all cases.
[H Asc] /[Pt(IV)] of 1:1 (Fig. 1). Reduction of the
2 tot
2
2

K. Lemma et al. / Inorganica Chimica Acta 331 (2002) 98–108
103
Table 1
Table 1 (Continued)
pH Dependence of second-order overall rate constants k for ascor-
bate reduction of the Pt(IV) complexes at 25 °C and I=1.0 M
−
1
s−1) a
Pt(IV) complex
pH
k (M
−
1
s−1) a
Pt(IV) complex
pH
k (M
3.00
1.8590.02
3.2590.08
6.0490.05
11.190.1
14.390.2
23.990.2
38.890.3
56.090.2
77.690.7
20991
3
.44
cis-[PtCl (NH ) ] (1)
4.01
0.87590.022
1.6890.03
3.0090.03
8.690.1
18.690.2
36.990.3
59.890.2
111.390.2
26293
3.70
4.10
4.35
4.57
4.85
5.06
5.23
5.74
6.25
6.49
6.87
7.20
4
3 2
4
4
5
5
5
6
6
6
6
7
7
.38
.70
.03
.47
.76
.01
.28
.66
.90
.01
.16
53294
902911
(1.8290.02)×10
(4.3290.13)×10
41292
51292
67599
3
3
trans-[PtCl (NH ) ] (2)
4.01
0.82790.022
1.6490.03
3.2890.04
8.290.1
18.490.2
36.590.5
60.990.3
10891
18091
25892
38993
51892
4
3 2
a
Errors are obtained as one standard deviation.
4
4
5
5
5
6
6
6
6
6
7
7
.38
.70
.08
.47
.75
.01
.27
.51
.66
.87
.01
.16
other Pt(IV) complexes is assumed to follow the same
stoichiometry.
3
.2. Kinetics
First-order kinetic traces were obtained in all cases
and the observed pseudo-first-order rate constants kobsd
were calculated by on-line non-linear least-squares fits
68198
+
trans-[PtCl (en)]2 (3)
of the absorbance versus time data [32]. Plots of kobsd
4.00
0.96890.011
2.0090.04
3.6190.01
6.5890.02
9.790.2
19.390.6
29.7490.64
58.690.6
10091
2
4
4
4
4
5
5
5
6
.27
.52
.78
.96
.25
.45
.75
.01
versus [H Asc] at constant pH are linear and pass
2
tot
through the origin, as illustrated in Fig. 2 for com-
pounds 2, 3, 5, and 6. Saturation kinetics as reported
previously [33] is most probably an artifact. It was not
observed in the present investigation, when Na H -
2
2
(edta) was present in the reaction solutions, acting as a
sequestering agent for trace transition metal ions such
as Fe(III) and Cu(II) which catalyse the autoxidation of
ascorbic acid/ascorbate [29–31]. Fig. 3 demonstrates
2+
trans-[PtBr (NH ) ]
(4)
1.75
3.9390.07
7.690.1
2
3 4
2
2
2
2
3
3
3
3
3
.02
.25
.50
.75
.00
.25
.50
.75
.96
14.090.2
28.3290.06
45.590.6
73.390.8
118.593.1
16892
2+
−5
the influence of added Cu
(1×10
M) on the
observed pseudo-first-order rate constant for ascorbate
2
−
reduction of [PtCl6]
(5). A similar observation has
been reported for the reduction of anticancer active
tetrachloroplatinum(IV) complexes by glutathione [34].
The electron transfer reactions follow the rate law
given by Eq. (1) where k denotes the pH-dependent
second-order overall rate constants.
24293
39491
−
PtCl ]2 (5)
[
4.01
0.3790.01
0.7490.01
1.4890.02
5.0190.04
9.590.2
16.190.1
26.990.1
50.990.4
84.690.6
127.190.4
20191
6
4
4
5
5
5
5
6
6
6
6
7
.38
.70
.14
.47
.74
.97
.28
.51
.68
.90
.15
−d[Pt(IV)]/dt=kobsd[Pt(IV)]=k[H
Asc]tot[Pt(IV)]
2
(1)
Since there are no protolytic equilibria associated with
the Pt(IV) complexes, the pH-dependence of k is at-
tributed to displacement of the protolytic equilibria
−
2−
involving the species H Asc, HAsc , and Asc
which
2
reduce the Pt(IV) complexes in parallel pathways. The
second-order overall rate constants k obtained from
linear least-squares analysis of the kinetics data at
different pH are presented in Table 1. Eq. (2) which
describes the pH-dependence of k is derived from
33992
PtBr ]2− (6)
[
2.25
0.40490.004
0.6390.01
1.1090.02
6
2
2
.50
.75
−
2−
Scheme 1 considering HAsc and Asc
as the redox

104
K. Lemma et al. / Inorganica Chimica Acta 331 (2002) 98–108
of 4 is too fast to be measured above pH 4.0 precluding
the determination of k3.
k2K
a1
k=
(3)
aH+K
a1
A separate data analysis was made for compound 6
in the region 2.255pH57.20. The rate constants k2
and k obtained from analyses of the two regions, i.e.
3
2
.255pH57.20 and 4.05pH57.20, are in excellent
agreement (Table 2). It then follows that the latter
interval is wide enough to determine these rate con-
stants fairly accurately. The pH profiles of the redox
reactions, i.e. plots of k versus pH are available as
Figures S1 and S2, Section 5.
Since HAsc constitutes more than 90% of the total
concentration of ascorbic acid above pH 5, one might
expect an almost pH-independent reaction in the region
Scheme 1.
active species. Reduction of the Pt(IV) complexes by
the unprotolysed H Asc (k ) was not observed under
−
2
1
the present experimental conditions.
5
5pH57. The kinetic data, however, show that the
k K a +k K K
a1 a2
2
2
a1
H
3
k=
(2)
redox reactions are pH-sensitive in this region as well.
The contribution of the Pt(IV)–Asc
overall reduction is significant although [Asc ] is very
low in this pH region. It is important to note that
Asc is up to seven orders of magnitude more reactive
than HAsc (Table 2). For instance, the Pt(IV)–Asc
a +K a +K K
H
a1
H
a1 a2
2−
pathway to the
2
−
In Eq. (2), k2 and k3 are the second-order rate
constants for reduction of Pt(IV) by HAsc and Asc
−
2−
,
2
−
respectively, and Ka1 and Ka2 are the protolysis con-
stants of H Asc reported to be pK 3.96 [16] and pKa2
−
2−
2
a1
1
1.24 [20] at 25 °C and 1.0 M ionic strength. The rate
pathway contributes 97% to the overall rate of reduc-
tion at pH 5.74 where the temperature-dependence of
the second-order overall rate constants k was investi-
gated. The activation parameters presented in Table 3
thus refer to reduction of the Pt(IV) complexes by
constants k and k were derived from the fits of Eq. (2)
2
3
to the experimental data by means of a weighted non-
linear least-squares analysis with aH as an independent
variable, k and k as adjustable and K and Ka2 as
2
3
a1
2
−
constant parameters. Data analysis was made in the
ascorbate, Asc
.
regions 4.005pH56.00 (3) and 4.005pH57.20 (1,
2
, 5, and 6). Eq. (2) does not fit to the experimental
data obtained for 4 in the region 1.755pH53.96. Eq.
3) which is derived from Scheme 1 by considering
3.3. Reaction mechanism
(
The observed redox reactions are fast, pseudo-first-
order in the Pt(IV) complexes, and independent of
added chloride or bromide. Since Pt(IV) complexes are
generally substitution inert [35] electron transfer follow-
−
HAsc as the predominant reductant fits well to the
data suggesting that reduction of 4 by the Asc
species is negligible in the pH region studied. Reduction
2
−
Table 2
−
2−
Second-order rate constants for reduction of the Pt(IV) complexes by HAsc (k ) and Asc (k ) at 25 °C and I=1.0 M, and cathodic reduction
2
3
potentials
−
1
s−1
k3 (M−1 s−1
)
Ecath (V) a
Compound
k2 (M
)
6
6
7
c-[PtCl (NH ) ] (1)
1.0790.02
1.1590.02
1.0090.02
76491
0.4590.01
17.8290.14
(9.8590.01)×10
(9.4590.02)×10
−0.15 (0.01)
−0.19 (0.01)
−0.03 (0.01)
4
3 2
t-[PtCl (NH ) ] (2)
4
3 2
2+
t-[PtCl (en) ]
(3)
(1.8890.08)×10
2
2
2
+
b
t-[PtBr (NH ) ]
(4)
2
3 4
−
PtCl6]2 (5)
6
[
[
(4.6390.08)×10
(5.3590.02)×10
(5.3590.02)×10
(4.4690.01)×10
−
PtBr6]2 (6)
c
7 c
7 d
6
d
1
7.5190.07
0.5590.01
0.3
e
t,c,c-[PtCl (OAc) (cha)(NH )] (7)
−0.04 (0.02)
−0.01 (0.02)
2
2
3
e
6
t,t,t-[PtCl (OAc) (cha)(NH )] (8) (OAc=OCOCH , cha=c-C H11NH2)
2×10
2
2
3
3
6
a
b
c
From Ref. [39].
Reaction with Asc
Obtained by analysis of data in the region 4.05pH57.2.
Obtained by analysis of data in the region 2.255pH57.2.
From Ref. [7].
2−
is too fast to be observed.
d
e

K. Lemma et al. / Inorganica Chimica Acta 331 (2002) 98–108
105
Table 3
Second-order overall rate constants k and activation parameters for reduction of the Pt(IV) complexes by ascorbate at pH 5.74 and I=1 M
−
1
s−1
)
"
DH (kJ mol−1) a
"
DS (J K−1 mol−1) a
Pt(IV) complex
T (°C)
k (M
cis-[PtCl (NH ) ] (1)
20
23.090.2
36.990.3
56.190.2
79.890.8
6092
−1497
4
3 2
2
3
3
5
0
5
trans-[PtCl (NH ) ] (2)
20
23.090.1
36.590.5
55.690.4
82.790.2
6191
7393
5291
5193
−993
36911
4
3 2
2
3
3
5
0
5
2+
trans-[PtCl (en) ]
(3)
15
22.990.3
42.490.3
70.390.2
11093
2
2
20
25
30
−
PtCl ]2 (5)
[
[
20
11.390.1
16.190.1
23.990.2
33.490.2
−4793
−29910
6
2
3
3
5
0
5
−
PtBr ]2 (6)
20
13391
20991
28193
39893
6
25
30
35
a
Activation parameters refer to reduction by Asc2− (cf. text).
ing an initial substitution of ascorbate for a co-ordi-
nated ligand is unlikely. The classical Pt(II)-catalysed
redox mechanism [36–38] can also be ruled out since
simple pseudo-first-order kinetic traces with no induc-
tion period were observed, and since addition of
bridged transition state of the type formulated for
compound 1 (Chart 1) is proposed. A concerted two-
electron transfer from ascorbate to the Pt(IV) centre
leading to the release of two halide ions and formation
of the reaction products, Pt(II) and dehydroascorbic
acid, is suggested. As expected, the Pt(IV) bromide
complexes are more reactive than their chloride ana-
logues reflecting the fact that bromide is a better bridg-
ing ligand than chloride [44,48].
2
−
[
PtCl4] up to a tenfold excess to a reaction mixture of
2
−
−
[PtCl6]
(5) and HAsc does not affect the pseudo-
first-order rate constants kobsd (supplementary material
Table S5).
It is tempting to conclude that the redox reactions
follow an outer-sphere mechanism given the fact that
the Pt(IV) complexes used are substitution inert. But
lack of a correlation between the rate constants k and
3
the cathodic reduction potentials [39] (Fig. 4) suggests
that electron transfer by an outer-sphere mechanism is
not operative either. The mechanism for reduction of
Pt(IV) halide complexes by inorganic [40–47] and bio-
logical [5–8,34] reductants has been reported to involve
an attack by the reductant on a halide co-ordinated
trans to good leaving groups forming a halide-bridged
activated complex resulting in reductive elimination.
Reactions of Pt(IV) complexes taking place by this
+
mechanism are formally equivalent to a transfer of X
(
X=Cl, Br) from the Pt(IV) centre to the reducing
molecule/ion [5,40–47].
Based on the kinetic observations a similar mecha-
Fig. 4. Second-order rate constants k3 for ascorbate reductions of
2
+
c-[PtCl (NH ) ] (1), t-[PtCl (NH ) ] (2), t-[PtCl (en) ]
(3), t,c,c-
2
−
4
3 2
4
3 2
2
2
nism involving a reductive attack by Asc
and/or
[
[
PtCl (OCOCH ) (c-C H NH )(NH )]
(7),
and t,t,t-
2
3 2
6
11
2
3
−
HAsc on a halide co-ordinated trans to a good leaving
PtCl (OCOCH ) (c-C H NH )(NH )] (8) plotted against cathodic
2
3 2
6
11
2
3
group (in these cases a chloride or bromide) forming a
reduction potentials Ecath from Table 2.

106
K. Lemma et al. / Inorganica Chimica Acta 331 (2002) 98–108
ions) in the Pt(IV) complexes facilitates such rapid
reductive elimination reactions [5–10,34].
5
. Supplementary material
Tables S1, S2, S3, S4, S5 and S6 giving the pH
dependence of observed pseudo-first-order rate con-
stants kobsd for ascorbate reduction of the complexes
1
–6 and Figs. S1 and S2 giving the pH profiles of the
Chart 1.
redox reactions.
Further mechanistic information is obtained from the
activation parameters presented in Table 3. A good
"
"
isokinetic relationship between DH and DS with an
isokinetic temperature of 260 K is observed, suggesting
that the reduction of all the Pt(IV) complexes studied
takes place by the same mechanism. This is further
discussed in Ref. [7]. The compounds trans,cis,cis-
[
PtCl (OCOCH ) (c-C H NH )(NH )] (JM349) (7) and
2
3 2
6
11
2
3
trans,trans,trans-[PtCl (OCOCH ) (c-C H NH )(NH )]
2
3 2
6
11
2
3
(
JM576) (8) also follow this correlation. In all these
cases, ascorbate reduction of Pt(IV) is proposed to take
place by a similar chloride-bridged two-electron trans-
fer mechanism [7]. The small variation of the rate
constants at 25 °C summarised in Table 2 is explained
"
by the observed compensation effect between DH and
"
TDS .
On the other hand, the Pt(IV) dicarboxylate com-
pounds cis,trans,cis-[PtCl (OCOCH ) (c-C H NH )-
2
3 2
6
11
2
(
NH )] (JM216) and cis,trans,cis-[PtCl (OCOC H ) -
3 2 3 7 2
(
c-C H NH )(NH )] (JM221), whose reduction by
6
11
2
3
ascorbate has been suggested to be outer-sphere deviate
from the isokinetic relationship [7].
4. Conclusion
Reduction of the Pt(IV) complexes by ascorbic acid/
ascorbate is dependent on pH and temperature. Elec-
tron transfer from ascorbate to the Pt(IV) centre is
suggested to take place by a mechanism involving a
2
−
−
reductive attack by Asc
and/or HAsc on any one
of the mutually trans co-ordinated halide ligands lead-
ing to their elimination and formation of a Pt(II)
complex and dehydroascorbic acid as the reaction
2
−
products. The ascorbate anion Asc
is up to seven
−
orders of magnitude more reactive than HAsc sug-
gesting that proton basicity is an important factor
governing the reactivity. Thus, ascorbate Asc
2
−
might
be an important reductant for anticancer active Pt(IV)
pro-drugs, capable of reductive elimination of the type
described, at the physiological conditions of pH 7.4 and
Fig. S1. Plots of the second-order overall rate constants k as a
function of pH. The solid lines represent the fit of Eq. (2) to the
experimental data obtained for the Pt(IV) complexes 3 and 6 and of
Eq. (3) to those obtained for 4.
37 °C. In general, the presence of halide ligands co-or-
dinated trans to a good leaving group (such as halide

K. Lemma et al. / Inorganica Chimica Acta 331 (2002) 98–108
107
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