Influence of the bridging ligand on the substitution behaviour of dinuclear Pt(ii) complexes. An experimental and theoretical approach

Article abstract of DOI:10.1039/b700770c

A series of dinuclear Pt(ii) complexes of the type [Pt₂(N,N, N′,N′-tetrakis(2-pyridylmethyl)diamine(H₂O) ₂]⁴⁺ were synthesized. Acid-base titrations, and concentration and temperature dependent stopped-flow measurements of the reaction with chloride were performed to study the thermodynamic and kinetic behaviour of the dinuclear bridged complexes. The results indicate that there is a clear interaction between the two Pt(ii) centres, which becomes weaker as the aliphatic chain increases in length. From a certain chain length onwards, the Pt(ii) centres become independent of each other and exhibit identical thermodynamic and kinetic properties. The experimental results are discussed in reference to structures obtained by DFT (BP86/LACVP*) calculations. The Royal Society of Chemistry.

Full text of DOI:10.1039/b700770c

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Influence of the bridging ligand on the substitution behaviour of dinuclear
Pt(II) complexes. An experimental and theoretical approach†
Hakan Ertu¨rk, Andreas Hofmann, Ralph Puchta and Rudi van Eldik*
Received 17th January 2007, Accepted 13th March 2007
First published as an Advance Article on the web 4th April 2007
DOI: 10.1039/b700770c
A series of dinuclear Pt(II) complexes of the type [Pt2(N,N,Nꢀ,Nꢀ-tetrakis(2-pyridylmethyl)-
diamine(H2O)2]4+ were synthesized. Acid–base titrations, and concentration and temperature
dependent stopped-flow measurements of the reaction with chloride were performed to study the
thermodynamic and kinetic behaviour of the dinuclear bridged complexes. The results indicate that
there is a clear interaction between the two Pt(II) centres, which becomes weaker as the aliphatic chain
increases in length. From a certain chain length onwards, the Pt(II) centres become independent of each
other and exhibit identical thermodynamic and kinetic properties. The experimental results are
discussed in reference to structures obtained by DFT (BP86/LACVP*) calculations.
loss of cytotoxicity.14 On the basis of these observations, we expect
that our complexes in which the platinum centres are coordinated
Introduction
Since Rosenberg and co-workers1 discovered the anti-tumour ac-
by a tridentate ligand should show a higher stability against the
tivity of cis-diamminedichloroplatinum(II) (cisplatin), it has been
trans influence of strong donor ligands. Furthermore, the selected
established as the leading compound for the treatment of different
types of cancer.2 Notwithstanding the success story of cisplatin,
chelate in this study coordinates via tertiary amines and forms
a planar and aromatic moiety with the pyridine rings. Even if
there are a number of problems that need to be considered during
these features violate the structure–activity relationship, there are
the treatment of cancer with cisplatin. For instance, there are
several cytostatic active substances known where the platinum
centre is coordinated by tertiary amines.12,15–18 Furthermore, we ex-
pect that the selected, sterically non-demanding picolylamine unit
enables an unhindered interaction of the complex with DNA,
which should lead to significant cytostatic activity (see Fig. 1).
This work is a continuation of an earlier study from our group on
numerous side effects such as nephrotoxicity, neurotoxicity and
emetogenesis that need to be taken into account, the anti-tumour
activity is limited to certain types of cancer, and some tumours
develop a resistance against cisplatin during the therapy.3 As
a result of these negative properties, research in recent years
has focused more on non-classical platinum complexes such as
multinuclear species and their anti-tumour activity, even if there is
still much effort put into improving the properties of mononuclear
complexes.4–7 These dinuclear complexes consist of either two or
three platinum centres that are linked through a flexible bridge
such as an aliphatic chain,8 or a rigid bridge that consists for
instance of azole molecules.9 The reason for the increasing interest
in multinuclear complexes is their ability to form DNA adducts
that differ significantly from those formed by cisplatin and related
complexes,10 which results in a completely different anti-tumour
behaviour.
Clinical tests have already been performed on multinuclear
platinum complexes synthesized by Farrell et al.11 The platinum
centres of these complexes are bridged by an aliphatic chain and
coordinated by primary amines. They are therefore in agreement
with the structure–activity relationship that requires at least
one NH moiety within the ligand.12,13 However, it has recently
been shown that these complexes react with sulfur containing
nucleophiles, which leads to the release of the bridging ligand and
Institute for Inorganic Chemistry, University of Erlangen-Nu¨rnberg,
Egerlandstr. 1, 91058, Erlangen, Germany. E-mail: vaneldik@chemie.uni-
erlangen.de
† Electronic supplementary information (ESI) available: Eyring plots for
the determination of the activation parameters for the reaction of the
complexes with chloride (Fig. S1a–e). See DOI: 10.1039/b700770c
Fig. 1 Schematic structures and abbreviations used for the investigated
complexes.
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propane and butane bridged platinum complexes,19 and is intended
to resolve the thermodynamic and kinetic properties of the com-
plexes as a function of the chain length of the bridging ligand. We
are particularly interested to know which chain length is required
for the two platinum centres to behave thermodynamically and
kinetically independent from each other. For this reason we
performed pKa titrations and nucleophilic substitution reactions
with the synthesized complexes. It is easier to distinguish between
two platinum centres with different reactivity toward nucleophiles
if the overall charge of the complex changes during the reaction.
Therefore, we selected chloride as the entering nucleophile. The
experimental work is supported by quantum chemical calculations
that allow distance correlations to be made.
4.5 Hz, 4H), d 3.78 (s, 8H), d 2.46 (t, 4H), d 1.46 (m, 4H), d 1.24
(m, 12H).
Synthesis of the complexes19
[Pt2(N,N,Nꢀ,Nꢀ-tetrakis(2-pyridylmethyl)-1,5-pentanediamine)Cl2]-
(ClO4)2 (5), [Pt2(N,N,Nꢀ,Nꢀ-tetrakis(2-pyridylmethyl)-1,5-hexa-
nediamnine)Cl2](ClO4)2 (6), [Pt2(N,N,Nꢀ,Nꢀ-tetrakis(2-pyridyl-
methyl)-1,7-heptanediamine)Cl2](ClO4)2 (7), and [Pt2(N,N,Nꢀ,Nꢀ-
tetrakis(2-pyridylmethyl)-1,10-decanediamine)Cl2 ](ClO4 )2 (8),
were all synthesized following the same procedure: To a solution
of 200 mg (0.48 mmol) K2PtCl4 in 50 mL 0.01 M HCl, a solution
of 0.24 mmol of the corresponding bridging ligand in 50 mL
0.01 M HCl was added. The mixture was refluxed for 24 h,
filtered if necessary, and the product was precipitated by addition
of 1.5 mL of saturated NaClO4 solution. The resulting powder
was filtered off, washed with H2O, EtOH and Et2O, and dried
under vacuum. The resulting product was recrystallized from
water if necessary. [Pt2(N,N,Nꢀ,Nꢀ-tetrakis(2-pyridylmethyl)-1,10-
decanediamine)(Cl)(TU)](ClO4)3 (9) was synthesized by adding
3.18 mg (0.04 mmol) of thiourea (TU) to a solution of 50 mg
(0,04 mmol) of 8 in 0.01 M CF3SO3H and refluxing the solution
overnight. The product was precipitated by addition of 1.5 mL of
a saturated NaClO4 solution. The resulting powder was filtered
off, washed with H2O, EtOH and Et2O, and dried under vacuum.
Experimental
Preparation of the ligands
N,N,Nꢀ,Nꢀ-tetrakis(2-pyridylmethyl)-1,5-pentanediamine (1),
N,N,Nꢀ,Nꢀ-tetrakis(2-pyridylmethyl)-1,6-hexanediamine (2),
N,N,Nꢀ,Nꢀ-tetrakis(2-pyridylmethyl)-1,7-heptanediamine (3) and
N,N,Nꢀ,Nꢀ-tetrakis(2-pyridylmethyl)-1,10-decanediamine (4)20
To a solution of 12 mmol 2-(chloromethyl)pyridinium in H2O
(0.5 mL), 3 mL 20% NaOH were added with stirring under nitro-
gen. To the resulting red solution, 3 mmol of the corresponding
diamine, 3 mL 20% NaOH, and 0.021 mL of a 25% hexadecyl-
trimethylammoniumchloride solution were added. The mixture
was stirred vigorously for 24 h at room temperature. It was then
extracted with CH2Cl2 (3 × 10 mL), the extract washed with 10 mL
H2O and dried over Na2SO4. After evaporation of the solvent,
the ligands 1, 2 and 4 were obtained as brown solids and 3 as a
brown oil. 1, 3 and 4 were purified by column chromatography
(Al2O3, CH2Cl2–EtOAc = 1 : 1, first fraction) and ligand 2 was
recrystallized from acetone, giving white solids in all cases.
5. Yield: 168 mg (1.49 mmol, 62%). Anal. Calc. for
C29H34Cl4N6O8Pt2: C, 30.92; H, 3.04; N, 7.46. Found: C, 30.33;
1
3
H, 3.22; N, 7.26%. H NMR (DMSO, 300 K): d 8.73 (d, JHH
=
6.7 Hz, 4H), d 8.26 ( t, 3JHH = 7.4 Hz, 4H), d 7.69 (m, 8H), d 5.23
(d, 3JHH = 15.2 Hz, 4H), d 4.69 (d, 3JHH = 16.8 Hz, 4H), d 2.27 (m,
4H), d 1.28 (m, 4H), d 1.09 (m, 2H).
6. Yield: 172 mg (1.51 mmol, 63%). Anal. Calc. for
C30H36Cl4N6O8Pt2: C, 31.59; H, 3.18; N, 7.37. Found: C, 30.97;
1
3
H, 2.88; N, 7.02%. H NMR (DMSO, 300 K): d 8.76 (d, JHH
=
1. Yield: 690 mg (1.48 mmol, 49%). Anal. Calc. for C29H34N6:
C, 74.65; H, 7.34; N, 18.01. Found: C, 74.43; H, 8.56; N, 18.01%.
1H NMR (DMSO, 300.0 K): d 8.46 (d, 3JHH = 4.9 Hz, 4H), d 7.73
5.6 Hz, 4H), d 8.27 ( t, 3JHH = 6.2 Hz, 4H), d 7.67 (m, 8H), d 5.27
(d, 3JHH = 15.4 Hz, 4H), d 4.69 (d, 3JHH = 16.8 Hz, 4H), d 2.27 (m,
4H), d 1.30 (m, 4H), d 0.97 (m, 4H).
3
3
(t, JHH = 6.5 Hz, 4H), d 7.47 (d, JHH = 6.8 Hz, 4H), d 7.23 ( t,
3JHH = 4.9 Hz, 4H), d 3.67 (s, 8H), d 2.38 (t, 4H), d 1.35 (m, 4H),
d 1.18 (m, 2H).
7. Yield: 194 mg (1.68 mmol, 70%). Anal. Calc. for
C31H38Cl4N6O8Pt2: C, 32.25; H, 3.32; N, 7.28. Found: C, 30.49;
1
3
H, 3.01; N, 6.60%. H NMR (DMSO, 300 K): d 8.76 (d, JHH
=
2. Yield: 865 mg ( 1.8 mmol, 60%). Anal. Calc. for C30H36N6:
C, 74.97; H, 7.55; N, 17.48. Found: C, 74.88; H, 8.39; N, 17.11%.
1H NMR (DMSO, 300.0 K): d 8.45 (d, 3JHH = 5.3 Hz, 4H), d 7.73
6.5 Hz, 4H), d 8.26 ( t, 3JHH = 7.1 Hz, 4H), d 7.67 (m, 8H), d 5.27
(d, 3JHH = 14.5 Hz, 4H), d 4.73 (d, 3JHH = 15.5 Hz, 4H), d 2.89 (m,
4H), d 1.37 (m, 4H), d 1.06 (m, 6H).
3
3
(t, JHH = 7.1 Hz, 4H), d 7.48 (d, JHH = 7.8 Hz, 4H), d 7.21 ( t,
3JHH = 4.9 Hz, 4H), d 3.69 (s, 8H), d 2.36 (t, 4H), d 1.39 (m, 4H),
d 1.09 (m, 4H).
8. Yield: 178 mg (1.49 mmol, 62%). Anal. Calc. for
C34H44Cl4N6O8Pt2: C, 34.12; H, 3.71; N, 7.02. Found: C, 33.62;
1
3
H, 3.99; N, 6.96%. H NMR (DMSO, 300 K): d 8.77 (d, JHH
=
3. Yield: 384 mg (0.78 mmol, 26%). Anal. Calc. for C31H38N6:
C, 75.27; H, 7.74; N, 16.99. Found: C, 73.33; H, 8.55; N, 15.53%.
1H NMR (DMSO, 300 K): d 8.45 (d, 3JHH = 5.3 Hz, 4H), d 7.73
6.0 Hz, 4H), d 8.27 ( t, 3JHH = 5.1 Hz, 4H), d 7.71 (m, 8H), d 5.30
(d, 3JHH = 16.5 Hz, 4H), d 4.76 (d, 3JHH = 15.0 Hz, 4H), d 2.95 (m,
4H), d 1.42 (m, 4H), d 1.08 (m, 4H), d 0.97 (m, 8H).
3
3
( t, JHH = 6.5 Hz, 4H), d 7.49 (d, JHH = 7.4 Hz, 4H), d 7.22 (t,
3JHH = 5.0 Hz, 4H), d 3.70 (s, 8H), d 2.39 (t, 4H), d 1.39 (m, 4H),
d 1.08 (m, 6H).
9. Yield: 40 mg (0.03 mmol, 72%). Anal. Calc. for
C35H48Cl4N8O12Pt2S: C, 31.45; H, 3.62; N, 8.38; S, 2.40. Found:
C, 30.98; H, 3.57; N, 7.80; S, 2.27%. 1H NMR (DMSO, 300 K): d
8.78 (t, 3JHH = 12 Hz, 4H), d 8.27 ( q, 3JHH = 33 Hz, 4H), d 7.71
(m, 8H), d 5.26 (t, 3JHH = 39 Hz, 4H), d 4.78 (t, 3JHH = 39 Hz, 4H),
d 2.99 (m, 4H), d 1.39 (m, 4H), d 1.06 (m, 4H), d 0.96 (m, 8H).
4. Yield: 820 mg (1.53 mmol, 51%). Anal. Calc. for C34H44N6:
C, 76.08; H, 8.26; N, 15.66. Found: C, 76.34; H, 8.91; N, 15.41%.1H
NMR (DMSO, 300 K): d 8.52 (d, 3JHH = 4.5 Hz, 4H), d 7.80 ( t,
3JHH = 6.6 Hz, 4H), d 7.57 (d, 3JHH = 6.0 Hz, 4H), d 7.28 (t, 3JHH
2296 | Dalton Trans., 2007, 2295–2301
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Preparation of complex solutions
instrument. Data acquisition was done with a J & M TIDAS 200–
620 nm rapid scan detector and a J & M TIDAS V 3.0 light source
connected with light guides to the stopped-flow instrument.
The desired solutions of the aqua complexes of Pen, Hex, Hep,
Dec and Dec-TU (see Fig. 1) were prepared by dissolving a known
amount of the chloro complexes 5–9 in 0.001 M trifluoromethane-
sulfonic (triflic) acid and adding a stoichiometric excess (with
respect to chloride) of silver triflate (150–200◦%). The mixture was
then stirred in the dark overnight at 40–50 C. The precipitated
silver chloride was filtered off, and the pH of the resulting solution
was adjusted to 10–11 by addition of 0.1 M NaOH, which resulted
in the precipitation of brown Ag2O. The precipitate was then
removed with a Millipore filter and the remaining solution was
acidified to pH = 2.0 with triflic acid. The resulting solution
was diluted with 0.01 M triflic acid to give the desired complex
concentration of 0.1 mM. For all investigations, the pH of the
solution was kept at 2.0 and the ionic strength was adjusted to
0.01 M.
Quantum chemical calculations
All structures were pre-optimized at the RHF/LANL2MB21–25
level of theory. The characterization as minima was done by
computation of vibrational frequencies at the same level. We per-
formed density functional structure optimizations with no other
constrains than symmetry using BP86/LCVP* as implemented in
Jaguar 6.5.26–34
Results and discussion
DFT calculations
In this study one of the most important structural parameters is
the distance between the Pt(II) coordination sites. We performed
RBP86/LACVP* calculations to obtain structures that are not
affected by solvent or neighbouring groups. Depending on the
number of (CH2)n groups in the bridge, we obtained C2h symmetry
when n is an even number and C2v symmetry when n is an odd
number (see Fig. 2). The best descriptor for the distance between
both Pt coordination sites is the distance covered by the N–(CH2)n–
N bridge, since this value shows in contrast to the Pt–Pt distance
no dependence on the symmetry. An analysis of the calculated
Instrumentation and measurement
NMR spectroscopy (Bruker Avance DPX 300) and a Carlo Erba
Elemental Analyser 1106 were used for characterization and
chemical analysis of the synthesized compounds. A Varian Cary
1G spectrophotometer equipped with a thermostated cell holder
was used to record UV-Vis spectra for the determination of the
pKa values of the diaqua complexes. Kinetic measurements were
performed on an Applied Photophysics SX 18MV stopped-flow
Fig. 2 (a) Calculated structure (C2v) BP86/LCVP* of Hep. (b) Calculated structure (C2h) BP86/LCVP* of Dec.
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˚
of significantly higher energy than the C2v or C2h structures. We,
therefore, consider the C2v and C2h structures as appropriate for
the further discussions.
distances shows that every additional CH2 group adds 1.3 A to
the distance covered by the N–(CH2)n–N bridge (see Fig. 3a). In
addition, a good correlation with the pKa values and substitution
rate constants is observed (see Fig. 3b and 3c).
The –(CH2)n– chain can adopt different conformers, of which
the gauche conformations will result in shorter Pt–Pt distances. To
obtain a significantly shorter Pt–Pt distance, a couple of gauche
conformations are necessary, which however result in structures
pKa determinations for the diaqua complexes
The pKa values of the diaqua complexes were determined by
performing a spectrophotometric pH titration with NaOH in the
pH range 2–9. To increase the pH from 2 to 3, solid NaOH was
used, whereas for the further increase in pH, NaOH solutions
of different concentrations were used. After each addition of
NaOH, 1 mL samples were taken from the complex solution
to measure the pH. The samples were discarded because of
probable contamination and subsequent substitution reactions
with chloride anions coming from the pH electrode. The pH
dependence of the diaqua complex was monitored by UV-Vis
spectroscopy. A typical example of the spectral changes observed
during the pH titration is shown in Fig. 4a. The spectral data
were analysed with Specfit Global Analysis software. The data
give an excellent fit for a system with two dissociation steps (see
Fig. 4b) with equilibrium constants Ka1 and Ka2, for which the
Fig. 3 (a) Correlation between the number of CH2 groups and the
calculated N–(CH2)n–N and Pt–Pt distances. (b) Correlation between
the calculated N–(CH2)n–N distances and the measured pKa1 and pKa2
values. (c) Correlation between the calculated N–(CH2)n–N distance and
the measured kobs1 and kobs2 values.
Fig. 4 (a) UV-vis spectra of the decane bridged diaqua complex recorded
as a function of pH in the range 2 to 10; I = 0.01 M (NaSO3CF3), T =
25.0 ◦C. (b) Plot of absorbance versus pH at 298 nm for the decane bridged
diaqua complex.
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overall process can be presented by reaction (1).
seems reasonable to assume that at least in the case of the decane
bridged diaqua complex, the two platinum centres are so far apart
from each other that we can exclude any interaction between them
and can expect a similar acidity for both aqua ligands. Under
such conditions Ka1/Ka2 should converge to the statistical value
of 4. This ratio for the decane bridged complex is close to 10
and indicates that the expected statistical factor has not yet been
reached.
K
a1
H2O-Pt-N-(CH2)n-N-Pt-OH4+ + H2O
−−−ꢀ
ꢁ−−−
2
H2O-Pt-N-(CH2)n-N-Pt-OH3+ + H3O+
K
a2
H2O-Pt-N-(CH2)n-N-Pt-OH3+ + H2O
(1)
−−−ꢀ
ꢁ−−−
HO-Pt-N-(CH2)n-N-Pt-OH2+ + H3O+
The pKa1 values (summarized in Table 1) for the two dissociation
steps move closer together as the length of the bridging ligand
increases along the series of complexes (see correlation in Fig. 3b).
This nicely corroborates earlier work performed in our group in
that the pKa value for the first deprotonation step of the dinuclear
complex is always lower than that of the mononuclear complex,
and the difference between these values becomes smaller as the
distance between the platinum centres of the dinuclear complexes
becomes longer.19 A short distance between the platinum centres
of dinuclear complexes results in the addition of the single charges
on the platinum centres. Because of this higher positive charge,
each platinum centre becomes more electrophilic and thus more
acidic, which leads to a lower pKa value than that of the +2 charged
platinum centre of the mononuclear complex. The effect of charge
addition becomes weaker as the distance between the Pt(II) centres
becomes longer.
Kinetic measurements
The substitution reactions of the series of diaqua complexes in
Fig. 1 with chloride as entering ligand were studied because of
the biological role of chloride in blood and in cells. At least a
20-fold excess of chloride over the complex concentration was
selected in our experiments in order to guarantee pseudo first
order conditions for the consecutive substitution processes shown
in reaction (2).
k
1
H2O-Pt-N-(CH2)n-N-Pt-OH4+ + Cl−−−−→
2
H2O-Pt-N-(CH2)n-N-Pt-Cl3+ + H2O
k
2
H2O-Pt-N-(CH2)n-N-Pt-Cl3+ + Cl−−−−→
Cl-Pt-N-(CH2)n-N-Pt-Cl2+ + H2O
(2)
For the same reason, the pKa2 values of the aquahydroxo
complexes generated during the first deprotonation reaction are
always higher than those of the diaqua complexes as a result of
the overall charge of +3. The difference between the pKa values
of the aquahydroxo and diaqua complexes becomes smaller as
the bridging chain becomes longer. On exceeding a specific chain
length, it is not possible to distinguish between the two metal
centres in terms of their electrophilicity and acidity anymore.
This observation is already known for the multinuclear platinum
complexes studied by Farrell and coworkers.35 In the case of the
decane bridged diaqua complex (Dec), analysis of the data in
terms of a single dissociation step resulted in a pKa1 value that is
slightly higher than the fit for a double dissociation step model. In
order to differentiate whether the decane bridged complex shows
one or two dissociation steps, we synthesized the decane bridged
thiourea-aqua complex (Dec-TU) to determine the pKa value for
this complex, which now has only one acid dissociation step.
Indeed, the pKa1 value of the Dec-TU complex has practically the
same value as that found for the decane bridged diaqua complex
using a double dissociation step model (see Table 1). Thus, it
The time dependent spectra observed for the reactions with
chloride were analyzed with Specfit Global Analysis software.
They indicated that the substitution reactions of complexes Pen,
Hex and Hep are best described by a two exponential fit. The
determined pseudo first order rate constants kobs(1,2) were plotted
against chloride concentration. The resulting linear dependence
on the chloride concentration with no intercept indicates that the
reverse reaction with water is too slow to contribute significantly
to the values of kobs(1,2). The first ligand substitution reaction is
faster than the second one as shown by the plots of kobs versus
[Cl−] for both reaction steps in Fig. 5a–e. This can be explained
in terms of the decrease in the overall charge on the complex
from +4 to +3 following the substitution of one water ligand by
chloride. The platinum centre becomes less electrophilic because of
the lower charge and the substitution of water by chloride becomes
slower. The addition of a singly charged nucleophile becomes less
efficient or even impossible during the stepwise lengthening of
the aliphatic chain due to a decrease in the electrophilicity of the
platinum centres. Thus the rate constants for the first substitution
reaction of complexes with longer chains are smaller than the
Table 1 Summary of pKa values for the first and second deprotonation steps of the aqua complexes, second order rate constants and activation
parameters for the displacement of coordinated water by chloride, and the calculated (BP86/LACVP*) N–(CH2)n–N and Pt–Pt distances
Pen
Hex
Hep
Dec
Dec
Dec-TU
pKa1
3.93 0.03
5.69 0.03
262 13
3.65 0.06
5.29 0.05
4.07 0.02
5.27 0.06
4.03 0.04
5.06 0.06
4.37 0.01
—
59.7 0.2
—
4.11 0.05
—
pKa2
k1at 25 ◦C/M−1 s−1
k2 at 25 ◦C/M−1 s−1
DH‡1/kJ mol−1
DH‡2/kJ mol−1
DS‡1/J K−1 mol−1
DS‡2/J K−1 mol−1
175
5
143
55
66
5
1
7
4
140
2
66
—
59
—
2
2
5
78
86
87
1
7
7
53.7 0.6
53 0.2
89
58
9
3
78
71
5
2
66
2
62
—
+87 22
+83 24
7.78
+96 29
−17 10
9.07
+16 23
−4 15
10.35
+58 16
−37
8
−60
+25
7
—
—
˚
d N–(CH2)n–N/A
d Pt–Pt/A
14.20
17.39
—
—
—
—
˚
10.68
12.33
13.34
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Fig. 5 (a) Plots of kobs1 and kobs2 versus chloride concentration for the reaction with the pentane bridged diaqua complex. I = 0.01 M (HSO3CF3), T =
25.0 ◦C, pH = 2.0. (b) Plots of kobs1 and kobs2 versus chloride concentration for the reaction of the hexane bridged diaqua complex. I = 0.01 M (HSO3CF3),
T = 25.0 ◦C, pH = 2.0. (c) Plots of kobs1 and kobs2 versus chloride concentration for the reaction of the heptane bridged diaqua complex. I = 0.01 M
(HSO3CF3), T = 25.0 ◦C, pH = 2.0. (d) Plots of kobs1 and kobs2 versus chloride concentration for the reaction of the decane bridged diaqua complex. I =
0.01 M (HSO3CF3), T = 25.0 ◦C, pH = 2.0. (e) Plot of kobs versus chloride concentration for the reaction of the decane bridged thiourea-aqua complex.
I = 0.01 M (HSO3CF3), T = 25.0 ◦C, pH = 2.0.
values for complexes with shorter bridges (see correlation in
Fig. 3c). Furthermore, the rate constants continuously decrease
as a function of the distance of the two platinum coordination
sites and the difference between the rate constants for the first and
second substitution steps also becomes smaller on lengthening
the aliphatic chain between the platinum centres (see Fig. 2c).
Thus we expect, as in the case of the complexes studied by Farrell
and co-workers,10 that the two platinum centres will reach the
same reactivity towards nucleophiles for a particular chain length.
The two platinum centres can only be distinguished if there is a
change in the charge of the complex during the reaction with the
nucleophile. Therefore Jaganyi et al. were only able to obtain one
rate constant for the reaction of their bridged platinum complexes
with thiourea, where the charge of the complex is unchanged.36
It is not clear whether in the case of the decane bridged complex
(Dec), the platinum centres act independently of each other and
have the same reactivity or not, since the nucleophilic substitution
reactions of this complex can be well described by both a double
and a single exponential function (see data in Table 1). We again
took the decane bridged aqua-thiourea complex (Dec-TU) to
resolve this question. This complex shows only one substitution
reaction for water by chloride since thiourea cannot be displaced
by chloride. In this way we obtained data for a closely related
system which we found to be best described by a single exponential
function. From the data in Table 1 it follows that the rate constant
for the decane bridged aqua-thiourea and diaqua complexes are in
good agreement when the kinetic behaviour of the diaqua complex
is described by a single exponential function.
The results in Table 1 also demonstrate that the ratio of the rate
constants k1/k2 decreases along the series and reaches a value of
2.6 for the decane bridged complex. This is close to the limiting
statistic factor of 2 expected for two equivalent platinum centres.
Temperature dependence
The activation parameters DH# and DS# were determined by
measuring the rate constant of each of the substitution reactions of
the complexes with 3 mM chloride as a function of temperature.
The parameters were calculated using the Eyring equation (see
Fig. S1–e, ESI†) and are summarized in Table 1. The values for the
activation enthalpy become smaller on lengthening the bridging
chain, which is compensated by a decrease in the activation
entropy. In general substitution reactions of square planar Pt(II)
complexes proceed according to an associative mechanism and
should be characterized by negative intrinsic DS# values as a
result of bond formation in the transition state. However, in
the present case the substitution reactions outlined in (2) are
accompanied by charge neutralization which will cause a decrease
in electrostriction and release of electrostricted solvent molecules.
This reorganization of the solvent will cause an increase in entropy
and offset the negative intrinsic contribution as a result of bond
formation. The overall activation entropies reported in Table 1 are
in many cases close to zero within the experimental error limits
as a result of this compensation effect. Nevertheless, there is no
reason to believe that the substitution reactions do not follow an
associative mechanism.
2300 | Dalton Trans., 2007, 2295–2301
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6 D. Jaganyi, F. Tiba, O. Q. Munro, B. Petrovic and Z. D. Bugarcic,
Dalton Trans., 2006, 2943.
Conclusions
7 N. Summa, W. Schiessl, R. Puchta, N. van Eikema Hommes and R.
van Eldik, Inorg. Chem., 2006, 45, 2948.
We studied the effect of increasing the aliphatic chain on
the bridged complexes [{Pt(OH2)(N,N,Nꢀ,Nꢀ-tetrakis(2-pyridyl-
methyl)}2N–(CH2)n–N]4+. We could observe an electrostatic inter-
action between the two platinum centres which becomes weaker
on lengthening the aliphatic bridge. There is an addition of the
separate charges on the platinum centres in complexes bridged
through a short aliphatic chain. This increases the electrophilicity
of the platinum centres, leads to lower pKa values for the
coordinated water ligands and a higher reactivity of the complex
towards chloride. This interaction observed for the complexes with
a shorter bridge cause each of the platinum centres to exhibit
different thermodynamic and kinetic properties. The interaction
reaches a minimum for the decane bridged complex where it
becomes very difficult to distinguish between the kinetic behaviour
of the two Pt(II) centres.
Analysis of the pH titration data by Specfit, in which the
complete wavelength range spectra was used, gave a factor of
10 between the values for Ka1 and Ka2 for the decane bridged
complex, although a value of 4 is expected for Ka1/Ka2 based on
the statistics for two Pt(II) centres completely independent of each
other. However, single wavelength analyses gave good fits for Ka1
and Ka2 within a factor of 4. The reported factor of 10 may thus
be subjected to large error limits and may strongly depend on the
method of analysis employed.
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Theoretical calculations assisted the analysis of the correlation
between the thermodynamic and kinetic parameters as a function
of the length of the bridging ligand. Further investigations will
include a study of the reactivity of the complexes with biological
relevant nucleophiles such as 5ꢀGMP2−/− and L-methionine under
physiological conditions. Because of the chosen chelate attached
to the Pt(II) centre, we expect a higher stability than in the case of
BBR3464 and BBR3610 for which the reaction with S-containing
nucleophiles leads to degradation of both complexes.14
Acknowledgements
The authors gratefully acknowledge financial support from the
Deutsche Forschungsgemeinschaft. We thank Prof. Tim Clark for
hosting this work at the CCC and the Regionales Rechenzentrum
Erlangen (RRZE) for a generous allotment of computer time.
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