Thermodynamic and kinetic behaviour of [Pt(2-methylthiomethylpyridine) (OH2)2]2+

Article abstract of DOI:10.1039/c1dt11453k

The diaqua complex [Pt(2-methylthiomethylpyridine)(OH₂) ₂]²⁺, Pt(mtp), was synthesized and investigated thermodynamically as well as kinetically. Spectrophotometric acid-base titrations were performed to determine the pK_a values of the two coordinated water ligands. A low pK_a1 value of 3.15 was observed for the water molecule trans to the pyridine donor, whereas a pK_a2 value of 6.84 was found for the water molecule trans to the labilising sulphur donor. The substitution of coordinated water by a series of sterically hindered S-containing nucleophiles, viz. thiourea (tu), N,N′-dimethylthiourea (dmtu) and N,N,N′,N′-tetramethylthiourea (tmtu), was studied under pseudo first-order conditions as a function of nucleophile concentration, pH (2, 4.75, 7.4), temperature and pressure, using stopped-flow techniques and UV-vis spectroscopy. In general the first substitution reaction takes place trans to the sulphur donor. At pH 2 the nucleophiles react in the order tu (634 ± 10) > dmtu (507 ± 5) ? tmtu (165 ± 3 M^-1 s ^-1 at 25 °C), which is caused by steric hindrance. The second observed reaction involves two steps, viz. the displacement of the second water ligand and dechelation of the pyridine ring with the third-order rate constants 73.3 ± 0.8 (tu), 22.1 ± 0.1 (dmtu) and 6.8 ± 0.2 M ^-2 s^-1 (tmtu) at 25 °C. At pH 4.75 the reactions are in general slower due to the presence of aqua-hydroxo species. The same order in reactivity was found, viz. tu (106 ± 1) > dmtu (72 ± 1) ? tmtu (14.1 ± 0.5 M^-1 s^-1 at 25 °C). No evidence for ring-dechelation could be observed under these conditions. At pH 7.4 the inert dihydroxo species is predominantly present in solution and consequently no substitution reaction was observed. Quantum chemical calculations were performed to support the interpretation and discussion of the experimental results.

Full text of DOI:10.1039/c1dt11453k

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PAPER
Thermodynamic and kinetic behaviour of
[Pt(2-methylthiomethylpyridine)(OH2)2]2+†‡
Stephanie Hochreuther,a Sharanappa T. Nandibewoor,a,b Ralph Puchtaa,c and Rudi van Eldik*a
Received 2nd August 2011, Accepted 21st September 2011
DOI: 10.1039/c1dt11453k
The diaqua complex [Pt(2-methylthiomethylpyridine)(OH2)2]2+, Pt(mtp), was synthesized and
investigated thermodynamically as well as kinetically. Spectrophotometric acid–base titrations were
performed to determine the pKa values of the two coordinated water ligands. A low pKa1 value of 3.15
was observed for the water molecule trans to the pyridine donor, whereas a pKa2 value of 6.84 was
found for the water molecule trans to the labilising sulphur donor. The substitution of coordinated
water by a series of sterically hindered S-containing nucleophiles, viz. thiourea (tu), N,N¢-dimethyl-
thiourea (dmtu) and N,N,N¢,N¢-tetramethylthiourea (tmtu), was studied under pseudo first-order
conditions as a function of nucleophile concentration, pH (2, 4.75, 7.4), temperature and pressure,
using stopped-flow techniques and UV-vis spectroscopy. In general the first substitution reaction takes
place trans to the sulphur donor. At pH 2 the nucleophiles react in the order tu (634 10) > dmtu (507
5) ꢀ tmtu (165 3 M-1 s-1 at 25 ◦C), which is caused by steric hindrance. The second observed
reaction involves two steps, viz. the displacement of the second water ligand and dechelation of the
pyridine ring with the third-order rate constants 73.3 0.8 (tu), 22.1 0.1 (dmtu) and 6.8 0.2 M-2 s-1
(tmtu) at 25 ◦C. At pH 4.75 the reactions are in general slower due to the presence of aqua-hydroxo
species. The same order in reactivity was found, viz. tu (106 1) > dmtu (72 1) ꢀ tmtu (14.1 0.5 M-1
s-1 at 25 ◦C). No evidence for ring-dechelation could be observed under these conditions. At pH 7.4 the
inert dihydroxo species is predominantly present in solution and consequently no substitution reaction
was observed. Quantum chemical calculations were performed to support the interpretation and
discussion of the experimental results.
prove structural and physiological disadvantages, such as sev-
Introduction
eral side effects, drug resistance and limitation in the field
of application. Most of the developed and studied platinum
complexes include nitrogen-containing monodentate, bidentate
or tridentate ligands.2–8 The ultimate aim of the modifications
of the parent drug is to make related analogues that produce a
different spectrum of DNA lesions and so circumvent the problem
of resistance to cisplatin.2,9 Therefore, non-classical platinum
derivatives were also investigated, which may violate the classical
structure–activity relationship.2 There are complexes known that
include sulphur-containing ligands and show antitumor activity.10
An example is [Pt(CH3SCH2CH2SCH3)Cl2], Pt(dt), a sulphur
analogue of the well-studied [Pt(H2NCH2CH2NH2)Cl2], Pt(en),
complex.10 Baltic´ et al. examined the antitumor activity of
Pt(dt) against the human breast cancer cell line and found
the complex to inhibit the growth of MCF-7 cells in a dose
and time dependent manner.10 Another example is the complex
dichloro(2-methylthiomethylpyridine)platinum(II), Pt(mtp)Cl2, a
complex with nitrogen as well as sulphur donor ligands. In
the literature different synthetic pathways are described11–13 and
the bidentate mixed N,S-complex was found to be a promising
cytostatic agent.14
Since Rosenberg1 discovered the cytostatic activity of cis-
diamminedichloroplatinum(II), significant efforts were made to
produce novel platinum-containing compounds in order to im-
aInorganic Chemistry, Department of Chemistry and Pharmacy, Univer-
sity of Erlangen-Nu¨rnberg, Egerlandstr. 1, 91058, Erlangen, Germany.
E-mail: vaneldik@chemie.uni-erlangen.de
bP.G. Department of Studies in Chemistry, Karnatak University, Pavate
Nagar, Dharwad, 580003, India
cComputer Chemistry Centre, Department of Chemistry and Pharmacy,
University of Erlangen-Nu¨rnberg, Na¨gelsbachstr. 25, 91052, Erlangen,
Germany
† Electronic supplementary information (ESI) available: Fig. SI 1 shows
calculated absorbance traces, Fig. SI 2 depicts quantum chemical calcu-
lations for proton-exchange, Figs. SI 3–SI 4 and Figs. SI 6–SI 9 show
the UV-vis spectra for the Pt(mtp) complex at different pH values. Fig.
SI 5 reports the isotopic pattern detected by mass spectrometry. Figs.
SI 10–SI 18 illustrate different concentration, temperature and pressure
dependent studies for all nucleophiles and pH values. Table SI 1 shows a
summary of the used wavelengths and Tables SI 2–SI 20 summarize all
values for kobs determined for all reactions at different concentrations,
pH values, temperatures and pressures for all nucleophiles. See DOI:
10.1039/c1dt11453k
‡ Dedicated to Raquel Urpi Bertran (January 26, 1977–July 31, 2011†)
512 | Dalton Trans., 2012, 41, 512–522
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1
In this study, we focus on the thermodynamic and ki-
netic behaviour of this mixed N,S-donor complex, [Pt(2-
methylthiometylpyridine)(OH2)2]2+, Pt(mtp). The complex con-
sists of a Pt(II) metal centre coordinated by a pyridyl unit
connected through a methylene group to a methylthioether unit as
shown in Fig. 1. We report here thermodynamic data (pKa values)
and kinetic results for the displacement of the two water ligands
with different sulphur-containing nucleophiles, viz. thiourea,
N,N¢-dimethylthiourea and N,N,N¢,N¢-tetramethylthiourea. Fur-
thermore, we also performed the kinetic experiments at different
pH values, viz. pH 2 (where the diaqua complex is the main
species in solution), pH 4.75 (where the aqua-hydroxo complex
is the main species in solution) and at the physiological pH
7.4. In addition, we compared the results obtained with in-
formation on the earlier studied analogous N,N-complex [Pt(2-
aminomethylpyridine)(OH2)2]2+, Pt(amp),15 to identify differences
and similarities in the thermodynamic and kinetic behaviour of
these complexes.
Yield: 2.1 g (14.9 mmol, M = 139.2 g mol-1, 75%). H NMR
3
(300.13 MHz, CDCl3, 298.2 K): d (ppm) 8.40 (d, JHH = 4.6 Hz,
1H), 7.53 (t, 3JHH = 7.6 Hz, 3JHH = 4.6 Hz, 1H), 7.23 (d, 3JHH = 7.6
Hz, 1H), 7.03 (t, 3JHH = 7.6 Hz, 1H), 3.67 (s, 2H), 1.93 (s, 3H). 13
C
NMR (75.4 MHz, CDCl3, 298.2 K): d (ppm) 158.3, 148.8, 136.3,
122.6, 121.5, 39.7, 14.8.
Synthesis of the complex [Pt(2-methylthiomethylpyridine)Cl2],
16
Pt(mtp)Cl2
A solution of 200 mg (0.48 mmol) K2PtCl4 in 30 mL H2O
was added under vigorous stirring to 67 mg (0.48 mmol) of
2-methylthiomethylpyridine using a dropping funnel at room
temperature. The reaction mixture was further stirred until the
characteristic red colour of dissolved [PtCl4]2- disappeared (3 h).
The resulting yellow precipitate was filtered off, washed with H2O,
EtOH and Et2O, and dried under vacuum.
Yield: 162 mg (0.40 mmol, M = 405.2 g mol-1, 83%). Anal. Calc.
for C7H9Cl2NPtS: C, 20.75; H, 2.24; N, 3.46; S, 7.91; Found: C,
20.89; H, 2.22; N, 3.24; S, 8.25. 1H NMR (300.13 MHz, dmso-d6,
298.2 K): d (ppm) 9.41 (d, 3JHH = 6.1 Hz, 1H), 8.16 (t, 3JHH = 7.7
Hz, 3JHH = 6.1 Hz, 1H), 7.81 (d, 3JHH = 7.7 Hz, 1H), 7.55 (t, 3JHH
= 7.7 Hz, 1H), 4.77 (d, AB-spin system, 2JHH = 16.9 Hz, 1H), 4.47
(d, AB-spin system, 2JHH = 16.9 Hz, 1H), 2.38 (s, 3H). MS (FAB,
m-NBS) m/z = 369 [M–Cl]+.
Preparation of the diaqua complex solution17
Desired solutions of the diaqua complex were prepared by
suspending a known quantity of the dichloro complex in 0.001 M
trifluoromethanesulfonic (triflic) acid and adding a stoichiometric
excess (with respect to chloride) of silver triflate (2.1 equiv). The
mixture was then stirred in the dark overnight at 45 ◦C. The
precipitated silver chloride was filtered off, and the pH of the re-
sulting solution was adjusted to 10–11 by addition of 0.1 M NaOH
solution, which resulted in the precipitation of brown silver oxide.
The silver oxide precipitate was then removed with a Millipore
filter and the remaining solution was acidified to pH 2 with triflic
acid to give the desired complex concentration of 0.25 mM and
an ionic strength of I = 0.01 M (triflic acid). For the investigations
at pH 4.75 a 0.1 M acetate buffer solution (I = 0.1 M, adjusted
with triflic acid) and for the measurements at pH 7.4 a 0.1 M Tris
buffer solution was used (I = 0.1 M, adjusted with triflic acid).
Fig. 1 Structures of the studied N,S-Pt(II) complex Pt(mtp) and its
N,N-analogue Pt(amp).
Experimental
Chemicals
The chemicals 2-picoline, dimethyldisulfide, trifluoromethanesul-
fonic (triflic) acid, silver triflate and the nucleophiles thiourea,
N,N¢-dimethylthiourea and N,N,N¢,N¢-tetramethylthiourea were
purchased from Sigma-Aldrich. Potassium tetrachloroplati-
nate(II) was purchased from Strem Chemicals. All other chemicals
used were of the highest purity commercially available and were
used without further purification. For all preparations of aqueous
solutions, ultra pure water was used.
Instrumentation and measurement
NMR spectroscopy (Bruker Avance DPX 300) and a Carlo Erba
Elemental Analyser 1106 were used for ligand and complex charac-
terization, and chemical analysis, respectively. Mass spectrometric
measurements were performed on an UHR-TOF Bruker Daltonik
(Bremen, Germany) maXis, an ESI-TOF mass spectrometer
capable of a resolution of at least 40,000 FWHM used by the group
of Prof. Ivana Ivanovic´-Burmazovic´ at the University of Erlangen-
Nu¨rnberg. A Varian Cary 1G spectrophotometer equipped with
a thermostatted cell holder was used to record UV-vis spectra
for the determination of the pKa values of the diaqua complex.
Kinetic measurements on fast reactions were performed on an
Applied Photophysics SX 18 MV stopped-flow instrument, and
for the study of slow reactions a Shimadzu UV-2010PC spec-
trophotometer with a thermo-electrically controlled cell holder
Synthesis of the ligand 2-methylthiomethylpyridine12
A solution of n-butyllithium (12 mL of a 1.6 M hexane solution,
19.0 mmol) was added dropwise to a stirred solution◦of 1.9 g
(20.0 mmol) 2-picoline in 50 mL absolute Et2O at -78 C under
nitrogen atmosphere. The reaction was allowed to warm to room
temperature, after which it was added dropwise to a stirred
solution of 1.8 mL dimethyl disulfide (20.5 mmol) in 50 mL
absolute THF at -78 ◦C. The solution was allowed to warm to
room temperature and stirred for 12 h. Water was then added and
the aqueous layer extracted with Et2O (3 ¥ 75 mL). The organic
phase was dried over Na2SO4 and the solvent removed under
reduced pressure resulting in a yellow oil. The product was verified
by NMR spectroscopy and used without further purification.
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was used. Experiments at elevated pressure were performed on a
laboratory-made high-pressure stopped-flow instrument for fast
reactions.18 The temperature of the instruments was controlled
throughout all kinetic experiments to an accuracy of 0.1 ◦C.
pH electrode. This electrode was calibrated using standard buffer
solutions at pH 4, 7 and 10, purchased from Fisher Scientific.
Afterwards the samples were discarded because of a possible
chloride ion contamination coming from the pH electrode. Each
pKa titration was performed at least two times and an average of
both values was taken. The pH dependence of the diaqua complex
was monitored by UV-vis spectroscopy.
Computational details
To obtain the pKa values, we followed the procedure of Gilson
and Durrant,19 who derived the pKa values by PCM20 single point
calculations (B3LYP(PCM)/LANL2DZ//B3LYP/LANL2DZ)
based on fully optimized structures of the diaqua complex and the
corresponding deprotonated species, applying B3LYP hybrid den-
sity functional21 and the LANL2DZ basis set.22 To investigate the
possible proton migration for the aqua-hydroxo Pt(mtp) complex,
we performed B3LYP calculations21 utilizing the LANL2DZ basis
set with effective core potentials,22 augmented with polarisation
functions on non-hydrogen atoms.23 The same method was used
in previous work for the Pt(amp) complex,15 which can therefore
be compared to the Pt(mtp) complex. The performance of this
level (denoted as B3LYP/LANL2DZp) has been documented
by us and others.24 Structures were characterized as minima or
transition structures by computation of vibrational frequencies.
Relative energies were corrected for zero point vibrational energy.
The Gaussian 03 suite of programs was used throughout.25
Fig. 2 shows the complete UV-vis spectra in the pH range 2–
10. The inset presents the plot of absorbance at 290 nm versus
pH. A closer look at the UV-vis spectra indicates that there are
three species present in solution. In the pH range 2–5 two clear
isosbestic points at 246 and 264 nm are observed (see Fig. 3a).
In this pH range the equilibrium between the diaqua and the
aqua-hydroxo species dominates the spectral changes and the
first dissociation step can be observed. Furthermore, in the pH
range 5–10 three new isosbestic points at 229, 249 and 285 nm are
observed (see Fig. 3b) and the isosbestic points found previously
disappeared. The spectral changes in this pH range are dominated
by the presence of the aqua-hydroxo and dihydroxo species and
the second deprotonation step can be observed. The existence of
isosbestic points for each acid dissociation step can be utilized
to determine the two pKa values separately. In consequence, by
Results and discussion
pKa determination
Spectrophotometric pH titrations with NaOH as base in the pH
range of 2–10 were performed to determine the pKa values of
the coordinated water ligands. The pH titration was done using a
Hellma optical flow-through cell attached to a peristaltic pump. It
was important to keep the concentration of the complex solution
constant, to avoid absorbance corrections due to dilution. This
could be achieved by using a 100 mL complex solution during the
titration. Starting at pH 2, the pH was increased by addition of
small portions of solid NaOH to the solution until a pH of 3 was
reached. For further increase in pH, a series of NaOH solutions
with different concentrations were used. After each addition of
base, samples of 500 mL were ta◦ken from the complex solution
and the pH was measured at 25 C using an InLab Semi-Micro
Fig. 2 UV-vis spectra of 0.1 mM Pt(mtp) in the pH range 2–10 at 25 ◦C.
Inset: Plot of absorbance at 290 nm versus pH.
Fig. 3 a) Spectral changes recorded for 0.1 mM Pt(mtp) in the pH range 2–5 at 25 ◦C. Inset: Plot of absorbance at 229 nm versus pH. b) Spectral changes
recorded for 0.1 mM Pt(mtp) in the pH range 5–10 at 25 ◦C. Inset: Plot of absorbance at 264 nm versus pH.
514 | Dalton Trans., 2012, 41, 512–522
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plotting the absorbance at 229 nm versus pH, the first pKa1
value of 3.14 can be determined using a single sigmoidal function
(Boltzmann). Due to the selected wavelength of 229 nm, spectral
changes occur only in the pH range 2–5, and the absorbance
remains constant from pH 5 to 10 as seen in the inset of Fig.
3a. Similarly, by plotting the absorbance versus pH at 264 nm,
the resulting titration trace again can be fitted perfectly to a single
sigmoidal function and the second pKa2 value of 6.91 can be found
as seen in the inset of Fig. 3b.
In addition, to verify the results obtained at specific wavelengths,
the spectral data were analysed using Specfit Global Analysis
software. Eigen vector analysis with Specfit indicates again that
there are three coloured species present in solution as a function
of pH within the whole wavelength range. The so-obtained acid
dissociation constants Ka1 and Ka2 and therefore the pKa1 and
pKa2 values are in good agreement with the results obtained
from the Boltzmann equation. For further discussion the values
obtained from Specfit were used because of the more accurate
analysis method (complete wavelength range instead of a single
wavelength). Fig. SI 1 (ESI†) shows the calculated absorbance
traces for each generated species in solution as a function
of pH. These calculated traces again agree perfectly with the
experimentally obtained absorbance traces shown in Fig. 3. The
pKa values for the Pt(mtp) complex, the recently reported values
for the Pt(amp) reference26 complex, as well as the quantum
chemical calculated values, are summarized in Table 1.
were also performed and an energy profile could be generated for
proton-transfer from water to the hydroxo ligand. Both isomers
can be described as energetically equal (difference of 0.1 kcal
mol-1). They are connected by an energy barrier of 2.8 kcal mol-1,
which was found to be very low (see Fig. SI 2, ESI†). Calculations
for the Pt(amp) reference complex showed a comparable energy
barrier of 1.6 kcal mol-1.15 In addition, it can be seen that the
calculated pKa1 values for Pt(mtp) are significantly lower than for
Pt(amp), which corroborates our experimental work.
As reported recently26 for the N,N-analogous complex Pt(amp)
(see Fig. 1), the distinction between the first and second deproto-
nation site was made and favoured the first step to occur trans to
the pyridine unit. In the case of Pt(mtp), the first deprotonation
step takes place trans to the pyridine donor as well. The sulphur
donor with its strong s-donor effect labilises the water ligand in
the trans position, which leads to a longer Pt–O bond trans to SR2
˚
(2.17 A, see Table 2) compared to the Pt–O bond trans to NH2R
˚
(2.13 A, see Table 2) and consequently to a higher pKa value. It
should be noted that the difference between the first and second
deprotonation steps is larger compared to Pt(amp) (pKa1 = 4.77
and pKa2 = 6.56).26 For the Pt(mtp) complex we found a rather low
pKa1 value of 3.15 compared to 4.77 for the Pt(amp) complex. In
both cases it concerns the water ligand trans to the pyridine ligand.
The question arises why the apparently similar water ligand shows
such a different acidity? The first suggestion was that the pKa1
value found did not belong to the platinum bound water ligand,
since there is also the possibility that the sulphur donor atom itself
can be protonated in acidic medium. In that case, we would expect
a relatively low pKa value for the deprotonation at the sulphur
donor atom. However, the orbital overlap of the soft Pt(II) centre
andthesoftsulphurdonorispreferred(HSAB principle), suchthat
a hard proton cannot compete with the Pt(II) centre. Furthermore,
there was no evidence for a third deprotonation step, neither at
lower pH values (for which we performed titrations staring at pH
0), nor at higher pH values up to 14. Consequently, we eliminated
the possibility of protonation at the sulphur donor site.
The experimental results nicely agree with the calculated values
as shown in Table 1. Calculations for the aqua-hydroxo species
Table 1 Summary of pKa values obtained for the stepwise deprotonation
of platinum bound water for the Pt(mtp) and Pt(amp) complex including
the calculated pKa values, respectively
Pt(mtp)a
Pt(mtp)b Pt(amp)26,a calc. Pt(mtp)19 calc. Pt(amp)19
pKa1 3.15 0.05 3.14 0.01 4.77 0.02
pKa2 6.84 0.07 6.91 0.03 6.56 0.04
2.9
6.4
4.9
6.9
a values obtained from Specfit Global Analysis, b values analysed with the
Boltzmann equation.
A closer look was taken on the calculated geometry of the
two complexes before and after the first deprotonation step using
Table 2 Calculated bond lengths and angles (B3LYP/LANL2DZp) for the diaqua species as well as for the aqua-hydroxo species for Pt(mtp) and
Pt(amp). Complex charges were omitted for clarity
a in (◦)
b in (◦)
g in (◦)
d in (◦)
85.4
96.4
85.1
93.1
2.30
2.00
2.17
2.14
81.8
92.7
91.9
94.3
2.03
2.01
2.13
2.14
85.5
98.9
75.0
100.6
2.28
2.07
2.16
1.99
80.7
99.9
75.0
104.3
2.04
2.06
2.11
2.00
˚
d Pt–X in A
˚
d Pt–Npy in A
˚
˚
d Pt–Otrans X in A
d Pt–Otrans py in A
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quantum chemical calculations. As depicted in Table 2, the lengths
of the Pt–O bond trans to the pyridine nitrogen are essentially
the same for both complexes. The differences in Pt–O trans to
X, where X is either NH2 or SCH3 (see drawing in Table 2), are
mainly due to the stronger s-labilisation in the case of Pt(mtp), but
have no influence on the first pKa1 value. Further differences can
be seen concerning the angles; the major difference is related to
the angle g, i.e. the angle between the two platinum bound water
ligands. During deprotonation trans to the pyridine nitrogen, g
changes from 85.1◦ to 75.0◦ in the case of Pt(mtp) and from 91.9◦
to 75.0◦ in the case of Pt(amp). This means that the necessary
rearrangement in geometry after deprotonation is more favoured
in Pt(mtp) and the resulting angle change in the Pt(mtp) complex
adds up to 10◦ compared to 17◦ in Pt(amp). Therefore, we assume
that the resulting aqua-hydroxo Pt(mtp) species is more stable and
consequently leads to a lower pKa1 value.
The second deprotonation step occurs trans to the SR2 unit.
Compared to the N,N-analogue Pt(amp) (6.56), we found a slightly
higher pKa2 value of 6.84. This can be attributed to the s-donating
effect. Sulphur offers by far the stronger s-donor effect which
consequently leads to a larger labilisation than that caused by the
secondary amine.
Soldatovic´ et al. worked on similar systems including a mixed
bidentate N,S ligand, viz. S-methyl-L-cysteine (SMC).27 They
found that the first deprotonation step occurred trans to the
secondary amine NHR2 (pKa1 = 3.49) and the second step at a
significantly higher value (pKa2 = 8.80) trans to the sulphur donor.
This work is in good agreement with our results, viz. a first very
acidic pKa1 value and a significantly higher pKa2 value. Soldatovic´
et al. used a ligand system without any p-acceptor units, which
results in a less electrophilic metal centre compared to our system
and therefore to a slightly higher pKa1 and significantly higher
pKa2 value.
to be 93% diaqua and 7% aqua-hydroxo species, at pH 4.75 to be
3% diaqua, 96% aqua-hydroxo and 1% dihydroxo species, and at
pH 7.4 to be 16% aqua-hydroxo and 84% dihydroxo species.
Kinetic measurements
The substitution behaviour of the Pt(mtp) complex was studied
for the sulphur-containing nucleophiles thiourea (tu), N,N¢-
dimethylthiourea (dmtu) and N,N,N¢,N¢-tetramethylthiourea
(tmtu), which differ significantly in their steric hindrance dur-
ing nucleophilic attack. The kinetic measurements were done
spectrophotometrically by following the change in absorbance
at suitable wavelengths (see Table SI 1, ESI†) as a function of
time. At least a 20-fold excess of nucleophile relative to the
complex concentration was used in all measurements to guarantee
pseudo first-order conditions for the consecutive substitution
reactions. Since it is known that triflate anions do not coordinate
to Pt(II) metal centres,28 0.01 M triflic acid was used as solvent
for measurements at pH 2 with an ionic strength of 0.01 M. For
the measurements at pH 4.75 a 0.1 M acetate buffer solution and
at pH 7.4 a 0.1 M TRIS buffer solution was used with an ionic
strength of 0.1 M. On using thiourea and its derivatives as neutral
nucleophiles, the charge of the complex during the substitution
reactions remains constant. The values of the reported pseudo
first-order rate constants are the average of at least four kinetic
measurements.
In addition, it should be pointed out that the Pt(mtp) complex
exhibits a stereogenic centre at the sulphur donor atom SR2.
Yates et al. studied the behaviour of the Pt(mtp)Cl2 complex in
solution using variable-temperature NMR spectroscopy.12 Their
experiments showed that the dichloro complex undergoes fluxional
processes in solution at ambient temperature, which was confirmed
by DFT calculations to be mainly (S)-pyramidal inversion at
the sulphur centre. The clear evidence for (S)-inversion is of
significant importance, because it explains why in solution a
mixture of all possible configurations was always observed and
that it is impossible to isolate one of them in a pure form. Since
the nucleophilic attack occurs above or below the square planar
coordination sphere of the Pt(II) complex, the configuration of the
sulphur donor atom has no effect on the substitution rate.
Scheme 1 summarizes the proposed reaction pathways for
all substitution reactions at specific pH, including the acid
dissociation process. For the further discussion and for clarity,
it should be noted that the rate constants k1,-1, k2,-2 and k3 belong
to reactions observed at pH 2, whereas the rate constants k4,-4 and
k5 belong to reactions observed at pH 4.75.
For the subsequent kinetic experiments at different pHs, it is
useful to gain more insight into the distribution of species as a
function of pH. Fig. 4 demonstrates the distribution of the three
consecutively generated species in solution as a function of pH for
a 0.05 mM solution of Pt(mtp). This distribution diagram was ob-
tained, using the Specfit Global Analysis software. On the basis of
such speciation diagrams, the distribution at pH 2 was determined
Kinetic measurements at pH 2
At such a low pH the Pt(mtp) complex exists predominantly in
its diaqua form (92%, see Fig. 4). Fig. 5 shows a typical example
of the spectral changes observed for 0.125 mM Pt(mtp) during
the reaction with 5 mM tu. The UV-vis spectra clearly indicate
that there is a rapid first reaction (studied at 310 nm), followed
by a much slower second reaction step (studied at 290 nm). The
reactions with dtmu and tmtu exhibited similar UV-vis spectra
such that the wavelength 310 nm for the first and 290 nm for the
second reaction steps could be used throughout the study (see also
Figs. S3 and S4, ESI†).
Fig. 4 Distribution of the different species present in solution for
0.05 mM Pt(mtp) at different pH.
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Scheme 1 Schematic presentation of all reactions studied for the Pt(mtp) diaqua complex as starting material (Nu = tu, dmtu and tmtu) including the
acid dissociation equilibria.
Table 3 Summary of rate constants and activation parameters for the
two successive substitution reactions of Pt(mtp) at pH 2 and 25 ◦C
tua
dmtub
tmtuc
k1, M-1 s-1
634 10
507
32
-84
-7.4 0.2
22.1 0.1
14.8 0.3
5
3
165
39
-71
3
5
DH#1, kJ mol-1
DS#1, J mol-1 K-1
DV#1, cm3 mol-1
k3K2, M-2 s-1
30
-90
1
1
2
3
-5.5 0.1
73.3 0.8
12.5 0.5
-13.9 0.2
6.8 0.2
DH#2,3, kJ mol-1
DS#2,3, J mol-1 K-1
24.6 0.6
-151
-169
2
-169
1
2
a tu = thiourea, b dmtu = dimethylthiourea, c tmtu = tetramethylthiourea.
Fig. 5 UV-vis spectra recorded for the reaction of 0.125 mM Pt(mtp) with
5 mM tu at pH 2 (0.01 M triflic acid) and 25 ◦C.
The pseudo first-order rate constants, kobs1, were plotted against
the nucleophile concentration, and resulted in a linear dependence
with no meaningful intercept (see Fig. 6 and also Table SI 2, ESI†).
This indicates that the reverse reaction with water is too slow and
can be neglected (see Scheme 1). The substitution of coordinated
water by the more sterically hindered nucleophiles dmtu and tmtu
shows a clear dependence on the steric bulk of the nucleophiles.
The values of the rate constants for the first substitution step k1
decrease in the order tu (634 M-1 s-1) > dmtu (507 M-1 s-1) ꢀ
tmtu (165 M-1 s-1) (see Table 3). It is noted that tu and dmtu show
rather similar reactivity whereas tmtu, the sterically most hindered
nucleophile, shows by far the lowest reactivity.
In contrast, the second reaction step was found to be two orders
of magnitude slower than the first and plots of kobs2 against the
nucleophile concentration resulted in a second-order dependence
as shown in Fig. 7 (see also Table SI 3, ESI†). It is not surprising
that the rate constants for the second reaction step decrease in the
order tu (73.3 M-2 s-1) > dmtu (22.1 M-2 s-1) > tmtu (6.8 M-2 s-1)
(see Table 3). The most sterically hindered nucleophile tmtu reacts
Fig. 6 Plots of kobs1 vs. nucleophile concentration for the first substitution
step of the reaction of 0.125 mM Pt(mtp) at pH 2, 310 nm and 25 ◦C (I =
0.01 M, triflic acid).
significantly slower than the less hindered tu and dmtu for both
reaction steps.
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generated peaks analysed. Peaks consisting of Pt(mtp)(tu)2 and the
tri-substituted product Pt(mtp)(tu)3 (see Scheme 1) were detected
as shown in Fig. SI 5 (ESI†).
Comparison of the substitution behaviour at pH 2 with that
for the Pt(amp)15 complex shows some significant differences. The
first substitution step for Pt(amp) with tu (233 M-1 s-1) is about
three times slower than that for the Pt(mtp) complex (634 M-1 s-1).
Actually, Pt(mtp) should react slower due to a less electrophilic
metal centre. Initially we found these results to be surprising,
but Hofmann et al.30 reported a similar unexpected behaviour.
They found faster reactions with complexes which should actually
react slower due to a less electrophilic Pt(II) centre, and considered
the competition between electrophilic (nucleophilic discrimination
factor) and trans-labilising effects (intrinsic reactivity) in terms of
the role of biphilic nucleophiles. The high reactivity of Pt(mtp)
is mainly due to the trans-labilising effect of the Pt–S bond
which induces a high intrinsic reactivity, whereas the reactivity
of Pt(amp) is due to the increased electrophilicity of the metal
centre that causes a high nucleophilic discrimination.30 On going
from Pt(amp) to Pt(mtp) by displacing the secondary amine NHR2
by a thioether SR2, two effects have to be considered. The Pt(II)
centre becomes less electrophilic and the water ligand trans to the
SR2 becomes more labilised. The crucial point is now the entering
nucleophile since tu and its derivatives have biphilic character
and are strong nucleophiles. Their high nucleophilicity is partly
due to their p-acceptor ability that assists the stabilization of
the electron rich five-coordinate transition state.31 This means
that the less electrophilic Pt(mtp) complex profits much from this
stabilization ability of the nucleophile, whereas the already very
electrophilic Pt(amp) complex cannot benefit from this effect. The
next difference can be seen in the second substitution step. Whereas
the Pt(mtp) complex exhibits a second-order nucleophile concen-
tration dependence, the Pt(amp) complex shows a clear linear
concentration dependence. We therefore assume that dissociation
of the pyridine unit on Pt(amp) is much slower than in the case of
Pt(mtp) and was therefore not studied in more detail.15
Fig. 7 Plots of kobs2 vs. [nucleophile]2 for the second substitution step of
the reaction of 0.125 mM Pt(mtp) at pH 2, 290 nm and 25 ◦C (I = 0.01 M,
triflic acid).
What is the reason for the second-order concentration de-
pendence observed for the second reaction step for all three tu
derivatives? Scheme 1 summarizes different pathways starting
with different Pt(mtp) species at specific pH. The pathway on
the left accounts for the observed reaction steps at pH 2, where
the complex predominates in the diaqua form. The first step
is the substitution of the most labile water ligand trans to the
sulphur donor atom, which nicely fits the determined pKa values.
The second step is the displacement of the second water ligand
trans to the pyridine unit. This reaction is expected to be rapid
since the two sulphur donors trans to each other will cancel
their electron donation and make the platinum centre more
electrophilic as a result of the p-back bonding of the in plane
pyridine ligand. However, the observed reaction is two orders of
magnitude slower than the first reaction step and furthermore
exhibits a second-order dependence on the entering nucleophile
concentration. We therefore suggest that the second reaction step
also involves dechelation of the N,S-ligand and the entrance of
a third nucleophile into the coordination sphere. The effective
dechelation is supported by the immediate protonation of the
pyridine nitrogen atom (pKa = 4.50)29 at pH 2, which avoids
re-chelation and therefore forces the reaction in one direction
without a back reaction (see Scheme 1). The coordination of the
second nucleophile can be treated as a fast pre-equilibrium (K2)
followed by the rate-determining binding of the third nucleophile
at the Pt(II) centre that involves dechelation and protonation of the
pyridine moiety. Eqn (1) and (2) express the corresponding rate
laws for the reactions at pH 2, and Table 3 summarizes the results.
Kinetic measurements at pH 4.75
At pH 4.75 the aqua-hydroxo species predominates in solution
(96%, see Fig. 4). Fig. 8 shows the spectral changes observed
during the reaction of 0.125 mM Pt(mtp) with 5 mM tu. It
can be seen at a first glance that the absorbance changes are
kobs1 = k1[Nu] k-1 ª k1[Nu] Nu = tu, dmtu, tmtu
(1)
2
]
k3K2 Nu
[
2
(2)
kobs2
=
≈ k3K2 Nu Nu = tu, dmtu, tmtu
[ ]
1+ K2 Nu
[
]
In addition, mass spectrometric measurements were performed
to confirm the formation of suggested final product, where three
nucleophile ligands are bound to the Pt(II) centre. Equal volumes
of 0.2 mM Pt(mtp) and 1 mM thiourea were mixed at pH 2.
After 24 h of reaction time mass spectra were recorded and the
Fig. 8 UV-vis spectra recorded for the reaction of 0.125 mM Pt(mtp) with
5 mM tu at pH 4.75 (I = 0.1 M acetate buffer solution) and 25 ◦C.
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Table 4 Summary of rate constants and activation parameters of the two
successive substitution reactions at pH 4.75 and 25 ◦C for Pt(mtp)
on going from lower to higher nucleophile concentrations, which
indicates the existence of a back reaction. The back reaction k-4
involving the displacement of a coordinated nucleophile by a water
molecule, is very slow and rather similar for the three nucleophiles:
tu (0.098 s-1) ~ dmtu (0.091 s-1) > tmtu (0.069 s-1) (see Table 4). This
is not surprising since the rate-determining step is the coordination
of the incoming nucleophile (water) to the vacant pz orbital, which
is expected to be somewhat sterically hindered by the substituents
on the thiourea derivates.
Plots of kobs5 for the second substitution reaction against the
nucleophile concentration result in a linear dependence with no
meaningful intercept (see Fig. 10 and also Table SI 5, ESI†). This
reaction is again much slower than the first reaction step, but does
not show a second-order concentration dependence as found for
pH 2. Scheme 2 summarizes the successive substitution steps at pH
4.75 with Nu = tu, dmtu and tmtu, respectively (see also reaction
pathway to the right in Scheme 1). In general the displacement of
the hydroxo ligand in [Pt(mtp)(Nu)(OH)]+ is expected to be orders
of magnitude slower than the displacement of a water molecule,
and is thought to involve protonation prior to its displacement.
At present we do not know what the pKa of the postulated
[Pt(mtp)(Nu)(OH2)]2+ intermediate will be, but it is reasonable
that it will be less acidic due to the additional donor effect of
the sulphur-containing nucleophile.
tua
dmtub
tmtuc
k4, M-1 s-1
106
30
1
72
32
1
1
14.1 0.5
DH#4, kJ mol-1
DS#4, J mol-1 K-1
DV#4, cm3 mol-1
k-4, s-1
1
37
2
-106
4
-103
3
-100
5
-10.3 0.2
-10.3 0.3
-15.1 0.3
0.098 0.006
0.091 0.003
0.069 0.002
DH#-4, kJ mol-1
DS#-4, J mol-1 K-1
k5, M-1 s-1
47
3
51
2
55
3
-107
1.92 0.03
37
-116
9
-93
1.19 0.01
39
-114
7
-85 11
0.10 0.01
DH#5, kJ mol-1
DS#5, J mol-1 K-1
1
1
45
-97
1
3
3
3
a tu = thiourea, b dmtu = dimethylthiourea, c tmtu tetramethylthiourea.
much smaller than at pH 2, and that there is no isosbestic point
around 310 nm. Nevertheless, there are two successive substitution
reactions observed for all three nucleophiles (see also Figs. SI 6
and SI 7, ESI†). The first rapid reaction was observed at 310 nm
for all three nucleophiles and the second very slow step at 310 nm
for tu and dmtu, and at 320 nm for tmtu, respectively (see also
Table SI 1, ESI†). Compared to the rate constants found at pH 2,
the reactions for all nucleophiles were in general found to be slower
at pH 4.75. This can be accounted for by the decrease in overall
charge on the complex from 2+ to 1+ due to the deprotonation of
one coordinated water molecule. Therefore the Pt(II) centre of the
aqua-hydroxo complex is less electrophilic compared to that of the
diaqua complex such that nucleophilic attack occurs slower.
The tendency observed in the rate constants at pH 2 was also
found at higher pH, viz. tu (106 M-1 s-1) > dmtu (72 M-1 s-1) ꢀ
tmtu (14.1 M-1 s-1) (see also Table 4). Fig. 9 shows the nucleophile
concentration dependence of the first substitution step kobs4 for
the three nucleophiles tu, dmtu and tmtu. The plots exhibit a
significant intercept for all the three nucleophiles, which was not
observed at pH 2 (see also Table SI 4, ESI†). This intercept can
either belong to a back reaction or to a parallel reaction. To solve
this problem, we had a closer look at the absorbance changes
observed during the substitution reaction (see also Fig. SI 8, ESI†).
We observed a slight increase in the overall absorbance change
Fig. 10 Plots of kobs5 vs. nucleophile concentration for the second
substitution step of the reaction of 0.125 mM Pt(mtp) complex at pH
4.75 and 25 ◦C (I = 0.1 M, acetate buffer solution).
Scheme 2 Schematic presentation of the proposed reactions observed for
the aqua-hydroxo complex as starting material (Nu = tu, dmtu and tmtu).
Furthermore, the absence of a second-order concentration
dependence confirms our postulated reaction mechanism (Scheme
1), since dechelation of the pyridine group suggested to in-
volve stabilization via protonation at pH 2, is not expected to
occur at pH 4.75. Therefore, dechelation is not favoured and
reverse complexation by water does not occur. Based on these
considerations, eqn (3) and (4) present the corresponding rate
Fig. 9 Plots of kobs4 vs. nucleophile concentration for the first substitution
reaction of 0.125 mM Pt(mtp) at pH 4.75, 310 nm and 25 ◦C (I = 0.1 M,
acetate buffer solution).
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laws for the two consecutive reactions at pH 4.75 and Table 4
summarizes the results.
These effects can account for the absence of substitution reactions
under these conditions.
kobs4 = k4[Nu] + k-4 Nu = tu, dmtu, tmtu
(3)
(4)
Activation parameters at different pH values
kobs5 = k5[Nu] + k-5 ª k5 [Nu] Nu = tu, dmtu, tmtu
Temperature and pressure dependence studies were performed to
gain more insight into the nature of the substitution mechanism
from the thermal and pressure activation parameters. The thermal
parameters DH# and DS# were determined by measuring the
rate constants of each substitution step at a fixed or at different
nucleophile concentrations when an intercept is involved (see
also Figs. SI 10–SI 15, ESI†) as a function of temperature. The
activation parameters were calculated using the Eyring equation
for which the observed first-order rate constants in the case of kobs1
at pH 2 and kobs5 at pH 4.75 were converted to second-order rate
constants (k = kobs/[Nu]) based on eqn (1) and (4). Fig. 11 and 12
show the Eyring plots for all three nucleophiles at the two different
pH values and the results are summarized in Table 3 for pH 2 and
Table 4 for pH 4.75, respectively (see also Tables SI 6–SI 15, ESI†).
As expected, the trend in the reactivity of the Pt(mtp) complex
for the different nucleophiles can also be seen in the activation
enthalpies for the investigated reactions (see Tables 3 and 4). When
the reaction becomes slower, the process is less favoured and the
Kinetic tests with tu at pH 7.4
No reaction could be observed at pH 7.4 for all studied nucle-
ophiles (see also Fig. SI 9, ESI†). Calculation of the speciation
of the Pt(mtp) complex as a function of pH showed that there
is no diaqua species present in solution any more. Only 16%
aqua-hydroxo species can be found at pH 7.4 and 84% dihydroxo
species. It is known that hydroxo ligands are practically inert to
substitution, presumably due to a back-bonding effect of the lone
pair electrons on the hydroxo ligand with the pz orbital of the
metal, by which the Pt–OH bond obtains a quasi-double-bond
character.32,33 In the case of pH 4.75, there are 96% aqua-hydroxo
species present in solution, which has one water ligand left to be
substituted. In contrast, at pH 7.4 the quasi inert dihydroxo species
is predominantly present in solution, the overall charge of the
complex is zero and therefore the Pt(II) centre is less electrophilic.
Fig. 11 Eyring plots for the determination of the thermal activation parameters for the first substitution step k1 (left) and the second step k3K2 (right)
of 0.1 mM Pt(mtp) for all three nucleophiles studied at 25 ◦C and pH 2 (I = 0.01 M triflic acid).
Fig. 12 Eyring plots for the determination of the thermal activation parameters for the first substitution step k4 (left) and the second step k5 (right) of
0.1 mM Pt(mtp) for all three nucleophiles studied at 25 ◦C and pH 4.75 (I = 0.1 M acetate buffer solution).
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Fig. 13 a) Plots of ln kobs1 vs. pressure for the first reaction step for all three studied nucleophiles (5 mM) at 25 ◦C and pH 2 (I = 0.01 M triflic acid). b)
Plots of ln k4 vs. pressure for the first reaction step for all three studied nucleophiles at 25 ◦C and pH 4.75 (I = 0.1 M acetate buffer solution).
activation enthalpy increases, which belongs to a destabilization of
the transition state. Accordingly, the activation entropy becomes
more negative with acceleration of the reaction. This general
result is valid for all three nucleophiles and both pH values. The
significantly negative activation entropies favour the operation of
an associative mechanism.
Furthermore, pressure dependence studies for the first substitu-
tion step were performed by measuring the rate constants at a fixed
nucleophile concentration in the case of pH 2 and by performing
concentration dependence studies in the case of pH 4.75 as a
function of pressure as seen in Fig. 13 (see also Figs. SI 16–SI 18,
ESI†). The volumes of activation DV#, calculated from the slope
of plots of ln kobs and ln k versus pressure, are summarized in Tables
3 and 4 (see also Tables SI 16–SI 20, ESI†).
Throughout the series of nucleophiles studied the substitution
reactions were accelerated on increasing pressure. The reported
negative activation volumes are typical for associative substitution
reactions on square-planar complexes and in good agreement
with the significantly negative activation entropies for all studied
reaction steps.34–36 Furthermore, it is noticed that the activation
volume for the first substitution step becomes more negative on
increasing the steric hindrance on the nucleophiles. At first glance
this behaviour seems strange, but it can be explained by a more
effective overlap of the molecules involved in forming the bond. As
the nucleophiles become larger in the order tu < dmtu < tmtu, the
van der Waals radii also increase and cause a more effective overlap
with the metal complex. This results in a larger volume collapse
during the formation of the five-coordinate transition state, i.e. a
more negative volume of activation. This behaviour is well-known
and was found also in previous work for thiourea derivatives,30,37,38
but also for other nucleophiles.39
step trans to the sulphur donor, because the strong s-donating
effect of sulphur leads to elongation of the Pt–O bond in the
trans position and therefore to a higher pKa value. Furthermore,
we suggest that the surprisingly low pKa1 value (3.15) compared
to the N,N-analogue (pKa1 = 4.77)26 arises from a favoured
rearrangement in geometry after deprotonation in the case
of Pt(mtp). The second deprotonation step, trans to the SR2
unit, shows a slightly higher pKa2 value of 6.84 compared to
its N,N-analogue Pt(amp) (pKa2 = 6.56),26 which again can be
attributed to the strong s-donor effect of sulphur.
Kinetic measurements were performed with thiourea (tu) and
its derivatives N,N¢-dimethylthiourea (dmtu) and N,N,N¢,N¢-
tetramethylthiourea (tmtu) as strong S-donor nucleophiles. Dif-
ferent pH values were chosen to investigate the different generated
diaqua, aqua-hydroxo and dihydroxo species. A reaction scheme
was postulated to explain the different observations at different pH
values. In general the first reaction step takes place trans to the sul-
phur donor atom, because sulphur has a strong trans-labilisation
effect on the water molecule. At pH 2, the predominant species is
the diaqua Pt(mtp) complex, which shows a clear first substitution
step with no intercept for all nucleophiles. The second observed
reaction includes two steps, namely the displacement of the second
water ligand and dechelation of the pyridine ring. Although these
two steps could not be separated kinetically, the final product could
be verified using mass spectrometric measurements. At pH 4.75,
predominantly the aqua-hydroxo species is present in solution
and we observed a linear concentration dependence including
a back reaction for displacement of the first water, and a clear
linear dependence for the substitution of the hydroxo ligand. No
evidence for ring-dechelation was observed under these conditions.
Furthermore, no reaction could be observed at pH 7.4 due to the
dihydroxo species being quasi inert against substitution.
The proposed reaction scheme is the same for all three studied
nucleophiles, but the rate constants differ as expected. The rate
constants decrease in the order tu > dmtu > tmtu, which can
be accounted for by the increase in steric hindrance. In addition,
temperature and pressure dependent studies were performed. The
acceleration of the reactions by pressure and the significantly
negative DV# values are typical for associative substitution
reactions, which is also supported by the negative DS# values found
for the reactions with all nucleophiles.
Conclusions
In this study the already known complex [Pt(2-
methylthiomethylpyridine)(OH2)2]2+ was investigated in more
detail. First, the acidity of the coordinated water ligands was
studied. We performed spectrophotometric pH titrations and
obtained a pKa1 value of 3.15 and a higher pKa2 value of 6.84,
respectively. Thereby, we ascribed the first deprotonation step
to occur trans to the pyridine nitrogen donor and the second
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21 (a) A. D. Becke, J. Chem. Phys., 1993, 98, 5648; (b) C. Lee, W. Yang and
R. G. Parr, Phys. Rev. B, 1988, 37, 785; (c) P. J. Stephens, F. J. Devlin,
C. F. Chabalowski and M. J. Frisch, J. Phys. Chem., 1994, 98, 11623.
22 (a) T. H. Dunning and P. J. Hay, in “Modern Theoretical Chemistry”,
1976, Vol. 3, pp. 1-28, Plenum, New York; (b) P. J. Hay and W. R. Wadt,
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Acknowledgements
The authors gratefully acknowledge continued financial sup-
port from the Deutsche Forschungsgemeinschaft. The authors
kindly thank Prof. Dr Ivana Ivanovic´-Burmazovic´ and Oliver
Tro¨ppner for their support with the mass spectrometric measure-
ments.
23 S. Huzinaga (Ed.), Gaussian Basis Sets for Molecular Calculations,
1984, Elsevier, Amsterdam.
24 See for example: (a) S. Klaus, H. Neumann, H. Jiao, A. Jacobi
von Wangelin, D. Go¨rdes, D. Stru¨bing, S. Hu¨bner, M. Hately, C.
Weckbecker, K. Huthmacher, T. Riermeier and M. Beller, J. Organomet.
Chem., 2004, 689, 3685; (b) R. W. Saalfrank, Ch. Deutscher, H. Maid,
A. M. Ako, S. Sperner, T. Nakajima, W. Bauer, F. Hampel, B. A. Heß,
N. J. R. van Eikema Hommes, R. Puchta and F. W. Heinemann, Chem.–
Eur. J., 2004, 10, 1899; (c) P. Illner, A. Zahl, R. Puchta, N. J. R. van
Eikema Hommes, P. Wasserscheid and R. van Eldik, J. Organomet.
Chem., 2005, 690, 3567; (d) A. Scheurer, H. Maid, F. Hampel, R. W.
Saalfrank, L. Toupet, P. Mosset, R. Puchta and N. J. R. van Eikema
Hommes, Eur. J. Org. Chem., 2005, 2566; (e) M. Galle, R. Puchta, N. J.
R. van Eikema Hommes and R. van Eldik, Z. Phys. Chem., 2006, 220,
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25 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C.
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