Substitution of aqua ligands from cis-platinum(II) complexes bearing 2-(phenylthiomethyl)pyridine spectator ligands

Article abstract of DOI:10.1007/s11243-017-0182-4

Cis-Pt(II) complexes, namely [Pt{2-(phenylthiomethyl)pyridine}(H₂O)₂](CF₃SO₃)₂Pt(pyS^Ph), [Pt{2-(4-tert-butylphenylthiomethyl)pyridine}(H₂O)₂](CF₃SO₃

Full text of DOI:10.1007/s11243-017-0182-4

Transit Met Chem (2017) 42:739–751
DOI 10.1007/s11243-017-0182-4
Substitution of aqua ligands from cis-platinum(II) complexes
bearing 2-(phenylthiomethyl)pyridine spectator ligands
Wakhiwe M. Mthiyane1 Allen Mambanda1
Deogratius Jaganyi1
•
•
Received: 22 June 2017 / Accepted: 4 September 2017 / Published online: 16 September 2017
Ó Springer International Publishing AG 2017
Abstract Cis-Pt(II) complexes, namely [Pt{2-(phenylth-
iomethyl)pyridine}(H2O)2](CF3SO3)2 Pt(pySPh), [Pt{2-(4-
tert-butylphenylthiomethyl)pyridine}(H2O)2](CF3SO3)2 Pt
(pySPh(t-But)) and [Pt{2-(4-fluorophenylthiomethyl)pyridine}-
(H2O)2](CF3SO3)2 Pt(pySPhF), were synthesised and charac-
terised. The pKa1 and pKa2 values of the complexes were
determined titrimetrically. Substitution of the aqua ligands
from these complexes by thiourea nucleophiles was studied
at a pH of 2 and ionic strength of 0.1 M under pseudo-first-
order conditions using stopped-flow and UV–visible spec-
trophotometric techniques. Substitution of the aqua ligands
depends on both the nature and concentration of the
incoming ligand, with low enthalpy and negative entropy of
activation values. Substitution of the first and second aqua
of the N,S-bidentate ligand to form a PtS4 species. The
crystal structure of Pt(pySPhF)Cl2 was elucidated by X-ray
diffraction analysis.
Introduction
A cis geometry is a common feature of currently approved
Pt-based drugs [1]. When the labile ligands of such com-
plexes are substituted, 1,2-DNA-Pt metallocycles are
formed [2]. However, these complexes can also react with
other intracellular nucleophiles, leading to toxicity and
development of drug resistance [3]. A careful choice of
both the non-leaving and leaving groups is therefore
important in regulating the pharmacokinetic properties of
an effective Pt drug [4]. Examples of Pt drugs designed to
reduce toxicity and resistance are carboplatin and oxali-
platin [5]. In line with structure–activity relationships, an
analogue of cisplatin bearing ammine and 1-methyl-7-
azaindole ligands has shown remarkable in vitro activity
against cisplatin-sensitive A2780 cells [6]. Similar activity
in HeLa cancer cells was also reported for Pt(II) complexes
ligands occurs sequentially and fits the rate laws: kobs (1/2)
=
k
(1/2) [Nu]. The second-order rate constant, k1, relates to the
substitution trans to sulphur, while k2 is the second-order
rate constant for the subsequent substitution of the aqua
ligand trans to pyridine. The rate of substitution of the
first aqua ligand decreases in the order: Pt(pySPh(t-But)
)
[ Pt(pySPhF) [ Pt(pySPh), while that of the second
decreases in the order: Pt(pySPh(t-But))[ Pt(pySPh) [
Pt(pySPhF), reflecting the influence of the substituents on
the spectator ligands. 195Pt NMR spectra of aged solutions
of complexes with the thiourea nucleophile suggest a
subsequent but rapid concentration-independent ring opening
with
2-(aminomethyl)pyridine
and
2-(pyrazolyl-
methyl)pyridine as spectator ligands [7].
The ligands around the Pt(II) centre can be designed to
improve selectivity towards cancerous cells, drug delivery
and availability, but at the same time minimising toxicity
[8]. For example, the hydroxyethyl group of Pt(1,4-bis(2-
hydroxyethyl))piperazine is intended to participate in
hydrogen bonding with appropriate functional groups on
the DNA backbone [9]. In another study, replacement of
the ammine ligands of cisplatin with the chelating 4,7-
diphenyl-1,10-phenanthroline ligand led to a Pt(II) com-
plex that could intercalate into DNA, in addition to forming
covalent cross-links [10].
Electronic supplementary material The online version of this
article (doi:10.1007/s11243-017-0182-4) contains supplementary
material, which is available to authorized users.
& Allen Mambanda
mambanda@ukzn.ac.za
1
School of Chemistry and Physics, University of Kwa-Zulu
Natal, Scottsville 3209, South Africa
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Square-planar Pt(II) complexes are often used as model
without further purification and stored as per the material
data sheet specifications. Thiourea (tu, 99%), N,N-
dimethylthiourea (dmtu, 99%) and N,N,N0,N0-tetram-
ethylthiourea (tmtu, 99%) were also purchased from Aldrich
and used without further purification. Ultrapure water
(MODULAB purification system) was used for all aqueous
reactions. All other chemicals and solvents were of reagent
grade and used as received.
complexes for understanding the mechanisms of substitu-
tion due to their moderate rates of ligand exchange kinetics
[11]. Mechanistic studies on the substitution reactions
of cis-Pt(II) and cis-Pd(II) complexes with N,N- and
N,S-bidentate or monodentate labile and/or inert ligands
have been reported [12, 13]. Due to their similar geometry
to cisplatin, such complexes are hypothesised to form
1,2-DNA adducts through ligand substitution processes,
resulting in cytotoxic effects whose potency can be mod-
ulated by the structure of the substitutional inert ligand
[14]. In keeping with the idea of altering the inert ligands
while keeping the cytostatic geometric features of cisplatin,
three mononuclear cis-Pt(II) complexes with a com-
mon substitutionally inert 2-(phenylthiomethyl)pyridine
(N,S-chelate) ligand were synthesised (Fig. 1). The rate of
substitution of the aqua ligands from these complexes by
thiourea nucleophiles was measured under pseudo-first-
order conditions in acidic medium. The thiolate nucle-
ophiles model the possible interactions between the Pt(II)
complexes and intracellular species such as sulphur-con-
taining proteins and peptides, which are known to have a
strong affinity for platinum [15].
Synthesis of the N,S-chelate proligands
The proligands 2-(phenylthiomethyl)pyridine pySPh, 2-(4-
tert-butylphenylthiomethyl)pyridine pySPh(t-But) and 2-(4-
fluorophenylthiomethyl)pyridine pySPhF were prepared via
nucleophilic S-alkylation reactions of thiophenol, 4-tert-
butylthiophenol or 4-fluorothiophenol, respectively, with
neutralised 2-(chloromethyl)pyridine hydrochloride in dry
ethanol, as reported by Malachowski et al. and described
for pySPh (vide infra) [16]. Yellow to orange brown oils
(yield: 57–89%) were obtained. The identity and purity of
the ligands were confirmed by 1H and 13C NMR, TOF-MS-
ESI? and elemental analysis (CHNS). Their IR spectra had
common bands at (cm-1): 3100–3000 (broad, medium,
Csp3–H stretch); 1583 (sharp and strong, Csp2=N stretch,
pyridyl rings).
pySPh 2-(Chloromethyl)pyridine hydrochloride (1.598 g,
9.74 mmol) was dissolved in ultrapure water (3 mL). A
solution of 5 M NaOH was added dropwise until a pink
emulsion appeared. A solution of thiophenol (1.073 g,
9.74 mmol) in EtOH (20 mL, 95%) was slowly added. The
mixture was stirred under reflux for 24 h, then allowed to
cool to room temperature and extracted four times with
CHCl3 (10 mL). The crude extract was concentrated and
further purified on a short column of Al2O3 using 50 mL of
an equal mixture of CH2Cl2 and CHCl3. The combined
organic phase was backwashed with 2 9 10 mL of
Experimental
Chemicals and procedures
The free ligands and Pt complexes were synthesised from
2-(chloromethyl)pyridine hydrochloride (98%), thiophenol
(97%), 4-tert-butylthiophenol (97%), 4-fluorothiophenol
(98%), potassium tetrachloroplatinate (K2PtCl4, 99%), sil-
ver trifluoromethanesulphonate (99%, Aldrich), lithium tri-
fluoromethanesulphonate (99%, Aldrich) and hydrochloric
acid (32%, Saarchem). All chemicals and reagents were used
2+
2+
2+
Pt(pySPh)
Pt(pySPh(t-But)
)
Pt(pySPhF
)
Fig. 1 Structures of cis-Pt(II) complexes
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741
deionised water and dried with anhydrous MgSO4. Filtra-
tion and removal of the solvent in vacuo gave pySPh as a
bright yellow oil. Yield: 1.528 g (78%). 1H NMR
(400 MHz: CDCl3): dH (ppm) referenced to TMS; 4.30 (s,
2H, –CH2–), 7.16 (t, 1H, Ph), 7.27 (t, 2H, Ph), 7.37 (d, 2H,
Ph), 7.33 (t, 1H, py), 7.52–7.54 (d, 1H, py), 7.60–7.64 (t,
1H, py), 8.56 (d, 1H, py). 13C NMR (100 MHz: CDCl3): dC
(ppm); 40.5; 122.1; 123.0; 126.4; 127.6; 128.9; 129.1;
129.7; 136.7; 149.3. IR (KBr, 4000–650 cm-1) m: 3055
(C=C–H Asymmetric stretch), 1583 (C=N, pyridyl). Time-
of-flight MS-ESI? m/z: 223.0930, 100 (M ? Na)?. Anal.
Calc. for C12H11NS: C: 71.60, H: 5.51, N: 6.96, S: 15.93%.
Found: C: 71.21, H: 5.58, N: 6.64, S: 16.09%.
under reflux for 24 h. The precipitate was collected via a
0.45 lm Millipore nylon filter paper and then washed with
small amounts of cold water, ethanol and diethyl ether. It
was left to dry under vacuum to give a powder. The
complexes were characterised by NMR (1H, 13C and 195Pt),
CHN elemental analysis, TOF MS-ESI? and IR
spectroscopy.
1
Pt(pySPh)Cl2 Yield: 0.4058 g (77%, yellow). H NMR
(400 MHz: DMF-d7): dH (ppm) referenced to TMS; 4.30
(d, 2H, –CH2–, AB-spin system), 7.16 (t, 1H, Ph), 7.27 (t,
2H, Ph), 7.37 (d, 2H, Ph), 7.33 (t,1H, py), 7.52–7.54 (d, 1H,
py), 7.60–7.64 (t, 1H, py), 8.56 (d,1H, py). 195Pt NMR
(400 MHz: DMF-d7): dPt (ppm); -2778. Infrared (KBr,
4000–650 cm-1) m: 3055 (C=C–H Asymmetric stretch),
1583 (C=N, pyridyl). Anal. Calc. for C12H11Cl2NPtS: C:
30.84, H: 2.37, N: 3.00, S: 6.68%. Found: C: 30.60, H:
2.24, N: 2.91, S: 6.49%.
The proligands pySPh(t-But) and pySPhF were synthe-
sised as described for pySPh, with 2-(4-tert-butylthiophe-
nol) and 2-(4-fluorothiophenol), respectively, replacing the
thiophenol. The resulting oils were stored in Schlenk tubes
until their coordination to platinum.
Pt(pySPh(t-But))Cl2 Yield: 0.3257 g (57%, light brown).
1H NMR (400 MHz: CDCl3): dH (ppm) referenced to
TMS; 1.30 (s, 9H, –C(CH3)3), 4.27 (d, 2H, –CH2–, AB-
spin system), 7.17–7.18 (t, 1H, py), 7.28 (d, 4H, Ph), 7.36
(d, 1H, py), 7.62–7.65 (t, 1H, py), 8.55 (d, 1H, py). 195Pt
NMR (400 MHz: DMF-d7): dPt (ppm); -2786. IR (KBr,
4000–650 cm-1) m: 3059 (C=C–H Asymmetric stretch),
1598 (C=N, pyridyl). Anal. Calc. for C16H19Cl2NPtS: C:
36.72, H: 3.66, N: 2.68, S: 6.13%. Found: C: 36.85, H:
3.53, N: 2.53, S: 7.06%.
1
pySPh(t-But) Yield: 1.457 g (57%, light brown). H NMR
(400 MHz: CDCl3): dH (ppm) referenced to TMS; 1.30 (s,
9H, –C(CH3)3), 4.27 (s, 2H, –CH2–), 7.17–7.18 (t,1H, py),
7.28 (d, 4H, Ph), 7.36 (d, 1H, py), 7.62–7.65 (t, 1H, py),
8.55 (d, 1H, py). IR (KBr, 4000–650 cm-1) m: 3059 (C=C–
H Asymmetric stretch), 1598 (C=N, pyridyl). Time-of-
flight MS-ESI? m/z: 258.1181, 100 (M ? 1). Anal. Calc.
for C16H19NS: C: 74.66, H: 7.44, N: 5.44, S: 12.46%.
Found: C: 74.47, H: 7.50, N: 5.58, S: 12.28%.
pySPhF Yield: 1.698 g (74%, light orange). 1H NMR
(400 MHz: CDCl3): dH (ppm) referenced to TMS; 4.19 (s,
2H, –CH2–), 6.91–7.00 (d, 2H, Ph), 7.12–7.15 (t, 1H, py),
7.23 (d, 1H, py), 7.32(d, 2H, Ph), 7.57–7.60 (t, 1H, py),
8.51–8.52 (d, 1H, py). 13C NMR (100 MHz: CDCl3): dC
(ppm); 41.8; 115.8; 116.1; 122.1; 123.1; 133.1; 136.6;
149.3; 157.6. IR (KBr, 4000–650 cm-1) m: 3066 (C=C–H
Asymmetric stretch), 1588 (C=N, pyridyl). Time-of-flight
MS-ESI? m/z: 220.0488, 100 (M ? 1). Anal. Calc. for
C12H10FNS: C: 65.73, H: 4.60, N: 6.39, S: 14.62%. Found:
C: 65.29, H: 4.31, N: 6.35, S: 14.43%.
Pt(pySPhF)Cl2 Yield: 0.698 g (74%, off-orange). 1H
NMR (400 MHz: CDCl3): dH (ppm) referenced to TMS;
4.19 (s, 2H, –CH2–, AB-spin system), 6.91–7.00 (d, 2H,
Ph), 7.12–7.15 (t, 1H, py), 7.23 (d, 1H, py), 7.32(d, 2H,
Ph), 7.57–7.60 (t, 1H, py), 8.51–8.52 (d, 1H, py). 195Pt
NMR (400 MHz: DMF-d7): dPt (ppm); -2796. IR (KBr,
4000–650 cm-1) m: 3066 (C=C–H Asymmetric stretch),
1588 (C=N, pyridyl). Anal. Calc. for C12H10Cl2FNPtS: C:
29.70, H: 2.08, N: 2.89, S: 6.60%. Found: C: 30.14, H:
2.05, N: 2.52, S: 6.20%. Single crystals suitable for X-ray
diffraction analysis were obtained by vapour diffusion of
ether into the nitromethane solution of its powder.
Synthesis of the Pt(II) complexes
Preparation of the diaqua Pt(II) complexes
The complexes [Pt{2-(phenylthiomethyl)pyridine}Cl2],
Pt(pySPh)Cl2, [Pt{2-(4-tert-butylthiophenol)pyridine}Cl2],
Solutions of Pt(pySPh)Cl2, Pt(pySPh(t-But)Cl2 and
Pt(pySPhF)Cl2 were prepared as described in the literature
[18]. A known amount of each Pt(II) dichloro complex was
added to a solution of AgCF3SO3 (1.98 eqv.) in 0.01 M
trifluoromethanesulphonic acid. The mixture was vigor-
ously stirred at 50 °C for 24 h in a light-protected vessel.
The white precipitate of AgCl was filtered off with a
0.45 lm nylon membrane. The filtrate was acidified with
0.01 M CF3SO3H in a volumetric flask to make up the
Pt(pySPh(t-But))Cl2
and
[Pt{2-(4-fluorothiophenol)
pyridine}Cl2], Pt(pySPhF)Cl2 were synthesised according
to a literature method, with minor modifications [17]. The
reaction was carried out in a light-protected flask. K2PtCl4
(0.47 g, 1.1 mmol) was dissolved in ultrapure water
(25 mL) and stirred for 10–15 min and then filtered. A
solution of the N,S-chelate ligand (1.1 mmol) in CHCl3
(2 mL) was added dropwise, and the mixture was stirred
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required concentration of the complex in solution. A pH of
2 ensured that only the diaqua form of the Pt(II) complexes
existed in the solutions used for kinetic studies. Also, the
ionic strength of the reaction medium was maintained
constant at 0.1 M, using LiCF3SO3.
than that of the Pt(II) complexes to simplify the reaction
kinetics to first order. The ionic strength was maintained at
0.1 M with
a mixture of 0.09 M lithium trifluo-
romethanesulphonate (LiOTf) and 0.01 M triflic acid
(HOTf). The triflate ion is known to coordinate weakly to
Pt(II) due to its low basicity and weak donor capacity.
Hence, only substitution of the aqua ligands was observed.
A pH of 2 ensured that the observed substitution reactions
were those of the coordinated aqua ligands. The reactions
were monitored on a stopped-flow spectrophotometer
equipped with a pressure-driven cross-plugging assembly
to ensure efficient mixing of the reactant solutions. All the
reported rate constants are averages of six to eight inde-
pendent kinetic runs. The temperature of the medium was
varied within the range of 15–35 °C to determine the
activation parameters, DH= and DS=, from the Eyring
equation.
Instrumentation and physical measurements
A Bruker NMR spectrometer (Bruker Avance DRX 400 or
DRX 500) and a FLASH 2000 CHN analyser were used for
the characterisation and chemical analysis. Low-resolution
electrospray ionisation (ESI?) mass spectra of the proli-
gands were recorded on a time-of-flight (TOF) micromass
spectrometer. A PerkinElmer Spectrum One FTIR spec-
trometer was used to obtain IR spectra. Rapid kinetic
measurements were followed with an Applied Photo-
physics SX-18 MV stopped-flow spectrophotometer cou-
pled to an online data acquisition system. The temperature
of the reactions was controlled to within 0.1 °C for all
measurements. A Cary 100 BIO UV–visible spectropho-
tometer equipped with a Varian Peltier temperature con-
troller with an accuracy of 0.05 °C was used for the
determination of the pKa values of the diaqua complexes.
The pH measurements were made on a Jenway 4330 pH
meter equipped with a 4.5 lm glass electrode. The
microelectrode was calibrated at 25 °C using standard
buffer solutions (Merck) at pH 4.0, 7.0 and 10.0. The pK
titration curves and time-resolved kinetic traces were
Computer simulation studies
The geometry-optimised molecular structures of the com-
plexes Pt(pySPh(OH2)221, Pt(pySPh(t-But)(OH2)221 and
Pt(pySPhF(OH2)221 were computed by DFT at the
(B3LYP(CPCM)/LANL2DZp//B3LYP/-LAN2DZp) level
of theory [20–22], using the Gaussian 09 software suite
[23]. The geometry optimisation structures were conducted
in the gaseous phase, and the calculated structural param-
eters are presented in Fig. 4 and Table 2, respectively. A
charge of ?2 was maintained for the cationic diaqua
complexes.
graphically analysed using the Origin 7.5Ò software
a
package [19].
X-ray crystallography
Determination of pKa values
Single-crystal diffraction data for Pt(pySPhF)Cl2 were
collected on a Bruker Apex II Duo diffractometer equipped
with an Oxford Instruments Cryojet operating at 100 K and
an Incoatec microsource operating at 30 W power. A Mo
Acid–base titrations were undertaken to determine the pKa
values of the diaqua complexes. The complexes were
spectrophotometrically titrated with NaOH (in the range
2–9). Initially, the base was added in small portions of
crushed pellets and subsequently as dilute solutions. After
each addition of NaOH, ca 0.5 mL of solution was sampled
for pH measurement. The portion was discarded to avoid
possible chloride contamination of the solution from elec-
trode leaching. The spectral data were analysed with Origin
7.5Ò to estimate stepwise pKa values of the diaqua ligands
by fitting experimental data to standard sigmoidal curves
using Boltzmann distribution parameters.
˚
Ka (k = 0.71073 A) beam at a crystal-to-detector distance
of 50 mm was used to collect the diffraction data. The
instrument was calibrated to have the following optimum
conditions: omega and phi scans with exposures taken at
30 W X-ray power and 0.50° frame widths using APEX2
[24]. Data reduction was performed with the SAINT [24]
suite of programmes using outlier rejection, scan speed
scaling and standard Lorentz and polarisation correction
factors. The structure was solved by direct methods using
SHELXS-97 [25] and refined using SHELXL-97 [25]. The
complex Pt(pySPhF)Cl2 crystallised in the monoclinic
space group, P21/c and contained one molecule with
Z = 4. The crystal structure and a summary of the crystal
data and selected data for comparison with the theoretical
data are shown in Fig. 9 and Tables 5 and 6, respectively.
Kinetic studies
Substitution of the coordinated aqua ligands from all three
complexes by thiourea nucleophiles was studied as a
function of concentration and temperature. The concen-
tration of the nucleophiles was kept at least tenfold greater
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Table 1 Summary of pKa for diaqua cis-Pt(II) complexes
Results
Pt(pySPh
)
Pt(pySPh(t-But)
)
Pt(pySPhF
)
pKa data for diaqua Pt(II) complexes
pKa1
pKa2
3.58 0.02
5.36 0.07
3.87 0.04
5.60 0.06
3.06 0.02
5.05 0.04
It is well established in the literature that the low ther-
modynamic pKa value of an aqua metal complex is related
to the electrophilicity of the metal centre [26]. To gain
insight into substitution behaviour, we have determined the
pKa values of our complexes by spectroscopic titration with
NaOH. Typical experimental data are plotted in Fig. 2, and
the pKa was estimated from the inset of the Figure. The pKa
data are presented in Table 1.
NMR arrays of the substitution process
Substitution of the dichloro ligands from Pt(pySPhF)Cl2 by
thiourea (tu) was monitored by H and 195Pt NMR spec-
1
troscopies to detect the possible intermediates and final
products. The 1H NMR array of spectra for the substitution
reaction of Pt(pySPhF)Cl2 and tu is given as the supple-
mentary data (Figure S3), while Fig. 3 shows the array of
195Pt NMR spectra acquired during the reaction.
Clearly, the trend in magnitude of the pKa1 values is a
reflection of the inductive effects of the phenylthiomethyl
group of the N,S-chelate. The positive inductive effect of
the tert-butyl group results in a higher pKa relative to the
unsubstituted chelate, while the negative inductive effect of
the fluoro group results in a lower pKa1 value due to
increased electrophilicity of the Pt atom. The pKa2 values
are always higher than the pKa1 values, which is in accord
with the reduction in overall charge of the complexes fol-
lowing deprotonation of the first aqua ligand [27]. Overall,
the deprotonation of the diaqua complexes in aqueous
medium occurs as summarised in Scheme 1.
The peak labelled as ‘a’ at -2796 ppm is assigned to Pt
nuclei in the unreacted Pt(pySPhF)Cl2 complex. Two new
peaks appear at -3414 ppm (b) and -3584 ppm (c) during
the sequential substitution. These are indicative of two new
species in solution, namely [Pt(pySPhF)(tu)Cl]1 and
[Pt(pySPhF)(tu)2]2?, formed by substitution of the first and
second chloro ligands, respectively [30].
The 195Pt nuclei of the ultimate product are observed at
-3884 ppm (d). It is known that d(195Pt) values within the
range -3800 to -4000 ppm correspond to PtS4 species
[30]. Given the bidentate nature of the N,S ligand and the
two labile ligands which are substituted, the species, PtS4
The hardness and p-acidity of the pyridyl nitrogen as
compared to the soft and polarisable thioether sulphur
contribute differently to the observed pKa values [28]. A
better p-acceptor more easily stabilises the electron-rich
hydroxo species formed by deprotonation of the aqua
ligands. Since pyridine is a strong electron p-acceptor, the
first deprotonation occurs on the aqua ligand trans to this
moiety [29].
(Pt(j1-SPhFpy)(tu)231
)
most
likely
forms
from
Pt(pySPhF)(tu)221 through fast decoordination of the pyr-
idyl moiety within the N,S ligand [31]. This dechelation is
independent of the concentration of thiourea nucleophile
and is induced by the stronger r-trans-influence of the
coordinated tu trans to the pyridine of the N,S-chelate. This
is consistent with previous observations by Bellici et al.
[32] for slow ring opening of a S,S-1,2-bis(phenylsul-
phanyl) chelate.
300 nm
0,45
0,40
1,5
0,35
DFT-optimised structures
0,30
0,25
The calculated ground state geometries of all three com-
plexes show a distorted square-planar coordination geom-
etry around the Pt atom. The mappings of the frontier
molecular orbitals of the ground states indicate that the
HOMOs are concentrated directly in the vicinity of the
Pt(II) centre. The LUMO is concentrated on the pyridyl and
thioether moieties of the ligands. Importantly, the LUMOs
for all three complexes encompass the metal centre, the
thioether and to a lesser extent the pyridine ring. Signifi-
cantly, high isodensities of the LUMOs are located on the
thioether compared to pyridine, a known p-acceptor moi-
ety; this is an indication that the thioether group can
potentially receive excess electron density from the Pt(II)
0,20
1,0
0,15
0,10
2
3
4
5
6
7
8
pH
0,5
0,0
300
400
500
Wavelength (nm)
Fig. 2 UV–visible spectra for the titration of 0.22 mM Pt(pySPh
with NaOH in the pH range 2–8 at T = 298 K. Inset Absorbance
versus pH data at 300 nm
)
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2+
Ka1
Ka2
+ 2 OH-
Scheme 1 Sequential deprotonation of the diaqua Pt(II) complexes
Fig. 3 195Pt NMR spectra
recorded for the reaction of
Pt(pySPhF)Cl2 and 2 eqv. of tu.
Peak ‘a’ (d = -2796.4 ppm) is
due to Pt(pySPhF)Cl2.
Intermediate products (‘b’ and
‘c’ at d = -3414.5 and
-3584.9 ppm) correspond to
[Pt(pySPhF)(tu)Cl]1 and
[Pt(pySPhF)(tu)2]21
respectively. Peak (‘d’,
,
d = -3884.7 ppm)
corresponding to [Pt(j1-
S
PhFN)(tu)3]21 (PtS4)
centre into its accessible p*-centred orbitals [33]. Hence,
the thioether is a good r-donor as well as a good p*
acceptor. The same argument has been corroborated by
Pitteri et al. [34] for substitution from a [Pt(N-S-N)Cl]?
complex. He argued that a thioether was not only capable
of labilising the trans-leaving ligand due to its strong r-
trans-influence but could also accept excess electron den-
sity from the metal centre. This in turn stabilised the
18-electron five-coordinate transition state, leading to a
higher rate of substitution.
accumulation of electron density. The NBO charges on the
Pt(II) centre [36] increase in the following order:
Pt(pySPh(t-But)) \ Pt(pySPh) \ Pt(pySPhF). The magni-
tude of the NBO charge on the Pt(II) centre is sensitive to
the r-inductive effect of the para-positioned substituent.
This is the same trend that has been observed for x, which
is a measure of the degree of electron deficiency in the
entire complex [35, 36]. The lower Pt NBO charge of
Pt(pySPhF) compared to Pt(pySPh(t-But)) reflects the accu-
mulation of electron density at the metal centre.
The calculated electrophilicity index (x) [35] increases
The calculated dipole moments of the complexes
decrease in the order: Pt(pySPh(t-But)) [ Pt(pySPhF) [
Pt(pySPh). This is a reflection of the trends in polarity of
the complexes as influenced by the r-inductive effect of
the substituents on the N,S-chelate [37, 38]. The DFT-op-
timised structures of the cis-Pt(II) complexes as well as the
calculated energies and molecular geometries are shown in
Fig. 4 and Table 2, respectively.
in the following order: Pt(pySPh(t-But)) (6.48) \ Pt(pySPh
)
(6.68) \ Pt(pySPhF) (6.84). The p-acceptor property of the
thioether of Pt(pySPhF) induced by the electron-with-
drawing fluoro substituent renders its Pt(II) centre more
reactive. Thus, its x value is the highest. The opposite is
true for Pt(pySPh(t-But)). However, this enhances the strong
r-trans-influence of the thioether, thereby labilising the
trans-ligand. The Pt(II) centre is less electrophilic due to
123

Transit Met Chem (2017) 42:739–751
745
Complex
Optimized structure
HOMO map
LUMO map
Pt(pySPh)
Pt(pySPh(t-But)
)
Pt(pySPhF
)
Fig. 4 Optimised structures (gaseous phase) and the HOMO and LUMO frontier molecular orbitals of Pt(II) complexes
Kinetic measurements
order rate constants, kobs(1/2), were plotted against nucle-
ophile concentration, and the second-order rate constants,
k1 and k2, were calculated from the slopes of the plots. An
example time-resolved kinetic trace for the first substitu-
tion step in the two-step reaction between Pt(pySPh) and a
20-fold excess of tu is shown in Fig. 6.
A mechanism of substitution of aqua ligands from the
complexes by thiourea nucleophiles is proposed in
Scheme 2.
The rapid initial substitution step occurs at the aqua
ligand trans to the thioether, while the second and slower
substitution is observed at the aqua ligand trans to the
pyridine moiety. The second coordinated thiourea nucle-
ophile triggers a fast chelate ring opening, followed by
coordination of the third nucleophile. The rate constants k1
and k2 represent the rates of sequential substitution of the
two aqua ligands. This is expected based on the unsym-
metrical structure of the N,S-bidentate non-leaving ligand.
The thioether donor is known to have a strong trans-la-
bilisation effect in square-planar complexes.
A representative plot of the linear regression passing
through the origin is shown in Fig. 7. The same trend was
observed for the other complexes investigated in this study.
The values of the obtained rate constants (k1 and k2) are
summarised in Table 3.
The substitution of the coordinated aqua ligands by the
thiourea nucleophiles followed the mechanism described
by Eqs. (1) and (2) [39].
kobsð1Þ ¼ k1½NuŠ þ kÀ1 ꢀ k1½NuŠ
kobsð2Þ ¼ k2½NuŠ þ kÀ2 ꢀ k2½NuŠ
ð1Þ
ð2Þ
Figure 5 shows a preliminary analysis of the reaction of
0.1 mM Pt(pySPh) with 7 mM dmtu for the determination
of the wavelengths chosen to monitor the two substitution
steps.
Activation parameters
The kinetic traces for each substitution step fitted well to
a single exponential function, giving the pseudo-first-order
rate constants, kobs(1) and kobs(2), for the first and second
substitution steps, respectively, at specific nucleophile
concentration and temperature. Average kobs(1/2) values
were calculated from stopped-flow data obtained from 6 to
8 independent kinetic runs. The observed pseudo-first-
The temperature dependence of the second-order rate
constants, k1 and k2, was studied within the temperature
range of 15–35 °C, at intervals of 5 °C. The calculated
values for DH= and DS= are summarised in Table 4, and a
typical Eyring plot for the reaction of Pt(pySPh(t-But)) and
thiourea nucleophiles is shown in Fig. 8.
123

746
Transit Met Chem (2017) 42:739–751
Table 2 DFT calculated data of cis-Pt(II) complexes
Property
Pt(pySPh
)
Pt(pySPh(t-But)
)
Pt(pySPhF
)
MO energy (eV)
LUMO
-3.18
-7.26
4.08
-3.09
-7.09
4.00
-3.23
7.30
HOMO
DEL-H
4.07
NBO charges
Pt
0.686
2.04
0.676
2.00
0.692
2.03
Chemical hardness (eV)
Chemical potential (eV)
Electrophilicity index (x)
-5.22
6.68
-5.09
6.48
-5.27
6.84
˚
Bond lengths (A)
d Pt–Npy
2.02
2.41
2.12
2.11
9.03
2.02
2.40
2.12
2.10
14.9
2.02
2.41
2.12
2.11
13.2
d Pt–S
d Pt–OH2 (1)
d Pt–OH2 (2)
Dipole moment (D)
c
b
(1)
H
a
d
R = t-Butyl
(2)
F
Crystal structure of Pt(pySPhF)Cl2
the higher polarisability of the S atom. This weakens the
trans Pt–Cl bond, since both the S and Cl use the same p-
orbital on the Pt for bonding. The strong r-trans-effect
labilises the Cl ligand trans to the S atom. Thus, in solution
the substitutions of the aqua ligands from the studied
complexes are expected to occur at distinct rates whereby
the aqua ligand trans to S will be substituted first in a
consecutive process, as already observed from the experi-
mental data.
The crystal structure of Pt(pySPhF)Cl2 is shown in Fig. 9.
The pySPhF ligand is coordinated to Pt in a cis fashion,
by means of the pyridyl N atom and thioether sulphur. The
other two coordination sites are occupied by chlorine
atoms, in a slightly distorted square-planar geometry. From
˚
the data in Table 5, the Cl(2)–Pt(1) bond length (2.3261 A)
which is trans to the thioether is significantly longer than
that which is trans to the pyridyl nitrogen, Cl(1)–Pt(1)
˚
(2.3049 A). This trend was also predicted by DFT calcu-
The phenyl ring lies out of plane of the complex (di-
hedral angle C7–S1–Pt1–Cl1 & 78.57°) and is closer to the
Cl atom trans to pyridine. This has potential to block the
approach of the nucleophile on one side of the complexes.
lations (Table 2) and can be assigned to the trans-effect of
the stronger r-bond between the thioether and Pt, due to
123

Transit Met Chem (2017) 42:739–751
747
Scheme 2 Sequential
substitution of aqua ligands
from the complexes
2+
2+
2+
k1
k2
+ Nu, -H2O
+Nu, -H2O
fast + Nu, -Npy
2+
R = H; t-But; F
Nu = tu; dmtu;tmtu
2,0
1,5
1,0
0,5
0,0
0,050
0,045
0,040
0,035
0,030
0,025
0,020
0,015
250
275
300
325
350
375
400
0
2
4
6
8
10
Wavelength (nm)
Time/ s
Fig. 5 UV–visible spectra recorded for the reaction of 0.1 mM
Pt(pySPh) with 7 mM dmtu at pH 2 (I = 0.1 M LiOTf/HOTf) and
25 °C
Fig. 6 A typical time-resolved kinetic trace for a reaction of 0.1 mM
Pt(pySPh) with 2 mM tu followed on the stopped-flow at wavelength
321 nm. pH 2 (I = 0.1 M LiOTf/HOTf) and 25 °C
Thus, the aqua (H2O(1)) ligand should be substituted even
more slowly when compared to the aqua trans to the
thioether. Further data on the crystal structure of the
complex are summarised in Table 5, and selected bond
lengths and angles are given Table 6.
and the kinetics of substitution of the aqua coligands were
studied using biologically relevant sulphur-containing
thiourea nucleophiles. The rate of substitution of the first
aqua ligand follows the trend Pt(pySPh(t-But)) [ -
Pt(pySPhF) [ Pt(pySPh). Taking k1 for the reaction of
Pt(pySPh(t-But)) and tu as a reference, the ratio of reactivity
is approximately 12: 1.3: 1 for Pt(pySPh(t-But))/Pt(pySPhF)/
Pt(pySPh), respectively. This initial substitution occurs at
the aqua ligand trans to the thioether for all three com-
plexes. This is consistent with the experimentally deter-
mined bond lengths of Pt(pySPhF) and is also in accord
with the acidities of the coordinated aqua ligands,
Discussion
In this study, three square-planar cis-Pt(II) complexes
comprising 2-(phenylthiomethyl)pyridine chelates with
different substituents were synthesised and characterised,
123

748
Transit Met Chem (2017) 42:739–751
40
35
30
25
20
15
10
5
tu
dmtu
tmtu
4
3
tu
dmtu
tmtu
2
1
0
0
-1
0,000 0,001 0,002 0,003 0,004 0,005 0,006 0,007 0,008 0,009
[Nu]/ M
0.00325
0.00330
0.00335
0.00340
0.00345
0.00350
1/T (K-1)
Fig. 7 Plots of kobs1 vs [Nu] for the first substitution step of the
reaction of 0.165 mM Pt(pySPh(t-But)) at pH 2 (I = 0.1 M LiOTf/
HOTf) and 25 °C
Fig. 8 Temperature dependence plots for the reaction of 0.05 mM
Pt(pySPh(t-But)) with 2.75 mM (Nu = tu, dmtu and tmtu)
Table 3 Summary of the rate constants for the consecutive substi-
tution steps of the Pt(II) complexes by tu, dmtu and tmtu (I = 0.1 M
LiOTf/HOTf)
directing ability of the thioether. Consequently, electron
density from the thioether is donated into the empty
6p orbital of the Pt atom. This leads to a stronger and
shorter Pt–S bond, while the trans Pt–O bond is weakened.
The latter is thus substituted more rapidly by the incoming
thiourea nucleophiles compared to the unsubstituted
Pt(pySPh) complex [40].
Nu
k1/M-1 s-1
k2/10-1 M-1 s-1
Pt(pySPh
)
tu
304
350
43
1
6
1
11
5
1
1
1
dmtu
tmtu
tu
3
Pt(pySPh(t-But)
)
4325 16
636 11
243 12
dmtu
tmtu
tu
172
66
4
1
7
1
1
The negative r-inductive effect of the para fluoro sub-
stituent in Pt(pySPhF) deactivates the phenylthiomethyl
group, making it more electron deficient relative to that of
the unsubstituted analogue Pt(pySPh). This stabilises the
LUMO (p-acceptors), which strengthens its capacity to
receive electron density from Pt and so renders the metal
centre more electrophilic. Hence, the rate of nucleophilic
127
463
387
61
2
1
6
1
Pt(pySPhF
)
dmtu
tmtu
4
0.44 0.02
determined as their pKa values. The relative magnitude of
k1 (Table 3) for the reactions scales with the r-inductive
effect of the para-substituents on the phenyl ring of the
N,S-bidentate ligands. The positive r-inductive effect of
the tert-butyl substituent at the para-position of the phenyl
group increases electron density of the phenyl ring and
hence the ligated thioether. This increases the r-trans-
substitution of the aqua ligands is greater for Pt(pySPhF
than for Pt(pySPh). The higher reactivity of Pt(pySPh(t-But)
)
)
relative to Pt(pySPhF) is an indication that the r-trans-
directing effect of the thioether is greater than the p-ac-
ceptor property of the fluoro substituent that would other-
wise be dominant in labilising the trans-aqua ligand.
Table 4 Summary of the
¼
¼
¼
¼
DH1 /kJ mol-1 DS1 /J mol-1 K-1 DH2 /kJ mol-1 DS2 /J mol-1 K-1
Nu
tu
activation parameters for the
consecutive substitution steps of
the investigated complexes by
tu, dmtu and tmtu, (I = 0.1 M
LiOTf/HOTf)
Pt(pySPh
)
31
1
1
1
1
2
1
2
1
2
-79
-91
-99
-72
-41
-84
-66
-66
-86
4
3
2
4
6
4
7
5
7
23
35
37
36
47
17
38
44
36
1
1
1
3
2
2
1
2
3
-152
-74
5
3
4
9
6
7
5
7
dmtu 30
tmtu
tu
40
28
-81
Pt(pySPh(t-But)
)
-100
-63
dmtu 45
tmtu
tu
36
38
-177
-66
Pt(pySPhF
)
dmtu 38
tmtu 37
-49
-91 10
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Transit Met Chem (2017) 42:739–751
749
Fig. 9 Thermal ellipsoid
diagram (50% probability
surfaces) of the molecular
structure of Pt(pySPhF)Cl2
Table 5 Crystal data of
Pt(pySPhF)Cl2
Parameter
Empirical formula
Formula weight
Temperature
C12H10C12FNPtS
485.26
100(2) K
˚
0.71073 A
Wavelength
Crystal system
Space group
Monoclinic
P21/c
˚
a = 10.136(5) A
Unit cell dimensions
a = 90°
˚
b = 9.345 (4) A
b = 100.366(5)°
c = 90°
˚
c = 14.305(6) A
3
˚
Volume
1332.9(10) A
Z
4
Density (calculated)
Absorption coefficient
F (000)
2.418 mg/m3
11.075 mm-1
904
0.220 9 0.190 9 0.140 mm3
Crystal size
Theta range for data collection
Reflections collected
Independent reflections
Completeness to theta = 25.242°
Absorption correction
Max. and min. transmission
Refinement method
Data/restraints/parameters
Goodness of fit on F2
Final R indices [I [ 2sigma(I)]
R indices (all data)
Largest diff. peak and hole
2.043–28.343°
23,313
3314 [R(int) = 0.0359]
99.9%
Semi-empirical from equivalents
0.318 and 0.183
Full-matrix least-squares of F2
3314/0/163
1.157
R1 = 0.0208, wR2 = 0.0480
R1 = 0.0216, wR2 = 0.0483
-3
˚
0.976 and -1.834 e A
The kinetically slower substitution of the second aqua
ligand occurs trans to the pyridine moiety. This is sug-
gested in the metrics of the complexes obtained from DFT
calculations as well as the Pt–Cl bond lengths from the
single-crystal data for Pt(pySPhF). The rate constant, k2, for
the substitution of the second aqua ligand when tu is con-
sidered, decreases in the ratio: 61: 3: 1 for Pt(pySPh(t-But))/
Pt(pySPh)/Pt(pySPhF), respectively. In general, the reac-
tivity of the complexes for the second substitution step
follows
the
trend:
Pt(pySPh(t-But)) [ Pt(pySPh) [
123

750
Transit Met Chem (2017) 42:739–751
but rapid concentration-independent ring opening of the
N,S-bidentate ligand to form a PtS4 species.
Table 6 Comparison of the X-ray diffraction and theoretical data
{bond lengths (A) and bond angles (°) of Pt(pySPhF)Cl2}
˚
The low and positive enthalpy of activation (DH=)
values and the high and negative entropy of activation
(DS=) values confirm an associative mode of substitution.
This study has demonstrated that the reactivity of square-
planar cis-Pt(II) complexes can be controlled by tuning the
electronic properties of the substituents on the non-leaving
bidentate (phenylthiomethyl)pyridine ligand.
X-ray
DFT
˚
Bond lengths (A)
(1)–Pt(1)
(1)–Pt(1)
N
2.027 (3)
2.2451 (10)
2.3049 (13)
2.3261 (10)
Pt–Npy
2.02
2.41
2.11
2.12
S
Pt–S
Cl(1)–Pt(1)
Pt–OH2 (1)
Pt–OH2(2)
Cl(2)–Pt(1)
Bond angles (°)
Acknowledgements We thank the University of KwaZulu-Natal and
the National Research Foundation of South Africa for financial sup-
port and a bursary to WMM.
N
(1)–Pt(1)–Cl(1)
175.42 (8)
177.68 (3)
\Npy–Pt–OH2 (1)
\S–Pt–OH2(2)
177.9
176.6
S(1)–Pt(1)–Cl(2)
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