Reactivity of cis-platinum(II) complexes with 2-(4-substituted)phenylthiomethyl)quinoline nonleaving ligands toward thiourea nucleophiles

Article abstract of DOI:10.1002/kin.21178

The sequential substitution of aqua ligands from [Pt{2-(phenylthiomethyl)quinoline}(H₂O)₂]CF₃SO₃, Pt(L1), [Pt{2-(4-tert-butylphenylthiomethyl)quinoline}(H₂O)₂]CF₃SO₃ Pt(L2), and [Pt{2-(4-fluorophenylthiomethyl) quinoline}(H₂O)₂]CF₃SO₃ Pt(L3) by thiourea nucleophiles (Nu) was studied under pseudo–first-order conditions as a function of concentration and temperature using stopped-flow and UV-visible spectrophotometric techniques. The observed pseudo–first-order rate constants for the substitutions can be described by the rate law: k_obs(1/2)=?k_2(1/2)[Nu], where the subscript denotes the consecutive substitution steps. The first aqua ligand was substituted opposite to the strong σ-trans-directing thioether followed by the aqua ligand opposite to the quinoline or pyridine moieties. Second-order rate constants, k_2(1st), for the substitution of the first aqua ligand by thiourea nucleophiles ranged between 9 and 22?M^?1 s^?1 for Pt(L1), 86 and 326?M^?1 s^?1 for Pt(L2), and 58 –287?M^?1 s^?1 for Pt(L3). The ranges of the second-order rate constant, k_2(2nd), were always lower than the k_2(1st)’s and are 0.3-9?M^?1 s^-1 for Pt(L1), 2-20?M^?1 s^?1 for Pt(L2), and 0.3-5?M^?1 s^?1 for Pt(L3). Aqua substitution from Pt(L2) is slower for both steps than from Pt4, its pyridyl derivative from our previous study. A Job's method of continuous variation plot suggests a species with a metal-to-nucleophile ratio of 1:3 as the ultimate product of the chloride substitution from the Pt(II) complexes by the incoming thiourea nucleophiles. The high and negative activation entropy and low and positive activation enthalpy values support an associative mechanism of activation, characteristic of substitution reactions occurring in square-planar complexes.

Full text of DOI:10.1002/kin.21178

Received: 21 November 2017
DOI: 10.1002/kin.21178
Revised: 13 March 2018
Accepted: 4 March 2018
A R T I C L E
Reactivity of cis-platinum(II) complexes
with 2-(4-substituted)phenylthiomethyl)quinoline
nonleaving ligands toward thiourea nucleophiles
Wakhiwe M. Mthiyane
Allen Mambanda
Deogratius Jaganyi
School of Chemistry and Physics, University
of KwaZulu-Natal, Scottsville, South Africa
Abstract
The sequential substitution of aqua ligands from [Pt{2-(phenylthiome-
Correspondence
AllenMambanda, Schoolof Chemistry
and Physics, Universityof KwaZulu-Natal,
Scottsville, 3209, South Africa.
Email:mambanda@ukzn.ac.za
thyl)quinoline}(H2O)2]CF3SO3,
Pt(L1),
[Pt{2-(4-tert-butylphenylthiome-
thyl)quinoline}(H2O)2]CF3SO3 Pt(L2), and [Pt{2-(4-fluorophenylthiomethyl)
quinoline}(H2O)2]CF3SO3 Pt(L3) by thiourea nucleophiles (Nu) was studied
under pseudo–first-order conditions as a function of concentration and temperature
using stopped-flow and UV-visible spectrophotometric techniques. The observed
pseudo–first-order rate constants for the substitutions can be described by the rate
law: k
= k2(1/2)[Nu], where the subscript denotes the consecutive substitution
steps. oTbhs(e1/2fi)rst aqua ligand was substituted opposite to the strong ꢀ-trans-directing
thioether followed by the aqua ligand opposite to the quinoline or pyridine moieties.
Second-order rate constants, k2(1st), for the substitution of the first aqua ligand by
thiourea nucleophiles ranged between 9 and 22 M−1 s−1 for Pt(L1), 86 and 326 M
−1
−1
−1 −1
s
for Pt(L2), and 58 –287 M
s
for Pt(L3). The ranges of the second-order
rate constant, k2(2nd), were always lower than the k2(1st)’s and are 0.3-9 M s-1 for
−1
−1 −1
−1 −1
Pt(L1), 2-20 M
s
for Pt(L2), and 0.3-5 M
s
for Pt(L3). Aqua substitution
from Pt(L2) is slower for both steps than from Pt4, its pyridyl derivative from our
previous study. A Job's method of continuous variation plot suggests a species with a
metal-to-nucleophile ratio of 1:3 as the ultimate product of the chloride substitution
from the Pt(II) complexes by the incoming thiourea nucleophiles. The high and
negative activation entropy and low and positive activation enthalpy values support
an associative mechanism of activation, characteristic of substitution reactions
occurring in square-planar complexes.
K E Y W O R D S
associative mechanism, consecutive reaction, Pt(II) mononuclear complexes, substitution
complexes required to optimize their antitumur potency.4
For example, despite the high reactivity of the square-planar
1
INTRODUCTION
Pd(II) complexes (factors of between 103 and 105 over their
Pt(II) analogues), there are several Pd(II)complexes which
have shown comparable in vitroantitumur activity5. Highly
reactive Pt(II)/Pd(II) complexes would rapidly hydrolyze
and be deactivated by nontargeted substrates in the plasmic
fluids.6 This also leads to high toxicity and development of
Square-planar Pt(II) complexes have been a subject of medic-
inal interest for years.1,2 The reactions of these complexes
with DNA nucleic bases provide one of the many mechanistic
pathways for anticancer activity against cancerous cells.3
Modification of both steric and electronic attributes of the
nonleaving ligand is key to adjusting the reactivity of Pt(II)
Int J Chem Kinet. 2018;1–13.
wileyonlinelibrary.com/journal/kin
© 2018 Wiley Periodicals, Inc.
1

2
MTHIYANE ET AL.
resistance.7 It can therefore be hypothesized that nonactive
anticancer Pd(II) compounds become active agents if their
reactivity can be reduced to levels commonly reported for
Pt(II) complexes. Possibilities include introducing sterically
bulky nonleaving ligands that retards a facile approach
of other extracellular bionucleophiles8 or ligands that are
stronger ꢀ-donors but weaker ꢁ-acceptors.
2+
2+
An important subgroup of square-planar Pt(II) complexes
has been those which possess two sites for substitution. The
remaining sites are occupied by two monodentates or a biden-
tate ligand. Examples are Pt(II) complexes, which have N,N-
Pt(L1)
Pt(L2)
2+
2+
or N,S-14,15 bidentate nonleaving ligands and these usu-
8–13
ally display a two-step consecutive substitution of the labile
leaving groups, with rates that are dependent on the elec-
tronic (ꢀ-donor/ꢁ-acceptor) and steric demands of the resi-
dent ligand as well as the nucleophilicity of the labile lig-
ands. Even in complexes where the coordinated bidentate
ligand is symmetrical, substitution occurred consecutively.16
A case in point is the chloride substitution from the Pt(II)
complex Pt(1,2-bis(phenylsulfanyl)ethane)Cl2 (S,S = 1,2-
bis(phenylsulfanyl)ethane) by pyridine.17 Substitution of the
first chloride ligand is followed by a ring opening of the S,S
ligand.
Pt(L3)
Pt4)
F I G U R E
1
Structures of the cis-Pt(II) complexes with 2-
(phenylthiomethyl)quinoline moieties [Color figure can be viewed at
wileyonlinelibrary.com]
When the nonleaving ligand has fused aromatic rings,
the rate of substitution of square-planar Pt(II) complexes is
increased due to the strong ꢁ-acceptor property of the ligand.
In principle, extending the ꢁ-surface of a strong ꢁ-acceptor
ring such as pyridine to a quinoline moiety is expected
to accelerate the rate of substitution due to an increased
propensity of the latter moiety to receive electron density
into its lower energy, extended molecular orbitals. How-
ever, recent reports18,19 have demonstrated an antithesis of
this observation. Relative to the reactivity of Pt(II)(terpy)Cl,
2
EXPERIMENTAL
2.1 Materials
Chemicals and solvents (analytical grade or better) were all
purchased from Aldrich and Merck (Johannesburg, South
Africa), respectively, and used without further purification.
Silver trifluoromethanesulfonate (AgCF3SO3; 99%; Aldrich)
was stored under nitrogen as per specifications. Ultrapure
water (MODULAB purification system) was used for all
aqueous solutions.
′
terpy = 2,2 :6-terpyridine, Pt(II) complexes bearing 2,6-
bis(iso/quinolyl)pyridine have been found to have surprisingly
lower rates of substitution.19 A stronger ꢀ-effect and poor ꢁ-
acceptor properties of the iso/quinolyl groups have been put
forward to explain this anomaly. As a result, electron density is
accumulated on the bis(iso/quinolyl)pyridine Pt(II) com-
plexes relative to that of Pt(II)(terpy)Cl, leading to a more
2.2 Synthesis of the N, S ligands
Synthesis of the ligands was carried out under inert con-
ditions using standard Schlenk techniques. Bidentate
N,S ligands, namely 2-(phenylthiomethyl)quinoline (L1),
2-(4-tert-butylphenylthiomethyl)quinoline (L2), and 2-(4-
fluorophenylthiomethyl)quinoline (L3), were prepared via
a nucleophilic S-alkylation reaction of either thiophenol
(0.62 mL, 6.8 mmol), 4-tert-butylthiophenol (1.20 mL,
6.9 mmol), or 4-fluorothiophenol (0.70 mL, 6.8 mmol) with
2-(chloromethyl)quinoline hydrochloride (1.5 g, 6.8 mmol)
under basic conditions.24,25 2-(Chloromethyl)quinoline
hydrochloride was dissolved in water (3 mL). To the stirring
solution, 5 M NaOH was added drop by drop until a pink
emulsion was observed. A solution of the thiophenol in
absolute EtOH (10 mL) was added dropwise. The mixture
was stirred under reflux for 36 h. Upon cooling, the product
was sequentially extracted with CHCl3 (4 × 10 mL). The
destabilized transition state in the former complexes.20,21
A
similar trend in reactivity was observed by Khusi et al.22 for
N,N bidentate coordinated Pt(II) complexes for which replac-
ing the pyridyl moiety of the bidentate with a quinolyl moiety
retarded the rate of stepwise substitution of the aqua leaving
groups positioned trans to the moiety.
This study extends the knowledge on the role of quinolyl
nonleaving ligand on the rate of aqua ligand substitu-
tion in cis-Pt(II) complexes bearing 2-(4-substituted)
phenylthiomethyl)quinoline
(N,S)
bidentate
ligands
(Figure 1). The entering thiourea nucleophiles were chosen
due to their neutral character, good aqueous solubility, and
nucleophilicity.23

MTHIYANE ET AL.
3
combined organic phases were back-washed with 2 × 10 mL
portions of cold ultrapure water. Yellow or orange brown
oils (yield: 58-64%) of adequate purity for further use for
platinum coordination were obtained after solvent removal
under vacuum. Suitable crystals for X-ray analysis of L1 and
L3 were obtained by slow vapor diffusion of hexane into
concentrated dichloromethane solutions of their oils.
thiophenol)quinoline}Cl2], Pt(L2)Cl2, and [Pt{2-(4-
fluorothiophenol)quinoline}Cl2], Pt(L3)Cl2, were synthe-
sized by reacting 1 equiv of the respective thioether ligand
with K2PtCl4 (0.46 g, 0.9 mmol) according to a literature
method.26
2.2.1 Spectroscopic characterisation
2.4 Spectroscopic characterisation
Pt(L1)Cl2: Yield: 0.36 g, 0.69 mmol (77%, orange pow-
1
L1: Yield: 1.07 g, 4.3 mmol (63%, brown orange oil). H
NMR (400 MHz: CDCl3): ꢂ (ppm) referenced to TMS;
4.47 (s, 2H, –CH2–), 7.16-7H.20 (t, 1H, Ph), 7.24-7.27 (t,
2H, Ph), 7.40-7.42 (d, 2H, Ph), 7.52-7.56 (d, 1H, Qn),
7.52-7.56 (t, 1H, Qn), 7.71-7.75 (t, 1H, Qn), 7.80-7.82
(d, 1H, Qn), 8.07 (d, 1H, Qn), 8.13 (d, 1H, Qn). 13C
1
der). H NMR (400 MHz: DMF-d ): ꢂ (ppm) referenced
7
to TMS; 4.30 (d, 2H, –CH2–, AB-spiHn system), 7.16 (t,
1H, Ph), 7.27 (t, 2H, Ph), 7.37 (d, 2H, Ph), 7.33 (t, 1H,
Qn), 7.52-7.54 (d, 1H, Qn), 7.60-7.64 (t, 1H, Qn), 8.56
(d, 1H, Qn). 195Pt NMR (400 MHz: DMF-d ): ꢂ (ppm);
7
Pt
NMR (100 MHz: CDCl3): ꢂ (ppm); 41.1; 120.9; 126.4;
C
–2717. Infrared (KBr, 4000-650 cm–1) ꢃ: 3055 (C=C–H
asymmetric stretch), 1583 (C=N, quinolyl). Anal. Calcd for
C16H13Cl2NPtS: C: 37.15, H: 2.53, N: 2.71, S: 6.20. Found:
C: 36.98, H: 2.42, N: 2.57, S: 6.02.
127.1; 127.5; 128.9; 129.1; 129.7; 136.9; 158.1. Infrared
(KBr, 4000-650 cm−1) ꢃ: 3056 (C=C–H asymmetric
+
stretch), 1596 (C=N, quinolyl). Time-of-flight MS-ESI
+
m/z: 252.0961, 100 (M) . Anal. Calcd for C16H13NS: C:
Pt(L2)Cl2: Yield: 0.2 g, 0.36 mmol (60%, yellow-orange
76.46, H: 5.21, N: 5.57, S: 12.76. Found: C: 76.31, H:
5.25, N: 5.21, S: 12.51.
powder). 1H NMR (400 MHz: CDCl3): ꢂ (ppm) referenced
H
to TMS; 1.30 (s, 9H, –C(CH3)3), 4.27 (d, 2H, –CH2–, AB-
spin system), 7.17-7.18 (t, 1H, Qn), 7.28 (d, 4H, Ph), 7.36 (d,
1H, Qn), 7.62-7.65 (t, 1H, Qn), 8.55 (d, 1H, Qn). 195Pt NMR
(400 MHz: DMF-d ): ꢂ (ppm); –2711. Infrared (KBr,
1
L2: Yield: 1.24 g, 4.0 mmol (58%, orange oil). H NMR
(400 MHz: CDCl3): ꢂ (ppm) referenced to TMS; 1.30
(s, 9H, –C(CH3)3), 4.H45 (s, 2H, –CH2–), 7.27 (d, 2H,
Ph) 7.35 (d, 2H, Ph) 7.51 (t,1H, Qn), 7.56 (d, 1H, Qn),
7.70-7.74 (t, 1H, Qn), 7.79-7.81 (d, 1H, Qn), 8.08 (d,
1H, Qn), 8.10-8.12 (d, 1H, Qn). 13C NMR (100 MHz:
7
Pt
4000-650 cm−1) ꢃ: 3059 (C=C–H asymmetric stretch), 1598
(C=N, quinolyl). Anal. Calcd for C20H21Cl2NPtS: C: 41.89,
H: 3.69, N: 2.44, S: 5.59. Found: C: 41.35, H: 3.30, N: 2.69,
S: 5.57.
CDCl3): ꢂ (ppm); 41.8; 115.8; 116.1; 122.1; 123.1;
C
130.3854; 133.1091; 136.6; 149.3; 157.6. Infrared (KBr,
4000-650 cm−1) ꢃ: 3059 (C=C–H Asymmetric stretch),
1598 (C=N, quinolyl). Anal. Calcd for C20H21NS: C:
78.13, H: 6.88, N: 4.56, S: 10.43. Found: C: 78.01, H:
6.62, N: 4.53, S: 10.84.
Pt(L3)Cl2: Yield: 0.2 g, 0.37 mmol (44%, yellow-orange
powder). 1H NMR (400 MHz: CDCl3): ꢂ (ppm) referenced
H
to TMS; 4.19 (d, 2H, –CH2–, AB-spin system), 6.91-7.00 (d,
2H, Ph), 7.12-7.15 (t, 1H, Qn), 7.23 (d, 1H, Qn), 7.32 (d, 2H,
Ph), 7.57-7.60 (t, 1H, Qn), 8.51-8.52 (d, 1H, Qn). 195Pt NMR
(400 MHz: DMF-d ): ꢂ (ppm); –2718. Infrared (KBr,
1
L3: Yield: 1.14 g, 4.2 mmol (64%, orange oil). H NMR
7
Pt
(400 MHz: CDCl3): ꢂ (ppm) referenced to TMS;
4000-650 cm−1) ꢃ: 3066 (C=C–H asymmetric stretch),
1588 (C=N, quinolyl). Anal. Calcd for C16H12Cl2FNPtS: C:
35.90, H: 2.26, N: 2.62, S: 5.98. Found: C: 35.64, H: 2.05,
N: 2.52, S: 6.06.
H
4.40 (s, 2H, –CH2–), 6.92-6-.96 (d, 2H, Ph), 7.34-7.38
(d,2H, Ph), 7.47–7.49 (d, 1H, Qn), 7.52-7.56 (t, 1H,
Qn), 7.70-7.74 (t, 1H, Qn), 7.79-7.81 (d, 1H, Qn), 8.05
(d, 1H, Qn), 8.11 (d, 1H, Qn). 13C NMR (100 MHz:
CDCl3): ꢂ (ppm); 42.3; 115.9; 116.1; 11.0; 126.5;
C
127.5; 129.8; 131.3; 133.1; 158.0. Infrared (KBr, 4000-
650 cm−1) ꢃ: 3057 (C=C–H asymmetric stretch), 1592
2.5 Preparation of the diaqua Pt(II)
complexes
+
(C=N, quinolyl). Time-of-flight MS-ESI m/z: 268, 100
(M-1). Anal. Calcd for C16H12FNS: C: 71.35, H: 4.49,
N: 5.20, S: 11.91. Found: C: 71.29, H: 4.31, N: 5.15, S:
11.43.
Solutions of the diaqua complexes, viz. Pt(L1), Pt(L2), and
Pt(L3), were prepared from their chloride derivatives via
a chloride metathesis with AgCF3SO3 followed by dilution
with a pH 2 triflic acid solution.27 Solutions of the thiourea
nucleophiles, viz. tu, dmtu, and tmtu, were prepared by
dissolving a known amount of the nucleophile in 0.1 M
LiOTf/HOTf solution.
2.3 Synthesis of Pt(II) complexes
Three mononuclear cis-Pt(II) complexes, viz. [Pt{2-(phenyl-
thiomethyl)quinoline}Cl2], Pt(L1)Cl2, [Pt{2-(4-tert-butyl

4
MTHIYANE ET AL.
ter following a manual mixing of the complex and the nucle-
ophile in a tandem Suprasil cuvette. For rapid reactions, an
automated stopped-flow analyzer equipped with a pressure-
driven cross-mixer for instant mixing of the complex and
nucleophile solutions was used. Prior to kinetics measure-
ments on the stopped-flow analyzer, trial kinetic reactions of
the Pt(II) metal complexes with the nucleophiles were briefly
undertaken by scanning the entire UV-visible wavelength
range. This was done to determine a suitable wavelength at
which kinetics of each reaction could be followed. Rate con-
stants from the UV-visible scanning kinetics of slow reactions
are averages of duplicates, whereas those from the stopped-
flow analyzer are averages of eight independent kinetic runs.
The temperature dependence of the rate of substitution was
2.6 Instrumentation and physical
measurements
NMR spectrometers (Bruker Avance DRX 400 or DRX 500)
and a FLASH 2000 CHNS analyzer were used for the char-
acterization and chemical analysis of the ligands and com-
plexes, respectively. A Waters Micromass LCT Premier mass
+
spectrometer (ESI -TOF) was used to acquire mass spectra
of the ligands and complexes. A Perkin Elmer Spectrum One
FTIR spectrometer was used to measure the characteristic fre-
quencies of vibration of the ligands and complexes. Rapid
kinetic measurements were performed on an Applied Photo-
physics SX 20MV stopped-flow spectrophotometer coupled
to an online data acquisition system. The temperature of the
◦
instrument was controlled to within
0.1 C for all mea-
◦
studied within the range of 15-35 C.
surements. A Cary 100 BIO UV-visible spectrophotometer
equipped with a Varian Peltier temperature controller (with an
2.9 Job's method of continuous variation
◦
accuracy of 0.05 C) was used for the determination of the
pKa values of the diaqua complexes. The pH measurements
were determined on a Jenway 4330 pH meter equipped with
a 4.5-ꢄm glass electrode. The micro-electrode was calibrated
The complex formation reaction of the Pt(II) complexes with
the thiourea nucleophiles was studied by preparing solutions
of Pt(L2) (0.1 mM) and tu (0.1 mM), adjusted to a constant
ionic strength I = 0.1 M LiOTf/HOTf and to a pH of 2, at var-
ious mole fractions of reactants. The reaction mixtures were
left for 10 h after which their absorbance was recorded at
293 nm.
◦
at 25 C using standard buffer solutions (Merck) at pH 4.0,
7.0, and 10.0. pKa titration curves. and time-resolved kinetic
traces were graphically analyzed using Origin 7.5® software
package.28
2.10 Density functional theory calculations
2.7 pKa determination for the diaqua
The geometry-optimized molecular structures of the com-
plexes Pt(L1), Pt(L2), and Pt(L3) were computed at the
density functional theory (DFT) level of theory (B3LYP
(CPCM)/LANL2DZp//B3LYP/-LAN2DZp)29–31 using the
Gaussian 09 software suite.32 The geometry-optimized struc-
tures were conducted in the gaseous phase, and the calcu-
lated structural parameters along with those of Pt4, a pyridyl
derivative of Pt(L2) from our previous report33, are presented
in Table 3 and Figure 4, respectively. A charge of +2 was
maintained for the cationic diaqua complexes.
complexes
Spectrophotometric acid-base titrations were undertaken for
the determination of pKa values of the diaqua complexes.
Changes in absorbance of the diaqua complex after addition
of aliquots of NaOH were plotted as a function of pH within
the range 2-9. In the low pH range (2-3), ΔpH for the titrated
solution was small and thus required crushed NaOH pellets.
For the subsequent increase in pH, dilute NaOH solutions of
varying concentrations were used. After each addition, about
0.5 mL of the solution was sampled for pH measurement.
These samples were discarded to avoid probable contamina-
tion from leached off chloride ions from the pH electrode. The
pKa values were obtained from a sigmoidal curve fitting of
data.
2.11 X-ray crystallographic analysis
X-ray crystallographic data of the ligands L1 and L3 (Table 1)
were collected on a Bruker Apex II Duo equipped with an
Oxford Instrument Cryojet operating at 100 K and an Incoatec
˚
microsource operating at 30 W power. A Mo Kꢅ (ꢆ = 0.71 A)
radiation induced at a crystal-to-detector distance of 50 mm
was used to collect the data. The Bruker instrument was opti-
mized for the ꢇ and ꢈ scans with exposures taken at 30 W
2.8 Kinetics measurements
The rate of substitution of the coordinated aqua ligands from
the Pt(II) complexes was undertaken under pseudo–first-order
conditions for which the concentration of nucleophile was at
least 10-fold more than the Pt(II) complex. At all times, the
solutions were kept at pH 2 to ensure the presence of only the
diaqua form of the complexes in solution. The rate of slow
reactions was followed on the UV-visible spectrophotome-
ο
X-ray power and 0.50 frame widths using APEX2. Data
reduction was done with SAINT34 suite of program using
outlier rejection, scan speed scaling, and standard Lorentz
and polarization correction factors. The structure was solved
and refined using SHELXS-97 and SHELXL-97 methods,
respectively.35

MTHIYANE ET AL.
5
TA B L E 1 Crystal data of L1 and L3
Parameter
L1
L3
Empirical formula
Formula weight
Crystal system
Space group
C
16H13NS
C16H12FNS
251.33
Triclinic
P -1
269.33
Monoclinic
P 21/c
◦
◦
◦
Unit cell dimensions
˚
˚
a = 7.4668(5) A
ꢅ = 84.427(3)
ꢉ = 76.236(2)
a = 28.5558(18) A
ꢅ = 90
◦
˚
˚
b = 9.4581 (6) A
b = 5.8129(4) A
ꢉ = 95.078(2)
◦
◦
˚
˚
c = 9.9116 (7) A
ꢊ = 70.928(4)
c = 7.7442(15) A
ꢊ = 90
3
3
˚
˚
Volume
642.41 (8) A
1280.43(15) A
Z
2
4
Density (calculated)
Absorption coefficient
Reflections collected
Independent reflections
Goodness-of-fit on F2
Final R indices [I > 2ꢀ(I)]
R indices (all data)
Largest difference peak and hole
1.299 mg/m3
1.397 mg/m3
−1
−1
0.232 mm
0.248 mm
2790
20940
2790
3130 [R(int) = 0.0192]
1.084
1.092
R = 0.0434, wR = 0.1308
R = 0.0371, wR = 0.0944
1
2
1
2
R = 0.0452, wR = 0.1337
R = 0.0386, wR = 0.0952
1
2
1 2
−3
−3
˚
˚
0.693 and –0.352 e A
0.428 and –0.352 e A
F I G U R E 2 Ortep structures of L1 (A) and L3 (B) drawn at 50% probability ellipsoids [Color figure can be viewed at wileyonlinelibrary.com]
The ligand L1 crystallized in the triclinic space group (with
Z = 2), whereas L3 crystallized in the monoclinic space group
P21/c (with Z = 4). Their crystal structures are shown in
3
RESULTS
3.1 X-ray diffraction data of ligands: L1
and L3
Figure 2, and
a
summary of their crystal data
and structure refinement details are summarized in
Table 4.
Figures 2 shows the crystal structures of the quinolyl N,S
bidentate ligands L1 (A) and L1 (B).

6
MTHIYANE ET AL.
1.0
0.5
0.0
2+
0.36
0.34
0.32
0.30
0.28
284 nm
Ka1
Ka2
+ NaOH
1
2
3
4
5
6
7
R = H; t-But; F
pH
Scheme 1. Deprotonation of the diaqua Pt(II) complexes [Color figure
can be viewed at wileyonlinelibrary.com]
300
400
The results in Table 2 show the sensitivity of the pKa val-
ues due to the differences in the electronic effects of the sub-
stituents on the phenyl para-position of the N,S ligand. The
pKa1 values for the deprotonation of the first coordinated aqua
ligand increase in the order: Pt4 < Pt(L3) < Pt(L1) < Pt(L2),
respectively. The positive ꢀ-inductive effect of the tert-butyl
group causes accumulation of electron density on the Pt(II)
metal center for Pt(L2). This makes the Pt atom less elec-
trophilic and the formation of the aqua-hydroxo species from
the diaqua kinetically unfavorable due to a weaker Pt–OH2
bond. This in turn makes deprotonation of the aqua ligand
more difficult. Consequently, a higher pKa1 value is observed
for Pt(L2) when compared to Pt(L1), which only has a weaker
ꢀ-donor phenyl ring.
Wavelength (nm)
F I G U R E 3 UV-visible spectra for the titration of 0.2 mM Pt(L1)
with NaOH in the pH range 2-7 at T = 298 K. Inset: Absorbance ver-
sus pH data at 284 nm [Color figure can be viewed at wileyonlineli-
brary.com]
TA B L E 2 pKa values of the diaqua Pt(II) complexes
Pt(L1)
Pt(L2)
Pt(L3)
Pt4
pKa1
pKa2
3.95 0.04
4.12 0.01
4.00 0.02
3.87 0.04a
5.85 0.02
6.10 0.05
5.67 0.03
5.60 0.06a
apKa values reproduced from Mthiyane et al.33
In the crystal structures of both the ligands, coordination
atoms N1 and S1 are spaced out by a flexible methylene carbon
and have an anticonformation. This conformation minimizes
electron-electron repulsions caused by the lone pairs on these
atoms in the packing. For coordination on the Pt metal center
to occur, the quinolyl and thioether groups must rotate about
the C8-C9 (L1) or C9-C10 (L3) bond. The acute angle (opti-
mal arrangement of two groups and two lone pairs of elec-
trons around S) made by the quinolyl and thioether groups is
significantly lower (showing more localization of the electron
density of the lone pairs around S) for the L1 compared to
its substituted analogue L3, in agreement with the negative
inductive effect of the fluoro substituent in the latter ligand.
Owing to the negative ꢀ-inductive effect of the fluoro sub-
stituent, electron density is withdrawn from the phenylth-
ioether group, making the Pt atom more electrophilic in
Pt(L3). Hence, it can stabilize more efficiently the hydroxo
species, which forms during the neutralization process. The
trend in the pKa from this study is the same as that reported
by Khusi et al.22 for similar Pt(II) complexes bearing N,N
bidentate ligands. The complex bearing electron-withdrawing
groups (–CF3) on the 3,5-positions of the pyrazole ring
had a lower pKa of 4.07 when compared to a pKa of 4.88
for the analogous complex with electron-donating methyl
substituents (–CH3).
The smaller pKa values for the complex Pt4 when com-
pared to its quinolyl analogue Pt(L2) is due to the difference
in ꢁ-acceptor properties of the nonleaving ligands. Relative
to the quinolyl group of Pt(L2), the pyridyl group of Pt4
is a superior ꢁ-acceptor of electron density from the Pt(II)
orbitals and thus stabilizes the hydroxo intermediate better.14
As a result, deprotonation of the first aqua ligand occurs at
lower pKa1 values for Pt4 when compared to its quinolyl
derivative.
3.2 Acidity of the diaqua Pt(II) complexes
Figure 3 shows an example of the spectral changes observed
during the spectrophotometric titration of Pt(L1) with NaOH.
The pKa values were calculated from separate single sig-
moidal curve fitting (not shown in the figure) of changes in
absorbance data using the Boltzmann distribution parameters
as shown from the inset in Figure 3 for complex Pt(L1). The
values are summarized in Table 2 along with those of Pt4.33
The acid-base neutralization reaction is a consecutive two-
step reaction process, wherein [Pt(N,S)(H2O)(OH)] is an
intermediate and is summarized in Scheme 1. The pKa val-
ues of the Pt4 was included for comparison with its quinolyl
analogue.
3.3 Density functional theory–calculated
structures
The three Pt(II) complexes all have a common quinolyl moi-
ety in the bidentate N,S nonleaving ligand and only differ
in the substituents in the phenyl ring of the thioether group.

MTHIYANE ET AL.
7
F I G U R E 4 DFT geometry-optimized structures of the Pt(II) complexes [Color figure can be viewed at wileyonlinelibrary.com]
DFT calculations were performed to compare the structural
parameters related to the subtle differences on the substituents
on the phenyl ring of the thioether group. The coordination
of the N,S-bidentate ligands to Pt is similar to that of Pt(II)
complexes previously reported.19,22,36 Geometry-optimized
structures and the highest molecular orbital (HOMO) and
lowest molecular orbital (LUMO) frontier molecular orbitals
are depicted in Figure 4, whereas the molecular geometry–
optimized parameters are summarized in Table 3. Bond angles
indicate a slightly distorted square-planar around the Pt(II)
metal center.
Pt(L1) and the electron-withdrawing fluoro for Pt(L3) sub-
stituents. The nonbonding orbital (NBO) charges (Table 3)
increase in the following order: Pt4 (0.641) < Pt(L1)
(0.645) < Pt(L3) (0.648) < Pt(L2) (0.676) and reflects the
strength of ꢁ-backbonding capacity of the ligands. A compar-
ison of the NBO values of Pt(L2) relative to Pt4 attests that
stronger ꢁ-acceptor pyridine ring makes the Pt atom of Pt4
more electrophilic.37,38
In addition, the electrophilicity indices (ꢇ) increase in the
order: Pt(L3) (7.06) < Pt(L1) (6.97) < Pt(L2) (6.85) < Pt4
(6.48), indicating the lesser tendency of Pt(L2) to accepting
electronic charge when compared to Pt(L3). Through posi-
tive inductive donation of electron density into the thiophenyl
group, the tert-butyl group of the former complex makes the
Pt atom less electrophilic whereas the fluoro group of Pt(L3)
withdraws electronic charge from the Pt atom inductively.
For the quinoline complexes, a significant isodensity of the
HOMOs lies on the quinoline moiety. The HOMOs are also
located on the Pt(II) metal center but at a much lower density.
A larger isodensity mapping of the HOMOs on the N,S biden-
tates of quinolyl complexes projects a less electrophilic Pt (II)
ion when compared to their pyridyl analogues. The LUMOs
are concentrated on the thioether and to a lesser extent on
the quinoline moiety. A larger LUMO mapping of electron
density on the thioether indicates a poor ꢁ-acceptor capacity
of this moiety and its propensity to accept electronic charge
from the metal center, making the latter more electroposi-
tive. There is no significant difference in the energy gaps,
3.4 Kinetic measurements
Substitution of the aqua coligands from the Pt(II) complexes
by thiourea nucleophiles proceeds by a two-step sequen-
tial process represented by k
and k
as depicted in
2(1st)
2(2nd)
ΔE
of the frontier orbitals, although the strong
Scheme 2. The mechanism of substitution is similar to what
has been reported for the reactions of pyridyl derivatives of
these complexes.
(HOMO-LUMO)
electron-donating tert-butyl moiety for Pt(L2) increases the
gap slightly when compared to the weak ꢀ-donor phenyl for

8
MTHIYANE ET AL.
0.0004
0.0003
0.0002
0.0001
0.0000
tu
dmtu
tmtu
TA B L E 3 DFT calculated parameters for the cis-Pt(II)
c
H
b
(1)
R = t-Butyl
a
d
F
(2)
Property
Pt(L1)
Pt(L2)
Pt(L3)
Pt4a
0.000
0.001
0.002
0.003
0.004
MO energy (eV)
[Nu]/M
LUMO
HOMO
∆E
−3.27
−7.20
3.93
−3.23
−7.19
3.96
−3.30
−7.22
3.92
−3.09
−7.09
4.00
F I G U R E 5 Plots of k
versus [Nu] for the first substitutions
obs1
steps of the reaction of 0.1 mM Pt(L1) at pH 2 (I = 0.1 M LiOTf/HOTf)
◦
NBLO-Hcharges
Pt
and 25 C [Color figure can be viewed at wileyonlinelibrary.com]
0.645
0.460
6.97
0.641
0.454
6.85
0.648
0.466
7.06
0.676
0.456
6.48
The first substitution forms B, which reacts with a second
nucleophile to form C, whose N-end of the N,S nonleaving
ligand is simultaneously labilized by the trans coordinated
thiourea nucleophile, facilitating the rapid coordination of a
third thiourea nucleophile to produce D, for which four S
atoms are coordinated to Pt(II) ion . This is also supported
by data from Job's method of continuous variation of mole
fraction of binary reactants on the absorbance of their solu-
tion in the complex formation reaction. This is illustrated in
Figure 6.
S
ꢇ (eV)
˚
Bond lengths (A)
b
d(Pt-Nqn/py
d(Pt-S)
)
2.04
2.40
2.13
2.11
2.04
2.39
2.13
2.10
2.04
2.40
2.13
2.10
2.02
2.41
2.12
2.11
d(Pt-OH2 (1)
d(Pt-OH2 (2)
)
)
Bond angle (o)
S-Pt-OH2 (1)
174.8
178.5
98.7
172.9
178.1
97.9
175.1
178.5
98.9
176.6
177.9
96.4
Substitution of the aqua ligand trans to the thioether by
thiourea nucleophiles, which is represented as step A → B
was monitored on the stopped-flow reaction analyzer.
Nqn/py-Pt-OH2(2)
a
b
82.5
83.0
82.5
83.9
The second-order rate constants k
were determined
2(1st)
aData from Mthiyane et al.33
from the slopes of the plots of k
versus [Nu], an exam-
bNqn/py = coordinated N-donor atom in the quinoline or pyridine ring.
obs.(1st)
ple of the plot is shown in Figure 5.
The rate law for the substitution process can be expressed
by Equation (1)39,40
:
2+
2+
2+
k1
k2
푘obs(1∕2) = 푘2(1st∕2nd)[Nu] + 푘−1(1st∕2nd) ≈ 푘2(1st∕2nd)[Nu]
(1)
+ Nu
+
Nu
+ Nu
A
C
B
R = -H; -t-But; -F
fast
where [Nu] = tu, dmtu, and tmtu.
Nu = tu; dmtu; tmtu
The values of k2(1st) for the aqua substitution from the com-
plexes by different nucleophiles are given in Table 4.
The second aqua substitution represented as B → C is
ascribed to the substitution of the aqua ligand trans to the
quinoline or pyridine moieties. The rate constant k2(2nd) for the
k2(2nd)
k2(1st)
fast
2+
A
C
B
D
D
second aqua substitution is calculated from the plot of k
obs.2nd
versus [Nu]. The substitution proceeds at a slower rate due to
ligand shielding in the square plane upon coordination of the
first thiourea nucleophile. The ꢀ-inductive donation due to the
coordinated thiourea nucleophile further increases the elec-
tron density onto the metal center making it less electrophilic.
Scheme 2. Schematic representation of the two-step substitution of the
aqua ligands from the Pt(II) complexes and the simultaneous decoordi-
nation of the N-end of the N,S ligand by entering thiourea nucleophiles
(Nu = tu, dmtu, and tmtu) [Color figure can be viewed at wileyonlineli-
brary.com]

MTHIYANE ET AL.
9
TA B L E 4 Rate constants k2(1st/2nd) for the consecutive substitution
steps
k2(1st)
k2(2nd)
Nu
(M−1 s−1
)
(M−1 s−1
)
Pt(L1)
tu
21
13
9
1
1
8.9 0.3
5.7 0.3
0.4 0.1
dmtu
tmtu
1
Mole fraction,
F I G U R E 6 Job plot of absorbance values (at 293 nm) of solutions
of Pt(L2)Cl2 (0.1 mM) and tu (0.1 mM) prepared in 0.1 M LiOTf/HOTf,
pH 2 and at different mole fractions recorded after a 10-h aging period
Pt(L2)
tu
335
254
86
2
19.6 0.1
11.5 0.2
2.4 0.1
dmtu
tmtu
2
1
1
The absorbance for the reaction mixtures peak at an approx-
imate tu mole fraction of 0.74, corresponding to complex for-
mation product, Pt(tu)3 in which three tu ligands are coor-
dinated to the metal center. This prompted us to propose a
mechanism of substitution shown in Scheme, and which is
similar to what has been previously proposed for the pyridyl-
supported analogues.33 The substitution of the second aqua
ligand to form C triggers a rapid and simultaneous trans labi-
lization of the N-end of the N,S nonleaving ligand by a third
thiourea nucleophile, resulting in the PtS4 species, D. Owing
to the strong trans influence of the thiourea nucleophile coor-
dinated trans to the quinolyl nitrogen, the Pt–N bond is weak-
ened significantly, making it more susceptible to nucleophilic
attack from a third thiourea nucleophile. A similar labilization
effect on nitrogen-coordinated nonleaving ligands by thiourea
has been reported before.43 In a chloride substitution from a
Pt(II) dinuclear complex linked by an ꢇ,ꢅ-alkanediamine with
NNN-non-leaving bridging head groups by tu, monitored by
I95Pt NMR spectroscopy, the final product of the substitution
reaction was similarly a PtS4 species (as evidenced by new
peak with a ꢂ (I95Pt) in the range –3800 to –3900 ppm at the
end of the reaction). Once the tu substituted the Cl leaving
group, it labilized the trans N of the NNN-linked headgroups
of the linker in a (rapid) very fast and not necessarily a rate-
limiting step.
Pt(L3)
tu
287
155
59
4
4
4.8 0.1
2.6 0.1
0.3 0.1
dmtu
tmtu
Pt4a
tu
4325 16
636 11
24.3 1.2
17.2 0.1
6.6 0.7
dmtu
tmtu
127
2
The temperature dependence of the second-order rate con-
stants was regressed according to the Eyring equation (2)44:
[
]
(
)
aData from Mthiyane et al.33
ln 푘2(1st∕2nd)∕푇 = − Δ퐻≠1st∕2nd∕푅 (1∕푇 )
[
(
)]
+ 23.8 + Δ푆≠1st∕2nd∕푅
(2)
Combined, these factors result in the slower rate of substitu-
tion of the second aqua ligand.
Examples of the Eyring plots are shown in Figure 7 for the
reactions of Pt(L1).
The activation enthalpy (ΔH≠1st/2nd) and activation entropy
(ΔS≠1st/2nd) were calculated from the slopes and y-intercepts
of the Erying plots, respectively. The data are summarized in
Table 5.
3.5 Job's method of continuous variation
A Job's plot (Figure 6)41,42 was obtained from data presented
in Figure SI 3 in the Supporting Information.

10
MTHIYANE ET AL.
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5
(A) 1.0
(B)
tu
dmtu
tmtu
tu
dmtu
tmtu
0.5
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
0.00325
0.00330
0.00335
0.00340
0.00345
0.00350
0.00325
0.00330
0.00335
0.00340
0.00345
0.00350
(1/T)/ K-1
(1/T)/ K-1
F I G U R E 7 Eyring plots for (A) first and (B) second substitution steps for the reactions of 0.1 mM Pt(L1) and thiourea nucleophiles (6.1 mM),
pH 2 (I = 0.1 M LiOTf/HOTf) [Color figure can be viewed at wileyonlinelibrary.com]
substituents in Pt(L3) and Pt(L1) are capable of delocaliz-
ing electron density away from the Pt atom, making it more
electrophilic. In contrast, the electron-donating tert-butyl sub-
stituent in Pt(L2) aids in the accumulation of electron density,
resulting in an observed higher pKa value.
4
DISCUSSION
The results in Table 4 indicate that the rate of substitution
of the aqua leaving groups is sensitive to the nature of the
substituents on the phenyl ring of the coordinated phenylth-
ioether. The aqua ligand which is trans to the thioether group
is substituted first. This is due to the strong ꢀ-trans-directing
ability of this moiety, which labilizes the Pt-OH2(1) bond
trans to its position. The substitution of the first aqua lig-
and by thiourea as the entering nucleophile decreases in the
following order: Pt4 < Pt(L2) < Pt(L3) < Pt(L1) and by fac-
tors of 204: 15: 14: and 1, respectively.
Replacing the pyridine group with a quinoline ring results
in a decrease in the rate of substitution of the aqua leav-
ing groups. A comparison of the rate constants for Pt4 and
Pt(L2) demonstrates this fact. The decreased reactivity for
Pt(L2) when compared to Pt4 is due to a decreased ꢁ-back-
donation into the quinolyl group orbitals, which increases
electron density on the Pt atom. Similar trends have been
reported previously.18,19
The strong positive ꢀ-inductive donation of the tert-butyl
substituent of Pt(L2) enhances the trans-directing ability of
the thioether. This leads to an increased rate of substitution via
the ground-state trans-influence when compared to the unsub-
stituted complex Pt(L1), which has a weaker ꢀ-donor capac-
ity. Owing to the high diffusity of atomic orbitals of the S atom
of the thioether, electron density can also be back donated into
the low-energy lying antibonding molecular orbitals localized
on the S atom thereby stabilizing the transition state during the
substitution process. The ꢁ-acceptor capacity of the thioether
is enhanced by the negative ꢀ-inductive withdrawal of the flu-
orosubstituent for Pt(L3) and leads to an increase in the rate
of substitution when compared to Pt(L1). As a result, elec-
tron density is back donated from the filled d-orbitals of the
Pt(II) ion of Pt(L3) into the empty but low-lying unoccu-
pied orbitals of its thioether, resulting in a more electropos-
itive metal center. Consequently, the formation of the bond
with the entering thiourea nucleophiles stabilizes the transi-
tion state of the reactions of Pt(L3) relative to that of Pt(L1).
These observations are supported by the low pKa values of
the complexes, which are sensitive to the nature of the sub-
stituent on the phenyl para position. The electron-withdrawing
The second substitution of the aqua leaving group occurs
trans to the quinoline moiety. Coordination of the first thiourea
nucleophile imparts a steric shielding along the plane of the
complex against nucleophilic attack from a second nucle-
ophile. The steric hindrance due to the coordinated thiourea
on the square-plane accounts for the slower substitution of
the second aqua ligand. The reactivity factors for the substitu-
tion of the second aqua when thiourea is used as the entering
nucleophile are 6: 5: 2: 1, and the order of reactivity of the
complexes is Pt4 < Pt(L2) < Pt(L3) < Pt(L1).
The nucleophilic character of thioureas at the Pt metal cen-
ter resembles that of thiols (ꢀ-donors) as well as thioethers
(ꢀ-donors/ꢁ-acceptors).45 Consequently, the thiourea ligand
trans to the coordinated quinoline or pyridine can poten-
tially weaken the Pt–N bond trans to these moieties via
its strong ꢀ-donor character.20 The labilization of the Pt–N
bonds leads to the facile substitution of Pt–N bond of the
N,S bidentate by a third thiourea nucleophile as outlined in
Scheme 2 and Figure 7. However, the N,S bidentate of the lig-
and remains coordinated to the Pt(II) metal center through the
S atom of the thioether. The inertness of the thioether toward

MTHIYANE ET AL.
11
TA B L E 5 Activation parameters for the consecutive substitution steps
횫H≠
횫S≠
횫H≠
횫S≠
(1st)
(2nd)
Nu
(kJ mol−1
)
(J K(−11st)mol−1
)
(kJ mol−1
)
(J K(−21ndm) ol−1
)
Pt(L1)
Pt(L2)
Pt(L3)
Pt4a
tu
44
38
41
69
57
43
53
53
40
28
45
36
2
1
3
3
2
2
3
2
3
1
2
1
−63
−66
−86
−93
−106
−86
−28
−28
−79
−72
−41
−84
7
5
9
8
6
7
9
6
8
4
6
4
39
56
38
56
49
38
43
69
34
36
47
37
1
2
4
1
1
3
2
3
2
3
2
2
−87
−79
−81
−89
−96
−81
−78
−73
−93
−100
−63
−177
3
5
10
3
3
8
6
8
6
9
6
7
dmtu
tmtu
tu
dmtu
tmtu
tu
dmtu
tmtu
tu
dmtu
tmtu
aData from Mthiyane et al.33
trans-labilization by thiourea is levered by its strong ꢀ-donor
capacity.
complexes decreases in the order: tu > dmtu > tmtu, which
reflects the influence of their steric bulk. Low enthalpies of
activation, negative entropies of activation, and dependence
of rate on the concentration of the nucleophiles all support
an associative mode of substitution of the labile ligands from
the complexes.
The DFT calculations were undertaken to help support the
observed trend in the substitution behavior of the complexes.
For the quinolyl complexes, the theoretical DFT parameters
namely electrophilicity indices (ꢇ) and NBO charges indi-
cate that the Pt(L3) complex is expected to have the high-
est reactivity due to its Pt atom being the most electrophilic.
This somehow is contrasted by the reactivity trend observed
experimentally, suggesting a ꢀ-trans-effect as the dominating
factor controlling the reactivity of the complexes. Owing to
the stronger positive ꢀ-inductive donation of the tert-butyl on
the phenylthioether, there is more ground-state labilization of
the trans bonded aqua ligand in Pt(L2) when compared to
Pt(L3). The reactivity of Pt(L3) is also influenced by the ꢁ-
acceptor capacity of the thioether apart from the negative ꢀ-
inductive withdrawal of the fluoro group. This explains the
high reactivity of Pt(L2) compared to Pt(L3).
ACKNOWLEDGMENTS
We thank the University of KwaZulu-Natal and the National
Research Foundation of South Africa for financial support and
a bursary to WMM.
ORCID
Allen Mambanda
http://orcid.org/0000-0002-8113-3643
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How to cite this article: Mthiyane WM, Mambanda
A, Jaganyi D. Reactivity of cis-platinum(II) complexes
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