A kinetic investigation of mononuclear trans-platinum(II) complexes with mixed amine ligands

Article abstract of DOI:10.1007/s11243-020-00381-0

This study was aimed at investigating the substitution behaviour of mononuclear trans-platinum(II) complexes with mixed amine ligands. The rate of substitution of the chloride moieties from the complexes trans-Pt(NH₃)(NH₂C₂H₅)Cl₂ (tPt2), trans-Pt(NH₃)(NH₂C₃H₇)Cl₂ (tPt3), trans-Pt(NH₃)(NH₂C₄H₉)Cl₂ (tPt4) and trans-Pt(NH₃)(NH₂C₅H₁₁)Cl₂ (tPt5), by three nucleophiles, viz. thiourea (TU), 1-methyl-2-thiourea (MTU) and 1,3-dimethyl-2-thiourea (DMTU), was studied by stopped-flow spectrophotometry using a large excess of nucleophile. Pseudo-first-order rate constants (k_obs) were measured as a function of nucleophile concentration and temperature. Reactions were first order in both [complex] and [nucleophile] and therefore second-order overall (rate = k_obs[complex] where k_obs = k₂[nucleophile]). The kinetics are consistent with a stepwise mechanism involving rate determining substitution of the first chloride followed by a fast second substitution step, with no intermediates being detected. The reactivity of the complexes was largely dependent on the length of the alkyl chain of the alkylamine moiety of the complexes. Computational modelling using density functional theory calculations showed that an increase in chain length by a methylene unit has no direct electronic consequence on the metal centre but did, however, pose significant steric hindrance on the substitution sites due to the flexibility of the alkyl chains and thus governed the overall reaction pattern. ¹⁹⁵Pt NMR kinetic studies established that the mixed amine ligands remain coordinated to the metal centre in the final kinetic product. This implies that mononuclear trans-platinum(II) complexes are resistant to complete substitution of ligands by the incoming thiourea nucleophiles at the reaction sites. The reactions follow an associative mechanism of substitution.

Full text of DOI:10.1007/s11243-020-00381-0

Transition Metal Chemistry
https://doi.org/10.1007/s11243-020-00381-0
A kinetic investigation of mononuclear trans‑platinum(II) complexes
with mixed amine ligands
Moses Ariyo Olusegun1 · Desigan Reddy1 · Deogratius Jaganyi2,3
Received: 9 December 2019 / Accepted: 5 March 2020
© The Author(s) 2020
Abstract
This study was aimed at investigating the substitution behaviour of mononuclear trans-platinum(II) complexes with mixed
amine ligands. The rate of substitution of the chloride moieties from the complexes trans-Pt(NH3)(NH2C2H5)Cl2 (tPt2),
trans-Pt(NH3)(NH2C3H7)Cl2 (tPt3), trans-Pt(NH3)(NH2C4H9)Cl2 (tPt4) and trans-Pt(NH3)(NH2C5H11)Cl2 (tPt5), by three
nucleophiles, viz. thiourea (TU), 1-methyl-2-thiourea (MTU) and 1,3-dimethyl-2-thiourea (DMTU), was studied by stopped-
fow spectrophotometry using a large excess of nucleophile. Pseudo-frst-order rate constants (kobs) were measured as a
function of nucleophile concentration and temperature. Reactions were frst order in both [complex] and [nucleophile] and
therefore second-order overall (rate=kobs[complex] where kobs =k2[nucleophile]). The kinetics are consistent with a stepwise
mechanism involving rate determining substitution of the frst chloride followed by a fast second substitution step, with no
intermediates being detected. The reactivity of the complexes was largely dependent on the length of the alkyl chain of the
alkylamine moiety of the complexes. Computational modelling using density functional theory calculations showed that an
increase in chain length by a methylene unit has no direct electronic consequence on the metal centre but did, however, pose
signifcant steric hindrance on the substitution sites due to the fexibility of the alkyl chains and thus governed the overall
reaction pattern. 195Pt NMR kinetic studies established that the mixed amine ligands remain coordinated to the metal centre
in the fnal kinetic product. This implies that mononuclear trans-platinum(II) complexes are resistant to complete substitu-
tion of ligands by the incoming thiourea nucleophiles at the reaction sites. The reactions follow an associative mechanism
of substitution.
Introduction
among synthetic inorganic chemists to the end that some
more potent and veritably less toxic anticancer agents can
be developed [1–3]. Platinum compounds with distinctively
diferent DNA binding modes from cisplatin are some of
the prospective anticancer agents that are currently under
consideration [4, 5]. Top among those compounds are com-
plexes in which the inert or spectator amine ligands are of
trans-stereochemistry [6–8]. It has been well established
that trans-diamminedichloroplatinum(II), i.e. transplatin, a
trans isomer of cisplatin is biologically inert against cancer
cell lines. Its dearth of activity has been suggested to have
originated in part from its kinetic instability thereby making
it susceptible to deactivation. This was the genesis of the
initial thinking amongst researchers in the feld that platinum
complexes with only the cis confguration are therapeutically
useful as cytotoxic drugs. When one or both ammine ligands
in transplatin are substituted by bulky ligands, the resulting
compounds have been found to be active with an increased
toxicity [4]. It is believed that the bulky ligands might have
restricted rapid ligand substitution of the chloride ions, thus
The faws that are associated with cisplatin anticancer treat-
ment such as severe side efects, lack of selectivity, inherent
and acquired resistance, and transient retention in the blood-
stream, have stimulated a great deal of research activity
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11243-020-00381-0) contains
supplementary material, which is available to authorized users.
* Moses Ariyo Olusegun
areeyol@gmail.com
1
School of Chemistry and Physics, University of KwaZulu-
Natal, Private Bag X01, Scottsville, Pietermaritzburg 3209,
South Africa
2
School of Science, College of Science and Technology,
University of Rwanda, P. O. Box 4285, Kigali, Rwanda
3
Department of Chemistry, Faculty of Applied Sciences,
Durban University of Technology, P. O. Box 1334,
Durban 4000, South Africa
Vol.:(0123456789)
1 3

Transition Metal Chemistry
Fig. 1 Structures of the
mononuclear trans-platinum(II)
complexes with mixed amine
ligands selected for the current
study
minimising the formation of by-products between platinum
and cellular components thereby enhancing platinum inter-
action with DNA.
These ideas have inspired the design and synthesis of
novel platinum complexes with trans-stereochemistry. Far-
rell et al. [4] and Navarro-Ranninger et al. [9] have reported
classes of biologically active trans-platinum compounds that
have led to some researchers jettisoning the previously held
structure–activity relationship that only cis-platinum com-
plexes are equipped with antitumor potential. In fact, Nav-
arro-Ranninger and co-workers have reported some novel
trans-platinum(II) complexes with asymmetric aliphatic
amines which showed cytotoxic properties against some
cisplatin-resistant cell lines. These compounds exhibited
radically diferent pharmacodynamics from those already
established for cisplatin. Consequently, the exigent need to
further explore these alternative potential platinum-based
anticancer agents cannot be over-emphasised. Despite the
burgeoning interest among medicinal inorganic chemists
to develop more efective trans-platinum complexes, the
detailed mechanistic study of these compounds is still rela-
tively non-existent when compared to the level of informa-
tion available on their cis-derivatives. Moreover, the dearth
of understanding of the substitution behaviours and stability
of these compounds have impeded the design possibilities
and synthesis of new and more active platinum-based chem-
otherapeutic agents with low toxicities. A recent controversy
on the interaction of transplatin with DNA has galvanised
our interest to investigate ligand substitution kinetics of
these complexes.
1-methyl-2-thiourea (99%) and 1,3-dimethyl-2-thiourea
(99%), were all purchased from Sigma-Aldrich and were
used without further purifcations. All other chemicals used
are of the highest purity available commercially. Ultrapure
water was used in the preparations of all aqueous solutions.
General synthetic procedure for the preparation
of the mixed trans‑platinum(II) complexes
The general synthetic procedure for the mixed trans-
platinum(II) complexes has been reported by Wilson and
Lippard [4]. Cisplatin (100 mg, 0.333 mmol) was sus-
pended in water (2 mL), and 8 equivalents of the appropri-
ate alkylamine ligand were added. The resulting mixture was
heated at 90 °C until the solution became colourless. After
the solution was cooled to room temperature, it was then
treated with 37% (v/v) concentrated HCl (2.5 mL) followed
by stirring and heating at 90 °C for 48 h. The resulting yel-
low solution was placed in an iced bath to induce precipita-
tion of the appropriate trans-platinum(II) complex which
was recovered by fltration, washed intensively with water
and diethyl ether, and air-dried at room temperature.
tPt2 yield: 49 mg (45%). 1H NMR (500 MHz, DMF-d7),
δ(ppm): 1.26 (t, 3H); 2.73 (sextet 2H); 3.72 (s, 3H), 4.38 (s,
2H). 195Pt NMR (107 MHz, DMF-d7), δ(ppm): − 2165.7.
TOF MS/ES+, m/z: (M+Na)+: 350.9 (C2H8NaN2PtCl2, spe-
cies). Anal. Cal for C2H10N2PtCl2: N, 8.54; C, 7.32; H, 3.07.
Found: N, 8.50; C, 7.00; H, 2.86.
Song et al. [10] have posited that transplatin is most prob-
ably transformed to the cis-isomer under UVA irradiation.
Their speculations were hinged on the fact that transplatin,
which is generally known to be non-toxic in the dark to all
tumour cell lines, was found to be relatively of the same
toxicity level with cisplatin under UVA irradiation. How-
ever, Brabec et al. [11] quashed that notion by employing
three independent methods to show that transplatin does not
isomerize to cisplatin in the presence of UVA light. This
paper is aimed to further extend the understanding of ligand
substitution kinetics of trans-platinum(II) complexes. To this
end, trans-platinum(II) complexes of mixed amine spectator
ligands, as presented in Fig. 1, were investigated.
1
tPt3 yield: 91 mg (80%). H NMR (500 MHz, DMF-
d7), δ(ppm): 0.93 (t, 3H); 1.77 (sextet, 2H); 2.65 (quintet,
2H), 3.74 (s, 3H), 4.36 (s, 2H). 195Pt NMR (107 MHz,
DMF-d7), δ(ppm): −2163. TOF MS/ES+, m/z: (M+): 340
(C3H10N2PtCl2, species). Anal. Cal for C3H12N2PtCl2: N,
8.19; C, 10.53; H, 3.54. Found: N, 8.12; C, 10.50; H, 3.27.
tPt4 yield: 89 mg (75%). 1H NMR (500 MHz, DMF-d7),
δ(ppm): 0.92 (t, 3H); 1.37 (sextet, 2H); 1.74 (quintet, 1.74);
2.69 (quintet, 2H), 3.74 (s, 3H), 4.34 (s, 2H). 195Pt NMR
(107 MHz, DMF-d7), δ(ppm): −2163. TOF MS/ES+, m/z:
(M+Na. CH3OH)+: 413 (C5H18N2NaOPtCl2, species). Anal.
Cal for C4H14N2PtCl2: N, 7.87; C, 13.49; H, 3.96. Found: N,
7.84; C, 13.59; H, 3.91.
Experimental
Chemicals
The ligands, ethylamine (70%), propylamine (99%), buty-
lamine (99.5%), amylamine (99%), HCl (37%), cisplatin
(99.9%), lithium trifluoromethanesulfonate, methanol,
lithium chloride (99.0%), the nucleophiles: thiourea (99%),
1 3

Transition Metal Chemistry
tPt5 yield: 68 mg (55%). 1H NMR (500 MHz, DMF-d7),
δ(ppm): 0.90 (t, 3H); 1.32 (sextet, 2H); 1.76 (quintets,
2H); 2.68 (quintet, 2H), 3.73 (s, 3H), 4.34 (s, 2H). 195Pt
NMR (107 MHz, DMF-d7), δ(ppm): − 2162. TOF MS/
ES+, m/z: (M + Na. CH3OH)+: 422 (C6H20N2NaOPtCl2,
species). Anal. Cal for C5H16N2PtCl2: N, 7.57; C, 16.22;
H, 4.36. Found: N, 7.50; C, 16.35; H, 4.57.
Table 1 A summary of the DFT-calculated data for the investigated
trans-platinum(II) complexes at B3LYP/LANL2DZ level of theory
Parameters
tPt2
tPt3
tPt4
tPt5
Bond length (Å)
Pt–Cl
2.446
2.447
2.445
2.445
NBO charge
Pt
0.099
0.090
0.092
0.090
–NH2R
−0.673
−0.685
−0.688
−0.698
MO energies (eV)
HOMO
LUMO
Instrumentation
−1.86
−6.22
4.36
−1.86
−6.23
4.37
−1.86
−6.23
4.37
−1.85
−6.22
4.36
A Waters Micro-mass LCT Premier spectrometer was
used for mass determination of the trans-platinum(II)
complexes. Elemental analyses of the synthesised com-
plexes were performed on a ThermoScientific Flash
ΔE
Dipole moment (D)
0.837
0.883
1.002
1.086
R alkyl group
1
2000. H and 195Pt NMR spectroscopic analyses were
carried out on a Bruker Avance III 500 MHz. This was
also employed to monitor 195Pt-NMR of the substitution
reactions of the trans-platinum(II) complex tPt3 with
Kinetic measurements
1
thiourea (TU). All H chemical shifts were referenced
Substitution of the chloride moieties from each of the four
trans-platinum(II) complexes (Fig. 1) by three diferent
thiourea nucleophiles: thiourea (TU), 1-methyl-2-thiourea
(MTU) and 1,3-dimethyl-2-thiourea (DMTU) was inves-
tigated under pseudo-frst-order conditions with at least a
20-fold excess of the nucleophile. Spectral changes resulting
from the mixing of the complex and the nucleophile solu-
tions were observed over the wavelength range 200–800 nm
to establish an appropriate wavelength at which the kinetic
measurements could be performed on the stopped-fow spec-
trophotometer. The reactions were initiated by the mixing
of equal volumes of a solution of the metal complex with
a solution of the nucleophile directly in the stopped-fow
machine. All reported rate constants represent an average
value of at least seven independent kinetic runs for each
experimental measurement. The temperature dependence of
the rate constants was observed over a range of 20–40 °C at
an interval of 5 °C.
to Si(CH3)4, and 195Pt NMR chemical shifts were exter-
nally referenced to K2[PtCl6]. For the determination of the
coordination features at the platinum centre, 195Pt NMR
is usually employed and this has been established as an
efective technique because its chemical shifts are largely
afected, among other things, by the nature of the coordi-
nated donor atoms [12]. All kinetic measurements were
carried out on an Applied Photophysics SX.20 stopped-
fow analyser coupled to an online data acquisition system
and kinetic traces were evaluated using the Origin 9.1®
software [13]. The temperature of the instrument was kept
within 0.05 °C for all the measurements.
Computational modelling
Prefatory density functional theoretical (DFT) optimi-
sation modelling of the trans-platinum(II) complexes
tPt2–tPt4 was performed at the DFT level B3LYP [14]
with the LANL2DZ basis set [15] using the Gaussian 09
programme suite (Table 1). B3LYP relates to the hybrid
functional Becke’s three-parameter formulation, which
has been proven to be superior to classical functionals.
LANL2DZ is double-zeta basis set which comprises efec-
tive core potential (ECP) representations of electrons near
the nuclei for transition metal complexes especially for
platinum complexes [3, 16, 17]. The theoretical calcula-
tions of the complexes were performed in methanol taking
into account the efects of the solvent by employing con-
ductor polarisable continuum model (CPCM) formalism
[18]. The complexes were optimised in their neutral form,
and at singlet states because of the low electronic spin of
platinum(II) complexes.
Results and discussion
The substitution of the labile chloride ligands from each of
the platinum(II) complexes (Fig, 1) by neutral thiourea-based
nucleophiles, viz. thiourea (TU), 1-methyl-2-thiourea (MTU)
and 1,3-dimethyl-2-thiourea (DMTU) was studied under
pseudo-frst-order conditions and monitored on a stopped-fow
spectrophotometer. The ionic strength of the reacting solu-
tion was maintained using lithium trifate because the trifate
−
ion (CF3SO3 ) does not coordinate to platinum(II). Spectra
changes resulting from mixing the complexes and the nucleo-
philes were recorded at an appropriate wavelength, and a typi-
cal representative kinetic trace obtained on the stopped-fow
spectrophotometer is shown in Fig. 2. All kinetic traces for
1 3

Transition Metal Chemistry
0.18
0.15
0.12
0.09
0.06
there is not a signifcant competing pathway involving solvent
nucleophilic attack on platinum atom [19, 20]. All reactions
for the displacement of the chloride ligands from the trans-
platinum(II) complexes were investigated in the presence of
a slight excess of chloride ions (10 mM) in order to suppress
spontaneous solvolysis reactions. The proposed mechanism for
the reaction of the mononuclear trans-platinum(II) complexes
with thiourea nucleophiles is given in Scheme 1.
(
)
(
)
At = A0 + A0 − A exp t −kobs
ꢀ
t
(1)
0
40
80
120
160
kobs = k2[Nu]
(2)
Time/s
The activation parameters, enthalpy of activation, ∆H# and
entropy of activation, ∆S# were determined using the Eyring
equation (Eq. 3) by measuring the rate constants for each of
the substitution reactions of the investigated platinum(II)
complexes with thiourea nucleophiles as a function of tem-
perature is shown in Fig. 4. The activation data from the
plots are summarised in Table 2.
Fig. 2 Kinetic trace obtained on the stopped-fow spectrophotometer
for the reaction of tPt2 and 40×TU (0.06 M) monitored at 335 nm in
methanol, I=0.09 M LiCF3SO3 and 10 mM LiCl at 298 K
0.32
0.24
(
)
(
)
(
)
ΔH#
ΔS#
k2
T
ln
= −
+
23.8 +
(3)
RT
R
Comparing the second-order rate constants for the substi-
tution of the chloride moieties from the trans-platinum(II)
complexes, tPt2–tPt5 by the nucleophile TU, the reactiv-
ity trends follows: tPt2 > tPt3 > tPt4 > tPt5 with tPt2 and
tPt5 being the most and the least reactive, respectively.
A similar reactivity trend is observed for the remaining
nucleophiles, viz. MTU and DMTU as shown in Table 2.
The observed reactivity of these trans-platinum(II) com-
plexes can be rationalised in terms of electronic and steric
efects. The notable diference in the second-order rate con-
stant for the substitution of the chloride ligands from these
complexes was largely controlled by the steric efect due
to the chain length of the fexible alkyl amine ligands. The
proposed mechanism of the substitution reactions of the
trans-platinum(II) complexes with thiourea nucleophiles is
described in Scheme 1. This agrees well with previously
reported work [21]. The stepwise substitution of the chloride
ligands from the trans-platinum(II) complexes were charac-
terised by a single rate determining step and this was veri-
fed by 195Pt NMR, which has been known to be profoundly
sensitive to the nature of the binding atoms or ligands on the
platinum centre [22]. The 195Pt NMR spectra for the chloride
substitution of tPt3 by TU are presented in Fig. 5.
0.16
Tu
Mtu
Dmtu
0.08
0.00
0.00
0.03
0.06
0.09
0.12
0.15
[Nu] /M
Fig. 3 Dependence of kobs on the concentration of entering nucleo-
philes for the chloride substitution of tPt2 in methanol, I=0.09 M
LiCF3SO3 and 10 mM LiCl at 298 K
the substitution reactions gave an excellent ft to frst-order
exponential growth to generate the observed pseudo-frst-order
rate constants, kobs using Eq. 1 at all concentrations and the
temperatures. This indicates a single rate determining step was
involved in the overall substitution process. These pseudo-frst-
order rate constants were plotted against the entering nucleo-
phile concentration to elicit the second-order rate constants,
k2, from the slopes (Fig. 3) ,and it obeyed the rate expression
described in Eq. 2. The plots gave straight line fts with zero
intercepts for each of the entering nucleophiles indicating that
Scheme 1 Proposed overall
pathway for the reaction of the
trans-platinum(II) complexes
with thiourea nucleophiles
1 3

Transition Metal Chemistry
-4.50
after 24 h. The fnal peak observed for the biadduct product
at around −3200 ppm agrees very well with previous reports
in the literature for the formation of [Pt(TU)2]2+ [23, 24].
Juxtaposing the summarised second-order rate constant val-
ues presented in Table 2 with the DFT-calculated parameters
that is shown in Table 1, it can be seen that the electronic
efect favours a higher reactivity of tPt2 compared to the
rest of the trans-platinum(II) complexes (tPt3–tPt5). From
Table 1, it is obvious that the increase in the chain length
by the addition of the methylene group results in veritably
a negligible change in the HOMO–LUMO energy gap in all
the complexes. The only parameter which increases mod-
erately as the chain length of the alkyl group increases by
the addition of the methylene unit is the dipole moment.
The dipole moment is a measure of the charge separation
within a molecule [25], and hence, an increase in the dipole
moment is expected with the addition of the methylene unit
in the alkyl chain length because the parameter correlates to
the inductive negative charge in the complexes.
-5.25
-6.00
-6.75
TU
MTU
-7.50
DMTU
0.00320 0.00325 0.00330 0.00335 0.00340 0.00345
T-1 /K-1
Fig. 4 Eyring plots for the determination of activation enthalpies and
entropies for the reaction of tPt2 with TU, MTU and DMTU
The initial peak of the pure tPt3 was at −2169 ppm and
the fnal peak of the biadduct trans-Pt(II) product formed
from the simultaneous substitution of the two chloride
ligands by thiourea (TU) was obtained at −3256 ppm within
twenty minutes of the reaction and remain at the same point
There is increase in the inductive negative charge result-
ing from the increasing chain length of the alkyl group.
This fact is underpinned by the successive increase in the
DFT-calculated NBO charge on the nitrogen atom of the
Table 2 Second-order rate
constants and activation
Complex
tPt2
Nucleophile
k2 ×10−2/M−1 s−1
∆H#/kJ mol−1
∆S#/J K−1 mol−1
parameters for the reactions of
mononuclear trans-platinum(II)
complexes with thiourea-
based nucleophiles in 0.09 M
LiCF3SO3 and 10 mM LiCl
methanolic solution
TU
110
68
39
1
1
1
58
56
58
55
57
43
53
55
62
65
68
63
2
1
2
3
1
2
1
4
1
2
1
2
−73
−65
−118
−64
−58
−108
−128
8
4
4
9
2
8
3
MTU
DMTU
TU
MTU
DMTU
TU
MTU
DMTU
TU
MTU
DMTU
tPt3
tPt4
tPt5
83 0.4
71 0.3
35
81
1
1
60 0.3
33 0.1
−126 13
−105
−91
−82
2
6
3
6
64
1
51 0.3
29 0.2
−104
t = 20 mins
t = 0 mins
Fig. 5 195Pt NMR spectra of the reaction mixture of tPt3 with six mole equivalents of TU, showing pure tPt3 (δ=−2169 ppm) before the reac-
tion, and the fnal stable biadduct product (δ=−3256 ppm) ascribed to [trans-Pt (NH3){NH2(CH2)2CH3}(TU)2]2+
1 3

Transition Metal Chemistry
alkylamine ligand in the complexes. However, the inductive
negative charge of the alkylamine ligand has very little or
no infuence on the platinum centre particularly as the chain
length increases from three to fve carbon atoms. With the
exception of tPt2, the DFT-calculated NBO charge of the
platinum centres for the remaining complexes is relatively
the same. Complex tPt2 is more electrophilic than the other
trans-platinum(II) complexes and this is refected by its
greater reactivity compared to the other complexes.
of the frst chloride ligand. The overall reaction pattern was
largely dominated by steric efects. An increase in chain
length of the alkylamine group by the addition of the meth-
ylene unit has veritably no signifcant infuence on the elec-
tronic properties of these complexes. Besides tPt2 whose
substitution reaction was driven by the electronic factor, the
rest of the trans-platinum(II) complexes, tPt3, tPt4 and tPt5
were nearly the same electronically, and hence, the notable
diference in their reactivity was largely due to the tendency
of the increasing carbon chain length of the alkylamine
group in the complexes that interferes with the reaction site
thereby shielding the entering nucleophiles from directly
attacking the platinum centre for the substitution of the chlo-
ride ligands. All the studied complexes followed an associa-
tive mode of activation as indicated by the large negative
activation entropy values.
However, the diference in reactivity of the complexes
tPt3–tPt5 cannot be ascribed to the electronic effects
because there are very small diferences in the electronic
properties of these complexes. Based on the electronic data
from the DFT-calculations the second-order rate constant
values for these complexes should have been relatively
the same. It is reasonable to conclude that the electronic
efect due to the increase in the chain length of the fexible
alkylamine ligand bears small infuence on the reactivity of
the trans-platinum(II) complexes with mixed amine ligands
[26]. However, the increasing chain length of the fexible
alkylamine ligand creates steric interruption at the reac-
tion sites resulting in the observed diference in the reactiv-
ity between the three other complexes tPt3, tPt4 and tPt5.
The tendency for steric interference at the platinum centre
increases as the chain length increases from three to fve
carbon atoms thereby causing a notable decrease in the sub-
stitution of the chloride ligands by the thiourea nucleophiles.
The chain length in the complexes only blocks the approach
of the entering nucleophiles to the substitution site, i.e. the
platinum centre [26].
Acknowledgements The authors gratefully acknowledge the support
from the University of KwaZulu Natal. We are also grateful to Mr.
Craig Grimmer for NMR analyses and Mrs. Caryl Janse van Rensburg
for mass and elemental analyses.
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The reactivity of the nucleophiles follows the trend:
TU > MTU > DMTU for all the trans-platinum(II) com-
plexes, and this is consistent with the order of increasing
steric hindrance due to the sizes of these nucleophiles. All
available activation parameters, ∆H# and ∆S#, presented in
Table 2 support the operation of an associative mechanism
[27, 28]. In general, the substitution of reactions of square-
planar platinum(II) complexes regardless of their stereo-
chemistry proceed according to an associative mechanism
[29–33]. The remarkably negative values of entropy of acti-
vation and moderately positive values of enthalpy of activa-
tion presuppose that the activation process in the investi-
gated trans-platinum(II) complexes is profoundly dominated
by bond making [34].
References
1. Komeda S, Yoneyama H, Uemura M, Muramatsu A, Okamoto N,
Konishi H, Takahashi H, Takagi A, Fukuda W, Imanaka T (2017)
Inorg Chem 56:802–811
2. Aztopal N, Karakas D, Cevatemre B, Ari F, Icsel C, Daidone MG,
Ulukaya E (2017) Bioorg Med Chem 25:269–276
3. Asman WP, Jaganyi D (2017) Int J Chem Kinet 49:545–561
4. Wilson JJ, Lippard SJ (2013) Chem Rev 114:4470–4495
5. Chua EY, Davey GE, Chin CF, Dröge P, Ang WH, Davey CA
(2015) Nucleic Acids Res 43:5284–5296
6. Du Z, Luo Q, Yang L, Bing T, Li X, Guo W, Wu K, Zhao Y, Xiong
S, Shangguan D (2014) J Am Chem Soc 136:2948–2951
7. Herrera JM, Mendes F, Gama S, Santos I, Navarro-Ranninger C,
Cabrera S, Quiroga AG (2014) Inorg Chem 53:12627–12634
8. Navas F, Mendes F, Santos I, Navarro-Ranninger C, Cabrera S,
Quiroga AG (2017) Inorg Chem 56:6175–6183
Conclusion
9. Montero EI, Díaz S, González-Vadillo AM, Pérez JM, Alonso C,
Navarro-Ranninger C (1999) J Med Chem 42:42–4268
10. Song H, Li W, Qi R, Yan L, Jing X, Zheng M, Xiao H (2015)
Chem Commun 51:11493–11495
This study has demonstrated the kinetic behaviour and
mechanistic data for the substitution reactions of mononu-
clear trans-platinum(II) complexes with asymmetric(mixed)
amine ligands. The reaction of these complexes with the
nucleophiles proceeds via a rate determining substitution
11. Brabec V, Vrana O, Novakova O, Kasparkova J (2016) Chem
Commun 52:4096–4098
1 3

Transition Metal Chemistry
12. Hofmann A, Dahlenburg L, van Eldik R (2003) Inorg Chem
42:6528–6538
25. Atkins P, de Paula J (2009) Elements of physical chemistry, 5th
edn. Oxford University Press, Great Britain
13. Seifert E (2014) OriginPro 9.1: scientifc data analysis and graph-
ing software: software review. ACS Publications, Washington,
D.C.
26. Mambanda A, Jaganyi D, Hochreuther S, van Eldik R (2010) Dal-
ton Trans 39:3595–3608
27. Asman PW (2017) J Coord Chem 2:1–20
14. Becke AD (1992) Journal of Chemical Physics 96:2155–2160
15. Hay PJ, Wadt WR (1985) J Chem Phys 82:299–310
16. Kinunda G, Jaganyi D (2016) Trans Met Chem 41:235–248
17. Papo TR, Jaganyi D (2015) Trans Met Chem 40:53–60
18. Cossi M, Rega N, Scalmani G, Barone V (2003) J Comput Chem
24:669–681
28. Asman PW (2018) Inorg Chim Acta 469:341–352
29. Jaganyi D, Hofmann A, van Eldik R (2001) Angew Chem Int Ed
40:1680–1683
30. Jaganyi D, Reddy D, Gertenbach J, Hofmann A, van Eldik R
(2004) Dalton Trans 2:299–304
31. Jaganyi D, Tiba F, Munro OQ, Petrović B, Bugarčić ZD (2006)
Dalton Trans 24:2943–2949
19. Bugarčić ZD, Nandibewoor ST, Hamza MS, Heinemann F, van
Eldik R (2006) Dalton Trans 24:2984–2990
32. Ongoma P, Jaganyi D (2012) Dalton Trans 41:10724–10730
33. Wekesa IM, Jaganyi D (2014) Dalton Trans 43:2549–2558
34. Hochreuther S, Nandibewoor ST, Puchta R, van Eldik R (2012)
Dalton Trans 41:512–522
20. Ertürk H, Puchta R, van Eldik R (2009) Eur J Inorg Chem
10:1331–1338
21. Belluco U, Cattalini L, Basolo F, Pearson RG, Turco A (1965)
JACS 87:241–246
22. Priquele JR, Butler IS, Rochon FD (2006) Appl Spectrosc Rev
41:185–226
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional afliations.
23. Norman RE, Ranford JD, Sadler PJ (1992) Inorg Chem
31:877–888
24. Ongoma PO, Jaganyi D (2014) Trans Met Chem 39:407–420
1 3