A kinetic and mechanistic study of analogous bifunctional dialkylamine platinum(ii) complexes

Article abstract of DOI:10.1039/d0nj00108b

This study was aimed at investigating the comparative substitution behaviour of analogous cis/trans-Pt(ii) complexes with inert dialkylamine ligands. The rate of substitution of the aqua ligands by three nucleophiles, viz. thiourea (TU), 1,3-dimethylthiourea (DMTU) and 1,1,3,3-tetramethylthiourea (TMTU), for the complexes: [cis-Pt(OH₂)₂(NH₃)₂](ClO₄)₂ (cPt), [cis-Pt(OH₂)₂(NH₂CH₃)₂](ClO₄)₂ (cPtM), [cis-Pt(OH₂)₂{NH₂CH(CH₃)₂}₂](ClO₄)₂ (cPtR), [trans-Pt(OH₂)₂(NH₃)₂](ClO₄)₂ (tPt), [trans-Pt(OH₂)₂(NH₂CH₃)₂](ClO₄)₂ (tPtM) and [trans-Pt(OH₂)₂{NH₂CH(CH₃)₂}₂](ClO₄)₂ (tPtR) was investigated under pseudo first-order conditions as a function of concentration and temperature by stopped-flow and UV/visible spectrophotometry. The reactions of the cis-complexes proceed in two concerted steps whereas those of the trans-complexes followed a stepwise mechanism involving rate determining substitution of the first chloride followed by a fast second substitution step, with no intermediates being detected. The pseudo first-order rate constants, k_obs obeyed the rate law: k_obs = k₂[nucleophile]. The trans-complexes were observed to be approximately 10³ times more reactive than their corresponding cis-analogues. The electronic and the steric hindrance due to the geometries of the complexes controlled the overall reaction pattern. The order of reactivity of the complexes is tPt > tPtM > tPtR > cPt > cPtM > cPtR. The reactivity of the nucleophiles with the complexes decreases with an increase in steric demand in the order: TU > DMTU > TMTU. The trans-dialkylamine complexes formed distinctly different kinetic products relative to their cis-analogues. ¹⁹⁵Pt NMR spectroscopic results confirmed the final kinetic products of each of the cis- and trans-complexes. The negative entropy of activation (ΔS^≠) values in all the complexes investigated assert an associative substitution mechanism, with the mechanism being more pronounced in the cis-complexes than in their trans-analogues.

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A kinetic and mechanistic study of analogous
bifunctional dialkylamine platinum(II) complexes†
Cite this:DOI: 10.1039/d0nj00108b
Moses Ariyo Olusegun, *a Desigan Reddya and Deogratius Jaganyibc
This study was aimed at investigating the comparative substitution behaviour of analogous cis/trans-Pt(II)
complexes with inert dialkylamine ligands. The rate of substitution of the aqua ligands by three nucleophiles,
viz. thiourea (TU), 1,3-dimethylthiourea (DMTU) and 1,1,3,3-tetramethylthiourea (TMTU), for the complexes:
[cis-Pt(OH2)2(NH3)2](ClO4)2 (cPt), [cis-Pt(OH2)2(NH2CH3)2](ClO4)2 (cPtM), [cis-Pt(OH2)2{NH2CH(CH3)2}2](ClO4)2
(cPtR), [trans-Pt(OH2)2(NH3)2](ClO4)2 (tPt), [trans-Pt(OH2)2(NH2CH3)2](ClO4)2 (tPtM) and [trans-Pt(OH2)2{NH2-
CH(CH3)2}2](ClO4)2 (tPtR) was investigated under pseudo first-order conditions as a function of concentration
and temperature by stopped-flow and UV/visible spectrophotometry. The reactions of the cis-complexes
proceed in two concerted steps whereas those of the trans-complexes followed a stepwise mechanism
involving rate determining substitution of the first chloride followed by a fast second substitution step, with no
intermediates being detected. The pseudo first-order rate constants, kobs obeyed the rate law: kobs
=
k2[nucleophile]. The trans-complexes were observed to be approximately 103 times more reactive than their
corresponding cis-analogues. The electronic and the steric hindrance due to the geometries of the complexes
controlled the overall reaction pattern. The order of reactivity of the complexes is tPt 4 tPtM 4 tPtR 4
cPt 4 cPtM 4 cPtR. The reactivity of the nucleophiles with the complexes decreases with an increase in
steric demand in the order: TU 4 DMTU 4 TMTU. The trans-dialkylamine complexes formed distinctly
different kinetic products relative to their cis-analogues. 195Pt NMR spectroscopic results confirmed the
Received 9th January 2020,
Accepted 7th March 2020
final kinetic products of each of the cis- and trans-complexes. The negative entropy of activation (DSa
)
DOI: 10.1039/d0nj00108b
values in all the complexes investigated assert an associative substitution mechanism, with the mechanism
rsc.li/njc
being more pronounced in the cis-complexes than in their trans-analogues.
monodentate amine ligands. Farrell et al. have reported that some
trans-complexes with general formula [PtCl2L2] showed significant
Introduction
The fortuitous revelation of cis-diamminedichloroplatinum(II), cytotoxities when L is a planar heterocyclic ligand such as pyridine
cisplatin, as an anticancer agent has galvanised interest in or thiazole.3 Similarly, Navarro-Ranninger et al. have reported a
medicinal inorganic chemistry research in the last five decades new class of biologically active trans-platinum(II) complexes with
with many more platinum-based chemotherapeutics being asymmetric aliphatic amines, trans-[PtCl2(L)(L0)].8 These discoveries
developed.1,2 The finding ab initio, that the trans-isomer of cisplatin have revolutionised the development of new platinum-based anti-
lacked any biological activity influenced the early structure–activity cancer agents because these trans-platinum compounds exhibited
relationships that a cis geometry of the two leaving groups is crucial significantly high cytotoxicity, both in vitro and in vivo, against
for the biological activity of platinum-based anticancer agents.2–7 cisplatin resistant tumour cell lines. Hence, their pharmaco-
Consequently, all trans-platinum complexes were presumably dynamics may be much more complex and completely different
thought to be impotent as antitumour drugs.
relative to that already established for cis configured platinum(II)
It has been suggested that the cytotoxic potential of trans- complexes.7 Efforts to further understand the mechanism
platinum complexes could be greatly enhanced by bulky spectator of action of cis-configured platinum(II) complexes have been
ubiquitous. Moreover, the kinetic and mechanistic study of
a School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X01,
Scottsville, Pietermaritzburg, 3209, South Africa. E-mail: areeyol@gmail.com
b School of Science, College of Science and Technology, University of Rwanda,
P. O. Box 4285, Kigali, Rwanda
substitution of platinum(II) complexes with cis configurations has
been well established. Both Jaganyi et al.9–12 and van Eldik et al.13
have reported that the substitution behaviours of platinum(II)
complexes of cis configuration with thiourea-based nucleophiles
undergo dechelation to give two or more thiourea-substituted
platinum(II) complexes in a two or more-steps process. Nonetheless,
the substitution kinetics and mechanism of platinum(II) complexes
c Department of Chemistry, Faculty of Applied Sciences, Durban University of
Technology, P. O. Box 1334, Durban, 4000, South Africa
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0nj00108b
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Sigma-Aldrich. All preparations of aqueous solutions were done
using ultrapure water.
Synthesis of complexes
The chlorido complexes cis-[Pt(ma)2Cl2] (cPtM) and cis-[Pt(ipram)2-
Cl2] (cPtR) were synthesised according to literature procedures
reported by Messori et al.2 and Pantoja et al.16 with slight modifica-
tions. K2PtCl4 (500 mg, 1.2 mmol) was dissolved in water (5 mL)
and treated with KI (1 g, 6 mmol) at room temperature to produce a
dark brown solution of K2PtI4 after 15 minutes of stirring.
The iodo derivative of cis-[Pt(ma)2Cl2] (cPtM) was first prepared
by slowing adding four equivalents of methylamine hydrochloride
(4.8 mmol) to the dark brown solution of K2PtI4. The mixture was
subsequently treated with four equivalents of KOH (269 mg,
4.8 mmol) in the dark at room temperature. After the addition
was completed, the reaction mixture was stirred in the dark
at room temperature for five hours to give a yellow precipitate,
cis-[Pt(ma)2I2]. The precipitate was obtained by filtration, washed
thoroughly with warm water, diethyl ether and air dried.
Fig. 1 Structures of the studied cis-platinum(II) complexes and their
trans-analogues. The counterions on the complexes have been omitted
for the sake of clarity.
in which the chloride/aqua leaving groups are trans to each other
on the platinum centre is still relatively unknown.
To prepare the iodo derivative of cis-[Pt(ipram)2Cl2] (cPtR),
four equivalents of isopropyl amine (4.80 mmol) was added
slowly to the dark brown solution of K2PtI4. The resulting
mixture was stirred for five hours at room temperature to produce
a yellow precipitate, cis-[Pt(ipram)2I2], which was filtered, washed
intensively with warm water, diethyl ether and allowed to dry by air.
The iodo complexes were converted to their chlorido analogues
by suspending the iodo complexes, viz. cis-[Pt(ma)2I2] (441 mg,
0.864 mmol)/cis-[Pt(ipram)2I2] (585 mg, 1.03 mmol), in 10 mL of
water and treated with 1.9 equivalent AgClO4. The mixture was
stirred overnight in the dark. A yellow precipitate of AgI was
removed by filtration through a 0.45 mm nylon membrane and to
the filtrate, four equivalents of KCl was added and stirred at
40 1C for six hours. The resulting precipitate was left overnight at
4 1C. The yellow solids, cis-[Pt(ma)2Cl2] and cis-[Pt(ipram)2Cl2]
respectively, were filtered, washed with water and air dried.
(cPtM) yield. 85 mg (30%). 1H NMR (500 MHz, DMSO-d6),
d(ppm): 2.26 (t, 6H); 4.88 (s, 4H). 195Pt NMR (107 MHz, DMSO-d6),
d(ppm): ꢁ2214.4. TOF MS/ES+ (Accurate mass), m/z: (M + Na)+:
350.97 (C2H10N2NaPtCl2, species). Anal. calc. for C2H10N2PtCl2:
N, 8.54; C, 7.32; H, 3.07. Found: N, 8.60; C, 6.99; H, 2.76.
Song et al.14 recently reported that there is a possibility of
transformation of transplatin to cisplatin under UVA irradiation.
Their findings are based on the fact that transplatin, which was
observed to be veritably non-toxic in the dark to all cell lines, was
observed to be of comparable toxicity with cisplatin under UVA
irradiation. The authors attribute this observation, among other
things, to the transformation of transplatin to cisplatin under
UVA light. However, Brabec and co-workers15 have demonstrated
through NMR spectroscopy that the loss of chloride ligands in
transplatin upon irradiation resulted in the formation of bifunc-
tional adducts and subsequently led to the remarkable increase
of its toxicity level in cancer cells. They debunked the claim that
transplatin is transformed to cisplatin under UVA irradiation by
using three independent methods after which they concluded
that transplatin upon UVA irradiation does not rearrange to its
cis isomer.
In order to further the understanding of the mechanistic
behaviours of these platinum(II) complexes, analogous cis and trans-
dialkylamine dichloroplatinum(II) complexes of the general form,
[PtX2L2], were investigated (Fig. 1). Our central aim is to ascertain
how bifunctional trans-platinum(II) complexes will substitute kineti-
cally relative to their cis isomers by using biorelevant thiourea-based
nucleophiles such as, thiourea (TU), 1,3-dimethyl-2-thiourea (DMTU)
and 1,1,3,3-tetramethyl-2-thiourea (TMTU).
1
(cPtR) yield. 296 mg (75%). H NMR (500 MHz, DMSO-d6),
d(ppm): 1.22 (d, 12H); 3.11 (sept., 2H); 4.75 (s, 4H). 195Pt NMR
(107 MHz, DMSO-d6), d(ppm): ꢁ2218.5. TOF MS/ES+ (Accurate
mass), m/z: (M + Na)+: 407.03 (C6H18N2NaPtCl2, species). Anal.
calc. for C6H18N2PtCl2: N, 7.29; C, 18.76; H, 4.72. Found:
N, 7.50; C, 18.54; H, 4.45.
trans-[Pt(ma)2Cl2] was obtained following the synthetic pro-
cedure outlined by Messori et al.2 with a few modifications.
A suspension of cis-[Pt(ma)2I2] (220 mg, 0.432 mmol) in water
Experimental
Chemicals and reagents
Methylamine hydrochloride (ma), isopropylamine (ipram) (99.5%), was treated with 5 equivalents of methylamine hydrochloride
K2PtCl4 (98%), cis-[Pt(NH3)2Cl2] (99.9%), trans-[Pt(NH3)2Cl2], KOH, (2.16 mmol). The resulting mixture was stirred at room tem-
AgClO4 (97%), NaClO4ꢀH2O (98%), HCl (32%) and HClO4 (70%) perature for 12 hours to give a colourless solution. The result-
were purchased from Sigma-Aldrich and were used without further ing solution was concentrated at 70 1C until a bright orange
purification. The nucleophiles: thiourea (TU, 99%), 1,3-dimethyl-2- precipitate was detected and then left to stand overnight at
thiourea (DMTU, 99%) and 1,1,3,3-tetramethyl-2-thiourea (TMTU, 4 1C. The orange solid, trans-[Pt(ma)2I2] was filtered, washed
98%) used for the kinetic determinations were also obtained from with warm water and air dried.
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trans-[Pt(ma)2I2] (177 mg, 0.346 mmol) was suspended in Preparation of platinum(II) aqua complexes and determination
10 mL of water and treated with 1.9 equivalents AgClO4. The of their pKa values
mixture was stirred overnight in the dark. AgI was removed by
filtration through a 0.45 mm nylon membrane and to the filtrate, a
The aqueous solutions of the complexes cPt, tPt, cPtM, tPtM,
cPtR and tPtR were prepared according to literature.9,11
A
four equivalent of KCl was added and stirred at 40 1C for six hours
to give a yellow precipitate of trans-[Pt(ma)2Cl2]. The solution was
left to stand overnight at 4 1C. The product was filtered, washed
thoroughly with warm water and air dried.
suitable amount of AgClO4 was added to each of the corres-
ponding chloro complexes at a molar ratio of 1 : 1.98. Both the
chloro complex and the AgClO4 were dissolved in 0.01 M HClO4
and the mixture was vigorously stirred in the dark at 45 1C for
24 hours. The AgCl precipitate obtained was filtered off through
a 0.45 mm nylon membrane. The filtrate was diluted to 300 mL
with 0.01 M HClO4.
Spectrophotometric pH titrations were performed using
NaOH as a base in the pH range of 2–10 at 25 1C. To avoid
absorbance corrections resulting from dilution, a large amount
(300 mL) of the complexes were used for the titrations. Adjust-
ments in pH were made by a stepwise addition of crushed
NaOH pellets in the pH range 1–3, while a Pasteur pipette was
used for dropwise additions of NaOH solutions of different
concentrations (1.0, 0.5, 0.1 and 0.01 M) or same concentra-
tions of HClO4 acid (for reversibility of the pH) were added to
the solution in the pH range of 4–10 until the desired pH was
attained prior to withdrawal of a 1.0 mL aliquot from the
solution for pH measurement and 2.0 mL aliquots for spectro-
photometric monitoring. The 1.0 mL aliquot after each pH
measurement was discarded to avoid in situ contamination of
the complex solution by chloride ions leaching from the pH
electrode.
1
(tPtM) yield. 12.8 mg (9%). H NMR (500 MHz, DMSO-d6),
d(ppm): 2.33 (t, 6H); 4.24 (s, 4H). 195Pt NMR (107 MHz, DMSO-d6),
d(ppm): ꢁ2195. TOF MS/ES+, m/z: (M + Na)+: 350.96 (C2H10N2-
NaPtCl2, species). Anal. calc. for C2H10N2PtCl2: N, 8.54; C, 7.32; H,
3.07. Found: N, 8.61; C, 6.97; H, 2.60.
The trans-[Pt(ipram)2Cl2] was synthesised following the
method reported by Navarro-Ranninger et al.17 To a suspension
of cis-[Pt(ipram)2Cl2] (200 mg, 0.521 mmol), 4 equivalents of
isopropylamine was added. The resulting mixture was heated at
70 1C and stirred until a colourless solution was obtained which
was then heated at reflux for 30 minutes. The solution was left
to cool to room temperature and concentrated HCl (0.364 mL)
acid was added and subsequently heated at reflux for 8 hours.
The yellow solution obtained was cooled in an ice bath and left
to stand at 4 1C overnight. The product was obtained by
filtration and thoroughly washed with water and dried in air.
(tPtR) yield. 80 mg (40%). 1H NMR (500 MHz, DMSO-d6),
d(ppm): 1.19 (d, 12H); 3.03 (sept., 2H); 4.20 (s, 4H). 195Pt NMR
(107 MHz, DMSO-d6), d(ppm): ꢁ2205. TOF MS/ES+, m/z: (M + Na)+:
407 (C6H18N2PtCl2, species). Anal. calc. for C6H18N2PtCl2: N, 7.29;
C, 18.76; H, 4.72. Found: N, 7.53; C, 18.51; H, 4.36.
Computational estimations
Density functional theoretical (DFT) estimations of the com-
plexes cPt, tPt, cPtM, tPtM, cPtR and tPtR were performed at
the DFT level B3LYP19 with the LANL2DZ basis set20 using the
Gaussian ’09 programme suite. B3LYP relates to the hybrid
functional Becke’s three-parameter formulation, which has
been proven to be superior to conventional functionals.
LANL2DZ is double-zeta basis set containing effective core
potential (ECP) representations of electrons near the nuclei
for transition metal complexes.21 The theoretical calculations
of the complexes were executed in water taking into account the
effects of the solvent by employing conductor polarisable con-
tinuum model (CPCM) formalism.22,23 The complexes were
optimized in their aqua form as cations of +2 charge, and the
singlet states were used because of low electronic spin of
platinum(II) complexes.
Instrumentation and physical measurements
1H, 13C and 195Pt NMR spectroscopic analyses were carried out
on a Bruker Avance III 500 MHz. All 1H and 13C NMR chemical
shifts were referenced to Si(CH3)4 while 195Pt NMR chemical
shifts were externally referenced to K2[PtCl6]. 195Pt NMR has
been established as an effective method for the determination
of the coordination details at the metal centre since its
chemical shifts are largely influenced, among other things, by
the nature of the coordinated donor atoms.18 A Waters Micro-
mass LCT Premier spectrometer was employed for mass deter-
mination of the complexes. Elemental analyses of synthesised
complexes were recorded on a Thermo Scientific Flash 2000.
The pH of the aqueous solutions of the complexes was recorded
using a Jenway 4330 Conductivity/pH meter fitted with a Micro
4.5 diameter glass electrode which was calibrated at 25 1C using
buffer solutions of pH 4.0, 7.0 and 10.0 purchased from Merck.
A Varian Cary 100 Bio UV/visible spectrophotometer thermo-
statted by a Varian Peltier temperature controller was used to
obtain the UV/visible absorption spectra for the determination
Results and discussion
pKa determination of the diaqua complexes
of pKa values and kinetic studies of slow reactions. Kinetic To obtain information on the acidity of the coordinated water
measurements of moderately fast reactions were monitored on moeities and the reactivity of all the aqua complexes, their pKa
an Applied Photophysics SX20 stopped-flow analyser coupled to values were determined. To this end, a spectrophotometric pH
an online data acquisition system. The temperature of the titration with NaOH as a base in the pH range 2–10 was carried
instrument was kept within ꢂ0.05 1C for all the measurements. out. The pH dependence of the aqua complex was observed by
Analyses of the pH and time-dependent kinetic spectral data UV/visible spectrophotometry. The pKa values of the coordinated
were performed using the Origin 9.1s software suite.
aqua ligands were obtained by plotting the absorbance at a
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involving analogous cis- and trans-complexes using NMR spectro-
scopy.25,26 Since pKa values are associated with the electrophilicity
of the metal centre,27 it can be inferred, therefore, that the geometry
of the complexes bears significant influence on the electrophilicity
of the metal centre in the investigated complexes. The DFT-
calculated NBO charges for the corresponding cis/trans-analogues
in Table 2 underpin the observed experimental data.
All the trans-configured platinum(II) complexes have a
slightly lower charge on the platinum centre as compared to
each of their corresponding cis isomers. The difference in NBO
charge on the platinum centre between analogous cis/trans-
platinum(II) complexes can be attributed to the remarkable
difference in charge distribution as expressed as the dipole
moment between the two configurations.28,29 The cis-configu-
ration enhances charge separation within a molecule compared
to the trans-configuration. Hence, whereas the charge separa-
tion in the trans-platinum(II) complexes are negligible, those of
their analogues cis-platinum(II) complexes are quite significant.
Fig. 2 UV/visible spectra of the diaqua tPtR complex recorded as a
function of pH in the range 2–10 at 25 1C. Inset: Titration curve at 230 nm.
specific wavelength as a function of pH. The typical spectral Furthermore, the dipole moment is expectedly the same, and
changes recorded during the pH titration with NaOH are pre- veritably zero, for all the trans-complexes. There is, however, a
sented in Fig. 2 for the trans-aqua complexes tPtR. The overall significant increase in the dipole moments in all the cis-com-
process can be presented by Scheme 1.
plexes as the steric bulk of the amine spectator ligands
The spectral data was analysed using Origin 9.1s24 to obtain increases from ammine to isopropylamine. This can be
the resulting pKa values for the aqua moieties by fitting the data ascribed to the increase in the inductive negative charge in
to a double sigmoidal function which gave the best statistical fit the cis-complexes resulting from the increase in the sigma
and afforded two pKa values which are indicative of the fact that donor abilities of the amine moieties.30,31
there are three coloured species for each of the aqua complexes
Additionally, contrary to what was previously reported by
present in solution as a function of pH. The data obtained for Cubo et al.,26 the nature of the aliphatic amine moieties has a
the deprotonation of the aqua moieties from the complexes are significant effect on the pKa values of all the studied complexes.
summarised in Table 1.
For instance, in the trans-complexes, the pKa value of transpla-
A closer inspection of the data in Table 1 shows that the pKa1 tin, tPt, is 0.32 and 1.68 pH units lower than that of tPtM and
and pKa2 values for the deprotonation of the first and second tPtR respectively. This is corroborated by the remarkable dif-
coordinated water molecules for all the trans-complexes are ference in the DFT-calculated NBO charges on the platinum
significantly lower than those of their corresponding cis- centres with tPt being more electrophilic than the other two
analogues. The trans-aqua complexes are clearly more acidic trans-complexes having bulkier amine ligands. Similarly, this
than their corresponding cis-counterparts. The deprotonation trend is also observed in the cis-complexes. Cisplatin, cPt is 0.41
of the first coordinated water ligand increases in the order tPt and 1.62 pH units lower than the bulkier cis-complexes, cPtM
(pKa1 4.24) o tPtM (pKa1 4.56) o cPt (pKa1 4.99) o cPtM (pKa1 and cPtR respectively. This phenomenon is quite consistent
5.40) o tPtR (pKa1 5.92) o cPtR (pKa1 6.61). A similar trend is with the electrophilicity of the platinum centres based on their
observed for the deprotonation of the second aqua molecule, NBO charges.
albeit at higher pH values relative to the first. The higher acidity
The pKa values of the second aqua ligands are higher than
of the trans complexes as compared to the analogous cis the first one i.e. pKa1 o pKa2. This has been previously
complexes has been previously reported in a related study observed1,9,25–27,32,35 and has been attributed to the general
Scheme 1 Proposed stepwise deprotonation for the pH dependence of the trans-platinum(II) complexes.
Table 1 Summary of pKa values for the deprotonation steps of aqua moieties from the analogous cis- and trans-platinum(II) complexes
cPt
tPt
cPtM
tPtM
cPtR
tPtR
pKa1
pKa2
4.99 ꢂ 0.01
7.26 ꢂ 0.01
4.24 ꢂ 0.05
6.91 ꢂ 0.04
5.40 ꢂ 0.29
7.52 ꢂ 0.12
4.56 ꢂ 0.06
7.05 ꢂ 0.03
6.61 ꢂ 0.62
7.62 ꢂ 0.12
5.92 ꢂ 0.07
7.28 ꢂ 0.16
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Table 2 A summary of the DFT calculated data for the investigated
analogous cis- and trans-platinum(II) complexes at B3LYP/LANL2DZ level
of theory
steps whereas those of the trans-platinum(II) followed a stepwise
mechanism involving a rate determining substitution of the first
chloride followed by a fast second substitution step, with no
detection of any intermediates. First rate determining step involves
a veritably simultaneous substitution of the two chloride ligands in
the cis-platinum(II) complexes, which is consistent with previously
reported work by Kinunda and Jaganyi,32 followed by the second
rate determining step involving the removal of the two amine
ligands resulting from the strong labilising trans effect of the first
coordinated thiourea-based nucleophiles to give a complete sub-
stitution at the platinum centre, which is in agreement with
previously reported studies involving cis-configured platinum(II)
complexes.31–34 The stepwise substitution of the two chloride
ligands in the trans-platinum(II) complexes is consistent with those
reported by Belluco et al.35 All the reaction steps in both the cis- and
the trans-platinum(II) complexes showed a clear dependence on the
concentration of the nucleophile. Kinetic traces for the cis-platinu-
m(II) complexes all gave an excellent fit to a double exponential
function which is indicative of two rate determining steps whereas
those of the trans-platinum(II) complexes fitted perfectly to a single
exponential, typical for reactions involving only a rate determining
step. The so-obtained pseudo-first-order rate constants, kobs1
and kobs2 for the cis-complexes and kobs for the trans-complexes,
computed from the kinetic traces were plotted against the concen-
tration of the entering nucleophiles (Fig. 3). A linear dependence,
without any intercept, on the nucleophile concentration was
observed for all the studied reactions. The linear fits pass through
the origin which is indicating that there is not a significant
competing pathway involving solvent nucleophilic attack on
platinum centre.36–38 The dependence of the observed pseudo-
first-order rate constants on the concentration of the entering
nucleophile obeyed the rate law presented in eqn (1), where k2
represent the second-order rate constants for the substitution
reactions of the analogous cis- and trans-dialkylamine platinum(II)
complexes.
Parameters
cPt
tPt
cPtM tPtM cPtR tPtR
Bond length/distance (Å)
cis/trans-Pt–OH2 2.106
2.058 2.116 2.063 2.120 2.066
2.575 2.535 2.984 2.455 3.116
3.460 3.415 3.446 3.435 3.465
a
b
2.482
3.458
NBO charge
Pt2+
Dipole moment 0.425
0.774
0.808 0.754 0.791 0.736 0.758
0.002 2.420 0.002 6.404 0.002
reduction in the overall charge from +2 to +1 on the platinum
centre resulting from the formation of the first hydroxo species.
Another reason posited for this observation is the possibility of
hydrogen bonding between the aqua/hydroxo groups resulting
from the first deprotonation step. However, this possibility is
much more prominent in the cis-configured complexes com-
pared to their trans-counterparts because of the proximity of the
aqua/hydroxo groups in the cis-complexes due to their geometry.
Kinetic analysis
The kinetics of the substitution of the coordinated water
ligands in the analogous cis- and trans-dialkylamine platinum(II)
complexes were investigated spectrophotometrically by monitoring
the changes in absorbance at suitable wavelengths as a function of
time at 298 K. The proposed reaction pathways for the reaction of
the analogous cis- and trans-platinum(II) complexes with the
neutral nucleophiles are presented in Schemes 2 and 3. The
reactions with the diaqua complexes were performed at pH 2 in
order to ensure that all the complexes cPt, cPtM, cPtR, tPt, tPtM
kobs = k2[Nu]
(1)
and tPtR are present in their diaqua form based on the reported The comparative second-order rate constants for the substitu-
pKa values in Table 1. tion processes of the corresponding analogous cis- and trans-
The substitution reactions of all the studied cis-platinum(II) dialkylamine platinum(II) complexes are summarised in
complexes proceed in two concerted rate determining reaction Table 3. In the case of the cis-platinum(II) complexes, the
Scheme 2 Proposed pathway for the reaction of the trans-platinum(II) complexes with the thiourea-based nucleophiles.
Scheme 3 Proposed pathway for the reaction of the cis-platinum(II) complexes with the thiourea-based nucleophiles.
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observed was assigned to the simultaneous removal of the two
aqua ligands.
NMR studies
Substitution of the chloride ligands in all the studied complexes with
an excess thiourea (TU) was investigated by 195Pt NMR spectroscopy.
A typical 195Pt NMR spectra for the substitution of cPtR and tPtR
with TU respectively are presented in Fig. 4 and 5. In both cases, at
t = 0, a signal due to the starting complexes [cis-Pt{NH2CH(CH3)2}Cl2]
and [trans-Pt{NH2CH(CH3)2}Cl2] were observed at ꢁ2218.5 ppm
and ꢁ2206 ppm respectively. In the case of the cis-configured
complex, there is the formation of an intermediate species at
ꢁ3382 ppm which is assigned to the substitution of the two
chloro ligands [cis-Pt{NH2CH(CH3)2}(TU)2]2+, followed by the
eventual substitution of the two amine moieties via a strong
trans effect of the TU to give the final product after 24 hours at
ꢁ4092 ppm assigned to [Pt(TU)4]2+. Notably, the final products of
all the cis-configured complexes were obtained at ꢁ4092 ppm.
However, in the case of the [trans-Pt{NH2CH(CH3)2}Cl2], the
signal of the final product was found at ꢁ3209 ppm within
20 minutes and remained the same after 24 hours. The signal
of the final product of the tPtR was ascribed to [trans-
Pt{NH2CH(CH3)2}(TU)2]. The final products of all the trans-
platinum(II) complexes, however, appear between ꢁ3170 ppm
and ꢁ3210 ppm.
Fig. 3 Pseudo first-order rate constants plotted as a function of the
concentration of the entering nucleophiles for the substitution reaction
of the diaqua tPtR complex by TU, DMTU, and TMTU at pH = 2.0 (0.09 M
NaClO4 + 0.01 M HClO4) and 298 K.
Table 3 Second-order rate constants for the reaction of the investigated
analogous diaqua cis- and trans-platinum(II) complexes with thiourea
nucleophiles at pH = 2.0 (0.9 M NaClO4 + 0.01 M HClO4) and 298 K
Complex Nucleophiles k2(1st) ꢃ 10ꢁ3/Mꢁ1 sꢁ1 k2(2nd) ꢃ 10ꢁ3/Mꢁ1 sꢁ1
cPt
TU
DMTU
TMTU
97.6 ꢂ 0.4
44.2 ꢂ 0.2
Too slow
21.4 ꢂ 0.06
8.6 ꢂ 0.03
Too slow
Based on the NMR results, it is reasonably concluded,
therefore, that the cis- and the trans-platinum(II) complexes
do not form the same kinetic product with TU. The presence of
the strong labilising thiourea nucleophiles at the platinum(II)
centre forces the substitution of the amine ligands attached to
the metal centre in all the cis-configured platinum(II) com-
plexes. This result is consistent with what have been previously
reported by other researchers in related studies.9,13,31–34 The
substitution of the amine groups was not observed in any of the
trans-configured platinum(II) complexes. Unlike the notion
posited by Song et al.,14 our current findings are congruous
with the earlier findings of Brabec et al.15
cPtM
cPtR
TU
DMTU
TMTU
58.3 ꢂ 0.2
36.3 ꢂ 0.1
Too slow
8.2 ꢂ 0.02
3.8 ꢂ 0.01
Too slow
TU
DMTU
TMTU
2.8 ꢂ 0.02
1.9 ꢂ 0.02
Too slow
Too slow
Complex
Nucleophiles
k2(1st) Mꢁ1 sꢁ1
k2(2nd) ꢃ 10ꢁ3/Mꢁ1 sꢁ1
tPt
TU
DMTU
TMTU
44.2 ꢂ 0.03
22.9 ꢂ 0.11
5.6 ꢂ 0.01
—
It has been well-established that the pKa values of coordi-
nated aqua ligands is an experimental indicator of the electron
density around the metal centre.27,37 Thus, the lower the pKa
value the more electrophilic and in most cases, the more
reactive a metal complex is. In this study, both the experimental
and the theoretical findings perfectly aligned. All the trans-
complexes are more electrophilic than their corresponding cis-
tPtM
tPtR
35.4 ꢂ 0.11
18.2 ꢂ 0.02
3.8 ꢂ 0.03
—
—
DMTU
TMTU
TU
DMTU
TMTU
19.0 ꢂ 0.0016
10.3 ꢂ 0.0001
2.2 ꢂ 0.0065
substitutions turned out to be rather slow in which the first and counterparts based on their respective pKa values and this
the second steps occurred in concert. The reactions with the phenomenon is underpinned by the DFT-calculated charges on
bulkiest nucleophile, TMTU, was too slow to be followed to the platinum centres for both the cis- and the trans-dialkylamine
completion for all the cis-configured platinum(II) complexes. platinum(II) complexes respectively. The general trend of the
The second-order rate constant, k2 1st, for the first step of the second order rate constants for the substitution of aqua ligands
reactions of the cis-platinum(II) complexes with the thiourea- by the entering nucleophiles is as follows: tPt 4 tPtM 4 tPtR 4
based nucleophiles was assigned to the substitution of both cPt 4 cPtM 4 cPtR. Each of the trans-platinum(II) complexes
labile aqua ligands, whereas the second step was ascribed to is ca. 103 times more reactive than its corresponding cis-platinum(II)
the displacement of the monodentate amine moieties conse- analogues. This trend agrees very well with the electrophilicity of
quent upon the strong trans the effect of coordinated thioureas. their respective platinum centre based on the experimentally
However, in the trans-platinum(II) complexes, the single step determined pKa values and the DFT-calculated NBO charges.
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Fig. 4 195Pt NMR spectra of the reaction mixture of cPtR-Cl with six mole equivalents of TU, showing pure cPtR-Cl (d = ꢁ2218.5 ppm) before the
reaction, the intermediate species (d = ꢁ3382 ppm) formed during course of the reaction, [cis-Pt{NH2CH(CH3)2}2(TU)2]2+ and the final degradation
product (d = ꢁ4092 ppm) corresponding to [Pt(TU)4]2+
.
Fig. 5 195Pt NMR spectra of the reaction mixture of tPtR-Cl with six mole equivalents of TU, showing pure tPtR-Cl (d = ꢁ2206 ppm) before the reaction,
and the final stable biadduct product (d = ꢁ3209 ppm) ascribed to [trans-Pt{NH2CH(CH3)2}2(TU)2]2+
.
A thorough look at the DFT-calculated data in Table 2 shows bulkiness of the amine moieties. In the same vein, the steric effect,
that the average bond length between the platinum centre and in the trans-complexes, increase as the amine ligands become
the aqua ligands is higher in all the cis-configured platinum(II) bulkier.
complexes compared to their corresponding trans-complexes.
Furthermore, the increased steric hindrance in the cis-con-
This implies that the substitution of the aqua moieties by the figured complexes is also enhanced through intramolecular hydro-
entering nucleophiles are ordinarily expected to occur faster in gen bonding. This is underpinned by the average inter-
the cis-complexes than those of their corresponding trans- atomic distance between the hydrogen atoms on the nitrogen of
counterparts because their aqua ligands should have been the amine moiety and the oxygen atom of the aqua ligand as well as
more labile in the ground state. Thus, the second order rate the average interatomic distance between the hydrogen of the aqua
constants of the cis-complexes in the first step should have ligand and the nitrogen atom of the amine ligands. These
been greater than those of their corresponding trans-analogues. distances are shorter in the cis-complexes compared to their
This is not unexpected because of the trans effect between H2O corresponding trans-counterparts. The increased possibility of
and NH3 with the ammine ligand having a greater trans effect intramolecular hydrogen bonding interactions in the cis-plati-
than the aqua ligand. This, however, was not the case based on num(II) complexes forestalls the entering nucleophiles from
the second-order rate constants obtained, which is summarised reaching the platinum centre, thereby retarding the reactivity of
in Table 3.
the cis-complexes relative to those of their trans-isomers. This
Moreover, the electronic factors such as the electrophilicity observation has been previously reported.12,38 Intramolecular
of the metal centre favouring a greater reactivity of the trans- hydrogen bonding increases steric hindrances around the
complexes over their corresponding cis-isomers, steric hindrances metal centre thereby retarding the activation of the substitution
also play a prominent role. Steric hindrance is greater in the cis- process in the cis-configured complexes. This possibility of
complexes as compared to their trans-analogues.16 The trans- steric hindrance due to intramolecular hydrogen bonding is
configuration greatly minimises steric hindrance which enhances remarkably minimised in the trans-configured complexes
the axial approach of the entering nucleophile. The cis-geometry, resulting in their increased reactivity.
on the other hand, amplifies steric hindrances which is anticipated
Another factor that contributed to the increased steric
to hinder the axial approach of the incoming nucleophile to the hindrance in the cis-complexes as compared to their corresponding
metal centre. This became more pronounced with the increasing trans-analogues, is the solvation of the hydrogen atoms on the
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The activation parameters DH# and DS# were calculated using
the Eyring equation (eqn (2)) by measuring the rate constants
for each of the substitution reactions of the investigated
platinum(II) complexes with the thiourea-based nucleophiles
as a function of temperature (Fig. 6) and are summarized in
Table 4. In general, ligand substitution for all the investigated
complexes, regardless of their configurations, followed an
associative mechanism and are characterized by negative
intrinsic activation entropy values resulting from bond for-
mation in the transition state.35–45 The activation entropies
for both the cis- and trans-configured complexes confirm the
associative character for the substitution process with this
character being generally more prominent in the cis-
complexes compared to their trans-counterparts. This implies
that bond-making in the transition state is more favoured in
the cis-complexes than in the trans-complexes.
Fig. 6 Plot of ln(k2/T) against 1/T for the reaction of tPtR with the
thiourea-based nucleophiles at various temperatures ranging from 293
to 313 K.
nitrogen atom of the amine moieties. The solvated hydrogen atom
increases steric crowdedness around the metal centre, thus,
slowed down the attack of the nucleophile on the reaction site.
This effect is also present in the trans-complexes. However, the
remote distance between the –NH2R moiety and the leaving
aqua ligands minimises the steric crowdedness around the
metal centre, hence, the unhindered approach of the nucleo-
phile. The proximity of aqua and amine moieties in the cis-
complexes enhances crowdedness around the substitution
sites. Generally, substitution of the aqua moieties from the
studied cis and trans-platinum(II) complexes exhibits an appar-
ent dependence on the steric hindrance of the entering nucleo-
philes. The reactivity of the thiourea nucleophiles with the
complexes decreases with increase in steric demand in the
following order: TU 4 DMTU 4 TMTU.
Conclusion
A series of analogues bifunctional dialkylamine cis- and trans-
platinum(II) complexes were synthesised, characterised and
investigated for comparative substitution reactions with
thiourea-based nucleophiles. Substitution of the cis-complexes
followed a concerted two rate determining steps while those of
the trans-complexes proceed by a single rate determining step.
The trans-complexes are ca. 103 more reactive than their cis-
analogues. Electronic as well as steric effects controlled the
overall reaction pattern. The negative entropy of activation
values obtained for all the studied complexes affirmed an
associative mode of substitution. The cis-complexes formed a
different kinetic product as compared to their trans analogues
as confirmed by 195Pt NMR spectroscopy. The trans-complexes
are thermodynamically more stable to complete substitution by
the thiourea-based nucleophiles and hence, their use as
ꢀ
ꢁ
ꢀ
ꢁ
k2
T
DH#
RT
DS#
R
ln
¼ ꢁ
þ
23:8 þ
(2)
Table 4 Summary of the activation parameters for substitution of coordinated aqua moieties from the investigated analogous cis- and trans-platinum(II)
complexes with thiourea nucleophiles in the temperature range 293–313 K
Complex
Nu
DH# (kJ molꢁ1
)
DH# (kJ molꢁ1
)
DS# (J molꢁ1 Kꢁ1
)
DS# (J molꢁ1 Kꢁ1
)
1
2
1
2
cPt
TU
DMTU
17 ꢂ 0.03
48 ꢂ 0.08
58 ꢂ 0.08
57 ꢂ 0.09
ꢁ189 ꢂ 0.1
ꢁ111 ꢂ 0.3
ꢁ84 ꢂ 0.3
ꢁ95 ꢂ 0.3
cPtM
cPtR
tPt
TU
DMTU
63 ꢂ 7
57 ꢂ 1
75 ꢂ 6
65 ꢂ 1
ꢁ57 ꢂ 3
ꢁ79 ꢂ 6
ꢁ34 ꢂ 2
ꢁ74 ꢂ 4
TU
DMTU
54 ꢂ 5
57 ꢂ 5
—
ꢁ112 ꢂ 16
ꢁ108 ꢂ 2
—
TU
DMTU
TMTU
63 ꢂ 2
55 ꢂ 1
68 ꢂ 2
—
ꢁ29 ꢂ 6
ꢁ61 ꢂ 4
ꢁ27 ꢂ 6
—
tPtM
tPtR
TU
DMTU
TMTU
58 ꢂ 3
62 ꢂ 1
60 ꢂ 2
—
—
ꢁ34 ꢂ 10
ꢁ43 ꢂ 3
ꢁ64 ꢂ 7
—
—
TU
DMTU
TMTU
58 ꢂ 2
54 ꢂ 2
57 ꢂ 1
ꢁ51 ꢂ 7
ꢁ69 ꢂ 5
ꢁ72 ꢂ 3
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17 A. K. Connors, Chemical Kinetics of the Reaction Rates in
Solution, Wiley-VCH, New York, 1990.
alternative platinum-based anticancer agents can be further
explored.
18 A. D. Becke, J. Chem. Phys., 1992, 96, 2155–2160.
19 P. J. Hay and W. R. Wadt, J. Chem. Phys., 1985, 82, 299–310.
20 T. A. Hilder and J. M. Hill, Nanotechnology, 2007, 18, 275704.
21 V. Barone and M. Cossi, J. Phys. Chem. A, 1998, 102,
1995–2001.
Conflicts of interest
There are no conflicts to declare.
22 M. Cossi, N. Rega, G. Scalmani and V. Barone, J. Comput.
Chem., 2003, 24, 669–681.
23 E. Seifert, OriginPro 9.1: Scientific Data Analysis and Graphing
Software Software Review, ACS Publications, 2014.
24 T. G. Appleton, A. J. Bailey, K. J. Barnham and J. R. Hall,
Inorg. Chem., 1992, 31, 3077–3082.
25 L. Cubo, A. G. Quiroga, J. Zhang, D. S. Thomas, A. Carnero
and C. Navarro-Ranninger, Dalton Trans., 2009, 3457–3466.
26 A. Hofmann, D. Jaganyi, O. Q. Munro, G. Liehr and R. van
Eldik, Inorg. Chem., 2003, 42, 1688–1700.
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.
References
´
´
1 L. Messori, L. Cubo, C. Gabbiani, A. Alvarez-Valdes, 27 P. Atkins and J. de Paula, Elements of Physical Chemistry,
E. Michelucci and G. Pieraccini, Inorg. Chem., 2012, 51,
1717–1726.
2 J. J. Wilson and S. J. Lippard, Chem. Rev., 2013, 114,
Oxford University Press, Great Britain, 5th edn, 2009.
28 K. Tiwari, P. Arora, N. Pandey, P. Pandey, H. C. Joshi and
S. Pant, J. Mol. Liq., 2014, 200, 460–464.
4470–4495.
29 D. Reddy and D. Jaganyi, Int. J. Chem. Kinet., 2011, 43,
161–174.
´
3 A. Quiroga, F. Ramos-Lima, A. Alvarez-Valdes, M. Font-
´
Bardıa, A. Bergamo and G. Sava, Polyhedron, 2011, 30, 30 S. Hochreuther, R. Puchta and R. van Eldik, Inorg. Chem.,
1646–1650.
2011, 50, 8984–8986.
4 A. Quiroga, J. Inorg. Biochem., 2012, 114, 106–112.
31 P. W. Asman, J. Coord. Chem., 2017, 1–20.
5 K. Ossipov, Y. Y. Scaffidi-Domianello, I. F. Seregina, 32 G. Kinunda and D. Jaganyi, Transition Met. Chem., 2016, 41,
M. Galanski, B. K. Keppler and A. R. Timerbaev, J. Inorg.
Biochem., 2014, 137, 40–45.
235–248.
33 A. Shoukry, M. Brindell and R. Van Eldik, Dalton Trans.,
6 W. B. Dirersa, Int. J. Chem. Pharm. Anal., 2014, 2, 40–47.
2007, 4169–4174.
´
´
´
7 E. I. Montero, S. Dıaz, A. M. Gonzalez-Vadillo, J. M. Perez, 34 P. W. Asman, Inorg. Chim. Acta, 2018, 469, 341–352.
C. Alonso and C. Navarro-Ranninger, J. Med. Chem., 1999, 35 U. Belluco, L. Cattalini, F. Basolo, R. G. Pearson and
42, 4264–4268.
8 W. P. Asman and D. Jaganyi, Int. J. Chem. Kinet., 2017, 36 S. Jovanovic, J. Bogojeski, M. Petkovic and Z. D. Bugarcic,
1371702. J. Coord. Chem., 2015, 68, 3148–3163.
ˇ ´
A. Turco, J. Am. Chem. Soc., 1965, 87, 241–246.
´
´
ˇ ´
´
´
´
9 P. O. Ongoma and D. Jaganyi, Transition Met. Chem., 2013, 37 B. Petrovic, Z. D. Bugarcic, A. Dees, I. Ivanovic-Burmazovic,
38, 587–601.
F. W. Heinemann and R. Puchta, Inorg. Chem., 2012, 51,
1516–1529.
38 H. Ertu¨rk, R. Puchta and R. van Eldik, Eur. J. Inorg. Chem.,
2009, 1331–1338.
39 B. B. Khusi, A. Mambanda and D. Jaganyi, Transition Met.
Chem., 2016, 41, 191–203.
40 G. Kinunda and D. Jaganyi, Transition Met. Chem., 2014, 39,
939–949.
10 P. O. Ongoma and D. Jaganyi, Dalton Trans., 2013, 42,
2724–2734.
11 P. O. Ongoma and D. Jaganyi, Transition Met. Chem., 2014,
39, 407–420.
12 S. Hochreuther, S. T. Nandibewoor, R. Puchta and R. van
Eldik, Dalton Trans., 2012, 41, 512–522.
13 H. Song, W. Li, R. Qi, L. Yan, X. Jing and M. Zheng, Chem.
Commun., 2015, 51, 11493–11495.
14 V. Brabec, O. Vrana, O. Novakova and J. Kasparkova, Chem.
Commun., 2016, 52, 4096–4098.
41 T. R. Papo and D. Jaganyi, J. Coord. Chem., 2015, 68,
794–807.
42 D. Reddy and D. Jaganyi, Dalton Trans., 2008, 6724–6731.
15 E. Pantoja, A. Gallipoli, S. van Zutphen, S. Komeda, 43 A. Shaira and D. Jaganyi, J. Coord. Chem., 2015, 68,
D. Reddy and D. Jaganyi, J. Inorg. Biochem., 2006, 100,
3013–3031.
´
´
ˇ ´
1955–1964.
44 T. Soldatovic, S. Jovanovic, Z. D. Bugarcic and R. van Eldik,
´
´
´
16 E. I. Montero, S. Dıaz, A. M. Gonzalez-Vadillo, J. M. Perez,
Dalton Trans., 2012, 41, 876–884.
C. Alonso and C. Navarro-Ranninger, J. Med. Chem., 1999, 45 P. A. Wangoli and G. B. Kinunda, New J. Chem., 2018, 42,
42, 4264–4268. 214–227.
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