Synthesis, reactivity and characterization of Pt(II) complexes with N,N′ chelating ligands; Structure and dimethylsulfoxide reactivity relationship

Article abstract of DOI:10.1039/c6dt04035g

Platinum(ii) complexes of the formula PtLCl₂ [L = 2-(2′-pyridyl)quinoxaline, (pqx) (1), 2,(2′-pyridyl)benzo[g]quinoxaline, (pbqx) (3) and 2,(2′-pyridyl)quinoline, (pqn) (5)] were synthesized and characterized by spectroscopic and X-ray diffraction methods. Also, monodentate coordination of the ligands pqx and pbqx formed the complexes trans-Pt(DMSO)pqxCl₂ (2) and trans-Pt(DMSO)pbqxCl₂ (4) as it is indicated from X-ray crystal structure and NMR studies. The reaction of the complexes (1), (3) and (5) with DMSO-d₆ revealed a ligand-release solvolysis, which was studied by means of NMR techniques. Correlation between the crystal structures of (1), (3), and (5) and the kinetic or thermodynamic parameters of the solvolysis reactions showed that the tendency of the ligands pqx, pbqx, and pqn to return to the anti-configuration in addition to their ability to form non-classical H-bonds are crucial factors for the ligand-release solvolysis. Instantaneous DMSO-d₆ solvolysis for the complexes (1) and (3) and slow kinetics solvolysis for (5) (k = 10^-4 ± 6.4 × 10^-6 s^-1) reflect their structural differences in ligand planarity. Based on NMR techniques a two-step mechanism of the chelate ring opening was suggested with equilibrium constants of the overall reaction at 298 K, K_eq = 4.1 ± 0.2 × 10^-4 M^-1 (1) and K_eq = 1.7 ± 0.2 × 10^-4 M^-1 (2).

Full text of DOI:10.1039/c6dt04035g

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SYNTHESIS, REACTIVITY AND CHARACTERIZATION OF Pt(II) COMPLEXES WITH N,N’ CHELATING
LIGANDS; STRUCTURE AND DIMETHYLSULFOXIDE REACTIVITY RELATIONSHIP.
Konstantinos Ypsilantis,a Theodoros Tsolis,a Andreas Kourtellaris,b Manolis J. Manos,a John C.
Plakatourasa and Achilleas Garoufisa*.
aDepartment of Chemistry, University of Ioannina, GR-45110 Ioannina, Greece
bDepartment of Chemistry, University of Cyprus, P.O. Box 20537, CY-1678 Nicosia, Cyprus
ABSTRACT
Platinum(II) complexes of the formula PtLCl2 [L= 2-(2’-pyridyl)quinoxaline, (pqx) (1) 2,(2’-
pyridyl)benzo[g]quinoxaline, (pbqx) (3) and 2,(2’-pyridyl)quinoline, (pqn) (5)] were synthesized and
characterized by spectroscopic and x-ray diffraction methods. Also, monodentate coordination of
the ligands pqx and pbqx formed the complexes trans-Pt(DMSO)pqxCl2 (2) and trans-
Pt(DMSO)pbqxCl2 (4) as it is indicated from x-ray crystal structure and NMR studies. The reaction
of the complexes (1), (3) and (5) with DMSO-d6 revealed a ligand-release solvolysis, which was
studied by means of NMR techniques. Correlation between the crystal structures of (1), (3), (5)
and kinetic or thermodynamic parameters of the solvolysis reactions showed that the tendency of
the ligands pqx, pbqx, and pqn to return in the anti- configuration in addition to the ability of non-
classical H-bonds, are crucial factors for the ligand-release solvolysis. Instantaneous DMSO-d6
solvolysis for the complexes (1) and (3) and slow kinetics solvolysis for (5) (k = 10-4 ± 6.4 × 10-6 s-1)
reflect their structural differences in ligand planarity. Based on NMR techniques a two-step
mechanism of the chelate ring opening was suggested with equilibrium constants of the overall
reaction at 298 K, Keq = 4.1 ± 0.2 × 10-4 M-1 (1) and Keq = 1.7 ± 0.2 × 10-4 M-1 (2).
Keywords: anticancer drugs, square planar Pt(II) complexes,
* Corresponding author

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Introduction
Platinum chemotherapeutic compounds are among the most potent drugs in cancer
chemotherapy [1]. Cisplatin, carboplatin and oxaliplatin bind coordinatively to DNA bases, causing
DNA bending and cell apoptosis [2]. Side effects and the limitation of an effective dose due to the
drugs toxicity draw the research interest in other types of platinum compounds as potential
anticancer drugs. Nowadays, two main classes of Pt(II) compounds with different action
mechanism from cisplatin are under intense investigation; dinuclear [3-7] or polynuclear
complexes [8, 9], and platinum metallointercalators [10-14]. The latter are, in general, cationic
complexes with a saturated platinum coordination sphere with four nitrogen donor atoms, which
usually come from aromatic diimines. Such compounds bind non-coordinatively to DNA through
their aromatic ligands, causing significant alterations to the DNA helix [15, 16]. Despite the stability
of these complexes, offered by the 5-membered chelate ring(s), in some cases the complexes
decompose in solvents such as DMSO [10].
On the other hand DMSO is a commonly used solvent, dissolving non-water soluble metal
complexes in order to study their biological activity [17]. In some cases the complexes solvolyse in
DMSO, and usually the chloro ligands are replaced, due to the high affinity of platinum to
coordinate with sulfur containing ligands [18]. Thus, the DMSO solvolysis of complexes with the
general formula PtCl2L (L is ethylenediamine [19] or various N-methylated ethylenediamines [20])
mainly leads to the replacement of the chloro ligand by DMSO.
However, the dissociation of an NN’ chelate aromatic diimine from platinum center by
DMSO is reported very rarely. Two decades ago it had been reported that complexes of the
formula PtLCl2 (L = 2,2’-bipyridyl-3,3’-dicarboxylic acid or 3,3’-dimethylol-2,2’-bipyridine) release
the chelate ligand L, after dissolution in DMSO-d6 [21]. More recently, J. Aldrich-Wright et al
reported that the complex [Pt(pqx)(dach)]Cl2 (pqx= 2,(2’-pyridyl) quinoxaline and dach = 1R,2R- or
1S,2S-diaminocyclohexane) decomposes in DMSO [10]. In both cases the studied complexes
deviate from the square planar geometry, while most significant is the deviation of the planarity of
the aromatic ligand.
In an attempt to clarify the above query and with the ambition to correlate the complex
structure with its reactivity with DMSO, complexes of the formula PtLCl2 [L= 2,(2’-pyridyl)
quinoxaline, (pqx) 2,(2’-pyridyl)benzo[g]quinoxaline, (pbqx) and 2,(2’-pyridyl)quinoline, (pqn)]
were synthesized and characterized, both in solution and solid state. Their reactivity with DMSO-
d6 was studied by means of NMR spectroscopic techniques. Also, the different binding modes of
the above ligands were discussed.

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Experimental
Materials and methods
All solvents were of analytical grade and were used without further purification. Potassium
tetrachloroplatinate(II) (99.9%) was purchased from Alfa Aesar. 2,(2’-pyridyl)quinoxaline [22],
2,(2’-pyridyl)benzo[g]quinoxaline [23] and 2,(2’-pyridyl)quinoline [24] were prepared as previously
described. The complex cis-PtCl2(DMSO)2 was prepared according to the literature methods [25].
C, H, N determinations were performed on a Perkin-Elmer 2400 Series II analyzer.
Absorption spectra were measured in a Jasco V-650 spectrophotometer in a 1 cm path length
cuvette for the region 900-220 nm. 1H NMR spectra were recorded on a Bruker Avance
1
spectrometer operating at H frequencies of 500.13 MHz or 400.13 MHz and processed using
Topspin 3.1 (Bruker Analytik GmbH). 195Pt NMR spectra were recorded operating at frequency
85.99 MHz. 195Pt chemical shifts were referenced relative to external standard K2[PtCl4] in D2O (δ
195Pt = -1630 ppm) [26]. Two-dimensional COSY and TOCSY experiments assisted the proton signal
assignments.
Solvolysis of complex (5) in DMSO-d6.
1
The solvolysis of the complex (5) in DMSO-d6 was monitored by H NMR spectroscopy in
DMSO-d6 at concentration of 10 mΜ at 298 K. The solvolysis reaction follows slow kinetic in the
NMR time scale at 298 K and the fraction (F) of the solvolysis products was calculated from the
ratio (ri) of relative integrals, between selected proton signals of the initial complex and the final
reaction product, according to equation (1). Then, the F was converted to concentration units (M),
based on the initial concentration of 10 mΜ.
F = ri/(1+ri)
(1)
Plot of concentration of the reaction product vs. time was fitted with pseudo-first order kinetics
equation (2) to give the rate constant k.
A = A1 - A2 e-kt
(2)
A1 and A2 are constants related to the initial and equilibrium concentration of (5).
X-Ray crystallography
Suitable single crystals covered with paratone-N oil were attached on the tip of glass fibers.
X-ray diffraction data were collected (ω-scans) with a Oxford Diffraction Xcalibur-3 diffractometer
under a flow of nitrogen gas at 100(2) K using Mo Kα radiation (λ = 0.71069 Å). Data were
collected and processed by using the CRYSALIS CCD and RED software [27] respectively. Empirical

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absorption corrections (multiscan based on symmetry related measurements) were applied using
CrysAlis RED software. The structures were solved by direct methods using SIR2014 [28] and
refined on F2 using full-matrix least-squares with the latest version of SHELXL [29]. All non-H atoms
were refined anisotropically and carbon-bound H-atoms were introduced at calculated positions
and allowed to ride on their parent atoms. The refinement of the structures was not without
problems and special details can be found in the deposited CIF files in addition to full structural
details. Geometric/crystallographic calculations were carried out using PLATON, [30] and WINGX
[31] packages; graphics were prepared with X-Seed [32]. The CCDC files 1510648 - 1510651
contain the supplementary crystallographic data for this paper. This data can be obtained free of
charge
from
the
Cambridge
Crystallographic
Data
Centre
via
ccdc.cam.ac.uk/products/csd/request.
Synthesis of the complexes
Pt(pqx)Cl2 (1): Although the synthesis of the Pt(pqx)Cl2 has been published very recently [10],
here a different method is presented. An amount of 20 mg (0.05 mmol) of cis-PtCl2(DMSO)2 was
dissolved in 10 mL of hot chloroform and a solution containing 10 mg (0.05 mmol) of pqx in 3 mL
of chloroform was added. The mixture was left to react for 24h at 50 °C in the dark without
stirring. During the reaction time a crystalline orange precipitate appeared which was collected
with filtration, washed with chloroform (2 × 5 mL) and dried under vacuum over P2O5. Some
crystals were of suitable size for X-ray diffraction measurements. Yield 93%. C13H9Cl2N3Pt: calc.% C,
1
33.00; H, 1.92; N, 8.88. Found C, 32.90; H, 2.01; N, 8.86. H NMR (CDCl3, 298 K, δ in ppm, 500
MHz), H3 9.44 (s, 1H); H5 8.27 (d, 1H); H6 7.98 (t, 1H); H7 8.05 (m, 1H); H8 9.87 (d, 1H); H3’ 8.28
(d, 1H); H4’ 8.29 (t, 1H); H5’ 7.75 (t, 1H); H6’ 10.00 (d, 1H).
trans-Pt(pqx)(DMSO)Cl2 (2): An amount of 20 mg (0.05 mmol) of cis-PtCl2(DMSO)2 was dissolved
in 50 mL of chloroform. After cooling the solution to about 10 °C, a solution containing 10 mg (0.05
mmol) of pqx in 3 mL of chloroform was added. The mixture was left to react for 24h in the dark at
10 °C. Slow diffusion of Et2O in the reaction mixture formed a crystalline light orange precipitate
which was collected with filtration, washed with cold chloroform (1 × 1 mL), diethyl ether (2 × 5
mL) and dried under vacuum over P2O5. Some of the crystals were suitable for X-ray
measurements. Yield 75%. C15H15Cl2N3OPtS: calc. (%) C, 32.72; H, 2.86; N, 7.58. Found C, 32.60; H,
2.71; N, 7.58. 1H NMR (CDCl3, 298 K, δ in ppm, 500 MHz), H3 10.18 (s, 1H); H5 8.81 (d, 1H); H6 7.48
(t, 1H); H7 7.97 (m, 1H); H8 8.61 (d, 1H); H3’ 8.24 (d, 1H); H4’ 7.97 (t, 1H); H5’ 7.99 (t, 1H); H6’ 9.31

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(d, 1H); DMSO-CH3 3.57 (s, 6H). 195Pt NMR (CDCl3, 298 K, ppm, 85.99 MHz), -3040 ppm. A few
crystals, suitable for X-ray diffraction analysis, were collected from the microcrystalline solid.
Pt(pbqx)Cl2 (3): An amount of 20 mg (0.05 mmol) of cis-PtCl2(DMSO)2 was dissolved in 10 mL of
hot chloroform and a solution containing 12 mg (0.05 mmol) of pbqx in 5 mL of chloroform was
added. The mixture was left to react for 24h at 50 °C in the dark without stirring. During the
cooling of the reaction mixture a crystalline red precipitate appeared which was collected with
filtration washed with chloroform (2 × 5 mL) and dried under vacuum over P2O5. Slow cooling of
the reaction mixture leads to crystals suitable for crystallographic characterization. Yield 90%.
1
C17H11Cl2N3Pt: calc.% C, 39.02; H, 2.12; N, 8.03. Found C, 39.90; H, 2.31; N, 7.96. H NMR (CDCl3,
298 K, δ in ppm, 500 MHz), H3 9.40 (s, 1H); H5 8.86 (s, 1H); H6 8.17 (d, 1H); H7 7.71 (m, 1H); H8
7.78 (m, 1H); H9 8.29 (s, 1H); H10 10.55 (s, 1H); H3’ 8.34 (d, 1H); H4’ 8.33 (t, 1H); H5’ 7.78 (t, 1H);
H6’ 10.07 (d, 1H).
Pt(pbqx)(DMSO)Cl2 (4): An amount of 20 mg (0.05 mmol) of cis-PtCl2(DMSO)2 was dissolved in 50
mL of chloroform. After cooling the solution to about 10 °C, a solution containing 12 mg (0.05
mmol) of pbqx in 5 mL of chloroform was added. The mixture was left to react for 24h in the dark
at 10 °C. Slow diffusion of Et2O in the reaction mixture formed a crystalline red precipitate which
was collected with filtration, washed with cold chloroform (1 × 1 mL), diethyl ether (2 × 5 mL) and
dried under vacuum over P2O5. Yield 80%. C19H17Cl2N3OPtS: calc. (%) C, 37.94; H, 2.85; N, 6.99.
Found C, 37.68; H, 2.91; N, 76.92. 1H NMR (CDCl3, 298 K, δ in ppm, 500 MHz), H3 10.30 (s, 1H); H5
9.86 (s, 1H); H6 8.20 (d, 1H); H7 7.74 (m, 1H); H8 7.75 (m, 1H); H9 8.36 (s, 1H); H10 8.39 (s, 1H);
H3’ 8.71 (d, 1H); H4’ 7.99 (t, 1H); H5’ 7.52 (t, 1H); H6’ 8.86 (d, 1H) ; DMSO-CH3 3.62 (s, 6H). 195Pt
NMR (CDCl3, 298 K, ppm, 85.99 MHz), -3038 ppm. A few crystals, suitable for X-ray diffraction
analysis, were collected from the crystalline solid.
Pt(pqn)Cl2 (5): An amount of 20 mg (0.05 mmol) of cis-PtCl2(DMSO)2 was dissolved in 10 mL of hot
methanol and a solution containing 10 mg (0.05 mmol) of pqn in 5 mL of methanol was added. The
mixture left to react for 24h at 50 °C in the dark without stirring. During the cooling of the reaction
mixture a crystalline red precipitate was appeared which was collected with filtration washed with
methanol (2 × 5 mL) and dried under vacuum over P2O5. Some of the crystals were suitable for X-
ray measurements. Yield 90%. C14H10Cl2N2Pt: calc.% C, 35.61; H, 2.13; N, 5.93. Found C, 35.92; H,
1
2.21; N, 5.86. H NMR (DMSO-d6, 298 K, δ in ppm, 500 MHz), H3 9.05 (d, 1H); H4 8.62 (d, 1H) H5
8.21 (d, 1H); H6 7.82 (t, 1H); H7 7.96 (t, 1H); H8 9.34 (d, 1H); H3’ 8.75 (d, 1H); H4’ 8.49 (t, 1H); H5’
7.89 (t, 1H); H6’ 9.50 (d, 1H).

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Results and discussion
Solution characterization of the complexes
Schematic demonstration of the structures of the prepared complexes (1)-(5), with atoms
numbering is presented in the following scheme.
1
The H NMR spectrum of complex (1) in CDCl3, (Fig. 1a) shows significant downfield shifts
for the protons H6’ (Δδ = + 1.23 ppm) and H8 (Δδ = + 1.72 ppm), while the other proton signals of
the pqx shifted significantly less. More particularly, the deshielding effect of platinum on the H8 is
remarkably large [33], indicating a possible alteration in the configuration of pqx. In addition, the
equivalence of H5 and H8 in the free ligand has been lifted, indicating that N1 participates to the
coordination sphere. Satellite signals in either side of the H6’ doublet, were observed, reflecting
3
3
the J spin–spin interactions with 195Pt nucleus (34%-abundant). The value of JPt-H6’ found equals
to 38.4 Hz, which is characteristic for vicinal Pt-H6 coupling of pyridine derivatives [34, 35]. The
4
long range coupling constant, JPt-H3 = 10.8 Hz, was also observed and it is within the accepted
values (10-16 Hz) [34, 35]. All the above observations confirm a N1N1’ chelate coordination of pqx.
1
Similarly, the H NMR spectrum of complex (2) in CDCl3, (Fig. 1b), shows significant
downfield shift for the neighboring to N4 protons, H3 (Δδ = + 0.29 ppm) and H5 (Δδ = + 1.23
ppm), while the proton signals of H6’ (Δδ = + 0.09 ppm) and H8 (Δδ = + 0.17 ppm), shifted
marginally. Since H6’ and H8 are adjacent to N1’ and N1, any possibility for coordination through

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FIGURE 1. (a) Aromatic region of 1H NMR spectrum of (1) in CDCl3 @400 MHz at 298K with proton
assignments. Inset, a magnification of H3 signal with the rarely observed (only in singets) long-
4
1
range JPt-H3 satellites was presented. (b) Aromatic region of H NMR spectrum of (2) in CDCl3
@250 MHz at 298K with proton assignments. The 195Pt satellites in H3 are more intense than (1)
due to the lower resonance field. Inset, the resonance of DMSO methyl groups observed at 3.57
ppm. (c) Aromatic region of 1H NMR spectrum of free pqx in CDCl3 @400 MHz at 298K with proton
assignments.

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these nitrogen donors atoms is excluded. Furthermore, the satellite-signals in both sides of H3
(3JPt-H3 = 35 Hz) and the absence of similar signals in H6’, indicates a monodentate coordination of
pqx only through N4. At higher fields (δ = 3.57 ppm) a singlet, with relative integral corresponding
to 6H, was assigned to the coordinated DMSO methyl groups (Δδ = + 1.06 ppm). This singlet is
3
followed by two satellite broad signals giving a JPt-CH3 = 18.5 Hz, which is characteristic for
coordinated DMSO through sulfur atom [36].
In general substitution reactions of Pt(II) square planar complexes proceed with retention
of the configuration [37]. However, the reaction of cis-Pt(DMSO)2Cl2 with pqx results to the
complex trans-Pt(DMSO)(pqx)Cl2 without retention of the cis- configuration [36]. An alternative
explanation includes the formation of the anionic complex [Pt(DMSO)Cl3]- and a subsequent
substitution of the trans- to DMSO chloro ligand [38]. However, no NMR evidence of the formation
of [Pt(DMSO)Cl3]- in CDCl3 was observed. Recently, it has been reported that the value of ΔG298 of
the reaction cis-Pt(DMSO)LCl2 ↔ trans -Pt(DMSO)LCl2 (L = (E)-N,N’-bis(2-pyridyl)iminoisoindoline)
is -5 kcal mol-1. This is in agreement with predomination of the trans- isomer [39] in the
equilibrium. Also, the possibility of a similar isomerization reaction of complex (2) cannot be
excluded.
However, the different binding mode of the ligand pqx in complexes (1) and (2) is an issue
of even greater interest. So far, many reports indicate that 2-(2’-pyridyl)quinoxaline acts as a
chelate ligand through N1 and N1’ with various metal ions [40]. Complex (2) is the first example
where pqx coordinates monodentately through N4, even though in the case of complex
[Hg(CH2COCH3)(pqx)]2, pqx forms a Hg-N1’ strong bond (2.175 Å) and a Hg-N1 very weak (2.560 Å)
bond in a bidentate highly asymmetric (anisobidentate) mode [41].
In the cases of (1) and (2) both complexes have been prepared in the same solvent (CHCl3),
with the same starting materials and in the same molar ratios of the reactants. However, the
reaction temperature and the time differ. At low temperature (≈ 15 °C) the monodentate (N4)
complex (2) was formed and at higher temperature (≈ 50 °C) the bidentate (N1N1’) was
precipitated. This observation can be explained considering the configurations of pqx, syn and anti
(Fig.2). The crystal structure of pqx shows that the preferable configuration in the solid state is the
anti [42]. In this configuration both H3 and H3’ form weak hydrogen bonds with N1’ and N1
1
correspondingly, increasing the deshielding effect on their nuclei. Therefore, their H NMR signals
should be expected downfield.

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FIGURE 2. Syn and anti configuration of ligand pqx with atom numbering. Dash lines in the anti-
conformer show the hydrogen bonds between N1-H3’ and N1’-H3.
Indeed, in the 1H NMR spectrum of pqx in CDCl3, the signals of H3’ (δ = 8.51 ppm) and H3 (δ
= 9.89 ppm) were observed significantly downfield, compared to the other aromatic protons of
pqx. Additionally, the absence of ROE signal between the H3 and H3’ in the ROESY spectrum of pqx
at various tm, confirms that pqx, most likely, prefers the anti configuration in CDCl3 as well as in the
solid state. With this in mind it would be easy to understand why complex (2) is formed at low
temperature and it remains stable at 7 °C in CDCl3 for several days.
1
On the other hand, at increasing the temperature to 50 °C in a sample of free pqx, no H
NMR evidence of changes in its conformation was observed. The chemical shifts of the indicator
protons H3 and H3’ almost remain unchanged, suggesting that pqx tends to adopt the anti
conformation. However, the reaction with cis-Pt(DMSO)2Cl2 at 50 °C leads to the formation of
complex (1) where ligand pqx acts bidentately and is forced to adopt the syn conformation. In
addition, at increasing the temperature of a sample of (2) in CDCl3, the complex (1) precipitates
almost quantitatively. It is reminded that in complex (2) the chloro ligands are in trans-
configuration, while in the resulted (1), the chloro ligands are in cis. This observation can be
explained assuming an intermolecular mechanism as presented in Fig. 3.
The first step of the proposed mechanism includes an intermolecular interaction of the
coordinated pqx N1, with platinum, the formation of a five-coordinated intermediate and the
secession of the DMSO from the metal coordination sphere. This results in the destruction of N1-
H3’ weak hydrogen bond and the weakness of the pqx anti configuration. Thus, the N1’ of
pyridinic moiety of pqx interacts with platinum, forming again a five-coordinated intermediate. In

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FIGURE 3. Proposed mechanism for transformation of complex (2) to (1)
this second step the Pt-N4 bond is cleaved due to the higher stability of the five-membered
chelate ring, forming the complex (1).

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In complex (1) the ligand pqx adopts the syn conformation, the H NMR signals of H3 and
H3’ shifted strongly upfield by -0.55 ppm (δ = 9.44 ppm) and -0.23 ppm (δ = 8.28 ppm)
respectively, reflecting the sum of a small downfield shift, due to Pt(II) coordination to N1 and N1’,
and the upfield shift, due to the abolition of the anti conformation. In general, the chemical shift
of H3 could be a good indicator of the conformation or the coordination mode of pqx. In an
1
acidified solution of CDCl3, the H NMR spectrum of (1) shows the singlet of H3 at δ = 9.70 ppm,
indicating that N4 of pqx is protonated. Thus, it could be concluded that the deshielding effect on
H3 nucleus increases with the order: pqxN4-platination (δ = 10.18 ppm) > pqx anti configuration (δ
= 9.89 ppm) > N1N1’-platination and N4-protonation (δ = 9.70 ppm) > N1N1’-platination (δ = 9.44
ppm). In other words, the interaction between H3 and N1’ in pqx anti conformer, is strong enough
to deshield significantly the H3.
1
The H NMR spectra of complexes (3) and (4) in CDCl3 show enough similarities with these of (1)
and (2). The spectrum of (3) shows significant downfield shifts for the protons H6’ and H10, which
are neighboring to the coordination sites N1’ and N1. The H6’ shifted by 1.27 ppm (δ = 10.07 ppm)
and the H10 by 1.80 ppm (δ = 10.55 ppm). The rest protons of pyridine moiety, shifted downfield
(H4’ and H5’), with the exception of H3’, which shifted upfield by 0.33 ppm.
The above observations, together with two satellite peaks on both sides of H6’ signal (3JPt-
= 39.2 Hz), clearly indicate that pbqx coordinates to Pt(II) through N1’and N1. A noteworthy
H6’
upfield shift of the proton H3 (Δδ = 0.87 ppm) reflects again the alteration of the pbqx
configuration from anti to syn. This value is higher than the corresponding upfield shift (Δδ = 0.64
ppm) of H3 in complex (1), probably due to the higher electron withdrawal from H3 as a result of
the additional aromatic ring of pbqx.
1
The H NMR spectrum of (4) in CDCl3 shows a downfield shift of H3 (-0.23 ppm) and H5 (-
1.10 ppm). The signals of H6’ and H10 which are close to N1’ and N1 respectively shifted
marginally by 0.03 and 0.10 ppm, excluding any possibility of coordination through these nitrogen
3
atoms. Furthermore the observation of JPt-H3 = 36 Hz confirms the monodentate coordination of
pbqx. A singlet peak at δ = 3.62 ppm (3JPt-CH3 = 20 Hz) with relative integral ratio to pbqx 6:1,
indicates that only one molecule of DMSO is included in the platinum coordination sphere. The
absence of crystallographic data does not allow the determination of complex (4) configuration
1
with assurance. However, the similarities of chemical shifts in H NMR signal of the coordinated
DMSO methyl groups and the 195Pt NMR (δ = -3037 ppm), indicate that most probably (4) is in the
same trans- configuration as complex (2).

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1
Complex (5) is insoluble in CDCl3 and the H NMR spectra of a freshly prepared sample of
1
(5), as well as the free ligand, were recorded in MeOD-d4. The H NMR of (5) shows a significant
downfield shift for the H6’ (Δδ = 0.73 ppm) while the other protons of the pyridinic moiety of pqn,
shifted downfield in a range of 0.1 - 0.5 ppm. It is worth mentioning that the Η3’ shifted downfield
by 0.12 ppm, in contrast to upfield shifts that were observed in the cases of complexes (1) (Δδ =
0.23 ppm) and (3) (Δδ = 0.33 ppm). In addition, a downfield shift was observed for H3 (Δδ = 0.52
ppm ) in contrast to upfield shifts observed in the cases of H3 in (1) (Δδ = 0.55 ppm) and (3) (Δδ =
0.87 ppm). These observations lead to the conclusion that the anti conformer in the case of free
pqn is less preferable than that of pqx and pbqx. A possible explanation may be derived from the
differences in δ+ charge of H3 that is less in the case of pqn than that of pqx, due to the less
electronegative C4 than the N4. Less δ+ charge means weaker hydrogen bonding with N1’ and
therefore less preferable the anti conformation. The downfield shift of pqn H8 (Δδ = 1.29 ppm),
that is relatively lower than those observed in the similar complexes (1) (Δδ = 1.72 ppm) and (3)
(Δδ = 1.80 ppm), confirms the N1N1’ coordination of pqn.
Crystal structures of (1), (2), (3) and (5)
Crystals of complexes (1) – (3) and (5) (Fig. 4) suitable for X-ray structure determination
were obtained from the parent solutions. Selected bond lengths and angles are presented in Table
1. As shown in Fig. 4, all of them have distorted square planar coordination about platinum.
Complex (2) is the trans isomer with monodentate coordination of the nitrogen ligand opposite to
DMSO’s sulfur atom, while the rest are cis, as imposed by the heterocycle chelate. Those structural
data provide us the opportunity to compare the effect of the multi-ring system to the geometry of
the coordination sphere and the overall complex. Detailed structural information can be found in
the supplementary material.

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(a)
(b)
(c)
(d)
FIGURE 4. Thermal ellipsoid presentations (50 % probability level) of the molecular structures of
compounds: a) [Pt(pqx)Cl2], (1), b) trans-[Pt(pqx)(DMSO)Cl2], (2), c) [Pt(pbqx)Cl2], (3), d)
[Pt(pqn)Cl2], (5).
The Pt – N bond distances span the range 2.003 to 2.079 Å, while the Pt – Cl lengths are in the
range 2.293 - 2.318 Å, and are in agreement with literature data [22, 43, 44]. The same appears
with the Pt – S bond distance which is 2.214 Å, and fits literature data (two examples are given in
[45]). The differences in the Pt – N bond distances, though small, appear to be systematic.
The entire Pt – Npyridine bonds are shorter than the adjacent Pt – N bonds, in complexes (1), (3) and
(5), indicating the increased nucleophilicity of the pyridine nitrogen atom. When the Pt – N bond
distances of the different complexes are compared, it seems that in deciding the differences, π-
back bonding is more important than σ-bonding. This way, the Pt – N bond distances in (3) are
shorter than the corresponding in (1) with consistency to the more extended LUMO orbital of
pbqx related to the same orbital of pqx (mean Pt – N for (1) and (3) are 2.054 and 2.036 Å,
respectively). When (5) is included in the discussion, it becomes obvious that the replacement of
the nitrogen atom of the quinoxaline heterocyclic ring (position 4 in Fig.4) with the less

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electronegative carbon, leads to increased negative charge on nitrogen and even stronger σ-
bonding, and shorter Pt – N bond distances (mean Pt – N for (5) is 2.025 Å).
TABLE 1. Coordination sphere bond distances (Å) and angles (o) of the structurally
characterized complexes.
[Pt(pqx)Cl2] (1)
Pt – Cl(1)
2.318(5)
2.079(13)
85.20(16)
176.7(4)
92.2(4)
Pt – Cl(2)
2.294(4)
2.029(17)
102.0(5)
172.1(5)
80.5(6)
Pt – N(1)
Pt – N(1')
Cl(1) – Pt – Cl(2)
Cl(1) – Pt – N(1')
Cl(2) – Pt – N(1')
Cl(1) – Pt – N(1)
Cl(2) – Pt – N(1)
N(1) – Pt – N(1')
trans-[Pt(pqx)(DMSO)Cl2] (2)
Pt – Cl(1)
2.314(3)
Pt – Cl(2)
2.303(3)
Pt – S(1)
2.214(2)
176.23(11)
90.1(2)
Pt – N(4)
2.053(8)
93.16(9)
90.07(10)
176.1(2)
Cl(1) – Pt – Cl(2)
Cl(1) – Pt – N(4)
Cl(2) – Pt – N(4)
Cl(1) – Pt – S(1)
Cl(2) – Pt – S(1)
S(1) – Pt – N(4)
86.7(2)
[Pt(pbqx)Cl2] (3)
Pt – Cl(1)
Pt – N(1)
Cl(1) – Pt – Cl(2)
Cl(1) – Pt – N(1')
Cl(2) – Pt – N(1')
2.306(3)
2.054(8)
86.86(9)
169.5(2)
92.8(2)
Pt – Cl(2)
Pt – N(1')
Cl(1) – Pt – N(1)
Cl(2) – Pt – N(1)
N(1) – Pt – N(1')
2.293(2)
2.019(7)
99.8(2)
173.2(2)
80.8(3)
[Pt(pqn)Cl2] (5)
Pt – Cl(1)
Pt – N(1)
Cl(1) – Pt – Cl(2)
Cl(1) – Pt – N(1')
Cl(2) – Pt – N(1')
2.302(2)
2.046(7)
88.10(7)
171.55(18)
93.3(2)
Pt – Cl(2)
Pt – N(1')
Cl(1) – Pt – N(1)
Cl(2) – Pt – N(1)
N(1) – Pt – N(1')
2.297(2)
2.003(8)
98.7(2)
172.7(2)
79.6(3)
The differences in the Pt – Cl bond distances are of the same or slightly smaller magnitude
as in the Pt – N distances, and they reflect the greater trans influence of the pyridine ring than the
part of the ligands that contain fused aromatic rings [46]. For example, in complex (1), the Pt –
Cl(1) bond distance, which is trans to the Pt – Npyridine bond, is longer than the Pt – Cl(2) bond
distance, which is trans to the Pt – Nquinoxaline bond. This rationalization can be applied successfully
to complexes (3) and (5), as well.
The distortions from the ideal square planar geometry can easily be realized comparing the
coordination sphere angles, with complex (2) been the less distorted. This is expected since all
ligands are monodentate, and the bite angle of the nitrogen chelate is absent. Those distortions

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can also be seen from the deviations of the least square planes calculated for the coordination
sphere of the complexes. Thus, compound (3), being the most distorted, has N(1’) 0.14 Å out of
the Pt(donor)4 least squares plane; in (5) the deviation is 0.08 for N(1’), while in complexes (1) and
(2), which are the less distorted from that point of view, Pt and Cl(1) deviate 0.04 Å, respectively.
As mentioned in the synthetic part, (1) has been synthesized previously [10]. Aldrich-
Wright’s compound has slightly different coordination sphere characteristics (it complies with the
above discussion) and it is crystallized in a different unit cell (monoclinic vs hexagonal). Those
differences indicate the dependence of the structural characteristics on the crystal form and the
sensitivity of the coordination sphere to the weak packing interactions. The major difference of
the two structures is that the published complex forms dimmers through metallophilic interactions
(Pt – Pt, 3.832 Å), whilst our product has stronger interactions, forming 1D chains parallel to c axis
(Pt – Pt, 3.472 Å). The existence of those two polymorphs resembles the red and yellow
polymorphs of Pt(bpy)Cl2. The red polymorph displays columnar Pt – Pt interactions [47] whilst the
yellow polymorph displays aromatic ring stacking without Pt – Pt interactions [48]. This explains
the color difference in the later pair of polymorphs; the former pair has no significant color
differences due to metallophilic interactions in both polymorphs.
Solvolysis of (1), (3) and (5) in DMSO-d6
Structure and ligand releasing relationships
The dissolution of (1) and (3) in DMSO-d6 leads to the complete and instantaneous release
of the ligands pqx and pbqx from the platinum center, resulting to the complex Pt(DMSO-d6)2Cl2
1
1
and the free ligands, as evidenced from H and 195Pt NMR spectroscopy. Thus, in the H NMR
spectra of (1) and (3), in DMSO-d6, only one set of signals was observed, corresponding to the free
ligands. Also, the 195Pt NMR spectra of the same samples show a signal at δ = -3442 ppm matching
the value of Pt(DMSO-d6)2Cl2 (δ = -3443 ppm). Similarly, complex (5) reacts with DMSO-d6,
releasing the ligand pqn and producing Pt(DMSO-d6)2Cl2 but in a significantly slower rate than (1)
1
and (3) (Fig. S1). This difference allowed the monitoring of the reaction by H NMR spectroscopy.
During the time, the intensities of the 1H NMR signals of the complex (5) decrease and new signals
pop up until the solvolysis reaction was completed, indicating a slow kinetics in the NMR time
scale at 298 K (k < 10-1 s-1). The new signals were matching exactly to the free pqn in DMSO-d6. A
plot of the free pqn concentration vs. time, based on relative integrals of selected signals, fitted
with the pseudo-first order kinetics equation (2) gives a rate constant kobs= 10-4 ± 6.4 × 10-6 s-1 (Fig.
5). It is well known that substitution reactions in Pt(II) complexes follow a two-term rate law: [49,
50]

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rate = k1[complex] + k2[complex] [nucleophilic]
(3)
(4)
Under pseudo-first order kinetics equation (3) is simplified to (4):
rate = k [complex]
(k = k1 + k2 [nucleophilic])
FIGURE 5. Plot of changes in pqn concentration (10-3 M) vs. time (s) during the solvolysis of (5) at
298 K, fitted by the first order equation A = A1 - A2 e-kt , using the software Origin v. 5 (Microcal
software Ltd).
So far, it is easy to conclude that the solvolysis of (1) and (3) is not related to the N4 of pqx
and pbqx, since complex (5), which has no such nitrogen atom, solvolysed as well. In addition,
from the first point of view, the differences in the Pt – N bond lengths do not justify the
differences in the stability of the complexes, especially if we take into account well known stable
complexes with similar bond distances. For example, platinum complexes with 3,3’ substituted
bpy, have shorter Pt-N bond distances than (1), (3) and (5), and comparable distances with bpy
and bpm complexes, but decompose in DMSO; Pt(bpy)Cl2 and Pt(bpm)Cl2 (bpy = 2,2’-bipyridine
and bpm = 2,2’-bipyrimidine), resisted to the ligand release in DMSO-d6 at 298K for several weeks.
It is easy to say that the common denominator in all these three complexes (1), (3) and (5)
is the bulky shape of the ligand, which causes a significant deviation from the square planar
geometry (as shown in the description of the structures), but the exact factors which affect the
stability remain unclear. The thorough study of the structural characteristics of the prepared
complexes in comparison with other complexes is essential to shed some light on the factors that
govern this behavior.
Hazell [51] has developed and applied geometric criteria to account for the distortions of
bpy in metal complexes, while Marzilli et al [43] have applied those, successfully, in a series of Pt
and Pd complexes. To assess the distortions and correlate them with the stability of our complexes
we can use two of the above mentioned criteria (θdi, the dihedral angle between the two best
least squares planes calculated for the ligand’s ring systems, and θs, the dihedral angle between

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the two best planes calculated for the donor atoms of the coordination sphere and the four
atoms, NCC’N of the chelated part of the ligand). Additionally, we can use the torsion angle (T)
formed by the NCC’N’, which readily proves a distorted planar ligand and the two dihedral angles
(θ1 and θ2) formed by the ligand rings and the plane formed by the donor atoms. The last two
angles are indicative of how symmetrical is the distortion of the chelated ligand relative to the
planar coordination sphere. These distortions in the prepared complexes are depicted in Fig. 6.
Table 2 summarizes crystallographic data of the distortion parameters of pqx, pbqx and pqn,
together with parameters from crystal structures of similar complexes retrieved from the
Cambridge Structural Database (CSD) [52] .
(a) θdi
(b) θS
(c) T
(d) θ1
(e) θ2
FIGURE 6. The structural criteria used to assess the distortions of the prepared complexes.
The purpose of the first two groups of compounds included in Table 2 is to show that the
geometrical characteristics of the pseudo square planar complexes of Pt(II) are dependent on the
solid state; those differences can be considered minor. In the first group are the two polymorphs
of Pt(bpy)Cl2, mentioned previously, and a complex which is co-crystallized with a salt formulated
as [(tppz)Pt2(bpy)2](BF4)4 (where tppz = tetra-(2-pyridine)pyrazine); Pt(bpy)Cl2 is stacked between
the bpy moieties of the dinuclear cation [53]. The second group contains Pt(bpm)Cl2, (bpm = 2,2’-
bipyrimidine) and two solvated compounds. Again, there are small structural differences and
distortions, which can be neglected from the discussion.
The third group contains six Pt(II) complexes, all of them with substituted bipyridines. A
comparison of their characteristics can be rather enlightening. Complexes Pt(4,4’-Me2bpy)Cl2 and
Pt(5,5’-Me2bpy)Cl2 present negligible distortions and are stable in DMSO, while the other four

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TABLE 2. Distortion parameters of (1), (3) and (5) and similar complexes.
Compounda
Pt(bpy)Cl2 (red)
Pt-Nb
θdi
θS
T
θ1
θ2
CSD code
Ref.
47
48
53
54
55
56
43
43
43
22
44
22
0.0
0.0
3.6
3.3
5.7
1.8
3.0
5.0
0.9
0.0
0.7
5.1
1.8
0.4
0.0
2.3
3.7
0.0
3.7
3.9
5.9
1.6
3.4
5.5
3.0
0.0 BPYCPT03
5.3 BPYCPT10
8.4 RIGLIE
6.6 XOZWUE
2.6 NOYXOO
3.4 RINNOR
7.3 TIHVEM
3.0 PERDIZ02
Pt(bpy)Cl2 (yellow)
Pt(bpy)Cl2
2.006c 4.1
6.9
Pt(bpm)Cl2
7.8
2.004c
2.4
Pt(bpm)Cl2∙DMF
Pt(bpm)Cl2∙NMP
Pt(4,4’-Me2bpy)Cl2
Pt(5,5’-Me2bpy)Cl2
Pt(6,6’-Me2bpy)Cl2
Pt(3,3’-(HOOC)2bpy)Cl2
4.4
2.025 2.8
2.017 5.4
2.026 20.3 36.8 5.2 39.0 35.5 TIHVIQ
2.009 26.2 8.8 22.7 15.0 20.1 NEKYAD
Pt(3,3’-(MeOOC)2bpy)Cl2 1.991 25.5 8.9 21.3 14.5 19.2 PERDOF
Pt(3,3’-(HOCH2)2bpy)Cl2
Pt(pqx)Cl2 (1)
Pt(pqx)Cl2
2.017 28.9 11.4 22.3 16.0 23.7 NEKYEH
11.8 12.4 7.2 10.7 17.5
2.033c
17.1 24.3 3.5 21.5 27.6 SUQLIB
10
Pt(pbqx)Cl2 (3)
Pt(pqn)Cl2 (5)
Pt(bqu)Cl2
2.039 9.1 20.3 5.4 19.5 21.3
2.026 17.8 24.9 6.7 21.0 30.1
2.031 17.6 35.7 4.3 37.9 34.7 GAWQOL
57
a See text for the abbreviations of the ligands; b mean values; c mean value for all compounds.
complexes are significantly distorted, and they decompose in DMSO. Compounds Pt(3,3’-
(HOOC)2bpy)Cl2, Pt(3,3’-(MeOOC)2bpy)Cl2, and Pt(3,3’-(HOCH2)2bpy)Cl2 show important
differences on the parameters presented in Table 2, related to the former groups, but their
distortions are very similar among the subgroup. The reason for those distortions in the complexes
of the 3,3’-disubstituted bipyridines and their subsequent decomposition is probably the tendency
of the ligands to return to the anti- conformation due to steric hindrance of the bulky substitutes
in 3 and 3’ sites. There are two opposite forces that affect the planarity of this family of ligands.
The first one is the repulsive force between the substituents on the 3 and 3’ positions of the
chelate, which tends to rotate the two rings in such a way so the 3 and 3’ substituents have the
longest possible distance; the other is the coordination to the transition metal, which is directional
and forces the NCC’N’ system to be as planar as possible. The combination of those two leads to
the bowing distortion as described by Hazell [51]. As an example, to prove this assumption, we can
take the case of 3,3’-dimethyl-2,2’-bipyridine; unfortunately there are no Pt(II) or Pd(II) complexes

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in the literature but there are quite a few complexes with other metals in CSD [52]. When 3,3’-
Me2bpy is bonded to a transition metal, the NCC’N’ torsion T, though it is big enough due to the
steric effect of the methyl groups, it is smaller than the same torsion T in rare earth complexes,
where the covalent character of the M – N bond is reduced and eventually the directionality of the
coordination to the metal ion.
Comparing the structural parameters of Pt(6,6’-Me2bpy)Cl2 with the other members of the
group we see that the θS angle is the biggest, while θ1 and θ2 are close to each other with the
torsion angle T comparable to the stable complexes. 6,6’-Me2bpy’s plane is folded relative to
coordination plane, and this is due to the strain induced by the repulsion between the methyl
group and the chloro ligand. Similar structural behavior can be found in the pair Pt(phen)Cl2 [58]
and Pt(2,9-Me2phen)Cl2 [59].
The forth group includes complexes with ligands containing fused aromatic rings. The
compounds (1), (3), and (5), synthesized in this work, the polymorph of (1) and a platinum(II)
complex with 2,2’-biquinoline. Obviously the distortions present in the compounds are different
from the other groups and when comparing the distortion parameters of this group with the
former groups, some important observations can be made.
The θdi angles are smaller than the corresponding in the complexes of 3,3’ – substituted
bpy’s and 6,6’ – Me2bpy, but are significantly larger than those in the complexes of the
unsubstituted bpy and 4,4’- a nd 5,5’- substituted bpy’s. Note, that there are no substitutions in
positions 3,3’ and 6,6’ to affect the torsion angle T or induce repulsion to the chloro ligands,
respectively. The variation of the θs angle follows a different pattern from θdi. θs is bigger than the
corresponding in all other complexes except the 6,6’-Me2bpy compound.
There are two intramolecular non-conventional H-bonding interactions, Cl ∙∙∙ H – C, formed
by the chloro ligands and the hydrogen atom on the 6 and 6’ positions of the pyridine rings in all of
the above mentioned complexes except in Pt(6,6’-Me2bpy)Cl2 (Fig. 7a). Additionally, in the cases
where an adjacent fused aromatic ring is present this H-bond is impossible; a different H-bonding
interaction is present (Fig. 7b), which, due to the size of the formed ring, leads to increased θ2
angle, and occasionally in asymmetry between θ1 and θ2. The dimensions of those non-
conventional H-bonds are presented in Table 3. This way, the distortion and the subsequent
instability of the compounds is caused by an attractive force (instead of repulsive as in the case of
6,6’-Me2bpy) that needs to be accommodated in a six membered ring instead of a five membered.
The torsion T is small as mentioned above.

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(a)
(b)
FIGURE 7. Schematic representation of the non – conventional H-bonds formed in the N,N’ bis
aromatic chelate platinum(II) complexes. The 5- (a) and 6-membered (b) rings are shown.
TABLE 3. Structural characteristics of the non – conventional H – bonds in (1), (3) and (5) and
similar complexes (distances in Å, angles in o).
Compound
Type1
a2
a2
a2
a2
a2
a2
a2
a
C – H
0.95
0.93
0.95
0.95
0.90
H ∙∙∙ Cl
2.63
2.74
2.66
2.63
2.64
C ∙∙∙ Cl
3.23
C – H ∙∙∙ Cl CSD code Ref
Pt(bpy)Cl2 (red)
122.1
119.4
121.6
122.3
124.0
BPYCPT03 47
Pt(bpm)Cl2
3.29
XOZWUE
TIHVEM
54
43
Pt(4,4’-Me2bpy)Cl2
Pt(5,5’-Me2bpy)Cl2
Pt(3,3’-(HOOC)2bpy)Cl2
Pt(3,3’-(MeOOC)2bpy)Cl2
Pt(3,3’-(HOCH2)2bpy)Cl2
3.26
3.24
PERDIZ02 43
3.22
NEKYAD
PERDOF
NEKYEH
22
44
22
3.193
0.93
0.93
0.93
0.95
0.95
0.95
0.95
0.93
0.93
0.93
2.64
2.57
2.45
2.66
2.49
2.56
2.44
2.69
2.26
2.64
3.24
122.0
121
3.15(2)
3.17(2)
3.20
Pt(pqx)Cl2 (1)
b
135
a
116.5
123.7
121
SUQLIB
10
3
Pt(pqx)Cl2
b
3.11
a
3.15(2)
3.14(2)
3.21(1)
3.17(1)
3.14
Pt(pbqx)Cl2 (3)
b
131
a
117
Pt(pqn)Cl2 (5)
b
121
Pt(bqu)Cl2
b2
115.4
GAWQOL 57
1 Refers to Figure 7; 2 Mean values; 3 Hydrogen atoms parameters are not given.
From the above discussion it seems that the structural distortion that reduces the stability
of these pseudo-square planar Pt(II) complexes is the angle θs, which is dependent on three

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distinct ligand features: the presence of substituents in (i) 3 and 3’, (ii) 6 and 6’ positions, and (iii)
the size of the ring formed by the C – H ∙∙∙ Cl interactions.
Titration of the complexes with DMSO-d6 in CDCl3 solution
The decomposition of complex (1) in DMSO-d6 was further investigated, monitoring the
1
changes of its H NMR spectrum in CDCl3, caused by the addition of small portions of DMSO-d6
1
(Fig. S2). During the titration two different effects take place. Initially the H NMR signals of the
complex shifted until the ratio [DMSO-d6]:[(1)] increased about to 1050:1 (fast exchange) and then
new signals pop up until the final ratio reaches the value, [DMSO-d6]:[(1)] = 2500:1 (slow
exchange). The new signals were exactly matched to the free pqx in an identical mixture of DMSO-
d6:CDCl3 1:2(v/v), as it is the resultant solvent mixture of the titration.
During the first step of the titration the signals of H8 and H6’ shifted upfield by 0.27 and
0.22 ppm, respectively. This observation reflects an almost equal electron density withdrawal from
the bonds Pt-N1 and Pt-N1’ and will be interpreted as the formation of both complexes (I) and (II),
which are presented in Fig. 8C. According to this suggested mechanism, the opening of the chelate
ring was achieved from the cleavage of the one Pt-N bond (Pt-N1 or Pt-N1’), followed by the
coordination of a DMSO-d6. Also, the signals of H3 and H3’ shifted downfield by 0.46 ppm and 0.40
ppm respectively, towards their values in free pqx in anti configuration. The other proton signals
shifted slightly in a range of ± 0.05 ppm. Clearly, in this step the DMSO-d6 does not cause the
complete release of pqx from (1), but causes the cleavage of the Pt-N1 or Pt-N1’ bond. This step is
in fast kinetics at the NMR time scale and 298 K, resulting in a rate constant k1 > 105 s-1 [60]. By
adding further portions of DMSO-d6 and until the ratio increases to the final 2500:1, the pqx
proton signals shifted slightly by ± 0.05 ppm, either due to diversification of solvents
(CDCl3:DMSO-d6) ratio or due to the equilibrium of (1) with the forms (I) and (II) and the final
products of the reaction second step.
Above the ratio 1050:1, the complex begins to release the pqx and it is transformed to the
final cis-Pt(DMSO-d6)2Cl2 as also indicated from the 195Pt NMR spectrum (δ 195Pt = -3443 ppm) of
the reaction products. This second step takes place in slow kinetics at the NMR time scale and 298
K (k2 < 10-1 s-1). The observed differences in the proton chemical shifts between forms (I) and (II)
and the free ligand, are in accordance with the reaction mechanism presented in Fig. 8C. Thus, H6’
and H8 signals shift upfield by 0.95 and 1.52 ppm respectively, indicating that pqx is completely

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1
FIGURE 8. (A) Plot of H NMR chemical shifts of (1) vs. [DMSO-d6], of a 2 mM solution of (1) in
CDCl3 titrated with DMSO-d6. In the plot are noted the [DMSO-d6] corresponding to fast and slow
1
reaction kinetics at 298 K. Also, the H chemical shifts of the free ligand in the reaction solution
corresponding to the [DMSO-d6] 5.03 M are plotted. (B) Plot of free [pqx] vs. [DMSO-d6], produced
from the relative integrals of the arising proton signals and the signals of complex (1), during the
titration. (C) Suggested mechanism for the reaction of (1) with DMSO-d6.
released from Pt(II). These Δδ values are significantly higher than those observed in the first
reaction step (H6’ = 0.27 and H8 = 0.22 ppm), indicating a small contribution of this step in the
overall reaction. Since the Δδ of H8 is higher to that of H6’, it is concluded that the bond Pt-N1 is

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mainly cleaved in the second step. Also, the Δδ value of H3 is significantly small (0.04 ppm),
indicating that the pyridine ring of pqx is oriented in anti configuration from the very first reaction
step, that applies only when the bond Pt-N1’ is cleaved. Linear fitting of the plot in Fig. 8B results
an equilibrium constant of the overall reaction, Keq = 4.1 ± 0.2 × 10-4 M-1.
Similar behavior was observed for complex (3) during the titration of a 1 mM solution of (3)
1
in CDCl3 with DMSO-d6 (Fig. 9). Initially, the H NMR signals of (3) shifted until the ratio [DMSO-
d6]:[(3)] reached the ratio 1750:1 (fast exchange) and then new signals pop-up until the ratio
reaches the value, of 3000:1 (slow exchange) (Fig. S3). The new signals were exactly matched to
the free pbqx proton signals in an identical mixture of DMSO-d6:CDCl3 (v/v) 1:1, as it is the
resultant solvent mixture of the titration. The equilibrium constants were estimated in a similar
manner of (1) and calculated as Keq = 1.7 ± 0.2 × 10-4 M-1. This value is slightly lower from that of
complex (1), and unfortunately the insolubility of complex (5) in CDCl3 or in other non-coordinative
solvents, did not allow a similar titration with DMSO-d6.
1
FIGURE 9. (A) Plot of H NMR chemical shifts of (5) vs. [DMSO], of a 1 mM solution in CDCl3,
titrated with DMSO-d6. In the plot are noted the [DMSO-d6] corresponding to fast and slow
1
reaction kinetics at 298 K. Also, the H chemical shifts of the free ligand in the reaction solution
corresponding to the [DMSO-d6] 7.0 M are plotted. (B) Plot of free [pbqx] vs. [DMSO-d6], produced
from the relative integrals of the arising proton signals and the signals of complex (1), during the
titration.

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Certainly, the correlation of structural characteristics in the solid state with solution
reactivity is a difficult task to accomplish, especially in the present case where the structural
distortions are sensitive to weak solid-state interactions. It appears that the angles θs and θ2 are
directly related with the equilibrium constants of compounds Pt(pqx)Cl2 and Pt(pbqx)Cl2, indicating
that obtuse dihedral angles facilitate the dissociation of the chelates.
Conclusions
1
Based in H NMR spectroscopic techniques it was showed that ligands pqx and pbqx in
CDCl3 solution prefer the anti configuration which stabilizes through two weak hydrogen bonds
between H3’-N1 and H3’-N1. This configuration leads to the N4 monodentate coordination of pqx
and pbqx in the complexes trans-Pt(DMSO)(pqx)Cl2 (2) and trans- Pt(DMSO)(pbqx)Cl2 (4) in low
temperature (~15 °C). The trans- configuration of the complexes (2) and (4) may be explained
assuming that the reaction mechanism passes through a five-coordinated intermediate, a
rearrangement of the ligands followed by a withdrawal of a DMSO.
The crystal structures of the complexes (1), (3) and (5) showed a significant deviation of the
planar geometry and high values of the distortion parameters θs and θ2 reflecting the effect of the
fused ring of the ligands pqx, pbqx, and pqn on the coordination geometry. This is most likely a
reasonable factor for the solvolysis of the above complexes in DMSO-d6, forming the complex cis-
Pt(DMSO-d6)2Cl2 and the free ligand. Instantaneous DMSO-d6 solvolysis for the complexes (1) and
(3) and slow kinetics solvolysis for (5) with rate constant k = 10-4 ± 6.4 × 10-6 s-1, reflect their
differences in the distortion parameters. The titration of the complexes (1) and (3) with DMSO-d6
revealed a two-step mechanism of the chelate ring opening, in fast (k1 > 105 s-1) and slow (k2 < 10-1
s-1) kinetics in the NMR time scale at 298 K. In the first step of the reaction, the cleavage of one Pt-
N bond was observed, which is more favorable for Pt-N1’. The equilibrium constants Keq for the
overall solvolysis reaction were calculated as Keq = 1.7 × 10-4 ± 0.2× 10-4 for (1), and Keq = 4.1 × 10-4
± 0.2 M-1 , for (2).
These findings may be useful in the synthesis of platinum complexes, cytotoxic
experiments, as well as in the design of platinum anticancer drugs, since ligands with high
distortions may be utilized as good leaving groups under proper conditions.

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Acknowledgments
We would like to thank Prof. A. J. Tasiopoulos at the University of Cyprus for facilitating of the X-
ray difractometer. Also, we acknowledge the Unit of Environmental, Organic and Biochemical high
resolution analysis-ORBITRAP-LC-MS and the NMR Center of the University of Ioannina for
providing access to the facilities.
Supplementary Material
Figures of 1H NMR titration with DMSO-d6 of the complexes (1) and (3) and 1H NMR spectra of (5)
vs. time during its solvolysis in DMSO-d6, are provided in the Supplementary Material in addition
to the CIF files.
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Chelated N-heterocycles can be replaced from the coordination sphere of square planar
Pt(II) complexes by DMSO.
Cl
Cl
Cl
Cl
N
N
N
N
DMSO
DMSO
DMSO
Pt
+
Pt
N
N