Kinetics and mechanistic study of polynuclear platinum(II) polypyridyl complexes; A paradigm shift in search of new anticancer agents

Article abstract of DOI:10.1016/j.ica.2017.08.065

This paper reports on a mechanistic interaction between mononuclear and polynuclear platinum(II) complexes viz; phenyl-dichlorido-2,2′-dipyridinylaminediaquaplatinum(II) (PtC1); di-2-pyridylaminomethylbenzenediaquaplatinum(II) (PtC2); 1,3,5-tris(2,2′dipyr

Full text of DOI:10.1016/j.ica.2017.08.065

Accepted Manuscript
Research paper
Kinetics and mechanistic study of polynuclear platinum(II) polypyridyl com-
plexes; A paradigm shift in search of new anticancer agents
Panyako Wangoli. Asman
PII:
S0020-1693(17)30847-2
http://dx.doi.org/10.1016/j.ica.2017.08.065
ICA 17885
DOI:
Reference:
Inorganica Chimica Acta
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Revised Date:
Accepted Date:
13 July 2017
25 August 2017
30 August 2017
Please cite this article as: P.W. Asman, Kinetics and mechanistic study of polynuclear platinum(II) polypyridyl
complexes; A paradigm shift in search of new anticancer agents, Inorganica Chimica Acta (2017), doi: http://
dx.doi.org/10.1016/j.ica.2017.08.065
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Full Title
Kinetics and mechanistic study of polynuclear platinum(II)
polypyridyl complexes; A paradigm shift in search of new
anticancer agents
Article type
Research paper
Keywords:
Corresponding author
Reactivity, rigidity, flexibility, methylene, associative
Panyako Wangoli. Asman, Ph.D.
University of KwaZulu-Natal,
3209, Scottsville,
Pietermaritzburg, South Africa
E-mail: pwangoli@yahoo.com
Cell-phone: +254720383345
Corresponding author’s University of KwaZulu Natal
institution
Abstract
This paper reports on a mechanistic interaction between mononuclear
and polynuclear platinum(II) complexes viz; phenyl-dichlorido-2,2’-
dipyridinylaminediaquaplatinum(II)
pyridylaminomethylbenzenediaquaplatinum(II)
(PtC1);
(PtC2);
di-2-
1,3,5-
tris(2,2’dipyridylamino)-benzenehexaquaplatinum(II) (PtC3); 1,3,5-
tris(2,2’dipyridylmethylamino)benzenehexaquaplatinum(II) (PtC4);
and 2,4,6-tris(2,2’-dipyridylamino)-1,3,5-triazinehexaquaplatinum(II)
(PtC5) with thiourea nucleophiles under pseudo-first-order conditions
as a function of nucleophile concentration and temperature using
stopped-flow and UV-Vis spectrophotometric techniques. The
reactivity of the complexes followed the order PtC5 > PtC1 > PtC3 >
PtC2 > PtC4 with thiourea (TU) as the entering nucleophile. The
study demonstrates that both rigidity and flexibility has an influence
on the kinetics of the complexes and governs by both steric and
electronic effects. Introduction of methylene groups destroys
conjugacy and lowers the acidity of the complexes. Kinetic and DFT
data concur and illustrates that electron donation by methylene bridge
leads to stabilization of the complexes. The study further shows that
replacement of the methyne (=CH-) groups with nitrogen atoms
enhances reactivity. The small positive enthalpy of activation and
large negative values of entropy of activation indicate an associative
mode of activation for aqua ligand substitutions and dechelation
processes.
1

Kinetics and mechanistic study of polynuclear platinum(II) polypyridyl complexes; A
paradigm shift in search of new anticancer agents
Panyako Wangoli. Asman*
School of Chemistry and Physics University of KwaZulu-Natal, 3209, Scottsville, Pietermaritzburg, South Africa
E-mail: pwangoli@yahoo.com
Abstract
This paper reports on a mechanistic interaction between mononuclear and polynuclear
platinum(II) complexes viz; phenyl-dichlorido-2,2’-dipyridinylaminediaquaplatinum(II)
(PtC1);
di-2-pyridylaminomethylbenzenediaquaplatinum(II)
(PtC2);
(PtC3);
1,3,5-
1,3,5-
tris(2,2’dipyridylamino)-benzenehexaquaplatinum(II)
tris(2,2’dipyridylmethylamino)benzenehexaquaplatinum(II) (PtC4); and 2,4,6-tris(2,2’-
dipyridylamino)-1,3,5-triazinehexaquaplatinum(II) (PtC5) with thiourea nucleophiles under
pseudo-first-order conditions as a function of nucleophile concentration and temperature using
stopped-flow and UV-Vis spectrophotometric techniques. The reactivity of the complexes
followed the order PtC5 > PtC1 > PtC3 > PtC2 > PtC4 with thiourea (TU) as the entering
nucleophile. The study demonstrates that both rigidity and flexibility has an influence on the
kinetics of the complexes and governs by both steric and electronic effects. Introduction of
methylene groups destroys conjugacy and lowers the acidity of the complexes. Kinetic and
DFT data concur and illustrates that electron donation by methylene bridge leads to
stabilization of the complexes. The study further shows that replacement of the methyne (=CH-
) groups with nitrogen atoms enhances reactivity. The small positive enthalpy of activation and
large negative values of entropy of activation indicate an associative mode of activation for
aqua ligand substitutions and dechelation processes.
2

Introduction
The search for more efficacious Pt-based drugs other than cisplatin has been amplified due to
the steady rise in cancer deaths globally.1,2 The clinical use of cisplatin and its analogous is
restricted by dose-limiting deleterious side effects such as nausea, ototoxicity, nephrotoxicity,
neurotoxicity, myelosuppression, and acquired resistance.3-5 This search has been extended to
multinuclear platinum(II) complexes such as BBR3464 and N,N,N’,N’,N”,N”-hexakis(2-
pyridylmethyl)-1,3,5-tris(aminomethyl)-benzene which have shown cytotoxicity in some cell
lines.6-8 This class of complexes [multinuclear Pt((II)] has distinctive mechanisms of action
compared to mononuclear analogues.9,10 They have shown the potential to expand the spectrum
of treatable tumours and to overcome clinical resistance in cisplatin cell lines.11-13 Their
increased cytotoxicity is due to different types of intra- and interstrand DNA cross-linking
adducts which they form.14,15 This is due to their ability to form flexible, non-directional and
mainly interstrand DNA-adducts that enhances conformational changes that leads to improved
antitumour activity.16,17 This improved antitumour activity has made them a class of clinically
relevant drug candidates.18,19 The distinct molecular characters of pharmacological action of
multinuclear complexes is contributed by the rigidity/flexibility of the bridging ligands in
conjunction with the intra-metal distances that offer the possibility of forming both intra- and
inter-strand DNA cross-linking adducts. The presence of more than one platinum centre causes
formation of multiple adducts that disrupt DNA’s helical structure with improved replication
and transcription.20,21 This is promoted by multinuclear Pt(II) complexes having appropriate
metal-metal separation which is significant in polymetallic biosites. This improved
mutagenicity is integrated to reach maximum level due to synergy of linking metal moieties.
In the development of the proposed antitumour agents, this study utilized 2,2’-dipyridylamine
as the core chelating agent to synthesize multi and mononuclear Pt(II) analogues. The influence
of this ligand on the reactivity of Pt(II) complexes and the ligand’s ability to modulate the
potential toxicity22 of the metal complexes is of interest. Both mononuclear and multinuclear
Pt(II) and Pd(II) complexes based on this core have showed high cytotoxicity as potential
anticancer agents23-25 which shows an area full of prospects that can be explored to give
potential anticancer drug candidates. They form complexes with cis configuration similar to
cisplatin which are likely to produce similar array of adducts with DNA but with improved
biological consequences than cisplatin.26 This study focuses on cis conformers since
3

cis/trans structure-activity relationship of platinum antitumor complexes, exemplified by
cisplatin shows that only the cis geometry is therapeutically active. The complexes are
designed by tuning the steric and electronic effects on reactivity. It is projected that such tuning
of the lability of antitumour Pt(II) complexes may improve the efficacy and overcome the side
effects of the present anticancer agents. The complexes designed herein are good models for
mechanistic and kinetic studies and suggest potential prospects as anticancer drugs with N-
donor ligands.27 The study further tunes the complexes by incorporating methylene groups and
heteroanalogues of benzene by replacing =CH- units with isovalent atoms of nitrogen. Such
tuning of the linker remains vital to determine the influence of nitrogen on cytotoxicity of
antitumour agents and as a π-acceptor atom on the reactivity of metal complexes.28 In
corporation of such chelating ligands that can interact with free or protein bound metal ions is
important in understanding mechanistic activities of newly designed chemotherapeutics. The
scope of this ligand substitution reactions is to determine the rate laws consistent of Pt(II)
complexes which offer two labile reaction sites in nucleophilic medium. The study focuses on
mechanistic overview based on experimental and computational calculations.
To gain insight into the mechanistic substitution reactions of these polynuclear Pt(II)
complexes with biological nucleophiles, viz thiourea (TU), N,N’-dimethylthiourea (DMTU)
and N,N,N’,N’-tetramethylthiourea (TMTU), a full kinetic and mechanistic investigation was
undertaken. The study determined the kinetics and bioactivity of trinuclear Pt(II) complexes
with 6-aqua ligands with sulphur donor molecules for the first time. The nucleophiles studied
are of special interest as they represent targets and competitors of anticancer platinum-based
therapeutics in the cellular cell lines and also play a role as chemoprotective agents.29,30 The
specific roles of these nucleophiles has been outlined in the previous paper.31 To achieve this
objective, the study determined the influence of structural flexibility and rigidity on reactivity
of complexes shown in Scheme 1. All the complexes are ligated by 2’2-dipyridylamine
backbone that ensures a similar structure to cisplatin. However, the ancillary ligands are varied
to investigate their influence on their substitution reactions. Such tailoring of the backbone
linker is anticipated to improve bio-stability and bioavailability of these trinulear Pt(II)
complexes as anti-tumour agents. Hence the goal of this investigation is to contribute towards a
mechanistic understanding of the interaction of multinuclear Pt(II) complexes with biologically
relevant molecules. This is due to multinuclear Pt(II) complexes showing wider spectrum of
4

activity that has given hope of forming clinically relevant candidates. This makes this class of
complexes the most promising alternatives to cisplatin since they can provide significant
cytostatic activity in several cisplatin resistant tumour cell lines. This paper shows how
tailoring the backbone of the metal complex leads to dramatic changes in their acidity and
reactivity. This tailoring of the bridging ligands is envisaged to provide special delivery
carriers to selectively transport metal-based agents tumour cell-lines.
(ClO4)6
(ClO4)2
(ClO4)2
OH2
H2O
OH2
Pt
N
N
N
Pt
Pt
OH2
H2O
OH2
N
N
N
N
N
N
N
OH2
N
Pt
N
OH2
N
PtC1
N
N
P
tC2
Pt
H2O
OH2
PtC3
(ClO4)6
(ClO4)6
OH2
N
OH2
Pt
OH2
N
OH2
N
Pt
N
OH2
N
N
H2O
Pt
N
N
N
N
N
Pt
OH2
N
N
H2O
N
N
N
N
N
N
N
N
Pt
OH2
Pt
H2O
H2O
OH2
PtC4
PtC5
Scheme 1:
Schematic structures and abbreviations for the aqua Pt(II) complexes.
Experimental Section
Materials and methods
All starting materials were obtained from commercial sources and used as received without
further purification. The nucleophiles TU, 99 %, DMTU, 99 % and TMTU, 98 %, benzyl
bromide, 98 %, bromobenzene, 99 %, cyanuric chloride (2,4,6-trichloro-1,3,5-triazine), 99 %,
1,3,5-tribromobenzene, 98 % and 1,3,5-tris(bromomethyl)benzene, 97 %, AgClO4 99.99 %,
were obtained from Sigma Aldrich while K2PtCl4 and 2,2’-dipyridylamine (dpa) were obtained
from Strem chemicals. De-ionized water was used in all experiments.
5

Synthesis of ligands
Three ligands; di-2-pyridylaminobenzene, di-2-pyridylaminomethylbenzene, and 1,3,5-
tris(bromomethyl)benzene were synthesized according to literature procedures.32,33a
A
weighed amount of bromoalkyl halide (0.855 g, 5.00 mmol) was dissolved in 3 mL DMF at
room temperature and 2,2’-dipyridylamine (0.856 g, 5.00 mmol) and KOH (1.137 g, 20.26
mmol) in 5.00 mL DMF added drop wise. The resulting solution was stirred under nitrogen at
room temperature for 24 hours and dried under vacuum. The residue was washed with water
and extracted into CHCl3 (3×50 mL). The extracts were dried over anhydrous sodium sulphate
and filtered. The filtrate was dried under vacuum and chromatographed on silica gel with
CHCl3:CH3OH (5:1) v/v. The resulting yellow product was recrystallized from an acetone-
water mixture.
1,3,5-Tris(di-2-pyridylaminomethyl)benzene was prepared by reacting di-2-pyridylamine
(0.856 g, 5 mmol) with potassium hydroxide (1.121 g, 20 mmol) in 5 mL of DMSO. The
mixture was stirred for 1 hour and 1,3,5-tris(bromomethyl)benzene (0.595 g, 1.667 mmol)
added and stirred for an additional 48 hours. Water was added drop-wise to induce
crystallization. On standing, a yellow powder formed and was filtered off, washed with plenty
of water and recrystallized from an ethyl acetate-petroleum ether mixture. The synthesized
ligands were characterized using 1H, 13C NMR, mass spectrometry and elemental analysis.
1
Di-2-pyridylaminobenzene, Yield, 0.604 g, (49 %). H NMR (400 MHz, CDCl3, 303 K) δ
8.28 (2H, d, py), 7.68 (2H, t, py), 7.60 (2H, d, py), 7.57 (2H, d, ph), 7.20 (1H, t, ph), 7.16 (2H,
13C NMR (100 MHz, CDCl3, 303 K) δ 157.5, 148.6, 139.5, 117.4,
d, ph), 6.94 (2H, t, py) ppm.
Anal. Calcd. for C16H13N3, C, 78.13, H, 5.79, N, 16.08, Found C, 78.34, H, 5.45, N,
112 ppm.
16.34; TOF MS ES+ m/z: [M+H]+ = 248.309.
1
Di-2-pyridylaminomethylbenzene, Yield, 0.277 g, (21 %). H NMR (400 MHz, CDCl3, 303
K) δ 8.40 (2H, d, py), 7.60 (2H, t, py), 7.37 (2H, d, py), 7.27 (2H, d, ph), 7.20 (1H, t, ph), 7.16
13C NMR (100 MHz, CDCl3, 303 K) δ
(2H, d, ph), 6.94 (2H, t, py), 5.55 (2H, s, CH2) ppm,
157.5, 148.6, 139.8, 137.4, 128.0, 117.4, 114.4, 51.3 ppm. Anal. Calcd for C17H15N3, C, 78.13,
H, 5.79, N, 16.08, Found C, 77.78, H, 5.55, N, 16.48, TOF MS ES+ (m/z): [M+H]+ = 262.134.
6

1
1,3,5-tris(di-2-pyridylaminomethyl)benzene, Yield, 0.578 g (55 %). For C39H33N9, H NMR
(400 MHz, CDCl3, 303 K) δ 8.22 (6H, d, py), 7.40 (6H, t, py), 7.09 (3H, s, ph), 6.92 (6H, d,
py), 6.81 (6H, t, py), 5.34 (6H, s, CH2) ppm. 13
C NMR (100 MHz, CDCl3, 303 K) δ 157.4,
148.6, 139.5, 136.6, 124.0, 117.0, 114.5, 51.6 ppm. Anal. Calcd. for C39H33N9, C, 74.67, H,
+
5.30, N, 20.10, Found C, 74.27, H, 5.12, N, 19.86, TOF MS ES+ (m/z): C39H34N9 = 628.2937.
1,3,5-tris(di-2-pyridylamino)benzene (tdab) was prepared according to literature procedure
using 1,3,5-tribromobenzene and di-2-pyridylamine via copper-mediated Ullmann
condensation.34 A mixture of 1,3,5-tribromobenzene (0.525 g, 1.67 mmol) in dichloromethane
(30 mL), di-2-pyridylamine (0.856 g, 5 mmol) in dichloromethane (20 mL), potassium
carbonate (0.8976 g, 6.448 mmol) in water (10 mL) and copper (II) sulphate pentahydrate
(0.1355 g, 0.5428 mmol) in water (10 mL) was stirred overnight at room temperature and
evaporated to dryness under vacuum. The dried mixture was ground in a mortar and 5 drops of
chloromethane added and heated at 210 οC for 8 hours under nitrogen. The mixture was cooled
to room temperature and dissolved in a mixture of dichloromethane (50 mL) and water (50
mL). The organic layer was washed with water (3×50 mL), dried over Na2SO4, and
concentrated to give a yellow residue that was purified by chromatographic column using
tetrahydrofuran (THF) and hexane (3:1) v/v to obtain a brown solid. The brown solid was
recrystallized from a mixture of CH2Cl2 – hexane to give a white crystalline compound.
1,3,5-tris(di-2-pyridylamino)benzene (tdab), Yield, 0.302 g, (57 %).1H NMR (400 MHz,
CDCl3, 303 K) δ 8.28 (6H, d, py), 7.56 (6H, dd, py), 7.14 (6H, d, py), 6.91 (6H, dd, py), 3.16
(3H, s, ph) ppm, 13C NMR (100 MHz, CDCl3, 303 K) δ 158.0, 148.7, 146.8, 137.9, 120.6,
118.9, 117.9 ppm. Anal. Calcd for C36H27N9: C, 73.83, H, 4.65, N, 21.52, Found C, 73.41, H,
4.81, N, 21.88.
2,4,6-tris(dipyridin-2-ylamino)–[1,3,5]-triazine (tdat) was prepared according to Gamez et
al. method.35 The synthesis was via sequential substitution of the three chlorides of cyanuric
chloride by 2,2’-dipyridylamine. 2,4,6-trichloro-[1,3,5]-triazine (cyanuric chloride) (0.307 g,
1.67 mmol) was dissolved in 25 mL tetrahydrofuran (THF) and 3 equivalent moles of N,N-
diisopropylethylamine (DIPEA, ‘Hünig’s base’ 0.646 g, 5.00 mmol) added while stirring. The
ο
resulting yellow solution was cooled down to 0 C. Subsequently, a solution of 2, 2’-
dipyridylamine (0.856 g, 5.00 mmol) in THF (20 mL) was added drop-wise and the reaction
7

mixture stirred at 0 οC for 1 hour. The reaction mixture was warmed to room temperature and
ο
refluxed for 48 hours at 67 C. The resultant white precipitate was isolated on a glass filter
washed with THF (3× 20mL) and with ethanol (3× 20 mL) to remove DIPEA.
1
2,4,6-tris(dipyridin-2-ylamino)–[1,3,5]-triazine (tdat), Yield 0.296 g (30 %). H NMR (400
MHz, CDCl3, 303 K)
δ 8.35 (6H, d, py), 7.51 (6H, dd, py), 7.42 (6H, d, py), 7.03 (6H, dd, py)
13
ppm, C NMR (100 MHz, CDCl3, 303 K) δ 165.8, 154.9, 148.2, 137.3, 122.9, 120.8 ppm.
Anal. Calc. for C33H24N12, C, 67.34, H, 4.11, N, 28.55, Found C, 66.98, H, 4.08, N, 28.80; TOF
MS ES+ (m/z): [M+Na]+ = 611.2141.
Preparation of PtC1, PtC2 and PtC4
The complexes were synthesized from their respective ligands according to a reported
procedure.36 A 50 mL solution of K2PtCl4 was stirred and the corresponding molar equivalent
of respective ligands dissolved in a small amount of ethanol was added drop-wise. The reaction
mixture was refluxed overnight at 50 °C. The resulting platinum(II) complexes were obtained
as precipitates, washed with ultrapure water and diethyl ether and dried in vacuum overnight.
They were characterized with similar techniques as ligands.
PtC1, Yield, 55 mg, (35 %). 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.80(d, 3H), 7.96
(t, 3H), 7.28(d, 3H), 7.12 (d, 3H) ppm, 13
(100 MHz, DMSO-d6)
C NMR
δ, 153.7, 148,6, 137.6,
195Pt NMR -2105 ppm. Anal. Calcd. for C16H13N3PtCl2, C, 37.35, H, 2.55, N,
117, 112.4 ppm,
8.17, Found C, 37.52, H, 3.02, N, 7.84, TOF MS ES+, m/z: [M-Cl]+ = 479.0607.
1
PtC2, Yield, 69 mg, (44 %). H NMR (400 MHz, DMSO-d6) δ 8.83(d, 2H), 8.04 (t, 2H),
7.68(d, 2H), 7.53 (d, 2H), 7.36 (t, 1H), 7.26 (ddd, 4H), 5.43 (s, 2H) ppm, 13
(100 MHz,
C NMR
DMSO-d6, 303 K)
δ, 153.4, 151.7, 148.4, 141.3, 136.2, 129.2, 127.3, 117.8, 114.8, 53.7 ppm,
195Pt NMR -2189.2 ppm. Anal. Calcd. for C17H15N3PtCl2, C, 38.72, H, 2.87, N, 7.97, Found C,
38.46, H, 3.07, N, 8.10; TOF MS ES+, m/z: [M+Na]+ = 550.0247.
PtC4, Yield, 120 mg, (53 %).1H NMR (400 MHz, DMSO-d6) δ 8.83(d, 6H), 8.04 (s, 3H), 7.74
13
(d, 4H), 7.30 (d, 14H), 5.34 (s, 6H) ppm,
(100 MHz, DMSO-d6
C NMR
303 K) δ, 153.5,
195Pt NMR -2190.3 ppm. Anal. Calcd. for
152.0, 141.5, 137.4, 127.3, 121.6, 116.8 and 53.9,
8

C39H33N9Pt3Cl6, C, 32.84, H, 2.33, N, 8.84, Found C, 32.36, H, 2.51, N, 8.60; TOF MS ES+,
m/z: [M-Cl]+ = 1390.0830.
Synthesis of complexes PtC3 and PtC5 (tdabPt3 and tdatPt3)
These complexes were synthesized according to the procedure reported by Corey et al.37,38
Synthesis of [(PtCl2)3(tdab) PtC3] and [(PtCl2)3(tdat) PtC5]: 93.9 mg (0.160 mmol) of tdat was
dissolved in 6 mL CH2Cl2 and placed in a reaction tank. Benzene (4 mL) and a solution of
K2PtCl4 (200 mg, 0.481 mmol) in a mixture of 3 mL of H2O and 5 mL of DMSO were layered
upon the solution of tdat in the reaction tank. The yellow K2PtCl4/H2O/DMSO solution sank
through the layer of benzene and settled upon the tdat/CH2Cl2 layer. The solvents were allowed
to diffuse for two weeks at ambient temperature under nitrogen to dryness. Yellow crystalline
solids were obtained weighed and characterized.
1
PtC3, Yield, 108 mg, (49 %). H NMR (400 MHz, DMSO-d6) δ 8.88(d, 6H), 7.96 (t, 6H),
7.30(d, 6H), 7.12 (t, 6H), 3.48 (s, 3H) ppm, 13
(100 MHz, DMSO-d6
C NMR
303 K) δ, 154.5,
195Pt NMR -2103.5 ppm. Anal. Calcd. for
152.2, 142.5, 137.4, 127.3, 121.6, 116.8 ppm,
C33H27N9Pt3Cl6, C, 29.41, H, 2.02, N, 9.35, Found C, 29.63, H, 1.98, N, 9.10.
1
PtC5, Yield, 118 mg, (53 %). H NMR (400 MHz, DMSO-d6) δ 8.80(d, 6H), 7.96 (t, 6H),
7.30(d, 6H), 7.10 (t, 6H) ppm, 13
(100 MHz, DMSO-d6)
C NMR
δ, 157.4, 154.8, 146.2, 137.2,
195Pt NMR -2104.2 and -2155.6 ppm. Anal. Calcd. for
122.9, 120.8, 117.2 ppm,
C33H24N12Pt3Cl6, C, 28.59, H, 1.74, N, 12.12, Found C, 28.93, H, 1.54, N, 11.80; TOF MS ES+,
m/z: [M-Cl]+ = 1351.0259.
Physical measurements
NMR spectra were recorded on a Bruker 400 MHz (1H) and a 100 MHz ((13C) spectrometer.
All chemical shifts are reported in δ (ppm). Elemental analyses were performed on Thermal
Scientific Flash 2000 and mass spectra recorded on LCT Premier micro-mass Spectrometer.
The Carbon shifts were recorded with reference to the relevant solvent signal while those of
protons were referenced to tetramethylsilane (Si(CH3)4) while 195Pt spectra were referenced to
K2PtCl6 in D2O. Kinetic studies for fast reactions were monitored using an Applied
Photophysics SX20 stopped-flow spectrophotometer coupled to an online data acquisition
system. A Varian Cary 100 Bio UV-Vis spectrophotometer thermostated by a Varian Peltier
9

ο
temperature controller to within 0.05 C was used for the slow kinetic measurements. The
kinetic traces were analyzed using the Origin 7.5® software package.39 The pH of the solutions
was recorded on a Jenway 4330 pH meter calibrated using standard buffer solutions of pH 4.0,
7.0 and 10.0.
Preparation of complex solutions
Owing to poor solubility of the chloro complexes they were converted to aqua analogues
according to reported method.40-44 Aqua solutions were prepared by refluxing chloro
complexes with equivalent amount of silver perchlorate. Perchlorate salts are preferred due to
their high solubility in water and are kinetically stable. The solutions were refluxed at 40-50 οC
for 48 hours in 0.1 M HClO4 (50 mL). Perchlorate salts and HClO4 acid were used as inert
-
electrolytes and ClO4 anion is non-complexing ion. It provides strong acidity with minimal
interference since it is weakly nucleophilic. Increased acidity results from the conjugate base of
-
HClO4 acid, ClO4 anion that has its negative charge distributed equally over the four oxygen
-
atoms. This delocalization of the conjugate base, ClO4 anion, contributes to the increased
acidity of HClO4 acid than HCl acid. Also HClO4 acid is not susceptible to hydrolysis. As such
HClO4 acid and perchlorate salts were used to adjust ionic strength in kinetic studies where
other electrolytes might complex the metal ion. The AgCl precipitate was removed by filtration
through 0.45 µmilli-pore membrane filter. The removal of the Cl- ions by Ag+ to form AgCl(s)
-
ensured presence of platinum aqua species, [Pt(OH2)2]2+ in the solution and ClO4 as the
counter ion.. This is supported by the pKa values that indicate at pH 2.0 the major species
involved in kinetics processes are aqua species. The resulting aqua solutions were titrated with
NaOH solution to determine the pKa values of the complexes for kinetic investigations.
pKa determination of the aqua complexes
Spectrophotometric pH titrations were carried out on UV-Vis spectra on a Varian Cary 100 Bio
spectrophotometer. NaOH was used as the base for spectrophotometric titration in the pH range
1 – 10. To avoid absorbance corrections due to dilution a large volume of the platinum aqua
complex (250 mL) was used. To avoid leaching of chloride ions, 500 µL of the sample taken in
ampoules were placed on the electrode and pH recorded then discarded. The pH was adjusted
by adding 0.01, 0.05, 0.10 and 0.50 M solutions of either NaOH or HClO4 acid. The pH of the
10

solution was maintained at pH 2.0 based on the pKa study and the ionic strength was
maintained at 0.1 M using NaClO4.
Kinetic measurements
Spectral changes resulting from mixing the trinuclear Pt(II) complex and nucleophile solutions
were recorded over the wavelength range 200 to 800 nm to establish a suitable wavelength at
which kinetic measurements were performed. A summary of the used wavelength for each
nucleophile is summarized in Table S1 (Electronic Supporting Information). All kinetic
measurements were performed under pseudo-first-order conditions at least 20 fold and 60-fold
excess of the nucleophile over that of the metal concentration for mononuclear and trinuclear
complexes respectively. This ensured at least 10-fold of nucleophiles concentration at each
platinum centre hence forced the reaction to completion. The temperature was controlled
ο
throughout all kinetic experiments within an accuracy of 0.05 C. Activation parameters
(∆H # and
were measured as a function of temperature over a temperature range of 15 to
∆S # )
ο
ο
40 C at an interval of 5 C. The reported rate constants represent an average value of at least
six to eight independent kinetic runs for each set of experimental conditions on the stopped
flow and a triplicate for UV-Visible spectrophotometer. All data obtained from both the UV-
Visible and stopped flow spectrophotometric techniques were fitted to first-order exponential
function to generate the pseudo-first-order rate constants (kobs). The reactions were followed by
the changes in absorbance at suitable wavelengths for both fast reactions on the stopped flow
and slow ones on the UV-Vis spectrophotometer.
Computational Calculations
Density functional theory (DFT) calculations were performed with the Gaussian 09 package.45
All these DFT calculations were performed using Becke’s46 three parameter exchange
functional (B3) combined with both Lee- Yang-Parr gradient corrected correlation functional
(LYP) using LanL2DZ as the basis set. B3LYP refers to a three parameter functional hybrid
exchange of Becke with functional correlation gradient of Lee, Yang and Parr,47 whereas
LANL2DZ refers to Los Alamos National Laboratory 2 Double ζ basis set.48 The study utilized
the B3LYP/LANL2DZ level of theory in gas phase to model the structural and electronic
properties of the complexes. The singlet states were used due to low electronic spin of Pt(II)
complexes. To understand the electronic structures of the studied complexes, DFT calculations
11

were carried out. The ground-states electronic structures were calculated to enable determine
the energies of molecular orbitals. The optimized structures and plots were created by Gauss
View.49 The optimized molecular structures are presented in Figure 1 while the labeling of the
atoms is shown in Figure 2. The DFT-optimized structure of PtC1 shows the dihedral and basal
angles between two pyridyl groups chelated to Pt(II) centre. Selected bond lengths, bond angles
and other parameters are given in Table 1.
12

LUMO-
map
LUMO
-15.32 eV
-8.78 eV
LUMO -14.26 eV
LUMO
-15.49 eV
LUMO
LUMO
HOMO
-8.77 eV
eV
∆E = 3.86
eV
eV
∆E = 3.11
∆E = 3.76
eV
∆E = 4.31
∆E = 4.77 eV
HOMO
-11.88 eV
-12.54 eV
-19.18 eV
HOMO
-18.57 eV
HOMO
-20.26 eV
HOMO
HOMO-
map
Planarity
Figure 1:
DFT optimized structures of HOMO and LUMO frontier molecular orbitals of the platinum(II) complexes at
B3LYP/LANL2DZ level theory (Isovalue = 0.02).
13

Figure 2:
Optimized molecular structure of PtC3 showing the coordination spheres of the
complex. Hydrogen atoms were not labeled for clarity. Extracted data is
summarized in Table 1.
Figure 3:
DFT-optimized structure of PtC1 showing the dihedral and basal angle between
two pyridyl groups. The dihedral and basal angles have minimal effect on the
reactivity of the complexes.
14

Table 1: Selected bond lengths (Å), bond angles (degrees) and NBO charges for
the various atoms of the complexes
Complex
HOMO-LUMO ∆E
LUMO/eV
PtC1 PtC2
PtC3
PtC4
PtC5
-8.78
-8.77 -15.32 -14.26 -15.49
HOMO/eV
-12.54 -11.88 -19.18 -18.57 -20.26
∆E/eV
3.76
3.11
3.86
4.31
4.77
Electrophilicity index (ɷ)
(eV)
30.22 34.20
77.09
62.41
66.88
NBO Charges on: Pt
0.755 0.760
0.786
0.786
0.786
0.781
0.772
0.772
0.786
0.786
0.786
Dipole moment (Debye)
Inter-atomic distance (Å)
5.9126 6.4378 2.6377 4.6285 2.7545
1.4736 1.5128 1.4530 1.5026 1.4122
C4-N10
C32-N10 1.4135 1.4112 1.4391 1.4195 1.4477
C43-N10 1.4135 1.4091 1.4391 1.4199 1.4467
Intermetallic distance (Å)
Pt73-Pt74
Pt73-Pt75
Pt74-Pt75
9.0082 11.1296 8.7157
9.8967 11.5317 9.7200
9.8964 12.6557 9.7201
Dihedral angle between
pyridyl rings (°)
45
50.37
55.84
40.23
54.49
Inter-atomic distance were obtained from Figure 2
Determination of pKa values for the aqua complexes
The pKa titration studies were carried out to ascertain the acidity of the complexes. The
established pKa values ensured that kinetic studies were carried out with complexes in their
aqua form. The pKa titrations showed all the complexes to exist in aqua species at pH 2.0.
Basing on this pKa titration data, reaction of aqua complexes were performed at pH 2.0 to
ensure that the complexes exist as aqua species. A typical UV-Vis spectrum recorded during
spectrophotometric titration of the six-aqua complex with NaOH is shown in Figure 4. The pKa
values were determined from Boltzmann Equation 1 by fitting a characteristic sigmoid curve
and locating the inflection point using the Origin 7.5® program. The pKa values of the
deprotonated complexes are summarized in Table 2 while the proposed deprotonation
mechanism is represented in equilibrium reaction in Scheme 2 for mononuclear analogue.
[1]
y = A2 +
(
A1 − A2
)
/
(1 + exp
(
x − x0 )/ ∂x )
15

where A and A2 are initial and final y values respectively, x0 = centre, ∂x = width.
1
x0
A
y
y
1
The value at
is half way between the two limiting values and A2 . The value changes
x
∂x
drastically within a range of variable. The width of this range is approximately
.
1.00
2.4
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
2.1
1.8
1.5
1.2
0.9
0.6
0.3
0.0
1
2
3
4
5
6
7
8
9
pH
210 240
270
300
330
360 390
420
450
480
510 540
Wavelength (nm)
Figure 4:
UV/Vis spectra for the titration of PtC5 complex recorded as a function of pH
in the range of 2 to 10 at 25 οC, Inset Plot of absorbance versus pH at λ = 295
nm.
Table 2:
A summary of pKa values obtained for stepwise deprotonation of aqua Pt(II)
complexes investigated
Complex
pKa1
PtC1
2.32 0.01
4.53 0.02
PtC2
2.87 0.02
6.97 0.11
PtC3
PtC4
PtC5
2.37 0.08
3.30 0.01
4.02 0.01
4.78 0.08
6.73 0.07
8.45 0.01
2.53 0.02
3.17 0.01
3.60 0.01
4.30 0.01
5.42 0.03
7.46 0.07
2.23 0.02
3.34 0.10
4.03 0.02
4.66 0.08
5.70 0.04
7.99 0.03
pKa2
pKa3
pKa4
pKa5
pKa6
The pKa values are in the order PtC5 > PtC1 > PtC3 > PtC4 > PtC2 which corroborates the
electronic properties of the bridging ligands. The trend shows complexes with rigid linkers to
have lower pKa values compared to those with methylene groups. The reduced acidity of the
complexes with flexible linkers is attributed to the inductive effect of methylene linker that
16

increases electron density on the dipyridyl rings.49b This makes deprotonation of the
coordinated aqua ligands difficult due to increased electron density around the Pt(II) centre.
The higher electron density in these compounds is supported by DFT calculations that show
raised HOMO orbitals in complexes possessing methylene linkers. Raised HOMO orbitals
signify addition of electrons to the respective orbitals. On the other hand, the low-lying LUMO
orbitals in rigid complexes PtC1, PtC3 and PtC5 augment a better π-back-donation of
electrons from the metal centre to the pendant phenyl ring. As mentioned earlier, back donation
to the heterocyclic ligand (PtC5) stipulates the transfer of negative charge into its delocalized
π-system i.e. the LUMO. The study shows the negative charge to be shared by more atoms in
PtC5 in Scheme 2 which is favourable for its reactivity. The low lying LUMO orbitals account
for extensive delocalization in the complex. Electronic factors in rigid complexes are also
exhibited by bond lengths of the atoms. For instance, the short C4-N10 in rigid complexes
(1.4122 – 1.4736 Å) are indicative of partial double bond character (sp2 hybridization)
compared to methylene linked complexes with longer bond length (1.5026 – 1.5128 Å)
indicating single bond character (sp3 hybridization). This findings show more extended and
effective delocalization in rigid complexes than flexible analogues. As such, higher acidity in
rigid complexes is expected due to more effective π-back donation. This results are also in
agreement with literature report50a,51-53 showing methylene group to have inductive effect. The
introduction of methylene spacers destroys the conjugacy of the complexes hence reduced
acidity and reactivity.54-56a
The subsequent deprotonation values are higher due to lowering of overall charge of the
complex. The decrease in charge in trinuclear complexes from 6+ to 5+ decreases the
electrophilicity of the metal centres decreasing the acidity the complexes upon formation of
hydroxo species. Thus, increase in pKa trend reported is due to the decrease in the overall
charge of the complexes. The higher pH values recorded for subsequent deprotonation was due
to formation of the hydroxo species. Higher pH values are recorded due to hydroxo-aqua
species in the solutions which are less reactive towards the entering ligands.
The introduction nitrogen atoms in the backbone of benzene (PtC5) lead to an increase in
acidity of the coordinated aqua molecules. This is due to the π-accepting properties of triazine
that reduce electron density from the metal centres. This increases electrophilicity of the metal
17

centres hence lower pKa values. This is also supported by low lying HOMO orbitals that
suggest removal of electrons from HOMO orbitals. Increased π-back bonding in PtC5 is
further supported by shorter C4-C10, C2-C11 and C6-N12 bond lengths (1.4122 Å) compared
to N10-C32, N10-C43, N11-C53, N11-C60, N12-C13, N12-C25 (1.4477 Å). The variation in
bond lengths in this complex indicates flow of electrons from 5d orbitals of the metal to the
antibonding orbitals of triazine ring. Similar observation was also reported by Wang et al.,38
and El-Ghayoury et al.56b Thus, the presence of hetero-atoms in the benzene ring enhances the
transfer of negative charge into its π delocalized system that supports resonance as proposed in
Scheme 2. The resonance property of the compound has a significant effect on both bond
lengths and the acidity of the coordinated aqua ligands in this complex.57 The conjugate base of
this complex is proposed to enjoy resonance stabilization making it more acidic. This is
reflected in the out-of ring nitrogen atoms showing sp2 hybridization while the inner benzene
nitrogen atoms possess high electron density due to increased π-back bonding in triazine
backbone. Thus, the resonance effect on pKa values in PtC5 moiety agrees with predictable
behaviour of the complex.
N
N
N
N
N
N
N
N
N
N
N
N
Out-of ring nitrogen
sp2-hybridized
inner nitrogen
Scheme 2:
The resonance hybrid structures of PtC5 complex with 1,3,5-triazine backbone
Kinetic studies
The substitution reactions of coordinated aqua ligands with bio-relevant nucleophiles viz. TU,
DMTU and TMTU was carried out under pseudo-first-order conditions using conventional
UV-Visible spectrophotometry and stopped flow techniques. The suitable wavelengths for
kinetics were determined by premixing equal volume of the complex with that of nucleophile
in a tandem cuvette then mixing the solutions. A typical spectral change in a kinetic trace is
shown Figure 5. The subsequent decrease in absorbance indicates the presence of two
18

subsequent reaction steps of PtC5 with TU. The recorded kinetic traces were fitted to a single
exponential function. Figure 6 shows typical plots of absorbance verses time for PtC5 with TU
and DMTU on the stopped flow while part (c) shows the kinetic trace with TMTU on the UV-
Vis spectrophotometer.
0.52
0.9
0.50
0.48
0.8
0.46
0.44
0.7
0.42
320 nm
0.40
0.38
0.6
0.36
0.34
0.5
0
10
20
30
40
50
60
70
80
90 100
Time (min)
0.4
0.3
0.2
0.1
300
310
320
330
340
350
360
370
1.2
1.0
0.8
0.6
0.4
0.2
0.0
Wavelength (nm)
(b)
(a)
290 300 310 320 330 340 350 360 370
Wavelength (nm)
Figure 5:
UV/Vis spectral changes during the reaction of PtC5 and TU at T = 298.15 K,
pH = 2.0 and I = 0.1 M NaClO4. (a) Initial spectrum before adding TU and (b)
spectrum at t = 30 s; successive spectra were recorded at an intervals of 5 min.
19

0.09
0.08
0.07
0.06
0.05
0.04
0.23
0.22
0.21
0.20
0.19
0.18
0.17
0.16
1.65
1.60
1.55
1.50
1.45
1.40
1.35
1.30
0
2
4
6
8
10
12
14
Time(Sec)
0
10
20
30
40
50
60
0
1000
2000
3000
4000
5000
6000
Time(sec)
Time (min)
(a)
(b)
(c)
Figure 6:
Typical kinetic traces showing a fast substitution reaction step of PtC5 with (a) TU (b) DMTU on the stopped-flow
while (c) is the last two steps of TMTU on UV-Vis spectrophotometer at T = 298.15 K, pH = 2.0, I = 0.1 M NaClO4.
The first step of TMTU was observed on the stopped-flow while the third step of DMTU was recorded on UV-Vis
spectrophotometer.
20

The observed pseudo-first order constants, kobs were obtained as average values of six to eight
independent kinetic runs for each experimental condition on the stopped-flow and in triplicates
on UV-visible spectrophotometry. The kobs values were plotted against the entering nucleophile
concentration. The plots are linear with zero or negligible intercept as shown in Figures 7, 8
and S3–S5 in the Electronic Supplementary Information. The rate constants (k2) are linearly
dependent on the concentration of entering of nucleophile. The kobs(1,2,3) is expressed by
Equation [2].
kobs(1,2,3) = k2(1st, 2nd,3rd)[Nu]
[2]
The second-order rate constants for reaction steps of the corresponding complexes at 25 οC are
summarized in Table 3.
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
TU
DMTU
TMTU
0.000
0.003
0.006
0.009
0.012
0.015
0.018
[Nu] M
Figure 7:
Plots of kobs(1) versus nucleophile concentration for the reaction of PtC1 at pH =
2.0, T = 298.15 K, I = 0.1 M NaClO4.
21

4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
TU
DMTU
TMTU
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
[Nu] M
Figure 8:
Plots of kobs(1) versus nucleophile concentration for the reaction of PtC5 at pH =
2.0, T = 298.15 K, I = 0.1 M NaClO4.
Table 3:
A summary of the second order rate constants, k2, for the reaction of the
investigated complexes at pH = 2.0, T = 298.15 K and at I = 0.1 M NaClO4
2nd order rate constant/M-1s-1
Complex
PtC1
Nu
k2(1st)
k2(2nd) x10-2
4 0.30
1 0.02
-
k2(3rd) x10-3
51.78 0.40
45.74 0.77
37.06 0.22
33.34 0.27
25.09 0.19
11.45 0.04
40.71 0.22
37.23 0.55
15.64 0.26
27.87 0.25
20.84 0.14
6.73 0.05
52.41 0.11
40.21 0.68
16.43 0.09
-
-
-
-
-
-
TU
DMTU
TMTU
TU
DMTU
TMTU
TU
3 0.40
1 0.01
1 0.02
5 0.30
1 0.01
-
6 0.40
2 0.04
0.5 0.01
4 0.10
64 0.30
7 0.10
PtC2
PtC3
PtC4
PtC5
DMTU
TMTU
TU
DMTU
TMTU
TU
-
-
-
-
-
4 0.1
Too slow
DMTU
TMTU
22

Activation parameters
To investigate thermodynamic and chemical stability of the complexes, reactivity was
performed at various temperatures (15 °C to 40 °C. This enabled examine the changes in
thermodynamic stability viz the enthalpy,
(
∆H #
)
and the entropy,
(
∆S #
of activation. These
)
activation parameters were determined from the Eyring plots illustrated in Figures 9 and 10 and
(S6-S8) using Equation 3. The complexes showed kinetic stability at all temperatures that
conferred thermostability of the investigated class of Pt(II) complexes.
∆H #
∆S # ∆H #
∆S

# 
k

k









2
B



In
= −
+ In

+
=
+ 23.8 +
[3]




T
RT
h
R
RT
R






where kB and h are Boltzmann’s and Planck’s constants respectively while R is gas constant
and T is absolute temperature.
-5.6
-5.8
-6.0
-6.2
-6.4
-6.6
TU
DMTU
TMTU
-6.8
-7.0
-7.2
-7.4
0.00325
0.00330
0.00335
1/T K-1
0.00340
0.00345
0.00350
Figure 9:
Eyring plots for first substitution step of PtC1 monitored on stopped-flow
spectrophotometer at I = 0.1 M NaClO4, pH = 2.
23

-4.2
-4.4
-4.6
-4.8
-5.0
-5.2
-5.4
-5.6
-5.8
-6.0
-6.2
-6.4
-6.6
-6.8
-7.0
-7.2
-7.4
TU
D M TU
TM TU
0.00325
0.00330
0.00335
1/T K -1
0.00340
0.00345
0.00350
Figure 10:
Eyring plots for the first substitution step of PtC5 monitored on stopped-flow
spectrophotometer at I = 0.1 M NaClO4, pH = 2.0.
24

Table 4:
A summary of the activation parameters for the substitution of aqua
ligands pH = 2.0 and at I = 0.1 M NaClO4
Activation Enthalpy/ kjmol-1
Activation entropy/ J mol-1K-1
Complex
PtC1
Nu
∆H1#
∆S1#
∆H2#
∆S2#
40.83 0.9
39.97 1.2
44.93 1.5
39.81 0.3
43.47 1.7
40.86 0.8
-114 3
-118 4
-103 5
-121 1
-111 6
-126 3
21.91 0.4
29.89 0.4
-
-229 1
-213 1
-
TU
DMTU
TMTU
TU
20.54 0.8
26.74 0.9
41.02 1.5
-249 2
-241 3
-179 5
PtC2
PtC3
PtC4
PtC5
DMTU
TMTU
39.58 0.8
40.48 0.7
53.30 1.2
38.60 0.9
30.00 0.5
45.22 1.1
39.49 0.3
44.04 1.4
52.10 0.8
-108 3
-106 2
-66 4
-116 3
146 2
-104 4
-107 1
-94 5
28.20 1.0
33.33 0.8
-
-209 3
-200 3
-
TU
DMTU
TMTU
TU
23.31 0.3
30.41 0.6
44.48 0.1
32.80 0.4
30.80 0.5
51.09 1.3
-221 1
-204 2
-164 1
-194 1
-165 2
-121 4
DMTU
TMTU
TU
DMTU
TMTU
-74 3
The small positive enthalpies and significantly large negative entropy values support an
associative mode of substitution mechanism commonly reported for the Pt(II) square-planar
complexes.58-61 In this mode of mechanism, the ML3X complex binds to the incoming ligand Y
to form a five-coordinate intermediates (ML3XY)# as shown in Scheme 3. Substitution of X
results in a 16 electron complex ML3Y in which the negative activation entropy indicates an
increase in the order of the transition state relative to the reactants.58,59 The small positive
enthalpy values reported in Table 4 is attributed to bond formation before bond breaking in the
transition state.60,61
Substitution reaction
Since it is unlikely for the entering nucleophile to displacement six water molecules by a single
kinetic phase, a biphasic reaction is proposed at each metal centre. The first step is attributed to
fast substitution of one water molecule at each metal centre. The second phase is composed of
two simultaneous reactions; where the second water molecule is displaced followed by a
dechelation process. The extent of the second step was governed by the steric hindrance caused
by coordination of the first nucleophile. The much slower second step was joined by the
displacement of the labilized linker due to the strong trans effect of thiourea coordination. The
25

proposed reaction mechanism with thiourea as the entering nucleophile is shown in Scheme 3.
This shows S-donor ligands as strong and efficient nucleophile that can compete with DNA for
binding to Pt(II) complexes.
#
2+
H2N
S
S
2+
H2N
NH2
OH2
OH2
N
NH2
+
H2N
NH2
-H2O
Pt
S
OH2
N
N
N
k2
1st
Pt
Pt
OH2
+
N
N
S
OH2
H2N
NH2
2+
#
NH2
N
N
S
Nu
Nu
Nu
Nu
H2N
Excess
H2N
-H2O k2(2nd)
H2N
Pt
NH2
+
S
NH2
S
N
Pt
[Pt(Nu)4]2+
Linker
Nu = Thiourea
H2O
N
Scheme 3:
Proposed substitution mechanism showing biphasic substitution at each Pt(II)
centre followed by the dechelation process
1
The dechelation step was confirmed using H and 195Pt NMR kinetics by monitoring
coordination details of the reactants and products (Figures 11 and 12). Coordination of the
ligand to the metal ion causes 1H chemical shifts. Figure 11 shows an array of 1H NMR spectra
for the reaction between PtC3 with 6 equivalents of thiourea. The spectra show net chemical
shifts of the coordinated pyridyl protons indicating changes in their coordination environment.
The dipyridyl protons denoted Ha were monitored due their proximity to N-donor atoms when
coordinated to the metal centre. Their resonance on the chloro complex appear downfield at δ =
8.88 ppm that indicates coordination of platinum atom. This downfield shift is due to the
change in electron density on coordination to the metal atom. On reaction with excess TU the
Ha protons shift to Ha’ which appear upfield at δ = 8.28 ppm similar to those of uncoordinated
26

ligand. A decrease in electron density on the pyridyl by the σ effect yields to this downfield
shift at all ring positions on complexation.
A signal peak shown at δ = -2103.5 ppm by 195Pt NMR is consistent with platinum(II)
complexes with cis-PtN2Cl2 configuration.62,63 On reaction with 6 equivalents of TU shows a
peak at -3905.6 ppm with no reaction intermediates (Figure 12). This shifting of the peak
indicates the preference of Pt(II) to coordinate to sulphur-donor ligands. The study show Pt-N
adducts to be converted to Pt-S adducts.64 The peak at -3906.6 ppm on 195Pt NMR denotes
2+
formation of Pt(TU)4 complex when reacted with excess thiourea.65,66 From experimental
1
data both the H and 195Pt NMR support the complexes to undergo displacement of the linker
induced by strong trans effect of the sulphur donor atoms.67
Figure 11:
Time dependent stacked plot of 1H NMR spectra of PtC3 with 6 equivalents of
TU undergoing dechelation to liberate the bridging linker.
2+
Figure 12:
Time dependent 195Pt NMR shifts of PtC3 in DMF forms [Pt(TU)4 ] on
reaction with excess TU.
27

Discussion
This work reports on the reactivity of mono and trinuclear dipyridylamine Pt(II) complexes
with biologically relevant molecules. With a view of shedding light on the role of rigidity
verses flexibility of bridging moieties, the study shows that introducing methylene groups in
the backbone of a complex significantly reduces its reactivity. However, the effect is opposite
when a hetero atom or rigidity is introduced as the two enhances reactivity. The experimental
results verifies this by showing a reactivity trend of PtC5 > PtC1 > PtC3 > PtC2 > PtC4 with
TU as the entering nucleophile. The trend is governed by both steric and electronic effects
arising from the methylene spacers and heteroatoms in the backbone of the ligands. The high
reactivity of PtC5 is due to the decrease of electron density at the Pt(II) centre caused by
enhanced π-back-donation to π* orbitals of triazine ligand. The stronger π-acceptor of triazine
stabilizes transition state by accepting electron density that is donated by the entering
nucleophile to the metal centre. This increases electrophilicity at the Pt(II) centres that leads to
high reactivity which is reflected in its lower pKa values of the coordinated water ligands. This
is caused by the presence of electronegative nitrogen atoms which leads to greater π-back-
donation from metal centre to the triazine ring. On the other hand, complexes with flexible
ligands (PtC2 and PtC4) show slower reactivity than with rigid spacers (PtC1 and PtC3). The
study suggests methylene groups to increase electron density on the pyridyl rings and prevent
effective π-back bonding.68 Also the presence of lone pair electrons on the amine nitrogen
makes them stronger σ donors than rigid counterparts. Thus, a combination of rigidity and
delocalization accounts for the enhanced reactivity of rigid appended complexes. Rigidity and
flexibility is proposed to have a significant influence on the reactivity of the complexes.
The high reactivity of PtC5 is also attributed to the increase in the number of ring electrons
when =CH- are replaced by nitrogen atoms. Each nitrogen atom introduces two additional
electrons making triazine ring to have six non-bonding electrons in addition to its π-electrons.
This unshared pair of electrons to some extent is delocalized and become part of the aromatic
π-electron system in both ground and excited states.69 This complex shows high π accepting
property but decreased σ-donor strength as electronegativity is within the ring is increased.
This leads to delocalization of the dπ electrons from the metal to the empty π* orbitals of the
triazine ring. The electron withdrawing effect of 1,3,5-triazine cycle is supported by the
lowered HOMO orbitals and wider HOMO-LUMO gap (∆E = 4.77 eV) Table 1. The
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withdrawal of electron density lowers and stabilizes the HOMO orbitals. This is also reinforced
by the presence of low-lying LUMO orbitals which increases π-back-bonding. It should also be
noted that in PtC3, the amino nitrogen lone pair does not favour conjugation with the central
benzene ring due to steric interactions with ortho hydrogen atoms. Hence there is reduced π-
back donation compared to PtC5. In PtC5 the amino nitrogen lone pair conjugates with
triazine ring due to absence of ortho hydrogen atoms.
Two consecutive steps were observed for trinuclear complexes PtC3 and PtC4 which supports
the notion that the three platinum centres are in the same chemical environment. In contrast,
PtC5 shows more reaction steps with sterically hindered nucleophiles supporting the likelihood
of fluxionality of the complex in solution.70,71 The complex is reported to undergo dynamic
interchange of chemically inequivalent groups.71,71 The rotations and unsymmetrical nature of
PtC5 in solution presents the possibility of chemically distinct metal centres as shown in
Figure 13. However, this behaviour was not observed in PtC3. The 195Pt NMR shows a single
peak (Figure 12) that corresponds to one set of dipyridyl unit coordinated to Pt centre from the
central benzene. This supports the previous study of PtC3 to have symmetric structure in
solution with all the three dipyridyl units in the same chemical environment.38 Similarly, PtC4
showed a single 195Pt NMR spectrum at -2190.3 ppm. This value is consistent with N2-PtCl2
environment. Single peaks in PtC3 and PtC4 supports the number of substitution steps
suggesting all the three metal atoms to be chemically equivalent.
In PtC5 an increase in π electrons makes the complex to have a fluxional behaviour. This
fluxionality favours the “up and down” structure that keeps the platinum centres in chemically
different environment contrary to the expected symmetry of C3 conformation. The “up and
down” structure, is as a result of the axial and equatorial pyridyl groups undergoing
interconversion through dynamic process in which the ring undergoes chair conformational
change. This makes the electronic structure of PtC5 to be different from PtC3 that accounts for
the difference in the kinetic and chemical shifts in PtC5.72 The two peaks at -2104.2 ppm and -
2156.6 ppm in the ratio of 2:1 by 195Pt NMR spectra indicates platinum centres to be a
chemically different environment. Based on this observation different number of substitution
steps is expected from fluxional behaviour of PtC5.
29