Crystal structure, electronic properties and cytotoxic activity of palladium chloride complexes with monosubstituted pyridines

Article abstract of DOI:10.1039/c1dt11412c

Palladium(ii) complexes attract great attention due to their remarkable catalytic and biological activity. In the present study X-ray characterization, UV-Vis and Time-Dependent Density Functional Theory (TD-DFT) calculations for six PdCl₂(XPy)₂ complexes (where: Py = pyridine; X = H, CH₃ or Cl) were applied in order to investigate substituent effects on their crystal structures and electronic properties and to combine the results with their catalytic and cytotoxic activity. The structures of complexes PdCl₂(3-MePy)₂, PdCl₂(4-MePy)₂ and PdCl₂(2-ClPy)₂, have been described for the first time and we compared our results with available data for the whole series of six complexes. All compounds exhibit a square planar coordination geometry in which the palladium ion coordinates two nitrogen atoms of pyridine ligands and two chlorine atoms in trans positions. For complexes with ortho substituted XPy ligands a cis disposition of substituents takes place, whereas for other ligands: 3-MePy and 3-ClPy - the substituents are in trans positions. For XPy the energies of π-π* and n-π* transitions depend on the position and nature of the X substituent in the XPy ring. After complex formation a hipsochromic shift (24-34 nm) of π-π* and a bathochromic shift of n-π* bands are observed. The UV-Vis spectra of PdCl ₂(XPy)₂ confirm that square planar coordination geometry of complexes I-VI and two dπ-π* transitions are expected. With the help of the TD-DFT calculations we proved that dπ-π* transitions in solutions of PdCl₂(XPy)₂ complexes result from MLCT (metal-to-ligand charge transfer) with contribution from chlorine atoms to palladium. We also studied substituent effects on cytotoxic properties of Pd(ii) complexes against the human breast cancer cell line MCF7, the human prostate cancer cell line PC3, and the human T-cell lymphoblast-like cell line CCRF. The studied complexes were the most active against the CCRF cell line and less or even no cytotoxic effect was observed for PC3 cells. Complexes with MePy ligands showed increased cytotoxic activity compared to unsubstituted pyridine ligands.

Full text of DOI:10.1039/c1dt11412c

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PAPER
Crystal structure, electronic properties and cytotoxic activity of palladium
chloride complexes with monosubstituted pyridines†
Agnieszka Krogul,*a Jakub Cedrowski,a Katarzyna Wiktorska,b Wojciech P. Ozimin´ski,b,c Jadwiga Skupin´skaa
and Grzegorz Litwinienko*a
Received 26th July 2011, Accepted 28th September 2011
DOI: 10.1039/c1dt11412c
Palladium(II) complexes attract great attention due to their remarkable catalytic and biological activity.
In the present study X-ray characterization, UV-Vis and Time-Dependent Density Functional Theory
(TD-DFT) calculations for six PdCl2(XPy)2 complexes (where: Py = pyridine; X = H, CH3 or Cl) were
applied in order to investigate substituent effects on their crystal structures and electronic properties
and to combine the results with their catalytic and cytotoxic activity. The structures of complexes
PdCl2(3-MePy)2, PdCl2(4-MePy)2 and PdCl2(2-ClPy)2, have been described for the first time and we
compared our results with available data for the whole series of six complexes. All compounds exhibit a
square planar coordination geometry in which the palladium ion coordinates two nitrogen atoms of
pyridine ligands and two chlorine atoms in trans positions. For complexes with ortho substituted XPy
ligands a cis disposition of substituents takes place, whereas for other ligands: 3-MePy and 3-ClPy – the
substituents are in trans positions. For XPy the energies of p–p* and n–p* transitions depend on the
position and nature of the X substituent in the XPy ring. After complex formation a hipsochromic shift
(24–34 nm) of p–p* and a bathochromic shift of n–p* bands are observed. The UV-Vis spectra of
PdCl2(XPy)2 confirm that square planar coordination geometry of complexes I–VI and two dp–p*
transitions are expected. With the help of the TD-DFT calculations we proved that dp–p* transitions in
solutions of PdCl2(XPy)2 complexes result from MLCT (metal-to-ligand charge transfer) with
contribution from chlorine atoms to palladium. We also studied substituent effects on cytotoxic
properties of Pd(II) complexes against the human breast cancer cell line MCF7, the human prostate
cancer cell line PC3, and the human T-cell lymphoblast-like cell line CCRF. The studied complexes
were the most active against the CCRF cell line and less or even no cytotoxic effect was observed for
PC3 cells. Complexes with MePy ligands showed increased cytotoxic activity compared to
unsubstituted pyridine ligands.
are efficient catalysts for industrially important processes, i.e.
Introduction
carbonylations,2,3 polymerizations4 and other organic reactions
Complexes of palladium are considered as promising novel materi-
like, for example, the Heck reaction, Suzuki–Miyaura cross-
als of wide applicability. Palladium square planar complexes with
coupling, Sonogashira coupling, Negishi coupling, Stille cross
coupling, etc.5,6 Moreover, palladium(II) complexes are supposed
pyridine ligands are relatively ease to prepare and have remarkable
catalytic activity,1–6 thus, complexes of palladium(II) with amines
to be potential anticancer agents and this expectation flows from
a close resemblance of Pd complexes to Pt complexes.7 The most
recognized anticancer agent is cis-diamminedichloroplatinum(II),
a compound colloquially named cisplatin. Unfortunately, thera-
aUniversity of Warsaw, Pasteura 1, 02-093, Warsaw, Poland. E-mail: litwin@
chem.uw.edu.pl, akrogul@chem.uw.edu.pl; Fax: (48) 22 8222380; Tel: (48)
peutic application of cisplatin has been limited by its serious side
effects like, for example, nephrotoxicity, ototoxicity, neurotoxicity,
allergy. An additional reason which has limited the applicability of
Pt complexes is that some kinds of tumor cells (i.e. ovarian or small
cell lung cancers) have shown a resistance after initial treatment
with cisplatin.8,9 This kind of chemoresistance has been also
observed by Reedijk et al.10 for other Pt complexes (being simple
analogs of cisplatin). Recently, some attention has been focused
on compounds with bulky planar ligands which are believed to
be kinetically and thermodynamically more stable than simple
22 8220211 ext. 378
bNational Medicines Institute, Chelmska 30/34, 00-725, Warsaw, Poland
cInstitute of Nuclear Chemistry and Technology, Dorodna 16, 03-195,
Warsaw, Poland
† Electronic supplementary information (ESI) available: Elemental analy-
sis of complexes I, II and VI. Structures of complexes III–V. Selected bond
distances and angles for complexes III–V. UV-Vis spectra of free XPy
ligands and PdCl2(XPy)2 complexes. Frontier Orbitals involved in dp–p*
transitions in complexes I and VI. Visualisation of dp–p* transitions in
complexes I and VI. Theoretical UV-Vis spectra of complexes I, III and VI.
CCDC reference numbers 837204–837206. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c1dt11412c
658 | Dalton Trans., 2012, 41, 658–666
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analogs of cisplatin.11 Most of the therapeutically investigated
complexes are cis isomers although sometimes trans conformers
also demonstrate high activity.12 Noticeable cytotoxic activity,
comparable to standard platinum-based anticancer agents, was
exhibited by some planar trans aminepalladium(II) complexes i.e.
trans-PdCl2L2 (where L = hydroxypyridine substituted in the 2-, 3-
or 4- position).13 Thus, design, synthesis and studies on anticancer
properties of trans palladium complexes are based on assumptions
that complexes with the new metal in the coordination center
will exhibit remarkable antitumor activity with less side effects.13
Indeed, there is a general agreement that DNA can be protected
not only by Pt(II) but also by Pd(II).14 Taking into account
all the above mentioned arguments, a particular interest has
been located on palladium(II) complexes with planar amines
where steric and electronic features of ligands may affect the
mechanism of substitution at the metal centre and DNA binding.
Pd(II) complexes with pyridine-type ligands, (e.g. pyrazole)11
and some other complexes, for example with 2,6-dimethyl-4-
nitro-pyridine ligand, reveal better cytotoxic properties than
cisplatin.7
Coordination compounds of palladium(II) are model substrates
for studies on crystal geometry of square planar complexes. Since
the catalytic and cytotoxic activity of these complexes depends
on their electronic and crystal structure15,16 an introduction of
different ligands to the coordination sphere is a simple and
convenient method that allows the steric and electronic environ-
ment to be modulated around the metal centre17 leading to an
improvement in the desired properties of a modified complex.
Recently, much effort has been devoted to the synthesis of new
palladium complexes with relatively complicated multifunctional
ligands such as pincer groups,17 multidentate pyridine-type ligands
like bis(2-pyridylmethyl)amine,18 pseudorotaxanes,19 or a combi-
nation of nitrogen donor – pyridine and N-heterocyclic carbene.
These complexes display intriguing coordination chemistry and
effective catalytic activities,6 however, full characterization of
simple complexes allows for improved design and synthesis of
much more advanced compounds. Although in the early sixties
and seventies of the last century the transition metal(II) halides
complexes with pyridine were extensively studied, the coordination
geometry and electronic properties for the series of palladium(II)
complexes with simple ligands i.e. MX2L2 (where: M is metal, X is
halide and L is pyridine or its derivative) still remain unexplored.20
This part of physical organometallic chemistry is unrecognized
though detailed, systematic studies on simple Pd(II) complexes
appear as an interesting area potentially resulting in data that
might be applied to design new compounds with higher antitumor
and higher catalytic efficiency.
Our studies have long been concerned with the structural
effects of substrates on the yield of carbonylation of amines and
nitrocompounds.24–28 We described the substituent effects in the ni-
trobenzene and aniline ring on the yield of ethyl N-fenylcarbamate
(EPC) in the carbonylation of a nitrobenzene (NB), mixture
NB/AN or AN (where AN is aniline), respectively.29,30 However,
our previous studies were limited to PdCl2 and PdCl2Py2 com-
plexes without detailed research on the nature of a ligand and
structure of a catalyst. Recently, we have focused on the synthesis
and catalytic activity of palladium(II) chloride complexes with
pyridine and its derivatives in the carbonylation of nitrobenzene.1
High turnover numbers were observed for complexes dependent
on a ligand present in the complex. We observed a correlation
between the catalytic activity of PdCl2(XnPy)2 complexes (where:
X = Cl or CH3, n = 0–2) and electron density on the nitrogen atom
in a pyridine ligand—described by the basicity of XnPy. Moreover,
incorporation of ortho-substituted pyridines to palladium catalyst
decreased the yield of the investigated reaction.1 Based on our
results we proposed the mechanism of carbonylation of NB where
electron transfer from the palladium atom to nitrobenzene is the
rate determining step.1 During previous studies we realized that,
according to our knowledge, no detailed systematic analysis of the
absorption spectra of square planar palladium(II) complexes with
substituted pyridines had been reported. Therefore, we decided to
compare crystal structures and electronic properties of a series of
sixPdCl2(XPy)2 (where:X=H, CH3 or Cl)complexes toinvestigate
substituent effects on structural and spectral properties and to
combine the results with catalytic and biological activity of these
complexes.
Results and Discussion
In order to investigate substituent effects on structural and
electronic properties of Pd(II) complexes we prepared model com-
pounds formed from PdCl2 and pyridine derivatives containing
methyl and chlorine substituents. In our previous work we showed
that PdCl2(XnPy)2 (where: X = CH3 or Cl; n = 0–2) complexes
are selective catalysts in the carbonylation of nitrobenzene in
the presence of the catalytic system PdCl2(XnPy)2/Fe/I2/XnPy.1
Moreover, the catalytic activity of the PdCl2(XnPy)2 compounds
depends on electronic properties and position of a substituent
in the pyridine ring – higher conversions of NB were observed
for complexes with pyridines containing electron donating methyl
groups and the highest turnover frequency (TOF) was observed
for PdCl2(4-MePy)2. The electron donating/electron withdrawing
properties of XnPy ligands were described by the basicity of pyri-
dine derivatives. We also noticed that the presence of substituents
in the ortho position of the pyridine ring decreased the yield of
the reaction. In the current studies on square planar palladium(II)
complexes with substituted pyridines we decided to explore the
substituent effects on molecular structure and electronic properties
of the complexes in order to find a possible correlation with their
catalytic and biological activity. The following PdCl2 complexes
with monosubstituted XPy ligands are described (with their
symbols in parentheses): PdCl2(Py)2 (I), PdCl2(2-MePy)2 (II),
PdCl2(3-MePy)2 (III), PdCl2(4-MePy)2 (IV), PdCl2(2-ClPy)2 (V)
and PdCl2(3-ClPy)2 (VI). The results and discussion are gathered
in four subsections: structure of the complexes, comparison of
electronic spectra of ligands/complexes, theoretical calculations
Pyridine and its derivatives are often regarded as model com-
pounds for studies of more complicated N-donor heterocyclic lig-
ands and many natural heterocyclic amines are based on pyridine
rings – the most prominent and most important derivatives such
as nicotine, nicotinamide and nicotinamide adenine dinucleotide
diphosphate (NADP) or pyridoxine (vitamin B6) occupy key
positions in biochemistry.21–23 A pyridine-type ring is also an
important building block of the purine system, which co-forms
DNA and plays a substantial role in cell division. Therefore, a
combination of pyridine derivatives with palladium to form Pd(II)
complexes are supposed to have a large affinity for DNA binding
sites.11
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Table 1 Crystal data and details of structure refinements for com-
pounds: PdCl2(3-MePy)2 (complex III), PdCl2(4-MePy)2 (complex IV) and
PdCl2(2-ClPy)2 (complex V)
and, finally, a description of the cytotoxic activity of the studied
PdCl2(XPy)2 complexes.
Complex III
Complex IV
Complex V
Crystal structures of PdCl2(XPy)2 complexes
Formula
Weight
Crystal system
C12H14Cl2N2Pd
363.57
C12H14Cl2N2Pd
363.57
Monoclinic
C10H8Cl4N2Pd
404.40
According to the literature, the crystallographic data for complexes
I, II, and VI are already known. Therefore, in this work the
crystal structures of three other complexes (III, IV and V) are
described for the first time and we compared our results with
available data for the whole series of six complexes. Single yellow
crystals of III, IV and V were obtained by slow evaporation of
their acetone solutions and all three compounds were found to
be neutral mononuclear palladium complexes. The crystal data
and details of structure refinements for these new complexes are
presented in Table 1 whi◦le Table 2 contains the selected bond
Triclinic
Triclinic
¯
¯
Space group
P1
P21/n
P1
˚
a/A
5.7438(5)
7.2880(8)
8.4654(9)
69.081(10)
79.744(8)
83.763(8)
325.33(6)
1
10.4617(5)
3.9801(2)
15.9063(9)
8.2008(18)
8.5307(18)
10.512(2)
91.866(17)
91.018(17)
115.73(2)
661.7(3)
2
˚
b/A
˚
c/A
a
b
g
98.734(4)
a
˚
V (A)
654.64(6)
2
1.844
1.803
0.0140(1356)
0.0342(1603)
Zb
Dc/g cm-3c
m/cm-1d
Re
1.856
1.814
0.0127(1533)
0.0337(1581)
2.030
2.186
0.0337(2321)
0.0761(3166)
˚
distances (A) and angles ( ) collected for all complexes I–VI.
f
Structure of complex III (Fig. 1A and Table 1) indicates that
3-methylpyridine rings show a trans disposition of methyl groups.
The resulting crystals have been proved to belong to the triclinic
Rw
a V = volume of the unit cell, b Z = number of formula units in unit cell,
c D = density, m = linear absorption coefficient e R is R-factor, f Rw is
d
¯
space group P1. Detailed analysis shows that the 3-methylpyridine
weighted R-factor.
ring is not orthogonal to the coordination plane (the dihedral angle
is 66.57◦). The square planar coordination geometry is confirmed
by angles [N–Pd–Cl] = 89.47(3)◦ and 90.53(3)◦, respectively as
it has been observed for complexes IV and V (data for these
complexes are listed in Table 2). Crystals of complex IV belong to
the monoclinic space group P21/n, the crystallographic data for
compound IV are presented in Table 1 and the structure of IV is
shown in Fig. 1B. Also in this complex a ligand (4-methylpyridine)
ring is not orthogonal to the coordination plane and the dihedral
angle between the coordination plane and the ring plane is 54.58◦.
The square planar coordination geometry is confirmed by [N–Pd–
Cl] angles, 89.48(3)◦ and 90.52(3)◦, respectively (see Table 2).
The palladium complex with 2-chloropyridine (compound V,
Fig. 1C) was significantly less soluble in common organic solvents
than complexes with methylpyridines. The crystals of V were
obtained by cooling the warm acetone solution and belong to
¯
the triclinic space group P1, i.e. to the same group as it was ob-
served for III. Surprisingly, in this complex two trans-coordinated
◦
a
˚
Table 2 Selected bond distances (A) and angles ( ) for complexes I–VI
III–V—this work
I, II, VI—literature data
Bond lengths
III
IV
V
I
II
VI
Pd–N(1)b
Pd–N(1A)
2.0191(11)
2.0191(11)
2.3027(5)
2.3027(5)
1.3477(17)
1.3448(17)
1.3477(17)
1.3448(17)
2.0139(11)
2.0139(11)
2.3054(3)
2.3054(3)
1.3472(19)
1.3408(18)
1.3472(19)
1.3408(18)
2.034(3)
2.032(3)
2.3045(11)
2.3036(11)
1.405(5)
1.328(5)
1.360(5)
1.338(4)
2.024(6)
2.023(6)
2.297(1)
2.297(1)
1.356(6)
1.356(6)
1.336(6)
1.336(6)
2.043(6)
2.033(6)
2.313(3)
2.300(3)
1.35(1)
1.34(1)
1.33(1)
2.010(7)
2.010(7)
2.315(3)
2.315(3)
1.362(10)
1.332(10)
1.362(10)
Pd–Cl(1)
Pd–Cl(1A)c
N(1)–C(1)d
N(1)–C(5)e
N(1A)–C(1A)
N(1A)–C(5A)
Bond angles
N(1)–Pd–N(1A)
N(1)–Pd–Cl(1)
N(1)–Pd–Cl(1A)
N(1A)–Pd–Cl(1)
N(1A)–Pd–Cl(1A)
Cl(1)–Pd–Cl(1A)
C(1)–N(1)–Pd
C(5)–N(1)–Pd
C(1A)–N(1A)–Pd
C(5A)–N(1A)–Pd
180.00
180.00(6)
89.48(3)
90.52(3)
90.52(3)
89.48(3)
180.00
120.62(9)
120.87(10)
120.62(9)
120.87(10)
178.88(12)
89.32(9)
89.93(9)
91.02(9)
89.65(9)
176.17(4)
119.7(2)
122.3(2)
117.6(2)
123.8(2)
180.00
177.5(2)
90.6(2)
90.0(2)
88.7(2)
90.6(2)
178.81(7)
117.2(5)
123.2(5)
177.5(2)
90.6(2)
180
89.47(3)
90.53(3)
90.53(3)
89.47(3)
180.00
119.36(9)
121.38(9)
119.36(9)
121.38(9)
90.83(7)
90.83(7)
89.17(7)
89.17(7)
178.3(1)
120.3(3)
120.8(3)
120.3(3)
120.8(3)
89.5(2)
90.5(2)
90.5(2)
89.5(2)
180
119.6(7)
120.6(6)
119.8(5)
120.6(6)
a Schematic picture showing the order of the atoms. b N(1) corresponds to N(1B) in PdCl2(2-ClPy)2 (see Fig. 1). c Cl(1A) corresponds to Cl(2) in
PdCl2(2-ClPy)2 (see Fig.1). d C(1) corresponds to C(1B) in PdCl2(2-ClPy)2 (see Fig.1). e C(5) corresponds to C(5B) in PdCl2(2-ClPy)2 (see Fig. 1).
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that this difference can be explained by the greater contribution of
back-donation of electrons from the central atom into ClPy than
into MePy, related to the inductive effect of chlorine atoms.34 As
far as N–C length is concerned, the distance between N and C
(substituted) in complex V is 5% shorter than the length of N–C
(C-unsubstituted). It can also be explained by the inductive effect
of the chlorine substituent which decreases the distance between
N and C (substituted) (see the structure in Fig. 1C).
The presence of an ortho substituent in the pyridine ring is
manifested by increasing the Pd–N distance in PdCl2(2-XPy)2 as
observed for II (Table 2) and for V (Table 2). Except for this “effect
of ortho group”, the introduction of methyl or chlorine in the ortho
position of the pyridine ligand causes differences in the Pd–N–C
bond angles in II and V.
Because of the symmetric disposition of methyl groups in 4-
MePy ligands (complex IV) the bond angles Pd–N–C(1) and Pd–
N–C(5) in this complex are equal (120.7 0.2◦) making compound
IV more similar to trans-dichlorobis(pyridine)palladium(II), while
in complex III a slight (ca. 2◦) difference between Pd–N–C(1)
and Pd–N–C(5) is observed (see Table 2). Another deviation
of complexes with ortho substituted pyridines from the rest of
investigated compounds is that the dihedral angles between the
ligands are about 18◦ for 2-XPy while they are 0◦ for complexes
containing 3- and 4-XPy. We suppose that the 2-XPy rings are not
in one plane because of the packing effect.
Concluding this section, the nature and position of substituents
in the aromatic ring is important to the structure of PdCl2(XPy)2
complexes. We observed a decrease in the distances between
selected atoms in complexes with X = Cl compared to compounds
with X = CH3. In addition, the introduction of X (= Cl, CH3) to
the ortho position increases the Pd–N length and C–N–Pd angle
values, however, we did not find a direct correlation between the
basicity of the ligand and the Pd–N distance.
Fig.
1
SHELXL93 drawings of the molecular structures of: A)
PdCl2(3-MePy)2 (compound III), B) PdCl2(4-MePy)2 (compound IV), C)
PdCl2(2-ClPy)2 (compound V). All drawings represent 50% probability.
2-chloroprydine rings show a cis disposition of the chlorine atoms
and the Pd(II) ion is not located in the inversion center, on the con-
trary to complexes III and IV. One 2-chloropyridine ring is canted
at an angle of 18.42◦ to the plane of another 2-chloropyridine ring
and the angles formed between both the pyridine rings and the
coordination plane are 86.49◦ and 75.09◦, respectively. The angles
[N–Pd–Cl] presented in Table 2 for complex V are close to 90◦
confirming its square planar coordination geometry.
Taking into account our experimental results (for compounds
III–V) and results for the complexes I, II and VI (accessible in
database CSD: H. Allen, Acta Crystallogr., 2002, B58, 380),31–33
we can state that in all six compounds the palladium ion
coordinates two nitrogen atoms of pyridine ligands and two
chlorine atoms in the trans positions, exhibiting a square planar
coordination geometry. We observe either cis or trans disposition
of methyl/chlorine substituents in pyridine rings. For complexes
with ortho substituted XPy ligands a cis disposition of substituents
takes place, whereas for other ligands: 3-MePy (complex III)
and 3-ClPy (complex VI)—the substituents are in trans position.
Consequently, complexes III and VI (with trans disposition of
substituents in the XPy ring) as well as compounds with 4-Me
(IV) and Py itself (I) have a centrosymmetric structure with the
palladium atom located in the inversion center, which is not
observed in complexes with ortho substituted ligands.
UV-Vis of XPy ligands and PdCl2(XPy)2 complexes
The absorption maxima and molar extinction coefficients e
(dm3 mol-1 cm-1) of XPy ligands dissolved in acetonitrile are
summarized in Table 3 and the spectra of the ligands are presented
in Fig. 2. All spectra exhibit an intense band at 250–270 nm due
*
to p–p transitions in the pyridine ring, in accordance with the
spectra of methylpyridines measured in 1,2-dichloroethane35 and
*
halopyridines (in heptane).36 The p–p bands are accompanied by a
*
shoulder on the low energy side corresponding to n–p transitions
*
*
of the C N chromophore.35 Strong charge transfer p–p and n–p
transitions are partially overlapped and one band (220–290 nm) is
Our previous studies resulted in determination of basicity
parameters of XPy’s decreasing in the following order: 4-MePy
(the strongest base) > 2-MePy > 3-MePy > Py > 3-ClPy > 2-
ClPy (the weakest base). It might be expected that nucleophilicity
and basicity of XPy would have a great impact on the Pd–N
length. Pd–N distances are presented in Table 2, but, surprisingly,
we do not observe a direct correlation between ligand basicity and
Pd–N bond length. The difference between Pd–N distances for
investigated complexes are too small and one can state that Pd–N
observed instead of two separated bands.37
For 2-or 3-substituted pyridines the p–p and n–p bands show
subtle (a few nanometres) red shifts in the visible region compared
to the spectrum of unsubstituted pyridine. This effect, observed
*
*
*
for all investigated pyridines, indicates that the energy of p–p
*
and n–p transitions is greatly dependent on the position of a
substituent, which is in agreement with the results reported by
others.38,39 The nature of the substituent also influences the energy
of these transitions and an electron-withdrawing substituent (e.g.,
chlorine) shifts the bands to a lower energy region, probably due
to the relative destabilization of the p levels of pyridine ring.40 The
wavelength of absorption maximum, lmax, increases in the order:
˚
(2.010–2.043 A) lengths are similar for all the complexes I–VI.
The only observation is that Pd–N distances are slightly longer
for complexes with MePy compared to complexes with ClPy and
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Table 3 UV-Vis spectroscopic features in acetonitrile for the free XPy
ligands described in the present work
No XPy
l (nm) ea (103 dm3 mol-1 cm-1) Energy (10-19J) Assignment
1
2
3
Py
251
256
261
2.87
2.81
2.56
3.73
3.88
2.83
3.73
3.88
3.41
3.76
3.40
4.07
4.83
3.31
3.25
3.49
2.55
7.93
7.77
7.62
7.77
7.59
7.42
7.71
7.56
7.39
7.80
7.62
7.74
7.56
7.37
7.62
7.48
7.31
—
p → p*
n → p*
—
p → p*
n → p*
—
p → p*
n → p*
p → p*
n → p*
—
p → p*
n → p*
—
2-MePy 256
262
268
3-MePy 258
263
Fig. 3 UV-Vis spectra of PdCl2(XPy)2 complexes (full size plots of UV-Vis
spectra are also presented in ESI†).
269
4
5
4-MePy 255
261
2-ClPy 257
263
transitions.41 Intensities of these transitions are smaller than the
*
intensities of p–p , thus, in order to clearly observe them, the more
270
concentrated solutions of PdCl2(XPy)2 in acetonitrile were applied
(see details in Fig. 3b).
All investigated complexes are diamagnetic square-planar com-
pounds, for which three spin-allowed d-d transitions are expected
6
3-ClPy 261
266
p → p*
272
n → p*
a e is molar extinction coefficient
1
1
to occur, corresponding to 1A1g → A2g, 1A1g → B1g and 1A1g
→
1Eg, however, strong dp–p or intra-ligand transitions may prevent
the observation of these d-d bands.42–45 Besides, d-d bands could
not be observed because the electronic spectra of all complexes
were recorded in solution.5,46
*
In summary to this section, the absorption spectra of free
*
*
XPy ligands show that the energies of p–p and n–p transitions
depend on the position and nature of the X substituent in the XPy
*
ring. After complexation a hipsochromic shift (24–34 nm) of p–p
*
and bathochromic shift of n–p bands are observed. The UV-Vis
spectra of PdCl2(XPy)2 confirm the square planar coordination
*
geometry of complexes I–VI, for which two dp–p transitions are
expected.
Theoretical calculations
*
Fig. 2 UV-Vis spectra of free XPy ligands (full size plots of UV-Vis
spectra are also presented in ESI†).
Two absorption bands assigned as dp–p (in experimentally
obtained spectra, see Fig. 3b) can be related to either MLCT
(metal-to-ligand charge transfer) or LMCT (ligand-to-metal charge
transfer) transitions.5,37,45,47 Therefore, the UV-Vis spectra of three
selected complexes with ligands without ortho substituents: com-
plex I, III and VI have been interpreted by TD-DFT calculations
4MePy £ Py < 2-MePy £ 3-MePy = 2-Cl < 3-Cl in agreement with
the results found in the literature.35,36
Having the UV-Vis spectra recorded for XPy ligands, we also
carried out the UV-Vis measurements of Pd(II) complexes I–VI
in acetonitrile and the results are listed in Table 4. The bands
*
to understand the origin of dp–p transitions. Our calculations
indicate that the transition from Pd to XPy (M→L) is favored,
*
within 220–300 nm region are caused by intra-ligand p–p and n–
which is consistent with the literature data.37,48,49 The first the-
*
*
*
p transitions. In each spectrum a n–p transition band is also
oretical dp–p transition occurs at values 320 nm, 319 nm and
330 nm for I, III and VI, respectively (see Table 5). The most
important frontier orbitals involved in the first dp–p transitions
*
observed as a shoulder on the p–p band, analogously to the
*
spectra of free XPy’s (see Fig. 3a). For complexes, a hipsochromic
*
*
shift (24–34 nm) of p–p bands and bathochromic shift of n–p
are the highest occupied molecular orbitals H-1 (HOMO-1) and
the lowest unoccupied molecular orbitals L+1 (LUMO+1) in all
three complexes (I, III, VI). The contributions of each part of these
complexes are listed in Table 6. Orbital H-1 is mainly located at the
chlorine ligands with a contribution from the Pd centre whereas
orbital L+1 is mostly centered at XPy ligands. The shapes of
these orbitals are presented in Fig. 4 for PdCl2 complex with 3-
MePy (see ESI† for complexes I and VI). Other important frontier
orbitals are H-3 (HOMO-3, placed at chlorine atoms with some
contribution from the palladium atom and pyridine ligands) and
LUMO (mainly located at the Pd centre). These results indicate
that the Pd-to-XPy charge transfer assigned as MLCT is preceded
*
bands are observed and the intensities of p–p bands are about ten
times higher than for free XPy (e is about 104, while for free ligands
it is 103 dm3 mol-1 cm-1). Another difference between the spectra
of ligands and the spectra of complexes is a broadening of p–p
and n–p bands for complexes, probably due to the contribution
of p–p transitions in which chlorine ligands are involved. Also
in this case the p–p bands energies are much more dependent on
*
*
*
*
the substituent position in the pyridine ring than on the nature of
substituents itself.
The presence of a central Pd atom in the complexes is manifested
*
by two absorption bands at 300–400 nm corresponding to dp–p
662 | Dalton Trans., 2012, 41, 658–666
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Table 4 UV-Vis spectroscopic features in acetonitrile for the PdCl2(XPy)2 complexes described in the present work
No
1
Compound PdCl2(XPy)2 (X = H, Cl, CH3)
l (nm)
ea (dm3 mol-1 cm-1)
Energy (10-19J)
Assignment
PdCl2(Py)2
226
298
326
391
231
270
317
394
229
273
325
391
226
298
327
391
239
296
317
382
233
292
375
397
3.67*103
2.46*102
2.54*101
2.43*101
2.57*104
1.02*104
1.86*102
1.61*102
2.93*104
8.22*103
1.87*102
1.67*102
1.95*104
1.32*103
1.83*102
1.62*102
2.01*104
1.28*103
1.81*102
1.87*102
2.08*104
7.13*103
3.98*102
3.98*102
8.80
6.67
6.10
5.09
8.57
7.53
6.27
5.05
8.69
7.51
6.12
5.09
8.80
6.67
6.08
5.09
8.32
6.72
6.28
5.21
8.54
6.81
5.30
5.00
p → p*
n → p*
dp → p*
dp → p*
p → p*
n → p*
dp → p*
dp → p*
p → p*
n → p*
dp → p*
dp → p*
p → p*
n → p*
dp → p*
dp → p*
p → p*
n → p*
dp → p*
dp → p*
p → p*
n → p*
dp → p*
dp → p*
2
3
4
5
6
PdCl2(2-MePy)2
PdCl2(3-MePy)2
PdCl2(4-MePy)2
PdCl2(2-ClPy)2
PdCl2(3-ClPy)2
a e is molar extinction coefficient.
Table 5 Calculated values of wavelength, oscillator strength, symmetry, type of orbitals involved, and change of fragments contribution to the orbital
during transition for selected electronic transitions
The change of a fragment contribution to the
orbital during transition
Orbitals involved in the
transition
Wave (nm)
Oscillator strength
Symmetry
Pd (%)
Cl (%)
XPy (%)
PdCl2(Py)2 I
353.7
328.7
319.6
PdCl2(3-MePy)2 III
352.7
329.5
318.9
PdCl2(3-ClPy)2 V
367.2
335.4
330.4
0.0004
0.0097
0.0131
Singlet-B
Singlet-A
Singlet-A
HOMO → L+1
H-3 → LUMO
H-1 → L+1
36 → 0 (-36)
10 → 49 (39)
21 → 0 (-21)
63 → 1 (-62)
85 → 28 (-57)
79 → 1 (-78)
2 → 99 (97)
5 → 23 (18)
0 → 99 (99)
0.0004
0.0107
0.0141
Singlet-A
Singlet-A
Singlet-A
HOMO → L+1
H-3 → LUMO
H-1 → L+1
35 → 0 (-35)
11 → 49 (38)
22 → 1 (-21)
62 → 1 (-61)
79 → 28 (-51)
79 → 1 (-78)
3 → 99 (96)
10 → 23 (13)
0 → 99 (99)
0.0005
0.0134
0.0118
Singlet-AU
Singlet-AU
Singlet-AU
HOMO → L+1
H-3 → LUMO
H-1 → L+1
34 → 0 (-34)
10 → 49 (39)
20 → 1 (-19)
63 → 1 (-62)
76 → 28 (-48)
79 → 1 (-78)
2 → 99 (97)
14 → 22 (8)
1 → 98 (97)
by Cl-to-Pd transition occurring with lower energy (i.e. higher
wavelength), in agreement with the literature data.44
TD-DFT calculations are consistent with experimental results (see
ESI† for theoretical UV-Vis spectra for complexes I, III and VI).
It can be concluded that the absorption spectra of PdCl2(XPy)2
complexes are dominated by intra-ligand (LL, ligand-to-ligand)
The most important frontier orbitals involved in second
*
dp–p transition are the occupied HOMO and the empty
*
*
L+1 (LUMO+1). The calculated contributions of each part of
PdCl2(Py)2; PdCl2(3-MePy)2 and PdCl2(3-ClPy)2 complexes are
listed in Table 6 and examples of shapes of these orbitals for
PdCl2(3-MePy)2 complex are given in Fig. 4. The HOMO is placed
on chlorine ligands with contribution of Pd metal while the L+1 is
located at XPy ligands. We do not observe such significant contri-
bution of Cl-to-Pd charge transfer as for previously observed first
p–p and n–p transitions, as well as MLCT (Pd-to-XPy) with CT
contribution from chlorine atoms to palladium. To summarize this
part of our research, on the basis of theoretical calculations for
*
the first time we proved that the observed dp–p transitions for
PdCl2(XPy)2 complexes in solutions result from MLCT (metal-
to-ligand charge transfer) with contribution of chlorine atoms to
palladium charge transfer.
*
higher energy dp–p transition. For each transition a contribution
*
Cytotoxic activity
of XPy increases, therefore, the dp–p origins from MLCT (Pd-
*
to-XPy). Predicted dp–p transitions are shown in Fig. 5. The
Apart from the analyses of the structural and chemical properties
of PdCl2(XPy)2 complexes, we performed preliminary analyses of
*
*
*
predictions of dp–p , p–p and n–p transitions energies using
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Table 6 Composition of selected frontier molecular orbitals in terms of
are interesting. The viability of control CCRF cells, i.e. cultured for
72 hinthe medium without anyadditions oftestedcompounds was
assumed to be 100% (which is the average of four measurements).
Some of the PdCl2(XPy)2 complexes at concentration below 1
mM were significantly more cytotoxic than cisplatin (see Fig. 6).
Compounds II and III used at concentrations of about 0.1 mM
reduced the viability to 60%, i.e. had significantly higher effect than
measured for cisplatin (90% of surviving cells). Incubation with
two other compounds I and VI resulted in 80% of cells surviving
the treatment, i.e. they were still more toxic than cisplatin. At
concentration about 1 mM complexes I and II showed very high
cytotoxicity about 60%, while results obtained for III were not
statistically significant. Experiments with two other cell lines PC3
and MCF7 indicated moderate cytotoxicity of complexes with
MePy: II, III and IV (slightly higher than PdCl2 with Py and
ClPy against PC3). 48 h long incubation of MCF7 cells in all
PdCl2(XPy)2 complexes did not result in the decrease of their
survival, while compounds II, IV and VI showed low cytotoxic
activity against MCF after 72 h.
Pd, Cl and XPy fragments
MO
E(eV) Symmetry Pd (%)
Cl (%)
XPy (%)
PdCl2(Py)2 I
L+1
LUMO
HOMO
H-1
-1.99
-2.32
-6.25
-6.61
-7.14
B
A
A
B
A
0
0
99
22
2
49
36
21
10
28
63
79
85
0
H-3
5
PdCl2(3-MePy)2 III
L+1
LUMO
HOMO
H-1
-1.89
-2.2
-6.15
-6.5
-7
A
A
A
A
A
0
0
99
22
3
0
9
49
35
22
11
28
62
79
80
H-3
PdCl2(3-ClPy)2 V
L+1
LUMO
HOMO
H-1
-2.35
-2.61
-6.48
-6.83
-7.33
Au
Ag
Ag
Ag
Au
0
0
99
21
2
1
13
50
34
20
10
29
63
79
77
H-3
Fig. 4 Frontier orbitals involved in dp–p* transitions in PdCl2(3-MePy)2:
HOMO-3, HOMO-1, HOMO, LUMO and LUMO+1: a) HOMO-3 Cl
centered (involved in first dp–p*), b) HOMO-1 Cl-Pd centered (involved
in first dp–p*), c) HOMO Cl-Pd centered (involved in second dp–p*),
d) LUMO Pd-Cl-3MePy centered (involved in first dp–p*), e) LUMO+1
3-MePy centered (involved in first and second dp–p*).
Fig. 6 Cytotoxicity of selected complexes (I, II, III, VI) and cisplatin
(cisDDP) against CCRF cells. The control sample is marked as 0%
concentration of drug.
Based on the results of the MTT test, significant differences have
been found in the cytotoxic activity of all the complexes depending
on the structure of the PdCl2(XPy)2 and depending on the cell
line used for the experiments. Palladium complexes were the most
active against the CCRF cell line and less or even no cytotoxic
effect was observed for PC3 cells. The cytotoxic activity depends
on the nature and position of substituents in the pyridine ring:
complexes with MePy have increased cytotoxic activity compared
to unsubstituted pyridine ligands. These findings are in accordance
with those obtained by Huq et al.13 for a series of PdCl2 complexes
with hydroxypyridines against A2780 cells. They reported that the
cytotoxic effect on cells viability depended on the position of OH
in the pyridine ring and decreased in the following order: 2-OH-
pyridine > 3-OH-pyridine > 4-OH-pyridine.13
Fig. 5 Visualisation of dp–p* transitions in PdCl2(3-MePy)2.
their cytotoxicity. For these studies three established cell lines were
selected. Human breast cancer cell line MCF7, human prostate
cancer cell line PC3, and human T-cell lymphoblast-like cell line
CCRF. Cells were incubated in the culture medium containing
complexes I–VI or cisplatin in selected concentrations either for
48 h (MCF7) or 72 h (MCF7, PC3, CCRF). Next, MTT50,51
assay allowing the analysis of cell viability, was performed. For
cisplatin the IC50 was determined as 3 mM, for CCRF cells.
Poor solubility of complexes in I–VI allowed us to do a limited
comparison of activity of our Pd(II) complexes with the activity of
cisplatin, however, even for concentrations below IC50 the results
Experimental section
Materials
PdCl2 was used as received. Pyridine (Py), substituted pyridines (2-
MePy, 3-MePy, 4-MePy, 2-ClPy, 3-ClPy), acetonirile and acetone
were distilled (or fractionally distilled) over CaH2 and stored under
argon. Human breast cancer cell line MCF7, human prostate
664 | Dalton Trans., 2012, 41, 658–666
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cancer cell line PC3 and human T-cell lymphoblast-like cell line
CCRF-SB were purchased from ATCC, Manassas, VA. RPMI-
1640 medium, Iscove’s Modified Dulbecco’s Medium (IMDM),
fetal bovine serum, antibiotic-antimycotic solution (100IU ml-1
penicillin, 100 mg ml-1 streptomycin, 250 ng ml-1 amphotericin),
glucose, MEM Non-essential Amino Acid Solution (100*), L-
glutamine were purchased from Sigma Aldrich.
corresponding oscilator strengths were simulated via TDDFT
methodology.63 The results were analyzed using GaussSum 2.2.5
package64 and visualized using ChemCraft program.65
Cytotoxic activity
MCF7 cells (from ATCC, USA) were grown in Iscove’s Modified
Dulbecco’s Medium containing L-glutamine (IMDM, Sigma-
Aldrich) supplemented with a 10% heat inactivated fetal bovine
serum (Sigma-Aldrich), antibiotics (100 IU ml-1 penicillin, 100 mg
ml-1 streptomycin, 250 ng ml-1 amphotericin, (Sigma-Aldrich),
0.4% glucose (Sigma-Aldrich) and nonessential amino acids
(1¥, Sigma-Aldrich). PC3 and CCRF cell lines (collected from
ATCC, USA) were grown in RPMI-1640 medium (Sigma-Aldrich)
supplemented with nonessential amino acids (1¥), antibiotics
(100 IU ml-1 penicillin, 100 mg ml-1 streptomycin, 250 ng ml-1
amphotericin), 0.4% glucose, L-glutamine and heat inactivated
bovine serum (10% for PC3 and 20% for CCRF-SB). Cells were
Synthesis of PdCl2(XPy)2 (compounds I–VI)
The procedure has been described elsewhere.1 Palladium chloride
complexes with pyridines were prepared under argon. PdCl2 (1.128
mmol) was placed in a 10 ml flask equipped with a magnetic stirrer
and 2.26 mmol of Py or substituted XPy in 10 ml acetonitrile were
added. Reaction was carried out at room temperature for 24 h.
X-ray structure determinations
All measurements of crystal structure were performed on a
KM4CCD k-axis diffractometer with graphite-monochromated
Mo-Ka radiation. The crystals were positioned at 62 mm from
the CCD camera. 1600 frames were measured at 0.5◦ intervals
with a counting time of 11 s. The data were corrected for Lorentz
and polarization effects. Empirical correction for absorption was
applied.52 Data reduction and analysis were carried out with the
Oxford Diffraction programs.53 The structures were solved by
direct methods54 and refined using SHELXL.55 The refinement
was based on F2 for all reflections except those with very negative
F2. Weighted R factors wR and all goodness-of-fit S values are
based on F2. Conventional R factors are based on F with F set to
◦
grown at 37 C in a humidified atmosphere containing 5% CO2.
MCF7 and PC3 cells were treated with PdCl2(XPy)2 (I–VI) and
cisplatin at the concentration range 0.6–85 mM, depending on
the solubility of the used complex. CCRF cells were treated with
compounds (I–VI) and cisplatin at the concentration range 0.002–
100 mM.
The cytotoxic properties of the compounds were evaluated by
MTT test.49,50 The assay measures the amount of formazan pro-
duced from 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (assigned as MTT) by living cells present in the culture.
Cells were seeded in a 96-well plate at density 5 ¥ 104 cells ml-1
(MCF7), 6 ¥ 104 cells ml-1 (PC3) and 5 ¥ 105 cells ml-1 (CCRF).
Next, the solutions of compounds prepared in dimethylformamide
(DMF)/growth medium (appropriate for cell line used in the
experiment—IMDM or RPMI) were added—the concentration
of DMF was 1% (v/v), and once (for low soluble compound)
the concentration of DMF reached 2% (v/v). To the control
samples of cells the DMF/growth medium without any other
additives were used. Cells were incubated with compounds for
48 h (MCF7 cells) and 72 h (all cell lines). After incubation time,
cells were washed in PBS and, subsequently, to each well 0.25
mg ml-1 of MTT was applied. After 3 h incubation at 37 ◦C,
isopropanol was added to dissolve formazan crystals (formed
from MTT). The absorbance (at 570 nm) was measured with
a spectrophotometer PowerWave XS (Biotek Instruments). The
results describing viability of cells are present in this paper as a
mean of 4 repetitions. Standard deviations (which are shown in
Fig. 6) were calculated from four measurements and the t-Student
test was performed with reference to the control sample at the
confidence level r < 0.05.
zero for negative F2. The F0 >2s(F0 ) criterion was used only for
calculating R factors and is not relevant to the choice of reflections
for the refinement. The R factors based on F2 are about twice
as large as those based on F. All hydrogen atoms were located
geometrically and their positions were refined. Temperature
factors for some hydrogen atoms were fixed. Scattering factors
were taken from Tables 6.1.1.4 and 4.2.4.2.56 The crystallographic
data for the complexes are summarized in Table 1.
2
2
UV-Vis measurements
Electronic spectra of XPy ligands and PdCl2(XPy)2 complexes (I–
VI) were recorded on a Cary 50 UV-Vis Spectrophotometer using
acetonitrile as a solvent in the 200–800 nm range with a 1 cm
quartz cell. Baseline was measured for acetonirile.
TDDFT calculations
All calculations were performed using Gaussian 03 software57
with the B3LYP functional.58,59 Three basis sets were employed.
For palladium atom, the MWB28 energy-consistent Stuttgart-
Dresden pseudo-relativistic basis set was used.60 In this case 60 core
electrons were replaced by Effective Core Potentials (ECP) and
the 18 valence electrons were treated explicitly. For all other atoms
standard Pople-style basis sets were employed: for geometry opti-
mizations 6-31G(d)61 and for TDDFT calculations 6-311+G(d).62
Optimization of geometric parameters of all complexes were
followed by frequency check to ensure that the stationary points
obtained are true minima on the potential energy surface. For each
optimized structure a total of 50 singlet excited states and their
Conclusions
In the present work the X-ray characterization, electronic proper-
ties and TD-DFT calculations for PdCl2(XPy)2 complexes (where:
Py = pyridine and X = H, Cl or CH3) are discussed. We
also studied substituent effects on cytotoxic properties of Pd(II)
compounds by monitoring anticancer activity of the complexes
against CCRF, PC3 and Mcf7 cell lines. We report that the nature
and position of substituents in the aromatic ring is important to
the structure of PdCl2(XPy)2 complexes. The absorption spectra
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*
*
˙
of free XPy ligands show that the energies of p–p and n–p
27 J. Skupin´ska, A. Zukowska and A. Chajewski, React. Kinet. Catal.
Lett., 2001, 72, 21.
transitions depend on the position and nature of the X substituent
in the XPy ring. After complexation a hipsochromic shift of p–p
and bathochromic shift of n–p bands are observed. The UV-Vis
spectra of PdCl2(XPy)2 confirm the square planar coordination
geometry of complexes I–VI, for which two dp–p transitions
are expected. On the basis of theoretical calculations for the first
time we prove that dp–p transitions in solutions of PdCl2(XPy)2
complexes result from MLCT (metal-to-ligand charge transfer)
with contribution of chlorine atoms to palladium and pyridine
(XPy) charge transfer. Anticancer activity depends on the nature
and position of substituents in the pyridine ring of the compound:
complexes with X = MePy have increased cytotoxic activity
compared with X = Py ligands.
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A. Krogul is thankful for the Mazowian Doctoral Scholarship in
2011. This work was partially supported by the Ministry of Science
and Higher Education of Poland, grant No. N N507 452937.
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