Different properties of P,C-donor Pd(II) and Pt(II); spectroscopic and X-ray analysis, catalytic potential and anti-proliferative potency

Article abstract of DOI:10.1016/j.jorganchem.2019.03.002

This account describes our recent studies on pallada-and platinaphosphacycle complexes with an unsymmetrical phosphonium ylide, Ph₂PC(CH₂)PPh₂ = C(H)C(O)C₆H₄-p-NO₂ (Y), derived from 1,1-bis(diphenylphosphino)ethylene (dppee). These complexes have been prepared through reactions between (Y) and [MCl₂(cod)] (M = Pd (C1) or Pt (C2); cod = 1,5-cyclooctadiene) in equimolar ratio in the hope of finding new compounds that may be useful in stereoselective catalysis and find use as antitumor metallodrugs. Characterization of these compounds was performed by elemental analysis, IR, ¹H, ¹³C, and ³¹P NMR spectroscopic methods. The structures of the Pd and Pt complexes were determined by single crystal x-ray structural analyses, showing that both complexes consist of five-membered rings formed by coordination of the phosphorus ylide (Y) through the phosphine group and the ylidic carbon atom to the metal center. The catalytic activity of the complexes, using the Mizoroki–Heck and Suzuki-Miyaura cross-coupling reactions, have been evaluated and compared. Moreover, both compounds have been found to have antitumor activity against AGS (gastric carcinoma), MCF-7 (breast carcinoma) and A549 (non-small lung carcinoma) cells with the average of IC₅₀ values from 61.19 to 290.17 μM. Generally, C2 reveals high anticancer activity than C1.

Full text of DOI:10.1016/j.jorganchem.2019.03.002

Accepted Manuscript
Different properties of P,C-donor Pd(II) and Pt(II); spectroscopic and X-ray analysis,
catalytic potential and anti-proliferative potency
Abed Yousefi, Seyyed Javad Sabounchei, Seyed Hamed Moazzami Farida, Roya
Karamian, Nosrat Rahmani, Robert W. Gable
PII:
S0022-328X(19)30080-4
DOI:
https://doi.org/10.1016/j.jorganchem.2019.03.002
JOM 20730
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 1 February 2019
Revised Date: 27 February 2019
Accepted Date: 2 March 2019
Please cite this article as: A. Yousefi, S.J. Sabounchei, S.H. Moazzami Farida, R. Karamian, N.
Rahmani, R.W. Gable, Different properties of P,C-donor Pd(II) and Pt(II); spectroscopic and X-ray
analysis, catalytic potential and anti-proliferative potency, Journal of Organometallic Chemistry (2019),
doi: https://doi.org/10.1016/j.jorganchem.2019.03.002.
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ACCEPTED MANUSCRIPT
Different properties of P,C-donorPd(II) and Pt(II);spectroscopic and X-ray
analysis, catalytic potential and anti-proliferative potency
a
Abed Yousefia, SeyyedJavadSabounchei ,SeyedHamedMoazzamiFaridab, Roya Karamianb,
NosratRahmanic, Robert W. Gable d
aFaculty of Chemistry, Bu-Ali SinaUniversity, Hamedan 65174, Iran
bDepartment of Biology, Faculty of Science, Bu-Ali Sina University, Hamedan, Iran
cDepartment of Biology, Faculty of Science, Shahed University, Tehran, Iran
dSchool of Chemistry, University of Melbourne, Victoria 3010, Australia
*Corresponding author. E–mail address: jsabounchei@yahoo.co.uk(S.J. Sabounchei).
1

ACCEPTED MANUSCRIPT
Different properties of P,C-donor Pd(II) and Pt(II); spectroscopic and X-ray
analysis, catalytic potential and anti-proliferative potency
a
Abed Yousefi, Seyyed Javad Sabounchei ,Seyed Hamed Moazzami Faridab, Roya Karamianb, Nosrat
Rahmanic, Robert W. Gable d
aFaculty of Chemistry, Bu-Ali SinaUniversity, Hamedan 65174, Iran
bDepartment of Biology, Faculty of Science, Bu-Ali Sina University, Hamedan, Iran
cDepartment of Biology, Faculty of Science, Shahed University, Tehran, Iran
dSchool of Chemistry, University of Melbourne, Victoria 3010, Australia
This account describes our recent studies on pallada- and platinaphosphacycle complexes with an
unsymmetrical phosphonium ylide, Ph2PC(CH2)PPh2=C(H)C(O)C6H4-p-NO2 (Y), derived from
1,1-bis(diphenylphosphino)ethylene (dppee). These complexes have been prepared through
reactions between (Y) and [MCl2(cod)] (M = Pd (C1) or Pt (C2); cod = 1,5-cyclooctadiene) in
equimolar ratio in the hope of finding new compounds that may be useful in stereoselective
catalysis and find use as antitumor metallodrugs. Characterization of these compounds was
1
performed by elemental analysis, IR, H, 13C, and 31P NMR spectroscopic methods. The
structures of the Pd and Pt complexes were determined by single crystal x-ray structural
analyses, showing that both complexes consist of five-membered rings formed by coordination
of the phosphorus ylide (Y) through the phosphine group and the ylidic carbon atom to the metal
center. The catalytic activity of the complexes, using the Mizoroki–Heck and Suzuki-Miyaura
cross-coupling reactions, have been evaluated and compared. Moreover, both compounds have
been found to have antitumor activity against AGS (gastric carcinoma), MCF-7 (breast
carcinoma) and A549 (non-small lung carcinoma) cells with the average of IC50 values from
*Corresponding author. E–mail address: jsabounchei@yahoo.co.uk (S.J. Sabounchei).
1

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61.19 to 290.17 µM. Generally, C2 reveals high anticancer activity than C1.
Keywords: pallada- and platinaphosphacycle complexes, phosphonium ylide, crystallography,
Mizoroki–Heck and Suzuki-Miyaura Cross-coupling reactions, antitumor activity.
Introduction:
Phosphorus ligands are one of the most diverse and important class of ligands in chemistry [1].
Diphenylphosphines form a significant group within the large family of phosphine ligands which
includes
ligands
such
as
1,1-bis(diphenylphosphino)methane
(dppm),
1,2-
bis(diphenylphosphino)ethane (dppe) and many others that play a key role in the synthesis of
transition metal complexes and have broad applications in industrial, biological and chemical
synthesis [2, 3]. Biphosphorus ylides can coordinate to metal ions in three modes as displayed in
Chart 1: monodentate (P-coordinated [4], C-coordinated [5] or O-coordinated[6]), bidentate (or
chelating) [3] and bridging modes [7] (chart 1).
Chart 1. Possible binding modes of phosphorus ylides to the metal M
One of the diphenylphosphine analogs is 1,1-bis(diphenylphosphino)ethylene (dppee), a ligand
that has extremely low-lying π* orbitals, mainly located around the sp2-hybridized phosphorus
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atoms, that have a marked tendency to engage in metal to phosphorus π-back bonding. This
property is useful for catalysis, leading to highly efficient organic transformations with a diverse
range of selectivity. Complexes derived from the IB and IIB groups (platinum, palladium,
rhodium and ruthenium), in particular, have shown a wide range of catalytic, biological and
industrial properties, among others [8-11]. Compared to other transition metal complexes, from
the catalytic point of view, palladium-based organometallic compounds are the most reactive in a
number of different coupling reactions, in particular their 0, I, II and IV oxidation states [12, 13].
Due to the importance of palladium-catalysis in scientific and industrial chemistry, a number of
publications and reviews describing various aspects of this topic have recently been published
[14]. The investigation of the reactivity and coordination chemistry of metal complexes (Pd, Pt
and Rh, especially) derived from various ylides has been an important research focus of our
group [2, 15, 16]. This article presents the significant catalytic application of new complexes
with new a phosphorus ligand containing a metallated sp3-carbon center (‘‘pallada- and
platinacycles’’) with a C-P chelate coordination. We have also shown that phosphorus analogs
have significant biological properties, such as antioxidant and antibacterial activity [17]. Many
cancers, such as lung, breast and gastric cancer, are still difficult to treat and are a source of
serious health problems in many countries, and every year cause many deaths worldwide [18].
Accordingly, researchers have attempted to produce compounds with high anticancer potential.
Among the drugs already discovered, inorganic compounds have a special role in this field [19,
20], in particular platinum and its derivatives, which are important chemotherapy drugs used to
treat various cancers[21]. After the discovery of the anticancer activity of cis-
diamineplatinum(II) dichloride (cisplatin) [22], a variety of inorganic anticancer drugs, such
ascarboplatin [23] andoxaliplatin [24], are being routinely used as a part of cancer treatment in
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patients. Although the platinum-based drugs have been used for about four decades, several side
effects, such as nephrotoxicity and drug resistance of the tumor cells, have raised real challenges
to researchers. In order to decrease these side effects, researchers have been prompted to look for
alternatives to inhibit or kill tumor cell growth [25, 26]. There seems to be a number of
properties that could explain the anti-proliferative activity of the Pt complexes. In addition to the
nature of platinum metal, the structure of the complex and the type of the ligands, are some of
the important properties. In the present study, our goal is to expand the scope of these complexes
to new pallada- and platinaphosphacycle complexes having both phosphorus and carbon donor
atoms and comparing their intriguing functionalities including anti-proliferative potency and
catalytic activities. Furthermore, we report in vitro testing of the preliminary anticancer activity
on the human AGS gastric, MCF-7 breast and A-549 lung cancer cell lines.
2. Experimental:
2.1. Materials and methods
Phosphorus ylide Ph2PC(CH2)2PPh2C(H)C(O)C6H4-p-NO2 (Y) was prepared according to
literature methods [27]. Synthesis of Pd/Pt(II) complexes was carried out with dry solvents and
under a nitrogen atmosphere using standard Schlenk techniques. [MCl2(cod)] (M = Pd or Pt)
complexes were prepared according to previously published procedures [28]. Dichloromethane
was used as reagent grade and dried over P2O5. Elemental analysis was performed on a Leco,
1
CHN-932 apparatus. The H, 13C and 31P NMR spectra were recorded on BrukerAdvance 250
MHz and Jeol 90 MHz spectrometers in CDCl3 or DMSO-d6 as solvents at 25ºC. IR spectra were
recorded on KBr pellets using a Shimadzu 435-U04 spectrophotometer in the region of 4000–
400 cm-1.
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2.2. Synthesis of data salt [(Ph2PC(CH2)PPh2CH2C(O)C6H4-p-NO2]Br(S)
An acetone solution (10 ml) of ketone (1 mmol) was added to an acetone solution (10ml) of
dppee (1 mmol). The mixture was stirred under nitrogen atmosphere for 15h. The resulting white
solid was filtered off and dried. Yield: 91%, M.p: 201-203. Anal. Calc. for C34H28O3NP2Br (%):
C, 63.76; H, 4.41; N, 2.19. Found: C, 63.84; H, 4.52, N, 2.27. Selected IR absorption in KBr
1
(cm-1): 1682 (CO). H NMR (89.6 MHz, CDCl3) δH (ppm): 6.21 (d, CH2, 2H, 2JP–H = 12.54 Hz);
6.96 (br, CH2, 2H merged with aromatics); 7.53–8.48 (m, 24H, Ar). 31P NMR (36.26 MHz,
2
2
CDCl3) δP (ppm): -15.26 (d, PPh2, JP–P = 102.25 Hz), 20.50 (d, PCH, JP–P = 102.25 Hz). 13C
NMR (62.89 MHz, CDCl3) δC (ppm): 38.63 (d, CH2); 116.27–150.98 (Ar and CH2); 191.24 (s,
CO).
2.3. Synthesis of data ylide (Ph2PC(CH2)PPh2CHC(O)C6H4-p-NO2(Y)
0.1 ml of Et3N was added dropwise to 10 mL toluene solution included 1 mmol of salt (S). After
2h the mixture was filtered and petroleum benzene was added to the filtrate to give a yellow
powder. Yield: 45%, M.p: 149-152. Anal. Calc. for C34H27NO3P2 (%): C, 72.98; H, 4.86; N,
1
2.51. Found: C, 73.09; H, 4.96; N, 2.59. Selected IR absorption in KBr (cm-1): 1588 (CO). H
NMR (89.6 MHz, CDCl3) δH (ppm): 4.27 (d, CH, 1H). 6.76 (br, CH2, 2H merged with
31
aromatics); 7.17–8.18 (m, 24H, Ar). P NMR (36.26 MHz, CDCl3) δP (ppm): -14.37 (d, PPh2,
2
2JP–P = 88.47 Hz), 16.55 (d, PCH, JP–P = 88.47 Hz). 13C NMR (62.90 MHz, CDCl3) δC (ppm):
52.90 (d, CH); 122.95–148.14 (Ar and CH2); 181.77 (s, CO).
2.4. Synthesis of data Pd(II) complex PdCl2(Ph2PC(CH2)PPh2CHC(O)C6H4-p-NO2 (C1)
A dichloromethane solution of 0.5 mmol of ylide (Y) (15 mL) was added to a 0.5 mmol
dichloromethane solution (5 mL) of PdCl2(cod). The mixture was stirred for 8h under a nitrogen
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atmosphere. Petroleum ether was added to the solution and the resulting yellow powder was
dried. Yield: 83%, M.p: 221-223. Anal. Calc. for C34H27NO3P2PdCl2 (%): C, 55.42; H, 3.69; N,
1
1.91. Found: C, 55.51; H, 3.62; N, 1.84. Selected IR absorption in KBr (cm-1): 1622 (CO). H
NMR (89.6 MHz, CDCl3) δH (ppm): 5.66 (d, CH, 1H, 2JP–H = 7.16 Hz); 6.91 (br, CH2, 2H merged
with aromatics); 7.35–8.21 (m, 24H, Ar). 31P NMR (36.26 MHz, CDCl3) δP (ppm): 32.02 (d,
2
2
PPh2, JP–P = 36.98 Hz), 35.77 (d, PCH, JP–P = 36.98 Hz). 13C NMR (62.89 MHz, CDCl3) δC
(ppm): 33.17 (d, CH); 120.00–151.30 (Ar and CH2); 193.82 (s, CO).
2.5. Synthesis of data Pt(II) complex PtCl2(Ph2PC(CH2)PPh2CHC(O)C6H4-p-NO2 (C2)
A dichloromethane solution of 0.027g (0.05mmol) of ylide (Y) (15mL) was added to a 0.018g
(0.05mmol) dichloromethane solution of PtCl2(cod) (5mL). The mixture was stirred for 8h under
nitrogen atmosphere. Petroleum ether was then added to the solution and the resulting white
powder was dried. Yield: 63%, M.p: 245-247. Anal. Calc. for C34H27NO3P2PtCl2 (%): C, 49.47;
H, 3.30; N, 1.70. Found: C, 49.55; H, 3.36; N, 1.75. Selected IR absorption in KBr (cm-1): 1629
(CO). 1H NMR (89.6 MHz, CDCl3) δH (ppm): 5.60 (d, CH, 1H, 2JP–H = 12.54 Hz); 6.65 (br, CH2,
31
2H merged with aromatics); 7.25–8.14 (m, 24H, Ar). P NMR (36.26 MHz, CDCl3) δP (ppm):
11.99 (d, PPh2, 2JP–P = 33.36 Hz, 1JPt-P = 895.62 Hz), 32.69 (d, PCH, 2JP–P = 33.36 Hz). 13C NMR
(62.89 MHz, CDCl3) δC (ppm): 26.32 (d, CH); 128.38–150.56 (Ar and CH2); 193.38 (s, CO).
2.6. Crystallography
Yellow crystals of C1 and pale yellow crystals of C2 were crystallized by vapour diffusion of
diethyl ether into deuterochloroform. The crystals were long thin needles, attempts to cut them to
smaller size resulted in them fracturing, or becoming too disordered to be usable. Crystals of
both compounds showed evidence of disorder, however attempts to obtain better crystals were
not successful. Both structures are isomorphous. Data collection for C1 was carried out on a
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Rigaku Oxford Diffraction SuperNova, Dual Source (Cu at zero) Atlas diffractometer at 130 K,
while data collection for C2 was carried out on an XtaLAB Synergy, Dualflex, HyPix
diffractometer at 100 K; for both crystals mirror monochromated Cu Kα radiation (λ = 1.54018
Å) was used. Gaussian absorption corrections [29] were applied to the data. Using Olex2 [30],
the structures were solved with the ShelXT [31]structure solution program using Intrinsic
Phasing and refined with the ShelXL [32] refinement package using Least Squares minimization
on F2, using all data. All non hydrogen atoms were refined with anisotropic displacement
parameters, while all hydrogen atoms were placed at geometrical estimates and refined using the
riding model with an isotropic displacement parameter equal to 1.2 times Ueq of the parent atom.
Both structures showed residual electron density peaks around the metal atoms due to minor
disorder, 2.47 eÅ-3 and -1.80 eÅ-3 for C1, and 2.41 eÅ-3 and -2.42 eA-3 for C2; attempts to model
this disorder were not successful.
2.7. Typical procedure for the catalytic coupling reactions
A vial charged with metalacycle as a catalyst (0.005 mmol), relevant reagent (olefin for
Mizoroki-Heck and arylbronic acid for Suzuki-Miyaura coupling reactions) (0.75 mmol), aryl
chloride (0.5 mmol), base (1.0 mmol) and solvent (2 ml) was heated to reflex temperature for 6 h
in the presence of air. The reactions were monitored by thin-layer chromatography (TLC). After
cooling, the mixture was extracted with n-hexane:EtOAc, filtered and purified by
recrystallization (from ethanol and water) or purified by silica gel column chromatography (n-
hexane:EtOAc).
Among the aryl halide reagents, couplings of aryl bromides and iodides investigations have
shown that aryl iodides and bromides were more reactive than aryl chlorides [4]. The small C–I
and C-Br bond dissociation energies, compared to the larger C–Cl bond dissociation energy, and
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easier oxidative addition to the Pd(0) species results in the aromatic iodides and bromides having
a higher reactivity compared to aryl chlorides in the coupling reactions. [33]. Aryl chlorides are
ideal substrates for coupling reactions since they are cheaper and more widely available than
their bromide or iodide analogues The challenge of activating the C–Cl bond of aryl chlorides, as
well as the financial aspects, means that research is now focused on increasing the efficiency of
aryl chlorides in cross-coupling reactions [34]. Accordingly, we have attempted to synthesize
compounds that can increase the catalytic properties of aryl chlorides in the Mizoroki-Heck and
Suzuki-Miyaura coupling reactions.
The activity of complexes C1 and C2 when used as as catalysts in the Mizoroki-Heck and
Suzuki–Miyaura coupling reactions has been determined. In order to obtain the optimum
experimental conditions, we carried out a model reaction including base, solvent and catalyst
loading (Tables 1 and 2).
Table 1. Reaction conditions for Mizoroki-Heck coupling reaction
Table 2. Reaction conditions for Suzuki–Miyaura coupling reaction
Catalyst
Yield
Catalyst
Yield
(%)
Base
Solvent
Entry
loading
(mmol)
Base
Solvent
Entry
loading
(mmol)
(%)
1
2
3
4
5
6
7
8
K3PO4
K2CO3
NEt3
K3PO4
K2CO3
NEt3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF/H2O
DMF/H2O
DMF/H2O
Methanol/H2O
Methanol/H2O
Methanol/H2O
H2O
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.005
0.1
61a/18b
69a/27b
51a/ - b
38a/13b
46a/24b
20a/ - b
43a/ - b
51a/18b
69a/ - b
51a/ - b
71a/30b
1
2
3
4
5
6
7
8
Cs2CO3
K2CO3
NEt3
Ethanol
Ethanol
Ethanol
Ethanol
Hexane
NMP
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.005
0.1
73a/34b
71a/21b
49a/ - b
51a/ - b
34a/21b
58a/28b
39a/21b
26a/ - b
69a/ - b
78a/41b
73a/34b
NaOAc
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
H2O
DMF
Toluene
Ethanol
Ethanol
Ethanol
9
Methanol
DMF/H2O
DMF/H2O
9
10
11
10
11
0.05
a Yielded for complex C1, b Yielded for complex C2
a Yielded for complex C1, b Yielded for complex C2
Mizoroki-Heck coupling reaction: The reaction of styrene with chlorobenzene in DMF/H2O
(1:1) at 110 ºC in the presence of K3PO4 (1 mmol) and 0.05 mmol of complexes C1 and C2 as
catalyst was chosen as a model reaction, which led to related product in 61% and 18% yields for
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complexes C1 and C2 respectively. (Table 1, entry 1). Subsequently, a series of experiments
were performed to find the optimum conditions. At the first stage, we studied the efficacy of base
and solvent on the coupling reaction. This optimization was done with commonly used bases and
solvents, including organic and inorganic bases and aqueous protic and aprotic solvents. Two
parameters of base potency; solubility and basicity; depend on the solvent that is used. thus the
coupling reactions give the desired products in moderate to high yields when carried out in the
presence of K2CO3 and K3PO4 (Table 1, entries 2, 5 and 1, 4). However, due to the low solubility
of this organic base in aqueous solvents, the reactions in the presence of NEt3 did not proceed
efficiently even after prolonged stirring at the reflux temperature of the solvents (Table 1, entries
3 and 6). Among the tested aqueous solvents, DMF/H2O gave higher yields of coupled product,
while the reactions in water or non-aqueous DMF led to lower yields, indicating the important
role of the solubility of the base in such catalytic systems (Table 1, entries 2, 7 and 8).
Suzuki–Miyaura coupling reaction: the catalytic performance of the complexes C1 and C2 in
the Suzuki–Miyaura cross-coupling reaction also was examined. The reaction of phenylboronic
acid with chlorobenzene in ethanol (1:1) at reflux temperature in the presence of Cs2CO3 (1
mmol) and 0.05 mmol of complexes C1 or C2 as catalyst was chosen as a model reaction, which
provided the coupled product in 73% yield for complex C1 and 34% for C2(Table 2, entry 1).
The solvent optimization stage was done with several common solvents and using ethanol as a
solvent gave the highest yield for this reaction. The reactions using water, however, required
additional time for completing the coupling reaction (Table 2, entry 7). As well, non-polar
solvents such as hexane and toluene gave low conversions (Table 2 entries 5 and 8). After that,
we optimized the base from those commonly used. As mentioned above, base plays an important
role in such cross-coupling reactions and has a striking accelerating effect on the reaction time.
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Among the tested bases, Cs2CO3 and K2CO3, were the most effective base for the reactions
(Table 2, entries 1 and 2), while other bases, such as NEt3 (as an organic base) or NaOAc, proved
to be less active (Table 2, entries 3 and 4). According to the optimized reaction conditions
(EtOH, Cs2CO3 and 0.005 mmol of catalyst) various types of functionalized aryl halides reacted
with arylboronic acid and were converted into the corresponding coupled products in high to
excellent yields.
2.8. Cytotoxic Studies:
Cell culture:
As malignant cells, the human breast (MCF-7; IBRC C10082), lung (A549; IBRC C10080) and
gastric (AGS; IBRC C10071) adenocarcinoma cell lines were purchased from Iranian Biological
Resource Center (IBRC; Tehran, Iran). Breast and lung cell lines were cultured in
DMEM:Ham’s F12 supplemented with 10% Fetal Bovine Serum (FBS), 100 units ml-1
penicillin, 100 µg ml-1 streptomycin, and L-glutamine. AGS cell line was also grown in Ham’s
F12 medium supplemented with the same materials. Cells were maintained at 37 °C in a
humidified atmosphere with 5% CO2 in the air.
Solutions:
Both compounds were dissolved in DMSO at a concentration of 20 mmol l-1 as a stock solution
and diluted in culture medium at concentrations of 1.56, 3.13, 6.25, 12.50, 25 and 50 mmol l-1 as
working solution. To evade DMSO toxicity, the concentration of DMSO was less than 0.5%
(v/v) in all experiments.
Cell viability assay:
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The assay was performed according to a modified cell viability (MTT) method. This assay
detects the reduction of MTT (3-[4,5-dimethylthiazolyl]- 2,5-diphenyltetrazolium bromide) by
mitochondrial dehydrogenase, to blue formazan product, which reflects the normal functioning
of mitochondrial and cell viability [35]. Briefly, the cells (5 × 104) were equally divided in each
well containing 100 µL of the RPMI medium supplemented with 10% FBS in a 96-well plate.
After 24 h for adhesion, a serial of doubling dilution of the compounds was added to triplicate
wells over the range of 0 to 50 µM. The final concentration of DMSO in the culture medium was
maintained at 0.5% (v/v) to avoid toxicity of the solvent [36]. After 12 h, 10 µl of MTT (5 mg
ml-1 stock solution) was added and the plates were incubated for an additional 4 h at 37 °C. The
medium was discarded and the formazan blue, which formed in the cells, was dissolved with 100
µl DMSO. The optical density (OD) values of each well were measured by using ELISA plate
reader (infinite F50, TECAN, Austria) at 490 nm wavelength. The cell survival curves were
calculated from cells incubated in the presence of 0.5% DMSO. Cytotoxicity is expressed as the
concentration of the compounds inhibiting cell growth by 50% (IC50), (y = 16.788x + 26.55; r2 =
0.968). All tests and analyses were run in triplicate and mean values recorded.
Statistical analysis:
The results were analyzed by Analysis of Variance (ANOVA) and Duncan test. The data were
expressed as mean value for 3 independent assays ± S.D. All significance tests were set at P ≤
0.05, and the statistics were analyzed using the SPSS software (IBM Corp. Released in 2013.
IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.) with the level of
significant difference between compared data sets being set at P< 0.05.
3. Results and discussion
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3.1. Spectroscopy
Based on various reports in literature, it can be concluded that the ylidic compounds are a
subclass of zwitterions. According to the Scheme 1, the ylidic form of Y without formal charges
can be represented as a zwitterionic form, which contains simultaneously one positive phosphine
and one negative carbonyl group. The molecule as a whole is electrically neutral and the reaction
of this bifunctionaldiphosphine-based dipolar ligand with either [MCl2(cod)] (M = Pd and Pt;
cod = 1,5-cyclooctadiene) led to the P,C-chelated palladium(II) and platinum(II) complexes C1
and C2, respectively, without any evidence of by-product formation.
Scheme 1. Synthesis of compounds S, Y, C1 and C2.
1
The spectroscopic methods used in the present study include H, 13C and 31P NMR and other
conventional techniques such as IR and elemental analysis. A brief summary of these data is
shown in Table 3. As well, the structures of the complexes C1 and C2 were determined by single
crystal X-ray structural analyses that confirming a 1:1 stoichiometry between the MCl2 (M = Pd
or Pt) and the phosphorus ylide in the complexes.
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Table 3. Selected spectroscopic data for compounds
31PNMR;δ(PCH) 1H NMR;
13C NMR; δ(CO)
ppm
IR; υ(CO) cm-1
Compound
and δ(PPh2) ppm δ(PCH) ppm
Salt (S)
Ylide (Y)
[P, C→Pd] (C1)
[P, C→Pt] (C2)
1682
1588
1622
1629
-15.26, 20.50
-14.37, 16.55
32.02, 35.77
11.99, 32.69
6.21
4.27
5.66
5.60
191.24
181.77
193.83
193.38
In the chelating coordination mode through the carbon atom there should be an increase in the
υ(CO) frequency, while for O-coordination a lower shift for this frequency in the IR region is
expected [37]. The υ(CO) occurs at 1588 cm-1 in the parent ylide Y, while this absorption band
of the complexes shows a significant shift to 1625 cm-1, compared with its phosphorus ylide Y.
This is a consequence of resonance removing between P+-C- and carbonyl group in Y. The
resonance between the zwitterionic and ylidic forms of Y decrease the bond order of the
carbonyl group and lead to lower C=O stretching frequency. However, the resonance was
disturbed in complexes (scheme 1) and accordingly, we see a shift to higher frequency in
complexes compared to Y [38]. Overally, these results are consistent with the chelation occurs
through the ylidic carbon atom and free PPh2 group of the ylide to Pd(II) and Pt(II) chlorides [7,
27].
1
Likewise, in the H NMR spectra, chemical shifts show all the expected resonances of these
complexes respect to the ylide Y (see Supplementary data). The values for both complexes
appear to be shifted downfield compared to the parent ylide, as a consequence of the P,C-
coordination character of the ylide [3, 16, 27, 39].
The 31P chemical shift values for the complexes also appear to be shifted downfield respect to the
parent ylide, indicating that coordination of the ylide has occurred (Fig. 1). Complexes C1 and
C2 have two unequal phosphorus groups, PPh2 and P(Ph2)CH. As expected, the 31P NMR
spectrum of C1 exhibits two doublets around 32 and 36 ppm attributed to the PPh2 and P(Ph2)CH
13

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phosphorous atoms, respectively (Fig. 1). The 31P NMR spectrum of C2 is more complex,
showing peaks with downfield shifts at around 10 and 33 ppm along with two satellite peaks,
around -7 and 31 ppm, due to 195Pt–31P coupling with the adjacent PPh2 phosphorous, one of
these peaks has almost merged with a peak due to the P(Ph2)CH phosphorous atom. It must be
noted that O-coordination of the ylides generally leads to the formation of cis and trans isomers,
giving rise to two different signals in the 1H and 31P NMR spectra [40].
Figure 1.31P NMR spectra of Y (a), C1 (b) and C2 (c).
13
The most important aspect of C NMR spectra of these complexes is the downfield shift of the
carbonyl group signals, around 193 ppm, compared to the same carbon in the parent free ylide,
181 ppm, indicating a much lower shielding of the carbon of the CO group in these complexes
(see Supplementary data). The change in hybridization of the ylidic carbon in complexes respects
to ylide leads to mentioned downfield shift that has been previously observed in the series of
Pd(II) and Pt (II) complexes [41]. Thus, the spectral data clearly indicates the bidentate
coordination of the ylides through both the phosphine group and the ylidic carbon atom.
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X-ray data collection and structure determination
Crystals, suitable for single-crystal X-ray analysis, of complexes C1 and C2 were grown by
vapor diffusion of diethyl ether into a CDCl3 solution. The molecular structures of these
complexes are shown in Figs. 2 and 3. Crystal data are given in Table 4, while selected bond
distances and angles for the two structures, C1 and C2, are presented in Table 5.
Figure 3. ORTEP view of X-ray crystal C2
Figure 2. ORTEP view of X-ray crystal C1
Table 4. Data collection and refinement statistics for C1 and C2.
C1
C2
Empirical formula
C34H27Cl2NO3P2Pd
C34H27Cl2NO3P2Pt
Formula weight
736.80
825.49
Crystal system
orthorhombic
orthorhombic
Space group
Pbca
Pbca
a/Å
18.8710(5)
18.9685(2)
b/Å
15.6752(3)
15.71890(16)
c/Å
21.0265(5)
20.8678(3)
α/°
90
90
β/°
90
90
γ/°
90
6219.8(3)
90
Volume/Å3
6222.01(12)
Z
8
8
ρcalcg/cm3
1.574
7.666
1.762
11.289
µ/mm-1
F(000)
2976.0
3232.0
Crystal size/mm3
2Θ range for data collection/°
Reflections collected
Independent reflections
Data/restraints/parameters
Final R indexes [I>=2σ (I)]
Final R indexes [all data]
Largest diff. peak/hole / e Å-3
0.511× 0.1 × 0.021
8.41 to 133.182
40481
5498
5498/0/388
R1 = 0.0808, wR2 = 0.2067
R1 = 0.0966, wR2 = 0.2202
2.47/-1.80
0.536 × 0.107 × 0.01
8.446 to 133.202
53272
5502
5502/0/388
R1 = 0.0397, wR2 = 0.0959
R1 =0.0455, wR2 = 0.1004
2.41/-2.42
C1 and C2 are isostructural, with only minor differences in bond lengths and angles. The
structure of C1 is described, with corresponding details for C2 in brackets. The Pd atom in C1
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and the Pt atom in C2 are both in a slightly distorted square planar environment, coordinated by
one phosphorous and one carbon atom, from the chelating ylide, and by two cis-coordinating
chlorides; the four coordinating atoms show a slight tetrahedral distortion with a rms deviation of
0.115 Å (0.096 Å) and with the Pd atom lying almost in the plane, the deviation being 0.005(2)Å
(0.0098(15) Å). The five-membered ring comprising Pd1, P1, P2 C21 and C1 is in an envelope
conformation, with C1 lying 0.820(8) Å (0.824(5) Å) out of the plane of the other four atoms.
The Pd-Cl distance trans to the ylidic carbon atom, 2.343(2) Å (2.3545(13)), is slightly shorter
than the corresponding distance trans to the phosphorous atom, 2.376(2)Å (2.3713(12)). The
dihedral angle between the keto group and the attached aromatic ring is 12.5(5)° (14.0(3)°),
while the dihedral angle between this aromatic ring and the nitro group is 18.6(15)° (18.5(8)°).
For both structures weak C-H…O, C-H…Cl hydrogen bonds,
interactions link the molecules into a 3D network.
π…π, C-H…π and NO…π
Table 5. Selected bond lengths [Å] and bond angles [°] for C1 and C2
C1
C2
Bond distances
Pd1-Cl1
2.343(2)
2.376(2)
2.231(2)
2.117(8)
1.855(8)
1.818(9)
1.233(11)
Pt1-Cl1
Pt1-Cl2
Pt1-P1
Pt1-C1
P1-C21
P2-C21
O1-C2
2.3545(13)
2.3713(12)
2.2096(13)
2.085(5)
Pd1-Cl2
Pd1-P1
Pd1-C1
P1-C21
1.842(5)
P1-C23
1.809(6)
O1-C2
1.233(7)
Bond angles
Cl1-Pd1-Cl2
P1-Pd1-Cl1
P1-Pd1-Cl2
C1-Pd1-Cl1
C1-Pd1-Cl2
C1-Pd1-P1
P2-C21-P1
92.80(8)
88.03(8)
174.01(8)
173.6(2)
90.3(2)
Cl1-Pt1-Cl2
P1-Pt1-Cl1
P1-Pt1-Cl2
C1-Pt1-Cl1
C1-Pt1-Cl2
C1-Pt1-P1
P2-C21-P1
90.66(4)
90.13(5)
174.64(5)
175.48(15)
89.16(15)
90.47(15)
109.2(3)
89.5(2)
109.1(4)
Catalytic coupling reaction
Several mechanistic pathways, depending on the nature of the catalyst, have been investigated
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for the Heck and Suzuki type reactions [42-49]. Based on the published results, [42, 50-53] a
possible mechanism for bidentate-chelation catalytic systems such as pallada- and platinacycle-
mediated for Suzuki–Miyaura and Mizoroki-Heck reactions are proposed in Scheme 2. We
considered the metal oxidation states 0 and II in a cationic catalytic cycle. By employing the
phosphine-based ligand and base as reducing agents, the active M(0) species were generated in
an exothermic reaction leads to the formation of a π-coordinated complex as an intermediate (the
mentioned reduction step is not a part of the catalytic cycle) [50, 51]
Scheme 2.Generic mechanisms for the Mizoroki–Heck and Suzuki– Miyaura reaction of the bidentate-chelation catalytic systems
The electrophilic attack of a metal center, Pd(0) or Pt(0), to the aryl chloride to form initially an
arylated M(II) speciesis is the key step of the catalytic cycle leading to the
π-coordinated
intermediate. The resulting M(II) complex reacts with an olefin in the Heck reaction, or an
arylboronic acid in the Suzuki reaction, respectively. Reductive elimination then produces the
unique product for each reaction and regenerates the catalyst to begin the catalytic cycle again.
Using the optimized reaction conditions, we have tested two kinds of functionalized aryl
chlorides bearing electron-donating to electron-withdrawing groups. Based on the above results
and literature, decreasing of electron density on the aryl chlorides increased the catalyst activity.
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That is, high yields are achieved when the relevant reagent reacts with aryl chlorides bearing the
electron-withdrawing substituents –CHO and –COCH3. Conversely, 4-chlorotoluene and 4-
chloroanisol deactivated aryl chlorides gave lower yields indicating that the reaction was
sensitive to the electron density on the aryl chlorides. The reaction of electronically neutral
chlorobenzene with another reagent also produced a high yield of the product. This law applies
to both Mizoroki-Heck and Suzuki–Miyaura coupling reactions. To extend the scope of our
work, we investigated the coupling reaction of aryl chloride substrates with the more reactive
reagent (ethyl acrylate for Heck and 4-ethylphenylbronic acid for another one). As expected, an
electron-withdrawing substituent on the reagent has an increasing effect on the yield of the
reaction.
Figure 4. Reaction conditions for Mizoroki-Heck coupling reaction: aryl chloride (0.5 mmol), olefin (0.75 mmol), K2CO3 (1 mmol), DMF/H2O (2
ml), catalyst C1 (0.005 mmol), in air
Figure 5. Reaction conditions for Suzuki– Miyaura coupling reaction: aryl chloride (0.5 mmol), arylboronicacid (0.75 mmol), K2CO3 (1 mmol),
DMF/H2O (2 ml), catalyst C1 (0.005 mmol), in air
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The first important aspect of this study is the comparison of the catalytic properties of Pd(II) and
Pt(II) complexes. Complex C2, in contrast to Complex C1, is expected to have less of an effect
in the above coupling reactions. The results of this test can assist in determining the nature of the
active species. As seen in the above mechanisms, we believe that reductive elimination of two
chloride atoms of the complexes leads to the formation of a catalytically active low-coordinate
M(0) species [54, 55]. It is possible that similar reductive processes occur for the platinum
complex; therefore, at this stage, we are not able to rule out the possibility of a Pt(II) cycle,
although the use of strongly π-acidic ligands tends to mitigate of reductive elimination. When the
activity of the complexes C1 and C2 in the couplings are compared, it can be seen that the order
of activity is C1>C2. The fact that C2 shows the lowest activity indicates the oxidative-addition
step is being retarded compared to when C1 is used. It would be expected that the rate of
oxidative-addition for the palladium center in C1 is higher, but the more difficult oxidative-
addition at the platinum appears to be deleterious. So, the rate-determining step is probably the
oxidative-addition step that makes Pd(II) complexs more active than Pt(II) complexs in the
Mizoroki-Heck and Suzuki– Miyaura coupling reactions.
Cytotoxicity in vitro
:
The preliminary in vitro anti-proliferative efficiency of the novel tested compounds was studied
by means of a colorimetric micro-culture assay (MTT assay) in the human gastric (AGS), breast
(MCF-7), and lung (A549) cancer cells. Comparative cytotoxicity patterns of the Pd/Pt(II)
compounds C1 and C2 for AGS, MCF-7, and A549 expressed as a percentage of cell viability
are shown in Figure 6. The half maximal inhibitory concentration (IC50 value) is a drug
concentration required for inhibiting and killing 50% of the cells. IC50 values of the compounds,
estimated from the dose-survival curves for the growth inhibition of three cell lines, are
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presented in Table 6. Generally, C2 reveals a high anticancer activity compared to C1. The
increase in potency for C2 may be related to the nature of center metal, as both complexes are
isostructural. Furthermore, AGS cells (Average of IC50 value; 61.19 µM) are more chemo-
sensitive to the compounds studied in the current study than the MCF-7 and A449 cells, based on
a comparison of IC50 amounts (Table 6).
b)
a)
c)
Figure 6.Graphical representation of the anticancer activity of the synthesized compounds in the human different cancer cells: (a) AGS, (b)
MCF-7, and (c) A-549 as obtained by the MTT assay. The experiment was performed in triplicate and expressed as mean ± SD.
Effects of the tested complexes on the viability of studied cancer cells, Figure 4-a and Table 4,
showed that the AGS cells were more susceptible to the compounds than the other two human
adenocarcinoma cell lines. Based on our results, compound C2 (IC50 values; 12.88 ± 1.09 µM)
was strongly cytotoxic, much more than C1 (IC50 values; 109.50 ± 36.22 µM). At lower doses,
both complexes were tolerated by the AGS, and their anticancer activity, at 1.56 µM
concentration, were > 87%. In contrast to the results obtained by Budzisz et al. [56], our results
showed that the Pt(II) complex had a higher antitumor impact towards the human gastric cell line
than that of the Pd(II) complex.
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Table 6. Comparison of cytotoxicity (IC50 values based on µM) of the
synthesized compounds.
Compound AGS
MCF-7
109.50±36.22 149.58±44.80 513.47±122.77
12.88±1.09 124.69±7.66 66.88±24.42
A549
C1
C2
*The experiment was performed in triplicate and expressed as mean ± SD.
Values along each column with different superscripts are significantly
different (P < 0.05).
Both compounds, C1 and C2, when used against cancer cells, namely, the human breast
adenocarcinoma (MCF-7), displayed IC50 values of 149.88 ± 44.88 and 124.69 ± 7.66 µM,
respectively (Table 6). At lower doses, the compound C1 reveals higher cytotoxic action than
C2. These findings were considerably higher than those reported by Ray et al. for the benchmark
drug cisplatin with IC50 of 15 ± 2 µM, for this cancer cells [57]. Likewise, in the test on the
human A549 cells at 1.56, 3.13, 6.25, 12.50, 25 and 50 µM concentrations of the studied
compounds, C2 exhibited the excellent cytotoxic properties with the half maximal inhibitory
concentration (IC50) of 66.88 ± 24.42 µM (Table 6). Our findings also indicated that compound
C1 had a weak cytotoxic activity.
Conclusions
In summary, we report the synthesis and full characterization of new phosphorus ylide, pallada-
and platinaphosphacycle complexes. On the basis of the spectroscopic data and X-ray analysis,
the ligand Y exhibits P, C-coordination behavior to the metal centers and affords a five-
membered ring. Furthermore, the catalytic activity of complexes towards the Mizoroki-Heck and
Suzuki-Miyaura coupling reactions of various aryl chlorides were investigated. The results show
that the coupling reactions with palladacycle as catalyst results in higher yields than the
platinacycle, because of an easier oxidative-addition step. Additionally, the current study
presents evidence that the investigated compounds induce the anti-proliferative effect in the
human gastric (AGS), breast (MCF-7), and lung (A549) cancer cells. Our data indicated that the
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compound C2 was most cytotoxic than C1 that it is due to Pt nature and ligand properties. It
should be noted that although all in vitro experiments hold limitations with respects to possible
in vivo efficiency, the results are very promising with regards to possible antineoplastic
chemotherapy and form a very sound basis for future research.
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