A new family of oxime palladacycles mixed with unsymmetrical phosphorus ylides; synthesis, structural, cytotoxicity and catalytic activity studies

Article abstract of DOI:10.1016/j.jorganchem.2019.120927

In the present investigation, the reactivity of an oxime-derived palladacycle [Pd{C,N–C₆H₄{C(Me) = NOH}-2}(μ-Cl)]₂ toward various unsymmetrical phosphorus ylides has been studied. When the ylide was added to a solution of

Full text of DOI:10.1016/j.jorganchem.2019.120927

Journal of Organometallic Chemistry 900 (2019) 120927
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
A new family of oxime palladacycles mixed with unsymmetrical
phosphorus ylides; synthesis, structural, cytotoxicity and catalytic
activity studies
,
Sepideh Samiee a *, Ahmadreza Shiralinia a, Elham Hoveizi b, Robert W. Gable c
a Department of Chemistry, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
b Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
c School of Chemistry, University of Melbourne, Victoria, 3010, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
In the present investigation, the reactivity of an oxime-derived palladacycle [Pd{C,N
Received 14 May 2019
Received in revised form
12 August 2019
Accepted 7 September 2019
Available online 9 September 2019
eC6H4{C(Me) ¼ NOH}-2}(
m-Cl)]2 toward various unsymmetrical phosphorus ylides has been studied.
When the ylide was added to a solution of oxime complex in dichloromethane (2:1 ratio), the new oxime
palladacycles of the types [Pd{C,NeC6H4{C(Me) ¼ NOH}-2}(Ph2PCH2PPh2C(H)C(O)C6H4X)]ClO4 (X ¼ Cl
(1), Br (2), NO2(3) or OCH3 (4)) were formed by means of bridge-splitting reaction. These are the first
description of oxime-based palladacycles mixed with phosphorus ylides. All of complexes were fully
characterized by elemental analysis, IR and NMR spectroscopies. The crystal structure of 3 were deter-
mined by single-crystal X-ray diffraction analysis that confirmed breaking of PdeCl bonds in the initial
precursor and allowing phosphorus ylide act as P,C-chelating ligand. In addition, the catalytic activity of 3
was evaluated in the Suzuki cross-coupling reactions of a variety of arylbromides with phenylboronic
acid. This complex was also used for the assessment of their anticancer activities against three human
carcinoma cell lines: A549 (human lung carcinoma), HT29 (human colon carcinoma), and HeLa (human
cervical carcinoma). The results show that the new family of oxime-derived palladacycles could be
introduced as promising innovative anticancer complexes and considered as an efficient catalyst in the
cross coupling reactions.
Keywords:
Oxime palladacycle
Unsymmetrical phosphorus ylide
Suzuki reaction
Cytotoxicity activity
© 2019 Elsevier B.V. All rights reserved.
1. Introduction
for wide range of CeC bond coupling reactions such as
SuzukieMiyaura, MizorokieHeck, Stille, MatsudaeHeck, Kumada,
Nowadays, the cyclometalated compounds in organometallic
chemistry are one of the most significant research topics due to
their applications in different areas [1e6]. In particular, a major
research effort has focused on the study of palladacycles mainly
due to the potential catalytic activity [3,6,7] of some of these
complexes and their interesting antitumor properties [5]. The
oxime-derived palladacycles established a great family of thermally
stable palladium complexes, not sensitive to air or moisture [8]. The
synthesis of theses complexes was started in 1970 by ortho-
palladation of oximes with alkali metal tetrachloropalladates in
the presence of sodium acetate [9]. These oxime palladacycles are
stable, easy to prepare, and very efficient and versatile pre-catalysts
Hiyama, Ullmann, Sonogashira, and Glasser, commonly when
compared with other palladium salts [6], 8e9] Among all of
coupling reactions, the Suzuki-Miyaure coupling reaction is a
powerful and straight forward methodology for the formation of
carbonꢀcarbon bond in both academic and industrial laboratories
[10e12]. Specifically, Najera and co-workers reported pioneering
work on oxime palladacycles, which are robust and highly active
palladium catalysts for various coupling reactions [6,7].
On the other hand, the properties of palladium(II) complexes
with chelate biphosphine ligand have attracted considerable
attention in recent years [13] because of their potential applications
in particular those involving pharmaceuticals and catalysts. It is
noteworthy that the use of palladium phosphine species is an
outstanding tactics for Suzuki couplings under very low palladium
loadings [14e16]. However, cross-coupling reactions under
phosphine-free conditions are still an important challenge for
* Corresponding author.
E-mail addresses: s.samiee@scu.ac.ir, samiee.sepideh@gmail.com (S. Samiee).
https://doi.org/10.1016/j.jorganchem.2019.120927
0022-328X/© 2019 Elsevier B.V. All rights reserved.

2
S. Samiee et al. / Journal of Organometallic Chemistry 900 (2019) 120927
researchers as these compound are expensive, toxic, and generally
air-sensitive and hydrophobic [14]. Recently, different phosphine-
free ligands as diverse as N-heterocyclic carbenes [17], diimines
[18] and amides [19], have attracted considerable attention as
competent ligands for Suzuki reactions [20]. Regarding the poten-
tial applications of these above-mentioned compounds in many
areas, we were interested in assembling the oxime-derived palla-
dacycles bearing phosphorus ligands to form more complex
structures. The present work is to introduce a new family of oxime
palladacycles mixed with unsymmetrical phosphorus ylides for the
first time. The results of these studies are also supported by
elemental analysis, IR, NMR and X-ray structural techniques.
Furthermore, the antioxidant capacity and catalytic behavior to-
wards Suzuki cross-coupling reaction is reported here.
(DMSO‑d6, 250.13 MHz) dH (ppm): 2.26 (s, 3H, CH3C]N), 4.93 (m,
2H, PCH2P), 5.48 (br s, 1H, PCH), 6.27e6.92 (m, 4H, C6H4), 7.27e8.01
(m, 20H, 2PPh2), 11.20 (br, 1H, OH). 13C{1H}NMR (DMSO‑d6,
62.90 MHz) dC (ppm): 13.69 (s, CH3), 37.82 (d, 1JPC ¼ 62.27 Hz, PCH),
122.23e140.03 (m, Ph), 144.89 (s, C3), 159.40 (s, C4), 176.92 (s, C2),
197.43 (s, CO).
2.2.3. Data for [Pd{C,NeC6H4{C(Me) ¼ NOH}-2}(L3)]ClO4 (3)
Yield: 83%; m.p. 208e210 ꢁC. Anal. Calc. for C41H35ClN2O8P2Pd:
C, 55.47; H, 3.97; N, 3.15. Found: C, 55.91; H, 3.29; N, 3.05%. Selected
IR absorption in KBr (cmꢀ1): 3433 (
nO]H), 1589 (nC]O), 1105, 623
(
n-ClO4). 31P{1H} NMR (CDCl3, 101.25 MHz) dP (ppm): 28.42 (d,
2JPP ¼ 38.8 Hz, PPh2), 30.43 (d, 2JPP ¼ 37.6 Hz, PCH). 1H NMR (CDCl3,
250.13 MHz) dH (ppm): 2.26 (s, 3H, CH3C]N), 4.07 (br, 2H, PCH2P),
5.43 (br s, 1H, PCH), 6.37e6.94 (m, 4H, C6H4), 7.12e8.21 (m, 20H,
2PPh2). 13C{1H}NMR (CDCl3, 62.90 MHz) dC (ppm): 13.38 (s, CH3),
2. Experimental
1
39.95 (d, JPC ¼ 60.38 Hz, PCH), 124.49e138.18 (m, Ph), 150.60 (s,
2.1. Materials and measurements
C3), 158.77 (s, C4), 177.73 (s, C2), 197.41(s, CO).
All manipulations were carried out under dry nitrogen using
standard Schlenk techniques unless otherwise noted. Commercially
available reagents and solvents were ofreagent grade and have
been used without further purification. The unsymmetrical
diphosphineylides [Ph2PCH2PPh2C(H)C(O)C6H4X] (X ¼ Cl (L1), Br
(L2), NO2 (L3), OCH3 (L4)) [21] and dinuclear chloro-bridged oxime
2.2.4. Data for [Pd{C,NeC6H4{C(Me) ¼ NOH}-2}(L4)]ClO4 (4)
Yield: 69%; m.p. 203e204 ꢁC. Anal. Calc. for C42H38ClNO7P2Pd: C,
57.81; H, 4.38; N, 1.60. Found: C, 57.79; H, 4.58; N, 1.63%. Selected IR
absorption in KBr (cmꢀ1): 3348 (
n
O]H), 1603(
nC]O), 1100, 624
(
n-ClO4). 31P{1H} NMR (DMSO‑d6, 101.25 MHz)dP (ppm): 29.44 (d,
2JPP ¼ 39.1 Hz, PPh2), 31.98 (d, JPP ¼ 38.9 Hz, PCH). 1H NMR
(DMSO‑d6, 250.13 MHz) dH (ppm): 2.32 (s, 3H, CH3C]N), 3.80 (s,
3H, OCH3), 4.93 (m, 2H, PCH2P), 5.44 (br s, 1H, PCH), 6.24e6.98 (m,
4H, C6H4), 7.25e8.06 (m, 20H, 2PPh2). 13C{1H}NMR (DMSO‑d6,
62.90 MHz) dC (ppm): 13.80 (s, CH3), 36.75 (d, 1JPC ¼ 57.23 Hz, PCH),
56.91 (s, CH3), 122.77e144.99 (m, Ph), 159.92 (s, C3), 164.02 (s, C4),
176.83 (s, C2), 197.16 (s, CO).
complex [Pd{C,NeC6H4{C(Me) ¼ NOH}-2}(
m
-Cl)]2 [8], were pre-
2
pared according to reported procedures. The 1H, 31P{1H} and13
C
{1H} NMR spectra were recorded at 25 ꢁC on 250 and 400 MHz
Bruker spectrometers with CDCl3 or DMSO‑d6 as the solvent. IR
spectra were recorded on a Perkin-Elmer spectrophotometer and
the measurements were made by the KBr disk method. Elemental
analyses (C, H, N) were performed using a Perkin-Elmer 2400 series
analyzer. Melting points were measured on a SMP3 apparatus
without correction.
2.3. X-ray crystallography
2.2. Synthesis of the Pd(II) complexes
Light yellow crystals of 3 were crystallized by solvent diffusion
of n-hexane into chloroform. A suitable crystal was selected and
mounted on a Rigaku Oxford Diffraction Supernova, Dual, Cu at
zero, Atlas diffractometer. The crystal was kept at 130.01(10) K
during data collection. Using Olex2 [22], the structure was solved
with the ShelXT [23] structure solution program using Intrinsic
Phasing and refined with the ShelXL [24] refinement package using
Least Squares minimisation on F2, using all data. Gaussian absorp-
tion corrections were applied to the 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. Several of the atoms showed high aniso-
tropic displacement parameters were high, suggestive of the
molecule being disordered. Accordingly the molecule was treated
as being disordered over two components, restrained to have the
same geometry with the displacement parameters of each atom
constrained to be equal; the final occupancy factors for the two
disordered components were 0.616(4):0.384(4). The difference
map showed a number of peaks consistent with the presence of
highly disordered molecules of included solvent. Attempts to
model this, as disordered chloroform, were unsuccessful. The
composition of solvent voids was determined using the OLEX2
solvent mask routine [22] which indicated that the electron density
and the solvent void were consistent with the presence of 5 mol-
ecules of chloroform (1.25 molecules per formula unit) in a solvent
void that could accommodate up to 8 molecules of chloroform (2
per formula unit). The final refinements were carried out using the
OLEX2 solvent mask routine to account for the contribution of the
unassigned disordered solvent.
To a suspension of oxime complex (0.022 g, 0.04 mmol) and
excess NaClO4$H2O (0.028 g, 0.2 mmol) in CH2Cl2 (15 mL), kept
under nitrogen atmosphere, was added phosphorus ylide
(0.08 mmol). The reaction mixture was continuously stirred and
allowed to react for 7 h. The mixture was then filtered, and the
volume of the filtrate was reduced to <2 mL under reduced pres-
sure and treated with n-hexane (15 mL) to afford the new oxime-
derived palladacycles (1e4).
2.2.1. Data for [Pd{C,NeC6H4{C(Me) ¼ NOH}-2}(L1)]ClO4 (1)
Yield: 77%; m.p. 205e207 ꢁC. Anal. Calc. for C41H35Cl2NO6P2Pd:
C, 56.15; H, 4.02; N, 1.59. Found: C, 56.29; H, 3.69; N, 1.54%. Selected
IR absorption in KBr (cmꢀ1): 3413 (
n
O]H), 1592(
nC]O), 1097, 623
(
n-ClO4). 31P{1H} NMR (DMSO‑d6, 101.25 MHz): dP (ppm): 29.04 (d,
2
2JPP ¼ 37.5 Hz, PPh2), 32.02 (d, JPP ¼ 37.5 Hz, PCH). 1H NMR
(DMSO‑d6, 250.13 MHz) dH (ppm): 2.26 (s, 3H, CH3C]N), 4.87 (m,
2H, PCH2P), 5.48 (br s, 1H, PCH), 6.24e6.99 (m, 4H, C6H4), 7.02e8.01
(m, 20H, 2PPh2), 11.21 (br, 1H, OH). 13C{1H}NMR (DMSO‑d6,
62.90 MHz) dC (ppm): 13.68 (s, CH3), 37.85 (d, 1JPC ¼ 61.01 Hz, PCH),
126.64e138.32 (m, Ph), 144.85 (s, C3), 159.38 (s, C4), 172.87 (s, C2),
197.31 (s, CO).
2.2.2. Data for [Pd{C,NeC6H4{C(Me) ¼ NOH}-2}(L2)]ClO4 (2)
Yield: 75%; m.p. 201e203 ꢁC. Anal. Calc. for C41H35ClBrNO6P2Pd:
C, 53.44; H, 3.82; N, 1.52. Found: C, 53.24; H, 3.94; N, 1.55%. Selected
IR absorption in KBr (cmꢀ1): 3368 (
nO]H), 1595 (nC]O), 1099, 623
(
n-ClO4). 31P{1H} NMR (DMSO‑d6, 101.25 MHz) dP (ppm): 28.97 (d,
2
2JPP ¼ 38.5 Hz, PPh2), 31.97(d, JPP ¼ 37.7 Hz, PCH). 1H NMR

S. Samiee et al. / Journal of Organometallic Chemistry 900 (2019) 120927
3
2.4. General procedure for the SuzukiꢀMiyaura reaction
Staining was repeated 3 times for each sample.
In a general procedure, to a round-bottom flask equipped with a
magnetic stirring bar a mixture of palladium catalyst 3 (0.5 mol%),
phenylboronic acid (0.6 mmol), aryl bromide (0.5 mmol) and K2CO3
(0.75 mmol) in 1:1 mixture of EtOH/H2O (2 mL) was added. The
mixture was stirred at room temperature in the presence of air and
the progress was monitored by thin layer chromatography (TLC).
After the completion of the reaction, catalyst was filtered and the
remaining reaction mixture was extracted with H2O and n-hexane.
The organic layer was dried over anhydrous Na2SO4 (1.5 g). Then n-
hexane was evaporated and pure biphenyl derivatives were ob-
tained in 84e96% of yields.
2.5.4. DAPI staining and morphology observation
DAPI staining was carried out on cells cultured for 24 h briefly,
three cell lines were cultured in 96 well plates with a density of
10 ꢂ 103 cells/well and treated with compound 3 with IC50 con-
centration for 24 h. Then the cells were washed with PBS and fixed
with 4% paraformaldehyde for 30 min stained with 1 mg/mL 4, 6-
diamidino-2-phenylindole, dihydrochloride (DAPI, Sigma) in the
dark. The samples were captured using a fluorescent microscope
with UV filter (OLYMPUS, Japan). For morphology observation, the
treated and control samples were viewed by an inverted micro-
scope with a digital camera after 24 h (Biorad, USA).
2.5. Cytotoxicity studies
3. Results and discussion
2.5.1. Cell culture
3.1. Synthesis and characterization
A549 (human lung carcinoma), HT29 (human colon carcinoma),
and HeLa (human cervical carcinoma), cell lines were obtained
from Iran Pasteur Institute, Tehran, Iran, and cultured in DMEM/F12
with 10% fetal bovine serum (FBS)and 1% antibiotics. The cells were
incubated at 37 ꢁC in an atmosphere of 5% CO2. Also, the cells were
subcultured by using 0.05% trypsin treatment procedure.
The dinuclear chloro-bridged oxime palladacycle of [Pd
{C,NeC6H4{C(Me) ¼ NOH}-2}(
m-Cl)]2 was prepared by stirring a
mixture containing Li2[PdCl4], acetophenone oxime and NaOAc in
methanol solvent at the first stage [9]. In addition, the unsym-
metrical phosphorus ylides (L1eL4) were synthesized from
diphosphine Ph2PCH2PPh2 (dppm) and the appropriate ketone
according to the literature [21].
2.5.2. Measurement of cell viability
The cell viability was analyzed with an MTT (3-(4,5-
dimehylthiazol-2yl)-2,5-diphenyl tetrazolium bromide, Sigma)
colorimetric assay. Three cell lines were cultured in 96 well plates
and incubated for 24 h. These cells were treated with the 0.01, 0.1,
and 1 mg/mL concentration of compound 3 for 1, 2, and 3 days.
After that, 100 mL of MTT solution with a concentration of 0.5 mg/
mL was applied to each well and after 4 h of incubation at 37 ꢁC,
100 ml of dimethyl sulfoxide (DMSO) were added and the level of
absorbance was measured at 570 nm with ELISA reader (Expert 96,
Asys Hitch, Ec Austria).
In continues, as shown in Scheme 1, the reaction of a solution of
L in dichloromethane, with 0.5 equiv of oxime complex in presence
of NaClO4$H2O gave in good yield the new mononuclear oxime
palladacycles (1e4). To sum up, this reaction led to the splitting of
the chloride bridge and obtained the mononuclear oxime com-
plexes that two bidentate ligands (C^N and P^C) are coordinated to
the metal center. All of the obtained compounds are stable towards
air and moisture and can be stored for several months without
apparent decomposition. The structure of new complexes (1e4)
was characterized by 1H, 31P and 13C NMR spectroscopic methods
and other conventional techniques as well as IR and elemental
analysis. The exact structure of the complex 3 was also determined
by a single crystal X-ray structural analysis. Analytical data of three
yellow complexes are in accordance with the proposed formula-
tion. Moreover, Table 1 shows the brief summary of the collected
data for all studied complexes.
2.5.3. Acridine orange/propidium iodide (AO/PI) double-staining
assay
A549, HT29, and HeLa cell lines obtained in the logarithmic
growth phase and cultured in DMEM/F12 medium containing 10%
FBS in each well of a 96 well plate with a density of 10 ꢂ 103 cells/
well. The next day, the cells were treated with compound 3 with
IC50 concentration and the plates were incubated for 24 h. The cells
were left untreated and considered as a control sample. After that,
the cells were suspended by trypsin and transferred to glass slides.
The IR spectra of 1e4 show a strong band around 1600 cmꢀ1
assigned to the vibration of the carbonyl group. This bond in each
complex is displaced towards higher frequencies as compared with
the free phosphorus ylide (see Table 1). As noted previously [21],
the coordination of the ylide through carbon or oxygen causes a
AO/EB solution (containing 100 mg/mL AO (Sigma) and 100 mg/mL
EB (Sigma)) was added to each slide for 5 min. The morphological
changes of three cell lines were viewed under a fluorescent mi-
croscope (OLYMPUS, Japan) with a filter range of 450e490 nm.
significant increase or decrease, respectively, in the n(CO) frequency
[25]. Accordingly, it is found that the chelation of each ylide to
oxime complex has occurred through the ylidic carbon atom. Note
Scheme 1. The synthesis route for preparation of oxime palladacycles mixed with various phosphorus ylides.

4
S. Samiee et al. / Journal of Organometallic Chemistry 900 (2019) 120927
Table 1
Spectroscopic data for compounds 1e4.
Compound
IR
1HNMR
(PCH)
31PNMR
(PPh2) (2JPeP
13CNMR
d(CO)
Ref.
n
(CO) (cmꢀ1
)
d
d
)
d
(PCH) (2JPeP
)
L1
1
1503
1592
1502
1595
1524
1589
1507
1603
4.23(br)
5.48(br)
4.22 (d)
5.49(br)
4.34(d)
5.19(br)
4.24 (br)
5.45(br)
ꢀ29.90(63.10)
29.04 (37.50)
ꢀ30.07 (63.67)
28.97 (38.50)
ꢀ30.4(62.50)
28.42 (38.80)
ꢀ29.67 (62.36)
29.44 (39.10)
11.35(63.10)
184.05
197.31
183.58
197.45
181.99
197.43
184.61
197.18
[28]
This work
[21]
This work
[28]
This work
[21]
32.02 (37.50)
11.39(62.98)
31.97 (37.70)
11.50(62.50)
30.43 (37.60)
11.15(62.36)
31.98 (38.90)
L2
2
L3
3
L4
4
This work
that the IR spectrum displays two bands of strong intensity around
1100 and 620 cmꢀ1, which are indicative of the presence of ClO4ꢀ
group. Moreover, OHꢀ vibrations give rise to a broad band around
3400 cmꢀ1 for all studied complexes. The aryl and/or heteroaryl
fragments in the oxime and phosphorus ligands must be respon-
sible for the presence of several bands in the 1500e1600 cmꢀ1 re-
As depicted in Fig. 1, the Pd atom is in a square planar envi-
ronment, surrounded by one C,N-chelating oxime ligand and one
P,C-chelating phosphorus ylide that forms two five-membered
rings. Noticeably, the N atom is trans to the P atom with both
coordinating carbon atoms being mutually trans. The RMS devia-
tion of the four coordinating atoms is 0.080 Å, with Pd lying
0.086(15) Å out of the plane. The angles subtended by the ligand at
the Pd(II) centre vary from 80.1(3)ꢁ to 95.7(3)ꢁ (the sum of the
angles is 359.97ꢁ), and 170.2(10)ꢁ to 174.1(2)ꢁ, indicating a slightly
distorted square planar environment. The oxime ligand is planar to
within 0.11(4) Å, with the Pd atom lying 0.19(3) Å out of the plane.
Although the bidentate phosphorurs ligand is partially warped, the
environment around the Pd is planar. The C4ePdeN1 and
P1ePdeC34 bond angles are statistically identical to those found in
the other ortho-palladated [26] and P,C-coordinated complexes
[13,21], respectively. It should be noted that the metal geometry
and conformation of the ligand are in good agreement with the
values found for similar palladium complexes. The two PdeC and
PdeN bonds are significantly shorter than the PdeP bonds, as ex-
gion, making it impossible to unequivocally assign the n(C]N)
absorption [26]. These values are consisted with the literature
values for most complexes containing the oxime moiety [26,27].
The most interesting aspect observed in the 31P NMR spectra of
these complexes is the change in chemical shift of phosphorus
atoms upon the complexation of ylides. 31P{1H} NMR character-
ization of all new complexes 1e4 displayed two doublets around 29
and 31 ppm, which can be assigned to the PCH and PPh2 groups,
respectively. These peaks were shifted remarkably downfield from
that of free ylide (see Table 1) due to the coordination of the ylide to
palladium through the free phosphine and phosphonium groups,
which was similarly reported for other P,C-chalated palladium
complexes [21]. The 1H NMR spectra of each complex exhibited that
the methynic group (PCH) is resonated as a broad singlet around
pected for the stronger s-donating nature of the ylidic carbon and
d
5.4 ppm. This signal is shifted to the down field relative to the
the nitrogen atom with respect to PPh2 group. As well, the
PdꢀCortho bonds are significantly shorter than the PdꢀCylidic bonds.
A point to be noted is that the two bond distances of oxime ring
around palladium center are shorter than ylide ring.
starting ligands (L1eL4), indicating that coordination of the ligand
occurs through ylidic carbon atom (see Table 1). Also, the 1H NMR
spectra of complexes 1e4 show the signal of the methylenic pro-
tons (PCH2P) as
a
multiplet or broad peak in the range
The stabilized resonance structure for the parent unsymmetrical
phosphorus ylide is destroyed due to the formation of the
4.07e4.93 ppm due to the coupling with neighbor phosphorus
atoms. In the 13C{1H} NMR spectra of 1e4, the C]NOH and the
C4emetallated carbon atoms appear downfield shifted by ca. 20
and 30 ppm, respectively, in relation to the free oxime ligand [27],
which is in agreement with the chelating coordination mode of the
oxime ligand via the iminic N and the C4 carbon atoms. Moreover,
the presence of the carbonyl group in all studied complexes is also
demonstrated by 13C{1H} NMR spectroscopy displaying signals
around 196 ppm, which is downfield shifted with respect to the
phosphorus ylides (183 ppm). Therefore, IR and NMR data confirm
that the interaction of unsymmetrical phosphorus ylides (L1eL4) to
oxime palladacycle are through both free phosphine part and ylidic
carbon atom, as proved for the crystal structure of 3.
3.2. X-ray crystal structure
The molecular structure of 3 was confirmed by X-ray diffraction.
A molecular drawing of entitled complex is shown in Fig.1. Relevant
parameters including data collection and refinement are given in
Table 2, while selected bond distances and angles are collected in
Table 3. Fractional atomic coordinates and equivalent isotropic
displacement coefficients (Ueq) for the non-hydrogen atoms of the
complexes are available as Supplementary data. The structure of 3
confirms the breaking of the PdeCl bonds in the initial oxime
complex and has demonstrated for the first time that an unsym-
metrical phosphorus ylide, namely [Ph2PCH2PPh2C(H)C(O)
C6H4NO2], can act as P,Cechelating ligand.
Fig. 1. Molecular structure of 3. Hydrogen atoms, ClO4 anion and minor disorder
components are omitted for clarity. Displacement ellipsoids are drawn at the 50%
probability level.

S. Samiee et al. / Journal of Organometallic Chemistry 900 (2019) 120927
5
palladacycle, as can be seen from a comparison of bond lengths. The
C34eC35 bond length (1.458(6) Å) is longer than the corresponding
distances found in similar free phosphorus ylides (1.396(7) Å [28]
and 1.388(3) Å [29]), while the bond lengths between ylidic carbon
and phosphorus (P2eC34) have considerably elongated to 1.757(5)
Å, in comparison with the similar ylides (1.711(5) Å and 1.712(2) Å)
[29]. The C35eO2 bond length (1.242(6) Å) is also shorter than that
observed in similar free phosphorus ylides (1.267(5) Å [28] and
1.259(3) Å [29]). In addition, the P2eO2 distance (3.006 Å) is
significantly shorter than the sum of the van der Waals radii of P
and O (3.3 A) [30]. indicating a strong intermolecular interaction
between Pþ and Oꢀ charge centers, which leads to the cis orien-
tation. The carbonyl group is almost perpendicular to the PdC2NP
plane, the torsion angle Pd1eC34eC35eO2 being 85.9(12)ꢁ while
the dihedral angle between the carbonyl group and the adjacent
phenyl ring is 27.5(12)ꢁ. The only complexes with this exact ligand
are two mercury complexes [31]. There are only weak intra- and
We found that K2CO3 gave the best results for this reaction (Table 4,
entry 5) and other bases such as Na2CO3, KOH, CH3COONa (NaOAc)
and triethylamine (Et3N) were not suitable (Table 4, entries 10e12).
The formation of cross-coupled product was not observed in the
absence of the base, it indicate that the presence of the base is an
essential requisite for the reaction (Table 4, entry 9). Various
catalyst concentrations were also tested and 0.5 mol % gave the best
result (Table 4, entries 5e8). Among the several organic solvents
examined, EtOH/H2O (1:1) was chosen as the most suitable solvent
under optimized reaction conditions (Table 4, entry 5). Finally, the
best reaction condition for the Suzuki cross coupling of bromo-
benzene and phenyl boronic acid reaction was selected using
0.5 mol % of the Pd catalyst in EtOH/H2O (1:1) as the solvent and
K2CO3 as the base at room temperature in 60 min, which worked
efficiently in Suzuki cross-coupling reaction.
With the optimized protocol for the Suzuki cross-coupling re-
action in hand, complex 3 were applied to a range of aryl bromides
bearing electron-withdrawing (Table 5, entries 1e4) and electron-
donating substituents (Table 5, entries 6 and 7) in Suzuki-
Miyaura reaction. As expected, electron-donating substituent on
aryl bromide has decreasing effect on the yield of reaction. That is,
increasing electron density on the aryl bromide lowered the cata-
lyst activity [33]. The excellent yields were achieved when phe-
nylboronic acid reacted with aryl bromides with electron
withdrawing substituent such as eNO2 (entry 4, Table 5). It is
noteworthy that the reactions of phenylboronic acid containing
electron-donating substituent with aryl bromides furnishes good
amounts of desired biaryls, albeit with reduced yields (Table 5,
entries 6 and 7).
Several mechanistic pathways, depending on the nature of the
catalyst, have been investigated for the Heck and Suzuki type re-
actions [34e37]. Based on the published results [38e40], a prob-
able mechanism for the formation of the coupled products is
proposed in Scheme 2. Initially, oxidative addition of bromo-
benzene results in the oxidation of Pd(II) (A) to Pd(IV) (B). Upon
addition of the base, the intermediate B produces an intermediate C
due to the metathetic exchange. Next, the intermediate C un-
dergoes transmetallation with phenylboronic acid to give D, which
on reductive elimination leads to the desired product.
To further evaluate the catalytic performance of compound 3, a
comparison was made with several literature-reported CeC
coupling reactions in the presence of other catalysts (see Table 6)
[33,41e43]. The reactions of bromobenzene with phenylboronic
acid were taken as the standard reactions, and the results are
gathered in Table 6. The comparison of data presented in this table
shows the efficiency of this new catalyst towards the coupling re-
actions. Comparing the catalytic performances between P,C-
coordinated complexes with two chloro-substituent (Table 6,
intermolecular contacts, mostly CeH/O hydrogen bonds and
p /
p
interactions, linking the molecules into a 3D network (Tables S4
and S5 in Supplementary data) [13,26,32].
3.3. Catalytic studies
It is well-known that the palladacyclic complexes bearing
phosphorus ylides have excellent catalytic activity in Suzuki cross-
coupling reactions [33]. The ability to use small amounts of catalyst
and still achieve high yields is a great concern in cross-coupling
reactions due to the high cost of metals and ligands. In this re-
gard, the catalytic applicability of compound 3 was evaluated for
the SuzukieMiyaura cross-coupling reaction for a representative
range of aryl bromides with phenylboronic acid. The rate of these
reactions is essentially depended on a variety of parameters such as
solvent, base and catalyst loading. Accordingly, a reaction model
involving bromobenzene (0.5 mmol) and phenylboronic acid
(0.6 mmol) was chosen, and various reaction parameters such as
solvent, catalyst loading and base were analyzed to find optimum
conditions. Table 4 summarizes our results for the Suzuki reactions.
Table 2
Crystal data and structure refinements of 3.
Identification code
3
Empirical formula
Formula weight
Temperature [K]
Crystal system
Space group
a (Å)
C42$25H36$25Cl4$75N2O8P2Pd
1036.71
130.01(10)
monoclinic
P21/n
14.82156(14)
17.89896(17)
17.3847(2)
95.9083(10)
4587.50(8)
4
1.501
6.906
b (Å)
c (Å)
b
(ꢁ)
Volume[Å3]
Z
Table 3
rcalc[g/cm3]
Selected bond lengths [Å] and angles [º] for 3.
m
/mmꢀ1
Bonds lengths
Bonds angles
F(000)
2098.0
Crystal size [mm3]
0.385 ꢂ 0.25 ꢂ 0.06
7.108 to 154.328
ꢀ18 ꢃ h ꢃ 14, ꢀ22 ꢃ k ꢃ 17,
ꢀ21 ꢃ l ꢃ 21
PdeP1
PdeC4
2.249(3)
2.034(6)
2.257(5)
2.106(5)
1.839(5)
1.801(5)
1.757(5)
1.382(8)
1.218(11)
1.229(11)
3.006(3)
1.458(6)
1.242(6)
P1ePdeC34
N1ePdeP1
N1ePdeC34
C4ePdeP1
C4ePdeN1
C4ePdeC34
C9eP1ePd
C9eP1eC21
C15eP1eC9
C22eP2eC21
C22eP2eC28
C28eP2eC21
C34eP2eC21
90.17(19)
174.1(2)
95.7(3)
94.0(3)
80.1(3)
170.2(10)
122.4(3)
101.5(4)
106.9(4)
107.7(4)
109.1(4)
108.8(4)
107.3(4)
2
Q
(ꢁ)
Index ranges
PdeC34
PdeN1
P1eC21
P2eC21
P2eC34
N1eO1
N2eO3
N2eO4
P2eO2
C35eC34
C35eO2
Radiation
Reflections collected
CuKa
(
l
¼ 1.54184)
35205
Independent reflection [Rint, Rsigma
Data/restraints/parameters
Goodness-of-fit on F2
]
9631 [0.0435, 0.0358]
9631/150/652
1.104
Final R indexes [I ꢄ 2
s
(I)]
R1 ¼ 0.0541, wR2 ¼ 0.1311
R1 ¼ 0.0589, wR2 ¼ 0.1346
1.40/-1.15
Final R indexes [all data]
Largest diff. peak/hole[eÅꢀ3
CCDC
]
1860197

6
S. Samiee et al. / Journal of Organometallic Chemistry 900 (2019) 120927
Table 4
Optimization of reaction condition on Suzuki-Miyaura reaction of arylbromides with phenylboronic acid.
Entry
Solvent
Base
Catalyst loading (mol%)
Yield (%)b
1
2
3
4
5
6
7
8
DMF
DMF/H2O
H2O
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
e
0.5
0.5
0.5
0.5
0.5
0.9
0.05
0.005
0.5
69
75
51
78
89
89
20
NC
NC
75
68
60
EtOH
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
9
10
11
12
Na2CO3
KOH
NaOAc
0.5
0.5
0.5
aReaction conditions for SuzukiꢀMiyaura coupling reaction: bromobenzene (0.5 mmol), phenylboronic acid (0.6 mmol), base (0.75 mmol), solvent (2 mL), catalyst 3, in air, at
room temperature, time 1 h, NC (no conversion).
b
Isolated yield.
Table 5
SuzukiꢀMiyaura coupling reaction of various arylbromides with phenylboronic acid.
Entry
R
Coupling Products
Yield (%)
1
2
3
4
5
6
7
CHO
COCH3
COOH
NO2
H
CH3
p-OHCꢀPhꢀPh
p-CH3OCꢀPhꢀPh
p-HOOCꢀPhꢀPh
p-O2NꢀPhꢀPh
PhꢀPh
92
94
90
96
89
87
84
p-H3C-PhꢀPh
p-H3COꢀPhꢀPh
OCH3
Catalyst 3 loading (0.5 mol %); phenylboronic acid (0.6 mmol); Aryl bromide (0.5 mmol); K2CO3 (0.75 mmol); solvent: EtOH:H2O (1:1, 2 mL).
entries 2, 5) and compound 3 with oxime-substituent, the com-
pound 3 was more active in the Suzuki cross coupling reactions.
Thus, the present of 2-(1-(hydroxyimino)ethyl)phenyl ligand could
be considered as an positive point in catalytic activity. The utiliza-
tion of this catalyst at low catalyst loading, high reactivity with
bromobenzene in short reaction time, stability toward air, good
yield and easy separation make it valuable. From green chemistry
view point, using nontoxic organic solvent in cross coupling reac-
tion provide an indisputable advantage than the other catalytic
systems. In all of the successful reactions, the 1H and 13C NMR data
of the products indicated no Suzuki coupling by products and some
NMR data of the CeC products are given in Supplementary data.
comparison between the cytotoxic activities against the A549 cell
line for compound 3 and some of the other palladium complexes
reported in the literature [44e48]. The results revealed that the
compound 3 exhibited similar and even higher cytotoxic activity
than that of the other palladium complexes. The possible mode of
bioactivity of our palladium complex maybe explained by Tweedy's
chelation theory [49]. Generally, the polarity of any central metal
ion is lessened considerably due to chelation. This is due to the
partial sharing of metal's positive charge with the ligand and
possible p-electron delocalization over the chelate ring [50]. In this
study, cancer A549 cell line was the most sensitive line when
exposed to compound 3 and our data demonstrated that the
treated cells with 1 mg/mL (as highest concentration) decreased
the cell viability to 18% (p < 0.001) and it was concluded about 24%
and 39% (p < 0.001) because of 0.1 mg/mL and 0.01 mg/mL con-
centration of compound 3, respectively in comparison to the non-
treated cells after 3 days (Fig. 2). Therefore, treatment with the
experimental concentration of compound 3 caused a significant
decline in the cell growth and viability in three cell lines as a
manner depended on cell type.
3.4. Cytotoxicity studies
3.4.1. Cell viability assay
Numerous palladium complexes have been investigated for
their anticancer activity [5]. In the present study Cell viability in-
hibition was detected by an MTT assay. Various concentrations of
compound 3 had varied effects on cell viability in three different
cell lines. Our results indicated that, by increasing the time and
dose, the rate of cell apoptosis also increased. The IC50 of A549,
3.4.2. AO/EB double staining
HT29, and HeLa cells were 10, 9, and 100
m
g/mL, respectively after
These cells were assayed by AO/EB staining 24 h after treatment
under a fluorescent microscope. In this method, non-apoptotic cells
were detected by fluorescent green with an intact cell membrane.
No considerable apoptosis was observed in the control samples
(Fig. 3). Apoptotic cells, labeled by granular orange-green AO
treatment for 24 h. Herein, compound 3 presented higher cytotoxic
effect on A549 cell line compared with that measured for
HT29 cells. Also, compound 3 showed a comparable cytotoxic effect
against HT29 cell line than the HeLa cell line. Table 7 presents a

S. Samiee et al. / Journal of Organometallic Chemistry 900 (2019) 120927
7
Scheme 2. Plausible mechanism for the observed Suzuki cross coupling reaction by complex 3.
Table 6
Comparison catalytic activity of some palladacycles complexes that promote the Suzuki coupling between phenylboronic acid and bromobenzene.
Entry
1
Catalyst, (mol%)
Conditions
Time (h)
1
Yield(%)a
89
Ref
compound 3, (0.5)
K2CO3,
This work
EtOH/H2O, r.t.
K2CO3,
2
3
4
5
6
[PdCl2(Ph2P(CH2)PPh2C(H)C(O)C6H4-m-OMe)], (1)
Pd16S7 NPs, (0.1)
6
70
87
68
85
75
[33]
[41]
[33]
[42]
[43]
DMF/H2O, 110 ꢁ
K2CO3,
C
C
5
DMF, 100 ꢁ
K2CO3,
C
[PdCl2(Ph2P(CH2)2PPh2C(H)C(O)C6H4-m-OMe)], (1)
Fe3O4@SiO2-NPs-supported oxime palladacycle, (0.3)
[{PdI(S-Phoz)}2], (0.02)
6
DMF/H2O, 110 ꢁ
t-BuOK,
18
3
EtOH/H2O, 25 ꢁ
K2CO3,
H2O, 90 ꢁ
C
C
a
Isolated yield.
Table 7
Comparison of cytotoxic effects against A549 cell line between the Compound 3 and other Compounds reported in the literature.
Entry
Compound
IC50(
mM)
Ref
1
2
3
4
5
6
Compound 3
10
23
40.3
>40
36
This work
[44]
[45]
[46]
[47]
[Pd(Ambim)Cl2], Ambim ¼ 2-aminomethyl benzimidazole
[Pd(terpy)Cl]þ
[Pd(sac)2(dppm)].H2O.$EtOH
[PdL(PPh3)], L ¼ N0-(4(Diethylamino)-2-hydroxybenzylidene) furan-2-carbohydrazide
[Pd(LH)2], L ¼ N-p-chlorophenylthiosemicarbazone
36
[48]
nuclear staining, were observed in the treated samples (Fig. 3).
Asymmetrical staining was detected within the cells evidently
more prominent in A549 cells than HT29 cells. Also, the number of
apoptotic cells increased in HT29 cells more than in HeLa cells.
These observations suggested that compound 3 induced apoptosis
in three cell lines, depending on the cell type.

8
S. Samiee et al. / Journal of Organometallic Chemistry 900 (2019) 120927
Fig. 2. The cytotoxic effect of compound 3 with concentrations of 0.01, 0.1 and 1 mg/mL on cell viability and proliferation of A549, HT29, and HeLa cells by MTT assay (a) at day 1 (b)
at day 2 (c) at day 3 (*: p < 0.05 and Values are mean (n ¼ 3)).
3.4.3. Morphology observation and DAPI staining results
by condensed nuclei, compromised membrane, apoptotic bodies,
and shiny blue fluorescence in three cell lines. However, these signs
were stronger in A549 cells than HT29 and HeLa cells (Fig. 4, B).
In this study, morphological characterization of cell lines
detected that compound 3 had toxic effects on cells so, treated cells
were rounded and shrunk with reduction of volumes and chro-
matin condensation as a comparison with the control sample
(Fig. 4, A). DAPI staining was carried out to observe nuclei
morphology in experimental cells compared to control cells. For the
cells treated with compound 3 for 24 h, the cells were characterized
4. Conclusion
In summary, the present study extends the information on the
structures and application of oxime-derived palladacycles
Fig. 3. AO/EB staining for A549, HT29, and HeLa cells. Cells were treated with the compound 3 with the IC50 concentration after 1 day.

S. Samiee et al. / Journal of Organometallic Chemistry 900 (2019) 120927
9
Fig. 4. (A) Inverted microscopic observation for a survey of the cytotoxic effect of 3 with the IC50 concentration in A549, HT29, and HeLa cells after 1 day. (B) DAPI staining for a
survey of the cytotoxic effect of 3 with the IC50 concentration in A549, HT29, and HeLa cells after 1 day.
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phosphorus ylides with an ortho-metallated backbone. The struc-
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characterization by X-ray diffraction of 3 confirmed the proposed
formula and revealed a chelate PeC coordination behavior to the
metal center affording a five-membered chelate ring. The new
palladacycle 3 was employed as efficient catalysts for promoting
the Suzuki cross-coupling reaction of various aryl bromides with
phenylboronic acid to produce the corresponding products in high
yields. In addition, anticancer activity of 3 in three cell lines has
been disclosed. Our studies clearly indicate that this palladacycle
exhibit anticancer properties and could be useful in the develop-
ment of novel therapeutic agents. Based on the cytotoxic results,
these compounds showed a considerable effect on the cytotoxicity
in the cell culture. The new compounds exhibited high activity
against human tumor cell lines that they can suggest as new cancer
drugs development. Furthermore, these synthesized compounds
showed amazing biological properties and antitumor activity to-
wards the three cell lines.
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Acknowledgements
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We gratefully acknowledge the financial support from the
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