A simple, efficient and green approach for the synthesis of palladium nanoparticles using Oxytocin: Application for ligand free Suzuki reaction and total synthesis of aspongpyrazine A

Article abstract of DOI:10.1016/j.jorganchem.2019.121093

A novel, green, eco-friendly and cost-effective biological route for the synthesis of palladium nanoparticles (PdNPs) from commercially available palladium chloride and easily isolable hormone Oxytocin as reducing agent is reported here. Characterization of PdNPs were done using various techniques, UV–visible spectroscopy, XRD, TEM and EDAX, characterization data confirmed the formation of Pd⁰ from Pd²⁺. The size of synthesized PdNPs were 15–20 nm. The scope of Pd nanoparticles was studied for the C–C bond formation Suzuki reaction. The catalytic activity of PdNPs was excellent in short reaction time and reaction works in green solvent water as well as catalyst can be recycled. Simple and efficient approach for total synthesis of aspongpyrazine A of the recently isolated natural substance is described.

Full text of DOI:10.1016/j.jorganchem.2019.121093

Journal Pre-proof
A simple, efficient and green approach for the synthesis of palladium nanoparticles
using Oxytocin: Application for ligand free Suzuki reaction and total synthesis of
aspongpyrazine A
Ameya D. Bendre, Viraj P. Patil, Santosh S. Terdale, Kisan M. Kodam, Suresh B.
Waghmode
PII:
S0022-328X(19)30536-4
DOI:
https://doi.org/10.1016/j.jorganchem.2019.121093
JOM 121093
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 7 October 2019
Revised Date: 16 November 2019
Accepted Date: 19 December 2019
Please cite this article as: A.D. Bendre, V.P. Patil, S.S. Terdale, K.M. Kodam, S.B. Waghmode, A
simple, efficient and green approach for the synthesis of palladium nanoparticles using Oxytocin:
Application for ligand free Suzuki reaction and total synthesis of aspongpyrazine A, Journal of
Organometallic Chemistry (2020), doi: https://doi.org/10.1016/j.jorganchem.2019.121093.
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A simple, efficient and green approach for the synthesis of
palladium nanoparticles using Oxytocin: Application for
ligand free Suzuki reaction and total synthesis of
Aspongpyrazine A
Ameya D. Bendre,# Viraj P. Patil,# Santosh S. Terdale, Kisan M. Kodam* and Suresh
B. Waghmode*
Address: Department of Chemistry, Savitribai Phule Pune University (Formerly
University of Pune) Ganeshkhind, Pune 411 007.
Email: Suresh B. Waghmode: Suresh.Waghmode@gmail.com and Kisan M. Kodam
kisan.kodam@gmail.com
*
Corresponding author
#
Both authors have equal contribution
1

Abstract
A novel, green, eco-friendly and cost-effective biological route for the
synthesis of palladium nanoparticles (PdNPs) from commercially available palladium
chloride and easily isolable hormone Oxytocin as reducing agent is reported here.
Characterization of PdNPs were done using various techniques, UV-visible
spectroscopy, XRD, TEM and EDAX, characterization data confirmed the formation
0
2+
of Pd from Pd . The size of synthesized PdNPs were 15-20 nm. The scope of Pd
nanoparticles was studied for the C-C bond formation Suzuki reaction. The catalytic
activity of PdNPs was excellent in short reaction time and reaction works in green
solvent water as well as catalyst can be recycled. Simple and efficient approach for
total synthesis of aspongpyrazine A of the recently isolated natural substance is
described.
Keywords
Palladium Nanoparticles, Suzuki reaction, Oxytocin, biological route, Aspongpyrazine
A
Introduction
In recent era of science, nanotechnology represents one of the major
breakthrough, enabling materials of desired composition, size, structure to be formed,
amazing chemical, physical and electronic properties and their uses. The study of
these properties has become an increasingly important area in chemistry, physics,
1
biology, medicine, and material sciences. Nobel metal nanoparticles have
considerable attention because of their excellent catalytic activites, properties
and potential applications [1]. They are mainly being used for organic
2

2
synthesis, fuel cells, and environmental protection, being tested for there use
in electronics, photonics, sensors, etc. [1-3] Palladium nanoparticles (PdNPs)
are expected to show high catalytic activity and selectivity in numerous catalytic
processes [4-6]. However, reliable preparation of the nanomaterial’s is required
for their exploitation, and this remains an area of active research [1d] The
l
igandless approach of metal for the C-C bond forming cross-coupling reactions has
attracted as it reduces the process cost effectively and avoids contamination of the
metal and ligands in the desired product, which can be achieved by PdNPs [1e, 5-7].
For synthesis of nano sized palladium, various chemicophysical (chemical and
physical) methods including synthesis on solid support like adsorption, sol-gel
method, vapor condensation and ultra-sonication were reported [5,8] For synthesis
0
of Pd the reducing reagent like sodium borohydride, potassium bitartrate and
hydrazine used, which leads to considerable cluster aggregation in synthesis and
9
reaction. The applications of unsupported noble metal nanoparticles is often limited
due to aggregation process, which may occur in the activation stage or during
catalytic reaction [9l]. To avoid the agglomeration of these nanoparticles surfactants
like cellulose acetate, hydrophilizedpolysulfone, polyacrylic acid-modified
polyethersulfone, polyvinylidene fluoride, and many others were used [10]. Although
they are widely used to appropriately control the formation of nanoparticles in terms
of size, morphology and composition, these routes are harmful and toxic, will cause
environmental hazard, which are responsible for cytotoxicity, genotoxicity and
carcinogenicity [1f,11,12]. Because of these drawbacks the choice of reducing and
capping agents is to be considered seriously from green chemistry and an economic
perspective. Therefore, there is an immense interest in recent decades in developing
3

environmentally sustainable and friendly methods for the synthesis of metal
nanoparticles [13l].
In this regard, bio inspired routes for the synthesis of metal nanoparticles are
eco-friendly greener, non toxic, inexpensive, can be easily scaled up to industrial
level and reliable route for synthesis of nanoparticles with diversity in chemical
composition, physicochemical properties, size, shape etc. This ’green‘ route is most
an attractive aspect of current nanoscience and nanotechnology [1c,14]. Biosynthetic
methods employing either microorganisms like bacteria, fungi, aglae or plant extracts
[
12-15]. The most prominent examples of plant extracts used for nanoparticles
synthesis of palladium and other metals includes Pulicaria glutinosa [13a], Delonix
regia [13b], Euphorbia thymifolia [13c], Stachyslavandulifolia [13d], Sapindus
mukorossi [13e], Glycyrrhiza glabra [13f], Pistacia
Origanumvulgare [13h], watermelon rind [13i], papaya peel [13j], and tea extract
13k], Lantana camara plant [13l], annona squamosa [13m], leaf extract of
atlantica
kurdica [13g],
[
Anacardium occidentale [13n], cinnamom zeylanicum (cinnamon) bark extract [13o],
and Musaparadisiaca (banana) peal extracts [13p] and so on.
Polypeptides are reported to reduce and stabilize metal salts[16]. Keeping this
properties of peptides in mind and to overcome the problems mentioned above can
be resolved by using oxytocin is used as a reducing agent for synthesis of PDNPs.
Oxytocin is a nonapeptide having amino acid sequence, Cys–Tyr–Ile–Gln–Asn–Cys–
Pro–Leu–Gly–NH [17]. Disulphide linkage is formed between two cysteine residues
2
present in the peptide resulting in the formation of ring like structure containing Asp,
Gly, Tyr and Ile residues. Therefore, the aim of present synthesis is to reduce the
palladium and stabilize the PdNPs with the help of amino acid residues present in the
hormone Oxytocin.
4

The palladium catalyzed Suzuki cross-coupling reaction between aryl halides
with arylboronic acids has become most significant and powerful method for the
construction of C-C bonds especially for the synthesis of biaryls, polyaryls, natural
products, intermediates of pharmaceuticals, agrochemicals, advanced materials,
polymers, liquid crystals. This reaction is scaled up on the industrial level due to its
wide range of functional group tollarance on both partners [18]. The Suzuki products
have become fundamental routes for ecofriendly synthesis. Most of the
pharmaceutical companies are approaching green chemistry and using water as a
potential and safe solvent [19]. In most recent decades the use of water as a sole
reaction medium is one of the latest challenge for the chemists [20]. Initially
Beletskaya [21a] reported the Suzuki coupling reactions of water-soluble aryl halide
(
iodo and bromo) using PdCl and Pd(OAc) as catalyst under inert atmosphere.
2 2
Later, Davydov [21b] studied PdCl and water-soluble triphenylphosphine in the
2
emulsion for coupling of aryl halides, where the conversions were less than 50%.
Various reserchers have attempted the use of water as green solvent for Suzuki
reactions [21]. Notwithstanding that even though the Suzuki reaction has mostly
benefited from aqueous solvents, most of the substrates are insoluble in water,
resulting in poor yield [19c]. To address this problem, various attempts have been
made, viz. synthesizing water-soluble ligands, utilizing an inorganic salt as a
promotor, adding surfactants, use co-solvents, phase-transfer agents, use of
microwave or ultrasound etc. [18-22]. On the contrary metal nanoparticles have a
high surface-to-volume ratio and very active surface atoms, attractive catalysts for a
wide variety of organic and inorganic reactions, compared to bulk catalysts. Herein,
we report the green biological route for synthesis of PDNPs and their utility for water
mediated ligand-free Suzuki–Miyaura cross coupling reactions and total synthesis of
aspongpyrazine A.
5

Results and Discussion
The PdNPs were prepared from aqueous PdCl solution using Oxytocin as a
2
reducing agent at room temperature. The XRD pattern of synthesized PdNPs
shows three prominent peaks at 39.9, 46.3, and 67.8° corresponding to (111),
(
200) and (220) Bragg reflection planes, respectively (Fig 1). The lattice
parameters of PdNPs shows cubic (fcc) crystal structure and it is in good
agreement with the literature report (JCPDS File No. 5-0681) [23]. The
crystallite size of the palladium was calculated using peak broadening profile of
(
111) peak at 40° and Sherrer’s formula.
600
400
200
0
3
9.9 (111)
4
6.3 (200)
6
7.8 (220)
30
40
50
60
70
80
2
θ
Fig. 1 X-ray diffraction pattern of palladium nanoparticles
2+
0
The UV-Visible spectroscopy is used to study the reduction of Pd to Pd in
presence of Oxytocin. The UV-Visible spectra of PdCl at different time
2
2+
intervals is shown in Fig. 2. The spectrum shows characteristic peak of Pd at
2+
~
420 nm at zero hours. As the reaction progress the peak of Pd disappears
2+
gradually and it can be seen until 60 hrs. The UV-Vis peak of Pd completely
2+
0
disappears after 72 hrs, which indicates the complete reduction of Pd to Pd
nanoparticles [23h-i]. Upon reduction an increase in absorbance toward lower
6

wavelengths side is observed and is represented by the pink spectrum in Fig.
2.
0
hrs
3.5
12 hrs
36 hrs
60 hrs
72 hrs
3.0
2.5
2.0
1.5
1.0
0.5
0.0
200
300
400
500
600
700
800
Wavelength (nm)
Fig. 2 UV-Visible spectra of reaction mixture at different time intervals
The peak at ~420 nm disappears with the formation of a broad absorbance
0
peak at lower wavelength which is characteristic of PDNPs formation of Pd
species. We have found that the Oxytocin acts as a reducing agent to reduce
2+
0
Pd
to form Pd nanoparticles at room temperature and our results
corroborated with earlier UV spectra of Pd nanoparticles [23]. As a control
2+
0
experiment to check whether Pd reduces to Pd in absence of Oxytocin at
2+
0
identical reaction conditions, we have found that Pd does not reduces to Pd .
So it is clear that Oxytocin is only responsible for the reduction of Pd at room
temperature. It can be postulated that the amino acids present in the ring of
oxytocin are responsible for the reduction and stabilization of palladium to
PdNPs. Precipitation was not observed during the nanoparticle synthesis,
suggesting that the interaction between the peptide and the nascent
7

nanoparticle surface is sufficient in magnitude to prevent bulk material
aggregation.
Fig. 3 EDXS pattern of palladium nanoparticles
Fig. 4 TEM image of palladium nanoparticles with protein capping
The EDAX analysis (Fig, 3) detected palladium metal only. The TEM
micrographs (Fig. 4) reveal that the nanoparticles are of polygonal shaped
films capped within protein. Many overlapping films can be observed in TEM
micrographs. The size of synthesized PdNPs were between 2 to 22 nm with
the maximum number of particles having size between ~16-18 nm. The size
distribution of PDNPs is shown in Fig. 5.
8

30
25
20
15
10
5
0
2-4
4-6
6-8
8-10 10-12 12-14 14-16 16-18 18-20 20-22
Particle diameter (nm)
Fig. 5 Particle size distribution of palladium nanoparticles
The bio-synthesized PdNPs were used as a catalyst for the Suzuki cross-
coupling reaction between aryl halide and phenylboronic acid as shown in
Scheme 1. The reaction was carried out by stirring the reaction mixture of aryl
halide (1 mmol), phenylboronic acid (1.6 mmol), the catalyst (1mg of Pd) and
potassium carbonate (2.3 mmol) in DMF+water (1:1) at 100°C under aerobic
conditions. Results are shown in Table 1, PDNPs catalyzed Suzuki cross-
coupling reaction of an aryl iodides or aryl bromide with various substituents
produced the corresponding coupling products in excellent yields with small
amount of the Pd (0.009 mol%) in a very short reaction time (5-15 min). In the
cross-coupling of iodobenzene at 100°C, 99.6% yield was obtained within 10
min by using 0.009 mol% of palladium (Table 1; entry 1). The reaction of less
reactive bromobenzene also proceeds smoothly with 100% conversion and
9
6.1% yield of biphenyl in 15 min (entry 2). 3-Iodotoluene and 3-iodoanisole
under similar reaction conditions, reaction completed within 10 and 5 min and
gave 98.3% and 98.5% yields, respectively (entries 3 and 4). Furthermore, the
9

catalytic activity of PdNPs was tested using the ’greener’ solvent water as
reaction medium. We have obtained excellent 98.7% conversion of
iodobenzene and 98.2% yield of biphenyl in 2h (entry 6). The reaction time in
water was slightly more as compare to organic solvent. The catalyst recycle
study was also carried slight decrease in catalytic activity for observed for
iodobenze reaction (entries 7 and 8).
Scheme 1 Suzuki cross coupling reaction of aryl halide and phenylboronic acid
Among the potential applications of this methodology, a short synthesis of
aspongpyrazine A, (4-(6-methylpyrazin-2-yl)benzene-1,2-diol)
4
is described
Scheme 2). Aspongpyrazine A is isolated from Aspongopus chinensis Dallas
Pentatomidae), and is widely distributed in the major provinces of China [24].
(
(
It is a traditional Chinese medicine commonly used for the treatment of erectile
dysfunction, pain, stomach disease, and cancer [25]. The results of
pharmacological studies also showed that the extract of Aspongopus chinensis
possesses pronounced antibacterial, anticancer, analgesic, antifibrotic, and
angiogenesis promoting activities.
1
0

Table 1. Catalytic activity of various aryl halides with PdNPs.
a
Sr
Substrates
Time
Conversion
(%)
Yield of 3 (%)
(
min)
10
15
10
5
1
Iodobenzene (1a)
Bromobenzene (1b)
3-Iodotoluene (1c)
3-Iodoanisole (1d)
2-Iodonapthalene (1e)
100
99.6
96.1
98.3
98.5
99.1
98.2
97.1
94.1
2
3
4
5
6
7
8
100
98.9
100
15
99.7
98.7
98.1
95.3
b
Iodobenzene (1a)
120
10
st
1 Recycle of 1a
nd
2 Recycle of 1a
10
Reaction conditions: aryl halide (1 mmol), PhB(OH) (1.6 mmol), Na CO (2.3 mmol),
2
2
3
Pd (1 mg), solvent 6 mL of 1:1 DMF:H O and temperature 100°C;
2
a
conversions and yields are based on GC;
b
only water as a solvent.
We envisioned the synthesis of aspongpyrazine A (4) from commercially
available 2-bromo-6-methylpyrazine (1f) using Suzuki coupling reaction with
aryl boronic acid over PdNPs in potassium carbonate as base and DMF+water
(
1:1) as a solvent at 100°C under aerobic conditions delivered 3f (90%) in very
short reaction time (15 min) (Scheme 2). Further deprotection of 3f using 47%
HBr and aliquat 336 as a catalyst delivered the desired compound in
4
excellent yield (96%) with overall 86.4% yield [26]. The detail experimental
procedure is given in electronic supplementary data.
1
1

Scheme 2 Total synthesis of aspongpyrazine A
Conclusion
In summary the biological route for the synthesis of PdNPs using hormone
peptide obtained from plant extracts, is reported as much easier, effective and
environment friendly method. It does not involve use of harmful chemicals or
extreme conditions like high temperatures and sophisticated instruments. This
new finding will eventually lead to more sustainable (green) synthetic
procedures benefiting global health and environment. Palladium nanoparticles
synthesized by above method could find potential uses in catalysis. Palladium
nanoparticles were highly active towards the Suzuki reaction and gave
excellent yields as well as selectivity. The applicability of this reaction has been
demonstrated by its efficient and easy incorporation for the synthesis of an
important aspongpyrazine A in good yields with the substrate generality. We
believe that this green biological route for the synthesis of PDNPs will find
tremendous applications due to its salient features viz. easy availability of
hormone Oxytocin, simple and environmentally friendly procedure, and highly
active and general applicability of PDNPs for Suzuki reactions.
1
2

Experimental
General Experimental Details
All reagents were obtained from commercial grade unless otherwise stated
and solvents were used as received with the following exceptions.
Tetrahydrofuran (THF) was distilled from benzophenone and sodium
immediately prior to use. All moisture sensitive reactions were carried out
under a nitrogen atmosphere with dry solvents under anhydrous conditions,
unless otherwise noted. The reactions were magnetically stirred and monitored
by analytical thin-layer chromatography (TLC) E. Merck 0.25 mm silica gel 60
F254. TLC plates were visualized by exposure to ultraviolet light (UV, 254 nm)
and/or exposure to an aqueous solution of potassium permanganate (KMnO4),
an acidic solution of anisaldehyde or a solution of ninhydrin in ethanol followed
by heating with a heat gun. Flash and simple chromatography was performed
using silica gel 100-200 and 200-400 mesh with solvents distilled prior to use,
respectively. Yields refer to chromatographically pure material and with
1
13
1
spectroscopy ( H and C NMR). All spectra’s were recorded at 25 °C, H NMR
13
spectra recorded on 300 MHz or 500 MHz spectrometers and C NMR
spectra were obtained at 300 (75MHz) or 500 NMR (126MHz) spectrometer
1
using CDCl as solvent. Tetramethylsilane served as an internal standard in H
3
13
(
0.00 ppm) and CDCl (77.0 ppm) in C NMR. Chemical shifts were recorded
3
in ppm, and coupling constants (J) in Hz. HRESIMS were taken on Bruker
Impact HD quadrupole plus ion trap. Infrared spectra’s were recorded on a
Nicolet Nexus 470 FT-IR spectrometer. The following abbreviations are used
for the multiplicities: s: singlet, d: doublet, t: triplet, m: multiple, bs: broad
singlet and dd: doublet of doublet for proton spectra.
1
3

UV-Visible spectra of standard palladium chloride solution and colloidal
reaction mixture after every 12 h interval were recorded using Shimadzu UV-
Visible spectrophotometer (UV-1800). PdNPs were examined using X-Ray
diffractometer (Bruker AXS-D8) with CuKα Radiation λ= 1.5405 Å over a wide
range of Bragg angles (30° ≤ 2θ ≤ 80°). Morphology and size of PdNPs were
investigated by transmission electron microscope (G2 Tecnai TF30 FEI,
Netherlands), using acceleration voltage of 100 kV. The elemental analysis of
the sample was examined by energy dispersive analysis of X-rays (EDAX) with
JEOL JED-2300 instrument.
Synthesis of Palladium Nanoparticles
Palladium chloride (100 mL, 5 mM) solution was prepared in ice cold
water and 1.5 mL of Oxytocin (10 µg/mL) was added to it. The mixture was
kept on magnetic stirrer for 5 min and then incubated at 4°C in the dark. After
every 12 h an aliquot of the reaction mixture was withdrawn, centrifuged at
7
500 x g at 4°C for 15 min and subjected to UV-visible spectra. After 72 h the
pellet of PdNP was collected in clean petri dish and washed was with absolute
methanol and air dried.
General Suzuki reaction procedure: To a 25 mL two neck round bottom
flask attached with a reflux condenser, were added the aryl halide (1 mmol),
boronic acid (1.25 mmol), Na CO (2 mmol), and Pd nanoparticles (1 mol. %)
2
3
in 4 mL DMF or DMF/H O (1:1), and the reaction mixture heated at the
2
appropriate temperature and duration. The reaction was monitored by gas
chromatography. After the reaction was complete, the mixture was extracted
with ethyl acetate three times, the combined organic extracts dried over
1
4

anhydrous Na SO and the solvent was evaporated at reduced pressure. The
2
4
crude products were then purified by column chromatography [hexane or
hexane/ethyl acetate (9:1)] and analyzed by GC, LC–MS, and NMR.
General Suzuki reaction procedure for recycle study: After each run the
reaction mixture was centrifuged, reaction mass decanted and catalyst was
washed thoroughly with DMF or DMF+H O. Then, the recovered catalyst was
2
dried at 60ꢀ°C for 12 h and reused in the next run as described in general
reaction procedure section.
Acknowledgements
We thank the UGC, New Delhi, India for financial support (F.No.41-329/ 2017(SR)).
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A novel, green, and cost-effective biological route for the synthesis of PdNPs
Hormone oxytocin acts as a reducing agent for synthesis of PdNPs
PdNPs show excellent catalytic activity in short time.
Water can be used as green solvent
Aspongpyrazine A synthesized with 86.4% overall yield

Savitribai Phule Pune University
Dr. Suresh B. Waghmode
Department of Chemistry
Ganeshkhind, Pune
India 411-007
Phone: +91-20-2560-1394 ext. 585
Fax: +91-20-2569-1728
suresh@chem.unipune.ac.in
th
Date: 5 Oct. 2019
To,
Prof. R.D. Adams
Dept. of Chemistry and Biochemistry,
University of South Carolina, 541 Main Street,
Horizon 239, Columbia, South Carolina, SC 29208,
USA
Subject: Submission of manuscript for publication in “Journal of Organometallic
Chemistry” and declaration of interest
Dear Sir,
I am submitting herewith the research article entitled “A simple, efficient and green
approach for the synthesis of palladium nanoparticles using Oxytocin: Application for ligand
free Suzuki reaction and total synthesis of Aspongpyrazine A” by Ameya D. Bendre, Viraj P.
Patil, Santosh S. Terdale Kisan M. Kodam and Suresh B. Waghmode for publication. We do
not have any declaration of interest.
Please do the needful.
Thanking you.
Dr. Suresh B. Waghmode