A solid supported palladium(0) nano/microparticle catalyzed ultrasound induced continuous flow technique for large scale Suzuki reactions

Article abstract of DOI:10.1039/c3ra41364k

An ultrasound-induced continuous flow technique was developed for the solid supported palladium(0) nano/microparticle (SS-Pd) catalyzed Suzuki cross coupling reaction of haloarenes (chloro, bromo and iodo) with phenyl boronic acid on a gram scale. An externally conjugated reservoir was fitted for easy operation of the reaction in water under mild basic conditions. The SS-Pd catalyst was found to be very stable in aqueous media, easily separable and recyclable up to five runs without significant loss of activity. Furthermore, the scaling of the well known Suzuki reaction up to 5 g scale under mild ultrasonic irradiation can be of industrial interest in the future.

Full text of DOI:10.1039/c3ra41364k

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A solid supported palladium(0) nano/microparticle
catalyzed ultrasound induced continuous flow
technique for large scale Suzuki reactions3
Cite this: RSC Advances, 2013, 3, 13671
Received 20th March 2013,
Accepted 2nd July 2013
Arun K. Shil, Nitul Ranjan Guha, Dharminder Sharma and Pralay Das*
DOI: 10.1039/c3ra41364k
www.rsc.org/advances
6
An ultrasound-induced continuous flow technique was devel-
oped for the solid supported palladium(0) nano/microparticle (SS-
Pd) catalyzed Suzuki cross coupling reaction of haloarenes
techniques. But the development of scalable processes, particu-
larly with flow reaction strategies for the synthesis of biaryls
through Suzuki reactions with simultaneous activation of the aryl–
Cl bond, are rarely reported. In most of the early reports, authors
described microwave assisted flow techniques with complicated
instrumentation for the Suzuki reaction of iodoaryls, bromoaryls
and aryl tosylates.
(chloro, bromo and iodo) with phenyl boronic acid on a gram
scale. An externally conjugated reservoir was fitted for easy
operation of the reaction in water under mild basic conditions.
The SS-Pd catalyst was found to be very stable in aqueous media,
easily separable and recyclable up to five runs without significant
loss of activity. Furthermore, the scaling of the well known Suzuki
reaction up to 5 g scale under mild ultrasonic irradiation can be of
industrial interest in the future.
Although many organic reactions with water soluble substrates/
reagents are carried out smoothly in aqueous media, some
reactions with rigorously heterogeneous substrate–reagent combi-
nations proceed very poorly in sealed tubes as well as in a
continuous flow leading to incomplete conversion. Many efforts
have been made to overcome the problem, particularly, the
introduction of a co-solvent or the use of water soluble substrates
1. Introduction
7
and catalysts are worth mentioning. Homogeneous catalysts often
create difficulties in the isolation of the product. The application
8
Flow reaction strategies have attracted huge interest in recent
years in organic synthesis, particularly in process development
of easily separable and recyclable heterogeneous catalysts allows
cleaner work-ups and avoids time-consuming tedious catalyst
purification. On the other hand, ultrasonic irradiation can offer an
additional advantage in aqueous phase organic synthesis by
means of a greater number of molecular collisions at mild
conditions.
In the course of our recent work, the development of an
efficient, fast and cost effective process for the synthesis of an SS-
Pd catalyst and its applications were investigated. Herein, we
report a methanol–water mediated flow reaction technique for the
Suzuki cross coupling reaction of aryl halides (Cl, Br and I) with
phenyl boronic acid under ultrasonic irradiation. The use of a
mild base, the recyclability of the SS-Pd catalyst and the ambient
temperature meet the essentialities of a green chemical approach
for biaryl synthesis through Suzuki cross coupling reactions.
1
with non conventional techniques. The application of hetero-
geneous palladium catalysts in large scale Suzuki cross coupling
reactions is an extremely versatile methodology for the synthesis of
biaryls, which are a widely abundant motif in common organic
compounds such as natural products, pharmaceuticals, liquid
2
crystalline materials and agrochemicals. In the last three decades,
ultrasound induced reactions have received an increasing interest
in aqueous as well as non-aqueous based organic synthesis
9
3
providing higher yields and shorter reaction times. In a similar
context, water mediated organic syntheses with the utilization of
mild ultrasonication have had a significant appeal predominantly
in the area of C–C bond formation reactions to achieve the target
4
molecule in a cleaner way benign to the environment. Limited
reports are available for laboratory scale Suzuki cross coupling
reactions under ultrasound conditions using ionic liquids and
5
water–co-solvent systems at ambient temperature. Moderate
2
. Results and discussion
yields of biaryls were found with combined microwave–ultrasound
The SS-Pd catalyst was prepared following our earlier process (ref.
a) and surface characterization was performed by scanning
Natural Plant Products Division, CSIR-Institute of Himalayan Bioresource
Technology, Palampur-176061, H. P., India. E-mail: pdas@ihbt.res.in;
pdas_nbu@yahoo.com; Fax: +91-1894-230433
9
electron microscopy (SEM). At the time of preparation of the SS-Pd
catalyst, the hydrophobic and hydrophilic combination of the
3
2
Electronic supplementary information (ESI) available: IHBT communication no.
214. See DOI: 10.1039/c3ra41364k
+
2
3 4
borohydride exchanged polymer (polystyrene–NR BH ) units
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Fig. 1 (A) Freshly prepared SS-Pd; (B) outer surface characterization of SS-Pd by
scanning electron microscopy (SEM); (C) inner surface characterization of SS-Pd by
transmission electron microscopy (TEM).
Fig. 2 Schematic outline of the continuous flow technique.
To perform the Suzuki cross coupling reaction under a
continuous flow, we first chose 4-iodotoluene (5 g, 0.022 mol),
played a crucial role to reduce the Pd(II) ion to Pd(0), and to
impregnate it into the hydrophobic pockets of the polymer matrix
as nano and microparticles (Fig. 1, A and B). Transmission
electron microscopy (TEM) of SS-Pd was also used to investigate
the Pd(0) nanoparticle distribution in the inner polymer matrix
2 3
phenylboronic acid (3.35 g, 0.027 mol), K CO (6.07 g, 0.044 mol)
mixed with MeOH : H O (2 : 3) in 200 ml and then injected
2
through a to the reservoir (Fig. 2). The reaction mixture was
circulated through c A e A f A b by a pump. The ultrasonication
was controlled at 20 kHz and the reaction was monitored by TLC
with samples from the reservoir. Experiments for the screening of
(
Fig. 1, C). Further, X-ray diffraction analysis indicated the
10
presence of Pd(0) nanoparticles inside the polymer matrix
ESI ). A steel reaction vessel preloaded with SS-Pd (14.8 g, 3 mol%
the catalyst loading, amplitude and flow rate were performed (ESI,
3
(
3
21
Table 1). Among these, a flow rate of 127 mL min , 30%
amplitude and a 3 mol% Pd (SS-Pd) catalyst loading gave the
highest yield of the product, and were adopted as the standard
reaction conditions.
Pd) catalyst equipped with a screw tight ultrasonicator probe
under sealed conditions containing a flow accessory was chosen to
carry out the Suzuki cross coupling reaction. The large unit size of
the SS-Pd catalyst facilitates it to remain inside the reaction vessel
during circulation of the reaction mixture, which also allows for an
easy crude product separation from the catalyst. The tight binding
of Pd(0) makes the SS-Pd catalyst very stable and the combination
of ions provides a driving force to enhance the rate of the cross
coupling reaction, presumably due to the formation of the
The high vibrational frequency produced through ultrasonic
irradiation increases the molecular kinetics of the substrate. The
kinetically excited hydrophobic substrate molecules can enter the
hydrophobic surface region where Pd(0) takes part in the
formation of the intermediate Ar–[Pd]–Ar9 for the successful
transformation to biaryls (Ar–Ar9) (Fig. 3). After completion, the
reaction mixture was collected from the reservoir through d and
outlet g (reaction vessel) and the catalyst was washed with MeOH
2
+
11
[
3 3
PhB(OH) –R N ] complex ion pair. An externally conjugated
reservoir was attached parallel to the reaction vessel connected
through a pump to circulate the reaction mixture continuously
(100 ml) and ready for the second run. The chosen reaction
through the flow system. MeOH : H O in the ratio of 2 : 3 (v/v)
2
conditions were further applied for the Suzuki coupling reaction
with different aryl halides. Reaction of various substituted aryl
iodides with phenylboronic acid gave excellent yields of the
desired products (Table 1, entries 1–6). Electron donating and
withdrawing groups attached to the aryl iodides were explored, but
no significant effect of the functional groups was observed.
Substituted aryl bromides (having both electron attracting as well
as releasing functionalisation) under standard reaction conditions
gave Suzuki cross coupling products with good and comparable
yields (Table 1, entries 7–9). Under the same catalytic conditions,
was used as the ideal solvent to give the highest solubility of the
aryl halides, phenyl boronic acid and K CO .
2 3
Sometimes, the main disadvantage of large scale Suzuki
reactions under thermal conditions is the volatility of the
haloarenes which separate from the reaction mixture resulting
in the incomplete conversion of the substrates. But in our flow
system under closed ambient temperature and externally con-
jugated reservoir conditions, the chances of biproduct formation
decrease facilitating the large scale process.
1
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Table 1 Suzuki–Miyaura cross coupling reaction of aryl halides with phenylboronic acid on a gram scale of substrate
a
Entry
1
Reactant
Product
Time (h)
3
% Yield
85
2
3
3
92
b
3.5
85
b
4
5
5
89
2.5
92
6
7
3
4
89
71
8
4
60
2
5
b
9
10
3
82
53
1
0
1
1
3.5
62
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Table 1 (Continued)
a
Entry
Reactant
Product
Time (h)
3.5
% Yield
b
1
2
87
1
3
3
26
a
b
All are isolated yields. Reactions were carried out with 1 g of substrate.
1
,4-dibromobenzene 1h reacted with phenylboronic acid to
3. Conclusion
produce di- (2h, 60%) and mono-substituted (2h9, 25%) products
Table 1, entry 8). The activation of the aryl-Cl bond was also
In summary, we have developed an environmentally benign
continuous flow strategy for the Suzuki cross coupling reaction of
aryl halides (chlorides, bromides and iodides) with phenylboronic
acid by using SS-Pd as a ligand free heterogeneous catalyst. The
scaling up of the biaryl synthesis to 5 g scale was successfully
achieved through a Suzuki cross coupling reaction under mild
conditions. Ultrasonication provided enough excitation energy to
carry out the reaction in methanol–water and increased the
(
observed under these mild reaction conditions which would be
otherwise difficult to achieve. Aryl chlorides gave moderate yields
of the corresponding biaryls that could be considered satisfactory
in comparison (Table 1, entries 10–13).
To validate the catalytic stability in methanol–aqueous media
under flow reaction conditions, the SS-Pd catalyst was analysed by
SEM (Fig. 4) after recycling five times using 2a. No significant loss
of activity was observed based on the isolated yields of product 2b
2 3
solubility of K CO to supply the extraordinary basic conditions,
which drove the reaction into products at ambient temperature
with satisfactory yields. Furthermore, easy isolation of the crude
products, negligible metal contamination and recyclability of the
SS-Pd catalyst can have a huge green impact and industrial
interest.
21
(
85–78%) (Fig. 5). The total TON (14 922) and TOF (994.8 h ) also
proved the comparably good performance of the catalyst. Further
SEM analysis of SS-Pd after 5 runs showed the presence of Pd(0)
nano/microparticles on the solid support which implies its
extraordinary reusability and minimum leaching of Pd from the
solid surface.
4. Experimental section
General methods
Reagents of high quality were purchased from Sigma Aldrich.
Silica gel (230–400 mesh size) for column chromatography was
procured from Sd Fine-Chem Ltd. Reagents and solvents were of
analytical grade, and were purified by standard procedures prior to
use. All the reactions were carried out in a probe ultrasonicator
(SONICS/VIBRA-CELL, model no. VCX750, serial no. 67348AD-02-
12, power 750 watts, frequency 20 kHz, volts. 230 VAC-50/60 Hz
NOM). The sample for the SEM analysis was mounted on an
aluminium stub using double sided tape. The completely dried
sample was coated with gold by a sputter coating unit at 10 Pascal
vacuum for 10 s (E1010 ion sputter Hitachi, Japan). The TEM
image was taken using carbon coated copper grid (Microscopy
Sciences) in a transmission electron microscope JEOL 2100F
(AIRF, JNU-New Delhi, India). XRD analysis of the prepared
powdered sample was carried out in a Rigaku 9 KW rotating anode
X-ray generator (under 4.5 KW, 45 kV/100 mA X-Ray, 2 theta/theta
Scanning mode, Fixed Monochromator). Data were taken for the
1
Fig. 3 A schematic diagram of the reaction outline on the catalyst surface; S = aryl
2
halide, S = phenyl boronic acid and P = product.
1
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Fig. 4 (A) SS-Pd after 5 runs; (B) scanning electron microscopy (SEM) image of SS-Pd after 5 runs.
2
H range of 5 to 90 degrees. Thin layer chromatography was
2
200 mL of MeOH : H O (2 : 3) was added to it. The resulting
254
performed using precoated silica gel plates 60 F (Merck) with a
mixture was homogenized by stirring at room temperature. The
SS-Pd (14.8 g, 0.0006 mol Pd) catalyst was charged in the reaction
vessel having a cotton plug at the outlet, and attached to the probe
holder with a screw. The previously prepared reaction mixture was
poured (through b) into the reservoir. The stopcock c was opened
and the pump was also turned on to circulate the reaction mixture
1
13
UV light detector. H NMR and C NMR spectra were recorded
using a Bruker Avance 300 spectrometer operating at 300 MHz
1
13
(
H) and 75 MHz ( C). Spectra were recorded at 25 uC in CDCl
3
and MeOD [residual CHCl (dH 7.26 ppm or dC 77.0 ppm) and
3
MeOD (d
standard] with TMS as the internal standard. Chemical shifts were
recorded in d (ppm) relative to the TMS and CDCl signals,
coupling constants (J) are given in Hertz (Hz) and multiplicities of
signals are reported as follows: s, singlet; d, doublet; t, triplet; m,
multiplet; br, broad singlet.
H C
3.30, 4.78 ppm or d 49.0 ppm) as the international
21
through the reaction vessel (flow rate 127 mL min ). After
approximately one cycle, the ultrasonicator was turned on and the
circulation of the reaction mixture was continued through the c A
e A f A b path. The progress of the reaction was monitored by
TLC by taking out small amounts of the reaction mixture from
stopcock d. On completion, the whole reaction mixture was
drained out through stopcock d and concentrated on a rotary
evaporator. The concentrated reaction mixture was extracted with
ethyl acetate (3 6 30 ml). The combined organic layers were dried
3
Typical experimental procedure (aparatus set up as in Fig. 2)
A mixture of 4-iodotoluene 1a (5 g, 0.022 mol), phenylboronic acid
(3.35 g, 0.027 mol), and potassium carbonate (6.07 g, 0.044 mol)
over anhydrous Na
reduced pressure. The crude residue was purified by silica gel
mesh 230–400) column chromatography using hexane as the
eluent to afford 2a as a crystalline white solid (3.70 g, 85%); mp
2 4
SO and the solvent was removed under
was placed in an oven dried 250 mL round bottomed flask and
(
1
4
6–50 uC; H NMR (300 MHz; CDCl ) d = 2.51 (s, 3H), 7.36 (d, J =
3
7
.84 Hz, 2H), 7.41–7.46 (m, 1H), 7.51–7.56 (m, 2H), 7.62 (d, J = 7.84
13
Hz, 2H), 7.70 (d, J = 8.12 Hz, 2H); C NMR (75 MHz, CDCl ) d =
3
21.02, 126.53 (3C), 127.12 (2C), 128.67 (2C), 129.44 (2C), 136.60,
138.38, 141.16.
Acknowledgements
Authors are grateful to the Director of IHBT for providing the
necessary facilities during the course of the work. We
gratefully acknowledge the financial assistance from the
Department of Science & Technology (Nano Mission), New
Delhi (Grant No. SR/NM/NS-95/2009) and the practical support
from ORIGIN (CSIR), CSC0108. AKS (SRF-CSIR), NRG (SRF-
UGC) and DS (SRF-CSIR) thank CSIR and UGC, New Delhi for
awarding fellowships.
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