An emerging reactor technology for chemical synthesis: Surface acoustic wave-assisted closed-vessel Suzuki coupling reactions

Article abstract of DOI:10.1016/j.ultsonch.2014.02.020

In this paper we demonstrate the use of an energy-efficient surface acoustic wave (SAW) device for driving closed-vessel SAW-assisted (CVSAW), ligand-free Suzuki couplings in aqueous media. The reactions were carried out on a mmolar scale with low to ultr

Full text of DOI:10.1016/j.ultsonch.2014.02.020

Ultrasonics Sonochemistry 21 (2014) 1305–1309
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultson
An emerging reactor technology for chemical synthesis: Surface acoustic
wave-assisted closed-vessel Suzuki coupling reactions
a
b
b
a,
⇑
Ketav Kulkarni , James Friend , Leslie Yeo , Patrick Perlmutter
a
School of Chemistry Monash University, Clayton 3800, Victoria, Australia
School of Electrical and Computer Engineering RMIT University, Melbourne 3000, Victoria, Australia
b
a r t i c l e i n f o
a b s t r a c t
Article history:
In this paper we demonstrate the use of an energy-efficient surface acoustic wave (SAW) device for driv-
ing closed-vessel SAW-assisted (CVSAW), ligand-free Suzuki couplings in aqueous media. The reactions
were carried out on a mmolar scale with low to ultra-low catalyst loadings. The reactions were driven
by heating resulting from the penetration of acoustic energy derived from RF Raleigh waves generated
by a piezoelectric chip via a renewable fluid coupling layer. The yields were uniformly high and the reac-
tions could be executed without added ligand and in water. In terms of energy density this new technol-
ogy was determined to be roughly as efficient as microwaves and superior to ultrasound.
Crown Copyright Ó 2014 Published by Elsevier B.V. All rights reserved.
Received 14 November 2013
Received in revised form 14 February 2014
Accepted 20 February 2014
Available online 28 February 2014
Keywords:
Surface acoustic waves
Suzuki couplings
Micro-reactor
Catalysis
1
. Introduction
reported [1,2]. For the studies disclosed here we required the reac-
tions to be carried out in a closed vessel. In order to exploit the en-
Very recently the first applications of surface acoustic waves
SAWs) in a lab on a chip device for use in organic chemical trans-
ergy contained in SAWs we employed paraffin oil, a high boiling
low viscosity fluid, as a liquid couplant [16], as shown in Fig. 1.
Under these conditions the SAWs are transmitted into the par-
affin oil as a bulk sound wave at a Rayleigh angle of 22.2 degrees
(Fig. 1). As the bulk wave approaches the glass vessel, a Lamb wave
is formed in the base of the vessel which acts to transmit the
acoustic energy into the reaction solution within [16].
(
formations on a drop scale have been described [1–3]. In this paper
we demonstrate the use of such a device for driving closed-vessel
SAW-assisted (CVSAW), ligand-free Suzuki couplings in aqueous
media. Operationally, this new technology obviates the need for
oil baths, heating mantles, hot plates, ultrasonic baths and micro-
wave cavities. Indeed it simply requires placing of a capped glass
vial onto the surface of the chip.
Typically, Suzuki reactions involve palladium catalysed cross
coupling between organoboronic acids and arylhalides [4]. Re-
cently, variants, including the use of trifluoroborates [5], organo-
boranes [6] or boronic esters [7] in place of boronic acids,
triflates [8] as pseudohalide coupling reagents and ionic liquids
2
. Materials and methods
2.1. SAW apparatus
All reactions were either performed on a 9.7 MHz, or a
1
3
9.5 MHz LiNbO device. The SAWs were generated by applying
[
9–11] as the reaction medium have been reported. However, the
a sinusoidal oscillating electrical signal output from an Agilent
3220A 20 MHz Function/Arbitrary waveform generator (Agilent
availability of a wide range of functionalized, stable and less toxic
boronic acids and halides still make them attractive partners for
Suzuki coupling.
Reactions generally require heating and many reports have ap-
peared on the use of microwave radiation as an excellent source of
such heating [12–15].
3
Technologies, Santa Clara, California, USA), amplified by a 10 W
RF amplifier (Amplifier Research, Souderton, Pennsylvania, USA),
which was connected to a pair of IDTs (Al with 1 % Cu alloy). All
four electrodes (two electrodes on each of the IDTs) were con-
nected to the RF output of the amplifier to generate a standing
wave. The signal generator was set to output a sine wave with
the appropriate frequency for the device in use, and an amplitude
of 230 mVrms when operating the 19.5 MHz SAW device or
450 mVrms when operating the 9.7 MHz device. The gain on the
amplifier was adjusted to provide the required power to the SAW
SAWs of well-defined wavelength and frequency (19.50 MHz)
were generated on a piezoelectric substrate (LiNbO ) as previously
3
⇑
Corresponding author. Tel.: +61 03 99054522.
E-mail address: patrick.perlmutter@monash.edu (P. Perlmutter).
http://dx.doi.org/10.1016/j.ultsonch.2014.02.020
350-4177/Crown Copyright Ó 2014 Published by Elsevier B.V. All rights reserved.
1

1
306
K. Kulkarni et al. / Ultrasonics Sonochemistry 21 (2014) 1305–1309
sin, USA), AK Scientific Inc. (Union City, California, USA), Merck
KGaA (Darmstadt, Hesse, Germany), Strem Chemicals, Inc. (New-
buryport, Massachusetts, USA), and Boron Molecular (Melbourne,
Victoria, Australia). CDCl
over Ag and anhydrous K
3
used for NMR spectroscopy was stored
CO
2
3
.
2
2
.4. Synthetic procedure
.4.1. General procedure for Suzuki coupling reactions using SAWs
Fig. 1. Propagation of ‘leaky’ SAW radiation through a fluid couplant to a glass vial.
A glass vial (1.5 mL) was charged with substituted aryl bromide
(
(
(
0.2 mmol), substituted phenylboronic acid (0.2 mmol), K
2
CO
solution
in
L drop of paraffin
substrate and the glass vial was
3
55 mg,
0.4 mmol),
3
l
L
of
Pd(OAc)
2
stock
device. Output power to the SAW device at the amplifier was mea-
sured using an Agilent U2004A 9 kHz to 6 GHz USB Power Sensor
ꢀ2
ꢀ3
ꢀ4
5.35 ꢁ 10 M, 5.35 ꢁ 10 M, or 5.35 ꢁ 10 M of Pd(OAc)
2
EtOH), EtOH (400
oil was pipetted onto the LiNbO
placed on the drop. The reaction mixture was heated using SAW
irradiation (5–6 W) to maintain reflux throughout the reaction.
The aqueous layer was extracted with CH
2
lL) and H O (200 lL). A 20 l
(
with a range of ꢀ60 to +20 dBm or 1 nW to 100 mW) and dis-
played real-time on computer screen using Power Panel
N1918A) software. To be within the measurable range of the
3
a
(
power sensor, high power radio frequency attenuation was re-
quired and achieved by 8498A High Power Attenuator, DC to
2 2
Cl (1.0 mL). The organic
phase was dried over MgSO , concentrated under vacuum, and
4
1
8 GHz, with 25 W average and 30 dBm fixed attenuation. The
purified by flash chromatography (EtOAc/hexanes 1:4) to afford
the required biaryl product. Analytical data in agreement with
the literature [17–22].
measured power was corrected for the applied attenuation in
dBm and converted to watts. Reaction temperature was monitored
using an analogue probe with an insulated K-type thermocouple
(
HH501BJK, Omega, Stamford, Connecticut, USA).
2
.4.2. Scale-up of Suzuki coupling reactions using SAWs
Following a procedure similar to that described in the general
The closed-vessel reactions were performed in glass vials
1.5 mL or 4.0 mL, flat-bottomed and screw capped), placed on
(
method 2.4.1, a 4.0 mL glass vial was charged with para-bromoani-
sole (125.5 L, 1.0 mmol), phenylboronic acid (122 mg, 1.0 mmol),
CO (275 mg, 2.0 mmol), of Pd(OAc) stock solution
2.67 ꢁ 10 M of Pd(OAc) in EtOH), EtOH (2.0 mL) and H
(1.0 mL), and refluxed using SAW irradiation (8–9 W) for 25 min.
The aqueous layer was extracted with CH Cl (5.0 mL). The organic
the SAW device, using paraffin oil as a couplant between the LiN-
bO substrate and the glass vial.
l
3
K
(
3
lL
2
3
2
ꢀ1
2
2
O
2
.2. Analytical equipment
2
2
Melting points were determined using Reichert hot stage melt-
phase was dried over MgSO , concentrated under vacuum, and
4
ing point apparatus (Reichert, Austria) or a Stuart Scientific SMP3
melting point apparatus (Stuart Scientific, Stone, Staffordshire, UK).
Optical rotations were obtained using a PolAAR 2001 automatic
polarimeter (Optical Activity Ltd., Huntingdon, Cambridgeshire,
purified by flash chromatography (EtOAc/hexanes 1:4) to afford
4-methoxybiphenyl 3 (164 mg, 89%) as a white solid. Analytical
data were in agreement with the literature [19,20].
UK) using a 1 dm cell in CHCl
3
, at a wavelength of 589 nm (sodium
, concentration c (g/100 mL), solvent
2.4.3. Method for Heck reaction using SAWs
D line), and are quoted as [
a
]
D
A 4.0 mL glass vial, flushed with N , was charged with Pd dba
3
2
2
and recorded at rt.
(16.4 mg, 18
lmol), and (S)-4-tert-butyl-2-[2-(diphenylphos-
Chiral HPLC was performed on an Agilent 1200 series HPLC sys-
tem (Agilent Technologies, Santa Clara, California, USA), using a
Chiracel OD-H (Daicel Chemical Industries Ltd., Kita-ku, Osaka, Ja-
phino)phenyl]-2-oxazoline (14 mg, 36
was added to the vial and the suspension was shaken intermit-
tently at r.t. over a period of 10 min. To the resulting solution
l
mol). Toluene (1.0 mL)
pan) chiral analytical column (0.46 ꢁ 25 cm with particle size of
was added a solution of phenyl triflate (97.2
dihydrofuran (227 L, 3 mmol), and 1,8-bis-(dimethylamino)
naphthalene (386 mg, 1.8 mmol) in toluene (1.0 mL). A 20 L drop
lL, 0.6 mmol), 2,3-
i
5
l
m), with hexanes and/or PrOH as eluents.
l
1
H NMR spectra were recorded at 300 MHz with a Bruker
l
Avance DPX300 spectrometer and at 400 MHz with a Bruker
of paraffin oil was pipetted onto the LiNbO substrate and the glass
3
Avance DRX400 spectrometer (Bruker BioSpin Corp., Billerica, Mas-
vial was placed on the drop. The reaction was heated at reflux
using SAW irradiation (8–9 W) for 3 h. After cooling, the reaction
1
sachusetts, USA). The H spectra were obtained in CDCl
3
with d
7
3
.26 ppm (residual CHCl ) used as an internal reference. Each res-
mixture was diluted with Et O (5.0 mL), and the resulting red sus-
2
onance was assigned according to the following convention: chem-
ical shift measured in parts per million (ppm), multiplicity,
coupling constant (J Hz), number of protons. Multiplicities are de-
noted as s (singlet), d (doublet), t (triplet), q (quartet), m (multi-
plet) or b (broad).
pension was filtered through Celite and washed with Et O (10 mL).
2
The combined organic phase was dried over MgSO , concentrated
4
under vacuum, and purified by flash chromatography (pentane/
Et O, 95:5) to afford (R)-2-phenyl-2,5-dihydrofuran 9 (62 mg,
2
71%) as a thick viscous oil. Analytical data were in agreement with
the literature [23].
13C NMR spectra were recorded at 75 MHz with a Bruker
Avance DPX300 spectrometer or at 100 MHz with a Bruker Avance
DRX400 spectrometer (Bruker BioSpin Corp., Billerica, Massachu-
2.4.4. Method for Suzuki coupling reaction using conventional
ultrasound [32]
3
setts, USA) and were obtained in CDCl with d 77.16 ppm used as
an internal reference. Each resonance was assigned according to
the following convention: chemical shift in parts per million
Sonochemical reactions were carried out in a thermostated
ultrasonic cleaning bath (Branson 5200; 120 W output power;
47 kHz). A direct comparison was made between the published
sonochemical [32] and our SAW reactions with 4-methoxybromo-
benzene and phenylboronic acid used as substrates for the Suzuki
cross couplings. The sonochemical reaction procedure was as fol-
lows: a mixture of aryl halide (0.5 mmol), phenylboronic acid
(
ppm).
2.3. Materials
Unless otherwise specified, all commercially available chemi-
cals were purchased from Sigma–Aldrich Co. (Milwaukee, Wiscon-
+
ꢀ
(0.5 mmol), [bbim] [BF ] (0.5 g), Pd(OAc) (0.001 g) and NaOAc
4 2

K. Kulkarni et al. / Ultrasonics Sonochemistry 21 (2014) 1305–1309
1307
0
(
0.045 g) in MeOH (1.0 mL) was sonicated under argon for 10 min.
2.5.6. 4-Acetyl-4 -methoxy-1,1-biphenyl (Table 1, entry 6)
The reactions were monitored by TLC/GC. After completion, H
2
O
O
Following the general procedure 2.4.1, using
3
l
L
of
ꢀ4
(
(
2.0 mL) was added and the mixture extracted with Et
2
5.35 ꢁ 10 M Pd(OAc)
2
stock solution and irradiating with SAWs
for 15 min, afforded, after purification, 4-acetyl-4 -methoxy-1,1-
0
2
2 ꢁ 5 mL). The Et O layer was separated, dried and the solvent
evaporated. The residue was subjected to column chromatography
to isolate pure product [32].
biphenyl 6 (44 mg, 97%) as a white crystalline solid, m.p. 154–
155 °C (lit. mp 154–155 °C) [18].
1
3
H NMR (400 MHz, CDCl ) d 8.01, (m, 2H); 7.64, (m, 2H); 7.58,
(
m, 2H); 7.00, (m, 2 H); 3.86, (s, 3H); 2.62, (s, 3H).
C NMR (100 MHz, CDCl ) d 197.8, 160.1, 145.5, 135.5, 132.4,
3
29.1, 128.5, 126.8, 114.6, 55.5, 26.7.
2
2
5
.5. Analytical data
1
3
1
.5.1. 4-Acetylbiphenyl (Table 1, entry 1)
Following the general procedure 2.4.1, using
3
l
L
of
0
ꢀ4
2.5.7. 4 -Methyl-4-biphenylamine (Table 1, entry 7)
.35 ꢁ 10 M Pd(OAc)
2
stock solution and irradiating with SAWs
Following the general procedure 2.4.1, using
3
l
L
of
for 10 min, afforded, after purification, 4-acetylbiphenyl
1
ꢀ3
5
.35 ꢁ 10 M Pd(OAc)
2
stock solution and irradiating with SAWs
(
39 mg, 99%) as a white crystalline solid, m.p. 116–118 °C (lit. mp
0
for 15 min, afforded, after purification, 4 -methyl-4-biphenylamine
7 (36 mg, 98 %) as a white crystalline solid, m.p. 98–100 °C (lit. mp
1
7
1
18–120 °C) [18].
1
H NMR (400 MHz, CDCl
3
) d 8.04, (m, 2H); 7.69, (m, 2H); 7.65–
9
7
1
2
5
8-100 °C).
.61, (m, 2H); 7.50–7.45, (m, 2H); 7.43–7.38, (m, 1H); 2.64, (s, 3H).
1H NMR (400 MHz, CDCl
1
3
3
) d 7.47–7.39, (m, 4H); 7.22, (d, J
C NMR (100 MHz, CDCl
3
) d 197.8, 145.9, 140.0, 136.1, 129.1,
.9 Hz, 2H); 6.76, (m, 2H); 3.64, (bs, 2H); 2.39, (s, 3H).
29.0, 128.4, 127.4, 26.8.
1
3
3
C NMR (100 MHz, CDCl ) d 145.7, 138.5, 136.0, 131.8, 129.5,
27.9, 126.4, 115.5, 21.2.
2.5.2. 4-Aminobiphenyl (Table 1, entry 2)
Following the general procedure 2.4.1, using
3
lL
of
.5.8. 4-Acetyl-3’-nitrobiphenyl (Table 1, entry 8)
ꢀ2
5
.35 ꢁ 10 M Pd(OAc)
2
stock solution and irradiating with SAWs
Following the general procedure 2.4.1, using
3
lL
of
for 8 min, afforded, after purification, 4-aminobiphenyl 2 (31 mg,
2 %) as a brown crystalline solid, m.p. 50–51 °C (lit. mp 51 °C)
19].
1H NMR (400 MHz, CDCl
.30–7.25, (m, 1H); 6.76, (m, 2H); 3.71, (bs, 2H).
ꢀ4
.35 ꢁ 10 M Pd(OAc)
2
stock solution and irradiating with SAWs
9
[
0
for 12 min, afforded, after purification, 4-acetyl-3 -nitrobiphenyl
8
mp 110–111 °C) [17].
(48 mg, 99%), as a white crystalline solid, m.p. 108–110 °C (lit.
3
) d 7.54, (m, 2H); 7.45–7.37, (m, 4H);
7
1
1
3
H NMR (400 MHz, CDCl ) d 8.47, (t, J 2.0 Hz, 1H); 8.25, (ddd, J
1
3
C NMR (100 MHz, CDCl
3
) d 146.0, 141.3, 131.8, 128.8, 128.2,
1
2
3
.0 Hz, 2.0 Hz, 8.0 Hz, 1H); 8.08, (m, 2H); 7.95, (ddd, J 1.0 Hz,
.0 Hz, 8.0 Hz, 1H); 7.72, (m, 2H); 7.65, (t, J 8.0 Hz, 1H); 2.66, (s,
26.5, 126.4, 115.5.
H).
13C NMR (75 MHz, CDCl
3
) d 197.6, 149.0, 143.2, 141.7, 137.1,
2.5.3. 4-Methoxybiphenyl (Table 1, entry 3)
1
33.3, 130.1, 129.3, 127.5, 123.0, 122.3, 26.8.
Following the general procedure 2.4.1, using
3
lL
of
ꢀ2
5
.35 ꢁ 10 M Pd(OAc)
2
stock solution and irradiating with SAWs
2
.5.9. (R)-2-Phenyl-2,5-dihydrofuran (9)
for 10 min, afforded, after purification, 4-methoxybiphenyl 3
33 mg, 90%) as a white crystalline solid, m.p. 86–88 °C (lit. mp
(R)-2-Phenyl-2,5-dihydrofuran 9 was synthesised following the
(
method for Heck reaction using SAWs 2.4.3. The product was deter-
mined to have an enantiomeric ratio of 94.5:5.5 by chiral HPLC
(
8
2
1
7–89 °C) [19,20].
1
3
H NMR (400 MHz, CDCl ) d 7.61–7.54, (m, 4H); 7.47–7.41, (m,
100% hexanes at 1.0 mL/min, detection at 197 nm, t(R) = 27 min
H); 7.36–7.30, (m, 1H); 7.01, (m, 2H); 3.87, (s, 3H).
1
3
for the major isomer and 36 min for the minor isomer) [23].
C NMR (100 MHz, CDCl
3
) d 159.3, 141.0, 133.9, 128.9, 128.3,
26.9, 126.8, 114.4, 55.5.
2
5
2
.5.10. Specific rotation ½
aꢂ
D
3
= +275 (c 0.59, CHCl )
1
3
H NMR (400 MHz, CDCl ) d 7.38–7.25, (m, 5H); 6.04, (tdd, J
2.5.4. 4-Methylbiphenyl (Table 1, entry 4)
1
1
2
1
.6 Hz, 2.3 Hz, 6.1 Hz, 1H); 5.90, (dtd, J 1.6 Hz, 2.5 Hz, 6.3 Hz,
H); 5.80, (ddd, J 2.0 Hz, 4.0 Hz, 7.9 Hz, 1H); 4.88, (dddd, J 1.7 Hz,
.4 Hz, 6.0 Hz, 12.8 Hz, 1H); 4.78, (dddd, J 1.6 Hz, 2.5 Hz, 4.1 Hz,
2.8 Hz, 1H).
Following the general procedure 2.4.1, using
3
lL
of
ꢀ2
5
.35 ꢁ 10 M Pd(OAc)
2
stock solution and irradiating with SAWs
for 8 min, afforded, after purification, 4-methylbiphenyl 4 (28 mg,
3%) as a white crystalline solid, m.p. 44–47 °C (lit. mp 46–47 °C)
21].
1H NMR (400 MHz, CDCl
.47–7.41, (m, 2H); 7.37–7.31, (m, 1H); 7.29–7.25, (m, 2H); 2.42,
s, 3H).
13C NMR (100 MHz, CDCl
27.1, 21.2.
8
[
13C NMR (100 MHz, CDCl
3
) d 142.2; 130.1, 128.6, 127.9, 126.8,
1
26.5, 88.1, 76.0.
3
) d 7.62–7.58, (m, 2H); 7.51, (m, 2H);
7
(
3
. Results and discussion
3
) d 141.3, 138.5, 137.2, 129.6, 128.9,
The reaction setup was quite simple. An ethanol/water mixture
1
containing Suzuki coupling partners was first added to the glass
reactor (typically a flat-bottomed, screw-capped 1.5 mL vial) and
0
2.5.5. 4-Methyl-4 -methoxybiphenyl (Table 1, entry 5)
Br
B(OH)
2
Following the general procedure 2.4.1, using
3
lL
of
R
2
ꢀ2
5
.35 ꢁ 10 M Pd(OAc)
2
stock solution and irradiating with SAWs
0
Pd(OAc)
2 2 3
, K CO
for 30 min, afforded, after purification, 4-methyl-4 -methoxybi-
R
1
R
phenyl 5 (33 mg, 83%) as a white crystalline solid, m.p. 105–
H O/EtOH, reflux
R
2
2
1
7
1
08 °C (lit. mp 109–110 °C) [20].
R
R
1
1-8
1
3
H NMR (400 MHz, CDCl ) d 7.53, (m, 2H); 7.47, (m, 2H); 7.26–
R = COCH
3
,
R
1
2
= H, OCH
= H, NO
3 3
, CH
.22, (m, 2H); 6.98, (m, 2H); 3.86, (s, 3 H); 2.40, (s, 3H).
NH
2
, CH
3
, OCH
3
R
2
1
3
3
C NMR (100 MHz, CDCl ) d 159.1, 138.1, 136.5, 133.9, 129.6,
28.1, 126.7, 114.3, 55.5, 21.2.
Scheme 1. Reaction scheme for Suzuki coupling reactions.

1
308
K. Kulkarni et al. / Ultrasonics Sonochemistry 21 (2014) 1305–1309
Table 1
e
SAW-assisted Suzuki cross-coupling of aryl halides with substituted arylboronic acids .
Entry
Biaryl product
Reaction time (min)
10
Energy density (kJ/mmol)
18.0
Yield (%)
>99a,d
1
2
3
4
5
6
7
8
.
.
.
.
.
.
.
.
COCH3
NH2
8
14.4
18.0
14.4
54.0
27.0
27.0
21.6
92c
10
8
90c
OCH3
3c
30
15
15
12
83c
H CO
3
97a,d
98b,d
>99a,d
H CO
COCH3
3
NH2
2
O N
COCH3
a
b
c
0
0
0
1
.0008 mol% catalyst loading.
.008 mol% catalyst loading.
.08 mol% catalyst loading.
00% conversion.
d
e
Temperature at reflux 87–88 °C.
Table 2
Comparison of energy densities for the Suzuki reaction between bromoanisole and phenylboronic acid carried out using SAW, ultrasound and microwaves.
Entry
Source of energy
Scale (mmol)
Power used (W)
Reaction time (min)
Catalyst loading (mol%)
Energy density (kJ/mmol)
Yield (%)
1
2
3
.
.
.
SAW
Microwave
Ultrasound
1
1
0.5
8
5
120
25
17
10
0.08
0.8
0.9
12
5.1
144
89
72
85
then an ethanolic suspension of the catalyst was added. The total
reaction volume was 600 L. After the vial was closed and placed
O
O
l
Pd
2
dba
3
, PHOX ligand
Ph
on the chip the device was switched on. The reaction mixture
immediately began to heat up and in all cases reflux became evi-
dent within two minutes. A range of electronically diverse arylbo-
ronic acids and halides (Scheme 1) was employed in this study.
Reaction times were typically 8–15 min. The only exception was
a case where both aromatic partners bore an electron-donating
substituent (Table 1 – entry 5) which resulted in the reaction tak-
ing 30 min to complete. In most cases the product precipitated as a
white crystalline solid once the reaction was allowed to cool to
room temperature.
At the scale employed in this paper (0.2 mmol substrate) only
about 6 W of power is consumed with reaction times comparable
to other methods. This compares very favorably with other sources
of energy, including microwaves [24–27], low and high power
ultrasound [28–30] as well as conventional heating. Also, as SAWs
are intrinsically safe no shielding was required during active
experiments.
proton sponge, toluene, reflux
TfO
9
Scheme 2. Reaction scheme for asymmetric Heck reaction.
with the energy densities for the same coupling reaction, on a similar
scale, using microwaves or ultrasound and was calculated by using
the values of power consumed and reaction times mentioned in
the literature (Table 2) [31,32]. The energy density for the SAW-as-
sisted reaction was slightly larger than that required for the micro-
wave-based process, but significantly less than that consumed by
ultrasound. It also needs to be noted that the SAW devices employed
in this study are very much at the prototype stage and have not yet
had the benefit of design engineering and optimization.
An asymmetric Heck (Scheme 2) was carried out on a 0.6 mmol
scale using a similar reaction setup to the Suzuki reactions, heated
using SAWs for 3 h at 110 °C, which resulted in 71% yield with 90%
ee (as measured by chiral HPLC of the major isomer on Daicel
Chiracel OD-H), both comparable to the literature [33–35].
Somewhat parenthetically, we also found that these ligand-free
Suzuki coupling reactions using traditional boronic acids proceed
with high efficiency with low to ultra-low catalyst loadings. Run-
ning each reaction on a 0.2 mmol scale, with 0.0008–0.08 mol%
catalyst loading, afforded the desired biaryl products in good to
excellent yields. Ultra-low catalyst loading has previously been
achieved by employing either (i) ligands with the palladium
acetate catalyst and conventional boronic acids [36] or (ii)
Scaled up, closed-vessel SAW reactions are also possible. For
example, entry 3 in Table 1 was scaled up to 1 mmol in a 4 mL glass
vial. The reaction required a longer reaction time of 25 min (as op-
posed to 10 min), providing the biaryl product in excellent yield
(
85–90%).
In order to provide some comparison with other heating meth-
ods we calculated the energy density1 required for the scaled up,
closed-vessel, SAW-assisted Suzuki reaction. This was compared
1
Energy density (kJ/mmol) = [Power (W) ꢁ Reaction time (sec)]/Moles of limiting
reagent (mmol).

K. Kulkarni et al. / Ultrasonics Sonochemistry 21 (2014) 1305–1309
1309
organotrifluoroborates [5] in combination with ligand-free palla-
dium catalysis.
[12] J.P. Tierney, P. Lidström, in: Microwave Assisted Organic Synthesis, Blackwell
Publishing, Oxford UK, 2005, p. 296.
[
13] D. Bogdal, Microwave-assisted organic synthesis – one hundred reaction
procedures, in: Tetrahedron Organic Chemistry Series, Elsevier Science &
Technology, Amsterdam, 2005, p. 202.
Reusable solid supported palladium catalysts have also been re-
ported for Suzuki couplings due to their ease and sustainable use.
However, higher loadings were required and solvent-free reactions
required much higher microwave power [37]. In examples where
lower loading of reusable supported Pd catalysts (0.4 mol%) were
used, longer reaction times (typically 20 h reflux) have been re-
ported [17]. Even with the lower loading of the solid supported cat-
alyst it has been reported that micro-equivalents of Pd are lost due
to leaching of the catalyst during the reaction [17]. These roughly
equate to the 0.0008 mol% catalyst used in entries 1, 6 and 8
[
14] E.V. Eycken, C.O. Kappe, Microwave-assisted synthesis of heterocycles, in: R.R.
Gupta (Ed.), Topics in Heterocyclic Chemistry, Springer-Verlag GmbH., Berlin
Heidelberg, 2006.
[15] C.O. Kappe, A. Stadler, Microwaves in organic and medicinal chemistry, in: R.
Mannhold, H. Kubinyi, G. Folkers (Eds.), Methods and Principles in Medicinal
Chemistry, Wiley-VCH Verlag GmbH & Co., Weinheim Germany, 2005, p. 409.
[
[
[
16] R.P. Hodgson, M. Tan, L. Yeo, J. Friend, Transmitting high power rf acoustic
radiation via fluid couplants into superstrates for microfluidics, Appl. Phys.
Lett. 94 (2009) 024102.
17] S. Schweizer, J.-M. Becht, C.L. Drian, Highly efficient and reusable supported Pd
catalysts for Suzuki-Miyaura reactions of aryl chlorides, Org. Lett. 9 (2007)
3777–3780.
(Table 1).
18] W. Solodenko, K. Mennecke, C. Vogt, S. Gruhl, A. Kirschning, Polyvinylpyridine,
a
versatile solid phase for coordinative immobilisation of palladium
precatalysts – applications in Suzuki-Miyaura reactions, Synthesis (2006)
873–1881.
4
. Conclusion
1
[
[
19] E. Alacid, C. Nájera, First cross-coupling reaction of potassium
aryltrifluoroborates with organic chlorides in aqueous media catalyzed by an
oxime-derived palladacycle, Org. Lett. 10 (2008) 5011–5014.
In conclusion, SAWs provide an operationally simple, excellent
energy source for thermally-driven homogeneous, transition-metal
catalyzed processes such as the Suzuki and Heck coupling reac-
tions described here. As evidenced by our calculations the energy
density for the SAW-assisted reaction was slightly larger than that
required for the microwave-based process, but significantly less
than that consumed by ultrasound. These results indicate that this
new, simple technology shows great potential for delivering en-
ergy to chemical reactions in a safe and efficient manner.
20] B. Lü, C. Fu, S. Ma, Application of
a readily available and air stable
monophosphine HBF4 salt for the Suzuki coupling reaction of aryl or 1-
alkenyl chlorides, Tetrahedron Lett. 51 (2010) 1284–1286.
[21] M. Kuriyama, R. Shimazawa, R. Shirai, Design and synthesis of thioether-
imidazolium chlorides as efficient ligands for palladium-catalyzed Suzuki-
Miyaura coupling of aryl bromides with arylboronic acids, Tetrahedron 63
(
2007) 9393–9400.
[22] K. Inada, N. Miyaura, Synthesis of biaryls via cross-coupling reaction of
arylboronic acids with aryl chlorides catalyzed by NiCl
complexes, Tetrahedron 56 (2000) 8657–8660.
2
/triphenylphosphine
[
[
23] F. Ozawa, A. Kubo, Y. Matsumoto, T. Hayashi, E. Nishioka, K. Yanagi, K.
Moriguchi, Palladium-catalyzed asymmetric arylation of 2,3-dihydrofuran
Acknowledgments
with phenyl triflate.
A Novel Asymmetric Catalysis Involving a Kinetic
Resolution Process, Organometallics 12 (1993) 4188–4196.
KK is grateful to Monash University for MGS and MFRS awards.
Supporting Information includes NMR spectra for the SAW-as-
sisted Suzuki coupling reactions and the Heck reaction.
24] M.L. Clarke, M.B. France, J.A. Fuentes, E.J. Milton, G.J. Roff, A convenient catalyst
system for microwave accelerated cross-coupling of a range of aryl boronic
acids with aryl chlorides, Beil. J. Org. Chem. 3 (2007) 1–5.
25] R.B. Bedford, C.P. Buttsa, T.E. Hurst, P. Lidström, The Suzuki coupling of aryl
chlorides under microwave heating, Adv. Synth. Catal. 346 (2004) 1627–1630.
26] N.E. Leadbeater, Fast, easy, clean chemistry by using water as a solvent and
microwave heating: the Suzuki coupling as an illustration, Chem. Commun.
[
[
References
(
2005) 2881–2902.
[
[
1] K. Kulkarni, J. Friend, L. Yeo, P. Perlmutter, Surface acoustic waves as an energy
source for drop scale synthetic chemistry, Lab Chip 9 (2009) 754–755.
2] K.P. Kulkarni, S.H. Ramarathinam, J. Friend, L. Yeo, A.W. Purcell, P. Perlmutter,
Rapid microscale in-gel processing and digestion of proteins using surface
acoustic waves, Lab Chip 10 (2010) 1518–1520.
3] G. Marchand, P. Dubois, C. Delattre, F. Vinet, M. Blanchard-Desce, M. Vaultier,
Organic synthesis in soft wall-free microreactors: Real-time monitoring of
fluorogenic reactions, Anal. Chem. 80 (2008) 6051–6055.
4] C.K.Y. Lee, A.B. Holmes, S.V. Ley, I.F. McConvey, B. Al-Duri, G.A. Leeke, C.D.S.
Regina, J.P.K. Seville, Efficient batch and continuous flow Suzuki cross-coupling
reactions under mild conditions, catalysed by polyurea-encapsulated
palladium(II) acetate and tetra-n-butylammonium salts, Chem. Commun.
[
[
[
27] G. Miao, P. Ye, L. Yu, C.M. Baldino, Microwave-promoted Suzuki reactions of
aryl chlorides in aqueous media, J. Org. Chem. 70 (2005) 2332–2334.
28] V. Polácková, M. Hut’ka, S. Toma, Ultrasound effect on Suzuki reactions. 1.
Synthesis of unsymmetrical biaryls, Ultrason. Sonochem. 12 (2005) 99–102.
29] A.C. Silva, A.L.F. de Souza, O.A.C. Antunes, Phosphine-free Suzuki cross-
coupling reactions under ultrasound, J. Organomet. Chem. 692 (2007) 3104–
[
[
3
107.
[
30] G. Cravotto, M. Beggiato, A. Penoni, G. Palmisano, S. Tollari, J.-M. Lévêque, W.
Bonrathd, High-intensity ultrasound and microwave, alone or combined,
promote Pd/C-catalyzed aryl–aryl couplings, Tetrahedron Lett. 46 (2005)
2
267–2271.
[
[
[
[
[
[
[
31] N.E. Leadbeater, R.J. Smith, In situ Raman spectroscopy as a probe for the effect
of power on microwave-promoted Suzuki coupling reactions, Org. Biomol.
Chem. 5 (2007) 2770–2774.
32] R. Rajagopal, D.V. Jarikote, K.V. Srinivasan, Ultrasound promoted Suzuki cross-
coupling reactions in ionic liquid at ambient conditions, Chem. Commun.
(
2005) 2175–2177.
[
5] R.K. Arvela, N.E. Leadbeater, T.L. Mack, C.M. Kormos, Microwave-promoted
Suzuki coupling reactions with organotrifluoroborates in water using ultra-
low catalyst loadings, Tetrahedron Lett. 47 (2006) 217–220.
[
[
6] A. Suzuki, Cross-coupling reactions via organoboranes, J. Organomet. Chem.
(
2002) 616–617.
6
53 (2002) 83–90.
33] P. Nilsson, H. Gold, M. Larhed, A. Hallberg, Microwave-assisted
enantioselective Heck reactions: expediting high reaction speed and
preparative convenience, Synthesis (2002) 1611–1614.
34] P. Kaukoranta, K. Källström, P.G. Andersson, Microwave-assisted asymmetric
intermolecular Heck reaction using phosphine-thiazole ligands, Adv. Synth.
Catal. 349 (2007) 2595–2602.
35] T. Tu, W.-P. Deng, X.-L. Hou, L.-X. Dai, X.-C. Dong, The regioselectivity of the
asymmetric intermolecular Heck reaction with planar chiral diphosphine ±
oxazoline ferrocenyl ligands, Chem. Eur. J. 9 (2003) 3073–3081.
36] J.P. Wolfe, R.A. Singer, B.H. Yang, S.L. Buchwald, Highly active palladium
catalysts for Suzuki coupling reactions, J. Am. Chem. Soc. 121 (1999) 9550–
7] H. Chaumeil, S. Signorella, C.L. Drian, Suzuki cross-coupling reaction of
sterically hindered aryl boronates with 3-Iodo-4-methoxybenzoic acid
methylester, Tetrahedron Lett. 56 (2000) 9655–9662.
8] G.W. Kabalka, L. Zhou, A. Naravane, Microwave enhanced ligand- and base-free
cross-coupling of potassium aryltrifluoroborates salts with aryl triflates,
Tetrahedron Lett. 47 (2006) 6887–6889.
[
[
9] C.J. Mathews, P.J. Smith, T. Welton, Palladium catalysed Suzuki cross-coupling
reactions in ambient temperature ionic liquids, Chem. Commun. (2000) 1249–
1
250.
[
[
10] B. Xin, Y. Zhang, L. Liu, Y. Wang, Water-promoted Suzuki reaction in room
temperature ionic liquids, Synlett (2005) 3083–3086.
11] F. McLachlan, C.J. Mathews, P.J. Smith, T. Welton, Palladium-catalyzed Suzuki
cross-coupling reactions in ambient temperature ionic liquids: evidence for
the importance of palladium imidazolylidene complexes, Organometallics 22
9
561.
37] G.W. Kabalka, R.M. Pagni, L. Wang, V. Namboodiri, C.M. Hair, Microwave-
assisted, solventless Suzuki coupling reactions on palladium-doped alumina,
Green Chem. 2 (2000) 120–122.
(
2003) 5350–5357.