Safe palladium-catalyzed cross-couplings with microwave heating using continuous-flow silicon carbide reactors

Article abstract of DOI:10.1021/op5001989

Herein we present a 200 mm × 3 mm _i silicon carbide (SiC) tube reactor for use in a commercially available microwave heated continuous-flow system. The SiC flow reactor enables palladium(0)-catalyzed reactions that, due to precipitation and subsequent hot spot formation, often followed by reactor failure, are unsuitable to conduct in standard microwave-transparent borosilicate glass reactors. We report continuous-flow protocols for the Mizoroki-Heck reaction (10 examples, 81-86% yield) as well as the Suzuki-Miyaura cross-coupling (14 examples, 70-87% yield), showing the utility of the SiC reactor. Furthermore, we performed a scale-out of the NSAID biphenylacetic acid, achieving outputs of 14 mmol/h of the Suzuki-Miyaura reaction, and a 72% overall yield over three steps. The SiC reactor enabled fast and efficient temperature control, high robustness, and easy maintenance.

Full text of DOI:10.1021/op5001989

Article
pubs.acs.org/OPRD
Safe Palladium-Catalyzed Cross-Couplings with Microwave Heating
Using Continuous-Flow Silicon Carbide Reactors
Vivek Konda,† Jonas Rydfjord,† Jonas Savmarker,‡ and Mats Larhed*,§
̈
‡
†Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Beijer Laboratory, Department of Medicinal Chemistry,
§
and Department of Medicinal Chemistry, Science for Life Laboratory, Uppsala University, Box-574, SE-751 23 Uppsala, Sweden
S
* Supporting Information
ABSTRACT: Herein we present a 200 mm × 3 mm Øi silicon carbide (SiC) tube reactor for use in a commercially available
microwave heated continuous-flow system. The SiC flow reactor enables palladium(0)-catalyzed reactions that, due to
precipitation and subsequent hot spot formation, often followed by reactor failure, are unsuitable to conduct in standard
microwave-transparent borosilicate glass reactors. We report continuous-flow protocols for the Mizoroki−Heck reaction (10
examples, 81−86% yield) as well as the Suzuki−Miyaura cross-coupling (14 examples, 70−87% yield), showing the utility of the
SiC reactor. Furthermore, we performed a scale-out of the NSAID biphenylacetic acid, achieving outputs of 14 mmol/h of the
Suzuki−Miyaura reaction, and a 72% overall yield over three steps. The SiC reactor enabled fast and efficient temperature
control, high robustness, and easy maintenance.
to accelerate these reactions in order to achieve full conversions
within minutes.
INTRODUCTION
■
Controlled microwave (MW) heating has found increased use
in small-scale batch synthesis, and dedicated MW instruments
are now routinely used in many research laboratories and
pharmaceutical companies.1−5 The advantages associated with
MW heating are commonly attributed to the efficient direct
manner of heating6 as the reaction mixture itself will be rapidly
heated, rather than the vessel, which is the case for classical
heating.7−9 Most importantly, MW instrumentation designed
for organic chemistry applications has provided a safe and
convenient way to perform small-scale batch chemistry at
elevated temperatures and pressures.
One foreseeable issue with homogeneous metal catalysis
under MW heating conditions is however the risks associated
with possible metal precipitation or deposits to the walls of
MW-transparent reactors. In a MW field these deposits will be
heated very rapidly which can lead to reactor failure.38−40 In
our initial palladium(0)-catalyzed MW flow reactions this did
indeed happen several times when using borosilicate tube
reactors; see Figure 1 for one example of a reactor failure. Thus,
Continuous-flow (CF) chemistry is another technology
which has attracted considerable interest in the last few
decades due to safety, handling, and scale-up advantages.10,11
Rather than heating a large volume of a reaction mixture in
batch mode, a small volume will be heated in a CF equipment,
which greatly improves safety.4,10,11 The predominant mode of
heating used in CF systems has been conductive heating.
However, the combination of MW heating and CF has
attracted interest,8,12−23 and we have reported on a purpose-
built system combining CF with a nonresonant MW applicator
for heating.24−27 The most prominent feature of this system is a
very uniformly distributed axial MW field, providing homoge-
neous heating of the reaction mixture when using 200 mm ×
2−10 mm Øi microwave transparent borosilicate tube reactors.
In addition the tubular wide bore reactor design prevents
clogging and facilitates physical cleaning of the reactor.28
Palladium(0)-catalyzed reactions such as the Mizoroki−Heck
reaction29−31 and the Suzuki−Miyaura coupling reaction32 have
found great use during the last few decades. Furthermore, these
cross-couplings have successfully been carried out both with
MW heating33−36 and by using CF equipment.37 Thus, the
importance of cross-coupling methods prompted us to
investigate the Mizoroki−Heck and Suzuki−Miyaura reactions
under MW heated CF conditions and whether it would possible
Figure 1. An intact and a disrupted 200 mm × 3 mm Øi borosilicate
glass reactor after carrying out a palladium(0)-catalyzed Mizoroki−
Heck reaction.
we decided to investigate another reactor material than the
standard borosilicate glass, namely, silicon carbide (SiC).41−43
SiC has several traits of interest in reactor design, being
chemically resistant, thermally resistant, and capable of
tolerating high pressures. In this application, the most
important characteristic is however SiC’s capability to
completely absorb MW radiation. This property allows for
Special Issue: Continuous Processes 14
Received: June 19, 2014
Published: July 24, 2014
© 2014 American Chemical Society
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mimicking conventional heating, since the reactor itself will be
heated by the MWs, allowing no direct MW in situ heating of
the reaction mixture inside.41,44 In addition the extremely fast
temperature response seen in MW heated solutions is shared by
the SiC material which has been shown by the Kappe group.41
Thus, this should allow for rapid palladium(0)-catalyzed flow
reactions to be carried out without subsequent reactor failure
due to metal deposits inside the reactor under MW heating.
The initial conditions resulted in 86% yield (Table 1, Entry
1). Next, the solvents acetonitrile, N,N-dimethylacetamide
Table 1. MW flow Mizoroki−Heck reaction with the SiC
reactor, optimization of reaction conditions
RESULTS AND DISCUSSION
■
Reactor. The reactor was made out of SiC tubing45 with an
outer diameter of 6 mm and an inner diameter of 3 mm which
was cut to 200 mm in length to make out one reactor; see
Figure 2. The total reactor volume is 1.4 mL, which equals the
heated volume as the outlet is actively cooled using circulating
water (see the Supporting Information).
Equiv
1a
a
Entry
precat.
Solvent
DMF
Base
TEA
(M)
2 (M) Yield
1
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.02
0.005
0.005
0.04
0.04
0.04
0.04
0.04
0.04
0.04
0.04
0.04
0.08
0.08
0.08
0.08
0.08
0.08
0.08
0.08
0.08
0.08
0.04
86%
67%
84%
2
acetonitrile
DMA
TEA
TEA
TEA
TEA
DIPEA
DBU
TEA
TEA
TEA
3
b
b
4
THF
traces
traces
80%
82%
92%
75%
71%
5
1,4-dioxane
DMF
6
7
DMF
8
DMF
9
DMF
Figure 2. New SiC tube reactor, 200 mm × 3 mm Øi.
10
DMF
a
1
Yield of the isolated product (>95% GC-MS and pure by H NMR
We opted to investigate the heating profile by using a FLIR
camera. This temperature determination resulted in the image
depicted in Figure 3, showing a very uniform heating profile of
spectroscopic analysis). Reaction conditions: a homogeneous solution
of Herrmann’s palladacycle (equiv precat.), 1a (M), 2 (M), base (0.08
M), and tri-tert-butylphosphonium tetrafluoroborate salt (2× equiv
Herrmann’s palladacycle) in the specified solvent was pumped through
the 200 mm × 3 mm Øi SiC reactor at a flow rate of 0.5 mL/min at
b
210 °C (calibrated IR sensor).27 Trace amounts of 3a detected by
GC-MS.
(DMA), THF, and 1,4-dioxane were evaluated, giving 67% and
84% yield for acetonitrile and DMA, respectively, while only
showing traces of product formation by GC-MS for THF and
1,4-dioxane (Table 1, Entries 2−5). Continuing with DMF as
the solvent of choice, we turned to the choice of base,
investigating soluble amine bases diisopropylethyl amine
(DIPEA) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as
alternatives to TEA, giving 80% and 82% yield, respectively
(Table 1, Entries 6−7). Next, choosing TEA as the base for the
protocol the precatalyst loading was investigated. An increased
precatalyst loading of 2% resulted in 92% yield (Table 1, Entry
8). Decreasing the amount of palladacycle to 0.5% resulted in
75% yield (Table 1, Entry 9). Finally, reversing the
stoichiometry to a 2:1 ratio of the bromide to the alkene
provided 71% yield at 0.5% precatalyst loading. The condition
screening thus resulted in the decision to maintain the original
conditions for further investigation of the scope of the reaction,
opting for the lower palladacycle concentration (1%) rather
than the slightly higher yield at the higher 2% precatalyst
concentration (compare Table 1, Entries 1 and 8).
Thereafter, the scope of the Mizoroki−Heck reaction was
investigated with regards to the aryl bromide (Table 2). It was
found that the protocol had a good tolerance for different 4-
substituted phenyl bromides, providing yields in between 84%
and 86% regardless of electronic nature (compare Table 2,
entries 1−4). Functional group tolerance was demonstrated
with formyl and nitrile substituted phenyl bromides, both
affording 86% isolated yield (Table 2, entries 5 and 6). Steric
hindrance was also investigated with 2-bromotoluene as a
substrate and was found to not affect the yield to any great
extent, furnishing 81% yield of the corresponding cinnamic
ester product 3g (Table 2, entry 7). Finally three different
Figure 3. Left, FLIR image depicting heating of 200 mm × 3 mm Øi
borosilicate glass reactor and SiC tube reactors under MW-CF
operation. Right, MW reactor cavity with helical antenna and a
borosilicate glass reactor.
the SiC reactor along the whole length. By comparison with a
flowing liquid in a borosilicate glass reactor, as illustrated to the
left in Figure 3, it can be observed that the SiC reactor is
homogeneously heated while the transparent borosilicate
reactor does not acquire a uniform temperature due to the
inflow of cold reaction mixture. The reaction mixture itself is
likely to show a flow-dependent temperature gradient
throughout the SiC reactor, as is observed for the borosilicate
glass reactor, even though it is not apparent using IR surface
measurements.
Chemistry. We started out investigating the Mizoroki−
Heck reaction by employing 1% Herrmann’s palladacycle46,47 as
the precatalyst with DMF as solvent, 2 equiv of triethyl amine
(TEA) as base, 2% tri-tert-butylphosphonium tetrafluoroborate
salt48 as a preligand, 2 equiv of n-butyl acrylate, 2, and yield-
determining 4-bromoacetophenone, 1a. The concentration of
1a in the solution was 0.04 M. A flow rate of 0.5 mL/min was
used, corresponding to a residence time of 168 s. All
preliminary attempts at higher flow rates indicated that full
conversion was not possible to obtain. Similarly lower
temperatures resulted in incomplete conversion of the starting
bromide.
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respectively. Importantly, all reactions were conducted without
reactor failure.
Table 2. MW flow Mizoroki−Heck reaction with the SiC
reactor, investigation of the scope
We thereafter decided to investigate the Suzuki−Miyaura
coupling reaction by employing Pd(PPh3)4 as the catalyst49
with a DMF:water mixture (95:5) as the solvent, 1.5 equiv of
DBU as a base, and finally 1.5 equiv of the aryl boronic acid 4a
to the yield-determining aryl bromide 1d. The concentration of
yield-determining 1d was 0.1 M. A flow rate of 1.0 mL/min was
used, resulting in an impressive residence time of 84 s.
Preliminary attempts at higher flow rates as well as at lower
temperatures indicated that full conversion was not possible to
obtain.
The initial conditions gave 87% yield of biaryl 5ad (Table 3,
entry 1), whilst the alternative precatalyst Pd(dppf)Cl2 afforded
Table 3. MW flow Suzuki−Miyaura cross-coupling with the
SiC reactor, optimization of reaction conditions
1a
(M)
4a
(M)
a
Entry
[Pd]
Solvent
Yield
1
2
3
4
5
6
7
Pd(PPh3)4
DMF−water 95:5
0.1
0.1
0.1
0.1
0.1
0.1
0.15
0.15
0.15
0.15
0.15
0.15
0.1
87%
85%
81%
74%
Pd(dppf)Cl2 DMF−water95:5
Pd(dppf)Cl2 acetonitrile−water 95:5
Pd(dppf)Cl2 DMA−water 95:5
Pd(dppf)Cl2 dioxane−water 95:5
Pd(dppf)Cl2 DMF:water95:5
Pd(dppf)Cl2 DMF:water 95:5
b
traces
70%
0.1
73%
a
1
Yield of the isolated product (>95% pure by GC-MS and H NMR
spectroscopic analysis). Reaction conditions: a homogeneous solution
of precatalyst (2%), 1d (M), 4-tolylboronic acid 4a (M), DBU (0.15
M), in the specified solvent was pumped through the 200 mm × 3 mm
Øi SiC reactor at a flow rate of 1 mL/min at 240 °C (calibrated IR
b
sensor).27 Trace amounts of 5ad detected by GC-MS.
85% (Table 3, entry 2) of product 5ad. Due to superior shelf
life of the Pd(dppf)Cl2 salt compared to the less stable
Pd(PPh3)4 complex it was used for the continued investigation,
providing a more preparatively convenient protocol. Next we
investigated other solvent systems such as acetonitrile−water
(95:5), N,N-dimethylacetamide (DMA)−water (95:5), and 1,4-
dioxane−water (95:5) noticing that, while the acetonitrile−
water and DMA−water systems were productive (81% and
74%, respectively, Table 3, entries 3 and 4), they did not
outperform the original conditions. Neither did the 1,4-
dioxane−water system, which did not furnish more than traces
of product 5ad in the GC-MS analysis of the reaction mixture
(Table 3, entry 5). Lowering the amount of aryl boronic acid 4a
to 1 equiv gave a slightly lower yield of 70% (Table 3, entry 6).
A similar outcome was also experienced when using 1.5 equiv
of 1d to 0.1 M of yield-determining 4a which produced a 73%
yield of 5ad (Table 3, entry 7).
The scope of the reaction with the SiC reactor was studied
with 4a as the boronic acid, changing the aryl bromide coupling
partner 1. Resulting yields at 1 mL/min were high regardless of
aryl bromide, affording between 81% and 87% of biaryl 5,
showing tolerance for different electronic nature of the aryl
bromide (substrate 1b and 1a, Table 4, entries 2 and 3), steric
hindrance in the 1-bromonaphthalene substrate 1k (Table 4,
entry 4), as well as functional group tolerance with aldehyde 1e
(Table 4, entry 5) and finally accepting 3-pyridyl bromide 1i
a
1
Yield of the isolated product (>95% pure by GC-MS and H NMR
spectroscopic analysis). Reaction conditions: a homogeneous solution
of Herrmann’s palladacycle (1%), aryl bromide 1 (0.04 M), 2 (0.08
M), TEA (0.08 M), and tri-tert-butylphosphonium tetrafluoroborate
salt (2%) in the specified solvent was pumped through the 200 mm ×
3 mm Øi SiC reactor at a flow rate of 0.5 mL/min at 210 °C
(calibrated IR sensor).27 Reaction was conducted at 190 °C.
b
heterocycles (3-bromothiophene, 3-bromopyridine, and 5-
bromoindole, Table 2, entries 8−10) were investigated as
substrates, giving yields of 82%, 82%, and 86% of 3h, 3i, and 3j,
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(Table 4, entry 6). Electron-rich arylboronic acid 4b similarly
performed good with electron-rich arylation agent 1l, neutral
1b as well as electron-deficient 1a and 1e giving 70, 85, 84, and
86% yield, respectively, of biaryl product 5. Finally electron-
deficient arylboronic acid 4c provided high yields of 87, 87, and
81% (5ba, 5cb, and 5ce), with electron-rich substrate 1d,
intermediary 1b as well as electron-deficient 1e. The cross-
couplings were carried out at slightly different temperatures
after GC-MS analysis of the reaction outcome at different
temperatures before collection for purification. The instrumen-
tation can change temperature within seconds, providing
excellent process control without reactor failure and allowing
for quick assessment of the optimal temperature for any given
combination of substrates.
Table 4. MW flow Suzuki−Miyaura cross-coupling with the
SiC reactor, investigation of the scope
Scale-Out Example. We decided to scale-out our Suzuki−
Miyaura protocol to produce a larger quantity of a known
NSAID, biphenylacetic acid, 5dm (Scheme 1), using our MW
flow SiC technology. Use of 4-bromophenylacetic acid, 1m, as
the coupling partner, failed due to facile decarboxylation of the
substrate. To circumvent this problem we opted to form the
methyl ester 1n from 1m, followed by a Suzuki−Miyaura cross-
coupling with phenylboronic acid, 4d, and batch hydrolysis to
form desired 5dm. The formation of 1n was performed in CF
using the SiC reactor and a protocol, which after quick
optimization had an output of 5.8 g/h of crude product at 190
°C and 1 mL/min. Crude 1n could subsequently be used in an
adapted version of our Suzuki−Miyaura protocol running at a
higher concentration of bromide (0.3 M) to produce, after
hydrolysis, the NSAID 5dm. The Suzuki−Miyaura reaction had
an output of 14 mmol/h at 180 °C and 1 mL/min, furnishing
an isolated 80% yield of the pure product, 5dm, after
hydrolysis. The overall yield of 5dm, starting from 1m, was
72%. In total we produced 2.56 g of 5dm, running both of the
flow protocols for 50 min each without any problems due to,
e.g., palladium metal precipitation. The use of HPLC pumps
limit to some extent this scale-out experiment in terms of
concentration of reaction mixture and duration. Reactor and
back-pressure regulator technology showed no apparent
drawbacks for continued operation.
CONCLUSION
■
Following the observation that reactor failure rapidly occurs in
many homogeneous metal-catalyzed or metal-mediated cross-
coupling reactions when using a borosilicate glass reactor for
MW heated CF processing, we decided to develop a new type
of tube reactor to circumvent the problem. Thus, we
investigated the use of SiC, a material that very effectively
absorbs MWs, as a reactor material to circumvent the problems
related to metal precipitation and subsequent hot-spot
formations in palladium(0)-catalyzed cross-coupling reactions
and found that this reactor design in fact did allow us to process
reactions without reactor failures. Effectively mimicking a
conventionally wall heated system, we were now able to
demonstrate the successful use of the SiC reactor in a CF
Mizoroki−Heck protocol to give yields between 81% and 86%
for a wide variety of substrates. Further, the Suzuki−Miyaura
reaction provided high yields of 70−87% employing the SiC
MW flow setup. Finally we demonstrated the use of the SiC
MW flow technology in a synthesis of the NSAID biphenyl-
acetic acid, achieving 72% overall yield over three steps and a
14 mmol/h output of the Suzuki−Miyaura reaction.
a
1
Yield of the isolated product (>95% pure by GC-MS and H NMR
spectroscopic analysis). Reaction conditions: a homogeneous solution
of Pd(dppf)Cl2 (2%), aryl bromide 1 (0.1 M), aryl boronic acid 4
(0.15 M), DBU (0.15 M), in DMF−water (95:5) was pumped
through the 200 mm × 3 mm Øi SiC reactor at a flow rate of 1 mL/
min at 240 °C (calibrated IR sensor).27 Reaction was conducted at
b
c
d
Throughout the optimization studies, the scope investiga-
tions and the scale-out no clogging or failure of the reactor or
220 °C. Reaction was conducted at 210 °C. Reaction was conducted
at 180 °C.
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Scheme 1. Synthesis of NSAID, biphenylacetic acid
a
Crude yield. Reaction conditions: A 0.46 M solution of 1m was prepared in 0.1 M methanolic HCl solution (prepared by taking 7.1 mL acetyl
b
chloride per 1L total volume) and pumped through the 200 mm × 3 mm Øi SiC reactor at a flow rate of 1 mL/min at 190 °C. Yield of the isolated
product (>95% pure by GC-MS and H NMR spectroscopic analysis). Reaction conditions: (a) a homogeneous solution of Pd(dppf)Cl2 (2%), 1n
1
(0.3 M), 4d (0.45 M), DBU (0.45 M), in DMF−water (95:5) was pumped through the 200 mm × 3 mm Øi SiC reactor at a flow rate of 1 mL/min
at 180 °C. (b) Crude product from (a) in ethanol (0.2 M) was treated with 1.0 M NaOH(aq) [NaOH(aq) (0.25 v/v): product solution (0.75 v/v)]
for 3 h at RT.
back-pressure regulator was observed. Stable process temper-
atures were reached within seconds, and the wash-out volume
(3 mL, which corresponds to two reactor volumes) was the
limiting factor for sampling during optimization (see the
Supporting Information). The reactor itself proved easy to
clean,50 and one reactor could be used throughout the whole
study without any problems, including possible problems
related to potential catalytic contribution from any formed
palladium deposits.51 The good results achieved with SiC as a
CF reactor material with all of its advantages will further
broaden the applications of MW flow systems in the future.
The short residence times achieved with the SiC reactor are
comparable to the short residence times commonly observed
when using MW heating and borosilicate glass reactors.24,25
In summary, we have shown the design and application of a
SiC reactor for a MW heated CF system to avoid hot spot
formation problems related to running metal-mediated or
metal-catalyzed reactions in high density MW fields.
washed with saturated NaHCO3 solution (2 × 20 mL) followed
by brine. The organic phase was then dried over anhydrous
Na2SO3 before removal of the solvent under reduced pressure
to give 4.80 g of crude product as a pale yellow liquid (91%
crude yield). The crude product was used in the next step
without further purification.
Procedure, Synthesis of 5dm. A solution of 1n (0.3 M),
4d (1.5 equiv), DBU (1.5 equiv), and Pd(dppf)Cl2 (2%) in
DMF−water (95:5) was prepared and then pumped at a flow
rate of 1 mL/min through the 200 mm × 3 mm Øi SiC reactor
at a temperature of 180 °C for 50 min. The reaction mixture
was concentrated under reduced pressure at 40 °C, and the
residue was then diluted with ethanol (50 mL) and treated with
activated charcoal. The mixture was filtered through Celite, and
the Celite bed was further washed with ethanol (20 mL). The
combined filtrates were subjected to hydrolysis by adding 1.0 M
sodium hydroxide (aq, 18 mL) and stirring for 3 h at RT. The
reaction mixture was concentrated under reduced pressure, and
the residue was dissolved in water (60 mL) and washed with
diethyl ether (30 mL). The aqueous phase was acidified to pH
2 with 2.0 M HCl (aq) while maintaining a temperature below
20 °C to precipitate 5dm as a white solid. The solid was filtered
off and dried to yield 2.56 g (80%) of 5dm.
EXPERIMENTAL SECTION
■
General Procedure, MW Flow Mizoroki−Heck Reac-
tion with the SiC Reactor. A solution of aryl bromide (0.04
M), n-butyl acrylate (2 equiv), TEA (2 equiv), tri-tert-
butylphosphonium tetrafluoroborate salt (2%), and Herrmann’s
palladacycle (1%) in DMF was prepared and then pumped at a
flow rate of 0.5 mL/min through the 200 mm × 3 mm Øi SiC
reactor at a temperature of 190−210 °C. The crude reaction
mixture was concentrated and thereafter subjected to silica gel
column chromatography to yield the desired product.
ASSOCIATED CONTENT
■
S
* Supporting Information
Compound characterization data and copies of spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
General Procedure, MW Flow Suzuki−Miyaura Cross-
Coupling with the SiC Reactor. A solution of aryl bromide
(0.1 M), aryl boronic acid (1.5 equiv), DBU (1.5 equiv), and
Pd(dppf)Cl2 (2%) in DMF−water (95:5) was prepared and
then pumped at a flow rate of 1 mL/min through the 200 mm
× 3 mm Øi SiC reactor at a temperature of 180−240 °C. The
crude reaction mixture was concentrated and loaded upon silica
and thereafter subjected to flash column silica gel chromatog-
raphy using a i-hexanes−ethyl acetate gradient to yield the
desired product.
Procedure, Synthesis of Methyl Ester 1n. A solution of
1m (0.46 M) in 0.1 M methanolic HCl (prepared by taking 7.1
mL acetyl chloride to 1L total volume) was prepared and then
pumped at a flow rate of 1 mL/min through the 200 mm × 3
mm Øi SiC reactor at a temperature of 190 °C for 50 min. The
reaction mixture was concentrated under reduced pressure, and
the residue was then diluted with ethyl acetate (50 mL) and
AUTHOR INFORMATION
■
Corresponding Author
*Fax: (+46) 18 471 44 74. E-mail: mats.larhed@orgfarm.uu.se.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Knut and Alice Wallenberg Foundation for
financial support. We also want to express our gratitude to
Magnus Fagrell and Wavecraft AB for their help with the
fabrication of the SiC reactors.
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