Meso-scale microwave-assisted continuous flow reactions utilizing a selective heating matrix

Article abstract of DOI:10.1039/c3ra40783g

Convergence of two powerful synthetic tools, microwave heating and flow chemistry, is described herein. Utilizing a selectively heated, microwave absorbing material as part of a packed reactor bed, several chemistries such as N-Boc pyrolysis, Michael additions, and Diels-Alder cycloadditions were performed at elevated temperatures. Scale-up from microwave batch to flow was readily accomplished and results showed that flow greatly increased product output while maintaining high yields. Product quantities of over 150 grams per hour were synthesized in this manner.

Full text of DOI:10.1039/c3ra40783g

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Meso-scale microwave-assisted continuous flow
reactions utilizing a selective heating matrix3
Cite this: DOI: 10.1039/c3ra40783g
Michael J. Karney,a Keith A. Porter,b E. Keller Barnhardta and Grace S. Vanier*a
Convergence of two powerful synthetic tools, microwave heating and flow chemistry, is described herein.
Utilizing a selectively heated, microwave absorbing material as part of a packed reactor bed, several
chemistries such as N-Boc pyrolysis, Michael additions, and Diels–Alder cycloadditions were performed at
elevated temperatures. Scale-up from microwave batch to flow was readily accomplished and results
showed that flow greatly increased product output while maintaining high yields. Product quantities of
over 150 grams per hour were synthesized in this manner.
Received 12th December 2012,
Accepted 1st March 2013
DOI: 10.1039/c3ra40783g
www.rsc.org/advances
regulator (BPR) designed to maintain system pressure and
consistent flow rate. A variety of different vessel setups have
Introduction
been reported such as coiled reactors,10 U-tube shaped
vessels,11 capillary tubes,12 or standard microwave vessels
packed with glass beads or sand, creating a matrix of micro-
channels to promote reactant mixing.13 However, accurate
temperature control in microwave flow reactors can be
problematic, as systems predominately monitor reaction
temperature from the outside of the vessel by means of a
focused IR lens,14 leading to inaccuracy in measurement.
New technologies are constantly being developed to simplify
chemical processes. Among these developments, continuous
flow reactors have received a large amount of attention for their
ability to scale up reactions, increase reaction rates, and
automate the reaction process.1 Recent reactor setups are
becoming quite advanced; some examples include those
equipped with immobilized scavenger columns to simplify
product purification,2 catalyst-plated columns for cross-cou-
pling and gas addition reactions,3 and those which incorporate
ultrasound to break up precipitates and promote homogeneity.4
Microwave-assisted heating as applied to batch reactions is
another advancing technology that, unlike conventionally
heated batch reactions, can reach and hold high temperatures
Results and discussion
Flow reactor design
and pressures in
a rapid, efficient, and safe manner.
A
new microwave-assisted continuous flow reactor was
Microwave energy couples directly with absorbing molecules
in a reaction mixture, resulting in accelerated heating that has
been shown to increase yields, decrease reaction times, and
improve purity;5 a large variety of different reaction types have
been examined to date (metal-catalyzed reactions,6 nanopar-
ticle synthesis,7 sintering,8 etc). Combined with emerging flow
technology, the field of microwave-assisted, continuous flow
organic synthesis has increased in popularity because of its
rapid adaptation from batch to flow.9 General system designs
involve a pumping system which pushes starting materials
into a reaction vessel inside a microwave cavity. The reaction
mixture is rapidly heated and exits through a back pressure
developed with several advantages over previously reported
designs. Starting materials from two separate inputs were
pumped through high pressure pumps with individual flow
controls. After a T-fitting combined the separate flow paths,
the reactor utilized a modified 10 mL microwave vessel tapered
to a threaded inlet (Fig. 1). The temperature of the reaction
was monitored internally with a fiber optic probe protected by
a sapphire thermowell; placement of the fiber optic probe
inside the flow path permitted more precise control over the
reaction temperature and increased reproducibility between
runs by feedback into a temperature-dependent microwave
power control. An o-ring sealed the vessel to the attenuator
head, where the reaction mixture flowed towards collection.
Product was collected in an external vessel which was
connected to a BPR15 and pressurized using a standard tank
of argon or nitrogen controlled by a regulator. As the vessel
filled with solution, it was emptied by opening the evacuation
valve while system pressure and flow rate were maintained
using the gas tank. By removing a mechanical BPR from the
direct flow path, pressure spikes caused by the BPR failing and
aLife Science Division, CEM Corporation, P.O. Box 200, Matthews, NC, 28104, USA.
E-mail: grace.vanier@cem.com; Fax: +1 (704) 821-7894; Tel: +1 (800) 726-3331
bBusiness Development Division, CEM Corporation, P.O. Box 200, Matthews, NC,
28104, USA
Electronic supplementary information (ESI) available: experimental
3
procedures, pictures of reactor setup, select temperature and power graphs,
select NMR spectra, and two input reagent flow rates. See DOI: 10.1039/
c3ra40783g
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Scheme 1 Selected microwave-assisted flow reactions.
modal microwave synthesizer that was capable of delivering up
to 300 W of power.17 The working volume of the cell exposed to
microwave irradiation was approximately 5 mL when packed
with the matrix and a total reaction time of up to 25 min was
Fig. 1 Representation of continuous flow reactor and collection vessel.
recorded using an HPLC pump at 0.2 mL min21
.
An N-Boc deprotection,18 Michael addition,19 and Diels–
Alder reaction20 were studied (Scheme 1) to explore the
functionality of this new flow vessel design. These reactions
were well suited for this system because they have been
previously reported to work well under high temperature
conditions, and each reaction could provide a metric to assess
the performance of instrument features. Carbon dioxide
generation of the N-Boc deprotection would test the safe
handling of excess pressure. The inefficient microwave
absorbing characteristics of the N-Boc indole reaction solution
and some Michael addition substrates would demonstrate the
efficacy of the microwave absorbing matrix. Finally, the Diels–
Alder cycloaddition was previously performed in flow in the
literature, offering a benchmark to determine overall function
of the current system.
regulator fouling due to particulate or highly viscous solutions
were eliminated all while allowing excess pressure generated
from gas evolution to be safely removed.
To promote mixing and increase residence time, the flow
vessel was packed with a particulate matrix (Fig. 2). For this
study, either sand or a mixture of Fe3O4 powder and sand was
used. The iron oxide passive heating element was selected as a
cheap, easily available, and generally unreactive additive. Iron
oxide: (1) facilitated high temperatures because of strong
microwave absorbing characteristics and (2) selectively heated,
leading to instantaneous temperatures much higher than the
bulk temperature.16 A glass frit or cotton batting was placed
just above the threaded inlet to preventing clogging from
sand/iron oxide particles. The portion of the vessel that
received microwave irradiation was filled with the Fe3O4/sand
matrix while the top of the vessel was filled with sand only.
Microwave irradiation was delivered using a dedicated mono-
Thermal N-Boc deprotections in microwave batch and flow
t-Butoxycarbonyl (Boc) is a common protecting group for
amines.21 In some cases, thermal removal of the Boc moiety22
is an attractive alternative to acidic reagents required for
deprotection, which can potentially catalyze side reactions.
Details of the N-Boc deprotection of tert-butyl-1-indolecarbox-
ylate (1) are shown in Table 1. Batch reactions were carried out
in standard 10 and 35 mL sealed glass vessels with 4 and 14
mL of solution respectively. Solutions of 1 dissolved in
acetonitrile were heated to 180 uC for 10 min resulting in
complete conversion to indole (2; Table 1; entries 1 and 2). Any
attempt to heat the reaction above 180 uC or use more than the
described volume failed as these conditions generated
pressures over the 300 psi safety limit of the instrument.
Approximately three complete reaction cycles per hour were
achieved after ramp times were factored in,23 with the batch
methods furnishing 1.62 and 6.06 grams of product per hour
for the 10 and 35 mL reactions respectively.
Fig. 2 Reaction vessel assembly.
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Table 1 Results of N-Boc pyrolysis using microwave-assisted methodsa
Entry
Method (Rxn vol.)
T/uC
Flow rate (mL min21
)
Timeb (min)
Recoveryc (g)
Yield (%)
g h21
1
2
3
4
5
6
10 mL batch (4 mL)
35 mL batch (14 mL)
Flow (sand only)d
Flowd
180
180
120
220
220
220
—
—
0.8
0.8
2
10
10
6.25
6.25
2.50
1.00
0.54
2.02
—
5.80
0.49f
0.94g
99
99
1.62
6.06
—
5.8
14.7
28.2
,5e
90
Flowd
91
70
Flowd
5
a
b
c
d
Batch reaction conditions: Standard method; 180 uC. Total time at target temperature. Isolated product. Collection container was
e
f
pressurized with 240 psi of N2. As determined by GC-MS. A 4 mL aliquot of unpurified reaction mixture was removed for product isolation.
g
A 10 mL aliquot of unpurified reaction mixture was removed for product isolation.
In an effort to maximize the amount of isolated product per
hour, this reaction was then examined under continuous flow
conditions with only sand filling the flow cell. A solution of 1
dissolved in acetonitrile was pumped through the aforemen-
tioned microwave-assisted continuous flow reactor at a rate of
0.8 mL min21, but achieved a maximum temperature of only
120 uC and generated minimal product (Table 1; entry 3).
While both acetonitrile and 1 are moderate microwave-
absorbing compounds, they could not heat sufficiently in a
low vessel concentration (relative to sand) with a short
residence time. Replacing the sand matrix with a 10% w/w
mixture of Fe3O4 and sand24 allowed the reaction solution to
reach a maximum temperature of 220 uC;25 the configuration
of the indirect BPR allowed a safe release of excess pressure
generated by CO2 formation without a loss of product or
bubble formation. At the target temperature, this method
produced 5.8 g h21 of product in a 90% yield26 (Table 1; entry
4). Increasing the flow rate to 2 mL min21 improved the hourly
production to 14.7 g while no decrease in yield was seen
(Table 1; entry 5). At 5 mL min21, incomplete conversion was
observed by GC-MS, and though the isolated yield dropped to
70%, overall production of 2 increased to 28.2 g h21 (Table 1;
entry 6).
of only 183 and 142 uC respectively (Table 2; entries 1 and 2).
Despite production rates of 5.73 and 17.0 grams per hour for
both entries,27 the unsatisfactory conversions wasted copious
amounts of starting materials. Addition of iron oxide28 as a
passive heating element allowed the batch reaction to reach
the target temperature29 and consequently improved the
isolated yield to 91% and the gram per hour production of
b-alanine derivative 5 to 7.41 (Table 2; entry 3).
Direct adaptation of this reaction to a flow format proved to
be inefficient with a sand matrix (Table 2; entry 5), however
switching to a 10% w/w Fe3O4/sand matrix again allowed the
reaction solution to reach the target temperature, drastically
improving the production per hour while maintaining a good
yield (Table 2; entry 6); a comparable reaction time in a batch
format proved to be inefficient (Table 2; entry 4), resulting in
poor conversion. Increased flow rates were surveyed in the
production of 5 (Table 3; entries 2 and 3), with a noticeable
drop off in yield occurring at the most rapid flow rate.30
Despite this inefficient conversion to product, amine 5 was
still produced at a rate of 97.5 g h21. This survey of flow rates
was extended to primary amine and carbon nucleophiles, to
furnish products 9 and 10. The rapid heating and short
residence times of the microwave continuous flow system
worked to reduce undesired bis-addition product (Table 3;
entries 4–6) and pyrrolidine addition product (Table 3; entries
7–9). This correspondingly resulted in only a minor reduction
Michael addition in microwave batch and flow
The neat Michael addition between diethyl amine (3) and
methyl acrylate (4) was examined next. Since 3 and 4 possess
poor microwave absorptivity, reactions were performed using a
maximum amount of power (300 W) to reach the target
temperature (Table 2; entries 1–4). After 15 min, the 10 mL and
35 mL batch reaction vessels reached maximum temperatures
of yield at higher flow rates as compared to 1 mL min21
,
despite decreased reaction temperatures; b-alanine derivative
9 and ketoester 10 could be produced at an impressive rate in
excess of 165 g h21
.
Table 2 Comparison of batch and continuous flow microwave-assisted Michael additionsa
Entry
Method (Rxn vol.)
T/uC
Flow rate (mL min21
)
Timeb (min)
Recoveryc (g)
Yield (%)
g h21
1
2
3
4
5
6
10 mL batch (4 mL)
35 mL batch (14 mL)
10 mL batch (4 mL)d
10 mL batch (4 mL)d
Flow (sand only)e
Flowe,h
183
142
220
215
124
220
—
—
—
—
1
15
15
15
5
1.91
5.65
2.47
0.89
—
70
60
91
5.73
17.0
7.41
7.12
—
33
5f
,5g
87
1
5f
2.31i
34.6
a
b
c
d
Batch reaction conditions: Fixed power method; 300W; 220 uC control temperature. Total reaction time. Isolated product. 200 mg of
e
f
g
Fe3O4 was added to the reaction vessel. Collection container was pressurized with 240 psi of N2. Total time at target temperature. As
determined by GC-MS. Flow cell packed with 10% w/w Fe3O4/sand. A 4 mL aliquot of unpurified reaction mixture was removed for product
isolation.
h
i
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Table 3 Survey of Michael additions at varied flow rates
Entry
Product
T/uC
Flow rate (mL min21
)
Timea (min)
Recoveryb (g)
Yield (%)
g h21
1
2
3
220
220
185
1
2
5
5
2.5
1
2.31c
2.43c
1.30c
87
92
49
34.6
72.9
97.5
4
5
6
220
220
175
1
2
5
5
2.5
1
1.41d
1.29d
1.11d
75
68
59
42.3
77.4
167
7
8
9
220
220
197
1
2
5
5
2.5
1
2.37c
2.30c
2.25c
96
93
90
35.6
69
169
a
b
c
d
Total time at target temperature. Isolated product. A 4 mL aliquot of unpurified reaction mixture was removed for product isolation. A 2
mL aliquot of unpurified reaction mixture was removed for product isolation.
use of a microwave-absorbing matrix aided the cycloaddition
in another manner, possibly by contributing to a more
uniform and efficient heating gradient. Results of the flow
reactions were comparable to established literature for a
similar transformation in a microwave flow format.20a
Diels–Alder cycloaddition in microwave batch and flow
The final reaction studied in flow was the Diels–Alder
cycloaddition between diethyl acetylenedicarboxylate (6) and
furan (7). Compounds 6 and 7 were mixed in a 1 : 3 molar
ratio and heated (according to optimized conditions) to 150 uC
for 10 min in a microwave reaction vessel producing 8 in 73%
yield (Table 4; entry 1).31
Conclusions
The reaction was then examined under flow conditions.
Unlike the previous examples from Scheme 1, the superior
microwave absorptivity of 6 and 7 meant that the target
temperature could be reached without a passive heating
element (Table 4; entry 5). While there was a moderate drop
in yield,32 the automated nature of flow chemistry still resulted
in more product collected per hour. Using a Fe3O4/sand matrix
(Table 4; entry 6), the isolated yield increased to 70%, resulting
in 10.5 g h21 production of heterocycle 8. To confirm the
absence of a microwave heating or catalytic effect, reactions
were performed thermally (Table 4; entries 3 and 4) and with
Fe3O4 added (Table 4; entries 2 and 4). All reactions generated
approximately the same yield, suggesting that in this case the
A new microwave-assisted, continuous flow reactor has been
constructed. The device is equipped with a fiber optic probe
for temperature measurement in the flow path and
a
pressurized collection vessel with attached BPR, eliminating
the need for an in-line BPR. Simple pyrolysis, addition, and
cycloaddition reactions were performed in good to excellent
yields, achieving meso-scale formation of products in a semi-
automated flow process. An easily removable flow cell means a
variety of matrices ranging from passive heating elements to
heterogeneous catalysts can be used, providing a convenient
way to scale complex catalyzed reactions in future work.
Table 4 Comparison of batch and continuous flow microwave-assisted Diels–Alder cycloadditionsa
Entry
Method (Rxn vol.)
T/uC
Flow rate (mL min21
)
Timeb (min)
Recoveryc (g)
Yield (%)
g h21
1
2
3
4
5
6
10 mL batch (4 mL)
10 mL batch (4 mL)d
10 mL batch (4 mL)e
10 mL batch (4 mL)d,e
Flow (sand only)f
Flowf,g
150
150
150
150
150
150
—
—
—
—
0.5
0.5
10
10
10
10
10
10
1.74
1.79
1.71
1.64
8.6
73
75
72
69
60
70
7.0
7.2
6.8
6.6
8.6
10.5
10.5
a
b
c
d
Batch reaction conditions: Standard method; 150 uC. Total time at target temperature. Isolated product. 200 mg of Fe3O4 was added to
e
f
g
the reaction vessel. Reaction performed thermally. Collection container was pressurized with 240 psi of N2. Flow cell packed with 10%
w/w Fe3O4/sand.
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Acknowledgements
The authors would like to thank Ed Thomas of CEM
Corporation for assistance with reactor and collection vessel
design.
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23 The total cycle time including heating ramp and cool down
was approximately 20 min. Therefore, 3 cycles could be
completed in an hour.
24 Higher concentrations of iron oxide resulted in more rapid
heating to the target temperature, but not additional
product formation.
25 Temperatures in excess of 220 uC resulted in an inaccurate
flow rate due to bubble formation in the product flow line.
26 Quantitative conversion of starting material to product was
determined by GC-MS, however the isolated yield was not
quantitative. TLC visualization of the crude reaction
mixture showed an unidentified baseline compound that
was easily removed with a plug of silica.
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27 The total cycle time including cool down was approxi-
mately 20 min. Therefore, 3 cycles could be completed in
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28 200 mg of iron oxide was the maximum amount that could
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29 Table 2, entry 3 remained at 220 uC for approximately 10
min.
30 Due to rapid flow rate and short residence time, reaction
solution collected at 5 mL min21 did not reach the target
temperatures. Additionally, the viscosity of the mixture and
rapid flow rate contributed to significant Fe3O4 leaching,
reducing the heating ability of the flow cell matrix. This
was seen for the three Michael addition reactions.
31 The total cycle time including heating ramp and cool down
was approximately 15 min. Therefore, 4 cycles could be
completed in an hour.
32 This can be attributed to the reduced time the starting
materials spend at reaction temperature in the continuous
flow set up as the temperature is most likely lower at the
extreme ends of the flow cell.
RSC Adv.
This journal is ß The Royal Society of Chemistry 2013