A Microreactor for MACOS
A R T I C L E S
geous if these reactions could be carried out at higher temper-
atures using microwave heating in a continuous flow, or stop
5
flow manner. During the course of our research, two methods
for continuous flow heating using microwaves on a microscale
have been published. One of these methods involved irradiating
a glass microreactor block placed in the cavity of a focused
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microwave and the second involved a U-shaped capillary with
a heterogeneous catalyst loaded on a solid support at the bottom
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of the U. Both methods involved coating the outside surface
of the reacting chamber with a gold film, which means that the
heating used was to a large extent heat exchange and not direct
heating of the solvent per se. In the case of the U-tube, the
solid supported catalyst had to be held in place with the aid of
a small glass rod inside of the U-tube to prevent it from being
simply washed out.
Herein, we report a new approach to organic synthesis that
consists of flowing a reaction through a short, straight capillary
that sits in a microwave synthesizer. This very simple method
combines the rate enhancement enjoyed by working in micro-
channels with microwave irradiation to expand the scope of
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reactions that can be conducted in a microreactor device. From
a practicality point of view, the capillaries involved are actually
just simple spotting tubes, available in any chemical laboratory
and requiring no special fabrication. Each “reactor” costs
fractions of a penny each and therefore there is no need to
attempt recovery or even reuse them, although we have done
so for demonstration purposes in our own chemistry.
Figure 1. Continuous flow MW microreactor schematic.
gave complete conversion to product. On the basis of this result,
we set out to examine Suzuki-Miyaura couplings under flow
conditions while varying a number of parameters (Table 1).
For our initial flow experiment (Table 1, entry 1) we repeated
the sealed capillary reaction between 1 and 2 with (PPh3)4Pd
Results and Discussion
The basic continuous flow reactor design (Figure 1) consists
of a stainless steel holding/mixing chamber with three inlet ports
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catalyst. The formation of 3 illustrated that the reaction mixture
picked up sufficient MW irradiation under continuous flow
conditions to drive the cross-coupling to a significant extent,
even with THF as solvent, which is known to be a poor
(in this case) that merge into one outlet. The inlets are con-
nected via Microtight fittings and Teflon tubing to an external
syringe pump(s). Capillary tubes of varying internal diameters
(200-1150 µm) can be interchangeably attached to the holder
1
a
absorbent of MW irradiation. When the reaction was per-
formed under identical flow conditions except no MW irradia-
tion was applied, no conversion took place (entry 2). Thus, in
this case, there appears to be no stand-alone rate acceleration
effect from the capillary itself. Full conversion of 1 to 3 was
realized by reducing the flow rate, which even allowed the
reaction to be run at a lower power setting (entry 3), a point
more fully demonstrated in Table 4. Reducing the flow rate,
we believe, simply allows kinetically slower reactions to
experience the irradiation for a longer time period on their trip
through the capillary.
The coupling of 4-bromobenzaldehyde (6) to phenylboronic
acid (7) (entries 5 to 8) proved to be noteworthy. When the
reaction was run with potassium carbonate base in DMF, the
biaryl product 8 was formed in poor conversion (entry 5).
Interestingly, when potassium hydroxide base was used, all other
parameters being unaltered, the palladium catalyst “blacked out”
during the reaction and coated the capillary wall with a thin
by Microtight fittings. After exiting the reaction capillary, the
reaction flows by Teflon tubing directly to a monitoring device
or collection vessel. The holder sits atop of the MW cavity of
a Biotage Smith Creator Synthesizer, thus the capillary is kept
in place within the irradiation chamber. The capillary is
irradiated with 2.45 GHz of single mode microwave power that
can be varied between 0 and 300 W, while the reaction
temperature is monitored by the internal IR sensor.
One of the perceived problems of MW heating in micro-
channels is that the narrow vessels lead to reaction volumes
too small to absorb the MW irradiation, especially in a flow
situation, where the solution is in the irradiation chamber for
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only a very short time. To examine this, we explored the
Suzuki-Miyaura coupling between 4-iodooct-4-ene (1) and
4-methoxyboronic acid (2) in a sealed 200 µm diameter capillary
tube that was placed inside of conventional microwave reaction
vial and irradiated.10 Relative to a control capillary that was
not irradiated and showed no conversion, the irradiated tube
(
10) A stock solution containing a solution of 1, 2 (1.1 equiv), TBAF-THF (5
(
5) We are aware of a large-scale, continuous flow microwave cell capable of
performing multigram synthetic transformations, see: Wilson, N. S.; Sarko,
C. R.; Roth, G. P. Org. Process Res. DeV. 2004, 8, 535-538.
2
equiv), and Pd(OAc) (5 mol %) was drawn into a capillary tube with a
200 µm inner diameter. The tube was sealed and placed in a standard MW
vial, and the Biotage Smith Synthesizer MW was set at 100 °C for 900 s
1
(
(
6) He, P.; Haswell, S. J.; Fletcher, P. D. I. Lab Chip 2004, 4, 38-41.
7) He, P.; Haswell, S. J.; Fletcher, P. D. I. Appl. Catal., A 2004, 274, 111-
to provide 100% conversion to 3 by H NMR spectroscopy.
(11) These and subsequent reactions were all performed with an MD-2000 Digital
Readout microwave leakage detector directly focused on the microwave
cavity (top and bottom) and the top of the microwave device including the
inlet lines from the syringes to monitor any stray MW irradiation. Irradiation
levels were found to well below acceptable safety standards.
1
14.
(
8) Organ, M. G.; Comer, E. U.S. Provisional Patent 60/605,505, 2004.
9) Organ, M. G. Personal communications with microwave designers and
engineers at Biotage Inc., Upsalla, Sweden.
(
J. AM. CHEM. SOC.
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VOL. 127, NO. 22, 2005 8161