the penetration depth is in the order of a few centimeters,
depending on the dielectric properties of the medium.
Scheme 1. 2-Methylbenzimidazole formation from
o-phenylendiamine
9
As a consequence of the apparent limitations of large-scale
batch microwave processing, recent efforts have focused on
performing microwave chemistry under continuous flow
5,10,11
conditions.
The typically short reaction timessin the order
Scheme 2. 3,5-Dimethyl-1-phenylpyrazole formation
of a few minutes or even secondssexperienced in high-
temperature microwave chemistry protocols form an ideal basis
for continuous flow processing where short residence times are
essential. Using either single-mode or multimode microwave
instruments, successful examples of microwave-assisted con-
tinuous flow processing have been reported in the literature
10,11
Scheme 3. Diels-Alder cycloaddition of
using a variety of different formats.
Applying a flow regime,
2
,3-dimethylbutadiene with acrylonitrile
many of the advantages of small-scale microwave heating (rapid
heating and cooling) are reinstated, with limited penetration
10,11
depths typically not being an issue.
However, because of
the comparatively low pressure limits of commercially available
7
14
microwave flow systems (∼20 bar), genuine high-temperature/-
changing improvements. The idea to deliberately explore, for
example, high-temperature/high-pressure or otherwise very
unusual process conditions for process intensification of chemi-
cal reactions is a recent concept termed “Novel Process
pressure processing is generally not possible.
In this contribution we evaluate the scale-up efficiencies for
several synthetic transformations executed at high temperature,
comparing batch microwave protocols with continuous flow
procedures that employ a conventionally heated high-temper-
ature/-pressure microreactor setup (350 °C/180 bar). Because
of the high surface-to-volume ratio in microreactors of this type,
heat transfer to the reaction mixture is very efficient, thus
mimicking the advantages of using microwave dielectric heating
15
Windows”. Here, the general notion is to operate at conditions
which considerably speed up conversion rates, while maintain-
ing selectivity. In order to evaluate the differences between batch
microwave and continuous flow processing in a high-temper-
ature regime, three model transformations were selected (Schemes
, 2, and 3). As a significant limitation of current continuous
flow/microreactor technology suitable for organic synthesis is
the more or less strict requirement for homogeneity,
1
12,13
on a small scale.
12,13
only
transformations were chosen that were completely homogeneous
and did not lead to direct product precipitation at the end of
the synthesis. In order to enable a high throughput in the flow
experiments, all reactions were initially optimized for the
shortest possible reaction time using different single-mode
microwave reactors on a millimolar scale. In a subsequent step,
these conditions were translated to a larger scale (∼200 mmol)
employing a multimode parallel batch microwave reactor
Results and Discussion
General Considerations. In the past few years, the chemical
industry has started to explore different means of so-called
“Process Intensification” technologies which demand abrupt
changes in traditional processing and a search for game-
(
9) (a) Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B. S.; Mingos,
D. M. P. Chem. Soc. ReV. 1998, 27, 213–224. (b) Horikoshi, S.; Iida,
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16
(Synthos 3000, Anton Paar GmbH), before ultimately being
adapted to a continuous flow regime which by definition has
1
2, 257–263.
17
the potential of production-scale capabilities.
(
10) Reviews: (a) Baxendale, I. R.; Hayward, J. J.; Ley, S. V. Comb. Chem.
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multivessel rotor system as compared to one large vessel) was
governed by penetration depth issues. With a typical penetration
(
11) For selected recent examples, see: (a) Moseley, J. D.; Lawton, S. J.
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Vol. 14, No. 1, 2010 / Organic Process Research & Development