Organic Process Research & Development 2008, 12, 41–57
Approaches for Scale-Up of Microwave-Promoted Reactions
¶
Matthew D. Bowman, Jennifer L. Holcomb, Chad M. Kormos, Nicholas E. Leadbeater,* and Victoria A. Williams
Department of Chemistry, UniVersity of Connecticut, 55 North EagleVille Road, Storrs, Connecticut 06269-3060, U.S.A.
Abstract:
number of different reactions.6–13 The drawbacks of a continu-
ous-flow microwave apparatus are that it can be difficult to
process solids, highly viscous liquids, or heterogeneous reaction
mixtures. Also, adaptation of conditions from simple small-
scale reactions to the continuous-flow cell could end up being
time-consuming. The other option is to use a batch-type process.
In this report, we look at a range of classes of reaction involving
microwave heating and show how different processing techniques
can be used to address scale-up needs. We look at both batch and
continuous-flow processing. We have shown that when using batch
methodologies working using an open reaction vessel offers
operational advantages while still giving good yields of desired
products. In cases where open-vessel conditions are not amenable
or where particularly volatile or toxic reagents are used, parallel
sealed vessels can offer an alternative approach. For continuous-
flow processing, homogeneity of the reaction mixture is key. When
the mixture is homogeneous, it is possible to move from small-
scale sealed-vessel conditions to the continuous-flow apparatus
without any modification of reaction conditions or loss in product
yield. When either the starting materials or the product mixture
contains particulate matter, continuous processing can prove a
challenge, but reoptimization of reaction conditions as well as
reduction of the concentration may allow these difficulties to be
overcome.
14–20
This could either involve using one large vessel
or parallel
21–23
batch reactors.
One of the key advantages of batch process-
ing is that heterogeneity does not prove an issue. However, there
are problems when moving to larger and larger batch reactors
due to the limited penetration depth of microwaves into the
sample. Indeed, depending on the reaction mixture, microwave
penetration is usually in the order of just a few centimeters.
There are two main categories of scientific microwave
apparatus. Monomode microwave units have been used with
great success for small-scale reactions using sealed glass tubes
up to a working volume of approximately 50 mL or open round-
(
4) For a discussion of scale-up of microwave-assisted organic synthesis,
see: Roberts, B. A.; Strauss, C. R. In Lidström, P., Tierney, J. P.,
Eds.; MicrowaVe-Assisted Organic Synthesis; Blackwell: Oxford, 2005.
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2
653.
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Introduction
(
(
6) For a recent review, see: Kappe, C. O.; Glasnov, T. N. Macromol.
Rapid Commun. 2007, 28, 395.
The use of microwave heating as a tool for preparative
chemistry is continuing to grow. By using microwave irradiation
it is often possible to reduce reaction times significantly as well
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1–3
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as improve product yields. The vast majority of the publica-
tions in the area of microwave-promoted organic synthesis relate
to small-scale chemistry. Within the chemical industry, the
technology is well established at the discovery level, and
potential drug candidates are being prepared using microwave
heating in at least one step. An area of increasing research
interest now is the scale-up of microwave-promoted chemistries.4,5
This clearly is an area that needs to be addressed if the
technology is going to impact process chemistry. There are two
possible scale-up options. The first is to use a continuous-flow
microwave cell, this technology being used successfully for a
4
52.
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(
(
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*
Corresponding author. E-mail: nicholas.leadbeater@uconn.edu.
Major contributor to this study.
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Guzman, M. C.; Hananel, M. A.; Kornreich, W. D.; Li, H.; Pathak,
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¶
(
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(
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4
3, 6250.
(
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0.1021/op700187w CCC: $40.75
2008 American Chemical Society
Vol. 12, No. 1, 2008 / Organic Process Research & Development
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Published on Web 11/10/2007