Organic Process Research & Development 2005, 9, 787−791
Grignard Exchange Reaction Using a Microflow System: From Bench to Pilot
Plant
Hideo Wakami and Jun-ichi Yoshida*,‡
†
The Research Association of Micro Chemical Process Technology (MCPT) and Department of Synthetic Chemistry and
Biological Chemistry, Graduate School of Engineering, Kyoto UniVersity, Nishikyo-ku, Kyoto 615-8510, Japan
Abstract:
tremely fast and highly exothermic reactions. In some cases,
product selectively can be enhanced signficantly by the use
of microflow systems. Easy numbering-up of microsystems
The Grignard exchange reaction of ethylmagnesium bromide
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(EtMgBr) and bromopentafluorobenzene (BPFB) to give pen-
tafluorophenylmagnesium bromide (PFPMgBr) was carried out
using small- and medium-scale microflow systems consisting
of a micromixer and a microheat exchanger. The results indicate
that the microflow systems are quite effective. On the basis of
the data obtained, a pilot that involves the Toray Hi-mixer
connected to a shell and tube microheat exchanger was
constructed. Continuous operation for 24 h was accomplished
without any problem to obtain pentafluorobenzene (PFB) after
protonation (92% yield).
for increasing the amount of production are also beneficial
from the viewpoint of industrial production.
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Thus, we envisioned that the use of a microflow system
solves the problem associated with the application of
Grignard exchange reactions to industrial production. Herein,
we report the results of our study on the Grignard exchange
reaction using microflow systems.
We focused on the reaction of ethylmagnesium bro-
mide with bromopentafluorobenzene (BPFB) to give pen-
tafluorophenylmagnesium bromide (PFPMgBr) (Scheme 1).9
PFPMgBr has been produced by this method in industry,
because it is difficult to prepare by the direct method using
1
. Introduction
Grignard reagents are useful reagents in organic syntheses
1
and are widely utilized in laboratory syntheses and industrial
production of fine chemicals. Although Grignard reagents
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2
are usually prepared by the reaction of organic halides with
magnesium metal, Grignard exchange reactions (halogen-
magnesium exchange reactions) are sometimes used for
Grignard reagents that are difficult to prepare by the direct
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3
method. Because Grignard exchange reactions are usually
very fast and highly exothermic, they are difficult to control,
especially in large-scale syntheses. Usually, slow addition
has been used to avoid rapid temperature increase. Therefore,
efficient heat removal has been a crucial point for industrial
applications of this useful reaction.
1
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Recently, microflow systems have been utilized for chem-
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These features are quite advantageous for conducting ex-
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*
Author for correspondence. E-mail: yoshida@sbchem.kyoto-u.ac.jp.
MCPT. Present Address: Nippon Shokubai.
Department of Synthetic Chemistry and Biological Chemistry.
†
‡
(
(
(
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2
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0.1021/op0501500 CCC: $30.25 © 2005 American Chemical Society
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Published on Web 10/01/2005