Communications
DOI: 10.1002/anie.201101977
Microreactors
Continuous In Situ Generation, Separation, and Reaction of
Diazomethane in a Dual-Channel Microreactor**
Ram Awatar Maurya, Chan Pil Park, Jang Han Lee, and Dong-Pyo Kim*
Performing organic transformations with toxic, sensitive, and
explosive volatile chemicals or gaseous intermediates has
always been challenging both in academia and industry.
Although the experience of various ill-effects or accidents is
not uncommon among those working with these chemicals,
most of the events remain unpublished unless large disasters
occur.[1] It is, therefore, not surprising that recently much
attention has been focused on developing safe or sustainable
routes to produce such invaluable reagents as ozone, hydra-
zoic acid, diazomethane, and hydrogen cyanide.[2]
Diazomethane, an extremely toxic, carcinogenic, odorless,
and explosive yellow gas,[3] is one of those most versatile
reagents available to the organic chemists for the preparation
of carbon–carbon and carbon–heteroatom bonds.[4] Despite
its interesting and versatile chemistry, use of diazomethane on
laboratory or pilot-plant scale is considered quite problematic
owing to the well-known safety concerns associated with its
preparation, separation, purification, transportation, and
decomposition.[3,4] Even when diazomethane can conven-
iently be generated under mild conditions by treating a
suitable precursor with an alkaline base, efficient separation
and proper purification of the prepared diazomethane for the
subsequent reaction is required owing to the chemical
vulnerability in the presence of alkaline bases and water or
alcohol impurities. Routine separation processes, such as
distillation, are certainly inappropriate for toxic gases.
Furthermore, the extraction and transportation of highly
reactive gaseous substances even using an inert gas (such as
N2) are also very risky, with possible leakage or detonation.
Ideally, it would be highly desirable to have a total reaction
system that self-contains a toxic and explosive material, and in
which the reagent is self-generated and then separated within,
and in turn consumed for the formation of the desired
product, all within the reaction system.
Microfluidic chemical systems are the most promising
tools to miniaturize the inventory of such toxic and explosive
substances owing to their extremely small internal volume
and continuous consumption capability.[5] Herein, we present
a concept and method in the form of a microchemical chip
based on a dual-channel microreactor[6] that enables self-
generation of the toxic and explosive reagent within, its
efficient separation, and subsequent reaction to yield desired
products, all within the same closed flow system (Figure 1).
The reaction system is validated with reactions involving
diazomethane. The unprecedented triple role of generation/
separation/reaction that is played by the reaction system is all
the more attractive in that the toxic and explosive reagent is
not only contained solely within the system but also is not
accumulated within, thus leaving no trace of the toxic material
after the desired product is obtained.
Recently, we presented a poly(dimethylsiloxane) (PDMS)
microreactor for oxidative Heck reactions in which two
parallel channels were separated by a thin PDMS mem-
brane.[6] PDMS membranes have also been utilized in various
separation devices, site isolation, and cascade reactions
because most small organic molecules have high flux rate
through the membrane whereas water and ionic salts are
blocked completely.[7] It is anticipated, therefore, that diazo-
methane could be selectively transported through the PDMS
membrane from the aqueous saline channel containing water
and KOH and other salts, where it is generated, to the other
channel above the membrane for subsequent organic reac-
tion. Thus, a proper microfluidic design of two parallel
channels separated by a membrane layer could be employed
for simultaneous generation, separation, and reaction of
diazomethane. This concept of a PDMS dual-channel micro-
chemical system is shown in Figure 1. Diazald (N-methyl-N-
nitroso-p-toluenesulfonamide) quickly reacts with KOH to
generate diazomethane in the bottom channel, the Diazo-
methane readily diffuses out to the upper channel where it
reacts with main reactant. The PDMS membrane, which is
extremely hydrophobic, prevents the diffusion of KOH,
water, and potassium p-toluenesulfonate from the bottom
channel to the upper channel. Similarly, the organic reactants
or the products from the reaction with diazomethane in the
upper channel have little tendency to diffuse into the aqueous
saline phase in the lower channel.
[*] Prof. Dr. D.-P. Kim
National Creative Research Center of Applied Microfluidic
Chemistry, Graduate School of Analytical Science and Technology
Chungnam National University, Daejeon, 305-764 (South Korea)
Fax: (+82)42-823-6665
E-mail: dpkim@cnu.ac.kr
Dr. R. A. Maurya,[+] Dr. C. P. Park,[+] J. H. Lee
National Creative Research Center of Applied Microfluidic
Chemistry
Chungnam National University, Daejeon, 305-764 (South Korea)
[+] Both authors contributed equally to this work.
To test the selective and efficient separation of thus-
generated diazomethane through a thin PDMS membrane, a
bulk reaction was firstly conducted (Supporting Information,
Figure S2, S3). The results were generally dependent on the
solvents used for the interior and exterior of the membrane
[**] This work was supported by a National Research Foundation of
Korea (NRF) grant funded by the Korean government(MEST) (No.
2008-0061983).
Supporting information for this article is available on the WWW
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 5952 –5955