Organic Process Research & Development
Article
Figure 1. Design of previously reported CSTR-type reactors for CH2N2 synthesis and extraction into nitrogen gas (left) compared with the plug
flow reactor (PFR)-type design that is the subject of this article (right). In the PFR design, the tubing diameter is large enough to allow the gas to
bypass the liquid, allowing it to experience a shorter residence time in the reactor.
this approach is appealing, the tubing needed is not widely
available. To the best of our knowledge, this concept has not
been extended beyond a laboratory demonstration.
we opted to use MNTS for our process. Anhydrous MNTS
suffers from thermal instability and can only be shipped in
small quantities due to its low self-accelerating decomposition
temperature, but it has been determined that bulk quantities
up to 50 kg can be safely handled and stored by preparing
MNTS wetted with 10−15% w/w water.11
Two examples of diazomethane synthesis that are reported
on a kilogram scale and beyond use an approach similar to
codistillation, but instead of using solvent vapor to carry the
diazomethane away from the preparation reaction mixture, the
diazomethane is extracted using a nitrogen sweep or
sparge.11,12 This approach can be performed using nonflam-
mable solvents such as DMSO, and the nitrogen flow rate can
be selected to keep the diazomethane headspace concentration
below the lower explosive limit (LEL). In both cases, the
reagents needed to prepare CH2N2 are mixed in an
overflowing vessel analogous to a continuous stirred tank
reactor (CSTR) enclosed within a larger vessel that is purged
with nitrogen (Figure 1). In one case, the large volume of the
reactor required the authors to perform a test to ensure that a
detonation within the reactor would not cause it to rupture.
Whereas the approach of gas−liquid extraction is attractive
because it allows access to high-quality diazomethane while
also avoiding the use of flammable solvents, the previously
reported reactor designs had a large headspace volume.
Minimizing headspace is a guiding principle for designing
systems with hazardous gaseous reagents, as a smaller
headspace will reduce the consequences in the event of a
violent decomposition of diazomethane. Herein, we present a
scalable reactor design to continuously produce and consume
diazomethane suitable for metal-catalyzed cyclopropanation
reactions. This reactor is based on a tubular reactor design that
provides safety advantages over the CSTR designs previously
reported (Figure 1), chiefly by operating with a much smaller
headspace volume.
A high-boiling solvent is required to avoid solvent
evaporation during the process of extracting diazomethane
into the gas phase from the aqueous/organic solvent system.
Though we drew inspiration from the DMSO solvent system
reported by Proctor and Warr,11 we elected to use sulfolane in
place of DMSO to avoid thermal instability issues that have
been recently reported in the literature.14 Various composi-
tions of sulfolane/H2O were examined, aiming for high
solubility and stability of MNTS in solution. The 95:5 (w/
w) mixture of sulfolane and H2O, a liquid at room
temperature, is a suitable solvent for MNTS at concentrations
up to 20% w/w and is stable up to 4 days when stored as a
solution at 2−8 °C without appreciable decomposition of the
reagent by high-performance liquid chromatography (HPLC)
1
or H NMR spectroscopy. Compared to the process reported
by Proctor and Warr, we also increased the concentration of
the KOH solution to reduce the amount of water in the
reaction mixture. This change made the process less prone to
crystallization in the reactor, a major challenge in earlier work
with diazomethane synthesis performed in our laboratories.
Reactor Design. Our reactor design is based on a coil of
relatively large diameter (1/4 in. i.d.; 3/8 in. o.d.) PFA tubing
oriented so that the axis of the coil is parallel to the ground,
like a wheel (Figure 2). This configuration allows for a gas to
advance through the reactor more quickly than the liquid by
bubbling through liquid-phase slugs at the bottom of the coil.
In one reported example, the liquid residence time was 3 times
longer than the corresponding gas phase (4 h for the liquid
phase versus 1.3 h for gas phase).15 We reasoned that this
effect would be beneficial for diazomethane synthesis because a
longer liquid residence time would allow more time for MNTS
to react, whereas a short gas residence time would allow the
unstable CH2N2 product to be removed from the reactor
quickly, minimizing decomposition. In our process, nitrogen
was used to extract the gaseous diazomethane from the liquid
medium. We took advantage of the same vertical tubing coil
reactor design for the downstream chemistry, which requires
the CH2N2 to be extracted from the gas phase into the liquid
phase. Photographs of the two reactors are shown in the
RESULTS AND DISCUSSION
■
Choice of Reagents and Solvent. Diazomethane can be
synthesized from several precursors, but N-methyl-N-nitroso-p-
toluenesulfonamide (MNTS) is attractive for gas-phase
extraction of CH2N2 due to its low vapor pressure (eq 1).1b
MNTS is also significantly less toxic than alternative precursors
derived from urea and guanidine.13 Given the concerns of
handling these materials and introducing trace quantities of
toxic N-nitroso compounds into the product of the reaction,
The reactor mixes the liquid reaction mixture with a
nitrogen carrier gas that serves three purposes. First, the carrier
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Org. Process Res. Dev. 2021, 25, 522−528