Multijet oscillating disc millireactor: A novel approach for continuous flow organic synthesis

Article abstract of DOI:10.1021/op2000699

This report discloses proof of concept and experimental results from a project involving design, development, and investigation of a novel approach for flow chemistry and the realization of equipment operating according to this new approach. This device is named multijet oscillating disk (MJOD) reactor and is dedicated to continuous flow organic synthesis in milliscale. Characteristics such as the importance of the multijet disk unit, with or without oscillating, and possible limitations, such as back-mixing, have been explored, and the flow system is benchmarked with other technologies. Several well-known reactions and syntheses usefully both in the chemical industry as well as in the research laboratory have been conducted using the new system, which have been benchmarked with batch- and microreactor protocols. In particular the Haloform reaction, the Nef reaction, nucleophilic aromatic substitution, the Paal-Knorr pyrrole synthesis, sodium borohydride reduction, O-allylation, the Suzuki cross-coupling reaction, the Hofmann rearrangement and N-acylation were performed during the study of the MJOD reactor performance. Our investigations revealed that the MJOD millireactor system can produce various organic compounds at a high rate concomitant with an excellent selectivity. A Hofmann rearrangement was conducted, a reaction that involves handling of a slurry of the substrate. This reaction was successfully conducted, achieving a quantitative conversion into the target molecule.

Full text of DOI:10.1021/op2000699

ARTICLE
pubs.acs.org/OPRD
Multijet Oscillating Disc Millireactor: A Novel Approach for
Continuous Flow Organic Synthesis
†
,†,‡
Lucia Liguori and Hans-Ren ꢀe Bjørsvik*
†
Fluens Synthesis, Thormøhlensgate 55, N-5008 Bergen, Norway
‡
Department of Chemistry, University of Bergen, All ꢀe gaten 41, N-5007 Bergen, Norway
ABSTRACT: This report discloses proof of concept and experimental results from a project involving design, development, and
investigation of a novel approach for flow chemistry and the realization of equipment operating according to this new approach. This
device is named multijet oscillating disk (MJOD) reactor and is dedicated to continuous flow organic synthesis in milliscale.
Characteristics such as the importance of the multijet disk unit, with or without oscillating, and possible limitations, such as back-
mixing, have been explored, and the flow system is benchmarked with other technologies. Several well-known reactions and
syntheses usefully both in the chemical industry as well as in the research laboratory have been conducted using the new system,
which have been benchmarked with batch- and microreactor protocols. In particular the Haloform reaction, the Nef reaction,
nucleophilic aromatic substitution, the PaalÀKnorr pyrrole synthesis, sodium borohydride reduction, O-allylation, the Suzuki cross-
coupling reaction, the Hofmann rearrangement and N-acylation were performed during the study of the MJOD reactor
performance. Our investigations revealed that the MJOD millireactor system can produce various organic compounds at a high
rate concomitant with an excellent selectivity. A Hofmann rearrangement was conducted, a reaction that involves handling of a slurry
of the substrate. This reaction was successfully conducted, achieving a quantitative conversion into the target molecule.
’
INTRODUCTION
in continuous flow as an alternative to the customary batch
protocols, that is the laboratory flask in the laboratory and the
stirred tank reactor in industry. Various microreactor platforms
The past decade brought a paradigm shift in organic synth-
esis by the introduction of flow chemistry in terms of micro-
reactor technology. The microreactor technology provides a
substantially improved heat- and mass-transfer performance
compared to the traditional batch technology by means of the
round-bottom flask in the laboratory and the stirred tank
reactor in the pilot- and full-scale industrial plants. Flow
chemistry has conquered both the field of academic synthesis
research and the industrial organic process research and devel-
opment. Moreover, within the fine chemical and pharmaceu-
tical ingredients production, the technology has exposed a
number of advantages compared with the traditional batch
4
are commercially available from a series of suppliers.
Two distinct classes of microreactors have been developed,
namely the micro-structured reactors finding application in
organic process chemistry and the chip-based microreactors that
5
usually are utilized for academic research purposes. Microreac-
tors are made of miniaturized channels embedded in a flat surface
6
7
8
made of glass, silicon, stainless steel, or even certain polymers,
9
for example polydimethylsiloxane.
Glass is the most customary material used for the manufac-
turing of equipment for chemistry purposes due to its resistance
towards various solvents, acids, bases, and other reagents.
Silicon shows optimal thermal conductivity and heat-transfer
capacity and possesses properties similar to those of glass when
it is in the oxidized form, and for those reasons, it is much
employed in reactions conducted both at high and low
1
processing methodology. The growth of the microreactor
technology brought also a new way of thinking regarding the
implementation of synthetic processes from the process labora-
tory and pilot plant to full-scale production. In principle, a fully
developed organic synthesis or process achieved from the
development laboratory can be transferred directly to the
production environment facilitated by the concept of num-
7
temperatures. Stainless steel is the favorite material for micro-
reactors that are applied for process chemistry purposes,
especially for the use in pilot plant and for the purpose of fine
chemical production with a battery of microreactors running in
parallel. Microreactors manufactured of polymers have re-
stricted performance due to the low tolerance (the most used
polymer) towards the most reagents and solvents, but examples
involving reactions performed at atmospheric pressure in aqu-
2
ber-up instead of sizing-up during the scale-up step.
During recent years, the fine chemical and the pharmaceutical
industries have exposed a noticeably and continuously growing
demand for environmental benign syntheses and processes that
3
are synthetic protocols providing target molecules in high
selectivity and yields concomitant with low production of
effluents and minimized need and use of toxic or hazardous
reagents. In addition to the impressive innovative development
of such synthetic reactions and catalytic processes, a new kind of
equipment, today known as microreactor technology, was devel-
oped and introduced as an excellent tool for conducting synthetic
reactions. Microreactors allow one to perform organic synthesis
1
0
eous medium are reported.
Microreactors have steadily conquered new areas of application
5
within both academic and organic process research; examples are
Received: March 18, 2011
Published: July 04, 2011
r 2011 American Chemical Society
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Organic Process Research & Development
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11
demonstrated for the MoffattÀSwern oxidation, for a dibal-H
reduction process for the production of butyraldehyde from
1
2
13
methyl butyrate, the BaylisÀHillman reaction, the KolbeÀ
1
4
Schmitt synthesis, in an ozonolysis process of acetic acid 1-vinyl-
hexyl ester, in the synthesis of 1,2-azoles, for the addition
of secondary amines to nitriles and unsaturated carbonyl com-
1
5
16
1
7
pounds and for the MizorokiÀHeck reaction with a low-
18
19,20
7
viscosity ionic liquid for nitration,
and in glycosylation.
This list of reports concerning flow chemistry in organic synthesis
and processes is not exhausting, but demonstrates the general
utility of various flow systems. Several moreexamples can be found
21À25
in some recent reviews.
Even if microreactor technology possesses outstanding proper-
ties as a tool for conducting synthetic reactions, several funda-
mental constraints exist: (1) reactions that involve two phases,
liquidÀsolid, represent a crucial limitation for the microreactors
since solid particles can block the network of the tiny channels of
the microreactor, (2) synthetic reactions that require the presence
of a solid catalyst necessitate the catalyst being present in the form
of cartridges embedded inside the reactor, placed in miniaturized
poles in the reactor channels, or embedded in the microreactor
Figure 1. Three-dimensional drawing of the MJOD millireactor (left)
shows the four various sections: (1) the input (base) section, (2) the
reactor body, (3) the output section, and (4) the oscillator unit. A
fraction of the reactor body (the heat exchanger chamber) is enlarged
and shown in transparent view (right) illustrating the reactor tube placed
in the centre of the heat exchanger. The multijet oscillating disk assembly
26À30
immobilized by grafting on the channel walls.
Even though
gasÀliquid two-phase reactions such as halogenations by elemen-
tal fluorine and chlorine gas have been reported and the selectivity
of such reactions in microreactors was observed to be better
compared with the process being conducted under batch
(that is the perforated discs (green coloured) fixed on the oscillator
piston shaft with “the spacers”) are placed in the center of the reactor
tube. This MJOD unit is connected to the oscillator unit that transfers an
po is sc ti ol l na t. ing vertical (upÀdown) movement of this “numerous-headed”
3
1,32
conditions,
it is not a common and simple task conducted
with microreactors. LiquidÀgasÀsolid multiphase reactions in
microreactors have been reported. For example, a commercially
available microreactor was used to conduct catalytic reduction
system but that maintains the advantages of such a system,
namely the excellent heat-transfer and mass-transfer abilities.
28,33
(hydrogenation) of imines to secondary amines
in the pre-
sence of catalyst cartridge; particularly, developed microtubular
34
reactors for the purpose of oxidation have also been disclosed.
’
METHODS AND RESULTS
Examples of multistep syntheses using microreactor technology
are few in the literature, albeit syntheses of radiolabeled
During the past decade, we have in our laboratories designed,
3
5
substances and highly substituted (nitro)pyrrolidine, nitropyr-
developed, and investigated various approaches for the purpose
of conducting organic synthesis in continuous flow. In contrast to
the now well established microreactor technology that involves
mixing of the substrate and reagents in a laminar flow in
microsized channels, our novel approach for continuous flow
processing is conducted in multimillimeter-sized channels, and is
thus rather a millireactor system. In this new approach, the
substrate, the reagents, and the catalysts are enforced a mechan-
ical mixing providing a concurrent excellent mass and heat-
transfer. The novel flow reactor system was designed and
manufactured for the purpose of milli-scale continuous flow
organic synthesis, an approach we have named for a “multi-jet
oscillating disc reactor system,” shortly a MJOD reactor.
36
rolizine, and (nitro)pyrrole derivatives have been reported.
Even though microreactors demonstrate a huge potential for a
wealth of reactions and processes, a number of drawbacks exist:
(1) solubility problems and the risk of clogging the tiny channels
due to the presence of solid particles, (2) the restrictions in the
production capacity, that is the through flow (which calls for a
vast number-up), (3) the lack of flexibility to conduct telescoped
synthesis, that is two or more reaction sequences in one reactor
body, (4) difficulties to conduct reaction systems comprising
several phases, that is gasÀliquid, solidÀliquid, and gasÀ
liquidÀsolid, and (5) long reaction times required by some
reactions (reactor residence time).
Alternative approaches for continuous flow organic syntheses
The MJOD reactor system is constituted by four various
sections: (1) the reagent feeding section(s), (2) the reactor and
heat exchanger section(s), (3) the outlet and pressure regulator
section, and (4) the oscillator section. Those units can easily be
coupled together in a flexibly fashion to provide both varying
reactor lengths and reagent inlet patterns adapted for the
particular requirement. This is made possible owing to the fact
that each reactor section is furnished with a set of matching male
and female joints, each embraces also a standard size flange (o.d.
40 mm). Moreover, the male joint of each unit is accomplished
are few, but conventional tubular (plug) flow reactors and
37
oscillatory flow mixing (oscillating baffled tube) reactor both
have serious drawbacks compared to the microreactor. Tubular
reactors require, in general, high length-to-diameter ratios for
reactions of long residence time and are difficult to control. For
oscillating baffled tube reactors, this is not a problem, but the
contact area versus reactor volume is still not comparable to the
microreactor, a parameter of paramount importance in order to
keep control with the reaction temperature and the heat devel-
oped during the course of exothermic reactions (and thus the
selectivity of the reaction).
38
with four reagent inlet channels. The various reactor elements
are interconnected by commercially available flange swing
39
Herein we report a novel continuous flow reactor system that
copes with several of the drawbacks of the common microreactor
clamps. The reactor system also includes several amendment
supporting units, namely: (1) a number of reagent feeding
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4
0
pumps with reservoirs, (2) heating and cooling machine(s) that
are furnished with a circulator pump to circulate the cooling/heating
liquid through the heat exchanger cap that surrounds the reactor
tube throughout its whole length, and (3) an adjustable direct
movement of the discs fixed on the oscillator shaft contributes also
substantially to an improved mixing capacity inside the reactor.
The reaction temperature is a critical parameter for most kinds
of synthetic organic reactions, which thus demands an out-
standing approach for the control of the heating or the cooling
of the reaction mixture. The reactor tube of the MJOD reactor
was for that reason surrounded by a coat in which heating- or
cooling fluid can be circulated. This cooling- and heating coat can
easily be divided into several separated sections, which thus
allows one to use several different temperature zones in one
reactor. This will be of great significance for telescoped reactions,
i.e. synthetic processes that are composed of several reactions,
and which can be carried out successively in the reactor.
41
current power supply for controlling the rotation of the electrical
motor, the number of revolutions, and thus the frequency of the
oscillator. Figure 1 shows (left) a 3D drawing of a MJOD reactor,
the input section (base), the reactor body, the output section, and
the oscillator unit. At the right-hand side, a 3D transparent view
drawing of the input (base) section and a part of the heat exchange
and reactor tube section. Inside the reactor tube, there is the MJOD
unit composed of the perforated discs (green coloured) that are
the multijet disks that are fixed on the oscillator piston shaft with
spacer part in between, providing a (standard) volume of 0.6 mL.
Each reactor section is furnished with a male and female joint
pair, which make the MJOD reactor system very flexible and easy
to assemble. The number of feeding sections and the length of
the reactor and heat-transfer chamber sections can easily be
varied and thus be adapted to the particular requirements of any
synthetic protocol. This design allows (a) adjusting the residence
time not only with the pump rate but also in an easy way by
prolonging or shortening the reactor body, (b) optimizing the
mass-throughput, and (c) retaining accurate temperature control
of the reaction mixture.
The oscillator is composed of two distinct parts, namely the
agitation and the engine unit, respectively. The agitation unit can
be described as a piston shaft with several perforated piston heads
mutually spaced in the longitudinal direction of the whole length
of the piston shaft. The length of the piston shaft corresponds to
the reactor length plus the distance from the end of the reactor
tube to the joining point on the cam wheel of the electrical motor.
The piston heads are ring-formed discs (o.d. = 10 mm, L =
4 mm) fabricated by a polymer of high chemical, thermal, and
mechanical resistance; we have for example used Teflon and
Polyzene-containing polymers. Each of the ring-formed discs is
perforated and bears four jets with a diameter in the range d =
1.00À1.30 mm. The piston shaft with the ring-formed discs fits
closely into the reactor tube so that an annular reaction cavity is
formed between the inner surface of the rector tube, two ring-
formed discs, and the piston shaft which provides the internal
surface of the reaction cavity. The number of reaction cavities N
can be varied. In the present study, a piston shaft bearing N + 1 = 60
ring-formed discs (10 mm o.d. with 4 Â 1.25 mm diameter jets)
were used. The discs were uniformly spaced along the longitudinal
piston shaft. The N = 59 interdisk cavities, the reaction cavities,
provided a net volume of ≈38 mL. The length of the reactor tube,
as described above, can be varied. However, we have observed
that a length of 100 cm from the first feeding point to the product
outlet point is suitable for a large selection of reactions and
processes and was thus used for all of the experiments described
herein. It is easy to construct various process set-ups with the MJOD
reactor system. Some few examples are shown as process flow
diagrams in Figure 2. The process flow diagram shown in Figure 2a
was used for all of the experiments described in this article.
Characteristics of the MJOD Millireactor. The first step of
the design and development of the MJOD reactor system
included a thorough analysis of existing microreactor technology
in order to identify the critical and important characteristics and
to discover the drawbacks and limitation of the benchmarked
technology. On this basis we outlined several curtailments and
goals in order to fulfill the final ambition of a milliscale reactor
system superior to or competitive with the existing technology.
Some of the more important parameters that were identified have
been investigated and optimized. In this context, (1) the internal
areas for heat transfer were optimized, that is the ratio of the
The reactor and the heat-transfer chamber are constructed of two
stainless steel tubes. The reactor tube (o.d. 12 mm, i.d. 10 mm) is
surrounded by the second stainless steel tube of larger diameter
o.d. 37 mm and i.d. 33 mm) so that an annular space is formed
o.d. 33 mm and i.d. 12 mm). This annular space is used for
(
(
circulating a heating or cooling fluid for the purpose of regulating
the temperature of the reaction mixture passing through the
reactor tube. The inlets and outlets can be arranged at several
different levels in relation to the longitudinal direction of the
reactor. Hence, the heat-transfer fluid can be introduced and
taken out at different locations on the reactor and thus divide the
reactor into various temperature zones. This feature is essential if
one wants to carry out telescoped multistep syntheses where the
various reaction steps require different reaction temperatures.
In order to achieve good mixing, the reactor tube was
furnished with an adjustable amplitude (0À25 mm) and
frequency (0À5 Hz) oscillator that moves the multijet disk
assembly, the MJOD unit (see the drawing in Figure 1), forward
and backward in the longitudinal direction of the reactor. The
MJOD unit can be considered a piston engine with several
piston heads assembled on one single piston shaft. Each of the
piston heads (the discs) is furnished with several jets. A large
number of the perforated discs (in general, we used 60À100
four-jet discs) are fixed in equal distances on the shaft of the
oscillating MJOD unit.
One or more pumps are used to feed the reactants into the
reactor body. The reactants will thereby be forced at a high
rate through the tiny perforations (the jets) of the discs that
are fixed on the (piston) shaft of the MJOD unit. Furthermore,
the reagent inlet lines were supplied with one-way valves in
order to avoid “back kick” of the reaction mixture into the
reagent feeding tubes, caused by the alternating pressure
imposed by the oscillating MJOD unit.
À1
surface area versus the net reactor volume, the A Â V fraction,
(2) the back-mixing characteristic were investigated, (3) the
mixing properties were examined and optimized, (4) the heat
exchanger properties for standard organic synthetic reactions
were investigated by performing a series of syntheses in a
temperature range of À30À150 °C, and (5) we also defined
that the reactor system should operate even with slow reaction
rates, that is reactions that require several hours to complete in
When the reaction mixture goes through the jets and enters into
an area of a larger cross section (reaction chamber or reactor cavity),
the flow rate decreases, resulting in the formation of vortexes and
thus movements in the liquid mixture. Such vortexes lead to an
exceptionally good mixing of the various reactants; moreover, the
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Figure 2. MJOD reactor system is extremely flexible, allowing easy building of special reactor compositions. The figure shows only a few set-ups that
frequently are needed in the fine chemical production and organic process R&D. (a) A standard MJOD reactor system for reaction between a reagent
and a substrate under heating or cooling. (b) Similar to the standard setup, but showing three various liquid inputs and one gas input. Such a setup can
be valuable both for oxidation processes that use molecular oxygen as the terminal oxidant, and for processes that need a protective atmosphere, for
example argon. (c) The flow scheme shows a MJOD reactor setup that involves a two-step reactor system with two different temperature zones allowing
the conduction of two reaction steps in a telescoped fashion. Two substances are introduced at the start, then in the second step two more reactants are
introduced. (d) The flow sketch shows a cross-flow MJOD reactor system, that allows additions of reagents (or sampling) during the course of the
reaction, here illustrated with K various zones/points.
1
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With the graphics of Figure 3 at hand, the contact area
À1
(
A Â V ) of the reactor could be optimized concomitant with
keeping a suitable net reactor volume available. The intercon-
nection between the two important parameters for the MJOD
millireactor, the available net volume (Vavailable) of the MJOD
À1
reactor and the contact area A Â V is evident from the
À1
graphics in Figure 3c. The A Â V number increases asymp-
À1
totically as the net volume decrease. Furthermore, the A Â V
ratio number increases asymptotically when the diameter of
the piston shaft increase (that is a decrease of the net reactor
volume Vavailable), see Figure 3b. Figure 3a displays a slightly
quadratic effect on the inter-relationship between the diameter
of the piston shaft and the available net volume (Vavailable) of
the reactor.
The red-coloured bullet introduced on the curve represents
the selected values for the performance for the reactor body that
we realized and utilized throughout the experimental work of the
present study. The MJOD reactor parameters were as the
following: the reactor length was selected to L = 1000 mm;
internal diameter, i.d. = 10 mm; the MJOD unit was furnished
with N = 60 four-jet disks equally spaced throughout the whole
length of the reactor, that provides in total 59 reaction cavities
each of a volume of 0.64 mL; the diameter of the jets was selected
to djet = 1.25 mm. The diameter of the piston shaft bearing the
multijet disks was dshaft = 6 mm, that provided a net available
reactor volume Vavailable ≈ 38 mL. The estimated value for
Figure 3. Computation of the effect of available net volume, diameter
À1
of the piston rod, and the contact area (A Â V ). (a) Diameter of the
piston shaft (D
) versus available volume,
MJOD unit piston shaft
(
V
available). (b) Diameter of the piston shaft (DMJOD unit piston shaft
)
)
À1
versus contact area (A Â V ). (c) Available volume, (Vavailable
À1
versus contact area (A Â V ).
À1
batch protocols (long residence times). Flow chemistry by means
of the MJOD reactor technology that requires extreme tempera-
tures (that is cryogenic and thermolysis conditions) was defined
in the specification for the reactor system. Currently, studies
involving reactions at low temperatures are in progress, results of
which will be disclosed in a future report.
the surface is per volume, that is A Â V ≈ 10. Comparing
À1
this value with the A Â V numbers of various sizes of batch
reactors and a typical microreactor shows that the MJOD reactor
À1
has a 10-fold A Â V value compared to that of a batch reactor
of a volume of 100 mL (a typical laboratory glass flask), but only a
À1
20th part of the A Â V number of a typical microreactor.
À1
The MJOD Millireactor System: Optimization of the Heat-
Transfer Capability of the Reactor Body. The internal reactor
Table 1 shows the data for the A Â V numbers for a standard
microreactor against various sizes of batch reactors (entries
À1
43
À1
surface area per net volume unit of the reactor (the A Â V
1À4). The estimated A Â V number for a MJOD milli-
fraction) is a factor of paramount importance for any synthesis
reactor of a length of H = 1 m is provided in entry 5. Comparing
À1
À1
reactor. A large A Â V number provides a reactor with good
the A Â V numbers reveals that a typical microreactor possess
À1
heat exchange capacity, of course on the precondition that the
construction material for the reactor has suitable thermal con-
ductivity ability.
an A Â V value, that is on an order of magnitude 3000Â the
3
À1
stirred tank reactor of 1 m capacity, and ≈200 Â the A Â V
number of a laboratory flask of volume of 100 mL. The novel
À1
À1
With the goal to optimize the A Â V number of the MJOD
MJOD millireactor is manufactured to hold an A Â V ≈ 10,
À1
À1
reactor, we used the relation between the surface area and the net
which corresponds to a value of A Â V ≈ 170 Â the A Â V of
3
À1
reactor volume (V ) as defined in eq 1:
net
a 1-m stirred tank reactor and 120 Â the A Â V value of a 50-
À1
gal stirred tank reactor. The A Â V number of the MJOD
millireactor is interconnected to the internal diameter of the
reactor tube and the diameter of the piston shaft (that thus also
operates as a space filler).
The optimization of the performance of the MJOD reactor
was a two-fold task, namely (1) the design and construction
of a reactor with a suitable net volume that we defined to be in
the range 20À60 mL, concomitant with (2) as high a value of
À1
A Â V as possible.
The MJOD Millireactor System: Back-mixing. The back-mix-
44
ing of a continuous flow reactor is the propensity of the
product(s) of a chemical reaction to intermingle with the feeding
of the substrate and the reagents. Back-mixing is a detrimental
feature of all sorts of flow reactors because this will influence
negatively on the desired reaction (negative influence on the
reactor kinetics). The ideal condition where no back-mixing
takes place is called plug flow.
where R = radius of the reactor tube (R = 10 mm), H = length of the
reactor tube (H = 1000 mm), h = the thickness of the multijet disks
(
h = 4 mm), N = number of multijet disks fixed on the centre shaft of
the MJOD unit. For a simple model reactor of a length of 1 m, N = 60
disks was used, which provided 59 reactor cavities of approximately
0
.65 mL volume each (Vnet =59Â 0.65 mL ≈38mL). Byusingeq1,
À1
varying the r (Δ reactor center core), V , and A Â V and using
net
Back-mixing will be especially unfavorable for telescoped
synthetic processes that are one-pot multistep reactions
42
Matlab version 6, we could produce the graphics shown in Figure 3.
1
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Table 1. Surface-to-volume ratio A Â VÀ1 characteristics of various types of synthesis reactors
0
1
a1
1
B
ak C
a
(A Â VÀ1
2
ÀÀ3
B
3 :
C
C
A
k
type of reactor
size
)
k
[cm cm
]
comparison matrix, B
3
@
ak
a1
1
1
2
3
4
5
flat micro channel microreactor
laboratory flask
100 μm
100 mL
50 gal
200
1
1
200
2381
3333
17
20
0.005
0.00042
0.0003
0.05
1
12
0.1
stirred tank reactor
0.084
0.060
10
0.084
0.06
10
1
1.4
0.0084
0.006
1
3
stirred tank reactor
1 m
0.714
119
1
b
MJOD millireactor
38 mL
167
a
b
See ref 43. Data estimated for a MJOD millireactor of a length, L = 1000 mm, and internal diameter, i.d. = 10 mm, furnished with 60 four-jet disks
equally spaced throughout the whole length of the reactor. The diameter of the piston shaft bearing the multijet disks is 6 mm. The net available reactor
volume is Vavailable ≈ 38 mL.
Scheme 1. PaalÀKnorr condensation producing 2-(2,5-di-
46,47
methylpyrrol-1-yl)ethanol 3
Figure 4. Investigation of the back-mixing behavior of the MJOD
millireactor system. An experiment involving the synthesis of 2-(2,5-
dimethyl-pyrrol-1-yl)ethanol 3 using a PaalÀKnorr synthesis protocol.
The MJOD millireactor setup involved in total 60 multijet disks forming
in total 59 reactor cavities. Each reaction cavity constitutes a volume of
0
.64 mL. During the course of the experiment, a carefully sampling was
conducted in continuous flow. Thus, the MJOD reactor system was
subjected to investigations to discern whether the MJOD milli-
reactor was saddled with the disadvantageous characteristics of
back-mixing. A synthetic protocol leading to 2-(2,5-dimethyl-
pyrrol-1-yl)ethanol (Scheme 1) using the PaalÀKnorr pyrrole
performed to collect in total 80 samples each of approximately 0.6 mL.
The samples #51À80 were analyzed by means of GC. The detector voltage
was recorded for each of those samples, the results are reproduced in the
graphics that shows a sharp “cut-off” at sample #60.
4
5
synthesis was used as a test reaction for this purpose.
A MJOD millireactor comprising a MJOD unit of 60-piece
four-jet disks that constitute 59 reactor cavities (each holding a
volume of Vcavity ≈ 0.64 mL) was used. Three various reagent
reservoirs were used: reservoir #1 for the dissolved substrate, reservoir
total 80 samples each of a volume Vcavity ≈ 0.64 mL (the cavity
volume). The samples were subsequently analyzed on
GCÀMS. The samples #1À59 were expected to give product
signal on the GC, while samples #60 f onward were expected
only to contain pure solvent. Figure 4 shows the recorded GC
data presented as a bar plot, from which one can conclude that
the MJOD-reactor shows a very small degree of back-mixing.
The MJOD Millireactor System: The Importance of the MJOD
Unit. In order to investigate the importance of the oscillating
multijet disk assembly, the MJOD unit, a phase transfer catalysis-
supported batch protocol for O-allylation of phenol under basic
conditions, Scheme 2, was transferred to the MJOD millireac-
tor system for investigation. We believed that the extreme mixing
created by the MJOD reactor mixing unit could eliminate the
need for a phase transfer catalyst in two-phase reactions, which
on the other hand is of paramount importance when such
reactions are conducted in batch mode.
Similar experiments were thus conducted in a batch reactor
and in the MJOD flow reactor (1) by using batch conditions as
described in the literature, see ref 48 and (2) using the MJOD
millireactor system as reactor platform under similar reaction
conditions, and (3) using the MJOD millireactor system as
reactor platform leaving out the PTC from the reaction mixture,
but keeping the other reaction conditions the same as those used
#2 for the dissolved reagent, and reservoir #3 for the pure reaction
solvent. These reservoirs were connected to the inlet section of the
reactor body by standard Teflon tubing (i.d. 2 mm) using precision
peristaltic pumps #1À3. The process flowcharts correspond to
Figure 2a (with three pumps and adjacent reservoirs).
The experiment was conducted in the following way: the
reaction was started by pumping the substrate and the reagent
using a calculated flow rate, whereof the product was collected at
the output section for a period of 10À15 min in order to ensure a
homogeneous reaction mixture flow in the MJOD reactor.
Then the feeding of the reagent and of the substrate was
terminated at the same time as we (1) started to collect samples
from the reactor, each sample of a volume corresponding to the
volume of a single reactor cavity (≈0.64 mL), and (2) pure
reaction medium was then pumped with a rate corresponding
to rsolvent = rsubstrate + rreagent. In this way, the flow rate (and
thus the residence time) was kept constant throughout the
entire experimental run. Carefully a series of samples were
collected during the whole period of the experimental run that
correspond to 1.5 Â the residence time. Thus, there were in
48
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Scheme 2. Synthesis of allyloxybenzene 6 reacting phenol 4
and 3-bromoprop-1-ene 5 in a two-phase reaction system
mediated by the phase transfer catalyst tetrabutylammonium
Scheme 4. Haloform reaction utilized for the preparation of
veratric acid 10 from acetoveratron 9
a
a
bromide (TBAB)
a
2-Chloro-4,5-dimethoxybenzoic acid 11 can be formed as a byproduct
during the haloform reaction, but it was not observed either in
a
the previously optimized batch protocol or the new flow chemistry
PTC = tetrabutylammonium bromide; entry #3: slightly changed
*
protocol. Optimized batch process; see ref 52.
conditions, prolonged residence time and higher concentration.
Scheme 3. Reduction of cyclohexanone 7 to cyclohexanol 8
by means of sodium borohydride
the reservoir and pump unit #1, and the sodium borohydride
solution was transferred to the reservoir and pump unit #2. The
pumps were adjusted to provide a residence time of 3 min inside
the MJOD reactor system.
From the results reported in the Scheme 3 it is evident that the
oscillator status, either “on” or “off” has a substantial influence on
the product yield. In fact, when the oscillator was running (status
“
on”) an outstanding mixing of the substrate and the reagent
furnished almost a quantitative yield (96%) of target molecule 8,
while in absence of agitation (status “off”) the yield was
considerably less, namely a yield of only 49% of target molecule.
Another sodium borohydride reduction experiment was also
conducted (with oscillator “on”) in order to evaluate the heat
transport, results are summarized in Scheme 7. The N-acylation
experiment summarized in Scheme 10 was also used to evaluate
the importance of the oscillating multijet unit. Without the
oscillating unit running, target product was not observed, in
contrast to a yield of 60% when the oscillator was running.
Proof of Concept: Results of Various Organic Synthetic
Reactions. Above, a series of important aspects related to the
MJOD reactor system have been investigated. However, the
most important feature for any reactor system is whether the
system can be utilized for a variety of reactions or if the system is
only suitable for limited type of chemical reactions. Moreover,
one more question that must be raised is whether the new system
is competitive with existing platforms.
in the batch reactor. The two experiments conducted in the
batch- and the MJOD-reactors that both used PTC in the
reaction mixture provided almost similar results, namely a yield
of 73% in batch mode, and a yield of 75% under continuous flow
conditions. In both cases, a conversion of 100% was observed
(
entries #1À2, Scheme 2). The third experiment using the
MJOD reactor system for continuous flow synthesis without
the PTC present revealed only small quantities of target product
6
along with large quantities of unconverted phenol 4. However,
under slightly altered reaction conditions, namely by prolonging
the residence time (20 min f 55 min) and augmenting the
concentration of the substrate 4 and the reagent 5 solutions (the
solvent volume was reduced 75 f 30 mL), a comparable yield
and conversion was achieved, see entry #3 of Scheme 2. This
investigation has demonstrated that the excellent mass-transfer
The following section discloses results from a series of
experiments where the multijet oscillating disk reactor system
has been used as the reactor platform. The investigations have
been conducted with the goal of discerning whether the reactor
system operates as a general reactor platform for conducting
reactions and processes.
(
mixing) properties of the oscillating MJOD unit may replace the
need for a PTC, although this is not a general conclusion valid for
all types of PTC-catalyzed reactions.
The MJOD Millireactor System: The Importance of the Multi-
jet Disk Unit with or without Oscillating. An obvious question
one might ask was whether it is necessary to use an oscillator
connected to the multijet disk unit. In order to answer this
question, we performed experiments using the sodium borohy-
dride reduction as a model reaction. Thus, experiments were
conducted both with and without connecting the oscillator to the
multijet disk unit (Figure 2a). Preliminary experiments reveled
that the borohydride reaction could be performed with great
success by means of the MJOD reactor operating in normal mode
that is with the oscillator switched on. In the experiments,
cyclohexanone 7 was used as substrate and sodium borohydride
dissolved in aquous ethanole. The substrate 7 was transferred to
The Haloform Reaction. 1-(3,4-Dimethoxyphenyl)ethanone
(acetovanillone), that is a side product in the production of
vanillin (4-hydroxy-3-methoxybenzaldehyde) that is basic hy-
drolysis and copper-catalyzed aerobic oxidation of lignosulpho-
4
9
nates, can be used as substrate in a process to veratric acid
(3,4-dimethoxybenzoic acid) 10, which constitutes a useful
building block for the synthesis of some pharmaceutical chemi-
cals, for example the muscle relaxant mebeverin. Acetovanillon
is first methylated to obtain acetoveratron 9 that in a second
step is transformed to veratric acid 10 by means of the haloform
5
0,51
reaction.
Previously, this process (in batch mode) was
52,53
investigated and thoroughly optimized by Bjørsvik and Norman
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Scheme 5. Nef reaction producting cyclohexanone 7 from
nitrocyclohexane 12
Scheme 6. Nucleophilic aromatic substitution producing
1-(2,4-dinitrophenyl)piperidine 15 reacting 1-chloro-2,4-di-
nitrobenzene 13 with piperidine 14
63 a
a
Reference 63: no experimental conditions were reported. The produc-
À1
tivity of 8 g h using the CPC micoreactor was claimed.
Nucleophilic Aromatic Substitution: Synthesis of 1-(2,4-
64
Dinitrophenyl)piperidine. Aromatic nucleophilic substitution
occurs under rather harsh reaction conditions and the yields are
frequently poor, unless the leaving group is activated by the
presence of several strong electron withdrawing groups for
example the nitro group. A classical aromatic nuclephilic sub-
stitution was examined in order to benchmark the MJOD reactor
performance with other existing methods. Thus, 2,4-dinitro-
chlorobenzene 13 was reacted with piperidine 14 at room
temperature using acetonitrile as solvent, see Scheme 6.
The flow rate of the substrate and reagent pumps was
adjusted to obtain a residence time of 22 min. Measurements
of the reaction mixture revealed a complete conversion and
nearly quantitative yield of target molecule 1-(2,4-dinitrophe-
nyl)piperidine 15. The achieved result is placed together with
data for reactions conducted under batch conditions (yield
to furnish a yield of 91% of the target product 10 using a batch
residence time of 2 h.
A serious problem with this process is that the chlorinated
byproduct 11 can be formed, although the improved and
optimized batch process furnished a byproduct-free reaction
mixture. We found it interesting to investigate this process
implemented on the MJOD reactor system. The experimental
trials were conducted using the previously optimized reaction
conditions as for the batch trial, see Scheme 4. The experi-
ments revealed the reaction to be significantly faster in the
MJOD reactor compared to the reactions performed in batch.
By means of the MJOD reactor system, target product veratric
acid 10 was achieved in a yield of 77% using a residence time of
only t = 22 min. The chlorinated derivative 11 was not detected.
Any further attempt to optimize the continuous flow synthesis
>
99%), and results previously disclosed conducted with a micro-
was not carried through. The productivity of the flow reactor
À1
reactor (yield ≈ 96%). The productivity of the MJOD reactor
setup corresponded to ≈25 g h
.
À1
5
4
setup corresponded to ≈27 g h .
Nef Reaction. The Nef reaction is an important synthetic
reaction that enables transformation of nitro compounds to the
corresponding carbonyl compounds. The reaction takes place by
formation of an alkaline nitronate starting from a primary or
secondary aliphatic nitro compound that is rapidly solvolyzed in
an aqueous or methanolic acid solution to the corresponding
45
The PaalÀKnorr Pyrrole Synthesis. The PaalÀKnorr synth-
esis was used in order to investigate the occurrence of back-
mixing in the MJOD reactor. In this section we will revisit this
synthetic reaction with the aim to study the MJOD system as a
reaction platform. The pyrrole skeleton constitutes an integral
part of several active pharmaceutical ingredients (APIs) used as
biological probes, molecular receptors for anions and cations, as
dyes (including fluorescent dyes), charge transfer agents, con-
6
5
55,56
aldehydes and ketones.
The literature covers a comprehensive list of procedures that
have been described as alternatives for the cleavage of the
66
56
ductive materials, polymers and polymer additives, nonlinear
carbonÀnitrogen bond under milder conditions. Hydrolysis
of the double CdN bond of the nitronates can be performed by
oxidative cleavage by means of a series of oxidants, such as
optical materials, and electroluminescent devices. Efficient syn-
thetic processes of the pyrrole skeleton are therefore highly
required both in the research laboratory and for industrial
purposes. One method to synthesize pyrroles is based on the
condensation of a 1,4-dicarbonyl compound with an excess of a
primary amine or ammonia. As a part of the investigation of the
MJOD reactor system we included the PaalÀKnorr synthesis in
the portfolio of processes because we wanted to transfer to a
continuous flow protocol and thus demonstrate the capabilities
of the MJOD reactor. We used a batch protocol for the
preparation of 2-(2,5-dimethylpyrrol-1-yl)ethanol 3 where β-
aminoethanol 1 and acetonylacetone 2 were reacted at room
temperature, see Scheme 1. This protocol was easily imported to
the flow format of the MJOD reactor. The β-aminoethanol and
acetonylacetone were transferred to reservoirs #1 and #2, re-
spectively. The pumps (peristaltic pumps) were adjusted to
5
7,58
59
60
KMnO4,
ozone, m-chloroperbenzoic acid, or dimethyl-
6
1
62
dioxirane. Ballini and collaborators reported a selective Nef
reaction of secondary nitroalkanes under mild conditions by
using 1,8-diazabicyclo[5.5.0]undec-7-ene (DBU) as tertiary ami-
dine base. In our laboratory we have investigated the original
protocol of the Nef reaction using continuous flow conditions by
means of the MJOD reactor system, where results were com-
pared with experiments conducted under batch condition (see
Scheme 5).
The Nef reaction conducted in the MJOD reactor system
proceeds with a significant elevated reaction rate compared to
the corresponding reaction conducted in batch. In the MJOD
reactor, a yield of 67% was achieved, using a residence time of only
À1
1
0 min. The Nef reaction conducted under batch conditions
provided a yield of 58% at a reaction time of 30 min and a yield of
2% at a reaction time of 24 h.
afford a flow rate of 2.1 mL min , which provided a quantitative
yield (>99%) after a total residence time of ≈18 min. The MJOD
7
total residence time was significantly inferior to that (72 min) of a
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Scheme 7. Reduction of cyclohexanone 7 to cyclohexanol 8
using the MJOD millireactor system
Scheme 9. Synthesis of aniline 20 from benzamide 19 using
the Hofmann rearrangement
fine chemical applications. In a previous project in our laboratory,
we needed a protocol for the synthesis of 2-nitrobiphenyls, which
resulted in a development program that furnished a flexible
and high-yielding batch protocol. In this study, we attempted
to transfer and adapt this protocol for continuous flow synthesis
using our MJOD millireactor system. The control experiment
that was conducted under batch conditions, that is in a laboratory
flask, was carried out by reacting phenylboronic acid 16 with
Scheme 8. Suzuki cross-coupling reaction for the synthesis of
71
2
-nitrobiphenyl 18 reacting 1-iodo-2-nitrobenzene 17 with
phenylboronic acid 16 with the presence of palladium acetate
as catalyst and potassium carbonate as base
1
-iodo-2-nitrobenzene 17 using acetone and water as the reac-
tion medium with a reaction time of 30 min to achieve a yield of
0% of 2-nitrobiphenyl 18 (Scheme 8). The adapted procedure
3
for continuous flow synthesis on the MJOD system provided a
conversion of 52% of 2-nitrobiphenyl using the MJOD reactor
with a residence time of only 15 min. The MJOD performance is
therefore comparable to the Suzuki cross-coupling reaction
micronit parallel multilayered reactor module used to ensure a
milliliter-scale production (98% yield, Scheme 1).
The procedure operated well in the reactor system and was
2
7
conducted in microreactors where yield range of 67 ( 7%
72
thus also utilized during the back-mixing study described above.
and conversion of 50À99% have been obtained.
73
The productivity of the MJOD reactor setup for this reaction
The Hofmann Degradation. In flow chemistry it is a
challenging task both in experimental chemistry as well as for
process operations to feed flow reactors with slurries. The
difficulties rely on a series of factors that includes (1) technical
issues related to the pumps, (2) difficulties to create homoge-
neous sludge and thus a homogeneous feeding of the solid
material, a problem that relies on the particle size, and thus (3)
a requirement of a uniform small-sized solid material that does
not form agglomerates, and (4) the restriction in the amount of
solids per volume unit.
À1
corresponded to ≈406 g h
.
Sodium Borohydride Reduction. Reduction is a fundamental
reaction in synthetic organic chemistry. Due to its high
chemoselectivity, stereoselectivity, and cost effectiveness,
67
NaBH has become an important reducing agent both in the
4
68
R&D laboratories and in the fine chemical industry. The
sodium borohydride reduction is a highly exothermic reaction
and also an interesting reaction to include in the curriculum of
test processes for the MJOD reactor system. In order to
investigate the value of such reactions we decided to conduct
the classical reduction of cyclohexanone 7 to the corresponding
cyclohexanol 8, see Scheme 7. The sodium borohydride reduc-
tion was conducted with various reaction media, namely ethanol/
water or water only. When a reactor residence time of approxi-
mately 15 min was utilized with the MJOD reactor system, a
quantitative yield was observed for the target product cyclohex-
anol 8. The borohydride reaction proceeded smoothly with full
control over the heat evolved during the reaction. Results
achieved by using the microreactor was a yield of 86% at 0 °C
with ethanol as reaction medium and a yield of 80% when
performed in batch.
If a microreactor is used with slurries, even more obstacles can
intervene, namely the size of the micro channels. The particle size
of the sludge in the reagent and/or substrate reservoirs will be
very critical since an oversized particle or agglomerates of
particles will result in clogging of the tiny micro channels of
the flow reactor body; thus, a tedious and continuous control of
the slurry and reactor will be required, but perhaps not sufficient
to achieve a proper operation of the flow system.
In the present example, the Hofmann degradation, several
reaction parameters of paramount importance were investigated
in order to asses if the MJOD reactor can be used for reactions
that involve slurries in one of the reservoirs. Moreover, the
reaction system also comprises inhomogeneous phases, namely
water phase/organic phase.
The Hofmann rearrangement is a reaction between a hypo-
halite ion and a primary amide, a reaction that takes place over
several steps including the formation of isocyanate as an inter-
mediate that is subsequently hydrolyzed to produce a primary
amine with one carbon less that the starting amide. The one-
carbon reduction takes place by shopping off the carbon as
carbon dioxide.
In a Hofmann degradation experiment (see Scheme 9) a slurry
of benzamide 19 in 1,4-dioxane and a solution of sodium
hypochlorite/sodium hydroxide were introduced into the MJOD
The Suzuki Cross-Coupling Reaction. The Suzuki cross-cou-
pling reaction was described for the first time in the 1979 by
69
Suzuki and Miyaura. Since then, the Suzuki reaction has been
widely studied and applied both in the academia and the
7
0
industry. The Suzuki coupling reaction is constituted by a
reaction of an organic halide and an organoboron derivative with
palladium as catalyst in basic media. Usually the reaction takes
place with high stereo- and regioselectivity and has become a
highly important coupling reaction for laboratory syntheses as
well as for industrial syntheses of a wide range of products
ranging from various polyolefins, styrenes, and substituted
biphenyls as intermediates for various pharmaceuticals and other
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1
Scheme 10. N-acylation of aniline 20 to obtain N-phenyla-
cetamide 22
Control spectra H NMR spectra were recorded on a NMR
spectrometer operating at 400 MHz. Chemical shifts were
referenced to internal TMS.
Starting materials and reagents were purchased commercially
and used without further purification if not otherwise indicated.
The MJOD Reactor System. Haloform Reaction. 3,4-Di-
methoxyacetophenone 9 (10.4 g, 58.0 mmol) was suspended
in a solution of NaOH (50%, 2.0 mL) and NaOCl (160.4 g,
1
33 mL, 9% active chlorine). The suspension was pumped into
the reactor at a temperature of 80 °C with a residence time of
0 min. The reaction mixture was quenched with sodium bisulphite,
2
and the pH was adjusted to ≈3À4 by using conc. sulphuric acid.
reactor by means of two peristaltic pumps. The feeding rate for
each of the two peristaltic pumps was 1.3 mL min , which
resulted in a residence time of 15 min. The reactor was heated at
The acidic aqueous phase was extracted with dichloromethane
À1
(
3 Â 50 mL). Target product, veratric acid 10, was isolated as a
pure solid in yield of 77.0% yield with 100% selectivity (8.20 g,
5.0 mmol). The highly problematic chlorinated byproduct 11
8
2
0 °C during the course of the experimental run. Target molecule
4
0 was isolated as oil in a quantitative yield.
was not observed.
The Nef Reaction. Batch Conditions. Nitrocyclohexane 12
74
In comparison, Ley and coworkers used a commercially
available microfluidic flow-reactor system to react benzamide
with N-bromosuccinimide (NBS) with the presence of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) as a base with either
methanol or ethanol as reaction media. The achieved yields were
(
1.0 g, 7.7 mmol) was suspended in an aqueous solution of
NaOH (0.4 g in 5.0 mL H O). This mixture was added to diluted
H SO (1.51 g, 98%, in 5.0 mL of H O) previously cooled at
1
cyclohexanone 7 was measured. After a period of 24 h, the
reaction mixture was extracted with ethyl acetate (3 Â 15 mL) to
obtain target product cyclohexanone in a yield of 72% at a
selectivity of 98%.
2
2
4
2
0 °C. After a period of 30 min, a yield of 58% (GC) of
7
9% and 32%, respectively.
N-Acylation and Long Residence Time Reactions. A task that
is often encountered in organic process R&D is one that at a
short notice must establish a process usable for preparation of a
target molecule on multigram or even kilogram scale. A custom-
ary manner used to solve such a task is to adapt a protocol
previously disclosed in the chemical literature, and then to
implement some sort of scale-up and optimization.
MJOD Reactor Conditions. Nitrocyclohexane 12 (5.0 g,
8.7 mmol) was suspended in an aqueous solution of NaOH
3
(
2.0 g in 25.0 mL H O). H SO (7.6 g, mmol, 98%) was diluted
2
2
4
in water (25 mL) and cooled at 10 °C. The two mixtures were
pumped into the reactor separately with a flow rate of 1.9 mL
During our project developing the MJOD reactor system, we
revealed that the various batch processes we implemented and
investigated were easily transferred to our MJOD flow reactor
system by changing only one of the process variables, namely a
substantially reduced residence time, but still at a level that appears
as a persistent problem for operating on a microreactor system. We
wanted therefore to investigate our MJOD reactor system as a
reactor platform in the place of a batch reactor using protocols
developed for batch synthesis that requires residence times of
several hours. For this purpose we investigated N-acylation of
aniline 20 that produces N-phenylacetamide 22. The reaction of
À1
min corresponding to a residence time of 10 min. The reaction
was conducted at 20 °C. Target product 7 was collected and
isolated in a yield of 67% with a selectivity of 98%.
Sodium Borohydride Reduction. Cyclohexanone 7 (10.4 g,
06 mmol, 11.0 mL) was suspended in ethanol (56 mL). NaBH4
106 mmol, 4.0 g) was dissolved in a mixture of ethanol (60 mL)
1
(
and water (7.0 mL). Each of the two mixtures was pumped
separately into the reactor, with flow rates of 1.02 and 1.21 mL
À1
min , respectively. The reduction reaction was conducted at a
temperature of 20 °C with a residence time of 17 min. The
collected reaction mixture (≈70 mL) was quenched with glacial
acetic acid and then extracted with ethyl acetate (3 Â 20 mL).
The combined extract was dried over sodium sulphate and
filtered, and finally the solvent was removed under reduced
pressure. Cyclohexanol 8 was isolated in a quantitative yield. The
same procedure can be conducted with water as the only reaction
medium, providing the same results in yield, selectivity, and
purity of isolated product.
75
Scheme 10 is reported in the literature to provide a yield of 66%
using a reaction time of 24 h when conducted at room temperature.
The flow protocol that we utilized was mainly as described in
75
the batch procedure; however, we increased the reaction
temperature from r.t.f 50 °C and reduced the reaction time
from 72 h f 40 min. (i.e., reactor residence time in the MJOD
reactor). In this “one-shot-trial” an isolated yield of ∼60% was
achieved for the target product N-phenylacetamide 22. A sum-
mary of the experiment conducted with the MJOD reactor is
shown in Scheme 10.
Multigram-Scale Protocol. Cyclohexanone 7 (37.0 g,
76 mmol) was diluted with ethanol until a volume of 200 mL.
3
The solution was transferred to reservoir #1 from which the solu-
À1
tion was pumped into the reactor with a flow rate of 0.68 mL min .
’
EXPERIMENTAL SECTION
Sodium borohydride (14.2 g, 376 mmol) was dissolved in a
mixture of ethanol (180 mL) and water (20 mL) and transferred
to reservoir #2 from which the solution was pumped into the
General Methods. GLC analyses were performed on a
capillary gas chromatograph equipped with a fused silica
column (L 25 m, 0.20 mm i.d., 0.33 μm film thickness) at a
helium pressure of 200 kPa, split less/split injector and flame
ionization detector.
À1
MJOD reactor with a flow rate of 0.68 mL min , providing a
residence time of 28 min. The reaction was conducted at a
temperature of 20 °C for 60 min. The collected post-reaction
mixture was diluted with water and quenched with glacial acetic
acid at a temperature of 5 °C. The aqueous ethanol phase
was extracted with chloroform. The organic phase was dried,
Mass spectra were obtained on a GCÀMS instrument, using a
gas chromatograph equipped with fused silica column (L 30 m,
0
.25 mm i.d., 0.25 μm film thickness) and He as carrier gas.
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evaporated at reduced pressure, and distilled under reduced pre-
ssure, giving pure (bp 75 °C at 20 mmHg) cyclohexanol (36 g) in
a yield of 96%.
(145 mg, 0.45 mmol) were dissolved in water (75 mL) that
was transferred to reservoir #1. Allyl bromide 5 (1.16 mL,
13.2 mmol) was dispersed in water (75 mL) and transferred
to reservoir #2.
1
-(2,4-Dinitrophenyl)piperidine 15. A solution of 1-chloro-
,4-dinitrobenzene 13 (8.1 g, 40.0 mmol) in acetonitrile (40 mL)
and a solution of piperidine 14 (6.8 g, 80 mmol) in acetonitrile
2
In Presence of the Phase Transfer Catalyst. Both the pumps
À1
worked at a flow rate of 0.95 mL min that provided a residence
(
40 mL) were pumped separately into the reactor, both at a flow
time of 20 min. The product was isolated in 75% yield,
In Absence of the Phase Transfer Catalyst. Under similar
conditions, but without PTC present, the reaction proceeded
with a low rate. GC analysis reveals small quantities of the
product 6 along with unconverted phenol.
Attempt To Improve the Yield without PTC Present. The
concentration of the solutions for both pumps #1 and #2 were
increased (changed 75 f 30 mL of water), and prolonged
the residence time (20f55 min) provided a similar reaction
profile as for the reaction conducted with PTC present, although
with a somewhat lower yield (60%).
À1
rate of 0.9 mL min , providing a residence time of 22 min. The
reaction was conducted at a temperature of 20 °C. The collected
reaction mixture (≈80 mL) was diluted with water (80 mL) and
extracted with ethyl acetate (2 Â 40 mL). The organic phases
were combined, dried over sodium sulphate, and filtered, and the
solvent was removed under reduced pressure to provide a
quantitative yield (10.0 g) of red crystals of target compound 15.
Suzuki Coupling. Phenylboronic acid 16 (1.22 g, 10 mmol)
and potassium carbonate (2.76 g, 20 mmol) were mixed in
acetone (25 mL) and water (20 mL). 2-Iodonitrobenzene 17
(
2.49 g, 10 mmol) and palladium(II) acetate (44.8 mg, 0.2 mmol,
%) were mixed in acetone (45 mL). The two mixtures were
Hofman Rearrangement. Batch Mode. The benzamide
(0.50 g, 4.2 mmol) was suspended in 1,4-dioxane (10.0 mL) as
solvent and NaOCl (10% active in chlorine, 6.2 mL, 10.1 mmol)
and NaOH (50% aqueous solution, 1.7 mL, 20.2 mmol) were
added. The mixture become dark red and was reacted at 80 °C for
2 h. The chromatographic analysis revealed the presence of the
intermediate isocyanatobenzene (PhÀNdCdO) (30%) and
the final aniline in a yield of 30%.
2
transferred to two various reservoirs and pumped into the MJOD
À1
reactor at a rate of 1.3 mL min , using two peristaltic pumps.
The reaction was conducted at 20 °C with a total residence time
of 15 min. The collected reaction mixture was analyzed by
GCÀMS that revealed a yield of 52% of desired 2-nitrobiphenyl
derivative. The same reaction, but with a batch reactor, provided
76
a yield of only 30%.
Flow Mode. The benzamide (1.0 g, 8.4 mmol) was suspended
in 1,4-dioxane (20.0 mL) as solvent. The solution of NaOCl
(10% active in chlorine, 12.4 mL, 20.2 mmol) was mixed with
NaOH (50% aqueous solution, 1.7 mL, 20.2 mmol. The amide
slurry and the NaOCl solution were pumped separately, each at a
7
7
PaalÀKnorr Condensation. Batch Mode. β-Aminoetha-
À1
nol 1 (5.4 g, F 1.012 g mL , 5.3 mL, 88.0 mmol) was
transferred to a round-bottom flask (50 mL), where acetonyl-
acetone 2 (10.0 g, F 0.973, 10.3 mL, 88.0 mmol) was added
dropwise (but rapidly), and left to stir overnight. The reaction
mixture was then distilled under vacuum (p = 1 mm Hg); at first
the temperature was kept at 40 °C in order to remove the water
formed during the condensation reaction. When the tempera-
ture reached 84 °C, the product 3 was then collected as a
colorless oil that solidified at room temperature. The product
was isolated in a yield of 74% (9.0 g, 65.1 mmol).
À1
rate of 1.3 mL min into the reactor, and the reaction was run at
80 °C with a retention time of 15 min. The target product, the
aniline, was separated from the aqueous reaction mixture as an oil
in a quantitative yield.
N-Acylation
Flow Mode. Aniline (51.1 g, 549 mmol, MW 93.13, δ 1.022)
was dissolved in acetic acid (120 mL) the resulting mixture of
which was transferred to reservoir and pump system #1. Acetic
anhydride (150 mL) and acetic acid (20 mL) were mixed and
transferred to reservoir and pump system #2. The two reagent
mixtures were pumped into the reactor input section at a rate
Flow Mode. β-Aminoethanol 1 (52.0 g, 851 mmol, 51.4 mL)
and acetonylacetone 2 (97.3 g, 852 mmol, 100 mL) were
pumped into the MJOD reactor utilizing standard piston
pumps at a rate of 0.71 and 1.38 mL min , respectively. The
reaction was conducted at room temperature with a residence
À1
À1
(0.95 mL Â min ) that provided a reactor residence time of
time of 18 min, that corresponds to a overall flow rate of
40 min. The oscillator was adjusted at a frequency of 1 Hz. The
reaction was conducted at a temperature of 50 °C.
À1
2
.1 mL min . The collected reaction mixture was distilled
under reduced pressure (p = 1 mm Hg), first at a temperature of
Work-Up. The collected postreaction mixture was diluted with
water (100 mL) and cooled at 4 °C overnight to promote the
precipitation of the acetanilide 23 as ivory coloured crystals in a
quantity of 44.5 g, that correspond to an isolated yield of 60%.
4
0 °C in order to remove water produced under the reaction,
then the product 3 was collected at 84 °C, to achieve a
quantitative yield (2837 mmol h ) of target product.
À1
O-Allylation of Phenol under Basic Conditions and with PTC
Present. Batch Mode. Phenol (282 mg, 3 mmol) was dissolved
in aqueous sodium hydroxide solution (144 mg, 3.6 mmol
NaOH in 100 mL of water). Allyl bromide (0.77 mL, 9 mmol)
and tetrabutyl ammonium bromide (96.7 mg, 0.3 mmol) were
then added. The reaction was left under good agitation for a
period of 1 h at a reaction temperature of 33 °C. The reaction
mixture was extracted with dichloromethane (3 Â 25 mL). The
combined organic extracts were dried over sodium sulphate and
filtered, and the solvent was removed under reduced pressure on
a rotary evaporator to achieve an oil in a yield of 73% and 100%
conversion.
’
CONCLUSION
We have designed, realized, developed and investigated a
novel flow reactor system that we have named multijet oscillating
disk (MJOD) millireactor system. This flow reactor approach
used net volumes in multimilliliter scale rather than in the
microliter-scale in reactors that are commercially available from
several suppliers. The MJOD reactor is benchmarked with both
previously published data from both batch and microreactor
experiments and demonstrates competitive features of the mi-
croreactor. Moreover, the MJOD reactor can be used for reac-
tions using slurries, two liquid-phase reaction systems, easy
transfer of batch protocols even for reactions that require several
Flow Mode. Phenol 4 (423 mg, 4.5 mmol), NaOH (216 mg,
5
.4 mmol), and (if used) tetra-butyl ammonium bromide
1
007
dx.doi.org/10.1021/op2000699 |Org. Process Res. Dev. 2011, 15, 997–1009

Organic Process Research & Development
ARTICLE
hours of reaction time, and the MJOD reactor provides high
throughput for reactions and processes that require short reac-
tion time.
(17) L €o we, H.; Hessel, V.; L €o b, P.; Hubbard, S. Org. Process Res. Dev.
2006, 10, 1144–1152.
(18) Liu, S.; Fukuyama, T.; Sato, M.; Ryu, I. Org. Process Res. Dev.
2
004, 8, 477–481.
19) Panke, G.; Schawalbe, T.; Stirner, W.; Taghavi-Moghadam, S.;
Wille, G. Synthesis 2003, 18, 2827.
20) Kulkarni, A. A.; Nivangune, N. T.; Kalyani, V. S.; Joshi, R. A.;
Joshi, R. R. Org. Process Res. Dev. 2008, 12, 995–1000.
21) Brivio, M.; Verboom, W.; Reinhoudt, D. N. Lab Chip 2006, 6,
29–344.
22) Ahmed-Omer, B.; Brandt, J. C.; Wirth, T. Org. Biomol. Chem.
Future Development. In our laboratories we have several
advanced MJOD reactor prototypes running on a daily basis, and
we are also approaching finalizing the first commercial version of
the system. Several investigations are underway and indicate that
the MJOD reactor system can be utilized for telescoped reac-
tions, gasÀliquid reactions (molecular oxygen as oxidant), olefin
metathesis reactions, various reactions that need to be conducted
under protecting atmosphere (argon or nitrogen), and metal-
organic reactions that need low reaction temperature.
(
(
(
3
(
2007, 5, 733–740.
(23) Watts, P.; Wiles, C. Chem. Commun. 2007, 443–467.
(
24) Wirth, T., Ed. Microreactors in Organic Synthesis; Wiley-VCH:
New York, 2008; pp 1À297.
25) Yoshida, J.; Nagaki, A.; Yamada, T. Chem.—Eur. J. 2008, 14,
450–7459.
26) Jensen, K. F. Chem. Eng. Sci. 2001, 56, 293.
(27) Greenway, G. M.; Haswell, S. J.; Morgan, D. O.; Skelton, V.;
Styring, P. Sens. Actuators, B 2000, 63, 153.
28) Saaby, S.; Knudsen, K. R.; Ladlow, M.; Ley, S. V. Chem.
Commun. 2005, 23, 2909.
29) Snyder, D. A.; Noti, C.; Seeberger, P. H.; Schael, F.; Bieber, T.;
Rimmel, G.; Ehrfeld, W. Helv. Chim. Acta 2005, 88, 1.
’
AUTHOR INFORMATION
(
Corresponding Author
7
*
E-mail: hans.bjorsvik@kj.uib.no. Telephone +47 55 58 34 52.
(
Fax +47 55 58 94 90.
(
’
ACKNOWLEDGMENT
(
Economic support from Innovation Norway and Bergen
Technology Transfer AS are acknowledged. Mr. Gianfranco
Liguori and Mr. Steinar Vatne are acknowledged for excellent
technical assistance realizing the various parts and sections that
constitute the MJOD reactor system.
(
(
30) Haswell, S. J.; O’Sullivan, B.; Styring, P. Lab Chip 2001, 1, 164.
31) De Mas, N.; Jackman, R. J.; Schmidt, M. A.; Jensen, K. F. In
Microreaction Technology - IMRET 5: Proceeding of the Fifth International
Conference on Microreaction Technology; Matlosz, M., Ehrfeld, W., Baselt,
J. P., Eds.; Springer: Berlin, 2002; p 60.
(
32) J €a hnisch, K.; Baerns, M.; Hessel, V.; Ehrfeld, W.; Golbig, K.;
’
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