Continuous Photo-Oxidation in a Vortex Reactor: Efficient Operations Using Air Drawn from the Laboratory

Article abstract of DOI:10.1021/acs.oprd.7b00153

We report the construction and use of a vortex reactor which uses a rapidly rotating cylinder to generate Taylor vortices for continuous flow thermal and photochemical reactions. The reactor is designed to operate under conditions required for vortex generation. The flow pattern of the vortices has been represented using computational fluid dynamics, and the presence of the vortices can be easily visualized by observing streams of bubbles within the reactor. This approach presents certain advantages for reactions with added gases. For reactions with oxygen, the reactor offers an alternative to traditional setups as it efficiently draws in air from the lab without the need specifically to pressurize with oxygen. The rapid mixing generated by the vortices enables rapid mass transfer between the gas and the liquid phases allowing for a high efficiency dissolution of gases. The reactor has been applied to several photochemical reactions involving singlet oxygen (¹O₂) including the photo-oxidations of α-terpinene and furfuryl alcohol and the photodeborylation of phenyl boronic acid. The rotation speed of the cylinder proved to be key for reaction efficiency, and in the operation we found that the uptake of air was highest at 4000 rpm. The reactor has also been successfully applied to the synthesis of artemisinin, a potent antimalarial compound; and this three-step synthesis involving a Schenk-ene reaction with ¹O₂, Hock cleavage with H⁺, and an oxidative cyclization cascade with triplet oxygen (³O₂), from dihydroartemisinic acid was carried out as a single process in the vortex reactor.

Full text of DOI:10.1021/acs.oprd.7b00153

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Article
pubs.acs.org/OPRD
Continuous Photo-Oxidation in a Vortex Reactor: Efficient
Operations Using Air Drawn from the Laboratory
Darren S. Lee,† Zacharias Amara,† Charlotte A. Clark,† Zeyuan Xu,‡ Bruce Kakimpa,‡ Herve P. Morvan,‡
Stephen J. Pickering,‡ Martyn Poliakoff,*,† and Michael W. George*,†,§
‡
†School of Chemistry, Department of Mechanical, Materials and Manufacturing Engineering, University of Nottingham, University
Park, Nottingham, NG7 2RD, U.K.
§Department of Chemical and Environmental Engineering, University of Nottingham Ningbo China, 199 Taikang East Road, Ningbo
315100, China
S
* Supporting Information
ABSTRACT: We report the construction and use of a vortex reactor which uses a rapidly rotating cylinder to generate Taylor
vortices for continuous flow thermal and photochemical reactions. The reactor is designed to operate under conditions required
for vortex generation. The flow pattern of the vortices has been represented using computational fluid dynamics, and the
presence of the vortices can be easily visualized by observing streams of bubbles within the reactor. This approach presents
certain advantages for reactions with added gases. For reactions with oxygen, the reactor offers an alternative to traditional setups
as it efficiently draws in air from the lab without the need specifically to pressurize with oxygen. The rapid mixing generated by
the vortices enables rapid mass transfer between the gas and the liquid phases allowing for a high efficiency dissolution of gases.
The reactor has been applied to several photochemical reactions involving singlet oxygen (1O2) including the photo-oxidations of
α-terpinene and furfuryl alcohol and the photodeborylation of phenyl boronic acid. The rotation speed of the cylinder proved to
be key for reaction efficiency, and in the operation we found that the uptake of air was highest at 4000 rpm. The reactor has also
been successfully applied to the synthesis of artemisinin, a potent antimalarial compound; and this three-step synthesis involving
1
a Schenk-ene reaction with O2, Hock cleavage with H+, and an oxidative cyclization cascade with triplet oxygen (3O2), from
dihydroartemisinic acid was carried out as a single process in the vortex reactor.
applied to photochemical reactions involving oxygen. Various
effective designs have been reported in the literature for these
reactions; falling film,18,19 bubble column,20 spinning disc,21−23
slug flow,24,25 high pressure,26−28 FEP tubular,29 parallel
tubular,30 rotating thin film,31 annular thin film,32 milling,33
and one recent design based on irradiating a nebulized liquid/
gas mixture for singlet oxygen chemistry.34
INTRODUCTION
■
Continuous flow chemistry is an increasingly popular
alternative to traditional synthetic batch operations in both
academic1,2 and industrial settings.3,4 As new developments are
made in synthetic methodology, fine chemical, and active
pharmaceutical ingredient (API) synthesis, there is parallel
interest in translating these methodologies to continuous
processes.5 Continuous flow chemistry can provide safer,
more efficient, and automated operations, and hence research
into this field is the focus of many academic groups. Reactions
where scalability in batch is problematic have often benefitted
from being applied to continuous reactors, and there have been
significant achievements in developing different approaches
with many reactor designs being developed that address specific
reaction difficulties.6−8
Photochemistry is an attractive synthetic tool, often deemed
a green methodology, as it is frequently associated with
efficient, mild and clean reaction conditions.9 Recently the field
has received much interest from both academic and industrial
groups and has been reviewed comprehensively.10−17 Con-
tinuous flow photochemistry presents significant advantages
over more traditional batch reactions, as smaller path length
reactors operating continuously can avoid issues such as light
penetration, over irradiation and reactor fouling allowing for
easier scale-up. For example photochemical reactions, where
the penetration of light is of key importance, have benefitted
greatly from a variety of innovative reactor designs.17 In this
paper we describe a new continuous flow reactor that we have
Reactions with molecular oxygen (O2) are highly desirable as
they are highly atom economical and environmentally benign,
and O2 is readily available and abundant in the atmosphere, but
scale-up can present issues. Molecular oxygen is often used as
an oxidant or as a reagent, where it can be incorporated into
molecules, in particular using photochemistry, where singlet
oxygen (1O2) is generated and reacted with electron-rich
functional groups.15,35−42 Such reactions are not often carried
out on a large scale because the use of pure oxygen poses
several risks.43 A recent example34 that highlights the dilemma
in scaling chemistry involving oxygen is a photoreactor design
in which reaction solutions are nebulized into an atmosphere of
O2 or air creating fine droplets that are then irradiated. The
large surface area of the droplets result in highly efficient
reactions because the interface between gas and liquid is
increased while the small diameter of the droplets means that
light can more easily penetrate the solution. When flammable
solvents are used, however, the problem of potential ignition or
Received: April 24, 2017
© XXXX American Chemical Society
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Figure 1. (a) Showing the deconstructed reactor with the motor and its control box. A drive belt connects the motor and the rotating cylinder.
During operation a protective housing (not shown) contains the motor, belt, and moving parts. (b) Showing the LEDs and mirror blocks mounted
place around the reactor. (c) Pipe diagram of the reactor setup showing the tubing connected to the reactor. Cooling is provided to the reactor by a
recirculating chiller. The 3 LED blocks are connected in series and are cooled by a separate recirculating chiller. (d) A cross-section (not to scale) of
the reactor showing the delivery and removal of reagents and the intake of air.
explosion of the solvent is always present. Safe operation is
often realized by working below the limiting oxygen
concentration (LOC), a region in which combustion is not
possible.44,45 In practice this is often achieved by using
atmospheric or “synthetic” air (≤20% O2 in N2) instead of
pure O2. Unfortunately, using mixtures of gases often results in
a loss of performance and slower reaction rates because lower
partial pressures of oxygen result in lower concentrations of O2
in the reaction mixture. Nonflammable solvents, such as
supercritical CO2 or H2O, can be used to reduce the
flammability issues associated with pure O2; even though
these solvents exhibit high gas solubility, many organic
substrates are virtually insoluble in them.46−48
Continuous flow reactors can be beneficial when using pure
oxygen,49−51 as the precise delivery of reagents and gases can be
controlled, thereby giving greater control over stoichiometry.
Furthermore, the reactors can be small, and the chances of
generating hazardous mixtures can be minimized. Continuous
flow reactors can be pressurized and have high interfacial areas
between the liquid and gas, allowing for greater dissolution of
gases into the solution. Pressurized systems introduce addi-
tional hazards into the overall process. The ideal reactor would
not be pressurized and would generate a large interfacial area
for the reaction solution to interact with the oxygen, which
would be supplied from the atmosphere. In essence, there is a
trade-off between the inherent safety of the reactor and the
volume of the gas phase and hence the area of the interface.
Here we describe a different approach with a large liquid
volume and relatively small gas phase volume but with a high
interface area because the gas is present as very small bubbles.
Our design is based on so-called “vortex reactors”52−59 which
have been developed over the past 30 years. Here we bring
together features from several previous reactors to make a
surprisingly efficient reactor for photochemical reactions
involving oxygen.60
A vortex reactor consists of a cylindrical outer vessel fitted
with a smooth inner cylinder such that there only a relatively
small gap between the inner and outer surfaces. The inner
cylinder is rotated at a relatively high speed, e.g., 4000 rpm
(revolutions per minute) and generates so-called “Taylor” or
“Taylor-Couette” vortices, relatively narrow toroidal vortices
threaded around the central cylinder; the precise nature of the
vortices and hence the degree of mixing depends quite strongly
on the dimensions of the reactor, the rotation speed of the
rotor, and the properties of the fluid. There are published
examples of vortex reactors operating in both vertical and
horizontal orientation. Our design brings together three key
features from earlier designs: (i) A vortex reactor for
photochemistry, first demonstrated for the cleanup of polluted
water using UV light and TiO2 particles suspended in the
water;58 (ii) the use of a vortex reactor for the thermal
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oxidation of benzaldehyde with O2 or air (unlike our reactor
this one operated horizontally).52,56 (iii) A non-chemical report
of an open-topped vortex reactor which drew air into the
reactor from the room as the rotor was spinning.57 Here we
explain how we have incorporated these three features, together
with modern high powered LED light sources, into a single
reactor for photochemical oxidations and validated our design
with dissolved oxygen studies. We then demonstrate its use
with four different reactions. Among the advantages of our
design is the fact that one does not require a separate supply of
oxygen or air; the reactor draws whatever air is needed from the
atmosphere of the laboratory.
The vortices within the annular gap occur when the
dimensionless Taylor number that characterizes the flow
conditions within the annulus is in excess of the critical value
of 1700 (see SI for more details). To visualize the vortex flow
structure, our reactor was modeled using computational fluid
dynamics (CFD). Water was modeled inside an annulus of the
same dimensions as the reactor with the inner cylinder rotating
at 100 rad s−1 (ca. 955 rpm), giving a Taylor number of about
100,000, well above the critical value for the formation of
Taylor vortices. Figure 2 shows the pattern of the vortices
RESULTS AND DISCUSSION
■
Reactor Design. The vortex reactor described in this study
was built in a vertical orientation such that LED blocks could be
more easily arranged around the outside of the reactor.61 The
reactor itself consists of a transparent Pyrex jacketed tube that is
sealed at the bottom and contains a polished stainless steel
cylinder with a narrow bore running coaxially through the
center. The gap between the cylinder and the jacket is ca. 1
mm. The rotation of the stainless steel cylinder is provided by a
spark free brushless motor that is housed to the side of the
reactor and is connected to the cylinder using a drive belt. The
top of the cylinder is held in place by an aluminum block to
ensure that it remains truly vertical; the block also houses
bearings to ensure that the rotor can be rotated freely at high
speeds (Figure 1).
Figure 2. (a) Zoomed-in view of vortices generated by modeling the
reactor with CFD, where the red areas, closest to the rotating shaft,
show a higher velocity fluid, and the dark blue areas show a lower
velocity fluid. (b) Generation of vortices along the length of the
reactor using CFD; again the red areas, closest to the rotating shaft,
show a higher velocity fluid, and the dark blue areas show lower
velocity fluid. (c) Photograph showing the bubble streams as the
reactor is spinning at 4000 rpm.
All moving parts, including the motor, drive belt, and the top
of the cylinder with its bearings are housed inside an aluminum
case so that they are contained during operation. The rotation
speed is adjusted by a control box connected to the motor; the
rotation speed can be set between 50−4000 rpm in both a
clockwise and anticlockwise direction. To deliver the reagents
into the reactor, the top of the reactor is fitted with a 1/16”
stationary Swagelok fitting that attaches to 1/16” tubing that
connects to a HPLC pump (JASCO Pu980). The reagents are
delivered by this pump into the top of the reactor and down
through the central bore of the stainless steel cylinder (Figure
1d). The jacketed Pyrex tube broadens out into a “cup” at the
top to allow the reagent solution to exit the vortex zone of the
reactor and be fed into an 1/8” PTFE tube connected to a
peristaltic pump (Masterflex L/S). The flow rate of the
peristaltic pump can be adjusted to suit the reagent delivery
flow rate so that there is no build-up of solution in the top of
the reactor. The presence of a free liquid surface at the top of
the reactor allows air to be entrained in the low-pressure region
generated by the rotation of the inner cylinder.
created inside the narrow gap of the reactor. The color shows
the velocity of the fluid, red is highest and dark blue is lowest.
Regular vortices can be observed along the length of the gap
between the cylinders. In previous work, the boundaries
between the vortices have been shown to contain gas and this is
often visualized as bubbles or streams of bubbles within the
reactor.57 Further modeling and calculations regarding the
generation of vortices in the reactor and description of our
dissolved oxygen studies are provided in the SI. Figure 2c
shows that, in reality, the streams of bubbles behave as
predicted, at least at a qualitative level. Not only does CFD
allow the fluid flow to be modeled, but it has the potential to be
developed to model the chemical reaction with light. This will
be done in further research, and such modeling can be used to
develop scaled up and optimized reactors.
Around the reactor sits a circular mount that holds three
LED blocks and three polished aluminum mirror blocks
(Figure 1a−b). Each LED block consists of 5 × 1400 lm
chips (Citizen Electronics part code: CL-L233-C13N1-C) and
are positioned ca. 0.5 cm away from the jacketed reactor. The
jacketed reactor and the LEDs are connected to recirculating
chillers to ensure that the reactor temperature is constant by
removing heat from operating the LEDs banks. The whole
reactor is mounted on a base which is dampened to limit any
vibrations created to by the reactor when it is operating at high
rotation speeds. Two pillars provide a guide to ensure the
housing containing the motor, drive belt, and the rotating
cylinder are positioned correctly and at the same height. This
allows for the whole set up to be easily removed, cleaned, and
replaced. Further details of the reactor are provided in the SI.
It has been shown previously that the UV−visible spectrum
of an aqueous alkaline solution of pyrogallol can act as a
quantitative measure of dissolved oxygen.62,63 As oxygen is
introduced, the initially colorless solution begins to turn yellow
and then an increasingly darker brown color as more colored
oligomeric and/or polymeric compounds are formed (Scheme
1). We used this approach to determine the effect of rotation
speed on the rate of oxidation of the pyrogallol solution and,
hence, as an indicator for the increased amount of O2 at higher
rotation speeds.
The results are shown in Figure 3. One can see from the
spectra that, as the rotation speed increases, there is a
corresponding growth in the intensity of the bands at 320
and 415 nm assigned to the products of oxidized pyrogallol.
There is a linear increase in the growth of the bands between 0
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Scheme 1. Oxidation of Pyrogallol with Air in an Alkaline
Solution
Scheme 2. Photo-Oxidation of α-terpinene 1 to Ascaridole 2
and the Common Byproduct p-Cymene 3
volumes were passed before the samples were taken to ensure
that the reactor had reached a steady state. The conversion of 1
and the yields of 2 and 3 are plotted against rotation speed in
Figure 4. Without any rotation, the yield of 2 was 35%; this
improved as the rotation speed was increased up to 3000 rpm
where the yield was 91%. Further increasing the spinning speed
to 3500 and 4000 rpm had a detrimental effect on the yield of 2
due to the increased formation of p-cymene (3). It is apparent
that as the speed was increased the reaction became more
efficient. At the higher speeds the shear forces and mixing will
be at their greatest; in addition gas−liquid interactions will be
at their highest. In other words, the amount of oxygen available
for reaction should increase as the rotation speed increases, and
it would appear that O2 is the limiting factor for the reaction at
the slower spin speeds. To test this, reactions at 1000 and 1500
rpm were repeated with double the concentration of photo-
sensitizer (4 mol %); the yields of 2 remained unchanged
suggesting that the amount of oxygen is indeed the limiting
factor at these speeds. In the case of 3500 and 4000 rpm, where
the yield of 2 drops as more p-cymene (3) is formed as a
byproduct, is possibly explained by the higher concentration of
oxygen at these speeds. In this case it is likely that the
photosensitizer is the limiting factor and the yield of 2 is less
because of the competing oxidation reaction forming 3 with
3O2. At 4000 rpm, when the concentration of Rose Bengal was
doubled (to 4 mol %) the ratio of 2 to 3 improved from 3.5:1
(at 2 mol %) to 9:1 (at 4 mol %) suggesting that the amount of
singlet oxygen generated was important for maintaining a high
selectivity. When 1 was flowed in the dark as a control
experiment, the amount of 3 increased with increasing rotation
speed, where the p-cymene (3) yield was 4, 8, 11, and 15% at
1000, 2000, 3000, and 4000 rpm, respectively.
Figure 3. (a) UV−vis absorption spectra of aqueous basic pyrogallol
solution (3 mM) measured after exiting the vortex reactor at several
rotation speeds (0−4000 rpm); the flow rate was maintained at 1.0 mL
−1
■
●
min . (b) Change in absorbance at 320 nm ( ) and 415 nm ( )
versus reactor rotation speed.
Next, the flow rate was changed while maintaining a fixed
rotation speed because it is possible that an increase in upward
flow could have an effect on the vortices. Flow rates of 0.5, 1.0,
1.5, and 2.0 mL min−1 were investigated (at 2000, 3000, and
4000 rpm). Increasing the flow rate, hence decreasing the
residence time in the reactor, led to a decrease in the yield of 1
at all rotation speeds. At 1.5 mL min−1 and more so at 2 mL
min−1, the yields of 1 are very similar regardless of the rotation
speed, suggesting that at these flow rates the amount of O2 is
comparable despite the difference in speed and suggests that
the higher upward flow rates have a greater or overriding effect
on the vortices (Figure 5).
and 3000 rpm with minimal further growth observed at 4000
rpm, suggesting oxygen saturation of the solution.
These results are in agreement with the general conclusions
of the modeling, which indicates that the flow regime in the
reactor is well above the Taylor number for vortices to occur
and that at higher speeds the mixing in the reactor will be more
vigorous. As further confirmation, we employed the vortex
reactor in several photochemical reactions involving oxygen; we
predicted that the yield should scale with the rotation speed.
Initially, the reactor was benchmarked against the some well-
known reactions before being applied to a more challenging
To confirm that the faster rotation speeds, i.e., 4000 rpm,
were the most efficient for reactions to be carried out, two more
photochemical reactions involving singlet oxygen were run in
the vortex reactor (Scheme 3). In the absence of a competing
1
3
reaction involving both O2 and O2.
The initial benchmark of the reactor was the photo-oxidation
of α-terpinene (1) (Scheme 2). The yield of ascaridole (2) was
measured at different rotation speeds and flow rates.
A solution of 1 in ethanol using Rose Bengal (2 mol %) was
flowed through the vortex reactor at a fixed flow rate of 0.5 mL
min−1 with the LEDs at full brightness. Beginning with the
cylinder stationary, the spinning speed was increased with
samples taken at increments of 500 rpm. Two full reactor
3
reaction with O2 reaction, it was hypothesized that a rotation
speed of 4000 rpm would be most efficient.
The photo-oxidation of furfural (4) with O2 is an unusual
1
reaction as the endoperoxide formed rearranges in the presence
of a nucleophilic solvent (i.e., water or alcohol) and results in
the breakage of a C−C bond to yield 5. When this reaction was
run in the vortex reactor, as expected, the yield increased with
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■
●
▲
Figure 4. Showing the effect of rotation speed on the conversion of 1 (− −) and the yields of 2 (− −) and p-cymene (− −). The reaction was
carried out on a 0.1 M solution of 1 in EtOH using Rose Bengal (2 mol %) with a fixed flow rate of 0.5 mL min−1 in air. The highest yield at 3000
rpm was 91% which is a productivity (prod.) of 2.73 mmol h−1 and a space time yield (STY) of 0.34 mmol h−1 mL−1. [Productivity = conc. × flow
rate × yield × 60 ; STY = productivity/reactor volume (8 mL)].
■
●
▲
Figure 5. Showing the effect of flow rate on yield of 2 with a fixed spin speed. (− − = 2000 rpm, − − = 3000 rpm, − − = 4000 rpm) using a 0.1
M solution of 1 in EtOH with Rose Bengal (2 mol %). Under these conditions the speed at which the reaction mixture was pumped was adjusted
1
and the yield of 2 monitored by H NMR.
the rotation speed, and at 4000 rpm the yield was highest at
73% (Scheme 3a). The second reaction run was a photoredox
reaction involving the generation of a superoxide radical anion
(O2•−) rather than the generation of singlet oxygen. The
photocatalytic hydroxylation of phenyl boronic acid (6)
proceeds from the incorporation of the superoxide radical
anion and subsequent rearrangement to the phenol.64,65 Using
Rose Bengal as the photosensitizer and NEt(i-Pr)2 (2 equiv) as
the reductive quencher, the reaction was run at different spin
speeds (Scheme 3b). At lower rotation speeds the conversion
of 6 was incomplete and resulted in significant quantities of
triphenylboroxine being formed; however, as the rotational
speed was increased from 1000 to 4000 rpm and thereby the
concentration of O2, the formation of this trimeric byproduct
was suppressed, and phenol (7) was formed as the major
product. Despite the vortex reactor showing a lower throughput
compared to the previously reported high pressure system (7.2
mmol h−1 vs 2.8 mmol h−1), it does show a 19-fold increase in
productivity when compared to that of previous batch reactions
that have been carried out in air.66 Furthermore, in previous
high pressure reactions the addition of 67 molar equiv of air (or
13 molar equiv of O2) at 2 MPa (20 bar) was required to obtain
complete conversion of 6.
In addition to photochemical reactions, a simple thermal
oxidation reaction was run in the vortex reactor. Using Stahl
aerobic oxidation conditions,67,68 the oxidation of benzyl
alcohol to benzaldehyde was carried out (Scheme 4). At
room temperature the reaction gave little conversion, but
increasing the temperature enhanced the conversion. As the
reactor is jacketed, the reaction temperature can simply be
controlled by adjusting the temperature settings on the
recirculating bath. At 80 °C the product was obtained in a
85% yield directly from the reactor.
Our next example involves both photochemical and thermal
steps and was carried out in the vortex reactor. Artemisinin
combination therapy is one of the most preferred methods for
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hydroperoxide 10 facilitated by H+, (iii) oxidation with triplet
O2 (3O2) and subsequent cyclization to afford 8.
Scheme 3. Yields against Rotation Speed for the Photo-
Oxidation for Furfural 4 and Phenyl Boronic Acid 6 in the
Vortex Reactor
a
While there are three steps from 9 to 8, the process is
generally carried out as a one-pot procedure as acid can be
added directly into the reaction mixture and the light source
1
can be turned off to stop the generation of O2.
The synthesis of artemisinin (8) has previously been
reported by our group, with aqueous mixtures of THF or
ethanol, which gave high yields for 8, employed as green
alternatives to more traditional reaction solvents, such as
dichloromethane.71 The previous batch protocol required
irradiation for 1−5 h followed by up to 24 h stirring with
bubbling O2. With the high gas liquid interface in the vortex
reactor, it was envisaged that the two steps could be carried out
simultaneously and produce artemisinin (8) directly from the
reactor. Initially, the steps were carried out independently to
verify the photo-oxidation step in the vortex reactor. A 0.05 M
solution of 9 in THF:H2O (3:2) containing [Ru(bpy)3]Cl2 (0.1
mol %) was flowed through the vortex reactor at 0.5 mL min−1
at 4000 rpm and 30 °C. Complete conversion of 9 to peroxides
10 and 11 (9:1) was observed in the mixture obtained from the
reactor outlet, so trifluoroacetic acid (TFA) was added to the
collected mixture of peroxides which were then stirred with
bubbling O2 for 24 h to yield artemisinin in 60% as previously
observed. When TFA was present in the reaction mixture from
the beginning, the results obtained after the reactor were more
complicated, and the overall conversion of 9 was reduced to
46% while the yield of 8 was obtained in just 5%. A variety of
conditions were screened to increase the conversion of 9 and
the yield of 8, as summarized in Table 1.
a
Prod. = productivity = flow rate × 60 × concentration × yield.
[Productivity = conc. × flow rate × yield × 60; STY = productivity/
reactor volume (8 mL)].
Scheme 4. Stahl Aerobic Oxidation Run in the Vortex
Reactor Using Air
a
Increasing the residence time by lowering the flow rate to
0.25 mL min−1 caused the yield of 8 increase accordingly to
10% (Table 1, entry 2), lower flow rates were attempted but led
a
Prod. = 2.55 mmol h−1. STY = 0.32 mmol h−1 mL−1 [Productivity =
conc. × flow rate × yield × 60 ; STY = productivity/reactor volume (8
mL)].
Table 1. Optimization of the Yield of 8 in the Vortex
Reactor
a
photosensitizer
TFA
temp. conv. yield 8
c c
b
the treatment of malaria at present.69,70 Hence there is
increased motivation for more efficient and cost-effective
routes to artemisinin (8) (Scheme 5),71−73 especially now as
the precursor dihydroartemisinic acid (9) can be prepared on
scale using bioengineered yeast.74 From 9 the synthesis of 8
proceeds in three steps (Scheme 5): (i) photo-oxidation of 9
with 1O2, (ii) Hock cleavage and rearrangement of the
entry
1
(mol %)
solvent
(equiv) (°C)
(%)
(%)
Ru (0.1)
Ru (0.1)
Ru (0.1)
Ru (0.1)
Ru (0.1)
THF:H2O
(3:2)
0.5
0.5
0.5
0.5
0.5
30
30
10
50
30
46
5
d
2
THF:H2O
(3:2)
64
10
e
3
4
THF:H2O
(3:2)
100
28
0
THF:H2O
(3:2)
<1
22
f
5
THF:H2O
(3:2)
100
Scheme 5. Formation of Artemisinin (8) from DHAA (9)
6
Ru (0.1)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
0.5
0.5
0.5
0.5
0.5
0.5
0.1
1
30
30
30
30
25
20
25
25
31
23
20
10
22
7
DCA (0.5)
DCA (2.0)
TPP (0.5)
TPP (0.5)
TPP (0.5)
TPP (0.5)
TPP (0.5)
8
41
9
100
100
100
100
100
45
g
10
11
12
13
50
39
49
48
a
Reactions run with 9 (0.05 M in solvent), 4000 rpm, 0.5 mL min−1.
b
Ru = [Ru(bpy)3]Cl2; DCA = 9,10-dicyanoanthracene; TPP =
c
1
tetraphenylporphyrin. Determined by H NMR with biphenyl as an
d
e
f
internal standard. 0.25 mL min−1. 10 77%, 11 23%. The reaction
g
mixture was recycled for 4 h. Prod. = 0.75 mmol h−1, STY = 0.094
mmol h−1 mL−1 [Productivity = conc. × flow rate × yield × 60 ; STY
= productivity/reactor volume (8 mL)].
F
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Scheme 6. Hock Cleavage Step from Peroxide 10 Leading to the Keto and Enol Intermediates, The Equilibrium of Which Likely
a
Determines the Rate at Which the Second Oxidation Occurs
a
In THF:H2O the equilibrium lies further to the keto form; hence the formation of 8 is slow. In nonpolar solvents, the enol form is likely to be more
favored which is demonstrated by an increase in the formation of 8.
to irreproducible results. Lowering the temperature to 10 °C
(Table 1, entry 3) slowed the Hock-cleavage step and yielded
predominantly the peroxides 10 and 11; however, this time, in
a 3.4:1 ratio, while no 8 was observed. Increasing the
temperature (Table 1, entry 4) proved detrimental to both
the yield and conversion. When the material was recycled for a
4 h period, the yield of 8 peaked at 22%, but after 6 h the yield
began to fall suggesting that product degradation was occurring
under prolonged irradiation in the vortex reactor. Since the
photo-oxidation step could be completed in one pass through
the reactor, it is likely that sufficient oxygen was present;
therefore, the limiting step was in the conversion of 10 to 8.
Considering the mechanism (Scheme 6) of the formation of 8
from 10 highlighted that the equilibrium constant of the keto
and enol tautomers and hence the rate of formation of 8.
Typically, keto tautomers are usually more stable than the enol.
This equilibrium, however, can be influenced by several
different factors favoring either form; in this case the type of
solvent appears to be the predominant factor.75 In polar protic
solvent mixtures where hydrogen bond donation to the ketones
will be prevalent, the keto form will be favored, as
demonstrated with aqueous THF or ethanol where the
formation of 8 from 10 is slow, up to 24 h.71 In less polar
solvents, such as CH2Cl2, toluene, or perfluorinated solvents,
the rate of formation of 8 from 10 is much faster; in this case,
intramolecular hydrogen bonding between the enol and
neighboring carbonyl will be predominant.72,76
reacted in the starting solution with TFA forming the
protonated porphyrin (TPP-H+), which is evident from the
mint green color of the reaction mixture. When TPP-H+ was
used, full conversion was observed, and a 45% yield of
artemisinin was obtained (Table 1, entry 9). When the
temperature was reduced to 25 °C, the yield increased further
to 50%. However, further reducing the temperature to 20 °C
proved to be detrimental to the overall yield (Table 1, entries
10−11). Finally, the concentration of TFA was changed to 0.1
and to 1 equiv, however, both of these concentration yielded
nearly identical results to using 0.5 equiv (Table 1, entries 12−
13). The similarity in yield of 8 at the three concentrations of
TFA is potentially indicative of greater mixing and mass transfer
properties of the vortex reactor and requires further studying as
the vortex reactor could be beneficial for other catalyst driven
reactions.
CONCLUSION
■
A continuous flow vortex reactor has been developed that
consists of a fast spinning rotor that sits tightly inside a jacketed
vessel; as it rotates toroidal vortices are generated in the narrow
space between the rotor and the jacket. This design brings
together key features of other vortex reactors; having a light
source for photochemistry and the introduction of air which is
drawn in from the laboratory atmosphere as the reactor spins.
CFD modeling of the parameters of the reactor gave
visualization of the vortex stream inside the reactor; this is
further supported by the visual appearance of streams of air
bubbles as the reactor spins. Rotation speed appears to be
directly linked to the amount of oxygen available to react, as at
4000 rpm, as reaction yields improved as the rotation speed was
increased. The synthesis of artemisinin was carried out in the
reaction, where the choice of solvent was key to successfully
transferring the reaction from batch to continuous; in polar
solvents, the final oxidation step was slow, but in nonpolar
solvents it was fast enough that artemisinin could be obtained
When toluene was used as the reaction solvent, the yield of 8
increased to 20%, but [Ru(bpy)3]Cl2 had poor solubility; hence
a poor conversion was observed (Table 1, entry 6). Switching
the photosensitizer to 9,10-dicyanoanthracene (DCA) afforded
1
a remarkably clean H NMR spectra showing 8, 9, and little
else, though both the yield and conversion were low (Table 1,
entry 7). When the concentration of DCA was doubled, the
conversion and yield increased 2-fold (Table 1, entry 8). When
tetraphenylporphyrin (TPP) was used in the reaction, it initially
G
DOI: 10.1021/acs.oprd.7b00153
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Organic Process Research & Development
Article
(6) Gutmann, B.; Kappe, C. O. Chim. Oggi. 2015, 33, 18−24.
directly from the reactor outlet in 50% yield when using TPP as
a photosensitizer. The concentration of acid made little
difference to the yield of artemisinin, suggesting that the
intrinsic mixing properties of the reactor are well-tuned for
catalytic reactions. It is possible that very low catalyst loadings
could be applied to reaction without any substantial loss in
efficiency. The reactors mixing properties could also be
beneficial for biphasic or triphasic mixtures, where having a
large interfacial area between two immiscible liquids or a
liquid−gas mixture greatly improves efficiency. Simple
modifications to the reactor would enable alternative gases to
be applied; furthermore hazardous gases could be diluted with
inert gases in the same way that oxygen is diluted in the air.
There is potential for scale up of the vortex reactor as one could
simply apply a rotor to an existing jacketed vessel much like the
kind already used in process chemistry. We are currently
developing a larger scale version of the vortex reactor and
exploiting the current reactor in new chemistry. The CFD
modeling will also be developed to include the photochemical
reactions and effects of the second phase. This will give better
understanding of the process to allow scale up with greater
confidence.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.7b00153.
■
S
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(PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: mike.george@nottingham.ac.uk.
*E-mail: martyn.poliakoff@nottingham.ac.uk.
■
ORCID
Darren S. Lee: 0000-0002-8288-1838
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(32) DeLaney, E. N.; Lee, D. S.; Elliott, L. D.; Jin, J.; Booker-Milburn,
K. I.; Poliakoff, M.; George, M. W. Green Chem. 2017, 19, 1431−1438.
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(34) Ioannou, G. I.; Montagnon, T.; Kalaitzakis, D.; Pergantis, S. A.;
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We thank EPSRC grants (EP/L021889/1), (EP/P013341/1),
and the University of Nottingham EPSRC Impact Acceleration
fund (EP/K503800/1) for supporting this work. The authors
also thank the Bill and Melinda Gates Foundation (grant no.
1070294). We also thank M. Dellar, C. Dixon, P. Fields, M.
Guyler, D. Lichfield, M. McAdam, and R. Wilson for technical
support at the University of Nottingham. D.S.L. and C.A.C.
would also like to thank Dr. Z. Abada, Dr. R. Horvath, E. N.
DeLaney, and S. Miller for their useful discussions.
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