A Study of aerobic photooxidation with a continuous-flow microreactor

Article abstract of DOI:10.1055/s-0034-1379698

We report the development of an aerobic photooxidation process with a continuous-flow microreactor that can form a slug flow region on the chip. The approach solved several problems raised by using batch systems.

Full text of DOI:10.1055/s-0034-1379698

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 412–415
letter
412
Y. Nagasawa et al.
Letter
Synlett
A Study of Aerobic Photooxidation with a Continuous-Flow Micro-
reactor
Yoshitomo Nagasawaa
LED lamp
Katsuya Tanbab
Norihiro Tadaa
O2
Eiji Yamaguchia
Akichika Itoh*a
a Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu
501-1196, Japan
itoha@gifu-pu.ac.jp
b Dexerials Corporation, 30 Kaganosakai, Takaraeniida, Nakada-
cho, Tome-shi, Miyagi, 987-0622, Japan
solution of substrate
microreactor
product
Received: 29.09.2014
Accepted after revision: 12.11.2014
Published online: 07.01.2015
large decrease in the energy of light traveling through the
reaction mixture. Initially, effective contact between the
gas and liquid phases is required for the gas–liquid reaction
to proceed smoothly. Furthermore, in general, the distance
light travels depends on both the molar extinction coeffi-
cient (ε) and the molar concentration (c).4 Thus, light can-
not pass through a reaction vessel when a substrate of high
concentration or high absorbance is used, because light is
absorbed only near the internal surface of the vessel. This
may decrease the reaction rate and/or produce by-products.
To increase the speed of this reaction, such problems must
be addressed. Additionally, we found a decrease in the yield
of the product, which was unstable under the reaction con-
ditions. For example, in our experiments, during the oxida-
tion of indane to 1-indanone, by-products were formed by
over-oxidation of the product under the irradiation condi-
tions mentioned above. Although it is necessary to quickly
remove the products from the reaction mixture, it is diffi-
cult to remove only the products in batch reactions. Fur-
thermore, processing the large amount of remaining oxy-
gen is important in batch reactions.
We attempted to solve these problems by using a glass
continuous-flow microreactor,5 which allows light to pene-
trate, as the reaction device. Continuous-flow microreac-
tors have commonly been used for gas-liquid reactions due
to their large specific interfacial area.6 In general, the for-
mation of by-products by over-reaction can be avoided
through control of the flow rate. Furthermore, the use of
continuous-flow microreactors is much safer than the op-
eration of batch reactors because the remaining oxygen is
quickly pushed out of the channel, thus reducing the risk of
explosion. Aerobic photooxidation with a continuous-flow
microreactor has been reported for the synthesis of endo-
peroxide and hydroperoxide, which are key intermediates
of ascaridole7 and artemisinin.8
DOI: 10.1055/s-0034-1379698; Art ID: st-2014-u0822-l
Abstract We report the development of an aerobic photooxidation
process with a continuous-flow microreactor that can form a slug flow
region on the chip. The approach solved several problems raised by
using batch systems.
Key words oxygen, photooxidation, green chemistry, microreactor,
slug flow
Oxidation is an important transformation in industrial
organic synthesis because it is necessary to produce func-
tional materials from crude oil, which is extracted in an ex-
tremely reduced form from underground reserves. Thus,
many methods and reagents for oxidation have been previ-
ously reported.1 Recently, catalytic oxidation processes us-
ing molecular oxygen as a terminal oxidant have also been
reported.2 Although molecular oxygen has garnered a great
deal of attention as the ultimate oxidant because it is pho-
tosynthesized by plants, produces little waste, costs little,
and has a higher atom efficiency than other oxidants, previ-
ously reported methods require drastic reaction conditions,
such as high pressure, high temperature, or the use of heavy
metals.
With the aim of improving the characteristics of the ex-
isting methods, we studied catalytic photooxidation with
molecular oxygen and have developed several oxidation
methods that involve the use of mild conditions.3 These ox-
idations are appealing in terms of green chemistry because
of the absence of heavy metals, waste reduction, and the
use of molecular oxygen; however, we found that longer re-
action times, on the order of 10 hours, were required to ox-
idize only 0.3 mmol of starting material in batch reactions.
This is due to both the small specific interfacial area and a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 412–415

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Y. Nagasawa et al.
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With these reaction characteristics in mind, we de-
signed a continuous-flow microreactor that can be used to
form a slug flow region on the chip that can be irradiated by
intense light from a very short distance. In slug flow, inter-
nal circulation occurs within each slug, accelerating the
mixing of the gas and liquid phases and increasing the reac-
tion rate.9 Furthermore, the high-speed internal circulation
within the liquid slugs of a gas–liquid slug-flow can prevent
precipitation on the channel walls and prevent blockages in
the channel by continually washing the channel surface.
Slug flow was also expected to be more suitable than pipe
flow in our case because the liquid phase flows along the
wall and the gas phase flows in the center of the channel.10
Here, we report the results of our detailed study of aerobic
photooxidation with our proposed continuous-flow micro-
reactor.
Figure 2 Microreactor with 375 nm LED
We used a flow microreactor constructed by Dexerials
Corporation that was fitted with a glass chip containing
channels measuring 500 μm width, 300 μm depth, and
2400 mm length (Figure 1). The chip was irradiated by
375 nm LED (sum: 11.4 W) at a distance of 1 mm from the
surface of the chip (Figure 2). Figure 3 shows the slug flow
formed by this reactor, which was used for subsequent re-
actions described here.
Figure 3 Slug flow formed by the microreactor
cates the time required to consume all starting material
(0.3 mmol); however, the actual reaction time on the chip is
only approximately 1–2 minutes. The yield relative to the
total electric energy of light sources (%/Wh) for this reactor
was much higher than that for batch reactor, which was
0.1% or less (footnotes b and c in Table 1).3l These results
show that reactions with the microreactor proceed much
Table 1 Study of Reaction Conditions
Figure 1 Glass chip of microreactor
The result of the oxidation of 4-tert-butyltoluene (0.3
mmol), a test substrate, to 4-tert-butylbenzoic acid in the
presence of 2-tert-butylanthraquinone (2-t-Bu-AQN) acting
as a photosensitizer under 0.1 MPa of oxygen flow, are
shown in Table 1.11 Although a reaction time of 10 hours
was required for a batch system and substrate concentra-
tions as low as 60 mmol/L were required due to the de-
crease in light permeability, this substrate was oxidized
much faster when using the microreactor for concentra-
tions up to 500 mmol/L. We examined the reaction rate,
and the product was consistently obtained in good yield. A
flow rate of 5 μL/min gave the best result, giving the prod-
uct in 83% yield. The reaction time shown in Table 1 indi-
O
2 (0.1 MPa)
CO2H
hν (375 nm LED)
2-t-Bu-AQN (0.1 equiv)
t-Bu
t-Bu
(0.3 mmol: 0.5 mol/L of EtOAc solution)
Entry
Flow rate (μL/min)
Time (h)
Yield (%)a
1
2
3
2
5
5
2
1
76
83b
70c
10
a Based on 1H NMR spectroscopic analysis.
b 3.6%/Wh.
c 6.1%/Wh
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 412–415

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Y. Nagasawa et al.
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faster than those with the batch system, meaning the con-
tinuous-flow microreactor is suitable as a reaction device
for aerobic photooxidation.
The scope and limitations of this reaction with the mi-
croreactor without further optimization are summarized in
Scheme 1. Although the yield varied depending on the com-
pound, in general, a considerable number of products could
be obtained much faster than were obtained by using a
batch system under our best reaction conditions.3l
Table 2 Oxidation of Indane to 1-Indanone
O
O2 (0.1 MPa)
hν (375 nm LED)
80 min
(0.32 mmol: 0.4 mol/L of EtOAc–MeOH = 1:1 solution)
Entry
2-t-Bu-AQN Solution rate O2 rate
1-Inda-
Recoveryof
(equiv)
(μL/min)
(mL/min)
none (%)a indane (%)a
1
2
3
4
5
6
7
8
9b
0.02
0.03
0.04
0.06
0.08
0.10
0.12
0.20
0.20
10
10
10
10
10
10
10
10
20
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.50
42
50
56
64
70
74
80
74
83
48
44
37
33
31
11
12
12
10
O
2 (0.1 MPa)
hν (375 nm LED)
2-t-Bu-AQN (0.1 equiv)
substrate
product
flow rate (5 μL/min)
(0.3 mmol: 0.5 mol/L of EtOAc solution)
CO2H
CO2H
CO2H
MeO
t-Bu
48%, 2 h
(58%, 24 h)
83%, 2 h
(97%, 12 h)
80%, 2 h
(86%, 18 h)
a Based on GC analysis.
b Reaction time was 40 min.
CO2H
CO2H
In conclusion, we have examined the development of an
aerobic photooxidation system with a continuous-flow mi-
croreactor, and solved several problems raised by the use of
batch systems. Although many reaction devices designed
for photoreactions have been studied previously, the glass
continuous-flow microreactor, which had not been previ-
ously studied, is a very suitable reaction device for photore-
actions. Studies on the mass production of larger reactor
chips and linking together series of chips are in progress in
our laboratory.
Cl
51%, 1 ha
30%, 2 h
(68%, 36 h)
(70%, 30 h)
Scheme 1 Scope and limitations of the flow microreactor. Yields based
on 1H NMR spectroscopic analysis. Numbers in parentheses are isolated
yields under obtained by using our previous batch reaction.3l a Flow
rate: 10 μL/min
As mentioned above, we found that oxidation of indane
to 1-indanone in the batch system resulted in the formation
of many by-products, such as 1,3-indandione or ring-
opened compounds, by over-oxidation of 1-indanone. Table
2 shows the results obtained by using the continuous-flow
microreactor. From our detailed examination of the amount
of catalysts, the rate of solution, and the presence of oxy-
gen, 80% of 1-indanone was successfully obtained when us-
ing 0.12 equivalent of 2-t-Bu-AQN, a solution flow rate of
10 μL/min, and an O2 flow rate of 0.25 mL/min (entry 7).
The product was obtained in 83% yield when using 0.20
equivalent of 2-t-Bu-AQN, a solution flow-rate of 20
μL/min, and an O2 flow rate of 0.50 mL/min (entry 9). By us-
ing a batch system, the maximum yield was 60%, many by-
products were formed, and the material balance too was
low (60%). Conversely, a high yield of 1-indanone and a
trace amount of recovered indane with a high material bal-
ance (93%) was obtained by using the continuous-flow mi-
croreactor. We believe that 1-indanone is quickly flushed
from the reactor channel and is thus no longer over-oxi-
dized under the continuous-flow reaction conditions.
References and Notes
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Y. Nagasawa et al.
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(11) Typical Procedure with Flow Microreactor: A solution of the
substrate (0.3 mmol) and photosensitizer (0.1 equiv) in EtOAc
(0.6 mL) was introduced into one of the channels by using a
syringe pump. Simultaneously, molecular oxygen (0.1 MPa) was
introduced into the second channel from a gas cylinder con-
trolled by a mass flowmeter. Both streams were mixed in the
channel of the reactor chip to form a slug flow. Light (375 nm)
from an LED array (sum: 11.4 W) was used to irradiate the slug
flow from a distance of 1 mm from the chip surface The product
1
was collected in a vial tube and analyzed by H NMR spectros-
copy.
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