Accelerated organic photoreactions in flow microreactors under gas-liquid slug flow conditions using N2 gas as an unreactive substance

Article abstract of DOI:10.1246/bcsj.20190117

In this work, the [2+2] photocycloaddition of carbonyl compounds with olefins, the Paternò-Büchi-type photoreaction, was performed in a flow microreactor under slug flow (two-phase flow) conditions which are constructed by alternatively introducing nitrog

Full text of DOI:10.1246/bcsj.20190117

Document type: Article
Accelerated Organic Photoreactions in Flow Microreactors under Gas-
Liquid Slug Flow Conditions Using N2 Gas as an Unreactive Substance
Momoe Nakano,1 Tsumoru Morimoto,1 Jiro Noguchi,1 Hiroki Tanimoto,1 Hajime Mori,2
Shin-ichi Tokumoto,2 Hideyuki Koishi,2 Yasuhiro Nishiyama,*2 and Kiyomi Kakiuchi*1
1Division of Materials Science, Graduate School of Science and Technology, Nara Institute
of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0101, Japan
2Department of Chemical Industry, Industrial Technology Center of Wakayama Prefecture (WINTEC),
60 Ogura, Wakayama 649-6261, Japan
E-mail: kakiuchi@ms.naist.jp (K. Kakiuchi), y-west@wakayama-kg.jp (Y. Nishiyama)
Received: April 26, 2019; Accepted: June 1, 2019; Web Released: August 24, 2019
Kiyomi Kakiuchi
Kiyomi Kakiuchi received his Ph.D. in 1982 from Osaka University under the direction of Professor
Yoshinobu Odaira. In 1982, he was appointed as an assistant professor at Osaka University. After spending
a year as a postdoctoral associate at the Scripps Research Institute with Professor K. Barry Sharpless
(1993–1994), he was promoted to associate professor in 1996. He then moved to the Nara Institute of
Science and Technology (NAIST) as a full professor in 1997. He has been the Executive Director and Vice
President in NAIST since 2017. He received the Incentive Award in Synthetic Organic Chemistry from The
Society of Synthetic Organic Chemistry, Japan in 1992 and the APA Award for Distinguished Achievements
to the APA form the Asian and Oceanian Photochemistry Association in 2018. His research interests include
synthetic organic chemistry, with emphasis on the development of novel skeletal transformations and their
applications and new methods for organic photoreactions using a microreactor.
Yasuhiro Nishiyama
Yasuhiro Nishiyama received his Ph.D. in 2008 from Osaka University under the direction of Professor
Yoshihisa Inoue. After working at Sumitomo Rubber Industries, Ltd. as a technical officer, he joined
Kakiuchi’s group at Nara Institute of Science and Technology (NAIST) as a postdoctoral fellow in 2010.
Between 2012 and 2017, he worked at that institute as an assistant professor. He then moved to the
Industrial Technology Center of Wakayama Prefecture (WINTEC) as a researcher. He was promoted to
Deputy Chief Researcher in 2018. He was the recipient of the Thieme Chemistry Journal Award and the CSJ
Presentation Award in 2015 (The 95th CSJ Annual Meeting). In addition, he received the Young Researcher
Award in the Graduate School of Materials Science (NAIST) in 2017. His research interest is in synthetic
organic chemistry, with emphasis on organic photoreactions using a microreactor.
Abstract
more, the use of N2 gas as an unreactive substance was found to
be applicable to other Paternò-Büchi-type photoreactions.
In this work, the [2+2] photocycloaddition of carbonyl com-
pounds with olefins, the Paternò-Büchi-type photoreaction, was
performed in a flow microreactor under slug flow (two-phase
flow) conditions which are constructed by alternatively intro-
ducing nitrogen gas as an unreactive substance into the organic
reaction phase. The use of N2 gas-liquid slug flow conditions
permitted the organic photoreactions to proceed more effi-
ciently compared to one-phase flow conditions. A detailed
investigation of the influence of the flow mode, the viscosity of
the solvents, and the segment length (length of each phase) on
the efficiency of the photoreaction was conducted. Based on the
results, we concluded that these three factors contribute to the
improvement in photoreaction efficiency under slug flow
conditions using N2 gas as an unreactive substance. Further-
Keywords: [2+2] Photocycloaddition
Slug flow
j
Flow microreactor
j
1. Introduction
Organic photoreactions that proceed via the excited state
permit the production of highly distorted or complex com-
pounds due to the very highly activated excited species.1 It
should be noted in this regard that it is very difficult to produce
these types of compounds by conventional thermal reactions
because excited species cannot be formed in a thermal reaction
process. Thus, the key for organic photoreactions to proceed
Bull. Chem. Soc. Jpn. 2019, 92, 1467–1473 | doi:10.1246/bcsj.20190117
© 2019 The Chemical Society of Japan | 1467

(a) One-phase flow mode
light source
Flow
Toluene
R. I. 1.50
Water
R. I. 1.33
(a) Light confinement
reactant solution
normal flow
FEP tube R. I. 1.34
(b) Two-phase flow mode
light source
(b) Thin layer
Toluene
Toluene
Water
reactant solution
mixer
Thin layer
unreactive substance
slug flow
(c) Internal vortex
mixing
Water
Figure 1. Experimental apparatus for photoreactions using
flow tube.
Figure 2. The three factors for highly efficient photo-
reaction in flow tube. R. I. means the refractive index.
smoothly depends on the efficient generation of such an excited
species by light irradiation, in other words, a high level of the
absorption of light by substances. The absorption of irradiated
light by reactants follows the Beer-Lambert law: A = ¾ © c © l
(where A is the absorbance, ¾ is the absorption coefficient
characteristic of the reactant, c is the molar concentration of the
reactant, and l is the length of the optical path). According to
this law, reactants near the irradiated surface of a reactor are
more easily excited, but, as the reactor becomes larger, it
becomes more difficult to irradiate the entire solution. The
highly concentrated solutions that are typically used to produce
large amounts of products also inhibit the penetration of light.
The prolonged irradiation time needed to overcome these
problems frequently results in the production of undesired side
reactions and over reactions.
factors:6 the light confinement effect7 in which the light irradi-
ated in the reactor is partially reflected at the interface between
the substrate solution segment and the unreactive segment, and
between the reactant solution segment and the tube wall
because of the difference in their refractive indices (Figure 2a).
In this environment, a photon can be confined in a small
segment of the organic solution, leading to the very effective
excitation of the reactant.
The second factor is the formation of a thin layer of the
reactant solution between the water segment and the FEP (fluor-
inated ethylene-propylene copolymer) tube wall (Figure 2b).
Such a thin layer of reactant solution is frequently found in a
flow microreactor.3b,8 For example, Oelgemöller et al. observed
a thin layer of a water solution between the air segment and the
tube wall, which was made of glass, under slug flow condi-
tions.9 The formation of a thin layer results in a quite efficient
photoirradiation through the extremely short path length.
The third is the effect of internal vortex mixing10 in a reac-
tant solution segment. The slug flow mode produces an internal
fluid vortex, which causes the rapid mixing in each segment
(Figure 2c). This internal vortex mixing is a characteristic fea-
ture of slug flow conditions and it can accelerate the reaction.
Hitherto, we have concentrated our interest on a slug flow in
which water is used as an unreactive substance; however, this
slug flow method cannot be applied to reactions of reagents that
are soluble in or reactive with water. Herein, we report on the
use of N2 gas as an unreactive substance under slug flow condi-
tions in the [2+2] photocycloaddition of ethyl benzoylformate
with 2,3-dimethyl-2-butene, i.e., Paternò-Büchi-type reactions.
The use of N2 gas as an unreactive substance can eliminate the
need to separate the unreactive substance from the reaction
mixture after the reaction. We also examined the issue of
whether the above three factors that improve reaction efficiency
are involved in slug flow conditions in which N2 gas is used in
place of water as an unreactive substance. We also performed
Paternò-Büchi-type reactions of other substrates under these
slug flow conditions.
A flow microreactor with a narrow flow channel has recently
attracted considerable interest in the area of organic photo-
chemistry,2 because the short path length (l) of such a
microreactor allows the reactants to be excited more efficiently.
In addition, the flow method can suppress the development
of over reaction owing to the long photoirradiation time by
discharging the primary products to the outside of the reactor.
Therefore, flow reactors are favorable for highly efficient and
productive reactions by virtue of the fact that the photo-
irradiation time can be shortened. Indeed, numerous reports on
the use of flow microreactors in organic photoreactions have
appeared over the past decade.3 Our group has also published
some reports on the use of flow microreactor techniques in
various organic photoreactions.4 Furthermore, we quite recently
developed some highly efficient organic photoreactions under
novel slug flow conditions.5 Slug flow conditions are generally
employed in heterogeneous reaction mixtures consisting of a
liquid and a liquid or a liquid and a gas phase, both of which
are involved in the transformation. On the other hand, the slug
flow conditions that we developed consisted of a reactant solu-
tion (organic solution) phase and an unreactive substance (a
water) phase which does not participate in the photoreaction.
Consequently, the slug flow mode using an unreactive sub-
stance phase (Figure 1b) resulted in a dramatic increase in both
the conversion of a substrate and the chemical yield of a final
product, compared to corresponding reactions in a one-phase
flow mode (Figure 1a).5 It was also shown that the slug flow
mode resulted in higher productivity.5b
2. Experimental
2.1 General Considerations. 1H and 13C NMR spectra
were recorded using a JEOL JNM-ECP500 spectrometer (500
MHz for 1H NMR, and 126 MHz for 13C NMR). Chemical
shifts are reported as δ values in ppm and referenced to the
In our last report,5b we concluded that the improvement in
reaction efficiency can be attributed to the following three
1468 | Bull. Chem. Soc. Jpn. 2019, 92, 1467–1473 | doi:10.1246/bcsj.20190117
© 2019 The Chemical Society of Japan

1
residual solvent peak (CDCl3: δ 7.26 for H NMR and δ 77.00
(MEMRECAMfx K5 made by nac Image Technology Inc.).
The original movies are included in the supporting information.
for 13C NMR). The abbreviations used are as follows: s
(singlet), d (doublet), t (triplet), q (quartet), br (broad), and m
(multiplet). Analytical gas chromatography (GC, Shimadzu
GC-2025) was carried out with a ZB-WAX plus column.
Helium gas was used as the carrier gas. Melting points were
measured using a Yanaco Micro melting point apparatus.
Infrared spectra were collected on a JASCO FT-IR-4200 spec-
trometer. Mass spectra were recorded using a JEOL JMS-700
MStaion [EI-magnetic sector (70 eV), ESI-TOF]. The progress
of the reactions was monitored by silica gel thin layer chroma-
tography (TLC) (Merck TLC Silica gel 60 F254). A phos-
phomolybdic acid ethanol solution was used to detect com-
pounds and a UV lamp was also used to detect compounds.
Flash column chromatography was performed using Merck
Silica gel 60. If necessary, crude materials were further purified
using an LC-908 recycling gel permeation chromatograph
equipped with a JAIGEL 2H-40 column (chloroform elution)
made by Japan Analytical Industry Co. Spectrograde toluene
was purchased from Wako Pure Chemical Industries. Ethyl
benzoylformate, 2,3-dimethyl-2-butene, 4,4¤-dimethylbenzo-
phenone, 3-methyl-2-buten-1-ol, pentadecane, nonadecane, m-
xylene, o-xylene and 1,2,4-trimethylbenzene were purchased
from Tokyo Chemical Industry, Co. Ltd. Triphenylmethane was
purchased from Sigma-Aldrich. All of the above reagents were
used without further purification. Among them, pentadecane,
nonadecane and triphenylmethane were used as an internal
3. Results and Discussion
3.1 Examination of Slug Flow Using N2 Gas. In this
work, the Paternò-Büchi type photoreaction of ethyl benzoyl-
formate with 2,3-dimethyl-2-butene was used as a model reac-
tion (Scheme 1).11 An FEP tube was used as a microcapillary
reactor (i.d.: 1 mm) in the experimental apparatus, as shown in
Figure 3. A 500 W high pressure mercury lamp (Hg lamp) was
employed as a light source. The slug flow was produced
through a ¯-mixer.
In initial experiments, photoreactions under various flow
modes were examined (Table 1). The reaction efficiency was
improved when N2 gas-slug flow conditions were used, similar
to water-slug. At the same 10 sec of photoirradiation, when slug
flow conditions were used, the conversion was 1.4 times higher
h
ν
O
O
(light source)
OEt
OEt
solvent, time
10°C, 0.01 M
flow conditions
O
O
2.0 eq
Scheme 1. Paternò-Büchi photoreaction of ethylbenzoylfor-
mate with 2,3-dimethyl-2-butene under various conditions.
High pressure
Hg lamp
1
standard material for H NMR and GC.
2.2 Apparatus for Photoreactions. A 500 W high pressure
Hg lamp (USHIO INC.) was utilized as the light source, with a
Pyrex immersion well. The reaction setup was placed in a water
cooled bath for temperature control (10 °C). For flow con-
ditions, FEP (Nirei Industry Co., Ltd.) tubing (inner diameter
(i.d.): 1.0 mm) was employed for irradiation units. FEP tubing
was tightly wound around a Pyrex immersion well (Figure 1).
The flow rates of both organic solutions containing reactants
and N2 gas were controlled by syringe pumps (YMC Co., Ltd.).
A μ-mixer ((MiChS Co., Ltd.) i.d.: 600 ¯m) was used as a T-
shaped connecter.
FEP tubing
Water bath
μ-mixer
Syringe pump
2.3 Photoreactions in a Flow Microreactor. FEP tubing
was utilized as an irradiation unit. An appropriate amount of
carbonyl compound (0.10 mmol, 0.01 M) and internal standard
(0.06 mmol, 0.60 equiv) were placed in a flask, and purged with
nitrogen gas for 5 min at room temperature. The solvent (10
mL) in the other flask was also purged with nitrogen gas for
10 min at room temperature, and moved to the first flask via
syringe. The olefin (0.20 or 1.0 mmol, 2.0 or 10 equiv) was then
added to the solution. This solution was loaded into a gas-tight
syringe, and attached to a syringe pump. Nitrogen gas was also
loaded into another gas-tight syringe when slug flow conditions
were used. T-shaped mixer inlets were connected to both gas-
tight syringes, and the outlet was connected to the irradiation
unit. The solution and nitrogen gas flow rates and the length of
the FEP tube were controlled based on the target irradiation
time. After irradiation, conversions and yields were determined
Figure 3. Reaction setup for Paternò-Büchi type photo-
reactions with the Hg lamp using FEP tube as flow
microreactors.
Table 1. Paternò-Büchi photoreactions in toluene using flow
microreactors under slug flow conditions with nitrogen
gasa.
Improvement
Unreactive
Phase
Conv. Yield
Entry
Modeb
(%)c
(%)c
Conv. Yield
1
2
3d
One
Two
Two
32
44
55
21
30
36
Nitrogen
Water
1.4
1.7
1.4
1.7
a) Photoirradiation time of 10 s, flow rate is the reactant
solution:unreactive substance = 1.178 ml/min:1.178 ml/min.
b) “One” stands for one-phase flow conditions, “two” stands
for slug flow conditions. c) Determined by gas chromatog-
raphy, average of two runs, internal standard is pentadecane.
d) Data from ref 5b.
1
by GC or H NMR.
2.4 Images of the Flow Conditions. Instant images of the
movie of flowing fluid were captured using a Nikon SMZ18
research stereo microscope equipped with a high-speed camera
Bull. Chem. Soc. Jpn. 2019, 92, 1467–1473 | doi:10.1246/bcsj.20190117
© 2019 The Chemical Society of Japan | 1469

100
90
80
70
60
50
40
30
20
10
0
70
60
50
40
30
20
10
0
Table 2. Paternò-Büchi photoreactions in toluene under
static conditions with nitrogen gasa.
(a)
(b)
Improvement
Conv. Yield
Conv.
(%)c
Yield
(%)c
Entry
Modeb
Slug flow
Slug flow
1
2
One
Two
26
37
17
22
One-phase flow
One-phase flow
1.4
1.3
10
30
50
time (s)
70
90
10
30
50
time (s)
70
90
a) Photoirradiation time of 10 s, length ratio is reactant solution
phase:nitrogen gas phase = 1:1. b) “One” stands for one-phase
conditions, “two” stands for slug conditions. c) Determined by
gas chromatography, average of two runs, internal standard is
pentadecane.
Figure 4. Time course plots of (a) conversion and (b) yield
in Paternò-Büchi-type photoreactions under one-phase
flow (red line) and slug flow conditions using N2 gas
(blue line).
Tol. sol.
(a)
One-phase
Toluene
N2
(b)
N2
Two-phase
Tol. sol.
N2
Figure 5. Photoreaction under static conditions (no flow
condition). Refractive index of toluene is 1.5, nitrogen gas
is 1.0, FEP tube is 1.34.
1 mm
Figure 6. Image taken with a stereomicroscope showing
(a) slug flow consisting of a toluene solution and nitrogen
gas, length ratio is reactant solution phase:nitrogen gas
phase = 1:1. (b) FEP tube with only flowing nitrogen gas.
than when one-phase flow conditions were used (Entries 1 and
2). N2 gas was found to be applicable as an unreactive sub-
stance for the slug flow conditions. In addition, this enhance-
ment was also observed at higher conversions and yields after a
more prolonged photoirradiation (Figure 4).
does so at the boundary between the toluene phase and N2 gas
phase as well as between the toluene phase and the FEP tube
wall. As a result, more photons remain in the organic solu-
tion segment, even under the two-phase mode using N2 gas as
an unreactive substance. Furthermore, the extent of improve-
ment in the conversion and yield from one-phase flow to two-
phase flow under flow conditions were nearly the same, com-
pared to those under static conditions. These results indicate
that the light confinement effect affects the reaction efficiency
under two-phase flow conditions.
3.2 Examination of Light Confinement Effect. Light
confinement through the reflection of the irradiated light should
be derived from the difference in the refractive indices between
the organic solution segment and the unreactive segment and
between an organic solution segment and a flow tube wall
(Figure 5). In order to determine whether this phenomenon
actually occurred, even when N2 gas is used as an unreactive
substance, we examined the influence of N2 gas on the effi-
ciency of the slug flow photoreaction under static conditions
(no flow mode). Although flow under slug flow conditions
generates internal vortex mixing in each segment, this type of
mixing can be ruled out when static conditions are used, thus
only the light confinement should affect the reaction effi-
ciency.12 Under two-phase conditions consisting of the reactant
solution and nitrogen gas, the solution was photoirradiated
without flowing after forming the slug regime. Table 2 includes
results of photoreaction of ethyl benzoylformate with 2,3-
dimethyl-2-butene under static conditions. Even under static
conditions, the two-phase reaction (Table 2, Entry 2) resulted
in a higher conversion of the substrate and product yield than
the one-phase reaction (Entry 1).
3.3 Examination of the Formation of a Thin Layer. We
attempted to directly observe the formation of a thin layer of
the organic reaction solution between the N2 segment and the
FEP tube wall, using a stereomicroscope.
Figure 6 shows an image of the direct observation of the
slug flow consisting of the reactant solution and N2 gas.
Compared to the state where only N2 gas flows in the FEP tube
(Figure 6b), we were not able to detect clear evidence for the
formation of a thin layer of toluene solution (Figure 6a).
On the other hand, we obtained some preliminary results to
indicate a thin layer of the reactant solution is actually formed
between the N2 gas segment and the FEP tube. It is well-known
that a thin layer of reactant solution is formed between a gas
phase and the flow tube wall due to the affinity of reactant solu-
tion for the flow tube.8 Therefore, if a thin layer of a reactant
solution were formed, the reaction efficiency would depend on
the length of the N2 gas segment. When the length of the N2
segment was extended with respect to that of the organic reac-
tion phase at a constant rate, both the conversion of the sub-
strate and the product yield were increased compared to the
These results show that a part of the irradiated light remains
in the organic reaction field through reflected light derived from
the difference in refractive indices between the organic solution
and N2 gas (refractive index: toluene 1.49; N2 1.00; FEP 1.34).
In the case of the one-phase mode, the irradiated light partially
reflects only at the boundary between the reactant solution and
the FEP tube wall, while, in the case of the two-phase mode, it
1470 | Bull. Chem. Soc. Jpn. 2019, 92, 1467–1473 | doi:10.1246/bcsj.20190117
© 2019 The Chemical Society of Japan

1.9
1.75
1.6
Table 3. The Paternò-Büchi photoreactions in toluene using
flow microreactors under slug flow conditions with various
nitrogen gas segment lengtha.
toluene
(1.49)
Improvement
m-xylene
(1.50)
Segment
Conv. Yield
Entry Modeb
Length (mm)c (%)d
(%)d
Conv. Yield
o-xylene
(1.50)
1
2
3
4
5
One
Two
32
21
30
38
35
35
1.45
1.3
trimethyl
benzene
(1.50)
1:1
44
54
50
49
1.4
1.7
1.6
1.5
1.4
1.8
1.7
1.7
1:3-4
1:5-6
1:12-15
0.6
0.7
0.8
0.9
1
1.1
1.2
1.3
Viscosity (cP)
a) Photoirradiation time is 10 s. b) “One” stands for one-
phase flow conditions, “two” stands for slug flow conditions.
c) Length ratio is reactant solution:nitrogen gas. d) Determined
by gas chromatography, average of two runs, internal standard
is pentadecane.
Figure 7. Yield improvement versus solvent viscosity. The
numbers in parentheses show the refractive index of
solvents. Length ratio is reactant solution phase:nitrogen
gas phase = 1:3-4. Photoirradiation time is 10 s.
Table 4. Paternò-Büchi photoreactions using 4,4¤-dimethyl-
benzophenone and 2,3-dimethyl-2-butene in flow micro-
reactors under slug flow conditions with nitrogen gasa.
result of the one-phase flow reaction (Table 3). However, this
improvement in conversion and yield did not increase when the
N2 gas segment length exceeded 3-4 mm. Detailed studies con-
cerning this observation are currently underway. These results
suggest that a thin layer of reactant solution may be formed
between the nitrogen gas phase and the FEP tube wall.
3.4 Examination of an Internal Vortex Mixing Effect. It
is well-known that high speed mixing can occur in flow
microreactors due to the presence of narrow channels.10 Under
slug flow conditions, there is difference in flow velocity
between the center of the stream and the vicinity of the tube
wall, resulting in highly efficient stirring accompanied by an
internal fluid vortex in each segment.10c Such an environment
would be predicted to increase the frequency of collisions of all
reactants and, as a result, would accelerate the intermolecular
reaction. Stirring efficiency is dependent on the viscosity of the
solvent:13 The lower the viscosity of the solvent, the higher will
be the mixing rate inside the reaction field. We investigated the
influence of solvent viscosity on the efficiency of the photo-
reaction under the conditions of Entry 3 in Table 3. Four kinds
of solvents with similar refractive indices but different viscos-
ities were examined to make the influence of light confinement
almost identical in all the solvent.
ν
h
(500 W Hg lamp)
Toluene
10°C, 0.01 M
O
O
10 eq
Improvement
Irr. Time Conv. Yield
(sec)
Entry Modeb
(%)c
(%)d
Conv. Yield
1
2
3
One
Two
30
30
180
32
49
96
16
26
54
1.5
1.6
a) Flow rate is the reactant solution:nitrogen gas = 1.178
ml/min:1.178 ml/min. b) “One” stands for one-phase flow con-
ditions, “two” stands for slug flow conditions. c) Determined by
1H NMR, average of two runs, internal standard is nonadecane.
d) Determined by gas chromatography, average of two times,
internal standard is nonadecane.
Table 5. Paternò-Büchi photoreactions using ethyl benzoyl-
formate and 3-methyl-2-buten-1-ol in flow microreactors
under slug flow conditions with nitrogen gasa.
ν
h
O
O
(500 W Hg lamp)
OEt
OEt
OH
Toluene
10°C, 0.01 M
O
O
As shown in Figure 7, improvement value of product yield
decreased with increasing solvent viscosity. Thus, from these
results, the effect of internal vortex mixing in the reaction field
is clearly related to the reaction efficiency.
10 eq
HO
Improvement
Irr. Time Conv. Yield
(sec)
Entry Modeb
(%)c
(%)c
Conv. Yield
3.5 Applications to Other Paternò-Büchi Type Organic
Photoreactions. We next examined the present slug flow
method using N2 gas to other Paternò-Büchi-type reactions.
Results for the reactions of 4,4¤-dimethylbenzophenone,14
instead of ethyl benzoylformate, as a substrate in a [2+2]
photocycloaddition reaction are shown in Table 4. The reaction
under slug flow conditions (Entry 2) proceeded more efficiently
to give the corresponding oxetane derivative than one-phase
flow conditions (Entry 1). Furthermore, when the reaction time
(irradiation time) was extended to 180 seconds, this photo-
reaction produced a product yield of 54% (Entry 3).
1
2
3
One
Two
10
10
100
54
76
100
19
31
40
1.4
1.6
a) Flow rate is the reactant solution:nitrogen gas = 1.178
ml/min:1.178 ml/min, steric configuration of product is
determined from NOESY analysis. b) “One” stands for one-
phase flow conditions, “two” stands for slug flow conditions.
c) Determined by 1H NMR, average of two runs, internal
standard is triphenylmethane, this internal standard added after
photoreaction.
When ethyl benzoylformate was reacted with 3-methyl-2-
buten-1-ol15 under a similar slug mode, the reaction proceeded
more efficiently to give a higher yield of the cycloaddition
product than was obtained when the one-phase flow mode was
used (Table 5). The reaction of 3-methyl-2-buten-1-ol is
characteristic of the present flow mode, because 3-methyl-2-
buten-1-ol is water-soluble and therefore not applicable to slug
Bull. Chem. Soc. Jpn. 2019, 92, 1467–1473 | doi:10.1246/bcsj.20190117
© 2019 The Chemical Society of Japan | 1471

Table 6. Paternò-Büchi photoreactions using 4,4¤-dimethyl-
benzophenone and 3-methyl-2-buten-1-ol in flow micro-
reactors under slug flow conditions with nitrogen gasa.
Science (JSPS), and a Grant-in-Aid for Scientific Research on
Innovative Areas in Middle Molecular strategy (JP18H04414)
from the Ministry of Education, Culture, Sports, Science, and
Technology (MEXT). M. N. is grateful to the NAIST Presi-
dential Special Fund for supporting this research. In addition,
this work was supported by JKA and its promotion funds from
KEIRIN RACE. We would like to thank Industrial Technology
Center of Wakayama Prefecture (WINTEC) for the stereo-
microscopes measurement.
ν
h
(500 W Hg lamp)
OH
Toluene
10°C, 0.01 M
O
O
10 eq
HO
Improvement
Irr. Time Conv. Yield
(sec)
Entry Modeb
(%)c
(%)c
Conv. Yield
Supporting Information
1
2
3
One
Two
10
10
100
32
43
98
16
25
54
1.3
1.6
The supporting information contains experimental details
including NMR analyses and characterization of compounds.
This material is available on https://doi.org/10.1246/bcsj.
20190117.
a) Flow rate is the reactant solution:nitrogen gas = 1.178
ml/min:1.178 ml/min. b) “One” stands for one-phase flow con-
ditions, “two” stands for slug flow conditions. c) Determined by
1H NMR, average of two runs, internal standard is nonadecane.
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This work was supported, in part, by a Grant-in-Aid for
Young Scientists (B) (No. 25870437, JP16H04333), a Grant-
in-Aid for Scientific Research (B) (No. 24310101,
JP15H03544) from the Japan Society for the Promotion of
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© 2019 The Chemical Society of Japan | 1473