Accepted Manuscript

Title: Utilization of Microflow Reactors to Carry Out

Synthetically Useful Organic Photochemical Reactions

Author: Kazuhiko Mizuno Yasuhiro Nishiyama Takuya

Ogaki Kimitada Terao Hiroshi Ikeda Kiyomi Kakiuchi

PII: S1389-5567(16)30021-1
DOI: http://dx.doi.org/doi:10.1016/j.jphotochemrev.2016.10.002
Reference: JPR 250

To appear in: Journal of Photochemistry and Photobiology C: Photochemistry

Reviews

Received date: 30-5-2016

Accepted date: 31-10-2016

Please cite this article as: Kazuhiko Mizuno, Yasuhiro Nishiyama, Takuya Ogaki,
Kimitada Terao, Hiroshi Ikeda, Kiyomi Kakiuchi, Utilization of Microflow
Reactors to Carry Out Synthetically Useful Organic Photochemical Reactions,
Journal of Photochemistry and Photobiology C:Photochemistry Reviews
http://dx.doi.org/10.1016/j.jphotochemrev.2016.10.002

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Utilization of Microflow Reactors to Carry Out Synthetically Useful Organic

Photochemical Reactions

Kazuhiko Mizuno,1,* Yasuhiro Nishiyama,1 Takuya Ogaki,2,3 Kimitada Terao,1

Hiroshi Ikeda,2,3 Kiyomi Kakiuchi1

1
Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST),

8916-5 Takayamacho, Ikoma, Nara 630-0101, Japan

2
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture

University, 1-1 Gakuen-cho, Nakaku, Sakai, Osaka 599-8531, Japan

3
The Research Institute for Molecular Electronic Devices (RIMED), Osaka Prefecture

University, 1-1 Gakuen-cho, Nakaku, Sakai, Osaka 599-8531, Japan

*Corresponding Author. Tel.:+81-743-72-6084

E-mail address: kmizuno@ms.naist.jp (K. Mizuno)

Keywords: Microreactor; Flow chemistry; Microreactor photochemistry; Synthetic organic

photochemistry; Slug flow

Graphical abstract

1
Abstract

This review focuses on recent advances that have been made in conducting synthetically useful

organic photochemical reactions by using microflow reactors. Attention is given to the

utilization of this technique in the scale-up of a variety of photochemical processes including

intermolecular photocycloadditions, intramolecular photocycloadditions and photocyclizations,

photoadditions, photoreductions, photoisomerizations, photosubstitutions, photooxidations,

photorearrangements, and heterogeneous photocatalytic reactions. In many examples, the use

of the microflow method is compared to those carried out in batch systems. Finally, advantages

and disadvantages of microflow photoreactions along with the possible employment of this

approach to scale-up industrial photochemical processes are discussed.

Contents

1. Introduction

2. Synthetic Photochemical Reactions

2
 2.1. Intermolecular Photocycloadditions

2.2. Intramolecular Photocycloadditions and Photocyclizations

2.3. Photoadditions

2.4. Photoreductions

2.5. Photoisomerizations

2.6. Photosubstitutions

2.7. Photooxidations

2.8. Photorearrangements

2.9. Heterogeneous Photocatalytic Reactions

3. Conclusion

4. Acknowledgements

References

1. Introduction

In the past two decades, the microflow reactor technology has been developed to become

a convenient approach for conducting a variety of synthetically useful organic reactions under

homogeneous and heterogeneous conditions [16]. This new technology has several

advantageous features. Firstly, the temperature of a reaction can be precisely controlled because

the specific surface area of the system is large and thermal (heat) capacity is small. Also, the

reaction time [the residence time (tR) in a flow system] can be readily controlled by the solution

flow rate and reactor size. The reaction vessel and attending apparatus are relatively small and

the mixing time of reactant solutions is short. Moreover, the surface to volume ratio of the

3
reaction system can be high [3,5]. In addition, efficient heterogeneous reactions can be

performed by using laminar flow and alternating flow (slug flow) systems. For example,

(photo)oxidations can proceed very efficiently in alternating flow systems composed of organic

solutions and molecular oxygen (see the section 2.7). This is because the contact area between

organic solution and oxygen gas increase dramatically under the alternating flow conditions.

Furthermore, the formation of secondary products and/or by-products is suppressed because of

the short residence times of the primary products. Lastly, solvent and reagent wastes are

minimized [3,5]. Because of the latter benefits, reactions in microflow reactors are

environmentally friendly. Although reactions performed using this approach have some

drawbacks including crystallization and polymerization occurring within the flow system and

some laborious scale-up procedures, microflow reactors recently can be alternative reactor to

traditional batch apparatuses in not only thermal reactions but also photoreactions, because of

many advantages, as already described.

Below, we describe recent advances in studies of large scale, synthetically useful, organic

photochemical reactions carried out in microflow reactors [734]. It should be noted that even

though the term microflow reactor is used in this review, a variety of terms have been utilized

to describe this system including flow microreactors, flow reactors and microreactors in the

original literatures. Microflow reactions were initially explored mainly by the use of stainless

reactors and high pressure pumps. However, to apply this technique to photochemical

processes, the materials employed are restricted because of the requirements associated with

light transmission and absorption. Therefore, transparent glass or resin microflow reactors have

been designed for this purpose. Also, it is important to note at this point that all the solution

4
phase photoreactions conform with the BeerLambert law governing light absorption by

substrates in solutions (Eq. 1, where I0 and I are incident and transmitted light intensities,

respectively). Specifically, light absorbance, A, depends on the molar extinction coefficient ()

and concentration (c) of the substrate, and the path length (l).

A = log (I0/I) = cl (Eq. 1)

General schematics showing the characteristics of batch and microflow photochemical reaction

systems are displayed in Fig. 1. In batch systems, only substrate molecules close to the surface

of the solution absorb light when they are present in high concentrations and have large molar

extinction coefficients. Another problem is that primary products, which have long residence

times in batch reactors, can also absorb light and be transformed to secondary products. In

contrast, light is absorbed through out the entire reaction solution in a microflow system, even

when the substrate is present in a high concentration and when it has a large molar extinction

coefficient. Moreover, the primary product is prevented from accumulating because of its short

residence time in the irradiated region.

Up to now, two types of microflow reactors have been employed conventionally. One is a plate

type reactor (Figs. 2a and 2b), which was initially the mainstream. This reactor is composed of

a microchannel, a cover glass, and some pumps, etc. Because these parts are integrated to the

sole apparatus, plate type reactors are generally robust. However, there are some disadvantages;

expensiveness, low flexibility (size, scale, and shape), and clogging, etc.

The other is a tubular reactor using fluorinated ethylene propylene (FEP) or

polytetrafluoroethylene (PTFE) tubes (Fig. 2c). Tubular reactors are the main current in these

days and widely used because of their many benefits; low cost, high flexibility, and ease of

5
replacement of used tubes, etc. These advantages of tubular reactors overcome the sole

disadvantage, relatively low robustness of tubes. In this review, we focus on the recent progress

in organic photochemistry synthesis using microflow reactors. Thus we do not handle the detail

of apparatuses or the matter of the chemical reaction engineering about microflow reactor. They

are shown in a recent review [32].

Batch systems

Lamp Lamp Lamp Lamp

hn hn hn hn

Diffusion Diffusion
Secondary
reaction
Starting materials
Microow systems Primary product
Lamp Secondary product

hn

Fig. 1. Photoreactions in batch and microflow systems.

Fig. 2. Photographs of microchannels in plate-type microflow reactors; (a) KeyChem-Lumino

6
(YMC) and (b) Dwell Device. (c) Photographs of the flow channel in FEP tubing equipped

with an Hg lamp.

2. Synthetic Photochemical Reactions

Many synthetically applicable, batch system promoted photochemical reactions, classified

as either being conducted using a direct irradiation or (photo)sensitized method (Scheme 1),

have been uncovered in the past several centuries. In these processes, a substrate (S) [either

reactant or (photo)sensitizer (PS)] absorbs light to produce its singlet excited state (1S*) that

can undergo intersystem crossing to form its triplet state (3S*), either of which can participate

in a variety of photochemical processes or undergo energy or electron transfer. Photoreactions

can be classified into a number of different categories depending on the nature of the molecular

change occurring. Examples of these categories include intermolecular photocycloadditions,

intramolecular photocycloadditions and photocyclizations, photoadditions, photoreductions,

photoisomerizations, photosubstitutions, photooxidations, photorearrangements, and

heterogeneous photocatalytic reactions.

In a photochemical reaction, the light absorbing species can serve as a photosensitizer that

promotes but is not consumed in the process. For unknown reasons, current day synthetic

organic chemists have coined the term photoredox catalysts for what has been used for years

termed photosensitizers. Furthermore, some chemists often confuse photoredox catalysts

and photocatalyst. It should be noted that, from the mechanistic point of view, photocatalyst

and photosensitizer are quite different, while photoredox catalysts is essentially the same

with photosensitizer. Photocatalyst was initially used for metal-oxide-semiconductors

7
such as TiO2. In this case, reactants are firstly adsorbed on the surface of photocatalysts, which

then react with an electron or a hole at the conduction or valence band, respectively, generated

upon excitation of photocatalyst. Therefore, in this sense, photocatalyst promotes the inner-

sphere electron transfer reactions in a heterogeneous manner. On the other hand,

photosensitizer, is initially used for materials which promote photoinduced energy-transfer

reactions of organic compounds, and afterward, is also used for those which trigger

photoinduced electron-transfer reactions in an outer-sphere manner. In the former case, the

excited state of the photosensitizer 1PS* undergoes energy transfer with the substrate S to form

its singlet excited state 1S* and the ground state of the photosensitizer PS (Scheme 1). Because

the intersystem crossing efficiencies of some substrates, in particular ketones, are high, energy

transfer from their excited triplet states 3PS* takes place to produce triplet states 3S*. The

excited states of photosensitizers PS* can also either accept or donate a single electron from or

to appropriate donors or acceptors, respectively. In photosensitized electron transfer reactions,

the redox properties of PS and S, and the excited state energies of PS are important in

determining the direction and energetics (thus rates) of electron transfer. Moreover, single

electron transfer between S and 1PS* and/or 3PS* generates radical ion pairs composed of

radical cations and radical anions, i.e. S+ and PS or S and PS+, whose properties govern the

nature of the chemical processes that take place. Recently, there are many reports about

photochemical organic synthesis using small amount of organometallic compounds containing

Ru or Ir. Usually, these organometallic compounds are utilized as catalyst in thermal

reactions; however, from photochemical point of view, these organometallic compounds

operate as a photosensitizer (Scheme 2) [35]. On the other hand, many organic chemists are

8
used to an expression catalyst to these compounds. Thus, from these perspectives, in this

paper, we distinguish clearly the term both photocatalyst and photosensitizer. For

organometallic compounds, we used the term photoredox catalyst.

In early studies in the area of organic photochemistry, both direct and sensitized methods

were used to carry out batch reactions. However, the use of this approach makes it difficult to

avoid secondary photoreactions and to achieve large-scale (mass) production. Because of the

large number of drawbacks that are associated with batch type large scale photochemical

reactions, new fundamentally different techniques were needed. This need led to the

development of microflow reactors that can be utilized to carry out both direct and energy and

electron transfer sensitized processes. In the following sections, we discuss the results of

studies that have shown that this approach is applicable to synthetically useful organic

photochemical transformations. This presentation follows a format that is based on the

categories for photochemical photoreactions presented above.

Photosensitized ! Photosensitized ! S: Substrate

Direct Irradiation
Energy Transfer Electron Transfer PS: Photosensitizer
P: Product(s)
1S* : Chemical Reactions

S + 1PS*
Potential Energy

P
S + 3PS*
3S* S+ + PS
or S + PS+
hn
PS hn
P
P

S + (PS)

Reaction Coordinate

9
 Scheme 1. Schematic representation of possible direct and sensitized pathways for

photochemical reactions of organic compounds.

1[PSn]*
A D PSn: Ru(II) or Ir(III) complex
3[PSn]*
D: sacrificial electron donor
A: sacrificial electron acceptor
S: Substrate
P: Product(s)
A D +
: Chemical Reactions

Oxidative Reductive
PSn+1 Quenching hn Quenching PSn1
Cycle Cycle

S S

PSn

S+ S

Scheme 2. A typical photoredox cycle using organometallic compounds as a photosensitizer.

2.1. Intermolecular Photocycloadditions

Intermolecular photocycloadditions are synthetically useful reactions that have been

applied to the one-step preparation of cyclic organic compounds that can only be difficulty

generated using ground state reactions. Because of their unique features, these processes have

served as key steps in synthetic routes targeted at a number of interesting natural products [36].

In one example, Ryu investigated the [2+2] photocycloaddition reaction of benzophenone

with 3-methyl-2-buten-1-ol in benzene, carried out using a microflow reactor, that affords 3,3-

dimethyl-4,4-diphenyl-2-oxetanemethanol in a regioselective manner (Scheme 3) [37]. The

10
yield of this process was found to be dependent on the light source [300-W high-pressure

mercury lamp, 15-W black light, and low power ultraviolet (UV) light-emitting diodes (LEDs)],

residence time (tR), and nature of the glassware (quartz, soda lime). A method for carrying out

regioselective oxetane forming reaction of 2,3-dihydrofuran with benzaldehyde was also

reported [38].

hn OH
O (Hg lamp, black light, LED lamp) O
OH
+
benzene Ph
Ph Ph Ph
Microflow Reactor (plate)
(Hg lamp, quartz) tR = 1.2 h 91%
(black light, quartz) tR = 1.2 h 65%
(black light, quartz) tR = 4 h 84%
(black light, soda lime) tR = 4 h 34%

Scheme 3. [2+2] Photocycloaddition of benzophenone with 3-methyl-2-buten-1-ol. Ph;

phenyl.

Yamashita and Yasuda found that the photoreaction of 4-penten-1-ol in an acetonewater

solution under batch conditions affords 8-hydroxy-2-octanone in a 66% yield along with two

oxetanes (83:17 ratio) in a 10% total yield (Scheme 4) [39]. In the absence of water, a

complicated mixture of products is produced. The formation of 8-hydroxy-2-octanone in this

process was explained in terms of Markovnikov-type addition of the MeCOCH2 radical, which

is generated by hydrogen abstraction of the excited triplet state of acetone from ground state

acetone, to 4-penten-1-ol. On the other hand, irradiation of 4-penten-1-ol in an acetonewater

23:77 solution using a microflow (channel) reactor gives rise to oxetanes (91:9 ratio) as major

products. The yields of the oxetanes were found to increase with an increase in the flow rate of

microflow reactor.

11
 Me
OH Me Me hn (Hg lamp) OH Me OH OH Me
+ + O +
O acetoneH 2O O Me O
Me
Batch Reactor 100% conversion
(Pyrex test tube), 40 min 66% 10% (83:17)
Microflow Reactor 92% conversion
(plate), tR = 2.0 min 5% 24% (91:9)
(based on consumed 4-penten-1-ol)

Scheme 4. Photoreaction of acetone with 4-penten-1-ol. Me; methyl.

Ralph and Booker-Milburn reported a scalable synthesis of cytotoxic lactone (+)-

goniofufurone involving PaternBchi reaction between a bicyclic enol ether and

benzaldehyde as a key step (Scheme 5) [40]. Using a three-layer FEP continuous microflow

reactor, this key reaction afforded over 40 g of a 67:33 mixture of a desired oxetane and a

structural regioisomer in a single 83-h run.

OAc H OAc H OAc H

H O
O hn (Hg lamp) O O 4 steps HO O
+ + O
Ph H MeCN Ph O
O O O Ph O
O H
H (1.4 equiv) Microflow Reactor H H HO H
(FEP tubing) Ph
(+)-goniofufurone
83 h, tR = 70 min 42 g, 97% (67:33)

Scheme 5. A photochemical approach to (+)-goniofufurone. Ac; acetyl.

Kakiuchi described the chemo- and diastereo-selective formation of oxetanes in the

photoreaction of l-menthyl benzoylformate with 2,3-dimethyl-2-butene by the use of slug flow

microcapillary reactors (Scheme 6) [41]. The slug flow is the specific flow mode where two

different phases (ex. liquid-gas or liquid-liquid) are flowing alternately in microflow reactors.

Compared to the reaction employing a batch reactor, the process is seven times faster under the

normal one-layer flow condition. Interestingly, the reaction carried out under the slug flow

condition using toluene as an organic solvent and unreactive substrates like nitrogen gas or

12
water is faster than that using a one-layer system owing to the high refractive index of toluene.

Although an enhancement of diastereoselectivity does not occur, a very efficient photoreaction

can be achieved by using only the simple flow mode.

O hn (Hg lamp)
+
O toluene, 0.05 M, 10 C
O

O O
+
O O
O O

major minor
Batch Reactor
(Pyrex test tube), 420 s 54% (50% de)
Microflow Reactor
(FEP tubing; one-layer flow), tR = 60 s 53% (50% de)
(FEP tubing; slug flow, N2), tR = 44 s 56% (50% de)
(FEP tubing; slug flow, H2O), tR = 30 s 56% (51% de)

Scheme 6. Photoreaction of l-menthyl benzoylformate with 2,3-dimethyl-2-butene.

It is well-known that photocyclodimerization of maleic anhydride gives an anti-

cyclobutane product, which is an industrially important raw material for the preparation of

polyimides. However, this photochemical process has problems associated with difficulties in

the selection of proper solvents, the control of temperature and the deposition of the crystalline

cycloadduct. Horie developed an excellent method for carrying out this photoreaction that

utilizes a microflow reactor with FEP tubing (Scheme 7) [42]. The problem of clogging caused

by crystallization of the cycloadduct was solved by the use of the liquid (ethyl acetate)/gas

(nitrogen) slug flow technique along with ultrasonication. Moreover, the precipitated

cyclobutane 1,2,3,4-tetracarboxylic dianhydride can be readily separated by using filtration and

the recovered maleic anhydride can be recycled (Fig. 3).

13
 O O O
hn (Hg lamp)
O O O
AcOEt, N 2,
O Microflow Reactor O O
(FEP tubing; slug flow, N2)
(see Fig. 3) 2969% conversion
tR = 5.911.8 min

Scheme 7. Photocyclodimerization of maleic anhydride. Et; ethyl.

N2
Filter unit
UV lamp

FEP tubing

Magnetic stirrer

ow liquid layer

N 2 gas precipitated FEP tubing

product
Plunger pump
Ultrasonic wave

Fig. 3. Continuous recycle microflow reactor with filter unit.

Photocyclodimerization reactions of cinnamates in acetonitrile in a microflow system

afford - and -truxinate derivatives in a 50:50 ratio. Addition of a bis(thiourea) sensitizer

enhances the reactivity and enables a moderate level of diastereoselectivity (-truxinate

selective) in this photoreaction (Scheme 8) [43].

14
 Scheme 8. Photocyclodimerization of cinnamate derivatives. dr; diastereomeric ratio.

Reprinted with permission from ref. [43]. Copyright 2015 Wiley-VCH Verlag GmbH & Co.

KGaA, Weinheim.

Regioselective photocycloaddition reactions of 2-cyclohexenone with electron-donating

alkenes such as 1,1-dimethoxyethene were reported over 50 years ago by Corey [44]. The

regiochemical course of these photoreactions was proposed to be a consequence of the

formation and reaction of excited state oriented -complexes, now referred to as

exciplexes. [2+2] Photocycloaddition reactions of a variety of alkenes to 2-cyclohexenones

and 2-cyclopentenones have been conducted by using a microflow reactor [37,4547].

Fukuyama and Ryu first described [2+2] photocycloadditions of 2-cyclohexenone with

electron-donating alkenes such as vinyl acetate and n-butyl vinyl ether in a microflow system

comprised of a glass-made microchannel having 1000-m width and 500-m depth. These

15
reactions generate the corresponding cyclobutanes as mixtures of diastereoisomers in high

yields (Scheme 9) [37,45]. The yields of this process (microreactor: 88%, batch reactor: 8 %)

are higher and the reaction times are shorter for the process performed under microflow

compared to those under batch conditions. Jensen also reported the [2+2] photocycloaddition

of 2-cyclohexenone with cyclopentene using a microflow system [46].

O O
hn (black light)
+
OR Microflow Reactor (plate)
OR
R = Ac, Bu 82% (R = Ac)
51% (R = Bu)
O O
hn (black light)
+
OR Microflow Reactor (plate)
OR
R = Ac, Bu 69% (R = Ac)
81% (R = Bu)

O O
hn (black light)
+
OR Microflow Reactor (plate)
OR
R = Ac, Bu
69% (R = Ac)
75% (R = Bu)

Scheme 9. [2+2] Photocycloadditions of a variety of alkenes to 2-cyclohexenones. Bu; butyl.

Kakiuchi investigated diastereoselective photocycloaddition reactions of 2-

cyclohexenones that possess chiral auxiliaries with cyclopentene, which take place efficiently

(Scheme 10) [4749]. Because the preferred conformation of the substrate determines

stereochemistry in these photoreactions, the level of diastereoselectivity can be enhanced by

lowering the temperature. Compared to reactions carried out using a batch reactor, processes

performed using a microflow reactor, in which the temperature can be precisely controlled,

take place with higher diastereoselectivities (syn-A:syn-B = 91:9 for microreactor, 86:14 for

16
batch reactor; anti-A:anti-B = 77:23 for microreactor, 72:28 for batch reactor).

O hn O O
H H H H
(Hg lamp, LED lamp)
+
toluene, 40 C
CO2 R*
Microflow Reactor R*O2 C H R*O 2C H
(plate) syn-A anti-A
100% conversion 50% 50%
(Ar = Ph) (91) (77)

R* : O O
H H H H
Ar

Ar = Ph, 4-MeOC 6H4, 2-Naphthyl

R*O2 C H R*O 2C H
syn-B anti-B
(9) (23)

Scheme 10. Diastereoselectiv.e photocycloadditions of 2-cyclohexenones containing chiral

auxiliaries with cyclopentene.

Intermolecular photocycloadditions of 2-cyclopenten-1-one with 2,5-dihydrofuran,

performed by using a liquid-liquid slug microflow reactor, yields a photochemically unstable

cyclobutane (Scheme 11) [50]. The primary product of this process can be obtained by using

the in situ filtering agent, 2-hydroxybenzophenone, which absorbs light at similar wavelengths

as does the cyclobutane (Figs. 4 and 5). The reaction in a batch system generates the [2+2]

cycloadduct initially, which then decomposes to form the [3.2.0]bicycloheptene derivative

through the Norrish I type reaction. Thus, the microreactor is superior to inhibit the

overreaction forming the secondary product.

17
 H
O O

O O
O H
hn (Hg lamp) hn
+ O O O
organic solventwater
Batch Reactor 97% conversion
(test tube) 7% 23%
Microflow Reactor 93% conversion
(plate; slug flow) 44% 8%
(see Fig. 4, 5) (based on consumed 2-cyclopenten-1-one)

Scheme 11. Intermolecular photocycloaddition of 2-cyclopenten-1-one with 2,5-dihydrofuran

and the secondary photodecomposition reaction.

H organic
O O solvent
lamp

inner ltering agent

hn

slug ow
O O

+ O O

reactant water product

Fig. 4. Liquid (inner filtering agent)liquid (substrates) slug microflow reactor.

Fig. 5. The design of the microflow reactor for the process shown in Scheme 11.

Intermolecular photocycloadditions of 1-chlorocyclopentene with cyclopentenone

18
derivatives by using of a flat-bed solar light collector under an argon gas affords [2+2]

photocycloadducts in a 54% yield. The product is a key intermediate in a route for preparation

of the taxane ABC ring system (Scheme 12 and Fig. 6) [51]. The photoreaction is four times

faster than that in batch systems when it is performed using a parabolic trough solar

concentrator.

O Cl O
Cl
hn (sunlight)
+
Microflow Reactor
RO2CO
(flat-bed solar OCO 2R
R = alkyl light collector)
(see Fig.6) 54%

Scheme 12. Intermolecular photocycloaddition of 1-chlorocyclopentene with cyclopentenone

derivative.

sunlight

1. Glass or plastic lm (with valve)

2. Reaction chamber
1 3 3. Reaction chamber oor (can be
2 mirrored and/or surface
4 structured)
4. Cooling chamber (e.g. water
5 cooling)
5. Heat exchanger
6 6. Ground

Fig. 6. The design of microflow reactor (flat-bed solar light collector) for the process shown

in Scheme 12.

Photocycloaddition reactions of maleimide with various alkenes, such as 1-octene and

allylamine, in a simple custom-made UV flow reactor, having residence time (tR) of 10 min,

were found to generate [2+2] cycloadducts more efficiently compared with those carried out

using a batch system (Scheme 13) [52]. Booker-Milburn described a variety of large scale [2+2]

19
photocycloadditions using a FEP tube based flow reactor, including those between maleimide

derivatives and 1,1,2-trichloroethene, and 1-hexyne and propargyl alcohol that give

cyclobutane and cyclobutene derivatives (Scheme 14) [38,53]. These workers investigated the

relative efficiencies of thirteen inter- and intra-molecular photocycloadditions,

photocyclizations, photocleavages and photorearrangements carried out in batch vs. flow

systems. Similarly, Ito reported that gram-scale intermolecular photocycloaddition reactions of

alkenes and ,-unsaturated carbonyl compounds can be conducted in a microflow system

(Scheme 15) [54]. In one example, the photocycloaddition of cyclopentene with 5,5-dimethyl-

4,6-dioxa-2-cyclohexenone occurs to give the corresponding cycloadduct, which subsequently

undergoes smooth de Mayo-type hydrolysis. These researchers also showed that the regio- and

the stereo-selective [2+2] photocycloaddition of 4-methoxy-2-quinolone with methyl acrylate

takes place in this system.

O O
R R
hn (Hg lamp)
HN + HN
MeCN
O Microflow Reactor O
(PFA tubing)
99% R = hexyl
tR = 10 min 98% R = CH2 NH2

Scheme 13. Photocycloadditions of maleimide with various alkenes.

O O
n-Bu n-Bu
hn (Hg lamp)
HN + HN
MeCN
O O
Batch Reactor
52%
(quartz immersion well)
Microflow Reactor
56%
(FEP tubing)

Scheme 14. Photocycloaddition of maleimide with 1-hexyne.

20
 O O
H H
O hn (Hg lamp) O
+
Me Microflow Reactor Me
O O
Me (plate) H H Me

MeO2C
OMe
MeO
CO2Me
hn (Hg lamp)
+
MeOH
N O N O
Microflow Reactor
H (plate) H
67%

Scheme 15. Photocycloadditions of alkenes to ,-unsaturated carbonyl compounds on gram

scales.

Oelgemller demonstrated that ultraviolet C (UVC, 100280 nm) light induced [2+2]

photocycloadditions of alkenes to 2-furanone occur in a flexible and inexpensive FEP

microcapillary reactor. 2-Furanone efficiently absorbs light in the microcapillary unit because

of the large surface-to-volume ratio (Scheme 16) [55].

O
O
hn (UVC lamp) 43%
O
MeCN O
Microflow Reactor
(FEP tubing) O

65%

Scheme 16. [2+2] Photocycloadditions of alkenes to 2-furanone.

Danheiser showed that photochemical reactions of ynamides and diazo-ketones using

microflow reactors give aromatic and heteroaromatic compounds (Scheme 17) [56]. The

processes follow pathways in which carbenes, formed by nitrogen extrusion from the excited

21
states of the diazo-ketones, undergo benzannulation type reactions with the ynamines.

Hex OH
O 1) hn (Hg lamp)
Hex
Microflow Reactor (FEP tubing)
N2 +
2) heat Me
N N
MeO2C Me CO 2Me
66%

Hex OH
O 1) hn (Hg lamp)
Hex
S N2 + Microflow Reactor (FEP tubing)

N 2) heat S Bn
(EtO)2OP Bn N
PO(OEt)2
79%

Scheme 17. Photoinduced benzannulation reactions of some ynamides with diazo ketones.

Hex; hexyl, Bn; benzyl.

[3+2] Cycloaddition reactions of alkenes with nitrile ylides, derived by photoreactions of

vinyl azides in a continuous microflow reactor, have been described by Kirschning (Scheme

18) [57]. In these processes, photo-denitrogenation of vinyl azides takes place to afford 2H-

azirines, which undergo photochemically induced ring-opening to give nitrile ylides. 1,3-

Dipolar cycloadditions of these ylides to dipolarophiles such as acrylonitrile and dimethyl

acetylenedicarboxylate then occur to produce 5-membered cycloadducts in high yields. A 2,5-

dihydrooxazole can also be generated by using this method via the intramolecular

photocyclization of a vinyl azide containing a tethered hydroxyl group, though the reaction

mechanism leaves room for discussion (Scheme 19).

22
 CN
N
CN

N3 N
MeO2C
64%
MeCN CO2Me
N2 CO2Me
MeO 2C MeO2C HN
hn (Hg lamp) MeO2C
97%
Microflow Reactor CO2Me
(FEP tubing)

MeO2C
26%

Scheme 18. 1,3-Dipolar cycloadditions of nitrile ylides with dipolarophiles involving

photoactivation of vinyl azides.

+
N3 N N OH N
O
OH
OH
benzene
N2

hn (Hg lamp) 95% 76%

Microflow Reactor
(FEP tubing)

Scheme 19. Intramolecular photocyclization reaction of a vinyl azide containing hydroxy

group.

Tiwari and Maurya reported the synthesis of structurally diverse imidazole derivatives by

a visible-light/photoredox-mediated coupling of vinyl azides and secondary amines in

microflow reactors (Scheme 20) [58]. Compared with batch system, a perfluoro alkoxy alkane

(PFA) capillary microflow system (inner diameter 0.76 mm, length 10 m) improved yields of

the product (55% in batch versus 65% in microflow) and reduced reaction times (12 h in batch

versus 44 min in microflow) because of a high photon flux and its homogeneity in the

23
microflow system.

MeO OMe
OMe
MeO
OMe hn (white LED lamp)
[Ru(bpy)3 ](PF6)2 (1 mol%)
N
OMe + HN t-BuOOH (5 equiv)
N
N3 MeCN O
O Batch Reactor (12 h)
(round bottom flask) 55%
Microflow Reactor (tR = 44 min)
(PFA tubing) 65%

Scheme 20. Coupling of vinyl azides with amines to yield imidazole derivatives mediated by

visible light and a photoredox catalyst in a batch and microflow reactors. bpy; 2,2-

bipyridine.

Benzocyclobutenes are produced by cycloaddition reactions of alkenes with benzyne,

generated by photo-extrusion of nitrogen and carbon dioxide. These processes have been

performed using a micro-engineered chemical reactors (Scheme 21) [59].

NH 2 N2 + R
NaNO2 hn R'
H+ N2, CO 2
CO2H CO2 R'
Microflow Reactor
(plate)

Scheme 21. Generation of benzyne from anthranilic acid and formation of

benzocyclobutenes.

The PausonKhand reaction, taking place by [2+2+1] co-cyclization between alkenes,

alkynes and carbon monooxide, is a useful method for the preparation of 3-cyclopenten-1-one

derivatives. Recently Yoshida demonstrated that this process takes place photochemically at

24
ambient temperature, without the use of additives, by using a microflow reactor (Scheme 22)

[60]. In one example, the photoreaction of the dicobaltoctacarbonylphenylacetylene complex

and 2-norbornene for 5 min was carried out at 25 C in the reactor using a Hg lamp. The 88%

yield of this process, when a microflow reactor was employed along with the following

parameters: microchannel [1000-m width, 200-m depth, 916.04-mm length and 55-s

residence time (tR)], was much higher than that obtained employing a batch system (32%). In

addition, large scale production of the product (85% yield at 85% conversion) can be carried

out using the flow system operating for 1 h. Both electron-rich and electron-poor arylacetylenes

and 1-hexyne can be used in this reaction, which generates corresponding cyclopentenone

derivatives. Moreover, intramolecular photochemical PausonKhand reactions can be carried

out using a microflow reactor.

Hg lamp
Ph

Co(CO)3
(CO)3Co
+
O
Ph
25 C

Batch Reactor (Pyrex flask) (5 min) 32%

Microflow Reactor (plate) (55 s) 88%

Hg lamp

TsN Ph

Co(CO)3
(CO)3Co TsN O
25 C
Ph
80%

Scheme 22. Photoinduced PausonKhand reactions.

25
 Maurya reported the synthesis of fused -carbolines via a visible light photoredox catalyzed

oxidation/[3+2] cycloaddition/oxidative aromatization reaction cascade in batch and

microflow reactors (Scheme 23) [61]. The yield of the product was slightly better in microflows

reactor (75%) than that in batch conditions (69%).

Scheme 23. Visible light photoredox catalyzed oxidation/[3 + 2] cycloaddition/oxidative

aromatization reaction cascade for the synthesis of fused -carboline derivatives. Reprinted

with permission from ref. [61]. Copyright 2015 the Partner Organisations.

2.2. Intramolecular Photocycloadditions and Photocyclizations

Intramolecular photoreactions of 2-(2-alkenyloxymethyl)-1-cyanonaphthalenes form [2+2]

cycloadducts at the 1,2-position of the naphthalene ring as well as minor amounts of [3+2]

cycloadducts when conducted in a batch reactor (Scheme 24) [6264]. In contrast, [2+2]

photocycloadducts are generated in a highly selective manner by using a glass microflow

reactor. The reason for this difference is associated with the fact that [2+2] cycloadducts

smoothly cyclorevert to the starting naphthalenes under batch reaction conditions. On the other

26
hand, in a flow system [2+2] cycloadducts have short residence times and, as a result, they are

quickly removed from the irradiation source (Fig. 7). Importantly, the ratios of [2+2] and [3+2]

cycloadducts do not change when microflow reactors with different thicknesses of the

irradiated area are employed (Type A and B) (Fig. 8).

CN
CN
hn (> 280 nm) NC H
O
O O
hn (> 280 nm)
H
benzene
Batch Reactor (4 h)
55 : 45
(Pyrex test tube)

Microflow Reactor (1min)

(plate; see Fig. 8) 96 : 4

Scheme 24. Intramolecular photoreaction of a 2-(2-alkenyloxymethyl)-1-cyanonaphthalene.

Fig. 7. Product ratios of the photoreaction shown in Scheme 24 under batch reactor (a) and

microflow reactor (b) conditions (Type A in Fig. 8).

27
 Fig. 8. Type A and B microflow systems used for the photoreaction shown in Scheme 24.

Vasudevan described [2+2] intramolecular photocycloaddition reactions of several simple

alkene-linked coumarins carried out employing a flow-based photochemical reactor, called

LOPHTOR (Scheme 25 and Fig. 9) [65]. The photoreactions in the flow system were found to

be faster (12 times) and to take place in higher yields (3 times) than those performed in a batch

system. In addition, the yields of cycloadduct formation were observed to be independent of

the concentration of the starting coumarins in the range from 0.085 to 0.425 M.
H
O O
hn (300 nm)
H
benzene
O O
O O Batch Reactor (24 h)
(round bottom flask) 30%
Microflow Reactor (2 h)
98%
(LOPHTOR; see Fig. 9)

H
O O
hn (300 nm)
H
benzene
O O
O O Batch Reactor (48 h)
(round bottom flask) 67%
Microflow Reactor (4 h)
(LOPHTOR; see Fig. 9) 99%

Scheme 25. [2+2] Intramolecular photocycloaddition reactions of simple alkene-linked

coumarins by using LOPHTOR.

28
 Fig. 9. Cross-sectional view of the LOPHTOR microflow reactor. The force exerted by

pressurized nitrogen produces a robust seal between the FEP and the channels formed in

stainless steel.

In an interesting study, Nettekoven carried out the thermal flowbatchphotochemical flow

reaction sequence shown in Scheme 26 [66]. In this cascade, thermal conversion of furan-

methanol generates a cyclopenten-4-ol, which couples with allyl chloromethyl ether to form

the substrate for intramolecular photoaddition that produces the tricyclic product.

thermal flow batch photochemical flow

O O H O
O pH 4 with HOAc O Cl hn (254 nm)

OH 240 C i-Pr2NEt, CH2Cl2 acetone

tR = 1 min Bu4NI Microflow Reactor H O
OH O
O (plate) O
66%
73% 60%

Scheme 26. Synthesis of tricyclic compound from furfuryl alcohol occuring via sequential

thermal flowbatchphotochemical flow reactions.

Rutjes reported that two conformationally restricted three-dimensional aminoketone

29
scaffolds have been synthesized using a continuous microflow [2+2] intramolecular

photocycloaddition of enaminones. This reaction can be conveniently scaled up under similar

conditions in a larger flow reactor (Scheme 27) [67].

Scheme 27. [2+2] Intramolecular photocycloadditions of enaminones using a continuous

microflow reactor. Boc; tert-butoxycarbonyl.

Kim reported an intriguing intramolecular photocycloaddition reaction of 1,7-dibenzoyl-

1,6-heptadiene in the presence of N,N-diisopropylethylamine and lithium tetrafluoroborate

using a fluoropolymer film microflow reactor (300-m width, 50-m depth, 88-mm length).

This process, photoredox catalyzed by using Ru(bpy)32+ (bpy; 2,2-bipyridine) and activated

by visible light (white LED), gives the [2+2] cycloadduct shown in Scheme 28 [68]. The

product is obtained quantitatively using a 1 min irradiation time, whereas the process using a

conventional flask proceeds to only 68% conversion after a 30 min irradiation period.

30
 Scheme 28. Intramolecular photocycloaddition of 1,7-dibenzoyl-1,6-heptadiene. Reprinted

with permission from ref. [68]. Copyright 2014 The Royal Society of Chemistry.

The interesting pentacyclo[5.4.0.02,6.03,10.05,9]undecane-8,11-dione cage compound has

been synthesized through an intramolecular [2+2] photocycloaddition reaction of 1,4,4a,8a-

tetrahydro-endo-1,4-methanonaphthalene-5,8-dione using a flow FEP tubing microflow

reactor (Scheme 29) [38,69]. The yield of this reaction, carried out to complete conversion

using a highly concentrated solution of the reactant and a short irradiation time, is higher than

that of a corresponding batch process. Several intramolecular photocycloaddition reactions

conducted using a spiral microflow reactor were reported by Booker-Milburn (Scheme 30)

[38,70].

H hn
O (Hg lamp or UVA lamp)
H
AcOEt or acetone O
O O
Batch Reactor
80%
(quartz immersion well)
Microflow Reactor
77%
(FEP tubing)

Scheme 29. Intramolecular [2+2] photocycloaddition reaction of 1,4,4a,8a-tetrahydro-endo-

1,4-methanonaphthalene-5,8-dione.

31
 H O NH O
N hn (365 nm)
NMe NMe
MeCN
O O
Batch Reactor (100 min)
(quartz cell) 77%

Microflow Reactor (19 min)

80%
(FEP tubing)

O O
Me Me Me Me
hn (254 nm) CO 2Et
Me N CO 2Et MeCN Me N

Batch Reactor (7 h)
(quartz cell) 77%

Microflow Reactor (74 min)

80%
(FEP tubing)

Scheme 30. Intramolecular [2+2] photocycloaddition reactions used to compare the

efficiencies of microflow and batch reactors.

Acetone sensitized photodecarboxylation reactions of phthalimide derivatives using a

microflow reactor were described by Oelgemller (Scheme 31) [7174].

O O
CO 2K hn (UVB lamp)
N N Me
acetoneH 2O
O Microflow Reactor O 92%
(plate)

O CO2 K HO
X
X hn (UVB lamp)
N N
acetoneH 2O
O Microflow Reactor O 82% (X = CH2)
(plate) 80% (X = S)

Scheme 31. Acetone sensitized photodecarboxylation of phthalimide derivatives. UVB;

ultraviolet B.

Booker-Milburn demonstrated that photoreactions of N-(4-pentenyl)maleimide derivatives

gave rise to formation of bicyclic azepine derivatives via a pathway involving [2+2]

32
intramolecular cycloaddition (Scheme 32) [53]. This process, carried out using a microflow

reactor employing spiral flow through micro tubing, was applied as a key step in the synthesis

of the alkaloid ()-neostenine (Scheme 33) [75].

O O O O
R R R R
hn (Hg lamp)
N N+ N+
R Microflow Reactor R R R N
O (FEP tubing) O O
O
R = Me, Cl 7980% (R = Me)
6768% (R = Cl)

Scheme 32. Intramolecular photoreactions of N-(4-pentenyl)maleimide derivatives.

Scheme 33. Synthesis of alkaloid ()-neostenine. Reprinted with permission from ref. [75].

Copyright 2008 American Chemical Society.

Several electron transfer sensitized photocyclization reactions, promoted by formation and

cyclization of carbon centered free radical and carried out in a microflow system, have been

reported by Stephenson (Scheme 34) [76].

33
 hn (blue LED lamp; 447 nm)
Ru(bpy)3Cl2 (1 mol%)
Bu3 N (2 equiv) CO 2Me
N N
Br DMF, tR = 1 min CO 2Me
Microflow Reactor
CO2Me (PFA tubing)
MeO2C 91%

hn (blue LED lamp; 447 nm)

Ru(bpy)3Cl2 (1 mol%) Me
Br Et3N (2 equiv) MeO2C
MeO2 C DMF, tR = 1 min MeO 2C
CO2Me
Microflow Reactor
(PFA tubing) 72%

hn (blue LED lamp; 447 nm)

O Ir(bpy)2 (dtbpy)PF6 (1 mol%) Ph O
Ph N Et3N (2 equiv)
Ph Br N
DMF, tR = 3 min
Microflow Reactor
(PFA tubing) 71%

Starting Materials
ow
+ hn Products

visible-light photoredox catalysis

(Ru or Ir complex)

blue LEDs

Scheme 34. Photocyclization reactions sensitized by Ru or Ir complexes. dtbpy; 4,4-di-tert-

butyl-2,2-bipyridine, DMF; dimethylformamide.

Photoinduced cyclization reaction of 2,6-dimethyl-1,5-heptadiene-1,1-dicarbonitrile,

taking place in the presence of 2,4,6-triphenylpyrylium tetrafluoroborate (TPPT) and by

employing a flat-bed solar light collector without devices for focusing the sunlight, was

reported by Demuth [51]. This reaction proceeds by way of a photoinduced electron-transfer

mechanism. In a similar manner, sunlight irradiation of 3-farnesylmethyl-2(5H)-furanone in

the presence of an electron acceptor leads to formation of 3-hydroxy-spongian-16-one, as part

of a synthesis of a substrate containing a steroid ABC ring system (Scheme 35).

34
 Me Me Ph
hn (sunlight), TPPT Me
CN
Me CN
MeCNMeOH MeO
CN Ph O + Ph
Microflow Reactor Me Me CN
BF4
(flat-bed solar light collector)
63% TPPT
(see Fig.6)
O O
H
hn (sunlight),
Me O trimethyldicyanobenzene, Me Me O
biphenyl
Me
MeCNH2O (91:9) H H
Me HO
Microflow Reactor H
Me (flat-bed solar light collector) Me Me
(see Fig.6) 15%

Scheme 35. Photoinduced cyclization reactions promoted by using sunlight.

Rueping reported a method for the enantioselective synthesis of substituted

tetrahydroquinolines that utilizes a photocyclizationBrnsted acid-catalyzed asymmetric

reduction sequence (Scheme 36) [77,78]. The first step in this sequence beginning with

aminochalcones uses a microflow reactor. The final product is generated by treatment of the

quinolinium salt with an appropriately substituted Hantzsch ester [HEH(R2)].

O hn (Hg lamp)
R1 chiral catalyst *BH (1 mol%) HEH(R2 )
*
Microflow Reactor (plate) N+ R1 N R1
NH 2
H *B H
Ar
R 2O 2C CO2R2 5284%
R1 = alkyl or aryl
O
O
P
OH N
O
H
Ar R2 = alkyl
*BH
HEH(R 2): Hantzsch ester

Scheme 36. PhotocyclizationBrnsted acid-catalyzed asymmetric reduction sequence of

aminochalcones followed by treatment of HEH(R2).

It is well-known that phenanthrenes and helicenes can be prepared by photocyclization

35
reactions of 1,2-diarylethenes followed by oxidation of dihydro-intermediates. However, the

scalability of these reactions employing classical photochemical reactors is often limited by

low reactant concentrations (ca. 103 mol L1) and long reaction times. It is significant that the

use of continuous microflow reactors for carrying out photocyclization reactions of 1,2-

diarylethenes enables efficient large scale preparation of arenes and functionalized

heteroarenes including phenanthrenes, phenacenes, helicenes, polyacenes and their aza

analogues (Scheme 37) [7982].

36
 hn (Hg lamp), I2
cyclohexane
Microflow Reactor 92%
(FEP tubing)

Br hn (Hg lamp) Br
I2, THF
toluene
Microflow Reactor
(FEP tubing)
64%

hn (Hg lamp)
I2, THF
F F
toluene
Microflow Reactor
(FEP tubing)
85%

N hn (Hg lamp) N
I2, THF
toluene
Me Microflow Reactor
(FEP tubing)
O O

Me
74%

OMe
OMe

OMe
R
OMe
hn (Hg lamp)
I2, THF Me
R = Br, 65%
R toluene
Microflow Reactor OMe
Me (FEP tubing) OMe

Me
R = Me, 58%
R = OMe, 52%

Scheme 37. Photocyclization reactions of 1,2-diarylethenes followed by oxidation. THF;

tetrahydrofuran.

In this regard, 5-helicene was synthesized using a visible light induced photocyclization

37
reaction by Collins (Scheme 38) [83]. A Cu(I) species, prepared in situ from Cu(MeCN)4(BF4)

and 2,2-bis(diphenylphosphino)diphenyl ether (DPEphos) or 4,5-bis(diphenylphosphino)-9,9-

dimethylxanthene (Xantphos) with 2,9-dimethyl-1,10-phenanthroline (dmp) serves as a

catalyst for this process, which takes place 12 times faster in a microflow reactor as compared

to a batch system.
hn (CFL)
Cu(MeCN)4BF4 (25 mol%)
DPEphos or Xantphos (25 mol%)
dmp (25 mol%), I2 , propylene oxide O
Ph2P PPh2
THF
DPEphos
Batch Reactor
42%
(round-bottom flask), 120 h
Microflow Reactor
(FEP tubing), 10 h 40%
hn (UV lamp) O
I2 Ph2P PPh2
Xantphos

+ +

N N
Me Me
25% overoxidized dmp
regioisomer
product
37% 38%

Scheme 38. Synthesis of 5-helicene using a visible light induced photocyclization reaction.

CFL; compact fluorescent lamp.

Czarnocki achieved a formal synthesis of ()-podophyllotoxin through the photocyclization

of a chiral atropisomeric bisbenzylidenesuccinate amide ester (Scheme 39) [84]. This strategy

was found to be more efficient when irradiation was performed in a continuous microflow

reactor.

38
 Scheme 39. Photocyclization of bisbenzylidenesuccinate amide ester via continuous

microflow process. TFA; trifluoroacetic acid.

Wu and Tung reported photocyclization reactions of stilbazole salts that occur within water

and methanol swollen Nafion membranes as microflow reactors [85]. Collins also reported a

visible light induced reaction in the presence of I2 or O2 that produces carbazoles from di- and

triarylamines and use a continuous microflow reactor. Although the Cu(I)-based photoredox

catalyst, comprised of Xantphos and dmp, was used to promote this reaction, the

Ru(bpy)3(PF6)2 and methyl viologen (MV2+) derivative (MV(PF6)2) can also be used. However,

the yields using the Cu(I) catalyst are much higher than those employing Ru(II) and MV2+

(Scheme 40) [86]. Carprofen analogues and carbazole derivatives with various substituents can

be prepared by using this continuous flow UV reactor based photocyclization strategy [87,88].

39
 hn (CFL)
I2, propylene oxide,
Ru(bby)3(PF6)2 (5 mol%) or
Cu(MeCN)4(BF4) (5 mol%),
Xantphos (5 mol%), dmp (5 mol%) Ph
Ph
N
N

THF, tR = 10 h
Microflow Reactor 5375%
(FEP tubing)

hn (CFL)
I2, propylene oxide
Cu(MeCN)4(BF4) (5 mol%),
Xantphos (5 mol%), dmp (5 mol%) R
R
N
N

THF, tR = 20 h
R = Me, Et, i-Pr Microflow Reactor 65% (R = Me)
(FEP tubing) 79% (R = Et)
65% (R = i-Pr)

Scheme 40. Synthesis of carbazoles from di- and tri-arylamines by using visible light

irradiation.

Brse reported that carbazole can be prepared from 2-azidobiphenyl in a 50% yield and

with a 95% selectivity by using laser irradiation in a miniaturized flow mode photoreactor [89].

Compared to the use of conventional UV sources, the procedure utilizing laser irradiation leads

to acceleration of the process from 18 h (Xe lamp) to 30 s (Nd:YAG laser) (Scheme 41).

H
N3 N
hn (Xe lamp & Nd:YAG laser)
+ N
benzene N
Microflow Reactor
(PEEK tubing)

Xe lamp (> 345 nm) 18 h, 50%

Nd:YAG laser (355 nm) 30 s, 50%
side product

Scheme 41. Synthesis of carbazole from 2-azidobiphenyl by using laser irradiation. PEEK;

polyether ether ketone.

40
 Enantiomerically pure trans--lactams have been synthesized from an -amino acid

derived -diazo--ketoamide using a photochemical reaction promoted by utilization of a

compact fluorescent lamp (CFL) in a continuous flow system by Konopelski (Scheme 42) [90].

Although the rate of the photoreaction using CFL is lower than that using a Hg lamp, the yield

is higher while the product distribution is comparable. The utilization of the continuous

microflow reactor shortened the time required for this reaction and simplified scale-up without

sacrificing yield.

O O OBn O OBn
Me N2 hn (Hg lamp, CFL) Me Me
N OBn N + N
MeO toluene MeO NTr MeO NTr
O Batch Reactor (Pyrex flask) O O
NHTr Microflow Reactor (FEP tubing)

Hg lamp (batch, 0.6 g, 7 h) 64% 26%

Hg lamp (flow, 1.0 g, 3.5 h) 61% 20%
CFL (batch, 0.1 g, 18 h) 75% 20%
CFL (flow, 1.0 g, 48 h) 70% 21%

Scheme 42. Photoreaction of -diazo--ketoamides by using a Hg lamp (batch or flow) and

CFL (batch or flow) irradiation.

This method was applied to the photochemical cobalt-catalyzed alkyl-Heck cyclization

reaction in a flow system (Scheme 43) [91]. The process yields 3-methylene-1-

oxacyclopentane derivatives in excellent yields that are comparable to those arising from use

of a batch mode, and requires a much reduced reaction time.

hn (blue LED lamp)
[Co]-catalyst (12 mol%)
O O
i-Pr2NEt (1.5 equiv)
I
MeCN, rt, 30 min
MeO Microflow Reactor MeO
(plate)
96%

Scheme 43. Cobalt-catalyzed photochemical alkyl-Heck cyclization using a blue LED lamp.

41
 Ryu studied Cossy photocyclization (5-exo-dig) of organo halides onto a CC triple bond

using a microflow reactor (Scheme 44) [92]. The reaction of trans-3-bromo-2-

(propargyloxy)tetrahydropyran in a microflow system proceeded well even at higher

concentration (0.1 M) to give the cyclized product in 92% yield, though the reaction in a batch

system gave the product only in 8% yield.

O O O O

Br
Batch Reactor (quartz test tube), 5 min 8%
hn (254 nm) Microflow Reactor (plate), tR = 5 min 92%
Et3N (10 equiv)
MeCN Et2N +
Br
O O
O O O O 5-exo-dig

Br

Et3N + Et3 N+Br Et3 N+Br

R1 O hn (254 nm), Et3N R1 O O O O O O O

O
MeCN
R2 Br R2
Microflow Reactor (plate)
tR = 58 min
4592% 91% 75% 70%
(10 example)

Scheme 44. Cossy photocyclization of organo bromide using a microflow system.

Sivaguru reported stereospecific intramolecular [2+2] photocycloadditions of

atropisomeric maleimides. High enantioselectivity (enantiomeric excess (ee) > 98%) and

diastereoselectivity (diastereomeric excess (de) > 98%) were observed on direct irradiation and

triplet-sensitized UV irradiation of thioxanthone. To evaluate the reaction efficiency on the

visible light irradiation, a flow system using a CFL as a light source was employed (Scheme

45) [93]. Complete conversion of the substrate (R = Me) was accomplished within 35 min in

42
microreactors; however, in batch reactors, only 23% conversion was observed for the same

photoirradiations. Similarly, a complete conversion of substrates (R = Ph) was achieved in less

than 60 min, while only 18% conversion was observed in batch reactors.

R
O R O R
hn (CFL)
O N O Thioxanthone (1020 mol%) N N
+
O MeCN O O
O O
(R = Me)
R = Me, Ph Batch Reactor (test tube), 35 min 23% conversion
Microflow Reactor (FEP tubing), tR = 35 min 100% conversion, dr = 79:21
(R = Ph)
Batch Reactor (test tube), 60 min 18% conversion
Microflow Reactor (FEP tubing), tR = 60 min 100% conversion, dr = >99:1

Scheme 45. Stereospecific intramolecular [2+2] photocycloadditions of atropisomeric

maleimides.

2.3. Photoadditions

Oelgemller reported the photoaddition of the potassium salt of a phenylacetic acid to a

phthalimide resulting in formation of 3-arylmethyleneisoindolin-1-ones (Scheme 46)

[72,74,94,95]. This process, involving addition of the benzyl radical generated photochemical

electron transfer induced decarboxylation followed by the dehydration of the primary

photoadduct, was performed in a microflow reactor. In both processes, 4,4-

dimethoxybenzophenone (DMBP) serves as an essential additive, probably a photoabsorbing

electron acceptor. The most likely mechanism for this reaction begins with the photoinduced

electron transfer from either the carboxylate anion moiety (CO2) or sulfur of the thiomethyl

ether group to DMBP. In the pathway initiated by the former mode, the formation and

43
decarboxylation a carboxyl radical (CO2) intermediate then generates the thiomethyl radical

precursor of the observed product. Alternatively, the sulfur centered radical cation produced in

the latter route could undergo the decarboxylation to generate the thiomethyl radical.

Simultaneously, anion transfer from DMBP to phthalimide takes place to give DMBP and the

phthalimide radical anion. A succeeding radical coupling between the benzyl radical or

thiomethyl radical and the phthalimide radical anion affords the final products. Oelgemller

also described the photodecarboxylative addition of -thioalkyl-substituted carboxylates to

alkyl phenylglyoxylates (Scheme 47) [96].

(a)
O hn (UVA lamp) HO Ph
Ph
PhCH 2CO2K, DMBP H+
N Me N Me N Me
MeCNH2O
O Microflow Reactor O O
(plate)

hn (UVA lamp) HO HO H O
SMe
MeSCH2CO 2K, DMBP
N Me + N Me
MeCNH2 O
O O MeO OMe
Batch Reactor DMBP
90 : 10
(Pyrex test tube)
Microflow Reactor
100 : 0
(plate)

(b) O
DMBP
hn N Me

O
HO
R
O
N Me
3DMBP* N Me
DMBP O
O

R CO2 R CO 2 RCH 2
CO2

Scheme 46. Decarboxylative addition of phenylacetate or -thioalkyl substituted

carboxylates to phthalimide under photoinduced electron-transfer conditions (a) and its

44
 proposed mechanism (b). UVA; ultraviolet A.

O SMe
HO
OMe hn (350 nm) OMe
+
MeS CO2 MeCNH2O
O O
Microflow Reactor (plate)
55%
Photoinduced
hn
Electron Transfer
+H +

O O
OMe + OMe +

MeS CO2 CO 2 MeS
O O

Scheme 47. Decarboxylative addition of -thioalkyl substituted carboxylates to alkyl

phenylglyoxylates under photoinduced electron-transfer conditions.

Jensen reported the use of benzopinacol formation by irradiation of benzophenone in 2-

propanol as a model reaction to explore microflow reactors [97]. Oelgemller studied a novel

photochemical carboncarbon bond forming reaction between 2-propanol and 2-furanones

sensitized by DMBP (Scheme 48). In the mechanism of this reaction, the triplet state of DMBP

abstracts a hydrogen from 2-propanol to give DMBPH and the 2-hydroxyl-2-propyl radical,

which adds to the 2-furanone to generate an -keto radical. This radical reduced by DMBPH

produces the adduct along with regenerated DMBP [98100]. The multimicrocapillary flow

reactor system was used for rapid screening, process optimization, scale-up and library

synthesis (Fig. 10) [101,102]. In addition, the use of this reactor enables simultaneous

performance of control experiments to evaluate the effects of substrate, concentration, solvent

and additives under the same photoirradiation conditions.

45
 O O R

OH
OH DMBPH OH
O hn OH
3DMBP*
Ar Ar HO R
O O O R
OH DMBP
DMBP
90% (R = H)
Ar = 4-MeOC6H4 Ar Ar 90% (R = rac-OEt)
DMBPH 87% (R = ()-Menthyloxy)

OH
OH

O O R

Scheme 48. Mechanism of the photoaddition reaction of 2-propanol with 2-furanones

sensitized by DMBP.

R' R'
R' R' OH
+
O O R
OH
O O R

Fig. 10. Multimicrocapillary flow reactor system used for the reaction shown in Scheme 48.

Matsushita and Jensen independently reported the photoaddition reaction of methanol to

limonene carried out in a microflow reactor. The de value in the adduct arising from this process

conducted in the flow system was slightly higher (31% de) than that obtained using a batch

system (29% de) (Scheme 49) [46,103].

46
 OMe MeO
hn (Hg lamp),
toluene (Sens)
+ +
MeOH

trans cis exo

Microflow Reactor 12% conversion
(plate) 2.71% 1.54% 3.70%
tR = 135 s 31% de
Batch Reactor
(quartz cell), 15 min 29% de

Scheme 49. Photoaddition reaction of methanol to limonene.

Redox-sensitized photoallylation of 1,1-dicyano-2-phenylethene with allyltrimethylsilane

in the presence of phenanthrene was reported by Mizuno (Scheme 50) [104,105]. Under batch

conditions, the allyl product is obtained in an 84% yield after 6 h irradiation. On the other hand,

when a microflow is used, a 40 min irradiation time quantitatively gave rise to the same product.
hn (> 280 nm)
SiMe3 phenanthrene
+
MeCN, rt
NC CN NC CN
Batch Reactor (6 h)
84%
(Pyrex test tube)

Microflow Reactor (40min)

(plate; see Fig. 8) ~100%

Scheme 50. Redox-sensitized photoallylation reaction of 1,1-dicyano-2-phenylethene with

allyltrimethylsilane.

Yamashita and Yasuda reported the acetone-sensitized addition of triethylamine (Et3N) to

1,1-diphenylethene (DPE) using a microflow reactor (Scheme 51) [39]. This process is initiated

by photoinduced electron transfer from Et3N to the excited triplet state of DPE formed by

acetone triplet sensitization to generate DPE and Et3N+. Proton transfer from Et3N+ to DPE

gives a radical pair of -aminoethyl radical and ,-diphenylethyl radical that couples to form

47
the products.

3
Ph Ph * Ph
hn (Hg lamp), acetone
+ Et3 N + Et3N Et3 N+
Ph Microflow Reactor Ph Ph
(plate)
DPE DPE
Ph Me
Ph Me Ph Me
Me
Ph +
Ph Me NEt2
NEt2
Ph NEt2
in-cage out-of-cage
21% conversion
61% 4% (based on consumed DPE)

Scheme 51. Acetone-sensitized photoaddition of Et3N to DPE.

Ravelli and Protti reported photosensitized acylations and alkylations of electron-poor

olefins via hydrogen-atom transfer, which were carried out on a multi-gram scale under

continuous microflow conditions (Scheme 52) [106]. The process is based on the use of tetra-

n-butylammonium decatungstate (TBADT), which is capable to activate selectively a variety

of CH bonds in different substrates including aldehydes, amides, ethers, and alkanes. The use

of a microflow reactor achieves reduction of the residence time, a notable increase of the

productivity values compared with those for the corresponding batch processes.

48
 (a)
hn (Hg lamp)
[W10O32 ]4 O
O
+ CO2 Me
MeCN C6H13 CO 2Me
C6H13 H CO2Me
CO 2Me
Batch Reactor (8 h) 80%
(immersion well apparatus) 15.50 g/day
Microflow Reactor (100 min) 79%
(FEP tubing) 73.46 g/day

(b)
O
[W10O 32 ]4 *
C6H13 H
hn

C6H13
[W10O32 ]4 H+[W 10 O32 ]5

CO2Me
CO2Me
O O

C6H13 CO2Me C6H13 CO2Me
CO2Me CO2Me

Scheme 52. Photoaddition reaction of heptanal with diethyl maleate under TBADT-sensitized

conditions via a microflow system (a) and proposed mechanism (b).

Also, photoaddition reactions of nucleophiles to N-phenyl-3,4-dihydroisoquinolin-2-ium

bromide, generated by blue LED irradiation of N-phenyl-1,2,3,4-tetrahydroisoquinoline, were

uncovered by Stephenson. Although the chemical yields of processes carried out in both batch

and flow systems are almost the same, the rate of the process in the flow system is much higher

than that in a batch system (Scheme 53) [76].

49
 hn [blue LED lamp (447 nm)]
Ru(bpy)3Cl2 (0.5 mol%)
BrCCl3 (3.0 equiv) Br Nu
N DMF, tR = 0.5 min N+ N
Ph Ph Ph
Microflow Reactor Nu
(PFA tubing)

N N N N
Ph Ph Ph Ph
CN Me
O 2N
89% 79% 85% 89%
Ph

Scheme 53. Photoaddition reaction of nucleophiles to N-phenyl-3,4-dihydroisoquinolin-2-

ium bromide.

Lefebvre, Hoffmann, and Rueping reported that photochemical trifluoromethylation of

electron-deficient olefins and (hetero)aromatics with sodium triflinate as a CF3 source and

DMBP as a photosensitizer in batch and microflow systems. The use of a microflow reactor

led to remarkable shortening of reactions times, showing that this method had a potential for

rapid scale-up and in-line synthesis (Scheme 54) [107].

O hn (350 nm)
O
CF3SO 2Na, HFIP CF3
Ar N DMBP Ar N
MeCN
O
O

Ar = Ph 4-ClC6 H4 2-OMeC 6H4

Batch Reactor
61% 39% 27%
(Pyrex tube), 6 h
Microflow Reactor
54% 47% 49%
(FEP tubing), tR = 30 min

Scheme 54. Photochemical trifluoromethylation of N-arylmaleimides in batch and flow

systems. HFIP; hexafluoroisopropanol.

Seeberger and Hartmann reported the synthesis of carbohydrate-functionalized sequence-

50
defined oligo-amidoamines by using a photoinduced thiolene coupling strategy and a

continuous FEP tubing based microflow reactor (Scheme 55) [108]. Photoreactions of water-

soluble O-allyl glycosides with thiols such as L-cysteine at 254 nm excitation in PTFE

(TeflonTM, AF-2400) in the absence of a radical initiator afford the thiolene coupling products

in high yields. A fluorenylmethyloxycarbonyl-protected glycosylated building block was

synthesized in a large scale utilizing this procedure.

HO OH HO OH O
hn (254 nm)
O O
HO L-cysteine (1.2 equiv) HO O
HO O H 2O, 25 C HO O S
Microflow Reactor
(Teflon AF-2400 tubing) H 2N CO2H
77%
Fmoc
OAc OAc
AcO O AcO O
AcO SH AcO S
OAc OAc
O
O hn (365 nm)
Fmoc N OH
N N AcOH, THF, tR = 30 min O
H H O
O Microflow Reactor Fmoc N OH
(FEP tubing) N N
H H
O
71%
29.6 g/day

Scheme 55. Synthesis of carbohydrate-functionalized sequence-defined oligo-amidoamines

by photoinduced thiolene coupling reactions. Fmoc; 9-fluorenylmethyloxycarbonyl.

Gagne reported the synthesis of key intermediates for C-glycoamino acids and C-

glycolipids that involves a photoredox-mediated process and uses a continuous microflow

reactor (Scheme 56) [109]. Light-promoted conjugate addition of acetate (AcO)- or pivalate

(PivO)-protected sugars to acrolein in the presence of [Ru(dmb)3]2+ (dmb; 4,4-dimethyl-2,2-

bipyridine) efficiently produce adducts, which are converted to C-glycoamino acids and C-

51
glycolipids. When a continuously operating microflow reactor is used to carry out the reaction,

5.5 g of the product (85% yield) is generated after a 24 h irradiation period.

hn (blue LED lamp) OP

OP [Ru(dmb)3]2+ (1 mol%)
O PO O
PO O i-Pr2NEt, HEH(i-Bu) PO O
PO + PO
PO H CH2Cl2, 24 h
Br H
P = Ac, Piv Microflow Reactor P = Ac 85%
(FEP tubing) P = Piv 85%

Scheme 56. Photoredox-mediated conjugate addition reactions of protected sugars with

acrolein.

Ru(bpy)32+ photosensitized oxyamination reactions of stable enolates such as silyl enol

ethers or 1,3-diketonates using a microflow reactor have been described by Knig (Scheme 57)

[110]. The photoreactions, performed using visible-LED light (455 nm) and a flow system,

take place in time periods that are significantly shorter (1030 min) than those needed for

processes carried out in a batch system (3 h).

hn (455 nm)
OTMS Ru(bpy)32+ (0.02 equiv) O
O O
(NH 4)2S2O8 (0.5 equiv)
+ N N
DMSO, 30 min, 20 C
R Microflow Reactor (plate) R

R = H, Me, Cl 6477%

hn (455 nm)
Ru(bpy)3 2+ (0.02 equiv) O
ONa O O (NH4 )2S2O8 (0.5 equiv) O
+ N
R1 R2 R1 N
DMSO, 10 min, 20 C
Microflow Reactor (plate) O R2
R 1 = Ph; R 2 = Ph
R 1 = Ph; R 2 = Me
8196%
R 1 = Me; R2 = Me
R 1 = Ph; R 2 = OEt

Scheme 57. Photosensitized oxyamination reactions of stable enolates. DMSO; dimethyl

sulfoxide.

52
 A photochemical continuous microflow process for the amination of sulfides or sulfoxides
was performed with trichloroethoxysulfonyl azide (TcesN3) in the presence of catalytic
iron(III) acetylacetonate [Fe(acac)3] (Scheme 58) [111].

hn (UVA lamp)
O O TcesN
Fe(acac)3 (1020 mol%)
S + S S+
R Me Cl3C O N3 R Me
CH2 Cl2
R = Ph, 4-FC6H 4, TcesN3 Microflow Reactor (PFA tubing) 5698%
2-thienyl, etc. tR = 5090 min

Scheme 58. Photoinduced amination of sulfides in the presence of Fe(acac)3 in a microflow

reactor.

Kappe reported a continuous microflow light-enhanced 1,2-bromoazidation of alkenes by

using in situ generated bromine azide (BrN3) (Scheme 59) [112]. Conventionally, BrN3 is a

useful but extremely toxic and explosive reagent, but is now safely generated from NaBr and

NaN3 in water in a microflow reactor, and is efficiently extracted into an organic phase

containing the alkene to avoid decomposition. Although the addition of BrN3 to ethyl

cinnamate in the dark resulted in poor conversion, the addition reaction was considerably

enhanced in an 85% yield by light irradiation at full conversion.

Br
oxone hn (CFL) CO2Et
NaN3 + NaBr BrN3 BrN3 + CO2Et Ph
Ph
rt N3
tR = ~10 min
85%
aqueous phase organic phase

Microflow Reactor (FEP tubing)

Scheme 59. Photosensitized 1,2-bromoazidation of ethyl cinnamate by using in situ generated

BrN3 in a microflow reactor.

53
 Jamison reported inter- and intra-molecular eneyne coupling reactions, which are

catalyzed by active [CpRu]+ complexes generated in situ via photolysis of CpRu(6-C6H6)PF6

using a microflow reactor (Scheme 60) [113].

+ +
PF6 PF6
hn (Hg lamp)
Ru Ru NCMe
MeCN, tR = 5 min MeCN
NCMe
Microflow Reactor
(PFA tubing) [CpRu]+

+
PF6
HO
5 Ru
HO
+ n-Bu
5
n-Bu acetone n-Bu
93%
n-Bu hn (Hg lamp)
tR = 10 min

+
PF6

Ru TMS
MeO 2C TMS
MeO2C
MeO 2C acetone MeO2C Me
Me
Me
hn (Hg lamp) 90%
tR = 2.5 min E/Z = 75:25

Scheme 60. Inter- and intra-molecular eneyne coupling reactions catalyzed by active

[CpRu]+.

Oelgemller also showed that terebic acid can be synthesized utilizing acetone promoted

(hydrogen atom abstraction) photoaddition of 2-propanol to maleic acid in batch and two

different microflow conditions (plate-type reactor and FEP microcapillary tubing) (Scheme 61)

[114].

54
 O
CO2H hn (UVB lamp)
OH O
+
CO2H acetone HO2C
Batch Reactor
180 min 84%
(Pyrex test tube)
Microflow Reactor
(plate) tR = 60 min 79%
(FEP tubing) tR = 30 min 83%

Scheme 61. Synthesis of terebic acid by using acetone promoted photoaddition of 2-propanol

to maleic acid.

2.4. Photoreductions

Seeberger described visible-light-promoted reduction reactions of azidobenzoate and -

chlorophenylacetate, and a reductive ring opening reaction of a chalcone-,-epoxide that rely

on the use of a continuous microflow reactor (Scheme 62) [115]. Ru(bpy)32+ sensitized

photoreduction of methyl 4-azidobenzoate in the presence of formic acid and N,N-

diisopropylethylamine was observed to afford methyl 4-aminobenzoate in a high yield. When

carried out in a flow system, the process promoted by 15 mol% of the catalyst proceeds to

complete conversion within a 120 min residence time (tR), compared to reaction performed

using batch conditions which requires a 24 h irradiation time. The photoreduction of 2-

phenylethyl 2-chloro-2-phenylacetate in a flow system takes place by cleavage of the CCl

bond. The reduction product is selectively generated much more rapidly than when a batch

system is used. Similarly, reductive ring opening of chalcone-,-epoxides proceeds in a high

yield to produce keto-alcohols.

55
 CO2Me CO 2Me

hn (white LED lamp), Ru(bpy)3Cl2

HCO 2H, i-Pr2NEt, DMF

N3 NH2
Batch Reactor (round bottom flask), 4 h 70%
Microflow Reactor (FEP tubing), tR = 2 min 93%

O O
hn (white LED lamp), Ru(bpy)3Cl2
Ph Ph Ph Ph
O O
HCO2 H, i-Pr2NEt, DMF
Cl Microflow Reactor (FEP tubing), tR = 30 min H
82%

O hn (white LED lamp), Ru(bpy)3Cl2 OH O

O
Ph Ph HCO2 H, i-Pr2NEt, DMF Ph Ph
Microflow Reactor (FEP tubing), tR = 10 min 84%

Scheme 62. Visible light promoted reduction reactions of azidobenzoate and -

chlorophenylacetates, and reductive ring opening of chalcone-,-epoxide.

Similar visible light induced photoredox reactions were reported by Zeitler. In this effort,

photocatalytic reductive dehalogenation reactions of -halocarbonyl compounds were carried

out using a microflow reactor to form products in an accelerated and high yielding manner

(Scheme 63) [116].

O O Br Br
R2 hn (530 nm), HEH(Et) R2 O O ONa+
R1 R1
Eosin Y (2.5 mol% )
X H
i-Pr2NEt (2 equiv) Br Br
Batch Reactor Microflow Reactor CO2Na+
(vial) (FEP tubing)
R1 = Ph, R2 = H, X = Br 12 h 40 s (97%)
R1 = (4-Br)BnO, R2 = Ph, X = Cl 18 h 20 min (89%) Eosin Y

Scheme 63. Photocatalytic reductive dehalogenation reactions of -halocarbonyl compounds.

Jamison reported that photoinduced electron transfer deoxygenation reactions of

selectively protected nucleosides by using a continuous microflow reactor equipped with an

56
aluminum mirror for reflection of the incident light give 2-deoxy- and 2,3-

dideoxynucleosides (Scheme 64) [117].

hn
(Hg lamp)
45 C
BzO Base MeO OMe BPR BzO Base
O O

20 psi
BzO O Ar N quartz BzO
tubing tR = 510 min
Et 6185%
O
hn
(Hg lamp)
Ar O 45 C BzO
Base MeO OMe BPR Base
O O
O
20 psi
Ar O O Ar N quartz 7378%
tubing tR = 1520 min
O O Et

O O NH2 O
Me
NH NH N N N NH
Ar = Base =
CF3 N O N O N N
N N

Scheme 64. Photoinduced electron transfer deoxygenation reactions of protected nucleosides.

The UV/H2O2 promoted photodegradation reaction of a 2,4-dichlorophenoxyacetic acid

using a flow photoreactor affords 2,4-dichlorophenol, 4-chlorophenol and 2-chlorophenol as

primary products [118]. Polybrominated diphenyl ethers, which are used as flame retardants in

plastics, are photochemically decomposed by the use of a microflow reactor. This

photodegradation process occurs much more rapidly in a flow system than it does using

nanoporous TiO2 under microwave conditions [119].

Very recently, Boyd reported a reaction that leads to removal of a 2-nitrobenzyl group from

NH protected amines that utilizes a microflow photochemical method. A significant

improvement in the yield, reaction time and scalability of the process was observed for the

reaction carried out under continuous microflow conditions. The reaction (0.04 M of substrate)

57
performed using five equivalents of hydrazine is complete after 1020-min passage through

the flow system (Scheme 65) [120].

O
N hn (UVA lamp)
+
dioxane
N N
+ O H
N O
Batch Reactor (14 h)
O (Pyrex tube) 67%
Microflow Reactor (10 min)
(FEP tubing) 80%

hn (UVA lamp) O
N H2NNH 2 (5 equiv)
+
dioxane, 20 min
N
+ O H N
N Microflow Reactor O
O (FEP tubing) 88%

Scheme 65. Photochemical removal of the 2-nitrobenzyl group.

Stephenson reported a one-pot deoxygenation reaction of alkyl alcohols using visible light

photoredox catalysis in a microflow reactor (Scheme 66 and Fig. 11) [121]. The flow reaction

is more efficient than the corresponding batch reaction as demonstrated by the observation that

the process produces the reduced product in 88% isolated yield when a flow rate of 75 L min

1
in a 1.34-mL reactor [ca. 18-min residence time (tR)] is employed along with 0.25 mol% of

fac-Ir(ppy)3. This translates into a 120-fold improvement of the conversion rate compared to

the same reaction run in a batch reactor (75% conversion after 144 h irradiation). Advantages

of employing a microflow reactor to carry out this visible light induced photoreaction include

an unlimited reaction scale, a lower catalyst loading and simplicity of the protocol.

58
 BnO BnO
OH 1) PPh3 (1.2 equiv) H
I2 (1.2 equiv) 88%
imidazole (1.2 equiv)
H
OH MeCN (5.0 mL), 2 h
N
2) hn (blue LED lamp) N
Ts
fac-Ir(ppy)3 (0.25 mol%) 85%
Ts
HO i-Pr2NEt (10 equiv) H
O MeOH (0.2 mL) O
O O
Microflow Reactor (PFA tubing);
HO O see Fig. 11 HO O

70%

Scheme 66. One-pot deoxygenation reactions of alcohols using visible-light photoredox

catalysis. Ts; tosyl.

photoreactor

pump

LED assembly

R OH R I R H

Fig. 11. Microflow reactor system for the reaction shown in Scheme 66.

Irradiation of micro-silica gel beads immobilizing diacetoxyantimony(V) derivatives of

5,10,15,20-tetraphenylporphyrin (TPP), which is prepared by the reaction of 3-aminopropyl

silica gel (SiO2NH2) through a 543-nm HeNe laser in a microflow reactor, affords

demetalated compounds quantitatively in the surface of beads (Scheme 67) [122]. These micro-

silica gel beads will be applicable as photosensitizer for a microflow reactor system, since they

catch and condense the reactants and also have a high transparency of visible light.

59
 +
O
OAc
Ph O
N SiO2
N H hn (543 nm)
N Sb SbIVTpp' N SiO2
Et2NH H
N
N Microflow Reactor (plate)
Ph
Ph
OAc Br SiO2 = micro-silica gel beads

O O
hn (543 nm)
SbIIITpp' N SiO2 Tpp'H2 N SiO2
Et2NH H SbIII H
Microflow Reactor (plate)

Scheme 67. Demetalation of micro-silica gel beads immobilizing diacetoxyantimony(V)

derivatives of TPP.

Ouchi described photoreduction reactions of flavones with NaBH4 carried out in a

microflow reactor using a KrF excimer laser as a light source (Scheme 68) [123]. This process

affords an ethyl salicylate initially via an intermediate flavanone. However, the flavanol,

generated by the ground state reduction of the flavanone, is formed as a major product when

the photoreaction is performed in using a homogeneous EtOH solution. In contrast, the

undesirable side reaction is suppressed when the photoreaction is promoted by irradiation of

the interface of a two phase mixture, created by dissolving the reagents and substrates in two

immiscible solvents (hexane and water). Under these conditions, salicylic acid is formed as a

major product of the photoreaction occurring in an aqueous solution.

60
 hn (KrF excimer laser) hn (KrF excimer laser)
O Ph O Ph OH
NaBH4 NaBH4
interface of hexane and water interface of hexane and water OH
microreactor (quartz tube) microreactor (quartz tube)
O O O
flavone flavanone salicylic acid

D NaBH4 2.7% conversion

55% (based on
consumed flavone)
O Ph

OH
flavanol
0%

Scheme 68. Photoreduction reactions of flavones with NaBH4 in microflow reactors using a

KrF excimer laser.

2.5. Photoisomerizations

Vitamin D3 is a vital natural substrate in humans. Recently, Takahashi reported a useful

method for its photochemical synthesis by the use of a two-stage continuous-flow process. The

photoreaction produces vitamin D3 from provitamin D3 via previtamin D3 (Scheme 69 and Fig.

12) [124126]. The first step in the pathway involves electrocyclic ring opening to generate

the previtamin D3, which exits in a photochemical equilibrium with tachysterol. The second

step is a thermal 1,7-hydrogen shift to give the vitamin D3. The process, conducted in the

manner described above, forms the vitamin D3 in a 32% isolated yield (60% crude yield), which

compares favorably with the yield (< 20%) of the currently used industrial process.

61
 H

HO
provitamin D3

Microflow Reactor
hn (Hg lamp)
(plate; see Fig. 12)

H H
hn (Hg lamp)

HO
previtamin D3, 12%

hn (Hg lamp) tachysterol, 6%

Microflow Reactor HO
+
(plate; see Fig. 12)
D
H

HO
vitamin D3
HO
60%
(isolated: 32%)

Scheme 69. Photochemical synthesis of vitamin D3 by the use of a two-stage continuous-flow

process from provitamin D3 via previtamin D3.

62
 provitamin D3

hn
micro- (313578 nm)
reactor I

previtamin D3
glass lter
hn (360 nm)
vitamin D3

oil bath (100 C)

microreactor II

Fig. 12. Two-stage continuous-flow system for the process shown in Scheme 69.

Reiser reported the photoisomerization of E-alkene to Z-alkene catalyzed by a recyclable

polyisobutylene (PIB)-tagged iridium(III) complex (Scheme 70) [127]. This catalyst features

high activity due to its homogeneous nature in solution. However, it is more important that the

catalyst allows automatic recovery and reuse in microflow systems making use of a

thermomorphic (90 C) or biphasic (room temperature) acetonitrileheptane solvent systems.

In the case of the biphasic system, light is absorbed by the photoredox catalyst in the heptane

phase while the reaction presumably takes place at the interface with the acetonitrile phase that

contains the substrate. Through the employment of a microflow reactor, a sufficiently high

surface area was generated due to a slug flow.

63
Scheme 70. Photochemical E/Z isomerization of E-alkene to Z-alkene in a microflow process

with continuous catalyst recycling. Reprinted with permission from ref. [127]. Copyright

2016 The Royal Society of Chemistry.

2.6. Photosubstitutions

Mateos and Kappe found that efficient benzylic bromination reactions can be performed

using N-bromosuccinimide (NBS). This photoinduced process is conducted in acetonitrile

utilizing a household CFL and a simple continuous microflow reactor based on transparent FEP

tubing (Scheme 71) [128].

hn (CFL)
Me NBS (1.05 equiv) Br
MeCN
R R
Microflow Reactor
(FEP tubing) 7094%
(19 examples)
R = H, Cl, Br, I, CN, NO2 etc.

Scheme 71. Benzylic bromination reactions using NBS with a household CFL.

64
 A bromomethylpyrimidine derivative, which serves as a precursor in the synthesis of

rosuvastatin, a member of the superstatin family, is efficiently produced by the reaction of NBS

using a photochemical microflow reactor (Scheme 72) [129]. The time for this process is

significantly shortened and the side product formation is reduced when the bromination is

conducted in the flow system compared to that in a batch system.

F F

H2 O
hn (Hg lamp)
+ NBS
N MeCN precipitation Br N

N N N N
SO2Me SO2Me
Batch Reactor
(quartz immersion well), 13 h 88%, 136 g/day
Microflow Reactor
(FEP tubing), tR = 5 min 86%, 583 g/day

Scheme 72. Synthesis of bromomethylpyrimidine derivative using NBS as bromine source.

Cycloalkanes are brominated by a photochemical process using molecular bromine under

microfluidic conditions. Formation of dibrominated products is suppressed by using the

continuous-flow method (Scheme 73) [130]. In addition, photoinduced benzylic

monobromination of toluene derivatives bearing a variety of substituents such as fluoro, azido,

methoxycarbonyl, and benzoyl groups can be carried out in a highly selective manner because

of the short residence time (tR) associated with the microfluidic conditions. Also, catalyst and

solvent-free visible light induced bromination of toluene derivatives by using HBrH2O2 and

a continuous microflow reactor was described [131].

65
 Br
hn (black light), Br2 Br Br
+
n n = 14 n n
Microflow Reactor 8499%
(plate)

Scheme 73. Photoinduced bromination reactions of cycloalkanes using molecular bromine.

Photochlorination of cycloalkanes such as cyclopentane and cyclohexane with molecular

chlorine and sulfuryl chloride, using a microflow reactor and natural room light or a 15 W

black light, proceeds smoothly to give the corresponding monochlorocycloalkanes (Scheme

74) [132].

hn (natural room light)

Cl

Cl2 (gas) 20%

hn (black light)

BPR

Cl
+ SO2Cl2
n n
4187%

Scheme 74. Photoinduced chlorination reactions of cycloalkanes with molecular chlorine or

sufuryl chloride.

In another example of a photosubstitution reaction, Seeberger described the Ru(bpy)32+

66
sensitized reaction of alcohols to give corresponding bromides (Scheme 75) [115]. The

photoreaction, which initially produces a formate derivative that is thermally transformed to

the target, is carried out by the use of a microflow reactor that has an about 30-min residence

time (tR).

OH hn (white LED lamp), Ru(bpy)3Cl2 (1 mol%) OCHO Br

n-Bu n-Bu CBr4 (2 equiv), DMF, 25 C, c = 0.2 M n-Bu n-Bu 100 C n-Bu n-Bu
Microflow Reactor (FEP tubing), tR = 31 min 80%

Scheme 75. Ru(bpy)32+-Sensitized photosubstitution reaction of an alcohol to give the

corresponding bromide.

Mono- and di-substituted arylboronic acids are photochemically converted to phenols using

a continuous microflow reactor fitted with a LED light source under aerobic conditions

(Scheme 76) [133]. To perform the photoreaction under high pressure condition, the reactor

made of sapphire was employed. Rose Bengal (RB) is used as a photosensitizer and N,N-

diisopropylethylamine as a reducing agent. The use of an EtOHH2O (50:50) solvent system

accelerated the conversion at 2 MPa (O2:phenylboronic acid = 93:7 in molar ratio). Moreover,

photochemical hydroxylation of 1,4-benzenediboronic acid using this condition and a high

pressure affords hydroquinone, while selective formation of 4-hydroxyphenylboronic acid

takes place at low pressure.

67
 I I
O O ONa+
hn (white LED lamp)
B(OH)2 air, RB (2 mol%) OH
I I
i-Pr2NEt (2 equiv) Cl CO 2Na+
EtOHH2O (50:50)
>99%
Microflow Reactor (sapphire tube) Cl Cl
Cl
RB

hn (white LED lamp)

B(OH)2 air, RB (2 mol%) B(OH)2 OH
i-Pr2NEt (2 equiv)
(HO)2B EtOHH2O (50:50) HO HO

Microflow Reactor (sapphire tube)

(2 MPa) >99%
(0.1 MPa) 43% conversion
64% selectivity

Scheme 76. Synthesis of phenols from mono- and diboronic acid derivatives of benzene by

using LED irradiation under aerobic conditions.

Li and Larionov independently reported the metal-free photochemical borylation of aryl

halides under batch and microflow conditions (Scheme 77) [134,135]. This reaction has a broad

scope and functional group tolerance. Mechanistic studies indicated that an aryl radical is a key

intermediate generated via homolysis of the CX bond in the excited state or heterolysis of the

CX bond in the radical anion generated by electron-transfer process with N,N,N,N-

teteramethyldiaminomethane (TMDAM).

68
 Scheme 77. Metal-free photochemical borylation of aryl halides under batch and microflow

conditions.

A ruthenium trisbipyridine [Ru(bpy)32+] sensitized, visible light promoted StadlerZiegler

reaction serves as a useful method to prepare thiophenols and alkyl thiols from anilines via

diazonium salts. This process has been performed using a continuous flow reaction system

(Scheme 78) [136]. The formation of the diaryl sulfides and the alkyl aryl sulfides in the

microflow reactor system occurs more efficiently than that in a batch system. For example, a

4-methoxyphenyl phenyl sulfide in a microflow reactor is formed in a 79% yield with a 15 s

residence time (tR) and a conversion of 13.2 mmol h1. On the other hand, the use of a batch

system requires a 5 h irradiation time that corresponds to a production efficiency of 0.17 mmol

h1. Notably, under dark conditions, monosulfides are not produced and disulfides are

generated.

69
 hn (blue LED lamp)
NH 2 Ru(bpy)3Cl26H2O SR
R' + RSH R'
t-BuONO
TsOHH 2O
R = Ph, 4-MeOC 6H4, octyl R' = H, 4-F, 3-CF3

S S F3C S

OMe F
Batch Reactor 85%, 5 h
(vial) 0.17 mmol h1
Microflow
Reactor 79%, tR = 15 s 80%, tR = 15 s 84%, tR = 15 s
(PFA tubing) 13.2 mmol h1 13.4 mmol h1 14.1 mmol h1

Scheme 78. Ru(bpy)32+ sensitized StadlerZiegler reaction promoted by using visible light

irradiation.

A convenient photochemical flow reaction for the formation of ArC bonds has been

developed by Protti and Fagnoni (Scheme 79) [137]. A triplet aryl cation generated from a

substituted electron-rich aryl halide is proposed as a reaction intermediate.

MeO
Cl Batch: 71%
hn (Hg lamp) Microflow: 74%
+
MeCNH2O (83:17)
MeO MeO
Batch Reactor
(immersion well apparatus)
or TMS MeO
Microflow Reactor
(FEP tubing) Microflow: 65%

Scheme 79. Photochemical reaction for the formation of ArC bonds in a microflow reactor.

Suzuki cross-coupling reactions of aryl halides with arylboronic acids have been carried

out using a microflow channel in which the Pd catalyst is immobilized. The microflow channel

70
reactor is prepared by utilizing a two-step method that begins with UV irradiation of N-[3-

(dimethylamino)propyl]methacrylamide in the presence of benzophenone. This process creates

a polymer framework in the microflow reactor that when treated with Pd(OAc)2 immobilizes

Pd in the reaction channel (Scheme 80) [138]. The coupling reaction takes place smoothly in

the microfluidic channels because the channel size is in the micrometer range and diffusion of

the molecules between the main stream and the channel surface takes place rapidly.
hn (Hg lamp)

H
N N
Pd(OAc)2
O Pd-immobilized
O acetone microchannel
Reactor
Ph Ph Photochemical immobilization
modification of Pd catalyst

Scheme 80. Construction of Pd-immobilized microchannel via photochemical reaction of N-

[3-(dimethylamino)propyl]methacrylamide in the presence of benzophenone.

Symmetric anhydrides can be synthesized using a microflow reactor through a visible light

promoted photoredox catalytic process. In the reaction, the VilsmeierHaack reagent, formed

by irradiation of Ru(bpy)3Cl2 and CBr4 in the presence of dimethylformamide (DMF), activates

the carboxyl group for the nucleophilic acyl substitution (Scheme 81) [139].

71
 hn (blue LED lamp)
O Ru(bpy)3 Cl2 (1.0 mol%) O O
CBr4 (1.0 equiv)
OH O
2,6-lutidine (2.0 equiv)
t-Bu DMF, tR = 6.4 min t-Bu t-Bu
Microflow Reactor 97%
(PFA tubing)

O O N
CBr4
R O R O H Ru(bpy)3Cl2

hn

O N+ R OH N+
Br Br
R O H Br H

Scheme 81. Synthesis of symmetric anhydrides using visible light promoted photoredox

catalysis by Ru(bpy)3Cl2.

Kitamura reported that the photocyanation reaction of pyrene (PyH) takes place in the

presence of DCB by using a two-phase microflow reactor comprised of water and propylene

carbonate. In the process, the photoinduced electron-transfer occurs from the excited singlet

state of PyH to DCB in the organic phase to afford PyH+ and DCB. The radical cation PyH+

is attacked at interphase by a cyanide anion from water phase to produce a radical intermediate

that is oxidized to give 1-cyanopyrene (PyCN) (Scheme 82 and Fig. 13) [140].

72
 hn (Hg lamp) DCB
1PyH* PyH+ + DCB
propyrene carbonate Electron
Microflow Reactor Transfer Na+CN
(plate) in water
PyH
H CN
CN

PyCN
73%

Scheme 82. Photocyanation reaction of PyH in the presence of DCB by the use of a two-

phase flow reactor system.

PyH + DCB PyCN + DCB

in propylene in propylene
carbonate carbonate

Interface

Na+CN NaOH
in H2O in H2O

Fig. 13. Two-phase flow reactor system for the reaction shown in Scheme 82.

Carreira decribed the photocatalytic synthesis of trifluoroethylstyrenes by blue LED light

irradiation of mixtures of styrenes in the presence of two equiv 2,2,2-trifluoroethyl iodide and

a catalytic amount of a cobalt complex in a microflow reactor. The reactions occur in 30 min

in good yields (Scheme 83) [91]. Although batch reactions also give the corresponding

trifluoroethylated compounds in high yields, they require a 24 h irradiation period.

73
 SnPh3
O H
hn (blue LED lamp) Me O
N
[Co]-catalyst (20 mol%) N
R Co2+ Me
i-Pr2 NEt (2 equiv) R Me
+ N
Ar I CF3 N
MeCNDMSO, rt, 30 min Ar CF3 O Me
2 equiv Microflow Reactor H O
6476%
(plate) N

Ar = 4-t-BuC6 H4, 4-MeOC 6H4, 4-AcOC 6H4

R = H, Ph
[Co]-catalyst

Scheme 83. Photoinduced trifluoroethylation reactions of styrenes.

Nol reported that photochemical the trifluoromethylation of thiols and heteroarenes using

a CF3I gas as a CF3 source and a visible light photoredox catalysis in a gas-liquid slug

microflow system (Scheme 84) [141].

Scheme 84. Photochemical trifluoromethylation of thiol and heteroarenes in a gas-liquid slug

microflow system. TMEDA; tetramethylethylenediamine.

Matsumoto and Yasuda also reported temperature-dependent photochemical nucleophile

olefin combination, aromatic substitution (photo-NOCAS) reactions, originally uncovered by

Arnold [142]. The photoreaction of 1,4-dicyanobenzene (DCB), 2,5-dimethyl-2,4-hexadiene,

and nucleophiles gives three-component adducts (Scheme 85) [143]. These photoreactions are

more efficient when aromatic hydrocarbons such as phenanthrene, triphenylene, and biphenyl

74
are utilized as redox-photosensitizers.

Me Me
Me hn (> 280 nm)
CN Nu
Me phenanthrene
+ Me + NuH
MeCNH2O (95:5) Me Me
NC Me NC
Microflow Reactor
DCB (plate) Nu = NHMe, OMe
9496% conversion
9396% (based on consumed DCB)

Scheme 85. Temperature-dependent photo-NOCAS reaction of DCB with 2,5-dimethyl-2,4-

hexadiene and some nucleophiles (NuH).

Rueping described photochemical CH functionalizations and cross-dehydrogenative

coupling reactions conducted in the presence of the photosensitizer (RB) and using a

continuous microflow reactor (Scheme 86 and Fig. 14) [144]. In this process, the substrate

containing solution is first introduced into the sample loop and then pumped through FEP

tubing in the irradiated area by using acetonitrile. These multicomponent photoreactions give

CC and CP bond coupling products in good yields.

hn (green LED lamp)

R1 R1
RB (5 mol%)
+ Nu
N Microflow Reactor N
R1 Ph R1 Ph
(FEP tubing; see Fig. 14)
R1 = H, MeO Nu
Nu = CH3NO2, TMSCN, CH 2(CO2Et)2, HPO(OEt)2 4992%

O
hn (green LED lamp)
N RB (5 mol%) N R2
N
+ CNR 2 + H 2O H
Microflow Reactor
R1 (FEP tubing; see Fig. 14) R1
5183%
R1 = H, 2-Me, 3-Me, 4-Me, 4-Br
R2 = TsCH 2, t-Bu, n-Bu, Bn, CH 2CO2Me, CH 2PO(OEt)2

Scheme 86. CH functionalization and cross-dehydrogenative coupling reactions in the

presence of RB. TMSCN; trimethylsilyl cyanide.

75
 HPLC pump BPR
500 psi
sample loop
2 mL

green LEDs
0.3 mL reaction coil

MeCN

Fig. 14. Microflow reactor system fused on the reaction shown in Scheme 86. BPR; back

pressure regulator.

Zeitler described [Ir(ppy)(dtbpy)2]PF6-sensitized (ppy; 2-phenylpyridine) photochemical

nitromethylation reactions carried out by using a FEP tube reactor (Scheme 87) [116]. The

visible-light photoredox aza-Henry reactions between arylamines and nitromethanes to give

nitromethylated products in high yields are remarkably accelerated by the use of the microflow

system. Specifically, formation of 1-nitromethyl-N-phenyl-1,2,3,4-tetrahydroisoquinoline in

the reaction using a microflow reactor is 20 times faster than the one conducted in a batch

system. Interestingly, N-methyl-N-(2-nitroethyl)-p-toluidine is efficiently formed in microflow

reactions, but it is not formed under batch conditions.

76
 hn (456 nm)
[Ir(ppy)(dtbpy)2]PF6
N CH 3NO 2 N
Ph Ph

NO2
Batch Reactor
92%
(round bottom flask), 10 h
Microflow Reactor
93%
(FEP tubing), tR = 30 min

hn (456 nm)
[Ir(ppy)(dtbpy)2]PF6 N
N
CH 3NO 2
NO 2
Batch Reactor
0%
(round bottom flask), 72 h
Microflow Reactor
77%
(FEP tubing), tR = 130 min

Scheme 87. [Ir(ppy)(dtbpy)2]PF6-sensitized photoalkylation of various amines with

nitromethane.

Zeitler also uncovered an Eosin Y promoted enantioselective photoredox -alkylation

reaction of alkanals using diethyl bromomalonate in the presence of a chiral catalyst and a

microflow reactor (Scheme 88) [116]. Microflow reactors can dramatically shorten the reaction

time achieving the high chemical yields and the ee value obtained by using batch reactors.

O
NH

N t-Bu
H
O CO2 Et
O CO2Et hn (530 nm), (20 mol %), Eosin Y (0.5 mol%)
+
H CO2Et
H 5 Br CO2Et lutidine (2 equiv)
5

Batch Reactor (vial) 18 h 85% (88% ee)

Microflow Reactor (FEP tubing), tR = 45 min 86% (87% ee)

Scheme 88. Enantioselective photoredox -alkylation reactions of alkanals using diethyl

bromomalonate in the presence of a chiral catalyst.

77
 Carbonyl compounds participate in efficient -trifluoromethylation reactions that take

place in a continuous-flow system. The two-step procedure, using metal-free visible-light

photosensitizers, begins with formation of the silyl enol ether from the ketone substrate using

the trimethylsilyl triflate (TMSOTf) in a thermal microflow reactor. The next step involves the

visible-light promoted reaction of the silyl enol ethers with trifluoromethanesulfonyl chloride

(CF3SO2Cl) serving as a CF3 radical source (Scheme 89) [145].

i-Pr2NEt CF3 SO2Cl

O
R' thermal flow
R
+
TMSOTf Microflow Reactor
(FEP tubing)
+
Eosin Y TMS O
O
R'
R' R
R
R = aryl, alkyl CF3
hn (CFL)
R' = H, alkyl
5687%

Scheme 89. Photochemical -trifluoromethylation reactions of ketones with CF3SO2Cl using

metal-free visible-light photosensitizers. TMS; trimethylsilyl.

2.7. Photooxidations

Dye sensitized photooxygenation reactions using molecular oxygen act as useful and

convenient methods for the functionalization of organic molecules. A variety of

pharmaceuticals, fragrances, perfumes and natural products can be synthesized by using this

method. One problem associated with these processes is associated with the formation of

explosive peroxides, which is a major issue when applied on a large scale. This problem can

be solved when a microflow reactor is employed, because the generated peroxides quickly flow

78
out the system where they can be reduced immediately.

De Mello reported the synthesis of ascaridole from -terpinene using singlet oxygen, which

was generated by RB sensitized photooxygenations in methanol in a nanoscale reactor [146].

This process is easily scaled up. De Mello also reported a method involving through-wall mass

transport for the safe generation of singlet oxygen using microcapillary films [147].

Jhnisch described the dye-sensitized photooxygenation reaction of cyclopentadiene by the

use of a falling-film microflow reactor that is useful for gas-liquid reactions (Scheme 90)

[148,149].
hn (xenon lamp)
O O thiourea
RB, O2 HO OH
MeOH MeOH
Microflow Reactor 20%
(falling-film)

Scheme 90. Photooxidization of cyclopentadiene sensitized by RB.

Continuous flow photooxygenation reactions of -terpinene and other monoterpenes such

as - and -pinenes, -limonene, and ()-citronellol using two types of microflow reactors

have been reported (Scheme 91) [150,151]. The monochannel microflow reactor (PEEK

tubing) employed in these processes contains gaseous oxygen between liquid slugs so that the

ratio of the contact area to volume is easily increased. The reaction time is shortened as

compared with those in batch system without a significant decreases of yield of the product,

though the daily output of products is unfortunately decreased. This problem was solved with

a duplicated microflow systems, i.e. the tube-in-tube reactor (Fig. 15), which is quite useful for

industrial applications; oxygen gas is injected into a gas-permeable inner tube and then it

diffuses into the liquid phase in the transparent outer tube. The daily output of the reaction

79
products (Scheme 91) using tube-in-tube reactor is ca. 300-fold higher than that generated in

monochannel microflow systems. In addition, the sunlight instead of an LED lamp can be used

to obtain reasonable conversion levels.

O N
hn (white LED lamp), O2
methylene blue O
N S+ N
MeOH Cl
methylene blue
-terpinene ascaridole
Batch Reactor
(round bottom flask), 180 min 92%, 18.4 mmol/day
Microflow Reactor
(PEEK tubing; slug flow), tR = 4 min 90%, 2.11 mmol/day
(tube-in-tube reactor), tR = 4 min 87%, 623 mmol/day

Scheme 91. Photooxidization of -terpinene sensitized by methylene blue.

LED lamp

Reagent +
Sensitizer O2 O2 Products
O 2 gas

Gas-permeable inner tube

Fig. 15. Illustration of the tube-in-tube reactor.

Vilela reported the photooxygenation reaction of -terpinene to give ascaridole that utilizes

a system comprised of a network of the conjugated microporous polymer (CMP),

poly(benzothiadiazole) as a photosensitizer in a flow apparatus (Scheme 92) [152].

80
 S N
N

N
S N

N
S
N
hn (420 nm), CMP, O2
-terpinene ascaridole
CDCl3 S N S N
Microflow Reactor up to 96% N N

(FEP tubing) conversion N N

S N S N

N N
S S
N N

CMP

Scheme 92. Photooxygenation reaction of -terpinene to give ascaridole by using networks

of CMP of poly(benzothiadiazole) in a microflow reactor.

Irradiation of a mixture of citronellol and RB with continuous air purging in a microflow

reactor affords two kinds of hydroperoxide products, which can be converted to rose oxide on

a hundreds of grams scale [51]. Similar photooxygenation of citronellol using Ru(dtbpy)3Cl2

(dtbpy; 4,4-di-tert-butyl-2,2-bipyridine) as a sensitizer can be utilized to produce rose oxide

(Scheme 93) [153,154]. Seeberger also reported that TPP-sensitized photooxygenation

reactions of various alkenes, 1,3-dienes and thioethers can be performed on a preparative scale

using this microflow system. Oxidation of citronellol affords two hydroperoxides in an 88%

total yield (52:48). 2-Methylfuran undergoes a photooxygenation reaction to give 4-oxo-2-

pentenoic acid, which serves as a key substrate for the synthesis of drugs. Also, 2-hydroxy

diethyl thioether undergoes the photooxidation followed by the triphenylphosphine reduction

to form the corresponding sulfoxide and sulfone [155].

81
 CH 2OH CH2OH CH2OH
hn (LED lamp; 468 nm), O 2
OOH
Ru(dtbpy)3Cl2 or +
OOH
methylene blue
()-citronellol Microflow Reactor 60% 40%
(plate)

CH2OH CH2 OH
Na2SO3 H 2SO4
+ OH
O
OH

rose oxide

Scheme 93. Photooxygenation of citronellol in the presence of a sensitizer. Reprinted with

permission from ref. [153]. Copyright 2006 Elsevier B.V.

Carofiglio and Maggini showed that [60]fullerene and silica gel- or tentagel-supported

[60]fullerene promote the photooxygenation of -terpinene and L-methionine in a glass-

polymer microstructured reactor to give ascaridole and methionine sulfoxide, respectively

(Scheme 94) [156].

EtO
O
Si silica gel
O

O O O
hn (white LED lamp)
S S N
OMe O2, SiC60 OMe CO2Me
NH2 D2 O NH 2
Microflow Reactor
(plate) 100% conversion
tR = 3342 s
SiC60

Scheme 94. Silica gel-supported [60]fullerene-promoted photooxygenation of L-methionine

methyl ester.

Kim described photooxygenation reactions of citronellol, allyl alcohols and -terpinene

82
using a triple-channel microflow reactor for biphasic gas-liquid reactions. The triple-channel

microflow reactor, in which the reaction channel is exposed to oxygen gas on two sides, was

prepared by using thin polydimethylsiloxane film [157].

The anti-malaria drug artemisinin can be synthesized using a continuous microflow reactor

(Scheme 95) [158,159]. In this system, dihydroartemisinic acid in dichloromethane undergoes

dye sensitized photoxidations to give the corresponding hydroperoxide, which results from an

ene-type reaction of singlet oxygen. TPP or 9,10-dicyanoanthracene (DCA) is used as a dye

sensitizer because of its high quantum yield for singlet oxygen production and high stability

against photobleaching. At 20 C, the hydroperoxide is produced more selectively in an 84%

yield. In addition, the oxygenation by molecular oxygen followed by Hock cleavage of the

hydroperoxide affords artemisinin in a 65% yield. The continuous-flow process is easily

scalable (16.08 g, 46% yield).

83
 Me
H CN Me Me
H H

Me 1O
H hn (Hg lamp) 2 Me
H Me
HO H H HOO H
Me CN HO HO
O Me Me
DCA
dihydroartemisinic or O O
acid TPP hydroperoxide

Microflow Reactor Me
H
(FEP tubing)
O
Me
O
O2 O
TFA HO H
Me
O
r.t. 60 C artemisinin, 3946%

Me Me Me Me
H H H H
Me Me
HO O
H+ 3O Me
O 2 O O O
Me O
HOO H Hock HO H O H H
H H HO
HO HO HO
Me cleavage Me Me
Me
O O
O O

Scheme 95. Synthesis of the anti-malaria drug artemisinin via photooxygenation.

Hexamethylbenzene is photochemically oxygenated by using a segmented microflow

reactor with oxygen gas bubbles and liquid slugs and methylene blue as a photosensitizer.

Primary product is an endoperoxide, which is further oxygenated to yield a hydroperoxy-

endoperoxide even in the flow system (Scheme 96) [160162]. The photooxygenation process

depends on the reaction temperature. The best yield in the microflow reactor is 96.4% after 30

min at 0 C, while the yield in the batch system is only 1.4% endoperoxide and 3.7%

hydroperoxy-endoperoxide after 90 min at 0 C.

84
 hn (white LED lamp) hn (white LED lamp) HOO
methylene blue, O2 methylene blue, O2
O O
acetone O acetone O

Microflow Reactor Microflow Reactor

(plate; slug flow) endoperoxide (plate; slug flow) hydroperoxy-
endoperoxide
96.4%

Scheme 96. Photochemical oxygenation of hexamethylbenzene.

Oelgemller reported the synthesis of Juglone (5-hydroxy-1,4-naphthoquinone) by using

dye-sensitized photooxygenation of 1,5-dihydroxynaphthalene in a falling film microflow

reactor (Scheme 97) [163]. Upon only 160 s visible-light irradiation in a gas-liquid system,

juglone is produced in a 31% conversion level. In contrast, the batch reaction gives a

conversion of 14% after 10 min irradiation. Similar photooxygenation reactions mediated by

porphyrinoid photosensitizer in a gas-liquid slug microflow system were also reported by

Oliveira and McQuade [164].

OH O
hn (CFL, white LED lamp)
RB
i-PrOH/H2O (9:1)
OH OH O
juglone
Batch Reactor
(Schlenk flask), 10 min 14% conversion
Microflow Reactor
(falling film), tR = 160 s 31% conversion

Scheme 97. Dye-sensitized photooxygenation of 1,5-dihydroxynaphthalene.

The photodegradation of 4-chlorophenol in the presence of molecular oxygen and

sulfonated zinc phthalocyanine (ZnPc) as a photosensitizer has been carried out using a

microflow reactor. This process affords maleic acid as its dianion through a pathway involving

85
formation of 1,4-benzoquinone and 1,4-hydroquinone. Deuterium oxide was used as a solvent

for this reaction to maximize the lifetime of singlet oxygen. The efficiency of the

photodegradation reaction is higher when carried out in a microflow reactor to using a batch

system (Scheme 98) [165,166].

OH O
hn (Hg lamp)
sulfonated ZnPc, O2 , NaOH
D2O, HCl
Microflow Reactor N N N (SO3H)x
Cl O
(plate)
N Zn N

N N N
CO2
OH
1O
CO2 2 / OH

HCO2
sulfonated ZnPc
CO32 OH

Scheme 98. Photodegradation of 4-chlorophenol by singlet oxygen.

1,3-Diphenylisobenzofuran is photochemically oxidized by singlet oxygen, generated on

nanoporous silicon in a green LED-powered microflow reactor [167]. Itoh reported the aerobic

photooxidation reactions of several toluene derivatives and indane performed using a

continuous microflow reactor and involving formation of a slug flow region on a chip. The

photoreactions are sensitized by 2-tert-butyl-9,10-anthraquinone and promoted using a LED

light (375 nm). A number of benzoic acid derivatives were generated in these reactions at rates

that are much larger than those using a batch system [168,169]. Similarly, indane is

photooxidized to give 1-indanone exclusively using the microflow conditions.

Kitamura showed that the photodecomposition of phenol takes place when a silica-

supported porphyrin derivative within a polymer microchannel chip is utilized (Fig. 16) [170].

86
Boyle reported that the photooxidations of cholesterol, -terpinene, and citronellol occurring

in a porphyrin immobilized microchannel chip is 150-times faster than that taking place in a

bulk suspension system [171].

Fig. 16. The use of a silica-supported porphyrin derivative as photosensitizer.

Matsushita studied the decolorization reaction of methylene blue as a dye in a model

wastewater treatment system using a glass microflow reactor. Under high pH conditions, the

decolorization process is much faster than when neutral conditions are employed [172].

Fluorinated -amino acids can be prepared via -amino nitrile intermediates, which are

generated by using the TPP-sensitized cyanation reaction of fluorinated amines. The

photoreaction of 4-fluorobenzylamine, for example, is conducted in a solution containing

trimethylsilyl cyanide (TMSCN), tetra-n-butylammonium fluoride (TBAF) and TPP, under an

oxygen atmosphere (7 bar) at 50 C. This process gives fluorinated -amino nitriles in high

yields when carried out in a microflow system and can be used to directly form aminoacids

without the need to isolate the nitrile intermediates when it is conducted under aqueous acidic

conditions (Scheme 99) [173].

hn (420 nm), TPP, O2 30% HCl aq
CN CO2H
TMSCN, TBAF CH3CO 2H
RF NH2 RF NH2 110 C, tR = 37 min RF NH3+Cl
MeTHF, 50 C, tR = 4 min
Microflow Reactor Microflow Reactor 67% (R F = 4-FC6 H4)
(FEP tubing) (FEP tubing) 60% (R F = 3,4-F2C 6H3)
63% (R F = CF3CH2 CH2)

87
 Scheme 99. Synthesis of fluorinated -amino acids initiated by TPP-sensitized cyanation of

fluorinated amines.

Nol reported the metal-free photocatalytic aerobic oxidation of thiols to give disulfides

quantitatively. This process uses Eosin Y as a sensitizer for the production of singlet oxygen

and takes place using the visible light irradiation under microflow conditions (Scheme 100)

[141, 174]. A similar visible light induced SS bond formation using RB as a sensitizer was

reported by Wacharasindhu [175].

hn (white LED lamp)
SH Eosin Y (1 mol%), O 2 R
S
R S
TMEDA (1 equiv), EtOH R
Microflow Reactor (PFA tubing)
9399%
R = H, 4-F, 4-MeO, 4-t-Bu, 4-Cl, 4-Me, 2-F

Scheme 100. Metal-free photocatalytic aerobic oxidation of thiols.

2.8. Photorearrangements

Jensen observed that the known photorearrangement of -santonin to lumisantonin and

mazdasantonin can be conducted efficiently using a microflow reactor (Scheme 101) [46]. The

ratio of products formed in this photoreaction is wavelength, irradiation time and solvent

dependent. For example, using unfiltered light with > 200 nm, the lumisantonin and

mazdasantonin ratio is 88:12 after only a 20 s pulse flow irradiation. However, when a 2 min

irradiation period is used, the product ratio is 9:91 under otherwise the same reaction conditions.

When the photoreaction is performed using > 280-nm light for 2 min, the product ratio is

71:29 (75%). These workers also reported that the photorearrangement of 4,4-dimethyl-2-

88
cyclohexen-1-one, promoted by utilizing 2 min irradiation and a high pressure lamp, gives a

mixture of bicyclo[3.1.0]hexan-1-one and 2-cyclopenten-1-one derivatives in 81%.

Me Me Me
Me Me
O O
hn (Hg lamp) hn
O Me MeCN Me Me
Me O Microflow Reactor O O
O (plate) O O
-santonin lumisantonin mazdasantonin
( > 200 nm), tR = 20 s 100% conversion (88:12)
( > 200 nm), tR = 2 min 100% conversion (9:91)
( > 280 nm), tR = 2 min 75% conversion (71:29)

O O O
hn (Hg lamp) +
Me
2-propanol
Me Me
Microflow Reactor
Me Me
(plate), tR = 2 min 81% Me

Scheme 101. Photorearrangement of -santonin and 4,4-dimethyl-2-cyclohexen-1-one.

The Barton reaction (nitrite photolysis) has been employed by Ryu to prepare a key

intermediate in the synthesis of an endothelin receptor antagonist employing a continuous

microflow and black light irradiation (Scheme 102) [176178].

OH O ONO O OH O
O O O
NOCl hn (black light)
acetone or DMF
NOH
O O Microflow Reactor O H
(plate)
up to 71%
5.3 g, 61% (40 h operation)

Scheme 102. Barton reaction of steroidal nitrite substrate.

The efficiency of the photoinduced Claisen rearrangement of mesityl naphthylmethyl ether

is enhanced by using a microflow reactor. In addition, this approach leads to an improved

89
selectivity of product formation by suppressing the secondary reaction (Scheme 103) [179].

Under batch conditions, both the mechanistically in-cage and out-of-cage (see below)

photoproducts are competitively formed under prolonged irradiation (480 min) conditions. On

the other hand, the 2,4-cyclohexadienone derivative is selectively generated in the reaction

conducted in the flow system (1 min). The mechanistic pathway for this process involves

excited state homolytic CO bond cleavage to afford a radical pair followed by radical

recombination (in-cage) giving 2,4-cyclohexadienone derivatives. The isolated

cyclohexadienone product does not rearrange to form phenylnaphthylmethane not only under

similar photoreaction conditions but also under thermal conditions (250 C, 1 h). However, in

the presence of a catalytic amount of 2,4,6-trimethylphenol (TMP), the out-of-cage product,

the cyclohexadienone smoothly rearranges to form phenylnaphthylmethane.

CO2Me CO2 Me
hn (Hg lamp)
CH 2
O Microflow Reactor O
(plate)

ArCH2

Ar

Ar
ArCH 2 ArCH 2 H
2
O HO HO

TMP
hn, TMP
Batch Reactor (480 min)
(Pyrex test tube) 22% 19% 12% 9% trace

Microflow Reactor (1 min)

51% 10% 2% 1% trace
(plate)

Scheme 103. Photoinduced Claisen rearrangement of phenyl naphthylmethyl ether.

Booker-Milburn reported the formation of aziridines from photorearrangement reactions of

N-3-butenylpyrroles by using flow conditions [180]. The level of productivity (21.8 g/day) of

90
this process is quite high compared with that arising from use of batch conditions (Scheme

104). The photoreaction proceeds through a route involving [2+2] cycloaddition followed by

the rearrangement via a biradical intermediate.

Scheme 104. Formation of aziridines in the photorearrangement of N-3-butenylpyrroles (a)

and its proposed mechanism (b). EWG; electron-withdrawing group. Reprinted with

permission from ref. [180]. Copyright 2013 Wiley-VCH Verlag GmbH & Co. KGaA,

Weinheim

Nitrones in the presence of a catalytic amount of trifluoroacetic acid (TFA) readily undergo

the photorearrangement to form amides by the use of a continuous microflow reactor (Scheme

105) [181]. Some di- and tetra-peptides can be efficiently prepared by using this photochemical

rearrangement. The tetrapeptide shown in Scheme 106 is formed from the nitrone in

acetonitrile (0.05 M) without TFA under photochemical microflow conditions (tR = 10 min) in

a 52% yield.

91
 hn (Hg lamp) hn (Hg lamp) O
Me +
TFA (0.25 equiv) Me TFA (0.25 equiv) Me
N N N
O H
O MeCN MeCN
Me Me Me
92 C, tR = 10 min
Microflow Reactor 93%
(quartz tubing)

Scheme 105. Photorearrangement of a nitrone to form an amide.

Ph
O O
H H
t-Bu N + N hn (Hg lamp)
O N N O Ph
H MeCN
O O Me O
Me Me tR = 10 min, 40 C
Microflow Reactor
(quartz tubing)
Ph
O O O
H H
t-Bu N N
O N N O Ph
H H
O Me O
Me Me
52%

Scheme 106. Formation of a tetrapeptide via photorearrangement of a nitrone.

Photorearrangements of 4-hydroxy-2-cyclobuten-1-ones by using a continuous microflow

reactor give the corresponding 2-furanones in excellent yields. A 2-pyridyl derivative reacts

photochemically to afford a 50:50 mixture of 2-furanone and 4H-quinolizin-4-one derivatives

(Scheme 107) [182].

MeO O O MeO OMe
hn (280370 nm) MeO
R MeCN, 90 min
MeO OH R O O
OH Microflow Reactor MeO
(PFA tubing) R 9299%

R = Ph, n-Bu, t-Bu, PhCC, 2-MeOC 6H4, 4-Me3 SiC 6H4, 4-t-BuC 6H4, 3-pyridyl

O
MeO O hn (280370 nm) MeO OMe MeO
N N
MeCN, 150 min +
MeO Microflow Reactor R O O MeO
OH (PFA tubing) OH
98% (50:50)

92
 Scheme 107. Photorearrangement of 4-hydroxy-2-cyclobuten-1-ones.

Irradiation of a mixture of 9,10-dihydro-9,10-ethenoanthracene (dibenzobarrelene)

derivative and acetophenone using a flat-bed solar light collector gives a di--methane

rearrangement product in an 81% yield (Scheme 108). The photoreaction of a

bicyclo[2.2.2]oct-5-en-2-one derivative affords a structurally and stereochemically complexed

product in a 48% yield (Scheme 109) [51]. Although a mechanism is unclear, an oxa-di--

methane type rearrangement may plausibly contribute to the initial reaction sequence.
CO2Me
MeO2 C CO 2Me
MeO2C hn (sunlight)
acetophenone
Microflow Reactor
(flat-bed solar
light collector) 81%
(see Fig.6)

Scheme 108. Di--methane rearrangement via solar light irradiation to 9,10-dihydro-9,10-

ethenoanthracene derivative.

MeO2C
MeO 2C O
hn (sunlight)
OH
O
MeCNH2O MeO 2C
Microflow Reactor
MeO2C
(flat-bed solar
light collector)
48%
(see Fig.6)

Scheme 109. Photoreaction of bicyclo[2.2.2]oct-5-en-2-one derivative involving plausibly

oxa-di--methane type rearrangement as a key step.

Fuse described the preparation of N-allyloxycarbonyl 3,5-dihydroxyphenylglycine, taking

place via a key photoinduced Wolff rearrangementnucleophilic addition process and carried

93
out in a microflow reactor (Scheme 110) [126,183].
O
O
O OH H
OC 6F5
C6F5OH

BnO OBn BnO OBn BnO OBn

hn
(UV lamp) 82%
1) triphosgene
2) TMSCHN2 MeCN
Microflow Reactor
(FEP tubing) O O O O
H
O N3 O N
N2 OH N OH
O
hn (UV lamp) O
MeCNH 2O Bn
BnO OBn Microflow Reactor BnO OBn BnO OBn HO OH
(FEP tubing)

Scheme 110. Formation of N-allyloxycarbonyl 3,5-dihydroxyphenylglycine via photoinduced

Wolff rearrangementnucleophilic addition as a key-step. TMSCHN2;

trimethylsilyldiazomethane.

Beeler developed an automated photochemical microfluidics platform for preparative

continuous flow photochemical reactions [184]. Using this method, a cyclobutanone product

was produced by irradiation of a bicyclic precursor through 1,3-acyl rearrangement (Scheme

111). The multidimensional photoreaction of indole derivatives following an intramolecular

[2+2] photocycloaddition route was also performed in this manner. In this process,

photocycloaddition competes with 1,3-migration of an R group [Ac, Boc, and mesyl (Ms)]

depending on the excitation wavelength.

94
 O
Me H
HO H H H
H hn (Hg lamp) H O +
H MeCN, 60 C Me MeCN
H H Me H Me
Microflow Reactor OH 120 C
O O
(plate) 14% 13%

R H
O
N H N
O R N O
OMe
hn (Hg lamp) Cl
OMe O OMe
X R
O MeCN H H O
Microflow Reactor Ph
(plate) F Ph
Ph 40% (R = Ac)
R = Ac, X = 5-F 16% (R = Boc) 16% (R = Ms)
R = Boc, X = 5-F
R = Ms, X = 6-Cl

Scheme 111. Photorearrangement of a tetracyclic compound and indole derivatives.

2.9. Heterogeneous Photocatalytic Reactions

TiO2 catalyzed photoreactions have been widely investigated from synthetic, mechanistic

and industrial viewpoints. Matsushita reported the photoreduction of benzaldehyde or 4-

nitrotoluene to give benzyl alcohol or p-toluidine, respectively, using a microflow reactor

coated with a transparent TiO2 thin film (Scheme 112) [8,185188]. In the process, the ethanol

solution containing benzaldehyde or 4-nitrotoluene flows through the TiO2 coated glass

microflow reactor with a 500-m width, 100-m depth and 40-mm length, and irradiated using

a 365-nm LED light under a nitrogen atmosphere. These researchers also uncovered the

efficient ethylation reaction of benzylamine to give N-ethylbenzylamine performed by

irradiation in ethanol via TiO2 thin film (Scheme 112) [187].

95
 CHO hn (365 nm LED) CH2OH

TiO2, EtOH
Microflow Reactor 11%
(plate), tR = 60 s
NO2 hn (365 nm LED) NH2

TiO2, EtOH
Me Me
Microflow Reactor 46%
(plate), tR = 60 s

NH2 hn (365 nm LED) N

H
TiO 2/Pt, EtOH
Microflow Reactor 98%
(plate), tR = 90 s

Scheme 112. TiO2 photocatalyzed reduction of benzaldehyde and 4-nitrotoluene, and

ethylation of benzylamine.

Matsushita reported TiO2 promoted photocatalytic oxidation reactions of 4-chlorophenol

and toluene under gas-liquid-solid multiphase flow conditions by the use of a microflow reactor

system containing immobilized thin photocatalytic TiO2 layers. The yield of the process is

remarkably increased with decreasing thicknesses of the liquid layer (Fig. 17) [189]. Similar

microflow reactors coated by nanoporous TiO2 films, bearing TiO2-coated porous ceramics and

using SiO2/TiO2 modified nanoparticles, have been prepared and employed for photocatalytic

degradation of methylene blue [190194]. TiO2-coated optical fiber bundles have been utilized

as a microflow reactor for the efficient decomposition of gaseous organic compounds such as

2-propanol and acetone [195].

96
 Fig. 17. Microfluidic chip-based analytical system for rapid screening of mesoporous

photocatalysts.

Microfluidic chip-based analytical systems based on the decomposition of methylene blue

for rapid screening of mesoporous photocatalysts such as MTiO2 (M = F, Si, K etc.) have been

developed (Fig. 18a) [196]. Kim reported that a photocatalytic system, comprised of TiO2

microbeads and using the inorganic polymer, allylhydridopolycarbosilane (AHPCS) as a

microflow reactor, can be used for photocatalytic degradation of 4-chlorophenol (Fig. 18b)

[197]. This microflow reactor has optical transparency and solvent resistance. A photocatalytic

microflow reactor containing immobilized TiO2 was also constructed and investigated for the

degradation of 4-chlorophenol (Fig. 18c) [198].

Fig. 18. Images of microflow reactors used in ref. [196198]. (a) Reprinted with permission

97
from ref. [196]. Copyright 2013 Elsevier B.V. (b) Reprinted with permission from ref. [197].

Copyright 2013 Elsevier B.V. (c) Reprinted with permission from ref. [198]. Copyright 2004

Elsevier B.V.

Methods for photocatalyzed reactions using microflow reactors were studied by Katayama.

In this system, photocatalysts such as TiO2, WO3 , nitrogen-doped TiO2, are coated inside a

fused silica capillary (inner diameter 1.1 mm, outer diameter 1.4 mm), which is transparent.

The system has been employed to photooxidize benzyl alcohol and reduce benzaldehyde and

nitrobenzene by the use of UV-LED and visible light [199]. Sun reported the NaBH4 reduction

reaction of 4-nitrophenol to form 4-aminophenol by the use of a silver microflow array reactor

that contains robust catalytic active sites [195].

Sohrabi reported the photodegradation reaction of 4-nitrophenol using a TiO2 film

immobilized on a fiberglass cloth [200].

Kitamori and Kim uncovered a photoinduced method for the synthesis of L-pipecolinic

acid from L-lysine that relies on the use of a TiO2modified microchannel chip (Scheme 113)

[201]. Although the reaction takes place in a complexed mechanism, the conversion rate using

the chip was found to be 70 times larger than that using a cuvette filled with nm-sized TiO2

particles with the same selectivity and ee.

CO 2H hn (Hg lamp), TiO2/Pt
H 2N NH2 H 2O N CO2H
H
Batch Reactor (cuvette), 60 min 14% (50% ee)
Microflow Reactor (plate), tR = 0.86 min 14% (47% ee)

Scheme 113. Photoinduced synthesis of L-pipecolinic acid from L-lysine by using TiO2

catalyst.

98
 Blechert reported photoinduced radical cyclization reactions of bromomalonate derivatives

by the use of mesoporous graphitic carbon nitride (mpg-C3N4) as a heterogeneous photocatalyst

and a flow reactor (Scheme 114) [202].

hn (blue LED lamp) MeO2C MeO 2C

Br CO 2Me CO2Me
mpg-C3 N4
MeO2C +
THF
MeO 2C Br
Microflow Reactor 95% (isolated: 80%)
(FEP tubing), tR = 5 min (19:1)

hn (blue LED lamp) MeO2C

Br CO 2Me
mpg-C3 N4
MeO2C
THF
MeO 2C
Microflow Reactor 86%
(FEP tubing), tR = 5 min (isolated: 72%)

Scheme 114. Photoinduced radical cyclization of bromomalonates by the use of mpg-C3N4 as

a heterogeneous photocatalyst.

Mizuno showed that photoisomerization and photooxygenation reactions of trans- and cis-

1,2-bis(4-methoxyphenyl)cyclopropanes can be carried out by the use of a TiO2 thin film-

coated microflow reactor with 15-mm width, 300-m depth, 50-mm length [203205]. The

photoisomerization occurs smoothly in aerated acetonitrile containing Mg(ClO4)2 to give a

trans:cis = 95:5 photostationary state. Under an oxygen atmosphere, trans- and cis-3,5-bis(4-

methoxyphenyl)-1,2-dioxolanes are obtained in high yields. These photoreactions, which are

likely initiated by electron transfer from 1,2-diarylcyclopropanes to excited TiO2 (Scheme 115),

are accelerated by Mg(ClO4)2 because of its ability to stabilize the cyclopropane radical cation

intermediates therefore suppressing back-electron transfer.

99
 hn (Hg lamp), hn (Hg lamp),
Mg(ClO4)2 O 2, Mg(ClO4 )2 Ar Ar
Ar Ar Ar Ar O O
TiO2, MeCN TiO2, MeCN
Ar = 4-MeOC6H4 84%
Microflow Reactor Microflow Reactor
(plate) (plate) (cis/trans = 80:20)

Scheme 115. Photoisomerization and photooxygenation of trans-bis(4-

methoxyphenyl)cyclopropanes by using TiO2 catalyst in the presense Mg(ClO4)2.

Capillaries coated on the inside with tungsten oxide have been employed as photocatalytic

microflow reactor bundles to decompose dyes such as methylene blue and Rhodamine 6G by

using sunlight [206]. Seeberger reported the efficient cleavage of photolabile 2-nitrobenzyl

linkers in Merrifield type solid phase synthesis by the use of a continuous microflow

photoreactor (FEP tubing, Scheme 116) [207]. In a batch system, the photoreaction results in

incomplete cleavage of the linkers. This method has been applied to the automated solid-phase

synthesis of chondroitin sulfate glycosaminoglycans [208] and -(1,3)-glucan

dodecasaccharide (Scheme 117) [209].

Scheme 116. Cleavage of photolabile 2-nitrobenzyl linker for solid-phase synthesis.

100
 Photograph shows resin distribution in the microflow photoreactor. Reprinted with

permission from ref. [207]. Copyright 2014 American Chemical Society.

Scheme 117. Automated solid-phase synthesis of -(1,3)-glucan dodecasaccharide.

3. Conclusion

In this review, a variety of organic photoreactions that have been performed using

microflow systems were described from a synthetic point of view. Where possible, the

advantageous features of the microflow photochemistry have been highlighted. Most of

photoreactions using microflow reactors take place with higher efficiencies and selectivities

compared with those conducted in batch systems. The formation of secondary products is often

effectively suppressed and the formation of insoluble polymeric or crystalline materials can be

101
avoided by utilizing different solvent, or using ultrasonification or slug flow conditions. In the

early days, the convenience and usefulness of microflow reactors were established using basic

photochemical reactions of simple organic compounds such as olefins and ketones. These

reactions are typically initiated by UV light and proceed by routes in which singlet and triplet

excited state species undergo chemical changes. The results of more recent studies show that

this convenient and useful technique is applicable to many complex photoreactions that take

place through electron-transfer promoted pathways and that involve the use of organic dyes

and organometallic photoredox catalysts such as Ru and Ir complexes. Importantly, visible-

light irradiation with LED (or laser) often can be employed to initiate the reactions, where

radicals, ions and radical ions are key intermediates.

The high reproducibility and low cost for scale-up of reactions are further advantages of

the microflow photochemistry. In conventional batch systems, scale-up, especially to the level

of industrial production, requires a large investment in plant and equipment to construct and

install large photoreactors. Therefore, the reproducibility associated with small scale reactions

is lost. In contrast, the microflow photochemistry can be readily utilized to scale-up reactions

simply by using a greater number of reactors and/or longer irradiation times. The advantages

of lower equipment costs should surpass the disadvantages associated with relatively long total

flow times of sample solutions. The fact that optimized conditions arrived at in studies of small

scale reactions can be simply applied to large scale reactions is a noteworthy feature of the use

of microflow reactors for photochemical reactions. As a matter of fact, several photoreactions

carried out in flow reactors have been performed on large scales as key steps in the industrial

synthesis of natural products.

102
 In this review, only micro flow photoreactions have been described. However,

continuous flow photochemical systems are also quite useful in the synthetic organic

photochemistry [210]. Recently, Garcia-Garibay reported the photodecarbonylation reaction of

an aqueous suspension of nanocrystalline (+)-(2R,4S)-2-carbomethoxy-4-cyano-2,4-diphenyl-

3-pentanone to gives (+)-(2R,3R)-2-carbomethoxy-3-cyano-2,4-diphenylbutane in a

quantitative chemical yield and 100% de and ee by the use of a continuous flow reactor [211].

Large-scale synthesis of molecules containing adjacent quaternary stereogenic centers has been

achieved by using continuous flow systems. It is also noteworthy that several kinds of micro-

size cage (or cage-like) compounds have been employed as microreactors that display

interesting phenomena [212,213]. Reviews of the use of these types of micro-size compounds

as microreactors have been presented by Ramamurthy, Fujita, and Tung [214217].

Furthermore, Yoshimi reported that a photoinduced decarboxylative radical addition of

carboxylic acids to electron-deficient alkenes was achieved by using a millitube (FEP tubing)

reactor with the short pathlength. Although the reaction setup is not a flow system, the

photoreaction is fairly efficient compared with the batch reactor photoreaction [218].

One current question that needs to be answered in this field is how to make a quantitative

comparison of photochemical reactions conducted in various types of reactors. Usually,

conversions or yields have been employed to compare performances although these parameters

may not necessarily accurately reflect actual production efficiencies. In batch reactors,

irradiation times are periods needed to carry out complete or nearly complete conversions of

reactants. On the other hand, in microflow reactors, residence times (tR) are not total flow times

correspond to actual reaction times. Thus, to compare the performances of different systems in

103
an accurate way, a method of expressing productivity (= the total amount of product / the total

reaction time) is required. Also a method is needed to express the value of the space-time yield,

STY = n / (VR t), where n is the amount of converted starting materials, VR is the reactor

volume, and t is the irradiation time. STY values are directly related to the geometry of reactors

and, thus, can be used to evaluate the performances of reactors independent of the reaction time.

The productivity and STY value are absolutely important to evaluate and compare the

efficiencies of flow systems, the notation of them is now one of necessary conditions for the

publication.

There is little doubt that, in the near future, most synthetic organic photochemists will use

(micro)flow reactors to carry out preparatively useful organic photochemical reactions. As a

result, a quantitative evaluation of the performance is desired so that workers can select proper

microflow reactors for the use in preparation of important targets and the discovery of new

reactions.

4. Acknowledgements

K.M. Y.N. H.I. and K.K thank the financial support of MEXT/JSPS KAKENHI Grant

Numbers 26410049, 25870437, 24109009, 22106532, 24106729, 24310101, and 15H03544.

The authors appreciate to Professors I. Ryu (Osaka Prefecture University), T. Fukuyama (OPU),

Y. Matsushita (Tokyo Institute of Technology), T. Takahashi (TIT), S. Fuse (TIT), H. Maeda

(Kanazawa University), A. Itoh (Gifu Phamaceutical University), H. Okamoto (Okayama

University) and P. S. Mariano (University of New Mexico) for helpful discussions about

photoinduced microflow reactions.

104
List of Abbreviations

Ac acetyl

acac acetylacetonate

AHPCS allylhydridopolycarbosilane

Bn benzyl

Boc tert-butoxycarbonyl

BPR back pressure regulator

bpy 2,2-bipyridine

Bu butyl

CFL compact fluorescent lamp

DCB 1,4-dicyanobenzene

de diastereomeric excess

DCA 9,10-dicyanoanthracene

dr diastereomeric ratio

dtbpy 4,4-di-tert-butyl-2,2-bipyridine

dmb 4,4-dimethyl-2,2-bipyridine

DMBP 4,4-dimethoxybenzophenone

DMF dimethylformamide

dmp 2,9-dimethyl-1,10-phenanthroline

DMSO dimethyl sulfoxide

105
DPE 1,1-diphenylethene

DPEphos 2,2'-bis(diphenylphosphino)diphenyl ether

ee enantiomeric excess

Et ethyl

EWG electron-withdrawing group

FEP fluorinated ethylene propylene

Fmoc 9-fluorenylmethyloxycarbonyl

HEH(R) Hantzsch ester (R ester)

Hex hexyl

HFIP hexafluoroisopropanol

LED light-emitting diode

LOPHTOR flow-based photochemical reactor

Me methyl

mpg-C3N4 mesoporous graphitic carbon nitride

Ms mesyl

MV2+ methyl viologen

NBS N-bromosuccinimide

NOCAS nucleophileolefin combination aromatic substitution

Nu(H) nucleophile

P product

PEEK polyether ether ketone

PFA perfluoro alkoxy alkane

106
Ph phenyl

PIB polyisobutylene

Piv pivaloyl

ppy 2-phenylpyridine

PS photosensitizer

PTFE polytetrafluoroethylene

PyCN 1-cyanopyrene

PyH pyrene

RB rose bengal

S substrate

TBADT tetra-n-butylammonium decatungstate

TBAF tetra-n-butylammonium fluoride

Tces trichloroethoxysulfonyl

TFA trifluoroacetic acid

THF tetrahydrofuran

TMDAM N,N,N,N-teteramethyldiaminomethane

TMEDA tetramethylethylenediamine

TMP 2,4,6-trimethylphenol

TMS trimethylsilyl

TMSCHN2 trimethylsilyldiazomethane

TMSCN trimethylsilyl cyanide

TMSOTf trimethylsilyl triflate

107
TPP 5,10,15,20-tetraphenylporphyrin

TPPT 2,4,6-triphenylpyrylium tetrafluoroborate

Ts tosyl

UV ultraviolet

UVA ultraviolet A

UVB ultraviolet B

UVC ultraviolet C

Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

YAG Yttrium Aluminum Garnet

ZnPc zinc phthalocyanine

References

[1] J. Yoshida, Flash Chemistry. Fast Organic Synthesis in Microsystems, Wiley-

Blackwell Chichester, 2008.
[2] V. Hessel, A. Renken, J. C. Schouten, J. Yoshida (Eds.), Micro Process Engineering.
A Comprehensive Handbook, Vol. 1, 2, 3, Wiley-VCH, Weinheim, 2009.
[3] W. Reschetilowski (Ed.), Microreactors in Preparative Chemistry, Wiley-VCH,
Weinheim, 2013.
[4] C. Wiles, P. Watts, Micro Reaction Technology in Organic Synthesis, CRC Press,
Boca Raton, 2011.
[5] T. Wirth (Ed.), Microreactors in Organic Chemistry and Catalysis, Second Completely
Revised and Enlarged Edition, Wiley-VCH, Weinheim, 2013.
[6] J. Yoshida (Ed.), Flow-Micro Synthesis, Kagaku-Dojin, 2014.
[7] T. Ichimura, Y. Matsushita, K. Sakeda, T. Suzuki, Photoreactions in T. R. Dietrich
(Ed.), Microchemical Engineering in Practice, Blackwell Publishing (2007) 385402.
[8] Y. Matsushita, N. Ohba, T. Suzuki, T. Ichimura, H. Tanibata, T. Murata, Recent
progress on photoreactions in microreactors, Pure Appl. Chem. 79 (2007) 19591968.

108
[9] P. Watts, C. Wiles, Homogeneous reactions II: photochemistry and electrochemistry
and radiopharmaceutical synthesis in T. Wirth, (Ed.), Microreactors in Organic
Chemistry and Catalysis, Wiley-VCH Verlag GmbH & Co. (2013) 133149.
[10] C. Wiles, P. Watts, Electrochemical and photochemical applications of micro reaction
technology in Micro reaction Technology in Organic Synthesis, CRC Press (2011)
289324.
[11] I. Ryu, T. Fukuyama, Radical chemistry by using flow microreactor technology in C.
Chatgillaloglu (Ed.), Encyclopedia of Radicals in Chemistry, Biology and Materials,
Wiley Online Library (2012) 12431258.
[12] K. Mizuno, Highly efficient and selective photochemical reactions by use of flow
microreactor in K. Mae (Ed.), R&D Frontiers in Microreactor for Production
Technology, CMC Publishing Co. (2012) 8995.
[13] K. Mizuno, Photochemical reactions in J. Yoshida (Ed.) Flow-Micro Synthesis,
Kagaku-Dojin (2014) 145166.
[14] Y. Nishiyama, K. Mizuno, Highly efficient and selective diastereodifferentiating
organic photoreactions using flow microreactor, J. Synth. Org. Chem. Jpn. 73 (2015)
460468.
[15] E. E. Coyle, M. Oelgemller, Micro-photochemistry: photochemistry in
microstructured reactors. The new photochemistry of the future? Photochem.
Photobiol. Sci. 7 (2008) 13131322.
[16] M. Oelgemller, O. Shvydkiv, Recent advances in microflow photochemistry,
Molecules 16 (2011) 75227550.
[17] M. Oelgemller, Highlights of photochemical reactions in microflow reactors, Chem.
Eng. Technol. 35 (2012) 11441152.
[18] M. Oelgemller, A. Murata, Continuous microflow photochemistry and its
application in pharmaceutical drug discovery, development and production, Med.
Chem. News (2012) 4, 3040.
[19] O. Shvydkiv, A. Yavorskyy, K. Nolan, M. Oelgemller, Microflow photochemistry
an advantegeous combination of synthetic photochemistry and microreactor
technology, EPA Newsletter, (2012) 6569.
[20] J. Wegner, S. Ceylan, A. Kirschning, Ten key issues in modern flow chemistry, Chem.
Commun. 47 (2011) 45834592.
[21] J. Wegner, S. Ceylan, A. Kirschning, Flow chemistry a key enabling technology for

109
 (multistep) organic synthesis, Adv. Synth. Catal. 354 (2012) 1757.
[22] C. Wiles, P. Watts, Recent advances in micro reaction technology, Chem. Commun.
47 (2011) 65126535.
[23] J. P. Knowles, L. D. Elliott, K. I. Booker-Milburn, Flow photochemistry: old light
through new windows, Beilstein J. Org. Chem. 8 (2012) 20252052.
[24] Y. Su, N. J. W. Straathof, V. Hessel, T. Nol, Photochemical transformations
accelerated in continuous-flow reactors: basic concepts and applications, Chem. Eur.
J. 20 (2014) 1056210589.
[25] A. M. Cubillas, S. Unterkofler, T. G. Euser, B. J. M. Etzold, A. C. Jones, P. J. Sadler,
P. Wasserscheid, P. St.J. Russel, Photonic crystal fibres for chemical sensing and
photochemistry, Chem. Soc. Rev. 42 (2013) 86298648.
[26] K. Gilmore, P. H. Seeberger, Continuous flow photochemistry, Chem. Rec. 14 (2014)
410418.
[27] J. Wahlerr, D. E. De Vos, P. A. Jacobs, P. L. Alsters, Solid materials as sources for
synthetically useful singlet oxygen, Adv. Synth. Catal. 346 (2004) 152164.
[28] D. G. Shchukin, D. V. Sviridov, Photocatalytic processes in spatially confined micro-
and nanoreactors, J. Photochem. Photobiol. C 7 (2006) 2329.
[29] K. Loubire, M. Oelgemller, T. Aillet, O. Dechy-Cabaret, L. Prat, Continuous-flow
photochemistry: a need for chemical engineering, Chem. Eng. Processing 104 (2016)
120132.
[30] I. Atodiresei, C. Vila, M. Rueping, Asymmetric organocatalysis in continuous flow:
opportunities for impacting industrial catalysis, ACS Catal. 5 (2015) 19721985.
[31] T. H. Rehm, Photochemical fluorination reactions a promising research field for
continuous-flow synthesis, Chem. Eng. Technol. 39 (2016) 6680.
[32] D. Cambie, C. Bottecchia, N. J. W. Straathof, V. Hessel, T. Nol, Applications of
continuous-flow photochemistry in organic synthesis, material science, and water
treatment, Chem. Rev. ASAP (DOI: 10.1021/acs.chemrev.5b00707).
[33] R. Porta, M. Benaglia, A. Puglisi, Flow chemistry: recent developments in the
synthesis of pharmaceutical products, Org. Process Res. Dev. 20 (2016) 225.
[34] R. Ciriminna, R. Delisi, Y.-J. Xu, M. Pagliaro, Toward the waste-free synthesis of fine
chemicals with visible light, Org. Process Res. Dev. 20 (2016), 403408.
[35] K. L. Skubi, T. R. Blum, T. P. Yoon, Dual catalysis strategies in photochemical
synthesis Chem. Rev. ASAP (DOI: 10.1021/acs.chemrev.6b00057).

110
[36] M. D. Krks, J. A. Porco, Jr., C. R. J. Stephenson, Photochemical approaches to
complex chemotypes: applications in natural product synthesis Chem. Rev. ASAP
(DOI: 10.1021/acs.chemrev.5b00760).
[37] T. Fukuyama, Y. Kajihara, Y. Hino, I. Ryu, Continuous microflow [2 + 2]
photocycloaddition reactions using energy-saving compact light sources J. Flow
Chem. 11 (2011) 4045.
[38] L. D. Elliott, J. P. Knowles, P. J. Koovits, K. G. Maskill, M. J. Ralph, G. Lejeune, L.
J. Edwards, R. I. Robinson, I. R. Clements, B. Cox, D. D. Pascoe, G. Koch, M. Eberle,
M. B. Berry, K. I. Booker-Milburn, Batch versus flow photochemistry: a revealing
comparison of yield and productivity, Chem. Eur. J. 20 (2014) 1522615232.
[39] T. Yamashita, S. Matsushita, T. Nagatomo, R. Yamauchi, M. Yasuda, Controlling the
photochemical reactions of alkenes by light-path length effects of a microchannel
reactor, Res. Chem. Intermed. 39 (2013) 111126.
[40] M. Ralph, S. Ng, K. I. Booker-Milburn, Short flow-photochemistry enabled synthesis
of the cytotoxic lactone (+)-goniofufurone, Org. Lett. 18 (2016) 968971.
[41] K. Terao, Y. Nishiyama, K. Kakiuchi, Highly efficient asymmetric PaternBchi
reaction in a microcapillary reactor utilizing slug flow, J. Flow Chem. 4 (2014) 35
39.
[42] T. Horie, M. Sumino, T. Tanaka, Y. Matsushita, T. Ichimura, J. Yoshida,
Photodimerization of maleic anhydride in a microreactor without clogging, Org.
Process Res. Dev. 14 (2010) 405410.
[43] R. Telmesani, S. H. Park, T. Lynch-Colameta, A. B. Beeler, [2+2] Photocycloaddition
of Cinnamates in Flow and Development of a Thiourea Catalyst, Angew. Chem. Int.
Ed. 54 (2015) 1152111525.
[44] E. J. Corey, J. D. Bass, R. LeMahieu, R. B. Mitra, A study of the photochemical
reactions of 2-cyclohexenones with substituted olefins, J. Am. Chem. Soc. 86 (1964)
55705583.
[45] T. Fukuyama, Y. Hino, N. Kamata, I. Ryu, Quick execution of [2+2] type
photochemical cycloaddition reaction by continuous flow system using a glass-made
microreactor, Chem. Lett. 33 (2004) 14301431.
[46] K. Pimparkar, B. Yen, J. R. Goodell, V. I. Martin, W.-H. Lee, J. A. Porco, Jr., A. B.
Beeler, K. F. Jensen, Development of a photochemical microfluidics platform, J. Flow
Chem. 2 (2011) 5355.

111
[47] K. Tsutsumi, K. Terao, H. Yamaguchi, S. Yoshimura, T. Morimoto, K. Kakiuchi, T.
Fukuyama, I. Ryu, Diastereoselective [2+2] photocycloaddition of chiral cyclic enone
and cyclopentene using a microflow reactor system, Chem. Lett. 39 (2010) 828829.
[48] K. Terao, Y. Nishiyama, S. Aida, H. Tanimoto, T. Morimoto, K. Kakiuchi,
Diastereodifferentiating [2+2] photocycloaddition of chiral cyclohexenone
carboxylates with cyclopentene by a microreactor, J. Photochem. Photobiol. A, Chem.
242 (2012) 1319.
[49] K. Terao, Y. Nishiyama, H. Tanimoto, T. Morimoto, M. Oelgemller, K. Kakiuchi,
Diastereoselective [2+2] Photocycloaddition of a chiral Cyclohexenone with Ethylene
in a Continuous Flow Microcapillary Reactor, J. Flow Chem. 2 (2012) 7376.
[50] T. Yamashita, M. Inoue, M. Yasuda, Isolation of a photochemically unstable product
by inner filtering of liquidliquid slug flow in a microreactor, Bull. Chem. Soc. Jpn.
88 (2015) 562564.
[51] M. Demuth, A. Ritter, Photochemical and thermochemical solar syntheses using flat-
bed solar collectors/solar reactors, US patent US 6,660,132 B1 (1999).
[52] M. Conradi, T. Junkers, Efficient [2 + 2] photocycloadditions under equimolar
conditions by employing a continuous UV-flow reactor, J. Photochem. Photobiol. A,
259 (2013) 4146.
[53] B. D. A. H. Hook, W. Dohle, P. R. Hirst, M. Pickworth, M. B. Berry, K. I. Booker-
Milburn, A practical flow reactor for continuous organic photochemistry, J. Org.
Chem. 70 (2005) 75587564.
[54] Y. Ito, H. Ueno, K. Shimada, M. Naito, Patent Japan, 2006255634.
[55] S. Bachollet, K. Terao, S. Aida, Y. Nishiyama, K. Kakiuchi, M. Oelgemller,
Microflow photochemistry: UVC-induced [2+2]-photoadditions to furanone in a
microcapillary reactor, Beilstein J. Org. Chem. 9 (2013) 20152021.
[56] T. P. Willumstad, O. Haze, X. Y. Mak, T. Y. Lam, Y.-P. Wang, R. L. Danheiser, Batch
and flow photochemical benzannulations based on the reaction of ynamides and diazo
ketones. Application to the synthesis of polycyclic aromatic and heteroaromatic
compounds, J. Org. Chem. 78 (2013) 1145011469.
[57] S. Cludius-Brandt, L. Kupracz, A. Kirschning, [3+2]-Cycloadditions of nitrile ylides
after photoactivation of vinyl azides under flow conditions, Beilstein J. Org. Chem. 9
(2013) 17451750.
[58] D. K. Tiwari, R. A. Maurya, J. B. Nanubolu, Visible-light/photoredox-mediated sp3

112
 CH functionalization and coupling of secondary amines with vinyl azides in flow
microreactors, Chem. Eur. J. 22 (2016) 526530.
[59] J. E. A. Shaw, R. E. Shute, A micro-engineered chemical reactor, Patent
WO2003037502 A1 (2003).
[60] K. Asano, Y. Uesugi, J. Yoshida, PausonKhand reactions in a photochemical flow
microreactor, Org. Lett. 15 (2013) 23982401.
[61] D. Chandrasekhar, S. Borra, J. S. Kapure, G. S. Shivaji, G. Srinivasulu, R. A. Maurya,
Visible-light photoredox catalysis: direct synthesis of fused -carbolines through an
oxidation/[3 + 2] cycloaddition/oxidative aromatization reaction cascade in batch and
flow microreactors, Org. Chem. Front. 2 (2015) 13081312.
[62] H. Maeda, H. Mukae, K. Mizuno, Enhanced efficiency and regioselectivity of
intramolecular (2+2) photocycloaddition of 1-cyanonaphthalene derivative using
microreactors, Chem. Lett. 34 (2005) 6667.
[63] H. Mukae, H. Maeda, K. Mizuno, One-step synthesis of benzotetra- and
benzopentacyclic compounds through intramolecular [2+3] photocycloaddition of
alkenes to naphthalene, Angew. Chem. Int. Ed. 45 (2006) 65586560.
[64] H. Mukae, H. Maeda, S. Nashihara, K. Mizuno, Intramolecular photocycloaddition of
2-(2-alkenyloxymethyl)naphthalene-1-carbonitriles using glass-made microreactors,
Bull. Chem. Soc. Jpn. 80 (2007) 11571161.
[65] A. Vasudevan, C. Villamil, J. Trumbull, J. Olson, D. Sutherland, J. Pan, S. Djuric,
LOPHTOR: a convenient flow-based photochemical reactor, Tetrahedron Lett. 51
(2010) 40074009.
[66] M. Nettekoven, B. Pllmann, R. E. Martin, D. Wechsler, Evaluation of a flow-
photochemistry platform for the synthesis of compact modules, Tetrahedron Lett. 53
(2012) 13631366.
[67] D. Blanco-Ania, S. A. Gawade, L. J. L. Zwinkels, L. Maartense, M. G. Bolster, J. C.
J. Benningshof, F. P. J. T. Rutjes, Rapid and scalable access into strained scaffolds
through continuous flow photochemistry, Org. Process Res. Dev. 20 (2016) 409413.
[68] J.-O. Kim, H. Kim, D.-H. Ko, K.-I. Min, D. J. Im, S.-Y. Park, D.-P. Kim, A monolithic
and flexible fluoropolymer film microreactor for organic synthesis applications, Lab
Chip, 14 (2014) 42704276.
[69] T. Aillet, K. Loubiere, O. Dechy-Cabaret, L. Prat, Photochemical synthesis of a cage
compound in a microreactor: Rigorous comparison with a batch photoreactor, Chem.

113
 Eng. Processing, 64 (2013) 3847.
[70] E. E. Blackham, J. P. Knowles, J. Burgess, K. I. Booker-Milburn, Combining
photochemistry and catalysis: rapid access to sp3 rich polyheterocycles from simple
pyrroles, Chem. Sci. 7 (2016) 23022307.
[71] O. Shvydkiv, S. Gallagher, K. Nolan, M. Oelgemller, From conventional to
microphotochemistry: photodecarboxylation reactions involving phthalimides, Org.
Lett. 12 (2010) 51705173.
[72] O. Shvydkiv, K. Nolan, M. Oelgemller, Microphotochemistry: 4,4-
Dimethoxybenzophenone mediated photodecarboxylation reactions involving
phthalimides, Beilstein J. Org. Chem. 7 (2011) 10551063.
[73] M. Oelgemller, Green photochemical processes and technologies for research &
development, scale-up and chemical production, J. Chin. Chem. Soc. 61 (2014) 743
748.
[74] S. Josland, S. Mumtaz, M. Oelgemller, Photodecarboxylations in an advanced meso-
scale continuous-flow photoreactor, Chem. Eng. Technol. 39 (2016) 8187.
[75] M. D. Lainchbury, M. I. Medley, P. M. Taylor, P. Hirst, W. Dohle, K. I. Booker-
Milburn, A Protecting group free synthesis of ()-Neostenine via the [5 + 2]
photocycloaddition of maleimides, J. Org. Chem. 73 (2008) 64976505.
[76] J. W. Tucker, Y. Zhang, T. F. Jamison, C. R. J. Stephenson, Visible-light photoredox
catalysis in flow, Angew. Chem. Int. Ed. 51 (2012) 41444147.
[77] H.-H. Liao, C.-C. Hsiao, E. Sugiono, M. Rueping, Shedding light on Brnsted acid
catalysis a photocyclizationreduction reaction for the asymmetric synthesis of
tetrahydroquinolines from aminochalcones in batch and flow, Chem. Commun. 49
(2013) 79537955.
[78] E. Sugiono, M. Rueping, A combined continuous microflow photochemistry and
asymmetric organocatalysis approach for the enantioselective synthesis of
tetrahydroquinolines, Beilstein J. Org. Chem. 9 (2013) 24572462.
[79] Q. Lefebvre, M. Jentsch, M. Rueping, Continuous flow photocyclization of stilbenes
scalable synthesis of functionalized phenanthrenes and helicenes, Beilstein J. Org.
Chem. 9 (2013) 18831890.
[80] H. Okamoto, T. Takane, S. Gohda, Y. Kubozono, K. Sato, M. Yamaji, K. Satake,
Efficient synthetic photocyclization for phenacenes using a continuous flow reactor,
Chem. Lett. 43 (2014) 994996.

114
[81] H. Okamoto, S. Hamao, H. Goto, Y. Sakai, M. Izumi, S. Gohda, Y. Kubozono, R.
Eguchi, Transistor application of alkyl-substituted picene, Sci. Rep. 4 (2014) 5048
5053.
[82] A. Yamamoto, Y. Matsui, T. Asada, M. Kumeda, K. Takagi, Y. Suenaga, K. Nagae,
E. Ohta, H. Sato, S. Koseki, H. Naito, H. Ikeda, Amorphous solid simulation and trial
fabrication of the organic field-effect transistor of tetrathienonaphthalenes prepared
by using microflow photochemical reactions: a theoretical calculation-inspired
investigation, J. Org. Chem. 81 (2016) 31683176.
[83] A. C. Hernandez-Perez, A. Viassova, S. K. Collins, Toward a visible light mediated
photocyclization: Cu-based sensitizers for the synthesis of [5]helicene, Org. Lett. 14
(2012) 29882991.
[84] K. Lisiecki, K. K. Krawczyk, P. Roszkowski, J. K. Maurin, Z. Czarnocki, Formal
synthesis of ()-podophyllotoxin through the photocyclization of an axially chiral 3,4-
bisbenzylidene succinate amide ester a flow photochemistry approach, Org. Biomol.
Chem. 14 (2016) 460469.
[85] X.-H. Li, L.-Z. Wu, L.-P. Zhang, C.-H. Tung, Controlled photocyclization,
photodimerization, and photoisomerization of stilbazole salts within Nafion
membranes, Org. Lett. 4 (2002) 11751177.
[86] A. C. Hernandez-Perez, S. K. Collins, A visible-light-mediated synthesis of
carbazoles, Angew. Chem. Int. Ed. 52 (2013) 1269612700.
[87] A. Caron, A. C. Hernandez-Perez, S. K. Collins, Synthesis of a carprofen analogue
using a continuous flow UV-reactor, Org. Process Res. Dev. 18 (2014) 15711574.
[88] A. C. Hernandez-Perez, A. Caron, S. K. Collins, Photochemical synthesis of complex
carbazoles: evaluation of electronic effects in both UV- and visible-light methods in
continuous flow, Chem. Eur. J. 21 (2015) 1667316678.
[89] E. Bremus-Kbberling, A. Gillner, F. Avemaria, C. Rethore, S. Brse, Photochemistry
with laser radiation in condensed phase using miniaturized photoreactors, Beilstein J.
Org. Chem. 8 (2012) 12131218.
[90] Y. S. M. Vaske, M. E. Mahoney, J. P. Konopelski, D. L. Rogow, W. J. McDonald,
Enantiomerically pure trans--lactams from -amino acids via compact fluorescent
light (CFL) continuous-flow photolysis, J. Am. Chem. Soc. 132 (2010) 1137911385.
[91] L. M. Kreis, S. Krautwald, N. Pfeiffer, P. E. Martin, E. M. Carreira, Photocatalytic
synthesis of allylic trifluoromethyl substituted styrene derivatives in batch and flow,

115
 Org. Lett. 15 (2013) 16341637.
[92] T. Fukuyama, Y. Fujita, M. A. Rashid, I. Ryu, unpublished results.
[93] E. Kumarasamy, R. Raghunathan, S. Jockusch, A. Ugrinov, J. Sivaguru, Tailoring
atropisomeric maleimides for stereospecific [2 + 2] photocycloaddition
photochemical and photophysical investigations leading to visible-light
photocatalysis J. Am. Chem. Soc. 136 (2014) 87298737.
[94] V. Belluau, P. Noeureuil, E. Ratzke, A. Skvortsov, S. Gallagher, C. A. Motti, M.
Oelgemller, Photodecarboxylative benzylations of phthalimide in pH 7 buffer, A
simple access to 3-arylmethyleneisoindolin-1-ones, Tetrahedron Lett. 51 (2010)
47384741.
[95] H. M. Pordanjani, C. Faderl, J. Wang, C. A. Motti, P. C. Junk, M. Oelgemller,
Photodecarboxylative benzylations of N-methoxyphthalimide under batch and
continuous-flow conditions, Aust. J. Chem. 68 (2015) 16621667.
[96] S. B. Tan, O. Shvydkiv, J. Fiedler, F. Hatoum, K. Nolan, and M. Oelgemller,
Photodecarboxylative additions of -thioalkyl-substituted carboxylates to alkyl
phenylglyoxylates, Synlett (2010) 22402243.
[97] H. Lu, M. A. Schmidt, K. F. Jensen, Photochemical reactions and on-line UV detection
in microfabricated reactors, Lab Chip 1 (2001) 2228.
[98] O. Shvydkiv, A. Yavorskyy, S. B. Tan, K. Nolan, N. Hoffmann, A. Youssef, M.
Oelgemller, Microphotochemistry: A reactor comparison study using the
photosensitized addition of isopropanol to furanones as a model reaction, Photochem.
Photobiol. Sci. 10 (2011) 13991404.
[99] A. Yavorskyy, O. Shvydkiv, K. Nolan, N. Hoffmann, M. Oelgemller, Photosensitized
addition of isopropanol to furanones in a continuous-flow dual capillary microreactor,
Tetrahedron Lett. 52 (2011) 278280.
[100] O. Shvydkiv, A. Yavorskyy, K. Nolan, A. Youssef, E. Riguet, N. Hoffmann, M.
Oelgemller, Photosensitized addition of isopropanol to furanones in a 365 nm UV-
LED microchip. Photochem. Photobiol. Sci. 9 (2010) 16011603.
[101] A. Yavorskyy, O. Shvydkiv, N. Hoffmann, K. Nolan, M. Oelgemller, Parallel
microflow photochemistry: process optimization, scale-up, and library synthesis, Org.
Lett. 14 (2012) 43424345.
[102] M. Oelgemller, N. Hoffmann, O. Shvydkiv, From lab & light on a chip to parallel
microflow photochemistry, Aust. J. Chem. 67 (2014) 337342.

116
[103] K. Sakeda, K. Wakabayashi, Y. Matsushita, T. Ichimura, T. Suzuki, T. Wada, Y. Inoue,
Asymmetric photosensitized addition of methanol to (R)-(+)-(Z)-limonene in a
microreactor, J. Photochem. Photobiol. A 192 (2007) 166171.
[104] H. Mukae, H. Maeda, K. Mizuno, unpublished results.
[105] K. Mizuno, M. Ikeda, Y. Otsuji, Dual Regioselectivity in the Photoallylation of
Electron-Deficient Alkenes by Allylic Silanes, Chem. Lett. (1988) 15071510.
[106] F. Bonassi, D. Ravelli, S. Protti, M. Fagnoni, Decatungstate photocatalyzed acylations
and alkylations in flow via hydrogen atom transfer, Adv. Synth. Catal. 357 (2015)
36873695.
[107] Q. Lefebvre, N. Hoffmann, M. Rueping, Photoorganocatalysed and visible light
photoredox catalysed trifluoromethylation of olefins and (hetero)aromatics in batch
and continuous flow, Chem. Commun. 52 (2016) 24932496.
[108] F. Wojcik, A. G. OBrien, S. Gtze, P. H. Seeberger, L. Hartmann, Synthesis of
carbohydrate-functionalised sequence-defined oligo(amidoamine)s by photochemical
thiol-ene coupling in a continuous flow reactor, Chem. Eur. J. 19 (2013) 30903098.
[109] R. S. Andrews, J. J. Becker, M. R. Gagne, A photoflow reactor for the continuous
photoredox-mediated synthesis of C-glycoamino acids and C-glycolipids, Angew.
Chem. Int. Ed. 51 (2012) 41404143.
[110] P. Schroll, B. Knig, Photocatalytic -oxyamination of stable enolates, silyl enol
ethers, and 2-oxoalkane phosphonic esters, Eur. J. Org. Chem. (2015) 309313.
[111] H. Lebel, H. Piras, M. Borduy, Iron-catalyzed amination of sulfides and sulfoxides
with azides in photochemical continuous flow synthesis, ACS Catal. 6 (2016) 1109
1112.
[112] D. Cantillo, B. Gutmann, C. O. Kappe, Safe generation and use of bromine azide under
continuous flow conditions selective 1,2-bromoazidation of olefins, Org. Biomol.
Chem. 14 (2016) 853357.
[113] A. C. Gutierrez, T. F. Jamison, Continuous photochemical generation of catalytically
active [CpRu]+ complexes from CpRu(6-C6H6)PF6, Org. Lett. 13 (2011) 64146417.
[114] S. Aida, K. Terao, Y. Nishiyama, K. Kakiuchi, M. Oelgemller, Microflow
photochemistrya reactor comparison study using the photochemical synthesis of
terebic acid as a model reaction, Tetrahedron Lett. 53 (2012) 55785581.
[115] F. R. Bou-Hamdan, P. H. Seeberger, Visible-light-mediated photochemistry:
accelerating Ru(bpy)32+-catalyzed reactions in continuous flow, Chem. Sci. 3 (2012)

117
 16121616.
[116] M. Neumann, K. Zeitler, Application of microflow conditions to visible light
photoredox catalysis, Org. Lett. 14 (2012) 26582661.
[117] B. Shen, M. W. Bedore, A. Sniady, T. F. Jamison, Continuous flow photocatalysis
enhanced using an aluminum mirror: rapid and selective synthesis of 2-deoxy and
2,3-dideoxynucleosides, Chem. Commun. 48 (2012) 74447446.
[118] M. D. Murcia, N. O. Vershinin, N. Briantceva, M. Gomez, E. Gomez, E. Cascales, A.
M. Hidalgo, Development of a kinetic model for the UV/H2O2 photodegradation of
2,4-dichlorophenoxiacetic acid, Chem. Eng. J. 266 (2015) 356367.
[119] Z. Vajglova, M. Vesely, J. Kristal, H. Vychodilova, J. Triska, V. Jiricny,
Photochemical degradation of polybrominated diphenyl ethers in micro photo-reactor,
Procedia Engineering, 42, 13781382 (2012).
[120] C. I. Wendell, M.J. Boyd, Reevaluation of the 2-nitrobenzyl protecting group for
nitrogen containing compounds: an application of flow photochemistry. Tetrahedron
Lett. 56 (2015) 897899.
[121] J. D. Nguyen, B. Reiss, C. Dai, C. R. J. Stephenson, Batch to flow deoxygenation
using visible light photoredox catalysis, Chem. Commun. 49 (2013) 43524354.
[122] J. Matsumoto, T. Matsumoto, Y. Senda, T. Shiragami, M. Yasuda, Preparation and
characterization of porphyrin chromophores immobilized on micro silica gel beads, J.
Photochem. Photobiol. A 197 (2008) 101109.
[123] A. Ouchi, T. Hyugano, M. Kaneda, T. Suzuki, C. Liu, Two-step laser photolysis of
flavone and NaBH4 at organic-aqueous liquid interface using a microchannel reactor:
a method to avoid secondary thermal side reactions, J. Flow Chem. 4 (2014) 189193.
[124] S. Fuse, N. Tanabe, M. Yoshida, H. Yoshida, T. Doi, T. Takahashi, Continuous-flow
synthesis of vitamin D3, Chem. Commun. 46 (2010) 87228724.
[125] S. Fuse, Y. Mifune, N. Tanabe, T. Takahashi, Continuous-flow synthesis of activated
vitamin D3 and its analogues, Org. Biomol. Chem. 10 (2012) 52055211.
[126] S. Fuse, T. Takahashi, Efficient organic synthesis based on microflow photo-reaction,
imidoylation, and acylation, J. Synth. Org. Chem. 73 (2015) 442451.
[127] D. Rackl, P. Kreitmeier, O. Reiser, Synthesis of a polyisobutylene-tagged fac-Ir(ppy)3
complex and its application as recyclable visible-light photocatalyst in a continuous
flow process, Green Chem. 18 (2016) 214219.
[128] D. Cantillo, O. de Frutos, J. A. Rincon, C. Mateos, C. O. Kappe, A scalable procedure

118
 for light-induced benzylic brominations in continuous flow, J. Org. Chem. 79, (2014)
223229.
[129] D. Sterk, M. Jukic, Z. Casar, Application of flow photochemical bromination in the
synthesis of a 5-bromomethylpyrimidine precursor of rosuvastatin: improvement of
productivity and product purity, Org. Process Res. Development 17 (2013) 145151.
[130] Y. Manabe, Y. Kitawaki, M. Nagasaki, K. Fukase, H. Matsubara, Y. Hino, T.
Fukuyama, I. Ryu, Revisiting the bromination of CH bonds with molecular bromine
by using a photo-microflow system, Chem. Eur. J. 20 (2014) 1275012753.
[131] W.-B. Yu, D.-P. Yu, M.-M. Zheng, S.-T. Shan, Y.-J. Li, J.-R. Gao, Catalyst and solvent-
free bromination of toluene derivatives by HBrH2 O2 with visible-light photocatalysis
using a continuous-flow micro reactor, J. Chem. Res. 36 (2012) 258263.
[132] H. Matsubara, Y. Hino, M. Tokizane, I. Ryu, Microflow photo-radical chlorination of
cycloalkanes, Chem. Eng. J. 167 (2011) 567571.
[133] I. G. T. M. Penders, Z. Amara, R. Horvath, K. Rossen, M. Poliakoff, M. W. George,
Photocatalytic hydroxylation of arylboronic acids using continuous flow reactors,
RSC Advances, 5 (2015) 65016504.
[134] K. Chen, S. Zhang, P. He, P. Li, Efficient metal-free photochemical borylation of aryl
halides under batch and continuous-flow conditions, Chem. Sci. 7 (2016) 36763680.
[135] A. M. Mfuh, J. D. Doyle, B. Chhetri, H. D. Arman, O. V. Larionov, Scalable, metal-
and additive-free, photoinduced borylation of haloarenes and quaternary
arylammonium salts, J. Am. Chem. Soc. 138 (2016) 29852988.
[136] X. Wang, G. D. Cuny, T. Nol, A Mild, One-pot StadlerZiegler synthesis of
arylsulfides facilitated by photoredox catalysis in batch and continuous-flow, Angew.
Chem. Int. Ed. 52 (2013) 78607864.
[137] M. Bergami, S. Protti, D. Ravelli, M. Fagnoni, Flow metal-free ArC bond formation
via photogenerated phenyl cations, Adv. Synth. Catal. 358 (2016) 11641172.
[138] H. Li, X. Gao, H. Ding, M. Yang, Q. Pu, Highly efficient Suzuki cross-coupling
reaction within an open channel plastic microreactor immobilized with palladium
complexes. Microfluid Nanofluid, 12 (2012) 981989.
[139] M. D. Konieczynska, C. Dai, C. R. J. Stephenson, Synthesis of symmetric anhydrides
using visible light-mediated photoredox catalysis, Org. Biomol. Chem. 10 (2012)
45094511.
[140] K. Ueno, F. Kitagawa, N. Kitamura, Photocyanation of pyrene across an oil/water

119
 interface in a polymer microchannel chip, Lab Chip 2 (2002) 231234.
[141] N. J. W. Straathof, Y. Su, V. Hessel, T. Nol, Accelerated gas-liquid visible light
photoredox catalysis with continuous-flow photochemical microreactors, Nat. Protoc.
11 (2016) 1021.
[142] D. Mangion, D. R. Arnold, Photochemical nucleophileolefin Combination, aromatic
substitution reaction. Its synthetic development and mechanistic exploration, Acc.
Chem. Res. 35 (2002) 297304.
[143] J. Matsumoto, Y. Yoshinaga, A. Hamasaki, T. Kawasaki, T. Yamashita, T. Shiragami,
M. Yasuda, Temperature dependence of photosensitized nucleophilic addition to
alkenes, Bull. Chem. Soc. Jpn. 84 (2011) 11301132.
[144] M. Rueping, C. Vila, T. Bootwicha, Continuous flow organocatalytic CH
functionalization and cross-dehydrogenative coupling reactions: visible light
organophotocatalysis for multicomponent reactions and CC, CP bond formations,
ACS Catalysis 3 (2013) 16761680.
[145] D. Cantillo, O. de Frutos, J. A. Rincon, C. Mateos, C. O. Kappe, Continuous flow -
trifluoromethylation of ketones by metal-free visible light photoredox catalysis, Org.
Lett. 16 (2014) 896899.
[146] R. C. R. Wootton, R. Fortt, A. J. deMello, A microfabricated nanoreactor for safe,
continuous generation and use of singlet oxygen, Org. Process Res. Dev. 6 (2002)
187189.
[147] K. S. Elvira, R. C. R. Wootton, N. M. Reis, M. R. Mackley, A. J. deMello, Through-
wall mass transport as a modality for safe generation of singlet oxygen in continuous
flows, ACS Sustainable Chem. Eng. 1 (2013) 209213.
[148] K. Jhnisch, Photochemische erzeugung und [4+2]-cycloaddition von singulett
sauerstoff im mikrofallfilmreaktor, Chemie Ingenieur Tech. 76 (2004) 630632.
[149] K. Jhnisch, U. Dingerdissen, Photochemical generation and [4+2]-cycloaddition of
singlet oxygen in a falling-film microreactor, Chem. Eng. Technol. 28 (2005) 426
427.
[150] C. Y. Park, Y. J. Kim, H. J. Lim, J. H. Park, M. J. Kim, S. W. Seo, C. P. Park,
Continuous flow photooxygenation of monoterpenes, RSC Adv. 5 (2015) 42334237.
[151] K. N. Loponov, J. Lopes, M. Barlog, E. V. Astrova, A. V. Maikov, and A. A. Lapkin,
Optimization of a scalable photochemical reactor for reactions with singlet oxygen,
Org. Process Res. Dev. 18 (2014) 14431454.

120
[152] K. Zhang, D. Kopetzki, P. H. Seeberger, M. Antonietti, F. Vilela, Surface area control
and photocatalytic activity of conjugated microporous poly(benzothiadiazole)
networks, Angew. Chem. Int. Ed. 52 (2013) 14321436.
[153] S. Meyer, D. Tietze, S. Rau, B. Schfer, G. Kreisel, Photosensitized oxidation of
citronellol in microreactors, J. Photochem. Photobiol. A 186 (2007) 248253.
[154] C. P. Park, R. A. Maurya, J. H. Lee, D.-P. Kim, Efficient photosensitized oxygenations
in phase contact enhanced microreactors, Lab Chip 11 (2011) 19411945.
[155] F. Levesque, P. H. Seeberger, Highly efficient continuous flow reactions using singlet
oxygen as a green reagent, Org. Lett. 13 (2011) 50085011.
[156] T. Carofiglio, P. Donnola, M. Maggini, M. Rossetto, E. Rossi, Fullerene-promoted
singlet-oxygen photochemical oxygenations in glass-polymer microstructured
reactors, Adv. Synth. Catal. 350 (2008) 28152822.
[157] R. A. Maurya, C. P. Park, D.-P. Kim, Triple-channel microreactor for biphasic gas
liquid reactions: Photosensitized oxygenations, Beilstein J. Org. Chem. 7 (2011)
11581163.
[158] F. Levesque, P. H. Seeberger, Continuous-flow synthesis of the anti-malaria drug
artemisinin, Angew. Chem. Int. Ed. 51 (2012) 17061709.
[159] D. Kopetzki, F. Levesque, P. H. Seeberger, A Continuous-flow process for the
synthesis of artemisinin, Chem. Eur. J. 19 (2013) 54505456.
[160] C. Y. Park, J. H. Park, H. J. Lim, G.-S. Hwang, C. P. Park, Photosensitized
oxygenations of hexamethylbenzene in phase contact enhanced microreactor, Bull.
Korean Chem. Soc. 35 (2014) 983984.
[161] C. J. M. van den Heuvel, H. Steinberg, Th. J. deBohr, The photo-oxidation of
hexaethylbenzene by singlet oxygen, Recl. Trav. Chim. Pays-Bas, 96 (1977) 157159.
[162] B. Sharma, K. Tazoe, X. Feng, T. Matsumoto, J. Tanaka, T. Yamato, Synthesis and
photoreaction of polymethyl substituted [2.2]metaparacyclophanes, J. Mol. Struc.
1037 (2013) 271275.
[163] O. Shvydkiv, C. Limburg, K. Nolan, M. Oelgemller, Synthesis of juglone (5-
hydroxy-1,4-naphthoquinone) in a falling film microreactor, J. Flow Chem. 2 (2012)
5255.
[164] K. T. de Oliveira, L. Z. Miller, D. T. McQuade, Exploiting photooxygenations
mediated by porphyrinoid photocatalysts under continuous flow conditions, RSC Adv.
6 (2016) 1271712725.

121
[165] S. Hedja, M. Drhova, J. Kristal, D. Buzek, P. Krystynik, P. Kluson, Microreactor as
efficient tool for light induced oxidation reactions, Chem. Eng. J. 255 (2014) 178
184.
[166] M. Vondrackova, S. Hedja, P. Stavarek, J. Kristal, P. Kluson, Combined effect of
temperature and dissolved oxygen on degradation of 4-chlorophenol in photo
microreactor, Chem. Engineering Processing: Process Intensification. 94 (2015) 35
38.
[167] A. A. Lapkin, V. M. Boddu, G. N. Aliev, B. Goller, S. Plisski, D. Kovalev, Photo-
oxidation by singlet oxygen generated on nanoporous silicon in a LED-powered
reactor, Chem. Eng. J. 136 (2008) 331336.
[168] Y. Nagasawa, K. Tanba, N. Tada, E. Yamaguchi, A. Itoh, A Study of aerobic
photooxidation with a continuous-flow microreactor, Synlett 26 (2015) 412415.
[169] Y. Nagasawa, E. Yamaguchi, N. Tada, A. Itoh, Study of aerobic-photooxidation
reactions with continuous flow micro reactor, J. Synth. Org. Chem. Jpn. 73 (2015)
469474.
[170] N. Kitamura, K. Yamada, K. Ueno, S. Iwata, Photodecomposition of phenol by silica-
supported porphyrin derivative in polymer microchannel chips, J. Photochem.
Photobiol. A 184 (2006) 170176.
[171] E. K. Lumley, C. E. Dyer, N. Pamme, R. W. Boyle, Comparison of photo-oxidation
reactions in batch and a new photosensitizer-immobilized microfluidic device, Org.
Lett. 14 (2012) 57245727.
[172] B. Ramos, S. Ookawara, Y. Matsushita, and S. Yoshikawa, Intensification of
photochemical wastewater decolorization process using microreactors, J. Chem. Eng.
Jpn. 47 (2014) 136140.
[173] S. Vukeli, D. B. Ushakov, K. Gilmore, B. Koksch, P. H. Seeberger, Flow Synthesis
of Fluorinated -Amino Acids, Eur. J. Org. Chem. (2015) 30363039.
[174] A. Talla, B. Driessen, N. J. W. Straathof, L.-G. Milroy, L. Brunsveld, V. Hessel, T.
Nol, Metal-Free Photocatalytic Aerobic Oxidation of Thiols to Disulfides in Batch
and Continuous-Flow, Adv. Synth. Catal. 357 (2015) 21802186.
[175] T. Tankam, K. Poochampa, T. Vilaivan, M. Sukwattanasinitt, S. Wacharasindhu,
Organocatalytic visible light induced SS bond formation for oxidative coupling of
thiols to disulfides, Tetrahedron 72 (2016) 788793.
[176] A. Sugimoto, Y. Sumino, M. Takagi, T. Fukuyama, I. Ryu, The Barton reaction using

122
 a microreactor and black light. Continuous-flow synthesis of a key steroid
intermediate for an endothelin receptor antagonist, Tetrahedron Lett. 47 (2006) 6197
6200.
[177] A. Sugimoto, T. Fukuyama, Y. Sumino, M. Takagi, I. Ryu, Microflow photo-radical
reaction using a compact light source: application to the Barton reaction leading to a
key intermediate for myriceric acid A, Tetrahedron 65 (2009) 15931598.
[178] I. Ryu, T. Fukuyama, A. Murata, H. Haibara, A. Sugimoto, M. Takagi, Manufacturing
process of photoproducts using flow photochemical reaction apparatus, Jpn patent
P200775682A (2007).
[179] H. Maeda, S. Nashihara, H. Mukae, Y. Yoshimi, K. Mizuno, Improved efficiency and
product selectivity in the photo-Claisen type rearrangement of an aryl naphthylmethyl
ether using a microreactor/flow system, Res. Chem. Intermed. 39 (2013) 301310.
[180] K. G. Maskill, J. P. Knowles, L. D. Elliott, R. W. Alder, K. I. Booker-Milburn,
Complexity from simplicity: tricyclic aziridines from the rearrangement of pyrroles
by batch and flow photochemistry, Angew. Chem. Int. Ed. 52 (2013) 14991502.
[181] Y. Zhang, M. L. Blackman, A. B. Leduc, T. F. Jamison, Peptide fragment coupling
using a continuous-flow photochemical rearrangement of nitrones, Angew. Chem. Int.
Ed. 52 (2013) 42514255.
[182] D. C. Harrowven, M. Mohamed, T. P. Goncalves, R. J. Whitby, D. Bolien, H. F.
Sneddon, An efficient flow-photochemical synthesis of 5H-furanones leads to an
understanding of torquoselectivity in cyclobutenone rearrangements, Angew. Chem.
Int. Ed. 51 (2012) 44054408.
[183] Y. Mifune, S. Fuse, H. Tanaka, Synthesis of N-allyloxycarbonyl 3,5-
dihydroxyphenylglycine via photochemical Wolff rearrangementnucleophilic
addition sequence in a micro-flow reactor, J. Flow Chem. 4 (2014) 173179.
[184] V. I. Martin, J. R. Coodell, O. J. Ingham, J. A. Porco, Jr., A. B. Beeler,
Multidimensional reaction screening for photochemical transformations as a tool for
discovering new chemotypes, J. Org. Chem. 79 (2014) 38383846.
[185] Y. Matsushita, S. Kumada, K. Wakabayashi, K. Sakeda, T. Ichimura, Photocatalytic
reduction in microreactors, Chem. Lett. 35 (2006) 410411.
[186] Y. Matsushita, N. Ohba, S. Kumada, T. Suzuki, T. Ichimura, Photocatalytic N-
alkylation of benzylamine in microreactors, Catal. Commun. 8 (2007) 21942197.

123
[187] Y. Matsushita, N. Ohba, T. Suzuki, T. Ichimura, N-Alkylation of amines by
photocatalytic reaction in a microreaction system, Catal. Today 132 (2008) 153158.
[188] Y. Matsushita, N. Ohba, S. Kumada, K. Sakeda, T. Suzuki, T. Ichimura, Photocatalytic
reactions in microreactors, Chem. Eng. J. 135 (2008) S303S308.
[189] Y. Matsushita, M. Iwasawa, T. Suzuki, T. Ichimura, Multiphase photocatalytic
oxidation in a microreactor, Chem. Lett. 38 (2009) 846847.
[190] N. Wang, L. Lei, X.M. Zhang, Y.H. Tsang, Y. Chen, H. L.W. Chan, A comparative
study of preparation methods of nanoporous TiO2 films for microfluidic
photocatalysis, Microelectronic Eng. 88 (2011) 27972799.
[191] S. Teekateerawej, J. Nishino, Y. Nosaka, Photocatalytic microreactor study using
TiO2-coated porous ceramics, J. Appl. Electrochem. 35 (2005) 693697.
[192] X. Li, H. Wang, K. Inoue, M. Uehara, H. Nakamura, M. Miyazaki, E. Abe, H. Maeda,
Modified micro-space using self-organized nanoparticles for reduction of methylene
blue, Chem. Commun. (2003) 964965.
[193] H. Lindstrom, R. Wootton, A. Iles, High surface area titania photocatalytic
microfluidic reactors, AlChE J. 53 (2007) 695702.
[194] H. Nakamura, X. Li, H. Wang, M. Uehara, M. Miyazaki, H. Shimizu, H. Maeda, A
simple method of self assembled nano-particles deposition on the micro-capillary
inner walls and the reactor application for photo-catalytic and enzyme reactions,
Chem. Eng. J. 101 (2004) 261268.
[195] R.-D. Sun, A. Nakajima, I. Watanabe, T. Watanabe, K. Hashimoto, TiO2-coated
optical fiber bundles used as a photocatalytic filter for decomposition of gaseous
organic compounds, J. Photochem. Photobiol. A 136 (2000) 111116.
[196] H. Zhang, J.-J. Wang, J. Fan, Q. Fang, Microfluidic chip-based analytical system for
rapid screening of photocatalysts, Talanta 116 (2013) 946950.
[197] T.-H. Yoon, L.-Y. Hong, D.-P. Kim, Photocatalytic reaction using novel inorganic
polymer derived packed bed microreactor with modified TiO2 microbeads, Chem. Eng.
J. 167 (2011) 666670.
[198] R. Gorges, S. Meyer, G. Kreisel, Photocatalysis in microreactors, J. Photochem.
Photobiol. A 167 (2004) 9599.
[199] K. Katayama, Y. Tanaka, K. Shimaoka, K. Yoshida, R. Shimizu, T. Ishikawa, A.
Nakamura, S. Kuwahara, A. Mase, T. Sugita, M. Mori, Novel method of screening
the oxidation and reduction abilities of photocatalytic materials, Analyst, 139 (2014)

124
 19531959.
[200] M. Jafarikojour, M. M. Mohammadi, M. Sohrabi, S. J. Royaee, Evaluation and
modeling of a newly designed impinging stream photoreactor equipped with a TiO2
coated fiberglass cloth, RSC Adv. 5 (2015) 90199027.
[201] G. Takei, T. Kitamori, H.-B. Kim, Photocatalytic redox-combined synthesis of l-
pipecolinic acid with a titania-modified microchannel chip, Catal. Commun. 6 (2005)
357360.
[202] M. Woznica, N. Chaoui, S. Taabache, S. Blechert, THF: an efficient electron donor in
continuous flow radical cyclization photocatalyzed by graphitic carbon nitride, Chem.
Eur. J. 20 (2014) 1462414628.
[203] H. Maeda, H. Nakagawa, K. Mizuno, unpublished results.
[204] H. Maeda, H. Nakagawa, K. Mizuno, Enhancement effect of Mg(ClO4)2 on TiO2-
catalyzed photooxygenation of 1,2-diarylcyclopropanes, Photochem. Photobiol. Sci.
2 (2003) 10561058.
[205] K. Mizuno, N. Kamiyama, N. Ichinose, Y. Otsuji, Photo-oxygenation of 1,2-
diarylcyclopropanes via electron transfer, Tetrahedron, 41 (1985) 22072214.
[206] K. Katayama, Y. Takeda, K. Kuwabara, S. Kuwahara, A novel photocatalytic
microreactor bundle that does not require an electric power source, Chem. Commun.
48 (2012) 73687370.
[207] M. Hurevich, J. Kandasamy, B. M. Ponnappa, M. Collot, D. Kopetzki, D. T. McQuade,
P. H. Seeberger, Continuous photochemical cleavage of linkers for solid-phase
synthesis, Org. Lett. 16 (2014) 17941797.
[208] S. Eller, M. Collot, J. Yin, H. S. Hahm, P. H. Seeberger, Automated solid-phase
synthesis of chondroitin sulfate glycosaminoglycans, Angew. Chem. Int. Ed. 52
(2013) 58585861.
[209] M. W. Weishaupt, S. Matthies, P. H. Seeberger, Automated solid-phase synthesis of a
-(1,3)-glucan dodecasaccharide, Chem. Eur. J. 19 (2013) 1249712503.
[210] Z. Amara, J. F. B. Bellamy, R. Horvath, S. J. Miller, A. Beeby, A. Burgard, K. Rossen,
M. Poliakoff, M. W. George, Applying green chemistry to the photochemical route to
artemisinin, Nat. Chem. 7 (2015) 489495.
[211] M. G. Hernandez-Linares, G. Guerrero-Luna, S. Perez-Estrada, M. Ellison, M.-M.
Ortin, M. A. Garcia-Garibay, Large-scale green chemical synthesis of adjacent
quaternary chiral centers by continuous flow photodecarbonylation of aqueous

125
 suspensions of nanocrystalline ketones, J. Am. Chem. Soc. 137 (2015) 16791684.
[212] X.-G. Fu, L.-P. Zhang, L.-Z. Wu, C.-H. Tung, Microreactor-controlled product
selectivity in photosensitized oxidation of alkenes. Electron transfer versus energy
transfer pathways, J. Photosci. 10 (2003) 175180.
[213] Z. Yuan, S. Zheng, Y. Zeng, J. Chen, Y. Han, Y. Li, and Y. Li, Photosensitized
oxidation of alkenes with dendrimers as microreactors: controllable selectivity
between energy and electron transfer pathway, New J. Chem. 34 (2010) 718722.
[214] V. Ramamurthy, B. Mondal, Supramolecular photochemistry concepts highlighted
with select examples, J. Photochem. Photobiol. C 23 (2015) 68102.
[215] M. Yoshizawa, J. K. Klosterman, M. Fujita, Functional molecular flasks: New
properties and reactions within discrete, self-assembled hosts, Angew. Chem. Int. Ed.
48 (2009) 34183438.
[216] C.-H. Tung, L.-Z. Wu, L.-P. Zhang, H.-R. Li, X.-Y. Yi, K. Song, M. Xu, Z.-Y. Yuan,
J.-Q. Guan, H.-W. Wang, Y.-M. Ying, X.-H. Xu, Microreactor-controlled selectivity
in organic photochemical reactions, Pure Appl. Chem. 72 (2000) 22892298.
[217] C.-H. Tung, L.-Z. Wu, L.-P. Zhang, B. Chen, Supramolecular systems as
microreactors: control of product selectivity in organic phototransformation, Acc.
Chem. Res. 36 (2003) 3947.
[218] Y. Yoshimi, A. Nishio, M. Hayashi, T. Morita, Sunlight-induced decarboxylative
radical addition of carboxylic acids to electron-deficient alkenes using a millitube
reactor, J. Photochem. Photobiol. A, Chem. ASAP (DOI:
10.1016/j.jphotochem.2016.03.012).

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Kazuhiko Mizuno was born in Osaka, Japan in 1947 and graduated from the Department of
Applied Chemistry at Osaka University with a BS degree in 1971 and a PhD in 1976 under
the supervision of Professors S. Tsutsumi and H. Sakurai, respectively. He began his
academic career at Osaka Prefecture University in 1976, was promoted to full professor in
1996 and remained at that institution until 2012 when he retired and became Professor
Emeritus. He is now serving as an adjunct professor at Nara Institute of Science and
Technology. He was Secretary of the Asian and Oceanian Photochemistry Association (APA)
(20042008) and President of the Japanese Photochemistry Association (JPA) (20082009).
He has received Progress Awards in Synthetic Organic Chemistry, Japan (1986), the JPA
Award (1996), JPA Lectureship Award (2006) and Award for Distinguished
Achievements to APA (2012) for research excellence. His current research interests focus on
photoinduced electron-transfer reactions, synthetic organic photochemistry, and microflow
photochemistry.

127
Yasuhiro Nishiyama was born in 1979 in Saitama, Japan. He received his BS (2003) and
PhD (2008) degrees from the Department of Applied Chemistry of Osaka University under
the direction of Professor Y. Inoue. After working in Sumitomo Rubber Industries, LTD. as a
technical officer, he joined Nara Institute of Science and Technology as a postdoctoral fellow
(2010). From 2012, he has worked at that Institute as an assistant professor. His current
research focuses on the development of original efficient photoreaction methods using flow
microreactor.

Takuya Ogaki was born in 1987 in Kyoto, Japan. He received his BS (2010) and MS (2012)
degrees from the Department of Applied Chemistry at Osaka Prefecture University under the
direction of Professors K. Mizuno and H. Ikeda. After working in SK-Electronics CO., LTD.

128
as an engineer, he received his PhD (2016) degree at Osaka Prefecture University under the
direction of Professor H. Ikeda. He is now a postdoctoral fellow in the Ikedas group. His
current research focuses on the synthesis of novel -conjugated molecules and their
application to organic electronics.

Kimitada Terao was born in 1985 in Nara, Japan. He received his BS degree (2009) from
Kyoto University and PhD degree (2014) from Nara Institute of Science and Technology
under the direction of Professor K. Kakiuchi. His research focuses on the development of
original efficient photoreaction method using flow microreactor.

129
Hiroshi Ikeda was born in Nagano, Japan in 1962 and graduated from the Department of
Chemistry at Tohoku University (TU) with a BS degree in 1985 and a PhD degree in 1990
under the supervision of Professors T. Mukai and T. Miyashi, respectively. He began his
academic career at TU as an Assistant Professor and became an Associate Professor of Osaka
Prefecture University (OPU) in 2006. He was promoted to Full Professor at OPU in 2011. He
carried out studies as a postdoctoral fellow at the University of Rochester (Professor J. L.
Goodman) in 1994 and as a guest scientist at Rutgers, the State University of New Jersey
(Professor H. D. Roth), in 2000. In 2010, he received the prestigious Japanese
Photochemistry Association Award. He is now serving as a Deputy Editor of J. Photochem.
Photobiol. C. Photochem. Rev. His current research is in the areas of photochemistry and
electron-transfer chemistry of organic compounds, physical organic chemistry including and
reaction mechanism and organic radical light-emitting diode.

130
Kiyomi Kakiuchi received his BS, MS, and PhD degrees from the Department of Applied
Chemistry at Osaka University, in 1977, 1979 and 1982, respectively, under the direction of
Professor Y. Odaira. Since 1997, he has been Full Professor in Graduate School of Materials
Science at Nara Institute of Science and Technology (NAIST). His research focuses on the
highly efficient chiral organic photochemistry. From 2009 to 2010, he served as Vice-
President of NAIST. Since 2013, he is serving as Dean of Graduate School of Materials
Science at NAIST.

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