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Applications of continuous-flow photochemistry in organicsynthesis, material science, and water treatmentCitation for published version (APA):Cambié, D., Bottecchia, C., Straathof, N. J. W., Hessel, V., & Noël, T. (2016). Applications of continuous-flowphotochemistry in organic synthesis, material science, and water treatment. Chemical Reviews, 116(17), 10276-10341. https://doi.org/10.1021/acs.chemrev.5b00707
DOI:10.1021/acs.chemrev.5b00707
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1
Applications of continuous-flow photochemistry in organic synthesis, material science and water treatment
Dario Cambié‡[a], Cecilia Bottecchia‡[a], Natan J. W. Straathof[a], Volker Hessel[a], Timothy Noël*[a,b]
‡ These authors contributed equally to this work.
[a] Department of Chemical Engineering and Chemistry
Micro Flow Chemistry and Process Technology
Eindhoven University of Technology
Den Dolech 2, 5600 MB Eindhoven (The Netherlands)
[b] Department of Organic Chemistry
Ghent University
Krijgslaan 281 (S4), 9000 Ghent (Belgium)
ABSTRACT: Continuous-flow photochemistry in microreactors receives a lot of attention from researchers in aca-demia and industry as this technology provides reduced reaction times, higher selectivities, straightforward scalability and the possibility to safely use hazardous intermediates and gaseous reactants. In this review, an up-to-date over-view is given of photochemical transformations in continuous-flow reactors, including applications in organic synthe-sis, material science and water treatment. In addition, the advantages of continuous-flow photochemistry are pointed out and a thorough comparison with batch processing is presented.
2
Contents 1 Introduction...................................................... 3
2 Fundamentals of flow photochemistry ............ 4
2.1 Nine good reasons why to go with
photoflow ........................................................ 4
2.1.1 Reason 1: Improved irradiation of the
reaction mixture .......................................... 4
2.1.2 Reason 2: Reliable scale-up ............... 5
2.1.3 Reason 3: Improved reaction
selectivity and increased reproducibility .... 7
2.1.4 Reason 4: Fast mixing ....................... 8
2.1.5 Reason 5: Fast heat exchange ............ 8
2.1.6 Reason 6: Multiphase chemistry ........ 9
2.1.7 Reason 7: Multistep reaction
sequences .................................................. 10
2.1.8 Reason 8: Immobilized catalysts ..... 12
2.1.9 Reason 9: Increased safety of
operation ................................................... 13
2.2 Materials used for photomicroreactor
fabrication ..................................................... 13
2.3 Solvent Choice ........................................ 15
2.4 Light sources ........................................... 15
3 Continuous-flow photochemistry in organic
synthesis ............................................................ 18
3.1 Short historical perspective of continuous-
flow photochemistry ..................................... 18
3.2 Photochemistry ....................................... 20
3.2.1 Photocycloadditions ......................... 20
3.2.2 Photoisomerizations ......................... 27
3.2.3 Cyclizations ..................................... 34
3.2.4 Singlet oxygen mediated oxidations 37
3.2.5 Photocleavage and photodeprotection
.................................................................. 49
3.2.6 Light-induced halogenation /
dehalogenation reactions .......................... 50
3.2.7 Photochemical decarboxylations ..... 53
3.2.8 Miscellaneous .................................. 54
3.3 Photocatalysis ......................................... 57
3.3.1 Ruthenium complexes ..................... 58
3.3.2 Iridium complexes ........................... 64
3.3.3 Copper complexes ............................ 69
3.3.4 Cobalt complexes ............................. 70
3.3.5 Decatungstates ................................. 70
3.3.6 TiO2 .................................................. 73
3.3.7 Mesoporous graphitic carbon nitride 74
3.3.8 Eosin Y ............................................. 74
3.3.9 Rose bengal ...................................... 77
3.3.10 Xanthones ...................................... 77
4 Continuous-flow photochemistry in material
science ............................................................... 78
4.1 Polymer synthesis ................................... 78
4.1.1 Continuous-flow synthesis of
polymers .................................................... 78
4.1.2 Late-stage modification of polymers 81
4.2 Polymer particle synthesis ...................... 83
4.3 Nanoparticles .......................................... 91
4.3.1 Polymer-based nanoparticles ........... 91
4.3.2 Metal-based nanoparticles ............... 91
5. Continuous-flow photochemistry for water
treatment ........................................................... 93
5.1 Water purification ................................... 93
5.1.1 Decontamination with TiO2 ............. 93
5.1.2 Photo-Fenton and Photo-Fenton-like
oxidations ................................................ 100
6. Conclusions ................................................. 102
7. List of acronyms ......................................... 103
REFERENCES ............................................... 106
3
1 Introduction
Sunlight strikes our planet every day with more energy
than we consume in a whole year. Therefore, many re-
searchers have explored ways to efficiently harvest and
use light energy for the activation of organic molecules.1-3
Light activation of molecules provides access to reaction
pathways which are otherwise impossible to reach with
classical thermochemical activation.4-12 Another fascinat-
ing aspect of photochemistry is the use of photons as
“traceless and green reagents”, hence rendering photo-
chemical processes green and sustainable.
In the last decade, visible light photoredox catalysis
emerged as a new and powerful mode to activate small
molecules.13-19 This new field exploits transition metal
complexes or organic dyes to harvest visible light photons
and convert this energy to an electrochemical potential,
thus facilitating subsequent single electron transfers with
organic substrates. Owing to the generally mild reaction
conditions, the use of visible light as a perennial energy
source and its broad applicability, visible light photoredox
catalysis has gained tremendous momentum over the past
five years and has triggered a renewed interest towards
photochemistry in general.
However, this renewed interest in photochemistry also
brought some old and unsolved problems to the surface.
Most of these issues are associated with the complexity of
photochemical processes. Scalability is hampered due to
the attenuation effect of photon transport (Bouguer-
Lambert-Beer law), which prevents the use of a dimen-
sion-enlarging strategy for scale-up. If larger reactors are
used, over-irradiation of the reaction mixture can become
an important issue as the reaction times are substantially
increased. This often results in the formation of byprod-
ucts, complicating the purification process significantly.
The use of continuous-flow microreactors for photochem-
ical applications has received a lot of attention as it allows
to overcome the issues associated with batch photochem-
istry.20-24 The narrow channel of a typical microreactor
provides opportunities to ensure a uniform irradiation of
the entire reaction mixture. Consequently, photochemical
reactions can be accelerated substantially (from
hours/days in batch to seconds/minutes in flow) and
lower photocatalyst loadings are often feasible. This re-
duction in reaction time minimizes potential byproduct
formation and increases the productivity of the photo-
chemical process. Furthermore, scale-up of photochemi-
cal reactions is facilitated in continuous-flow reactors.
This can be achieved by continuous introduction of reac-
tants into the flow reactor and by placing several devices
in parallel (numbering-up). Other advantages of microre-
actors are the improved mass- and heat-transfer charac-
teristics, enhanced safety, ease of processing multiphase
reaction mixtures and potential to include inline analyti-
cal technologies, allowing to develop fully automated
and/or self-optimizing processes.25-42
This review will highlight the use of continuous-flow
photoreactors for applications in organic synthesis, mate-
rial science and water treatment. Some fundamentals of
continuous-flow photochemistry are given in the intro-
duction section, which will help the reader to understand
4
the basic principles behind this technology. Moreover,
this section will allow researchers new to the field to get
the maximum out of their flow devices. Next, an overview
is given of different materials, solvents and light sources
that can be used to carry out photochemical reactions in
flow. Throughout this manuscript, we have sought to
highlight and explain the differences between batch and
flow reactors. Although the main focus of this review is
the use of microreactor technology for photochemistry,
we have also included mesoscale reactors where appro-
priate.
2 Fundamentals of flow photochemistry
2.1 Nine good reasons why to go with photoflow
2.1.1 Reason 1: Improved irradiation of the reac-
tion mixture
Photochemical reactions are driven by the absorption of
photons. Consequently, a homogeneous energy distribu-
tion inside a photoreactor is crucial to obtain high yields
and high selectivities. According to the well-known
Bouguer-Lambert-Beer equation (Eq. 1), the radiation
distribution will not be uniform in a reactor due to ab-
sorption effects.
𝐴 = log10 𝑇 = log10𝐼0
𝐼=𝜀𝑐𝑙 (1)
This equation shows a clear correlation between the ab-
sorption and the molar extinction coefficient (ε) of the
light absorbing molecules, their concentration (c) and the
path length of light propagation (l). By plotting this rela-
tionship between absorption and reactor radius, the im-
portance of reactor size can be conclusively shown
(Figure 1). With strong absorbers, such as common pho-
tocatalysts and organic dyes, the light intensity is rapidly
decreasing towards the center of the reactor. In order to
keep the radiation distribution uniform and thus maxim-
ize the efficiency of the photochemical process, microre-
actor technology can be used.24
Figure 1 Transmission of light as a function of distance
in a photocatalytic reaction using Ru(bpy)3Cl2 (c = 0.5, 1
and 2 mM, ε = 13,000 cm-1 M-1) utilizing the Bouguer-
Lambert-Beer correlation (Eq. 1).
The absorption of photons is crucial to carry out photo-
chemical reactions. However, not every photon will give
rise to the conversion of one molecule of starting materi-
al; excited states can return to their ground state by radia-
tive or non-radiative processes (e.g. heating). The quan-
tum yield is an important parameter to describe the effi-
ciency of the photochemical reaction:
𝜙 =number of molecules of product formed
number of photons absorbed by reactive medium (2)
The quantum yield is typically between 0 and 1 for non-
chain mechanisms.43 Quantum yields above 1 indicate
that a chain reaction occurs, e.g. in photoredox catalysis44-
46 or polymerization reactions.47 In such chain reactions,
5
photon absorption leads to the generation of e.g. a radical
(i.e. photo initiation) which is subsequently propagated
until termination occurs. The quantum yield can be de-
termined by carrying out photon flux measurements and
subsequently performing the reaction in the same setup.48
The photon flux is defined as the number of photons
observed per unit time. It is important to understand that
not every photon emitted by the light source will end up
in the photoreactor. By using refractors or miniaturized
light sources, the photon flux through the reactor can be
improved. Loubière and co-workers have compared the
photon flux for a microreactor and batch reactors.49 The
batch reactor received a photon flux of 7.4 x 10-6 ein-
stein/s, while the microreactor had a photon flux of 4.1 x
10-6 einstein/s. However, this value needs divided by the
reactor volume to obtain the absorbed photon flux densi-
ty. For the microreactor, 5.02 einstein/(m3s) was ob-
served, while the batch reactor only had 0.033 ein-
stein/(m3s). This 150-fold higher absorbed photon flux
density explains clearly why photochemical reactions can
be substantially accelerated in microreactors. The photon
flux strongly affects the intrinsic reaction rate of photo-
chemical processes; the higher the photon flux, the faster
the reaction will be completed.
Another important definition for photochemical process-
es is the so-called photonic efficiency (ξ), which is defined
as follows:
𝜉 =reaction rate
photon flux (3)
The photonic efficiency in batch reactors is typically
around 0.0086-0.0042.50 In microreactors, this value can
be substantially improved by using microscale light
sources (e.g. LEDs) or refractors. Noël and co-workers
reported values up to 0.66 for a photomicroreactor using
LED irradiation.51
2.1.2 Reason 2: Reliable scale-up
Increasing the productivity of photochemical reactions to
industrial scale has proven to be a formidable challenge
for chemists and chemical engineers in the past. Due to
the Bouguer-Lambert-Beer limitation of photon
transport, scalability has been problematic even on a
laboratory scale. In fact, advantages of photochemical
syntheses observed on a small scale cannot be fully ex-
ploited on a larger scale when using a classical dimen-
sion-enlarging strategy. Consequently, the wide imple-
mentation of photochemical transformations in the
pharmaceutical and fine-chemical industry has been se-
verely hampered.52-54
Due to the attenuation effect of photon transport, the
diameter of the photoreactor has to be kept as small as
possible to avoid non-uniform energy profiles. Microreac-
tor technology has been embraced by the scientific com-
munity as the ideal reactor to scale photochemistry.55-59
Essentially two strategies can be distinguished to scale-up
photochemistry with photomicroreactors: 1) longer opera-
tion times and increasing the throughput by increasing
the flow rates and 2) numbering-up.
The first strategy is the most popular one on a laboratory
scale as it is simple and straightforward to do. Reaction
conditions are often optimized using only small amounts
of starting materials in a microreactor. The same device
6
can be subsequently used, without tedious reoptimization
of the reaction conditions, to produce the desired amount
of material by continuous introduction of starting materi-
als. Higher throughputs can be achieved by increasing the
flow rates while keeping the residence time constant. One
should note that in flow reactors this will lead to a change
in the hydrodynamics and the heat transfer. However,
this is not a drawback as higher flow rates usually provide
higher mass- and heat-transfer characteristics, which
allows to reduce the reaction times. A drawback of this
approach is that the pressure drop, and thus energy dissi-
pation, over the reactor will increase. Importantly, photo-
chemical transformations are already substantially accel-
erated in microreactors; reaction times are usually re-
duced from hours in batch to the minutes/seconds range
in flow. This benefit also provides a substantial increase
in productivity compared to batch technology. With this
strategy, typically several milligrams to hundreds of
grams can be prepared in a reasonable time frame. This is
often enough to prepare sufficient amount of material for
the initial stages of a drug discovery process or to screen
the properties of new materials.
More material can be prepared by placing several micro-
reactors in parallel. This strategy is called numbering-up
and one can distinguish basically two different approach-
es, i.e. internal and external numbering-up (Figure 2).
External numbering-up is achieved by placing several
microreactors along with their pumping system and pro-
cess control in parallel. So, the entire microreactor setup
is copied several times until the desired amount of prod-
uct can be reached. This is a reliable way of scaling up
since individual reactor failure will not influence the
throughput of the other reactors. However, this is a very
costly strategy as typically the most expensive parts of any
microreactor setup are the pumps and the process con-
trol. Examples of external numbering-up can be found in
literature and in the industry.60 Researchers from Heraeus
Noblelight GmbH developed an external numbering-up
setup with 12 parallel photomicroreactors which allowed
to produce 2 kg of 10-hydroxycamptothecine per day
(Figure 2).61
In contrast, internal numbering is more economically
feasible as only the reactor itself is numbered-up while
the process control and pumping system is shared. The
essential part in the design of efficient internal number-
ing up is the distributor section, which equalizes and
regulates the reaction streams over the different microre-
actors. Small differences in pressure drop will lead to
significant maldistribution and thus in non-equal reac-
tion conditions in the different reactors. Noël and co-
workers have developed a convenient numbering-up
strategy for gas-liquid photocatalytic reactions (Figure
2c).62 The modular design allows to scale the photocata-
lytic aerobic oxidation of thiols to disulfides within 2n
photomicroreactors (n = 0, 1, 2, 3 was reported). Excellent
flow distribution was observed in the presence of a pho-
tochemical reaction, showing a standard deviation < 10%
for the mass flow rates. The variation in yield between
individual reactors was about 5%. Other examples of
internal numbering-up for photochemical applications
7
are the falling film microreactor (Figure 2a),63 microcapil-
lary films64-66 and a Corning Advanced-Flow G1 Photo
Reactor.67
Figure 2 Examples of numbering-up for the scale-up of
photochemical transformations: (a) Internal number-
ing-up in a falling film microreactor. Reprinted with
permission from ref. 63. Copyright 2005 Wiley and Sons.
(b) External numbering-up of a photochemical produc-
tion unit by Heraeus Noblelight GmbH. (c) Internal
numbering-up of photomicroreactor for gas-liquid visi-
ble light photocatalysis.
2.1.3 Reason 3: Improved reaction selectivity
and increased reproducibility
One of the key aspects in any chemical reaction is the
product selectivity. It is generally accepted that microre-
actors provide opportunities to increase the reaction
selectivity substantially. This is often attributed to the
enhanced mass-, heat- and photon-transport phenomena
observed in microchannels, which offers a high reproduc-
ibility of the reaction conditions. Such benefits can be
related to the increased surface-to-volume ratio in micro-
channels.
A typical flow setup can be schematically represented as
depicted in Figure 3 and consists of a mixing zone, a reac-
tion zone and a quenching zone. In batch, reaction time
is defined by how long the reactants are residing in the
vessel. In contrast, in flow reactors, reaction time (also
called residence time) is defined by the average time that
the reactants spend in the reactor. Consequently, reac-
tion/residence time is related to the flow rate. Due to the
presence of a quencher, reaction times can be precisely
controlled and thus follow-up reactions (e.g. degradation
of the compound) can be avoided by minimizing the time
spent in the reaction zone. This was demonstrated in the
photocatalytic aerobic oxidation of 2-furylmethanethiol.68
Prolonged light exposure resulted in batch in the for-
mation of overoxidized byproducts before full conversion
could be reached. Because of the homogeneous irradia-
tion and precise control over reaction times in flow, the
reaction could be completed in only 20 minutes in very
high selectivity.
8
Scheme 1 Schematic representation of a photochemi-
cal microreactor setup including (i) a mixing zone,
(ii) a reaction zone, and (iii) a quenching zone.
2.1.4 Reason 4: Fast mixing
One of the key features of microreactors is their size. In
this review, we define microreactors as continuous-flow
reactors that have an inner diameter ≤ 1 mm. Flow reac-
tors with a diameter larger than 1 mm are called milli- or
meso-reactors. Actually, the size of the reactor is very
important to explain the observed mixing phenomena in
continuous-flow photochemistry.69-70
In microscale photomicroreactors, the observed flow
pattern is laminar flow (Scheme 2). In this flow regime,
fluid is flowing in parallel layers and mixing is governed
by diffusion across parallel lamellae. It is easy to under-
stand that the smaller the diameter of the reactor, the
faster a uniform concentration of reactants across the
channel will be obtained. This insight led to the develop-
ment of micromixers in which the diffusion distance is
minimized to obtain mixing times in the milliseconds
range.71-73
Scheme 2 Laminar flow regime encountered in mi-
crochannels. Note that the velocity profile in the
fully developed region (after t2n) is parabolic. The
velocity at the wall is much lower than the velocity in
the center of the capillary.
Mixing is especially important to prevent the formation of
byproducts which originate because of local concentra-
tion gradients. This is called disguised chemical selectivi-
ty and occurs when the mixing time is much larger than
the reaction time.74 On a macroscale, such selectivity
issues are overcome by lowering the reaction temperature
as this will slow down the reaction kinetics significantly.
However, in microscale reactors, the mixing efficiency
can be substantially increased due to the small size of the
reactor. This provides opportunities to carry out reactions
at higher temperatures than in conventional batch
equipment.
2.1.5 Reason 5: Fast heat exchange
Fast heat transfer to the environment is important to
keep the reaction temperature inside the reactor stable
and to avoid byproduct formation via thermal pathways.
For photochemical processes, increases in reaction tem-
9
perature can occur due to heating from the light source
and exothermic reactions, e.g. singlet oxygen reactions.75
Due to the high surface-to-volume ratio, microreactors
provide in general an efficient heat dissipation. Conse-
quently, hot spot formation can be largely avoided and
microreactors are often considered as isothermal reactors.
In addition, material properties and surface characteris-
tics play a pivotal role in the heat management of micro-
reactors. The higher the heat conductivity of the reactor
material, the faster heat can be transferred to the coolant
(Table 1). Silicon microreactors provide excellent thermal
conductivities and are easy to make.76 Another important
material used for the fabrication of photomicroreactors
are polymer-based capillaries. They are commercially
available, inexpensive, chemically stable and provide
optimal transparency properties, however, they have a
low thermal conductivity.
Table 1 Thermal properties of common materials used for the fabrication of photomicroreactors.
Material Thermal conductivity [W m-1 K-1]
PFA 0.195
FEP 0.19-0.24
Glass (e.g. Quartz) 1
Silicon 149
2.1.6 Reason 6: Multiphase chemistry
Multiphase reactions are very common in the chemical
industry, e.g. oxidations, hydrogenations, halogenations
and phase-transfer catalysis reactions. They involve the
combination of two or more immiscible phases (e.g. liq-
uid-liquid or gas-liquid reactions). When mass transfer
from one phase to the other is the rate-determining step,
it is crucial to maximize the interfacial area. In batch, the
interfacial area is low and poorly defined, which leads to
prolonged reaction times. Due to the small characteristic
dimensions of microreactors, large and well-defined in-
terfacial areas are observed, which can reach up to 9000
m2·m-3. These large interfacial areas lead to efficient mass
transfer between the two phases. More specifically, the
mass transfer between two phases can be described with
the overall volumetric mass transfer coefficient (kLa),
which is for microreactors one to two orders of magni-
tude higher than for classical multiphase reactors.
Several microreactor designs have been developed to
carry out multiphase reaction conditions (Scheme 3).77-78
A first design involves single channel microreactors, e.g.
transparent polymer-based capillaries, which are com-
monly used in photochemical applications. Two flow
regimes are typically used in single channel microreac-
tors, i.e. segmented flow (also known as Taylor flow or
slug flow) and annular flow (sometimes referred to as
pipe flow). Segmented flow is characterized by liquid
slugs and elongated bubbles of an immiscible phase (e.g.
gas or liquid). In both, toroidal vortices are established
which cause a powerful mixing effect and intensify the
mass transfer from one phase to the other. The bubble is
separated from the reactor walls by a thin liquid film. In
photochemical applications, this thin film will receive the
highest intensity of photons and it can be anticipated that
reaction rates are locally very high. The internal circula-
tion patterns will result in a thin-film renewal exposing
different fluid to high photon fluxes. Annular flow is ob-
tained when one phase flows at a higher velocity in the
center of the capillary, while the wetting phase forms a
10
thin layer at the channel wall. This thin film will be in
close contact with the phase flowing in the center of the
reactor and will receive the highest photon flux. A second
design concerns the falling film microreactor in which the
liquid phase is directed over the channels by using gravi-
tational forces. The gas phase can be subsequently di-
rected co- or counter-currently in front of the liquid
phase. A third design is the membrane reactor in which
the two phases are separated by a permeable membrane.
Through the membrane, reactants can diffuse from one
phase to the other. A notable and popular example of
membrane reactors are the so-called tube-in-tube reac-
tors.79
Scheme 3 Overview of the most common microreac-
tor types used for multiphase flows.
Multiphase flows are also important for the preparation of
polymeric particles (Scheme 4). In laminar flow regimes,
axial dispersion leads to a broad residence time distribu-
tion. In other words, not every particle stays the same
time in the reactor which results in a relatively large par-
ticle size distribution. Particles at the channel walls are a
bit larger due to the lower velocity, while those in the
center will be smaller. A lower polydispersity can be ob-
tained by adding an immiscible phase to generate a seg-
mented flow regime. Each segment can be considered as
an individual reactor in which all particles spend exactly
the same time. Due to the internal circulation, excellent
micromixing and low dispersion is obtained and homo-
geneous reaction conditions are observed in the segment
which leads to a small size distribution.
0 2 4 6 8 10 12 140 2 4 6 8 10 12 14
Scheme 4 Schematic representation of the influence
of the flow regime on the polydispersity of particles.
2.1.7 Reason 7: Multistep reaction sequences
The synthesis of complex organic molecules typically
involves several synthetic steps along with intermediate
11
purifications. This traditional way of performing organic
reactions is very time consuming and, in times of increas-
ing labor costs, very expensive to carry out. Throughout
the years, chemists and chemical engineers have sought
ways to simplify the synthetic process. One attractive
technology to facilitate multistep reaction sequences is
microreactor technology (Scheme 5). It allows to combine
several reaction and purification steps in one continuous
streamlined flow process.38, 80 Such flow networks require
less manual handling for the practitioner and results in
substantial time and economic gains. Furthermore, inline
spectroscopic tools, self-optimization protocols and au-
tomation allow to further reduce human interaction.28, 81-82
The use of multistep flow sequences is especially interest-
ing when hazardous intermediates have to be prepared,
such as singlet oxygen, diazonium salts, azides.83-84 Such
intermediates can be generated in flow in small quantities
and are immediately reacted away. Consequently, the
total inventory of hazardous chemicals is kept low and
safety risks associated with these chemicals can be mini-
mized.
12
Scheme 5 Multistep reaction sequence in batch and flow.
2.1.8 Reason 8: Immobilized catalysts
Immobilization of photocatalysts is an interesting way of
recuperating and recycling the catalyst and thus increas-
ing the economic viability of the photocatalytic process.70,
85-86 Heterogeneous photocatalysts, such as semiconduc-
tors (e.g. TiO2 and ZnO), are extensively used in photo-
chemical applications due to their abundance, low cost,
and robustness.87-89 These catalysts can be introduced in
the reactor as a slurry. However, such an approach can
lead rapidly to reactor clogging when using microstruc-
tured photoreactors and a downstream separation step is
required to remove the catalyst from the products. An
alternative approach is the immobilization of this catalyst
on the reactor walls or in a packed bed (Figure 3).90-91 The
use of packed-bed reactor is often not desired as light will
not be able to penetrate to the center of the catalyst bed.
Alternatively, wall-coated photomicroreactors have been
reported in literature.92 In these examples, a thin layer of
photocatalyst is immobilized on the reactor walls and the
catalyst can be irradiated from the front or the backside
of the catalyst. Due to the short diffusion distances and
the large surface-to-volume ratios in the microchannels,
enhanced performances are usually observed. The illumi-
nated catalyst surface area per unit of liquid in the reactor
(κ) is high for microreactors (κ = 11,667 m2·m-3), compared
to slurry photoreactors (κ = 2,631 m2·m-3) or external type
annular photoreactors (κ = 27 m2·m-3).93 Photocatalysts
can also be immobilized on a membrane.94
Figure 3 TiO2 – based photocatalytic microreactors: (a)
Micro packed-bed photomicroreactor with TiO2 nano-
13
particles. (b) Schematic representation of membrane
photomicroreactor with TiO2 immobilized on the po-
rous membrane. (c) Picture of a photocatalytic microre-
actor in which TiO2 is deposited on the Pyrex lid. (d)
Field emission SEM image of the TiO2 nanotubes from
the side. (e) TEM image of the TiO2 nanotubes from the
top.
2.1.9 Reason 9: Increased safety of operation
Increasing the operational safety of hazardous reactions is
one of the main arguments for the chemical industry to
switch to a continuous-flow protocol. Microreactors have
small dimensions which reduces the total inventory of
hazardous chemicals and thus avoids any safety risks
associated with its handling. Furthermore, the impact of
an explosion is directly related to the total amount of
explosive materials present in the reactor to the power of
1/3. Despite the advantages of microreactors, one must
still be careful as explosions can propagate into the
neighboring storage vessels which might contain larger
amounts of explosive material.95 This also demonstrates
the need of suitable quenchers at the reactor outlet,
which can prevent explosion propagation.
Due to the increased safety, reaction conditions which are
impossible to carry out in batch are now accessible in
flow microreactors. This is especially true for photochem-
ical reactions involving singlet oxygen. It is known that
pure oxygen results into higher reaction rates and, in
flow, such processing conditions become accessible. Sev-
eral examples of singlet oxygen generation are discussed
in this review.
2.2 Materials used for photomicroreactor fabrica-
tion
Microflow reactors can be constructed from a wide varie-
ty of materials. However, for photochemical reactions, it
is imperative that at least one of the reactor walls is
transparent, so that the desired wavelength can reach the
reaction medium. Glass microreactors have been demon-
14
strated to be excellent for such purposes. In addition,
they also act as a wavelength filter. A list of different,
commonly applied, glass-based materials are given in
Table 2. Notably, these glass microreactors are quite diffi-
cult to construct and require chemical etching techniques
and clean room facilities, which are not always present in
a standard laboratory environment.96 Another drawback
of glass microreactors is the incompatibility with strong
basic reaction conditions and extreme reaction tempera-
tures.97-98
Figure 4 Different materials used for microphotoreac-
tor. (a) Fluoropolymer film wrapped around a cylindri-
cal LED lamp. Reprinted with permission from ref. 99.
Copyright 2014 The Royal Society of Chemistry. (b) glass
microchip irradiated with 5 UV-B lamps. Reprinted with
permission from ref. 55. Copyright 2008 The Royal Socie-
ty of Chemistry. (c) A FEP-capillary coiled around a
mercury lamp. Copyright 2012 Knowles et al.
Nowadays, photomicroreactors are increasingly con-
structed from polymer-based materials, such as
polymethylmethacrylate (PMMA), polydimethylsiloxane
(PDMS), perfluoroalkoxyalkane (PFA) or polytetrafluoro-
ethylene (PTFE), and many more.100 These polymer-based
materials have excellent light transmission, are easy to
handle and are commercially available at affordable pric-
es. However, PMMA and PDMS are susceptible to swell-
ing when subjected to organic solvents for a prolonged
time, rendering them unpractical for some photochemical
transformations. One way to increase the solvent re-
sistance of such polymers is applying a protective coating.
Several methods have been suggested in the literature,
such as transparent glass coatings via sol-gel methods.101-
102 In contrast, fluorinated polymers (e.g. PTFE, PFA and
FEP) provide a high chemical stability and good optical
properties towards both UV and visible light. Moreover,
they can withstand relative high temperatures and show
excellent physical properties. These materials are com-
mercially available as capillary tubing in a wide variety of
different lengths and diameters. Given the ease of han-
dling of these capillaries and low cost, such materials
have become increasingly popular in the photochemical
community. However, it should be noted that for UV
applications these polymers tend to degrade after pro-
longed irradiation times.103 In addition, high purity poly-
mers should be used, as leaching of the plasticizers from
the polymer (e.g. PFA) can occur, with a negative impact
on the photocatalytic process.103
15
Table 2 Overview of different materials used to construct photo microreactors. a Wavelength cut-off at 50% transmittance. b UV wavelength: 250-400 nm. c visible light: 400-700 nm.
Reactor Material Wavelength cut-off Pro / Consb,c Ref.
Quartz glass 170 nm
Incompatible with anisotropic etching
Incompatible with strong alkaline reaction mixtures
UV wavelength cut-off
96
Vycor glass 220 nm
Corex glass 260 nm
Pyrex glass 275 nm
Polymethylmethacryate (PMMA) 248 nm Incompatible with some organic solvents (swelling)
UV wavelength cut-off
High visible light transmittance
104-106
Polydimethylsiloxane (PDMS) ±255 nm
Polytetrafluoroethylene (PTFE) ±200 nm High chemical resistance, pressure and temperature resilience
UV wavelength cut-off
High visible light transmittance
107
Perfluoroalkoxyalkane (PFA) ±180 nm
Perfluoroethylenepropylene (FEP) ±180 nm
2.3 Solvent Choice
The selection of a proper solvent is a crucial step in the
development of any chemical reaction. However, in con-
tinuous-flow reactions, this is even more important as the
solvent needs to be able to solubilize all the chemicals
and products to prevent reactor clogging and undesired
light scattering. Solvents should also be selected based on
their optical properties (e.g. wavelength cut-off, see Table
3). Preferentially, solvents are transparent to the wave-
lengths required to facilitate the photochemical reaction.
Notably, solvents can have a strong influence on the life-
time of the excited state.108 In some cases, the solvent
might even have a sensitizing function, e.g. acetone.109
Table 3 Most common solvents utilized for photo-chemical applications.
Solvent Cut-off Wave-length (λ / nm)
Relative dielec-tric constant (εr)
water 185 78.3
acetonitrile 190 35.94
n-hexane 195 1.88
ethanol 204 24.5
methanol 205 32.66
cyclohexane 215 2.02
diethyl ether 215 4.20
1,4-dioxane 230 2.21
methylene chlo-ride
230 8.93
chloroform 245 4.81
tetrahydrofuran 245 7.58
acetic acid 250 6.17
ethyl acetate 255 6.02
carbon tetrachlo-ride
265 2.23
dimethylsulfoxide 277 46.45
benzene 280 2.27
toluene 285 2.38
pyridine 305 12.91
acetone 330 20.56
2.4 Light sources
The selection of a proper light source for photochemical
applications depends mainly on the overlap between the
emission spectrum of the light source and the absorption
characteristics of the photoactive reactants or catalysts.
16
Other important selection criteria are cost, energy effi-
ciency, lifetime of the light source and match between the
light source dimensions and the photoreactor.
Figure 5 Different light sources applied to continuous-
flow photochemistry. (a) Blue LED array wrapped inside
a disposable plastic syringe to irradiate a coiled capil-
lary microreactor.110 (b) Photomicroreactor with quartz
top plate irradiated with UV LEDs (360 nm). Reprinted
with permission from ref. 111. Copyright 2011 Akademiai
Kiado. (c) Same reactor as (b) irradiated with a black
light (360 nm). Reprinted with permission from ref. 111.
Copyright 2011 Akademiai Kiado. (d) Highpower cold
white LED lamps irradiated a FEP capillary microreac-
tor. Reprinted with permission from ref. 112. Copyright
2012 The Royal Society of Chemistry.
Perhaps the most common artificial light sources are
mercury-based light sources for UV applications and
compact fluorescent light bulbs (CFL) for visible light-
induced transformations. These light sources have a long
life span, have a relative efficient light emittance (lumen
per watts) and can emit a broad range of wavelengths
(Scheme 6). Medium and low pressure mercury lights are
often utilized for mid and low UV-wavelengths (UV-A
and UV-B, 350–250 nm), while high-pressure mercury
light sources emit wavelengths up to 600 nm. In contrast
to medium pressure mercury sources, fluorescent black
lights are more practical in use and have an UV emission
between 310 and 450 nm. The lamp emission can be tuned
by application of a phosphor coating which absorbs mon-
ochromatic Hg irradiation and reemits less energetic
irradiation. Compact fluorescent light bulbs are also
prominently applied in numerous visible light photo-
chemical transformations. Despite the practicality of
these light bulbs, they are not always easy to use in mi-
croflow applications as the dimensions do not match with
those of the microchannels.10, 100 Consequently, the energy
efficiency of the setup is low since a lot of light is not
directed towards the reaction channels (Figure 5). In this
regard, the application and integration of Light Emitting
Diodes (LEDs) in microfluidic applications has become
very popular. LEDs are much more flexible because of
their relative small footprint and very narrow emission
bands (± 20 nm). The emitted wavelength can be tailored
and matched with the photochemical application
(Scheme 6).10, 93, 113-115 Furthermore, LEDs are energy effi-
cient, inexpensive and their temperature can be con-
trolled with cheap and low energy cooling systems (e.g.
fans for air cooling).
17
Scheme 6 Overview of common light sources used for photochemical applications and their emission spec-
tra. A legend is provided with icons for the different light sources which are used in this manuscript.
The utilization of solar energy to drive chemical trans-
formations would be a huge breakthrough for the
chemical industry in terms of sustainability and cost
efficiency. However, sunlight is generally diffuse due
to scattering and reflections by trees or built environ-
ment. Furthermore, shading due to clouds and day-
night cycles reduces the performance of the photo-
chemical process significantly. Specialized equipment,
such as continuous-flow reactors in combination with
reflectors, has been developed and can be used in
countries that have a high amount of solar irradiation
(Figure 6). Another important issue is the poor match
between the emission spectrum of the sun and the
absorption characteristics of the photocatalyst. In-
compatible light energy can enable undesired reaction
pathways, giving rise to substantial byproduct for-
mation. However, the application of solar energy for
large scale water purification and processing is more
established, specifically in combination with hetero-
geneous detoxification and disinfection at water
treatment plants.116-117
Figure 6 PROPHIS (Parabolic Trough Facility for
Organic Photochemical Synthesis) in Cologne. Re-
printed with permission from ref. 118. Copyright 2001
The Royal Society of Chemistry
18
3 Continuous-flow photochemistry in
organic synthesis
3.1 Short historical perspective of continuous-
flow photochemistry
The first experimental account of a chemical modifica-
tion induced by light dates back to 1834, when Her-
mann Trommsdorff described the effects of sunlight
exposure on α-santonin crystals, a sesquiterpene lac-
tone used as febrifuge and isolated from Artemisia
plants.119 Remarkably, through the use of a prism, he
understood the dependence of the wavelength on the
crystal decomposition (“Das Santonin, wird sowohl
durch den unzerlegten, als durch den blauen und vio-
letten Strahl gefärbt… der gelbe, grüne und rothe bring-
en nicht die mindeste Veränderung hervor”, santonin is
turned yellow not only by the undivided, but also by
the blue and violet rays… whereas… the yellow, green
and red ones cause not even the slightest changes).120
The photodegradation of santonin was further investi-
gated by another pioneer of photochemistry, Stanislao
Cannizzaro.121-122 Starting from his seminal work, his
disciples Paternó, Ciamician and Silber took the first
steps towards modern photochemistry. Paternó first
discovered in 1909 the eponym [2+2] photocycloaddi-
tion between alkenes and carbonyls, further expanded
by Büchi.123-124 Around the same period, Giacomo
Ciamician and Paolo Silber laid the foundation of
modern photochemistry through a systematic investi-
gation of photochemical reactions (photoreductions125,
photocycloadditions126, α- and β-cleavage of ke-
tones127).128-129 The importance of Ciamician’s work lies
also in the awareness that photochemistry could be a
more sustainable alternative to thermally-induced
transformations, which depend on non-renewable
fossil sources.130 In this visionary paper, he also made
the following statement:
“On the arid lands there will spring up industrial col-
onies without smoke and without smokestacks; for-
ests of glass tubes will extend over the plains and
glass buildings will rise everywhere; inside of these
will take place the photochemical processes that
hitherto have been the guarded secret of the plants,
but that will have been mastered by human industry
which will know how to make them bear even more
abundant fruit than nature, for nature is not in a hurry
and mankind is. And if in a distant future the supply
of coal becomes completely exhausted, civilization will
not be checked by that, for life and civilization will
continue as long as the sun shines!”
The highlighted part can be regarded as one of the
first statements of continuous-flow reactors for photo-
chemical applications.
In the days of Ciamician, photochemistry was almost
exclusively done with sun irradiation as light source.
Therefore, it can be described in modern terms as
“green” and “sustainable”. Carl Theodore Liebermann,
in 1895, first experimented with arc lamps as alterna-
tive light sources.131
Deriving from these earliest approaches, photochem-
istry continuously evolved.132 In the late 20th century,
fundamental applications emerged: among them the
19
synthesis of cubane133, lycopodine134, estrone135 and
ginkgolide B136.
It did not take long before the usefulness of photo-
chemistry was implemented in the chemical industry.
For example, the industrial synthesis of vitamin D3
proceeds through a photochemical step. More specifi-
cally, the 9,10 double bond in provitamin D is cleaved
via UV irradiation to yield the E and Z isomers of pre-
vitamin D.137 Moreover, since the installation of the
first photochemical production unit in 1963, the syn-
thesis of ε-caprolactam through the photonitrosation
of cyclohexane (Toray process) has been an important
step towards Nylon 6.137 The nitrosation of the alkane
is based on the photoinduced cleavage of NOCl in the
presence of HCl. This photochemical strategy was
later replaced by the catalytic air oxidation of cyclo-
hexane. However, it is estimated that a small portion
(10%) of the yearly Nylon 6 world production still
relies on photonitrosation.
The first examples on the application of microflow
technology to photochemical synthesis date back to
the beginning of the 2000s.105, 138 However, the concept
of flow reactors and its use in synthetic chemistry
were not new to the chemical community. In fact,
already in the 1960’s, larger tubular reactors were
employed for photochemical transformations139-140 and
their optimization from an engineering point of view
was also investigated.141
By the late 1980’s, PTFE tubing photoreactors started
to be employed as integrated post-column analytical
systems for HPLC.142 With an online photochemical
derivatization, the products eluting from the HPLC
column could be more easily identified. Both com-
mercially available photoreactor and home-made ones
were developed for this purpose. Typically, a PTFE
tubing reactor (ID 300 μm) assembled in a crocheted
geometry was placed between the analytical column
and the detector (e.g. DAD).143 The reactor was illumi-
nated with one or multiple 8 W low pressure mercury
UV-lamp, causing the products to be photoderivat-
ized. Owing to the changes in the spectral properties
of the eluted compounds, hard-to-detect species could
be unequivocally identified.144
The advent of miniaturization techniques, represented
the real paradigm shift in flow photochemistry. In-
deed, the effective exploitation of the microscale,
allowing for homogeneous and efficient light irradia-
tion (e.g. LED lights145), enabled unprecedented ap-
proaches. As such, a new unmatched level of process
intensification for photochemical reactions was possi-
ble. Every year, the number of papers on photochemi-
cal reactions in continuous-flow are steadily increas-
ing, as shown in Figure 7.
Figure 7 Number of citation per year on Web of Sci-
ence to papers responding to the query ((photo-
0
100
200
300
400
500
600
700
800
199
51
996
199
71
998
199
92
000
200
12
002
200
32
004
200
52
006
200
72
008
200
92
010
201
12
012
201
32
014
201
5Nu
mb
er o
f ci
tati
on
s
Year
Citations to papers on flow photochemistry
20
chemistry OR photocatalysis OR photochemical OR
photocatalytic) AND (continuous-flow OR "flow
chemistry" OR "microreactor")), starting from 1995
up to December 31st 2015.
3.2 Photochemistry
3.2.1 Photocycloadditions
Photocycloadditions have been extensively carried out
in continuous-flow photomicroreactors.146 The popu-
larity of photocycloadditions lies in the possibility to
rapidly prepare highly complex organic molecules,
such as substituted cyclobutanes.5, 147-151 Moreover,
short reaction times and equimolarity of the reaction
partners are advantages observed when they are per-
formed in flow. Loubière et al.152-153 reported a simpli-
fied model for the rigorous comparison between a
photomicroreactor and a conventional photo batch
reactor. The model combines reaction kinetics, mass
and radiative transfer equations for an intramolecular
[2+2] photocycloaddition. The results demonstrate
that higher conversions and a higher energy efficiency
are typically observed in a photomicroreactor.
One of the first photocycloadditions in flow has been
reported in 2004 by Ryu et al.,154 who demonstrated
the [2+2] cycloaddition of cyclohexenones with vinyl
acetates (Scheme 7).
Scheme 7 Photocycloaddition of cyclohexenone
with vinylacetate.
21
The photomicroreactor contained a channel with a
rectangular section of 0.5 x 1 mm and was irradiated
with a 300 W high pressure mercury lamp. In compar-
ison with batch, a significant decrease in reaction time
was observed (71% yield in 2 hours in flow, 22% in 4
hours in batch). The same reaction was further inves-
tigated with respect to the nature of the light source.111
Different energy-saving light sources were tested, and
the results underscore how uncompetitive mercury-
vapor UV-lamps are in comparison with black light
and UV LEDs in terms of yields, irradiation times and
energy consumption (0.12 yield/Wh for the mercury
lamps, vs 2.70 yield/Wh for the black light and 214
yield/Wh for the UV-LEDs) (Scheme 7, table). In the
model reaction between cyclohexenone and vinyl
acetate, a product yield of 71% and 82% was obtained
in two hours with mercury lamp and black light re-
spectively, while the use of UV-LED resulted in a 91%
yield in just 15 minutes.
Another early example of photocycloadditions in flow
has been published in 2005 by Booker-Milburn and
co-workers.155 In the total synthesis of Stemona alka-
loids, a key [5+2] intramolecular photocycloaddition
was needed, whose scale-up had proven especially
difficult in batch (Scheme 8).156
Scheme 8 Intramolecular [5 + 2] photocycloaddi-
tion in flow.
The product underwent photodegradation after pro-
longed exposure, while the substrate concentration
had to be kept low (0.02 M) to prevent dimerization.
Short reaction times (30 min) were required to in-
crease the product selectivity, however, this prevented
the full conversion of the substrate. The low substrate
concentration further aggravates the scale-up poten-
tial of this reaction in batch. It was rationalized that
these limitations could be surmounted by using a
continuous-flow reactor. The reactor consists of a
simple design in which FEP capillary tubing (ID 700
μm) was coiled around the UV lamp. The simplicity of
realization combined with the reuse of the readily
available glassware for batch immersion wells made
this reactor setup popular among the flow photo-
chemistry community. In this review, we will refer to
modified versions of this reactor design as a FEP
coiled reactor. The positive results obtained with the
22
capillary microreactor and the need for a higher
productivity led to the fabrication of a reactor with a
meso-sized capillary (ID 2.7 mm), whose lower pres-
sure drop allowed higher flowrates (up to 10 mL/min).
Because of the substrate absorbance at 280-300 nm,
further improvements were obtained by using Vycor
instead of Pyrex as material for the immersion well. In
particular, the substrate concentration could be in-
creased from 0.1 to 0.4 M, resulting in a projected
yield over 24 hours of 685 g, compared to 50 g/day
with the first reactor. A similar Vycor coiled FEP
mesoreactor was used by Aggarwal et al. for the scale
up of the photochemical step in the synthesis of a
bicyclic chiral sulfide.157 Another highly UV-
transparent glass material (Schott 8337, λcutoff ≈ 200
nm) was used for microreactor fabrication by the
Jensen group.158
In a coiled capillary photomicroreactor, Conradi and
Junkers observed a four-fold increase in yield (from 6
to 23%) by switching the solvent from ethyl acetate to
acetonitrile for the [2+2] photocycloaddition of ma-
leimide with octene. This result was rationalized by
the more favorable UV cut-off of acetonitrile (Scheme
9A).159 A further improvement (from 23 to 99% yield)
was obtained by upgrading the light source from a 16
W to a 400 W UV-lamp. Notably, with the optimized
conditions, up to 265 g of product per day could be
produced in an atom-efficient way (enone:alkene ratio
1:1). Particularly striking is the comparison with batch,
where a ten-fold excess of ene is required to achieve
similar conversions. Moreover, traditional immersion
well or multilamp batch reactors, required several
hours (respectively 12 and 8 hours) for reaction com-
pletion, while the microflow reactor reached full con-
version in less than 10 minutes.159
Scheme 9 [2+2] Photocycloadditions in flow.
23
A similar ene-enone reaction in microflow was report-
ed by Oelgemöller and co-workers.160 The [2+2] pho-
tocyclization of 2-furanone with either cyclopentene
or 2,3-dimethylbut-2-ene was studied, both in batch
and in a microflow reactor. The flow setup was made
by wrapping 10 m FEP capillary tubing (ID 800 μm)
around a Pyrex glass cylinder. The reactor was subse-
quently placed in a Rayonet chamber hosting 8 UV-C
lamps. For the batch experiments, the same chamber
was used with quartz test tubes. The microreactor
showed a five-fold decrease in reaction time compared
to batch, owing to its higher light and photonic effi-
ciencies (Scheme 9B).
The development of another gas-liquid flow photore-
actor was reported by Horie et al.161 Interestingly, the
reactor was specially designed to handle solid-forming
reactions (Scheme 9C). The photodimerization of
maleic anhydride to yield cyclobutane tetracarboxylic
dianhydride, a highly insoluble compound, was tested.
The reactor featured a FEP capillary (ID 1.2 mm)
coiled around a quartz beaker containing a mercury
UV-lamp. The beaker was then positioned in an ultra-
sonic bath. Ultrasonic waves were used to prevent
deposition of the solid product on the reactor wall and
to break-up particle agglomerations.104, 106, 162-164 A N2
stream was added to form a segmented flow regime.
Consequently, the suspended solid particles were kept
into solution through the intensified mixing in such
flow regime and were eventually pushed out of the
microchannel.
Diastereoselective photocycloadditions were also
performed in microfluidic devices.165-170 Enhanced
enantioselectivity compared to batch reactors was
observed in most cases, thanks to the improved con-
trol over reaction temperature.171-172 Mizuno et al. re-
ported the intramolecular [2+2] photocycloaddition of
1-cyanonaphtalene derivatives in a PDMS reactor
(Scheme 10).171 Reactions with 2-butenyloxymethyl
substituted cyanonaphthalene resulted mainly in the
photocycloadduct at the 1,2 position on the naphtha-
lene. The formation of the photocycloadduct at the 3,4
position could be minimized in flow (yield 1,2-/3,4-
adduct: 56%/17% in 180 min in batch, 55%/7% in 3.4
min in flow). A marginal enantiomeric excess (e.e.) of
2.0 % was obtained in the presence of Eu(hfc)3. In the
absence of any chiral auxiliary, higher conversions
were obtained in a commercially available Pyrex mi-
croreactor.173
Scheme 10 Diastereoselective [2+2] photocycload-
dition of 1-cyanonaphtalene.
Kakiuchi and co-workers investigated the [2+2] Pater-
nò-Büchi reaction between 2,3-dimethyl-2-butene and
a benzoylformic acid esterified with a chiral auxiliary
(Scheme 11-A).174 A FEP coiled reactor (ID 1.0 mm)
irradiated with a 500 W high-pressure mercury lamp
24
was compared with batch, resulting in shorter reac-
tion times (420 vs. 60 seconds) but similar d.e. (about
50%) despite cooling at 10 ˚C. A further increase in
efficiency was observed when a slug flow regime was
adopted by adding an immiscible phase, e.g. gaseous
nitrogen or water (in both cases full conversion was
achieved in only 30 seconds). This improved result can
be ascribed to (i) the light dispersion effect of the slug
bubbles, (ii) the improved mixing efficiency and (iii)
the presence of a highly irradiated thin layer of reac-
tion mixture formed between the channel wall and the
slug.
Scheme 11 Diastereoselective [2+2] photocycload-
dition with chiral auxiliary.
Terao et al. also investigated photocycloadditions with
gaseous ethylene, exploiting the convenient handling
of multiphase reaction systems in microflow.77-78, 175-180
In particular, the diastereoselective cycloaddition of a
chiral auxiliary-bearing cyclohexenone with gaseous
ethylene was studied (Scheme 11-B).181 A FEP microca-
pillary reactor (ID 1.0 mm, 1.18 mL) was coiled around
a quartz immersion well containing a 500 W high
pressure UV-lamp and the reactor was placed in a
cooling bath. A large excess of ethylene gas was dosed
into the reaction mixture by means of a mass flow
controller generating a slug flow regime. Consequent-
ly, a thin liquid layer of reaction mixture was generat-
ed between the reactor wall and the ethylene gas bub-
bles. In this confined space, no gas-liquid mass trans-
fer limitations are observed and the light intensity is
maximized. The microreactor assembly displayed a
substantial improved performance in terms of yield
and diastereoselectivity when compared to a conven-
tional Pyrex test-tube (full conversion in 1 min with
52% d.e. in flow vs 15 min in batch with 47% d.e.). The
higher diastereoisomeric excess (d.e.) observed in flow
was ascribed to the superior heat transfer observed in
microchannels. More specifically, the precise control
over the reaction temperature, favored the thermody-
namically more stable s-trans conformation. The same
reaction with a non-gaseous alkene (cyclopentene)
was also investigated in two different microfluidic
reactors yielding similar enhancement over the dia-
stereoselectivity.182-183
The enhanced diastereoselectivity observed in micro-
reactors can be further improved using supercritical
carbon dioxide (scCO2) as a solvent.184 The [2+2] pho-
tocycloaddition of a cyclohexenone bearing a menthol
chiral auxiliary with cyclopentene was studied in a
microreactor made of Pyrex glass (ID 600 μm) and
was irradiated with UV-LEDs. The reaction selectivity
in scCO2 was higher than in conventional organic
solvents (60% d.e. in scCO2 vs. 36% in toluene), thus
25
suggesting a clustering effect of scCO2 at critical den-
sity.
Beeler et al. reported the continuous-flow [2+2] pho-
tocycloaddition of cinnamates in a cone-shaped reac-
tor (Figure 8), which was irradiated with a Xenon(Hg)
UV source.185 The dimerization of methylcinnamate
yielded solely the head-to-head β-truxinate and δ-
truxinate in a 1:1 mixture with higher yields and con-
versions than the corresponding batch protocol.185
Interestingly, the addition of a thiourea catalyst (8
mol%) increased the diastereoselectivity (3:1 δ/β)
(Scheme 12). 1H-NMR studies showed peak-sharpening
of the amidic hydrogens of the thiourea catalyst indi-
cating hydrogen bonding with the carbonyl moiety.
Moreover, a possible triplet sensitization by the thiou-
rea was suggested, implicating a dual role of the cata-
lyst.
Scheme 12 [2+2] photocycloaddition of cinnamates
in flow.
Figure 8 The cone-shaped reactor reported by Beeler
et al. Reprinted with permission from ref. 185. Copy-
right 2015 John Wiley & Sons
Pauson–Khand reactions are often applied to prepare
cyclopentenone scaffolds by co-cyclization of alkynes,
alkenes and CO.186-188 The decarbonylation step from
an alkyne-cobalt complex can be promoted thermally,
but an improved functional group tolerance can be
obtained with other activation methods such as mi-
crowave, ultrasound and especially light irradiation.189
26
Asano and Yoshida reported a microflow protocol for
the photoinitiated Pauson–Khand reaction.190 In par-
ticular, a microchip with a serpentine channel (200 x
1000 μm section) was irradiated with a medium pres-
sure mercury lamp. After a residence time of 55 sec-
onds, most of the dicobalt complexes were fully con-
verted into the corresponding cyclopentenones with
moderate to high yields (Scheme 13).
Scheme 13 Pauson–Khand reaction in flow.
An unexpected UV-induced photocyclization was
reported by Booker-Milburn and co-workers.191 The
authors serendipitously observed the formation of a
tricyclic, fused aziridine ring system (Scheme 14). The
postulated mechanism proceeds through a [2+2] pho-
tocycloaddition followed by a UV-initiated bond
cleavage. The obtained biradical intermediate ulti-
mately evolves in the final aziridine ring through a C–
C bond formation. The photoreactor consisted of a
FEP capillary (ID 2.7 mm, 90 mL) wrapped around a
quartz tube containing a 36 W germicidal UV-C lamp
(λmax = 254 nm) and the solution was pumped with a
valveless piston pump at controlled flow rates.
Scheme 14 UV-induced photocyclization yielding
a tricyclic fused aziridine ring system.
27
3.2.2 Photoisomerizations
The excited states, reached through light absorption,
may induce reversible or irreversible isomerizations of
organic substrates. Consequently, relatively simple
starting materials can be converted in complex struc-
tures (e.g. cyclobutenone rings), which are often elu-
sive to prepare via other thermal or chemical path-
ways. Reversible photoisomerization reactions are also
key in the design of chemical switches and molecular
motors.192-196
The continuous-flow photochemical rearrangement of
nitrones was exploited by Jamison and co-workers to
synthesize amide bonds.197 An immersion-well 450 W
UV-B lamp was used to irradiate a quartz capillary
microreactor (ID 760 μm, 625 μL), which was con-
nected to a back pressure regulator (20 psi). In this
reactor, alkyl-aryl nitrones could be converted to the
desired amide in 60-90% yield within 5-20 minutes in
the presence of catalytic amounts of trifluoroacetic
acid (TFA, 0.25 eq.). The methodology was subse-
quently used for the synthesis of di- and tetra-
peptides (Scheme 15).197 Lower yields (around 50%)
compared to the alkyl-aryl nitrones were obtained, but
no epimerization of the stereocenters was observed.
Photochemical rearrangement of N-oxides were also
performed in flow.198 Bauer, Bach and co-workers used
a meso Duran tube reactor to suppress the undesired
[2+2] photodimerization of a 4-substituted quinolone
product obtained by a photoinduced N-oxide rear-
rangement.199-200
Scheme 15 Photochemical rearrangement of
nitrones yielding amides.
28
The formation of ketenes from α-diazo ketones is
known as the Wolff rearrangement.201-203 An efficient
way to induce this transformation is by photolysis.
Due to the reactivity and synthetic versatility of ke-
tenes, several photoinduced transformations based on
this reaction have been reported also in flow.
Basso et al. developed a ketene three-component reac-
tion (K-3CR), including a diazo ketone, a carboxylic
acid and an isocyanide (Scheme 16).204-205 Specifically,
an α-diazo ketone generates a reactive ketene inter-
mediate through a UV-induced Wolff rearrangement.
This intermediate further reacts with the isocyanide
and the carboxylic acid to yield the final olefin. The
use of a FEP water-cooled microreactor (ID 800 μm),
irradiated with 16x8 W black light, allowed to obtain
the desired olefin with similar yield and Z/E selectivity
than in batch, but with higher efficiency and sustaina-
bility (in term of both STY and PMI).
Scheme 16 Ketene three-component reaction in
flow.
An intramolecular variant of the Wolff rearrangement
has been reported by Konopelski et al.206 Enantiomeri-
cally pure trans-β-lactams can be prepared in contin-
uous-flow starting from α-amino acid-derived β-
ketoamides (Scheme 17). In particular, a Weinreb α-
diazo-β-ketoamide derived from L-serine was irradiat-
ed in batch and in flow with a medium-pressure mer-
cury lamp. The coiled-FEP capillary reactor needed
rigorous cooling due to the thermal instability of the
diazo intermediate. Compared to batch, the flow syn-
thesis showed a reduced reaction time and ease of
scale up, and was therefore preferred despite the
slightly diminished yields (81% instead of 90%). Ow-
ing to the concerns associated with the use of a UV
lamp, a compact fluorescent light (CFL) was also eval-
uated, resulting in improved yields (95% batch and
91% flow), greater safety and lower costs despite the
lower throughput.
Scheme 17 Intramolecular Wolff rearrangement
yielding enantiomerically pure β-lactams in flow.
29
Figure 9 FEP coiled reactor used for the photochem-
ical benzannulation based on the reaction of yna-
mides and diazoketones. Reprinted with permission
from ref. 207. Copyright 2013 American Chemical Soci-
ety
The synthetic value of the Wolff rearrangement is well
exemplified by its key role in triggering a pericyclic
cascade reaction as shown by Danheiser et al.207 A
wide range of benzofused nitrogen heterocyclic com-
pounds was obtained from the reaction of α,β-
unsaturated α-diazo ketones with ynamines. The
mechanism involves an initial Wolff rearrangement of
the diazo ketone to the corresponding vinylketene.
This vinyl ketene is subsequently engaged in a regiose-
lective [2+2] photocycloaddition with an ynamide
partner, yielding a substituted vinylcyclobutenone.
After light-induced electrocyclic cleavage of the cyclo-
butenone and subsequent ring-closure, the final pol-
ysubstituted aniline product is obtained (Scheme 18).
The reaction cascade was performed in both a conven-
tional immersion well reactor and a continuous-flow
FEP coiled reactor (ID 760 μm, 1.2 mL, Figure 9). In
flow, no significant improvement in yield was ob-
served. However, a more straightforward scale up and
reduced reaction time (from 3-8 hours to 21 minutes)
became possible.
Scheme 18 Pericyclic cascade yielding benzofused
anilines.
A Wolff rearrangement is also the concluding step in
the Arndt-Eistert homologation sequence, yielding
enantiopure β-amino acids starting from the corre-
sponding α-amino acids.208 Kappe and co-workers
developed a fully continuous four-step process to
prepare β-amino acids (Scheme 19).209 α-diazoketones,
obtained via the in situ generation of diazomethane,
were introduced in a PFA coiled (ID 760 μm, 3 mL)
reactor and irradiated with a UV-CFL light source (256
nm). A model reaction was used to optimize the pho-
tochemical step, and it was found that an irradiation
time of 10 minutes afforded the desired products in
57% isolated yield. The complete homologation se-
30
quence was applied to several Boc and Cbz-protected
amino acids, resulting in the corresponding β-amino
acid derivatives in moderate to good yields (23-54%).
Similarly, Fuse and co-workers performed a continu-
ous-flow Arndt-Eistert synthesis for the preparation of
α-aryl carboxylic acids.210
Scheme 19 Continuous-flow synthesis of β-amino
acids via Arndt-Eistert homologation, featuring a
light-induced Wolff rearrangement.
The synthesis of N-arylacetyl oxazolidinone, a precur-
sor for the preparation of the non-natural amino acid
3,5-dihydroxyphenylglycine (Dpg), also involved a
Wolff rearrangement.211 After a preliminary screening
in a 50 μL reactor, the optimized reaction conditions
were translated to a flow protocol using a FEP coiled
reactor (ID 1.0 mm, 500 μL). The flow procedure ena-
bled efficient scale up (gram scale) employing a porta-
ble 4 W UV lamp as light source (5 min irradiation
time, 82% yield).
The rearrangement of 4-hydroxycyclobutenones to
yield 5H-furanones was studied in a photochemical
reactor by Harrowven et al. (Scheme 20).212 In a PFA-
coiled capillary reactor (ID 1.0 mm, 19 mL), different
low-energy 9 W light sources were evaluated. Using a
UV-B lamp with a broad emission, 54% yield of the
desired product was obtained in 120 min residence
time. However, significant byproduct formation was
observed. Switching the solvent to acetonitrile and
using an UV-B lamp (310-320 nm), resulted in im-
proved yields up to 97% in 90 minutes residence time.
The improved results can be attributed to the avoid-
ance of light absorption by the product, which initi-
ates product decomposition. Interestingly, the use of
an UV-A lamp (350-395 nm) resulted in a reduced
reaction rate, while the use of an UV-C lamp (254 nm)
afforded full conversion albeit with the formation of
byproducts. Furthermore, the hypothesized torquose-
lectivity of the ring opening of cyclobutenone was
confirmed through DFT calculations. In fact, the cal-
culations showed that the photoinduced electrocyclic
opening of cyclobutene yields both the E and Z vinyl-
ketene. The E isomer reacts further to the correspond-
ing furan, while the Z isomer reacts back to the start-
ing material. However, in presence of an internal nu-
cleophile, the Z isomer can further react to quinoliz-
inones (Scheme 20).
31
Scheme 20 Photorearrangement of 4-
hydroxycyclobutanones to 5H-furanones.
Another photochemical transformation successfully
accelerated in flow is the nitrite photolysis, also
known as the Barton reaction. Ryu et al. reported a
gram-scale application for the production of a key
intermediate en route to myriceric acid A, an endo-
thelin receptor antagonist (Scheme 21).213 After a pre-
liminary optimization of the reactor material, light
source and residence time, the best conditions were
found to be a 12 minute irradiation of the reaction
mixture with a 15 W black light in a Pyrex-covered
reactor. The small scale 0.2 mL reactor was then re-
placed by two 4 mL reactors with 8 black lights (20 W
each) allowing a throughput of 3.1 g in 20 hours. In a
follow-up paper, the use of UV-LEDs (365 nm) was
also investigated and an automated photomicroreac-
tor system, employing an array of 48 LEDs, yielded 5.3
g of product in 40 hours.214
Scheme 21 Barton reaction in flow on a steroidal
substrate en route to myriceric acid A.
The photolysis of phenyl azides can be exploited to
generate reactive nitrenes. These compounds can
subsequently rearrange in the presence of water to
yield 3H-azepinones. The mechanistic details of the
phenyl azide photolysis were subject of intense re-
search in the last decades and are now understood in
detail.215 However, due to the technical difficulties in
scaling photochemical reactions, this transformation
was not widely applied. Seeberger and co-workers
reported a continuous-flow UV-induced photolysis of
aryl azides yielding azepinones (Scheme 22).216 The
adoption of microreactor technology allowed to scale
the reaction while keeping the yields in the same
range as small scale batch reactions. The reactor was
made of FEP capillary (760 μm, 14 mL) coiled around a
450 W medium pressure mercury lamp and surround-
32
ed by a cooling jacket. A 6.9 bar back pressure regula-
tor was used to prevent the formation of gaseous ni-
trogen slugs and to accurately control the residence
time. With this setup, a variety of 3H-azepinones were
prepared in moderate to good yields (35-75%) and
allowed to synthesize a pharmaceutically relevant
benzodiazepine scaffold. Azide photolysis in flow was
also applied to the synthesis of dihydropyrroles start-
ing from aromatic vinyl azides and activated
alkenes.217
Scheme 22 Photolysis of aryl-azides yielding 3H-
azepinones
A photochemical strategy for the amination of sulfides
and sulfoxides was reported by Lebel and co-
workers.218 The reaction proceeds through the decom-
position of trichloroethoxysulfonyl azide (TcesN3),
catalyzed by iron(III) acetylacetonate (Fe(acac)3), to
yield a reactive nitrene intermediate that further re-
acts with sulfides or sulfoxides. Optimization studies
showed the ability of Fe(acac)3 to absorb UV-A light.
Therefore, a photochemical flow set-up consisting of
three cylinder reactors connected in series (ID 1.0 mm,
37.5 mL), each wrapped around a 8 W black-light blue
UV-A lamp, was employed. Within 90 minutes resi-
dence time, an array of sulfides and sulfoxides was
successfully aminated in good to excellent yields (71-
98 %) (Scheme 23). Notably, the amination of sulfox-
ides derivatives was found to be stereoselective, with
retention of the initial enantiomeric ratio.
Scheme 23 Azide mediated amination of sulfide
and sulfoxide.
Microreactor technology is particularly useful to re-
duce the safety hazards associated with the handling
of highly toxic and explosion-prone materials such as
halogen azides.83 The in situ generation and photo-
decomposition of bromine azide has been recently
performed in a continuous flow setup by Kappe and
co-workers (Scheme 24).219 BrN3 was generated in situ
by mixing NaN3 and NaBr in the presence of oxone as
oxidizing agent . BrN3 was subsequently extracted
into the organic phase where it reacted with an olefin
33
substrate. The influence of UV irradiation (CFL 365
nm, 105 W) on the reaction was investigated in a FEP
coiled reactor (ID 760 μm, 18mL). The accelerated
photodecomposition of the halogen azide enabled the
reaction with less reactive olefins (e.g. ethyl cin-
namate, 99% conversion with light, 43% without). The
selectivity was also increased under photochemical
conditions with less ionic Markovnikov-like mecha-
nism byproduct.
Scheme 24 Photodecomposition of bromine azide
in a continuous-flow microreactor.
Recently, a photo-Favorskii rearrangement in flow was
reported by Baxendale et al. to prepare ibuprofen in
flow.220 In contrast to previously reported flow synthe-
ses of this anti-inflammatory drug,221-222 the arylpropi-
onic scaffold was not obtained through a Friedel-
Crafts acylation with propionic acid followed by a 1,2-
aryl migration. Instead, chloropropionyl chloride was
used as an acylation partner. The conversion of the
obtained α-chloropropiophenone towards ibuprofen
was achieved in a photoflow process, resulting in an
84% yield for the product and a 13% Norrish type I
derived byproduct (Scheme 25).
Scheme 25 Flow synthesis of ibuprofen through
photo-Favorskii rearrangement.
A photo-Claisen-type ortho-rearrangement of an aryl
naphthylmethyl ether was also achieved in flow. The
reaction was performed in a Pyrex microchip (200 x 90
μm channels, 1.08 mL), irradiated with a 300 W high
pressure mercury lamp.223 Compared to batch, higher
conversions and a better product-to-byproducts ratio
was observed.
Performing a photochemical reaction in flow allows to
easily tailor several reaction parameters, such as reac-
34
tor temperature, flow rate and concentration. Re-
searchers from Genzyme, took advantage of this pos-
sibility and applied a design of experiment (DoE)
technique to optimize the flow photoisomerization of
an intermediate in the doxercalciferol (vitamin D2)
synthesis.224 Under optimized conditions, a 4 wt%
loading of photosensitizer (9-acetylanthracene) was
used at 10 ˚C resulting in a product yield of 96%.
3.2.3 Cyclizations
Photocyclization reactions frequently result in the
formation of highly complex photoactive π-conjugated
systems. Consequently, the reduced reaction time
provided by microreactor technology offers a mean to
prevent the photodegradation of these compounds,
which is often observed in batch.
An intriguing example of continuous-flow photocycli-
zations was reported by Seeberger and co-workers,
who described the synthesis of several pyridocarba-
zoles.225 These compounds all featured a common
scaffold which, through complexation with transition
metals, affords high affinity kinase inhibitors (Scheme
26).
Scheme 26 Mallory photocyclization in the syn-
thesis of pyridocarbazoles.
35
The key synthetic step involved a Mallory photocy-
clization. In batch, this transformation is plagued by
the formation of a significant amount of byproduct,
which greatly complicates the compound purification.
On the contrary, the flow synthesis proceeded cleanly
towards the desired product (see NMR spectra in
Figure 10) in only 15 minutes, while the corresponding
batch experiment required 4.75 hours.
Figure 10 Comparison of the NMR spectra of starting
material and products of the Mallory reaction. The
product obtained in batch is contaminated with the
formation of a byproduct (see arrows) absent in
flow. Reprinted with permission from ref. 225. Copy-
right 2013 Royal Society of Chemistry
Rueping and co-workers introduced another continu-
ous-flow Mallory reaction, i.e. the oxidative photocy-
clization of stilbene derivatives.226-227 The initial opti-
mization was performed in a FEP capillary (5 ml),
which was irradiated with a 150 W high-pressure mer-
cury lamp. The photocyclization of (E)-stilbene to
yield phenanthrene proceeded smoothly (95% yield)
within 83 minutes. The mechanism proceeds through
a photoisomeration of (E)-stilbene to (Z)-stilbene
which subsequently undergoes an oxidative photocy-
clization in the presence of iodine.
Scheme 27 Photoisomerization followed by pho-
tocyclization of stilbenes.
It is important to note that oxygen cannot be used as
the final oxidant as this would form singlet oxygen,
resulting in oxidation byproducts. In a larger setup (24
ml volume), the scope and scale-up potential of this
reaction was evaluated (Scheme 27). Several trisubsti-
tuted olefins were converted into functionalized phe-
nanthrenes in moderate to good yields (34 to 89%).
Moreover, a two-step synthesis of helicene derivatives
was developed by combining a standard Wittig reac-
tion with a subsequent photochemical cyclization.
Similarly, Okamoto and co-workers, accomplished a
continuous-flow synthesis of several polycyclic aro-
matic hydrocarbons on gram scale.228
Czarnocki and co-workers recently reported the use of
a continuous-flow photocyclization for the formal
synthesis of (-)-podophyllotoxin, a lignan known for
its antineoplastic properties.229 Starting from 3,4-
36
bisbenzylidene succinate cyclic amide ester, the core
framework of podophyllotoxin could be obtained via a
UV-induced cyclization (Scheme 28). The reactor
featured a quartz tube (3 m) coiled to form a rectangu-
lar section and was irradiated with a UV mercury
lamp. The desired compound could be obtained in
61% yield.
Scheme 28 UV-induced continuous flow cycliza-
tion for the synthesis of (-)-podophyllotoxin.
A tandem photocyclization-reduction of 2-
aminochalcones yielding enantiomerically pure tetra-
hydroquinolines was reported by Sugiono and
Rueping (Scheme 29).230 Three commercially available
glass reactors were connected in parallel and posi-
tioned in a water bath to keep the reaction tempera-
ture at 55 °C. The channels were subjected to irradia-
tion emitted by a 150 W high pressure mercury lamp.
The reaction proceeds through the photocyclization of
the 2-aminochalcones to the corresponding quinoline.
In the presence of a chiral Brønsted acid and a
Hantzsch dihydropyridine, acting as hydride source,
the final tetrahydroquinolines were achieved in good
yields and enantioselectivities (63-88%, e.e. up to
96%).
Scheme 29 Synthesis of enantiomerically pure
tetrahydroquinolines via a photocyclization-
reduction cascade.
The beneficial use of laser radiation in photochemical
reactions was demonstrated by Bräse and co-workers.
They reported the photochemical decomposition of
arylazides into carbazoles (Scheme 30).231 Special min-
iaturized polyether ether ketone (PEEK) and polytet-
37
rafluoroethylene (PTFE) tubing were covered with
quartz plates, which was housed in a stainless frame
(Figure 11). Multiple capillaries of different volumes
were hosted in the miniaturized reactor, allowing to
perform a series of parallel reactions. Frequency-
tripled Nd:YAG laser radiation of 355 nm with a sin-
gle-pulse power of 0.16 to 3 W was selected, resulting
in an impressive reduction of the reaction time (30
seconds in flow, 18 hours in batch). Furthermore, the
high energy and the focused beam, typical for a laser,
contributed in diminishing any byproduct formation,
i.e. diazocompounds. Because of the increasing availa-
bility of affordable laser systems, which provide a
precise control over the wavelength and size of the
light beam, it is likely that the use of laser light
sources in combination with microreactor technology
will further spread in the coming years. Another ex-
ample of laser irradiation in microflow has been re-
ported by Ouchi et al.232 The irradiation of flavone
with a XeCl excimer laser (248 nm) in the presence of
NaBH4 was performed in a quartz microreactor (irra-
diated volume: 0.1 x 0.4 x 16.5 mm, 660 μL). This re-
sulted in an accelerated reaction and increased selec-
tivity towards flavanone and flavanol.
Scheme 30 Laser-assisted arylazides photolysis
into carbazoles.
Figure 11 Miniaturized reactor used for the laser
irradiation of 2-azidobiphenyl in flow. From left to
right, the increasing depth of the different reactors,
is noticeable. Reprinted with modifications from ref.
231. Copyright 2012 Bräse and co-workers.
3.2.4 Singlet oxygen mediated oxidations
Molecular oxygen is an attractive oxidant due to its
atom efficiency, reduced cost and sustainable
nature.75, 233 Singlet oxygen can be produced starting
from triplet oxygen, that is oxygen in its ground state,
by light irradiation in the presence of a suitable pho-
tosensitizer.234-236 Some frequently used photosensitiz-
ers with their maximum absorption wavelength are
enlisted in Scheme 31. Organic dyes, such as meth-
ylene blue, Rose Bengal and tetraphenylporphyrin
(TPP), are among the most commonly used sensitiz-
ers. Metal-based photosensitizers can also be em-
38
ployed. However, virtually any photoactive molecule
generating an excited state with a sufficiently long life
span can be quenched by O2 to produce singlet oxy-
gen. Photosensitizers absorb light in a specific wave-
length region depending on their structure. In the
presence of oxygen, energy transfer from the excited
state of the photosensitizer can occur, yielding singlet
oxygen. Compared to triplet oxygen, singlet oxygen
shows higher electrophilicity, which allows to oxidize
substrates which are otherwise unreactive to
oxygen.237-241 The lifetime of singlet oxygen is highly
dependent on the solvent in which the reactions are
carried out: typically, chlorinated solvents afford a
longer lifetime than polar protic solvents.242
Due to its high reactivity, singlet oxygen-mediated
oxidations are often plagued by undesired byproduct
formation due to overoxidation or other non-selective
oxidation processes. However, by preventing product
degradation through precise control over irradiation
time, flow photochemistry provides a key advantage.
Scheme 31 Common photosensitizer for the generation of singlet oxygen and relative wavelength of absorp-
tion.
39
One of the first examples of continuous-flow generation
and safe use of singlet oxygen was reported in 2002 by
de Mello and co-workers.243 The formation of ascaridole
endoperoxide starting from α-terpinene was used as
model reaction (Scheme 32).244 The glass microreactor
was made using direct-write laser lithography. The
etched channels (50 x 150 μm) resulted in a total reactor
volume of 375 μL. A conversion of > 80% was obtained
in less than 5 seconds using a 20 W tungsten lamp.
More recently, the same group reported the use of a
microcapillary film reactor composed of 10 parallel FEP
channels (ID 100 μm) embedded in a plastic ribbon.64
To perform the ascaridole reaction, oxygen was sup-
plied to the reactor by exploiting the gas permeability
of the FEP tubing. Different wall thicknesses and exter-
nal oxygen pressure were studied to assess the through-
wall mass transport of oxygen. A yield of 90% of asca-
ridole was observed using a 14 minutes residence time
in a capillary with a wall thickness of 61.5 μm and an
oxygen pressure of 65 psi.
Scheme 32 Synthesis of ascaridole through [4+2]
photooxygenation of α-terpinene in a glass micro-
chip.
Park and co-workers investigated the continuous-flow
photooxygenation of monoterpenes.245-246 A monochan-
nel microreactor was employed for the optimization of
the reaction conditions, while a tube-in-tube reactor
allowed for a higher throughput and thus for scale-up
of the reaction conditions (Figure 12). Generation of
singlet oxygen was obtained through irradiation with 16
W LEDs. Both reactors performed better than corre-
sponding batch experiments, providing higher conver-
sions (e.g. for citronellol photooxygenation, full conver-
sion was obtained in 2 minutes in both the microreac-
tors, while reaction took 3 hours in batch). The use of
solar energy was also investigated in the monochannel
microreactor, however lower yields (48% solar vs.
99.9% LED irradiation) were observed despite the im-
plementation of a convex lens to focus the sunlight
towards the reaction channels.
Figure 12 Tube in tube reactor for the photooxygena-
tion of monoterpenes. Reprinted with permission
from ref. 246. Copyright 2015 The Royal Society of
Chemistry
The continuous-flow TPP-sensitized singlet oxygen-
mediated oxidation of α-pinene to pinocarvone was
extensively studied by Lapkin and co-workers with
respect to different lamp-reactor designs and flow re-
gimes (Scheme 33).247 Microreactors afforded up to 10
times higher space-time yields compared to traditional
immersion-well reactors, with photonic efficiencies
mostly similar or higher as a result of the better light
40
use in the reactor. Among the tested conditions, the
best results in terms of photonic efficiency were ob-
tained when the reaction was performed in a homoge-
neous flow. However, the conversion was limited by the
oxygen solubility in the solvent. Higher space-time
yields could be obtained when using a segmented oxy-
gen-liquid regime. Interestingly, a cost objective func-
tion was included in the reactor model and the operat-
ing cost ($/mol of pinocarvone produced) had its mini-
mum when using microchannels in the 100-1000 μm
range (Figure 13).
Scheme 33 TPP-sensitized photooxidation of α-
pinene to pinocarvone in continuous-flow.
Figure 13 Operating cost in $/mol as function of mi-
crochannel depth (x axis). Reprinted with permission
from ref. 247. Copyright 2014 American Chemical Socie-
ty
For the same benchmark reaction, Carofiglio et al. used
a silica-immobilized fullerene as a photosensitizer,
therefore providing an example of heterogeneous pho-
tooxidation.248 The microreactor (ID 500 μm, 152 μL)
was fabricated by a thiol-ene rapid prototyping tech-
nique and encased between two glass plates. White
LEDs were used a light source. Despite the full conver-
sion of the starting material, the reported yields were
low to moderate (e.g. 53% yield at 97% conversion),
which was attributed to the poor oxygen solubility in
the reaction mixture.
Similarly, Boyle and co-workers accomplished the fabri-
cation of a 16-channel glass chip with an immobilized
porphyrin as a photosensitizer (Figure 14).249 Through
silanization of the glass surface of the chip with (3-
aminopropyl)triethoxysilane (APTES), the introduction
of an amine linker was achieved. Next, the isothiocya-
nate group on the porphyrin was reacted with this
amine linker to yield a thiourea moiety, thus covalently
binding the photosensitizer to the chip. The efficiency
of the microreactor was then tested for the photooxida-
tion of cholesterol, α-terpinene and citronellol.
Figure 14: 16 parallel channel glass reactor used for the
photooxygenation of cholesterol. Reprinted with
41
permission form ref. 249. Copyright 2012 American
Chemical Society
Supported photosensitizers for the generation of singlet
oxygen in supercritical CO2 (scCO2) were developed by
Poliakoff and co-workers.250-251 The high pressure need-
ed to perform reactions in scCO2 requires specialized
equipment.252 However, due to the absence of mass
transfer limitations (high diffusivities and complete
miscibility of gaseous O2 in scCO2) and the extended
lifetime of 1O2, scCO2 processes are in general sustaina-
ble and attractive.253 Poliakoff et al. prepared supported
porphyrin photosensitizers on PVC beads and success-
fully applied these to the photooxygenation of α-
terpinene and citronellol (Scheme 34).250
The photochemical oxidation of (S)-(–)-β-citronellol to
its corresponding hydroperoxides isomers is one of the
key steps required for the synthesis of (–)-rose oxide,
which is of interest to the fragrance industry (Scheme
34). This singlet oxygen-mediated reaction has been
used as another popular model reaction for the optimi-
zation and validation of different photomicroreactors.
Using this benchmark reaction, Meyer et al. compared a
Schlenk-tube batch reactor (40 ml total volume, of
which only 7.46 ml was effectively irradiated) and a
glass microreactor (ID 1.0 mm, 0.47 ml).254 In both cas-
es, the reaction mixture was saturated with compressed
air as the oxygen source. Blue LEDs were chosen as a
suitable light source. In the industrial process of rose
oxide, Rose Bengal is commonly used as photosynthe-
sizer. However, the authors selected Ru(tbpy)3Cl2 (tbpy=
tert-butyl bipyridine) as a sensitizer as it displays a
higher quantum yield for singlet oxygen production.
Space-time yield comparisons showed a slight ad-
vantage for the microreactor. Furthermore, the micro-
reactor was tested to compare the performance of
Ru(tbpy)3Cl2 with Rose Bengal, and the light source was
switched to a 450 W Xe-lamp to match the absorption
of both sensitizers. Despite the higher quantum yield
and stability postulated for Ru(tbpy)3Cl2, Rose Bengal
showed a higher conversion rate (55% conversion with
Ru-based catalyst vs. 75% with Rose Bengal after 400
minutes of irradiation).
Kim and co-workers reported the oxidation of β-
citronellol to validate their dual- and triple-channel
microreactor concept (Scheme 34).255-256 This multiple
channel design was developed to improve the reaction
rate of biphasic gas-liquid reactions by dramatically
increasing the interfacial area between the gaseous
phase and the liquid reaction stream. In the dual-
channel microreactor (ID 220 μm, 38.9 μL), oxygen
diffuses into the liquid phase from the bottom channel
through a gas-permeable PDMS membrane. The liquid
solution-containing channel had to be coated with a
layer of polyvinylsilazane (PVSZ) to prevent swelling of
the PDMS layer. Interestingly, the PVSZ coating could
be avoided in the triple-channel microreactor (250 x 40
μm, 3.3 μL), where the channel containing the reaction
mixture is surrounded by two oxygen channels (Figure
15). This triple-channel microreactor design proved to
be easier to fabricate, and featured an overall increased
interfacial area. When compared to batch, both micro-
reactor designs showed a significant improvement in
42
reaction rate for the oxidation of citronellol using
methylene blue as a photosensitizer. Full conversion
was obtained within 2 and 3 minutes for the triple- and
dual-channel microreactor respectively, while the batch
reactor required 3 hours. The methylene blue-mediated
photooxygenation of (i) allylic alcohols to allyl hydrop-
eroxide alcohols and (ii) α-terpinene to ascaridole were
also successfully performed in these reactors.
43
Scheme 34 Different microflow conditions for the photooxygenation of citronellol and role of this photo-
chemical step in the synthesis of the fragrance rose oxide.
Figure 15 A: Graphical representation of dual and triple-channel microreactor for photooxidation of allylic alco-
hol. B: Photograph of the chip. Reaction channel (red) and outer channels (blue) are filled with dye solution for
demonstration purposes. Copyright 2011 Kim and co-workers.
44
Lévesque and Seeberger used a 78 μl silicon-glass mi-
croreactor to generate singlet oxygen in the presence of
Rose Bengal and green LEDs.257 As a model reaction, the
photooxidation of citronellol was selected. The silicon
device was ideal to rapidly screen various reaction pa-
rameters while keeping the total consumption of rea-
gents small. However, to increase the productivity, a
FEP coiled reactor (ID 760 μm) was used instead and
was irradiated with a 450 W mercury lamp. Rose Bengal
was also replaced by tetraphenylporphyrin as photosen-
sitizer due to an increased photostability. With this
reactor, full conversion was observed with only 1.6
equivalents of oxygen, which significantly reduced the
risks associated with unreacted oxygen. A further in-
crease in throughput was achieved by increasing the
reactor volume (from 5 to 14 mL) using an HPLC pump,
a mass flow controller and a back pressure regulator. A
variety of substrates were successfully oxidized in good
yields and high productivity (Scheme 35).257
Scheme 35 Singlet oxygen mediated reactions per-
formed in a continuous-flow FEP coiled reactor.
From left to right, oxidation of 2-methylfuran, α-
pinene and a sulfide.
45
Seeberger et al. reported an innovative and practical
synthesis of the anti-malaria drug artemisinin258 start-
ing from dihydroartemisinic acid and employing a key
singlet oxygen reaction in flow.259 The reaction se-
quence from dihydroartemisinic acid, a waste product,
to artemisinin involved a singlet oxygen ene reaction
resulting in an allylic hydroperoxide (Scheme 36).
This hydroperoxide was converted through an acid
mediated Hock cleavage and a subsequent oxidation
delivered the target artemisinin. The three reactions
were individually optimized and ultimately integrated
in a fully continuous process. This process was further
scaled for industrial application in a follow-up paper.260
In particular, TPP was substituted with 9,10-
dicyanoanthracene (DCA) as a singlet oxygen sensitizer,
as it provided a higher quantum efficiency and acid
photostability. In addition, performing the ene reaction
at -20 ˚C improved the selectivity towards the for-
mation of the desired product. The industrial suitability
of this process, was demonstrated in 2014, when Sanofi
started to exploit this novel semisynthetic route to
artemisinin. In the production site of Garessio (Italy),
the current production of artemisinin reaches 50-60
metric tons per year, nearly a third of the annual global
need.261
Scheme 36 Continuous-flow synthesis of the anti-
malarian drug artemisinin starting from artemis-
inc acid.
The synthesis of rhodomyrtosone A involves a [4+2]-
cycloaddition with singlet oxygen and was carried out
in flow to provide a scalable production of this inter-
mediate.262 A methanolic solution of the starting mate-
rial, saturated with oxygen, was pumped in a PFA capil-
lary (ID 1.5 mm, 3.1 mL), which was coiled around a UV
lamp and cooled to -10 ˚C. The corresponding endoper-
oxide was obtained as a 1:1 mixture of diastereomers in
50% yield (Scheme 37).
46
Scheme 37 Total synthesis of rhodomyrtosone A. The highlighted step is performed in flow.
47
In batch, the oxidation of indane to yield 1-indanone
resulted in the production of several byproducts, such
as 1,3-indanedione or ring-opened compounds, and
reached a maximum conversion of only 60% (Scheme
38). The same reaction was performed in a commercial
glass microreactor (500 x 300 μm, 360 μL) using oxygen
in a slug flow regime. Interestingly, the formation of
byproducts was suppressed in flow and the desired
compound could be obtained in 83% yield.263
Scheme 38 Photooxidation of indane with oxygen
slug flow in a glass microreactor.
Kappe and co-workers presented the use of singlet oxy-
gen for the oxidation of 5-hydroxymethylfurfural (5-
HMF), a common intermediate for the synthesis of
biofuels and polyester precursors.264-266 Oxidation of 5-
HMF results in the formation of 5-hydroxy-5-
(hydroxymethyl)-furan-2(5H)-one (H2MF), a highly
functionalized building block with similar applications
as 5-HMF. The reactor consists of a 10 ml PFA capillary
(ID 1.0 mm) which is subjected to 60 W compact fluo-
rescent light (CFL) irradiation. The liquid stream, con-
taining a solution of starting material in i-PrOH/H2O
(1:1) and Rose Bengal (1 mol%), was merged with mo-
lecular oxygen. At an operational pressure of 17 bar, a
homogeneous flow regime was observed and full con-
version was reached with a 93% isolated yield for the
desired product (Scheme 39). The reaction conditions
were then applied to a small array of 5-HMF derivatives.
Scheme 39 Flow photooxygenation of 5-
hydroxymethyl-furfural, platform molecule for
biofuels and polyester precursors.
Singlet oxygen photochemistry was also used for the
oxidative cyanation of primary and secondary amines as
demonstrated by Seeberger and co-workers (Scheme
40).267 A FEP coiled reactor (ID 760 μm, 7.5 mL) was
irradiated with low-energy LEDs (420 nm). The first
step involved an oxidative transformation yielding the
corresponding imine in high selectivity. Subsequently,
these imine intermediates were cyanated in the pres-
ence of trimethylsilyl cyanide (TMSCN) to afford the
desired α-aminonitrile. Tetraphenylporphyrin was se-
lected as photosensitizer and tetra-n-butylammonium
fluoride (TBAF) was added in catalytic amounts to acti-
vate TMSCN, allowing to decrease the amount of
TMSCN from 5 to 2.5 eq. With a controlled reaction
temperature of -50 °C, a small array of activated and
unactivated amines were subjected to the oxidative
cyanation protocol to synthesize α-aminonitriles in
good to excellent yields (71-99%). More recently,
48
Seeberger et al. reported a detailed mechanistic study
correlating the regioselectivity, obtained in the oxida-
tion of primary and secondary amines, with the bond
dissociation energy of the competing C-H bonds adja-
cent to the nitrogen atom.268
Scheme 40 Continuous-flow oxidative photocya-
nation of amines and subsequent use of the cya-
nated derivatives for fluorinated amino acids syn-
thesis.
In another report, the photooxidative cyanation proce-
dure was coupled in a semi-continuous-flow process to
the acid-mediated hydrolysis of the nitrile group, to
yield an array of α-amino acids (Scheme 40).269 Primary
benzyl and homobenzyl amines containing different
fluorine substituents were converted, providing access
to fluorinated amino acids. However, no control over
the chirality of the amino acidic stereocenter was possi-
ble, resulting in the formation of a racemic mixture.
The photochemical generation of singlet oxygen was
reported in a falling-film reactor by Jӓhnisch and Ding-
erdissen.63 The microreactor features a reaction plate
with 32 parallel channels (ID 600 μm) covered with a
quartz window (Figure 16). This design uses gravity to
produce a thin layer of liquid which is co-currently
brought into contact with the oxygen gas phase. The
photooxygenation of cyclopentadiene, yielding an en-
doperoxide intermediate and a cyclopentene diol as
final product, was performed in the reactor in the pres-
ence of Rose Bengal as photosensitizer. The use of the
falling film microreactor allowed for an easier and safer
handling of the explosive endoperoxide intermediate,
and afforded the desired product in preparative scale
(0.95 g, 20% yield). The same reactor had been previ-
ously reported for the photochlorination of toluene-2,4-
diisocyanate, showing better selectivity and space-time
yield compared to a conventional batch reactor.270
Figure 16 Falling film microreactor for the photooxy-
genation of cyclopentadiene. Reprinted with permis-
sion from ref. 63. Copyright 2005 John Wiley & sons.
49
3.2.5 Photocleavage and photodeprotection
Protecting groups (PGs) are of paramount importance
in the synthetic chemists toolbox to enable multistep
organic synthesis.271-272 Photolabile PGs exhibit appeal-
ing cleavage conditions (mild and neutral) and orthog-
onality to traditional PG.273
Beeler and co-workers reported the continuous-flow
deprotection of several amine substrates through the
removal of the photolabile 2-methoxy-9-
methylxanthene (Scheme 41).274 In a FEP-coiled reactor
(ID 800 μm, 350 μL) equipped with a mercury lamp (λ >
305 nm), deprotection of all the substrates (including a
Boc-protected piperazine, amino alcohol and phenylal-
anine methyl ester) was achieved in good yields (61-
83%) within 10 minutes residence time. Stability of the
protecting group in acid and basic conditions and at
high temperatures was proven. Furthermore, the ap-
plicability of this protection strategy was demonstrated
in a three-step flow synthesis, where the orthogonality
with a Boc protecting group and the compatibility with
amidation and acylation steps was demonstrated.
Scheme 41 Photodeprotection of the photolabile
xanthene-derived amine protecting group in con-
tinuous-flow.
The troublesome cleavage of the 2-nitrobenzyl PG is the
main reason why its wider adoption has been ham-
pered. Wendell and Boyd described a flow protocol
highly simplifying the deprotection of this photo-PG.275
A commercial UV flow reactor (10 mL, 105 W medium
pressure mercury lamp) was used. With the continu-
ous-flow removal methodology, the deprotection of the
amine function of electron poor indoles, indazoles and
few pyrazoles could be achieved. Compared to batch,
higher deprotection yields (e.g. 84 % in flow vs. 40% in
batch) were obtained and the reaction time could be
significantly reduced (from several hours in batch to 10
minutes in flow).
Photolabile groups were also exploited as useful linkers
for solid phase synthesis. Seeberger and co-workers
reported the use of a nitrobenzyl ether-based linker to
conveniently connect a standard Merrifield resin to a
monosaccharide (Scheme 42).276-277 The linker proved to
be compatible with the strong basic and acidic reaction
conditions required for the solid phase synthesis of a
hexasaccharide glycosaminoglycan (GAG) and of a 30-
mer mannoside derivative through automated synthe-
sis. In both cases, the photocleavage of the desired
product from the resin was performed through a FEP-
coiled microreactor (ID 760 μm, 12 mL) irradiated with
a 450 W mercury lamp equipped with a UV Pyrex filter.
The resin-bound oligosaccharides were flushed through
the microreactor with a syringe pump. After reaction,
50
the solid support was easily filtered off providing an
efficient way of purifying the target compound.
Scheme 42 Continuous-flow photocleavage of a
nitrobenzyl ether linker in sugar solid phase syn-
thesis.
In a later report, Seeberger et al. thoroughly investigat-
ed the cleavage efficiency of this photolabile linker in
batch and in flow.278 A double-jacketed batch reactor
irradiated with a UV lamp and a Pyrex filter was used as
a reference. The coiled FEP-tubing microflow setup was
entirely built in a sealed aluminium box. A 450 W lamp
with a Pyrex filter was employed and inserted into a
double-jacketed immersion well. The FEP tubing (ID
760 μm or 1.5 mm, 12 or 15 mL respectively) was coiled
around the jacket. A PS resin loaded with the photola-
bile linker and a fluorescein thiourea (FTU) was pre-
pared to assess the stability and the impact of the cleav-
age step (Scheme 43). Evaluation of the efficiency was
performed by comparing the beads fluorescence before
and after cleavage via laser confocal microscopy. In
batch photocleavage experiments, irradiation for 30
minutes without shaking resulted in a highly heteroge-
neous population of the resin, with some beads com-
pletely cleaved, while others still carrying the fluores-
cent moiety. When the batch reactor was shaken, al-
most all beads displayed partial cleavage but the overall
cleavage efficiency was still poor. Improved results were
obtained in flow, where the use of a wide 1.5 mm ID
tubing provided a vigorous turbulent mixing, ultimately
resulting in a uniform and efficient photocleavage. It
was postulated that the mixing observed in the larger
diameter FEP tubing allowed every bead to be efficient-
ly irradiated. A less efficient mixing was observed in an
760 μm ID tubing. Herein, the formation of multilayer
slugs prevented optimal irradiation of the system.
Scheme 43 Preparation of polystyrene (PS) resin
loaded with the photocleavable linker and FTU.
Subsequent cleavage in continuous-flow afforded a
more efficient and homogeneous deprotection
compared to batch.
3.2.6 Light-induced halogenation / dehalogen-
ation reactions
Casar and co-workers improved the benzylic bromina-
tion of a 5-methyl-substituted pyrimidine. This com-
pound constitutes a crucial intermediate in the synthet-
51
ic route towards rosuvastatin, a top selling drug for the
treatment of hypercholesterolemia (Scheme 44).279 The
batch procedure showed complete conversion, howev-
er, the formation of regioisomers and poly-brominated
byproducts could not be prevented. Furthermore, the
removal of such byproducts proved problematic, which
represented a risk hampering the further steps to the
final product. To better control the rate of bromination,
and prevent the formation of the polybrominated by-
products, a photoflow procedure was envisioned. A FEP
capillary (ID 760 μm, 18 mL) was coiled around a quartz
cooling jacket and irradiated with a 150 W medium-
pressure mercury lamp. With a residence time of 5
minutes, the reaction could be completed and afforded
an astonishing 58.3 mmol/h of product, nearly 4 times
higher than could be obtained in batch. Moreover, no
overbromination of the 5-benzylic position and a lower
overall level of impurities were observed.
Scheme 44 Benzylic flow bromination of an inter-
mediate for the production of rosuvastatin.
Benzylic bromination was described in a milli photore-
actor by Kappe and co-workers.280 The FEP-coiled reac-
tor (ID 3.2 mm, 13 mL) was irradiated with a 25 W
black-light compact fluorescent lamp (CFL). Full con-
version of a wide range of benzylic substrates was ob-
tained, including halogenated toluenes and a pyridine
derivative, within 13 to 25 minutes residence time
(Scheme 45). By increasing the reaction temperature
(40-60 °C), unreactive substrates could also be convert-
ed, while in the case of highly reactive substrates, the
cooling of the reaction medium (0 °C) proved to be
beneficial to prevent any dibrominated byproducts.
Furthermore, the reaction scalability was proved by
building a larger reactor equipped with a 100 W black
light CFL. High efficiency was retained in the scale-up
setup, giving access to up to 180 mmol/h of brominated
compounds.
Scheme 45 NBS-mediated benzylic bromination of
toluene and derivatives in flow.
Similar brominations were reported in continuous-flow
by Ryu and co-workers.281 Unlike other examples re-
porting the use of N-bromosuccinimide (NBS) as Br
source, molecular bromine was used instead, providing
a more atom efficient methodology. Several alkanes and
alkylarenes were successfully halogenated using a slug-
flow regime in a commercial chip microreactor (0.5 x 1.0
mm section, 950 μL) (Scheme 46). For alkanes, a solu-
tion of bromine in the substrate was mixed with water.
For alkylarenes, the substrate and bromine were dis-
solved in trifluorotoluene and mixed with water. A 15 W
black light was used for photoexcitation. High yields
52
and selectivity were observed (58 to 99% yield and 84-
99% selectivity), with no dibromo byproducts formed.
Substrates containing photoreactive moieties, such as
azides, were found to be compatible with the method-
ology as no decomposition of the starting material was
observed.
Scheme 46 Bromination of alkanes and alkylarenes
with molecular-bromine.
Quartz capillary tubing (1.5 mm ID, 12.5 mL) was used
for the photochemical defluorination of 3,5-diamino-
trifluoromethyl-benzene (Scheme 47), a derivative of
the water pollutant 3,5-dinitro-
trifluoromethylbenzene.282 A total of twelve 15 W UV-B
tubes (310 nm) were placed around and inside the reac-
tor coil. Within 5 minutes residence time, full conver-
sion of the starting material was observed in water.
However, the desired 3,5-diaminobenzoic acid partly
dimerized through an amide bond formation resulting
in poor selectivity. Up to now, no further synthetic
applications were reported for this transformation.
Scheme 47 Defluorination of 3,5-diamon-
trifluoromethyl-benzene with UV-B light in flow.
53
3.2.7 Photochemical decarboxylations
The controlled extrusion of CO2 from organic mole-
cules, so-called decarboxylation reaction, is a valuable
transformation in organic chemistry. The popularity of
this transformation can be explained by the abundance
of carboxylic groups in biomass sources.283
Microflow photochemistry has also been used to facili-
tate photodecarboxylation chemistry. In particular, a
mixture of acetone and pH 7 buffer was used as solvent
for the benzylation of unprotected phthalimides in a
glass microreactor (ID 1.5 mm) (Scheme 48).284
Scheme 48 Photodecarboxylative benzylation of
phthalimides in flow.
Acetone served both as triplet sensitizer and as cosol-
vent, while a pH 7 buffer was needed to selectively
deprotonate the phenylacetates (pKa = 5-6) and to keep
the phthalimide protonated (pKa = 8.3). After irradia-
tion, acetone was evaporated and, in most cases, the
precipitated photoproduct could be isolated by simple
filtration. A commercially available glass microreactor
was irradiated with 5 UV-B lamps resulting in a shorter
reaction time and higher yields compared to batch (e.g.
98% yield after 2 hours vs. 80% in 3 hours). Similarly,
the photodecarboxylation of phthaloyl glycine and
other N-protected phthalimides was also performed in
an acetone/water mixture.109 In this case, an accurate
comparison of the flow photoreactor with the batch
reaction was made. The calculated space-time yields
clearly favored the microreactor compared to the batch
setup (see Figure 17), especially when an identical num-
ber of UV lamps was used (i.e. 5). This reaction was
further implemented in preparative scale-up with a
falling film reactor using a XeCl excimer laser.285 Inter-
estingly, when 4-4’-dimethoxybenzophenone (DMBP)
was used instead of acetone as sensitizer, the photode-
carboxylation of phthalimides derivatives showed no
differences in conversion from batch to flow.286
Figure 17 space-time yields comparison of microreac-
tor and batch irradiation for the acetone-sensitized
photodecarboxylation of phtalimides. Reprinted with
permission from ref. 109. Copyright 2010 American
Chemical Society.
A similar photodecarboxylative methodology was used
for the addition of α-thioalkyl-substituted carboxylates
to alkyl phenylglyoxylates (Scheme 49).287 Reactions
were performed in a commercially available microreac-
tor featuring a bottom serpentine channel (0.5 x 2 mm
section, 1.15 mL), through which the reaction mixture
was flown, and a top channel where water was circulat-
ed in order to control the reaction temperature. 5 UV-A
lamps (350 nm) were used to irradiate a mixture of α-
thioalkyl-substituted carboxylate and alkyl phenylgly-
54
oxylate in aqueous acetonitrile. In all tested cases, the
formation of the desired alkylated product was accom-
panied with the dimerization byproduct. However, the
decarboxylative protocol with a sulfur-containing car-
boxylate showed higher chemoselectivity (77:23, prod-
uct vs. byproduct) than the simple thioether strategy
(20:80) (Scheme 49). Hence, it was postulated that the
carboxylate group in α-position of the thioether en-
hances and directs the alkylation of the phenylglyox-
ylates by facilitating a photoinduced electron transfer.
Scheme 49 Photodecarboxylative addition of α-
thioalkyl-substituted carboxylates to alkyl phenyl-
glyoxylates in flow.
3.2.8 Miscellaneous
The sensitized addition of isopropyl alcohol to 2-
furanone has been extensively used as a model reaction
by Oelgemöller and co-workers.60, 288-290 DMBP was used
as triplet sensitizer to generate a ketyl radical by hydro-
gen abstraction. Subsequently, the ketyl radical adds to
the conjugated double bond of the furanone. The stabi-
lized oxoallyl radical can engage in a second hydrogen
abstraction event, closing the cycle and leading to the
final product (Scheme 50). Initially, an LED-driven
microchip reactor (150 x 150 μm, 13 μL) employing UV-
LEDs (365 nm) was introduced.288 The microreactor
proved to be superior in terms of reaction time com-
pared to the batch irradiation of a Pyrex glass tube in a
Rayonet chamber reactor (flow: full conversion in 2.5
min; batch: 90% conversion in 5 min).
Scheme 50 Sensitized addition of isopropyl alcohol
to 2-furanone in a microchip reactor.
The synthesis of terabic acid from maleic acid was used
as model reaction by Oelgemöller and co-workers to
compare three different reactor systems (Scheme 51): a
batch tube irradiated in a Rayonet chamber, a glass
microreactor and a FEP capillary (ID 760 μm, 5 mL)
coiled around a UV-B lamp.290 Based on conversion, the
microcapillary photoreactor showed the best perfor-
mance (99% conversion in 15 min vs. 68% in 20 min for
the microreactor device and 71% in 15 min for batch).
When energy efficiencies were taken into account, the
batch setup results were similar to the glass chip, while
the microcapillary unit was nearly three-times more
efficient. The stereoselectivity aspects of the photosen-
sitized addition of methanol to limonene were also
studied in microreactors by Inoue and co-workers.291
Scheme 51 Synthesis of terabic acid from maleic
acid in a glass microreactor.
55
Switching from a traditional immersion well reactor to
a flow microreactor has the immediate advantage of an
easier scale up of the reaction protocol. This feature was
exploited by Jamison and co-workers for the flow syn-
thesis of a cyclopentadienylruthenium complex.292 An
additional gain of the flow protocol is the possibility to
directly use the photoproduct in a subsequent trans-
formation, thus effectively utilizing the continuous
nature of consecutive flow processes. This second as-
pect is exemplified by a follow-up paper from the same
group employing the in-situ photogenerated ruthenium
catalyst for an ene-yne coupling.103 In particular, the
final photochemical step in the synthesis of
CpRu(MeCN)3PF6 was adapted to flow using a high
purity PFA-coiled reactor (ID 760 μm, 250 μL) irradiat-
ed with a 450 W medium-pressure mercury lamp. High-
purity PFA was required due to the leaching of a poly-
mer plasticizer which hampered the reaction. The sub-
strate concentration could be increased three-fold in
flow compared to batch without loss in conversion,
resulting in a final throughput of 1.56 g per hour in a
preparative-scale photoreactor (5 mL).292 A modified
version of this flow synthesis was then applied to the in
situ generation of a catalytically active ruthenium spe-
cies, which was directly intercepted by an ene-yne sub-
strate (Scheme 52). In the reaction optimization, the
capillary material was changed to quartz due to darken-
ing/degradation of the HPFA capillary after repeated
use. Finally, a Pyrex filter was added to prevent any E/Z
isomerization.103 Interestingly, the homogeneous Ru
catalyst could be recovered quantitatively from the
reaction mixture by precipitation in a hexane/ether 1:1
mixture. Its further use in other reactions did not cause
any observable decrease in catalytic activity. An effec-
tive recycling strategy for rare earth metal-based cata-
lysts (as ruthenium and the platinum group in general)
is of increasing importance, due to their forthcoming
exhaustion.70
Scheme 52 Photochemical generation of [CpRu]+ as
active catalytic species for ene-yne coupling in
continuous-flow.
56
Another successful integration of a photochemical step
in a multistep process was the continuous-flow synthe-
sis of 2’-deoxynucleosides.293-294 Quartz tubing (ID 1.0
mm, 1.84 mL) was coiled around a 450 W medium pres-
sure mercury lamp. A layer of aluminum foil was placed
around the reactor to reflect the UV photons back to-
wards the tubing. It was shown that indeed an in-
creased photon flux was obtained which led to a higher
conversion. This procedure was subsequently applied in
a 3-step continuous-flow protocol starting with the (i)
glycosylation of the protected ribose, followed by the
(ii) photochemical deoxygenation and (iii) deprotection
of the hydroxyl in the 3’ and 4’ position (Scheme 53).
Scheme 53 Continuous-flow synthesis of 2’-
deoxynucleosides.
Microreactor technology has also been recently applied
to the radical C-H arylation of heteroarenes. In particu-
lar, Kappe and co-workers investigated the reactivity of
in situ generated diazonium salts in presence of a pho-
tocatalyst (Scheme 54).295 Surprisingly, it was found
that neither photocatalyst nor light were required for
the reaction process. Nevertheless, the reaction was
significantly accelerated in the presence of light irradia-
tion and under continuous-flow conditions (from 24
hours in the dark to 5 hours in batch and 45 minutes in
flow). A FEP coiled reactor (ID 1.0 mm, 10 mL) was
irradiated with a medium pressure mercury lamp. In-
terestingly, the enhanced light irradiation in microflow
resulted in a higher selectivity, presumably preventing a
competing thermal process. The proposed mechanism,
which accounts for these experimental observations,
involves the formation of diazo anhydrides from self-
condensation of the corresponding nitrosoamine.
Scheme 54 C-H arylation of heteroarenes in con-
tinuous-flow through in situ generated diazo an-
hydrides.
The synthesis of vitamin D3 is one of the few industrial
photochemical processes. Takahashi and co-workers
recently reported an elegant synthesis of vitamin D3
starting from provitamin D3 in a continuous-flow pho-
tomicroreactor (Scheme 55).296 This two-step transfor-
mation begins with the UV-B induced isomerization of
provitamin D3, yielding previtamin D3 and isomers in
equilibrium.297 Consequently, previtamin D3 is thermal-
ly converted into the final product, vitamin D3. The
authors anticipated that irradiating the reaction mix-
ture during the thermal isomerization could improve
57
the yield, since the photoisomerization of the byprod-
ucts would shift to produce more previtamin D3. A
continuous-flow setup consisting of two quartz micro-
reactors (0.2 x 1 mm, respectively 50 and 100 μL) was
designed so that the first would receive direct irradia-
tion from a Vycor-filtered 400 W high-pressure mercu-
ry lamp. The second reactor was placed in a 100 °C oil
bath and irradiated by the same light source through a
glass filter (λ > 360 nm). This two-stage continuous-
flow synthesis resulted in an isolated yield of 32%, and
was further applied to the synthesis of vitamin D3 ana-
logues.298-299
Scheme 55 Continuous-flow conversion of provita-
min D3 into vitamin D3.
3.3 Photocatalysis
In the last decade, photocatalysis positioned itself as an
important photochemical strategy, allowing for unprec-
edented and challenging transformations. Because of its
distinctive traits, photocatalysis will be treated in a
dedicated section. For photocatalytic applications in
wastewater treatment, e.g. photo-Fenton and TiO2
catalytic reactions, we refer to section 5.1.
Scheme 56 Example of possible mechanisms for a
photocatalytic cycle. Adapted from ref. 44.
The mechanism of photocatalytic redox reactions is
often controversial. In particular, two school of
thoughts debate on whether chain processes might be
involved in photoredox transformations.43, 300 On one
hand, closed catalytic cycles are considered as the
mechanistic path to the final neutral product. On the
other hand, recent in depth studies demonstrated that
radical chain propagation cycles might play a major role
in the mechanism of certain photocatalytic reactions
(Scheme 56).44 Quantum yield measurements were used
to prove the presence of radical propagating chains.45
An experimental quantum yield higher than 1 means
that, on average, each excited state of the photocatalyst
produces more than one molecule of product. There-
fore, quantum yields < 1 are compatible with a closed
catalytic cycle, while quantum yields >> 1 indicate a
58
radical chain propagating mechanism. In a recent re-
port, Cismesia and Yoon proved the chain propagating
nature of three previously reported reactions, through
quantum yield and luminescence quenching measure-
ments.44 In particular, a 4+2 oxidative quenching,301-302 a
2+2 reductive quenching303-304 and a neutral radical
initiated reaction305 were investigated: in all three cases,
values well above 1 were found for the quantum yields.
However, as underlined by the authors, the mechanism
of the photoredox transformation is always reaction
specific. Therefore, accurate (control) experiments are
crucial to propose a reliable photoredox mechanism.306
Transition metal photocatalysts
The use of transition metal complexes in photoredoxca-
talysis flourished in the last decade.13-19 The ability of
these complexes to engage in single electron transfer
(SET) processes originates from the formation of highly
reactive excited states upon visible light irradiation.
Ruthenium and iridium complexes (especially tris(2,2’-
bipyridine) ruthenium (II) and fac-Ir(ppy)3(ppy=2-
phenylpyridine)) are the most common used metal-
based photocatalysts for photoredox-catalysis, although
reports employing other metals (e.g. cobalt, copper
etc.) exist as well.
The lifetime of the excited state of metal-based photo-
catalyst is crucial for their ability to participate in elec-
tron-transfer reactions. This lifetime depends highly on
the reaction medium (e.g. solvent) and on the nature of
the ligand associated with the metal. Visible-light pho-
tocatalysis can use simple and inexpensive light
sources, such as CFL and LEDs. Since the majority of
organic molecules does not absorb in the visible right
range, side reactions can be minimized. Finally, despite
their high cost, metal-based photocatalysts exhibit high
efficiency even at low catalyst loading (< 1 mol %).
3.3.1 Ruthenium complexes
Gagné and co-workers reported the synthesis of C-
glycoamino acids and C-glycolipid derivatives.307 The
production of the key intermediate α-C-glycoside was
needed on a gram scale (Scheme 57). The photocatalytic
route to this product, involving the reductive quench-
ing of Ru(bpy)32+, was found to depend heavily on the
reaction vessel diameter (i.e. 1 h reaction time in an
NMR tube compared to 24 h in a 25 mL flask). The high
molar extinction coefficient of the photocatalyst was
identified as the main cause, limiting the light penetra-
tion to the first millimeter of reaction mixture. Switch-
ing to flow was envisioned as the solution to obtain
both efficient irradiation and high productivity. A FEP
coiled reactor (ID 1.6 mm, 15.9 mL) irradiated with blue
LEDs was used, resulting in the production of 5.5 grams
of product per day (85% yield).
Scheme 57 Gram-scale continuous-flow synthesis
an α-C-glycoside via a reductive quenching Ru cy-
cle (HAT = Hydrogen Atom Transfer).
59
Stephenson and co-workers demonstrated several visi-
ble-light transformations catalyzed by Ru and Ir com-
plexes, thus enabling a completely new variety of un-
precedented reactions. Transferring these reactions to a
microflow photoreactor came as a natural strategy to
reduce reaction times and improve irradiation efficien-
cy.308 An operationally simple reactor was constructed
from 105 cm of PFA tubing (ID 760 μm, 479 μL) coiled
around some standard glass tubes in an eight-shaped
fashion. Seven blue LED lights were used for illumina-
tion, and a silver coated beaker was positioned above
the reactor as a reflecting mirror. Radical cyclization of
heteroaromatic and terminal olefins catalyzed by
Ru(bpy)32+ reached completion within only 1 minute
residence time in good to excellent yields (71-91% vs.
incomplete conversion in 2 days in batch)(Scheme 58A
and B). In the same way, intramolecular malonation of
indoles catalyzed by Ru(bpy)32+ using triarylamine as
reductive quencher afforded the target compound with
77% yield in 1 minute reaction time (Scheme 58B).
Scheme 58 Continuous-flow radical cyclization of
heteroaromatic olefins (A), intermolecular indole
functionalization (B) and intermolecular atom
transfer radical addition (ATRA) catalyzed by
Ru(bpy)32+.
Furthermore, intramolecular atom transfer radical addi-
tions (ATRAs) with terminal alkenes and alkyl-
bromides rapidly afforded the desired product (Scheme
58C).308 The oxidative quenching cycle was catalyzed by
an Ir(dF(CF3)ppy)2(dtbbpy)PF6 (dF(CF3)ppy=2-(2,4-
difluorophenyl)-5-(trifluoromethyl)pyridine; dtbbpy =
4,4’-di-tert-butyl-2,2’-bipyridine) catalyst and required
between 6.5 to 9 minutes residence time for comple-
tion. The oxidative formation of iminium ions, starting
from N-arylated tetrahydroisoquinolines, was also im-
plemented in the same photoreactor. The reaction con-
ditions in DMF required BrCCl3 as terminal oxidant and
Ru(bpy)32+ as photocatalyst. The formation of an imini-
um ion and its subsequent trapping by a nucleophile
(such as nitromethane) resulted in the formation of a
variety of α-functionalized tetrahydroisoquinolines
within 30 seconds residence time (Scheme 59).
Scheme 59 Photoredox-catalyzed intramolecular
atom transfer radical additions in continuous flow.
60
Interestingly, a similar aza-Henry reaction was de-
scribed concurrently by Neumann and Zeitler in a
commercial glass chip photoreactor (500 x 600 μm, 100
μL total volume).309 Not only tetrahydroisoquinoline
was used as substrate, but also N-phenyl pyrrolidine
and dimethylaniline, generating far less stabilized imin-
ium ions. All substrates could be converted to the final
nitromethane addition product within 30 and 130 min
residence time in good to excellent yields (59-93%).
Another continuous-flow Ru-catalyzed tetrahydroiso-
quinoline-based reaction has been recently reported by
Maurya and co-workers.310 Structurally diverse imidaz-
oles were obtained starting from a vinyl azide and sec-
ondary amines (Scheme 60). The flow reactor consisted
PFA tubing (ID 760 μm, 4.5 mL) wrapped around a LED
lightsource. The flow protocol allowed for improved
yields (65 vs. 55%) and shorter reaction times (44 min
vs. 12 h) compared to batch.
Scheme 60 Ru-catalyzed imidazole synthesis in
continuous-flow.
The synthesis of symmetric anhydrides via photoredox
catalysis was demonstrated by Stephenson and co-
workers (Scheme 61).311 The oxidative quenching of
Ru(bpy)32+ by CBr4 in DMF allowed the in situ formation
of the corresponding iminium ion (Vilsmeier-Haack
reagent) which further reacted with a carboxylic acid to
form the anhydride. An array of substituted aryl- and
alkyl-carboxylic acids were successfully converted to
the corresponding anhydrides (61-99% yield) with the
exception of α-amino acids (5% yield). When the reac-
tion of 4-tert-butylbenzoic acid was integrated in a
continuous-flow photoreactor, 97% of the desired an-
hydride was obtained in 6.4 minutes residence time (vs.
85% yield in 18 h in batch).
Scheme 61 Continuous-flow synthesis of symmetric
anhydrides using visible light-mediated
photoredox catalysis.
Bou-Hamdan and Seeberger reported the application of
some previously published Ru(bpy)32+-catalyzed reac-
tions in a continuous-flow microreactor.112 The micro-
fluidic set-up consisted of a FEP capillary (760 μm, 4.7
ml, 100 psi BPR) wrapped around two vertical rods and
placed between two 17 W white LED lamps. Among the
tested transformations, the reduction of α-
chlorophenylacetates, inspired by the photocatalytic
C—Br reduction reported by the Stephenson group,312
was achieved (Scheme 62). Within 30 minutes resi-
dence time, 82% of the reduced product was obtained
in the presence of Ru(bpy)32+ and with total absence of
the formate ester byproduct, observed in batch. The
61
same reactions in batch required 24 hours for similar
conversions with a 14% yield of side product.
Scheme 62 Photocatalytic dehalogenation of α-
chlorophenylacetates in continuous flow.
Noёl and Wang developed a photoredox-mediated
Stadler-Ziegler reaction for the preparation of aryl-alkyl
and diaryl sulfides (Scheme 63).313 A variety of aryl
amines were converted in situ to the corresponding
diazonium salts in the presence of tert-butylnitrite and
catalytic amounts of p-toluenesulfonic acid (PTSA).
Subsequently, the phenyl radical generated by oxidative
quenching of Ru(bpy)32+* is coupled to aliphatic or aro-
matic thiols. Reactions were performed in a PFA capil-
lary reactor (ID 540 μm, 460 μL) coiled around a 50 mL
syringe and positioned inside an aluminum-coated
beaker containing an array of 3.12 W blue LEDs. Control
over the reaction temperature was obtained through
air-cooling of the reactor. Good to excellent yields and
an impressive acceleration of the transformation were
obtained in flow (79-84% in 15 seconds vs. 5 h in batch).
In the process, nitrogen evolution from the diazonium
salt resulted in the formation of a slug flow. Further-
more, the small volume provided a safe environment,
reducing the hazards correlated with the handling of
potentially explosive diazonium salts and diazosulfide
intermediates.
Scheme 63 Continuous-flow Stadler-Ziegler
synthesis of arylsulfides facilitated by photoredox
catalysis.
62
The uniform irradiation and the safe handling of fluori-
nating reagents makes continuous-flow particularly
appropriate for the synthesis of fluorine-containing
groups.314 Trifluoromethylation and perfluoroalkylation
of five-membered heterocycles was achieved by Noёl
and co-workers (Scheme 64).315 By implementing a
similar reactor reported for the synthesis of diaryl sul-
fides, the perfluoroalkylation of pyrrole and indole
derivatives was accomplished via a Ru(bpy)32+ mediated
reductive quenching cycle in the presence of TMEDA
(N,N,N’,N’–tetramethyl-1,2-diaminoethylene) as elec-
tron donor. The reaction reached completion within 10-
20 minutes residence time in good to excellent yields
(53-99%). Furthermore, trifluoromethylation of the
same substrates and of a broad variety of other five-
membered heteroarenes was obtained in a segmented
gas-liquid reaction. Gaseous CF3I was used as a cheap
trifluoromethylating agent and dosed via a mass flow
controller. The liquid phase and gaseous phase were
combined in a T-shaped micromixer prior to entering
the irradiated zone of the reactor. All substrates were
converted to the corresponding trifluoromethylated
derivatives in good to excellent yields (55-95%) within
few minutes (8-16 minutes vs. 12-72 hours in batch).
Scheme 64 Trifluoromethylation and perfluoroal-
kylation of heterocycles by photoredox catalysis in
flow.
63
Similarly, the CF3 radical generated via reductive
quenching of Ru(bpy)32+, was coupled to a series of aryl,
heteroaryl and alkyl thiols, affording a visible light-
mediated strategy for the formation of S-CF3 bonds
(Scheme 65).316 The method revealed its compatibility
towards a wide variety of functional groups, such as free
carboxylic acids, alcohols and amines. Aliphatic thiols
could be efficiently converted in the presence of tri-
phenylphosphine and water as reducing agents, mini-
mizing the formation of the disulfide side product. All
substrates were converted within one minute residence
time in excellent yields (47-96%). The segmented-flow
observed in the presence of gaseous CF3I afforded excel-
lent mixing and facilitated the gas-liquid mass transfer
of the gaseous reagent, therefore further accelerating
the reaction. Interestingly, in flow, near equimolar
reaction conditions (thiol: CF3I 1:1.1) could be used while
batch required a large excess to reach full conversion
(thiol:CF3I 1:4). This can be attributed to the improved
contact between gas and liquid phase in flow. In batch,
the gas is present in the head space and diffuses mar-
ginally back into solution.
Scheme 65 Photocatalytic trifluoromethylation of
thiols in flow.
Another strategy for the radical trifluoromethylation of
arenes and heteroarenes was recently published by
Stephenson and co-workers.317 The use of inexpensive
and readily available trifluoroacetic anhydride (TFAA)
was made possible by appending a sacrificial redox
auxiliary (N-oxide) to lower the high reduction poten-
tial of the trifluoroacetic anion. The TFAA adduct, re-
sulting from the addition of N-oxide, can oxidatively
quench the excited state of Ru(bpy)32+, ultimately re-
sulting in CO2 evolution, formation of CF3• and pyridine
(Scheme 66). The methodology demonstrated high
tolerance to various functional groups and did not show
any air or moisture sensitivity. The trifluoromethylation
of 20 g of N-Boc-pyrrole was also performed in a com-
mercially available photochemical reactor. PFA tubing
(ID 1.3 mm, 10 mL volume) was irradiated with 450 nm
light (24 W). With a residence time of 10 minutes, the
formation of 71% of product (both mono- and di-
trifluoromethylated in position 2 and 5) was observed.
Scheme 66 Radical trifluoromethylation of arenes
and heteroarenes using trifluoroacetic anhydride.
Several photocatalytic reactions involve the functionali-
zation of a single unreactive C—H bond, but in a recent
paper from Maurya and co-workers, multiple C—C
64
bond forming events were obtained in a reaction cas-
cade induced by an initial photocatalytic step.318 In the
proposed mechanism, the Ru-induced formation of the
iminium ion of the tetrahydro-β-carboline tricycle cou-
ples with a dipolarophile, yielding the cycloaddition
product that oxidatively rearomatizes to the final com-
pound (Scheme 67). Several derivatives of the naturally
occurring β-carboline scaffold were obtained in batch,
and one test reaction was transferred to flow. The white
LED irradiated PFA coiled reactor (ID 540 μm, 980 μL),
afforded slightly better yields (75% vs. 69%) and signifi-
cantly reduced reaction time (8 minutes in flow, 12
hours in batch) compared to batch.
Scheme 67 Flow synthesis of β-carboline deriva-
tives via photoredox catalysis.
Schroll and König investigated the Ru(bpy)3 catalyzed
SET to 2,2,6,6-tetramethylpiperidine nitroxide
(TEMPO). The resulting one-electron oxidized product,
TEMPO+ was reacted with stable enolates yielding the
corresponding α-oxyaminated derivative. When a
commercial glass chip reactor (ID 1.0 mm, 1.7 mL) irra-
diated with blue LEDs was used, the reaction time was
shortened from 3 hours to 10 minutes.319
Kim and co-workers recently fabricated a novel mono-
lithic and flexible fluoropolymer microreactor made of
perfluoropolyether (PFPE) through soft litography.320
This material resembles PDMS in terms of low surface
energy and toxicity, with high elasticity and gas perme-
ability. However, PFPE is also chemical resistant, suita-
ble for strongly acidic or basic reaction mediums and
for high temperatures. Among the reactions tested, a
photochemical [2+2] enone intramolecular cyclization16
catalyzed by Ru(bpy)3Cl2 was performed (Scheme 68).
The reactor (300 x 50 μm) was illuminated with a 30 W
white LED lamp, placed 5 cm away from the reactor.
Compared to a batch reactor illuminated in the same
way, the same yield could be obtained in shorter reac-
tion time (80% in flow within 1 min residence time vs
30 min in batch).
Scheme 68 Intramolecular [2+2] enone cyclization
in a fluoropolymer reactor.
3.3.2 Iridium complexes
Stephenson and co-workers reported a novel visible-
light induced radical reductive deiodination, which was
applied to a variety of alkyl, alkenyl and aryl iodides
(Scheme 69).321 Upon formation of the carbon radical,
the substrate showed efficient intramolecular cycliza-
tion affording a convenient strategy for the formation of
65
several heteroatom-containing ring structures. Opti-
mized conditions for the alkyl and aryl substrates in-
volved the use of fac-Ir(ppy)3 as catalyst in presence of
either Hantzsch ester/tributylamine or formic ac-
id/tributylamine serving as an electron donor/H donor
system. The proposed mechanism proceeds through the
oxidative quenching of the excited Ir catalyst by the
iodide substrate. The reductive cleavage delivers a car-
bon radical able to cyclize/subtract an H atom from
tributylamine, the Hantzsch ester or the formate. The
reaction was then transferred to a microflow reactor
(PFA tubing, 760 μm, 1.33 ml, 5.88 W blue LEDs)
providing a reduction of the reaction time (40 min vs.
30 h in batch). Similar yields were obtained with only
half the catalyst loading (93% yield with 0.05% catalyst
vs. 95% with 1% catalyst in batch).
Scheme 69 Ir-catalyzed radical reductive de-
iodination of alkyl, alkenyl, and aryl substrates in
flow.
The same authors later implemented this reactor in a
two-step deoxygenation protocol of primary and sec-
ondary alcohols (Scheme 70).322 First, alkyl alcohols
were converted in batch into aryl iodides following the
Garegg-Samuelsson reaction.323 In the second step, a
radical reductive deiodination afforded the hydrogenat-
ed products. The reaction proceeded within 18 minutes
residence time and with only 0.25 mol% of Ir catalyst,
giving an array of desired products in good to high
yields (67-87%). Flow provided a 120 fold improvement
over the batch conditions (75% conversion in 144 h).
The overall protocol exhibited a good functional group
tolerance, with one case showing the selective reduc-
tion of a primary alcohol in the presence of a secondary
alcohol.
Scheme 70 Deoxygenation of primary and second-
ary alcohols using Ir-mediated photocatalysis.
Stephenson and co-workers exploited an identical flow
setup to perform a two-step visible-light Ir-catalyzed
strategy for lignin degradation. The reaction was ham-
pered in batch by the presence of the dark colored im-
purities which are characteristic for lignosulfonates.324
Rueping and co-workers demonstrated the visible-light
catalyzed (E)- to (Z)-isomerization of stilbenes in a
continuous-flow photoreactor including a catalyst recy-
cling strategy.325 Unlike the well-known UV-induced
isomerization of stilbene derivatives, this methodology
prevented the formation of any byproducts.192 The pro-
posed mechanism relies on the excitation of an iridium
catalyst (namely [Ir(ppy)2(bpy)](PF6)) which can subse-
quently excite the (E)-stilbene isomer through an ener-
gy transfer that ultimately causes the isomerization to
(Z)-stilbene (Scheme 71). Due to a difference in energy
between the triplet state of the two isomers, only the
(E)-isomer can be engaged in energy transfer processes
66
with the photocatalyst, providing a high selectivity
(around 99:1 Z/E ratio for most substrates). By exploit-
ing favorable extraction kinetics of the catalyst by an
ionic liquid ([bmim][BF4], bmim = 1-butyl-3-
methylimidazolium), continuous recycling of the cata-
lyst proved possible. A solution of the stilbene in n-
pentane and a solution of [Ir(ppy)2(bpy)](PF6)] immobi-
lized with the ionic liquid in DMF were pumped
through a glass millireactor and irradiated with high
power blue LEDs. Upon exiting the microreactor, the n-
pentane phase readily separated from the catalyst con-
taining ionic liquid phase.
Scheme 71 Continuous recycling of Ir catalyst in
ionic liquids applied to the E/Z isomerization of
stilbenes.
Another strategy for the continuous recycling of an Ir
catalyst was recently published by Reiser and co-
workers.326 Firstly, the synthesis of the polyisobutylene-
tagged Ir(ppy)2(PIB-ppy) was achieved. (Scheme 72).
Scheme 72 Structure of Ir(ppy)2(PIB-ppy) catalyst.
(PIB = polyisobutylene).
The polyisobutylene (PIB) tether allows for the recovery
of the catalyst through liquid/liquid extraction with
heptane in a thermomorphic solvent system.327 In such
a system, solvents of different polarity exhibit no recip-
rocal solubility at room temperature, while they be-
come miscible when a certain temperature is reached.
After cooling, the two phases are separated again, mak-
ing the process completely reversible. A photocatalytic
test reaction (i.e. the E to Z isomerization of styrenes
via uphill catalysis328) was performed in a commercially
available glass reactor in an acetonitrile/heptane ther-
momorphic solvent system. To obtain miscibility of the
system, the reaction was carried out at 90 °C and irradi-
ated with 8 blue LEDs. A 60 psi BPR was added to the
set-up to prevent boiling of the solvent mixture. Upon
exiting the reactor, the solvent mixture was led into a
cooling unit where separation of the two phases occurs.
The catalyst-containing heptane phase was guided back
to the inlet of the reactor and re-used up to 30 times.
The product dissolved in the acetonitrile phase was
collected and isolated (Figure 18).
Figure 18 Schematic representation of the continuous-
ly operating, catalyst recycling setup. Reprinted from
ref. 326. Copyright 2016 The Royal Society of Chemistry.
To verify whether thermochemical effects occurred, the
same reaction was also performed at room temperature
by keeping the system biphasic. The use of the micro-
chip afforded a sufficiently high surface area for the
67
reaction to take place at the interface of the two sol-
vents without efficiency loss. However, slightly reduced
reaction times (82:18 Z/E ratio with a flow rate of 20
μmol/min at 90 °C and 82:18 Z/E ratio with a flow rate
of 10 μmol/min at 19 °C) were observed.
Jamison and co-workers developed a visible light-
induced decarboxylative radical cyclization for the
preparation of pyrrolo[1,2-a]quinoxalines.329 Starting
from ortho-heterocycle-substituted arylisocyanides and
using hypervalent phenyliodine dicarboxylates as
source of alkyl radicals, the desired pyrrolo[1,2-
a]quinoxaline product was obtained with fac-Ir(ppy)3 as
optimal photocatalyst (Scheme 73). The method
showed high functional group tolerance and the sub-
strate scope was broadened by replacing the pyrrole
ring with other nitrogen-containing heterocycles (e.g.
indole, imidazole and benzoimidazole). The photocy-
clization procedure was further integrated in a conven-
ient three-step continuous-flow synthesis. The multi-
step protocol involves the preparation of the desired
phenyliodine (III) dicarboxylate, which reacted in the
presence of pyrrole and photocatalyst/light to yield
pyrrolo[1,2-a]quinoxaline. The process was performed
in three different PFA capillary reactors (ID 760 μm,
volumes of 90, 228 and 1140 μL respectively, 20 psi BPR)
connected in series (See microfluidic setup in Scheme
73). The photo-cyclization step involved solely the third
reactor which was irradiated with a 26 W CFL and
placed in a water cooling bath to maintain the reaction
temperature at 25 °C. The overall synthesis was com-
pleted in 14.6 minutes residence time, with 9.5 minutes
required for the photo-cyclization product (vs. 5 hours
in batch). The desired compound could be obtained in
an overall yield of 47% (corresponding to 78% yield per
step).
Scheme 73 Synthesis of functionalized polycyclic
quinoxaline derivatives via photoredox catalysis.
The application of continuous-flow photoredox cataly-
sis to the synthesis of complex natural products was
demonstrated by Beatty and Stephenson with the pho-
tocatalytic fragmentation of the alkaloid (+)-
catharanthine.330 This fragmented intermediate can be
further employed in the synthesis of (-)-
pseudotabersonine, (-)-pseudovincadifformine and (+)-
coronaridine. It was postulated that (+)-catharanthine
oxidizes as a result of a SET from the excited state of
the Ir(dF(CF3)ppy)2(dtbbpy)PF6 catalyst. In the pres-
ence of trimethylsilyl cyanide (TMSCN), the radical
form of (+)-catharanthine can be stereoselectively
trapped. A final reduction and deprotonation step af-
fords the key intermediate (Scheme 74). The flow appa-
ratus consists of a PFA capillary (ID 760 μm, 1.34 mL)
68
irradiated with 5.88 W blue LEDs. A solution of (+)-
catharanthine, Ir catalyst, TMSCN in MeOH was
pumped into the photomicroreactor affording the de-
sired intermediate within 2 minutes residence time in
96% yield. Notably, the use of microreactor technology
not only afforded shorter reaction times and easy scala-
bility, but also provided a safer strategy for the handling
and controlled release of HCN formed in the reaction.
Scheme 74 Synthesis of natural products via photo-
redox catalysis in flow.
Hoffmann, Rueping and co-workers achieved the tri-
fluoromethylation of electron-deficient olefins using
sodium triflinate as CF3 source and
Ir(dF(CF3)ppy)2(dtbbpy)PF6 as photocatalyst (Scheme
75).331 The same reaction could also be performed with
near-UV light (350 nm) and a benzophenone photoor-
ganocatalyst. Also in this case, it was possible to accel-
erate the reaction kinetics (from 6 h to 30 min) by per-
forming the reaction in continuous flow. The flow setup
consisted of 10 meters of FEP tubing (ID 760 μm, 5.0
mL) wrapped around 8 glass rods and irradiated with 16
black light lamps (8 W each, 350 nm) inside the cham-
ber of a Rayonet reactor.
Scheme 75 Trifluoromethylation of electron-
deficient olefins with sodium triflinate.
The same heteroleptic iridium photocatalyst was em-
ployed by Knowles and co-workers for the indoline
oxidation of an intermediate en route to elbasvir, an
anti-hepatitis C drug (Scheme 76).332 Standard oxida-
tion conditions were associated with the epimerization
of an hemiaminal stereocenter, with the only exception
of permanganate, whose industrial use was environ-
mentally problematic. A multi-parallel experimentation
campaign of several photocatalysts coupled with differ-
ent stoichiometric oxidants lead to the identification of
Ir(dF(CF3)ppy)2(dtbbpy)PF6 and tert-butylperacetate
(tBPA) as competent oxidant system without significant
69
loss of enantiopurity (e.e.up to 99.9%). The absence of
epimerization was rationalized through extensive
mechanistic studies. The industrial suitability of the
process was prove on a 100 g scale flow synthesis. In
particular, 19 m of PFA tubing (ID 3.175 mm, 150 mL)
was coiled around a glass condenser, used to control
the reaction temperature (-5 ˚C), and irradiated with
720 UV-LEDs (440 nm). A flowrate of 2.5 mL/min, cor-
responding to a residence time of one hour, resulted in
an 85% isolated yield and 99.8% e.e.
Scheme 76 Ir-catalyzed indoline oxidation.
The spin-selective generation of triple nitrenes from
azidoformates was reported by Yoon and co-workers
and applied to the photocatalytic aziridination of ali-
phatic and styrenic alkenes.333 [Ir(ppy)2(dttbpy)]PF6 was
chosen as photocatalyst, and 2,2,2-trichloroetyl az-
idoformate (TrocN3) proved to be the most effective
reagent. With the optimized conditions, a variety of
alkenes underwent the desired transformation in good
yields (61-91%) within 4 hours. However, batch experi-
ments showed that the reaction rate was inversely pro-
portional to the reaction scale (77% in 4 h on 0.1 mmol
scale vs. 75% in 20 h on 0.4 mmol scale) suggesting that
the transformation was photon-limited. A higher irradi-
ation efficiency and scalability of the reaction was
demonstrated in a FEP-coiled reactor (ID 760 μl, 1.9
mL) exposed to with 15 W blue LED lamp irradiation
(Scheme 77). Shorter residence time was required for
the aziridination of cyclohexene (72% in 2.3 h vs 77% 4h
in batch) and a preparative scale reaction afforded 785
mg (70%) of pure product within 16 hours.
Scheme 77 Photocatalytic aziridination of cyclo-
hexene.
3.3.3 Copper complexes
Collins and co-workers reported the use of a copper-
based sensitizer, namely [Cu(XantPhos)(dmp)]BF4
(XantPhos = 4,5-Bis(diphenylphosphino)-9,9-
dimethylxanthene, dmp = 2,9-dimethyl- 1,10-
phenanthroline), for the successful synthesis of
[5]helicenes and N-substituted carbazoles (Scheme
78).334 The copper catalyst could be synthesized in situ
(from Cu(MeCN)BF4XantPhos and neocuproine), mixed
with a solution of the reactants and then recirculated
multiple times in a commercially available photoreac-
tor. This reactor consists of FEP tubing (ID 1.0 mm)
wrapped around two CFL light sources (30 W each) and
was used to demonstrate the synthesis of [5]helicenes
starting from a stilbene precursor.334 Compared to pre-
viously reported UV-catalyzed synthesis of helicenes,
this strategy allowed the use of visible light and afford-
ed the desired product without the generation of over-
70
oxidized and regioisomerized byproducts. The flow set-
up compared positively to the batch reactor, yielding a
gram-scale synthesis with a notable reduction in reac-
tion time (40% in 10 h in flow vs. 42% in 120 h in batch).
Scheme 78 Cu-based sensitized synthesis of
[5]Helicene.
The same group reported a different microflow photo-
reactor for the effective synthesis of carbazole deriva-
tives enabled by a [Cu(XantPhos)(dmp)]BF4 photocata-
lyst (Scheme 79).335 The reactor featured three 10 ml
units connected in series, each one irradiated with a 23
W CFL. Starting from triarylamines or tertiary diaryl
amines, a wide variety of N-substituted carbazoles were
successfully isolated in good to excellent yields (50-
95%) within a residence time of 10 hours, which was
considerably shorter than the corresponding batch
reaction (14 days).
Scheme 79 Visible light mediated synthesis of car-
bazoles.
Finally, a similar UV-induced strategy was applied to
enable the synthesis of the carbazole-containing anti-
inflammatory drug caprofene (80% yield in 3 hours).336
3.3.4 Cobalt complexes
Carreira and co-workers demonstrated the synthesis of
allylic trifluoromethanes starting from styrene deriva-
tives.337 2,2,2-trifluoroethyliodide was used as the cou-
pling partner and a triphenyltin-Co complex functioned
as the photocatalyst (Scheme 80). The reaction was first
optimized in batch, but due to the long reaction times
(24 h) it was later implemented in a commercially avail-
able millichip glass reactor. The reactor (8 mL internal
volume) was placed in between two water-cooled layers
and irradiated with an array of 48 blue LEDs (total
power 240 W). Conversions up to 65% were observed
within 30 minutes residence time. Next, the authors
assessed their previously reported intramolecular co-
balt-catalyzed alkyl-Heck cyclizations in flow. For this
reaction, similar conversions to those observed in batch
were obtained within only 30 minutes residence time
(vs. 24-48 hours in batch).
Scheme 80 Photocatalytic flow synthesis of allylic
trifluoromethyl substituted styrenes.
3.3.5 Decatungstates
Among polyoxometalates (POMs, i.e. transition metal
oxygen–anion clusters), decatungstates occupy an im-
portant position in photocatalysis.338 Particularly, the
71
tetrabutylammonium salt of decatungstate (TBADT) is
often used due to its absorption in the 350-400 nm
range. The excited state of decatungstate anion is par-
ticularly apt in hydrogen abstraction reactions from
unactivated alkanes. The selectivity of the reaction
depends on the accessibility of carbons, which can be
attributed to the size and charge of the photocatalyst.338
Recently, the Britton group reported the use of this
photocatalyst in continuous-flow microreactors. In
particular, a TBADT-catalyzed benzylic C-H fluorina-
tion with N-fluorobenzenesulfonimide (NFSI) was re-
ported.339 The only limit of the reported protocol lies in
the slow reaction time (typically 16 hours) due to ineffi-
cient irradiation. As a model reaction, the fluorination
of ibuprofen methyl ester was tested in flow. The use of
a flow reactor made of FEP tubing (3 m, 1.4 mL) coiled
around a black light tube (365 nm) resulted in a re-
duced reaction time, from 24 to 5 hours. Later, Britton
et al. published, in collaboration with researchers from
Merck, the C—H fluorination of leucine methyl ester in
flow with sodium decatungstate.340 The synthesis of γ-
fluoroleucine is of great interest, since this non-natural
amino acid is a crucial intermediate in the synthesis of
odanacatib. Odanacatib is a potent and selective ca-
thepsin K inhibitor, recently submitted to the FDA
(Food and Drug Administration) for final approval. To
underline the importance of this product, researchers
from Merck reported no less than six different synthetic
routes to this intermediate in the last ten years.341-345
The investigation started with the desamino derivative
of leucine, whose TBADT-catalyzed NFSI-mediated γ-
fluorination had already been reported.346 Switching to
leucine, the protection of the amine as a salt was need-
ed to prevent the direct reaction with the fluorinating
agent (Scheme 81). While the batch reaction took up to
18 hours, with a PFA capillary (ID 1.5 mm, 60 mL) coiled
around two black light tubes (16 W each), the reaction
was completed in flow within two hours. The setup was
tested on 190 mmol scale resulting in the formation of
the product in 90% yield (44.7 g), making this approach
the most feasible route to the product.
Scheme 81 Direct photocatalytic C-H fluorination
of leucine methyl ester.
72
Fagnoni and co-workers also used a TBADT-mediated
photocatalytic reaction for the synthesis of substituted
γ-lactones.347 The hydrogen atom transfer capabilities of
the photocatalyst were exploited to convert aliphatic
aldehydes into the corresponding acyl radical. This
radical then adds to an electron-poor double bond, and
the radical adduct is reduced by the catalyst via a back
hydrogen-atom transfer, yielding a γ-keto ester. To
afford the final compound, the ketone was reduced
with NaBH4 and engaged in an acid-promoted cycliza-
tion (Scheme 82). This reaction sequence was per-
formed both in batch and in flow. For the flow protocol,
a PTFE coiled reactor (ID 1.3 mm, 12 mL) was irradiated
with a medium pressure Hg lamp (125 W). Despite simi-
lar yields (66% in batch vs. 67% in flow), the flow pro-
cess was three time faster (2 h vs. 6h).
Scheme 82 Synthesis of γ-lactones via tetrabu-
tylammonium decatungstate-mediated photoca-
talysis in continuous flow.
In a follow-up paper, Fagnoni et al. further investigated
the reaction with different carbon-centered radicals
precursors and olefin partners, resulting in TBADT-
catalyzed acylation and alkylation reactions.348 The
photoreactor was upgraded to a preparative scale ana-
logue with FEP tubing (ID 2.1 mm, 50 mL) irradiated
with a 500 W medium pressure Hg lamp. A wide range
of aldehydes, amides and ethers were used as substrates
for H-abstraction, and coupled with several electron-
poor olefins (Scheme 83). The results obtained in flow
were then compared by means of green metrics to the
batch and batch solar counterparts. Thanks to the im-
proved light irradiation in flow, a higher substrate con-
centration could be used, resulting in a higher produc-
tivity (STY) and sustainability (process mass intensity,
PMI).
Scheme 83 Tetrabutylammonium decatungstate-
photocatalyzed acylation and alkylation in flow.
73
Heterogeneous photocatalysts
3.3.6 TiO2
TiO2 is the most widely used semiconductor photocata-
lyst for photochemical transformations. However, its
application remains mainly limited to the field of water
and air purification (see section 5.1.1).349-350 TiO2 is sensi-
tive to UV-radiation, however, progress has been made
in making TiO2 responsive to visible light, through so-
called doping. For a more detailed explanation of the
physical properties of this semiconductor and the
mechanism involved in its activity we refer to Section
5.1.1.
As a photocatalyst, TiO2 is exclusively used with a parti-
cle size in the nano range. Therefore, photocatalytic
reactions reporting its use are heterogeneous. Kappe
and co-workers developed a continuous-flow synthesis
of TiO2 nanocrystals capped with oleic acid.351 Such
nanoparticles could be efficiently dispersed in toluene,
creating concentrated colloidal dispersions. Their pho-
tocatalytic activity was tested for the tandem addition-
cyclization reaction of N-methylmaleimide and N,N-
dimethylaniline in continuous flow (Scheme 84). A
spiral of PFA capillary (ID 760 μm, 650 μL) was irradiat-
ed with UV-LEDs at 365 nm. A solution containing both
substrates and the TiO2 colloidal dispersion was recir-
culated in the microreactor. The desired tetrahydro-
quinoline was obtained in 91% yield after 5 h of reaction
time.
Scheme 84 Photocatalytic addition of N,N-
dimethylaniline to N-methylmaleimide.
To overcome the issues associated with the handling of
solid particles in microreactors (i.e. clogging/fouling), a
solution was found in the immobilization of the TiO2
nanoparticles on the channel of the microreactor, or on
a specific surface (i.e. membranes, filters). Thanks to
the use of microchannels, a large interfacial area can be
kept, which compares to the surface area observed for
the nanoparticles in suspension. Examples highlighting
the use of immobilized TiO2 include the synthesis of L-
pipecolinic acid starting from L-Lysine (Scheme 85).352
The reaction was performed in a Pyrex glass chip (770
μm x 3.5 μm) containing a Pt/TiO2 thin film (0.2 wt% of
Pt). Irradiation of UV light afforded 87% conversion of
the starting material in less than one minute, with a 70
times higher conversion rate compared to batch. How-
ever, no improvement was observed in the e.e., which
was similar to batch (around 50% in both cases).
Scheme 85 Photocatalytic synthesis of pipecolinic
acid in a microreactor.
74
3.3.7 Mesoporous graphitic carbon nitride
Mesoporous graphitic carbon nitride (mpg-C3N4) has
recently been reported as an efficient heterogeneous
photocatalyst.353-354 The activity of heterogeneous cata-
lysts is dependent on the area exposed to the light.
Light penetration in batch reactors is limited to the
outer layer of the reaction vessel, while theoretically, in
flow, a more efficient irradiation could be achieved.
However, as previously stated for titanium oxide, the
use of heterogeneous photocatalysts in continuous-flow
is not trivial.
Recently, Blechert and co-workers, reported a continu-
ous-flow radical cyclization catalyzed by graphitic car-
bon nitride.355 Since mpg-C3N4 has redox properties
comparable to ruthenium catalysts, the cyclization of
bromomalonates was chosen as a model reaction
(Scheme 86).356 Similar to the Ru photocatalysts, blue
LEDs can be used as an inexpensive and energy-
efficient light source. A packed-bed reactor was con-
structed loading a mixture of 2.5 wt% of photocatalyst
with silica and glass beads in a FEP capillary (ID 2 mm,
620 μL). Notably, the activity of the ground catalyst was
found to be higher than the non-ground one, indicating
that a particle size reduction caused by grinding led to
an increase of active surface. Interestingly, the presence
of triethylamine as a sacrificial electron donor was not
needed, suggesting the presence of a different reaction
mechanism compared to the homogeneous reaction
system. Indeed, changing the reaction solvent from
THF to deuterated THF resulted in a slower reaction
(from 99% to 15% conversion in 4 hours), indicating an
active role of the solvent in the reaction. Moreover, a
correlation was found between the rate of hydrogen
abstraction by the alkyl radical and the C–H bond dis-
sociation energy (BDE) values of the H-donor solvent.
Using optimized reaction conditions, an array of bro-
momalonates were cyclized in good to excellent yields
(74-99%), with the catalyst showing only a marginal
reduction in efficiency even after 60-70 reaction cycles.
Overall, the use of a heterogeneous catalyst, together
with the absence of any additive, made this reaction
sustainable.
Scheme 86 Continuous flow radical cyclization
photocatalyzed by graphitic carbon nitride.
Organic Photocatalysts
Organic photocatalysts have been utilized for single
electron redox pathways for decades, yet, in recent
years, they gained comparatively less attention than
metal complexes with organic ligands and heterogene-
ous catalysts.357-358 This is somehow surprising owing to
their lower cost, wide availability and synthetic versatil-
ity, often resulting in better performances than, e.g. Ru-
or Ir-based photocatalysis.359-363
3.3.8 Eosin Y
The use of the organic dye eosin Y as a photocatalyst
has recently emerged as a low-cost, metal-free alterna-
tive to transition metal complexes for visible light
transformations.45, 364 Noël and co-workers used Eosin Y
75
to enable the aerobic oxidation of thiols to disulfides
(Scheme 87).68 It was found that ruthenium and iridium
complexes were not suitable for this transformation.
Eosin Y provided a much reduced reaction time for the
conversion of p-methoxythiophenol to the correspond-
ing disulfide (full conversion in 16 hours, compared
with 50% of Ru and 10% of Ir catalyst). The optimized
reaction conditions (1 mol% catalyst loading, 1 equiva-
lent of TMEDA and ethanol as green solvent) were next
applied to flow, using pure oxygen in a Taylor flow
regime.51, 365 This flow regime allowed to overcome any
mass transfer limitations, which were present in the
batch protocol.51 An in-house developed photoreactor
was used, which was obtained by coiling PFA capillary
(ID 760 μm, 950 μL) around a disposable syringe
wrapped with aluminium-foil, and was irradiated with a
white LED strip.110 A variety of disulfides were synthe-
tized in excellent yields (87-99%) in only 20 minutes
residence time. Moreover, the precursor of the
nonapeptidic hormone oxytocin, was converted in wa-
ter to its active form through formation of an intramo-
lecular disulfide bridge with an irradiation time of 200
seconds.
Scheme 87 Eosin Y catalyzed aerobic oxidation of
thiols to disulfides in flow.
Noël et al. found that eosin Y was the best tradeoff
between conversion and scope in a screening of differ-
ent organic dyes for the perfluoroalkylation of het-
eroarenes.366 The perfluoroalkylation of N-
methylpyrrole with heptafluoro-1-iodopropane was first
investigated, both in batch and in flow (Scheme 88).
The same in-house reactor previously described was
used110, this time with a reactor volume of 480 μL. After
an initial base screening, TMEDA was chosen as sacrifi-
cial electron donor, and the catalyst loading was in-
creased to 5% to reach full conversion. Other perfluoro-
alkyl halides were used to afford the corresponding
perfluoroalkylated pyrrole and indole derivatives in
good yields.
Scheme 88 Metal-free trifluoromethylation of 5-
membered heterocyclic structures in flow.
Kappe and co-workers reported an eosin Y-mediated α-
trifluoromethylation of ketones via a continuous-flow
two-step process (Scheme 89).367 The ketone was first
converted to the corresponding silyl enol ether and
subsequently exposed to light irradiation in presence of
the photocatalyst and a suitable trifluoromethylating
agent (triflyl chloride, CF3SO2Cl). Using acetophenone
as model substrate, the nature of different photocata-
lysts was evaluated in batch. Also in this case, Eosin Y
proved to be a better photocatalyst than Ru(bpy)3Cl2,
both in terms of conversion and selectivity (respectively
76
85 and 95% for eosin Y vs. 20 and <10% for the Ru com-
plex). A continuous-flow process was designed for this
protocol, including a first reactor (2.0 mL) for the con-
version of the ketone into the silyl enol and a second
photoreactor (FEP, ID 3.2 mm, 28 mL, 30 W CFL) for
the trifluoromethylation step. Using this flow process, a
wide range of phenones and heteroaromatic ketones
were trifluoromethylated in good to high yields (56-
87%).
Scheme 89 Eosin Y photocatalyzed continuous-flow
trifluoromethylation of ketones.
A careful batch-to-flow comparison of an eosin Y cata-
lyzed reaction was carried out by Neumann and Zeit-
ler.309 The reductive dehalogenation of α-
bromoacetophenone catalyzed by eosin Y in the pres-
ence of DIPEA and Hantzsch ester, already reported in
batch,368 was reinvestigated in flow. A commercial glass
chip photoreactor (500 x 600 μm, 100 μL) was used and
subjected to green LED irradiation to match eosin Y
absorption maximum (λmax = 530 nm). The product was
obtained in 40 seconds to 20 minutes in flow, while
batch required 12 to 18 hours to reach a similar conver-
sion. Moreover, the authors reported an enantioselec-
tive reaction in flow, which was first reported by Nice-
wicz and MacMillan.305, 368 Using 0.5% of eosin Y and 20
mol% of imidazolidinone catalyst in flow resulted in a
similar yield and enantiomeric excess than observed in
batch. However, the reaction time was significantly
reduced (45 minutes vs. 18 hours).
77
3.3.9 Rose bengal
The role of rose bengal as photosensitizer for singlet-
oxygen mediated reactions has already been described
in a dedicated section (3.2.4). Recently, rose bengal has
also been proposed as an organophotocatalyst in other
photocatalytic synthetic transformations. For example,
Rueping et al. used Rose bengal for the continuous-flow
generation of α-aminoalkyl radical derived from N,N-
dimethylaniline and N-aryl tetrahydroisoquinoline.369
Known reactions from literature were converted to
continuous-flow using a FEP coiled reactor (ID 760 μm,
9.3 mL) irradiated with a green LED strip. N-aryl tetra-
hydroisoquinoline was reacted with nitroalkanes, cya-
notrimethylsilane, dialkyl malonates and dialkyl phos-
phites yielding the corresponding products in moderate
to excellent yields (49-92%) (Scheme 90) and with
shorter reaction time (3-5 h) compared to the original
reports. A similar acceleration of the reaction kinetics
was also observed in the oxidative Ugi multicomponent
reaction.369 Rose bengal also proved to be superior to
[Ru(bpy)3]2+ as photocatalyst for the flow hydroxylation
of phenyl boronic acid to phenols.370
Scheme 90 Nucleophilic trapping of -N-aryl tetra-
hydroisoquinolines in flow.
3.3.10 Xanthones
Kappe and co-workers reported a benzylic fluorination
in flow using Selectfluor as F-source and xanthone as
organic photocatalyst (Scheme 91).371 A photoreactor
made of FEP tubing (ID 1.6 mm, 28 mL) was coiled
around a glass cylinder and irradiated with a 105 W
black light CFL. With the optimized conditions (1.2 eq.
selectfluor, 5 mol% cat., MeCN 0.1 M) in hand, a wide
variety of fluorinated derivatives was obtained in good
to excellent yields (60-89%) with a residence time of 28
minutes. The advantages offered by the flow protocol
became clear in the fluorination of the common fra-
grance celestolide, which was unstable in acetonitrile.
However, by reducing the residence time to 9 minutes
and including an inline dilution of the reaction stream
with dichloromethane, the corresponding product
could be obtained in high yield (88%). This result high-
lights the potential of flow chemistry to provide a fine
control over irradiation/reaction time.
Scheme 91 Continuous flow benzylic fluorination
using xanthone as photo-organocatalyst.
Xanthone and thioxanthone have also been used as a
triplet sensitizer for the visible-light photocatalytic [2 +
2] cycloaddition of atropoisomeric maleimides with an
alkenyl tether (Scheme 92).372 High enantioselectivities
(e.e. > 99%) were observed both in batch and in a FEP
78
coiled reactor (ID 1.6 mm, 28 mL). Relative to the batch
process, the flow setup provided an increased efficiency
and scalability (full conversion in 60 min in flow vs. 18%
conversion in batch with the same conditions).
Scheme 92 photocycloaddition of atropoisomeric
maleimides.
4 Continuous-flow photochemistry in ma-
terial science
4.1 Polymer synthesis
Scheme 93 Polymer synthesis in microflow: (1) Pho-
topolymerization (2) Co-polymerization (3) Photo-
functionalization of polymers.
The synthesis of high performance polymeric materials
can be substantially facilitated by the use of microreac-
tor technology.373-376 Recently, the number of examples
showing efficient polymer synthesis in flow have in-
creased exponentially.373, 377 Among these studies, a
significant fraction utilizes light energy to initiate
polymerizations or to allow late-stage modification of
the polymer.378-383
The small length scales encountered in microreactor
technology provide several benefits for polymerizations
processes. First, the typical high surface-to-volume ratio
observed in microreactors allows a more effective con-
trol over highly exothermic polymerization reactions
(high heat transfer characteristics). Consequently, mi-
croreactors can be seen as near isothermal reactors and
provide equal processing conditions throughout the
entire reactor. Second, fast mixing allows to control
polymerizations with very fast kinetics, such as free
radical polymerizations (high mass transfer). Third,
microreactors provide a safe and reliable environment
for the handling of toxic and potentially explosive ma-
terials while being apt for harsh experimental condi-
tions (e.g. high temperature and pressure). Fourth and
specifically for photopolymerizations, an important
benefit is presented by the homogenous light irradia-
tion of the entire reaction mixture. Last, the often prob-
lematic scale-up of photopolymerizations can also be
addressed by using continuous-flow reactors. All these
benefits make microreactors ideally suited to prepare
high performance polymers with a narrow polydispersi-
ty index (PDI) and well-defined properties.
4.1.1 Continuous-flow synthesis of polymers
The flow photopolymerization of n-butyl acrylate was
one of the first examples reported.384 A glass serpentine
reactor with an internal diameter of 1.5 mm and a wall
thickness of 6 mm was subjected to UV irradiation. The
79
effect of photoinitiator concentration, light intensity
and exposure time were studied with respect to mono-
mer conversion, polymer PDI and molecular weight
distribution and the results were compared to thermal
polymerizations, both in microreactor and in batch.
The reaction kinetics were substantially faster for the
photoinitiated system in the microreactor (38 s vs. 180 s
to achieve ≈ 80 % conversion). Moreover, lower PDI
was observed in the microreactor compared to batch
(2.03 vs. 9.61). A follow-up paper investigated the effect
of the channel diameter (from 1.5 to 0.5 mm) and
demonstrated that a more uniform irradiation was
obtained in the narrow diameter reactor.385 This result-
ed in a higher conversion (≈ 15% more in flow within 9.5
s) and lower polymer branching (0.42 % molar branch-
ing at 30 °C by keeping the temperature constant,
1.334% molar branching without control over the tem-
perature). Efficient light distribution within the reactor
vessel becomes increasingly important when scattering
effects are more pronounced. Scattering phenomena are
observed in opaque systems, like emulsions or mini-
emulsions, which are commonly encountered in the
synthesis of hybrid polymer latexes.386
While translating their recently reported387 visible light-
mediated photocatalytic radical polymerization of
methacrylates to flow, Poelma, Hawker and co-workers
undertook an extensive screening of tubing materials
(Scheme 94).388 For their air-sensitive reaction, it was
found that the oxygen permeability of the channel was
more important than its light transparency. In particu-
lar, a reactor made of Halar tubing (ID 500 μm, total
length 550 cm) performed slightly better than Tefzel,
FEP and PFA (Halar has a 35 time lower oxygen perme-
ability). Yet, the increase in reaction rate was only 30%,
while the polymer PDI was in the same range as the
corresponding batch protocol.
Scheme 94 Influence of tubing material on conver-
sion and polydispersity index in the visible light-
mediated photocatalytic radical polymerization of
methacrylates.
80
The same tubing material has been used successfully by
Chen and Johnson.389 Halar tubing (ID 760 μm) was
coiled around a glass bottle and irradiated by UV lamps.
This setup enabled the photocontrolled radical
polymerization (photoCRP) of trithiocarbonates in flow
(Scheme 95).
Scheme 95 Continuous-flow photocontrolled living
radical polymerization of trithiocarbonates.
Compared to batch, this setup exhibited a four-fold
increase in reaction rate and allowed to achieve mo-
lecular weights above 100 kDa and narrow PDIs (1.09-
1.19). Interestingly, those excellent results could be
achieved as well with challenging triblock copolymers.
The scale-up potential of continuous-flow microreac-
tors was proven by synthetizing 2.95 grams of
poly(DMA) (DMA = N,N-dimethylacrylamide) in 400
minutes.
Gardiner and co-workers reported a photo-initiated
RAFT polymerization of methacrylates and acrylamides
in a continuous-flow reactor.390 PFA was preferred as
material for the tubing due to its high transparency
(better than Tefzel and Halar) and increased durability
(compared to FEP). The oxygen permeability of the
capillary was circumvented by continuous flushing of
the reactor coil with a pre-cooled nitrogen stream, serv-
ing both as cooling agent and inert gas. A commercial
photoreactor (ID 1.3 mm, 10 mL) was irradiated with a
medium pressure mercury lamp (150 W). Depending on
the molar ratio of RAFT agent and photoinitiator, full
and fast conversion with high polydispersity (5 min at
30 ˚C, PDI > 1.5) or good conversion with control over
molecular weight and polydispersity (PDI < 1.3)were
achieved.
The copper-mediated photocontrolled radical polymer-
ization of methyl acrylate has been performed in milli-
and microreactors by Junkers and co-workers.391 For the
milli setup, 25 m of PFA tubing (ID 750 μm, 11 mL) was
coiled around a 400 W medium pressure UV-lamp,
while the glass chip microreactor (19.5 μL) was placed
under a UV flood lamp. Low dispersity indexes and high
conversions were obtained in both reactors (e.g. PDI =
1.16 for a diblock copolymer in the microreactor) within
very short residence times (maximum 20 minutes). A
later paper from the same group reports the flow condi-
tions for the synthesis of methyl acrylate/methyl meth-
acrylate (MMA) block copolymers. The reactor consists
of 25 m PFA tubing wrapped around a quartz glass tube
(ID 750 μm) in which a 15 W 365 nm UV lamp was
placed.392 Similar PDIs were obtained (1.15-1.37 in batch,
1.15-1.40 in flow) but the reaction time was significantly
shortened in flow (3-7 h in batch, 5-60 min in flow ow-
ing to the higher irradiation efficiency).
81
The improved thermal control of microreactors can also
impact the quality of the polymer. In a recently report-
ed photoinduced Co-mediated radical polymerization,
Junkers, Detrembleur and co-workers, observed that
the reaction could be carried in flow (19.5 µL glass chip)
at elevated temperatures without the formation of
crosslinked side-products, which are typically observed
in batch experiments.393 Furthermore, a 4-fold accelera-
tion in reaction rate was observed compared to batch.
4.1.2 Late-stage modification of polymers
Late-stage chemical modification of polymers is often
regarded as challenging because of the difficulty in
obtaining a site-selective functionalization while keep-
ing the main polymer chain intact. This strategy is of
high interest as it allows to rapidly tune material prop-
erties by preparing a large panel of slightly modified
polymers derived from a common lead polymer.
Seeberger and co-workers reported the innovative use
of a photochemical [2+2] cycloaddition to afford glyco-
conjugated polymers (Scheme 96).394-395 These designed
polymers are obtained by an UV-induced reaction be-
tween a polylysine polymer bearing a maleimide motif
and a nonapodal or tripodal sugar-based dendrimer,
which is decorated with an alkyne moiety. The reaction
was carried out in water at room temperature in a con-
tinuous-flow microreactor (FEP tubing, ID 760 μm, 450
W medium pressure mercury lamp). A set of glyco-
dendronized polylysines were obtained within 40 min
residence time in good to excellent yields. The flow
protocol provided a fast and easily scalable synthetic
route. These photofunctionalized polymers were subse-
quently assessed for their ability to act as probes for the
detection of mannose-binding invasive strains of E.
Coli, displaying optimal binding selectivity and sensitiv-
ity towards the tested pathogens. The same group later
reported the synthesis of sequence-defined carbohy-
drate-functionalized poly-oligo(amidoamine) polymers
via a photochemical thiol-ene coupling in continuous-
flow.394-395
82
Scheme 96 Continuous-flow functionalization of polymers with glyco-dendronized polylysine via a [2+2]
photocycloaddition. The biocompatible products are used for the detection of bacteria.
83
As demonstrated above, continuous-flow [2+2] cy-
cloadditions can be regarded as smart tools for various
site-selective modifications of polymeric structures in a
time-efficient fashion. Furthermore, flow procedures
provide means to rapidly fine-tune the reaction condi-
tions.396 For instance, Conradi and Junkers reported a
photoinduced [2+2] cycloaddition to provide a control-
lable switch to functionalize maleimide-containing
polymers with a small array of different alkenes
(Scheme 97).397 The reactor was made from transparent
PFA tubing (ID 760 μm, 11 mL) wrapped around a
quartz cooling mantle (4°C). The reactor was exposed
to UV irradiation from a 400 W medium pressure UV
lamp. The reported examples showed reduced reaction
times (several minutes) in flow under optimized reac-
tion conditions. Thioxanthone (TXS) was used as an
organic photosensitizer and further allowed to reduce
the amount of byproduct formation by avoiding photo-
degradation. Interestingly, the advantages of using TXS
for the [2+2] cycloaddition are not observed in batch.
Scheme 97 UV-induced cycloaddition for polymer
modification. The terminal maleimide group is
reacted quantitatively with a small array of alkenes
in 1 minute in a flow photomicroreactor.
4.2 Polymer particle synthesis
Polymer particles with a narrow polydispersity have a
broad application potential, e.g. chromatography, en-
capsulation of drugs, resins, optical data storage, etc.
Microreactor technology has made great contributions
in the fabrication of such monodispersed polymer par-
ticles, as this technique provides a great control over
particle size, shape and composition.398-404 However, it
must be noted that essentially all examples on the light-
assisted continuous-flow synthesis of particles use UV-
light exclusively for the final curing or solidification of
the particles,405 with their actual preparation based
mainly on micro-emulsification.406-407
Whitesides, Stone and co-workers have developed dif-
ferent microfluidic flow-focusing devices (MFFDs),
which allow to prepare polymer particles in various
shapes and sizes by a stringent control of the hydrody-
namics.408-409 MFFD are typically obtained in
poly(dimethylsiloxane) (PDMS) or in polyurethane
(PU) through standard soft lithography techniques.405,
408-409 These devices use a flow-focusing geometry inte-
grated in a planar microchannel design, as depicted in
Figure 19. Two immiscible liquids are forced through a
small orifice, with one liquid representing the dispersed
phase, flowing in the central channel, and another im-
miscible liquid, representing the continuous phase,
flowing through the outer channels. The pressure and
the viscous stress caused by the continuous phase on
the dispersed phase forces the latter into forming a
narrow thread that breaks up into small droplets when
84
passing through the orifice. The dispersed droplets,
flowing in the continuous phase, present monodisperse
or polydisperse patterns, and their size can be easily
fine-tuned by regulating flow rates through the orifice
as well as by other important variables (channel diame-
ter, interfacial tension, etc.). Notably, the produced
droplets are significantly smaller than the orifice, with a
particle size ranging in the order of hundreds of na-
nometers to micrometers. Once the droplets are re-
leased, they are collected and solidified via photochem-
ical or thermal methods.
Figure 19 (a) Representation of a MFFD associated
with light- (b) or thermally-induced (c) curing of the
droplets. Different droplets shapes can be prepared in
the microfluidic channel. When the droplet volume is
higher than the channel section, the spherical droplet
(d) is forced into a discoidal (e) or rod (f) shape. Re-
printed with permission from ref. 405. Copyright 2005
John Wiley & Sons.
Initially, all reported synthetic strategies for polymer
particles employed a two-stage process, including an in-
flow emulsification step followed by a subsequent batch
treatment for particle solidification.398 Around 2004-
2005, more reports appeared in which both steps were
carried out in continuous-flow.398, 405 Nevertheless, still
a lot of examples describing off-chip photopolymeriza-
tion are reported in current literature,410-411 however, a
full description of all these methods is beyond the
scope of this review.
MFFDs employing a downstream photopolymerization
step have been extensively reported in the literature
and have been applied for the fabrication of several
microparticles, including liquid-containing capsules.412-
413 By means of a constriction module (i.e. a channel
morphology change), placed after the emulsion for-
mation and before the UV-induced hardening step, it is
also possible to shape the particles into cylinders414 or
disks (Figure 19).398, 415 In-situ UV polymerization has
also been used to encapsulate and protect crystalline
colloidal arrays from ionic impurities.99, 416
Kumacheva and co-workers reported a microfluidic
synthesis of Janus and three-phase particles.407 This was
achieved by an emulsification of immiscible monomer
liquid streams followed by a photopolymerization of
the monomer droplets to a solid state. The desired
droplets were formed through the use of a MFFD and
were irradiated by a 400 W UV-light source to induce
photopolymerization (Figure 20). The Janus and ternary
particles could be obtained in a size range from 40 to
100 μm, with high control over their structure and par-
ticle size distribution, which was provided by careful
changes in flow rates.
85
Figure 20 (a) Generation of Janus droplets irradiated
with UV light in the downstream channel (b) Optical
image of the droplet formation in the MFFD. Reprint-
ed from ref. 407. Copyright 2006 American Chemical
Society
Other reports showed diverse synthetic strategies for
the photoassisted formation of Janus particles in micro-
fluidic devices.417-418 Through a MFFD, monodispersed
colloid-filled hydrogel Janus granules were obtained
using a simple Y-junction operated at low flow rate to
minimize the mixing between the co-flowing streams.417
Consequently, convective mass transport across the
interface can be avoided and even Janus particles from
miscible solutions can be made. Later on, a more broad-
ly applicable fabrication of Janus particles from highly
diverse immiscible fluids was reported, with an empha-
sis on the formation of particles featuring both a hy-
drophilic and lipophilic part, dispersed in different
carrier mediums.418
An operationally simple microfluidic device for the
synthesis of polymeric beads was reported by Serra and
co-workers.419 The device essentially consists of a T-
junction in which a needle delivers the dispersed phase
into the continuous phase (Figure 21). The formed
droplets are introduced in a transparent PTFE tubing
exposed to UV-light. This design allows to focus the
particle formation towards the channel center and pre-
vents the adhesion of the particles to the channel wall.
Consequently, microreactor clogging can be avoided.
An additional advantage is that the PMMA beads could
be produced without using any surfactant. Finally, the
polymer particles are collected in a convergent pipe
ending in a clogged needle to stack them and create a
necklace-like structure. This device was successfully
applied by the same group to the continuous-flow en-
capsulation of ketoprofen. The beads proved to be suit-
able for use in drug delivery sytems.420
Figure 21 Schematic representation of the setup used
by Serra and co-workers. The device consists of a T-
junction in which a needle delivers the dispersed
phase into the continuous phase. Polymerization
occurs downstream under UV-irradiation. Reprinted
with permission from ref. 419. Copyright 2008 Elsevier
86
To increase the UV exposure time while keeping a high
flowrate in the droplet formation zone, Zourob et al.
etched a spiral microflow reactor with an increased
channel size in the polymerization part (from 200 x 200
μL to 500 x 300 μL).421 This reactor was subsequently
applied in the synthesis of polymer beads, which were
molecularly imprinted with propranolol.
Another easy and reliable strategy to obtain monodis-
perse monomer droplets in microfluidic devices is the
perpendicular insertion of a needle into the continuous
phase tubing (Figure 22).
Figure 22 A schematic drawing of the microfluidic
device used by Du Prez and co-workers. A needle de-
livering the reagent phase was inserted perpendicu-
larly into the continuous phase, thus creating mono-
disperse monomer droplets. Polymerization under
UV-irradiation afforded the functionalized polymer
beads. Reprinted with permission from ref. 422. Copy-
right 2010, The Royal Society of Chemistry.
This approach was applied by Du Prez and co-workers
to prepare functionalized macroporous polymer beads,
useful as supports for solid phase peptide synthesis
(SPPS).422-423 Similarly, high internal phase emulsion
(HIPE) acrylates droplets were photopolymerized in
flow. This allowed to prepare highly porous capsules,
which were further functionalized with azide functional
groups for Copper(I)-catalyzed Azide-Alkyne Cycload-
dition (CuAAC).424
To increase the throughput of microfluidic devices and
to match the productivity demands of industrial appli-
cations, Nisisako and Torii reported a numbering-up
design fitting 256 droplet-formation units on a 4.2 x 4.2
cm squared chip with only two inlets (continuous and
dispersed phase) and a single outlet.425 Production of
both homogeneous and biphasic Janus particles with a
coefficient of variation (CV) as low as 1.3% was feasible
and a throughput up to several kilograms per day was
obtained. Compared to other numbering-up strategies,
this approach made a more efficient use of the UV light
source for the photopolymerization process.
Figure 23 Scale-up of a microfluidic flow-focusing
device (128 channels). Reprinted with permission
87
from ref. 425. Copyright 2008 The Royal Society of
Chemistry
Wen and co-workers reported the manufacturing of
porous polymer particles through a binary UV-induced
reaction.426 H2O2 droplets were first encapsulated into a
liquid photocurable polymer precursor mixture of
tripropylene glycol diacrylate (TPGDA) using liquid
paraffin as the continuous phase. Polymer microspheres
containing various amounts of H2O2 were obtained by
controlling the flow rates of the continuous medium
and by the addition of polyvinyl alcohol (PVA) as sur-
factant. After the initial formation, the microspheres
were delivered to a larger diameter tubing where the
photopolymerization of the polymer precursor and the
H2O2 decomposition, with release of O2, were carried
out simultaneously. This strategy provided highly po-
rous poly-TPGDA microspheres, with a maximum void
of 70%.
An interesting application constitutes the manufactur-
ing of hydrogel particles containing an enzyme.427 Here-
to, a hydrogel solution, containing the biocatalyst, is
introduced in the microfluidic device and is surrounded
by an immiscible mineral oil isolating it form the reac-
tor wall. The obtained hydrogel droplets can be subse-
quently polymerized under UV light irradiation. This
strategy enables simultaneous microbead formation
and enzyme immobilization. Notably, no noticeable
deactivation of the biocatalyst was reported. Several
attempts for the continuous-flow encapsulation of cells
in polymer microgels were also described. However,
photopolymerization is often avoided in these applica-
tions because of the negative influence of UV irradia-
tion on the cells.428 One example reported the synthesis
of acrylate-based microcapsules containing yeast
cells.429 By virtue of almost instantaneous photopoly-
merization, solidification of the capsules was achieved
rapidly without any consequences for the cell function-
alities.
Hollow particles and microcapsules were also obtained
via photopolymerization strategies in microfluidic de-
vices. Tunable hollow microcapsules featuring a poly-
meric shell and a hydrophilic core are of great interest
for drug delivery systems. These capsules provide a
triggered release of the Active Pharmaceutical Ingredi-
ent (API), which can be obtained through a post-
administrational control of the polymeric layer. Lee and
co-workers reported the continuous-flow synthesis of
monodispersed poly(n-isopropylacrylamide) (PNIPAM)
microcapsules through a photopolymerization reaction
occurring at the interface of two immiscible phases.430 A
water dispersed phase containing NIPAM and a cross-
linker, and a hexadecane continuous phase containing a
photoinitiator were pumped in the microfluidic device
and resulted in the formation of microdroplets. Next,
the monomer and the cross-linker migrated to the sur-
face of the droplet, while the photoinitiator diffused
from the continuous phase to the particle surface. Upon
UV irradiation, a photopolymerization process occurs
at the particle shell, delivering aqueous core-polymer
shell hollow microcapsules (Figure 24).
88
Figure 24 Schematic diagram of the MFFD employed
to synthesize monodisperse hollow particles and
microcapsules. (a) Droplets formed in the aqueous
dispersed phase, (b) enlarged representation of the
NIPAM and cross-linker (BIS) containing droplets in
the hexadecane phase, (c) UV-induced interfacial
photopolymerization, (d) final microcapsule. Re-
printed with permission from ref. 430. Copyright 2008
The Royal Society of Chemistry
Using a similar strategy, Chu and co-workers obtained
poly(hydroxyethyl methacrylate-methyl methacrylate)
(poly(HEMA-MMA)) hollow and porous microspheres
through the use of a glass MFFD for the preparation of
monodispersed oil-in-water microcapsules.431 The inter-
face-initiated photopolymerization was used to obtain a
hollow particle solidification, while polymerization on
the inside of the particle in presence of an appropriate
porogen agent was used to encapsulate porous micro-
spheres.
Asua and co-workers reported a mini-emulsion photo-
polymerization in flow to prepare waterborne polyure-
thane/acrylic hybrids. A photopolymerization in an
aqueous dispersed medium could be carried out with a
20% solid content emulsion in water without reactor
clogging.432 An isocyanate terminated polyurethane
(PU) was mixed with a liquid stream containing acry-
late monomers, 0.4% of 2-hydroxyethyl methacrylate
(HEMA), and variable amounts of photoinitiator. The
miniemulsion was introduced into a reactor made of 15
quartz tubes of 40 cm length with an inner diameter of
1 mm. The reactor was subjected to UV light to promote
the acrylate photopolymerization. During this process,
the isocyanate moiety of the PU reacts with the free
hydroxyl of the HEMA monomer in the acrylate poly-
mer yielding a sol-gel hybrid latex. In the absence of
polyurethanes, only the acrylate sol suspension was
observed. Monomer conversion was increased with
prolonged residence times and increasing photoinitia-
tor concentrations. By tuning the process parameters, a
broad range of gel contents (from 0.4 to 0.7) and sol
molecular weights (from 30 to 160 kDa) were obtained.
On the other hand, when using the same formulation
(in the absence of any photoinitiator) at 70 ˚C in a re-
dox mini-emulsion polymerization, only a latex could
be obtained with a gel content of 0.62 and molecular
weight of the sol of 214 kDa. This setup could not be
applied directly to the synthesis of adhesives due to the
relatively low solids content (20 wt%). Higher solid
loadings resulted in reactor clogging due to the adhe-
sion of the polymer to the channel wall. A detailed
study of the clogging mechanism provided insights to
design a new reactor made of two distinct sections.433
The first section was optimized to obtain a monomer
conversion of about 45% and was made of low surface
energy material (i.e. silicone) to avoid interaction of the
channel wall with the polymeric droplets. The second
section was made from quartz material which provided
a high UV transparency for the photopolymerization.434
89
With the improved reactor design, mini-emulsion pho-
topolymerization with a solid content up to 46 wt% was
possible, allowing the continuous-flow synthesis of
pressure sensitive adhesives.435 Despite the time-
consuming optimization of the reactor to avoid clog-
ging,436 the tunable characteristics of the system finally
afforded hybrid polymer with diverse polymerization
rate and microstructure. The irradiation parameters
were then related with the performances of the adhe-
sives. In Figure 25, a probe-tack test, indicative for the
stress resistance of pressure sensitive adhesives, shows
how the different intensity of irradiation influences the
performance of the hybrid polymer.
Figure 25 Effect of irradiation power on pressure sen-
sitive adhesive performance in a probe-tack test. Re-
printed with permission from ref. 435. Copyright 2014
Elsevier
MFFD were also successfully applied to the synthesis of
tripropylene glycol diacrylate and acrylic acid copoly-
meric particles.437 The heat generated by the exother-
mic acrylate photopolymerization has been exploited by
Li et al. to trigger a second reaction, i.e. the polycon-
densation of a urethane oligomer yielding polymeric
particles with an interpenetrating polymer network
structure.438
The synthesis of magnetic microparticles by MFFD has
proven challenging due to the high UV absorption of
inorganic materials preventing an efficient photopoly-
merization of the droplets. To address this issue,
Hwang et al. embedded a piece of aluminum foil in the
microfluidic chip as back reflector for the UV-exposed
region.439 This offers a multidirectional light exposure
and an increased UV energy flux to the droplets, thus
preventing shape deformation. In this way, magnetic
hydrogel microparticles exhibiting a superparamagnetic
behavior were obtained in sphere, disk and plug shape.
Figure 26 Microfluidic flow-focusing device applied to
the synthesis of magnetic microparticles. Reprinted
with permission from ref. 439. Copyright 2008 The Roy-
al Society of Chemistry
Doyle and co-workers reported the first example of
continuous-flow lithography.440 This technique relies on
the combined use of microfluidic technology and mi-
croscope projection photolithography to afford the
continuous-flow synthesis of complex shaped and Ja-
nus-like polymer particles. The simple yet effective
setup, features a PDMS device through which an acry-
90
late oligomer stream containing a photoinitiator is
flown. A transparent mask, containing the planar ge-
ometry of the desired particle, is inserted in the field-
stop plane of an inverted optical microscope. Through
the microscope objective, the size of the printed geome-
try on the transparent mask is reduced by 7.8 up to 39
times. A pulsing UV beam exiting the microscope is
focused on the PDMS device, causing the ultra-rapid (<
0.1 seconds) continuous photopolymerization of the
polymeric monomer. This results in the formations of
particles with a mask-defined shape (Figure 27).
Figure 27 Schematic representation of the continuous-
flow lithography setup. The transparency mask be-
tween UV light source and objective determines the
shape of the polymerized objects. Reprinted with
permission from ref. 440. Copyright 2006 Nature Pub-
lishing Group.
Furthermore, the presence of molecular oxygen, which
diffuses from air through the gas-permeable PDMS
reactor walls, enables the formation of a non-
polymerized monomer layer at the surface of the mi-
crochannel. This layer acts as a lubricant and facilitates
the freshly formed particle to flow out of the reactor. It
was postulated that the role of oxygen in preventing
polymerization close to the PDMS walls derives from its
interaction with the photogenerated free radicals, form-
ing chain terminating peroxide species. Through this
successful strategy, a broad array of different particles
was synthesized, as represented in Figure 28. The parti-
cle planar geometry corresponds to the dimensions
obtained after reduction of the image by the micro-
scope objective, while its height corresponds to the
difference between the channel height and the lubrica-
tion oxygen layers. With the same device, Janus parti-
cles could be prepared, adding the unprecedented pos-
sibility to control the proportion of the two constituting
chemical entities. This was achieved by adjusting the
position of the light beam in the channel and the thick-
ness of the flowing streams.
Figure 28 Array of shapes obtained through continu-
ous-flow lithography. A-C: Flat structures (20-µm-high
channel). D: Cuboid ( 9.6-µm-high channel). E-F:
High-aspect-ratio structures (38-µm-high channel). G-
I: Curved particles (20-µm-high channel). Reprinted
with permission from ref. 440. Copyright 2006 Nature
Publishing Group
The limitations of continuous-flow photolithography lie
in the optical resolution and depth of field of the in-
verted microscope, with the former influencing the size
of the smallest attainable particle, and the latter caus-
91
ing the edges to bevel. To circumvent these technical
obstacles, stop-flow lithography and analogous strate-
gies were successfully introduced.402 Due to their non-
continuous nature, they will not be treated in this con-
text.441-443 The continuous-flow lithography technique
has also been applied to the synthesis of self-assembled
amphiphilic polymeric microparticles444 and multifunc-
tional encoded particles for high-throughput assays.445
4.3 Nanoparticles
4.3.1 Polymer-based nanoparticles
Seminal work on polymeric nanoparticle synthesis in a
photochemical reactor was reported in 2014 by
Chemtob and co-workers.446-447 Microemulsions, con-
taining monofunctional acrylates or difunctional thiol-
ene monomers in presence of a photoinitiator, were
prepared in water through high shear homogenization.
The prepared microemulsions were flown through a
microreactor with a volume of 1.7 mL and an inner
diameter of 1 mm. The reaction stream was irradiated
with two 36 W UV lamps.446 The difunctional thiol-ene
monomers afforded the formation of a linear
poly(thioether) latex and performed better than the
acrylates in terms of yields, with full conversion ob-
served within 10 min (latex size 155 nm). Acrylates and
methacrylates showed only partial conversion at room
temperature, but their reactivity was improved either
by decreasing the initial particle size of the microemul-
sion or by increasing the reaction temperature. This
provided polyacrylate latexes with a particle size rang-
ing from 75 and 125 nm.
4.3.2 Metal-based nanoparticles
Particularly challenging and interesting for their appli-
cation in different fields (e.g. catalysis, biomedicine,
surface-enhanced Raman scattering) is the synthesis of
noble metal nanoparticles with a high degree of homo-
geneity in size and shape.448 Only a limited amount of
reports account for continuous-flow photochemical
synthesis of metal nanoparticles.115, 449-450 Carofiglio and
co-workers reported two different microfluidic setups
for the photochemical nucleation (under a UV mercury
lamp) and the light-induced shape-selective growth of
silver nanoparticles (under monochromatic LED irradi-
ation).115 By selecting the proper irradiation wavelength,
silver nanoparticles (AgNPs) could be converted into
larger spherical, decahedral or triangular nanoparticles
(Figure 29).
Figure 29 UV-Vis spectra of the silver nanoparticles
colloids obtained after irradiation at different wave-
length. Solid black line: pristine sample; circles: after
irradiation at 627 nm; dash-dotted line: after irradia-
tion at 455 nm; dotted line: after irradiation at 627 nm.
Reprinted with permission from ref. 115. Copyright 2012
The Royal Society of Chemistry
Micro-segmented flow regimes are an interesting flow
pattern to prepare narrow-sized nanoparticles.451 In a
micro-segmented flow an immiscible phase, often re-
ferred to as carrier medium, is used to break the con-
tinuous phase in discrete and reproducible slugs or
92
droplets (Figure 30). In such a droplet, toroidal vortices
are established which enable a fast and intensified mix-
ing. Segmented flow regimes in microreactors are con-
sidered to be ideal plug flow reactors in which all the
fluid elements have the same residence time distribu-
tion. This is especially important for the preparation of
nanoparticles, as differences in residence time will lead
to a broader size distribution. Furthermore, the homog-
enous and fast convective mixing in segmented flow
prevents the formation of localized concentration gra-
dients. In the case of a droplet segmented-flow, an
additional advantage is given by preventing the reacting
phase from being in contact with the microreactor
wall.452 Such particle-wall interactions often lead to
nanoparticle aggregation and thus reactor fouling.
Figure 30 Comparison of continuous (a) and segment-
ed (b, c) flow regimes in circular channels. The para-
bolic velocity profile of continuous-flow is prevented
by slug flow when an immiscible phase is present.
Recently, the first photochemical synthesis of gold
nanoparticles in a continuous-flow process was report-
ed by Hafermann and Köhler.449 A solution of tetrachlo-
roaurate and a solution of the photoinitiator and poly-
vinylpyrrolidone were mixed in a segmented flow by
using a crossed mixer. The originated segments exhibit-
ed an ID of 500 μm and were irradiated under UV light.
It was found that particles which were subjected to
prolonged UV exposure, were significantly smaller than
those obtained with shorter UV exposure times (2.5 vs 4
nm respectively). This can be rationalized by consider-
ing the radical concentration in the channel. Longer
exposure times result in the formation of larger initiator
concentrations for the same quantity of metal, causing
a higher amount of gold particles to start nucleating
independently. The same group later reported the con-
tinuous-flow synthesis of other noble metal nanoparti-
cles, such as platinum, palladium, rhodium and iridium
particles, in the range of a few nanometers (2.5 nm) by
using the same microfluidic device.453
A borderline case between inorganic and polymer-
based particle synthesis is represented by the work of
Serra, Köhler and co-workers.454 The authors reported a
continuous-flow preparation of homogeneous polymer-
ic microbeads filled with ZnO and Au nanoparticles.
Similarly, Kim, Lee and co-workers reported the prepa-
ration of monodispersed inorganic-organic hybrid Janus
particles, featuring a perfluoropolyether-based hydro-
phobic lobe and a more hydrophilic carbosilane-based
hemisphere.455
93
5. Continuous-flow photochemistry for
water treatment
5.1 Water purification
Due to the rapid depletion of clean water sources on
the planet, together with the unsustainable rate of pop-
ulation growth, the need to develop technologies for
the recycling of wastewater is as relevant as ever.456
Additionally, the strict policies regulating the standards
of wastewater pollution for industrial applications im-
pose the need for effective decontamination treatments.
Current purification methods, based primarily on phys-
ical separation of contaminants and biological oxida-
tion, fail to provide an efficient solution for the decon-
tamination of toxic, non-biodegradable organic com-
pounds. In this context, Advanced Oxidation Processes
(AOPs), employing highly reactive oxygen species,
prove to be one of the most efficient processes for water
purification.457-458 Among these, photocatalytic reactors
represent a promising solution to facilitate highly effi-
cient and sustainable water treatments.459
In photocatalytic reactors, highly reactive oxygen spe-
cies are generated through heterogeneous or homoge-
neous photocatalysis by means of UV and/or visible
light irradiation.460 In both cases, the in situ photogen-
erated reactive oxygen species (ROS) afford disinfection
of water pathogens through peroxidation of the phos-
pholipids in the lipid membrane.461 This results in the
progressive loss of cell functions and, eventually, leads
to cell death. Organic water contaminants can be min-
eralized by the in situ photogenerated ROS through
partial or complete oxidation, ultimately yielding CO2,
H2O and environmentally friendly byproducts.
With a few exceptions, heterogeneous photocatalysis
for water treatment coincides with TiO2 photocatalysis,
while homogeneous photocatalysis is mainly represent-
ed by iron-catalyzed photo-Fenton reactions.462
To date, the main application for TiO2 and photo-
Fenton reactions are large scale solar photocatalytic
treatment plants.116-117, 463 Several examples show the
efficiency of solar plants in the removal of different
contaminants from wastewater including reports of
demineralization of recalcitrant contaminants.464-466
Solar photocatalytic plants are generally operated in
recirculating batch mode, therefore their description is
beyond the scope of this review. For an extensive review
on the design and optimization of solar plants for water
treatment, we refer to the work from Malato et al.467-468
Figure 31 Solar detoxification plant “SOLARDETOX”.
Left: TiO2 separation system; right: solar parabolic
collectors. Reprinted with permission from ref. 467.
Copyright 2009 Elsevier.
In the next sections, both TiO2 and iron catalyzed pho-
to-Fenton reactions will be discussed, mainly focusing
on examples of microreactors for water treatment.
5.1.1 Decontamination with TiO2
Heterogeneous photocatalysis for water treatment is
primarily based on the use of semiconductor catalysts,
94
with TiO2 being by far the most commonly used.469
Unlike other known semiconductors (e.g. ZnO, CdS and
GaP), nanoscale TiO2 features a high reactivity upon
irradiation between 300 and 390 nm and a high stability
during consecutive catalytic cycles.467 Additionally,
operational advantages regarding the use of TiO2 lie in
the room temperature and atmospheric pressure condi-
tions. The solid photocatalytic particles used for water
purification are in the nanoscale range (typically ≈ 25
nm). This small size affords a large surface area and
optimal interaction with the pollutants; moreover, TiO2
nanoparticles have enhanced capacity to scatter UV
light, when compared to the bulk material.470 This can
easily be explained by taking into account that light
scattering is governed by Rayleigh’s theory471 for fine
particles, while the bulk metal oxide abides to Mie’s
theory.472 As a consequence, bulk TiO2 is a white opaque
material able to scatter visible light, while TiO2 nano-
particles are transparent to visible light but scatter UV
light efficiently.
In photocatalytic reactors, TiO2 nanoparticles are either
dispersed in the liquid phase (i.e. slurry reactors) or
immobilized on a solid support (i.e. packed-bed or wall-
coated reactors). For the comparison of the different
reactors and their operational conditions, the golden
standard is represented by the Degussa P-25 TiO2 cata-
lyst473 containing 75% of TiO2 anatase and 25% rutile.474
Mechanism of TiO2 decontamination
Examples of the photocatalytic properties of TiO2 have
been extensively reported in literature, demonstrating
its ability to allow both reductive and oxidative reaction
pathways.475 This reactivity is due to the peculiar char-
acteristics of the lone electron pair in the external or-
bital. This lone electron pair can be photoexcited when
the TiO2 surface is irradiated with light of higher energy
than the band gap between the valence and conduction
band of the catalyst. This band gap corresponds to pho-
tons that have an energy between 3.0-3.2 eV (depending
on the polymorphous form considered). Consequently,
UV light with λ < 400 nm is needed for the excitation.
The direct effect of the photoexcitation is the formation
of an electron-hole pair (e--h+), enabling a series of
chain oxidative-reductive reactions on the surface of
the catalyst.
𝑇𝑖𝑂2 ℎ𝜈→ 𝑒− + ℎ+ (4)
The interaction of the electron-hole pair with water
generates superoxide and hydroxyl radicals, as shown in
the following equations.
𝑂2 + 𝑒− → 𝑂2
∙ − (5)
𝑂𝐻− + ℎ+ →𝑂𝐻∙ (6)
It is widely accepted that the presence of radical scav-
engers is crucial for an efficient photocatalytic
process.457 These scavengers prevent the recombination
of the photoexcited electrons with the valence band.
Moreover, the presence of dissolved oxygen was found
to be essential in averting the fast recombination of the
electron-hole pair, by promoting the formation of a
superoxide radical (O2•–). This superoxide can subse-
quently be protonated to a hydroperoxyl radical (HO2•)
and, eventually, to H2O2. The presence of water mole-
cules is also a prerequisite for the formation of highly
reactive hydroxyl radicals.476
95
Reactor engineering aspects for continuous-flow
decontamination with TiO2
Crucial for the successful engineering of photocatalytic
reactors is the fundamental understanding of the indi-
vidual mechanistic steps occurring at the surface of the
TiO2 solid particle. The first step to be considered is the
mass transfer of the organic contaminants from the
water phase to the TiO2 surface (Scheme 98, step 1).
Mass transfer limitations are especially relevant in reac-
tors featuring TiO2 particles immobilized on an inert
support. In fact, the immobilization of the catalyst cre-
ates a lower surface area, reduces the number of active
catalyst sites and hinders the light penetration through
the catalyst layer, compared to slurry TiO2 particles.
However, due to the large surface-to-volume ratio char-
acteristic for microflow technology, mass transfer limi-
tations can be largely avoided.
Scheme 98 Mechanism of photodecontamination
with TiO2.
The second important step is the adsorption of the
pollutants onto the activated surface of the TiO2 nano-
particles (Scheme 98, step 2). A published report
proved the direct correlation between the rate of pho-
tocatalytic decontamination and the percentage of
molecules adsorbed on the photocatalyst.477 This find-
ing underscores the significance of the adsorption step
for the reaction efficiency. Similarly, the vicinity of
pathogens to the activated surface of TiO2 particles is
also crucial for photodisinfection.
Once the pollutants are adsorbed on the TiO2 surface,
the photocatalytic reaction can occur (Scheme 98, step
3) followed by desorption of the intermediate product
and a net diffusion from the surface to the bulk liquid
phase (Scheme 98, step 4 and 5).
Evidently, the overall reaction rate will depend mainly
on the slowest of these steps, i.e. the rate determining
step. In case of no mass transfer limitations, the con-
centration of the pollutants in the proximity of the
activated catalyst can be considered equal to the con-
centration in the bulk solution. In such cases, the reac-
tion rate will depend on the intrinsic reaction rate and
the photon transport efficiency. However, when mass
transfer limitations do occur, preventive measures can
be taken by carrying out the reaction in a microreactor.
Further intensification of the transport phenomena can
be achieved by increasing the flow rate or by reducing
the channel diameter.
Up to date, the major drawback for the industrial scale
application of TiO2-based AOPs lies in the post-
operational separation of the photocatalyst from the
slurry.459 Importantly, particle agglomeration of TiO2, a
direct consequence of its fine size particle and large
surface energy, hampers the post-separation, prevents
the particle size preservation, and shortens the lifespan
of the catalyst. To circumvent the post-separation issue,
two main strategies are currently in use: (i) coupling
the photocatalytic reactor with systems capable of
96
physically removing the TiO2 particles, either by mem-
brane filtration,478 sedimentation,479 or cross-flow
filtration480 or (ii) immobilizing the photocatalyst on a
solid inert support.
Despite the aforementioned limitations of photoreac-
tors with immobilized TiO2 particles, great interest
remains for their possible application in large scale
plants, where the total removal of the metal oxide from
purified water needs to be guaranteed.
Several materials have been developed to enable the
immobilization of TiO2 nanoparticles, including meso-
porous clays,481-482 nanofibers483 and nanowires484. Mi-
crofiltrating photocatalytic membranes of different
materials have also been reported,485-490 with some ex-
amples displaying TiO2 particles embedded in the
membrane structure.491-493 In these systems, the photo-
catalytic degradation of the contaminants occurs at the
surface of the membrane with no need of post-
operational removal of the catalyst. Despite the conven-
ient design, these membranes are often subject to dete-
rioration and loss of the TiO2 layer. Other improve-
ments in the catalyst design have been achieved by the
so-called catalyst doping: metallic (Pt, Pd etc.) or non-
metallic (N, F, S etc.) elements can be incorporated on
the nanoparticle surface. Semiconductor doping allows
to narrow the energy band gap between the valence and
conduction band of the metal oxide catalyst, therefore
broadening its applicability to visible light excitation.
Because of the high costs associated with the use of
noble metals, the attention is now shifted to non-
metallic dopes, which are suitable for industrial scale
applications.89
The next paragraph will focus on examples of TiO2
immobilized microreactors, considering important
aspects in their design, applicability and scale up poten-
tial. For an extensive overview on the use of batch reac-
tor technology for water treatment, featuring both im-
mobilized and dispersed TiO2 particles, we refer to
specialized reviews.484, 494-498
Microflow reactors
The importance of an increased surface-to-volume ratio
in microflow reactors for water treatment is well exem-
plified by the UV-mediated N-alkylation of amines
reported by Matsushita et al (Scheme 99).114 The mech-
anism of this transformation involves the dehydrogena-
tion of the alcoholic solvent to form the corresponding
aldehyde and H2, followed by a condensation with an
amine-bearing substrate. Finally, the resulting imine is
reduced by H2 to yield the desired N-alkyl derivative. In
batch, the alkylation of benzylamine with ethanol oc-
curred in 4 hours with a yield of 84% using Pt-loaded
TiO2 and a 400 W high-pressure mercury lamp. In a
TiO2-coated microreactor (Figure 32) with UV-LEDs as
light source, the same reaction was observed with simi-
lar yield in only 6-150 seconds residence time.499-500 Both
the Pt-free catalysis and the acceleration effect were
attributed to the increased illuminated surface-to-
volume ratio obtained with microreactor technology.
97
Figure 32 Schematic view of the photocatalytic micro-
reactor for UV-mediated N-alkylation of amines. Re-
printed with permission from ref. 499. Copyright 2007
Elsevier.
Scheme 99 UV-mediated N-alkylation of amines
serendipitously discovered during wastewater
treatment degradation studies in a TiO2-
immbolized microreactor.
In microreactor devices, a substantial increase in specif-
ic photocatalytic surface area is observed due to the
high surface-to-volume ratio. Consequently, the rate
determining step for photocatalytic degradation be-
comes the oxygen concentration in water. For example,
in the branched microreactor proposed by Lindstrom et
al. the conversion rate for the degradation of methylene
blue increased by a factor five by adding gaseous oxy-
gen to the dye solution.501
The use of microreactor technology for photocatalytic
wastewater treatment with TiO2 also allows an im-
proved mass transfer to the heterogeneous photocata-
lyst.459 The absence of any mass transfer limitations was
confirmed in a microreactor employing TiO2 as photo-
catalyst. In this example, the reaction rate was only
limited by the low photonic efficiency of the immobi-
lized TiO2.93
In a recent comparison of different reactor designs for
TiO2-based photocatalytic wastewater treatment, a new
metric was introduced. The so-called photocatalytic
space-time yield (PSTY), accounts for the reactor space-
time yield normalized to the power of the light
source.502
𝑃𝑆𝑇𝑌 = 𝑆𝑇𝑌
𝐿𝑃 (7)
Where STY is the space-time yield and LP the lamp
power. In particular STY, for the comparison of the
continuous-flow examples, is calculated using a plug
flow reactor model.
𝑆𝑇𝑌 = 1𝑚3
𝜏 (8)
The lamp power (LP) is normalized to the reactor vol-
ume (V) expressed in cubic meters.
𝐿𝑃 = 𝑃 ×1𝑚3
𝑉 (9)
By means of this parameter the authors were able to
directly compare slurry and immobilized catalyst reac-
tors. The overall comparison showed that slurry reac-
tors performed better than the TiO2-immobilized ones.
Nevertheless, this difference in performance might be
attributed to the higher illumination efficiency ob-
tained in larger reactors. Even so, the microreactor
proposed by Visan et al. was found to be the best
among the immobilized catalyst reactors.503 The reactor
design is based on a chip obtained by bonding a TiO2
coated substrate with a PDMS slab featuring a ≈ 6 cm
long channel with a cross-section of 500 x 50 μm
(Figure 33). As outlined by Van Gerven and co-workers,
the performance of such a reactor is even more relevant
98
when taking into account that the light source (a 120W
arc-lamp) could be replaced by a more energy-efficient
UV-LED array.502 While there was no apparent impact
on the process performance, the use of UV-LEDs pro-
vided massive energy savings. The use of UV-LEDs to
promote TiO2-mediated photodegradation of pollutants
was first introduced by Ye and co-workers back in
2005.113
Figure 33 Production of microreactors for water
treatment with soft lithography and bonding on TiO2-
coated substrate. Reprinted with permission from ref.
503. Copyright 2013 Elsevier.
An overview of different nanoparticle-based photomi-
croreactors reported in the literature is summarized in
Table 4. One of the most studied model pollutants is
methylene blue. Nevertheless, its use has been criti-
cized because of its photosensitive nature, its compli-
cated degradation pathways and its possible adsorption
to hydrophobic materials (e.g. silica-gel used as support
for TiO2).504-505
Table 4 Microfluidic reactors used for photocatalytic water treatment.
Type of microreactor Light-source Model pollutant Channel size PSTYb
Capillary – single UV lamp (254 nm) Methylene blue 530 μm506-507 5.24 x 10-5
200 μm506-507 1.86 x 10-5
UV LED (365 nm) Rhodamine 6G 530 μm508
UV LED (365 nm) p-chlorophenol 500 μm509
UV LED (365 nm) Phenol 200-1000 μm510
UV-LED (365 nm) New coccine etc. 530 μm504
99
Capillary – array UV lamp (254 nm) Methyl orange 320 μm511 1.15 x 10-6
Chip – single channel UV-LED (365/385 nm) Bisphenol A etc. 500 x 100 μm114
UV-LED (365 nm) Cu-EDTA 100 x 19 μm512
UV lamp (352-368 nm) p-chlorophenol 1000 x 100 μm513
UV lamp (365 nm) Salicylic acid 1.0 x 0.5 mm514 2.59 x 10-3
1.5 x 0.5 mm514 3.45 x 10-3
2.0 x 0.5 mm514 5.19 x 10-3
Chip – array of channels UV LED (385 nm) p-chlorophenol 300 x 200 μm93 7.24 x 10-4
Chip – serpentine UV lamp (365 nm) Methylene blue 1 x 0.5 mm94
UV light Cortisone-21-acetate 500 x 50 μm503 1.08 x 10-2
UV light Methylene blue 500 x 100 μm483
UV light Dichloroacetic acid 500 x 500 μm515
UV-LED Methylene blue 100 x 40 μm516-517
UV-LED (365 nm) Several dyes 400 x 50 μm518 9.10 x 10-3
Chip – branched UV light Methylene blue 150 x 50 μm501
Planar microreactor Blue LEDa Methylene blue 10 x 10 x 0.1 mm511
Solar light Methylene blue 50 x 18 x 0.1 mm519
UV lamp (310-400 nm) Methylene blue 20 x 10 x 0.25520
UV lamp Methylene blue 50 x 18 x 0.1 mm521 9.85 x 10-2
a BiVO4 as photocatalyst
b PSTY values as reported by Leblebici et al.502 or calculated assuming no mass-transfer limitation. Missing values could not be derived due to missing experimental details (e.g. UV lamp power).
100
5.1.2 Photo-Fenton and Photo-Fenton-like oxi-
dations
Photo-Fenton reactions represent an alternative strate-
gy for the production of hydroxyl radicals, starting from
H2O2.522 The degradation of H2O2 in the presence of Fe2+
was first reported by H.J.H. Fenton in 1894.523 Later, it
was discovered that UV and visible light up to 600 nm
could be used to accelerate the Fenton reactions signifi-
cantly.524 Applications of the photo-Fenton process for
the treatment of wastewater date back to the late 90’s
and early 2000’s with the work from the groups of Pig-
natello, Kiwi, Pulgarín, Bauer and others.525-529 Ever
since, the so-called photo-Fenton reactions evolved as
one of the most efficient AOPs to afford degradation of
water pollutants. This reaction appears to be especially
useful for large scale solar plants for water
purification.467
The reason behind the acceleration of Fenton reactions
in the presence of light lies in the photochemical regen-
eration of Fe2+ from Fe3+ with the concomitant for-
mation of yet another hydroxyl radical. The mechanism
of the Fenton reaction and the photochemical regenera-
tion of Fe3+ are shown in the following equations:
𝐹𝑒(𝑎𝑞)2+ + 𝐻2𝑂2 → 𝐹𝑒(𝑎𝑞)
3+ + 𝑂𝐻− + 𝑂𝐻 ∙ (10)
Fe(𝑎𝑞)3+ + 𝐻2O
ℎ𝜈→ 𝐹𝑒(𝑎𝑞)
2+ + 𝑂𝐻 ∙ + 𝐻+ (11)
Compared to semiconductor photocatalysis, the photo-
Fenton reaction is feasible with visible light due to the
fact that iron-hydroxy and iron-organic complexes
present in the water adsorb in the visible light range.
Recent studies suggest the possibility to use alternating
light/dark cycles during the photodegradation
process.530-531 It was found that precursors susceptible to
photodegradation can accumulate during the dark
period and promptly decompose when exposed to light.
Such an alternating illumination could improve the cost
efficiency of the whole water treatment by reducing the
energy cost for the illumination and by simplifying the
design of the reactor in case of solar plants.
A major drawback for the applicability of photo-Fenton
reactions is the need to control the wastewater pH
throughout the degradation process. The optimal pH
for operation was calculated to be 2.8.524, 532 Under these
conditions, the precipitation of iron salts is avoided and
the concentration of mono- and dihydroxylated
iron(III) complexes is maximized.533 These complexes
absorb UV light better than non-hydroxylated iron
complexes. Nevertheless, because of the ability of iron
to form complexes with different Lewis bases and due
to the presence of organic acids in the wastewater, the
necessity to operate at a pH of 2.8 is no longer re-
quired.534-536 In fact, when the ferric ion is complexed,
its photoreduction to Fe2+ can occur with visible light.
Furthermore, organic acids, present in wastewater, can
have a positive influence on the control of the pH. For
all this reasons, a pH value of 4-5 is generally consid-
ered sufficient to prevent any iron complex precipita-
tion.530
To date, Fenton and photo-Fenton reactions remain
one of the most investigated AOPs for wastewater
treatment. Several examples of lab scale and pilot-scale
solar or UV reactors have been reported, describing the
demineralization of organic pollutants such as dyes,537-
538 drugs464, 528, 539 and byproducts from the plastic indus-
try.466 Furthermore, enhanced photo-Fenton reactions
101
can be obtained through coupling with other methods
for water purification, such as ozone,540 ultrasounds541
and TiO2.542-544 Plenty of examples show the favorable
consecutive combination of photo-Fenton and biologi-
cal treatments.545 The use of photo-Fenton reactions as
a pretreatment has been shown to increase the biodeg-
radability of wastewater by forming intermediates,
which are easily decomposed by microorganisms.546
Notably, only a few examples show the sole use of pho-
to-Fenton reactions for water disinfection. One study
reported the use of photo-Fenton for the successful
disinfection of E. Coli from lake water at a neutral pH
and low iron and H2O2 concentrations (ppm).530
Despite the fact that photo-Fenton reactions generally
belong to homogeneous catalysis, few cases have been
reported in literature in which different iron minerals
are immobilized on inert supports547-549 or incorporated
in novel iron-based materials.550-551 The advantages of
heterogeneous photo-Fenton reactions are the easy
post-operational separation of iron and the avoidance
of pH control, with reactions possible up to a pH of
around 7. On the down side, mass transfer limitations
and less efficient light irradiation are the unavoidable
drawbacks associated with the use of a heterogeneous
catalyst464, as highlighted in section 3.3.6 for TiO2.
The number of reports on the use of continuous-flow
reactors for photo-Fenton waste water treatment is
limited. The only example is a Y-shaped 0.9 x 1 mm
channel in PMMA which is covered with a quartz
plate.552 This device was used to study the degradation
of an azo dye. Several important process parameters
were evaluated, such as pH, H2O2 dye and Fe2+ concen-
trations, and flowrate. The best performance resulted in
an 86% discoloration of the model pollutant with a
residence time of about one second. This result outper-
forms those results obtained with conventional batch
technology, which typically requires longer reaction
times due to a lower mixing efficiency.553-554
Figure 34 Y-shaped Photo-Fenton reactor for azo dye
degradation. Reprinted with permission from ref. 552.
Copyright 2013 Balaban Desalination Publications.
102
6. Conclusions
Photochemistry has recently witnessed a remarkable
increase of attention from researchers in academia and
industry. In our opinion, there are two important rea-
sons for that. The first reason is the emergence of visi-
ble light photoredox catalysis for organic synthetic
chemistry. The use of this novel catalysis mode provid-
ed access to unprecedented reaction pathways, which
could be carried out in a highly selective and mild fash-
ion (room temperature, visible light, avoidance of toxic
chemicals). The second reason is the use of continuous-
flow reactors which gives a great degree of operational
flexibility in the handling of such photochemical reac-
tions.
As exemplified throughout this review, the implemen-
tation of continuous-flow photoreactors is crucial to
facilitate photochemical transformations in organic
synthetic chemistry, material science and even water
treatment. The most important features of this technol-
ogy is the reduced reaction times, the straightforward
scalability and the possibility to safely use highly reac-
tive and hazardous chemicals. Some recent examples
have begun to venture into more complex applications,
such as the continuous-flow synthesis of complex bio-
logically active molecules.80 Notably, continuous-flow
photoreactors have also been implemented in pharma-
ceutical companies to produce APIs on a ton scale.83, 555-
558
While significant progress has clearly been made, mov-
ing forward is not without a challenge. Visible light
photoredox catalysis has only recently emerged as a
potential alternative compared to traditional organic
chemistry. Therefore, it is evident that it will further
impact synthetic chemistry in the coming years. An
intriguing application would be the use of this catalysis
mode to prepare polymer beads which encapsulate cells
or other UV-sensitive biologically active compounds.
Furthermore, the use of hazardous chemicals or other
difficult-to-handle reagents (e.g. gases) has been avoid-
ed in the last couple of decades due to their unsustain-
able nature. However, as shown in this review, such
compounds can now be safely processed in microreac-
tors and thus novel applications and opportunities can
be envisioned. Automated and self-optimizing flow
processes have been developed in the past and reduce
the manual labor to an absolute minimum. It would be
very exciting to see when the first ChemDraw structure
can be inserted in a computer, after which the comput-
er prepares the compound for us. Currently, these are
still wild and almost science fiction ideas but these
remarkable times show us already that we are able to
overcome challenging problems which were decades
ago impossible to do.
In order to overcome the remaining hurdles in chemis-
try, a multidisciplinary approach will probably be the
best strategy to use. This includes intense collabora-
tions between academia and industry. In times of drop-
ping funding opportunities, support from the industry
becomes even more vital to address the challenges of
the future. This represents not only financial support
but also implementation of these novel technologies in
existing plants, which will facilitate its widespread use,
reduce the overall cost of the technology and will stim-
ulate new research efforts in real life examples.
103
7. List of acronyms
Acronym Description
5-HMF 5-Hydroxymethylfurfural
AgNP Silver nanoparticle
AOP Advanced Oxidation Process
API Active Pharmaceutical Ingredient
APTES (3-Aminopropyl)triethoxysilane
ATRA Atom Transfer Radical Addition
BDE Bond Dissociation Energy
bmim 1-Butyl-3-Methylimidazolium
Boc tert-Butyloxycarbonyl
BPR Back Pressure Regulator
bpy 2,2’-bipyridine
Cbz Carboxybenzyl
CF3SO2Cl Triflyl Chloride
CFL Compact Fluorescent Lamp
CuAAC Copper(I)-Catalyzed Azide-Alkyne Cycloaddition
CV Coefficient of Variation
DCA 9,10-dicyanoanthracene
DCE Dichloroethane
d.e. Diastereomeric excess
DMAP 4-Dimethylaminopyridine
DMA N,N-Dimethylacrylamide
DMBP 4-4’-Dimethoxybenzophenone
dmp 2,9-Dimethyl-1,10-Phenanthroline
Dpg 3,5-dihydroxyphenylglycine
e.e. Enantiomeric excess
FDA Food and Drug Administration
FEP Fluorinated ethylene propylene
FTU Fluorescein Thiourea
GAG Glycosaminoglycan
H2MF 5-Hydroxy-5-(Hydroxymethyl)-Furan-2(5 H)-one
HEMA 2-Hydroxyethyl Methacrylate
HIPE High Internal Phase Emulsion
ID Internal diameter
MFFD Microfluidic Flow-Focusing Device
MMA Methyl Methacrylate
mpg-C3N4 Mesoporous Graphitic Carbon Nitride
NBS N-Bromosuccinimide
NFSI N-Fluorobenzenesulfonimide
NMR Nuclear Magnetic Resonance
PDI Polydispersity Index
PDMS Polydimethylsiloxane
PG Protecting Group
photo-CRP Photo-Controlled Radical Polymerization
PIB Polyisobutylene
PFA Perfluoroalkoxy alkane
PMI Process Mass Intensity
PMMA Poly(Methyl Methacrylate)
104
PNIPAM Poly(N-Isopropylacrylamide)
poly(HEMA-MMA) Poly(Hydroxyethyl Methacrylate-Methyl Methacrylate)
POM Polyoxometalate
ppy 2-Phenylpyridinato-C2,N
PSTY Photocatalytic Space-Time Yield
PTSA p-Toluensulfonic Acid
PU Polyurethane
PVA Polyvinyl Alcohol
PVSZ Polyvinylsilazane
ROS Reactive Oxygen Species
scCO2 Super critical CO2
SET Single Electron Transfer
SPPS Solid Phase Peptide Synthesis
STY Space-Time Yield
TBADT Tetrabutylammonium Decatungstate
TBAF Tetra-N-Butylammonium Fluoride
tbpy tert-Butyl Bipyridine
TEMPO 2,2,6,6-Tetramethylpiperidine Nitroxide
TFA Trifluoroacetic Acid
TFAA Trifluoroacetic Anhydride
THF Tetrahydrofuran
TMEDA N,N,N’,N’–Tetramethyl-1,2-diaminoethylene
TMSCN Trimethylsilyl cyanide
TPGDA Tripropylene glycol diacrylate
TPP Tetraphenylporphyrin
TXS Thioxanthone
UV Ultraviolet light
VIS Visible light
XantPhos 4,5-Bis(Diphenylphosphino)-9,9-Dimethylxanthene
105
ACKNOWLEDGMENT
D.C., C.B. and T.N. would like to acknowledge the European Union for a Marie Curie ITN Grant (Photo4Future, Grant No. 641861). We also acknowledge the Dutch Science Foundation (NWO) for a VIDI grant for T.N. (SensPhotoFlow, No. 14150) and the European Union for a Marie Curie CIG grant for T.N. (Grant No. 333659) and for an ERC Advanced Grant for V.H. (Grant No. 267443).
106
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AUTHOR INFORMATION
Dario Cambié was born in 1989 and grew up near Bergamo, Italy. He studied Chemistry and Phar-maceutical Technologies at the University of Milan, where he obtained his M.Sc. degree in 2014. His master thesis was conducted under the supervision of Professor S. Romeo. Previously, he has been an intern at Bayer in Leverkusen, Germany. He is currently a Ph.D. student at Eindhoven University of Technology in the group of Dr. Timothy Noël. His work focuses on photocatalysis in novel photomi-croreactors.
Cecilia Bottecchia was born in Milan, Italy in 1989. In 2014 she received her M.Sc. degree in Chemis-try and Pharmaceutical Technologies at the University of Milan. Previously, she conducted her master thesis under the supervision of Prof. A. Madder at Ghent University, Belgium. After her undergradu-ate studies, Cecilia joined the group of Dr. Timothy Noël, where she is currently pursuing her Ph.D. Her research interests focus on biomolecule functionalization via photocatalysis in continuous-flow.
Natan J. W. Straathof was born in 1984 in Den Haag, Netherlands. In 2011 he graduated at the Uni-versity of Leiden, where he obtained his M.Sc degree under the supervision of Professor H. Overkleeft and Professor G. van der Marel.Currently, he is pursuing a Ph.D. under the supervision of Dr. Timo-thy Noël at Eindhoven University of Technology. His research interests focus on novel synthetic methodologies using visible light photoredox catalysis, as well as its application in continuous micro-flow technology.
Volker Hessel studied chemistry at Mainz University. In 1999 he was appointed Head of the Micro-reaction Technology Department at Institut fur Mikrotechnik Mainz (IMM) GmbH. In 2002, he was appointed Vice Director and in 2007 he was appointed Director R&D at IMM. In 2011 he was appoint-ed full Professor for the chair of “Micro Flow Chemistry and Process Technology” at Eindhoven Uni-versity of Technology. In 2009, he was appointed Honorary Professor at the Technical University of Darmstadt and is Fellow of their Cluster of Excellence “Smart Interfaces”. He received the AIChE “Ex-cellence in Process Development Research” award in 2007, and in 2010 he received the ERC Advanced Grant on “Novel Process Windows”.
Timothy Noël obtained his M.Sc. (Industrial Chemical Engineering) in 2004. In 2009, he received his Ph.D. at the University of Ghent. He then moved to the Massachusetts Institute of Technology as a Fulbright Postdoctoral Fellow with Professor Stephen L. Buchwald (MIT-Novartis Center for Contin-uous Manufacturing). In 2012, he accepted a position as an assistant professor at Eindhoven Universi-ty of Technology. He received an Incentive Award for Young Researchers (2011). In 2012, he received a Veni grant (NWO) and was nominated for the European Young Chemist Award. Since 2014, he has been serving as an associate editor of the Journal of Flow Chemistry. Recently, he received a prestig-ious Vidi grant (NWO) and he coordinates the Marie Skłodowska-Curie ETN program “Pho-to4Future”, which deals with continuous-flow photochemistry.
Corresponding Author
* Timothy Noël, e-mail: T.Noel@tue.nl, Homepage: http://www.noelresearchgroup.com, Twitter: @NoelGroupTUE
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