Applications of continuous-flow photochemistry in organic ... · 1 Applications of continuous-flow photochemistry in organic synthesis, material science and water treatment Dario

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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https://research.tue.nl/en/publications/applications-of-continuousflow-photochemistry-in-organic-synthesis-material-science-and-water-treatment(e3aa54c3-b242-4e43-a78e-30cce1ae1458).html

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)


High visible light transmittance

104-106

Polydimethylsiloxane (PDMS) ±255 nm

Polytetrafluoroethylene (PTFE) ±200 nm High chemical resistance, pressure and temperature resilience


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-


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-



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-


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


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-


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: [email protected], Homepage: http://www.noelresearchgroup.com, Twitter: @NoelGroupTUE

mailto:[email protected]

http://www.noelresearchgroup.com/

https://twitter.com/NoelGroupTUE

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Applications of continuous-flow photochemistry in organic ... · 1 Applications of continuous-flow photochemistry in organic synthesis, material science and water treatment Dario