Review

pubs.acs.org/CR

The Hitchhiker’s Guide to Flow Chemistry∥

Matthew B. Plutschack,§,† Bartholomaü s Pieber,§,† Kerry Gilmore,*,† and Peter H. Seeberger*,†,‡
†
Department of Biomolecular Systems, Max-Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany
‡
Institute of Chemistry and Biochemistry, Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Arnimallee 22,
14195 Berlin, Germany

ABSTRACT: Flow chemistry involves the use of channels or tubing to conduct a

reaction in a continuous stream rather than in a flask. Flow equipment provides chemists
with unique control over reaction parameters enhancing reactivity or in some cases
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enabling new reactions. This relatively young technology has received a remarkable
amount of attention in the past decade with many reports on what can be done in flow.
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Until recently, however, the question, “Should we do this in flow?” has merely been an
afterthought. This review introduces readers to the basic principles and fundamentals of
flow chemistry and critically discusses recent flow chemistry accounts.

CONTENTS 3.8. Optional Zones 11812

3.8.1. Analysis 11812
1. Introduction 11797 3.8.2. Purification 11812
2. Why Run a Reaction in Flow? 11797 4. Considerations for Flow Experiments 11812
2.1. Multiphasic Systems 11797 4.1. Key Parameters 11813
2.1.1. Gas−Liquid Reactions 11798 4.2. Common Problems 11814
2.1.2. Solid−Liquid Reactions 11799 5. Multiphasic Reactions 11814
2.1.3. Liquid−Liquid Reactions 11799 5.1. Gas−Liquid Reactions 11814
2.2. Mixing 11799 5.1.1. Carbon Monoxide 11815
2.3. Temperature 11800 5.1.2. Carbon Dioxide 11816
2.3.1. Exothermic Reactions 11800 5.1.3. Oxygen 11817
2.3.2. High-Temperature/High-Pressure 11800 5.1.4. Ozone 11820
2.3.3. Small Temperature Profile 11801 5.1.5. Fluorine, Chlorine, and HCl 11820
2.4. Photo- and Electrochemistry 11802 5.1.6. Hydrogen 11821
2.4.1. Photochemistry 11802 5.1.7. Ethylene 11821
2.4.2. Electrochemistry 11802 5.1.8. Ammonia 11821
2.5. Batch Versus Flow Analysis 11804 5.1.9. Diazomethane 11822
2.6. Automation 11805 5.1.10. Phosgene 11823
3. Anatomy of a Flow Reaction 11805 5.2. Solid−Liquid Reactions 11823
3.1. Connecting Flow Zones 11806 5.2.1. Heterogeneous Catalysis Involving Met-
3.2. Fluid and Reagent Delivery 11806 als 11824
3.2.1. Liquid Delivery 11806 5.2.2. Heterogeneous Organocatalysis 11830
3.2.2. Gas Delivery 11807 5.3. Gas−Liquid−Solid Reactions 11834
3.2.3. Solid Delivery 11807 5.4. Liquid−Liquid Reactions 11835
3.3. Mixer 11807 5.5. Liquid−Liquid−Solid Reactions 11837
3.3.1. Single-Phase Reactions 11807 6. Mixing 11838
3.3.2. Multi-Phase Reactions 11808 6.1. Outpacing Intermediate Decomposition 11838
3.4. Reactor Unit 11809 6.2. Outpacing Intramolecular Reactions 11840
3.4.1. Chip-Based Reactor Units 11809 6.3. Nucleophilic Reactions with Multiple Elec-
3.4.2. Coil-Based Reactor Units 11809 trophiles 11841
3.4.3. Packed Bed Reactor Units 11810 6.4. Selective Carbonyl Syntheses 11843
3.4.4. Electrochemical Devices 11810
3.4.5. Miscellaneous 11811
3.5. Quenching Unit 11811 Special Issue: Natural Product Synthesis
3.6. Pressure Regulating Unit 11811
3.7. Collection Unit 11812 Received: March 30, 2017
Published: June 1, 2017

© 2017 American Chemical Society 11796 DOI: 10.1021/acs.chemrev.7b00183

Chem. Rev. 2017, 117, 11796−11893
Chemical Reviews Review

6.5. Reductions with DIBAL-H 11845 covers reports only where flow enhancements were exper-
6.6. Electrophilic Trapping for Subsequent Cross- imentally observed or easily inferred from the flow conditions
Coupling Reactions 11845 employed. One of the challenges of discussing flow chemistry,
6.7. Miscellaneous Fast Reactions 11847 however, stems from the difference of interests between
7. Temperature 11849 industry and academia. Industrial interests are largely founded
7.1. Heated Reactions below 100 °C 11850 in cost. With the rising cost of energy, energy management is a
7.2. Heated Reactions between 100 and 200 °C 11851 key element in chemical industry.81 For this reason, a reaction
7.3. Reactions above 200 °C 11857 in flow which can reduce energy input might be particularly
8. Traceless Reagents in Flow: Photo- and Electro- interesting from an industrial perspective, however, is likely
chemistry 11860 irrelevant to an academic whose interest likely pertains to yield
8.1. Photochemistry 11860 or convenience.
8.1.1. Photoexcitation of Substrates 11860 Accordingly, industry’s interest in flow chemistry is outside
8.1.2. Singlet Oxygen-Mediated Reactions 11862 the scope of this review unless the impact in a laboratory can be
8.1.3. Photoredox Catalysis 11864 envisioned. For example, multistep syntheses74 or end-to-end
8.2. Electrochemistry 11868 production82 of active pharmaceutical ingredients is currently
8.2.1. Anodic Oxidation 11868 an attractive area in flow chemistry since these processes have a
8.2.2. Cathodic Reduction 11871 lower space-time demand. However, too much time and
9. Feedback Optimization 11872 resources need to be allocated for the production of one
10. Conclusions 11873 compound for this to be useful for the average synthetic lab.
11. Diagram Legend 11874 Therefore, this literature is not included unless one of the steps
Author Information 11874 illustrates a benefit in flow. Additionally, terms like scale or
Corresponding Authors 11874 scaling in the context of this review refers to laboratory scale
ORCID 11874 reactions transitioning from optimization scale to preparative
Author Contributions 11874 scale. For instance, “easy to scale” in this review should not be
Notes 11874 taken as the progress from discovery to pilot and production
Biographies 11874 scales.
Acknowledgments 11874
References 11874 2. WHY RUN A REACTION IN FLOW?
Continuous flow has affected many fields over the last 20 years,
1. INTRODUCTION and the rapid increase in flow chemistry publications has led to
a vast collection of examples with many authors reporting what
The aim of technology is to enhance or facilitate the ability to can be done utilizing continuous flow conditions. As of late,
complete a task. In chemistry, microfluidic equipment emerged scientists have begun to contemplate which tasks should be
as a technology which aimed to enhance a researcher’s ability to done with continuous flow.16,20,83 In an attempt to help
perform chemical reactions since the small dimensions of the chemists address this question, this section summarizes reaction
reactors provided unique control over key reaction parameters. conditions that can be improved and/or intensified by adopting
At one point the flow community seemingly wanted to phase continuous flow conditions. Our discussion of these reaction
out the round-bottom flask,1 and over the past decade, the field parameters pertain to optimization and preparatory quantities,
of flow chemistry has received remarkable attention.2−79 Even and any scaling benefits refer to the transition from
so, flow chemistry is not implemented in every synthetic optimization to preparatory experiments. In addition, a decision
laboratory. Rather, scientists are left sifting through a vast diagram is constructed from these concepts to facilitate a batch
collection of literature which has been poorly indexed and versus flow verdict. A critical analysis of potential obstacles and
scattered throughout reports with generalized flow enhance- overarching goals is presented to show that while many
ment claims. Among these commonly reported benefits are microscale reactions outperform their batch counterparts, the
better mixing, more efficient heat transfer, and easy scale-up. financial and time costs of some processes outweigh the
While these enhancements are generally true, they are benefits flow has to offer.
occasionally reported with little relevance to the topic of the
paper, leaving readers wondering if it is really worth the time to 2.1. Multiphasic Systems
run the reaction in flow. Recently, Whitesides noted that a clear Many relevant chemical transformations involve multiple
interest in new technology was an underlying problem for this phases (gas−liquid, solid−liquid, liquid−liquid, or solid−
flood of information.80 “It is that the devices that have been liquid−gas). For productive reactivity, efficient phase mixing
developed have been elegantly imagined, immensely stimulat- is necessary. In the case of liquid−liquid reactions, methods
ing in their requirements for new methods of fabrication, and exist to combat poor interfacial mixing via phase-transfer
remarkable in their demonstrations of microtechnology and catalysis (PTC) which shuttle reactants from one phase to the
fluid physics, but they have not solved problems that are other. Several disadvantages, however, prevent this method
otherwise insoluble. Although they may have helped the from being applied universally. Therefore, reactor design is
academic scientist to produce papers, they have not yet important for achieving efficient phase mixing. Generally,
changed the world of those with practical problems in microfluidic systems increase surface area to volume ratios due
microscale analysis or manipulation.” to the decreased size of the reactor. In multiphasic systems, the
The aim of this review is to take a critical look at the past five interfacial area plays an important role in phase transfer which
years of literature and summarize which reports exploit can be rate limiting. For this reason, microfluidic systems tend
microfluidic devices in order to improve the state of synthetic to outperform their batch counterparts. For each of these
chemistry in a research laboratory. To this end, this review multiphasic systems, different multiphase flow regimes exist.
11797 DOI: 10.1021/acs.chemrev.7b00183
Chem. Rev. 2017, 117, 11796−11893
Chemical Reviews Review

For gas−liquid mixtures, bubble, slug, and annular flow

regimes are commonly observed in microreactors (Figure 1).

Figure 1. At a constant liquid flow rate, three flow regimes are

commonly observed for gas−liquid mixtures in microfluidic devices.
Common conditions in tube reactors (>0.25 mm) usually result in slug
flow.
These regimes are influenced by flow rates, viscosities, and
channel properties. Typical tubing reactors (0.25−0.75 mm
i.d.) highlighted in this review most likely exhibit slug flow
behavior.
For solid−liquid reactions, three different reactor beds are
predominantly used (Figure 2). Packed beds are characterized
Figure 2. Different solid−liquid reactors, characterized by solid mass
transfer. Within each bed, liquids typically exhibit slug flow or
turbulent flow.
Figure 3. Laminar and slug flow regimes for immiscible liquid−liquid
mixtures. Common conditions in tubing reactors (>0.25 mm) usually
result in slug flow.
ν), and large channels (A) generally produce laminar flow (Re <
2040).85
QDH
Re =
νA (1)
Most tubing reactors, however, will exhibit slug flow (Figure
3, bottom) which is often achieved using a T-mixer (section
3.3.1). Slugs are formed when the perpendicular phase (phase
2) plugs the channel, causing a buildup of pressure behind it in
phase 1. When the pressure becomes high enough, a droplet is
broken off. This process occurs over and over, forming
alternating slugs of each phase.
2.1.1. Gas−Liquid Reactions. Gas−liquid reactions
include a wide range of very powerful chemistries. Gaseous
reagents tend to be very atom economical but tend to be used
in large stoichiometric excess due to poor interfacial mixing.59
Poor interfacial mixing can result in extended reaction times
making processes prohibitively slow. Microfluidic systems can
eliminate headspace and increase the surface area per reactor
volume (Table 1). While small round-bottom flasks can provide

by the entire column or channel being filled with a solid Table 1. Interfacial Surface Areas for Various Reactorsa
material so that particle movement is restricted. Liquid flow type of reactor interfacial area (m2 m−3)
within this bed is generally plug flow but can be turbulent at 5 mL round-bottom flask (rbf) b
141
higher flow rates. In a fluidized bed reactor, the particles are 50 mL rbfb 66
free-flowing and suspended within the channel by the turbulent 250 mL rbfb 38
flow of the liquid phase. These reactors offer benefits such as tube reactors, horizontal and coiled 50−700
improved heat distribution, however, are not typically used in a tube reactors, vertical 100−2000
laboratory setting as they are still not completely understood gas−liquid microchannel 3400−18000
and optimal conditions are time-consuming to achieve.84 Mixed a
Reproduced from Mallia et al.59 bCalculated for half-filled round-
beds are a combination of a packed bed and a fluidized bed. a 150
The movement of the solid at the bottom of the reactor is bottom flasks when the liquid is static using, v = 3 .
1/2 3v / 4 π
restricted, while the top layers are suspended and mixed via the
flowing liquid phase. In the context of this review, packed beds sufficient interfacial areas with vigorous stirring, flow conditions
and mixed beds offer the most convenience, owing to the are advantageous, especially if the end-goal is synthetic scale
limited experience required for their set up and use. preparation.
Many different flow regimes can exist for liquid−liquid Additionally, the increased surface area to volume ratio of
mixtures; however, laminar and slug flow are most commonly microreactors effectively increases mass transfer by 2 orders of
described for reactions in microchips and tube reactors (Figure magnitude, enhancing rates of reactions where mass transfer is
3). Laminar flow occurs when parallel phases do not interrupt rate limiting.20 Additionally, Taylor flow is a type of gas−liquid
each other’s longitudinal flow (Figure 3, top). The Reynolds mixing where the slug flow of gas and liquid adopts a certain
number (Re) is a dimensionless mass transfer coefficient that geometry creating a thin film of liquid on the channel wall,
can be used to predict whether the flow conditions lead to separating the gas from the reactor (Figure 4).86 This internal
laminar flow (eq 1). Low flow rates (Q), viscous liquids (high mixing created within the liquid phase increases mass transfer
11798 DOI: 10.1021/acs.chemrev.7b00183
Chem. Rev. 2017, 117, 11796−11893
Chemical Reviews
Figure 4. Taylor flow within the liquid phase of a gas−liquid mixture
in a microfluidic channel.
and can reduce mixing lengths by 2- to 3-fold when compared
to similar passive mixing with patterned side walls or three-
dimensional channel geometries.87
Finally, gas solubility will play a role because gas−liquid
reactions occur in solution with soluble gas. Compared to most
reagents, gas solubility is low at room temperature. Henry’s law
is used to quantify the solubility of gases in solvents (eq 2)
where the partial pressure (p) is related to the concentration of
gas in solution (c) by a temperature-dependent constant (kH).
p = kHc
In general, fluidic devices can withstand higher pressures
than screw-cap and sealed vessels (Table 2), permitting better
Table 2. Relative Pressure Ratios for Various Reaction
Vessels
reaction vessel pressure rating (bar)a
2 mL screw-cap vial 10
0.2−30 mL microwave tubes 30
250 mL screw-cap flask ∼4
polymer-based tubing ∼30
stainless steel tubing >100
a
Values are approximated from ratings or recommendations of
commercial vendors and are not indicative of the burst pressure.
gas solubility. Additionally, scaling out optimized conditions in
flow is a significant advantage, considering that sealed vessel
reactions are limited to approximately 30 mL.
Flow chemistry with gas−liquid mixtures offers benefits such
as improved interfacial mixing and safely achieving high
pressures. For these reasons, the reaction rate, scalability, and
safety can be improved by adopting flow conditions. In
addition, controlling the stoichiometry of gases is possible with
a mass-flow controller, and quenching toxic gases can be more
convenient.
2.1.2. Solid−Liquid Reactions. Heterogeneous reactions
involving solids and liquids are especially attractive due to the
ease of separation upon workup. Heterogeneous catalysis, in
particular, is an important field as many of the present industrial
processes use a heterogeneous catalyst.88,89 Recently, continu-
ous flow has been exploited to enhance heterogeneous catalysis
by essentially combining the reaction and separation into one
step using a packed bed reactor. Gas−liquid−solid reactions
such as hydrogenation reactions are exceptionally valuable
transformations and comprise the majority of heterogeneous
catalysis reactions in flow.19,90 These hydrogenations take
advantage of the high interfacial area which facilitates better
mass transfer. Beyond this type of chemistry is a wide variety of
transformations involving diverse heterogeneous catalysts and
Review
supported catalysts.15,47,91 Packed beds simulate high concen-
trations and can have improved lifetime due to decreased
exposure to the environment.26 Additionally, the ease of
screening continuous reaction parameters for a given catalyst
makes continuous flow attractive. On the other hand, when a
catalytic system is not purely heterogeneous, catalyst leaching is
a dilemma for which flow does not offer advantages. In this
case, selecting a homogeneous precatalyst may be more
appropriate since reactivity and selectivity can be modulated
by changing the ligand.37
2.1.3. Liquid−Liquid Reactions. Like other heteroge-
neous transformations, the small dimensions of microreactors
can enhance phase mixing. The challenges associated with
liquid−liquid mixtures in flow, however, deal with maintaining
a stable fluid distribution, which subsequently leads to poor
residence time distributions.92 The flow rates and flow patterns
are particularly important. At lower flow rates (longer residence
times), different flow patterns have equal mass transfer
efficiency. At higher flow rates, however, the importance of
the reactor structure is apparent and the presence of obstacles
enhances the liquid−liquid surface area and mass transfer.
Reactors packed with inert materials such as stainless steel
(2) beads create “tortured paths” and have been employed to create
chaotic mixing which improves mass transfer.93 While these
types of reactors are useful for scaling out a reaction, they tend
to use large amounts of material because of the high flow rates
required to achieve efficient mixing. Therefore, if complications
in scaling a reaction are not anticipated then small scale batch
reactions with rapid stirring may be sufficient to achieve the
desired results.
2.2. Mixing
Often mixing is highly influential in the conversion and
selectivity of reactions. Therefore, the degree to which mixing
influences a reaction should be a major question when deciding
whether or not to conduct an experiment in flow. Mixing
describes the way two phases come together and become
intertwined. Batch and flow reactors exhibit different mixing
mechanisms which in combination with reaction kinetics will
determine if flow conditions are beneficial.
The Reynolds number (Re) is used to predict flow patterns
in fluids, where ranges of Re divide mixing into three regimes:
laminar, transitional, and turbulent. Low Re values correspond
to laminar flow, whereas high Re values describe turbulent flow.
Typically, mixing in laboratory-size batch reactors is laminar or
transitional.94 A transitional regime normally results in
segregation inside the vessel, with turbulent mixing near the
stir bar and laminar regimes at outlying parts. The movement of
molecules to and from these isolated regions generally relies on
diffusion.95 Smaller vessels have smaller diffusion times;
however, they are not capable of completely eliminating this
segregation of mixing regimes.
Tube reactors inherently have much smaller diffusion times
and achieve mixing much faster than in batch. Mixing, however,
is more complicated than simple diffusion and requires analysis
of the Damköhler number (Da). This dimensionless unit is a
ratio of the rate of the reaction to the rate of mass transfer by
diffusion (eq 3).
χdt2
Da =
4τD (3)
For reactions where Da is less than 1, mixing (>95%
homogeneity) can be achieved before the reaction occurs.
11799 DOI: 10.1021/acs.chemrev.7b00183
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Chemical Reviews
However, for reactions where Da is greater than 1, the reaction
is faster than mass transport, causing concentration gradients
within the system. Usually, these gradients have adverse effects
on ideal reactor performance and may affect the overall
selectivity of the reaction. For instance, mixing greatly
influences a competitive, consecutive side reaction, where A +
B → C and C + B → S (Da > 1). Since diffusion is slower than
the rate of the reaction, A and B will react before achieving
homogeneity. Local concentrations of B in proximity to C are
created (Figure 5b, middle), which subsequently react to form
higher quantities of side-product S (Figure 5b, right).
Figure 5. (a) Reactions where the Damköhler number is less than 1
and/or high-intensity mixing is applied. Homogeneity is reached
resulting in high selectivity for the formation of the desired product C.
(b) Poorly mixed reactions where the Damköhler number is greater
than 1. The reaction is too fast to achieve homogeneity, creating local
concentrations of B and C which react to give higher quantities of side-
product S. Adapted from Handbook of Industrial Mixing: Science and
Practice.94
When Da is high, specialized mixers must be used to achieve
rapid mixing (see section 3.3). The proper application of a
mixer can better achieve homogeneity, and this reduces the
amount of side-products. For certain reactions, flow reactors are
used in fine chemical and pharmaceutical applications because
high-intensity mixing can only be achieved using inline
mixers.94 These types of chemistries which benefit greatly
from enhanced mixing under flow conditions are commonly
referred to as “flash chemistry” (section 6).96
Importantly, flow chemistry does not change the chemistry
or kinetics of a reaction.97 Rather, flow chemistry is a tool for
chemists to eliminate or reduce concentration gradients that
may be detrimental to extremely fast reactions. The rate of the
reaction and mixing should be one of the major considerations
when deciding whether or not to develop a flow process.
2.3. Temperature
Reactions where mixing is not highly influential can still benefit
from continuous flow conditions. For example, flow conditions
often outperform batch reactors for highly exothermic reactions
that require cooling (runaway reactions). On the other side of
the spectrum, transformations where the rate is orders of
magnitude smaller than “flash reactions” require heating. Here,
process intensification (high-temperature/high-pressure) can
greatly reduce the reaction time. Finally, both heated and
cooled reactions will be enhanced in flow when the product to
side-product ratio is dictated by a small difference in transition
state energies.
2.3.1. Exothermic Reactions. “Runaway” reactions are
transformations where the heat of reaction increases the
temperature of the medium, thereby increasing the rate of the
11800
Review
reaction. This regime can lead to side-products or dangerous
safety issues such as rapid boiling of solvents, occasionally
resulting in an explosion. The small dimensions of tube reactors
enhance the performance of these reactions not only with
better mixing but also with more efficient heat transfer. An
overall heat transfer coefficient (U) is commonly applied to the
calculation of heat transfer in heat exchangers. In this
application, U can be used to determine the heat transfer rate
(q) where A is the heat transfer surface area and ΔTLM is the
logarithmic mean temperature difference (eq 4).
q = UAΔTLM (4)
By this relationship, the rate of heat transfer is directly
proportional to the surface area; thus, dissipation of heat is
faster with larger surface areas. As a point of reference, a 10 mm
flask reactor with vigorous stirring and a 400 × 400 μm flow
reactor have the same resistance to heat transfer.20 For this
reason, small-scale optimizations (<1 mL) may be more
convenient in batch given that multiple reaction conditions can
be screened simultaneously. The advantage flow conditions
have over batch pertains to the reaction scale. The resistance to
heat transfer increases linearly with the size of the reactor
channel. Scaling batch reactors is less predictable because
convective heat transfer is not only dependent on the size of
the flask but also dependent on the impellor and liquid level.
Therefore, when a synthesis employs a runaway reaction,
preparative quantities of a material are more reliably produced
in flow without knowledge of higher-level engineering concepts.
Prolonging the operation time, or scaling out, produces more
material.
2.3.2. High-Temperature/High-Pressure. The temper-
ature dependence of reactions is typically expressed using the
Arrhenius rate law (eq 5), derived from the observation that the
reaction rate increases exponentially as the absolute temper-
ature is increased. Since it is derived empirically, it is ignorant of
mechanistic considerations and only takes into account the
activation energy (Ea) of the overall process. In contrast,
transition state theory gives the Eyring equation (eq 6), which
analyzes a single-step transformation and is useful in
determining activation parameters such as ΔG‡, ΔH‡, and
ΔS‡. While these equations describe two fundamentally
different phenomena, they both illustrate a direct relationship
between the absolute temperature and the rate constant of the
reaction (k). Therefore, reactions which are prohibitively slow
at room temperature can be sped up by heating.
k = Ae−Ea /(RT ) (5)
kBT −ΔG‡ / RT
k= e
h (6)
For a heated batch reaction, the reaction vessel is equipped
with boiling chips or a stir bar and a condenser to prevent a loss
of solvent. Until recently, methods for heating a vessel included
Bunsen burners, steam baths, sand baths, oil baths, hot plates,
and heating mantles.
For reactions that take less than 48 h at room temperature, it
may not make sense to adopt flow conditions since moderate
heating (<80 °C) can reduce reaction times to under an hour
(Table 3). However, higher temperatures are required for
reactions which do not occur or take more than a week (>172
h) at room temperature. Heating a reaction mixture to higher
temperatures in batch under reflux conditions necessitates high-
DOI: 10.1021/acs.chemrev.7b00183
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Chemical Reviews
Table 3. Reaction Time Dependence on Temperaturea
a
An illustrative table for the theoretical decrease in the reaction time.
Adapted from Flow Chemistry: Fundamentals.98
boiling solvents. This not only limits solvent options but also
can complicate reaction workup and product purification.
The use of sealed vessels permits lower boiling point solvents
for high-temperature reactions since solvents can be super-
heated above their boiling points. In combination with
microwave irradiation, high temperatures (300 °C) can be
achieved easily, reducing month long reaction times to mere
seconds.99 Recently, however, the demystification of the “magic
microwave effect”100 has shifted focus to flow chemistry in
order to reach these “novel process windows” (see Figure 6).101
Figure 6. Drawbacks of batch reactions that can be overcome by flow
chemistry.
One advantage high-temperature flow chemistry has over
microwave batch chemistry is the ability to safely and easily
synthesize preparative quantities. Microwave scale preparations
are generally limited to 30 mL reaction volumes. Larger setups
are available but are largely limited by the penetration of
microwaves. This depends on the dielectric properties of the
solvent but is generally on the order of a centimeter.99 Another
benefit of high-temperature/high-pressure flow conditions over
batch microwave processes is the elimination of headspace.
Reactions with low-boiling point reagents consistently proceed
more efficiently in pressurized flow reactors.102,103 Vaporization
of the reagents into the headspace of the batch microwave
reactor decreases the concentration in solution. Pressurized
flow reactors eliminate headspace, thereby maintaining uniform
reagent concentrations.
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2.3.3. Small Temperature Profile. In both high- and low-
temperature reactions, flow chemistry has an edge over
conventional batch chemistry due to the smaller temperature
gradients derived from chips’ and tube reactors’ large surface-
to-volume. Even with conventional conductive heating and
cooling methods, temperature gradients remain small; however,
reactor material plays a role in heat transfer efficiency and needs
to be chosen accordingly to reduce temperature gradients
between inlet and outlet sections of the reactor (Table 4).
Table 4. Relative Conductivity for Different Flow Reactors
reactor material conductivity (WmK−1)
PTFE 0.1
stainless steel 10
silicon 150
Reactions where the product-to-side-product ratios are
dictated by the Curtin-Hammett Principle are particularly
successful under flow conditions. For example, in this
hypothetical situation where the interconversion between
conformations is fast and the barrier for converting
intermediates I1 and I2 to products P1 and P2 is much higher,
selectivity will be dictated by the difference in transition state
energies, ΔΔG‡ (Figure 7). Batch reactors tend to have large
Figure 7. In this example, P1 is the desired product and P2 is a side-
product. The blue area signifies the window for selective reactivity.
Here, a small difference in transition state energies (ΔΔG‡) lead to
unselective reactivity in batch due to the large temperature profile.98
energy profiles. While an average temperature will lead to the
effective conversion of I1 to P1, the broad distribution of
temperature within the reaction medium leads to lower yields
through conversion of I2 to P2. Lowering the set-point
temperature can occasionally reduce selectivity issues; however,
it will also lead to longer reaction times. Tube reactors and
especially chips have narrow temperature distributions. Here,
the average temperature can be adjusted for optimal conversion
from I1 to P1, with little risk of loss of selectivity.
This selectivity enhancement is not limited to these types of
reactions. Reactions where A + B → C can also benefit from the
smaller temperature profile, if for instance, C decomposes at
higher temperatures or if a competing side reaction, C + B → S,
requires a higher temperature to occur. Any reaction where the
temperature has an effect on selectivity warrants an
investigation in flow.
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2.4. Photo- and Electrochemistry
Photo- and electrochemistry have reemerged as sustainable
means for synthesis.104,105 Both of these methods provide
“traceless” reagents in the form of photons or electrons and
electron holes and benefit from the small dimension of flow
reactors as well. Flow conditions offer more efficient and
uniform irradiation of reactions mixtures for photochemistry,
and for electrochemistry, the small dimensions eliminate the
need for supporting electrolytes. While both of these processes
can be scaled to preparative amounts in batch, scaling can be
more convenient and reproducible in flow.106,107 Finally, these
branches in combination with other flow chemistry benefits
prove particularly advantageous (gas−liquid reactions and flash
chemistry).
2.4.1. Photochemistry. Photochemical reactions occur
when light provides energy to trigger a reaction. This includes
chemistry where the excited state of a molecule decomposes,
rearranges, or combines with another molecule but can also
include electron transfer chemistry initiated by the excitation of
a chromophore (photoredox catalysis). The latter is an
attractive method for organic synthesis, owing to the fact that
these reactions are mediated by visible light, of which starting
materials and products generally do not absorb.104,108 Photo-
chemistry in general relies on efficient irradiation of the
reaction mixture. Starting materials, products, photosensitizers,
and photocatalysts, at the point of incident light, can all act as
filters reducing the light intensity available for the rest of the
reaction mixture. According to the Beer−Lambert-Bouguer law
(eq 7), this attenuation of light is dependent on the molar
attenuation coefficient of the molecule (ε) and the concen-
tration of the molecule (c).
A = εcl (7)
To illustrate how attenuation of light affects a reaction, the %
transmittance of a common photocatalyst, tris(bipyridine)-
ruthenium(II) chloride [Ru(bpy)3]2+, was plotted against the
path length for different concentrations (Figure 8). For a
typical catalyst concentration (2.5 mM), less than 0.1% of light
Figure 8. % transmittance109 plotted against the path length for
[Ru(bpy)3]Cl2 in methanol (ε = 14600 M−1 cm−1).110 The dashed
vertical line represents the inner diameter of 0.02 in. tubing (0.5 mm).
% T = 100% × 10(−εcl).
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is transmitted past a length of 0.1 cm from the point of incident
light. This means that even in a 1 cm vial, the majority of the
reaction mixture is not being irradiated. Even after reducing the
catalyst concentration 10-fold (0.25 mM), there would be ∼1%
of the incident light transmitted to the center of the reaction
vessel. Lowering the concentration of the catalyst, however, will
also lower the rate. Unfortunately for batch reactors, this trade-
off has serious implications, especially for scaling a photo-
reaction.
On the other hand, the dimensions of flow reactors fall
within the region for sufficient exposure to light. For example, a
2.5 mM solution of [Ru(bpy)3]Cl2 in methanol would transmit
>1% of incident light when flushed through tubing with an
inner diameter of 0.02 in. (0.5 mm). This means that the
reaction will not be limited by the ability of the reagent or
catalyst to absorb light. In addition to better irradiation, all of
the other benefits of flow chemistry apply. This is particularly
the case for biphasic gas−liquid photoreactions, where both
phase mixing and photon absorption can be limiting. For this
reason, flow reactors can be highly beneficial to photochemical
reactions.
2.4.2. Electrochemistry. Organic electrochemistry is a
sustainable method to replace stoichiometric oxidants and
reducing agents for organic transformations. The synthetic
community is increasingly applying this method for the mild
conditions and high chemoselectivity it offers.105 Essentially,
electrochemical reactions are redox reactions that are mediated
by the application of an external voltage via the incorporation
of electrodes in the reaction vessel. Within the reaction media,
molecules are reduced at the cathode and oxidized at the anode.
Solid electrodes are most often used, but alternatively packed or
fluidized beds can be used.111 In electrochemical analysis,
proper placement of the electrodes is not a problem since the
instrumentation employs small electrodes. In bulk electrolysis
methods, however, the placement is critical. Inconsistent ohmic
drops (or IR drops) produce a nonuniform potential across the
working electrode which can cause undesired side reactions or
ineffective use of the total electrode area.112
Another challenge bulk electrolysis faces are high cell
resistances. This is particularly a problem when nonaqueous
solvents are used since they have lower dielectric constants than
water and therefore lower conductivities. As most organic
transformations are performed in an organic solvent,
supporting electrolytes are used to improve the conductivity
of the solution. Since large scale reactions can require one or
more equivalents by weight, this can be costly and is
counterproductive to sustainability.113,114 While some recycla-
ble electrolytes are available, eliminating the need for them
would be ideal. Even with supporting electrolytes, however,
batch scale up can lead to an undesirable evolution of heat
caused by larger distances between electrodes. For these
reasons, scaling electrochemistry, even on a laboratory scale, is
not trivial.
Flow chemistry offers solutions to these problems.40 First,
the associated resistance can be described by eq 8, where I is
the current, Rdrop is the electrolyte ohmic resistance, i is the
current density, d is the distance between electrodes, and κ is
the specific ionic conductivity. The distance between electrodes
and conductivity of electrolytes are directly proportional,
therefore if the distance between electrodes is reduced 10-
fold, the conductivity of the electrolytes can similarly be
reduced. For this reason, the small dimensions of flow reactors
permit the removal of supporting electrolytes. As such,
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Figure 9. Decision diagram for flow chemistry.118

electrochemistry in flow is preferred when purification, cost, d

IR drop = i
κ (8)
time, and sustainability are important to the end goal.
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Batch electrochemistry setups can suffer from unwanted heat
formation necessitating the use of a heat exchanger. Generally,
heat exchangers add or remove heat by passing a fluid over a
surface. Flow electrochemistry setups are advantageous to batch
setups because the reaction mixture is essentially a heat
exchanger fluid. The continuous flow of the reaction mixture
over the surface of the electrodes permits operation at quasi-
isothermal conditions, offering better control over reaction
temperatures. This, in combination with continuous removal of
products and other impurities, can result in higher current
yields and better product qualities.115
Finally, in the case of gas formation, flow conditions can
outperform batch setups. Under batch conditions, the
formation of gas bubbles on the surface of the electrode can
lead to temporary or even permanent areas of low conductivity,
resulting in the formation of heat and reduced performance.
Coalescence of gas bubbles in a microreactor has an overall
opposite effect to performance. As gas bubbles grow inside the
microreactor, gas−liquid slug flow is created, increasing mass
transfer by Taylor flow (section 2.1.1.).116 Continuous addition
of the reaction mixture forces the slugs through the reactor,
removing the gas which could otherwise be detrimental to the
electrolysis.
2.5. Batch Versus Flow Analysis
Flow conditions are not the cure-all for chemistry. This section
has pointed out that flow is advantageous for certain
transformations; however, developing a flow process can be
time-consuming. For this reason, a flow versus batch analysis
must be conducted in order to strike a balance between
convenience and achieving the overall goal. Since a flow versus
batch decision is never black and white, to pigeonhole similar
reactions as batch or flow would be foolhardy. However, several
generalizations can be made in order to expedite a cost-benefit
analysis. For this decision diagram (Figure 9), discovery and
preparative scales are taken into consideration.
First, a safety assessment is a suitable starting point.
Hazardous materials, heat exchange, and pressurized reactions
pose safety hazards in which flow conditions can alleviate or
nullify risks. Chip reactors, in particular, allow chemists in the
discovery phase to work with very small quantities of hazardous
materials, reducing exposure risks for the chemist. Additionally,
built in quenches avoid equipment manipulations, eliminating
human error which can result in spills. Finally, the small
dimensions of flow reactors promote efficient heat exchange
and are conducive to high-pressure conditions, reducing
dangers involved with runaway reactions and “extreme”
conditions, respectively.
The next question requires an evaluation of one’s over-
arching goals. For “safe” reactions that are already reported in
batch, a chemist must decide whether or not literature
conditions meet a project’s needs. If it is not broken, do not
fix it. Nonetheless, some discovery scale procedures may not be
conducive to preparative scales. As such, the immediate goal
should also be taken into consideration. For new trans-
formations, it is more convenient to screen reagents, solvents,
and additives in batch. All of these variables can be tested
simultaneously, whereas they must be done sequentially in flow.
One exception might be screening conditions where starting
materials are scarce. Here, small volume chip reactors enable a
chemist to perform and analyze a large number of reactions
using minimal quantities of a reagent. Additionally, temperature
and time optimizations are generally easier in flow because the
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reactor temperature can easily be changed and precise control
of the reaction time can be varied via flow rates.
Further analysis of the reaction involves multiphasic systems.
Generally, flow reactions outperform batch reactions when one
of the reagents is a gas. The headspace to solvent ratio is lower
and pressurizing the reactor increases the solubility of the gas in
solution. Small-scale pressurized batch reactions are feasible;
however, preparative scales are not possible or are dangerous.
Circumstances involving solids can be broken into three
categories. First, a batch setup is more convenient when
precipitation drives a reaction to completion. Precipitation in
flow frequently results in the mixer, channel, or pressure
regulator clogging. While specialized equipment exists for
preventing clogging, there is no universal solution to this
problem and troubleshooting involves a higher degree of
engineering experience. Similarly, the accurate delivery of
suspensions remains a challenge for laboratory scales with
reagents which are insoluble in the reaction medium. In this
scenario, batch reactions are more convenient and reliable. For
reactions with heterogeneous catalysts, on the other hand, flow
conditions are preferred. Packed beds simulate high catalyst
loadings, reducing reaction times and performing especially well
under triphasic conditions.
Likewise, two considerations should be taken into account
for liquid−liquid reactions. In batch, vigorous stirring can
efficiently produce emulsions and the setup is also simpler in
batch. These emulsions, however, are less homogeneous in
terms of droplet size. Therefore, when homogeneous, highly
reproducible emulsions are required, flow conditions are
necessary. Fields producing droplets and particles take
advantage of flow in particular because narrower size
distributions can be obtained.117 In flow, there are tortured
path reactors which maintain emulsions via turbulent mixing;
however, for convenience, a batch reaction is a better starting
point unless scaling is the issue.
Other considerations mostly pertain to the reaction’s rate
and selectivity. For extremely fast reactions mixing is very
important. Generally, these reactions are performed in batch by
cooling the reactor to a temperature in which no reactions are
occurring, followed by reagent addition. After brief stirring to
reach homogeneity, the reaction mixture is warmed up to a
temperature in which the reaction can occur. For small scale
preparations, batch is convenient. For preparative scales,
however, some reactions are lower yielding due to poorer
mixing and/or heat transfer. Generally, in flow, faster mixing
and better heat transfer will benefit the yield of fast, exothermic
reactions greatly. Similarly, selectivity can be enhanced in flow
as well. Since flow reactors generally have a narrower
temperature profile than batch reactors, side reactions close
in energy to the desired reaction can be reduced or eliminated.
Additionally, for extremely slow reactions, intensification of
reaction conditions can produce compounds in a timely
fashion. While sealed vessels are a convenient small scale
option, preparative scale high-temperature, high-pressure
reactions are much safer in flow.
Finally, reactions which are photochemically or electro-
chemically driven benefit from flow conditions. The Beer−
Lambert−Bouguer law describes the attenuation of light as path
length increases. Therefore, reaction mixtures will experience
more uniform irradiation in flow because of the small
dimensions of the reactor. If reactions employ gas−liquid
mixtures, flow conditions offer further enhancements. Electro-
chemistry also benefits from the small dimensions of flow
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conditions. Since reactions can be carried out without
supporting electrolytes, the cost may be reduced and the
purification simplified. Continuous removal of products and
improved mass transfer can also benefit the product quality.
Additionally, scaling the reaction to multiple grams can be more
convenient for flow via simply extending the operation time of
the flow process. This is equally the case for photochemistry,
where the attenuation of light is problematic for large
dimension reaction vessels.
2.6. Automation
As technologies become more developed and commercialized,
they may shift from high-cost/limited-benefit laboratory
methods to tools for expediting research. While some of
these processes are being developed mostly for industrial
purposes, others aim to enhance discovery and synthesis for
research laboratories. Currently, these methods are not practical
for the average laboratory. Automated feedback optimization
was chosen as an emerging reason to perform flow chemistry
since recent progress in this field has shown promise for the
everyday chemist. Currently, however, the equipment and
process setup are too costly for the occasional user. These areas
currently target very specific tasks and usually require a larger
engineering effort. Even so, this area is showing promise for
reducing the time of reaction optimization.
The scientific method is a thought process for testing
hypotheses and obtaining new knowledge. A reaction
optimization follows this method (Figure 10). A researcher
Figure 10. Scientific method and the role of automation.
identifies a target reaction, collects literature on how similar
reactions were carried out, and creates a hypothesis about the
best conditions to start the reaction optimization. Currently, a
chemist designs and executes experiments then collects and
analyzes data. Depending on the outcome of the original
experiments, the chemist changes certain parameters in order to
test their effects on the desired outcome. These parameters can
be categorized as continuous or discrete. Continuous
parameters include the reaction time, temperature, and
concentration, while discrete parameters are variables such as
solvent, catalyst, or ligand. Recently, high-throughput exper-
imentation (HTE) has accelerated the discovery of new
reactions and drugs by increasing the number of experiments,
in particular, screening of discrete parameters.33,119 HTE
provides researchers with a vast amount of data, accelerating
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the redesign and optimization steps, however, generally
struggles to screen continuous parameters effectively. In
addition, only the experiment execution step is expedited and
many parameters are tested which are unlikely to work or be
informative.
Inline and online analytics permit feedback optimization,
accelerating the entire central loop (Figure 10, green).
Continuous parameters are conveniently screened in flow.
The reaction time and the concentration are modulated by the
solvent and reagent flow rates, and the reactor temperature is
adjusted by a heating or cooling unit. These parameters can be
adjusted in real-time, avoiding the need for the setup of
individual batch reactions. Recent reports on “black box” and
various kinetic optimizations have demonstrated the power of
automated feedback optimizations;120 however, like non-
automated flow processes are unable to effectively screen
discrete variables. Collecting data and determining an optimal
starting point is becoming an important part of cheminfor-
matics. In combination with continuous flow optimization,
these two fields could expedite black box optimization, saving
significant time and money for the chemists.
3. ANATOMY OF A FLOW REACTION
In the previous section, the reasons for performing a process
utilizing flow chemistry methodologies were presented and
discussed based on the characteristics of the respective chemical
transformation. Once the decision for the development of a
continuous process is made, a flow unit suiting the specific
requirements of the transformation needs to be designed.
Developing a novel reaction system in flow, or conducting a
known chemical transformation using this enabling technology,
is not, at least initially, as trivial as utilizing traditional batch
techniques where the respective reagents are simply dissolved
or suspended in a solvent and stirred at a defined temperature
until the limiting reagent is consumed. A continuous flow
process is significantly more complex from a technological
point of view, which may explain why, in the previous century,
this technique was predominantly used only in bulk chemical
processing and engineering sciences. However, around the turn
of the millennium, interest in continuous processing began to
increase in the synthetic chemistry community. This rise
resulted from the considerable advantages offered over
traditional round-bottomed-flask chemistry and/or the access
given to otherwise forbidden or impossible transformations. In
the subsequent years, a plethora of relatively simple and user-
friendly reactor setups have been introduced which are
dedicated for synthetic applications on the laboratory scale
ranging from home-built systems to fully integrated commercial
equipment.
For those who wish to apply this enabling technology and are
not yet familiar with flow chemistry techniques, a detailed
description of all parts necessary for developing a flow reactor
unit will be given in this section. In order to give the reader an
idea of the potential of such devices, the key features of each
component will be discussed in detail with a particular focus on
their applicability in synthetic organic chemistry. This review
will not discuss fully integrated commercial flow reactors. For
recent contributions which cover this topic, see Glasnov and
Darvas et al.76,121
Flow chemistry is a modular technique which provides a
toolbox for synthetic chemists. A typical continuous flow setup
for synthetic applications can be broken down into eight basic
zones: fluid and reagent delivery, mixing, reactor, quenching,
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Figure 11. Zones of a standard two-feed continuous flow setup. For definitions of the individual flow elements, see the diagram legend at the end of
the review.

pressure regulation, collection, analysis, and purification (Figure control is, in most instances, achieved by pressure-driven flow
11). techniques (hydrodynamic pumping), where a pressure differ-
First, a fluid and reagent delivery system is necessary to ence between the inlet and the outlet of the reactor unit is
accurately feed the respective substances into the flow system. created.8,76 In other words, the fluid delivery system always
These feeds are combined in the next module by a dedicated needs to be able to surpass the pressure set by the pressure
mixing device before entering the reactor unit where the regulation module (section 3.6), and different methods are
chemical reaction occurs. This core unit is directly connected to available for the delivery of homogeneous and heterogeneous
a quenching module, which allows for accurate control of the solutions as well as gases (vide infra).
residence time. Elevated pressure regimes are easily achieved 3.2.1. Liquid Delivery. The vast majority of flow chemistry
with a pressure regulator, usually located immediately before reactor units incorporate at least one liquid delivery unit.
the final collection of the product stream. In addition, several Depending on the flow rate, the system pressure, and the
tools for analysis,120,122−125 as well as continuous purification nature of the liquid phase, three different types of pumps are
modules can be implemented.126 Importantly, all of these commonly utilized (Figure 12).129
individual parts can be arranged interchangeably and
repetitively, resulting in an infinite number of possible
modifications. Highly complex multistep sequences can be
applied to natural product synthesis or on-demand production
of pharmaceuticals.32,82
3.1. Connecting Flow Zones
Standardized connections between zones make interchange-
ability a strength of flow chemistry. Generally, the connections
between the different basic zones consist of tubings and
nonwetted parts, such as nuts and ferrules used to securely
attach the tubing to each respective unit. In most cases, all the
components required for connecting the modules are identical
to those used in standard HPLC devices and are therefore
readily available.
The dimensions and composition of the tubing are crucial
since it is in direct contact with the reagent stream. Physical
parameters like the desired system pressure and chemical
compatibility must be considered. In general, for low and
medium pressure applications (<30 bar), inert perfluorinated
polymers (PTFE, PFA, PEEK, and FEP) are adequate. High-
pressure processes (e.g., reactions far above the boiling point of
the reaction medium or reactions using supercritical solvents)
require more robust materials such as stainless steel or special
alloys.17,27,127 For specific applications, especially in case of
microfluidic reactor units and lab-on-a-chip devices, more
sophisticated interfaces may be necessary. These devices are
beyond the scope of this review and have been discussed
elsewhere.3,128
3.2. Fluid and Reagent Delivery
Precise control over the movement of fluids is important for a
continuous flow process; it not only regulates the residence Figure 12. Principle components of liquid pumps commonly used in
time but also influences the stoichiometry if two or more flow chemistry. (a) HPLC pumps. (b) Syringe pumps (single and
reagent streams are combined in a subsequent mixing unit. This dual). (c) Peristaltic pump.

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HPLC pumps (single and dual piston reciprocating) are
commonly utilized for low to high-pressure applications at flow
rates higher than 0.1 mL min−1 (Figure 12a). Single piston
reciprocating pumps are cheaper but have a higher degree of
periodic pressure pulses and therefore should be avoided when
mixing is highly important or if well-defined biphasic flow
patterns (liquid/liquid, gas/liquid) need to be generated. One
complication with HPLC pumps is that pumping problems can
be observed when volatile solvents such as Et2O, DCM, or
CHCl3 are used. This can be circumvented by degassing and/or
prepressurization of the liquids.
Lower flow rates can be accurately pumped with simple
“single shot” syringe pumps (Figure 12b). These pumps dose a
predefined amount of liquid, which limits the time and scale of
operation. Standard units also cannot operate at elevated
pressures. More advanced versions of these pump types consist
of two independent syringes in which one is delivering the
liquid phase into the flow system while the second is
simultaneously being filled. Once the “delivering syringe” is
empty, the role of the two syringes is switched, thus allowing
for a truly continuous operation. For both HPLC and syringe
pumps, the liquid is in direct contact with the pumping system
and therefore issues may arise due to fouling and blocking via
precipitation with some reagents. Peristaltic pumps have been
applied to avoid these problems and are capable of pumping
well-suspended slurries by movement of a central rotor which
presses on a flexible tubing (Figure 12c).129
All of the above hydrodynamic pumping techniques result in
a parabolic velocity profile. This means that the fluid moves
faster in the middle of the channel than at the channel wall,
which leads to diffusion and a distribution of the residence
time. One alternative to pressure-driven pumping are electro-
kinetic flow techniques, where a potential bias is applied
between the beginning and the end of the reactor unit. This can
be used for a more accurate flow pattern,8,76 however, is almost
exclusively used in micro- and nanofluidic devices such as lab-
on-a-chip applications. Importantly, the methodology is
restricted to polar solvents and a limited number of reactor
materials capable of developing surface charges (glass, silicon,
and treated PDMS).130−132 Due to the scale utilized, fluidic
delivery via electrokinetic flow is outside the scope of this
review.
While the most straightforward way to feed a substrate/
reagent into a flow reaction unit is to pump it as a solution
using the above-described pressure-driven pumping techniques,
this may not be feasible with small quantities and/or moisture
or oxygen-sensitive materials. In these instances, sample loops
may be used, where the sample is loaded into a coil of variable
size similar to an HPLC. Sample loops can be incorporated into
a flow system using a 6-way valve, which creates a bypass for a
pump-driven flow stream that can be switched to introduce the
sample (Figure 13). This methodology further allows for
combinations with autosampler units for conditions in an
automated fashion.133
3.2.2. Gas Delivery. As discussed in section 2.1.1, flow
chemistry is an ideal tool for the utilization of gases, particularly
those that are toxic or associated with severe safety issues.59 In
the simplest case, a gas bottle can be connected to the flow
reactor via a pressure regulator. However, in most cases, precise
control of the gas stream is necessary to control the
stoichiometry of a gaseous reagent or for generating a distinct
biphasic flow pattern (section 2, Figure 1). Precise control can
be easily achieved by thermal mass flow controllers (MFC).
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Figure 13. Working principle of reagent delivery via sample loop using
a 6-way-valve.
These commercially available devices measure and regulate the
gas flow rate via heat transfer phenomena and can be used for a
broad range of gases.134
3.2.3. Solid Delivery. Feeding a solid into a flow system is
a relatively difficult task and usually avoided. Instead, packed
bed columns (section 3.4.3) are utilized in most instances for
reactions involving heterogeneous catalysts or reagents.15,19,44
However, a few examples of dosing strategies based on the
pumping of magnetically stirred slurries have been reported and
reviewed.135,136
3.3. Mixer
From an operational point of view, mixing in continuous flow
units can be divided into two basic principles: active and passive
mixing.5 The term active mixing refers to methods where an
external energy input, such as ultrasonication, is used to
improve mixing within a flow reactor. Passive mixing, on the
other hand, occurs at a rate proportional to the fluid properties,
pumping speed, and physical path through the respective
mixing unit. Principles of the latter approach are applied by the
vast majority of continuous flow procedures for synthetic
purposes and are broken down based on the design of the
mixing unit.
3.3.1. Single-Phase Reactions. In many cases, simple T-
or Y-shaped connection units are used in order to combine two
or more reagent streams in a flow reactor unit. This is an
acceptable strategy for relatively slow reactions which are not
improved by faster mixing. Such reactions usually benefit from
other advantages gained by flow techniques such as process
intensification.
If fast mixing is crucial, as in reactions involving highly
reactive species,96 more specialized micromixing units have to
be used in order to reduce the mixing time. In its simplest form,
this could be a T-mixer with a very small internal diameter in
combination with high flow rates.137 More efficient mixing is
achieved using specialized mixers with optimized micro-
structures using obstacles within the microstructures (static
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mixers) or special flow arrangements to induce chaotic mixing
by eddy formation.5,138
Another micromixing technique involves splitting each
stream into multiple segments followed by rotation and
recombination (split and recombine, SAR). By repeating this
procedure several times, a multitude of small segments is
created with the effect of shortening the diffusion distance.5,138
Alternatively, multilamination type micromixers are commonly
used for mixing-controlled reactions (Figure 14). In these
Figure 14. Multilamination mixers operate through the splitting of
streams into a multitude of smaller laminae, vastly increasing the
interfacial areas to enhance diffusive mixing.
microstructured devices, the liquid feeds are split into a high
number of small streams, which are then allowed to interact,
greatly increasing the contact area and thus facilitating diffusion
(Scheme 3).5
An example exploiting multilamination mixing, and an
excellent example of mixing in general, was given by Yoshida
and co-workers in 2005.139 During their study on the mixing
controlled Friedel−Crafts acylation of reactive aromatics with
N-acyliminium ions, the authors observed relatively low yields
for the monoalkylated product 2a with a T-shaped micromixer
(36%) and even with an SAR mixing unit (50%, Table 5).
Table 5. Effect of Different Micromixers on the Friedel-
Crafts Acylation N-Acyliminium Ions
micromixer 2a [%] 2b [%]
T-shaped 36 31
SAR-type 50 14
multilamination-type 92 4
However, utilization of a multilamination type mixer for this
very fast reaction increased the selectivity for the desired
product up to 92% yield under otherwise identical conditions.
The results obtained from that study clearly show the
importance of evaluating whether fast mixing is vital for the
designed continuously performed reaction or not. It is,
therefore, necessary to be aware of the kinetics of any given
transformation in order to properly design a suitable flow setup.
In that context, Roberge and co-workers have classified three
reaction types where continuous flow processes would be
advantageous based on their kinetics.140 Type A reactions with
a half-life of less than one second are mainly controlled by the
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mixing process and often require micromixers in order to
obtain the best possible result; type B reactions, occurring
between 1 s and 10 min, can also benefit from microstructured
devices, but mixing is not as crucial; and for type C reactions
where the reaction time is greater than 10 min, mixing is not
important, and such reactions should be only considered for
flow if a continuous process would provide other advantages
such as process intensification or increased safety.
3.3.2. Multi-Phase Reactions. Biphasic liquid/liquid or
gas/liquid reactions are extremely appealing for continuous
applications as a high interfacial area can be generated. In
general, the same junctions or micromixers are used as for
single-phase reactions, with T- or Y-mixers being most
common for laboratory scale flow devices. Once combined,
the type of flow patterns (section 2.1) depend on the channel
characteristics, respective fluid(s) properties, and the flow rates
of the two phases.
The slug flow arrangement commonly generated creates
toroidal currents in each slug providing enhanced mixing and
increased mass transfer (section 2.1). If the flow rate of one
fluid is significantly faster than the other, annular regimes can
be observed (section 2.1). With gas/liquid phases, more
specialized designs such as falling-film microreactors and gas
permeable membrane reactors are available, combining mixing
and reaction modules.59 The latter has become an increasingly
popular technique, as a homogeneous (saturated) solution of
the respective gas in the reaction medium is obtained which can
be easily handled in subsequent downstream processes.30
Among several different designs, the commercially available
“tube-in-tube” setup developed by Ley and colleagues is the
most widely used.50
In principle, this device consists of a gas-permeable Teflon
AF-2400 membrane tubing (inner tube) that is fixed within
larger impermeable tubing (outer tube) (Figure 15). These
tubes are separated by T-pieces allowing for an independent
feed of both channels. Only gaseous reagents can pass the
membrane, which can either react with substrates in the liquid
phase or simply saturate the solvent for subsequent use. Jensen
Figure 15. Principle and schematic view of the tube-in-tube gas
addition.
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and co-workers recently communicated a quantitative model
for predicting gas and substrate concentration profiles in the
tube-in-tube gas addition unit. Despite the aforementioned
advantages, the authors concluded the general applicability of
the device is limited due to the low gas loading, insufficient
radial mixing, and heating characteristics.141
Finally, active mixing techniques are used for multiphase
reactions predominantly when solids are generated during the
mixing of two streams to avoid clogging.135,136 In many
instances, the most straightforward way to overcome such
blocking issues is by submerging the mixing unit in an
ultrasonic bath.142 Ultrasonication or mechanical agitation is
also commonly used for reactions in which the precipitate is
slowly formed in the reactor unit.143−148 Moreover, active
mixing by magnetic stirring in a specialized device has been
applied to solid/liquid and liquid/liquid/gas reactions by the
Ley group.149,150
3.4. Reactor Unit
This is core unit of every flow system where the chemical
reaction occurs. The reactors can generally be divided into
three main types: chip, coil, and packed bed reactors (Figure
16).
Figure 16. Reactor types for continuous flow chemistry.
The nature of the respective transformation (exo- or
endothermic, electrochemical, photochemical, multiphasic,
etc.) determines the reactor type and material. In general,
heating and cooling of all these units can be reached either by
conventional means, such as submersion of the reactor unit in a
dedicated cooling/heating bath, or by using more specialized
technologies such as cryogenic cooling units, microwave
irradiation, or inductive heating techniques.43 Photochemical
applications require a light transparent reactor unit and a
dedicated light source.64 Electrochemistry has potential as an
expanding area within flow chemistry and requires more
specialized reactors.40,151
3.4.1. Chip-Based Reactor Units. Among all three reactor
types, chip-based reactors offer the best heat transfer character-
istics due to the extremely high surface-to-volume ratios.34
Thermal reactions can be controlled by an otherwise
unreachable accuracy, making these reactors an ideal tool for
process development, despite their low throughput and
tendency to clog.
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Chip reactors are usually machined from silicon, glass,
ceramics, or stainless steel by specialized techniques and, in
strong contrast to coil-based reactor systems, such systems
often incorporate a mixing section within one microfabricated
unit (Figure 17).153 Recent advances in 3D printing have made
Figure 17. A silicon chip reactor with an integrated mixing section.152
such integrated reactor design fast, convenient, and easy.154
The choice of material depends both on chemical compatibility
and type of chemistry. Photochemical transformations can be
performed when the chip is constructed from a light permeable
material such as glass.64 Additionally, certain materials allow for
the immobilization of a catalyst on the channel wall, providing
access to reactions which are heterogeneous. As an illustrative
example for the versatility of chip reactors, Boyle and co-
workers fabricated a glass chip reactor for the production and
utilization of singlet oxygen (1O2).155 The surface of the
channel was functionalized with a free amine via silanization.
An isothiocyanate-functionalized porphyrin was subsequently
reacted, resulting in a photosensitizer-functionalized channel
wall (Scheme 1). The proof of concept study nicely
Scheme 1. Photo-Oxidation of α-Terpinene Using Porphyrin
Immobilized on the Glass Channel Wall
demonstrated this strategy as a feasible means for the
photochemical generation of singlet oxygen and its subsequent
use for the oxidation of α-terpinene 3 and cholesterol in a gas/
liquid continuous flow environment.
3.4.2. Coil-Based Reactor Units. Due to the high cost of
chip-based reactors and their inherent limitations, coil reactors
have emerged as the most widely used alternative in synthetic
flow chemistry. Coil reactors are usually made out of simple,
commercially available tubings made either from inert
fluoropolymers (PTFE, PFA, and FEP) or stainless steel
(SST). These tubings commonly have outer diameters of 1/8″
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or 1/16″ and various inner diameters (0.01″, 0.02″, 0.03″,
0.04″, 1/16″, etc.). The selection of the right material depends
on the respective application (Table 6).
Table 6. Application Range of Coil Materialsa
application PTFE PFA FEP SST
low T/p (<50 °C, < 5 bar) * * * *
high T/p (<150 °C, < 20 bar) ○ ○ ○ *
very high T/p (>150 °C, > 20 bar) × × × *
UV−vis ○ ○ * ×
corrosive reagents * * * ○
a
* = ok to use; ○ = some concerns, check datasheet; × = not feasible.
The temperature and pressure stability of fluoropolymers
depends on the wall thickness (outer diameter−inner
diameter), and this data is usually provided by the supplier.
For UV/vis irradiation, FEP has proven to be ideal due to its
excellent transmission properties.64,156 Stainless steel is the
material of choice for high-temperature and -pressure
applications. It has limited resistance to highly corrosive
reagents/conditions however, and special alloys such as
Hastelloy need to be used for such applications. While poor
chemical resistance is normally disadvantageous, the reactor
material can also be utilized as a catalyst, as demonstrated for
azide−alkyne cycloadditions, Sonogasahira reactions, and
Ullmann-type couplings.48
For all reactor types, the temperature is easily controlled by
submerging the coil in a cooling or heating bath or by
mounting it on a dedicated thermostatic unit. Similarly,
photochemical activation can easily be carried out by wrapping
the coil around a light source156 or by placing the coil reactor
adjacent to a lamp (Figure 18).64 Importantly, thermal and
photochemical techniques can be combined resulting in
variable-temperature flow photoreactors.64,157
Figure 18. Different arrangements for photochemistry in a coil reactor
unit (left, reprinted from Knowles et al.158).
3.4.3. Packed Bed Reactor Units. If heterogeneous
catalysts or reagents are required in a continuous chemical
transformation, packed bed reactors are generally utilized.15,44
These units are defined as a volume of solid material(s)
embedded between filter units through which the reaction
solution is passed at a specific position of the flow path.
Common packed bed reactors involve columns or cartridges
made from glass, polymeric materials, or stainless steel with
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dedicated, resealable end pieces which incorporated a filter frit
(Figure 19).
Figure 19. Representative example of a packed bed reactor.
The particle size of the heterogeneous material is important.
Big particles suffer from a relatively low surface-to-volume ratio,
and since the reaction occurs on the surface, conversion might
be inefficient. Small particles, on the other hand, may cause a
high back pressure or can clog the filter unit. Moreover,
uncontrolled fluid dynamics and heat transfer limitations have
to be taken into account for the design of the reactor.
There are several advantages of heterogeneous catalysis in a
packed bed as opposed to a batch reactor. First, this reactor
type affords a significantly higher effective molarity of the
catalyst/reagent, decreasing reaction times. Second, as the
catalyst/reagent is contained by the frit, there is no subsequent
separation step of the reaction mixture from the catalyst.
Continuous heterogeneous catalysis in a packed bed reactor is
not always trivial, however. In particular, for immobilized
transition-metal catalysis, leaching of the catalytic material can
occur, resulting in contamination of the product and
deactivation of the column.37
The most popular application of this reactor type is for
catalytic hydrogenations in a triphasic gas/liquid/solid
system.19 Hydrogen is delivered either from a gas bottle or
from electrolysis of H2O and subsequently mixed with a stream
of the respective substrate. The gas/liquid mixture then flows
through a heated packed bed reactor containing the
heterogeneous hydrogenation catalyst (e.g., Pd/C, Pt/C,
PtO2, Raney-Ni). High pressures can be applied to expedite
the desired reduction.
Importantly, when a reaction is carried out using a
heterogeneous material in a packed bed reactor, different
molecules can have different affinities for the solid material.
This may lead to a “chromatographic effect” causing incorrect
reaction stoichiometry at the initial phase of a continuous
experiment.159 It is, therefore, important to wait until steady
state conditions are achieved in order to obtain reliable results.
3.4.4. Electrochemical Devices. In electrochemical syn-
thesis, chemical reactions take place at the interface of an
electrode (section 2.4.2).40,151 In general, there are two types of
electrochemical flow reactors: undivided and divided cell
microreactors. In the former, both electrodes are in direct
contact with the flow channel, cut from a polymer foil/gasket
sandwiched between the electrodes (Figure 20).40,151 In
contrast, divided cell reactors are separated by a membrane
or diaphragm with individual channels for the anode and
cathode.40,151 The latter concept was used in the so-called
“cation flow” method for generating N-acyliminium ions 6,
where the anionic stream generated goes directly to waste. The
free cations can react with nucleophiles such as allyltrime-
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Figure 20. An electrochemical flow reactor with undivided cells.
thylsilane 7 to afford the desired C−C coupling products 8
(Scheme 2).160 A similar approach to the divided cell reactor
Scheme 2. “Cation Flow” Method Using a Divided Cell
Electrochemical Flow Reactor
employs one inlet and one outlet, where the electric current
flow and the liquid flow are parallel, permitting conversion of
the starting material without the supporting electrolyte.161
3.4.5. Miscellaneous. It is important to note that,
especially for highly reactive species, the initial mixing unit
itself acts to an extent as a reactor unit. A concrete example is
the use of organolithium compounds in microreactor units,
where efficient mixing enables an otherwise inaccessible control
over highly reactive intermediates (section 6).96 Another
example utilizes a tube-in-tube unit59 for the carboxylation of
Grignard reagents with CO2,162 where a rapid gas/liquid
reaction occurs in the liquid phase immediately upon
introduction of the gas.
If solid materials are generated during the reaction, an
agitated cell reactor has been used in order to avoid clogging
(Figure 21).147 The system is based on a reactor block
containing interconnected cells equipped with agitators and can
be operated in a temperature range from −40 up to 140 °C.
The entire reactor block is mounted on a shaking motor which
causes the free agitators to rapidly move in the cells for
mechanical mixing of the flowing mixture.
Figure 21. Schematic representation of the reactor block from the
agitated cell reactor. Reprinted from Browne et al.147 Copyright 2011
American Chemical Society.
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Other reactor types such as falling film reactors4 or rotating
reactor devices28 are less commonly used by the synthetic
community on a laboratory scale.
3.5. Quenching Unit
Accurate control of the reaction time for any given flow
reaction requires an appropriate quenching procedure since
most reactions (or side reactions) can otherwise continue in the
collection flask leading to unreliable results. The termination
strategy depends on the chemical reaction and the flow process
itself. For example, with packed bed catalysis, a quenching
module is not necessary since the reaction immediately stops
when the reaction mixture leaves the packed bed column.
Electro- and photochemical reactions generally exhibit
instantaneous quenching once the reaction mixture leaves the
reactor unit due to separation from the electrode materials or
photon source, respectively.
For other homogeneous transformations, the reaction time is
controlled either by thermal or chemical quenching. In the
former case, a purely thermal reaction can be immediately
stopped by rapid cooling, effective due to the enhanced heat
transfer characteristics in a micro- or meso-flow environment
(section 2.3). For all other situations, chemical quenching of
the reaction is required, where a quenching reagent is added to
the stream via a mixing unit. Several micromixing devices can
be used to facilitate and expedite mixing events, allowing for an
accurate control of the reaction time (section 3.3). This
strategy allows for the control of extremely fast reactions which
cannot be done in conventional batch systems.96
3.6. Pressure Regulating Unit
Back pressure regulators (BPR) are special valves which are
installed to operate at a constant upstream system pressure.
Working at elevated pressures not only allows processes to be
performed above the boiling point of the reaction media but
also enables superior control and rate enhancement when
volatile or gaseous reagents or intermediates are employed.102
BPRs are necessary for reproducibility in transformations where
gases are generated since increasing the pressure can keep the
gas in solution, reducing residence time deviations. Moreover,
high pressures are essential for supercritical conditions. The
majority of back pressure units do not measure the actual
system pressure, and to obtain this information, installation of
pressure sensors within the flow setup is necessary. Such
sensors are often integrated into the pumping unit or can be
attached at virtually any stage in the flow path.
Two types of back pressure regulators are commonly found
in continuous flow devices. Preset BPRs operate at a predefined
pressure value, avoiding the need for an additional pressure
sensor. These are often small cartridge-type devices where the
fluid presses against a spring-loaded plunger, thus opening the
flow path when a predefined pressure is reached (Figure 22a).
After this point, the fluid flows through the BPR as long as the
pressure remains above the predefined value. A more versatile,
albeit more expensive, alternative is a BPR capable of adjusting
the system pressure without interrupting the flow process. In
these systems, a reference pressure against a diaphragm is used
to precisely set the system pressure via mechanical forces or gas
pressurization (Figure 22b). Both models usually cover a broad
pressure range up to 70 bar and can be used for single- and
biphasic (gas/liquid, liquid/liquid) reactions. Processing of
reaction mixtures involving solid particles or viscous materials
at elevated pressure regimes are best realized via the utilization
of a pressurized collection vessel.163,164
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Figure 22. Working principle of (a) preset and (b) adjustable back
pressure regulators.
3.7. Collection Unit
After depressurization of the reaction stream following the BPR
unit, the final mixture is usually collected in a flask. For
analyzing residence time distribution or automated screening
applications, fraction collectors may be installed.
3.8. Optional Zones
3.8.1. Analysis. Analysis of reaction mixtures can be carried
out in three different ways during a continuous flow synthesis.
For laboratory scale experiments, offline analysis is most
commonly used, meaning reaction mixtures are manually
collected and subjected to analysis (GC, HPLC, NMR, etc.).
This conventional approach is often sufficient in synthetic
projects. However, if extensive optimization of reaction
parameters, the kinetics/mechanism of the transformation,
permanent quality control of a continuous process, or the
generation and downstream processing of reactive and toxic
intermediates is of interest, online or inline analysis techniques
may be useful.120,123−125
Online analysis means that the reaction mixture is periodi-
cally analyzed without manual transfer via systems which
automatically sample aliquots and transfer them to the
respective analytical instrument. This allows for the utilization
of the vast majority of analytical techniques such as HPLC, GC,
mass spectroscopy, fluorescence spectroscopy, and X-ray
spectroscopy.120,123−125 If the analytical method is (i) non-
destructive and (ii) allows for “real-time analysis” as in FTIR,
Raman, UV−vis, and NMR spectroscopy, such integration of
the analysis unit in the flow process (inline) via an analytical
flow-through cell is feasible.120,123−125 The choice for the
proper technique depends on the application and is made on a
case-by-case basis.
3.8.2. Purification. Similar to analytical procedures, most
purification steps rely on conventional methods following
collection of the reaction mixture from the flow system.
However, if complex target molecules like active pharmaceutical
ingredients (APIs) should be synthesized in a fully continuous
fashion, inline purification is often necessary between respective
chemical transformations.
Liquid/Liquid Separation. The most common technique
used in the field of continuous flow synthesis is liquid/liquid
extraction using membrane-based separation techniques.75 The
working principle of such a continuous extraction is
straightforward. Initially, the extraction solvent is added to
the reaction stream via a mixing unit, and the resultant biphasic
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mixture is passed through a residence time unit for extraction.
The mixture then enters the membrane separation unit which
usually consists of a PTFE membrane sandwiched between two
flow channels (Figure 23). The organic phase is able to pass
through the hydrophobic membrane, allowing both phases to
be used for further downstream processing.
Figure 23. Working principle of continuous liquid/liquid separation
using a hydrophobic membrane.
If gases are generated or a gas/liquid reaction is used in the
initial stage of a reaction, membrane technologies can also be
used for phase separation. The tube-in-tube gas addition device
can be simply converted into a gas separator by connecting it to
a vacuum line. This strategy has been successfully used to
remove the ethylene generated during olefin metathesis
reactions.165 Another effective and common technique for
inline purification at a laboratory scale is the use of scavenger
cartridges to remove impurities.166 Such scavenger cartridges
are, in principle, packed bed reactors filled with a suitable
material (acidic, basic, etc.). These packed beds are installed at
proper positions in the flow path to remove excess reagents or
impurities.
A number of other purification techniques are much more
sophisticated and require significant time, financial, and
personnel investments. Solvent switching, for instance, remains
a challenge on a laboratory scale and only a few examples of this
process have been reported.167−169 While potentially interesting
for industry, simulated moving-bed chromatography (SMB)
requires a great deal of engineering experience.170−172 Similarly,
continuous crystallizations have been performed;32,82,172
however, they have yet to impact the synthetic laboratory.
4. CONSIDERATIONS FOR FLOW EXPERIMENTS
When looking at some protocols for running a reaction under
continuous flow mode, it often appears that these processes are
straightforward: assemble a flow reactor, set the proper
conditions, load the respective starting materials, catalysts and
reagents, hit the start button, and wait until the (pure) product
leaves the flow reactor. More realistically, any given flow
process is the result of a series of experiments involving an in-
depth optimization of the flow reactor unit and finding suitable
conditions for the reaction. Some transformations which are
trivial in a flask can be tedious in flow and may require special
equipment or even a completely new approach to the process.
No single flow setup is capable of accommodating all reactions
in continuous synthesis, but the modular design allows for facile
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adaption of reaction conditions to access most transformations.
A carefully elaborated flow process offers highly reproducible
and scalable protocols or expands the possibilities of synthetic
chemistry into new areas.27,96
Flow chemistry requires an understanding of chemical and
engineering aspects, but in our hands, experience is gained by
performing reactions. To facilitate the entry into this readily
available enabling technology, this section will give a brief
overview of important parameters and potential pitfalls that
should be considered during the development of a flow
chemical process.
4.1. Key Parameters
There are a plethora of important parameters for distinguishing
a flow chemical process from a conventional batch reactor
setup. These are either related to theoretical considerations why
flow chemistry should be applied (section 2) or are of more
practical nature and important for process development itself.
One of the most fundamental differences between chemistry in
a flask and in a continuous environment is related to
concentration changes. For instance, the substrate concen-
tration decreases over time and is uniformly distributed
throughout the flask. Conversely, in a flow reaction, the
concentration of the starting material decreases along the
reactor unit reaching a minimum at its end. If ideal plug-flow
behavior is assumed, the length dependency leads to a constant
concentration of substrate and product at a certain position
under steady state conditions. This position is reflected in the
so-called residence time which is the time between initiation
and termination of a continuous transformation and is often
incorrectly compared with the reaction time of a batch process.
The residence time can be varied either via changing the flow
speed (ν) or the length/volume of the flow path (V) (eq 9).
V
tres =
ν (9)
Prediction of the residence time is therefore relatively simple
for single-phase transformations since the reactor volume as
well as the flow rate is set by the user. For liquid/solid reactions
in packed bed reactors and reactions involving a gas, this is less
trivial since it depends on several factors such as the dead
volume of the packed bed reactor, the solubility of the
respective gas in the liquid phase, and the system pressure. It is,
therefore, difficult to calculate and easier to simply measure the
residence time manually by injecting a dye solution.
Regulating the residence time is a nontrivial task since this
strongly depends on the respective chemical transformation.
The key steps for accurate residence time control are the
precise initiation and termination of the reaction. Initiation is
carried out by the mixing of reactive reagents with the
respective substrate (section 3.3) or physical activation by
heating or irradiation. In packed bed applications, initiation is
carried out at the moment the liquid substrate stream gets in
contact with a solid catalyst/reagent species. Termination, on
the other hand, is carried out via an appropriate quenching
technique (section 3.5).
Importantly, pressure-driven flow techniques (section 3.2)
result in laminar flow profiles rather than an ideal plug flow
behavior. The parabolic velocity profile which is a consequence
of axial convection and radial diffusion leads to sample
dispersion which is usually referred to as residence time
distribution (Figure 24).173
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Figure 24. Parabolic velocity profile in a flow reactor unit resulting in
residence time distribution. Adapted from Golbig et al.173
The residence time distribution is important for multistep
synthesis, especially when the reaction volume is significantly
smaller than the reactor volume. Estimating the controlled
addition of reagents in downstream processes becomes
challenging. Imprecise residence times can be overcome by
using inline analysis techniques in combination with automated
collection and/or reagent addition.174,175 Moreover, this
distribution phenomenon sometimes plays an important role
in reporting conversion and yield during the optimization of
single-step processes (Figure 25). Overall conversion/yield
Figure 25. Difference between overall and steady state values for
conversion and yield.
means that the entire reaction mixture was collected and
analyzed/isolated, while the conversion/yield under steady
state conditions reflects the values under stable conditions.
When communicating yields, it is often useful to report
productivity (amount of generated product per time) and
space-time-yield (amount of generated product per volume per
time) to compare different flow and batch approaches.
Control over the reaction stoichiometry in a round-bottomed
flask depends solely on the concentration of the respective
reagents in the reaction medium. In a continuous flow reactor,
the flow rate additionally influences this value with more than
one reagent stream (eq 10). Thus, molar flow rates (ṅ) are
calculated from the concentration of the individual substances
(c) and the flow rate of the respective feed (ν).
n ̇ = cν (10)
The flow rate (ν), the length (L), and diameter (d) of the
reactor unit, as well as the dynamic viscosity (μ) of the reaction
medium influence the pressure drop (Δp) in a hydrodynami-
cally driven continuous flow reactor and can be estimated by
the Hagen−Poiseuille equation (eq 11).
32μLν
Δp =
d2 (11)
This pressure difference is important as it is always higher at
the beginning of the reactor unit than at the end. Therefore,
this pressure phenomenon should be kept in mind for choosing
reactor dimensions/materials and pumping systems to avoid
malfunctions such as stalling or bursting.
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4.2. Common Problems
In flow chemistry, as in every experiment, there are things
which can go wrong. This section gives a brief overview of
common mistakes and pitfalls during continuous flow processes
which usually can be avoided.
Various process conditions can be changed for the
development/optimization of a continuous flow process. In
the case of a simple, completely homogeneous reaction
involving two separate reagent streams, these would be the
two respective flow rates (ν1, ν2) and reagent concentrations
(c1, c2), the reactor volume (V), the temperature (T), and the
system pressure (p) (Figure 26).
Figure 26. Adjustable conditions for a simple two-feed flow process.
Notably, varying some of these conditions may entail other
parameter changes. For instance, if a single flow rate is altered
but all other parameters stay constant not only will the
stoichiometry be different but also the final concentration and
the residence time. Consequently, it is sometimes not clear
which of the parameter changes cause the desired or undesired
change in the process outcome, which is significant for
optimization. Usually, the reactor volume (V) can be changed
without altering other conditions if the reactor material and
inner diameters are kept constant. Temperature changes may
require adjustments of the pressure if processes are conducted
above the boiling point of the reaction medium. Special care
has to be taken in the case of processes where gases are used or
generated since pressure changes affect the solubility of gases
and consequently can influence the residence time.
Before starting any flow process, the user should understand
the system limitations of all units in order to avoid equipment
troubles. Problems and reproducibility issues are often related
to the pumping system. Many syringe and peristaltic pumps are
not capable of working at high system pressures, and severe
problems such as stalling can occur. Piston pumps, on the other
hand, function well under high pressure, however, may give
irreproducible results at lower flow rates. Moreover, small
particles, bubbles, and variations in the liquid phase can affect
check valves and wetted parts, interrupting or stopping fluid
delivery. Priming the pumps and filtration of the liquid phase
can reduce the risk of these problems. Sample loops for reagent
injection can assist with overcoming such issues. Various
commercially available pumping systems come with an
integrated monitoring system capable of detecting incorrect
pumping or stalling and are helpful for troubleshooting
unsuccessful or irreproducible experiments.
The operation of a flow reactor, especially at higher
pressures, can lead to leaking, which not only causes pressure
fluctuations but also imposes severe safety risks when using
toxic and hazardous reagents. Therefore, connections should be
carefully checked before starting a flow reaction.
One of the main limitations for continuous processing is
fouling and/or clogging of the flow unit, which can happen at
virtually any place in the flow device.46 Fouling of flow reactor
units can be, depending on its origin, classified into (i)
crystallization fouling as a result of crystallization or freezing
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processes, (ii) particulate fouling due to accumulation of solids
on the channel surface, (iii) chemical reaction fouling via
deposition of materials resulting from chemical reactions, and
(iv) corrosion fouling.176 Some of these processes, such as
corrosion and chemical reaction fouling can be avoided by
using materials which are inert to the corresponding reagents or
conditions.176 Crystallization and particulate fouling events, on
the other hand, are less easily handled. Droplet reaction
techniques can minimize particle−wall interactions and
suppress fouling.7,176−178 Additionally, “in situ cleaning” via
ultrasonication can be used to tackle reactor fouling during a
chemical reaction.145,176 On the other hand, more difficult
clogging issues may require specialized reactors such as the
agitated cell reactor (section 3.4.5).147 To avoid clogging at the
BPR, an additional solvent may be introduced in order to
dissolve the precipitate after the reactor unit. Alternatively, Parr
bomb collection vessels can be employed when dissolution is
not feasible or desirable.163,164
The following sections highlight the advances reported in the
past five years exploiting flow chemistry to enhance reactions.
These reports were selected based on the batch versus flow
decision diagram (section 2.5). The schemes summarize the
equipment used to carry out each transformation, and a legend
of the flow components can be found at the end of this review.
5. MULTIPHASIC REACTIONS
Multiphase reactions involve the combination of two or more
immiscible phases. Mass transfer is often the rate-determining
step in this class of reactions, and therefore, such trans-
formations can benefit from micro- or mesofluidic flow devices.
The improved interfacial area is the main reason for doing such
transformations in a continuous flow regime. Importantly, in
many cases, this reason overlaps with other strategies (high
temperature/pressure, safety, etc.) to improve the respective
process. In this section, multiphase literature examples are
discussed.
5.1. Gas−Liquid Reactions
Laboratory-scale batch approaches involving gaseous reagents/
reactants are usually carried out using a round-bottomed flask
equipped with a septum and a balloon containing the respective
gas. These reactions are often inefficient as they suffer from a
small interfacial area and are restricted to the boiling point of
the reaction solvent or atmospheric pressure if no dedicated
pressurizable stirred reactor is available. For these reasons,
chemical reactions involving gases can be generally seen as one
of the ideal classes of transformations for continuous flow
chemistry.59
The solubility of the gas in the reaction medium can be
significantly increased in flow by placing the system under
pressure (section 2.1). By using dedicated tools such as mass
flow controllers or tube-in-tube mixing units, accurate and
reproducible dosing of the gas into the continuous flow reactor
makes handling easier and enables the user to precisely regulate
the reaction stoichiometry. Toxic gases such as CO35 and
explosive gas−liquid mixtures such as organic solvents with
O266,179−181 pose safety hazards. These risks can be minimized
in flow mode as reactions are scaled over time rather than over
volume, meaning the amount of dangerous reagent(s) exposed
to the reaction conditions is considerably less in flow than in
batch. Moreover, highly reactive or toxic gaseous reagents such
as phosgene or diazomethane can be generated on-demand and
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subsequently used in downstream processes, avoiding their
storage and transportation.59
Consequently, a plethora of gases has been extensively
utilized in continuous flow mode. As mentioned in section
3.3.2, the tube-in-tube gas loading tool for saturating the liquid
stream with a gaseous reagent or mass flow controllers in
combination with mixing units are predominantly used for
laboratory applications. Slug flow patterns generated with an
MFC are the predominant regime unless otherwise stated. Gas/
liquid reactions involving photochemical activation will be
discussed in section 5.
5.1.1. Carbon Monoxide. Carbon monoxide (CO) is a
colorless, odorless, and tasteless gas which is extremely toxic,
even at low concentrations. Nevertheless, this hazardous gas is
an important C1 building block offering the possibility to install
a carbonyl group into organic molecules via the transition metal
catalyzed formation of two new σ-bonds.182−184 Various
research groups have evaluated the feasibility of continuous
flow chemistry as a safe and efficient tool for catalytic
carbonylation reactions using gaseous CO35,185−191 and CO
surrogates.150,192,193
A very general procedure for continuous palladium-catalyzed
carbonylations was presented by Ley and co-workers using a
tube-in-tube gas loading tool in combination with a coil reactor
(Scheme 3).190 The initial design suffered from precipitation of
Scheme 3. General Flow Approach for Palladium-Catalyzed
Carbonylations Using a Tube-in-Tube Gas Loading Tool
Pd(0) in the tube-in-tube reactor unit, necessitating system
modifications. The authors used a different reactor config-
uration, where the reagents were mixed with a second liquid
stream containing the dissolved gas before entering the heated
reactor unit. Palladium black precipitation was further
minimized by optimizing the solvent system (DMF/toluene).
A scavenger cartridge (Quadrapure TU) was used for the inline
separation of the catalyst.
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High conversions for several aryl iodides were obtained at
100 °C within 37.5 min at a back pressure of 6.9 bar utilizing
Pd(OAc)2 in combination with Xantphos, Et3N, and MeOH.
Less reactive aryl bromides necessitated a different solvent (1,4-
dioxane), higher back pressure (15 bar), and hydrazine to
facilitate the Pd(II) reduction. Even still, electron-rich
bromobenzene derivatives suffered from low conversions.
Further modifications of the reaction conditions enabled the
methoxycarbonylation of vinyl iodides (r.t. instead of 100 °C)
and intramolecular coupling reactions (no additional nucleo-
phile, addition of hydrazine) in the continuous flow mode. By
changing the nucleophile from methanol to amines, several
amides were synthesized in good-to-excellent yields in the
presence of 10 mol % hydrazine. Furthermore, the authors
adapted the reactor setups for the utilization of water and
gaseous MeNH2, showcasing the modularity of their flow
approach.
While safer than batch protocols, Ley’s conditions still
required pressurized CO canisters as a gas source. An
alternative approach is the on-demand generation of CO
from surrogates such as 2,4,6-trichlorophenyl formate192 or
oxalyl chloride.150 Arguably, the most sustainable CO source is
formic acid, which can be dehydrated in the presence of sulfuric
acid.194 This strategy was applied to the continuous Koch-Haaf
reaction of adamantols195 and Pd-catalyzed Heck carbon-
ylations.193 The latter example was first carried out in a two-
chamber batch reactor invented by the Skydstrup group
(Scheme 4a).196 This reactor unit enables an ex situ generation
Scheme 4. Heck-Type Carbonylation Using ex Situ
Generated CO in (a) a Dual Chamber Batch Reactor and (b)
a Tube-in-Tube Gas Loading Unit
of CO from stable precursors in one chamber and its utilization
in the second chamber. The authors realized, however, that this
batch reactor is analogous to a tube-in-tube gas loading tool and
hypothesized that they can pump a mixture of formic acid and
H2SO4 through the inner tube to generate CO which would
pass the gas permeable membrane where it could be consumed
in an organic stream containing the reaction mixture (Scheme
4b).193 After optimizing the reaction conditions for the
carbonylation of 4-iodoanisole 9 and n-hexylamine 10 in
batch, the authors ultimately validated their hypothesis using a
home-built tube-in-tube system. While the yields for the
continuous approach were lower even at longer reaction times,
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the proof-of-concept study demonstrated that the presented
flow approach may be a promising option to scale the chemistry
developed in the dual-chamber reactor.
Fukuyama et al. described a continuous synthesis of dienol
silyl ether 13 from (1-trimethylsilyl)allyllithium 14 and CO via
a 1,2-anionic silicon shift (Scheme 5).197 In the optimized flow
Scheme 5. Generation of 1-Silylallyllithium Intermediates
Followed by Gas-Liquid Carbonylation and Inline
Quenching
setup, a solution of n-BuLi in hexane was mixed with
allytrimethylsilane 12 and delivered to the first coil reactor,
generating an allyl lithium intermediate. Subsequently, an
MFC-regulated stream of carbon monoxide was added via a T-
mixer and heated at 80 °C before depressurization. A quench
with TMSCl yielded the desired silyl enol ether 13 in 93%
isolated yield with a selectivity of 93% for the E-isomer.
Expansion of the reaction scope by varying both the alkylsilane
and the electrophile resulted in good-to-excellent yields and
diastereomeric ratios. This protocol not only exhibits increased
safety but also improved the yield and rate of the CO trapping
reaction significantly compared to conventional batch proce-
dures.
Takebayashi et al. showed that under extreme conditions a
continuous flow unit gave superior results compared to a batch
autoclave reactor in the high temperature/pressure reductive
carbonylation of nitrobenzene using a Pd catalyst (Scheme
6).198 A comparison of the reaction at 220 °C and 10 bar
showed a significantly higher isocyanate 15 concentration for
the flow reaction. Moreover, the batch reaction resulted in a
black, heterogeneous reaction mixture, whereas the flow reactor
produced no precipitation or discoloration. The precipitates
observed in batch were attributed to several side products
(azoxybenzene, azobenzene, and oligomers) and Pd(0)
Scheme 6. Comparison of the Reductive Carbonylation of
Nitrobenzene in Flow and Batch. Reprinted with permission
from ref 198. Copyright 2012 Elsevier.
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particles most likely originating from imprecise temperature
control and/or local overheating. Moreover, a comparison of
different coil reactors (i.d.: 1 or 0.5 mm) showed significantly
better results for the reactor with a smaller inner diameter,
rationalized by the smaller segments and thus an increased
interfacial area. The turnover numbers were reported to be
relatively low, however (>5 in flow compared to <1 in batch).
5.1.2. Carbon Dioxide. Carbon dioxide (CO2) is a very
attractive building block not only because it is widely abundant
and inexpensive but also since it is nontoxic and nonflammable.
It is however only a weak electrophile, thus requiring strong
nucleophiles for noncatalytic transformations.199 As such,
several groups have investigated the use of CO2 with Grignard
reagents 162,200,201 and organolithium compounds in
flow.202−204 Kupracz et al. developed a continuous synthesis
of the antidepressant amitriptyline.205 The key step in this
synthetic route is the synthesis of dibenzosuberone 18 from 1-
bromo-2-(bromomethyl)benzene 16 (Scheme 7). The reaction
Scheme 7. Continuous Multistep Synthesis of
Dibenzosuberone Using Gaseous CO2
is initiated by a Wurtz-type dimerization yielding 17 followed
by a Parham cyclization.206 The original one-pot batch
procedure is tedious: 16 was initially treated with n-BuLi at
−100 °C for 1 h forming [2-(2-bromophenethyl)phenyl]
lithium. Then CO2 was bubbled through the reaction mixture
for 1.5 h at −100 °C, and the temperature was raised to 25 °C
(1.5 h). Anhydrous N2 is bubbled through the mixture for 1.5 h
to remove unreacted CO2. Cooling back to −100 °C, slow
addition of n-BuLi, warming up to r.t. and stirring for 6 h
afforded 18 in 56% yield.206 After a careful optimization of the
flow reactor setup and conditions, Kirschning performed the
same synthesis under milder conditions with 33 s overall
residence time and a maximum isolated yield of 76% of
dibenzosuberone 18, translating to a productivity of 7.62 g h−1
(Scheme 7). A T-shaped micromixer (i.d. 250 μm) for rapid
mixing was key to the success of the initial Wurtz-type coupling
and enabled the reaction to be run at −50 °C with good
selectivity. Then CO2 was added using the membrane-based gas
loading tool and the carboxylation smoothly proceeded at room
temperature in a couple of seconds. CO2 was removed using a
gas permeable tubing before the final cyclization to avoid side
reactions with n-BuLi.
More recently, Kozak et al. developed an efficient reaction
system for the synthesis of cyclic carbonates from CO2 and
epoxides under continuous flow conditions by using catalytic
amounts of N-bromosuccinimide (NBS) and benzoyl peroxide
(BPO) (Scheme 8). 207 On the basis of mechanistic
investigations, the authors proposed that BPO accelerates the
generation of Br2, which activates the epoxide via the formation
of a bromo-oxonium species 19. Since the reaction required
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Scheme 8. Catalytic Synthesis of Cyclic Carbonates from
CO2 and Epoxides in Continuous Flow
either DMF, DMA, or NMP, the authors concluded that these
solvents activate CO2 to form 20, which can further react with
the activated epoxide species. The reactions were carried out
using a two-feed setup consisting of a syringe pump, a mass
flow controller, and a Y-mixing unit which led into a stainless
steel coil reactor. A sampling loop connected via a 6-way-valve
was used for product sampling, and a collection vessel
pressurized by N2 served as a back pressure regulating unit. A
broad range of epoxides reacted smoothly under the optimized
conditions within 30 min, resulting in good-to-excellent NMR
yields under steady state conditions. Moreover, the synthesis of
the model compound 4-hexyl-1,3-dioxolan-2-one was carried
out continuously over 14 h, resulting in 82% isolated yield after
chromatography (87% NMR yield).
Combining epoxidation and carboxylation, Sathe et al.
converted olefins into cyclic organic carbonates in a continuous
sequence (Scheme 9).208 The initial epoxidation was carried
Scheme 9. Sequential Epoxidation/Carboxylation of Olefins
for the Synthesis of Cyclic Carbonates in Continuous Flow
out with hydrogen peroxide as oxidant in a biphasic liquid−
liquid reaction using methyltrioxorhenium (MTO) as catalyst
and 3-methylpyrrazole as a N-donor ligand. After combining
the immiscible liquid streams, a packed bed reactor filled with
sand was used to increase mixing of the aqueous and organic
phases. A membrane separator was used to remove the aqueous
waste, and the organic stream was mixed with a highly Lewis
acidic Al(III) catalyst and TBAI. Subsequently, CO2 was added
via a T-mixer and a mass flow controller. The resulting gas−
liquid slug flow was then heated to 100 °C in a second sand-
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filled packed bed reactor. A residence time of 45 min for the
first step and 40 min for the carboxylation was sufficient for the
synthesis of several cyclic carbonates from the corresponding
styrenes or aliphatic olefins. The main limitation of the protocol
is that polar olefins/epoxides which are miscible with water are
not compatible with the membrane separation strategy.
Moreover, analysis of the organic and aqueous phases after
the epoxidation step revealed similar rhenium concentrations in
both, preventing the authors from developing an efficient
recycling strategy.
Carbon dioxide can be utilized to convert photochemically
generated α-amino nitriles into N,N-unsubstituted hydantoins
which have a number of applications as, for example, herbicides
or fungicides (Scheme 10).209 Initial experiments at room
Scheme 10. Continuous Synthesis of Hydantoins from α-
Amino Nitriles and CO2
temperature and atmospheric pressure gave just 5% of the
desired compound within 10 min residence time. An
intensification of this continuous process showed that the
reaction significantly benefits from higher temperatures and
pressures, and full conversion could be obtained at 80 °C and
7.5 bar within 20 min. Benzylic substrates bearing neutral or
electron withdrawing groups reacted smoothly under these
conditions resulting in the desired products in good-to-
excellent yields. Electron-rich and aliphatic substrates, on the
other hand, suffered from poor isolated yields in this route to
hydantoins.
5.1.3. Oxygen. The economic and environmental advan-
tages of using oxygen or air as a reagent in chemistry are
apparent due to its high abundance. However, oxidations using
molecular oxygen in the presence of organic solvents are
associated with safety risks, especially at elevated temperatures
and pressures. These hazards can be elegantly addressed by
continuous flow technology, as the small volumes and channel
dimensions minimize the possibility of an explosion inside the
reactor.66,179,180,210
Jensen and co-workers took advantage of continuous flow
technology during their study on the metal-free oxidation of
picolines in a silicon nitride chip reactor with an integrated
mixing zone (Scheme 11).211 By optimizing the reaction for
each isomer, the authors found conditions which enabled the
utilization of air instead of oxygen. The reaction is proposed to
proceed via an initial deprotonation of the methyl group,
Scheme 11. Aerobic Oxidation of Picolines in Continuous
Flow
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followed by an anionic oxidation step. Depending on the
substrate, the solvent was important for high conversion. While
2-picoline gave the best results in a mixture of dimethoxyethane
and THF, 3-picoline was oxidized smoothly in DMPU/THF.
The 4-substituted analog, on the other hand, worked equally in
both solvent systems.
Pure oxygen has been used to study a catalyst-free oxidation
of aldehydes at room temperature in a coil reactor unit
(Scheme 12).212 The reaction is known to take place in three
Scheme 12. Oxidation of Aldehydes Using O2 in Flow
consecutive stages. First, a free radical chain reaction occurs to
form the corresponding peracid, which adds to another
aldehyde. The resultant intermediate then undergoes a
rearrangement, resulting in the corresponding carboxylate.
The authors assumed that the radical chain was initiated by
trace amounts of an impurity in the starting material. However,
for less reactive substrates, the authors had to add a catalytic
amount of a homogeneous Mn(II) catalyst to maintain mild
conditions and a short reaction time. The same group later
went on to use a similar flow setup for systematic studies on the
catalytic aerobic oxidation of aldehydes213,214 and for
mechanistic investigations concerning the Mukaiyama epox-
idation.215
The Jamison group developed an unconventional approach
for the continuous synthesis of phenols from Grignard reagents
using molecular oxygen (Scheme 13).216 Previous work on the
Scheme 13. Synthesis of Phenols from Aryl Grignard
Reagents and Air
reactions of Grignard reagents with oxygen in batch showed
that high yields can be obtained in the case of alkyl Grignard
reagents, but for aromatic derivatives complex reaction mixtures
and poor yields are usually observed.217 The researchers
attributed this phenomenon to the ArMgX species’ low
reactivity toward O2 and hypothesized that the enhanced
mass transfer in continuous flow mode may allow them to
overcome these reactivity issues. An initial comparison of the
phenol synthesis from phenylmagnesium bromide and
molecular O2 showed low yields in batch (9−15%), whereas
a simple flow setup (Scheme 13) provided the desired product
in 53% isolated yield. Following further optimization, the final
flow process (−25 °C, 10 bar, 3.4 min residence time) provided
phenol in almost quantitative yields. The synthetic procedure
showed excellent results for substrates with electron-donating
groups. For electron-deficient phenylmagnesium reagents and
heteroarylmagnesium bromides, higher reaction temperatures
were necessary to obtain full consumption of the starting
material.
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Kappe and co-workers used a mixture of hydrazine hydrate
and O2 in a high T/p environment for the reduction of olefins
in flow (Scheme 14a).218 Oxidation of hydrazine yields a highly
Scheme 14. Continuous Generation of Diazene and Its
Utilization for the Reduction of (a) Alkenes, (b) Artemisinic
Acid 21, and (c) Thebaine 24
reactive diimide which acts as a selective transfer hydrogenation
agent for carbon−carbon double bonds. Unfortunately, the
oxidation of hydrazine is rather slow and requires catalysts
under mild conditions. In flow, harsh conditions can be safely
applied to this extremely hazardous reaction mixture (120 °C,
20 bar), eliminating the need for a catalytic species. Good-to-
excellent isolated yields were obtained for various simple
olefins, and the products were often isolated by solvent
evaporation, as the only byproducts of the process are nitrogen
and water. As a result of studies on the hydrazine oxidation in
flow, the authors subsequently developed a multi-injection
strategy to overcome efficiency problems due to hydrazine
overoxidation, a problem associated with more challenging
substrates. A multi-injection protocol allowed for the selective
reduction of artemisinic acid 21,219 directly yielding the
precursor 22 for the antimalarial drug artemisinin 23 (Scheme
14b). Moreover, thebaine 24 was selectively reduced and
ultimately converted into the active pharmaceutical ingredient
hydrocodone 25 in good yield and selectivity (Scheme 14c).210
Coil reactor-based setups for high T/p reactions where the
oxygen/air stream is controlled by an MFC and mixed with the
liquid stream(s) containing the substrate and catalyst were used
for the oxidation of primary alcohols,220 ethylbenzene,221 and
2-benzylpyridines.222
Gutmann et al. developed a system for the aerobic oxidation
of 14-hydroxymorphinone 26 to the corresponding 1,2-
oxazolidine 27 using Pd(OAc)2. (Scheme 15).223 The resulting
non-natural opioid 27 was subsequently transformed into
noroxymorphone 28, an important precursor for the synthesis
of several important opioid antagonists. In a preliminary batch
study, the authors realized that in situ generated colloidal Pd(0)
is the active catalyst. Thus, a mixture of the substrate 26,
Pd(OAc)2, and AcOH in DMA was preheated to 120−140 °C
to form the active catalytic species prior to injection into the
continuous flow reactor. The colloidal Pd(0) did not lead to
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Scheme 15. Pd-Catalyzed Aerobic Oxidation of 14-
Hydroxymorphinone in Continuous Flow
clogging of the reactor unit or problems with the back pressure
regulating unit. The flow reaction gave almost quantitative
conversions and sufficient purity within 10 min at 120 °C and 7
bar. The crude reaction mixture was directly hydrolyzed in
batch before the final continuous hydrogenation step using a
heterogeneous catalyst. Importantly, a batch reaction on a
similar scale required 2 h at the same temperature to fully
consume the starting material. More recently, the same group
presented an alternative flow approach for the synthesis of
noroxymorphone via Pd-catalyzed N-demethylation of 14-
hydroxymorphinone-3,14-diacetate with O2 using a similar
setup.224
A continuous Heck-type cross-dehydrogenative coupling of
olefins and indoles catalyzed by Pd(OAc)2 at atmospheric
pressure was developed by Noël and co-workers (Scheme
16).225 In this reaction, oxygen is used to reoxidize Pd(0) after
Scheme 16. Cross-Dehydrogenative Coupling of Olefins and
Indoles in Continuous Flow
reductive elimination to close the catalytic cycle. The optimal
temperature for the coupling reaction was 110 °C, which
resulted in moderate-to-excellent yields within 10−20 min.
Higher temperatures gave lower conversions, most likely due to
catalyst decomposition. Also, a combination of higher flow rates
and a longer coil reactor increased the efficiency while keeping
the residence time constant. This positive effect was attributed
to better internal mixing in the slug flow regime.
An aerobic anti-Markovnikov Wacker oxidation in flow was
reported by Bourne et al. using the tube-in-tube gas loading
unit (Scheme 17).226 The setup consisted of two liquid pumps
and sample loops to feed the substrate and the catalyst/additive
stream into a T-mixer. The combined stream entered the gas
loading tool for O2 addition. The final reaction mixture was
pumped into a coil reactor heated at 60 °C at a system pressure
of 25 bar. A mixture of toluene and tert-butanol was used as a
solvent, with the tertiary alcohol necessary to obtain the desired
selectivity. A broad range of styrenes containing electron-
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Scheme 17. Aerobic Anti-Markovnikov Wacker Oxidation in
Flow
withdrawing or electron-donating groups reacted in good yields
with excellent selectivity for the anti-Markovnikov product.
Interestingly, the oxygen pressure plays an important role on
the selectivity and was optimal at 8 bar with the reactor unit
pressurized at 25 bar. Moreover, a scale-up approach was
demonstrated by adding an additional gas loading and reactor
unit right after the first reactor unit to process higher
concentrations.
Similar tube-in-tube-based strategies using O2 have been
reported for aerobic coupling reactions such as the Glaser-Hay
coupling of terminal alkynes,227 Fe-catalyzed nitro-Mannich
reactions,228 catalytic Chan-Lam couplings,229 and oxidative
Heck reactions.230 The groups of Stahl and Root developed a
variant of the tube-in-tube gas loading tool by using PTFE
tubing instead of the commonly used and relatively expensive
Teflon-AF 2400.231 The authors realized that the gas
permeability of PTFE is sufficient at elevated temperatures
and pressures for the aerobic oxidation of alcohols using a
homogeneous catalytic system consisting of [Cu(CH3CN)4]-
OTf, a bipyridyl species (bpy or 4-MeObpy), TEMPO or
ABNO, and N-methyl imidazole (NMI).232 In order to use the
PTFE tubing as a gas loading tool and reactor unit, the authors
build a tube-in-shell device by coiling the tubing inside a
stainless steel shell (Scheme 18). The shell was connected to an
Scheme 18. Tube-in-Shell Reactor Configuration for the
Aerobic Oxidation of Alcohols
oxygen cylinder and a pressure regulator to maintain an O2
pressure of 24 bar. The device was heated to 100 °C in an oven.
A substrate solution was mixed with a stream containing the
catalyst/additive mixture and entered the tube-in-shell reactor
at a pressure of 25 bar. The quantitative oxidation of primary
and secondary alcohols proceeded with excellent selectivity.
The oxidation of 10 g benzyl alcohol over 20 h nicely
showcased the stability of their cost-saving gas addition tool.
Multiple PTFE tubes mounted in a pressure vessel formed a
multitube-in-shell reactor, which was used to oxidize the same
amount of benzyl alcohol (10 g) within 45 min. This device,
however, is presumably limited to harsh conditions in order to
provide acceptable gas permeability.
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5.1.4. Ozone. The oxidative cleavage of unsaturated
molecules via ozonolysis is a powerful technique with a
plethora of synthetic applications.233 Nevertheless, safety
concerns force chemists to look for alternative synthetic
strategies. Flow reactors provide an opportunity to tame this
reaction, as presented by the Ley lab during the early
development of the tube-in-tube gas addition unit.234 Later,
Gavriilidis and co-workers used a coil reactor setup and a wavy-
annular regime for the ozonolysis of several alkenes to obtain
moderate-to-excellent yields of the desired aldehydes in
seconds (Scheme 19).235,236 The scope was expanded to
Scheme 19. Ozonolysis in Continuous Flow Mode Using the
Tube-in-Tube Gas Delivery Unit
furanyl benzenes and aliphatic furans yielding the respective
carboxylic acids after workup. Similar coil-based ozonolysis
setups were successfully applied by the groups of Baxendale237
and Kappe.238
5.1.5. Fluorine, Chlorine, and HCl. Halogenation
reactions represent one of the most important classes of
transformations in organic chemistry. Halide reagents are not
only used for synthesis but also can be used to tune the
chemical, physical, or biological properties of a molecule. For
instance, fluorine is often introduced in organic compounds
due to its unique properties.239 Therefore, a plethora of
fluorination strategies have been developed, using reagents such
as Selectfluor, NFSI, DAST, TBAF, or PhenoFluor.239 From an
atom-economic point of view, elemental fluorine (F2) is the
most attractive source. However, the gaseous reagent is highly
poisonous and corrosive. Realizing the potential for continuous
flow to improve the safety aspects of reactions involving
fluorine,73 Chambers et al. developed a single-channel micro-
reactor fabricated from a nickel block with a PTFE window
(Scheme 20).240−242 Fluorine gas (10% in N2 v/v) was used for
Scheme 20. Synthesis of 4-Fluoropyrazole Using F2
the synthesis of 4-fluoropyrazoles from 1,3-diketones by mixing
a substrate solution with the gaseous stream in a T-mixer. The
biphasic reaction mixture was immediately introduced to a
cooled reactor unit (5−10 °C), where selective monofluorina-
tion occurred. After leaving the reactor, a hydrazine solution
was added to form the pyrazole scaffold in an attached coil
reactor.
The same reactor configuration was used for the generation
of a hypofluorous acid acetonitrile complex (HOF·MeCN)
which can be used to epoxidize alkenes241 or to oxidize amines
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and azides to give the corresponding nitro compounds
(Scheme 21).243 Importantly, HOF·MeCN has a half-life of
just 4 h, which makes its continuous generation from water and
fluorine potentially interesting for other applications.244
Scheme 21. On-Demand Synthesis of HOF·MeCN
Recently, the same group published a one-step continuous
flow synthesis of flucytosine 30 using F2.245 The conventional
batch process for the production of flucytosine 30 starts by the
fluorination of uracil followed by chlorination, amination, and
hydrolysis. The authors claimed that a one-step protocol via the
direct fluorination of cytosine 29 could be a valuable alternative.
Initially, this process was evaluated in batch but suffered from
poor selectivity (38%) due to a difluorinated side-product.
Therefore, the researchers hypothesized that the accurate
control of process conditions, in combination with the excellent
heat and mass transfer characteristics of a flow reactor could be
highly beneficial for this transformation. Initially, a solution of
cytosine 29 in formic acid was mixed with F2 (10% in N2) via a
T-mixer and reacted in a stainless steel coil reactor held at room
temperature and atmospheric pressure. By optimizing the flow
rates, the authors found suitable conditions for complete
consumption of the starting material, affording 30 in 63% yield.
Next, the authors carried out a scale-up study using a chip
reactor made out of silicon carbide (Scheme 22). At a reaction
temperature of 10 °C, this reactor yielded flucytosine 30 in 83%
on a gram scale within a 1 h process time.
Scheme 22. Continuous Synthesis of Flucytosine by Direct
Fluorination of Cytosine
Similar to F2, Cl2 is a powerful reagent which is associated
with severe safety risks. To mitigate these risks, an on-demand
generation of anhydrous Cl2 was realized by Strauss et al.
(Scheme 23).246 The spontaneous reaction of HCl with NaOCl
Scheme 23. Continuous On-Demand Production of Cl2
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delivered Cl2, which was extracted with CHCl3 in a liquid−
liquid slug flow regime. A membrane separator was used to
obtain a solution of Cl2 in CHCl3 which was used for the direct
chlorination of silanes and the selective oxidation of secondary
alcohols using an in situ formed chlorine-pyridine complex.
While excellent conversions and selectivities were observed for
the latter transformation, the isolated yields were relatively low
after purification.
Hessel and colleagues used gaseous HCl for the chlorodehy-
droxylation of alcohols at elevated temperatures and pressures
(Scheme 24).247 Special care had to be taken to eliminate
Scheme 24. Chlorodehydroxylation of Alcohols Using
Gaseous HCl
moisture from the gas delivery system to avoid corrosion. This
was achieved through the rigorous purging of the system with
nitrogen. In the final process, neat alcohols were mixed with the
dry HCl gas in a T-mixer and subsequently heated in an ETFE
coil reactor at 120 °C and 10 bar. After 10−15 min, the
reaction mixture was cooled to room temperature before
depressurization. Importantly, 1.2 equiv of HCl, controlled via
the MFC apparatus, were sufficient in all cases.
5.1.6. Hydrogen. Hydrogenations are frequently used in
organic chemistry. However, the majority of hydrogenation
reactions are carried out in the presence of a heterogeneous
catalyst in a gas−liquid−solid reaction. Nevertheless, hetero-
geneous catalysts usually do not allow for asymmetric
reductions, and more sophisticated homogeneous metal
complexes have to be used. A flow example used a tube-in-
tube gas loading tool (Scheme 25).248 After screening several
Scheme 25. Asymmetric Hydrogenation in Continuous Flow
catalysts, the Ubaphox catalyst proved best for the asymmetric
hydrogenation of compound 31. Full conversion and a
diastereomeric ratio of 76% was obtained within a residence
time of 80 min at a back pressure of 10 bar using 2.5 mol % of
the iridium catalyst. Moreover, extensive optimization studies
were performed to reduce the amount of catalyst as well as
apply it to other substrates using a recirculation approach.
5.1.7. Ethylene. The palladium-catalyzed cross-coupling of
aryl iodides and gaseous ethylene was studied in a continuous
flow reactor using a setup consisting of a tube-in-tube gas
loading tool in combination with a coil reactor made out of
PFA (Scheme 26).249 Initial experiments with Pd(OAc)2 as
catalyst suffered from Pd black formation. This was suppressed
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Scheme 26. Palladium-Catalyzed Mizoroki-Heck Couplings
of Aryl Iodides and Ethylene
by adding the electron rich tert-Bu3P·HBF4 ligand salt. During
an extensive optimization study, the authors realized that
addition of substoichiometric amounts of tetrabutylammonium
iodide and Cy2NMe improved the conversion significantly
leading to a reaction time of 20 min at 130 °C and 20 bar. With
the optimized conditions in hand, several (hetero)aryl iodides
were converted into the corresponding styrene derivatives in
good-to-excellent yields and selectivity. Aryl bromides, on the
other hand, gave poor conversions under all tested conditions.
To increase the versatility of their methodology, the authors
further telescoped their flow system for the synthesis of
asymmetric stilbenes via a subsequent Mizoroki-Heck reaction
using the resulting styrenes from the first reaction. This
sequential cross-coupling procedure uses the same catalyst/
ligand/base mixture in both steps and allowed for the synthesis
of a small stilbene library in good-to-moderate overall yields.
The authors further expanded the styrene formation by a
subsequent continuous, Rh-catalyzed hydroformylation using
Syngas (CO/H2) in a semicontinuous process.249 More
recently, the same group coupled the biphasic Mizoroki-Heck
reaction with an anti-Markovnikov Wacker oxidation.250 The
intermediate acetaldehyde of the Wacker was further used for
the semicontinuous synthesis of an important precursor to the
active pharmaceutical ingredient sacubitril.
5.1.8. Ammonia. Ammonia is commonly utilized as an
aqueous solution (i.e., ammonium hydroxide) or dissolved in
organic solvents such as MeOH and THF. However, the range
of solvents in which NH3 is commercially available is limited,
and the concentration diminishes rapidly upon opening the
bottle. Moreover, the volatility of ammonia may strongly affect
the efficiency in a batch reaction. Aware of these disadvantages,
Cranwell et al. used gaseous NH3 in the continuous synthesis of
pyrroles via condensation with 1,4-diketones in a Paal-Knorr
reaction (Scheme 27).251 A solution of the respective substrate
Scheme 27. Paal-Knorr Reaction with Gaseous NH3
in methanol was pumped through a tube-in-tube unit to add
NH3, and the final reaction mixture was reacted in a heated coil
reactor unit at 110 °C and 20 bar with an overall residence time
of 120 min.
Importantly, the same group showed that the uptake of NH3
varies significantly depending on the solvent, the residence
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time, and the temperature of the gas loading unit (Figure
27).252
Figure 27. Temperature effect on the ammonia uptake in the tube-in-
tube gas loading tool at a residence time of 300 s. Reprinted from ref
252. Copyright 2013 American Chemical Society.
On the basis of these results, the authors developed a simple,
continuous two-step procedure for the synthesis of the anti-
inflammatory agent fanetizole 35 (Scheme 28). To start,
Scheme 28. Two-Step Procedure for the Synthesis of
Fanetizole with NH3
commercially available 2-phenylethyl isothiocyanate 32 was
dissolved in DME and passed through a cooled tube-in-tube gas
loading tool to dissolve the gaseous reagent. The reaction
mixture was subsequently heated to 100 °C in a coil reactor for
20 min at 6 bar to generate a thiourea intermediate 33. After
the addition of a 3-bromoacetophenone 34 solution, another
coil reactor heated at 100 °C promoted the formation of the
final thiazole scaffold within 5 min. Notably, the active
pharmaceutical ingredient was isolated quantitatively without
any chromatographic purification techniques.
5.1.9. Diazomethane. Diazomethane is an extremely
versatile carbon building block, but its utilization in chemistry
laboratories is often limited by severe safety concerns. The
powerful gaseous reagent is highly toxic and extremely sensitive
to heat, light, and friction, often leading to explosions.253 To
tame this hazardous reagent, strategies for the generation and
utilization of diazomethane from diazald (N-methyl-N-nitroso-
p-toluenesulfonamide) and KOH were developed in simple
continuous flow devices by the groups of Maggini254 and
Stark.255 In these early examples, the Diazald and KOH streams
were mixed to produce diazomethane before a third stream
containing a carboxylic acid was added. The in situ formed
diazomethane ultimately reacted with the acid, forming the
corresponding methyl ester and neatly avoiding any exposure of
the toxic intermediate to the environment. However, these
systems require highly polar solvents such as water to dissolve
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the reagents which limit their applicability. To tackle this
disadvantage, Kim and co-workers utilized a home-built chip
reactor, where a PDMS membrane was sandwiched between
two reactor channels (Scheme 29).256 A solution of diazald was
Scheme 29. Dual Channel Reactor with a PDMS Membrane
for Diazomethane Generation, Separation, and Utilization
mixed with aqueous KOH, entering the lower channel of the
reactor unit. Since PDMS is extremely hydrophobic, only
CH2N2 can pass the membrane where it reacts with acetic acid
36. The productivity of the system was quite low, with an
output of 2.88 mmol methyl acetate per day. Moreover, many
nonpolar solvents are not compatible with PDMS due to
swelling of the material.
Solvent limitations were solved by Kappe and co-workers
utilizing the tube-in-tube gas loading tool instead of the dual
channel reactor (Scheme 30).257 Similar to the PDMS
Scheme 30. Diazomethane Generation and Separation Using
the Tube-in-Tube Gas Loading Unit
membrane reactor process, diazald and KOH were mixed to
produce CH2N2 in the inner tube, whereupon the gaseous
reagent passes the gas permeable membrane to enter the
substrate stream in the outer tube. Importantly, virtually any
solvent can be used in the outer tube as the gas-permeable
Teflon AF-2400 does not suffer from the same problems as
PDMS. The authors demonstrated the feasibility of their
continuous system for various transformations such as
methylations, [2 + 3] cycloadditions, cyclopropanations of
alkenes, and Arndt-Eistert type homologations of acyl chlorides.
Importantly, no methyl benzoate was observed when benzoyl
chloride was used as the substrate, confirming that their
approach is able to produce anhydrous diazomethane solutions.
The same group ultimately expanded their methodology for the
multistep synthesis of chiral α-halo ketones from N-protected
amino acids258 and also applied this principle to the generation
of CF3CHN2 from the respective amine hydrochloride and
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NaNO2.259 Additionally, they published an alternative, a
semicontinuous tube-in-flask reactor in which diazomethane is
generated in a gas permeable coil reactor which is placed in a
flask containing the respective reaction mixture.260,261
Similarly, Lehman published a continuous multistep
procedure for the generation of diazomethane from NMU
and utilized it in a liquid−liquid membrane separator instead of
a gas permeable membrane (Scheme 31).262 The semi-
Scheme 31. (a) Diazotization of N-Methylurea (NMU) and
(b) Diazomethane Generation from N-Nitroso-N-
Methylurea (NNMU) and KOH for the Methylation of
Carboxylic Acids
continuous process starts with diazotization of NMU in a coil
reactor at room temperature in a biphasic liquid−liquid system,
which enables the extraction of NNMU 38 with the organic
phase (Scheme 31a). After depressurization, a membrane
separator was used to isolate the organic stream. This solution
was ultimately fed into a second coil reactor setup and mixed
with KOH (Scheme 31b) where diazomethane was generated
at 0 °C in a segmented liquid−liquid flow pattern. Another
liquid−liquid separation unit was utilized to remove the
aqueous phase before the respective carboxylic acid was
introduced via a T-mixer. Residence times of less than 20 s
were sufficient for the methylation of several carboxylic acids in
excellent yields (96−99%) and high productivity (16.4−27.9 g
h−1).
5.1.10. Phosgene. Similar to diazomethane, phosgene is a
useful reagent which is usually avoided in research laboratories
due to its high toxicity. Among other applications, phosgene
can be used to activate carboxylic acids which can subsequently
react with an amine to provide an amide bond. This activation
strategy only generates CO2 and HCl as byproducts, making its
utilization as a condensation agent very interesting. Takahashi
and co-workers developed a continuous strategy for the in situ
generation of phosgene from triphosgene for amide syn-
thesis.263,264 Two T-mixers were connected via Teflon tubing
and immersed in a water bath to keep the temperature constant
at 20 °C (Scheme 32). In the first mixing unit, a solution of the
carboxylic acid and DIPEA in DMF were merged with a stream
of triphosgene in MeCN. The in situ generated phosgene
activated the carboxylic acid within a residence time of 0.5 s.
The respective amine was added via the second T-mixer, and
the mixture was subsequently quenched with 1 M HCl after an
additional residence time of 4.3 s. In general, high-to-excellent
yields were obtained for all substrate combinations. A
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Scheme 32. Activation of Carboxylic Acids by in Situ
Generated Phosgene for Amide Couplings
comparison of these reactions in batch turned out to be
relatively difficult to perform due to the generation of copious
amounts of CO2 and phosgene. Thus, the authors used
different reaction times in batch for getting reproducible results
(activation 30 s, amidation 30 s). Overall, significantly lower
yields were obtained in batch in all cases. When Boc or Trt
protection groups were present in the starting material,
deprotection was observed during the reaction in a flask.
Moreover, easily racemizable substrates did not suffer from
epimerization using the continuous methodology. Interestingly,
by using inline IR analysis, the authors identified the
symmetrical anhydride instead of the expected acyl chloride.
A modified procedure was utilized for the late stage amide
coupling in the synthesis of the selective neurotensin probe
meclinertant.265
5.2. Solid−Liquid Reactions
In continuous flow, chemical reactions involving solids are
predominantly carried out in packed bed reactors. Among those
transformations, heterogeneous catalysis is the main arena
where continuous flow technology is advantageous.15,44,47,266
Herein, a purely heterogeneous catalyst or an immobilized
version of a homogeneous catalyst is placed at a specific region
of the flow path, through which the reaction solution is passed.
Importantly, such setups afford a higher effective molarity of
the catalyst which often accelerates a chemical transformation.
Since no additional step for catalyst recovery is necessary, this
technology ultimately leads to time- and cost-effective strategies
which open up novel, sustainable processing opportunities as
well as facilitating telescoped multistep processes. In the case of
robust catalysts, the loading becomes a function of time, leading
to higher turnover numbers for longer runs. For instance, some
flow reactions utilizing immobilized whole cells have very high
turnover numbers.57 These accounts, however, are excluded
from this review due to the lack of easily comparable batch and
flow experiments. Heterogeneous and immobilized reagents, on
the other hand, are consumed during a continuous flow
experiment, necessitating the periodic reactivation or refilling/
exchange of the packed bed unit. Thus, such chemistries are
generally more convenient to be carried out in conventional
batch environments and are not covered in this review.
Nevertheless, such strategies are used for the synthesis of
unstable or toxic intermediates,267−269 multistep synthesis,270
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or overcoming general shortcomings associated with batch
chemistry.271,272
5.2.1. Heterogeneous Catalysis Involving Metals.
Catalysis on metal surfaces or by using metallic nanoparticles
and organometallic complexes plays an important role in
organic chemistry and is used for a broad range of important
transformations. Palladium currently reigns as one of the most
popular elements for catalytic applications as it facilitates
various powerful carbon−carbon and carbon−heteroatom
couplings, with significant impact in academia and industry.273
Generally, in these reactions an aryl(pseudo)halide reacts with
a coupling partner with the aid of a Pd catalyst. Depending on
the coupling partner, several variations exist including the
Suzuki-Miyaura (organoboron), Mizoroki-Heck (alkene), and
Negishi (organozinc) coupling reactions. Not surprisingly,
numerous continuous flow protocols for Pd-catalyzed cross-
coupling reactions have been developed involving both
homogeneous and heterogeneous catalysis.22
Packed beds of palladium (nano)particles supported on inert
materials, immobilized Pd-complexes, and functionalized chip/
coil reactors have been used to study Suzuki-Miyaura,274−280
Mizoroki-Heck,281,282 Sonogashira,283,284 and Negishi285,286
coupling reactions in flow. However, since the mechanism of
all cross coupling reactions involves palladium in at least two
different oxidation states [Pd(0)/Pd(II)], leaching of the
catalytically active material from the support frequently occurs.
In fact, several groups have proposed that a leached Pd species
may be responsible for catalysis.287−289 In a critical assessment
on metal leaching during Pd-catalyzed coupling reactions in
flow, Cantillo and Kappe concluded that this phenomenon
limits the application of packed bed reactors, and a
homogeneous metal (pre)catalyst in combination with a
suitable ligand may be the better option.37
Nevertheless, such chemistries can benefit from flow
applications in packed bed reactors or similar solid−liquid
systems as the higher effective molarity of the catalyst increases
reaction rates. In this vein, the Kappe group executed a detailed
continuous flow study on leaching resistance of four
commercially available heterogenized Pd-supported catalysts
(polymer-bound Pd Tetrakis, FiberCat 1001, EnCatTPP 30,
and SiliaCat DPP-Pd) for Suzuki-Miyaura and Mizoroki-Heck
reactions using different solvents and bases (Scheme 33).159
The system was stabilized until steady state conditions were
reached for obtaining reliable information on the performance
Scheme 33. Continuous Flow Setup for Leaching Studies on
Different Supported Pd Catalysts in Suzuki-Miyaura and
Mizoroki-Heck Reactions
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of the catalysts. At high substrate concentrations (0.5 M),
significant amounts of leached Pd (12−28%) were detected in
the collected reaction mixtures for all catalysts during long run
experiments (110−170 min) at elevated temperatures (100−
120 °C). Consequently, chemical conversions steadily
decreased over time in several cases.
By analyzing the FiberCat 1001 catalyst after the flow
process, the authors realized that Pd is gradually moving
through the packed bed reactor during the continuous process,
leading to a visible change in the homogeneity of the packed
bed (Figure 28). This is attributed to heterogeneous Pd(0)
Figure 28. Content of a used Fibrecat 1001 packed bed reactor.
Different Pd concentrations and colors of the material were observed
depending on the region in the flow path. Reprinted from ref 159.
Copyright 2015 American Chemical Society.
species transforming into a “soluble” Pd(II) complex. After the
reductive elimination, Pd(0) is redeposited on the support
leading to a constant migration of Pd along the packed bed.
However, an optimization of the reaction system with SiliaCat
DPP-Pd resulted in stable conversions for both reactions over
110 min using an optimized solvent system (THF/EtOH/
H2O), a lower temperature (80 °C), K2CO3, and a lower
substrate concentration (0.25 M). Nevertheless, metal leaching
(1−7%) was still observed as analyzed by ICP/MS. Not
surprisingly, a further reduction of metal leaching could be
achieved by shifting to low concentrated reaction mixtures
(0.05 M, leaching <1%).
Alcázar and co-workers showed the potential of the SiliaCat
DPP-Pd material as an efficient and relatively low leaching
catalyst (Scheme 34).285 Under optimized conditions, a broad
range of biaryl compounds were synthesized in good-to-
excellent yields from different organoboron derivatives and
various electrophiles including aryl chlorides and an aryl triflate.
Remarkably, a residence time of just 5 min at 60 °C was
sufficient for substrate concentrations of 0.15 M. A long run
study showed no decrease in conversion or selectivity over 8 h,
and very low amounts of Pd were found in the resulting
reaction mixture (30 ppb), showing the potential of this
immobilized palladium catalyst for flow applications.
Verboom and co-workers evaluated functionalized microchip
channel walls with dendrimers encapsulating Pd nanoparticles
for cross couplings in flow (Scheme 35.).290,291 Surface
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Scheme 34. Continuous Suzuki-Miyaura Coupling Using
SiliaCat DPP-Pd in a Packed Bed Reactor
Scheme 35. Continuous Suzuki-Miyaura Coupling Using
Dendrimer Encapsulated Pd Nanoparticles in a
Functionalized Glass Chip Reactor
functionalization of a 13 μL glass microreactor with Pd loaded
PAMAM G3 dendrimers was carried out using established
techniques, and total reflection X-ray fluorescence (TXRF)
revealed a total of 0.12 μg Pd within the system. With the
reactor unit in hand, the authors studied its long-term stability
for the Suzuki-Miyaura coupling of iodobenzene (10 mM) with
tolylboronic acid and Bu4NOH at 80 °C with a residence time
of 13 min. During a continuous experiment over 7 days, only a
low decrease in conversion was observed with an overall
catalyst leaching of around 10%. This slow loss of Pd over time,
in combination with the high turnover number (TON) of
39,650, underlines the promising potential for the dendrimeric
immobilization technique of Pd nanoparticles. The authors
synthesized a library of biaryl compounds to test the general
applicability of their reaction system. Iodobenzene derivatives
containing electron-withdrawing groups gave very high yields,
while electron-donating groups or aryl bromides resulted in
significantly lower conversion.
Leaching is not restricted to cross coupling reactions but is
rather a general problem. For example, Asadi et al. observed
0.54% palladium leaching in the Fukuyama reduction of 1
mmol of thioester 39 with Pd supported on Amberlite XAD-4
(Scheme 36).292
Scheme 36. Continuous Fukuyama Reductions Using Pd
Supported on Amberlite XAD-4
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Therefore, the term “heterogeneous” catalysis is somewhat
misleading if an immobilized catalyst is used for reactions which
proceed via a “homogeneous” mechanism, and such reactions
may, therefore, be more accurately referred to as (quasi)-
homogeneous.37 However, due to the aforementioned
problems resulting from the gradual dissolution and loss of
catalyst, economic benefits, and process advantages disappear if
long-term packed bed stability is not sufficiently high,
particularly for expensive (noble) metal species such as
palladium. It is, therefore, futile to immobilize a properly
working homogeneous catalyst, as purification steps are
necessary to remove the leached material, nullifying the
separation advantage of packed bed reactors.
Nevertheless, leaching of metals into the reaction stream
does not limit catalysis to homogeneous conditions. If the metal
catalyst is cheap and can be supported with high catalyst
loadings or even used as pure metal then the advantages due to
the high effective molarity can outweigh the issues associated
with leaching. Furthermore, the extremely high amounts of the
catalytically active material guarantee a long lifetime and high
reproducibility under continuous flow conditions. A powerful
example is the use of elemental copper for 1,3-dipolar
cycloadditions.48 This transformation is initiated by Cu2O
species on the surface of the zerovalent copper metal.293
Kirschning and colleagues used copper turnings for the
Huisgen-type cycloaddition of vinyl azides and alkynes in a
packed bed reactor (Scheme 37).294 The authors heated the
Scheme 37. Huisgen-Type Cycloaddition of Vinyl Azides
and Alkynes via Inductive Heating of Cu Turnings in a
Packed Bed Reactor
metal catalyst directly by electromagnetic induction.295,296 The
temperature measurement was carried out on the reactor
surface by means of an IR pyrometer. Optimization studies
revealed that DMF and a reaction temperature of 70 °C were
optimal, as higher temperatures led to substrate decomposition.
With the optimized conditions in hand, a library of 12 1,4-
disubstituted-1,2,3-triazoles was synthesized in good-to-moder-
ate yields.
Fülöp and colleagues used copper powder in a packed bed
reactor for a detailed study on continuous copper-catalyzed
click reactions of azides and alkynes (Scheme 38).297,298
Initially, a careful investigation of all process parameters was
carried out using benzyl azide and phenylacetylene as model
substrates. The authors realized that the reaction benefits
slightly from a higher system pressure and therefore used a BPR
set at 100 bar. The reaction was further intensified, with a
temperature of 100 °C and a residence time of 1.5 min
providing full conversion. Alternatively, a process at room
temperature was developed using DIPEA and AcOH, resulting
in similar yields at the same residence time and pressure. Both
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Scheme 38. Continuous Huisgen-Type Cycloaddition at
Ambient Temperatures in a Packed Bed Reactor Containing
Copper Powder
conditions were used, producing ∼1.5 g (99%) of the respective
triazole within 2.5 h to showcase the scalability of their
protocol. In addition, the two protocols were applied to a broad
set of alkynes and azides. Interestingly, the milder continuous
flow conditions outperformed the heated conditions. More
recently, the use of copper powder was reported for the
synthesis of azobenzenes via homocoupling of anilines,299 and
C−N cross coupling of phenylboronic acids with amines.300
Bogdan and Sach published a pioneering study on the use of
a copper coil reactor for the intermolecular Husigen 1,3-dipolar
cycloaddition (Scheme 39a).301 The authors used a commer-
Scheme 39. (a) Husigen 1,3-Dipolar Cycloaddition in a
Copper Coil Reactor Mounted in an Automated Continuous
Flow Reactor System Using (b) Slug Flow Technology for
the Prevention of Residence Time Distribution Phenomena
cially available, automated continuous flow reactor system
operating in a slug flow pattern. The system consists of a pump
delivering a carrier solvent, a reagent delivery system connected
via a 6-way-valve, the copper coil reactor, a back pressure
regulator, a fraction collector, and an integrated online LC−MS
analysis. In the reagent delivery system, the respective reagent
solutions are delivered into a sample loop via aspiration from
source vials. An immiscible fluorous solvent (perfluoromethyl-
decalin) is added at the beginning and the end of the reaction
mixture acting as a spacer. Therefore, once the mixture is
introduced into the carrier solvent stream, discrete reaction
segments are generated (Scheme 39b). This not only allows for
simultaneous reaction optimization and library screening but
also suppressed residence time distribution phenomena. An
automated optimization of the stoichiometry, reaction temper-
ature, and residence was carried out by linking the systems
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Review
analysis output to design-of-experiment software. The final
conditions were used for the synthesis of a library of 1,2,3-
triazoles via in situ formation of the respective organic azide
species in good-to-excellent yields. Notably, the preparation of
the alkyne, halide, and sodium azide solutions were the only
manual steps in the library generation, and scaling was achieved
by running several reaction segments containing the same
reaction mixture consecutively. This same reactor was used in a
series of intramolecular macrocyclization studies using Cu-click
chemistry.302−304 Moreover, the system was modified by
incorporating a packed bed reactor filled with SiliaCat DPP-
Pd for a subsequent Suzuki-Miyaura reaction.305
Recently, the Jamison group utilized a copper coil in the
continuous multistep synthesis of rufinamide 42, an anti-
convulsant used in the treatment of the Lennox-Gastaut
syndrome (Scheme 40).306 The convergent reaction sequence
Scheme 40. Continuous Multistep Synthesis of Rufinamide
Using a Copper Coil Reactor
involves the SN2 substitution of 2,6-difluorobenzyl bromide 40
with sodium azide at room temperature and the amidation of
methyl propiolate 41 with an aqueous ammonia solution at 0
°C. The two resulting streams containing the organic azide and
propiolamide were subsequently mixed and heated in a copper
coil reactor at 110 °C and 6.9 bar. After a residence time of 6.2
min, the active pharmaceutical ingredient 42 was isolated in
92% without the need for chromatography. Importantly, the
entire process required just 11 min, with a productivity of 217
mg h−1. This type of copper coil setup was applied to various
other chemistries, including macrocyclizations of linear
peptoids,307 Ullmann reactions, Pd-free Sonogashira couplings,
and protiodecarboxylation reactions (Scheme 41).308
Examples with a low amount of metal leaching were recently
reported. An IrCp* catalyst immobilized on a polymeric
monolith (polystyrene cross-linked with divinylbenzene) was
utilized for transfer hydrogenations under continuous flow
conditions.309 After demonstrating catalytic activity for the
reduction of benzaldehyde and acetophenone using a simple
flow setup, the authors evaluated the catalyst in an automated
flow system (Scheme 42). Solutions of the substrate and 3 mol
% tBuOK in isopropyl alcohol were loaded using an
autosampler and fed into the packed bed reactor heated at 90
°C with a back pressure of 6.9 bar. After depressurization, the
material was collected automatically by a fraction collector and
subsequently analyzed by GC-MS or NMR (offline). With this
setup, 40 benzylic and aliphatic aldehydes and ketones were
tested. All substrates resulted in good-to-excellent conversion
except for compounds bearing an acidic hydrogen since they
were strongly retained on the column. Rigorous purging was
necessary to elute these compounds from the packed bed to
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Scheme 41. Application of a Copper Coil Reactor for (a)
Ullmann Reactions, (b) Pd-Free Sonogashira Couplings, and
(c) Protiodecarboxylations
Scheme 42. Transfer Hydrogenations with an Immobilized
Ir Cp* Complex Using an Automated Flow Setup for Library
Generation
avoid cross contamination. Moreover, the authors realized that
storing the catalyst in alcoholic solvents or with residual
alcohols led to deactivation over time, which was most likely
due to the formation of a catalytically inactive iridium hydride
species. When the authors studied the long-term stability, stable
conversion was observed over more than 93 h (TON 744)
followed by a slow linear decrease. Since no leaching was
observed via ICP-MS analysis, this deactivation is most likely
caused by the formation of the same catalytically inactive
iridium species due to the alcoholic solvent.
Kim and colleagues developed a chip reactor made out of
PDMS with an allylhydridopolycarbosilane (AHPCS) coating.
Further functionalization with chitosan, generated a nanobrush-
like layer on the channel surface.310 The polysaccharide is an
excellent material for immobilizing transition metals as it is
hydrophilic, insoluble in organic solvents, and has a nitrogen
content of ∼8% (Scheme 43).311 Different metal catalysts were
loaded onto the chitosan layer by filling the microreactor with a
solution containing the respective metal species, drying, and
washing to remove unsupported catalyst species. The authors
successfully immobilized CuBr2 to serve as a catalyst for
Huisgen-type 1,3-dipolar cycloadditions, a gold species for
conducting hydrations of alkynes, PdCl2 for Suzuki-Miyaura
reactions, and a ruthenium complex for the oxidation of alkenes
to the respective 1,2-diketones. For all of the tested reactions,
excellent isolated yields were obtained at short residence times
(1−4 min) under the applied conditions. Most importantly,
experiments with the gold-, copper-, and palladium-function-
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Scheme 43. Microchip Reactor Functionalized with Chitosan
for Immobilizing Cu, Au, Pd, and Ru Catalysts
alized microreactors provided stable results over several days,
resulting in high turnover numbers. The authors further
reported that no leaching was detected over 3−4 days except
for the ruthenium complex. The same group further used a
similar design principle for immobilizing OsO4 via a nanobrush
polymer.312 The resulting functionalized wall reactor was
utilized for the dihydroxylation and oxidative cleavage of
alkenes and also showed low amounts of leaching during their
studies, demonstrating the potential of this immobilization
strategy to combat leaching.
Pericàs and co-workers recently reported a polystyrene-
linked cationic tris(triazolyl)methanecopper(I) catalyst (PS-
TTMCu(NCMe)PF6) for carbene transfer reactions with ethyl
diazoacetate 43 in a packed bed reactor (Scheme 44).313 The
Scheme 44. Carbene Insertion Using a Polystyrene-Linked
Cationic Tris(triazolyl)methane Copper(I) Catalyst in a
Packed Bed Reactor
authors hypothesized that the cationic Cu complex could have a
strong interaction with the immobilized TTM ligand to
minimize catalyst leaching. Initial recycling experiments in
batch showed promising results for various carbene insertion
reactions, which ultimately forced the authors to test the
heterogenized copper catalyst in flow. To investigate this, a
mixture of 43 and ethanol in DCM was pumped through a
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Scheme 45. Fully Continuous Synthesis of (S)-Rolipram Using Several Consecutive Packed Bed Reactors
packed bed reactor containing the catalyst. An optimization of
the flow rate resulted in a residence time of 1 min for the
quantitative formation of ethyl 2-ethoxyacetate 44. A long-term
study only showed a slight decrease in the catalytic activity after
38 h, which was attributed to contraction of the polymer matrix
due to the generated pressure inside the packed bed. Thus,
pure DCM was pumped through the reactor to effect a
reswelling of the support. After this reactivation, full conversion
was again achieved and the system was operated for 10 more
hours without any significant decrease in conversion. Overall,
12.6 g of the pure title compound was obtained after 48 h of
operation. The copper content in the final reaction mixture was
low (0.8−1.6 ppm), confirming the high stability of the
heterogeneous catalyst.
Kobayashi and co-workers developed an immobilized
calcium catalyst for the continuous, asymmetric 1,4-addition
of 1,3-dicarbonyl compounds and nitroalkanes.314 A chiral
pybox ligand was immobilized on polystyrene and mixed with
CaCl2·2H2O and Celite. The resulting catalyst powder was used
in a packed bed reactor and showed excellent yields and
selectivity for all tested substrates without a loss of activity over
8.5 days of operation. On the basis of these results, the authors
developed a fully continuous synthesis of enantiomerically pure
rolipram 48 in a continuous flow approach involving exclusively
heterogeneously catalyzed steps (Scheme 45).315 Initially, a
base-catalyzed nitroaldol reaction of aldehyde 45 and nitro-
methane was carried out in a packed bed reactor containing
silica-supported amine at 75 °C. The resulting nitroalkene 46
was mixed with malonate 47 and passed through a packed bed
containing molecular sieves to remove water. The solution was
then precooled in a small coil reactor and fed into two
consecutive packed bed reactors containing the chiral Ca-
catalyst for the asymmetric Michael-type addition. A subse-
quent hydrogenation of the nitro group over a palladium
catalyst supported on carbon and polysilane (Pd@DMPSi-C)
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resulted in the respective γ-lactam, which was collected in a
receiving unit to separate excess H2. The crude reaction mixture
was mixed with water and ortho-xylene in a packed bed of
Celite and finally converted into (S)-rolipram 48 via hydrolysis
and decarboxylation using another packed bed reactor
containing a silica-supported carboxylic acid catalyst. Overall,
50% (productivity of ∼1 g d−1) of the target compound 48 was
isolated by preparative TLC in high enantiomeric excess, and
the system was operated for 1 week.
A particularly appealing strategy is the use of supported
nanoparticles as catalysts, since these materials can be
considered as a bridge between homo- and heterogeneous
catalysts.316 The high surface area enhances the contact with
reactants dramatically, and the activity of the nanocatalyst can
often be fine-tuned by optimizing the properties of the material
(size, shape, composition, and morphology). Nevertheless, the
material is insoluble in the reaction medium similar to classical
heterogeneous catalysts. The challenge lies in identifying
nanoparticles which can selectively enhance a specific reaction
and also finding a convenient and robust preparation strategy
for generating supported nanocatalysts.
Schröder et al. used supported gold nanoparticles as a
catalyst for the synthesis of spiroindoles via a cycloisomerisa-
tion in a packed bed reactor (Scheme 46). 317 The
heterogeneous material was prepared by ball-milling HAuCl4·
3H2O and an alumina containing mesoporous silica support (Al
SBA-15) for 10 min and subsequently calcining at 400 °C. The
final material showed high activity for the desired trans-
formation in the presence of water as a proton shuttle. Good-
to-excellent yields were achieved within 5.5 min at a
temperature of 120 °C and a back pressure of 5.5 bar.
However, the authors realized that the activity of the catalyst
decreased after a couple of single pass transformations. ICP-
OES measurements showed no detectable amounts of gold in
the reaction mixture excluding leaching as the reason for the
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Scheme 46. Synthesis of Spiroindoles via a
Cycloisomerisation in a Packed Bed Reactor
drop in the catalytic activity. Interestingly, TEM analysis
showed that the size of the Au particles which were used
increased from 1 to 5 (unused) to 70 nm, and XPS analysis
indicated the generation of significant amounts of a Au(III)
species. Both findings were attributed to being the origin for the
decrease in the catalytic activity over time. Nevertheless, this
study shows the high potential of nanocatalysis as a leaching-
free alternative for the (quasi)homogeneous reactions discussed
above but also indicates that the preparation of stable material
is not trivial.
Moghaddam et al. used iron oxide nanoparticles supported
on alumina (Fe3O4@Al2O3) for nitro reductions at high
temperature and pressure (Scheme 47).318 The catalytic
Scheme 47. Hydrazine-Mediated Nitro Reduction Catalyzed
by Iron Oxide Nanoparticles Supported on Alumina in a
Packed Bed Reactor
material was prepared by heating a mixture of Fe(acac)3 and
hydrazine hydrate in the presence of basic Al2O3 to 150 °C for
10 min. The resulting heterogeneous material had finely
dispersed and homogeneously distributed Fe3O4 nanoparticles
with an average particle size of ∼6 nm on the alumina surface
with an iron content of 0.67 wt %. In batch experiments using
microwave heating, the material demonstrated excellent activity
for the selective reduction of several nitrobenzene derivatives in
the presence of hydrazine hydrate at 150 °C within 2−6 min.
The catalyst could be reused several times without any
significant reduction in activity, and the material was bench
stable over at least 10 weeks. Thus, the authors decided to
evaluate the Fe3O4@Al2O3 catalyst using a packed bed reactor.
Optimization revealed that residence times of 35−70 s were
sufficient to quantitatively reduce several nitroaryl compounds
at 150 °C and a back pressure of 30 bar. However, long-term
stability studies led to unexpected relationships with the
process conditions. Changing the solvent to acetonitrile led
to slow deactivation over time, although no leaching was
detected. While the process performance was stable over 5 h in
methanol at a flow rate of 1 mL min−1, a drop in conversion
was observed at higher flow rates. However, even with lower
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flow rates, a total process time of 10 h resulted in a productivity
of 30 mmol h−1.
Ideally, catalysis in packed bed reactors should be truly
heterogeneous and not prone to deactivation or leaching. Such
reactions proceed by adsorption of the substrate on the surface
of the catalyst and after the respective reaction, the final
product desorbs, leaving the catalyst unaltered. Hydrogenations
and aerobic oxidations are common examples; however, most
others are related to the production of bulk and not fine
chemicals.
Ley and co-workers developed a continuous Meerwein-
Ponndorf-Verley reduction of aldehydes and ketones in the
presence of isopropyl alcohol catalyzed by a heterogeneous
zirconia catalyst (Scheme 48).319 The simple and easily
Scheme 48. Continuous Reduction of Aldehydes and
Ketones Using Calcinated Zirconium Hydroxide As
Heterogeneous Catalyst
accessible approach uses partially hydrated zirconium oxide in
a packed bed reactor. The substrates were dissolved in
isopropyl alcohol and pumped through the heated packed
bed at a back pressure of 6.9 bar. The system worked for a
broad range of aldehydes and ketones resulting in quantitative
conversion to the corresponding primary or secondary alcohol,
in most cases within 6−75 min at elevated temperatures.
Ketones generally required harsher conditions and longer
residence times, and the authors showed that when a mixture of
acetophenone and benzaldehyde was processed under mild
conditions (60 °C, 12 min) the aldehyde was selectively
reduced. In a follow-up report, the authors presented the
opposite Oppenauer oxidation in an identical setup.320
The same group utilized MnO2 as a heterogeneous catalyst
for the hydration of nitriles yielding the respective amides
under continuous flow conditions (Scheme 49).321 A solution
of the respective nitrile in a mixture of water and cosolvent
(isopropyl alcohol or acetone) was passed through a heated
packed bed reactor at a system pressure of 6.9 bar. The reaction
was selective for a broad range of aromatic and aliphatic nitriles
with excellent functional group tolerance. Analysis of the final
reaction mixture showed negligible amounts of manganese
Scheme 49. Hydration of Nitriles Using MnO2 in a Packed
Bed Reactor
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leaching, underlining the heterogeneous character of the
catalytic system. Remarkably, with a single catalyst cartridge
containing 2.5 g MnO2, more than 200 g of products were
synthesized in multiple runs. For dinitriles, the degree of
hydration could be tuned by adjusting the temperature and
residence time.
5.2.2. Heterogeneous Organocatalysis. Albeit a rela-
tively new research field, organocatalysis has rapidly become an
important area in synthetic organic chemistry.322 They use
readily available chiral organic compounds to catalyze a broad
range of enantioselective carbon−carbon and carbon−heter-
oatom couplings without the need of any metal species.
Therefore, covalent anchoring of such catalysts on a polymer
support eliminates the risk of leaching. Immobilization is
usually carried out using spacers and linkers on solid supports
such as silica, polystyrene, or copolymers, and the resulting
material can be loaded into a packed bed reactor. Organo-
catalytic reactions usually require high catalyst loadings and are
often relatively slow with low turnover numbers (TON) even
under flow conditions, making the utilization of continuous
processing sometimes unnecessary. The decision whether to
turn to flow or not has to be carried out on a case-by-case basis
depending on the respective application as well as the catalyst’s
activity and stability over time.45,51,54
Asymmetric aldol reactions have been carried out in
continuous flow using immobilized peptide catalysts323,324
and proline derivatives.325−329 As an illustrative example,
Pericàs and co-workers developed the aldol reaction of
benzaldehyde derivatives and cyclohexanone (Scheme 50). A
proline derivative was immobilized on a homemade Merrifield
resin containing 8% 1,4-divinylbenzene as cross-linker. The
resin was functionalized with 4-ethynylbenzyl chloride, and the
catalytically active residue was attached via a Huisgen-type
Scheme 50. Asymmetric Aldol Reaction Using an
Immobilized Proline Catalyst
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cycloaddition to give 51. In an initial solvent study, the authors
realized that water was crucial for high selectivity. A similarly
immobilized catalyst without the p-phenylene spacer gave lower
activity and diastereoselectivity, most likely as a result of the
decreased separation between the hydrophilic catalyst and the
hydrophobic backbone. Batch experiments showed promising
recyclability, which encouraged the researchers to test the
catalyst in a continuous packed bed reactor. The reaction
mixture was fed via a syringe pump into a fritted glass column
which was loaded with the swollen resin (600 mg, 20 mm bed
height), and the final reaction mixture was subsequently
collected. Under optimized flow conditions, the aldol reaction
of p-nitrobenzaldehyde 49 and cyclohexanone 50 was
monitored over 45 h. The activity of the catalyst 51 was stable
over 30 h without any deterioration of the stereoselectivity
(Scheme 50), allowing for the production of 4.87 g of the chiral
aldol product 52. Three additional aldol compounds were
produced with good conversion and excellent enantiomeric
excess during 8 h runs under similar conditions.
The same group reported continuous anti-Mannich reactions
using supported pyrrolidine330 and an immobilized threonine
derivative in a similar reactor setup.331 The latter case utilized
inline IR analysis for determining the optimal flow rate
(Scheme 51). The signal ratio of the respective product and
Scheme 51. Three Component, Asymmetric anti-Mannich
Reaction Using an Immobilized Threonine Catalyst
the corresponding in situ formed imine indicated that a flow
rate of 30 μL min−1 was suitable at room temperature. With the
optimized conditions in hand, a small library was prepared
consisting of five anti-Mannich adducts all in good-to-excellent
yields and stereoselectivity.
The continuous 1,4-addition of aldehydes to nitroalkenes was
presented by Fülöp and colleagues using a peptide catalyst
immobilized on polystyrene with a 4-methylbenzhydrilamine
linker (Scheme 52).324 The heterogeneous catalyst was packed
into a stainless steel cartridge and connected to a pump and an
adjustable back pressure regulator. The authors studied the
effects of the flow rate and the system pressure on yields and
selectivity for the 1,4-conjugate addition of propanal 53 and E-
β-nitrostyrene 54 under continuous flow conditions. Interest-
ingly, long residence times did not increase conversion and had
a significant negative effect on the diastereoselectivity. In a
control experiment, they realized that the enantiomeric ratio
decreased from 11:1 to 4:1 upon a second cycle in the
continuous packed bed reactor. Therefore, it was assumed that
the immobilized peptide also induces epimerization. Higher
pressures resulted in higher conversion, reaching a maximum at
60 bar. Since an experiment with 50% reduced catalyst loading
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Scheme 52. Asymmetric 1,4-Addition Reaction with an
Immobilized Peptide Catalyst at High Pressures
showed no proportional decrease of the product formation, the
authors concluded that the reaction rate is strongly influenced
by transport phenomena. They argued that reactions involving
a swellable support are diffusion-controlled, and the increased
pressure improves the diffusion of reactants into the swollen
polymer matrix.
Other studies have used peptidic catalysts,332,333 quinine,334
pyrrolidine derivatives,335,336 and squaramides on polymeric
supports as heterogeneous organocatalysts.337,338 Pericàs and
co-workers realized a continuous two-step synthesis of
pyranonaphthoquinones (Scheme 53).339 In batch, the Wang
Scheme 53. Continuous Two-Step Synthesis of
Pyranonaphtoquinones with a PS-Supported Squaramide
Catalyst
resin showed the best results out of several PS-supported
squaramides. This was attributed to its bis-phenylmethylene
ether moiety, the longest linker used in their study. In flow, the
substrates were pumped into the packed bed reactor in a single
feed, due to the absence of an uncatalyzed background reaction.
The asymmetric Michael addition worked under all tested
conditions and was immediately merged with the subsequent
cyclization step. Thus, a second feed containing an aqueous
NaHCO3 solution was connected via a Y-mixer and the
resulting biphasic stream was introduced into a PTFE coil
reactor. Thereafter, a membrane separator was used to remove
the aqueous phase, and the organic product stream was
collected. The residence time for the overall process was 30
min. With this setup, a small library of pyranonaphtoquinones
was synthesized under identical conditions in good-to-excellent
yields and stereoselectivity.
Authors by the same group also used an enantiopure
benzotetramisole catalyst for the domino Michael addition/
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cyclization of phenylacetic acid 56 and tosylimine 58 (Scheme
54).340 First, a mixed anhydride was generated from 56 and
Scheme 54. Asymmetric Domino Michael Addition/
Cyclization of Phenylacetic Acid 56 and Tosylimine 58
pivaloyl chloride 57 in a coil reactor at room temperature and
subsequently mixed with a stream of the imine 58 in a mixing
junction. Then the combined stream entered a packed bed
reactor containing the polystyrene supported organocatalyst. A
residence time of 7.5 min was sufficient for high conversions to
the desired dihydropyridinone 59 and was continuously
monitored over 11 h using an inline FTIR analysis module.
Inline quenching with water, subsequent phase separation using
membrane technology, and recrystallization yielded the title
compound 59 in 70% with excellent enantioselectivity on a
gram scale (TON 22.5).
Wang et al. developed an organocatalytic cascade reaction for
the synthesis of enantioenriched cyclopropanes.341 An initial
organocatalytic Michael addition of a bromomalonate species to
an α,β-unsaturated species generates an enamine intermediate,
which subsequently undergoes an intramolecular cyclization.
Depending on the base, the resulting cyclopropane adduct can
undergo a subsequent undesired base-mediated ring opening,
generating significant amounts of a side product. Llanes et al.
hypothesized that this process can be minimized in continuous
flow since the base could be subsequently removed from the
reaction mixture using inline separation strategies.342 Thus, the
substrates were combined with N-methylimidazole by a T-
shaped mixing unit and pumped through a packed bed reactor
containing the immobilized catalyst (Scheme 55). Subse-
Scheme 55. Synthesis of Enantioenriched Cyclopropanes
Using a Silylated Diarylprolinol Catalyst Grafted onto
Polystyrene
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quently, an aqueous solution of NH4Cl was added downstream
to extract the base, which was then separated using membrane
technology. By comparing different anchoring strategies and
polymeric supports, a silylated diarylprolinol catalysts grafted
onto polystyrene through a benzyl linker exhibited relatively
stable conversion over 48 h (from 56 to 41%, 12 min residence
time) with excellent enantioselectivity (94% average). Using
this catalyst, the authors synthesized a library of 12 cyclo-
propane derivatives in excellent ee and dr. The isolated yields
were low-to-moderate as a result of poor conversion due to the
short residence time. However, electron-rich enals, a significant
reduction of the ring-opened side product was obtained using
the continuous strategy. Furthermore, a telescoped process
with a consecutive Wittig reaction was presented to
demonstrate the synthetic potential of the methodology.
The Benaglia group studied immobilized MacMillan-type
imidazolidinone catalysts for asymmetric Diels−Alder reac-
tions.343−345 By using different immobilization techniques and
silica nanoparticles, the authors found significant differences in
the conversion and stereoselectivity for the cycloaddition of
trans-cinnamaldehyde 60 and cyclopentadiene 61 (Scheme
56).345 For continuous experiments, a stainless steel HPLC-
Scheme 56. Asymmetric Diels-Alder Reaction in Continuous
Flow Using a Heterogeneous Imidazolidinone Catalyst
column was filled with the respective catalytic material and the
reactions were monitored over several days.345 An imidazoli-
dinone catalyst grafted onto silica nanoparticles (8 μm) showed
the best results but residence times above 10 h were necessary
for sufficient conversions, greatly limiting its application for
synthetic purposes. Nevertheless, in some cases, the material
was stable over 170 h, and catalytic material could be
reactivated by washing with HBF4 in MeCN if a loss in its
activity was observed. In follow-up work, a similar imidazoli-
dinone catalyst immobilized on mesoporous silica nanoparticles
and a polystyrene support was used for studying the
continuous, enantioselective α-alkylation of aldehydes with
1,3-benzodithioylium, tropylium, and bis[4-(dimethylamino)-
phenyl]methylium cations as electrophiles.346
In the synthesis of complex molecules, the asymmetric α-
functionalization of aldehydes is a powerful strategy,347
especially α-aminations with azodicarboxylate esters. This
well-established technique in organocatalysis has been trans-
ferred into a heterogeneous continuous protocol.348,349 Fülöp
and co-workers used a peptide catalyst supported on TentaGel
for the amination of aldehydes with dibenzyl azodicarboxylate
(DBAD, 63) in a PEEK column (Scheme 57).348 Since the
resulting α-hydrazino aldehydes 64 are prone to racemization,
the authors subsequently reduced them to the more stable
alcohols. The amination of n-propanal 62 was chosen as a
model reaction for optimization. Three equivalents of the
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Scheme 57. Asymmetric α-Amination of n-Propanal 62 with
Dibenzyl Azodicarboxylate 63 in a Packed Bed Reactor
aldehyde were optimal for high conversion and ee at a reaction
time of 8 min, with 200 mg of the supported catalyst (0.48
mmol g−1). At longer residence times, the conversion was
slightly higher, albeit with lower stereoselectivity due to
racemization. A batch comparison with a reaction time of 22
h resulted in full conversion, but ee values were as low as 79%.
Therefore, the precise control of the reaction time gained by
flow techniques was important in the present catalytic system.
The pressure dependence agreed with their previous studies on
the continuous 1,4-addition of aldehydes to nitroalkenes324
with an optimum pressure of 60 bar. With optimized conditions
in hand, a gram scale synthesis of α-hydrazino alcohol 65 was
carried out. The catalyst was stable over 20 h showing an
average conversion of 87% with 90% ee, producing 3.5 g (81%)
of the title compound 65. Other simple aldehydes also resulted
in excellent conversions and selectivites at relatively high
productivity rates.
Pericàs and colleagues used a heterogeneous Brønsted acid
catalyst for the asymmetric allylborylation of aldehydes in a
continuous flow device.350 The active material (PS-TRIP) was
prepared by copolymerization of the respective divinyl BINOL-
derivative with styrene and divinylbenzene followed by
phosphorylation, resulting in functionalization levels of 0.2−
0.23 mmol g−1. During the optimization in batch, a reaction
temperature of −30 °C was suitable for high enantiomeric
excess. The reaction gave excellent results with a broad range of
aldehydes and three different allylating reagents using 5 mol %
of PS-TRIP within 6 h under conventional conditions. In the
case of 3-pyridinecarboxaldehyde, a racemic product was
obtained, which was attributed to a possible interaction of the
acidic catalyst with the basic heterocyclic moiety. However, the
entire scope (21 examples) was synthesized with the same
sample of PS-TRIP, and no decrease in its activity was detected.
This observation prompted the researchers to develop a
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continuous protocol (Scheme 58). The authors chose to study
the reaction of benzaldehyde 66 and allylboronic pinacol ester
Scheme 58. Asymmetric Allylborylation of Benzaldehyde
Using a Heterogeneous Brønsted Acid Catalyst in a Packed
Bed Reactor
67, as this reaction can be carried out at room temperature
maintaining excellent stereoselectivity. The authors realized
that an uncatalyzed background reaction of unreacted
substrates in the collection flask diminished their ee values.
Thus, an inline quenching technique was used to scavenge the
unreacted aldehyde with NaHSO3. The optimized flow system
allowed for the synthesis of 4.6 g of (R)-1-phenylbut-3-en-1-ol
68 with an enantiomeric excess of 91% during a continuous 28
h experiment. Notably, a similar BINOL-derived phosphoric
acid catalyst was used for the continuous aza-Friedel−Crafts
reaction of sulfonylimines and indoles by the same group.351
Enantiopure alcohols were synthesized from aldehydes and
diethylzinc using PS-supported 3-exopiperazinoisoborneol.352
The study was based on the authors’ previous work where an
immobilized analog of (R)-2-piperidino-1,1,2-triphenylethanol
had a limited lifetime for the same reaction class due to base-
induced fragmentation of the C−C bond in the β-amino
alcohol moiety.353,354 The authors hypothesized that this
fragmentation process is favored by the aromatic system
which stabilizes an α-amino carbanion product, prompting
them to prepare a catalytic material which lacks such structural
motifs. To this end, (2S)-(−)-3-exoaminoisoborneol was
converted into the corresponding piperazine derivative and
covalently attached to a Merrifield resin (0.78 mmol g−1). Batch
experiments showed that the catalytic activity of the
immobilized catalyst is marginally lower compared to the
unsupported derivative, and a catalyst loading of 10 mol % was
sufficient for converting several aldehydes into the correspond-
ing secondary alcohols in excellent yields and selectivities
within 6 h at 0 °C. A recycling study further showed no
decrease of the catalytic activity over five cycles, which
compelled the authors to test the applicability of their material
in continuous flow (Scheme 59). Quantitative conversion of
benzaldehyde 66 was obtained with an ee of 98% at a residence
time of 6 min at 0 °C using two equivalents of the organozinc
reagent 69. The system was stable over 20 h maintaining high
stereoselectivity with only a small drop in the conversion
(∼85% conversion after 30 h). Notably, 13 g of the enantiopure
alcohol 70 was isolated from one continuous experiment.
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Scheme 59. Enantioselective Addition of Et2Zn to Aldehydes
by Solid Supported 3-Exo-Piperazinoisoborneol
Massi and colleagues studied the utilization of immobilized
N-heterocyclic carbenes (NHC) catalysts for umpolung
reactions under continuous flow conditions.355 The authors
prepared a polymeric monolith inside a stainless steel column
by a free-radical polymerization of styrene, DVB, and a 4-
methylthiazole-containing monomer. The thiazole residue was
subsequently N-alkylated with benzyl bromide to obtain the
final catalytically active material with a thiazolium loading of
0.55 mmol g−1. SEM analysis showed a macroporous material
which exhibited good mechanical stability, and almost no
swelling could be observed in the tested solvents. Initially, the
authors showed its applicability in the benzoin condensation of
benzaldehyde 66 (Scheme 60). A mixture of an aqueous buffer
Scheme 60. Benzoin Condensation Using an Immobilized
NHC Catalyst in a Continuous Packed Bed Reactor
(pH 8) and DMSO (10% v/v) was used for a fully
homogeneous solution. Offline analysis revealed that a
residence time of 116 min is necessary for full conversion to
benzoin 71. The heterogeneous catalyst started to lose its
activity after 35 h and was completely inactive after 50 h.
Interestingly, when the authors performed a similar acyloin-
type condensation, stable conversion was maintained for 180 h
under almost identical conditions, however with EtOH as a
solvent. Stetter reactions also performed nicely for over 90 h.
The quick degradation of the catalytic material after the
respective processing time was attributed to temperature
effects, which are considered the most severe limitation of
immobilized organocatalysts in continuous flow. The benefits
gained by reduced reaction times and continuous processing
using a packed bed reactor are overshadowed by limitations
resulting from catalytic materials which do not allow for a
continuous production over a reasonably long time range. It is
thus necessary to develop robust, supported catalysts with
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excellent stability and high activities to fully explore the power
of continuous manufacturing.
5.3. Gas−Liquid−Solid Reactions
As discussed in the previous section, gas−liquid−solid reactions
involve important transformations which operate via truly
heterogeneous mechanisms and are therefore perfectly suited
for continuous processing. Hydrogenation reactions are the
exemplar, as the substrate and hydrogen adsorb on the metal
surface. Hydrogen dissociates into atomic hydrogen and adds to
the unsaturated carbon−carbon bond, whereupon the desired
compound finally desorbs from the catalytic surface. This
process is cheap, often selective, and most solvents can be used
for such reactions. Moreover, the high atom economy, small
amount of chemical waste, and the normally simple workup
(filtration of catalyst and solvent evaporation) is in good
agreement with green chemistry principles.356 A plethora of
heterogeneous catalysts are available typically being noble
metals (Pd, Pt, Rh, and Ni) on a solid support (carbon,
alumina, silica, etc.) or finely grained alloys such as Raney
nickel. This powerful class of reactions can be used for a
breadth of important transformations such as saturating
alkenes, alkynes, or aromatic systems, for the reduction of
many functional groups, including nitriles, amides, azides, nitro
groups and carbonyl compounds, or the removal of protecting
groups via hydrogenolysis. However, the utilization of hydrogen
comes with severe safety issues, and reactions under ambient
conditions are occasionally slow.
It is not surprising that many of the above-mentioned
transformations are already routinely carried out in flow and
continuous processing. This area of research has been
extensively reviewed19,52,59 and is already a standard technology
in many research laboratories. Therefore, this section will only
briefly introduce the basic strategies for continuous flow
applications. Typically, control of the hydrogen addition is
achieved by the use of mass flow controllers (Scheme 61a).357
Also the tube-in-tube gas addition module can be applied, but
its limited pressure resistance does not allow for the high
pressures sometimes necessary for efficient hydrogenation
processes.19,52,59,358
Scheme 61. Basic Concepts for Hydrogenation Reactions:
(a) Conventional Approach Using Mass Flow Controllers
and (b) on-Demand Generation of H2 via the Hydrolysis of
Water (H-Cube)
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However, Jones and colleagues introduced a revolutionary
system for continuous hydrogenation reactions which uses an
incorporated electrolytic cell for the on-demand generation of
hydrogen from deionized water (Scheme 61b).359 Thus, safety
risks are dramatically reduced as no hydrogen cylinders are
required. The addition of the generated H2 is controlled by a
motorized valve and added to the reaction mixture through a
porous titanium frit to ensure efficient mixing. Moreover, the
commercially available system (H-Cube) consists of a pump
which delivers the solubilized substrate, a bubble detector to
determine whether H2 is properly delivered, a heating block
controlled via a Peltier system to accurately heat the packed bed
reactor, an adjustable back pressure regulator, and two pressure
sensors for process monitoring. The packed bed reactor unit
itself is a stainless steel cartridge containing the catalytically
active material (CatCart) which can be quickly installed in the
heating block. Importantly, a range of cartridges packed with
the common hydrogenation catalysts are commercially
available, but it is also possible to load any given material
into the empty cartridges. The latest version of this system can
be used at temperatures from 10 to 150 °C and a maximum
pressure of 100 bar, allowing one to safely perform hydro-
genation reactions under harsh conditions. Moreover, a
particularly useful advantage of this device is the convenient
incorporation of deuterium into organic molecules by using
D2O instead of ordinary water.360−362
The aerobic oxidation of alcohols into the corresponding
carbonyl compound is a fundamental reaction in organic
synthesis and a plethora of selective methodologies exist.
Unfortunately, common strategies involve stoichiometric
amounts of oxidants such as NMO in the presence of TPAP,
permanganates, activated DMSO, chromium(VI) complexes
(Collins reagent, PDC, and PCC), or hypervalent iodine
reagents (Dess-Martin periodinane, IBX). Some of these
relatively expensive reagents are toxic, and all suffer from
poor atom economies. In contrast, aerobic oxidations with
reusable heterogeneous noble metal catalysts facilitate this
reaction and generate water as the only byproduct. In flow, such
reactions can be safely performed under the harsh conditions
which are often necessary for a high productivity, and the
utilization of packed bed reactors reduces the necessary work
up steps.66,179−181
The development of suitable conditions for the selective
continuous oxidation of benzylic and allylic alcohols to the
corresponding aldehydes and ketones has been carried out by
several groups using a broad range of heterogeneous catalysts,
including Pt/C,363 Ru(OH)x on alumina,364 Pd nanoparticles
supported on MOFs,365 Au/TiO2,366 Au-doped superparamag-
netic nanoparticles,367 and supported iron oxide nano-
particles.368
Jensen and co-workers took advantage of this straightforward
strategy and utilized Ru/Al2O3 in a telescoped process to
synthesize amides from various benzylic alcohols and secondary
amines (Scheme 62).369 For the initial aerobic oxidation of
benzylic alcohols, a mass flow controller was used to regulate
the oxygen stream. The mixture of the reactive gas and the
alcohol solution entered a packed bed reactor containing the
supported catalyst which was heated to 80 °C. A residence time
of 19 s was sufficient for the oxidation of benzylalcohol, and a
stable conversion was observed during a 24 h experiment. For
the downstream process, oxygen was removed in a membrane
separator and the liquid stream then entered a silicon-Pyrex
microreactor where it was mixed with an excess of the
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Scheme 62. Continuous Two-Step Amide Synthesis by
Aerobic Alcohol Oxidation Using a Heterogeneous Catalyst
respective amine and a urea hydroperoxide adduct (UHP) as
the oxidant. With dependence on the substrate, the amide
synthesis required 90−120 °C for full conversion within 22
min. A sampling loop was used to determine the yield of the
target compounds via offline GC analysis.
Hermans et al. developed a metal-free protocol for the
oxidation of primary and secondary alcohols to the
corresponding aldehydes or ketones via an NOx propagated
chain oxidation using O2 as a terminal oxidant (Scheme 63).370
Scheme 63. Metal-Free Aerobic Oxidation of Alcohols Using
Amberlyst-15 in a Packed Bed Reactor
The reaction requires catalytic amounts of HNO3 as an oxygen
shuttle in combination with a packed bed reactor of Amberlyst-
15. The oxidation proceeded rapidly (4−25 s) for various
substrates at 100 °C with excellent selectivity for the desired
carbonyl compounds as analyzed by GC. After passing the
packed bed reactor, the mixture was depressurized and the
phases were separated. The gaseous stream was analyzed using
an inline transmission IR cell for monitoring the generated
N2O to get valuable information on the radical chain
propagation. In addition, an inline ATR-IR was used to
continuously monitor the substrate/product ratio. Compared
to batch, the reaction showed a significantly increased reaction
rate, which was not only attributed to the higher effective
molarity of the catalyst but also to an elongation of the radical
chain propagation in the triphasic flow system. A milder
protocol (55 °C) was recently introduced by the same group
which uses TEMPO immobilized on silica instead of
Amberlyst-15.371
5.4. Liquid−Liquid Reactions
An early example showcasing the beneficial effect of the
increased interfacial area of liquid−liquid transformations in
continuous flow mode was carried out by Wirth and
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colleagues.372 The authors compared the biphasic hydrolysis
of para-nitrophenyl acetate 72 with sodium hydroxide in a
biphasic solvent system (toluene/water) in both batch and
continuous flow mode (Scheme 64).
Scheme 64. Biphasic Hydrolysis of p-Nitrophenyl Acetate
In flow, syringe pumps delivered each respective phase
generating a slug flow pattern with a T-mixer unit. The
interfacial area in this reaction was studied in a PTFE coil
reactor (i.d. 0.3 mm) and a PMMA chip reactor (i.d. 0.3 mm)
with identical internal volumes. Overall, the reaction suffered
from poor yields (<10%) within 2 min in a stirred flask,
whereas the flow experiments gave significantly better results
within the same reaction time (40−95% depending on
conditions). Several trends could be observed under continuous
flow conditions. The reaction performed slightly better at room
temperature in the microchip unit than in the coil reactor,
rationalized by the smaller segments observed. In contrast to
the batch experiments, higher temperatures (50 °C) led to
significantly higher conversions in the slug flow approach using
the PTFE coil reactor unit. Most importantly, the biphasic
hydrolysis could be further improved by generating smaller
segments or by reducing the channel cross-section to increase
the interfacial area.
More recently, detailed studies were carried out to compare
biphasic mixing effects in batch and flow for the benzylation of
4-tert-butylphenol 74 and 2,3,6-trimethylbenzenthiol 75 using
tetrabutylammonium bromide (TBAB) as a phase-transfer
catalyst (Table 7).93 The phenol 74 resulted in relatively good
Table 7. Comparison of Phase Transfer Catalysis in Batch
and Flowa
a
Microwave autoclave reactor, stirring with 720 rpm. bStainless steel
coil (i.d. of 0.02″). cGlass chip (width: 391 μm, depth 1240 μm).
d
Packed bed reactor (i.d. 15 mm) packed with stainless steel beads
(60−125 μm).
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yields in a batch microwave reactor at 70 °C but could be
further improved in either a coil, chip, or packed bed
microreactor filled with stainless steel spheres to induce
turbulent mixing of the immiscible liquids. All reactions were
carried out above the boiling point of the organic solvent
(DCM), which necessitated the use of a microwave autoclave
apparatus in batch and the utilization of a BPR unit (5−10 bar)
for continuous flow experiments. When the authors used the
more reactive thiol 75, a smaller amount of the PTC and a
shorter reaction time was necessary. In the case of the thiol 75,
a significant improvement was observed for all continuous flow
experiments. In addition, a clear trend was observed as the
microchip reactor gave higher conversions than the mesoscale
coil unit, which is in good agreement with the difference in the
interfacial area. Moreover, the packed bed reactor gave the best
results, which clearly shows the positive impact of chaotic
mixing in liquid−liquid systems.
The packed bed strategy was further applied for biphasic,
palladium-catalyzed C−N and C−C cross-coupling reac-
tions.373−376 These powerful synthetic transformations usually
require inorganic bases which are insoluble in most organic
solvents or further produce insoluble salts, which would lead to
the clogging of a continuous flow reactor.22 To solubilize all
organic and inorganic components, biphasic liquid−liquid
mixtures have utilized in combination with phase transfer
catalysts373,375,376 or amphiphilic cosolvents374 for flow
processing. A comparison of a coil reactor with a packed bed
reactor (filled with stainless steel spheres) illustrated the
importance of passive mixing elements for the biphasic cross-
coupling of 2-chloroanisole 76 and ethyl 2-aminobenzoate 77
(Scheme 65).373 Importantly, a series of batch experiments
Scheme 65. Comparison of Coil and Packed Bed Reactors
for the C−N Cross Coupling of 2-Chloroanisole and Ethyl 2-
Aminobenzoate under Biphasic Conditions. Reprinted with
permission from ref 22. Copyright 2011 Royal Society of
Chemistry
revealed that the stirring rate has a strong influence, and under
vigorous stirring conversions are similar to the packed bed
reactor results.
The above-discussed examples clearly indicate that such
biphasic liquid/liquid reactions principally benefit from
interfacial area and mass transfer related effects in a mesoscale
continuous flow approach. However, a significant effect is only
observable for relatively fast reactions, whereas others need
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additional mixing strategies such as a packed bed reactor filled
with inert material. On a laboratory scale, vigorous mixing in a
round-bottomed flask may be more convenient since
comparable results can generally be obtained. In fact, slow
biphasic reactions such as the chlorodehydroxylation of primary
alcohols with aqueous HCl have been shown to be identical
under batch and flow conditions even at high temperature/
pressure conditions.377 Nevertheless, scaling such biphasic
transformations in batch to large quantities is accompanied by a
plethora of process challenges (reactor size, shape, agitation,
etc.), and thus continuous flow technology can be a valuable
alternative, as is the case for large-scale oxidations with H2O2 or
bleach,378−380 or other industrially relevant transforma-
tions.381,382
If a liquid−liquid reaction has to be carried out at
temperatures above the boiling point of one of the respective
solvents to gain a significant reduction of the reaction time,
flow becomes a powerful technique for research laborato-
ries.93,377,383 An illustrative example is the synthesis of adipic
acid 80 from cyclohexene 79 (Scheme 66a).384 The batch
Scheme 66. Synthesis of Adipic Acid from Cyclohexene in
(a) Batch and (b) Continuous Flow
synthesis required 8 h at 90 °C, with Na2WO4 in combination
with CH3(n-C8H17)3N]HSO4 and H2O2. In a continuous flow
reactor, this industrially relevant oxidation was significantly
enhanced by increasing the reaction temperature to 120 °C at
15 bar, resulting in a reaction time of only 20 min in the
absence of a PTC (Scheme 66b). Neat cyclohexene 79 was
mixed with an aqueous solution of hydrogen peroxide and
tungstic acid in a T-mixer to generate a slug flow pattern before
entering a heated PFA coil reactor. The reaction mixture
became homogeneous after a few minutes in the reactor unit
due to the formation of more polar intermediates. Importantly,
when the oxidation was carried out in a sealed vessel (batch
microwave reactor), explosions were occasionally observed.
The exothermic decomposition of H2O2 was favored instead of
the desired cyclohexene oxidation when the mixture was not
vigorously stirred under these harsh conditions. Hessel and co-
workers studied the same reaction using packed bed reactors
filled with glass spheres for better biphasic mixing385 and
temperature ramping.386 They also presented a high T/p (115
°C, 70 bar) protocol in a stainless steel coil reactor using a two-
stage temperature ramping with H3PO4 as an additive to
suppress undesired H2O2 decomposition, resulting in a yield of
59%.387
Kappe and co-workers used a biphasic high T/p approach for
the synthesis of hydantoins via the Bucherer-Bergs reaction
(Scheme 67).388 In this multicomponent reaction, an aldehyde
or ketone and a cyanide anion combine to form the respective
cyanohydrin, which ultimately reacts with ammonia and CO2 to
give the desired heterocyclic scaffold.389 The gaseous reagents
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Scheme 67. Continuous Bucherer-Bergs Hydantoin
Synthesis
are usually generated in situ via thermal decompositions of
(NH4)2CO3. In batch, the reaction is generally carried out by
refluxing a mixture of the carbonyl compound, KCN, and
(NH4)2CO3 in water and ethanol for several hours or even
days. In the continuous approach, the starting material in
EtOAc is mixed with an aqueous solution of the reagents,
generating a well-defined slug flow pattern which is heated to
120 °C in a Hastelloy coil reactor at 20 bar. The high pressure
and lack of gaseous headspace kept the generated gas in
solution resulting in significantly shortened reaction times.
Biphasic liquid−liquid transformations provide the oppor-
tunity to use membrane separation technology immediately
following the desired reaction. However, for single stage
reactions, the classical separatory funnel is usually more
convenient, as it does not require any process optimization.
Nevertheless, if a toxic or hazardous intermediate is formed,
such separators can be used to couple production with an
immediate consumption in a continuous downstream process.
An early proof-of-concept study was presented by Jensen et al.
for the biphasic synthesis of acyl azides from acyl chlorides and
NaN3 and their subsequent consumption in a Curtius
rearrangement (Scheme 68a).390 In a similar approach, Kim
Scheme 68. Generation and Downstream Processing of
Hazardous Intermediates in Liquid−liquid Flow Regimes:
(a) Synthesis of Acyl Azides for Subsequent Curtius
Rearrangement. (b) Preparation of Ethyl Diazoacetate and
Condensation with Aldehydes
and co-workers developed a two-step procedure for the
preparation and utilization of ethyl diazoacetate (Scheme
68b).391 Toluene and an aqueous mixture of glycine ethyl ester
hydrochloride 81 and NaNO2 were fed into a coil reactor unit
where the desired diazo compound was generated and
ultimately extracted into the organic phase. After inline
separation of the two phases, the hazardous intermediate was
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reacted with aldehydes in a base-catalyzed condensation
reaction in an additional coil reactor.
5.5. Liquid−Liquid−Solid Reactions
Liquid−liquid−solid reactions are relatively rare in the scientific
literature except for liquid−liquid reactions which significantly
benefit from packed bed reactors containing inert mixing
elements.The same positive effect can be observed when the
packed bed unit contains a heterogeneous catalyst, and
therefore, such triphasic systems should be superior over
batch protocols.
One example in continuous flow was reported for the
triphasic oxidation of alcohols.392 Bogdan et al. immobilized
TEMPO on a commercially available AMBERZYME oxirane
resin and packed the material into a polymer tubing. An
aqueous phase containing NaOCl and KBr was mixed with a
solution of benzaldehyde in DCM in a Y-mixer in order to
generate a slug flow pattern (Figure 29). When the mixture
Figure 29. Phase mixing during the liquid−liquid−solid oxidation of
alcohols with NaOCl and immobilized TEMPO. Reprinted from ref
392. Copyright 2009 Beilstein-Institut zur Foerderung der Chem-
ischen Wissenschaften.
entered the packed bed reactor, the slugs immediately
emulsified, and after leaving the packed bed, the organic and
aqueous phases coalesced and the resulting slugs were
significantly longer. With a residence time of 4.8 min and a
temperature of 0 °C, various primary and secondary alcohols
were successfully oxidized to the corresponding aldehydes and
ketones in good-to-excellent GC yields. Moreover, the system
was stable for more than 9 h.
Most multiphasic reactions can definitely benefit from
continuous processing and are often applied in combination
with other strategies (e.g., high T/p processing). Generally,
reactions involving gases are better-suited for flow than for
batch due to better controllability and reduced safety issues.
The latter can be further reduced if a reactive gas/reagent can
be generated and purified on-demand in order to avoid any
exposure to the environment. For solid materials, the batch
versus flow decision is not as clear and has to be made on a
case-by-case basis. Solid reagents are usually easier to use in
batch and for catalytic materials; special care has to be taken if
the material leaches out of the packed bed reactor. If leaching
can be excluded, flow may be the perfect solution. Further, if
the metal catalyst is cheap and large amounts are used in the
respective reactor, the inherent advantages of flow processing
can outperform the issues associated with leaching. Finally,
liquid−liquid reactions also may benefit from flow, but the
advantages for these processes are more associated with
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reactions on large scales since vigorous stirring in batch can
lead to similar results on a laboratory scale.
6. MIXING
Fast reactions, where the rate of the reaction is faster than the
rate of diffusion (Da > 1), are highly dependent on mixing. Due
to the small dimensions of microreactors, mixing can be
achieved in very short time (<1 min).393 Many types of fast
reactions have been deemed “flash chemistry”.96 This section
highlights chemistry where the reagents can react with
themselves and/or the product because of poor mixing or
where the stability of an intermediate was time-dependent at a
given temperature. Flow conditions enhance mixing and permit
precise control of residence time, mitigating side reactions and/
or decomposition of reactive intermediates. For simplicity,
many similar low-temperature chemical transformations in flow
have been left out since their residence times (minutes−hours)
are not indicative of a mixing-dependent reaction at the given
temperature, and/or their batch counterparts function com-
parably.
Recently, chemists are under increasing pressure to construct
compounds more efficiently. Eliminating protection and
deprotection steps is a stride toward “ideal syntheses”.394
Flow chemistry has enabled protecting-group free synthesis by
the fast, efficient generation and utilization of reactive
intermediates, bypassing the need for protecting groups.395 A
hypothetical example of a flash reaction with competing
undesired pathways is shown in Scheme 69. Fast mixing and
Scheme 69. Hypothetical Side Reactions for Mixing-
Dependent Transformations
quantitative generation of a reactive intermediate 83 occurs in
seconds or even fractions of a millisecond.396 While cryogenic
conditions are normally required to prevent the decomposition
or suppress undesired reactivity to form 84, flow conditions
permit the generation and utilization of 83 in seconds and
therefore tolerate reactions at higher temperatures without
significant decomposition (section 6.1). Similarly, the efficient
formation of the desired product 87 can be difficult if 83 can
react intramolecularly. Extremely fast mixing in flow enables
intermolecular trapping of 83, suppressing the formation of the
side-product 86 from an intramolecular reaction (section 6.2).
Finally, inefficient mixing in batch can lead to local
concentrations of 83 in proximity to the desired product 87,
producing over-reacted side-products 88 and 89 (competitive
consecutive side reactions). Better mixing in flow eliminates
these heterogeneous local concentrations, suppressing the
production of 88 (section 6.3) and 89 (sections 6.4 and 6.5).
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6.1. Outpacing Intermediate Decomposition
Alkenyl halides are useful intermediates for further function-
alization via coupling reactions.397−399 However, synthesizing
functionalized alkenyl halides using trans-1,2-dichloroalkenes
via its deprotonation requires cryogenic conditions,400,401 due
to their proclivity to eliminate lithium chloride to form alkynes.
Yoshida and co-workers showed that with the use of flow
chemistry, functionalized trans-1,2-dichloroalkenes can be
synthesized at much higher temperatures (Scheme 70a).402
Scheme 70. Synthesis of (a) Tri- and Tetrasubstituted
Alkenes, and (b) Propargyl Alcohols from trans-1,2-
Dichloroethene
Decomposition was not significant in flow when a solution of
trans-1,2-dichloroethene was deprotonated with n-butyllithium
at 0 °C and trapped with benzaldehyde within 0.055 s. The
subsecond time before quenching yields the dichloropropenol
from 90, whereas the propargyl alcohol 91 is the major product
in a batch reactor. This sequence was used to produce four
trisubstituted alkenes in 85−93% yield. This synthesis is a
particularly good demonstration of fast generation and
utilization of reactive intermediates that cannot be achieved
in batch. The process was expanded with a second
deprotonation at −78 °C using sec-butyllithium, followed by
quenching with TMSOTf producing compound 92 in 72%
yield. This process produced four tetrasubstituted alkenes in
62−73% yield. Alternatively, a very similar setup was used for
the second deprotonation at a higher temperature (0 °C) with
twice the amount of base (2.31 equiv) to yield propargyl
alcohol 92 (Scheme 70b).
Trifluoroisopropenyllithium is similarly unstable because of
its propensity to form 1,1-difluoroallene via elimination of
lithium fluoride. Batch reactions with trifluoroisopropenyl-
lithium must be carried out below −100 °C.403,404 Yoshida
developed a three-component reaction using a trifluoroiso-
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proenyllithium species under noncryogenic conditions (Scheme
71).405 A solution of 3,3,3-trifluoropropene 93 and sec-
Scheme 71. Three-Component Flow Reaction Utilizing
Trifluoroisopropenyllithium under Noncryogenic
Conditions
butyllithium were mixed at −78 °C to generate trifluoroiso-
propenyllithium 94 and quenched with various electrophiles
0.38 s later. The authors demonstrated the utility of this setup
by trapping this intermediate with various electrophiles,
producing nine compounds in 62−90% yield. Batch reactions
are often carried out using excess trifluoropropene and lithium
reagent. Notably, the flow conditions permitted the preparation
of these substrates without excess reagents. The setup for
reactions with isocyanates was expanded to include an
additional nucleophile 95, which added 1,4 to the α,β-
unsaturated carbonyl intermediate 96. The authors synthesized
five α-trifluoro-substituted amides 97 using this setup.
Halomethyllithiums are employed in the Kowalski ester
homologation406 as a safer alternative to the Arndt-Eistert
synthesis407 and the Nierenstein reaction,408 which employ
diazomethane. The first step in the Kowalski homologation is
the formation of a halomethyllithium 98 under cryogenic
conditions followed by addition to an ester. In batch,
temperatures above −78 °C result in significant decomposition
of this intermediate to form methylene 99. Degennaro and co-
workers showed that under flow conditions, chloromethyl-
lithium 98 could be generated and reacted at significantly
higher temperatures than in batch (Scheme 72).409 Attempts to
add chloromethyllithium 98 to benzaldehyde in batch at −20
°C yielded no desired product 100 but rather 48−53% of 1-
phenylethanol, the result of methyllithium addition to
benzaldehyde. In flow, mixing chloroiodomethane and
methyllithium at −20 °C followed by a benzaldehyde quench
Scheme 72. Rapid Generation and Trapping of
Chloromethyllithium in the Flow Synthesis of Chlorohydrins
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Review
produced the desired product in 30% yield. Lowering the
temperature to −40 °C produced 100 quantitatively (>98%).
The authors demonstrated that these conditions can be used
for the addition of chloromethyllithium to numerous aryl
aldehydes, ketones, imines, Weinreb amides, and an isocyanate
in 70−98% isolated yields. Additionally, by employing MeLi·
LiBr as a lithiating agent, 100 was obtained at −20 °C without a
loss in yield.
In a related flow process, Hafner et al. lithiated methylene
chloride (DCM) for the synthesis of β,β-dichlorocarbinols.410
The utilization of dichloromethyllithium 102 is relatively
limited due to its proclivity to decompose to the carbene
103. Cryogenic conditions (< −78 °C) must be applied for
batch preparations to suppress decomposition, and as such
upscaling is particularly difficult. Hafner and co-workers
commenced DCM lithiation using a flow reactor at −30 °C
with 1.2 equiv of n-BuLi and a 3-methoxybenzaldehyde 101
quench (Scheme 73a). An HPLC yield of 96% resulted after
Scheme 73. Synthesis and Application of β,β-
Dichlorocarbinols in a Continuous Flow Reactor for the
Synthesis of (a) Aminothiazoles and (b) Benzylic Boronic
Pinacol Esters
only one second total residence time. To demonstrate the
usefulness of this setup, the process was run continuously for 5
min, affording 4.85 g (99%) of β,β-dichlorocarbinol 104.
Another eight examples were prepared on a 21.25 mmol scale
producing dichlorocarbinols in 82−99% yield (3.5−6.2 g).
Selected carbinols were utilized in batch and reacted with
thiourea to generate aminothiazoles such as 105. Alternatively,
an arylboronic acid pinacol ester quench was employed for the
synthesis of α-chloroboronic esters 107 in good-to-very good
yields (Scheme 73b). These α-chloroboronic esters react with
nucleophiles such as Grignard reagents or alkoxides and are
useful in the synthesis of secondary benzylic boronic pinacol
esters 108 and methoxylated compounds 109. Both the
aminothiazoles and α-functionalized boronic esters were
prepared on a gram scale using this flow/batch procedure.
The tetrahydroisoquinoline motif is common in natural
products and biologically active compounds.411 The core
structure is often formed via the Pictet-Spengler reaction412
or the Bischler-Napieralski reaction.413 Giovine et al. showed
that functionalized isoquinolines can be constructed via
isomerization of aziridines and that under microfluidic
conditions the selectivity between isomerization and an
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intermolecular reaction of benzylic anions could be controlled
by residence times and temperature (Scheme 74).414 Higher
Scheme 74. Temperature Control for (a) Isomerization and
(b) Intermolecular Reactions of Benzylic Anions Utilizing
Flow Conditions
temperatures and longer residence times led to the ring-
opening isomerization of the aziridine 110 (Scheme 74a).
Attack of the lithium amide 111 on the benzylic position
creates 112, and after trapping with TMSCl, 113 is produced in
78% yield. Attempts to produce 112 and trap it at 60 °C were
unsuccessful in batch. Alternatively, a lower temperature (0 °C)
and a shorter residence time produced aziridines 114a and
114b in 68% yield (Scheme 74b).
Unlike batch setups, flow conditions permit the rapid and
quantitative generation of reactive intermediates and rapid
mixing facilitates trapping before decomposition. Under these
conditions, higher temperatures and lower equivalents are often
tolerated, producing comparable or higher yields to the
corresponding cryogenic, high-equivalent batch conditions.
6.2. Outpacing Intramolecular Reactions
Intramolecular reactions involve the reaction of functional
groups within the same molecule and are typified by high
reaction rates in comparison to intermolecular reactions. The
rapid mixing and trapping that is possible in microfluidic
devices present chemists with the opportunity to intercept
intermediates and achieve better or unique selectivity. Yoshida
and co-workers investigated the intra- and intermolecular
reactions of 2-lithio-2′-(trimethylsilyl)biphenyl in flow.415
Previously, they showed that in flow the monolithiation of
2,2′-dibromobiphenyl 115 and trapping with TMSCl worked
well at 0 °C (Scheme 75),416 whereas −78 °C was required for
batch conditions.417,418 A second lithiation at higher temper-
atures (20 °C) produced the cyclized product 116 in 94% yield.
When the second lithiation was carried out at −40 °C and
trapped with isopropoxyboronic acid pinacol ester within 0.53
s, 117 was produced in 71% yield. This method shows that with
short residence times (<1 s), fast mixing, and temperature
control this intramolecular reaction can be suppressed.
The anionic Fries rearrangement (Scheme 76) is another
intramolecular reaction common in organic synthesis. Trapping
the anionic intermediate is not possible in batch since the
rearrangement occurs rapidly even at temperatures below −90
°C.419 Initially, Kim et al. considered modifying stainless steel
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Scheme 75. Outpacing the Intramolecular Reaction of 2-
Lithio-2′-(trimethylsilyl)biphenyl in Flow
Scheme 76. Outpacing the Anionic Fries Rearrangement
with Submillisecond Mixing in a Microfluidic Reactor
T-mixers to change selectivity in flow.396 The largest stainless
steel microreactor (628 ms residence time) produced the Fries
rearrangement product 119 exclusively in 91% yield. Reducing
the volume of the reactor (4 ms residence time) yielded the
desired intermolecular product 118 in 84% with 96% selectivity
for the carbamate derivative. Esters were more challenging
however, and under the same conditions, only 67% yield of 118
was obtained. Since they were limited to residence times of a
few milliseconds with T-mixers, Kim and co-workers modeled,
constructed, and tested a microfluidic device which achieves
95% mixing in less than a millisecond. Testing mixing efficiency
using computational fluid dynamics showed the 3D serpentine
microchannel structure (Scheme 76) was the only design which
could induce sufficient chaotic mixing and achieve 95% mixing
in 0.3 ms. The reactor was constructed by thermally binding six
polyimide films which were patterned by UV laser ablation.
With this microreactor, 91% and 86% yields were achieved for
the model carbamates and esters, respectively. Under these
conditions, 4 carbamates and 11 esters were reacted, producing
the unrearranged product in 61−98% yield. The anthelmintic
compound afesal 120 was obtained in 67%, demonstrating the
potential for this technology to construct biologically active
compounds that batch conditions cannot.
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These examples illustrate how flow conditions can influence Scheme 78. Flow Synthesis of Thioquinazolinones via
synthesis via the generation and swift trapping of intermediates. Highly Reactive 2-Lithiophenyl Isothiocyanates
Such conditions cannot be imitated in batch, and therefore,
intramolecular reactions cannot be avoided unless flow
conditions are employed.
6.3. Nucleophilic Reactions with Multiple Electrophiles
In the quest for protecting-group free synthesis, the develop-
ment of reactions or conditions where nucleophiles can react
with a molecule selectively in the presence of multiple
electrophiles is paramount. In batch, reaction selectivity can
be complicated for a few reasons. First, if an electrophilic
moiety is on the molecule that is acting as the nucleophile,
inefficient generation of the nucleophilic species can result in
homocoupling-type reactions, necessitating cryogenic condi-
tions or a large excess of the nucleophile. Second, when the yield. Furthermore, a multifunctionalized S-benzylic thioquina-
electrophilic partner contains more than one reactive center, zolinone was prepared from 2-bromo-4-methylphenyl isothio-
mixtures of mono- and di- coupled compounds can result from cyanate, 4-methoxyphenyl isocyanate, and 4-bromobenzyl
poor mixing. In this case, flow offers better mixing of the bromide on a gram scale (1.25 g, 91%) by scaling out the
nucleophile/electrophile, usually outperforming their batch process (5 min operation time).
counterparts. Benzyllithiums such as 127 are highly reactive species whose
Typically, the introduction of fluorine to aryl compounds use as a nucleophile is relatively limited because of a Wurtz-type
requires harsh conditions.420−422 Yoshida and co-workers coupling 128 (Scheme 79). To avoid this side reaction,
utilized flow conditions for the synthesis of aryl fluorides via
aryllithium compounds.423 Initial optimization showed that 4- Scheme 79. Generation and Reaction of Benzyllithiums
methoxyphenyllithium, generated under fluidic conditions from Bearing Electrophilic Functional Groups
4-bromoanisole and n-butyllithium, could be rapidly trapped
(0.017 s) at 0 °C with N-fluorobenzenesulfonimide (NFSI) or
2-fluoro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole-1,1-diox-
ide (N-fluorosultam) in 69% and 85% yield, respectively. The
synthesis of various aryl fluorides containing esters,424
nitriles,425 and ketones,395 electrophilic moieties benefited
from flow conditions. For example, lithiation of tert-butyl-2-
iodobenzoate 121 with phenyllithium followed by trapping
with NSFI at −28 °C produced the 2-fluorobenzoate 122 in
73% yield (Scheme 77). Various aryl iodides and bromides
were reacted using this setup yielding aryl fluorides in 45−83%
yield for NSFI and 31−85% yield for N-fluorosultam.
cryogenic conditions (−95 °C) and a three-solvent system were
Scheme 77. Flow Synthesis of Aryl Fluorides via
employed in batch.428 Nagaki et al. showed that under flow
Electrophilic Fluorination
conditions, benzyllithiums can be generated at higher temper-
atures and efficiently trapped with various electrophiles.429 In
flow, benzyl bromide was used as a starting material, whereas
batch conditions did not tolerate the use of bromides. This was
attributed to the extremely fast 1:1 mixing of benzyl halide and
lithium naphthalenide. Benzyl chloride, benzyl bromide, and 2-
chloromethylthiophene were used in 12 examples generating
products in 42−97% yield. Various benzyllithiums bearing
electrophilic functional groups were employed (Scheme 79). In
this setup, benzyl halides were combined with lithium
Kim et al. demonstrated that similar nucleophiles bearing naphthalenide at −78 °C, to prevent addition to the carbonyl,
isothiocyanates 124 can be generated from 2-bromophenyl and quenched with various electrophiles within 0.38 s. These
isothiocyanates 123 and used for the synthesis of thioquina- conditions facilitated the production of 17 compounds bearing
zolinones (Scheme 78).426 When a solution of 123 was mixed ketones or aldehydes in 41−88% yield. These substrates are
with n-butyllithium at ambient temperature and quenched with very difficult or impossible to obtain using a round-bottom
phenyl isocyanate within 16 ms, 125 was produced in 86% flask.
yield. Similar batch reactions required low temperatures (−78 The selective monoalkylation of a compound bearing two
°C) and offered moderate yields (50−79%).427 Using these electrophilic centers usually requires protection and depro-
flow conditions, 124 was reacted with various electrophiles, tection steps in order to avoid statistical mixtures of products.
providing the corresponding products in good-to-excellent For instance, when 4-benzoylbenzaldehyde was reacted with
yield. For isocyanate electrophiles, the process was expanded by one equivalent of phenyllithium at −78 °C, a maximum of 28%
the reaction with benzyl bromide to form 126 in 80% yield. yield of the desired monoalkylated product 129 was observed.
The three-step flow setup produced ten examples in 75−98% The dialkylated side-product 130 was produced in 25% yield,
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Chemical Reviews
Scheme 80. Flow Setups for the Selective Monoalkylation of Dielectrophiles with (a) Phenyl Lithium and (b) 4-
Bromobenzonitrile
Scheme 81. Flow Setups for (a) Monoarylation of 1,4-Cyclohexanedione and (b) Dilithiation of 1,4-Dibromobenzene toward
the Synthesis of [10]Cycloparaphenylene
while 35% of the starting material remained. Yoshida’s group
demonstrated that when these same substrates were reacted
under fluidic conditions (Scheme 80a), the desired product 129
was obtained in 78% yield with only 7% of the dialkylated side-
product 130.430 Even at a higher temperature (−40 °C),
significant improvements over batch conditions resulted.
Similar improvements were observed for the reaction of
phenyllithium with various other dielectrophiles to produce
the desired monoalkylated compounds (131, 133, and 134).
This strategy was expanded to other aryllithiums where the
corresponding aryl iodides and bromides were first reacted with
n-butyllithium or phenyllithium at −40 °C before a quench
with various dielectrophiles (Scheme 80b). For example, 135,
containing an electrophilic carbon center itself, was reacted
with dielectrophile 136 using this setup to produce compound
137 in 78% yield. This approach demonstrates how flow
chemistry is a powerful tool for protecting group free synthesis.
Flow conditions enabled the synthesis of [10]-
cycloparaphenylene ([10]CPP).431 First, 1,4-dibromobenzene
138 was reacted in flow at 0 °C with n-butyllithium to
selectively produce the monolithiated species,432 which was
immediately quenched (16 ms) with 1,4-cyclohexanedione
(Scheme 81a). This process afforded the monoalkylated
product 141a in 92% yield. An additional quench of
bromomethyl methyl ether (MOMBr) was incorporated for a
flow/batch process for the production of MOM-protected
alcohol 141b in 80% yield. The batch process only produced
11842
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141a in 11% likely due to poor mixing which results in a second
alkylation of 139 to produce 140, the major side product. Next,
the authors performed a flow dilithiation of 1,4-dibromoben-
zene using tert-butyllithium at 25 °C, accompanied by a quench
with 141b (Scheme 81b). This setup was convenient since
cryogenic conditions were required in batch. Scaling out the
flow process gave 1.23 g (73%) of the unprotected alcohol
143a. Again, a MOMBr quench was incorporated in a flow/
batch process to obtain 143b in 68% yield. In two subsequent
batch steps, the U-shape 143b was dimerized and aromatized to
provide [10]CPP in the highest yield to date; 11% overall yield,
double the previous yield of 5%. This synthesis is an excellent
example of how flow chemistry can expedite synthetic routes.
Octafluorocyclopentene 145 is similar to dicarbonyls in that
it has two electrophilic centers. Asai et al. investigated the
selective monoarylation of octafluorocyclopentene 145 with
aryllithiums toward the synthesis of asymmetric photochromic
diarylethenes (Scheme 82).433 In batch, the lithiation and
substitution must be conducted at temperatures below −78 °C.
Even then, only 24% of the desired monoarylated product 147
was obtained, while 18% of the diarylated compound was
produced. In flow, lithiation of the 3-bromothiophene 144 was
carried out at 0 °C and quickly trapped (0.28 s) with 145
yielding 147 in 81% yield. Only 9% of the diarylated compound
was observed. Enhanced mixing in flow significantly improved
both yield and selectivity for this reaction. Two monoarylated
cyclopentenes were made in this fashion and with a second
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Scheme 82. Flow Sequence for the Synthesis of Asymmetric
Photochromic Diarylethenes from Octafluorocyclopentene
substitution reaction, seven asymmetric diarylethenes were
synthesized in 35−94% yield. Alternatively, diarylethenes were
produced in one process (Scheme 82). Lithiation of 144,
trapping with 145, and subsequent mixing with the output from
the lithiation of bromothiophene 146 produced 58% of the
diarylated compound 148. Two other asymmetric diarylethenes
were synthesized with this setup in 51% and 66% yield.
6.4. Selective Carbonyl Syntheses
Organic chemists face a similar problem when a nucleophilic/
electrophilic coupling reaction results in another electrophilic
center. For instance, when electrophiles such as acid chlorides
and esters react with a nucleophile, ketones are produced.
Overreaction can occur since their reactivity is similar or higher.
In equimolar ratios, poor mixing can result in mixtures of
starting material, product, and overreacted product. Since
mixing in flow is generally faster than in batch, similar
enhancements for yield and selectivity are seen in the synthesis
of ketones.
The synthesis of α-keto esters is commonly conducted via
oxalyl chloride or dialkyl oxalates. This method suffers from
poor yields due to competitive consecutive side reactions.
Mixtures of diketones and tertiary alcohols result and are
difficult to suppress even with 1:1 stoichiometry of the
nucleophile and oxalate. Attempts to avoid competitive
reactivity using flow conditions were made as early as
1998.434 In this report, a stirred solution of aryllithium at
−80 °C and a solution of diethyl oxalate were drawn through
Teflon tubing, a T-mixer, and a 1 mL syringe using a vacuum
pump. With this make-shift flow reactor, four α-keto esters
were synthesized in 64−83% yield with negligible amounts of
side-products.
Yoshida employed modern flow techniques for the synthesis
of α-ketoesters.435 First, the arylation of diethyl oxalate was
conducted in batch at −20 °C, and only 55% of the desired α-
keto ester was produced with 18% of the diaryl diketone side-
product. When the lithium/halogen exchange with bromoben-
zene and n-butyllithium was carried out in flow and mixed with
diethyl oxalate at −20 °C, 93% of the α-keto ester and only 5%
of the diketone resulted. Various stable aryllithiums were
reacted with diethyl, dimethyl, and di-tert-butyl oxalates at −20
°C (16 examples). Highly reactive aryllithiums were generated
from aryl iodides such as 149, at −60 °C using phenyllithium
and trapped within 0.4 s using diethyl oxalate to produce 150 in
88% yield (Scheme 83).
A similar process for the synthesis of α-ketoamides via the
reaction of carbamoyl anions with acyl chlorides was
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Review
Scheme 83. Flow Setup for the Monoarylation of Diethyl
Oxalate in the Synthesis of α-Keto Esters
reported.436 The reaction of N,N-bis(para-methoxybenzyl)-
carbamoyl chloride 151 with lithium naphthalenide generates a
carbamoyllithium 152. When the carbamoyllithium was reacted
with methyl chloroformate under batch conditions, the target
153 was obtained in 44% yield. A competitive consecutive
reaction formed a tricarbonyl side-product in 18% and
decomposition of the carbamoyllithium occurred even at −78
°C, giving carbon monoxide and a lithium amide which reacted
to give carbamate 154 in 14%. When the carbamoyllithium was
generated in flow using a 1000 μm diameter T-mixer, and
combined with methyl chloroformate using the same size T-
mixer, batch conditions were essentially duplicated (48% of
153, 18% of the tricarbonyl, and 10% of 154). Reducing the
diameter of both T-mixers to 250 μm increased the yield of 153
to 83% and reduced side-product formation (13% tricarbonyl,
2% 154). Rapid quenching of the carbamoyllithium reduced its
decomposition and enhanced mixing decreased the formation
of the tricarbonyl side-product. This two-step sequence was
performed substituting methyl chloroformate with various
electrophiles, yielding products in 38−90% yield (eight
examples). The carbamoyl anion was also exchanged,
producing compounds in 47−85% yield (11 examples). For
substrates from methyl chloroformate, the output of this
process was joined with the output of various organolithium
reagents at −40 °C, providing α-ketoamides in 51−70% yield
(Scheme 84). Aryl bromide 155 was used in this three-step
process to produce 156, an intermediate in the synthesis of
GW356194, a sodium channel blocker.
Luisi and co-workers exploited flow conditions for the
synthesis of tert-butyl esters.437 First, hexyllithium was reacted
with di-tert-butyldicarbonate (Boc2O) at 25 and −78 °C under
Scheme 84. Flow Setup for the Synthesis of GW356194 by
the Sequential Reaction of a Carbamoyl Anion with Methyl
Chloroformate and an Aryllithium Reagent
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batch conditions. The conversion was low, and the desired tert-
butyl ester was obtained in only 7% and 15%, respectively. The
major product for both temperatures was the tertiary alcohol
(37% and 25%), accounting for the poor conversion and yields.
When this reaction was adapted to flow at −50 °C, the ester
and alcohol were produced in 44% and 56%, respectively.
Reducing the residence time from 24 to 5.6 s increased the
yield significantly (96%) and reduced the alcohol side product
to 4%. The setup was expanded to include the generation and
reaction of various aryl, vinyl, and alkynyllithiums to produce
tert-butyl esters in 50−95% yield (19 examples). Notably, many
of these reactions had comparable yields at 0 and 25 °C. Next,
utilizing Yoshida’s conditions for the generation of highly
reactive aryllithiums, diester 158 was synthesized from 157 in
65% yield, demonstrating the power of this process to create
molecules containing multiple handles with varying reactivity
(Scheme 85).
Scheme 85. Flow Setup for the Synthesis of tert-Butyl Esters
via Organolithium Compounds and di-tert-Butyldicarbonate
Similar processes were developed for the synthesis of ketones
from acyl chlorides438 and esters.439 Ordinarily, Grignard and
other organometallic reagents are reacted with carboxylic acid
halides for the synthesis of tertiary alcohols rather than
ketones.440 Moon et al. combined aryllithiums with acyl
chlorides in flow under noncryogenic conditions toward the
synthesis of various ketones in 42−86% yield (19 examples).
Similarly, researchers from AstraZeneca performed a ketone
synthesis starting from an ester and methylmagnesium
bromide.439 Unlike acyl chlorides, esters are less reactive than
ketones resulting in significant alcohol formation via
dialkylation. The transformation of ester 159 to ketone 160
was optimized in batch producing 160 in 60% yield. The
significant formation of tertiary alcohol 161 and aldol product
162, however, prevented crystallization of the product 160. In
an attempt to reduce these side-products, this reaction was
adapted to flow. Under flow conditions, 80% yield was obtained
at 0 °C. While lowering the temperature to −20 °C had no
beneficial effects, reducing the residence time (13 to 6 s)
increased the yield (85%). At higher concentrations (0.8 M vs
0.6 M) the system was unstable due to clogging by
precipitation. Connecting this setup to a second chip facilitated
the expedient quenching of the basic reaction mixture (Scheme
86). With the use of these reaction conditions, 300 g of ester
159 was converted to 160 in 12 h. The significant reduction of
side products 161 and 162 permitted the crystallization of
ketone 160 from an isopropanol/water mixture in 72% isolated
yield (192 g). In this case, flow conditions facilitated a
significant reduction of side-products, not only improving the
yield but also enabling purification by crystallization.
Carboxylic acids are important handles in organic synthesis
that can be formed traditionally by the oxidation of alcohols,
alkenes, or alkynes. Alternatively, carboxylic acids can be made
by reacting organometallic reagents with carbon dioxide.199 In
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Review
Scheme 86. Synthesis of a Ketone Using Methyl Grignard
and an Ester in Glass Chip Reactors
batch, benzoic acid can be synthesized with phenyllithium and
carbon dioxide at −78 °C in 87% yield. The highly reactive
aryllithium compounds, however, can cause side reactions at
higher temperatures. As an illustration, when this reaction was
carried out at 0 °C, benzoic acid was obtained in only 28%
yield, while benzophenone (34%) and triphenylmethanol
(27%) constituted the rest of the mixture. Yoshida and co-
workers adapted this reaction to flow and found that at 0 °C,
benzoic acid was produced in 87% yield. The increased yield is
likely due to improved mixing which suppresses competitive
consecutive side reactions.203 The authors went on to utilize
their previously developed conditions424 to generate para-
ethoxycarbonylphenyllithium and rapidly trap it to synthesize
the corresponding carboxylic acid 164 in 83% yield (Scheme
87). Various aryl bromides and iodides such as 163 were used
Scheme 87. Flow Synthesis of Carboxylic Acids and Their
Corresponding Activated Esters
following this setup to prepare 13 examples in 59−89% yield.
Furthermore, when the output of this flow setup was collected
in a solution of N,N,N′,N′-tetramethyl-O-(N-succinimidyl)-
uronium tetrafluoroborate (TSTU), the active esters 165 could
be prepared without intermediate purification in good-to-
excellent yield.
A flow procedure for the synthesis of asymmetric ketones
(Scheme 88)204 started with a carboxylation of an organo-
lithium compound by mixing the liquid stream with carbon
dioxide in a Y-mixer before entering a PFA coil reactor
(residence time <1 min) at room temperature. Subsequent
removal of excess carbon dioxide in a degassing chamber
allowed for the nucleophilic addition of a second organolithium
compound (Scheme 88a). For several ketones such as 166, no
gas separation unit was necessary since the equimolar amount
of carbon dioxide was consumed quantitatively (Scheme 88b).
Overall, more than 30 diaryl, alkyl−aryl, alkyl−vinyl, and alkyl−
alkyl ketones were synthesized in moderate-to-excellent yields
in a faster and more selective manner than traditional batch
approaches, which suffer from the formation of symmetric
ketones, tertiary alcohols, and other side-products. Equimolar
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Scheme 88. Synthesis of Asymmetric Ketones from Carbon
Dioxide and Organolithium or Grignard Reagents (a) with
and (b) without a Gas Separation Unit
amounts or a slight excess of carbon dioxide permits the use of
lower equivalents of the second organometallic reagent. This
advantage, in combination with better mixing, reduced side
products from competitive consecutive reactions.
6.5. Reductions with DIBAL-H
The reduction of esters to aldehydes with diisobutylaluminum
hydride (DIBAL-H) is attractive in theory. However, in practice
it generally leads to unacceptable levels of overreduction
leading to the primary alcohol441−443 or is completely avoided
because of its erratic reactivity.444−446 Various groups identified
that DIBAL-H performs better in a flow reactor.175,447−450
Jamison’s group incorporated an inline quench was incorpo-
rated to prevent overreduction to the alcohol (Scheme 89).448
Scheme 89. Selective Flow Reduction of Esters Using
Diisobutylaluminum Hydride
In this reaction, T-mixers outperformed Y-mixers. As Y-mixers
provide poorer mixing than T-mixers, the selective reduction
appeared to be highly mixing dependent.451 The authors also
noted that with higher flow rates, albeit shorter residence times,
the conversion increased. Since more energy is put into the
system as the flow rate is increased, mixing is stimulated.452
Temperature influenced both flow and batch procedures.
However, at −42 °C, overreduction was negligible in flow,
whereas the alcohol was the major product in batch. The setup
facilitated the rapid optimization of six examples affording
>95% GC yields for all substrates with undetectable or
negligible amounts of alcohol.
An ester homologation process via a selective reduction-
olefination sequence was established by Webb et al.453 Rather
than quenching the reduction stream with methanol, it was
combined with a phosphonate carbanion which was generated
by mixing ethyl diethylphosphonoacetate with n-butyllithium
(Scheme 90). Efficient mixing for the reduction tolerated a 1:1
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Review
Scheme 90. Homologation of Silylated Ethyl Lactate via a
Selective DIBAL-H Reduction and Horner-Wadsworth-
Emmons Olefination
ratio between the ester and DIBAL-H, eliminating any possible
repercussions stemming from excess DIBAL-H reacting with
the phosphonate. Ten examples were isolated in very good-to-
excellent yield. Interestingly for some reactions, the E/Z
selectivity was significantly higher than previously reported
conditions.454 The homologation of the silyl ether of ethyl
lactate 167 is the best illustration of benefits of this sequence
since the intermediate aldehyde is both volatile and prone to
racemization. In this system, the homologation product 168
was obtained in 89% with >19:1 E/Z selectivity (Scheme 90).
Recently, DIBAL-H reductions in flow have been applied to
the synthesis of complex molecules.455,456 Researchers at Eisai
turned to flow chemistry in their synthesis of eribulin mesylate
173 (Scheme 91a). The batch reduction of ester 169 to
aldehyde 170 was achieved in excellent selectivity, however at
−80 °C. In flow, comparable conversion and selectivity were
achieved at −50 °C. Like the Jamison group, the authors also
found that at both −30 and −40 °C, the conversion and
selectivity benefited by increasing the flow rate by way of better
mixing. Although mixing efficiency was improved, it eventually
plateaued. Therefore, two COMET X-01 micromixers (M)
were connected in tandem to further enhance mixing (Scheme
91b). With optimal conditions in hand, the researchers
investigated the performance for continuous operation.
DIBAL-H and 169 were mixed and quenched with acetone
in toluene. A line delivering 1 M HCl was incorporated for a
final quench in a collection bottle. After 87 min of continuous
operation, aldehyde 170 was isolated in 97% yield (306 g).
The following coupling of aldehyde 170 and sulfone 171 did
not go to completion in batch. The authors hypothesized that
the anion generated from 171 is protonated by the α-proton of
the resulting product 172 before it can couple with the
aldehyde. Additionally, the optimized batch conditions were
run below −70 °C, whereas in flow, adequate results were
obtained at −10 °C. Increasing the flow rate also increased the
conversion, confirming incomplete conversion in batch was
mixing related. Increasing the residence time had little influence
on conversion; however, an increase in the reactor temperature
to 10 °C gave the best conversion (only 3.5% of sulfone 171
remaining).
6.6. Electrophilic Trapping for Subsequent Cross-Coupling
Reactions
The electrophilic trapping of organolithium compounds is a
common route to boronic acid esters457 and alkylzinc
reagents458 for subsequent palladium-catalyzed coupling
reactions.459 Recently, the groups of Yoshida and Buchwald
advanced this type of chemistry in continuous flow
reactors.460−462 Since enhanced mixing improves lithiation
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Scheme 91. (a) Synthesis of Eribulin Mesylate by (b) Selective DIBAL-H Reduction and (c) n-Butyllithium-Mediated
Deprotonation in Flow
and electrophilic trapping, this section highlights these steps
and their corresponding coupling reactions.
Arylboronic esters can be synthesized from aryl halides,
triflates, and amines via palladium-catalyzed cross-coupling
reactions with tetraalkoxydiborane reagents.463−465 While these
conditions tolerate a wide range of functional groups,
tetraalkoxydiboron reagents are expensive, and therefore
methods for the synthesis of arylboronic esters via trialkyl
borates are in demand. Early work by Ley demonstrated various
boronic acid esters can be prepared in flow under cryogenic
conditions.466 While convenient for scaling out reactions, this
process does not fully utilize the mixing benefits of micro-
dimensions. Researchers at Novartis developed a flow process
for the synthesis of various boronic acids at elevated
temperatures and determined that the yield is mixing-
dependent.467 Aryllithiums were generated from 1-bromo-4-
fluoro-2-(trifluoromethyl)benzene or 4-bromoanisole and n-
butyllithium at varying flow rates before being quenched with
methanol. The yields of 1-fluoro-3-(trifluoromethyl)benzene
and anisole were directly related to the total flow rate through
the T-mixer. At flow rates >14 mL min−1, the conversion
increased significantly, indicative of mixing-dependent reac-
tions.468 Switching methanol with a solution of trimethyl borate
and including a batch quench with 10% citric acid (Scheme 92),
the authors prepared 11 boronic acids in fair-to-quantitative
yields. Aryl bromides bearing fluorine and cyano groups were
prepared; both of which are difficult to access in batch. All of
Scheme 92. Flow Setup for the Rapid Synthesis of Boronic
Acids via Aryllithiums
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Review
the boronic acids were synthesized on gram scales and in high
purity (>95% by HPLC) with only a liquid−liquid extraction
workup. These conditions, which produce about 1 g/min (5
mmol min−1), were easily scaled up for the production of
multiple kilograms per day (30 mmol/min).469
Highly efficient mixing tolerates 1:1 ratios of aryl bromides
and organolithiums in the generation and utilization of
aryllithiums containing electrophilic moieties.424 Nagaki et al.
utilized this technique for the synthesis of arylboronic esters
bearing functionalities such as esters, nitriles, and nitro
groups.470 When tert-butyl para-bromobenzoate 174 and sec-
butyllithium were combined in a 1:1 ratio at −28 °C and
quenched using isopropoxyboronic acid pinacol ester, com-
pound 175 was produced in 75% yield. Using this method, 12
arylboronic acid pinacol esters were produced in 64−92% yield.
Substituting isopropoxyboronic acid pinacol ester with
trimethyl borate permitted the process to be connected with
a downstream Suzuki-Miyaura cross-coupling reaction (Scheme
93). In this process, the resulting arylboronic acid dimethyl
Scheme 93. Flow Synthesis of Arylboronic Ester Bearing
Electrophilic Functional Groups
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ester 175 was hydrolyzed, prior to being combined at 50 °C Scheme 95. Continuous Flow Zincation and Subsequent
with a mixture of aryl bromide 176, palladium(II) acetate, and Batch Negishi Coupling
tritert-butylphosphine. This process did not require any
additional base, producing the biaryl compounds such as 177
in 52−97% yield.
Modification of this process by incorporating a monolithic
palladium catalyst allowed for activated boronic acid esters to
be generated and coupled with aryl iodides in a semicontinuous
flow process (Scheme 94).471 First, 179 was generated using

Scheme 94. Semicontinuous (a) Arylboronic Acid Ester

Synthesis and (b) Suzuki-Miyaura Coupling in Flow
quenched via a batch Negishi cross-coupling. Arylmagnesium
species were also formed by this method using magnesium
chloride instead of ZnCl2·2LiCl. Various arenes and hetero-
cyclic compounds were coupled using this method in fair-to-
excellent yields. A later report by Roesner generated ortho-
fluoro arylzinc species in flow and telescoped this process with
a subsequent Negishi coupling; however, this process required
sonication to avoid clogging.478
6.7. Miscellaneous Fast Reactions
Similar to the coupling reaction in the synthesis of eribulin
mesylate, researchers at Merck reported a Mannich-type
reaction which performed better in flow compared to batch
(Scheme 96).479 In the synthesis of verubecestat, the coupling

Scheme 96. Flow Setup for a Mannich-Type Reaction toward

the previously developed conditions and collected in a flask the Synthesis of Verubecestat
(Scheme 94a). A solution of aryl iodide 180 was added to the
mixture and pumped through a monolithic material supporting
Pd(0) at 100 °C, producing 1.55 g (85%) of adapalene 181
(Scheme 94b). Various biaryl compounds that are difficult to
prepare in batch were synthesized using this process. Catalyst
leaching was not investigated; however, the Pd column
functioned for greater than 21 h without a loss of activity.
Similar to the Suzuki-Miyaura cross-coupling, the Negishi
coupling is broadly applicable,472 whereby transmetalation of
organozinc reagents to a palladium catalyst allows for the
coupling to a wide range of unsaturated halides. Organozinc
reagents can be prepared by oxidative addition to zinc metal,473
transmetalation, and iodide or boron−zinc exchange.474
Recently the Knochel group reported the zincation of
functionalized arenes via a lithium/zinc transmetalation using
lithium 2,2,6,6-tetramethylpiperidide (TMPLi) for the depro-
tonation of various aryl compounds in the presence of zinc(II)
chloride at −78 °C.475 While these conditions tolerated some
reactive functional groups, the authors faced problems related of 182 and imine 184 resulted in 73% yield and required
to decomposition, unwanted side reactions, and difficulties with temperatures below −70 °C. The authors determined via a
scaling-up. For these reasons, Knochel and co-workers deuterated acetic acid quench that low conversion and yield was
developed flow processes using this zincation method.476,477 due to the deprotonation of 184 by 186 to form enamine 185
Preliminary experiments indicated that higher temperatures (87% deuterium incorporation). This side reaction could,
were tolerated (0 °C vs −78 °C). In particular, in batch at −78 therefore, be alleviated by better mixing. When this reaction
°C, the iodination of ethyl 4-bromobenzoate resulted in the was adapted to flow (Scheme 96), initial conversion at −10 °C
desired aryl iodide in only 53% yield, whereas flow conditions was low (55%). However, increasing the flow rate significantly
yielded the product in 95% at 0 °C. Flow conditions tolerated a increased conversion (86−88%) supporting their hypothesis
broader range of functional groups and was more easily scaled related to mixing. However, the process was haunted by
up. The authors also noted that the less bulky, cheaper lithium increasing pressure as a result of gradual clogging of the mixer.
dicyclohexylamide (Cy2NLi) was tolerated in flow because of To combat erratic pressure, an inline tube mixer that is less
better mixing. The bulky TMPLi base was required in batch to prone to clogging was incorporated and the temperature was
reduce reactivity and prevent side reactions. With this modified lowered to −20 °C to prevent decomposition of 183. Under
setup (Scheme 95), solutions of an aryl compound, zinc(II) these flow conditions, 87−91% yield was obtained for
chloride, and lithium chloride were mixed with a stream of prolonged periods of time without detectable pressure
Cy2NLi at 0 °C. The newly formed arylzinc species was fluctuations.
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The Brook rearrangement involves the migration of an
organosilyl group from a carbon to an oxygen.480 In the
presence of a strong base, the equilibrium is shifted and silyl
ethers can be employed in the construction of carbon−silicon
bonds.481 Michel et al. investigated the performance of the
retro-Brook rearrangement under flow conditions (Scheme
97).482 The reaction using n-butyllithium generally requires
Scheme 97. Retro-Brook Rearrangement in Flow for the
Synthesis of 2-Trimethylsilyl Nonafluorobutylsulfonates
cryogenic conditions (< −100 °C) and produces a number of
side-products which can be difficult to separate from the target
compound. When a solution of bromophenol 188 was
combined with a stream of n-butyllithium at room temperature,
the retro-Brook reaction took place within 1 min to afford
ortho-TMS phenols in 75−96% yield. The high purity led the
authors to incorporate a downstream quench with trifluor-
omethanesulfonic anhydride (Tf2O) for the two-step flow
production of 2-trimethylsilylaryl trifluoromethylsulfonates in
75−97% yield. The process was scaled out by continuous
operation for 30 min yielding 2.7 g of 2-(trimethylsilyl)phenyl
trifluoromethylsulfonate (91% yield). Aryl nonaflates share
similar reactivity to triflates, however, are more resistant to
hydrolysis. Also, 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl
fluoride (NfF) is more stable and cheaper than Tf2O. For
these reasons, the authors employed similar conditions in the
synthesis of arylnonafluorobutylsulfonates (Scheme 97). Since
NfF was less reactive than Tf2O, it required activation by 4-
pyrrolidinopyridine 189. After a retro-Brook rearrangement,
189 and NfF were added and mild heating produced
arylnonafluorobutylsulfonates in very good yield.
Vinylmetals are effective reagents for the construction of
molecules containing carbon−carbon double bonds. The
conditions developed by Seebach are a generally applicable
method for the generation of terminal vinyllithiums via a Br/Li-
exchange with tert-butyllithium (Scheme 98a).483 These
conditions, however, require < −100 °C and at least two
equivalents of tert-butyllithium. Yoshida and co-workers
explored the generation and utilization of vinyllithiums under
microfluidic conditions.484 When various lithiating reagents
were tested under batch conditions at −78 °C, sec-butyllithium
performed the best (100% conversion, 59% yield). When the
same lithiating reagents were tested under flow conditions,
much higher temperatures were tolerated (0 °C) and sec-
butyllithium similarly outperformed the others reagents (96%
conversion, 86% yield). The improved yield was a result of
expedient quenching. Therefore, the authors tested the effect of
residence time (R1) on the conversion and yield. Keeping the
flow rates constant, the length of the reactor was varied
(Scheme 98). At both 20 and 0 °C, the yield of 190 increased
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Review
Scheme 98. (a) Generation and Reaction of Vinyllithiums in
Flow. (b) Importance of Residence Time Control
with decreasing residence time (Scheme 98b). Above 10 s, the
yield dropped off considerably, suggesting that the lifetime of
these vinyllithiums is limited at this temperature. Reducing the
residence time to 55 ms produced allyl alcohol 190 in 95%
yield. Various vinyl bromides and electrophiles were combined
using this setup generating compounds in 43−98% yield.
Radicals are dynamic intermediates in natural product
synthesis.485 Since radical reactions are faster than the rate of
diffusion,486 they are attractive reactions to carry out in flow. In
early reports,487−490 carbon-centered radicals were generated
via a well-known redox process where catalytic iron(II) reduces
hydrogen peroxide forming a hydroxyl radical. This radical
reacts with dimethyl sulfoxide promoting decomposition which
generates a methyl radical. The highly reactive methyl radical
abstracts iodine from an alkyl iodide to finally form a new
carbon-centered radical. The coupling of this radical with an
alkene results in a new radical that is finally oxidized by
iron(III) to close the catalytic cycle.
Under batch conditions, hydrogen peroxide typically has to
be dosed dropwise and used in a large excess. A crude kinetic
model suggested that >90% conversion should be reached in a
fraction of a second. The fast nature of this reaction suggests
that enhanced mass transfer in flow would enhance reactivity.
Monteiro et al. designed a flow setup for the production and
coupling of electrophilic radicals using this method (Scheme
99).491 When an injection loop containing the electron-rich
aromatic substrate and electron-deficient alkyl iodide was mixed
with hydrogen peroxide in flow, high conversion (91%) was
obtained in as little as 0.1 s. Substrates 191, 192, and 193,
which are intermediates in the synthesis of fipronil, tolmetin,
and ketorolac were prepared using this setup in comparable
yields to previously reported values.492 Additionally, the
trifluoromethylation of dihydroergotamine mesylate 194 was
performed under fluidic conditions yielding the monotrifluor-
omethylated compound 195 in 83% yield on a 0.6 kg scale. The
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Scheme 99. Flow Setup for the Creation and Reaction of
Electrophilic Carbon-Centered Radicals
primary benefit of these conditions is the ability to reduce the
equivalents of the substrate, alkyl iodide, and hydrogen
peroxide (1:1.6:1.6) when compared to previous batch reports
which utilize as much as 15−75 equiv of the aromatic
compound and 2−12 equiv hydrogen peroxide.
Benzyne is a highly reactive intermediate with diverse
reactivity for the formation of multiple carbon−carbon and
carbon-heteroatom bonds.493 However, three component
coupling reactions with benzyne can be difficult or impossible
in batch because of the short lifetimes of the intermediates.
Yoshida developed a flow setup consisting of stainless steel
tubing and T-mixers for efficiently performing this three
component reaction (Scheme 100).494 Solutions of 1-bromo-2-
Scheme 100. Three-Component Flow Setup for the
Generation, Trapping, and Quenching of Benzyne
iodobenzene 196 and phenyllithium were pumped through
precooling loops before mixing to form an ortho-bromolithiated
species 197, which quickly decomposes to form benzyne 198.
Concomitantly, para-chlorophenyllithium is generated at 0 °C
before adding to the solution of benzyne 198 at −70 °C. The
newly formed biaryllithium species was quenched with
tetrabromomethane, producing 202 in 63% yield. In batch,
the yield was 15%, with significant amounts of 199 and 200.
The flow conditions tolerated electrophiles such as MeOTf,
TMSOTf, diethyl oxalate, TsN3, and NFSI. Cyanophenyl-
lithiums, para-nitrophenyllithium, 2-pyridyllithium, and 2-
thiophenyllithium were used as nucleophiles.
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Review
Pyridine rings are common motifs in pharmaceuticals,
agrochemicals, and materials.495 Various methods are reported
for the synthesis of functionalized pyridine rings,496−499 one of
which is the introduction of a functional group via a Br/Li-
exchange of bromopyridines. These reactions, however, are
complicated by lithium migration and addition to the ring,
leading to numerous side reactions. For instance, lithiation of
2,3-dibromopyridine with n-butyllithium and trapping with
methyl iodide resulted in a complex mixture at −78 °C with the
target 2-bromo-3-methylpyridine comprising only 48%.500
Raising the temperature to −28 °C resulted in 0% yield of
the desired product. Nagaki et al. developed a flow process for
this reaction where 2,3-dibromopyridine 203 was lithiated with
n-butyllithium at 0 °C and promptly trapped (0.055 s) with a
solution of an electrophile (E1, Scheme 101).501,502 Under
Scheme 101. Flow Setup for the Consecutive Lithiation and
Trapping of Dibromopyridines
these conditions, the target compound was obtained in 87%
yield, a substantial improvement over batch conditions.
Incorporating an additional lithiation and trapping step using
a second electrophile (E2) afforded seven examples of
difunctionalized pyridines in 47−75% yield.
Liu et al. found similar enhancements for the functionaliza-
tion of other heteroaromatic compounds using a split and
recombine mixer in flow.503 Lithiation of 2-bromopyridine 206
and quenching with methanol was used as a model reaction for
the optimization of the flow setup. In batch, the yield of
pyridine was below 50% at −40 °C and dropped by nearly half
after warming to 20 °C. Using two T-mixers and a residence
time of one second, approximately 80% of pyridine was
produced at −40 °C. A significant drop-off in yield did not
occur until 0 °C. Integrating an inline mixer into the setup
increased the yield and operating temperature (Scheme 102a).
Using this flow method, 17 examples such as the conversion of
204 to 205 were performed in 45−94% yield. To demonstrate
the ease of scaling out a process, the authors also prepared 5.60
g (62%) of 207 in 40 min (Scheme 102b).
Most fast reactions (<1 min) benefit from continuous flow
due to faster mixing, which not only can simplify reaction
setups by permitting noncryogenic conditions but also can
improve reproducibility and safety for scaling up reactions for
synthesis.
7. TEMPERATURE
Contrary to flash reactions, slow reactions are sped up by
heating the reaction mixture. Traditional batch reactions are
limited to the boiling point of the solvent, and therefore, high-
boiling solvents must be employed to reach high temperatures.
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Scheme 102. (a) Br/Li Exchange and Trapping toward
Functionalized Heteroaromatic Compounds in Flow. (b)
Flow Process Scale Out
7.1. Heated Reactions below 100 °C
Methylene chloride (DCM) is a very good solvent, capable of
dissolving many organic substances.504 However, DCM is
highly volatile and reaction temperatures are limited to 40 °C
under reflux. Since there are safety hazards and scaling issues
when performing reactions in a sealed vessel, reactions using
volatile solvents such as DCM are more conveniently run at
high temperatures in flow. Newton et al. demonstrated this in
their report of the synthesis of spirocyclic polyketides,455 where
intermediate 209 was prepared via a silylation-acetonide
opening reaction and connected to a downstream ozonolysis
(Scheme 103). First, the protection of the secondary alcohol

Scheme 103. Protection with TESOTf and in Situ Enol Ether

Formation

The use of high-boiling solvents, however, can complicate

purification. Sealed vessels and microwave heating have enabled
chemists to reduce reaction times from hours to minutes while
employing solvents easily removed via a rotary evaporator.99
Recently a microwave-to-flow paradigm has developed,
particularly due to scalability problems in microwave batch
systems.101 These minute long microwave reactions are
particularly well-suited for laboratory scale flow reactors since
the short reaction times permit high flow rates and thereby
synthetically useful quantities.17 In addition, higher temperature
and pressure can be attained in flow, further reducing reaction
times. 208 was carried out at 0 °C. The subsequent acetonide
Convective heating, using oil baths or gas chromatography opening, however, was accelerated by heating at 80 °C under
(GC) ovens, as well as microwave and inductive heating have 6.9 bar back pressure to produce enol ether 209. Similar in situ
been utilized in flow to raise the temperature of the solvent enol ether preparations in DCM were carried out at room
above the boiling point (Table 8). In flow, boiling is suppressed temperature and required 5−16 h for complete conver-
sion.505,506 Running the acetonide ring opening in flow also
Table 8. Boiling Points for Solvents in This Section facilitated a subsequent ozonolysis234,238 which yielded 210 in
54% yield.
solvent boiling point (°C)
In most cases, aromatic amines are produced via the
acetic acid 118 reduction of nitro compounds since a wide variety can be
acetonitrile 82 prepared economically.507 Similarly, carboxylic acids represent
1-butanol 118 widely available and cheap starting materials508 and can be
chloroform 61 converted to anilines via the Schmidt reaction.509 For this
dimethyl carbonate (DMC) 90 reason, the Schmidt reaction of carboxylic acids offers a
dimethylformamide (DMF) 153 convenient alternative to nitration/reduction protocols which
1,4-dioxane 101 can result in mixtures or regioisomers. Chen and co-workers
ethanol 79 utilized chloroform and elevated temperatures for the
ethyl acetate 77 amination of arenes and the Schmidt reaction of carboxylic
hydrochloric acid (30−36%) 61−90 acids in flow to produce anilines.510 Initial batch screenings
methanol 65 showed that toluene could be aminated in as little as 30 min at
methylene chloride 40 60 °C. Increasing the temperature to 90 °C in a microwave
N-methyl-2-pyrrolidinone (NMP) 202 reactor decreased the reaction time to just 5 min. Similarly,
2-propanol 82 Schmidt reactions of carboxylic acids in batch were complete
tetrahydrofuran (THF) 65 after 1 h at 70 °C and a further increase of temperature to 90
toluene 111 °C, reduced the reaction time to 5 min.
water 100 For the Schmidt reaction in particular, scaling can be
challenging from a safety standpoint due to the formation of
by applying pressure to the system by means of a back-pressure stoichiometric amounts of nitrogen and carbon dioxide. For
regulator. This section highlights “high-temperature” reactions this reason, this reaction is especially suitable for flow (Scheme
which we have defined as reactions where the optimized 104). An injection loop containing 4-chlorobenzoic acid 211
temperature is above the boiling point of the solvent and and triflic acid (TfOH) in chloroform was mixed with a
therefore not able to be performed in batch under reflux or solution of trimethylsilyl azide in chloroform. This mixture was
scaled easily in a sealed vessel. Literature examples which use reacted at 90 °C, and after a residence time of less than 5 min,
elevated temperatures, however, employ high-boiling solvents 4-chloroaniline 212 was obtained in 73−78% yield. With the
(ex. NMP, DMSO, and DMF) have been omitted if the same use of these optimized conditions, various alkyl- and halogen-
temperatures can be obtained in batch under reflux. substituted anilines were prepared from their corresponding
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Scheme 104. Flow Setup for the Schmidt Reaction of
Carboxylic Acids
carboxylic acids in fair-to-very good yield. Not surprisingly,
aromatic carboxylic acids containing strongly electron-with-
drawing groups such as nitro- and trifluoromethyl function-
alities were not as reactive, yielding their respective anilines in
only 18−28% yield.
Building upon their previous work in flow,476 the Knochel
group investigated the magnesiation and zincation of
acrylonitriles, acrylates, and nitroolefins under fluidic con-
ditions.511 While some of their substrates were more reactive at
higher flow rates (indicative of a mixing dependence), most
substrates reacted optimally at elevated temperatures with
longer residence times (>1 min). For example, E-cinnamoni-
trile 213 reacted smoothly with TMPZnCl·LiCl in THF at 90
°C with a 10 min residence time producing zincate 214
(Scheme 105a), which was combined with a solution of allyl
Scheme 105. (a) Continuous Flow Zincation and Copper-
Catalyzed Allylation and (b) Selected Examples
bromide and CuCN·2LiCl to produce 215. After quench,
workup and column chromatography, 215 was isolated in 75%
yield. Repeating the reaction under identical conditions, but
with a longer operation time (∼35 min versus ∼7 min), 1.4 g
(83%) of 215 was isolated. This 5-fold increase in scale
demonstrates the ease of scaling when compared to a sealed
vessel reaction. In addition to reactions with 213, the
metalation of 4,5-substituted butenolides was carried out with
the same setup producing compounds 216−218 in 59−87%
yield (Scheme 105b). These reactions were carried out near or
above the boiling point of THF with the same setup, illustrating
the ease with which a reaction can be transitioned from sub-
boiling to superheated. The same group expanded upon this
process with the high-temperature zincation of arenes and
heteroarenes.512 Not only were they able to use (Cy2N)2Zn·
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2LiCl as a base (1% the price of TMPZnCl·LiCl), but they
were also able to run zincation reactions well above the boiling
point of THF (100 °C).
Microwave heating was highly influential for increasing the
rate of reactions. Inherent scaling issues have led to the
combination of microwave heating and flow chemistry which is
comparably easy to scale out or number up to produce
synthetically useful quantities. The Organ group has done
extensive work developing and utilizing their microwave-
assisted continuous-flow organic synthesis (MACOS) process
in medicinal and combinatorial chemistry.513−520 Their reactor
is comprised of a stainless steel mixing chamber connected to
glass capillaries which are positioned inside a microwave
chamber. With their setup, a single capillary can be used to
scale out a reaction to produce larger quantities of a single
compound or in a recent report,521 four capillaries can be used
for the simultaneous synthesis of four different compounds
(Scheme 106). Four stock solutions in isopropanol containing a
Scheme 106. Microwave-Assisted Synthesis of 1,2,5-
Thiadiazepane 1,1-Dioxides Using a Multicapillary Flow
Reactor
sulfonamide 219, DBU, and a different amine 220 for each
capillary were reacted simultaneously. The output from each
capillary was collected in separate sealed vials producing four
different analogs. Only the optimization of a single capillary was
necessary for the production of a library of 48 different 1,2,5-
thiadiazepane 1,1-dioxides 221 in 50−80% yield using this four-
capillary reactor setup.
7.2. Heated Reactions between 100 and 200 °C
The Strecker reaction522 is one of the earliest one-pot
multicomponent reactions. It has garnered much attention
since the products, α-aminonitriles, are well-known precursors
to α-amino acids.523 Our laboratory synthesized primary α-
aminonitriles via a Strecker reaction utilizing a cooled
photoreactor.157 We utilized this process for the synthesis of
various fluorinated amino acids.524 Hydrolysis of the α-
aminonitriles in batch took hours to days even under reflux.
This was due to the loss of acid to the headspace of the batch
reactor. For this reason, the hydrolysis step was incorporated
into a flow reactor. Crude aminonitrile 222 from the
photooxidative Strecker reaction was dissolved in a 30%
HCl(aq)/acetic acid mixture and introduced to a heated reactor
via an injection loop (Scheme 107). An 8 bar back pressure was
applied to prevent boiling, and after a 37 min residence time,
full conversion was obtained with no observable amide
intermediate. In combination with the flow Strecker process,
good-to-very good yields were achieved for the two-step
production of fluorinated amino acids 223 from their
corresponding fluorinated amines.
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Scheme 107. Hydrolysis of α-Aminonitriles toward the
Synthesis of Fluorinated Amino Acids
Recently, the biaryl moiety of odanacatib, a bone resorption
inhibitor, was synthesized in a combined batch/flow process
(Scheme 108).525 First, the authors optimized the stereo-
Scheme 108. Batch/Flow Process for the Synthesis of the
Biaryl Moiety of Odanacatib
selective reduction of 224 using E. coli cells overexpressing the
alcohol dehydrogenase ADH-A, NADH, and isopropanol.
Chiral alcohol 224 was obtained in excellent yield (98%) and
high enantiomeric excess (98%). In an attempt to improve the
overall process efficiency, the crude reaction mixture containing
chiral alcohol 225 was used directly for the subsequent
palladium-catalyzed Suzuki coupling. Initial experiments in a
batch microwave reactor showed that E. coli cells had a
devastating effect on the yield (2%). This challenge was
overcome by centrifugation of the biocatalytic reaction mixture
prior to addition of the coupling reagents. With microwave
conditions in hand, the reaction was translated to flow (Scheme
108). A solution of alcohol 225 with tetrakis-
(triphenylphosphine)palladium(0) in isopropanol, and a
solution of potassium carbonate and boronic acid 226 were
introduced into a heated reactor at 110 °C. A 3 bar back
pressure regulator prevented boiling and with a 5 min residence
time, biaryl compound 227 was isolated in 45% yield after
column chromatography.
Aryl halides are useful substrates for nucleophilic aromatic
substitution reactions.526 Primary and secondary amines, as well
as alkoxides, are generally good nucleophiles for this reaction.
Aryl ether linkages such as those found in natural products like
vancomycin can be formed using this method.527 Unless the
compound is activated by an electron-withdrawing group, many
of these reactions require elevated temperatures.528 Alam et al.
utilized a heated chip reactor for the formation of C−O bonds
in heteroaromatic compounds via an SNAr substitution.529
Initial experiments were carried out in THF, however, due to
the formation of NaCl, clogging prevented extended reactions.
A THF/water (3:2) solvent mixture was ideal and used for
further studies. When chloropyrimidine 228 was combined
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Review
with a solution of phenoxide 229, and heated to 90 °C, 54%
yield of 230 was obtained (Scheme 109). Increasing the heat to
Scheme 109. SNAr Substitution under Flow Conditions
100 and 110 °C further increased the yield to 71% and 87%,
respectively. Additional increases in the temperature did not
significantly improve the yield. With these conditions, nine
other heteroaromatic chloro compounds were reacted with
phenoxides and alkoxides in good-to-very good yields.
The discovery of nifedipine, used for the treatment of
hypertension, sparked interest in the synthesis and pharmaco-
logical properties of 1,4-dihydropyridines.530,531 Dihydropyr-
idine chemistry began much earlier, however, with pioneering
work from Hantzsch, for which the pyridine synthesis is
named.532 Baraldi et al. published an accelerated Hantzsch
pyridine synthesis in a flow reactor (Scheme 110).533 In the
Scheme 110. Flow Setup for the Preparation of 1,4-
Dihydropyridines
synthesis of darodipine 232, aldehyde 231, ethyl acetoacetate,
and ammonium hydroxide in ethanol was pumped through a
PFA reactor heated at 120 °C and 6.9 bar. At 6 min residence
time, daropine 232 was obtained in 76% yield. Using the same
setup, nine other dihydropyridines were synthesized with
residence times of 6−11 min in 45−88% yield.
The complexity of macrocycles provides them with valuable
pharmacological properties attractive for use in therapeutics.534
Due to the ring size, however, macrocyclization is normally
slow and low concentrations must be employed to prevent
oligomerization. The Collins group developed microwave
conditions for the macrocyclization of diynes via a Glaser-
Hay coupling reaction employing PEG400, which facilitates high
concentrations with short reaction times (hours vs days).535
They proceeded to adapt this reaction to flow, following the
microwave-to-flow paradigm.536 Employing CuCl2·2H2O, a
TMEDA ligand, triethylamine, and a Ni(NO 3 ) 2 ·6H 2 O
cocatalyst, the authors found the optimal temperature to be
the same in flow as in a microwave batch reactor (120 °C) with
a residence time of 1.5 h. Their previously reported microwave
batch conditions afforded a 21-membered lactone in 81% yield,
while their new flow conditions yielded the same lactone in
97%. The reaction was scaled, and the macrolactone was
obtained in a comparable 93% isolated yield. Given the
promising scalability of this cyclization, the Collins group
applied this process toward the formal synthesis of ivorenolide
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Chemical Reviews
A, a macrolide with immunosuppressive activity (Scheme
111).537 A solution containing diyne 233 was injected into a
Scheme 111. Flow Setup for the Catalytic Macrocyclization
in a Formal Synthesis of Ivorenolide A
reactor heated at 120 °C via an injection loop, and after a 1.5 h
residence time, the corresponding macrolactone 234 was
obtained in 52% isolated yield.
β-Amino alcohols 236 are common motifs in active
pharmaceuticals such as oxycodone, carvedilol, and metoprolol.
One of the most common ways to construct β-amino alcohols
is by the aminolysis of epoxides.538 Since many of these
reactions require lengthy reaction times, this reaction has been
optimized in a microwave reactor.539 Elevated temperatures
promote epoxide opening without the use of Lewis acid
catalysts. The groups of Jamison and Jensen compared the
aminolysis of various epoxides in a heated flow reactor.102,103
They found that flow conditions could match or even improve
the reactivity when compared to the equivalent batch
microwave reactions. With low-boiling amines, product
distributions (mono- vs dialkylation) varied with the amount
of headspace in microwave batch reactions. The lack of
headspace in flow led to consistent product distributions. Our
group capitalized on this advantage for the synthesis of various
β-blockers 237−241 (Scheme 112).540 Epoxides 235 were
Scheme 112. Aminolysis of Epoxides at Elevated
Temperatures in Continuous Flow
mixed with either tert-butylamine or isopropylamine and heated
to 120−150 °C. Styrene oxides, required 150 °C and a 50 min
residence time for full conversion, while epoxides derived from
epichlorohydrin were more reactive and only required 120 °C
with a 20 min residence time.
Induction heating is the process whereby electrically
conducting materials, usually metals, are heated using a rapidly
alternating magnetic field. The Kirschning group applied this
method in flow using materials such as magnetic nano-
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Review
particles,541 copper wire,294,296 metal oxides,542 and steel
beads.543 In their synthesis of olanzapine, they employed a
steel capillary reactor encased by a high-frequency generator
(Scheme 113).544 Using this setup, aniline 242, was flowed
Scheme 113. Flow Setup for the Acid-Catalyzed Cyclization
toward Olanzapine
through the heated reactor producing a solution temperature of
140 °C. With less than a 1 min residence time (<10 min
reaction time), cyclized product 243 was obtained in 98% yield.
The batch yields were comparable at 92%; however, 2 h were
required for full conversion of only 0.060 mmol of the product.
Indoles are one of the most prevalent structures in nature,
and molecules such as triptans have found widespread use for
the treatment of migraines.545 As such, the structure and
synthesis of indoles has been reviewed extensively.546−549 The
Fischer indole synthesis550 is one of the most prominent routes
to construct this motif and was implemented in flow several
times.551−554 The Kappe group performed an in-depth study of
the mechanism for the Fischer indole synthesis of 7-
ethyltryptophol 246 in flow.555 Initial studies focused on
reproducing previously reported results which employed a
three-pump, two-reactor flow system using a glycol/water/50%
sulfuric acid mixture.553 The authors found that under identical
conditions, only 35−41% yield was obtained, and varying the
temperature, flow rates, stoichiometry, and concentrations had
very little effect on the yield which was consistently around
40%. The investigation into the dimerization and oligo-/
polymerization of 246 indicated that an equilibrium of the
hydrazine and hydrazine 244/dihydrofuran 245 hemiaminal
was unavoidable. Therefore, the original three-pump, two-
reactor setup did not offer any benefits over a premixed
solution pumped through a single reactor (Scheme 114). With
Scheme 114. Flow Setup for the Fischer Indole Synthesis of
7-Ethyltryptophol
this setup, the authors found that comparable yields were
obtained using a methanol/water (2:1) solvent mixture and no
added acid. At 150 °C and 40 bar, 7-ethyltryptophol 246 was
obtained in 41% yield with only 3 min residence time.
Numerous methods exist for the conversion of alcohols to
alkyl halides.556 Most methods employ electrophilic reagents
containing halides such as thionyl chloride or generate reactive
intermediates like in the Vilsmeier−Haack reaction. The
halodehydroxylation is used far less often; however, under
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Scheme 115. Flow Synthesis of Cinnarizine. (a) Chlorodehydroxylation of Diphenylmethanol for the (b) Alkylation of
Piperazine. (b) Concurrent Chlorodehydroxylation of Cinnamyl Alcohol for the (d) Production of Cinnarizine
microwave conditions, this reaction has been shown to be
particularly effective.557 Since then, this process was transferred
to flow by the Kappe group.377 Borukhova et al. utilized this
process for the synthesis of cinnarizine 253 and other
derivatives by an amine alkylation using the newly generated
alkyl chlorides (Scheme 115).558 First, diphenylmethanol 247
in acetone was chlorodehydroxylated at 100 °C and 6.9 bar.
After a quench with aqueous sodium hydroxide and inline
separation, chlorodiphenylmethane was produced in 97% yield
(Scheme 115a). This solution was used to alkylate piperazine
249 at 150 °C and 17.2 bar to produce 250 in 95% yield
(Scheme 115b). Concurrently, cinnamyl chloride 252 was
prepared by the chlorodehydroxylation of cinnamyl alcohol 251
(Scheme 115c). This stream was quenched with aqueous
sodium hydroxide, separated inline, collected, and combined
with the output containing 250. Methanol was added in
equivolume amounts to prevent precipitation of the HCl salts,
and the mixture was heated at 100 °C at 6.9 bar (Scheme
115d). With this complete process, cinnarizine 253 was isolated
in 82% yield with respect to diphenylmethanol 247. The
chlorodehydroxylation setup was used to produce 13 different
alkyl chlorides in 12−99% yield. The alkylation setup was also
utilized to synthesize five alkylated tertiary amines in 63−97%
yield.
The 1,3-dipolar cycloaddition reaction between azides and
alkynes was pioneered by Huisgen in the 1960’s.559 Later, this
reaction reemerged with the coinage of the term “click
chemistry”560 and the development of the Cu alkyne−azide
cycloaddition (CuAAC).561 Conveniently, small molecules
bearing 1,2,3-triazole groups have a wide range of biological
activities.562 The 1,2,3-triazole rufinamide 42 is an anticonvul-
sant that has been targeted by various groups for greener, less-
expensive syntheses. Zhang et al. used methyl propionate in the
continuous flow total synthesis of rufinamide 42.306 Mudd et al.
reported batch conditions using (E)-methyl 3-methoxyacrylate
256; however, these conditions necessitated multiple reagent
additions over the course of 28 h at elevated temperatures.563
Noël and Hessel argued that the high cost of methyl propionate
and its demand for a transition-metal catalyst may be a hurdle
for production scale. For this reason, they developed a flow
process for Mudd’s conditions which were inconveniently long
and posed safety risks.564 They found that at 210 °C, the
residence time decreased from hours to minutes. Using their
previously developed conditions for the synthesis of alkyl
chlorides with HCl gas,247 the authors combined the two
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processes in a formal synthesis of rufinamide starting from 2,6-
difluorobenzyl alcohol 254 (Scheme 116).565 Hydrogen
Scheme 116. Flow Synthesis of Rufinamide Precursor
chloride gas was reacted with a stream of neat 2,6-
difluorobenzyl alcohol 254 at 110 °C at 7 bar. The
corresponding benzyl chloride was obtained after a 40 min
residence time and was combined with an aqueous solution of
sodium hydroxide and sodium azide which reacted at 160 °C
for 40 min. After exiting the back pressure regulator, the
mixture was separated inline and collected, yielding azide 255
in 98%. The azide was finally combined with (E)-methyl 3-
methoxyacrylate 256 and reacted at 210 °C for 15 min before
being quenched with methanol. Upon cooling, the target
compound 257 was obtained in 82% overall yield.
Imidazoles are biologically important molecules, especially as
herbicides and potential drug candidates.566 Common indus-
trial methods utilize the Debus-Radzisewski reaction567,568 or
the dehydrogenation of imidazolines.569 Alternatively, imida-
zoles can be synthesized by the cyclization of α-amido ketones
with ammonia. Researchers at Eli Lilly conducted the synthesis
of imidazole 260 using two continuous flow reactors (Scheme
117).570 The cyclization was accomplished by mixing a solution
of α-amido ketone 258 and acetic acid in methanol with a
solution of ammonium acetate in methanol. The process was
operated for 20 h at 140 °C and 69 bar, producing a total of
1009.5 g (75%) of imidazole 259. A second flow process was
applied for the tert-butyloxycarbonyl (Boc) deprotection. A
solution of 259 in THF/MeOH was pumped through a heated
reactor at 270 °C and 69 bar with a 15 min residence time,
producing deprotected imidazole 260 in 80% yield.
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Scheme 117. Rapid Synthesis of a 1H-4-Substituted
Imidazole Intermediate in a Flow Reactor
Carneiro et al. developed a similar imidazole process for the
synthesis of a daclatasvir intermediate 266 starting from N-Boc-
L-proline 261 and the corresponding α-bromo ketone 264.571
First, the authors showed that proline 261 and α-bromo ketone
262 could be coupled, mixed with ammonium acetate, and
heated at 160 °C to produce imidazole 263 in 77% yield
(Scheme 118a). With the use of this process, 13 imidazoles
Scheme 118. (a) Synthesis of 1H-4-Substituted Imidazoles
under Flow Conditions. (b) Batch-Flow Synthesis of
Daclatasvir Intermediate
were produced in 39−94% yield. The first coupling reaction
was quick even at room temperature; therefore, flow conditions
offered no enhancement to reactivity. For this reason, α-acyloxy
ketone 265 was prepared in batch (Scheme 118b). Ketone 265
was mixed with ammonium acetate and pumped through a
reactor heated at 160 °C and 17 bar. Bisimidazole 266 was
obtained in 71% yield. In this reaction, high temperature and
especially high pressure facilitated a fast reaction, as batch
reactions lost in situ generated ammonia to the headspace of
the reactor.
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Since scaling microwave reactions is difficult, Yokozawa et al.
developed a highly efficient microwave flow reactor.572 The
authors tested their setup using two typical high-temperature
reactions: the Diels−Alder reaction and the Fischer indole
synthesis (Scheme 119). A solution of alkyne 267 and furan
Scheme 119. Continuous Flow Microwave Reactor for a
Multi-Gram (a) Diels−Alder Reaction and (b) Fischer
Indole Synthesis
268 in n-propanol was pumped through the microwave reactor.
A constant temperature of 194 °C and 25 bar was maintained,
and in only 5 min operation time, 4.91 g (76%) of cyclized
product 269 was obtained (Scheme 119a). Additionally, a scale-
out of the Fischer indole synthesis was performed using
cyclohexanone 270 and phenylhydrazine 271. For this reaction,
the temperature was maintained at 240 °C, and after 1 h
operation time, 115 g (75%) of indole 272 was produced
(Scheme 119b).
Ketenes are very reactive intermediates and commonly
employed in cycloadditions573 such as the Staudinger synthesis
of β-lactams.574 Various methods exist for the generation of
ketenes,575 among them is the Wolff rearrangement of α-diazo
ketones.576 Recently, Musio et al. utilized a microwave-flow
reactor for Staudinger cycloadditions using ketenes generated
by the Wolff rearrangement.577 High temperature and a
stoichiometric release of nitrogen upon formation of the
ketene pose safety risks, especially when scaling a reaction. The
authors first optimized conditions for trapping ketenes using
benzyl amine. The optimal temperature and residence time was
165 °C and 7 min, respectively. Using these conditions, six
carboxamides were synthesized in fair to quantitative yields.
The setup was operated continuously for 7 h to scale out the
production of one of the amides. The reactor demonstrated
great temperature and pressure stability for the entire run.
Interestingly, the authors were unable to reproduce similar
results in a batch microwave reactor and a heated flow reactor.
Next, the authors synthesized 18 β-lactams using the same
setup (Scheme 120). Solutions of α-diazo ketones 273 and
aldimines 274 were mixed and heated at 165 °C and 20 bar. At
7 min residence time, the β-lactams 275 were produced in 30−
85% yield.
Scheme 120. Continuous Flow Wolff-Staudinger Reaction
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Approximately 80−90% of hydrazine is incorporated into
organic derivatives such as pesticides and pharmaceuticals.578
The remainder of the applications utilize hydrazine as a
reducing agent.579 Cantillo et al. utilized hydrazine for the
reduction of aromatic nitro compounds 276 by employing in
situ generated iron oxide nanocrystals as a catalyst.580,581
Optimized batch microwave conditions indicated that just 0.25
mol % of Fe(acac)3 precatalyst in methanol was required for full
conversion of nitrobenzene at 150 °C after 2 min. The same
reaction mixture was pumped through a heated reactor (150
°C), resulting in complete conversion to aniline 277 with a 1.8
min residence time (Scheme 121). The authors found that the
Scheme 121. Flow Setup for the Reduction of Nitro Groups
Catalyzed by in Situ Generated Iron Oxide Nanocrystals
residence time could be reduced to 1.6 min, and after a 15 min
operation time, 8.9 g (96%) of aniline was produced. This
process was applied to the synthesis of 20 anilines 277 with
>95% yield for each substrate. Notably, compounds 278, 279,
and 280 were produced on gram scales in excellent yield. This
process was also applied to the reduction of various aliphatic
nitro compounds as well as several azides.
Heck-type chemistry has become a staple for the assembly of
molecules.582 Heck reactions are well-known to perform better
at higher temperatures as long as the reagents, substrates, and
products can survive such intense conditions.583 Microwave
conditions have improved various Heck reactions, and while
some substrates have improved yield,584 substantially reduced
reaction times is the largest benefit over conventional heating at
reflux. The Kappe group investigated the ligandless Heck
reaction using microwave batch and continuous flow setups.585
They found that batch experiments under reflux (ca. 80 °C)
using a heterogeneous Pd/C catalyst required 2−3 h for full
conversion. On the other hand, both batch conditions
employing microwave heating and conventional heating in a
sealed vessel at elevated temperature (105 °C) required less
time (20 min), and at 150 °C, the reaction was complete in as
little as 2 min. No significant differences were observed
between the two batch processes; however, when this reaction
was adapted to flow using a packed bed, the number of side
products increased significantly. The authors attributed this to a
higher effective molarity in the packed bed where alternate
mechanisms leading to the dehalogenation of aryl halides has
been proposed.586,587 For this reason, they developed a
homogeneous method employing Pd(OAc)2 as a catalyst. At
170−200 °C, full conversion of aryl iodides and bromides was
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achieved in less than 20 min. A later report by researchers at
Pfizer created temperature-residence time maps and reaffirmed
the Kappe group’s findings that high catalyst loadings favor side
reactions.588 In their setup, a solution of aryl iodide, n-butyl
acrylate, N,N-diisopropylethylamine, and 0.05 mol % Pd(OAc)2
in acetonitrile was pumped through a heated reactor at 200 °C
(Scheme 122). Gram scale reactions for five substrates resulted
in good-to-very good yields at only 5 min residence time.
Scheme 122. Phosphine-Free Heck Reactions in Flow
Decarbonylation reactions have found applications in the
synthesis of chromene derivatives589 as well as more complex
molecules such as 17-azolyl steroids.590 Early decarbonylation
reports struggled to make this reaction catalytic in transition
metal catalyst, with rhodium carbonyl complexes such as
[RhCl(CO) (PPh3)2] being stable at as high as 260 °C.591
Since then, catalytic decarbonylation reactions have been
reported using rhodium,592 palladium,593−595 and iridium.596,597
Le Châtelier’s principle dictates that systems in equilibrium can
be driven in one direction by the removal of one or more
components of the equilibrium. Gutmann et al. applied this
principle to the decarbonylation of various aldehydes via
annular flow in a continuous reactor (Scheme 123).598 Initial
Scheme 123. Decarbonylation Driven by Annular Flow
batch investigations in sealed microwave vials showed that the
amount of headspace in the reactor had a significant effect on
the conversion of the reaction. Heating 0.6 mmol of 4-
cyanobenzaldehyde with 4 mol % Rh(OAc)2 and 8 mol % 1,2-
bis(diphenylphosphanyl)propane (dppp) at 180 °C for 15 min
in a 10 mL vial resulted in full conversion. When the scale was
increased to 1.4 mmol (less head space), the conversion
decreased to 26%. Similarly, when the reaction was performed
in a pressurized flow reactor (no head space), the conversion
was only 30%. The authors incorporated a nitrogen feed into
their flow system in order to drive the reaction forward by
removing carbon monoxide from the reaction mixture. The
reaction mixture and nitrogen were combined at 0.5 and 15
mL/min, respectively, and heated at 180 °C and 6 bar. Carbon
monoxide was detected at the outlet in as little as 3−4 min,
while the product was not detected until 8−9 min. This result is
indicative of an annular flow regime where the rapidly flowing
gas phase passes quickly through the center of the reactor, and
the more viscous, slower reaction mixture travels along the
surface of the reactor (Scheme 123). Increasing the temper-
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ature to 200 °C and the gas flow rate to 25 mL min−1, 4-
cyanobenzaldehyde was fully converted to benzonitrile in 25
min. Ten different aldehydes were decarbonylated in fair-to-
very good yields. Notably, decarbonylation of 281 yielded
chromene 282 85% yield. The previously reported batch
conditions employed diglyme at reflux (∼162 °C) for 16 h and
only afforded 39% yield.
7.3. Reactions above 200 °C
In the synthesis of amitriptyline 285, the Kirschning group
prepared ketone 18 in flow via a Wurtz-type coupling and a
Parham cyclization.205 Addition to the ketone using Grignard
283, followed by the elimination of water using 7 M HCl to
form amitriptyline was reported in batch.599 To avoid using
such highly corrosive conditions, the authors envisaged an
elimination reaction of alcohol 284 under high-temperature
conditions without added acid (Scheme 124). The Grignard
Scheme 124. Continuous Flow Grignard Addition and
Elimination with Inductive Heating
addition proceeded smoothly at room temperature with just a
30 s residence time. After an ethanol quench, the reaction
mixture was passed through a reactor packed with steel beads
which were heated by induction (210 °C). Elimination
occurred with a 36 s residence time, and a 1 M HCl quench
initiated crystallization producing amitriptyline hydrochloride
285 in 71% yield. The corresponding elimination reaction in
batch yielded no product after 20 h.
Similar to other reports of nucleophilic aromatic substitu-
tions in flow,600−604 Charaschanya and co-workers used high-
temperature flow conditions to accelerate the nucleophilic
reaction of amines with 2-chloroquinazoline 286.605 Unlike
many of these reports which employ high boiling solvents, the
authors utilized ethanol and high pressure to suppress boiling.
Side reactions were more prevalent above 325 °C, and an
increase to 400 °C led to significant decomposition. Reactions
run at 225 °C with a 16 min residence time led to 97% yield for
the reaction of 2-chloroquinazoline 286 and benzylamine 287
(Scheme 125). The majority of substrates were produced in
fair-to-excellent yields. The hydrochloride amine salts were less
reactive, and anilines also resulted in poor yields. With the use
of this setup, reactions with 2-chloroquinoxaline and 2-
chlorobenzimidazole yielded aminated compounds 288 in
42−78%.
In a related report for the synthesis of N,N-dimethylami-
noarenes, Petersen et al. used high temperatures for the
generation of dimethylamine via the decomposition of DMF.606
The generation of dimethylamine and subsequent nucleophilic
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Scheme 125. Nucleophilic Aromatic Substitution of
Heterocycles in Flow
aromatic substitution in batch requires 8−32 h at reflux in a
formamide solvent (153 °C for DMF).607,608 Acidic additives
such as para-toluenesulfonic acid, acetic acid, and ammonium
chloride afforded dimethylaminopyrdine in poor yield. Aqueous
potassium carbonate produced the product in 45% yield in a
microwave batch reactor; however, precipitation occurred
preventing this process from being adapted to flow. When an
aqueous ammonia solution was used, the N,N-dimethyl-3-
nitropyridine-2-amine was produced in 76% and 93% in
microwave and flow reactors, respectively. With the use of
ammonia as an additive, the optimal temperature for the
generation of dimethylamine was 240 °C with a residence time
of 30 min. Half of the substrates were reacted under these
conditions (Scheme 126a); however, some substrates or
Scheme 126. (a) Nucleophilic Aromatic Substitutions Using
Dimethylamine Generated in Situ by Decomposition of N,N-
Dimethylformamide. (b) Pre-Generation of Dimethylamine
for Temperature Sensitive Substrates
products were not stable at such high temperatures. Therefore,
the authors developed an alternative setup consisting of a
stream of aqueous ammonia/DMF heated at 240 °C for 40 min
prior to mixing with a line of aryl halide (Scheme 126b). A
temperature of 30−50 °C was sufficient for the second reactor,
producing dimethylamino arenes 289 in 68−97% yield. Since
high-temperature/pressure reactions are difficult or dangerous
to scale, the authors applied the setup (Scheme 126a) to the
gram-scale synthesis N4,N4,6-trimethylpyrimidine-2,4-diamine
291.
The Kondrat’eva reaction is a general method for synthesiz-
ing annulated pyridines.609,610 It has widespread use, including
the synthesis of vitamin B6 by Roche.611 In general, this method
involves an inverse electron demand Diels−Alder cyclo-
addition, followed by loss of water. Typically, these reactions
are carried out at reflux or in a sealed tube.612,613 Lehmann et
al. described a convenient flow setup using a GC oven to heat a
reactor at 230 °C for the Kondrat’eva synthesis of 11
pyridines.614 Initial investigations were conducted in a micro-
wave reactor at 180 °C using 1,2-dichlorobenzene as a solvent.
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Temperatures from 120 to 210 °C provided no product, and
the addition of DBU to promote the loss of water also failed.
The addition of Brønsted acids such as trifluoroacetic acid
(TFA), led to the production of small amounts of the annulated
pyridines; however, the conversion could not be increased due
to high pressure (>13.8 bar) and subsequent instrument
shutdown. In light of this, the authors adapted this reaction to
flow since higher temperatures and pressures are safely reached.
Increasing the temperature from 210 to 230 °C increased the
yield from 17% to 58%. Extending the residence time from 60
to 120 min further increased the yield to 75% (Scheme 127).
Scheme 127. Kondrat’eva Reaction in Flow
This setup was used for the synthesis of 12 different annulated
pyridines and was run continuously for 6.75 h without
significant fluctuations in the pressure to produce 6.9 g of
pyridine 296 in 60% yield (Scheme 127).
Alternatively, annulated pyridines can be reached via an
inverse-electron-demand Diels−Alder reaction with pyrimi-
dines and alkynes.615 Martin et al. revisited this reaction owing
to the ease with which high-temperature and pressure can be
reached in flow.616 Previous reports used high boiling solvents
such as nitrobenzene which is toxic and must be removed by
column chromatography. Flow conditions using a 17.2 bar back
pressure regulator permitted the use of toluene as a solvent.
Initially, the reaction of pyrimidine 297 at 210 °C produced
only 1% of the desired pyridine 298. Increasing the temperature
to 250 °C resulted in a considerable increase in yield (49%) and
extending the residence time from 20 to 50 min resulted in 96%
conversion. However, with extended operation times, the
channel clogged with a black polymer-like substance.
Hypothesizing that this was a result of HCN polymerization,
the authors included 3-pentanone (1% v/v) in order to trap
HCN by the formation of a cyanohydrin. These conditions
were stable over many hours without pressure spikes or reactor
fouling. For example, after several hours, 21 g (84%) of 5-
chloro-2,3-dihydro-1H-indene (R1 = Cl, A = CH2, R2, R3, R4 =
H) was produced using this setup. Since substrates where A =
O or NH are known to be much less reactive, the temperature
was elevated to 310 °C, and the pressure increased to 51.7 bar
(Scheme 128). With the use of these conditions, 20 other
examples were produced in 16−95% yield. Alkoxy-substituted
Scheme 128. Annulated Pyridines by an Intramolecular
Inverse-Electron−Demand Hetero Diels-Alder Reaction
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pyrimidines (R1 = OMe, O(CH2)2CCH) were significantly less
reactive, with yields of 23% and 16%, respectively.
Dimethylcarbonate (DMC) is a green solvent and reagent.617
At lower temperatures, it can be used as a methoxycarbonylat-
ing reagent, while at higher temperatures it acts as a
methylating reagent. Various examples are reported for
methylation in flow, most of which focus on ether syn-
thesis.618−624 In one example, Glasnov et al. described the use
of catalytic base for methylating indoles, phenols, thiophenols,
and carboxylic acids.625 Microwave batch optimization using
indole 299 showed that at low temperatures (90 °C)
conversion was low and the formation of N-methoxycarbonyl
was favored. Increasing the temperature to 230 °C resulted in
99% conversion with the N-methylated compound 300 as the
primary component. Increasing the reaction time from 10 to 20
min resulted in full conversion and no detectable methox-
ycarbonyl compound. Without added base, the conversion was
lower (85%) and product selectivity favored the N-methox-
ycarbonyl product. Transition to a flow reactor and further
intensification showed that at 285 °C and 150 bar, the
conversion of indole 299 to 1-methylindole 300 was complete
with only a 3 min residence time (Scheme 129). Using this
setup, ten substrates were methylated in fair-to-excellent yields.
Scheme 129. Methylation Using Dimethylcarbonate in Flow
The tert-butyloxycarbonyl (Boc) protecting group is by far
the most widely used group for amines, constituting over 50%
of all amine-related protecting group manipulations in the
synthesis of drug candidates.626 Acidic conditions are widely
employed for deprotection; however, electron-rich substrates
and other acid labile groups are not tolerated. As such, more
tolerant conditions have been developed like the thermal
removal of Boc.627−629 Recently, researchers from AbbVie
described a continuous flow reactor for the Boc-deprotection of
amines in mere minutes.630 Initially, when Boc-protected 301
was pumped through a reactor at 200 °C with a residence time
of 8 min, no product was observed. An 8 min batch microwave
reaction corroborated these results. Increasing the temperature
to 300 °C resulted in full conversion; however, only 52% of the
desired product was formed as a result of numerous other side-
products. Shortening the residence time to 2 min reduced the
number of side-products and resulted in 80% yield of the
desired compound 302 (Scheme 130a). Another 13 amines
such as secondary amine 304 were produced by Boc-
deprotection in over 90% yield. An additional six compounds
containing a second protecting group were selectively
deprotected in 54−95% yield (Scheme 130b, 305−307).
Finally, the authors demonstrated the versatility of this setup
by incorporating it into a multistep process (Scheme 130c).
Sulfonylation of amine 309 with sulfonyl chloride 308 was
carried out at ambient temperature before mixing with a
solution of 2-chloro-5-nitropyridine 310. This solution was
reacted at 300 °C and 100 bar, which was sufficient for Boc
deprotection of 311. The subsequent nucleophilic aromatic
substitution yielded 312 in 81% after flash chromatography.
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Scheme 130. (a) Continuous Flow Boc Cleavage. (b)
Selected Examples Which Demonstrate Excellent Functional
Group Tolerance. (c) Multistep Process Incorporating Boc
Cleavage Process
The Claisen rearrangement offers chemists a powerful tool
for the synthesis γ,δ-unsaturated ketones and C-allylphenols via
a [3,3]-sigmatropic rearrangement.631 Its discovery has led to
the development of numerous related [3,3]-sigmatropic
rearrangements, further expanding the synthetic chemists’
toolbox.632−634 Many of these rearrangements, however,
require high temperatures and frequently employ high boiling
solvents like xylenes. For this reason, a number of groups have
investigated its performance under continuous flow.17,601,635,636
Recently, Ouchi and co-workers reported a solvent-free Claisen
rearrangement in flow.637 When O-allylphenol 313 was
pumped through a reactor heated at 320 °C, only a 1 min
residence time was required for full conversion to 2-allylphenol
314. To demonstrate the potential impact in a laboratory
environment with regard to production time frame and solvent
waste, the reactor was run continuously for 30 min, producing
240 g of 314 in 94% yield (Scheme 131). A subsequent
reduction at 120 °C and 20 bar using hydrogen over a packed
bed of 20% palladium on carbon produced 2-propylphenol 315
selectively in 94% yield (Scheme 131a). The combined two-
step sequence was capable of producing 100 g of 315 in 50 min.
A simple reduction in flow rate and an increase in the
temperature and pressure resulted in a complete conversion of
phenol 314 to 2-propyl-cyclohexanone 316 (Scheme 131b).
Under these conditions, 21.9 g of 316 was produced in 45 min.
Numerous routes have been reported for the synthesis of
quinoline derivatives.638,639 Among them are the Conrad-
Limpach640−642 and Gould-Jacobs syntheses.643,644 These
reactions require extremely high temperatures and have been
reported at >250 °C in mineral oil. For this reason, Lengyel and
co-workers applied flow conditions.645 The authors used THF
as a solvent and began optimizations varying temperature and
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Scheme 131. Continuous Flow Claisen Rearrangement and
Downstream Hydrogenations in the Synthesis of (a) 2-
Propylphenol and (b) 2-Propyl-Cyclohexanone
flow rate. The ease with which temperature and reaction time
can be varied facilitated rapid parameter screening and
optimization for each individual substrate. For example, the
unsaturated compound 317 was reacted at 350 °C with a 10
min residence time affording biphenyl compound 318 in 96%
yield (Scheme 132a). Other substrates such as imine 319,
Scheme 132. (a) Thermal Cyclization Reactions of
Alkylidene Esters in Flow, and the Similar (b) Conrad-
Limpach and (c) Gould-Jacobs Syntheses
tolerated higher temperatures and reached completion in under
a minute producing hydroxyquinoline 320 in 92% yield
(Scheme 132-b). The similar Gould-Jacobs synthesis produced
hydroxyquinoline 322 in excellent yield when reacted at 350 °C
with a 4.5 min residence time (Scheme 132c). Not only did this
process greatly reduce the production time, it also facilitated
purification. In most cases, the output from the reactor was
concentrated, washed with diethyl ether, and filtered. Other
reports employing high-boiling solvents required column
chromatography just to remove the solvent.
Nitriles are important starting materials for polymers,
pharmaceuticals, and agrochemicals.646 There are many routes
to nitriles,647 among them a nitrile exchange using acetoni-
trile.648 The exchange proceeds through an equilibrium which
requires high temperatures in an autoclave649 or super-
stoiciometric sulfuric acid.650 Cantillo et al. developed a high-
temperature flow process for the conversion of carboxylic acids
323 to nitriles 324 without high-boiling solvents or added
acid.651 Microwave batch reactions of benzoic acid in
acetonitrile required 1 h at 250 °C. At this temperature, the
pressure was around 31 bar, the upper limit of the instrument.
Stainless steel reactors on the other hand safely handle
temperatures greater than 350 °C and pressures greater than
200 bar. For this reason, the authors opted for flow conditions.
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The temperature was gradually increased from 250 to 350 °C.
The best conversion occurred at 350 °C and notably, there
were no side-products observed. Increasing the residence time
from 10 to 25 min resulted in 94% conversion of benzoic acid
to benzonitrile (Scheme 133). This setup tolerated functional
Scheme 133. Continuous Flow Preparation of Nitriles from
Carboxylic Acids in Supercritical Acetonitrile
groups well. Nitriles containing halo-, nitro-, phenol, and ester
groups were produced in good-to-excellent yield. Furans,
thiophenes, and alkyl carboxylic acids were also obtained in
good-to-very good yields.
Water at very high temperature and pressure exhibits very
different properties than at room temperature. The polarity is
lower, and the ionic constants and diffusion coefficient are
increased. This helps to improve solubility of organic
compounds and can increase the rates of reactions. Addition-
ally, workup and purification procedures can be expedited after
cooling back to room temperature. Nagao et al. exploited these
benefits in the synthesis of benzazoles using water as a solvent
at high temperature and pressure.652 Benzazole derivatives have
diverse applications as fluorescent molecules, pharmaceuticals,
veterinary anthelmintics, and fungicides.653−655 Benzazole
synthesis is commonly achieved by reaction of ortho-phenyl-
enediamines by reaction with carbonyls or carbonyl equiv-
alents.656 For initial optimization, Nagao et al. cyclized N-[2-
(phenylamino)phenyl]benzamide. At 400 °C and 300 bar, the
corresponding benzazole 327 was produced in 59% yield.
Increasing the pressure from 300 to 450 bar increased the yield
to 94%, and increasing the temperature to 445 °C afforded the
benzazole product quantitatively. Attempts to perform this
reaction in batch were fruitless, yielding only 9−12% of the
desired product after 24 h at reflux. To demonstrate the
applicability of this process, the N-acylation and cyclization
were performed (Scheme 134). A solution of anhydride 325
Scheme 134. Flow Synthesis of Benzazole Derivatives in
Water
and diamine 326 in NMP were combined with preheated water
and reacted at 445 °C and 450 bar. Benzazoles containing halo-,
nitro-, methoxy-, and trifluoromethyl groups were produced in
90−99% yield. Additionally, benzoxazoles (X = O) and
benztohiazoles (X = S) were produced in 69−99% yield.
While many heated reactions can be carried out in sealed
vials with conventional or microwave heating, flow conditions
offer an easy option for scaling reactions. Additionally, stainless
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steel reactors offer temperature and pressure regimes that
cannot easily be reached in batch.
8. TRACELESS REAGENTS IN FLOW: PHOTO- AND
ELECTROCHEMISTRY
When continuous processing entered organic chemistry
laboratories, researchers immediately realized that flow
techniques complimented photo- as well as electrochemical
transformations. These reactions use traceless reagents (i.e.,
photons or electrons) and strongly benefit from the small
dimensions. In addition, the accurate control of process
parameters (reaction time and temperature) enhances the
potential of these powerful reactions. Therefore, flow chemical
techniques strongly contributed to the recent revitalization of
these long-known methodologies.
8.1. Photochemistry
Using light to accelerate a chemical reaction is undoubtedly one
of the most promising possibilities to access more sustainable
chemical manipulations. In contrast to conventional reagents,
photons are not only traceless but also nontoxic. However, a
serious problem limiting photochemical transformations on
larger scales arises from the logarithmic decrease of the
transmission of light as a function of path length through a
liquid medium (Beer−Lambert−Bouguer law). Consequently,
the reaction mixture is inefficiently irradiated, and low reaction
rates are obtained. This issue is elegantly avoided by changing
from conventional batch processes to continuous flow
approaches.657 The large surface-to-volume ratio ensures
increased irradiation efficiency for the entire solution. This
not only results in significantly intensified protocols but also
allows for scaling these chemistries to synthetically useful
quantities. Due to these fundamental advantages, flow
processing is routinely used in all areas of photochemistry
and one of the most important subfields of continuous organic
synthesis. A recent review covering the theoretical, techno-
logical, and historical aspects of the field of flow-photo-
chemistry in organic synthesis was recently published.64
Therefore, this section will be restricted to representative
examples and publications which appeared since 2016.
Most flow reactors for photochemical applications are
basically light transparent chips or coil reactors placed adjacent
to a light source. A number of different home-built or
commercially available setups and arrangements exist, and the
technological aspects of continuous photoreactors have been
discussed thoroughly.62,64,658−660
8.1.1. Photoexcitation of Substrates. Reactions which
are induced by UV light involve various powerful trans-
formations such as rearrangements, cycloadditions, cyclizations,
or radical chain processes and have a plethora of applications in
the synthesis of valuable molecules.661 Under photochemical
conditions, an active molecule can be transformed into its
excited electronic state, enabling transformations that are
usually inaccessible by other synthetic methods. Chemical
structures with high complexity can be generated in a single
photochemical step, sometimes even without any additional
reagents. Such strategies are therefore particularly interesting in
the context of green and sustainable manufacturing.
Among all photochemical transformations, [2 + 2] cyclo-
additions are one of the most studied classes of transformations
in organic synthesis and are a straightforward approach to
cyclobutane derivatives from olefins. One of the first reports on
continuous [2 + 2] photocycloadditions between cyclo-
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hexenones and vinyl acetates was published by Ryu and co-
workers,662 and since then a plethora of studies utilizing a broad
range of starting materials and conditions were reported.64 In
an attempt to extend the scope of this transformation to more
challenging starting materials, Beeler and co-workers studied
the [2 + 2] photocycloaddition of methyl cinnamate 328 in
flow (Scheme 135).663 Initial experiments using a coil reactor
Scheme 135. Continuous [2 + 2] Photocycloaddition of
Methyl Cinnamate Using a Hydrogen-Bonding Catalyst
illuminated at wavelengths above 305 nm gave modest
conversions within 8 h. On the basis of earlier reports using
macromolecular host−guest systems,664,665 the authors hy-
pothesized that this process can be improved by a dual
hydrogen-bonding catalyst to template the substrates and thus
facilitate dimerization. Moreover, the catalyst could further
contribute to reaction enhancement by lowering the HOMO/
LUMO gap of the coupling partners. A thiourea derivative 329
improved the conversion from 29 to 76% (60% isolated). The
diastereoselectivity also improved significantly compared to the
uncatalyzed process. As a result of mechanistic investigations,
the authors suggested a triplet sensitization effect in addition to
the proposed templating. The generality of their catalytic
methodology was tested on several cinnamates, and similar
improvements were obtained in all cases.
Rearrangements are another class of important photo-
chemical reactions. They can offer useful strategies for the
synthesis of valuable molecules via reversible or irreversible
isomerization. The synthesis of the anti-inflammatory drug
ibuprofen is one the classic examples for API production in
continuous flow and has been accomplished by the groups of
Jamison666 and McQuade667 using purely thermal reactions. In
2016, Baxendale and co-workers presented an alternative
approach based on a photochemical Favorskii rearrangement
of an α-halopropiophenone intermediate 330 which can be
synthesized via a Friedel−Crafts acylation of isobutylbenzene
with chloropropionyl chloride.668 The α-chloroketone 330 and
2-methyloxirane were dissolved in an acetone/water mixture
and pumped through a coil reactor which was wrapped around
a medium pressure metal halide lamp (Scheme 136). A detailed
study on the reaction conditions revealed that temperatures
above 80 °C led to full conversion of 330 within 20 min, but a
Scheme 136. Continuous Synthesis of Ibuprofen by a Photo-
Favorskii Rearrangement
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Review
complex reaction mixture was obtained. Conversely, a temper-
ature of 30 °C gave a cleaner reaction profile but the conversion
was below 80%. This issue was resolved by using a filter placed
between the coil and light source which provided an almost
monochromatic irradiation of 365 nm. These modified
conditions resulted in full conversion and good selectivity
(84%) without the need for active cooling. On a preparative
scale, the authors isolated 1.56 g (76%) of the API 331 within 4
h, thus showing the potential of photochemical flow techniques
for larger scale synthesis of valuable molecules.
UV irradiation can be used to trigger chemical reactions via
photoinduced electron transfer processes. When an organo-
halide is irradiated in the presence of a stoichiometric amount
of an electron donor such as a tertiary amine, a radical
dehalogenation can take place to generate a carbon radical. This
strategy can be used for intramolecular cyclizations, which
usually require an H-donating radical mediator such as
Bu3SnH.669 Ryu and co-workers used a stainless steel chip
reactor (width 1 mm, depth 200 μm) equipped with a quartz
cover to initiate 5-exo-dig cyclizations in continuous flow
(Scheme 137).670 Residence times of 3.8−8 min were sufficient
Scheme 137. Photochemically Induced 5-exo-dig Radical
Cyclizations in a Chip Reactor
for moderate-to-excellent yields using a low-pressure mercury
lamp (254 nm) at a concentration of 0.1 M. For comparison, a
reaction in a quartz test tube (1.3 cm i.d.) showed low
conversion (13%) under these conditions. The authors used a
larger flow reactor (width 2 mm, depth 1 mm) to produce ∼4 g
of a representative cyclic product within 18 h (residence time
20 min).
Photochemistry is a standard technique for the chlorination
of hydrocarbons on an industrial scale.671 These free-radical
chain reactions are initiated by homolytic fission of Cl2 under
UV irradiation. Reactions involving Cl2 are usually avoided on
laboratory scales due to safety hazards. To circumvent these
safety limitations, the groups of Kappe246 and Ryu672 reported
on the continuous, on-demand generation of Cl2, which was
utilized for the photochlorination of alkanes in a downstream
process. Aqueous solutions of HCl and NaOCl were mixed in a
T-mixer which ultimately resulted in the formation of gaseous
Cl2.672 The resulting stream was mixed with the neat
hydrocarbon and pumped through a glass chip reactor
irradiated with a 352 nm light source (Scheme 138). After
the reactor unit, the reaction mixture was quenched with
Scheme 138. Photochemical Chlorination of Hydrocarbons
Using On-Demand Generated Cl2
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Na 2 SO 3 . For all tested substrates, the photochemical
chlorination was complete within a maximum residence time
of 1 min, yielding the desired products in good-to-excellent
yields as determined by GC-analysis.
Similarly, Kappe and co-workers demonstrated the in situ
generation of bromine azide for the photochemical 1,2-
bromoazidation of aromatic olefins (Scheme 139).673 The
Scheme 139. In Situ Generation of BrN3 for Photochemical
1,2-Bromoazidation of Olefins
liquid−liquid biphasic system consisted of an organic feed
containing the respective starting material in DCM and two
aqueous feeds for delivering oxone and NaBr/NaN3. Upon
mixing of NaN3/NaBr with the oxidizing agent, the highly
explosive intermediate (BrN3) was formed. The water sensitive
compound was directly extracted with DCM or ethyl acetate in
the slug flow regime and reacted with various alkenes. Since the
nonphotochemical ionic addition was slow, a continuous
photoreactor was installed to access the more efficient radical
addition pathway. FEP tubing was wrapped around a compact
fluorescent lamp (max 365 nm), and a BPR (7 bar) was
installed to properly control the residence time. Under
optimized conditions, the researchers synthesized nine different
1,2-bromine azide adducts within a residence time of 10 min in
good-to-excellent yields without chromatography. The high
purity profile allowed the authors to use the crude reaction
mixture for several follow-up reactions in batch such as the
formation of aziridines, azirines, and indoles.
Fagnoni and co-workers used a coil-based photoreactor for
the continuous arylation of π nucleophiles with aryl halides
(Scheme 140).674 Upon irradiation with a medium pressure Hg
Scheme 140. Continuous Arylation of Aryl Halides under
Photochemical Conditions
lamp, heterolytic cleavage of an Ar-X bond yielded a triplet
phenyl cation, which could be subsequently trapped with
mesitylene, resulting in the desired biphenyl motif. The batch
protocol suffered from long reaction times (up to 45 h), which
was dramatically reduced in the flow system with residence
times of 75−300 min. The scope was expanded by using other
π nucleophiles such as allyltrimethylsilane, ethyl vinyl ether,
pentenoic acid, and 1-hexyne.
Li and co-workers reported the photochemical borylation of
aryl halides under continuous flow conditions (Scheme 141).675
During an initial screening in batch using 4-iodoanisole and
bis(pinacolato)diboron, the authors realized that a MeCN/
H2O/acetone solvent mixture in combination with 50 mol %
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Scheme 141. Photochemical Borylation of Aryl Halides
under Continuous Flow Conditions
N,N,N′,N′-tetramethyldiamino methane (TMDAM) was nec-
essary for a successful transformation. In batch, decomposition
of B2(pin)2 was observed and the researchers hypothesized that
the desired reaction could outpace this side reaction under flow
conditions. A flow setup using a FEP coil reactor irradiated by a
mercury lamp led not only to a significantly reduced reaction
time (15 min instead of 4 h) but also to a reduction of the
amount of B2(pin)2 (1.5 instead of 2 equiv). With the
optimized conditions in hand, the authors examined the
scope and limitation of their photochemical process. In general,
good-to-excellent yields were obtained using aryl iodides and
bromides. Moreover, the authors showed that diboronic acid
can be used to prepare aryl boronic acids, which could be
subsequently transformed into the corresponding potassium
aryltrifluoroborates using KHF2.
Lebel and co-workers developed an iron-catalyzed photo-
chemical amination of sulfides and sulfoxides (Scheme 142).676
Scheme 142. Iron-Catalyzed Photochemical Amination of
Sulfides and Sulfoxides in Flow
The authors suggested that Fe(acac)3 is activated by UV light
(365 nm) and reacts with trichloroethoxysulfonyl azide
(TcesN3) forming an Fe nitrene or nitrenoid species, which
subsequently induces amination. In their continuous setup, the
reaction mixture was introduced via a sample loop and
irradiated at 365 nm in a coil reactor made out of PFA. No
active cooling was used since the reaction worked equally well
at a higher temperature (40 °C). Since stoichiometric nitrogen
is formed, a backpressure regulator was used to control the
residence time. Under optimized conditions, 10 mol % of the
iron catalyst and 1.5 equiv of the azide were used. Good-to-
excellent yields were observed with residence times of 50−90
min. Moreover, the authors showed that their methodology is
stereospecific, and the enantiomeric ratio of the sulfoxide
starting materials was retained.
8.1.2. Singlet Oxygen-Mediated Reactions. Flow
conditions which combine both gas−liquid and photochemical
reactions are clearly appealing, making the chemistry of singlet
oxygen (1O2) particularly attractive. This highly energetic,
short-lived oxygen species is generated by irradiation of a
suitable photosensitizer in the presence of O2 and can be used
for ene reactions, cycloadditions, or oxidations.677 The most
common sensitizers for 1O2 generation are methylene blue
(MB), rose bengal (RB), porphyrins such as tetraphenylpro-
phyrin (TPP), and 9,10-dicyanoanthracene (DCA) which, from
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a practical point of view, mainly differ in their solubility and
absorption spectra in the visible region of light.
The vast majority of examples were performed in similar
gas−liquid photochemical reactors (Scheme 143).677 In
Scheme 143. General Continuous Flow Setup for the
Generation and Utilization of Singlet Oxygen
general, a solution of the substrate and catalytic amounts of
the photosensitizer are mixed with O2 whose rate of addition is
controlled via a MFC. The gas−liquid mixture subsequently
enters a coil or chip-based reactor unit that is irradiated by a
light source. The reaction is further enhanced by installing a
back pressure regulator to increase the amount of the gaseous
reagent in the liquid phase while simultaneously enabling a
better control of the residence time. The above-mentioned
sensitizers can also be immobilized on either the channel wall
of a reactor or on dedicated supports.677
The synthesis of artemisinin in continuous flow is an
illustrative example,678,679 since artemisinin combination
therapies (ACTs) are the recommended first-line treatment
for malaria.680 Currently, artemisinin 23 is extracted from
Artemisia annua, which also contains significant amounts of the
biological precursors dihydroartemisinic acid 22 and artemisinic
acid 21. While the total synthesis of artemisinin is too
laborious, its semisynthesis from 22 can be rapidly achieved
through photooxidation. Moreover, 21 can be transformed into
22 via a selective reduction.219 When DHAA reacts with 1O2, it
forms an allylic hydroperoxide, which undergoes Hock cleavage
in the presence of acid. Oxidation by 3O2 triggers a
condensation cascade, eventually yielding the desired com-
pound 23.
Our laboratory optimized the entire reaction sequence
resulting in a single, fully continuous process using a sequence
of coil reactors (Scheme 144).25 In the final process, a solution
Scheme 144. Continuous Synthesis of Artemisinin from
Dihydroartemisinin Acid Using 1O2
of DHAA 22, 9,10-anthracenedicarbonitrile (DCA), and TFA
in toluene was mixed with O2 and fed into an irradiated coil
reactor which was cooled to −20 °C. Then, the mixture was
slowly warmed in two consecutive coil reactors to accomplish
the nonphotochemical steps, resulting in 57% of the final
antimalaria drug 23 after isolation. A continuous isolation of
artemisinin from the crude reaction mixture was also
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demonstrated by using simulated moving bed chromatography
and continuous crystallization.172 The optimized continuous
system enabled the isolation of the target compound in 62%
with a purity of 99.9%. We expanded our flow protocol for the
synthesis of all active pharmaceutical ingredients for ACTs
following a modular approach, which also included inline
purification via continuous filtration, multicolumn chromatog-
raphy, and crystallization.270
Amara et al. developed a more sustainable alternative to the
aforementioned approach using liquid CO2 and a dual-function
heterogeneous catalyst (Scheme 145).681 The catalyst was
Scheme 145. Continuous Synthesis of Artemisinin Using a
Dual-Function Heterogeneous Catalyst. Catalyst is reprinted
with permission from ref 681. Copyright 2015 Nature
Publishing Group
prepared by noncovalently anchoring meso-tetraphenylporphyr-
in to an Amberlyst-15 via protonation of the porphyrin core.
The resulting material not only generates singlet oxygen but
also catalyzes the Brønsted-acid mediated Hock cleavage. In the
final continuous protocol, O2 was mixed with CO2 using a
modified 6-way-valve and combined with a solution of 22 in
toluene at a system pressure of 180 bar. The reaction mixture
was fed into the packed bed reactor made out of sapphire
containing the solid dual-catalyst. The reactor unit was cooled
to 5 °C, and irradiation was carried out using an array of LEDs
emitting light in the visible region. A residence time of 20 min
was sufficient to quantitatively convert 22 in a single pass,
resulting in 48% of 23 as determined by NMR. In addition, a
second continuous strategy utilizing [Ru(bpy)3]Cl2 and TFA in
an aqueous solvent mixture of THF/H2O produced artemisinin
23 inasmuch as 66% yield.
Singlet oxygen is also useful for the oxidation of amines to
the corresponding imines.682 The condensation of the
unreacted amine with the primary aldimine, however, is a
main drawback of the original procedure. Our group developed
a continuous procedure for the formation of primary aldimines
which can subsequently undergo oxidative cyanation to provide
valuable α-aminonitriles (Scheme 146a).157 A flow reactor
cooled to −50 °C suppressed the nucleophilic addition, thus
enabling a quantitative photooxidation. In our final protocol, a
solution of the substrate, TPP, TMSCN, and substoichiometric
amounts of TBAF were mixed with O2 and pumped through
the cooled photoreactor (420 nm LEDs). The resulting α-
aminonitriles were utilized for the synthesis of fluorinated α-
amino acids524 and hydantoins.209 Moreover, a similar flow
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Scheme 146. Photooxidation of Amines using 1O2 in (a)
Synthesis of α-Aminonitriles by a Low-Temperature Flow
Approach and (b) Direct Utilization of Imines in a
Consecutive Mannich Reaction/Epoxidation
approach was used for studying the regioselectivity of the
photooxidation of unsymmetrical secondary amines.683
During the photooxidative imine generation, stoichiometric
amounts of H2O2 are generated, which potentially limits the
possibility of directly using the resulting imine for downstream
processes. We developed a consecutive process to utilize the
H2O2 byproduct. The newly generated imine was reacted with a
nucleophile such as methyl cyanoacetate in a deaminative
Mannich coupling forming an olefin, which reacted with H2O2
forming the corresponding epoxide in good yields. (Scheme
146b).684
8.1.3. Photoredox Catalysis. Over the past decade, radical
chemistry, in particular photoredox catalysis, has emerged as a
valuable tool for synthetic organic chemistry and is a highly
active research area.104,685,686 In general, a photoredox catalyst
(PRC) absorbs light promoting an electron to an excited state
(PRC*, Figure 30). This species can undergo a single-electron
Figure 30. Quenching cycles in photoredox catalysis.
transfer (SET) with either an electron donor (D) or acceptor
(A), in a quenching cycle. Overall oxidative, reductive, and
redox neutral reaction are possible depending on the substrates
and conditions. The catalytically active species are most often
ruthenium or iridium polypyridyl complexes,104,685,686 but also
organic catalysts687 have been applied. The photoredox
catalysts used in the continuous flow examples discussed in
this section are depicted in Figure 31.
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Review
Figure 31. Photoredox catalysts used in continuous flow experiments
discussed in this section.
A significant enhancement was identified for the visible light-
mediated decarboxylative Michael addition of a threonine
derivative 338 with methyl acrylate 339, in the formal synthesis
of L-ossamine (Scheme 147).688 In the optimized batch
Scheme 147. Visible Light Decarboxylative Michael Addition
Using an Iridium-Based Photoredox Catalyst under Flow
Conditions
procedure, a mixture of 338, methyl acrylate 339, [Ir[dF-
(CF3)ppy]2(dtbpy)][PF6] 332, and Cs2CO3 in DMF was
irradiated for 45 h with two 6.5 W LED bulbs producing 340 in
70% yield (d.r. 65:35). A different solvent system (DMF/H2O
10:1) resulted in a homogeneous solution, albeit significantly
lower isolated yields (50%). When the same reaction mixture
was passed through a transparent chip reactor illuminated with
a 48 W LED bulb, the isolated yield increased to 80% (d.r.
62:38) at a residence time of just 4 h.
In order to avoid the use of photoredox catalysts based on
rare noble metal such as Ru and Ir, researchers from Merck in
collaboration with the group of Nicewicz prepared a set of
acridinium-based PRCs. The most promising candidate 336
was applied to the decarboxylative conjugate addition of Cbz-
proline 341 to dimethyl maleate 342 under continuous flow
conditions (Scheme 148).689 During the course of the reaction
more than 50% of the catalyst decomposed by HPLC. This
serves as an example showcasing that replacement of expensive
Ir and Ru bipyridyl complexes by organic dyes is generally
possible, but further catalyst modifications must be carried out
to reduce catalyst degradation over time.
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Chemical Reviews
Scheme 148. Visible Light Decarboxylative Michael Addition
Using an Acridinium Photoredox Catalyst under Flow
Conditions
Several groups developed methodologies in which a PRC was
used to activate substrates for use by another catalyst in a dual-
catalytic process. Dual-catalytic processes involve the combina-
tion of photoredox chemistries with Lewis acid-, organo-,
transition metal-, Brønsted acid/base-, as well as electro- and
biocatalysis.690−692 Among those, the combination of photo-
redox and nickel catalysis, which was pioneered by the groups
of MacMillan and Molander, has resulted in a number
possibilities for the construction of carbon−carbon
bonds.691−693
Adapting a reaction from Tellis et al.,694 Ley and colleagues,
developed a continuous protocol for the C(sp2)-C(sp3)
coupling of boronic esters with aryl bromides (Scheme
149a).695 The authors obtained the coupling products within
2 3
Scheme 149. Continuous C(sp )-C(sp ) Couplings Using (a)
Dual Photoredox Nickel Catalysis of Boronic Esters with
Aryl Bromides and (b) Photoredox Catalysis for the
Coupling of Electron-Deficient Cyanoarenes and
Organoboron Compounds
a residence time of 50 min in a coil reactor using 420 nm LEDs
as the light source. Compared to the original protocol, the flow
process allows for a significant reduction of the reaction time
(24 h in batch). Electron-rich organoboron compounds gave
good-to-excellent yields, whereas electron-poor derivatives did
not work as well. In addition, the authors also evaluated an
alternative protocol using electron-deficient cyanoarenes 345
instead of the organohalide 344 coupling partners (Scheme
149b).695 In the case of cyanoarenes, the use of an
organometallic catalyst was not necessary as the reaction is
photoredox neutral, where the organoboron compound is
oxidized and the cyanoarene is reduced.
Researchers from Vertex Pharmaceuticals reported a very
similar dual catalytic cross-coupling for the synthesis of
cycloalkyl substituted 7-azaindoles, which are utilized in a
variety of drug discovery programs (Scheme 150).696 Several
modifications to the original protocols were made to obtain
homogeneous conditions necessary for translating this coupling
procedure to flow. In this case, 2,6-lutidine and a DMA/
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Review
Scheme 150. Dual Catalytic Cross-Coupling in Flow for the
Synthesis of Cycloalkyl-Substituted 7-Azaindoles
dioxane solvent system avoided clogging issues. Moderate-to-
good isolated yields were obtained within 40 min for a broad
range of cycloalkyl-substituted 7-azaindoles. Moreover, the
same group expanded the scope of their reaction system for the
synthesis of a small library of alkyl-substituted quinazolines.697
Dual catalysis for the decarboxylative coupling of readily
available carboxylic acids with aryl halides was originally
reported in 2014.698 Due to the high potential of this
transformation for replacing thermal catalytic cross-coupling
reactions, Abdiaj and Alcázar developed homogeneous
conditions for translating the light-mediated coupling protocol
to continuous flow (Scheme 151).699 Cesium carbonate was
Scheme 151. Dual Photoredox Nickel Catalysis for
Continuous Decarboxylative Coupling Reactions
replaced by DBU. Moreover, [Ir(dtbbpy) (ppy)2][PF6] 333
showed better results than the original photoredox catalyst 332.
With this homogeneous reaction system, the authors moved to
flow using a two feed approach and a coil reactor which was
irradiated with a 450 nm light source. Interestingly, slightly
elevated temperatures (40−60 °C) proved to be ideal for the
continuous coupling procedure using residence times of 20−40
min (vs 72 h in batch).
The utilization of gaseous reagents in photoredox processes
has also been used with continuous processing techniques.
Oxygen, for instance, is an electron acceptor, generating
superoxide (O2•−) which can be used as a reactant. Noël and
co-workers utilized the reactive species to oxidize thiols to
disulfides in flow (Scheme 152a).700−704 Eosin Y 337 gave
significantly better results compared to common Ru and Ir
complexes in an initial batch screening.700 Substoichiometric
quantities of tetramethylethylenediamine (TMEDA) signifi-
cantly increased the reaction rate using EtOH as a sustainable
reaction medium. The rate of the biphasic batch reaction was
strongly influenced by the stirring speed. Therefore, the
researchers argued that the oxidation could be significantly
enhanced in flow by taking advantage of the increased mixing/
interfacial area and the highly efficient irradiation achieved in
thin tubing. In fact, MFC-controlled O 2 addition, in
combination with an illuminated PFA coil reactor decreased
the reaction time from 2 to 16 h (batch) to 20 min. Under
optimized conditions, excellent isolated yields were obtained.
Notably, the continuous protocol was utilized for a selective
synthesis of oxytocin, a cyclic peptide hormone.
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Scheme 152. Photocatalytic Aerobic Oxidation of Thiols to
Disulfides Using (a) Homogeneous and (b) Heterogeneous
Photoredox Catalysts
higher activity compared to other PRCs such as Ru2+(bpy)3 and
Ir3+(ppy)3. In the final flow approach, a solution of 335 and
substrate in THF was pumped through a tube-in-tube gas
loading unit and subsequently irradiated in a coil reactor at a
back pressure of 8 bar. Within a 3.33 h residence time, a series
of carbazoles were synthesized in good-to-excellent yields.
Moreover, a numbering-up strategy was presented to improve
the productivity to ∼1 g d−1.
The incorporation of trifluoromethyl groups into organic
compounds is an extremely active research area due to the
importance of this structural motif for medicinal chemistry as
well as crop and material sciences.710 Among the plethora of
reagents which can be used as CF3 sources, CF3I is particularly
interesting due to its high atom economy and relatively low
cost. Noël and co-workers developed a series of strategies for
utilizing this gaseous reagent in the continuous trifluoromethy-
lation of thiols,711,712 heterocycles,713,714 and styrenes715 via
photoredox catalysis. The latter is particularly interesting since
it not only allows for trifluoromethylations (Scheme 154a) but

Scheme 154. Utilization of CF3I for the Continuous (a)

Trifluoromethylation and (b) Hydrotrifluoromethylation of
Styrenes Using Photoredox Catalysis

One of the main challenges in photoredox catalysis is the

replacement of homogeneous PRCs by heterogeneous catalysts
such as semiconductors.705,706 This represents a highly
interesting opportunity for potential large-scale applications,
as the classical homogeneous PRCs are often very expensive,
usually difficult to recycle, and necessitate additional
purification steps. Therefore, the Noël group tested the
applicability of TiO2 nanoparticles for the disulfide formation
using a packed bed reactor (Scheme 152b).707 TiO2 has a
relatively high energy band gap (3.2 eV for anatase) which
requires UV irradiation. However, if amines, such as TMEDA,
are present in the heterogeneous reaction mixture, surface
interactions enable excitation by light in the visible
region.705,706 Taking advantage of this phenomenon, the
authors realized a continuous protocol utilizing a packed bed
reactor of TiO2 nanoparticles and glass beads. With this setup,
reaction times of 3−5 min proved sufficient for the triphasic
also can be modified by replacing the base with a suitable H
transformation, whereas the batch reactions needed up to 8 h
atom donor to access hydrotrifluoromethylated compounds
for full conversion. Importantly, the authors showed that during
349 (Scheme 154b).715 In both protocols, CF3I is controlled by
a 28 h experiment, the yield did not decrease, showcasing the
an MFC and mixed with the liquid phase before irradiation with
high potential of the semiconducting material for heteroge-
blue light in a coil reactor at room temperature. The desired
neous photoredox catalysis. Additionally, the continuous
compounds were obtained in good-to-excellent yield with 30−
formation of an unsymmetrical disulfide 348 was performed
90 min residence times. Moreover, the authors also showed that
by using an excess of the less reactive thiol 347 (Scheme 152b).
this catalytic system is applicable to other perfluoroalkyl halides.
Building on their previous results,708 the Collins group
In another approach to incorporate fluorine into organic
developed a sustainable photocyclization system using [Fe-
molecules using continuous photoredox catalysis, McTeague et
(phen3)][(NTf2)2] 335 in combination with O2 (Scheme
al. reported the use of gaseous SF6 for deoxyfluorinations of
153).709 The iron phenanthroline complex showed significantly
allylic alcohols (Scheme 155).716 The reaction system was
Scheme 153. Photochemical Synthesis of Carbazoles Using
Scheme 155. Continuous Deoxyfluorination of Allylic
Oxygen as Oxidant
Alcohols Using SF6 by Continuous Photoredox Catalysis

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optimized in batch, resulting in a combination of [Ir-
(ppy)2(dtbbpy)][PF6] 333, DIPEA, and DCE for acceptable
conversion and selectivity. The realization of a continuous
version of their protocol was achieved by mixing the gaseous
reagent with the liquid producing a slug flow regime. Prior to
irradiation, a small residence time unit was installed for better
mixing. Further, a system pressure of 6.9 bar was utilized to
increase the solubility of the gaseous fluorine source.
More recently, the same group developed a photoredox
process for the activation of carbon dioxide in the α-
carboxylation of amines (Scheme 156).717 The potential of
Scheme 156. Carboxylation of Amines with CO2 Using
Continuous Photoredox Catalysis
CO2 (E0 = −2.21 V vs SCE) is too high for common PRCs
which absorb visible light. A combination of para-terphenyl (E0
= −2.63 vs SCE) and UV irradiation was chosen to overcome
this. A base screening revealed that potassium trifuoroacetate
(CF3CO2K) provided the highest yield in DMF. Optimization
using a two-feed gas−liquid photoflow setup resulted in a
system pressure of 3.4 bar and a residence time of 10 min for
the synthesis of a broad range of aromatic amino acid
derivatives in moderate-to-excellent yields.
The vast majority of photoredox protocols suffer from the
utilization of expensive transition metal based PRCs which are
normally not recycled. Therefore, the development of effective
recovery strategies for these powerful catalysts is important. In
order to tackle this problem, Kappe and co-workers
immobilized a Ru polypyridyl complex on a G2-PAMAM
dendrimer which enabled a recycling strategy via nanofiltration
(Scheme 157).718 A liquid−liquid separator was equipped with
Scheme 157. Nanofiltration Recycling Strategy for a
Macromolecular Ru Photoredox Catalyst
a nanofiltration membrane instead of the usual hydrophobic
material in order to separate the catalyst from the reaction
material. While the catalytic material showed promising
reactivity in several photoredox catalysis processes, continuous
recycling was problematic. The catalytic material was retained
on the membrane in certain solvents, and the dendritic material
decomposed in the presence of acids. Nevertheless, the authors
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Review
found that for the photocatalytic reduction of azides with
hydrazine, their recycling strategy is applicable without a
significant decrease in the catalytic activity over five process
cycles (Scheme 157).
Rackl et al. synthesized a polyisobutylene-tagged fac-Ir(ppy)3
complex [Ir(ppy)2(PIB-ppy)] which could be continuously
recycled and reused with a thermomorphic solvent system
(Scheme 158).719 The photoredox-catalyzed isomerization of
Scheme 158. Continuous Recycling of Polyisobutylene-
Tagged fac-Ir(ppy)3 Complex [Ir(ppy)2(PIB-ppy)] Using a
Thermomorphic Solvent System
(E)-3-phenylallyl acetate 350 was chosen as a model reaction
for their proof-of-concept study.720 In their setup, the substrate
350 and DIPEA were dissolved in heptane-saturated MeCN
and mixed with a solution of the modified catalyst in heptane.
The resulting biphasic mixture (slug flow pattern) was pumped
through a photoreactor (455 nm) heated to 90 °C. At this
temperature, the mixture becomes monophasic, thus setting the
stage for an efficient photoredox reaction. After cooling, a
biphasic mixture was collected in a receiving flask. The MeCN
phase contained the product, whereas the heptane phase
contained the catalyst which could be recycled. Constant E/Z
ratios of 3-phenylallyl acetate were measured over the entire
experiment, and loss of the Ir catalyst in the heptane phase was
only observed at the beginning. NMR analysis revealed that
only catalyst molecules with shorter PIB chains were lost into
the MeCN phase due to their higher polarity.
The development of cheap, readily available and recyclable
catalysts is not the only obstacle for sustainable (continuous)
photochemical processes. To date, the vast majority of
processes rely on the utilization of artificial light sources such
as LEDs rather than natural sunlight. While flow reactors for
sunlight-mediated chemical transformations have been devel-
oped, solar concentrators are usually highly engineered reactor
setups limited to areas with a high amount of solar irradiation.63
A novel reactor concept combines continuous microreactor
technology with the concept of luminescent solar concentrators
(LSCs).721 A “classical” LSC device is made by dispersing a
luminophore in a waveguide which can be made out of
polymeric materials or glass (Figure 32a).722 Light can
penetrate the surface of the waveguide where it is absorbed
by the luminophore. The re-emitted light is guided and
concentrated by total internal reflection toward the edge of the
device where a photovoltaic cell is attached. The researchers
adapted this principle to continuous flow synthesis, by building
a chip-based reactor made out of PDMS doped with the
fluorescent dye Lumogen F red 305 (Figure 32b). This dye
absorbs visible light from ∼400−600 nm and re-emits light at
∼600−700 nm, which perfectly overlaps with the absorption
spectrum of methylene blue (MB), a common photosensitizer.
They studied the singlet oxygen cycloaddition to 9,10-
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Chemical Reviews
Figure 32. (a) Concept of luminescent solar concentrators (LSCs).
(b) A LSC chip reactor fabricated from PDMS doped with the
fluorescent dye Lumogen F red 305 for harvesting sunlight. Reprinted
with permission from ref 721. Copyright 2017 John Wiley and Sons.
diphenylanthracene using sunlight during a partly cloudy
summer day; the researchers showed that this reactor is
significantly more efficient than a nondoped version. Never-
theless, this promising concept has to be expanded to a broader
range of wavelengths to access more powerful photocatalysts, in
particular PRCs which usually absorb wavelengths below 500
nm.
8.2. Electrochemistry
In electrochemical processes, chemical reactions take place at
the interface of an electrode and an ionic conductor
(electrolyte). The setups are either undivided cells where the
anodic oxidation and the cathodic reduction occur within the
same compartment or divided cells where the oxidation and
reduction chamber are physically separated by a semiporous
membrane (section 3.4.4). Electrochemical methods are used
on an industrial scale for the production of commodity
chemicals such as the chloralkali process for the production Cl2
and caustic soda, the electrochemical production of elemental
Al from aluminum oxide in the Hall-Héroult process, and the
electrosynthesis of adiponitrile from acrylonitrile.723 Never-
theless, examples of electrochemistry in synthetic organic
chemistry are extremely rare in the scientific literature, which is
relatively surprising since instead of stoichiometric oxidants/
reductants, electric current is used as a traceless re-
agent.105,724−726 In a recent outlook on synthetic organic
electrochemistry, it was argued that electrochemistry is feared
by organic chemists due to sophisticated setups and a lack of
“standard” instrumentation for preparative electrolysis.105 In
other words, electrochemistry is not considered a standard
technique in organic synthesis but more as the last option when
other possibilities have failed.
The availability of commercial flow electrochemistry devices
may be able to address these issues, allowing for a
straightforward and convenient access to organic electro-
chemistry.40,151 Electrochemical reactions in flow offer the
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possibility to reduce/remove supporting electrolytes.727 Never-
theless, continuous synthetic organic electrochemistry is still in
its infancy.40,151 This section discusses recent developments in
continuous electrochemical organic synthesis. The literature
examples are divided into anodic and cathodic reactions.
8.2.1. Anodic Oxidation. The anodic oxidation of amides
to N-acyl iminium ions and its subsequent reaction with
nucleophiles (Shono oxidation) is among the most studied
electrochemical reactions in organic synthesis.728 This opera-
tionally straightforward reaction forms a new carbon−carbon
bond generating H2 as the only byproduct.
Brown and Pletcher studied the methoxylation of N-
formylpyrrolidines in continuous flow utilizing several un-
divided electrochemical flow devices (Scheme 159). In all cases,
Scheme 159. Dehydrogenative Methoxylation of N-
Formylpyrrolidine in Flow
a carbon/polymer anode (C-Anode) and a stainless steel
cathode (SS-Cathode) was utilized with different reactor
geometries such as a rectangular device with a “snaking”
microchannel729,730 and a round cell design with a star-
shaped116 or spiral107,731 channel pattern. In the latter case, the
authors showed that by using a 0.2 M solution of 352 at high
flow rate (16 mL min−1) and cell currents (12 A), 353 was
produced in high yields (84%) within a residence time of 19 s
(productivity of 20.7 g h−1). Pitting of the carbon-based anode
was observed at cell currents above 10 A but had no effect on
the performance of the reaction system. Nevertheless, this
pitting issue is detrimental to long-term experiments, and
therefore alternative anode materials or less aggressive
conditions should be considered.
Similarly, Ley and co-workers applied the continuous Shono
oxidation methodology to access the natural product Nazlinine
and related congeners (Scheme 160).732 The authors did not
Scheme 160. Shono Oxidation of N-Protected Cyclic Amines
in Flow
observe any conversion with a stainless steel or platinum-coated
anode. A carbon anode, on the other hand, gave quantitative
conversions and excellent selectivity (95%) at a current density
of 49 mA cm−2 in the presence of Et4NBF4. The system proved
completely stable during a 14 h experiment in which 10 mmol
of the N-Boc pyrrolidine was successfully processed. The
authors further showed that LiBF4 lowered selectivity (85%).
Under optimized conditions, a small library of α-methoxylated
N-protected cyclic amines was prepared in excellent isolated
yields. The researchers further presented a subsequent Pictet-
Spengler reaction between the electro-synthesized N-Boc α-
methoxypyrrolidine and tryptamine derivatives yielding nazli-
nine and related congeners in a batch microwave reactor.
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In the Kolbe electrolysis, a carboxylic acid undergoes
electrochemical decarboxylation generating a carbon-centered
radical which reacts with alkenes forming a new C−C bond.725
In 1991, Uneyama reported the generation of a CF3 radical
from trifluoroacetic acid for trifluoromethylation reactions.733
On the basis of their previous experience with the continuous
Kolbe electrolysis,734 Wirth and colleagues chose TFA due to
the high economic potential as a CF3 source. The electro-
chemical reactor consisted of a cathode and anode made out of
Pt foil with a FEP flow channel situated between (Scheme
161).735 The reaction of acrylates with TFA, forming the
Scheme 161. Electrochemical Trifluoromethylation
Reactions of Electron-Deficient Alkenes with TFA
respective trifluoromethylated dimeric species, was chosen for
initial investigations. Optimization of the reaction parameters
resulted in a cell current of 50 mA and a residence time of 66 s.
Notably, these results are comparable to those obtained using
the original batch procedure (2 A, 16 h).733 Moreover, by
changing the conditions to a lower cell current (10 mA) and a
significantly longer residence time (10.5 min) a trifluoromethyl
acetamidation was carried out, affording 354 from methyl
methacrylate in 25% yield. The mechanism most likely
proceeds via a nucleophilic attack of acetonitrile to a
carbocation intermediate during the electrolytic process.736 By
using a high excess of TFA in combination with a high cell
current (200 mA), the bis(trifluoromethylated) product 355 of
acrylamide was obtained in good isolated yield (67%). Similar
results were obtained in all cases for the respective
difluoromethylation reaction when difluoroacetic acid was
used instead of TFA.
Anodic oxidation processes are potential tools for C−C
coupling reactions via the Shono oxidation of amides or the
decarboxylative Kolbe electrolysis. Alternatively, Waldvogel and
co-workers developed a regioselective, direct cross coupling of
phenols and arenes.737 The reaction proceeds via anodic
oxidation of an alcoholic solvent generating an alkoxy radical
which subsequently abstracts a hydrogen atom from the phenol
substrate to generate a reactive electrophilic radical inter-
mediate. This species is trapped by an electron-rich arene
affording the desired biphenyl motif 358. 1,1,1,3,3,3-Hexa-
fluoroisopropanol (HFIP) was used to stabilize the anodically
generated radical species. In flow, a boron-doped diamond
(BDD) anode and a Ni cathode were used in an undivided cell
continuous flow reactor (Scheme 162).738 A broad range of
supporting electrolytes and solvent systems were tested for the
anodic coupling of creosol 356 with 1,2,4-trimethoxybenzene
357. The most promising results were obtained with formic
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Review
Scheme 162. Anodic Coupling of Creosol with 1,2,4-
Trimethoxybenzene in Flow
acid, but this reaction suffered from a large amount of
homocoupling. Methanol was used to reduce homocoupling;
however, also had a negative impact on the overall yield.
The in situ electrogeneration of ortho-benzoquinone 360
from catechol 359 in the reaction with thiophenols by a
Michael-type addition resulted in unsymmetrical aromatic
disulfides (Scheme 163).739 Initial experiments of this reaction
Scheme 163. In Situ Generation of ortho-Benzoquinone for
the Continuous Generation of Unsymmetrical Aromatic
Disulfides
using a batch electrolysis cell gave low yields (13%), as the
oxidation potentials of both substrates are similar. When
catechol was oxidized followed by addition of the thiophenol,
just 32% of the desired coupling product was obtained due to
decomposition of ortho-benzoquinone 360. The researchers
designed a flow setup where a solution of 359 and NaClO4 in
MeCN was oxidized on a graphite (G) anode for the desired
electrochemical transformation. Upon leaving the electrolytic
cell, a solution of the respective para-substituted thiophenol
was fed into the flow system via a mixing unit. By optimizing
the flow rates and cell currents, decomposition and over-
oxidation of 360 were minimized, yielding the respective
sulfides in good-to-excellent yields.
The oxidative esterification of aldehydes using NHCs
proceeds via the formation of a Breslow intermediate 362,
oxidation, and subsequent alcoholysis to regenerate the
NHC.740 The crucial oxidation step is usually carried out
with a stoichiometric oxidant; however, it can also be carried
out via anodic oxidation (Scheme 164a), though with reactions
times of 2−36 h required for full conversion.741 Green et al.
hypothesized that this process could benefit from continuous
processing to achieve a significantly more productive procedure
(Scheme 164b).742 The respective aldehyde, thiazolium salt
361, and alcohol were dissolved in THF/DMSO and mixed
with DBU in a T-mixer. The resulting reaction mixture was fed
into an undivided cell reactor (carbon anode, stainless steel
cathode) set to a cell current of 850 mA. Full conversion was
achieved within a residence time of less than 13 s for a range of
different aldehyde and alcohol combinations, affording the
respective esters in moderate-to-excellent isolated yields.
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Chemical Reviews
Scheme 164. (a) Anodic Oxidation of a Breslow
Intermediate Resulting in an Activated Acyl Species and Its
Application for the Oxidative (b) Esterification and (c)
Amidation of Aldehydes in Continuous Flow
Importantly, the productivity was high in all cases (1.5−4.3 g
h−1), showing the potential of the electrochemical flow process.
Moreover, attempts to reduce the amount of the thiazolium salt
361 indicated that the reaction can also be carried out
catalytically. More recently, the scope of this synthetic strategy
was expanded by the synthesis of amides in a similar process
(Scheme 164c).743 A simple replacement of the alcohol by an
amine was not feasible, presumably due to a competing imine
formation. Therefore, the respective amines were added after
the formation of the Breslow intermediate 362, and a heated
chip reactor was installed after the electrochemical cell to
enhance the reaction of the amine with the acyl thiazolium
intermediate. Under optimized conditions, the desired amides
were obtained in good-to-excellent yields with an overall
residence time of less than 1 min.
Stoichiometric co-oxidants such as NaOCl in the TEMPO-
mediated oxidation of alcohols can be substituted by anodic
oxidation on preparative scales (Scheme 165).744 By using 30
mol % TEMPO and a mixture of tert-butanol and a carbonate-
bicarbonate buffer for the oxidation of cyclohexanol, a good
balance between conversion (86%) and selectivity (99%) was
Scheme 165. TEMPO-Mediated Electrochemical Oxidation
of Alcohols in Flow
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Review
achieved using a cell current of 20 mA. At 10 mA, a significantly
lower conversion (54%) was obtained, whereas higher currents
resulted in a drop in selectivity. The optimized conditions were
applied on a set of 15 different primary and secondary alcohols,
including benzylic, allylic, and aliphatic species. Most benzylic
and allylic alcohols resulted in good-to-excellent isolated yields,
whereas aliphatic alcohols were somewhat less reactive.
Overoxidation was observed at longer residence times
inhibiting further improvements to yield.
Organic electrochemistry is not just a potentially useful tool
for accessing sustainable alternatives for synthetic procedures
but can be used to simulate the metabolism of drugs.745 In the
liver, a drug can be oxidized by cytochrome P450 (CYP450)
and the outcome of this hepatic oxidation is crucial for drug
development processes. Stalder and Roth utilized a continuous
flow electrolytic cell to mimic this oxidation process for five
different commercially available drugs in order to produce 10−
100 mg of the respective metabolites for full characterization.746
The main electrochemical oxidation products for the anodic
oxidation of diclofenac 363, primidone 366, albendazole 368,
and chlorpromazine 370 in an undivided cell reactor were in
good agreement with known metabolites (Scheme 166). The
Scheme 166. Continuous Anodic Oxidation of Drugs to
Mimic Metabolic Oxidation Processes
oxidation of tolbutamide 372 was carried out in a divided cell
where a carbon anode and a platinum cathode were separated
by a spectra/por membrane (Scheme 167). Interestingly, while
the oxidation is governed by the most redox-active site, the
resulting oxidation product has not been reported as a
metabolite. Nevertheless, the authors concluded that flow
electrosynthesis can complement biosynthetic methods due to
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Chemical Reviews
Scheme 167. Oxidation of Tolbutamide in a Divided Cell
Reactor
its scalability, allowing for straightforward access to isolatable
quantities of metabolic products for full characterization.
8.2.2. Cathodic Reduction. For the reduction of func-
tional groups, chemists usually consider well-established
methods using metal hydrides (LAH, NaBH4, and DIBAL),
transition metal catalyzed hydrogenation/hydrogenolysis re-
actions, or single electron-reducing agents such as sodium.
Electrochemistry offers a sustainable alternative via cathodic
reduction which overcomes the economic and environmental
implications associated with traditional procedures. Waldvogel
and co-workers surveyed different methods for the dehaloge-
nation of the spirocyclopropane-proline derivative 374, which is
a key step in the synthetic route toward NS5A inhibitors.747,748
A Birch reduction gave 65% of the desired compound, though a
significant amount of ring-opening side products were obtained.
Further, hydrogenolysis with Pd/C (48% yield) also suffered
from several side products and a tedious product purification.
Therefore, the authors developed an electrochemical process
via reduction on a leaded bronze (LB, CuSn7Pb15) cathode in
an electrochemical batch reactor to afford the desired
compound 375 in 93% isolated yield on a multigram scale. In
order to make this process industrially applicable, the authors
developed a divided flow electrolysis cell (Scheme 168).747 By
Scheme 168. Anodic Dehalogenation of 374 in a Divided
Cell Reactor
optimizing the flow rate, applied electricity and current density,
the authors were able to obtain 375 in good isolated yield
(70%) in a scalable continuous procedure. Moreover, a simple
offline procedure for electrolyte and solvent recycling was
presented to improve the sustainability of the dehalogenation
process.
An undivided cell reactor was utilized by Wirth and Arai for
the continuous electrochemical deprotection of isonicotinylox-
ycarbonyl (iNoc) protected phenols.749 A mixture of the
protected substrate and tetrabutylammonium iodide (TBAI) in
DMF/water was pumped through an electrochemical flow
reactor consisting of a cathode and anode made out of platinum
(Scheme 169). Under optimized conditions, 43−61% of the
respective unprotected phenol derivatives were obtained within
92 s. A comparison reaction carried out in batch gave slightly
lower yield, but a reaction time of 6.5 h was required for full
conversion. When the authors tried to apply their methodology
on iNoc protected thiols, the respective disulfides were
obtained instead. Unfortunately, no deprotection occurred in
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Scheme 169. Deprotection of iNoc Protected Phenols in an
Electrochemical Flow Reactor
the case of iNoc protected amines, as the carbamate seems to
be stable under their electrochemical conditions.
The group of Atobe utilized a cathodic reduction process for
generating a 2-pyrrolidone anion 377,750 which can be used as a
reagent for follow up chemistries (Scheme 170).751,752 Their
Scheme 170. Electrogeneration of a 2-Pyrrolidine Anion for
(a) Trichloromethylation of Benzaldehyde and (b)
Monoalkylation of Methyl Phenylacetate
approach used a laminar flow regime in order to mimic a
divided cell reactor. With this special feature, a solution
containing 2-pyrrolidone 376 can be fed into the reactor near
the “cathodic part” where the reductive generation of the base
occurs. The separation of the two streams prevents the reactive
anion from being reoxidized at the anode. By adding a mixture
of benzaldehyde and chloroform immediately after the
electrolytic cell, the researchers synthesized 2,2,2-trichloro-1-
phenylethanol 378 in good yields within less than 15 s (Scheme
170a).752 In this transformation, the 2-pyrrolidone anion 377
deprotonates CHCl3, generating a trichlorocarbanion which
ultimately reacts with the aldehyde. The authors showed that
the reaction gives a significantly lower yield (20%) when no
laminar flow was created. Moreover, no reaction occurred if
benzaldehyde and chloroform are present during the initial
electrochemical step. The same concept was applied to the
monoalkylation of methyl phenylacetate 379 with MeI
(Scheme 170b).751 The reaction was highly selective in flow
at room temperature, whereas the same experiment in a divided
cell batch reactor required cooling to −70 °C for high
selectivity.
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Table 9. Recent Publications for the Automated Optimization of Reactions in Flow Reactors
entry reaction parameters analysis notes
1 CdSe nanoparticle synthesis761 temperature, residence time, and fluorescence
stoichiometry
2 Knoevenagel condensation, benzyl temperature, residence time, and HPLC yield, throughput, and selectivity were optimized
alcohol oxidation762 concentration
3 Diels−Alder763 temperature, residence time, and HPLC kinetic information was used for a 500-fold scale-up.
concentration
4 Heck reaction764 residence time and stoichiometry HPLC 50-fold scale up
5 alcohol etherification in temperature, pressure, sCO2 flow rate, and GC and IR
sCO2624,765−767 stoichiometry
6 Paal-Knorr reaction768 temperature and residence time IR incorporation of an Armijo-type line-search
algorithm increased efficiency
7 nucleophilic aromatic substitution769 temperature, residence time, HPLC
concentration, and stoichiometry
8 phenylisocyanate with t-butanol770 temperature, residence time, and IR time-varying experiments reduce the amount of
concentration material used
9 Petasis-Ugi reactions771 temperature and residence time UPLC
10 monoalkylation of an amine759 temperature, residence time, LC−MS droplet screening system which permitted
stoichiometry, and solvent automated solvent screening
772
11 imine formation residence time and volume fraction NMR
12 nitrile hydrolysis to an amide, Appel temperature, residence time, MS and IR
reaction773 concentration, and stoichiometry
13 Heck-Matsuda reaction774 temperature, residence time, GC-MS optimized for maximum yield, highest throughput,
stoichiometry, and catalyst loading and lowest production cost
14 aminocarbonylation775 temperature, residence time, GC and IR
stoichiometry, and pressure
776
15 amidation temperature, residence time, and HPLC
stoichiometry
16 Suzuki-Miyaura cross-coupling760 temperature, residence time, catalyst HPLC droplet screening system enabling discrete variable
loading, catalyst, and ligand screening
17 amidation777 temperature, residence time, and MS
stoichiometry
18 linear chain growth free radical temperature, residence time, concentration UV/vis,
polymerization778 viscometer,
MALS
19 Pd-catalyzed aziridination779 temperature, residence time, and UV and GC
stoichiometry

As discussed in this section, flow chemical techniques, in
combination with “traceless” reagents such as photons and
electrons, are highly appealing from a sustainable standpoint,
and due to the benefits of flow reactors, these protocols are
generally more efficient and easier to scale compared to batch.
While photochemical reactions are already routinely carried out
under continuous flow conditions, electrochemistry in flow is
still in its infancy, which can be attributed to the fact that
electrochemistry is generally feared by organic chemists. Due to
the availability of commercial flow electrochemistry devices, this
uneasiness toward electrochemistry may change in the future,
resulting in the discovery of new exciting chemical trans-
formations and pathways.
reactions utilizing feedback optimization have been summarized
(Table 9).25,120,124,125,756−758 In general, these setups are
comprised of a reagent delivery system, a temperature-
controlled reactor, an inline or online analysis device, and a
computer (Figure 33). A LabVIEW program controls the
delivery system, usually syringe pumps or HPLC pumps, and by
varying the flow rates of the respective reagent or solvent feeds,
it controls the time, stoichiometry, and concentration of the
reaction. The temperature, and in some cases pressure (Table

9. FEEDBACK OPTIMIZATION
High-throughput experimentation (HTE) has led to the rapid,
cost-effective identification of optimal conditions for new
transformations.33,119,753 This method facilitates the swift
screening of discrete variables such as solvent, reagents,
catalysts, and ligands. It is, however, less effective at scanning
continuous variables like temperature, reaction time, and
concentration. Automated continuous flow, on the other
hand, can easily vary continuous parameters such as temper-
ature, reaction time, stoichiometry, and concentration but
struggles with changing discrete variables. Recently, feedback
algorithms and real-time reaction optimization methods have
been realized due to the establishment of online and inline flow
analysis.754,755 This area has been reviewed recently, and those Figure 33. Main components of an automated optimization system.

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Chemical Reviews
9, entries 5 and 14), are also controlled by LabVIEW. Upon
exiting the reactor, the reaction flows through an inline analysis
device or is automatically sampled for online analysis. Data
from this analysis is often exported to Microsoft Excel and
analyzed using MATLAB. A number of mathematical
optimization methods exist for maximizing properties such as
percent conversion, product yield, productivity, and selectivity.
With this algorithm, new reaction parameters are identified and
employed in the next experiment.
Since flow setups struggle to efficiently scan discrete
variables, the majority of the examples to date only optimize
continuous parameters. This is in part due to the setup where
the delivery of stock solutions is invariable. That is, stock
solutions are usually delivered by a single syringe or static lines
for each input stream. By this setup, syringes must be manually
changed or reagent lines manually transferred to other stock
solutions. Entries 10 and 16, on the other hand, varied discrete
parameters with a droplet-based reaction design using a liquid
handler.759,760 These two examples are particularly promising
for the rapid self-optimization of discrete and continuous
variables for a given transformation.
Reizman et al. utilized the droplet-based system for the
optimization of the temperature, residence time, stoichiometry,
and solvent for the monoalkylation of 1,2-diaminocylochexane
382 with 4-methoxylbenzyl chloride.759 Their setup, in contrast
to other reports, utilized a liquid handler for the injection of
samples into the system (Scheme 171). This permitted the
Scheme 171. Primary Components of the Microliter Slug
Flow Self-Optimization System with Solvent Screening
formation of droplets of 4-methoxylbenzyl chloride in different
solvents. Nitrogen carried the slugs through the tubing, and a
refractive index sensor was used to detect slugs and guarantee
accurate injection of 382 into the droplet. The droplets were
reacted at 30−120 °C for 1−10 min. A continuous stream of
acetic acid in acetonitrile was used as a quench, and a third
refractive index sensor was used to time the sampling for
analysis by HPLC. The pressure of the system was controlled
with a nitrogen-regulated Parr bomb at 6.9 bar. Increasing the
temperature too high led to overalkylation. Additionally, the
authors were able to correlate H-bond-donating capacity of the
solvent with the predicted reaction yield. Polar aprotic solvents
like DMSO, DMF, and pyridine outperformed other solvents.
After 93 slug experiments, the yield was optimized to 62%, with
a residence time of 7.5 min, 78 °C, and 4-methoxylbenzyl
chloride (1.00 M in DMSO). A scale-up using these optimized
conditions afforded 383 in 59% (0.5 g) isolated yield.
Using a nearly identical setup (Scheme 172), authors by the
same group carried out an optimization for a Suzuki-Miyaura
coupling.760 Samples of precatalyst, ligand, aryl halide, boronic
acid or boronic pinacol ester, and an internal standard were
prepared in THF and stored under argon prior to droplet
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Review
Scheme 172. Setup for the Automated Optimization of
Suzuki-Miyaura Cross-Couplings with Precatalyst and
Ligand Screening
formation. Refractive index sensors were used to time the
addition of a solution of DBU in THF to the droplet. The
reaction was quenched with a 1:1 solution of acetone/water
after exiting the reactor. Online HPLC analysis was performed,
and the data was used to optimize turnover number and yield
for various heteroaryl substrates. Additionally, investigations
using this system revealed information about the ligands and
the mechanism. Between 0.2 and 0.8 equiv of ligand were ideal,
and the yield decreased significantly with 2.0 equiv. The
optimal conditions for classes of ligands showed trialkyl/
triarylphosphine ligands worked best at high temperatures with
short residence times, whereas dialkylbiarylphosphine ligands
were best at lower temperatures and longer residence times.
These two examples highlight how automated feedback
optimization in flow is a promising alternative to high-
throughput experimentation. It permits the intelligent design
of subsequent reactions, saving time and materials. In addition
to reaction optimization, screening discrete variables can
simultaneously offer insight into reaction mechanisms which
can aid in scale-up or the design of new reactions.
10. CONCLUSIONS
Continuous flow has made immense progress and has been
applied to a vast number of transformations over the past
decade. Recently, the research community has focused on using
the available technology to carry out reactions which
underperform in batch. As such, flow chemistry is finding its
niche in the laboratory. Biphasic reactions, especially gas−liquid
reactions, are becoming more common in flow since mass-flow
controllers enable the precise control over flow rates and
equivalents. Extremely fast reactions, notably lithiations, have
remained a prominent part of flow chemistry as subsecond
mixing facilitates reactions that cannot be conducted in batch.
Interestingly, high-temperature and -pressure flow reactions are
becoming a complementary technique to microwave batch
reactions that are poorly scalable. Meanwhile, photochemistry
has seen a reemergence in the past decade, and the small
dimensions of flow reactors have ushered in many reports of
photoflow reactions. While electrochemistry remains under-
developed by comparison, it still remains a promising field since
the short path lengths allow for reactions to be run with no
added electrolytes. Finally, self-optimizing systems are promis-
ing for expediting organic synthesis. Online and inline analytics
enable feedback optimization, and useful kinetic and mecha-
nistic details can be gleaned from the data. The question now is
whether or not these processes can find their place in the
organic chemists’ everyday toolbox.
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Chemical Reviews
11. DIAGRAM LEGEND
AUTHOR INFORMATION
Corresponding Authors
*E-mail: peter.seeberger@mpikg.mpg.de.
*E-mail: Kerry.Gilmore@mpikg.mpg.de.
ORCID
Kerry Gilmore: 0000-0001-9897-6017
Peter H. Seeberger: 0000-0003-3394-8466
Author Contributions
§
M.B.P. and B.P. contributed equally.
Notes
∥ 1487−1503.
The title of this review is a rewording of the comedy science
fiction novel The Hitchhiker’s Guide to the Galaxy by Douglas
Adams. Additionally, the first question in our batch versus flow
diagram plays on the quote “Answer to the Ultimate Question
of Life, the Universe, and Everything” from the same book.
The authors declare no competing financial interest.
Biographies
Matthew B. Plutschack studied chemistry at the University of
Wisconsin-Madison with the guidance of Professor Howard E.
Zimmerman. He received his master’s degree under the supervision
of Prof. D. Tyler McQuade at Florida State University in the field of
continuous flow. He is currently a Ph.D. candidate at the Freie
Universität Berlin, conducting research at the Max Planck Institute of
Colloids and Interfaces under the supervision of Professor Peter H.
Seeberger.
Bartholomäus Pieber studied chemistry at the University of Graz and
the Graz University of Technology in Austria. He received his master’s
degree under the supervision of Professor C. Oliver Kappe in the field
of microwave-assisted organic synthesis. He proceeded with Ph.D.
studies in the same group working on multiphasic reaction systems in
11874
Review
continuous flow. After receiving his Ph.D. in 2015, he joined the group
of Professor Peter H. Seeberger for postdoctoral studies. His current
research relates to heterogeneous photoredox catalysis using semi-
conducting materials in batch and flow systems.
Dr. Kerry Gilmore was born in Brewster, Massachusetts in 1984. He
received his Ph.D. in 2012 from Florida State University, during which
time he was a Fulbright Scholar. He then moved to the Max-Planck
Institute of Colloids and Interfaces for postdoctoral work, and in 2014,
he was promoted to Group Leader of the Continuous Chemical
Systems team. His current research interests stem from the controlled
conditions achievable in flow and span mechanistic studies, photo-
chemistry, and the development of novel approaches towards modular
chemical synthesis.
Prof. Peter H. Seeberger studied chemistry in Erlangen (Germany)
and completed his Ph.D. in biochemistry in Boulder (CO). After
postdoctoral work at the Sloan-Kettering Cancer Center in New York,
he was Firmenich Associate Professor with tenure MIT (1998−2003).
After six years as Professor at ETH Zurich, he assumed positions as
Director at the Max-Planck Institute in Potsdam and Professor at the
Free University Berlin. His research interests include the glycosciences
as well as flow chemistry.
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support from the Max-
Planck Society and the DAAD.
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11893 DOI: 10.1021/acs.chemrev.7b00183

Chem. Rev. 2017, 117, 11796−11893