How To Approach Ow Chemistry: Chemical Society Reviews November 2020

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How to approach flow chemistry
Article in Chemical Society Reviews · November 2020

DOI: 10.1039/c9cs00832b
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How to approach flow chemistry

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Mara Guidi,ab Peter H. Seebergerab and Kerry Gilmore *a
49, 8910
Flow chemistry is a widely explored technology whose intrinsic features both facilitate and provide
reproducible access to a broad range of chemical processes that are otherwise inefficient or
problematic. At its core, a flow chemistry module is a stable set of conditions – traditionally thought of
as an externally applied means of activation/control (e.g. heat or light) – through which reagents are
passed. In an attempt to simplify the teaching and dissemination of this field, we envisioned that the key
advantages of the technique, such as reproducibility and the correlation between reaction time and
position within the reactor, allow for the redefinition of a flow module to a more synthetically relevant
one based on the overall induced effect. We suggest a rethinking of the approach to flow modules,
distributing them in two subclasses: transformers and generators, which can be described respectively
as a set of conditions for either performing a specific transformation or for generating a reactive inter-
mediate. The chemistry achieved by transformers and generators is (ideally) independent of the substrate
introduced, meaning that they must be robust to small adjustments necessary for the adaptation to
different starting materials and reagents while ensuring the same chemical outcome. These redefined
modules can be used for single-step reactions or in multistep processes, where modules can be
Received 22nd July 2020 connected to each other in reconfigurable combinations to create chemical assembly systems (CAS)
DOI: 10.1039/c9cs00832b targeting compounds and libraries sharing structural cores. With this tutorial review, we provide a guide
to the overall approach to flow chemistry, discussing the key parameters for the design of transformers
rsc.li/chem-soc-rev and generators as well as the development of chemical assembly systems.
Key learning points

How the attributes of flow chemistry can be fully exploited to enable chemical synthesis.
Flow chemistry provides reproducible access to experimental conditions and should be thought in terms of capabilities, not components.
Flow modules are the conditions (including equipment) to chemoselectively either induce a functional group transformation/coupling or generate a reactive
intermediate
Flow modules can be used in isolation or interchangeable to create assembly lines for chemical synthesis.
Processes can be developed to target core functionalities instead of specific molecules, significantly increasing the capabilities and output.
The use of flow chemistry has seen a meteoric rise in the are exposed. Precise control results in excellent reproducibility
chemical community. The broad versatility in applications is and safety – making flow chemistry applicable not only to a
thanks to the modular nature of the approach, allowing for the range of disciplines, but also to researchers from university
facile integration of new conditions, equipment, analytics, teaching labs to production-scale process chemists.
automation, and types of reagents for both single and multistep Organic synthesis has arguably benefited the most from the
processes. The foundational, distinguishing feature of the approach incorporation of flow chemical methodology, bringing reproduci-
is a high degree of precision in the delivery of reagents/solutions bility and expanded potential to a highly physical skill-based field
and excellent control over the conditions to which the solutions of research. Flow chemistry is at least partially responsible for the
recent rapid development and incorporation of photochemistry in
synthesis, while access to reactive intermediates has allowed for
a
Department of Biomolecular Systems, Max-Planck-Institute of Colloids and
transformations to be efficiently utilized that are essentially
Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany.
E-mail: kerry.m.gilmore@uconn.edu
impossible to perform otherwise. Increasingly, both home-
b
Freie Universität Berlin, Institute of Chemistry and Biochemistry, Arnimallee 22, built and commercial flow chemical systems are being auto-
14195 Berlin, Germany mated, opening the door to standardization of data generation,
8910 | Chem. Soc. Rev., 2020, 49, 8910--8932 This journal is © The Royal Society of Chemistry 2020
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Tutorial Review Chem Soc Rev
incorporation of optimization and machine learning algorithms, be used, and more importantly how flow chemistry is discussed
and most importantly the significant increase in access to the and approached. The key attribute of the technique is the high
products and potential of organic synthesis to non-specialists. degree of control over the physical process/conditions that pro-
In order to fully exploit the potential of flow chemistry, a vides excellent reproducibility. This affords the opportunity to
chemist must primarily be able to discern when and how flow expand the concept of modularity in flow chemistry from one
could be beneficial. This ability comes first and foremost with a focused on what equipment can be used to how processes can be
firm grasp on the chemistry that is to be performed and the used to expand our synthetic capabilities and potential.
inherent issues – both process and mechanistic – thereof. The Organic synthesis is traditionally taught as a collection of
stumbling block often comes as chemists focus on the what of concepts, such as types of reactions (e.g. oxidation, reduction,
flow, which tools/equipment to use in order to perform a substitution) and reactive intermediates (e.g. carbocation,
transformation or sequence continuously. Knowledge of the carbanion, radicals), that can be exploited – either individually
available flow chemistry equipment – at least the capabilities or in conjunction – to successfully synthesize a given target.
and strengths/weaknesses – is important. This information has The exact conditions/process for a specific transformation are
been covered extensively in both broad and hyper-specific secondary – the primary focus remains how one can use the
research and review articles over the last twenty years, creating available tools to better perform chemical synthesis.
an ever-expanding encyclopedia of flow chemistry hardware In this tutorial review, we present flow chemistry in the same
and examples of its capabilities.1 way, to show current and future users how flow chemistry can
With the ‘‘facts’’ of flow chemistry – the what – readily available be thought of, approached, and utilized to maximize efforts in
to researchers, it is prudent to discuss how flow chemistry should synthesis, methodology, and process development. We will
discuss how flow chemistry should be approached in terms of
its capacity to reproducibly perform processes where and when
it is desired, providing standardizable access to types of trans-
Mara Guidi is a PhD student in the formations and reactive intermediates. This standardizable
Biomolecular Systems department access to both transformations/intermediates is defined as a
at the Max Planck Institute of flow chemistry module, and is further broken down as
Colloids and Interfaces in described below. These modules can be used individually for
Potsdam (Germany), under the single step processes, or together as interchangeable pieces of a
supervision of Prof. Seeberger. multistep – or telescoped – process.
Her research focuses in flow
chemistry and development of
automated platforms for organic
synthesis.
1. Definitions
1.1 Modules
At its core, a flow chemistry module is a stable set of conditions
Mara Guidi inducing an overall effect on a flowing stream of reagents: with
Prof. Peter H. Seeberger studied Dr Kerry Gilmore was born in

chemistry in Erlangen (Germany) Brewster, Massachusetts in 1984.
and completed his PhD in He received his PhD in 2012 from
biochemistry in Boulder (CO). After Florida State University, during
performing research at the Sloan- which time he was a Fulbright
Kettering Cancer Center in New Scholar. He then moved to the
York, he built an independent Max-Planck Institute of Colloids
research program at MIT where he and Interfaces for postdoctoral
was promoted to Firmenich work, and in 2014 was promoted
Associate Professor with tenure. to group leader of the Continuous
After six years as Professor at ETH Chemical Systems team. His
Zurich he assumed positions as current research interests include
Peter H. Seeberger Director at the Max-Planck Institute Kerry Gilmore the development of technology
in Potsdam and Professor at the Free and approaches to advance
University Berlin. His research covers the glycosciences from chemistry to methodologies of small molecule synthesis, as well as to improve the
immunology as well as flow chemistry. fundamental understanding of reactivity necessary to efficiently and
selectively perform transformations. In 2020, he moved to the
University of Connecticut as an Assistant Professor in the Chemistry
department.
This journal is © The Royal Society of Chemistry 2020 Chem. Soc. Rev., 2020, 49, 8910--8932 | 8911
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Chem Soc Rev Tutorial Review
this effect being a specific transformation or the generation of a process. Further, by seeing flow modules as transformers/generators
reactive intermediate. Herein, we propose to classify these types as opposed to reagent-specific operations, it can be seen that these
of modules as ‘‘transformers’’ and ‘‘generators’’, respectively. modules are interchangeable as determined by the desired order of
A transformer is a flow module where a specific set of chemical operations. This approach of using transformers/generators inter-
conditions and equipment are used to chemoselectively and changeably to target structural cores is a generalized method
reproducibly introduce a coupling or functional group modifica- called chemical assembly systems3 that allow for the rapid
tion. A generator is a flow module whose sole purpose is to synthesis not only of variants of certain motifs, but also different
generate a reactive intermediate (cation, radical, anion, excited classes of compounds simply by rearranging the modules.
state) at a specific space/time in a process, which can be utilized
for study, trapped in situ, or consumed in a subsequent module.

1.2 Telescoping 2. Know your flow

Transformers and generators are excellent means of reproducibly Performing reactions in flow requires a bit more thought and
performing single step transformations. However, one of the planning than the equivalent batch process. This is due to a
strengths of flow chemistry is the relative ease in the ability to number of considerations. The first question is whether there are
connect two or more modules to create a multi-step process; actually chemical or process reasons for running the reaction in
whether that is combining synthesis and work-up/purification, flow1 as opposed to more simply in a flask. Once justified, one
or stitching together multiple synthesis operations in the pursuit must design both the experiment and the process (equipment,
of a target molecule. In flow chemistry, when multiple units of arrangement, and conditions). The simplest flow process is mono-
operation are linked together in a continuous system it is called a phasic where no precipitation occurs – as this causes clogging of
telescoped process. the tubing and thus failure of the process. Homogeneous
The advantages of such a process are significant, with conditions allow you to deliver premade solutions via syringe
reductions in purification steps, time of synthesis, waste, and or HPLC pumps at the desired flow rates (determining stoichio-
manual operations. That said, there are several considerations metry) to a mixing unit. The mixed solution then flows into the
and limitations that must be considered as well. The flow rate reactor under pre-set conditions (heat, cold, light, electricity,
is always increasing (due to the addition of feed lines), meaning etc.) and is exposed to those conditions for a length of time
that if one of the latter transformations requires a long residence determined by the size of the reactor divided by the total flow
time, a larger reactor is required to accommodate. Byproducts and rate of the solution. The entire system can be pressurized using
unused reagents from previous steps are carried through to the a back pressure regulator, used to increase solubility of gases or
subsequent modules. These can sometimes be removed via inline perform reactions above the boiling points of reagents/solvents
workups (creating more complex processes), but if not they can (Fig. 1). Exhaustive descriptions of every component of a wide
have a significant impact on the yield, selectivity, or even the range of potential flow processes can be found in recent publications
composition of the molecular structure produced.2 The same goes and references therein.1,4
for solvents. While prototypes and reagent-specific workarounds While monophasic processes are simplest, there are numerous
exist, the general rule of thumb is once something is added to a and significant advantages to performing multiphasic reactions in
multistep flow process, it is there throughout – for better, or flow. Gases or immiscible solvents can be added to a flow solution
more commonly, for worse. via a simple T- or Y-mixer to easily generate a series of alternating
slugs, the relative sizes of which are determined by the respective
1.3 Chemical assembly systems flow rates. Biphasic reactions and/or work-ups are generally
As implied above, the more units are linked together, the more accelerated using this technique when compared to batch
complex the system becomes. This is true from a hardware processes due to the significant increase in surface areas
perspective – having enough compatible equipment – an operations between the layers and the increased mixing within each liquid
perspective – getting all equipment running correctly and slug. Gas/liquid reactions do not suffer from headspace issues
simultaneously, reaching steady-state – and a chemical perspec- and the solubility of the gas in the solution can be increased by
tive – potential solvent/byproduct/solubility issues. Perhaps the pressurization.5
most painful aspect, however, is that each telescoped process is While the undesired formation of solids can present challenges
typically designed to make one specific molecule, meaning that in a flow system, solid reagents and catalysts can be used in flow
once complete, the entire process must be broken down and effectively, in particular when preloaded into a column or
redesigned and rebuilt for the next target. cartridge to create a packed bed reactor. Fully heterogeneous
Desirable small molecules – whether pharmaceuticals or catalytic reactions perform well in packed bed reactors, as the
otherwise – often share similar structural cores, and chemists effective molarity of the catalyst at the point of reaction is
typically synthesize libraries of derivatives where side chains of significantly higher than in a batch catalytic process. The
these cores are varied. By developing telescoped processes turn-over number of the catalyst is determined by the concen-
which aim to synthesize structural cores as opposed to specific tration of the solution, the residence time, and how long the
molecules, entire libraries can be rapidly created simply by process runs for. The only potential issues with this approach
changing the starting materials/reagents being added to the unique to flow would be leaching of the catalyst into solution,
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Fig. 1 Breakdown of the basic components of a continuous flow system.
resulting in at best uneven distribution of catalyst within the packed at the beginning or end doesn’t matter. One periodically takes
bed and at worst loss of catalyst from the column.6 The leaching of samples, runs a TLC, and waits until the starting material is
catalyst and reagents from a packed bed can be used to deliver consumed. Unfortunately, you cannot do this in flow – which is
poorly soluble species, such as sodium fluoride (NaF) or sodium why our group and others will, generally, quickly screen con-
borohydride (NaBH4), however this is not a widely used technique.1 ditions in batch prior to developing a flow process to get a feel
for the parameters and potential challenges.
In flow, we must decide on the process set-up supported by
3. Approaching flow solubility tests, equipment geometry, etc. and then select an initial
set of conditions, including: flow rates that determine stoichiometry
Returning briefly to the thought process behind performing and reaction time, concentrations, as well as reactor conditions and
reactions in flow. There are a few types of chemistries that size. The solution exiting the reactor is collected, worked up if
perform better under continuous conditions than in batch due required, and analysed. Based on the results, a next set of conditions
to the inherent advantages of the flow reactor and process. can then be tested. The procedures can be partially accelerated by
Using well designed mixing units, two miscible solutions can using in-line analytics when the stream directly passes through an
be fully mixed down to the nanosecond timescale,7 making fast analytical device like an IR, NMR, or UV. However, in-line analytics
reactions an excellent choice for flow chemistry. As reaction are both expensive and can complicate reaction set-ups during the
time is directly related to the position in a reactor, the flow exploratory phase.
regime allows for precise control of intermediate generation With an ever increasing number of literature examples to
and utilization (vide infra). The increased surface area of flow base initial tests on, initial screening and development is becoming
reactors affords excellent temperature control and light penetration, easier. Therefore, we can begin to think more generally about how
providing a general increase in control and efficiency of related we approach a new flow process. Each transformation or synthesis
transformations. in flow should not be developed in isolation or considered a ‘‘one-
One significant challenge to those new to the field – and off’’. While there are certainly specialized reactors/conditions, in
often those experienced in it as well – is how to start a new general the set-ups and conditions that have been developed can be
investigation in flow. In batch this is more straight-forward, we considered reproducible and (ideally) selective means of performing
would simply weigh the solid reagents, dissolve or suspend the a chemical reaction. This includes functional group modifications,
reagent mixture into a solvent, add liquid reagents neat or as coupling reactions, or the generation, study, and utilization of
diluted solutions, and apply the required conditions (heat, reactive intermediates. Categorized as such, the flow chemistry
cooling, light). Whether the reaction mixture is heterogeneous literature can be reorganized from a series of specific examples
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to a collection of modules, equipment, and parameters to affect chemical challenges connected to working with toxic, flammable,
a desired chemical process, that can be utilized either in isolation and/or explosive oxidative reagents. While examples exist using
or in combination to achieve our chemical goal. This toolbox for heterogeneous oxidants, the majority of oxidation modules can
mechanistic and synthetic chemists can be utilized to minimize be broken down into two classes of oxidation modules; the use of
the challenges and hurdles in adopting the technique and hope- oxygen in gas/liquid modules and soluble oxidants in liquid/
fully providing a means of improved reproducibility and efficiency liquid systems, the latter also covering monophasic oxidations.
of research. In the following sections, we break down the flow 4.1.1 Gas–liquid oxidation with molecular oxygen (triplet
literature into two types of modules – transformers, where flow state). Molecular oxygen represents an excellent oxidizing agent
conditions effect a specific chemical modification, and generators, as it is green, traceless, and widely abundant. However, it is
where flow conditions effect the production of a reactive inter- potentially dangerous to use in batch systems due to the large
mediate to be utilized in a multistep process. Finally, we will show volumes of flammable solvents and gas together. It is also
how these modules can be used in interchangeable combinations advantageous to pressurize reactors when using oxygen gas to
to create multistep syntheses targeting cores for the rapid increase solubility of gas in the solvent, which is not trivial in a
synthesis of collections of molecules. standard batch reactor. In flow these issues are easily addressed,
creating systems with excellent mixing and mass transfer.8
4. Transformers Showcased below are two set-ups for this class of transformers
with complementary advantages, differentiated by the means of
Organic chemistry is traditionally broken down into sets and series delivering oxygen gas.
of functional group transformations and flow modules can be Transformer 1 (oxidation). The simplest way to deliver
categorized similarly. The conditions to reproducibly induce a given oxygen gas to a reaction stream is through a standard two feed
transformation are comprised of the reagents required, the environ- approach where the oxygen flow rate is regulated by a Mass
mental parameters, and the equipment setup. If the chemistry is Flow Controller (MFC) and the liquid is introduced by a pump
designed well, these conditions can result in a transferrable module (syringe, HPLC, or peristaltic pump). The two feeds are mixed
capable of reproducible, selective functional group modification(s) together at a mixing unit (e.g. T/Y-mixer) to generate a segmented
independent of the starting material utilized. Just as in batch flow where liquid and gas droplets alternate – a flow pattern
processes, different methods exist to induce a given transformation, called Taylor or slug flow (Fig. 2). In each liquid slug, small
and the module utilized should be based on chemical compatibility, vortices, known as toroidal currents, are generated inside each
availability of equipment, and byproducts generated. In this section liquid segment resulting in excellent mixing and enhanced mass
we will discuss flow transformers that have been developed for the transfer between the two phases.
adaptable and substrate independent induction of types of organic Aerobic oxidations in such setups often use soluble catalysts
reactions. These transformers have been organized by the class of containing precious metals, palladium being the most studied.
chemical transformation, and representative examples of each are Reagents and catalysts are contained in a premade solution,
discussed. which is mixed with oxygen gas or air and delivered to a reactor –
generally at ambient or elevated temperature.8,9 Cheaper catalysts
4.1 Oxidation modules have also been studied and a good example of such a two phase
Numerous techniques and protocols have been developed to process is a gas–liquid continuous flow reactor used for the
perform oxidation reactions in flow addressing practical and aerobic oxidation of 2-benzylpyridines that employs FeCl3.10
Fig. 2 Transformer 1 – oxidation: using oxygen, creating a biphasic gas–liquid system using a T-mixer, exemplified by a benzylic oxidation procedure
with iron(III) chloride.10
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Similar transformers employing more expensive and elaborate 4.1.2 Liquid phase oxidations. The two flow setups
homogeneous catalysts are used to oxidize alkenes, alcohols, described above, while straightforward to set-up and operate,
aldehydes and ketones.8 present the challenge of handling gas. For those who would
This process uses synthetic air and an inexpensive iron(III) rather avoid using gases – for safety, complexity minimization,
chloride homogeneous catalyst (5 mol%). The reaction can be or for lack of equipment reasons – many monophasic oxidation
run fairly concentrated (starting material [1.2 M]) and at high reactions that still benefit from being carried out in flow have
temperature (200 1C). The setup consists of a liquid and a gas been described.
feed mixed by a T-mixer containing a pressure reducer and a Transformer 3 (oxidation). The simplest system for liquid
repurposed GC oven containing a stainless steel coil as a reactor. phase oxidation is composed of two feeds, one containing the
However, reactions using oxygen gas/air can also be performed starting material and one with the homogeneous oxidant, which
using simple T-mixers and in fluorinated polymer tubing such as meet at a T-mixer. Such systems are numerous and used for many
PTFE or FEP. The specific temperature required for the oxidation different processes, including KMnO4-mediated oxidations. With a
will be reaction specific. single set-up, it is possible to oxidize alcohols and aldehydes to
Transformer 2 (oxidation). The second arrangement for this carboxylic acids as well as nitroalkane derivatives to the corres-
class of modules delivers oxygen (and other) gases to a flow ponding carbonyls and carboxylic acids (Nef oxidation).13 The
system using a tube in tube reactor. This more complicated reagent and oxidant streams are delivered by HPLC pumps to a
flow setup, pioneered by the Ley group, provides excellent gas T-piece before entering a simple PFA (per-fluoro-alkoxy) tubing coil
mixing into a liquid phase, and has been used for a wide range (here with a 14 ml internal volume).
of gases and chemistries.11 The reactor consists of two con- However, even with simple and general applications such as
centric tubes. The inner tube is made of a semi-permeable this, issues can arise. While precipitation can occur anywhere
polymer such as Teflon AF-2400. This material displays high in a flow system, the two main places are either inside a reactor
permeability for many gases and is impermeable to non-fluorinated due to product/byproduct crashing out, or at the mixer when
liquids. Liquid is passed through the inner tube, while the two solutions first meet. In this work, there were issues with
pressurized gas is passed through the outer tube, allowing for manganese dioxide falling out of solution at the exit of the
the gas to dissolve into the solution across the entire length of T-mixer. The challenge was easily addressed by submerging the
the tube-in-tube reactor. T-mixer in an ultrasonic bath that prevented any aggregation of
A showcase of this oxidation module is the anti-Markovnikov manganese dioxide precipitate (Fig. 4).
Wacker oxidation of styrenes to arylacetaldehydes.12 Oxygen was
efficiently delivered to a solution containing styrene and a
homogeneous palladium/copper catalytic system (each 5 mol%) 4.2 Reductions
under pressure (25 bar) maintained by a back pressure regulator. Reductions can be performed using gaseous hydrogen or soluble
The oxygen-enriched monophasic solution exited the tube-in- reductants, by using adaptations of the oxidation setups described
tube reactor and passed into a reactor coil held at 60 1C. Using above. Safety and control over reductions is much better in flow
this setup, a number of styrenes were converted to the anti- than in Bach syntheses. Hydrogenations generally require high
Markovnicov aldehyde in good yields and exhibited good selectivity pressures and combine pyrophoric catalysts with a highly
over the potential Markovnikov and the over-oxidation products flammable gas.14 Liquid reductants, such as hydride sources,
(Fig. 3). often face selectivity issues, as products may be susceptible to
Fig. 3 Transformer 2 – oxidation: using oxygen, delivered by a tube-in-tube reactor, showcased with the transformation of styrenes into aldehydes.12
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Transformer 5 (reduction). An alternative approach to hydrogen

introduction in a flow system is its in situ generation, which both
minimizes equipment and maximizes safety. While protocols for
DIY systems exist, the easiest method uses commercial equipment
that produces hydrogen via the electrolysis of water. The H-cubes
couples an electrolytic cell (producing hydrogen) to a gas–liquid
mixer creating a supersaturated, pressurized solution that directly
feeds into an exchangeable packed bed (B140 mg catalyst) with
temperature control by a heater block (Fig. 6). A variety of available
pre-packed catalyst columns open-up access to a wide range of

hydrogen-mediated reductions using this single transformer, for

example using RANEYs Ni or Pd/C cartridges for the reduction of
nitro groups, nitriles, and oxymes to amines as well as the
hydrogenolyses and saturation of double and triple C–C bonds are
Fig. 4 Transformer 3 – oxidation: using a liquid phase oxidant and an possible.16
ultrasonic bath (green box) to avoid aggregation of precipitants resulting Transformer 6 (reduction). Flow transformer modules have
from oxidation byproducts.13 also been developed for homogeneous reductions. An archetypical
example of how better process control of flow modules can
harness reactions difficult to be controlled in batch is the con-
over-reduction. These issues can be reproducibly addressed tinuous flow reduction of esters to aldehydes using diisobutyl-
using flow reduction transformers. aluminum hydride (DIBALH).17 Ester reductions with DIBALH
Transformer 4 (reduction). Hydrogenations are exceedingly are notoriously difficult to reproduce due to significant over-
well suited for flow due to the facility of pressurization and reduction to primary alcohols. In order to stem overreduction,
enhanced safety. One approach uses the same equipment as such processes often need cryogenic temperatures and slow
Transformer 2 (Fig. 3), with hydrogen introduced via a tube-in- addition of DIBALH. Both aspects can be easily addressed in flow.
tube reactor in combination with either a homogeneous or Transformer 6 consists of two PFA reactors – for reduction
heterogeneous catalyst in a subsequent reactor. An example of and subsequent quenching – held at low temperature (Fig. 7).
the latter approach is the hydrogenation of cinnamates, where Solutions first pass through precooling loops to ensure con-
the starting material solution is enriched with hydrogen under trolled reactivity at sub-ambient temperatures and mixing is
pressure.15 The gas–laden solution then feeds directly into a achieved using T-mixers. Mixing is critical for the efficiency of
packed bed reactor, allowing for the heterogeneous catalyst, this reaction, and while this can be achieved using structured
in this case 10% palladium on carbon, to be used in super- mixers, better mixing with T-mixers can be achieved using
stoichiometric amounts and separated from the solution post higher flow rates. The reduction of esters to aldehydes at
reaction. The entire system is pressurized by a back pressure cryogenic temperature ( 78 1C) was fully selective and with
regulator, as the conversion is roughly linearly dependent on an extremely short residence time (o50 ms), allowing for very
the pressure (Fig. 5). When used as a stand-alone transformer, high throughput for this transformer (41.8 kg per day for ethyl
the solution can easily be cycled back through the system to hydrocinnamate) with only a 23 ml reactor (R1).17
increase conversion, as there are no byproducts and excess
hydrogen gas is removed upon depressurization. Increased 4.3 Olefination reactions
catalyst loading or lengthening of the packed bed reactor can Numerous flow protocols exist for highly adaptable homo-
improve conversion in this type of transformer. geneous olefinations, including Wittig, Knoevenagel, and
Fig. 5 Transformer 4 – reduction: using hydrogen gas delivered by a tube in tube reactor and catalyst via a packed bed reactor (where the reduction
takes place).15
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Fig. 6 Transformer 5 – reduction: using in situ generated hydrogen by electrolysis of water, which under pressure creates a saturated solution that
passes through a packed bed reactor containing the catalyst.16
Fig. 7 Transformer 6 – reduction: controlled homogeneous partial reduction of esters to aldehydes using hydride.17 Blue box corresponds to the chilled
section of the transformer.
Horner–Wadsworth–Emmons couplings. These reactions are byproduct remains bound to the resin, while the formed alkene
generally carried out in ambient or elevated temperature tub- cleanly exits the reactor. The column can be regenerated and
ular reactors with reagents delivered by at least two liquid used more than ten times, and the Transformer can be used for
feeds. In flow, reaction times can sometimes be significantly a wide range of aldehydes.
shortened for these reactions due to the accessible high tem-
peratures and pressures.1,18 4.4 Huisgen cycloadditions
Transformer 7 (olefination). A dedicated module for Horner– Cycloadditions are powerful class of transformations, often
Wadsworth–Emmons olefinations was developed employing characterized by their selectivity and minimal byproducts. The
what was termed a PASSFlow reactor.19 The reactor is a column Huisgen 1,3-dipolar cycloaddition of an azide and alkyne is the
packed with polymeric beads (polyvinylchlorobenzene cross- classic example, and has become the epitome of ‘‘click’’ chemistry.20
linked with 2–20% of divinylbenzene) inside the microchannel The Cu(I)-catalyzed version of the azide–alkyne cycloaddition
pore system of highly porous glass rods resulting in a composite reaction (CuAAC) leads to 1,4-disubstituted 1,2,3-triazoles and
material capable of swelling and shrinking – minimizing issues its extreme versatility and robustness has resulted in a wide
resulting from channeling or high pressure drops observed in range of applications. The reaction benefits from continuous
other polymer-based packed reactors (Fig. 8). The column acts conditions due to its safety in handling potentially explosive
as both base and method for purification. The beads can be azides even under harsh conditions, better mixing to potentially
loaded with hydroxide ions, which serve to deprotonate diethyl lower catalyst loading, and inline separation/purification.
phosphonoacetonitrile to form the required phosphonate ion. Transformer 8 (CuAAC). The first transformer for CuAAC
This intermediate reacts with the aldehyde present in the same chemistry combines enhanced safety and mixing with a set of
solution to yield the desired olefin. The diethyl phosphate conditions that does not require an externally added catalyst.
Fig. 8 Transformer 7 – olefination: a packed bed reactor capable of catalyzing and purifying Horner–Wadsworth–Emmons olefinations.19
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Fig. 9 Transformer 8 – CuAAC: a copper coil serves as both reactor and catalyst source.21
The azide is formed in situ with the desired halide and sodium The specialization comes via the integrated inline workup/extraction,
azide, selectively in the presence of a terminal alkyne – all three where an aqueous ethylenediaminetetraacetic acid (EDTA) solution
feeds are mixed via a 4-way cross-piece. Mixing in the system quenches the reaction by extraction of the catalyst via chelation. The
is enhanced by the addition of an immiscible carrier fluid product is extracted with ethyl acetate, and the two phases can be
(perfluoromethyldecalin) via a T-mixer, creating reaction slugs efficiently separated, when the aqueous stream is in large (7.5)
with volumes of approximately 400 ml. This biphasic mixture excess, using a membrane-based liquid/liquid separator.23
then enters the specialized reactor, a copper coil (0.75 mm i.d.) Transformer 10 (CuAAC). Scavenging units can also be used
placed between two copper plates (Fig. 9). At the elevated to remove catalyst and excess reagents by packing resins into
reaction temperatures (150 1C), Cu(0) leaches from the tubing columns. For CuAAC-chemistry, copper is removed using Quadra-
and is used to effectively catalyze the reaction.21 A wide range of puret TU (QP-TU) metal-scavenging resin and excess azide using a
halides and alkynes can be rapidly transformed using this column packed with phosphine resin (PS–PPh2) (Fig. 11).24
module. This copper coil reactor was used by the authors to
catalyze hundreds of reactions and no loss of catalytic activity
5. Generators
was reported.
Transformer 9 (CuAAC). A simpler approach to perform The ‘‘generator’’ concept is commonly used to indicate a module
CuAAC chemistry is the normal two-feed setup using a homo- for the continuous in situ production of hazardous materials.25
geneous copper source (Fig. 10).22 A premade mixture of an Here, we expand this concept to include all reactive intermediates
azide and alkyne is delivered to a T-mixer where it meets the that can be generated in situ and on-demand.
stream of copper(I) iodide in NMP. The pressurized solution One of the most important, but often underestimated features
then enters a standard PFA reactor held at elevated temperature. of flow chemistry is the direct correlation between reaction time
Fig. 10 Transformer 9 – CuAAC: homogeneous system with in-line copper scavenging/work-up and liquid/liquid separation.
Fig. 11 Transformer 10 – CuAAC: a packed-bed system for CuAAC with modular scavenging units for both metal and excess azide.24
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5.1 Carbocations
Carbocations are positively charged intermediates that play key roles
in various organic reactions, but are, due to their unstable and
transient nature, difficult to isolate and accumulate. Generating
carbocations continuously via continuous flow techniques provides
stable access to these valuable species, which can then be trapped
by nucleophiles prior to undergoing side reactions.
Generator 1 (iminium). The seminal work in this area was
the ‘‘cation flow method’’ by the Yoshida group, generating

carbocations by electrochemical oxidation that are trapped in a
subsequent reactor. The module consists of two feeds containing

supporting electrolytes leading to the respective cathodic and
Fig. 12 (top) A typical example of how chemists write out a reaction. anodic chambers – separated by a PTFE membrane – of the low-
(bottom) Aryllithium generator, where an organolithium is generated temperature electrolysis reactor. A sacrificial proton source drives
cleanly and delivered directly to the electrophile – creating a flow system the reaction forwards by forming hydrogen gas in the cathodic
identical to the ‘‘ideal’’ written process.
chamber, while the carbamate is oxidized to give the corres-
ponding iminium ion (Fig. 13). The cation generation can be
and physical position in flow reactors. In a given reactor, the monitored inline using FTIR on the stream exiting the generator
reaction time is a function of flow rate and volume (a factor of that is combined with an additional stream or vessel allows for
both tube diameter and length). The implications are significant, efficient and selective nucleophilic trapping. The module is
particularly for fast reactions or those proceeding through reactive tolerant of a range of carbamate carbocationic precursors as
intermediates. When one writes out a reaction, reagents are well as nucleophilic trapping agents.
drawn coming together, creating an intermediate such as an
organolithium species that then reacts e.g. with an electrophile 5.2 Benzyne
to give the desired product. Traditionally, all these species are Generator 2 (benzyne). Benzynes bridge the gap between
present together presenting multiple potential reaction pathways, isolated cations and anions but are difficult to harness in synth-
and cryogenic conditions are required to attempt to control esis. A straightforward three-component coupling can be achieved
reactivity. However, flow modules can be designed to create a where benzyne is formed and sequentially reacted with a nucleo-
system identical to how it is drawn (Fig. 12). Thereby, intermedi- phile followed by an electrophile. Expanding on the carbolithiation
ates and processes are reproducibly accessable that cannot be module (vide infra), o-disubstituted benzenes can be rapidly
effectively or safely carried out in batch. synthesized from 1,2-dihalobenzenes via the formation of benzyne
This concept is best exemplified by the ‘‘flash chemistry’’ of following lithium–halogen exchange.28 Precise control over the
Yoshida, whose work perfectly exploited the space-time correlation mixing and positioning (via flow rates) in the system allows for the
of flow chemistry. Flash chemistry relies on very fast reactions (a efficient sequential trappings with an aryl lithium or a range of
second or less) involving highly reactive and unstable species that electrophiles. 1-Bromo-2-iodobenzene was found to be the best
cannot be harnessed by traditional methods.26 benzyne precursor and the module is operated in three distinct
Generators are modules that utilize liquids or gases to create temperature zones (Fig. 14).
a reactive species and are modules incorporated into larger flow
processes. As with transformers, we will organize our discussion of 5.3 Carbanions
generators based on capability (i.e. type of intermediate formed) and One of the most commonly employed carbanionic synthons are
will highlight for each the most relevant example(s) in the literature. organometallic species such as organolithium and organomagnesium
Fig. 13 Generator 1 – cations: electrolytic generation of iminium ions, capable of inline monitoring, delivered to a stream containing the nucleophile.27
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Fig. 14 Generator 2 – benzyne: fully adjustable three-component system for generating and utilizing benzyne with different nucleophiles and
electrophiles.28 The three temperature zones are shown with colored boxes.
compounds that contain a very polar carbon–metal bond with ketones efficiently gave the corresponding substituted bromo-
electron density heavily concentrated on the carbon atom. These benzene derivatives.
highly reactive species are potentially hazardous due to the
exothermicity of their reactions, thus rendering control over 5.4 Radicals
chemoselectivity and overreactions difficult. Organometallic Besides carbocations and carbanions, radicals are the third
species are popular among flow chemists as they can be safely major class of electronically unsatisfied reactive species. Radicals
generated and manipulated in situ. are molecules with an unpaired valence electron and are very
Generator 3 (aryllithium). As discussed with Generator 2, reactive and as such, transient. As widely reported, microfluidic
precision in both time and temperature are key to controlling devices can overcome mass and energy transport limitations even
the reactivity of carbanions. With modules capable of very short for fast and exothermic reactions, making the generation and
residence times, even intramolecular reactions can be out-competed utilization of radicals better controlled in microflow systems.
by the desired bimolecular trapping of carbanions. One example is Generator 4 (carbon-centered radicals). A simple setup for
the mono-functionalization of 1,2-dibromobenzene.29 The flow the generation of carbon radicals from alkyl iodides uses Minisci-
setup for this generator is very simple, composed of two microtube type conditions.30 This highly exothermic and fast two-stage
reactors for the lithiation and subsequent trapping, two T-shaped reaction employs hydrogen peroxide (H2O2), dimethylsulfoxide
micromixers submerged in a cooling bath ( 78 1C), and syringe (DMSO), and an Fe(II) catalyst to generate a methyl radical. This
pumps to introduce all reagent solutions (Fig. 15). The best intermediate abstracts an iodide atom from the substrate in a
conditions for the generation of o-bromophenyllithium was very fast equilibrium reaction that leads to the desired alkyl
70 1C with a residence time of 0.8 seconds. A wide range of radical. In the model reaction (Fig. 16), the alkyl radical is
electrophiles, such as methyl triflate, chlorodimethylsilane, trapped by a double bond forming a carbon–carbon bond.
trimethylsilyl triflate, chlorotributyl-stannane, aldehydes, and In batch, the process is difficult to control, requiring careful
dosing and low temperatures.
Fig. 15 Generator 3 – aryllithium: precise design allows for trapping of Fig. 16 Generator 4 – alkyl radicals: two-step process for formation of
o-haloaryl lithium species prior to side reactions.29 alkyl radicals, with selective trapping with an in situ alkene.30
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Operationally, the generator is a straight-forward two-feed diazomethane passes through the membrane to react with the
flow setup driven by syringe pumps. In the first feed there is a liquid reagents passing through the outer tube. The aqueous waste
solution containing the aromatic substrate, the alkyl iodide, stream can be directly fed into concentrated acetic acid to decom-
FeSO47H2O (as Fe(II) catalyst) and H2SO4 (added to enhance pose any unconsumed diazomethane, while the product stream is
the solubility of the Fe(II) salt and to prevent its oxidation) in collected and similarly quenched with acetic acid. A wide range of
DMSO while the second feed contains hydrogen peroxide. The products can be generated using this approach (Fig. 18).
residence time unit can be either a micromixer of various Generator 7 (alkyl diazo compounds). Fluorinated diazo
designs or a combination of Y-connections and PFA tubing. compounds can also be generated using a tube-in-tube system
by simple modification of the aqueous stream to trifluoroethyl-
5.5 Diazo compounds amine hydrochloride and sodium nitrite under aqueous acidic
Diazo compounds are highly reactive organic molecules well conditions.34 Trifluoromethyl diazomethane efficiently passes
known for both their synthetic potential as well as for the safety through the inner tubing to mix efficiently with the outer
hazards associated with them. These reasons – as well as the stream, here containing an aldehyde solution. In the model
facility of pressurization to control the liberated gas – are example, this solution was then passed through two packed bed
excellent arguments for the development of a flow generator reactors containing alumina and an immobilized base (DBU) to
for these inherently unstable compounds. A thorough review obtain a range of aldol products (Fig. 19).
article on the use of continuous flow for safe generation and Generator 8 (benzyl diazo compounds). Another well documen-
use of diazo compounds details numerous good examples of ted protocol to generate diazo compounds is the oxidation of
flow generators for such species.31 Here, we highlight four of hydrazones. Manganese dioxide (MnO2) has is an effective oxidizing
them, which exploit different chemistries and flow setups, agent for such oxidations in batch, although these protocols
approaching the challenge in distinct but valuable ways. These suffer from low efficiency and are limited to very specific
can be further broken down into gaseous (diazomethane) and substrates. Alternatively, a flow generator has been reported
liquid diazo generators. capable of delivering reactive, unstable diazo compounds on
Generator 5 (diazomethane). Diazomethane generators rely demand using a column packed with activated MnO2.35 The
on having two streams separated by a membrane. In one, flow-generated transient species could be transferred into
diazomethane generation occurs. The gaseous reagent then another chemical environment in order to react with a suitable
diffuses through the membrane into the second stream, where partner. This sequence of generation/translocation/reaction of diazo
the reagent solution is flowing. In one approach, a hydrophobic compounds provides a new pool of reactions for these reactive
membrane is built into a dual-channel microreactor (Fig. 17).32 intermediates, and was showcased with carbon–carbon sp2–sp3
Diazomethane is generated from the basic elimination of a coupling between tosylhydrazone and boronic acids (Fig. 20).
nitroso compound called Diazald (N-methyl-N-nitroso-p-toluene- While the column is consumed/deactivated during the course
sulfonamide) using potassium hydroxide. Upon generation, dia- of the reaction, a protocol for the regeneration and re-use of the
zomethane then diffuses through the membrane to react with a MnO2 column was also established. The spent manganese oxide
range of different partners, yielding methyl esters or ethers, diazo could be oxidized by passing a solution of tert-butyl hydroperoxide
ketones, and Arndt–Eistert homologation products. through the column. Interestingly, the regenerated column
Generator 6 (diazomethane). The second approach to generate produced diazo compound without the need for a pre-
and use diazomethane efficiently is using the tube-in-tube reactor conditioning phase. MnO2 was recycled over three cycles with
described earlier. Diazomethane is a gas at room temperature, just a slight decrease in reactivity after each time.
thus it is possible to envision a process in which generation,
separation, and chemical transformations of diazomethane are a 5.6 Phosgene
single integrated process.33 A stream of Diazald and KOH is passed Phosgene is a very useful gaseous reagent in organic synthesis.
through the inner tube of the reactor. Upon generation, the However, it is toxic and hazardous – making handling and
Fig. 17 Generator 5 – diazomethane: dual stream in situ generation and reaction of diazomethane via a membrane reactor.32
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Fig. 18 Generator 6 – dizaomethane: generation of diazomethane and reactions thereof in a tube-in-tube reactor.33
Fig. 19 Generator 7 – alkyl diazo compounds: generation of fluorinated diazo compounds and use via a tube-in-tube reactor. The generator is coupled
with a packed-bed reactor to catalyze an aldol coupling of the formed diazo intermediate.34
Fig. 20 Generator 8 – benzyl diazo compounds: MnO2 packed bed module generates diazo compounds via oxidation of hydrazones.
accumulation of such species dangerous. As discussed for in the presence of Hünig’s base (to avoid downstream precipitation
diazomethane, flow generators can enable continuous in situ issues) is delivered to a stream of carboxylic acid and base via a
generation and consumption of hazardous gases within a stainless steel T-mixer. The mixer and subsequent process is
closed system, opening the doors to their application in many immersed in a water bath (20 1C) for thermodynamic control
types of chemistries otherwise carefully avoided. (Fig. 21). The system generates a near-equimolar amount of
Generator 9 (phosgene). A simple two-stage set-up allows for phosgene that is completely consumed in the subsequent
the continuous in situ generation of phosgene and its use in reaction such that no phosgene is emitted from the reactor.
acid chloride formation.36 The phosgene precursor (triphosgene) The generator was used to synthesize a range of amides from
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Fig. 21 Generator 9 – phosgene: safe in situ generation and use of phosgene, exemplified by its use in the synthesis of acid chlorides – immediately
used in a telescoped synthesis of amides.36
carboxylic acids via the acid chlorides produced using the to give an intermediate peroxide. When the reaction is performed
in situ generated phosgene. in the presence of triflic acid, this unstable intermediate under-
goes a cascade of reactions resulting in the active pharmaceutical
5.7 Singlet oxygen ingredient (API) artemisinin. Without any changes to the generator
Singlet oxygen (1O2) is a low cost and green reagent attractive and simply replacing the starting material solution, primary and
for its versatility in a plethora of reactions, including hetero- secondary amines can be rapidly oxidized to the corresponding
atom oxidations, ene-reactions, and cycloaddition reactions. imine, which can be quantitatively trapped by an in situ cyanide
1
O2 is usually generated through the excitation of triplet oxygen source (unreactive in the generator) to give a-aminonitriles.41
(3O2) by using a photoinitiator and light. It is a highly reactive,
unstable, and explosive species and these features, together 6. Chemical assembly systems
with the already mentioned benefits of microreactors in gas–liquid
and photochemical processes, make 1O2 an excellent candidate Thus far we have covered the best approaches to exploit flow
for flow. reactors as reproducible sets of conditions with space and time
Generator 10 (singlet oxygen). The first flow generator for the directly linked by flow rate to induce a transformation. The
preparation of 1O2 from 3O2 showcased a variety of oxidations to synthetic potential further increases – as does the technical
synthesize allyl alcohols, endoperoxides, keto-acids, and sulfoxides/ difficulty – when multiple transformers, generators, and com-
sulfones.37 The generator is based on a photoreactor design38 where binations thereof are linked in series. These individual modules
a fluorinated ethylene propylene (FEP) tubing is wrapped around a are designed to be chemoselective, and can be used inter-
Schenk photochemical reactor hosting a 450 W medium pressure changeably to create reconfigurable multistep processes. The
mercury lamp maintained at 25 1C (Fig. 22). A biphasic stream of processes, called chemical assembly systems (CAS)3 due to the
oxygen/solvent is created by a T-mixer outside of the reactor, with their similarity to traditional assembly lines, combine modules
the solution phase containing the photosensitizer (here tetraphenyl- focused solely on functional group transformations, can be used
porphyrin) and the reagent(s). to target cores motives as opposed to specific target molecules.
This generator can also be driven by visible light LEDs, and a As such, compound collections can be generated by simply
truly wide breadth of chemistry has been achieved using singlet changing the starting materials entering the CAS sequence. A
oxygen in flow with these simple generators and a simple room second layer of control over product outcome is derived from
temperature residence time unit.8 Two examples showcase the the reagents chosen, allowing for further functional groups or
flexibility of this generator. Dihydroartemisinic acid reacts with branching points to be included by e.g. transforming an aldehyde
singlet oxygen, generated either using a pure dye39 or crude into an a,b-unsaturated ester via either a Horner–Wadsworth–
chlorophyll from Artemisia annua extraction,40 in an ene reaction Emmons or Knovenagel olefination. Finally, the order and choice
of modules provides access to very different classes of target core
structures (Fig. 23).
Even when targeting different structural classes of compounds,
reactions within their syntheses are often repeated, on different
substrates or at a different point of the process. Therefore, the
same modules can be exploited within the syntheses of different
compounds simply by rearranging the combination of modules
and passing different substrates through them. CAS are synthetic
platforms presenting a pool of modules and reagents that can be
Fig. 22 Generator 10 – singlet oxygen: continuous generation and use of
arranged in different combinations in order to cover significant
singlet oxygen driven by energy transfer from an excited dye, driven by chemical space. In this section, we will highlight several multistep
either a UV or LED lamp.37–41 processes where several generators, transformers, or combinations
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Fig. 23 The concept of a chemical assembly system, exhibiting three levels of control over product outcome.3
thereof are linked together to create multistep processes targeting structures can be achieved from the same starting material by
different structural cores. using a different series of modules. By coupling the a-aminonitrile
generator to a high temperature/pressure reactor introducing an
HCl solution, racemic a-amino acids can be produced, with side
CAS 1 (artemisinin derivatives). An example of CAS that chains determined by the starting amine.44 Exchange of HCl for
targets different products by controlling the choice of reagents CO2 gas provides access to a class of heterocycles called hydantoins –
is a four-step system for the synthesis of artemisinin-derived though removal of the oxygen gas from the singlet oxygen generator
molecules.42 This CAS combines the generator for singlet oxygen is first required for this two-step CAS.45 Finally, replacement of the
and a reduction module that leaches sodium borohydride,43 cyanide with a different carbon nucleophile, malononitrile, provides
directly reducing the lactone of artemisinin to the hemiacetal. access to a-cyanoepoxides through a two-stage oxidation, where
This hemiacetal is then trapped either in an etherification or singlet oxygen generates both the imine and an equivalent of
esterification to give the corresponding API. All currently utilized hydrogen peroxide, that in the second module oxidizes the
artemisinin-derivative APIs can be generated from the same intermediate electron-poor a,b-unsaturated ester into the corres-
CAS simply by changing the reagent in the last step (Fig. 24). ponding epoxide (Fig. 25).2
Combination with a three-step purification module will generate CAS 3 (asymmetric ketones). Library diversification through
499% pure API (not shown). both starting material and reagent selection is exemplified by
CAS 2 (divergence from imines). Singlet oxygen generators the synthesis of asymmetrical ketones from carbon dioxide
have been used in a variety of CAS, owing to the selectivity and using organolithium and Grignard reagents in a three-step
robustness of the generator as well as the minimal byproducts CAS.46 The first generator transforms aryl halides into the
produced. Such features make the singlet oxygen generator corresponding organometallic species using either n-BuLi
perfect for even more complex chemical assembly systems. or i-PrMgClLiCl. This species is trapped with gaseous carbon
The a-aminonitriles produced upon amine oxidation/trapping dioxide. The resulting carboxylate is further reacted with different
in Fig. 22 are valuable intermediates towards a variety of core organolithium species to create a range of asymmetric ketones
functionalities. This example illustrates how different target (Fig. 26).
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Fig. 24 CAS 1 – artemisinin derivatives: a modular system for the synthesis of antimalarial APIs. Level of control: starting material choice.
Fig. 25 CAS 2 – divergence from imines: generator 10 (singlet oxygen) is coupled with one of three different modules to give three classes of
compounds. Levels of control: starting material choice and order of modules.
CAS 4 (convergent: b-amino alcohols). Branched CAS are also transformer for the regioselective nucleophilic opening of an
possible, providing access to either a broader scope of a target epoxide with a primary amine. By judicious path and starting
functionality, or to different classes of targets simply by changing material selection, five different vicinyl amino alcohol APIs can be
the type or order of transformers in the CAS. A convergent CAS was generated with the same convergent CAS (Fig. 27).
developed to access two types of b-amino alcohol starting from CAS 5 (divergent: b-amino acids, c-lactams, c-amino acids).
either primary alcohols or phenols.47 The two routes, either a two- Divergent chemical assembly systems arguably offer more syn-
stage biphasic oxidation/Corey–Chaykovsky epoxidation or an thetic potential, where multiple targets and derivatives thereof
alkylation with epichlorohydrin, converge onto a straightforward can be produced simply by changing the order of modules and
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Fig. 26 CAS 3 – asymmetric ketones: carbon dioxide is transformed into asymmetric ketones via reaction with two different organometallic species,
allowing for a range of products to be obtained simply by changing either the starting alkyl halide or organolithium species. Levels of control: starting
material and reagent choice.
Fig. 27 CAS 4 – b-amino alcohols: a convergent CAS accesses variants of the same structural core using two pathways approaching the same final
Transformer. Levels of control: starting material, reagent choice, and modules used.
the introduced starting materials. One example is a five module carboxylic acids. Derivatives of the target cores – via one of three
CAS transforming alcohols or carbonyls into three classes of core module arrangements – were synthesized by simply changing the
functionalities: b-amino acids, g-lactams, or g-amino acids starting material entering the CAS, and five APIs could efficiently
(Fig. 28).3 Five transformers were developed for selectivity, solvent be generated using the 1-2-3-4 or 1-2-3-5-4 CAS sequence.
tolerance, and minimal byproducts: alcohol oxidation using CAS 6 – pyrazoles. A six module divergent CAS was developed
bleach and TEMPO (module 1), carbonyl olefination via either to access highly substitute pyrazole cores, where the degree and
Knovenagel or Horner–Wadsworth–Emmons (module 2), Michael location of functionalization was easily controlled by the order
addition of nitromethane using tetrabutylammonium fluoride of modules (Fig. 29).48 Module 1 is a generator for difluoro- or
(module 3), hydrogenation via an H-Cube (module 4), and trifluoromethyl diazo methane, through diazotation of an amine
biphasic hydrolysis using LiOH (module 5). Liquid/liquid workup using tert-butyl nitrite and acetic acid as catalyst. Module 2 is a
modules were included either for quenching/work-up or for transformer for the [3+2] cycloaddition of the diazo compound
purification via basificiation/acidification/back-extraction of with alkenes or alkynes. Module 3 is a transformer that mediates
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Fig. 28 CAS 5 – b-amino acids, g-lactams, g-amino acids: a divergent CAS synthesizes libraries of three different functional cores. Levels of control:
starting material choice, reagent choice, and order of modules.
a Chan–Lam–Evans C–N arylation. Module 4 performs a standardization of chemical processes – where being in flow is
N-methylation with iodomethane and DBU. Module 5 performs already an advantage.
direct amidation of pyrazole esters using LiHMDS. Finally, We will highlight two systems that use automation to control
module 6 performs TMS removal using TBAF buffered with available reaction modules for single steps, linking them together
AcOH. Modules can be combined in a telescoped manner or in different combinations to achieve different multistep processes.
used in a stepwise approach, applying each individually and The automated platforms are distinct based on their approach to
submitting the product to the next after module isolation how the respective modules are arranged, defined, and utilized in
and purification. One example is the synthesis of measles the system.
therapeutic AS-136A, where the combination of modules 1-2-4-
5 resulted in a 34% yield when modules were telescoped and Auto-CAS 1 (linear syntheses). One approach to the providing
75% yield when they were used individually. access to different modules in different combinations is a modular
continuous-flow platform that is automatically reconfigured by a
7. Automated CAS robotic arm.49 This system has a set of reactors held in a storage
location that can be selected and inserted into the CAS using a six-
The chemical assembly systems presented above need manual axis robotic manipulator, which is also capable of connecting the
intervention for modifications, whether the recombination of requisite tubing from system to reactor.
their modules between synthetic pathways or exchanging start- The reagents are connected to the process stack through a
ing materials/reagents. Recent efforts have seen the evolution robotically manipulated switchboard, that connects the fluid
of flow chemistry towards automation, to accelerate and facil- pumps, outlets, and waste streams to each process module as
itate synthesis. Automation will also significantly help with the required by the chosen chemical process. Two pumps are
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Fig. 29 CAS 6 – pyrazole library: a six module divergent CAS exhibits controlled functionalization of multiple positions of the formed pyrazole moiety.48
Fig. 30 Auto-CAS 1 – linear syntheses: an automated, robotic platform for the flow synthesis of organic compounds informed by AI planning.49 From
Science, 2019, 365, eaax1566. Reprinted with permission from AAAS.
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equipped with selector valves, which enable selection from up separator unit for liquid–liquid extraction. Fluid connections
to 24 feedstocks each, thus allowing a wide variety of syntheses between adjacent units are achieved by vertically stacking them
to be performed. The reaction modules include different in the required order and a continuous stream of reagents is then
laminar flow reactors of different volumes (100 ml to 3 ml), packed passed through the sequence. The concept was demonstrated
bed reactors (1 to 2 ml) capable of operating at temperatures from synthesizing six different active pharmaceutical ingredients
ambient to 200 1C and pressures up to 250 psig, and a membrane (aspirin, secnidazole, lidocaine, diazepam, (S)-warfarin, and
Fig. 31 Auto-CAS 2 – radial syntheses: automated synthesis using a radial arrangement of equipment for the synthesis of organic molecules.50 From
Nature, 2020, 579, 379–384.
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safinamide) and two libraries of quinapril and celecoxib deriva- and reproducibility to generate reactive intermediates or per-
tives (Fig. 30). form selective transformations where and when they are needed
Such robotic systems have also been combined with software in a synthetic process. While this still allows for target oriented
for artificial intelligence-driven synthesis planning. This allows for synthesis, it also broadens our definition of target from a single
the automated proposal of synthetic routes through generalization molecule to a core functionality. In doing so, our processes
of millions of published chemical reactions, validation in silico, become more modular and their components more transfer-
then performing the synthesis on the automated platform. rable, ideally allowing for new processes to be developed more
Auto-CAS 2 (radial syntheses). The second approach uses a readily than we could previously. With the automation of these
non-linear arrangement of reactors in a concept called radial systems, we approach the point of true standardization within
synthesis, in which single transformations or multistep sequences the field, where desired transformations and syntheses can be
are performed as a sequential, not simultaneous series of reproducibly transferred between labs and literature while
operations. This radial paradigm decouples the subsequent human error and physical skill can be increasingly removed
steps, allowing for reactor reuse under different conditions from the chemical equation.
and residence times, thus making each synthetic step functionally
independent of any previous one.50
The system is composed of ten valves (three injection valves Conflicts of interest
and seven multi-position valves) that create different flow path-
ways through the instrument and the equally accessible reaction There are no conflicts to declare.
modules arranged radially in the central switching station (CSS).
A reagent pool stores up to 14 solvents, liquid reagents, homo-
genous solutions, or synthesized intermediates in pressurized Acknowledgements
vessels. Reagents and solvents are delivered by two syringe We gratefully acknowledge the Max Planck Society and the
pumps and allow for inline dilution. After each step, the reaction Deutsche Forschungsgemeinschaft (FOR 2177) for their financial
solution can be collected, cycled back through the system for the support. Open Access funding provided by the Max Planck Society.
next step, or delivered to reagent storage. This final path allows
for both convergent syntheses and multistep optimizations with-
out manual intervention (Fig. 31). References
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How to approach ﬂow chemistry

Article in Chemical Society Reviews · November 2020

Mara Guidi Kerry Gilmore

5 PUBLICATIONS 270 CITATIONS

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How to approach flow chemistry

Cite this: Chem. Soc. Rev., 2020,

Key learning points

Tutorial Review Chem Soc Rev

Prof. Peter H. Seeberger studied Dr Kerry Gilmore was born in

Chem Soc Rev Tutorial Review

for study, trapped in situ, or consumed in a subsequent module.

1.2 Telescoping 2. Know your flow

Tutorial Review Chem Soc Rev

Fig. 1 Breakdown of the basic components of a continuous flow system.

Chem Soc Rev Tutorial Review

Tutorial Review Chem Soc Rev

Chem Soc Rev Tutorial Review

Transformer 5 (reduction). An alternative approach to hydrogen

pre-packed catalyst columns open-up access to a wide range of

hydrogen-mediated reductions using this single transformer, for

Tutorial Review Chem Soc Rev

Chem Soc Rev Tutorial Review

Tutorial Review Chem Soc Rev

the ‘‘cation flow method’’ by the Yoshida group, generating

subsequent reactor. The module consists of two feeds containing

Chem Soc Rev Tutorial Review

Tutorial Review Chem Soc Rev

Chem Soc Rev Tutorial Review

Tutorial Review Chem Soc Rev

Chem Soc Rev Tutorial Review

Tutorial Review Chem Soc Rev

Chem Soc Rev Tutorial Review

Tutorial Review Chem Soc Rev

Chem Soc Rev Tutorial Review

Tutorial Review Chem Soc Rev

Chem Soc Rev Tutorial Review

Tutorial Review Chem Soc Rev

9 J. F. Greene, J. M. Hoover, D. S. Mannel, T. W. Root and 24 C. D. Smith, I. R. Baxendale, S. Lanners, J. J. Hayward,

Chem Soc Rev Tutorial Review

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