Chemical Science: Review

Chemical
Science
View Article Online
REVIEW View Journal | View Issue
A field guide to flow chemistry for synthetic organic

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
Cite this: Chem. Sci., 2023, 14, 4230

chemists†
Open Access Article. Published on 15 March 2023. Downloaded on 3/22/2024 10:27:53 AM.
Luca Capaldo, ‡ Zhenghui Wen ‡ and Timothy Noël *
Flow chemistry has unlocked a world of possibilities for the synthetic community, but the idea that it is
a mysterious “black box” needs to go. In this review, we show that several of the benefits of microreactor
Received 22nd February 2023
Accepted 15th March 2023
technology can be exploited to push the boundaries in organic synthesis and to unleash unique
reactivity and selectivity. By “lifting the veil” on some of the governing principles behind the observed
DOI: 10.1039/d3sc00992k
trends, we hope that this review will serve as a useful field guide for those interested in diving into flow
rsc.li/chemical-science chemistry.
scalability, and improved reproducibility.3,4 As a consequence,

1. Introduction ow chemistry allows for precise control over reaction condi-
Flow chemistry is a discipline in synthetic organic chemistry tions and enables real-time monitoring and analysis of reaction
that uses a continuous stream of different reagents, which are kinetics, resulting in high-quality products and streamlined
introduced by pumps and mixed in a continuous reactor, such processes. These benets have led to the increasing adoption of
as a plug ow reactor (PFR) or continuous-stirred tank reactor ow chemistry in academia and various industries for phar-
(CSTR).1,2 Compared to conventional batch processing which is maceuticals, ne chemicals, and materials science.5–8
oen carried out in round-bottom asks, it offers several While undoubtedly ow chemistry has numerous advan-
advantages such as enhanced mass and heat transfer, improved tages, it was received with the skepticism of the synthetic
safety, increased reaction efficiency, reduced waste, better community,9 therefore its implementation experienced an
induction period. This can be attributed to a lack of interdis-
ciplinary knowledge, perceived complexity, and high invest-
Flow Chemistry Group, Van ‘t Hoff Institute for Molecular Sciences (HIMS), University ment costs (see ESI†). Indeed, ow chemistry is an
of Amsterdam, 1098 XH Amsterdam, The Netherlands. E-mail: [email protected] interdisciplinary eld that requires knowledge from both
† Electronic supplementary information (ESI) available: See DOI:
chemistry and chemical engineering. However, some basic
https://doi.org/10.1039/d3sc00992k
understanding of these principles of ow chemistry should
‡ These authors contributed equally to this manuscript.
Luca Capaldo is a MSCA post- Zhenghui Wen was born in 1993

doctoral researcher in the Flow in Wenzhou, China and received
Chemistry Group at the Univer- his MSc in chemical engineering
sity of Amsterdam. Under the at the Dalian Institute of
guidance of Prof. Noël, he is Chemical Physics in 2017
developing novel synthetic (advisor: Prof. Guangwen Chen).
methodologies based on photo- Later on, he joined the ow
catalyzed hydrogen atom trans- chemistry group of Prof. T. Noël
fer in ow. He earned his and obtained his doctorate in
doctorate in Chemical and chemical engineering at the
Pharmaceutical Sciences from University of Amsterdam in
the University of Pavia in 2019 2022, working on green, scalable
(PI: Prof. M. Fagnoni), aer and automated photochemistry
a visiting period in the Yoon Group at the University of Wisconsin– in ow. Currently, he is working as a postdoctoral researcher in the
Madison. Before joining the Noël Research Group, Luca completed frame of the HORIZON network Photo2Fuel on developing an
a 2 years postdoctoral fellowship in Pavia (PI: Prof. D. Ravelli) automated continuous-ow platform and LSC-PM system.
where he studied photoelectrochemical approaches via photo-
catalyzed hydrogen atom transfer.
4230 | Chem. Sci., 2023, 14, 4230–4247 © 2023 The Author(s). Published by the Royal Society of Chemistry
View Article Online
Review Chemical Science
already allow one to begin setting up ow experiments. reaction mixture: the better the mass transfer, the more efficient
Furthermore, recent advancements in “Do It Yourself”-assem- the mixing.
bled ow setups,10–12 3D-printing technology,13 and cheap elec- This parameter is especially crucial in the case of multiphase
tronic toolkits14 have made technology more intuitive, reactions, e.g. gas–liquid reactions where one of the reagents
accessible and affordable. As a consequence, adoption of ow needs to migrate by diffusion from one phase to another.18
technology in synthetic organic chemistry has been growing in As an example, Noël and co-workers reported the photo-
recent years. With the rise of photo- and electrochemistry, ow catalytic Giese-type alkylation using gaseous light hydrocarbons
technology has become a popular and indispensable choice due (i.e., methane, ethane, propane, isobutane) via hydrogen atom
to its capability to handle the scalability challenges of these transfer photocatalysis in ow (Fig. 1).19 Hereto, the authors
synthetic modes. Flow chemistry is also favored for its ability in exploited the decatungstate anion (DT, W10O324−) as a versatile
safely and effectively conducting reactions with challenging or and inexpensive polyoxometalate-based hydrogen atom transfer
hazardous reagents, expanding the chemical frontiers. (HAT) photocatalyst:20 upon activation by UV-light irradiation,
Frequently, our lab gets asked to help young MSc and PhD this photocatalyst can cleave homolytically C(sp3)–H bonds to
students start using the technology.15,16 Although they may feel yield C-centered radicals which can be subsequently exploited
intimidated at rst, we oen see how quickly they grasp the for various synthetic purposes.21 While this chemistry is docu-
concepts and start reaping the benets of ow technology for mented to be efficient in the case of homogeneous solutions
their research. To further increase the adoption of ow chem- (i.e., single solution phase), the activation of gaseous alkanes is
istry in synthetic organic chemistry, this review seeks to provide more challenging due to their limited solubility in common
some basic guidelines for the use of continuous-ow reactors. organic solvents. The immediate consequence is that the tar-
The goal is to deliver a concise overview to help researchers gain geted chemistry is particularly slow due to poor gas-to-liquid
a basic understanding of the principles behind this technology, mass transfer limitations. The authors tackled this challenge
allowing them to get the most out of their experiments. We have by resorting to ow chemistry: by increasing the pressure in the
highlighted three relevant examples to clarify each fundamental reactor through use of simple back-pressure regulators, the
principle. Our aim is not to provide an exhaustive overview of gaseous alkanes could be forced into the liquid phase,
continuous-ow chemistry,17 but rather to offer simple and increasing the odds of C(sp3)–H bond activation of the gaseous
easy-to-follow guidelines for readers to determine if ow components. Thus, when a CD3CN : H2O (7 : 1) solution of olen
chemistry is relevant to their research. Consequently, our 1.1 was irradiated with UV light (365 nm, 150 W) in the presence
objective is to educate the broader synthetic community about of tetrabutylammonium decatungstate and methane (20 equiv.)
this innovative technology and demonstrate how and when it at a pressure of 45 bar, the corresponding methylated product
can make a difference. 1.2 was obtained in 42% yield aer 6 hours residence time.
Intriguingly, ow chemistry allowed to conduct the entire scope
2. Mass transfer (38 examples) at high pressure in a timely and scalable yet safe
fashion, which is by no means possible in conventional batch
The rst, and arguably most potent, advantage of ow chem- reactors. Very recently, the same authors extended this tech-
istry for synthetic organic chemists is the improved mass nology for the C(sp3)–H carbonylation with gaseous carbon
transfer. Mass transfer is dened as the net movement of one monoxide (CO), obtaining unsymmetrical ketones (41 exam-
species, e.g. one of the reactants, from one point to another ples) in good to excellent yields.22
within the reactor due to diffusion and/or convection. In other Another synthetic discipline that relies heavily on the
words, mass transfer denes the degree of mixing in the optimal mass transfer offered by microow technology is that of
Timothy Noël is a Full Professor

and Chair of Flow Chemistry at
the University of Amsterdam,
where he focuses on the delicate
synergy between synthetic
organic chemistry and tech-
nology. He has received several
awards for his research in ow
chemistry, including the
DECHEMA prize (2017), the
Hoogewerff Jongerenprijs (2019),
the IUPAC-ThalesNano prize
(2020), the KNCV Gold Medal
Fig. 1 Microflow technology improves gas–liquid mass transfer,
(2021), and the ACS Sustainable Chemistry & Engineering which can be exploited for the functionalization of gaseous light
Lectureship Award (2022). In addition, he serves as Editor-in-Chief hydrocarbons. TBADT: tetrabutylammonium decatungstate; BPR:
of the Journal of Flow Chemistry and is co-organizer of #RSCPoster. back-pressure regulator; MFC: mass-flow controller.
© 2023 The Author(s). Published by the Royal Society of Chemistry Chem. Sci., 2023, 14, 4230–4247 | 4231
View Article Online
Chemical Science Review
ash chemistry.23,24 Flash chemistry can be considered

a subdiscipline of ow chemistry, where extremely fast reac-
tions are conducted in a highly controlled manner to produce
the desired compounds with high selectivity. In 2016, Yoshida,
Kim and co-workers exploited this concept to outpace the very
rapid anionic Fries rearrangement for the chemoselective
functionalization of iodophenyl carbamates at the ortho posi-
tion (Fig. 2).25 Thus, when compound 2.1 is subjected to iodine/
lithium exchange, intermediate 2.2 is obtained; the latter
compound rapidly undergoes anionic Fries rearrangement at

room temperature to give 2.3. To outpace this rearrangement

and functionalize the ortho position of 2.2 with an electrophile,
the authors developed a chip microreactor with a 3D serpentine
microchannel design made of six layers of UV-laser-ablated
Fig. 3 Adoption of flow chemistry in an industrial setting allows to
uoroethylene propylene-polyimide lms. The chemically avoid undesired fast deprotonation in the synthesis of 3.3, an inter-
inert reactor is capable of withstanding high pressure and low mediate for the manufacturing of verubecestat (MK-8931). STM: static
reaction temperatures, while its volume is merely 25 nanoliters. tube mixer.
Such reduced internal volume enables exceedingly fast mixing
times (as low as 330 ms), which is crucial to quench 2.2 with
a suitable electrophile to yield 2.4 before its premature rear- the inefficient mixing: in fact, once anion 3.4− is formed, it
rangement. When prolonging the mixing time to the milli- tends to overreact by deprotonating 3.2 to give 3.5− (Fig. 3). This
second range, the selectivity was already reversed in favor of would eventually lead to disguised selectivity and diminished
product 2.3. The same technology was successfully used for the yields; which is typical for reactions where the mixing time is
synthesis of Afesal, a biologically active compound having longer than the reaction time.28,29 By switching to ow, and by
anthelmintic activity, with a productivity of 5.3 g h−1. Overall, incorporating different static mixing elements in their setup
ow chemistry allowed to steer reactivity favoring an intermo- (Koo Stratos™ mixers), the authors managed to steer the
lecular reaction over an intramolecular one, which is not selectivity towards the desired product (3.3, 5 g h−1 based on
possible in batch. assay yield) and outpace the fast deprotonation of the electro-
A third example where ow chemistry was adopted to tackle phile. A few years later, the researchers were able to scale the
an issue related to mass transfer was reported by scientists from process up to pilot-plant scale by relying on ow chemistry.30
Merck for the synthesis of verubecestat (MK-8931).26 This drug
was projected to be a breakthrough drug for Alzheimer's
disease. However, during late-stage trials, the compound turned 3. Heat transfer
out to be not benecial and displayed increased adverse
effects.27 In their original synthetic approach, the crucial inter- The high area-to-volume ratio of microchannels makes heat
mediate 3.3 was prepared in batch by reacting the organo- transfer much more efficient than in conventional reactors,
lithium derived from compound 3.1 with sulnamide 3.2 under such as round-bottom asks. With a large heat exchange
cryogenic conditions (#60 °C) with moderate assay yield (73%). surface, hot spots can be prevented and the dangers of thermal
According to the authors, the reason for this modest result was runaways mitigated.31–33 The main benets of efficient heat
transfer in ow chemistry for organic synthesis are the ability to
operate under isothermal conditions and to operate under
superheated conditions.
The nearly isothermal behaviour of microreactors allows
chemists to precisely control the temperature of the reaction,
resulting in improved chemical selectivity and safer handling of
exothermic reactions, such as nitration,34,35 halogenation,36,37
and organometallic-based reactions.38,39 For example, Noël and
co-workers reported a safe and scalable synthesis of diary-
liodonium triates under ow conditions (Fig. 4).40 Diary-
liodonium salts have been widely used as aryl electrophile
sources in many arylation reactions;41 however, the reaction is
highly exothermic, which poses a signicant safety risk when
carried out on a large scale. By adopting ow conditions, such
exothermic reactions can be performed safely due to the effi-
Fig. 2 Ultra-fast mixing provided by flow technology allows to out-
cient heat exchange. In this way, with residence times varying
pace undesired anionic Fries rearrangement in the functionalization of from 2 to 60 seconds and room temperature conditions, the
iodophenyl carbamates at the ortho position. tR: residence time. authors obtained different diaryliodonium salts (44 examples)
View Article Online

Fig. 4 Use of flow technology for the handling of the exothermic

synthesis of diaryliodonium triflates. m-CPBA: meta-chloroperox-
ybenzoic acid. Fig. 6 Schematic representation of a 5-stage multi-step flow
synthesis of a rufinamide precursor under superheated conditions.
ETFE: ethylene tetrafluoroethylene.
on a gram scale from a wide range of electron-rich and electron-
decient arenes.
Similarly, Alcazar et al. reported the direct preparation of using a simple back pressure regulator (BPR). For example,
Grignard reagents at 40 °C using a magnesium-packed-bed runamide, an important antiseizure medication, has been
reactor in ow, which greatly expanded the application of this extensively reported in patents and literature and its synthesis
powerful methodology.42 The synthesis of Grignard reagents benets from this superheating effect.33 The formation of
typically requires low temperatures (<0 °C) to avoid the dangers a 1,2,3-triazole precursor 6.5 through a 1,3-dipolar Huisgen
of thermal runaways, but this type of synthesis can be easily cycloaddition of 2,6-diuorobenzylazide 6.3 with an appropriate
achieved at room temperature in ow conditions. In addition, dipolarophile is a key step in the synthesis of runamide. Mudd
with the use of a magnesium-packed-bed ow reactor, freshly and Stevens utilized a nontoxic and inexpensive (E)-methyl 3-
made solutions of Grignard reagents can be generated and methoxyacrylate 6.4 as a dipolarophile, obtaining the desired
immediately consumed in a subsequent transformation. As an 1,4-cycloadduct.44 However, this method requires 28 hours of
example of this feature, Noël and co-workers developed a tele- reaction time to achieve full conversion at 135 °C and under
scoped Fe-catalyzed C(sp)–C(sp3) cross-coupling trans- solvent-free conditions, which poses a safety concern about
formation, resulting in higher yield and selectivity in ow runaway decomposition with gas formation and concomitant
(Fig. 5).43 pressure build-up during batch processing. Noël and Hessel
Another benet of the enhanced heat transfer in ow reac- presented an intensied method with 210 °C and 69 bar reac-
tors is the ability to handle superheated reactions at increased tion conditions, signicantly boosting the reaction rate and
pressure, i.e. the increase of the reaction temperature above the obtaining the targeted 1,2,3-triazole precursor 6.5 in only 10
atmospheric boiling temperature of the solvent. Many reactions minutes of residence time.45 Furthermore, a 5-stage 3-step
are still slow even under reux conditions, but the reaction rate continuous synthesis with integrated separation steps delivered
can be further boosted under such superheated conditions a total yield of 82% and productivity of 9 g h−1 of runamide
precursor. The process minimizes the isolation and handling of
energetic intermediates while minimizing water and organic
solvent consumption (Fig. 6).46
4. Multi-step synthesis
The possibility to streamline several transformations in
a “single, continuous and uninterrupted reactor network”47 is
a riveting opportunity offered by ow chemistry. In fact, multi-
step syntheses in batch are tedious, time-consuming and labor-
intensive undertakings. For example, the product of one step
must oen be puried before the subsequent one can be
executed. In contrast, organic chemists can use a one-ow,
multi-step synthesis approach to expedite their synthetic
Fig. 5 Combining Grignard reagent synthesis with iron-catalyzed
routes. However, to be successful, some major challenges have
cross-coupling reaction in a telescoped flow process for C(sp)–C(sp3) to be tackled, such as solvent compatibilities and byproduct
bond formation. formation, requiring oen inline purication strategies.
View Article Online
Jamison and co-workers reported the continuous-ow pharmaceuticals: notably, the corresponding batch synthesis
synthesis of the antibiotic linezolid by combining seven required more than 60 hours.
consecutive steps without purication of any intermediate Interestingly, the concept of multi-step ow synthesis is also
(Fig. 7A).48 Notably, all of the steps are compatible with each receiving a great deal of attention from the pharmaceutical
other, requiring neither solvent exchanges nor intermediate industry.49 Continuous manufacturing has tremendous advan-
work-ups. The entire process involves a convergent synthesis tages over batch manufacturing in terms of improved perfor-
based on three modules. In the rst module, (+)-epichlorohy- mance and safety, together with decreased capital expenditures.
drine 7.1 was reacted with boron triuoride etherate as a stoi- This is even more true when the concept of small-volume
chiometric Lewis acid in the presence of acetonitrile to obtain continuous manufacturing (SVCM) is adopted. In such
the corresponding Ritter product; next, epoxide formation was a scenario, small-size equipment that ts a exible environ-
achieved under basic conditions to get 7.2. Second, in parallel ment, such as a standard laboratory fumehood, is operated in
with the rst module, aniline 7.4 was obtained from nitroarene a continuous fashion to reach productivities of several kg per
7.3 via SNAr with morpholine and subsequent heterogeneous day. For example, scientists at Eli Lilly reported the synthesis of
hydrogenation with a palladium packed-bed reactor. In the prexasertib monolactate monohydrate, a checkpoint kinase 1
third module, the streams containing 7.2 and 7.4 were inhibitor, on a kilogram scale by taking advantage of the SVCM
combined to afford linezolid (7.6) aer reaction with N,N-car- concept (Fig. 7B).50 Starting from compound 7.7, pyrazole 7.8
bonyldiimidazole (7.5). Overall, linezolid was synthesized in was prepared by reaction with hazardous NH2NH2: unlike
73% yield with a total residence time of 27 minutes, corre- batch, the ow approach required only a slight excess of
sponding to a productivity of 816 mg h−1. This protocol show- hydrazine and allowed to minimize exposure to the operators.
cases how a careful tuning of the reaction conditions and the Aer a solvent exchange in an automated 20 L rotary evaporator,
ow parameters allows to accelerate the synthesis of a SNAr reaction was conducted with pyrazine 7.9 to afford
Fig. 7 Application of flow chemistry for multi-step synthesis. PAT: process analytical technology. TFAA: trifluoroacetic anhydride.
View Article Online
compound 7.10, which was puried via a continuous crystalli-

zation using two mixed-suspensions, mixed-product removal
vessels. In addition to being time-efficient, this custom puri-
cation solution eliminated the potential for operator exposure
to 7.10 (for which the occupational exposure limit is 1 mg m−3).
Finally, aer Boc-deprotection and formation of the lactate salt,
prexasertib monolactate monohydrate (7.11) was obtained.
Overall, the researchers were able to produce 24 kg of the drug
for use in human clinical trials. It is very important to stress that
an extensive use of process analytical technologies (PATs) was

implemented in the continuous-ow process allowing for

informed process adjustments to ensure high end-product
quality.
As a nal example, Ley and colleagues reported the multi-
step synthesis of the alkaloid oxomaritidine (7.15) by exploit- Fig. 8 Flow technology-enabled high throughput for the formal
ing the concept of immobilized reagents, scavengers and catch/ photocatalytic amination of C(sp3)–H bonds.
release techniques (Fig. 7C).51,52 Using this strategy,53 the
authors managed to develop an automated ow sequence to
yield oxomaritidine in less than a day. First, compound 7.12 was capitalized on the hydroalkylation of azadicarboxylates to
converted into the corresponding azide by exploiting an azide deliver Boc-protected hydrazides in ow.61 The custom-made
exchange resin; the exiting stream was directed over a second photochemical reactor consists of a peruoroalkoxy capillary
column containing a polymer-supported phosphine. The aza- reactor (PFA, 750 mm ID, 5 mL volume) cooled by a fan, which is
Wittig intermediate was formed and retained on the resin in irradiated with six dimmable high-intensity UV-A chip-on-board
the column. In parallel, benzyl alcohol 7.13 was oxidized to the LEDs, providing a maximum of 144 W optical power. When
aldehyde by adopting a pre-packed column of tetramethy- a CH3CN/HCl0.1M 7 : 1 solution containing 8.1 and 8.2 was
lammonium perruthenate and the stream was subsequently irradiated (l = 365 nm, 144 W) in the presence of TBADT
passed through the column containing the aza-Wittig inter- (0.2 mol%), compound 8.3 was isolated in 73% yield (corre-
mediate to form the targeted imine. The latter compound was sponding to 12 mmol h−1). With this new powerful technology
then reduced and, aer a manual solvent switch, the secondary in hand, the authors pushed the productivity of 8.3 up to 2.15 kg
amine was triuoroacetylated. In a nal sequence, oxidative per day by simply adjusting ow rates and the capillary length.
phenolic coupling, N-deprotection and spontaneous cyclization In addition, telescoped approaches were developed for the
afforded the targeted oxomaritidine. Interestingly, the use of synthesis of pyrazoles (8.4) and phthalazinones (8.5). Overall,
immobilized reagents reduces the overall number of pumps the ow approach allowed to improve the efficiency of the
needed for the platform, cutting the costs of the entire ow reaction compared to batch alternatives, enabling both small
approach. However, one potential drawback of this strategy is scale (1 mmol) and pilot scale (>1 kg) operation in a single
that the productivity of the entire process is dependent on, and photochemical microreactor.
limited by, the amounts of immobilized reagents loaded in the Another recent example involves the modular allylation of
packed-bed cartridges. unactivated C(sp3)–H bonds via a telescoped approach in ow
(Fig. 9).62 Hereto, the authors merged decatungstate photo-
catalysis with classical Horner–Wadsworth–Emmons (HWE)
5. Photochemistry
Continuous-ow technology is oen coupled with photochem-
istry and photocatalysis in synthetic campaigns, making it
arguably the most popular application of ow chemistry.54–59
Light absorption is governed by the Beer–Lambert law, leading
to a rapid decline of the light intensity when travelling through
a reaction mixture that contains photon-absorbing molecules.
Consequently, the center of the reactor receives almost no light,
creating a “dark zone” where there is no reaction occurring. By
exploiting microreactor technology, the entire reaction mixture
experiences the same light intensity, leading to reduced reac-
tion times, less deleterious side-product formation and high
productivities.56,58
Noël and co-workers reported on the use of ow chemistry to
develop a scalable and accelerated protocol for the formal
amination of C(sp3)–H bonds via decatungstate-photocatalyzed Fig. 9 Use of flow chemistry to devise a flexible approach for the
HAT (Fig. 8).60 To realize the C–N bond formation, the authors installation of allyl moieties at strong aliphatic C(sp3)–H bonds.
View Article Online
olenation chemistry, exploiting the intrinsic modularity of gradually in three steps using ow technology. In the rst step,
ow chemistry, to append hydroalkanes with an allyl functional 3.5 kg of 10.1 was converted to 10.3 in 88 LCAP and 94% assay
group. First, an acetonitrile solution of acrylate 9.2, benzo- yield with a residence time of 3.75 minutes; in the second step,
dioxole (9.1) and decatungstate as the photocatalyst was injec- 50 kg of 10.1 was converted to 10.3 in 91 LCAP and 93% assay
ted into a Vapourtec UV-150 photochemical reactor (tR = 5 min) yield with a residence time of 1.5 minutes. Finally, the
equipped with a 60 W UV-A LED light source (l = 365 nm) to researchers adopted a numbering-up approach to deliver more
deliver the corresponding Giese adduct. In contrast, when the than 100 kg per day (91 LCAP and 94% assay yield) of the
same reaction was conducted in batch, full conversion was product. In this case, the synthetic advantage offered by ow
reached only aer 20 hours. Second, the stream containing the chemistry is the improved chemoselectivity because it enabled
Giese adduct was subsequently merged with a stream contain- a precise control over reaction time, which prevented undesired
ing LiOtBu and paraformaldehyde to perform a HWE olena- reactions such as overbromination of 10.1.
tion. By doing so, the allylated product 9.3 was isolated in an
overall 70% yield, requiring no intermediate purication. The
developed two-step ow process could be subsequently 6. Electrochemistry
extended to a wide variety of aliphatic and aromatic aldehydes,
Another eld that has beneted signicantly from the adoption
as well as deuterated paraformaldehyde, to prepare various
of microuidic technologies is electrochemistry.67–71 Electro-
highly functionalized allylated compounds. These moieties are
chemical reactions are by denition heterogeneous processes,
difficult to prepare via conventional radical allylation
as they rely on a redox event between an electrode surface and
approaches.63,64
a molecule in solution. Accordingly, mass transfer from the
As a nal example, scientists at Merck have reported a scal-
bulk to the electrode surface becomes a very important
able continuous-ow photochemical process for the bromina-
consideration. However, using microuidic setups, the impact
tion of intermediate 10.1, which is required to produce
of poor mass transfer can be minimized due to the larger
belzutifan (Fig. 10), a drug for the treatment of renal cell
surface-to-volume ratio. Notably, the small interelectrode
carcinoma.65,66 In the traditional synthetic route, the radical
distances in microreactors reduces the observed ohmic voltage
benzylic bromination was achieved through the use of azobisi-
drop, enabling a net reduction of the amount of supporting
sobutyronitrile (AIBN) as initiator and reagent 10.2 as the
electrolyte needed in the reaction mixture.
bromine source. Under these reaction conditions, 10.1 is rela-
A collaborative effort between Buchwald, Jensen et al.
tively unstable and undergoes sudden di-bromination and de-
resulted in the development of a mRN-eChem (microuidic
ketalization. By replacing AIBN with blue light, the authors
redox-neutral electrochemical) cell to perform redox-neutral
found that the reaction could be conveniently stopped to get the
transformations (Fig. 11).72 Although these transformations
product in 91% LCAP (Liquid Chromatography Area Percent) in
could in principle be run under photoredox catalytic conditions,
batch in only 3 minutes. The scale up of the process occurred
the use of photocatalysts might bring around some inconve-
niences, such as the challenging tuning of redox potentials, the
use of expensive transition metals and the instability of pho-
tocatalysts under operating conditions. The ow cell consists of
two laser-micromachined glassy carbon electrodes separated by
Fig. 10 Adoption of flow chemistry in an industrial setting to improve Fig. 11 Microfluidic electrochemical cells with short inter-electrode
chemoselectivity and facilitate scalability in the synthesis of 10.3, an gaps enable redox-neutral transformations in the absence of sup-
intermediate en route to belzutifan. porting electrolytes. GC: glassy carbon.
View Article Online
a FEP gasket with a reduced thickness (25 mm). Due to the short (e.g., Pt) on a relatively small scale (gram scale). However, the
inter-electrode distance, it is possible to reduce the time authors managed to translate the reaction to ow on a 120 g
required for interelectrode migration (as governed by the scale by using cheap electrodes: a graphite anode and two
following equation: t = d2/D; d: interelectrode distance, D: stainless steel cathodes, connected in a monopolar fashion. Full
molecular diffusivity) signicantly, so that it is shorter than the electrolysis was reached in 10 hours under galvanostatic
lifetime of open-shell intermediates generated upon electrol- conditions at 2.5 A, delivering ca. 100 g of 12.2 (85% yield aer
ysis, which paves the way to efficient redox-neutral manifolds. isolation), which corresponds to a productivity of 10.1 g h−1. In
For example, the authors coupled Kolbe electrolysis with arene comparison, when the reaction was run in batch on a 5 g-scale,
reduction to develop a decarboxylative arylation by capitalizing a productivity of 0.75 g h−1 was achieved. Finally, compound
on the persistent radical effect.73 Thus, arene 11.2 is reduced at 12.2 was converted to 12.3 via reduction by Red-Al and esteri-
the cathode generating a persistent radical anion 11.2c−; the cation. Overall, ow chemistry enabled in this specic case
latter radical intermediate migrates towards the anode, where a straightforward and safe scale up of a value-added interme-
Kolbe electrolysis yields transient alkyl radicals. Subsequent diate (12.2), which should facilitate the development of a safe
radical–radical anion coupling occurs to afford the arylated industrial process of 12.3.
product 11.3 aer decyanation. Intriguingly, the small inter- Flow electrochemistry is also extremely appealing to the
electrode gap also reduces the ohmic drop, thus eliminating chemical industry due to the ability to use “green” electricity
the need for additional supporting electrolyte. A similar derived from solar and wind energy. Furthermore, the reduced
approach could be used for different alkyl radical progenitors inter-electrode gap introduces a series of advantages that cut
(e.g., arylamines or triuoroborate salts). the costs of conducting electrochemical reactions. Indeed,
Baran and co-workers used a ow electrochemical approach voltages needed to promote reactivity are generally lower (due to
to synthesize compound 12.2, an intermediate for the synthesis a reduced overpotential), which also allows to reduce the
of cyclobutane-containing tetranitric esters (Fig. 12).74 One of amount of expensive supporting electrolyte and thus facilitates
these compounds, namely cyclobutane-1,1,2,2- the purication processes. Flow electrochemistry is also safer
tetrayltetrakis(methylene) tetranitrate (12.3), proved to be compared to batch because it enables a tighter heat manage-
valuable as a potential melt-castable energetic. As the original ment control, avoiding thermal runaways,31 and due to its
route for the synthesis of 12.2 posed several concerns in terms continuous nature, it also prevents occurrence of dead zones
of safety and expenses,75 the authors were eager to nd a more (i.e., regions in a reactor where the reaction mixture is
practical alternative. Compound 12.1 was synthesized starting stagnant).
from Meldrum's acid followed by acidic hydrolysis; next, elec- Very recently, scientists at Merck developed a scalable ow
trolytic conditions were adopted to promote cyclization to give process for the selective anodic oxidation of thioethers.76 In this
compound 12.2. In the original route, the latter step was con- process, thioether (13.1) was oxidized to the corresponding
ducted in batch and required the use of expensive electrodes sulfone (13.2) (Fig. 13). Compound 13.1 is a fragment of a drug
candidate but its chemical oxidation with classical oxidants
(e.g., oxone, m-CPBA, periodate or tungstate) led to a complex
Fig. 12 Flow electrochemistry facilitates the safe scale-up of Fig. 13 Adoption of flow electrochemistry in an industrial context for
a promising melt-castable energetic intermediate. C: graphite elec- the highly scalable, selective anodic oxidation of thioether 13.1. trecirc:
trode; S. S: stainless steel electrode. time of recirculation.
View Article Online
mixture of the corresponding sulfoxide and sulfone. Aer ideal mixing between the oxygen and the liquid solution.
a brief reaction optimization in batch, the authors successfully Within 90 minutes of residence time and 5 mol% TBADT
translated their protocol into ow by exploiting a recirculating loading, the authors demonstrated that artemisinin (14.1) could
mode operation. It was possible to gradually scale the process be converted to its natural derivative artemisitone-9 in 59%
from gram-to kilogram-scale by systematically increasing the yield (14.2, 5 mmol scale) with this methodology. Furthermore,
electrode surface area, whilst keeping the current density and most of the activated and unactivated aliphatic bonds (30
electron equivalents constant. Ultimately, it was possible to examples) such as (−)-ambroxide 14.3, pregnenolone acetate
prepare 1.11 kg of 13.2 using 1600 cm2 electrodes and applying 14.4, eucalyptol 14.5 and (+)-sclareolide 14.6, could be selec-
a current density of 30 mA cm−2, a current of 48 A, 4.5 F mol−1, tively oxidized in moderate to excellent yield (43–91%).
for ca. 19 h of processing time, thus meeting the criteria for pilot In addition to safely handling toxic reagents in ow, micro-
production (1.21 kg per day). reactor technology allows for the generation and utilization of
sensitive reaction intermediates without the need to store
hazardous quantities of materials. For example, dinitrogen
7. Safety trioxide (N2O3) is a powerful nitrosating reagent with an
In addition to fast heat and mass transfer of microreactor appealing atom economy, but it is only stable under cryogenic
technology, the overall safety of the process is greatly improved conditions and in a NO atmosphere. Furthermore, nitrosation
due to the small reactor volumes and precise control of reaction with pure N2O3 is fast and highly exothermic, which limits its
conditions.32,77,78 Hazardous reactions or even reactions that are use both in laboratories and industry. Recently, Monbaliu et al.
impossible in conventional conditions can be carried out with developed a continuous-ow methodology for the synthesis and
relatively low risk in ow conditions, such as processes use of anhydrous N2O3 solution, minimizing the safety
involving toxic, reactive gases and explosive reagents. concerns associated with this toxic gas and exothermic reac-
It is understandable that the use of toxic and dangerous tions (Fig. 15).83 The anhydrous N2O3 solution (up to 1 M) was
gases is highly restricted in modern synthetic laboratories. In generated in a ow setup using NO and O2 streams as starting
order to perform gas-based transformations and achieve decent materials. A telescoped method was then developed to synthe-
results, dedicated high-pressure gas reactors with multiple size two types of N-heterocycles (i.e., benzotriazoles 15.1 and 3-
detectors are required. This is why the direct use of molecular substituted sydnones, >30 examples) in moderate to excellent
oxygen79,80 as a simple, green oxidant is discouraged in yield (54–99%).
conventional batch systems. However, Noël et al. developed Diazonium salts, which are typically unstable and generate
a simple, selective, and safe decatungstate-photocatalytic large volumes of nitrogen gas during synthetic transformations,
aerobic oxidation of C(sp3)–H bonds under ow conditions can be problematic to scale up in batch systems and raise many
(Fig. 14).81 The oxygen stream was delivered by a mass ow safety concerns. Chemists at Novartis have reported a scalable
controller (MFC) and merged with the liquid stream infused by and multi-step continuous-ow procedure for synthesizing 2H-
a syringe pump, delivering a uniform segmented ow regime in indazoles in which hazardous diazonium salt and azide
the continuous-ow photoreactor (PFA tubing, 750 mm I.D.). A
typical interfacial area from 3400 to 9000 m2 m−3 could be ob-
tained through Taylor recirculation patterns,82 leading to an
Fig. 14 Decatungstate-mediated C(sp3)–H oxidation with oxygen in Fig. 15 Continuous-flow setup for the generation of N2O3 and its
continuous flow. TBADT: Tetra-n-butylammonium decatungstate. subsequent use in synthetically-relevant contexts. CV: check valve;
Reproduced from ref. 81 with the permission of Wiley-VCH, copyright 6PV: six-position switch valve. MFC: Mass-Flow Controller. Repro-
2018. duced from ref. 83 with the permission of Wiley-VCH, copyright 2022.
View Article Online
Remdesivir, the rst COVID-19 drug approved by the U.S.

FDA, has been highly sought aer due to the rapid spread of the
COVID-19 pandemic. The synthetic pathway towards Remdesi-
vir starts with the C-glycosylation of the halogenated pyrrolo-
triazinamine 17.1 with benzyl-protected D-ribonolactone 17.2 to
obtain the key intermediate 17.3, which was identied as an
obstacle for large-scale production.88,89 The reported organo-
metallic step using organolithium reagents generally requires
long addition periods and cryogenic temperatures due to their
fast and exothermic characteristic, while beneting the most

from the enhanced mass and heat transfer of the ow system.
Kappe et al. reported a ve-step continuous ow process, facil-
itating this highly exothermic C-glycosylation (Fig. 17A).90
Before translating the reported reaction conditions to ow, they
Fig. 16 Continuous flow synthesis of indazole 16.5, involving a three-
repeated the reaction in batch to rule out the potential issues,
step synthetic sequence containing diazonium salts and azide
generation. TFA: trifluoroacetic acid. such as the formation of solids directly aer the addition of 1,2-
bis(chlorodimethylsilyl)ethane (BCDSE) in the rst step. The
precipitation was assumed to be the protonated by-product of
chemistries are safely handled on a 200 gram scale (Fig. 16).84 heterocycle 17.1 and its formation would lead to microreactor
The key intermediate, 2H-indazole 16.5, is used to synthesize clogging. The solid was indeed observed within approximately
compound 16.6, a highly potent and selective inhibitor for the 5 s at ambient temperature, leaving only a narrow window to
treatment of autoimmune disorders. The researchers initiated add a base for scavenging HCl. Such a short residence time can
the synthetic route with amino-aldehyde 16.1 and applied be easily achieved in ow. Through a careful analysis of the
a diazotization and azidation protocol using sodium nitrite with reaction sequence and precise control of the process parame-
triuoroacetic acid followed by a reaction with sodium azide at ters, the authors achieved a 60% yield of glycosylated product
17.3 at a moderate temperature (−30 °C) in a total residence
a lower temperature to obtain azide 16.3. Instead of isolating
the latter compound, the researchers obtained a 0.3 M solution time of only 8 s. A stable and scalable process was further
of azide in dichloroethane (91% yield and 14.1 g h−1 produc- demonstrated for 2 h (Fig. 17B), providing a throughput of 8.5 g
tivity). Aer further concentrating the azide solution to 0.45 M, h−1 (10.4 kg L−1 h−1 space-time yield) within a small reactor
a cyclization reaction was conducted with amine 16.4 through volume of only 0.815 mL. These results present the potential to
two 10 mL copper coils to afford 217 g of indazole 16.5 in 94% reach even higher production of the key glycosylated interme-
purity and 95% yield (86% total yield). 16.5 was then used diate 17.3 and remdesivir exploiting the general scale-up strat-
without additional purication in the subsequent steps to egies in ow, such as numbering up.
Numbering up is a common strategy in the scale-up of ow
obtain the target compound 16.6 in high quality and acceptable
yield. Notably, the continuous-ow procedures were suitable for chemistry because it enables the retention of the hydrodynamics
scale up with only minor modications, affording 16.5 on and transfer properties associated with the micro-environment
a kilogram scale. (e.g., mixing, heat transfer, irradiation efficiency). This allows
reactions to occur under conditions that are identical to those in
an individual microreactor. Kim and co-workers presented a scale-
8. Scalability up process of ultrafast sub-second chemistry to synthesize drug
scaffolds via 16 numbered-up printed metal microreactors (16N-
The use of ow chemistry in large-scale production has several
PMR).91 As previously mentioned, reactions with organolithium
advantages over traditional batch chemistry, among which an
reagents are fast and highly exothermic. To precisely control the
easier adaptation of laboratory-scale reactions to larger
lithiated intermediates, an optimal residence time of around 16
production scales without sacricing reaction performance.85,86
ms with a ow rate of 7.5 mL min−1 was used, which created
Two approaches can be followed for scaling up ow chemistry
a signicant pressure drop in the microreactor. To address this
reactions: numbering up and sizing up.54,87 Numbering up
issue, the authors developed a modied microreactor with a larger
involves increasing the number of channels in the microreactor,
circular channel diameter, reducing the pressure drop by 28 times
while sizing up involves increasing the length and/or diameter
under the same ow conditions (Fig. 18A). Aer simulating the
of the channels. These strategies can be described mathemati-
maldistribution factor of the internal bifurcation distributor
cally by the equation of the volume of the microreactor, where V,
(<1%), a monolithic 4N-PMR with a validated structure was
N, L, and D represent the volume of the reactor, the number of
fabricated, which was further demonstrated with ultrafast chem-
channels, the length of the channels, and the diameter of the
istry, giving yields of 84–99% of 12 products. To further scale up
channels, respectively.87
this type of chemistry, a 16N-PMR was assembled by connecting
p four 4N-PMRs and four external ow distributors with 1/8-inch
V¼ NLD2
4 tubes (Fig. 18B). The 16N-PMR module exhibited a high output
View Article Online

Fig. 17 Continuous-flow process to generate remdesivir intermediates. LDA: lithium diisopropylamide. Reproduced from ref. 90 with the
permission of American Chemical Society, copyright 2021.
rotating disk reactors,92–94 oscillatory ow reactors,95–97 thin-lm

rotating reactors,98 CSTR99,100 and ultrasonic reactors.101,102 To
demonstrate the advantages of such ow chemistry technology,
Van der Schaaf and Noël et al. reported a high-throughput
photochemical rotor-stator spinning disk reactor (pRS-SDR) to
enhance the gas–liquid mass transfer and perform a large-scale
gas–liquid photooxygenation of a-terpinene (19.1).93 A previous
report103,104 and some preliminary experiments in batch and
ow (which increased selectivity from 50% to 70%) indicated
Fig. 18 Scale-up strategy for an ultrafast sub-second flash chemistry

exploiting aryllithium intermediates using numbered-up 3D-printed
microreactors. Reproduced from ref. 91 with the permission of
American Chemical Society, copyright 2022.
efficiency of 1–2 g min−1 (approximately 3 kg per day) of three drug

scaffolds 18.1b–18.3b.
Besides passive microreactors (which exploit the ow energy
delivered by the pumps to induce mixing), active microreactors
Fig. 19 Scale up of the [4 + 2] cycloaddition between terpinene and
that utilize external energy are also commonly employed,
photochemically generated singlet oxygen using rotor-stator spinning
particularly for scaling heterogeneous chemistry up. Multiple disk reactor technology. Reproduced from ref. 93 with the permission
types of active continuous reactors have been reported, such as of Elsevier, copyright 2020.
View Article Online
that better light irradiation and mass transfer were critical to

this transformation, which suffers from deleterious side reac-
tions due to overoxidation and triplet oxygen-enabled oxida-
tions. Furthermore, scaling up gas–liquid oxidation chemistry
in batch systems is challenging due to poor gas dispersion and
the potential for hazardous situations related to the oxygen-rich
environment in the headspace. The developed pRS-SDR enables
efficient dispersion and rapid mixing of the gas–liquid phases
by the fast-rotating disk between two stators positioned at
a short distance (1–2 mm) (Fig. 19A), resulting in an enhanced

mass transfer rate,105 which is benecial for gas–liquid trans-

formations. The reaction solution was irradiated from a quartz
window by a 120 W white LED light source, affording an illu-
minated volume of 27 mL. Aer investigating all the reaction
parameters, such as gas/liquid ratio and rotational speed,
a productivity of 1.1 kg per day of ascaridole 19.2 (87% yield and
90% selectivity) was reached with a residence time of only 27 s,
which convincingly proved that the enhanced mass transfer
rates obtained in the pRS-SDR are crucial to achieving excellent
multiphase transformations. Fig. 21 Development of a droplet-based flow-HTE platform to
prepare API libraries in a time- and resource-efficient fashion.
Reproduced from ref. 121 with the permission of Springer Nature,
9. High-throughput experimentation copyright 2020.
and automation
By integrating high-throughput experimentation (HTE)106–109 allowing to produce a large dataset of 5760 reactions at a rate of
with process analytical technology (PAT),110–113 optimization of over 1500 samples per day.120
continuous-ow reactions can be done efficiently and with Stephenson and colleagues also developed a droplet-based
a wealth of data (Fig. 20). This integration results in fast data microuidic platform for ow-based HTE to generate pharma-
acquisition, closed-loop experimentation,114,115 and improved ceutically relevant compound libraries (Fig. 21).121 The platform
discovery and reproducibility of organic synthesis in ow, utilized an oscillatory ow photoreactor and electrospray
leading to data-driven or algorithm-driven autonomous ionization-mass spectrometry (ESI-MS) to analyse the reactions.
experimentation.116,117 With a throughput of 0.3 samples per second, ESI-MS detected
Batch-based HTE106,108,109,118,119 suffers from some limitations, 37 hit conditions, and seven of nine selected reactions were
such as a lack of pressure and temperature screening, the need successfully validated through product isolation. This droplet-
for non-volatile solvents, and the potential for cross- based method can quickly discover photochemical reactions
contamination. In contrast, Pzer researchers showed that and generate compound libraries in ow (e.g., 21.1–21.3).
ow-based HTE with two LC/MS instruments could be effec- More researchers have been exploring automated telescoped
tively handled to screen thousands of Pd-catalyzed Suzuki– multistep ow synthesis,111,122–128 with a common approach
Miyaura couplings under high pressure and temperature being to combine modular unit devices in a linear sequence,
conditions, by simply adding a back pressure regulator, known as “Lego-like synthesis”.122,129 The integration of process
Fig. 20 General configuration of an automated and modular continuous-flow platform.
View Article Online
analytical technology (PAT) tools and advanced data analysis industry as a way to explore high-dimensional chemical space
models can further improve reaction understanding and and achieve optimal conditions with fewer experiments.107,130–136
acceleration of the optimization rate.111 There have also been There are three main types of algorithms applied for self-
reports of unique approaches, such as a radical synthesizer with optimization experimentation: local optimization algorithms
a central hub and access to individual reactors, enabling the such as design of experiments (DoE)137,138 and Nelder–Mead
storage of chemical intermediates and removing limitations simplex,139,140 global optimization algorithms like SNOBFIT141,142
from previous steps.128 Using this strategy, several analogues of and Bayesian Optimizations,114,130,143–145 and machine learning
runamide were prepared without the need for physical algorithms like deep reinforcement learning.146
reconguration of the system. Jensen et al. are pioneers in this growing eld, having
Another approach combines solid-phase synthesis and developed various versions of automated continuous-ow plat-
continuous-ow chemistry to perform automated multistep forms, including a fridge-size recongurable platform,147
synthesis of active pharmaceutical ingredients (APIs) a ‘plug-and-play’ platform,142 and a robotic platform.148 Their
(Fig. 22)124. In this method, starting materials are covalently most recent development is a bayesian optimization-driven
attached to a solid support and undergo growth through automated robotic ow platform that includes computer-
sequential treatment with different reagents, avoiding inter- aided synthesis planning (CASP),149 multi-objective optimiza-
mediate isolation and compatibility issues. A compact system tion and robotic-enhanced multistep synthesis (Fig. 23).150 To
design, including multi-position selection valves, pumps, and demonstrate the power of this platform, the authors selected
a stainless-steel column reactor, was able to perform a six-step a high-ranked synthetic pathway for the molecule sonidegib
synthesis of prexasertib with a 65% isolated yield in 32 hours 23.4 using open-source CASP soware (ASKCOS) and manual
of continuous execution. The procedures were converted to assessment of synthetic feasibility. This pathway was then
a computerized chemical recipe le (CRF) and successfully used optimized on a modular platform that included a fast-moving 4-
for the synthesis of 23 prexasertib analogues with moderate to axis gantry robot, two types of reactors (heated and packed bed),
good yields (e.g., 22.1–22.6, 49–70%). and three analytical modules (inline FT-IR, LC-MS, HPLC). Five
Besides the use of human intervention to rene the auto- optimization variables (two categorical parameters, i.e. activa-
mated continuous-ow platforms, algorithm-driven optimization reagent and coupling reactor volume, and three continuous
tion has gained signicant attention in both academia and parameters, i.e. activation time, 23.1 : 23.3 ratio and coupling
Fig. 22 Schematic representation of an automated SPS-flow synthesis of prexasertib and derivatives. LDA: lithium diisopropylamide. Repro-
duced from ref. 124 with the permission of Springer Nature, copyright 2021.
View Article Online

Fig. 23 Overall approach for bayesian optimization algorithm-driven multistep-synthesis of Sonidegib on an automated robotic platform.
DIPEA: N,N-diisopropylethylamine, HATU: hexafluorophosphate azabenzotriazole tetramethyl uronium. Reproduced from ref. 150 with the
permission of American Chemical Society, copyright 2022.
temperature) and two objective functions (yield and produc- overlooked by the community. However, as shown in this
tivity of sonidegib) were considered in a multiple-step campaign review, ow chemistry is packed with perks that can push the
using the bayesian optimization algorithm. In just 15 total boundaries and unleash unique reactivity and selectivity in
experiments over a 13 hours period (8 initialization and 7 synthetic organic chemistry. Flow reactors not only make new
renement runs), the algorithm identied the optimal condi- synthetic routes a reality, they fast-track them from lab to large
tions with simultaneous high yields and productivities of the scale production. And, as ow chemists master both chemical
product (93% yield, 7.4 g h−1), showcasing the potential for and engineering principles, they become valuable links between
machine learning, automation, and robotics to enhance lab discovery and production engineering.
manual experimentation. With this review showcasing how ow chemistry can team up
Finally, the integration of automated and ow-based high- with methodological development, we aimed to provide a helpful
throughput experimentation (HTE) platforms enables fast and eld guide for those eager to dive in. And with the continued
large-scale data generation, opening the door to data-driven growth of interest in ow chemistry, we expect even more explo-
techniques151–154 for discovering valuable reactivity insights ration and optimization of synthetic organic chemistry. We believe
and exploring novel synthesis strategies. Contributing to the ow technology will become a must-have in every chemical lab and
open reaction database155 or following the FAIR principles156 in be just as familiar as the classic round-bottom ask.
data sharing will further facilitate the integration of data
science in organic synthesis. As the eld continues to evolve, it
holds signicant potential for closed-loop experimentation and
Data availability
full autonomy in synthesis operations. The most common hurdles to enter the eld of ow chemistry
and an overview of essential accessories are provided in the
ESI.†
10. Conclusions
Synthetic chemistry has been a major player in discovering new Author contributions
medicines, materials, and ne chemicals. While the primary
focus of synthetic chemists has always been on the development L. C. and Z. W. wrote the review and contributed equally. The
of new reactivity concepts, the reactor has systematically been concept and the editing of this review was done by T. N.
View Article Online
22 F. Raymenants, T. Masson, J. S. J. Orduna and T. Noël,

Conflicts of interest
Chemrxiv, 2023, DOI: 10.26434/chemrxiv-2023-jbjh2.
There are no conicts to declare. 23 J.-i. Yoshida, Y. Takahashi and A. Nagaki, Chem. Commun.,
2013, 49, 9896–9904.
24 J.-I. Yoshida, Chem. Rec., 2010, 10, 332–341.
Acknowledgements 25 H. Kim, K.-I. Min, K. Inoue, D. J. Im, D.-P. Kim and
J.-I. Yoshida, Science, 2016, 352, 691–694.
We are grateful to have received generous funding from the
26 D. A. Thaisrivongs, J. R. Naber and J. P. McMullen, Org.
European Union Horizon Europe research and innovation
Process Res. Dev., 2016, 20, 1997–2004.
program under the Marie S. Curie Grant Agreement (L. C.: HAT-
27 S. A. Doggrell, Expert Opin. Pharmacother., 2019, 20, 2095–
TRICK, No. 101023615; Z. W. & T. N.: Photo2Fuel, No
2099.
101069357).
28 P. Rys, Angew. Chem., Int. Ed., 1977, 16, 807–817.
29 P. Rys, Acc. Chem. Res., 1976, 9, 345–351.
References 30 D. A. Thaisrivongs, J. R. Naber, N. J. Rogus and G. Spencer,
Org. Process Res. Dev., 2018, 22, 403–408.
1 C. Hu, J. Flow Chem., 2021, 11, 243–263. 31 N. Kockmann, P. Thenée, C. Fleischer-Trebes, G. Laudadio
2 N. Cherkasov, S. J. Adams, E. G. A. Bainbridge and and T. Noël, React. Chem. Eng., 2017, 2, 258–280.
J. A. M. Thornton, React. Chem. Eng., 2023, 8, 266–277. 32 B. Gutmann, D. Cantillo and C. O. Kappe, Angew. Chem., Int.
3 A. Laybourn, K. Robertson and A. G. Slater, J. Am. Chem. Ed., 2015, 54, 6688–6728.
Soc., 2023, 145, 4355–4365. 33 V. Hessel, D. Kralisch, N. Kockmann, T. Noël and Q. Wang,
4 R. L. Hartman, J. P. McMullen and K. F. Jensen, Angew. ChemSusChem, 2013, 6, 746–789.
Chem., Int. Ed., 2011, 50, 7502–7519. 34 Z. Wen, F. Jiao, M. Yang, S. Zhao, F. Zhou and G. Chen, Org.
5 M. Baumann, T. S. Moody, M. Smyth and S. Wharry, Org. Process Res. Dev., 2017, 21, 1843–1850.
Process Res. Dev., 2020, 24, 1802–1813. 35 A. A. Kulkarni, Beilstein J. Org. Chem., 2014, 10, 405–424.
6 D. L. Hughes, Org. Process Res. Dev., 2020, 24, 1850–1860. 36 D. Cantillo and C. O. Kappe, React. Chem. Eng., 2017, 2, 7–
7 S. G. Koenig and H. F. Sneddon, Green Chem., 2017, 19, 19.
1418–1419. 37 A. Steiner, P. M. C. Roth, F. J. Strauss, G. Gauron,
8 J. Alcazar, A. de la Hoz and A. Dı́az-Ortiz, Flow chemistry in G. Tekautz, M. Winter, J. D. Williams and C. O. Kappe,
drug discovery, Springer, 2021. Org. Process Res. Dev., 2020, 24, 2208–2216.
9 F. E. Valera, M. Quaranta, A. Moran, J. Blacker, 38 T. Noël, Y. Su and V. Hessel, in Organometallic Flow
A. Armstrong, J. T. Cabral and D. G. Blackmond, Angew. Chemistry, ed. T. Noël, Springer International Publishing,
Chem., Int. Ed., 2010, 49, 2478–2485. Cham, 2016, pp. 1–41, DOI: 10.1007/3418_2015_152.
10 C. A. Hone and C. O. Kappe, Chem. Methods, 2021, 1, 454– 39 M. Colella, A. Nagaki and R. Luisi, Chem. – Eur. J., 2020, 26,
467. 19–32.
11 J. Britton and T. F. Jamison, Nat. Protoc., 2017, 12, 2423– 40 G. Laudadio, H. P. L. Gemoets, V. Hessel and T. Noël, J. Org.
2446. Chem., 2017, 82, 11735–11741.
12 N. J. W. Straathof, Y. Su, V. Hessel and T. Noël, Nat. Protoc., 41 E. A. Merritt and B. Olofsson, Angew. Chem., Int. Ed., 2009,
2016, 11, 10–21. 48, 9052–9070.
13 C. R. Sagandira, M. Siyawamwaya and P. Watts, Arab. J. 42 L. Huck, A. de la Hoz, A. Dı́az-Ortiz and J. Alcázar, Org. Lett.,
Chem., 2020, 13, 7886–7908. 2017, 19, 3747–3750.
14 G. R. D. Prabhu and P. L. Urban, Chem. Rev., 2020, 120, 43 Y. Deng, X.-J. Wei, X. Wang, Y. Sun and T. Noël, Chem. – Eur.
9482–9553. J., 2019, 25, 14532–14535.
15 K. P. L. Kuijpers, W. M. A. Weggemans, C. J. A. Verwijlen 44 W. H. Mudd and E. P. Stevens, Tetrahedron Lett., 2010, 51,
and T. Noël, J. Flow Chem., 2021, 11, 7–12. 3229–3231.
16 B. König, P. Kreitmeier, P. Hilgers and T. Wirth, J. Chem. 45 S. Borukhova, T. Noël, B. Metten, E. de Vos and V. Hessel,
Educ., 2013, 90, 934–936. ChemSusChem, 2013, 6, 2220–2225.
17 M. B. Plutschack, B. Pieber, K. Gilmore and P. H. Seeberger, 46 S. Borukhova, T. Noël, B. Metten, E. de Vos and V. Hessel,
Chem. Rev., 2017, 117, 11796–11893. Green Chem., 2016, 18, 4947–4953.
18 S. Han, M. A. Kashpour, M. Ramezani and M. Abolhasani, 47 D. Webb and T. F. Jamison, Chem. Sci., 2010, 1, 675–680.
Chem. Commun., 2020, 56, 10593–10606. 48 M. G. Russell and T. F. Jamison, Angew. Chem., Int. Ed.,
19 G. Laudadio, Y. Deng, K. van der Wal, D. Ravelli, M. Nuño, 2019, 58, 7678–7681.
M. Fagnoni, D. Guthrie, Y. Sun and T. Noël, Science, 2020, 49 K. Lovato, P. S. Fier and K. M. Maloney, Nat. Rev. Chem.,
369, 92–96. 2021, 5, 546–563.
20 D. Ravelli, S. Protti and M. Fagnoni, Acc. Chem. Res., 2016, 50 K. P. Cole, J. M. Groh, M. D. Johnson, C. L. Burcham,
49, 2232–2242. B. M. Campbell, W. D. Diseroad, M. R. Heller,
21 L. Capaldo, D. Ravelli and M. Fagnoni, Chem. Rev., 2022, J. R. Howell, N. J. Kallman, T. M. Koenig, S. A. May,
122, 1875–1924. R. D. Miller, D. Mitchell, D. P. Myers, S. S. Myers,
View Article Online
J. L. Phillips, C. S. Polster, T. D. White, J. Cashman, 73 D. Leifert and A. Studer, Angew. Chem., Int. Ed., 2020, 59, 74–
D. Hurley, R. Moylan, P. Sheehan, R. D. Spencer, 108.
K. Desmond, P. Desmond and O. Gowran, Science, 2017, 74 L. Chen, L. M. Barton, J. C. Vantourout, Y. Xu, C. Chu,
356, 1144–1150. E. C. Johnson, J. J. Sabatini and P. S. Baran, Org. Process
51 I. R. Baxendale, J. Deeley, C. M. Griffiths-Jones, S. V. Ley, Res. Dev., 2021, 25, 2639–2645.
S. Saaby and G. K. Tranmer, Chem. Commun., 2006, 2566– 75 L. M. Barton, J. T. Edwards, E. C. Johnson, E. J. Bukowski,
2568. R. C. Sausa, E. F. C. Byrd, J. A. Orlicki, J. J. Sabatini and
52 M. Colella, C. Carlucci and R. Luisi, in Accounts on P. S. Baran, J. Am. Chem. Soc., 2019, 141, 12531–12535.
Sustainable Flow Chemistry, ed. T. Noël and R. Luque, 76 C. Bottecchia, D. Lehnherr, F. Lévesque, M. Reibarkh, Y. Ji,
Springer International Publishing, Cham, 2020, pp. 29–65, V. L. Rodrigues, H. Wang, Y.-H. Lam, T. P. Vickery,
DOI: 10.1007/978-3-030-36572-1_2. B. M. Armstrong, K. A. Mattern, K. Stone, M. K. Wismer,

53 S. V. Ley, O. Schucht, A. W. Thomas and P. John Murray, J. A. N. Singh, E. L. Regalado, K. M. Maloney and
Chem. Soc., Perkin Trans. 1, 1999, 1251–1252. N. A. Strotman, Org. Process Res. Dev., 2022, 26, 2423–2437.
54 L. Buglioni, F. Raymenants, A. Slattery, S. D. A. Zondag and 77 C. J. Mallia and I. R. Baxendale, Org. Process Res. Dev., 2016,
T. Noël, Chem. Rev., 2022, 122, 2752–2906. 20, 327–360.
55 K. Donnelly and M. Baumann, J. Flow Chem., 2021, 11, 223– 78 M. Movsisyan, E. I. P. Delbeke, J. K. E. T. Berton,
241. C. Battilocchio, S. V. Ley and C. V. Stevens, Chem. Soc.
56 C. Sambiagio and T. Noël, Trends Chem., 2020, 2, 92–106. Rev., 2016, 45, 4892–4928.
57 T. H. Rehm, Chem. – Eur. J., 2020, 26, 16952–16974. 79 G. H. S. Rosa, T. I. S. Santos, T. J. Brocksom and K. T. de
58 D. Cambié, C. Bottecchia, N. J. W. Straathof, V. Hessel and Oliveira, React. Chem. Eng., 2023, DOI: 10.1039/
T. Noël, Chem. Rev., 2016, 116, 10276–10341. D2RE00385F.
59 L. Yang, Y. Sun and L. Zhang, ChemPlusChem, 2023, 88, 80 J. M. de Souza, T. J. Brocksom, D. T. McQuade and K. T. de
e202200349. Oliveira, J. Org. Chem., 2018, 83, 7574–7585.
60 T. Wan, Z. Wen, G. Laudadio, L. Capaldo, R. Lammers, 81 G. Laudadio, S. Govaerts, Y. Wang, D. Ravelli,
J. A. Rincón, P. Garcı́a-Losada, C. Mateos, M. O. Frederick, H. F. Koolman, M. Fagnoni, S. W. Djuric and T. Noël,
R. Broersma and T. Noël, ACS Cent. Sci., 2022, 8, 51–56. Angew. Chem., Int. Ed., 2018, 57, 4078–4082.
61 F. Bonassi, D. Ravelli, S. Protti and M. Fagnoni, Adv. Synth. 82 J. Yue, G. Chen, Q. Yuan, L. Luo and Y. Gonthier, Chem. Eng.
Catal., 2015, 357, 3687–3695. Sci., 2007, 62, 2096–2108.
62 L. Capaldo, S. Bonciolini, A. Pulcinella, M. Nuño and 83 Y. Chen, S. Renson and J. M. Monbaliu, Angew. Chem., Int.
T. Noël, Chem. Sci., 2022, 13, 7325–7331. Ed., 2022, 61, e202210146.
63 H.-M. Huang, P. Bellotti and F. Glorius, Chem. Soc. Rev., 84 H. Lehmann, T. Ruppen and T. Knoepfel, Org. Process Res.
2020, 49, 6186–6197. Dev., 2022, 26, 1308–1317.
64 X.-Q. Chu, D. Ge, Y.-Y. Cui, Z.-L. Shen and C.-J. Li, Chem. 85 G. M. Martins, M. F. A. Magalhães, T. J. Brocksom,
Rev., 2021, 121, 12548–12680. V. S. Bagnato and K. T. de Oliveira, J. Flow Chem., 2022,
65 Y. Ji, C. Bottecchia, F. Lévesque, K. Narsimhan, 12, 371–379.
D. Lehnherr, J. P. McMullen, S. M. Dalby, K.-J. Xiao and 86 S. D. A. Zondag, D. Mazzarella and T. Noël, Annu. Rev. Chem.
M. Reibarkh, J. Org. Chem., 2022, 87, 2055–2062. Biomol. Eng., 2023, 4, 5.1–5.18.
66 C. Bottecchia, F. Lévesque, J. P. McMullen, Y. Ji, 87 Z. Dong, Z. Wen, F. Zhao, S. Kuhn and T. Noël, Chem. Eng.
M. Reibarkh, F. Peng, L. Tan, G. Spencer, J. Nappi, Sci.: X, 2021, 10, 100097.
D. Lehnherr, K. Narsimhan, M. K. Wismer, L. Chen, 88 F. Xue, X. Zhou, R. Zhou, X. Zhou, D. Xiao, E. Gu, X. Guo,
Y. Lin and S. M. Dalby, Org. Process Res. Dev., 2022, 26, J. Xiang, K. Wang, L. Yang, W. Zhong and Y. Qin, Org.
516–524. Process Res. Dev., 2020, 24, 1772–1777.
67 T. Noël, Y. Cao and G. Laudadio, Acc. Chem. Res., 2019, 52, 89 D. Siegel, H. C. Hui, E. Doerffler, M. O. Clarke, K. Chun,
2858–2869. L. Zhang, S. Neville, E. Carra, W. Lew, B. Ross, Q. Wang,
68 M. Atobe, H. Tateno and Y. Matsumura, Chem. Rev., 2018, L. Wolfe, R. Jordan, V. Soloveva, J. Knox, J. Perry,
118, 4541–4572. M. Perron, K. M. Stray, O. Barauskas, J. Y. Feng, Y. Xu,
69 D. Pletcher, R. A. Green and R. C. D. Brown, Chem. Rev., G. Lee, A. L. Rheingold, A. S. Ray, R. Bannister,
2018, 118, 4573–4591. R. Strickley, S. Swaminathan, W. A. Lee, S. Bavari,
70 K. Mitsudo, Y. Kurimoto, K. Yoshioka and S. Suga, Chem. T. Cihlar, M. K. Lo, T. K. Warren and R. L. Mackman, J.
Rev., 2018, 118, 5985–5999. Med. Chem., 2017, 60, 1648–1661.
71 M. A. Bajada, J. Sanjosé-Orduna, G. Di Liberto, S. Tosoni, 90 T. von Keutz, J. D. Williams and C. O. Kappe, Org. Process
G. Pacchioni, T. Noël and G. Vilé, Chem. Soc. Rev., 2022, Res. Dev., 2021, 25, 1015–1021.
51, 3898–3925. 91 J. H. Kang, G. N. Ahn, H. Lee, S. J. Yim, S. Lahore, H. J. Lee,
72 Y. Mo, Z. Lu, G. Rughoobur, P. Patil, N. Gershenfeld, H. Kim, J. T. Kim and D. P. Kim, ACS Cent. Sci., 2022, 8, 43–
A. I. Akinwande, S. L. Buchwald and K. F. Jensen, Science, 50.
2020, 368, 1352–1357.
View Article Online
92 A. Chaudhuri, S. D. A. Zondag, J. H. A. Schuurmans, J. van 111 P. Sagmeister, R. Lebl, I. Castillo, J. Rehrl, J. Kruisz,
der Schaaf and T. Noël, Org. Process Res. Dev., 2022, 26, M. Sipek, M. Horn, S. Sacher, D. Cantillo, J. D. Williams
1279–1288. and C. O. Kappe, Angew. Chem., Int. Ed., 2021, 60, 8139–
93 A. Chaudhuri, K. P. L. Kuijpers, R. B. J. Hendrix, 8148.
P. Shivaprasad, J. A. Hacking, E. A. C. Emanuelsson, 112 A. Gioiello, A. Piccinno, A. M. Lozza and B. Cerra, J. Med.
T. Noël and J. Van Der Schaaf, Chem. Eng. J., 2020, 400, Chem., 2020, 63, 6624–6647.
125875. 113 P. Sagmeister, J. D. Williams, C. A. Hone and C. O. Kappe,
94 D. S. Lee, M. Sharabi, R. Jefferson-Loveday, S. J. Pickering, React. Chem. Eng., 2019, 4, 1571–1578.
M. Poliakoff and M. W. George, Org. Process Res. Dev., 114 N. H. Angello, V. Rathore, W. Beker, A. Wołos, E. R. Jira,
2020, 24, 201–206. R. Roszak, T. C. Wu, C. M. Schroeder, A. Aspuru-Guzik,

95 M. Wernik, G. Sipos, B. Buchholcz, F. Darvas, Z. Novák, B. A. Grzybowski and M. D. Burke, Science, 2022, 378,
S. B. Ötvös and C. O. Kappe, Green Chem., 2021, 23, 5625– 399–405.
5632. 115 C. P. Breen, A. M. K. Nambiar, T. F. Jamison and
96 C. Rosso, S. Gisbertz, J. D. Williams, H. P. L. Gemoets, K. F. Jensen, Trends Chem., 2021, 3, 373–386.
W. Debrouwer, B. Pieber and C. O. Kappe, React. Chem. 116 C. W. Coley, N. S. Eyke and K. F. Jensen, Angew. Chem., Int.
Eng., 2020, 5, 597–604. Ed., 2020, 59, 22858–22893.
97 Z. Wen, A. Maheshwari, C. Sambiagio, Y. Deng, 117 C. W. Coley, N. S. Eyke and K. F. Jensen, Angew. Chem., Int.
G. Laudadio, K. Van Aken, Y. Sun, H. P. L. Gemoets and Ed., 2020, 59, 23414–23436.
T. Noël, Org. Process Res. Dev., 2020, 24, 2356–2361. 118 S. Lin, S. Dikler, D. Blincoe William, D. Ferguson Ronald,
98 C. A. Clark, D. S. Lee, S. J. Pickering, M. Poliakoff and P. Sheridan Robert, Z. Peng, V. Conway Donald,
M. W. George, Org. Process Res. Dev., 2016, 20, 1792–1798. K. Zawatzky, H. Wang, T. Cernak, W. Davies Ian,
99 K. C. Harper, E.-X. Zhang, Z.-Q. Liu, T. Grieme, T. B. Towne, A. DiRocco Daniel, H. Sheng, J. Welch Christopher and
D. J. Mack, J. Griffin, S.-Y. Zheng, N.-N. Zhang, S. Gangula, D. Dreher Spencer, Science, 2018, 361, eaar6236.
J.-L. Yuan, R. Miller, P.-Z. Huang, J. Gage, M. Diwan and 119 A. Buitrago Santanilla, E. L. Regalado, T. Pereira,
Y.-Y. Ku, Org. Process Res. Dev., 2022, 26, 404–412. M. Shevlin, K. Bateman, L.-C. Campeau, J. Schneeweis,
100 K. C. Harper, E. G. Moschetta, S. V. Bordawekar and S. Berritt, Z.-C. Shi, P. Nantermet, Y. Liu, R. Helmy,
S. J. Wittenberger, ACS Cent. Sci., 2019, 5, 109–115. C. J. Welch, P. Vachal, I. W. Davies, T. Cernak and
101 Z. Dong, S. D. A. Zondag, M. Schmid, Z. Wen and T. Noël, S. D. Dreher, Science, 2015, 347, 49–53.
Chem. Eng. J., 2022, 428, 130968. 120 D. Perera, J. W. Tucker, S. Brahmbhatt, C. J. Helal,
102 D. Fernandez Rivas and S. Kuhn, Top. Curr. Chem., 2016, A. Chong, W. Farrell, P. Richardson and N. W. Sach,
374, 70. Science, 2018, 359, 429–434.
103 C. Y. Park, Y. J. Kim, H. J. Lim, J. H. Park, M. J. Kim, 121 A. C. Sun, D. J. Steyer, A. R. Allen, E. M. Payne,
S. W. Seo and C. P. Park, RSC Adv., 2015, 5, 4233–4237. R. T. Kennedy and C. R. J. Stephenson, Nat. Commun.,
104 F. Ronzani, N. Costarramone, S. Blanc, A. K. Benabbou, 2020, 11, 6202.
M. L. Bechec, T. Pigot, M. Oelgemöller and S. Lacombe, J. 122 D. J. Blair, S. Chitti, M. Trobe, D. M. Kostyra, H. M. S. Haley,
Catal., 2013, 303, 164–174. R. L. Hansen, S. G. Ballmer, T. J. Woods, W. Wang,
105 M. Meeuwse, J. van der Schaaf and J. C. Schouten, AlChE J, V. Mubayi, M. J. Schmidt, R. W. Pipal, G. F. Morehouse,
2012, 58, 247–255. A. M. E. Palazzolo Ray, D. L. Gray, A. L. Gill and
106 N. Prieto Kullmer Cesar, A. Kautzky Jacob, W. Krska Shane, M. D. Burke, Nature, 2022, 604, 92–97.
T. Nowak, D. Dreher Spencer and W. C. MacMillan David, 123 S. Yalamanchili, T. A. Nguyen, A. Zsikla, G. Stamper,
Science, 2022, 376, 532–539. A. E. DeYong, J. Florek, O. Vasquez, N. L. B. Pohl and
107 N. S. Eyke, B. A. Koscher and K. F. Jensen, Trends Chem., C. S. Bennett, Angew. Chem., Int. Ed. Engl., 2021, 60,
2021, 3, 120–132. 23171–23175.
108 S. M. Mennen, C. Alhambra, C. L. Allen, M. Barberis, 124 C. Liu, J. Xie, W. Wu, M. Wang, W. Chen, S. B. Idres,
S. Berritt, T. A. Brandt, A. D. Campbell, J. Castanon, J. Rong, L. W. Deng, S. A. Khan and J. Wu, Nat. Chem.,
A. H. Cherney, M. Christensen, D. B. Damon, J. E. de 2021, 13, 451–457.
Diego, S. Garcia-Cerrada, P. Garcia-Losada, R. Haro, 125 T. Jiang, S. Bordi, A. E. McMillan, K.-Y. Chen, F. Saito,
J. Janey, D. C. Leitch, L. Li, F. F. Liu, P. C. Lobben, P. L. Nichols, B. M. Wanner and J. W. Bode, Chem. Sci.,
D. W. C. MacMillan, J. Magano, E. McInturff, S. Monfette, 2021, 12, 6977–6982.
R. J. Post, D. Schultz, B. J. Sitter, J. M. Stevens, 126 T. Hardwick and N. Ahmed, Chem. Sci., 2020, 11, 11973–
J. I. Strambeanu, J. Twilton, K. Wang and M. A. Zajac, 11988.
Org. Process Res. Dev., 2019, 23, 1213–1242. 127 N. Collins, D. Stout, J. P. Lim, J. P. Malerich, J. D. White,
109 S. W. Krska, D. A. DiRocco, S. D. Dreher and M. Shevlin, Acc. P. B. Madrid, M. Latendresse, D. Krieger, J. Szeto,
Chem. Res., 2017, 50, 2976–2985. V. A. Vu, K. Rucker, M. Deleo, Y. Gorfu,
110 M. A. Morin, W. Zhang, D. Mallik and M. G. Organ, Angew. M. Krummenacker, L. A. Hokama, P. Karp and S. Mallya,
Chem., Int. Ed., 2021, 60, 20606–20626. Org. Process Res. Dev., 2020, 24, 2064–2077.
View Article Online
128 S. Chatterjee, M. Guidi, P. H. Seeberger and K. Gilmore, 145 P. Frazier, arXiv, 2018, preprint, arXiv:abs/1807.02811.
Nature, 2020, 579, 379–384. 146 Z. Zhou, X. Li and R. N. Zare, ACS Cent. Sci., 2017, 3, 1337–
129 J. Li, S. G. Ballmer, E. P. Gillis, S. Fujii, M. J. Schmidt, 1344.
A. M. E. Palazzolo, J. W. Lehmann, G. F. Morehouse and 147 A. Adamo, R. L. Beingessner, M. Behnam, J. Chen,
M. D. Burke, Science, 2015, 347, 1221–1226. T. F. Jamison, K. F. Jensen, J.-C. M. Monbaliu,
130 A. D. Clayton, E. O. Pyzer-Knapp, M. Purdie, M. F. Jones, A. S. Myerson, E. M. Revalor, D. R. Snead, T. Stelzer,
A. Barthelme, J. Pavey, N. Kapur, T. W. Chamberlain, N. Weeranoppanant, S. Y. Wong and P. Zhang, Science,
A. J. Blacker and R. A. Bourne, Angew. Chem., Int. Ed., 2016, 352, 61–67.
2023, 62, e202214511. 148 C. W. Coley, D. A. Thomas, J. A. M. Lummiss, J. N. Jaworski,
131 A. F. Zahrt, Y. Mo, K. Y. Nandiwale, R. Shprints, E. Heid and C. P. Breen, V. Schultz, T. Hart, J. S. Fishman, L. Rogers,
K. F. Jensen, J. Am. Chem. Soc., 2022, 144, 22599–22610. H. Gao, R. W. Hicklin, P. P. Plehiers, J. Byington,
132 W. Wang, Y. Liu, Z. Wang, G. Hao and B. Song, Chem. Sci., J. S. Piotti, W. H. Green, A. J. Hart, T. F. Jamison and
2022, 13, 12604–12615. K. F. Jensen, Science, 2019, 365, eaax1566.
133 S. Knoll, C. E. Jusner, P. Sagmeister, J. D. Williams, 149 C. W. Coley, W. H. Green and K. F. Jensen, Acc. Chem. Res.,
C. A. Hone, M. Horn and C. O. Kappe, React. Chem. Eng., 2018, 51, 1281–1289.
2022, 7, 2375–2384. 150 A. M. K. Nambiar, C. P. Breen, T. Hart, T. Kulesza,
134 K. Y. Nandiwale, T. Hart, A. F. Zahrt, A. M. K. Nambiar, T. F. Jamison and K. F. Jensen, ACS Cent. Sci., 2022, 8,
P. T. Mahesh, Y. Mo, M. J. Nieves-Remacha, 825–836.
M. D. Johnson, P. Garcı́a-Losada, C. Mateos, J. A. Rincón 151 E. Shim, J. A. Kammeraad, Z. P. Xu, A. Tewari, T. Cernak
and K. F. Jensen, React. Chem. Eng., 2022, 7, 1315–1327. and P. M. Zimmerman, Chem. Sci., 2022, 13, 6655–6668.
135 Y. Shen, J. E. Borowski, M. A. Hardy, R. Sarpong, A. G. Doyle 152 W. L. Williams, L. Zeng, T. Gensch, M. S. Sigman,
and T. Cernak, Nat. Rev. Methods Primers, 2021, 1, 23. A. G. Doyle and E. V. Anslyn, ACS Cent. Sci., 2021, 7,
136 A. Thakkar, S. Johansson, K. Jorner, D. Buttar, 1622–1637.
J.-L. Reymond and O. Engkvist, React. Chem. Eng., 2021, 6, 153 Y. Mo, Y. Guan, P. Verma, J. Guo, M. E. Fortunato, Z. Lu,
27–51. C. W. Coley and K. F. Jensen, Chem. Sci., 2021, 12, 1469–
137 B. J. Reizman, Y.-M. Wang, S. L. Buchwald and K. F. Jensen, 1478.
React. Chem. Eng., 2016, 1, 658–666. 154 D. Reker, E. A. Hoyt, G. J. L. Bernardes and T. Rodrigues,
138 S. A. Weissman and N. G. Anderson, Org. Process Res. Dev., Cell Rep. Phy. Sci., 2020, 1, 100247.
2015, 19, 1605–1633. 155 S. M. Kearnes, M. R. Maser, M. Wleklinski, A. Kast,
139 V. Fath, N. Kockmann, J. Otto and T. Roder, React. Chem. A. G. Doyle, S. D. Dreher, J. M. Hawkins, K. F. Jensen and
Eng., 2020, 5, 1281–1299. C. W. Coley, J. Am. Chem. Soc., 2021, 143, 18820–18826.
140 V. Sans, L. Porwol, V. Dragone and L. Cronin, Chem. Sci., 156 A. Jacobsen, R. de Miranda Azevedo, N. Juty, D. Batista,
2015, 6, 1258–1264. S. Coles, R. Cornet, M. Courtot, M. Crosas, M. Dumontier,
141 N. Cherkasov, Y. Bai, A. J. Expósito and E. V. Rebrov, React. C. T. Evelo, C. Goble, G. Guizzardi, K. K. Hansen,
Chem. Eng., 2018, 3, 769–780. A. Hasnain, K. Hettne, J. Heringa, R. W. W. Hoo,
142 A.-C. Bédard, A. Adamo, K. C. Aroh, M. G. Russell, M. Imming, K. G. Jeffery, R. Kaliyaperumal,
A. A. Bedermann, J. Torosian, B. Yue, K. F. Jensen and M. G. Kersloot, C. R. Kirkpatrick, T. Kuhn, I. Labastida,
T. F. Jamison, Science, 2018, 361, 1220–1225. B. Magagna, P. McQuilton, N. Meyers, A. Montesanti,
143 J. A. G. Torres, S. H. Lau, P. Anchuri, J. M. Stevens, M. van Reisen, P. Rocca-Serra, R. Pergl, S.-A. Sansone,
J. E. Tabora, J. Li, A. Borovika, R. P. Adams and L. O. B. da Silva Santos, J. Schneider, G. Strawn,
A. G. Doyle, J. Am. Chem. Soc., 2022, 144, 19999–20007. M. Thompson, A. Waagmeester, T. Weigel,
144 B. J. Shields, J. Stevens, J. Li, M. Parasram, F. Damani, M. D. Wilkinson, E. L. Willighagen, P. Wittenburg,
J. I. M. Alvarado, J. M. Janey, R. P. Adams and A. G. Doyle, M. Roos, B. Mons and E. Schultes, Data Intell., 2020, 2,
Nature, 2021, 590, 89–96. 10–29.

Chemical Science: Review

Uploaded by

Copyright:

Available Formats

Chemical Science: Review

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Chemical Science: Review

Uploaded by

Copyright:

Available Formats

Chemical

A ﬁeld guide to ﬂow chemistry for synthetic organic

Cite this: Chem. Sci., 2023, 14, 4230

Luca Capaldo, ‡ Zhenghui Wen ‡ and Timothy Noël *

scalability, and improved reproducibility.3,4 As a consequence,

Luca Capaldo is a MSCA post- Zhenghui Wen was born in 1993

Review Chemical Science

Timothy Noël is a Full Professor