Ready, Set, Flow! Automated Continuous Synthesis and Optimization

The merger of continuous flow and automated synthesis leverages the many advantages afforded by these technologies.Closed-loop experimentation is becoming an increasingly accessible approach for accelerating molecular discovery.The combination of an automated general reaction platform with computational route planning presents a powerful strategy for the democratization of complex molecule synthesis. Synthetic chemistry provides access to advanced materials that facilitate innovation in key industries such as medicine, energy, and agriculture. Automation is poised to challenge the traditional process of chemical synthesis and development. Continuous flow chemistry has recently come into maturity and provides a flexible platform amenable to automation. The merger of synthesis and automation promises to democratize access to custom complex small molecules for non-experts as well as accelerate the development of new synthetic protocols by relieving expert chemists of routine tasks. In this contribution, we discuss recent case studies that present strategies towards realizing automated synthesis with a further focus on works that leverage continuous flow chemistry as an enabling technology. Synthetic chemistry provides access to advanced materials that facilitate innovation in key industries such as medicine, energy, and agriculture. Automation is poised to challenge the traditional process of chemical synthesis and development. Continuous flow chemistry has recently come into maturity and provides a flexible platform amenable to automation. The merger of synthesis and automation promises to democratize access to custom complex small molecules for non-experts as well as accelerate the development of new synthetic protocols by relieving expert chemists of routine tasks. In this contribution, we discuss recent case studies that present strategies towards realizing automated synthesis with a further focus on works that leverage continuous flow chemistry as an enabling technology. Synthetic chemistry has delivered useful molecules that address humankind’s most pressing challenges, such as treating life-threatening diseases, protecting life-sustaining crops, and harnessing renewable energy for a sustainable future [1.Campos K.R. et al.The importance of synthetic chemistry in the pharmaceutical industry.Science. 2019; 363eaat0805Crossref PubMed Scopus (147) Google Scholar, 2.Burke D.J. Lipomi D.J. Green chemistry for organic solar cells.Energy Environ. Sci. 2013; 6: 2053-2066Crossref Scopus (221) Google Scholar, 3.Lamberth C. et al.Current challenges and trends in the discovery of agrochemicals.Science. 2013; 341: 742-746Crossref PubMed Scopus (272) Google Scholar]. The rate at which we discover and deploy the molecules of tomorrow is dependent on how quickly we can perform experiments in the lab to synthesize compounds, optimize a structure–activity relationship, and develop processes to manufacture them at scale [4.Scannell J.W. Bosley J. When quality beats quantity: decision theory, drug discovery, and the reproducibility crisis.PLoS One. 2016; 11e0147215Crossref PubMed Scopus (138) Google Scholar]. Improvements in experimental frequency, however, must accompany a commensurate increase in efficiency, thereby maximizing the amount of knowledge gained per experiment conducted while minimizing waste. This important association becomes particularly salient due to narrowing development budgets and compressed project timelines. High-throughput experimentation (HTE) platforms began to address these issues. In Santanilla [5.Buitrago Santanilla A. et al.Nanomole-scale high-throughput chemistry for the synthesis of complex molecules.Science. 2015; 347: 49-53Crossref PubMed Scopus (285) Google Scholar] and Perera’s [6.Perera D. et al.A platform for automated nanomole-scale reaction screening and micromole-scale synthesis in flow.Science. 2018; 359: 429-434Crossref PubMed Scopus (157) Google Scholar] respective demonstrations, for example, miniaturized automated experimentation (see Glossary) platforms were capable of screening thousands of Pd-catalyzed cross-coupling reactions on the nanomole scale. In the HTE framework, integrated experimental execution hardware and process analytical technology (PAT) obviate human involvement in tasks prone to error, resulting in large, high-fidelity datasets. Reaction design space, however, is exhaustively screened and, among other issues, the total number of experiments can grow to an impractical number in complex screening schemes [7.Bibette J. Gaining confidence in high-throughput screening.Proc. Natl. Acad Sci. U. S. A. 2012; 109: 649-650Crossref PubMed Scopus (18) Google Scholar]. The development and integration of decision-making algorithms into automated experimentation platforms reflects a current trend towards closed-loop experimentation (Figure 1A , Key Figure). Once the user defines the objective and bounds of the search space, the algorithm assumes control by designing experiments and iteratively refining a mathematical surrogate model describing the relationship between inputs and outputs. Such systems are occasionally claimed to be autonomous, but they require human intervention in different parts of the process and are constrained to narrow, well-defined search spaces. As discussed in detail by Coley and coworkers, an autonomous experimentation system not only makes algorithm-based decisions but is also able to adapt in response to unexpected outcomes [8.Coley C.W. et al.Autonomous discovery in the chemical sciences part I: progress.Angew. Chem. Int. Ed. 2020; 59: 22858-22893Crossref PubMed Scopus (101) Google Scholar,9.Coley C.W. et al.Autonomous discovery in the chemical sciences part II: outlook.Angew. Chem. Int. Ed. 2020; 59: 23414-23436Crossref PubMed Scopus (83) Google Scholar]. The speed, efficiency, and quality of experimentation, as well as the experimentally accessible search space, also depend on the judicious selection of reaction hardware. Continuous flow chemistry has long been a technology of choice for the production of certain commodity chemicals and has recently matured into a valuable technique for fine chemical synthesis that can complement and often outperform existing batch chemistry protocols [10.Jensen K.F. Flow chemistry—microreaction technology comes of age.AIChE J. 2017; 63: 858-869Crossref Scopus (288) Google Scholar]. The unique properties associated with lab-scale flow systems have created novel process windows, wherein accelerated reaction rates and traditionally impractical batch reactor conditions are unlocked [11.Hessel V. Novel process windows – gates to maximizing process intensification via flow chemistry.Chem. Eng. Technol. 2009; 32: 1641Crossref Scopus (24) Google Scholar]. Small reactor dimensions lead to short length scales for heat and mass transfer, resulting in uniform temperatures across the reactor and well-characterized mixing that enable enhanced reproducibility and predictable scaling behavior [12.Steiner A. et al.Multikilogram per hour continuous photochemical benzylic brominations applying a smart dimensioning scale-up strategy.Org. Process. Res. Dev. 2020; 24: 2208-2216Crossref Scopus (31) Google Scholar]. Continuous reactors also benefit from design flexibility as discrete reactor parts are modular and can be adapted or exchanged to suit process demands [13.Guidi M. et al.How to approach flow chemistry.Chem. Soc. Rev. 2020; 49: 8910Crossref PubMed Google Scholar]. Moreover, the ability to link unit operations established the concept of telescoped multistep flow synthesis [14.Snead D.R. Jamison T.F. A three-minute synthesis and purification of ibuprofen: pushing the limits of continuous-flow processing.Angew. Chem. Int. Ed. 2015; 54: 983-987Crossref PubMed Scopus (152) Google Scholar,15.Ogasawara S. Hayashi Y. Multistep continuous-flow synthesis of (–)-oseltamivir.Synthesis. 2017; 49: 424-428Google Scholar]. This is an increasingly popular approach to multistep synthesis that involves a simultaneous, uninterrupted sequence of synthetic steps. Immobilized reagents have proven particularly advantageous in this context and have been largely pioneered and popularized by the Ley group [16.Lau S.-H. et al.Synthesis of a precursor to sacubitril using enabling technologies.Org. Lett. 2015; 17: 5436-5439Crossref PubMed Scopus (30) Google Scholar, 17.Baumann M. et al.An integrated flow and batch-based approach for the synthesis of O-methyl siphonazole.Synlett. 2011; 2011: 1375-1380Crossref Scopus (36) Google Scholar, 18.Newton S. et al.Accelerating spirocyclic polyketide synthesis using flow chemistry.Angew. Chem. Int. Ed. 2014; 53: 4915-4920Crossref PubMed Scopus (115) Google Scholar]. The facile integration of PAT and computational tools is key to achieving closed-loop experimentation in flow. A number of PAT systems are amenable to flow and encompass analytical techniques and physical measurements commonly used in synthetic chemistry [19.Sagmeister P. et al.Laboratory of the future: a modular flow platform with multiple integrated PAT tools for multistep reactions.React. Chem. Eng. 2019; 4: 1571-1578Crossref Google Scholar]. Rapid, integrated data acquisition facilitates data-rich experimentation that is ideal for processing by automated optimization algorithms and essential for closing the information feedback loop. This review aims to demonstrate, via representative examples, that when flow technology is a suitable choice for the reaction of interest, combining the advantages of flow reactors with automation and decision-making algorithms can unleash its full potential for accelerated and efficient experimentation. We conclude by identifying potentially promising avenues for future work in automated flow synthesis motivated by unsolved challenges and outstanding questions. The benefits characteristic to flow reactors combined with PAT tools and automation have enabled rapid, material-efficient, and data-rich studies to measure kinetic and thermodynamic parameters and generate mechanistic understanding. In visible-light photoredox catalysis, identifying effective photocatalyst-quencher combinations and designing reactor hardware that ensures precisely controlled reaction conditions are two key chemistry and engineering challenges, respectively [20.Straathof N.J.W. Noël T. Accelerating visible-light photoredox catalysis in continuous-flow reactors.in: Stephenson C. Visible Light Photocatalysis in Organic Chemistry. Wiley-VCH, 2018: 389-413Crossref Scopus (8) Google Scholar]. To this end, Kuijpers, Bottecchia, and coworkers developed a Python-automated flow platform integrated with inline UV/Vis spectroscopy for performing fluorescence quenching studies and Stern–Volmer analysis (Figure 2A ) [21.Kuijpers K.P.L. et al.A fully automated continuous-flow platform for fluorescence quenching studies and Stern–Volmer analysis.Angew. Chem. Int. Ed. 2018; 57: 11278-11282Crossref PubMed Scopus (48) Google Scholar]. Benefits arising from the flow setup include: (i) flow tubing creates a closed environment around the sample and minimizes oxygen interference during quenching studies, (ii) small microreactor dimensions result in uniform LED light irradiation throughout the sample volume, and (iii) low sample volume requirement (useful when screening expensive photocatalysts). By using an autosampler for quencher selection, inline dilution for varying quencher concentration, and Python scripts for automating experiment execution and data analysis, the authors identified promising photocatalyst–quencher combinations and measured reproducible quenching rate constants with minimal labor and time (within hours). In synthetic organic electrochemistry, cyclic voltammetry (CV) is an essential technique for measuring a molecule’s redox potential (thermodynamics) and studying the reactivity and mechanism (kinetics) of electrochemical reactions [22.Elgrishi N. et al.A practical beginner’s guide to cyclic voltammetry.J. Chem. Educ. 2018; 95: 197-206Crossref Scopus (1108) Google Scholar]. Building on prior work on electrochemical flow cell design [23.Atobe M. et al.Applications of flow microreactors in electrosynthetic processes.Chem. Rev. 2018; 118: 4541-4572Crossref PubMed Scopus (196) Google Scholar, 24.Pletcher D. et al.Flow electrolysis cells for the synthetic organic chemistry laboratory.Chem. Rev. 2018; 118: 4573-4591Crossref PubMed Scopus (259) Google Scholar, 25.Elsherbini M. Wirth T. Electroorganic synthesis under flow conditions.Acc. Chem. Res. 2019; 52: 3287-3296Crossref PubMed Scopus (113) Google Scholar], Mo and coworkers [26.Mo Y. et al.A multifunctional microfluidic platform for high-throughput experimentation of electroorganic chemistry.Angew. Chem. Int. Ed. 2020; 59: 20890-20894Crossref PubMed Scopus (15) Google Scholar] constructed an automated microfluidic platform for electro-analysis and reaction screening (Figure 2B). A precisely machined flow cell with fixed channel height and embedded electrodes (glassy carbon working electrode, platinum counter electrode, and silver reference electrode) ensured consistent cell geometry for CV studies. The results were comparable with those obtained with a standard-size CV cell and required significantly lower quantities of reagent to generate. To determine kinetic constants for electrochemically driven oxidation reactions for a range of substrates, the catalytic current was measured for droplets with different concentrations that were automatically prepared by a LabVIEW-controlled liquid handler. In batch reactors, data collected over time in a single experiment can be used for kinetic analysis. In continuous flow, to collect data at multiple time points, typically multiple steady state experiments are run at different residence times. A more time- and material-efficient approach for gathering kinetic data in flow involves continuously manipulating the flow rate and analyzing the reaction at various points during this controlled transient to obtain data corresponding to multiple residence times in a single experiment [27.Mozharov S. et al.Improved method for kinetic studies in microreactors using flow manipulation and noninvasive Raman spectrometry.J. Am. Chem. Soc. 2011; 133: 3601-3608Crossref PubMed Scopus (89) Google Scholar,28.Moore J.S. Jensen K.F. Batch kinetics in flow: online IR analysis and continuous control.Angew. Chem. Int. Ed. 2014; 53: 470-473Crossref PubMed Scopus (111) Google Scholar]. This method works best when there are small deviations from plug flow and with analytical tools with fast sampling rates, such as inline Fourier transform infrared (FTIR), Raman, and NMR spectroscopy. By combining flow reactors with scripts that dynamically update process conditions, this approach has been used for identifying suitable kinetic models [29.Waldron C. et al.An autonomous microreactor platform for the rapid identification of kinetic models.React. Chem. Eng. 2019; 4: 1623-1636Crossref Google Scholar,30.Fath V. et al.Efficient kinetic data acquisition and model prediction: continuous flow microreactors, inline Fourier transform infrared spectroscopy, and self-modeling curve resolution.Org. Process. Res. Dev. 2020; 24: 1955-1968Crossref Scopus (11) Google Scholar] and estimating kinetics for multistep reactions [31.Hone C.A. et al.Rapid multistep kinetic model generation from transient flow data.React. Chem. Eng. 2017; 2: 103-108Crossref PubMed Google Scholar] and has been extended to include simultaneous variations in temperature [32.Aroh K.C. Jensen K.F. Efficient kinetic experiments in continuous flow microreactors.React. Chem. Eng. 2018; 3: 94-101Crossref Google Scholar]. Recent examples demonstrating two-dimensional sinusoidal trajectories [33.Wyvratt B.M. et al.Multidimensional dynamic experiments for data-rich process development of reactions in flow.React. Chem. Eng. 2019; 4: 1637-1645Crossref Google Scholar] and transient photochemical reaction studies with online HPLC [34.Haas C.P. et al.Automated generation of photochemical reaction data by transient flow experiments coupled with online HPLC analysis.React. Chem. Eng. 2020; 5: 912-920Crossref Google Scholar] highlight the utility of dynamic experiments not just for kinetic analysis but also for more efficient, extensive, and data-rich exploration of flow reaction parameter spaces. Synthesizing novel polymeric materials leads to innovation in areas such as drug delivery and sustainable materials [35.Shieh P. et al.Cleavable comonomers enable degradable, recyclable thermoset plastics.Nature. 2020; 583: 542-547Crossref PubMed Scopus (90) Google Scholar,36.Johnson J.A. et al.Drug-loaded, bivalent-bottle-brush polymers by graft-through ROMP.Macromolecules. 2010; 43: 10326-10335Crossref PubMed Scopus (256) Google Scholar]. Continuous synthesis has been a standard practice in production of some commodity polymers but has recently been adopted to prepare bespoke materials [37.Walsh D.J. et al.General route to design polymer molecular weight distributions through flow chemistry.Nat. Commun. 2020; 11: 3094Crossref PubMed Scopus (45) Google Scholar, 38.Reis M.H. et al.Polymerizations in continuous flow: recent advances in the synthesis of diverse polymeric materials.ACS Macro Lett. 2020; 9: 123-133Crossref Scopus (58) Google Scholar, 39.Leibfarth F.A. et al.Scalable synthesis of sequence-defined, unimolecular macromolecules by Flow-IEG.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 10617-10622Crossref PubMed Scopus (118) Google Scholar]. Controlled polymerization procedures, such as reversible addition-fragmentation chain transfer (RAFT) polymerization, have emerged as effective synthetic tools amenable to continuous flow [40.Perrier S. 50th anniversary perspective: RAFT polymerization—a user guide.Macromolecules. 2017; 50: 7433-7447Crossref Scopus (595) Google Scholar]. Wenn and Junkers leveraged a continuous microreactor for the PhotoRAFT polymerization of acrylates with fine control of number average molecular weight (Mn), dispersity (Ð), and end-group fidelity [41.Wenn B. Junkers T. Continuous microflow photoRAFT polymerization.Macromolecules. 2016; 49: 6888-6895Crossref Scopus (49) Google Scholar]. Rubens and coworkers advanced this research by intensifying the photoinduced iniferter RAFT polymerization to encompass telescoped sequences for the synthesis of well-defined block copolymers with excellent retention of dispersity [42.Rubens M. et al.Visible light-induced iniferter polymerization of methacrylates enhanced by continuous flow.Polym. Chem. 2017; 8: 6496-6505Crossref Google Scholar]. Further work into telescoped synthesis of block copolymers of even greater molecular weights and more unit operations will continue to push the boundaries of this unique approach [43.Lin B. et al.Programmable high-throughput platform for the rapid and scalable synthesis of polyester and polycarbonate libraries.J. Am. Chem. Soc. 2019; 141: 8921-8927Crossref PubMed Scopus (45) Google Scholar]. In another advancement, Rubens, Vrijsen, and coworkers constructed a platform for closed-loop optimization of thermal and photoinitiated iniferter RAFT processes (Figure 3A ) [44.Rubens M. et al.Precise polymer synthesis by autonomous self-optimizing flow reactors.Angew. Chem. Int. Ed. 2019; 58: 3183-3187Crossref PubMed Scopus (68) Google Scholar]. LabVIEW was used to modulate reaction parameters via pump control as well as optimize the process based on user-defined optimization criteria. The user could direct the optimization algorithm towards a desired Mn, weight average (MW), or peak molecular weight (Mp) with impressive accuracy (<2.5%). A size exclusion chromatography module was crucial to implementation of the closed-loop optimization since traditional small molecule PAT was not suitable. The flexibility of this approach was shown by tasking the system with chain extensions for block-copolymer synthesis and scale-out of optimized target Mn conditions. Proteins are uniform, sequence-defined biopolymers assembled from amino acid monomers that may be synthesized by either biological expression or chemical synthesis. Biological expression is efficient, but largely limited to proteins composed of canonical amino acids, whereas chemical methods are free from this barrier. Automated chemical peptide synthesis has largely been performed using batch-wise solid phase peptide synthesis (SPPS), but flow-based SPPS has gained traction [45.Vanier G.S. Microwave-assisted solid-phase peptide synthesis based on the Fmoc protecting group strategy (CEM).in: Jensen K.J. Peptide Synthesis and Applications. Methods in Molecular Biology. Humana Press, 2013: 235-249Crossref Scopus (23) Google Scholar,46.Mándity I.M. et al.Continuous-flow solid-phase peptide synthesis: a revolutionary reduction of the amino acid excess.ChemSusChem. 2014; 7: 3172-3176Crossref PubMed Scopus (42) Google Scholar]. Mijalis, Thomas, and coworkers have shown that using a flow reactor with high flow rate regimes (~100 ml/min) can rapidly construct peptides with residue cycling times on the order of 1 minute [47.Mijalis A.J. et al.A fully automated flow-based approach for accelerated peptide synthesis.Nat. Chem. Biol. 2017; 13: 464-466Crossref PubMed Scopus (157) Google Scholar]. A UV/Vis spectrophotometer offered relative quantitation of coupling efficiency through monitoring of Fmoc protecting group byproducts from cycle turnovers. Truex, Holden, and coworkers continued this work by tasking the system with preparing tumor neoantigen peptides (up to 29-mers) suitable for personalized immunotherapy, showing how a flexible and automated flow device can be used to rapidly construct personalized medicines on-demand [48.Truex N.L. et al.Automated flow synthesis of tumor neoantigen peptides for personalized immunotherapy.Sci. Rep. 2020; 10: 723-733Crossref PubMed Scopus (13) Google Scholar]. Most recently, Hartrampf and coworkers further optimized the system to accommodate even greater chain lengths (Figure 3B) [49.Hartrampf N. et al.Synthesis of proteins by automated flow chemistry.Science. 2020; 368: 980-987Crossref PubMed Scopus (80) Google Scholar]. In one example, the barnase protein, which consists of 110 amino acid residues, was prepared in just 4.5 hours of synthesis time. Following purification, the protein was folded and found to have enzymatic activity comparable with recombinant barnase. Droplet-based segmented flow reactors have received considerable attention for the synthesis of nanomaterials such as quantum dots and perovskite nanocrystals with potential applications in LED displays and photovoltaics [50.Nette J. et al.Microfluidic synthesis of luminescent and plasmonic nanoparticles: fast, efficient, and data-rich.Adv. Mater. Technol. 2020; 52000060Crossref Scopus (25) Google Scholar]. In segmented gas–liquid or liquid–liquid flow, short length scales for heat and mass transfer and fast mixing timescales due to recirculating flow within moving droplets (Figure 4A ) provide tight control over reaction conditions and, therefore, critical quality attributes (e.g., nanoparticle size distribution, shape). Consequently, automated segmented flow reactors integrated with in situ characterization are well-suited for studying nanoparticle growth kinetics and closed-loop engineering of optical properties. Epps [51.Epps R.W. et al.Automated microfluidic platform for systematic studies of colloidal perovskite nanocrystals: towards continuous nano-manufacturing.Lab Chip. 2017; 17: 4040-4047Crossref PubMed Google Scholar] and Abdel-Latif [52.Abdel-Latif K. et al.Facile room-temperature anion exchange reactions of inorganic perovskite quantum dots enabled by a modular microfluidic platform.Adv. Funct. Mater. 2019; 291900712Crossref Scopus (59) Google Scholar] leveraged a microreactor screening platform to study the fast nucleation, growth, and anion exchange kinetics (on the order of seconds) of inorganic lead halide perovskite (LHP) nanocrystals under controlled mixing conditions (Figure 4B,C). A flow cell for in situ absorption and photoluminescence (PL) spectroscopy programmed to translate along the reactor and record spectra at up to 40 different positions provided access to reaction timescales spanning four orders of magnitude (100 milliseconds to 17 minutes). For hybrid organic–inorganic perovskite synthesis, Lignos and coworkers [53.Lignos I. et al.Exploration of near-infrared-emissive colloidal multinary lead halide perovskite nanocrystals using an automated microfluidic platform.ACS Nano. 2018; 12: 5504-5517Crossref PubMed Scopus (99) Google Scholar,54.Lignos I. et al.Unveiling the shape evolution and halide-ion-segregation in blue-emitting formamidinium lead halide perovskite nanocrystals using an automated microfluidic platform.Nano Lett. 2018; 18: 1246-1252Crossref PubMed Scopus (83) Google Scholar] developed a microfluidic platform with online absorption and PL spectroscopy for elucidating the formation mechanism of stable red-emitting [53.Lignos I. et al.Exploration of near-infrared-emissive colloidal multinary lead halide perovskite nanocrystals using an automated microfluidic platform.ACS Nano. 2018; 12: 5504-5517Crossref PubMed Scopus (99) Google Scholar] and blue-emitting [54.Lignos I. et al.Unveiling the shape evolution and halide-ion-segregation in blue-emitting formamidinium lead halide perovskite nanocrystals using an automated microfluidic platform.Nano Lett. 2018; 18: 1246-1252Crossref PubMed Scopus (83) Google Scholar] LHP nanocrystals. The examples described herein could collect ~10 000 unique spectra/day while only consuming micro- to milliliter quantities of precursors, underscoring their incredible speed and efficiency. For closed-loop optimization of LHP nanocrystal composition, Bezinge and coworkers applied a Kriging-based algorithm entitled ‘MARIA’ to synthesize nanocrystals with target emission wavelengths (i.e., color) (Figure 4D) [55.Bezinge L. et al.Pick a color MARIA: adaptive sampling enables the rapid identification of complex perovskite nanocrystal compositions with defined emission characteristics.ACS Appl. Mater. Interfaces. 2018; 10: 18869-18878Crossref PubMed Scopus (50) Google Scholar]. The algorithm identified optimal compositions with fewer experiments than an exhaustive screen and was also able to predict other optical properties such as full width at half-maximum (FWHM) and PL intensity. Recently, Epps and coworkers applied a neural network-based algorithm for simultaneously optimizing PL quantum yield and FWHM (to within 1 meV) for perovskite quantum dots with 11 different target colors (Figure 4E) [56.Epps R.W. et al.Artificial chemist: an autonomous quantum dot synthesis bot.Adv. Mater. 2020; 322001626Crossref PubMed Scopus (84) Google Scholar]. Scaling up the optimal conditions produced quantum dots at roughly 220 g/day. Discoveries in visible-light photoredox catalysis have yielded methods for the construction of high-value targets that have been rapidly adopted by the pharmaceutical industry [57.Li P. et al.Visible-light photocatalysis as an enabling technology for drug discovery: a paradigm shift for chemical reactivity.ACS Med. Chem. Lett. 2020; 11: 2120-2130Crossref PubMed Scopus (33) Google Scholar, 58.Brill Z.G. et al.Continuous flow enables metallaphotoredox catalysis in a medicinal chemistry setting: accelerated optimization and library execution of a reductive coupling between benzylic chlorides and aryl bromides.Org. Lett. 2020; 22: 410-416Crossref PubMed Scopus (23) Google Scholar, 59.McAtee R.C. et al.Illuminating photoredox catalysis.Trends Chem. 2019; 1: 111-125Abstract Full Text Full Text PDF Scopus (202) Google Scholar]. The intense and uniform light exposure often achieved in continuous reactor designs makes it an ideal development technology [60.Sambiagio C. Noël T. Flow photochemistry: shine some light on those tubes!.Trends Chem. 2020; 2: 92-106Abstract Full Text Full Text PDF Scopus (146) Google Scholar]. Hsieh and coworkers have reported a droplet-based segmented flow reactor for closed-loop optimization of a photoredox decarboxylative arylation reaction (Figure 5A ) [61.Hsieh H.-W. et al.Photoredox iridium–nickel dual-catalyzed decarboxylative arylation cross-coupling: from batch to continuous flow via self-optimizing segmented flow reactor.Org. Process. Res. Dev. 2018; 22: 542-550Crossref Scopus (72) Google Scholar,62.Zuo Z. et al.Merging photoredox with nickel catalysis: coupling of α-carboxyl sp3-carbons with aryl halides.Science. 2014; 345: 437-440Crossref PubMed Scopus (1011) Google Scholar]. The platform was equipped with a liquid handling system for reagent selection, a 34 W blue LED light, and a HPLC for analytical measurements. Individual experiments were performed by injecting a microslug into the reactor analogous to a miniaturized batch reaction, but with flow characteristics. Both MATLAB and LabVIEW were used to control hardware and a mixed-integer nonlinear optimization algorithm was capable of handling discrete variables. Photocatalysts, stoichiometric bases, and Ni-precatalysts were successfully optimized along with the traditional set of continuous variables such as temperature and stoichiometry. Synthetic organic electrochemistry is a sustainable method to perform complex redox chemistry that exchanges chemical reagents with precisely tunable electrochemical potential [63.Fu N. et al.Metal-catalyzed electrochemical diazidation of alkenes.Science. 2017; 357: 575-579Crossref PubMed Scopus (378) Google Scholar, 64.Laudadio G. et al.Sulfonamide synthesis through electrochemical oxidative coupling of amines and thiols.J. Am. Chem. Soc. 2019; 141: 5664-5668Crossref PubMed Scopus (99) Google Scholar, 65.Kawamata Y. et al.Scalable, electrochemical oxidation of unactivated C–H bonds.J. Am. Chem. Soc. 2017; 139: 7448-7451Crossref PubMed Scopus (253) Google Scholar]. Electrochemical flow devices provide tangible benefit