Continuous-flow synthesis has attracted considerable attention as a subject of fundamental scientific research and as a key technology for advanced manufacturing.¹  In comparison with batch systems, flow systems bring great advantages to chemical processes in terms of sustainability, efficiency, and safety. Continuous-flow systems can be classified into four categories based on the types of reactions that are to be performed under the flow conditions (Figure 1.1).²  The most straightforward case is when all reagents are continuously fed into a tube- or pipe-flow reactor, and the product is continuously collected (type I). This process has been developed mainly as microflow chemistry, and to date, several remarkable achievements have been made in this area. However, unreacted starting materials and by-products are often eluted along with the product, and quenching and work-up processes are necessary. The use of immobilized reagents packed into a column flow reactor has been investigated to reduce coproduction of by-products (type II). The drawback to this approach is that overreactions may occur, and when a supported reagent is consumed, a flow reactor must be changed. Since modern organic chemistry is heavily reliant upon catalysis to improve the efficiency and selectivity of reactions, flow reactions can be conducted by feeding homogeneous catalysts with substrates (type III). Utilization of homogeneous catalysts for desired reactions is a straightforward approach for realizing a catalytic process under flow. Usability of a homogeneous catalyst without any further processing and the sustainability of product quality during the whole process offer great advantages; however, further processing to quench the catalytic reaction and to remove the catalyst cannot be avoided, and this may interrupt the seamless operation of a multistep flow reaction. On the other hand, use of heterogeneous catalysts with column-type fixed-bed reactors, categorized as type IV flow reactions, would reduce inactivation and loss of the catalysts, and contamination of catalyst residue in the output of reactions can be avoided. From the viewpoint of the construction of multistep sequential continuous-flow production of high value-added compounds, type IV is ideal. Given that numerous efforts for achieving efficient noncatalytic continuous-flow organic reactions are discussed in other chapters and that a number of excellent reviews concerning homogeneous and heterogeneous catalytic continuous-flow organic reactions are available,³  here we provide an overview of recent advances in flow heterogeneous catalytic processes especially in enantioselective reactions, photocatalytic reactions, integration of more than two continuous-flow processes for sequential transformation of organic compounds, and progress in engineering aspects for establishing efficient processes.

Enantioselective catalysis plays a key role in the synthesis of fine chemicals such as biologically active compounds and natural products, which are usually chiral compounds. In this context, flow heterogeneous catalysis is an ideal method for the efficient syntheses of such compounds, not only because of the general advantages of flow reactions over batch reactions, but also because contamination by catalysts of the products can be avoided and the amount of catalyst can be reduced. Therefore, synthetic chemists have been trying to develop efficient heterogeneous flow catalysis by precise design of heterogeneous catalysts. The history of catalytic enantioselective reactions under continuous-flow began in the early 1990s, when immobilized chiral ligands on solid supports were typically used.⁴  Since then, various types of heterogeneous catalysts have been developed by using a range of immobilization strategies. However, there remain general problems to overcome such as decreased activity and selectivity compared with homogeneous catalysts. In this chapter, significant developments in heterogeneous flow reactions that have been achieved since 2013 are discussed in two sections. The first section discusses immobilized organocatalysis (non-metal catalysis); in the second section, the use of metal catalysis is covered.

Since the development of MacMillan catalyst in 2000, various kinds of efficient chiral organocatalysts (non-metal catalysts) have been developed, such as Hayashi–Jørgensen catalysts, Akiyama–Terada catalysts, and thiourea catalysts.⁵  Currently, asymmetric organocatalysis has become one of the most powerful tools to synthesize chiral compounds. Thanks to their stability and easily modifiable nature, various covalent methods have been developed to immobilize active species on solid supports. In particular, postmodification of functionalized polystyrene resins has become a common technique. Since 2013, much effort has been devoted to expanding the scope of catalysts and types of catalysis.

In 2014, Benaglia and Cozzi et al. reported the enantioselective α-alkylation of an aldehyde with a stable carbocation, in which MacMillan-type catalysts were immobilized through covalent bonds to polystyrene or silica support. The catalyst activity was first evaluated with different electrophiles under batch conditions (Figure 1.2).⁶ 

It was revealed that silica-supported catalyst 1 showed slightly higher activity than the polystyrene-supported catalyst 2, whereas 2 showed higher enantioselectivity than 1 in most cases, although the structure of the active site is identical. Moreover, higher enantioselectivity was observed compared with the homogeneous catalyst for some electrophiles. This clearly indicated that support material has a non-negligible effect on catalyst performance. Continuous-flow catalysis was also examined using polystyrene-immobilized catalyst 2, and the same level of enantioselectivity under batch conditions was achieved, although there remained room for improvement in yield (Figure 1.3).

Also, in 2014, Pericàs and colleagues developed the first example of a three-component asymmetric Mannich reaction under continuous-flow conditions.⁷  They investigated several kinds of immobilized natural primary amino acid catalysts under batch conditions, and finally threonine-derived catalyst 3, which showed similar levels of stereoselectivity, was determined to be the best catalyst. Notably, each heterogeneous catalyst showed significantly different activity and selectivity. Solvent screening revealed that swelling of the polymer catalyst was critical for the catalytic activity. Unfortunately, catalyst deactivation was observed during recycling experiments, and the authors concluded that, based on the IR spectrum, the cause of deactivation was loss of a carboxylate group. By using the best catalyst, the continuous-flow three-component Mannich reaction was investigated (Figure 1.4). In-line IR analysis was employed to determine the conversion of the substrate and the best flow rate. Under the optimized reaction conditions, excellent stereoselectivity was achieved, and the turnover number (TON) was increased twofold compared with batch conditions. Finally, Pericàs and coworkers demonstrated that the system could also be employed for the construction of a small library of products by changing the substrate solution every hour. This is a rather unique application of the continuous-flow process.

The lifetime of heterogeneous catalysts remains a significant hurdle to realizing sustainable flow synthesis. Pericàs's group addressed this point and in 2015 developed a robust enamine catalyst for continuous-flow reaction.⁸  It is known that immobilized Hayashi–Jørgensen catalyst gradually deactivates during recycling experiments because of desilylation of the TMS ether. To overcome this issue, a robust homogeneous catalyst was developed by Gilmour and coworkers by replacing TMS ether with a fluorine substituent.⁹  It was found that catalyst 4 was much more robust than the original catalyst and did not suffer from significant loss of selectivity. Therefore, the authors investigated the immobilization of the fluorinated catalyst for 1,4-addition of aldehydes to nitrostyrenes. As a result, the polymer-supported catalyst demonstrated excellent activity and selectivity under batch conditions. Recycling experiments revealed that although the catalyst remained active until the eighth run, gradual deactivation was still observed. Control experiments revealed that deactivation was caused by oxidation of the enamine intermediate by oxygen from the air. Therefore, it was decided to employ continuous-flow conditions, which can minimize contact with air. As expected, the catalyst kept its activity for more than 13 h and the TON reached over 60 without loss of enantioselectivity. A library construction was also performed using different substrate solutions and the same catalyst column (Figure 1.5).

Pericàs's group also investigated the effect of an anchoring strategy and the type of polymeric support for the catalyst activity. Asymmetric cyclopropanation was selected as a model reaction and several types of immobilized Hayashi–Jørgensen catalysts were evaluated under continuous-flow conditions.¹⁰  Notably, significant activity and selectivity difference were observed for each catalyst. As a general tendency, monolith catalyst showed lower activity but slightly higher selectivity. Immobilization through the diaryl part resulted in lower activity, probably because of the short distance between the support and active site. Substrate scope was investigated by using 5a as a heterogeneous catalyst through the construction of a product library. Different substrate solution was flowed into the reactor every 6 h using the same catalyst column. The resulting product solution could be directly connected to the flow Horner–Wadsworth–Emmons reaction without any purification (Figure 1.6).

In 2017, Pericàs's group developed a novel type of chiral primary amine catalyst for asymmetric Robinson annulation.¹¹  A t-leucine-derived 1,2-diamine 8 was chosen as the target catalyst for immobilization based on the reported homogeneous catalysis. A novel immobilized catalyst was synthesized in six steps starting from t-leucine and evaluated for Robinson annulation. During optimization of the reaction conditions, it was revealed that the activity of the heterogeneous catalyst depended significantly on the reaction temperature, and that the reaction reached completion within 1 h at 55 °C. Interestingly, such temperature dependence was not observed using a homogeneous catalyst, and lower activity was observed. It was suggested that the nonpolar environment of the polymer had a positive effect on catalyst activity and that the higher temperature enhanced the mass transfer in the polymer matrix. Continuous-flow catalysis of 8 was investigated using meso triketones formed in situ, because vinyl ketones were found to be a catalyst poison due to aza-Michael addition reaction. Eight kinds of chiral diketones could be synthesized in moderate to good yield with good enantioselectivity (Figure 1.7).

BINOL-derived chiral phosphoric acid (CPA) catalysts—commonly known as Akiyama–Terada catalysts and developed independently in 2004—have been revealed to be highly active, highly selective, and robust chiral Brønsted acid catalysts.^5c  They can activate imines, aldehydes, and α,β-unsaturated carbonyl compounds by protonation, and at the same time create an ideal chiral environment for enantioselective catalysis. Since 2013, there have been a number of significant advances in the field of flow CPA catalysis. The first immobilized CPA catalysis was reported by Pericàs and colleagues in 2014 in asymmetric aminoalkylation of indoles.¹²  The anchor was introduced at the 6-position on the binaphthyl backbone, and covalently immobilized on Merrifield resin. The prepared heterogeneous catalyst 9 showed similar enantioselectivity to that of the homogeneous catalyst even at room temperature under batch conditions. Catalyst 9 was found to be robust and it could be easily reactivated by simple acid treatment after deactivation. With successful results under batch conditions, catalysis under continuous-flow conditions was also examined. Catalyst 9 showed high activity and selectivity, and the total TON reached 102. Under the same reaction conditions, five kinds of chiral products were synthesized in excellent yield and enantioselectivity (Figure 1.8).

The other example of heterogeneous CPA catalysis is an asymmetric allylboration of aldehydes, which was reported in 2016 by Pericàs's group.¹³  Here, the method of preparation of the heterogeneous catalyst was improved by changing the structure of the anchor. By using the same intermediate for the preparation of homogeneous catalysts, dibromination at the 6,6′-position of BINOL followed by Suzuki–Miyaura coupling afforded BINOL with a vinyl group. Copolymerization with styrene and DVB was then conducted to afford the desired chiral BINOL-immobilized polymer. Finally, postfunctionalization of PS-BINOL with POCl₃ gave the heterogeneous CPA catalyst PS-TRIP 10, which exhibited high activity and selectivity under both batch and continuous-flow conditions. In particular, no catalyst deactivation was observed over 28 h, and the target product was obtained in excellent yield and selectivity with a TON of 282 (Figure 1.9).

In recent years, several other types of organocatalyst have been transferred into heterogeneous phases and applied to continuous-flow catalysis. Although such examples are still limited compared with enamine catalysis or CPA catalysis, they provide a new and unique methodology to synthesize chiral molecules.¹⁴ 

In 2015, Pericàs and coworkers developed for the first time a polymer-supported benzotetramisole catalyst as an organic Lewis base catalyst for flow reaction. The catalyst could be prepared from enantiopure alkynyl epoxy ether in four steps, and immobilized on Merrifield resin by Huisgen cyclization. The prepared catalyst 11 was evaluated for domino Michael addition/cyclization reaction between acid anhydride and α,β-unsaturated imines.¹⁵  It was revealed that stoichiometry of PivCl was crucial to prevent catalyst deactivation, and, interestingly, demonstrated higher diastereoselectivity compared with a homogeneous catalyst. Continuous-flow catalysis was performed using a solution of mixed anhydride formed in-line. The use of in-line quenching and a liquid–liquid separator allowed continuous production and collection of the crude organic phase. The target product was obtained in 70% yield with >99% ee with a TON of 22.5 (Figure 1.10).

In 2017, Puglisi's group developed immobilized N-picolylimidazolidinines as a new class of chiral heterogeneous Lewis base catalysts. The same group previously discovered that N-picolylimidazolidinines could act as asymmetric hydrosilylation catalysts of imines, and the authors subsequently succeeded in immobilization of their catalysts to conduct continuous-flow reactions.¹⁶  Three heterogeneous catalysts 12 could be prepared from tyrosine and immobilized on different supports and with different anchors. The catalysts were evaluated for the asymmetric hydrosilylation of a ketimine under batch conditions. It was found that polystyrene-supported catalysts showed higher activity and selectivity than silica-supported catalysts. In particular, triazole-anchored catalysts showed significantly lower selectivity. The best catalyst was also applied for continuous-flow reaction. Although activity remained excellent and constant, a reduction in the level of enantioselectivity was observed over time. The cause of the deactivation was suggested to be partial degradation of the imidazolidinone ring (Figure 1.11).

Hydrogen-bonding organocatalysts have gained attention as powerful acid/base catalysts. Unlike enamine catalysis, they do not provide a covalent bond with the substrate in a transition state; therefore, undesirable catalyst decomposition pathways can be minimized. Such a feature is also attractive for those who investigate heterogeneous catalysts, because stability is a key factor to develop efficient and recyclable catalysts. Pericàs and colleagues developed the first heterogeneous thiourea catalysts as a representative H-bonding catalyst, and employed it for asymmetric amination reaction of 1,3-dicarbonyl compounds.¹⁷  The authors had often used Huisgen cyclization as an anchoring reaction to immobilize the active site onto a polystyrene matrix. However, the initial investigation revealed that the use of the heterogeneous thiourea catalyst prepared by such a protocol led to inconsistent results. It was reasoned that the Cu contamination during Huisgen cyclization was a problem, and therefore a triazole-free thiourea catalyst was prepared. As expected, the newly prepared catalyst 13 showed excellent activity and selectivity for α-amination of 1,3-dicarbonyl compounds. Although deactivation was observed during recycling experiments, the authors identified that the deactivation was caused by partial protonation of the tertiary amine rather than degradation of the thiourea part, and the catalyst could be reactivated by amine treatment. Therefore, continuous-flow catalysis was performed in the presence of a catalytic amount of triethylamine to minimize catalyst deactivation and enhance reactivation. As a result, the catalyst remained active for over 7.5 h operation with >90% enantioselectivity (Figure 1.12).

In 2016, Pericàs and coworkers further improved the immobilization method by avoiding the use of expensive CF₃-substituted carboxylic acid linker as well as Huisgen cyclization.¹⁸  A chiral squaramide was chosen as the target H-bonding catalyst, and it was immobilized in a similar manner to that of the previous thiourea catalyst.¹⁸  The prepared catalysts were evaluated in the 1,4-addition to nitro styrenes. It was found that the simple 4-carboxylate group worked as a sufficient linker, and its performance improved further by introducing a longer spacer between the active site and the polymer backbone. Continuous-flow catalysis was examined using the best catalyst 14, and excellent activity and selectivity were observed. Furthermore, the resulting product solution could be connected to base-promoted oxy-cyclization reaction to synthesize chiral pyranonaphthoquinones in a stereoselective manner (Figure 1.13).

Chiral N-heterocyclic carbene (NHC) catalysts provide a new and nonconventional synthetic strategy to produce chiral molecules because of their umpolung nature. Massi's group reported the first use of chiral heterogeneous NHC catalysts under continuous-flow conditions in 2017.¹⁹  The heterogeneous catalyst was prepared from chiral aminoindanol and immobilized by copolymerization with styrene as a BF₄ salt. The prepared heterogeneous catalyst was employed for intramolecular Stetter reaction under batch conditions. Reactions were carried out in the presence of a catalytic amount of base to form NHC in situ, and KHMDS was found to be the best initiator. Under the optimized reaction conditions, the target cyclized compound could be obtained in good yield with excellent enantioselectivity. For the continuous-flow reaction, monolith catalyst precursor 15 was prepared inside a column reactor. The flow catalysis was initially investigated in the presence of 50 mol% of KHMDS in the substrate solution. However, undesired side product generated by the base-promoted vinylogous aldol condensation was obtained. On the other hand, decreasing the amount of KHMDS resulted in poor conversion of the starting material. Finally, it was found that NEt₃ was a suitable base to form active NHC from imidazolium salt and to suppress undesired base-promoted side reaction. Under the optimized reaction conditions, seven kinds of chiral chromanones could be obtained in excellent yield and selectivity (Figure 1.14).

Chiral metal catalysis has been the principle and most powerful methodology to prepare a large range of chiral molecules in the field of homogeneous catalysis. Furthermore, the applications of such species to heterogeneous catalysis and continuous-flow reactions have a long history. Indeed, the first asymmetric flow reaction with a heterogeneous metal-mediated catalyst was an enantioselective diethylzinc addition reaction using an immobilized chiral ligand.⁴  However, the successful examples are still limited despite the significant advances in enantioselective homogeneous catalysis. In general, heterogeneous enantioselective catalysis suffers from lower activity and selectivity compared with original homogeneous catalysts. Furthermore, the lifetime of catalysts is a problem and should be considered for every system. This is mainly due to lower stability against oxygen and moisture. In this section, recent achievements in this field are introduced, with the two major immobilization strategies presented as two subsections.

Immobilization of chiral ligands on solid supports through covalent bonds is one of the most straightforward methods to attain chiral heterogeneous catalysts. Indeed, most of the reported enantioselective heterogeneous catalysts are included in this category. However, until recently, the scope of reactions was mostly limited to simple acid/base catalysis and hydrogenation reactions. Since 2013, new types of catalysis under continuous-flow reactions have appeared.

Asymmetric C–F bond formation has gained attention due to the high synthetic utility especially for drug molecules. Xu's group reported the first asymmetric fluorination reaction catalyzed by heterogeneous Cu Lewis acid catalyst in 2018.²⁰  A chiral aniline-linked BOX was immobilized by copolymerization with styrene. Three kinds of polymer catalysts were prepared with different cross-linking and evaluated under batch conditions. It was found that either too much or too little cross-linking led to lower enantioselectivity. Unfortunately, significant decreases in enantioselectivity were observed for almost all catalysts in recycling experiments. In contrast, the best catalyst, 16, possesses an extremely long lifetime under continuous-flow conditions. The enantioselectivity was kept over 90% ee for over 30 days continuous-flow reaction (Figure 1.15).

Asymmetric 1,4-addition of arylboronic acid is an important C–C bond formation reaction that allows the enantioselective introduction of aryl groups. In this field, Rh-chiral diene catalysts have gained much attention because of their superior activity and selectivity over conventional phosphine catalyst systems. Uozumi's group developed polymer-immobilized chiral diene-Rh catalyst 17 and applied it in continuous-flow reactions.²¹  The catalyst was evaluated under batch conditions using water as the sole solvent, and showed high activity and selectivity as well as excellent recyclability. On the other hand, the continuous-flow reaction was examined using water–ethanol mixed solvent because of the solubility of organic substrate. This might show a clear difference between batch and flow. Homogeneity of the reactant in the solution phase is crucial for reactivity in flow. Optimization of reaction conditions revealed that a stoichiometric amount of KOH was necessary to promote the reaction, whereas no strong base was required under batch conditions. Under such flow conditions, the target compound was obtained in moderate yield with excellent enantioselectivity and the TON reached 1073 (Figure 1.16).

Transition-metal-catalyzed asymmetric carbene insertion provides a unique method to construct stereogenic centers because of the highly reactive metal–carbene intermediate. Such transformations were already reported under continuous-flow conditions. However, the type of reaction was limited to cyclopropanation reactions. In 2018, Maguire's group investigated a flow intramolecular asymmetric C–H insertion reaction.²²  A chiral bisoxazoline ligand was immobilized by copolymerization and its heterogeneous copper complex 18 was utilized in the reaction. The prepared catalyst was first examined under batch conditions and the activity was comparable with that of the homogeneous catalyst, although decreased selectivity and partial leaching of Cu were observed (Figure 1.17).

Another important example of carbene insertion catalysis was reported by Davies and Jones et al. in 2018. A series of chiral Rh(ii) carboxylate dimers are known to be powerful tools for highly enantioselective C–H insertion reactions. In this context, a silica-immobilized chiral carboxylate, prepared by postmodification with a silane coupling technique, was applied for flow enantioselective reaction with Rh catalysis.²³  Here, diazo compounds formed in situ by oxidation of hydrazones were employed, and the catalyst showed excellent performance not only for simple cyclopropanation reactions, but also for more challenging C–H insertion reactions (Figure 1.18).

Noncovalent-bond immobilization of transition-metal complexes is a promising method to develop heterogeneous catalysts without any structural change of the original ligands. However, there are still only a limited number of successful examples of applications for continuous-flow catalysis compared with immobilized ligand strategies. Indeed, before 2014, most reported methods relied on one immobilization method, termed the Augustine method.²⁴  However, new types of immobilization methods have emerged since 2014 and this chapter describes the development of such examples. In 2015, Leitner's group reported a supported ionic liquid phase (SILP) catalyst for continuous-flow hydrogenation of enol esters using scCO₂ as the mobile phase.²⁵  A biphasic reaction between IL and scCO₂ was examined first. The cationic Rh catalyst stayed in the IL phase and the substrate was introduced in the scCO₂ solution with H₂ gas. Continuous-flow catalysis was performed by collecting the scCO₂ phase. Unfortunately, significant decreases in both activity and enantioselectivity were observed. Therefore, they developed a SILP catalyst by mixing Rh complex, ionic liquid, and silica. The prepared catalyst systems 20 and 21 showed significantly improved stability over simple IL phase catalyst. The catalytic activity remained for more than 130 h without significant loss of either activity or selectivity. Later, the same method was employed to prepare a key intermediate to synthesize an active pharmaceutical intermediate (Figure 1.19).

A unique heterogeneous catalyst was developed by Shibasaki's group in 2009.^26a  They found that mixing of neodyum salt, sodium salt, and chiral amide formed a chiral heterobimetallic compound by self-assembly that worked as an efficient heterogeneous acid/base catalyst for the asymmetric Henry reaction. Later, the group applied it to continuous-flow conditions by immobilizing onto MWCNT (catalyst 22). Recently, the method was expanded for the synthesis of a key intermediate of API (Figure 1.20).^26b 

Metal–organic frameworks (MOFs) have gained much attention from synthetic organic chemists as a new material for catalyst supports. These materials can be considered as a suitable support for single-site catalysis, especially for asymmetric catalysis because of the homogeneity of the active site. Cui's group reported the first example of the application of MOF-immobilized catalyst for continuous-flow reactions.²⁷  The group designed a linker containing a chiral phosphoric acid with a carboxylic acid moiety, and employed it for MOF formation. Mn(ii) was used as a node metal, and it was expected to work as a chiral Lewis acid as well. The prepared MOF 23 showed good crystallinity, porosity, and chemical stability. This catalyst was used for asymmetric Friedel–Crafts reaction and it showed significantly higher enantioselectivity than that of the homogeneous catalyst. It also showed excellent activity and selectivity under continuous-flow conditions (Figure 1.21).

Photoredox catalysis has recently shaken up the global chemist's community by making possible a myriad of unsolved synthetic issues through single-electron transfers promoted by light sources.²⁸  In addition to using an infinite energy supply, applications to continuous-flow processes have shown tremendous advantages because of the efficacy of light penetration and irradiation control, allowing significant accelerations in reaction rate.²⁹  This physical property of light, associated with the Beer–Lambert law, pushed the organic synthesis community to design new reactors to optimize the light penetration to promote efficient and reproducible organic transformations.³⁰  Transition-metal complexes and organic dyes have been widely utilized as homogeneous catalysts, and they have been shown to have a wide range of uses in continuous-flow systems. On the other hand, the utilization of heterogeneous photocatalysts, which have the advantage of being more sustainable with respect to their recyclability, remains scarce because of light penetration effects. In this section, the advantages afforded by flow photocatalysis that have been identified after 2013 are emphasized. These efforts extend from work on well-established homogeneous photocatalysis to recent efforts toward the development of efficient heterogeneous photocatalysts for flow organic synthesis.

The most commonly used strategy for flow homogeneous catalysis relies on transition-metal complexes, such as iridium and ruthenium polypyridines. Benefiting from their absorbance in the visible-light region, reactor designs have been highly simplified and reaction conditions softened. Since 2013, iridium and ruthenium catalysis has been involved in many flow transformations. A widely covered area concerns fluorination reactions, which were made possible by safe handling of fluorinating gasses in flow.³¹  Noël and coworkers developed trifluoromethylation transformations by combining inexpensive CF₃I gas in a microflow reactor with Ru(bpy)₃ under irradiation with visible light (blue LEDs) (Figure 1.22).^32,33 

In particular, thiols and heterocycles could be functionalized safely thanks to accurate delivery of CF₃I, which was monitored by mass-flow controllers. Noël's group also used photoactivated styrenes³⁴  and aliphatic double bonds,³⁵  which are normally challenging species because of the possibility of radical polymerization, to promote photocatalytic trifluoromethylation, hydrofluoromethylation, and difluoroalkylation reactions through the use of fac-Ir(ppy)₃ and CF₃I. The utilization of continuous flow not only allowed reaction acceleration compared with batch systems but also increased the selectivity of the transformations in all cases. Around the same period, Jamison's group pioneered the practical use of SF₆ fluorinating reagent in organic synthesis, and showed its application to the deoxyfluorination of allylic alcohols activated by Ir(ppy)₂(dtbbpy)PF₆ as photoredox catalyst (Figure 1.22).³⁶  Although regioselectivity remained moderate in continuous flow, significant improvement in yields, operational simplicity, and product throughput were demonstrated. Ir- and Ru-photocatalyzed flow reactions have found numerous applications in synthetic methods, including in the total syntheses of natural products. In 2014, Stephenson reported the semisynthesis of (−)-pseudotabersonine, (−)-pseudovincadifformine, and (+)-coronaridine from natural (+)-catharanthine enabled by photoredox catalysis.³⁷  In this work, the combination of visible light and Ir(dF(CF₃)ppy)₂(dtbbpy)PF₆ catalyzed the formation of a common intermediate in flow, allowing tremendous reaction acceleration (from 3 h in batch to 2 min in flow), and an unprecedented high-yielding strategy for accessing these natural skeletons. The same photoredox catalyst was utilized by Fujimoto and coworkers for the formal total synthesis of l-ossamine via decarboxylative functionalization.³⁸  In this example, decarboxylative functionalization of threonine derivatives was achieved in flow, which allowed improvement of the yield from 50% to 80% and a reduction in the reaction time from 47 h to 4 h.

In another recent application, Ir and Ru photocatalysts were engaged in dual catalysis for flow systems. In 2016, Ley's group developed a new activation procedure of boronic esters to promote C(sp²)–C(sp³) cross-couplings in flow.³⁹  In this method, an iridium photoredox catalyst (Ir(dF(CF₃)ppy)₂(dtbbpy)PF₆) was coupled with another nickel catalyst in the presence of two equivalents of a pyridine-derived Lewis base, inducing cross-coupling of bromo and cyano arenes with boronic esters. As a particular asset, this procedure enabled the replacement of insoluble potassium trifluoroborate salts with soluble and easily accessible boronic esters, and could be utilized as an efficient and high-throughput continuous-flow process. Van der Eycken and Noël also described a dual photoredox/transition-metal catalyzed room-temperature protocol for the C-2 acylation of indole in batch and flow.⁴⁰  As fac-Ir(ppy)₃ and Pd(OAc)₂ were found to be suitable catalytic partners, comparison of batch versus flow always afforded better yields in a microflow reactor, while highlighting significant reaction acceleration (from 20 h in batch to 2 h in flow) as well as enabling a decrease of catalyst loading (from 2 to 0.5 mol%).

One issue that has been addressed in recent years is the continuous recovery of Ir and Ru photocatalysts to increase processes sustainability.⁴¹  Rueping's group exploited the properties of ionic liquids to promote continuous recycling of an Ir photocatalyst ((Ir(ppy)₂(bpy))(PF₆)) for photoisomerization of stilbenes (Figure 1.23).⁴² 

In this work, the transition-metal catalyst was immobilized on [bmim][BF₄] ionic liquid, subsequently flowed, and connected with a separated solution of trans-stilbene in n-pentane. The resulting biphasic system profited from efficient mixing in a loop photoflow reactor to induce high conversion of isomerization, resulting in reduced reaction times and higher productivity. Importantly, the outgoing reaction mixture afforded the desired cis-stilbene product in the upper pentane phase, while photocatalyst was still trapped in the ionic liquid phase, facilitating its continuous recycling. In a different approach, Reiser and colleagues synthesized a polyisobutylene-tagged fac-Ir(ppy)₃ complex that could be used as a recyclable homogeneous photocatalyst in a flow system thanks to the use of a thermomorphic or biphasic solvent system.⁴³  Alternatively, Kappe and coworkers implemented a macromolecular ruthenium complex that could be separated in flow by size-exclusion nanofiltration.⁴⁴  Here, [Ru(bpy)₃]²⁺ was anchored to a polyamidoamine (PAMAM) dendrimer, and showed similar efficiency to that of monomeric [Ru(bpy)₃]²⁺ photocatalysts for a set of three model reactions (phosphine-free Appel reaction, reductive opening of α,β-epoxide chalsone, and arylazide reduction).

Despite their intense utilization, Ir- and Ru-based transition-metal catalysts are increasingly problematic because of their high cost and toxicity. Although recyclability trials have shown promise, replacement in favor of more abundant transition metals has had a strong impact on photoredox processes. Nickel is one of the most earth-abundant transition metals, and it has found several applications in flow photoredox chemistry. Recently, Alcázar and colleagues developed a visible-light-induced nickel-catalyzed Negishi cross-coupling procedure through the use of photosensitizer-free photocatalysis (Figure 1.24a).⁴⁵  This method clearly stands out from previous dual catalysis reports by working without exogenous photosensitizer, enabling for the first time the acceleration of Negishi cross-couplings by visible-light irradiation, and thereby extending the general scope of the reaction. As key to the success, fresh organozinc reagents were prepared in-line, leading to higher conversion than with commercially available equivalents. Although no comparison with batch was shown, the utilization of flow allowed the nickel loading to be reduced in some cases from 5 to 2 mol%, and enabled the direct scalability of the transformation.⁴⁶  Collins’ group has devoted serious efforts in recent years to utilizing environmentally benign transition metals in flow photocatalysis.^47–49  They reported a photochemical dual-catalytic synthesis of alkynyl sulfides in which NiCl₂ was associated with a soluble organic carbazole photocatalyst 24 to promote cross-coupling of thiols and bromoalkynes under visible-light irradiation (Figure 1.24b).⁵⁰  The utilization of flow conditions allowed a short reaction time (30 min) and high reproducibility on a gram scale. It also enabled the unprecedented preparation of a 19-membered macrocycle, in which flow conditions again afforded better yield and lower reaction time. Lebel et al. developed a photochemical amination of thioethers and sulfoxides protocol to produce sulfimines and sulfoximines catalyzed by Fe(acac)₃ (Figure 1.24c).⁵¹  Of particular interest was the in-line decomposition of readily available trichloroethoxysulfonyl azide into reactive metal nitrene species that was safely achieved by using a continuous-flow reactor. Subsequent amination reactions afforded high yields of sulfilimines and sulfoximines with low residence times (<2 h), while being stereospecific for thioanisole sulfoxides.

C–H bond functionalization is an essential catalytic method in modern organic chemistry. Among other approaches, C–H activation by photocatalysts is possible through hydrogen-atom transfer (HAT) mechanisms. Several methods have been developed in flow using polyoxometalate as HAT catalysts.⁵²  For example, decatungstates have proven to be efficient hydrogen abstraction catalysts under near-UV irradiation, and Noël's group utilized them as inexpensive catalysts for continuous Csp³-H oxidation reactions (Figure 1.25a).⁵³  They developed a simple and selective aerobic oxidation method using tetrabutylammonium decatungstate (TBADT) as a photocatalyst. The entire strategy was conducted in flow mode, and allowed the safe use of molecular oxygen as a green and sustainable oxidant. The versatility of this method was highlighted by a large substrate scope (30 substrates), including activated and inactivated aliphatic C–H bonds, as well as natural product scaffolds. Moreover, the flow system was designed to make this transformation safe, readily scalable, and showed reaction accelerations compared with those of the batch method (45 min instead of 4 h). As another C–H activation reaction, late-stage C–H fluorination was developed by DiRocco and Britton for the synthesis of γ-fluoroleucine methyl ester, a key intermediate in the large-scale synthesis of odanacatib (selective inhibitor of cathepsin K; Figure 1.25b).⁵⁴  Interestingly, the combination of Na₄W₁₀O₃₂ as the photocatalyst and N-fluorobenzenesulfonimide (NFSI) as the fluorine source converted γ-leucine methyl ester into γ-fluoroleucine methyl ester in 90% yield in a single flow step, amenable to 45 g scale production using a Booker-Milburn-type photoreactor.^30a  These results out-performed previous industrial syntheses of γ-fluoroleucine methyl ester by Merck, and were found to be the first demonstration of late-stage fluorination of an unactivated C–H bond for process research purposes.

While homogeneous transition-metal photoredox catalyzed reactions have been demonstrated to be advantageous in various flow processes, transition-metal-free photochemistry has become a popular approach that addresses environmental concerns, while sometimes surpassing transition-metal photocatalytic properties.

Natural organic dyes have been widely utilized as inexpensive, nontoxic, and readily available photocatalysts in continuous flow. Predominantly, since 2013, eosin Y has been exploited as an efficient catalytic photosensitizer by Noël's group.⁵⁵  In particular, a selective arylation of cysteine by combining eosin Y and aryldiazonium salts was achieved. This method showcased a direct comparison between batch and flow modes and underscored a significant acceleration by using a microflow reactor (from 2 h to 30 s) along with better yields. In-line formation of potentially explosive diazonium salts was another noteworthy asset of this flow procedure. Interestingly, eosin Y was also found to be more efficient than Ru(bpy)₃Cl₂ in a two-step continuous-flow protocol for the α-trifluoromethylation of ketones described by Rincon and Kappe.⁵⁶  Common methylene blue and rose bengal have also been utilized in isolated cases.⁵⁷ 

Although natural organic dyes are green and readily available, their limited photophysical properties can lead to compatibility issues with certain transformations, especially with supposedly inert reactants. One of the most versatile synthetic photosensitizers is metal-free porphyrinoid photocatalysts, such as tetraphenylporphyrins (TPPs).⁵⁸  The reduction potential of TPPs is generally higher than natural organic dyes, making them very attractive for photoredox transformations. Miller and McQuade developed a simple protocol for the photooxygenation of activated naphthols to naphthoquinones in continuous flow by screening some porphyrinoid photocatalysts.⁵⁹  Once again, the robustness of the flow reactor allowed easy scalability for the production of relevant bioactive naphthoquinones, while using a reduced amount of photosensitizer (0.1–0.5 mol%) and keeping the system running for 24 h. TPPs have also been found to be superior for the Csp²–H arylation of enol-acetates in flow.⁶⁰ 

Utilization of feedstock chemicals is essential for a greener chemical society. One of the most attractive reagents in recent years has been the abundant CO₂ gas. However, integration of CO₂ in flow photoredox catalysis is relatively limited because of its high reduction potential (E°=−2.21 V vs. SCE in DMF).⁶¹  Jamison and coworkers overcame this limitation by generating single-electron reduction of CO₂ through a combination of p-terphenyl as compatible photosensitizer (E°=−2.63 V versus SCE in acetonitrile) and KOCOCF₃ as base (Figure 1.26a).⁶²  Benefiting from higher gas–liquid mixing efficiency as well as better light penetration, α-carboxylation of amines with CO₂ was achieved in high yields. This CO₂-mediated photocatalytic combination was further applied by Jamison's group for the continuous β-selective hydrocarboxylation of styrenes using a flow setup developed by Beeler's group (Figure 1.26b).⁶³  In this case, utilization of flow allowed the formation of a stable benzyl radical anion intermediate, providing anti-Markovnikov CO₂ insertion on styrene derivatives.

As most photoredox catalytic systems need an external photosensitizer, certain transformations such as photochemical cycloadditions do not. As noted, Beeler's group developed a UV-photoflow platform with controllable wavelengths coupled with a conical flow device for the [2+2] photocycloadditions of cinnamates.⁶³  Using a bis(thiourea) as dual-hydrogen-bonding catalyst, this flexible setup promoted better conversion than equivalent batch reactions. The same group ameliorated the previous flow system by promoting dimerizations of cinnamates and cinnamides under a biphasic liquid–liquid slug flow regime. Once again, this machine-assisted photocycloaddition resulted in significant residence time accelerations (from 8 h to 110 min).⁶⁴ 

In contrast to homogeneous photocatalysis, heterogeneous photocatalysis in flow systems remains underexploited. The difficulties associated with light penetration through solid materials have considerably slowed down the application of heterogeneous photocatalysis in organic synthesis, and therefore in continuous flow. Despite these fundamental issues, recent efforts have been made and continuous-flow procedures have been emerging.⁶⁵ 

By analogy with homogeneous photocatalysis, photosensitizer immobilization is the most intuitive strategy to promote heterogeneous photocatalysis. The first immobilized photosensitizer applied to continuous flow was conducted by Poliakoff and George in 2011 for the production of peroxides via ¹O₂ generation in supercritical CO₂ (scCO₂), using immobilized TPPs sensitizers through covalent bonding on PVC beads.⁶⁶  More recently, the same group applied a similar strategy to the synthesis of the antimalarial drug artemisinin (Figure 1.27a).⁶⁷  In this work, the advantages of flow chemistry were directly related to green chemistry principles, in addition to serving the pharmaceutical industry. One key to the success relied on utilization of scCO₂, the main property of which is to completely solubilize gasses such as O₂. It is also considered to be a nontoxic, abundant, and inert solvent, making it ideal for continuous processes. A second important point was the immobilization of meso-TPP and meso-TPFPP (tetrakis(pentafluorophenyl)porphyrin) on Amberlyst 15 (polystyrene immobilized sulfonic acid) through ionic anchoring such as 25. This resulted in bifunctional heterogeneous photocatalysts bearing both acidic and photosensitizer functionalities on the same support material. This catalyst was packed into a fixed-bed photoreactor, and provided with about 50% of pure artemisinin within a single column, directly from dehydroartemisinic acid. Although the process lifetime was relatively moderate (catalyst leached out in a few hours), this result represents the first successful example of heterogeneous photosynthesis of artemisinin in continuous-flow that proceeds with yields comparable with those of current industrial processes. Alternatively, Cormack and Vilela utilized a polymerization strategy to immobilize a 2,1,3-benzathiadiazole (BTZ, 26) as a photoactive cross-linking monomer that functions at visible wavelength (400–420 nm; Figure 1.27b).⁶⁸  Playing with the physical format of polymers (beads (beads-BTZ) and monoliths (pHIPE-BTZ)), singlet oxygen generation and subsequent conversion of α-terpinene into ascaridole were made possible implementing flow photoreactor setups. Conversion of arylboronic acids into phenol derivatives via superoxide radical anion formation with the same catalysts was also described. For the case of pHIPE-BTZ, advantages associated with the reusability of the polymer catalyst were highlighted in a series of six subsequent reuses, corresponding to more than 80 h operation, enabled by a chemically stable polystyrene matrix. As a comparable alternative, Zhang and colleagues proposed an organic sponge photocatalyst made of polydimethylsiloxane (PDMS; Figure 1.27c).⁶⁹  This highly transparent polymer material was functionalized with rose bengal through ionic exchange (catalyst 27), and could catalyze cross-dehydrogenative coupling of tertiary amines. Although only one substrate was shown in flow in the latter example, these methods confirmed that the application of a relevant transparent polymer can solve light-penetration issues for flow heterogeneous photocatalysis.

As an extensively used heterogeneous photocatalyst for VOCs or water treatment, the use of TiO₂ has also been proven in continuous-flow synthesis.⁷⁰  Although the activity of this species is typically associated with UV irradiation, surface interactions with organic substrates could sometimes fill in its energy gap to undergo photoirradiation under visible-light conditions.⁷¹  Accordingly, Noël's group succeeded in the creation of disulfide bonds from the corresponding thiols by using TiO₂ as a heterogeneous catalyst under visible-light irradiation (Figure 1.28a).⁷²  As a tremendous asset, TiO₂ could be easily recycled and comparison between batch and flow modes showed reduced reaction times from hours to minutes when the catalyst was packed into a flow photoreactor. In 2017, Rueping and Rehm also utilized TiO₂ as a heterogeneous photocatalyst within a microstructured falling film flow reactor, to carry out C–H arylation of heteroarenes (Figure 1.28b).⁷³  In addition to the excellent catalyst stability, the transfer to flow system led to an outstanding increase in reactor performance up to a factor of 6000 due to optimal substrate–catalyst–light interactions.

Graphitic carbon nitrides (g-C₃N₄) are a class of carbon nitrides having a high structural stability and a band-gap in the medium range, making them attractive as metal-free heterogeneous photocatalysts that operate in the visible-light region. The first application of g-C₃N₄ as a photocatalyst for flow reactions was recently achieved by Blechert and coworkers for the radical cyclization of 2-bromo-1,3-dicarbonyl compounds (Figure 1.29a).⁷⁴  In this report, mesoporous graphitic carbon nitrides (mpg-C₃N₄) were found to be efficient polymer photocatalysts thanks to their larger surface area. Furthermore, promotion of the reaction in a continuous-flow reactor that was easily constructed from a FEP tube packed with the catalyst and a 1 : 1 mixture of glass beads and silica gel allowed a dramatic reduction in reaction time from 4 h to 40 min compared with similar batch experiments. The selectivity of the reaction was also increased in flow mode, while the efficiency and stability of the mpg-C₃N₄ catalyst were highlighted in the course of an impressive 60–70 reaction cycles. Following up this work, Seeberger and Gilmore combined a copper- and boron-doped (CMB) g-C₃N₄ photocatalyst with serial micro-batch reactors (SMBRs) for the decarboxylative fluorination of various carboxylic acid derivatives with Selectfluor (Figure 1.29b).⁷⁵  Circumventing light penetration issues associated with packed-bed reactors, SMBRs afforded an elegant alternative to enhance light penetration and internal mixing. The utilization of a flow system was particularly appreciated for precise segmentation of micro-batch reactors, uniformly dosing the catalyst suspension, the starting material solution, and the gas fraction. One of the keys for keeping CMB-C₃N₄ as a homogeneous solution was to mix it with viscous solvents such as ionic liquids. Ultimately, the final fluorinated products could be isolated from the crude reaction mixture by additional filtration, and the catalysts could be recovered by extraction from the ionic liquid.

Compared with batch systems, it is easy to apply continuous-flow systems to increase the productivity by allowing long periods of operation, and to directly apply the system to larger-scale production of desired materials. An ultimate goal of continuous-flow fine synthesis is to produce complex organic molecules in a continuous and sequential manner from readily available substrates, without isolation or purification. Avoiding a lengthy isolation process and purification of intermediates would save time, resources, and production of waste while effectively increasing chemical yields. Moreover, the ability to switch modules of a continuous-flow system can provide access to a wide breadth of chemical space in short order compared with the same reactions in round-bottom flasks. Although such integration of multistep continuous-flow reactions has been investigated in recent decades, examples of sequences of semi- or all-catalytic systems are scarce. In this section, we outline integrated continuous-flow systems, including catalytic multistep continuous-flow synthesis reported since 2013, which may not only enjoy advantages but also address disadvantages of one-pot synthesis.

Continuous-flow processing platforms permit the integration of microanalytics into the reaction process, which provides vital information about the progress of the reaction in real time, ultimately reducing the time required for reaction screening. In 2014, Ley's group reported a machine-assisted multistep flow process for the preparation of pyrazine-2-carboxamide and its reduced derivative piperazine-2-carboxamide, using an open-source software package and a Raspberry Pi^® computer to control the multistep continuous-flow chemistry devices.⁷⁶  Flow IR was used in the first step process as an analytic tool and NMR spectroscopic analysis was used for the second step. A solution of nitrile in ethanol/H₂O was passed through the column reactor to obtain a quantitative yield of the primary amide after concentration of the reactor output. The heterogeneous catalytic hydration of pyrazine-2-carbonitrile 28 was achieved in only 20 min yielding 100% of pyrazine amide 29. These two reaction steps, i.e. hydration and reduction, were combined by employing a camera and reservoir containing a float. Notably, the use of microanalytic tools with automated continuous-flow systems simplifies the reaction processes. This semicontinuous protocol is useful for reaction steps that are not easy to telescope, require different flow rates, or include an easy separation or purification step such as solvent extraction (Figure 1.30).

Thieno[2,3-c]isoquinolin-5(4H)-one-A (31) is an important pharmacological tool and building block for PARP-1 inhibitors. In 2014, Gioiello's group developed a multistep process for the continuous-flow synthesis of 31, involving a Suzuki coupling reaction to generate intermediate 3-phenylthiophene-2-carboxylic acid, which is then further transformed into acyl azide and cyclized by a thermal Curtius rearrangement.⁷⁷  They used a set of central composite designs, each focused on the optimization of the Suzuki coupling reaction and cyclization step. Suzuki coupling of 32 and 33 was carried out in the presence of palladium triphenylphosphine and TBAB phase transfer catalyst. Finally, the desired compound 31 was obtained in 48% yield. It is worth noting that this is a typical example that demonstrates how the statistical design of experiments cuts down tremendously the amount of time required for reaction screening and optimization. Moreover, the large-scale applicability of this continuous-flow method was tested on multigram scale, producing 31 in 50% yield (versus 33% in batch mode) (Figure 1.31).

The use of heterogeneous catalysts in a continuous-flow system is very attractive for the multistep flow system, as described in the introduction of this chapter. Kobayashi's group demonstrated the all-heterogeneously catalytic multistep continuous-flow synthesis of (R)- and (S)-rolipram (34), an anti-inflammatory drug, by using four types of catalyst-embedded column reactors.^2a  They integrated the catalytic condensation reactions of nitromethane and aromatic aldehyde, asymmetric addition reaction of malonate with polymer supported chiral PyBOX/CaCl₂ catalyst, nitro reduction by using hydrogen over Pd/DMPSi-C catalyst, and a hydrolysis–decarboxylation–lactonization sequence with COOH-functionalized silica gel. Impressively, only commercially available reagents were required as starting materials to produce the desired rolipram in 42 mg/h (50% based on starting aldehyde) with high enantiomeric excess (96% ee) (Figure 1.32).

Multistep continuous-flow platforms are essentially several reactors connected into a single flow sequence. In 2016, Kobayashi and colleagues reported the synthesis of β-nitrostyrene derivatives and their following reactions through multistep continuous-flow protocol with heterogeneous catalysts.⁷⁸ 

C–N bond formation is one of the most common transformations in organic chemistry; however, these typically take place by using alkylation of amine under basic conditions. In 2018, Kobayashi's group reported a continuous-flow procedure for direct reductive amination of secondary and primary amines with aromatic and aliphatic aldehydes as well as ketones and applied it to a multistep continuous-flow system for synthesizing key intermediates of APIs. A two-step sequence converted ketone into chiral amine through reductive amination and chiral auxiliary removal in an overall yield of 1.2 kg L⁻¹ day⁻¹ with 70% enantiomeric excess (Figure 1.33).⁷⁹ 

In 2015, Seeberger's group developed a chemical assembly system for a continuous-flow process, which provides control on three different levels and can be used to synthesize series of APIs with similar structural cores.⁸⁰  This system is based on five individual reaction modules with tolerant and robust reactions capable of being interchangeably linked together; therefore, reactors can be interchanged to access a large breadth of chemical space. The first level of complexity affords the core of the APIs, and by changing the starting material entering the system, different APIs can be accessed with the same core (Figure 1.34). Sequentially passing the core through a series of sequential modular transforms elaborates the structure to generate β-amino acids, γ-amino acids, and γ-lactones in good yields. Furthermore, switching modules determines whether γ-amino acids or γ-lactones are produced. Three classes of molecules, β-amino acids, γ-amino acids, and γ-lactams, can be produced. The ability to generate large libraries of compounds through a modular continuous-flow platform is beneficial.

In 2017, Hayashi's group developed a multistep continuous-flow synthesis of (−)-oseltamivir 35, which is an effective drug for the treatment of influenza.⁸¹  This continuous-flow system consists of five flow units, involving the asymmetric Michael reaction, domino reaction of Michael and intermolecular Horner–Wadsworth–Emmons reactions, TMSCl treatment to protonation, epimerization, and reduction (Figure 1.35). The first step proceeds within 1 h to afford the product in good yield with high syn-selectivity and excellent enantioselectivity by using toluene as solvent. In this multistep continuous-flow system, (−)-oseltamivir with three continuous chiral centers was successfully realized without isolating any intermediates by using a single flow. The total residence time through the five flow units was 310 min, and 58 mg of (−)-oseltamivir per 15 h (13% yield) can be obtained.

One of the advantages of continuous-flow systems is the ease with which the systems can be scaled up. Although continuous manufacturing is traditionally the realm of large-scale production, it has recently begun to attract attention from the pharmaceutical industry. In 2015, Kobayashi's group developed a poly(dimethyl)silane-modified Pd catalyst that can be used in the continuous-flow hydrogenation of a range of substrates.⁸²  The Pd catalyst is readily prepared from Pd(OAc)₂, poly(dimethyl)silane, and Al₂O₃ and was found to have higher hydrogenation activity and stability than typical Pd/C. Vegetable oils, squalenes, and phosphatidylcholine were successfully hydrogenated on gram to kilogram scales, and the production of castor oil could be increased to 1.5 kg h⁻¹ by using a large column (100 mm diameter, 1000 mm length). Moreover, the system was found to be stable for more than 1 month (Figure 1.36).

Poliakoff's continuous-flow asymmetric hydrogenation described above could also be expanded into large-scale synthesis.^25b  As shown in Figure 1.19, a commercially available chiral catalyst (Rh/(S,S)-EthylDuphos) immobilized on a SILP system via strong interaction resulting from the requirement of electroneutrality (catalyst 21) was used for the synthesis of an intermediate of an API with constant high conversion (>95.0%) and enantioselectivity (>98.6% ee). This asymmetric hydrogenation on kilogram scale was realized with a space-time yield (STY) of up to 9.6 kg L⁻¹ day⁻¹ at predefined conversion and enantiopurity levels.

Organic photovoltaics have emerged as an attractive technology that is complementary to other types of solar cells; thus, developing an effective and scalable polymer synthesis process is critical to the economic success of organic photovoltaic materials. In 2015, Maes and colleagues used a step-by-step approach to turn the batch process into a repeatable and scalable continuous process for the synthesis of high-performance benzodithiophene-thienopyrroledione (PBDTTPD) copolymer.⁸³  Initial continuous-flow PBDTTPD synthesis was performed with conditions similar to those of the batch protocol. After quenching the reaction and complex Pd and purification by Soxhlet extraction, precipitation was induced in methanol and the precipitate was filtered to give 200 mg of the desired PBDTTPD, resulting in a total polymerization yield of 90%. The scalability of the flow polymerization reaction was investigated subsequently. To achieve an efficient scale-up, minor adjustments were made to the fluidic setup. For example, instead of using injectors, the monomer and catalyst solutions were pumped directly from solvent bottles (under inert atmosphere) into the system. Finally, by using flow runs of 8 h, 1.55 g of PBDTTPD were afforded in a high overall polymerization yield of 95% (Figure 1.37).

In 2017, Monbaliu and coworkers developed a scalable continuous-flow strategy for the photocatalytic oxidation of methionine toward methionine sulfoxide.⁸⁴  The continuous-flow setup involved a compact commercial glass mesofluidic module integrated with static mixers and sandwiched in a high-capacity heat exchanger. Process and reaction parameters were monitored in real time with in-line NMR spectroscopic analysis. The best results were obtained with 0.1 mol% rose bengal at room temperature under white-light irradiation and a slight excess of oxygen, providing the target product in 79% isolated yield (99% purity). The authors then applied the best conditions for the catalytic photooxidation of methionine with rose bengal with a similar light input and surface to volume ratio in a Corning advanced-flow G1 photoreactor to allow ca. 72 mL min⁻¹ (daily productivity of 31.1 mol day⁻¹ or 5.1 kg day⁻¹) to be processed. A Corning advanced-flow G3 reactor with similar process conditions would increase the productivity up to 6 T per year. Very recently, the same group reported a solvent-free organocatalyzed process for the transesterification of dimethyl carbonate (DMC) with 1,2-diols under scalable continuous-flow conditions.⁸⁵  The homogeneous organocatalyst 2-tert-butyl-1,1,3,3-tetramethylguanidine was found to be the most effective for this transformation, providing glycerol carbonate at 87% selectivity and a conversion of 94% as the best result. However, heterogeneous catalysts, such as polystyrene-supported (PS) organic superbases of the amidine, guanidine, and phosphazene types, faced the problem of reduced conversion rates during long runs. The most valuable process from the industrial perspective was transesterification under mesofluidic conditions. Therefore, the microfluidic conditions were successively applied to lab-scale and then finally pilot-scale continuous-flow reactors without reoptimization, affording the target cyclic carbonate with a productivity of 68.3 mol day⁻¹ (ca. 8 kg day⁻¹) (Figure 1.38).

Continuous-flow chemistry is now a key technology in the manufacturing of not only bulk or common chemicals but also fine and specialty chemicals. The approach brings more convenient on-demand and on-site production as well as helping to adopt a more sustainable society. In particular, the applications of heterogeneous catalysts in continuous flow are very promising because catalysts and products are physically separated, and waste by-products are minimized; however, compared with noncatalytic or catalytic liquid–liquid flow reactions, the use of heterogeneous catalysts in flow has just begun to be explored. New synthetic methodologies based on addition and condensation reactions with heterogeneous catalysis, in place of substitution reactions, will become important to avoid carrying over undesirable by-products in multistep flow systems. To attain this goal, more efficient heterogeneous catalysts for various atom-economical organic transformations under continuous-flow conditions must be developed.

As a side note, to evaluate continuous-flow synthesis of fine chemicals, different parameters—productivity per time, productivity per catalyst, space–time yield, TON, and TOF under a particular space velocity—may be important metrics in addition to yield and selectivity.