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Scalability of photochemical reactions in continuous flow mode

Scalability of photochemical reactions in continuous flow mode Continuous flow photochemistry as a field has witnessed an increasing popularity over the last decade in both academia and industry. Key drivers for this development are safety, practicality as well as the ability to rapidly access complex chemical structures. Continuous flow reactors, whether home-built or from commercial suppliers, additionally allow for creating valuable target compounds in a reproducible and automatable manner. Recent years have furthermore seen the advent of new energy efficient LED lamps that in combination with innovative reactor designs provide a powerful means to increasing both the practicality and productivity of modern photochemical flow reactors. In this review article we wish to highlight key achievements pertaining to the scalability of such continuous photochemical processes. . . . . Keywords Flow synthesis Photochemistry Scalability Throughput Continuous processing Introduction continuous flow processing over batch mode operation of photochemical processes concerns their scalability. Whilst Over the last decade continuous flow photochemistry has ma- scale-up in batch mode is primarily actualised through an in- tured into a powerful field within synthetic organic chemistry. crease in vessel size, analogous flow processes can be scaled- Key features that enable effective photochemical transforma- up through prolonged process times as well as specific design tions in flow mode are the ability to uniformly irradiate solu- features that render a variety of reactions more productive [8]. tions of substrates that are continuously pumped through nar- A crucial parameter to be considered during any photo- row diameter tubing or microchannels [1–3]. High spatiotem- chemical reaction is that of light penetration. Light is absorbed poral control furthermore allows the effects from over- by the reaction medium, and this light attenuation is depen- irradiation to easily be minimised as in principle each mole- dent on the irradiated reactor size as dictated by the Beer- cule resides within the irradiated section of the flow reactor for Lambert law (Fig. 1). As the size of a reactor increases so the same amount of time, which can be controlled with high too does the path length (distance from the light source), precision in flow mode [4]. Together with facile temperature resulting in non-uniform irradiation. This typically is one of control and various light sources being available (UV and the key issues for scaling up photochemical reactions in batch visible), both commercial and home-built reactor systems ren- mode, however the analogous flow processes overcome this der easy access to photochemical reactions. In addition, im- issue through miniaturisation strategies in order to shorten the portant advances in the field of photo-redox catalysis [5–7] path length. mean that synthetic chemists can choose between directly ir- In 2014 Booker-Milburn and co-workers published an im- radiated and modern photo-catalysed reactions that provide portant account [9] comparing the scalability and efficiency of mild and selective means to manipulate and functionalise flow and batch based photoreactions and concluded at that compounds of ever-increasing complexity. One important ar- stage that there is very little difference when key parameters gument frequently put forward by practitioners in favour of are kept the same. In their work a dozen transformations in- cluding [2 + 2]-cycloadditions between maleimides and al- kenes or alkynes (intra- and intermolecular), a Paterno-Büchi * Marcus Baumann cycloaddition, a di-π-methane rearrangement as well as sev- marcus.baumann@ucd.ie eral radical-based processes were evaluated. Productivities of several decagrams per day were typically achieved for these School of Chemistry, Science Centre South, University College Dublin, D04 N2E2, Dublin, Ireland optimised processes. At this stage flow reactor configurations 224 J Flow Chem (2021) 11:223–241 Fig. 1 Attenuation of light through a reactor vessel expressed via transmittance and absorbance were commonly based on FEP-coil reactors (single and mul- Discussion tiple layers) in combination with UV-C or medium-pressure Hg-lamps whereas immersion type reactors using the same This first section will highlight several modern as well as lamps were used in batch mode. Despite the slightly different classical photochemical transformations that are difficult to set-ups and irradiation profiles, the conclusion of equal per- execute and scale in batch mode. Transferring the initial batch formance for batch and flow processing could be drawn. It reaction into continuous flow mode thus provides a means of should be noted that this comparison focused on reactions in generating gram quantities of desired target products in a time which substrates are directly irradiated, and therefore the con- and cost-effective manner. These laboratory scale examples clusions may not extend to more complex reactions involving therefore demonstrate approaches for increasing the produc- photocatalysts. tivity and practicality of various light-driven reactions. Simple More recently, a variety of new photoreactors designed flow setups are thereby utilised to satisfy the demand of ma- for continuous processing have been developed. These terials of interest whose scaled preparation can be advanced include commercial systems such as the Vapourtec UV- further by scale-out and numbering up strategies. Subsequent 150 reactor and its high-power LED extension [10–14], sections will then expand on this theme by introducing setups the Corning photoreactor system [15–17], the Uniqsis and concepts enabling productivities of several kilograms per PhotoSyn [18, 19], or the Firefly system from day. The productivities thus reached will in many cases be Cambridge Reactor Design [20]. Furthermore, studies sufficient to meet the current demand for specific branches employing a modified rotary reactor (coined PhotoVap) within industry (pharmaceutical, fragrances and fine [21], a vortex reactor [22, 23] or oscillatory flow reactors chemicals), although it is understood that these are subject to for heterogeneous reactions [24, 25] have been reported. further changes over time. It is not surprising that the design of such newer systems and the implementation of chemical engineering knowl- Laboratory scale (< 100 g/day) edge increases the performance and therefore scalability of the resulting applications. In addition, a growing body Photoredox catalysis has experienced a surge in interest in of today’s literature is based on photosensitised transfor- recent years [26–31], in part, due to the advancement of equip- mations that oftentimes exploit visible rather than UV ment such as LED lamps used for photochemical reactions. light. Transition metal-mediated photoredox catalysis is generally In view of these manifold developments, we wish to pro- characterised by two coupled catalytic cycles. Firstly, a cycle vide an update on recent contributions by discussing rele- activating the photocatalyst, which then turns over the sub- vant studies and highlight new knowledge pertaining to the strate in the second catalytic cycle. Photoredox catalysis can scalability of flow-based photochemistry. Specifically, we be exploited for a wide range of reactions including various will discuss scalability as a function of the equipment used, carbon-carbon bond forming reactions [29–31]. Recently, the the underlying photo-transformation as well as the com- MacMillan group reported a batch method for the photoredox 3 2 plexity of substrates and products involved. We hope that catalysed formation of C -C bonds [32]. This was per- sp sp this review allows interested readers to find not only inter- formed by coupling aryl halides to alkyl halides in the pres- esting applications of continuous photochemical reactions, ence of an iridium-nickel co-catalytic system and a silyl rad- but moreover appreciate the complex interplay of different ical precursor (Scheme 1). The methodology proved to be factors that determine success and ultimately scalability in robust giving the desired products in good yields, however, these light-driven processes. the reaction was only carried out on small scale. J Flow Chem (2021) 11:223–241 225 Scheme 1 Photochemical C - sp C coupling sp In order to utilise this reactivity in a scalable manner, the offered significantly shorter reaction times (30-min residence Jensen group developed a continuous stirred-tank reactor time vs 15 h in batch) and higher productivity than a batch (CSTR) system for carrying out photochemical reactions reactor of similar size. Based on the reactor design this pro- [33]. The reaction reported by MacMillan required the pres- ductivity could be further improved by a relatively straightfor- ence of an insoluble inorganic base, which typically is incom- ward increase in reactor size. patible with carrying out reactions in a continuous manner due The applicability of continuous flow to scaling up to reactor blocking and fouling. However, the use of a CSTR photoredox processes has also been demonstrated by the could mitigate this issue through careful reactor design. Collins group [35], who reported the synthesis of alkynyl Previously, the Jensen group had reported the design of a sulfides 6 via C(sp)-S bond formation (Scheme 2). The cou- CSTR cascade used for heterogenous reactions [34], which pling of alkynyl bromides 5 and thiols 4 was performed using was adapted for this photochemical reaction. a 4CzIPN (an organic carbazole-based sensitiser [36]) and The reactor consisted of five single chambers (total volume nickel co-catalysed system. While the reaction could be car- 5.3 mL), connected by a drilled channel, which could be irra- ried out successfully in batch on a small scale (0.24 mmol) diated through a glass window (Fig. 2). Mixing was achieved with excellent yields (92%) the long reaction time of 4 h was using magnetic stir bars which could be operated using a con- unfavourable. The use of a continuous flow system allowed ventional magnetic stirring plate. Using this setup, in combi- for significantly shorter reaction times of 30 min while main- nation with a slurry pump, the heterogeneous mixture could taining high yields. be administered to the reactor while maintaining an inert The simple continuous flow setup consisted of a syringe atmosphere. pump and a homemade PFA coil reactor which surrounded a Under these conditions facile direct transfer of the previous portion of blue LED ribbon (λ = 465 nm, Fig. 3). Scale-up max batch method to continuous flow was possible, eliminating the of the photochemical reaction in batch proved challenging need for re-optimisation to incorporate a soluble organic base. with a significantly reduced yield of 26% being obtained The flow system was then used to synthesise compound 3 on a when carried out on a gram-scale (5 mmol). Furthermore, gram scale in 13 h (77 mg/ h) with similar yields to the batch the low concentration required for the reaction (50 mM) process (77% in flow, 80% in batch). would make further scale-up in batch impractical due to the While the application of flow chemistry to this reaction did requirement for increasingly large reactor vessels. In contrast, not offer an improvement in yield, as is sometimes the case, it a scale-out of the reaction in continuous flow yielded over 1.2 g of product with significantly improved productivity over batch (1.16 mmol/h vs 0.33 mmol/h). An issue that commonly arises during photochemical reac- tions is that of over-irradiation of either substrate or the resulting reaction product. This can lead to a variety of side reactions occurring and is typically unavoidable in batch. The advantage offered by spatiotemporal processing in continuous flow typically eliminates this issue allowing sensitive reac- tions to be carried out on a larger scale. The improvement in flow technology in recent years has provided chemists with the opportunity to revisit chemistry that previously had not been scalable. One such example is the photo-electrocyclization of 2-pyrone derivatives which was first reported by Corey in 1964 [37]. The resulting cyclobutene lactone product 8 is a synthetically versatile chemical building block due to its high ring strain [38–41]. Fig. 2 Image of CSTR setup. Reprinted with permission from [33]. Copyright (2019) American Chemical Society Recently, the Kappe group investigated the applicability of 226 J Flow Chem (2021) 11:223–241 Scheme 2 Continuous flow 4CzIPN (2 mol%) synthesis of alkynyl sulfides NiCl .dme (10 mol%) pyridine (2 equiv) N N Br NC CN + R R SH 2 1 R SR 4 5 (1 equiv) (1.1 equiv) MeCN/DMF (23:1) (0.05M) t =30min,rt 4CzIPN flow chemistry to improving the scalability of this reaction order to isolate multiple grams of the desired material. As an [42]. Careful optimisation of reaction conditions found the alternative, researchers have increasingly begun to utilise con- correct selection of light source to be of critical importance, tinuous flow as part of their synthetic strategy. One recent with an improvement in yield being observed using a com- example was published by the Beeler group who developed mercially available medium pressure mercury lamp (with the the gram scale photochemical synthesis of aglain analogues, a appropriate light filter) when compared to a weaker 8 W UV precursor to rocaglate natural product analogues. [45] A com- lamp emitting at 303 nm. Use of the correct light source mon strategy for the synthesis of aglain 12 is the photochem- allowed the researchers to synthesise the desired cyclobutene ical [3 + 2]-cycloaddition of 3-hydroxyflavone 10 and methyl lactone 8 in high yields (> 95%) with significantly reduced trans-cinnamate (11). [46, 47] Previous reports in batch typi- reaction times when compared to batch (20-min residence cally provide <150 mg of product per reaction in 40–50% time vs 24 h in batch). To scale up the flow process the com- yield with long reaction times of up to 12 h. [47] mercially available Vapourtec UV-150 reactor (10 mL) was Initial optimisation was carried out using a reactor used (Scheme 3). While attempting to scale-out the process by consisting of a 150 W metal-halide lamp (>300 nm) placed running the reactor for 8 h, significant reactor fouling was at the centre of a FEP coil reactor (3.5 mL). Recirculating observed due to the formation of an insoluble polymeric ma- glycol was used to cool the inner chamber of the reactor. terial, as is the case in batch. This was resolved by decreasing Under the optimised conditions the desired product 12 could the reaction temperature from 50 °C to 10 °C, however, a be synthesised with a residence time of 30 min giving a conversion decrease of 2.3% per hour was still observed. throughput of ~180 mg/h compared to the batch throughput Despite this, the continuous flow setup achieved a productiv- of ~11 mg/h. To further scale up the reaction, the volume of ity of 144 mg/h (~3.5 g/day) over an 8-h run, significantly the photochemical reactor was increased to 12.5 mL (Scheme higher than previously reported batch reactions (14–21 mg/ 4). Numbering up this larger reactor to three gave a total vol- h, 336—504 mg/day) [41]. ume of 37.5 mL, which, with a slight increase in residence Photochemically induced cyclisation reactions have been time to 35 min, further increased the throughput to 1.92 g/h. applied to the synthesis of a range of natural product deriva- This strategy exemplifies the ease at which scalability of a tives. [43, 44] Typically, such synthetic projects do not require continuous flow process can be achieved when compared to kilograms of product but the isolation of anything more than its batch counterpart. hundreds of milligrams can prove challenging in batch. This Conformationally restricted three dimensional molecules results in the chemist having to carry out multiple reactions in are becoming increasingly important scaffolds for medicinal chemistry applications [48, 49]. One method by which these Vapourtec UV-150 (10 mL) t =20min,50℃ in MTBE (0.05 M) Fig. 3 Image of continuous flow setup (reproduced with permission from Scheme 3 Photochemical synthesis of 2-oxabicyclo[2.2.0]hex-5-en-3- [35]) one 8 J Flow Chem (2021) 11:223–241 227 OMe O Scheme 4 Photochemcial Metal-Halide Lamps OH synthesis of aglain 12 HO OH HO MeO MeO O CO Me OMe Ph MeO O 12 OMe OMe structures can be accessed is through photochemical intra- or much-improved throughput of ~30–50 g/day, achieved intermolecular cycloaddition reactions [50]. This strategy was through a straightforward increase in reactor size. used by the Rutjes group for the scalable synthesis of cyclic While the above examples demonstrate how flow chemis- aminoketones in continuous flow mode (Scheme 5)[51]. try can be used to scale photochemical reactions, generally For optimisation purposes reactions were carried out on a most reactions must be reoptimized to transfer from batch to small scale using a ‘home-made’ reactor. This small-scale flow. This can typically result in lost time trying to find the reactor consisted of FEP tubing (11.6 mL) wrapped around a optimal flow rate to achieve sufficiently high yields. Recently condenser, which was then irradiated using a commercially the Booker-Milburn group undertook a study in an attempt to available Rayonet RMR-600 photochemical reactor. Low rectify this issue [52]. It was reported that the transfer of substrate concentrations (30–40 mM) were found to provide optimised batch conditions to flow could be simplified by excellent yields when irradiated at 254 nm for 30–40 min calculating the flow rate based on batch parameters. This depending on the substrate. would help reduce development time as reactions can be Using these optimised conditions, a throughput of ~5.6 g/ optimised more rapidly in batch due to the ability to easily day was achieved. However, this scale was insufficient for the monitor them in real time, without the need for additional required synthesis of these compounds. Further scale-up was expensive equipment. To verify this hypothesis, various reac- therefore achieved through design of a larger reactor (Fig. 4). tions were transferred from batch to continuous flow. Among This system consisted of FEP tubing (volume: 105 mL) these was the photorearrangement of N-substituted wrapped around a commercially available UV-C lamp. succinimides 17 to keto-caprolactams 20 (Scheme 6)[53, 54]. Cooling of the reactor was achieved using an external stream While well-known, this reaction proves difficult to scale due of water, and the system was encased with a metal jacket to to alternative competing reaction pathways leading to the for- protect the user from harmful UV radiation. Using this high mation of insoluble side-products, particularly at higher con- throughput setup 10 g of compounds 14 and 16 could be centrations. The flow rate in UV photochemistry is of prime synthesised in 4.8 and 7.3 h, respectively. This equated to a importance due to the ease at which reaction mixtures can be Scheme 5 Photochemical synthesis of conformationally strained scaffolds h (254 nm) MeCN (0.04 M) Boc t = 30 min Boc Boc 13a 15 96 % (4:1) hυ (254 nm) MeCN (0.03 M) t = 40 min Boc r Boc 13b (95%) 228 J Flow Chem (2021) 11:223–241 various examples of equivalent batch reactions on this scale exist [9]. However, as reaction scale approaches the order of hundreds of grams the use of a batch setup becomes increas- ingly impractical due to the requirement for significantly larg- er equipment as well as limitations regarding heat transfer. Low concentrations and high lamp powers required for suc- cessful photochemical reactions add to these complications. Carbon-carbon bond formation reactions are of extreme importance in a chemist’s toolbox for which a range of meth- odologies exist [31, 55, 56]. Recently, Alcázar and co-workers reported the visible-light induced Negishi reaction for C(sp )- C(sp ) cross couplings (Scheme 7)[57, 58]. This two-step reaction involves firstly the formation of an organozinc re- agent 22, which is then coupled with an aryl bromide 23 under photochemical conditions in the presence of a nickel catalyst. This photochemical methodology presented a broader scope than the traditional nickel-catalysed Negishi reaction and was Fig. 4 Medicinal chemistry scale continuous flow setup scaled to achieve a throughput of 800 mg/h using a commer- cially available Vapourtec reactor. While useful for screening over-irradiated, leading to diminished yields and side-product purposes, a larger scale was required for ‘pilot’ scale. Good formation. Based on previous reports stating that FEP flow yields had been reported using the Vapourtec system, howev- reactors have similar productivities per Watt to batch [9], the er, its scalability was limited by its fixed reactor volume of optimal flow rate could be calculated based on the power of the 10 mL. To overcome this limitation, the authors opted to use a flow setup. To test this, a reactor consisting of FEP tubing larger Corning G1 reactor (40 mL) for the photochemical wrapped around 3 × 36 W UV-C lamps was used. Based on process (Fig. 5). the increase in power compared to batch (18 W) a flow rate of The continuous flow setup consisted of a column filled −1 7.5 mL min was calculated. Through re-optimisation of the with powdered zinc, to generate the required organozinc re- −1 flow procedure a flow rate of 8 mL min was found to be ideal, agent (22) in a continuous process that was monitored using closely matching the calculated value. While no improvement in-line NMR, which was combined with a stream of aryl bro- in the yield of 20 was observed, the productivity of the reaction mide and nickel catalyst prior to entering the photoreactor. was significantly improved to 96 g/day compared to the previ- The use of a high-powered LED lamp (100 W, 405 nm) pro- ously reported 2.2 g/day in batch [54]. While using a continu- vided the desired product in excellent yield matching that of ous flow setup does not lead to an increase in reaction efficien- the previous Vapourtec example. Optimisation of the reaction cy, it does allow for facile scale up due to the potential for found that a slightly shorter residence time could be utilised increased reactor power as a function of the presence of multi- further improving the throughput to 5.6 g/h. Use of the larger ple lamps. However, it should be noted that this conclusion may reactor offered a sevenfold increase in throughput (134 g/day only be drawn for the reaction included in the survey, as vs 19 g/day) when compared to the smaller Vapourtec reactor photocatalysed pathways may display different behaviour due despite only a fourfold increase in volume (Scheme 7). It is to their increased complexity. worth noting that this non-linear increase may be attributed to the increased light power-to-surface area offered by using glass plate reactors in place of the traditional FEP tubing Pilot scale (100+ g/day) setup. The incorporation of fluorine into organic molecules is While the above examples demonstrate the advantages of con- highly relevant to the pharmaceutical industry due to their tinuous flow in scaling of reactions to the decagram scale, Scheme 6 Photorearrangement OH R of N-substituted succinimide O HO hυ N N NH O O 17 18 20 19 J Flow Chem (2021) 11:223–241 229 Br Zn Br Zn F CO F CO 3 3 21 22 F CO CO Me 3 2 Br Ni catalyst (2 mol%) MeO C Vapourtec Corning G1 Yield (%) 93 93 Time (min) 20 15 Reactor size (mL) 10 40 Throughput (g/h) 0.8 5.6 Scheme 7 Visible-light induced Negishi-coupling reactions potential to alter biological properties of molecules [59, 60]. tubing wrapped around the outside. The total reactor volume However, there remains a lack of scalable methodology to measured approximately 150 mL and the assembly was achieve this. This limitation arises, in part, due to the cost, housed within a steel casing. Cooling of the reactor was both monetary and environmental, associated with typical achieved through filling of both cavities with water. This setup fluorinating and trifluoromethylating reagents. Recently, the fulfilled the predetermined requirements of low cost and hav- Stephenson group developed a photochemical method for in- ing a small footprint (Fig. 6). Using this ‘home-made’ reactor corporating trifluoromethyl groups into various arenes and the trifluoromethylation of pyrrole 25 was carried out on the heteroarenes [61, 62]. This reaction involved the photochem- kilogram scale. Running the reactor continuously for 48 h ical decarboxylation of trifluoroacetic anhydride (26) facilitat- provided 0.95 kg of product 27, equating to 20 g/h. The equiv- ed by pyridine N-oxide in the presence of a ruthenium catalyst alent reaction in batch would prove impractical due to the size (Scheme 8). Blue LEDs (13 W) were found to be a sufficiently of the reaction vessel required, in addition to the size and powerful light source, and the desired trifluoromethylated power of the light source. products could be obtained from a range of substrates in good Many examples of continuous flow photochemical reactors yields. Despite promising results, this methodology had not in the literature consist of tubing wrapped around a light previously been utilised for scales larger than 20 g. source [1, 3, 64]. However, various other creative solutions In order to further scale up this reaction, the Stephenson to benefit from the advantages of continuous flow have been group opted for a continuous flow setup based on a coil reac- reported [65]. In 2016 the George group presented a photo- tor design [63]. The reactor consisted of blue LED lights chemical reactor comprised of a converted rotary evaporator contained within a glass beaker with a single layer of PFA which was coined the PhotoVap [66]. This setup could be run Fig. 5 Continuous flow setup: 1. G1-photoreactor; 2. Zinc column; 3. Reagents; 4. Mass flow controller; 5. Back pressure regulator; 6. Collection vessel; 7. Zinc activation waste; 8. Pressure and temperature monitor; 9. Needle valve; 10. Pressure sensor. (Reproduced with permission from [58]) 230 J Flow Chem (2021) 11:223–241 Scheme 8 Continuous flow Boc photochemical trifluoromethylation CO Me Boc F C CO Me 3 2 MeCN (0.57 M) Ru(bpy) Cl (0.1 mol%) 3 2 pyridine N-oxide (2.0 equiv) 0.95 kg, 20 g/h 50% yield O O F C O CF 3 3 (2.1 equiv) MeCN (1.37 M) t = 30 min, 45 C, 48 h in a semi-continuous manner and required little modification flask, and the mixture was irradiated using 1000 lm white to the conventional, widely available laboratory rotary evap- LEDs. To run the reaction semi-continuously, a 50 mL portion orator (Fig. 7). of substrate feed was administered and irradiated in the rotat- The reactor consisted of two thin PTFE tubes which were ing flask until reaction completion was reached. Rotation was threaded through the neck of a rotating flask, which were used then ceased, and the resulting product was removed before to dose starting material and subsequently withdraw product. repeating the cycle. Using a 3 L flask, a productivity of The flask was surrounded by LEDs with temperature control 1 mmol/min (which extrapolates to approximately 10 g/h, achieved using the rotary evaporator bath. Dosing of reagents 240 g/day) could be achieved. While there are various scalable and rotation speed were controlled using an external comput- examples of this specific reaction in the literature, this reaction er. By rotating the flask, a thin film of reaction mixture on the design presents a potentially versatile alternative to plug flow vessel wall was generated, which provided more efficient ra- reactors for chemistry with short reaction times. diation than might be observed in batch mode. Additionally, [2 + 2]-Cycloadditions remain one of the most common the scale of the reaction could be adjusted by increasing the methods for accessing cyclobutanes [69]. Most of these reac- size of the reaction flask up to 3 L (other rotary evaporator tions are carried out under photochemical conditions, in some models can facilitate larger flasks). cases in the presence of a photosensitiser. The Kappe group In order to demonstrate the scalability of this semi- recently reported a scalable method for the photochemical continuous approach the photo-oxidation of α-terpinene 28 [2 + 2]-cycloaddition of ethylene to cyclic anhydrides [70]. to ascaridole 29 was selected (Scheme 9)[67]. This reaction LEDs offer the advantage of being more efficient and gener- utilises Rose Bengal as a photosensitiser, which in combina- ating less heat than their medium- or low-pressure mercury tion with light can generate singlet oxygen from either ambi- lamp counterparts. Additionally, they can be used to emit ent air, or a stream of oxygen gas [68]. This highly reactive specific near-monochromatic wavelengths, however they gen- oxygen species then efficiently oxidises α-terpene to the de- erally are limited to longer wavelengths (>350 nm). Typically, sired product 29. Oxygen gas was bubbled through the reac- the use of longer wavelengths requires the presence of a tion mixture, by passing an additional PTFE tube into the photosensitiser for certain reactions to facilitate the energy Fig. 6 Kilogram-scale continuous flow setup (reproduced with permission from [61]) J Flow Chem (2021) 11:223–241 231 (~240 g/day), with a 10-h run yielding 101 g of 32. While the photochemical reaction may be feasible in batch, the use of ethylene gas on this scale would be unfavourable due to the potential safety risks, which are mitigated in continuous flow [71]. Production scale (> 1 kg/day) While there are various examples exemplifying the advan- tages of continuous flow photochemistry for scale up, the transfer of these reactions from the laboratory scale to produc- tion scale is non-trivial. The previously discussed studies are generally limited by the volume of the reactor utilised, how- ever, an increase in volume by increasing tubing diameter may alter the fluid dynamics of a reaction whilst also increasing the path length of the incoming light. Therefore, additional reac- tion optimisation may be required when attempting to perform Fig. 7 ‘PhotoVap’ setup. Reprinted with permission from [66]. Copyright (2016) American Chemical Society continuous photochemical reactions at the kilogram scale. However, it should be noted that these differences in fluid transfer. This study by the Kappe group highlighted the im- dynamics observed during scale up are significantly smaller portance of the selection of the correct photosensitiser and than those observed in batch. found thioxanthone (31) to be ideal for the reaction between With the scalability of the synthesis of cyclobutanes from citraconic anhydride (30) and ethylene to produce the corre- ethylene being demonstrated by the Kappe group on the sponding cyclobutane 32 (Scheme 10). hundred-gram scale [70], no attempts had been reported of The fact that ethylene is present as a gas makes carrying out performing this reaction on manufacturing scale. Recently, this reaction non-trivial, in particular in batch, due to the as- Beaver, Zhang and co-workers set out to develop a continuous sociated hazards and complications of using a liquid-gas bi- flow platform for the synthesis of cyclobutane 34 (Scheme 11) phasic mixture. Initial experiments and optimisation were car- in order to prepare >5 kg/day of the target compound [72]. To ried out using a commercially available plate reactor achieve this, a multistage approach was executed. This in- (2.77 mL), which was irradiated using two LED panels volved focused reaction optimisation, proof of concept (375 nm). Starting anhydride 30 and photosensitiser 31 were through an intermediate scale-up (500 g/day) and finally, the dosed using integrated pumps and were combined with ethyl- design of a production scale skid (>5 kg/day). ene, with gas flow being regulated by a mass flow controller. As is often the case when scaling up a reaction to industrial A back pressure of 12 bar was applied to ensure a homoge- scales, development and optimisation of a product isolation nous system, maximising contact between the substrates. method becomes increasingly important. As previously re- Optimisation of the reaction found a residence time of ported [70, 73], the presence of a photosensitiser, benzophe- 5.2 min to be sufficient for full conversion, corresponding to none, is crucial for the reactivity of maleic anhydride with a productivity of 2.1 g/h (~58 g/day). To demonstrate the ethylene. Increasing the quantity of benzophenone resulted scalability of this reaction, a switch to the Corning G1 in increased reaction efficiency, however, a negative impact photoreactor was made. This consisted of five 2.77 mL plate on crystallisation efficiency (and overall isolated yield) was reactors connected in series giving a total volume of 13.85 mL also observed. Therefore, an amount of 10 mol% was chosen (Fig. 8). Adjustment of the flow rate to maintain the constant to strike the balance between the two parameters. The contin- ~5.5 min residence time provided a productivity of ~10 g/h uous flow setup consisted of a stream of maleic anhydride/ benzophenone, which was combined with ethylene gas in a mixing tank, with the mixture then passing through a photoreactor (Scheme 12). photosensitizer While a standard T-piece mixer was sufficient for the in- termediate scale (500 g/day), as flow rate was increased the airorO ,hυ presence of ethylene slugs was observed. This slug flow could be eliminated using a mixing tank with a residence time of 30 min. To increase productivity, the internal diameter of the 28 29 reactor tubing was increased to 10 mm (compared to the lab Scheme 9 Photooxygenation of α-terpinene scale ~1–2 mm). Due to the significantly increased diameter, a 232 J Flow Chem (2021) 11:223–241 Scheme 10 Photochemical [2 + 6.25 mL/min 2]-cycloaddition of ethylene O 30 LED (375 nm) 0.5 M in EtOAc O O 12 bar 2.5 mL/min 2.77 mL 4 x 2.77 mL 96%, 101.3 g 10 h 2.5 mol% matched increase in lamp power was required. For the inter- the tubing may lead to rupture when operated under pressure. mediate scale setup, 2 × 300 W LED panels (365 nm) were Additionally, reactor fouling can be a common issue [70, 73], found to be sufficient. However, with the increase in volume while oftentimes reversible by flushing solvent through the to the production scale (from 1.56 L to 20.76 L irradiated reactor, this fouling/blocking can be irreversible in some volume) a corresponding increase in lamp power was required cases. This results in the need to replace the entire length of (6 × 3 kW LED panels for production scale). As is the case tubing within the reactor which is highly wasteful on large with any increase in lamp power, significant additional scale (lengths of tubing exceed hundreds of metres in some cooling was required to maintain a constant temperature. cases). In order to mitigate these issues, a collaboration be- This was achieved simply by adjusting the flow rate of the tween industrial groups and the Booker-Milburn group devel- cooling medium. The final optimised production scale skid oped a quartz reactor which they coined the ‘Firefly’ reactor was then run uninterrupted for a period of one week, produc- (Fig. 10)[20]. ing 51.8 kg (7.4 kg/day) of cyclobutane 34 thus exceeding the The Firefly reactor consists of an array of axially arranged initial target of 5 kg/day with the setup being used to eventu- quartz tubes (internal volume 120 mL) around a light source. ally generate >250 kg of 34. While significant safety consid- The use of quartz offers the advantage of near-complete UV erations were required for such a scale, many of the concerns transparency in addition to increased durability when com- that are associated with such a reaction were minimised using pared to FEP. A standard high-power medium pressure mer- continuous flow chemistry (Scheme 12). This combined with cury lamp was used in this case, but the light source could be the relatively small footprint (Fig. 9) makes it difficult to de- easily exchanged to suit a range of photochemical reactions. velop a safe batch reactor with comparable efficiency. To protect the user from powerful UV radiation, the reactor While highly efficient for carrying out photochemical re- was placed in a metal jacket, which offered the additional actions, the use of FEP reactors can prove problematic on benefit of reflecting any light back towards the reactor. larger scales. While FEP is a highly versatile material, it is Despite the presence of a cooling jacket surrounding the reac- not completely UV transparent and any weak spots within tor tubing, the introduction of a metal reflector caused signif- icant overheating. This could be overcome through the intro- duction of a fan to displace stagnant air caught between the light source and reactor tubing. In order to test the reactor, a range of [2 + 2]-cycloaddition reactions were investigated, including the synthesis of “Cookson’sdione” (36, Scheme 13)[74]. This involves the intramolecular [2 + 2]-cycloaddition of the ene-dione 35 which had previously been demonstrated using a FEP reactor [9]. Using the Firefly reactor at 1.5 kW and a concentration of C H (gas) 2 4 365 nm LED benzophenone (10 mol%) solvent, ambient temp 33 34 Fig. 8 Corning G1 photoreactor. Reprinted with permission from [70]. Copyright (2019) American Chemical Society Scheme 11 Photochemical synthesis of cyclobutane 34 J Flow Chem (2021) 11:223–241 233 Scheme 12 Kilogram-scale continuous flow setup. Reprinted with permission from [72]. Copyright (2020) American Chemical Society 0.5 M a productivity of ~4 kg/day could be achieved. required oxygen being supplied by air drawn into the reac- Doubling of the concentration and light power corresponded tor. While innovative, this design was not suitable to larger to a doubling of productivity (8 kg/day) which was demon- scales (>10 g/day) due to volume constraints. strated by synthesising 1165 g of 36 in just 3.5 h. Based on In order to develop a system capable of producing kilo- these results using the full 5 kW power rating a total produc- grams of product, a reactor of approximately 20 times the tivity of 13 kg/day could be achieved. Comparison of this volume was developed (Fig. 11)[76]. The reactor consisted methodology to the previously published FEP reactor [9] of a polymer rotor housed within a jacketed filter-tube sealed found the Firefly system to be almost 30% more power effi- with a steel base and polymer cap. Inlet pores were bored cient which while not crucial on laboratory scale, is of prime through the steel base and outlets were found in the polymer importance for manufacturing. cap. Cooling was provided by a recirculating chiller connected The majority of novel innovative reactor designs for to a jacketed glass vessel and a gap of 2 mm was employed kilogram-scale continuous flow photochemical synthesis between the glass jacket and polymer rotor giving a total re- have only been reported over the last decade [20, 61, 72, actor volume of 280 mL. The reactor was irradiated using a 75–77]. Many of these involve scaling up reactors that light source housed outside the cooling jacket. were designed for laboratory scale synthesis, such as the To demonstrate the utility of this reactor the photo- vortex reactor reported by Poliakoff, George and co- oxidation of citronellol (37) was once again chosen workers [22, 76]. The design of a reactor that utilised a (Scheme 14). In contrast to small scale experiments, air, which rotating cylinder inside a static cylinder in order to gener- provides the required oxygen, could not reliably be drawn in ate Taylor vortices was reported in 2017 [22]. This reactor due to the increased volume of the reactor and the reduced was used for the photooxidation of citronellol with the rotation speed of the internal rotor. Fig. 9 Image of photochemical skid. Reprinted with permission from [72]. Copyright (2020) American Chemical Society 234 J Flow Chem (2021) 11:223–241 Fig. 10 ‘Firefly’ photochemical reactor (reproduced with permission from [20]) Using a stream of oxygen gas, coupled with a sufficiently this class of reactor, extremely efficient mixing can be high rotation speed, rendered the photoproducts in yields of up achieved through modification of the speed at which the in- to 92% (both isomers 38 and 39). In order to determine the ternal disk rotates. The reactor consisted of a rotor housed rotation speed required for sufficient mixing, various within a 64 mL reactor, a quartz window was employed to Computational Fluid Dynamics (CFD) calculations were car- allow the mixture to be irradiated, giving an irradiated volume ried out, this aided optimisation of the reaction and is typically of 27 mL. 120 W white LEDs were utilised to irradiate the an extremely valuable tool in the scaling up of reactions. The reaction mixture. optimised conditions used a concentration of 0.2 M with a In order to demonstrate the utility of this class of reactors residence time of 7 min, through which a productivity of for photochemical processes, the photo-oxidation of α- ~2 kg/day could be achieved. This corresponded to a ~ 10-fold terpinene was selected (Scheme 9). The setup consisted of a increase in space-time-yield compared to the previous small- stream of Rose-Bengal and α-terpinene, which were com- scale reactor. It is worth noting that the [2 + 2]-cycloaddition bined with a separate stream of O gas in a T-piece mixer, of “Cookson’sdione” (Scheme 13) was also carried out with a before entering the RS-SDR. To monitor the effect of rotation productivity comparable to that achieved by the Firefly reactor speed on mixing, a high-speed camera was used to image the [20] (~7.5 kg/day vs ~8 kg/day), emphasising that similar disk (Fig. 12). Optimisation studies revealed the benefit ob- results can be achieved utilising different reactor designs. tained from high rotation speeds plateaued at approximately As an alternative approach for carrying out photochemical 2000 rpm, this value decreased with an increase in oxygen oxidations in a continuous manner the Noël group recently concentration, presumably due to the increased excess present reported the use of a spinning disk reactor [78]. Biphasic re- in the reaction mixture leading to shortened reaction times. actions are typically highly mass-transfer dependant, with ef- Using the optimised conditions of low concentrations ficient mixing being required in order to obtain high conver- (0.1 M) and high rotation speeds and flow rate (2000 rpm sions. In order to achieve efficient mixing in plug flow reac- and 50 mL/min), a productivity approximately 2.6 times tors, supplementary mixing devices are typically required. In higher than the equivalent microflow reactor could be order to overcome this requirement, the Noël group opted to achieved. This equated to a productivity of up to 1.1 kg/day, use a Rotor-Stator Spinning Disk Reactor (RS-SDR). Using with a short residence time of 27 s. In addition to higher productivity, the use of the RS-SDR allows for simple adjust- ment of mass transfer by modifying the rotational speed of the internal disc. This versatility demonstrates the potential appli- cability of this system to other mass-transfer limited photo- hυ chemical processes. While LED technology has developed significantly over the past decade, there still exists a lack of available high- intensity monochromatic LEDs. As an alternative, Harper, 35 Moschetta and co-workers developed a CSTR setup which utilised a 25 W 450 nm fibre coupled laser system [77]. One Scheme 13 Synthesis of ‘Cookson’sdione’ J Flow Chem (2021) 11:223–241 235 Fig. 11 Kilogram-scale vortex reactor. Reprinted with permission from [76]. Copyright (2020) American Chemical Society of the disadvantages of tubular flow reactors is the require- constant at 100 mL with a depth of 5 cm (Scheme 15). ment for a fixed fluid volume within a reactor of a fixed Using this setup, the reactor was run at steady state for 32 h length. In contrast, variable fluid volumes can be utilised with- yielding 1.54 kg (85% yield) of 42.Thiscorresponded to a in a fixed volume CSTR. To overcome this a CSTR setup was productivity of 1.2 kg/day, which could be increased further designed which could theoretically operate at different vol- using more powerful lasers or a stream of cascading CSTRs. umes. The penetration of light through a reaction mixture is After this long run, a fine coating was observed on the reactor consistently cited as a limitation for scaling up photochemical walls which was not found to measurably affect the reactor reactions in batch. However, this limitation can also apply to performance. This is to be expected as the fouling did not CSTRs with the Beer-Lambert law describing the relationship affect light absorption, however, it is worth noting that reactor between light absorption and path length (reactor depth). fouling using a typical tubular flow reactor typically results in In order to explore this correlation and demonstrate the use diminished yields. In addition to demonstrating the applicabil- of high-power lasers as an alternative light source, the iridium- ity of alternative light sources, the use of CSTRs could also nickel co-catalysed C-N coupling of aryl bromides [79]was allow for photochemical transformations, which involve investigated (Scheme 15). Experiments in batch found that the solids, on kilogram scale. absorption of light by the reaction mixture was highly depen- Another approach to the scale up of the same reaction, dent on the catalyst concentrations, with over 99% of the using high-power LEDs was investigated by Lévesque, Di incident light being absorbed at 1 cm of depth with a catalyst Maso and co-workers [80]. Having previously designed a concentration of 6 mM. Through reaction optimisation, the large volume photoreactor capable of throughputs up to optimal catalyst concentration was found to be 2 mM, at 10 kg/day [81], a smaller footprint reactor which maintained which the light could penetrate a depth of 5 cm. This depth similar throughput was desired. This smaller reactor was built was the basis for the subsequent CSTR parameters. The final to fit within a 5.5-gal (~20 L) aquarium and consisted of FEP CSTR consisted of inlet and outlet pumps, a 25 W fibre optic tubing (total volume 890 mL) submerged in a recirculating laser and a beam expander. The reactor volume was kept water bath for temperature control. Panels consisting of fifteen Scheme 14 Photo-oxidation of HO citronellol HO Rose Bengal (1 mol%) EtOH, O ,hυ HO HO OH 236 J Flow Chem (2021) 11:223–241 Fig. 12 Comparison of rotation speeds in RS-SDR (reproduced with permission from [78]) 100 W LED chips (440–450 nm) were placed either side of economy. Another strategy involves the in-situ generation of the reactor, with cooling being achieved by flowing water bromine [85], which was recently explored by the Kappe through copper piping embedded in the panels (Scheme 16). group [75]. The relatively green reaction between NaBrO To efficiently scale up a reaction, light absorption by the re- and hydrobromic acid provides access to Br with the forma- action mixture must be maximised. This was done by increas- tion of water as a by-product [86]. However, due to the exo- ing the tubing diameter from 3.18 to 7.94 mm which signifi- thermic nature of the reaction, precise temperature control is cantly increased productivity while maintaining complete required. light transmittance through the solution. Using the optimised Initial reports of the process intensified photochemical ben- conditions (concentration 0.4 M), the reaction was run for zyl bromination, using in-situ generated bromine, within a lab 130 min at steady state, producing 1.14 kg of product (90% scale Corning photochemical reactor (volume: 2.8 mL) pro- assay yield). This corresponds to a productivity of 12.6 kg/ vided a throughput of 300 g/h [86]. To further scale up to day, higher than the previous larger footprint reactor [81]. pilot-scale the significantly larger Corning G3 reactor (vol- Additionally, the authors noted that this throughput could be ume: 50 mL) was employed. The setup consisted of two flu- increased significantly, at the cost of conversion, by increas- idic modules (FMs); one to carry out the photochemical reac- ing the flow rate from 105 to 925 mL/min. Using these con- tion and a subsequent FM for quenching of excess Br with ditions 1.12 kg (42% assay yield) of product was obtained in sodium thiosulfate. Separate streams of neat 2,6- just 37 min (43.4 kg/day). dichlorotoluene substrate (43) and aqueous NaBrO were Bromination reactions represent an important transforma- combined prior to being mixed with hydrobromic acid, to tion in the synthesis of building blocks for the pharmaceutical form Br which subsequently passed through the photochem- and fine chemical industries [82]. A range of methodologies ical reactor (Scheme 17). LED panels (405 nm) were used to exist, including various photochemical transformations using irradiate the mixture with a lamp temperature of <20 °C being either molecular bromine or an alternative bromine source maintained using a Lauda Proline RP 890 thermostat, while a [83]. The direct use of molecular bromine for these reactions separate thermostat was used to regulate reactor temperature. is unfavourable due to safety concerns on larger scales, and Gear pumps were used to dose the non-acidic streams while a while N-bromosuccinimide can act as a safer alternative [84], metal-free FUJI pump was utilised for administration of HBr. its use is not ideal due to poorer reactivity and modest atom A small webcam was also positioned within the reactor box Scheme 15 Laser-mediated Fibre Optic Laser photochemical aryl amination (450 nm, 26 W) Br 5 mL/min N Beam Expander F C F C (3 equiv) Ir catalyst (0.025 mol% 1.54 kg (85 % yield) NiBr •3H O (5 mol %) 2 2 32 h DABCO (1.4 equiv) DMA (0.8 M) 100 mL (5 cm depth) 70 C J Flow Chem (2021) 11:223–241 237 Scheme 16 LED-mediated photochemical aryl amination for visual monitoring of the reaction, in particular the Conclusions and future directions quenching of excess bromine. Due to the biphasic nature of the reaction effective mass transfer is important and a short While this review is not intended to provide a comprehensive residence time of 22 s with a reactor temperature of 65 °C list of examples, it is clear that through the advancement of were found to be optimal. Longer residence times resulted in available technology the scalability of photochemical reac- lower yields as a function of insufficient mixing of the biphas- tions has changed over the past decade. Prior to the last five ic system. years there were scarce reports of kilogram scale photochem- Using these optimised conditions, 44 could be synthesised ical processes carried out in continuous flow, however, this with a maximum productivity of 4.1 kg/h (88% H-NMR has been rectified in recent years, largely driven by the devel- yield), which provided a 14-fold increase on the previous lab opment of innovative photochemical reactors. While flow scale result (0.3 kg/h) [86]. It should be noted that this pro- photochemistry may present various advantages over its batch ductivity was extrapolated from a short reaction run as a long counterpart, both methodologies can be used in a synergistic run was not possible due to restraints in the quantity of avail- manner. Batch offers the advantage of simple real time anal- able starting material. While the G3 reactor provided a higher ysis through common laboratory methods such as TLC and productivity than the previous lab-scale report, the space-time- HPLC, providing powerful insight to a process. This allows yield was lower (82 kg/L/h vs 108 kg/L/h). This can be for relatively rapid screening of conditions on a small scale, accounted for by the poorer heat and mass transfer provided which may not be possible in flow due to the prohibitive cost by the single photochemical G3 FM, which was operated at a of analytical equipment required to perform similar monitor- lower than recommended flow rate. Therefore, one would ing of reactions in continuous flow. Additionally, various pho- assume that this space-time-yield could be further increased tochemical processes can be scaled up to the decagram scale through the use of 5 x G3 FMs which would be more compa- in batch with ease. However, this is generally limited to reac- rable to the lab scale design [75]. This high space-time-yield tions that do not suffer from photochemical degradation and highlights the advantages that can be achieved through con- other factors that can be mitigated though flow processing, tinuous processing when compared to batch, in particular for thus reducing the complexity of chemical structures accessible processes that require both high mass transfer and photon flux. through such batch-based methodology. Na S O �5H O (2.64 M) 2 2 3 2 Cl Cl 405 nm 43 (neat) Br HBr (47%) Cl Cl NaBrO (2.2 M) 3 44 50 mL 88 % assay yield Quench Br generator (1.1 equiv) 4.1 kg/h 50 mL t = 22 s, 65 C Scheme 17 Kilogram-scale benzylic bromination 238 J Flow Chem (2021) 11:223–241 Open Access This article is licensed under a Creative Commons The statement that batch and flow photochemistry exhibit Attribution 4.0 International License, which permits use, sharing, adap- similar performance when corrected for factors such as light tation, distribution and reproduction in any medium or format, as long as power-to-surface area, as concluded by Booker-Milburn and you give appropriate credit to the original author(s) and the source, pro- co-workers in 2014 [9], is still relevant. However, this may be vide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included limited to uncatalysed cyclisation reactions. In contrast, sev- in the article's Creative Commons licence, unless indicated otherwise in a eral of the discussed reactions, with higher comparable com- credit line to the material. If material is not included in the article's plexity, seem to benefit significantly from continuous flow. Creative Commons licence and your intended use is not permitted by Additionally, it is evident that practical scalability is achieved statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this more easily through the use of continuous flow technology. licence, visit http://creativecommons.org/licenses/by/4.0/. Various examples have been presented on a kilogram scale using small-footprint reactors, where the equivalent batch pro- cess would require prohibitively large vessels and light sources. 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Scalability of photochemical reactions in continuous flow mode

Journal of Flow Chemistry , Volume 11 (3) – Sep 1, 2021

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10.1007/s41981-021-00168-z
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Abstract

Continuous flow photochemistry as a field has witnessed an increasing popularity over the last decade in both academia and industry. Key drivers for this development are safety, practicality as well as the ability to rapidly access complex chemical structures. Continuous flow reactors, whether home-built or from commercial suppliers, additionally allow for creating valuable target compounds in a reproducible and automatable manner. Recent years have furthermore seen the advent of new energy efficient LED lamps that in combination with innovative reactor designs provide a powerful means to increasing both the practicality and productivity of modern photochemical flow reactors. In this review article we wish to highlight key achievements pertaining to the scalability of such continuous photochemical processes. . . . . Keywords Flow synthesis Photochemistry Scalability Throughput Continuous processing Introduction continuous flow processing over batch mode operation of photochemical processes concerns their scalability. Whilst Over the last decade continuous flow photochemistry has ma- scale-up in batch mode is primarily actualised through an in- tured into a powerful field within synthetic organic chemistry. crease in vessel size, analogous flow processes can be scaled- Key features that enable effective photochemical transforma- up through prolonged process times as well as specific design tions in flow mode are the ability to uniformly irradiate solu- features that render a variety of reactions more productive [8]. tions of substrates that are continuously pumped through nar- A crucial parameter to be considered during any photo- row diameter tubing or microchannels [1–3]. High spatiotem- chemical reaction is that of light penetration. Light is absorbed poral control furthermore allows the effects from over- by the reaction medium, and this light attenuation is depen- irradiation to easily be minimised as in principle each mole- dent on the irradiated reactor size as dictated by the Beer- cule resides within the irradiated section of the flow reactor for Lambert law (Fig. 1). As the size of a reactor increases so the same amount of time, which can be controlled with high too does the path length (distance from the light source), precision in flow mode [4]. Together with facile temperature resulting in non-uniform irradiation. This typically is one of control and various light sources being available (UV and the key issues for scaling up photochemical reactions in batch visible), both commercial and home-built reactor systems ren- mode, however the analogous flow processes overcome this der easy access to photochemical reactions. In addition, im- issue through miniaturisation strategies in order to shorten the portant advances in the field of photo-redox catalysis [5–7] path length. mean that synthetic chemists can choose between directly ir- In 2014 Booker-Milburn and co-workers published an im- radiated and modern photo-catalysed reactions that provide portant account [9] comparing the scalability and efficiency of mild and selective means to manipulate and functionalise flow and batch based photoreactions and concluded at that compounds of ever-increasing complexity. One important ar- stage that there is very little difference when key parameters gument frequently put forward by practitioners in favour of are kept the same. In their work a dozen transformations in- cluding [2 + 2]-cycloadditions between maleimides and al- kenes or alkynes (intra- and intermolecular), a Paterno-Büchi * Marcus Baumann cycloaddition, a di-π-methane rearrangement as well as sev- marcus.baumann@ucd.ie eral radical-based processes were evaluated. Productivities of several decagrams per day were typically achieved for these School of Chemistry, Science Centre South, University College Dublin, D04 N2E2, Dublin, Ireland optimised processes. At this stage flow reactor configurations 224 J Flow Chem (2021) 11:223–241 Fig. 1 Attenuation of light through a reactor vessel expressed via transmittance and absorbance were commonly based on FEP-coil reactors (single and mul- Discussion tiple layers) in combination with UV-C or medium-pressure Hg-lamps whereas immersion type reactors using the same This first section will highlight several modern as well as lamps were used in batch mode. Despite the slightly different classical photochemical transformations that are difficult to set-ups and irradiation profiles, the conclusion of equal per- execute and scale in batch mode. Transferring the initial batch formance for batch and flow processing could be drawn. It reaction into continuous flow mode thus provides a means of should be noted that this comparison focused on reactions in generating gram quantities of desired target products in a time which substrates are directly irradiated, and therefore the con- and cost-effective manner. These laboratory scale examples clusions may not extend to more complex reactions involving therefore demonstrate approaches for increasing the produc- photocatalysts. tivity and practicality of various light-driven reactions. Simple More recently, a variety of new photoreactors designed flow setups are thereby utilised to satisfy the demand of ma- for continuous processing have been developed. These terials of interest whose scaled preparation can be advanced include commercial systems such as the Vapourtec UV- further by scale-out and numbering up strategies. Subsequent 150 reactor and its high-power LED extension [10–14], sections will then expand on this theme by introducing setups the Corning photoreactor system [15–17], the Uniqsis and concepts enabling productivities of several kilograms per PhotoSyn [18, 19], or the Firefly system from day. The productivities thus reached will in many cases be Cambridge Reactor Design [20]. Furthermore, studies sufficient to meet the current demand for specific branches employing a modified rotary reactor (coined PhotoVap) within industry (pharmaceutical, fragrances and fine [21], a vortex reactor [22, 23] or oscillatory flow reactors chemicals), although it is understood that these are subject to for heterogeneous reactions [24, 25] have been reported. further changes over time. It is not surprising that the design of such newer systems and the implementation of chemical engineering knowl- Laboratory scale (< 100 g/day) edge increases the performance and therefore scalability of the resulting applications. In addition, a growing body Photoredox catalysis has experienced a surge in interest in of today’s literature is based on photosensitised transfor- recent years [26–31], in part, due to the advancement of equip- mations that oftentimes exploit visible rather than UV ment such as LED lamps used for photochemical reactions. light. Transition metal-mediated photoredox catalysis is generally In view of these manifold developments, we wish to pro- characterised by two coupled catalytic cycles. Firstly, a cycle vide an update on recent contributions by discussing rele- activating the photocatalyst, which then turns over the sub- vant studies and highlight new knowledge pertaining to the strate in the second catalytic cycle. Photoredox catalysis can scalability of flow-based photochemistry. Specifically, we be exploited for a wide range of reactions including various will discuss scalability as a function of the equipment used, carbon-carbon bond forming reactions [29–31]. Recently, the the underlying photo-transformation as well as the com- MacMillan group reported a batch method for the photoredox 3 2 plexity of substrates and products involved. We hope that catalysed formation of C -C bonds [32]. This was per- sp sp this review allows interested readers to find not only inter- formed by coupling aryl halides to alkyl halides in the pres- esting applications of continuous photochemical reactions, ence of an iridium-nickel co-catalytic system and a silyl rad- but moreover appreciate the complex interplay of different ical precursor (Scheme 1). The methodology proved to be factors that determine success and ultimately scalability in robust giving the desired products in good yields, however, these light-driven processes. the reaction was only carried out on small scale. J Flow Chem (2021) 11:223–241 225 Scheme 1 Photochemical C - sp C coupling sp In order to utilise this reactivity in a scalable manner, the offered significantly shorter reaction times (30-min residence Jensen group developed a continuous stirred-tank reactor time vs 15 h in batch) and higher productivity than a batch (CSTR) system for carrying out photochemical reactions reactor of similar size. Based on the reactor design this pro- [33]. The reaction reported by MacMillan required the pres- ductivity could be further improved by a relatively straightfor- ence of an insoluble inorganic base, which typically is incom- ward increase in reactor size. patible with carrying out reactions in a continuous manner due The applicability of continuous flow to scaling up to reactor blocking and fouling. However, the use of a CSTR photoredox processes has also been demonstrated by the could mitigate this issue through careful reactor design. Collins group [35], who reported the synthesis of alkynyl Previously, the Jensen group had reported the design of a sulfides 6 via C(sp)-S bond formation (Scheme 2). The cou- CSTR cascade used for heterogenous reactions [34], which pling of alkynyl bromides 5 and thiols 4 was performed using was adapted for this photochemical reaction. a 4CzIPN (an organic carbazole-based sensitiser [36]) and The reactor consisted of five single chambers (total volume nickel co-catalysed system. While the reaction could be car- 5.3 mL), connected by a drilled channel, which could be irra- ried out successfully in batch on a small scale (0.24 mmol) diated through a glass window (Fig. 2). Mixing was achieved with excellent yields (92%) the long reaction time of 4 h was using magnetic stir bars which could be operated using a con- unfavourable. The use of a continuous flow system allowed ventional magnetic stirring plate. Using this setup, in combi- for significantly shorter reaction times of 30 min while main- nation with a slurry pump, the heterogeneous mixture could taining high yields. be administered to the reactor while maintaining an inert The simple continuous flow setup consisted of a syringe atmosphere. pump and a homemade PFA coil reactor which surrounded a Under these conditions facile direct transfer of the previous portion of blue LED ribbon (λ = 465 nm, Fig. 3). Scale-up max batch method to continuous flow was possible, eliminating the of the photochemical reaction in batch proved challenging need for re-optimisation to incorporate a soluble organic base. with a significantly reduced yield of 26% being obtained The flow system was then used to synthesise compound 3 on a when carried out on a gram-scale (5 mmol). Furthermore, gram scale in 13 h (77 mg/ h) with similar yields to the batch the low concentration required for the reaction (50 mM) process (77% in flow, 80% in batch). would make further scale-up in batch impractical due to the While the application of flow chemistry to this reaction did requirement for increasingly large reactor vessels. In contrast, not offer an improvement in yield, as is sometimes the case, it a scale-out of the reaction in continuous flow yielded over 1.2 g of product with significantly improved productivity over batch (1.16 mmol/h vs 0.33 mmol/h). An issue that commonly arises during photochemical reac- tions is that of over-irradiation of either substrate or the resulting reaction product. This can lead to a variety of side reactions occurring and is typically unavoidable in batch. The advantage offered by spatiotemporal processing in continuous flow typically eliminates this issue allowing sensitive reac- tions to be carried out on a larger scale. The improvement in flow technology in recent years has provided chemists with the opportunity to revisit chemistry that previously had not been scalable. One such example is the photo-electrocyclization of 2-pyrone derivatives which was first reported by Corey in 1964 [37]. The resulting cyclobutene lactone product 8 is a synthetically versatile chemical building block due to its high ring strain [38–41]. Fig. 2 Image of CSTR setup. Reprinted with permission from [33]. Copyright (2019) American Chemical Society Recently, the Kappe group investigated the applicability of 226 J Flow Chem (2021) 11:223–241 Scheme 2 Continuous flow 4CzIPN (2 mol%) synthesis of alkynyl sulfides NiCl .dme (10 mol%) pyridine (2 equiv) N N Br NC CN + R R SH 2 1 R SR 4 5 (1 equiv) (1.1 equiv) MeCN/DMF (23:1) (0.05M) t =30min,rt 4CzIPN flow chemistry to improving the scalability of this reaction order to isolate multiple grams of the desired material. As an [42]. Careful optimisation of reaction conditions found the alternative, researchers have increasingly begun to utilise con- correct selection of light source to be of critical importance, tinuous flow as part of their synthetic strategy. One recent with an improvement in yield being observed using a com- example was published by the Beeler group who developed mercially available medium pressure mercury lamp (with the the gram scale photochemical synthesis of aglain analogues, a appropriate light filter) when compared to a weaker 8 W UV precursor to rocaglate natural product analogues. [45] A com- lamp emitting at 303 nm. Use of the correct light source mon strategy for the synthesis of aglain 12 is the photochem- allowed the researchers to synthesise the desired cyclobutene ical [3 + 2]-cycloaddition of 3-hydroxyflavone 10 and methyl lactone 8 in high yields (> 95%) with significantly reduced trans-cinnamate (11). [46, 47] Previous reports in batch typi- reaction times when compared to batch (20-min residence cally provide <150 mg of product per reaction in 40–50% time vs 24 h in batch). To scale up the flow process the com- yield with long reaction times of up to 12 h. [47] mercially available Vapourtec UV-150 reactor (10 mL) was Initial optimisation was carried out using a reactor used (Scheme 3). While attempting to scale-out the process by consisting of a 150 W metal-halide lamp (>300 nm) placed running the reactor for 8 h, significant reactor fouling was at the centre of a FEP coil reactor (3.5 mL). Recirculating observed due to the formation of an insoluble polymeric ma- glycol was used to cool the inner chamber of the reactor. terial, as is the case in batch. This was resolved by decreasing Under the optimised conditions the desired product 12 could the reaction temperature from 50 °C to 10 °C, however, a be synthesised with a residence time of 30 min giving a conversion decrease of 2.3% per hour was still observed. throughput of ~180 mg/h compared to the batch throughput Despite this, the continuous flow setup achieved a productiv- of ~11 mg/h. To further scale up the reaction, the volume of ity of 144 mg/h (~3.5 g/day) over an 8-h run, significantly the photochemical reactor was increased to 12.5 mL (Scheme higher than previously reported batch reactions (14–21 mg/ 4). Numbering up this larger reactor to three gave a total vol- h, 336—504 mg/day) [41]. ume of 37.5 mL, which, with a slight increase in residence Photochemically induced cyclisation reactions have been time to 35 min, further increased the throughput to 1.92 g/h. applied to the synthesis of a range of natural product deriva- This strategy exemplifies the ease at which scalability of a tives. [43, 44] Typically, such synthetic projects do not require continuous flow process can be achieved when compared to kilograms of product but the isolation of anything more than its batch counterpart. hundreds of milligrams can prove challenging in batch. This Conformationally restricted three dimensional molecules results in the chemist having to carry out multiple reactions in are becoming increasingly important scaffolds for medicinal chemistry applications [48, 49]. One method by which these Vapourtec UV-150 (10 mL) t =20min,50℃ in MTBE (0.05 M) Fig. 3 Image of continuous flow setup (reproduced with permission from Scheme 3 Photochemical synthesis of 2-oxabicyclo[2.2.0]hex-5-en-3- [35]) one 8 J Flow Chem (2021) 11:223–241 227 OMe O Scheme 4 Photochemcial Metal-Halide Lamps OH synthesis of aglain 12 HO OH HO MeO MeO O CO Me OMe Ph MeO O 12 OMe OMe structures can be accessed is through photochemical intra- or much-improved throughput of ~30–50 g/day, achieved intermolecular cycloaddition reactions [50]. This strategy was through a straightforward increase in reactor size. used by the Rutjes group for the scalable synthesis of cyclic While the above examples demonstrate how flow chemis- aminoketones in continuous flow mode (Scheme 5)[51]. try can be used to scale photochemical reactions, generally For optimisation purposes reactions were carried out on a most reactions must be reoptimized to transfer from batch to small scale using a ‘home-made’ reactor. This small-scale flow. This can typically result in lost time trying to find the reactor consisted of FEP tubing (11.6 mL) wrapped around a optimal flow rate to achieve sufficiently high yields. Recently condenser, which was then irradiated using a commercially the Booker-Milburn group undertook a study in an attempt to available Rayonet RMR-600 photochemical reactor. Low rectify this issue [52]. It was reported that the transfer of substrate concentrations (30–40 mM) were found to provide optimised batch conditions to flow could be simplified by excellent yields when irradiated at 254 nm for 30–40 min calculating the flow rate based on batch parameters. This depending on the substrate. would help reduce development time as reactions can be Using these optimised conditions, a throughput of ~5.6 g/ optimised more rapidly in batch due to the ability to easily day was achieved. However, this scale was insufficient for the monitor them in real time, without the need for additional required synthesis of these compounds. Further scale-up was expensive equipment. To verify this hypothesis, various reac- therefore achieved through design of a larger reactor (Fig. 4). tions were transferred from batch to continuous flow. Among This system consisted of FEP tubing (volume: 105 mL) these was the photorearrangement of N-substituted wrapped around a commercially available UV-C lamp. succinimides 17 to keto-caprolactams 20 (Scheme 6)[53, 54]. Cooling of the reactor was achieved using an external stream While well-known, this reaction proves difficult to scale due of water, and the system was encased with a metal jacket to to alternative competing reaction pathways leading to the for- protect the user from harmful UV radiation. Using this high mation of insoluble side-products, particularly at higher con- throughput setup 10 g of compounds 14 and 16 could be centrations. The flow rate in UV photochemistry is of prime synthesised in 4.8 and 7.3 h, respectively. This equated to a importance due to the ease at which reaction mixtures can be Scheme 5 Photochemical synthesis of conformationally strained scaffolds h (254 nm) MeCN (0.04 M) Boc t = 30 min Boc Boc 13a 15 96 % (4:1) hυ (254 nm) MeCN (0.03 M) t = 40 min Boc r Boc 13b (95%) 228 J Flow Chem (2021) 11:223–241 various examples of equivalent batch reactions on this scale exist [9]. However, as reaction scale approaches the order of hundreds of grams the use of a batch setup becomes increas- ingly impractical due to the requirement for significantly larg- er equipment as well as limitations regarding heat transfer. Low concentrations and high lamp powers required for suc- cessful photochemical reactions add to these complications. Carbon-carbon bond formation reactions are of extreme importance in a chemist’s toolbox for which a range of meth- odologies exist [31, 55, 56]. Recently, Alcázar and co-workers reported the visible-light induced Negishi reaction for C(sp )- C(sp ) cross couplings (Scheme 7)[57, 58]. This two-step reaction involves firstly the formation of an organozinc re- agent 22, which is then coupled with an aryl bromide 23 under photochemical conditions in the presence of a nickel catalyst. This photochemical methodology presented a broader scope than the traditional nickel-catalysed Negishi reaction and was Fig. 4 Medicinal chemistry scale continuous flow setup scaled to achieve a throughput of 800 mg/h using a commer- cially available Vapourtec reactor. While useful for screening over-irradiated, leading to diminished yields and side-product purposes, a larger scale was required for ‘pilot’ scale. Good formation. Based on previous reports stating that FEP flow yields had been reported using the Vapourtec system, howev- reactors have similar productivities per Watt to batch [9], the er, its scalability was limited by its fixed reactor volume of optimal flow rate could be calculated based on the power of the 10 mL. To overcome this limitation, the authors opted to use a flow setup. To test this, a reactor consisting of FEP tubing larger Corning G1 reactor (40 mL) for the photochemical wrapped around 3 × 36 W UV-C lamps was used. Based on process (Fig. 5). the increase in power compared to batch (18 W) a flow rate of The continuous flow setup consisted of a column filled −1 7.5 mL min was calculated. Through re-optimisation of the with powdered zinc, to generate the required organozinc re- −1 flow procedure a flow rate of 8 mL min was found to be ideal, agent (22) in a continuous process that was monitored using closely matching the calculated value. While no improvement in-line NMR, which was combined with a stream of aryl bro- in the yield of 20 was observed, the productivity of the reaction mide and nickel catalyst prior to entering the photoreactor. was significantly improved to 96 g/day compared to the previ- The use of a high-powered LED lamp (100 W, 405 nm) pro- ously reported 2.2 g/day in batch [54]. While using a continu- vided the desired product in excellent yield matching that of ous flow setup does not lead to an increase in reaction efficien- the previous Vapourtec example. Optimisation of the reaction cy, it does allow for facile scale up due to the potential for found that a slightly shorter residence time could be utilised increased reactor power as a function of the presence of multi- further improving the throughput to 5.6 g/h. Use of the larger ple lamps. However, it should be noted that this conclusion may reactor offered a sevenfold increase in throughput (134 g/day only be drawn for the reaction included in the survey, as vs 19 g/day) when compared to the smaller Vapourtec reactor photocatalysed pathways may display different behaviour due despite only a fourfold increase in volume (Scheme 7). It is to their increased complexity. worth noting that this non-linear increase may be attributed to the increased light power-to-surface area offered by using glass plate reactors in place of the traditional FEP tubing Pilot scale (100+ g/day) setup. The incorporation of fluorine into organic molecules is While the above examples demonstrate the advantages of con- highly relevant to the pharmaceutical industry due to their tinuous flow in scaling of reactions to the decagram scale, Scheme 6 Photorearrangement OH R of N-substituted succinimide O HO hυ N N NH O O 17 18 20 19 J Flow Chem (2021) 11:223–241 229 Br Zn Br Zn F CO F CO 3 3 21 22 F CO CO Me 3 2 Br Ni catalyst (2 mol%) MeO C Vapourtec Corning G1 Yield (%) 93 93 Time (min) 20 15 Reactor size (mL) 10 40 Throughput (g/h) 0.8 5.6 Scheme 7 Visible-light induced Negishi-coupling reactions potential to alter biological properties of molecules [59, 60]. tubing wrapped around the outside. The total reactor volume However, there remains a lack of scalable methodology to measured approximately 150 mL and the assembly was achieve this. This limitation arises, in part, due to the cost, housed within a steel casing. Cooling of the reactor was both monetary and environmental, associated with typical achieved through filling of both cavities with water. This setup fluorinating and trifluoromethylating reagents. Recently, the fulfilled the predetermined requirements of low cost and hav- Stephenson group developed a photochemical method for in- ing a small footprint (Fig. 6). Using this ‘home-made’ reactor corporating trifluoromethyl groups into various arenes and the trifluoromethylation of pyrrole 25 was carried out on the heteroarenes [61, 62]. This reaction involved the photochem- kilogram scale. Running the reactor continuously for 48 h ical decarboxylation of trifluoroacetic anhydride (26) facilitat- provided 0.95 kg of product 27, equating to 20 g/h. The equiv- ed by pyridine N-oxide in the presence of a ruthenium catalyst alent reaction in batch would prove impractical due to the size (Scheme 8). Blue LEDs (13 W) were found to be a sufficiently of the reaction vessel required, in addition to the size and powerful light source, and the desired trifluoromethylated power of the light source. products could be obtained from a range of substrates in good Many examples of continuous flow photochemical reactors yields. Despite promising results, this methodology had not in the literature consist of tubing wrapped around a light previously been utilised for scales larger than 20 g. source [1, 3, 64]. However, various other creative solutions In order to further scale up this reaction, the Stephenson to benefit from the advantages of continuous flow have been group opted for a continuous flow setup based on a coil reac- reported [65]. In 2016 the George group presented a photo- tor design [63]. The reactor consisted of blue LED lights chemical reactor comprised of a converted rotary evaporator contained within a glass beaker with a single layer of PFA which was coined the PhotoVap [66]. This setup could be run Fig. 5 Continuous flow setup: 1. G1-photoreactor; 2. Zinc column; 3. Reagents; 4. Mass flow controller; 5. Back pressure regulator; 6. Collection vessel; 7. Zinc activation waste; 8. Pressure and temperature monitor; 9. Needle valve; 10. Pressure sensor. (Reproduced with permission from [58]) 230 J Flow Chem (2021) 11:223–241 Scheme 8 Continuous flow Boc photochemical trifluoromethylation CO Me Boc F C CO Me 3 2 MeCN (0.57 M) Ru(bpy) Cl (0.1 mol%) 3 2 pyridine N-oxide (2.0 equiv) 0.95 kg, 20 g/h 50% yield O O F C O CF 3 3 (2.1 equiv) MeCN (1.37 M) t = 30 min, 45 C, 48 h in a semi-continuous manner and required little modification flask, and the mixture was irradiated using 1000 lm white to the conventional, widely available laboratory rotary evap- LEDs. To run the reaction semi-continuously, a 50 mL portion orator (Fig. 7). of substrate feed was administered and irradiated in the rotat- The reactor consisted of two thin PTFE tubes which were ing flask until reaction completion was reached. Rotation was threaded through the neck of a rotating flask, which were used then ceased, and the resulting product was removed before to dose starting material and subsequently withdraw product. repeating the cycle. Using a 3 L flask, a productivity of The flask was surrounded by LEDs with temperature control 1 mmol/min (which extrapolates to approximately 10 g/h, achieved using the rotary evaporator bath. Dosing of reagents 240 g/day) could be achieved. While there are various scalable and rotation speed were controlled using an external comput- examples of this specific reaction in the literature, this reaction er. By rotating the flask, a thin film of reaction mixture on the design presents a potentially versatile alternative to plug flow vessel wall was generated, which provided more efficient ra- reactors for chemistry with short reaction times. diation than might be observed in batch mode. Additionally, [2 + 2]-Cycloadditions remain one of the most common the scale of the reaction could be adjusted by increasing the methods for accessing cyclobutanes [69]. Most of these reac- size of the reaction flask up to 3 L (other rotary evaporator tions are carried out under photochemical conditions, in some models can facilitate larger flasks). cases in the presence of a photosensitiser. The Kappe group In order to demonstrate the scalability of this semi- recently reported a scalable method for the photochemical continuous approach the photo-oxidation of α-terpinene 28 [2 + 2]-cycloaddition of ethylene to cyclic anhydrides [70]. to ascaridole 29 was selected (Scheme 9)[67]. This reaction LEDs offer the advantage of being more efficient and gener- utilises Rose Bengal as a photosensitiser, which in combina- ating less heat than their medium- or low-pressure mercury tion with light can generate singlet oxygen from either ambi- lamp counterparts. Additionally, they can be used to emit ent air, or a stream of oxygen gas [68]. This highly reactive specific near-monochromatic wavelengths, however they gen- oxygen species then efficiently oxidises α-terpene to the de- erally are limited to longer wavelengths (>350 nm). Typically, sired product 29. Oxygen gas was bubbled through the reac- the use of longer wavelengths requires the presence of a tion mixture, by passing an additional PTFE tube into the photosensitiser for certain reactions to facilitate the energy Fig. 6 Kilogram-scale continuous flow setup (reproduced with permission from [61]) J Flow Chem (2021) 11:223–241 231 (~240 g/day), with a 10-h run yielding 101 g of 32. While the photochemical reaction may be feasible in batch, the use of ethylene gas on this scale would be unfavourable due to the potential safety risks, which are mitigated in continuous flow [71]. Production scale (> 1 kg/day) While there are various examples exemplifying the advan- tages of continuous flow photochemistry for scale up, the transfer of these reactions from the laboratory scale to produc- tion scale is non-trivial. The previously discussed studies are generally limited by the volume of the reactor utilised, how- ever, an increase in volume by increasing tubing diameter may alter the fluid dynamics of a reaction whilst also increasing the path length of the incoming light. Therefore, additional reac- tion optimisation may be required when attempting to perform Fig. 7 ‘PhotoVap’ setup. Reprinted with permission from [66]. Copyright (2016) American Chemical Society continuous photochemical reactions at the kilogram scale. However, it should be noted that these differences in fluid transfer. This study by the Kappe group highlighted the im- dynamics observed during scale up are significantly smaller portance of the selection of the correct photosensitiser and than those observed in batch. found thioxanthone (31) to be ideal for the reaction between With the scalability of the synthesis of cyclobutanes from citraconic anhydride (30) and ethylene to produce the corre- ethylene being demonstrated by the Kappe group on the sponding cyclobutane 32 (Scheme 10). hundred-gram scale [70], no attempts had been reported of The fact that ethylene is present as a gas makes carrying out performing this reaction on manufacturing scale. Recently, this reaction non-trivial, in particular in batch, due to the as- Beaver, Zhang and co-workers set out to develop a continuous sociated hazards and complications of using a liquid-gas bi- flow platform for the synthesis of cyclobutane 34 (Scheme 11) phasic mixture. Initial experiments and optimisation were car- in order to prepare >5 kg/day of the target compound [72]. To ried out using a commercially available plate reactor achieve this, a multistage approach was executed. This in- (2.77 mL), which was irradiated using two LED panels volved focused reaction optimisation, proof of concept (375 nm). Starting anhydride 30 and photosensitiser 31 were through an intermediate scale-up (500 g/day) and finally, the dosed using integrated pumps and were combined with ethyl- design of a production scale skid (>5 kg/day). ene, with gas flow being regulated by a mass flow controller. As is often the case when scaling up a reaction to industrial A back pressure of 12 bar was applied to ensure a homoge- scales, development and optimisation of a product isolation nous system, maximising contact between the substrates. method becomes increasingly important. As previously re- Optimisation of the reaction found a residence time of ported [70, 73], the presence of a photosensitiser, benzophe- 5.2 min to be sufficient for full conversion, corresponding to none, is crucial for the reactivity of maleic anhydride with a productivity of 2.1 g/h (~58 g/day). To demonstrate the ethylene. Increasing the quantity of benzophenone resulted scalability of this reaction, a switch to the Corning G1 in increased reaction efficiency, however, a negative impact photoreactor was made. This consisted of five 2.77 mL plate on crystallisation efficiency (and overall isolated yield) was reactors connected in series giving a total volume of 13.85 mL also observed. Therefore, an amount of 10 mol% was chosen (Fig. 8). Adjustment of the flow rate to maintain the constant to strike the balance between the two parameters. The contin- ~5.5 min residence time provided a productivity of ~10 g/h uous flow setup consisted of a stream of maleic anhydride/ benzophenone, which was combined with ethylene gas in a mixing tank, with the mixture then passing through a photoreactor (Scheme 12). photosensitizer While a standard T-piece mixer was sufficient for the in- termediate scale (500 g/day), as flow rate was increased the airorO ,hυ presence of ethylene slugs was observed. This slug flow could be eliminated using a mixing tank with a residence time of 30 min. To increase productivity, the internal diameter of the 28 29 reactor tubing was increased to 10 mm (compared to the lab Scheme 9 Photooxygenation of α-terpinene scale ~1–2 mm). Due to the significantly increased diameter, a 232 J Flow Chem (2021) 11:223–241 Scheme 10 Photochemical [2 + 6.25 mL/min 2]-cycloaddition of ethylene O 30 LED (375 nm) 0.5 M in EtOAc O O 12 bar 2.5 mL/min 2.77 mL 4 x 2.77 mL 96%, 101.3 g 10 h 2.5 mol% matched increase in lamp power was required. For the inter- the tubing may lead to rupture when operated under pressure. mediate scale setup, 2 × 300 W LED panels (365 nm) were Additionally, reactor fouling can be a common issue [70, 73], found to be sufficient. However, with the increase in volume while oftentimes reversible by flushing solvent through the to the production scale (from 1.56 L to 20.76 L irradiated reactor, this fouling/blocking can be irreversible in some volume) a corresponding increase in lamp power was required cases. This results in the need to replace the entire length of (6 × 3 kW LED panels for production scale). As is the case tubing within the reactor which is highly wasteful on large with any increase in lamp power, significant additional scale (lengths of tubing exceed hundreds of metres in some cooling was required to maintain a constant temperature. cases). In order to mitigate these issues, a collaboration be- This was achieved simply by adjusting the flow rate of the tween industrial groups and the Booker-Milburn group devel- cooling medium. The final optimised production scale skid oped a quartz reactor which they coined the ‘Firefly’ reactor was then run uninterrupted for a period of one week, produc- (Fig. 10)[20]. ing 51.8 kg (7.4 kg/day) of cyclobutane 34 thus exceeding the The Firefly reactor consists of an array of axially arranged initial target of 5 kg/day with the setup being used to eventu- quartz tubes (internal volume 120 mL) around a light source. ally generate >250 kg of 34. While significant safety consid- The use of quartz offers the advantage of near-complete UV erations were required for such a scale, many of the concerns transparency in addition to increased durability when com- that are associated with such a reaction were minimised using pared to FEP. A standard high-power medium pressure mer- continuous flow chemistry (Scheme 12). This combined with cury lamp was used in this case, but the light source could be the relatively small footprint (Fig. 9) makes it difficult to de- easily exchanged to suit a range of photochemical reactions. velop a safe batch reactor with comparable efficiency. To protect the user from powerful UV radiation, the reactor While highly efficient for carrying out photochemical re- was placed in a metal jacket, which offered the additional actions, the use of FEP reactors can prove problematic on benefit of reflecting any light back towards the reactor. larger scales. While FEP is a highly versatile material, it is Despite the presence of a cooling jacket surrounding the reac- not completely UV transparent and any weak spots within tor tubing, the introduction of a metal reflector caused signif- icant overheating. This could be overcome through the intro- duction of a fan to displace stagnant air caught between the light source and reactor tubing. In order to test the reactor, a range of [2 + 2]-cycloaddition reactions were investigated, including the synthesis of “Cookson’sdione” (36, Scheme 13)[74]. This involves the intramolecular [2 + 2]-cycloaddition of the ene-dione 35 which had previously been demonstrated using a FEP reactor [9]. Using the Firefly reactor at 1.5 kW and a concentration of C H (gas) 2 4 365 nm LED benzophenone (10 mol%) solvent, ambient temp 33 34 Fig. 8 Corning G1 photoreactor. Reprinted with permission from [70]. Copyright (2019) American Chemical Society Scheme 11 Photochemical synthesis of cyclobutane 34 J Flow Chem (2021) 11:223–241 233 Scheme 12 Kilogram-scale continuous flow setup. Reprinted with permission from [72]. Copyright (2020) American Chemical Society 0.5 M a productivity of ~4 kg/day could be achieved. required oxygen being supplied by air drawn into the reac- Doubling of the concentration and light power corresponded tor. While innovative, this design was not suitable to larger to a doubling of productivity (8 kg/day) which was demon- scales (>10 g/day) due to volume constraints. strated by synthesising 1165 g of 36 in just 3.5 h. Based on In order to develop a system capable of producing kilo- these results using the full 5 kW power rating a total produc- grams of product, a reactor of approximately 20 times the tivity of 13 kg/day could be achieved. Comparison of this volume was developed (Fig. 11)[76]. The reactor consisted methodology to the previously published FEP reactor [9] of a polymer rotor housed within a jacketed filter-tube sealed found the Firefly system to be almost 30% more power effi- with a steel base and polymer cap. Inlet pores were bored cient which while not crucial on laboratory scale, is of prime through the steel base and outlets were found in the polymer importance for manufacturing. cap. Cooling was provided by a recirculating chiller connected The majority of novel innovative reactor designs for to a jacketed glass vessel and a gap of 2 mm was employed kilogram-scale continuous flow photochemical synthesis between the glass jacket and polymer rotor giving a total re- have only been reported over the last decade [20, 61, 72, actor volume of 280 mL. The reactor was irradiated using a 75–77]. Many of these involve scaling up reactors that light source housed outside the cooling jacket. were designed for laboratory scale synthesis, such as the To demonstrate the utility of this reactor the photo- vortex reactor reported by Poliakoff, George and co- oxidation of citronellol (37) was once again chosen workers [22, 76]. The design of a reactor that utilised a (Scheme 14). In contrast to small scale experiments, air, which rotating cylinder inside a static cylinder in order to gener- provides the required oxygen, could not reliably be drawn in ate Taylor vortices was reported in 2017 [22]. This reactor due to the increased volume of the reactor and the reduced was used for the photooxidation of citronellol with the rotation speed of the internal rotor. Fig. 9 Image of photochemical skid. Reprinted with permission from [72]. Copyright (2020) American Chemical Society 234 J Flow Chem (2021) 11:223–241 Fig. 10 ‘Firefly’ photochemical reactor (reproduced with permission from [20]) Using a stream of oxygen gas, coupled with a sufficiently this class of reactor, extremely efficient mixing can be high rotation speed, rendered the photoproducts in yields of up achieved through modification of the speed at which the in- to 92% (both isomers 38 and 39). In order to determine the ternal disk rotates. The reactor consisted of a rotor housed rotation speed required for sufficient mixing, various within a 64 mL reactor, a quartz window was employed to Computational Fluid Dynamics (CFD) calculations were car- allow the mixture to be irradiated, giving an irradiated volume ried out, this aided optimisation of the reaction and is typically of 27 mL. 120 W white LEDs were utilised to irradiate the an extremely valuable tool in the scaling up of reactions. The reaction mixture. optimised conditions used a concentration of 0.2 M with a In order to demonstrate the utility of this class of reactors residence time of 7 min, through which a productivity of for photochemical processes, the photo-oxidation of α- ~2 kg/day could be achieved. This corresponded to a ~ 10-fold terpinene was selected (Scheme 9). The setup consisted of a increase in space-time-yield compared to the previous small- stream of Rose-Bengal and α-terpinene, which were com- scale reactor. It is worth noting that the [2 + 2]-cycloaddition bined with a separate stream of O gas in a T-piece mixer, of “Cookson’sdione” (Scheme 13) was also carried out with a before entering the RS-SDR. To monitor the effect of rotation productivity comparable to that achieved by the Firefly reactor speed on mixing, a high-speed camera was used to image the [20] (~7.5 kg/day vs ~8 kg/day), emphasising that similar disk (Fig. 12). Optimisation studies revealed the benefit ob- results can be achieved utilising different reactor designs. tained from high rotation speeds plateaued at approximately As an alternative approach for carrying out photochemical 2000 rpm, this value decreased with an increase in oxygen oxidations in a continuous manner the Noël group recently concentration, presumably due to the increased excess present reported the use of a spinning disk reactor [78]. Biphasic re- in the reaction mixture leading to shortened reaction times. actions are typically highly mass-transfer dependant, with ef- Using the optimised conditions of low concentrations ficient mixing being required in order to obtain high conver- (0.1 M) and high rotation speeds and flow rate (2000 rpm sions. In order to achieve efficient mixing in plug flow reac- and 50 mL/min), a productivity approximately 2.6 times tors, supplementary mixing devices are typically required. In higher than the equivalent microflow reactor could be order to overcome this requirement, the Noël group opted to achieved. This equated to a productivity of up to 1.1 kg/day, use a Rotor-Stator Spinning Disk Reactor (RS-SDR). Using with a short residence time of 27 s. In addition to higher productivity, the use of the RS-SDR allows for simple adjust- ment of mass transfer by modifying the rotational speed of the internal disc. This versatility demonstrates the potential appli- cability of this system to other mass-transfer limited photo- hυ chemical processes. While LED technology has developed significantly over the past decade, there still exists a lack of available high- intensity monochromatic LEDs. As an alternative, Harper, 35 Moschetta and co-workers developed a CSTR setup which utilised a 25 W 450 nm fibre coupled laser system [77]. One Scheme 13 Synthesis of ‘Cookson’sdione’ J Flow Chem (2021) 11:223–241 235 Fig. 11 Kilogram-scale vortex reactor. Reprinted with permission from [76]. Copyright (2020) American Chemical Society of the disadvantages of tubular flow reactors is the require- constant at 100 mL with a depth of 5 cm (Scheme 15). ment for a fixed fluid volume within a reactor of a fixed Using this setup, the reactor was run at steady state for 32 h length. In contrast, variable fluid volumes can be utilised with- yielding 1.54 kg (85% yield) of 42.Thiscorresponded to a in a fixed volume CSTR. To overcome this a CSTR setup was productivity of 1.2 kg/day, which could be increased further designed which could theoretically operate at different vol- using more powerful lasers or a stream of cascading CSTRs. umes. The penetration of light through a reaction mixture is After this long run, a fine coating was observed on the reactor consistently cited as a limitation for scaling up photochemical walls which was not found to measurably affect the reactor reactions in batch. However, this limitation can also apply to performance. This is to be expected as the fouling did not CSTRs with the Beer-Lambert law describing the relationship affect light absorption, however, it is worth noting that reactor between light absorption and path length (reactor depth). fouling using a typical tubular flow reactor typically results in In order to explore this correlation and demonstrate the use diminished yields. In addition to demonstrating the applicabil- of high-power lasers as an alternative light source, the iridium- ity of alternative light sources, the use of CSTRs could also nickel co-catalysed C-N coupling of aryl bromides [79]was allow for photochemical transformations, which involve investigated (Scheme 15). Experiments in batch found that the solids, on kilogram scale. absorption of light by the reaction mixture was highly depen- Another approach to the scale up of the same reaction, dent on the catalyst concentrations, with over 99% of the using high-power LEDs was investigated by Lévesque, Di incident light being absorbed at 1 cm of depth with a catalyst Maso and co-workers [80]. Having previously designed a concentration of 6 mM. Through reaction optimisation, the large volume photoreactor capable of throughputs up to optimal catalyst concentration was found to be 2 mM, at 10 kg/day [81], a smaller footprint reactor which maintained which the light could penetrate a depth of 5 cm. This depth similar throughput was desired. This smaller reactor was built was the basis for the subsequent CSTR parameters. The final to fit within a 5.5-gal (~20 L) aquarium and consisted of FEP CSTR consisted of inlet and outlet pumps, a 25 W fibre optic tubing (total volume 890 mL) submerged in a recirculating laser and a beam expander. The reactor volume was kept water bath for temperature control. Panels consisting of fifteen Scheme 14 Photo-oxidation of HO citronellol HO Rose Bengal (1 mol%) EtOH, O ,hυ HO HO OH 236 J Flow Chem (2021) 11:223–241 Fig. 12 Comparison of rotation speeds in RS-SDR (reproduced with permission from [78]) 100 W LED chips (440–450 nm) were placed either side of economy. Another strategy involves the in-situ generation of the reactor, with cooling being achieved by flowing water bromine [85], which was recently explored by the Kappe through copper piping embedded in the panels (Scheme 16). group [75]. The relatively green reaction between NaBrO To efficiently scale up a reaction, light absorption by the re- and hydrobromic acid provides access to Br with the forma- action mixture must be maximised. This was done by increas- tion of water as a by-product [86]. However, due to the exo- ing the tubing diameter from 3.18 to 7.94 mm which signifi- thermic nature of the reaction, precise temperature control is cantly increased productivity while maintaining complete required. light transmittance through the solution. Using the optimised Initial reports of the process intensified photochemical ben- conditions (concentration 0.4 M), the reaction was run for zyl bromination, using in-situ generated bromine, within a lab 130 min at steady state, producing 1.14 kg of product (90% scale Corning photochemical reactor (volume: 2.8 mL) pro- assay yield). This corresponds to a productivity of 12.6 kg/ vided a throughput of 300 g/h [86]. To further scale up to day, higher than the previous larger footprint reactor [81]. pilot-scale the significantly larger Corning G3 reactor (vol- Additionally, the authors noted that this throughput could be ume: 50 mL) was employed. The setup consisted of two flu- increased significantly, at the cost of conversion, by increas- idic modules (FMs); one to carry out the photochemical reac- ing the flow rate from 105 to 925 mL/min. Using these con- tion and a subsequent FM for quenching of excess Br with ditions 1.12 kg (42% assay yield) of product was obtained in sodium thiosulfate. Separate streams of neat 2,6- just 37 min (43.4 kg/day). dichlorotoluene substrate (43) and aqueous NaBrO were Bromination reactions represent an important transforma- combined prior to being mixed with hydrobromic acid, to tion in the synthesis of building blocks for the pharmaceutical form Br which subsequently passed through the photochem- and fine chemical industries [82]. A range of methodologies ical reactor (Scheme 17). LED panels (405 nm) were used to exist, including various photochemical transformations using irradiate the mixture with a lamp temperature of <20 °C being either molecular bromine or an alternative bromine source maintained using a Lauda Proline RP 890 thermostat, while a [83]. The direct use of molecular bromine for these reactions separate thermostat was used to regulate reactor temperature. is unfavourable due to safety concerns on larger scales, and Gear pumps were used to dose the non-acidic streams while a while N-bromosuccinimide can act as a safer alternative [84], metal-free FUJI pump was utilised for administration of HBr. its use is not ideal due to poorer reactivity and modest atom A small webcam was also positioned within the reactor box Scheme 15 Laser-mediated Fibre Optic Laser photochemical aryl amination (450 nm, 26 W) Br 5 mL/min N Beam Expander F C F C (3 equiv) Ir catalyst (0.025 mol% 1.54 kg (85 % yield) NiBr •3H O (5 mol %) 2 2 32 h DABCO (1.4 equiv) DMA (0.8 M) 100 mL (5 cm depth) 70 C J Flow Chem (2021) 11:223–241 237 Scheme 16 LED-mediated photochemical aryl amination for visual monitoring of the reaction, in particular the Conclusions and future directions quenching of excess bromine. Due to the biphasic nature of the reaction effective mass transfer is important and a short While this review is not intended to provide a comprehensive residence time of 22 s with a reactor temperature of 65 °C list of examples, it is clear that through the advancement of were found to be optimal. Longer residence times resulted in available technology the scalability of photochemical reac- lower yields as a function of insufficient mixing of the biphas- tions has changed over the past decade. Prior to the last five ic system. years there were scarce reports of kilogram scale photochem- Using these optimised conditions, 44 could be synthesised ical processes carried out in continuous flow, however, this with a maximum productivity of 4.1 kg/h (88% H-NMR has been rectified in recent years, largely driven by the devel- yield), which provided a 14-fold increase on the previous lab opment of innovative photochemical reactors. While flow scale result (0.3 kg/h) [86]. It should be noted that this pro- photochemistry may present various advantages over its batch ductivity was extrapolated from a short reaction run as a long counterpart, both methodologies can be used in a synergistic run was not possible due to restraints in the quantity of avail- manner. Batch offers the advantage of simple real time anal- able starting material. While the G3 reactor provided a higher ysis through common laboratory methods such as TLC and productivity than the previous lab-scale report, the space-time- HPLC, providing powerful insight to a process. This allows yield was lower (82 kg/L/h vs 108 kg/L/h). This can be for relatively rapid screening of conditions on a small scale, accounted for by the poorer heat and mass transfer provided which may not be possible in flow due to the prohibitive cost by the single photochemical G3 FM, which was operated at a of analytical equipment required to perform similar monitor- lower than recommended flow rate. Therefore, one would ing of reactions in continuous flow. Additionally, various pho- assume that this space-time-yield could be further increased tochemical processes can be scaled up to the decagram scale through the use of 5 x G3 FMs which would be more compa- in batch with ease. However, this is generally limited to reac- rable to the lab scale design [75]. This high space-time-yield tions that do not suffer from photochemical degradation and highlights the advantages that can be achieved through con- other factors that can be mitigated though flow processing, tinuous processing when compared to batch, in particular for thus reducing the complexity of chemical structures accessible processes that require both high mass transfer and photon flux. through such batch-based methodology. Na S O �5H O (2.64 M) 2 2 3 2 Cl Cl 405 nm 43 (neat) Br HBr (47%) Cl Cl NaBrO (2.2 M) 3 44 50 mL 88 % assay yield Quench Br generator (1.1 equiv) 4.1 kg/h 50 mL t = 22 s, 65 C Scheme 17 Kilogram-scale benzylic bromination 238 J Flow Chem (2021) 11:223–241 Open Access This article is licensed under a Creative Commons The statement that batch and flow photochemistry exhibit Attribution 4.0 International License, which permits use, sharing, adap- similar performance when corrected for factors such as light tation, distribution and reproduction in any medium or format, as long as power-to-surface area, as concluded by Booker-Milburn and you give appropriate credit to the original author(s) and the source, pro- co-workers in 2014 [9], is still relevant. However, this may be vide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included limited to uncatalysed cyclisation reactions. In contrast, sev- in the article's Creative Commons licence, unless indicated otherwise in a eral of the discussed reactions, with higher comparable com- credit line to the material. If material is not included in the article's plexity, seem to benefit significantly from continuous flow. Creative Commons licence and your intended use is not permitted by Additionally, it is evident that practical scalability is achieved statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this more easily through the use of continuous flow technology. licence, visit http://creativecommons.org/licenses/by/4.0/. Various examples have been presented on a kilogram scale using small-footprint reactors, where the equivalent batch pro- cess would require prohibitively large vessels and light sources. 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Journal

Journal of Flow ChemistrySpringer Journals

Published: Sep 1, 2021

Keywords: Flow synthesis; Photochemistry; Scalability; Throughput; Continuous processing

References