Abstract
Photochemistry and photoredox catalysis have witnessed a remarkable comeback in the last decade. Flow chemistry has been of pivotal importance to alleviate some of the classical obstacles associated with photochemistry. Herein, we analyze some of the most exciting features provided by photo flow chemistry as well as future challenges for the field.
1. Introduction
The current enthusiasm for photochemistry can be partially attributed to the booming interest of the synthetic community in photoredox catalysis. Photoredox catalysis has enabled nontraditional reaction pathways allowing for previously deemed elusive bond constructions [1]. This field exploits the increased redox activity of the photo-excited photocatalysts, making them act both as a stronger oxidant and reductant than their corresponding ground state. Owing to the mild reaction conditions (room temperature, visible light, non-hazardous reagents), this activation mode has the potential to revolutionize the way pharmaceuticals are made.
However, along with the renewed interest in photochemistry, the old technical problems related to scalability of such processes resurged. When a photochemical reaction is performed on a small scale, the conditions do not simply translate to a larger scale. The culprit here is the absorption of the photons as dictated by the Bouguer–Lambert–Beer law. This means that the outskirts of the reactor observe a higher energy density than the center, resulting in unrealistically long reaction times on larger scale. It is this specific aspect that can be targeted by continuous-flow reactors [2, 3]. Typically, microscale capillaries are used to carry out the photochemical reaction in a continuous fashion. Due to the short length scale, an optimal energy distribution is observed leading to spectacular reaction time reductions, lowered catalyst loadings, and less byproducts. Scalability can be achieved by either using longer operation times or by numbering-up.
The purpose of this perspective is not to give a comprehensive overview of continuous-flow photochemistry but rather to provide the reader with some of the most recent and exciting areas of research and where these findings could lead to in the future. Furthermore, we aim to point out the current limitations and challenges for flow photochemistry. As such, we intend to stimulate research in these directions in the hope that continuous-flow photochemistry becomes standard in both academia and industry once these challenges have been overcome.
2. Equipment
A major reason why the uptake of flow photochemistry has been embraced so fast in the last decade is the simplicity of the most basic flow reactors [4, 5]. Simply by wrapping polymeric capillaries around a light source, many research groups built their own photoflow devices and started experimenting (Figure 1). Notable advantages such as reduced reaction times and scalability gained the attention of others working in the photochemistry field. There is just no other conventional solution to scale photochemistry in a facile way in the laboratory. Some tried to set up tens of mini-batch reactions to get the target compound in sufficient quantities. However, it is immediately clear that this is a far more time- and labor-consuming effort than building a flow reactor and pump the entire solution through it.
Easy-to-assemble photomicroreactor devices using (A) LEDs (Reprinted with permission from Ref. [5]. Copyright (2016) American Chemical Society) or (B) 400 W medium-pressure Hg lamp (Reprinted with permission from Ref. [6]. Copyright (2005) American Chemical Society)
Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00022
In recent years, many small- and medium-sized enterprises have emerged to commercialize flow reactors. This includes also dedicated photoflow reactors with interchangeable light sources (e.g., Vapourtec's UV-150 photochemical reactor). Especially for those who are scared away from the technology aspects, such reactors can be of high importance to overcome skepticism. Furthermore, these reactors are standardized equipment and provide opportunities to increase the inter-laboratory reproducibility.
Challenges with regard to equipment can be divided into two parts: (1) light sources and (2) the reactor itself. As light source, light-emitting diodes (LEDs) have gained increased attention due to their limited energy consumption, narrow emission bands, and small size. In the visible light spectrum, a multitude of LEDs are commercially available, providing access to different colors and intensities. However, the ranges of powerful LEDs in the ultraviolet (UV) range are quite limited and, if they exist, UV–LEDs remain expensive. Given the importance of LEDs, it can be foreseen that in the next decade substantial progress will be made in UV–LEDs, making them as easy to use as their VIS counterparts. Despite their limited heat generation, on large scale, still substantial amounts of heat have to be dissipated to the environment. Engineers will have to come up with easy and energy-efficient solutions for heat removal. On small scale, computer fans or pressurized air are used, but these are far too complicated to scale to industrial-sized equipment.
Besides progress in light sources, also the reactor material needs to be improved. For UV photochemistry, perfluoroalkoxyalkane (PFA) and perfluoroethylenepropylene (FEP) capillaries are commonly used. However, these polymeric materials tend to degrade rapidly, especially at higher energy wavelengths. Jamison et al. have demonstrated that quartz capillaries can be used as an alternative yet expensive solution [7]. Similarly, glass microchips have been fabricated which can be used in the UV light range. Nevertheless, cheap and UV-stable polymeric capillaries would be of high interest to the community.
It would be of interest to increase the energy efficiency of current photoreactors. This can be done by using refracting mirrors and microscale LEDs [8]. However, also the reactor material could be tuned by combining its transparency with a wave-guiding effect so that the light cannot escape from the reactor. Nature and recent advances in material science could serve as an inspiration source to develop such novel photomicroreactors. As an example, Noel et al. have recently developed luminescent solar concentrator photomicroreactors which allow to harvest solar energy efficiently and waveguide the energy to the microchannels (Figure 2) [9]. As such, the light reaching the channels can be color-shifted to match the requirements of the chemistry. Furthermore, the overall energy efficiency of the reactor can be substantially enhanced due to the waveguiding effect inside luminescent solar concentrators. Given the high surface-to-volume ratio, photomicroreactor material can and should be given even more exciting functions. It could serve as a selective barrier to remove the product to avoid byproduct formation (i.e., membrane technology) [10]. The channel walls can serve as photocatalytic walls, which facilitates catalyst reuse [11], or as mixing elements, which can increase the interfacial mass transfer in multiphase reactions.
Luminescent solar concentrator-based photomicroreactors (LSC-PM): (A) picture of the device (courtesy of Dario Cambie/TU Eindhoven). (B) Possible fates of the photons hitting the device. 1, Top reflection; 2, transmission; 3, side emission (3a: top emission, 3b: bottom emission); 4, edge emission; 5, reaction media absorption (5a: direct irradiation, 5b: luminescent photons); 6, non-radiative losses. (C) Photon balance, obtained via Monte-Carlo ray tracing simulations, of the device demonstrating the increased solar harvesting potential (Reprinted with permission from Ref. [9b]. Copyright (2017) Royal Society of Chemistry)
Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00022
3. Synthetic Photochemistry
UV irradiation has a high energy content (200–350 nm corresponds with 590–342 kJ/mol) and can therefore directly be harnessed to activate organic molecules and thus induce chemical transformations. These UV-induced synthetic transformations are often unique and allow the formation of a high degree of molecular complexity starting from simple building blocks [12]. It is therefore not surprising that UV photochemistry has been very popular in the total synthesis of complex natural products. In total synthesis, typically large quantities of intermediate compound need to be converted to reach eventually the targeted natural product. Booker-Milburn et al. were one of the first to realize that continuous-flow technology was crucial to obtain these large quantities of product [6]. Furthermore, the use of flow reactors to prepare densely functionalized molecules provides opportunities to improve the yield and selectivity due to the avoidance of over-irradiation. Two notable examples are shown in Scheme 1 which display the distinct advantages of using flow technology for UV-triggered cyclizations. To avoid extensive photodegradation of the target product, the [5 + 2] cycloaddition of N-pentenyl-3,4-dichloromaleimide has to be done in batch on small scale (0.5–1 g) (Scheme 1 (A)) [6]. In contrast, this reaction can be carried out in flow in only 6 min to yield a similar isolated yield. Notably, to prepare a similar amount of product would require 120 individual batch experiments (0.5 g scale). Another interesting example constitutes the [5 + 2] photocycloaddition of a key intermediate towards the synthesis of neostenine [13]. This reaction works only on small amounts of product while increasing the scale results in poor yields despite the complete conversion of the starting material. In flow, however, 1.3 g of the target compound could be obtained, while 20% of the starting material could be recovered. Continuous introduction of starting material allowed to prepare 38.5 g in only 11 h of total operation time. It is reasonable to expect that UV photochemistry, in combination with flow reactors, will continue to attract attention from the chemical community as an attractive option to prepare complex organic compounds with biological and medicinal relevance.
Some notable examples on UV-induced photocyclizations in flow
Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00022
In contrast to UV-triggered photochemistry, photoredox catalysis allows to harvest the visible light part of the solar spectrum and convert this energy into chemical bond energy. Despite the fact that photoredox catalysis was already known for several decades [14], it was the MacMillan group that brought this intriguing activation mode into the limelight [15]. Since then, photoredox catalysis has become a hot topic and has been pursued by many to overcome previously deemed elusive synthetic transformations. Due to the high absorption capacity of common photocatalysts, the use of flow reactors became even more essential to enable scalability. Jamison and Stephenson translated some of their early work in photoredox catalysis to flow and demonstrated exceptional reductions in reaction time [16]. Also, enhancements in selectivity [17] and catalyst reduction were feasible utilizing photomicroreactors [18]. An intriguing example concerning selectivity switches between batch and flow was reported by the Noël group (Scheme 2 (A)) [19]. In the photocatalytic decarboxylation of ortho-substituted cinnamic acids, the kinetic and thermodynamic product is the E isomer. However, due to a triplet–triplet energy transfer process, the E isomer can be converted into the thermodynamically less stable Z isomer (so-called uphill catalysis). In batch, the Z isomer could be selectively obtained due to the generally longer reaction times in such reactors. However, the selectivity could be completely reversed in flow. Flow allowed to reduce the reaction time substantially, and the reaction could be stopped before E/Z isomerization occurred, giving access to the E isomer in excellent selectivity. Another advantage of flow processing is that gaseous reactants can be easily handled and mass transfer limitations can be overcome using a Taylor flow regime [20, 21]. As an example, the photocatalytic aerobic oxidation of furfuryl thiol could give the corresponding disulfide in excellent yield in flow, while in batch no product was obtained due to over-oxidation of the thiophene moiety (Scheme 2 (B)) [22]. A notable feature of microreactor technology is the possibility to safely generate hazardous reagents in situ, which can be consumed in a follow-up process [23]. Consequently, the total amount of this hazardous reagent is kept small at all times. A notable example is the generation and use of diazonium salts in photocatalytic transformations (Scheme 2 (C)) [24]. It is reasonable to state that more unique photocatalytic reactions will be discovered in the coming years using microreactor technology. Excellent control over reaction times, optimal mass, heat and photon transfer characteristics, and the possibility to safely use hazardous reagents will enable transformations which are not easily accessible in conventional batch reactors.
Examples of photocatalytic reactions which highlight some of the most important advantages of micro-flow processing
Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00022
One downside of photoredox catalysis is that most examples utilize expensive homogeneous transition metal-based photocatalysts which are difficult to recycle. Several strategies can be used to enable recuperation and reuse of these powerful homogeneous catalysts. However, these catalysts can be immobilized on beads and packed in microreactors [25]. Alternatively, Reiser et al. tagged fac-Ir(ppy)3 with a polyisobutylene tether which allowed to recover the catalyst through a liquid–liquid extraction with heptane [26]. Kappe et al. prepared a dendrimer version of Ru(bpy)3, which could be recovered using organic solvent nanofiltration [27]. All these catalysts could be recycled several times and show great promise. Nevertheless, more research is necessary to make this strategy widely applicable for a broad range of photocatalysts and reaction conditions.
In recent years, the use of semiconductor photocatalysts has shown great promise to enable photochemical transformations with cheaper and recyclable catalysts compared to homogeneous alternatives. These catalysts can be used in flow as a suspension [28] or can be immobilized as a packed bed [29] or on the reactor walls [30]. While these semiconductors show great recyclability without substantial deactivation, most of them require UV light to be active. Consequently, there is great need for semiconductor photocatalysts which can be used in the visible light range. This can be achieved by doping or through surface interactions [31].
4. Solar Photochemistry
“On the arid lands there will spring up industrial colonies without smoke and without smokestacks; forests of glass tubes will extend over the plains and glass buildings will rise everywhere; inside of these will take place the photochemical processes that hitherto have been the guarded secret of the plants, but that will have been mastered by human industry which will know how to make them bear even more abundant fruit than nature, for nature is not in a hurry and mankind is. And if in a distant future the supply of coal becomes completely exhausted, civilization will not be checked by that, for life and civilization will continue as long as the sun shines!” (Giacomo Ciamician, 1912) [32].
Every day the impact of climate change becomes clearer and gives rise to disturbing weather patterns, global warming, and melting of the polar ice caps. Consequently, one cannot ignore the urgency to develop new sustainable technologies which can harvest solar energy and release mankind from its addiction to fossil fuels [33]. As Giacomo Ciamician, most photochemists dream of the ability to make complex organic molecules using solar energy. With the advent of photoredox catalysis, chemists can make more efficient use of the abundant visible light energy present in the solar irradiation. Nevertheless, solar photochemistry is not straightforward and suffers from a number of disadvantages. First, fluctuations of the solar energy supply (day-night cycles, weather conditions, diffuse nature of solar irradiation) make chemical production erratic. Second, the use of solar energy is most favorable in sun-rich regions. Despite these drawbacks, progress has been made throughout the years and continuous-flow reactors have gained a prominent position in the newest discoveries [34]. These flow reactors are often combined with reflectors and sun-tracking units to increase their efficiency. A novel approach to increase the solar energy efficiency of continuous-flow reactors was reported by Noel et al. combining so-called luminescent solar concentrators with microreactor technology [9]. These spectral converters can be used to convert solar energy into photons which are more effectively captured by the photocatalytic process [35]. Furthermore, due to internal reflection, more photons can be waveguided to the reaction channels. The increased harvesting capacity of these luminescent solar concentrator (LSC)-based photomicroreactors make them of interest to be used at higher latitudes.
In the future, we foresee more use of advanced flow reactors to harvest solar energy, which will hopefully lead to the first industrial applications. While currently solar energy is not yet cost efficient, it can be anticipated that future increases in fossil fuel-derived energy prices will be able to tilt the odds in favor of solar energy. Alternatively, solar energy could also be harvested with photovoltaics, subsequently stored in batteries and finally released upon demand to power LED or other light sources.
5. Automation
The combination of continuous-flow chemistry, inline analytics, and automation technology has shown great potential to gather accurate reaction data [36]. Such integrated systems allow to reduce the total optimization time and the required amount of material. Recently, Jensen et al. developed a microfluidic platform to screen and optimize continuous (e.g., reaction time, LED power, temperature) and discrete (i.e., substrate scope) parameters for photocatalytic transformations (Figure 3) [37]. The system consisted of a single-droplet oscillatory flow reactor in which droplets of 15 μL are introduced and oscillated within a gas-filled capillary. The oscillatory movement of the droplet allowed to intensify gas–liquid mass transfer and mixing. After a given time, reaction samples could be taken which were automatically injected in a liquid chromatography–mass spectrometry (LC–MS) unit. This automated microfluidic screening platform allowed to carry out 150 different reaction conditions using only 4.5 mL of reaction solution. While this is the first example to really take advantage of automation protocols for photochemistry purposes, I am confident that it will definitely not be the last one. The progress that has been made in flow automation is spectacular, so it is only a matter of time before these ideas will penetrate the field of flow photochemistry [36].
Schematic overview of an automated microfluidic screening platform for photoredox catalysis (Reprinted with permission from Ref. [37]. Copyright (2017) Wiley VCH)
Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00022
6. Scaling Photochemistry
In the past, the popularity of photochemistry has always suffered from its limited scale-up potential. The poor scalability can be attributed to the attenuation effect of photon transport; the intensity decreases exponentially with the path length of light propagation (Bouguer–Lambert–Beer law). Consequently, a classical dimension-enlarging strategy cannot be used to scale up photochemical transformations. However, continuous-flow technology allowed to overcome these scale-up challenges. Researchers at Merck have developed a large scale photoreactor which consists of 440 m of PFA capillary tubing (internal diameter [ID], 3.2 mm; volume, 3.5 L) (Figure 4 (A)). This reactor allowed to produce 2.7 kg/h of product with an irradiation efficiency of 24% (2.2 kW energy use). Recently, Elliott et al. have developed a high-capacity photoflow reactor called “FireFly” (Figure 4 (B)) [38]. The reactor consists of a series of quartz tubes which are positioned around a variable power mercury lamp (1.5–5 kW). Due to the high power, a lot of heat was generated in the “FireFly.” To dissipate this heat, the quartz tubes were inserted in another quartz or pyrex tube and cooled with water. Also, a cooling fan was used to remove the stagnant hot air. The “FireFly” was tested in various UV-induced photochemical transformations and could produce 21–335 g product per hour. Microfluidic chemistry can be scaled up by numbering-up or parallelization of the individual reactors. Noel et al. have developed a cheap and simple protocol to enable the numbering up of capillary photomicroreactors [39]. The reaction mixture was partitioned over the different reactors using cheap T-mixers, resulting in a good flow distribution. A similar strategy was used to scale up luminescent solar concentrator-based photomicroreactors (LSC-PMs) (Figure 4 (D)) [40]. In contrast to other numbered-up microreactor systems, the inter-channel spacing within the LSC-PM plays a crucial role. Similar as in a tree leaf, this inter-channel spacing functions as a light-harvesting area. Monte-Carlo ray-tracing simulations demonstrated that the photon flux increased with increasing inter-channel spacing.
Scale-up of photomicroreactors: (A) Merck's manufacturing scale photomicroreactor. (courtesy of Merck). (B) The “FireFly” (Reprinted with permission from Ref. [38]. Copyright (2016) American Chemical Society). (C) Numbering-up of capillary photomicroreactors. (Reprinted with permission from Ref. [39b]. Copyright (2016) Royal Society of Chemistry). (D) Numbering-up of luminescent solar concentrator-based photomicroreactors (courtesy of Dario Cambie/TU Eindhoven)
Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00022
7. Conclusions
In summary, the combination of photochemistry and continuous-flow technology has been a fruitful one as described in this perspective. Arguably, the application of flow within photochemistry has become the most popular flow application in recent years and has provided irrefutable proof against technology skeptics with regard to the usefulness of flow. There is simply no way around flow if you want a scalable photochemical process. However, many chemists see flow technology still too much as an engineering tool with no real added scientific value. Some of the examples highlighted in this perspective show that this statement is rather naive. Flow technology not only provides reduced reaction times and lower catalyst loadings but also supplies especially a high degree of control over the reaction parameters. This allows for a highly controlled environment to enable multiphase reactions, to use hazardous reagents, and furthermore, it can provide in some cases even complimentary selectivity compared to batch technologies. The use of automated reaction protocols can advance the field substantially, allowing to gather reaction data with greater fidelity and to speed up the reaction optimization process. Consequently, I firmly believe that chemists and engineers should keep working together to push the field forward and to unleash the hidden potential of photochemistry. In times of increasing environmental awareness, it seems only logical that the best is yet to come for photon-driven technologies.
Acknowledgments
T.N. would like to thank the Dutch Science Foundation (NWO) for a VIDI grant (SensPhotoFlow, grant number 14150).
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