• Photoredox catalysis is a powerful tool in the field of organic synthesis.

The future development of synthetic organic chemistry involves environmentally friendly and sustainable alternatives in terms of energy to promote chemical transformations, using “light” as an abundant and renewable energy source (Narayanam and Stephenson, 2011; Shaw et al., 2016). Photochemical reactions are based on the use of light (ultraviolet, visible or solar) to provide the activation energy to induce the synthesis of a target molecule from a simple substrate. In this way, researchers explore ways to efficiently collect and use light energy for the activation of organic molecules (Noël, 2017; Crisenza and Melchiorre, 2020).

In the last decade, photoredox catalysis has emerged as a versatile platform for catalytic methodologies for organic synthesis, using photons of visible light as a reagent without tracking. In a general sense, this approach is based on the ability of metallic complexes and organic dyes to get involved in single electron transfer (SET) processes with the organic substrate after photoexcitation with visible light (Nicholls et al., 2016). This technology has become an indispensable tool in the search for new biologically active compounds for applications in medicine, fine chemical and pharmaceutical industries, as well as in many other fields of science, materials and the environment (Aillet et al., 2013; Loubière et al., 2016). Moreover, recent progress in the use of photoredox catalysis as a new conceptual approach to mediate synthetic organic reactions using visible light has been promoted by the combined efforts of three research groups: MacMillan (Shaw et al., 2016), Stephenson (Narayanam and Stephenson, 2011), Yoon (Schultz and Yoon, 2014) and many other researchers.

However, this growing interest in photochemistry has also brought to light some old and unresolved challenges such as reproducibility, scale and efficiency (Corrigan et al., 2016). Most of these issues are associated with the complexity of photochemical processes. The scale increase is hampered by the photon transport attenuation effect (Bouguer-Lambert-Beer law). Excessive radiation can be a relevant issue in using larger reactors, as reaction times would increase substantially and would also result in the formation of undesired by-products (Cambié et al., 2016). However, these problems associated with batch photochemistry can be overcome with the use of continuous flow systems.

Continuous flow microreactors have recently emerged as promising instruments for chemical synthesis. Due to the small size of the reaction channel, the microreactors favor the heat and mass transport, allow precise control of the reaction and also allow extensive penetration of light (even in concentrated solutions) becoming quite advantageous in micro (photo)chemical reactions. Several studies report that this technology is also suitable and has many benefits for photochemical transformations, increasing interest in flow photochemistry (Coyle and Oelgemöller, 2008; Knowles et al., 2012; Jensen et al., 2014; Su et al., 2014; Loubière et al., 2016; Straathof et al., 2016; Su et al., 2016).

Despite many studies aimed at the application of microreactors for organic synthesis, this approach is mostly laboratory research (Weissman and Anderson, 2015). The experimental methods provide an overview of the process and do not allow a local analysis inside the reactor. To achieve higher levels of accuracy and more rigorous and detailed analysis, microscopic models based on transport phenomena must be employed. In this sense, computational fluid dynamics (CFD) can be highlighted as a useful simulation tool.

These methods simulate the reactive flow within the entire reactor, considering the coupling of all phenomena that occur (fluid flow, mass and heat transport, and photon transport) (Oliveira de Brito Lira et al., 2021). Modeling organic reactions can be challenging due to complex reaction profiles (Armstrong et al., 2019). Therefore, once the model is validated, relevant information regarding the reactive flow in the microchannels and results regarding the yield and selectivity of the photoredox-type reaction can be easily obtained. Furthermore, prediction of the effect of different operating conditions and evaluation of different geometric configurations of the microfluidic device can also be estimated.

Thus, this article aims to assist researchers in the fundamentals of photoredox catalysis and CFD-based technology for simulation of the reaction environment in photoredox catalysis, from the compilation of data in the literature as research gaps were identified on this theme, justifying further investigation.

Photoredox catalysis is a branch of catalysis that uses light energy to accelerate a chemical reaction through simple electron transfer events. As the same name implies, “photo” refers to light and “redox” is an expression that represents the chemical processes of reduction and oxidation.

In photoredox catalysis, the absorption of a photon by the photoredox catalyst in the visible or UV region is necessary. The catalyst excited by light allows electron transfer processes to occur with the agents, and oxidation and reduction reactions may be possible. When the photoredox catalyst is excited, an electron moves from the HOMO orbital (abbreviation of the highest occupied molecular orbital) to the LUMO orbital (abbreviation of the lowest unoccupied molecular orbital). As a result, there is a lack of an electron in HOMO and an electron available in LUMO (Anslyn and Dougherty, 2006; Romero and Nicewicz, 2016; Bonardi et al., 2018). That is why the excited photoredox catalyst is both a stronger oxidizer and a stronger reducer than its ground state. Therefore, the photocatalyst (PC) can easily react with an external oxidizer or reducer. Most of the photoredox catalytic reactions follow the catalytic cycle described in Figure 1.

Following light absorption, the photoexcited species perform the redox reactions in two different ways, depending on the reaction conditions employed and the properties of the sensitizer (Corrigan et al., 2016). As illustrated, the excited photocatalyst (PC*) reacts first with an oxidizing agent (A₁, electron acceptor), which leads to PC^•+ and A₁ ^•−. Then, the PC can be regenerated by a reduction reaction with a reducing agent (D₂, electron donor), featuring the oxidative quenching cycle. On the other hand, in a reductive cycle, the PC* reacts first with the reducing agent (D₁) which leads to the PC^•− and D₁ ^•+. Again, the PC can be regenerated from a reaction with an oxidizing agent (A₂) (Koike and Akita, 2014; Romero and Nicewicz, 2016; Bonardi et al., 2018). Such a single electron transfer (SET) events have led to a better radical generation and give new life to a radical transformation in synthesis. The terms reductive and oxidative can be confusing and require explanations. Oxidative means oxidation of the photo-excited species PC* concomitant with reduction of the external electron acceptor A. Reductive refers to the reduction of photo-excited species PC*, while the external electron donor D is oxidized in the same process. In either case, by adding external redox agents, the photocatalyst can be regenerated.

Despite a large number of studies on photoredox catalysis, a very small set of photoredox catalysts are employed. They can be represented by transition metals complexes or by organic dyes capable of absorbing visible light, resulting in a kind of excited state. Among the catalyzed reactions based on transition metals, they typically employ metallic polypyridyl complexes, such as Ru (II) polypyridine complexes and cyclometalated Ir (III) complexes, offering charge transfer properties for metal binders (Koike and Akita, 2014; Wang et al., 2018; Glaser and Wenger, 2020). On the other hand, metal-free conditions have been developed using organic dyes such as Eosin, Rhodamine, rose Bengal, 9-fluorenone, xanthone, methylene blue, acridinium, etc., capable of absorbing light in or near the visible region (Nicewicz and Nguyen, 2014; Wang et al., 2018; Zhou et al., 2019).

For a compound to be efficient as a photoredox catalyst, there are some desirable characteristics (Arias-Rotondo and Mccusker, 2016; Romero and Nicewicz, 2016):

1) Strong light absorption on the spectral region of the agents of interest;

These catalysts were successfully implemented for the discovery of new organic reactions and the synthesis of added-value chemicals, with excellent control of selectivity and stereoregularity, creating a new approach to organic transformations.

In recent years, the field of photoredox catalysis has experienced exponential growth, resulting in the development of a wide variety of new synthesis methodologies (Shaw et al., 2016; McAtee et al., 2019). In this scenario, the successful application of processes mediated by visible light to pharmaceutical products and biologically relevant molecules is essential for its continued expansion. Here, we will discuss some applications of the utility of photoredox catalysis in the synthesis of added-value chemicals. Table 1 presents a simplified summary of works reported in the literature for photoredox catalysis in the synthesis of added-value chemicals.

As a result, it is evident that the photoredox catalysis has become a powerful research area for chemical synthesis, with an increasing number of publications. This technology has found applications in a variety of synthetically useful reactions of organic compounds, even using metallic complexes or organic dyes as catalysts.

Photochemical reactions occur when light provides energy to trigger a reaction (Plutschack et al., 2017). It includes electron transfer chemistry initiated by the excitation of a chromophore (photoredox catalysis), an attractive method for organic synthesis. Thus, it is evident that photochemistry, in general, is heavily dependent on the efficient irradiation of the reaction mixture. There are currently two main types of reactor systems that researchers use for photochemistry: batch and flow (Figure 2).

Continuous flow (micro) reactors have been highlighted as a technology of choice for photochemical reactions to overcome the bottleneck of dependence on efficient irradiation of the reaction mixture (Cambié et al., 2016; Reischauer and Pieber, 2021). The main benefits of continuous-flow microreactors over batch reactors are high surface-to-volume ratio and small scale, favorable characteristics for improving mass and photon transfer (Van Gerven et al., 2007; Lira et al., 2021). In addition, other advantages are short molecular diffusion distances, laminar flow, and fast and efficient heat dissipation (Vesborg et al., 2010; Padoin et al., 2016; Heggo and Ookawara, 2017; Yusuf et al., 2018). However, to achieve higher reaction rates, the distance required for the interaction between the components must be shorter. The smaller dimensions of the channels favor the decrease of sample volumes, which leads to a reduction in the amount of reagents used for tests and analyzes (Nge et al., 2013). Therefore, recent advances in this field mean better efficiency in terms of kinetics, safety and cost (Wang et al., 2002; Plutschack et al., 2017). Because of these advantages, the synthesis of high added-value compounds in continuous flow microreactors has become a promising area in recent years (Wiles and Watts, 2012; Rashmi Pradhan et al., 2019).

Additionally, when it comes to light-dependent systems (photochemical reactions), the use of continuous microreactors leads to improved irradiation on the reaction mixture due to better light penetration throughout the reactor depth and greater homogeneity of space lighting (Matsushita et al., 2007; Krivec et al., 2013). As revealed by the well-known Beer-Lambert-Bouguer law, the radiation distribution will not be uniform in a reactor due to absorption effects (Cambié et al., 2016). This equation establishes the light absorption ( A ) is dependent on the molecule’s molar attenuation coefficient ( ε ) , their concentration ( c ) , and the path length of the light propagation ( l ) (Eq. 1). A = log 10 T = log 10 I 0 I = εcl  . (1)

Unfortunately for batch reactors, this compensation has serious implications, especially for sizing a photochemical reaction. The decrease in radiation intensity with distance from the light source in batch reactors becomes one of the main disadvantages for photochemistry (Knowles et al., 2012; Oelgemoeller, 2012). In addition to avoiding this disadvantage of conventional reactors, microfluidic devices are also attractive for catalytic reactions due to their large surface-to-volume ratio and the excellent control over the reaction conditions they offer. Consequently, photochemical reactions in continuous flow reactors can be substantially accelerated and scaled to larger quantities (Reischauer and Pieber, 2021).

Cambié et al. (2016) reported two important reasons for photochemistry to reach so much repercussion in academic and industrial areas. The first one is the exposure of visible photo-redox catalysis to organic synthetic chemistry. The second reason is the use of continuous flow reactors. Additionally, the same authors list nine good reasons for using photoflow: 1) better irradiation of the reaction mixture; 2) reliable increase; 3) better reaction selectivity and greater reproducibility; 4) fast mixing; 5) rapid heat exchange; 6) multiphase chemistry; 7) reaction sequences in several stages; 8) immobilized catalysts and 9) greater operational safety.

Noël et al. (2011) compared the results of the microfluidic system with those obtained in batch experiments. The authors noted that there was no loss of activity when performed inflow. In fact, in the flow reaction, they observed greater activity in very short residence times. This result demonstrated one of the main advantages of flow chemistry. The authors stated that the increase in heat and mass transfer allowed the microreactor to heat more quickly and efficiently. Therefore, these properties make it ideal for quick reactions. Similarly, Nair et al. (2019) demonstrated that continuous-flow reactors have a competent configuration compared to batch reactors due to the high conversion rates and selectivity for the selective organic synthesis of aromatic alcohols. In addition, Abdiaj and Alcázar (Abdiaj and Alcázar, 2017) demonstrated an improved efficacy for photoredox and nickel catalysis for C(sp²)-C(sp³) cross-coupling using a continuous-flow reactor instead of a batch system. The authors mentioned that the space-time yield was 430 times better than the batch method, thus resulting in a more suitable procedure for drug discovery in terms of productivity per unit of time. Interestingly, Oelgemöller and Shvydkiv (Oelgemöller and Shvydkiv, 2011) summarized advances in microflow photochemical transformations. The authors presented comparative details between the batch system vs. microreactor for several examples of homogeneous and heterogeneous reactions, including photoadditions, photorearrangements, photoreductions, photodecarboxylations, photooxygenations and photochlorinations. In general, microfluidic devices have resulted in reduced irradiation times, greater selectivity and greater light efficiency. Therefore, the microreactors demonstrated their superiority over conventional techniques.

Although, in theory, the use of flow reactors for photochemical reactions has numerous benefits, as shown in this section, compared to batch reactors; however, developing a flow process can be time-consuming and there are still several limitations. One of the biggest limitations of flow chemistry is the handling of solids (Gisbertz and Pieber, 2020). Plutschack et al. (2017) developed a very interesting decision diagram to try to facilitate decision-making for flow versus batch analysis with the aim of finding the balance between convenience and achieving the overall goal. Therefore, it is expected that new equipment concepts applied to organic synthesis are expected to emerge as an important future area of research and development (R&D) and production methodology to improve synthetic efficiency through process automation and optimization.

As technologies become more developed and commercialized, they can help and speed up research based on experimental laboratory tests (Plutschack et al., 2017). Simulation and numerical modeling have become a more widely used tool to gain deeper insights into the system and to examine features that are difficult in experiments (Dong et al., 2021). Computational methods can be employed in the prediction and design of photochemical reactions, and also it allows scientists to gain deeper physical insights that are not easily accessible experimentally (Lira et al., 2021). Thus, computational fluid dynamics (CFD) has been widely and consistently used in reactive systems modeling. This development was made possible by significant advances in computing power and numerical models due to the high dimensionality, complexity, and highly non-linear dependencies on the properties and responses of continuous-flow devices. This area requires a greater computational effort, but even so, it shows promise in reducing the time of analysis and optimization of the photochemical reaction.

Photoredox catalytic processes in continuous-flow reactors are significantly more technologically complex, i.e., not as trivial as traditional batch techniques, in which the reactants are simply added into a vessel and stirred at a defined temperature until that the limiting reagent is consumed (Plutschack et al., 2017). Therefore, the limitations of photon and mass transfer can be addressed through the development of mathematical models that characterize the effect of fluid dynamics on photochemical reactions and represent the transport of light through the flow reactor. Thus, a set of partial nonlinear differential equations must be solved for a complete description of coupling, the fluid flow, mass transport, and photon transport (irradiation distribution) for photoredox catalytic processes in continuous flow reactors (Lira et al., 2021). The three-dimensional governing equations for continuity, momentum, and mass conservation of chemical species in Cartesian coordinates can be given by Eqs 2–4, respectively, according to Bird et al. (2007). ∂ ρ ∂ t + ∇ ⋅ ( ρ v ) = 0 , (2) ρ D D t v = − ∇ p + μ ∇ 2 v + ρ g , (3) ∂ C i ∂ t = − ∇ ⋅ ( v C i ) + ∇ ⋅ ( D i ∇ C i ) + r i ( { C i } ) , (4) where, ρ is the density of the mixture, v is the velocity vector, p is the pressure, μ is the dynamic viscosity of the mixture, ρ g is the gravitational force, C i is the concentration of species i, D i is the diffusion coefficient of the species i and r i ( { C i } ) term represents the consumption or production rate of species i.

However, the main challenge for reaction engineering in photoredox catalysis processes is that, in addition to all the parameters that govern a catalytic reaction, the photocatalyst must first be activated by light. The photons distribution becomes more problematic with increasing reactor dimensions because they have a non-homogeneous light distribution. This scenario presents a non-trivial problem in modeling and optimizing the reaction parameters since the reaction rate must take into account the local volumetric rate of photon absorption (Bloh and Marschall, 2017), as the problems associated with the radioactive and chemical reaction are well interconnected. In a photoreaction, these two problems are coupled and the solution of the governing equations (mass balance of reactive species and radiative transfer) ends up being a very complex problem (Martin et al., 1999). Besides that, in the last decades, the study of photochemical processes has mainly involved research for the formation of new products, reaction kinetics and mechanisms; however, the implementation of the energy source is often neglected (Su et al., 2014). This is the main reason why very little is known today about how photon transport influences photoredox catalysis and opens new horizons for the development of studies, modeling, simulation and optimization for this type of reaction.

Photoredox catalysis has been a transforming force in synthetic organic chemistry in the last decade, mainly for the pharmaceutical sector. This means that academic discoveries have a better chance of being promptly converted into future technology. There are no doubt that the photoredox catalysis processes will continue to use (micro) flow reactors to perform organic photochemical reactions. This growing popularity of the microreactors can be attributed to the high yields (in terms of space/time), high selectivity, and few side reactions (when compared to batch reactors) achieved by the majority of these reactors.

However, as the field of photoredox catalysis advances, a better understanding of how the process of refining chemical techniques works is required to enable advancements in this technology. For the design of microreactors and optimization of the synthesis of added-value compounds, a comprehensive understanding of the principles between the reagents, as well as a perception of the influence of light on the photoredox catalysis process, would be crucial. Nevertheless, the challenge is to integrate the complexity of continuous flow photochemical processes in order to elucidate some gaps found when approaching this subject.

For that, computational tools can provide, in the research and development of microfluidic devices for photoredox catalysis, an immediate qualitative and quantitative analysis of the species′ behavior and light distribution. Furthermore, knowledge of fluid flows is also essential to adequate the design and optimization of micro(photo)reactors. The great advantages of following the computational path are the decrease in the time-consuming and money expenses and the possibility of providing increasingly efficient models. In this sense, CFD can stand out as a powerful tool for solving and analyzing transport equations. However, difficulties linked to light efficiency, such as dissipation, penetration, and transmission of light, are still not taken into account in those CFD simulations. Other computational methods capable of simulating this phenomenon are being sought as a solution to this problem. Therefore, the framework consisting of the combination of photon fate modeling and CFD can be crucial to improve the performance of the photoredox catalysis process.

In this present literature review, we summarized the advances made in photoredox catalysis, highlighting the computational numerical approach. It was noteworthy that great efforts have been made to improve the understanding of the fundamentals and application of this technology for the added-value chemicals synthesis. Furthermore, the advantages of working with a continuous flow system were also understood. Despite efforts, photoredox catalysis is still a challenging issue as it involves the consideration of several simultaneous phenomena. Therefore, computer simulation of these reaction systems is a scientific hotspot for researchers to clarify improves the interaction between reagents and the influence of light on the reaction medium. However, the simulation of photoredox catalysis for the added-value chemicals synthesis still has a lot to be explored to establish itself as a reliable approach.