Emerging trends in flow chemistry enabled by 3D printing: robust reactors, biocatalysis and electrochemistry

This contribution reviews the state of the art in the employment of additive manufacturing for the development of continuous-flow reactors, highlighting their potential for developing green and sustainable chemical processes. Additive manufacturing, commonly known as 3D printing has an untapped potential for the design and development of sustainable chemical processes. The integration of multiple enabling technologies is facilitated by the freedom of design inherent to these techniques. In this way, safer and efficient processes with integrated capabilities can be realised in a simple and cost-effective fashion. This relatively young field is evolving towards more robust and functional devices. Two trends are discussed here. First, the employment of robust materials, including metal and ceramics for the fabrication of the reactors. Secondly, the integration of flow reactors with biocatalysis and electrochemistry, both of them key technologies for the sustainable synthesis of chemicals and fuels.


Introduction
Continuous-flow manufacturing, also known as flow chemistry is a core technology for the development of green and sustainable chemical processes. [1]Flow chemistry technologies contribute to the development of green chemistry and engineering in a number of ways, including improved safety, faster reactions, reduction in the use of solvents, waste generation and energy needs. [2] Optimal mixing of the reagents in single or multiple-phase reactions and better contact of substrates with catalysts, heatexchanging units, etc. eliminates heat and mass transfer limitations ensuring the transformations take place with maximum efficiency. [3][4] This is particularly suited for fast, highly exothermic reactionsThe employment of flow chemistry conditions facilitates the digitisation of the synthetic processes,integrating analytical tools and machine learning techniques to improve the quality, reproducibility, efficiency and sustainability of the synthetic processes. [5] Furthermore, flow chemistry can be combined with other enabling technologies, including catalysis, biocatalysis, [6] microwave dielectric heating, [7] electrochemistry or photochemistry. [8] Additive manufacturing (AM), commonly known as 3D printing (3DP), are a set of manufacturing techniques characterised by fabricating parts by adding materials, typically in a layer-by-layer fashion. [9] These techniques enable a big degree of freedom of design and the possibility to generate tailored complex geometries that would not be possible, or would be very expensive, with traditional manufacturing techniques. AM techniques have been introduced in the literature [10][11][12][13] and therefore a brief introduction of the relevant techniques will be done. Extrusion techniques include Fused Deposition Modelling (FDM) and Direct Ink Writing (DIW). A thermoplastic polymer is extruded through a hot end in FDM, while the platform and nozzle move along XYZ axis.
DIW extrudes a paste through a thin needle, allowing the processing of relatively dense and viscous materials compared to other AM techniques. However, DIW typically offer limited spatial resolution. Powder bed techniques include selective laser sintering (SLS), selective laser melting (SLM) and electron beam melting (EBM). [10] In these techniques a powder bed of granular material (metal or polymer) is solidified layer-by-layer with a laser or an electron beam as energy sources. The powder layer is renewed by employing a rake or a roll. In vat photopolymerisation, a liquid monomer formulation is deposited in a bath and selectively polymerised employing a laser, known as stereolithography (SLA); a projector, digital light processing (DLP) or a liquid crystal display (LCD). The UV light selectively polymerises a layer of the monomeric formulation, then the stage adjusts the position and the process is repeated.
The employment of 3DP to manufacture continuous flow reactors was first reported by Kitson et al.[14] The field has rapidly grown to develop a broad range of applications in the synthesis of chemicals, materials [15] and crystallisation processes. [16] The digitalisation of the manufacturing process allows advanced design, where simulation of properties (e.g. flow, electric fields, pressure drop) enables the fabrication of optimised reactor geometries. [17][18][19] There are several excellent reviews which showcase the developments in the field. [13,[19][20][21] The focusing of this contribution is on recent trends identified in the literature which represents areas of potential growth for continuous-flow green and sustainable process development.

Robust materials for 3DP reactors
Early examples in 3DP devices employed polymers with limited chemical and thermal resistance. Most FDM commercial printers are limited to temperatures <300 °C. The use of polypropylene (PP) considerably improved the chemical stability and offer a window of temperature slightly over 100 °C. Flow reactors manufactured with 3DP have been demonstrated in PP. [14,22,23]. Commercial low cost printers can be employed to 3DP PP, thus enabling the development of a broad range of budget applications. [24,25] Polyether ether ketone (PEEK) is a thermally and mechanically robust polymer and resistant to a broad range of chemicals. It is very challenging to print by FDM due to its high melting point. [26] Typically, high thermal stresses result in excessive warping and  More recently, the same groups reported SS 3DP reactors with embedded in-line oxygen sensors for the oxidation of Grignard reagents. A split and recombine flow reactor and a cascade micro CSTR reactors were manufactured. [29] The resulting systems were employed for the aerobic oxidation of chlorophenylmagnesium bromide with oxygen, which is a green oxidant due to its low cost, high atom economy and lack of by-products.
The optimal mixing generated in the printed reactors led to higher selectivity compared

Integrating functionality in 3DP flow reactors
Another area with a huge growth potential is the integration of multiple enabling technologies. Here, recent advances in the integration of 3DP of flow reactors with biocatalysis and electrochemistry will be discussed. Thorough kinetic studies revealed important mass transfer limitations, which severely affected the performance of the biocatalytic reactors. This is probably due to the fact that the enzymes were trapped within the hydrogel matrix, obviously hindering the mass transfer of substrates and products to the catalytic centres. An increase in surface area would lead to an improved performance due to better contact between reagents and enzymes. Another strategy is to functionalise the surface of the support to avoid mass transfer limitations. [37] Electrochemical flow reactors are gaining interest for the development of sustainable chemical transformations. Redox processes can be efficiently carried out electrochemically, reducing the need for oxidant and oxidising species. There are several examples in the literature of employing 3DP for the development of electrolyser cells. [41,42] In synthetic chemistry, the main advantages offered by electroreactors are the need of low or no support electrolyte, due to the short distance between the electrodes and a high electrode surface to volume ratio, which improves mixing and shortens reaction times compared to traditional batch reactors. [43] The low distance between electrodes reduces the ohmic losses and facilitates mass transfer, even though in many cases mass transfer of reagents and products to and from the electrodes limits the overall performance. [44] Hence, typically, the electrochemical reactors are limited to microfluidic or parallel plate configurations. In an early example, 3DP has been employed to generate the spacers of electrochemical reactors to accurately control the distance between electrodes. [45] The employment of 3DP facilitates the development of parts of electrochemical devices that can fit in with commercially available equipment (e.g.  Figure 3A), showed mass transfer limited reactions ( Figure 3E). When turbulence promoters were added, residence time distribution studies indicated low axial dispersion and higher mass transfer coefficients were observed for the reduction of [Fe(CN)6] 3-( Figure 3F). The filter press configuration makes this an interesting approach, since it is easily scalable. Emerging trends in the field include the development of more robust reactors, employing metal and ceramics. Besides, the integration of multiple technologies, including electrochemistry, chemo-and biocatalysis are areas with a huge growth potential. There is no limitation in further integrating multiple technologies to perform multiple transformations, telescoping separation, analytics, etc.
A big challenge ahead in the field is to address issues related to scalability. Currently, the technology is limited to relatively small-scale machines and with slow manufacturing processes. Large scale 3D printing is mostly limited to extrusion methods, [52] but the integration of robots is opening new avenues, which can translate into developing largescale applications with different types of materials and additive manufacturing techniques. [53] This is necessary to increase the industrial uptake of these technologies. Circular economy aspects related to the recycling and disposal of reactors, catalysts and materials at the end of their use is another area of development. [54] There is a lot of potential for optimisation in the recycling and disposal at the end of life of the reactors and materials employed for reactor manufacturing. Comprehensive life cycle assesments will help selecting materials and manufacturing techniques to minimise environmental impacts. [55]

Conflicts of interest
No conflicts of interest are declared