Flow Chemistry: Integrated Approaches for Practical Applications
Published:18 Sep 2019
Special Collection: 2019 ebook collection , ECCC Environmental eBooks 1968-2022Series: Green Chemistry
Flow Chemistry: Integrated Approaches for Practical Applications, ed. S. V. Luis and E. Garcia-Verdugo, The Royal Society of Chemistry, 2019, pp. P007-P010.
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Since the publication of “Chemical Reactions and Processes under Flow Conditions”,1 a decade ago, the field of flow chemistry has experienced important advances and achievements. At that time flow chemistry was a hot topic that was being explored intensively in academia following two parallel approaches involving chemistry and chemical engineering, and it was facing important challenges in order to progress outside the academic realm. While processes under flow conditions were often the standard approaches in bulk chemical industries, they were relatively uncommon in fine chemicals or in pharmaceutical industries. An important driver for progress in this area was the development of microreactors as a key tool allowing reactions to be achieved that could be considered as highly demanding in terms of the associated hazards (like those for very exothermic reactions or for processes requiring explosive or otherwise dangerous reagents) and, simultaneously, facilitate their scale-up. A second important driver was the large advance in the production of a variety of heterogeneous or heterogeneized catalytic systems whose intrinsic properties (stable materials with appropriate porosity and the ability to be packed into continuous flow reactors) enabled the simple development of flow processes. Finally, the use of neoteric solvents, in particular ionic liquids and supercritical fluids, was seen as a new opportunity to create new processes based on multiphasic systems easily implemented for working under flow conditions.
However, flow processes still had to overcome a substantial number of significant challenges in order to become standard and almost universal tools in chemistry and the chemical industries, and an essential contribution towards green chemistry. The present work contains a series of contributions from well-known leaders in their respective fields, approaching the most recent advances in the area with a proper combination of engineering aspects, organic chemistry elements, technological innovations and industrial perspectives. The integration of all these aspects is a key element in this book and represents a fundamental stage in implementing flow processes as a regular green chemistry tool for pharma and fine chemicals industries.
Thus, the first chapter of the book, presented by Prof. Kobayashi and coworkers summarizes some of the essential concepts in the area and the most important advances achieved in recent years, particularly in the last 5–6 years. The chapter focuses on three main aspects, representing important challenges for processes under flow conditions: enantioselective processes, mostly involving organocatalytic and metal-based catalytic systems; photocatalytic processes; and multistep processes combining several catalytic systems or even catalytic and non-catalytic transformations. Some of these areas are further elaborated or considered in other chapters of the book.
The incorporation of phototransformations to flow processes has represented a significant challenge for a long time, as it imposed important restrictions on the materials to be used for the construction of the corresponding reactors and reacting systems. Other technological constraints, such as the size of the path for the flow of substrates and catalysts, were also to be taken into account. Remarkable work by a large number of research groups, including academic and industrial chemists and engineers, has allowed for impressive advances in this area. As mentioned, these contributions are considered in the corresponding section of Chapter 1, but they are also systematically explored in the contribution from Prof. K. Mizuno and coworkers in Chapter 4. In the same way, developing electrochemical transformations under flow also faced significant challenges and technological constraints. The approaches to overcome those challenges are clearly illustrated and explored in the contribution presented by Prof. T. Wirth and coworkers in Chapter 5. As well as in-batch processes, photochemistry and electrochemistry are now important tools used to carry out a growing number of chemical transformations. Chemists and engineers developing flow processes can currently use such transformations as an additional available tool.
Organometallic chemistry is an essential instrument for developing complex synthetic transformations, but their implementation is not always straightforward for flow chemistry, in particular when involving species highly sensitive to variations in the medium (air, moisture…), species with low solubility or even, directly, solid reagents. Several chapters in this book deal specifically with the application and implementation of organometallic chemistry in flow. Thus, in Chapter 3 Dr J. Alcazar and coworkers provide a general vision of the approaches in this field, with the added value of the perspective from an industrial research laboratory. C–H functionalization is currently a very important process in which organometallic chemistry plays an essential role. The available methodologies for such transformations are presented by Prof. L. Vaccaro and coworkers in Chapter 6. The use of solid metals for the in situ preparation of organometallic species in flow is a particularly challenging task, but examples reported in Chapter 3 and in Chapter 12 (Dr P. Loeb and coworkers) highlight how a proper integration of chemistry and engineering concepts make this feasible.
The integration of biochemical transformations in flow processes, including multistep processes, has always been a complex task due to the environmental restrictions associated with the efficient use of biocatalysts (enzymes, cells…) for a broad range of transformations. However, examples gathered in Chapter 2 by Prof. P. Lozano and coworkers, show that, not only is flow chemistry possible with biocatalysts using a variety of approaches, but also that flow chemistry can help to achieve systems with a high efficiency and, more importantly still in this field, with a remarkably high long-term stability.
Chemical processes in which solid materials are formed represent an intrinsically difficult case for the development of continuous flow alternatives. As in the examples mentioned for organometallic chemistry, flow processes involving just fluids are much simpler than those in which solids are formed as a result of the transformation. In spite of this, relevant examples of the preparation of different families of materials under flow conditions have been reported. In this regard, Prof. A. Kulkarni and coworkers in Chapter 9 highlight the available methodological approaches towards the synthesis of namomaterials in flow, while the contributions from Prof. I. Baxendale and coworkers in Chapters 7 and 8 illustrate in a systematic way the preparation of polymeric materials though a large variety of methods under flow conditions.
Many of the above considered transformations have only been implemented in flow through the tight integration of chemical and engineering concepts and with the development of new reactor designs at different scales. Several chapters in this book deal with these aspects from different perspectives. An essential breakthrough in this area has been the availability of additive manufacturing processes (3D printing) for the preparation of reactors and flow systems. In this field, in Chapter 13 Prof. V. Sans and coworkers analyse the different methodologies that have been explored for the preparation of reactors or devices of utility in flow chemistry using a variety of 3D printing methodologies. The potential of additive manufacturing for the preparation of flow systems to fill the gap between academic research and industrial applications is highlighted in the contribution by Dr P. Loeb and coworkers in Chapter 12. On the other hand, Prof. J. Sanchez-Marcano and coworkers in Chapter 11 reveal the advantages of flow systems based on membranes for an efficient integration of transformation and separation steps. Finally, in Chapter 14 Prof. G. Luo and coworkers show how conventional equipment can be integrated with microdevices for the development of flow systems with a broader scope of applications.
On the path towards industrial applications of flow processes, the incorporation of efficient monitoring is essential. A plethora of methods have been reported in this regard. In Chapter 10, Prof. M. V. Gomez Almagro deals with one of the most challenging, but also one of the most powerful, technologies for the monitoring of flow processes: NMR spectroscopy. The integration of the different available reactor designs and developed chemical transformations in flow with the proper monitoring and automatization has been successfully achieved at different scales, as illustrated by Prof. T. M. Jamison and coworkers in Chapter 15, the final target being the development of automatized chemical minifactories accomplishing impressive space-time-yields. The industrial application of flow processes requires a detailed consideration of two important additional factors. The first one is the scale-up. It is commonly claimed that flow chemistry is simple and easy to scale-up, but this is not always demonstrated in academic reports. The work presented by Dr R. Ferrito and coworkers in Chapter 16 shows clear examples of how scale-up can be approached for different flow processes to reach scales of interest to the chemical industry. Finally, industrial-level production requires different standardization procedures to be completed, in general well defined in the pharma and fine chemicals industries when batch processes are concerned. Thus, industrial flow chemistry requires development and application of the corresponding GMP protocols (cGMP), as illustrated in Chapter 17 by Dr R. Moylan and coworkers.
In summary, although much additional progress may be achieved in the near future, we expect this book will highlight the maturity of flow chemistry at different scales and how, in the last decade, research in this field has been able to overcome some of the more significant challenges to allow their industrial implementation and to become a common element of the green toolbox, not only for academic research but also for chemical industry including the pharma and fine chemicals sectors.
Santiago V. Luis
S. V. Luis and E. García-Verdugo, Chemical Reactions and Processes under Flow Conditions, RSC, Cambridge, 2009.