Ten Key Issues in Modern Flow Chemistry Jens Wegner, Sascha Ceylan and Andreas Kirschning*
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View Article Online / Journal Homepage / Table of Contents for this issue ChemComm Dynamic Article Links Cite this: Chem. Commun., 2011, 47, 4583–4592 www.rsc.org/chemcomm HIGHLIGHT Ten key issues in modern flow chemistry Jens Wegner, Sascha Ceylan and Andreas Kirschning* DOI: 10.1039/c0cc05060a Ten essentials of synthesis in the flow mode, a new enabling technology in organic chemistry, are highlighted as flashlighted providing an insight into current and future issues and developments in this field. Why flow? An effort to today. We all work with standardised chemical and biotechnological production.2 provide a brief introduction glassware, use somewhat sophisticated Several advantages have been recognised ways of stirring and after a battle of at such as facile automation, secured For chemists from Liebig’s time being least two decades we accept that micro- reproducibility, improved safety and transferred into a common synthetic wave radiation can beneficially be added process reliability. Indeed, with continu- laboratory of the 20th century, most to the portfolio of classical heating ous flow processes constant reaction equipment would look very familiar devices.1 Indeed chemists have mainly parameters (temperature, time, amount been focused on the chemistry occurring of reagents and solvents, efficient mixing, Institute of Organic Chemistry and Center of inside the flasks or reaction vessels and etc.) can easily be assured. Over the past Biomolecular Drug Research (BMWZ), they have done so in a very elaborated 15 years, miniaturisation has entered the Leibniz Universita¨t Hannover, and successful manner. Despite their field of flow chemistry and modern Schneiderberg 1b, 30167 Hannover, Germany. many advantages continuous flow developments commonly deal with E-mail: [email protected]; Fax: +49 (0)511 7623011; processes have commonly flourished micro- and microfluidic (or mesofluidic) Tel: +49 (0)511 7624614 only in the industrial environment of flow devices (see issue 1 below).3 With Jens Wegner (left) was born in 1982 in Nordhorn, Germany. He studied chemistry at the Leibniz University Hannover where he received his diploma degree in 2008. He is currently performing Published on 15 March 2011. Downloaded by Technische Informationsbibliothek (TIB) 26/10/2017 08:50:51. his doctoral studies at Hannover under the supervision of Prof. Andreas Kirschning with the aid of a scholarship by the Fonds der Chemischen Industrie. In 2010 he spent several months in the group of Prof. S. V. Ley at Cambridge University (UK). His research is focussed on the development of an inductively heated micro flow system for organic synthesis. A key aspect of his work is the implementation of a multi- step reaction and an immobilised catalyst into micro flow systems. Sascha Ceylan (right) was born in Augsburg, Germany, in 1981 and studied chemistry at Leibniz University Hannover and at Jens Wegner, Andreas Kirschning and Sascha Ceylan Imperial College London under the guidance of Prof. A. G. M. Barrett (UK). He received his diploma degree in 2007 and thereafter began his doctoral studies in Hannover under the supervision of Prof. A. Kirschning. Following a research stay at the University of Hong Kong (Prof. P. Toy) he received his PhD early 2011. His scientific interest focuses on developing micro flow systems, especially inductively heated reactors, and investigations on palladium catalysed Umpolung reactions. Andreas Kirschning studied chemistry at the University of Hamburg and Southampton University (UK). In Hamburg, he joined the group of Prof. E. Schaumann and received his PhD in 1989 working in the field of organosilicon chemistry. After a postdoctoral stay at the University of Washington (Seattle, USA) with Prof. H. G. Floss, supported by a Feodor-Lynen scholarship of the Alexander-von Humboldt foundation, he started his independent research at the Clausthal University of Technology in 1991, where he finished his habilitation in 1996. In 2000 he moved to the Leibniz University Hannover and became a director of the institute of organic chemistry. He is one of the editors of RO¨MPP online, Natural Products Reports and The Beilstein Journal of Organic Chemistry. His research interests cover structure elucidation as well as the total synthesis and mutasynthesis of natural products, biomedical biopolymers, and synthetic technology (solid-phase assisted synthesis, microreactors, inductive heating). This journal is c The Royal Society of Chemistry 2011 Chem. Commun., 2011, 47, 4583–4592 4583 View Article Online respect to heat and mass transfer, Undoubtedly, flow chemistry will not Issue 1: size matters—micro efficient mixing as well as precise completely or generally change the way versus minifluidic parameter control miniaturised flow chemists are performing synthesis in the devices have proven very beneficial for future, despite the fact that the field (or mesofluidic) reactors performing chemistry that is difficult to experiences a dramatic increase in interest Common miniaturised bench-sized flow conduct under batch conditions e.g. with both in academia and industry. But flow devices rely on reactors that have highly reactive reagents or synthesis via chemistry will become a common enabling channels or tubes sized between 10 mm unstable intermediates (see issue 4 technology for performing synthesis in the to a few mm in inner diameter. The below). Furthermore, continuous flow laboratory.5 It is beyond the scope of this dimension categorises whether a micro reactors are generally smaller than account to provide an exhaustive overview or minifluidic (or mesofluidic) flow reactor batch reactors but in an ideal setup and over the rapidly expanding field of flow is at hand (Fig. 1).6 under optimised conditions these bench chemistry. By specifically covering TEN This scale range is sufficiently broad to sized reactors are able to produce ISSUES of importance, we rather wish allow synthesis of approximately 10 mg more product in a given time than an to address the latest trends and what we to an annual production rate of several analogous batch reactor (see issue 2 believe are the most important topics to be tens of tons of material of a desired below).4 Particularly, chemical engineers considered now and in the near future in compound. Today microfluidic devices and process chemists have stressed that flow chemistry and bring that to the are mainly found in academic labora- optimised reaction parameters developed attention of the broad readership of tories and in analytical and diagnostic in a bench-sized micro- or minifluidic Chemical Communications.Wedosoina applications. Mesofluidic devices are also (or mesofluidic) flow device can be trans- purely highlight format and at the same of academic interest, particularly when ferred directly to large scale production time are fully aware that our perspective is combined with functionalised fixed bed without the need for substantial further based on our own experience in this field materials but have also become popular optimisation which is in stark contrast that we gained over the past ten years, thus in the industrial context.7 The heat trans- to upscaling batch processes (see issue 10 likely leaving out some other important fer capacity, which is a very important below). topics of concern. issue for chemical engineers, is heavily influenced by channel size since it determines the heat transfer area per unit volume. For micro reactors parameters are commonly between 5000–50 000 m2 mÀ3 while for mini reactors the common values are between 100–10 000 m2 mÀ3. Thus, high heat transfer capacities are achieved with small diameter channels favouring micro over mini flow reactors. But high pressure drops, a limited flow capacity and a tendency to block, are common problems with micro reactors. Published on 15 March 2011. Downloaded by Technische Informationsbibliothek (TIB) 26/10/2017 08:50:51. They are also often fabricated in a manner which makes cleaning and dismantling difficult or impossible. Practically, micro reactors also suffer from the fact that it is very difficult to utilise them for the production of substantial amounts of material. Technically it is Fig. 1 Micro versus mini (meso) flow reactors. difficult to overcome this problem even when massive parallelisation is achieved. However, the scale of micro flow reactors makes them ideal tools for process development experiments. An illustrative and telling example for advantageously utilising microreactors in practice was recently disclosed by Jensen et al.8 The authors set out to rapidly find the ideal parameters for a Heck reaction by designing a self-optimising flow system (Scheme 1). It was known that product 3 readily reacts with an excess of aryl chloride 1 to yield diarylated dihydro Scheme 1 Self-optimising microfluidic flow system using an inline HPLC analysis. furan 4. The analytical ‘‘feedback’’ 4584 Chem. Commun., 2011, 47, 4583–4592 This journal is c The Royal Society of Chemistry 2011 View Article Online system based on HPLC allowed them to time. Under optimised conditions a flow rates heating through the walls of a monitor and to individually change the reactor can be operated continuously as preheated reactor has to be very rapid. flow rates of the two components being long as starting materials are available If ‘‘flash’’ heating can be guaranteed and pumped into the microreactor and their and are pumped through the reactor. pressure resistant microstructured flow initial concentrations in the reaction E.g. Hessel and Lo¨we provided an reactors are chosen the reaction tempera- mixture. Within a short time, optimised illustrative example of an industrial ture can be set well above the boiling conditions at 90 1C were found batch process, the oxidation of ethanol point of the solvent even up to super- (3 : 4 = 5 : 1, reaction time 5.5 min) to acetic acid using hydrogen peroxide, critical conditions thus leading to very which led to a yield of 3 of 82%. and compared the relevant parameters short reaction times.10 Importantly, the authors showed that with the respective miniaturised flow Several strategies have been pursued these conditions could directly be used process (Fig.