Flow Chemistry

Integrated Approaches for Practical Applications

Santiago V Luis, Eduardo Garcia-Verdugo, Santiago V Luis, Eduardo Garcia-Verdugo

• Publisher: Royal Society of Chemistry
• Year: 2019
• eBook ISBN: 9781788018937
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Physical & Theoretical Chemistry

Historically pharmaceutical and fine chemical products have been synthesised using batch methods, but increasingly chemists are looking towards flow chemistry as a greener and more efficient alternative. In flow chemistry reactions are performed in a reactor with the reactants pumped through it. It has the benefit of being easily scaled up and it is straightforward to integrate synthesis, workup and analysis into one system. Flow chemistry is considered a greener alternative to batch chemistry because it is easier to control and minimise hazardous intermediates and by-products. There is significant interest in the use of flow chemistry both in the lab and on an industrial scale.

Flow Chemistry provides an update on recent advances that have been made in the field. Particular emphasis is given to the new integrated approaches that bring together several elements to implement flow processes as a regular green chemistry tool for the chemical industries. With chapter contributions from several well-known experts in the field, this book is a valuable resource for researchers working in green chemistry and synthesis, chemical engineers and industrial chemists working in the pharmaceutical and fine chemicals industries.

CHAPTER 1

Recent Perspectives in Catalysis under Continuous Flow

HARURO ISHITANI,^a YUKI SAITO,^b BENJAMIN LAROCHE,^b XIAOFENG RAO^b AND SHŪ KOBAYASHI*^a,b

^a Green & Sustainaible Chemistry Cooperation Laboratory, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

^b Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-kuTokyo 113-0033, Japan

*Email: [email protected]

1.1 Introduction

Continuous-flow synthesis has attracted considerable attention as a subject of fundamental scientific research and as a key technology for advanced manufacturing.¹ In comparison with batch systems, flow systems bring great advantages to chemical processes in terms of sustainability, efficiency, and safety. Continuous-flow systems can be classified into four categories based on the types of reactions that are to be performed under the flow conditions (Figure 1.1).² The most straightforward case is when all reagents are continuously fed into a tube- or pipe-flow reactor, and the product is continuously collected (type I). This process has been developed mainly as microflow chemistry, and to date, several remarkable achievements have been made in this area. However, unreacted starting materials and by-products are often eluted along with the product, and quenching and work-up processes are necessary. The use of immobilized reagents packed into a column flow reactor has been investigated to reduce coproduction of by-products (type II). The drawback to this approach is that overreactions may occur, and when a supported reagent is consumed, a flow reactor must be changed. Since modern organic chemistry is heavily reliant upon catalysis to improve the efficiency and selectivity of reactions, flow reactions can be conducted by feeding homogeneous catalysts with substrates (type III). Utilization of homogeneous catalysts for desired reactions is a straightforward approach for realizing a catalytic process under flow. Usability of a homogeneous catalyst without any further processing and the sustainability of product quality during the whole process offer great advantages; however, further processing to quench the catalytic reaction and to remove the catalyst cannot be avoided, and this may interrupt the seamless operation of a multistep flow reaction. On the other hand, use of heterogeneous catalysts with column-type fixed-bed reactors, categorized as type IV flow reactions, would reduce inactivation and loss of the catalysts, and contamination of catalyst residue in the output of reactions can be avoided. From the viewpoint of the construction of multistep sequential continuous-flow production of high value-added compounds, type IV is ideal. Given that numerous efforts for achieving efficient noncatalytic continuous-flow organic reactions are discussed in other chapters and that a number of excellent reviews concerning homogeneous and heterogeneous catalytic continuous-flow organic reactions are available,³ here we provide an overview of recent advances in flow heterogeneous catalytic processes especially in enantioselective reactions, photocatalytic reactions, integration of more than two continuous-flow processes for sequential transformation of organic compounds, and progress in engineering aspects for establishing efficient processes.

Figure 1.1 Classification of flow reaction for fine organic synthesis.

1.2 Advantages of Catalytic Enantioselective Reactions under Continuous Flow

Enantioselective catalysis plays a key role in the synthesis of fine chemicals such as biologically active compounds and natural products, which are usually chiral compounds. In this context, flow heterogeneous catalysis is an ideal method for the efficient syntheses of such compounds, not only because of the general advantages of flow reactions over batch reactions, but also because contamination by catalysts of the products can be avoided and the amount of catalyst can be reduced. Therefore, synthetic chemists have been trying to develop efficient heterogeneous flow catalysis by precise design of heterogeneous catalysts. The history of catalytic enantioselective reactions under continuous-flow began in the early 1990s, when immobilized chiral ligands on solid supports were typically used.⁴ Since then, various types of heterogeneous catalysts have been developed by using a range of immobilization strategies. However, there remain general problems to overcome such as decreased activity and selectivity compared with homogeneous catalysts. In this chapter, significant developments in heterogeneous flow reactions that have been achieved since 2013 are discussed in two sections. The first section discusses immobilized organocatalysis (non-metal catalysis); in the second section, the use of metal catalysis is covered.

1.2.1 Immobilized Organocatalysts (Non-metal Catalysts)

Since the development of MacMillan catalyst in 2000, various kinds of efficient chiral organocatalysts (non-metal catalysts) have been developed, such as Hayashi–Jørgensen catalysts, Akiyama–Terada catalysts, and thiourea catalysts.⁵ Currently, asymmetric organocatalysis has become one of the most powerful tools to synthesize chiral compounds. Thanks to their stability and easily modifiable nature, various covalent methods have been developed to immobilize active species on solid supports. In particular, postmodification of functionalized polystyrene resins has become a common technique. Since 2013, much effort has been devoted to expanding the scope of catalysts and types of catalysis.

1.2.1.1 Enamine and Iminium Catalysis

In 2014, Benaglia and Cozzi et al. reported the enantioselective α-alkylation of an aldehyde with a stable carbocation, in which MacMillan-type catalysts were immobilized through covalent bonds to polystyrene or silica support. The catalyst activity was first evaluated with different electrophiles under batch conditions (Figure 1.2).⁶

Figure 1.2 Supported organocatalysts for enantioselective alkylation.

It was revealed that silica-supported catalyst 1 showed slightly higher activity than the polystyrene-supported catalyst 2, whereas 2 showed higher enantioselectivity than 1 in most cases, although the structure of the active site is identical. Moreover, higher enantioselectivity was observed compared with the homogeneous catalyst for some electrophiles. This clearly indicated that support material has a non-negligible effect on catalyst performance. Continuous-flow catalysis was also examined using polystyrene-immobilized catalyst 2, and the same level of enantioselectivity under batch conditions was achieved, although there remained room for improvement in yield (Figure 1.3).

Figure 1.3 Continuous-flow enantioselective alkylation with supported organocatalyst 2.

Also, in 2014, Pericàs and colleagues developed the first example of a three-component asymmetric Mannich reaction under continuous-flow conditions.⁷ They investigated several kinds of immobilized natural primary amino acid catalysts under batch conditions, and finally threonine-derived catalyst 3, which showed similar levels of stereoselectivity, was determined to be the best catalyst. Notably, each heterogeneous catalyst showed significantly different activity and selectivity. Solvent screening revealed that swelling of the polymer catalyst was critical for the catalytic activity. Unfortunately, catalyst deactivation was observed during recycling experiments, and the authors concluded that, based on the IR spectrum, the cause of deactivation was loss of a carboxylate group. By using the best catalyst, the continuous-flow three-component Mannich reaction was investigated (Figure 1.4). In-line IR analysis was employed to determine the conversion of the substrate and the best flow rate. Under the optimized reaction conditions, excellent stereoselectivity was achieved, and the turnover number (TON) was increased twofold compared with batch conditions. Finally, Pericàs and coworkers demonstrated that the system could also be employed for the construction of a small library of products by changing the substrate solution every hour. This is a rather unique application of the continuous-flow process.

Figure 1.4 Continuous flow three-component...

Table of contents

• Cover
• Title
• Copyright
• Contents
• Chapter 1 Recent Perspectives in Catalysis under Continuous Flow
• Chapter 2 Green Biotransformations under Flow Conditions
• Chapter 3 Organometallic Chemistry in Flow in the Pharmaceutical Industry
• Chapter 4 Perspectives on the Use of Flow Systems to Carry Out Organic Photochemical Reactions
• Chapter 5 Electrochemistry under Flow Conditions
• Chapter 6 Sustainable Approaches to C–H Functionalizations Through Flow Techniques
• Chapter 7 Radical Polymerisation under Flow Conditions
• Chapter 8 Ionic Polymerisation and New Approaches to Polymerisation under Flow Conditions
• Chapter 9 Continuous Flow Synthesis of Nanomaterials
• Chapter 10 NMR Microcoils for On-line Reaction Monitoring
• Chapter 11 Flow Chemistry Systems Based on Membranes
• Chapter 12 New Microreactor Designs for Practical Applications Realized by Additive Manufacturing
• Chapter 13 Additively Manufactured Advanced Flow Reactors for Enhanced Heat and Mass Transfer
• Chapter 14 Integrated Microreaction Systems of Microdevices with Conventional Equipment
• Chapter 15 Automation of Flow Chemistry
• Chapter 16 Upscaling the Aza-Diels–Alder Reaction for Pharmaceutical Industrial Needs in Flow Chemistry
• Chapter 17 Industrial Continuous-flow Chemistry under cGMP Conditions
• Subject Index