Machine-Assisted Organic Synthesis

Abstract

In this Review we describe how the advent of machines is impacting on organic synthesis programs, with particular emphasis on the practical issues associated with the design of chemical reactors. In the rapidly changing, multivariant environment of the research laboratory, equipment needs to be modular to accommodate high and low temperatures and pressures, enzymes, multiphase systems, slurries, gases, and organometallic compounds. Additional technologies have been developed to facilitate more specialized reaction techniques such as electrochemical and photochemical methods. All of these areas create both opportunities and challenges during adoption as enabling technologies.

Keywords: machine-assisted synthesis; sustainable chemistry; synthetic methods.

Figure 1

The topic of machine‐assisted organic synthesis has been divided into eight sections in this Review.

Figure 2

Continuous photo‐oxidation under supercritical CO₂ conditions for the production of antimalarial trioxanes. A series of UV LEDs and sapphire reactors were used to expose the reagents to UV radiation.

Figure 3

a) Furfural was used as a feed material, alongside H₂, in the twin‐column system. b) Hydrogenation products of furfural under supercritical conditions.

Figure 4

a) Annular, tube‐in‐tube fluid‐flow regions. The semipermeable membrane tubing is placed inside an impermeable PTFE outer layer. b) Prototype reactor used to facilitate gas–liquid reactions.27 Reproduced with permission from The Royal Society of Chemistry. c) The Gastropod reactor from Cambridge Reactor Design, a commercially available unit that was developed from this study.29

Figure 5

The various reactions carried out by Kim and co‐workers using a membrane microreactor to facilitate the generation and subsequent consumption of diazomethane.32

Figure 6

A photocatalytic reactor in which a gas stream was used to fluidize catalyst particles to form styrene from ethylbenzene.

Figure 7

The performance of various equipment layouts was compared for a fluidized bed system. a) All gases were fed together into the reactor through one injection point. b) A two‐zone injection system with gaseous nitrogen and hydrogen streams fed from the base and benzene and oxygen fed from the top. c) A similar two‐zone injection system, but hydrogen and oxygen inputs were switched.

Figure 8

The HEL FlowCAT trickle‐flow reactor has been used for the hydrogenation of ethyl nicotinate over a packed‐bed catalyst.

Figure 9

Expanded view of the Polar Bear Plus from Cambridge Reactor Design showing the refrigeration loops and other key components.29

Figure 10

A schematic representation and photograph of the first reported capillary microwave flow reactor. Reprinted from Ref. 51.

Figure 11

An inductive system used for the machine‐assisted heating of a continuous‐flow reactor column. Reprinted from Ref. 54a.

Figure 12

Schematic representation of a combustion jet reactor used for the production of metallic nanoparticles from a precursor solution. The size of the particles can be manipulated by adjusting the dimensions of the inner chamber.

Figure 13

Preparation of the natural product grossamide by using immobilized horseradish peroxidase.

Figure 14

Three‐step flow cartridge system used for the preparation of carbohydrate products. The middle cartridge can be switched to adjust the chirality of the final compound.

Figure 15

Preparation of a β‐ketohydroxyester from a diketone using immobilized acetyl acetoin synthase.

Figure 16

Encapsulated glutaminase has been used during the synthesis of theanine. Increased temperature control of such a reactor system led to higher than normal enzyme activity.

Figure 17

a) The Coflore ACR is used for reactions that include slurries or involve precipitation of significant quantities of solids. b) Equipment layout used for the preparation of a hydroiodide salt product.

Figure 18

The Multijet Oscillating Disc microreactor (MJOD) promotes excellent mixing through the axial movement of a series of perforated discs in a liquid stream.

Figure 19

An R2/R4+ reactor system and FlowIR were combined to effectively manage organometallic reagents in continuous‐flow reactions.

Figure 20

Synthesis of nazlinine and unnatural congeners by a two‐step, electrocatalyzed and microwave process.

Figure 21

The commercially available Syrris Asia electrocatalytic reactor system.

Figure 22

A modular plate‐based microfluidic cell has been used for benzylic methoxylation and oxidation.

Figure 23

The efficiencies of five reactor configurations were tested: a) an immersed well, batch‐mode reactor; b) a recirculating annular reactor; c) a microfluidic single pass reactor; d) a microfluidic recirculating reactor; and e) a biphasic‐flow, single‐pass microfluidic system. Reprinted from Ref. 97 with permission. Copyright 2014, American Chemical Society.