What

Flow chemistry is a technology for organic synthesis where, using an apparatus of microfluidics, reactants are brought together within small reaction volumes and reaction products are collected as part of an ongoing flow process.  In such a flow process the reaction is initiated and continues with a constant fresh supply of reactants until such time when reagents are exhausted or the reaction is stopped by the chemist or operator. 

Why

Flow chemistry offers an interesting possibility to execute chemistry in a completely scalable fashion without being concerned that the reaction dynamics shift as they do when we perform reactions at increasing scale within bigger and bigger reaction vessels.  Despite the reaction volume in the flow chemistry setting being small, over time it is possible to generate large volumes of product.  This contrasts with traditional synthetic methodology for scale up that is usually based on multiple batch synthesis. The technology also allows dangerous or difficult to scale reactions to be performed safely and efficiently within a small volume with excellent control of all of the relevant parameters.

Where/when/what

Several types of reaction have proven to be very applicable to the Flow setting and we at Selvita have been able to usefully exploit the technology in these diverse cases.  Chemistry involving a photochemical reaction, chiral switch, azide chemistry, chemoenzymatic transformations, use of ionic liquid solvents, and electrochemical transformations have been adapted for execution on a Flow chemistry apparatus.

See: “Continuous Flow Chemo-Enzymatic Baeyer–Villiger Oxidation with Superactive and Extra-Stable Enzyme/Carbon Nanotube Catalyst: An Efficient Upgrade from Batch to Flow” https://pubs.acs.org/doi/abs/10.1021/acs.oprd.9b00132

The technology offers an opportunity to exactly reproduce the quality of material even when the “batch” sizes are varied from one synthesis run to the next.  The high degree of control that can be achieved may also offer improved yield and purity of the desired product. The system is really versatile, the scope of the possibilities can be checked on Vapourtec web page.

How

The technical set ups designed to bring different reagents into contact with each other are numerous as reactions may occur between reactants that exist in different phases (gases, liquids and solids) and so there is a need for equipment to accommodate at least gas-liquid (e.g. methoxycarbonylation of an aryl halide, solid-liquid (e.g. hydrogenations) and liquid-liquid reaction interfaces or combinations of all three phases (e.g. hydrogenation of a dissolved substrate using a heterogeneous catalyst).  Furthermore, the dynamics of mixing depends on parameters such as flow rates and the nature of the interface, transverse or longitudinal, that are present within the microreactor.  No single flow chemistry apparatus set up will accommodate all reactions and the blend of chemistry and engineering know-how that must come together in a successful continuous reaction system is dealt with excellently and at length within the review from Plutschack et al. in their 2017 Chemical Reviews paper.[1] 

The most important parameter that need to be fulfilled is solubility of all components, intermediates and final products in reaction media. It seems trivial because in batch reaction this parameter is also taken into account but in flow we need to think broadly and even intermediate or side products that may precipitate during the process can clog the system and prevent further reaction. That’s why the planning of the reaction sequence, understanding of the reaction mechanism and selection of proper solvents and reaction temperature is crucial during optimization. Nevertheless there are also several options to run heterogenous reaction with special pump allowing to use suspensions, light slurries, or by application of immobilized media on solid support (silica, polymers, nanoparticles).

[1] Matthew B. Plutschack, Bartholomaus Pieber, Kerry Gilmore and Peter H. Seeberger, Chem. Rev. 2017, 117, 18, 11796–11893, https://doi.org/10.1021/acs.chemrev.7b00183

VAPOURTEC R2 PUMP MODEL

  • 2 pumps
  • 42 bar maximum reaction pressure across all flow rates
  • 0.05 to 10 ml/min per reagent channel
  • Full tubing kit
  • Touch screen module and mounting kit

STANDARD PFA COILED TUBE REACTOR

  • Ambient to 150oC
  • Strong acid resistance
  • 2, 5, 10 ml reactor size
  • Residence times from 10 seconds to 200 minutes

STANDARD PFA COILED TUBE REACTOR

  • Ambient to 250oC
  • “Post cooling” tube to return products to safe temperature before re-entering PFA tubing
  • 2, 5, 10 ml reactor size
  • Material 316L stainless steel
  • Double insulated manifold (safe to touch)

PHOTOCHEMICAL UV-150 REACTOR

  • Medium pressure mercury lamp + led 450 nm
  • Three wavelengths filters: 254 nm, 310 nm, 370 nm
  • Temperature range of -40°C to 80°C
  • Strong acid resistance

STANDARD COLUMN REACTOR

  • For heterogeneous reactions
  • Ambient to 150oC
  • Ideal for scavengeres resin, immobilised catalysts, solid supported reagents
  • Accepts standard omnifit glass columns
  • Full visibility of column contents
  • Precise temperature control

COOLED TUBE REACTOR

  • Ambient down to -70oC
  • Cooled mixing
  • Cooled post reaction quenching
  • 2, 5, 10 ml reactor size
  • Strong acid resistance (PFA)
  • Good visibility of reactants

Summary

The flow chemistry approach is giving us new possibilities especially with scaling-up but also with more demanding or dangerous chemistry. Never the less technology also have some limitations and require good understanding of chemistry and technological way of thinking to maximize the potential of this methodology. The kay factors that need to be taken int account are:

  • Solubility of all components including raw starting materials, intermediates, products
  • Residence time (time which is needed for reagents to stay in reactor for full conversion)
  • Need of use any of inorganic (base, acid, salt), catalyst
  • Temperature and pressure stability of the reagents and products
  • Gas evolution during the process

Future potential of this methodology is still growing and new applications can be found basically every day that reflect in the number of publications that are available in recent years.

We were also able to successfully adapt the process of the preparation of α,α-difluoroalcohols (represented on the following scheme (I)) via photomediated addition of alkyl radicals to terminal 1,1-difluoroalkenes to the conditions of flow chemistry by UV-150. Work on this project is still ongoing but initially we managed to obtained the products with 50% isolated yield.