Flow chemistry

In flow chemistry, a chemical reaction is run in a continuously flowing stream rather than in batch production. In other words, pumps move fluid into a tube, and where tubes join one another, the fluids contact one another. If these fluids are reactive, a reaction takes place. Flow chemistry is a well-established technique for use at a large scale when manufacturing large quantities of a given material. However, it is relatively new to use it in the laboratory environment.

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Batch vs. flow

Comparing parameters in Batch vs Flow:

• Reaction stoichiometry. In batch production this is defined by the concentration of chemical reagents and their volumetric ratio. In Flow this is defined by the concentration of reagents and the ratio of their flow rate.
• Reaction time. In batch production this is determined by how long a vessel is held at a given temperature. In flow this is determined by the volume of the reactor, and the bulk flow rate.

Flow Reactor scale

It is possible to have flow reactors operating at large scale; however for use in the laboratory, channel/tube scale is likely to be in the region of 50μm to 500μm. Nonetheless, this channel scale range is sufficiently broad to allow single experiments with approximately 10 mg of starting material per observation point in a similar environment to an annual production rate of several tens of tons of material (Fast transfer from research to production).

In as far as synthetic efficiency is concerned, there are a number of benefits to do with thermal and mass transfer as well as mass transport that allow chemistry to perform efficiently. For a review of synthesis benefits from enhanced physical reaction control see Microflow Synthesis and literature cited therein.

The scale of micro flow reactors can make them ideal for process development experiments. For a review on the types of processes which can be conducted in these and the benefits afforded see Optimised Chemistry Using a Flow Reactor System and literature cited therein.

Continuous flow reactor

A Continuous flow reactor is a device that allows chemical reactions to be performed as a continual process rather than batch-wise. Reagents are continually added to the input of the reactor and product continually collected from the output. The reactor is typically tube like and can be manufactured from a variety of materials including stainless steel, glass and polymers. Mixing methods include diffusion alone (if the diameter of the microreactor is small e.g. <1 mm) and static mixers.

Continuous flow reactors allow good control over reaction conditions including heat transfer, time and mixing.

The residence time of the reagents in the reactor (i.e. the amount of time that the reaction is heated or cooled) is calculated from the volume of the reactor and the flow rate through it.

Residence time = Reactor Volume / Flow Rate

Therefore, to achieve a longer residence time, reagents can be pumped more slowly and/or a larger volume reactor used. Production rates can vary from nano litres to litres per minute.

Examples ... spinning disc reactor (Colin Ramshaw); spinning tube reactor; oscillatory flow reactor; microreactor; hex reactor; 'aspirator reactor' (this has another name ... it is based on a water pump where one reagent is pumped through it which causes a reactant to be sucked up by it. A patent is available (1941???, Nobel companies) that describes it being used to prepare nitroglycerin. From memory, the acid mixture was pumped through and the glycerin was sucked up).

Benefits of flow

• Reaction temperature can be far above the solvent's boiling point due to easy ability to contain pressure.
• Mixing can be achieved within seconds at the smaller scales used in flow chemistry.
• The thermal mass of the fluid is typically far lower than the thermal mass of the system (and orders of magnitude less than with batch chemistry). This makes controlling the temperature of the media both faster and easier ensuring that exothermic and endothermic process can be conducted without issue.
• Multi step reactions can be arranged in a continuous sequence. This can be especially beneficial if intermediate compounds are unstable, since they will exist only momentarily and in very small quantities
• Position along the flowing stream and reaction time point are directly related to one another. This means that it is possible to arrange the system such that further reagents can be introduced into the flowing reaction stream at precisely the time point in the reaction that is desired.
• It is possible to arrange a flowing system such that purification is coupled with the reaction. There are three primary techniques that are used:
  • Solid phase scavenging
  • Chromatographic separation
  • Liquid/Liquid Extraction
• By coupling the output of the reactor to a detector system, it is possible with appropriate controls to create an unattended system which can sequentially investigate a range of possible reaction parameters (varying stoichiometry, residence time and temperature) and therefore optimise reactions with little or no intervention.
• Scaleup of a proven reaction can be achieved rapidly with little or no process development work, by either changing the reactor volume or by running several reactors in parallel, provided that flows are recalculated to achieve the same residence times.

Other uses of flow

It is possible to run experiments in flow using more sophisticated techniques, such as solid phase chemistries. Professor Steven Ley's group at the University of Cambridge has pioneered work that has demonstrated how valuable the coupling of flow chemistry and solid supported chemistries can be. http://leygroup.ch.cam.ac.uk[1]

Running flow experiments

The practicalities of running flow experiments in normal chemistry laboratories are not simple. It requires the coupling of a range of equipment that is not commonly used by chemists. Additionally it is beneficial have a software control system to help manage all of the systems that are allowing the experiment to be performed. The chemist needs to have access to specialist microfabricated devices, tubing connectors and tubing as well as the pumps to displace the reagents.

The challenges of controlling flow experiments should not be underestimated however several of the commercial systems available address these well. It is important to consider both the equipment control and the "tracking" of reaction products especially when multiple reactions are being conducted sequentially.

See also

• Microreactor