Basics of Flow Chemistry

A continuous flow chemistry system provides for the introduction, mixing and reaction conditions (time, temperature, pressure and mole ratios) to perform a desired chemical transformation.

The time needed to perform a reaction in batch is simply measured with a timer. In a continuous flow system, this same reaction time is determined by the volume of the reactor divided by the flowrate (V/Vdot) which also results in units of time and the two methods are directly comparable. A simplified flow chemistry system would consist of at least two pumps, a mixing junction, a flow tube or reactor coil long enough to provide the time necessary for the reaction to proceed and a receiver for the reaction products. Because these flow reactions can operate at high pressures, the providers of these systems impose a pressure on the system (through a back pressure regulator) or resistance at the end of the flow path. This is needed to let these precision pumps operate liquid filled (hydraulic) so that they deliver precise volumes of reagents or solvents to the reactor. Priming of these pumps in conjunction with the back pressure regulator eliminates the presence of gas bubbles or air that will keep them from accurately dispensing liquids. Upstream of the mixing junction one can add a “mixing chip” which consists of hundreds of static mixers packed into a small volume that enables reactants to come into intimate contact prior to being raised to reaction temperature or prior to adding a third reagent. This mixing is especially significant when the two reactant streams differ markedly in their solubility parameters.

From this basic starting point comes a plethora of reaction conditions that can be manipulated by the researcher to accomplish project objectives. Reaction conditions that were either avoided or difficult to achieve can now be easily accomplished.  Added to this is the ability to do multiple reactions with, in essence, a robot then dramatically expands the experimental space worth considering.

Examples of reaction strategies that are fully supported by flow chemistry systems are:

• Highly Exothermic: The surface area to volume ratio of flow chemistry systems is one to two orders of magnitude greater than traditional batch reactors. Thus reactions that might have required dry ice baths or low temperature control units can now be done at much higher temperatures because one can remove the heat without starting a run-away reaction. Reactions that are usually done at low temperatures due to the heat constraint can now be run at much higher temperatures revealing previously hidden reaction selectivity information.
• Corrosive Resistant: While glass is corrosion resistant, it also provides poor heat transfer. Reactions can be run in Hastelloy-C metal flow tubes or with silicon carbide heat exchange plates that resist corrosion from high concentrations of nitric and sulfuric acid.
• Photochemical Range: Due to the excessive light path required when doing reactions of significant volume in batch, flow tubes made of PFA with short paths, on the order of millimeters, allow for photochemical reactions through the entire fluid volume ranging from wavelengths of deep blue, 360nm all the way to white light.
• Extreme Temperature Range: The stated range for manufacturers is from -78^oC to +300^oC which are unattainable without specialized dedicated reactor systems.
• High Pressure: Pressure range is up to 300 bar (atmospheres).
• Employs Highly Volatile Reactive Gases like Hydrogen and Ethylene. – These can be introduced into a flowing reactant stream via a semi-permeable membrane configured in a flow tube made by Dupont that allows for saturation of liquid feed streams.
• Exact Stoichiometry: Flow systems can be set up to provide the exact ratio of reactants required by feeding them through precision pumps that are accurate to +/-0.5%.
• Automated Sequential Reactions: Reactions can be run and samples from each collected by running reactions that vary temperature, reaction time or mole ratio in an automated sequence under computer control. The computer also provides a platform for electronically recording both reaction conditions and for data acquisition (temp, pressures, flows etc.)

Common applications for continuous flow processes include producing pharmaceuticals, advanced polymers and other complex reactions too hazardous or toxic for large-scale batch production. These include:

• Nitration
• Oxidation
• Halogenation
• Hydrogenation
• Diazotization

In short, flow chemistry makes difficult reactions easier to run on a continuous basis and achieves results that can’t easily be reached by traditional batch chemistry. The overall result of continuous flow chemistry systems is a product with higher quality, fewer impurities, and faster reaction cycle time, which is preferable for any industry.

As flow chemistry process systems have gained traction, the number of reactions that can be performed with continuous flow chemistry has increased substantially. It has also gained popularity for its ability to take on common issues in the chemical industry.

Just a few examples of how flow chemistry may be applied are:

• Chemical synthesis: Reactive chemical syntheses like catalysis, hydrogenation and polymer synthesis require close analysis of chemical processes and continuous optimization to improve the quality of reactions. Flow chemistry has become essential to chemical synthesis reactions for its modular nature and simplified optimization, especially with the assistance of automation and analysis tools.
• Reaction kinetics studies: Flow chemistry systems with in-situ analytical tools allow chemists to understand the mechanisms and pathways behind reactions more thoroughly. With easily-adjusted flow rates and conditions, scientists can alter conditions quickly to collect a range of data for experiments and studies. This way, chemists can more thoroughly and accurately describe reaction behaviors for immediate application.
• Impurity profiling: Flow chemistry system analysis allows chemists to gain an improved understanding of impurities in reactions. Chemists can easily set up and analyze reactions for impurities and adjust conditions to better understand the kinetics and mechanisms of impurity formations with accurate, reproducible data. This data is essential in improving productivity for future reactions.
• Heat transfer profiling: Flow chemistry reactions allow researchers to accurately measure and model temperature changes during exothermic reactions. This research is essential when scaling up reactions, as they need to design the system to handle the heat produced from the reaction.