Continuous Flow Chemistry Reactors
“Flow chemistry,” also called “continuous flow chemistry” or “plug flow chemistry,” is used to describe a range of chemical reactions that occur in a continuously flowing stream as contrasted to classic static batch reactor systems. What the two have in common is the ‘reaction time’. The chemical industry has used flow chemistry systems for decades due to their speed, repeatability, inventory control and scalability. What is new is the ability to perform multiple and repeatable flow chemistry reactions on an automated platform, rapidly with very low volumes.
What Is a Continuous Flow Chemistry System?
A continuous flow chemistry systems 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 (see below), 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 are now in sight. 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:
1. 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.
2. Highly Corrosive – 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.
3. Photochemical – 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.
4. Require Extremely High or Low Temperatures – The stated range for manufacturers is from -78 to +300C which are unattainable without specialized dedicated reactor systems.
5. Require High Pressures – Pressure range is up to 300 bar (atmospheres).
6. 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.
7. Requires Exacting 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%.
8. Provides Automatic 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.)
What Are the Benefits of Flow Chemistry?
Some of the key benefits of flow chemistry are listed below:
· Combinatorial Compound Libraries: Instead of being limited by a small number of potential reagents, flow chemistry systems tailored to make libraries of compounds quickly and with the ability for the robot system to choose from tens of reagent compounds by simply filling out an experimental plan.
· Faster reactions: Flow reactors can easily be pressurized, allowing for use with solvents that can be superheated to a temperature far above their boiling point. This helps speed up reactions significantly and allows for using low boiling solvents at high temperatures.
· Cleaner Products: Flow chemistry reactors use rapid diffusion mixing, which enables excellent reaction selectivity. While batch chemistry may result in products containing unreacted reagent, flow chemistry reduces this impurity significantly through thorough mixing and reaction control.
· Greater control: The high surface area to volume ratio of a flow chemistry process reactor enables users to tightly control the conditions of the reaction, such as temperature, light exposure and other environmental factors. The issue of ‘order of addition’ for reagents goes away because batch systems enable concentration gradients in mixing vessels that are eliminated in a flow path system.
· Safer reactions: Flow chemistry uses small amounts of material at a time, meaning that hazardous intermediates are also formed in small quantities. Greater control of temperatures also makes it easier to control exothermic reactions.
· Simplified analysis: Reaction products exiting a flow reactor can easily be analyzed by flowing them into a workup system or scavenger column for analysis.
· Customizability and optimization: Flow chemistry equipment is highly modular, making it easy to configure equipment to meet the needs of specific reactions. Additionally, more advanced systems with automation can be designed to change the conditions of the flow chemistry system to improve the quality of the reaction.
· Easy scalability: Flow chemistry is able to produce large quantities of product on a continuous basis, but these systems can also easily be scaled up to produce larger quantities by using higher flow rates and larger reactors.
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.
Common Applications of Flow Chemistry
Flow chemistry has been a popular system design for decades in the chemical industry, and it has quickly gained traction in various other applications for its numerous advantages in quality, safety and cost-efficiency. For example, flow chemistry reactors for the pharmaceutical industry, fine chemicals, green chemistry, catalytic reactions and polymer chemistry have quickly gained popularity.
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 listed below:
· 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.
Flow chemistry systems are expected to continue expanding in use and versatility with time.
MICROFLU Flow Chemistry
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