Flow chemistry is the pumping of a continuous flow of dissolved reaction mixture through a reactor. The reactor can either be a fixed bed type reactor, where the reaction mixture is passed through a solid catalyst or reagent, or a tubular type reactor where the starting material, reagent, or catalyst are homogeneously dissolved in solution and pumped through a heated or cooled zone. The internal diameter of the reaction line is typically in the micron to low millimeter range. The key point to take away from this is that reactions are performed continuously, so only a small part of the reaction mixture undergoes a reaction at any one time. Performing chemistry this way leads to a number of advantages over standard batch processes.
The larger volume the batch the reactor the more difficult it is to achieve homogeneous mixing as the below figure illustrates.
Reference: John Goodell presentation in Flow Chemistry
The low volumes of flow chemistry reactors coupled with precise control of reaction mixture flow means accurate and reproducible mixing via diffusion can be achieved over only a few cms.
This leads to an increase in reproducibility for the reaction.
Improved mixing can also lead to improved reaction times, especially when utilizing fixed bed reactors.
In a fixed bed reactor the reaction mixture is pushed through the solid reagent or catalyst. The ratio of the catalyst/reagent compared to the reaction mixture is much higher. The reaction mixture travels through the channels created by the solid particles and interacts continuously as it passes down the length of the reactor. The reaction mixture can’t help, but interact with the solid catalyst/reagent. This can lead to increased reaction rates of several orders of magnitude. If you compare this to a batch reaction, the solid catalyst is stoichiometrically low in comparison to the rest of the reaction mixture, so adsorption of all the material onto the catalyst surface will take longer. The H-Cube series all utilize fixed bed reactors to drastically improve reaction times.
In flow chemistry reactors, the surface area to volume ratio is much higher than in normal batch reactors. This has two consequences. Heat can either be removed more efficiently or heat can be put into the reaction mixture very rapidly.
Putting heat in quickly
If the solvent has a dipole moment, then Microwave technology is the fastest way of heating up a solvent in a batch reaction, especially when compared to an oil bath heating method. The improved surface area to volume ratio of flow chemistry reactors means that flow chemistry reactors are also able to mimic microwave’s rapid heat transfer, where reaction mixtures are heated up to the set temperature in only a few seconds. This has led to flow chemistry reactors being utilized for microwave reaction scale up. The added advantage of flow reactors is that solvents without dipole moments may be used.
Heat transfer comparison experiment for flow chemistry reactor, microwave, or oil bath.
High temperature and pressure capabilities
Flow chemistry reactors often adopt HPLC parts. HPLC is another form of flow chemistry, but for separation. Back pressure regulators, where a valve creates a resistance against the flow of reaction mixture, can generate high pressures. At ThalesNano, we utilize these back pressure reactors to generate pressures over 100 bar. When combined with rapid heat transfer, this means we can heat up low boiling point solvents to way past their boiling point. The high temperature is limited by the pressure applied and decomposition of the solvent. This method allows the user to avoid having to use high boiling point solvents, which are either more expensive or more difficult to remove.
With our Phoenix Flow Reactor™, we can achieve reaction parameters up to 450°C and 100 bar. We utilized this to great effect when we used THF at temperatures over 300°C in the synthesis of bicyclic heterocycles, see figure below. The application of high temperatures and pressures is particularly useful when applied to endothermic reactions and reactions which have long reaction times.
Heat out: Making high energy reactions safer
The low reaction mixture volume coupled with a high surface area to volume ratio also means that any heat generated during the reaction can be removed very rapidly giving a greater degree of reaction control in flow chemistry compared to batch, as demonstrated in the lithium bromide exchange example below.
Highly exothermic reactions, such as lithiation, nitration, or ozonolysis may now be safer to perform in flow chemistry compared to batch. This greater degree of control also means that reaction temperatures need not be performed so low. It is often seen that chemists will apply a standard low temperature of -78°C in order to take into account any exotherm generated during a reaction. With flow chemistry the higher degree of reaction temperature means that the same reactions may be performed at 0°C or room temperature. ThalesNano’s new IceCube system is specifically designed to take advantage of this and allow highly energetic reactions to be performed safer.
Multistep synthesis in flow chemistry, where the elution of product of one reactor is directly mixed with through another reagent and passed through another reactor to perform another reaction, is a highly useful synthesis method, but also one of the most difficult to master. Apart from the obvious time savings of performing 2 or more reactions in one flow there are also other advantages. Compounds, such as azides, which may decompose explosively when formed may be immediately reacted using flow to form a more stable product.
Ref: Yoshida, Flash Chemistry: Fast Organic Synthesis in Microsystems, 2008 John Wiley & Sons, Ltd
The compound need not be isolated and is only generated in small quantities continuously for added safety. The main difficulty in multi-step synthesis lies in maintaining a common solvent mixture in all steps where the starting materials, reagents, and products are all soluble. Purification between steps may also increase the difficulty, but Prof. Steve Ley and his group at the University of Cambridge have become masters at multistep synthesis and have routinely demonstrated the use of inline scavengers to aid purification between steps.
ThalesNano’s new IceCube system is specifically designed to perform the multistep synthesis, including the formation of potentially explosive materials and react them immediately in a different reactor zone to render them safe.
Another advantage of flow chemistry is that the time of the reaction mixture in the reaction zone (residence time) can be very precisely controlled. This is very useful when dealing with reactions that can generate 2 or more products. The residence time may be extended or shortened by adjusting the flow rate until the optimum selectivity has been achieved. Such a precise control is not possible in batch. We have combined residence time control and catalyst screening to obtain high selectivities. An example is given below.