Just Keep Flowing

Just Keep Flowing

By Nour Tanbouza (twitter @Nour_Tanbouza), PhD student, Laval University

Flow chemistry is a synthetic technique that enables chemical reactions to take place in a continuously flowing manner as opposed to running a reaction in a flask, sometimes termed batch chemistry. It has become incredibly mainstream and has been adopted by many chemical industries as a means to increase efficiency of large-scale reactions in highly controlled setups.1 What is flow chemistry, and why is it important? Furthermore, the main question, how does it contribute to sustainability?

Let us start by putting on a lab coat and safety goggles and strolling through a modern synthetic chemistry lab. Now, have a look around. What you will absolutely recognize and remember is a vast space of fume hoods and benches with different apparatus lying around like round bottom flasks, chromatography columns, stirrers, hot plates, etc. After that, take a browse through images of those same types of laboratories from the 1900s or even from the 1700s. Surely you will notice some improved safety features but what will strike you the most is how similar they are in terms of the equipment used then and now. We indeed currently have better stirring and heating equipment etc., but we still do reactions in round bottom flasks as batches.

Figure 1. on the left: 18th century laboratory used by Antoine Lavoisier (credits Sandstein / CC BY (https://creativecommons.org/licenses/by/3.0)); on the right: Modern synthetic chemistry laboratory ( credits Elrond / CC BY-SA (https://creativecommons.org/licenses/by-sa/4.0)

In 2005, the catastrophic T2 laboratories explosion occurred after a thermal runaway and high-pressure build-up of their 2,500-gallon batch reactor producing MMT (methylcyclopentadienyl manganese tricarbonyl).2 These types of accidents pose a huge risk to human life and the environment in addition to the legal and financial troubles that the company could face. Thus, there is an exigent need for safe and practical technologies that enable an efficient scale up of chemical reactions. These pursuits explain the recent uptake of flow chemistry by many manufacturing companies, especially those in the pharmaceutical industry.

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Figure 2. Aerial view of T2 Laboratories explosion

Flow chemistry can be thought of as a bench chemist’s very own cherry tree. The raw material is fed into the roots (pumps). Roots are the heart of the tree, and the same holds for the pumps of a flow system, so it is pivotal that they are well taken care of and are in perfect shape. Those nice healthy roots then flow the raw material over a large surface area up into the stems and leaves where reaction conditions are highly controlled and in perfect balance to elute the desired product continuously. Thus, whether targeting a few milligrams or multi-kilograms of product, it is dependent on how much feed material is flowed into the reactor. A flow reactor can be as small as a chip and still produce the needed amount of product. In 2019, flow chemistry was announced by the IUPAC (International Union of Pure and Applied Chemistry) as one of the ten chemical innovations that will change our world.3 There has been a significant paradigm shift by many industries, especially the pharmaceutical industry, to adopt flow chemistry. It is a technology that promises on-demand drug production, which is vital primarily for developing countries to access drugs in a decentralized manner.1

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Figure 3. An academic flow system (equipped with a photoreactor)

Green chemistry principles and a chemical industry’s agenda align when it comes to large scale reactions. Thus, it is not so surprising to see a significant uptake of flow chemistry by many companies. This kind of endorsement has helped spark research in continuous flow which is beginning to become a dominating area of study. Among the UN Sustainability Goals is responsibility for consumption and production, which is achieved in flow because it minimizes the amount of material needed for screening and allows reactions to take place in highly concentrated media. Reaction conditions being highly controlled (such as temperatures, pressure, mixing, etc.), allow reactions to be more selective and thus decreases any by-products and increases productivity.4 Also, hazardous chemicals can be safely manipulated in flow because there is no significant build-up at any given time. It is very versatile and modular where multiple reactions can be installed in sequence to consume any reactive intermediates in situ, and purification systems can be added directly as well. A reaction can be run at extremely high temperatures that go above boiling points which can enable reactions to proceed faster while being inherently safer and consuming significantly less energy when compared to a batch reactor.

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Figure 4. Illustration of a flow chemistry setup

This type of “thinking outside the flask” means stepping outside of a long-standing comfort zone which is not always trivial. However, this type of venture and side-by-side work of engineers and chemists is what made flow chemistry possible, and it is changing our world. Flow chemistry is still in its early stages, yet so much innovation has already been introduced. Give it a few years, and when you walk back into that synthetic chemistry lab, prepare to be flabbergasted by a space that resembles nothing of the past.

 

References:

  1. Malet-Sanz, L.; Susanne, F., Continuous flow synthesis. A pharma perspective. J. Med. Chem. 2012, 55, 4062-4098.
  2. http://www.csb.gov/UserFiles/file/T2%20Final%20Report.pdf
  3. Gomollón-Bel, F., Ten Chemical Innovations That Will Change Our World. Chemistry International 2019.
  4. Jensen, K. F.; Rogers, L., Continuous manufacturing – the Green Chemistry promise? Green Chemistry 2019, 21, 3481-3498.

Green Chemistry: From the Bench Top to Industry, A Chemical Engineer’s Perspective

By Cynthia Cheung, Member-at-Large for the GCI

As a chemist, do you ever think about how to scale up your chemical reactions, or your chemical processes? For most of us, the answer is no. However, this idea of industrial scale is something that is constantly addressed in the Chemical Engineering and Applied Chemistry department. Consequently, the 12 Principles of Green Chemistry become fundamental to scale up a reaction from the bench top in a research lab to mass production in a chemical plant (Figure 1).

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Figure 1. Example of a chemical plant design [1]

For me, the biggest difference I have found moving from the Chemistry department to the Chemical Engineering department is that the principles of Green Chemistry are not concepts that Chemical Engineers often have to think about or address, because these principles are integrated and engrained into their work as objectives and limitations. A process can be thrown out simply because it uses columns for purification (which cannot be done on a large scale, because you would need truckloads of solvent) or because one of the reagents is toxic.

As a chemist, we do what works and worry about alternatives after we have established what we targeted. So pause and think about it for a second: can you continue what you’re doing and upscale it from milligrams to tonnes? Even theoretically speaking, if you could produce that much product, would that process make sense? For example, would that Stille coupling reaction be safe when you’re using tonnes of tin2, or could you afford to be using or making catalysts when you need tens of kilograms of it? So how to do you go about engineering your process so that it would be suitable for industry? Rather, how do the engineers do it?! Well, broadly speaking (and from asking around) a few of the main considerations that seem to be in common are:

Cost Analysis

How much are all of the reagents and solvents going to cost, and where are there substitutes for cheaper alternatives?

Rate of Reaction

How long is this reaction going to take? Because time is money.

Waste

How much waste is produced, what type of waste and is it recyclable? Also to keep in mind is if the waste is hazardous, then what alternatives can be used from the beginning to avoid any hazardous waste generation? In addition, if there’s pollution, then that also has to be reduced or eliminated altogether.

Work up

This consideration is often tricky, as most organic labs usually use techniques that are not scalable (I’m looking at those purification columns). In addition to that, side products and by-products are also something that often can give engineers a headache. Atom economy is very important for industry, as it lessens the amount of waste produced, and also aids in producing a good product yield.

Energy Consumption

How much energy is required for a reactor and for a chemical plant to run is also part of the cost analysis for a process. It would definitely be preferential to be using less energy (so lower temperature reaction conditions and reactions that generate no heat). Essentially, if all reactions could be at room temperature, that would be perfect.

So with these considerations in mind, could you re-engineer your synthesis?

 

References:

[1] http://en.citizendium.org/wiki/File:FCC.png

[2] Stille, J. Palladium Catalyzed Coupling Of Organotin Reagents With Organic Electrophiles. Pure and Applied Chemistry 1985, 57.