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7 Things to Keep in Mind When Adopting Flow Chemistry

Flow Chemistry is the process of performing chemical reactions in a tube or pipe, where two or more streams of different reactants are pumped together at a mixing junction and flowed down through a temperature-controlled pipe or tube. In this continuous process, the product leaves the reactor as a continuous stream and reagents are pumped into the flow reactor where they mix and react.

The chemical industry has been using Flow Chemistry for decades, and the pharmaceutical and fine chemical industries are recently adopting this technology. The inherent increased safety, improved product quality, cost efficiency, and overall production flexibility are drivers for the growing use of continuous flow chemistry. 

One of the biggest challenges chemists face when adopting flow chemistry is the length of time to convert a batch process into a seamless flow set-up. We outline below 7 points to consider before converting your batch process into a continuous flow.

1. What is your application and is it suitable for continuous flow?

There are several publications from chemists using continuous flow techniques to perform various chemical reactions. In summary, if it is possible to be done using traditional chemistry, it can often also be accomplished using flow chemistry.

While many chemists are performing their entire process in continuous flow, it is important to note that some reactions may benefit from a combination of continuous flow chemistry and traditional batch techniques. This combined approach may offer the best of both worlds, enabling you to perform specific portions of a reaction pathway in flow, rather than the entire process. Commonly, synthesis to and from intermediates are used in batch processes downstream. In continuous flow, some applications that might seem inaccessible can be performed reliably, such as:

Reactions reliant on heterogeneous solid-liquid phase chemistry

As part of “flow” chemistry, the use of solids does not seem an obvious option, but several works have been done using packed bed columns and flowing reagents over a packed bed solid catalyst/substrate. It is important to note that many chemists can eliminate the need for solids in their chemistry because of the advantages of flow chemistry when adapting it to continuous flow.

Reactions using extremely sensitive or dangerous reagents

Compared with conventional ways of dosing hazardous reagents into the entire contents of a round-bottomed flask or jacketed reactor, the nature of flow chemistry means that hazardous and intermediate reagents are by far more accessible using small volume reactors that restrict danger.

2. What would you like to achieve using continuous flow chemistry?

Product synthesis

It is possible to synthesize product(s) anywhere from small scale, to pilot, or manufacturing scale quantities in continuous flow.

If you imagine flow chemistry as a tap, when you turn it on you can fill a cup, but if you leave it running, you can fill up a bath. Although the necessary equipment will vary when you move up or down each scale, the idea remains the same, as the manufacturing-scale synthesis will involve pumps that can manage very high flow rates to produce more product in less time.

As the quantity of reagents reacting at any one time in batch reaction is smaller than in flow chemistry, there is a common misconception that continuous flow chemistry is slower. In fact, the increased pressures and temperatures flow can substantially reduce the time required for each reaction, allowing much faster reaction optimization.

Reaction optimization

Optimising batch chemistry reactions can be time-consuming, often involving many vials/round-bottomed flasks/jacketed reactors, each with changes in the reaction conditions. In continuous flow, you use automated liquid handling modules along with automation software, to automatically run 10s-100s of reactions on one system.

Inline sample analysis

You can analyse a sample immediately after producing, to ensure you are creating the right product. It is only possible as continuous flow systems offer the capability to perform inline sample collection, dilution, and injection directly into your preferred online analysis method.

3. Don’t reinvent the wheel: read relevant papers that are related to the chemistry you would like to perform

It is likely that similar chemistry (whether it’s direct application, methodology, or both) has already been performed, thanks to the vast library of papers now available using flow chemistry across a wide range of applications. Browse as much literature as you can and use this knowledge to improve the initial idea and design of your experiment going forward.

4. Design your initial experiment

The main components of a flow chemistry reactor system are flow chemistry pumps, pressure, the reactor(s), and some form of manual or automated collection. Each parameter of your chemistry that requires precise control is paramount in considering which components you will need to add to this, and ultimately, the final design. View a full list of the available flow chemistry systems here. The various reaction parameters (and the technology that enables them) are explained below:

Pumping and flow rates

You need to find out what flow rates your chemistry requires to obtain the residence times. The Asia Flow Chemistry Syringe Pump offers highly accurate flow rates from 1 μL to 10 mL/min, enabling both extremely long and extremely fast residence and times.

The nature of the pump also plays a role. At ultra-slow and rapid flow rates, syringe pumps have substantially smoother flow and no cavitation compared, for example, to peristaltic pumps.

Temperature

The temperature must also be taken into account. What temperature extremes do you need to achieve? Is one heating/cooling module going to be adequate, or do you need multiples for your different chemistries? Most commercial lab-scale flow chemistry systems offer various heating/cooling modules and the ability to heat/cool different types of reactors, depending on your needs. We recommend chemists to use Syrris Asia Flow Chemistry System. Asia is a modular range of flow chemistry systems from Syrris, suitable for regular or advanced configurations, that can be manually controlled or fully automated.

Residence time (reaction time) and type of chemistry

How long does your chemistry need to fully react? Glass microreactors offer very high temperatures but relatively short residence times, whereas tube reactors offer much longer residence times but usually lower temperatures (unless stainless steel is used). Column reactors enable the use of solid phase catalysts in your chemistry if required.

Pressure

Operating at pressure allows much higher solvent boiling points, enabling quicker reactions and opening new chemistry spaces. You need to consider what pressure your chemistry requires, and whether you will be working with gases, air, and moisture sensitive reagents etc.

The Asia Pressure Controller enables you to pressurize the system up to 20 bar. The Pressurized Input Store enables the use of air and moisture sensitive reagents but also assists in delivering an extremely smooth flow by minimizing input cavitation and gas bubble formation during pumping at high flow rates.

Inline work-up

Many continuous flow chemistry systems allow in-line work-up and analytics to be used. For example, the Asia FLLEX (Flow Liquid-Liquid EXtraction) Separator Module is the flow chemistry equivalent of a separatory funnel. Operating continuously, this aqueous workup/extraction module initially mixes the organic product stream with an aqueous phase, then allows time for diffusion to occur before finally splitting the flow back to its constituent parts. It also enables two-phase mixtures to be isolated, which would be extremely difficult using conventional methods.

The Asia Sampler and Dilutor (SAD) Module permits on-line reaction analysis by offering automated sample extraction, dilution, and transfer to virtually any LCMS, GCMS, UPLC, etc without stopping the experiment.

5. Perform your first experiments

Once you’ve decided which components you need for your chemistry, it’s time to build your system by setting up each of your separate components and connect them using tubes, and then you’re ready to go.

As all scientists are aware, perfect results are unlikely to be achieved after your very first experiment. Here are a few tips that can help you to make your initial experiments smoother and avoid early frustration:

Prime your flow system and ensure you avoid leaks!

Leaks lead to the loss of solvents or precious reagents, reducing the system pressure and introducing air/contaminants. Each of these are counterproductive to the smooth running of any flow system.

Run initial experiments at low concentrations

For first-time continuous flow chemists, the efficacy of reactions may be shocking. Blockages can occur inside the reactor if your product is susceptible to crashing out of solution. Clearing a blockage isn’t particularly difficult but can be frustrating, so is best avoided. It is possible to increase concentration during optimization, and it is recommended starting too low than too high.

Avoid using the most extreme parameters immediately

Now that you have an exciting new set-up available, it is tempting to test the maximum performance of your system straight away. You may come out with less than ideal results, but it is good to become comfortable with the processes that occur and ensure that reactions are safe.

6. Change your experiments to help optimize your reaction

After finishing your initial experiments, if you notice the yield of your product is not as high as you would like, it is time to begin the optimisation stage where variables such as concentrations, temperatures, pressures, residence times can be adjusted. All parameters will have an effect, so based on the initial chemistry and your system’s capabilities you can decide which are the best to change. Many flow chemists choose to change one parameter at a time to analyse the effect of each.

Using Design of Experiment (DoE) software allows you to create a matrix of experiments which can alter specific parameters automatically and allow easier observation into the effect of each change.

7. Develop experience, gain confidence (and maybe even get published!)

From the initial stages, you’ll quickly gain experience and confidence in:

• Setting up flow experiments
• Expected results versus the actual results
• Optimizing experiments to help achieve their aims

With time and experience comes confidence, and with confidence comes great chemistry (and with great chemistry comes the chance to be published!).