Syrris webinar- an introduction to flow chemistry and its first principles

We have 3 modules to control the temperature on the Asia system:

1. • The Asia Chip Climate Controller can be used with Microreactor chips (of volumes 62.5 µL, 250 µL, or 1000 µL) and the temperature range is -15 °C to +150 °C
   • The Asia Heater comes with several adapters: a Microreactor Chip Adapter, a Tube Reactor Adapter, and a Solid Bed Column Adapter
     • • The Microreactor Chip Adapter can heat microreactors from +40 °C to +250 °C
       • The Tube Reactor Adapter can heat the tube reactors from +40 °C to +125 °C for the fluoropolymer one (PFA) or +250 °C for the stainless steel one.
       • The Solid Phase Reactor Adapter can heat the solid bed columns from +40 °C to +150 °C
   • The Asia Cryo Controller can be used with a low -temperature microreactor adaptor or a low-temperature tube reactor adaptor
     • • The Microreactor Chip Adapter can cool microreactor chips from room temperature down to -100 °C
       • The Tube Reactor Adapter can cool tube reactors down to -70 °C

The maximum pressure the Asia system can go to is 20 bar. It is possible to work with a gas/solid heterogeneous system by using a gas cylinder with a mass flow controller you’d control the gas flow rate and by using a solid bed column packed with your catalyst, scavenger, or any other solid reagents it is possible to have them react with each other.

Ideally when working under flow conditions you’d want to work with homogeneous reagents which are totally dissolved in the solvent. If this isn’t possible there are a few ways of working around this limitation. If your chemistry isn’t hydrolyzable and therefore can handle water you can add a small amount of water to help with the dissolution of your bases – this helps a lot when working with solvents that are slightly miscible with water such as DMF or MeCN.

It is helpful to know that not all batch conditions are easily converted to flow and sometimes we need to alter the original condition such as solvents, concentrations, or maybe swapping inorganic bases for organic bases etc.

A column reactor can also help as we’ve seen plenty of examples and subject with immobilized carbonate bases when he was working in the pharmaceutical industry. One method of forming this chemistry is to mix the inorganic base with an inert media (such as sand or quartz) in a packed column – this will also help reduce channeling within the reactor as the solid substrate is depleted when the reagent stream is flowing through.

As you mentioned it is not recommended to pump slurries and suspension through syringe pumps and through flow reactors as they might block the channels.

There are basically 2 ways of increasing the residence time in a flow chemistry system. You can either change the flow rate or change the reactor volume. With the Asia Flow Chemistry System, the reactor volumes can go from 62.5 µL up to 16 mL and the flow rate can be adjusted between 1 µL/min and 10 mL/min – this gives the flexibility of having residence times ranging from a couple of seconds to several hours. We’re able to achieve these ultra-slow, ultra-smooth flow rates in the Asia Syringe Pump due to the unique use syringe pumping, rather than peristaltic pumps which are known for causing cavitations.

Ideally, you’d want to maintain the reaction temperature in the resident time unit and the added extra tubing after the reactor wouldn’t be heated or cooled therefore the reaction could stop or slow down which isn’t recommended for reproducibility.

If your reaction occurs at room temperature then the reagents would start reacting at the mixing junction and continue to react along the whole fluidic pathway – in this instance adding extra tubing would absolutely increase the residence time. Usually, with reactions that occur at room temperature you would add a quenching step at the end to stop the reaction as soon as it exits the reactor.

Yes, absolutely – This is the main application for which our quartz microreactors have been developed. We are also currently developing our Asia Photochemistry module/add-on. We have quartz microreactors in volumes of 62.5 µL and 250 µL with either 2-input or 3-input.

Yes, they can absolutely be a liquid and a gas. Here’s a video showing Andrew performing gas/liquid partitions through the Asia Flow Chemistry System for the synthesis of Carboxylic Acids from Grignard Reagents using CO₂ gas.

The Back Pressure Regulator (BPR) creates the resistance to the flow, and this resistance generates the pressure in the reactor. It is the same kind of BPR technology that is used in chromatography systems. It has to be used for gas/liquid applications because if the system isn’t pressurized with a BPR then the gas pressure would simply force the liquid out of the reactor. Basically, the BPR is controlling the flow of the liquid/gas partition.

One of the many benefits flow chemistry systems offer is the ability to perform reactions at high pressures, which in turn leads to faster reactions but also opens up novel chemistries by enabling you to take reagents far beyond their usual boiling point. The “why perform your chemistry in continuous flow?” blog post goes into more detail on this.

To maintain a steady pressure/flow in the system you need a fixed back pressure that doesn’t fluctuate. To maintain the gas/liquid partition flowing through the system the gas pressure needs to be slightly higher than the system pressure, i.e. the pressure reading of the Back Pressure Regulator. If the system pressure is greater than the gas pressure then the liquid will start to flow back into the gas stream. We’d recommend having a check valve installed between the gas cylinder/gas source and the reactor. We found that a pressure difference between gas and reactor pressure of 0.5 bar is sufficient to assure a steady flow. You can also integrate a gas flow controller (for example Aalborg or Bronkhorst) after the cylinder – this will assure you to have a controlled flow of gas in the system and should help to avoid pressure fluctuation.

Yes, absolutely – it’s even recommended to pressurize your flow system when working with gas/liquid reaction otherwise the gas pressure would just force the liquid out of the reactor. You need a system pressure to counterbalance this effect. We’ve found that 0.5 bar difference between the gas pressure and the system pressure is sufficient to control the gas/liquid partition in an efficient way.

The heat transfer is constant throughout the whole microreactor or tube reactor. When we speak about heat transfer area it’s mainly about the channels where the reagents are in contact with a heating source.

The vaporization, or boiling, of one of your reaction components within the flow reaction is controlled by setting the system pressure (or back pressure) at a suitable value that is high enough to keep that boiling/vaporization component in its liquid state – this technique is also called “superheating”.

If you notice vaporization/boiling in the reactor then it is recommended to increase the back pressure, this is generally enough to stop it from occurring. However, a little caveat is when setting up a back pressure relative to the vapor pressure of your reaction mixture you need to consider all components/reagents involved in that reaction mixture.

There is a range of methods for performing in-line analytical monitoring, the most common being UV, IR, and Raman which require 3^rd-party equipment (Brucker for example).

One of the Asia Flow Chemistry System modules – the Asia Sampler and Dilutor (SAD) can also take an aliquot from the flowing stream, dilute it to a set value, and pass it to an offline analytical device such as LC/MS etc. These are mainly to monitor reaction completion. You can place these analytical tools wherever you want in the flow stream as they are easy to integrate into the stream. Monitoring material mixing can be a little bit trickier but usually, if a classic 2 or 3-Input microreactor doesn’t offer optimal mixing it is possible to upgrade to a static mixer called a “micromixer” that offers better mixing than classic “mixing by diffusion” chips.

Most flow reactors will have 2 or 3 inputs – however, it is possible to mix reagents that are inert with each other prior to entering the reactor either by using T-pieces or even before pumping them in the system. If you wish to add 5 discrete reagents you will also need 5 independent pumping channels – most pumps are equipped with 2 channels, therefore, you’d require a lot of them! There is also the possibility of creating custom microreactors with 5 inputs in case reagents can’t be pre-mixed. Contact the flow team to discuss this further if your application requires it.

By robot I believe that you are mentioning the Asia Automated Product Collector. This is a fraction collector that will automatically collect products in separate vials prior to analysis. When the Asia Automated Collector is paired with the Asia Automated Reagent Injector and the Asia Manager PC Software you basically can create libraries and/or screen for reaction conditions in a 100% automated way. You’d create a recipe on the software, start the experience, and collect the vials for analysis automatically.

Both are absolutely acceptable and would bring similar results. When pumping reagents at 2 different flow rates you just need to be careful because having flow rates that are too different isn’t ideal. Under laminar flow we’d recommend a maximum differential ratio of 1 to 10 between both flow rates – having reagent A pumped at 1 mL/min and reagent B pumped at 10 mL/min. If you need to have extremes of flow rates – more than 1 to 10 ratio – we’d recommend altering the concentrations accordingly to avoid mixing issues.

There is little difference really. In a flow chemistry reactor, mixing occurs by diffusion after the junction so the junction geometry itself doesn’t dictate any mixing behavior or rate of reaction. It’s usually a manufacturing design decision.

As is often the case with these things, the short answer is – “it depends”.

Depending on your chemistry, converting a batch process into a flow process can be a straight-forward process. for example, a homogeneous simple amine-ketone condensation or an easy Wittig Reaction can easily be mimicked in continuous flow. Some chemistries, however, can require you to re-think the entire process; it really is case by case.

The best thing when considering working under flow conditions is to design the whole synthetic pathway with the flow chemistry limitations in mind. When converting a batch process to a flow process there are a multitude of parameters to consider such as:

• • • Solubility: do you have any solids or suspension in your starting material? Do you have solids crashing out of the solution after the reaction is done?
    • Concentration
    • Residence Time (or reaction time)
    • Temperature
    • Mixing
    • Pressure

We’re planning a future webinar on “Converting Batch to Continuous Flow”, so enter your details in the form above and tick the “subscribe” box to be kept informed!

The main limitation of flow chemistry is the use of solids, suspensions, and slurries, but the main takeaway should be that you can often adapt your chemistry to avoid using these, or use them in different ways (such as using column reactors).

Solids can block the tubing or reactors when introduced, whereas suspensions and slurries will settle in the syringe pumps, therefore altering the flow rates and volumes.

It is highly recommended to use flow chemistry in a homogeneous way with soluble reagents. Another thing to consider is the formation of solids (precipitation, salts etc.) during the reaction – this can happen at the mixing stage, or at any stage where the temperature changes. There are ways to avoid this issue: for example, working with low concentration or with wider tubing. Continuous flow chemistry is a great way to synthesize metal nanoparticles that are solids so small (~10-100 µm) that they won’t block the system.

It’s also possible to use solid bed column that would contain the solid (scavenger or catalyst, for example) and the liquid stream would just flow through it – this is great to generate Grignard reagents in situ.

Something to be aware of is that continuous flow chemistry isn’t always the perfect way to do chemistry – it’s a great complementary tool to batch chemistry. Some chemistry is better suited for batch, some is better suited for continuous flow, and both techniques can be used in parallel to get the best of both worlds.

When you’re working in a continuous process you’re basically working with a sealed system. There are methods of removing by-products by continuous work up applications; for example, through membrane technology. Basically, the organic stream is mixed with an aqueous stream (can be neutral, acidic, or alkaline) to allow liquid-liquid extraction and by adjusting the correct cross-membrane pressure you’d be able to separate the organic stream from the aqueous stream again. This allows for liquid-liquid extraction to remove unwanted material from the reaction mixture. It’s also possible to use solids scavengers in packed bed column; for example, we’ve seen chemists use supported sulfuric acid to remove excess amine.

Honey has a viscosity of around 10,000 cPs and this is typically too high to be efficiently used in a flow system. You would have issues when pumping materials that are too viscous because you would generate too much back pressure and the material would just not flow through the channels.

The Syrris Asia Syringe Pump can pump up to 1,000 cPs – for example, we can pump neat sulfuric acid and polymer up to PEG400. Using a pressurized Input Store (a bottle under 1 bar of inert gas) can help pumping viscous material but anything above 1,000 cPs is a bit high for lab-scale R&D flow systems.

Most flow chemistry systems will have a level of automation available via software. Automation is a great way of speeding up processes such as reaction conditions optimization, method development, and library screening by varying parameters such as temperature, residence time, pressure, reagents etc.

It is possible to create and design recipes that will fully automate a system from the injection of reagents through to product collection.

It is also possible to integrate analytical equipment. In-line techniques such as UV, IR, and Raman can be used; even small benchtop NMR are available. It’s also possible to integrate offline analytics tools such as LC/MS; the Syrris Asia Sampler and Dilutor Module takes an aliquot from the flowing stream, dilutes it by a set factor, and sends it to the machine.

We haven’t heard of any examples so far which integrates combiflash and automated column chromatography apparatus. If done correctly flow chemistry often deliver cleaner chemistry with fewer by-products.

This is mainly experimental. You can estimate or calculate the required flow rate based on the size of your microreactor and the required residence time (reaction time). It mainly depends on scale, throughput, and actual chemical transformation kinetics.

If you don’t know how long the reaction should take to complete, you’d try a range of residence times and by analyzing the products you’d know how close to completion your transformation is, and then tweak and modify the residence time (and flow rate) accordingly.

The geometry plays a big part in the residence time distribution and is being studied by engineers across the globe. Basically, the larger the diameter of your channel the easier it is to move from a laminar flow into a turbulent flow. It doesn’t really have any impact on residence time, only on mixing properties. For more details on residence time distribution I’d suggest looking up online as there are loads of interesting articles explaining the challenges of this phenomena.

Continuous flow electrochemistry is a novel and exciting field of research and it would require a whole webinar dedicated to this application!

As you might know, Syrris developed the first flow electrochemical cell with a wide range of applications focused around red/ox transformations. The key application is late stage oxidation of drug candidates for metabolite studies. Use the form above and tick the “subscribe” box to be kept informed of future webinars, or contact us to discuss flow electrochemistry further.

It is really easy to run flow chemistry reactions under inert atmosphere as the system is ultimately sealed. First, you need to dry the whole fluidic pathway by flushing a dry solvent through it. The other challenge is to keep your feeding vessel under inert atmosphere as well.

Syrris has developed a pressurized input store that will keep the starting reagent in a bottle under 1 bar pressure of inert gas (it can be N₂ or Ar). Once the flow system has been flushed with a dry solvent and the feeding vessels are also under inert atmosphere the whole system will stay dry. We have examples of users performing air and moisture sensitive chemistry with n-BuLi, Grignard reagents or DIBAL-H reductions.