This is Part #2 in The Flow Chemistry Collection, a regularly-updated round-up of the best content on flow chemistry, including blog posts and commentary from thought-leaders on a number of flow chemistry topics. Be sure to subscribe to be kept in the loop on future updates.
Andrew Mansfield Head of Flow Chemistry, Syrris
Minute read
This is Part #2 in The Flow Chemistry Collection, a regularly-updated round-up of the best content on flow chemistry, including blog posts and commentary from thought-leaders on a number of flow chemistry topics. Be sure to subscribe to be kept in the loop on future updates.
Minute read
Why perform your chemistry in continuous flow?
By Andrew Mansfield on May 15th, 2018 in Flow chemistry, Scale-up, The Flow Chemistry Collection
What benefits will your lab see by performing chemistry in continuous flow?
In brief, the main reasons chemists in various industries are switching to continuous flow chemistry techniques are; (click on a benefit to go straight to it)
- Faster reactions
- Safer reactions
- Faster reaction optimization
- Fast serial library synthesis
- Reaction conditions not possible in batch
- Reactions are usually more selective
- Scale up is easier in flow than batch
- Easy integration of reaction analysis
- Reactions are easier to work-up in flow
But you’re a scientist and we don’t expect you to take our word for it – after all, we might be a little biased given that we developed the R&D100 Award-winning Syrris Asia Flow Chemistry system in 2012 – so continue reading to find detailed explanations, examples, and publications to support the claims.
If you’re not familiar with how flow chemistry works then it’s worth reading our “what is flow chemistry?” blog post before this post.
A little caveat here, though: not all chemistry can be performed in continuous flow. If you’re looking into flow chemistry systems, make sure you have a thorough discussion with the provider to go over every aspect of your process and see if they can run feasibility studies or provide examples of similar customers successfully using that product.
A not-so-subtle plug for us – we’ve got over 16 years’ experience creating lab- and pilot-scale flow chemistry systems and would love to discuss your batch and flow chemistry needs.
How does flow chemistry achieve faster reactions?
The increase in reaction rate possible in flow largely result from the ability to achieve higher temperatures.
It is much easier to pressurize flow chemistry systems than batch chemistry systems, and higher pressures enable higher temperatures; according to the Arrhenius equation, higher temperatures result in faster reaction rates.
The table below demonstrates the boiling points of dichloromethane, methanol, and water at a variety of pressures. Flow chemistry systems, such as Syrris Asia, can pressurize to 20 bar, enabling an increase in the boiling point of solvents by 100-150 °C
| Solvent | 1 bar | 7 bar | 17 bar |
|---|---|---|---|
| Dichloromethane | 41 °C | 109 °C | 153 °C |
| Methanol | 65 °C | 138 °C | 185 °C |
| Water | 100 °C | 181 °C | 231 °C |
The Arrhenius rate law tells us that reactions are 2 x faster for every 10 °C rise, therefore a 100 °C rise would result in 1000 x faster reactions (2x2x2x2x2x2x2x2x2x2 faster).
An example of superheating in continuous flow (Tibotec, Johnson & Johnson (Belgium))
In this example, Tibotec and Johnson & Johnson were experiencing incomplete nucleophilic aromatic substitution reactions using batch chemistry techniques despite one week of reflux; the yield of the reaction was poor. By switching to flow chemistry techniques, the researchers were able to superheat the THF up to 140 ºC, achieving 100% conversion for a variety of substrates at 140 ºC with a 1-hour residence time. (Reaction time, reaction temperature, and equivalent of reagents were varied for each of the two reactions).
How does flow chemistry enable safer reactions?
The safer reactions capable in flow are made possible because the quantity of reaction occurring at any one time is minimized. Reactions in continuous flow occur as small amounts of liquids are mixed through glass chips, whereas in a batch chemistry reactor, the entire reactor contents are mixed at once.
As an example, if a 10 L batch reactor were to explode, the consequences could be incredibly serious, or fatal. The same 10 L of reagents could be passed through a 10 mL flow microreactor chip, ensuring that only 10 mL is reacting at any time. A fast batch reaction – e.g. a one-minute reaction in a batch reactor – can be achieved with an overnight run in a flow system. In this example, the risk in continuous flow is 1/1000th of the risk in batch.
“Continuous-flow reactions have the potential to be much safer than batch reactions, as only a small amount of reactive and potentially hazardous material is heated or converted to product at any given time.”
An example of safer triazole synthesis in continuous flow
- Hazard: azide compound. Use in medium and large scale is prohibited
- β-azidoethyl phenyl sulfide: bp =65ºC, TSU showed exotherm at 155ºC
In this example by Wyeth, triazole was synthesized in a safer way using continuous flow techniques compared to using batch chemistry techniques.
- Previous methods for the batch synthesis of the above triazole suffer from low yields, regioisomers and significant safety hazards due to the use of ethyl azide, an explosive reagent
- Researchers employed β-azidoethyl phenyl sulphide as an ethyl azide surrogate, as it showed much improved thermal stability under reaction conditions
- Running the reaction in flow further improves safety by limiting the amount of azide formed/reacting at any one time, and offers significant improvements in yield
An excerpt taken from the publication states that “continuous-flow reactions have the potential to be much safer than batch reactions, as only a small amount of reactive and potentially hazardous material is heated or converted to product at any given time.”
How does flow chemistry enable faster reaction optimization?
One of the main reasons chemists are switching to or investigating flow chemistry is its ability to enable much faster reaction optimization, thereby reducing costs and saving chemists valuable time.
In a continuous flow chemistry reactor is it extremely easy to vary;
- The reaction time, by varying the total flow rate
- The reaction temperature, due to low thermal mass
- The ratio of reagents, by varying the flow rate ratio of reagents being pumped
- The concentration, by varying the solvent stream
In continuous flow, one reaction is flushed out by the next – separated by a solvent – therefore only one continuous flow chemical reactor is needed.
In the lab, chemists can investigate 50-100 reaction conditions with just 15 minutes set-up time.
An example of rapid optimization of thiazole synthesis at the Burnham Institute
Researchers at Sanford-Burnham Medical Research Institute (SBMRI) optimized a Hantzsch thiazole synthesis and subsequent deketalisation in one step, using a Syrris AFRICA® synthesis station (now replaced by the Syrris Asia Flow Chemistry System).
By varying residence time, reaction temperature, and water equivalent, optimum reaction conditions for the Hantzsch thiazole synthesis were identified in 9 experiments in a total experiment time of just 37.5 minutes.
Read the full, free-to-access publication (N. Pagano, N. D. P. Cosford, J. Flow Chem. 2011) here.
What is library synthesis, and how does continuous flow achieve it more efficiently than using traditional batch techniques?
Library synthesis (or high-throughput chemistry) describes the synthesis of many analogous compounds for the purposes of testing. Library synthesis is a crucial technique for rapidly exploring the chemical space of a molecule, allowing for the quick identification of lead compounds and is especially useful in drug discovery and development chemistry.
Traditionally, library synthesis is performed using traditional batch methods in multiple small flasks and vials, such as the Atlas Orbit system. However, modern sophisticated flow chemistry systems enable fast, serial library synthesis and purification of 10s – 100s of compounds a day with total automation of liquid handling through the use of automated reagent addition and product collection modules.
An example of multistep continuous flow synthesis of 5-(Thiazol-2-yl)-3,4-Dihydropyrimidin-2(1H)-ones
Researchers at Sanford-Burnham Medical Research Institute (SBMRI) optimized the multistep continuous flow synthesis of 5-(Thiazol-2-yl)-3,4-Dihydropyrimidin-2(1H)-ones using a Syrris AFRICA® synthesis station (now replaced by the Syrris Asia Flow Chemistry System).
The researchers discovered that consecutive Hantzsch thiazole synthesis, deketalization, and Biginelli multicomponent reactions provide rapid and efficient access to highly functionalized and pharmacologically significant 5-(thiazol-2-yl)-3,4-dihydropyrimidin-2(1H)-ones without isolation of intermediates. These complex small molecules are generated in reaction times of under 15 minutes and in high yields of 39–46%, over three continuous chemical steps.
- Sequential thiazole formation-multicomponent to synthesize DHPMs
- Rapid reaction optimization of each step
- In-situ generation of HBr deprotects the ketone and promotes the multicomponent reaction
- Yields shown are isolated yields over entire flow sequence
- Rapid multistep synthesis of a variety of complex, drug like compounds
How does continuous flow chemistry achieve reaction conditions not possible in traditional batch methods?
Flow chemistry techniques enable chemists to access novel chemistries not previously possible with traditional batch chemistry methods. The two main reasons for this are;
- Mixing happens by diffusion. Diffusional mixing is much, much faster and more reliable than using traditional batch chemistry methods
- Reactors are pre-heated and pre-cooled, meaning the reaction can change temperature almost instantly (compared to a batch reactor where the entire reactor contents must heat up or cool down gradually
- Heat up and cool down times are much faster than a microwave, therefore ultra hot, ultra-fast reactions are easily possible
As an example, chemists can deprotonate a substrate at low temperature then add a nucleophile and instantly heat to a high temperature.
Using a Syrris Asia Flow Chemistry system, drug discovery researchers at innovative pharmaceutical company, Gedeon Richter, have been able to create new heterocyclic scaffolds – chemistry that was impossible to them before adopting flow chemistry techniques.
“The system has extended the range of chemistries available to us, allowing us to work at much higher pressures and temperatures – sometimes above a solvent’s boiling point – to create completely new heterocyclic scaffolds.”
How can continuous flow reactions be more selective than in traditional batch reactions?
Poor selectivity in chemistry stems from variations in temperature, concentration, and addition/stirring rates. Advanced batch reactor systems, such as the automated Atlas HD jacketed reactor system, automate the chemical steps, helping to minimize these variations, but for finer control and selectivity, continuous flow chemistry systems are the answer.
Due to a high surface area:volume ratio and diffusional mixing, flow chemistry systems enable much better selectivity, through;
- Excellent temperature control. Reactions are flowed through pre-heated and pre-cooled reactors, ensuring the entire reaction is performed at the required temperature (compared to jacketed reactors where there may be variation throughout the vessel)
- Minimal concentration gradient
“In the case of a hazardous reaction, the risk of an incident is minimized as the accumulation of potentially dangerous intermediates is avoided.”
An example of a highly selective, cleaner reaction in continuous flow
Researchers at AstraZeneca reported the facile, fast, and safe process development of nitration and bromination reactions using a Syrris continuous flow reactor. Their paper describes how the potentially hazardous reactions were efficiently performed using continuous flow techniques, and advocates that the advantages of continuous flow chemistry in organic synthetic chemistry will be exemplified by the large-scale production of raw materials under safe, green, and reproducible conditions.
“In the case of a hazardous reaction, the risk of an incident is minimized as the accumulation of potentially dangerous intermediates is avoided.”
Facile, Fast and Safe Process Development of Nitration and Bromination Reactions Using Continuous Flow Reactors
Jacques Pelleter and Fabrice Renaud
Organic Process Research & Development 2009 13 (4), 698-705
DOI: 10.1021/op8002695
An example of better control in continuous flow chemistry
To demonstrate the improved reaction control flow chemistry can offer, Syrris chemists performed the reaction of CaCl₂ and Na₂CO₃ to synthesize CaCO3 in traditional batch and continuous flow. The chemists used exactly the same concentration, temperature, and reaction/residence time across both experiments. The following microscopic images show the results.
Reaction of CaCl₂ and Na₂CO₃ to synthesize CaCO₃ in traditional batch
Reaction of CaCl₂ and Na₂CO₃ to synthesize CaCO₃ in continuous flow
The images show the quality and reproducibility of the reaction is clearly much higher in continuous flow than traditional batch.
Why is scale-up easier to achieve in continuous flow chemistry?
Flow chemistry techniques aren’t confined to lab scale as the principles are easily scaled-up and avoid some of the common issues encountered when scaling up in batch reactors.
Traditionally, scaling up from lab scale can be difficult and risky. Performing a reaction that is safe at lab scale (e.g. 5 liters) in a much larger volume (e.g. 50 liters) may result in a catastrophic exothermic runaway, hence the requirement for reaction calorimetry.
With continuous flow, if you’re looking for 10-100x scale up, it is possible to simply flow the reaction for a longer time to make more product, i.e. you could fill a small cup or a large bath from the same time, over different timescales.
For 1000x scale-up, the fundamental principles of a higher surface area to volume ratio means that scaling up in flow will reduce the heat transfer effect, and the ability to use static mixers means that mixing is faster and more reproducible. Overall, continuous flow chemistry can save time and money when scaling up reactions.
An example of Scale-up of nucleophilic substitution in continuous flow
- 16ml Tube Reactor
- Flow rates, 2.5 mL/min per input – Residence time: 3.2 min
- Reaction at 150 ºC c.f. atm bp of dioaxane 100 ºC
- Produces 50g of product
How does continuous flow chemistry enable easier reaction analysis?
In traditional batch chemistry, analyzing multiple reactions can require multiple probes (one per reactor). In continuous flow chemistry, however, many different reactions can flow “under” the same probe, with the reaction automatically moving to the analytical system because it is flowing.
Intelligent flow chemistry systems can include sampling and diluting modules which automatically divert a tiny amount of each reaction for analysis.
What do sampling and diluting modules do?
Sampling and diluting modules – such as the Sampler and Dilutor (SaD) module for the Syrris Asia Flow Chemistry system – automatically divert a tiny amount of each reaction for analysis.
The Syrris Sampler and Dilutor does the following;
- Takes a 5 µL sample from the flowing stream, dilutes it (from x5 to x250), and injects it onto a chromatography system
- The dilution is important to avoid full-scale deflection issues with the chromatography detector
- It can be operated from the front panel of the SaD module or controlled from the PC (using Asia Manager PC Software)
- It can be set up to take a sample from the middle of the reaction (for optimization experiments) or at defined intervals (as quality control in a production run)
- It can interface with virtually any modern HPLC/UPLC/LCMS
How does the Sampler and Dilutor module work?
- The reaction continuously flows through the 20 bar valve loop and on to the collector
- When the middle of the reaction sample is in the loop, the 20bar valve switches to take the loop out of the main flow
- The transfer syringe pushes the 5ul sample out of the 20bar valve loop and into a T-piece. Simultaneously, a dilution solvent is pumped by the dilution syringe into the other side of the T-piece
- As the middle of the diluted sample flows into the HPLC valve, the valve switches to inject the sample into the chromatographic system (while simultaneously sending a “start” signal to the HPLC)
Why is reaction work-up easier in flow?
Traditional batch chemistry relies on a separate operation to perform a work-up, e.g. aqueous work-up, filtration, or solid phase scavenging. In continuous flow chemistry, the reaction is already mobile, enabling in-line (integrated) work-up of liquid-liquid extraction and solid phase reagents/scavengers/filtration.
Solid phase reagents/scavengers/filtration
Syrris makes difficult aqueous work-ups possible for Eindhoven University of Technology with the Asia flow chemistry FLLEX liquid-liquid extraction module
The unique Asia FLLEX (Flow Liquid Liquid EXtraction) module helping is researchers in the Netherlands perform liquid-liquid copper extractions in flow. The Eindhoven University of Technology in the Netherlands is taking advantage of the Asia FLLEX system’s excellent separation performance, as Assistant Professor Dr. Timothy Noël explained:
“We employed the Asia FLLEX module as a copper extraction device in a recently published application. The system’s flexibility to connect to our existing microflow apparatus was key to the success of the project, and we already have several more applications in the pipeline.”
An example of multistep synthesis and work-up of oxomaritidine
- Researchers at the University of Cambridge have reported the multistep synthesis of oxomaritidine using the Syrris AFRICA® synthesis station (now replaced by the Syrris Asia Flow Chemistry System). A mix of homogeneous and heterogeneous reactions (including gas phase), with synthesis, evaporation and workup all under flow conditions, providing oxomaritidine in good yield (40%) Read the full publication here.
An example of 3-Hydroxymethylindoles synthesis and work-up
Shea et al. demonstrated an automated sequential approach for the generation and reactions of 3‐hydroxymethylindoles in continuous‐flow microreactors. The synthetic flow strategy could be coupled with an in line continuous liquid–liquid extraction workup protocol for each reaction. Further elaboration of each of these indoles within the fluidic setup was achieved by acid‐catalysed nucleophilic substitutions with allyltrimethylsilane and methanol used as nucleophiles. Overall, a set of four 3‐iodoindoles was converted into thirty‐six indole derivatives by a range of transformations including iodo–magnesium exchange/electrophile trapping and acid‐catalysed nucleophilic substitution in a fully automated sequential fashion.
“Our current goal is to develop automated, sequentially performed homogeneous reactions with in-line continuous liquid–liquid extraction of the products”
3-Hydroxymethylindoles synthesis by O’Shea et al.
Tricotet, T. and O’Shea, D. (2010), Automated Generation and Reactions of 3‐Hydroxymethylindoles in Continuous‐Flow Microreactors. Chemistry – A European Journal, 16: 6678-6686. DOI:10.1002/chem.200903284
Why perform your chemistry in continuous flow: Conclusion
If you’ve read this far then you’ve discovered the 9 main reasons chemists are switching to continuous flow processes for their chemistry and you’re probably curious as to how it could benefit your lab.
It’s worth bearing in mind that you can introduce continuous flow chemistry into your existing methods to get the best of batch and flow. Speak to us to discuss how your particular chemistry may benefit from
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Asia Flow Chemistry System
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Speak to the Syrris chemistry team
So there you have it; 9 substantial reasons to consider performing your lab’s chemistry using continuous flow chemistry techniques.
Each application is different, so discuss your specific chemistry with a member of the Syrris chemistry team to see if continuous flow is the right choice for your lab.
About Dr. Andrew Mansfield
Andrew was formerly a Research Chemist at Pfizer and spent much of his career focusing on introducing flow chemistry technologies, meaning Andrew is well placed to lead Syrris’ flow chemistry offering. Read Andrew’s bio here.
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