Advantages of continuous flow production - Vapourtec

The advantages of Continuous Flow Production of fine chemicals when compared to traditional Batch Chemistry are:

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Safer reactions when handling hazardous materials

The high surface area to volume ratio of flow reactors provides improved heat removal. This ensures that highly exothermic reactions can be safely controlled. Continuous Flow Production allows small amounts of hazardous intermediate to be formed at any instant and then reacted to achieve the desired (and less hazardous) product. The inventory of hazardous material being processed at any one time can be minimised in flow when compared with batch.

Safer reactions involving gas evolution

Reactions that evolve gas are much safer in flow as the maximum rate of gas evolution is limited by the rate at which the reagents are pumped. In batch reactors where all of the reactants are present at the same time, should the reaction “run away” then the rate of gas evolution can be uncontrolled possibly resulting in an explosion.

Safer reactions at high pressures

Flow reactors do not require a head space. The pressure within the reactor is controlled by a device called a back pressure regulator (BPR) and not by pressurizing the gas within the headspace as with traditional batch reactors. This eliminates the hazard associated with a volume of high-pressure compressed gas/vapour.

Reaction conditions simply not possible in batch reactors

Reaction times in Continuous Flow Production can be precisely controlled down to a few seconds or less, allowing the rapid generation of reactive intermediates to be reacted immediately in another reaction step. Multistep, telescoped reactions provide a route to complex organic transformations avoiding the steps of isolating intermediates.

Faster reactions

Flow reactors can be easily and safely pressurised (Vapourtec’s R-Series can achieve reactor pressures of 200 bar). This allows reaction temperatures well above the normal boiling point of the solvents (e.g. liquid phase reactions with ethanol at 250 °C) providing reaction rates ’s times faster than under reflux conditions.

Rapid route to scale-up

The difficulties of scaling up batch reactions are well documented. Continuous Flow Production can be scaled up much more easily, simply by running for longer or by using higher flow rates and correspondingly larger reactors. However, the requirements for mass transfer and heat transfer in the larger reactors must be considered.

Photochemical reactions in continuous flow production

Traditional batch photochemical reactors have limitations, particularly when scaling up photochemical reactions. Combining continuous flow with photochemistry provides a powerful synthetic tool for accessing reaction pathways utilising singlet and triplet states. The key benefits of continuous flow are; the products of the reactions are removed from the irradiated area, problems of photon penetration depth and mixing can be largely avoided, and reactions are safer as the volume of solvent in proximity to a hot lamp is significantly reduced.

Integration of downstream processes

Downstream processes, work-up, and analysis can be integrated into the flow process. Operations such as aqueous workup, metal scavenging columns, or ion exchange resins can be added to the flowing process. Online analytical techniques of UV, conductivity, PH, and even FTIR can be easily implemented. Offline techniques such as LC / MS can be integrated either through automated fraction collection or using a sampling valve / dilutor for approaching real-time analysis.

Reaction optimisation and reagent screening

Adding automation to Flow Chemistry provides a rapid variation of reaction conditions, and reactions can be run at small scale (with Vapourtec reactors down to 500 µl of solution). Parameters can be rapidly varied, including stoichiometry reaction time, and temperature. A solvent is used to clean the reactor between separate reactions. In this way, kinetic data can be rapidly derived. If an autosampler is added to the system then it is also possible to change reagents for each reaction in an unattended and automated manner allowing library synthesis or reagent/catalyst screening.

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9 Reasons to Perform Flow Chemistry

Flow Chemistry is everywhere. Chemistry students are studying it, chemistry professors are perfecting it and R&D labs are working with it every day.

But do you know why chemists across all industries and academia are switching to continuous flow techniques for their chemistry? They know how it works and what they can achieve from it.

You might know what Flow Chemistry is, but do you know what benefits will your lab see by performing chemistry in continuous flow?

The chemistry experts at Syrris put together 9 excellent reasons why chemists - of all sorts or industries - are moving to continuous flow chemistry:

• Faster reactions
• Safer reactions
• Faster reaction optimisation
• 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

If you’d like to get more familiar with flow chemistry before going in too deep, be sure to read our blog post about Flow Chemistry Basics & Key Elements.

Even though Flow Chemistry can bring numerous benefits, not all chemistry can be performed in continuous flow. If you are looking into flow chemistry systems, make sure you have a thorough look over every aspect of your processes.

Be sure to get in touch with our Sales Team. We would love to discuss your chemistry needs - whether it is Flow or Batch! Remember that together with our partner Syrris, we deliver over 16 years’ experience creating lab- and pilot-scale flow chemistry systems and will be happy to provide you with feasibility studies or examples of similar customers successfully using one of the systems we have available.

Reasons to Perform Flow Chemistry:

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 the 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

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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 x faster reactions (2x2x2x2x2x2x2x2x2x2 faster).

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 minimised. 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/th 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.” Tinder, T. Storz, Org. Process Res. Dev., 13, Wyeth

How does flow chemistry enable faster reaction optimisation?

One of the main reasons why chemists are switching to or investigating flow chemistry is its ability to enable much faster reaction optimisation, thereby reducing costs and saving chemists valuable time.

In a continuous flow chemistry reactor it is 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.

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.

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.

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 minimise 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

Why is scale-up easier to achieve in continuous flow chemistry?

Flow chemistry techniques are not 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 litres) in a much larger volume (e.g. 50 litres) may result in a catastrophic exothermic runaway, hence the requirement for reaction calorimetry.

With continuous flow, if you are 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 x 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.