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Flow Chemistry

Dr Claudio Battilocchio and Prof Steven V. Ley (Innovative Technology Centre, University of Cambridge, United Kingdom)


The concept of "flow chemistry" defines a very general range of chemical processes that occur in a continuous flowing stream, conventionally taking place in a reactor zone. The application of flow chemistry relies on the concept of pumping reagents using many reactors types to perform specific reactions. The most common types of reactors are plug flow reactors and column reactors, whilst for specific chemistries more sophisticated reactor designs might be needed (e.g., photoreactors, electrochemical reactors, etc).

Flow Chemistry: Set-Up, Advantages and Parameters

System set-up

Shown below is a general schematic representation for a flow chemistry set-up (see Darvas F., Dorman G., Hessel V. Flow Chemistry, Volume 1: Fundamentals).

a) Pumps: used to deliver reproducible quantities of solvents and reagents; the usual types are piston, peristaltic, syringe or gear centrifugal pumps
b) Reaction loops: used to introduce small volumes of reagents
c) T-piece: primary mixing point, where reagents streams are combined
d) Coil reactor: provides residence time for the reaction
e) Column reactor: packed with solid reagents, catalysts or scavengers
f) Back pressure regulator: controls the pressure of the system
g) Downstream unit: in-line analytics, work-up operations, etc.

Figure 1. Examples of commercially available flow systems

Advantages of flow chemistry

There are well-defined key advantages using flow technologies as compared to standard batch chemistry methods:

Parameters in flow chemistry

Beyond the aforementioned advantages, running a reaction under flow conditions requires knowledge of many reaction parameters (e.g. stoichiometry, reaction time, concept of steady state, etc).

a) Stoichiometry

Whilst under batch conditions the stoichiometry is set by the molar ratio of the reagents used, in a flow process the ratio of parameters such as flow rate and molarity is used to set the specific stoichiometry.

b) Residence time as "reaction time"

In batch mode synthesis the reaction time is determined by the time a vessel is stirred under fixed conditions, whereas the concept of reaction time in a flow process is expressed by the residence time, i.e., the time reagents spend in the reactor zone. Residence time is given by the ratio of the reactor volume and the reaction flow rate (overall flow rate).

τ = V/q
where τ is the variable corresponding to the residence time, V is the volume of the system, and q is the flow rate for the system

c) Flow rates

While in batch mode, the reaction kinetics are controlled essentially by the reagent exposure time under the specified reactions conditions, under flow conditions reactions kinetics are controlled by the flow rates of the reagents streams. The flow rates of the reagents indeed will influence the residence time of the reaction and have an impact on the outcome of the transformation.

q = dV/dt
q is usually expressed in units such as mL min-1

d) Volume vs space (steady state)

When considering a batch reaction, the reagent and product concentrations vary over the time, and mixing becomes a relevant aspect (especially when increasing the scale of the reaction) in order to reduce concentration gradients that affect the kinetics of a reaction. Under flow conditions, each portion of the reactor is defined by specific concentrations of the starting material(s) and product(s): in this sense, the reaction profile within a flow reactor can be defined within space rather than time. A very important parameter in flow chemistry is the steady state that defines a condition where all the parameters are defined and remain unchanged (steady) at a particular point in time.

e) Mixing and mass transfer

Mixing in a flow process is highly advantageous, compared to batch mode, as it is determined by diffusion within very small volumes of reagents. A high degree of mixing translates into better reaction profiles. Under flow conditions, indeed, mass transfer is considered very effective and determines the specific and enhanced kinetics observed. There are specific aspects of mixing that should be considered (e.g. axial vs. vortex mixing) and are dependent on specific fluid behaviours, namely plug or laminar flow patterns.

e) Temperature control and heat transfer

The control of temperature in flow processes can be achieved very accurately, due to the high surface area-to-volume ratio.
Accordingly, heat transfer can be very efficient although this parameter depends on the specific aforementioned aspects of the fluid behaviour. Indeed, depending on whether the flow is laminar or turbulent, heat transfer can follow different patterns.

Standard Types of Flow Reactors

a) Plug flow reactors

This type of reactor has cylindrical geometry (e.g. coil reactors). Examples of plug flow reactors can be found in the literature.
See: Org. Lett., 2015, 17, 3218-3221 (Ley et al.); Org. Biomol. Chem. 2014, 12, 3611-3615 (Kirschning et al.); Angew. Chem. Int. Ed. 2015, 54, 678-682 (Seeberger et al.); Angew. Chem. Int. Ed., 2013, 52, 11628-11631 (Buchwald et al.); Synlett 2016, 27, 159-163 (Baxendale et al.)

A specific example of the miniaturized plug flow reactor is described by the group of Prof Yoshida, who have implemented the concept of flash chemistry, whereby the transformations are run within seconds (for example, see: Angew. Chem. Int. Ed. 2015, 54, 1914-1918)

b) Column reactors

Column reactors can be packed with specific materials that can either act as catalysts or stoichiometric reagents. In either case, there are important implications for the downstream processing operations. Examples of column reactors can be found in the literature.
See: Angew. Chem. Int. Ed., 2014, 54, 263-266 (Buchwald et al.); Chem. Sci. 2015, 6, 1120-1125 (Ley et al.); Nature, 2015, 520, 329-332 (Kobayashi et al.); Nature Chemistry, 2016, DOI: 10.1038/nchem.2439 (Battilocchio et al.)

c) Gas reactors

Using gases as reagents can represent several challenges in batch mode. Scientists have realised several gas flow reactor designs that reduce the issues of dealing with gases, increasing the process efficiency and robustness under flow conditions. Examples of gas reactors can be found in the literature.
See: Org. Lett. 2010, 12, 1596-1598 (Ley et al.); Angew. Chem. Int. Ed., 2012, 51, 1706 -1709 (Seeberger et al.); Org. Lett., 2013, 15, 5590-5593 (Kappe et al.)

Particularly interesting is the case of the tube-in-tube, which was invented by the group of Prof Steven Ley (Acc. Chem. Res., 2015, 48, 349-362) and used for a myriad of gases.

d) Reactors for slurries

Reactions can form slurries and these can represent a real challenge, especially from the perspectives of micro- and meso-fluidics. Chemists have come up with a solution to overcome these issues, in order to process slurries continuously. Examples of reactors for slurries can be found in the literature.
See: Chem. Eng. Technol. 2015, 38, 259-264 (Ley et al.)

e) Photochemical flow reactors

Flow photochemical reactors have revolutionised the way chemists deal with this area of chemistry. These systems can be very easy to set up and use, and allow chemists to manage either small- or large-scale reactions without any major challenges. Examples of photochemical flow reactors can be found in the literature.
See: React. Chem. Eng., 2016, DOI: 10.1039/C5RE00037H (Baxendale et al.); React. Chem. Eng., 2016, 1, 73-81 (Noel et al); Angew. Chem. Int. Ed. 2013, 52, 1499 -1502 (Booker-Milburn et al.); Green Chem., 2013, 15, 177-180 (Poliakoff et al.)

f) Trickle bed reactors (TBRs)

Trickle bed reactors represent a powerful system to run triphasic processes under flow conditions. The fixed bed is usually packed with a catalyst (solid) and the system can be run using various gas and liquid feeds.
Examples of trickle bed reactors can be found in the literature.
See: Org. Process Res. Dev., 2014, 18, 1560-1566 (Ley et al.); ACS SusChemEng, DOI: 10.1021/acssuschemeng.6b00287 (Battilocchio et al);

Links of Interest

Flow Chemistry Equipment Suppliers
Flow Chemistry Calculation Tools

Recent Literature

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The use of titanium silicalite (TS-1) in a packed-bed microreactor and H2O2 in methanol as solvent enable the formation of various pyridine N-oxides in very good yields. This flow process is a safer, greener, and more highly efficiency process than using a batch reactor. The device was used for over 800 hours of continuous operation while while the catalyst remained active.
S. Chen, S. Yang, H. Wang, Y. Niu, Z. Zhang, B. Qian, Synthesis, 2022, 54, 3999-4004.

A continuous-flow direct azidation of various alcohols with TMSN3 is mediated by Amberlyst-15 as a recyclable catalyst. While reactions of 3-hydroxy-2-oxindoles provide azide-functionalized quaternary stereocenters, peroxyoxindole generate 2-azido-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives. Continuous-flow Cu-catalyzed click reactions and reductions with PPh3 are also reported.
A. M. Pandey, S. Mondal, B. Gnanaprakasam, J. Org. Chem., 2022, 87, 9926-9939.

A practical continuous flow reaction of readily accessible N-(tert-butylsulfinyl)-bromoimine with Grignard reagents provides various enantioenriched α-substituted piperidines in good yields and high diastereoselectivities within minutes. The reaction can be scaled-up smoothly and an efficient synthesis of a drug precursor further showcases its utility.
C. Shan, J. Xu, L. Cao, C. Liang, R. Cheng, X. Yao, M. Sun, J. Ye, Org. Lett., 2022, 24, 3205-3240.

Deprotonation of quaternary aromatic salts with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or N,N,N',N'-tetramethylquanidine (TMG) under visible light irradiation followed by ring-expansion provides mono- and polycyclic functionalized azepines in very good yields. This dearomative photochemical rearrangement uses two straightforward steps and simple starting materials.
M. J. Mailloux, G. S. Fleming, S. S. Kumta, A. B. Beeler, Org. Lett., 2021, 23, 525-529.

The generation of highly unstable chloromethylmagnesium chloride in a continuous flow reactor and a subsequent reaction with aldehydes and ketones provides chlorohydrins and epoxides in good yields within a total residence time of only 2.6 s. The outcome of the reaction can be tuned by simply using either a basic or an acidic quench.
T. von Keutz, D. Cantillo, C. O. Kappe, Org. Lett., 2020, 22, 7537-7541.

A continuous flow process converts isoxazoles into their oxazole counterparts via a photochemical transposition reaction. A series of di- and trisubstituted oxazoles were realized through this rapid and mild flow process.
C. Bracken, M. Baumann, J. Org. Chem., 2020, 85, 2607-2617.

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