Flow Chemistry – Fundamentals

Ferenc Darvas, György Dormán, Volker Hessel, Steven V. Ley, Ferenc Darvas, György Dormán, Volker Hessel, Steven V. Ley

• Publisher: De Gruyter
• Year: 2021
• ISBN:
  9783110693775
• Edition: 2
• Topic: Technology & Engineering
• Subtopic: Chemical & Biochemical Engineering
• Index: Technology & Engineering

The fully up-dated edition of the two-volume work covers both the theoretical foundation as well as the practical aspects. Presenting the complete insight into driving a chemical reaction provides a deep understanding for new potential technologies. Updated overview on devices and new key concepts of experimental procedures.

Vol. 2: Applications.

1 Fundamentals of flow chemistry

Ferenc Darvas

György Dormán

Objective of this chapter

This chapter intends to summarize all the important basic theoretical features of flow chemistry and flow reactors. A detailed discussion of particular topics can be found in the following chapters.

1.1 General theory of flow chemistry

1.1.1 Basic features of continuous-flow operation

The typical operation sequence of traditional flask (batch) reaction in laboratory practice is shown in Fig. 1.1 [1].

Fig. 1.1: Typical batch laboratory setup (adapted from Baxendale, I. R. (2013) The integration of flow reactors into synthetic organic chemistry. J Chem Technol Biotechnol, 88, 519–552).

The typical arrangement of continuous-flow apparatus containing reagent pumps, mixing units (T-mixer), reaction zone, quenching inlet, backpressure regulator, and product collection vessel is shown in Fig. 1.2.

Fig. 1.2: Typical setup for flow reactions (based on Ley, S. V., & Baxendale, I. R. (2009). New tools for molecule makers: emerging technologies. Eds. M. Hicks and C. Kettner. Proc. Beilstein Symp. on Systems Chemistry, Bozen, pp. 65–85. and Gutmann, B., Cantillo, D., & Kappe, C. O. (2015). Continuous‐flow technology – a tool for the safe manufacturing of active pharmaceutical ingredients. Angew Chem Int Ed, 54(23), 6688–6728).

Chemical synthesis in the traditional laboratory has been carried out in standardized glassware, and this has not been changed over a century [2]. There are significant differences between batch and flow processes in terms of the important measures of the reactions. In batch reaction, time is determined by how long a reaction vessel is held at a given temperature. In contrast, in continuous processes, the residence time, which refers to how long the reactants stay in the reactor zone, is determined by the reactor volume and the bulk flow rate (Fig. 1.3, Fig. 1.4).

Stoichiometry in flow reactors is defined by the concentration of reagents and the ratio of their flow rate. Flow rate is the volume of fluid that passes through a given channel per unit time (Tab. 1.1).

In batch processes, this is defined by the concentration of chemical reagents, and the ratio of their molar quantities.

Fig. 1.3: Mixing A and B reagents under flow conditions (Plutschack, M. B., Pieber, B., Gilmore, K., & Seeberger, P. H. (2017). The hitchhiker’s guide to flow chemistry, Chem Rev, 117(18), 11,796–11,893).

Tab. 1.1:Comparison of the major reaction characteristics in batch and flow.

	Batch	Flow
Stoichiometry	Concentration/ratio of the molar quantities	Concentration/ratio of the flow rates
Reaction time	Time spent under the defined condition	Residence time spent in the reaction zone, depending on the flow rate and reaction volume
Reaction progress	Time spent in the flask	Distance traveled in the channel
Steady-state characteristics	It has a uniform concentration at each position within the flask at a particular moment	It has a steady but different concentration at each position throughout the length of the reactor

If a single flow rate (v1 or v2) is altered but all other parameters stay constant, it leads to changes in stoichiometry, final concentration, and residence time.

Stoichiometry can be set by the flow rates and the concentration of the reagent streams.

(For further details on this issue, please see Volume 1, Chapter 4, Title: Practical aspects of performing continuous flow Chemistry; and Chapter 5, Title: When and how to start flow chemistry?)

Fig. 1.4: Calculation of the residence time and its relationship with flow rate and the length of the reactor (S is the cross section, L is the length, and V is the flow rate).

The concentration of the reactant decays exponentially with time in the flask reactor [3], according to the rate law:

$\begin{array}{rl}& \mathrm{R}\mathrm{a}\mathrm{t}\mathrm{e}=\frac{-d\left[\mathbf{A}\right]}{dt}=k\left[\mathbf{A}\right]\\ & \mathrm{R}\mathrm{a}\mathrm{t}\mathrm{e}=\frac{-d\left[\mathbf{A}\right]}{dt}=k\left[\mathbf{A}\right]\left[\mathbf{B}\right]\mathrm{o}\mathrm{r}\mathrm{R}\mathrm{a}\mathrm{t}\mathrm{e}=\frac{-d\left[\mathbf{A}\right]}{dt}=k{\left[\mathbf{A}\right]}^2\end{array}$

The reaction rate is proportional to the decrease in concentration of the reactant (A) in time t, and k is the rate constant for the particular reaction (first-order reaction). The rate of a second-order reaction is proportional to the concentration of two reactants, or to the square of the concentration of one.

Fig. 1.5: Reactant concentration versus time (flask reactor) or distance (flow reactor) for a simple first-order reaction, under well-mixed homogeneous conditions (adapted from Valera, F. E., Quaranta, M., Moran, A., Blacker, J., Armstrong, A., Cabral, J. T., & Blackmond, D. G. (2010). The flow is the thing … or is it? Assessing the merits of homogeneous reactions in flask and flow, Angew Chem Int Ed, 49, 2–10; and Lummiss, J. A., Morse, P. D., Beingessner, R. L., & Jamison, T. F. (2017). Towards more efficient, greener syntheses through flow chemistry, Chem Rec, 17(7), 667–680).

In a microfluidic device with a constant flow rate, the concentration of the reactant decays exponentially with dist...