Flow advantages

With respect to batch reactions, CF-processes offer significant improvements in mixing and heat management, scalability, energy efficiency, waste generation, safety, access to a wider range of reaction conditions and unique opportunities in heterogeneous catalysis, multistep synthesis, and more.¹⁵²

Efficient Mixing and Heat Transfer. Both micro- and meso- reactors possess a high surface to volume ratio, which allows for a more efficient heat absorption compared to any batch

1.4 If Sustainability is the goal, Green Chemistry will show the way!

| 51 reactor. Moreover, the high quality and precision of the mixing regime is achieved over a short distance (a few cm).

Figure 1.25 shows the profiles of the heating and mixing distribution for the model exothermic neutralisation reaction between HCl and NaOH are described.¹⁵³ In a batch reactor the exothermic reaction brings about a strong temperature gradient, since the cooling takes place only at the surface of the reactor (Figure 1.25, left, top). A much flatter gradient – almost at the detection limit – is noted for a microreactor (Figure 1.25, left, bottom). A similar behaviour is also observed for the reagent mixing.

Figure 1.25. Exothermic neutralisation reaction of HCl with NaOH: heath distribution in a batch reactor (top-left) and in a microreactor (top-right); mixing efficiency in a batch reactor (bottom-(top-left) and in a microreactor

(bottom-right ).¹⁵³

Reaction efficiency and product intensification.

The atmospheric boiling point of solvents and reagents often limits the batch reaction conditions. By contrast, flow reactors allow for the safe manipulation of both the pressure and the temperature far beyond atmospheric conditions, resulting in improved energy, time, and space efficiency.¹⁵⁴ The use of smaller reactor volumes in flow also reduces the risks associated with reactor failure and facilitates reactor containment. Moreover, although more energy may be required to reach elevated temperatures, the CF-system is well suited to insulation to prevent heat loss, and to the recycling of the energy given off from exothermic reactions.

These aspects greatly contribute to improve the efficiency on a commercial scale.¹⁵⁵

In batch reactors, rapid and exothermic reactions are tricky and the corresponding quenching operations are scale dependent.¹⁵⁶ As mentioned above, the effective heat transfer of flow

Microreactor Batch reactor

Heat transfer

Reagent mixing

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reactors allows for the reactions to be run at higher concentrations than in batch systems with a major benefit in term of product intensification. The material production may often increase by a factor of 200-250 at identical reactor volumes.

Handling of poorly stable intermediates.

Flow chemistry techniques allow for an easier manipulation of unstable intermediates without the loss of yields and side-reaction runaways. A model example is the Moffat-Swern CF-oxidation of alcohols carried out in a MR (Scheme 1.18).¹⁵⁷

Scheme 1.18. Moffat-Swern alcohols oxidation (top); undesired Pummerer rearrangements (bottom).¹⁵⁷

This flow reaction operates with a short residence time, which ensures a double advantage: i) the minimisation of undesired side-reactions such as Pummerer rearrangements (Scheme 1.18, bottom). Unstable sulfonium intermediates proceed straight to the target ketone; ii) the use of remarkably higher temperatures (0-20 °C) in comparison to the batch reactions that require cryogenic temperatures (-70 °C). In this case, the MR provides a narrow temperature profiles (closer to the ideal one) limiting the access to multiple reaction pathways.¹⁵⁸

Heterogeneous catalysis and recycling. In a continuous process, the (heterogeneous) catalyst is usually confined inside the reactor, while the reagent mixture is allowed to flow over it. This is the best configuration to combine reaction and product separation in a single step and, at the same time, to reactivate and recycle the catalyst. Moreover, the decreased exposure of the catalyst to the environment may improve its lifetime.¹⁵⁹

Telescoping multistep reactions. The synthesis of fine chemicals sometimes requires multistep sequences involving extractions, additions of several agents (quenching, drying etc.), filtration, evaporation, purification, distillation and/or recrystallization. These procedures require significant input of energy and materials that ultimately results in the production of large

1.4 If Sustainability is the goal, Green Chemistry will show the way!

| 53 amounts of waste. Continuous processing is particularly suitable for ‘telescoping’ reaction sequences by integrating several operations into one (or a few) continuous process.¹⁶⁰

Scale-up.

Continuous techniques allow for the scale-up of reactions from grams to kilograms, without variations in yields, purities or safety. This can be achieved in three different ways (Figure 1.26): i) by using a single flow reactor for an extended time; ii) with multichannel parallel reactors (numbering-up process), or iii) with a larger flow reactor by which an increase of the total flow rate is allowed.

Figure 1.26. The reaction scale-up under flow conditions: three possible configurations.

Continuous processing has demonstrated a great flexibility for both laboratory and pilot-plant scale-up of pharmaceuticals and fine chemicals.¹⁶¹ Particularly, the MR approach has proved efficient for the scale-up of chemical reactions.¹⁶² Probably one of the most important features that distinguishes a continuous flow apparatus from a batch reactor is that the amount of product generated is determined by the length of time the entire flow regime is operated. In batch reactors, on the other hand, the maximum quantity of product produced per reaction is predetermined by the amount of starting material.

Albeit higher initial investments are required, the MR plant saves scaling efforts, requires fewer operating personnel, increases yields and reduces (moderately) the consumption of solvent. In addition, since MR-based technologies operate with very small volumes, they minimise safety concerns when performing dangerous reactions involving explosive or toxic reagents.¹⁶³

CF-systems have also been applied in combination with renewable reagents for the setup of greener synthesis, as well as in the upgrading of bio-based derivatives. In a first example, the CF-synthesis of cyclic organic carbonates from epoxides and CO2, has been considered (Figure

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1.27). Compared to previously reported batch reactions,¹⁶⁴ the CF-protocol afforded the same yields of desired products, but using much milder reaction conditions (120 °C, 6.9 bar).¹⁶⁵

Figure 1.27. (a) Synthesis of cyclic carbonates from epoxides and carbon dioxide in flow. (b) Representative batch reactor synthesis of cyclic carbonates from epoxides and carbon dioxide.¹⁶⁶

CF-systems were also explored for the conversion of glycerol and its derivatives by a number of reactions including deoxydehydrations,¹⁶⁷ hydrogenolysis,¹⁶⁸ acetalysations,¹⁶⁹ carbonations and transesterifications.^170,171 Several biomass reforming CF-processes, involving different feedstocks, were also developed.¹⁷²

In the present PhD Thesis, CF-reactions have been successfully carried out for the implementation of both the etherification of some OH-bearing platform molecules and the synthesis of symmetric organic carbonates. The results will be described in Chapters 2–3.