1.2.1 Diffusion, Mixing and Mass Transfer
The extent of mixing within a reactor influences the conversion and selectivity of reactions. The flow pattern of fluids can be defined by the Reynolds number (Re), and calculated according to [Eq (7)], where ρ = density, ν = velocity, D = diameter and μ = viscosity. For example, flow in a tube can be characterised as laminar (Re <
2000), transitional (2000 < Re < 3000) and turbulent (Re > 3000).8 Turbulent flow has chaotic changes in flow velocity which creates effective mixing between the fluid layers. In contrast, laminar flow has a constant flow velocity resulting in no disruption between the parallel fluid layers. Therefore, mixing in the laminar regime is dependent on the rate of diffusion. Laboratory-scale flow reactors generally operate under the laminar regime due to a combination of low flow rates and small dimensions. Segregated mixing regimes are observed in conventional batch reactors, where turbulent regimes occur in close proximity to the stirrer and laminar regimes occur towards the walls of the vessel.9 As tubular flow reactors inherently have a higher surface area to volume ratio compared to batch reactors, the rate of diffusion, and therefore the rate of mixing, is significantly higher.
𝑅𝑒 = 𝜌𝜈𝐷
𝜇 (7)
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For reactions with consecutive steps, the Damköhler number (Da) can be used to describe reaction selectivity. The Damköhler number defines the ratio of the rate of reaction to rate of diffusion [Eq (8)], where k = rate constant, C0 = initial concentration, n = order of reaction, dt = diameter of tube and D = diffusion coefficient. Therefore, if Da < 1, greater than 95% homogeneity is achieved before the reaction takes place. However, if Da > 1, the reaction is diffusion limited resulting in the formation of concentration gradients.10
𝐷𝑎 = 𝑘𝐶0𝑛−1𝑑𝑡2
4𝐷 (8)
Consider a reaction with a competitive consecutive side-reaction (S1 + S2 → P1 and P1 + S2 → P2). When Da > 1, S1 and S2 react before the reaction mixture is fully homogeneous. This results in a localised concentration of P1 forming, which can react with S2 to form significant amounts of P2 (Figure 6). This is a phenomenon known as ‘mixing-disguised selectivity’.11 Flow reactors can be used to eliminate these concentration gradients due to their enhanced mixing properties, making them well suited for very fast reactions.12
Figure 6. Graphical representation of a reaction with a competitive consecutive side-reaction where Da > 1: (a) reactants S1 and S2 prior to mixing; (b) incomplete mixing of reactants S1 and S2 before the reaction starts; (c) localised concentration of desired product P1; (d) S2 reacts with P1 to form significant amounts of P2.
Many chemical reactions involve a combination of multiple phases (gas, liquid and solid), particularly in industry where high concentrations are utilised to reduce the use of solvents. In these systems, efficient mixing is crucial to maximise the
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interfacial area between the phases and ensure a high rate of mass transfer. Hence, flow reactors generally perform better than batch reactors for multiphasic reactions. One of the major challenges for performing flow chemistry in microreactors is processing solids which can clog the channels. To circumvent this, solid reagents can be encapsulated in a column to create a packed-bed reactor. This enables heterogeneous catalysed reactions to be conducted in flow, and removes the need to separate the catalyst downstream.13 However, the reagents often require immobilisation on solid supports to prevent leaching, and the precipitation of solid by-products still remains problematic.
For gas-liquid and liquid-liquid reactions, slug flow is most commonly observed in microfluidic reactors (Figure 7). Slug flow is achieved by mixing in a tee-piece, which creates a build-up of pressure behind one of the perpendicular phases, resulting in droplet formation.14 The transverse interfaces between the slugs provide a high surface area to volume ratio, and therefore an enhanced rate of mass transfer. Furthermore, formation of a thin film of gas along the walls of the tube creates Taylor recirculation patterns in the liquid phase. This increases the rate of mass transfer by minimising the concentration gradients within the slugs.15
Taylor recirculation gas-liquid biphasic conditions.
1.2.2 Enhanced Heat Transfer
Flow reactors have superior heat transfer compared to batch reactors due to a higher surface area to volume ratio. This provides rapid dissipation of heat generated during exothermic reactions, enabling: better temperature control, safer scale-up and a reduced use of energy intensive cryogenic conditions.16 Furthermore,
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reaction selectivity is increased by preventing side-reactions or decomposition of thermally unstable products from occurring. Given this, flow reactors have been utilised for aromatic nitration reactions owing to a strong exotherm and tendency for poor regioselectivity.17 For example, the nitration of 2-isopropoxybenzaldehyde 1.1 with fuming HNO3 to form 1.2 was investigated (Scheme 1). On kilogram scale in batch, the heat evolved from the reaction resulted in a poor regioselectivity (1.2:1.3, 40:60) and isolated yield (30%). Optimisation of this procedure in a microreactor gave an improved regioselectivity (1.2:1.3, 87:13) and yield (65%), as the enhanced heat transfer prevented the formation of a significant temperature gradient within the reactor.18
Scheme 1. Nitration of 2-isopropoxybenzaldehyde 1.1 to form desired regioisomer 1.2 and undesired by-product 1.3. The flow process compared favourably to batch, with a higher regioselectivity and isolated yield, due to rapid dissipation of the exotherm.
1.2.3 Greater Control of Reaction Conditions
The residence time defines the length of time a molecule spends within a reactor. For flow reactors, the residence time can be precisely controlled by adjusting the length of the reactor and the flow rates. This, coupled with better control over mixing and temperature, enables chemical reactions that cannot be achieved in batch.19, 20 These properties have contributed towards the drive in ideal synthesis by offering protecting-group-free synthesis. For example, it was shown that organolithium transformations could be achieved on ketone bearing aromatics using a microreactor, mitigating the need for wasteful protection and deprotection steps (Scheme 2).21 Initially, in situ generated o-pentanoyl-substituted phenyllithium 1.5 was trapped using methanol as an electrophile. At a 3 s residence time, only a 30% yield of 1.6 was achieved due to undesired dimerisation of 1.5 to
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give 1.7 in 70% yield. A reduction in residence time to 0.003 s resolved the reactions and afforded 1.6 in a 90% yield. Hence, the high-resolution reaction time control offered by flow reactors enables transformations that better align with sustainable chemistry.
Scheme 2. Lithiation of aryl iodide 1.4 with MesLi yielding o-pentanoyl-substituted phenyllithium 1.5, followed by quenching with methanol to produce protonated product 1.6. Dimerisation of 1.5 forms undesired by-product 1.7.
1.2.4 High T/p Reactors and Safer Use of Hazardous Reagents
Increasing the temperature of a reaction increases the rate of reaction, as defined by the Arrhenius equation. Therefore, in cases where selectivity is not reduced at higher temperatures, the simplest and cheapest way to increase productivity is to increase the reaction temperature.22 However, batch reactions are often limited to the boiling point of the solvent, as high-pressure batch reactors in manufacturing are large and expensive. In contrast, the pressure and temperature of continuous flow reactors can be safely manipulated above atmospheric conditions. This often results in a reduction in reaction time and reactor size, thereby offering significant benefits in terms of process intensification.23
A key consideration during process development is the safety of the reagents used and/or intermediates generated during a reaction. Under continuous flow operation, only small amounts of the chemical species are exposed to the reaction conditions at any given time. This mitigates the risks linked with the accumulation of hazardous intermediates, and enables hazardous reagents to be used in
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combination with high-temperature/high-pressure conditions.24 For example, the use of a silicon carbide microreactor allowed the development of a rapid Wolff-Kishner reduction (Scheme 3a).25 The use of flow conditions removed the risks associated with build-up of explosive hydrazine gas in the headspace of the reactor. Similarly, explosive hydrazoic acid gas was generated in situ to achieve a 100% atom economical synthesis of tetrazoles (Scheme 3b).26 Furthermore, the use of high T/p conditions reduced the reaction time from 24 h in batch to 10 min in flow.27
Scheme 3. Examples of processes benefitting from high T/p conditions and improved safety in flow: (a) Wolff-Kishner reduction using hydrazine; (b) synthesis of tetrazoles using NaN3 generated in situ.