This thematic issue demonstrates the development of flow chemistry from a prerogative of the petrochemical industry to a technology of enormous value for chemical synthesis and a key for sustainable manufacturing. Transformations viewed impracticable under batch conditions can be enabled by the precise reaction control of flow reactors: photochemical applications, handling of reactive intermediates or reactive reagents, and new heating concepts now allow for accelerated synthesis while only a small volume of the reaction mixture inside the flow reactor is exposed to extreme conditions. Technological advances, including miniaturization and automation, have rendered continuous flow processes an enabling technology for organic synthesis.
Graphical Abstract
Scheme 1: Radical chain mechanism for a photo-induced C–H chlorination reaction.
Figure 1: Components for photoflow setup: (a) MiChS LX-1 reactor and (b) MiChS LED-s (365 ± 5 nm, 60–600 W).
Scheme 2: Model reaction: photoflow C–H chlorination of ethylene carbonate (1) to chloroethylene carbonate (2...
Figure 2: Photoflow setup for the C–H chlorination of ethylene carbonate (1).
Graphical Abstract
Scheme 1: Methods for accessing 1,3,4-oxadiazoles.
Scheme 2: Synthesis of acyl hydrazones 1a–j.
Scheme 3: Iodine-mediated cyclisation of hydrazones 1a–j yielding oxadiazoles 2a–j. Reaction conditions: 1a–j...
Scheme 4: Synthesis of complex oxadiazoles.
Scheme 5: Continuous flow scale-up reaction with in-line quench and extraction.
Scheme 6: Continuous flow setup equipped with in-line extraction and purification.
Graphical Abstract
Figure 1: Reaction sequence starting from GlcNAc with ManNAc as an intermediate. Pyr is added in the second s...
Figure 2: Enzyme loading after immobilization of the epimerase and aldolase on different carriers.
Figure 3: Evaluation of immobilized epimerase on different carriers with respect to specific activity. Reacti...
Figure 4: Evaluation of immobilized aldolase on different carriers with respect to specific activity. Reactio...
Figure 5: Relative activities in repetitive batch experiments of the immobilized epimerase on polymethacrylat...
Figure 6: Relative activities in repetitive batch experiments of the immobilized aldolase on amino methacryla...
Figure 7: Recycling study of immobilized epimerase and aldolase. Assay conditions: 100 mM Tris, pH 8, 40 °C, ...
Figure 8: Measured reaction rates of the immobilized epimerase. The dashed line is the fit according to the M...
Figure 9: Measured reaction rate of the immobilized epimerase as a function of pyruvate and pressure. Dashed ...
Figure 10: Measured reaction rate (left) and the determined inhibition constant by pyruvate (right) at differe...
Figure 11: Measured kinetics of the aldolase when varying the pyruvate and ManNAc concentration (given in mM) ...
Figure 12: Circular reactor, vessel mixing was achieved with a magnetic stirrer and samples were taken directl...
Figure 13: Aldolase: Change of the equilibrium constant at different pressures. Starting concentrations were v...
Figure 14: Progress curve of the circular reactor with both reactions at varying pressures. Starting condition...
Figure 15: Residence time distributions of the stand-alone system and the reactor integrated into the system. ...
Figure 16: Reactor set-up (left to right): UHPLC pump, heated fixed-bed reactor, capillaries (ID: 25 µm or 50 ...
Graphical Abstract
Scheme 1: Synthesis of cyclochexene oxide via epoxidation with air in the presence of isobutyraldehyde.
Figure 1: Epoxidation of cyclohexene with air bubbling in batch at various temperature.
Figure 2: Schematic diagram (a) and photo (b) of the flow reactor used for cyclohexene epoxidation with air. ...
Figure 3: Investigation of reaction temperature in flow epoxidation of cyclohexene at residence time of 0.35 ...
Figure 4: Investigation of residence time in flow epoxidation of cyclohexene at 100 °C.
Scheme 2: Plausible reaction pathway of the epoxidation of cyclohexene with air in the flow system.
Figure 5: Continuous production of cyclohexene oxide.
Figure 6: Effect of concentration of cyclohexene and eqivalent of aldehyde.
Graphical Abstract
Figure 1: Inductive heating, a powerful tool in industry and the Life Sciences.
Figure 2: Electric displacement field of a ferromagnetic and superparamagnetic material.
Figure 3: Temperature profiles of reactors heated conventionally and by RF heating (Figure 3 redrawn from [24]).
Scheme 1: Continuous flow synthesis of isopulegol (2) from citronellal (1).
Scheme 2: Dry (reaction 1) and steam (reaction 2) methane reforming.
Scheme 3: Calcination and RF heating.
Scheme 4: The continuously operated “Sabatier” process.
Scheme 5: Biofuel production from biomass using inductive heating for pyrolysis.
Scheme 6: Water electrolysis using an inductively heated electrolysis cell.
Scheme 7: Dimroth rearrangement (reaction 1) and three-component reaction (reaction 2) to propargyl amines 8 ...
Figure 4: A. Flow reactor filled with magnetic nanostructured particles (MagSilicaTM) and packed bed reactor ...
Scheme 8: Claisen rearrangement in flow: A. comparison between conventional heating (external oil bath), micr...
Scheme 9: Continuous flow reactions and comparison with batch reaction (oil bath). A. Pd-catalyzed transfer h...
Scheme 10: Continuous flow reactions and comparison with batch reaction (oil bath). A. pericyclic reactions an...
Scheme 11: Reactions under flow conditions using inductively heated fixed-bed materials serving as stoichiomet...
Scheme 12: Reactions under flow conditions using inductively heated fixed-bed materials serving as catalysts: ...
Scheme 13: Two step flow protocol for the preparation of 1,1'-diarylalkanes 77 from ketones and aldehydes 74, ...
Scheme 14: O-Alkylation, the last step in the multistep flow synthesis of Iloperidone (80) accompanied with a ...
Scheme 15: Continuous two-step flow process consisting of Grignard reaction followed by water elimination bein...
Scheme 16: Inductively heated continuous flow protocol for the synthesis of Iso E Super (88) [91,92].
Scheme 17: Three-step continuous flow synthesis of macrocycles 89 and 90 with musk-like olfactoric properties.
Graphical Abstract
Figure 1: The olfactory spectrum wheel ordering different types of odorants from fruity to musky.
Figure 2: Classification of odorants as “top note”, “middle note” and “base note” depending on their substant...
Scheme 1: Synthesis of raspberry ketone (5) and raspberry ketone methyl ether (6) in two steps in flow.
Scheme 2: Autoxidation of (+)-valencene (7) to (+)-nootkatone (8) under catalyst and solvent-free conditions ...
Scheme 3: Enzyme-catalyzed acetylation of isoamyl alcohol (9) in a biphasic n-heptane/water mixture utilizing...
Scheme 4: Esterification of alcohols by transesterification, catalyzed by immobilized acyltransferase in a pa...
Scheme 5: Synthesis of homologated alcohols 20 by iterative homologation of terpenyl boronate esters 17 follo...
Scheme 6: Sequential three-step synthesis of (S)-α-phellandrene (30) from (R)-carvone (25) via selective hydr...
Scheme 7: Selective hydrogenation of alkyne 31 to “leaf alcohol” 32 employing a solid-supported palladium cat...
Scheme 8: A) Synthesis of jasmonal (35) by crossed aldol condensation of benzaldehyde (33) and heptanal (34) ...
Scheme 9: Synthesis of thymol (41) from m-cresol (39) and isopropyl alcohol via Fries-type rearrangement of e...
Scheme 10: Preparation of coumarin (46) by reaction of salicylaldehyde (44) with potassium acetate, acetic aci...
Scheme 11: Synthesis of phthalide (50) by photoinduced decatungstate catalysis.
Scheme 12: Synthesis of woody acetate (54) by reduction of cyclohexanone 51 and subsequent acetylation; ADH200...
Scheme 13: Synthesis of juniper lactone (56) by pyrolysis of triperoxide 55 generated by oxidation of cyclohex...
Scheme 14: Synthesis of macrocyclic olefine 60 by ring-closing metathesis of diene 58 in a continuously stirre...
Scheme 15: Synthesis of macrocycles 65 and 66 by ring-closing metathesis of dienes 62 or 63, respectively, in ...
Scheme 16: Z-Selective synthesis of civetone (69) enabled by metathesis catalyst 68 in a tube-in-tube reactor.
Scheme 17: Synthesis of macrocyclic olefine 72 by ring-closing metathesis of diene 70.
Graphical Abstract
Scheme 1: Baeyer–Mills reaction of AB (1a) involving nucleophilic attack of aniline (2a) to nitrosobenzene (3...
Figure 1: Flow setup for optimization of the Baeyer–Mills reaction with aniline (2a) and nitrosobenzene (3). ...
Figure 2: Optimization of the Baeyer–Mills reaction of nitrosobenzene (3) with aniline (2a) to AB (1a). The n...
Figure 3: Flow setup after prior optimization with unsubstituted aniline (2a) and nitrosobenzene (3) to AB (1a...
Scheme 2: Large-scale synthesis of AB 1t from aniline 2t and nitrosobenzene (3) in >99% yield within 3 days.
Graphical Abstract
Figure 1: Different approaches to heterogeneous photochemistry in flow. a) Serial micro-batch reactors (SMBR)...
Figure 2: Light-mediated carbon–heteroatom cross-couplings. The yields reported are the NMR yields obtained i...
Figure 3: Flow diagram of the experimental setup loaded in an injection loop with the reaction mixture.
Figure 4: Flow diagram of the experimental setup adopted and time necessary to obtain steady-state conditions...
Figure 5: The production campaign of 1 for a seven day experiment.
Figure 6: Photo of the packed column with a helical static mixer (polished SS316, 10 cm length, 15 mixing ele...
Scheme 1: C–O coupling between 4-iodobenzotrifluoride and N-(Boc)-proline.