The automation of chemical synthesis with the resulting savings in time and materials and reduction in the use of environmentally harmful chemicals has been the goal of many academic and industrial chemists for a long time. Over recent years the application of flow devices in laboratories has been gaining acceptance with increased sophistication in their control and ease of use. The advantages that flow devices bring are many, for example: easier scale up, better and precise control of reaction conditions, better mixing, easier handling of unstable intermediates, in-system purification. An important field of research is the optimization and adaptation of known reactions and reaction sequences for use in flow systems. Continuous-flow processes can be further improved by techniques that use immobilized reagents or catalysts, or by using fixed bed reactors in parallel. These developments in flow techniques using mini and micro flow reactors have initiated changes that will pave the way for a technological step forward in chemical synthesis.
See also the Thematic Series:
Chemistry in flow systems III
Chemistry in flow systems II
See videos about flow chemistry at Beilstein TV.
Graphical Abstract
Scheme 1: Sequential introduction of two electrophiles onto dibromobiaryls using Br-Li exchange reactions.
Scheme 2: Br-Li exchange reaction of 2,2′-dibromobiphenyl (1) with n-BuLi using a conventional macrobatch rea...
Figure 1: Microflow system for Br-Li exchange reaction of 2,2′-dibromobiphenyl (1). T-shaped micromixer: M1 (...
Figure 2: Effect of temperature and residence time in Br-Li exchange reaction of 2,2′-dibromobiphenyl (1) usi...
Figure 3: A microflow system for sequential introduction of two electrophiles. T-shaped micromixer: M1 (ø = 2...
Scheme 3: Br-Li exchange reaction of 4,4′-dibromobiphenyl (17) with n-BuLi using a conventional macrobatch re...
Figure 4: Microflow system for Br-Li exchange reaction of 4,4′-dibromobiphenyl (17). T-shaped micromixer: M1 ...
Figure 5: Effect of temperature and residence time in Br-Li exchange reaction of 4,4′-dibromobiphenyl (17) us...
Graphical Abstract
Scheme 1: Preparation of azide-modified AO resin 2.
Scheme 2: Preparation of AO-TEMPO 6.
Figure 1: The simplified microreactor setup. Empty tubing (A) is packed with functionalized AO resin and atta...
Figure 2: The organic (colored solution) and aqueous phases (colorless solution) forming plugs at the Y-junct...
Scheme 3: The AO-TEMPO-catalyzed oxidation of benzyl alcohol.
Figure 3: The long-term activity of AO-TEMPO packed beds in the oxidation of 4-chlorobenzyl alcohol. A soluti...
Graphical Abstract
Scheme 1: Enantioselective addition of trimethylsilyl cyanide to benzaldehyde.
Scheme 2: Asymmetric catalytic hydrogenation in a falling-film microreactor.
Scheme 3: Aldol reaction catalyzed by 5-(pyrrolidine-2-yl)tetrazole.
Scheme 4: Enantioselective addition of diethylzinc to aryl aldehydes.
Scheme 5: Glyoxylate-ene reaction in flow.
Scheme 6: Asymmetric synthesis of ß-lactams.
Scheme 7: α-Chlorination of acid chlorides in flow.
Scheme 8: Asymmetric Michael reaction in continuous flow.
Scheme 9: Enantioselective addition of Et2Zn to benzaldehyde using monolithic chiral amino alcohol.
Scheme 10: Continuous-flow hydrolytic dynamic kinetic resolution of epibromohydrin (32).
Scheme 11: Continuous-flow asymmetric cyclopropanation.
Scheme 12: Continuous asymmetric hydrogenation of dimethyl itaconate in scCO2.
Scheme 13: Continuous asymmetric transfer hydrogenation of acetophenone.
Scheme 14: Asymmetric epoxidation using a continuous flow membrane reactor.
Scheme 15: Enzymatic cyanohydrin formation in a microreactor.
Scheme 16: Resolution of (R/S)- 54 with immobilized lipase in a continuous scCO2- flow reactor.
Scheme 17: Enantioselective separation of Acetyl-D-Phe in a continuous flow reactor.
Graphical Abstract
Scheme 1: Preparation of Pd(0) nanoparticles inside flow reactors.
Figure 1: Top: Reactor (1–2 mL dead volume) with functionalized Raschig-rings; bottom: TEM-micrographs of Pd(...
Figure 2: Repeated Suzuki reaction of 4-bromotoluene (6) with phenylboronic acid (10) under flow conditions. ...
Figure 3: Repeated Heck–Mizoroki reaction of 4′-iodoacetophenone (23) with styrene (29) under flow conditions....
Graphical Abstract
Figure 1: The Uniqsis FlowSyn™ continuous flow reactor comprising of a column holder and heating unit (A) and...
Scheme 1: General procedure for the flow synthesis of α-ketoester products 4a–j.
Scheme 2: General procedure for the batch synthesis of nitroolefinic esters 1a–j.
Scheme 3: General procedure for the flow synthesis of nitroolefinic esters 1a,c.
Figure 2: α-Ketoesters prepared and isolated yields.
Graphical Abstract
Scheme 1: Illustration of the chemo-enzymatic epoxidation of an alkene; involving the biocatalytic perhydroly...
Scheme 2: Illustration of the chemo-enzymatic epoxidation of 1-methylcyclohexene (6) to 1-methylcyclohexene o...
Scheme 3: Model reaction used to compare the continuous flow epoxidation strategy with the conventional batch...
Figure 1: Schematic of the reaction set-up used to evaluate the continuous flow chemo-enzymatic epoxidation o...
Figure 2: Graph illustrating the effect of flow rate (hence residence time) on the conversion of 1-methylcycl...
Figure 3: Graph illustrating the effect of (a) flow rate and (b) residence time on the conversion of 1-methyl...
Figure 4: Graph illustrating the effect of oxidant stoichiometry on the conversion of 1-methylcyclohexene (6)...
Figure 5: Illustration of the enzyme 4 stability to H2O2 (2) for the conversion of 1-methylcyclohexene (6) to...
Scheme 4: Illustration of the reaction products obtained when conducting the continuous flow epoxidation of c...
Graphical Abstract
Scheme 1: Synthesis of 4-methoxybiphenyl (4-MeOBP) and by-products in the Kumada reaction.
Figure 1: Stainless steel single column flow reactor for discovery scale synthesis.
Figure 2: (a): Schematic diagram of the parallel reactor housing (dimensions in mm); (b) the stainless steel ...
Figure 3: Schematic diagram of the pneumatic pumping system.
Scheme 2: Proposed catalytic cycles for the transformation of 4-haloanisole (Ar-X) and Grignard reagent (RMgX...
Figure 4: Comparative study of flow rates in a single channel meso flow reactor. The output was sampled hourl...
Figure 5: Kumada reaction carried out in a parallel channel meso reactor at a flow rate of 95 ml h−1.
Figure 6: Kumada reaction carried out in a parallel channel meso reactor over a 31-hour period at a flow rate...
Figure 7: Kumada reaction carried out in a parallel channel meso reactor at a flow rate of 190 ml h−1.
Graphical Abstract
Figure 1: Mechanism of Au(III)-catalyzed benzannulation between aromatic carbonyls and alkynes.
Figure 2: X-ray analysis of the metal films used in this benzannulation study. Panels a–e are scanning-electr...
Graphical Abstract
Figure 1: Synthetic strategy for asparagine-linked oligosaccharide on solid support and application of microf...
Figure 2: β-Mannosylation using an integrated microfluidic/batch system. Yield and β/α-ratio are analyzed by 1...
Scheme 1: Synthesis of pristane.
Figure 3: Process synthesis of pristane via microfluidic dehydration as a key step.
Scheme 2: Microfluidic dehydration.
Graphical Abstract
Figure 1: Biologically active diarylmethanol derivatives.
Figure 2: Structures of (R)-1,1,2-triphenyl-2-(piperidin-1-yl)ethanol (1) and its polystyrene-immobilized ana...
Scheme 1: Generation of the mixed ArZnEt species from a boronic acid and Et2Zn.
Scheme 2: Generation of the mixed ArZnEt species from a triarylboroxin and Et2Zn.
Scheme 3: Synthesis of the immobilized amino alcohol 2.
Scheme 4: Phenylation of tolualdehyde catalyzed by 2.
Figure 3: Experimental set-up for the continuous flow experiments. (A) Schematic representation and (B) Actua...
Scheme 5: Continuous flow enantioselective preparation of diarylmethanols.
Graphical Abstract
Figure 1: Experimental setup for heating tubular flow reactors by passing electric current directly through t...
Scheme 1: Acid catalyzed hydrolysis of methyl formate.
Figure 2: Conversion as a function of temperature for 3 different residence times.
Figure 3: Arrhenius plot for the measured rate constants.