WO2023027630A2 - Réacteur à écoulement, procédés de fabrication et réactions de celui-ci - Google Patents

Réacteur à écoulement, procédés de fabrication et réactions de celui-ci Download PDF

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Publication number
WO2023027630A2
WO2023027630A2 PCT/SG2022/050557 SG2022050557W WO2023027630A2 WO 2023027630 A2 WO2023027630 A2 WO 2023027630A2 SG 2022050557 W SG2022050557 W SG 2022050557W WO 2023027630 A2 WO2023027630 A2 WO 2023027630A2
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Prior art keywords
flow
flow reactor
methylthio
heterogeneous catalyst
fibrous matrix
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PCT/SG2022/050557
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English (en)
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WO2023027630A3 (fr
WO2023027630A9 (fr
Inventor
Kian Ping Loh
Zhongxin CHEN
Jingting SONG
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National University Of Singapore
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Publication of WO2023027630A3 publication Critical patent/WO2023027630A3/fr
Publication of WO2023027630A9 publication Critical patent/WO2023027630A9/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/24—Stationary reactors without moving elements inside
    • B01J19/248—Reactors comprising multiple separated flow channels
    • B01J19/2485—Monolithic reactors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/24—Stationary reactors without moving elements inside
    • B01J19/2405—Stationary reactors without moving elements inside provoking a turbulent flow of the reactants, such as in cyclones, or having a high Reynolds-number
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/24—Stationary reactors without moving elements inside
    • B01J19/248—Reactors comprising multiple separated flow channels
    • B01J19/2495—Net-type reactors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J35/00—Catalysts, in general, characterised by their form or physical properties
    • B01J35/50—Catalysts, in general, characterised by their form or physical properties characterised by their shape or configuration
    • B01J35/56—Foraminous structures having flow-through passages or channels, e.g. grids or three-dimensional monoliths
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00049—Controlling or regulating processes
    • B01J2219/00051—Controlling the temperature
    • B01J2219/00132—Controlling the temperature using electric heating or cooling elements
    • B01J2219/00135—Electric resistance heaters
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00819—Materials of construction
    • B01J2219/00835—Comprising catalytically active material
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00819—Materials of construction
    • B01J2219/00844—Comprising porous material
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/24—Stationary reactors without moving elements inside
    • B01J2219/2401—Reactors comprising multiple separate flow channels
    • B01J2219/2402—Monolithic-type reactors
    • B01J2219/2409—Heat exchange aspects
    • B01J2219/2416—Additional heat exchange means, e.g. electric resistance heater, coils

Definitions

  • the present invention relates, in general terms, to a flow reactor and methods of fabricating the flow reactor thereof.
  • the present invention also relates to reactions performable in the flow reactor.
  • a high flow rate usually results in lower residence time for reactants, thus lowering conversion yield.
  • the present disclosure relates to a flow reactor that allows for localized turbulent flow within itself, thus allowing fast chemical conversion. Additionally, a laminar flow is maintained in the external tubing connections in order to quickly deliver the reagents to the flow reactor under a low pressure. The partitioning of flow and reaction space allows high reaction efficiency.
  • the present invention provides a flow reactor, comprising: a) an inlet and an outlet; and b) a heterogeneous catalyst module positioned between the inlet and the outlet, the heterogeneous catalyst module in fluid communication with the inlet and the outlet; wherein the heterogeneous catalyst module comprises a flow channel and heterogeneous catalysts on a fibrous matrix within the flow channel, the flow channel in fluid communication with the inlet and the outlet; and wherein the heterogeneous catalyst module is configured to produce a turbulent flow at at least a central portion of a transverse section of the flow channel when in use under ambient pressure.
  • the fibrous matrix comprises matted fibers, fibres with non- uniform or random orientation or arrangement.
  • the orientation or arrangement of the fibres causes the fibres to obstruct the flow of a fluid, thereby forcing the fluid to flow in a tortuous route. This breaks up the flow path between the inlet and the outlet, reducing laminar flow.
  • the fibrous matrix is positioned at at least a central portion of a transverse section of the flow channel.
  • the fibrous matrix may comprise one portion, or two or more portions at spaced locations in the flow channel.
  • the flow reactor further comprises a tubing connected to the inlet and a tubing connected to the outlet, the tubings configured to produce laminar flow when in use under ambient pressure.
  • the turbulent flow is characterised by a Reynolds number of about 2000 to about 10000.
  • the heterogeneous catalyst is selected from a metal particle, metal cluster, ion, atom or a combination thereof, wherein the metal is selected from iron, cobalt, nickel, copper, palladium, platinum, gold, ruthenium, silver, or a combination thereof.
  • the heterogeneous catalyst comprises transition metal atoms incorporated between at least two transition metal dichalcogenide (TMD) layers attached to the fibrous matrix.
  • TMD transition metal dichalcogenide
  • the TMD is selected from the group consisting of molybdenum disulfide (M0S2), tungsten disulfide (WS2), titanium disulfide (TiS2), tantalum sulfide (TaS2), vanadium disulfide (VS2), molybdenum diselenide (MoSe2), tungsten diselenide (WSe2), tellurium sulphide (TeS2) and tellurium diselenide (TeSe2).
  • M0S2 molybdenum disulfide
  • WS2 tungsten disulfide
  • TiS2 titanium disulfide
  • TaS2 tantalum sulfide
  • VS2 vanadium disulfide
  • MoSe2 molybdenum diselenide
  • WSe2 tungsten diselenide
  • TeS2 tellurium sulphide
  • TeSe2 tellurium diselenide
  • the heterogenous catalyst module is characterised by a TMD loading on the fibrous matrix of about 1 wt% to about 80 wt%, or preferably about 20 wt% to about 50 wt%.
  • the transition metal atom is a transition metal selected from iron, cobalt, nickel, copper, palladium, platinum, gold, ruthenium, silver, or a combination thereof.
  • the heterogenous catalyst module is characterised by a transition metal atom loading on the TMD of about 0.01 wt% to about 10 wt%, or preferably about 0.2 wt% to about 2 wt%, or preferably about 0.5 wt%.
  • the fibrous matrix characterised by a porosity of about 30% to about 95%, or preferably about 90% to about 95%.
  • the fibrous matrix characterised by a pore size of about 50 nm to about 100 pm, or preferably about 65 pm.
  • the fibrous matrix is selected from a graphite felt, carbon felt, graphite paper, carbon paper, carbon cloth, or a combination thereof.
  • the heterogeneous catalyst module is characterised by a porosity of about 30% to about 95%, or preferably about 90% to about 95%.
  • the heterogeneous catalyst module is characterised by a pore size of about 50 nm to about 100 pm, or preferably about 65 pm.
  • the fibrous matrix is characterised by a compressive stress at 50% strain of about 0.1 MPa to about 0.2 MPa, or preferably about 0.12 MPa to about 0.15 MPa.
  • the fibrous matrix is characterised by a reversible deformation when deformed up to about 90%.
  • the heterogeneous catalyst module has a length of about 0.5 cm to about 50 cm, a breadth of about 0.5 cm to about 50 cm, and/or a width or thickness of about 0.01 mm to about 50 mm.
  • the heterogeneous catalyst module has an area of about 0.25 cm 2 to about 2500 cm 2 .
  • the heterogeneous catalyst module has a volume of about 2.5 x 10 s cm 3 to about 1250 cm 3 .
  • the heterogeneous catalyst module is modular.
  • the flow reactor comprises two or more heterogeneous catalyst modules.
  • the flow reactor further comprises a body for housing the heterogeneous catalyst module.
  • the flow reactor further comprises temperature control means.
  • the temperature control means comprises stainless stain plates with heating rods electrically connected to a thermocouple and a digital controller.
  • the temperature control means is capable of varying the temperature from about -20 °C to about 100 °C, or preferably about 20 °C to about 70 °C.
  • the flow reactor further comprises flow control means.
  • the flow control means is selected from a peristaltic pump, a syringe pump or a high performance liquid chromatography (HPLC) pump.
  • the flow reactor further comprises voltage control means.
  • the voltage control means is an electrochemical workstation (potentiostat).
  • the flow reactor further comprises light control means.
  • the light control means is selected from a light-emitting diode (LED), a xenon lamp or a mercury lamp.
  • the flow reactor further comprises sampling means.
  • the flow reactor further comprises purification means.
  • the flow reactor is modular.
  • the present invention also provides a heterogeneous catalyst module, comprising a flow channel and heterogeneous catalysts on a fibrous matrix within the flow channel, wherein the heterogeneous catalyst module is configured to produce a turbulent flow at at least a central portion of a transverse section of the flow channel when in use under ambient pressure.
  • the present invention also provides a method of fabricating a flow reactor, comprising: a) positioning a heterogeneous catalyst module between an inlet and an outlet, the heterogeneous catalyst module in fluid communication with the inlet and the outlet; wherein the heterogeneous catalyst module comprises a flow channel and heterogeneous catalysts on a fibrous matrix within the flow channel, the flow channel in fluid communication with the inlet and the outlet; and wherein the heterogeneous catalyst module is configured to produce a turbulent flow at at least a central portion of a transverse section of the flow channel when in use under ambient pressure.
  • the present invention also provides a method of fabricating a heterogeneous catalyst module, comprising: a) attaching at least two layers of transition metal dichalcogenide (TMD) on a fibrous matrix; b) incorporating a transition metal precursor between the at least two TMD layers; c) annealing the transition metal precursor in order to form transition metal atoms between the at least two TMD layers as the heterogeneous catalyst on the fibrous matrix; and d) positioning the heterogeneous catalyst on the fibrous matrix within a flow channel.
  • TMD transition metal dichalcogenide
  • the fibrous matrix is selected from graphite felt, carbon felt, graphite paper, carbon paper, carbon cloth, or a combination thereof.
  • the at least two layers of TMD is attached by hydrothermally treating the fibrous matrix with a TMD precursor.
  • the TMD precursor is a mixture of sodium molybdate and thiourea.
  • a molar ratio of sodium molybdate to thiourea is about 1:2.
  • the hydrothermal treatment is performed at about 190 °C.
  • the hydrothermal treatment is performed for about 24 h.
  • the heterogenous catalyst module is characterised by a TMD loading on the fibrous matrix of about 45 mg cm 2 .
  • the transition metal precursor is a transition metal complex or a transition metal salt selected from the group consisting of metal phthalocyanine complex, metal 5,10,15,20-(tetra-N-methyl-4-pyridyl)porphyrin tetrachloride complex, metal 5,10,15,20-(tetraphenyl)porphyrin complex, metal 5,10,15,20-(tetra-N,N,N- trimethyl-4-anilinium) porphyrin tetrachloride complex, metallocene complexes, metal salen complex, metal phenanthroline complex, metal a cetyl aceton ate complex, metal acetates, metal chlorides, metal nitrates, and a combination thereof.
  • metal phthalocyanine complex metal 5,10,15,20-(tetra-N-methyl-4-pyridyl)porphyrin tetrachloride complex
  • the transition metal precursor has a transition metal selected from iron, cobalt, nickel, copper, palladium, platinum, gold, ruthenium, silver or a combination thereof.
  • the transition metal precursor is physically or chemically anchored on the TMD surface, doped in the TMD lattice or intercalated between the at least two TMD layers.
  • the incorporation step is performed at about 40 °C to about 100 °C.
  • the incorporation step is performed at about 80 °C.
  • the incorporation step is performed for about 1 h to about 24 h.
  • the incorporation step is performed for about 2 h.
  • the annealing step is performed at about 150 °C to about 1000 °C.
  • the annealing step is performed at about 300 °C to about 700 °C.
  • the annealing step is performed for about 0.5 h to about 24 h.
  • the annealing step is performed for about 2 h.
  • the annealing step is performed under inert conditions, oxidative conditions or reductive conditions.
  • the heterogenous catalyst module is characterised by a transition metal loading on the TMD of about 0.5 wt%.
  • the present invention also provides a method of catalysing a reaction using the flow reactor as disclosed herein, wherein the flow rate is about 0.01 mL min 1 to about 100 mL min -1 .
  • the method is performed at a pressure of about 1 atm.
  • the method is performed at a temperature of about 5 °C to about 100 °C.
  • the method is performed for at least 5 sec.
  • the reaction is an oxidation of a compound having a sulphide moiety.
  • the sulphide moiety is oxidised to a sulfone moiety or sulfoxide moiety.
  • the compound having a sulphide moiety is selected from thioanisole, 4-(methylthio)-benzaldehyde, 4-(methylthio)benzyl alcohol, 4- (methylthio)benzylamine, 4-(methylthio)anisole, 4-(methylthio)aniline, 4- (methylthio)phenyl boronic acid, 4-thioanisoleboronic acid, pinacol ester, 4'- (methylthio)acetophenone, phenyl propargyl sulfide, 4-(methylthio) benzoyl chloride, 4-(methylthio)benzoic acid, 4-(methylthio) benzonitrile, l-methoxy-4- (methylthio)benzene, 4-bromophenyl methyl sulfide, allyl phenyl sulfide, allyl sulfide, diphenyl sulfide, phenyl disulfide, dibenzyl sulfide, 2,
  • the method when a compound having a sulphide moiety is oxidised, the method is characterised by a chemoselectivity of at least 90%.
  • the method when a compound having a sulphide moiety is oxidised, the method further comprises flowing an oxidising agent into the flow reactor.
  • the oxidising agent is an organic oxidising agent or an inorganic oxidising agent.
  • the oxidising agent is an organic or inorganic peroxide.
  • a mole ratio of the oxidising agent to the compound having a sulphide moiety is about 1: 1 to about 5:1.
  • a solvent is selected from acetonitrile (AN), water, hydrocarbyl aliphatic alcohols (such as ethanol, isopropanol), ethyl acetate (EA), N,N-dimethylformamide (DMF), N-methyl-2- pyrrolidone (NMP) and dimethyl sulfoxide (DMSO), or a combination thereof.
  • the reaction is a reduction of a compound having a nitro moiety.
  • the compound having a nitro moiety is a compound of Formula (Ha):
  • compound of Formula (Ila) is reduced to a compound having an aniline moiety.
  • the method when a compound having a nitro moiety is reduced, the method is characterised by a chemoselectivity of at least 90%.
  • the compound having a nitro moiety is selected from nitrobenzene, 4-nitrotoluene, 4-nitroanisole, 4-nitrobiphenyl, l-fluoro-4-nitrobenzene, l-chloro-4-nitrobenzene, l-bromo-4-nitrobenzene, l-iodo-4-nitrobenzene, 4- nitrobenzyl bromide, 4-nitrobenzotrifluoride, pentafluoronitrobenzene, 4-nitroaniline, 4- nitrophenol, 4-nitrobenzoic acid, 2-nitroaniline, 4-nitrophenyl isocyanate, 4- nitrobenzenesulfonamide, 4-nitrobenzonitrile, methyl 4-nitrobenzoate, 3-nitrostyrene, 4-nitrostyrene, trans-p-nitrostyrene, trans-2-nitrocinnamic acid, trans-4-nitro-cinnamic acid, l-ethynyl-4-nitrobenzene, l-
  • the method when a compound having a nitro moiety is reduced, the method further comprises flowing a reducing agent into the flow reactor.
  • the reducing agent is an organic reducing agent or an inorganic reducing agent.
  • the reducing agent is selected from ammonia borane complex (NH3BH3), sodium hydroborate (NaBFU), lithium aluminium hydride (LiAIFU), hydrazine (N2H4), formic acid, ascorbic acid, hydrogen gas, or a combination thereof.
  • NH3BH3 ammonia borane complex
  • NaBFU sodium hydroborate
  • LiAIFU lithium aluminium hydride
  • N2H4 hydrazine
  • formic acid ascorbic acid
  • hydrogen gas or a combination thereof.
  • a mole ratio of the reducing agent to the compound having a nitro moiety is about 1 : 1 to about 5: 1.
  • a solvent is selected from acetonitrile (AN), water, hydrocarbyl aliphatic alcohols (such as ethanol, isopropanol), ethyl acetate (EA), or a combination thereof.
  • the present invention also provides a method of catalysing a reaction, comprising : a) contacting a compound having a nitro moiety with a heterogeneous catalyst and a reductant, the heterogeneous catalyst comprising: i) a substrate; ii) at least two layers of transition metal dichalcogenide (TMD), the at least two TMD layers attached to the substrate; and iii) transition metal atoms incorporated between the at least two TMD layers; and b) reducing the nitro moiety.
  • TMD transition metal dichalcogenide
  • the present invention also provides a method of synthesising Clethodim and/or Tamiflu or a salt, solvate or derivative thereof, comprising flowing precursors through the flow reactor as disclosed herein.
  • Figure 1A shows a flow cell setup showing the local turbulent flow inside reaction compartment.
  • Figure IB shows a graphite plate with a flow path design.
  • Figure 2 shows (A) False-coloured micro-CT image showing the 3D fibrous structure of catalyst module; (B) Mercury intrusion porosimetry and (C) Compressive strain-stress curves of single atom modified catalyst module and blank support.
  • Figure 3 shows sulfide oxidation in the flow setup, (a) Comparison between flow and batch setup for sulfide oxidation; (b) Catalytic performance using flow reactor; (c) A 20 h on-stream demonstration at various flow rates; (d) Substrate scope.
  • Figure 4 shows selective nitro-reduction in the flow setup.
  • A A 24 h on-stream demonstration with rate capability test at the 20th hour;
  • B Substrate scope.
  • Figure 5 shows thermal imaging and computational fluidic dynamics of the flow cell under operational condition.
  • Figure 6 shows a flow reactor with a quartz window for photochemical setup.
  • Figure 7 shows a flow reactor with gold -coated current collectors for an electrochemical setup.
  • Figure 8 shows a 3-layers (50 cm 2 ) flow reactor with additional catholyte chamber for gas-liquid-solid 3-phase reaction (e.g., CO2 reduction).
  • gas-liquid-solid 3-phase reaction e.g., CO2 reduction
  • Figure 9 shows the pressure change in the flow reactor when in use.
  • the present invention is predicated on the understanding of modularized continuous- flow production of fine chemicals and specialty chemicals, which can be particularly advantageous in the chemical and pharmaceutical industry to improve the productivity and quality chemicals (e.g., pharmaceuticals and agrochemicals).
  • productivity and quality chemicals e.g., pharmaceuticals and agrochemicals.
  • the continuous-flow and modularized production allows the flexibility to adjust the productivity according to the market.
  • Such flow facilities also have smaller ecological footprint and a higher level of automation, thus allowing lower operational cost at maximized quality control. This is important for contaminant-susceptible processes in pharmaceutical production, where continuous production together with real-time monitoring can identify such contaminations and only discard a small portion of the product instead of the entire batch.
  • Flow operation also enables the use of highly reactive or toxic reagents that are not suitable in batch processes, thus opening a completely new field in chemical production.
  • the present invention relates to a flow reactor for chemoselective liquid-phase transformations to produce fine chemicals.
  • the present invention also relates to methods of fabricating highly compressible 3D fibrous catalyst matrix in the catalyst module and the corresponding flow reactor for continuous flow production of fine chemicals under ambient condition.
  • the flow reactor allows transition of laminar flow to local turbulent flow inside the reactor and strong liquid-catalyst interaction, such setup allows much faster fluidic dynamics and reaction kinetics, thus enabling high productivity under ambient condition.
  • the presently disclosed flow reactor is advantageous in fast fluidic dynamics and reaction kinetics owing to enhanced liquidcatalyst interaction under local turbulent fluidic field in the 3D fibrous catalyst module.
  • This enables a high flow rate under ambient pressure.
  • the flow production of multifunctional sulfones and sulfoxides is achieved by a chemoselective oxidation process with excellent functional group tolerance (> 50 examples).
  • Sulfoxide-modified Tamiflu and many other bioactive molecules can be produced at gram-level within an hour.
  • continuous manufacturing of multifunctional aniline is conducted by chemoselective reduction of nitro-compounds (> 60 examples).
  • the flow reactor is also capable for long-term operation without performance degradation.
  • the flow reactor is highly applicable in process transfer from a laboratory setting to an industrial setting.
  • the present invention provides a flow reactor, comprising: a) an inlet and an outlet; and b) a heterogeneous catalyst module positioned between the inlet and the outlet, the heterogeneous catalyst module in fluid communication with the inlet and the outlet; wherein the heterogeneous catalyst module comprises a flow channel and heterogeneous catalysts on a fibrous matrix within the flow channel, the flow channel in fluid communication with the inlet and the outlet; and wherein the heterogeneous catalyst module is configured to produce a turbulent flow at at least a central portion of a transverse section of the flow channel when in use under ambient pressure.
  • the heterogeneous catalyst module is configured to produce a turbulent flow by the fibrous matrix of that module being configured to produce a turbulent flow.
  • the flow reactor is also applicable to photo/electrochemical reaction to promote those sluggish reactions at ambient condition.
  • the centre refers to a middle position in the flow channel of the heterogeneous catalyst module and which is at least some distance away from the sides of the flow channel.
  • the fibrous matrix is present at least the central portion of a transverse section of the flow channel.
  • the fibrous matrix can be held at the central portion by supports extending inwardly from the walls of the flow channel, or by a recess at one or more internal surfaces of the flow channel and into which projects a portion of the fibrous matrix or a support that holds the fibrous matrix in position in the flow channel.
  • the turbulent flow can also occur at positions around the centre of the flow channel, partway between the centre and side of the flow channel, or near the sides of the flow channel.
  • the turbulent flow occurs throughout the flow channel.
  • the turbulent flow may be imparted by the design of the flow channel. For example, by having sharp turns and corners in the flow channel, turbulence can be created.
  • the turbulent flow may be imparted by the presence of the fibrous matrix in the flow channel through the disruption of fluid flow within the flow channel. In this sense, the fibrous matrix completely fills the transverse section of the flow channel, or the whole cavity of the flow channel.
  • the flow reactor comprises: a) an inlet and an outlet; and b) a heterogeneous catalyst module positioned between the inlet and the outlet; wherein the heterogeneous catalyst module comprises a flow channel and heterogeneous catalysts on a fibrous matrix within the flow channel, the flow channel in fluid communication with the inlet and the outlet; and wherein the fibrous matrix is configured to produce a turbulent flow within the flow channel when in use under ambient pressure.
  • the fibrous matrix comprises matted fibers.
  • the fibers are randomly tangled into a mass. The random orientation of the fibers relative to each other acts to obstruct the flow of a fluid and forces the fluid to flow in a tortuous route, thus breaking up the flow path between the inlet and the outlet.
  • the fibers of the fibrous matrix can be loosely or tightly packed. Because the fibers randomly crisscross each other, gaps are present between the fibers.
  • the fibrous matrix is porous.
  • the fibrous matrix acts as a platform for supporting the catalyst and also as a localised flow regulator to provide high flow rate and excellent chemoselectivity toward fast flow reactions under ambient pressure.
  • the porosity of the fibrous matrix allows fluid to flow through but at the same time disrupts its flow. In contrast, traditional packed bed reactor failed to do so due to dense stacking of powder catalyst and side reaction during long retention period.
  • the flow channel is homogenously filled with the fibrous matrix. This ensures that turbulent flow is created throughout the whole cavity of the flow channel. It was found that turbulent flow inside the reactor allows for an overall high flow rate and high catalytic turnover. As the reactants flow over an increased number of catalyst in a given volume during turbulent flow, the productivity of the flow reactor is improved over that of a packed bed flow reactor. This is due to the random arrangement of the fibrous matrix, which breaks up the flow path between the inlet and the outlet.
  • the flow reactor further comprises a tubing connected to the inlet. In other embodiments, the flow reactor further comprises a tubing connected to the outlet. The tubings are configured to produce laminar flow when in use under ambient pressure.
  • Turbulent flow is fluid motion characterized by chaotic changes in pressure and flow velocity.
  • unsteady vortices appear of many sizes which interact with each other, consequently drag due to friction effects increases. It is in contrast to a laminar flow, which occurs when a fluid flows in parallel layers, with no disruption between those layers.
  • the transition of laminar flow to local turbulent flow inside the catalyst module allows a strong interaction between fluent and solid catalyst, thus promotes the reaction kinetics for operation in ambient conditions. It was found that high productivity can be realised by partitioning the flow space into external laminar flow in the outer circuit (tubing and other connections) and local turbulent flow inside the flow channel of the flow reactor, allowing overall high flow rate and high catalytic turnover.
  • the transition from laminar to turbulent flow also ensures that excessive pressure is not built up within the flow reactor, and that a constant flow output can be maintained.
  • the flow reactor allows fast flow and yet good conversion yield because of the use of compressible 3D fibrous catalyst module that creates a local turbulent flow inside reaction compartment, leading to enhanced liquid-catalyst interaction to promote the reaction kinetics, while the external flow is laminar in nature.
  • the partitioning of laminar and turbulent flow allows a high flow rate without sacrificing reaction efficiency.
  • the Reynolds number is the ratio of inertial forces to viscous forces within a fluid which is subjected to relative internal movement due to different fluid velocities.
  • flows tend to be dominated by laminar (sheet-like) flow, while at high Reynolds numbers flows tend to be turbulent.
  • the turbulence can result from differences in the fluid's speed and direction, which may sometimes intersect or even move counter to the overall direction of the flow (eddy currents). These eddy currents begin to churn the flow, using up energy in the process.
  • the external flow (for example in the tubings) has a Reynolds number of about 350 or even lower at the flow path (0.8 mm to 5 mm).
  • the Reynolds number increases at least 10 folds to 4000 at the same apparent flow rate (at 20 mL min 1 ), leading to the formation of turbulent flow to enhance diffusion kinetics.
  • the use of compressible 3D fibrous catalyst matrix to induce turbulent flow has never been demonstrated for fine chemical production in liquid phase flow reactor.
  • the productivity per module may be about 1 g h -1 to about 5 g h 1 compared to less than 0.1 g h 1 in packed bed flow reactor.
  • the turbulent flow is characterised by a Reynolds number of about 2000 to about 10000.
  • the Reynolds number is about 2500 to about 10000, about 3000 to about 10000, about 3500 to about 10000, about 4000 to about 10000, about 4000 to about 9000, about 4000 to about 8000, about 4000 to about 7000, about 4000 to about 6000, or about 4000 to about 5000. In other embodiments, the Reynolds number is about 4000.
  • the turbulent flow is due to the fibers obstructing the flow path of the flow solvent.
  • the fibers in the fibrous matrix are substantially perpendicular to a flow direction of the flow solvent.
  • the fibers in the fibrous matrix are at an angle to a flow direction of the flow solvent.
  • the fibers are randomly oriented. Due to the turbulent flow, the solvent "swirls" around the fibers and the catalyst, thus allowing for a minimal amount of solvent in order to complete the reaction. It was found that the pressure increase due to the turbulence is minimal due to high porosity of fibers.
  • the generation of turbulent flow occurs while the pressure is maintained at about 1 atm.
  • the pressure within the flow channel is maintained to be around 1 atm. In this way, the flow reactor allows for an increased contact rate with the catalyst while not increasing the difficulty of operating the flow reactor.
  • the heterogeneous catalyst is covalently bonded to the fibrous matrix. In some embodiments, the heterogeneous catalyst is physically bonded to the fibrous matrix.
  • the heterogeneous catalyst is selected from a metal particle, metal cluster, ion, atom or a combination thereof, wherein the metal is selected from iron, cobalt, nickel, copper, palladium, platinum, gold, ruthenium, silver, or a combination thereof.
  • the heterogeneous catalyst comprises transition metal atoms incorporated between at least two transition metal dichalcogenide (TMD) layers attached to the fibrous matrix. In some embodiments, the heterogeneous catalyst comprises transition metal atoms intercalated between at least two transition metal dichalcogenide (TMD) layers attached to the fibrous matrix. In some embodiments, the heterogeneous catalyst comprises transition metal atoms anchored on a surface of the at least two transition metal dichalcogenide (TMD) layers attached to the fibrous matrix. In some embodiments, the heterogeneous catalyst comprises transition metal atoms doped into a lattice of the at least two transition metal dichalcogenide (TMD) layers attached to the fibrous matrix.
  • the transition metal dichalcogenides are 2-D materials and have a generalized formula of MX2 where M is a transition metal of groups 4-10 and X is a chalcogen (such as sulfur or selenium).
  • the TMD is selected from the group consisting of molybdenum disulfide (M0S2), tungsten disulfide (WS2), titanium disulfide (TiS2), tantalum sulfide (TaS2), vanadium disulfide (VS2), molybdenum diselenide (MoSe2), tungsten diselenide (WSe2), tellurium sulphide (TeS2) and tellurium diselenide (TeSe 2 ).
  • M0S2 molybdenum disulfide
  • WS2 tungsten disulfide
  • TiS2 titanium disulfide
  • TaS2 tantalum sulfide
  • VS2 vanadium disulfide
  • MoSe2 moly
  • the at least two TMD layers are aligned in one plane and attached to the substrate at an edge of the plane.
  • the TMD layers are stacked one on top of the other and each of the at least two TMD layers is attached to the substrate.
  • the grown structure of the TMD on the substrate can be aligned with its edge sites exposed, thus can enable a fast diffusion kinetics of reactants.
  • the at least two TMD layers are aligned in one plane and perpendicularly (vertically) attached to the substrate at an edge of the plane.
  • the TMD layers are, for example, vertically aligned with respect to a surface of the substrate.
  • the at least two TMD layers are aligned in one plane and are attached to the substrate at an angle. The angle can be about 85°, about 80°, about 75°, about 70°, about 65°, or about 60° .
  • the alignment of the TMD layers on the substrate advantageously allows for a catalyst with high active surface area and activity.
  • each of the at least two TMD layers has a thickness of about 5 nm. In other embodiments, the thickness is about 4 nm, about 6 nm, about 7 nm, about 8 nm, about 9 nm, or about 10 nm.
  • each of the at least two TMD layers has a plane dimension of about 400 nm. In other embodiments, the plane dimension is about 500 nm, about 600 nm, about 700 nm, about 800 nm, about 900 nm or about 1 pm.
  • the spacing between the TMD layers as formed may vary.
  • the interlayer spacing of M0S2 is 0.615 nm
  • MoSe? is 0.646 nm
  • WS2 is 0.618 nm
  • WSe2 is 0.651 nm
  • TiS2 is 0.569 nm
  • VS2 is 0.573 nm
  • SnS2 is 0.589 nm
  • TaS2 is 0.601 nm.
  • the at least two layers of TMD is at least 3 layers, at least 4 layers, at least 5 layers, at least 6 layers, at least 7 layers, at least 8 layers, at least 9 layers, or at least 10 layers. In other embodiments, the at least two layers of TMD is at least 10 layers of TMD.
  • the transition metal atoms are intercalated and/or incorporated between the at least two TMD layers.
  • the transition metal atoms are inserted between the TMD layers.
  • the inventors have found that incorporation of transition metal atoms within the TMD layers enables the modification of electronic structure of the composite such that it can act as a catalyst to significantly improve catalytic activity and selectivity.
  • the transition metal atoms are chemically bonded to the transition metal dichalcogenides (host material) by the formation of a tunable coordination environment of M-CxOyXz structure, where M represents a transition metal atom, C represents a carbon atom, 0 represents an oxygen atom, X represents a chalcogen atom, x is the number of carbon atom located in the first coordination shell of transition metals (with a typical number of 0 ⁇ 4), y is the number of oxygen atom located in the first coordination shell of transition metals (with a typical number of 0 ⁇ 6) and z is the number of chalcogen atom located in the first coordination shell of transition metals (with a typical number of 0 ⁇ 6).
  • M-CxOyXz structure can serve as the catalytically active center.
  • the heterogenous catalyst module is characterised by a TMD loading on the fibrous matrix of about 1 wt% to about 80 wt%. In other embodiments, the TMD loading is about 5 wt% to about 80 wt%, about 10 wt% to about 80 wt%, about 10 wt% to about 70 wt%, about 10 wt% to about 60 wt%, about 10 wt% to about 50 wt%, about 10 wt% to about 40 wt%, or about 10 wt% to about 30 wt%. In some embodiments, the heterogenous catalyst module is characterised by a TMD loading on the fibrous matrix of about 20 wt% to about 50 wt%.
  • the intercalation and/or incorporation of transition metal atoms may change the spacing between the TMD layers. For example, due to the repulsion between the electron densities of the TMD layers and the transition metal atoms, the spacing may be increased. The increase in layer spacing can be beneficial for edge-site promoted catalysis owing to a higher accessible surface area.
  • the interlayer spacing is about 0.56 nm, about 0.58 nm, about 0.6 nm, about 0.62 nm, about 0.64 nm, about 0.66 nm, about 0.68 nm, about 0.7 nm, about 0.75 nm, about 0.8 nm, about 0.85 nm, about 0.9 nm, about 0.95 nm, about 1 nm, about 1.05 nm, about 1.1 nm, or about 1.2 nm.
  • the interlayer spacing is about 0.56 nm to about 1.2 nm, about 0.58 nm to about 1.2 nm, about 0.6 nm to about 1.2 nm, or about 0.6 nm to about 1.1 nm.
  • each transition metal atom is coordinated to 4 chalcogens in the at least two TMD layers.
  • 2 of the chalcogens are located on one TMD layer and the other 2 chalcogens are located on the other TMD layer.
  • each transition metal atom has a valency of 3, 4, 5 or 6. In other embodiments, each transition metal atom has a valency of 4.
  • the transition metal atoms occurs as individual atoms within the interstitial space of two TMD layers.
  • each transition metal atom is isolated and spaced apart from each other.
  • the transition metal atoms are selected from the group consisting of iron, cobalt, nickel, copper, palladium, platinum, gold, ruthenium, silver and a combination thereof.
  • the transition metal atoms occurring as individual atoms is uniformly distributed within the interstitial space of two TMD layers.
  • the atom to atom distance may vary.
  • the transition metal atoms are spaced apart about 5 A from each other. In other embodiments, the spacing is about 3 A, about 4 A, about 6 A, about 7 A, about 8 A, about 9 A, about 1 nm, about 1.1 nm, about 1.2 nm, about 1.3 nm, about 1.4 nm or about 1.5 nm.
  • the transition metal atom is a transition metal selected from iron, cobalt, nickel, copper, palladium, platinum, gold, ruthenium, silver, or a combination thereof.
  • the heterogeneous catalyst module is characterised by a transition metal atom loading on the TMD of about 0.01 wt% to about 10 wt%.
  • the transition metal atom loading is about 0.1 wt% to about 10 wt%, about 0.1 wt% to about 9 wt%, about 0.1 wt% to about 8 wt%, about 0.1 wt% to about 7 wt%, about 0.1 wt% to about 6 wt%, about 0.1 wt% to about 5 wt%, about 0.1 wt% to about 4 wt%, about 0.1 wt% to about 3 wt%, about 0.1 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt%.
  • the heterogenous catalyst module is characterised by a transition metal atom loading on the TMD of about 0.2 wt% to about 2 wt%. In some embodiments, the heterogenous catalyst module is characterised by a transition metal atom loading on the TMD of about 0.5 wt%.
  • the heterogeneous catalyst is characterised by a turnover frequency (TOF) of about 500 h 1 to about 2000 h 1 .
  • the turnover frequency is about 500 h 1 to about 1800 h 1 , about 500 h 1 to about 1600 h 1 , about
  • the turnover frequency is about 800 h 1 to about 1200 h 1 . This is much higher than those values in conventional packed bed reactors ( ⁇ 100 h 1 ).
  • the heterogeneous catalyst forms at least a layer on the fibrous matrix.
  • the heterogeneous catalyst forms at least a layer on the fiber of the fibrous matrix.
  • the fibrous matrix has a macroporous structure. In some embodiments, the fibrous matrix characterised by a porosity of about 30% to about 95%. In other embodiments, the porosity is about 40% to about 95%, about 50% to about 95%, about 60% to about 95%, about 70% to about 95%, or about 80% to about 95%. In some embodiments, the fibrous matrix characterised by a porosity of about 90% to about 95%.
  • the fibrous matrix characterised by a pore size of about 50 nm to about 100 pm.
  • the pore size is about 100 nm to about 100 pm, about 200 nm to about 100 pm, about 300 nm to about 100 pm, about 400 nm to about 100 pm, about 500 nm to about 100 pm, about 600 nm to about 100 pm, about 700 nm to about 100 pm, about 800 nm to about 100 pm, about 900 nm to about 100 pm, about 1 pm to about 100 pm, about 10 pm to about 100 pm, about 20 pm to about 100 pm, about 30 pm to about 100 pm, about 40 pm to about 100 pm, about 50 pm to about 100 pm, about 50 pm to about 90 pm, about 50 pm to about 80 pm, or about 50 pm to about 70 pm.
  • the fibrous matrix characterised by a pore size of about 65 pm.
  • the fiber diameter of the fibrous matrix may correlate with the pore size of the matrix, and thus the degree of turbulence.
  • the fibrous matrix comprises fibers having a diameter of about 1 pm to about 20 pm.
  • the diameter is about 1 pm to about 18 pm, about 1 pm to about 16 pm, about 1 pm to about 15 pm, about 1 pm to about 14 pm, about 1 pm to about 13 pm, about 1 pm to about 12 pm, about 1 pm to about 11 pm, about 1 pm to about 10 pm, about 2 m to about 10 pm, about 3 pm to about 10 pm, about 4 pm to about 10 pm, or about 5 pm to about 10 pm.
  • the fibrous matrix is a random fiber network. In other embodiments, the fibrous matrix is an orderly network of fibers.
  • the orderly network of fibers can be a network of fibers aligned along their length, or a quasi-aligned network of fibers.
  • the fibrous matrix is a graphite felt, carbon felt, graphite paper, carbon paper, or carbon cloth.
  • the fibrous matrix can be a woven or non-woven material. For example, mesh with a particular mesh number can be used. When multiple meshes are stacked but offset relative to each other (rotationally and/or transversely), an obstruction is created such that fluid flow is disrupted.
  • the fibrous matrix is chemically modified in order to alter the flow kinetics within the flow channel.
  • the fibrous matrix may be surface coated with a hydrophilic or hydrophobic coating to improve its solvent resistance. This may also prevent the reagents from penetrating and be retained within the fibrous matrix.
  • the fibrous matrix is treated with oxygen to improve the hydrophilicity of the fibrous matrix and/or bonding of its surface with the heterogeneous catalyst.
  • the fibrous matrix is treated with a microporous layer coating and/or hydrophobic coating.
  • the coating can be a PTFE coating.
  • the 'flow channel' as used herein refers to a conduit in which a fluid can flow through.
  • the flow channel can have rigid or flexible walls, and can be of any cross sectional shape (for example circular or rectangular).
  • the flow in the channel can be closed or open; open channel flow is fluid flow in a conduit which is open to air while closed channel flow is entirely in contact with the boundaries of the channel.
  • the flow channel is closed.
  • the flow channel has a cross sectional width or diameter of about 0.5 mm to about 20 mm, about 0.5 mm to about 18 mm, about 0.5 mm to about 16 mm, about 0.5 mm to about 14 mm, about 0.5 mm to about 12 mm, about 0.5 mm to about 10 mm, about 0.5 mm to about 8 mm, about 0.5 mm to about 6 mm, about 0.5 mm to about 5 mm, about 0.5 mm to about 4 mm, about 0.5 mm to about 3 mm, about
  • the flow channel has a length of about 1 cm to about 100 cm.
  • the length is about 1 cm to about 90 cm, about 1 cm to about
  • the heterogeneous catalyst module or at least the fibrous matrix is characterised by a porosity of about 30% to about 95%. In other embodiments, the porosity is about 40% to about 95%, about 50% to about 95%, about 60% to about 95%, about 70% to about 95%, or about 80% to about 95%. In some embodiments, the heterogeneous catalyst module is characterised by a porosity of about 90% to about 95%.
  • the heterogeneous catalyst module or at least the fibrous matrix is characterised by a pore size of about 50 nm to about 100 pm.
  • the pore size is about 100 nm to about 100 pm, about 200 nm to about 100 pm, about 300 nm to about 100 pm, about 400 nm to about 100 pm, about 500 nm to about 100 pm, about 600 nm to about 100 pm, about 700 nm to about 100 pm, about 800 nm to about 100 pm, about 900 nm to about 100 pm, about 1 pm to about 100 pm, about 10 pm to about 100 pm, about 20 pm to about 100 pm, about 30 pm to about 100 pm, about 40 pm to about 100 pm, about 50 pm to about 100 pm, about 50 pm to about 90 pm, about 50 pm to about 80 pm, or about 50 pm to about 70 pm.
  • the heterogeneous catalyst module is characterised by a pore size of about 65 pm.
  • the heterogeneous catalyst module (or at least the fibrous matrix) is characterised by a compressive stress at 50% strain of about 0.1 MPa to about 0.2 MPa.
  • the compressive stress is about 0.1 MPa to about 0.19 MPa, about 0.1 MPa to about 0.18 MPa, about 0.1 MPa to about 0.17 MPa, about 0.1 MPa to about 0.16 MPa, or about 0.1 MPa to about 0.15 MPa.
  • the heterogeneous catalyst module is characterised by a compressive modulus at 50% strain of about 0.12 MPa to about 0.15 MPa.
  • the heterogeneous catalyst module (or at least the fibrous matrix) is characterised by a reversible deformation when deformed up to about 90%. In other embodiments, the deformation is reversible when deformed up to about 85%, 80%, 75% or 70%.
  • the heterogeneous catalyst module has a length of about 0.5 cm to about 50 cm. In other embodiments, the length is about 0.5 cm to about 45 cm, about 0.5 cm to about 40 cm, about 0.5 cm to about 35 cm, about 0.5 cm to about 30 cm, about 0.5 cm to about 25 cm, about 0.5 cm to about 20 cm, about 0.5 cm to about 15 cm, about 0.5 cm to about 10 cm, or about 0.5 cm to about 5 cm.
  • the heterogeneous catalyst module has a breadth of about 0.5 cm to about 50 cm. In other embodiments, the breadth is about 0.5 cm to about 45 cm, about 0.5 cm to about 40 cm, about 0.5 cm to about 35 cm, about 0.5 cm to about 30 cm, about 0.5 cm to about 25 cm, about 0.5 cm to about 20 cm, about 0.5 cm to about 15 cm, about 0.5 cm to about 10 cm, or about 0.5 cm to about 5 cm.
  • the heterogeneous catalyst module has an area of about 0.25 cm 2 to about 2500 cm 2 .
  • the area is about 0.25 cm 2 to about 2000 cm 2 , about 0.25 cm 2 to about 1800 cm 2 , about 0.25 cm 2 to about 1600 cm 2 , about 0.25 cm 2 to about 1400 cm 2 , about 0.25 cm 2 to about 1200 cm 2 , about 0.25 cm 2 to about 1000 cm 2 , about 0.25 cm 2 to about 800 cm 2 , about 0.25 cm 2 to about 600 cm 2 , about 0.25 cm 2 to about 400 cm 2 , or about 0.25 cm 2 to about 200 cm 2 .
  • the heterogeneous catalyst module has a width or thickness of about 0.01 mm to about 50 mm. In other embodiments, the width is about 0.1 mm to about 50 mm, about 0.5 mm to about 50 mm, about 1 mm to about 50 mm, about 5 mm to about 50 mm, about 10 mm to about 50 mm, about 15 mm to about 50 mm, about 20 mm to about 50 mm, about 25 mm to about 50 mm, about 30 mm to about
  • the heterogeneous catalyst module has a volume of about 2.5 x 10 s cm 3 to about 1250 cm 3 .
  • the volume is about 2.5 x 10 s cm 3 to about 1000 cm 3 , about 2.5 x 10 s cm 3 to about 1000 cm 3 , about 2.5 x 10 s cm 3 to about 1000 cm 3 , about 2.5 x 10 s cm 3 to about 800 cm 3 , about 2.5 x 10 s cm 3 to about 600 cm 3 , about 2.5 x 10 s cm 3 to about 400 cm 3 , about 2.5 x 10 s cm 3 to about 200 cm 3 , about 2.5 x 10 s cm 3 to about 100 cm 3 , about 2.5 x 10 s cm 3 to about 10 cm 3 , or about 2.5 x 10 s cm 3 to about 1 cm 3 .
  • the heterogeneous catalyst module is modular.
  • the heterogeneous catalyst module can be replaced when it is expended, or a number of heterogeneous catalyst modules can be stacked together to extend the reaction.
  • the flow reactor comprises two or more heterogeneous catalyst modules.
  • the heterogeneous catalyst modules can be stacked either in a parallel configuration or in series. Additionally, when two or more heterogeneous catalyst modules are stacked, the catalyst can be the same or different.
  • the fibrous matrix (and its associated heterogeneous catalyst) is modular.
  • the fibrous matrix may be replaced when it is expended, or a number of fibrous matrix can be arranged in series to conduct a reaction in a step- wise manner.
  • the flow reactor further comprises a body.
  • the body acts as a housing for containing the heterogeneous catalyst module.
  • the body can include at least two stainless-steel cover plates, at least two copper conducting plates, graphite plate, strews, PTFE gaskets, O-rings, tubing, and plug-in adaptors. The setup ensures that the flow reactor does not leak when in use.
  • flow reactor further comprises a graphite plate.
  • Graphite plate can have grooves which acts a flow-guide to direct a flow of reagents. By aligning graphite plate with the inlet and the outlet, the flow direction can be regulated.
  • titanium plates or stainless steel plates can be used.
  • the graphite plate can have a parallel path design on one side (open configuration), and a flat unmodified configuration (closed configuration) on the other side.
  • the graphite plate has a parallel path design on both sides where the flow path can be the same or different.
  • the graphite plate has a parallel path design on one side, and an open gas-diffusional configuration on the other side.
  • the graphite plate(s) can be multiple stacked to allow the flow direction in series or parallel configuration, and with multiple heterogeneous catalyst modules. This allows multiple reactions to be performed in parallel in a single flow reactor.
  • the flow reactor further comprises temperature control means.
  • the temperature control means comprises stainless stain plates with heating rods electrically connected to a thermocouple and a digital controller. The heating rods can be plugged into the stainless-steel plates to avoid direct contact with organic solvent and catalyst.
  • the temperature control means is capable of varying the temperature from about -20 °C to about 100 °C. In some embodiments, the temperature control means is capable of varying the temperature from about 20 °C to about 70 °C.
  • the flow reactor further comprises flow control means.
  • the flow control means is selected from a peristaltic pump, a syringe pump or a high performance liquid chromatography (HPLC) pump.
  • the flow control means is a peristaltic pump for high flow rate and operation in ambient pressure.
  • the flow reactor further comprises voltage control means.
  • the voltage control means is an electrochemical workstation (potentiostat). The voltage control means allow a supply of voltage on the copper conducting plates in the body. A separated membrane such as National or Celgard membrane can be further inserted between the copper plates to avoid short circuit.
  • the flow reactor further comprises light control means.
  • the light control means is selected from a light-emitting diode (LED), a xenon lamp or a mercury lamp.
  • the stainless steel cover plates and copper conducting plates in the body can be modified with an optical window (quartz or fused silica) for light transmission (Figure 6), modified with current collectors for electrochemical reactions (Figure 7), and/or modified with catholytic chamber for gas-liquid-solid 3- phase reaction (Figure 8).
  • the flow reactor further comprises sampling means.
  • the sampling means allows for an aliquot to be extracted for sampling, and also to allow for a fraction of the reaction to be isolated.
  • the flow reactor further comprises purification means.
  • the purification means isolates and purifies the final product.
  • the flow reactor is modular.
  • the flow reactor can be combined with another flow reactor to extend the reaction. Due to its stack-by-stack architecture, extra flexibility in hardware modification is provided compared to packed bed reactors (fixed hardware).
  • the present invention also provides a heterogeneous catalyst module, comprising a flow channel and heterogeneous catalysts on a fibrous matrix within the flow channel, wherein the heterogeneous catalyst module is configured to produce a turbulent flow at at least a central portion of a transverse section of the flow channel when in use under ambient pressure.
  • the heterogeneous catalyst module comprises a flow channel and heterogeneous catalysts on a fibrous matrix within the flow channel, wherein the fibrous matrix is configured to produce a turbulent flow at at least a central portion of a transverse section of the flow channel when in use under ambient pressure.
  • the present invention also provides a method of fabricating a flow reactor, comprising: a) positioning a heterogeneous catalyst module between an inlet and an outlet, the heterogeneous catalyst module in fluid communication with the inlet and the outlet; wherein the heterogeneous catalyst module comprises a flow channel and heterogeneous catalysts on a fibrous matrix within the flow channel, the flow channel in fluid communication with the inlet and the outlet; and wherein the heterogeneous catalyst module is configured to produce a turbulent flow at at least a central portion of a transverse section of the flow channel when in use under ambient pressure.
  • the present invention also provides a method of fabricating a heterogeneous catalyst module, comprising: a) attaching at least two layers of transition metal dichalcogenide (TMD) on a fibrous matrix; b) intercalating a transition metal precursor between the at least two TMD layers; c) annealing the transition metal precursor in order to form transition metal atoms between the at least two TMD layers as the heterogeneous catalyst on the fibrous matrix; and d) positioning the heterogeneous catalyst on the fibrous matrix within a flow channel.
  • TMD transition metal dichalcogenide
  • the method of fabricating a heterogeneous catalyst module comprises: a) attaching at least two layers of transition metal dichalcogenide (TMD) on a fibrous matrix; b) incorporating a transition metal precursor between the at least two TMD layers; c) annealing the transition metal precursor in order to form transition metal atoms between the at least two TMD layers as the heterogeneous catalyst on the fibrous matrix; and d) positioning the heterogeneous catalyst on the fibrous matrix within a flow channel.
  • TMD transition metal dichalcogenide
  • the at least two layers of TMD is attached by hydrothermally treating the fibrous matrix with a TMD precursor.
  • Hydrothermal synthesis can be defined as a method of synthesis of single crystals that depends on the solubility of minerals in hot water under high pressure. The crystal growth is usually performed in an apparatus consisting of a steel pressure vessel called an autoclave, in which a precursor is supplied along with water. A temperature gradient is maintained between the opposite ends of the growth chamber. At the hotter end the nutrient solute dissolves, while at the cooler end it is deposited on a seed crystal, growing the desired crystal.
  • the TMD precursor is a mixture of sodium molybdate and thiourea.
  • a molar ratio of sodium molybdate to thiourea is about 1 :2 to about 1 :5. In other embodiments, the molar ratio is about 1:2 to about 1 :4, or about 1 :2 to about 1:3. In some embodiments, a molar ratio of sodium molybdate to thiourea is about 1:2.
  • the concentration of the transition metal precursor is about 0.1 mM to about 10 mM. In other embodiments, the concentration is about 1 mM to about 10 mM, about 2 mM to about 10 mM, about 3 mM to about 10 mM, about 3 mM to about 9 mM, about 3 mM to about 8 mM, or about 3 mM to about 7 mM.
  • the hydrothermal treatment is performed at about 150 °C to about 300 °C, about 150 °C to about 280 °C, about 150 °C to about 260 °C, about 150 °C to about 240 °C, about 150 °C to about 220 °C, about 150 °C to about 200 °C, about 160 °C to about 200 °C, or about 180 °C to about 200 °C. In other embodiments, the hydrothermal treatment is performed at about 190 °C.
  • the hydrothermal treatment is performed for about 1 h to about 48 h. In other embodiments, the duration is about 2 h to about 48 h, about 4 h to about 48 h, about 6 h to about 48 h, about 8 h to about 48 h, about 12 h to about 48 h, about 16 h to about 48 h, about 20 h to about 48 h, about 20 h to about 44 h, about 20 h to about 40 h, about 20 h to about 36 h, about 20 h to about 32 h, or about 20 h to about 28 h. In some embodiments, the hydrothermal treatment is performed for about 24 h.
  • the heterogenous catalyst module is characterised by a TMD loading on the fibrous matrix of about 30 mg cm -2 to about 100 mg cm' 2 , about 30 mg cm' 2 to about 90 mg cm' 2 , about 30 mg cm' 2 to about 80 mg cm' 2 , about 30 mg cm' 2 to about 70 mg cm' 2 , about 30 mg cm' 2 to about 60 mg cm' 2 , about 30 mg cm' 2 to about 50 mg cm' 2 , or about 40 mg cm' 2 to about 50 mg cm' 2 .
  • the heterogenous catalyst module is characterised by a TMD loading on the fibrous matrix of about 45 mg cm' 2 .
  • the transition metal precursor is a transition metal complex or a transition metal salt selected from the group consisting of metal phthalocyanine complex, metal 5,10,15,20-(tetra-N-methyl-4-pyridyl)porphyrin tetrachloride complex, metal 5,10,15,20-(tetraphenyl)porphyrin complex, metal 5,10,15,20-(tetra-N,N,N- trimethyl-4-anilinium) porphyrin tetrachloride complex, metallocene complexes, metal salen complex, metal phenanthroline complex, metal a cetyl aceton ate complex, metal acetates, metal chlorides, metal nitrates, and a combination thereof.
  • metal phthalocyanine complex metal 5,10,15,20-(tetra-N-methyl-4-pyridyl)porphyrin tetrachloride complex
  • the transition metal precursor has a transition metal selected from iron, cobalt, nickel, copper, palladium, platinum, gold, ruthenium, silver or a combination thereof.
  • the transition metal precursor is physically or chemically anchored on the TMD surface, doped into the TMD lattice or intercalated between the at least two TMD layers.
  • the intercalation and/or incorporation step is performed at about 40 °C to about 100 °C. In other embodiments, the temperature is about 50 °C to about 100 °C, about 60 °C to about 100 °C, about 70 °C to about 100 °C, or about 70 °C to about 90 °C. In some embodiments, the intercalation and/or incorporation step is performed at about 80 °C.
  • the intercalation and/or incorporation step is performed for about 1 h to about 24 h. In other embodiments, the duration is about 1 h to about 20 h, about 1 h to about 16 h, about 1 h to about 12 h, about 1 h to about 8 h, or about 1 h to about 4 h. In some embodiments, the intercalation and/or incorporation step is performed for about 2 h.
  • the transition metal precursor is electrochemically intercalated between the at least two TMD layers. In some embodiments, the transition metal precursor is subjected to a negative voltage for intercalating the plurality of transition metal precursors between the at least two TMD layers.
  • the annealing step allows for the thermal decomposition of the transition metal precursor to the transition metal atom.
  • the annealing step also allows for the thermal decomposition of the co-intercalant, if present. This step ensures the complete conversion of the transition metal precursors to transition metal atoms within the TMD layers. This also allows for the increased binding of the transition metal atom to the TMD layers.
  • the annealing step is performed at about 150 °C to about 1000 °C.
  • the temperature is about 150 °C to about 900 °C, about 150 °C to about 800 °C, about 150 °C to about 700 °C, about 200 °C to about 700 °C, about 300 °C to about 700 °C, about 400 °C to about 700 °C, or about 500 °C to about 700 °C.
  • the annealing step is performed at about 300 °C to about 700 °C.
  • the annealing step is performed for about 0.5 h to about 24 h. In other embodiments, the duration is about 0.5 h to about 20 h, about 1 h to about 20 h, about 1 h to about 16 h, about 1 h to about 12 h, about 1 h to about 8 h, or about 1 h to about 4 h. In some embodiments, the annealing step is performed for about 2 h.
  • the annealing step is performed under inert conditions, oxidative conditions or reductive conditions.
  • the heterogenous catalyst module is characterised by a transition metal loading on the TMD of about 0.5 wt%.
  • the method further including a step after step (a) of contacting the at least two TMD layers with a co-intercalant.
  • the co-intercalant is selected from the group consisting of cetyltrimethylammonium bromide (CTAB), tetrapropylammonium chloride (TRAC), tetramethylammonium salts (TMA), tetrabutylammonium salts (TBA) and tetraethylammonium salts (TEA).
  • CTAB cetyltrimethylammonium bromide
  • TMA tetrapropylammonium chloride
  • TMA tetramethylammonium salts
  • TSA tetrabutylammonium salts
  • TEA tetraethylammonium salts
  • the present invention also provides a method of catalysing a reaction using the flow reactor as disclosed herein.
  • the flow rate is about 0.01 mL min- 1 to about 100 mL min 1 .
  • the chemoselectivity toward fine chemical production is not only attributed to chemical modification of the support (catalyst layer), but also the inherent nature of fast reaction kinetics in flow setup compared to batch reaction. This allows the differentiation in the reactivity of various functional groups to prevent typical side reactions in late stage functionalization of pharmaceuticals.
  • the flow rate is about 0.01 mL min 1 to about 90 mL min 1 , about 0.01 mL min 1 to about 80 mL min 1 , about 0.01 mL min 1 to about 70 mL min 1 , about
  • the flow rate is about 0.1 mL min 1 to about 100 mL min 1 , about 0.5 mL min 1 to about 100 mL min 1 , about 1 mL min 1 to about 100 mL min 1 , about 2 mL min 1 to about 100 mL min 1 , about 3 mL min 1 to about 100 mL min 1 , about 4 mL min 1 to about 100 mL min 1 , about 5 mL min 1 to about 100 mL min 1 , about 10 mL min 1 to about 100 mL min 1 , about 10 mL min 1 to about 90 mL min 1 , about 10 mL min 1 to about 80 mL min 1 , about 10 mL min 1 to about 70 mL min 1 , about 10 mL min- 1 to about 60 mL min 1 , or about 10
  • the method is performed at a pressure of about 1 atm.
  • pressure is changed whenever an obstacle is presented in the flow path.
  • the front end or inlet experiences a higher hydraulic pressure while the back end experiences lower pressure. This leads to an abrupted flow rate (usually much higher flow rate due to higher pressure gradient) in flow path and this is one of the underlying reasons why laminar-to-turbulent flow occurs inside the reactor.
  • the change in pressure is about 0.01 atm to about 0.1 atm.
  • the method is performed at a temperature of about 5 °C to about 100 °C.
  • the temperature is about 10 °C to about 100 °C, about 15 °C to about 100 °C, about 20 °C to about 100 °C, about 30 °C to about 100 °C, about 40 °C to about 100 °C, about 50 °C to about 100 °C, about 60 °C to about 100 °C, or about 70 °C to about 100 °C.
  • the temperature is about 10 °C to about 80 °C, or about 20 °C to about 80 °C.
  • the method is performed for at least 5 sec.
  • the duration is at least 10 sec, 20 sec, 30 sec, 1 min, 5 min, 10 min, 20 min, 30 min, 1 h, 2 h, 4 h, 6 h, 12 h or 24 h.
  • continuous operation for at least 24 hours is verified without performance degradation in chemical production.
  • Conversion is a term used in the art to describe as a ratio (or percentage) of how much of a reactant has reacted.
  • Corollary, yield is a term used in the art to describe as a ratio (or percentage) of how much of a desired product was formed relative to the reactant consumed.
  • Selectivity or chemoselectivity is a term used in the art to describe as a ratio (or percentage) of how much desired product was formed relative to the total products (desired + undesired).
  • the reaction has a conversion rate of at least 90%. In other embodiments, the conversion rate is at least 92%, at least 94%, at least 96% or at least 98%. In other embodiments, the conversion rate is at least 99%.
  • the reaction is an oxidation of a compound having a sulphide (or sulfide) moiety. In other embodiments, the reaction is an oxidation of a compound having a sulfoxide moiety. In some embodiments, the reaction is chemoselective for sulphide and/or sulfoxide. In some embodiments, the sulphide moiety is oxidised to a sulfone moiety or sulfoxide moiety.
  • Chemoselectivity refers to a preferential outcome of a chemical reaction over a set of possible alternative reactions. Chemoselectivity can also refer to the selective reactivity of one functional group in the presence of others. Chemoselectivity of a reaction is difficult to predict, as the physical outcome of a reaction is dependent on a number of factors that are practically impossible to predict to any useful accuracy (solvent, atomic orbitals, etc.).
  • a reaction from la 2a can be completed within less than 10 sec with a 99% chemoselectivity using the flow reactor, in contrast to a batch synthesis which requires about 20 min.
  • the compound having a sulphide moiety is a compound of Formula (I): wherein Ri and 2 are independently selected from optionally substituted amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • Ri is selected from optionally substituted aryl and optionally substituted heteroaryl.
  • 2 is selected from optionally substituted amino, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl.
  • the compound having a sulphide moiety is selected from thioanisole, phenyl disulfide, diphenyl sulfide, dibenzyl sulfide, 2-(methylthio) thiophene and 2-(methylthio)pyridine.
  • the compound having a sulphide moiety is selected from thioanisole, 4-(methylthio)-benzaldehyde, 4-(methylthio)benzyl alcohol, 4-(methylthio)benzylamine, 4-(methylthio)anisole, 4-(methylthio)aniline, 4- (methylthio)phenyl boronic acid, 4-thioanisoleboronic acid, pinacol ester, 4'- (methylthio)acetophenone, phenyl propargyl sulfide, 4-(methylthio) benzoyl chloride, 4-(methylthio)benzoic acid, 4-(methylthio) benzonitrile, l-methoxy-4- (methylthio)benzene, 4-bromophenyl methyl sulfide, allyl phenyl sulfide, allyl sulfide, diphenyl sulfide, phenyl disulfide, dibenzyl sulfide, 2,
  • the method when a compound having a sulphide moiety is oxidised, the method is characterised by a chemoselectivity of at least 90%. In other embodiments, the chemoselectivity is at least 85%, 80%, 75% or 70%. In other embodiments, the selectivity is at least 92%, at least 94%, at least 96% or at least 98%. In other embodiments, the selectivity is at least 99%.
  • the method when a compound having a sulphide moiety is oxidised, the method further comprises flowing an oxidising agent into the flow reactor.
  • the oxidising agent is an organic oxidising agent or an inorganic oxidising agent.
  • the oxidising agent is an organic or inorganic peroxide.
  • the oxidant is H2O2.
  • the oxidant is selected from ozone (O3), metal peroxides (such as Na2O2), organic peroxides (such as tertbutylhydroperoxide, tBuOOH), and peroxycarboxylic acids (such as metachloroperoxybenzoic acid (mCPBA)).
  • the oxidant is selected from H2O2 and meta-chloroperoxybenzoic acid (mCPBA).
  • R can be optionally substituted alkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted arylalkyl or optionally substituted cycloalkyl.
  • a mole ratio of the oxidising agent to the compound having a sulphide moiety is about 1: 1 to about 5: 1. In other embodiments, the molar ratio is about 1: 1 to about 4: 1, about 1: 1 to about 3: 1, or about 1: 1 to about 2: 1. In some embodiments, a mole ratio of the oxidising agent to the compound having a sulphide moiety is about 1: 1.
  • the catalytic oxidation of sulphide to either sulfone or sulfoxide can be controlled by varying the amount of oxidant.
  • sulphide is oxidised to sulfone.
  • the at least two or more equivalence of oxidant can be at least about 2 equivalence, about 2.1 equivalence, about 2.2 equivalence, about 2.3 equivalence, about 2.4 equivalence, about 2.5 equivalence, about 3 equivalence, about 5 equivalence, or about 10 equivalence.
  • the at least one or less than two equivalence of oxidant can be about 1 equivalence to less than 2 equivalence, about 1 equivalence to about 1.9 equivalence, about 1 equivalence to about 1.8 equivalence, about 1 equivalence to about 1.7 equivalence, about 1 equivalence to about 1.6 equivalence, about 1 equivalence to about 1.5 equivalence, about 1 equivalence to about 1.4 equivalence, about 1 equivalence to about 1.3 equivalence, about 1 equivalence to about 1.2 equivalence, or about 1 equivalence to about 1.1 equivalence.
  • the at least one or less than two equivalence of oxidant can be about 1 equivalence, about 1.1 equivalence, about 1.2 equivalence, about 1.3 equivalence, about 1.4 equivalence, or about 1.5 equivalence.
  • the sulfoxide can be subsequently further oxidised to a sulfone. This can be performed by providing further oxidant (of at least 1 equivalence in the presence of the catalyst of the present invention) to the sulfoxide.
  • a solvent is selected from acetonitrile (AN), water, hydrocarbyl aliphatic alcohols (such as ethanol, isopropanol), ethyl acetate (EA), N,N-dimethylformamide (DMF), N-methyl-2- pyrrolidone (NMP) and dimethyl sulfoxide (DMSO), or a combination thereof.
  • AN acetonitrile
  • water hydrocarbyl aliphatic alcohols
  • EA ethyl acetate
  • DMF N,N-dimethylformamide
  • NMP N-methyl-2- pyrrolidone
  • DMSO dimethyl sulfoxide
  • the solvent has a boiling point of about 60 °C to about 250 °C.
  • the heterogeneous catalyst is selected from C01-M0S2, Nii-MoS?, Fei-MoS?, CU1-M0S2 and Pti-MoS2.
  • the reaction is a reduction of a compound having a nitro moiety.
  • the reaction is chemoselective to the nitro moiety.
  • other functional group such as alkyne, alkene, ketone, aldehyde, carboxylic acid, boronic acid and ester, isocyanate, nitrile, heterocycle or a combination thereof are not reacted. Accordingly these functional groups can form part of the compound.
  • 5 grams of multifunctional aniline can be produced in flow within 1 hour by chemo-selective nitro-reduction using a 16 cm 2 Pti-MoS? module. This is at least 10 folds increase in productivity (per hour) than packed bed reactor.
  • the compound having a nitro moiety is a compound of Formula (II):
  • the compound having a nitro moiety is a compound of Formula (Ha):
  • compound of Formula (Ila) is reduced to a compound having an aniline moiety.
  • the method when a compound having a nitro moiety is reduced, the method is characterised by a chemoselectivity of at least 90%. In other embodiments, the chemoselectivity is at least 85%, 80%, 75% or 70%. In other embodiments, the selectivity is at least 92%, at least 94%, at least 96% or at least 98%. In other embodiments, the selectivity is at least 99%.
  • the compound having a nitro moiety is selected from nitrobenzene, 4-nitrotoluene, 4-nitroanisole, 4-nitrobiphenyl, l-fluoro-4-nitrobenzene, l-chloro-4-nitrobenzene, l-bromo-4-nitrobenzene, l-iodo-4-nitrobenzene, 4- nitrobenzyl bromide, 4-nitrobenzotrifluoride, pentafluoronitrobenzene, 4-nitroaniline, 4- nitrophenol, 4-nitrobenzoic acid, 2-nitroaniline, 4-nitrophenyl isocyanate, 4- nitrobenzenesulfonamide, 4-nitrobenzonitrile, methyl 4-nitrobenzoate, 3-nitrostyrene, 4-nitrostyrene, trans-p-nitrostyrene, trans-2-nitrocinnamic acid, trans-4-nitro-cinnamic acid, l-ethynyl-4-nitrobenzene, l-
  • the method when a compound having a nitro moiety is reduced, the method further comprises flowing a reducing agent into the flow reactor.
  • the reducing agent is an organic reducing agent or an inorganic reducing agent.
  • the reducing agent is selected from ammonia borane complex (NH3BH3), sodium hydroborate (NaBFU), lithium aluminium hydride (LiAIFU), hydrazine (N2H4), formic acid, ascorbic acid, hydrogen gas, or a combination thereof.
  • NH3BH3 ammonia borane complex
  • NaBFU sodium hydroborate
  • LiAIFU lithium aluminium hydride
  • N2H4 hydrazine
  • formic acid ascorbic acid
  • hydrogen gas or a combination thereof.
  • a mole ratio of the reducing agent to the compound having a nitro moiety is about 1 : 1 to about 5: 1. In other embodiments, the molar ratio is about 1 : 1 to about 4: 1, about 1: 1 to about 3:1, or about 1 : 1 to about 2: 1. In some embodiments, a mole ratio of the oxidising agent to the compound having a nitro moiety is about 1: 1.
  • a solvent when a compound having a nitro moiety is reduced, is selected from acetonitrile (AN), water, hydrocarbyl aliphatic alcohols (such as ethanol, isopropanol), ethyl acetate (EA), or a combination thereof.
  • AN acetonitrile
  • water hydrocarbyl aliphatic alcohols (such as ethanol, isopropanol), ethyl acetate (EA), or a combination thereof.
  • the solvent has a boiling point of about 60 °C to about 250 °C.
  • the heterogeneous catalyst is selected from C01-M0S2, Nii-MoS2, Fei-MoS2, CU1-M0S2 and Pti-MoS2.
  • the heterogeneous catalyst when the heterogeneous catalyst is transition metal atoms intercalated and/or incorporated between at least two TMD layers, the heterogeneous catalyst is selective to sulphide or nitro moieties.
  • Sensitive functional groups alkenes, ketones, aldehydes, carboxylic acids, boronic acids, benzyl alcohol, pyridine, quinolone, esters, and amines can also be retained (not modified).
  • the compound further comprises at least one moiety which is not sulphide, sulfoxide and/or nitro.
  • the moiety can be alkynes, alkenes, ketones, aldehydes, carboxylic acids, boronic acids, esters, amines, heterocyclyl or a combination thereof.
  • the at least one moiety is not modified by the method. In other words, the moiety is at least not oxidised or reduced by the method.
  • the present invention also provide a method of synthesising Tamiflu or a salt, solvate or derivative thereof, comprising flowing precursors for synthesising Tamiflu through the flow reactor as disclosed herein.
  • Gram-level production of sulfoxide-modified Tamiflu can be obtained by continuous-flow sulfide oxidation using a 16 cm 2 C01-M0S2 module.
  • the present invention also provide a method of synthesising Clethodim or a salt, solvate or derivative thereof, comprising flowing precursors for synthesising Tamiflu through the flow reactor as disclosed herein.
  • the present invention also provides a method of catalysing a reaction, comprising : a) contacting a compound having a nitro moiety with a heterogeneous catalyst and a reductant, the heterogeneous catalyst comprising: i) a substrate; ii) at least two layers of transition metal dichalcogenide (TMD), the at least two TMD layers attached to the substrate; and
  • TMD transition metal dichalcogenide
  • the method of catalysing a reaction comprises: a) contacting a compound having a nitro moiety with a heterogeneous catalyst and a reductant, the heterogeneous catalyst comprising: i) a substrate; ii) at least two layers of transition metal dichalcogenide (TMD), the at least two TMD layers attached to the substrate; and
  • TMD transition metal dichalcogenide
  • the substrate can be the fibrous matrix as disclosed herein.
  • the present invention allows operation under ambient pressure with a flow rate of 20 mL min 1 . This leads to a huge improvement in the efficiency to fully convert the reaction (typically less than 2 mins) and an extremely high turnover frequency value of ⁇ 1,200 h 1 . As a demonstration, the production of 5 grams of multifunctional anilines can be furnished in one hour, much faster than those using packed bed reactors ( ⁇ 24 h). Additionally, the setup also provides excellent flexibility on the exchangeable catalyst module, designable flow path (both size/series or parallel configuration) and multifunctional purpose (suitable for electrochemistry and photochemistry), which are very challenging in packed bed reactors.
  • the flow reactor can be constructed with compressed reactor cells arranged in series or parallel with customized modifications on the catalyst modules and flow channels to endow catalytic activity and enable the operation in corrosive organic solvents.
  • a typical configuration of the flow cell is provided in Figure 1.
  • Chemical modification of the 3D fibrous support may be employed to promote the chemoselectivity in redox reactions.
  • a chemoselectivity of > 99% for sulfide oxidation and nitro-reduction is shown which facilitates production of multifunctional building blocks and pharmaceuticals using single atom catalyst modules. This paves the way toward successful process transfer from academy to industry.
  • the mechanical robustness is validated by compressive strain-stress measurement in Figure 2C.
  • the catalyst module shows a much higher compressive strength than blank support ( ⁇ 200% increase in stress at 50% strain and ⁇ 150% increase in compressive modulus), and tolerates at least 5 independent compressive cycles with a 90% of shape deformation without any structural degradation or powder detachment. This proves the excellent adhesion of active component on the support for its use in flow reaction, where local stress concentration is expected to be a primary catalyst deactivation factor.
  • the surface wettability of such catalyst module is highly tailorable. For instance, annealing in air together with chemical modification lead to the conversion of a hydrophobic surface into hydrophilic.
  • Semi-oxidation product is detected at a low flow rate of 0.2 or 0.5 mL min 1 owing to poor interaction between fluent and solid catalyst in the laminar flow, proving the importance to induce local turbulence in reactor designs.
  • the flow reactor allows fast screening on the reaction temperature, concentration of reactant, reagent ratio and flow rate within a reasonable period, thus superior to conventional batch process.
  • Various sulfides bearing oxidation prone functionalities are examined to assess the generality of our flow setup.
  • Figure 3D shows some examples of sulfones and sulfoxides that can be formed using the flow reactor.
  • the sulfide derivative of Tamiflu treatment of influenza
  • an electron-deficient alkene that is prone to traditional oxidation in batch process
  • Ultrapure compounds at gramscale can be obtained by recrystallization.
  • Clethodim selective postemergence herbicide for annual and perennial grasses
  • Clethodim selective postemergence herbicide for annual and perennial grasses
  • the sulfide subunit in the phenothiazine family can be distinguished from more reactive sulfide group on the side chain, where selective oxidation of the latter occurs at a lower reaction temperature to produce a wide assortment of phenothiazine pharmaceuticals (Mesoridazine, Dimetotiazine etc).
  • the turnover frequency remains at a very high number of > 800 h 1 in a wide range of 5 to 15 mL min 1 , proving good productivity in real operation with flow rate fluctuation.
  • our chemo-selective reduction protocol is compatible with other sensitive functionalities. For instance, multifunctional amines with alkyl (2a, 2b)-, aryl- (2d), alkoxyl- (2c), halogen- (2e ⁇ 2i, 2w), amino- (2j), sulfonamide- (2/), ester- (2m), methylthio- (2q) and boronic acid pinacol ester (2r) substitutions at the para position can be efficiently synthesized (65 ⁇ 99% yield).
  • 6-nitrochromone (2u) and 4-nitrochalcone (2iz) bearing multiple reducible groups (ketone and internal alkene) can also be selectivity reduced to the corresponding amines, which has never been achieved by previous methods owing to the difficulty to avoid unfavorable side reactions.
  • the continuous-flow production is also applicable toward anthracene (2z) and heterocycles, including pyridine (2y), quinoline (2x), oxindole (2aa) and phthalide (2aft), despite of apparently lower yields in some cases.
  • the flow reactor and catalyst module is easily scalable and has a lower manufacturing cost than packed bed reactor. It has designable internal flow channels, and is upgradable to multiple stacks for tandem operation and multiple functions for electrochemistry or photochemistry.
  • the flow reactor as disclosed herein can be used in prototyping and processes for continuous production.
  • pharmaceutical production where a high chemoselectivity is required can be facilitated using this flow reactor.
  • It serves as a high flow rate, modularized and multifunctional replacement of current packed bed reactors (such as R-Series by Vapourtec and H-Cube by ThalesNano) using powder catalyst.
  • Advantages include lower cost ( ⁇ 2,000 SGD per unit versus > 60,000 SGD in commercial setup), smaller foot print ( ⁇ 0.1 m 2 ), no operational pressure (vs. ⁇ 10 bar in standard packed bed reactor), high flow rate (20 mL min 1 vs. ⁇ 1 mL min 1 ) and multifunctional purpose (suitable for electrochemistry and photochemistry).
  • the catalyst module serves as a low-cost, modularized replacement of catalyst cartridge (nanoparticle powder catalyst) in packed bed reactors.
  • a key technology advance lies in the bifunctionality of catalyst module, where its mechanical robustness, porosity and chemical tunability allow chemoselective flow operation under ambient pressure. It can also be used in flow batteries and fuel cells for energy storage and conversion.
  • Fine chemicals and specialty chemicals e.g. synthesis of multifunctional sulfoxides, sulfoxides or anilines containing intermediates and pharmaceuticals, which are prone to side reaction in batch processes can be consistently produced using the flow reactors.
  • the flow reactor is also a low-cost alternative to packed -bed reactors for those applications involving heterogeneous catalysis.
  • the flow reactor is especially beneficial for start-up companies or laboratories on small-quantity production where flexibility on the catalyst module, flow path (both size/series or parallel configuration) and on-task function can be met.
  • Example 1 Typical flow cell configuration:
  • the flow cell was assembled with two stainless-steel cover plates, two copper plates, two monopolar graphite plates with a parallel path design for organic solvent distribution on one side and a closed configuration on the other side, a 4 x 4 cm 2 graphite felt catalyst, PTFE gaskets, O-rings, and plug-in adaptors for silicone tubing.
  • Flow rate was controlled by a peristaltic pump and temperature was controlled by two heating rods with thermocouple and digital controller. The heating rods were plugged into the stainless-steel plates to avoid direct contact with organic solvent.
  • Example 2 An example of fabricating the catalyst module (C01-M0S2 module):
  • M0S2 nanosheets were directly grown on Ch-treated, hydrophilic graphite felt by a simple hydrothermal method.
  • 4.355 g of Na2MoO4'2H2O and 3.648 g of thiourea were dissolved in 100 mL of deionized water. After gentle stirring for 30 min, the solution was then transferred to a 250 mL Teflon-lined stainless-steel autoclave with a piece of graphite felt (4 x 4 cm 2 ). The autoclave was sealed and heated at 190 °C for 24 h in an oven and then cooled down to room temperature naturally. The product was taken out, rinsed with deionized water and ethanol several times and dried at 60 °C in air.
  • the loading of M0S2 nanosheet on graphite felt was ⁇ 45 mg cm' 2 .
  • as-grown M0S2 materials were immersed into 100 mL of CoCl2'6H2O aqueous solution (10 mM) at 80 °C for 2 h, and then rinsed with DI water and ethanol before dried at 60 °C.
  • the modified material was loaded into a quartz tube mounted inside a tube furnace under 95%/5% Ar/H? mixture and heated at 300 °C for 2 h at 10 °C min- T
  • the Co loading on M0S2 was determined as ⁇ 0.5 wt%.
  • Pti, Fei, Nil or CU1-M0S2 modules can be fabricated by a similar method.
  • a C01-M0S2 module was loaded into the flow cell.
  • a pre-mixed solution of 0.025 M thioanisole and 0.125 M H2O2 in acetonitrile was supplied to the flow cell by peristaltic pump and the flow rate was regulated to desired values e.g., 2 mL min 1 ).
  • the flow cell was heated to desired temperatures (e.g., 70 °C) with the heating unit.
  • the clear solution was collected after a stable period of 30 mins for each temperature or flow rate.
  • the product was examined by GC-MS to determine the conversion and yield.
  • a pre-mixed solution of 0.25 M phenyl propargyl sulfide and 1.25 M H2O2 in acetonitrile was supplied to the flow cell with a C01-M0S2 module by peristaltic pump and the flow rate was regulated to 2 mL min 1 .
  • the flow cell was heated to 70 °C with the heating unit.
  • the clear solution was collected for a continuous operation of 60 mins to afford ⁇ 120 mL of crude solution.
  • Isolated compound ( ⁇ 5.4 g, > 98% selectivity) was obtained by rotary evaporation and the conversion, yield and selectivity were determined by NMR.
  • Tamiflu (Oseltamivir phosphate) was first subjected to sulfuration by reacting with 2- (phenylthio)acetyl chloride in anhydrous tetra hydrofuran for 12 hours and purified by flash column chromatography.
  • a pre-mixed stock solution of 0.01 M sulfurized Tamiflu and 0.015 M H2O2 in acetonitrile was supplied to the flow cell with a C01-M0S2 module by peristaltic pump and the flow rate was regulated to 5 mL min 1 .
  • the flow cell was heated to 40 °C with the heating unit.
  • the clear solution was collected for a continuous operation of 60 mins to afford ⁇ 300 mL of crude solution.
  • Isolated compound ( ⁇ 1.0 g, ⁇ 75% selectivity) was obtained by rotary evaporation and the conversion, yield and selectivity were determined by NMR.
  • Example 6 Typical flow setup for selective nitro-reduction to aniline:
  • a Pti-MoS? module was loaded into the flow cell.
  • a pre-mixed solution of 0.025 M nitrobenzene and 0.050 M ammonia borane in an acetonitrile/FW mixture (5: 1, v/v) was supplied to the flow cell by peristaltic pump and the flow rate was regulated to desired values ⁇ e.g., 1 mL min 1 ).
  • the flow cell was heated to desired temperatures (e.g., 70 °C) with the heating unit.
  • the clear solution was collected after a stable period of 30 mins for each temperature or flow rate.
  • the product was examined by GC-MS to determine the conversion and yield.
  • Example 7 Gram-level synthesis (3 a) of multifunctional aniline in a continuous manner: A pre-mixed solution of 0.25 M 4-nitrochalcone (bearing reduction-prone functionalities such as ketone and alkene) and 0.50 M ammonia borane (2 equiv.) in an acetonitrile/H2O mixture (5: 1, v/v) was supplied to the flow cell with a Pti-MoS2 module by peristaltic pump and the flow rate was regulated to 1 mL min 1 . The flow cell was heated to 70 °C with the heating unit. The clear solution was collected for a continuous operation of 60 mins to afford ⁇ 60 mL of crude solution.

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Abstract

La présente divulgation concerne un réacteur à écoulement et des procédés de fabrication du réacteur à écoulement. La présente invention concerne également des réactions pouvant être mises en œuvre dans le réacteur à écoulement. Le réacteur à écoulement comprend une entrée, une sortie et un module catalyseur hétérogène positionné entre et en communication fluidique avec l'entrée et la sortie. Le module catalyseur hétérogène comprend un canal à écoulement et des catalyseurs hétérogènes sur une matrice fibreuse à l'intérieur du canal à écoulement, le canal à écoulement étant en communication fluidique avec l'entrée et la sortie. Le module catalyseur hétérogène est conçu pour produire un écoulement turbulent au niveau d'au moins une partie centrale d'une section transversale du canal à écoulement lorsqu'il est utilisé sous pression ambiante.
PCT/SG2022/050557 2021-08-25 2022-08-03 Réacteur à écoulement, procédés de fabrication et réactions de celui-ci WO2023027630A2 (fr)

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