A Flow Reactor, Methods of Fabrication and Reactions Thereof

Technical Field

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.

Background

To date, all major pharmaceutical producers have commercial-scale continuous manufacturing facilities such as homogeneous-catalysed tubular reactors or heterogeneous-catalysed packed bed reactors. However, such facilities are built for slow reactions that typically operated under high operational pressure (10 bar).

With the development of heterogeneous catalysts to be more precise and with a higher turnover rate, synthetic protocols are now able to produce the final product in a shorter timeframe. Heterogeneous-catalysed packed bed reactors cannot meet this need due to their setup, and the final chemical product even though it has already been formed, cannot be eluted quickly enough. This limits productivity. Additionally, when the final product is not removed efficiently, undesirable side reactions can possible occur with or in the presence of the final product.

There is a missing reaction space for fast reactions requiring faster flow speed of the reactants in the flow system, which is not met by conventional packed bed flow reactor. This calls for an alternative design that can be operated under ambient pressure with a high flow rate for application in fast chemical reactions.

It would be desirable to overcome or ameliorate at least one of the above-described problems.

Summary

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.

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.

In some embodiments, 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. In some embodiments, the fibrous matrix is positioned at at least a central portion of a transverse section of the flow channel. Notably, the fibrous matrix may comprise one portion, or two or more portions at spaced locations in the flow channel.

In some embodiments, 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.

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 mass transport of reactant/product such that a constant flow output can be maintained.

In some embodiments, the turbulent flow is characterised by a Reynolds number of about 2000 to about 10000.

In some embodiments, 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.

In some embodiments, 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 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).

In some embodiments, 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%.

In some embodiments, the transition metal atom is a transition metal selected from iron, cobalt, nickel, copper, palladium, platinum, gold, ruthenium, silver, or a combination thereof.

In some embodiments, 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%.

In some embodiments, the fibrous matrix characterised by a porosity of about 30% to about 95%, or preferably about 90% to about 95%.

In some embodiments, the fibrous matrix characterised by a pore size of about 50 nm to about 100 pm, or preferably about 65 pm.

In some embodiments, the fibrous matrix is selected from a graphite felt, carbon felt, graphite paper, carbon paper, carbon cloth, or a combination thereof.

In some embodiments, the heterogeneous catalyst module is characterised by a porosity of about 30% to about 95%, or preferably about 90% to about 95%.

In some embodiments, the heterogeneous catalyst module is characterised by a pore size of about 50 nm to about 100 pm, or preferably about 65 pm.

In some embodiments, 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.

In some embodiments, the fibrous matrix is characterised by a reversible deformation when deformed up to about 90%.

In some embodiments, 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.

In some embodiments, the heterogeneous catalyst module has an area of about 0.25 cm ² to about 2500 cm ² .

In some embodiments, the heterogeneous catalyst module has a volume of about 2.5 x 10 ^s cm ³ to about 1250 cm ³ .

In some embodiments, the heterogeneous catalyst module is modular.

In some embodiments, the flow reactor comprises two or more heterogeneous catalyst modules.

In some embodiments, the flow reactor further comprises a body for housing the heterogeneous catalyst module.

In some embodiments, the flow reactor further comprises temperature control means.

In some embodiments, the temperature control means comprises stainless stain plates with heating rods electrically connected to a thermocouple and a digital controller.

In some embodiments, 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.

In some embodiments, the flow reactor further comprises flow control means.

In some embodiments, the flow control means is selected from a peristaltic pump, a syringe pump or a high performance liquid chromatography (HPLC) pump.

In some embodiments, the flow reactor further comprises voltage control means.

In some embodiments, the voltage control means is an electrochemical workstation (potentiostat).

In some embodiments, the flow reactor further comprises light control means.

In some embodiments, the light control means is selected from a light-emitting diode (LED), a xenon lamp or a mercury lamp.

In some embodiments, the flow reactor further comprises sampling means.

In some embodiments, the flow reactor further comprises purification means.

In some embodiments, 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.

In some embodiments, the fibrous matrix is selected from graphite felt, carbon felt, graphite paper, carbon paper, carbon cloth, or a combination thereof.

In some embodiments, the at least two layers of TMD is attached by hydrothermally treating the fibrous matrix with a TMD precursor.

In some embodiments, the TMD precursor is a mixture of sodium molybdate and thiourea.

In some embodiments, a molar ratio of sodium molybdate to thiourea is about 1:2.

In some embodiments, the hydrothermal treatment is performed at about 190 °C.

In some embodiments, the hydrothermal treatment is performed for about 24 h.

In some embodiments, the heterogenous catalyst module is characterised by a TMD loading on the fibrous matrix of about 45 mg cm ² .

In some embodiments, 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.

In some embodiments, the transition metal precursor has a transition metal selected from iron, cobalt, nickel, copper, palladium, platinum, gold, ruthenium, silver or a combination thereof.

In some embodiments, 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.

In some embodiments, the incorporation step is performed at about 40 °C to about 100 °C.

In some embodiments, the incorporation step is performed at about 80 °C.

In some embodiments, the incorporation step is performed for about 1 h to about 24 h.

In some embodiments, the incorporation step is performed for about 2 h.

In some embodiments, the annealing step is performed at about 150 °C to about 1000 °C.

In some embodiments, the annealing step is performed at about 300 °C to about 700 °C.

In some embodiments, the annealing step is performed for about 0.5 h to about 24 h.

In some embodiments, the annealing step is performed for about 2 h.

In some embodiments, the annealing step is performed under inert conditions, oxidative conditions or reductive conditions.

In some embodiments, 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 .

In some embodiments, the method is performed at a pressure of about 1 atm.

In some embodiments, the method is performed at a temperature of about 5 °C to about 100 °C.

In some embodiments, the method is performed for at least 5 sec.

In some embodiments, the reaction is an oxidation of a compound having a sulphide moiety.

In some embodiments, the sulphide moiety is oxidised to a sulfone moiety or sulfoxide moiety.

In some embodiments, 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, 2,2'-thiodiacetic acid, 2,2'- dithiodibenzoic acid, (phenylmercapto)acetic acid, triphenylphosphine sulfide, thiochroman-4-one, trifluoromethyl phenyl thioether, 4-(trifluoromethylthio)phenol, azidomethyl phenyl sulfide, phenothiazine, 4-oxothiane, 2-(methylthio)pyridine, 2- (methylthio)thiophene, trimethyl({2-[4-(methylthio)phenyl]ethynyl}) silane, 4- (methylthio)quinoline, ethyl 2-diazo-2-(4-(methylthio)phenyl)-acetate, bis(trimethylsilyl) sulfide, 3,3'-tetrathiobis(propyl-triethoxysilane), Oseltamivir phosphate (Tamiflu), mesoridazine, dimetotiazine, thiothixene and clethodim.

In some embodiments, when a compound having a sulphide moiety is oxidised, the method is characterised by a chemoselectivity of at least 90%.

In some embodiments, when a compound having a sulphide moiety is oxidised, the method further comprises flowing an oxidising agent into the flow reactor.

In some embodiments, the oxidising agent is an organic oxidising agent or an inorganic oxidising agent.

In some embodiments, the oxidising agent is an organic or inorganic peroxide.

In some embodiments, a mole ratio of the oxidising agent to the compound having a sulphide moiety is about 1: 1 to about 5:1.

In some embodiments, when a compound having a sulphide moiety is oxidised, 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.

In some embodiments, the reaction is a reduction of a compound having a nitro moiety.

In some embodiments, the compound having a nitro moiety is a compound of Formula (Ha):

Z-^NO ₂

( A ) wherein ring A is optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, compound of Formula (Ila) is reduced to a compound having an aniline moiety.

In some embodiments, when a compound having a nitro moiety is reduced, the method is characterised by a chemoselectivity of at least 90%.

In some embodiments, 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-(2-iodoethynyl)-4-nitrobenzene, 4-nitrobenzamide, 4-nitrothioanisole, 4-nitrophtha lonitrile, 4-nitrophenylboronic acid, 4-nitrophenyl- boronic acid pinacol ester, l-(methylsulfonyl)-4-nitrobenzene, 6-nitrochromone, 4- nitrochalcone, 5-nitroisatin, 4-chloro-3-nitrocoumarin, 4'-nitroacetophenone, 2'- nitroacetophenone, 4-nitrobenzophenone, 4-nitrobenzaldehyde, 2-nitrobenzaldehyde, 6-nitroquinoline, 4-nitropyridine, 2-nitropyridine, 2-bromo-5-nitropyridine, 2- nitrothiophene, 5-nitro-2-furoic acid, 5-nitro-2-oxindole, 6-nitrophthalide, 1,5- dinitronaphthalene and 9-nitroanthracene.

In some embodiments, when a compound having a nitro moiety is reduced, the method further comprises flowing a reducing agent into the flow reactor.

In some embodiments, the reducing agent is an organic reducing agent or an inorganic reducing agent.

In some embodiments, the reducing agent is selected from ammonia borane complex (NH3BH3), sodium hydroborate (NaBFU), lithium aluminium hydride (LiAIH^), hydrazine (N2H4), formic acid, ascorbic acid, hydrogen gas, or a combination thereof.

In some embodiments, a mole ratio of the reducing agent to the compound having a nitro moiety is about 1 : 1 to about 5: 1.

In some embodiments, when a compound having a nitro moiety is reduced, 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.

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.

Brief description of the drawings

Embodiments of the present invention will now be described, by way of non-limiting example, with reference to the drawings in which:

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).

Figure 9 shows the pressure change in the flow reactor when in use.

Detailed description

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). Compared to batch production with process know-hows in step-by-step scaling-up, 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.

Compared to traditional packed bed reactors, 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. For example, 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. In another example, 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.

Accordingly, 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.

Other than higher productivity in flow organic synthesis, the flow reactor is also applicable to photo/electrochemical reaction to promote those sluggish reactions at ambient condition. In contrast, it is very difficult (if not impossible) to conduct electrochemistry in conventional packed bed reactor due to the lack of paired electrodes.

The centre (or center) 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. To produce the turbulent flow at at least a central portion of a transverse section of the flow channel, the fibrous matrix is present at least the central portion of a transverse section of the flow channel. For example, 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. In other embodiments, 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. Alternatively, 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.

Accordingly, in some embodiments, 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.

In some embodiments, the fibrous matrix comprises matted fibers. In this sense, 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. In some embodiments, 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.

In some embodiments, 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.

Additionally, the inventors have found that limitation in productivity in conventional packed bed reactors, which require a high operational pressure of ~ 10 bar for a satisfactory flow rate of 1 mL min ¹ can be overcome by the flow reactor of the present invention. Additionally, unsatisfactory chemoselectivity owing to the occurrence of side reactions during long retention time, especially when traditional nanoparticle catalysts with multiple adsorption configurations of reactants (reaction pathways) are employed, can be avoided.

In some embodiments, 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. In turbulent flow, 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.

Fast flow allows for high rate of chemical reaction. 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.

This can be reflected in the changes in Reynolds number (judgement of laminar or turbulent flow). 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. At low Reynolds numbers, 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). Owing to the narrowed flow path inside the compressible 3D fibrous catalyst matrix, 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.

This allows continuous-flow production of fine chemicals by chemoselective organic reactions under ambient condition, which is traditionally conducted in packed bed flow reactor at high operational pressure and a much lower flow rate (productivity). For example, 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.

In some embodiments, the turbulent flow is characterised by a Reynolds number of about 2000 to about 10000. In other embodiments, 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. In some embodiments, the fibers in the fibrous matrix are substantially perpendicular to a flow direction of the flow solvent. In some embodiments, the fibers in the fibrous matrix are at an angle to a flow direction of the flow solvent. In other embodiments, 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.

Preferably, the generation of turbulent flow occurs while the pressure is maintained at about 1 atm. In this regard, when the flow channel is in use under ambient pressure, 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.

In some embodiments, the heterogeneous catalyst is covalently bonded to the fibrous matrix. In some embodiments, the heterogeneous catalyst is physically bonded to the fibrous matrix.

In some embodiments, 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.

In some embodiments, 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 (TMDs) are 2-D materials and have a generalized formula of MX? where M is a transition metal of groups 4-10 and X is a chalcogen (such as sulfur or selenium). In some embodiments, the TMD is selected from the group consisting of molybdenum disulfide (M0S2), tungsten disulfide (WS2), titanium disulfide (TiS?), tantalum sulfide (TaS?), vanadium disulfide (VS2), molybdenum diselenide (MoSe?), tungsten diselenide (WSe?), tellurium sulphide (TeS?) and tellurium diselenide (TeSe ₂ ).

In some embodiments, the at least two TMD layers are aligned in one plane and attached to the substrate at an edge of the plane. In this regard, 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. In some embodiments, the at least two TMD layers are aligned in one plane and perpendicularly (vertically) attached to the substrate at an edge of the plane. In this regard, the TMD layers are, for example, vertically aligned with respect to a surface of the substrate. In other embodiments, 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.

Depending on the type of TMD, the layer thickness of the TMD may vary. In some embodiments, 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.

In some embodiments, 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.

Similarly, depending on the type of TMD, the spacing between the TMD layers as formed may vary. For example, 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, and TaS2 is 0.601 nm.

In some embodiments, 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. In this regard, the transition metal atoms are inserted between the TMD layers. In contrast to doping methods where a small amount of the TMD atoms are replaced with transition metal atoms are or surface functionalisation where the transition metal atoms are attached to an external surface of the TMD, 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). The presence of such M-CxOyXz structure can serve as the catalytically active center.

In some embodiments, 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. In some embodiments, 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. In other embodiments, 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.

The intercalation and/or incorporation is preferably non-reversible. In some embodiments, each transition metal atom is coordinated to 4 chalcogens in the at least two TMD layers. In this regard, 2 of the chalcogens are located on one TMD layer and the other 2 chalcogens are located on the other TMD layer. In other embodiments, 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. In this regard, each transition metal atom is isolated and spaced apart from each other. In some embodiments, the transition metal atoms are selected from the group consisting of iron, cobalt, nickel, copper, palladium, platinum, gold, ruthenium, silver and a combination thereof. In other embodiments, the transition metal atoms occurring as individual atoms is uniformly distributed within the interstitial space of two TMD layers.

Depending on the size of the transition metal atoms, the atom to atom distance may vary. In some embodiments, 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.

In some embodiments, the transition metal atom is a transition metal selected from iron, cobalt, nickel, copper, palladium, platinum, gold, ruthenium, silver, or a combination thereof.

In some embodiments, the heterogeneous catalyst module is characterised by a transition metal atom loading on the TMD of about 0.01 wt% to about 10 wt%. In other embodiments, 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%. In some embodiments, 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%.

In some embodiments, the heterogeneous catalyst is characterised by a turnover frequency (TOF) of about 500 h ¹ to about 2000 h ¹ . In other embodiments, the turnover frequency is about 500 h ¹ to about 1800 h ¹ , about 500 h ¹ to about 1600 h ¹ , about

500 h ¹ to about 1500 h ¹ , about 500 h ¹ to about 1400 h ¹ , about 500 h ¹ to about 1300 h ¹ , or about 600 h ¹ to about 1300 h ¹ . In other embodiments, 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. In particular, the heterogeneous catalyst forms at least a layer on the fiber of the fibrous matrix. By using a material which is fibrous and randomly arranged as a substrate for the catalyst, a tortuous flow path is provided which generates local turbulent flow, allowing for homogenous mixing and fast reaction in the reaction compartment by using porous fibrous support impregnated with catalysts.

In some embodiments, 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%.

In some embodiments, the fibrous matrix characterised by a pore size of about 50 nm to about 100 pm. In other embodiments, 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. In some embodiments, 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. In some embodiments, the fibrous matrix comprises fibers having a diameter of about 1 pm to about 20 pm. In other embodiments, 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.

In some embodiments, 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. In some embodiments, the fibrous matrix is a graphite felt, carbon felt, graphite paper, carbon paper, or carbon cloth. In other embodiments, 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.

In some embodiments, the fibrous matrix is chemically modified in order to alter the flow kinetics within the flow channel. For example, 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. In some embodiments, 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. In other embodiments, the fibrous matrix is treated with a microporous layer coating and/or hydrophobic coating. For example, 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. Preferably, the flow channel is closed.

In some embodiments, 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

0.5 mm to about 2 mm, or about 0.5 mm to about 1 mm. In other embodiments, the width or thickness of about 1 mm. In other embodiments, the width or thickness of about 0.8 mm.

In some embodiments, the flow channel has a length of about 1 cm to about 100 cm.

In other embodiments, the length is about 1 cm to about 90 cm, about 1 cm to about

80 cm, about 1 cm to about 70 cm, about 1 cm to about 60 cm, about 1 cm to about

50 cm, about 1 cm to about 40 cm, about 1 cm to about 30 cm, about 1 cm to about

20 cm, or about 1 cm to about 10 cm.

In some embodiments, 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%.

In some embodiments, the heterogeneous catalyst module or at least the fibrous matrix is characterised by a pore size of about 50 nm to about 100 pm. In other embodiments, 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. In some embodiments, the heterogeneous catalyst module is characterised by a pore size of about 65 pm.

In some embodiments, 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. In other embodiments, 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. In some embodiments, the heterogeneous catalyst module is characterised by a compressive modulus at 50% strain of about 0.12 MPa to about 0.15 MPa.

In some embodiments, 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%.

This prevents catalyst deactivation or leaching by stress concentration in the local turbulent flow.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, the heterogeneous catalyst module has an area of about 0.25 cm ² to about 2500 cm ² . In other embodiments, 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 .

In some embodiments, 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

50 mm, about 35 mm to about 50 mm, or about 40 mm to about 50 mm. In other embodiments, the width or thickness of about 1 mm to about 20 mm, about 1 mm to about 18 mm, about 1 mm to about 16 mm, about 1 mm to about 14 mm, about 1 mm to about 12 mm, or about 1 mm to about 10 mm. In other embodiments, the width or thickness of about 7 mm. It is found that the thickness does not change the behaviour of flow (turbulent or laminar) when the thickness is at least 1 mm.

In some embodiments, the heterogeneous catalyst module has a volume of about 2.5 x 10 ^s cm ³ to about 1250 cm ³ . In other embodiments, 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 .

In some embodiments, the heterogeneous catalyst module is modular. In this regard, 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. In some embodiments, 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.

In some embodiments, the fibrous matrix (and its associated heterogeneous catalyst) is modular. In this regard, 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.

In some embodiments, 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.

In some embodiments, 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. Alternatively, 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. In other embodiments, the graphite plate has a parallel path design on both sides where the flow path can be the same or different. In other embodiments, 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.

In some embodiments, the flow reactor further comprises temperature control means. In some embodiments, 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.

In some embodiments, 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.

In some embodiments, the flow reactor further comprises flow control means. In some embodiments, the flow control means is selected from a peristaltic pump, a syringe pump or a high performance liquid chromatography (HPLC) pump. In a preferred embodiment, the flow control means is a peristaltic pump for high flow rate and operation in ambient pressure.

In some embodiments, the flow reactor further comprises voltage control means. In some embodiments, 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 Nation or Celgard membrane can be further inserted between the copper plates to avoid short circuit.

In some embodiments, the flow reactor further comprises light control means. In some embodiments, 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).

In some embodiments, 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.

In some embodiments, the flow reactor further comprises purification means. The purification means isolates and purifies the final product.

In some embodiments, the flow reactor is modular. In this regard, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, the TMD precursor is a mixture of sodium molybdate and thiourea.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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 . In some embodiments, the heterogenous catalyst module is characterised by a TMD loading on the fibrous matrix of about 45 mg cm' ² .

In some embodiments, 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.

In some embodiments, the transition metal precursor has a transition metal selected from iron, cobalt, nickel, copper, palladium, platinum, gold, ruthenium, silver or a combination thereof.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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. In some embodiments, the annealing step is performed at about 150 °C to about 1000 °C. In other embodiments, 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. In some embodiments, the annealing step is performed at about 300 °C to about 700 °C.

In some embodiments, 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.

In some embodiments, the annealing step is performed under inert conditions, oxidative conditions or reductive conditions.

In some embodiments, the heterogenous catalyst module is characterised by a transition metal loading on the TMD of about 0.5 wt%.

In some embodiments, the method further including a step after step (a) of contacting the at least two TMD layers with a co-intercalant.

In some embodiments, 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).

The present invention also provides a method of catalysing a reaction using the flow reactor as disclosed herein. In some embodiments, 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.

In some embodiments, 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

0.01 mL min ¹ to about 60 mL min ¹ , about 0.01 mL min ¹ to about 50 mL min ¹ , about

0.01 mL min ¹ to about 40 mL min ¹ , about 0.01 mL min ¹ to about 30 mL min ¹ , about

0.01 mL min ¹ to about 20 mL min ¹ , or about 0.1 mL min ¹ to about 20 mL min ¹ . In some embodiments, 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 mL min ¹ to about 50 mL min ¹ .

In some embodiments, the method is performed at a pressure of about 1 atm. From CFD calculations (Figure 9), 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.

In some embodiments, the method is performed at a temperature of about 5 °C to about 100 °C. In other embodiments, 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. In some embodiments, the temperature is about 10 °C to about 80 °C, or about 20 °C to about 80 °C.

In some embodiments, the method is performed for at least 5 sec. In other embodiments, 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. In particular, continuous operation for at least 24 hours is verified without performance degradation in chemical production.

Conversion (or conversion rate) 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).

In some embodiments, 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%.

In some embodiments, 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.).

For example, 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.

In some embodiments, 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.

In some embodiments, Ri is selected from optionally substituted aryl and optionally substituted heteroaryl. In some embodiments, 2 is selected from optionally substituted amino, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl.

In some embodiments, the compound having a sulphide moiety is selected from thioanisole, phenyl disulfide, diphenyl sulfide, dibenzyl sulfide, 2-(methylthio) thiophene and 2-(methylthio)pyridine. In some embodiments, 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, 2,2'-thiodiacetic acid, 2,2'- dithiodibenzoic acid, (phenylmercapto)acetic acid, triphenylphosphine sulfide, thiochroman-4-one, trifluoromethyl phenyl thioether, 4-(trifluoromethylthio)phenol, azidomethyl phenyl sulfide, phenothiazine, 4-oxothiane, 2-(methylthio)pyridine, 2- (methylthio)thiophene, trimethyl({2-[4-(methylthio)phenyl]ethynyl}) silane, 4- (methylthio)quinoline, ethyl 2-diazo-2-(4-(methylthio)phenyl)-acetate, bis(trimethylsilyl) sulfide, 3,3'-tetrathiobis(propyl-triethoxysilane), Oseltamivir phosphate (Tamiflu), mesoridazine, dimetotiazine, thiothixene and clethodim.

In some embodiments, 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%.

Owing to its high chemoselectivity and efficiency, the chemical products can be easily isolated by simple removal of the composite from the reaction medium. Small amounts of excess H2O2 will be eventually converted into water, thus bypassing the tedious separation or purification steps in conventional sulfide oxidations. This is remarkably attractive for the synthesis of sulfone containing biomolecules.

In some embodiments, when a compound having a sulphide moiety is oxidised, the method further comprises flowing an oxidising agent into the flow reactor.

In some embodiments, the oxidising agent is an organic oxidising agent or an inorganic oxidising agent.

In some embodiments, the oxidising agent is an organic or inorganic peroxide. In some embodiments, the oxidant is H2O2. In other embodiments, 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)). In other embodiments, the oxidant is selected from H2O2 and meta-chloroperoxybenzoic acid (mCPBA). When the peroxide is an organic peroxide (ROOH), R can be optionally substituted alkyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted arylalkyl or optionally substituted cycloalkyl.

In some embodiments, 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. When an at least two or more equivalence of oxidant is added, 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. When an at least one or less than two equivalence of oxidant is added, sulphide is oxidised to sulfoxide. 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.

If the sulphide is partially oxidised to a sulfoxide, 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.

In some embodiments, when a compound having a sulphide moiety is oxidised, 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. In some embodiments, the solvent has a boiling point of about 60 °C to about 250 °C.

In some embodiments, when a compound having a sulphide moiety is oxidised, the heterogeneous catalyst is selected from C01-M0S2, Nii-MoS?, Fei-MoS?, CU1-M0S2 and Pti-MoS2.

Other examples of the sulfone or sulfoxide compounds are:

In some embodiments, the reaction is a reduction of a compound having a nitro moiety. In other embodiments, the reaction is chemoselective to the nitro moiety. In this regard, 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.

For example, 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.

In some embodiments, the compound having a nitro moiety is a compound of Formula (II):

R ^R 3- ^N ° ² (II) wherein R3 is selected from optionally substituted amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

In some embodiments, the compound having a nitro moiety is a compound of Formula (Ha):

O^NO ₂ ( A ) O (Ila) wherein ring A is optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, compound of Formula (Ila) is reduced to a compound having an aniline moiety.

In some embodiments, 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%.

In some embodiments, 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-(2-iodoethynyl)-4-nitrobenzene, 4-nitrobenzamide, 4-nitrothioanisole, 4-nitrophtha lonitrile, 4-nitrophenylboronic acid, 4-nitrophenyl- boronic acid pinacol ester, l-(methylsulfonyl)-4-nitrobenzene, 6-nitrochromone, 4- nitrochalcone, 5-nitroisatin, 4-chloro-3-nitrocoumarin, 4'-nitroacetophenone, 2'- nitroacetophenone, 4-nitrobenzophenone, 4-nitrobenzaldehyde, 2-nitrobenzaldehyde, 6-nitroquinoline, 4-nitropyridine, 2-nitropyridine, 2-bromo-5-nitropyridine, 2- nitrothiophene, 5-nitro-2-furoic acid, 5-nitro-2-oxindole, 6-nitrophthalide, 1,5- dinitronaphthalene and 9-nitroanthracene.

In some embodiments, when a compound having a nitro moiety is reduced, the method further comprises flowing a reducing agent into the flow reactor.

In some embodiments, the reducing agent is an organic reducing agent or an inorganic reducing agent.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, when a compound having a nitro moiety is reduced, a solvent is selected from acetonitrile (AN), water, hydrocarbyl aliphatic alcohols (such as ethanol, isopropanol), ethyl acetate (EA), or a combination thereof. In some embodiments, the solvent has a boiling point of about 60 °C to about 250 °C.

In some embodiments, when a compound having a nitro moiety is reduced, the heterogeneous catalyst is selected from C01-M0S2, Nii-MoS2, Fei-MoS2, CU1-M0S2 and Pti-MoS2.

In some embodiments, 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).

In some embodiments, 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

Hi) transition metal atoms intercalated between the at least two TMD layers; and b) reducing the nitro moiety.

In some embodiments, 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

Hi) transition metal atoms incorporated between the at least two TMD layers; and b) reducing the nitro moiety.

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.

As shown in Figure 1, 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. As demonstrated, 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 development of mechanically robust, highly porous catalyst module facilitates operation at high flow rate in ambient condition. We have conducted X-ray microtomography (so-called micro-CT) to examine the 3D structure of catalyst module. As shown in Figure 2A, the catalyst module is made of strains of carbon fibers that are woven together, leaving a void space for the fluent to pass through. This is reflected in the very large pores in the mercury intrusion porosimetry (Figure 2B). Both the blank support and modified catalyst module (C01-M0S2) reveal a typical pore size of around 65 microns with a porosity of 91 ~ 95%. Such macropores allow fast diffusion kinetics of the reactants in the flow cell, which is distinctive from packed bed reactor. 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.

We choose the chemoselective oxidation of sulfides as a model reaction to examine the utility of such flow cell. As shown in Figure 3, we can achieve > 99% of conversion and yield toward full oxidation product (sulfone) at 50 °C, while a slightly lower selectivity due to the formation of semi-oxidation product (sulfoxide) is observed for other conditions. Such flow production can be performed at a very high concentration of 0.25 M, giving a productivity of 4.7 g h ¹ of isolated product (methyl phenyl sulfone) at normal flow rate (2 mL min ¹ ). A highly reproducible performance is observed in the 20h onstream demonstration in Figure 3C. 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. Notably, the sulfide derivative of Tamiflu (treatment of influenza) containing an electron-deficient alkene that is prone to traditional oxidation in batch process can be successfully functionalized to the corresponding sulfoxide or sulfone analogues. Ultrapure compounds at gramscale can be obtained by recrystallization. Similarly, Clethodim (selective postemergence herbicide for annual and perennial grasses) with a sulfide group at its side chain can be successfully converted. 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).

To demonstrate its usefulness as modularized reactor, we examine the use in chemoselective nitro-reduction in Figure 4. Full conversion and yield to the corresponding aniline are obtained for the model reaction using Pti-MoSz. The catalytic efficiency varies significantly with the nature of transition metals. The replacement of Pt by Fe or Co can also promote the reduction effectively at a higher temperature (70 °C). The Nii-MoS? or CU1-M0S2 module only affords a moderate performance toward the reduction, while the control experiments using M0S2 module or blank support gives poor or even no performance. We believe this is closely related to the dissociation energy of the H* absorbent on the metal site, where Pt and Fe are known to be more reactive toward hydrogenative reactions. The stability of our reactor is proven by a 24 hour onstream testing at 70 °C without any performance decay. Rate capability testing at extremely fast flow rate (20 mL min ¹ ) serves as a good indication on the maximized productivity for such reaction. 100% conversion is observed at low to mediate flow rates, while it gradually drops at higher flow rates owing to kinetic diffusion limitations. Nevertheless, no side product can be detected in the whole range and the selectivity toward aniline remains to be > 99%. This indicates that the thermodynamic nature of selectivity due to the preferred interaction between nitro functionality and the atomic metal site. Meanwhile, the turnover frequency of the active metal reaches the highest of ~ 1200 h ¹ at a flow rate of 7.5 mL min ¹ , far superior to the literature. 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. Interestingly, 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). Most commonly occurring and versatile functionalities, including those with potentially reducible functional groups such as ketones (2s ~ 2v), alkenes (2o, 2u, 2v), nitriles (2n, 2p), isocyanate (2k), and quinoline (2x), can be well -tolerated by our protocol (84 to 99% yield), highlighting its remarkable chemoselectivity compared to existing methods. Notably, 3-aminostyrene (2o, 99% yield) from the reduction of 3-nitrostyrene is an important feedstock chemicals, where original production method by gas-phase reduction using hydrogen inevitably suffers from low selectivity with the use of noble metal at high temperature. 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. As part of the demonstration, we also perform gram-scale synthesis of 4-amino-chalcone (anti-proliferative agent) for an extended period of 1 hour at a higher concentration of 0.25 M, where 3.0 grams of isolated compound (90% selectivity) is obtained.

To understand the heat distribution of our reactor under operational condition, thermal imaging using infrared camera is conducted in Figure 5A. Uniform heat distribution at the catalytic component (~ 70 °C as expected) is observed at the side-view image. Hot flow-out solution (~ 64 °C) is also detected compared to that of flow-in solution (environmental temperature). Meanwhile, computational fluid dynamics (CFD) based on reconstructed 3D model from micro CT is performed to calculate the fluidic behaviors including the influence of carbon fibers on localized velocity field. As shown in Figure 5B, undisturbed flow channels (open area) are observed in the void spaces closed to the outer edge of the model. The red arrows indicate those areas where fluent strongly interact with catalyst, leading to much slower flow rates and local turbulence. Surprisingly, preferred flow channels in between carbon fibers are also found owing to the emerging obstacles, leading to a laminar to local turbulent flow transition for promoted reaction kinetics in our flow cell.

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. In particular, 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 (consumable part) 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.

Examples

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 . To prepare C01-M0S2 catalyst, 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.

Example 3. Typical flow setup for sulfide oxidation to sulfone:

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.

Example 4. Gram-level synthesis (5 a) of alkyne-functional sulfone in a continuous manner:

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.

Example 5. Gram-level synthesis (1 a) of sulfoxide-modified Tamiflu in a continuous manner:

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/H2O 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. 30 mL of ethyl acetate and 20 mL of DI water were added to the crude solution. The organic layer was separated, and the aqueous solution was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried with anhydrous sodium sulfate. Isolated compound (~ 3.0 g of 4-amino-chalcone, 90% selectivity, anti-proliferative agent) was obtained by rotary evaporation. The conversion, yield and selectivity were verified by NMR.

It will be appreciated that many further modifications and permutations of various aspects of the described embodiments are possible. Accordingly, the described aspects are intended to embrace all such alterations, modifications, and variations that fall within the spirit and scope of the appended claims.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Throughout this specification and the claims which follow, unless the context requires otherwise, the phrase "consisting essentially of", and variations such as "consists essentially of" will be understood to indicate that the recited element(s) is/are essential i.e. necessary elements of the invention. The phrase allows for the presence of other non-recited elements which do not materially affect the characteristics of the invention but excludes additional unspecified elements which would affect the basic and novel characteristics of the method defined. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.