Functionalization of liquid organic substrates via plasma activation

Abstract

The present invention relates to a novel chemical synthesis method for adding a chemical function to a carbon atom of an organic substrate in the liquid phase in the presence of a gas plasma. The functionalizations obtained make it possible, for example, to synthesize new building blocks, which can be used for new chemical reactions a posteriori, or to perform end-of-synthesis functionalizations in order to obtain complex molecules and to reduce the number of synthesis steps.

Description

[0001] Description

[0002] Title: Functionalization of liquid organic substrates by plasma activation. Scope of the invention.

[0003] The present invention relates to a chemical synthesis method allowing the addition of a chemical function to a carbon atom of an organic substrate introduced in liquid form in the presence of a gaseous plasma.

[0004] STATE OF THE ART

[0005] The synthesis of "building blocks" and complex molecules used in the perfume, cosmetics, and pharmaceutical industries is polluting. The main causes are energy consumption and waste production. Indeed, current synthesis methods often require high temperatures and pressures coupled with catalysts to activate reactions. In order to apply the principles of green chemistry, safer, less energy-intensive, and less polluting alternative activation methods are being sought.

[0006] Among the alternative activation methods developed are ultrasound, microwaves, and novel heterogeneous catalysts. However, these strategies primarily serve to optimize conventional methods by incorporating improved heating techniques, safer conditions, and less polluting waste. Meanwhile, new disruptive activations circumvent these limitations by completely altering the activation mechanisms. These activation methods include photochemistry, electrochemistry, and plasma chemistry. They notably enable reactions to proceed under enhanced safety conditions. The generation of high-energy radicals for the selective functionalization of organic molecules is being explored through dual catalytic systems.These systems typically involve a light-absorbing catalyst to activate organic substrates, while a second type of transition metal catalyst modulates the reactivity of the photogenerated intermediates. Although this strategy yields good results in terms of efficiency and selectivity, there are still some obvious drawbacks. First, the use of complex and expensive catalysts, often involving metals, can pose problems, particularly in the pharmaceutical sector. Second, the lack of atom economy when radicals are produced from complex precursors is also a limitation.

[0007] Electrochemistry, on the other hand, promotes more atom-efficient reactions because it does not require additional chemical reagents. It can replace or reduce the use of expensive and potentially toxic metal catalysts, which is particularly beneficial in pharmaceutical applications. However, some substrates may not be compatible with the electrochemical conditions and electrolytes, which severely limits the range of possible reactions.

[0008] Plasma discharges can also be generated directly in liquids, thereby directly generating reactive species within them, without the use of a gas phase. This approach has been little explored. Like plasma / liquid reactors, they do not require catalysts. However, they appear to cause non-selective activation of the liquids, which reduces the yield of the desired products. Tezuka et al. (Thin Solid Films, March 22, 2002, pp. 169–173) describe, for example, the cyanation of aromatic molecules by contact glow discharge electrolysis. For this reaction, the electrodes are immersed in the liquid phase, and it is necessary to add an electrolyte to the solution to ensure the desired level of electrical conductivity.Mengxue et al. (Plasma Processes and Polymers, December 6, 2017) describe the functionalization of DPMO by radical addition of -OH and -H in a microfluidic system where an electrode is in contact with the aqueous liquid phase. Gas / liquid systems have been developed to allow the use of low-volatility or even non-volatility reagents, as described in WO2019166570A1, particularly in microfluidic reactors. The liquid phase then assumes a dual role: that of a substrate reservoir and that of protecting the formed products to limit their overreaction. This paper shows that it is possible to substitute cyclohexane with a hydroxyl, ketone, CO, or Nth group, resulting from the activation of various gases such as oxygen, CO, CO2, or NH3 in the plasma. A radical is formed in the gas phase from a gas introduced in the gas phase into the reactor, while the substrate, cyclohexane, is introduced in the liquid phase.The stoichiometry of the reaction requires a gas flow rate significantly higher than the liquid flow rate to achieve a satisfactory cyclohexane substitution yield. This strategy therefore implies the use of large volumes of gas relative to the liquid, which is restrictive in terms of process setup and spatiotemporal yield.

[0009] This document does not demonstrate any particular selectivity regarding the substitution position on the organic substrate. Furthermore, it does not allow for the introduction of new functional groups onto the substrate that would not be present in a gas, which greatly limits the range of functional groups. Therefore, there remains a real need to develop this technology to insert diverse functional groups onto organic substrates, and in particular onto substrate carbons, with good efficiency and high selectivity, both at the micro and industrial scales.

[0010] SUMMARY

[0011] The invention consists of using a molecule from the liquid phase as the source of the functionalizing atom or group of atoms, and a substrate also present in the liquid phase that serves as the target for functionalization. This broadens the range of radicals that can be generated, and therefore the products, compared to using a plasma-forming gas. It also allows the use of smaller gas volumes. This is a method for functionalizing an organic substrate in the liquid phase, comprising the steps of:

[0012] An organic substrate S to be functionalized and an activatable substrate R1-R2 are brought together, the whole forming a liquid phase; said liquid phase being in contact with a gaseous phase;

[0013] A plasma is generated in the gas phase by applying an electric field between two electrodes not in contact with the liquid phase; The plasma activates at least partially the activatable substrate R1-R2 to form a reaction intermediate Ri*;

[0014] The reaction intermediate Ri* couples to at least one carbon of the organic substrate S, possibly previously activated, to form a product P.

[0015] The gaseous phase is preferably free of catalyst and / or electrolyte.

[0016] The invention enables the generation of the reaction intermediate in greater abundance compared to using a gas as the source of the functionalizing atom or group of atoms. This abundance can improve the selectivity of certain products. The major product can be controlled by the composition of the liquid and gas phases, as well as by the reaction conditions.

[0017] Preferably, the plasma is generated in the gas phase, at least close to the surface of the liquid phase. It is understood that the liquid phase is not subjected to an electric current, and no electrode is in direct contact with the liquid phase.

[0018] In the context of the invention, the plasma is generated by applying an electric field between two electrodes that are not in contact with the liquid phase. Unlike reactions involving the generation of plasmas by discharge in the liquid phase, it is not necessary here to use an electrolyte in the liquid phase. In one embodiment, the liquid phase is therefore devoid of electrolyte.

[0019] The invention enables the design and development of processes for producing organic compounds. The resulting functionalizations allow, for example, the synthesis of "building blocks" that can be used for further chemical reactions, or the performance of "end-of-synthesis functionalizations" to obtain complex molecules. This makes it possible to add chemical functions that would otherwise require multiple synthesis steps using other activation methods.

[0020] The molecules produced by the method of the invention find applications, for example, in the fields of perfumery, cosmetics, agrochemistry or pharmaceuticals, as a final molecule or as a synthetic intermediate.

[0021] DEFINITIONS

[0022] In the present invention, the terms below are defined as follows.

[0023] An "alkane" or "alkane group" refers to a hydrocarbon or part of a molecule composed of carbon atoms (C) linked together by single bonds. The carbons are substituted by hydrogens (H). An alkane or alkane group can be substituted, meaning that one or more hydrogens can be replaced by other atoms or groups of atoms. An alkane can be linear or branched. The alkane or alkane group described here comprises at least two saturated carbons.

[0024] An "alkene" or "alkene group" refers to a hydrocarbon or part of a molecule comprising carbon atoms (C), characterized by the presence of at least one double covalent bond between two carbon atoms. The carbons are substituted by hydrogens (H). An alkene or alkene group can be substituted, meaning that one or more hydrogens can be replaced by other atoms or groups of atoms. An alkene can be linear or branched. The alkene or alkene group described here comprises at least two carbons.

[0025] An "alkyne" or "alkyne group" refers to a hydrocarbon or part of a molecule containing carbon atoms (C), characterized by the presence of at least one triple covalent bond between two carbon atoms. The carbons are substituted by hydrogens (H). An alkyne or alkyne group can be substituted, meaning that one or more hydrogens can be replaced by other atoms or groups of atoms. An alkyne can be linear or branched. The alkyne or alkyne group described here comprises at least two carbons.

[0026] An "aromatic organic molecule" or "aromatic organic group" refers to a hydrocarbon whose molecular structure comprises a ring with alternating single and double bonds. Carbon atoms are substituted by hydrogen atoms (H), which may be substituted by other atoms or groups of atoms. An aromatic organic group may contain heteroatoms within its ring.

[0027] In general, the terms alkane, alkene, alkyne, and aromatic are used here in the senses normally attributed to them by a person skilled in the art. The invention is not specific to or limited to certain substrates, but is applicable to any functionalization of a carbon atom in an organic molecule.

[0028] A millifluidic or microfluidic reactor is a system that handles small volumes of fluids, on the order of milliliters or microliters, using channels ranging in size from a few tens to hundreds of micrometers. Preferably, a millifluidic or microfluidic reactor is designed for continuous flow reactions.

[0029] An industrial reactor here refers to a production facility capable of implementing the method of the invention on a scale ranging from a few milliliters to several hundred or even thousands of liters. An industrial reactor can operate in continuous flow or discontinuously (batch). An industrial reactor can operate in continuous flow using methods other than millifluidics or microfluidics, for example, by using liquid films or aerosols.

[0030] An addition is a reaction by which two molecules combine through covalent bonds. It requires the presence of multiple bonds, double or triple, on at least one of the reactants.

[0031] Substitution is a reaction in which an atom or group of atoms, covalently bonded to a substrate, is replaced by another atom or group of atoms. This substitution can occur by addition followed by an elimination reaction of the leaving group, or by ablation of the functional group and then reaction with the new substituent group.

[0032] A catalyst is any chemical species, including its activated or supported forms, capable of altering the kinetics of a chemical reaction by lowering the activation energy, without being irreversibly consumed and remaining regenerable during the process. A catalyst can be homogeneous (dissolved in a liquid phase) or heterogeneous (in solid form in a liquid phase).

[0033] An electrolyte is a dissolved ionic compound, either dissociated or forming ions, which in solution is capable of conducting an electric current by facilitating the migration of ions between electrodes during an electrolysis process. Electrolytes can include salts, acids, bases, conductive additives, etc.

[0034] DETAILED DESCRIPTION

[0035] The present invention relates to a method for functionalizing an organic substrate in the liquid phase, comprising the steps of:

[0036] An organic substrate S to be functionalized and an activatable substrate R1-R2 are brought together, the whole forming a liquid phase; said liquid phase being in contact with a gaseous phase;

[0037] A plasma is generated in the gaseous phase;

[0038] The plasma activates at least partially the activatable substrate R1-R2 to form a reaction intermediate Ri*, and

[0039] The reaction intermediate Ri* couples to at least one carbon of the organic substrate S, possibly previously activated, to form a product P.

[0040] Preferably, the plasma is generated in the gas phase, at least near the surface of the liquid phase. It is understood that the liquid phase is not subjected to an electric current, and no electrode is in direct contact with the liquid phase. In the context of the invention, the plasma is generated by applying an electric field between two electrodes that are not in contact with the liquid phase. Unlike reactions involving the generation of plasmas by discharge in the liquid phase, it is not necessary here to use an electrolyte in the liquid phase to ensure electrical conduction between the electrodes. In one embodiment, the liquid phase is therefore devoid of electrolyte. Preferably, the electrodes used to generate the plasma are also not in direct contact with the gas phase.

[0041] As illustrated in Figure 1, the method of the invention involves the use of at least one gaseous phase and one liquid phase. The gaseous phase, called the plasma-generating gas, is transformed into plasma by applying electric fields, at least in the vicinity of the gas / liquid interface. The liquid phase does not participate in the generation of the plasma; the plasma is generated exclusively in the gas. By way of example in Figure 1, to simplify the explanation but without restricting its scope, the liquid molecule providing the chemical function Ri, i.e., here the activatable substrate R1-R2, is activated by the plasma to form two radical reaction intermediates, Rf (the reaction intermediate) and R2'. This activation can occur in the gaseous phase, by evaporation of the molecule, or at the plasma / liquid interface. The radicals Rf and R2 - then react directly with the organic substrate to be functionalized S to form the product P.

[0042] Typically, reaction intermediates Ri* can be radical, ionic, or Ri in nature. + or Rf, or simply neutral, Ri-H or Ri(-H) after reorganization or intramolecular transfer following activation, in an excited or non-excited state. Preferably, the reaction intermediate is radical or ionic in nature. For example, the formation of the reaction intermediate Ri* involves the dissociation of a covalent bond.

[0043] The activation of the activatable substrate R1-R2 can be carried out in the gas phase, by at least partial evaporation of the activatable substrate, or at the liquid-gas interface. In one particular embodiment, the activation of the activatable substrate Ri-R2 occurs exclusively in the gas phase. The reaction of the activated substrate with the substrate to be functionalized can take place in the gas phase (if the vapor / liquid equilibrium allows), at the gas / liquid interface, or in the liquid phase. In the latter case, the liquid can act as a filter, favoring the presence of desired intermediates, increasing the lifetime of the intermediate Ri*, or decreasing the lifetime of potentially other undesired intermediates.

[0044] Preferably, the activatable substrate is activated by a dissociation reaction.

[0045] In one embodiment, the reaction intermediate is of a radical nature.

[0046] In a particular embodiment, product P is formed by a radical recombination reaction, preferably in the gas phase. This recombination involves the activation of both the solvent and the substrate. The reaction is preferably not a radical addition (addition of the activated solvent to the unactivated substrate).

[0047] The nature of the liquid phase can be engineered to optimize the transfer of specific radicals in order to maximize the yield and selectivity of the functionalization reaction. This engineering involves mixing various liquid compounds, some of which may or may not participate in the reaction.

[0048] The liquid phase refers to all the liquid species. This phase can be homogeneous, when all the liquid compounds are miscible, or heterogeneous, in the case where some liquid components are not miscible with each other.

[0049] In one embodiment, the liquid phase comprises only the organic substrate S to be functionalized and the activatable substrate R1-R2. In particular, it is devoid of catalyst and electrolyte.

[0050] In other embodiments, the liquid phase may include an inert solvent, i.e. one that does not participate in the reaction, which may, for example, allow the dissolution of solid species under the temperature and pressure conditions of the reaction.

[0051] In one embodiment, the liquid phase comprises at least 30% by weight of the activatable substrate R1-R2. Preferably, the liquid phase comprises at least 35% by weight, at least 40% by weight, at least 50% by weight, or more of the activatable substrate R1-R2. The activatable substrate can, for example, serve as a solvent for the organic substrate to be functionalized. Preferably, the activatable substrate is in excess relative to the organic substrate to be functionalized, thereby increasing the yield and / or selectivity of the functionalization reaction.

[0052] The method of the invention is particularly suitable when the organic substrate to be functionalized is chosen from a list consisting of an alkane, an alkene, an alkyne, an aromatic organic compound...

[0053] In a particular embodiment, the method of the invention allows the formation of a carbon-carbon bond or a carbon-nitrogen bond between the organic substrate to be functionalized and the reaction intermediate, preferably a carbon-carbon bond.

[0054] The organic substrate to be functionalized can be a complex molecule comprising one or more functional groups chosen from a list including an alkane, an alkene, an alkyne, an aromatic organic compound, a functional group with a carbon atom forming a double or triple bond with a heteroatom (other than C and H), etc. In this case, the designated functional group is the one containing the carbon atom that couples to the reaction intermediate from the activatable substrate. In the case of an alkane or an aromatic compound, the designated functional group is the one that undergoes substitution. In the case of an alkene or an alkyne, the designated functional group is the one that undergoes addition. In other words, when it is specified that the organic substrate to be functionalized is an alkane, an alkene, an alkyne, an aromatic organic compound, etc.This does not exclude that substrates may also include other organic functions, but these are not the site of the functionalization reaction which is the object of the method of the invention.

[0055] In one embodiment, the organic substrate S is an aromatic organic compound, i.e., the functionalization occurs on an unsaturated carbon of an aromatic organic group, and the substitution of an aromatic carbon by the reaction intermediate Rf formed by the plasma can be carried out without prior activation of the substrate S to functionalize it (Reaction 1). The prior activation consists of the preliminary removal of a functional group using plasma attack (electrons, excited argon, excited neutral, etc.).

[0056] [Chem.l]

[0057]

[0058] Reaction 1

[0059] The selectivity of the addition is determined by the nature of the substrate and the reaction intermediate. Here, an R3 substitution on the aromatic ring is illustrated, but the aromatic organic compound can be more complex, i.e., include several substituents, be polycyclic, contain heteroatoms, etc.

[0060] In one embodiment, the organic substrate S is an alkane, i.e., the functionalization occurs on a saturated carbon of an alkane chain, and the substitution by the plasma-formed reaction intermediate Rf can be carried out with or without prior activation of the substrate S to functionalize it, preferably with prior activation (Reaction 2). Prior activation consists of the preliminary ablation of a hydrogen atom H' using plasma attack (electrons, excited argon, excited neutral atom, etc.) or a first reaction intermediate Y' (CN radical, atomic oxygen atom, etc.). The selectivity of the ablation is determined by the structure of the substrate S.

[0061] [Chem.2]

[0062]

[0063] Reaction 2. In one embodiment, the organic substrate S is an alkene, i.e., the functionalization occurs on an unsaturated carbon of an alkene chain or on the saturated carbon in the α position of the double bond, and the addition via the plasma-formed reaction intermediate Rf can be carried out with or without prior activation of the substrate S to functionalize it (Reaction 3). The reaction can proceed via the preliminary ablation of a hydrogen atom by means of plasma attack (electrons, excited argon, excited neutral, etc.) on an unsaturated carbon of the alkene F, forming an allylic radical. The reaction can also proceed via the addition of the plasma-formed reaction intermediate Rf to the unsaturated carbon of the alkene, potentially after the preliminary addition of a second intermediate to the second unsaturated carbon. The pathway depends on the nature of the intermediates and the phase in which the reaction takes place.

[0064] [Chem.3]

[0065]

[0066] Reaction 3

[0067] The preliminary activation consists of the preliminary ablation of a hydrogen H' using a plasma attack (electrons, excited argon, excited neutral, etc.) or a first radical intermediate Y' (CN radical, atomic O, etc.).

[0068] In the case where a preliminary ablation of a hydrogen occurs on a saturated carbon in position a of the double bond, the formation of tautomers can be observed.

[0069] Preferably, neither the activatable substrate nor the organic substrate S to be functionalized is a spin trap, i.e., a compound capable of reacting selectively with a transient radical species to form a more stable radical adduct, detectable or quantifiable by spectroscopic methods, particularly electron paramagnetic resonance (EPR), such as compounds containing an N-oxide function like 5,5-dimethylpyrroline-N-oxide (DPMO), a C-nitroso function, or a nitrone function, whose reactive radicals will rapidly add together to form a nitrile radical. A definition of spin trapping is given by IUPAC (IUP AC - spin trapping (S05878)).

[0070] Preferably, neither the activatable substrate nor the organic substrate S to be functionalized is 5,5-dimethylpyrroline-N-oxide (DPMO).

[0071] Preferably, the plasma is formed at a pressure between 0.1 and 10 bar. The plasma formation pressure can depend on the operating conditions, particularly the scale at which the reaction is carried out. The desired pressure depends on the type of plasma required and the volatility of the various reactants.

[0072] Preferably, the plasma is formed at a temperature such that the organic substrate S to be functionalized and the activatable substrate R1-R2 are liquid at plasma pressure, preferably with controlled saturated vapor pressures. Preferably, the plasma is formed at a temperature between 0°C and 150°C.

[0073] The gaseous phase can include any plasma-forming gas.

[0074] In a preferred embodiment, the gaseous phase consists of an inert plasma-forming gas, such as argon or helium. Thus, the gaseous species do not participate in the final structure of product P. The use of such gases also allows for the use of smaller gas volumes.

[0075] Alternatively, the gas phase could contain at least partially a non-inert plasma-forming gas, which could participate in the reaction or facilitate the formation of reaction intermediates, for example nitrogen, methane, dihydrogen, tetrafluoromethane, hexafluoroethane, ammonia, or dioxygen, while not necessarily participating in the final structure of product P. The method of the invention is applicable to any scale of synthesis. It is also applicable to continuous flow reactions and batch reactions.

[0076] In one embodiment, the method of the invention is carried out in continuous flow within a millifluidic or microfluidic reactor. Preferably, in this case, both the gaseous and liquid phases are in flow. The reaction takes place in the flow channel.

[0077] In one embodiment, the method of the invention is carried out in an industrial reactor.

[0078] BRIEF DESCRIPTION OF THE FIGURES

[0079] Figure 1 illustrates the general principle of the method of the invention.

[0080] EXAMPLES

[0081] The present invention will be better understood by reading the following examples which illustrate the invention in a non-limiting way.

[0082] The reactions in Examples 1 and 2 were carried out in a ceramic microreactor consisting of a channel with a cross-section of 170 µm x 1.8 mm (height x width) and a length of 55 cm, with walls 85 µm thick, as described by Dedieu et al. in Lab on Chip, 2024, 24, 3898-3908 (doi.org / 10.1039 / D4LC00315B). Electrodes were placed on either side of the channel. One electrode was connected to ground while a 2 kHz sinusoidal voltage was applied to the other. A segmented gas / liquid flow was generated in the channel using a T-junction. The amounts of reactants and products in the liquid phases were obtained from the chromatogram obtained from the liquid phases by gas chromatography.

[0083] The quantities are understood to be in molar quantities.

[0084] The conversion X is calculated from the amount of substance of the substrate S in the liquid phase before (ns, in) and after (ns, out) the reaction:

[0085] [Math 1]

[0086]

[0087] The selectivity SA of a product A in the liquid phase is calculated by dividing the amount of substance of product A in the liquid phase (DA) by the total amount of substance of product in the liquid phase:

[0088] [Math 2]

[0089]

[0090] Example 1: Functionalization via radical attack

[0091] Reaction 1.1: Cyation of benzene (volatile) by acetonitrile

[0092] [Chem.4]

[0093]

[0094] Reaction 1.1 A 0.1 mol / L solution of benzene in acetonitrile is introduced into the microreactor, maintained at 10°C, at a flow rate of 50 pL / min. A segmented flow is generated at Injunction T with a flow rate of 10 pL / min of argon. A sinusoidal voltage with a frequency of 1.5 kHz and a peak-to-peak voltage of 10 kV is applied to the high-voltage electrode. A 91% conversion of benzene to benzonitrile is achieved, with a liquid selectivity of 62%.

[0095] Reaction 1.2: Methylation of dodecene (non-volatile) by acetone

[0096] [Chem.5]

[0097]

[0098] Reaction 1.2

[0099] A 0.1 mol / L solution of 1-dodecene in acetone is introduced into the microreactor, maintained at 25°C, at a flow rate of 59 pL / min. A segmented flow is generated at the T-junction with a flow rate of 500 pL / min of argon. A sinusoidal voltage with a frequency of 2 kHz and a peak-to-peak voltage of 12 kV is applied to the high-voltage electrode. A 92% conversion of dodecene to 2-methyldodecane is achieved, with a liquid selectivity of 39%.

[0100] The other products obtained are dodecane (selectivity 29%) and tridecane (6%).

[0101] Example 2: Functionalization by radical recombination

[0102] Reaction 2.1: Methyl chlorination of cyclohexane (volatile) by dichloromethane

[0103] [Chem.6]

[0104]

[0105] Reaction 2.1

[0106] A 0.3 mol / L cyclohexane solution in dichloromethane is introduced into the microreactor, maintained at 25°C, at a flow rate of 100 pL / min. A segmented flow is generated at the T-junction with a flow rate of 200 pL / min of argon. A sinusoidal voltage with a frequency of 2 kHz and a peak-to-peak voltage of 8 kV is applied to the high-voltage electrode. A 99% conversion of cyclohexane to chloromethylcyclohexane is achieved, with a liquid selectivity of 30%.

[0107] Reaction 2.2: Methyl-cyanation of cyclohexane (volatile) by acetonitrile

[0108] [Chem.7]

[0109] NC— - >H2NHC— + CN + CH3 + H'

[0110]

[0111] Reaction 2.2

[0112] A 0.1 mol / L cyclohexane solution in acetonitrile is introduced into the microreactor, maintained at 10°C, at a flow rate of 10 pL / min. A segmented flow is generated at Injunction T with a flow rate of 50 pL / min of argon. A sinusoidal voltage with a frequency of 1.5 kHz and a peak-to-peak voltage of 10 kV is applied to the high-voltage electrode. An 89% conversion of cyclohexane is achieved, with a liquid selectivity of 28%, to cyanomethylcyclohexane.

[0113] Example 3 - Batch reaction at the non-micrometer scale. Although developed in microreactors, these reactions are applicable to any system allowing contact between a liquid phase and a plasma. For example, reaction 2.1 was carried out using a conventional batch system.

[0114] A 10 mL volume of a 1.0 mol / L cyclohexane-dichloromethane solution was placed in a 50 mL glass flask sealed with a septum. A metal needle, serving as a high-voltage electrode through which a flow rate of 25 mL / min of argon passed, was positioned 2 mm above the liquid surface. A sinusoidal voltage with a frequency of 2 kHz and a peak-to-peak voltage of 20 kV was applied to the high-voltage electrode. A selectivity of 22% for chloromethylcyclohexane in the liquid was achieved with a yield of 0.04% after 20 min of treatment.

Claims

DEMANDS 1. Method for functionalizing an organic substrate in the liquid phase comprising the following steps: an organic substrate S to be functionalized is placed in the presence of an activatable substrate R1-R2, the whole forming a liquid phase; said liquid phase being in contact with a gaseous phase; a plasma is generated in the gaseous phase by applying an electric field between two electrodes not in contact with the liquid phase; The plasma activates at least partially the activatable substrate R1-R2 to form a reaction intermediate Ri*; The reaction intermediate Ri* couples to at least one carbon of the organic substrate S, possibly previously activated, to form a product P.

2. Functionalization method according to claim 1, wherein the liquid phase comprises at least 30% by weight of the activatable substrate R1-R2.

3. Functionalization method according to one of claims 1 and 2, wherein the liquid phase is devoid of catalyst.

4. Functionalization method according to any one of claims 1 to 3, wherein the liquid phase is devoid of electrolyte.

5. Functionalization method according to any one of claims 1 to 4, wherein the liquid phase is devoid of a chemical species having an N-oxide, C-nitroso or nitrone function.

6. A functionalization method according to any one of claims 1 to 5, wherein the liquid phase is devoid of a chemical species called a spin trap.

7. A functionalization method according to any one of claims 1 to 6, wherein the activatable substrate R1-R2 is introduced in excess relative to the organic substrate S to be functionalized.

8. Functionalization method according to any one of claims 1 to 7, wherein the plasma is formed at a pressure between 0.1 and 10 bars.

9. Functionalization method according to any one of claims 1 to 8, wherein the plasma is formed at a temperature such that the organic substrate S to be functionalized and the activatable substrate R1-R2 are liquid at plasma pressure, and preferably between 0°C and 150°C.

10. Functionalization method according to any one of claims 1 to 8, wherein the activation of the activatable substrate R 1-R2 is carried out in the gaseous phase, by at least partial evaporation of the activatable substrate or at the interface of the liquid and gaseous phases.

11. Functionalization method according to any one of claims 1 to 10, wherein the reaction intermediate Ri* is of a radical nature.

12. Functionalization method according to claim 11, wherein the product P is formed by a radical recombination reaction.

13. Functionalization method according to any one of claims 11 and 12, wherein the organic substrate S to be functionalized is also activated by plasma to form a radical and the product P is formed by recombination of two radicals.

14. Radical functionalization method according to any one of claims 1 to 13, wherein the organic substrate to be functionalized is chosen from the list consisting of an alkane, an alkene, an alkyne, an aromatic organic compound.

15. A radical functionalization method according to any one of claims 1 to 14, wherein the reaction intermediate Ri* couples to at least one carbon of the organic substrate S to form a carbon-carbon or carbon-nitrogen bond, 16. A radical functionalization method according to any one of claims 1 to 15, carried out in continuous flow in a milli-fluidic or micro-fluidic reactor.

17. Radical functionalization method according to claim 16, wherein the gaseous phase and the liquid phase are both in flow and the reaction takes place in the flow channel.

18. Method of radical functionalization according to any one of claims 1 to 17, carried out in an industrial reactor.

19. Radical functionalization method according to any one of claims 1 to 18, wherein the gas phase consists of an inert plasmagenic gas, such as argon or helium.

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