Activation of molecular oxygen in liquid alkenes for the synthesis of oxiranes with air

Abstract

The invention relates to a method for activating molecular oxygen via the prior aggregation of alkene bonds in the liquid phase without any additives or solvents, which allows for the transformation of alkenes into oxiranes with high yield, using air as the only reagent, and occasionally ozone and free radical scavengers to prevent possible degradation.

Description

[0001] MOLECULAR OXYGEN ACTIVATION IN LIQUID ALKENES FOR THE SYNTHESIS OF OXIRANES WITH AIR of the invention

[0002] The present invention (hereinafter called “oxirair”) describes a procedure for the activation of molecular oxygen (also that contained in air) through the prior addition of alkene bonds in liquid phase without any additive or solvent, which allows the transformation of alkenes into oxiranes (oxiranes) in high yield with air as the only reagent, and occasionally ozone and free radical scavengers to prevent possible degradation.

[0003] Background

[0004] The epoxidation reaction of alkenes is one of the fundamental reactions in synthetic chemistry, both industrially and in the laboratory. Millions of tons of oxiranes are produced annually worldwide through this reaction, and some of these oxiranes are among the fifty most produced and sold chemicals globally (ethylene oxide, propylene oxide, limonene oxide, essential oil oxides, among others). The applications of these oxiranes range from chemical fixatives, adhesives, disinfectants, polymer precursors, lubricants, perfumes, and chemical additives in general (food, resins, among others). Modern life would be inconceivable without these oxiranes, as they are essential in virtually every field encompassed by organic materials chemistry (eXPRESS Polymer Lett. 2013, 7, 910-924; Nature 2023, 621, 306-311).

[0005] All these oxiranes, except ethylene oxide (which is explained later), are produced industrially using hydrogen peroxide (H₂O₂) or peroxides / hydroperoxides (R₂O₂ / ROOH) as oxygenated reagents for the corresponding alkene. When hydrogen peroxide is used, which is only in cases where the alkene is structurally simple, a catalyst (usually metallic) is required for the reaction to proceed efficiently, at temperatures below 70 °C where hydrogen peroxide does not decompose. In the case of peroxides and hydroperoxides, this catalyst may or may not be necessary, as these species are more reactive. In any case, the transformation of alkenes to oxiranes (except, as discussed above, the case of ethylene oxide) requires the use of additives, a solvent to bring the hydrophobic alkenes and hydrophilic peroxygenated species into contact, and the catalyst if necessary.

[0006] Ethylene oxide is the only oxirane that is industrially produced using molecular oxygen (air) and a supported silver catalyst at temperatures >400 °C (Ind. Eng. Chem. Res. 2005, 44, 645-650). The use of molecular oxygen is possible in this case due to the exceptional size, volatility, and electronic properties of ethylene, the smallest (two carbon atoms), volatile, and electronically neutral alkene, which allows it to react with oxygen over a metallic catalyst at high temperatures without competing polymerization or degradation processes. This characteristic has made ethylene oxide one of the fifteen most produced chemicals worldwide and the second most produced organic product after ethylene itself.However, this process is unique and absolutely incompatible with any other alkene. In fact, propylene (just one more carbon atom, three carbon atoms in total) is industrially epoxidized with hydrogen peroxide using an organic solvent (methanol, acetonithol, among others) over a metal catalyst. Note that the price and handling of hydrogen peroxide, which is a much more dangerous reagent than air, increases production costs by at least an order of magnitude. The situation is even more unfavorable for any alkene other than ethylene or propylene, where peroxides or hydroperoxides are almost always used, either as preformed pure agents or produced on-site, so production costs can increase by another order of magnitude (one hundred times more than with air).In any case, the use of hydrogen peroxide, peroxide or hydroperoxide is accepted in the industry since there is currently no alternative procedure with air and the oxiranes produced are basic in the chemical value and supply chain, on a global scale (ChemSusChem 2019, 12, 2911-2935).

[0007] Research on the epoxidation of alkenes with air (excluding ethylene) has yielded little success for potential industrial applications. In all the cases described, an additive is required in stoichiometric quantities to activate the oxygen, making the process too expensive (Catal. Lett. 2009, 132, 487-491; US3265716A Eastman Kodak C. 1966). When catalysts (usually metallic) are used, the yields to oxiranes are insufficient (<20%), or the process requires an additional stoichiometric activator or an excessively large amount of catalyst (J. Mol. Catal. A 2010, 321, 22-26; Catal. Sc. Tech. 2013, 3, 371-379; Appl. Catal. B, 2018, 221, 681-690). For example, it has been described that the in-situ generation of peroxides with air requires isopropylbenzene and carbonate-based solvents (ACS Sustainable Chem. Eng.2020, 8, 1178-1184); or that for continuous reactor operation, a photo-stimulated solid catalyst is required for the generation of the necessary peroxide radicals (WO 20009 / 0611715 A1) or electrochemistry (US 00527436A). In addition, halogenated compounds have been used, either as solvents or additives, for the formation of oxirane (patents US3238229A Monsanto Co. 1966, and US3959367A Dow Co. 1976).

[0008] The few catalysts capable of activating molecular oxygen without additives (J. Catal. 2006, 244, 208-218; Ind. Eng. Chem. Res. 2011, 50, 9069-9076; Nat. Commun. 2016, 7, 12855; J. Am. Chem. Soc. 2023, 145, 11085-11096) show that the reactivity of the studied catalytic system (alkene plus molecular oxygen under the described reactions) is zero (or simply not commented on) when the catalyst is not added to the reaction.

[0009] Fundamental studies in classical organic chemistry on the mechanism of alkene oxidation with air, of interest in food processing such as oil rancidity, have shown that the process begins with the abstraction of the allylic hydrogen atom from the alkene's double bond to form the corresponding hydroperoxide. This hydroperoxide initiates a series of chain reactions to break down the molecule and generate, for example, carboxylic acids. However, these seminal works already demonstrate that the so-called direct addition of oxygen to the alkene (to generate the oxirane) is possible (J. Org. Chem. 2015, 80, 11869-11876), although yields <5% in the cases studied. All these cases used high molecular oxygen pressures (between 5 and 70 bar) and solvents (J. Am. Chem. Soc. 1965, 87, 4824-4832); Org. Chem. 1988, 53, 1695-1702), in addition to metallic reactors in many cases, which trigger further alkene decomposition reactions (Chem. Engineer. Se.1999, 54, 3967-3976; Ind. Eng. Chem. Res. 2004, 43, 3289-3296). One example describes a procedure for obtaining a specific oxirane, tetramethyloxirane, by liquid-phase epoxidation (patent EP0074009B1, Bayer AG, 1983), but the reaction conditions, which determine the solubility of molecular oxygen in the liquid mixture and, therefore, the reaction yield, are not disclosed. In this patent, we describe that, under certain reaction conditions, the pure alkene can activate molecular oxygen for epoxidation in high yields by means of the direct addition of molecular oxygen promoted by the addition of liquid alkene.

[0010] Pure liquid alkenes exhibit weak Van der Waals interactions (“jt-stacking”) between alkene functional groups, which slightly modify the overall electronic properties of the alkene. This effect, known for years (J. Am. Chem. Soc. 1961, 83, 231-236; J. Phys. Chem. 1982, 86, 2516-2522), has traditionally been considered insufficient to have any impact on reactivity. Only recently has it been found that pure liquid alkenes are capable of activating complex organic groups (Green Chem., 2023, 25, 7073-7078; Aggregate 2023, 4, e346), although the specific molecular mechanism of activation has not yet been determined.

[0011] If we model using the classical theory of valence molecular orbitals, we observe that weak Van der Waals interactions (jt-stacking) between alkene functional groups cause a decrease in the energy associated with the highest occupied molecular orbital (and a consequent increase in the energy corresponding to the highest unoccupied molecular orbital; Angew. Chem. Int. Ed. 2023, 62, e202313028). Because the epoxidation reaction of alkenes requires that the electrons of the alkene in the highest occupied molecular orbital (HOMO, Chem. zvesti 1981, 35, 797–807) be transferred to the unoccupied molecular orbital of the oxygen-containing species (SOMO, AJCE, 2018, 8, 1–6), we considered the possibility that this effect might lead to the activation of molecular oxygen by transfer of electrons activated by rc-stacking from pure alkenes (Figure 1). Note that no external electrical stimulus is required (J. Am. Chem. Soc.2023, 145, 17515-17526) but is a controlled phenomenon inherent to the chemical structure of the pure alkene and molecular oxygen.

[0012] For this activation to occur, a series of conditions (at least five) are required that apparently have not yet been studied in the literature all at once: 1) the alkene must be at least 90% pure (except for the most neutral groups such as linear alkanes where up to 50% dilution can be accepted), since dilution of the alkene with any other functional group would break the poly-coordination of the alkene groups and consequently the activation of the oxygen; 2) the alkene must be in the liquid phase, since Van der Waals interactions are too weak if the alkene is in the gaseous or solid phase; 3) the molecule to be activated by the alkene (in this case oxygen) must be present in very small quantities within the liquid alkene so as not to break the activation;4) the molecule to be activated by the alkene (in this case oxygen) must have an empty orbital accessible to the newly excited electrons of the alkene, so that it is spontaneously activated in the pure alkene reaction medium; and 5) the reactive process must be compatible with an oxidizing atmosphere.

[0013] The alkene functions not only as a reactant but also as the matrix necessary for the molecular oxygen present in the air to dissolve in the required amount and activate the reaction. The conditions found in this patent are suitable for an oxygen dissolution in the pure alkene of between 5000 and 100 parts per million (Ind. Eng. Chem. Res. 2014, 53, 19331-19337); at any other range above or below this value, the reaction is inefficient. The oxygen concentration is easily controlled by the system's pressure and temperature, and only alkanes with the same oxygen-dissolving capacity (Fluid Phase Equilibria 2003, 209, 229-243) as the alkenes used in this patent are compatible with the system. For higher oxygen concentrations, undesirable reactions such as alkene degradation or over-oxidation of the oxirane product will occur (J. Am. Chem. Soc. 2015, 137, 8206-8218; Green Chem. (2016), 18(2), 497-507; J. Am.Chem. Soc. 2022, 144, 15954-15968); for lower oxygen concentrations, the epoxidation reaction does not occur.

[0014] The present “oxirair” synthesis procedure strictly complies with the requirement to operate under reaction conditions below the flash point of any alkene, since it can be operated with 5% (v:v) diluted oxygen in an inert gas (e.g. nitrogen), which is an oxygen concentration below most known flash points for alkenes.

[0015] The invention described herein allows for the use of both batch and flow reactors. In both cases, the reaction conditions required for the oxirair synthetic system can be obtained, although continuous reactor operation is preferable from an operational and production standpoint.

[0016] Uncontrolled activation of molecular oxygen would lead to the generation of ozone and oxygen free radicals through the breaking of oxygen-oxygen bonds before the alkene epoxidizes, generating undesirable products and a loss of selectivity towards the oxirane. Therefore, the present invention also includes the use of ozone and free radical inhibitors, which will aid in the selective formation of the oxirane from the pure liquid alkene. Examples of these radical inhibitors compatible with the new oxirane production system are nanoceria (J. Catal. 2009, 264, 44-53; J. Mater. Chem. A, 2014, 2,16459), supported (Appl. Catal. B 2001, 33, 217-222) or unsupported (Catal. Commun. 2018, 106, 25-29) metal oxides, and in combination or not with organic molecules (Appl. Catal. B 1997, 14, 117-129).

[0017] Description of the invention

[0018] The present invention describes a process for the activation of molecular oxygen (which may or may not contain air) through the prior addition of alkene bonds in the liquid phase without any additives or solvents. This allows the transformation of alkenes into oxiranes with high yield and using air as the only reagent, and occasionally ozone and free radical scavengers to prevent potential degradation. This process is referred to herein as “oxirair”.

[0019] Thus, the present invention relates to a process for activating molecular oxygen with alkenes in the liquid phase, comprising at least the following steps:

[0020] - A first stage in which the liquid or liquefiable alkene is brought into contact with oxygen, either pure or mixed with inert gases, where the pressure of pure oxygen, or the partial pressure of the mixed oxygen, is between 0.5 and 5 bar in the reactor, more preferably between 1 and 2 bar.

[0021] - A second heating stage of the resulting mixture, between 25 and 350 °C, preferably between 50 and 150 °C.

[0022] - A third stage of releasing unreacted molecular oxygen (i.e., oxygen extraction from the reactor). - A fourth stage of recovering the product (oxirane) as well as the ozone scavenger and unreacted free radicals.

[0023] In a preferred embodiment, air is used as the oxygen-containing gas mixture. The inert gases are preferably N2 or Ar.

[0024] Alkenes that can be used as starting material must be liquid or liquefiable at the reaction temperature and pressure of the system, and are described by the following molecular formula (they can be cis or trans): where R1 to R4 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, halide (F, Cl, Br or I), oxygenated groups selected from ether (-O-alkyl and -O-aromatic), ester (-COO-alkyl and -COO-aryl), carbonyl (-COH, -CO-alkyl and -CO-aryl) and carboxyl (-COOH), and nitrogenous functional groups selected from amines (-NH2), nitros (-NO2), oximes (-C=N-OH), amides (-CONH2) and nitriles (-CN).

[0025] The term “alkyl” in the present invention refers to aliphatic hydrocarbon chains, linear or branched, preferably having 1 to 8 carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, etc.

[0026] The term “alkenyl” in the present invention refers to linear or branched aliphatic hydrocarbon chains, preferably having from 1 to 8 carbon atoms, comprising at least one double bond. For example,

[0027] The term “alkynyl” in the present invention refers to linear or branched aliphatic hydrocarbon chains, preferably having 1 to 8 carbon atoms, comprising at least one triple bond.

[0028] The term “aryl” in the present invention refers to an aromatic carbocyclic chain, having from 6 to 12 carbon atoms, which may be a single or multiple ring, in the latter case with separate and / or fused rings. A non-limiting example of an aryl group is a phenyl group.

[0029] Alkyl, alkenyl, alkynyl, and aryl groups can be functionalized, for example, with halogens, oxygenated groups selected from ether, ester, carbonyl, and carboxyl, and nitrogenous groups selected from amines, nitros, oximes, amides, and nitriles.

[0030] In a preferred embodiment, R1 to R4 are independently selected from hydrogen and alkyl.

[0031] According to a particular embodiment of the present invention, the amount of alkene that the liquid mixture can contain is between 50%-100% by weight, preferably between 80%-100%.

[0032] According to another particular embodiment of the present invention, the only modifier of the pure alkene concentration that can be used are long-chain alkanes, which dissolve a similar amount of molecular oxygen to the pure alkene, and whose chain is between 6 and 16 carbon atoms, preferably between 8 and 12 carbon atoms, and particularly with 8 carbon atoms (octane).

[0033] According to the procedure of the present invention, the concentration of molecular oxygen in the liquid mixture can be between 0.01% (100 ppm) and 0.001% (10 ppm), preferably between 0.005% (50 ppm) and 0.002% (20 ppm).

[0034] In addition, in the first stage an inert gas can be added in a proportion (nitrogen or argon) that can be between 0% and 99% by volume, preferably between 95% and 99% by volume.

[0035] As previously mentioned, the process of the present invention allows for the addition of an ozone and free radical scavenger in the first stage. According to this particular embodiment, this ozone and free radical scavenger can be present in a catalytic amount of between 0.01% and 5% by weight of the alkene, preferably between 0.1% and 1%. According to the process of the present invention, the reaction temperature can be between 25 and 350 °C, preferably between 25 and 150 °C. The range is quite broad because it depends on the liquid stability of the alkene; higher temperatures result in a faster reaction rate. The reaction can be carried out under total pressures between 1 and 100 bar, preferably between 2 and 5 bar, and with contact times between 1 and 72 hours, preferably between 2 and 24 hours.

[0036] The reaction described in the present invention can be carried out in a batch or flow reactor. However, these reactors cannot be metallic, as decomposition of the oxirane produced occurs in the presence of the reactor metal, due to metal-catalyzed over-oxidation with oxygen.

[0037] According to a particular embodiment of the present invention, the reaction can be carried out in a batch reactor where the liquid alkene and gas-phase molecular oxygen are added, at temperatures between 25 and 350 °C, in the presence or absence of the ozone and free radical inhibitor.

[0038] According to another particular embodiment of the present invention, the reaction can be carried out in a flow reactor where the liquid or liquefiable alkene and gaseous molecular oxygen are passed through at temperatures between 50 and 250 °C, with contact times between 1 and 48 h. The molecular oxygen dissolved in the inert material can be injected at different points in a tubular reactor. If an ozone and free radical inhibitor is used, it can be added along the reactor as a solid.

[0039] According to the present invention, the products recovered in the fourth stage are oxiranes.

[0040] Thus, the product may be solely oxirane or comprise oxirane and an unreacted alkene in molar ratios of 1:99 to 99:1, preferably 80:20. Both organic compounds are easily separated by distillation or column chromatography. If an ozone and free radical inhibitor is added, this material will be present in the final mixture and can also be recovered by filtration or centrifugation.

[0041] Throughout the description and claims, the word "comprises" and its variations are not intended to exclude other technical features, additives, components, or steps. For those skilled in the art, other objects, advantages, and features of the invention will become apparent partly from the description and partly from the practice of the invention.

[0042] BRIEF DESCRIPTION OF THE FIGURES

[0043] Figure 1: Possible activation of molecular oxygen by “jt-stacking” of pure liquid alkenes, represented by the classical theory of valence orbitals.

[0044] EXAMPLES

[0045] The following are non-limiting examples of the present invention:

[0046] Example 1: Batch reaction procedure in an autoclave reactor under molecular oxygen pressure.

[0047] For the synthesis of the different oxiranes using this procedure, a 7.5 mL autoclave reactor equipped with a 0-10 bar pressure gauge and a magnetic stir bar was used. 0.5 mmol of alkene was added, and the reactor was charged with 4.5 bar of oxygen. The reaction was stirred until complete conversion (approximately 2 hours), and the reaction was monitored by gas chromatography. Subsequently, the product was purified by flash chromatography on alumina using a hexane:ethyl acetate (20:1) mixture as the eluent, obtaining the yields shown below for three different oxiranes:

[0048] 43.6 mg of 2,3-dipropyloxirane were obtained (68% yield).

[0049] 19.3 mg of 2-methyl-3-pentyloxirane was obtained (30% yield).

[0050] 41.6 mg of 9-oxabicyclo[6.1.0]nonane were obtained (66% yield).

[0051] Example 2: Reaction procedure in a reflux batch reactor open to air.

[0052] For the synthesis of the different oxiranes using this procedure, a 5 mL glass flask connected to an open reflux condenser and equipped with a magnetic stir bar was used. 5 mmol of the corresponding alkene were added, and the mixture was stirred under reflux (oil or hot sand bath, typically at 200°C) for 16 hours. Subsequently, the resulting mixture was purified by flash chromatography using a hexane:ethyl acetate (20:1) mixture as the eluent, yielding the following oxiranes:

[0053] 612 mg of 13-oxabicyclo[10.1.0]thdecane were obtained (yield 67%).

[0054] 394 mg of 2,3-dihexyloxirane were obtained (yield 37%).

[0055] Example 3: Reaction procedure in a batch autoclave reactor with air diluted with nitrogen.

[0056] For the synthesis of the different oxiranes using this dilute air procedure, a 7.5 mL autoclave reactor equipped with a 0-10 bar pressure gauge and a magnetic stir bar was used. 0.1 mmol of alkene was added, and the reactor was charged with 1 bar of air and 4 bar of nitrogen. The system was stirred for 3 hours, and the reaction was monitored by gas chromatography. Subsequent analysis was performed by gas chromatography using n-dodecane as an internal standard.

[0057] 3.2 mg of 2,3-dihexyloxirane were obtained (15% yield).

[0058] Example 4: Reaction procedure in a tubular flow reactor.

[0059] For the synthesis of the different oxiranes using this flow-through procedure, a tubular reactor measuring 1 cm wide by 25 cm long was used. The reactor was thermostated with a jacket connected to a temperature controller via a thermocouple, positioned at the midpoint of the reactor. The liquid alkene cyclododecene was introduced by countergravity using a syringe connected to a pump, which controlled the liquid flow. Air was introduced through the same countergravity inlet using a T-valve. The pressure was monitored with a manometer attached to the reactor, and the reaction was monitored by gas chromatography analysis of the liquid samples collected in a flask at the reactor outlet.

Claims

CLAIMS 1. A process for activating molecular oxygen with alkenes in the liquid phase comprising at least the following steps: a) a first step in which at least one alkene, liquid or liquefiable at the pressure and temperature of the process, is brought into contact with oxygen, either pure or mixed with inert gases, wherein the pressure of pure oxygen, or the partial pressure of oxygen in the mixture, is between 0.5 and 5 bar in the reactor, b) a second step of heating the resulting mixture to between 25 and 350 °C, c) a third step of releasing unreacted molecular oxygen, d) a fourth step of recovering the product, and wherein the starting alkene is pure or mixed with a long-chain alkane comprising between 6 and 16 carbon atoms as a solvent.

2. A process for activating molecular oxygen with alkenes in the liquid phase, according to claim 1, characterized in that the starting alkenes are described by the following molecular formula: where R1 to R4 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, halide, oxygen-containing functional groups selected from ether, ester, carbonyl and carboxyl, and nitrogen-containing functional groups selected from amines, nitros, oximes, amides and nitriles.

3. A process for activating molecular oxygen with alkenes in the liquid phase according to any of claims 1 and 2, characterized in that, in the case that the alkene is mixed with a long-chain alkane, the amount of alkene contained in the liquid mixture is between 50%-100% by weight.

4. Procedure for activating molecular oxygen with alkenes in liquid phase according to any of the preceding claims, characterized in that in the first stage an inert gas is added which will be between 0% and 99% by volume.

5. A process for activating molecular oxygen with alkenes in the liquid phase, according to any of the preceding claims, characterized in that the first step comprises adding an ozone and free radical inhibitor.

6. A process for activating molecular oxygen with alkenes in the liquid phase, according to claim 5, characterized in that the ozone and free radical inhibitor is present in an amount between 0.01% and 5% by weight with respect to the alkene.

7. Procedure for activating molecular oxygen with alkenes in liquid phase, according to any of the preceding claims, characterized in that the reaction temperature is between 25 and 150 °C.

8. A process for activating molecular oxygen with alkenes in the liquid phase, according to any of the preceding claims, characterized in that the reaction is carried out under total pressures between 1 and 100 bar.

9. Procedure for activating molecular oxygen with alkenes in liquid phase, according to any of the preceding claims, characterized in that the reaction is carried out in a “batch” or flow reactor.

10. A process for activating molecular oxygen with alkenes in the liquid phase, according to claim 9, characterized in that the reaction (steps a) plus b)) is carried out with times of between 1 h and 72 h for the batch reactor and 1 h and 4 h in the flow reactor.

11. A liquid-phase molecular oxygen activation process with alkenes, according to any of the preceding claims, characterized in that the products recovered in the fourth stage are oxiranes.

12. A process for activating molecular oxygen with alkenes in the liquid phase, according to claim 11, characterized in that the recovered product further comprises an unreacted alkene, in molar proportions of 1:99 to 99:

1.

13. Procedure for activating molecular oxygen with alkenes in liquid phase, according to any of the preceding claims, characterized in that the reactors used are non-metallic.

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