Process for the synthesis of propargyl alcohol by reacting formaldehyde with acetylene in the presence of a homogeneous copper catalyst

Abstract

A process for producing propargyl alcohol, which comprises reacting acetylene with formaldehyde in the liquid phase in the presence of a copper catalyst and at least one phosphine.

Description

[Technical field]

[0001] The object of the present invention relates to a process for the preparation of propargyl alcohol by homogeneous catalysis, in which acetylene is reacted with formaldehyde in the presence of a copper complex comprising at least one phosphine as ligand. [Background technology]

[0002] Propargyl alcohol is currently produced from acetylene and formaldehyde using heterogeneous copper acetylide catalysts, which usually have relatively low selectivity and produce a significant amount of 1,4-butynediol as a by-product. Therefore, a more selective synthetic method for economically synthesizing propargyl alcohol from acetylene and formaldehyde is needed to meet the market demand for propargyl alcohol.

[0003] Justus Liebigs Annalen der Chemie, 1955, 596, 25-38 describes the reaction of aqueous formaldehyde with acetylene at a pressure of 20 bar using a heterogeneous copper acetylide catalyst and tetrahydrofuran as solvent at 100° C. After isolating the products, 62% propargyl alcohol and 30% 1,4-butynediol (depending on the formaldehyde used) can be obtained (ratio of propargyl alcohol:1,4-butynediol=2.1:1). The disadvantages of this procedure are the 30% of unwanted 1,4-butynediol and the need for a high acetylene pressure of 20 bar, which requires high safety measures.

[0004] US Patent No. 2996552A discloses the use of acetylene at atmospheric pressure, 10% KOH as catalyst, dimethylsulfoxide as solvent and solid paraformaldehyde as formaldehyde source to synthesize propargyl alcohol. The conversion of paraformaldehyde to propargyl alcohol is 40% and the conversion to 1,4-butynediol is 9% (ratio of propargyl alcohol:1,4-butynediol=4.4:1). The disadvantages of this method are the low conversion of paraformaldehyde, the production of unnecessary 1,4-butynediol, and the need to neutralize the catalyst at the end of the reaction, which therefore cannot be reused and results in waste salt.

[0005] German Patent No. 4415380 discloses the reaction of acetylene with aqueous formaldehyde at a pressure of up to 1.4 bar using a heterogeneous copper acetylide catalyst and dimethylformamide as the solvent. It discloses that the conversion of paraformaldehyde to propargyl alcohol and 1,4-butynediol is up to 75%, with a maximum ratio of propargyl alcohol to 1,4-butynediol of 3:1. The drawback of this approach is that undesired 1,4-butynediol is still produced in relatively large amounts.

[0006] EP 1658256 discloses the reaction of acetylene with aqueous formaldehyde at 3.3 bar pressure using a heterogeneous copper acetylide catalyst in a moving bed and tetrahydrofuran as the solvent. The maximum ratio of propargyl alcohol to 1,4-butyendiol achieved is 0.17:1. The drawback of this approach is the production of large amounts of unwanted 1,4-butynediol, which is the main product in the process.

[0007] Certain transition metal catalyzed systems are known for the synthesis of other alkynols based on terminal alkynes.

[0008] In Organic Letters, 2005, 7, 4395-4398, a series of alkynols are synthesized from terminal alkynes such as phenylacetylene and various aldehydes using a homogeneously dissolved silver catalyst with phosphine ligands and trialkylamines as additives in water as a solvent. The drawback of this system is that it has not been shown that it also works selectively with acetylene and formaldehyde to give propargyl alcohols, and in this case, when attempting to use this system for the reaction of acetylene, silver can form highly explosive silver acetylides.

[0009] In Journal of Organic Chemistry, 2007, 72, 9560-9596, a series of alkynols was synthesized from terminal alkynes and various ketones and aldehydes using a rhodium catalyst with homogeneously dissolved phosphine ligands in dioxane as a solvent. The drawbacks of this system are that it was not possible to demonstrate that the system also works selectively with acetylene and formaldehyde to give propargyl alcohols, and the use of the very expensive noble metal rhodium as a catalyst.

[0010] In RSC Advances, 2015, 5, 13220-13223, a series of alkynols was synthesized from terminal alkynes and paraformaldehyde using copper(I) iodide in the presence of one equivalent of inorganic base and one equivalent of trialkylamine base in dimethylsulfoxide as solvent. The study states that in the presence of phosphine (PPh3) as a ligand, under the given conditions, propargyl alcohols are not produced, instead only dimerization of alkynes occurs. The drawbacks of this system are that it was not possible to show that the system also works selectively with acetylene and formaldehyde to give propargyl alcohols, and furthermore, a stoichiometric amount of base is required as an additive, which increases the production costs and generates waste. Summary of the Invention [Problem to be solved by the invention]

[0011] The object of the present invention was to provide a process for the synthesis of propargyl alcohol from formaldehyde and acetylene, which can be carried out at low acetylene pressures and with high selectivity to propargyl alcohol without the use of additional stoichiometric amounts of co-reagents. [Means for solving the problem]

[0012] In accordance with this, a process has been found for the preparation of propargyl alcohol, in which acetylene is reacted with formaldehyde in the liquid phase in the presence of a copper catalyst and at least one phosphine.

[0013] Preferably, the process is carried out using a homogeneous copper catalyst having at least one phosphine as a ligand. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 shows the results of GC. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Formaldehyde Formaldehyde can be used in the disclosed process in various forms: as a technical aqueous solution with a formaldehyde content of up to 50% by weight, as a solution in various alcohols such as methanol (up to 55% by weight of formaldehyde), butanol (up to 40% by weight of formaldehyde), as paraformaldehyde, trioxane, acetals (e.g., dimethoxymethane, diethoxymethane) or as pure gaseous formaldehyde.

[0016] copper catalyst The homogeneous copper catalyst Cu(I) can be used in the form of a preformed copper complex containing copper, the required phosphine ligand, and one or more other ligands. Alternatively, the catalyst system is formed in situ in the reaction mixture by combining a copper compound, also referred to herein as a catalyst precursor, with one or more suitable phosphine ligands to form a catalytically active copper complex in the reaction mixture.

[0017] Suitable catalyst precursors are selected from neutral copper complexes, copper oxides and salts. Copper compounds useful as catalyst precursors include, for example, [CuBr(Me2S)], [Cu(CF3SO3)2], [CuBr], [CuCl], [CuI], [CuF], [Cu(OAc)2], [Cu(OAc)2]·H2O, [Cu(OAc)], [(PPh3)2Cu][NO3], [Cu(AcAc)2], [Cu((CH3)2CHCOO)2], [CuCl2], [CuCl2]·2H2O, [Cu(CN)], [Cu(HCOO)2]·(H2O). x , [Cu(OCH3)2], [Cu(CO3)2]·3H2O, [Cu(O2CCO2)]·0.5H2O, [Cu(ClO4)2]·6H2O, [Cu (CCPh)], [Cu2C2]·H2O[Cu(SO4)], [Cu(SO4)]·5H2O, [Cu(NO3)2], [Cu(BF4)2]·H2O x , [Cu(SCN)], [Cu(CF3SO3)2], [Cu(CH3CN)4][PF6], [Cu(CH3CN)4][BF4], [Cu(CH3CN)4][NO3] and [Cu(CH3CN)4][ClO4].

[0018] In order to carry out the alkynylation process of the present invention, a suitable phosphine ligand must be used in combination with copper.

[0019] Suitable phosphine ligands of the catalyst system used for the alkynylation of formaldehyde in the process according to the invention are, for example, those of formulae I and II shown below: [ka] (In the formula, n is 0 or 1, R 1 ~R 9 are each independently unsubstituted or at least monosubstituted C1-C 10 -Alkyl, C3-C 10 -Cycloalkyl, C3-C containing at least one heteroatom selected from N, O and S 10 -Heterocyclyl, C5-C 14 -Aryl or C5-C containing at least one heteroatom selected from N, O and S 10 -heteroaryl (wherein the substituents are: F, Cl, Br, OH, CN, NH2 and C1-C 10 -alkyl); A is, i) Unsubstituted or at least monosubstituted N, O, P, C1-C6-alkanes, C3-C 10 -Cycloalkane, C3-C containing at least one heteroatom selected from N, O and S 10 -Heterocycloalkanes, C5-C 14 - selected from the group of aromatics and C5-C6-heteroaromatic containing at least one heteroatom selected from N, O and S where the substituents are: C1-C4-Alkyl, Phenyl, F, Cl, Br, OH, OR 15 , NH2, NHR 15 or N(R 15 ) 2 selected from the group consisting of R 15 is C1~C 10 -Alkyl and C5-C 10 -aryl), a bridging group; or ii) Formula (III) or (IV): [ka] (m, q are, independently of each other, 0, 1, 2, 3 or 4; R 10 , R 11 are independent of each other, C1 to C10 -Alkyl, F, Cl, Br, OH, OR 18 , NH2, NHR 18 and N(R 18 )2 groups (where R 18 is C1~C 10 -Alkyl and C5-C 10 - selected from aryl); X 1 , X 2 are, independently of each other, NH, O or S; X 3 is a bond, NH, NR 17 , O, S or CR 18 R 19 and; R 17 is unsubstituted or at least monosubstituted, C1-C 10 -Alkyl, C3-C 10 -Cycloalkyl, C3-C containing at least one heteroatom selected from N, O and S 10 -Heterocyclyl, C5-C 14 -Aryl or C5-C containing at least one heteroatom selected from N, O and S 10 -heteroaryl (wherein the substituents are: F, Cl, Br, OH, CN, NH2 and C1-C 10 - selected from the group consisting of alkyl; R 18 , R 19 are each independently unsubstituted or at least monosubstituted C1-C 10 -Alkyl, C1-C 10 -Alkoxy, C3~C 10 -Cycloalkyl, C3-C 10 -Cycloalkoxy, C3-C containing at least one heteroatom selected from N, O and S 10 -Heterocyclyl, C5-C 14 -Aryl, C5-C 14 -aryloxy or C5-C containing at least one heteroatom selected from N, O and S 10 -heteroaryl (wherein the substituents are: F, Cl, Br, OH, CN, NH2 and C1-C 10 -alkyl); Y 1 , Y 2 , Y 3 are each independently a bond, unsubstituted or at least monosubstituted methylene, ethylene, trimethylene, tetramethylene, pentamethylene, or hexamethylene. (wherein the substituents are: F, Cl, Br, OH, OR 15 , CN, NH2, NHR 16 , N(R 16 )2 and C1~C 10 -alkyl, R 16 is C1~C 10 -Alkyl and C5-C 10 -aryl)) are monodentate, bidentate, tridentate and tetradentate phosphines.

[0020] A is a bridging group. A is an unsubstituted or at least monosubstituted C1-C6-alkane, C3-C 10 -Cycloalkanes, C3-C 10 -Heterocycloalkanes, C5-C 14 -aromatic and C5-C6-heteroaromatic, and when (n=0), two hydrogen atoms of the bridging group are adjacent to the substituent Y 1 and Y 2 When (n=1), three hydrogen atoms of the bridging group are replaced by bonds to the adjacent substituent Y 1 , Y 2 and Y 3 is replaced by three bonds to

[0021] When A is P (phosphorus), the phosphorus is adjacent to the substituent Y when (n=0). 1 and Y 2 and one bond to a substituent selected from the group consisting of C1-C4-alkyl and phenyl. In the case (n=1), phosphorus is adjacent to the substituent Y 1 , Y 2 and Y 3It forms three bonds to

[0022] When A is N (nitrogen), the nitrogen is adjacent to the substituent Y when (n=0). 1 and Y 2 and one bond to a substituent selected from the group consisting of C1-C4-alkyl and phenyl. In the case of (n=1), the nitrogen is adjacent to the substituent Y 1 , Y 2 and Y 3 It forms three bonds to

[0023] When A is O (oxygen), n=0. The oxygen is adjacent to the substituent Y 1 and Y 2 It forms two bonds to

[0024] In a preferred embodiment, the process according to the invention is carried out in the presence of at least one donor phosphorus ligand of general formula (II) in addition to the copper complex catalyst.

[0025] In a preferred embodiment, the process according to the invention comprises at least one copper complex catalyst and a compound of general formula (V): [ka] (In the formula, R 4 ~R 7 are each independently unsubstituted or at least monosubstituted C1-C 10 -Alkyl, C3-C 10 -Cycloalkyl, C3-C containing at least one heteroatom selected from N, O and S 10 -Heterocyclyl, C5-C 14 -Aryl or C5-C containing at least one heteroatom selected from N, O and S 10 -heteroaryl (wherein the substituents are: F, Cl, Br, OH, CN, NH2 and C1-C 10 -alkyl; A is, i) Unsubstituted or at least monosubstituted N, O, P, C1-C6-alkanes, C3-C 10 -Cycloalkane, C3-C containing at least one heteroatom selected from N, O and S 10 -Heterocycloalkanes, C5-C 14 - selected from the group of aromatics and C5-C6-heteroaromatic containing at least one heteroatom selected from N, O and S where the substituents are: C1-C4-Alkyl, Phenyl, F, Cl, Br, OH, OR 16 , NH2, NHR 16 Or N(R 16 ) 2 selected from the group consisting of R 16 is C1~C 10 -Alkyl and C5-C 10 -aryl), which is a bridging group.

[0026] In one embodiment, the process according to the invention is carried out in the presence of a copper complex catalyst and a monodentate ligand of formula I, as used herein, R 1 , R 2 and R 3 is phenyl or alkyl, each optionally having one or two C1-C4-alkyl substituents, and R 1 , R 2 and R 3 are each C5-C8-cycloalkyl or C2-C 10 R is preferably -alkyl. 1 ~R 3 The groups may be different or identical. Preferably, R 5a Base~R 6The radicals are identical and are selected from the substituents mentioned herein, especially those indicated as preferred. Examples of preferred monodentate ligands I are triphenylphosphine (TPP), triethylphosphine, tri-n-butylphosphine, tri-n-octylphosphine, tri-tert-butylphosphine and tricyclohexylphosphine, triadamantylphosphine, diadamantyl-n-butyl-phosphine.

[0027] In another embodiment, the process according to the invention comprises the step of reacting a copper complex catalyst with 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp), 1,4-bis(diphenylphosphino)butane (dppb), 1,2-bis(dicyclohexylphosphino)ethane (dcpe), 1,3-bis(dicyclohexylphosphino)propane (dcpp), 1,4 -Bis(dicyclohexylphosphino)butane (dcpb), 1,2-bis(di-tert-butylphosphino)ethane (dtpe), 1,3-bis(di-tert-butylphosphino)propane (dtpp), 1,4-bis(di-tert-butylphosphino)butane (dtpb), 1,2-bis(diisopropylphosphino)ethane (dcpe), 1,3-bis(diisopropylphosphino)propane (dcpp) , 1,4-bis(diisopropylphosphino)butane (dcpb), 1,2-bis(diphenylphosphino)benzene, 1,2-bis(dicyclohexylphosphino)benzene, 1,2-bis(diisopropylphosphino)benzene, 1,2-bis(dtertbutylphosphino)benzene, 1,2-bis-(diphenylphosphinomethylene)benzene, 1,2-bis-(diisopropylphosphinomethylene)benzene, 1,2-bis-(ditertbutylphosphinomethylene)benzene, 1,2-bis-(dicyclohexyl)ylphosphinomethylene)benzene, in particular in the presence of at least a bidentate ligand which is a ligand of formula V selected from the group consisting of 1,4-bis(dicyclohexylphosphino)butane (dcpb) and 1,2-bis-(ditertbutylphosphinomethylene)benzene.

[0028] C1 to C related to the present invention10 -Alkyl is understood to mean branched, unbranched, saturated and unsaturated groups. Alkyl groups having 1 to 6 carbon atoms (C1-C6-alkyl) are preferred. Alkyl groups having 1 to 4 carbon atoms (C1-C4-alkyl) are more preferred.

[0029] Examples of saturated alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, amyl and hexyl.

[0030] Examples of unsaturated alkyl groups (alkenyl, alkynyl) are vinyl, allyl, butenyl, ethynyl and propynyl.

[0031] C1~C 10 -Alkyl groups may be unsubstituted or may be selected from the group consisting of F, Cl, Br, hydroxy (OH), C1-C 10 -Alkoxy, C5~C 10 -Aryloxy, C5-C 10 -Alkylaryloxy, C5-C containing at least one heteroatom selected from N, O, and S 10 -Heteroaryloxy, oxo, C3-C 10 -C5-C containing at least one heteroatom selected from cycloalkyl, phenyl, N, O, and S 10 Heteroaryl, C5-C containing at least one heteroatom selected from N, O, and S 10 -Heterocyclyl, naphthyl, amino, C1-C 10 -Alkylamino, C5-C 10 -C5-C containing at least one heteroatom selected from arylamino, N, O, and S 10 -Heteroarylamino, C1-C 10 -Dialkylamino, C 10 ~C 12 -Diarylamino, C 10 ~C 20 -Alkylarylamino, C1-C 10 -Acyl, C1-C 10 -Acyloxy, NO2, C1~C 10-Carboxy, carbamoyl, carboxamido, cyano, sulfonyl, sulfonylamino, sulfinyl, sulfinylamino, thiol, C1-C 10 -Alkylthiol, C5-C 10 -Arylthiol or C1-C 10 -alkylsulfonyl.

[0032] C1~C 10 The above definition of alkyl is C1-C 30 This also applies to -alkyls and C1-C6-alkanes.

[0033] C3~C 10 -Cycloalkyl is understood in this case as meaning saturated, unsaturated, monocyclic and polycyclic radicals. 10 Examples of -cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloalkyl groups may be unsubstituted or may have a C1-C 10 - optionally substituted by one or more substituents as defined above in relation to the alkyl group.

[0034] The active copper catalyst can be generated in situ in the reaction mixture by adding the ligand to the precursor described above. The molar ratio of metallic copper to ligand is in the range of 2:1 to 1:50, preferably in the range of 1:1 to 1:10, and most preferably in the range of 1:2 to 1:5.

[0035] The active copper catalyst can also be generated in a step prior to the alkynylation reaction by adding the ligand to the above-mentioned precursor in a suitable organic solvent, such as benzene, toluene, xylene, chlorobenzene or chloroform, at a temperature between 25°C and 120°C, which creates a mixing gap with water, for 10 minutes to 10 hours. In one embodiment, acetylene is present in this catalyst activation step. The acetylene is either added dissolved in an organic solvent or added under pressure to the mixture at activation, at a pressure between 1 bar and 20 bar. In one embodiment, if any insoluble material is formed after the catalyst generation, it is filtered off. The resulting solution containing the active catalyst is then used for the alkynylation reaction.

[0036] In addition to one or more ligands selected from the group of ligands described above, the catalyst system of the process of the present invention may also comprise at least one further ligand selected from halides, alkynes, amides, carboxylates, acetylacetonates, aryl- or alkylsulfonates, hydrides, CO, olefins, dienes, cycloolefins, nitriles, aromatic and heteroaromatic, ethers, PF3, phospholes, phosphabenzenes, and monodentate, bidentate and polydentate phosphinite, phosphonite, phosphoramidite and phosphite ligands.

[0037] The active catalyst can also be preformed in a dedicated synthesis step. Suitable preformed catalysts can be [Cu2(dcpb)3][PF6]2, [Cu2(dcpb)3][NO3]2, [Cu2(dcpb)3][BF4]2, [Cu2(dcpb)3][ClO4]2[Cu2(dppe)3][PF6]2, [Cu2(dppe)3][NO3]2[Cu(dcpb)Cl], [Cu(dcpb)Cl], [Cu(PPh3)2][NO3] and [Cu(PCy3)2][NO3], [CuCCPh] and [Cu2C2]·H2O.

[0038] When a preformed active catalyst is used, it may be advantageous to add additional ligands of formula I or V to the reaction mixture.

[0039] The amount of copper catalyst used in the process of the invention, based on the formaldehyde used, can vary within a wide range. Usually, the copper catalyst is used in a substoichiometric amount relative to the amount of formaldehyde. Usually, the amount of copper catalyst is 50 mol % or less, often 20 mol % or less, in particular 10 mol % or less or 5 mol % or less, based on the amount of formaldehyde. In the process of the invention, the amount of copper catalyst is preferably 0.001 to 50 mol %, often 0.001 mol % to 20 mol %, in particular 0.005 to 5 mol %, based on the amount of formaldehyde. It is preferred to use the copper catalyst in an amount of 0.01 to 5 mol %. All amounts of copper catalyst given here are calculated as metallic copper, based on the amount of formaldehyde.

[0040] The reaction of formaldehyde with acetylene can be carried out in principle according to any process known to those skilled in the art suitable for the reaction of formaldehyde with acetylene.

[0041] The acetylene used in the reduction reaction can be used in pure form or, if desired, in the form of a mixture with other inert gases, preferably nitrogen, methane, ethane, propane, butane or argon, etc. It is preferred to use acetylene in undiluted form.

[0042] The acetylene can be applied discontinuously or continuously, for example, by bubbling acetylene gas into the reaction mixture.

[0043] The acetylene can also be applied to the reaction dissolved in an organic solvent, or it can be introduced into the alkynylation reaction dissolved in an organic solvent after saturating the solvent with acetylene prior to the reaction.

[0044] The processes described herein can also be used to prepare substituted propargyl alcohols, such as phenylpropargyl alcohol or trimethylsilylpropargyl alcohol. Thus, in this type of process, instead of acetylene, a substituted acetylene, such as phenylacetylene or trimethylsilylacetylene, is used in the reaction with formaldehyde (see Examples 1-7 and Example 8).

[0045] The reaction is typically carried out at a cold pressure of acetylene in the range of 0.1 to 20 bar, preferably in the range of 0.5 to 20 bar, more preferably in the range of 0.5 to 10 bar.

[0046] In the method of the present invention, the reaction is carried out in the presence of an organic solvent. A "solvent" is a substance that dissolves a solute (chemically distinct liquid, solid or gas), resulting in a solution. A solution is a homogeneous mixture in which a gaseous, liquid or solid solute is dissolved in a solvent. In turn, a homogeneous mixture is one that is composed of two or more substances in which the solute particles are not visible to the naked eye and do not scatter light. In this context, a solvent is a liquid at 20°C.

[0047] The organic solvent is preferably selected from the group consisting of alkanes, cycloalkanes, aromatics, halogenated alkanes, halogenated aromatics.

[0048] Examples of suitable organic solvents are benzene, toluene, xylene (mixtures of isomers and pure isomers), chloroform, (cyclo)hexane, heptane or chlorobenzene.

[0049] The formaldehyde is preferably present in an amount of 0.1 to 25% by weight, more preferably 0.5 to 20% by weight, especially 1 to 20% by weight, for example 1 to 15% by weight, based on the total weight of all solvents used in the alkynylation reaction.

[0050] The work-up of the reaction mixture of the process of the invention and the isolation of the propargyl alcohol can of course be carried out in other conventional manner, for example by filtration or aqueous extraction work-up or by distillation. The propargyl alcohol is generally obtained in sufficient purity by applying such means or a combination thereof, such that no additional purification steps are necessary. The remaining copper catalyst, for example the copper catalyst remaining in the sump of the distillation column or in the organic phase after aqueous extraction, can be reused in the alkynylation reaction.

[0051] In one embodiment, the reaction is carried out in the presence of water, and a second liquid phase is formed during and after the reaction. In this embodiment, one of the organic solvents mentioned above is used, which creates a mixing gap with water. Water can be added as pure water or, if aqueous formaldehyde is used as the formaldehyde source, can be added via an aqueous formaldehyde solution. In this embodiment, the copper catalyst is preferably dissolved in an organic solvent, and the propargyl alcohol is preferably dissolved in the aqueous phase after the reaction.

[0052] The ideal mixing ratio of organic solvent and water will vary depending on the particular organic solvent, formaldehyde source, catalyst, their respective concentrations and phase separation method used, and can be determined by one of ordinary skill in the art.

[0053] The organic solvent and water added to the alkynylation reaction are suitably present in amounts such that the overall weight ratio is preferably from 95:5 to 5:95, more preferably from 80:20 to 20:80.

[0054] The two liquid phases are generally separated by gravity phase separation, which can be carried out using standard apparatus and standard methods as described, for example, in E. Mueller et al., "Liquid-Liquid Extraction" in Ullmann's Encyclopedia of Industrial Chemistry, 2005, Wiley-VCH Verlag GmbH&Co KGaA, DOI:10.1002 / 14356007.b03_06, chapter 3 "Apparatus".

[0055] On a laboratory scale, phase separation can be carried out, for example, in a separatory funnel; on an industrial scale, countercurrent extraction apparatus such as mixer-settler apparatus, extraction columns, stirred extraction columns, continuous packed bed liquid-liquid extractors, etc. are suitable.

[0056] The organic solvent phase is rich in copper catalyst when the distribution coefficient of the copper catalyst is P = [concentration of copper catalyst in organic phase] / [concentration of copper catalyst in aqueous phase] It means that the partition coefficient is > 1. The partition coefficient is preferably > 2, particularly preferably > 5.

[0057] The aqueous phase is rich in propargyl alcohol, and the distribution coefficient of propargyl alcohol is P = [concentration of propargyl alcohol in the aqueous phase] / [concentration of propargyl alcohol in the organic phase] It means that the partition coefficient is > 1. The partition coefficient is preferably > 2, particularly preferably > 5.

[0058] The propargyl alcohol can be isolated from the aqueous phase, for example by distillation or extraction to obtain the product.

[0059] The organic phase containing the copper catalyst can be reused as the catalytic phase for the alkynylation reaction, and the conversion after the first turnover is also satisfactory. Even after several regenerations, the catalytic activity is still satisfactory.

[0060] The reaction can be carried out primarily continuously, semi-continuously or discontinuously, with a continuous process being preferred.

[0061] The reaction can be carried out in any reactor known to the skilled artisan in the field of reactions of this type, and the skilled artisan will therefore select the reactor accordingly. Suitable reactors are described and reviewed in the relevant prior art, for example in K. Henkel, “Reactor Types and Their Industrial Applications”, Ullmann's Encyclopedia of Industrial Chemistry, 2005, Wiley-VCH Verlag GmbH & Co. KGaA, chapter 3.3: “Reactors for gas-liquid reactions”.

[0062] The process of the present invention can be carried out over a wide temperature range. Preferably, the reaction is carried out at a temperature in the range of from 20°C to 200°C, more preferably in the range of from 50°C to 180°C, especially in the range of from 60°C to 120°C. [ka]

[0063] [Table 1] EXAMPLES

[0064] Experimental procedures for screening ligands (Examples 1-6): In an argon-filled glove box, a crimp vial (10 mL capacity, disposable glass vial with beaded rim, sealed with a crimp aluminum cap with a Teflon / butyl rubber septum seal) was charged with copper(I) hexafluorophosphate tetrakis(acetonitrile) (18.6 mg, 50.0 μmol, 5.00 mol%) and ligand (monodentate: 150 μmol, 15.0 mol%; bidentate: 75.0 μmol, 7.50 mol%; e.g.: tributylphosphine, 30.3 mg, 150 μmol, 15.0 mol%). The catalyst system was then dissolved in anhydrous toluene (5.00 mL, 47.2 mmol, 47.2 equiv) and added to phenylacetylene (102 mg, 1.00 mmol, 1.00 equiv). A Teflon-coated magnetic stir bar was added, the vial was sealed, and the solution was stirred at room temperature for several minutes. The reaction mixture was then removed from the glove box, and a formaldehyde solution (approximately 30 wt in H2O, traces of methanol, 0.200 mL, 2.00 mmol, 2.00 equiv.) was injected into the reaction vessel through the septum using a syringe. The reaction mixture was then stirred and heated at 70°C using a metal heating block for 16 hours. The vial was then cooled to room temperature, and the reaction mixture was diluted with ethyl acetate (approximately 10 mL), washed twice with ammonium hydroxide solution (approximately 10 mL) and once with saturated brine (approximately 10 mL). The organic phase was then dried over MgSO4, filtered, and mesitylene (30.0 μL) was added as a GC internal standard. The reaction mixture was then analyzed on a calibrated GC (t R (phenylacetylene) = 5.70 min;t R (phenylpropargyl alcohol) = 10.83 min).

[0065] The analysis was carried out on an Agilent Technologies 6890N gas chromatograph equipped with a split / splitless injector and an FID detector. An Agilent Technologies DB-1 capillary column (30 m×0.25 mm, 1 μm) was used as the column, and helium was used as the carrier gas.

[0066] GC method: split ratio: 50 / 1, 1.1 mL / min, constant pressure, 80°C (1 min) ~ 15°C / min ~ 250°C (5 min).

[0067] It can be seen that only a trace amount of product was produced in Comparative Example 1, which did not contain a phosphine ligand. Examples 2 to 6 show that the addition of a phosphine ligand produces propargyl alcohol as the main product. [ka]

[0068] Example 7: GC Area: Starting material / Product: 4 / 96 [ka]

[0069] Example 8: GC Area: Starting material / Product: 22 / 78 Experimental procedures for the ethynylation of formaldehyde with acetylene derivatives (Examples 7 and 8): In an argon-filled glove box, a crimp vial (10 mL capacity, disposable glass vial with a rolled neck, sealed with a crimped aluminum cap with a Teflon / butyl rubber septum seal) was charged with tetrakis(acetonitrile)copper(I) hexafluorophosphate (3.7 mg, 10.0 μmol, 2.00 mol %) and phosphine ligand (tributylphosphine: 6.1 mg, 30.0 μmol, 6.00 mol % or 1,2-bis(di-tert-butylphosphino)xylene: 5.9 mg, 15.0 μmol, 3.00 mol %). The catalyst system was then dissolved in anhydrous toluene (5.00 mL, 47.2 mmol, 94.4 equiv.) or m-xylene (5.00 mL, 41.0 mmol, 82.0 equiv.) and phenylacetylene (51.1 mg, 500 μmol, 1.00 equiv.) or trimethylsilylacetylene (49.1 mg, 500 μmol, 1.00 equiv.) was added. A Teflon-coated magnetic stir bar was added, the vial was sealed, and the solution was stirred and heated at 90° C. for several minutes. The reaction mixture was then cooled to room temperature, removed from the glove box, and a formaldehyde solution (approximately 30 wt. in H2O, traces of methanol, 0.100 mL, 1.00 mmol, 2.00 equiv.) was added to the reaction vessel through the septum using a syringe. The reaction mixture was then stirred and heated at 90° C. or 110° C. using a metal heating block for 16 hours. The vial was then cooled to room temperature and the reaction mixture was analyzed by GC (t R (Phenylacetylene) = 3.52 min;t R (phenylpropargyl alcohol) = 9.50 min;t R (TMS-acetylene) = 1.39 min;t R (TMS-propargyl alcohol) = 4.83 min).

[0070] The analysis was carried out on an Agilent Technologies 6890N gas chromatograph equipped with a split / splitless injector and an FID detector. An Agilent Technologies DB-FFAP capillary column (30 m × 0.32 mm, 0.25 μm) was used as the column, and helium was used as the carrier gas.

[0071] GC method: split ratio: 50 / 1, 2.3 mL / min, constant pressure, 80°C (1 min) ~ 20°C / min ~ 250°C (5 min). [ka]

[0072] [Table 2]

[0073] Experimental procedures for screening ligands using acetylene (Examples 9-12): In a glove box (Ar), a crimp vial (10 mL capacity, disposable glass vial with a rolled neck, sealed with a crimped aluminum cap with a Teflon / butyl rubber septum seal) was charged with copper(I) hexafluorophosphate tetrakis(acetonitrile) (6.5 mg, 17.5 μmol, 3.50 mol%) and ligand (monodentate: 52.5 μmol, 10.5 mol%; bidentate: 35.0 μmol, 7.00 mol%; e.g.: tributylphosphine, 10.6 mg, 52.5 μmol, 10.5 mol%). The catalyst system was then dissolved in anhydrous solvent (5.00 mL) and a Teflon-coated magnetic stir bar was added. The vial was sealed and the solution was stirred at room temperature for several minutes. The reaction mixture was then removed from the glove box and acetylene was injected by bubbling a stream of 3 Å molecular sieve dried acetylene neat through a cannula into the solution for 2 min (acetylene reaches saturation concentration at atmospheric pressure, saturation concentration was previously determined by calibrated GC, acetylene concentration in toluene is about 0.100 M, 0.500 mmol, 1.00 equiv). The reaction mixture was then stirred at room temperature for an additional 10 min and a formaldehyde solution (about 30 wt in H2O, traces of methanol, 70.1 μL, 0.700 mmol, 1.40 equiv) was added to the reaction vessel through the septum using a syringe. The reaction mixture was then stirred and heated at 70 °C for 16 h using a metal heating block. The vial was then cooled to room temperature and the reaction mixture was diluted with water (about 2 mL) and stirred for an additional 10 min. The aqueous phase was then separated, filtered and DMSO (30.0 μL) was added as a GC internal standard. The aqueous phase was then analyzed by a calibrated GC (t R (Propargyl alcohol) = 2.59 min;t R (butynediol) = 6.75 min).

[0074] The analysis was carried out on an Agilent Technologies 6890N gas chromatograph equipped with a split / splitless injector and an FID detector. An Agilent Technologies DB-1 capillary column (30 m×0.25 mm, 1 μm) was used as the column, and helium was used as the carrier gas.

[0075] GC method: split ratio: 50 / 1, 1.1 mL / min, constant pressure, 80°C (1 min) ~ 15°C / min ~ 250°C (5 min). [ka]

[0076] [Table 3]

[0077] Experimental procedures for screening solvents (Examples 13-18): In an argon-filled glove box, a crimp vial (10 mL capacity, disposable glass vial with rolled neck, sealed with a crimped aluminum cap with a Teflon / butyl rubber septum seal) was charged with copper(I) hexafluorophosphate tetrakis(acetonitrile) (amount determined based on acetylene concentration in the solvent, for the toluene example (0.100 M CH, 0.500 mmol, 1.00 equiv): 9.3 mg, 25.0 μmol, 5.00 mol%) and 1,4-bis(dicyclohexylphosphino)butane (amount determined based on acetylene concentration in the solvent, for the toluene example (0.100 M CH, 0.500 mmol, 1.00 equiv): 22.5 mg, 50.0 μmol, 10.0 mol%). The catalyst system was then dissolved in anhydrous solvent (5.00 mL) and a Teflon-coated magnetic stir bar was placed in the vial. The vial was sealed and the solution was stirred at room temperature for several minutes. The reaction mixture was then removed from the glove box and acetylene was injected by bubbling a stream of acetylene dried over 3 Å molecular sieves neat through a cannula for 2 minutes into the solution (acetylene reaches saturation concentration at atmospheric pressure, which was previously determined by a calibrated GC). The reaction mixture was then stirred for an additional 10 minutes at room temperature and a formaldehyde solution (approximately 30 wt in H2O, traces of methanol, 0.100 mL, 1.00 mmol, 2.00 equiv.) was added to the reaction vessel through the septum using a syringe. The reaction mixture was then stirred and heated at 70° C. for 16 hours using a metal heating block. The vial was then cooled to room temperature and the reaction mixture was diluted with water (approximately 1 mL) and stirred for an additional 10 minutes. The aqueous phase was then separated, filtered, and DMSO (30.0 μL) was added as a GC internal standard. The aqueous phase was then analyzed by a calibrated GC (t R (Propargyl alcohol) = 2.59 min;t R (butynediol) = 6.75 min).

[0078] The analysis was carried out on an Agilent Technologies 6890N gas chromatograph equipped with a split / splitless injector and an FID detector. An Agilent Technologies DB-1 capillary column (30 m×0.25 mm, 1 μm) was used as the column, and helium was used as the carrier gas.

[0079] GC method: split ratio: 50 / 1, 1.1 mL / min, constant pressure, 80°C (1 min) ~ 15°C / min ~ 250°C (5 min). [ka]

[0080] [Table 4]

[0081] [ka]

[0082] [Table 5]

[0083] [ka]

[0084] [Table 6]

[0085] [ka]

[0086] Example 29: GC yield of OH: 46% / GC yield of 2OH: 10% Experimental procedures for screening experiments with acetylene (Examples 19-29): In an argon-filled glove box, crimp vials (10 mL capacity, disposable glass vials with rolled necks, sealed with crimped aluminum caps with Teflon / butyl rubber septum seals) were charged with copper(I) tetrakis(acetonitrile)hexafluorophosphate (0.2 mg–9.3 mg, 0.500–25.0 μmol, 0.100–5.00 mol%) and 1,4-bis(dicyclohexylphosphino)butane (0.5 mg–22.5 mg, 1.00–50.0 μmol, 0.200–10.0 mol%). The catalyst system was then dissolved in anhydrous toluene (5.00 mL, 47.2 mmol, 94.4 equiv.) and a Teflon-coated magnetic stir bar was placed in the vial. The vial was sealed and the solution was stirred at room temperature for several minutes. The reaction mixture was then filtered and loaded into a new crimp vial along with a new Teflon coated magnetic stir bar. If necessary, paraformaldehyde (30.0 mg, 1.00 mmol, 2.00 equiv) was added. The vial was sealed and removed from the glove box. The reaction mixture was then spiked with acetylene by bubbling a stream of 3 Å molecular sieve dried acetylene neat through a cannula into the solution for 2 minutes (acetylene reaches saturation concentration at atmospheric pressure, saturation concentration was previously determined by calibrated GC, acetylene concentration in toluene is approximately 0.100 M, 0.500 mmol, 1.00 equiv). The reaction mixture was then stirred at room temperature for an additional 10 min and, if necessary, formaldehyde solution (approximately 30 wt in HO, traces of methanol, 25-500 μL, 0.250-5.00 mmol, 0.500-10.0 equiv.) was added to the reaction vessel through the septum using a syringe. The reaction mixture was then stirred and heated at 70 °C using a metal heating block for 16 h. The vial was then cooled to room temperature and the reaction mixture was diluted with water (approximately 1 mL) and stirred for an additional 10 min. The aqueous phase was then separated, filtered and DMSO (30.0 μL) was added as a GC internal standard. The aqueous phase was then analyzed on a calibrated GC (usually t R (Propargyl alcohol) = 3.90 min;t R (butynediol) = 8.60 min).

[0087] The analysis was carried out on an Agilent Technologies 6890N gas chromatograph equipped with a split / splitless injector and an FID detector. An Agilent Technologies DB-1 capillary column (30 m×0.25 mm, 1 μm) was used as the column, and helium was used as the carrier gas.

[0088] GC method: split ratio: 50 / 1, 1.1 mL / min, constant pressure, 80°C (1 min) - 15°C / min - 250°C (5 min). The results are shown in Figure 1. [ka]

[0089] Experimental procedure for kinetic studies (Example 30): In a glove box (Ar), a round-bottom flask (50 mL capacity) was charged with copper(I) tetrakis(acetonitrile)hexafluorophosphate (18.6 mg, 50.0 μmol, 4.00 mol%) and 1,4-bis(dicyclohexylphosphino)butane (45.1 mg, 100 μmol, 8.00 mol%). The catalyst system was then dissolved in dry toluene (25.0 mL, 236 mmol, 189 equiv.) and a Teflon-coated magnetic stir bar was added. The solution was stirred at room temperature for several minutes. The reaction mixture was then filtered and loaded (5 mL each) into four crimp vials (10 mL capacity, disposable glass vials with rolled neck, sealed with crimped aluminum caps with Teflon / butyl rubber septum seals) along with a Teflon-coated magnetic stir bar. The vials were sealed and removed from the glove box. The reaction mixtures were then injected with acetylene by bubbling a stream of 3 Å molecular sieve dried acetylene neat through a cannula into the solution for 2 min (acetylene reaches saturation concentration at atmospheric pressure, saturation concentration was previously determined by calibrated GC, acetylene concentration in toluene is approximately 0.100 M, 0.500 mmol, 2.00 equiv). The reaction mixtures were then stirred at room temperature for an additional 10 min and a formaldehyde solution (approximately 30 wt in HO, traces of methanol, 4×25.0 mg, 4×0.250 mmol, 4×1.00 equiv) was added to each reaction vessel through the septum using a syringe. The reaction mixtures were then stirred and heated at 70 °C using a metal heating block for 1-4 h. The vials were then cooled to room temperature and the reaction mixtures were diluted with water (approximately 2 mL each) before being transferred to a separatory funnel. The reaction vessels were washed with water (2×1 mL). The aqueous phase was then separated and the organic phase was washed twice with water (2 mL). The aqueous phase was collected and DMSO (30.0 μL) was added as a GC internal standard. The combined aqueous phase was then analyzed by a calibrated GC (t R (Propargyl alcohol) = 3.40 min;t R (butynediol) = 9.15 min).

[0090] The analysis was carried out on an Agilent Technologies 6890N gas chromatograph equipped with a split / splitless injector and an FID detector. An Agilent Technologies DB-FFAP capillary column (30 m × 0.32 mm, 0.25 μm) was used as the column, and helium was used as the carrier gas.

[0091] GC method: split ratio: 50 / 1, 2.3 mL / min, constant pressure, 80°C (1 min) ~ 20°C / min ~ 250°C (5 min). [ka]

[0092] Example 31: First run: GC yield of OH / GC yield of 2OH: 60% / 5% Second run: GC yield of OH / GC yield of 2OH: 59% / 8% Experimental procedure for catalyst reuse (Example 31): The organic phase obtained after 4 hours of kinetic experiments (see above) was placed in a crimp vial (10 mL volume, disposable glass vial with rolled neck, sealed with a crimped aluminum cap with a Teflon / butyl rubber septum seal) together with a Teflon-coated magnetic stir bar. The vial was sealed, and the reaction mixture was then spiked with acetylene by bubbling a stream of acetylene dried over 3 Å molecular sieves neat through a cannula for 2 minutes into the solution (acetylene reaches saturation concentration at atmospheric pressure, saturation concentration was previously determined by calibrated GC, acetylene concentration in toluene is about 0.100 M, 0.500 mmol, 2.00 equiv.). A formaldehyde solution (about 30 wt in H2O, traces of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was then added to the reaction vessel through the septum using a syringe. The reaction mixture was then stirred and heated at 70° C. using a metal heating block for 4 hours. The vial was then cooled to room temperature and the reaction mixture was diluted with water (approximately 2 mL) before being transferred to a separatory funnel. The reaction vessel was washed with water (2×1 mL). The aqueous phase was then separated and the organic phase was washed twice with water (2 mL). The aqueous phase was collected and DMSO (30.0 μL) was added as a GC internal standard. The combined aqueous phase was then analyzed on a calibrated GC (t R (Propargyl alcohol) = 3.40 min;t R (butynediol) = 9.15 min. Furthermore, both the aqueous and organic phases were subjected to inductively coupled plasma mass spectrometry (ICP MS), which was performed at a certified central analytical department at BASF SE, Ludwigshafen, Germany.

[0093] The analysis was carried out on an Agilent Technologies 6890N gas chromatograph equipped with a split / splitless injector and an FID detector. An Agilent Technologies DB-FFAP capillary column (30 m × 0.32 mm, 0.25 μm) was used as the column, and helium was used as the carrier gas.

[0094] GC method: split ratio: 50 / 1, 2.3 mL / min, constant pressure, 80°C (1 min) ~ 20°C / min ~ 250°C (5 min). ICP-MS results: [Cu] in toluene: 15 mg / kg; [Cu] in H2O: <1 mg / kg. [ka]

[0095] Example 32: Experimental setup under ambient conditions, OH yield / 2OH yield by GC: 62% / 2% Experimental procedure for ethynylation of formaldehyde under ambient conditions (Example 32): A crimp vial (10 mL capacity, disposable glass vial with rolled neck, sealed with a crimp aluminum cap with a Teflon / butyl rubber septum seal) was charged with copper(I) hexafluorophosphate tetrakis(acetonitrile) (3.7 mg, 10.0 μmol, 4.00 mol%) and 1,4-bis(dicyclohexylphosphino)butane (9.0 mg, 20.0 μmol, 8.00 mol%). The catalyst system was then dissolved in toluene (5.00 mL, 47.2 mmol, 189 equiv.) and a Teflon coated magnetic stir bar was added. The solution was stirred at room temperature for several minutes. The reaction mixture was then filtered and charged into a new crimp vial along with a new Teflon coated magnetic stir bar. The vial was then sealed and the reaction mixture was injected with acetylene by bubbling a stream of acetylene dried over 3 Å molecular sieves neat through a cannula into the solution for 2 minutes (acetylene reaches saturation concentration at atmospheric pressure, saturation concentration was previously determined by calibrated GC, acetylene concentration in toluene is about 0.100 M, 0.500 mmol, 2.00 equiv.). A formaldehyde solution (about 30 wt in H2O, traces of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was added to the reaction vessel through the septum using a syringe. The reaction mixture was then stirred and heated at 70° C. for 4 hours using a metal heating block. The vial was then cooled to room temperature and the reaction mixture was diluted with water (about 2 mL) before being transferred to a separatory funnel. The reaction vessel was washed with water (2×1 mL). The aqueous phase was then separated and the organic phase was washed twice with water (2 mL). The aqueous phase was collected and DMSO (30.0 μL) was added as a GC internal standard. The combined aqueous phase was then analyzed by a calibrated GC (t R (Propargyl alcohol) = 3.40 min;t R (butynediol) = 9.15 min).

[0096] The analysis was carried out on an Agilent Technologies 6890N gas chromatograph equipped with a split / splitless injector and an FID detector. An Agilent Technologies DB-FFAP capillary column (30 m × 0.32 mm, 0.25 μm) was used as the column, and helium was used as the carrier gas.

[0097] GC method: split ratio: 50 / 1, 2.3 mL / min, constant pressure, 80°C (1 min) ~ 20°C / min ~ 250°C (5 min). [ka]

[0098] Experimental procedure for catalyst reuse (Example 33): In a glove box (Ar), a crimp vial (10 mL capacity, disposable glass vial with rolled neck, sealed with a crimped aluminum cap with a Teflon / butyl rubber septum seal) was charged with copper(I) hexafluorophosphate tetrakis(acetonitrile) (3.7 mg, 10.0 μmol, 4.00 mol%) and 1,4-bis(dicyclohexylphosphino)butane (9.0 mg, 20.0 μmol, 8.00 mol%). The catalyst system was then dissolved in toluene (5.00 mL, 47.2 mmol, 189 equiv.) and a Teflon-coated magnetic stir bar was added. The solution was stirred at room temperature for several minutes. The reaction mixture was then filtered and loaded into a new crimp vial along with a new Teflon-coated magnetic stir bar. The vial was then sealed and removed from the glove box. The reaction mixture was then heated at 70° C. for 15 min and cooled to room temperature, after which acetylene was injected by bubbling a stream of acetylene dried over 3 Å molecular sieves neat through a cannula into the solution for 2 min (acetylene reaches saturation concentration at atmospheric pressure, saturation concentration was previously determined by calibrated GC, acetylene concentration in toluene is about 0.100 M, 0.500 mmol, 2.00 equiv.). A formaldehyde solution (about 30 wt in H2O, traces of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was added to the reaction vessel through the septum using a syringe. The reaction mixture was then stirred and heated at 70° C. for 16 h using a metal heating block. The vial was then cooled to room temperature and the reaction mixture was diluted with water (about 2 mL) before being transferred to a separatory funnel. The reaction vessel was washed with water (2×1 mL). The aqueous phase was then separated and the organic phase was washed twice with water (2 mL). The aqueous phase was collected and DMSO (30.0 μL) was added as a GC internal standard. The aqueous phases were then combined and analyzed on a calibrated GC.

[0099] The organic phase was placed in a crimp vial (10 mL capacity, disposable glass vial with a rolled neck, sealed with a crimped aluminum cap with a Teflon / butyl rubber septum seal) along with a Teflon-coated magnetic stir bar. The vial was then sealed and the reaction mixture was injected with acetylene by bubbling a stream of acetylene dried over 3 Å molecular sieves neat through a cannula for 2 minutes into the solution (acetylene reaches saturation concentration at atmospheric pressure, saturation concentration was previously determined by calibrated GC, acetylene concentration in toluene is about 0.100 M, 0.500 mmol, 2.00 equiv.). A formaldehyde solution (about 30 wt in H2O, traces of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was then added to the reaction vessel through the septum using a syringe. The reaction mixture was then stirred and heated on a metal heating block at 80° C. for 16 h. The vials were then cooled to room temperature, the standard work-up procedure was performed (see above), and the aqueous phases were combined and analyzed on a calibrated GC after addition of DMSO (30.0 μL) as a GC internal standard.

[0100] The organic phase was once again placed in a crimp vial (10 mL capacity, disposable glass vial with rolled neck, sealed with a crimped aluminum cap with a Teflon / butyl rubber septum seal) along with a Teflon coated magnetic stir bar. The vial was then sealed and the reaction mixture was spiked with acetylene by bubbling a stream of 3 Å molecular sieve dried acetylene neat through a cannula for 2 minutes into the solution (acetylene reaches saturation concentration at atmospheric pressure, saturation concentration previously determined by calibrated GC, acetylene concentration in toluene is approximately 0.100 M, 0.500 mmol, 2.00 equiv.). A formaldehyde solution (approximately 30 wt in H2O, traces of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was then added to the reaction vessel through the septum using a syringe. The reaction mixture was then stirred and heated on a metal heating block at 90° C. for 16 h. The vials were then cooled to room temperature, the standard work-up procedure was performed (see above), and the aqueous phases were combined and analyzed on a calibrated GC after addition of DMSO (30.0 μL) as a GC internal standard.

[0101] The analysis was carried out on an Agilent Technologies 6890N gas chromatograph equipped with a split / splitless injector and an FID detector. An Agilent Technologies DB-FFAP capillary column (30 m × 0.32 mm, 0.25 μm) was used as the column, and helium was used as the carrier gas.

[0102] GC method: split ratio: 50 / 1, 2.3 mL / min, constant pressure, 80°C (1 min) ~ 20°C / min ~ 250°C (5 min). [ka]

[0103] Experimental procedure for catalyst recycling using bis(triphenylphosphine)copper(I) nitrate (Example 34): In a glove box (Ar), a crimp vial (10 mL capacity, disposable glass vial with a rolled neck, sealed with a crimped aluminum cap with a Teflon / butyl rubber septum seal) was charged with bis(triphenylphosphine)copper(I) nitrate (6.5 mg, 10.0 μmol, 4.00 mol %) and 1,4-bis(dicyclohexylphosphino)butane (9.0 mg, 20.0 μmol, 8.00 mol %). The catalyst system was then dissolved in toluene (5.00 mL, 47.2 mmol, 189 equiv.) and a Teflon-coated magnetic stir bar was added. The solution was stirred at room temperature for several minutes. The vial was then sealed and removed from the glove box. The reaction mixture was then charged with acetylene by bubbling a stream of acetylene dried over 3 Å molecular sieves neat through a cannula into the solution for 2 minutes (acetylene reaches saturation concentration at atmospheric pressure, saturation concentration was previously determined by calibrated GC, acetylene concentration in toluene is about 0.100 M, 0.500 mmol, 2.00 equiv). The reaction mixture was then heated at 90° C. for 16 hours. After cooling to room temperature, the reaction mixture was once again charged with acetylene (see above). A formaldehyde solution (about 30 wt in H2O, traces of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv) was then added to the reaction vessel through the septum using a syringe. The reaction mixture was then stirred and heated at 80° C. for 3 hours using a metal heating block. The vial was then cooled to room temperature and the reaction mixture was diluted with water (about 2 mL) before being transferred to a separatory funnel. The reaction vessel was washed with water (2 x 1 mL). The aqueous phase was then separated and the organic phase was washed twice with water (2 mL). The aqueous phase was collected and DMSO (30.0 μL) was added as a GC internal standard. The aqueous phases were then combined and analyzed on a calibrated GC.

[0104] The organic phase was placed in a crimp vial (10 mL capacity, disposable glass vial with a rolled neck, sealed with a crimped aluminum cap with a Teflon / butyl rubber septum seal) along with a Teflon-coated magnetic stir bar. The vial was then sealed and the reaction mixture was injected with acetylene by bubbling a stream of acetylene dried over 3 Å molecular sieves neat through a cannula for 2 minutes into the solution (acetylene reaches saturation concentration at atmospheric pressure, saturation concentration was previously determined by calibrated GC, acetylene concentration in toluene is about 0.100 M, 0.500 mmol, 2.00 equiv.). A formaldehyde solution (about 30 wt in H2O, traces of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was then added to the reaction vessel through the septum using a syringe. The reaction mixture was then stirred and heated on a metal heating block at 80° C. for 16 h. The vials were then cooled to room temperature, the standard work-up procedure was performed (see above), and the aqueous phases were combined and analyzed on a calibrated GC after addition of DMSO (30.0 μL) as a GC internal standard.

[0105] The organic phase was once again placed in a crimp vial (10 mL capacity, disposable glass vial with rolled neck, sealed with a crimped aluminum cap with a Teflon / butyl rubber septum seal) along with a Teflon coated magnetic stir bar. The vial was then sealed and the reaction mixture was spiked with acetylene by bubbling a stream of 3 Å molecular sieve dried acetylene neat through a cannula for 2 minutes into the solution (acetylene reaches saturation concentration at atmospheric pressure, saturation concentration previously determined by calibrated GC, acetylene concentration in toluene is approximately 0.100 M, 0.500 mmol, 2.00 equiv.). A formaldehyde solution (approximately 30 wt in H2O, traces of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was then added to the reaction vessel through the septum using a syringe. The reaction mixture was then stirred and heated on a metal heating block at 90° C. for 16 h. The vials were then cooled to room temperature, the standard work-up procedure was performed (see above), and the aqueous phases were combined and analyzed on a calibrated GC after addition of DMSO (30.0 μL) as a GC internal standard.

[0106] The analysis was carried out on an Agilent Technologies 6890N gas chromatograph equipped with a split / splitless injector and an FID detector. An Agilent Technologies DB-FFAP capillary column (30 m × 0.32 mm, 0.25 μm) was used as the column, and helium was used as the carrier gas.

[0107] GC method: split ratio: 50 / 1, 2.3 mL / min, constant pressure, 80°C (1 min) ~ 20°C / min ~ 250°C (5 min). [ka]

[0108] Experimental procedure for ethynylation of formaldehyde with copper(II) nitrate (Example 35): In a glove box (Ar), a crimp vial (10 mL capacity, disposable glass vial with rolled neck, sealed with a crimped aluminum cap with a Teflon / butyl rubber septum seal) was charged with copper(II) nitrate trihydrate (2.4 mg, 10.0 μmol, 4.00 mol%) and 1,4-bis(dicyclohexylphosphino)butane (9.0 mg, 20.0 μmol, 8.00 mol%). The catalyst system was then dissolved in anhydrous toluene (5.00 mL, 47.2 mmol, 189 equiv.) and a Teflon-coated magnetic stir bar was added. The solution was stirred at room temperature for several minutes. The vial was then sealed and removed from the glove box. A syringe was then used to add formaldehyde solution (approximately 30 wt in HO, traces of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) to the reaction vessel through the septum. The reaction mixture was then stirred and heated at 80° C. for 1 h on a metal heating block. After the reaction mixture was cooled to room temperature, acetylene was injected by bubbling a stream of acetylene dried over 3 Å molecular sieves neat through a cannula for 2 min into the solution (acetylene reaches saturation concentration at atmospheric pressure, saturation concentration was previously determined by calibrated GC, acetylene concentration in toluene is about 0.100 M, 0.500 mmol, 2.00 equiv.) using a syringe to add formaldehyde solution (about 30 wt in H2O, traces of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) through the septum, and the reaction mixture was then heated at 80° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (about 2 mL) and then transferred to a separatory funnel. The reaction vessel was washed with water (2×1 mL). The aqueous phase was then separated and the organic phase was washed twice with water (2 mL). The organic phase was placed in a crimp vial (10 mL capacity, disposable glass vial with a rolled neck, sealed with a crimped aluminum cap with a Teflon / butyl rubber septum seal) along with a Teflon-coated magnetic stir bar. After sealing the vial, the reaction mixture was injected with acetylene (see above).A formaldehyde solution (approximately 30 wt in HO, traces of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv) was then added to the reaction vessel through the septum using a syringe. The reaction mixture was then stirred and heated at 80° C. using a metal heating block for 16 h. The vial was then cooled to room temperature and the reaction mixture was diluted with water (approximately 2 mL) before being transferred to a separatory funnel. The reaction vessel was washed with water (2×1 mL). The aqueous phase was then separated and the organic phase was extracted twice with water (2 mL), the aqueous phases were combined and analyzed on a calibrated GC after adding DMSO (30.0 μL) as a GC internal standard.

[0109] The analysis was carried out on an Agilent Technologies 6890N gas chromatograph equipped with a split / splitless injector and an FID detector. An Agilent Technologies DB-FFAP capillary column (30 m × 0.32 mm, 0.25 μm) was used as the column, and helium was used as the carrier gas.

[0110] GC method: split ratio: 50 / 1, 2.3 mL / min, constant pressure, 80°C (1 min) ~ 20°C / min ~ 250°C (5 min). [ka]

[0111] Experimental procedure for carrying out ethynylation using high acetylene pressure (Example 36): A round-bottom flask (500 mL capacity) was charged with copper(I) tetrakis(acetonitrile)hexafluorophosphate (149 mg, 400 μmol, 4.00 mol%) and 1,4-bis(dicyclohexylphosphino)butane (270 mg, 600 μmol, 6.00 mol%). The catalyst system was then dissolved in toluene (200 mL, 1.89 mol, 189 equiv.) and a Teflon-coated magnetic stir bar was added. The solution was stirred at room temperature for 5 minutes and then decanted into a new round-bottom flask (500 mL capacity) containing a Teflon-coated stir bar. The catalyst mixture was then heated in an 80° C. oil bath with stirring for 30 minutes. The reaction mixture was then cooled to room temperature and transferred to a stainless steel autoclave (300 mL capacity) equipped with a mechanical stirrer. After addition of formaldehyde solution (approximately 30 wt in H2O, traces of methanol, 1.00 mL, 10.0 mmol, 1.00 equiv.), the autoclave was sealed and pressurized with acetylene (16 bar) and nitrogen (2 bar; total pressure 18 bar) at 90°C. The reaction mixture was stirred and heated at 90°C for 5 h while keeping the acetylene pressure constant. The autoclave was then cooled to room temperature and depressurized. The reaction mixture was diluted with water (approximately 40 mL) and then transferred to a separatory funnel. The reaction vessel was washed with water (2 x 40 mL). The aqueous phase was then separated and the organic phase was washed twice with water (40 mL each). The aqueous phase was collected and analyzed by a calibrated GC. [ka]

[0112] Experimental procedure for the ethynylation of formaldehyde using copper(I) phenylacetylide (Example 37): In a glove box (Ar), a crimp vial (10 mL capacity, disposable glass vial with rolled neck, sealed with a crimped aluminum cap with a Teflon / butyl rubber septum seal) was charged with copper phenylacetylide (1.6 mg, 10.0 μmol, 4.00 mol %) and 1,4-bis(dicyclohexylphosphino)butane (6.8 mg, 20.0 μmol, 6.00 mol %). The catalyst system was then dissolved in toluene (5.00 mL, 47.2 mmol, 189 equiv.) and a Teflon-coated magnetic stir bar was added. The vial was then sealed and removed from the glove box. The reaction mixture was then heated at 70° C. for 20 min until the solids dissolved, and after cooling to room temperature, acetylene was injected by bubbling a stream of acetylene dried over 3 Å molecular sieves neat through a cannula for 2 min into the solution (acetylene reaches saturation concentration at atmospheric pressure, saturation concentration was previously determined by calibrated GC, acetylene concentration in toluene is about 0.100 M, 0.500 mmol, 2.00 equiv.) using a syringe to add formaldehyde solution (about 30 wt in H2O, traces of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) through the septum to the reaction vessel. The reaction mixture was then stirred and heated at 70° C. for 3 h using a metal heating block. The vial was then cooled to room temperature and the reaction mixture was diluted with water (about 2 mL) before being transferred to a separatory funnel. The reaction vessel was washed with water (2×1 mL). The aqueous phase was then separated and the organic phase was washed twice with water (2 mL). The aqueous phase was collected and DMSO (30.0 μL) was added as a GC internal standard. The combined aqueous phase was then analyzed by a calibrated GC (t R (Propargyl alcohol) = 3.27 min;t R (butynediol) = 8.97 min).

[0113] The analysis was carried out on an Agilent Technologies 6890N gas chromatograph equipped with a split / splitless injector and an FID detector. An Agilent Technologies DB-FFAP capillary column (30 m × 0.32 mm, 0.25 μm) was used as the column, and helium was used as the carrier gas.

[0114] GC method: split ratio: 50 / 1, 2.3 mL / min, constant pressure, 80°C (1 min) ~ 20°C / min ~ 250°C (5 min). [ka]

[0115] Experimental procedure for the ethynylation of formaldehyde using copper(I) acetylide hydrate (Example 38): In a glove box (Ar), a crimp vial (10 mL capacity, disposable glass vial with a rolled neck, sealed with a crimped aluminum cap with a Teflon / butyl rubber septum seal) was charged with copper acetylide hydrate (0.8 mg, 5.00 μmol, 2.00 mol%) and 1,4-bis(dicyclohexylphosphino)butane (6.8 mg, 20.0 μmol, 6.00 mol%). The catalyst system was then dissolved in toluene (5.00 mL, 47.2 mmol, 189 equiv.) and a Teflon-coated magnetic stir bar was added. The vial was then sealed and removed from the glove box. The reaction mixture was then heated at 70° C. for 30 min, resulting in a dark suspension. After cooling to room temperature, the vial was charged with acetylene by bubbling a stream of acetylene dried over 3 Å molecular sieves neat through a cannula into the solution for 2 minutes (acetylene reaches saturation concentration at atmospheric pressure, saturation concentration was previously determined by calibrated GC, acetylene concentration in toluene is about 0.100 M, 0.500 mmol, 2.00 equiv.). A formaldehyde solution (about 30 wt in H2O, traces of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was added to the reaction vessel through the septum using a syringe. The reaction mixture was then stirred and heated at 70 °C using a metal heating block for 16 hours. The vial was then cooled to room temperature and the reaction mixture was diluted with water (about 2 mL) before being transferred to a separatory funnel. The reaction vessel was washed with water (2 x 1 mL). The aqueous phase was then separated and the organic phase was washed twice with water (2 mL). The aqueous phase was collected and DMSO (30.0 μL) was added as a GC internal standard. The combined aqueous phase was then analyzed by a calibrated GC (t R (Propargyl alcohol) = 3.27 min;t R (butynediol) = 8.97 min).

[0116] The analysis was carried out on an Agilent Technologies 6890N gas chromatograph equipped with a split / splitless injector and an FID detector. An Agilent Technologies DB-FFAP capillary column (30 m × 0.32 mm, 0.25 μm) was used as the column, and helium was used as the carrier gas.

[0117] GC method: split ratio: 50 / 1, 2.3 mL / min, constant pressure, 80°C (1 min) ~ 20°C / min ~ 250°C (5 min).

Claims

1. A process for producing propargyl alcohol, the process comprising reacting acetylene with formaldehyde in a liquid phase in the presence of a copper catalyst and at least one phosphine.

2. The process according to claim 1, wherein the copper catalyst is a homogeneous catalyst containing at least one phosphine as a ligand.

3. The phosphine is of formula I or II: 【Chemical 1】 (wherein, n is 0 or 1, R １ to R ９ are, independently of one another, unsubstituted or at least monosubstituted C １ to C １０ -alkyl, C ３ to C １０ -cycloalkyl, C containing at least one heteroatom selected from N, O and S ３ to C １０ -heterocyclyl, C ５ to C １４ -aryl or C containing at least one heteroatom selected from N, O and S ５ to C １０ -heteroaryl (Here, the substituent is selected from the group consisting of F, Cl, Br, OH, CN, NH ２ and C １ to C １０ -alkyl). A is i) N, O, P, C, with no substitution or at least one substitution １ ~C ６ -alkane, C ３ ~C １０ -cycloalkane, C containing at least one heteroatom selected from N, O and S ３ ~C １０ -heterocycloalkane, C ５ ~C １４ -aromatic and C containing at least one heteroatom selected from N, O and S ５ ~C ６ -selected from the group of heteroaromatics (where the substituents are: C １ ~C ４ -alkyl, phenyl, F, Cl, Br, OH, OR １５ 、NH ２ 、NHR １５ or N(R １５ ) ２ selected from the group consisting of, R １５ is either a C １ to C １０ -alkyl or a C ５ to C １０ -aryl selected), a crosslinking group; or ii) of formula (III) or (IV): 【Chemical 2】 (m, q are independently of each other 0, 1, 2, 3 or 4; R １０ 、 R １１ are, independently of each other, C １ to C １０ -alkyl, F, Cl, Br, OH, OR １８ , NH ２ , NHR １８ and N(R １８ ) ２ selected from the group of (Here, R １８ is selected from C １ to C １０ -alkyl and C ５ to C １０ -aryl); X １ 、 X ２ is, independently of one another, NH, O or S; X ３ is a bond, NH, NR １７ , O, S or CR １８ R １９ ; R １７ is unsubstituted or at least monosubstituted C １ to C １０ -alkyl, C ３ to C １０ -cycloalkyl, C containing at least one heteroatom selected from N, O and S ３ to C １０ -heterocyclyl, C ５ to C １４ -aryl or C containing at least one heteroatom selected from N, O and S ５ to C １０ -heteroaryl (Here, the substituent is selected from the group consisting of: F, Cl, Br, OH, CN, NH ２ and C １ to C １０ -alkyl); R １８ 、R １９ are, independently of each other, unsubstituted or at least monosubstituted C １ to C １０ - alkyl, C １ to C １０ - alkoxy, C ３ to C １０ - cycloalkyl, C ３ to C １０ - cycloalkoxy, C containing at least one heteroatom selected from N, O and S ３ to C １０ - heterocyclyl, C ５ to C １４ - aryl, C ５ to C １４ - aryloxy or C containing at least one heteroatom selected from N, O and S ５ to C １０ - heteroaryl (Here, the substituent is: F, Cl, Br, OH, CN, NH ２ and C １ to C １０ - alkyl selected from the group consisting of)); is a crosslinking group Y １ , Y ２ , Y ３ are, independently of one another, bonded, unsubstituted or at least monosubstituted methylene, ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene (Here, the substituents are: F, Cl, Br, OH, OR １５ , CN, NH ２ , NHR １６ , N(R １６ ), ２ and C １ to C １０ - alkyl, and are selected from the group consisting of: R １６ is a phosphine selected from C １ to C １０ -alkyl and C ５ to C １０ -aryl)), the process according to claim 1.

4. The phosphine is of formula V: [Chemical Formula 3] (wherein, R ４ ~R ７ are, independently of one another, unsubstituted or at least monosubstituted C １ ~C １０ -alkyl, C ３ ~C １０ -cycloalkyl, C containing at least one heteroatom selected from N, O and S ３ ~C １０ -heterocyclyl, C ５ ~C １４ -aryl or C containing at least one heteroatom selected from N, O and S ５ ~C １０ -heteroaryl (Here, the substituent is selected from the group consisting of: F, Cl, Br, OH, CN, NH ２ and C １ to C １０ -alkyl); A is i) Unsubstituted or at least monosubstituted N, O, P, C １ ~C ６ -alkane, C ３ ~C １０ -cycloalkane, C containing at least one heteroatom selected from N, O and S ３ ~C １０ -heterocycloalkane, C ５ ~C １４ -aromatic and C containing at least one heteroatom selected from N, O and S ５ ~C ６ -selected from the group of heteroaromatics (where the substituents are: C １ ~C ４ -alkyl, phenyl, F, Cl, Br, OH, OR １６ 、NH ２ 、NHR １６ or N(R １６ ) ２ selected from the group consisting of, R １６ is a bidentate phosphine by a crosslinking group (wherein R is selected from C~C-alkyl and C~C-aryl), the process according to claim 1. １ to C １０ -alkyl and C ５ to C １０ -aryl), which is a bidentate phosphine by a crosslinking group), the process according to claim 1. It should be noted that the original text seems a bit fragmented and might need some context clarification for a more seamless and accurate translation. The translation attempts to make sense of the overall structure and meaning based on the available elements.

5. The process according to claim 1, wherein the copper complex is prepared in situ during the reaction of the formaldehyde with acetylene.

6. The process according to claim 5, wherein 0.1 to 10 moles of phosphine per mole of copper are used in the preparation of the copper complex.

7. The process according to claim 1, wherein the copper complex is used in an amount of 0.01 to 5 mol% based on the amount of formaldehyde.

8. The process according to claim 1, wherein the reaction mixture contains an organic solvent.

9. The process according to claim 1, wherein acetylene is supplied to the reaction at a pressure of 1 to 20 bar.

10. The process according to claim 1, wherein the reaction is carried out at a temperature of 50 to 200 °C.

11. The process according to claim 1, wherein the reaction is carried out in a system containing two liquid phases, one phase being a water-rich phase and the other being an organic solvent-rich phase.

12. The process according to claim 10, wherein after the reaction, the organic phase is rich in the copper catalyst and the aqueous phase is rich in the propargyl alcohol.

13. The process according to claim 10, wherein after the reaction, the organic phase is rich in the copper catalyst and is reused as a catalyst in the alkynylation reaction.

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