PROCESS FOR THE SYNTHESIS OF PROPARGYLIC ALCOHOL BY REACTING FORMALDEHYDE WITH ACETYLENE IN THE PRESENCE OF A HOMOGENEOUS COPPER CATALYST

Abstract

A process to produce propargylic alcohol, wherein acetylene is reacted with formaldehyde in the liquid phase in the presence of a copper catalyst and at least one phosphine.

Claims

1.-13. (canceled)

14. A process to produce propargylic alcohol comprising reacting acetylene with formaldehyde in a liquid phase in the presence of a copper catalyst and at least one phosphine.

15. The process according to claim 14, wherein the copper catalyst is a homogeneous catalyst comprising at least one phosphine as ligand.

16. The process according to claim 14, wherein the phosphine is a phosphine of formula I or II ##STR00026## where n is 0 or 1; R.sup.1 to R.sup.9 are, independently of one another, unsubstituted or at least monosubstituted C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocyclyl comprising at least one heteroatom selected from N, O and S, C.sub.5-C.sub.14-aryl or C.sub.5-C.sub.10-heteroaryl comprising at least one heteroatom selected from N, O and S, where the substituents are selected from the group consisting of: F, Cl, Br, OH, CN, NH.sub.2 and C.sub.1-C.sub.10-alkyl; A is i) a bridging group selected from the group unsubstituted or at least monosubstituted N, O, P, C.sub.1-C.sub.6-alkane, C.sub.3-C.sub.10-cycloalkane, C.sub.3-C.sub.10-heterocycloalkane comprising at least one heteroatom selected from N, O and S, C.sub.5-C.sub.14-aromatic and C.sub.5-C.sub.6-heteroaromatic comprising at least one heteroatom selected from N, O and S, where the substituents are selected from the group consisting of: C.sub.1-C.sub.4-alkyl, phenyl, F, Cl, Br, OH, OR.sup.15, NH.sub.2, NHR.sup.15 or N(R.sup.15).sub.2, where R.sup.15 is selected from C.sub.1-C.sub.10-alkyl and C.sub.5-C.sub.10-aryl; or ii) a bridging group of the formula (III) or (IV): ##STR00027## m, q are, independently of one another, 0, 1, 2, 3 or 4; R.sup.10, R.sup.11 are, independently of one another, selected from the group C.sub.1-C.sub.10-alkyl, F, Cl, Br, OH, OR.sup.18, NH.sub.2, NHR.sup.18 and N(R.sup.18).sub.2, where R.sup.18 is selected from C.sub.1-C.sub.10-alkyl and C.sub.5-C.sub.10-aryl; X.sup.1, X.sup.2 are, independently of one another, NH, O or S; X.sup.3 is a bond, NH, NR.sup.17, O, S or CR.sup.18R.sup.19; R.sup.17 is unsubstituted or at least monosubstituted C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocyclyl comprising at least one heteroatom selected from N, O and S, C.sub.5-C.sub.14-aryl or C.sub.5-C.sub.10-heteroaryl comprising at least one heteroatom selected from N, O and S, where the substituents are selected from the group consisting of: F, Cl, Br, OH, CN, NH.sub.2 and C.sub.1-C.sub.10-alkyl; R.sup.18, R.sup.19 are, independently of one another, unsubstituted or at least monosubstituted C.sub.1-C.sub.10-alkyl, C.sub.1-C.sub.10-alkoxy, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-cycloalkoxy, C.sub.3-C.sub.10-heterocyclyl comprising at least one heteroatom selected from N, O and S, C.sub.5-C.sub.14-aryl, C.sub.5-C.sub.14-aryloxy or C.sub.5-C.sub.10-heteroaryl comprising at least one heteroatom selected from N, O and S, where the substituents are selected from the group consisting of: F, Cl, Br, OH, CN, NH.sub.2 and C.sub.1-C.sub.10-alkyl; Y.sup.1, Y.sup.2, Y.sup.3 are, independently of one another, a bond, unsubstituted or at least monosubstituted methylene, ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene, where the substituents are selected from the group consisting of: F, Cl, Br, OH, OR.sup.15, CN, NH.sub.2, NHR.sup.16, N(R.sup.16).sub.2 and C.sub.1-C.sub.10-alkyl, where R.sup.16 is selected from C.sub.1-C.sub.10-alkyl and C.sub.5-C.sub.10-aryl.

17. The process according to claim 14, wherein the phosphine is a bidentate phosphine according formula V ##STR00028## where R.sup.4 to R.sup.7 are, independently of one another, unsubstituted or at least monosubstituted C.sub.1-C.sub.10-alkyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocyclyl comprising at least one heteroatom selected from N, O and S, C.sub.5-C.sub.14-aryl or C.sub.5-C.sub.10-heteroaryl comprising at least one heteroatom selected from N, O and S, where the substituents are selected from the group consisting of: F, Cl, Br, OH, CN, NH.sub.2 and C.sub.1-C.sub.10-alkyl; A is i) a bridging group selected from the group unsubstituted or at least monosubstituted N, O, P, C.sub.1-C.sub.6-alkane, C.sub.3-C.sub.10-cycloalkane, C.sub.3-C.sub.10-heterocycloalkane comprising at least one heteroatom selected from N, O and S, C.sub.5-C.sub.14-aromatic and C.sub.5-C.sub.6-heteroaromatic comprising at least one heteroatom selected from N, O and S, where the substituents are selected from the group consisting of: C.sub.1-C.sub.4-alkyl, phenyl, F, Cl, Br, OH, OR.sup.16, NH.sub.2, NHR.sup.16 or N(R.sup.16).sub.2, where R.sup.16 is selected from C.sub.1-C.sub.10-alkyl and C.sub.5-C.sub.10-aryl;

18. The process according to claim 14, wherein the copper complex is prepared in situ during the reaction of the formaldehyde with acetylene.

19. The process according to claim 18, wherein 0.1 to 10 mol of phosphine per mol of copper are used in the preparation of the copper complex

20. The process according to claim 14, wherein the copper complex is used in an amount of 0.01 to 5 mol % based on the amount of formaldehyde.

21. The process according to claim 14, wherein the reaction mixture comprises an organic solvent.

22. The process according to claim 14, wherein acetylene is fed to the reaction with a pressure of 1 to 20 bar.

23. The process according to claim 14, wherein the reaction is performed at a temperature of 50 to 200? C.

24. The process according to claim 14, wherein the reaction is carried out in a system containing two liquid phases, wherein one phase is a water rich phase and the other enriched with an organic solvent.

25. The process according to claim 23, wherein the copper catalyst is enriched after the reaction in the organic phase and the propargylic alcohol is enriched in the aqueous phase.

26. The process according to claim 23, wherein the copper catalyst is enriched after the reaction in the organic phase is reused as catalyst in the alkynylation reaction.

Description

EXPERIMENTAL PROCEDURE FOR THE LIGAND SCREENING (EXAMPLES 1-6)

[0091] Inside a argon filled Glove Box, a crimp vial (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) was charged with tetrakis(acetonitrile)copper(I) hexafluorophosphate (18.6 mg, 50.0 ?mol, 5.00 mol %), and ligand (monodentate: 150 ?mol, 15.0 mol %; bidentate: 75.0 ?mol, 7.50 mol %; for example: Tributylphosphine, 30.3 mg, 150 ?mol, 15.0 mol %). The catalyst system was then dissolved in absolute toluene (5.00 mL, 47.2 mmol, 47.2 equiv.) and phenylacetylene (102 mg, 1.00 mmol, 1.00 equiv.) was added. A Teflon coated magnetic stirring bar was added, the vial was sealed and the solution was stirred for a few minutes at room temperature. The reaction mixture was then transferred outside of the glovebox and formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 0.200 mL, 2.00 mmol, 2.00 equiv.) was added via syringe through the septum of the reaction container. The reaction mixture was then stirred and heated by a metal heating block for 16 h at 70? C. The vial was then cooled to room temperature, the reaction mixture was diluted with ethyl acetate (ca. 10 mL) and washed twice with ammonium hydroxide solution (ca. 10 mL) and once with brine (ca. 10 mL). The organic phase was then dried over MgSO.sub.4, filtered and mesitylene (30.0 ?L) was added as an internal GC standard. The reaction mixture was then analyzed by calibrated GC (t.sub.R(phenylacetylene)=5.70 min; t.sub.R(phenylpropargylalcohol)=10.83 min).

[0092] Analysis was done on an Agilent Technologies 6890N gas chromatograph with a split/splitless injector and an FID detector. The column used was an Agilent Technologies DB-1 capillary column (30 m*0.25 mm, 1 ?m) with Helium as carrier gas.

[0093] GC method: Split: 50/1, 1.1 mL/min, const. pressure, 80? C.-1 min-15? C./min-250? C.-5 min.

[0094] The comparative example 1 shows, that without a phosphine ligand, only traces of the product are formed. The examples 2 to 6 are showing, that by adding a phosphine ligand, the propargylic alcohol is formed as the main product.

##STR00007##

##STR00008##

EXPERIMENTAL PROCEDURE FOR THE ETHYNYLATION OF FORMALDEHYDE WITH ACETYLENE DERIVATIVES (EXAMPLES 7 AND 8)

[0095] Inside a argon filled Glove Box, a crimp vial (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) was charged with tetrakis(acetonitrile)copper(I) hexafluorophosphate (3.7 mg, 10.0 ?mol, 2.00 mol %), anphosphine ligand (Tributylphosphine: 6.1 mg, 30.0 ?mol, 6.00 mol % or 1,2-bis(di-tert- butylphosphino)xylene: 5.9 mg, 15.0 ?mol, 3.00 mol %). The catalyst system was then dissolved in abs. 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 ?mol, 1.00 equiv.) or trimethylsilylacetylene (49.1 mg, 500 ?mol, 1.00 equiv.) was added. A Teflon coated magnetic stirring bar was added, the vial was sealed and the solution was stirred and heated to 90? C. for a few minutes. The reaction mixture was then cooled to room temperature, transferred outside of the glovebox and formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 0.100 mL, 1.00 mmol, 2.00 equiv.) was added via syringe through the septum of the reaction container. The reaction mixture was then stirred and heated by a metal heating block for 16 h at 90? C. resp. 110? C. The vial was then cooled to room temperature and the reaction mixture was analyzed by GC (t.sub.R(phenylacetylene)=3.52 min; t.sub.R(phenylpropargylalcohol)=9.50 min; t.sub.R(TMS-acetylene)=1.39 min; t.sub.R(TMS-propargylalcohol)=4.83 min).

[0096] Analysis was done on an Agilent Technologies 6890N gas chromatograph with a split/splitless injector and an FID detector. The column used was an Agilent Technologies DB-FFAP capillary column (30 m*0.32 mm, 0.25 ?m) with Helium as carrier gas.

[0097] GC method: Split: 50/1, 2.3 mL/min, const. pressure, 80? C.-1 min-20? C./min-250? C.-5 min.

TABLE-US-00002 [00009] Example Phosphine GC yield OH GC yield 2OH 9 [00010] 43% 10% 10 [00011] 25% 12% 11 P(Cy)3 10% no 12 P(nOct)3 12% no

EXPERIMENTAL PROCEDURE FOR THE LIGAND SCREENING WITH ACETYLENE (EXAMPLES 9-12)

[0098] Inside a Glove Box (Ar), a crimp vial (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) was charged with tetrakis(acetonitrile)copper(I) hexafluorophosphate (6.5 mg, 17.5 ?mol, 3.50 mol %), and phosphine ligand (monodentate: 52.5 ?mol, 10.5 mol %; bidentate: 35.0 ?mol, 7.00 mol %; for example: Tributylphosphine, 10.6 mg, 52.5 ?mol, 10.5 mol %). The catalyst system was then dissolved in abs. solvent (5.00 mL) and a Teflon coated magnetic stirring bar was added. The vial was sealed and the solution was stirred for a few minutes at room temperature. The reaction mixture was then transferred outside of the glovebox and charged with acetylene by bubbling a stream of solvent-free and molecular sieve 3 ? dried acetylene via cannula for 2 minutes through the solution (acetylene concentration reaches saturation for atmospheric pressure, saturation concentration determined beforehand by calibrated GC, concentration of acetylene in toluene ca. 0.100 M, 0.500 mmol, 1.00 equiv.). The reaction mixture was then stirred for additional 10 minutes at room temperature and formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 70.1 ?L, 0.700 mmol, 1.40 equiv.) was added via syringe through the septum of the reaction container. The reaction mixture was then stirred and heated by a metal heating block for 16 h at 70? C. The vial was then cooled to room temperature, the reaction mixture was diluted with water (ca. 2 mL) and stirred for an additional 10 minutes. The water phase was then separated, filtered and DMSO (30.0 ?L) was added as an internal GC standard. The water phase was then analyzed by calibrated GC (t.sub.R(propargyl alcohol)=2.59 min; t.sub.R(butyne diol)=6.75 min).

[0099] Analysis was done on an Agilent Technologies 6890N gas chromatograph with a split/splitless injector and an FID detector. The column used was an Agilent Technologies DB-1 capillary column (30 m*0.25 mm, 1 ?m) with Helium as carrier gas.

[0100] GC method: Split: 50/1, 1.1 mL/min, const. pressure, 80? C.-1 min-15? C./min-250? C.-5 min.

TABLE-US-00003 [00012] GC yield GC yield Example Solvent c(Acetylene) OH 2OH 13 m-Xylene 0.075 M (0.23 wt) 52% 47% 14 Benzene 0.1 M (0.30 wt) 42% 45% 15 CHCl3 0.11 M (0.19 wt) 37% 3% 16 Cyclohexane 0.05 M (0.17 wt) 23% 12% 17 Chlorbenzene 0.09 M (0.21 wt) 39% 14% 18 Toluene 0.1 M (0.30 wt) 43% 21%

EXPERIMENTAL PROCEDURE FOR THE SOLVENT SCREENING (EXAMPLES 13 TO 18)

[0101] Inside a argon filled Glove Box, a crimp vial (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) was charged with tetrakis(acetonitrile)copper(I) hexafluorophosphate (amount determined by the concentration of acetylene in solvent, example for toluene (0.100 M C.sub.2H.sub.2, 0.500 mmol C.sub.2H.sub.2, 1.00 equiv.): 9.3 mg, 25.0 ?mol, 5.00 mol %), and 1,4-bis(dicyclohexylphosphino)butane (amount determined by the concentration of acetylene in solvent, example for toluene (0.100 M C.sub.2H.sub.2, 0.500 mmol C.sub.2H.sub.2, 1.00 equiv.): 22.5 mg, 50.0 ?mol, 10.0 mol %). The catalyst system was then dissolved in abs. solvent (5.00 mL) and a Teflon coated magnetic stirring bar was added. The vial was sealed and the solution was stirred for a few minutes at room temperature. The reaction mixture was then transferred outside of the glovebox and charged with acetylene by bubbling a stream of solvent-free and molecular sieve 3 ? dried acetylene via cannula for 2 minutes through the solution (acetylene concentration reaches saturation for atmospheric pressure, saturation concentration determined beforehand by calibrated GC). The reaction mixture was then stirred for additional 10 minutes at room temperature and formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 0.100 mL, 1.00 mmol, 2.00 equiv.) was added via syringe through the septum of the reaction container. The reaction mixture was then stirred and heated by a metal heating block for 16 h at 70? C. The vial was then cooled to room temperature, the reaction mixture was diluted with water (ca. 1 mL) and stirred for an additional 10 minutes. The water phase was then separated, filtered and DMSO (30.0 ?L) was added as an internal GC standard. The water phase was then analyzed by calibrated GC (t.sub.R(propargyl alcohol)=2.59 min; t.sub.R(butyne diol)=6.75 min).

[0102] Analysis was done on an Agilent Technologies 6890N gas chromatograph with a split/splitless injector and an FID detector. The column used was an Agilent Technologies DB-1 capillary column (30 m*0.25 mm, 1 ?m) with Helium as carrier gas.

[0103] GC method: Split: 50/1, 1.1 mL/min, const. pressure, 80? C.-1 min-15? C./min-250? C.-5 min.

TABLE-US-00004 [00013] mol % GC yield GC yield Example ligand x[Cu] OH 2OH 19 7.5 1.5 38% 15% 20 10 2 44% 29% 21 15 3 44% 27%

TABLE-US-00005 [00014] Catalyst loading Catalyst loading GC yield OH/yield Example [Cu]: [P]: 2OH 22 5% 10 mol % 45%/26% 23 2% 4 mol % 46%/18% 24 1% 2 mol % 38%/15%

TABLE-US-00006 [00015] Example H.sub.2CO equiv. GC yield OH/yield 2OH 25 1 52%/9% 26 2 57%/40% 27 5 57%/29% 28 10 40%/5% *calculated for H.sub.2CO

##STR00016##

EXPERIMENTAL PROCEDURE FOR SCREENING EXPERIMENTS WITH ACETYLENE (EXAMPLES 19-29)

[0104] Inside a argon filled Glove Box, a crimp vial (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) was charged with tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.2 mg-9.3 mg, 0.500-25.0 ?mol, 0.100-5.00 mol %), and 1,4-bis(dicyclohexylphosphino)butane (0.5 mg-22.5 mg, 1.00-50.0 ?mol, 0.200-10.0 mol %). The catalyst system was then dissolved in abs. toluene (5.00 mL, 47.2 mmol, 94.4 equiv.) and a Teflon coated magnetic stirring bar was added. The vial was sealed and the solution was stirred for a few minutes at room temperature. The reaction mixture was then filtered into a fresh crimp vial with a fresh Teflon coated magnetic stirring bar. If necessary, paraformaldehyde (30.0 mg, 1.00 mmol, 2.00 equiv.) was added. The vial was sealed and transferred outside of the glovebox. The reaction mixture was then charged with acetylene by bubbling a stream of solvent-free and molecular sieve 3 ? dried acetylene via cannula for 2 minutes through the solution (acetylene concentration reaches saturation for atmospheric pressure, saturation concentration determined beforehand by calibrated GC, concentration of acetylene in toluene ca. 0.100 M, 0.500 mmol, 1.00 equiv.). The reaction mixture was subsequently stirred for additional 10 minutes at room temperature and formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 25-500 ?L, 0.250-5.00 mmol, 0.500-10.0 equiv.) was added, if necessary, via syringe through the septum of the reaction container. The reaction mixture was then stirred and heated by a metal heating block for 16 h at 70? C. The vial was then cooled to room temperature, the reaction mixture was diluted with water (ca. 1 mL) and stirred for an additional 10 minutes. The water phase was then separated, filtered and DMSO (30.0 ?L) was added as an internal GC standard. The water phase was then analyzed by calibrated GC (usually t.sub.R(propargyl alcohol)=3.90 min; t.sub.R(butyne diol)=8.60 min).

[0105] Analysis was done on an Agilent Technologies 6890N gas chromatograph with a split/splitless injector and an FID detector. The column used was an Agilent Technologies DB-1 capillary column (30 m*0.25 mm, 1 ?m) with Helium as carrier gas.

[0106] GC method: Split: 50/1, 1.1 mL/min, const. pressure, 80? C.-1 min-15? C./min-250? C.-5 min. The results are shown in FIG. 1.

##STR00017##

EXPERIMENTAL PROCEDURE FOR THE KINETIC INVESTIGATION (EXAMPLE 30)

[0107] Inside a Glove Box (Ar), a round-bottomed flask (50 mL volume) was charged with tetrakis(acetonitrile)copper(I) hexafluorophosphate (18.6 mg, 50.0 ?mol, 4.00 mol %), and 1,4-bis(dicyclohexylphosphino)butane (45.1 mg, 100 ?mol, 8.00 mol %). The catalyst system was then dissolved in abs. toluene (25.0 mL, 236 mmol, 189 equiv.) and a Teflon coated magnetic stirring bar was added. The solution was stirred for a few minutes at room temperature. The reaction mixture was then filtered into four crimp vials (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) with Teflon coated magnetic stirring bars (5 mL each). The vials were sealed and transferred outside of the glovebox. The reaction mixtures were then charged with acetylene by bubbling a stream of solvent-free and molecular sieve 3 ? dried acetylene via cannula for 2 minutes through the solution (acetylene concentration reaches saturation for atmospheric pressure, saturation concentration determined beforehand by calibrated GC, concentration of acetylene in toluene ca. 0.100 M, 0.500 mmol, 2.00 equiv.). The reaction mixtures were subsequently stirred for additional 10 minutes at room temperature and formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 4?25.0 mg, 4?0.250 mmol, 4?1.00 equiv.) was added via syringe through the septum of each reaction container. The reaction mixtures were then stirred and heated by a metal heating block for 1-4 h at 70? C. The vials were then cooled to room temperature, the reaction mixture was diluted with water (ca. 2 mL each) and then transferred into a separation funnel. The reaction vessel was washed with water (2?1 mL). The water phase was then separated and the organic phase was extracted two times with water (2 mL). The aqueous phases were collected and DMSO (30.0 ?L) was added as an internal GC standard. The combined aqueous phase was then analyzed by calibrated GC (t.sub.R(propargyl alcohol)=3.40 min; t.sub.R(butyne diol)=9.15 min).

[0108] Analysis was done on an Agilent Technologies 6890N gas chromatograph with a split/splitless injector and an FID detector. The column used was an Agilent Technologies DB-FFAP capillary column (30 m*0.32 mm, 0.25 ?m) with Helium as carrier gas.

[0109] GC method: Split: 50/1, 2.3 mL/min, const. pressure, 80? C.-1 min-20? C./min-250? C.-5 min.

##STR00018##

EXPERIMENTAL PROCEDURE FOR THE CATALYST RECYCLING (EXAMPLE 31)

[0110] The organic phase obtained by the 4 h kinetic experiment (vide supra) was placed into a crimp vial (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) with a Teflon coated magnetic stirring bar. The vial was sealed and the reaction mixture was then charged with acetylene by bubbling a stream of solvent-free and molecular sieve 3 ? dried acetylene via cannula for 2 minutes through the solution (acetylene concentration reaches saturation for atmospheric pressure, saturation concentration determined beforehand by calibrated GC, concentration of acetylene in toluene ca. 0.100 M, 0.500 mmol, 2.00 equiv.). Formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was then added via syringe through the septum of the reaction container. The reaction mixture was then stirred and heated by a metal heating block for 4 h at 70? C. The vial was then cooled to room temperature, the reaction mixture was diluted with water (ca. 2 mL) and then transferred into a separation funnel. The reaction vessel was washed with water (2?1 mL). The water phase was then separated and the organic phase was extracted two times with water (2 mL). The aqueous phases were collected and DMSO (30.0 ?L) was added as an internal GC standard. The combined aqueous phase was then analyzed by calibrated GC (t.sub.R(propargyl alcohol)=3.40 min; t.sub.R(butyne diol)=9.15 min). Furthermore, both the aqueous phase and the organic phase were subjected to inductively coupled plasma mass spectrometry (ICP MS), performed in the certified central analytical department of BASF SE in Ludwigshafen, Germany.

[0111] Analysis was done on an Agilent Technologies 6890N gas chromatograph with a split/splitless injector and an FID detector. The column used was an Agilent Technologies DB-FFAP capillary column (30 m*0.32 mm, 0.25 ?m) with Helium as carrier gas.

[0112] GC method: Split: 50/1, 2.3 mL/min, const. pressure, 80? C.-1 min-20? C./min-250? C.-5 min.

[0113] ICP-MS result: [Cu] in toluene: 15 mg/kg; [Cu] in H.sub.2O: <1 mg/kg.

##STR00019##

EXPERIMENTAL PROCEDURE FOR THE ETHINYLATION OF FORMALDEHYDE UNDER AMBIENT CONDITIONS (EXAMPLE 32)

[0114] A crimp vial (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) was charged with tetrakis(acetonitrile)copper(I) hexafluorophosphate (3.7 mg, 10.0 ?mol, 4.00 mol %), and 1,4-bis(dicyclohexylphosphino)butane (9.0 mg, 20.0 ?mol, 8.00 mol %). The catalyst system was then dissolved in toluene (5.00 mL, 47.2 mmol, 189 equiv.) and a Teflon coated magnetic stirring bar was added. The solution was stirred for a few minutes at room temperature. The reaction mixture was then filtered into a fresh crimp vial with fresh Teflon coated magnetic stirring bar. The vial was then sealed and the reaction mixture was charged with acetylene by bubbling a stream of solvent-free and molecular sieve 3 ? dried acetylene via cannula for 2 minutes through the solution (acetylene concentration reaches saturation for atmospheric pressure, saturation concentration determined beforehand by calibrated GC, concentration of acetylene in toluene ca. 0.100 M, 0.500 mmol, 2.00 equiv.). Formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was added via syringe through the septum of the reaction container. The reaction mixture was then stirred and heated by a metal heating block for 4 h at 70? C. The vial was then cooled to room temperature, the reaction mixture was diluted with water (ca. 2 mL) and then transferred into a separation funnel. The reaction vessel was washed with water (2?1 mL). The water phase was then separated and the organic phase was extracted two times with water (2 mL). The aqueous phases were collected and DMSO (30.0 ?L) was added as an internal GC standard. The combined aqueous phase was then analyzed by calibrated GC (t.sub.R(propargyl alcohol)=3.40 min; t.sub.R(butyne diol)=9.15 min).

[0115] Analysis was done on an Agilent Technologies 6890N gas chromatograph with a split/splitless injector and an FID detector. The column used was an Agilent Technologies DB-FFAP capillary column (30 m*0.32 mm, 0.25 ?m) with Helium as carrier gas.

[0116] GC method: Split: 50/1, 2.3 mL/min, const. pressure, 80? C.-1 min-20? C./min-250? C.-5 min.

##STR00020##

EXPERIMENTAL PROCEDURE FOR THE CATALYST RECYCLING (EXAMPLE 33)

[0117] Inside a Glove Box (Ar), a crimp vial (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) was charged with tetrakis(acetonitrile)copper(I) hexafluorophosphate (3.7 mg, 10.0 ?mol, 4.00 mol %), and 1,4-bis(dicyclohexylphosphino)butane (9.0 mg, 20.0 ?mol, 8.00 mol %). The catalyst system was then dissolved in toluene (5.00 mL, 47.2 mmol, 189 equiv.) and a Teflon coated magnetic stirring bar was added. The solution was stirred for a few minutes at room temperature. The reaction mixture was then filtered into a fresh crimp vial with fresh Teflon coated magnetic stirring bar. The vial was then sealed and transferred outside the Glove Box. The reaction mixture was then heated to 70? C. for 15 min, cooled to room temperature and afterwards charged with acetylene by bubbling a stream of solvent-free and molecular sieve 3 ? dried acetylene via cannula for 2 minutes through the solution (acetylene concentration reaches saturation for atmospheric pressure, saturation concentration determined beforehand by calibrated GC, concentration of acetylene in toluene ca. 0.100 M, 0.500 mmol, 2.00 equiv.). Formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was added via syringe through the septum of the reaction container. The reaction mixture was then stirred and heated by a metal heating block for 16 h at 70? C. The vial was then cooled to room temperature, the reaction mixture was diluted with water (ca. 2 mL) and then transferred into a separation funnel. The reaction vessel was washed with water (2?1 mL). The water phase was then separated and the organic phase was extracted two times with water (2 mL). The aqueous phases were collected and DMSO (30.0 ?L) was added as an internal GC standard. The combined aqueous phase was then analyzed by calibrated GC.

[0118] The organic phase was placed into a crimp vial (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) with a Teflon coated magnetic stirring bar. The vial was sealed and the reaction mixture was then charged with acetylene by bubbling a stream of solvent-free and molecular sieve 3 ? dried acetylene via cannula for 2 minutes through the solution (acetylene concentration reaches saturation for atmospheric pressure, saturation concentration determined beforehand by calibrated GC, concentration of acetylene in toluene ca. 0.100 M, 0.500 mmol, 2.00 equiv.). Formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was then added via syringe through the septum of the reaction container. The reaction mixture was then stirred and heated by a metal heating block for 16 h at 80? C. The vial was then cooled to room temperature, the standard workup procedure was performed (vide supra) and the combined aqueous phases were, after addition of DMSO (30.0 ?L) as internal GC standard, analyzed by calibrated GC.

[0119] The organic phase was once more placed into a crimp vial (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) with a Teflon coated magnetic stirring bar. The vial was sealed and the reaction mixture was then charged with acetylene by bubbling a stream of solvent-free and molecular sieve 3 ? dried acetylene via cannula for 2 minutes through the solution (acetylene concentration reaches saturation for atmospheric pressure, saturation concentration determined beforehand by calibrated GC, concentration of acetylene in toluene ca. 0.100 M, 0.500 mmol, 2.00 equiv.). Formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was then added via syringe through the septum of the reaction container. The reaction mixture was then stirred and heated by a metal heating block for 16 h at 90? C. The vial was then cooled to room temperature, the standard workup procedure was performed (vide supra) and the combined aqueous phases were, after addition of DMSO (30.0 ?L) as internal GC standard, analyzed by calibrated GC.

[0120] Analysis was done on an Agilent Technologies 6890N gas chromatograph with a split/splitless injector and an FID detector. The column used was an Agilent Technologies DB-FFAP capillary column (30 m*0.32 mm, 0.25 ?m) with Helium as carrier gas.

[0121] GC method: Split: 50/1, 2.3 mL/min, const. pressure, 80? C.-1 min-20? C./min-250? C.-5 min.

##STR00021##

EXPERIMENTAL PROCEDURE FOR THE CATALYST RECYCLING WITH BIS(TRIPHENYLPHOSPHINE)COPPER(I) NITRATE (EXAMPLE 34)

[0122] Inside a Glove Box (Ar), a crimp vial (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) was charged with bis(triphenylphosphine)copper(I) nitrate (6.5 mg, 10.0 ?mol, 4.00 mol %), and 1,4-bis(dicyclohexylphosphino)butane (9.0 mg, 20.0 ?mol, 8.00 mol %). The catalyst system was then dissolved in toluene (5.00 mL, 47.2 mmol, 189 equiv.) and a Teflon coated magnetic stirring bar was added. The solution was stirred for a few minutes at room temperature. The vial was then sealed and transferred outside the Glove Box. The reaction mixture was then charged with acetylene by bubbling a stream of solvent-free and molecular sieve 3 ? dried acetylene via cannula for 2 minutes through the solution (acetylene concentration reaches saturation for atmospheric pressure, saturation concentration determined beforehand by calibrated GC, concentration of acetylene in toluene ca. 0.100 M, 0.500 mmol, 2.00 equiv.). The reaction mixture was then heated to 90? C. for 16 h. After cooling to room temperature, the reaction mixture was then charged once more with acetylene (vide supra). Formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was then added via syringe through the septum of the reaction container. The reaction mixture was then stirred and heated by a metal heating block for 3 h at 80? C. The vial was then cooled to room temperature, the reaction mixture was diluted with water (ca. 2 mL) and then transferred into a separation funnel. The reaction vessel was washed with water (2?1 mL). The water phase was then separated and the organic phase was extracted two times with water (2 mL). The aqueous phases were collected and DMSO (30.0 ?L) was added as an internal GC standard. The combined aqueous phase was then analyzed by calibrated GC.

[0123] The organic phase was placed into a crimp vial (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) with a Teflon coated magnetic stirring bar. The vial was sealed and the reaction mixture was then charged with acetylene by bubbling a stream of solvent-free and molecular sieve 3 ? dried acetylene via cannula for 2 minutes through the solution (acetylene concentration reaches saturation for atmospheric pressure, saturation concentration determined beforehand by calibrated GC, concentration of acetylene in toluene ca. 0.100 M, 0.500 mmol, 2.00 equiv.). Formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was then added via syringe through the septum of the reaction container. The reaction mixture was then stirred and heated by a metal heating block for 16 h at 80? C. The vial was then cooled to room temperature, the standard workup procedure was performed (vide supra) and the combined aqueous phases were, after addition of DMSO (30.0 ?L) as internal GC standard, analyzed by calibrated GC.

[0124] The organic phase was once more placed into a crimp vial (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) with a Teflon coated magnetic stirring bar. The vial was sealed and the reaction mixture was then charged with acetylene by bubbling a stream of solvent-free and molecular sieve 3 ? dried acetylene via cannula for 2 minutes through the solution (acetylene concentration reaches saturation for atmospheric pressure, saturation concentration determined beforehand by calibrated GC, concentration of acetylene in toluene ca. 0.100 M, 0.500 mmol, 2.00 equiv.). Formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was then added via syringe through the septum of the reaction container. The reaction mixture was then stirred and heated by a metal heating block for 16 h at 90? C. The vial was then cooled to room temperature, the standard workup procedure was performed (vide supra) and the combined aqueous phases were, after addition of DMSO (30.0 ?L) as internal GC standard, analyzed by calibrated GC.

[0125] Analysis was done on an Agilent Technologies 6890N gas chromatograph with a split/splitless injector and an FID detector. The column used was an Agilent Technologies DB-FFAP capillary column (30 m*0.32 mm, 0.25 ?m) with Helium as carrier gas.

[0126] GC method: Split: 50/1, 2.3 mL/min, const. pressure, 80? C.-1 min-20? C./min-250? C.-5 min.

##STR00022##

EXPERIMENTAL PROCEDURE FOR THE ETHINYLATION OF FORMALDEHYDE WITH COPPER(II) NITRATE (EXAMPLE 35)

[0127] Inside a Glove Box (Ar), a crimp vial (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) was charged with copper(II) nitrate trihydrate (2.4 mg, 10.0 ?mol, 4.00 mol %), and 1,4-bis(dicyclohexylphosphino)butane (9.0 mg, 20.0 ?mol, 8.00 mol %). The catalyst system was then dissolved in abs. toluene (5.00 mL, 47.2 mmol, 189 equiv.) and a Teflon coated magnetic stirring bar was added. The solution was stirred for a few minutes at room temperature. The vial was then sealed and transferred outside the Glove Box. Formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was then added via syringe through the septum of the reaction container. The reaction mixture was then stirred and heated by a metal heating block for 1 h at 80? C. After cooling to room temperature the reaction mixture was charged with acetylene by bubbling a stream of solvent-free and molecular sieve 3 ? dried acetylene via cannula for 2 minutes through the solution (acetylene concentration reaches saturation for atmospheric pressure, saturation concentration determined beforehand by calibrated GC, concentration of acetylene in toluene ca. 0.100 M, 0.500 mmol, 2.00 equiv.). Formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was added via syringe through the septum of the reaction container and the reaction mixture was then heated to 80? C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (ca. 2 mL) and then transferred into a separation funnel. The reaction vessel was washed with water (2?1 mL). The water phase was then separated and the organic phase was washed two times with water (2 mL). The organic phase was placed into a crimp vial (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) with a Teflon coated magnetic stirring bar. The vial was sealed and the reaction mixture was then charged with acetylene (vide supra). Formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was then added via syringe through the septum of the reaction container. The reaction mixture was then stirred and heated by a metal heating block for 16 h at 80? C. The vial was then cooled to room temperature, the reaction mixture was diluted with water (ca. 2 mL) and then transferred into a separation funnel. The reaction vessel was washed with water (2?1 mL). The water phase was then separated and the organic phase was extracted two times with water (2 mL). and the combined aqueous phases were, after addition of DMSO (30.0 ?L) as internal GC standard, analyzed by calibrated GC.

[0128] Analysis was done on an Agilent Technologies 6890N gas chromatograph with a split/splitless injector and an FID detector. The column used was an Agilent Technologies DB-FFAP capillary column (30 m*0.32 mm, 0.25 ?m) with Helium as carrier gas.

[0129] GC method: Split: 50/1, 2.3 mL/min, const. pressure, 80? C.-1 min-20? C./min-250? C.-5 min.

##STR00023##

EXPERIMENTAL PROCEDURE FOR THE ETHYNYLATION WITH HIGH ACETYLENE PRESSURE (EXAMPLE 36)

[0130] A round bottomed flask (500 mL volume) was charged with tetrakis(acetonitrile)copper(I) hexafluorophosphate (149 mg, 400 ?mol, 4.00 mol %), and 1,4-bis(dicyclohexylphosphino)butane (270 mg, 600 ?mol, 6.00 mol %). The catalyst system was then dissolved in toluene (200 mL, 1.89 mol, 189 equiv.) and a Teflon coated magnetic stirring bar was added. The solution was stirred for 5 minutes at room temperature and then decanted in a fresh round bottomed flask (500 mL volume) with Teflon coated stirring bar. The catalyst mixture was then heated to 80? C. by an oil bath and stirred for 30 minutes. The reaction mixture was then cooled to room temperature and transferred into a stainless steel autoclave (300 mL volume) equipped with a mechanical stirrer. Formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 1.00 mL, 10.0 mmol, 1.00 equiv.) was added and the autoclave was then sealed and pressurized at 90? C. with acetylene (16 bar) and nitrogen (2 bar; 18 bar total pressure). The reaction mixture was stirred and heated for 5 h at 90? C. while preserving a constant acetylene pressure. The autoclave was then cooled to room temperature and depressurized. The reaction mixture was diluted with water (ca. 40 mL) and then transferred into a separation funnel. The reaction vessel was washed with water (2?40 mL). The water phase was then separated and the organic phase was extracted two times with water (40 mL each). The aqueous phases were collected and analyzed by calibrated GC.

##STR00024##

EXPERIMENTAL PROCEDURE FOR THE ETHYNYLATION OF FORMALDEHYDE WITH COPPER(I) PHENYLACETYLIDE (EXAMPLE 37)

[0131] Inside a Glove Box (Ar), a crimp vial (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) was charged with copper phenylacetylide (1.6 mg, 10.0 ?mol, 4.00 mol %), and 1,4-bis(dicyclohexylphosphino)butane (6.8 mg, 20.0 ?mol, 6.00 mol %). The catalyst system was then dissolved in toluene (5.00 mL, 47.2 mmol, 189 equiv.) and a Teflon coated magnetic stirring bar was added. The vial was then sealed and transferred outside the Glove Box. The reaction mixture was then heated to 70? C. for 20 min until all solids were dissolved, cooled to room temperature and afterwards charged with acetylene by bubbling a stream of solvent-free and molecular sieve 3 ? dried acetylene via cannula for 2 minutes through the solution (acetylene concentration reaches saturation for atmospheric pressure, saturation concentration determined beforehand by calibrated GC, concentration of acetylene in toluene ca. 0.100 M, 0.500 mmol, 2.00 equiv.). Formaldehyde solution (ca. 30 wt in H.sub.2O, trace amount of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was added via syringe through the septum of the reaction container. The reaction mixture was then stirred and heated by a metal heating block for 3 h at 70? C. The vial was then cooled to room temperature, the reaction mixture was diluted with water (ca. 2 mL) and then transferred into a separation funnel. The reaction vessel was washed with water (2?1 mL). The water phase was then separated and the organic phase was extracted two times with water (2 mL). The aqueous phases were collected and DMSO (30.0 ?L) was added as an internal GC standard. The combined aqueous phase was then analyzed by calibrated GC (t.sub.R(propargyl alcohol)=3.27 min; t.sub.R(butyne diol)=8.97 min).

[0132] Analysis was done on an Agilent Technologies 6890N gas chromatograph with a split/splitless injector and an FID detector. The column used was an Agilent Technologies DB-FFAP capillary column (30 m*0.32 mm, 0.25 ?m) with Helium as carrier gas.

[0133] GC method: Split: 50/1, 2.3 mL/min, const. pressure, 80? C.-1 min-20? C./min-250? C.-5 min.

##STR00025##

EXPERIMENTAL PROCEDURE FOR THE ETHYNYLATION OF FORMALDEHYDE WITH COPPER(I) ACETYLIDE HYDRATE (EXAMPLE 38)

[0134] Inside a Glove Box (Ar), a crimp vial (10 mL volume, single use glass vial with beaded rim, sealed with crimpable aluminum caps with Teflon/butyl rubber septum seal) was charged with copper acetylide hydrate (0.8 mg, 5.00 ?mol, 2.00 mol %), and 1,4-bis(dicyclohexylphosphino)butane (6.8 mg, 20.0 ?mol, 6.00 mol %). The catalyst system was then dissolved in toluene (5.00 mL, 47.2 mmol, 189 equiv.) and a Teflon coated magnetic stirring bar was added. The vial was then sealed and transferred outside the Glove Box. The reaction mixture was then heated to 70? C. for 30 min, yielding a dark suspension. After cooling to room temperature, the vial was charged with acetylene by bubbling a stream of solvent-free and molecular sieve 3 ? dried acetylene via cannula for 2 minutes through the solution (acetylene concentration reaches saturation for atmospheric pressure, saturation concentration determined beforehand by calibrated GC, concentration of acetylene in toluene ca. 0.100 M, 0.500 mmol, 2.00 equiv.). Formaldehyde solution (ca. 30 wt in H2O, trace amount of methanol, 25.0 mg, 0.250 mmol, 1.00 equiv.) was added via syringe through the septum of the reaction container. The reaction mixture was then stirred and heated by a metal heating block for 16 h at 70? C. The vial was then cooled to room temperature, the reaction mixture was diluted with water (ca. 2 mL) and then transferred into a separation funnel. The reaction vessel was washed with water (2?1 mL). The water phase was then separated and the organic phase was extracted two times with water (2 mL). The aqueous phases were collected and DMSO (30.0 ?L) was added as an internal GC standard. The combined aqueous phase was then analyzed by calibrated GC (t.sub.R(propargyl alcohol)=3.27 min; t.sub.R(butyne diol)=8.97 min).

[0135] Analysis was done on an Agilent Technologies 6890N gas chromatograph with a split/splitless injector and an FID detector. The column used was an Agilent Technologies DB-FFAP capillary column (30 m*0.32 mm, 0.25 ?m) with Helium as carrier gas.

[0136] GC method: Split: 50/1, 2.3 mL/min, const. pressure, 80? C.-1 min-20? C./min-250? C.-5 min.