PHOTOOXIDATION OF 2,4,6-TRIMETHYLPHENOL

Abstract

The present invention relates to the photooxidation of 2,4,6-trimethyl-phenol to yield 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one using methylene blue as photosensitizer in a solvent mixture of water and alcohols using light of the high wavelength range of the visible spectrum. This process allows 5 obtaining 4-hydroxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one and 2,3,5-trimethyl-hydroquinone in high yields and selectivity from 2,4,6-trimethylphenol.

Claims

1. A process of manufacturing a compound of the formula (I) from a compound of the formula (II) by photooxidation ##STR00009## using oxygen and a photosensitizer of the formula (III) ##STR00010## wherein R.sup.8, R.sup.8, R.sup.8 and R.sup.8 independently from each other represent either a H, or a C.sub.1-4 alkyl group; or wherein R.sup.8 and R.sup.8 and/or R.sup.8 and R.sup.8 form together with N a five or six membered ring; with the proviso that at least one of the residues R.sup.8, R.sup.8, R.sup.8 and R.sup.8 is different from H; and X.sup. represents an anion; in a solvent mixture of water and at least one C.sub.1-8 alkanol or at least one C.sub.2-4 alkylene diol; and using light which has a peak wavelength (.sub.max) in its spectrum in the range of between 580 and 780 nm.

2. The process according to claim 1 wherein used light has a peak wavelength (.sub.max) in its spectrum in the range of between 625 and 740 nm.

3. The process according to claim 1, wherein more than 80% of the light has a wavelength of between 525 and 780 nm, preferably more than 80% of the emitted light has a wavelength of between 525 and 700 nm.

4. The process according to claim 1, wherein the solvent mixture is a mixture of water and methanol and/or ethanol and/or isopropanol.

5. The process according to claim 1, wherein the light source for the light is a red LED lamp.

6. The process according to claim 1, wherein the light source for the light is a white LED lamp in combination with a filter blocking wavelengths below 500 nm, particularly below 625 nm.

7. The process according to claim 1, wherein R.sup.8R.sup.8R.sup.8R.sup.8CH.sub.3.

8. The process according to claim 1, wherein X.sup. represents a halide, particularly chloride.

9. The process according to claim 1, wherein the concentration of the compound of the formula (II) is in the range of between 0.002 to 2.0 mol/l, preferably 0.01 to 0.2 mol/l at the beginning of the photooxidation.

10. The process according to claim 1, wherein the ratio of the compound of the formula (III) to the compound of the formula (II) is in the range of between 0.005 and 20 mol %, preferably between 0.05 and 20 mol %, more preferably between 0.2 and 10 mol %.

11. The process according to claim 1, wherein that the process is a continuous process.

12. A process of preparing compound of the formula (IV) from compound of the formula (II) comprising the steps a) photooxidation of compound (II) according to claim 1 to yield the compound of the formula (I); ##STR00011## b) reduction of the compound of the formula (I) by means of a reducing agent (red-a) to yield the compound of the formula (IV) ##STR00012##

13. The process according claim 12 wherein the step b) is performed in a continuous way.

14. A process of preparing compound of the formula (V) from compound of the formula (II) comprising the steps a) photooxidation of compound (II) according to claim 1 to yield the compound of the formula (I); ##STR00013## b) reduction of the compound of the formula (I) by means of a reducing agent to yield the compound of the formula (IV) ##STR00014## c) treatment of compound of the formula (IV) with a basic substance at a temperature of >200 C., preferably >240 C., to yield the compound of the formula (V) ##STR00015##

15. The process according claim 14 wherein the steps b) and/or c) are performed in a continuous way.

Description

FIGURES

[0122] FIG. 1a shows a schematic representation of a photooxidation using a light source and a filter to produce a light with a peak wavelength (.sub.max) in its spectrum in the range of between 580 and 780 nm.

[0123] FIG. 1b shows a schematic representation of a photooxidation using a light source with a peak wavelength (.sub.max) in its spectrum in the range of between 580 and 780 nm.

[0124] FIG. 2a shows a schematic representation of one of the experimental layout.

[0125] FIG. 2b shows a schematic representation of a different experimental layout.

[0126] FIG. 2c shows a schematic representation of another different experimental layout.

[0127] FIG. 3 represents the normalized emission spectrum of light for the photooxidation using different filter as well as of the white light and the red LED used in the experiments.

[0128] FIG. 4a shows a schematic representation of a continuous reactor for step b).

[0129] FIG. 4b shows a schematic representation of an embodiment where step b) is taken place at the end of the photoreactor of step a).

[0130] FIG. 5a shows a schematic representation of a continuous reactor for step c).

[0131] FIG. 5b shows a schematic representation of an embodiment where step c) and b) are taken place at the end of the photoreactor of step a).

[0132] FIG. 6 shows a schematic reaction scheme overview of the steps a) and b) and c).

[0133] In FIG. 2a, one preferred experimental layout is represented. A vessel comprising a premixture (10), comprising at least the compound of the formula (II) and the photosensitizer of the formula (III) and the solvent mixture of water and at least one C.sub.1-8 alkanol or at least one C.sub.2-4 alkylene diol, is pumped by a pump (7) into the photoreactor (5). Before entering the photoreactor (5), oxygen (11), preferably in the form of air, is admixed to the premixture forming the photooxidation reaction mixture (3). The amount of oxygen admixed is controlled by a mass flow controller (8). Around the transparent wall (4) of the linear tubular photoreactor (5) the light source (1) is arranged, particularly in a helical arrangement of LEDs. The light source (1) is in one embodiment a white LED. Between the transparent wall (4) and the light source (1) a filter (6) is positioned, allowing to provide a light (2a) which has a peak wavelength (.sub.max) in its spectrum in the range of between 580 and 780 nm. The filter (6) is particularly an orange filter or an red filter, respectively, to provide particularly a light which has a peak wavelength (.sub.max) in its spectrum in the range of between 585 and 625 nm or 625 and 740 nm, respectively. The light source (1) is in another preferred embodiment either an orange LED or a red LED, particularly a red LED, in the case of which the filter (6) is not present. The photoreactor (5) is preferably a spiral flow reactor. At the outlet of the photoreactor a backpressure regulator (9) is positioned before the product is collected in the collection vessel (12).

[0134] This experimental layout, particularly the combination of light source and photoreactor, is preferably used for higher volume photoreactions.

[0135] In FIG. 2b, another preferred experimental layout is represented. A vessel comprising a premixture (10), comprising at least the compound of the formula (II) and the photosensitizer of the formula (III) and the solvent mixture of water and at least one C.sub.1-8 alkanol or at least one C.sub.2-4 alkylene diol, is pumped by a pump (7) into the photoreactor (5). Before entering the photoreactor (5), oxygen (11) is admixed to the premixture forming the photooxidation reaction mixture (3). The amount of oxygen admixed is controlled by a mass flow controller (8).

[0136] The light source (1) is in one embodiment a white LED. Between the transparent wall (4) of the photoreactor (5) and the light source (1), a filter (6) is positioned, allowing to provide a light (2a) which has a peak wavelength (.sub.max) in its spectrum in the range of between 580 and 780 nm. In the present representation only one light source (1) and one filter (6) is shown. It is, of course, possible that several such light sources (1), combined with the filter (6) are positioned around the photoreactor (5), in the form of a spiral flow reactor, can be positioned to allow an even irradiation of the whole photoreactor (5). The filter (6) is particularly an orange filter or an red filter, respectively, to provide particularly a light which has a peak wavelength (.sub.max) in its spectrum in the range of between 585 and 625 nm or 625 and 740 nm, respectively. The light having undesired wavelengths (2b) is filtered off by the filter (6). The light source (1) is in other preferred embodiment either an orange LED or a red LED, more preferably a red LED, in the case of which the filter (6) is not present. At the outlet of the photoreactor a backpressure regulator (9) is positioned before the product is finally collected in the collection vessel (12).

[0137] This experimental layout, particularly the combination of light source and photoreactor, is preferably used for smaller volume photoreactions.

[0138] In FIG. 2c, another preferred experimental layout is represented. A vessel comprising a premixture (10), comprising at least the compound of the formula (II) and the photosensitizer of the formula (III) and the solvent mixture of water and at least one C.sub.1-8 alkanol or at least one C.sub.2-4 alkylene diol, is pumped by a pump (7) into the photoreactor (5). Before entering the photoreactor (5), oxygen (11), preferably in the form of air, is admixed to the premixture forming the photooxidation reaction mixture (3). The amount of oxygen admixed is controlled by a mass flow controller (8).

[0139] In this embodiment a light source (1), preferably a red LED, is arranged in the hollow space formed by the helical windings of the spiral flow reactor (5).

[0140] The light source (1) is in one embodiment a white LED. Around the light source (1), i.e. between the transparent wall (4) of the photoreactor (5) and the light source (1), a filter (6) is positioned, allowing to provide a light (2a) which has a peak wavelength (.sub.max) in its spectrum in the range of between 580 and 780 nm. The filter (6) is particularly an orange filter or an red filter, preferably a red filter, respectively, to provide particularly a light which has a peak wavelength (.sub.max) in its spectrum in the range of between 585 and 625 nm or 625 and 740 nm, respectively. The light having undesired wavelengths (2b) is filtered off by the filter (6). The light source (1) is in other preferred embodiment either an orange LED or a red LED, preferably a red LED, in the case of which the filter (6) is not present. At the outlet of the photoreactor a backpressure regulator (9) is positioned before the product is finally collected in the collection vessel (12).

[0141] This experimental layout, particularly the combination of light source and photoreactor, is preferably used for smaller volume photoreactions.

[0142] In an even further embodiment the light source (1) and filter (6) of FIGS. 2b) and 2c) are combined. In other words the filter and light source can be arranged outside of the photoreactor walls arranged inside as well as outside of the space formed by the helical winding of the spiral flow photoreactor (5).

[0143] In FIG. 4a, a preferred experimental layout of the reaction step b) of is shown allowing the reduction of compound of the formula (I) to be performed in a continuous way. The compound of formula (I) (13) is transferred by means of a pump (7) into the reactor for reduction (14) to which also the reducing agent (15) is added by a pump (7). In a variation to this, the adding of the compound of formula (I) and reducing agent is realized before the entering of compound of the formula (I) into reactor (14). In case further ingredients (not shown in FIG. 4a) are used for the reduction, said additional ingredients may be added either to the reducing agent (15) or to the compound of the formula (I) (13) or separately fed into the reduction reactor (14). In the reactor for reduction (14) the compound of the formula (I) is reduced to the compound of the formula (IV) which is transferred from the reactor to the collection vessel (12) for the compound of the formula (IV).

[0144] In FIG. 4b, a more preferred experimental layout of the reaction steps a) and b) is shown allowing the photoreaction of mesitol and the reduction of compound of the formula (I) to be performed both in a continuous way. In the embodiment shown corresponds basically the combination of representation shown in FIG. 2c and FIG. 4a. In this embodiment, however, the compound of the formula (I) is transferred from the outlet of the photoreactor (5) directly to the entry of the reactor for the reduction of compound of the formula (I) to the compound of the formula (IV).

[0145] In FIG. 5a, a preferred experimental layout of the reaction step c) is shown. The compound of formula (IV) (16) is transferred by means of a pump (7) into the reactor for thermal treatment (17) to which also the basic substance (18) is added by a pump (7). In a variation to this, the adding of the compound of formula (IV) and basic substance is realized before the entering of compound of the formula (IV) into reactor (17). In case further ingredients (not shown in FIG. 5a) are used for the thermal treatment, said additional ingredients may be added either to the basic substance (18) or to the compound of the formula (IV) (16) or separately fed into the reactor for thermal treatment (17).

[0146] In the reactor for thermal treatment (17) the compound of the formula (IV) is transformed to the compound of the formula (V) which is transferred from the reactor to the collection vessel (12) for the compound of the formula (V).

[0147] In FIG. 5b, a more preferred experimental layout of the reaction steps a) and b) and c) is shown allowing the photoreaction of mesitol and the reduction of compound of the formula (I) and the thermal treatment of the compound of the formula (IV) to be performed all in a continuous way. In the embodiment shown corresponds basically the combination of representation shown in FIG. 4b and FIG. 5a. In this embodiment, however, the compound of the formula (IV) is transferred from the outlet of the reduction reactor (14) directly to the entry of the reactor for the thermal treatment of compound of the formula (IV to the compound of the formula (V).

LIST OF REFERENCE SIGNS

[0148] 1 Light source [0149] 2a Light of desired wavelength [0150] 2b Light of undesired wavelength [0151] 3 Photooxidation reaction mixture [0152] 4 Transparent wall of photoreactor [0153] 5 Photoreactor [0154] 6 Filter [0155] 7 Pump [0156] 8 Mass flow controller [0157] 9 Backpressure regulator [0158] 10 Premixture [0159] 11 Oxygen [0160] 12 Collection vessel [0161] 13 Compound of formula (I) [0162] 14 Reactor for reduction [0163] 15 Reducing agent [0164] 16 Compound of formula (IV) [0165] 17 Reactor for thermal treatment [0166] 18 Basic substance

EXAMPLES

[0167] The present invention is further illustrated by the following experiments.

Example 1: Photooxidation of 2,4,6-trimethylphenol (Step a)

[0168] In the following experiment an experimental layout has been used as schematically represented in FIG. 2c:

[0169] A vessel comprising a premixture (10) of solvent, respectively solvent mixture and the substances to be photooxidized as well as the photosensitizer is pumped by a pump (7) into the photoreactor (5) which is a spiral flow reactor. Before entering the photoreactor (5), oxygen in the form of air (11) is admixed to the premixture forming the photooxidation reaction mixture (3). The amount of air admixed is controlled by a mass flow controller (8). The light of the light source (1) is red LED (12OSLON SSL Hyper red, .sub.max=660 nm, ca. 9 W & 700 lm for 12 LED, GH CSSPM1.24, 120 viewing angle, CPU cooling system (10 V) to maintain ambient temperature (ca. 20 C.)) (no filter is used) (see spectrum shown as LSr in FIG. 3) so that the light of the desired wavelengths (2a) is falling on the transparent walls (4) of the photoreactor (5). The photoreactor (5) is coiled over an inner glass cylinder around a LED lamp (1) cooled with a fan. At the outlet of the photoreactor a backpressure regulator (9) is positioned before the product is finally collected in the collection vessel (12).

More precisely, the photooxidation has been performed as followed:

[0170] A solution of 2,4,6-trimethylphenol (20.0 mmol.Math.L.sup.1, 2.00 mmol [for the duration of the reaction], 1.0 eq.) and methylene blue hydrate (0.180 nmol, 0.900 mol % [CAS: 122965-43-9]) in methanol and water (4:1, v/v) is prepared to give a homogenous blue solution. The solution is pumped through a high-pressure liquid chromatography pump (Dionex P580) into the photoreactor (tubing system: 0.75 mm internal diameter, 1.58 mm outer diameter, PFA coil) (liquid flow rate: 0.093 m L/m in, HPLC regulated piston pump) with a constant pressure of 10 bar (regulated by back pressure regulator, Equilibar Zero-Flow ZF1 back pressure regulator, computer controlled).

[0171] Before entering the photoreactor, the solution is enriched with air (air flow rate: 0.500 mL/min, mass flow controller, Bronkhorst El-FLOW, Modell: FG200CV-AAD-22-K-DA-000 S/N: M19209993A). Inside the photoreactor, the reaction mixture is exposed to a red LED light source (12OSLON SSL Hyper red, .sub.max=660 nm, ca. 15 W & 700 lm for 12 LED, GH CSSPM1.24, 120 viewing angle) (see spectrum shown as LSr in FIG. 3) during a residence time of 40 minutes. Complete conversion confirmed by thin layer chromatography (4:1 Cyclohexane/EtOAc, R.sub.f(substrate)=0.63, R.sub.f(product)=0.3). The photoreactor is kept at ambient temperature (20 C.) by 2 vans (one inside the photoreactor: CPU cooling system, one outside the photoreactor: regular van). The reaction mixture (100 mL) is collected by a 250 mL round bottom flask equipped with a septum and a needle outlet to prevent overpressure. Methanol is removed under reduced pressure until constant residual amount (15 mbar). Water (50 mL) is added to the residue and the solution is extracted with ethyl acetate (350 mL). The combined organic layers are washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and the organic solvent is removed under reduced pressure (15 mbar) to yield 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one as a green-greyish viscous wax (340 mg, 99% yield).

Example 2: Reduction of 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (Step b)

[0172] In a 50 mL round bottom flask a yellow solution of 4-hydroperoxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (300 mg, 1.78 mmol, 1.0 eq.), as prepared by example 1, and sodium thiosulfate (1.40 g, 8.90 mmol, 5.0 eq.) in methanol and water (25 mL, 4:1 v/v) is prepared. The reaction mixture is stirred at ambient temperature until complete conversion monitored by thin layer chromatography (4:1 cyclohexane/EtOAc, R.sub.f(substrate)=0.3, R.sub.f(product)=0.2). A color change of the solution from yellow to pink is observed. Methanol is removed under reduced pressure. Water (30 mL) is added to the residue and the solution is extracted with ethyl acetate (325 mL). The combined organic layers are washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and the organic solvent is removed under reduced pressure (15 mbar) to yield 4-hydroxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one as a yellow green viscous wax (253 mg, 93% yield).

Example 3: Formation of 2,3,5-trimethylhydroquinone (Step c)

[0173] In the following experiment an experimental layout has been used as schematically represented in FIG. 5a:

[0174] A solution of 4-hydroxy-2,4,6-trimethyl-2,5-cyclohexadien-1-one (4.7 g, 30 mmol), as obtained by example 2, in an aqueous NaOH solution (440 ml, 0.008 mol/l), methanol (50 ml) and sodium sulphite (235 mg, 1.9 mmol) was pumped through a flow reactor (diameter 1.5 mm, length: 2000 mm) with 10 ml/min at 250 C. The solution was neutralized at the end of the flow reactor with sulfuric acid (1.47 ml). The reaction mixture was extracted with ethyl acetate, dried over MgSO.sub.4, and concentrated in vacuo. 2,3,5-trimethylbenzoquinone (4.45 g, 95%) was obtained in 92% yield.