US20110308963A1

US20110308963A1 - Process for producing aromatic halogen compound utilizing electrolysis

Info

Publication number: US20110308963A1
Application number: US13/203,597
Authority: US
Inventors: Fumitoshi Kakiuchi
Original assignee: Keio University
Current assignee: Keio University
Priority date: 2009-03-10
Filing date: 2010-03-08
Publication date: 2011-12-22
Also published as: JPWO2010104028A1; WO2010104028A1

Abstract

In an electrolytic bath partitioned with an anion exchange membrane, water is supplied to the cathode chamber and an aromatic compound and a polar organic solvent, and depending on the case also a transition metal catalyst, are supplied to the anode chamber, and then electrolysis is carried out in the presence of a halogenating agent, to introduce a halogen onto the aromatic ring of the aromatic compound.

Description

TECHNICAL FIELD

The present invention relates to a process for producing an aromatic halogenated compound, and more specifically, it relates to a method for producing an aromatic halogenated compound from an aromatic compound by electrolysis using a transition metal catalyst and a halogenating agent.

BACKGROUND ART

Known processes for producing aromatic halogenated compounds include processes in which a highly reactive oxidative halogenating agent such as N-chlorosuccinimide or N-bromosuccinimide is used for chlorination and bromination of the aromatic ring of an electron-rich aromatic compound (see Non-patent document 1, for example). However, the halogenating agents such as N-chlorosuccinimide and N-bromosuccinimide used in such processes are expensive and must necessarily be used in excess quantities, while it is necessary to inactivate such halogenating agents for separation of the product after reaction, and remove the halogenating agent-derived by-products, and therefore large amounts of organic solvents must be used in the process.
There have also been developed halogenation reactions employing the aforementioned halogenating agents in the presence of palladium catalysts (see Non-patent documents 2-4, for example). In this case as well, however, a stoichiometric amount of halogenating agent must be used, leading to the problem of difficulties in reaction post-treatment and reaction control.

CITATION LIST

Non-Patent Literature

[Non-patent document 1] Goldberg, Y.; Alper, H. J. Org. Chem. 1993, 58, 3072-3075.
[Non-patent document 2] Dick, A. R.; Hull. K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300-2301.
[Non-patent document 3] Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Tetrahedron 2006, 62, 11483-11498.
[Non-patent document 4] Whitfield, S. R.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 15142-15143.

SUMMARY OF INVENTION

Technical Problem

It is an object of the invention to provide a novel process for producing aromatic halogenated compounds, which solves the aforementioned problems of the prior art.

Solution to Problem

As a result of much diligent research directed toward solving these problems, the present inventors have found that by, in an electrolytic bath partitioned with an anion exchange membrane, supplying water to the cathode chamber and supplying an aromatic compound, a polar organic solvent and, depending on the case, a transition metal catalyst, to the anode chamber, and then carrying out electrolysis in the presence of a halogenating agent, a halogen is introduced onto the aromatic ring of the aromatic compound and an aromatic halogenated compound is produced, and the invention has been completed upon this finding.
The mechanism of this reaction is not fully understood, but it is believed that the carbon-hydrogen bonds of the aromatic compound are broken, and the halogenium ion generated by electrolysis from the halogenating agent reacts at those sites, such that a halogen is introduced onto the aromatic ring.
Specifically, the invention provides the following.
1. A process for producing an aromatic halogenated compound, wherein, in an electrolytic bath partitioned with an anion exchange membrane, water is supplied to the cathode chamber and an aromatic compound and a polar organic solvent are supplied to the anode chamber, and then electrolysis is carried out in the presence of a halogenating agent, thereby introducing a halogen onto the aromatic ring of the aromatic compound.
2. The production process of 1. above, wherein the halogenating agent is a hydrogen halide, and it is supplied to the cathode chamber.
3. The production process of 2. above, wherein the halogenating agent is hydrogen chloride or hydrogen bromide.
4. The production process of 1. above, wherein the halogenating agent is a combination of a halogenated alkali metal salt with a strong acid selected from the group consisting of sulfuric acid and nitric acid, and the halogenated alkali metal salt is supplied to the anode chamber while the strong acid is supplied to the cathode chamber.
5. The production process of 4. above, wherein the halogenating agent is a combination of potassium iodide and sulfuric acid.
6. The production process of any one of 1. to 5. above, wherein the electrolysis is carried out in the presence of a transition metal catalyst supplied to the anode chamber.
7. The production process of 6. above, wherein the transition metal catalyst is a palladium catalyst.
8. The production process of any one of 1. to 7. above, wherein the aromatic compound is an aromatic hydrocarbon compound selected from the group consisting of benzene, biphenyl, naphthalene, biphenylene and phenanthrene, or an aromatic heterocyclic compound selected from the group consisting of benzoquinoline and phenanthridine.
9. The production process of any one of 1. to 7. above, wherein the aromatic compound is a compound comprising an aromatic hydrocarbon compound and an aromatic heterocyclic compound which are bonded by a single bond.
10. The production process of 9. above, wherein the aromatic compound is selected from the group consisting of 2-phenylpyridines, 2-(1-naphthyl)pyridines, 2-phenylpyrimidines, 2-(1-naphthyl)pyrimidines, 1-phenylisoquinolines and 2-phenylquinolines.

Advantageous Effects of Invention

According to the process of the invention, it is possible to introduce a halogen onto an aromatic ring in a regioselective manner. The halogenating agent used may be a hydrogen halide such as hydrogen chloride or hydrogen bromide, or a halogenated alkali metal salt, with a strong acid such as sulfuric acid or nitric acid, which are inexpensive and easily manageable compounds.
According to the process of the invention, the reaction proceeds with conversion of the halide ion of the halogenating agent to halogenium ion in the system by an electrochemical process, and it therefore differs from conventional processes in that removal of a highly reactive halogenating agent (N-succinimide, N-bromosuccinimide or the like) after the reaction is unnecessary.
As a result, water and an organic solvent (diethyl ether, ethyl acetate or the like) may be used to separate the product simply by liquid separation of the reaction mixture, thereby allowing a high-purity product to be obtained at high yield by a simple separation procedure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram illustrating the process for producing an aromatic halogenated compound according to the invention, using a hydrogen halide as the halogenating agent.

FIG. 2 is a schematic diagram illustrating the process for producing an aromatic halogenated compound according to the invention, using a halogenated alkali metal salt and a strong acid as the halogenating agent.

FIG. 3 is a graph showing the time-related change in the voltage and current values between an anode and a reference electrode, under constant current value (20 mA) conditions.

FIG. 4 is a graph showing the time-related change in the voltage and current values between an anode and a reference electrode, under constant current value (10 mA) conditions.

DESCRIPTION OF EMBODIMENTS

The “aromatic compound” used as the starting material according to the invention refers to a monocyclic or polycyclic aromatic hydrocarbon compound or aromatic heterocyclic compound. The aromatic compound used as the starting material of the invention is not particularly restricted so long as it has a site that can be halogenated, i.e., so long as it has at least one carbon-hydrogen bond on the aromatic ring.
There are no particular restrictions on the aromatic hydrocarbon compound, and examples include benzene, biphenyl, indene, indane, naphthalene, biphenylene, acenaphthylene, phenanthrene, anthracene and pyrene, with benzene, biphenyl, naphthalene, biphenylene and phenanthrene being preferred.
The aromatic heterocyclic compound is a compound having one or more atoms other than carbon (for example, oxygen, sulfur or nitrogen) among the atoms composing the ring of the aromatic hydrocarbon compound, and examples include furan, oxazole, benzooxazole, isooxazole, thiophene, thiazole, benzothiazole, isothiazole, thiadiazole, pyrrole, pyrazole, imidazole, benzimidazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, isoindole, indole, quinoline, benzoquinoline, naphthylidine, quinazoline, purine, acridine, phenanthridine, phenazine, phenothiazine and phenoxazine, with pyridine, pyrimidine, benzoquinoline and phenanthridine being preferred.
Compounds in which the aromatic hydrocarbon compound and the aromatic heterocyclic compound are bonded by a single bond are also preferred, examples thereof including 2-phenylpyridines, 2-(1-naphthyl)pyridines, 2-phenylpyrimidines, 2-(1-naphthyl)pyrimidines, 1-phenylisoquinolines and 2-phenylquinolines.
These aromatic compounds may have substituents in a range that does not inhibit the reaction of the invention, and such substituents include alkyl, alkenyl, alkoxy, alkoxycarbonyl, haloalkyl, haloalkoxy, halogen atoms, hydroxy, formyl, cyano, nitro, sulfonyl, carboxy, nitro, amino, acetyl, acetoxy and thioalkoxy.
According to the invention, the following are specific examples of aromatic compounds that may be most preferably used.
(In the formula, R is hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, a halogen atom, cyano or alkoxycarbonyl.)
The “halogenating agent” used for the invention is not particularly restricted, and there may be used submetallic halogenated compounds such as hydrogen halides, phosphorus halides, triphenylphosphine phosphonates, alkyl halides, sulfonyl halogenides, thionyl halides, acid halides, boron halides and silicon halides, and metal halogenated compounds such as halogenated alkali metal salts, titanium halides and tin halides, and there may also be used combinations of halogenated alkali metal salts and strong acids selected from the group consisting of sulfuric acid and nitric acid.
The halogenating agent will usually be supplied to the cathode chamber, but when the halogenating agent used is a combination of a halogenated alkali metal salt with a strong acid selected from the group consisting of sulfuric acid and nitric acid, the halogenated alkali metal salt is supplied to the anode chamber while the strong acid is supplied to the cathode chamber.
According to the invention, it is preferred to use a hydrogen halide, such as hydrogen chloride, hydrogen bromide or hydrogen iodide, and most preferably hydrogen chloride or hydrogen bromide. Furthermore, according to the invention, a halogenated alkali metal salt such as a potassium halide is preferably used in combination with the strong acid, and most preferably potassium iodide is used.
The amount of halogenating agent used will usually be 2-200 mol and preferably 4-100 mol with respect to 1 mol of the aromatic compound, and a solution dissolved to a concentration of 0.5-5 mol/L and preferably 1-3 mol/L may be used. When a strong acid is used, the strong acid concentration is 0.05-2 mol/L and preferably 0.1-0.5 mol/L, the amount of halogenating agent used is 1-10 mol and preferably 2-4 mol with respect to 1 mol of the aromatic compound, and a solution dissolved to a concentration of 0.01-1 mol/L and preferably 0.02-0.1 mol/L may be used.
The “transition metal catalyst” used for the invention is not particularly restricted, but nickel, palladium, platinum, cobalt, rhodium, iridium, iron, ruthenium, osmium, copper, silver, gold or the like may be used, and their salt or complex compounds may also be used. Preferred transition metal catalysts are palladium catalysts, which may be used as metals, salts or complexes, and palladium chloride, palladium bromide and palladium acetate, which are readily available, are preferably used. The amount of transition metal catalyst used will be usually 0.2-100 mol % and preferably 2-20 mol %. For increased reactivity, an alkali metal carbonate such as K₂CO₃may be added.
A transition metal catalyst may not be necessary for the reaction, depending on the conditions. Electron-rich aromatic compounds such as toluene are also halogenated under catalyst-free conditions.
The “polar organic solvent” used for the invention is not particularly restricted so long as it is a polar organic solvent in which the aromatic compound substrate dissolves, and examples include N,N-dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), acetonitrile, N-methyl-2-pyrrolidone (NMP), hexamethylphosphoramide (HMPA) and N,N,N′,N′-tetramethylurea (TMU), and their mixtures may also be used. The aromatic compound is used as a solution dissolved in the polar organic solvent at usually 0.01-1 mol/L and preferably 0.02-0.5 mol/L.
The process of the invention can be carried out in an anode/cathode separated electrolytic bath partitioned with an anion exchange membrane.
There are no particular restrictions on the anion exchange membrane, and commercially available strongly basic or weakly basic membranes may be used as appropriate. A strongly basic membrane is preferred, and specific examples include SELEMION AHA (product of Asahi Glass Co., Ltd.) and NEOSEPTA AHA (product of Astom Corp.).
The electrode material is not particularly restricted so long as it has acid resistance, and conventionally known materials may be used, such as platinum, glass carbon, carbon, stainless steel and nickel, as well as other machined electrodes, as appropriate.
For the electrolysis of the invention, the current density will usually be selected as appropriate in the range of 0.1-100 mA/cm², preferably 1-50 mA/cm²and most preferably 10-20 mA/cm². The electrical quantity of electrification will usually be 1-40 F and preferably 1.5-25 F, for 1 mol of the aromatic compound.
The reaction time is appropriately selected based on the electrification current and current density, but it will usually be within 24 hours. The reaction temperature will normally be 40-100° C. and is preferably 70-100° C.
The process of the invention may be carried out either in a batch process or a continuous system.
Upon completion of the reaction in the process of the invention, the reaction mixture may simply be subjected to a liquid separation procedure using water and an organic solvent (for example, diethyl ether or ethyl acetate), to obtain a pure product.
According to the process of the invention, the halogen is introduced into the aromatic ring of the aromatic compound in a regioselective manner. For example, in the case of a compound in which a phenyl group has been substituted at the 2-position of the pyridine ring, the halogen is regioselectively introduced at the y position, based on the position of the pyridine nitrogen, without being affected by substituents on the aromatic ring, as explained below.
By adjusting the reaction conditions including the catalyst, current value and reaction time, it is possible to control the halogen substitution position and the yield.
FIG. 1 is a schematic diagram illustrating a process for producing an aromatic halogenated compound according to the invention. The electrolytic bath 1 comprises an anode chamber 2, a cathode chamber 3 and an anion exchange membrane 4 partitioning them. Platinum electrodes 5 are inserted in the anode chamber 2 and cathode chamber 3, and a stirrer 6 is placed in the anode chamber 2. An aqueous solution dissolving a halogenating agent (hydrogen halide: HX) is supplied to the cathode chamber 3, and an aromatic compound as the substrate, a polar organic solvent and in some cases a transition metal catalyst, are supplied to the anode chamber 2. Electrolysis is conducted while stirring the anode chamber with the stirrer 6. Halogenium ion is generated in the anode chamber 2, and the halogen is introduced onto the aromatic ring where the carbon-hydrogen bond has been broken.
FIG. 2 is a schematic diagram also illustrating a process for producing an aromatic halogenated compound according to the invention. The electrolytic bath 1 comprises an anode chamber 2, a cathode chamber 3 and an anion exchange membrane 4 partitioning them. Platinum electrodes 5 are inserted in the anode chamber 2 and cathode chamber 3, and a stirrer 6 is placed in the anode chamber 2. An aqueous solution dissolving a strong acid is supplied to the cathode chamber 3, and an aromatic compound as the substrate, a polar organic solvent, a halogenating agent (halogenated alkali metal salt: MeX) and in some cases a transition metal catalyst, are supplied to the anode chamber 2. Electrolysis is conducted while stirring the anode chamber with the stirrer 6. Halogenium ion is generated in the anode chamber 2, and the halogen is introduced onto the aromatic ring where the carbon-hydrogen bond has been broken.
Examples of the invention will now be explained in greater detail by examples.

EXAMPLES

Example 1

An anion exchange membrane (NEOSEPTA AHA, Astom Corp.) was cleaned with purified water, methanol and acetone, and cut to fit the size of a space holder. Next, the cut ion-exchange membrane was used to assemble an anode/cathode separated electrolytic bath. To the anode chamber there were added benzo[h]quinoline (44.8 mg, 0.25 mmol), PdCl₂(4.4 mg, 0.025 mmol) and DMF (10 ml), and to the cathode chamber there was added a 2M HCl aqueous solution (10 ml). Next, the electrolytic bath was dipped in an oil bath heated to 90° C., and a platinum electrode was used for electrification at 20 mA for 2.5 hours. The reaction was followed by GCMS, and consumption of the entire starting material after 2 hours was confirmed.
Upon completion of the reaction, the reaction system was cooled to room temperature. After pouring a saturated K₂CO₃aqueous solution into the anode chamber for neutralization, it was washed through a separatory funnel with AcOEt and water. The organic layer and aqueous layer were separated, and the aqueous layer was extracted twice with AcOEt. All of the organic layers were combined, washed twice with water and once with brine, dried over anhydrous Na₂SO₄, and concentrated with a rotary evaporator.
The crude product was purified by silica gel column chromatography (inner diameter: 10 mm, silica gel 10 g, hexane: AcOEt=9:1, 0.5 vol % Et₃N) to obtain 10-chlorobenzo[h]quinoline (52.4 mg, 98% yield, white solid).
The ¹H-NMR spectrum of the obtained 10-chlorobenzo[h]quinoline was as follows. ¹H NMR (270.05 MHz) (CDCl₃): δ 7.31-7.50 (m, 5H, 4), 7.53 (d, J=8.7 Hz, 1H, 3), 7.78-7.90 (m, 3H, 2), 8.81 (d, J=4.3 Hz, 1H, 1).

Examples 2-16

Reaction was conducted in the same manner as Example 1, except for changing the reaction temperature and reaction time as listed in Table 1 (electrification at 10 mA only for Example 14). The target compound yields are shown in Table 1.

TABLE 1

		Reaction
Example		temperature	Reaction
No.	Starting compound	(° C.)	time (hr)	Target compound yield (%)

2		100° C.	4 hrs

3		90° C.	4 hrs

4		90° C.	5 hrs

5		100° C.	5 hrs

6		90° C.	2.5 hrs

7		90° C.	6.5 hrs

8		100° C.	3 hrs

9		90° C.	4.5 hrs

10		90° C.	3 hrs

11		90° C.	5 hrs

12		90° C.	6 hrs

13		100° C.	3.5 hrs

14		90° C.	2 hrs

15		90° C.	6 hrs

16		90° C.	2 hrs

Examples 17-19

Reaction was conducted in the same manner as Example 1, except for using 10 mol % PdBr₂as the transition metal catalyst (15 mol % PdBr₂only for Example 19), using a 2M HBr aqueous solution as the halogenating agent, and changing the reaction temperature and reaction time as listed in Table 2 (electrification at 10 mA only for Example 18). The target compound yields are shown in Table 2.

TABLE 2

		Reaction
Example		temperature	Reaction
No.	Starting compound	(° C.)	time (hr)	Target compound yield (%)

17		100° C.	15 hrs

18		90° C.	4 hrs

19		100° C.	6 hrs

Examples 20-23

The following reaction was conducted. The conditions were the same as in Example 1, except for the changes specified below.
The results are shown in Table 3.

Example 24

TABLE 3

		Reaction
Example		temperature	Reaction
No.	Starting compound	(° C.)	time (hr)	Target compound yield (%)

20		90° C.	5.5 hrs

21		90° C.	3 hrs

22		90° C.	5 hrs

23		100° C.	5.5 hrs

24		100° C.	5.5 hrs

Reaction Without Catalyst

Example 25

The following reaction was conducted without a catalyst. The conditions were the same as in Example 1, except for the changes specified below.

Control of Selectivity

Examples 26-28

The following reaction was conducted. The conditions were the same as in Example 1, except for the changes specified below. No transition metal catalyst (PdCl₂) was used only in Example 26.
The results are shown in Table 4.

TABLE 4

Example	Current	Electrical	Conversion	Yield

No.	value	Time	quantity	rate		1	2	3

26	20 mA	10 hrs	29.8 F/mol	90%	69%	Undetected	Undetected
27	20 mA	3 hrs	9.0 F/mol	>99%	Undetected	15%	73%
28	10 mA	2 hrs	3.0 F/mol	>99%	Undetected	Undetected	92%

Control of Selectivity by Current Value

Examples 29 and 30

The following reaction was conducted. The conditions were the same as in Example 1, except for the changes specified below.
The results are shown in Table 5.

TABLE 5

Example	Current	Electrical	Conversion	Yield

No.	value	Time	quantity	rate		1	2	3

29	20 mA	3 hrs	6.0 F/mol	100%	Undetected	84%	16%
30	10 mA	3 hrs	3.0 F/mol	100%	Undetected	Undetected	93%

In this case, the voltage and current value between the anode and the reference electrode were measured under conditions with constant current values of 20 mA and 10 mA (Examples 29 and 30, respectively). The obtained results are shown in FIG. 3 and FIG. 4. Since there was no significant difference in the voltage between the anode and reference electrode in reactions with different current values, this suggests that the reaction selectivity can be controlled by the current value during electrification.

INDUSTRIAL APPLICABILITY

The process of the invention allows production of aromatic halogenated compounds that are useful as starting compounds in the field of agricultural chemicals and medicine, as well as fine chemicals including organic electronic materials and organic optical materials, under efficient and selective reaction conditions with a low burden on the environment, and it is therefore highly useful for industrial production of products in these fields.

EXPLANATION OF SYMBOLS

1: Electrolytic bath, 2: anode chamber, 3: cathode chamber, 4: anion exchange membrane, 5: platinum electrode, 6: stirrer, 7: anode, 8: cathode.

Claims

1-10. (canceled)

11. A process for producing an aromatic halogenated compound, wherein, in an electrolytic bath partitioned with an anion exchange membrane, water is supplied to the cathode chamber and an aromatic compound, a polar organic solvent and a transition metal catalyst are supplied to the anode chamber, and then electrolysis is carried out in the presence of a halogenating agent, to introduce a halogen onto the aromatic ring of the aromatic compound.

12. The process according to claim 11, wherein the halogenating agent is a hydrogen halide, and it is supplied to the cathode chamber.

13. The process according to claim 12, wherein the halogenating agent is hydrogen chloride or hydrogen bromide.

14. The process according to claim 11, wherein the halogenating agent is a combination of a halogenated alkali metal salt with a strong acid selected from the group consisting of sulfuric acid and nitric acid, and the halogenated alkali metal salt is supplied to the anode chamber while the strong acid is supplied to the cathode chamber.

15. The process according to claim 14, wherein the halogenating agent is a combination of potassium iodide and sulfuric acid.

16. The process according to claim 11, wherein the transition metal catalyst is a palladium catalyst.

17. The process according to claim 11, wherein the aromatic compound is an aromatic hydrocarbon compound selected from the group consisting of benzene, biphenyl, naphthalene, biphenylene and phenanthrene, or an aromatic heterocyclic compound selected from the group consisting of benzoquinoline and phenanthridine.

18. The process according to claim 11, wherein the aromatic compound is a compound comprising an aromatic hydrocarbon compound and an aromatic heterocyclic compound which are bonded by a single bond.

19. The process according to claim 18, wherein the aromatic compound is selected from the group consisting of 2-phenylpyridines, 2-(1-naphthyl)pyridines, 2-phenylpyrimidines, 2-(1-naphthyl)pyrimidines, 1-phenylisoquinolines and 2-phenylquinolines.