RU2803737C1 - Method for producing monohalo-o-xylenes - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: halogen-substituted aromatic compounds, in particular a method for producing monohalo-o-xylenes by electrophilic aromatic substitution in o-xylene. In this case, N-halosaccharins are used as a halogenating agent, and the reaction is carried out in N,N-dimethylformamide at a temperature of 40-100°C and a mass ratio of at least five parts of N,N-dimethylformamide to one part of o-xylene. O-xylene ratio: N-halosaccharin is 1: (1-2) (eq.).

EFFECT: development of a new, cost-effective method for the halogenation of o-xylene using commercially available reagents, without the use of catalysts, with a high conversion of the initial o-xylene.

2 cl, 2 tbl, 16 ex

Description

The invention relates to the chemistry of halogen-substituted aromatic compounds, namely to the reaction of electrophilic aromatic substitution in o-xylene with the formation of monohalogen-o-xylenes.

The most common method for producing monohalo-o-xylenes is the halogenation of o-xylene with molecular bromine using iron-based catalysts (Patent CN 101659647, 03/03/2010; US Patent 5107045, 04/21/1992; PCT Application WO 9113047, 09/05/1991; Patent EP 0492594, 01.07.1992) or chlorine using zeolite type KL (Patent JP 2003342206, 03.12.2003; Patent JP 2005261992, 09.29.2005; Patent JP 2003342205, 03.12.2003) with the release target products 70-94%. A significant disadvantage of this approach is the incomplete use of expensive molecular halogens in the reaction due to the formation of hydrogen halide as one of the reaction products.

There is a known method for the halogenation of o-xylene using hydrogen halide in the presence of an oxidizing agent. When using hydrogen bromide and sodium hypochlorite as an oxidizing agent, the yield of monobromo-o-xylenes is 84% (Author's certificate SU 1097592, 06/15/1984). The disadvantage of this approach is the formation of a large amount of wastewater, as well as the low stability of sodium hypochlorite during storage.

There are known examples of the use of hydrogen peroxide as an oxidizing agent: in the case of bromination, it is necessary to use a twofold excess of hydrogen bromide, namely the ratio of o-xylene: HBr: H ₂ O ₂ is 1: 2: 1 (Author's certificate SU 636217, 05.12.1978), chlorination is carried out in a stream of hydrogen chloride in the presence of iron and urea (Patent CN 103408391, 11/27/2013). The disadvantage of this approach is the need to introduce an excess of hydrogen halide into the reaction to ensure a high yield of the product, as well as the use of a catalyst in the case of chlorination.

The closest to the proposed method is the method of producing monohalo-o-xylenes using N-halosuccinimides, in particular N-chlorosuccinimide (Bovonsombat P. et al. Novel regioselective aromatic chlorination via catalytic thiourea activation of A^-chlorosuccinimide // Tetrahedron Letters. - 2015. - T. 56. - No. 17. - pp. 2193-2196.). The authors of the article carry out the synthesis in acetonitrile at room temperature for 5 hours. When carrying out the synthesis using an excess of N-chlorosuccinimide, the conversion of the initial o-xylene reaches only 46%; the use of thiourea allows the conversion to be increased to 86%, but in this case the formation of dihalogen-o-xylene occurs. The disadvantages of this approach are the need to use an excess of N-chlorosuccinimide and a catalyst to ensure completeness of the reaction and high yield, as well as a long time for the synthesis of monochloro-o-xylenes.

The technical result of the present invention is the development of a new, cost-effective method for the halogenation of o-xylenes using commercially available reagents, without the use of catalysts, with high conversion of the original o-xylene.

The technical result is achieved through the use of N-halosaccharins (N-chlorosaccharin and N-bromosaccharin) as halogenating agents, which act as a source of electrophilic halogen atom in the electrophilic aromatic substitution reaction. N-Halosaccharins are commercially available reagents due to the low cost of the starting sodium saccharinate, while the reactivity of such halogenating agents is higher than N-halosuccinimides due to the greater polarization of the N-halogen bond (pKa for saccharin is 1.3, for succinimide - 9.6).

As a result of the reaction, saccharin, insoluble in monohalo-o-xylenes, is formed, which greatly facilitates its isolation from the reaction mass and provides the possibility of reuse.

In general, the process is carried out as follows. N-halosaccharin is added to a mixture of o-xylene and N,N-dimethylformamide (hereinafter referred to as DMF) with stirring, the reaction mass is kept at a temperature of 40-100°C (Figure 1). In this case, the reaction is carried out in no less than a 5-fold excess of DMF at a ratio of o-xylene: N-halosaccharin equal to 1: (1-2) (equiv.).

The conversion of the initial o-xylene is 70-99%, the reaction product is a mixture of 3- and 4-halogen-o-xylenes in a ratio of approximately 1:2, respectively, dihalogen-o-xylenes and 1-methyl are formed as by-products -2-halomethylbenzene. When using N-halosaccharins, significantly fewer by-products of dihalogen derivatives are formed than when carrying out halogenation by more common methods. It is possible to regulate the formation of by-products by changing the reaction temperature, the amount of solvent and the N-halosaccharin used.

It is preferable to use DMF, acetonitrile or acetic acid as a solvent. The best results are obtained when using DMF. When using acetonitrile or acetic acid, the reaction time significantly increases in the case of N-chlorosaccharin, or, in the case of N-bromosaccharin, the amount of by-products, in particular 1-methyl-2-halomethylbenzene, increases. When the reaction is carried out without a solvent, only 1-methyl-2-halomethylbenzene is formed.

It is preferable to use at least 5 parts DMF to 1 part o-xylene. When the volume of solvent is reduced to 3 parts per 1 part o-xylene, the reaction time increases. Increasing the amount of DMF used does not affect the course of the reaction, but complicates the process of isolating the target product.

The reaction can be carried out in the temperature range of 40-100°C; as the temperature increases, the content of byproducts increases. As the process temperature decreases, the reaction time increases significantly.

With an increase in the amount of N-halosaccharin from 1 eq. up to 2 eq. o-xylene conversion and the amount of dihalogen substitution products increase, so it is preferable to use 1 equivalent. N-halosaccharin. When using N-halosaccharins in amounts greater than 2 eq. or less than 1 eq. either the proportion of by-products increases significantly or the conversion of o-xylene decreases, respectively.

Isolation of products is carried out by evaporation of DMF under reduced pressure, followed by extraction of the product with a mixture of dichloromethane and 10% alkali solution; after separation of the organic phase, dichloromethane is evaporated under reduced pressure. The residue is distilled using a packed column with Raschig rings.

The invention is illustrated by the following examples.

Example 1

To a mixture of 1 g (0.009 mol) o-xylene and 5 ml DMF, add 2.05 g (0.009 mol) N-chlorosaccharin (Cl-Sac) with stirring, the reaction mixture is kept at 25°C for 10 hours. According to GC data -MS product after isolation contains 17% o-xylene, 65% 4-chloro-o-xylene, 15% 3-chloro-o-xylene (ratio of 4- and 3-substituted isomers 81:19, respectively) and 3% dichloro -o-xylene (Table 1, line 1).

Example 2

To a mixture of 1 g (0.009 mol) o-xylene and 5 ml DMF, add 2.05 g (0.009 mol) N-chlorosaccharin with stirring, the reaction mass is heated to 40°C and incubated for 1.5 hours. According to GC data The MS product after isolation contains 8% o-xylene, 69% 4-chloro-o-xylene, 21% 3-chloro-o-xylene (ratio of 4- and 3-substituted isomers 77: 23, respectively) and 2% dichloro- o-xylene (Table 1, line 2).

Example 3

To a mixture of 1 g (0.009 mol) o-xylene and 5 ml DMF, add 2.05 g (0.009 mol) N-chlorosaccharin with stirring, the reaction mass is heated to 70°C and incubated for 1 hour. According to GC-MS data, the product after isolation contains 15% o-xylene, 60% 4-chloro-o-xylene, 20% 3-chloro-o-xylene (ratio of 4- and 3-substituted isomers 75: 25, respectively), 3% dichloro-o- xylene and 2% 1-methyl-2-chloromethylbenzene (Table 1, line 3).

Example 4

To a mixture of 1 g (0.009 mol) o-xylene and 5 ml DMF, add 2.05 g (0.009 mol) N-chlorosaccharin with stirring, the reaction mass is heated to 100°C and incubated for 0.5 hours. According to GC data The MS product after isolation contains 24% o-xylene, 54% 4-chloro-o-xylene, 20% 3-chloro-o-xylene (ratio of 4- and 3-substituted isomers 73: 27, respectively), 1% dichloro- o-xylene and 1% 1-methyl-2-chloromethylbenzene (Table 1, line 4).

Example 5

To a mixture of 1 g (0.009 mol) o-xylene and 3 ml DMF, add 2.05 g (0.009 mol) N-chlorosaccharin with stirring, the reaction mass is heated to 40°C and incubated for 1.5 hours. According to GC data The MS product after isolation contains 27% o-xylene, 53% 4-chloro-o-xylene, 17% 3-chloro-o-xylene (ratio of 4- and 3-substituted isomers 76:24, respectively), 2% dichloro- o-xylene and 1% 1-methyl-2-chloromethylbenzene (Table 1, line 5).

Example 6

To a mixture of 1 g (0.009 mol) o-xylene and 1 ml DMF, add 2.05 g (0.009 mol) N-chlorosaccharin with stirring, the reaction mass is heated to 40°C and incubated for 10 hours. According to GC-MS data, the product after isolation contains 30% o-xylene, 51% 4-chloro-o-xylene, 16% 3-chloro-o-xylene (ratio of 4- and 3-substituted isomers 76:24, respectively), 2% dichloro-o- xylene and 1% 1-methyl-2-chloromethylbenzene (Table 1, line 6).

Example 7

To a mixture of 1 g (0.009 mol) o-xylene and 5 ml DMF, add 2.9 g (0.0135 mol) /V-chlorosaccharin with stirring, the reaction mass is heated to 40°C and incubated for 3.5 hours. According to GC-MS, the product after isolation contains 2% o-xylene, 55% 4-chloro-o-xylene, 33% 3-chloro-o-xylene (ratio of 4- and 3-substituted isomers 62: 38, respectively) and 10 % dichloro-o-xylene (Table 1, line 7).

Example 8

To a mixture of 1 g (0.009 mol) o-xylene and 5 ml DMF, 3.9 g (0.018 mol) N-chlorosaccharin is added with stirring, the reaction mass is heated to 40°C and incubated for 5 hours. According to GC-MS data, the product after isolation contains 46% 4-chloro-o-xylene, 24% 3-chloro-o-xylene (ratio of 4- and 3-substituted isomers 66:34, respectively) and 30% dichloro-o-xylene (Table 1, line 8).

Example 9

To a mixture of 1 g (0.009 mol) o-xylene and 5 ml DMF, add 2.4 g (0.009 mol) N-bromosaccharin (Br-Sac) with stirring, the reaction mass is kept at 25°C for 120 hours. According to GC data -MS product after isolation contains 23% o-xylene, 56% 4-bromo-o-xylene, 21% 3-bromo-o-xylene (ratio of 4- and 3-substituted isomers 73:27, respectively), 1% dibromo -o-xylene (Table 2, line 1).

Example 10

To a mixture of 1 g (0.009 mol) o-xylene and 5 ml DMF, 2.4 g (0.009 mol) N-bromosaccharin is added with stirring, the reaction mass is heated to 40°C and incubated for 9 hours. According to GC-MS data, the product after isolation contains 14% o-xylene, 62% 4-bromo-o-xylene, 24% 3-bromo-o-xylene (ratio of 4- and 3-substituted isomers 72: 28, respectively) (Table 2, line 2) .

Example 11

To a mixture of 1 g (0.009 mol) o-xylene and 5 ml DMF, 2.4 g (0.009 mol) N-bromosaccharin is added with stirring, the reaction mass is heated to 70°C and incubated for 6 hours. According to GC-MS data, the product after isolation contains 35% o-xylene, 48% 4-bromo-o-xylene, 17% 3-bromo-o-xylene (ratio of 4- and 3-substituted isomers 74: 26, respectively) (Table 2, line 3) .

Example 12

To a mixture of 1 g (0.009 mol) o-xylene and 5 ml DMF, 2.4 g (0.009 mol) N-bromosaccharin is added with stirring, the reaction mass is heated to 100°C and incubated for 1 hour. According to GC-MS data, the product after isolation contains 39% o-xylene, 44% 4-bromo-o-xylene, 17% 3-bromo-o-xylene (ratio of 4- and 3-substituted isomers 72: 28, respectively) (Table 2, line 4) .

Example 13

To a mixture of 1 g (0.009 mol) o-xylene and 3 ml DMF, 2.4 g (0.009 mol) N-bromosaccharin is added with stirring, the reaction mass is heated to 40°C and incubated for 7 hours. According to GC-MS data, the product after isolation contains 27% o-xylene, 55% 4-bromo-o-xylene, 18% 3-bromo-o-xylene (ratio of 4- and 3-substituted isomers 74:26, respectively) (Table 2, line 5) .

Example 14

To a mixture of 1 g (0.009 mol) o-xylene and 1 ml DMF, 2.4 g (0.009 mol) N-bromosaccharin is added with stirring, the reaction mass is heated to 40°C and incubated for 8 hours. According to GC-MS data, the product after isolation contains 27% o-xylene, 54% 4-bromo-o-xylene, 19% 3-bromo-o-xylene (ratio of 4- and 3-substituted isomers 74:26, respectively) (Table 2, line 6) .

Example 15

To a mixture of 1 g (0.009 mol) o-xylene and 5 ml DMF, 4.1 g (0.0158 mol) N-bromosaccharin is added with stirring, the reaction mass is heated to 40°C and incubated for 6 hours. According to GC data, The MS product after isolation contains 7% o-xylene, 69% 4-bromo-o-xylene, 23% 3-bromo-o-xylene (ratio of 4- and 3-substituted isomers 75:25, respectively) and 1% dibromo- o-xylene (Table 2, line 7).

Example 16

To a mixture of 1 g (0.009 mol) o-xylene and 5 ml DMF, 4.7 g (0.018 mol) N-bromosaccharin is added with stirring, the reaction mass is heated to 40°C and incubated for 6 hours. According to GC-MS data, the product after isolation contains 68% 4-bromo-o-xylene, 21% 3-bromo-o-xylene (ratio of 4- and 3-substituted isomers 76:24, respectively) and 11% dibromo-o-xylene (Table 2, line 8 ).

Claims (2)

1. A method for producing monohalo-o-xylenes by electrophilic aromatic substitution in o-xylene, characterized in that N-halosaccharins are used as a halogenating agent, and the reaction is carried out in N,N-dimethylformamide at a mass ratio of at least five parts N,N- dimethylformamide to one part of o-xylene and at a component ratio of o-xylene: N-halosaccharin equal to 1: (1-2) (equiv.) at a temperature of 40-100°C. 2. The method according to claim 1, characterized in that N-chloro- and N-bromosaccharin are used as N-halosaccharins.