GB2291871A

GB2291871A - Preparation of nitrofluoroaromatic compounds

Info

Publication number: GB2291871A
Application number: GB9415313A
Authority: GB
Inventors: Richard Dickinson Chambers; Christopher John Skinner
Original assignee: Zeneca Ltd; BNFL Fluorochemicals Ltd
Current assignee: F2 Chemicals Ltd; Syngenta Ltd
Priority date: 1994-07-29
Filing date: 1994-07-29
Publication date: 1996-02-07
Also published as: GB9415313D0

Abstract

A method for the introduction of one or more fluorine atoms and one or more nitro groups into an aromatic compound with comprises the step of reacting the aromatic compound with a nitrating agent in the presence of elemental fluorine the two thereby providing a fluoronitrating agent.

Description

The preparation of organic comPounds The present invention relates to the preparation of organic compounds. In particular, it relates to the synthesis of nitrofluoroaromatic compounds.

Nitrofluorination of aromatic compounds is not readily achievable. The incorporation of a fluorine atom and a nitro group into an aromatic compound has in the prior art therefore been achieved only in two steps; viz (a) initial fluorination via elemental fluorine, halex exchange with an alkali metal fluoride or most commonly by Balz-Schieman chemistry; and (b) nitration of this product via an H2S04/NH03 mixture or the use of nitronium salt in the presence of a strong acid.

According to the present invention there is provided a method for the introduction of one or more fluorine atoms and one or more nitro groups into an aromatic compound which comprises the step of reacting the aromatic compound with a nitrating agent in the presence of elemental fluorine.

Surprising, we have found that the present invention provides a high yield route which may be carried out in a single step to the synthesis of nitrofluoroaromatics. The process may be operated at easily obtainable temperatures and allows the solvents required to be used to be minimised. This reduces the problem of disposing of such solvents after use.

The nitrating agent and the fluorine together form a fluorinating agent.

The fluoronitrating agent conveniently comprises a source of electrophilic nitronium ions, such as nitric acid, in combination with elemental fluorine. The fluoronitrating agent may also comprise a source of nitronium ions, such as nitronium tetrafluoroborate, in combination with a protic acid, such as sulphuric acid or formic acid or trifluoroacetic acid, and elemental fluorine.

The aromatic compound may be benzene or naphthalene which may optionally be substituted in the or each ring.

The single or multiple ring substituents (which may themselves contain optional substituents) may be independently selected from alkyl, alkoxy, halogen, -CN, -OH, -NO2, -NH2, -NHalkyl, -N(alkyl)2, -NHCOalkyl, -COOalkyl, -COOH, -COalkyl, -CONH2, -CONH(alkyl), -CON (alkyl)2, COY, -CY13 and S02Y2, wherein: Y is -H, -F, C1, -Br, alkyl -OH or -Oalkyl yl is -F or C1 y2 is -F -C1, -Br, -NH2, NHalkyl, or -N(alkyl)2.

In each of these subsituents alkyl is preferably C14 alkyl, alkoxy is preferably C14 alkoxy and halogen is preferably -F or -Br or -C1 or -I.

When the aromatic compound is substituted benzene it is preferably mono- or di-substituted. When benzene is di-substituted it is preferably substituted in the 1- and 4-positions. Preferred ring substituents for the aromatic compound are selected from -OH, -CN, -NO21 -NHCOH3, -OCH3,-COOH, -COOCH3, -CH3, -C1, -Br, -I and -CONH2 and combinations thereof.

The aromatic compound may be dissolved in nitric acid optionally together with one or more other solvents, eg to act as a solvent for fluorine. Where the reaction medium comprises nitric acid, the acid may contain up to 50% by volume of water (100% being the acid/water solution). Use of from 60% to 95% nitric acid is particularly advantageous and allows multiple insertion of fluorine atoms and/or nitro groups. Other inert diluents, particularly perfluorinated solvents such as perfluorocyclohexane and perfluorodecane may also be used in the acid medium.

Although the method according to the present invention is suitable for operation at ambient temperatures (eg lO0C to 200C) it may be carried out at temperatures over a wide range eg from OOC to 1000C, especially OOC to 400C.

The elemental fluorine employed in the method according to the present invention may be fluorine gas which is preferably diluted before use by mixing with an inert gas such as nitrogen or helium. The concentration of fluorine is preferably from 1% to 50% by volume, more preferably from 2% to 25% and especially from 5% to 15% of the applied gas.

The ratio of fluorine to aromatic compound may be varied within wide limits although it is preferred that the molar ratio of fluorine to aromatic compound is from 2:1 to 6:1, especially from 2.5:1 to 4.5:1. Use of the higher ratio of fluorine to aromatic compound ensures that multiple fluorine atoms and nitro groups are introduced into the aromatic compound forming polyfluorinated products.

When fluoronitration is substantailly complete the fluorinated products may be isolated by purging the reaction mixture with nitrogen to remove any residual fluorine gas followed by dilution with excess water, extraction into a suitable solvent then followed by distillation. The fluorinated products may be separated by fractional distillation, chromatography or by crystallisation from a suitable solvent.

The method according to the present invention offers a convenient synthetic route to mono- and polyfluoronitrated aromatic compounds which are difficult to prepare by other processes or may only be prepared in poor yield. This method also minimises the need to dispose of waste fluorinated solvents. The mono- and polyfluoronitrated products will find known uses in the preparation of agrochemicals and pharmaceuticals for example.

Embodiments of the present invention will now be described in the following Examples.

Example 1 Fluorination of fluorobenzene in nitric acid Fluorobenzene (15.0g, 156mmol) was slowly added to cooled 90% nitric acid (150ml) and placed in fluorination apparatus with an attached soda lime filled drying tube and allowed to reach ambient temperature. Fluorine gas (165mmol) as a 10% mixture by volume in a in nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at a rate of about 40 ml/ min-1. After the addition of fluorine was completed the mixture was purged with N2. The mixture was added to an excess of water (100ml), extracted with dichloromethane (3x50ml) and dried (MgSO4). The dichloromethane was removed under rotary evaporation to leave a yellow oil (15.5g).Analysis of the resulting mixture by 19F nmr against an external standard of trifluoroluene (3.0g, 2lmmol) showed a conversion of 100% from fluorobenzene. The product contained 4-fluoronitrobenzene (5.6g), 5F -108.9 (1F, s); m/z, (EI+), 141 (M+, 71.4%); 3,4-difluoronitrobenzene (6.0g), 5F -128.3 (1F, s) -131.5 (F1, s)m/z, (EI+), 159 (M+, 92.9%), 2,4,5-trifluoronitrobenzene (0.7g) aF-118.6 (lF,s) -123.3 (1F, s), -138.9 (1F, s) (1F, s); m/z, (EI+), 177 (M+, 92.9%) 2, 3, 4-trifluoronitrobenzene (0.2g), 8F123.9, (1F, s) -128.9 (1F, s) -159.6 (1F, s) m/z (EI+), 177 (M+, 92,9%); 3,4,5-trifluoronitrobenzene (0.8g), 5F - 131.5 (2F, s) -151.1 (1F, s); m/z, (EI+), 177 (M+, 92.9%) and 2,4-dinitrofluorobenzene (0.6g), 5F -104.0 (1F, s); m/z (EI+), 186 (M+, 100%) and unidentified material (1.6g)- Fluorination of 4-fluorobenzoic acid in nitric acid 4-fluorobenzoic acid (11.5g, 82.lmmol) was slowly added to cooled 90% nitric acid (150ml) in a fluorination apparatus with an attached soda lime filled drying tube and allowed to reach ambient temperature. Fluorine gas (165mmol) 10% by volume in a mixture in nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at a rate of about 40 ml/min-l. After the addition of fluorine was completed the mixture was purged with N2.

The mixture was added to an excess of water (1000ml), extracted with dichloromethane (3x50ml) and dried (MgsO4).

The dichloromethane was removed under rotary evaporation to leave a yellow solid (9.3g). Analysis of the resulting mixture by 19F nmr against an external standard of trifluorotoluene (2.4g, 16.6mmol) showed a conversion of 100% from 4-fluorobenzoic acid. The product contained 3nitro-fluorobenzoic acid (2.2g), AF- 110.9 (1F, s) m/z, CI+(CH4), 258(M+, 100%);3-nitro4,5-difluorobenzoic acid (4.7g), 5F - 131,9 (1F, s) -135.0 (1F, s), m/z, CI+(CH4), 276 (M+, 100%); 2,4 -difluoronitrobenzene (0.8g) 5F - 107.8 (2F, s), m/z (EI+) 186(M+, 100%), 233(-CH3, 93.98) and unidentified material (1.6g).

Claims

1. A method for the introduction of one or more fluorine atoms and one or more nitro groups into an aromatic compound with comprises the step of reacting the aromatic compound with a nitrating agent in the presence of elemental fluorine the two thereby providing a fluoronitrating agent.

2. A method as in Claim 1 and wherein the fluoronitrating agent comprise a source of electrophilic nitronium ions together with elemental fluorine.

3. A method as in Claim 2 and wherein the fluoronitrating agent comprises nitric acid together with elemental fluorine.

4. A method as in Claim 2 or Claim 3 and wherein the fluoronitrating agent comprises a source of nitronium ions together with elemental fluorine.

5. A method as in Claim 4 and wherein the source of nitronium ions comprises nitronium tetrafluoroborate.

6. A method as in Claim 4 or Claim 5 and wherein the protic acid is selected from sulphuric acid, trifluoroacetic acid and formic acid.

7. A method as in Claim 3 and wherein the nitric acid is present in a solution with water in which the water content is up to 50% by volume of the acid/water solution.

8. A method as in Claim 7 and wherein the said solution comprises from 60% to 95% by volume of nitric acid.

9. A method as in Claim 7 or Claim 8 and wherein one or more other inert diluents or solvents are added to the acid/water solution.

10. A method as in any one of the preceding claims and wherein the fluorine gas is diluted before use in the fluoronitration reaction with an inert gas.

11. A method as in Claim 1 and substantially the same as any one of the specific examples of such method described hereinbefore.