HUTCHINSON JOHN (GB)
SKINNER CHRISTOPHER JOHN (GB)
THOMSON JULIE (GB)
CHAMBERS RICHARD DICKINSON (GB)
HUTCHINSON JOHN (GB)
SKINNER CHRISTOPHER JOHN (GB)
THOMSON JULIE (GB)
| EP0566268A1 | 1993-10-20 | |||
| EP0018606A1 | 1980-11-12 |
| 1. | A process for the selective introduction of one or more fluorine atoms into a disubstituted aromatic compound by reaction of the aromatic compound in an acid medium with fluorine gas characterised in that the acid medium has a dielectric constant of at least 20 and a pH of less than 3. |
| 2. | A process according to Claim 1 in which the acid medium is selected from formic and sulphuric acids and oleum. |
| 3. | A process according to Claim 1 or Claim 2 in which the acid medium is sulphuric or formic acid. |
| 4. | A process according to any one of Claims 1 to 3 in which the fluorine gas is diluted with an inert gas. |
This invention relates to a process for the fluorination of aromatic compounds.
Processes for the fluorination of aromatic compounds are known where fluorine gas is used as a fluorinating agent but the strong oxidising properties of fluorine cause the aromatic compound to decompose and poor yields of the required products are obtaine d . Th e dilution of the fluorine gas with an inert gas, such as nitrogen, is described in EP-A2-0512715 and this moderates the oxidising effect of the fluorine allowing the introduction of one fluorine atom into the aromatic compound in good yield. Known processes for the preparation of polyfiuoroaromatic compounds involves using more severe fluorinating conditions with a consequent increase in the formation of decomposition products or involves halogen exchange or reaction of an aromatic compound with a fluorinating agent such as cobalt trifluori d e.
The direct fluorination of. certain aromatic compounds in acetonitrile is known but is generally inconvenient because low reaction temperatures are required. Further problems occur where fluorination is carried out in solvents such as acetonitrile since reaction with the solvent leading to tar formation can occur.
The object of the present invention is to provi d e a fluorination process for making specific fluorinated compounds by the selective introduction of one or more fluorine atoms into an aromatic compound in good overall yield which may be operated at easily obtainable temperatures and which minimises reaction between fluorine and the solvent.
According to the present invention there is provided a process for the selective introduction of one or more fluorine atoms into a disubstituted aromatic compound by reaction of the aromatic compound in an acid medium with fluorine gas characterised in that the acid medium has a dielectric constant of at least 20 and a pH of less than 3.
The present process provides a cost effective means of selectively introducing one or more fluorine atoms into an aromatic compound in good overall yield.
The aromatic compound is preferably benzene which may be substituted by from one to five substituents. Suitable substituents may be independently selected from εlkyl, alkoxy, halogen, -CN, -OH, -N0 2 , -N(alkyl) 2 , -NHCOalkyl, -COOalkyl, -COOH, -COalkyl, -C0N(alkyl) 2 , -COY, -CY X 3 and -S0 2 Y 2 in which Y is -H, -F, -Cl, -Br, Y 1 is -F or -Cl, and Y 2 is -F, -Cl, -Br, -N(alkyl) 2 . In each of these substituents alkyl is preferably C^-alkyl, alkoxy is preferably C 1 __,- alkoxy and halogen is preferably -F, -Cl or Br.
Preferred substituents for the aromatic compound are selected from -CN, -OH, -N0 2 , -NHCOCH 3 , -OCH 3 , -COOCH 3 , -COOH, -COCH 3 , -CH 3 , -Cl, -Br and -F and combinations thereof. The aromatic compound is preferably disubstituted in the 1- and 4-positions or in the 1- and 2-positions and more preferably disubstituted in the 1- and 4- positions.
Where the aromatic compound is disubstituted the 1-position is preferably occupied by a meta-directing group and the 2- or 4- position is preferably occupied by an ortho/para-directing group.
In a preferred embodiment of the present invention the aromatic compound is of Formula (1):
Formula C O
wherein:
R 1 is a meta-directing group; X 1 , X 3 and X 5 each independently is -H, -F or an ortho/para-directing group; X 2 and X* each independently is -H, halogen; provided that at least one of X 1 , X 2 , X 3 , X*, X 5 is -H.
The meta-directing group represented by R 1 is preferably selected from -Br, -Cl, -F, -N0 2 , -CN, -COY, -CY X 3 and -S0 2 Y 2 in which Y is -H, -F, -Cl, -Br, -Cj.,.-alkyl, -OH or -OC-^-alkyl; Y 1 is -F or -Cl;
Y 2 is -F, -Cl, -Br, -NH 2 , -NH(Cι_<-alkyl) and -NHCC^-alkyl) 2 .
The ortho/parc-directing groups represented by X 1 , X " and X 5 are preferably selected from -OH, -OCj.g-alkyl, C^g-alkyl and -NHCOC j . g - alkyl.
Where one of the groups represented by X 2 and - is halogen it is preferably -F or -Cl and where any of these groups are alkyl, alkoxy, -NH(alkyl) or -N(alkyl) 2 it is preferred that each alkyl or alkoxy contains from 1 to 6 carbon atoms.
Compounds of Formula (1) are preferably those in which R 1 . is a meta-directing group, one of X 1 , X 3 or X 5 is an ortho/para- directing group or -F and X 2 and X are hydrogen, more preferably those in which R 1 is a meta-directing group, X 3 is an ortho/para-directing group or -F and X 1 , X 2 , X ή and X 5 are hydrogen.
Especially preferred compounds of Formula (1) are those in which R 1 is selected from -CN, -N0 2 , -COOCH 3 , -COOH, -COCH 3 , -Br, -Cl and -F, X 3 is selected from -OH, -0CH 3 , -CH 3 , -NHCOCH 3 and -F and X 1 , X 2 , X - and X 5 are hydrogen.
The acid medium preferably has a dielectric constant from 20 to 90, more preferably from 30 to 90, especially from 50 to 90. The acid medium preferably has a pH of less than 3, more preferably less than 2 and especially less than 1.
The acid medium is preferably selected from formic and sulphuric acids and oleum. Where the acid medium is formic or sulphuric acid it may contain water preferably from 5 to 0Z water, more preferably from 2 to 0Z water and especially from 1 to 0Z water. Where the acid medium is oleum it is preferably from 1Z to 30Z oleum more preferably from 20Z to 30Z oleum. Inert diluents, particularly fluorinated solvents such as 'ARKLONE' P (ARKLONE is a trade mark of ICI PLC) may be present in the acid medium such solvents should be substantially free from water. The acid medium is preferably sulphuric or formic acid, more preferably from 95Z to 100Z sulphuric or formic acid, more preferably from 98Z to 100Z formic acid and especially from 99Z to 100Z formic acid..
The use of from 98Z to 100Z sulphuric or particularly from '98Z to 100Z formic acid as the acid medium is advantageous where multiple fluorine atoms are to be introduced into the aromatic compound
because such acids allow high conversion of the aromatic compound of Formula (1) to di-, tri-, tetra- and penta-fluorinated derivatives.
The process may be carried out at a temperature from 10°C to 90°C, preferably at a temperature from 10°C to 40°C and especially from 10°C to 20°C.
The fluorine gas is preferably diluted before use by mixing with an inert gas such as nitrogen or helium. The concentration of fluorine in inert gas is preferably from 1Z to 50Z by volume, more preferably from 2Z to 25Z and especially from 5Z to 15Z.
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 1.2:1 to 6:1, depending on the degree of fluorination required. Use of the higher ratio of fluorine to aromatic compound ensures that multiple fluorine atoms are introduced into the aromatic compound forming polyfluorinated products.
When fluorination is substantially complete the fluorinated product(s) may-be isolated by purging the reaction mixture with nitrogen to remove any residual fluorine and hydrogen fluoride followed by dilution with excess water and extraction into a suitable solvent followed by distillation. The fluorinated products may be separated by fractional distillation or by crystallisation from a suitable solvent. •
Under the above process condir. ons a mixture of products is obtained where one or more fluorine atoms have been introduced into the aromatic compound. For example when 4-fluorobenzoic acid is the aromatic compound and 98Z sulphuric acid is used as the acid medium the mixture of products obtained comprises 2,4- and 3,4-difluoro-, 2,4,5-, 2,3,4- and 3,4,5-trifluoro-, 2,3,4,5-tetrafluoro- and 2,3,4,5,6- pentafluorobenzoic acids.
The present process thus offers a convenient synthetic route to mono- and polyfluorinated aromatic compounds'which are difficult to prepare by other processes or may only be prepared in poor yield and minimises the need to dispose of waste fluorinated tars and other by-products. The mono- and polyfluorinated products find uses as synthetic intermediates in the preparation of agrochemicals and pharmaceuticals.
The invention is further illustrated by the following examples.
A comparative example. Example A, is provided to illustrate the effect of replacing the acid medium by an organic solvent (acetonitrile) in which only one fluorine atom is introduced in relatively poor yield into the starting material. No more highly fluorinated aromatic could be isolated from the reaction mixture.
Example 1
Fluorination of 4-Cyanophenol
A stirred reaction vessel charged with 4-cyanophenol (11.9g, O.lmol) and 98Z formic acid (200cm 3 ) was purged with nitrogen and cooled to 10°C. Fluorine (0.2mol) , diluted with nitrogen to 102, was passed through the cooled, stirred solution over a period of about 6 hours. The vessel was purged with nitrogen and allowed to warm to ambient temperature. The reaction mixture was poured into water and extracted with diethyl ether. The extracts were dried and the solvent was removed by distillation to leave a tan solid (12.4g). Short path distillation of the crude product (3.9g) at reduced pressure gave an off white solid (3.4g) which was shown to comprise three main compounds by nmr and GC analysis. The mixture was shown to contain 4-cyano-2- fluorophenol (δ F -134.7ppm[d 6 -Me 2 CO]) and 4-cyano-2,6-difluorophenol (δ F - 131.0ppm[d 6 -Me 2 Cθ] ) in yields of 64Z and 10Z, respectively, with a conversion of 84Z. (NB The chemical shifts in this and all other examples were relative to CFC1 3 .)
Example 2
Fluorination of 4-Nitrophenol
In a similar manner to that described in Example 1, 0.2-inol fluorine diluted with nitrogen to 10Z was passed through a solution of 4-nitrophenol (O.lmol) in 98Z formic acid over 4.5 hours at 10°C. The reaction mixture was poured into water and extracted with diethylether. The ether solution was dried and the solvent removed using a rotary evaporator to leave a brown liquid. This was transferred to a short path distillation apparatus and distilled at reduced pressure to yield pale yellow crystals (12.9g). GC/MS and 19 Fnmr (CDC1 3 ) analysis showed these to be mainly unreacted starting material, 2-fluoro-4-nitrophenol [(M + 157, δ F -137.5ppm, yield 70Z), and 2,6-difluoro-nitrophenol (M + 175, δ F -131.7ppm, yield 7Z). The conversion was 75Z.
Example 3
Fluorination of 4-Nitroacetanilide
By the method outlined in Example 1 , 4-nitroacetanilide was fluorinated to give 2-fluoro-4-nitroacetanilide (M + 198 , δ F -125 .8ppm [ CDC1 3 ] , yield 60Z ) and 2 , 6-dif luoro-4-nitroacetanilide ( δ F -112.8ppm [ CDC1 3 ] , yield 8Z ) . Conversion 100Z .
Example 4
Fluorination of Methyl 4-methoxybenzoate
By the method outlined in Example 1, methyl 4- methoxybenzoate was fluorinated to give methyl 3-fluoro-4- methoxybenzoate (M + 184, δ F -135.3ppm [CDC1 3 ], yield 50Z) and methyl 3,5- difluoro-4-methoxybenzoate (M + 202, δ F -128.3ppm [CDC1 3 ], yield 10Z). Conversion 90Z.
Example 5
Fluorination of- 4-Methoxybenzonitrile
By the method outlined in Example 1, 4-methoxybenzonitrile was fluorinated to give 3-fluoro-4-methoxybenzonitrile (δ F -125.8ppm [CDC1 3 ], yield 35Z) and 3,5-difluoro-4-methoxybenzonitrile (δ F -132.5ppm [CDC1 3 ], yield 10Z). Conversion 90Z.
Example 6
Fluorination of 4-Hydroxyacetophenone
By the method outlined in Example 1, 4-hydroxyacetophenone was fluorinated to give 3-fluoro-4-hydroxyacetophenone (δ F -133.1ppm [d 6 -Me 2 CO], yield 40Z) and 3,5-difluoro-4-hydroxyacetophenone (δ F - 132.9ppm [d 6 -Me 2 CO], yield 7Z). Conversion 83Z
Example 7
Fluorination of Methyl 4-hydroxybenzoate
By the method outlined in Example 1, methyl 4- hydroxybenzoate was fluorinated to give methyl 3-fluoro-4- hydroxybenzoate (δ F -133.2ppm [d 6 -Me 2 CO], yield 30Z) and methyl 3,5- difluoro-4-hydroxybenzoate (δ F -129.1ppm [d 6 -Me 2 CO], yield 17Z). Conversion 100Z.
Example 8
Fluorination of 4-Nitrotoluene
By the method outlined in Example 1, 4-nitrotoluene was fluorinated to give 2-fluoro-4-nitrotoluene (M + 155, δ F -113.4ppm [CDC1 3 ], yield 502) and a trace of 2,6-difluoro-4-nitrotoluene (M + 173, δ F -110.2ppm [CDC1 3 ]). Conversion 632.
Example 9
Fluorination of 4-Nitroanisole
By the method outlined in Example 1, 4-nitroanisole was fluorinated to give 2-fluoro-4-nitroanisole (M + 171, δ F -131.6ppm [CDC1 3 ], yield 502) and 2,6-difluoro-4-nitroanisole (M + 189, δ F -125.1ppm [CDC1 3 ], yield 202). Conversion 602.
Example 10
Fluorination of 4-cyanotoluene
By the method outlined in Example 1, p-tolunitrile was fluorinated to give 4-cyano-2-fluorotoluene (M + 135, δ F -114.5ppm [CDC1 3 ], yield 602) and 4-cyano-2,6-difluorotoluene (M + I53, δ F -lll.lppm [CDC1 3 ], yield 2Z). Conversion 862.
Example 11
Fluorination of 4-Chloroanisole
3y the method outlined in Example 1, 4-chloroanisole was fluorinated to give 4-chloro-2-fluoroanisole (M + 160, δ F -132.7ppm [CDC1 3 ], yield 502) and 4-chloro-2,6-difluoroanisole (M + 178, δ F -127.1ppm [CDC1 3 ], yield 72). Conversion 802.
Fluorinations of 4-Fluorobenzoic acid
In each of the following examples the mixtures of fluoro and polyfluorobenzoic acids were analysed first, by comparison of the 19 F nmr spectra of the mixtures, with the spectra of authentic samples. More accurate quantitative analysis of the components in these mixtures was obtained by conversion of the carboxylic acids to their more volatile silyl esters, by treatment with bis(trimethylsilyl)acetamide (BSA) and then analysis of g.c./mass spec. Therefore the quoted mass- spectrometry data refers to the corresponding silyl esters.
£
Example 12
Formic acid (substrate to f]uorine ratio 1:1.6)
A solution containing 4-fluorobenzoic acid (11.5g, 82.1mmol) in 98Z formic acid (200cm 3 ) was placed in a fluorination apparatus with attached soda lime filled drying tube. Fluorine gas (133mmol) as a 10Z mixture in nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca 60cm 3 /min _1 . The mixture was added to an excess of water (1000cm- 4 ) and the resulting solid product was filtered off under vacuum. The filtrate was then extracted with dichloromethane (3x50cm 3 ). After drying (MgS0 A ), the dichloromethane was removed under vacuum and an off-white solid resulted (10.5g).
Analysis of the resulting solid by 19 Fnmr against an external standard of fluorobenzene (7.3g, SO.lmmol) showed a conversion of 32Z from 4-fluorobenzoic acid. The product contained 4- fluorobenzoic acid (7.8g), δF-104.2, electron impact, m/z 212 (M + , 3.2Z), 197 (-CH 3 , 100Z); 3,4-difluorobenzoic acid (2.7g), δF-128.7 and -136.5, electron impact, m/z 230 (M + , 2.42), 215 (-CH 3 , 1002) and unidentified material (O.lg).
Example 13
Formic acid (substrate to fluorine ratio 1:2)
A solution containing 4-fluorobenzoic acid (11.5g, 82.1mmol) in 982 formic acid (200cm 3 ) was placed in a fluorination apparatus with attached soda lime filled drying tube. Fluorine gas (165mmol) as a 102 mixture in nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca 60cm 3 /min _1 . The mixture was added to an excess of water (1000cm 3 ) and the resulting solid product was filtered off under vacuum. The filtrate was then extracted with dichloromethane (3x50cm 3 ). After drying (MgS0 A ), the dichloromethane was removed under vacuum and an off-white solid resulted (8.8g).
Analysis of the resulting solid by 19 Fnmr against an external standard of fluorobenzene (10.2g, 69.9mmol) showed a conversion of 51.52 from 4-fluorobenzoic acid. The product contained 4-fluorobenzoic acid (5.6g), δF-104.2, electron impact, m/z 212 (M + , 3.242), 197 (-CH 3 , 1002); 3,4-difluorobenzoic acid (2.8g,), δF-128.7
and -136.5, electron impact, m/z 230 (M + , 2.402), 215 (-CH 3 , 100Z) and unidentified material (0.4g).
Example 14
Formic acid (substrate to fluorine ratio 1:3)
A solution containing 4-fluorobenzoic acid (4.0g, 28.2mmol) in 982 formic acid (200cm 3 ) was placed in a fluorination apparatus with attached soda lime filled drying tube. Fluorine gas (82.5mmol) as a 102 mixture in nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca 60cm 3 /min" 1 . The mixture was added to an excess of water (1000cm 3 ) and the resulting solid product was filtered off under vacuum. The filtrate was then extracted with dichloromethane (3x50cm 3 ). After drying (MgS0 ), the dichloromethane was removed under vacuum and an off-white solid resulted (3.1g).
Analysis of the resulting solid by 19 Fnmr against an external standard of trifluorotoluene (1.7g, 11.6mmol) showed a conversion of 65.32 from 4-fluorobenzoic acid. The product contained 4-fluorobenzoi'c acid (1.4g), δF-104.2, electron impact, m/z 212 (M + , 3.22), 197 (-CH 3 , 1002); 3,4-difluorobenzoic acid (1.6g,), δF-128.7- and -136.5, electron impact, m/z 230 (M + , 2.42), 215 (-CH 3 , 100Z) and unidentified material (0.2g).
Example 15
Formic acid (substrate to fluorine ratio 1:4)
A solution containing 4-fluorobenzoic acid (6.0g, 42.9mmol) in 982 formic acid (200cm 3 ) was placed in a fluorination apparatus with attached soda lime filled drying tube. Fluorine gas (165mmol) as a 102 mixture in nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca 60cm /min "1 . The mixture was added to an excess of water (1000cm 3 ) and the resulting solid product was filtered off under vacuum. The filtrate was then extracted with dichloromethane (3x50cm 3 ). After drying (MgS0 A ), the dichloromethane was removed under vacuum and a white solid resulted (5.3g).
Analysis of the resulting solid by 19 Fnmr against an external standard of trifluorotoluene (5.7g, 38.9mmol) showed a conversion of 79.22 from 4-fluorobenzoic acid. The product contained 4-fluorobenzoic acid (1.2g), δF-104.2, electron impact, m/z 212 (M + ,
3.2Z), 197 (-CH 3 , 100Z); 3,4-difluorobenzoic acid (3.5g), δF-128.7 and -136.5, electron impact, m/z 230 (M + , 2.42), 215 (-CH 3 , 1002); 2,4,5-trifluorobenzoic acid (0.2g), δF-108.2, -123.4 and -141.3, electron impact, m/z 248 (M + , 1.22), 233 (-CH 3 , 1002); 2,3,4- trifluorobenzoic acid (O.lg), δF-124.4, -128.7 and -158.7, electron impact, m/z 233 (-CH 3 , 5.12); 3,4,5-trifluorobenzoic acid (0.2g), δF-132.6 and -151.3, electron impact, m/z 248 (M + , 1.52), 233 (-CH 3 , 94.62) and unidentified material (0.3g).
Example 16
Sulphuric acid (982) (substrate to fluorine ratio 1:1.6)
A solution containing 4-fluorobenzoic acid (14.4, 102.9mmol) in 982 sulphuric acid (150cm 3 ) was placed in a fluorination apparatus with attached soda lime filled drying tube. Elemental fluorine (165mmol) as a 102 mixture in nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca 60cm 3 /min" 1 . The resulting mixture was worked up by adding the mixture to an excess of water (1000cm 3 ) and the resulting solid product was filtered off under vacuum. The filtrate was then extracted with dichloromethane (3x50cm 3 ). After drying (MgS0 ), the dichloromethane was removed under vacuum and a white solid resulted (11.6g).
Analysis of the resulting solid by 19 Fnmr against an external standard of trifluorotoluene (mmol) showed a conversion of 82.62 from 4-fluorobenzoic acid. The product containing 4- fluorobenzoic acid (2.5g), δF-104.2, electron impact, m/z 212 (M + , 3.282), 197 (-CH 3 , 100Z); 3,4-difluorobenzoic acid (6.8g), δF-128.7 and -136.5, electron impact, m/z 230 (M + , 2.76Z), 215 (-CH 3 , 1002); 2,4,5- trifluorobenzoic acid (1.3g), δF-108.2, -123.3 and -141.2, electron impact, m/z 248 (M + , 1.092), 233 (-CH 3 , 1002); 2,3,4-trifluorobenzoic (0.6g), δF-124.3, -128.7 and -158.6, electron .impact, m/z 248 (M + , 2.292), 233 (-CH 3 , 93.902); 3,4,5-trifluorobenzoic acid (0.3g), δF- 132.6 and -151.2, electron impact, m/z 248 (M + , 1.312), 233 (-CH 3 , 1002) and unidentified material (0.2g).
Example 17
Sulphuric acid (982) (substrate to fluorine ratio 1:2)
A solution containing 4-fluorobenzoic acid (11.5g, 82.5mmol) in 982 sulphuric acid (150cm 3 ) was placed in a fluorination apparatus with attached soda lime filled drying tube. Elemental fluorine (165mmol) as a 10Z mixture in nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca 60cm 3 /min -1 . The resulting mixture was worked up by adding the mixture to an excess of water (1000cm 3 ) and the resulting solid product was filtered off under vacuum. The filtrate was then extracted with dichloromethane (3x50cm 3 ). After drying (MgSO^,), the dichloromethane was removed under vacuum and a white solid resulted (10.6g).
Analysis of the resulting solid by 19 Fnmr against an external standard of trifluorotoluene (3.2g, 21.8mmol) showed a conversion of 84.82 from 4-fluorobenzoic acid. The product containing 4-fluorobenzoic acid (1.8g), δF-104.2, electron impact, m/z 212 (M + , 3.3Z), 197 (-Cfl 3 , 1002); 3,4-difluorobenzoic acid (6.2g), δF-128.7 and -136.5, electron impact, m/z 230 (M + , 2.82), 215 ' (-CH 3 , 1002); 2,4,5- trifluorobenzoic acid (0.8g), δF-108.2, -123.3 and -141.2, electron impact, m/z 248 (M + , 1.-12), 233 (-CH 3 , 1002); 2,3,4-trifluorobenzoic (0.4g), δF-124.3, -128.7 and -158.6, electron impact, m/z 248 (M + , 2.32), 233 (-CH 3 , 93.92); 3,4,5-trifluorobenzoic (0.4g), δF-132.6 and - 151.2, electron impact, m/z 248 (M + , 1.32), 233 (-CH 3 , 1002); 2,3,4,5- tetrafluorobenzoic acid (0.7g), δF-133.3, -137.9, -142.7 and -151.2, electron impact, m/z 266 (M + , 0.52), 251 (-CH 3 , 60.32) and unidentified material (0.4g).
Example 18
Sulphuric acid (982) (substrate to fluorine ratio 1:3)
A solution containing 4-fluorobenzoic acid (7.7g, 55.0mmol) in 982 sulphuric acid (150cm 3 ) was placed in a fluorination apparatus with attached soda lime filled drying tube. Elemental fluorine (165mmol) as a 10Z mixture in nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca 60cm 3 /min" 1 . The resulting mixture was worked up by adding the mixture to an excess of water (1000cm 3 ) and the resulting solid product was filtered off under vacuum. The filtrate was then extracted with dichloromethane
(3x50cm 3 ). After drying (MgSO,-), the dichloromethane was removed under vacuum and a white solid resulted (5.9g).
Analysis of the resulting solid by 19 Fnmr against an external standard of trifluorotoluene (3.6g, 24.9mmol) showed a conversion of 92.32 from 4-fluorobenzoic acid. The product contained 4-fluorobenzoic acid (0.6g), δF-104.2, electron impact, m/z 212 (M + , 3.282), 197 (-CH 3 , 1002); 3,4-difluorobenzoic acid (3.4g), δF-128.7 and -136.5, electron impact, m/z 230 (M τ , 2.82), 215 (-Ch 3 , 1002); 2,4,5- trifluorobenzoic acid (0.6g), δF-108.2, -123.3 and -141.2, electron impact, m/z 248 (M + , 1.12), 233 (-CH 3 , 1002); 2,3,4-trifluorobenzoic acid (0.2g), δF-124.3, -128.7 and -158.6, electron impact, m/z 248 (M + , 2.32), 233 (-CH 3 , 93.92); 3, ,5-trifluorobenzoic acid (0.5g), δF-132.6 and -151.2, electron impact m/z 248 (M + , 1.3Z), 233 (-CH 3 , 100Z); 2,3,4,5-tetrafluorobenzoic acid (0.3g), δF-133.3, -137.9, -142.7 and -151.2, electron impact, m/z 266 (M + , 0.52), 251 (-CH 3 , 60.32) and unidentified material (0.3g).
Comparative Example A
Fluorination of 4-Fluorobenzoic Acid in Acetonitrile
« A solution containing 4-fluorobenzoic acid (1.6g, 11.3mmol) in acetonitrile (80cm 3 ) was placed in a fluorination apparatus fitted with a tube filled with soda lime. Fluorine gas (35mmol) as a 102 mixture in nitrogen was then passed through the stirred solution at
25°C using narrow bore PTFE tubing at ca 4.0cm 3 /min "1 . The mixture was added to an excess of water (500cm 3 ) followed by extraction with dichloromethane (3x25cm 3 ). After drying (MgS0 4 ), dichloromethane was removed under vacuum leaving brown solid (1.6g).
.Analysis of the solid by 19 Fnmr after preparing the silyl ester derivatives by reacting the product with bis trimethylsilyl acetamide against an external standard of fluorobenzene (0.2g, 3.9mmol) showed a conversion of 85Z from 4-fluorobenzoic acid. The product contained 4-fluorobenzoic acid, δF-104.4, electron impact, m/z 212 (M + ,
3.5Z), 197 (-CH 3 , 1002) and 3,4-difluorobenzoic acid, 662, δF -128.8 and -136.7, electron impact, m/z 230 (M + , 2.62), 215 (-CH 3 , 1002) in a ratio of 332 to 66Z and unidentified material.
Example 19
Fluorination of 4-Fluorobenzoic Ac:α in Formic Acid
A solution containing 4-fluorobenzoic acid (1.6g, 11.3mmol) in 98Z formic acid (80cm 3 ) was placed in a fluorination apparatus fitted with a tube filled with soda lime. Fluorine gas (35mmol) as a 10Z mixture in nitrogen was then passed through the stirred solution at 25°C using narrow bore PTFE tubing at ca 4.0cm 3 /min "1 . The mixture was added to an excess of water (500cm- 1 ) followed by extraction with dichloromethane (3x25cm 3 ). After drying (MgS0 ή ), dichloromethane was removed under vacuum leaving an off-white solid (0.7g).
Analysis of the solid by 19 Fnmr after preparing the silyl ester derivatives by reacting the product with bis trimethylsilyl acetamide against an external standard of fluorobenzene (0.2g, 3.9mmol) showed a conversion of 982 from 4-fluorobenzoic acid. The product contained 4-fluorobenzoic acid, δF -104.2, electron impact, m/z 212 (M + , 3.22), 197 (-CH 3 , 1002); 3, -difluorobenzoic acid, δF -128.7 and -136.5, electron impact, m/z 230 (M + , 2.42), 215 (-CH 3 , 1002) ; 2,4,5- trifluorobenzoic acid, δF -108.2, -123.4 and -141.3, electron impact, m/z 248 (M + , 1.22), 233 (-CH 3 , 1002); 2,3,4-trifluorobenzoic, δF -124.4, -128.7 and -158.7, electron impact, m/z 233 (-CH 3 , 5.12) and 3,4,5-trifluorobenzoic acid, δF -132.6 and -151.3, electron impact, m/z 248 (M + , 1.52), 233 (-CH 3 , 94.6Z) in a ratio of 82:732:82:42:72 and unidentified material.
Example 20
Fluorination of 4-Fluorobenzoic Acid in Sulphuric Acid (982)
A solution containing 4-fluorobenzoic acid (1.6g, 11.3mmol) in 982 sulphuric acid (80cm 3 ) was placed in a fluorination apparatus fitted with a tube filled with soda lime. Fluorine gas (35mmol) as a 102 mixture in nitrogen was then passed through the stirred solution at 25°C using narrow bore PTFE tubing at ca 4.0cm 3 /min _1 . The mixture was added to an excess of water (500cm 3 ) followed by extraction with dichloromethane (3x25cm 3 ). After drying (MgS0 4 ), dichloromethane was removed under vacuum leaving an off-white solid (1.3g).
Analysis of the solid by 19 Fnmr after preparing the silyl ester derivatives by reacting the product with bis trimethylsilyl acetamide against an external standard of fluorobenzene (0.2g, 2.3mmol)
showed a conversion of 972 from 4-fluorobenzoic acid. The product contained 4-fluorobenzoic acid, δF -104.2, electron impact, m/z 212 (M + , 3.32), 197 (-CH 3 , 1002); 2,4-difluorobenzoic acid, δF -97.6, -100.0; 3,4-difluorobenzoic acid, δF -128.7 and -136.5, electron impact, m/z 230 (M + , 2.82), 215 (-CH 3 , 1002) ; 2,4,5-trifluorobenzoic acid, δF -108.2, -123.3 and -141.2, electron impact, m/z 248 (M + , 1.12), 233 (-CH 3 , 1002); 2,3,4-trifluorobenzoic, δF -124.3, -128.7 and -158.6, electron impact, m/z 248 (-CH 3 , 2.32); 3,4,5- trifluorobenzoic acid, δF -132.6 and -151.2, electron impact, m/z 248 (M + , 1.32), 233 (-CH 3 , 1002); 2,3,4,5-tetrafluorobenzoic acid, δF -133.3, -137.9, -142.7 and -151.2, electron impact, m/z 266 (M + , 0.52), 251 (-CH 3 , 60.32); 2,3,4,5,6-pentafluorobenzoic acid, δF -136.9, -146.8 and -158.6, electron impact, m/z 269 (-CH 3 , 0.92) in a ratio of 6Z:2Z:61Z:92:6Z:9Z:6Z:1Z and unidentified material.
Example 21
Fluorination of 4-Fluorobenzoic Acid in Oleum (302. S0-.)
A solution containing 4-fluorobenzoic acid (1.6g, 11.3mmol) in 302 oleum (80cm 3 ) was placed in a fluorination apparatus fitted with
« a tube filled with soda lime. Fluorine gas (35mmol) as a 102 mixture in nitrogen was then passed through the stirred solution at 25°C using narrow bore PTFE tubing at ca 4.0cm 3 /min _1 . The mixture was added to an excess of water (500cm 3 ) followed by extraction with dichloromethane
(3x25cm 3 ). After drying (MgS0 ), dichloromethane was removed under vacuum leaving a white solid (1.3g).
Analysis of the solid by 19 Fnmr after preparing the silyl ester derivatives by reacting the product with bis trimethylsilyl acetamide against an external standard of fluorobenzene (0.4g, 4.6mmol) showed a conversion of 882 from 4-fluorobenzoic acid. The product contained 4-fluorobenzoic acid, δF -104.3, electron impact, m/z 212
(M + , 3.42), 197 (-CH 3 , 1002); 3,4-difluorobenzoic acid, δF -128.9 and
-136.5, electron impact, m/z 230 (M + , 2.62), 215 (-CH 3 , 1002); 2,4,5- trifluorobenzoic acid, δF -108.2, -123.3 and -141.2, electron impact, m/z 248 (M\ 1.32), 233 (-CH 3 , 100Z); 2,3,4-trifluorobenzoic, δF
-124.3, -128.7 and -158.6, electron impact, m/z 248 (-CH 3 , 2.52), 233
(-CH 3 , 93.22); 3, ,5-trifluorobenzoic acid, δF -132.7 and -151.5, electron impact, m/z 248 (M + , 1.2Z), 233 (-CH 3 , 94.3Z); 2,3,4,5-
tetrafluorobenzoic acid, δF -133.3, -137.9, -142.7 and -151.2, electron impact, m/z 251 (-CH 3 , 60.32); 2,3, 4 ,5,6-pentafluorobenzoic acid, δF -136.9, -146.8 and -158.6 in a ratio of 242:552:52:4Z:8Z :3 :IZ and unidentified material.
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