Preparation of fluoronitrobenzene compounds in dispersion of potassium fluoride

An improved process is disclosed for preparing fluoronitrobenzene compounds wherein chloronitrobenzene compounds are reacted with potassium fluoride in a solvent dispersion thereof prepared from a mixture including the solvent, the fluoride, methanol and an aromatic compound.

BACKGROUND OF THE INVENTION 
The present invention relates to an improved process for preparing 
fluoronitrobenzene compounds wherein chloronitrobenzene compounds are 
reacted with potassium fluoride in a solvent dispersion thereof prepared 
from a mixture including the solvent, the fluoride, methanol and an 
aromatic compound. 
Fluoronitrobenzene compounds such as 2-fluoronitrobenzene, 
4-fluoronitrobenzene, and 2,4-difluoronitrobenzene, are useful as 
intermediates for the synthesis of various herbicidal compounds, dyes, and 
the like. Such compounds have been prepared from corresponding 
chloronitrobenzene compounds by so-called halogen exchange reactions, 
illustrated as follows: 
##STR1## 
wherein MF represents an alkali metal fluoride salt. The reaction is 
generally conducted in an aprotic, polar, organic solvent, such as 
dimethylsulfoxide, dimethylformamide, tetramethylenesulfone (sulfolane), 
and the like. 
Alkali metal fluoride salts are not soluble in such solvents. Therefore, 
the reaction mixtures usually contain two phases, i.e., solid and liquid 
phases or two immiscible liquid phases. Finger, et al., J. Am. Chem Soc., 
78, 6034 (1956) and Duesel, et al., U.S. Pat. No. 3,064,058 (1962), 
describe the reaction of chloronitrobenzene compounds with finely-divided, 
solid potassium fluoride in aprotic polar solvents to produce 
corresponding fluoronitrobenzene compounds. Boudakian, et al., U.S. Pat. 
No. 3,240,824 (1966), describe the reaction of o-chloronitrobenzene with 
solid potassium fluoride at elevated temperatures, without any solvent or 
diluents, to produce o-fluoronitrobenzene. Napier and Starks, U.S. Pat. 
No. 3,992,432 (1976), describe a reaction involving two liquid phases. In 
the Napier and Starks reaction, the inorganic fluoride salt is dissolved 
in an aqueous phase, and the chloronitrobenzene compound is dissolved in a 
water-immiscible, organic phase. The reaction is catalyzed by a quaternary 
salt, which reportedly transfers ions across the phase interface. 
Use of quaternary salt phase-transfer catalysts in solid-liquid, two phase 
reactions also has been known. For instance, Kunz, U.S. Pat. No. 4,069,262 
(1978), describes the production of 2-fluoronitrobenzene by reacting 
2-chloronitrobenzene with ultrafine particulate potassium fluoride in 
tetramethylenesulfone solvent using a macrocyclic ether (crown ether) or a 
quaternary ammonium halide (such as tetrabutylammonium chloride, 
benzyltrimethylammonium chloride, benzyltrimethylammonium fluoride or 
benzyltriethylammonium chloride) as the catalyst. 
Tull, et al., U.S. Pat. No. 4,140,719 ( 1979), describes the production of 
2,4-difluoro-5-chloronitrobenzene by reacting 2,4,5-trichloronitrobenzene 
with a solid fluorinating agent selected from NaF, KF, CsF, and C.sub.1-4 
alkyl quaternary ammonium fluoride, and mixtures thereof under 
substantially anhydrous conditions in the presence of a quaternary 
compound solid-liquid phase transfer catalyst. The liquid phase comprises 
an organic solvent in which the trichloro compound is soluble and the 
fluorinating agent is essentially insoluble. 
Starks, "Selecting a Phase Transfer Catalyst," Chemtech (February 1980), 
pages 110-117, describes patterns that purportedly enable prediction of 
catalysts for anion transfer from aqueous or solid inorganic phases to 
organic phases. 
North, U.S. Pat. No. 4,287,374 (1981) discloses a process for the 
production of a monofluoronitrobenzene in which a monochloronitrobenzene 
is heated with an alkali metal fluoride and a phase transfer catalyst at a 
temperature of no more than 200.degree. C., preferably 
125.degree.-170.degree. C., especially 140.degree.-150.degree. C. North 
discloses, as examples of such catalysts which may be used, long chain 
alkylammonium halides. 
In general, halide-exchange reactions for preparing fluoronitrobenzene 
compounds by reacting chloronitrobenzene compounds with fluoride salts in 
aprotic, polar organic solvents in the presence of quaternary ammonium 
salt phase-transfer catalysts proceed at faster rates when conducted at 
elevated temperature relative to rates obtainable at lower temperature. 
However, quaternary ammonium phase-transfer catalysts employed in 
heretofore known methods are less stable at higher temperature and have 
been found to decompose or lose their catalytic activity at elevated 
reaction temperatures. Moreover, U.S. Pat. No. 4,418,229 (to White), 
incorporated herein by reference, discloses that lower molecular weight 
catalysts, i.e., those having a total number of carbon atoms less than 
about 16, are less stable under the conditions (including elevated 
temperature) of the method of the invention disclosed therein than the 
therein preferred catalysts of higher molecular weight having about 16 or 
more carbon atoms. 
The above cited White patent discloses the finding that in the conversion 
of chloronitrobenzene compounds to corresponding fluoronitrobenzene 
compounds using a quaternary ammonium salt phase-transfer catalyst at 
elevated temperatures, a high level of catalytic activity can be 
maintained by adding the catalyst to the reaction mixture incrementally 
during the course of the reaction. 
However, there remains a substantial need in the art for new and improved 
processes for preparing fluoronitrobenzenes. The present invention 
substantially fufills such need. 
DESCRIPTION OF THE INVENTION 
Generally stated, the present invention provides an improved process for 
preparing a fluoronitrobenzene compound by reaction of a corresponding 
chloronitrobenzene compound with potassium fluoride in an aprotic polar 
organic solvent under substantially anhydrous halide-exchange conditions 
in the presence of a catalyzing amount of a phase-transfer catalyst. 
The improvement comprises effecting the reaction in a substantially 
anhydrous dispersion of ultra-fine particulate potassium fluoride in an 
aprotic polar organic solvent, said dispersion prepared by a method 
comprising 
(a) preparing a solution of potassium fluoride in methanol, 
(b) preparing a mixture by adding to said solution (i) an aromatic compound 
selected from aromatic hydrocarbons, aromatic chlorohydrocarbons and 
aromatic fluorohydrocarbons, said aromatic compound being an azeotrope 
former with methanol, and (ii) an aprotic polar solvent having a boiling 
point at a selected pressure at least 30.degree. C. higher than the 
boiling point at said pressure of said aromatic compound, 
(c) distilling said mixture at said pressure to prepare a distillation 
residue consisting essentially of said dispersion. 
DETAILED DESCRIPTION OF THE INVENTION AND OF THE MANNER AND PROCESS OF 
MAKING AND USING IT 
Suitable aromatic compounds include for example toluene, benzene, xylene, 
isopropyl benzene, chlorobenzene and fluorobenzene. Toluene is preferred. 
Suitable aprotic polar solvents include for example sulfolane, 
N-methylpyrrolidone, dimethyl formamide and dimethylsulfoxide. Sulfolane 
is preferred. 
Per gram of crude potassium fluoride there can be used for example about 
0.5 to about 0.6 ml of methanol (preferably about 0.55 ml), about 2 to 
about 3 grams of the aprotic polar solvent (preferably about 2 grams of 
sulfolane) and about 40 to about 60 ml of the aromatic compound 
(preferably about 50 ml of toluene). 
The aromatic compound preferably is a compound which also forms an 
azeotrope with water, thereby resulting in removal by the distillation 
step of water which may be present in the potassium fluoride. Toluene and 
the other aromatic compounds set forth above each from azeotropes with 
water. 
Although the solution and mixture can be prepared at any suitable 
temperature, 20.degree.-25.degree. C. is preferred. The solution and 
mixture are prepared by adding together the respective indicated 
ingredients with stirring. 
Methanol and the aromatic compound (and water if present) are then removed 
from the resulting mixture in the distillation step. 
Distillation is effected at a temperature and pressure effective for 
removing the methanol and aromatic compound from the mixture. It is 
critical that the aprotic polar solvent have a boiling point at the 
distillation pressure (e.g. 760mm Hg) at least 30.degree. C. higher than 
the boiling point at such pressure of the aromatic compound in order to 
effect removal of substantially all the aromatic compound and methanol by 
simple distillation. 
The preferred combination of toluene as the aromatic compound and sulfolane 
as the aprotic polar solvents satisfies this boiling point differential at 
all pressures up to at least 30 psi. 
Distillation is preferably continued until substantially all the methanol, 
aromatic compound and water (if present) are removed. The distillation 
pressure is preferably atomspheric or subatmospheric. 
Potassium fluoride, which is insoluble in the aprotic polar organic 
solvent, is precipitated by the distillation step, resulting in formation 
of the dispersion of substantially anhydrous ultra-fine particulate 
potassium fluoride in the solvent. 
The reaction mixture for the above reaction of chloronitrobenzenes (CNB) 
with the fluoride can be effected by adding the desired CNB and phase 
transfer catalyst (PTC) to the dispersion, preferably in the order given 
and with stirring. The PTC can be any PTC which catalyzes the reaction, 
such as quaternary ammonium or phosphonium salts having known catalytic 
utility therefor. 
The halide-exchange conditions generally include elevated reaction 
temperatures, which are high enough to provide sufficient energy of 
activation for the reaction. Although such reaction temperatures might 
cause some catalyst inactivation, the temperature is preferably not so 
high as to cause rapid decay of catalytic activity or substantial 
decompostion of the reactants, the products, or the solvent. Although the 
reaction temperature may vary, depending upon the particular catalyst, 
solvent, and reactants used, generally it may be, for example, from about 
120.degree. C. to about 220.degree. C., preferably from about 160.degree. 
C. to about 215.degree. C., and more preferably from about 205.degree. C. 
to about 215.degree. C. 
Those skilled in the art will appreciate that a variety of equipment and 
techniques may be utilized in the method of the present invention, and the 
invention is not limited to any particular equipment or technique. The 
method is generally conducted by charging the reactants, solvent and PYR 
salt catalyst into a reaction vessel which is equipped with agitating and 
heating means. Advantageously, the entire amount of the reactants, solvent 
and PTC salt catalyst to be employed can be added initially. The reaction 
vessel may also advantageously include a reflux condenser or other means 
of recovering solvent vapors and means for blanketing the reaction mixture 
with a dry inert gas, e.g., nitrogen. The reaction mixture is heated to 
the desired reaction temperature and agitated. 
The halide-exchange reaction conditions employed in the present invention 
advantageously include substantially anhydrous reaction conditions. The 
presence of water in the reaction can diminish yields and result in 
undesirable by-products. Various techniques may be used for dehydrating 
the reactants and solvent, such as vacuum drying, azeotropic distillation, 
chemical drying and the like. Azeotropic distillation, for example with 
benzene, can be used for drying all of the reactants and solvents; 
however, any convenient and operable technique may be employed. Due to the 
deleterious effect of water, the reaction mixture is preferably 
substantially devoid of water. Small amounts of water may be tolerated; 
however, a corresponding reduction in yield is generally experienced. 
Advantageously, the concentration of water in the reaction mixture is 
below about 5 wt. % and is preferably below about 1 wt. %, based on the 
weight of the reaction mixture. 
The solvent for the catalyst, chloronitrobenzene compound, and 
fluoronitrobenzene compound is an aprotic, polar, organic solvent, which 
preferably has a relatively high boiling point, e.g., a boiling point 
above about 190.degree. C. Lower boiling solvents may be used; however, 
pressure reactors may be required for their containment. Solvents having 
boiling points below a desired reaction temperature may be employed by 
conducting the reaction under superatmospheric pressure in such reactors. 
Examples of reaction solvents include dimethylsulfoxide, sulfolane, 
bis(2-methoxyethyl)ether, bis 2-(2-methoxyethoxy) ethyl ether, 
hexamethylphosphoramide, N-methylpyrolidinone, and dimethylformamide. 
Dimethylformamide and sulfolane are preferred solvents. Sulfolane is most 
preferred from the standpoint of commercial attractiveness. 
The phase-transfer catalyst employed in the present method is soluble in 
the reaction solvent in an amount sufficient to catalyze the reaction. The 
PTC salt may be employed in any catalyzing amount, i.e., in any amount 
effective for catalyzing the conversion of the chloronitrobenzene compound 
to the corresponding fluoronitrobenzene compound. In general, the amount 
may correspond, for example, to a molar ratio of PTC salt to 
chloronitrobenzene compound of from about 0.005:1 to about 0.5:1, 
preferably from about 0.04:1 to about 0.15:1, most preferably about 
0.08:1. In general, amounts of PTC salt corresponding to molar ratios of 
less than about 0.005:1 may not provide sufficient catalytic activity, 
while amounts corresponding to molar ratios of more than 0.5:1 may result 
in insufficient additional benefit to justify the additional cost. As 
indicated above, the entire amount of PTC salt to be used is preferably 
added initially. However, if desired, a portion may be added initially 
with incremental addition of the remainder during the course of the 
reaction. Incremental addition may be, for example, substantially in 
accordance with the invention disclosed in the above-cited White patent. 
The fluoride ion is provided by an alkali metal fluoride salt which is 
generally present in an amount at least substantially stoichiometric to 
the chloronitrobenzene reactant. Preferred fluoride salts are potassium 
fluoride, rubidium fluoride, and cesium fluoride, and potassium fluoride 
is particularly preferred. The fluoride salt is advantageously 
finely-divided, to provide a greater superficial surface area which is 
accessible to the catalyst and the chloronitrobenzene compound. Preferred 
concentrations of the fluoride salt range from about 1 to about 2 times 
the stoichiometric amount, most preferably from about 1.2 to about 1.6 
times such amount. For example, in a method for producing a 
monofluoronitrobenzene compound, a preferred molar ratio of fluoride salt 
to chloronitrobenzene compound is about 1.5:1. Lower concentrations of 
fluoride salts can result in diminished reaction rates, and, although 
higher concentrations can be used, no appreciable benefit is generally 
realized therefrom. In the chloronitrobenzene compound used as a starting 
material in the present invention, the relative positions of the nitro and 
chloro substituents, and the presence of other substituents on the ring 
can affect the reactivity of the starting compound. Generally, halogen 
exchange reactions involve compounds in which the chloride is in the ortho 
or para position with respect to the nitro group, and reactivity may 
increase when other electron-withdrawing groups are present on the ring. 
Compounds having chloro substituents in the meta as well as ortho and/or 
para positions may be used as starting materials, but usually only the 
chloro groups in the ortho and para positions will undergo halogen 
exchange. Accordingly, the method of this invention may be used for 
example for the synthesis of compounds such as 2-fluoronitrobenzene, 
2-fluoro-3-chloronitrobenzene, 4-fluoronitrobenzene, 
2,4-difluoronitrobenzene, 5-chloro-2,4-difluoronitrobenzene, and the like, 
from corresponding chloronitrobenzene compounds. The present method is 
particularly useful for the preparation of 4-fluoronitrobenzene from 
4-chloronitrobenzene and 2-fluoronitrobenzene from 2-chloronitrobenzene. 
The reaction is generally allowed to proceed until substantially all the 
chloronitrobenzene compound has been converted to the corresponding 
fluoronitrobenzene compound. A reaction time of from about 10 minutes to 
about 20 hours may typically be used, and the reaction will often be 
substantially complete after about 1 to about 6 hours. After the reaction 
is completed, the product can be recovered by any suitable procedure, such 
as extraction, distillation, steam distillation and the like. For some 
purposes, the purity of the crude reaction product, recovered as an 
organic phase after addition of water to the reaction mixture, will be 
satisfactory. 
The method of this invention has been found to produce fluoronitrobenzene 
compounds in good yields with little formation of by-products.

Practice of this invention is further illustrated by the following 
non-limiting examples. All parts, percents and other amounts throughout 
this disclosure are by weight unless otherwise indicated. 
The N-(2-ethylhexyl)-4-(N',N'-dimethylamino)pyridinium chloride salt 
employed in the following examples can be prepared in accordance with the 
procedure described by Brunelle in U.S. Pat. No. 4,460,778, incorporated 
herein by reference. As described therein, a mixture of 12.217 grams of 
dimethylaminopyridine, 20.833 grams of 2-ethylhexylmethane sulfonate was 
stirred and heated at 110.degree. C. for 1 hour. There was added to the 
resulting mixture 25 grams of toluene and the solution was refluxed for an 
additional hour. Toluene was then removed from the mixture under reduced 
pressure and the resulting crude mesylate salts were washed with hexane. 
The mesylate salts were then dissolved in the methylene chloride and 
washed twice with a saturated sodium chloride solution. Methylene chloride 
was then removed under reduced pressure from the resulting product. There 
was obtained 31.728 grams of a product having a melting point of 
189.degree.-190.degree. C. Based on method of preparation, the product was 
N-2-ethylhexyldimethylaminopyridine chloride (EHDMAPC). 
EXAMPLE 
To a 250-ml reaction vessel equipped with a stirrer, thermometer and reflux 
condenser were added 27.5 grams of commercially available potassium 
fluoride containing approximately 1 to 5% water and 50 ml of methanol. The 
resulting mixture was refluxed for one half hour, thereby dissolving the 
potassium fluoride in methanol. To the resulting solution at about 
64.degree. to 67.degree. C. was added with stirring 55.2 grams of 
sulfolane, followed by adding 50 ml of toluene with stirring. Next, 
substantially all the toluene and methanol were removed by distillation at 
atmospheric pressure and 64.degree.-110.degree. C., followed by heating at 
160.degree. C. under subatmospheric pressure (approx. 200 mm Hg absolute 
pressure). There was obtained a dispersion of finely divided particulate 
potassium fluoride in sulfolane, which was judged to be substantially free 
of water (i.e. not containing more than about 0.5% water based on the 
weight of the potassium fluoride). 
The dispersion was cooled to 100.degree. C. (for additional safety in 
making the following additions). Then p-chloronitrobenzene (50.3 grams, 
0.319 mole) was added, followed by adding 
N-2-ethylhexyl-4-(N',N'-dimethylamino)pyridinium chloride (0.6 gram, 
0.0022 mole). The resulting reaction mixture was heated to 
210.degree.-215.degree. C. While maintaining the reaction mixture at such 
temperature and with stirring, the progress of the reaction was followed 
by sampling the reaction mixture from time to time. Each sample was 
analyzed by high pressure liquid chromatography (HPLC) using a Waters 
Bondapak.TM. C18 reverse phase column, a 2-microliter sample loop, a UV 
detector at 254 nanometers and a dual pump. The solvent system was a 1:1 
mixture of the flows from pump A (1:1 methanol:water) and pump B 
(methanol). The combined flow rate was 1.5 microliters per minute. For 
each sample, the peak area of the resulting fluoronitrobenzene was 
measured using a digital integrator. Results are shown below: 
______________________________________ 
AREA PERCENT OF 
TIME, HOURS 4-FLUORONITROBENZENE 
______________________________________ 
1.0 45.4 
4.0 87.9 
5.0 92.7 
______________________________________ 
At the end of 5 hours or more, the resulting para-fluoronitrobenzene 
product can be recovered in approximately 85% or more yield by 
discontinuing heating and removing the product as distillate by simple 
distillation under increasingly lower pressure (to about 100 mm Hg 
absolute), while heating as necessary to maintain an acceptable 
distillation rate (e.g. at a temperature of the mixture of approximately 
135.degree.-150.degree. C. 
Experience has shown that under the same conditions except that the above 
treatment of the potassium fluoride is omitted, as best a 50% conversion 
of p-chloronitrobenzene to p-fluoronitrobenzene is obtainable. 
BEST MODE CONTEMPLATED 
The best mode contemplated for carrying out this invention has been set 
forth in the above description, for example, by way of setting forth 
preferred materials and operating conditions, including but not limited to 
preferred ranges and values of amounts and other non-obvious variables 
material to successfully practicing the invention in the best way 
contemplated at the time of executing this patent application. 
It is understood that the foregoing detailed description is given merely by 
way of illustration and that many modifications may be made therein 
without departing from the spirit or scope of the present invention.