Process for the preparation of phenyl ketones

A process for the preparation of phenyl ketones, characterized in that, in a first stage, a halo- or trihalomethylbenzene is reacted with a trihalomethylated aliphatic or aromatic compound in the presence of boron trifluoride in an amount such that the absolute pressure of boron trifluoride within the reaction vessel exceeds 1 bar, and in the presence of hydrofluoric acid as a solvent, and in that, in a second stage, the resultant product is hydrolyzed. The products are used as intermediates in the synthesis of compounds having a pharmaceutical or phytosanitary (e.g., herbicidal) activity.

The instant invention is directed to a process for the preparation of 
phenyl ketones from halo- or trihalomethylbenzenes and trihalomethylated 
aliphatic or aromatic compounds. 
Processes for the preparation of phenyl ketones are already known in the 
art. For example, in Friedel-Crafts and Related Reactions III, Part II, 
Interscience Publishers (1964), G. Olah describes the reaction of a 
trihalomethylated aliphatic or aromatic derivative with a halo- or 
trihalomethylbenzene in the presence of catalysts such as AlCl.sub.3, 
AlBr.sub.3, FeCl.sub.3 and SbCl.sub.5 in an organic solvent medium; in 
this process, the substrate can also be the solvent. The resultant product 
is then hydrolyzed to obtain the desired ketone. 
These processes have drawbacks which can be attributed above all to the 
nature of the catalyst. It is necessary to use a substantial quantity of 
catalyst, because the catalyst forms a complex with the trihalomethyl 
group of the aromatic or aliphatic compound and with the product resulting 
from the first stage. The large quantity of, e.g., AlCl.sub.3 employed 
requires a correspondingly large amount of water for its elimination. 
Moreover, its recovery on an industrial scale is impossible. 
A process has now been developed which palliates the drawbacks of the prior 
art processes. 
This invention is directed to a process for the preparation of phenyl 
ketones characterized in that, in a first stage, a halo- or 
trihalomethylbenzene is reacted with a trihalomethylated aliphatic or 
aromatic compound in the presence of boron trifluoride in an amount such 
that the absolute pressure of boron trifluoride within the reaction vessel 
exceeds 1 bar, and in the presence of hydrofluoric acid as a solvent, and 
in that, in a second stage, the resultant product is hydrolyzed. 
For purposes of this invention, the terms halobenzene or 
trihalomethylbenzene refer both to these compounds themselves and to their 
analogues with one or more substituents on the benzene nucleus. 
More particularly, the invention is directed to the reaction of compounds 
of the formula: 
##STR1## 
wherein n is 0 or 1; X.sub.1, X.sub.2 and X.sub.3 are identical or 
different and represent chlorine, bromine, iodine or fluorine; and R.sub.1 
represents at least one element or moiety selected from hydrogen, OH, Cl, 
Br, I, F, alkyl and alkoxy radicals having from 1 to 6 carbon atoms, and 
phenyl and phenoxy radicals substituted by at least one group more 
deactivating than the C.sub.n X.sub.1 (X.sub.2).sub.n (X.sub.3).sub.n 
group. 
The phenyl and phenoxy radicals R.sub.1 must be substituted by groups that 
are more deactivating than the C.sub.n X.sub.1 (X.sub.2).sub.n 
(X.sub.3).sub.n group so that the acylation reaction takes place on the 
benzene nucleus carrying the C.sub.n X.sub.1 (X.sub.2).sub.n 
(X.sub.3).sub.n group. Otherwise, the acylation reaction would take place 
on the phenyl or phenoxy radical. Examples of groups that are more 
deactivating than the C.sub.n X.sub.1 (X.sub.2).sub.n (X.sub.3).sub.n 
group include NO.sub.2, COOH, CN and keto groups. 
When n=1, compounds of the formula I in which X.sub.1, X.sub.2 and X.sub.3 
are identical are preferred. Among the latter, those compounds in which 
X.sub.1, X.sub.2 and X.sub.3 represent fluorine are particularly 
preferred. 
The following are examples of compounds of the formula I: chlorobenzene; 
fluorobenzene; bromobenzene; iodobenzene; trifluoromethylbenzene; 
difluorobromomethylbenzene; trichloromethylbenzene; 
dichlorofluoromethylbenzene; tribromomethylbenzene; 
dibromofluoromethylbenzene; triodomethylbenzene; o-, m- and 
p-fluorotoluene; o-, m- and p-dichlorobenzene; o-, m- and p-fluorophenol; 
o-, m- and p-fluorochlorobenzene; o-, m- and p-fluoroanisole; o-, m- and 
p-difluorobenzene; o-, m- and p-chlorotoluene; o-, m- and p-chloroanisole; 
4-trifluoromethyl-4'-chlorobiphenyl; and 
4-trifluoromethyl-2,4'-dichlorodiphenyl oxide. 
Within the scope of the instant invention, the terms trihalomethylated 
aliphatic or aromatic compound refer to a compound of the formula: 
EQU R.sub.2 CX.sub.4 X.sub.5 X.sub.6 (II) 
wherein R.sub.2 represents an aliphatic or aromatic radical and X.sub.4, 
X.sub.5, and X.sub.6 are identical or different and represent Br, Cl or F. 
Particularly well suited for use according to the invention are compounds 
of the Formula II in which R.sub.2 represents an alkyl, phenyl, 
alkylphenyl or phenylalkyl radical or a phenyl radical bearing at least 
one substituent, such as, for example, halogen, NO.sub.2, CN, NH.sub.2 or 
COOH. 
Examples of such compounds of Formula II include 1,1,1-trichloroethane, 
trichloromethylbenzene, trifluoromethylbenzene, 
parafluorotrichloromethylbenzene, parachlorotrifluoromethylbenzene, 
parachlorotrichloromethylbenzene, orthochlorotrichlormethylbenzene, 
metanitrotrichloromethylbenzene and 3,4-dichlorotrichloromethylbenzene. 
The first stage of the process according to the invention is preferably 
carried out by using a quantity of hydrofluoric acid such that the molar 
ratio of hydrofluoric acid to the halo- or trihalomethylbenzene is between 
5 and 50. Even more preferably, this ratio is between 10 and 30. 
The hydrofluoric acid utilized is preferably anhydrous. The use of aqueous 
hydrofluoric acid would result in a useless consumption of boron 
trifluoride in the form of a complex of HF, BF.sub.3 and H.sub.2 O 
(H.sub.3 O.sup.+ BF.sub.4.sup.-). 
The halo- or trihalomethylbenzene and the compound of Formula II are used 
in substantially equimolar amounts. An excess of the compound of Formula 
II may, however, be desirable in order to minimize the formation of 
polycondensation compounds. 
It is particularly preferred to use a quantity of boron trifluoride such 
that the initial absolute pressure of BF.sub.3 in the reaction vessel is 
between 6 and 20 bars. A pressure in excess of 20 bars is not excluded 
from the scope of the invention but does not offer any particular 
advantage. The more the pressure is increased, the higher the reaction 
velocity. The pressure will therefore be adjusted to maximize the 
efficiency of the process. If a trichloromethylated compound of Formula I 
or II is employed, an increase in pressure attributable to Cl-F exchange 
is observed. 
The first stage of the process of the invention is preferably carried out 
at a temperature between -20.degree. C. and 150.degree. C. The reaction 
times are generally between a few minutes and several hours. The second 
stage is a hydrolysis that can be performed in an acid or basic medium as 
is conventional in the art. 
A practical method for carrying out the process according to the invention 
is to effect the hydrolysis on the raw mixture or a mixture partially 
freed from HF solvent generated in the first stage. The reaction will be 
carried out in the presence of HF and, therefore, in an acid medium. 
Complete elimination of HF prior to the second stage makes it possible to 
operate in either a basic or acid medium. The hydrolysis is preferably 
carried out at a temperature between 0.degree. C. and 80.degree. C. 
The process according to the invention can be schematically illustrated as 
follows: 
##STR2## 
The CCl.sub.3, CBr.sub.3, CI.sub.3, CF.sub.2 Br, CCl.sub.2 F, CBr.sub.2 F, 
etc., groups are converted into CF.sub.3 during the reaction in an HF 
medium, while the Cl, Br and I substituents are not affected. 
The position of the COR.sub.2 group with respect to the CF.sub.3, X.sub.1 
and R.sub.1 groups is in conformity with the substitution rules well known 
to the organic chemist. 
The phenyl ketones obtained according to the process of the invention are 
useful as intermediates in the synthesis of compounds having a 
pharmaceutical or phytosanitary (e.g., herbicidal) activity. 
The following are examples of compounds that can be prepared by the process 
according to the invention: 4-fluoroacetophenone; 4-chloroacetophenone; 
2-fluoro-5-methylbenzophenone; 3-fluoro-6-methylbenzophenone; 
2,4-dichlorobenzophenone; 2,4'-dichlorobenzophenone; 
4-chloro-4'-bromobenzophenone; 4-fluoro-4'-bromobenzophenone; 
4,4'-difluorobenzophenone; 4-trifluoromethyl-4'-fluorobenzophenone; 
4,4'-difluoro-3-methylbenzophenone; 4,4'-difluoro-3-methoxybenzophenone; 
2-fluoro-2'-chloro-5-methylbenzophenone; 
3-fluoro-2'-chloro-6-methylbenzophenone; 
2-fluoro-4'-chloro-5-methylbenzophenone; 
3-fluoro-4'-chloro-6-methylbenzophenone; 
4-fluoro-4'-chloro-3-methylbenzophenone; 
2-trifluoromethyl-2'-fluoro-5-methylbenzophenone; and 
2-trifluoromethyl-3'-fluoro-6'-methylbenzophenone. 
In order to disclose more clearly the nature of the present invention, the 
following drawings and examples illustrating specific embodiments of the 
invention are given. It should be understood, however, that this is done 
solely by way of example and is intended neither to delineate the scope of 
the invention nor limit the ambit of the appended claims.

EXAMPLE 1 
Into a 250 ml stainless steel reactor equipped with a magnetic stirrer 
system, 100 ml of anhydrous HF, 42.7 g (0.2 mole) of 
p-fluorotrichloromethylbenzene, and 22 g (0.2 mole) of orthofluorotoluene 
were introduced at about 0.degree. C. The reactor was closed, after which 
gaseous boron trifluoride was introduced until a constant pressure of 6 
bars was achieved. The reaction was then allowed to proceed with stirring 
at ambient temperature for 3 hours. After reaction, the reactor was 
decompressed to atmospheric pressure, and the reaction mixture poured over 
200 g of crushed ice. Following warming up to ambient temperature, the 
heterogeneous mixture was stirred for one to two hours, then extracted 
three times with 200 ml of methylene chloride. The organic phases were 
washed three times with 200 ml of water, once with 200 ml of an aqueous 3% 
potassium hydroxide solution, and twice with 200 ml of water. The organic 
phase was dried over magnesium sulfate and the solvent eliminated by 
distillation under reduced pressure. 35.3 g (yield: 61.5%) of raw 
4,4'-difluoro-3-methylbenzophenone was recovered. 
EXAMPLE 2 
The reaction was carried out as in Example 1 with the following compounds 
and under the following conditions: 
______________________________________ 
Anhydrous hydrofluoric acid 
100 g 
Trichloromethylbenzene 
19.6 g (0.1 mole) 
Fluorobenzene 9.6 g (0.1 mole) 
Boron trifluoride 6 bars at 20.degree. C. 
Temperature 50.degree. C. 
Duration 4 hours 
______________________________________ 
18.5 g (yield: 92.5% of raw 4-fluorobenzophenone was recovered. 
EXAMPLE 3 
The reaction was carried out as in Example 1 with the following compounds 
and under the following conditions: 
______________________________________ 
Anhydrous hydrofluoric acid 
100 g 
p-chlorotrifluoromethylbenzene 
18 g (0.1 mole) 
Chlorobenzene 11.2 g (0.1 mole) 
Boron trifluoride 6 bars at 20.degree. C. 
Temperature 80.degree. C. 
Duration 15 hours 
______________________________________ 
21 g (yield: 89.4%) of a mixture of raw 2,4'-dichloro- and 
4,4'-dichlorobenzophenone was recovered. 
EXAMPLE 4 
The reaction was carried out as in Example 1 with the following compounds 
and under the following conditions: 
______________________________________ 
Anhydrous hydrofluoric acid 
100 g 
p-chlorotrichloromethylbenzene 
23 g (0.1 mole) 
Chlorobenzene 11.2 g (0.1 mole) 
Boron trifluoride 9 bars at 20.degree. C. 
Temperature 80.degree. C. 
Duration 18 hours 
______________________________________ 
20.2 g (yield: 86%) of a mixture of raw 2,4'-dichloro- and 
4,4'-dichlorobenzophenone was recovered. 
EXAMPLE 5 
The reaction was carried out as in Example 1 with the following compounds 
and under the following conditions: 
______________________________________ 
Anhydrous hydrofluoric acid 
100 g 
p-fluorotrichloromethylbenzene 
21.4 g (0.1 mole) 
Fluorobenzene 9.6 g (0.1 mole) 
Boron trifluoride 10 bars at 20.degree. C. 
Temperature 100.degree. C. 
Duration 8 hours 
______________________________________ 
19.2 g (yield: 88%) of a mixture of raw 4,4'-difluoro- and 
2,4'-difluorobenzophenone was recovered. 
EXAMPLE 6 
The reaction was carried out as in Example 1 with the following compounds 
and under the following conditions: 
______________________________________ 
Anhydrous hydrofluoric acid 
100 g 
Trifluoromethylbenzene 
29.2 g (0.2 mole) 
Bromobenzene 31.4 g (0.2 mole) 
Boron trifluoride 10 bars at 20.degree. C. 
Temperature 50.degree. C. 
Duration 4 hours 
______________________________________ 
49 g (yield: 93.8%) of raw 4-bromobenzophenone was recovered. 
EXAMPLE 7 
The reaction was carried out as in Example 1 with the following compounds 
and under the following conditions: 
______________________________________ 
Anhydrous hydrofluoric acid 
100 g 
Trifluoromethylbenzene 
14.6 g (0.1 mole) 
o-dichlorobenzene 22 g (0.15 mole) 
Boron trifluoride 10 bars at 20.degree. C. 
Temperature 60.degree. C. 
Duration 4 hours 
______________________________________ 
24.9 g (yield: 99.2%) of a mixture of raw 2,3-dichloro- and 
3,4-dichlorobenzophenone was recovered. 
EXAMPLE 8 
The reaction was carried out as in Example 1 with the following compounds 
and under the following conditions: 
______________________________________ 
Anhydrous hydrofluoric acid 
100 g 
Trifluoromethylbenzene 
29.2 g (0.2 mole) 
Boron trifluoride 10 bars at 20.degree. C. 
Temperature 80.degree. C. 
Duration 6 hours 
______________________________________ 
27 g (yield: 54%) of raw 3-trifluoromethylbenzophenone was recovered. 
EXAMPLE 9 
The reaction was carried out as in Example 1 with the following compounds 
and under the following conditions: 
______________________________________ 
Anhydrous hydrofluoric acid 
100 g 
1,1,1-trichloroethane 
27 g (0.2 mole) 
Orthodichlorobenzene 14.7 g (0.1 mole) 
Boron trifluoride 6 bars at 20.degree. C. 
Temperature 80.degree. C. 
Duration 24 hours 
______________________________________ 
8.2 g (yield: 43%) of a mixture of raw 2,3-dichloro- and 
3,4-dichloroacetophenone was collected. 
The terms and expressions which have been employed are used as terms of 
description and not of limitation, and there is no intention in the use of 
such terms and expressions of excluding any equivalents of the features 
shown and described or portions thereof, but it is recognized that various 
modifications are possible within the scope of the invention claimed.