Process of converting a carboxylic acid or carboxylic acid halide group to a trihalomethyl group

Carboxylic acid or carboxylic acid halide groups on aryl or heterocyclic aryl rings are directly converted to trihalomethyl groups by using a phenylhalophosphorane, optionally generated in situ by reaction of a phenylphosphonous halide and chlorine.

BACKGROUND OF THE PRESENT INVENTION 
1. Field of the Present Invention 
The present invention relates to a method for converting a carboxylic acid 
or carboxylic acid halide group to a trihalomethyl group. 
2. Description of the Prior Art 
U.S. Pat. No. 4,419,514, McKendry, teaches that carboxylic acid groups on 
aryl or heteroaryl rings can be converted to trichloromethyl groups if 
contacted with a mixture of phenylphosphonic dichloride (C.sub.6 H.sub.5 
P(O)Cl.sub.2) and phosphorus pentachloride. 
DESCRIPTION OF RELATED DEVELOPMENT 
More recently, U.S. Pat. No. 4,634,771, Shim et al., proposed a similar 
conversion by using a mixture of phenylphosphonous dichloride (C.sub.6 
H.sub.5 PCl.sub.2), phosphorus trichloride and chlorine. This particular 
process was found by the present inventor to give a good yield of crude 
product. However, when attempts were made to distill the crude reaction 
product obtained using the Shim et al. procedure, a reddish residue 
remained in the distillation vessel which produced a lower than 
anticipated yield of the desired end product. Apparently, the reaction 
mixture obtained by Shim et al. contained undesired by-products that had 
not been fully characterized by those investigators, which precluded the 
obtaining of the desired level of yield of final product when the reaction 
product mixture was distilled. 
SUMMARY OF THE PRESENT INVENTION 
The present invention is an improvement in the Shim et al. procedure which 
results in yields of distilled product from the reaction product mixture 
which are higher than obtainable using the Shim et al. process. The 
present process relies upon the use of a phenylhalophosphorane 
chlorinating agent to convert a carboxylic acid or carboxylic acid halide 
group on an aryl or heterocyclic aromatic ring to a trihalomethyl group. 
If desired, the phenylhalophosphorane chlorinating agent can be generated 
in situ by use of a phenylphosphonous chlorinating agent 
(phenylphosphonous dihalide and halogen). No addition of phosphorus 
trihalide is used in the present process.

DETAILED DESCRIPTION OF THE PRESENT INVENTION 
The present invention is directed to conversion of one or more carboxylic 
acid or carboxylic acid halide groups on an aryl or heterocyclic aromatic 
ring to a trihalomethyl group or groups. Representative heterocyclic 
compounds are based on N-heteroaromatic structures, such as pyridine ring 
compounds. The carboxylic acid or carboxylic acid halide moiety can 
include one or two such groups in non-sterically hindered ring positions 
(e.g., in non-adjacent positions.) If desired, the carboxylic starting 
compounds can be additionally substituted with sterically compatible, 
non-interfering substituents such as halogen (chloro, fluoro), nitro, 
cyano, alkyl, alkoxy, aryl, alkyl-substituted aryl, alkoxy-substituted 
aryl, aryloxy, and/or trihalomethyl. 
The chlorinating agent of the present invention is a 
phenylchlorophosphorane chlorinating agent, preferably C.sub.6 H.sub.5 
PCl.sub.4. In its broadest context, the phenylchlorophosphorane 
chlorinating agent used herein includes those phenylchlorophosphorane 
compounds having a sufficient number of chloro groups (e.g., from 2-4) to 
achieve the desired chlorination reaction. The molar ratio of this 
chlorinating agent to carboxylic acid starting material may range from 
about 2:1 to about 3:1. The reaction is conducted at temperatures of from 
about 110.degree. C. to about 180.degree. C. in a solvent medium of 
phenylphosphonic dichloride. The phosphorane chlorinating agent can have 
its ring substituted with electron withdrawing groups such as fluoro, 
nitro and the like. 
If desired, the phenylchlorophosphorane chlorinating agent of the present 
invention can be generated in situ by reaction of a phenylphosphonous 
halide and chlorine. 
The product of such reaction, between a carboxylic acid group and a 
phenylchlorophosphorane chlorinating agent, is a trichloromethyl group. 
In accordance with another aspect of this invention, trihalomethyl groups 
can be obtained by conversion of a carboxylic acid halide group with a 
phenylchlorophosphorane chlorinating agent. The carboxylic acid halide 
compound may be used as the starting material in this process or it may be 
obtained by conversion of a carboxylic acid group with a suitable 
chlorinating agent, e.g., phosgene, thionyl halides, etc., as known. The 
resulting acid halide, when reacted with a suitable amount of phosphorane 
chlorinating agent (e.g., in a molar ratio of about 1:1 to 3:1) results in 
the desired trihalomethyl groups by conversion of the carbonyl linkage 
between the ring and the acid halide atom. If desired, the phosphorane 
chlorinating agent can be generated in situ by reaction of chlorine and 
phenylphosphonous halide as earlier described. 
Reaction of a phenylchlorophosphorane chlorinating agent with a carboxylic 
acid chloride produces a trichloromethyl group. In another embodiment of 
this invention, a mixed halogen trihalomethyl group, e.g., a 
dichlorohalomethyl group in which the third halogen is other than chloro, 
can be obtained. This is performed by reacting a phenylchlorophosphorane 
chlorinating agent with an acid halide group in which the halogen is other 
than chloro; i.e., with an acid bromide or fluoride. Acid halides of this 
type may be obtained by conventional means, for instance, reacting the 
corresponding carboxylic acid chloride with hydrogen fluoride, producing 
the carboxylic acid fluoride. The carboxylic acid halide (nonchloride 
type) can be reacted with the phenylchlorophosphorane under the previously 
described conditions to produce a dichlorohalo (e.g., 
dichlorofluoro)methyl group. 
For example, 6-hydroxynicotinic acid can be reacted with thionyl chloride 
in the conventional manner, producing 6-chloronicotinic acid chloride. 
This can then be reacted with hydrogen fluoride, producing 
6-chloronicotinic acid fluoride, which can be then reacted with a 
phenylchlorophosphorane as described above to produce 
2'-chloro-5-dichlorofluoromethylpyridine. 
The present invention is further illustrated by the examples which follow. 
EXAMPLE 1 
Nicotinic acid [225 grams (g), 1.83 moles]was added in one portion to a 
solution of phenylphosphonic dichloride [600 milliliters (ml)]and 
phenylphosphonous dichloride (655 g, 3.66 moles) in a 3-liter, 4-necked, 
round-bottom flask fitted with an overhead stirrer, reflux condenser, 
thermocouple, and gas inlet tube. Chlorine gas (260 g, 3.66 moles) was 
metered into the reaction mixture below the surface of the solution. The 
chlorine was added at the rate of about 4.5 g per minute. The 
phenylphosphonous dichloride and chlorine react to form 
phenyltetrachlorophosphorane in situ. An ice bath was placed on the 
reaction setup to keep the temperature below 90.degree. C. After all the 
chlorine was added, the milky white slurry was heated to 170.degree. C. 
for 4 hours. During this time the solution became a clear dark red. The 
stirrer was stopped, and the reaction mixture was allowed to cool and 
stand at room temperature under a nitrogen atmosphere. 
The reaction mixture from the preceding step was a solid orange mass of 
crystals after standing at room temperature over a weekend. The 
thermocouple was removed and the solids were broken up into a fine slurry 
by mechanical stirring. Hexane (500 ml) was added to aid in breaking up 
the slurry. The mixture was stirred at room temperature for 30 minutes. 
The solid product was filtered out through a sintered glass filter and was 
dried in a vacuum desiccator. The product (407.6 g) was the hydrochloride 
salt of 3-trichloromethylpyridine and was a light yellow-orange solid. The 
yield was calculated as 96%. 
The filtrate containing the phenylphosphonic dichloride and the hexane was 
distilled. The hexane was removed at 460 mm Hg giving a head temeprature 
of about 50.degree.-55.degree. C. The vacuum was then lowered to 6 mm/Hg 
giving a phenylphosphonic dichloride boiling at 110.degree.-119.degree. C. 
A total of 1526 g of phenylphosphonic dichloride was recovered. The 
calculated amount of phenylphosphonic dichloride present was 1538.5 g, 
giving a recovery of 99%. 
EXAMPLE 2 
The phenylphosphonic dichloride recovered in Example 1 (400 ml) was mixed 
with 875 g (4.89 moles) of phenylphosphonous dichloride in a 3-liter, 
4-necked flask fitted with an overhead stirrer, condenser, thermocouple, 
and chlorine inlet tube. To this solution nicotonic acid (300 g, 2.44 
moles) was added in one portion. The temperature in the reactor pot rose 
about 10.degree. to about 35.degree. C. during this addition. An ice bath 
was placed around the reactor flask, and chlorine (347 g, 4.89 moles) was 
added just below the surface of the slurry at the rate of 4 g per minute. 
The reaction mixture was a white slurry that was noticeably thicker after 
the first 30 minutes of chlorine addition. The temperature continued to 
climb and the slurry thinned out a little. The reactor reached a 
temperature of about 68.degree.-70.degree. C. when about one-half of the 
chlorine was added (about 50 minutes into the chlorine addition). 
Thereafter, the temperature began falling to about 50.degree.- 55.degree. 
C. The ice bath was lowered and the temperature began to slowly climb. The 
last 30 g of chlorine was added at a rate slower than 4 g per minute in 
order to have it absorbed by the reaction mixture. After all the chlorine 
had been added, the heating mantle was placed on the flask, and the 
reaction mixture was slowly heated to 140.degree. C. over a period of 
about 1.5 hours. The slurry continued to thin out during this time. The 
reaction mixture became a clear light orange color aftr 1 hour at 
140.degree. C. The mixture was heated with stirring for another 1.5 hours. 
The heating mantle was removed and the reaction mixture allowed to cool to 
70.degree. C. A water bath was placed on the reaction, and the mixture was 
cooled to 55.degree. C. Seed crystals were added and as soon as crylstals 
started forming, 250 ml of hexane was added. The slurry was allowed to 
cool without the water bath with stirring overnight. 
The room temperature reaction slurry was then poured in one portion into a 
3000 ml, coarse sintered glass funnel. The phenylphosphonic dichloride and 
and hexanes were removed by vacuum filtration. The product was slurried 
with 500 ml of hexane in a filter funnel and this hexane portion was 
removed by vacuum filtration. The off-white product was dried in a vacuum 
desiccator. Approximately 444.1 g of materials was obtained after drying, 
giving a crude yield of 78%. The product was the hydrochloride salt of 
3-trichloromethylpyridine. 
Sodium carbonate (70 g, 0.66 mole) was added slowly to 200 g (0.86 mole) of 
the above-described pyridinium salt dissolved in 500 ml of water and 200 
ml of methylene chloride. After carbon dioxide evolution stopped, the 
slurry was filtered to remove any solid nicotinic acid, and the water 
layer was separated with a separatory funnel. The methylene chloride layer 
was dried using magnesium sulfate and the resulting material was rotary 
concentrated giving 137.4 g of a clear yellow liquid product (81% yield) 
which was judged to be 98% pure by VPC analysis. 
EXAMPLE 3 
This example shows another procedure wherein the pyridinium salt was 
reacted with sodium carbonate to form the desired product. 
The hydrochloride salt of 3-trichloromethylpyridine (650 g, 2.79 moles) was 
mixed with 650 ml of methylene chloride and 600 ml of water. To this 
slurry was slowly added 230 g of sodium carbonate (2.17 moles) dissolved 
in 1000 ml of water. The mixture was rapidly stirred during the addition 
and much carbon dioxide was evolved. The mixture was transferred to a 
large separatory funnel and the organic layer was removed. This layer was 
washed once with water and dried using magnesium sulfate. The solvent was 
removed by rotary concentration. Vacuum distillation at 
78.degree.-80.degree. C. and 0.5 mm Hg gave 430.5 g of the desired 
3-trichloromethylpyridine product (79% yield). 
EXAMPLE 4 
Phenylphosphonic dichloride (1600 ml) and phenylphosphonous dichloride 
(3500 g, 19.55 moles) were mixed in a 12-liter, 4-necked flask fitted with 
a reflux condenser, nitrogen atomsphere inlet, overhead stirrer, 
thermocouple, and chlorine inlet tube. The flask was in an ice bath. 
Nicotinic acid (1200 g, 9.76 moles) was added in one portion with stirring 
and a small temperature increase of about 10.degree. C. was observed. 
Chlorine (1388 g, 19.55 moles) was then added through a tube immersed 
below the surface of the solution at the rate of about 4 g per minute. 
After addition of the chlorine, the reaction mixture was allowed to stand 
at room temperature overnight. 
The reaction mixture was then heated with stirring to 130.degree. C. and 
was maintained at that temperature for about 5 hours. The heating mantle 
was removed, and the reaction was allowed to cool to 55.degree. C. Seed 
crystals of product (the hydrochloride salt of 3-trichloromethylpyridine) 
were added along with 2000 ml of hexane. The pyridinium salt product 
crystallized, and the resulting slurry was cooled to room temperature. The 
product was filtered and washed with hexane. The product was placed in a 
large filter flask which was attached to a vacuum line to remove any 
residual hexanes from the product. The weight of vacuum dried product was 
2076 g for a yield of 91%. 
EXAMPLE 5 
The 3-trichloromethylpyridinium hydrochloride salt (2836 g, 12.17 moles) 
was placed in a 22-liter pot with 2800 ml of methylene chloride and 2600 
ml of water. A solution of 1000 g of sodium carbonate in 4300 ml of water 
was then added slowly so that the gassing could be controlled. The 
temperature was maintained with an ice bath between 15.degree.-20.degree. 
C. The lower organic phase was then separated and was dried with magnesium 
sulfate. The mixture was filtered and the methylene chloride was removed 
by rotary evaporation. The concentrated material was distilled at 
77.degree.-79.degree. C. and 0.5 mm Hg giving 1918 g of the desired 
3-trichloromethylpyridine product. The yield was 80%. 
EXAMPLE 6 
This example illustrates the use of this invention to produce a mixed 
halogen trihalomethyl group from a carboxylic acid halide. 
(a) A solution of thionyl chloride (149 g, 1.25 moles) and a catalytic 
amount of N,N-dimethylformamide (1 g, 0.14 mole) were placed in a 500 ml 
4-neck flask fitted with an overhead stirrer, reflux condenser, 
thermometer and solids additional funnel. This solution was heated with 
stirring to 60.degree. C. and the solid 6-hydroxynicotinic acid (69.5 g, 
0.5 mole) was added portionwise from the solids addition funnel. After the 
addition was complete, the reaction mixture was heated to 85.degree. C. 
over a two hour period. At this point, gas evolution had nearly stopped, 
and the reaction mixture was cooled under a nitrogen atmosphere. The 
reaction mixture was then transferred to a still pot, and the excess 
thionyl chloride was distilled at atmospheric pressure. The residue was 
vacuum distilled giving 88.2 g of 6-chloronicotinic acid chloride (b.p.: 
68.degree.-71.degree. C./0.5 mmHg) as an oil that solidified upon 
standing. The yield was 86%. 
(b) The following reaction was conducted under a nitrogen atmosphere. The 
off gases from the reaction were vented to a caustic scrubber. 
6-Chloronicotinic acid chloride (65.7 g, 0.37 mole) from step (a) was 
placed in a 125 ml Teflon.RTM. fluorocarbon polymerlined flask fitted with 
an ice water cooled Teflon.RTM. polymer-lined condenser and a magnetic 
stirrer. Anhydrous hydrogen fluoride (14 g, 0.70 mole) was condensed into 
the reaction flask through the condenser. The reaction mixture was warmed 
with a water bath, and the contents of the flask liquified with the 
evolution of hydrogen chloride. The condenser was removed when the 
evolution of hydrogen chloride ceased. The reaction mixture was warmed to 
a temperature of 100.degree. C., and the excess hydrogen fluoride was 
vented to the scrubber. The reaction product solidified upon cooling. The 
only material present (by vapor phase chromatography (VPC) analysis) was 
6-chloronictonic acid fluoride. 
(c) 6-Chloronicotinic acid fluoride (60 g, 0.38 mole) from step (b) was 
melted and added in one portion to a 500 ml, 4-neck flask containing 
phenylphosphonic dichloride (70 ml). The reaction flask was fitted with an 
overhead stirrer, thermometer and reflux condenser. The reaction was 
carried out under a nitrogen atmosphere. Phenylphosphonous dichloride (69 
g, 0.39 mole) was then added to the reaction mixture. The flask was fitted 
with a gas inlet tube, and chloride gas (28 g, 0.39 mole) was bubbled into 
the stirred reaction mixture. The chlorine was added at the rate of 1 
g/minute. The temperature of the reaction was kept below 35.degree. C. 
with an ice bath during the chlorine addition. The ice bath was replaced 
with a heating mantle when the chlorine addition was complete, and the 
reaction was heated to a temperature of 130.degree. C. overnight. The 
reaction mixture was cooled and was analyzed. The reaction was found to be 
6% unreacted starting material along the 25% 
2-chloro-5-trichloromethylpyridine, 32% 
2-chloro-5-dichlorofluoromethylpyridine (the desired product) and 37% 
6-chloronicotinic acid chloride. 
EXAMPLE 7 
This example illustrates the use of this invention to produce 
2-chloro,5-trichloromethylpyridine. 
In a flask were mixed 6-chloronicotinic acid (30 g, 0.19 mole), 
phenylphosphonous dichloride (69 g, 0.39 mole), and phenylphosphonic 
dichloride (70 ml). The mixture was stirred while chlorine (28 g, 0.39 
mole) was bubbled in at 2 g/min. The temperature rose to 90.degree. C. and 
was maintained during chlorine addition at 90.degree.-100.degree. C. using 
an ice bath. After the chlorine addition was complete the mixture was then 
heated and maintained at 130.degree.-140.degree. C. for 4 hours. VPC 
analysis indicated the presence of some starting material; heating was 
then continued for an additional 18 hours at 150.degree. C. Attempts to 
vacuum distill off the phenylphosphonic dichloride resulted in 
codistillation of this compound and the reaction product. 
The distilled reaction mixture was slowly added to diulte hydrochloric 
acid. The temperature rose to 80.degree. C.; ice was then added until the 
solution was at a temperature of 25.degree. C. Then, portions of sodium 
carbonate were added until the solution was basic. It was then extracted 
with methylene chloride; the combined extracts were washed with water, 
dried over magnesium sulfate and evaporated. The last traces of methylene 
chloride were removed by a vacuum pump. There was obtained 20 g of a white 
solid, melting point 47.degree.-49.degree. C., which was identified as the 
desired product by NMR spectroscopy. 
The foregoing examples should not be construed in a limiting sense since 
they are only intended to be illustrative of certain embodiments of the 
claimed invention. The scope of protection that is claimed is set forth in 
the claims which follow.