Chlorodifluoroacetic acid

Difluoroacetic acid undergoes reactions typical of a carboxylic acid such as forming an ester when heated with an alcohol and sulfuric acid. Typical esters are methyl difluoroacetate [433-53-4], bp, 85.2°C, and ethyl difluoroacetate [454-31-9], bp, 99.2°C. It can also be photochemicaHy chlorinated to chlorodifluoroacetic acid [76-04-0] or brominated in the presence of iron to bromodifluoroacetic acid [667-27-6] (37,38). 

The discussion of acylation reactions in this chapter is focused on fluonnated carboxylic acid derivatives and their use to build up new fluorine-containing molecules of a general preparative interest Fifteen years ago, fluonnated carboxylic acids and their derivatives were used mainly for technical applications [/] Since then, an ever growing interest for selectively fluonnated molecules for biological applications [2, 3, 4, 5] has challenged many chemists to use bulk chemicals such as tnfluoroacetic acid and chlorodifluoroacetic acid as starting materials for the solution of the inherent synthetic problems [d, 7,, 9]... 

Sodium chlorodifluoroacetate is prepared from chlorodi-fluoroacetic acid (K K Laboratories) as follows To a cooled, stirred solution of 60.7 g. (1.52 moles) of sodium hydroxide in 700 ml. of methanol is slowly added a solution of 198 g. (1.52 moles) of chlorodifluoroacetic acid in 300 ml. of methanol, the temperature being kept below 40°. The methanol is removed under reduced pressure at 40°. The salt, which is pulverized and dried overnight at room temperature at 1 mm., is obtained in essentially quantitative yield. The salt is again dried in the same way immediately before use. 

Acids that are used in addition to trifluoroacetic acid include trifluoroacetic acid with added sulfuric acid203 or boron trifluoride etherate,210,211 perfluorobu-tyric acid,212 hydrogen chloride/aluminum chloride,136,146,213 perchloric acid in chloroform,214 p-loluenesull onic acid alone134 or with aluminum bromide or aluminum chloride,192 concentrated sulfuric acid in two-phase systems with dichloromethane, alcohol, or ether solvents,209,215 trifluoromethanesulfonic acid,216 chlorodifluoroacetic acid,134 and the monohydrate of boron trifluoride... 

Chlorodi-rec-butylphosphinc, 48, 50 Chlorodi-f-butylphosphine, 48, 50 Chlorodicyclohexylphosphine, 48, SO Chlorodifluoroacetic acid, 48, 118 Chlorodiisobutylphosphine, 48, 50... 

Esters of chlorodifluoroacetic acids, like the esters of monofluoroacetic acid, can acylate anions (e.g., organometallic derivatives, enolates, lithiated sulfones). They lead to chlorodifluoromethylketones and to S-ketosulfones and jS-ketoesters which have the —CFj motif (Figure 2.16). ... 

Grignard addition to chlorodifluoroacetic acid constitutes the classic method for the synthesis of chlorodifluoromethyl ketones. A recent example [181] was... 

The generation of difluorocarbene has been the subject of intense investigation. Difluorocarbene has been successfully formed from a wide range of fluorinated precursors, including metal salts of chlorodifluoroacetic acid, methyl chlorodifluoroacetate, ethyl chlorodi-fluoroacetate, difluorodiiodomethane, " chlorodifluoromethane." " difiuorotris(trifluoro-methyl)-A -phosphane hexafluoropropylene oxide,tetrafluoroethylene... 

Alkali metal salts of chlorodifluoroacetic acid decarboxylate generating difluorocarbene (carbenoid) which undergoes addition to alkenes to give 1,1-difluorocyclopropanes (Houben-Weyl, Vol. E19b, pp 1476-1478). 

The difluorocarbene thus generated does not undergo addition to alkenes of low reactivity. The highly hygroscopic salts of chlorodifluoroacetic acid must also be thoroughly dried before use. Finally, a very large excess of the carbene source is often required to achieve good yields of the products. 

Slagel12 reports that the lithium salt of chlorodifluoroacetic acid is superior to the sodium salt for generation of difluorocarbene and difluoromethylenetriphenylphos-phorane. Thus the yield of 4,5-dicarbethoxy-l,l-difluoronorcarane from the lithium salt was 50.6% and from the sodium salt was 25.7%. 

Taylor and McKillop5 have also found that the thallous salts of trichloroacetic acid and chlorodifluoroacetic acid decompose in the presence of olefins to give di-... 

A solution of chlorodifluoroacetaldehydc (1.67g, 14.6 mmol) derived from chlorodifluoroacetic acid in... 

TOF-SIMS spectra of poly(l,3-butylene adipate) treated with chlorodifluoroacetic acid. (A) Mass range 750-1700 Da. (B) Theoretical patterns for species containing 2,3, and 4 chlorines. (Reprinted with permission from Ref. 47, Copyright 1994 American Chemical Society) (Continued)... 

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