Difluoroacetic acid

Difluoroethanol is prepared by the mercuric oxide cataly2ed hydrolysis of 2-bromo-l,l-difluoroethane with carboxyHc acid esters and alkaH metal hydroxides ia water (27). Its chemical reactions are similar to those of most alcohols. It can be oxidi2ed to difluoroacetic acid [381-73-7] (28) it forms alkoxides with alkaH and alkaline-earth metals (29) with alkoxides of other alcohols it forms mixed ethers such as 2,2-difluoroethyl methyl ether [461-57-4], bp 47°C, or 2,2-difluoroethyl ethyl ether [82907-09-3], bp 66°C (29). 2,2-Difluoroethyl difluoromethyl ether [32778-16-8], made from the alcohol and chlorodifluoromethane ia aqueous base, has been iavestigated as an inhalation anesthetic (30,31) as have several ethers made by addition of the alcohol to various fluoroalkenes (32,33). Methacrylate esters of the alcohol are useful as a sheathing material for polymers ia optical appHcations (34). The alcohol has also been reported to be useful as a working fluid ia heat pumps (35). The alcohol is available ia research quantities for ca 6/g (1992). 

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). 

Difluoroacetic acid is much less toxic than fluoroacetic acid (LD q = 180 mg/kg mouse iv) (41). It is available in research quantities for about 5/g... 

To bracket the N1 site of thymine, we will use dichloroacetic acid (Hjcid = 328.4 kcal/mol), difluoroacetic acid (331.0), hydrochloric acid (333.3), pyruvic acid (333.5), 2-bromo-butyric acid (336.8), 2-chloropropionic acid (337.0), and trifluoro-m-cresol (339.3). These acids have acidities in the range that should allow us to bracket the acidity... 

Difluoroacetic acid and its derivatives (esters, aldehyde) are excellent reagents for introducing a difluoromethyl group. However, because they are expensive, they are used relatively infrequently. Their reactivity is close to that of trifluoroacetic derivatives. ... 

A convenient synthesis of difluoroacetic acid (21) is found in first converting the amide 19 to the difluoro derivative 20 by potassium fluoride in ethylene glycol at 180,JC followed by hydrolysis.53... 

Difluoroacetic acid (21), which is useful as an intermediate for agrochemicals and pharmaceuticals has been manufactured by an analogous process as described by substituting the chlorine atoms in 7V,N-diethyldichloroacetamide (22) with fluorine by heating with potassium fluoride in ethylene glycol at 150 °C followed by hydrolysis of the N, A-diethyldifluoroacetamide (23).54... 

Tetrafluoroethene has been used as a 2-carbon difluoroacetic acid equivalent, methodology developed by Normanl and co-workers, in the synthesis of inhibitors of Cobra venom phospholipase A2.13 Conversion of the allyl alcohols into the 2,2-difluoropent-4-enoic acids 32 is performed in one pot. The crude acids 32 are then converted into the methyl esters 33. Although esters 33 can be obtained directly from the acyl fluorides 29, as originally described by Normant and co-workers,10 a two-step procedure facilitates the workup after the Claisen rearrangement. 

CHF2COOH (liq.). Swarts4 (see Kharasch1) measured the heat of combustion of difluoroacetic acid. 

Diferrocenylpentanoyl chloride, 3853 Difluoroacetic acid, 0698 Difluoroacetylene, see Difluoroethyne, 0619b Difluoroacetyl hypochlorite, 0649 (Difluoroamino)difluoroacetonitrile, 0626 2-(Difluoroamino)-2,2-dinitroacetamide, 0697 2-(Difluoroamino)-2,2-dinitroacetonitrile, 0620... 

Dibromo-l,3-dimethylcyclopropanoic acid, 2357 /V,/V-Dich Iorogl ycine, 0735 Difluoroacetic acid, 0698 Dihydroxymaleic acid, 1443... 

A series of 2-trifluoromethyl and 2-difluoromethyl substituted benzothiazoles 30 has been synthesized by a one-pot reaction of trifluoroacetic acid and difluoroacetic acid, respectively, with 2-aminobenzenethiol <07TL3251 >. The reaction pathway presumably involves the imidolyl chloride intermediate 29, which undergoes intramolecular nucleophilic substitution by neighbouring thiol under basic conditions to give benzothiazole 30. 

Fluorosulfonyl-2,2-difluoroacetic acid can be obtained from Aldrich Chemical Co., Inc., Oakwood... 

A 3.5-4 fold excess of chlorotrimethylsilane is required for full conversion of the 2-fluorosulfonyl-2,2-difluoroacetic acid. Residual acid can be difficult to separate from the ester. 

---