Difluoroacetic Acid: Environmental Behavior & C-H Difluoromethylation

Difluoroacetic acid is an important intermediate within the class of fluorinated organic carboxylic acids. This substance exists as a colourless, transparent liquid at ambient temperature, exhibiting strong corrosive and irritant properties. With a boiling point of 133°C, it readily dissolves in polar and non-polar solvents such as water, ethanol, and diethyl ether. Its acidity surpasses that of acetic acid and monofluoroacetic acid. The structure combining a carboxyl group with a difluoromethyl group confers both the reactivity of carboxylic acids and the distinctive properties of fluorinated alkyl groups. Its core applications span pharmaceuticals, pesticides, and materials synthesis. It serves as a key precursor for fluorinated drugs and fluorinated herbicides, while also functioning as a fluorinating agent and carboxylating reagent in organic synthesis. It finds extensive use in the development of fluorinated fine chemicals.

Difluoroacetic Acid in Chlorofluorocarbon-Contaminated Ground Water

Trifluoroacetic acid (TFA) is very stable in the environment with an estimated half-life of several hundreds of years and is found worldwide in oceans and water bodies, though no accumulation in biota has been observed. A total TFA release of 20,650,000 metric tons by 2050 to the global environment via abiotic breakdown of refrigerants containing a trifluoromethyl moiety has been estimated. In addition, a natural oceanic source for TFA has been suggested on the basis of concentration patterns. Little is known about the origin and behavior of environmental difluoroacetic acid (DFA) and its natural source has not been identified to the best of our knowledge. Significant DFA levels were found in the Detroit river and the urban atmosphere. The limited literature on DFA formation suggests reductive defluorination of TFA to DFA and further to monofluoroacetic acid under certain anaerobic conditions. The relevance of DFA formation during the pyrolysis of fluoropolymers as a source for environmental DFA levels is unclear, and the formation of Difluoroacetic acid by the oxidative metabolization of compounds such as the pesticide flupyradifurone containing the difluoromethyl moiety appears negligible compared to currently observed environmental DFA concentrations.A survey of short-chain fluorocarboxylic acids in urban aqueous environments revealed compartment-depending differing levels and ratios of TFA and DFA. In the following, this observation is outlined and discussed regarding the potential origin of Difluoroacetic acid in ground water with historic chlorofluorocarbon (CFC) contamination.[1]

Assuming a depuration effect by the first rainfall after a longer dry period, the TFA concentration decreased in the consecutive rainfall. This TFA concentration range resembled the average concentration levels observed in the USA. The TFA:DFA ratio of about 10:1 in both rainwater samples correlates well with the airborne TFA:DFA ratio reported for urban areas in Ontario, Canada. Both surface waters contain considerable TFA levels, but notably no detectable Difluoroacetic acid. Similar observations were made along the Detroit river, where TFA levels always exceeded DFA levels, which were partly not detectable. The TFA concentration levels at the investigated ground water sites are similar to those of surface water. The local geology displays a low permeability of barrier layers and hydrodynamic flow direction from the canal towards the ground water site. This, and the absence of CFCs containing the CF3-group in the ground water as a potential source for TFA, suggest a surface water origin of the TFA in the ground water. The atmospheric origin of Difluoroacetic acid found in the rainwater has to remain an open question. As significant volatilization of TFA and DFA from water bodies can be excluded due to their physicochemical characteristics, the possible options are atmospheric oxidation of some difluoromethyl compounds or reductive defluorination of TFA that has not been observed in the atmosphere so far. To the best of our knowledge, this is the first evidence for a relevant formation pathway of Difluoroacetic acid in the environment.

Difluoroacetic Acid as a New Reagent for Direct C−H Difluoromethylation

The presumption that the difluoromethyl group is a hydrophobic hydrogen donor being a bioisoster of hydroxy, amino and sulfanyl groups has inspired studies of the effect of replacing these groups with difluoromethyl moieties. However, these studies have been hampered by the limited number of synthetic routes available for the introduction of the CF2H into heteroaromatic compounds. Herein, we report the direct and innate C−H functionalization and mono-selective introduction of one difluoromethyl moiety into heteroaromatic compounds using difluoroacetic acid as the difluoromethyl radical source. The methodology furthermore offers for the first time the opportunity to introduce two difluoromethyl moieties in a controllable manner by varying the reaction conditions. As part of a ongoing project on the design and synthesis of fusaric acid analogues, we recently applied the Minisci reaction to introduce alkyl groups to the pyridine ring via a well-established radical process. To our delight, in the presence of difluoroacetic acid, a difluoromethylated derivative was obtained by a silver(I)-catalyzed reaction. This exciting discovery encouraged us to develop and optimize a new protocol for difluoromethylation of heteroaromatic rings using off-the-shelf difluoroacetic acid and to further investigate the scope and limitations of this novel reaction.[2]

In conclusion, we have discovered that difluoroacetic acid can be used as a new reagent for innate C−H difluoromethylation of heteroaromatic compounds. The procedure presented is technically simple, scalable, inexpensive, controllable and a direct C−H activation synthetic methodology for preparation of both mono- and bis-difluoromethylated derivatives of N-containing heteroaromatics. Remarkably, the present protocol employs the easily accessible and off-the-shelf difluoroacetic acid as starting material. Furthermore, the late-stage one-step access to bis-difluoromethylated products is novel and has enabled synthesis of several compounds, which were not available using previously reported reaction conditions. Since the protocol makes a broad number of difluoromethylated derivatives of heteroaromatic compounds available, this report enables preparation of previous inaccessible tool compounds for biological assays and predictably important lead structures for drug discovery. Intensive studies on the mechanism as well as expanding the scope of this reaction are currently being performed in our lab.

References

[1]Dorgerloh U, Becker R, Kaiser M. Evidence for the Formation of Difluoroacetic Acid in Chlorofluorocarbon-Contaminated Ground Water. Molecules. 2019 Mar 15;24(6):1039. doi: 10.3390/molecules24061039. PMID: 30875997; PMCID: PMC6471106.

[2]Tung, Truong Thanh et al. “Difluoroacetic Acid as a New Reagent for Direct C-H Difluoromethylation of Heteroaromatic Compounds.” Chemistry (Weinheim an der Bergstrasse, Germany) vol. 23,72 (2017): 18125-18128. doi:10.1002/chem.201704261

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