Fluoroacetate properties

Fluoroacetic acid [144-49-OJ, FCH2COOH, is noted for its high, toxicity to animals, including humans. It is sold in the form of its sodium salt as a rodenticide and general mammalian pest control agent. The acid has mp, 33°C bp, 165°C heat of combustion, —715.8 kJ/mol( —171.08 kcal/mol) (1) enthalpy of vaporization, 83.89 kJ /mol (20.05 kcal/mol) (2). Some thermodynamic and transport properties of its aqueous solutions have been pubHshed (3), as has the molecular stmcture of the acid as deterrnined by microwave spectroscopy (4). Although first prepared in 1896 (5), its unusual toxicity was not pubhshed until 50 years later (6). The acid is the toxic constituent of a South African plant Dichapetalum i mosum better known as gifirlaar (7). At least 24 other poisonous plant species are known to contain it (8). 

The above reaction is rather remarkable in view of the un-leactivity of the fluorine atom in fluorobromoethane towards many reagents. In order to establish the identity of sesqui-fluoro-H , it was synthesized by an alternative unambiguous method (p. 130). Sesqui-fluoro-H is a mobile liquid, devoid of vesicant properties and non-toxic. The lack of toxicity is understandable since the animal body is probably unable to rupture this C—S link, and hence the compound cannot easily give rise to fluoroacetic acid. 

The group Cl CH2 CH2 N< occurs in the nitrogen mustards which are powerful vesicants, e.g. CH3,N(CH2,CH2C1)2. It was decided therefore to introduce this group into the fluoroacetamide molecule in the hope of combining vesicant properties with the delayed convulsant action of the fluoroacetates. For this purpose N-2 hydroxyethylfluoroacetamide (IV) was prepared by the action of monoethanolamine on methyl fluoroacetate and was readily converted into N-2-chloroethylfluoroacetamide (V) by the action of thionyl chloride ... 

Fluoroethyl fluoroacetate was found to possess rather enhanced toxic properties. The l.c. 50 by inhalation for rabbits was 0-05 mg./l. This shows that it is about twice as toxic (weight for weight) as fluoroethanol or methyl fluoroacetate. This seems to indicate that the toxicity of 2-fluoroethyl fluoroacetate cannot be due entirely to that of its hydrolysis products according to the equation... 

From a study of the fluoroacetates so far mentioned, it appears that any compound which can give rise to fluoroacetic acid (or the fluoroacetate ion), either by hydrolysis or by oxidation (or both), is toxic. The toxic grouping is thus F-CH2-CO, and any substitution in this radical destroys the toxicity as far as relatively simple compounds are concerned. We had reached this conclusion by May 1943.1 We subsequently showed that esters of / -fluoropropionic acid were non-toxic, whereas esters of y-fluorobutyric acid were shown by American workers to be toxic. In 19442 we reported the synthesis of ethyl 5-fluoro-pentanecarboxylate, F,[CH2]g C02Et (I). This is a stable, colourless liquid and we showed that it possessed very potent toxic properties of the fluoroacetate type. By subcutaneous injection of the propylene glycol solution into mice the l.d. 50 was 4 mg./kg. Methyl fluoroacetate (II) may be taken as a convenient standard (p. 115) and has a l.d. 50 of about 6 mg./kg. for saline solutions, and 15 mg./kg. for propylene glycol solution.3 Therefore ethyl 5-fluoropentanecarboxylate was about 7 times as toxic as methyl fluoroacetate (molecule for molecule).4... 

We see from the above that there is a striking alternation in the physiological properties of w-fluorocarboxylic esters of the general formula of F- [CH2]w-C02.R. Thus when n is an odd number the compound is highly toxic to animals, whereas when n is even the compound is non-toxic. All the toxic compounds are powerful convulsant poisons and showed symptoms of the fluoroacetate type. 

Chemically they are extremely inert, being much more un-reactive even than the fluoroacetates. The inertness of the fluorocarbons and their nearly perfect physical properties arise from the strength of the F—C linkage and from their compact structure. The effective atomic radius of covalently bound fluorine is 0-64 A., which although greater than hydrogen (0-30) is smaller than other elements, e.g. Cl 0-99 A., Br 1-14 A. 

Lagowski, J. J., Ed., The Chemistry of Non-Aqueous Solvents, Academic, New York. This series contains detailed accounts of the purification, properties, and handling of some major solvents Vol. 2(1967), hydrogen halides, amides, and ammonia Vol. 3(1970), sulfur dioxide and acetic acid Vol. 4 (1976), tetramethylurea, cyclic carbonates, and sulfolane Vol. 5A (1978), tri-fluoroacetic acid, hafosuffuric acids, interhalogens, inorganic halides and oxyhalides. 

Elucidation of the mechanism of toxicity of fluoroacetate in living organisms led to increased interest into the preparation and properties of a-fluoroesters. More recently, the use of fluorine substituted esters as analytical probes and diagnostic tools in metabolic processes has added to their stature as important compounds in biochemistry(7). In addition, a-fluoroesters have served as useful building blocks to more complex and interesting biological substrates. 

The amide of fluoroacetate, fluoroacetamide (4) is a rodenticide with similar properties (Chapman and Phillips, 1955). Its toxicity to mammals is somewhat lower than that of sodium fluoroacetate, and it is probably safer to handle. 

Etherification of lower organic acids improves their chromatographic properties and enhances the detection sensitivity. To determine sodium fluoroacetate, Stahr [135] devised a method based on preliminary formation of methyl fluoroacetate. The fluoroacetate was extracted from the sample with methanol, and the water was removed by heating after adding a certain amount of an alkali in order to prevent volatilization of the fluoroacetate. The dehydrated sample was etlierifled in a sulphuric acid—methanol solution, yielding 85% of ethyl ether. The latter was analysed by GC. The detection limit was 1 10" %. 

Ihe diverse chemical, biological, and industrial applications of the numerous synthetic carbon-fluorine compounds are almost legendary. In 1944, Marais identified fluoroacetate in the leaves of the South African shrub Dichapetalum cymosum since then chemists and biologists continue to be intrigued by the natural occurrence, synthesis, and properties of the C-F bond. 

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