Fluorinated compounds fluoroacetate

Chloroacetate esters are usually made by removing water from a mixture of chloroacetic acid and the corresponding alcohol. Reaction of alcohol with chloroacetyl chloride is an anhydrous process which Hberates HCl. Chloroacetic acid will react with olefins in the presence of a catalyst to yield chloroacetate esters. Dichloroacetic and trichloroacetic acid esters are also known. These esters are usehil in synthesis. They are more reactive than the parent acids. Ethyl chloroacetate can be converted to sodium fluoroacetate by reaction with potassium fluoride (see Fluorine compounds, organic). Both methyl and ethyl chloroacetate are used as agricultural and pharmaceutical intermediates, specialty solvents, flavors, and fragrances. Methyl chloroacetate and P ionone undergo a Dar2ens reaction to form an intermediate in the synthesis of Vitamin A. Reaction of methyl chloroacetate with ammonia produces chloroacetamide [79-07-2] C2H ClNO (53). 

For standardizing the estimation of fluorine in fluoroacetates, a compound of undisputed purity containing the CH2F group is re-... 

Trifluorothreonine is one of the rare fluorinated compounds found in nature (cf. Chapter 4). The best method for the synthesis of fluorothreonines is the acylation of an equivalent of glycinate anion by a fluoroacetic derivative. The four stereoisomers of monofluorothreonine have been prepared. A completely stereoselective chiral approach involves the alkylation of the Seebach imidazolidinone by fluoroacetyl chloride (Figure 5.16). ... 

Fluoroacetate does not cause direct tissue damage and is not intrinsically toxic but requires metabolism to fluoroacetyl CoA (Fig. 7.61). Other fluorinated compounds that are metabolized to fluoroacetyl CoA therefore produce the same toxic effects. For instance,... 

Buffa, P., Guarriero-Bobyleva, V., Pasquali-Ronchetti, J. (1972). Biochemical effects of fluoroacetate poisoning in rat liver. In Carbone-Fluorine Compounds, pp. 303-30. Associated Scientific Compounds, Amsterdam. 

Peters, R.A. (1972). Some metabolic aspects of fluoroacetate especially related to fluorocitrate. In Carbon Fluorine Compounds. A Ciba Foundation Symposium, pp. 55-70. Associated Scientific Publishers., Amsterdam. 

Monofluoroacetic acid (fluoroacetate, figure 7,39) is a compound found naturally in certain South African plants, and which causes severe toxicity in animals eating such plants. The compound has also been used as a rodenticide. The toxicity of fluoroacetate was one of the first to be studied at a basic biochemical level, and Peters coined the term lethal synthesis to describe this biochemical lesion. Fluoroacetate does not cause direct tissue damage and is not intrinsically toxic but requires metabolism to fluoroacetyl CoA (figure 7,39). Other fluorinated compounds which are metabolized to fluoroacetyl CoA therefore produce the same toxic effects. For instance, compounds such as fluoroethanol and fluorofatty acids with even numbers of carbon atoms may undergo /1-oxidation to yield fluoroacetyl CoA. 

CAUTION Monofluoroacetates are intermediates for some literature syntheses of fluorinated heterocycles. Fluoroacetic acid and its derivatives, such as fluoroacetamide and ethyl fluoroacetate, and compounds which could be metabolically converted into fluoroacetate, such as 2-fluoroethanol, are extremely toxic and have no antidote. A lethal dose of the acid in humans may be as low as 100 mg. They should be avoided if at all possible, but if their use is essential, they must only be used under rigorous control. 

In Chapter rv we have described toxic fluorine compounds containing the POF grouping. Such compounds possessed quick knock-out action, and many of them were powerful myotics. Compounds of the fluoroacetate series are characterized by the CH2F- group. Many of them are highly toxic with delayed action, but are completely devoid of myotic activity. The action is, broadly speaking, that of a convulsant poison (but see p. 136). 

The two types of fluorine compounds are (a) compounds containing the P—F link, e.g. the phosphorofluoridates (6) compounds containing the C—F link and known collectively as fluoroacetates. 

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. 

Gravimetric analysis is a technique in which the mass of a substance in a mixture is determined. A mixture containing no fluorine compound except methyl fluoroacetate, FCHjCOOCHg (MFA), yields 12.1 mg CaFj. Find the mass of MFA in the mixture,... 

Nucleocidin. Until comparatively recently, other than higher plants, the only organism known to elaborate a fluorinated compound was the bacterium Streptomyces calvus. The antibiotic nucleocidin 5 was first isolated from this organism in 1957 (19, 20) but it was not until twelve years later that the presence of fluorine in this compound was realised (21), The structure of the compound was confirmed by total synthesis in 1976 (22). Nucleocidin 5 is an intriguing compound as it is difficult to envisage a mechanism by which the fluorine in the molecule can be derived from fluoroacetate 1 and it therefore seems likely that the fluorination enzyme involved in biosynthesis of nucleocidin is unique to S. calvus, A recent attempt to re-isolate the compound from 51 calvus failed and sadly it appears that the strain may have lost the capability of producing this fascinating secondary metabolite (23). 

Fluorothreonine. In 1986 a second Streptomyces species capable of the biosynthesis of fluorinated compounds was identified (24). In the course of studies with Streptomyces cattleya to improve the yield of the 6-lactam antibiotic, thienamycin, it was discovered that when fluoride was present in tiie culture medium both fluoroacetate 1 and 4-fluorothreonine 6 accumulated in millimolar concentrations during fermentation. 4-fluorothreonine is the only naturally ocurring fluorinated amino acid known. When 4-fluorothreonine was initially isolated (24) the absolute stereochemistry of 4-fluorothreonine was predicted to be analogous to L-threonine. We have recently confirmed this by asymmetric synthesis (25) and demonstrated that natural 4-fluorothreonine has the (25, 3S) configuration. The... 

In the past 20 years, the application of fluorinated reagents in chemistry experienced tremendous growth Some well known denvatives of hydrofluoric acid and tri-fluoroacetic acid found new applications, and many new classes of synthetically useful fluorinated organic and inorganic compounds have been synthesized... 

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. 

It is interesting to note that the toxic sodium fluoroacetate (above, p. 11) occurs in the poisonous South African plant gifblaar (Dichapetalum cymosum, PI. I). It has recently been shown that sodium fluoroacetate is a highly effective systemic insecticide, but it is difficult to say exactly how this substance will be applied on a large scale.6 There are many other insecticides containing fluorine and phosphorus, and special precautions must be taken when handling these toxic compounds. 

The fluorine atom in methyl fluoroacetate (and in many other compounds containing the CH2F group) is quite firmly bound. When M.F.A. was boiled with 10 per cent aqueous potassium hydroxide for 1 hr., no free fluoride was formed. 

Fluoroethyl fluoroacetate is a compound of considerable toxicity. Its l.c. 50 for rabbits (inhalation) is 0-05 mg./l., i.e. about half as great as for M.F.A. It is therefore placed in class A. Other factors apart from hydrolysis to fluoroethanol and fluoroacetic acid appear to be operative, and it seems that the molecule is toxic per se. The related fluoroacetylimino-2-fluoro-ethyl ether hydrochloride, [CH2F C( NH2) O CH2 CH2F]+CT, is also placed in class A. This is understandable as it is readily hydrolysed by water to 2-fluoroethyl fluoroacetate. Other fluoroacetylimino ether hydrochlorides containing, however, only one fluorine atom fall into class B, as does also fluoroacet-amidine hydrochloride itself. 

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