Fluoroethyl fluoroacetate

Ethyl fluoroacetate 2-Chloroethyl fluoroacetate 2-Fluoroethyl acetate 2-Fluoroethyl chloroacetate 2-Fluoroethyl fluoroacetate Phenyl fluorothiolacetate 2-Chloroethyl fluorothiolacetate... 

Fluoroacetamide, FCHaCONHa, and many new substituted amides of the type FCHaCONHI2, were all convulsant poisons with delayed action. The magnitude of their toxicities suggested that they were hydrolysed in the animal body to fluoroacetic acid. In short, the effective part of the molecule was the FCHsCO grouping.3 Swarts4 was unable to obtain fluoroethyl... 

In view of the fact that fluoroethyl alcohol produced a toxic effect comparable with that of fluoroacetic acid, it seemed worth... 

VIII R CH2 CH2F) Comparable to that of 2-fluoroethyl fluoroacetate... 

It was to be expected that the imino ether hydrochlorides would be hydrolysed in the animal body to give the corresponding fluoroacetate and ammonium chloride, and the toxicities should be roughly the same as those of the fluoroacetates. The results show this to be the case. The compound (VIII iZ = CH2,CH2F) was expectedly more toxic than the other compounds, as this would be hydrolysed to 2-fluoroethyl fluoroacetate which is known to be twice as toxic as methyl or ethyl fluoroacetate,1 as indicated below. 

In view of the fact that fluoroethanol is as toxic as methyl fluoroacetate (or as fluoroacetic acid), it seemed worth while preparing a compound in which the active parts of these molecules were combined, in the hope of obtaining a compound of increased potency. Such a compound is 2-fluoroethyl fluoroacetate, first prepared and described by us in 1943.1 This ester was readily prepared by the action of fluoroacetyl chloride on fluoroethanol. It is a stable, mobile liquid possessing an extremely faint odour. 

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... 

The hydrochloride (XIII) had a l.d. 50 of ca. 10 mg./kg. by subcutaneous injection into mice. The corresponding figure for 2-fluoroethyl betaine hydrochloride was 45 mg./kg. Both (XIII) and (XIV) produced fluoroacetate-like symptoms. 

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. 

On p. 129 it was shown that 2-fluoroethyl fluoroacetate was about twice as toxic as methyl fluoroacetate (M.F.A.) by inhalation. By analogy then it seemed that 2-fluoroethyl-5-fluoropentanecarboxylate (III) might be a compound of exceptionally high toxicity. This proved to be correct, for its l.d. 50... 

Comparable to that of methyl fluoroacetate Comparable to that of methyl fluoroacetate Comparable to that of methyl fluoroacetate Comparable to that of 2-fluoroethyl fluoroacetate... 

In class B are placed all simple esters, CHjF CO i , of fluoro-aoetic acid, where iZ = Me, Et, Pr , Pr , Ph, etc. When substitution takes place in the a-hydrogen atoms, e.g. in methyl a-fluoropropionate or a-fluoroisobutyrate, then the compound is devoid of toxicity. This indicates the importance of the unsubstituted fluoromethyl group. On pp. 125 et seq. it was shown that fluoroacetamide and a variety of substituted amides such as CHjF CO NH CHg CHjCl were, molecule for molecule, equally toxic with fluoroacetic acid and produced the same symptoms. The 2 chloroethyl group therefore contributed nothing appreciable to the toxicity of the molecule. The majority of the esters of fluoroethanol showed the toxicity of the parent alcohol, e.g. 2-fluoroethyl chlorosulphonate, CHgF CHg O SOjCl, di-(2-fluoroethyl) sulphate and 2-fluoroethylglycine hydrochloride. 

Ethyl 9 fluorononanecarboxylate (VII) was found to be even more toxic than ethyl 5 fluoropentanecarboxylate by injection into rabbits, the l.d. 50 for a propylene glycol solution of (VII) being 0-2 mg./kg. Mice and rats were sbghtly more resistant, but exhibited convulsions of the general fluoroacetate type. On account of the high boiling-point of the material, no inhalation experiments were attempted. 2 Fluoroethyl 9 fluorononanecarboxylate (VIII) was found to be no more toxic than the corresponding ethyl ester by injection into mice. Each had a l.d. 50 of about 10 mg./kg. This anomaly is discussed later. 

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