Fluorocarboxylic acids and derivatives

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-CHj-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. We subsequently showed that esters of y -fluoropropionic acid were non-toxic, whereas esters of y-fluorobutyric acid were shown by American workers to be toxic. In 1944 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. Therefore ethyl 5-fluoropentanecarboxylate was about 7 times as toxic as methyl fluoroacetate (molecule for molecule).  

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 

The comparison of the toxicities of compounds (I), (II) and (III) by intravenous injection into rabbits also revealed a similar gradation, as shown herewith . d. 50 

The very high toxicity of ethyl 5-fluoropentanecarboxylate and its derivatives and the fluoroacetate-like symptoms produced seemed to us to be of particular interest, since by a process of ) -oxidation in the animal body 5-fluoropentanecarboxyhc acid would readily give rise to the toxic fluoroacetic acid. Similar remarks apply to y-fluorobutyric acid and its derivatives prepared independently by American workers. The non-toxicity of y -fluoropropionic acid and its derivatives may, on the other hand, be due to the inability of this acid to give the toxic fluoro-acetic acid by a process of yff-oxidation. 

In order to prove that fluorine was responsible for the lethal action in (I) and (II), the intermediate bromo esters were examined physiologically. Ethyl 5-bromopentanecarboxylate was found to be entirely without toxic action, and the toxicity of its 2-fluoroethyl ester was also of a low order, the l.d. 50 being about 75 mg./kg. 

We then set out to determine whether this remarkable alternation in toxic properties could be observed among other w-fluorocarboxylic acids. 

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Fluorocarboxylic Acids and Derivatives containing an Oxygen Atom as a Chain Member... 

Synthetic methods employed in this series of compounds As direct chlorination or bromination of a carboxylic acid usually gives the a-substituted acid, such methods are useless for the preparation of the w-substituted acids ad hoc methods therefore had to be found for the preparation of each individual w-fluorocarboxylic acid and its derivatives. 

Synthesis from a-Fluorocarboxylic Acids and Their Derivatives... 

Takeuchi and co-workers5 have recently prepared a number of a-fluorocarboxylic acid derivatives 1 and 2 and it is very interesting that they emphasized that no explosion occurred in more than 200 fluorinations performed 17 however, they recommend the use of perchloryl fluoride diluted with nitrogen and synthesized in the laboratory. 

Electrolytic coupling of two molecules of a fluorocarboxylic acid accompanied by decarboxylation, according to Kolbe, is a general method for the preparation of suitable fluoro derivatives and the early literature on this has been dealt with in Houben-Weyl, Vol. 5/3.24... 

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