Fluoro acetate

It will readily be seen in our series of w-fluorocarboxylic acids, that when n is odd, / -oxidation would yield the toxic fluoro-acetic acid, whereas when n is even, the compound would presumably be oxidized only as far as the non-toxic yff-fluoro-propionic acid.1 The pharmacological results obtained are in complete accord with this hypothesis, and provide verification, of a kind not hitherto achieved, of the process of / -oxidation in the living animal body. However, Weinhouse, Medes and Floyd2 have inoculated rat-liver slices with one or two fatty acids containing isotopic carbon, and have obtained some evidence for a process of /7-oxidation. 

The lower members, e.g. CF4 and C2F6, are colourless, odourless gases of very low toxicity. By comparison with the fluoro-acetates they may be said in general to be non-toxic. This is understandable, particularly with regard to the simple saturated fluorocarbons, as they do not contain the FCH2CO group and are not likely to give rise to it in the animal body. Recently,... 

The toxicity of the acaricide 2-fluoro-A-methyl-A-(naphth-l-yl)acet-amide (MNFA) (4.152) to mammals is related to its hydrolysis. In this case, however, toxicity was mainly due to the acid formed. Indeed, the 2-fluoro-acetic acid (4.153) liberated by hydrolysis was further metabolized to fluoro-citrate, which inhibits the tricarboxylic acid cycle [101]. 

Various steroids can be fluorinated, to provide vicinal fluoro acetates with predominant or exclusive syn addition, with acetyl hypofluorite or a mixture of acetyl hypofluorite and fluoroxy compounds,4"10 e.g. reaction of 18 and 19. 

There are two Krebs cycle inhibitors that are worth mentioning. Malonate inhibits succinate dehydrogenase because of its very similar structure. Fluoro-acetate inhibits cis-aconitase, which is an Fe-S enzyme. The fluoroacetate replaces acetate as a substrate in the citrate synthase reaction when this combines with cis-aconitase, however, no further reaction becomes possible. 

Insects utilize propionate and methylmalonate in the biosynthesis of ethyl branched juvenile hormones and methyl branched cuticular hydrocarbons. The sources of propionate and methylmalonate in some insects appear to differ from those in mammals. Succinate is the precursor of propionate and methylmalonate in a termite, whereas valine and probably other amino acids are the sources of propionate and methylmalonate in several other species. An unusual pathway for propionate metabolism has been shown to occur in insects and it may be related to the absence or low levels of vitamin B found in many species. Propionate is converted directly to acetate with carbon 1 of propionate lost as C02> carbon 2 of propionate becoming the methyl carbon of acetate and carbon 3 of propionate becoming the carboxyl carbon of acetate. This pathway suggested the possibility that 2-fluoropropionate might be selectively metabolized in insects to the toxic 2-fluoro-acetate. However, preliminary data indicate that 2-fluoropropionate is not toxic to the housefly or the American cockroach. 

A two-step synthesis of modified 2 -C-nucleoside precursor, ethyl [2-(5-methyl-2,4-dioxo-3,4-dihydro-2i/-pyrimidin-l-yl)-4-hydroxyl-5-hydroxymethyltetra-hydrofuran-3-yl]fluoro-acetate 172, from protected glycal 170 and xanthate has been developed following the same idea, and a diastereomeric 1 1 mixture of 2,3-trans product 171 was obtained in 57% yield (O Scheme 46). The use of triethylborane as a free-radical initiator was less successful and a longer reaction time was also required. Interestingly, introducing th)miine at C-1 in the presence of silver triflate at 0°C was highly stereoselective, and only a C, C2-trans linked product was detected. 

Oxidation of primary amino group in aromatic compounds by peroxytri-fluoro acetic acid has been reported by Clarke and Steele [69]. The yield was... 

LIkik. E., and Imbeaux, M., A convenient synthesis of ethyl (diethoxyphosphoryl)fluoroacetate from ethyl fluoro acetate. Synthesis, 861, 1989. 

Similarly, the 6-(tetraethyl phosphorodiamide) of l,2 3,4-di-0-iso-propylidene-a-D-galactopyranose gives the corresponding halogen derivative with methyl iodide, benzyl bromide, benzyl chloride, and ethyl fluoro-acetate. ... 

Di 2 fluoroethyl phosphorofluoridate (XVIII) was prepared with the idea of combining the toxic principles of the fluoro-acetates and of the phosphorofluoridates. It was readily obtained by the action of phosphorus oxydichlorofluoride on... 

Sodium fluoroacetate was prepared with the idea of obtaining a stable water-soluble compound containing the CHjF CO group, suitable for feeding experiments. The method of obtaining this salt is described in detail below. It consists essentially in adding cold aqueous sodium hydroxide to methyl fluoro-acetate and evaporating the solution. Subsequent to our initial work, sodium fluoroacetate has been recommended and used as a rodenticide. 

In view of these facts and of the known toxic action of fluoro-acetates it seemed worth while investigating compounds containing both fluorine and the above-mentioned groups. We prepared the flrst of a series of nitrogen compounds in 1943, namely, ethyl jluoroacetamidoacetate, CHjF CO NH CHg COjEt (XH). It was a colourless crystalline solid which, when injected into mice, had a l.d. 50 of 20 mg./kg. The corresponding figure for methyl fluoroacetate is 6 mg. /kg. The symptoms were similar in each case (delayed convulsant action). 

Class B Fluoroacetic acid and salts, e.g. sodium fluoro-acetate, triethyl-lead fiuoroacetate all simple esters of fiuoroacetic acid fluoroacetamide and substituted amides fluoroacetamidine hydro-chloride fiuoroacetyl chloride and fluoride fluoro-ethanol and its simple esters fluoroacetaldehyde. 

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. 

The term non-toxic is used relatively to the highly toxic methyl fluoro-acetate. At hi concentrations (e.g. several hundr mg./kg.) it is probable that some symptoms would be observed even with the non-toxic materials. 

Other workers have demonstrated the specificity of antagonisms among the fluoro acids. Kalnitsky and Barron found the inhibition of butyrate oxidation to be more profound with fluorobutyrate than with fluoroacetate. Kandel and Chenoweth could prevent or reverse the toxic manifestations of fluoro-acetate with glyceryl monoacetate and those of fluorobutyrate with glyceryl monobutyrate in vivo, but they could not demonstrate cross protections with these compounds. 

Fig. 9 36. Hydrogen bonding patterns in the crystal structures of acetic acid and its halo derivatives, (a) acetic acid, (b)fluoro acetic acid, (c) chloro acetic acid, (d) bronw acetic acid...

The discovery in 1943 by Marais (12) that potassium fluoro-acetate was the toxic material present in a mmiber of South African plants attracted notable attention, though the reasons for the toxicity were not then known. Further exploration showed the presence of the similarly toxic u-fluorooleic acid in other plants. 

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 fluoro-acetate, first prepared and described by us in 1943. This ester was readily prepared by the action of fluoroacetyl chloride on fluoroethanol. It is a stable, mobile hquid possessing an extremely faint odour. 

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