Fluoroacetates general

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). 

Thus it can be seen that evidence for the A-l mechanism, even if one accepted that this followed from a linear rate coefficient-acidity function correlation, was scant. On the other hand, there have been a very large number of carefully documented studies in which general acid catalysis has been observed leading to the A-Se2 mechanism for the reaction, or it has been shown that the conclusions from an acidity function dependence are not rigorous. One such study has already been described above, and Satchell478 also found that in the detritiation of [4,6-3H2]-l,2,3-trimethoxybenzene by potassium bisulphate, dichloro- and tri-fluoroacetic acids, plots of log kl versus —H0 were linear with a slope of ca. 1.0... 

Combination of fluoroacetate activity and certain other recognizable physiological effects have been successfully combined in fluoroaspirin (drugged sleep), triethyl-lead fluoroacetate (sternutation), difluoroethyl phosphorofluoridate (myosis, but not powerful). In general, quaternary ammonium... 

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. 

Fluoroacetate produces its toxic action by inhibiting the citric acid cycle. The fluorine-substituted acetate is metabolized to fluoroci-trate that inhibits the conversion of citrate to isocitrate. There is an accumulation of large quantities of citrate in the tissue, and the cycle is blocked. The heart and central nervous system are the most critical tissues involved in poisoning by a general inhibition of oxidative energy metabolism. ... 

A few natural organofluorine compounds exist, most notably in plants (Fig. 1c). These are generally noted for their toxicity most importantly, fluoroacetate enters the tricarboxylic acid (TCA) cycle and as fluorocitrate inhibits c/s-aconitase [4,106,107]. Of course, toxicity provides an opportunity to generate specific poisons and fluoroacetate is widely used as a rodenticide providing opportunities for NMR [108]. F NMR has been used for extensive studies of body fluids such as milk and urine with respect to xenobiotica [109-115]. 

The toxicity of fluoroacetic acid and of its derivatives has played an historical decisive role at the conceptual level. Indeed, it demonstrates that a fluorinated analogue of a natural substrate could have an activity profile that is far different from that of the nonfluorinated parent compound. The toxicity of fluoroacetic acid is due to its ability to block the citric acid cycle (Krebs cycle), which is an essential process of the respiratory chain. The fluoroacetate is transformed in vivo into 2-fluorocitrate by the citrate synthase. It is generally admitted that aconitase (the enzyme that performs the following step of the Krebs cycle) is inhibited by 2-fluorocitrate the formation of aconitate through elimination of the water molecule is a priori impossible from this substrate analogue (Figure 7.1). 

In the early synthesis of deamino-dicarba-oxytocin, the intermediate Z-Asu(OMe)-OH was used which requires a saponification step prior to cyclizationJ1-2 Subsequently, a synthesis more consistent with the general protection strategies in peptide synthesis was developed with the intermediate Z-Asu(OtBu)-OH.12,24 As outlined in Scheme 9, upon selective deprotection of the side-chain carboxy group of the Asu residue by exposure to TFA, the octapeptide derivative 26 is converted into the 2,4,5-trichlorophenyl ester 27 using the tri-fluoroacetate method.129,20 Hydrogenolytic Na-deprotection of 27 in dilute solution leads to... 

The hydrolysis of esters by esterases and of amides by amidases constitutes one of the most common enzymatic reactions of xenobiotics in humans and other animal species. Because both the number of enzymes involved in hydrolytic attack and the number of substrates for them is large, it is not surprising to observe interspecific differences in the disposition of xenobiotics due to variations in these enzymes. In mammals the presence of carboxylesterase that hydrolyzes malathion but is generally absent in insects explains the remarkable selectivity of this insecticide. As with esters, wide differences exist between species in the rates of hydrolysis of various amides in vivo. Fluoracetamide is less toxic to mice than to the American cockroach. This is explained by the faster release of the toxic fluoroacetate in insects as compared with mice. The insecticide dimethoate is susceptible to the attack of both esterases and amidases, yielding nontoxic products. In the rat and mouse, both reactions occur, whereas sheep liver contains only the amidases and that of guinea pig only the esterase. The relative rates of these degradative enzymes in insects are very low as compared with those of mammals, however, and this correlates well with the high selectivity of dimethoate. 

Thus, ethanol-water (7 3 v/v) and methanol-water in various ratios for flavonoids, methanol-25 % HCl (9 1 v/v), methanol-acetic acid (5%), methanol-tri-fluoroacetic acid (3%) for unstable anthocyanins, acetone, methanol-acetone mixtures for carotenoids, acetone and petroleum ether for chlorophylls, and so forth. The pigments are fairly stable in their natural environment, but they generally become unstable in extracts this has to be taken into consideration in the development of new, more efficaceous extraction procedures. 

Acute fluoroacetate poisoning can result in nausea, vomiting, cardiac arrhythmia, cyanosis, generalized convulsions, hypotension, and death from ventricular fibrillation or respiratory failure. Residual effects are uncommon if the patient survives the acute toxicity. 

One understands especially the incorporation by living organisms of fluoroacetic acid in place of acetic ° acid or of 5-fluoro-nicotinic acid and 5-fluoro-uracil as antimetabolites. This fraudulent incorporation leads to lethal syntheses. This is generally not the case with the corresponding chlorinated, brominated, or iodinated analogs. 

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