2-Fluoroethanol acidity

Difluoroethanol [359-13-7], F2CHCH2OH, is a colorless Hquid with an alcohol-like odor mp, 28.2°C, bp, 96°C d[, 1.3084 n], 1.3320 heat of combustion, —1026 kJ/mol(—245.3 kcal/mol). It is stable to distillation and miscible with water and many organic solvents. As expected, its acidity Hes between that of 2-fluoroethanol and 2,2,2-trifluoroethanol both ia the gas phase (25) and ia 50% aqueous ethanol solution (26), where its of 1.0 x 10 is about 4.8 times smaller than that of trifluoroethanol. 

In this work on compounds containing the C—F link, it was obviously desirable to prepare 2-fluoroethanol, both for toxicity tests on the compound itself, and as a starting material for the production of other fluorine compounds. Swarts1 was unable to obtain 2-fluoroethanol by the action of silver fluoride or mercuric fluoride on either ethylene chlorohydrin or ethylene bromohydrin. He obtained acetaldehyde in each case. He ultimately obtained fluoroethanol in very poor yield by the indirect method of hydrolysing fluoroacetin (from bromoacetin and mercuric fluoride) for 80 hr. with dilute mineral acid. 

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. 

It seems possible to draw certain deductions from the above toxicities. It is to be noted that ethyl fluoroacetamidoacetate (XII) would almost certainly be hydrolysable in the animal body to free fluoroacetic acid, and that (XIII) and (XIV) would similarly give 2-fluoroethanol (oxidizable in vivo to fluoroacetic acid). These three compounds do, in fact, show toxicities of the same order as that of methyl fluoroacetate (or of fluoroacetic acid) (XIV) is, however, rather less toxic than might be expected. 

All the toxic compounds mentioned above are either hydro-lysable or oxidizable to fluoroacetic acid.1 In this connexion it should be noted that l-chloro-2-fluoroethane was relatively nontoxic. The chlorine atom in this compound was shown to be rather unreactive chemically, hence hydrolysis to the toxic fluoroethanol in the animal body would be unlikely. 

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. 

Fluoroethanol itself is innocuous towards a variety of tissue constituents, a series of enzymes in rat-liver mince, and the respiration and metabolism in liver, kidney, heart and brain slice.3 After a period of incubation in those tissues known to contain alcohol dehydrogenase, e.g. liver and kidney, the respiration and pyruvate oxidation were strongly inhibited. Likewise, following a period of incubation with yeast, acetate oxidation was blocked. These inhibitions were similar to those produced by fluoroacetate, and the facts can best be explained by the oxidation of fluoroethanol to fluoroacetic acid by alcohol dehydrogenase. 

Oxidation of 3,6-diamino-1,2,4,5-tetrazine (198) with oxone in the presence of hydrogen peroxide yields 3,6-diamino-l,2,4,5-tetrazine-2,4-dioxide (201) (LAX-112). The same reaction with 90 % hydrogen peroxide in trifluoroacetic acid yields 3-amino-6-nitro-1,2,4,5-tetrazine-2,4-dioxide (202). Treatment of 3,6-diamino-1,2,4,5-tetrazine (198) with 2,2,2-trinitroethanol and 2,2-dinitro-2-fluoroethanol generates the Mannich condensation products (203) and (204) respectively. 

The alcoholysis rate decreases by either increasing the steric bulk of the alcohol or decreasing its nucleophUicity (i.e., MeOH > EtOH > PrOH > BuOH 2,2,2-tri-fluoroethanol). Parallel to the decrease of the chain-transfer rate, the molecular weight of the copolymer increases. An effective role of water as hydrolysis agent in alcoholic media appears very unlikely as HOOC-terminated polyketone or oligo-ketone have never been observed. Obviously, in neat water, hydrolysis is a feasible chain-transfer path, leading to acid-terminated materials [13]. 

Novotny found that neat trifluoroacetic acid could be hydrogenated to 2,2,2-tri-fluoroethanol in the presence of rhodium or iridium catalyst under much milder con-... 

Fio. 10. Enthalpy-entropy compensations in reductions of Compound I by hydrogen donors (1) 2-fluoroethanol, (2) ethanol, (3) aliyl alcohol, (4) methanol, (6) pro-pargyl alcohol, (6) hydrogen peroxide, and (7) formic acid. Horse erythrocyte catalase in 5 m.M phosphate, pH 7 (llSb). 

The Zv - complex of the merocyanine system (57) releases the zinc when it is irradiated with visible light and this results in the formation of the colourless closed spiropyranindoline (58, R = H). When the irradiation is stopped the Zn " complex reforms but this does not happen with the nitro derivative (58, R = NO2) in which it is thought that the nitro group stabilises the phenoxide ion in the open form. Other workers have also studied the complexation of spiropyran based merocyanines with transition and rare earth metal ions. An investigation of the influence of Lewis acids (hexa-fluoropropanol, trifluoroethanol and 2-fluoroethanol) on the stability of the coloured form of spiropyran and spirooxazines has been reported. Protonation of the open system produces a form that is photochemically inert and the behaviour of these acids is markedly different from that of acetic acid with such systems. 

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 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. 

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