Fluoride as leaving group

The substitution of choline side-chains for alkoxy into sarin and tabun also produces compounds with very high toxicity. A series of these compounds was first prepared by Tammelin l In the choline series (X = OCH2CH2N Me3), potent activity is observed only in the presence of fluoride as leaving group, as shown in Table 11. 

Donors possessing other halogens as leaving groups, such as glycosyl chloride and bromide, are not effectively activated in contrast to glycosyl fluoride. 

The extent of this failure is evident from comparisons of experimental measurements of rate and equilibrium constants. One comparison in the literature is provided by Ritchie and coworkers study of the relatively stable cation, pyronin (the 3,6-bis(dimethylamino)xanthylium cation 71) with a series of nucleophiles.252 Another example is McClelland s measurements of rate and equilibrium constants for the reactions of halide and acetate ions with the trityl cation.19 As already mentioned fluoride and acetate are less reactive than bromide and chloride despite their equilibrium affinities being much greater. This is reflected indeed in the much lower rates of solvolysis of the fluoride and acetate than bromide or chloride as leaving groups... 

In the simple series R0P(0)CNNMe2, activity reaches a maximum where R is iso- or n-propyP LD50 values are shown in Table 8. Increasing the length of the alkyl substituent on nitrogen decreases toxicity, as does substitution of fluoride for cyanide as leaving group. 

Nitro group can be also used as leaving group, thus, 2-fluorothiazole has been synthesized from the corresponding nitro derivatives by treatment with fluoride ion in N-methyl-2-pyrrolidone, however, the yield was only 20 % [88] ... 

The order of alkyl halide reactivity in nucleophilic substitutions is the same as their order m eliminations Iodine has the weakest bond to carbon and iodide is the best leaving group Alkyl iodides are several times more reactive than alkyl bromides and from 50 to 100 times more reactive than alkyl chlorides Fluorine has the strongest bond to car bon and fluonde is the poorest leaving group Alkyl fluorides are rarely used as sub states m nucleophilic substitution because they are several thousand times less reactive than alkyl chlorides... 

Fluoride-induced /S-elimination reactions of silanes having leaving groups in the position are important processes in synthetic chemistry, as, for, example in the removal of / -trimethylsilylethoxy groups. 

Condensation of sodium phenoxide witli 2,2,2-trifluoroethyl iodide gives a product of direct substitution in a low yield, several other ethers are formed by eliminatton-addition reactions [7] Use of mesylate as a leaving group and hex amethyl phosphoramide (HMPA) as a solvent increases the yield of the substitution [S] Even chlorine can be replaced when the condensation is performed with potassium fluoride and acetic acid at a high temperature [9] (equations 6-8)... 

Cyclohexyl bromide, for exfflnple, is converted to cyclohexene by sodium ethoxide in ethanol over 60 times faster than cyclohexyl chloride. Iodide is the best leaving group in a dehydrohalogenation reaction, fluoride the poorest. Fluoride is such a poor leaving group that alkyl fluorides are rarely used as starting materials in the preparation of alkenes. 

Alkyl fluorides can be prepared by the Finkelstein reaction. The fluoride anion is a bad leaving group the reverse reaction thus does not take place easily, and the equilibrium lies far to the right. As reagents potassium fluoride, silver fluoride or gaseous hydrogen fluoride may be used. 

The reaction with 4-nitrophenol and pentafluorophenol in the presence of KF-18-crown-6 has been investigated. Pentafluorophenoxide anion was found to be a better leaving group [82JFC(20)439]. Alkali metal fluorides on graphite can act as catalysts for nucleophilic substitution of pentafluor-opyridine [90JFC(46)57]. 

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