PMC

There were striking differences between 2,2,2-[¹⁸F]trifluoroethyl tosylate and iodide as a [¹⁸F]trifluoroethylating agent. [¹⁸F]Trifluoroethylation of an alcohol, such as 3-chloro-1,2-propanediol, 3-bromo-1,2-propanediol or glycidol, with 2,2,2-[¹⁸F]trifluoroethyl tosylate proceeds smoothly affording a [¹⁸F]trifluoroethylether such as the key intermediate for the [¹⁸F]TFMISO production: 1,2-epoxy-3-(2,2,2-[¹⁸F]trifluoroethoxy)propane (6) ( and ). By contrast, our attempt of O-[¹⁸F]trifluoroethylation of the same alcohol using 2,2,2-[¹⁸F]trifluoroethyl iodide failed since unusual substitution reactions occurred in which the iodide leaving group was not replaced with the same oxygen nucleophile. Instead one or two of the 3 fluorine atoms of the CF₃- group were replaced, resulting in the formation of 1-iodo-2,2-[¹⁸F]difluoroethyl and 1-iodo-2-[¹⁸F]fluoro-vinyl ethers. As a consequence, the reaction between 2,2,2-[¹⁸F]trifluoroethyl iodide and glycidoxide led to the production of 1-iodo-2,2-[¹⁸F]difluoroethoxy and 1-iodo-2-[¹⁸F]fluoro-vinyloxy analogs of [¹⁸F]TFMISO (). Obviously, the same oxygen nucleophile which reacts on the carbon attached to the tosyl group of 2,2,2-trifluoroethyl tosylate and replaced the tosyl leaving group attacks on the CF₃ site of 2,2,2-trifluoroethyl iodide, replacing one or two of the fluorine atoms instead of the iodide leaving group. Similar complications have been observed in nucleophilic substitution reactions with 2,2,2-trifluoroethyl halides. The differences observed in this investigation between trifluoroethyl halide and tosylate as a trifluoroethylaing agent are in part similar to the differences between alkyl tosylates and halides. Alkyl tosylates are considered to be “harder” electrophiles than the counterpart halides, which makes tosylates more reactive in nucleophilic substitution reactions and less reactive in accompanying and competing side reactions. Depuy et al. observed that the S_N2 reactivity of phenylethyl tosylate toward sodium ethoxide is 4 times higher than that of the counterpart iodide whereas the accompanying elimination reaction was 68 times slower with the tosylate than with the iodide, as a result of which the yield of the nucleophilic substitution product, phenylethyl ether, was approximately 20-30 times higher with the tosylate than the iodide^,. Similar differences in S_N2 and E2 reactivity between ethyltosylate and ethylbromide have also been reported. In the case of O-[¹⁸F]trifluoroethylation reported here, the differences between [¹⁸F]trifluoroethyl tosylate and iodide as an electrophile appeared to be more pronounced. Besides the general differences as electrophiles between tosylates and halides, the most striking difference which makes [¹⁸F]trifluoroethyl tosylate a superior [¹⁸F]trifluoroethylating agent is that the two different nucleophiles, [¹⁸F]fluoride and an alkoxide such as glycidoxide, react on the 2 different carbon sites of the trifluoroethyl moiety of the tosylate, i.e. [¹⁸F]fluoride on C-2 and glycidoxide on C-1, whereas, in contrast, these nucleophiles both attack on the same carbon of trifluoroethyl iodide (). Further empirical and theoretical investigations are needed to elucidate the mechanisms by which trifluoroethyl halide and trifluoroethyl tosylate react with a nucleophile differently.

Silyl tosylate 28 to access 1,2-cycloheptadiene (29).

Short chain (n ≤ 2) ¹⁸Flabeled aliphatic building blocks (Born et al. ): [¹⁸F]Fluoromethyl bromide/ iodide/ tosylate, [¹⁸F]Fluoroethyl bromide/ tosylate/ triflate/ nosylate/ brosylate/ -3,4-dibromobenzenesulfonate, and [¹⁸F]Fluoroform