6-Fluorinated analogues of the mutagenic and carcinogenic benzo[a]pyrene 7,8-diol 9,10-epoxides have been synthesized by epoxidation of metabolically formed (-)-trans-(7 R, 8R)-7,8-dihydroxy-7,8-dihydro-6-fluorobenzo[a]pyrene to produce (7R,8S,9R,10S)-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-6-fluorobenzo[a]pyrene (1a) and (7R,8S,9S,10R)-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-6-fluorobenzo[a]pyrene (2a). NMR spectra indicate that the 7,8-diol group of 1a is almost exclusively pseudoaxial whereas the diol group in 2a prefers the pseudoaxial orientation to a lesser extent. In both cases the preference for the pseudoaxial conformation of the diol group is much stronger in the flurinated diol epoxides than in the corresponding benzo[a]pyrene derivatives. Like the benzo[a]pyrene diol expoxides, 1a and 2a undergo hydrolysis and rearrangement in aqueous solutions to give tetraols and a 9-keto 7,8-diol, according to the rate law kobsd = kHaH+ + K0. Studies with 9,10-epoxy-7,8,9,10-tetrahydro-6-fluorobenzo[a]pyrene (3a) and its corresponding benzo[a]pyrene derivative 3b indicated that the electronic effect of the 6-fluoro group decreases kH by .apprx. 7-fold and k0 by .apprx. 11-fold. Relative magnitudes of kH for the fluorinated and unfluorinated diol epoxides can be accounted for solely by this electronic effect. On the other hand, k0 for 1a is much smaller and k0 for 2a is much larger than predicted when only the electronic substituent effect of fluorine is considered. The pH-independent rates for solvolysis of the fluorinated diol epoxides are thus markedly affected by their altered conformational equilibria due to the presence of fluorine. The observed differences in conformation of the fluorinated diol epoxides may account for the reduced mutagenicity of 1a and 2a as well as the lack of high tumorigenicity for 2a relative to their benzo[a]pyrene counterparts, since bay-region diol epoxides in which the hydroxyl groups prefer the pseudoaxial conformation are known not to be highly carcinogenic.
