Is gauche attraction between the fluoro atom and the incoming nucleophile really the determining factor in cissoid stereochemistry?

Abstract

Recently we described the unexpected concomitant formation of the ‘antigauche’ trans isomer during the synthesis of 5-fluoro-6-alkoxyuracils ( J. {Fluorine Chem., 54} (1991) 190). With respect to their conformation, in both the cis and the trans compounds, the anomeric effect (substituent at C 6 axial to N 1) appeared to be the predominant factor (see diagram). ▪ R = Me, Et, n−Pr, i−Pr, n−Bu, t−Bu. Both 5-F-6-OR isomers were found to undergo substitution reactions at C 6 under acidic conditions. By carrying out these substitution reactions (with variation of the group R) in different alcohols (R′OH) or alcohol mixtures (R′OH + R″OH) at different temperatures and in the presence or absence of CH 3CN, we found that in all cases the trans compound was more stable against substitution than its corresponding cis compound. Also their substitution pattern differed invariably: the trans compounds gave exclusively S N2 substitution products, the cis compounds (mainly) S N1 products. Within the concept of the unifying ion-pair mechanism it will be suggested that, because in the trans compound the fluoro atom destabilizes the formation of a developing carbocation, the trans compound is ‘blocked’ in the intimate protonated intermediate state while the cis compound, having the fluoro atom orthogonal to the developing empty π-orbital, reacts through a solvent separated intermediate and partly through a dissociated intermediate. Consequently, a refinement of the nature of the cissoid sreochemically will be proposed.