S2 versus E2 reactions in a complex microsolvated environment: theoretical analysis of the equilibrium and activation steps of a nucleophilic fluorination.

The reactivity of the fluoride ion towards alkyl halides is highly dependent on the solvating environment. In polar aprotic solvents with large counter-ions is highly reactive and produces substantial E2 product, whereas in polar protic solvents leads to slow kinetics and high selectivity for S2 reactions. The use of a more complex environment with stoichiometric addition of tert-butanol to acetonitrile solvent is able to module the reactivity and selectivity of tetrabutylammonium fluoride (TBAF). In the present work, we have performed a detailed theoretical analysis of this complex reaction system by density functional theory, continuum solvation model, and including explicit tert-butanol molecules. A kinetic model based on the free energy profile was also used to predict the reactivity and selectivity. The results indicated that the TBAF(tert-butanol) complex plays the key role to increase the S2 selectivity, whereas higher aggregates are not relevant. The E2 product is formed exclusively via free TBAF, because the solvating tert-butanol in the TBAF(tert-butanol) complex inhibits the E2 pathway. Our analysis suggests that diols or tetraols could produce an improved selectivity.