Reversal of Regioselectivity in the Nucleophilic Fluorination of 1,2-Dimesylate with Potassium Fluoride and 18-Crown-6

The control of chemoselectivity and regioselectivity in chemical reactions is a crucial area of research, focused on achieving the desired product with high yield. An example is the selective monofluorination of vicinal dimesylates, which can open a route for the synthesis of β-fluoroamines, β-fluorohydrins, and alkenyl fluorides. This study examined the reactivity of a terminal vicinal dimesylate with potassium fluoride and 18-crown-6 through experimental methods and theoretical calculations. We found an unexpected higher reactivity of the dimesylate toward a nucleophilic substitution on the C2 carbon rather than C1 carbon. In addition, the S_N2 product is favored over E2. Extensive theoretical calculations using conformational sampling were done to understand this preferential reaction pathway. Our findings show that electrostatic interactions between the oxygen of the vicinal dimesylate and the potassium ion in the KF(18-crown-6) complex favor S_N2 at C2 over C1 and also enhance selectivity for S_N2 over E2. In addition, one hydrogen of CH₃ in the vicinal mesylated group interacts with the incoming fluoride ion, favoring S_N2 and E2 reactions involving C1 and C2, while reducing E2 products involving C3. Our results open an avenue for exploring this selectivity, which can be useful for further functionalization.