Investigating the Reactivity and Selectivity in Nucleophilic Fluorination of Secondary Alkyl Bromides and Mesylates: Assessment of the Effect of Counterion and Bulky Alcohols

Synthesis of secondary alkyl fluorides via nucleophilic substitution faces the problem of high competition with E2 processes. This competition depends on the chemical environment of the substrate, the counterion, and the hydrogen bonding to the fluoride ion. Herein, we combined reliable theoretical calculations and experimental studies to probe the reactivity and selectivity of different substrates. The calculations have shown the significance of S N 2 versus E2 competition in various chemical environments. In the experiments, we have tested the use of potassium fluoride combined with 18‐crown‐6 and the bulky alcohols pinacol and 2‐trifluoromethyl‐2‐propanol (TBOH‐F3) with several alkyl bromides and mesylates. The combination of tetrabutylammonium fluoride (TBAF) with these alcohols was also evaluated. We have found that potassium fluoride, combined with the crown ether and the bulky alcohols, is more selective than TBAF combined with these alcohols, although TBAF is more reactive. Alkyl mesylates are less prone to the formation of E2 products, and high fluorination yields can be obtained when using KF (potassium fluoride) combined with 18‐crown‐6 and pinacol in acetonitrile solvent. We have also identified 2‐bromo‐1‐phenylpropane as a very challenging substrate. Even when using a high concentration of 1,1,1,3,3,3‐hexafluoro‐2‐propanol in acetonitrile solution, fluorination of this substrate was not achieved.