Effects of Hydrogen Bonding Solvation by Diverse Fluorinated Bulky Alcohols on the Reaction Rate and Selectivity in Crown Ether Mediated Nucleophilic Fluorination in an Aprotic Solvent

Solvent effects play a critical role in ionic chemical reactions and have been a research topic for a long time. The solvent molecules in the first solvation shell of the solute are the most important solvating species. Consequently, manipulation of the structure of this shell can be used to control the reactivity and selectivity of ionic reactions. In this work, we report extensive experimental and insightful computational studies of the effects of adding diverse fluorinated bulky alcohols with different solvation abilities to the fluorination reaction of alkyl bromides with potassium fluoride promoted by 18-crown-6. We found that adding a stoichiometric amount of these alcohols to the acetonitrile solution has an important effect on the kinetics and selectivity. The most effective alcohol was 2-trifluoromethyl-2-propanol (TBOH-F3), and the use of 3 equiv of this alcohol to fluorinate a primary alkyl bromide led to a 78% fluorination yield in just 6 h of reaction time at a mild temperature of 82 °C, with 8% of E2 yield. The more challenging secondary alkyl bromide substrate obtained 44% fluorination yield and 56% E2 yield at 18 h of reaction time. More fluorinated alcohols with six or more fluorine atoms have resulted in relatively acidic alcohols, leading to large amounts of the corresponding ethers of these alcohols as side products. The widely used hexafluoroisopropanol (HFIP) was the least effective one for monofluorination, indicating that both acidity and bulkiness are important features of the alcohols for promoting fluorination using KF salt. Nevertheless, the ether of HFIP can be easily formed with the substrate, generating a highly fluorinated ether product. Theoretical calculations predict Δ<i>G</i> ^‡ in close agreement with the experiments and explain the higher selectivity induced by the fluorinated bulky alcohols in relation to the use of crown ether alone.