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

Solvent effects play\na critical role in ionic chemical reactions\nand have been a research topic for a long time. The solvent molecules\nin the first solvation shell of the solute are the most important\nsolvating species. Consequently, manipulation of the structure of\nthis shell can be used to control the reactivity and selectivity of\nionic reactions. In this work, we report extensive experimental and\ninsightful computational studies of the effects of adding diverse\nfluorinated bulky alcohols with different solvation abilities to the\nfluorination reaction of alkyl bromides with potassium fluoride promoted\nby 18-crown-6. We found that adding a stoichiometric amount of these\nalcohols to the acetonitrile solution has an important effect on the\nkinetics and selectivity. The most effective alcohol was 2-trifluoromethyl-2-propanol\n(TBOH-F3), and the use of 3 equiv of this alcohol to fluorinate a\nprimary alkyl bromide led to a 78% fluorination yield in just 6 h\nof reaction time at a mild temperature of 82 °C, with 8% of E2\nyield. The more challenging secondary alkyl bromide substrate obtained\n44% fluorination yield and 56% E2 yield at 18 h of reaction time.\nMore fluorinated alcohols with six or more fluorine atoms have resulted\nin relatively acidic alcohols, leading to large amounts of the corresponding\nethers of these alcohols as side products. The widely used hexafluoroisopropanol\n(HFIP) was the least effective one for monofluorination, indicating\nthat both acidity and bulkiness are important features of the alcohols\nfor promoting fluorination using KF salt. Nevertheless, the ether\nof HFIP can be easily formed with the substrate, generating a highly\nfluorinated ether product. Theoretical calculations predict Δ<i>G</i><sup>‡</sup> in close agreement with the experiments\nand explain the higher selectivity induced by the fluorinated bulky\nalcohols in relation to the use of crown ether alone.