What Makes Chiral Hydrogen-Bond Donor Species Successful in Promoting Enantioconvergent Nucleophilic Fluorination?

Abstract Asymmetric nucleophilic fluorination of alkyl bromides with inorganic salts such as KF and CsF faces substantial challenges because it requires a molecular framework that can transfer asymmetry to the small nucleophilic fluoride ion. However, this feature alone does not enable enantioconvergent fluorination. In this work, we have explored the TADDOL chiral diol combined with the 18-crown-6 and potassium fluoride salt for the asymmetric fluorination of an α-bromo-ketone. Despite the ability of TADDOL to provide a chiral environment, enantioselectivity was not observed. We employed both high-level theoretical calculations and experimental methods to clarify why TADDOL fails and why a chiral bisurea succeeds. This study points out that TADDOL can be easily deprotonated, generating the corresponding alkoxide and the HF2– ion. The alkoxide may react with the product, causing racemization, or with the substrate, resulting in alkylation. The racemic product and the alkylated TADDOL were experimentally observed. For chiral bisurea, calculations indicate that it is less prone to deprotonation. More importantly, the high free energy barrier for product racemization in the chiral bisurea system prevents this process from occurring. These results highlight the need to consider deprotonation, driven by stable HF2– ion formation, when developing asymmetric nucleophilic fluorination with hydrogen bond donors, even in apolar solvents like toluene.