The Effects of Structural Modifications of Bis‐tert‐alcohol‐Functionalized Crown‐Calix[4]arenes as Nucleophilic Fluorination Promotors and Relations with Computational Predictions

We prepared four structurally modified bis‐tert‐alcohol functionalized crown ether‐strapped calix[4]arene promoters, that is, bis‐tert‐alcohol functionalized crown‐5‐calix[4]arene (BA5C), bis‐tert‐alcohol functionalized crown‐7‐calix[4]arene (BA7C), bis‐1,1‐dimethylbutanol functionalized crown 6‐calix[4]arene (B3A6C), and bis‐1,1‐dimethylhexanol functionalized crown 6‐calix[4]arene (B5AC6C). Nucleophilic fluorinations were conducted using alkali metal fluorides to investigate phase‐transfer catalytic activities with respect to the sizes of crown ether‐strapped calix[4]arene (CEC) subunits and lengths of alkyl chain spacers between tert‐alcohol and CEC subunits. The reactivity of potassium fluoride was significantly enhanced by BA5C promoter because its crown‐5‐calix[4]arene subunit had cavity size appropriate for K+ capture. In contrast, BA7C did not efficiently enhance cesium fluoride SN2 fluorination because its crown‐7‐calix[4]arene cavity was too large to capture Cs+. The alkyl spacer of bis‐tert‐alcohol functionalized CEC provided sufficient distance between F– and Cs+. In particular, the three‐component alkyl carbon chain of B3A6C was optimal in terms of increasing CsF reactivity. Systematic quantum chemical analysis predicted that fluorination reactions facilitated by bis‐tert‐alcohol‐substituted crown‐6‐calix[4]arene (BACCA) and B3A6C might proceed via separated ion‐pair type pre‐reaction complexes, which suggested that these two promotors act as Lewis bases that essentially separate CsF ion‐pairs. The lower (by 0.4 kcal/mol) Gibbs free energy of activation for the reaction promoted by B3A6C than that facilitated by BACCA concurred with the experimentally observed slightly greater efficiency of B3A6C than BACCA. Structurally modified bis‐tert‐alcohol functionalized crown ether‐strapped calix[4]arenes (CECs) were studied and their catalytic activities in alkali‐metal fluoride‐based SN2 fluorinations were examined. Systematic quantum chemical calculations were also performed to identify the drivers of the fluorination reaction rates achieved using bis‐tert‐alcohol functionalized CEC derivatives.