Organotrifluoroborate Hydrolysis: Boronic Acid Release Mechanism and an Acid–Base Paradox in Cross-Coupling

The hydrolysis of potassium organotrifluoroborate (RBF₃K) reagents to the corresponding boronic acids (RB(OH)₂) has been studied in the context of their application in Suzuki–Miyaura coupling. The “slow release” strategy in such SM couplings is only viable if there is an appropriate gearing of the hydrolysis rate of the RBF₃K reagent with the rate of catalytic turnover. In such cases, the boronic acid RB(OH)₂ does not substantially accumulate, thereby minimizing side reactions such as oxidative homocoupling and protodeboronation. The study reveals that the hydrolysis rates (THF, H₂O, Cs₂CO₃, 55 °C) depend on a number of variables, resulting in complex solvolytic profiles with some RBF₃K reagents. For example, those based on p-F-phenyl, naphthyl, furyl, and benzyl moieties are found to require acid catalysis for efficient hydrolysis. This acid–base paradox assures their slow hydrolysis under basic Suzuki–Miyaura coupling conditions. However, partial phase-splitting of the THF/H₂O induced by the Cs₂CO₃, resulting in a lower pH in the bulk medium, causes the reaction vessel shape, material, size, and stirring rate to have a profound impact on the hydrolysis profile. In contrast, reagents bearing, for example, isopropyl, β-styryl, and anisyl moieties undergo efficient “direct” hydrolysis, resulting in fast release of the boronic acid while reagents bearing, for example, alkynyl or nitrophenyl moieties, hydrolyze extremely slowly. Analysis of B–F bond lengths (DFT) in the intermediate difluoroborane, or the Swain–Lupton resonance parameter (ℛ) of the R group in RBF₃K, allows an a priori evaluation of whether an RBF₃K reagent will likely engender “fast”, “slow”, or “very slow” hydrolysis. An exception to this correlation was found with vinyl-BF₃K, this reagent being sufficiently hydrophilic to partition substantially into the predominantly aqueous minor biphase, where it is rapidly hydrolyzed.