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

Abstract

The hydrolysis of potassium organotrifluoroborate (RBF(3)K) 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 RBF(3)K 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, H(2)O, Cs(2)CO(3), 55 °C) depend on a number of variables, resulting in complex solvolytic profiles with some RBF(3)K 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/H(2)O induced by the Cs(2)CO(3), 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 RBF(3)K, allows an a priori evaluation of whether an RBF(3)K reagent will likely engender "fast", "slow", or "very slow" hydrolysis. An exception to this correlation was found with vinyl-BF(3)K, this reagent being sufficiently hydrophilic to partition substantially into the predominantly aqueous minor biphase, where it is rapidly hydrolyzed.

Eco-Friendly Physical Activation Methods for Suzuki–Miyaura Reactions

“…[136] An US-induced continuous flow technique has been developed by Shil et al [137] for the gram scale SMC reaction of haloarenes (chloro, bromo and iodo) with phenylboronic acid catalyzed by solid supported Pd(0) nano/microparticle (SS-Pd). They previously reported [138] a facile process for the in situ generation of Pd(0) nano-and microparticles and their stable deposition over the amberlite IRA 900 resin.…”

Chemoselective Suzuki–Miyaura Cross‐Coupling via Kinetic Transmetallation

“…H2O. 20 (1) Equilibration increased as H2O increased, thereby reducing selectivity due to the formation of a competing boronic acid from the BPin component (see Scheme 3). (2) Introduction of a bulk basic aqueous phase promotes phase transfer of boronic acid from the organic phase to the aqueous as its cognate boronate.…”

“…(2) Introduction of a bulk basic aqueous phase promotes phase transfer of boronic acid from the organic phase to the aqueous as its cognate boronate. 19 Assuming a largely organic phase bound Pd catalyst, 15,20 this lowers the concentration of boronic acid available for transmetallation in the organic phase, instead requiring a contrathermodynamic transfer of boronic acid boronate from the aqueous phase to the organic, 15,20 and thereby negatively impacting both reaction efficiency and selectivity. Spectroscopic investigations supported these hypotheses -the key solution events are shown in Scheme 4.…”

The Suzuki–Miyaura Cross-Coupling as a Versatile Tool for Peptide Diversification and Cyclization

“…The mechanism of this reaction originally proposed by Miyaura and Suzuki has been revisited recently, which provides insights useful for rational reaction optimization [24][25][26]. Besides classical organoboronic acids, new boron-derived reagents have been developed with improved shelf life and controlled release of reactant and stability versus deborylation during cross-coupling [4][5][6][7][8][9]27,28]. In this review, we focus on the derivatization of amino acids up to protein substrates.…”

“…Catalysts 2017, 7, 74 2 of 31 improved shelf life and controlled release of reactant and stability versus deborylation during crosscoupling [4][5][6][7][8][9]27,28]. In this review, we focus on the derivatization of amino acids up to protein substrates.…”