Hydrolytic stability and protodeboronation of boronic esters

Abstract

Boronic acids and esters are indispensable building blocks in modern synthetic chemistry. Furthermore, their usage is widespread, spanning a broad range of applications, and yet it is often hampered by the inescapable nature of these substrates to undergo decomposition, commonly by means of protodeboronation, involving formal protonation of the C-B bond. In different circumstances, the ability to effectively remove remaining boronic acid/ester starting material post process is highly desirable. Therefore, studying the kinetics and mechanism of protodeboronation is of importance to understand and modulate their reactivity as required. Whilst the protodeboronation of a diverse range of boronic acids has been extensively studied in the Lloyd-Jones group, revealing an assortment of behaviors for electron-rich, polyfluorinated examples and heteroaromatic systems, the pathway by which their boronic esters react is relatively unknown. Given the complexity of pH-rate profiles for the protodeboronation of boronic acids and the dependence upon the exact nature of the substrate, the prospect of direct protodeboronation of boronic esters or alternatively the potential for a hydrolysis-protodeboronation sequence presents a more difficult kinetic challenge.

This research has centred on discerning the various pathways by which boronic esters undergo protodeboronation, with the ultimate aim of understanding and controlling the efficient application of these substrates in modern synthetic chemistry. By exploiting the use of in-situ and stopped flow (19F, 1H and 11B) NMR spectroscopy for reaction monitoring, the kinetics and mechanism of the base-catalysed hydrolysis and protodeboronation of a series of boronic esters, encompassing eight different polyols, and including ten polyfluoroaryl and heteroaryl moieties have been probed. These investigations were facilitated by pH-rate dependence studies, isotopic entrainment, 1H/2H KIEs and KS-DFT computations. The study reveals the phenomenological stability of boronic esters in basic 50% aq.-dioxane media, at 27 °C, to be highly nuanced (Scheme 1). Contrary to common assumption, esterification does not necessarily impart greater stability compared to the corresponding boronic acid. In fact, protodeboronation by the pre-hydrolytic pathway dominates for most esters studied, and the rate of hydrolysis is augmented by self-, auto- and phenolic catalysis when the pH is close to the pKₐ of the boronic acid/ester.