Cox, Paul Alan
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Boronic acids are key reagents in a host of chemical applications. In particular, they have been utilised in a range of metal-catalysed coupling reactions, involving the facile formation of carbon-carbon or carbon-heteroatom bonds under mild conditions that often boasts high yields and selectivity, thus becoming a vital tool in the design of complex molecules. Alongside the increased application of boronic acids, there has been a substantial increase in their commercial availability and now a wide range of elaborate boronic acids exist. However, many of these motifs are prone to undesired and troublesome side reactions, namely protodeboronation. Although many efforts have been made towards mitigating decomposition during coupling, the general mechanistic understanding of in situ protodeboronation is remarkably limited and outdated. pH-rate profiles for the protodeboronation of many heterocyclic, vinyl and cyclopropyl boronic acids (1:1 H2O/dioxane, pH 1-13, 70 °C) have been constructed using NMR spectroscopy. A general model was constructed to allow the simulation of pH-rate profiles and allow facile extrapolation of equilibrium and rate constants. With computational support, a range of novel protodeboronation mechanisms have been elucidated. Concentration-dependent processes (self-/auto-catalytic protodeboronation and disproportionation of boronic acid into borinic acid and boranes) are present when both boronic acid and boronate are present in high concentrations. Non-basic heterocyclic, vinyl and cyclopropyl boronic acids display common acid- and base-catalysed protodeboronation mechanisms, however basic heterocyclic boronic acids exhibit additional pathways. The formation and subsequent fragmentation of zwitterion water adducts (particularly for 2-pyridyl, 5-thiazolyl and 5- pyrazolyl boronic acids) leads to surprisingly rapid protodeboronation at neutral pH values, which can be attenuated (2-pyridyl) or accelerated (5-thiazolyl/5-pyrazolyl) with various Lewis acid additives. Protodeboronation of a series of polyfluorophenyl boronic acids under alkaline conditions revealed an immense range of reactivity, spanning several orders of magnitude (phenyl boronic acid, t½ ≈ months; pentafluorophenyl boronic acid, t½ ≈ milliseconds). Ortho-fluorine substituents were found to heavily influence the reactivity of such substrates. Detailed KIE and computational studies indicate the presence of a unique mechanism involving rate-limiting fragmentation of aryl boronate to form an aryl anion intermediate. Strong correlations with LFER and computational parameters indicate this mechanism is predominant with extremely electron deficient or ortho-fluoro substituted substrates, and can be used as a predictive model for the reactivity of aryl and polyfluorophenyl boronic acids.