title: Protodeboronation of Heteroaromatic, Vinyl, and Cyclopropyl Boronic Acids: pH-Rate Profiles, Autocatalysis, and Disproportionation.
abstract: pH-rate profiles for aqueous-organic protodeboronation of 18 boronic acids, many widely viewed as unstable, have been studied by NMR and DFT. Rates were pH-dependent, and varied substantially between the boronic acids, with rate maxima that varied over 6 orders of magnitude. A mechanistic model containing five general pathways (k1-k5) has been developed, and together with input of [B]tot, KW, Ka, and KaH, the protodeboronation kinetics can be correlated as a function of pH (1-13) for all 18 species. Cyclopropyl and vinyl boronic acids undergo very slow protodeboronation, as do 3- and 4-pyridyl boronic acids (t0.5 > 1 week, pH 12, 70 °C). In contrast, 2-pyridyl and 5-thiazolyl boronic acids undergo rapid protodeboronation (t0.5 ≈ 25-50 s, pH 7, 70 °C), via fragmentation of zwitterionic intermediates. Lewis acid additives (e.g., Cu, Zn salts) can attenuate (2-pyridyl) or accelerate (5-thiazolyl and 5-pyrazolyl) fragmentation. Two additional processes compete when the boronic acid and the boronate are present in sufficient proportions (pH = pKa ± 1.6): (i) self-/autocatalysis and (ii) sequential disproportionations of boronic acid to borinic acid and borane.
authors.affiliation: School of Chemistry, University of Edinburgh , Joseph Black Building, David Brewster Road, Edinburgh EH9 3FJ, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Cox
authors.affiliation: School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Byrom Street, Liverpool L3 3AF, United Kingdom.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Leach
authors.affiliation: Pharmaceutical Technology and Development, AstraZeneca , Silk Road Business Park, Macclesfield SK10 2NA, United Kingdom.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Campbell
authors.affiliation: School of Chemistry, University of Edinburgh , Joseph Black Building, David Brewster Road, Edinburgh EH9 3FJ, United Kingdom.
authors.forename: Guy C
authors.initials: GC
authors.lastname: Lloyd-Jones