Ring Structure and Aromatic Substituent Effects on the pK_aof the Benzoxaborole Pharmacophore

Abstract

In this work, we present an investigation into the physical properties of a unique class of aromatic boronic acids, the benzoxaboroles. Using spectrophotometric methods, the ionization constants of a family of substituted benzoxaboroles are determined. Heterocyclic ring modifications are examined to determine their effects on the ionization of the boronic acid moiety. It is also shown that the substituent effects about the aromatic ring follow a Hammett relationship with the compounds' measured pK a values. Finally, these substituent effects are also shown to extend to the sugar binding properties of these compounds under physiologically relevant conditions. Combined, these data will inform medicinal chemists wishing to tailor the ionization and/or ability of this class of compound to bind diol-containing biomolecules.

Benzosiloxaboroles: Silicon Benzoxaborole Congeners with Improved Lewis Acidity, High Diol Affinity, and Potent Bioactivity

“…25 This is also consistent with the effect of two methyl groups at the 3-position observed for 1,3-dihydro-1-hydroxy-3,3-dimethyl-2,1-benzoxaborole (3,3-dMe-BnOB). 26 The basic structural motif in 3e is based on centrosymmetric H-bonded dimers (d O1···O2 = 2.774(1) Å, d H1···O2 = 1.94 Å) resembling those typical of benzoxaboroles. 3 Acidity of Benzosiloxaboroles.…”

Investigating a Relationship between the Mutagenicity of Arylboronic Acids and 11B NMR Chemical Shifts

“…Therefore, a 4:1 mixture of chloroform and methanol was utilized for this series of arylboronic acids. The 11 B NMR chemical shift for most of the chemicals was similar in both chloroform and the chloroform/ methanol mixture; however, 3,5-difluorophenylboronic acid gave different results in the two solvent systems (CDCl 3 , 28.217 ppm; CDCl 3 /CD 3 OD (4:1), 23.661 ppm). This is presumably a result of interactions between 3,5-difluorophenyl boronic acid and methanol, possibly resulting in a boronate species forming in the presence of methanol, which would lower the NMR chemical shift.…”

“…In addition, the boron center in the borole ring is strained and sterically hindered, resulting in a lower pK a than the corresponding arylboronic acid. 28 The nonmutagenic 5-fluorobenzoxaborole 25 has an 11 B NMR chemical shift of 31.1 ppm in DMSO, 29 which is evidence that benzoxaboroles are nonmutagenic because of steric hindrance.…”

Coordination Networks Based on Boronate and Benzoxaborolate Ligands

“…The pKa of the benzoxaborole/benzoxaborolate couple is ~7.3 due to the cyclic form of the organoboron function. For benzoxaboroles, pKa values vary depending on the nature of the substituents on the aromatic ring, as well as on the methylene group [19]. It is worth noting that the pKa values of boronic acids and their derivatives are globally higher compared to those of other organic acids such as carboxylic and phosphonic (Table 1).…”