Lewis or Brønsted? A Rectification of the Acidic and Aromatic Nature of Boranol-Containing Naphthoid Heterocycles

Abstract

Boron-containing heterocycles are important in a variety of applications from drug discovery to materials science; therefore a clear understanding of their structure and reactivity is desirable to optimize these functions. Although the boranol (B−OH) unit of boronic acids behaves as a Lewis acid to form a tetravalent trihydroxyborate conjugate base, it has been proposed that pseudoaromatic hemiboronic acids may possess sufficient aromatic character to act as Brønsted acids and form a boron oxy conjugate base, thereby avoiding the disruption of ring aromaticity that would occur with a tetravalent boronate anion. Until now no firm evidence existed to ascertain the structure of the conjugate base and the aromatic character of the boron-containing ring of hemiboronic "naphthoid" isosteres. Here, these questions are addressed with a combination of experimental, spectroscopic, X-ray crystallographic, and computational studies of a series of model benzoxazaborine and benzodiazaborine naphthoids. Although these hemiboronic heterocycles are unambiguously shown to behave as Lewis acids in aqueous solutions, boraza derivatives possess partial aromaticity provided their nitrogen lone electron pair is sufficiently available to participate in extended delocalization. As demonstrated by dynamic exchange and crossover experiments, these heterocycles are stable in neutral aqueous medium, and their measured pK a values are consistent with the ability of the endocyclic heteroatom substituent to stabilize a partial negative charge in the conjugate base. Altogether, this study corrects previous inaccuracies and provides conclusions regarding the properties of these compounds that are important toward the methodical application of hemiboronic and other boron heterocycles in catalysis, bioconjugation, and medicinal chemistry.

Investigation of a benzodiazaborine library to identify new pH-responsive fluorophores

“…and F. I. of the bDABs occur differ. Furthermore, the fluorescence responses of the bDABs ( E14 , I16 , J7 , and L10 ) fluctuate under basic conditions; we believe that these fluctuations are due to the sensitivity of the boranol units (behaving like a Lewis acid) of the bDABs to hydroxide ions (OH − ), as described in a recent study by Kazmi et al 37…”

“…36 Inspired by these interesting and unique characteristics of bDAB, we synthesized a combinatorial bDAB library to develop a potential pH-sensitive fluorescent structure that exhibits a pH-dependent fluorescence response owing to the alteration of its boranol unit, which behaves like a Lewis acid. 37 In this study, a library consisting of 238 bDABs with different substituents, including electron-donating and electron-withdrawing substituents, was prepared using various o -formylphenylboronic acid and phenylhydrazine derivatives. The fluorescence-based, high-throughput screening of this library revealed that the bDABs are highly sensitive to a wide pH range, from neutral to extremely basic.…”

Diazaborines Are a Versatile Platform to Develop ROS‐Responsive Antibody Drug Conjugates**

“…[15,19,23] Despite this,ascorroborated by recent studies, this architecture does not suppress the Lewis acidity of the boron center. [24] Therefore,w ee nvisioned that, if DAB's boron center retains the BA'so xidative sensitivity in the presence of ROS, the improved stability of this scaffold could contribute to bridge the technological gap that limits the construction of well-defined ROS-responsive linker for targeting drug conjugates.T he demonstration of this hypothesis constitutes the main focus of this study (Figure 1c).…”

Development of Diazaborines as ROS Sensitive Linkers for the Construction of Stimuli-Responsive Antibody Drug Conjugates

“…12,16,20 Despite this, as corroborated by recent studies, this architecture does not suppress the Lewis acidity of the boron centre. 21 Therefore, we envisioned that, if DAB's boron center retains the BA's oxidative sensitivity in the presence ROS, the improved stability of this scaffold could contribute to bridge the technological gap that limits the construction of well-defined ROS-responsive linker for targeting drug conjugates. The demonstration of this hypothesis constitutes the main focus of this study (Fig.…”