Designing Functional and Responsive Molecules with Boronic Acids

Boronic acids (BAs) are one of the most important classes of reagents in modern synthesis, enabling a wide range of powerful transformations that facilitate the formation of key carbon-carbon and carbon-heteroatom bonds. While their success as reagents is well-known, their remarkable potential as building blocks for creating functional molecules is often overlooked. At the core of BAs' uniqueness is their ability to form reversible covalent bonds, thanks to the interconversion of the boron atom between its uncharged trigonal planar structure and an anionic sp³-hybridized form. This coordination chemistry has paved the way for exciting developments in fields such as medicinal chemistry and chemical biology. In recent years, BAs have been used to create a wide variety of materials, including small-molecule drugs, bioconjugates, drug delivery vehicles, polymeric nanomaterials, sensors, and even photosensitizers. What makes this strategy particularly unique is the structural diversity that can be achieved by functionalizing the BA coordination sphere, along with the possibility of incorporating stimuli-responsive mechanisms. This reactivity is further enhanced by the well-known oxidation of BAs in the presence of reactive oxygen species (ROS). A detailed understanding of the mechanisms governing the dynamic nature of BAs enables the engineering of sophisticated materials that can respond to specific molecular stimuli, such as changes in pH, carbohydrate or glutathione concentrations, and hydrogen peroxide. These stimuli are often key indicators of diseases such as cancer, inflammation, and neurodegeneration, placing BAs at the forefront of tools for designing materials that can potentially influence the mechanisms behind these diseases. In this Account, we draw on our group's expertise to explore the exciting potential of BAs in the design of functional materials. The focus is on the response of different boron complexes to biologically relevant stimuli. We describe the preparation of boronated esters (BEs), BA-salicylhydroxamic acid (BA-SHA) complexes, iminoboronates, diazaborines, and boronated thiazolidines and discuss how these chemotypes respond to disease-relevant triggers. Given the growing importance of using external stimuli to control the efficacy of modern drugs, we also explore how some of these compounds respond to specific chemicals. While this Account is not meant to be an exhaustive survey of every example of BA stimulus-responsiveness, we aim to integrate existing chemotypes and their chemical triggers. Our goal is to provide an overview of the mechanisms enabled by BAs for designing functional materials that could one day lead to innovative therapeutic options for human diseases.