Abstract

Well-defined synthetic molecules that replicate key structure and/or reactivity patterns of metalloenzymes can provide structure/function correlations and answers to biochemical questions that are otherwise challenging to address. In contrast to the suite of inter/intramolecular interactions that facilitate small molecule binding and activation in enzymes found in nature, the commonly used strategies to construct analogous synthetic molecular systems are limited. The current paradigm in the synthetic community to prepare such analogues primarily focuses on a single active metal site with ligands that impart steric and electronic tunability to achieve substrate binding and activation, with limited attention paid to the secondary interactions of appended groups. Taking inspiration from biological systems, our group is working to develop strategies to exploit acidic and basic groups (hydrogen bond donors, Lewis acids/bases) to promote cooperative interactions and address unanswered mechanistic biochemical questions. This presentation will emphasize how acidic groups can be used to augment metal-based reactivity, as well as to show how incorporation of these units within a ligand scaffold can provide access to unique activation/functionalization processes. Key outcomes include the ability of acidic groups to modify the electronic environment and redistribute charge within a metal-coordinated ligand. The generality of these principles will be illustrated within the context of transformations relevant to both reductive as well as oxidative transformations using small molecule substrates.