Oxidized small molecules are routinely activated and reduced using reductase enzymes. The active site(s) often feature a network of nearby secondary sphere hydrogen bonding residues that are broadly appreciated to facilitate substrate binding/activation at metal sites that would otherwise show low affinity. Secondary sphere acids can serve numerous roles to achieve an overall challenging bond transformation. Synthetic model systems can enable key structure/function studies decouple the role(s) of primary/secondary groups. Our group has been working to systematically evaluate the criteria needed for cooperative substrate binding/activation and this presentation will provide an overview of some of these efforts to understand ways by which acidic groups can be leveraged for reductase-type chemistry. Considerations for how the overall thermodynamic landscape of challenging reactions can be adjusted by modifying binding affinity and/or redox potentials. Specific examples will be described that include cases where the substrate binding event and redox processes are dramatically changed or actually turned on/off by secondary sphere acidic groups. These broader principles will be outlined within the context of reactions that include oxygen atom transfer, hydroxyl rebound, and functionalization from O2 as well as oxyanions (e.g. perchlorate, nitrite/nitrate).