Efforts toward upgrading biomass are hindered by challenges in understanding and designing catalytic pathways in the condensed phase. It remains challenging to predict how solvents and ions will interact with reacting species and organize within and around catalytic active regions. Since these interactions can strongly influence catalytic outcomes, we seek to delineate the origins of solvent and ion driven changes in catalytic rates using a combined computational and experimental approach. To achieve atomic level resolution on these effects, we study a representative (Pd2L4)4+ cage. This system is known to catalyze Diels-Alder reactions between p-toluquinone and 1,3-pentadiene up to 103 times homogeneous rates in the presence of dichloromethane solvent. However, in dimethyl sulfoxide and acetonitrile solvents, catalysis is inhibited. Binding affinities also decrease by three-fold in these solvents. By resolving atomic interactions with classical molecular dynamics, we find that counterion localization, solvent coordination, and intermolecular interactions like pi-pi stacking combine to determine substrate binding affinity. Experimentally, we characterize the cage environment with liquid phase spectroscopy and find that binding in the cage breaks dienophile symmetry and shifts vibrational frequency of coordinating carbonyl groups by over 25 cm-1. We differentiate inductive and electric field contributions to this frequency shift by applying hybrid density functional theory (DFT) to compute electric fields in the cage environment and quantify frequency shifts both when constraining and allowing substrate polarization. Extending this method to other systems, we quantify how counterions and solvation environments modulate local electric fields and induction in coordinating guests. These insights inform design of cage linkers in cooperation with the local solvent and counterions to form cavities with favorable electrostatic environments for Diels-Alder catalysis. This work elucidates the role that solvents and counterions can play in confined catalytic environments and provides new approaches to make sense of infrared shifts within catalytic active sites.
