Classical physical organic molecular descriptors, such as logP, Hammett, Taft, or Charton values are often used for elucidating reaction mechanisms, yet, cannot always account for the intricate molecular interactions invoked in modern synthetic chemistry. Comprehensive experimental inquiry, complemented by data-intensive physical organic analysis, can bridge this gap and enable the study and optimization of increasingly complex systems. The overarching goal of our research program is to understand structural effects at the origin of chemical reactivity, selectivity, and functionality. To this end, we develop novel molecular descriptors and data analysis strategies, allowing the prediction of chemical outcomes and the study of reaction mechanisms. We use these strategies to study catalytic processes, and in particular the in situ modification of organocatalysts to control and tune secondary-sphere interactions. Modifying a catalyst structure in-situ is challenging due to the required orthogonality between the binding mode and catalytic activity. Nonetheless, this approach is appealing as it can uncover general molecular design principles for the facile introduction of highly modular selectivity- and reactivity-controlling handles into a variety of catalytic systems.