Abstract
Tuning the local environment around a metal center controls its reactivity, allowing for thermodynamic and kinetic control in catalysts. Beyond the primary coordination sphere, control of residues outside the metal coordination range (the secondary coordination sphere) can significantly impact substrate binding and reactivity, controlling substrate orientation, facilitating proton and electron transfer, etc. The tris(amido)amine, or TREN, scaffold is a well-recognized C₃-symmetric, trianionic, tetradentate ligand set. Development of new strategies to break this C₃ symmetry expands the scope of TRENs, enabling changes in charge, steric impact, electron donation, and secondary coordination sphere functionalities within a single ligand. The syntheses, spectroscopic characterization, and reactivity of a new series of TREN-based ligands are discussed. This ligand flexibility through two novel symmetry-breaking mechanisms, based on carbon-nitrogen coupling and copper (II) catalysis, is characterized by NMR and X-ray crystallography. Indole is a well-known organic group with a wide range of pharmacological activities due to the different mechanisms of action that can result from its interaction with biological receptors. With an increased need to treat mental health disorders including anxiety, post-traumatic stress disorder, and addiction, studying the structure-activity relationship (SAR) of indole-based small molecules at the serotonin receptors is of great significance. Minor modifications in structure can greatly alter the binding, pharmacology and activity of these molecules at human receptors. In order to experimentally (qualitatively and quantitatively) determine the relationship between their chemical structure and biological activity, various indole-based tryptamine derivatives were synthesized and systematically modified in this research work. NMR and X-ray crystallography are used to characterize the analytically pure tryptamines that will provide perspective for researchers to strategically design novel indole derivatives having diverse pharmacological activity.