The article by Sharon R. Neufeldt and Melanie S. Sanford from the University of Michigan, Department of Chemistry, focuses on the development of site-selective palladium-catalyzed C–H bond functionalization reactions over the past decade. The authors explore three main approaches to achieve this goal: substrate-based control through the use of directing groups, substrate control through the use of electronically activated substrates, and catalyst-based control. 1. **Substrate-Based Control**: This approach involves the use of directing groups to guide the activation and functionalization of specific C–H bonds. The authors have identified trends in selectivity for both sp² and sp³ C–H bonds, such as preferential functionalization at the less hindered sp² C–H bond ortho to the directing group and at primary sp³ C–H bonds β to the directing group. 2. **Substrate-Based Control through Electronically Activated Substrates**: This approach leverages the electronic properties of substrates to bias the palladation step towards specific C–H bonds. The authors have successfully achieved site-selective arylation of indoles and pyrroles using diaryliodonium oxidants, with selectivity altered when the C-2 site is blocked. 3. **Catalyst-Based Control**: This approach involves modifying the structure of the supporting ligands on the Pd catalyst to control site selectivity. The authors have demonstrated that the structure of N–N bidentate ligands can significantly influence selectivity, such as achieving exquisite selectivity for α-arylation of naphthalene and reversing the site selectivity of a 1,3-dimethoxybenzene/benzol[6]quinoline coupling reaction by changing the ligand from acetate to carbonate. The article highlights the potential of catalyst-based control in achieving site-selective C–H bond functionalization, a frontier area that has seen growing interest in recent literature. The authors anticipate significant advancements in this field, particularly in the development of practical and selective methods without the need for activating or directing groups.The article by Sharon R. Neufeldt and Melanie S. Sanford from the University of Michigan, Department of Chemistry, focuses on the development of site-selective palladium-catalyzed C–H bond functionalization reactions over the past decade. The authors explore three main approaches to achieve this goal: substrate-based control through the use of directing groups, substrate control through the use of electronically activated substrates, and catalyst-based control. 1. **Substrate-Based Control**: This approach involves the use of directing groups to guide the activation and functionalization of specific C–H bonds. The authors have identified trends in selectivity for both sp² and sp³ C–H bonds, such as preferential functionalization at the less hindered sp² C–H bond ortho to the directing group and at primary sp³ C–H bonds β to the directing group. 2. **Substrate-Based Control through Electronically Activated Substrates**: This approach leverages the electronic properties of substrates to bias the palladation step towards specific C–H bonds. The authors have successfully achieved site-selective arylation of indoles and pyrroles using diaryliodonium oxidants, with selectivity altered when the C-2 site is blocked. 3. **Catalyst-Based Control**: This approach involves modifying the structure of the supporting ligands on the Pd catalyst to control site selectivity. The authors have demonstrated that the structure of N–N bidentate ligands can significantly influence selectivity, such as achieving exquisite selectivity for α-arylation of naphthalene and reversing the site selectivity of a 1,3-dimethoxybenzene/benzol[6]quinoline coupling reaction by changing the ligand from acetate to carbonate. The article highlights the potential of catalyst-based control in achieving site-selective C–H bond functionalization, a frontier area that has seen growing interest in recent literature. The authors anticipate significant advancements in this field, particularly in the development of practical and selective methods without the need for activating or directing groups.