Relative Strength of Common Directing Groups in Palladium-Catalyzed Aromatic C−H Activation

• Published in: iScience Vol. 20; pp. 373 - 391
• Main Authors: Tomberg, Anna, Muratore, Michael Éric, Johansson, Magnus Jan, Terstiege, Ina, Sköld, Christian, Norrby, Per-Ola
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.10.2019; Elsevier
• Subjects: Catalysis; Computational Molecular Modelling; Organic Reaction; Organic Reaction; Computational Molecular Modelling; Catalysis
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2019.09.035

Efficient functionalization of C−H bonds can be achieved using transition metal catalysts, such as Pd(OAc)2. To better control the regioselectivity in these reactions, some functional groups on the substrate may be used as directing groups, guiding the reactivity to an ortho position. Herein, we describe a methodology to score the relative strength of such directing groups in palladium-catalyzed aromatic C−H activation. The results have been collected into a scale that serves to predict the regioselectivity on molecules with multiple competing directing groups. We demonstrate that this scale yields accurate predictions on over a hundred examples, taken from the literature. In addition to the regioselectivity prediction on complex molecules, the knowledge of the relative strengths of directing groups can also be used to work with new combinations of functionalities, exploring uncharted chemical space. [Display omitted] •Directing group strength for ortho-palladation can be predicted quantum chemically•Correlation with fragments allow regioselectivity predictions in complex molecules•Directing strength is enhanced by deprotonation under the reaction conditions•Palladation in between two directing groups is disfavored sterically; no synergy Catalysis; Computational Molecular Modelling; Organic Reaction