Experimental–Computational Synergy for Selective Pd(II)-Catalyzed C–H Activation of Aryl and Alkyl Groups

C-H activation and functionalization are on the forefront of modern synthetic chemistry. Imagine if any C-H bond of a molecule could be converted to a C-X bond, where X is the target functionality-this would alter the synthetic blueprints for complex target molecules since it would provide novel disconnections in retrosynthetic analysis. Collaborations between many experimental and computational groups have led to rapid developments of new C-H functionalization methods. Our groups represent an example of this; we were brought together as part of the NSF-supported Center for Selective C-H Functionalization. Many examples of experimental-computational synergy for selective Pd(II)-catalyzed C-H activation of aryl and alkyl groups are described in this Account. We describe computations by the Houk group made in response to experimental stimuli by the Yu group. The first section discusses the experimental and computational investigations of oxazoline-directed stereoselective Pd(II)-catalyzed C(sp3)-H bond activation that occurs through the concerted metalation-deprotonation (CMD) pathway involving a monomeric Pd(II) complex. The second section involves two types of bidentate ligands, mono-N-protected amino acid (MPAA) and acetyl-protected aminoethyl quinoline (APAQ) ligands that promote the C-H activation reactions with the ligand as the internal base. In the MPAA-assisted remote C-H bond activation, the basic dianionic amidate ligand participates in the deprotonation of a specific C-H bond. This mechanism accounts for the improved reactivity and selectivity in C-H activation reactions with MPAA ligands. The chiral APAQ ligands enable asymmetric palladium insertion into prochiral C-H bonds on a single methylene carbon center. The dianionic amidate of the APAQ ligand acts as an intramolecular base to deprotonate the methylene C-H asymmetrically and facilitate chiral Pd-C bond formation. The origins of the dramatic differences of five-membered (relatively inactive) and six-membered (highly active) chelation in β-methylene C(sp3)-H activation reactions by a Pd(II) catalyst were explained with density functional theory (DFT) calculations. This is mainly due to the steric repulsions between the ArF group of the substrate and the quinoline group of the ligand. The steric repulsion between the ArF group of the substrate and the quinoline group of the APAQ ligand destabilizes the five-membered chelate transition structure, increasing the energy of the transition state. The third section discusses a mechanism involving a Pd-Ag heterodimeric complex intermediate in the template-directed, Pd(II)-catalyzed remote meta functionalization of toluene derivatives and benzoic acid derivatives. The nitrile directing group of the template coordinates with Ag while the Pd is placed adjacent to the meta-C-H bond in the transition state, leading to the observed high meta selectivity. The selective activation of remote meta-C-H bonds at various distances can be achieved by tuning the template. The dual role of AgOAc as both an oxidant and part of the heteronuclear active species in the mechanism involving PdAg(OAc)3 was determined by DFT calculations and is in accord with literature information about complexes. For the systems discussed in these three sections, the similarity is that they all proceed via the CMD mechanism. The differences lie in the proton acceptors and the active Pd species. Common CMD involves a monomeric Pd mechanism with acetate as the proton acceptor. Both MPAA and APAQ ligands react via monomeric Pd mechanisms with a ligand moiety (the amidate oxygen) as the proton acceptor. Nitrile-containing template-mediated meta-C-H activations proceed via a Pd-Ag heterodimeric mechanism, still with acetate as the proton acceptor. The interaction between our two groups, experts in experiment and computation, and the discoveries made possible by that interplay are highlighted in this Account.