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

Abstract

CONSPECTUS 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 target functionality. 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 functionality. The second section involves two types of bidentate ligands, mono-N-protected amino acid (MPAA) and acetyl-protected aminoethyl quinoline (APAQ) ligands that facilitate the C–H activation reactions in an internal base mechanism. 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 the asymmetric palladium insertion into prochiral C–H bonds on a single methylene carbon center. The origins of the dramatic differences of 5-membered (relatively inactive) and 6-membered chelation (highly active) in the β-methylene C(sp3)–H activation reactions by Pd(II) catalyst were explained with density functional theory (DFT) calculations. This is mainly due to the steric repulsions between the ArF group of substrate and the quinoline group of the ligand. The steric repulsion between the ArF group of substrate and the quinoline group of the acetyl-protected aminomethyl quinoline ligand destabilizes the 5-membered chelate transition structure, increasing the energy of transition state. The third section discusses a mechanism involving a Pd-Ag heterodimeric complex intermediate in the template-directed, Pd(II)-catalyzed 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 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 calculation. The interaction between the experimental and computational groups, and the interplay that led to these discoveries, are highlighted in this Account.

Strong Preference of the Redox‐Neutral Mechanism over the Redox Mechanism for the TiIV Catalysis Involved in the Carboamination of Alkyne with Alkene and Diazene

“…Although we used the M06‐L//B3LYP combination in this study, Houk and co‐workers recommended the M06//B3LYP combination to study transition‐metal‐catalyzed reactions . Encouraged by their recommendation, we performed single‐point energy calculations at the M06 level, as well as at other levels (Table ), to ascertain whether the redox‐neutral preference of Ti IV catalysis also holds true for other levels of calculation.…”

“…Althoughw eu sed the M06-L//B3LYP combination in this study,H ouk and co-workersr ecommended the M06//B3LYP combination to study transition-metal-catalyzed reactions. [23] Encouraged by their recommendation, we performed singlepoint energy calculations at the M06 level,a sw ell as at other levels (Table 1), to ascertain whether the redox-neutral preference of Ti IV catalysis also holds true for other levels of calculation. The data in Table 1s howt hat the fivel evels unanimously predict that the barriers (TS5, TS12,a nd TS16)f or the redoxneutralp rocessesa re significantly lower than their counterparts (TS5 a OS , TS12 b OS ,a nd TS16 a OS )i nr edox processes.…”

Stereoelectronic Effects in Ligand Design: Enantioselective Rhodium‐Catalyzed Hydrogenation of Aliphatic Cyclic Tetrasubstituted Enamides and Concise Synthesis of (R)‐Tofacitinib

“…Thes ame method was also employed by Gridnev in calculations of TangPhos-catalyzed enantioselective hydrogenation, [20] and by Houk and Yu [21] in studying Pd-and Ag-catalyzed C À Hf unctionalization, with the Los Alamos Effective Core Potential for Rh, and aGaussian type 6-31G(d) basis set for all other atoms. Thes ame method was also employed by Gridnev in calculations of TangPhos-catalyzed enantioselective hydrogenation, [20] and by Houk and Yu [21] in studying Pd-and Ag-catalyzed C À Hf unctionalization, with the Los Alamos Effective Core Potential for Rh, and aGaussian type 6-31G(d) basis set for all other atoms.…”

Computational exploration of Pd‐catalyzed C–H bond activation reactions

“…Computational organic chemistry has become an essential tool for understanding the mechanisms of chemical reactions . The close collaborations between experimentalists and theorists have made great advances in the field of C–H bond activation and functionalization . Reaction progress kinetic analysis (RPKA) provides mechanistic insights into both simple and complex catalytic networks .…”