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Computational chemistry has become an established tool for the study of the origins of chemical phenomena and examination of molecular properties. Because of major advances in theory, hardware and software, calculations of molecular processes can nowadays be done with reasonable accuracy on a time-scale that is competitive or even faster than experiments. This overview will highlight broad applications of computational chemistry in the study of organic and organometallic reactivities, including catalytic (NHC-, Cu-, Pd-, Ni-catalyzed) and noncatalytic examples of relevance to organic synthesis. The selected examples showcase the ability of computational chemistry to rationalize and also predict reactivities of broad significance. A particular emphasis is placed on the synergistic interplay of computations and experiments. It is discussed how this approach allows one to (i) gain greater insight than the isolated techniques, (ii) inspire novel chemistry avenues, and (iii) assist in reaction development. Examples of successful rationalizations of reactivities are discussed, including the elucidation of mechanistic features (radical versus polar) and origins of stereoselectivity in NHC-catalyzed reactions as well as the rationalization of ligand effects on ligation states and selectivity in Pd- and Ni-catalyzed transformations. Beyond explaining, the synergistic interplay of computation and experiments is then discussed, showcasing the identification of the likely catalytically active species as a function of ligand, additive, and solvent in Pd-catalyzed cross-coupling reactions. These may vary between mono- or bisphosphine-bound or even anionic Pd complexes in polar media in the presence of coordinating additives. These fundamental studies also inspired avenues in catalysis via dinuclear Pd(I) cycles. Detailed mechanistic studies supporting the direct reactivity of Pd(I)-Pd(I) with aryl halides as well as applications of air-stable dinuclear Pd(I) catalysts are discussed. Additional combined experimental and computational studies are described for alternative metals, these include the discussion of the factors that control C-H versus C-C activation in the aerobic Cu-catalyzed oxidation of ketones, and ligand and additive effects on the nature and favored oxidation state of the active catalyst in Ni-catalyzed trifluoromethylthiolations of aryl chlorides. Examples of successful computational reactivity predictions along with experimental verifications are then presented. This includes the design of a fluorinated ligand [(CF3)2P(CH2)2P(CF3)2] for the challenging reductive elimination of ArCF3 from Pd(II) as well as the guidance of substrate scope (functional group tolerance and suitable leaving group) in the Ni-catalyzed trifluoromethylthiolation of C(sp(2))-O bonds. In summary, this account aims to convey the benefits of integrating computational studies in experimental research to increase understanding of observed phenomena and guide future experiments.

Full control over the selectivity of carbon–carbon double-bond migrations would enable access to stereochemically defined olefins that are central to the pharmaceutical, food, fragrance, materials, and petrochemical arenas. The vast majority of double-bond migrations investigated over the past 60 years capitalize on precious-metal hydrides that are frequently associated with reversible equilibria, hydrogen scrambling, incompleteE/Zstereoselection, and/or high cost. Here, we report a fundamentally different, radical-based approach. We showcase a nonprecious, reductant-free, and atom-economical nickel (Ni)(I)-catalyzed intramolecular 1,3-hydrogen atom relocation to yieldE-olefins within 3 hours at room temperature. Remote installations ofE-olefins over extended distances are also demonstrated.

Learning to stabilize palladium dimers Catalyst optimization is often difficult to do rationally. Once something works, it may be unclear which specific features underpin the performance. A case in point is the stabilization of palladium(I) dimers, which has relied on a very small class of phosphine ligands. Hueffel et al . used machine learning to search for patterns in this known class of ligands and thereby guide the discovery of variants that likewise stabilize the dimers. The authors were able to synthesize eight previously unreported dimers. —JSY

The direct and selective functionalization of C-H bonds of arenes is one of the most challenging yet valuable aims in organic synthesis. Despite notable recent achievements, a pre-installed directing group proved to be essential in most of the methodologies reported so far. In this context, the use of a transient directing group that can be generated in situ has attracted attention and demonstrated the great potential of this strategy. Here we report the use of an in situ generated palladacycle to accomplish remote-selective C-H alkylation reactions of arenes. Following the C-H functionalization event, the alkylated aryl ring undergoes a formal migration to provide diversely substituted benzofuran and indole scaffolds. Computational studies revealed that a palladium(IV) intermediate is not involved in the alkylation step. The aryl migration was found to proceed through a sequential C-C bond cleavage, insertion and β-hydride-elimination process. The increasing steric bulk that builds up during the C-H functionalization step drives the unusual C-C bond cleavage in a non-strained system.

Building on our recent disclosure of catalysis at dinuclear Pd(I) sites, we herein report the application of this concept to the realization of the first catalytic method to convert aryl iodides into the corresponding ArSeCF3 compounds. Highly efficient C-SeCF3 coupling of a range of aryl iodides was achieved, enabled by an air-, moisture-, and thermally stable dinuclear Pd(I) catalyst. The novel SeCF3 -bridged dinuclear Pd(I) complex 3 was isolated, studied for its catalytic competence and shown to be recoverable. Experimental and computational data are presented in support of dinuclear Pd(I) catalysis.

Dinuclear PdI complexes have found widespread applications as diverse catalysts for a multitude of transformations. Initially their ability to function as pre‐catalysts for low‐coordinated Pd0 species was harnessed in cross‐coupling. Such PdI dimers are inherently labile and relatively sensitive to oxygen. In recent years, more stable dinuclear PdI−PdI frameworks, which feature bench‐stability and robustness towards nucleophiles as well as recoverability in reactions, were explored and shown to trigger privileged reactivities via dinuclear catalysis. This includes the predictable and substrate‐independent, selective C−C and C−heteroatom bond formations of poly(pseudo)halogenated arenes as well as couplings of arenes with relatively weak nucleophiles, which would not engage in Pd0/PdII catalysis. This Minireview highlights the use of dinuclear PdI complexes as both pre‐catalysts for the formation of highly active Pd0 and PdII−H species as well as direct dinuclear catalysts. Focus is set on the mechanistic intricacies, the speciation and the impacts on reactivity.

The reduction of Pd(II) intermediates to Pd(0) is a key elementary step in a vast number of Pd-catalyzed processes, ranging from cross-coupling, C-H activation, to Wacker chemistry. For one of the most powerful new generation phosphine ligands, PtBu, oxidation state Pd(I), and not Pd(0), is generated upon reduction from Pd(II). The mechanism of the reduction of Pd(II) to Pd(I) has been investigated by means of experimental and computational studies for the formation of the highly active precatalyst {Pd(μ-Br)(PtBu)}. The formation of dinuclear Pd(I), as opposed to the Pd(0) complex, (tBuP)Pd was shown to depend on the stoichiometry of Pd to phosphine ligand, the order of addition of the reagents, and, most importantly, the nature of the palladium precursor and the choice of the phosphine ligand utilized. In addition, through experiments on gram scale in palladium, mechanistically important additional Pd- and phosphine-containing species were detected. An ionic Pd(II)Br dimer side product was isolated, characterized, and identified as the crucial driving force in the mechanism of formation of the Pd(I) bromide dimer. The potential impact of the presence of these side species for in situ formed Pd complexes in catalysis was investigated in Buchwald-Hartwig, α-arylation, and Suzuki-Miyaura reactions. The use of preformed and isolated Pd(I) bromide dimer as a precatalyst provided superior results, in terms of catalytic activity, in comparison to catalysts generated in situ.