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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.

The manipulation of the steric nature of ligands is a key design principle in organometallic reactivity. While general intuition assumes steric effects to be repulsive, recent reports counterintuitively suggested that highly crowded hydrocarbon molecules may be stabilized more strongly than their less bulky analogues as a consequence of dispersion interactions. With the objective of investigating the significance of such attractive intramolecular dispersion forces in organometallic catalysis, we herein studied the effect of dispersion on the accessible geometries and reactivities for two trialkylphosphine ligands of different sizes in Pd-catalyzed cross-coupling reactions: i.e., L = PtBu 3 and its smaller analogue L = P(iPr)(tBu 2 ). Those methods that account well for dispersion (e.g., ωB97XD, B3LYP-D3) allowed the first location of bisphosphine-ligated transition states for the oxidative addition of Pd 0 L 2 to aromatic C−O bonds, involving the bulky and widely employed ligand L = PtBu 3 . DFT methods without dispersion gave rise to dissociation of one phosphine ligand in all cases examined. To probe whether dispersion may even be a reactivity-controlling factor, we also examined the favored site selectivity of the reaction of Pd 0 L 2 with 4-chlorophenyl triflate, for which the selectivity has previously been shown to be dependent on the ligation state of the reactive palladium species. Various DFT methods (PBE, B3LYP, M06L) and basis sets and different solvent models (COSMO-RS, CPCM) were assessed. While for Pd(PtBu 3 ) 2 dispersion-free and dispersion-containing methods predicted the monophosphine pathway via PdL and reaction at C−Cl to be favored, striking differences were observed for Pd[P(iPr)(tBu 2 )] 2 . Dispersion-free DFT predicted C−OTf addition by Pd[P(iPr)(tBu 2 )] 2 to be disfavored by ΔΔG ⧧ ≈ 20 kcal/mol, despite being experimentally accessible. In stark contrast, the involvement of dispersion adequately described the selectivity. The attractive dispersion forces of the crowded trialkyl substituents are therefore a key controlling factor in the competition between mono-and bisligated pathways. ■ INTRODUCTIONDesired reactivities and selectivities of transition-metalcatalyzed reactions are generally achieved through the manipulation of the steric and electronic properties of the employed phosphine ligands. 1 In this context, the ideal ligand is frequently identified as a result of elaborate screening approaches. However, owing to enormous developments in computing power, methods, and software, the employment of computational tools in the prediction and design of ligands is gaining increasing significance. 2,3 In particular, the implementation of dispersion in DFT has been a tremendous methodological advance. 4 As a result, several experimental reactivity phenomena could at last be explained with computational means. 5 These include the findings by Schreiner, Fokin, and co-workers that only dispersion-corrected DFT methods could explain their experiments, counterintuitively indicating that bulky tBu...