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Abstract Recent computational studies highlighting the importance of accounting for dynamic effects on organic reactivity are discussed, accompanied by descriptions of the factors that led the author to pursue these projects. 

Abstract Electrostatic drag in the intramolecular Schmidt reactions of azidopropylcyclohexanones is characterized using density functional theory (DFT) calculations and direct dynamics simulations. Despite resulting from enthalpically favorable interactions, electrostatic drag slows down N₂loss during formation of bridged lactam products, an effect with implications for controlling product selectivity. 

Abstract The direct formation of aryl C−O bonds via the intramolecular dehydrogenative coupling of a C−H bond and a pendant alcohol represents a powerful synthetic transformation. Herein, we report a method for intramolecular arene C−H etherification via an umpoled alcohol cyclization mediated by an I(III)N‐HVI reagent. This approach provides access to functionalized chromane scaffolds from primary, secondary and tertiary alcohols via a cascade cyclization‐iodonium salt formation, the latter providing a versatile functional handle for downstream derivatization. Computational studies support initial formation of an umpoled O‐intermediate via I(III) ligand exchange, followed by competitive direct and spirocyclization/1,2‐shift pathways. magnified image 

Intramolecular C–H insertions with donor/donor dirhodium carbenes provide a concise and highly stereoselective method to set two contiguous stereocenters in a single step. Herein, we report the insertion of donor/donor carbenes into stereogenic carbon centers allowing access to trisubstituted benzodihydrofurans in a single step. This study illuminates, for the first time, the stereochemical impact on the carbene center and delineates the structural factors that enable control over both stereogenic centers. Sterically bulky, highly activated C–H insertion centers exhibit high substrate control yielding a single diastereomer and a single enantiomer of product regardless of the catalyst used. Less bulky, less activated C–H insertion centers exhibit catalyst control over the diastereomeric ratio (dr), where a single enantiomer of each diastereomer is observed with high selectivity. A combination of experimental studies and DFT calculations was used to elucidate the origin of these results. First, hydride transfer from the stereogenic insertion site proceeds with high stereoselectivity to the carbene center, thus determining the absolute configuration of the product. Second, the short lived zwitterionic intermediate can diaster-eoselectively ring-close by a hitherto unreported S E 2 mechanism that is either controlled by the substrate or the catalyst. These results demonstrate that donor/donor carbenes undergo uniquely stereoselective reactions that originate from a stepwise reaction mechanism, in contrast to the analogous concerted reactions of carbenes with one or more electron-withdrawing groups attached. 

Abstract This review summarizes approaches and caveats in computational modeling of transition-metal-catalyzed sigmatropic rearrangements involving carbene transfer. We highlight contemporary examples of combined synthetic and theoretical investigations that showcase the synergy achievable by integrating experiment and theory. 1 Introduction 2 Mechanistic Models 3 Theoretical Approaches and Caveats 3.1 Recommended Computational Tools 3.2 Choice of Functional and Basis Set 3.3 Conformations and Ligand-Binding Modes 3.4 Solvation 4 Synergy of Experiment and Theory – Case Studies 4.1 Metal-Bound or Free Ylides? 4.2 Conformations and Ligand-Binding Modes of Paddlewheel Complexes 4.3 No Metal, Just Light 4.4 How To ‘Cope’ with Nonstatistical Dynamic Effects 5 Outlook