Computational Investigations of Pd-Catalyzed C–H Functionalization Reactions

The use of an inert C–H bond towards the generation of a functional group is advantageous, as these bonds are the most abundant chemical moieties in organic molecules. A one-step conversion of a C–H bond to the desired functionality reduces the number of synthetic steps, which in turn minimizes the use of costly reagents, solvent, and time. Selective activation of a particular C–H bond in an organic molecule where C–H bonds are ubiquitous, however, is a challenging task. Among the most challenging aspects of developing robust C–H functionalization methodologies is identifying catalyst and reagent combinations capable of site-selective as well as stereoselective reactions. Therefore, directed C–H bond functionalization using a directing group and a suitable transition metal is of current interest. Palladium complexes are highly selective and have shown efficiency in various areas of organic synthesis, which make palladium catalysts particularly useful in the field of C–H functionalization. Palladium is incredibly powerful for the construction of carbon–carbon and carbon–heteroatom bonds by C–H activation of aryl and alkyl groups. Palladium-catalyzed ligand-directed C–H functionalization is a key goal towards the synthesis of complex multifunctional substrates. Understanding the mechanism and origins of stereoselectivity of palladium-catalyzed C–H functionalization reactions is essential to progress this field. The collaboration between experiment and computations has provided a deeper mechanistic understanding and insight than any of the isolated techniques can provide. Kinetics and isolation of intermediates provide information on mechanistic pathways, while computations can provide details of both structures and energetics in specific steps in the whole catalytic cycle. Computations have become vital to elucidate structures of molecules, mechanisms, and selectivities of reactions. Due to the rapid development of hardware, software, and theoretical methods, computational chemistry has evolved into a very powerful and routine tool to study complex mechanisms. The work in this thesis has stemmed from several collaborations through the NSF Center for Selective C–H Functionalization (CCHF), which is comprised of synthetic methodologists, physical organic chemists, catalyst developers, enzymologists, computational chemists, and several partners in the pharmaceutical industry. Motivated by the potential of understanding C–H functionalization transformations in order to promote the development of new reactions, this thesis focuses on using computational methods to understand systems of relevance to C–H activation using palladium as a catalyst. Early projects aim to use computations to make proposed models for nonlinear effects to serve as a meaningful mechanistic probe for predicting reaction kinetics (Chapters 1-2). The second section delves into elucidating the mechanisms as well as the role of various substrates, ligands, and oxidants, particularly silver (I) acetate, on how each particular reaction is performed (Chapters 3-6). Later in this thesis, the focus diverges to highlight the elucidation of an enantioselective -C–H functionalization where stereoselectivity arises from attractive aryl–aryl interactions (Chapter 7)