Reactivity and selectivity in homogeneous nickel catalysis and in the formal conia-ene reaction : a computational and experimental approach

Chapter 1: Incorporation of fluorine or fluorine-containing moieties into organic molecules significantly impacts several physical properties. Consequently, a large number of agrochemicals and pharmaceuticals on the market contain fluorine. In this context, the SCF3 group is of high current interest. While several methods have successfully been developed to incorporate the SCF3 group into small molecules, the functionalization of Csp2-O bonds had remained inaccessible. This chapter describes a combined computational and experimental approach to the development of the trifluoromethythiolation of Csp2-O bonds (vinyl and aryl) under homogeneous nickel catalysis. This work emphasizes that when harnessing Nickel’s activity to introduce potentially reactive groups, such as SCF3, the reactivity of the functional groups in the starting material and in the product require matching in order to prevent deactivation side-reactions. In this context, computational chemistry allowed us to identify the match/mismatch functionalities and guide the substrate scope. Chapter 2: While many of the processes catalyzed by Pd can also be mediated by Ni, the assumption that the elementary steps are mechanistically congruent is an oversimplified view. Nickel possesses unique properties, such as its higher reactivity towards bonds otherwise considered inert as well as its interconversion between different oxidation states, predominantly Ni(0), Ni(I) and Ni(II), under cross coupling conditions. These specific factors make both chemoselectivity and the distinction between active intermediates and off-cycle species disproportionately difficult. Achieving understanding and - ultimately - control over the interplay of reactivity and oxidation state is a crucial step towards harnessing Nickel’s unique reactivity. Therefore, a catalytic application of Ni(I)-NHC dimers has been developed with the first Nickel catalysed C-SeCF3 bond formation. This protocol allows for the discrimination between, among others, Ar-I , Ar-Cl and Ar-Br functionalities, a feature not known in the same way for Pd catalysis. Mechanistic investigations by NMR spectroscopy and DFT studies support dinuclear reactivity consistently. Chapter 3: Enders and co-workers have developed a protocol for the enantioselective one-pot synthesis of five-membered spiropyrazolones. This process consists of two distinct steps, an asymmetric Michael addition catalyzed by a squaramide and a 5-exo-dig-cyclization, which was mediated by Silver catalysis. Depending on the substitution pattern of the alkyne moiety, the reaction has been observed to proceed even in the absence of Silver. In order to shed light on this intriguing feature, computational studies were performed, considering different mechanistic pathways (neutral, radical, ionic). Computations suggest an ionic pathway for the Ag-mediated cyclization step. In the absence of Silver, and when the alkyne moiety is substituted by a phenyl ring, computations suggest a radical pathway to be operative. Subsequent experiments were performed under inert atmosphere and the reaction without Silver was not productive anymore but instead stopped at the Michael addition intermediate, suggesting oxygen being involved in the initial radical formation step