Optimizing selectivity in heterocycle C-H functionalization through computational design

This thesis describes the application of quantum chemical methods to understand Pdcatalyzed C-H activation of aromatic and heteroaromatic molecules, with a view to establishing the factors that enable predictions of site-selectivity to be made. The first chapter introduces palladium catalyzed C-C bond formation and the synthetic field of direct (C-H/C-X) and oxidative cross-couplings (C-H/C-H), the postulated mechanisms of C-H activation, and the theoretical background to the project. The focus of Chapter 2 is the mechanism and site-selectivity of Pd catalyzed direct arylation of N-methyl indole. The mechanism is shown to proceed via a concerted metalation deprotonation of N-methyl indole followed by transmetalation with PhB(OH)2. Importantly, this second step determines the C2 regioselectivity observed experimentally, and the key transition structure is stabilized through a π-polar bond between AcOH and the C2-C3 π system of indole. In Chapter 3 we apply DFT calculations to examine the mechanism of Pd catalyzed activation of N-methyl indole in an oxidative cross-coupling. Calculations predict the mechanism to proceed via initial C-H activation of the indole followed by C-H activation of benzene. Concerted metalation deprotonation is favoured, and assisted by coordinating solvent molecules. Alternative mechanisms, previously postulated in the literature, are calculated and do not support observed experimental results. We extend our examination into the C-H activation and oxidative arylation of N-acetyl indole by investigating a co-catalyst Pd/Cu system in Chapter 4. Calculations demonstrate that a Pd-Cu dimer is energetically viable and leads to initial cleavage at C3. The regioselectivity of the mechanism is determined through the subsequent C-H activation of benzene and completed with a facile reductive elimination step. In Chapter 5 we apply a combination of DFT and kinetic modelling on the trifluoroacetic acid (TFA) tuned homocoupling of benzene and the heterocoupling of benzene and anisole. Concentration terms are applied with the implementation of transition state theory to develop kinetic models. Various catalytic models are investigated to show that Pd(OTFA)2, formed at high concentrations of TFA, favours homocoupling, while at lower TFA concentrations the catalytic species will be Pd(OAc)2-TFA which favours heterocoupling. Finally, Chapter 6 presents DFT studies on the Pd-catalyzed homocoupling and chemoselectivity of p-xylene. Pd(OTFA)2 is computed to display greater activity than Pd(OAc)2 in oxidative C-H cross coupling. Benzylic (sp3) C-H activation of p-xylene is computed to be relatively difficult compared with sp2 activation, but can nonetheless occur via an eight membered intermolecular deprotonation transition state.