This dissertation describes the density functional theory (DFT) computational modelling of reactions between organolithium nucleophiles and various substituted quinoxalines. These reactions result in the functionalisation of the C (sp2)–H bond, thus substituting the sigma-hydrogen. The reactions are known as nucleophilic substitution of hydrogen (SNH) and are used by experimental chemists to form new C–C bonds. The SNH reactions are very important in various industries, e.g. in designing and manufacturing of pharmaceuticals. Quinoxaline is widely used in medicinal chemistry due to its various biological activities; these reactions play a crucial role in the synthesis of new classes of compounds. The reactions of 2-phenyl- (A), 2-butyl- (B), and 6-nitro-2-phenyl- (C) quinoxaline with lithiofuran (a) and lithiothiophene (b) involves a direct (1) nucleophilic attack on an activated electron-deficient system, leading to the intermediate sigma^H-complex. This is followed by hydrolysis (2), where an sp2-type nitrogen is changed to an sp3 while forming Li---OH as a by-product. The presence of Li---OH then allows the departure of an sigma-proton via oxidation reaction, concomitantly forming H2O2 as the second by-product. All approaches to functionalise the C(sp2)–H bond involve elimination of a proton, and an oxidant is needed for the departure of the sigma-hydrogen. Although the sequence of steps and mechanisms of these C–H transformations are the same, various factors have shown to affect the reactions differently. The theoretical study of this catalytic-free transformation, shows that the formation of sigma^H-adducts is not easily reversible, and that their formation is spontaneous. The reaction does not just require an oxidant to eliminate the sigma-hydrogen with the pair of electrons, but rather requires the presence of water for hydrolysis prior to oxidation. We must stress the crucial role of the oxidant since the key problem of the SNH reactions is associated with the elimination of sigma-hydrogen. However, the main objective of this study is to present a correct and complete mechanistic picture of oxidative nucleophilic substitution of hydrogen (ONSH). Previous reports indicated that the presence of an electron donating/withdrawing group on the quinoxaline ring had a significant influence on the yield and selectivity. This is between reactions A+a, A+b, and B+a. These experimental observations correlated well with the modelling results when the potential energy surfaces (PES) of the reactions were compared. / Dissertation (MSc)--University of Pretoria, 2020. / National Research Foundation (NRF) / Chemistry / MSc / Unrestricted

Ce travail a tout d’abord porté sur la réactivité des dérivés borés puis sur la réaction de O-alkylation des alcools aromatiques. L’utilisation des composés borés est en plein essor. Ils sont employés comme partenaires de couplage dans la réaction de Suzuki et les réactions d’additions [1,4] catalysées au rhodium pour la synthèse de molécules à hautes valeurs ajoutées. La polarisation de la liaison C-B induit le caractère nucléophile de ces composés. Cette réactivité a été exploitée pour la formation de liaisons C-F par fluoration électrophile. L’utilisation de Selectfluor® comme agent de fluoration aboutit à de bons rendements. Toutefois, la nucléophilie des composés alkylborés peut être inversée par substitution nucléophile oxydante. Ainsi, une méthode créant des liaisons C-N a pu être développée et a permis la synthèse d’amides à partir de nitriles et de sels de trifluoroborates de potassium en présence de Cu(OAc)2 et BF3.OEt2. En vue de l’importance de la chimie des éthers en synthèse organique, une méthode de préparation d’éthers aryliques a été développée au laboratoire. En partant d’un système stœchiométrique en trifluorure de bore, un système catalytique impliquant du triflate de cérium a été mis au point. Afin de répondre au mieux au concept de la chimie verte, un système catalytique hétérogène, sans solvant, a été décrit. Dans ce cas, le catalyseur employé est le Nafion® NR50, facilement recyclable, sans perte d’activité, et conduisant à de bons rendements avec les alcools aliphatiques et aromatiques. Des amines aromatiques secondaires peuvent également être préparées par cette méthode / This thesis describes the study of the reactivity of boron compounds and the O-alkylation of aromatic alcohols. The use of boronic derivatives increased considerably over the past decades. There are used as cross-coupling partners in the Suzuki reaction and for 1,4 rhodium-catalyzed addition reaction. The nucleophilic nature of these compounds was induced by the C-B bond polarization. This peculiar reactivity was studied for the C-F bond formation. The use of Selectfluor® as fluorinating agent leads to good yields. Nevertheless, the polarity of the C-B bond could be reversed by oxidative nucleophilic substitution. Thus, C–N bond could be formed from nitriles and potassium trifluoroborate salts promoted by Cu(OAc)2 in the presence of BF3.OEt2. Due to the importance of ether chemistry in organic synthesis, the O-alkylation of phenol derivatives was achieved in the laboratory. From a stoichiometric amount of Lewis acid, BF3.OEt2, a catalytic system was developed involving cerium triflate. Then, the focus on green chemistry led to use a heterogeneous catalyst. Where Nafion® NR50 appears as a suitable catalyst for the ether synthesis