Mechanistic studies on the copper-catalysed C-N cross-coupling reaction

Abstract

The copper-catalysed C-N cross-coupling reaction dates back to the early 1900s and is one of the first reported transition-metal mediated cross-coupling reaction. Several drawbacks to this classical reaction such as high reaction temperatures, long reaction times and the need for stoichiometric copper loadings have since been overcome through the incorporation of auxiliary ligands. This improved reaction is known as the “modified Ullmann reaction”. The low cost and toxicity of copper coupled with the use of cheap ligands have made it an attractive alternative to the palladium-catalysed Buchwald-Hartwig amination reaction. However, the mechanism of the copper-catalysed reaction is not well understood, with contradictory mechanistic proposals being published since the 1960s. Therefore, mechanistic studies have been carried out on the modified Ullmann amination reaction using a combination of synthetic, spectroscopic and kinetic techniques in this thesis. Mechanistic data obtained from these studies were subsequently used to design new and improved catalytic systems. A range of commonly used first-generation auxiliary ligands were evaluated for the C-N cross-coupling reaction using the reaction progress kinetic analysis (RPKA) methodology in Chapter 2. Results obtained here not only revealed the influence of the ligand on the rate of reaction but also its impact on catalyst degradation rates. Further analysis on catalyst deactivation using synthetic and spectroscopic techniques showed the presence of unreactive off-cycle species most notably with the 1,10-phenanthroline ligand (L7). Moreover, the ability of the amine, auxiliary ligand and base to competitively coordinate to the copper catalyst was demonstrated here. N-methylglycine ligand (L18) was shown to give the best performance in terms of low catalyst deactivation rate and high rate of reaction and it was used to develop an improved room-temperature reaction system with 27 different examples reported. In Chapter 3, a range of ammonium and phosphonium bases were synthesised with the aim of developing a sub-mol % (≤ 1 mol %) room-temperature Ullmann reaction system and improving its substrate scope. Bis(tetra-(n-butyl)phosphonium) malonate (TBPM) gave superior performance over other bases when sub-mol % catalyst loadings (0.5 mol %) were used in the C-N cross-coupling reaction and a substrate scope with 14 different examples is reported. This is the first reported sub-mol % Ullmann reaction system that can be carried out at room temperature without the need for an excess of auxiliary ligand relative to the cooper catalyst. The stability of phosphonium and ammonium bases at elevated temperatures were studied, which revealed that unlike bis(tetra-(n-butyl)ammonium) malonate (TBAM), TBPM did not undergo decomposition but instead it underwent deprotonation at the α-CH2 to form phosphonium yildes. Nonetheless, this did not have an adverse effect on the activity of TBPM in the cross-coupling reaction as it gave the highest yields in coupling reactions involving structurally complex amines relative to ammonium and inorganic bases. Mechanistic studies on second-generation oxalic diamide ligands were carried out in Chapter 4. The rate order in the [amine] and [aryl chloride] was obtained using variable time normalisation analysis, which showed first order dependence in both substrates. In addition, positive order in the [ligand] and [Cu]total was observed. Same excess experiments revealed the presence of catalyst deactivation, which is likely to proceed via disproportionation of active copper(I) to inactive copper(II) and copper(0) species. Attempts were made to identify catalytic intermediates using ESI-MS, which revealed the presence of a mono-ligated copper(I) oxalic diamide complex. A mechanism for the CuI/Oxalic diamide reaction system was proposed based on kinetic and spectroscopic data and it is markedly similar to first-generation reaction systems. The key difference being the absence of off-cycle di-ionic species in the oxalic diamide reaction. These mechanistic studies also showed that it is the high electron density of oxalic diamide ligands which enable the coupling of challenging aryl chloride substrates. While small-scale reactions were mass transfer limited, attempts to study these effects in large-scale reactors were hindered by the rapid oxidation of the active copper(I) catalyst to inactive copper(II). As a result, no useful kinetic data could be obtained for large-scale reactions.