Computational modelling of ruthenium catalysed C–H alkylation of heteroarenes

Abstract

A mechanistic study of the C–H alkylation of 2-phenylpyridine (2-ppy) using alkyl halides and catalysed by [Ru(2-ppy)(MeCN)4] + has been carried out using density functional theory (DFT). A general mechanism has been proposed for the reaction of primary alkyl halides, modelled as 1-bromopropane, in the presence of a carboxylate additive (Chapter 3). Following C–H activation and cyclometallation via deprotonation by the additive, an SN2 mechanism was identified for the C–Br activation step, leading to an ortho-alkylated product after reductive coupling and product release. The latter has been identified as the rate-determining step in catalysis. Subsequently, the role of the carboxylate additive has been assessed by studying the above reaction in its absence (Chapter 4). The results have shown that the substrate can perform the deprotonation. It was found that the rate limiting-determining step in catalysis becomes the formation of the C–H activation precursor, but the C–Br activation is not significantly affected. A complete mechanistic study of the C–X activation (with X = Cl, Br, I) of 1- chloro-, 1-iodo-, 2-bromopropane and 2-bromo-2-methylpropane in the presence of a carboxylate has also been performed (Chapter 5). While the nature of the halide does not significantly influence either the mechanism or the selectivity of the reaction, it was found that secondary and tertiary alkyl halides can follow a radical mechanism, affording some or exclusive meta-alkylation. Finally, the key results obtained in this thesis have been subjected to a benchmark study, compared against the available experimental data (Chapter 6), and GGA functionals have been proposed as the most appropriate method for this system