Transition Metal-Free Hydroxylation of (Hetero)aromatic Halides

This thesis describes the development of a transition metal-free procedure for hydroxylation
of (hetero)aromatic halides. Chapter 1 outlines previous efforts in the areas of arene
hydroxylation and substitution through electron transfer. A rationally designed, universal
oxime-based nucleophile was synthesised and used as a hydroxide surrogate in the attempted
hydroxylation of halides, which was described in Chapter 2. It was demonstrated through an
extensive scoping that most of the electron-poor aromatic substrates, in particular the aryl
halides bearing an electron-withdrawing group (EWG) in para-position to halide, were
compatible with the mild conditions proposed and successfully underwent transformation at a
temperature as low as 30°C. The reactions of dihalogenated compounds exhibited a level of
selectivity. The scope of the proposed transformation was expanded after re-optimisation at
higher temperatures (60 and 100°C), and the procedure’s performance was significantly
improved in substrates such as halides bearing an EWG in meta-position and less electron deficient substrates. Mechanistic studies involving radical trapping indicated that the process is of at least partially
radical nature – participation of SRN1 processes is suspected. UV-vis spectroscopy studies
were also performed, revealing possible participation of a 1:1 nucleophile to halide chargetransfer complex in the initiation stage. The potential of the developed method for late-stage
functionalisation was explored and confirmed through experiments on aryl halide-containing
drug molecules.