Polar- and Enthalpic Effects on the Selectivity of Aromatic Substitution by Cationic Radicals

Abstract

The field of radical aromatic substitution consistently receives attention from synthetic organic community, in parts due to the versatile reactivity of radicals towards formation of valuable carbon–heteroatom bonds. One of the biggest goals associated with the development of useful radical aromatic substitution reactions is to achieve sufficient degree of regiocontrol, so that the maximum yield of a specific target molecule can be obtained. On the other hand, it may also be of synthetic value to develop an aromatic substitution reaction that is able to generate a wide spectrum of constitutional product isomers from a single starting material. It would be especially so if such a reaction also does not discriminate much between differentially activated aromatic substrates, thereby achieving a broad substrate scope. The subject of this dissertation is on the efforts to understand fundamental chemical effects that govern radical reactivity, and to address the above-mentioned challenges based on the reactivity principles. In Chapter 1 is described a non-chelation-assisted, highly para-selective aryl C–H substitution reaction with a doubly cationic nitrogen radical. High degree of charge-transfer in the transition state of radical addition is attributed to the predictable, exquisite positional selectivity. The high electron affinity of the bond-forming species engenders significant polar effects that are responsible for the sensitivity of the reaction towards substituent directing effects. In Chapter 2, the synthetic utility of the para-selective C–H functionalization is extended by using the functionalized product as a branch point for installation of valuable functional groups. Efficient transition-metal-catalyzed cross-coupling reactions convert the aryl ammonium intermediate into methylarenes, constituting an overall para-selective aryl C–H methylation sequence. In Chapter 3, aromatic substitution by another highly reactive nitrogen radical cation is introduced. While also possessing high electron affinity, the novel sp2-nitrogen radical cation exhibits unexpectedly low positional selectivity, and at the same time, is able to functionalize an unprecedentedly broad range of aromatic substrates in terms of electronic activation. Dominant reactivity control by enthalpic effects is elucidated by investigation of selectivity relationships. The C–N bond forming reaction is applied towards late-stage amination of (hetero)arenes with a substrate scope that addresses the limitations of current C–H amination methodology.