Abstract
ConspectusAromatic functionalization reactions are some of the most fundamental transformations in organic chemistry and have been a mainstay of chemical synthesis for over a century. Reactions such as electrophilic and nucleophilic aromatic substitution (EAS and S(N)Ar, respectively) represent the two most fundamental reaction classes for arene elaboration and still today typify the most utilized methods for aromatic functionalization. Despite the reliable reactivity accessed by these venerable transformations, the chemical space that can be accessed by EAS and S(N)Ar reactions is inherently limited due to the electronic requirements of the substrate. In the case of EAS, highly active electrophiles are paired with electron-neutral to electron-rich (hetero)arenes. For S(N)Ar, highly electron-deficient (hetero)arenes that possess appropriate nucleofuges (halides, -NO(2), etc.) are required for reactivity. The inherent limitations on (hetero)arene reactivity presented an opportunity to develop alternative reactivity to access increased chemical space to expand the arsenal of reactions available to synthetic chemists.For the past decade, our research has concentrated on developing novel methods for arene functionalization, with a particular focus on electron-neutral and electron-rich arenes and applying these methods to late-stage functionalization. Specifically, electron-rich arenes undergo single electron oxidation by a photoredox catalyst under irradiation, forming arene cation radicals. These cation radicals act as key intermediates in various transformations. While electron-rich arenes are typically unreactive toward nucleophiles, arene cation radicals are highly reactive and capable of engaging with common nucleophiles.This Account details the dichotomy of reactivity accessed via arene cation radicals: C-H functionalization by nucleophiles under aerobic conditions or cation radical accelerated nucleophilic aromatic substitution (CRA-S(N)Ar) in anaerobic settings. Based on experimental and computational studies, we propose that reversible nucleophilic addition to arene cation radicals can occur at the ipso-, para-, or ortho-positions relative to the most electron-releasing group. Under aerobic conditions, intermediates formed by para- or ortho-addition typically undergo an additional irreversible oxidation step, resulting in C-H functionalization as the major outcome. Conversely, in the absence of an external oxidant, C-H functionalization is not observed, and ipso-addition predominates, releasing an alcohol or HF nucleofuge, leading to S(N)Ar products. Building on the success of these arene functionalization transformations, we also explored their applications to positron emission tomography (PET) radiotracer development. Both C-H functionalization and S(N)Ar with (18)F(-) and (11)CN(-) have been applied to radiofluorination and radiocyanation of arenes, respectively. Applications of the radiotracers synthesized by these methods have been demonstrated in preclinical and clinical models.