Methylation of organohalides represents a valuable transformation, but typically requires harsh reaction conditions or reagents. We report a radical approach for the methylation of (hetero)­aryl chlorides using nickel/photoredox catalysis wherein trimethyl orthoformate, a common laboratory solvent, serves as a methyl source. This method permits methylation of (hetero)­aryl chlorides and acyl chlorides at an early and late stage with broad functional group compatibility. Mechanistic investigations indicate that trimethyl orthoformate serves as a source of methyl radical via β-scission from a tertiary radical generated upon chlorine-mediated hydrogen atom transfer.

Photoredox catalysis has provided many approaches to C(sp3)–H functionalization that enable selective oxidation and C(sp3)–C bond formation via the intermediacy of a carbon-centered radical. While highly enabling, functionalization of the carbon-centered radical is largely mediated by electrophilic reagents. Notably, nucleophilic reagents represent an abundant and practical reagent class, motivating the interest in developing a general C(sp3)–H functionalization strategy with nucleophiles. Here we describe a strategy that transforms C(sp3)–H bonds into carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar crossover. The resulting carbocation is functionalized by a variety of nucleophiles—including halides, water, alcohols, thiols, an electron-rich arene, and an azide—to effect diverse bond formations. Mechanistic studies indicate that HAT is mediated by methyl radical—a previously unexplored HAT agent with differing polarity to many of those used in photoredox catalysis—enabling new site-selectivity for late-stage C(sp3)–H functionalization.

This Perspective surveys the progress and current limitations of nucleophilic fluorination methodologies. Despite the long and rich history of C(sp 3 )−F bond construction in chemical research, the inherent challenges associated with this transformation have largely constrained nucleophilic fluorination to a privileged reaction platform. In recent years, the Doyle group�along with many others�has pursued the study and development of this transformation with the intent of generating deeper mechanistic understanding, developing user-friendly fluorination reagents, and contributing to the invention of synthetic methods capable of enabling radiofluorination. Studies from our laboratory are discussed along with recent developments from others in this field. Fluoride reagent development and the mechanistic implications of reagent identity are highlighted. We also outline the chemical space inaccessible by current synthetic technologies and a series of future directions in the field that can potentially fill the existing dark spaces.