Fluorinated Radicals in Divergent Synthesis via Photoredox Catalysis

ConspectusFluorine is an essential element in pharmaceuticals, agrochemicals, and material sciences, significantly enhancing the bioactivity, metabolic stability, and physicochemical properties of organic molecules. In medicinal chemistry, nearly 20% of marketed drugs contain at least one fluorine atom within their core structure. Despite its widespread importance, naturally occurring organofluorine compounds are exceedingly rare, necessitating the development of productive synthetic strategies for fluorine incorporation. The majority of fluorination protocols at the industrial level rely on reagents made from highly reactive and hazardous hydrogen fluoride (HF) or elemental fluorine (F₂), which present substantial challenges in handling and safety at the laboratory scale. Moreover, considerations of cost, availability, and synthetic performance have led to a renewed interest in utilizing readily accessible, bulk-manufactured compounds such as fluorinated acids and anhydrides. The activation of these redox-active reagents presents a promising avenue to achieve selective, efficient, and sustainable fluoroalkylation reactions.Over the past four decades, advancements in classical organic synthesis have given rise to new and transformative fields, enabling access to previously elusive chemical reactions. Among these, photoredox catalysis has emerged as a powerful tool, driving the evolution of synthetic organic chemistry through innovative concepts such as late-stage functionalization, atom economy, bifunctional reagents, switchable divergent synthesis, and multicomponent reactions. This account details our five-year journey in advancing radical fluoroalkyl chemistry through a detailed reactivity exploration of redox-active fluorinated acids and anhydrides. We also highlight the key concept of switchable divergent synthesis through photoredox catalysis as an elegant tool for facilitating molecular design. By carefully tuning reaction parameters, such as solvent, gas pressure, concentration, and additives, we achieve precise control over reaction intermediates, allowing for the selective generation of multiple fluorine-containing products from a common set of starting materials. This strategy not only improves synthetic efficiency but also broadens the chemical space accessible to fluorinated molecules, reducing costs and streamlining synthetic workflows. These photoredox methodologies have enabled the direct synthesis of a diverse range of fluorinated compounds, including trifluoromethylated ketones, γ-lactones, γ-lactams, esters, with high selectivity and remarkable functional group tolerance. Furthermore, the scalability and operational simplicity of these photoredox protocols make them attractive for broader applications, aligning with the goals of sustainable and cost-effective synthetic methods. Beyond synthetic applications, we have focused on elucidating the mechanistic aspects of these transformations. Through a combination of spectroscopic, experimental and computational studies, including a newly designed DLPNO-CCSD(T)-based reactivity scale, we have gained valuable insights into the origins of divergence, radical reactivity, and a deeper understanding of the effects of radical polarity.