In the realm of synthetic chemistry, the manipulation of carbon–fluorine (C–F) bonds stands as a formidable challenge due to the extraordinary strength and inertness of these bonds. Fluorine’s presence in organic molecules is pervasive, especially in pharmaceuticals and agrochemicals, where it imparts unique properties such as metabolic stability and altered bioactivity. However, the ability to selectively activate specific C–F bonds within polyfluorinated arenes without disturbing other sites remains an elusive goal, often thwarting efforts to diversify fluorinated frameworks. A groundbreaking development has now been reported that not only confronts these challenges but also redefines the landscape of selective C–F bond functionalization, opening avenues for the efficient synthesis of partially fluorinated biaryls with unprecedented site selectivity.
This pioneering study unveils a photoexcited nickel-catalyzed strategy that achieves highly selective cross-electrophile coupling between polyfluoroarenes and aryl chlorides, showcasing a marked preference for arylation at atypical C–F positions. The utilization of nickel as a central catalytic metal, combined with light excitation, presents a powerful platform that transcends the limitations of traditional methods. Unlike palladium-catalyzed or visible-light photoredox processes previously established for defluorinative functionalization, this nickel-centered approach demonstrates unique regioselectivity, accessing sites on the fluorinated aromatic rings that were formerly considered intractable.
One of the remarkable aspects of this method lies in the synergistic role of lithium salts, which emerge as key modulators in this intricate transformation. Through robust mechanistic studies involving both empirical and theoretical tools, researchers have illuminated how lithium ions interact with both pentafluorobenzene and the nickel catalyst. These interactions play a crucial role in lowering the energy barriers associated with C–F bond cleavage and subsequent arylation, effectively steering the reaction pathway and dictating the preferential activation of specific C–F bonds. The orchestration of these subtle yet impactful interactions highlights the nuanced control achievable in modern catalysis when specific additives are judiciously employed.
The versatility of this nickel-photocatalyzed procedure is exemplified in its broad substrate scope, encompassing structurally diverse fluorine-containing biaryls. The yields reported range from commendable 33% to an impressive 94%, underscoring both efficiency and robustness. Of paramount importance is the consistent regioselectivity, which not only complements existing defluorinative strategies but also extends the synthetic toolbox to previously uncharted functionalizations. This multifaceted utility ensures that chemists can now access an array of partially fluorinated products with tailor-made substitution patterns, fueling innovation in medicinal chemistry and material science.
Delving into the mechanistic underpinnings reveals that the excitation of the nickel catalyst with visible light promotes an effective cross-electrophile coupling cycle. This light-induced activation facilitates oxidative addition to the aryl chloride, followed by selective cleavage of the strong C–F bond in polyfluoroarenes. The process is finely tuned by lithium salts, which appear to coordinate with the fluorine-containing substrate, possibly stabilizing transient intermediates and influencing electronic properties. Such insights emphasize the importance of combining experimental mechanistic probes, including kinetic studies and spectroscopic analyses, with computational modeling to understand and optimize complex catalytic systems.
The distinctive regioselectivity achieved defies the conventional wisdom established in palladium- and photoredox-catalyzed protocols, which typically favor activation at the most electronically or sterically accessible C–F sites. Here, the activation targets “atypical” positions that expand the chemical space accessible through C–F bond functionalization. This complementary site selectivity introduces new dimensions in the design of fluorinated molecules, allowing for strategic installation of substituents at positions that could modulate properties in novel ways.
From a synthetic perspective, the strategic late-stage functionalization capability presented by this nickel-based methodology is especially compelling. Late-stage modification enables the diversification of complex molecules without the need for de novo synthesis, a feature that is invaluable for drug discovery and optimization. The potential to sequentially functionalize multiple C–F bonds through controlled reaction conditions affords a modular strategy for constructing multifaceted fluorinated architectures, streamlining synthetic sequences while enhancing molecular complexity and diversity.
Beyond fundamental chemistry, the application scope of this transformation reaches into biologically relevant domains. Fluorinated biaryls are prominent motifs in numerous therapeutic agents, catalyzing the demand for robust synthetic routes that provide regio- and chemoselective control. The new methodology’s capacity to deliver such compounds with precision and efficiency can accelerate drug development pipelines by furnishing medicinal chemists with access to novel fluorinated scaffolds, optimizing pharmacokinetic and pharmacodynamic profiles.
The research further underscores the emerging prominence of nickel catalysis as a cost-effective and environmentally friendly alternative to precious metals like palladium. Nickel’s earth abundance and distinctive reactivity patterns make it an attractive candidate for challenging bond activations, such as C–F activation. When paired with visible-light excitation, nickel catalysis bridges the gap between sustainable chemical practices and cutting-edge synthetic innovation, promoting greener methodologies in chemical manufacturing.
This advancement also enriches the fundamental understanding of fluorine chemistry, which has historically been constrained by the reluctance of C–F bonds to participate in or undergo transformations under mild conditions. The strategic deployment of light and metal coordination effects to circumvent these hurdles illuminates pathways to harness the latent reactivity in polyfluoroarenes, encouraging further exploration of photochemical strategies in organofluorine synthesis.
Crucially, the study’s integration of experimental observations with theoretical calculations epitomizes the power of interdisciplinary approaches in modern catalysis research. Computational insights revealing energy landscapes and transition states complement laboratory data, guiding rational design and fine-tuning of catalysts and reaction conditions. This synergy accelerates discovery and enhances reproducibility, setting a benchmark for future endeavors targeting selective C–F bond functionalization.
While the field continues to grapple with the innate challenges posed by fluorine’s unique chemistry, this work represents a transformative stride. It expands the chemist’s arsenal, delivering a methodology that not only achieves the coveted selective activation of otherwise difficult C–F bonds but does so with a level of precision and versatility that had remained out of reach.
Looking ahead, the implications of this nickel-photoinduced approach ripple through multiple sectors beyond pharmaceuticals, including agrochemical synthesis, material science, and molecular electronics, where fine control over the positioning of fluorine atoms can profoundly affect function and performance. By enabling modular and selective construction of partially fluorinated biaryls, this research opens pathways toward the tailored design of molecules with desirable electronic, lipophilic, and steric characteristics.
In conclusion, the reported selective activation of atypical C–F bonds in polyfluoroarenes through a light-driven nickel catalytic system, synergized by lithium salt additives, redefines the possibilities of organofluorine chemistry. The method’s high regioselectivity, broad substrate tolerance, and synthetic versatility represent a landmark advancement that is poised to influence the future course of fluorine science and synthetic strategy development. This innovation exemplifies how the convergence of photoactivation, transition metal catalysis, and strategic additive use can surmount longstanding challenges, catalyzing new directions in the synthesis of functionally rich, partially fluorinated organic molecules.
Subject of Research: Selective activation and functionalization of atypical carbon–fluorine bonds in polyfluoroarenes via photoexcited nickel catalysis.
Article Title: Selective arylation of atypical C–F bonds in polyfluoroarenes with aryl chlorides.
Article References:
Liu, Z., Du, C., Han, J. et al. Selective arylation of atypical C–F bonds in polyfluoroarenes with aryl chlorides. Nat. Chem. (2025). https://doi.org/10.1038/s41557-025-01962-1
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