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Since the pioneering work of Kochi in the 1970s, iron has attracted great interest for cross-coupling catalysis due to its low cost and toxicity as well as its potential for novel reactivity compared to analogous reactions with precious metals like palladium. Today there are numerous iron-based cross-coupling methodologies available, including challenging alkyl-alkyl and enantioselective methods. Furthermore, cross-couplings with simple ferric salts and additives like NMP and TMEDA ( N-methylpyrrolidone and tetramethylethylenediamine) continue to attract interest in pharmaceutical applications. Despite the tremendous advances in iron cross-coupling methodologies, in situ formed and reactive iron species and the underlying mechanisms of catalysis remain poorly understood in many cases, inhibiting mechanism-driven methodology development in this field. This lack of mechanism-driven development has been due, in part, to the challenges of applying traditional characterization methods such as nuclear magnetic resonance (NMR) spectroscopy to iron chemistry due to the multitude of paramagnetic species that can form in situ. The application of a broad array of inorganic spectroscopic methods (e.g., electron paramagnetic resonance, 57 Fe Mössbauer, and magnetic circular dichroism) removes this barrier and has revolutionized our ability to evaluate iron speciation. In conjunction with inorganic syntheses of unstable organoiron intermediates and combined inorganic spectroscopy/gas chromatography studies to evaluate in situ iron reactivity, this approach has dramatically evolved our understanding of in situ iron speciation, reactivity, and mechanisms in iron-catalyzed cross-coupling over the past 5 years. This Account focuses on the key advances made in obtaining mechanistic insight in iron-catalyzed carbon-carbon cross-couplings using simple ferric salts, iron-bisphosphines, and iron- N-heterocyclic carbenes (NHCs). Our studies of ferric salt catalysis have resulted in the isolation of an unprecedented iron-methyl cluster, allowing us to identify a novel reaction pathway and solve a decades-old mystery in iron chemistry. NMP has also been identified as a key to accessing more stable intermediates in reactions containing nucleophiles with and without β-hydrogens. In iron-bisphosphine chemistry, we have identified several series of transmetalated iron(II)-bisphosphine complexes containing mesityl, phenyl, and alkynyl nucleophile-derived ligands, where mesityl systems were found to be unreliable analogues to phenyls. Finally, in iron-NHC cross-coupling, unique chelation effects were observed in cases where nucleophile-derived ligands contained coordinating functional groups. As with the bisphosphine case, high-spin iron(II) complexes were shown to be reactive and selective in cross-coupling. Overall, these studies have demonstrated key aspects of iron cross-coupling and the utility of detailed speciation and mechanistic studies for the rational improvement and development of iron cross-coupling methods.

Development and Evolution of Mechanistic Understanding in Iron-Catalyzed Cross-Coupling