Insight into Radical Initiation, Solvent Effects, and Biphenyl Production in Iron–Bisphosphine Cross-Couplings

[Image: see text] Iron–bisphosphines have attracted broad interest as highly effective and versatile catalytic systems for two- and three-component cross-coupling strategies. While recent mechanistic studies have defined the role of organoiron(II)–bisphosphine species as key intermediates for selective cross-coupled product formation in these systems, mechanistic features that are essential for catalytic performance remain undefined. Specifically, key questions include the following: what is the generality of iron(II) intermediates for radical initiation in cross-couplings? What factors control reactivity toward homocoupled biaryl side-products in these systems? Finally, what are the solvent effects in these reactions that enable high catalytic performance? Herein, we address these key questions by examining the mechanism of enantioselective coupling between α-chloro- and α-bromoalkanoates and aryl Grignard reagents catalyzed by chiral bisphosphine–iron complexes. By employing freeze-trapped (57)Fe Mössbauer and EPR studies combined with inorganic synthesis, X-ray crystallography, reactivity studies, and quantum mechanical calculations, we define the key in situ iron speciation as well as their catalytic roles. In contrast to iron–SciOPP aryl–alkyl couplings, where monophenylated species were found to be the predominant reactive intermediate or prior proposals of reduced iron species to initiate catalysis, the enantioselective system utilizes an iron(II)-(R,R)-BenzP* bisphenylated intermediate to initiate the catalytic cycle. A profound consequence of this radical initiation process is that halogen abstraction and subsequent reductive elimination result in considerable amounts of biphenyl side products, limiting the efficiency of this method. Overall, this study offers key insights into the broader role of iron(II)–bisphosphine species for radical initiation, factors contributing to biphenyl side product generation, and protocol effects (solvent, Grignard reagent addition rate) that are critical to minimizing biphenyl generation to obtain more selective cross-coupling methods.