π‑Complexation in Nickel-Catalyzed Cross-Coupling Reactions S. Kyle Sontag, †,∥ Jenna A. Bilbrey, †,‡,∥ N. Eric Huddleston, † Gareth R. Sheppard, † Wesley D. Allen,* ,†,‡ and Jason Locklin* ,†,§ † Department of Chemistry, ‡ Center for Computational Chemistry, and § College of Engineering, University of Georgia, Athens, Georgia 30602, United States * S Supporting Information ABSTRACT: The kinetic isotope effect (KIE) is used to experimentally elucidate the first irreversible step in oxidative addition reactions of a zerovalent nickel catalyst to a set of haloarene substrates. Halogenated o-methylbenzene, dimethoxy- benzene, and thiophene derivatives undergo intramolecular oxidative addition through irreversible π-complexation. Density functional theory computations at the B3LYP-D3/TZ2P- LANL2TZ(f)-LANL08d level predict η 2 -bound π-complexes are generally stable relative to a solvated catalyst plus free substrate and that ring-walking of the Ni(0) catalyst and intramolecular oxidative addition are facile in these intermedi- ates. T he Kumada−Tamao−Corriu (KTC) reaction is com- monly used for carbon−carbon cross-coupling in small molecule synthesis. 1 In such reactions, a zerovalent nickel catalyst undergoes a fundamental catalytic cycle involving oxidative addition (OA) to a reactive substrate, transmetalation with a Grignard reagent, and reductive elimination to form a carbon−carbon bond. The OA reaction, which initiates the catalytic cycle by conversion of starting materials to reactive intermediates, is known to be a two-step process with the transition metal catalyst first undergoing initial complexation with the substrate followed by nickel insertion. 2 The resulting intermediate is generally stable and proceeds as the substrate for transmetalation in organometallic reactions. Some computa- tional work has examined the role of oxidative addition for zerovalent group 10 metals in various cross-coupling reactions, mostly focusing on the nickel insertion step with limited substrates. 3 In the KTC system, a π-complex is formed between the Ni(0) d-orbitals and the antibonding π-orbitals of the aryl substrate prior to halogen bond cleavage. 4 For an aryl bromide substrate initial π-complexation drives preferential bond activation even in the presence of a more reactive aryl iodide substrate. 5 This selectivity suggests that the Ni(0) species does not dissociate from the π-complex and must move along the conjugated framework (ring-walk) toward the active carbon− halogen site. Recently, small molecule competition reactions by the McNeil group have shown that intramolecular oxidative addition occurs. 6 The nickel-mediated cross-coupling reaction is often used in the synthesis of near monodisperse, conjugated polymers. 7 The π-complexation of zerovalent nickel with aromatic substrates plays a critical role in polymerization control, and weak association leads to uncontrolled polymerization. 8 The Ni(0) catalyst “chain-walks” along the aromatic polymer backbone, and the nature of the aromatic system can alter this chain- walking phenomenon. A recent review by the McNeil group discusses our limited knowledge of the binding and whether the substrate is in η 2 -, η 4 -, or η 6 -coordination with Ni(0). 9 An experimental and theoretical understanding of the interaction of Ni(0) catalysts with aromatic substrates promises to provide more efficient, selective catalysts for polymerization. Though the formation of π-complexes plays an important role in many cross-coupling reactions, isolation or direct observation is often not possible due to the short lifetimes of these metastable species. 10 However, the kinetic isotope effect (KIE) can provide information on the atoms involved in the first irreversible step (FIS) when a catalyst is involved. 2c,3a,11 In reactions such as OA involving bond rearrangements, substitution of heavier isotopes tends to enhance activation barriers and reduce reaction rates. 12 When probing carbon isotope effects, substrates containing the lighter 12 C atom will preferentially react, leaving 13 C enrichment at the active site in recovered starting material. An increased KIE (>1.000 relative to an internal standard) at an atomic position indicates involvement of this site in the FIS. Carbon-specific KIEs can be quantified by 13 C NMR through comparison of 13 C ratios in the substrate before and after reaction. 13 In this case, deliberate isotopic labeling is unnecessary because the natural abundance of 13 C is sufficient for high-field NMR methods. In this report, we perform KIE experiments on various haloarene derivatives to elucidate the OA mechanism. Aryl halides are coupled with alkyl or aryl magnesium halides using Received: October 10, 2013 Published: February 3, 2014 Note pubs.acs.org/joc © 2014 American Chemical Society 1836 dx.doi.org/10.1021/jo402259z | J. Org. Chem. 2014, 79, 1836−1841