As an emerging technology for bond construction, nickel-mediated reductive cross-electrophile coupling (RCEC) leverages different rates of electrophile activation to achieve selective cross-coupling. RCEC reactions commonly implicate a key reaction step between a transient reactive intermediate, often a carbon-centered radical, and an accumulated organonickel complex. Realized by the optimization of reaction conditions, such a concentration difference helps tune the rate of radical addition in relation to the deleterious diffusion-limited radical homocoupling. Nonetheless, factors governing the intrinsic kinetic viability (i.e., rate constant) of radical addition to organonickel remain poorly understood. Consequently, applying these methods to elaborated substrates with stereoelectronic modifications may require laborious re-optimizations due to the perturbance to the original optimized reaction rates. To reveal factors underpinning kinetic favorability, we determined reaction intermediates of kinetic relevance and analyzed its reactivity in RCEC alkenylations reported by the Reisman lab. Spectroscopic studies support that the catalyst resting state is the synthetically elusive alkenyl nickel whose calculated thermodynamic parameters, such as reduction potential, insufficiently describe the apparent kinetically controlled reaction outcomes. We hypothesize that the rate of the radical addition is influenced by the polarity-match between alkenyl nickel and carbon radical. The extent of transition state stabilization afforded by polarity match can be quantified by Klopman-Salem equation. This new insight has successfully guided the rational design of new RCEC reactions in our lab. Furthermore, our quantitative findings advance the literature rationalization of observed reactivity with organic radicals offered only qualitatively thus far. We belive these considerations are crucial to the emergent field of chemical data science.

Polarity-matched molecular orbital interaction enables facile radical addition by alkenyl nickel in reductive cross-electrophile coupling

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