Nickel-catalyzed selective C1–C8 bond cleavage of benzocyclobutenones: theoretical insights into mechanism, substituent effects on regioselectivity, ligand effects on reactivity, and chemoselectivity

Theoretical calculations were performed to gain a deeper understanding of the nickel-catalyzed C1–C8 bond cleavage of benzocyclobutenones. Calculations involving representative reactions involving diphenylacetylene and indole coupling partners confirmed that these processes involve cleavage of the C1–C8 bond of the benzocyclobutenone rather than the traditional C1–C2 bond cleavage mechanism. The results of this work explain the regioselectivity of these reactions associated with certain substituents on the benzocyclobutenone and also the effects of ligands on reactivity. A distortion/interaction analysis established that the C3 position of the benzocyclobutenone is substituted and that the C1–C8 bond cleavage pathway is always more favorable because a lower distortion energy is involved. The distortion/interaction analysis, together with frontier molecular orbital theory and a percent buried volume analysis, confirmed that the experimentally observed ligand-controlled reactivity can be attributed to a combination of electronic and steric effects during the rate-determining C1–C8 bond cleavage step. Our calculations also successfully explained the origin of chemoselectivity in conjunction with the nickel-catalyzed coupling of benzocyclobutenones and indoles.