LAUSR

Abstract The regioselectivity in Pd(II)-catalyzed C H direct functionalization of C2-substituted naphthalenes has been a long-term issue in synthetic organic chemistry due to its existence of competitive reaction sites, including C1-, C3- and even C4-sites. Our recent achievement in Pd(II)-catalyzed C1-dearomatization of 2-naphthyl ureas encouraged us to find out the key factors for determining the C1- and C3- regioselectivity of 2-naphthyl ureas based on density functional theory (DFT). In this work, we identified a plausible reaction pathway, which led to the experimental C1-functionalized product with a reasonable energy profile. A homologous pathway giving C3-spirocycle was also calculated to investigate the nature of C1-regioselectivity in this reaction. According to the calculated results, we found that in our reaction C H cleavage was the regioselectivity-determining step, and that C1 was the kinetically favorable site in this step due to electronic effect which makes C1 a more vulnerable site to electrophiles compared to C3, as reflected by the condensed Fukui function and its larger proportion of the highest occupied molecular orbital. Energy decomposition analyses and electronic structure analyses were further performed, which were in good accordance with our conclusion yet indicated C1 was a more sterically hindered site. This result provided us with the inspiration that steric hindrance may play an important role in frequently reported transition metal-catalyzed C3-arylation in the literature. We then selected a recently reported reaction Pd-catalyzed C3-arylation of 2-naphthyl aniline to study the regioselectivity. The result was in line with our assumption that in C3-arylation of 2-naphthyl aniline the preferential functionalization of C3-site is due to its less steric hindrance than C1-site. This work is thus instructive for understanding the regioselectivity in Pd(II)-catalyzed C H direct functionalization of C2-substituted naphthalenes.