Combined experimental and computational investigations of rhodium- and ruthenium-catalyzed C-H functionalization of pyrazoles with alkynes

Detailed experimental and computational studies are reported on the mechanism of the coupling of alkynes with 3-arylpyrazoles at [Rh(MeCN) ₃Cp*][PF₆]₂ and [RuCl₂(p- cymene)]₂ catalysts. Density functional theory (DFT) calculations indicate a mechanism involving sequential N-H and C-H bond activation, HOAc/alkyne exchange, migratory insertion, and C-N reductive coupling. For rhodium, C-H bond activation is a two-step process comprising κ²-κ¹ displacement of acetate to give an agostic intermediate which then undergoes C-H bond cleavage via proton transfer to acetate. For the reaction of 3-phenyl-5-methylpyrazole with 4-octyne k _H/k_D = 2.7 ± 0.5 indicating that C-H bond cleavage is rate limiting in this case. However, H/D exchange studies, both with and without added alkyne, suggest that the migratory insertion transition state is close in energy to that for C-H bond cleavage. In order to model this result correctly, the DFT calculations must employ the full experimental system and include a treatment of dispersion effects. A significantly higher overall barrier to catalysis is computed at {Ru(p-cymene)} for which the rate-limiting process remains C-H activation. However, this is now a one-step process corresponding to the κ²-κ¹ displacement of acetate and so is still consistent with the lack of a significant experimental isotope effect (k_H/k_D = 1.1 ± 0.2).