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 kH/kD = 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 (kH/kD = 1.1 ±
0.2).