Decoding <i>ortho</i> regiospecificity and high <i>endo</i> stereoselectivity in pyrazole synthesis <i>via</i> the activation/strain model

A comprehensive density functional theory investigation was conducted to elucidate the regio- and stereoselectivity of the 1,3-dipolar cycloaddition reaction (13-DCR) between a diazo compound (1,3-dipole D-1) and an electron-deficient nitroethylene derivative (dipolarophile Dph-2), which serves as the key initiating step in a recently reported domino synthesis of pyrazole derivatives. Experimentally performed in dichloromethane at 80 °C, the reaction exhibits exclusive formation of the <i>ortho</i> regioisomer. Calculated activation free energies and rate constants quantitatively reproduce the experimentally observed complete <i>ortho</i> regioselectivity and high <i>endo</i> stereoselectivity. Activation strain model (ASM) analysis reveals that the regioselectivity is primarily governed by stabilizing interaction energies. Subsequent energy decomposition analysis using the recently developed sobEDA method identifies orbital interactions, particularly HOMOD-1 to LUMODph-2 charge transfer, as the main contributors. The Extended Transition State-Natural Orbitals for Chemical Valence (ETS-NOCV) analysis confirms this dominant orbital interaction, rationalizing the <i>ortho</i> selectivity. The stereoselectivity favoring the <i>endo</i> pathway is attributed to lower total strain energy, mainly originating from the flexibility of the D-1 fragment. This combined computational study offers a detailed mechanistic understanding of the 13-DCR regio- and stereoselectivity, providing results in excellent agreement with experimental outcomes.