Toward understanding regioselectivity and molecular mechanism in the synthesis of CF2H-containing 2-pyrazolines: A molecular electron-density theory study

The domino process between a CF2H-containing diazoalkane, DAA 2, and an electron-deficient alkene, ANT 3, in the presence of chloroform was theoretically studied at the DFT-MPWBT K/6-311G(d,p) computational level. The initializing step in this domino process is associated with the Cl nucleophilic attack of DAA 2 at the C4 carbon atom of ANI 3 over the course of a polar zw-type 32CA reaction in an entirely C1-C4 regioselective manner to furnish corresponding 1-pyrazoline derivative CA1n. While a stepwise 1,3-H shift reaction assisted by an acetate anion and/or a thermal N-2 extrusion reaction can subsequently convert CA1n into corresponding 2-pyrazoline PYZ 4 or cyclopropane CP 5 derivatives, respectively, exploration of the relative Gibbs free energy profile evidently demonstrates that experimentally isolated PYZ 4 is the only reachable product of the studied domino reaction. Analysis of the calculated nucleophilic and electrophilic Parr functions at the reactive sites of DAA 2 and ANI 3, respectively, rationalizes the C1-C4 regioselectivity observed experimentally. An electron localization function (ELF) topological analysis of some selected points along the most favorable reactive channel involved in the initializing 32CA reaction allows establishing a non-concerted two-stage one-step molecular mechanism for the 32CA reaction of DAA 2 toward ANT 3.