Unexpected Reactivity of C4-Bromopyrazolyl-α-aminonitrile

We report an unexpected reaction product C4-Bromovinyl pyrazole (Py-N-ene), during the course of an otherwise anticipated bimolecular nucleophilic (SN2) reaction between C4-Bromopyrazolyl-α-aminonitrile (4-BrPyCN) and dibromoethane in the presence of sodium hydride (NaH) suspended in dimethyl sulfoxide (DMSO), instead of a chemically intuitive C4-Bromopyrazolyl cyclopropane carbonitrile. Experimental screenings of solvents, structural analogs of 4-BrPyCN, and analogs of disubstituted ethane (as co-reactant) confirmed the differential chemical reactivity of 4-BrPyCN. Mechanistically, we report an unusual intramolecular substituent effect based on density functional theory, frontier molecular orbital, and Fukui functions calculations in conjunction with advanced conformational search using the Auto3D package to identify key transition states and intermediates for this unexpected reaction. Specifically, our calculations predicted a specific conformation as the key intermediate based on reactivity and molecular orbital (MO) symmetry calculations that results in the differential reactivity of 4-BrPyCN, such that it does not lead to SN2 reaction at its α-aminonitrilic site, in contrast to C4-Iodopyrazolyl-α-aminonitrile (4-IPyCN), under identical experimental conditions. Using MO symmetry analysis, we propose a mechanistic model to balance steric and inductive effects and show that an intramolecular electrocyclic rearrangement for 4-BrPyCN but not for 4-IPyCN resulted in a plausible yet non-intuitive reaction route to rationalize the differential chemical reactivity of 4-BrPyCN to form Py-N-ene.