A molecular electron density theory study of the chemo- and regioselective [3 + 2] cycloaddition reactions between trifluoroacetonitrile N-oxide and thioketones

Abstract The [3 + 2] cycloaddition (32CA) reaction between trifluoroacetonitrile N -oxide (NO 7 ) and 2,2,4,4-tetramethyl-3-thioxocyclobutan-1-one (THK 12 ) as well as the self-dimerization of NO 7 as a competitive pathway were studied within the Molecular Electron Density Theory (MEDT) using several DFT functionals together with def2-TZVP basis set. Taking CCSD(T)/TZVP activation energies as reference, among the employed functionals, just the B2PLYP-D3(BJ) one is able to portray complete predominance of 32CA reaction over self-dimerization process in excellent agreement with the experimental outcomes. Analysis of the global reactivity indices permits to characterize NO 7 and THK 12 as a strong electrophile and a strong nucleophile, respectively, while analysis of the Parr functions allows explaining the chemo- and regioselectivity observed experimentally. The electron localization function (ELF) analysis of several points along the IRC profile associated with the energetically most favorable reaction channel permits to establish a non-concerted two-stage one-step molecular mechanism for this polar pmr-type 32CA reaction.