Understanding the molecular mechanism in a regiospecific [3 + 2] cycloaddition reaction including C–O and C–S interactions: an ELF topological analysis

Abstract

A theoretical study at the MPWB1K/6-311G(d) level was performed on the [3 + 2] cycloaddition (32CA) reaction of (Z)-2,2,2-trifluoro-N-methylethan-1-imine oxide (nitrone 10) toward propane-2-thione (thioketone 11) as a reduced computational model considered for experimentally studied 32CA reaction between (Z)-2,2,2-trifluoro-N-phenylethan-1-imine oxide (nitrone 6a) and 2,4-dimethylpentane-3-thione (thioketone 8f). Exploration of relative Gibbs free energy profile in the presence of THF obviously showed that among two feasible meta and ortho regioisomeric channels, the former is completely preferred over the latter both kinetically, ΔΔG_activation = 11.1 kcal mol⁻¹, and thermodynamically, ΔΔG_reaction = −16.1 kcal mol⁻¹. The energetic results of the modelled reaction, in complete agreement with the experimentally studied reaction, emphasize that the meta cycloadduct is the unique observable formal [3 + 2] yield. The moderate global nucleophilicity and electrophilicity characters found in nitrone 10 and thioketone 11, respectively, are responsible for a very low polar character of the studied 32CA reaction. The complete regioselectivity in the modelled 32CA reaction can be explained using calculated electrophilic and nucleophilic Parr functions at the interacting sites of reagents. The ELF topological patterns indicate that in the 32CA reaction between nitrone 10 and thioketone 11 while the formation of a C–S single bond at one terminal takes place exactly according to the recently proposed Domingo's model, formation of an O–C single bond at the other terminal is a direct consequence of donation of some electron density of oxygen lone pairs of nitrone 10 to the carbon atom of thioketone 11.