Understanding the regioselectivity and molecular mechanism in the synthesis of isoxazoles containing pentafluorosulfanyl substitution via a [3+2] cycloaddition reaction: A DFT study

•A 32CA reaction in which SF5 group plays a key role was theoretically studied.•The studied 32CA reaction takes place via a complete regioselective pathway.•Total regioselectivity is controlled by steric effects rather than electronic ones.•An ELF analysis supports a non-concerted two-stage one-step molecular mechanism.

A theoretical study was performed on the [3+2] cycloaddition (32CA) reaction of benzonitrile oxide, BNO 4, toward phenyl SF5-acetylene, PAC 5, in the presence of tetrahydrofuran (THF) at the DFT-B3LYP/6-31G* level. Calculated relative Gibbs free energies indicate that the studied 32CA reaction takes place via a complete C1C4 regioselective channel passing through TS1 affording the unique formal [3+2] cycloadduct CA1 observed experimentally. While based on the calculated Parr functions on the interacting sites of reagents this cycloaddition should proceed via energetically unfavorable C1C5 channel passing through TS2, a natural steric analysis evidently showed that destabilizing repulsion effects, rather than the electronic ones, are responsible for the complete C1C4 regioselective fashion provided by the considered 32CA reaction. An ELF topological analysis of the bonding changes along this 32CA reaction supports a non-concerted two-stage one-step molecular mechanism in which the formation of second O3C5 single bond takes place when the formation of first C1C4 one is almost complete.

Graphical abstractThe complete regioselective 32CA reaction of benzonitrile oxide toward phenyl SF5-acetylene in the presence of THF takes place via a non-concerted two-stage one-step molecular mechanism.Figure optionsDownload full-size imageDownload as PowerPoint slide