A molecular electron density theory study of the Grignard reagent-mediated regioselective direct synthesis of 1,5-disubstituted-1,2,3-triazoles

The [3 + 2] cycloaddition (32CA) reaction of phenyl azide 4 with ethynylbenzene 5 in presence of ethyl magnesium bromide (EtMgBr) has been studied within the Molecular Electron Density Theory with the aim to rationalise the high-yielding direct regioselective synthesis of 1,5-disubstituted-1,2,3-triazoles. Topological analysis of the electron localisation function (ELF) of phenyl azide 4 indicates that it has a zwitterionic structure participating in zw-type 32CA reactions. Computed activation parameters along the two feasible reaction paths for this 32CA reaction makes the rationalisation of the experimental outcomes possible. Grignard reagent-mediated processes have a polar character and complete regioselectivity, which is in line with the fast, clean, and high yielding reaction experimentally observed. The reaction follows a one-step mechanism involving a high asynchronous transition state structure. Topological analysis of the ELF and calculated quantum theory of atoms-in-molecule parameters indicate that formation of new C-N single bonds does not begin exactly at the corresponding transition state structure.