Cycloaddition Reaction of Azides with Di-Alkynes: a Quantum Chemistry Study

Azide-alkyne cycloaddition reaction affords mixtures of 1,4- and 1,5-regioisomers while copper catalyzed alkyne-azide cycloaddition (CuAAC) provides 1,4-disubstituted 1,2,3-triazoles. In the present research, we have focused on the cycloaddition reaction of dialkynes with azides that leads to a statistical mixture of monotriazoles and ditriazoles [1]. It should be noticed that copper catalysis dramatically improves regioselectivity to afford 1,4-regioisomer. The origins of regioselective behavior of azide-dialkyne cycloaddition reaction were investigated from the structural, electronic and thermodynamical viewpoints via Density Functional Theory (DFT) methods [2] in combination with Quantum Theory of Atoms in Molecules (QTAIM) analysis [3]. We have determined the ground state structures of all reagents, products and transition states without any symmetry restrictions using GAMESS suite of programs [4] based on M08-HX functional in connection with 6-311G** orbital basis sets. Then, we calculated thermochemical data, including reaction energies (with and without zero-point energy corrections), enthalpies and Gibbs free energies in the gas and two solution phases via polarized continuum model (PCM) [5]. The obtained results confirmed the experimentally observed in the presence of mixture of monotriazoles and ditriazoles. Finally, electronic aspect of aforementioned reaction was investigated via topological QTAIM analysis of electron density and electronic energy density indicators at selected critical points that mainly participate in cycloaddition reaction.