A molecular electron density theory study to understand the strain promoted [3+2] cycloaddition reaction of benzyl azide and cyclooctyne.

The strain promoted [3+2] cycloaddition reaction of benzyl azide with cyclooctyne has been studied within the molecular electron density theory (MEDT) at the MPWB1K/6-311G(d,p) computational level. This reaction takes place through a one-step mechanism with activation free energy of 27.1 kcal mol-1 in gas phase and 30.2 kcal mol-1 in acetonitrile. The activation enthalpies are 13.8 and 16.5 kcal mol-1, respectively in gas phase and acetonitrile. Topological analysis of the electron localization function (ELF) of the reagents shows zwitter-ionic type character of this reaction. The calculated activation free energy is lowered by 5.0 kcal mol-1 in gas phase and 4.2 kcal mol-1 in acetonitrile relative to the analogues reaction with acetylene. The corresponding activation enthalpy is lowered by 6.4 kcal mol-1 in gas phase and 5.9 kcal mol-1 in acetonitrile. A comparative bonding evolution theory (BET) analysis of the two reactions reveals lower energy requirements for the depopulation of the alkyne framework and the formation of pseudoradical centers along the reaction path of the cyclooctyne reaction. Topological analysis of the ELF and the Quantum Theory of Atoms in Molecules (QTAIM) parameters reveal early transition states with no covalent bonding interactions between the reacting nuclei, which is consistent with the forming bond distances greater than 2 Å in each case. [ABSTRACT FROM AUTHOR]