Elucidation of the molecular mechanisms of 1,2,3,5- and 1,2,4,5-tetrazines with strained and electron-rich alkynes

Abstract

The mechanisms of the domino reactions between 4,6-diphenyl-1,2,3,5-tetrazine (TTZ 1) and 3,6-diphenyl-1,2,4,5-tetrazine (TTZ 2) with ynamine 3 and cyclooctyne 4, have been studied by DFT method. The domino reactions of TTZs with alkynes comprise two consecutive reactions, an aza Diels-Alder (ADA), and a retro Diels-Alder (rDA) reaction which leads to the resulting aromatic rings through loss of N2. Accordingly, the ADA step of the reaction of TTZ 1 with ynamine 3 proceeds through a stepwise mechanism, when the formation of the C4–C6 bond leads to zwitterionic intermediate IN1a in a regioselective manner. The second step consists of cyclization and spontaneously N2 loss. A stepwise ADA reaction between TTZ 2 and ynamine 3 results in zwitterionic intermediate IN1e and bicyclic intermediate IN2e. Subsequently, N2 removes with no significant energy barrier. The electron localization function (ELF) analysis shows that the ADA reactions of cyclooctyne 4 with TTZs 1 and 2 occur through a two-stage one-step mechanism, and a symmetric synchronous one-step mechanism, respectively. The global electron density transfer (GEDT) calculations indicated that the ADA reactions of TTZs with ynamine 3 and cyclooctyne 4 have strong and moderate polar natures, respectively.