Theoretical Studies On The Mechanism Of Reaction From Nitriles And Azides Forming The 5-substituted Tetrazoles By Lewis Acid Catalyzed

In this study, the mechanisms of 5-substituted tetrazoles synthesis from the reactions of organoaluminium azides with nitriles and the copper-catalyzed reactions of trimethylsilyl azides with nitriles were studied using the DFT method, at the B3LYP/6-311+G(d,p) level. We fully considered various possible reaction mechanisms, and have located those key intermediates and transition states, and found the most predominant mechanism under experimental conditions. Factors that may influent the reaction mechanism and kinetic parameters (especially for reaction activation energies), such as coordination effect, inducing effect, solvation effect and steric effect etc., were considered. Our theoretical results provided good explanation to the catalysis roles of Al and Cu in tetrazoles synthesis, and can explain the experimental findings. These results also provide a good base and suggestions for the developememt of tetrazole syntheses. The results of this work show that:1. Density function theory study on the mechanism of organoaluminium azides and nitriles yielding 5-substituted tetrazoleWe studied the reaction of five different nitriles with organoaluminium azides by density functional method. Various possible reaction paths were calculated. The stationary structures, including reactants, intermediates, transition states and products were fully optimized in the B3LYP/6-311+G(d,p) level and we also found the transition state for each pathway. Analyzing the computed results, we concluded that:(1) For PhCH2SC≡N, and 3-and 4-pyridylnitrile, their most preferable mechanism is: One nitrile molecule coordinates to one Al atom of Et2AlN3 dimer to form intermediates, then intermediates transform to tetrazoles via intramolecular concerted mechanism by overcoming a moderate barrier (33.8 , 36.7 and 36.3kcal/mol, repectively for PhCH2SC≡N, 3-pyridylnitriles and 4-pyridylnitriles ). These barrier heights are in good agreement to the experimental fact that the reactions can be carried out at room temperature or slightly above.(2) For 2-pyridylnitrile, two molecules of Et2AlN3 coordinate to both the N atoms of–CN group and pyridine ring lead to key intermediate 3d, and the intramolecular concerted mechanism of 3d has the most smaller barrier height, which is only about 25.7 kcal/mol. This quite small barrier suggests the reaction of 2-pyridylnitrile+Et2AlN3 can happen below room temperature.(3) For EtO2C(O1)CN, its"d"and"b"types of intermediates can transform to tetrazole ring products by overcoming similar barrier heights, 32.6 kcal/mol and 33.6 kcal/mol, respectively. So both the mechanisms are important and the reaction can be performed at room temperature. 2. Density functional method study on the mechanism for copper-catalyzed synthesis of 5-substituted tetrazoles from nitriles and trimethylsilyl azidesWe have considered the various mechanisms of the in-situ generated CuN3 with p-MeO-C6H5CN, such as direct concerted mechanism, coordination concerted mechanism and coordination stepwise mechanism. The main conclusions are:(1) The direct concerted mechanism of p-MeO-C6H5CN + CuN3 has very high barrier height (about 50 kcal/mol) and it has less meaning in tetrazoles formation.(2) Molecules such as MeOH, Et3N, p-MeOC6H5CN and DMF etc. coordinate to CuN3 to form L_CuN3 intermediates. These Intermediates can react with another p-MeOC6H5CN via intermolecular concerted mechanism, but their barriers are all above 45kcal/mol. p-MeOC6H5CN_CuN3 can happen stepwise reaction to form tetrazoles, but the rate determining barrier is higher than 50kcal/mol. When another ligand L coordinates (L=MeOH, Et3N, p-MeOC6H5CN and DMF) to the Cu atom of p-MeOC6H5CN_CuN3, the barrier height of the stepwise mechanism will be reduced to 40-43 kcal/mol.(3) p-MeOC6H5CN_CuN3 reacts with CuN3 via intermolecular concerted mechanism with barrier height of 42kcal/mol. But p-MeOC6H5CN_CuN3 with various L_CuN3 (L=MeOH, Et3N, p-MeOC6H5CN and DMF), the barrier heights of the intermolecular concerted mechanism are in the ranging of 23-32kcal/mol, and the stronger of the coordination effect in L_CuN3, the lower of the barrier height. (4) p-MeOC6H5CN reacting with CuN3 dimer involves intermediate p-MeOC6H5CN_CuN3_CuN3, which can happen intramolecular concerted reaction that lead to tetrazoles. Its barrier height is 42.8 kcal/mol. L ligand bounds to the Cu'atom will form p-MeOC6H5CN_CuN3_Cu'(L)N3, and the barrier heights of the intramolecular concerted reactions of p-MeOC6H5CN_CuN3_Cu'(L)N3 are in the ranging of 29-32 kcal/mol.In summary, the predominant mechanism for the reaction of CuN3 with organic nitriles may vary with the change of reaction conditions. When excess amount CuN3 was used, the predominant mechanism should be the intermolecular concerted reaction between two p-MeOC6H5CN_CuN3 molecules. The presence of ligands with strong coordination effect to CuN3, such as Et3N, may promote the reaction of p-MeOC6H5CN with CuN3, by adding new intermolecular concerted channel p-MeOC6H5CN_CuN3+Et3N_CuN3.