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Density functional calculations SMD(chloroform)//B3LYP/6-311+G(2d,p) were employed in the computational study of 1,3-dipolar cycloadditions of azides with guanidine. The formation of two regioisomeric tetrazoles and their rearrangement to cyclic aziridines and open-chain guanidine products were modeled. The results suggest the feasibility of an uncatalyzed reaction under very drastic conditions since the thermodynamically preferred reaction path (a), which involves cycloaddition by binding the carbon atom from guanidine to the terminal azide nitrogen atom, and the guanidine imino nitrogen with the inner N atom from the azide, has an energy barrier higher than 50 kcal mol−1. The formation of the other regioisomeric tetrazole (imino nitrogen interacts with terminal N atom of azide) in direction (b) can be more favorable and proceed under milder conditions if alternative activation of the nitrogen molecule releases (e.g., photochemical activation), or deamination could be achieved because these processes have the highest barrier in the less favorable (b) branch of the mechanism. The introduction of substituents should favorably affect the cycloaddition reactivity of the azides, with the greatest effects expected for the benzyl and perfluorophenyl groups.

A proposed mechanism of the reaction of guanidinium chlorides with dimethyl acetylenedicarboxylate in a tandem aza-Michael addition reaction/intramolecular cyclization was investigated by DFT M06-2X and B3LYP computational approaches. The energies of the products were compared against the G3, M08-HX, M11, and wB97xD data or experimentally obtained product ratios. The structural diversity of the products was interpreted by the concurrent formation of different tautomers formed in situ upon deprotonation with a 2-chlorofumarate anion. A comparison of relative energies of the characteristic stationary points along the examined reaction paths indicated that the initial nucleophilic addition is energetically the most demanding process. The overall reaction is strongly exergonic, as predicted by both methods, which is primarily due to methanol elimination during the intramolecular cyclization step producing cyclic amide structures. Formation of a five-membered ring upon intramolecular cyclization is highly favored for the acyclic guanidine, while optimal product structure for the cyclic guanidines is based on a 1,5,7-triaza [4.3.0]-bicyclononane skeleton. Relative stabilities of the possible products calculated by the employed DFT methods were compared against the experimental product ratio. The best agreement was obtained for the M08-HX approach while the B3LYP approach provided somewhat better results than the M06-2X and M11 methods.