A theoretical DFT study on the structural parameters and azide–tetrazole equilibrium in substituted azidothiazole systems

Azido–tetrazole equilibrium is sensitive to: substitution, solvent, temperature and phase. In this work, the effects of the type and position of substitution on the thiazole ring of azidothiazoles on its structural parameters and on the azido–tetrazole equilibrium have been theoretically investigated using the density functional procedures at the B3LYP/6-311G∗∗ level of theory. This study includes the investigation of the equilibrium geometry, the transformation of the trans-conformer to the cis one then the ring closure to the tetrazole isomer. The transition states of the two steps were located, confirmed and the structural parameters were calculated. In all the steps of calculations, geometry optimization was considered.The results obtained indicate that substitution by: –NO2 and –CN group shifts the equilibrium to the azide side and in some cases the tetrazole isomer is not obtained. On the other hand, substitution by: –NH2 and –OH groups shifts the equilibrium to the tetrazole side and in some cases the azide isomer is not obtained and if formed changes spontaneously to the tetrazole isomer.The decisive parameters which determine the position of the equilibrium are: charge density on atoms N3 and N8, rearrangement of bond length and bond angles during the process of cyclization and variation of dipole moment as a result of cyclization.Results of this work indicate that substitution on C5 is more efficient than substitution on C4 of the thiazole ring.

Graphical abstractThe literature is rich in experimental data which report the effect of substituent on the azide → tetrazole equilibrium in the system: 2-azido-1,3-thiazole but without a theoretical basis. Here, the effect is investigated theoretically using the B3LYP/6311G∗∗ level of theory. The two steps involved in the reaction, namely, azide group rotation from the trans to the cis conformer and the ring closure of the azide group to the tetrazole ring are investigated, the PES of each step is constructed, the TS of each step is identified and confirmed.Electron donor substituents shift the equilibrium to the tetrazole isomer and in some cases the azide isomer cannot be isolated. Electron withdrawing substituents shift the equilibrium the azide isomer, in some cases, the tetrazole isomer cannot be isolated.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► The rotational barrier of the azido group in 4-nitro 2-azidothiazole from the trans to the cis conformer is 6.71 kcal/mol. ► The energy barrier of ring closure of the azide group to the tetrazole ring in 4-nitro-2-azidothiazole is 27.27 kcal/mol. ► 4-Nitro, 4-cyano, 5-nitro and 5-cyano 2-azidothiazoles exist only in the azide conformer. ► 4-Hydroxy, 4-amino, 5-hydroxy and 5-amino 2-azidothiazoles exist only in the tetrazole conformer. ► Sulfur atom is a stronger efficient electron carrier than the nitrogen atom.