Semi-empirical treatment of intramolecular nitrogen heterocyclic triazenes ring closure C. Karvellas a , C.I. Williams a , M.A. Whitehead a, * , B.J. Jean-Claude b a Theoretical Chemistry Laboratory. Department of Chemistry, McGill University, 801, Sherbrooke Street West, Montreal, Que., Canada H3A 2K6 b Department of Oncology, McGill University, 3655 Drummond Street, Ste. 701, Montreal, Que., Canada H3G 1Y6 Received 17 April 2000; accepted 28 April 2000 Abstract The semi-empirical MNDO, AM1 and PM3 methods are used to study nitrogen heterocyclic ring-closure reactions. Geome- tries, energies and reactivities involved in the ring closure of azidopyridine to tetrazolazine are examined. The ring-closure mechanisms of o-diazoaniline to benzotriazole, and of o-diazobenzamide to benzo-1,2,3-triazin-4-one through protonated intermediates are determined. The effect of aryl ring substituents on ring closure is investigated for all structures. Transition states for the o-diazoaniline, and the enol mechanism of o-diazobenzamide ring closures are investigated. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Ring closure; Azidopyridine; Tetrazolazine 1. Introduction Molecular mechanics, ab initio and semi-empirical quantum mechanical methods have been used exten- sively to study the ground state structures, energies and reactivities of a wide variety of molecules [1], and recently, nitrogen heterocyclic compounds [2,3]. Semi-empirical MNDO, AM1 and PM3 methods have been used to examine 2-, 4- and 5-imidazolone tauto- merizations [4]. Nitrogen heterocyclic compounds containing the N±NyN triazene linkage, such as imidazotetrazines [5] and tetrazepinones (TZP) [6], have interesting anti-tumor properties. The ring open/ring close equilibrium and the substi- tuent dependence of the ring closure appear crucial for triazene/tetrazepinone anti-tumor activity. Therefore, intramolecular ring-closure reactions are investigated computationally for the azidopyridine/tetrazolazine, the o-diazoanaline/benzotriazole, and the 2,3-diazo- benzamide/benzo-1,2,3-triazin-4-one nitrogen hetero- cycles. Tetrazolazines (2) isomerize readily to the corre- sponding ring-opened azidopyridine [7] (1) (Fig. 1). According to experimental studies [7], the electron- donating ability of the heterocycle fused to the tetra- zole ring, controls the azido±tetrazolo isomerization. Electron-donating groups stabilize the N±N bond formed during ring closure and the ring-closed tetra- zole form (2). Substituent effects on ring closure are examined through semi-empirical calculations. The ring closure of o-diazoaniline (3) to benzotria- zole (5), is also examined. Contrary to the azido/tetra- zolo ring closure (Fig. 1), the o-diazoanaline/ benzotriazole ring closure is an intramolecular diazo coupling reaction (Fig. 2). Nucleophilic attack of the Journal of Molecular Structure (Theochem) 535 (2001) 199±215 0166-1280/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S0166-1280(00)00594-7 www.elsevier.nl/locate/theochem * Corresponding author. Fax: 11-514-398-3797. E-mail address: tony@maw.chem.mcgill.ca (M.A. Whitehead).