Spin-Polarized Conceptual Density Functional Theory Study of the Regioselectivity in Ring Closures of Radicals B. Pinte ´r, ²,‡ F. De Proft,* ,‡ V. Van Speybroeck, § K. Hemelsoet, § M. Waroquier, § E. Chamorro, |,‡ T. Veszpre ´mi, ² and P. Geerlings ‡ Inorganic Chemistry Department, Budapest UniVersity of Technology and Economics (BUTE), Szent Gelle ´ rt te ´ r 4, 1521 Budapest, Hungary, Eenheid Algemene Chemie (ALGC), Faculteit Wetenschappen, Vrije UniVersiteit Brussel (VUB), Pleinlaan 2, 1050 Brussels, Belgium, Center For Molecular Modeling, Ghent UniVersity, Proeftuinstraat 86, 9000 Ghent, Belgium, and Departmento de Ciencias Quı ´micas, Facultad de Ecologı ´a y Recursos Naturales, UniVersidad Andre ´ s Bello, AVenida Repu ´ blica 275, Santiago, Chile fdeprof@Vub.ac.be ReceiVed July 5, 2006 The regioselectivity of ring-forming radical reactions is investigated within the framework of the so- called spin-polarized conceptual density functional theory. Two different types of cyclizations were studied. First, a series of model reactions of alkyl- and acyl-substituted radicals were investigated. Next, attention was focused on the radical cascade cyclizations of N-alkenyl-2-aziridinylmethyl radicals (a three-step mechanism). In both of these reactions, the approaching radical (carbon or nitrogen centered) adds to a carbon-carbon double bond within the same molecule to form a radical ring compound. In this process, the number of electrons is changing from a local point of view (a charge transfer occurs from one part of the molecule to another one) at constant global spin number N s (both the reactant and the product ring compound are in the doublet state). It is shown that the experimentally observed regioselectivities for these ring-closure steps can be predicted using the spin-polarized Fukui functions for radical attack, f NN 0 (r). Introduction In 1976, Baldwin introduced a set of simple rules governing the regioselectivity of ring closures. 1 On the basis of the acceptor part of these molecules, containing the carbon atom at which the ring-closure reaction occurs, he divided these reactions into three main groups: the tetrahedral 2 systems, trigonal systems, and diagonal systems. On the other hand, for the donor part of the system, one can classify the reactions as nucleophilic, electrophilic, or radicalar intramolecular additions. In the past three decades, these rules have proven to be useful to predict the major outcome of ring-forming reactions. 3 However, numer- ous papers have stressed the limitations of and exceptions to these rules. 4 For radical cyclization processes, Beckwith at al. 5 ² Budapest University of Technology and Economics. ‡ Vrije Universiteit Brussel. § Ghent University. | Universidad Andre ´s Bello. (1) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. (2) This is the prevalent nomenclature, describing the geometry of the acceptor atom, sp 3 center as tet- (tetrahedral), sp 2 center as trig- (trigonal), and sp center as dig- (digonal). Another nomenclature indicates where the displaced electrons end up: if the electron pair ends up outside, then this is denoted as endo-; if the electron pair ends up within (smaller ring formation), the terminology exo is used. (3) For reviews, see: (a) Jasperse, C. J.; Curran, P. D.; Fevig, L. T. Chem. ReV. 1991, 91, 1237. (b) Kochi, J. K. Free Radicals, Wiley: New York, 1973. (c) Julia, M. Pure Appl. Chem. 1974, 40, 553. (d) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073. (e) Hart, D. J. Science 1984, 223, 883. (f) Giese, B. Radicals in Organic Synthesis: Formation of Carbon- Carbon Bonds; Pergamon: New York, 1986. (g) Jung, M. E; Cho, M. Y.; Jung, H. Y. Tetrahedron Lett. 1996, 37, 3. (h) Ingold, K. U.; Beckwith, A. L. J. Free-Radical Rearrangements. In Rearrangements in Ground and Excited States; de Mayo, P., Ed.; Academic Press: New York, NY, 1980; Vol. 1, p 161. (4) (a) Wilt, W. J. Tetrahedron 1985, 41, 3979. (b) Curran, D. P.; Chang, C. T. J. Org. Chem. 1989, 54, 3140. (c) Struble, D. L.; Beckwith A. L. J.; Gream, G. E. Aust. J. Chem. 1972, 25, 1081. 348 J. Org. Chem. 2007, 72, 348-356 10.1021/jo0613885 CCC: $37.00 © 2007 American Chemical Society Published on Web 12/21/2006