title: Substituent-dependent negative hyperconjugation in 2-aryl-1,3-N,N-heterocycles. fine-tuned anomeric effect?
abstract: The epimerization reactions of conformationally inflexible 2-aryl-1,3-N,N-heterocycles were used as model systems to study the role of the nitrogen lone pair-C2 associated antibonding orbital hyperconjugative interactions in the experimentally observed substituent-dependent generalized anomeric effect. The measured reaction free enthalpies were found to correlate well with the sum of the hyperconjugative stabilization energies of all the vicinal donor-acceptor orbital overlaps around C2, obtained from ab initio NBO analysis, and both quantities correlated linearly with the Hammett-Brown substituent constant. The individual stereoelectronic interactions (n(N)-sigma(C2)(-)(N), n(N)-sigma(C2)(-)(Ar), n(N)-sigma(C2)(-)(H)) were also observed to exhibit a substituent dependence, despite their distance from the 2-aryl substituent and their nonperiplanar arrangement. The higher the electron-withdrawing effect of the 2-aryl substituent, the larger was the stabilization for n(N)-sigma(C2)(-)(Ar), while the overlaps n(N)-sigma(C2)(-)(N) and n(N)-sigma(C2)(-)(H) changed in the opposite sense. The different polarization of the acceptor sigma orbitals, caused by the 2-aryl substituent, accounted for the observed propagation of the substituent effect. These results promote a detailed explanation of the useful tautomeric behavior of the 2-aryl-1,3-X,N-heterocycles, and reveal the nature of the connection between the anomeric effect and the Hammett-type linear free energy relationship.
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, POB 121, Hungary.
authors.forename: Anasztázia
authors.initials: A
authors.lastname: Hetényi
authors.forename: Tamás A
authors.initials: TA
authors.lastname: Martinek
authors.forename: László
authors.initials: L
authors.lastname: Lázár
authors.forename: Zita
authors.initials: Z
authors.lastname: Zalán
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fülöp