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.

Substituent effects in the ring‐chain tautomerism of 4‐alkyl‐2‐aryl substituted oxazolidines and tetrahydro‐1,3‐oxazines

“…For the equilibria of oxazolidines (5)(6)(7)(8), the best correlations were observed for the Meyer parameter (V a ), while for the equilibria of 1,3-oxazines (17)(18)(19)(20), none of the four alkyl substituent parameters resulted in a significant value of R (Table 4). It is interesting to note that, in contrast with the corresponding tautomeric equilibria of 1-alkyl-3-arylnaphth[1,2-e][1,3]oxazines [12], the slopes of the alkyl substituent parameters ( R ) for the …”

“…13: yield: 3.04 g (68%); bp 95-97 ºC (21 torr General Procedure for the Preparation of 4-Alkyl-2-arylsubstituted oxazolidines (5-8) and tetrahydro-1,3-oxazines (17)(18)(19)(20). To a solution of the corresponding amino alcohol (1-4 or 13-16) (3 mmol) in absolute MeOH (20 mL), an equivalent amount of aromatic aldehyde was added (for liquid aldehydes, a freshly distilled sample was used), and the mixture was allowed to stand at ambient temperature for 1 h. The solvent was then evaporated off.…”

“…With regard to the similarities in the 1 H nmr data for the members a-g of each set of oxazolidines (5)(6)(7)(8) and tetrahydro-1,3-oxazines (17)(18)(19)(20), the full spectra of the major tautomers are described only for eight representatives of these sets of compounds (5a, 6a, 7a, 8a, 17a, 18a, 19a, 20a). The protons of the open form (A) are numbered according to the corresponding protons of the cyclic oxazolidine or tetrahydro-1,3-oxazine forms (B or C).…”

“…The protons of the open form (A) are numbered according to the corresponding protons of the cyclic oxazolidine or tetrahydro-1,3-oxazine forms (B or C). In consequence of the small relative concentrations, only the characteristic O-CHAr-N and N=CHAr protons are listed for the detectable minor tautomeric forms (see Tables 6 and 7 Table 7 Physical and nmr spectroscopic data on and 4-alkyl-2-aryl-3,4,5,6-tetrahydro-2H-1,3-oxazines (17)(18)(19)(20) …”

Recent Developments in the Ring‐Chain Tautomerism of 1,3‐Heterocycles

“…This anomeric effect is presumed to play an important role in the ring-chain tautomeric equilibria of conformationally inflexible 2-aryl-1,3-N,N-heterocycles. [24] Both the substituent on the nitrogen atom and the presence of an annelated ring had marked effects on the ringchain tautomeric processes of 2-arylhexahydropyrimidines. No open tautomer could be detected in CDCl 3 solutions of the N-methyl-substituted derivatives 63 and 66. The Nunsubstituted, the N-isopropyl-substituted and the N-phenyl-substituted compounds 62, 64, 65, 67 and 68 proved to be tautomeric mixtures (Scheme 18), the equilibria of which could be described by Equation (1).…”