β-Nitroso-o-Quinone Methides: Potent Intermediates in Organic Chemistry and Biology : The impact of the NO group on their Structure and Reactivity Profile: a Theoretical Insight

The structure and reactivity profile of prototype o-quinone methides 1, 2 and their ß-nitroso analogues 6-9 have been investigated by means of DFT and MP2 calculations. These highly reactive unstable species are generated by oxidative dearomatization of their precursor oximes. The destabilization of their structure is more pronounced in the ß-nitroso congeners 7-9. There is only a weak π conjugation across the nitrosoalkene arm. The latter gives rise to E and Z conformations and causes some distortion on the ring -frame while the π-frame is weakly perturbed. The Z conformation is the most stable in all structures. Their geometry is also affected by the o-quinone ring and the 1,2-(7 and 8) and 2,3-(9) isomer pattern. The stability of these conformations is rationalized in terms of ortho- or peri- ring formations. The impact of their geometry profile on their reactivity pattern has been studied by means of reactivity descriptors such as Fukui function f(r), chemical potential and hardness, HOMO and LUMO energies and their separation (HOMO-LUMO gap) as well as aromaticity indices such as HOMA and out-of-plane deformability. All descriptors consistently demonstrate that the reactivity is dominated by an intramolecular ortho or peri-cyclization mode to fused 1,2-oxazoles or 1,2-oxazines, respectively. Intermolecular primary reactions can occur at the quinone alkene bond or that of the nitrosoalkene arm.Peer reviewe

Arene-fused 1,2-oxazole N-oxides and derivatives. The impact of the N-O dipole and substitution on their aromatic character and reactivity profile. Can it be a useful structure in synthesis? A theoretical insight

DFT calculations have shown that the N-O dipole of benzene- and naphthalene-fused 1,2-oxazole N-oxides causes a distortion of their σ and π frame, concentrated on the 1,2-oxazole ring, such that it increases its susceptibility to opening. The distortion forces the benzene ring into some diene geometry, thus, reducing π delocalization over the bi- or tricyclic structure and ultimately their aromatic character. C-3 substitution has a marked influence mainly on the naphthalene-fused N-oxides. C-5 and particularly C-6 substitution, as the position of most extended interaction with the N-O dipole through the π ring density, contribute to the distortion of the 1,2-oxazole geometry and thereby to the decrease of aromaticity of the structure. Bond uniformity (IA), average bond order (ABO) and Harmonic Oscillator Model of Aromaticity (HOMA) indices have been recruited to measure aromaticity changes. IA and ABO appear to be more credible to 1,2-benzoxazole N-oxides and 1,2-naphthoxazole N-oxides, respectively, while HOMA has been found equally reliable to both. Hardness and dipole moments follow similar trends. Energies, localization and separation of the four frontiers orbitals, i.e. HO, HO-1, and LU, LU+1, indicate a rather notable aromatic character of the N-oxides. Their reactivity profile, portrayed by descriptors such as Fukui and electro(nucleo)philicity Parr functions, shows good agreement with experimental outcomes towards electrophiles but succumbs to discrepancies towards nucleophiles due to the susceptibility of the hetero-ring to opening. The "push-pull" character of the N-O dipole and more importantly the extent of its double bonding direct site selectivity.Peer reviewe