Insight into the lipophilicity of the aromatic N-oxide moiety.

Abstract

A systematic study to assess the influence of N-oxygenation on the lipophilicity of aromatic weak bases was performed. The methods used were experimental (CPC and shake-flask techniques) and computational (AMI semi-empirical method). The intrinsic increment in the log P(oct) system for an oxygen atom added to form an aromatic N-oxide, designated as diff(log PN(O) -N), was -1.91, but the presence of para-substituents markedly affected this value. The good linear relationship (r2 = 0.92) between diff(log PN(O) - N), and the electronic density on the oxygen atom suggests that H-bond acceptor basicity is the main structural factor responsible for the variations in lipophilicity of aromatic N-oxides. Partition coefficients of aromatic N-oxides in dodecane/buffer and chloroform/buffer systems also support this hypothesis. The solvent-dependent polarity of the N-oxide moiety is mainly due to its marked H-bond acceptor basicity.