Circular dichroism, optical rotation and absolute configuration of 2-cyclohexenone-cis-diol type phenolmetabolites: redefining the role of substituents and 2-cyclohexenone conformation in electronic circular dichroism spectra

Abstract

The absolute configurations of 2-cyclohexenone cis-diol metabolites resulting from the biotransformation of the corresponding phenols have been determined by comparison of their experimental and calculated circular dichroism spectra (TDDFT at the PCM/B2LYP/Aug-cc-pVTZ level), optical rotations (calculated at the PCM/B3LYP/Aug-cc-pVTZ level) and by stereochemical correlation. It is found that circular dichroism spectra and optical rotations of 2-cyclohexenone derivatives are strongly dependent on the ring conformation (M or P sofa S(5) or half-chair), enone non-planarity and the nature and positions of the hydroxy and alkyl substituents. The effect of non-planarity of the enone chromophore, including the distortion of the CC bond, is determined for the model structures by TDDFT calculations at the PCM/B2LYP/6-311++G(2d,2p) level. Non-planarity of the CC bond in the enone chromophore is commonly encountered in 2-cyclohexenone derivatives and it is a source of significant rotatory strength contribution to the electronic circular dichroism spectra. It is shown that the two lowest-energy transitions in acrolein and 2-cyclohexenone and its derivatives are n_CO–π_CO* and π_CC–π_CO*, as expected, while the shorter-wavelength (below 200 nm) transitions are of more complex nature. In 2-cyclohexenone and its alkyl derivatives it is predominantly a mixture of π_CC–π_CC* and π_CC–σ* transitions, whereas the presence of hydroxy substituent results in a dominant contribution due to the n_OH–π_CO* transition. A generalized model for correlation of the CD spectra of 2-cyclohexenones with their structures is presented.