Difficulties to determine the absolute configuration of guaiaretic acid

Abstract

An account of the difficulties to determine the absolute configuration (AC) of guaiaretic acid (1a), using contemporary methodology, is described in commemoration of the century of its structure elucidation. In fact, the herein studied molecule was the derived diacetate 1b, since the natural lignan slowly decomposes upon manipulation. Single crystal X-ray diffraction of 1b demonstrated the structure, but calculation of Flack and Hooft parameters to know the AC was unsuccessful since the crystals were triclinic, P-1, which is a centro-symmetric space group. In turn, manual band to band comparison of experimental and DFT B3LYP/DGDZVP calculated VCD spectra of 1b allowed ascertaining its AC, although automatic comparison using the CompareVOA software was not very successful. This behavior is associated to the fact that the studied molecule has a sole stereogenic center located on the acyclic portion of a carbon chain possessing two quite similar substituents. The behavior is discussed in relation to cases where the molecular flexibility also generates a very large number of conformers.