The geometry and electronic structure of Aristolochic acid: possible implications for a frozen resonance

Molecular mutagens and carcinogens are structures which carry chemical and electronic properties that disturb and interact with the genomic machinery. Principally, a rule of thumb for carcinogens is that carcinogens are expected to introduce covalent irreversible bonding to one or several types of DNA bases, causing errors in the reading frame for the polymerases. 8‐methoxy‐6‐nitrophenanthro3,4‐d]1,3]dioxole‐5‐carboxylic acid, better known as Aristolochic acid (AA1) is a recognized carcinogen which causes urotherial cancer and is found in certain plants. Its structure is particularly interesting given that it is closely related to phenanthrene in its polycyclic arrangement, and has four functional groups, a carboxyl‐, a nitro‐, a methoxy‐ and a dioxolane group. In this work, the structure of AA1 has been resolved at the MPWPW91 density functional theory method in combination with Aug‐cc‐pVDZ basis sets. A geometry analysis shows that in AA1 the carboxyl group's torsion is caused by steric strain from the nitro group, which elevates the molecular plane of the first phenanthrene ring with 0.1Å. The wavefunction analysis of AA1 shows that the ring deformation enhances a double π‐bond localization in the first ring, adjacent to the dioxalane group, and results in a decrease of ring aromaticity and induces a potentially frozen resonance. Intermolecular and intramolecular interactions were characterized by atoms in molecules and reduced density gradient analysis. This study brings novel information on the geometry and electronic structure of AA1, which are important for the further knowledge of its transformation in vivo and in situ. Copyright © 2013 John Wiley & Sons, Ltd.