A multi-technique approach to predicting the molecular structure of cuprizone in the gas phase and in the crystalline state

Abstract

Cuprizone (oxalic acid bis(cyclohexylidene hydrazide)) is a potent neurotoxin that is known to induce the destruction of the myelinic sheath which covers the cells of the central nervous system (CNS). The mechanism of action has not yet been elucidated due to lack of structural information. We have performed an ab initio prediction of the molecular structure by high-level quantum chemical methods, leading to two possible conformers of a nearly identical energy: A, for which an analysis of the electron density distribution shows more propensity for intermolecular bonding, and B, with stronger intramolecular liaison. Having obtained suitable single crystals, we report a detailed study of the crystal and molecular structure, which reveals that the molecular and crystal centers of symmetry coincide, and that the actual conformer is A, as expected, and in agreement with the ab initio prediction. Further information is gained by optimization of the crystal structure by Car-Parrinello molecular dynamics, yielding good agreement with observation. Infrared and Raman spectra show mutual exclusion, suggesting a centrosymmetric molecule with carbonylic bonds in trans configuration; moreover, vibrational frequencies calculated ab initio also show excellent agreement with observations. We thus present a multi-technique approach to the prediction and interpretation of various aspects of the complex interplay between intra- and intermolecular forces.