Can topological analysis of intermolecular interactions explain differences in the physico-chemical properties of related chiral compounds?

Abstract

Interactions between chiral molecules play a fundamental role for the most biological and many chemical processes. Due to the complexity of the interactions that range from normal hydrogen bonds to weaker interactions like C-H—O hydrogen bonds and stacking, it can be difficult to relate overall thermodynamic properties to the nature of the intermolecular interactions. The topological analysis developed by R.W. Bader for theoretical electron densities has proven to be a powerful tool to analyse intermolecular interactions in crystals based on an analysis of experimental electron densities obtained from accurate high resolution X-ray diffraction data. Our recent investigations of the molecular crystal naphthalene revealed that the topological analysis could reveal and characterize unexpected interatomic interactions [1]. The two pentose epimers xylitol and ribitol differ in the physico-chemical properties, the acentric xylitol being the higher melting and the less dense than ribitol. All possible hydrogen bond donors participate in the hydrogen bond interactions in both compounds, and the topological analysis confirms the energetic similarity of these interactions. The investigations suggest that the origin of the differences in physico-chemical properties is related to differences in the weaker intermolecular interactions and in the entropy. Crystallization of a racemate may lead to racemic compound composed of equal amounts of the two enantiomers or to a spontaneous resolution of crystals that are formed by the pure enantiomers, and the outcome of the process depends on differences in enthalpy and entropy. We have investigated the intermolecular interactions in closely related crystal structures, e.g. a racemic para-fluoromandelic acid and its corresponding enantiomer. The racemic para-fluoromandelic acid showing the unusual behaviour of being the higher melting. An earlier investigation showed that the two forms have an identical hydrogen bond pattern. This was confirmed by the topological analyses based on accurate X-ray diffraction data. Though additional features were revealed from the topological analysis it also showed the significance of supplementing the investigations with theoretical calculations.