A combined theoretical and crystallographic investigation of racemic and enantiopure aryl benzyl sulfoxides

The separation of enantiomers by crystallization is of great interest to the pharmaceutical industry. The existence of a stable conglomerate is a necessary (but not sufficient) condition for the application of a preferential crystallization [1]. So, the comparison between the crystal structure of an enantiopure molecule and the corresponding racemate is an important point. In the past, it was generally accepted that the crystal structure of a racemate is tightly and denser than that of pure enantiomers (a statement sometimes referred as the “Wallach rule”). This result had been based upon the inspection of a limited number of pairs from the literature [2]. On the other hand, a slightly larger comparison in the crystallographic database showed that the validity of this empirical rule can be questioned [3]. Further analysis confirmed the complexity of the question [4-6] and also found some counterintuitive results, such as a racemic mixture that crystallises in a non centro-symmetric space group [4]. Research in this field is discouraged by the fact that it is not easy to make efficient queries to the Cambridge Crystallographic Database to extract information about pairs of racemic and enantiopure compounds. Some relevant active pharmaceutical ingredients are chiral sulfoxides, such as (S)-omeprazole one of the world's best-selling drugs. This drug is an aryl benzyl sulfoxide. In this communication, a series of 7 simple racemic and enantiopure aryl benzyl sulfoxides was investigated. The main interactions that make up the crystal structures were identified, and the energetic calculations were performed. This research was aided by the recent release of the CrystalExplorer17 program [7], that is able also to estimate reliable lattice energies, starting from the experimental coordinates deriving from the X-ray diffraction experiments It is interesting to observe that these molecules can organise themselves in both a gauche- or in an anti- conformation depending on the interactions that form the crystals. As a final result, in the majority of cases, the energetic calculations seem to confirm the “Wallach rule”, but interesting exceptions emerge.