Are racemic crystals favored over homochiral crystals by higher stability or by kinetics? Insights from comparative studies of crystalline stereoisomers.

Abstract

The crystal and molecular structures of 134 pairs of diastereoisomers and of 279 racemic-homochiral pairs were retrieved from the Cambridge Structural Database. Lattice and intramolecular energies are calculated. Density differences between crystals of stereoisomers of all kind are mostly within 5%, as observed also for crystal polymorphs. Racemic crystals are predominantly, but not exclusively, more stable and more dense. Denser crystals are predominantly more stable, but there is no quantitative correlation between density and energy differences between partners in the chosen pairs. Second-order symmetry operators are neither ubiquitous in the racemic nor patently superior to first-order operators in promoting crystal cohesion. Thermodynamic, energetic factors in the final crystalline products are not enough to explain the (largely) predominant occurrence of racemic crystallization from racemic solution. At least for homogeneous nucleation, a probabilistic factor, from kinetics or from statistical predominance of mixed versus enantiopure aggregates, must be in action during the early separation of liquid-like particles, which are thought to be the precursors of crystal nucleation.