Pasteur’s Tweezers Revisited: On the Mechanism of Attrition-Enhanced Deracemization and Resolution of Chiral Conglomerate Solids

Abstract

Insights into the mechanism of attrition-enhanced deracemization and resolution of solid enantiomorphic chiral compounds are obtained by crystal size and solubility measurements and by isotopic labeling experiments. Together these results help to deconvolute the various chemical and physical rate processes contributing to the phenomenon. Crystal size measurements highlight a distinct correlation between the stochastic, transient growth of crystals and the emergence of a single solid enantiomorph under attrition conditions. The rapid mass transfer of molecules between the solution and solid phases under attrition is demonstrated, and the concept of a crystal-size-induced solubility driving force is exploited to overcome the stochastic nature of the crystal growth and dissolution processes. Extension to non-racemizing conditions provides a novel methodology for chiral resolution. Implications both for practical chiral separations and for the origin of biological homochirality are discussed.

Chiral Symmetry Breaking in Peptide Systems During Formation of Life on Earth

“…The number of works in this area could be made a subject of a separate research. Vast number of models of chiral symmetry breaking were proposed over the years and numerous experiments were performed, for example (Frank 1953;Avetisov and Goldanskii 1996;Plasson et al 2004Plasson et al , 2007Saito and Hyuga 2004;Weissbuch et al 2005;Brandenburg et al 2007; van der Meijden et al 2009;Noorduin et al 2010;Blackmond 2011;Coveney et al 2012;Hein et al 2012;Ribó et al 2013;Konstantinova 2013, 2014), and many others. However, most, if not all, theories and experiments related to chiral symmetry breaking during formation of life on Earth considered only a very limited number of substances and reactions, whereas the actual number of possible substances and reactions among them must have been extremely large, as we will soon discuss.…”

“…Alternative models of chiral symmetry breaking are based on inter-conversion of enantiomers. These models can be grouped into two classes: the models based on epimerization (Plasson et al 2004(Plasson et al , 2007Weissbuch et al 2005;Brandenburg et al 2007) and the models based on the deracemization process (Hein et al 2012;van der Meijden et al 2009;Noorduin et al 2010).…”

“…On the opposite side, deracemization utilizes a phase transition process of crystallization and nonlinearity due to the rate of crystallization being proportional to the surface area of the crystals (Hein et al 2012;van der Meijden et al 2009;Noorduin et al 2010). In contrast to basic chemical reactions, which are polynomial functions of concentrations, a phase transition, if viewed as a mathematical function, exhibits some discontinuity.…”

Resolution of Omeprazole Using Coupled Preferential Crystallization: Efficient Separation of a Nonracemizable Conglomerate Salt under Near-Equilibrium Conditions

“…11 Two crystallization flasks containing suspensions of crystals both equilibrated at the same temperature (Figure 1a illustrated for the case of Pasteur's salt) are used. The racemic mixture is held in flask A and subjected to attrition, while crystals of the pure enantiomer are suspended in flask B, which is stirred gently.…”

“…11,15 The magnitude of this temperature differential ( Figure 5, ΔT = T 1 − T 2 ) is critical to allow efficient resolution of the conglomerate solid. If ΔT is too large, primary nucleation of the undesired crystal antipode in flask B will result, whereas a low ΔT will result in an insufficient solubility gradient between the flasks, leading to very slow mass transfer.…”