Reactive crystallization of chiral molecules Asymmetric amplification and deracemization

Chirality control and chiral amplification are central topics in chemistry, spanning origin-of-life scenarios and pharmaceutical manufacturing, where the undesired enantiomer may cause adverse effects. This thesis elucidates and exploits crystallization-induced deracemization, wherein minute initial chiral imbalances are amplified to full enantiopurity through combining a racemization reaction with continued cycles of crystal growth and dissolution. We first demonstrate that crystal growth under racemizing conditions can itself already amplify enantiomeric excess. High ee-products can even be obtained from low-ee seed crystals. A mechanistic framework shows how the relative rates of racemization and crystallization determine whether seeds undergo erosion, consolidation, or strong amplification, with faster growth of the majority enantiomorphic crystal population as the driver. We then reveal that crystal size and number distributions decisively steer asymmetric crystallization: cumulative growth-rate imbalances generate non-linear effects that can outweigh initial enantioenrichment and can be tuned—or inverted—by controlling the growth mechanism. By dissecting the contributions of crystal growth and dissolution, we next uncover a ratchet-effect: growth-driven enantioenrichment consistently exceeds dissolution-induced erosion. A fundamental dissymmetry between the ways crystals grow and dissolve is the reported origin. These insights guide more efficient deracemization strategies (e.g. disabling racemization during dissolution). Capitalizing on lessons learned, an autonomous solvent-cycling approach is introduced to deracemize a blockbuster building block to full enantiopurity within near-record time. Finally, we argue that non-equilibrium crystallization and directed-evolution strategies can expand the scope of chiral crystallization beyond thermodynamically stable conglomerates, suggesting that kinetic conglomerates may be accessed for almost half the chiral molecules.