Herein, we report the chiral symmetry breaking of 2-methoxy-1-naphthamide atropisomers through temperature cycling without the use of any racemization reagent. The racemization rate (k 1 ) controls the deracemization process when the cooling of the slurry is slow enough to keep the system close to equilibrium. The productivity appears proportional to the racemization rate (k 1 ) multiplied by the solubility.

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Temperature-cycle-induced deracemization (TCID) has been widely studied in the field of chiral separation, ranging from fundamental research to applications. In this study, the secondorder asymmetric transformation (SOAT) of 2-methoxy-1-naphthamide in an azeotropic mixture of ethyl acetate and cyclohexane is compared with TCID, in terms of process productivity. The results indicate that the volumetric productivity using SOAT was over 100times higher than that using TCID, such that a scale-up by a factor of 10 was easily implemented.

A productive deracemization process based on a quaternary phase diagram study of a naphthamide derivative is reported. New racemic compounds of an atropisomeric naphthamide derivative have been discovered, and a quaternary phase diagram has been constructed that indicated that four solids are stable in a methanol/H2O solution. Based on the results of a heterogeneous equilibria study showing the stable domain of the conglomerate, a second‐order asymmetric transformation was achieved with up to 97 % ee. Furthermore, this methodology showcases the chiral separation of a stable racemic compound forming system and does not suffer from any of the typical limitations of deracemization, although application is still limited to conglomerate‐forming systems. We anticipate that this present study will serve as a fundamental model for the design of sophisticated chiral separation processes.

In this paper, macroscopic chiral symmetry breaking refers to as the process in which a mixture of enantiomers departs from 50–50 symmetry to favor one chirality, resulting in either a scalemic mixture or a pure enantiomer. In this domain, crystallization offers various possibilities, from the classical Viedma ripening or Temperature Cycle-Induced Deracemization to the famous Kondepudi experiment and then to so-called Preferential Enrichment. These processes, together with some variants, will be depicted in terms of thermodynamic pathways, departure from equilibrium and operating conditions. Influential parameters on the final state will be reviewed as well as the impact of kinetics of the R ⇔ S equilibrium in solution on chiral symmetry breaking. How one can control the outcome of symmetry breaking is examined. Several open questions are detailed and different interpretations are discussed.

A racemic compound has been identified for the system: (+)-(-) BINOL-OBn despite having been reported as a conglomerate. This heterochiral phase appears to be more stable than the conglomerate irrespective of the temperature. Its melting point exceeds by 20°C that of the racemic eutectic. In conjunction with the revised phase diagram, the crystal structures of the racemic compound and of the pure enantiomer have been compared. In the structure of the racemic compound (Z' = 3) hydrogen bonds can be found whereas in the structure of the pure enantiomer (Z' = 1) only π-π and Van der Waals interactions are observed. The likelihood that a more stable racemic compound appears when processing a conglomerate (e.g. in preferential crystallization) is discussed.

Phase diagrams play a critical role for tuning crystallization. This study explains the basics of phase diagrams starting from the ternary system to a quaternary system with and without fast racemization in the liquid phase. Experimentally, an atropisomeric naphthamide derivative in MeOH/H2O serves as an example. Deracemization is ensured by a second‐order asymmetric transformation up to 97% ee. Readers are encouraged to look at the animation (in the Supporting Information) detailing the construction of the degenerated quaternary system in a step‐by‐step manner. More information can be found in the Full Paper by G. Coquerel et al. on page 13890.

Stable NH-form of the threonine-based Schiff base 4, (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(((E)-(2-hydroxynaphthalen-1-yl)methylene)amino)butanamide, was synthesized and characterized in the crystalline state by means of IR spectroscopy and X-ray crystallographic analysis. This is the first X-ray determination of an amino acid-based Schiff base that was locked in the NH-form. Comparison of the characteristic bond lengths based on the X-ray structure of 4 with previously reported NH-forms of other Schiff bases revealed that the structure of 4 was a hybrid of two canonical structures, namely, zwitterion and quinoid, contributing to the resonance. It was also found that 4 exist in the OH-form in solution and its phenolic proton is wellconstrained via intramolecular hydrogen bonding with the imine functionality.