When a small amount of an enantiopure tailor-made additive is added to a racemic conglomerate undergoing attrition-enhanced deracemization (Viedma ripening), two enantiospecific mechanisms act antagonistically on the solid phase: kinetic inhibition of crystal growth of the additive's own enantiomorph (the rule of reversal) and thermodynamic incorporation of the additive into the lattice of the like-configured enantiomer as an enantiospecific solid solution. Which mechanism dominates — and hence the direction in which the solid phase deracemizes — is not predictable from any published framework. This problem asks for a quantitative, experimentally validated framework that predicts the sign and time course of deracemization from operational parameters (additive identity and loading, solubility behavior, temperature, racemization rate, grinding intensity), separates kinetic from thermodynamic contributions even when they favor the same enantiomer, and accounts for the additional counteracting processes that operate under racemizing conditions — catalyst-induced solubility changes, racemization of the additive itself, and enantiospecific dissolution inhibition.

Background

A racemic conglomerate is a crystalline system in which the two enantiomers of a chiral molecule crystallize as separate, enantiopure crystals (rather than mixed racemic crystals). Under attrition-enhanced deracemization (Viedma ripening), such a suspension, combined with a racemization catalyst that interconverts the enantiomers in solution, spontaneously evolves from a near-racemic mixture of left- and right-handed crystals toward a single enantiomorph — a pure experimental realization of chiral symmetry breaking.

Tailor-made additives are small amounts (typically a few weight percent) of a chiral molecule structurally related to the substrate. By the 'rule of reversal' (Addadi, Weinstein, Lahav, and Leiserowitz's stereospecific adsorption framework), an additive adsorbs preferentially onto crystals of the same handedness and inhibits their growth, so kinetic growth inhibition favors the additive's opposite enantiomer. Conversely, if the additive is sufficiently structurally compatible, it can be incorporated substitutionally into the bulk lattice of the like-configured enantiomer — enantiospecific solid-solution formation — a thermodynamic effect that lowers the lattice free energy of that enantiomer's crystals and favors the additive's own configuration. These two mechanisms push the solid phase in opposite directions, and grinding-enhanced dissolution–recrystallization cycles decide which contribution propagates through the crystal population.

The problem originates in an experimental study (Baglai, Leeman, Wurst, Kellogg, and Noorduin, Angew. Chem. Int. Ed. 2020, 59(47), 20885–20889, DOI 10.1002/anie.202009719) of two families of sterically hindered chiral substrates (families 1a/1b) with their enantiopure additive analogues (2a/2b). With one family, grinding allowed the solid-solution contribution to override growth inhibition so the solid phase converged to the additive's configuration; with the other, growth inhibition dominated. The opposite outcomes showed that the balance between the two mechanisms depends on the compound family, but this rested on a two-family comparison, not on deliberate parameter variation. A same-group follow-up (Baglai, van Dongen, Leeman, Kellogg, Kaptein, and Noorduin, Isr. J. Chem. 2021, 61(9–10), 645–649, DOI 10.1002/ijch.202100086) showed that adding the base racemization catalyst DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) to a growth-inhibition-dominated system flips the sign of the solid phase and completes deracemization — while simultaneously racemizing the additive itself (S-2 to R-2, which then forms a solid solution with the opposite enantiomer) and raising solubilities, so at least three counteracting enantiospecific processes operate at once. Related but distinct questions have been settled for the additive-free case: rate-balance criteria distinguishing erosion, consolidation, and amplification regimes when racemization competes with asymmetric crystal growth (van Dongen et al., JACS 2023, 145(1), 436–442, DOI 10.1021/jacs.2c10584, online December 2022), and an exact deracemization condition that crystal dissolution be faster than growth (Deck, Hosseinalipour, and Mazzotti, JACS 2024, 146(6), 3872–3882, DOI 10.1021/jacs.3c11332). None of these address additive-driven antagonistic mechanisms. A further generality result — additive-directed deracemization of p-anisoin directed by 16 of the 19 proteinogenic amino acids (Washio et al., Cryst. Growth Des. 2021, 21(4), 2423–2428, DOI 10.1021/acs.cgd.1c00036; Miyazaki et al., Cryst. Growth Des. 2022, 22(8), 4673–4679, DOI 10.1021/acs.cgd.2c00480) — proceeds via a different mechanism (solution-phase asymmetric transformation) and likewise leaves the kinetic-versus-thermodynamic balance question untouched.

Problem Statement

Deliver a predictive, quantitative framework — and its experimental validation — for how enantiospecific tailor-made additives steer attrition-enhanced deracemization (Viedma ripening) of racemic conglomerates, resolving the antagonism between kinetic surface growth inhibition (rule of reversal, favoring the additive's opposite enantiomer) and thermodynamic enantiospecific solid-solution formation (favoring the additive's own enantiomer). A complete solution must: (1) predict, from independently measurable inputs — additive identity and loading, substrate–additive solubility behavior, temperature, racemization rate, and grinding/attrition intensity — the sign and time course of the solid-phase enantiomeric excess, including the experimentally observed sign reversals, with stated operational parameter ranges in which each mechanism dominates; in particular, it must address the question posed in the 2021 follow-up — whether, at low additive loading, the initial symmetry breaking follows the pathway observed at high loading or the contributions of solid-solution formation take over the contributions of enantiospecific growth inhibition; (2) provide and demonstrate an experimental (or experiment-plus-computation) protocol that separates the kinetic from the thermodynamic contribution, including the hardest case in which both favor the same enantiomer (as when enantiospecific dissolution inhibition joins solid-solution formation in favoring the additive's configuration), and that controls for the confounders identified in the literature (additive racemization in solution, dissolution inhibition, additive loading drift, lattice-occupancy refinements without quantified uncertainties); and (3) account for the further counteracting processes that operate under racemizing conditions — the catalyst-induced increase in substrate solubility and the associated extra dissolution of the solid phase, racemization of the additive itself (S-2 to R-2, which then forms a solid solution with the opposite enantiomer's crystals), and enantiospecific dissolution inhibition — rather than treating the additive's influence as a single mechanism. Progress on parts of the problem (for example, a demonstrated disentanglement protocol, or a model that correctly predicts the dominance balance under a subset of the crystallization conditions) constitutes partial progress; validation across additional compound families or condition sets would strengthen the evidence of generality but is not itself a completion requirement.

References

  1. Iaroslav Baglai, Michel Leeman, Klaus Wurst, Richard M. Kellogg, Willem L. Noorduin, "Enantiospecific Solid Solution Formation Triggers the Propagation of Homochirality", Angewandte Chemie International Edition 59(47), 20885–20889 (2020). DOI: 10.1002/anie.202009719, https://doi.org/10.1002/anie.202009719
  2. Iaroslav Baglai, Sjoerd W. van Dongen, Michel Leeman, Richard M. Kellogg, Bernard Kaptein, Willem L. Noorduin, "Counteracting Enantiospecific Behavior of Tailor-Made Additives During Chiral Symmetry Breaking: Growth Inhibition versus Solid-Solution Formation", Israel Journal of Chemistry 61(9–10), 645–649 (2021). DOI: 10.1002/ijch.202100086, https://doi.org/10.1002/ijch.202100086
  3. Sjoerd W. van Dongen, Imane Ahlal, Michel Leeman, Bernard Kaptein, Richard M. Kellogg, Iaroslav Baglai, Willem L. Noorduin, "Chiral Amplification through the Interplay of Racemizing Conditions and Asymmetric Crystal Growth", Journal of the American Chemical Society 145(1), 436–442 (2023; published online 2022). DOI: 10.1021/jacs.2c10584, https://doi.org/10.1021/jacs.2c10584
  4. Aoi Washio, Momoka Hosaka, Naohiro Uemura, Yasushi Yoshida, Takashi Mino, Yoshio Kasashima, Masami Sakamoto, "Asymmetric Anisoin Synthesis Involving Benzoin Condensation Followed by Deracemization", Crystal Growth & Design 21(4), 2423–2428 (2021). DOI: 10.1021/acs.cgd.1c00036, https://doi.org/10.1021/acs.cgd.1c00036
  5. Norika Miyazaki, Kazutaka Sanada, Takumi Nakamura, Aoi Washio, Yasushi Yoshida, Takashi Mino, Yoshio Kasashima, Masami Sakamoto, "Behavior of All Chiral Standard Amino Acids for Chiral Symmetry Breaking of p-Anisoin", Crystal Growth & Design 22(8), 4673–4679 (2022). DOI: 10.1021/acs.cgd.2c00480, https://doi.org/10.1021/acs.cgd.2c00480
  6. Leif-Thore Deck, Mercedeh Sadat Hosseinalipour, Marco Mazzotti, "Exact and Ubiquitous Condition for Solid-State Deracemization in Vitro and in Nature", Journal of the American Chemical Society 146(6), 3872–3882 (2024). DOI: 10.1021/jacs.3c11332, https://doi.org/10.1021/jacs.3c11332