Review and Modeling of Crystal Growth of Atropisomers from Solutions

Abstract

In this paper, theories on anisotropic crystal growth and crystallization of atropisomers are reviewed and a model for anisotropic crystal growth from solution containing slow inter-converting conformers is presented. The model applies to systems with growth-dominated crystallization from solutions and assumes that only one conformation participates in the solute integration step and is present in the crystal lattice. Other conformers, defined as the wrong conformers, must convert to the right conformer before they can assemble to the crystal lattice. The model presents a simple implicit method for evaluating the growth inhibition effect by the wrong conformers. The crystal growth model applies to anisotropic growth in two main directions, namely a slow-growing face and a fast-growing face and requires the knowledge of solute crystal face integration coefficients in both directions. A parameter estimation algorithm was derived to extract those coefficients from data about temporal concentration and crystal size during crystallization and was designed to have a short run time, while providing a high-resolution estimation. The model predicts a size-dependent growth rate and simulations indicated that for a given seed size and solvent system and for an isothermal anti-solvent addition crystallization, the seed loading and the supersaturation at seeding are the main factors impacting the final aspect ratio. The model predicts a decrease of the growth inhibition effect by the wrong conformer with increasing temperature, likely due to faster equilibration between conformers and/or a decrease of the population of the wrong conformer, if of low energy, at elevated temperatures. Finally, the model predicts that solute surface integration becomes the rate-limiting mechanism for high solute integration activation energies, resulting in no impact of the WC on the overall crystal growth process.

Co-crystals of tetrachloroauric acid and 1,3,5-(methylacetamide)benzene-based tectons: consistent trapping of high energy molecular conformation

“…NMR spectra of the free compounds 1 and 2 in organic solution exhibited sharp peaks, consistent with a single, low energy conformation in solution with no evidence for slow conformational exchange. 43 Co-precipitation experiments were conducted by mixing separate solutions of 1 or 2 in CHCl 3 with equimolar amounts of HAuCl 4 or HAuBr 4 in dibutyl carbitol. The formation of a co-precipitate was virtually immediate in all cases, and recrystallization of each co-precipitate yielded single crystals suitable for analysis by X-ray diffraction.…”

Simultaneous Processing of Antagonistic Chemical Events (SPACE): An Atroposelective Dynamic Kinetic Resolution of MRTX1719

“…5 In contrast, selective crystallization is an established and straightforward protocol for obtaining a single enantiomer or diastereomer. 6 Crystallization is perhaps viewed less favorably than asymmetric synthesis, however, since a reduced yield is implied via at least 50% loss of the undesired epimer. In the case of atropisomers, the desired stereoisomer can be regenerated by effecting rotation about the axis of chirality, where heat is the typical impetus for epimerization.…”

Conformational Interconversion Kinetics, Boundary Layer Transport, and Crystal Growth Impedance

“…Garside and co-workers considered resistances from solute diffusion beyond the resistance of incorporation at the crystal surface but did not consider these effects in the presence of reactions or conformer interconversion processes. 18−21 Derdour and Skliar 22,23 developed a model for crystal growth in the presence of interconverting conformers based on the step advance theory. 24,25 They assume that only one of the two conformers can be integrated into the crystal surface, that growth is not limited by diffusion, and that conformers consumed by crystallization are instantaneously replaced in solution by an equilibrium mixture of the conformers.…”

“…Derdour and Skliar , developed a model for crystal growth in the presence of interconverting conformers based on the step advance theory. , They assume that only one of the two conformers can be integrated into the crystal surface, that growth is not limited by diffusion, and that conformers consumed by crystallization are instantaneously replaced in solution by an equilibrium mixture of the conformers. On the basis of these assumptions, they develop expressions for crystal growth kinetics and population balance models to predict how crystal sizes change with time.…”