Are the Crystal Structures of Enantiopure and Racemic Mandelic Acids Determined by Kinetics or Thermodynamics?

Mandelic acids are prototypic chiral
molecules where the sensitivity
of crystallized forms (enantiopure/racemic compound/polymorphs) to
both conditions and substituents provides a new insight into the factors
that may allow chiral separation by crystallization. The determination
of a significant number of single crystal structures allows the analysis
of 13 enantiopure and 30 racemic crystal structures of 21 (F/Cl/Br/CH3/CH3O) substituted mandelic acid derivatives. There
are some common phenyl packing motifs between some groups of racemic
and enantiopure structures, although they show very different hydrogen-bonding
motifs. The computed crystal energy landscape of 3-chloromandelic
acid, which has at least two enantiopure and three racemic crystal
polymorphs, reveals that there are many more possible structures,
some of which are predicted to be thermodynamically more favorable
as well as slightly denser than the known forms. Simulations of mandelic
acid dimers in isolation, water, and toluene do not differentiate
between racemic and enantiopure dimers and also suggest that the phenyl
ring interactions play a major role in the crystallization mechanism.
The observed crystallization behavior of mandelic acids does not correspond
to any simple “crystal engineering rules” as there is
a range of thermodynamically feasible structures with no distinction
between the enantiopure and racemic forms. Nucleation and crystallization
appear to be determined by the kinetics of crystal growth with a statistical
bias, but the diversity of the mandelic acid crystallization behavior
demonstrates that the factors that influence the kinetics of crystal
nucleation and growth are not yet adequately understood.

扁桃酸（Mandelic acids）是典型的手性分子，其结晶态（对映纯/外消旋化合物/多晶型）对环境条件与取代基的敏感性，为理解可通过结晶实现手性分离的相关因素提供了全新视角。本研究通过测定大量单晶结构，完成了21种被氟（F）、氯（Cl）、溴（Br）、甲基（CH3）、甲氧基（CH3O）取代的扁桃酸衍生物的13种对映纯晶体结构与30种外消旋晶体结构的分析。尽管部分外消旋与对映纯结构的基团间存在共通的苯基堆积基序，但二者的氢键基序差异显著。对3-氯扁桃酸的晶体能量景观计算表明，该物质至少存在2种对映纯晶型与3种外消旋晶型，且存在大量潜在晶体结构，其中部分预测结构的热力学稳定性更优，密度也略高于已知晶型。对孤立态、水及甲苯环境中扁桃酸二聚体的模拟结果无法区分外消旋与对映纯二聚体，同时提示苯环相互作用在结晶机制中发挥主导作用。观测到的扁桃酸结晶行为并不符合任何简单的“晶体工程规则”，因为存在大量热力学可行的结构，且无法区分对映纯与外消旋形式。晶体成核与结晶过程似乎由晶体生长动力学与统计偏倚共同决定，但扁桃酸结晶行为的多样性表明，目前尚未充分阐明影响晶体成核与生长动力学的相关因素。