Disorderly Conduct of Benzamide IV: Crystallographic and Computational Analysis of High Entropy Polymorphs of Small Molecules

Benzamide,
a simple derivative of benzoic acid and a common intermediate
of pharmaceutical compounds, was reported to form two polymorphs in
1832, but the single crystal structure of the more stable form was
not solved until 1959. Nearly 50 years later, the second form was
characterized by powder diffraction, followed shortly thereafter by
characterization of a third form, a polytype of the most thermodynamically
stable Form I. These two new forms, Forms II and III, are metastable. Herein, we describe a fourth
polymorph, Form IV, discovered by melt crystallization
concurrently with its crystallization under confinement at small length
scales (<10 nm), where it is stable indefinitely. Form III exists under confinement in larger pores, and melting point data
for different pore sizes corroborate the existence of Form IV below 10 nm. Form IV is highly disordered, precluding
indexing of powder diffraction data other than hk0 reflections. Nonetheless, a combination of powder X-ray diffraction
and computational crystal structure prediction reveals that Form IV contains a 2D motif resembling that of Form II, but with long-range order in the third dimension masked by ubiquitous
stacking faults. This approach relies on distilling a large number
of candidate structures to a few possible disorder models based on
benzamide tetrads that organize in 2D parquet-like tiles, with organization
along the third dimension, that can be modeled with various stacking
fault configurations having distinct intermolecular interactions and
translations in the dimension orthogonal to the tiling planes. These
observations reveal a bewildering crystallographic complexity for
such a simple molecule. Nonetheless, the approach described herein
demonstrates that challenging structures that may be abandoned prematurely
because of poor crystallinity, twinning, or disorder can be solved.

苯甲酰胺（Benzamide）是苯甲酸（benzoic acid）的简单衍生物，亦是一类常见的药物化合物中间体。1832年，研究人员首次报道其存在两种多晶型（polymorphs），但直至1959年才解析出更稳定晶型的单晶结构。近50年后，研究人员通过粉末衍射（powder diffraction）表征了第二种晶型，不久后又完成了第三种晶型的表征——该晶型为热力学最稳定的晶型I的多型体（polytype）。上述两种新晶型（晶型II与晶型III）均为亚稳晶型。本文报道了第四种多晶型——晶型IV，其通过熔融结晶（melt crystallization）法发现，且在小尺度（<10 nm）限域环境下结晶时可长期稳定存在。在孔径更大的限域体系中仅存在晶型III，不同孔径下的熔点数据佐证了10 nm以下体系中晶型IV的存在。晶型IV具有高度的无序性，除hk0衍射峰外，无法对其粉末衍射数据进行索引解析。尽管如此，结合粉末X射线衍射（powder X-ray diffraction）与计算晶体结构预测（crystal structure prediction）的结果可知，晶型IV拥有与晶型II相似的二维基元（2D motif），但第三维度的长程有序被普遍存在的堆垛层错（stacking faults）所掩盖。该研究方法基于苯甲酰胺四聚体（benzamide tetrads）构建的大量候选结构，筛选出若干基于二维镶木地板状铺层的无序模型；这类铺层沿第三维度排布，可通过不同堆垛层错构型进行建模，这些构型在垂直于铺层平面的维度上具有不同的分子间相互作用与平移参数。这些观测结果揭示了这类简单分子所具备的复杂晶体学特性。尽管存在上述挑战，本文所提出的研究方法仍证明，那些因结晶度差、存在孪晶或无序结构而可能被过早放弃的高难度晶体结构，仍可得到解析。