Crystallization of Organic Molecules: Nonclassical Mechanism Revealed by Direct Imaging

Abstract

Organic crystals are of primary importance in pharmaceuticals, functional materials, and biological systems; however, organic crystallization mechanisms are not well-understood. It has been recognized that "nonclassical" organic crystallization from solution involving transient amorphous precursors is ubiquitous. Understanding how these precursors evolve into crystals is a key challenge. Here, we uncover the crystallization mechanisms of two simple aromatic compounds (perylene diimides), employing direct structural imaging by cryogenic electron microscopy. We reveal the continuous evolution of density, morphology, and order during the crystallization of very different amorphous precursors (well-defined aggregates and diffuse dense liquid phase). Crystallization starts from initial densification of the precursors. Subsequent evolution of crystalline order is gradual, involving further densification concurrent with optimization of molecular ordering and morphology. These findings may have implications for the rational design of organic crystals.

Figure 1

(A) Molecular structure of 1. (B) UV–vis spectra of 1 recorded during crystallization: 0 (blue), 24 (red), 5, 7, 9, 11, and 15h (top to bottom in gray). (C) Absorption intensity at 530 nm over time (dots—measurements every 5 min). (D) Schematic of the free-energy profile for the crystallization of 1.

Figure 2

Cryo-TEM images, crystallization of 1. (A) Spherical aggregates formed immediately after sample preparation. (B) Aging 30–50 min, distorted densified spheres are observed (indicated by red arrows). Inset: an example of aggregate densification, scale bar is 50 nm.(C) A faceted intermediate with apparent crystallinity (indicated by a black arrow). Red arrows denote distorted densified spheres. (D) Ruptured aggregate exhibiting crystallinity (4.5 h of aging). Inset: magnified view of the marked area, showing lattice fringes. Scale bar is 20 nm. (E) Fibrous crystals growing from distorted (faceted) spherical cores (5 h of aging). (F) Developed elongated crystals (24 h of aging). Inset (magnified view of the marked area): lattice fringes. Scale bar is 5 nm. Inset: FFT analysis showing periodicity of 0.9 and 1.7 nm. Scale bar is 1 nm^–1.

Figure 3

Cryo-TEM images, crystallization of 2. (A) Molecular structure of compound 2 and its UV–vis spectra in water/THF = 7/3 (v/v) mixture, 10^–5 M, immediately after preparation (blue), and after 3 h (red). (B–H) Cryo-TEM images of 2 in water/THF = 1/1 (v/v) mixture, 10^–4 M. (B) Unstructured amorphous liquidlike aggregate (30 min of aging). (C) Dense elongated structure forming within the amorphous aggregate (30 min of aging). (D–H) Early order evolution stages (30 min of aging). (D) Underformed needle shrouded in remains of an amorphous aggregate. (E, F) Magnified views of the areas marked in parts D and E, respectively. (F) Fibrous features within the underformed needle are indicated by red arrows. (G) Underformed needle shrouded in an amorphous phase. An amorphous aggregate is indicated by a red arrow. (H) Magnified view of the area marked in G showing fibrous features composing the evolving crystal. (I) 2 in water/THF = 7/3 (v/v) mixture, 10^–5 M, showing an underformed needle shrouded in amorphous phase (30 min of aging). Top inset: magnified view of the marked area. Scale bar is 30 nm. Bottom inset: FFT analysis of the marked area showing lattice fringes periodicity of 1.1 and 1.6 nm. Scale bar is 1 nm^–1.

Figure 4

Cryo-TEM images of 2 in water/THF (1/1 v/v) solution, 10^–4 M. (A) Partly developed needle. (B) Magnified view of the marked area in part A showing misaligned and partly parallel patches of ordered domains. (C) Magnified view of the marked area in part B. Inset: FFT analysis of part C showing periodicities of 1.7 and 0.9 nm with wide angular spread, demonstrating misalignment of lattice fringe patches. Scale bar is 2 nm^–1.

Figure 5

Schematic representation of crystallization pathways of compounds 1 (top) and 2 (bottom). Three main stages of continuous order development are depicted: initial densification, early ordering, and evolution of molecular order (crystal packing) and morphology.