Abstract
The disposition of functional groups can induce variations in the nature and type of interactions and hence affect the molecular recognition and self-assembly mechanism in cocrystals. To better understand the formation of cocrystals on a molecular level, the effects of disposition of functional groups on the formation of cocrystals were systematically and comprehensively investigated using cresol isomers (o-, m-, p-cresol) as model compounds. Consistency and variability in these cocrystals containing positional isomers were found and analyzed. The structures, molecular recognition and self-assembly mechanism of supramolecular synthons in solution and in their corresponding cocrystals were verified by a combined experimental and theoretical calculation approach. It was found that the heterosynthons (heterotrimer or heterodimer) combined with O-H⋯N hydrogen bonding played a significant role. Hirshfeld surface analysis and computed interaction energy values were used to determine the hierarchical ordering of the weak interactions. The quantitative analyses of charge transfers and molecular electrostatic potential were also applied to reveal and verify the reasons for consistency and variability. Finally, the molecular recognition, self-assembly and evolution process of the supramolecular synthons in solution were investigated. The results confirm that the supramolecular synthon structures formed initially in solution would be carried over to the final cocrystals, and the supramolecular synthon structures are the precursors of cocrystals and the information memory of the cocrystallization process, which is evidence for classical nucleation theory.
Highlights
Supramolecular chemistry is a very active area (Zhao & Truhlar, 2007)
The molecular recognition and self-assembly mechanism of supramolecular synthons of cresol–piperazine in toluene solution and its evolution pathway was investigated by means of spectroscopy, Process Analysis Tools/technologies (PAT) and theoretical calculations
We found that the formation of these three cocrystals can be divided into three steps: (i) heterotrimer or heterodimer formation, (ii) cocrystal nucleation and (iii) cocrystal growth
Summary
Supramolecular chemistry is a very active area (Zhao & Truhlar, 2007). An important part of crystal engineering and supramolecular chemistry (Wouters & Quere, 2012) – cocrystals – which are single-crystal structures composed of two or more components in a certain stoichiometric ratio with no proton transfer between components and are formed by noncovalent bonds, have been known for a long time (Wang et al, 2017, 2018a,b). In order to further understand and explore the formation mechanism of cocrystals (or complexes) of organic molecules, especially isomers, many researchers have done extensive research on the cocrystals of different organic molecules (Varughese et al, 2015; Saha & Desiraju, 2018; Portalone & Rissanen, 2018; Sanchez-Guadarrama et al, 2016; Wang et al, 2018a,b, 2019) Most of these studies focused on either describing the crystal structure of the molecular complex obtained in detail, or studying the properties of the cocrystal from the crystal structure and/or the type of synthons by using spectroscopic analysis. The evolution pathway of the synthons in solution during the formation of cocrystals were investigated using Process Analysis Tools/technologies (PAT), and classical nucleation theory was supported by the data obtained
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