(310g) Mechanism of Selective Co-Crystallization of Cresol Isomers with Urea

The separation of m-cresol from mixtures of m-cresol and p-cresol has been a great challenge in industry since the physicochemical properties of m-cresol and p-cresol are pretty similar. In this work, co-crystallization method was used to separate m-cresol and p-cresol and the co-crystal preparation was attempted by cooling crystallization. The selective co-crystallization of m-cresol and p-cresol with urea was evaluated, based on the principle of supramolecular chemistry and crystal engineering strategy. It was found that the co-crystal former, urea, can only form co-crystal with m-cresol. One supramolecular synthon was formed between m-cresol and urea with the help of intermolecular mutual recognition and self-assembly process among them. Consequently, m-cresol can be effectively separated from p-cresol by the way of selective co-crystallization. The m-cresol _urea co-crystal (MC_U) was prepared on 1:1 molar ratio, which exhibits a regular hexagonal shape and belongs to orthorhombic system with space group P b c a and cell parameters a = 11.2502(5)Å, b = 7.1880(4) Å, c = 21.7868(15) Å. The hydroxyl group of m-cresol forms a H-bond with the carbonyl group in amide moiety of urea. The MC_U molecules adopt a chained layer structure. The solid-state properties of MC_U were characterized using X-ray Power Diffractometry (PXRD), Differential Scanning Calorimetry (DSC), ¹H nuclear magnetic resonance (¹H NMR) and Fourier Transformed Infrared Spectrometer (FTIR). Meantime, the selective co-crystallization process was on-line monitored by process analytical technologies/tools (PAT), such as Raman spectroscopy (Raman), Attenuated Total Reflection Fourier Transformed Infrared Spectroscopy (ATR-FTIR) and Focused Beam Reflectance Measurement (FBRM). Combined with the on-line monitoring data, ¹H NMR and the single crystal structure data, the mechanism of molecular recognition and self-assembly between m-cresol and urea is revealed. It was found that the whole co-crystal formation process can be divided into three steps: (1) m-cresol-urea dimers formation process, (2) MC_U nucleation process, and (3) MC_U growth process. And the reason for the selective co-crystallization is elucidated from the molecular level by using the corresponding calculation method. The mechanisms of selective co-crystallization as well as molecular recongnition and self-assembly between m-cresol and urea were proposed by analyzing the structure of m- and p-cresol, the single crystal structure data of cocrystal and the on-line monitoring data of Raman and ATR-FTIR. It was found that a chain supramolecular synthon was formed by the carbonyl oxygen (C=O) of the urea and the hydroxyl hydrogen (O-H) of the m-cresol relying on stronge hydrogen bonds. However, no obvious non-covalent bonds between p-cresol and urea molecules were observed. This failure is probably due to the position of the phenolic hydroxyl in toluene, which is affected by the methyl group. The electron cloud density of hydroxyl groups on p-cresol is reduced because of the presence of methyl groups, which could lead to the decrease of the electronegativity of oxygen, and thus will reduce the degree of exposure to the hydrogen atom attached to it. Obviously, m-cresol _urea co-crystal could be formed because of the contribution of the more exposed hydrogen atoms.