Selective Cocrystallization Method For Separation Of Isomers And Its Mechanism

The separation of organic molecules by cocrystallization technology,which is also a new and effective technology for designing and synthesizing new crystalline materials,is one of the frontlines of crystal engineering and chemical engineering applications.However,the molecular recognition and self-assembly mechanism of the cocrystal formation process has not yet been revealed from a scientific perspective.The general laws and particularity existing in the process of cocrystallization have not been fully understood,which severely limits the development and application of cocrystallization technology.Under the above background,using cresol isomers(MC,OC and PC)as model compounds and urea(U),oxalic acid(OXA),piperazine(PP)and imidazole(IMZ)as selective coformers,the general law and particularity of cocrystal formation are systematically studied in detail through the combination of experimental verification,theoretical analysis and molecular simulation calculation,from the molecular and supramolecular view of points.Thermodynamic mechanism and molecular recognition mechanism of selective cocrystallization were revealed and discussed.Molecular self-assembly evolution mechanism and models of cocrystallization process were established.And the new selective cocrystallization technology was successfully developed for the separation and purification of the cresol mixture to obtain cresol monomer with high purity and high yield.The results will provide theoretical guidance for the development of cocrystal products and cocrystallization separation technology.Firstly,the selective cocrystals containing cresol isomers were obtained by grinding,melting crystallization and slurry conversion crystallization.The single cocrystals with appropriate size and shape for structure determination were acquired by slow cooling crystallization and slow evaporation crystallization.Sructural information of 8 different cocrystals were determined and analyzed.The results of Xray diffractometer,thermal analysis,spectral analysis and structural analysis showed that U and PP molecules have the same selectivity to MC and OC,while OXA molecule has selectivity to PC.Moreover,cocrystals with similar selectivity exhibit consistency in structure and physicochemical properties,while cocrystals with different selectivity exhibit obvious variability.Secondly,the thermodynamic mechanism of selective cocrystallization and the thermodynamic properties of cresol isomers cocrystals were investigated using a combination of dynamic and static methods with the aid of process analysis tools(PAT)and molecular dynamic(MD)simulation.The ternary phase diagram(TPD)of “MCU-PC” system is a modification of general TPD,and is composed of “four regions and one invariant point”.As the temperature increases,the cocrystal regions become narrower and the invariant point moves to the region with high MC content.The MD simulation results revealed the selective cocrystallization’s thermodynamic mechanism which are mainly caused by the orientation of H-bonding and the dominant H-bonding type(O-H···O).Thirdly,the conformation search of monomer molecules and configuration search of supramolecular synthons were performed,respectively,to obtain different but stable monomer conformations and supramolecular synthon configurations,by using molecular simulatin and wavefunction analysis methods.And the common molecular recognition mechanism of cocrystallization was revealed from the perspectives of interaction type,energy and quantitative molecular surface by analyzing AIM,RDG,CDFT and MESP.It was found that the formation of cocrystal is mainly dominated by the local surface poperties of monomers.Additionally,based on the above-mentioned mechanism,the guiding principles for selection of cocrystal conformer was proposed.Then,the molecular recognition,self-assembly and evolution process(mechanism)of supramolecular synthons in solution were investigated using PAT and molecular simulation.The cocrystallization process of cresol molecules with CCFs in solution indicates that the chemical configuration in solution and in crystallographic structures has correlation and continuity: the supramolecular synthon(or multimers)structures are the precursor of cocrystal and the information memory of the cocrystallization process.And the self-assembly evolution process(mechanism)in solution can be summarized as: dimers/trimers formation → cocrystals nucleation →cocrystals growth.Finally,new selective cocrystallization technology was developed and optimized for the separation of cresol mixture(mainly a mixture of MC and PC).This new technology has the advantages of low energy consumption,high selectively and high separation efficiency.This technology can be used to get pure MC and PC,with the purity of MC can be as high as 99.9%,and the yield is 77.9% ～ 82.8%.