Many natural chemical and physical transformations take place in solution. Tremendous research has thus been invested to understand the nature of intermolecular interactions in the liquid-phase. The research reported in this dissertation deals with the molecular basis of organic crystal nucleation from solution. Our understanding of this process is still incomplete, and any breakthrough in nucleation science will require a fundamental understanding of the molecular evolution taking place prior to nucleation.
The crystallisation of imidazole from water and ethanol was investigated with several analytical and computational techniques probing the local interactions between solute and solvent molecules. FTIR, X-ray Raman scattering (XRS) and total X-ray scattering and the associated X-ray pair distribution function (XPDF) analysis were combined with density functional theory (DFT) and empirical potential structure refinement (EPSR) simulations to obtain a realistic model of the intermolecular interaction between solute and solvent molecules in aqueous and ethanolic solutions of imidazole.
While hydrated imidazole molecules with very few direct imidazole-imidazole interactions are predicted to be the most probable structural motifs in aqueous solutions, direct imidazole-imidazole interactions are anticipated in the ethanolic solutions. The change in the solvation structure between aqueous and ethanolic solutions is expected due to the difference in the number of hydrogen bonds that can be formed by ethanol (2 bonds) and water (4 bonds). This should facilitate direct imidazole – imidazole interactions in the ethanolic solutions.
The local solvation structure in aqueous and ethanolic solutions of imidazole does not seem to be disturbed by changing the concentration of imidazole in the solution, as indicated by FTIR, XRS and XPDF. For the first time, the molecular structure of the solutions was also probed during cooling crystallisation, utilising XRS and XPDF. Negligible changes are observed in the XRS and XPDF data acquired in supersaturated solutions, indicating that the average solvation structure around imidazole molecules does not change significantly while traversing the thermodynamically metastable zone. This indicates that breakage of solute-solvent bonds during desolvation is the key step in nucleation of imidazole from the solution-phase.
