First-Principles Modeling of Molecular Crystals: Crystal Structure Prediction and Vibrational Properties

Understanding the structure and stability, as well as response properties of molecular crystals at certain thermodynamic conditions is crucial for the engineering of new molecular materials and the design of pharmaceuticals. A reliable description of the polymorphic energy landscape of a molecular crystal would provide an extensive insight into the development of drugs in terms of the existence and the likelihood of late-appearing polymorphs. Furthermore, accurate modeling of low-frequency vibrational spectra would be important for the characterization of molecular crystal polymorphs. However, an accurate description of molecular crystals is very challenging since many properties highly depend on the crystal-packing arrangement of the involved molecules and the temperature. The difficulties for computational predictions of molecular crystal polymorphs lie in the high dimensionality of crystallographic and conformational space, and the need for very accurate relative free energies. It was shown that accurate lattice energies can be obtained by using density-functional theory (DFT) calculations supplemented by a high-level model for long-range van der Waals (vdW) dispersion interactions, such as the many-body dispersion (MBD) model. Therefore, this thesis utilizes throughout vdW-inclusive DFT using the MBD and the related pairwise Tkatchenko-Scheffler (TS) dispersion model and the importance of dispersion interactions is highlighted for several properties. A hierarchical stability-ranking approach based on the DFT+MBD framework for the final stage of a molecular crystal structure prediction procedure is presented and analyzed. This approach provides excellent stability rankings over the diverse set of molecular crystals studied in the latest blind test of the Cambridge Crystallographic Data Centre. The results suggest that accounting for many-body dispersion effects and vibrational free energies can be crucial for the description of relative stabilities, especially for highly polymorphic systems. The presented approach enables the calculation of reliable structures and thermodynamic stabilities for pharmaceutically relevant systems, contributing to a better understanding of complex polymorphic energy landscapes. Furthermore, many first-principles calculations are performed by using fully optimized structures and free energies obtained within the harmonic approximation, neglecting the thermal expansion of the studied molecular crystal and further anharmonic effects. Therefore, this thesis illustrates that the majority of the thermal expansion of molecular crystals can be captured with the used methods by applying the quasi-harmonic approximation. In addition, we estimate further anharmonic effects on the vibrational frequencies by utilizing Morse oscillators.