Molecular crystals are commonly used in pharmaceuticals, organic semi-conductor materials, explosives, and many other areas of Chemistry. Molecular crystal packing interactions are governed by subtle balances between intra- and intermolecular interactions, providing a severe challenge for theoretical crystal structure modeling. Additionally, molecular crystals can expand appreciably upon heating due to both zero-point and thermal vibrational motion, yet this expansion is often neglected in molecular crystal modeling studies. Quasi-harmonic (QHA) approaches provide an economical route to modeling the temperature dependence of molecular crystal structures and properties but can be cost-prohibitive when evaluated at higher levels of theory.

In this thesis, we introduce a hierarchy of models (tiered-QHA) in which the energies, geometries, and phonons are computed either with correlated methods (such as second-order Møller-Plesset perturbation theory (MP2)) or density functional theory (DFT). We examine which combinations produce useful predictions for properties such as the molar volume, enthalpy, and entropy as a function of temperature. Compared to performing the entire calculation using pure MP2, this leads to a modest loss in chemical accuracy and provides a necessary increase in the speed of computation. Additionally, employing this method increases the system size we can feasibly simulate to over 100 atoms per central unit cell, allowing us to simulate pharmaceutically-relevant molecular crystals. We apply this new tiered-QHA method to examine the phase-transition properties of α- and β- resorcinol.

Finally, neglecting thermal expansion can significantly affect simulated spectroscopic properties. In particular, nuclear magnetic resonance (NMR) chemical shift predictions will suffer since a small change in atomic position translates to a large change in the chemical shift spectra. We investigate how accounting for thermal expansion in molecular crystals via the QHA refines isotropic 68 13C and 28 15N predicted chemical shifts on a number of molecular crystals. We demonstrate that chemical shifts computed using quasi-harmonic room-temperature structures rival those based on the experimental unit cell parameters. We also show increased discrimination between candidate structures amongst five theophylline structures that were generated via crystal structure prediction.