The majority of marketed pharmaceuticals are low-molecular-weight organic compounds, commonly referred to as small molecules . In solution, flexible small molecules are dynamic entities, giving rise to a Boltzmann-weighted ensemble of different conformations, which depends on the nature of the surrounding solvent. Weak interactions can vary dramatically between different solvents, resulting in critical differences between the corresponding conformational ensembles . Therefore, understanding even slight variations in the populations of conformers is crucial for a variety of applications. These include the synthesis of regio-and stereo-specific molecules , optimization and understanding of passive membrane permeability , as well as fine-tuning physical properties . In addition, differing conformational ensembles also give rise to distinct experimental observables, and thus, they strongly influence the interpretation of experimental techniques. For instance, nuclear magnetic resonance (NMR) , infrared (IR) spectroscopy , or vibrational circular dichroism (VCD) spectroscopy among others exhibit all conformational dependencies.