Context-Dependent Significance of London Dispersion.

ConspectusLondon forces constitute an attractive component of van der Waals interactions and originate from transient correlated momentary dipoles in adjacent atoms. The in-depth investigation of London dispersion forces poses notable challenges, especially in solution, owing to their inherently weak and competing character. Our objective in this Account is to shed light on the context-dependent significance of London dispersion forces by contrasting our own experimental findings with those from other research endeavors. Specifically, we will explore how factors such as the choice of system and solvent can influence the apparent role of London dispersion forces in molecular recognition processes. We initiate our Account by scrutinizing the Wilcox balance, which has yielded diverse and occasionally contradictory results. Following that, we provide an overview of the role of London dispersion forces and their context-dependent variations, encompassing alkyl-alkyl, halogen-π, alkyl-π, and aromatic stacking interactions.Several experimental investigations have revealed how difficult it is to measure the significance of London dispersion in solution. Indeed, dispersion forces seldom act as the exclusive driving force in molecular recognition processes, and solvation energetics also strongly influence equilibria and kinetics. Molecular balances that bring apolar functional groups into contact have proven to be instrumental in the experimental measurement of dispersion. The intramolecular approach avoids the need to pay the entropic cost of bringing interacting groups into contact, while also enabling solvent screening. Such experimental studies have found dispersion interactions between functional groups to be very weak (<5 kJ mol -1 ), meaning that they frequently take backstage to electrostatic contributions and solvophobic effects and are readily damped by competitive dispersion interactions with the solvent. By using such approaches, competitive dispersion interactions with the solvent have been shown to be described by the bulk polarizability of the solvent (perfluoroalkanes have the lowest bulk polarizabilities, while carbon disulfide has one of the highest). Dispersion interactions are also strongly distance-dependent, which results in considerable context-dependent outcomes across different investigations. For example, we caution against the risk of attributing the stability of a "more sterically hindered" isomer as arising from intramolecular dispersion forces. The total energy of the system can reveal other contributions to stability, such as nonintuitive minimization of strain elsewhere in the molecule. Indeed, the delicate distance-dependent balance between sterics and London dispersion means that even subtle changes in size and geometry can lead to disparate behavior. Similarly, solvophobic effects also contribute to stabilizing contacts between bulky functional groups, which can be revealed if there is a correlation with the cohesive energy density of the solvent.