Which halogen to choose? Comparing the effects of chlorine and fluorine as bioisosteric substituents in drug design

The effects of fluorine and chlorine on pharmaceutical systems are compared using a molecular matched pair analysis. Effects on binding constants, physicochemical properties such as lipophilicity and solubility, as well as on metabolic properties will show the differences and similarities between the elements in a medicinal context. Factors such as the difference in electronegativity, polarizability, hydrogen-bond acceptor ability, as well as conformational effects are discussed to put the differences between the elements into context, using real case studies taken from the literature.