Parametrization of substituents: Effects of fluorine and other heteroatoms and OH, NH, and CH acidities

Abstract

Fluorine leaves nobody indifferent; it inflames emotions, be that affections or aversions. As a substituent it is rarely boring, always good for a surprise, but often completely unpredictable. It behaves nonconformingly even when fundamental properties such as ionic dissociation are under consideration. Although fluorine scores highest in the Pauling scale of electronegativity, its Hammett constants (σ(m) + 0.34, σ(p) + 0.06) are all but spectacular. Alanine and α-fluoroalanine have virtually the same pK(a) values, whereas trifluoroalanine proves to be a fairly strong acid. Apparently, the smallest halogen emits different kinds of electronic effects which, depending on the given situation, may counterbalance or amplify each other. To gain better insight, a new approach is undertaken. A comparison between thermodynamic acidity (proton dissociation in aqueous medium and in the gas phase) and kinetic proton mobility (rates of base-catalyzed hydrogen isotope exchange and stoichiometric hydrogen/metal interconversion processes) allows key issues to be addressed, in particular to identify medium effects on acidity and to probe the additivity of substituent effects. In this way fluorine, the heterosubstituent par excellence, which can have a stronger impact on the reactivity in its vicinity than any other element, may serve as a crucial test of any model concerning the origin and transmission of electronic effects. There are, however, also practical implications. Organometallic compounds carrying one, two, or several fluorine atoms are versatile intermediates in organic synthesis; they allow access to a variety of pharmaceutically, agrochemically, or technically attractive products. For this reason, organofluorine chemistry surely must welcome any information that helps to generate more members of this family of reactive species or aids the development of new methodical concepts such as optional site selectivity.