Determining the Ionization Constants of Organic Acids Using Fluorine Gauche Effects

Using NMR spectroscopy,
the conformational studies of two fluoroethylsulfonamides
(N-(2-fluoroethyl)-p-tolylsulfonamide
(1) and N-(2-fluoroethyl)­trifluoromethanesulfonamide
(2)) revealed that fluorine gauche effects are a function
of ionization. While acids 1 and 2 exhibited
gauche effects (with gauche populations of 87% and 92% in DMSO-d6, respectively), their anions, on the other
hand, preferred the anti conformer (with gauche populations of 35%
and 55%, respectively). The ability of these compounds to undergo
conformational changes as a function of ionization enabled their application
as molecular probes (standards) for determining the acidity (pKa) of organic compounds in DMSO, which was achieved
with the aid of the equation Krel = [(3JAH – 3Jobs)/(3Jobs – 3JA)]2, where Krel is the ratio of ionization
constants of two acids (standard and test acids), 3JAH and 3JA are the proton–fluorine vicinal coupling constants of the
standard acid and its anion, respectively, and 3Jobs represents the proton–fluorine vicinal
coupling constant observed at the midpoint of an acid–base
equilibrium. As a means of demonstrating its utility, this equation
accurately calculated the ionization constants (Ka) of several organic compounds in DMSO. Taking advantage
of fluorine’s unique gauche effect as a strategy for molecular
design has the potential to open a new frontier in structural chemistry.