American Chemical Society
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Determining the Ionization Constants of Organic Acids Using Fluorine Gauche Effects

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journal contribution
posted on 2020-03-09, 10:44 authored by Bright U. Emenike, Simran S. Dhami
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 = [(3JAH3Jobs)/(3Jobs3JA)]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.