Fluorine NMR is a highly sensitive technique for characterizing protein conformational states and has shown great potential in drug discovery and in understanding protein function. Here, we explore the possibility of implementing a CF3 reporter containing an amplifier, enabling greater chemical shift sensitivity. Fluorinated protein tags utilize fluorine’s wide chemical shift dispersion to detect subtle changes in conformation and topology. The chemical shift sensitivity can be further amplified with the addition of a fluorine or trifluoromethyl reporter within a pyridone. Pyridones undergo rapid tautomerization, exhibiting a greater range of electron delocalization and correspondingly greater 19F NMR chemical shift dispersion. We assessed the chemical shift sensitivity of monofluorinated and trifluoronated tautomeric tags to local environment with 19F-NMR in methanol/water mixtures. We also investigated the utility of a tautomeric tag through incorporation on the G-alpha subunit of the stimulatory G protein (Gsα) in the presence and absence of membrane-mimetic phospholipid nanodiscs, and through conjugation of the reporter to a single cysteine residue on serum albumin. In both cases, the chemical shift dispersion is dramatically improved by this pyridone based tautomer.