2-fluorohistidine and 4-fluorohistidine, analogues of the natural amino acid histidine, are found to be valuable probes to study biological systems. Four decades ago Yeh et al. carried out NMR experiments on 2F & 4F -histidine/imidazole/(5-methyl)-imidazole to study the effect of imidazole ring protonation on chemical shifts. It was found that after acid titration, 2F and 4F analogues showed opposite direction in fluorine chemical shifts: downfield and upfield, respectively. Thus, the explanation for opposite directions in 19F NMR chemical shifts for 2F and 4F –histidine/imidazole/(5-methyl)-imidazole isomers upon acid titration has been a long-standing question. Electronic structure calculations (BHandHLYP/6-311++G(3df,2p) with SMD water solvation model) are able to replicate the results, and analysis of the resulting molecular orbitals works to explain the enigma. A reduction in calculated fluorine electrostatic charges describes deshielding upon protonation of the 2F-species, giving rise to the downfield shift. For 4F-imidazole derivatives, charges do not correlate with chemical shifts. Rather, analysis of molecular orbitals is required to understand the upfield shift upon protonation. In 4F-(5-methyl)-imidazole, the fluorine electron density is completely delocalized. When protonated, however, fluorine electron density localizes into a fluorine lone pair orbital. We posit that this localization of fluorine’s electrons results in higher shielding of the nucleus, resulting in the upfield shift. These findings may have relevance for the interpretation and understanding of fluorine chemical shifts of other fluorinated amino acids, and we are currently investigating their electronic structures. This work puts forward a foundation for future studies to interpret the differences in chemical shifts due to protein environment when fluorinated amino acids are incorporated into proteins. Current efforts are in this direction.

Electronic structure calculations aid in the interpretation of 19F NMR chemical shifts

251st National Meeting (2016)

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