Understanding fluorine chemical shifts and the molecular properties of organic molecules

Abstract

Fluorinated molecules have emerged as important probes in drug design, and as strategies for enhancing protein stability and altering physicochemical properties of biological systems. Fluorine NMR plays a crucial role in studying protein structure, dynamics and protein-ligand interactions. Histidine is an important amino acid involved in many enzymatic reactions and protein functions. 2-fluorohistidine and 4-fluorohistidine are fluorinated analogues of histidine, offering valuable tools in biophysical studies with their altered pKa values compared to the canonical amino acid. In this dissertation, the molecular properties of 2-fluorohistidine, 4- fluorohistidine, and analogues are studied with different electronic structure calculations. Among the two tautomeric states of histidine at neutral pH, it was found that 2- fluorohistidine prefers the τ-tautomeric state, whereas 4-fluorohistidine exclusively stays in the π-tautomeric state. While the 1 H signal shifts downfield in both isomers upon ring protonation, the 19F signal of 2-fluorohistidine also shifts downfield but 19F in 4- fluorohistidine shifts upfield. The reason for this unusual behavior is explained here. The effect of different environments (solvation effects, intramolecular hydrogen bonding effect, backbone effects) on tautomeric stabilities and fluorine chemical shifts are discussed. This work explains the role of histidine’s C4-H bond as a potential hydrogen bond donor. The results indicate that the C4-H bonds in histidine and 2-fluorohistidine in the τ-tautomeric states act as strong hydrogen bond donors.