Unexpected Intermolecular C–H···O Hydrogen Bonds and ¹H NMR Chemical Shifts in a Key Linker for Fluorine-18 Labeling of Dimeric Drugs

Abstract

The compound 2-{[(trifluoromethyl)sulfonyl]oxy}propane-1,3-diyl bis(4-methylbenzenesulfonate) (TPB) is a crucial intermediate in the synthesis of 18 F-radiolabeled cromolyn derivatives. In this work, we combine 1 H NMR spectroscopy, Xray crystallography, ab initio molecular dynamics, and NMR calculations to examine the structure, interactions, and solvation dynamics of the TPB molecule. In CDCl 3 , the CH 2 groups within its glyceryl-derived linker exhibit a single set of proton signals in the 1 H NMR measurements. However, when TPB is dissolved in DMSO-d 6 , distinct splitting patterns emerge despite its seemingly symmetric chemical structure. Crystallographic analysis further unveils the absence of overall symmetry in its three-dimensional arrangement. To elucidate these unique NMR features, we carry out ab initio molecular dynamics simulations and characterize the solvation structures and dynamics of TPB in CHCl 3 and DMSO solutions. In contrast to the predominantly nonpolar nature of the CHCl 3 solvents, DMSO directly participates in C−H•••O hydrogen-bonding interactions with the solute molecule, leading to the splitting of its −CH 2 chemical shifts into two distinct distributions. The comprehensive understanding of the structure and solvation interactions of TPB provides essential insights into its application in the radiofluorination reactions of cromolyn derivatives and holds promise for the future development of radiolabeled dimeric drugs.