Structural and Stereochemical analysis of Trolox methyl ester THP ethers by integrated spectroscopic and...

Tetrahydropyranyl (THP) ethers of selected vitamin E model compounds were studied to evaluate the influence of etherification on the electronic, stereochemical, and dynamic properties of the chromanol system. α-Tocopherol, δ-tocopherol, and Trolox methyl ester derivatives were analysed using single-crystal X-ray diffraction (XRD), variable-temperature ¹³C nuclear magnetic resonance (NMR) spectroscopy, High-Performance Liquid Chromatography-Electronic Circular Dichroism (HPLC-ECD), Density Functional Theory (DFT) and Time-Dependent Density Functional Theory (TDDFT) calculations. The study focused in particular on dynamic effects arising from restricted rotation of the THP substituent, manifested in the temperature-dependent behaviour of aromatic and methyl carbon resonances in the ¹³C NMR spectra. Chiroptical analysis showed that the ECD response is highly sensitive to both the substitution pattern of the aromatic ring and the absolute configuration of the stereogenic centres, allowing stereochemical assignment of the obtained products. Crystallisation and chiroptical analysis also made it possible to access structurally defined, and in selected cases pure stereoisomeric forms from mixtures, which was crucial for detailed structural characterization. The results demonstrate that etherification significantly reshapes the electronic response of vitamin E model chromanols and affects their conformational mobility, providing new insight into the relationship between substitution, stereochemistry, and dynamic behaviour in this class of compounds.