Solvation of 2-(hydroxymethyl)-2,5,7,8-tetramethyl-chroman-6-ol revealed by circular dichroism: a case of chromane helicity rule breaking

Abstract

The primary goal of this work is to clarify why 2-(hydroxymethyl)-2,5,7,8-tetramethyl-chroman-6-ol {(S)-TMChM} deviates from the chromane helicity rule under solvent change. The rule, applicable to determining the absolute configuration of molecules containing the chromane chromophore, binds the sign of the ¹L_b Cotton effect (CE) with the helicity of the dihydropyran ring. In case of TMChM, however, this CE exhibits extreme solvent dependence: it is negative in non-coordinating solvents and positive in coordinating ones, irrespective of the helicity of the heterocyclic ring. TD-DFT calculations using PCM and hybrid solvation models were performed to explain origin of this phenomenon. It turned out that the ¹L_b CE sign directly depends on the position of the phenolic OH group at carbon atom C6 (OH^C6). In the absence of interactions with solvents (as in CCl₄ or nC₆H₁₄) or when a solvent plays proton donor role (as in CHCl₃), the OH^C6 lies in the phenyl plane and the ¹L_b CE sign follows the P/M helicity rule. In contrast, in proton acceptor solvents, like DMSO, CH₃OH or CH₃CN, the OH^C6 group is deflected from the phenyl plane, and the ¹L_b CE sign of individual (S)-TMChM conformers depends on the sector in which the OH^C6 is located. Thus, in solution, the ¹L_b CE sign is an average over different orientations of the OH^C6 group and can be positive (as in DMSO and CH₃OH) or negative (as in CH₃CN) which means that it does not follow the chromane helicity rule. The impact of OH^C6 on the ¹L_b CE sign and thus the conclusions for the stereochemistry of chromans are demonstrated here for the first time. Additionally, a comparison of experimental and simulated ECD spectra, supported by VCD data, allowed to determine the geometry of intermolecular clusters formed in different solvents.