Rotational spectroscopy of chiral tetrahydro-2-furoic acid: Conformational landscape, conversion, and abundances

The conformational landscape of tetrahydro-2-furoic acid (THFA), a chiral carboxylic acid which is often used as a precursor in syntheses of pharmaceuticals, was investigated using rotational spectroscopy and theoretical modeling. Extensive manual searches were carried out to identify possible conformers related to the relative orientations of the carbonyl and hydroxyl groups in the COOH functional group, the COOH rotation, and the ring puckering motions in the system. A large number of initial conformational geometries were generated in parallel using a joint semiempirical-molecular dynamics simulation program. The final geometry optimizations were carried out at the B3LYP-D3(BJ)/def2-TZVP, B3LYP-D3(BJ)/6-311++G(2d,p), and MP2/6-311G++(2d,p) levels of theory. Eight conformers within a relative energy span of 10 kJ mol^-1 after zero-point energy corrections were identified. Rotational spectra of three conformers were detected experimentally and assigned, as were the spectra of all the ¹³C isotopologues of the most stable conformer. Based on the achieved experimental sensitivity and the predicted relative abundances at the sample source, some conformers are unexpectedly missing or experience significant depletion, whereas others show noticeable enrichment. Detailed analyses of the conformational conversion barriers were carried out to satisfactorily explain the observed phenomena. The combined experimental rotational spectroscopic and theoretical investigation provides significant insights into the complex conformational landscape of THFA.