Conformational Panorama and Chirality Controlled Structure–Energy Relationship in a Chiral Carboxylic Acid Dimer

Abstract

Chirality recognition in dimers of tetrahydro‐2‐furoic acid (THFA), a biologically active carboxylic acid, was studied in a conformer‐specific manner using rotational spectroscopy and theoretical approaches. The THFA monomer is known to have a strong preference for the trans ‐ over the cis ‐COOH configuration. Two drastically different scenarios are possible for the detectable THFA dimer: the kinetically controlled formation of a dimer bound by feeble interactions between two trans subunits or the thermodynamically controlled formation of a dimer with a double hydrogen‐bonded ring structure between two cis subunits. To identify the conformers responsible for the extremely dense, broadband rotational spectra, it was essential not only to locate several hundred homo/heterochiral (THFA) 2 minima but also to evaluate the energetic connectivities among the minima. In addition, a series of experiments with different carrier gases and nozzle temperatures were carried out to aid the understanding of the very unusual dimer conformational distribution. The study further reveals an interesting chirality dependent structure‐energy ordering relationship. A method for enantiomeric excess (ee) determination of THFA is presented using a recently proposed chiral self‐tag approach. Even with the complicated conformational cooling paths present, a normalization step in the ee analysis can remove intensity anomalies, suggesting that the method is effective in providing accurate ee values.