NMR spectral analysis of second-order 19F-19F, 19F-1H and 13C-19F coupling constants in pentafluorobenzene and tetrafluoro-4-(morpholino)pyridine using ANATOLIA

Abstract

A new and simple to use line-shape analysis method ANATOLIA (ANAlysis of TOtal LIneshApe) optimised all and 19F-19F and 19F-1H coupling constants in pentafluorobenzene (AA'BB’C'H) within 10 s. This free and open-source NMR analysis method, which works within the Bruker Topspin-4 software and can import Bruker/JEOL/Varian data, was able to accommodate grossly inaccurate input coupling constants to provide an accurate result even for the second-order interactions 4JAA’ and 4JBB’. The 13C spectrum and the 19F-13C-satellites share the same coupling values, but required manual intervention to achieve an acceptable fit, especially for the 19FBB’-13C-satellites which are deceptively simple but have significant second-order effects and display Δδ 19FB – 19FB’ of ˜100 Hz. A real-world analysis of a new compound, that has potential anti-cancer drug activity, tetrafluoro-4-(morpholino)pyridine molecule, is shown for the first time. The 19F spectrum consists of a spin-system of 8 coupling nuclei (AA'BB’-H4) which was analysed within 20 s. The 13C satellites in the 19F spectrum consist of 9-spins (AA'BB’-13C-H4) and the carbon spectrum shows a series of 13C isotopomer multiplets consisting of 5 coupling nuclei (13C-AA'BB’) was optimised in less than a minute using a laptop computer. Ab initio structure optimisations were carried out using B3LYP/6-31G*, and chemical shifts and coupling constants were calculated with the basis-set B3LYP/6-311++G**. Fluorine and carbon chemical shifts were in reasonable agreement with experimental values, and nJFF and 2−4JCF couplings were close to the experimental values, such that these were reasonable starting values for the ANATOLIA optimisation.