Fluorine detected 2D NMR experiments for the practical determination of size and sign of homonuclear F–F and heteronuclear C–F multiple bond J-coupling constants in multiple fluorinated compounds

Abstract

The use of fluorine in molecules obtained from chemical synthesis has become increasingly important within the pharmaceutical and agricultural industry. NMR characterization of these compounds is of great value with respect to their structure elucidation, their screening in metabolomics investigations and binding studies. The favorable NMR properties of the fluorine nucleus make NMR with fluorine detection of great value in this respect. A suite of NMR 2D F–F- and F–C-correlation experiments with fluorine detection was applied to the assignment of resonances, nJCF- and nJFF-couplings as well as the determination of their size and sign. The utilization of this experiment suite was exemplarily demonstrated for a highly fluorinated vinyl alkyl ether. Especially F–C HSQC and J-scaled F–C HMBC experiments allowed determining the size of the J-couplings of this compound. The relative sign of its homo- and heteronuclear couplings was achieved by different combinations of 2D NMR experiments, including non-selective and F2-selective F–C XLOC, F2-selective F–C HMQC, and F–F COSY. The F2-one/two-site selective F–C XLOC versions were found highly useful, as they led to simplifications of the common E.COSY patterns and resulted in a higher confidence level of the assignment by using selective excitation. The combination of F2-one/two-site selective F–C XLOC experiments with a F2-one-site selective F–C HMQC experiment provided the signs of all nJCF- and nJFF-couplings in the vinyl moiety of the test compound. Other combinations of experiments were found useful as well for special purposes when focusing for example on homonuclear couplings a combination of F–F COSY-10 with a F2-one-site selective F–C HMQC could be used. The E.COSY patterns in the spectra demonstrated were analyzed by use of the spin-selective displacement vectors, and in case of the XLOC also by use of the DQ- and ZQ-displacement vectors. The variety of experiments presented shall contribute to facilitate the interpretation of F–C correlations as well as to open alternative pathways for the determination of size and signs of homo- and heteronuclear couplings of multiply fluorinated small molecules.