Anomalous H NMR chemical shift behavior of substituted benzoic acid esters.

Benzoic acid esters represent key building blocks for many drug discovery and development programs and have been advanced as potent PDE4 inhibitors for inhaled administration for treatment of respiratory diseases. This class of compounds has also been employed in myriad industrial processes and as common food preservatives. Recent work directed toward the synthesis of intermediates for a proprietary medicinal chemistry program led us to observe that the H NMR chemical shifts of substituents ortho to the benzoic acid ester moiety defied conventional iterative chemical shift prediction protocols.

J-modulated F- and H-detected dual-optimized inverted J 1,n-ADEQUATE: A universal ADEQUATE experiment.

The recently reported F-detected dual-optimized inverted J 1,n-ADEQUATE experiment and the previously reported H-detected version have been modified to incorporate J-modulation, making it feasible to acquire all 1,1- and 1,n-ADEQUATE correlations as well as J and J homonuclear scalar couplings in a single experiment. The experiments are demonstrated using N,N-dimethylamino-2,5,6-trifluoro-3,4-phthalonitrile and N,N-dimethylamino-3,4-phthalonitrile.

F-detected dual-optimized inverted J 1,n-ADEQUATE.

Modification of the recently reported F-detected 1,1-ADEQUATE experiment that incorporates dual-optimization to selectively invert a wide range of J correlations in a 1,n-ADEQUATE experiment is reported. Parameters for the dual-optimization segment of the pulse sequence were modified to accommodate the increased size of J homonuclear coupling constants of poly- and perfluorinated molecules relative to protonated molecules to allow broadband inversion of the J correlations. The observation and utility of isotope shifts are reported for the first time for 1,1- and 1,n-ADEQUATE correlations.

Development of F-detected 1,1-ADEQUATE for the characterization of polyfluorinated and perfluorinated compounds.

Polyfluorinated and perfluorinated compounds in the environment are a growing health concern. F-detected variants of commonly employed heteronuclear shift correlation experiments such as heteronuclear single quantum correlation (HSQC) and heteronuclear multiple bond correlation (HMBC) are available; F-detected experiments that employ carbon-carbon homonuclear coupling, in contrast, have never been reported. Herein, we report the measurement of the J and J coupling constants of a simple perfluorinated phthalonitrile and the first demonstration of a F-detected 1,1-ADEQUATE experiment.