Fluorine-Decoupled Carbon Spectroscopy for the Determination of Configuration at Fully Substituted, Trifluoromethyl- and Perfluoroalkyl-Bearing Carbons: Comparison with¹⁹F–¹H Heteronuclear Overhauser Effect Spectroscopy

Abstract

The synthesis of a series of α-trifluoromethylcyclohexanols and analogous trimethylsilyl ethers by addition of the Ruppert-Prakash reagent to substituted cyclohexanones is presented. A method for the assignment of configuration of such compounds and of related α-trifluoromethylcyclohexylamines and of quaternary trifluoromethyl-substituted carbons is described based on the determination of the 3JCH coupling constant between the fluorine decoupled 13CF3 resonance and the vicinal hydrogens. This method is dubbed Fluorine-Decoupled Carbon Spectroscopy and abbreviated FDCS. The method is also applied to the configurational assignment of substances bearing mono-, di-, and perfluoroalkyl rather than trifluoromethyl groups. The configuration of all substances was verified by either 1H,19F heteronuclear Overhauser spectroscopy (HOESY) or by X-ray crystallography. The relative merits of FDCS and HOESY are compared and contrasted. 2JCH, 3JCH, and 4JCH to 19F decoupled CF3 groups in alkenes and arenes have also been determined and should prove useful in the structural assignment of trifluoromethylated alkenes and arenes.

Optimized synthesis of a pentafluoro- gem -diol and conversion to a CF2Br -glucopyranose through trifluoroacetate-release and halogenation

“…Assignment of the relative stereochemical configuration was accomplished by COSY, HMQC, HMBC, NOESY, and 1 H– 19 F 2D HOESY NMR data (see Scheme 4). The utility of 1 H– 19 F 2D HOESY experiments in assigning stereochemical configuration of centers on cyclic structures has been elegantly described by Crich and coworkers, 29 and the data for 13 was in excellent agreement with this precedent.…”

Exposing the Origins of Irreproducibility in Fluorine NMR Spectroscopy

“…BMS = bulk magnetic susceptibility). [6] Analyzing 19 FNMR samples at eleven institutions gave adistributiono fresults (B), which converged upon inclusion of acalibrated tertiary reference (C). The orange bullet point represents the "true" chemical shift of PhCF 3 in chloroform-d with respect to neat CFCl 3 .…”

“…[6] In 1 H and 13 CNMR spectroscopy,d istinctive patterns of multiple signals can be analyzed, and residual solvent signals are present. [6] In 1 H and 13 CNMR spectroscopy,d istinctive patterns of multiple signals can be analyzed, and residual solvent signals are present.…”

“…Overarchingmethods for referencing heteronuclear NMR spectra, specifically exemplified here for 19 FNMR spectroscopy.Spectra can be referenced indirectly with asecondary NMR channel (A or B)ordirectly with aheteronuclear reference via the observe channel (C-E). [6] Analyzing 19 FNMR samples at eleven institutions gave adistributiono fresults (B), which converged upon inclusion of acalibrated tertiary reference (C). BMS = bulk magnetic susceptibility).…”

“…Given the prominence of 19 FNMR spectroscopy,wewere confounded by the relatively large discrepancies in 19 FNMR chemical shifts reported even for simple compounds. [6] In 1 H and 13 CNMR spectroscopy,d istinctive patterns of multiple signals can be analyzed, and residual solvent signals are present. [7] In contrast, the 19 FNMR chemical shifts of partially fluorinated compounds often provide the sole information about the nature of af luorine environment and are thus of utmost significance.…”