Determining the Enantiomeric Excess and Absolute Configuration of In Situ Fluorine-Labeled Amines and Alcohols by ¹⁹F NMR Spectroscopy

Abstract

The determination of the enantiomeric excess and absolute configuration of chiral compounds is indispensable in synthetic, pharmaceutical, and biological chemistry. In this article, we describe an efficient 19 F nuclear magnetic resonance (NMR)based analytical protocol for determining the enantiomeric excess and absolute configuration of in situ fluorine-labeled amines and alcohols. 2-Fluorobenzoylation was used to convert analytes to fluorinated amides or esters. The resulting F-labeled analytes were mixed with a cationic cobalt(III) complex, [Co]BArF, resulting in clean baseline peak separations of analyte enantiomers in 19 F{ 1 H} NMR spectra. The measured Δδ RS signs were unambiguously used to correlate the absolute configurations of amines, amino alcohols, and alcohols. Moreover, the structure-dependent 19 F{ 1 H} NMR signals enabled absolute configuration determination by analyzing the relative chemical shifts of enantiopure analyte samples with [Co]BArF and ent-[Co]BArF.

Stereospecific recognition of a chiral centre over multiple flexible covalent bonds by19F-NMR

“…5 Nuclear magnetic resonance (NMR) spectroscopy is a powerful analytical method that provides a variety of structural and dynamic information of analytes and is able to discriminate between enantiomers by derivatizing analytes or using chiral solvating agents. 6–14 The power of NMR in the stereospecific discrimination of enantiomers has been demonstrated in early seminal reports by using chiral or optically pure solvating agents. 15 In contrast to optical methods, NMR does not require sample separation and allows qualitative and even quantitative analysis of the analyte mixture.…”

Accuracy of quantum chemistry structures of chiral tag complexes and the assignment of absolute configuration

“…The confidence in the assignment of the analyte absolute configuration can be significantly increased in favorable cases. Rotational spectroscopy, in principle, offers perhaps the highest confidence for absolute configuration determinations of any spectroscopy technique because it can yield direct structural information through the analysis of 13 C isotopomers in natural abundance (and other isotopes, such as 15 N and 18 O, when the atom is present and there is sufficient measurement sensitivity). For example, Fig.…”

“…The physical chemistry community continues to develop spectroscopy methods to assign the absolute configuration of molecules. [16][17][18][19][20][21] Spectroscopy methods ultimately require quantum chemistry predictions of the spectrum for analysis. Perhaps the most successful technique is vibrational circular dichroism (VCD) and its related method of Raman optical activity.…”

Rapid and Selective 19F NMR-Based Sensors for Fingerprint Identification of Ribose

“…Moreover, the lack of naturally occurring fluorinated compounds in the body fluid eliminates background signals and makes the spectrum analysis easier . Consequently, fluorine-labeled molecules combined with 19 F NMR to generate characteristic signals as powerful sensors have been extensively utilized, ranging from organic small molecule discrimination, − biological relevant molecule sensing, − chiral recognition, − drug studies, , and so forth. Furthermore, the combination of fluorinated phenylboronic acid compounds with 19 F NMR has turned out to be a powerful method for sensing of diol-containing analytes. − In particular, a series of fluorinated phenylboronic acid sensor molecules were synthesized by Schiller and co-workers for the identification and discrimination of diols. , Despite remarkable progress, it is still a challenge to identify specific saccharides in a mixture containing multiple potential interferents.…”