Chiral Derivatizing Agents, Macrocycles, Metal Complexes, and Liquid Crystals for Enantiomer Differentiation in NMR Spectroscopy

Abstract

Enantiomerically pure chiral auxiliary agents are often used in NMR spectroscopy to facilitate the differentiation of enantiomers. Chiral derivatizing agents are covalently bound to the substrate and differences in chemical shifts of the resulting diastereomeric complexes are used in the analysis. Macrocycles such as cyclodextrins, crown ethers, and calix[4]resorcinarenes are chiral solvating agents that associate with the substrate through non-covalent interactions. Enantiomeric differentiation occurs in the NMR spectrum because of the diastereomeric nature of the associated complexes and/or because of the differences in association constants between the two enantiomers and the chiral reagent. Metal complexes are Lewis acids that bind to suitable Lewis base donor compounds. Exchange of substrate can be slow or fast depending on the particular metal ion, mimicking the behavior of a chiral derivatizing or solvating agent, respectively. Chiral liquid crystals undergo a partial alignment in an applied magnetic field and enantiomers dissolved in the liquid crystal undergo a partial alignment as well. If the alignment of the two enantiomers is different, enantiomeric differentiation can potentially be observed by differences in chemical shifts, differences in dipolar coupling constants, and different magnitudes of splitting of quadrupolar nuclei such as deuterium. The chiral reagents described herein can be used to determine enantiomeric composition and sometimes to assign absolute configuration. Significant discoveries as well as recent findings with each of these types of systems are described.

Synergistic Effects of Trace Amounts of Water in the Enantiodiscrimination Processes by Lipodex E: A Spectroscopic and Computational Investigation

“…Among them the most popular are chromatographic [1][2][3][4][5][6] and spectroscopic methods, and, particularly, nuclear magnetic resonance (NMR). [6][7][8][9][10] The easy commercial accessibility of chiral stationary phases for high-performance liquid chromatography / gas chromatography (HPLC/GC) and of chiral auxiliaries for NMR spectroscopy has made these analytical methods very popular and has led to the recognition, especially in chromatography, of the critical dependence of the reproducibility of analytical separations from the presence of intentional additives or unintentional impurities. 11,12 A source of irreproducible chromatographic separation consists of the traces of water or moisture, the content of which is very difficult to control and, in general, constitutes an undesired presence.…”

Chiral Recognition by Dissolution DNP NMR Spectroscopy of 13C-Labeled dl-Methionine

“…T 1 values of C1 of dissolved dl -[1- 13 C]-methionine with and without (−)-18C6H4 in the dissolution were 8.3 and 12.5 s, respectively (see Experimental Section). As expected, T 1 ( 13 C) decreased by the formation of the diastereoisomeric complexes between the enantiomeric analytes and the CSA that takes place in the enantiodifferentiation experiment. − This is an important aspect to consider when designing experiment for other samples.…”

“…The recognition of enantiomeric molecules by chemical analytical techniques is still a challenge. , Among the different techniques, NMR spectroscopy together with the use of chiral auxiliaries (CA) has given excellent results being nowadays an active field of research. − Compared to other CA, chiral solvating agents (CSA) present interesting advantages, such as no derivatization of the analyte or chromatographic steps, no problems of kinetic resolution, and a quick way to perform the experiment. − Enantiomeric differentiation is especially challenging when the chiral recognition is meant to be done under biological sample conditions, that is, in aqueous media, at millimolar concentration and within complex matrices. This is the case of chiral metabolomics, a concept we recently introduced to integrate chiral recognition into metabolomic studies and which comprehends all the aforementioned complexity.…”

Direct distinction of ibuprofen and flurbiprofen enantiomers by ion mobility mass spectrometry of their ternary complexes with metal cations and cyclodextrins in the gas phase

“…Many technologies and methods have been developed for enantioselective analysis, including HPLC [11][12][13][14], CE [15][16][17][18], GC [19,20], supercritical fluid chromatography [21], and nuclear magnetic resonance (NMR) [22,23]. These methods have been widely applied and intensively investigated and developed over the past several decades.…”