Recent Advances in Multinuclear NMR Spectroscopy for Chiral Recognition of Organic Compounds

molecules Review Recent Advances in Multinuclear NMR Spectroscopy for Chiral Recognition of Organic Compounds Márcio S. Silva Centro de Ciências Naturais e Humanas—CCNH—Universidade Federal do ABC—UFABC, Av. Dos Estados 5001, 09210-180 Santo André –SP, Brazil; [email protected]; Tel.: +55-11-4996-8358 Academic Editor: Roman Dembinski Received: 4 January 2017; Accepted: 30 January 2017; Published: 7 February 2017 Abstract: Nuclear magnetic resonance (NMR) is a powerful tool for the elucidation of chemical structure and chiral recognition. In the last decade, the number of probes, media, and experiments to analyze chiral environments has rapidly increased. The evaluation of chiral molecules and systems has become a routine task in almost all NMR laboratories, allowing for the determination of molecular connectivities and the construction of spatial relationships. Among the features that improve the chiral recognition abilities by NMR is the application of different nuclei. The simplicity of the multinuclear NMR spectra relative to 1H, the minimal influence of the experimental conditions, and the larger shift dispersion make these nuclei especially suitable for NMR analysis. Herein, the recent advances in multinuclear (19F, 31P, 13C, and 77Se) NMR spectroscopy for chiral recognition of organic compounds are presented. The review describes new chiral derivatizing agents and chiral solvating agents used for stereodiscrimination and the assignment of the absolute configuration of small organic compounds. Keywords: chiral recognition; NMR spectroscopy; chirality; multinuclear; enantiopurity; enantiomeric excess; stereochemistry; absolute configuration 1. Introduction Stereoisomers are compounds with the same molecular formula, possessing identical bond connectivity but different orientations of their atoms in space [1]. Enantiomers are stereoisomers that are mirror images of each other, but at the same time are not superimposable. Chirality is important in chemical, physical, pharmaceutical, and biological systems, inspiring new biomimicry-based innovations [2,3]. Moreover, the need to discriminate between enantiomers and quantify enantiomeric excess (ee) is of extreme importance in the pharmaceutical industry and for asymmetric synthesis [4–6]. Nowadays, the use of chromatography separation of enantiomers on chiral stationary phases is still the approach most often applied in modern chemical research [7,8]. However, the search for new chiral discriminating procedures that allow for quick analysis, high resolution, and utility for many non-volatile or thermally unstable compounds is increasing [9–12]. Among the several stereodiscrimination methods, including X-ray, circular dichroism, fluorescence spectroscopy, and electrophoresis, nuclear magnetic resonance (NMR) spectroscopy continues to be a useful tool for determining the enantiomeric purity and assigning the absolute configuration of chiral molecules [13–21]. NMR active nuclei are isochronous in an achiral medium and do not permit their discrimination, but in a chiral environment these nuclei are anisochronous and chiral discrimination is possible. Therefore, to perform the enantiopurity analysis, a chiral derivatization or solvating agent is essential to produce a nonequivalent diastereomeric mixture and relevant differences in the NMR spectra. Chiral derivatizing agents form a covalent bond with a reactive moiety of the substrate and chiral solvating agents associate with the substrate through non-covalent interactions, such as dipole–dipole Molecules 2017, 22, 247; doi:10.3390/molecules22020247 www.mdpi.com/journal/molecules Molecules 2017, 22, 247 2 of 21 and ion pairing. In this context, strategies based on different intermolecular reactivities, interactions, and packing orders for a pair of enantiomers are in constant development. Among the active NMR nuclei, 1H is the most important. The characteristics of 1H, such as its natural abundance (99.98%) and its high sensitivity to environmental modifications, make it immensely Molecules 2017, 22, 247 2 of 22 versatile in NMR chiral analysis [22]. Nevertheless, 1H-NMR spectroscopy poses some limitations. 1 The H-NMRdipole–dipole spectra and for ion chiral pairing. analysis In arethis severelycontext, hamperedstrategies based dueto on the different numerous intermolecular scalar couplings, and thereactivities, overlap combined interactions, with and broad packing and orders featureless for a pair spectra of enantiomers leads to enormousare in constant difficulties development. in 1H-NMR analysis, evenAmong for the small active molecules. NMR nuclei, Consequently, 1H is the most theimportant. comparison The characteristics of the enantiomers of 1H, such using as its NMR spectranatural and theabundance assignment (99.98%) of absolute and its high configuration sensitivity canto environmental be unclear. Themodifications, application make of differentit immensely versatile in NMR chiral analysis [22]. Nevertheless, 1H-NMR spectroscopy poses some NMR nuclei, mainly 19F and 31P, overcomes these limitations. The simplicity of the multinuclear 1 limitations. The H-NMR1 spectra for chiral analysis are severely hampered due to the numerous NMR spectrascalar couplings, relative and to the the overlapH and thecombined larger with shift broad dispersion and featureless make these spectra nuclei leads especially to enormous suitable for analysis.difficulties in 1H-NMR analysis, even for small molecules. Consequently, the comparison of the Inenantiomers this review, using new NMR chiral spectra derivatization and the assignment agents of (CDAs), absolute chiralconfiguration solvating can be agents unclear. (CSAs), The and modernapplication methods of for different stereodiscrimination NMR nuclei, mainly and 19F assignment and 31P, overcomes of the these absolute limitations. configuration The simplicity of organic compoundsof the multinuclear by 19F-, 31P-, NMR13C-, spectra and relative77Se-NMR to the spectroscopy 1H and the larger are shift described. dispersion The make focus these is nuclei on articles from 2007especially to the suitable present for date. analysis. Furthermore, the 2H nucleus is not described because of the necessity of In this review, new chiral derivatization agents (CDAs), chiral solvating agents (CSAs), and discussing the physical bases in order to understand the quadrupolar electric moment and residual modern methods for stereodiscrimination and assignment of the absolute configuration of organic dipolarcompounds coupling contentsby 19F-, 31P-, [23 13C-,]. and 77Se-NMR spectroscopy are described. The focus is on articles from 2007 to the present date. Furthermore, the 2H nucleus is not described because of the necessity of 19 2. F-NMRdiscussing Chiral the physical Recognition bases in order to understand the quadrupolar electric moment and residual 19dipolarF is one coupling of the contents most useful [23]. nuclei for NMR studies [24]. The fluorine element has polar and steric properties2. 19F-NMR Chiral as a substituent Recognition and the effects that fluorinated groups can have on the physical and chemical properties of molecules have increased the number of new methods for incorporating 19F is one of the most useful nuclei for NMR studies [24]. The fluorine element has polar and fluorine into target compounds. Furthermore, 19F-NMR spectroscopy has proved to be a valuable tool steric properties as a substituent and the effects that fluorinated groups can have on the physical and to studychemical the structure properties and of functionmolecules ofhave nucleic increased acids the by number incorporating of new methods fluorine for labels incorporating into DNA and RNA [25fluorine]. into target compounds. Furthermore, 19F-NMR spectroscopy has proved to be a valuable Sincetool to the study19F-NMR the structure frequency and function and sensitivity of nucleic are acids similar by incorporating to the proton fluorine (the labels fluorine into spectraDNA is at 282 MHzand and RNA the [25]. proton spectrum is at 300 MHz), it is convenient to transition from proton to fluorine NMR experiments.Since the 19F-NMR frequency and sensitivity are similar to the proton (the fluorine spectra is at A282 wide MHz varietyand the ofproton fluorine-containing spectrum is at 300 MHz), reagents it is haveconvenient been to developedtransition from for proton NMR to chiral fluorine NMR experiments. discrimination [26,27]. In 2015, Nemes et al. described the chiral recognition studies of α-(nonafluoro- A wide variety of fluorine-containing reagents have been developed for NMR chiral 19 tert-butoxy)carboxylicdiscrimination [26,27]. acid byIn F-NMR2015, Nemes spectroscopy et al. described [28]. Carboxylic the chiral acids recognition1 and 2 werestudies synthesized of to be enantiomericallyα-(nonafluoro-tert-butoxy)carboxylic enriched in order acid toby obtain19F-NMR a spectroscopy CDA (Scheme [28].1 ).Carboxylic The synthesis acids 1 ofand racemic 2 carboxylicwere acidssynthesized1 and to2 bewas enantiomeric carried outally in enriched two steps. in order Chiral to obtain recognition a CDA (Scheme studies 1). were The synthesis performed of with (S)-phenylethylamine.racemic carboxylic Inacids the 1 NMR and 2 measurements, was carried out Cin6D two6 solvent steps. Chiral was more recognition favorable studies than were CDCl 3 in the differencesperformed ( Dwithδ) of (S diastereomeric)-phenylethylamine. signals. In the TheNMR benefits measurements, of these C6D CDAs6 solvent include was more the favorable presence of an than CDCl3 in the differences

Load more