Differentiation of Enantiomers II

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.

This chapter will describe the general features and main categories of chiral solvating agents (CSAs) for NMR spectroscopy, spanning from low-medium sized CSAs to macrocyclic ones. CSAs based on chiral ionic liquids (CILs) will be introduced in view of their increasing popularity, and, finally, a short paragraph will be dedicated to special applications of CSAs in particular experimental conditions. Several valuable works, which are mainly devoted to investigate enantiodifferentiation mechanisms by NMR, will not be discussed. The main objective is to identify the current trend in the research areas dedicated to the development of new CSAs for NMR spectroscopy.

Differentiation of enantiomers remains one of the most attractive and important research areas in analytical chemistry due to its impact on pharmaceutical, chemical, biotechnology, and food industries. For a long time chiral separation techniques, such as high performance liquid chromatography (HPLC), gas chromatography (GC), and capillary electrophoresis (CE), have represented the gold standard for the separation and determination of enantiomers. These techniques, besides being time consuming and expensive, are also not suitable for real time analysis. Therefore, the development of fast and reliable chiral sensors remains a challenge to achieve on-line analysis of enantiomers in both gas and liquid samples. The scope of this chapter is to provide an overview on the basic functioning principles, as well as on the performance level, of solid-state sensing devices for enantiomers differentiation. Particular attention is paid to work providing a set of analytical figures of merit (sensitivity, repeatability, reproducibility, limit-of-detection, etc.) as well as to studies involving miniaturized (or miniaturizable) analytical devices that can deliver real-time, on-line, and label-free information on chiral compounds.

Enantiopure compounds are ubiquitous in the chemical sciences and present a particular interest in the field of molecular recognition and host-guest systems. Indeed, chiral molecular receptors are at the basis of numerous biological recognition processes and have important implications in biochemistry or pharmacology. Chemists have been investigating this field for several decades, which has led to the development of the synthesis of chiral hosts, their enantiomeric differentiation, and the studies of their recognition properties towards important and bio-relevant chiral guest substrates. The design of molecular cages is a rather difficult task that is even more demanding when enantiopure molecules are required. In this review we chose to present the main families of synthetic organic supramolecular cages that have been developed, whose structures contain stereogenic centers or present an inherent chirality, giving rise to chiral supramolecular cages. Particular attention is given to obtaining enantiopure compounds. Their recognition properties are also underlined. A last important aspect of the review is to present how chiroptical spectroscopies can be used to characterize the recognition phenomena displayed by supramolecular cages.

The investigation of the molecular dynamics of stereoisomers is of fundamental interest in chemistry, biochemistry, medicine, and related areas. In recent years enantioselective dynamic chromatography and enantioselective dynamic capillary electrophoresis (DCE) have been established as versatile tools to investigate the kinetics of interconversions of stereoisomers. The term dynamic chromatography and dynamic electrophoresis, following the term dynamic NMR (DNMR) (Grathwohl and Wüthrich, Biopolymers 20:2623–2633, 1981; Wüthrich, Angew Chem Int Ed 42:3340–3363, 2003; Binsch et al., Angew Chem Int Ed 10:570–572, 1971), stresses the dynamic (Herschbach, Angew Chem Int Ed 26:1221–1243, 1987) behavior of analytes to interconvert between two stereoisomeric forms during the separation process. If the interconversion process is slow compared to the separation of the enantiomers, which can be achieved by accelerating the separation process or lowering the temperature, partial separation with characteristic plateau formation or peak broadening is observed.

This chapter gives an overview of recent advances in the study of stereodynamics of molecules by dynamic chromatography (Trapp et al., Chirality 13:403–414, 2001; D’Acquarica et al., J Sep Sci 29:1508–1516, 2006; Wolf, Chem Soc Rev 34:595–608, 2005; Wolf, Dynamic stereochemistry of chiral compounds – principles and applications. RSC Publishing, Cambridge, 2008) and capillary electrophoresis. Models and algorithms to evaluate interconversion profiles obtained by separation techniques are discussed with respect to the challenging demands of high separation efficiencies typical of modern separation techniques. Models used for evaluation are based on iterative computer simulation algorithms using the theoretical plate model (TPM) or stochastic model of chromatography, empirical calculation methods, derived from equations used in chemical engineering, namely Damköhler analysis, and direct access using the approximation function, and more recently the unified equation of chromatography, which can be applied to all kinds of first-order reactions taking place during a chromatographic or electrophoretic separation. Furthermore, areas of applications to investigate stereodynamic processes are presented and discussed to give a practical guide for using dynamic chromatography and capillary electrophoresis.

All biopolymers are composed of homochiral building blocks, and both d-sugars and l-amino acids uniquely constitute life on Earth. These monomers were originally enantiomerically differentiated under prebiotic conditions. Particular progress has recently been made in support of the photochemical model for this differentiation: the interaction of circularly polarized light with racemic molecules is currently thought to have been the original source for life’s biological homochirality. The differential asymmetric photoreactivity of particular small molecules can be characterized by both circular dichroism and anisotropy spectroscopy. Anisotropy spectroscopy, a novel derivative of circular dichroism spectroscopy, records the anisotropy factor g = Δε/ε as a function of the wavelength. Anisotropy spectroscopy promisingly affords the wavelength-dependent determination of the enantiomeric excess (ee) inducible into chiral organic molecules by photochemical irradiation with circularly polarized light. Anisotropy spectra of small molecules therefore provide unique means for characterizing the different photochemical behaviors between enantiomers upon exposure to various wavelengths of circularly polarized light. This chapter will: (1) present the theory and configuration of anisotropy spectroscopy; (2) explain experimentally recorded anisotropy spectra of selected chiral biomolecules such as amino acids; and (3) discuss the relevance of these spectra for the investigation of the origin of the molecular homochirality observed in living organisms. This review describes a new chiroptical technique that is of significance for advances in asymmetric photochemistry and that is also highly relevant for the European Space Agency Rosetta Mission, which will determine enantiomeric excesses (ees) in chiral organic molecules in cometary ices when it lands on Comet 67P/Churyumov–Gerasimenko in November 2014.

This review describes self-disproportionation of enantiomers (SDE) of non-racemic mixtures, subjected to distillation, sublimation, or chromatography on achiral stationary phase using achiral eluent, which leads to the substantial enantiomeric enrichment and corresponding depletion in different fractions, as compared to the enantiomeric composition of the starting material. This phenomenon is of a very general nature as SDE has been reported for different classes of chiral organic compounds bearing various functional groups and possessing diverse elements of chirality. The literature data discussed in this review clearly suggests that SDE is typical for enantiomerically enriched chiral organic compounds and special care should always be taken in evaluation of the stereochemical outcome of enantioselective reactions as well as determination of enantiomeric ratios of non-racemic mixtures of natural products after any purification process. The role of molecular association of enantiomers on the magnitude and preparative efficiency of SDE, as a new, nonconventional method for enantiomerc purifications, is emphasized and discussed.