Self-disproportionation Of Enantiomers Research Articles

ChemInform Abstract: Self‐Disproportionation of Enantiomers of Chiral, Non‐Racemic Fluoroorganic Compounds: Role of Fluorine as Enabling Element

AbstractReview: ca. 80 refs.

Self-Disproportionation of Enantiomers of Chiral, Non-Racemic Fluoroorganic Compounds: Role of Fluorine as Enabling Element

This review discusses all available literature on the self-disproportionation of enantiomers (SDE) of fluorine-containing compounds, resulting in a separation of racemic form from the excess enantiomer. Included are examples of the SDE via distillation, sublimation and achiral chromatography. The role of fluorine on the magnitude and preparative efficiency of the SDE, as a new, nonconventional method for optical purifications, is emphasized and critically discussed. 1 Introduction 2 General Aspects of Fluorine Influence on the Self-Disproportionation of Enantiomers 3 Self-Disproportionation of Enantiomers via Distillation 4 Self-Disproportionation of Enantiomers via Sublimation 5 Self-Disproportionation of Enantiomers via Achiral Chromatography 6 Conclusions

Self-disproportionation of enantiomers of non-racemic chiral amine derivatives through achiral chromatography

Efficient self-disproportionation of enantiomers of several non-racemic chiral amines was achieved through conversion to N-acetamides and subsequent MPLC using an achiral column. The MPLC of these non-racemic N-acetamide derivatives gave the chart having a clear boundary between two fractions. Thus, in the less polar fraction, remarkable enantiomer enrichment was observed (>99%ee), while the ee of more polar fraction was considerably reduced. The magnitude of the enantiomer enrichments and depletions strongly depended on substituent on the amino group.

Self-disproportionation of enantiomers via achiral chromatography: a warning and an extra dimension in optical purifications

This tutorial review describes the self-disproportionation of enantiomers (SDE) of chiral, non-racemic compounds, subjected to chromatography on an achiral stationary phase using an achiral eluent, which leads to the substantial enantiomeric enrichment and the corresponding depletion in different fractions, as compared to the enantiomeric composition of the starting material. The physicochemical background of SDE is a dynamic formation of homo- or heterochiral dimeric or oligomeric aggregates of different chromatographic behavior. This phenomenon is of a very general nature as the SDE has been reported for different classes of organic compounds bearing various functional groups and possessing diverse elements of chirality (central, axial and helical chirality). The literature data discussed in this review clearly suggest that SDE via achiral chromatography might be expected for any given chiral enantiomerically enriched compound. This presents two very important issues for organic chemists. First, chromatographic purification of reaction products can lead to erroneous determination of the stereochemical outcome of catalytic asymmetric reactions and second, achiral chromatography can be used as a new, nonconventional method for optical purifications. The latter has tremendous practical potential as the currently available techniques are limited to crystallization or chiral chromatography. However, a further systematic study of SDE is needed to develop understanding of this phenomenon and to design practical chromatographic separation techniques for optical purification of non-racemic mixtures by achiral-phase chromatography.

Self-Disproportionation of Enantiomers via Sublimation; New and Truly Green Dimension in Optical Purification

This Review article presents all available in the literature data on optical purification of enantiomerically enriched organic compounds via simple procedure of sublimation. The material is arranged in a chronological order from early publications to current research. Relatively small amount of the results reported in the literature suggest that this area of research is still in its infancy it terms of commonly accepted experimental procedures, generalizations, interpretation or prediction of the stereochemical outcome of sublimation. On the other hand, the available data clearly show the potential of sublimation as most economical and greener alternative to the conventional optical purification techniques such as chromatography on chiral stationary phase or fractional crystallization. Another important goal of this Review is to bring to the attention of scientific community a warning that special care should always be taken in evaluation of the stereochemical outcome of enantioselective reactions. Thus, due to the always different sublimation rates of racemic and enantiomerically pure crystals, such a routine procedure as drying reaction products in vacuum or even removal of solvents under reduced pressure can significantly alter the true enantiomeric composition (% ee) of a compound under study and lead to erroneous results. Keywords: Sublimation, chiral purification, self-disproportionation of enantiomers, non-linear effects, green methodology, optical purification, chromatography, fractional crystallization, enantioselective resctions, biocatalysis

Theoretical investigations into the enantiomeric and racemic forms of α-(trifluoromethyl)lactic acid

There are many different hypotheses on the origin of biomolecular homochirality. One possible scenario concerns the enantiomeric enrichment of a nearly racemic solid via self-disproportionation of enantiomers. In particular, in a recent paper Soloshonok and co-workers showed a first example of optical self-purification of α-(trifluoromethyl)lactic acid by sublimation [V. A. Soloshonok et al., J. Am. Chem. Soc. 2007, 129, 12112]. Here we present detailed theoretical studies of α-(trifluoromethyl)lactic acid in the solid state as well as in the gas-phase dimeric form. The calculations of energy differences between dimers show that in the solid state the enantiomeric pure compound is energetically preferred, while in the gas phase the equilibrium shifts towards the racemic mixture although thermodynamic corrections cannot be neglected, thus providing a detailed microscopic explanation for the enantio-purification process for the first time.

Reply to the ‘Comment on “Theoretical investigations into the enantiomeric and racemic forms of α-(trifluoromethyl)lactic acid”’ by M. A. Suhm and M. Albrecht, Phys. Chem. Chem. Phys., 2011, 13, DOI: 10.1039/c0cp02455d

We argue that Suhm and Albrecht's key point that the homo/heterochiral dimers do not play any role in the process of self-disproportionation of enantiomers of α-(trifluoromethyl)lactic acid through sublimation might be valid under a particular set of experimental conditions. However, the formation of dimers in the gas-phase cannot be completely ruled out, in particular under the originally reported conditions of evaporative sublimation at ambient pressure and temperature. Molecular dynamic simulations of the sublimation process together with more accurate experimental data are required to fully explain this intriguing phenomenon.

Enantiomer self-disproportionation and chiral stationary phase based selective chiral separation of organic compounds

In modern chromatography, chiral stationary phase (CSP) and enantiomer self-disproportionation (ESD) are new inventions of packing material offer a guarantee for a successful enantiomeric separation. All CSPs were synthesized by chemical bonding of the relevant organic moieties onto a porous parent silica material for the separation of various racemic mixtures whereas achiral silica matrix was used for separation of non-racemic mixtures in ESD. Our present study provides to establish an understanding on the entire enantio-selective profile of amino alcohol based CSP as well as ESD and their precise utilization for high success rates for selective enantiomer separation with its appropriateness.

Rational application of self-disproportionation of enantiomers via sublimation—a novel methodological dimension for enantiomeric purifications

The preliminary results presented in this work show that an enantiomer purification approach based on SDE via sublimation can be extended to non-volatile liquid compounds such as α-(phenyl)ethylamine and its β-fluoro-derivatives by way of their rational modification with a sublimation enabling tag. 3,3,3-Trifluoro-2-(trifluoromethyl)-2-methyl-propanoic acid was found to perfectly serve the role of such a modifying tag. Thus, the corresponding amides derived from the amines and the fluorinated propanoic acid were highly crystalline and reasonably volatile compounds allowing for their sublimation at room temperature under normal pressure. All of these derivatives showed substantial self-disproportionation of enantiomers (SDEs) via sublimation under kinetic conditions (on a Petri dish in the open air). These preliminary results serve as a proof of a new principle that may extend the generality of enantiomer purification via sublimation to various organic compounds with physico-chemical properties of which render them otherwise unsuitable for a sublimation procedure. In particular, the very attractive cost structure of sublimation procedure renders this approach of potentially high practical and economic efficiency.

First principle lattice energy calculations for enantiopure and racemic crystals of α-(trifluoromethyl)lactic acid: Is self-disproportionation of enantiomers controlled by thermodynamic stability of crystals?

The lattice energies for the enantiopure and racemic crystals of α-(trifluoromethyl)lactic acid were calculated by a combination of the DFT calculations with the periodic boundary condition and the MP2 calculations of the interactions with neighboring molecules. The lattice energies calculated for the two crystals (−16.56 and −17.35 kcal/mol, respectively) show that the racemic crystals are thermodynamically more stable, although the racemic crystals sublime faster than the enantiopure crystals. The calculations suggest that the relative thermodynamic stability is not the cause of the faster sublimation rate of the racemic crystals compared with the enantiopure crystals. Although the crystals have hydrogen-bonding networks, the dispersion interactions contribute to the lattice energies significantly. The MP2 calculations for the evaluation of the dispersion interactions with the neighboring molecules are important for an accurate evaluation of the lattice energies. The relative thermodynamic stability of the two crystals is not determined solely by the hydrogen bonds. The interactions with other neighboring molecules also play important roles in determining the relative stability. We demonstrate that the geometry optimization is essential for an accurate evaluation of the lattice energy by the first principle calculation. The interaction energies calculated using the structure by X-ray diffraction often have large errors.

Self-disproportionation of enantiomers of heterocyclic compounds having a tertiary trifluoromethyl alcohol center on chromatography with a non-chiral system

Self-disproportionation of enantiomers of heterocycles having a tertiary trifluoromethyl alcohol center on an achiral silica-gel stationary phase is discussed. During the chromatographic separation of an enantiomerically enriched mixture of 1-(3,4-dimethoxyphenethyl)-3-hydroxy-3-(trifluoromethyl)-6,7-dihydro-1 H-indole-2,4(3 H,5 H)-dione ( 1) by eluting with ether on a non-chiral regular silica-gel significant enantiomeric enrichment was observed. Separation of non-racemic samples of 1 with enantiomeric excess values of 10–54% was carefully investigated: enantiomerically pure 1 with 99.9% ee was obtained by the use of 1 with at least 40% ee. A remarkable enantiomeric enrichment in the faster eluting fractions was also observed for compound 1 with only 30% ee to transform into 80% ee. Other enantiomeric mixtures of heterocyclic molecules containing a trifluoromethyl alcohol moiety at their quaternary carbon center were also examined from an SDE view point.

Self-disproportionation of enantiomers of isopropyl 3,3,3-(trifluoro)lactate via sublimation: Sublimation rates vs. enantiomeric composition

The presented results convincingly demonstrate that self-disproportionation of enantiomers via sublimation is substantially more complex phenomenon then was previously believed. We demonstrate that the racemic form of isopropyl 3,3,3-trifluoro-2-hydroxypropanoate ( 1) sublimed faster regardless of the starting enantiomeric composition of the enantiomerically enriched mixtures studied in the range from 20.8, 36.8, 58.7 to 79.4% ee. This preferential sublimation of the racemic form allowed for, the most possibly simple, preparation of optically pure samples of compound 1. In this work we also suggest some general experimental procedures, which may be easily used to facilitate the interpretation of the data collected in different laboratories.

Self-disproportionation of enantiomers of α-trifluoromethyl lactic acid amides via sublimation

Preparation of racemic and enantiomerically enriched α-trifluoromethyl lactic acid amide [NHPh, NH(4-Cl-C 6H 5), NHBn, NH t-Bu] derivatives have been developed. Ph, 4-Cl-C 6H 5, and tert-Bu derivatives were found to have substantial magnitude of the self-disproportionation of enantiomers (SDE) via sublimation. For example, when the optically enriched Ph, 4-Cl-C 6H 5, and tert-Bu amide derivatives were subjected to sublimation under kinetic conditions (Petri dish in open air), the enantiomeric excess of the remainder has noticeably increased. On the other hand, the SDE of Bn amide derivative by sublimation resulted in almost no change in the optical purity of the remainder. These preliminary results on the SDE of the compounds under study, as well as their excellent chemical and physico-chemical characteristics, render these amide derivatives as readily available and very promising substrates for systematic study of SDE via sublimation.

NMR spectral enantioresolution of spirobrassinin and 1-methoxyspirobrassinin enantiomers using ( S)-(−)-ethyl lactate and modeling of spirobrassinin self-association for rationalization of its self-induced diastereomeric anisochromism (SIDA) and enantiomer self-disproportionation on achiral-phase chromatography (ESDAC) phenomena

The phytoalexin spirobrassinin is known to exhibit the unusual phenomenon of enantiomer self-disproportionation on achiral-phase chromatography (ESDAC) whereby the enantiomeric composition of a non-racemic mixture varies across the eluting chromatographic peak. However, spirobrassinin is exceptional since both early and late fractions are enantioenriched in comparison to the starting enantiomeric composition. This behavior is rationalized by the formation of two different complexes, substantiated by DFT calculations at the B3LYP/TZVP level of theory, both of which are in dynamic equilibrium with the free molecules. Concomitant with complexation under chromatographic conditions, complexation was also evident by NMR including the observation of distinct NMR signals for each enantiomer for some spins in a non-racemic mixture—the phenomenon of self-induced diastereomeric anisochromism (SIDA). Enantioresolution of various 1H, 13C and 15N NMR signals were also induced for the enantiomers of spirobrassinin and another phytoalexin, 1-methoxyspirobrassinin, by application of the chiral solvating agent ( S)-(−)-ethyl lactate, a cheap reagent with potentially broad applications. For spirobrassinin, the observed NMR signals were evaluated against values calculated using the GIAO method at the B3LYP/cc-pVTZ level of theory.

Self-disproportionation of enantiomers of 3,3,3-trifluorolactic acid amides via sublimation

Preparation of racemic and enantiomerically enriched N-phenyl- and N-benzyl-3,3,3-trifluorolactic acid amides has been developed. These compounds were found to have substantial magnitude of the self-disproportionation of enantiomers (SDE) via sublimation. For example, when N-phenyl-3,3,3-trifluorolactic acid amide of 87% ee was sublimed (12 h) from a Petri dish at 80 °C open to the atmosphere, the enantiomeric excess of the remainder increased to 96% ee. On the other hand, when a sample of the same compound of 67% ee was subjected to SDE via sublimation under the same conditions, the enantiomeric excess has decreased to 18% ee. These preliminary results as well as excellent chemical and physico-chemical characteristics of these amide derivatives render them as readily available and very promising substrates for systematic study of SDE via sublimation.

NMR and molecular modeling of the dimeric self-association of the enantiomers of 1,1′-bi-2-naphthol and 1-phenyl-2,2,2-trifluoroethanol in the solution state and their relevance to enantiomer self-disproportionation on achiral-phase chromatography (ESDAC)

Molecular modeling of the homo- and heterochiral dimeric self-associates of the enantiomers of 1,1'-bi-2-naphthol and 1-phenyl-2,2,2-trifluoroethanol in solution has been performed in order to understand their NMR behavior and in light of the phenomenon of "enantiomer self-disproportionation on achiral-phase chromatography" (ESDAC). For 1,1'-bi-2-naphthol in C(6)D(6), distinct NMR signals for each enantiomer arise for some spins in non-racemic mixtures-the phenomenon of self-induced diastereomeric anisochronism (SIDA). The linear divergence of these split signals across an enantiomeric titration (a series of samples in which the percentage of one enantiomer is varied from 50-100% whilst maintaining a constant total concentration), as well as the near linear migration of certain signals in CDCl(3) across a similar enantiomeric titration, where signals were not observed to be split, is consistent with the calculated small energy differences between the homo- and heterochiral associates. For an enantiomeric titration of 1-phenyl-2,2,2-trifluoroethanol in n-hexane, NMR signals also remained unsplit but the noticeable migration of some revealed a skew indicative of a preference for the heterochiral associate. This was duly reflected in the calculations which provided a DeltaG value favoring the heterochiral associate by 2.4 kJ mol(-1). The relevance of these results to evaluating the likely occurrence of ESDAC is considered.

Enantiomer self‐disproportionation of chiral compounds on achiral ordered mesoporous silica M41S and regular silica gel as a stationary phase

Chromatographic behavior of nonracemic mixtures, viz., mandelic acid and stilbene oxide as analytes has been studied in detailed by enantiomer self-disproportionation on achiral ordered mesoporous material M41S and regular silica gel as stationary phases. Enantiomer self-disproportionation gave enhanced separation of analytes. The extent and magnitude of enantiomer self-disproportionation is dependent on the optical purity of the starting non-racemic molecules, presence of intermolecular hydrogen bonding/pi-pi interactions and the nature of eluents used. The present study and previous literature data suggest that percentage ee of a nonracemic mixture needs to be determined before any chromatographic purification is taken up as enantiomer self-disproportionation phenomenon could occur during purification. The data show that enantiomer self-disproportionation of nonracemic mixtures can be harnessed for its enantioenrichment on inexpensive achiral stationary phases.

Remarkable Amplification of the Self‐Disproportionation of Enantiomers on Achiral‐Phase Chromatography Columns

Getrennte Wege: Die Enantiomere von chiralen Verbindungen, in denen eine Trifluormethylgruppe direkt an ein stereogenes Kohlenstoffatom gebunden ist, neigen stark zur Selbstdisproportionierung auf Säulen aus achiralem Kieselgel (siehe Bild). Daher sollten alle F-haltigen chiralen Reagentien und Wirkstoffe, ebenso wie Literaturdaten zum stereochemischen Resultat asymmetrischer Umwandlungen mit F-haltigen Verbindungen, nochmals überprüft werden.

Self-disproportionation of enantiomers of ( R)-ethyl 3-(3,5-dinitrobenzamido)-4,4,4-trifluorobutanoate on achiral silica gel stationary phase

The very unusual phenomenon of separation of enantiomers by self-disproportionation on achiral silica gel stationary phase has been studied in detail using ( R)-ethyl 3-(3,5-dinitrobenzamido)-4,4,4-trifluorobutanoate as an example. The appearance and magnitude of self-disproportionation were shown by this study to depend on the optical purity of the starting compounds and the nature (polarity) of an eluent used. Based on the results described by us and on previous literature data we conclude that it is not safe to assume that any type of chromatography is a reliable method for purification of non-racemic mixtures for determination of their enantiomeric purities. We recommend that chemists dealing with non-racemic compounds should first run an ESD-test (enantiomer self-disproportionation test) proposed herein before using chromatography for any purification. Moreover, one of the serious consequences of our finding is that all fluorine-containing chiral reagents and drugs, which are currently on the market, as well as all previously reported literature data on the stereochemical outcome of asymmetric transformations involving fluorine-containing compounds, should be carefully re-evaluated if column chromatography on silica gel was involved as a purification step.