NMR of Oriented Molecules, Fields of Research, Molecular Structure Determination


NMR Enantiomeric Analysis in Liquid Crystal Solvents.

New NMR Method for determination of enantiomeric purity and absolute configuration.

New useful NMR analytical tool for visualization of enantiomeric purity
Very sensitivity and simplicity.
Quantitative determination by peak integration.

Introduction

There are many independent methods for determination of enantiomeric purity of chiral compounds, used in chemistry. Although progress has been made in the last years in developing sensitive and accurate various methods of analysis, many practicing organic chemist traditionally use NMR methods.
There are many limitations in traditional NMR methods, which decreasing accuracy and reliability of results, and shrinking a number of organic compounds, which can be investigated by these methods.
Recently Jacques Courtieu with coworkers from the Laboratoire de Chimie Structurale Organique, Universite de Paris-Sud, France developed a new NMR tool for the measurement of enantiomeric excesses (see Reference [1-34].
All of NMR methods based on the nonequivalence of the chemical shifts of the signals, provided by different diastereotopic groups. Enantiotopic groups can be transformed (converted) to diastereotopic by internal or external influence on the investigated molecules.
Internal influence is confining by direct chemical transformation the mixture of enantiomers into the mixture of diastereomers by chiral reagent. The molecules of substrate and chiral reagent link together by covalent bond.
Diastereotopity by external influencing may be realised by:
Chiral solvating solvents and agents forms diastereoisomeric complexes with molecules of mixture of enantiomers. The origin of complex formation is the hydrogen bonding, charge transfer or ionic pair formation. The anisochronity can be distinguished by dipole-dipole or Van-der-Vaalse type interactions between molecules of chiral reagents and substrate. If substrate tends to associations, then the self induced anisochronity phenomenon may occure. One or more of these factors take place in mechanisms of chiral reagents influence.
The nature of the diastereotopy induction in liquid crystal solvent are entirely another.
The cholesteric liquid crystals are a chiral environment. The R and S enantiomers have different ordering properties in these solvents which implies that their NMR spectra are different.
Three type of NMR parameters of R and S species can be different:
All of these parameters we can not be seen in isotrope solutions, because they canceled by the chaotic motion and reordering in isotrope liquid state.
In the liquid crystal solvents these parameters may occure because the molecules of solute have a partial ordering. Only intramolecular interactions provide the change in NMR spectra, at the time that intermolecular interactions meanings to zero the corresponding NMR parameters.
Dipolar coupling constants and chemical shift anisotropy have all magnetic nuclei. Quadrupole constants have only nuclei with spins more than half. In comparing with isotropic NMR parameters (i.e. chemical shifts and indirect coupling constants) the value of anisotropic parameters are extremely bigest.
The difference between the values of these parameters for pairs of enantiomers reflect on the NMR spectra as the additional splitting or frequencies shifting of observed spectral lines. Maximal difference in values of anisotropic NMR parameters of enantioforms occure for quadrupole couplings, then for dipole-dipole couplings, and finally, for chemical shift anisotropy.

Quadrupolar Splittings of Enantiomers in Cholesteric Liquid Crystals

Quadrupolar interactions is the strongest NMR interactions and consequently are the most sensitive to the differential ordering effect of enantiomers. Each enantiomers in proton-decoupled deuterium spectra show two lines. The distance between them are the quadrupolar splittings, which are proportional to the corresponding order parameters.
For example, the quadrupolar splittings of S-enantiomers is more than 13 times differs from R-enantiomers of 2-deuterium-propionic acid [7].

Fig. 1. Proton-decoupled deuterium NMR spectrum of an R-enriched mixture of CH3-CHD-COOH enantiomers (ee 72%) dissolved in PBLG/CH2Cl2 liquid crystal at 300K [7].

Whenever deuteration is difficult, other anisotropic NMR interactions may be used.

Differencies of Dipole-dipole Couplings Constants of Enantiomers

The second strongest anisotropic interaction is the residual dipolar coupling. Unfortunately, the magnitude and the number of dipole-dipole couplings are such that the proton or carbon-13 spectra are often not resolved when the number of interacting magnetic nuclei in molecule is large.

Fig. 2. Doubled quartet associated to the methyl group of ()-S-methyl-S-P-tolyl-N-tosylsulfoximine observed on the proton coupled carbon-13 spectrum in PBLG at 300K. The peaks due to each enantiomer are labelled by (o) and (*) [14].

Differencies of Anisotropies of Chemical Shifts of Enantiomers

Fig. 3. (a) Expansion of the 13C-{1H} spectrum of -oct-1-yn-3-ol dissolved in PBLG/CDCl3 at 300K. (b)13C-{1H} spectrum of C-1 and C-2 of an R-enriched sample (87.3%) [14].

The quantitative determination of enantiomeric purity was made using peak integration.

Experimental Details

For experimental details see Jacques Courtieu page.

Solvents Some information about NMR solvent you can find in Liquid Crystal solvents for NMR spectroscopy page.

Reference

1. J.Am.Chem.Soc., 1989, 111, 21, 8294-8296. E.Lafontaine, J.P.Bayle, J.Courtieu. -High-resolution NMR in cholesteric medium: visualization of enantiomers.
2. Liq.Cryst., 1990, 7, 2, 293-298. E.Lafontaine, J.M.Pechine, J.Courtieu, C.L.Mayne.- Visualization of enantiomers in cholesteric solvents through deuterium NMR.
3. New J.Chem., 1992, 16, 8/9, 837-838. J.P.Bayle, J.Courtieu, E.Gabetti, A.Loewenstein, J.M.Pechine.- Enantiomeric analysis in a polypeptide lyotropic liquid crystal through proton decoupled deuterium NMR.
4. Tetrahedron Asymm., 1993, 4, 1, 31-34. J.L.Canet, A.Fadel, J.Salaun, I.Canet-Fresse, J.Courtieu.- Enantiomeric excess analysis of sesquiterpene precursors through proton decoupled deuterium NMR in cholesteric lyotropic liquid crystal.
5. Liq.Cryst., 1994, 16, 3, 405-412. I.Canet, J.Lovschall, J.Courtieu.- Visualization of enantiomers through deuterium NMR in cholesterics. Optimization of the chiral liquid crystal solvent.
6. J.Am.Chem.Soc., 1994, 116, 5, 2155-2156. I.Canet, A.Meddour, J.Courtieu.- New, and accurate method to determine the enantiomeric purity of amino acids based on deuterium NMR in a cholesteric lyotropic liquid crystal.
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11. Tetrahedron Asymm., 1995, 6, 2, 333-336. I.Canet, J.Courtieu, G.Dauphin, J.-G.Gourcy, H.Veschambre.- Enantiomeric excess analysis of (2R,3S)-3-deuterio-2-methylcyclohexanone and (1S,2R,3S)-3-deuterio-2-methylcyclohexanol, through deuterium NMR in a polypeptide lyotropic liquid crystal.
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Last Update: August 27th, 2001
By: Alexan Shahatuni (alexsh@msrc.am)