Institut de Chimie Moléculaire et des Matériaux d'Orsay

Laboratoire de RMN en milieu orienté - LRMN

Email: Nicolas Giraud

Nicolas Giraud
Toward Enantiomeric Discrimination in Chiral Liquid Crystalline Solvent by NMR

PROTON NMR IN CHIRAL LIQUID CRYSTALS:

Nuclear Magnetic Resonance is a particularly well suited tool to study molecules which are dissolved in liquid crystals (1) : whereas intermolecular interactions from the spin Hamiltonian are averaged to zero by the translational and rotational diffusion of organic molecules from the mesophase, anisotropic intramolecular interactions are only partially averaged by molecular dynamics and, in the case of a uniaxial phase, reduced to a single – order sensitive – value for every molecule in the sample.(2) 

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 These anisotropic measurements (mainly dipolar or quadrupolar couplings, or even chemical shift anisotropy which is weaker) have been successfully used to probe both the structure and the dynamics of molecules solvated in liquid crystals, and have notably led to the quantization of the difference in orientation between enantiomers diluted in a chiral liquid crystal, which results from diastereomeric interactions between the solute and the anisotropic solvent : the best results so far have been obtained using a lyotropic liquid crystal composed of poly-(γ-benzyl)-L-glutamate (PBLG) dissolved in various -non denaturing- organic solvents. This chiral differentiation process can be monitored through either 2H - {1H}, 13C - {1H}, 1H coupled 13C, or even natural abundance 2H - {1H} NMR spectra.(3-6)

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 However, because of numerous long-range dipolar couplings, proton spectra of enantiomers, though resulting from the most sensitive experiments, are usually overcrowded, and coupling fine structures are generally not resolved, which makes proton NMR useless as such in that field.  



HOMONUCLEAR SELECTIVE REFOCUSING SPECTROSCOPY: 2D SERFph EXPERIMENT:

Our group is studying in what extent it is possible to simplify proton spectra, and enhance their resolution, to a point where the accurate measurement of enantiomeric excesses is reachable. We have shown how the use of homonuclear selective refocusing 2D NMR experiments (SERF), which was initially developed by Fäcke and Berger (7), and extensively studied since then, allows us to extract the coupling between proton spins at given resonance frequencies, out of their whole coupling network, in small chiral organic compounds. (8) 

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 In order to gain resolution, we have added to the SERF sequence (which is based on the well known J-resolved approach) a z gradient filter before the acquisition, which allows to defocus every antiphase single-quantum coherence, and only retains the in-phase coherences which have evolved during t1, yielding a -phaseable- SERFph pulse sequence. Notably, we demonstrate that the two refocusing pulses can be applied successively, under some specific experimental conditions, preventing coherence transfers during double irradiation, and thus yielding better sensitivity than the initial pulse sequence.
 However, different artefacts are inherent to the initial sequence when consecutive semi-selective refocusing pulses are used. First the signal is modulated by the evolution during the semi-selective pulse on the X nucleus. Second zero quantum coherences evolve during the initial non selective z gradient filter. This two sideband effects lead up to a signal which is in part of absorption and dispersion. To greatly improve the sensitivity, and obtain pure absorption lineshapes on the resulting phased 2D map, we show that it is necessary to add a π refocusing pulse and a zero quantum filter.

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 Finally, we show that it is possible to apply this approach to oriented samples, and increase the quality of the resulting spectra by optimizing the selective excitation and refocusing pulses, as well as the phase and gradient cyclings of this SERFph pulse sequence. (9) 



APPLICATION OF SAMPLE SPATIAL ENCODING AND SELECTIVE ECHOES TO 2D δ-RESOLVED NMR SPECTROSCOPY:

We also have recently developed an approach which consists in using pulsed field gradients as a tool to handle individually proton spins coherences in different parts of the NMR sample. Our goal is to apply this concept in order to edit any relevant NMR information (chemical shift, couplings ...) along the NMR tube (or rotor). Schematically, the combination of a π/2 pulse with a z field gradient induces a frequency sweep, which allows to encode the sample spatially along its z-axis: schematically, each spin of the molecule is individually excited in one "slice" of the sample.

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 In this context, we have applied an experiment, which was initially implemented by Zangger and Sterk (10) for the indirect acquisition of proton broadband homodecoupled spectra, to the visualisation of the differences in proton chemical shift anisotropy between enantiomers which are interacting with a chiral environment. We have implemented an enhanced -phased- version of this pulse sequence: the resulting 2D δ-resolved spectra allow to discriminate enantiomers when the variation of the proton chemical shift anisotropy is measurable.

Principle of the delta-resolved experiment

 We have used an enhanced pulse sequence of this "δ-resolved" experiment to probe two chiral differentiation processes. Firstly, we use a lanthanide complex as a chiral shift reagent, and we probe its interaction with racemic isoborneol:delta-res isoborneol Secondly, we exploit the differential ordering effect on enantiomers of butynol of a chiral liquid crystalline solvent composed of Poly-(γ-Benzyl)-L-Glutamate dissolved into deuterated chloroform (PBLG/CDCl3):delta-res butynol

For each sample, within one single 2D δ-resolved spectrum, we show that it is possible to probe the chiral differentiation process through every proton chemical shift where the variation in the chemical shift between each enantiomer is detectable.(11)



2D FREQUENCY-SWEPT SERFph EXPERIMENT: PURE J-RESOLVED SPECTROSCOPY ALONG THE NMR SAMPLE:

We have applied this concept of creating a sample spatial encoding to a further development of the homonuclear SERF pulse sequence, which we call G-SERFph (for phaseable Gradient encoded homonuclear SElective ReFocusing spectroscopy). This sequence is also based on the use of semi-selective excitations and refocusing pulses in the presence of field gradients: each coupling which involves a given proton from the molecule is selected on the basis of the proton chemical shift of the coupling partner, and evolves in an individual "slice" of the sample.

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  We have applied this approach to a model enantiomeric organic compound (propylene oxide dissolved in PBLG/CDCl3), and we observe on the resulting spectrum an edition of multiplets which all involve the selected proton spin.

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 These multiplets appear at the resonance frequencies from every other protons to which it is coupled: we show that this pulse sequence allows the observation of enantiomeric discrimination between both enantiomers dissolved in the PBLG/CDCl3 chiral liquid crystalline phase.(12)



References
(1) Dong, R. Y., Nuclear Magnetic Resonance of Liquid Crystals (Partially Ordered Systems), Springer-Verlag Berlin 1994, Ed. Springer-Verlag.
(2) Emsley, J.W., Nuclear Magnetic Resonance of Liquid Crystals, Kluwer Academic Publishers1984, D Reidel Pub Co.
(3) Merlet, D.; Ancian, B.; Courtieu, J.; Lesot, P., 1999, J. Am. Chem. Soc., 121, (22), 5249
(4) Sarfati, M.; Courtieu, J.; Lesot, P., Chem. Comm. 2000, (13), 1113-1114.
(5) Canet, I.; Courtieu, J.;Loewenstein, A.; Meddour, A.; Péchiné, J.M., 1995, J. Am. Chem. Soc., 117, 6520
(6) Meddour, A.; Berdague, P.; Hedli, A.; Courtieu, J.; Lesot, P., 1997, J. Am. Chem. Soc., 119, 4502
(7) Fäcke, T. and Berger,
S., J. Magn. Reson. 1995, 113, 114-116.
(8) Béguin, L. ; Courtieu, J. ; Ziani, L. ; Merlet, D., Magn. Reson. Chem. 2006, (44), 1096-1101.
(9) Béguin, L., Giraud, N., Ouvrard, JM., Courtieu, J. and Merlet, D. J. Magn. Res. 2009.
(10) Zangger, 
K. and Sterk., H. J. Magn. Reson. 1997, 124, 486-489.
(11) Giraud, N., Joos, M., Courtieu, J. and Merlet, D., Magn. Res. Chem. 2009.
(12) Giraud, N., Béguin, L., Courtieu, J. and Merlet, D. 2009, submitted.



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