Enantiomeric excess measurements in weakly oriented chiral liquid crystal solvents through 2D H selective refocusing experiments

In this article, a simple and robust method is proposed for simplifying the analysis of proton spectra of molecules dissolved in weakly oriented chiral media. The NMR approach investigated is based on the use of proton selective refocusing 2D experiments (SERF) to measure proton–proton dipolar couplings from unresolved lines. This technique is applied to the case of enantiomers dissolved in chiral polypeptide liquid crystals. It is shown that an accurate determination of enantiomeric excess is possible within a short experimental time.     

Visualisation of enantiomers via insertion of a BIRD module in X-H correlation experiments in chiral liquid crystal solvent

Several 13C-1H NMR techniques are derived simplifying the visualisation of enantiomers in chiral ordering solvents. They proceed through various heteronuclear 2D experiments where a bilinear rotation decoupling sequence (BIRD) is inserted in the middle of the t1 evolution period. In this way, the small couplings are refocused while the large couplings are preserved. The methods allow extracting precise values of one-bond carbon-proton residual dipolar couplings for each enantiomer out of unresolved proton-coupled 13C or carbon-coupled 1H spectra. Illustrative examples are analysed and discussed using various pulse sequences.     

Application of z-COSY experiment and its variant for accurate chiral discrimination by 1H NMR

We report the application of z-COSY experiment and a band selected version of it by employing a selective 90° pulse entitled BASE-z-COSY for precise chiral discrimination, quantification of enantiomeric excess and the analyses of the ¹H NMR spectra of chiral molecules aligned in the chiral liquid crystalline solvent poly-γ-benzyl-l-glutamate (PBLG). We have demonstrated their applicability for obtaining very high resolution in the ¹H NMR spectra of small organic molecules. It is well known that the commonly employed z-COSY experiment disentangles the spectral complexity, provides pure phase spectra with high resolution, aids in the complete spectral analyses, in addition to yielding information on relative signs of the couplings. The BASE-z-COSY experiment possesses all these properties, permits the measure of enantiomeric excess, in addition to large saving of instrument time.     

Chemical shift anisotropy edited complete unraveling of overlapped 1H NMR spectra of enantiomers: application to small chiral molecules

The differential values of NMR spectral parameters like chemical shift anisotropies, dipolar couplings and quadrupolar couplings of enantiomers in chiral liquid crystalline media are employed not only for their visualization but also for their quantification. Large differences in chemical shift anisotropies and the quadrupolar couplings between the enantiomers enable the use of 13C and extensive 2H NMR detection for such a purpose. In spite of high magnetic moment, high sensitivity and abundant presence of protons in all the chiral molecules, 1H detection is not routinely employed due to severe overlap of unresolved transitions arising from short and long distance couplings. Furthermore, the doubling of the spectra from two enantiomers and their indistinguishable overlap due to negligible difference in chemical shift anisotropies hampers their discrimination. The present study demonstrates the use of proton chemical shift anisotropy as an exclusive parameter for such a discrimination. The method employs the non-selective excitation of homonuclear Nth quantum coherence of N coupled protons. The simultaneous flipping of all the coupled spins results in a single transition in the multiple quantum dimension at the cumulative sum of their anisotropic chemical shifts for each enantiomer, with the measurable difference between them, resulting in their complete unraveling.     

Coherently controlled asymmetric synthesis with achiral light

A laser-based method of increasing the enantiomeric excess of a chiral enantiomer in a racemic mixture is described. Neither the initial reagents nor the incident light need be chiral. Both formal and computational results show that enhancement of the enantiomer of choice, controlled by laser parameters, can be extensive.     

Spin state selective coherence transfer: a method for discrimination and complete analyses of the overlapped and unresolved 1H NMR spectra of enantiomers

In general, the proton NMR spectra of chiral molecules aligned in the chiral liquid crystalline media are broad and featureless. The analyses of such intricate NMR spectra and their routine use for spectral discrimination of R and S optical enantiomers are hindered. A method is developed in the present study which involves spin state selective two dimensional correlation of higher quantum coherence to its single quantum coherence of a chemically isolated group of coupled protons. This enables the spin state selective detection of proton single quantum transitions based on the spin states of the passive nuclei. The technique provides the relative signs and magnitudes of the couplings by overcoming the problems of enantiomer discrimination, spectral complexity and poor resolution, permitting the complete analyses of the otherwise broad and featureless spectra. A non-selective 180 degrees pulse in the middle of MQ dimension retains all the remote passive couplings. This accompanied by spin selective MQ-SQ conversion leads to spin state selective coherence transfer. The removal of field inhomogeneity contributes to dramatically enhanced resolution. The difference in the cumulative additive values of chemical shift anisotropies and the passive couplings, between the enantiomers, achieved by detecting Nth quantum coherence of N magnetically equivalent spins provides enhanced separation of enantiomer peaks. The developed methodology has been demonstrated on four different chiral molecules with varied number of interacting spins, each having a chiral centre.     

(1)H-(13)C INEPT MAS NMR correlation experiments with (1)H-(1)H mediated magnetization exchange to probe organization in lipid biomembranes

Two-dimensional (1)H-(13)C INEPT MAS NMR experiments utilizing a (1)H-(1)H magnetization exchange mixing period are presented for characterization of lipid systems. The introduction of the exchange period allows for structural information to be obtained via (1)H-(1)H dipolar couplings but with (13)C chemical shift resolution. It is shown that utilizing a RFDR recoupling sequence with short mixing times in place of the more standard NOE cross-relaxation for magnetization exchange during the mixing period allowed for the identification and separation of close (1)H-(1)H dipolar contacts versus longer-range inter-molecular (1)H-(1)H dipolar cross-relaxation. These 2D INEPT experiments were used to address both intra- and inter-molecular contacts in lipid and lipid/cholesterol mixtures.     

NMR Studies of Drugs. Applications of Achiral and Chiral Wthanide Shift Reagents to Bupropion

Abstract

The ¹H NMR spectra of racemic samples of the antidepressant drug, bupropion, 1, have been studied in CDCl₃ solution at 60 and 200 MHz with the achiral lanthanide shift reagent (LSR), tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium (III), 2, and the chiral reagent, tris[3-(heptafluoropropylhydroxymethylene)-d-camphorato]europium(III), 3. Both LSR produced substantial lanthanide induced shifts consistent with ¹H assignments, but the bound complexes of 1 with 2 versus 3 may not be isostructural. With 3, substantial enantiomeric shift differences were observed for the t-butyl, CH ₃CH, NCH, and the aryl H-2 and H-6 signals, which should permit potential direct determination of enantiomeric excess.     

葡糖衍生手性N-杂环卡宾前体波谱学数据分析

以溴代正丁烷与1-（2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖基）咪唑（化合物1）为原料合成了溴化1-（2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖基）-3-正丁基咪唑盐（化合物2）,它是葡萄糖衍生的手性N-杂环卡宾前体.化合物2的结构中存在多个手性碳原子,导致它的核磁共振（NMR）谱较为复杂.在此,用元素分析、红外吸收光谱（IR）以及液相色谱-高分辨质谱（LC-HRMS）对它的组成进行了分析,然后利用1D和2D NMR谱（包括¹H NMR、¹³C NMR、DEPT135、DEPT90、DEPT45、COSY、¹H-¹³C HSQC、¹H-¹³C HMBC）对化合物2的¹H和¹³C NMR信号进行了归属.     

NMR Studies of Drugs. Applications of Lanthanide Shift Reagents to Afloqualone,an Axially Chiral Quinazolinone.

The skeletal muscle relaxant, aflogualone, 1, has been studied by ¹H NMR in CDC1₃ at 60 and 300 MHz in the presence of added chiral [Eu(HFC)₃] or achiral [Eu(FOD)₃] lanthanide shift reagents (LSR). With Eu(HFC)₃, significant enantiomeric shift differences, ΔΔδ, can be induced for most of the nuclei of 1, with near-baseline resolution obtainable for the H-5 signals of each enantiomer, indicating excellent analytical potential for direct determination of enantiomeric excess of samples of 1. Observation of ΔΔδ directly confirms hindered rotation about the bond between N (3) and the 2-methylphenyl group, i.e., the N (sp²) - C(sp²) bond, leading to axial chirality in 1 with slow rotation on the NMR timescale. Assignments are supported by 2D COSY spectra at 300 MHz. Relative lanthanide-induced shift magnitudes for the protons of 1 are compared.     

Selective detection of single-enantiomer spectrum of chiral molecules aligned in the polypeptide liquid crystalline solvent: Transition selective one-dimensional 1H–1H COSY

One-dimensional (1D) proton NMR spectra of enantiomers are generally undecipherable in chiral orienting poly-γ-benzyl-l-glutamate (PBLG)/CDCl₃ solvent. This arises due to large number of couplings, in addition to superposition of spectra from both the enantiomers, severely hindering the ¹H detection. On the other hand in the present study the benefit is derived from the presence of several couplings among the entire network of interacting protons. Transition selective 1D ¹H–¹H correlation experiment (1D-COSY) which utilizes the coupling assisted transfer of magnetization not only for unraveling the overlap but also for the selective detection of enantiopure spectrum is reported. The experiment is simple, easy to implement and provides accurate eanantiomeric excess in addition to the determination of the proton–proton couplings of an enantiomer within a short experimental time (few minutes).     

Spin-spin coupling edition in chiral liquid crystal NMR solvent

The application of the G-SERFph pulse sequence is presented on enantiomeric mixtures dissolved in a chiral liquid crystal. It aims at editing, within one single 2D spectrum, every proton coupling which is experienced by a given proton site in the molecule, and leads to real phased T-edited spectroscopy (T=J+2D). This NMR experiment is based on the combination of homonuclear semi-selective refocusing techniques with a spatial frequency encoding of the sample. This approach, which consists in handling selectively each coupling in separate cross sections of the sample, is applied to the visualization of enantiomers dissolved in a chiral liquid crystalline phase. Advantages and limits of this methodology are widely discussed.     

A computer simulation study of racemic mixtures

A simple model for a chiral molecule is proposed. The model consists of a central atom bonded to four different atoms in tetrahedral coordination. Two different potentials were used to describe the pair potentials between atoms: the hard sphere potential and the Lennard-Jones potential. For both the hard sphere and the Lennard-Jones chiral models, computer simulations have been performed for the pure enantiomers and also for the racemic mixture. The racemic mixture consisted of an equimolar mixture of the two optically active enantiomers. It is found that the equations of state are the same, within statistical uncertainty, for the pure enantiomer fluid and for the racemic mixture. Only at high pressures does the racemic mixture seem to have a higher density, for a given pressure, than the pure enantiomer. Concering the structure, no difference is found in the site-site correlation functions between like and unlike molecules in the racemic mixture either at low or at high densities. However, small differences are found for the site-site correlations of the pure enantiomer and those of the racemic mixtures. In the Lennard-Jones model, similar conclusions are drawn. The extension of Wertheim's first-order perturbation theory, denoted bonded hard sphere theory (ARCHER, A. L., and JACKSON, G., 1991, Molec. Phys., 73, 881; AMOS, M. D., and JACKSON, G., 1992, J. chem. Phys., 96, 4604), successfully reproduces the simulation results for the hard chiral model. Virial coefficients of the hard chiral model up to the fourth have also been evaluated. Again, no differences are found between virial coefficients of the pure fluid and of the racemic mixture. All the results of this work illustrate the quasi-ideal behaviour of racemic mixtures in the fluid phase.     

核磁共振光谱法测定(S)-(-)-α-苯乙胺的对映体纯度

以 (2R ,3R) 二苯甲酰酒石酸为手性溶解剂 ,用1HNMR的方法测定了 (S) (- ) α 苯乙胺样品的对映体纯度。以氘代氯仿为溶剂 ,当样品浓度为 0 0 5 1mol·L-1,手性溶解剂与样品的摩尔比为 0 33时 ,α 苯乙胺甲基双峰的化学位移不等价为 0 0 8ppm(基线分离 )。由甲基吸收峰的面积可以计算样品的对映体纯度。测量结果的相对标准偏差与样品的对映体纯度有关 ,当样品的ee值高达 99 1%时 ,RSD为 0 3 % (n =4)。     

High-resolution heteronuclear correlation spectroscopy in solid state NMR of aligned samples

A new two-dimensional scheme is proposed for accurate measurements of high-resolution chemical shifts and heteronuclear dipolar couplings in NMR of aligned samples. Both the (1)H chemical shifts and the (1)H-(15)N dipolar couplings are evolved in the indirect dimension while the (15)N chemical shifts are detected. This heteronuclear correlation (HETCOR) spectroscopy yields high-resolution (1)H chemical shifts split by the (1)H-(15)N dipolar couplings in the indirect dimension and the (15)N chemical shifts in the observed dimension. The advantages of the HETCOR technique are illustrated for a static (15)N-acetyl-valine crystal sample and a (15)N-labeled helical peptide sample aligned in hydrated lipid bilayers.     

Experimental aspects of multidimensional solid-state NMR correlation spectroscopy.

The experimental parameters critical for the implementation of multidimensional solid-state NMR experiments that incorporate heteronuclear spin exchange at the magic angle are discussed. This family of experiments is exemplified by the three-dimensional experiment that correlates the (1)H chemical shift, (1)H-(15)N dipolar coupling, and (15)N chemical shift frequencies. The broadening effects of the homonuclear (1)H-(1)H dipolar couplings are suppressed using flip-flop (phase- and frequency-switched) Lee-Goldburg irradiations in both the (1)H chemical shift and the (1)H-(15)N dipolar coupling dimensions. The experiments are illustrated using the (1)H and (15)N chemical shift and dipolar couplings in a single crystal of (15)N-acetylleucine.     

NMR Studies of Drugs. Application of a Chiral Lanthanide Shift Reagent for Potential Direct Determination of Enantiomeric Excess of Methsuximide

The 200 MHz ¹H NMR Spectra of methsuximide, 1,3-dimethy1-3-ogebt1-2,5-otrrikudubeduibem 1, havebeen studied in CDC13 solution with the chiral reagent, tris[3-(heptafluoropropy1-hydroxymethylene)-d-camphorato] europium (III), 2, Eu(HFC)3. Substantial lanthanide-induced shifts are seen. In addition, significant enantiomeric shift differences are observed for several of the nuclei of 1. With a 2:1 molar ratio near 1.0, the CCH3 and NCH3 signals show nearly baseline resolution between the peaks from each enantiomer, providing excellent potential for direct determinations of enantiomeric excess of samples of 1. As little as 2% of a minor enatiomer should be readily detectable.     

果糖二丙酮的结构全归属

2,3：4,5-双-O-（1-甲基亚乙基）-β-D-吡喃果糖又称为果糖二丙酮（diacetonefructose）,是一类重要的药物合成中间体,它是抗癫痫药物托吡酯中的母体部分,在药物合成中具有重要的作用.果糖二丙酮结构中含有手性碳原子,核磁共振（NMR）谱图较为复杂,本文首先应用¹H NMR、¹³C NMR、DEPT135、¹H-¹³C HMBC、¹H-¹³C HSQC、¹H-¹H COSY和NOESY实验对果糖二丙酮的¹H和¹³C NMR信号进行了指认归属,确定了其空间构型.然后,利用计算化学的方法对其结构进行了模拟,进一步佐证了该构型的正确性.     

Theoretical and experimental investigation of (13)C relayed (2)H-(2)H-COSY 2D experiments: application to the analysis of weakly aligned solutes

We describe new NMR 2D experiments denoted DECADENCY for DEuterium CArbon DEuterium Nuclear Correlation spectroscopY dedicated to the analysis of anisotropic deuterium spectra. They belong to the class of X-relayed Y,Y-COSY 2D experiments that was initially explored in the case of a (1)H-X-(1)H fragment (I(X)=1/2) in isotropic medium. DECADENCY 2D experiments permit to correlate the quadrupolar doublets associated with two inequivalent deuterium nuclei in an oriented CD(2) fragment through heteronuclear polarization transfers. Two kinds of pulse sequences are described here using either a double INEPT-type or DEPT-type process. DECADENCY 2D experiments provide an interesting alternative to (2)H-(2)H COSY experiments when the geminal (2)H-(2)H total coupling (scalar and dipolar) is null or too small to provide visible cross-correlation peaks. Such a situation is typically observed for geminal deuteriums in prochiral or chiral molecules dissolved in chiral liquid crystals. The efficiency of these techniques is illustrated using dideuterated prochiral molecules, the phenyl[(2)H(2)]methanol and the 1-chloro[1-(2)H(2)]nonane, both dissolved in organic solutions of poly-gamma-benzyl-l-glutamate. The advantages of each sequence are presented and discussed. It is shown that the relative sign of the quadrupolar doublets can be determined.