2 H QUOSY 2D-NMR Experiments in Weakly Aligning Systems: From the Conventional to the Ultrafast Approach.

We describe three anisotropic ultrafast (UF) QUadrupolar Ordered SpectroscopY (QUOSY) 2D-NMR experiments (referred to as ADUF 2D NMR spectroscopy) designed for recording the 2 H homonuclear 2D spectra of weakly aligned (deuterated) solutes in sub-second experiment times. These new ADUF 2D experiments derive from the Q-COSY, Q-resolved and Q-DQ 2D pulse sequences (J. Am. Chem. Soc. 1999, 121, 5249) and allow the correlation between the two components of each quadrupolar doublet, and then their assignment on the basis of 2 H chemical shifts. The UF 2D pulse sequences are analyzed by using the Cartesian spin-operator formalism for spin I=1 nuclei with a small quadrupolar moment. The optimal experimental/practical conditions as well as the resolution, sensitivity and quantification issues of these ADUF 2D experiments are discussed on comparison to their conventional 2D counterparts and their analytical potentialities. Illustrative ADUF 2D experiments using deuterated achiral/prochiral/chiral solutes in poly-γ-benzyl-L-glutamate based chiral liquid crystals are presented, as well as the first examples of natural abundance deuterium (ANADUF) 2D spectrum using 14.1 T magnetic field and a basic gradient unit (53 G.cm-1 ) in oriented solvents.

Multinuclear NMR in polypeptide liquid crystals: Three fertile decades of methodological developments and analytical challenges.

NMR spectroscopy of oriented samples makes accessible residual anisotropic intramolecular NMR interactions, such as chemical shift anisotropy (RCSA), dipolar coupling (RDC), and quadrupolar coupling (RQC), while preserving high spectral resolution. In addition, in a chiral aligned environment, enantiomers of chiral molecules or enantiopic elements of prochiral compounds adopt different average orientations on the NMR timescale, and hence produce distinct NMR spectra or signals. NMR spectroscopy in chiral aligned media is a powerful analytical tool, and notably provides unique information on (pro)chirality analysis, natural isotopic fractionation, stereochemistry, as well as molecular conformation and configuration. Significant progress has been made in this area over the three last decades, particularly using polypeptide-based chiral liquid crystals (CLCs) made of organic solutions of helically chiral polymers (as PBLG) in organic solvents. This review presents an overview of NMR in polymeric LCs. In particular, we describe the theoretical tools and the major NMR methods that have been developed and applied to study (pro)chiral molecules dissolved in such oriented solvents. We also discuss the representative applications illustrating the analytical potential of this original NMR tool. This overview article is dedicated to thirty years of original contributions to the development of NMR spectroscopy in polypeptide-based chiral liquid crystals.

2 H and 13 C NMR-Based Enantiodetection Using Polyacetylene versus Polypeptide Aligning Media: Versatile and Complementary Tools for Chemists.

In this work, the practical/analytical potential of an L-valine-derived polyacetylene (PLA) lyotropic liquid crystal (LLC) is examined to spectrally discriminate enantiomers (racemic mixture) or enantiotopic directions of a large collection (23) of (pro)chiral model compounds (from rigid to flexible and polar to apolar ones), thus covering various important aspects of enantiomorphism. Experimental 2 H-{1 H} (deuterated analytes and at natural abundance level) and 13 C-{1 H} NMR results are discussed in terms of the difference of 2 H-RQCs or 13 C-RCSAs and compared to those obtained in polypeptide-type LLCs (PBLG). The analysis of the NMR results provides an overview of the enantiodifferentiation capabilities of PLA and gives useful/practical hints for the chemist to select the most appropriate chiral oriented system. Astonishing NAD NMR results were obtained in the case of one of the simplest, chiral alkanes, 3-methylhexane. From a theoretical viewpoint, the data collected highlight the key molecular factors involved in orientation/discrimination processes, as a basis for optimizing computational prediction (molecular dynamics simulation), as well as designing novel helically chiral polymers as new enantiodiscriminating aligning media. In addition, a new, robust and efficient protocol to synthesize PLA and its enantiomer (PDA) on a large scale and with small polydispersities is proposed.

2 H and 13 C NMR-Based Enantiodetection Using Polyacetylene versus Polypeptide Aligning Media: Versatile and Complementary Tools for Chemists.

Invited for this month's cover are the collaborating groups of Dr. Philippe Lesot (DR CNRS) at Université Paris-Sud/Université Paris-Saclay, France, and Professor Michael Reggelin at TU Darmstadt, Germany. The cover shows the proton-decoupled natural abundance deuterium (NAD-{1 H}) Q-resolved Fz 2D-NMR spectrum of (±)-3-methylhexane measured in the anisotropic lyotropic chiral liquid-crystalline phase formed by a concentrated solution of a helically chiral polyarylacetylene in chloroform solvent. Seventeen out of the twenty possible deuterium quadrupolar doublets are observed, demonstrating the enormous enantiodifferentiating capability of the system, even for an unfunctionalized chiral alkane. Read the full text of the article at 10.1002/cplu.201800493.

Chiral solutes can seed the formation of enantiomorphic domains in a twist-bend nematic liquid crystal.

The twist-bend nematic, an enantiomorphic liquid-crystalline phase, exhibited by the structurally symmetric liquid-crystal dimer CB7CB is induced to form a single domain of uniform handedness, in the bulk, by the addition of the dopant chiral solute (S)-1-phenylethanol. Addition of a nonracemic (or scalemic) mixture of both R and S enantiomers of this solute produced equal volumes of P and M chiral domains for the twist-bend nematic phase. This seeding of the domains in an enantiomorphic nematic conglomerate is revealed using deuterium NMR spectroscopy.

The use of exchangeable nuclei to observe enantiomers through deuterium NMR in chiral liquid crystalline solvents.

It is demonstrated that (2)H NMR in chiral liquid crystalline solvents can be used to measure enantiomeric excesses using exchangeable deuterons in alcohols. This is performed in a trivial way at low temperature (260-270 K) where a slow exchange regime was reached. Among the various alcohols used to explore the possibilities of this technique, an unusually large isotopic effect on molecular orientation between two isotopomers has been observed.

On the elucidation of the mechanism of Vinca alkaloid fluorination in superacidic medium.

Detailed investigations on one of the key steps of the superacidic fluorination of Vinca alkaloids that is the origin of C20' activation are reported. While two different pathways can be envisioned for the emergence of the transient secondary carbocationic intermediate, isotopic labeling experiments unambiguously revealed the involvement of a 1,2-hydride shift mechanism.

Enantioselective intramolecular hydroamination catalyzed by lanthanide ate complexes coordinated by N-substituted (R)-1,1'-binaphthyl-2,2'-diamido ligands.

Ytterbium and lutetium ionic complexes derived from enantiopure substituted (R)-binaphthylamine ligands, of the general formula [Li(THF)n][Ln[(R)-C20H12(NR)2]2], have been investigated for the hydroamination/cyclization of several aminopentenes and an aminohexene. Complexes with isopropyl or cyclohexyl substituents on nitrogen atoms were found to be efficient catalysts under mild conditions for the formation of N-containing heterocycles with enantiomeric excesses up to 78%.

Enzymatic fluorination in Streptomyces cattleya takes place with an inversion of configuration consistent with an SN2 reaction mechanism.

The stereochemical course of the recently isolated fluorination enzyme from Streptomyces cattleya has been evaluated. The enzyme mediates a reaction between the fluoride ion and S- adenosyl-L-methionine (SAM) to generate 5'-fluoro-5'-deoxyadenosine (5'-FDA). Preparation of (5'R)-[5-(2)H(1)]-ATP generated (5'R)-[5-(2)H(1)]-5'-FDA in a coupled enzyme assay involving SAM synthase and the fluorinase. The stereochemical analysis of the product relied on (2)H NMR analysis in a chiral liquid-crystalline medium. It is concluded that the enzyme catalyses the fluorination with an inversion of configuration consistent with an S(N)2 reaction mechanism.

Assay for the enantiomeric analysis of [2H1]-fluoroacetic acid: insight into the stereochemical course of fluorination during fluorometabolite biosynthesis in streptomyces cattleya.

A sensitive method for the configurational analysis of (R)- and (S)-[2H1]-fluoroacetate has been developed using 2H[1H]-NMR in a chiral liquid crystalline solvent. This has enabled biosynthetic experiments to be conducted which reveal stereochemical details on biological fluorination occurring during the biosynthesis of fluoroacetate and 4-fluorothreonine in the bacterium Streptomyces cattleya. In particular, feeding experiments to S. cattleya with isotopically labeled (1R, 2R)- and (1S, 2R)-[1-2H1]-glycerol 3d and 3e and [2,3-2H(4)]-succinate 4a gave rise to samples of enantiomerically enriched [2-2H1]-fluoroacetates 1a. The predominant enantiomer resulting from each experiment suggests that the stereochemical course of biological fluorination takes place with an overall retention of configuration between a glycolytic intermediate and fluoroacetate 1. Consequently, this outcome suggests that the stereochemical course of the recently identified fluorinase enzyme which mediates a reaction between fluoride ion and S-adenosyl-l-methionine (SAM), occurs with an inversion of configuration.

Monitoring the differential ordering of enantiomers included into cyclodextrins through deuterium NMR in lyotropic liquid crystals.

Deuterium NMR in an aqueous non-chiral liquid crystal allows the discrimination of enantiomers through their ordering inside beta-cyclodextrins.

Extreme enantiomeric discrimination of fluoroalkanes using deuterium NMR in chiral liquid crystalline media.

The enantiomeric assay of fluoroalkanes using 2H-NMR in a chiral liquid crystalline medium is demonstrated, and at its limit the enantiomers of [5-(2)H]-5-fluorodecane were successfully resolved.

Synthesis and Solution State Characterization by Gradient-Enhanced 2D Multinuclear NMR Spectroscopy of a Fluorine-Bridged Dimethyltin(IV) Salicylaldoximate Derivative.

The reaction of [(Me(2)Sn)(2)(Me(2)SnO)(ONZOH)(HONZO)(ONZO)] (HONZOH = o-HON=CHC(6)H(4)OH, salicylaldoxime) with ammonium fluoride yields a fluorotris(dimethyltin) disalicylaldoximate complex, compound 4, containing one seven-coordinate and two five-coordinate tin atoms, with a fluoride anion bridging the five-coordinate tin atoms. Though 4 can be obtained in a crystalline form, its crystals are unsuitable for X-ray analysis. Its structure has been completely characterized in solution by 1D (1)H, (13)C, (119)Sn, and (19)F NMR spectra and 2D gradient-assisted (1)H-(119)Sn and (1)H-(13)C HMQC and HMBC NMR spectra. In solution, 4 is involved in an equilibrium with several species. It is shown that the Sn(2)-F-Sn(3) moiety of 4 is the reactive site amenable to nucleophilic substitution with weak nucleophiles like water and methanol. The preservation of the splitting of the (1)J((119/117)Sn(3)-(19)F) coupling but not the (1)J((119/117)Sn(2)-(19)F) coupling evidences a reaction intermediate where the entering nucleophile is bound to the Sn(2) tin atom whereas the fluorine is still linked to the Sn(3) atom. Overall, &mgr;(2)-nucleophilic substitutions on compound 4 with hydroxylated nucleophiles should be viewed as addition-elimination reactions.