Achieving high resolution and optimizing sensitivity in spatial frequency encoding NMR spectroscopy: from theory to practice.

A detailed analysis of NMR spectra acquired based on spatial frequency encoding is presented. A theoretical model to simulate gradient encoded pulses is developed in order to describe the spatial properties of the NMR signals that are locally created throughout the sample. The key features that affect the efficiency of the slice selection process during excitation as well as refocusing pulses are investigated on a model ABX spin system, both theoretically and experimentally. It is shown that the sensitivity and resolution of the pure shift and J-edited experiments based on a spatial frequency encoding can be optimized to a point where high-resolution techniques based on a spatial frequency encoding approach show optimal performance compared to other methods.

Correction: Achieving high resolution and optimizing sensitivity in spatial frequency encoding NMR spectroscopy: from theory to practice.

Correction for 'Achieving high resolution and optimizing sensitivity in spatial frequency encoding NMR spectroscopy: from theory to practice' by Bertrand Plainchont et al., Phys. Chem. Chem. Phys., 2016, 18, 22827-22839.

Fully resolved NMR correlation spectroscopy.

A new correlation experiment cited as "push-G-SERF" is reported. In the resulting phased 2D spectrum, the chemical shift information is selected along the direct dimension, whereas scalar couplings involving a selected proton nucleus are edited in the indirect domain. The robustness of this pulse sequence is demonstrated on compounds with increasing structural and spectral complexity, using state-of-the-art spectrometers. It allows for full resolution of both dimensions of the spectrum, yielding a straightforward assignment and measurement of the coupling network around a given proton in the molecule. This experiment is intended for chemists who want to address efficiently the structural analysis of molecules with an overcrowded spectrum.

Fine Tuning of ß-Peptide Foldamers: a Single Atom Replacement Holds Back the Switch from an 8-Helix to a 12-Helix.

Cyclic homologated amino acids are important building blocks for the construction of helical foldamers. N-aminoazetidine-2-carboxylic acid (AAzC), an aza analogue of trans-2-aminocyclobutanecarboxylic acid (tACBC), displays a strong hydrazino turn conformational feature, which is proposed to act as an 8-helix primer. tACBC oligomers bearing a single N-terminal AAzC residue were studied to evaluate the ability of AAzC to induce and support an 8-helix along the oligopeptide length. While tACBC homooligomers assume a dominant 12-helix conformation, the aza-primed oligomers preferentially adopt a stabilized 8-helix conformation for an oligomer length up to 6 residues. The (formal) single-atom exchange at the N terminus of a tACBC oligomer thus contributes to the sustainability of the 8-helix, which resists the switch to a 12-helix. This effect illustrates atomic-level programmable design for fine tuning of peptide foldamer architectures.

Combining J-edited and correlation spectroscopies within a multi-dimensional spatial frequency encoding: toward fully resolved 1H†NMR spectra.

J-resolved at a glance: Passive coupling refocusing-COSY experiments based on a frequency encoding of the sample along two directions of space are presented. It allows various spin evolutions to be triggered in different parts of the sample in a selective and fully controlled manner. This yields 2D spectra in which the whole proton network appears as a series of fully resolved and straightforwardly assignable doublets, triplets or quartets (see figure).

Solution state conformational preferences of dipeptides derived from N-aminoazetidinecarboxylic acid: an assessment of the hydrazino turn.

Four model compounds and four dipeptides containing N-aminoazetidinecarboxylic acid (AAzC) and a particular stereoisomer of 2-aminocyclobutanecarboxylic acid (ACBC) were studied to establish their solution state conformational preferences, particularly regarding the ability of AAzC to induce a three-center hydrogen-bonded folding feature known as a "hydrazino turn". On the basis of IR and NMR experiments, supported by molecular modeling, the AAzC residue adopted a trans configuration amenable to the formation of a cyclic eight-membered hydrogen bond conformation in solution, in all cases studied. The implication of the heterocyclic nitrogen atom of AAzC in the trans-like structure was demonstrated via a refined (1)H-(15)N HMBC experiment giving exploitable data at natural (15)N isotopic abundance, providing unprecedented evidence for the solution state hydrazino turn conformation. The predominance of this secondary structural feature depended on the configuration of the neighboring ACBC residue in the dipeptides: while the trans-ACBC derivatives prefer the hydrazino turn, the cis-ACBC derivatives may also populate low-energy 10-membered hydrogen-bonded ring structures. X-ray diffraction analysis of three compounds confirmed the presence of a solid state hydrazino turn in two cases, with geometries similar to those deduced from the solution state studies, but in the third compound, no intramolecular hydrogen-bonding feature was in evidence.

Fast-pulsing NMR techniques for the detection of weak interactions: successful natural abundance probe of hydrogen bonds in peptides.

Structural investigations of peptides using NMR spectroscopy rarely include the detection of N-H···O=C and N-H···N hydrogen bonds, because the relevant heteronuclei have a low natural abundance while the small trans hydrogen bond scalar couplings reduce the sensitivity. Fast repetition NMR techniques combined with state of the art spectrometer specifications allowed the enhancement of the sensitivity for detection of hydrogen bonds at natural isotopic abundance.

29Si-1H IMPACT HMBC: a suitable tool for analyzing silylated derivatives.

A modified version of the IMPACT heteronuclear multiple bond correlation (HMBC) has allowed the characterization of an organosilane and a tetrasilylated yttrium complex. With the help of this sequence, an average gain in sensitivity close to 2 has been obtained compared with the standard HMBC experiment for disilanes as well as for yttrium complexes containing silylated ligands. This modified version of this long-range correlation experiment opens the way for following kinetics in the range of a fraction of a minute and to study by NMR low concentrated samples and low abundant nuclei.

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.

The conformation and orientational order of a 1,2-disubstituted ethane nematogenic molecule (I22) in liquid crystalline and isotropic phases studied by NMR spectroscopy.

The structure, conformation and orientational order of the mesogen I22 have been studied by proton, carbon-13 and deuterium 1D and 2D-NMR spectroscopies at natural abundance and at various magnetic fields when in the nematic phase, the isotropic phase close to the nematic-isotropic phase transition, and as a solute in the chiral nematic solution comprised of the polypeptide PBLG dissolved in chloroform. It is concluded that 95% of conformers have a trans arrangement about the central C-C bond of the ethane fragment in all phases.

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.

Application of a (1)H delta-resolved 2D NMR experiment to the visualization of enantiomers in chiral environment, using sample spatial encoding and selective echoes.

We present the application of a 2D broadband homodecoupled proton NMR experiment to the visualization of enantiomers. In a chiral environment, the existence of diastereoisomeric intermolecular interactions can yield-generally slight-variations of proton chemical shifts from one enantiomer to another. We show that this approach, which relies on a spatial encoding of the NMR sample, is particularly well suited to the analysis of enantiomeric mixtures, since it allows, within one single 2D experiment, to detect subtle chemical shift differences between enantiomers, even in the presence of several couplings. This sequence, which uses semiselective radio-frequency (rf) pulses combined to a z-field gradient pulse, produces different selective echoes in various parts of the sample. The resulting homonuclear decoupling provides an original delta-resolved spectrum along the diagonal of the 2D map where it becomes possible to probe the chiral differentiation process through every proton site where the resulting variation in the chemical shift is detectable. We discuss the advantages and drawbacks of this approach, regarding other experiments which provide homodecoupled proton spectra. This methodology is applied to the observation of enantiomers of (1) ( +/- )2-methyl-isoborneol coordinated to europium (III) tris[3-(trifluoromethyl-hydroxymethylene)-(+)-camphorate] in isotropic solution, and (2) ( +/- )3-butyn-2-ol dissolved in a chiral liquid-crystal solvent, in order to show the robustness of this pulse sequence for a wide range of chiral samples.

Density Functional Theory based study on structural, vibrational and NMR properties of cis - trans fulleropyrrolidine mono-adducts.

Since the early nineties, countless publications have been devoted to the study of possible uses of [60] fullerene (C60) and its derivatives in the fields of materials and nano-biomedical sciences. However, in spite of the importance of conformers notably from the pharmacological point of view, the cis/trans isomerization of C60 mono-adducts has been rarely seldom investigated. Here we present the results of DFT calculations of the structural, vibrational and NMR properties of both cis and trans isomers of fulleropyrrolidine mono-adduct obtained by photo-addition of glycine methyl ester to C60. Taken together, our results have shown that the cis isomer is more stable than the trans one. For the cis conformation, the simulated vibrational spectrum shows a more intense peak at 1298 cm-1. While 13C spectra revealed no significant differences between the two isomers as compared to experimental results, the calculated 1H chemical shifts show a significant difference between the two conformers in both the gas phase and in solution. The trans isomer presents a proton at 5.86 ppm, which is more deshielded than the proton of the cis conformer (5.24 ppm).

Assessing the stable conformations of ibuprofen in solution by means of Residual Dipolar Couplings.

Detailing the conformational equilibria between global and local minimum energy structures of anti-inflammatory α-arylpropionic acids directly in solution is of the utmost importance for a better understanding of the structure-activity relationships, hence providing valuable clues for rational structure-based drug design studies. Here the conformational preferences of the widely used pharmaceutical ibuprofen were investigated in solution by NMR spectroscopy in weakly ordering phases. A thorough theoretical treatment of the anisotropic interactions that are relevant for NMR spectra led to a conformational model characterized by six pairs of symmetry-related conformers, in particular four couples of gauche structures, with a total probability of 93%, and 2 couples of trans structures, counting for the remaining 7%.

A comprehensive NMR methodology to assess the composition of biobased and biodegradable polymers in contact with food.

A nuclear magnetic resonance (NMR) methodology was assessed regarding the identification and quantification of additives in three types of polylactide (PLA) intended as food contact materials. Additives were identified using the LNE/NMR database which clusters NMR datasets on more than 130 substances authorized by European Regulation No. 10/2011. Of the 12 additives spiked in the three types of PLA pellets, 10 were rapidly identified by the database and correlated with spectral comparison. The levels of the 12 additives were estimated using quantitative NMR combined with graphical computation. A comparison with chromatographic methods tended to prove the sensitivity of NMR by demonstrating an analytical difference of less than 15%. Our results therefore demonstrated the efficiency of the proposed NMR methodology for rapid assessment of the composition of PLA.

Pushing the limits of signal resolution to make coupling measurement easier.

Probing scalar couplings are essential for structural elucidation in molecular (bio)chemistry. While the measurement of JHH couplings is facilitated by SERF experiments, overcrowded signals represent a significant limitation. Here, a new band selective pure shift SERF allows access to δ(1)H and JHH with an ultrahigh spectral resolution.

Modified z-gradient filtering as a mean to obtain phased deuterium autocorrelation 2D NMR spectra in oriented solvents.

We describe a modified z-gradient filter scheme specifically designed to obtain pure absorption mode deuterium 2D NMR spectra recorded in oriented solvents. The proposed technique is investigated by analysing the evolution of the density operator for a spin I=1. The method is applied to the recently designed Q-COSY and Q-resolved 2D experiments to simplify the analysis of chiral molecules dissolved in weakly orienting chiral liquid crystals. The efficiency of this z-gradient filtering technique is illustrated using the perdeuterated 1-butanol, a prochiral molecule of average Cs symmetry, dissolved in an organic solution of poly-gamma-benzyl-L-glutamate (PBLG). The experimental results as well as the advantages of the new experiments compared with the previous ones are described and discussed.

Conformational investigation in solution of a fluorinated anti-inflammatory drug by NMR spectroscopy in weakly ordering media.

The structural and conformational elucidation of flexible bioactive molecules in solution is currently a crucial goal for the scientific community, but it is rarely achievable by available techniques. The anti-inflammatory drug diflunisal is presented here as a model case for supporting the efficiency of NMR spectroscopy combined with the use of weakly ordering media as a promising methodology for the conformational investigation of small bioactive molecules. Starting from NMR anisotropic data (40 independent dipolar couplings), a quite accurate description of its torsional distribution around the inter-ring C-C bond was found, characterized by a pair of two couples of conformers. According to the relative configuration of the carboxylic group and the fluorine atom in the ortho position to the inter-ring C-C bond, the more stable couple of conformers are defined as "trans" type conformers (F opposite to the carboxylic group) whereas the less stable couple are "cis" type conformers (F and carboxylic group on the same side). In order to study the influence of fluorine nuclei on the structure and conformational distribution, the same analytical strategy has been applied to investigate the phenylsalicylic acid, its nonfluorinated analogue.