Magnetic Resonance in Chemistry

Freitas, Jair C. C.; Wong, Alan; Smith, Mark E.

doi: 10.1002/mrc.2328pmid: 18985623

Natural abundance solid‐state 25Mg NMR measurements were made of the disodium salt of magnesium ethylenediaminetetraacetate tetrahydrate (Na2MgEDTA·4H2O). Both magic angle spinning (MAS) and static experiments were employed to determine the quadrupole coupling constant (Cq) and the asymmetry parameter (ηq) of the electric field gradient (EFG) tensor associated with 25Mg in this compound, giving the values Cq = 1.675(5) MHz and ηq = 0.15(1). The isotropic chemical shift was determined to be δiso = 0.25(10) ppm (relative to 11 M MgCl2 aqueous solution) and a small chemical shift anisotropy (CSA) contribution (∼− 13 ppm) was detected, one of the first CSA reports in 25Mg NMR. This compound exhibited remarkably good 25Mg NMR sensitivity, due to its fast spin‐lattice relaxation and modest quadrupole coupling, which allowed its use as a secondary shift reference and as a test sample for the implementation and optimisation of signal‐enhancement methods in 25Mg NMR spectroscopy, such as double frequency sweeps (DFS) and the use of adiabatic hyperbolic secant (HS) and WURST pulses. Copyright © 2008 John Wiley & Sons, Ltd.

Schmidt, Jürgen M.; Howard, Mark J.; Maestre‐Martínez, Mitcheell; Pérez, Carlos S.; Löhr, Frank

doi: 10.1002/mrc.2337pmid: 18853398

Four types of polypeptide 1JCαX couplings are examined, involving the main‐chain carbon Cα and either of four possible substituents. A total 3105 values of 1JCαHα, 1JCαCβ, 1JCαC′, and 1JCαN′ were collected from six proteins, averaging 143.4 ± 3.3, 34.9 ± 2.5, 52.6 ± 0.9, and 10.7 ± 1.2 Hz, respectively. Analysis of variances (ANOVA) reveals a variety of factors impacting on 1J and ranks their relative statistical significance and importance to biomolecular NMR structure refinement. Accordingly, the spread in the 1J values is attributed, in equal proportions, to amino‐acid specific substituent patterns and to polypeptide‐chain geometry, specifically torsions ϕ, ψ, and χ1 circumjacent to Cα. The 1J coupling constants correlate with protein secondary structure. For α‐helical ϕ, ψ combinations, 1JCαHα is elevated by more than one standard deviation (147.8 Hz), while both 1JCαN′ and 1JCαCβ fall short of their grand means (9.5 and 33.7 Hz). Rare positive ϕ torsion angles in proteins exhibit concomitant small 1JCαHα and 1JCαN′ (138.4 and 9.6 Hz) and large 1JCαCβ (39.9 Hz) values. The 1JCαN′ coupling varies monotonously over the ϕ torsion range typical of β‐sheet secondary structure and is largest (13.3 Hz) for ϕ around − 160 . All four coupling types depend on ψ and thus help determine a torsion that is notoriously difficult to assess by traditional approaches using 3J. Influences on 1J stemming from protein secondary structure and other factors, such as amino‐acid composition, are largely independent. Copyright © 2008 John Wiley & Sons, Ltd.

Mocci, Francesca; Usai, Michele; Cerioni, Giovanni

doi: 10.1002/mrc.2339pmid: 18942071

A number of diazenedicarboxylates have been studied by multinuclear magnetic resonance (17O, 15N, 13C) and compared with analogous fumaric, maleic, and phthalic diesters; the investigation of selected compounds of these classes was complemented by density functional theory (DFT) calculations using a polarizable continuum model (PCM) for the solvent, employing the PBE0 functional together with the 6‐311G(d,p) basis set for geometry optimization, and the 6‐311 + G(2d,p) basis set for calculating the NMR shielding using the gauge‐including atomic orbital (GIAO) method. This combined approach provided important information about the preferred conformations in chloroform and their influence on the NMR parameters. Copyright © 2008 John Wiley & Sons, Ltd.

Keyes, Philip; Hernandez, Gonzalo; Cianchetta, Giovanni; Robinson, James; Lefebvre, Brent

doi: 10.1002/mrc.2347pmid: 18991323

Since the introduction of NMR prediction software, medicinal chemists have imagined submitting their compounds to corporate compound registration systems that would ultimately display a simplified pass/fail result. We initially implemented such a system based on HPLC and liquid chromatography mass spectrometry (LCMS) data that is embedded within our industry standard sample submission and registration process. By using gradient‐heteronuclear single quantum coherence (HSQC) experiments, we have extended this concept to NMR data through a comparison of experimentally acquired data against predicted 1H and 13C NMR data. Integration of our compound registration system with our analytical instruments now provides our chemists unattended and automated NMR verification for collections of submitted compounds. The benefits achieved from automated processing and interpretation of results produced enhanced confidence in our compound library and released the chemists from the tedium of manipulating large amounts of data. This allows scientists to focus more of their attention to the drug discovery process. Copyright © 2008 John Wiley & Sons, Ltd.

Zielinski, Matthew E.; Morris, Kevin F.

doi: 10.1002/mrc.2348pmid: 19006104

Diffusion‐ordered NMR spectroscopy resolves mixture components on the basis of differences in their respective diffusion coefficients or molecular sizes. However, when components have near‐identical diffusion coefficients, they are not resolved in the diffusion dimension of a diffusion‐ordered spectroscopy (DOSY) spectrum. Adding surfactant micelles to these mixtures has been shown to enhance resolution when the component molecules interact differentially with the micelles. This approach is similar to that used in electrokinetic chromatography (EKC) where modifiers like micelles or polymers are used to enhance the separation of mixture components. In this study, perdeuterated surfactants are added to analyte mixtures studied with the DOSY technique. Since no micelle resonances appear in the mixture spectra, the difficulty associated with performing biexponential analyses in spectral regions where analyte and surfactant resonances overlap is avoided. The approach is demonstrated using mixtures of peptides with near‐identical diffusion coefficients. Copyright © 2008 John Wiley & Sons, Ltd.

Klochkov, Vladimir V.; Baikeev, Roustem F.; Skirda, Vladimir D.; Klochkov, Anton V.; Muhamadiev, Farhat R.; Baskyr, Igor; Berger, Stefan

doi: 10.1002/mrc.2349pmid: 18942069

The gated decoupled 13C NMR spectra of a dipeptide (Glu‐Trp) and a tetrapeptide (NAc‐Ser‐Phe‐Val‐Gly‐OMe) were recorded in D2O and in a lyotropic alignment medium (pentaethylene glycol monododecyl ether/n‐hexanol). The residual dipolar couplings were extracted as the differences between the observed couplings for the magnetic nuclei dissolved in the latter and former media. Using a computational optimization, the spatial structures of the compounds were calculated starting from their respective low energy conformations obtained on a semiempirical basis. The uniformity of each conformation was confirmed by the solid‐state 13C NMR spectra of powder samples. Differences between the starting structures and final ones, optimized when employing residual dipolar couplings, are discussed. Copyright © 2008 John Wiley & Sons, Ltd.

Dybiec, Katarzyna; Gryff‐Keller, Adam

doi: 10.1002/mrc.2350pmid: 18951367

Predicting 13C chemical shifts by GIAO‐DFT calculations appears to be more accurate than frequently expected provided that: (a) the comparison between experimental and theoretical data is performed using the linear regression method, (b) a sufficiently high level of theory (e.g. B3LYP/6‐311 + + G(2d,p)//B3LYP/6‐311 + + G(2d,p) or PBE1PBE/6‐311 + G(2df,p)//B3LYP/6‐311 + + G(2d,p)) is used, (c) the experimental data originate from the measurements performed in one solvent whose influence is taken into account at the molecular geometry optimization step and, first of all, during the shielding calculation, (d) the experimental data are free of heavy atom effects or such effects are appropriately treated in calculations, and finally (e) the conformational compositions of the investigated objects are known. Copyright © 2008 John Wiley & Sons, Ltd.

Imanari, Mamoru; Tsuchiya, Hiroyuki; Seki, Hiroko; Nishikawa, Keiko; Tashiro, Mitsuru

doi: 10.1002/mrc.2351pmid: 18932263

The 13C spectra and 13C longitudinal relaxation times (T1) were measured to investigate the segmental motion of the neat ionic liquid 1‐butyl‐3‐methylimidazolium bromide ((bmim)Br) in the super cooled state. The 13C signals of the imidazole ring significantly broadened at 283 K, whereas many other signals were unchanged. In the process of lowering temperature, the (bmim)Br changed to the solid state at ca 273 K without showing the rapid phase transition. Only the 13C signal of the terminal methyl group in the butyl chain was still observed at 263 K, indicating that the motion of the imidazole ring was extremely restricted, whereas the methyl group in the butyl chain was active even in the solid state. The 13C‐T1 values measured as a function of temperature also supported the discrete segmental motions of the (bmim)+ cation. Copyright © 2008 John Wiley & Sons, Ltd.