Tailoring the nuclear Overhauser effect for the study of small and medium-sized molecules by solvent viscosity manipulation

Abstract

The nuclear Overhauser effect (NOE) is a consequence of cross-relaxation between nuclear spins mediated by dipolar coupling. Its sensitivity to internuclear distances has made it an increasingly important tool for the determination of throughspace atom proximity relationships within molecules of sizes ranging from the smallest systems to large biopolymers. With the support of sophisticated FT-NMR techniques, the NOE plays an essential role in structure elucidation, conformational and dynamic investigations in liquid-state NMR. The efficiency of magnetization transfer by the NOE depends on the molecular rotational correlation time, whose value depends on solution viscosity. The magnitude of the NOE between 1 H nuclei varies from +50 % when molecular tumbling is fast to -100% when it is slow, the latter case corresponding to the spin diffusion limit.In an intermediate tumbling regime, the NOE may be vanishingly small. Increasing the viscosity of the solution increases the motional correlation time, and as a result, otherwise unobservable NOEs may be revealed and brought close to the spin diffusion limit. The goal of this review is to report the resolution of structural problems that benefited from the manipulation of the negative NOE by means of viscous solvents, including examples of molecular structure determination, conformation elucidation and mixture analysis (the ViscY method).3.7. Overview of advantages/disadvantages of viscous solvents in molecule mixture analysis 68 Conclusion 71Acknowledgements References 71Glossary 82

Use of Diethanolamine as a Viscous Solvent for Mixture Analysis by Multidimensional Heteronuclear ViscY NMR Experiments

“…44,45 The operating temperature is a critical factor in ViscY experiments owing to its immediate influence on solvent viscosity and thus on overall rotational correlation times τ C . 23,24,32,33 As a result, we have determined the optimized temperature at which NOE cross-peaks were positive (negative NOE enhancements, slow-motion regime, see Figure 3a), well-resolved, and as intense as possible between protons not supposed to be near enough to present a NOE in low-viscous medium. The optimal temperature of 278 K has been chosen via 2D NOESY experiments (see Fig- Owing to resonance peaks overlapping in the 1D and 2D spectra of the four fluorine-and phosphorus-containing molecules within mixture, it has been somewhat difficult to unambiguously assign each proton resonance to a specific compound.…”

“…8,16,17 The use of viscous solvents has initiated the way to alternative NMR approaches for mixture analysis that depend on the tailoring of molecular dynamics of the dissolved molecules. Indeed, the tumbling rate of small and medium-sized molecules can be lowered in aqueous and organic viscous solvents [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] since the value of the overall correlation time τ c is governed by the medium viscosity according to the microviscosity theory of Gierer and Wirtz. 33 As a result, the analytes unveil a negative NOE regime, and their resonances can be clustered according to their ability to exchange magnetization through intramolecular spin diffusion.…”

“…The exploitation of 1 H NMR spectra may become intractable due to massive 1 H resonance overlapping when complex mixtures are analyzed. A traditional alternative solution consists in the spreading of the spectroscopic information along a second and sometimes a third dimension that encodes chemical shifts of nuclei other than 1 H. ,− , This method to mixture analysis is exemplified in the viscous binary DEA/DMSO- d 6 solvent using the 2D 1 H– 19 F and 1 H– 31 P HSQC-NOESY and 3D 1 H– 19 F– 1 H, 1 H– 31 P– 1 H HSQC-NOESY experiments, providing 1 H/ 19 F/ 31 P chemical shift lists for the mixture of four low-polarity fluorine- and phosphorus-containing compounds (see Figure ).…”

“…The exploitation of 1 H NMR spectra may become intractable due to massive 1 H resonance overlapping when complex mixtures are analyzed. A traditional alternative solution consists in the spreading of the spectroscopic information along a second and sometimes a third dimension that encodes chemical shifts of nuclei other than 1 H. 20,[23][24][25][26][27][28]39 This method to mixture analysis is exemplified in the viscous binary DEA/DMSO-d 6 solvent using the 2D 1).…”

Taxonomy-Focused Natural Product Databases for Carbon-13 NMR-Based Dereplication

“…The use of LC hyphenated with nuclear magnetic resonance (NMR) spectroscopy is frequently limited by the amount of purified compound that can be analyzed, NMR being far less sensitive than MS. Methods have recently been made available for mixture analysis by NMR with applications to crude natural extracts or to series of extract fractions [10][11][12][13]. NMR characterizes molecular compounds at the atomic level so that NMR experimental data are less prone than MS data to be compatible with a high number of molecular structures.…”