Say goodbye to erroneous NMR structures

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  • Published: Apr 24, 2017
  • Channels: X-ray Spectrometry / NMR Knowledge Base
thumbnail image: Say goodbye to erroneous NMR structures

For any molecule that can't be determined by X-ray crystallography, and generally that means anything that doesn't form a firm crystal structure, then NMR is usually the go-to technique of choice. However, particularly in the case of complex molecules, NMR doesn't always come up with the correct solution since large molecules are difficult to resolve due to the fact that different atoms may be in different chemical environments which will therefore give a similar chemical shift to a completely different structure leading to a false assignment. This month however a team from Merck working in collaboration with researchers in the US and The Netherlands have modified a method used most commonly by protein scientists to confirm if the proposed structure is indeed correct.

Headed up by Yizhou Lu, Gary Martin and their team at Merck's Structural Elucidation Group, they have shown that by incorporating the molecule to be studied within a polymer gel that has been compressed or extended can yield additional information since the molecules within the pores of the gel will align along the direction of constraint. This new information includes residual dipolar coupling (RDC) data, and generally this means the couplings between hydrogen nuclei and those direct carbon atoms bonded to them. These bondings can be accurately predicted with the angle of the C-H bonds and the applied magnetic field. The second new source of information comes from the residual chemical shift anisotropy (RCSA). In liquids, due to the fast and random molecular rotation, the chemical shift is averaged out to an isotropic value, but when the molecule is constrained within the gel, certain alignments become more likely than others with the average chemical shift tends towards values that correspond to the preferred direction, and hence you have a chemical shift that can be observed.

Aquatolide constrained within a polymer gel, allowing for extraction of RDC and RCSA parameters.

The advantage of this method therefore is that by having this extra RDC and RCSA data, this can be calculated for the molecular structure and then compared with the experimental data. If this calculated data is in agreement with the experimental data then the correct structure has been determined, but if there is disparity between calculated and observed then it is likely that an incorrect structure has been determined.

The team studied several molecules including aquatolide and cryptospirolepine. For each of the molecules they applied structural elucidation software to predict the RDC and RCSA values and then by comparing this with the experimental values, they were able to identify the correct structure.

Gary Martin, who has recently been appointed as Editor-in-Chief of the journal, Magnetic Resonance in Chemistry, pointed out that aquatolide was originally incorrectly identified and took many years to solve using a combination of computational analysis and X-ray crystallography and ultimately, a total synthesis. But now using RDC and RCSA the correct structure can be elucidated within just a few days.

Source: Y. Liu et al., Science, 2017, 356, 43.

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