PhD Thesis: Development of Resolution-Enhanced NMR Techniques for Improved Small Molecules Structural Analysis

Last July 14th 2018 Núria Marcó defended her PhD Thesis entitled: Development of Resolution-Enhanced NMR Techniques for Improved Small Molecules Structural Analysis

The present doctoral thesis is framed within the field of Nuclear Magnetic Resonance (NMR) spectroscopy.

NMR spectroscopy is an analytic technique and, therefore, one of its main objectives is to unravel the correct structure of the molecules analyzed.This present doctoral thesis is focused on this main objective. This work consists in a compendium of 7 publications, written in several prestigious scientific journals, that develop in depth the efficient and accurate determination of the constitution, configuration and conformation of small molecules thanks to the application of resolution improvements techniques.

In order to do that it is studied the accurate and efficient measurement of isotropic (homo- and heteronuclear scalar coupling constants) for the 2D structre determination, as well as the anisotropic parameters (RDCs, RCSAs and RQCs) for the 3D structure analysis. These anisotropic parameters allows us the discrimination of the different conformers of a molecule and can be found in weakly alignment media. PMMA gel provides an easy, reusable, and practical way to obtain this weakly alignment media. In this work, It has been researched the best way to get these anisotropic parameters, developing and adapting new pulse sequences to this type of media.

To get the correct structure (2D and 3D) it is important to obtain a precise and accurate measurement. In this thesis the great accuracy of isotropic and anisotropic parameters has been achieved through the use of resolution improvement techniques such as Pure-Shift, Spectral Aliasing and Non Uniform Sampling.

In addition it has been applied protocols for the easy automatization and measurement of coupling constants in isotropic and anisotropic media.

Also it has been design improved pulse sequences to achieve the measurement of longer- range heteronuclear connectivities that will increase the amount of information that we will have available to do the structural analysis

Each experiment has been discussed from a methodological point of view. An assessment on its application has been also performed.

Pulse Programs and Data Set Examples:

Publication 1:

Saurí, Josep, Núria Marcó, R. Thomas Williamson, Gary E. Martin & Teodor Parella. 2015. Extending long-range heteronuclear NMR connectivities by HSQMBC-COSY and HSQMBC-TOCSY experiments. Journal of Magnetic Resonance 258. 25–32. DOI: 10.1016/j.jmr.2015.06.004

Pulse Program Code for Bruker:

Data set Example:

Strychnine

Publication 2:

Marcó, Núria, André Fredi & Teodor Parella. 2015. Ultra high-resolution HSQC: application to the efficient and accurate measurement of heteronuclear coupling constants. Chemical Communications 51(15). 3262–3265. DOI: 10.1039/c4cc10279g

Pulse Program Code for Bruker:

SAPS-HSQC (see post “Simultaneous 1H and 13C NMR enantiodifferentation from highly-resolved pure shift HSQC spectra” for details).

Data set Example:

Fluoropyridine

Publication 3:

Marcó, Núria, Roberto R. Gil & Teodor Parella. 2018. Isotropic/Anisotropic NMR Editing by Resolution-Enhanced NMR Spectroscopy. ChemPhysChem 19(9). 1024–1029. DOI: 10.1002/cphc.201800094