Solid-state NMR crystallography trough residual dipolar couplings – SHARP

During this project, we have developed new methods to accurately measure interatomic distances. Accurate measurements of interatomic distances in solid-state NMR were the major scientific obstacle of this project.
We have introduced a new NMR method that allows precise measurement of interatomic distances greater than 300 picometers and demonstrated that these distances can be used to determine molecular conformation) but also to inter-molecular distances, essential for determining the crystal packing.
On the other hand, we have also studied microcrystalline powders at natural isotopic abundance using dynamic nuclear polarization (DNP). Interestingly, DNP can increase the intensity of the NMR signal by transferring the spin polarization from an unpaired electron to the nuclei under the effect of microwave irradiation. As a result, we obtained an amplification of the NMR signal by a factor of 50, rendering possible the measurement of 13C-13C distances in the case of microcrystalline powders at natural isotopic abundance.

During this project, it has been shown that dynamic nuclear polarization (DNP) technique can remove the scientific obstacles that have long limited the use of solid NMR for the characterization of powders. Indeed, isotopic enrichment is no longer required for the study of samples at natural isotopic abundance thanks to the sensitivity improvement provided by DNP. In addition, we have demonstrated, for the first time, that working with samples at natural isotopic abundance greatly simplifies the measurement of a specific internuclear distance. The methodology developped here contrasts with the laborious process of internuclear distance measurements in samples uniformly enriched in 13C or 15N.

During this project, many scientific obstacles have been lifted in solid NMR, notably the spectacular improvement in sensitivity obtained through the development of DNP. In particular, it is now possible to obtain structural information for samples at natural isotopic abundance and that cannot be characterized by traditional techniques. The prospects for this project are now to combine solid state NMR data with ab initio structural prediction programs to determine the structure of most organic powders.

The results obtained were published in international peer-review journals; a total of 6 scientific publications were produced during this project. Notably, some results have been published in Angewandte Chemie and Chemical Communications, two prestigious journals in chemistry. In addition, the results obtained here have been presented in 10 national or international conferences. Finally, some results have been published as a short communication on the website of the “Institut de Chimie” of CNRS.

The goal of this proposal is to investigate molecular crystals that cannot be studied with conventional analytical methods. For that purpose, we will take advantage of the Residual Dipolar Coupling (RDC) approach, a solid-state Nuclear Magnetic Resonance methodology (SSNMR), recently developed in our laboratory.
As demonstrated by recent works and preliminary results, the RDC approach gives now access to structural information that were unreachable with established SSNMR methodologies. In fact, the RDC approach allows the measurement of short and long-range inter-nuclear distances in multiple spin-networks. Interestingly, long-range inter-nuclear distances can be used to probe the crystal structure of organic molecules. In fact, experimental data obtained with the RDC approach give access not only to intra-molecular distances (essential for determining the molecular conformation) but also to inter-molecular distances, essential for determining the crystal packing. On the basis of these arguments, we believe that the RDC approach can be used to investigate the crystal structures of powder samples, in particular in the case of high relevance small pharmaceutical molecules.
In this project, we intend first to study uniformly carbon-13/nitrogen-15 isotopically enriched powder samples for which the crystal structures have already been determined using single crystal X-ray diffraction. Comparison between the SSNMR determined crystal structure with the single crystal X-ray diffraction determined crystal structure will allow us to explore the frontiers of the RDC approach. Subsequently, we will extend the RDC approach to the challenging study of long-range proton-proton distances in natural isotopic abundance samples. For that purpose two distinct strategies will be explored. The first strategy is based on the use of sample spinning at frequencies that are equivalent to the proton-proton dipolar interaction, while the second strategy is based on imperfect homonuclear decoupling. It should be noted that these two distinct strategies share the same objective, i.e. to manipulate a spin-system that is governed only by weak proton-proton dipolar couplings. Preliminary results for both strategies have either been published by our research group or are provided in the scientific document.
Finally the RDC approach will be integrated into the so-called “NMR crystallography” procedure in order to investigate the unknown crystal structures of the different polymorphs of latrepirdine, a pharmaceutical compound with the potential to combat neurodegenerative diseases. For that purpose, we will combine powder X-ray diffraction, SSNMR experiments and RDC data with ab-initio computations to probe the crystal structures of latrepirdine. We believe that this strategy will provide significant insights into the three dimensional structures of latrepirdine and hence improve the bioactivity comprehension of this promising pharmaceutical molecule.