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De novo structural elucidation of functional organic powders at natural isotopic abundance

Periodic Reporting for period 3 - STRUCTURE (De novo structural elucidation of functional organic powders at natural isotopic abundance)

Reporting period: 2021-01-01 to 2022-06-30

Organic, molecular materials have received growing attention recently because of their favourable properties in a plethora of applications in fields ranging from energy, to medicine, pharmacy and electronics. These materials are very prone to polymorphism, i.e. they can exist as distinct crystalline forms (the polymorphs). While remaining chemically identical, the different polymorphs of a chemical compound might display radically different properties, with huge economic and practical consequences for industrial applications. If, on one side, polymorphism potentially provides a great opportunity for tuning the performance of the material, on the other side, manufacture or storage-induced, unexpected, polymorph transitions can also compromise the end-use of the solid product because it can modify its properties.

In the permanent quest for new materials adapted for specific applications, materials scientists need to establish relationships between the structure and the properties of the material in its end-use solid form. In other words, they need to have access to the structure of materials to an atomic level of detail. Unfortunately, in their final form, molecular materials often exist as powders (i.e. they are composed of very small - nm to μm – particles), for which no general and reliable structure-determination technique exists.
Importantly, the lack of a general and reliable method for atomic-level structural analysis of polymorphic molecular solids not only prevents accurate characterization of the final powder structure, but also limits the ability to observe the structural changes occurring during the formation of the end-use solid form, hence hampering the ability to control how a specific polymorph is produced.
STRUCTURE aims at developing innovative experimental methods for structure determination of molecular solids based on sensitivity-enhanced solid-state NMR combined with computational approaches. Specifically, STRUCTURE focuses on:
a) devising new approaches based on dynamic nuclear polarization (DNP) magic-angle spinning (MAS) solid-state NMR (ssNMR) spectroscopy for accessing the atomic-level structure of solid, sub-um sized particles or agglomerates that are currently difficult or impossible to characterize using standard diffraction techniques;
b) developing new time-resolved, MAS DNP ssNMR approaches to investigate crystallizing solutions at an atomic level and decipher the structural process leading to the formation of a specific polymorph.
The results of STRUCTURE will impact materials science by:
• clarifying structure-properties relationships in molecular materials with applications in pharmacy or energy
• rationalizing how a given solid form is obtained from solution, so as to control its final structure, and hence, its properties.
During these first 30 months, the STRUCTURE team obtained results on the following research axes:
- The development of new NMR crystallography methods to access the molecular conformation of organic powders. Accessing the conformation of organic solids is today a complex issue and constitutes a real limitation to the ability of fully determining the crystalline structure of an organic powdered material, preventing the development of new materials for tailored applications. The efforts of the research team were focused on trying to find quantitative relationships between long-range J couplings (3J) and torsional angles, which can give access to the molecular conformation in the solid phase. By combining simulation work and ssNMR experiments the STRUCTURE team provided the experimental a precious practical tool for local structural analysis of molecular solids: the first mathematical expression relating dihedral angles to the value of measured long-range J couplings for organic solids.
- The development of new methods for atomic-level investigation of crystallizing solutions. Notably, two distinct experimental approaches based on solid-state NMR were devised, which produced an increase in both the temporal and spatial resolution of the analysis of crystallizing systems. Both these approaches take advantage of the unique features of “MAS DNP” solid-state NMR spectrometers. Notably, MAS DNP experiments are carried out at cryogenic temperatures, allowing the investigation of frozen samples. These conditions inspired the team to devise two approaches to either i) slow down or ii) completely stop (“quench”) the crystallization process occurring in solution, hence increasing the temporal resolution of the analysis. The team developed: an in-situ NMR approach, enabling the analysis of metastable polymorphs and their structural evolution; an ex-situ NMR DNP approach, enabling the atomic-level analysis of the different forms (solvated, amorphous, crystalline) coexisting into the crystallization medium at different time points. Importantly, this last development enabled the detection of pre-nucleation clusters present in the crystallization medium, which is a major advance.
Recently, it has been shown that bad initial guess of the molecular conformation can limit the accuracy of crystal structure prediction for molecular materials and even lead to erroneous results, especially for challenging, flexible, molecules. To address the experimental challenge of accessing the molecular conformation of solids, we developed a novel solid-state NMR approach that gives access to torsional angles in molecular fragments of organic molecular crystals containing carbon atoms. The developed method enables a clear correlation between the experimental 3J value and the value of torsional angle. Using this method, torsional angles can be determined on compounds containing C, O, N and H atoms only, with an accuracy of 10 degrees. The approach we developed constitutes a unique practical tool for determining the local geometry of molecular solids and can be a real game changer for structure determination of polymorphic solids, helping materials science to move forward. The next step will consist in making the developed technology applicable to the characterization of organic powders at natural isotopic abundance.
Moreover, we have introduced a novel, unconventional application of MAS DNP. Specifically, we introduced new experimental protocols that allow MAS DNP to be used for investigating the process of formation of crystals. These procedures can now be exploited to reveal atomic level details of all the phases present in a crystallizing system, with the aim of achieving a better understanding of the formation of a solid, which remains one of the big mysteries of science. Until the end of the project, the developed approaches will be employed with the aim of trying to catch the first instants of phase formation/transformation and possibly shed light on the atomic level mechanism of nucleation.