Mogul in Action: Structural Validation of Isoflavones
September 27, 2023
This blog highlights the work from a paper published in CrystEngComm, where the solid-state structures of three very similar compounds were studied to investigate the relationship between supramolecular packing, conformation, and macroscopic properties. The use of Mogul, as part of the CSD-Core suite, validated the geometry of the structures, and then compared them with structurally related compounds from the Cambridge Structural Database (CSD).
Isoflavones are compounds that have attracted attention as they can bind to human estrogen receptors (hERα) and are found in plants. In this work, scientists synthesized isoflavone 5-deoxy-3′-prenylbiochanin A (4, Figure 1), to study the anti-infective activities of metabolites derived from E. sacleuxii to bacterial pathogens.
The group noticed that despite having a similar molecular structure, compound 4 and the precursors compound 2 and 3 showed remarkably different macroscopic properties. The melting point of compound 3 was 10 K higher than compound 4, while compound 2 was ca. 100 K lower than compounds 3 and 4. Considerable different solubilities were seen between the three compounds: while 2 dissolved well both in polar and nonpolar organic solvents, compound 4 was only soluble in polar organic solvents, and 3 dissolved only in DMSO.
Solubility is a key parameter for pharmaceutical molecules as the bioavailability of a drug is strongly dependent to its dissolution rate. Aiming to find the relationship between the supramolecular structures of these compounds and their macroscopic properties, the group analysed the solid-state structures of compounds 2, 3 and 4.
The structures of compounds 2, 3 and 4 can be seen in Figure 2 (left). Those compounds are 3-aryl benzopyran derivatives, and they only differ by the substituents on C2 and C14, highlighted by the blue and red dashed circles in Figure 2 (left). The arrangement of the molecules of the three compounds in the crystal structures are, however, extremely different. Compounds 2, 3 and 4 crystallize in different space groups (Pna21, P-1 and P21/n respectively), and exhibit different lattice energies, meting points, and solubilities.
To rationalize these findings, the group analysed the geometric conformation parameters and the intermolecular non-covalent interactions for compounds 2, 3 and 4. Using Mogul, as part of the CSD-Core suite, the geometry of the compounds was validated and compared with 640 structurally related compounds found in the CSD.
As can be seen in Figure 2 (right), compound 3 presents an unusual torsion angle of 68.14° between the bonds highlighted in green in the structure in Figure 2 (left). The Mogul search shows that only three compounds out of 640 have a similar small angle seen in compound 3. The fact that two of those compounds were also 3-aryl benzopyran derivatives with the hydroxy group in the same position raised the hypothesis that the torsional angles could be dictated by intermolecular interactions. More specifically, a deviation from the ideal 45° (resp. 135°) angle is expected when the structure presents two aromatic rings, in this case an aryl group and a benzopyran group, that can be independently influenced by intermolecular interactions.
The group then tested the assumption that a large deviation from the expected torsion angle was correlated to the formation of stronger intermolecular interactions. The compound with the smallest torsion angle deviation (2) also exhibits the lowest lattice energy, while the one with the biggest angle deviation (3) exhibits instead the highest lattice energy.
For these reasons, the scientists studied the intermolecular interactions (hydrogen bonds and stacking interactions) present in the structures performing Hirshfeld surface analysis and using the Aromatics Analyser feature within the CSD-Materials suite.
Analysis revealed the physicochemical properties of compounds 2, 3 and 4.
For compound 2, the low lattice energy and melting point were attributed to the absence of a strong intermolecular O-H···O hydrogen bonds, and to the repulsion between the bulky ring substituents that prevents the formation of strong stacking interactions. The presence of non-polar groups, added to the lack of intermolecular interactions, explains the good solubility in organic solvents of compound 2.
Compounds 3 and 4 present instead strong one-dimensional O-H···O hydrogen bonds from the OH group at C2, and strong parallel-displaced stacking interactions between the rings, which explain their higher melting points when compared to compound 2. The presence of the OH group at C2 is also responsible for the lower solubilities in nonpolar solvents.
Geometry analysis showed that when only weak hydrogen and stacking interactions are present in the structure (compound 2), the rings are not locked in a specific orientation, hence exhibiting a torsion angle with a small deviation from the ideal one. When instead the benzopyran ring is fixed by both strong hydrogen and stacking interactions, which is the case in compounds 3 and 4, the torsion angle is strongly influenced by the intermolecular interactions on the aryl ring. This leads to a greater deviation from the ideal torsion angle for compounds 3 and 4 when compared to compound 2, with compound 3 showing the larger deviation due to the presence of two sets of strong stacking interactions, one of which is not present in compound 4.
The use of Mogul for geometry validation of the investigated structures showed that a greater deviation from the ideal torsion angle is seen when there is an increase in number and strength of intermolecular interactions. This trend is also followed when considering the macroscopic properties of compounds 2, 3, and 4, with stronger interactions leading to increased lattice energies and melting point, and decreased solubilities.
Mogul is a tool that is used by academic researchers and industry leaders to validate the geometry of experimental or predicted structures. Mining the entire CSD, Mogul identifies intra and intermolecular geometry preferences, and predicts the likely chemical conformations.
As part of the CSD-Core suite, Mogul is easily accessible and can be launched directly from Mercury. It can be used to quickly identify unusual features in a structure, performing a general geometry analysis or a more targeted feature search depending on the research goals. Mogul can also display the distribution of bond lengths, angles, ring geometries, and torsions of the expertly curated structures in the CSD.
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