*3.4. Analysis of Intramolecular Interactions in Fagopyrin Derivatives*

Changes in aromaticity must be related to the changes in electron density of the polycyclic system. To describe the possible intermolecular interactions and arrangement of the electron density, the QTAIM [37] (Quantum Theory of Atoms in Molecules) analysis for the fagopyrin F conformers has been performed. In the frame of the QTAIM theory, a molecule consists of maximum, minimum, and saddle points of the electron density ρ(r). The saddle point indicates bond-critical points (BCPs) or ring-critical points (RCPs). The points representing the maximum electron density correspond to atoms. Figure 8 shows QTAIM graphs of fagopyrin F conformers. The structure of fagopyrin F is characterized by the presence of numerous substituents in a polycyclic system. Such structure allows for the occurrence of numerous intramolecular interactions of diverse nature [38]. QTAIM analysis confirms the presence of the hydrogen bond interactions in the "peri" region of fagopyrin F. Hydroxyl groups directed to carbonyl oxygen form a stable moiety as in the case of hypericin and sennidin [13,14]. QTAIM analysis indicates that OHN interaction can be formed in both the "peri" and "bay" region. The strong OHO hydrogen bonds in the anthrone moiety can be broken and replaced by weaker OHN hydrogen bonds. The electron density values at the bond critical points ρ(r) presented in Figure 8 reflect the strength of the OHO and OHN hydrogen bonds. The structures 33, 34, 35, and 36 show the formation of OHN hydrogen bonds characterized by lower values of ρ relative to the OHO hydrogen bonds in the "peri" region. However, conformer 32 (b) is characterized by the formation of OHN hydrogen bonds in the "bay" region. These bonds are characterized by

a similar value of ρ(r) relative to the strong OHO hydrogen bonds in the "peri" region. This conformer shows the lowest energy; thus, the formation of strong OHN hydrogen bonds to the piperidine substituents stabilizes the anthrone system. The proximity of the piperidine ring affects the adjacent hydroxyl groups even if they do not form a direct bond. In addition, the close position of the methyl groups also introduces intermolecular interactions.

**Figure 8.** QTAIM plots for (**a**) **31**, (**b**) **32**, (**c**) **33**, (**d**) **34**, (**e**) **35**, and (**f**) **36** fagopyrin F conformers. Green points correspond to RCPs. Red points indicate BCPs.

To confirm the presence of the interactions, the non-covalent interactions [32] (NCI) analysis was performed. Figure 9 shows the conformers of fagopyrin F, showing multiple intramolecular interactions. The blue isosurfaces in the "peri" and "bay" moiety confirm the presence of strong hydrogen bonds in the fagopyrin F molecule. Conformer 31 (a) shows similarity to hypericin in the formation of strong OHO hydrogen bonds. The lowest energy conformer 32 (b) confirms the formation of OHN hydrogen bonds in the "bay" region. Structure 33 (c) confirms the possibility of breaking the strong OHO hydrogen bond in favor of OHN hydrogen bond formation with the nitrogen atom of the piperidine ring. The interactions between the methyl groups can be described as dispersive.
