*3.2. Analysis of Geometry of Fagopyrin Structures*

A parameter that describes the geometry of the fagopyrin conformers is the angle between the planes formed by the peripheral rings A–C, F–H, A–F, and C–H (Scheme 2). For hypericin, (Table 1) these angles are of degrees: A–C: 13.334, F–H: 12.363, A–F: 23.188, and C–H: 30.095. Selected conformers of fagopyrin A–F show significant similarity to the structure of hypericin. These conformers are 1, 7, 13, 19, 25, and 31. These conformers are characterized by different substitutions at the R1–R4 position but the hydroxyl groups in the "bay" and "peri" regions are oriented as in the hypericin molecule and form the same type OHO hydrogen bonds. The difference in the angle between the ring plane is the greatest for fagopyrin C and D. These fagopyrins have an asymmetric substitution with a methyl group and a proton at the R3 and R4 position.

Transfer of the OHO hydrogen bond in the "peri" region to the piperidine or pyrrolidine results in the formation of an OHN hydrogen bond (structures 3, 9, 15, 21, 27, and 33) and causes little change in the angles between the A–C and A–F planes. Formation of another OHN hydrogen bond in molecules 5, 11, 17, 23, 29, and 35 causes more significant changes in the polycyclic system. The changes are visible in the angle between F–H and C–H planes, so the effect of the OHN hydrogen bonds in the "peri" region on the geometry of the fagopyrin molecule is apparent and may have a real impact on the electron structure. Additionally, breaking the OHO hydrogen bond and leaving the hydroxyl group in the "peri" region as free causes deformation of the polycyclic system (structures 4, 10, 16, 22, 28, and 34). Larger differences can be observed when two free hydroxyl groups in the molecule are present (structures 6, 12, 18, 24, 30, and 36). This arrangement of the hydroxyl groups causes strong deformation of the polycyclic system of fagopyrins, which is reflected in the high energy of these conformers. So far, two similarities of the fagopyrin molecules to the hypericin molecule can be given. These are a strong influence on the geometrical structure of substituents at the R3 and R4 positions (methyl groups) and the preferred formation of the OHO hydrogen bonds in the "peri" region formed by hydroxyl groups and carbonyl oxygen.


**Table 1.** Angles between the ring planes in fagopyrin and hypericin conformers. σ = 0.001 [deg.].

The structures corresponding to the energy minima (2, 8, 14, 20, 26, and 32) differ from hypericin in the "bay" region. The hydroxyl groups in the "bay" region are directed to the nitrogen atom in the piperidine and pyrrolidine substituents. In the case of hypericin, the hydroxyl groups prefer the OHO hydrogen bonding. The introduction of piperidine or pyrrolidine rings at the R1 and R2 positions favors the formation of an OHN hydrogen bond and decreasing of the fagopyrin energy to a minimum.

Changes in the angles between the plane rings of the peripheral rings of fagopyrins result from a number of substituents and the intramolecular interactions. As fagopyrin F is the major form in the plant material [18], an analysis of hydrogen bond parameters has been performed for the structures shown in Figure 6. The length and angles of OHO and OHN hydrogen bonds are summarized in Table 2. The parameters of OHN hydrogen bonds directed to the pyrrolidine and piperidine rings are highlighted in bold. The results calculated for the fagopyrin F conformers have been compared with hypericin. The letters

in parentheses in Table 2 identify the hydrogen bond location described according to Scheme 2.

**Figure 6.** Conformers (**31**–**36**) of fagopyrin F.




**Table 2.** *Cont.*

Structure 31 is characterized by an arrangement of substituents similar to hypericin. The length of hydrogen bonds in the "peri" region is similar to the length of analogous bonds in hypericin. In the "bay" region, the OHO bond length is shorter than in the hypericin molecule. The OHN hydrogen bond is characterized by a length of 1.5386 Å and an angle of 156.683◦. The lowest energy conformer (structure 32) is characterized by "peri"-OHO hydrogen bond lengths similar to hypericin. In structure 32, two OHN hydrogen bonds are presented in the "bay" region. The bond labeled as C(F)-O-H····N(R2) is characterized by length and angle similar to the OHO "peri" bonds. The bond labeled as C(A)-O-H···N(R1) is elongated up to 1.7233 Å. Additionally, the "peri" OHN hydrogen bond in structure 33 is longer (1.7164 Å) than the "peri" OHO hydrogen bonds.
