*3.3. Aromaticity of Fagopyrin*

The aromaticity of polycyclic compounds is related to their structure and reactivity. There are many indices describing aromaticity; however, the classical HOMA index (Harmonic Oscillator Measure of Aromaticity) is convenient for the description of aromaticity in organic compounds and relates it directly to the structure [36]. In typical aromatic compounds, the values of the HOMA index are in the range from 0 to 1, where 0 corresponds to a non-aromatic ring, and the value of 1 corresponds to a fully delocalized benzene structure, and only in special cases, the HOMA value can exceed the 0–1 range. Figure 7 shows the HOMA values calculated for the rings of the fagopyrin F conformers. The rings are marked according to Scheme 2. For hypericin, the HOMA values for particular rings are: A—0.7186, B—0.3937, C—0.8054, D—0.4712, E—0.5138, F—0.7863, G—0.4010, and H—0.7979. For the fagopyrin F structures, the peripheral rings A, C, F, and H show the highest HOMA value indicating the aromatic character of the ring. The aromaticity of the rings D and E is about 0.5. The HOMA value for rings B and G is the most variable, and for the structures 34 and 36, it is negative. Structure 31 is characterized by a hypericin-like arrangement of the substituents. The HOMA values of rings A and F are lower relatively to the hypericin; thus, the presence of the piperidine ring decreases the aromaticity of the rings. However, the D ring in structure 31 gains aromaticity relative to the hypericin moiety. The formation of the strong OHO hydrogen bonds in the "peri" region stabilizes the polycyclic system and increases the aromaticity of the central B and G rings. In general, structure 31 shows aromaticity of the rings similar to hypericin, with the influence of piperidine substituents on the aromaticity of rings A, D, and F. The lowest energy structure 32 is characterized by the formation of two OHN hydrogen bonds to the piperidine substituent in the "bay" region. This arrangement increases the aromaticity of the A, D, and F ring. Structure 33 is characterized by the breaking of the strong OHO bond in the "peri" region and the formation of an OHN hydrogen bond to the piperidine ring. Such conformation causes an increase in the energy of the system, an increase in the HOMA value of the F ring, and a

decrease in the HOMA value of the B ring up to 0.1644. Breaking of another OHO bond in the "peri" region (structure 34) deepens the loss of aromaticity of the B ring. The HOMA parameter below zero indicates a complete loss of aromaticity of the ring. In structures 35 and 36, two OHN bonds in the "peri" region are present and such conformation of the hydroxyl groups causes an increase in the HOMA value in the A and F ring with significant aromaticity decreasing in the B and G ring. These changes cause increasing the total energy of the molecular system (Figure 6).

**Figure 7.** HOMA values calculated for (**a**) **31**, (**b**) **32**, (**c**) **33**, (**d**) **34**, (**e**) **35**, and (**f**) **36** fagopyrin F conformers.
