Crystal structures of (E)-3-(4-hydroxybenzylidene)chroman-4-one and (E)-3-(3-hydroxybenzylidene)-2-phenylchroman-4-one

Two biologically active compounds were synthesized and their crystal structures were determined. The characteristic feature of both structures is molecular layers in the crystal lattice formed via C—H⋯O and O—H⋯O interactions. The molecular Hirshfeld surfaces analysis were explored with two-dimensional fingerprint plots for the title compounds and other known structures from the literature. Additionally, the lipophilicity parameters (logP) were determined and related to the C⋯H contact contribution in the Hirshfeld surface.

The synthesis and crystal structures of (E)-3-(4-hydroxybenzylidene)chroman-4-one, C 16 H 12 O 3 , I, and (E)-3-(3-hydroxybenzylidene)-2-phenylchroman-4-one, C 22 H 16 O 3 , II, are reported. These compounds are of interest with respect to biological activity. Both structures display intermolecular C-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonding, forming layers in the crystal lattice. The crystal structure of compound I is consolidated byinteractions. The lipophilicity (logP) was determined as it is one of the parameters qualifying compounds as potential drugs. The logP value for compound I is associated with a larger contribution of CÁ Á ÁH interaction in the Hirshfeld surface.

Chemical context
Chromanone (chroman-4-one) and flavanone (2-phenylchroman-4-one) belong to the class of heterocyclic compounds and are composed of a benzene ring fused to a 2,3-dihydro-pyranone ring (Emami & Ghanbarimasir, 2015). 3-Arylidenechromanones/flavanones and their derivatives are naturally occurring homoisoflavones, and can be obtained by condensing the corresponding aryl aldehydes with chromanone/flavanone. These compounds were synthesized for the first time by Robinson in the early 1920s by the condensation reaction of chromanone or flavanone with the appropriate aryl aldehyde using a catalyst (alcohol potassium hydroxide) (Perkin et al.,1926). In 1979, Levai and Schag synthesized E-3arylidenechroman-4-one using piperidine as a catalyst (Levai & Schag, 1979). Several years later, in 1993, Pijewska and coworkers (Pijewska et al., 1993) obtained the series of 3-arylideneflavanones derivatives substituted by various groups using flavanones with aromatic aldehydes in the presence of piperidine. Flavonoid compounds belong to one of the largest and most interesting groups of chemical compounds. They are of interest to many scientists because they show biological properties (Nijveldt et al., 2001;Williams et al., 2004). Natural and synthetic flavonoids have a wide range of antioxidant, anti-allergic, anti-inflammatory, antimicrobial, anti-coagulant, anti-cholesterol or anti-cancer activities (Czapliń ska et al., 2012). ISSN 2056-9890

Structural commentary
The molecular structures of I and II are shown in Fig. 1. The main chroman skeleton of each molecule consists of a benzene ring fused with a pyran ring. In position 3 of the chroman moiety, a para-hydroxybenzylidene (I) or a meta-hydroxybenzylidene (II) substituent is connected to give the E-isomer, similar to the previously mentioned structure (Kupcewicz, et al., 2013). Moreover in compound II, the chroman moiety is subsituted at position 2 by a phenyl ring. The pyran rings adopt an envelope conformation with puckering parameters Q T = 0.371 (2) Å , ' 2 = 233.8 (4) , 2 = 120.0 (3) for I, and Q T = 0.423 (3) Å , ' 2 = 65.9 (5) , 2 = 58.5 (4) for II. The dihedral angles between the hydroxybenzylidene rings and the main chroman skeleton are 47.54 (8) and 69.46 (12) , respectively, for I and II (Fig. 2).

Supramolecular features
In the crystal packing of I, molecules are connected into layers parallel to the bc plane via C-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds (Table 1, Fig. 3). The stability of the layers is further enhanced bystacking interactions occurring between the benzene rings fused with the pyran rings and the aromatic rings of adjacent hydroxybenzylidene groups (Table 2). In the crystal packing of II, molecules are also linked by O-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds (Table 3, Fig. 4) into layers parallel to the ab plane.

Figure 1
The molecular structures of compounds I and II with displacement ellipsoids drawn at the 50% probability level.

Figure 2
Overlay of compound I (green) and compound II (red). Table 2 Geometrical parameters (Å , ) for thestacking interactions for compound I. Cg(1) and Cg(2) are the centroids of the C5-C10 and C12-C17 rings, respectively; refers to the dihedral angle between planes (I) and (J); refers to the angle between the Cg(I))-Cg(J) vector and normal to plane (I); refers to the angle between the Cg(I))-Cg(J) vector and normal to plane (J).

Figure 5
Reference moiety for database survey.
In the 41 chromanone derivatives, the bond distances and angles within the chroman moiety are in good agreement with those found in compound I.

Experimental and theoretical lipophilicity of compounds I and II
Lipophilicity is one of the descriptors that is currently used in the design of new drugs and in assessing the activity of medicinal substances (Jó źwiak et al., 2001). Most often, the increase in lipophilicity increases the biological activity of compounds as a result of the affinity of substances with biological membranes and better permeability (Dołowy, 2009). However, a further increase in lipophilicity results in greater affinity for lipids and hinders the transport of compound molecules through the aqueous phase. That is why it is important to choose substances with optimal hydrophobic and hydrophilic properties and partition coefficient logP (Dołowy, 2009). The experimental lipophilicity (logP) of compounds I and II was determined using the RP-TLC method. The values of logP obtained are 2.95 and 3.98, respectively for I and II, the difference being due to the different, bulky substituent at the C2 position of the pyran ring. The theoretical values of lipophilicity (miLogP) also show the same trend, the value for compound I is lower (miLogP = 3.14) than that for compound II (miLogP = 4.70). This is in agreement with the values previously reported for similar arylidenochromanone/flavanone derivatives (Adamus-Grabicka et al., 2018). The theoretical values of lipophilicity were calculated using the online Molinspiration Cheminformatics software (http://www.molinspiration.com). According to the 'rule of five' proposed by Lipinski et al. (2001), compounds I and II may be potential anti-cancer drugs, the most important parameters according to Lipinski being the logP value (logP < 5) and molar mass (< 500 Da).
indicate contacts with distances shorter, longer and equal to the van der Waals radii. The decomposition of the HS into 2D fingerprint plots for particular contacts is presented in Fig. 7, together with the relative percentage of contributions of different contacts. The dominant interaction in all derivatives is the HÁ Á ÁH interaction. The contribution to the Hirshfeld surface is in the range 39.2-55.5% for III and V. Comparing the CÁ Á ÁC contacts, we can observe a large spread of percentage contribution ranging from 0.3% for V to 13.1% for compound I. This is also reflected in the presence ofstacking interactions observed in compound I ( Table 2).
As in our previous studies (Małecka et al., 2014;Kupcewicz et al., 2103), we found a relationship between the logP value and the fraction of the Hirshfeld surface covered by different

Synthesis and crystallization
The synthesis of compounds I and II is based on the condensation of chromanone or flavanone with an aryl aldehyde in the presence of piperidine (Fig. 8). Compound I was prepared according to a slightly modified procedure with respect to that described in the literature (Levai & Schag, 1979). A mechanically stirred mixture of chroman-4-one (0.01 mol), p-methoxybenzaldehyde (0.01 mol) and five drops of piperidine was heated at 413 K in an oil bath for four h. The progress of the synthesis was controlled by thin layer chromatography (TLC) using toluene/methanol (9:1 v/v) as eluent. After cooling the reaction mixture was left for 24 h at room temperature. The solidified product was filtered and crystal-lized from methanol. Compound I was obtained as a yellow powder. The isolated solid was further recrystallized by slow evaporation at room temperature of an acetone solution. Compound II was synthesized according to the procedure described by Pijewska et al., (1993). A mixture of 2-phenylchroman-4-one (0.01 mol), 3-hydroxybenzaldehyde (0.01 mol) and five drops of piperidine was heated under reflux in an oil bath with mechanical stirring. The reaction proceeded at 413 K for 5 h. The progress of the reaction was controlled by TLC (eluent: toluene/methanol, 9:1 v/v). After cooling at room temperature, the mixture was dissolved in methanol. After 24 h compound II precipitated as a light-cream fine crystalline powder and was purified by crystallization from methanol. Crystal suitable for X-ray analysis were obtained by slow evaporation of an ethanol solution at room temperature.

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq O3 0.5127 (4) 0.21588 (6)   where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.23 e Å −3 Δρ min = −0.29 e Å −3 Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.