Synthesis, crystal structure, DFT calculations and Hirshfeld surface analysis of 3-butyl-2,6-bis(4-fluorophenyl)piperidin-4-one

The title compound consists of two fluorophenyl groups and one butyl group equatorially oriented on a piperidine ring, which adopts a chair conformation. The dihedral angle between the mean planes of the phenyl rings is 72.1 (1)°. In the crystal, weak N—H⋯O and C—H⋯F interactions, which form [14] motifs, link the molecules into infinite C(6) chains propgagating along [001].

The title compound, C 21 H 23 F 2 NO, consists of two fluorophenyl groups and one butyl group equatorially oriented on a piperidine ring, which adopts a chair conformation. The dihedral angle between the mean planes of the phenyl rings is 72.1 (1) . In the crystal, N-HÁ Á ÁO and weak C-HÁ Á ÁF interactions, which form R 2 2 [14] motifs, link the molecules into infinite C(6) chains propagating along [001]. A weak C-HÁ Á Á interaction is also observed. A Hirshfeld surface analysis of the crystal structure indicates that the most significant contributions to the crystal packing are from HÁ Á ÁH (53.3%), HÁ Á ÁC/CÁ Á ÁH (19.1%), HÁ Á ÁF/ FÁ Á ÁH (15.7%) and HÁ Á ÁO/OÁ Á ÁH (7.7%) contacts. Density functional theory geometry-optimized calculations were compared to the experimentally determined structure in the solid state and used to determine the HOMO-LUMO energy gap and compare it to the UV-vis experimental spectrum.

Chemical context
Piperidin-4-one compounds have various biological properties and have applications as anti-viral, antitumor, and antihistaminic agents (El-Subbagh et al., 2000;Mobio et al., 1989;Katritzky & Fan, 1990;Arulraj et al., 2020). 2,6-Disubstituted piperidine-4-ones commonly adopt a chair conformation for the heterocyclic ring (see, for example, Rajkumar et al., 2018). However, on varying the substituents attached to the phenyl ring, the conformation of the ring may change (e.g. Ramachandran et al., 2007;Arulraj et al., 2020). Additionally, the attached functional group on the crystalline compound is important to determine the activity of the compound in the area of drug discovery.
As part of our studies in this area, we now describe the synthesis and structure of the title compound, C 21 H 23 F 2 NO, (I), in order to establish the structural effects of the butyl and fluoro groups on the conformation. DFT calculations and a Hirshfeld analysis have also been carried out.

Hirshfeld surface analysis
A Hirshfeld surface (HS) analysis (Spackman & Jayatilaka, 2009) was carried out using CrystalExplorer17.5 (Turner et al., 2017) to visualize the intermolecular interactions in (I). The bright-red spot near H1 indicates its role as a hydrogen-bond donor to O1 (Fig. 3) and another red region near H7 correlates with the C7-H7Á Á ÁF1 interaction. The shape-index of the HS represents a way to visualizestacking by the presence of red and/or blue triangles but there are none in in the title compound (see Figure S1 in the supporting information). The curvedness of the HS can be used to divide the molecular surface into contact patches with each neighbouring molecule thereby using it to define a coordination number in the crystal (see Figure S2 in the supporting information).  Table 1 Hydrogen-bond geometry (Å , ).

Figure 2
Crystal packing for C 21 H 23 F 2 NO viewed along the a-axis direction.

Figure 1
A view of the molecular structure of C 21 H 23 F 2 NO, showing displacement ellipsoids drawn at the 30% probability level.

Figure 3
A view of the three-dimensional Hirshfeld surface for C 21 H 23 F 2 NO, plotted over d norm in the range À0.39 to 1.31 a.u. Two-dimensional fingerprint plots show the relative contributions of the various types of contacts to the Hirshfeld surface for (I) (McKinnon et al., 2007). The overal plot is shown in Fig. 4a. The HÁ Á ÁH contacts (53.3%) are the most important interactions (Fig. 4b), presumably because of the large hydrogen content of (I), with a pair of blue-coloured blunt spikes directing towards the bottom left, in the region 1.20 Å < (d e + d i ) < 1.19 Å . The pair of wings for the HÁ Á ÁC/ CÁ Á ÁH contacts ( Fig. 4c; 19.1% contribution to the HS) is in the region 1.04 Å < (d e + d i ) < 1.58 Å and includes the weak C-HÁ Á Á interaction. The HÁ Á ÁF/FÁ Á ÁH contacts ( Fig. 4d; 15.7% contribution) are seen as a pair of wings in the region 1.04 Å < (d e + d i ) < 1.38 Å . The wings for the HÁ Á ÁO/OÁ Á ÁH contacts ( Fig. 4e; 7.7% contribution) are in the region of 0.88 Å < (d e + d i ) < 1.20 Å while the blunt wings in the plot for FÁ Á ÁF contacts ( Fig. 4f; 2.6%) are in the region 1.60 Å < (d e + d i ) < 1.70 Å . The CÁ Á ÁC contacts (Fig. 4g) make a negligible 0.1% contribution and are viewed as a dash pattern pointing diagonally left. The OÁ Á ÁO contacts (Fig. 4h) make no contribution to the HS. The most significant of these contributions to the overall Hirshfeld surface are shown in Figure S3 in the supporting information.

DFT Calculations
A density functional theory (DFT) geometry-optimized calculation for (I) was carried out using WebMo Pro (Schmidt & Polik, 2007) in the GAUSSIAN 09 program package (Frisch et al., 2009) using the 6-31+G(d) basis set (Hehre et al., 1986). The starting geometry was taken from the crystal structure and no solvent correction was applied. A comparison of bond angles and bond distances in the crystal to those from the DFT calculation are listed in supplementary Table S1, which generally shows good agreement. An overlay of the geometryoptimized calculation with the crystal structure has an r.m.s. deviation of 0.478 Å . The major difference between the experimental and calculated structures occurs in the orientation of the C12-C17 rings, which are rotated by 41.8 (6) with respect to each other.
The calculated energies (eV) for the frontier molecular orbitals are shown in Fig. 5 and key parameters are listed in supplementary Table S2. Both the HOMO and HOMOÀ1 are localized largely on the piperidine ring. For the LUMO, LUMO+1 and LUMO+2, the orbitals are delocalized over the piperidine ring as well as both phenyl rings. The observed UV/ vis absorption spectrum (Fig. 6) shows two band envelopes with max values located at ca 256 and 216 nm ($4.84 and 5.74 eV). The molar extinction coefficients, ", are 1.12 and 2.50 l mol À1 cm À1 , respectively. We tentatively assign the first absorption band envelope at 256 nm to overlapping contri-    Rajkumar et al., 2018). The piperidine ring in the title compound is in a slightly distorted chair conformation, similar to that observed in ACEZUD and PEXDOO but different from the chair conformation seen in RUGLOV and PEXDII. The dihedral angle between the mean planes of pendant phenyl rings is 72.(1) in the title compound compared to 76.1 (1) in PEXDOO, whereas it is 59.90 (5), 59.1 (1) and 63.4 (1) in RUGLOV, PEXDII and ACEZUD, respectively. In all five compounds, various N-HÁ Á ÁO and weak C-HÁ Á ÁO, C-HÁ Á Á or C-HÁ Á ÁF interactions occur in the crystal.

Synthesis and crystallization
A mixture of ammonium acetate (0.100 mol, 7.71 g), 4-fluorobenzaldehyde (0.200 mol, 22.0 ml) and 2-heptanone (0.100 mol, 14.2 ml) in distilled ethanol was heated first to boiling. After cooling, the viscous liquid obtained was dissolved in ether (200 ml) and shaken with 100 ml concentrated hydrochloric acid. The precipitated hydrochloride of 3butyl-2,6-bis(4-fluorophenyl)piperidin-4-one was removed by filtration and washed first with a 50 ml mixture of ethanol and ether (1:1) and then with ether to remove most of the coloured impurities. The resulting yellowish base was liberated from an alcoholic solution by adding aqueous ammonia (15 ml) and then diluted with water (200 ml). Then, 1.0 g of the crude sample was dissolved in 100 ml of absolute alcohol, warmed until the sample dissolved, and 2.0 g of animal charcoal added in the resulting solution. The hot solution was filtered and the procedure repeated again. The filtered solution was left for 48 h and colourless prisms of (I) were collected in 75% yield.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The C-bound H atoms were geometrically placed (C-H = 0.93-0.98 Å ) and refined as riding atoms. The N-bound H atom was located in a difference map and its position was fixed. The methyl group was allowed to rotate, but not to tip, to best fit the electron density. The constraint U iso (H) = 1.2U eq (carrier) or 1.5U eq (methyl carrier) was applied in all cases.

3-Butyl-2,6-bis(4-fluorophenyl)piperidin-4-one
Crystal data 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.