Synthesis, crystal structure and computational analysis of 2,7-bis(4-chlorophenyl)-3,3-dimethyl-1,4-diazepan-5-one

The seven-membered 1,4-diazepane ring adopts a chair conformation with the 4-chlorophenyl groups in equatorial orientations. The title compound possesses a docking score of −8.9 kcal mol−1 with the human oestrogen receptor 3ERT protein.


DFT Studies
The theoretical optimized structure of (I) for the disordered molecule with higher site occupancy in the gas phase was computed using Gaussian 09W, Revision A.02 (Frisch et al., 2009) by applying the B3LYP/6-31G(d,p) level basis set.The optimized structure, HOMO and LUMO energies, and molecular electrostatic potential were generated using GaussView 5.0 (Dennington et al., 2009)   revealed that they are generally in good agreement (Table 2).
The slight variations between the geometrical parameters observed for the gas phase (theoretical) and those of the solid phase (experimental) are quite explicable.The electron density in highest occupied molecular orbital and lowest unoccupied molecular orbital computed are shown in Fig. 3.In the HOMO, the electron density largely resides over the diazepanone ring and the phenyl ring at C7 whereas in the LUMO, the electron density is delocalized and largely resides over the phenyl ring at C2.The energies of frontier molecular orbitals E HOMO and E LUMO are À 6.4148 eV and À 0.7333 eV, respectively.The energy gap �E (E LUMO -E HOMO ) is 5.6815 eV.The electron affinity (A = -E LUMO = 0.7333 eV) and ionization potential (IP = -E HOMO = 6.4148 eV) were used to calculate the electronegativity (� = 3.5740 eV), chemical hardness (� = 2.8407 eV) and chemical softness (S = 0.1760 eV).From the values of chemical hardness and the high energy gap, it is understood that the molecule is chemically hard and less polarizable.
The molecular electrostatic potential (MEP) surface (Fig. 4) provides information about the reactive sites of (I).The red region on the MEP surface over the carbonyl oxygen atom indicates an electron-rich centre with partial negative charge, which is vulnerable to electrophilic attack, whereas the yellow region over both the chlorine atoms shows a less electron-rich region and the pale-blue region spread all over the molecule indicates the less electron-deficient region (Politzer & Murray, 2002).

Hirshfeld surface and two-dimensional fingerprint plots
The Hirshfeld surface and two-dimensional fingerprint plots including all orientations of the disordered molecule were generated using CrystalExplorer 21.5 (Spackman et al., 2021) to study the molecular interactions with enhanced details (see also Fig. S1 in the supporting information).The Hirshfeld surface plotted over d norm in the range À 0.5371 to 1.5160 a.u. is shown in Fig. 5.The intense red spots indicating contacts shorter than the sum of van der Waals radii seen between N-H� � �O represent the shortest intermolecular contacts between nearest molecules while the other red spots indicated the interactions between C-H� � �O.The blue region denotes the longest interactions and the white medium-length interactions.

Table 2
Comparison of selected (X-ray and DFT) bond lengths, angles and torsion angles (A ˚, � ).

Crystal void analysis
The effectiveness of the packing of molecules in the unit cell of the crystal can be assessed with void analysis.The crystal void surfaces, i.e. the empty region of the crystal structure, define the isosurface of the procrystal electron density, and are generally calculated for the whole unit cell (Turner et al., 2011).The spatial void volume of the crystal of (I) (Fig. 7, see also Fig. S2 in the supporting information) in the unit cell was calculated (including all the orientations of the disordered molecule with partial site occupancies) to be 237.16A ˚3, i.e., 12.46%, of the crystal volume, which shows the mechanical strength of the crystal is high.

Interaction energies and Energy frame works
The intermolecular interaction energies were calculated for the disordered model with the higher site occupancy using CE-HF/6-31G(d,p) energy model in CrystalExplorer (Mackenzie et al., 2017;Turner et al., 2015).A cluster of molecules is generated with respect to a selected central molecule within a radius of 3.8 A ˚and the interaction energies computed (see also Fig. S3 in the supporting information).The calculated interaction energies are shown in the form of the graphicalcylindrical representation known as energy frameworks (Fig. 8).The frameworks constructed for E ele (red cylinders), E dis (green cylinders) and E total (blue cylinders) help to visualize the supramolecular architecture of (I).From the energy framework representation, it is evident that the dispersion energy of the title compound is greater than the electrostatic energy.Crystal voids in (I).

Molecular docking study
A molecular docking study was performed to examine the binding affinity of the title ligand with the human oestrogen receptor alpha (hER alpha) protein, for which the structural coordinates were retrieved from the Protein Data Bank (https://www.rcsb.org;PDB ID: 3ERT) in CIF format.The input file for the ligand was obtained by converting the CIF file (containing only the major component of the disorder) to pdb format using Mercury (version 2023.2.0; Macrae et al., 2020) and the docking studies carried out using the PyRx virtual screening tool (version 1.0; Dallakyan & Olson, 2015) and the results viewed using Discovery Studio Visualizer (v21.1.0.20298;Biovia, 2017) software.The molecular docking of (I) with 3ERT protein is shown in Fig. 9, revealing a good binding affinity, with a score of À 8.9 kcal mol À 1 .The KUZBUE compound also has a chair conformation of the 1,4-diazepane group with diaxial phenyl groups.The structure of PUGZAT is closely related to that of the title compound having phenyl groups in place of the chlorophenyl groups.In QADRUL, the planar 4-methylphenyl rings substituted at the C2 and C7 positions of the 1,4-diazepane ring, in a chair conformation, are in an equatorial orientation, as are the planar 2-chlorophenyl rings substituted at these positions in QADSAS.On the other hand, in WUPNED, which is closely related to the title compound, both chlorophenyl rings are in axial positions on the 1,4-diazepane chair ring.This makes a difference with the reported structure, where these substituents are in equatorial positions.

Figure 1
Figure 1View of the molecular structure of (I), showing 30% probability displacement ellipsoids (arbitrary spheres for the H atoms).The minor component of the disorder is not shown for clarity.

Figure 2 A
Figure 2 A partial packing diagram of the title compound viewed along the a axis showing the C-H� � �O and N-H� � �O hydrogen-bond interactions (dashed lines).

Figure 4
Figure 4Molecular electrostatic potential surface diagram of (I).

Figure 5
Figure 5 Hirshfeld surface for (I) showing hydrogen-bonding interactions with a neighbouring molecule.The minor component of the disorder is not shown for clarity.

Figure 8
Figure 8 Graphical representation of energy frameworks of (I): (a) electrostatic energy, (b) dispersion energy, (c) total energy and (d) colour-coded diagram of (I).

Figure 9
Figure 9Molecular docking: (a) three-dimensional and (b) two-dimensional views of the interaction of (I) with 3ERT protein.

Table 3
Experimental details.