Crystal structure, Hirshfeld surface analysis, crystal voids, interaction energy calculations and energy frameworks and DFT calculations of ethyl 2-cyano-3-(3-hydroxy-5-methyl-1H-pyrazol-4-yl)-3-phenylpropanoate

In the title molecule, the five- and six-membered rings are oriented at a dihedral angle of 75.88 (8)°. In the crystal, N—H⋯N hydrogen bonds form chains of molecules extending along the c-axis direction that are connected by inversion-related pairs of O—H⋯N into ribbons. The ribbons are linked by C—H⋯π(ring) interactions, forming layers parallel to the ab plane.


Chemical context
As part of our ongoing investigation into the use of pyrazoles to develop new heterocyclic systems (Moukha-Chafiq et al., 2006;Elmachkouri et al., 2022;Moukha-Chafiq et al., 2007a;Irrou et al., 2022), particularly those likely to exhibit intriguing biological activities, we note that compounds sharing structural similarities with pyrazole have demonstrated potential in various biological domains, exhibiting analgesic (Gursoy et al., 2000), antifungal and antibacterial (Prasath et al., 2015;Akbas et al., 2005), antiviral (Moukha-Chafiq et al., 2007b) and anticancer (Bensaber et al., 2014) activities.Consequently, the development of innovative synthetic pathways aims to obtain new molecules with structures that are better adapted to cellular receptors.In this respect, we recently reported the synthesis of some pyranopyrazoles (Ait Elmachkouri et al., 2023a) and pyrazolopyranopyrimidines (Ait Elmachkouri et al., 2023b).In our ongoing research, we focus our interest on pyrazole derivatives and present there the synthesis of ethyl 2cyano-3-(3-hydroxy-5-methyl-1H-pyrazol-4-yl)-3-phenylpropanoate, (I).For this synthesis, we adopted a threecomponent approach, using 3-methyl-1H-pyrazol-5-ol, ethyl 2cyanoacetate and benzaldehyde in ethanol in the presence of piperidine as base.Additionally, we conducted a Hirshfeld surface analysis and performed calculations on intermolecular interaction energies and energy frameworks.We compared the molecular structure optimized using density functional theory (DFT) at the B3LYP/6-311G(d,p) level, with the experimentally determined molecular structure in its solid state.

Structural commentary
As the title compound (I), (Fig. 1) crystallizes in a centrosymmetric space group (P1), the sample is racemic although the trans disposition of substituents about the C4-C10 bond is established.The dihedral angle between the mean planes of the five-and six-membered rings is 75.88 (8) � , while the sum of the angles about N1 is 360 � within experimental error, impli-cating involvement of its lone pair in intra-ring � bonding.The rotational orientation of the five-membered ring may be partially determined by a C4-H4� � �O3 hydrogen bond (H4� � �O3 = 2.41 A ˚) although the C4-H4� � �O3 angle of 115 � is quite small for such an interaction.

Hirshfeld surface analysis
In order to visualize the intermolecular interactions in the crystal of the title compound (I), a Hirshfeld surface (HS) analysis (Hirshfeld, 1977;Spackman & Jayatilaka, 2009) was carried out using Crystal Explorer 17.5 (Turner et al., 2017).In the HS plotted over d norm (Fig. 4), the white surface indicates contacts with distances equal to the sum of van der Waals radii, and the red and blue colours indicate distances shorter (in close contact) or longer (distant contact) than the van der Waals radii, respectively (Venkatesan et al., 2016).The bright-

Figure 1
Perspective view of the title molecule with labelling scheme and 50% probability ellipsoids.
Cg1 is the centroid of the five-membered ring.

D-H�
red spots indicate their roles as the respective donors and/or acceptors; they also appear as blue and red regions corresponding to positive and negative potentials on the HS mapped over electrostatic potential (Spackman et al., 2008;Jayatilaka et al., 2005) shown in      (Hathwar et al., 2015).

Crystal voids
The strength of the crystal packing is important for determining the response to an applied mechanical force.If the crystal packing results in significant voids, then the molecules are not tightly packed and a small amount of applied external mechanical force may easily break the crystal.A void analysis was performed to check the mechanical stability of the crystal by adding up the electron densities of the spherically symmetric atoms contained in the asymmetric unit (Turner et al., 2011).The void surface is defined as an isosurface of the procrystal electron density and is calculated for the whole unit cell where the void surface meets the boundary of the unit cell and capping faces are generated to create an enclosed volume.The volume of the crystal voids (Fig. 9a,b) and the percentage of free space in the unit cell are calculated as 100.94A ˚3 and 13.20%, respectively.Thus, the crystal packing appears compact and the mechanical stability should be substantial.
Energy frameworks combine the calculation of intermolecular interaction energies with a graphical representation of their magnitude (Turner et al., 2015).Energies between molecular pairs are represented as cylinders joining the centroids of pairs of molecules with the cylinder radius proportional to the relative strength of the corresponding interaction energy.Energy frameworks were constructed for E ele (red cylinders), E dis (green cylinders) and E tot (blue cylinders) (Fig. 10a,b,c).The evaluation of the electrostatic, dispersion and total energy frameworks indicate that the stabilization is dominated by the electrostatic energy contribution in the crystal structure of (I).

Database survey
A search of the Cambridge Structural Database (Groom et al., 2016; updated to November 2023) located no other structures similar to (I) until the search fragment was simplified to (II) (Fig. 11).With this, five hits were obtained with (III) (RUWZUH; Zonouz et al., 2020)

DFT calculations
The theoretical optimization of the molecular structure in the gas-phase was carried out using density functional theory (DFT) with the standard B3LYP functional and 6-311G(d,p) basis-set calculations (Becke, 1993) as implemented in GAUSSIAN 09 (Frisch et al., 2009).The resulting optimized parameters (bond lengths and angles) agreed satisfactorily with the experimental structural data (Table 2).The largest

Figure 10
The energy frameworks for a cluster of molecules of the title compound viewed down the a-axis direction showing (a) electrostatic energy, (b) dispersion energy and (c) total energy diagrams.The cylindrical radius is proportional to the relative strength of the corresponding energies and they were adjusted to the same scale factor of 80 with cut-off value of 5 kJ mol À 1 within 2 � 2 � 2 unit cells.

Figure 11
The closest matches to the title compound (I) according to the results obtained from the database survey.
differences between the calculated and experimental values are observed for the O1-C2 (0.06 A ˚) and O2-C3 (0.03 A ˚) bond lengths and the C3-O1-C2 and N2-C6-O3 bond angle (1.07 � ).These disparities can be linked to the fact that these calculations relate to the isolated molecule, whereas the experimental results correspond to interacting molecules in the crystal where intra-and intermolecular interactions with neighbouring molecules are present.The highest-occupied molecular orbital (HOMO), acting as an electron donor, and the lowest-unoccupied molecular orbital (LUMO), acting as an electron acceptor, are very important parameters for quantum chemistry.When the energy gap is small, the molecule is highly polarizable and has high chemical reactivity (Elmachkouri et al., 2023a).The numerical reactivity descriptors (ionization potential, electron affinity, chemical hardness, chemical softness, electronegativity, chemical potential, electrophilicity index and total energy), which are mainly based on the HOMO-LUMO energies, are summarized in Table 3.The optimized frontier molecular orbitals (HOMO and LUMO) are shown in Fig. 12.The LUMO is mainly centered on the 2-cyano group and spans the entire ethyl propanoate chain while the HOMO is primarily centered on the 3-phenyl substituent and spans the 3-(3-hydroxy-5methyl-1H-pyrazol-4-yl) portion.The energy band gap [(E = E LUMO -E HOMO ) of the molecule is about 5.77 eV, and the frontier molecular orbital energies, E HOMO and E LUMO , are À 6.59 eV and À 0.82eV, respectively.

Synthesis and crystallization
To a solution of pyrazolone (4 mmol), benzaldehyde (4 mmol) and ethyl 2-cyanoacetate (4 mmol, 0.42 ml) in absolute ethanol (12 ml), were added two drops of piperidine and the reaction mixture was refluxed with magnetic stirring for 2 h.The progress of the reaction was monitored by TLC using an ethyl acetate/hexane mixture as eluant.Finally, the resulting precipitate was filtered and the isolated solid was purified by recrystallization from ethanol to afford colourless crystals in 96% yield.The melting point was 454 K.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 4. Hydrogen atoms attached to carbon were included as riding contributions in idealized positions with isotropic displacement parameters tied to those of the attached atoms while those attached to nitrogen and to oxygen were located in a difference map and refined with DFIX 0.91 0.01 and DFIX 0.85 0.01 instructions, respectively.

Special details
Experimental.The diffraction data were obtained from sets of frames, each of width 0.5° in ω or φ, collected with scan parameters determined by the "strategy" routine in APEX4.The scan time was sec/frame.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.Refinement.Refinement of F 2 against ALL reflections.The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 .The threshold expression of F 2 > 2sigma(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement.R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.H-atoms attached to carbon were placed in calculated positions (C-H = 0.95 -1.00 Å) and were included as riding contributions with isotropic displacement parameters 1.2 -1.5 times those of the attached atoms.Those attached to nitrogen and to oxygen were placed in locations derived from a difference map and refined with DFIX 0.91 0.01 and DFIX 0.85 0.01 instructions, respectively.

Figure 2 A
Figure 2 A portion of one ribbon viewed along the b-axis direction with N-H� � �N and O-H� � �N hydrogen bonds depicted, respectively, by blue and darkpink dashed lines.Hydrogen atoms not involved in these interactions are omitted for clarity.[Symmetry codes: (i) x, y, z + 1; (ii) À x + 1, À y + 2, À z + 1.]

Fig. 5 .
The blue regions indicate positive electrostatic potential (hydrogen-bond donors), while the red regions indicate negative electrostatic potential (hydrogenbond acceptors).The shape-index of the HS is a tool to visualize �-� stacking by the presence of adjacent red and blue triangles; if there are no adjacent red and/or blue triangles, then there are no �-� interactions.Fig. 6 clearly suggests that there are no �-� interactions in (I).The overall two-dimensional fingerprint plot, Fig. 7a, and those delineated into H� � �H, H� � �N/N� � �H, H� � �C/C� � �H, H� � �O/O� � �H, C� � �O/O� � �C and N� � �O/O� � �N interactions (McKinnon et al., 2007) are illustrated in Fig. 7b-g respectively, together with their relative contributions to the Hirshfeld surface.The most abundant interaction is H� � �H, contributing 45.9% to the overall crystal packing, which is reflected in Fig. 7b as widely scattered points of high density due to the large hydrogen content of the molecule with the tip at d e = d i = 1.15A ˚.The symmetrical pair of spikes in the fingerprint plot delineated into H� � �N/N� � �H contacts

Figure 4
Figure 4View of the three-dimensional Hirshfeld surface of the title compound plotted over d norm .

Figure 5
Figure 5View of the three-dimensional Hirshfeld surface of the title compound plotted over electrostatic potential energy using the STO-3 G basis set at the Hartree-Fock level of theory.Hydrogen-bond donors and acceptors are shown as blue and red regions, respectively, around the atoms corresponding to positive and negative potentials.

Figure 6
Figure 6Hirshfeld surface of the title compound plotted over shape-index.
Figure 7 The full two-dimensional fingerprint plots for the title compound, showing (a) all interactions, and delineated into (b) H� � �H, (c) H� � �N/ N� � �H, (d) H� � �C/C� � �H, (e) H� � �O/O � � � H, (f) C� � �O/O� � �C and (g) N� � �O/O� � �N interactions.The d i and d e values are the closest internal and external distances (in A ˚) from given points on the Hirshfeld surface.

Figure 9
Figure 9Graphical views of voids in the crystal packing of (I) (a) along the a-axis direction and (b) along the b-axis direction.

Table 2
Comparison of selected X-ray and DFT geometric data (A ˚, � ).

Table 4
Experimental details.