Crystal structure determination, Hirshfeld surface, crystal void, intermolecular interaction energy analyses, as well as DFT and energy framework calculations of 2-(4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetic acid

The bicyclic ring system is planar with the carboxymethyl group rotated out of this plane by 81.05 (5)°. In the crystal, corrugated layers are generated by N—H⋯O, O—H⋯N and C—H⋯O hydrogen-bonding interactions. The layers are associated through additional C—H⋯π(ring) interactions.

In the title molecule, C 7 H 6 N 4 O 3 , the bicyclic ring system is planar with the carboxymethyl group inclined by 81.05 (5) to this plane. In the crystal, corrugated layers parallel to (010) are generated by N-HÁ Á ÁO, O-HÁ Á ÁN and C-HÁ Á ÁO hydrogen-bonding interactions. The layers are associated through C-HÁ Á Á(ring) interactions. A Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from HÁ Á ÁO/OÁ Á ÁH (34.8%), HÁ Á ÁN/NÁ Á ÁH (19.3%) and HÁ Á ÁH (18.1%) interactions. The volume of the crystal voids and the percentage of free space were calculated to be 176.30 Å 3 and 10.94%, showing that there is no large cavity in the crystal packing. Computational methods revealed O-HÁ Á ÁN, N-HÁ Á ÁO and C-HÁ Á ÁO hydrogen-bonding energies of 76.3, 55.2, 32.8 and 19.1 kJ mol À1 , respectively. Evaluations of the electrostatic, dispersion and total energy frameworks indicate that the stabilization is dominated via dispersion energy contributions. Moreover, the optimized molecular structure, using density functional theory (DFT) at the B3LYP/6-311G(d,p) level, was compared with the experimentally determined one. The HOMO-LUMO energy gap was determined and the molecular electrostatic potential (MEP) surface was calculated at the B3LYP/6-31G level to predict sites for electrophilic and nucleophilic attacks.
As a continuation of our research in this context, the title compound, (I), was synthesized by basic hydrolysis of the methyl ester of 2-(4-oxo-4, 5-dihydro-1H-pyrazolo[3,4d]pyrimidin-1-yl)acetate. We report herein its synthesis, molecular and crystal structures along with Hirshfeld surface analysis, crystal void and intermolecular interaction energies. Moreover, the optimized molecular structure carried out at the B3LYP/6-311 G(d,p) level is compared with the experimentally determined structure, and energy framework as well as molecular electrostatic potential (MEP) surface computations carried out at the B3LYP/6-31G level to predict the reactive sites for the electrophilic and nucleophilic attacks on (I) are presented.

Structural commentary
The pyrazolopyrimidine moiety is planar to within 0.0143 (10) Å (r.m.s deviation = 0.0082 Å ) with the flap atom N1, which is part of the NH group, being the furthest from the mean plane. The plane of the carboxyl group is inclined to the above plane by 81.05 (5) . There are no unusual bond lengths or interatomic angles in the molecule (Fig. 1).

Figure 3
View of the crystal packing along the a-axis direction with N-HÁ Á ÁO, O-HÁ Á ÁN and C-HÁ Á ÁO hydrogen bonds shown, respectively, by lightblue, pink and black dashed lines. C-HÁ Á Á(ring) interactions are shown by green dashed lines.  (Table 1 and Fig. 3).

Hirshfeld surface and crystal void analysis
In order to visualize the intermolecular interactions in the crystal of (I), a Hirshfeld surface (HS) analysis (Hirshfeld, 1977) was carried out by using Crystal Explorer (Spackman et al., 2021). 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 or longer than the sum of the van der Waals radii, respectively (Venkatesan et al., 2016). The bright-red spots indicate sites of donor and/or acceptor interactions and they also appear as blue and red regions corresponding to positive (hydrogen bond donors) and negative (hydrogen bond acceptors) potentials on the HS mapped over electrostatic potential (Spackman et al., 2008;Jayatilaka et al., 2005), as shown in Fig. 5. The shape-index of the HS is a tool to visualize the presence ofstacking by the appearance of adjacent red and blue triangles. Fig. 5 clearly suggests that there are no significantinteractions in (I), as the above pattern is absent. The overall two-dimensional fingerprint plot, Fig. 6a, and those delineated into HÁ Á ÁO/OÁ Á ÁH, HÁ Á ÁN/NÁ Á ÁH, HÁ Á ÁH, HÁ Á ÁC/CÁ Á ÁH, CÁ Á ÁO/OÁ Á ÁC, NÁ Á ÁO/OÁ Á ÁN, CÁ Á ÁN/NÁ Á ÁC, CÁ Á ÁC and OÁ Á ÁO contacts (McKinnon et al., 2007), and their relative contributions to the Hirshfeld surface, are illustrated in Fig. 6b-j. The most important interaction is HÁ Á ÁO/OÁ Á ÁH, contributing 34.8% to the overall crystal packing, which is shown in Fig. 6b where the pair of spikes have tips at d e + d i = 1.81 Å . The pair of spikes in the fingerprint plot delineated into HÁ Á ÁN/NÁ Á ÁH contacts, Fig. 6c, with a 19.3% contribution to the HS has a symmetric distribution of points with the tips at d e + d i = 1.74 Å . The HÁ Á ÁH contacts contribute with 18.1% to the HS and are shown in Fig Hirshfeld surface of the title compound plotted over shape-index.

Figure 6
The full two-dimensional fingerprint plots for the title compound  View of the three-dimensional Hirshfeld surface of the title compound, plotted over d norm in the range À0.6986 to 1.3450 a.u.
high density due to the large hydrogen content of the molecule with the tip at d e = d i = 1.28 Å . The high contribution of these interactions suggest that van der Waals interactions play the major role in the crystal packing (Hathwar et al., 2015). The presence of C-HÁ Á Á interactions is shown by the pair of wings in the fingerprint plot delineated into HÁ Á ÁC/CÁ Á ÁH contacts with the tips at d e + d i = 2.93 Å ( 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. To check the mechanical stability of the crystal, a void analysis was performed 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. 8a and b) and the percentage of free space in the unit cell are calculated as 176.30 Å 3 and 10.94%, 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. 9a, b and c). The results indicate that the stabilization is dominated via dispersion energy contributions in (I).

DFT and Molecular electrostatic potential (MEP) calculations
Density functional theory (DFT) using the standard B3LYP functional (Becke, 1993) and Pople's basis set 6-31G(d,p) implemented in GAUSSIAN 09 (Frisch et al., 2009) was used to optimize the molecular structure of (I) in the gas phase. The minimum was confirmed by frequency calculations, and the resulting optimized parameters (bond lengths and angles) agreed satisfactorily with the experimental structural data ( Table 2). As a result, energies and other physico-chemical properties obtained from the optimized structure could be safely used to describe those of (I). The corresponding HOMO and LUMO energies were then used to estimate some parameters of global chemical reactivity, such as electronegativity (), hardness (), ionization potential (I), electrophilicity (!) and softness () (Table 3). In addition, the molecular electrostatic potential (MEP) map, and dipole moment () of (I) were similarly calculated.
Minor differences between theory and experiment are likely due to optimized values being obtained in the isolated gas phase, neglecting interactions in the solid phase. Briefly, the average O2-C7 and N4-C5 bond lengths calculated at  The energy framework for a cluster of molecules of (I) viewed down the a-axis direction (the b axis is vertical and the c axis is horizontal) 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 À1 within 1 Â 1 Â 1 unit cells.

Table 2
Comparison of selected (X-ray and DFT) bond lengths and angles (Å , ).  the DFT/B3LYP/6-31G(d,p) level are 1.3767 and 1.3412 Å , respectively, which is slightly higher than the experimental values of 1.3148 (17) and 1.3182 (19) Å , respectively. Moreover, the torsion angles N4-N3-C3-N2 = À179.92 and C3-N2-C2-N1 = À0.53 agree well with the experimental ones of À178.88 (12) and À0.6 (2) . The optimized frontier molecular orbitals (HOMO and LUMO) are shown in Fig. 10. These orbitals play an important role in intramolecular charge transfer (ICT). The topological characteristics of these levels are important for interpreting kinetic stability and therefore potential chemical reactivity. The calculated energy band gap [ÁE = E LUMO -E HOMO ] of the molecule is 5.25 eV which indicates a hard molecule with low polarizability and low chemical and biological activities but high kinetic stability. The LUMO is mainly centered on the plane extending over the whole aromatic ring system of (I). The numerical reactivity descriptors, which are mainly based on HOMO-LUMO energies, are summarized in Table 3. The ionization potential (I) is defined as the amount of energy required to remove an electron from a molecule. The high ionization energy indicates also high stability and hence chemical inertness. Electron affinity (A) is defined as the energy released when an electron is added to a neutral molecule. Therefore a large value indicates the tendency of the molecule to retain its electrons. A negative chemical potential () reflects molecular stability while hardness () char-acterizes the resistance of the cloud of molecular electrons to deformation during small disturbances. The overall electrophilicity index (!) of a molecule is a measure of its stabilization energy following the addition of an external electronic charge or its resistance to exchange electron(s) with the system (Parr et al., 1999). For (I), the ionization energy of 6.66 eV indicates high stability.
The molecular electrostatic potential (MEP) of the surface was calculated on the optimized B3LYP/6-31G (d,p) level using Gaussview software (Frisch et al., 2009). The MEP surface (Fig. 11) gives information about the reactive sites. The total electron density on which the electrostatic potential surface has been mapped is shown in Fig. 12 where a visual representation of chemically active sites and the comparative reactivity of atoms is also shown. The red regions denote the most negative electrostatic potential, the blue regions represent most positive electrostatic potential, and green regions represent the region of zero potential. Fig. 12 confirms the existence of intermolecular N-HÁ Á ÁO, O-HÁ Á ÁN and-HÁ Á ÁO hydrogen-bonding interactions. Contour surface of the electrostatic potential of (I).

Figure 10
The optimized frontier molecular orbitals (HOMO and LUMO) with the energy band gap of (I).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 4. Hydrogen atoms attached to carbon were placed in idealized positions while those attached to nitrogen and to oxygen were placed in locations derived from a difference-Fourier map and their parameters adjusted to give N-H = 0.91 and O-H = 0.87 Å . All H atoms were included as riding contributions with isotropic displacement parameters tied to those of the attached atoms.

Synthesis and crystallization
Ethyl 2-(4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1yl)acetate (5 mmol) was dissolved in 10 ml of ethanol to which 10 ml of NaOH (aqueous, 10% wt ) were added. The reaction mixture was stirred magnetically at room temperature for 4 h. After evaporation of ethanol and washing the aqueous phase with ethyl acetate, the mixture was acidified with an aqueous solution of HCl (3 N). The formed precipitate was filtered off and rinsed with ether. The crude product was recrystallized from ethanol to obtain colourless crystals of (I) in 72% yield.

Funding information
JTM acknowledges NSF-MRI grant No. 1228232 for the purchase of the diffractometer and Tulane University for support of the Tulane Crystallography Laboratory. TH is grateful to Hacettepe University Scientific Research Project Unit (grant No. 013 D04 602 004).

Figure 13
The molecular moiety used for the database search procedure. Computer programs: APEX3 and SAINT (Bruker, 2016), SHELXT (Sheldrick, 2015a), SHELXL (Sheldrick, 2015b), DIAMOND (Brandenburg & Putz, 2012) and publCIF (Westrip, 2010 Data collection: APEX3 (Bruker, 2016); cell refinement: SAINT (Bruker, 2016); data reduction: SAINT (Bruker, 2016); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL (Sheldrick, 2015b); molecular graphics: DIAMOND (Brandenburg & Putz, 2012); software used to prepare material for publication: publCIF (Westrip, 2010). where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.25 e Å −3 Δρ min = −0.33 e Å −3 Extinction correction: SHELXL 2018/3 (Sheldrick, 2015b), Fc * =kFc[1+0.001xFc 2 λ 3 /sin(2θ)] -1/4 Extinction coefficient: 0.0304 (14) 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. 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 -0.99 Å) while those attached to nitrogen and to oxygen were placed in locations derived from a difference map and their parameters adjusted to give N-H = 0.91 and O-H = 0.87 Å. All were included as riding contributions with isotropic displacement parameters 1.2 -1.5 times those of the attached atoms.