Structural Chemistry & Crystallography Communication

Keywords

Lattice energy; Crystal structure; Pyrazole

Introduction

Studying intermolecular interactions in molecular crystals has been a very important aspect of supramolecular chemistry [1-3]. Both strong and weak intermolecular interactions have been observed to be responsible for the 3D arrangement of molecules in a crystal [4-6] and hence a detailed analysis of their nature is very important. Strong intermolecular interactions such as N-H… O/N, O-H…O/N [7-9] has been well studied and documented in the literature. In the past 15-20 years, in addition to strong interactions, weak interactions such as C-H…O/N [10,11], C-H…X (X=-F, -Cl, -Br, -I) [12-17], C-H…π [18,19], lp…π [20,21], X…X(X =F, Cl, Br, I ) [22-25] has garnered attention across the world. Apart from this, various studies have also been performed to understand the interplay between strong and weak interactions within the same molecule in the crystal [26-28]. Along with experimental analysis, detailed computational studies have also become an important tool in delineating the strength and nature of intermolecular interactions [12,29-31].

In our study, we have performed a complete structural analysis on a pyrazole derivative, namely 4-(2-(ethoxymethyl) phenyl)- 1H-pyrazol-3-ol (PRZ). Pyrazoles are five membered heterocyclic molecules with two nitrogens adjacent to each other. These are aromatic systems with six delocalized π electrons. It has been observed that pyrazole derivatives are biologically important with applications in antimicrobial [32], analgesic [33], anticancer activities [34] and hence it is important to understand the molecular conformation and intermolecular interactions in pyrazole derivatives. In PRZ, we have two nitrogen atoms and two oxygen atoms in different electronic environments which can participate in hydrogen bonding. Apart from this, PRZ have C-H bonds which can act as weak hydrogen bond donors. The π rings present in the molecule can also participate in the formation of intermolecular interactions and can play a role in crystal packing. Due to the above-mentioned properties, it was of interest to study the nature and strength of intermolecular interactions in PRZ.

Synthesis of PRZ

0.190 g (0.1 mol) of 4-(2-(hydroxymethyl) phenyl)-1H-pyrazol- 3-ol, was dissolved in 10 ml ethanol and 2 drops of H₂SO₄. The reaction mixture was refluxed for 6 hr at 80°C temperature and cooled to separate out the final product PRZ. The compound is recrystallized by dissolving it in ethanol. By the process of slow evaporation colorless crystals of the product were obtained. The scheme of the reaction is as shown in (Figure 1).

Figure 1: Schematic representation of synthesis of PRZ with its chemical name.

Crystal growth and single-crystal X-ray diffraction

Suitable crystals for X-ray diffraction studies were grown in ethanol at room temperature through solvent evaporation method. White transparent single crystals were obtained. Single crystal X-ray measurements were carried out on a Bruker AXS Kappa Apex 2 CCD diffractometer using monochromated MoKα radiation (λ=0.71073 Å) in phi (φ) and omega (ω) scans at 292(2) K. Unit cell measurement, data collection, integration, scaling and absorption corrections were performed using Bruker Apex II software [35]. The intensity data were processed by using the Bruker SAINT [36] suite of programs. The crystal structure was refined by the full matrix least squares method using SHELXL14 [37] present in the program suite WinGX [38]. Empirical absorption correction was applied using SADABS [39]. The non-hydrogen atoms were refined anisotropically and the hydrogen atoms bonded to C and N atoms were positioned geometrically and refined using a riding model with U_iso(H)=1.2U_eq (C, N). The molecular connectivity and the crystal packing diagrams were generated using the Mercury 3.1 (CCDC) program [40]. Geometrical calculations were done using PARST [41] and PLATON [42]. The details of data collection and crystal structure refinement are shown in (Table 1).

Table 1: Single crystal data collection and refinement details of PRZ.

Theoretical calculations

Optimization of the crystal structure was performed at MP2 level of theory at 6-311G** basis set using Gaussian09 [43]. The minima of the optimized structure were confirmed by the absence of imaginary frequencies. All calculations for the analysis of the crystal structure and intermolecular interactions were performed at the crystal geometry. The C-H bond length was moved to its neutron value of 1.08 Å while O-H and N-H bond was fixed at 1.00 Å. The molecular electrostatic potential were plotted on a Hirshfeld iso-surface using Crystal Explorer 3.1 [44] at 6-311G** basis set with wave functions generated using TONTO [45]. Lattice energy and intermolecular interaction energies were calculated using PIXEL code present in the CLP computer program [31]. The program PIXEL provides the advantage of partitioning the total interaction energy for the different molecular pair’s into the corresponding coulombic, polarization, dispersion and repulsion components respectively. Coulombic terms are handled by Coulomb’s law while the polarization terms are calculated utilizing the linear dipole approximation in PIXEL,where the incoming electric field acts on local polarizabilities and generates a dipole with its associated dipole separation energy. The treatment of the dispersion terms are simulated in London’s inverse sixth power approximation, involving ionization potentials and polarizabilities and the repulsion is represented as a modulated function of wave function overlap. Some selected molecular pairs were further analyzed by using AIMALL [46] which is based on Bader’s theory of atoms in molecules [47]. It gives us properties like ρ, ∇²ρ, local potential energy (V_b), and kinetic potential energy (G_b) at the bond critical point [44]. For AIMALL, ab initio calculations for all the molecular pairs were performed at the MP2/6-311G** level of theory (with “density = current” keyword) using Gaussian 09. Then the formatted checkpoint file (fchk) was considered as the input for AIMALL, which is then used to generate the wave function file (.wfx file) by the software itself and followed by the topological analysis. Contributions from different interactions were also analyzed by fingerprint plot [49] generated using Crystal Explorer 3.1.

Results and Discussion

The ORTEP of PRZ has been shown in (Figure 2). PRZ crystallized in a monoclinic system in P2₁/n space group with Z = 4. The molecule can be broadly divided into two different parts. The first was the pyrazol-3-ol and the second is the phenyl group to which a flexible ethoxymethyl group is attached. A superimposition of the structure of PRZ obtained from the crystal geometry and the optimized geometry has been shown in (Figure 3). Torsion I and II values showed that the geometry of the pyrazole group connected to the phenyl ring is nearly equal to each other. The major difference was observed in the flexible ethoxy methyl group where the experimental value for Torsion III was 97.30(2) ° while that obtained from the theoretical calculation was 85.31° (Table 2).

Figure 2: ORTEP of PRZ at 50% ellipsoidal probability along with the atom numbering. Hydrogen atoms omitted for clarity.

Figure 3: Structural overlay diagram of PRZ at crystal geometry (in yellow) with that of the optimized geometry (in orange).

Table 2: Experimental and theoretical values obtained for selected torsion angles in PRZ.

The lattice energy of the molecule was calculated to be -162.2 kJ/ mol (Table 3). Energy partitioning showed that the maximum contribution towards the lattice stabilization is coming from the coulombic and dispersion component with each contribution around 40% while the remaining contribution comes from the polarization energy.

Table 3: Lattice energy of PRZ partitioned into different energy components.

The molecular electrostatic potential map was plotted on Hirshfeld iso surface with electrostatic potential ranging from 0.05 a.u. (blue) to −0.05 (red). The molecular electrostatic potential (MEP) map of PRZ revealed that the regions of negative potential are concentrated around the electronegative oxygen and nitrogen atom present in the molecule (Figure 4). The region around the hydrogen atom and C-H bond of the ethoxy methyl group constituted the positive region in the molecule. The π system present in the molecule also exhibited a negative potential but as clearly visible from the MEP plot the magnitude of the potential is less as compared to those observed for the oxygen and nitrogen atoms.

Figure 4: MEP plotted on the Hirshfeld iso surface of PRZ. The ranges of ESP are from 0.05 a.u. (blue) to -0.05 a. u. (red).

Different intermolecular interactions present in PRZ along with geometrical parameters, symmetry and interaction energies partitioned into different energy components has been represented in (Table 4). The packing diagram of PRZ down the bc plane is shown in (Figure 5). The most stabilized molecular pair was observed to be a short O-H…N H-bond along the c-axis having H…N distance of 1.71 Å and O-H…N angle being 171° (I). The stabilization energy was calculated to be -69.7 kJ/mol. The stability of this molecular pair is driven by the coulombic contribution (~56%), followed by polarization (~33%) and dispersion (~11%) components respectively (Table 4). The second most stabilized molecular pair also contained a short N-H…O H-bond along with the presence of C-H…π interactions. The interaction energy for this molecular pair was calculated to be -56.6 kJ/mol. In this molecular pair, the contribution of the dispersion component was observed to be greater than that of the polarization component. The reason for the increased contribution from the dispersion component can be attributed to the presence of weak C-H…π interactions which are of a dispersive nature (Figure 5). Motif III consisted of two weak interactions. The first was a weak C-H…O interaction and the other being a C-H…π interaction. This molecular pair was of a dispersive nature with the dispersion component dominating with 71.5% contribution towards the total stabilization (Table 4). Motif- IV has stabilization energy of -17.6 kJ/mol because of the presence of a weak C-H…O interaction. As observed for the previous molecular pairs with weak interactions, also in the current case, the stability was governed by dispersion component (~72%) followed by coulombic (~20%) and polarization (~8%) contribution. Motif-V represents a unique molecular pair with the presence of short and highly directional H…H contacts (Table 4). The crystal packing clearly depicts the presence of side chain interactions involving the ethoxy methyl (em) group of one molecule with a similar group of a centrosymmetrically related molecule and this leads to the formation of a molecular pair which can be best described as arising from purely dispersive forces (Figure 5). The dispersive nature is clearly evident from the decomposition of the energy component indicating a contribution of ~82% towards the total stabilization (Table 4). The least stabilized molecular pair consists of a C-H…O interaction, the interaction energy being -9.3 kJ/mol.

Figure 5: Crystal packing of PRZ down the bc plane showing strong O-H…N and N-H…O H-bonds along with weak C-H…O, C-H…p and H…H contacts.

Table 4: List of intermolecular interaction energies (kJ/mol) present in PRZ.

QTAIM analysis using AIMALL was performed on motif I and II which contains strong hydrogen bonds and on motif V which contained a short H…H contact. (Table 5) shows the topological parameters obtained from the analysis and (Figure 6) shows the Bond Critical Point (BCP) obtained between the interacting atoms marked with arrow in (Figure 6). The ρ value for H…N contact was 0.340 e/ų while for H…O interaction was observed to be 0.163 e/ų. Similarly the ∇²ρ for H…N interaction was higher than that of H…O contact. For motif II, a BCP was also observed between hydrogen and carbon atom confirming the presence of a C-H…π interaction.

Figure 6: Presence of Bond Critical Points (BCP) [marked with arrows] in I, II, V of PRZ. Only the most relevant BCP’s has been shown.

Table 5: Topological parameters at BCP for I, II, V in PRZ.

In V, multiple bcp were observed between hydrogen atoms further establishing the significance of H…H contacts. The most relevant BCP in V was between H11B and H16C with ρ and ∇²ρ values of 0.035e/ ų and 0.367e/Å⁵ respectively. The obtained value is similar to values reported previously for H…H interactions [50]. As expected, the magnitude of ρ and ∇²ρ clearly depicts that the strength of H…H interactions is much lower relative to strong hydrogen bonds.

We have further analyzed the crystal structure of PRZ by looking at the fingerprint plot for different interactions (Figure 7). Fingerprint plot is a unique tool to represent the intermolecular interactions present in the crystal structure. The maximum contribution in the fingerprint plot is from H…H contacts (52.4 %). This high contribution can be attributed to the presence of ethoxy methyl group in the molecule which involves the existence of dispersion interactions as discussed earlier. The next contribution is from C…H contacts (23.3%) on account of the presence of C-H…π interactions. N…H and O…H contributed equally to the extent of 19.3% (Figure 8).

Figure 7: Fingerprint plot for different interactions present in PRZ.

Figure 8: Percentage distribution of different interactions present in PRZ as obtained from fingerprint plots.

Conclusion

In this study, we have quantitatively analyzed the intermolecular interactions present in the crystal structure of 4-(2-(ethoxymethyl) phenyl)-1H-pyrazol-3-ol. The geometry of the crystal structure is largely similar to the optimized geometry with slight deviation in the flexible ethoxy methyl region. Coluombic and dispersion energies both have nearly equal contributions towards the stabilization of the crystal lattice. Calculations on the intermolecular interaction energies showed that in case of strong H-bonds such as N-H…O or O-H…N, coluombic contribution played a dominating role but in presence of the weak interactions, dispersion becomes a dominating factor. This study can help us in designing different biologically active derivatives of pyrazoles by changing the strength of donor and/or acceptor atom which can give rise to interactions of different strength and nature which in turn can help in identifying binding capabilities of such molecules with enzymes. Due to the biological activity of pyrazole derivatives, polymorphism studies on PRZ will be of interest with regard to pharmaceutical industry.

Acknowledgements

RS thanks DST for INSPIRE-PhD fellowship. DC thanks IISERB for providing infrastructure and research facilities.

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