Crystal structure, computational study and Hirshfeld surface analysis of ethyl (2S,3R)-3-(3-amino-1H-1,2,4-triazol-1-yl)-2-hydroxy-3-phenylpropanoate

The mean planes of the phenyl and triazole rings are nearly perpendicular to one another as a result of the intramolecular C—H⋯O and C—H⋯π(ring) interactions. In the crystal, layers parallel to (101) are generated by O—H⋯N, N—H⋯O and N—H⋯N hydrogen bonds. The layers are connected by inversion-related pairs of C—H⋯O hydrogen bonds.


Chemical context
The triazole ring system has attracted considerable interest among synthetic organic chemists and those dealing with medicinal compounds because of its versatile potential to interact with biological systems (Martins et al., 2015). Many of its derivatives are important as agrochemicals (Dayan et al., 2000;Huang et al., 2006;Ling et al., 2007). There is also a continuing need for the development of new drugs as those currently available are becoming ineffective because of the drug resistance developed by pathogens. Moreover, lifethreatening infections caused by pathogenic fungi are becoming increasingly very common (Leather & Wingard, 2006;Walsh et al., 2004;Chai et al., 2011). Triazole compounds have shown great efficacy against fungal infections. In 1944, Woolly discovered the excellent antifungal properties of azole derivatives, which led to the development of fluconazole, variconazole, albaconazole and itraconazole (Dismukes et al., 2000;Zonios et al., 2008;Gupta et al., 2003). Further structural modifications of this ring system are expected to result in potential candidates for antifungal agents. These modifications use different functionalities such as aliphatic chains, aromatic rings, heterocyclic ring systems etc. (Calderone et al., 2008;Kim et al., 2010;Giffin et al., 2008;Wang et al., 2005). As a continuation of our research on the synthesis, functionalization, physico-chemical and biological properties of triazole ISSN 2056-9890 derivatives (El Bakri et al., 2018, 2019a, we report herein on the crystal structure, DFT calculations and Hirshfeld surface analysis of ethyl (2S,3R)-3-(3-amino-1H-1,2,4-triazol-1-yl)-2-hydroxy-3-phenylpropanoate (1).

Structural commentary
The conformation of the molecule is controlled in part by two intramolecular interactions, a C2-H2Á Á ÁO1 hydrogen bond and a C-HÁ Á Á(ring) interaction between C5-H5 and the triazole ring (Table 1 and Fig. 1). This leads to a dihedral angle of 87.12 (4) between the phenyl and triazole rings. Atoms N4 and C3 are displaced from the mean plane of the triazole ring by 0.046 (1) and À0.056 (1) Å , respectively. All bond distances and interbond angles are as expected for the formulation given.
The second search, using 1-benzyl-1H-1,2,4-triazole as the search fragment, found fifteen structures, but in most of these the phenyl group is oriented with the line joining the ortho carbon atoms approximately parallel to that joining the atoms  Table 1 Hydrogen-bond geometry (Å , ).

Figure 1
The title molecule with the labelling scheme and 50% probability displacement ellipsoids. The intramolecular C-HÁ Á ÁO hydrogen bond is shown by a black dashed line while the C-HÁ Á Á(ring) interaction is shown by a green dashed line.

calculation of the electronic structure
The structure in the gas phase of 1 was optimized by means of density functional theory. The DFT calculation was performed by the hybrid B3LYP method, which is based on the idea of Becke and considers a mixture of the exact (HF) and DFT exchange utilizing the B3 functional, together with the LYP correlation functional (Becke, 1993;Lee et al., 1988;Miehlich et al., 1989). In conjunction with the basis set def2-SVP, the B3LYP calculation was performed (Weigend & Ahlrichs, 2005). After obtaining the converged geometry, the harmonic vibrational frequencies were calculated at the same theoretical level to confirm the number of imaginary frequencies is zero for the stationary point. Both the geometry optimization and harmonic vibrational frequency analysis of 1 were performed using the Gaussian 16 program (Frisch et al., 2016).

comparison between the gas-and solid-phase geometries
From a comparison of selected geometrical parameters obtained from the B3LYP geometry optimization for 1 ( Fig. 3) with those from the crystallographic study (Table 2), it is evident that the B3LYP-optimized geometry shows little deviation from the X-ray structure. To quantify the difference between the calculated and experimental geometries, the structure comparer built into the ChemCraft software (https:// www.chemcraftprog.com) was used to obtain their r.m.s. deviation. A weighted r.m.s.d. of 0.5684 was obtained with r.m.s. deviations of 0.7365, 0.4474, 0.1926, and 0.2606 for the H, C, N and O atoms, respectively. The B3LYP-optimized geometry (Å ) of the title compound. Table 2 Bond lengths and angles (Å , ) in the B3LYP-optimized and the X-ray structures. B3LYP X-ray B3LYP X-ray regions where the electron distribution of a sum of spherical atoms for the molecule dominates over the corresponding sum of the crystal. As it is derived from Hirshfeld's stockholder partitioning, the molecular surface is named as the Hirshfeld surface. In this study, the Hirshfeld surface analysis of 1 was performed using CrystalExplorer (Turner et al., 2017).

Hirshfeld surface analysis
The standard resolution molecular Hirshfeld surface (d norm ) of 1 is depicted in Fig. 4. This surface can be used to identify very close intermolecular interactions. The value of d norm is negative (positive) when intermolecular contacts are shorter (longer) than the van der Waals radii. The red regions on the surface represent closer contacts with a negative d norm value while the blue regions represent longer contacts with a positive d norm value while, the white regions represent contacts equal to the van der Waals separation and have a d norm value of zero. As depicted in Fig. 4, the important interactions in 1 are HÁ Á ÁO and HÁ Á ÁN hydrogen bonds. In order to understand the relative importance of HÁ Á ÁO hydrogen bonds versus HÁ Á ÁN hydrogen bonds, we calculated the two-dimensional fingerprint plots for 1 (Fig. 5), which highlight particular atompair contacts and enable the separation of contributions from different interaction types that overlap in the full fingerprint. The most important interaction involving hydrogen in 1 is the HÁ Á ÁH contact. The contributions of the HÁ Á ÁO, HÁ Á ÁN, and HÁ Á ÁH contact are 13.6%, 16.1% and 54.6%, respectively.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3.

Funding information
The support of NSF-MRI grant No. 1228232 for the purchase of the diffractometer and Tulane University for support of the Tulane Crystallography Laboratory are gratefully acknowledged.

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.