Crystal structure and Hirshfeld surface analysis of 2-azido-N-(4-fluorophenyl)acetamide

The asymmetric unit consists of two independent molecules differing in the orientation of the azido group. Each molecule forms N—H⋯O hydrogen-bonded chains extending along the c-axis direction with its symmetry-related counterparts. The chains are connected by C—F⋯π(ring), C=O⋯π(ring) and slipped π-stacking interactions. A Hirshfeld surface analysis of these interactions was performed.


Chemical context
Azides are a class of versatile organic compounds having the basic structure RN 3 where R can be an alkyl, acyl or aryl group. They have found valuable applications in medicinal chemistry (Contin et al., 2019) and molecular biology (Ahmed & Abdallah, 2019). On the other hand, amide bonds are a key structural unit in many physiologically active compounds and have ubiquitous presence in biopolymers such as proteins and glycoproteins (Cheng et al., 2016;Pattabiraman & Bode, 2011;Zheng et al., 2016). Acetamides are useful building blocks for the preparation of biologically active natural products, especially depsipeptide compounds. In particular, N-arylacetamides are significant intermediates for the synthesis of medicinal, agrochemical, and pharmaceutical compounds (Valeur & Bradley, 2009;Allen & Williams, 2011;Missioui et al., 2022a,b). They have been identified as inhibitors of methionine aminopeptidase-2 and HIV protease, display potent antitumor activity, and play an important role in medicinal chemistry. As a result of the significance of this core, and in a continuation of our research efforts to synthesize N-arylacetamide-based heterocycles (Missioui et al., 2020;Al-Taifi et al., 2021;Guerrab et al., 2021;Missioui et al., 2022c,d), we report here the synthesis, molecular and crystal structures and a Hirshfeld surface analysis of the title compound.

Figure 3
Perspective view of the chain structure with N-HÁ Á ÁO hydrogen bonds and C15 O2Á Á ÁCg1 interactions depicted, respectively, by violet and light-blue dashed lines. Non-interacting hydrogen atoms are omitted for clarity.

Figure 1
The asymmetric unit with labeling scheme and 50% probability ellipsoids. The C15 O2Á Á ÁCg1 interaction is depicted by a dashed line.

Database survey
A search of the Cambridge Structural Database (CSD, version 5.43, updated to March 2022;Groom et al., 2016) with the search fragment A gave eleven hits of which three contained the 2-azidoacetamide unit while 30 hits resulted from a search with fragment B, of which six contained the 2-azidoacetamide unit.
In the first group, the aromatic ring has a -CO 2 Et group in the 2-position (ARAPIU: Yassine et al., 2016a), the second has i PrS-groups in the 2-and 3-positions (CEMRUJ: Okamura et al., 2013)  . In ARAPIU and OVIBAY, the amide hydrogens form intramolecular N-HÁ Á ÁO hydrogen bonds with the carboxyl oxygen while in CEMRUJ an intramolecular interaction of the amide hydrogen with the sulfur atom in the 2-position is postulated. Thus, none of these structures show the formation of chains as seen in the present case nor do any have more than one molecule in the asymmetric unit. Among the others, ASEDIO has two independent molecules in the asymmetric unit and it also, like QAGNOF and BEBPIJ, forms chains through N-HÁ Á ÁO hydrogen bonds. In ASEDIO, the chains are connected by -interactions between the terminal two nitrogens of the azide group and a phenyl ring, while in QAGNOF the chains are connected by C-HÁ Á ÁO and C-HÁ Á ÁN hydrogen bonds. The remaining structures in the first group all contain the -N N-C fragment while the remainder of the second group all contain triazoles as the N 3containing fragment and are not considered relevant to the present structure.

Hirshfeld surface analysis
A Hirshfeld surface analysis was performed with Crystal-Explorer 21.5 (Spackman et al., 2021) with the details of the pictorial output described in a recent publication (Tan et al., 2019). Fig. 5a and 5c, respectively, show the d norm surfaces of the molecule containing O1 and that containing O2 plotted over the range À0.4316 to 1.3253 in arbitrary units while Fig. 5b and 5d show the corresponding shape-index functions. In both, two adjacent molecules that are part of the hydrogenbonded chains are included with the N-HÁ Á ÁO and C-HÁ Á ÁO interactions shown by dashed lines. The pattern of orange and blue triangles indicative of a -interaction is clearly evident in the lower part of Fig. 5b and corresponds to the C4-F1Á Á ÁCg1 interaction. This is less clear in Fig. 5d but the data in Table 1 clearly support a similar interaction for this molecule. Fig. 6 presents fingerprint plots for the molecule containing O1 with Fig. 6a showing all intermolecular interactions and Fig. 6b-6f those delineated into NÁ Á ÁH/HÁ Á ÁN (34.3%), HÁ Á ÁH (13.5%), OÁ Á ÁH/HÁ Á ÁO (12.2%), CÁ Á ÁH/ HÁ Á ÁC (11.9%) and FÁ Á ÁH/HÁ Á ÁF (9.7%), respectively. The two spikes in Fig. 6d  Packing viewed along the c-axis direction showing the linking of chains via C-FÁ Á Á(ring) (green dashed lines) and C15 O2Á Á ÁCg1 (light-blue dashed lines) and slipped -stacking (orange dashed lines) interactions. N-HÁ Á ÁO hydrogen bonds and non-interacting hydrogen atoms are omitted for clarity.

Figure 5
The (a) d norm and (b) shape-index surfaces for the molecule containing O1, and the (c) d norm and (d) shape-index surfaces for the molecule containing O2 together with the two closest molecules of each type. tips indicate the contributions from C-HÁ Á ÁO hydrogen bonds. Fig. 7 shows the fingerprint plots for the molecule containing O2 with Fig. 7a showing all intermolecular interactions and Fig. 7b-7f those delineated into NÁ Á ÁH/HÁ Á ÁN (28.8%), HÁ Á ÁH (18.2%), CÁ Á ÁH/HÁ Á ÁC (12.6%), FÁ Á ÁH/HÁ Á ÁF (12.6%) and OÁ Á ÁH/HÁ Á ÁO (11.6%), respectively. Although the ordering of interactions based on their percentage of the total is not the same as in the other molecule, the percentages are not greatly different between the two and the corresponding plots are very similar type by type.

Synthesis and crystallization
2-Chloro-N-(4-fluorophenyl)acetamide (0.011 mol), and sodium azide (0.015 mol) were dissolved in a mixture of ethanol/water (70:30) and refluxed for 24 h at 353 K. After completion of the reaction (monitored by thin-layer chromatography, TLC), the 2-azido-N-(4-fluorophenyl)acetamide that precipitated was filtered off and washed with cold water. A portion of the product was dissolved in hot ethanol, the solution was filtered, and the filtrate was left undisturbed for 7 days to form colorless, thick plate-like crystals.

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 were placed in locations derived from a difference map and their parameters adjusted to give N-H = 0.91 Å. All were included as riding contributions with isotropic displacement parameters 1.2 -1.5 times those of the attached atoms.