Structural investigation of N-[2-(4-fluoro-3-phenoxybenzoyl)hydrazinecarbothioyl]benzamide and N-[2-(4-fluoro-3-phenoxybenzoyl)hydrazinecarbothioyl]-4-methoxybenzamide

Crystal structure analysis of N-[2-(4-fluoro-3-phenoxybenzoyl)hydrazinecarbothioyl]benzamide and its 4-methoxy derivative highlights the significance of strong and weak hydrogen bonds. The difference in the contributions of atom–atom contacts obtained from Hirshfeld surface analysis and fingerprint plots helps in distinguishing the variations in the crystal packing of the two compounds.


Chemical context
Substituted thiosemicarbazides (TSCs) constitute an important class of organic compounds with the general formula R-(C O)-NH-NH-(C S)-R 0 and find application in the synthesis of five-and six-membered heterocyclic compounds (Gazieva & Kravchenko, 2012) and transition-metal complexes (Campbell, 1975). The chemical diversity of thiosemicarbazides, and their synthesis, including their role in biological applications, is nicely summarized in a recent review article (Acharya et al., 2021). Dibenzoylated TSCs have been synthesized and explored for their antibacterial activity (Qandil et al., 2006). Furthermore, molecular modelling studies establish the relevance of both geometry and electrondensity distribution in the observed antibacterial activity (Paneth et al., 2016). Piperidin-4-yl-based TSCs have been examined for cytotoxicity in breast cancer cell lines in addition to being possible potential topoisomerase inhibitors (Siwek et al., 2014). 1-(2-Hydroxybenzoyl)-thiosemicarbazides have been observed to exhibit antimicrobial activity and structureactivity relationship (SARs) studies establish that the 2-hydroxybenzoyl group plays an important role in enzyme inhibition, in addition to these exhibiting low cytotoxicity (Ameryckx et al., 2018). Furthermore, triazole-substituted benzoylthiosemicarbazides have been synthesized and their effect on the inhibition of corrosion on mild steel has been investigated (Yan et al., 2018). Keeping in mind the abovementioned applications of substituted TSCs, we have performed the synthesis and crystal structure analysis of two compounds, namely N-[2-(4-fluoro-3-phenoxybenzoyl)- ISSN 2056-9890 hydrazinecarbothioyl]benzamide (A1) and N-[2-(4-fluoro-3phenoxybenzoyl)hydrazinecarbothioyl]-4-methoxybenzamide (A2) in the current study. The molecular conformations have been studied with respect to the various flexible bonds and the occurrence of various intermolecular interactions that contribute towards the stability of the molecules in the crystalline lattice has been investigated in detail via an investigation of the crystal packing and quantitative insights from Hirshfeld surface analysis.

Table 2
Hydrogen-bond geometry (Å , ) for A2. contacts involving chalcogens are well-recognized in the literature [Pramanik & Chopra, 2020]. Furthermore, additional C21-H21Á Á ÁO3 hydrogen bonds form centrosymmetric dimers and provide additional stability to the crystal packing.  Groom et al., 2016) . No hits were obtained. Thus, further systematic studies related to the investigation of the role of differently substituted thiosemicarbazide molecules towards the crystal packing, including a detailed investigation of polymorphism in this class of compounds, is of relevance.

Hirshfeld surface analysis and fingerprint plots
The relevance of different intermolecular interactions can be established via Hirshfeld surface analysis (Spackman & Jayatilaka, 2009). These surfaces, along with the two-dimensional fingerprint plots, were evaluated using Crystal Explorer 17.5 (Turner et al., 2017). The surfaces mapped over d norm for A1, Fig. 5(a), and A2, Fig. 5  Crystal packing of A1 showing the formation of the crystal structure primarily via N-HÁ Á ÁO and C-HÁ Á ÁO intermolecular interactions.

Synthesis and Crystallization
The title compounds were synthesized in accordance with the procedure reported in the literature (Mohan, 2006). Crystallization was performed in 5.0 ml beakers at room temperature via the slow evaporation method from methanol solvent.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. H atoms were placed in idealized positions (N-H = 0.86 Å , C-H = 0.93 Å ) and refined using a riding model with U iso (H) = 1.2U eq (C, N) or 1.5U eq (C-methyl).