The crystal structures and Hirshfeld surface analyses of four 3,5-diacetyl-2-methyl-2,3-dihydro-1,3,4-thiadiazol-2-yl derivatives

The crystal structures of four 3,5-diacetyl-2-methyl-2,3-dihydro-1,3,4-thiadiazol-2-yl derivatives, viz. 4-phenyl benzoate, 4-phenyl isobutyrate, 4-phenyl propionate and 4-phenyl cinnamate, are described and the intermolecular contacts in the crystals are analysed using Hirshfeld surface analysis and two-dimensional fingerprint plots.


Chemical context
Nitrogen-containing heterocyclic compounds are one of the most important classes of biologically active compounds, exhibiting antimicrobial, antitumour and anti-inflammatory (Sethuram et al., 2013;Huq et al., 2010, Rajkumar et al., 2014, 2015Thirunavukkarsu et al., 2017;Babu et al., 2014a,b) activities. Suitably substituted 1,3,4-thiadiazoles that incorporate the toxiphoric -N C-S-linkage have attracted great attention owing to their broad spectrum of biological activities, including anti-inflammatory (Udupi et al., 2000), herbicidal antimicrobial, bactericidal (Tehranchian et al., 2005), antiviral and anti-HIV-1 (Invidiata et al., 1996) properties. Their action depends on the type and location of the polar substituents on the heterocyclic ring. In general, the pharmacological effect of potential drugs depends on the stereochemistry and ring conformations. The amide linkage [-NHC(O)-] is known to be strong enough to form and maintain protein architectures and has been utilized to create ISSN 2056-9890 various molecular devices for a range of purposes in organic chemistry. Depending on the types of substitution at the , and keto C atoms, and the conformational flexibility of the substituent groups, a variety of ss-acetamido ketones offering the possibility of intermolecular interactions can be obtained. Recognizing the importance of such compounds in drug discovery and as part of our ongoing investigation of acetamide derivatives, the promising biological potency of 1,3,4thiadiazoles and variously substituted 1,3,4-thiadiazole frameworks, the title compounds have been prepared and their crystal structures are reported on herein.

Structural commentary
The molecular structures and conformations of the two crystallographically independent molecules (A and B), of compounds I, II, III and IV are illustrated in Figs. 1, 2, 3 and 4, respectively. In all four compounds, the bond lengths and angles in the two independent molecules agree with each other. The normal probability plot analyses (International Tables for X-ray Crystallography, 1974, Vol. IV, pp. 293-309) for both bond lengths and bond angles show that the differences between the two independent molecules are of a statistical nature. The geometric parameters (bond lengths and bond angles) are very similar to those observed in previously reported structures (Aridoss et al., 2008).

Figure 2
View of the molecular structure of compound II, with atom labelling. Displacement ellipsoids are drawn at the 30% probability level. The solvent water molecule and the minor disordered component have been omitted.
In three of the compounds there is a certain disorder; in compound I the phenyl benzoate group is disordered, in compound II the methyl propanoate group is disordered, and in compound III the O atom of the ester group is disordered. The geometries were regularized using soft restraints; see x7, Refinement.

Supramolecular features
In all compounds, the crystal packing is stabilized by strong N-HÁ Á ÁO intermolecular hydrogen bonds (see Tables 1, 2, 3  View of the molecular structure of compound III, with atom labelling. Displacement ellipsoids are drawn at the 30% probability level. The minor disordered component has been omitted.

Figure 4
View of the molecular structure of compound IV, with atom labelling. Displacement ellipsoids are drawn at the 30% probability level. The solvent CHCl 3 molecule has been omitted. Table 1 Hydrogen-bond geometry (Å , ) for I. Cg2, Cg3 and Cg6 are the centroids of the C8A-C13A, C15A-C20A and C8B-C13B rings, respectively. In the crystals of all four compounds, the A and B molecules are linked via strong N-HÁ Á ÁO hydrogen bonds and generate centrosymmetric four-membered R 4 4 (28) ring motifs. There are C-HÁ Á ÁO hydrogen bonds present in the crystals of all four compounds. For I they link the rings to form layers parallel to the ab plane, while for II they link the rings, that stack up the a axis, to form columns. For III, neighbouring rings are linked by C-HÁ Á ÁO hydrogen bonds to form ribbons propagating along the b-axis direction. Finally, for IV, the rings that stack up the b-axis are linked by C-HÁ Á ÁO hydrogen bonds to form columns, which are linked by a further C-HÁ Á ÁO hydrogen bond to form a supramolecular three-dimensional structure.
In the crystals of I and II, there are also C-HÁ Á Á interactions present. In the former they link the layers, while in the latter they link the columns, to form supramolecular threedimensional structures.  Table 2 Hydrogen-bond geometry (Å , ) for II.

Figure 7
The crystal packing of compound III, viewed along the b axis. The hydrogen bonds (see Table 3) are shown as dashed lines. For clarity, the H atoms not involved in the hydrogen bonding have been omitted.

Figure 8
The crystal packing of compound IV, viewed along the b axis. The hydrogen bonds (see Table 4) are shown as dashed lines. For clarity, the H atoms not involved in the hydrogen bonding have been omitted.

Hirshfeld surface analysis
A recent article by Tiekink and collaborators (Tan et al., 2019) reviews and describes the uses and utility of Hirshfeld surface analysis (Spackman & Jayatilaka, 2009), and the associated two-dimensional fingerprint plots (McKinnon et al., 2007), to analyse intermolecular contacts in crystals. The various calculations were performed with CrystalExplorer17 (Turner et al., 2017). The Hirshfeld surfaces of compounds I-IV mapped over d norm are given in Fig. 9, and the intermolecular contacts are illustrated in Fig. 10 for I, Fig. 11 for II, Fig. 12 for III and Fig. 13 for IV. They are colour-mapped with the normalized contact distance, d norm , ranging from red (distances shorter than the sum of the van der Waals radii) through white to blue (distances longer than the sum of the van der Waals radii). The d norm surface was mapped over a fixed colour scale of À0.763 (red) to 1.539 (blue) for compound I, À0.593 (red) to 1.357 (blue) for compound II, À0.593 (red) to 1.607 (blue) for compound III and À0.617 (red) to 2.422 (blue) for compound IV, where the red spots indicate the intermolecular contacts involved in the hydrogen bonding.

Figure 12
A view of the Hirshfeld surface mapped over d norm of compound III, showing the various intermolecular contacts in the crystal.

Synthesis and crystallization
Synthesis of 4-(3,5-diacetyl-2-methyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)phenyl benzoate (I) To a clean and dry 250 ml twoneck round-bottom flask fitted with condenser and addition funnel containing 4-hydroxy acetophenone (0.5 mol) was added chloroform (200 ml) under continuous stirring and the reaction mixture was cooled to 288-293 K. Benzoyl chloride (0.5 mol) was added dropwise and stirring continued for a further 15 min and then potassium carbonate (0.5 mol) was slowly added. The reaction continued for another 4 h, monitored using TLC. The reaction mass was transferred into a 1 l beaker and washed twice with water (2 Â 250 ml). The chloroform layer was separated and washed with a 10% NaOH solution (2 Â 250 ml) and dried with anhydrous sodium sulfate followed by concentration under reduced pressure using rotary vacuum before being cooled and hexane added. Thiosemicarbazide (0.1 mol) dissolved in 20 ml of 1 N hydrochloric acid was added slowly under stirring to 4acetylphenyl benzoate (0.1 mol) dissolved in 50 ml of ethanol. After the addition of thiosemicarbazide, 4-[(1-(2-carbamothioylhydrazinylidene)ethyl]phenyl benzoate (in solid form) was formed within 4 min. The precipitate was filtered and washed with water, followed by hexane. 4-[(1-(2-Carbamothioylhydrazinylidene)ethyl]phenyl benzoate (0.5 mol) was dissolved in 10 ml of acetic anhydride and the mixture heated at 383 K for 3 h with magnetic stirring. The reaction was monitored using TLC, and once complete the reaction mass was quenched in crushed ice with stirring. The solid product obtained was filtered, washed with cold water followed by hexane and then air-dried. Recrystallization using chloroform yielded colourless block-like crystals of compound I.
Synthesis of 4-(3,5-diacetyl-2-methyl-2,3-dihydro-1,3,4thiadiazol-2-yl)phenyl isobutyrate (II) To a clean and dry 250 ml two-neck round-bottom flask fitted with condenser and addition funnel containing 4-hydroxy acetophenone (0.5 mol) was added chloroform (200 ml) under continuous stirring and the reaction mixture was cooled to 288-293 K. Isobutyryl chloride (0.5 mol) was added dropwise and stirring continued for a further 15 min and then potassium carbonate (0.5 mol) was slowly added. The reaction continued for another 4 h, monitored using TLC. The reaction mass was then transferred into a 1 l beaker and washed twice with water (2 Â 250 ml). The chloroform layer was separated and washed with a 10% NaOH solution (2 Â 250 ml) and dried with anhydrous sodium sulfate then concentrated under reduced pressure using a rotary vacuum, cooled and hexane was added. Thiosemicarbazide (0.91 g, 0.01 mol) was added to a 50 ml ethanolic solution of 4-acetylphenyl isobutyrate (0.01 mol) under continuous stirring. The resulting mixture refluxed at 333 K and the purity of the products as well as the composition of the reaction was monitored by TLC using ethyl acetate: hexane (3:7). The reaction mixture was cooled to room temperature and the separated product was filtered. 4-[(1-(2-Carbamothioylhydrazinylidene)ethyl]phenyl 2-methylpropanoate (0.5 mol) was dissolved in 10 ml of acetic anhydride and the mixture was heated at 383 K for 3 h under magnetic stirring. The reaction was monitored using TLC, and once complete the reaction mass was quenched in crushed ice cubes with stirring. The solid product obtained was filtered, washed with cold water followed by hexane and then air-dried. Recrystallization using chloroform yielded colourless blocklike crystals of compound II.
Synthesis of 4-(3,5-diacetyl-2-methyl-2,3-dihydro-1,3,4thiadiazol-2-yl)phenyl propionate (III) To a clean and dry 250 ml two-neck round-bottom flask fitted with condenser and addition funnel containing 4-hydroxy acetophenone (0.5 mol) was added chloroform (200 ml) under continuous stirring and the reaction mixture was cooled to 288-293 K. Propanoyl chloride (0.5 mol) was then added dropwise. Stirring continued for another 15 min and then potassium carbonate (0.5 mol) was slowly added. The reaction was continued for another 4 h and monitored using TLC. The reaction mass was transferred into a 1 l beaker and washed twice with water (2 Â 250 ml). The chloroform layer was separated and washed with a 10% NaOH solution (2 Â 250 ml) and dried with anhydrous sodium sulfate followed by concentration under reduced pressure using a rotary vacuum, cooled and hexane was added to it. Thiosemicarbazide (0.91g, 0.01 mol) was added to 50 ml of an ethanolic solution of 4-acetylphenyl propionate (0.01 mol) under continuous stirring. The resulting mixture was refluxed at 333 K and the purity of the products as well as composition of the reaction was monitored by TLC using ethyl acetate:hexane (3:7). The reaction mixture was cooled to room temperature and the separated product was filtered. 4-[(1-(2 Carbamothioyl hydrazinylidene)ethyl]phenyl propanoate (0.5 mol) was dissolved in 10 ml of acetic anhydride and the mixture was heated at 383 K for 3 h under magnetic stirring. The reaction was monitored using TLC, and once complete the mass was quenched in crushed ice under stirring. The solid product obtained was filtered, washed with cold water followed by hexane and then air-dried. Recrystallization using chloroform yielded colourless block-like crystals of compound III.
Synthesis of 4-(3,5-diacetyl-2-methyl-2,3-dihydro-1,3,4thiadiazol-2-yl)phenyl cinnamate (IV) To a clean and dry 250 ml two-neck round-bottom flask fitted with condenser and addition funnel containing 4-hydroxy acetophenone (0.5 mol) was added chloroform (200 ml) under continuous stirring and the reaction mixture was cooled to 288-293 K. Cinnamoyl chloride (0.5 mol) was then added dropwise. Stirring continued for another 15 min and potassium carbonate (0.5 mol) was slowly added. The reaction continued for another 4 h and was monitored using TLC. The reaction mass was transferred into a 1 l beaker and washed twice with water (2 Â 250 ml). The chloroform layer separated and was washed with a 10% NaOH solution (2 Â 250 ml) and dried with anhydrous sodium sulfate followed by concentration under reduced pressure using a rotary vacuum, cooled and hexane added. Thiosemicarbazide (0.1 mol) dissolved in 20 ml of 1 N hydrochloric acid was added slowly under stirring to 4acetylphenyl cinnamate (0.1 mol) dissolved in 50 ml of ethanol. After the addition of thiosemicarbazide, 4-[(1-(2carbamothioylhydrazinylidene)ethyl]phenyl benzoate (in solid form) was formed within 4 min. The precipitate was filtered off and washed with water, followed by hexane. 4-[(1-(2-Carbamothioylhydrazinylidene)ethyl]phenyl-3-phenylprop-2-enoate (0.5 mol) was dissolved in 10 ml of acetic anhydride and the mixture was heated at 383 K for 3 h under magnetic stirring. The reaction was monitored using TLC, and once complete the reaction mass was quenched in crushed ice under stirring. The solid product obtained was filtered, washed with cold water followed by hexane and then air-dried. Recrystallization using chloroform yielded colourless blocklike crystals of compound IV.

4-(5-Acetamido-3-acetyl-2-methyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)phenyl benzoate (I)
Δρ max = 0.38 e Å −3 Δρ min = −0.56 e Å −3 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.

Hydrogen-bond geometry (Å, º)
Cg2, Cg3 and Cg6 are the centroids of the C8A-C13A, C15A-C20A and C8B-C13B rings, respectively.  where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max = 0.002 Δρ max = 0.48 e Å −3 Δρ min = −0.38 e Å −3 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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq Occ. (