X-ray Single Crystal Structure, Tautomerism Aspect, DFT, NBO, and Hirshfeld Surface Analysis of a New Schiff Bases Based on 4-Amino-5-Indol-2-yl-1,2,4-Triazole-3-Thione Hybrid

: Four different new Schiff basses tethered indolyl-triazole-3-thione hybrid were designed and synthesized. X-ray single crystal structure, tautomerism, DFT, NBO and Hirshfeld analysis were explored. X-ray crystallographic investigations with the aid of Hirshfeld calculations were used to analyze the molecular packing of the studied systems. The H ··· H, H ··· C, S ··· H, Br ··· C, O ··· H, C ··· C and N ··· H interactions are the most important in the molecular packing of 3 . In case of 4 , the S ··· H, N ··· H, S ··· C and C ··· C contacts are the most signiﬁcant. The results obtained from the DFT calculations indicated that the thione tautomer is energetically lower than the thiol one by 13.9545 and 13.7464 kcal/mol for 3 and 4 , respectively. Hence, the thione tautomer is the most stable one which agree with the reported X-ray structure. In addition, DFT calculations were used to compute the electronic properties while natural bond orbital calculations were used to predict the stabilization energies due to conjugation effects. Both compounds are polar where 4 (3.348 Debye) has a higher dipole moment than 3 (2.430 Debye).


Introduction
Schiff bases are the compounds carrying imine or azomethine (-C=N-) functional groups.These compounds were reported and synthesized for the first time by Hugo Schiff via condensation of carbonyl compounds with the primary amines [1].Schiff bases are important pharmacological pharmacophores distributed in variety of organic compounds and have many applications in different fields such as inorganic chemistry, biological and analytical chemistry.In the field of pharmaceutical and medicinal chemistry, these compounds also, possess a variety of pharmacological activities including anti-cancer [2], anti-tubercular [3], analgesic [4,5], anti-oxidant [6], anti-inflammatory [7], anthelmintic [8], anti-microbial [9], and so forth.
Our research group has been engaged in a research program about design, synthesis, and spectrophotometric investigations of a variety of heterocyclic systems have been recently reported [22][23][24][25][26][27].In this context, we reported the synthesis of four different Schiff bases with the core structure of the indolyl-triazole-3-thione hybrid.The structure of the studied systems was confirmed using a set of spectrophotometric tools and the 3D structure of molecules 3 and 4 is further elucidated unambiguously by single crystal X-ray diffraction technique.Thione-thiol tautomerism was investigated using DFT calculations.In addition, Natural Bond Orbitals (NBO) and Hirshfeld surface analyses of the most stable tautomer were also discussed.

General
"Melting points were measured using a melting-point apparatus (SMP10) in open capillaries and are uncorrected.The progress of the reaction was observed by thin layer chromatography (TLC) and detection was achieved by UV light.Nuclear magnetic resonance ( 1 H-and 13 C-NMR) spectra were determined in DMSO-d 6 and were recorded on a Bruker AC 400 MHz spectrometer using tetramethylsilane as an internal standard.Chemical shifts are described in δ (ppm) and coupling constants are given in Hz.Elemental analysis was performed on a Flash EA-1112 instrument".

Hirshfeld Surface Analysis
The topology analyses were performed using Crystal Explorer 17.5 program [33].

Computational Methods
"All DFT calculations were performed using Gaussian 09 software package [34,35] with theB3LYP/6-31G(d,p) method.Natural bond orbital analyses were performed using NBO 3.1 program as implemented in the Gaussian 09W package [36].The self-consistent reaction field (SCRF) method [37,38] was used to model the solvent effects when calculated the optimized geometries in solution".

Crystal Structure Description
The X-ray structures of 3 and 4 were determined at 120(2) K. Processing parameters and crystal data are listed in Table 1.Both structures agreed very well with the spectral analyses.

Crystal Structure Description
The X-ray structures of 3 and 4 were determined at 120(2) K. Processing parameters and crystal data are listed in Table 1.Both structures agreed very well with the spectral analyses.
Compound 3 crystallized in the triclinic system and 1 space group with unit cell parameters of a = 5.9989( 2 2. The asymmetric unit comprised one molecule of compound 3 and one acetic acid molecule (Figure 1A).In this compound, the indole and the triazole rings are almost coplanar.The tilt angle between the planes passing through these moieties is found to be 1.64( 12)°.In contrast, the 4-bromo-phenyl moiety and the triazole rings are significantly twisted from one another by 59.51( 14)°.The structure of this compound is stabilized by the intramolecular C11-H11•••N1 hydrogen bond where the donor-acceptor distance is 3.045(5) Å and hydrogen-acceptor distance of 2.56 Å (Table 3).On the other hand, the molecular units of  3 while presentation of the molecular units held together by these hydrogen bonding contacts is shown in Figure 1C.2)

D-H•••A d(D-H) d(H••
The compound 4 crystallized in the more symmetric tetragonal system and the I4 1 /a space group.The unit cell parameters are a = b = 32.0004(4)Å, c = 6.65620(10)Å with unit cell volume of 6816.1(2)Å 3 and Z = 16.There is one molecular formula per asymmetric unit (Figure 2A).In this case, the indole and the triazole rings are more twisted from one another by 14.34(13) • compared to that in 3 (1.64(12)• ).In addition, the aryl moiety was found less twisted (5.69(11) • ) relative to the triazole moiety compared to that in 3 (59.51(14)• ).Presentation for the different twists among the connected rings is shown in Figure 3. Similar to 3, the molecular structure of compound 4 is stabilized by intramolecular C7-H7•••S1 interaction with hydrogen-acceptor and donor-acceptor distances of 2.38 and 3.1578( 16) Å, respectively (Table 3).Other intermolecular hydrogen bond contacts affecting the molecular packing are shown in Figure 2B while the molecular packing via these hydrogen bonding interactions is shown in Figure 2C.most important hydrogen bond contacts (B) and hydrogen bonding interactions (C) in 4.
Similar to 3, the molecular structure of compound 4 is stabilized by intramolecular C7-H7•••S1 interaction with hydrogen-acceptor and donor-acceptor distances of 2.38 and 3.1578( 16) Å, respectively (Table 3).Other intermolecular hydrogen bond contacts affecting the molecular packing are shown in Figure 2B while the molecular packing via these hydrogen bonding interactions is shown in Figure 2C.Similar to 3, the molecular structure of compound 4 is stabilized by intramolecular C7-H7•••S1 interaction with hydrogen-acceptor and donor-acceptor distances of 2.38 and 3.1578( 16) Å, respectively (Table 3).Other intermolecular hydrogen bond contacts affecting the molecular packing are shown in Figure 2B while the molecular packing via these hydrogen bonding interactions is shown in Figure 2C.

Analysis of Molecular Packing
The Hirshfeld surfaces of 3 are shown in Figure 4.Many red spots were recognized in the d norm map.These regions represent the atomic site included in short intermolecular interactions.

Analysis of Molecular Packing
The Hirshfeld surfaces of 3 are shown in Figure 4.Many red spots were recognized in the dnorm map.These regions represent the atomic site included in short intermolecular interactions.In order to decide which intermolecular contacts are the most significant, the dnorm map was decomposed and the results are shown in Figure 6.In this figure, only the contacts appeared as red spots are presented.The results indicated that, the H  In order to decide which intermolecular contacts are the most significant, the d norm map was decomposed and the results are shown in Figure 6.In this figure, only the contacts appeared as red spots are presented.The results indicated that, the H Also, the presence of some short C•••C contacts (5.2%) related to the aromatic π-system revealed the presence of π-π stacking interactions.This fact was further confirmed by the presence of large green flat area in the curvedness and the complementary red/blue triangles in the shape index (Figure 4).
For compound 4, the dnorm, shape index and curvedness maps are presented in Figure 7.In addition, there are a large number of red spots in dnorm map indicating the presence of short contacts which are important for the molecular packing and the crystal stability.These contacts were further analyzed using the fingerprint plot, and their percentages were calculated.The results of decomposed fingerprint plots are depicted in Figure 8 Also, the presence of some short C•••C contacts (5.2%) related to the aromatic π-system revealed the presence of π-π stacking interactions.This fact was further confirmed by the presence of large green flat area in the curvedness and the complementary red/blue triangles in the shape index (Figure 4).
For compound 4, the d norm , shape index and curvedness maps are presented in Figure 7.In addition, there are a large number of red spots in d norm map indicating the presence of short contacts which are important for the molecular packing and the crystal stability.These contacts were further analyzed using the fingerprint plot, and their percentages were calculated.The results of decomposed fingerprint plots are depicted in    In addition, all S•••H and N•••H intermolecular contacts appeared in the corresponding decomposed fingerprint plots as two sharp pikes for each interaction.This observation revealed not only the significance of these two contacts in the molecular packing but also In addition, all S•••H and N•••H intermolecular contacts appeared in the corresponding decomposed fingerprint plots as two sharp pikes for each interaction.This observation revealed not only the significance of these two contacts in the molecular packing but also shed the light on the contribution of the molecular unit inside the surface in these interactions as hydrogen bond donor and acceptor.As expected, the N•••H interactions appeared as sharper spikes indicating shorter interaction distances than the S•••H contacts.The importance of these interactions in the molecular packing was also revealed from the appearance of these interactions as intense red regions in the corresponding decomposed d norm maps (Figure 9).
On the other hand, the S•••C and C•••C contacts appeared as faded red regions in their decomposed d norm maps.In addition, these intermolecular contacts have shorter distances than the vdW radii sum of the interacting atoms.A list of all possible short contacts is given in Table 5.Some other short contacts were also detected such as the Cl1 shed the light on the contribution of the molecular unit inside the surface in these interactions as hydrogen bond donor and acceptor.As expected, the N•••H interactions appeared as sharper spikes indicating shorter interaction distances than the S•••H contacts.The importance of these interactions in the molecular packing was also revealed from the appearance of these interactions as intense red regions in the corresponding decomposed dnorm maps (Figure 9).Table 5.Most important contacts and the corresponding shortest interaction distances.The studied compounds could exist in two possible tautomeric forms which are the thione and thiol tautomers.The optimized molecular structures of the thione and thiol tautomers of 3 and 4 are shown in Figure 10.The calculated total energies of both tautomers are listed in Table 6.It is clear that the thione tautomer is energetically lower than the thiol one by 13.9545 and 13.7464 kcal/mol for 3 and 4, respectively.Hence, the most stable tautomer in gas phase of the studied compounds is the thione form.This conclusion is in good agreement with the reported X-ray structure of the studied compounds.In addition, in solution of the compounds in DMSO, the thione tautomer is energetically lower and could be considered the most stable one.On the other hand, the calculated thermodynamic parameters indicated that the thione tautomer is the most stable thermodynamically as it has more negative Gibbs free energy compared to the thiol one.

Optimized Geometry
The calculated optimized structures of the most stable tautomer of 3 and 4 agreed very well with the reported X-ray structures as indicated from the excellent matching between them (Figure 11).The geometric parameters of the optimized structures are close to the experimental results with some little deviations in the bond distances and bond angles (Table S1 in Supplementary data).In addition, the deviations of the calculated bond distances from the experimental values are very small.For example, the largest deviations occurred for the C22-N5 and C20-N6 in compounds 3 and 4, respectively.The maximum errors in these cases are 0.027 and 0.019 Å, respectively.The corresponding percentage relative errors are 2.03 and 1.42%, respectively.These deviations could be attributed to the fact that the optimized structures belong to a single molecule in the gas phase which is free from the crystal packing effects.Generally, there are very good straight-line correlations with correlation coefficients (R 2 ) of 0.994 and 0.968-0.990for bond distances and angles, respectively (Figure 12).
The studied systems comprised CHNSX (where X=Cl or Br) backbone and differ only in the substituent attached to the phenyl moiety.Graphical presentations of the natural charges at the different atomic sites are shown in Figure 13.The N and S atoms are electronegative where the NH nitrogen is the most electronegative in both compounds.The calculated natural charges at the amine nitrogen are almost the same for both compounds (−0.547 e).The other nitrogen atoms have smaller negative natural charges ranging from −0.225 to −0.303 e and −0.224 to −0.393 e for 3 and 4, respectively.In addition, the thione S-site has smaller negative natural charges than any of the nitrogen sites which are calculated to be −0.219 and 0.202 e for 3 and 4, respectively.In contrast, all hydrogen atoms are electropositive where the NH proton has the most positive natural charges.Their natural charge values are calculated to be 0.452 and 0.461 e for 3 and 4, respectively.On the other hand, the majority of carbon atoms have negative natural charges except those bonded to the N or S atoms where the most positive carbon is the one located between two nitrogen sites in the triazole moiety.

Optimized Geometry
The calculated optimized structures of the most stable tautomer of 3 and 4 agreed very well with the reported X-ray structures as indicated from the excellent matching between them (Figure 11).The geometric parameters of the optimized structures are close to the experimental results with some little deviations in the bond distances and bond angles (Table S1 in Supplementary data).In addition, the deviations of the calculated bond distances from the experimental values are very small.For example, the largest deviations occurred for the C22-N5 and C20-N6 in compounds 3 and 4, respectively.The maximum errors in these cases are 0.027 and 0.019 Å, respectively.The corresponding percentage relative errors are 2.03 and 1.42%, respectively.These deviations could be attributed to the fact that the optimized structures belong to a single molecule in the gas phase which is free from the crystal packing effects.Generally, there are very good straight-line correlations with correlation coefficients (R 2 ) of 0.994 and 0.968-0.990for bond distances and angles, respectively (Figure 12).Both compounds are polar molecules with a net dipole moment of 2.430 and 3.348 Debye for 3 and 4, respectively.The compound with two chloro substituents at the phenyl ring (4) has higher polarity than the one with bromo substituent (3).The direction of the dipole moment vector is the same in both compounds as can be seen from Figure 14.In the same figure, the molecular electrostatic potential map (MEP), HOMO and LUMO levels were presented.In MEP map, there are red regions related to the atomic sites with high electron density while the blue regions are related to the atomic sites with the lowest electron density.
On the other hand, the HOMO and LUMO levels have almost similar patterns in both compounds.The HOMO level is located mainly over the delocalized π-system and the thione S-atom while the LUMO level is distributed over the π-system (Figure 14).Hence, the excitation from the HOMO to LUMO level could be described as mixed π-π* and n-π* excitations.The HOMO→LUMO excitation energies are calculated to be 3.466 and 3.462 eV for 3 and 4, respectively.
site has smaller negative natural charges than any of the nitrogen sites which lated to be −0.219 and 0.202 e for 3 and 4, respectively.In contrast, all hydroge electropositive where the NH proton has the most positive natural charges.Th charge values are calculated to be 0.452 and 0.461 e for 3 and 4, respectively.O hand, the majority of carbon atoms have negative natural charges except those the N or S atoms where the most positive carbon is the one located between tw sites in the triazole moiety.S2; Supplem data).S2; Supplementary data).ring (4) has higher polarity than the one with bromo substituent (3).The direction of the dipole moment vector is the same in both compounds as can be seen from Figure 14.In the same figure, the molecular electrostatic potential map (MEP), HOMO and LUMO levels were presented.In MEP map, there are red regions related to the atomic sites with high electron density while the blue regions are related to the atomic sites with the lowest electron density.On the other hand, the HOMO and LUMO levels have almost similar patterns in both compounds.The HOMO level is located mainly over the delocalized π-system and the thione S-atom while the LUMO level is distributed over the π-system (Figure 14).Hence, the excitation from the HOMO to LUMO level could be described as mixed π-π* and nπ* excitations.The HOMO→LUMO excitation energies are calculated to be 3.466 and 3.462 eV for 3 and 4, respectively.

NBO Analysis
The process of conjugation has a great importance in the stability of the molecular system [45,46].These intramolecular charge transfer (IMCT) and their stabilization energies (E (2) ) are summarized in Table 8.

Figure 1 .
Figure 1.Structure of the asymmetric unit with atomic numbering and thermal ellipsoids drawn at 30% probability (A), most important hydrogen bond contacts (B) and hydrogen bonding interactions (C) in 3.

Figure 1 .
Figure 1.Structure of the asymmetric unit with atomic numbering and thermal ellipsoids drawn at 30% probability (A), most important hydrogen bond contacts (B) and hydrogen bonding interactions (C) in 3.

21 Figure 2 .
Figure 2. Structure of the asymmetric unit with atomic numbering and thermal ellipsoids drawn at 30% probability (A), most important hydrogen bond contacts (B) and hydrogen bonding interactions (C) in 4.

Figure 2 .
Figure 2. Structure of the asymmetric unit with atomic numbering and thermal ellipsoids drawn at 30% probability (A), most important hydrogen bond contacts (B) and hydrogen bonding interactions (C) in 4.

Figure 3 .
Figure 3.The capped stick model showing the different twists among the three connected ring systems (indole, triazole and aryl moieties) in 3 (higher) and 4 (lower).

21 Figure 3 .
Figure 3.The capped stick model showing the different twists among the three connected ring systems (indole, triazole and aryl moieties) in 3 (higher) and 4 (lower).

Figure 4 .
Figure 4. Hirshfeld surfaces of 3. Decomposition of the fingerprint plot gave the percentages of all intermolecular contacts in the crystal.The percentages of all possible intermolecular interactions and the decomposed fingerprint plots of the short contacts are presented in Figure 5.It is clear that the H•••H (31.8%),H•••C (22.4%),S•••H (9.8%) and Br•••H (8.9%) contacts are the most dom-

Figure 5 .
Figure 5. Decomposed fingerprint plots of the most dominant contacts and the percentages of all possible intermolecular interactions in the crystal structure of 3.
and N•••H interactions are the most important as these contacts having shorter distances than the van der Waals radii sum of the interacting atoms.List of the short interaction distances are given in Table 4.The shortest contacts are Br1•••C19 (3.421 Å), S1•••H3 (2.252 Å), C14•••C10 (3.297 Å), H15•••C3 (2.693 Å), N4•••H18C (2.529 Å), H2•••H2 (2.070 Å) and O2•••H5 (2.140 Å).Both of the H•••C and S•••H contacts appeared as two spikes in the fingerprint plot indicating that the molecule inside the surface acting as hydrogen bond donor and acceptor.In contrast, the O•••H and N•••H appeared as sharp spikes at the lower left and lower right of the corresponding fingerprint plots, respectively.As a result, the molecule inside the surface acting as hydrogen bond acceptor with respect to the O•••H contacts and the hydrogen bond donor is the crystallized acetic acid molecule.The opposite is true for the N•••H contacts.

Figure 6 .
Figure 6.Decomposed dnorm maps of the most important contacts in 3.Both of the H•••C and S•••H contacts appeared as two spikes in the fingerprint plot indicating that the molecule inside the surface acting as hydrogen bond donor and acceptor.In contrast, the O•••H and N•••H appeared as sharp spikes at the lower left and lower right of the corresponding fingerprint plots, respectively.As a result, the molecule inside the surface acting as hydrogen bond acceptor with respect to the O•••H contacts and the hydrogen bond donor is the crystallized acetic acid molecule.The opposite is true for the N•••H contacts.

Figure 6 .
Figure 6.Decomposed d norm maps of the most important contacts in 3.

Figure 8 .
Figure 8. Decomposed fingerprint plots of the most dominant contacts and the percentages of all possible intermolecular interaction in the crystal structure of 4.

Figure 8 .
Figure 8. Decomposed fingerprint plots of the most dominant contacts and the percentages of all possible intermolecular interaction in the crystal structure of 4.

Figure 9 .
Figure 9. Decomposed dnorm maps of the most important contacts in 4. On the other hand, the S•••C and C•••C contacts appeared as faded red regions in their decomposed dnorm maps.In addition, these intermolecular contacts have shorter distances than the vdW radii sum of the interacting atoms.A list of all possible short contacts is given in Table 5.Some other short contacts were also detected such as the Cl1•••C17, Cl1•••N5, Cl2•••H16 and S1•••N2 having interactions distances of 3.239, 3.217, 2.829 and 3.304Å, respectively.

Figure 9 .
Figure 9. Decomposed d norm maps of the most important contacts in 4.

Figure 10 .
Figure 10.The optimized structures of the thione (upper) and thiol (lower) tautomers of the studied systems.

Figure 10 . 21 Figure 11 .
Figure 10.The optimized structures of the thione (upper) and thiol (lower) tautomers of the studied systems.Crystals 2021, 11, x FOR PEER REVIEW 15 of 21

Figure 11 .
Figure 11.Overlay of the optimized with experimental structures for the studied compounds.Figure 11.Overlay of the optimized with experimental structures for the studied compounds.

Figure 11 .
Figure 11.Overlay of the optimized with experimental structures for the studied compounds.

Figure 12 .
Figure 12.The straight-line correlations between the calculated and experimental geometric parameters.

Figure 12 .
Figure 12.The straight-line correlations between the calculated and experimental geometric parameters.

Figure 13 .
Figure 13.Natural charge population at the different atomic sites for the studied compounds (TableS2; Supplem data).

Figure 13 .
Figure 13.Natural charge population at the different atomic sites for the studied compounds (TableS2; Supplementary data).

Figure 14 .
Figure 14.The MEP, HOMO and LUMO for the studied compounds.

Figure 14 .
Figure 14.The MEP, HOMO and LUMO for the studied compounds.

Table 4 .
Most important contacts and the corresponding shortest interaction distances.

Table 4 .
important contacts and the corresponding shortest interaction distances.

Table 6 .
Calculated total energies and thermodynamic properties of the thione and thiol tautomers of the studied systems.
a ZPVE: Zero point vibrational energy correction, b E + ZPVE.

Table 7 .
Reactivity parameters of the studied compounds.
a Atom numbering refer to Figure10.