Intermolecular interactions in crystalline 1-( adamantane-1-carbonyl )-3-substituted thioureas with Hirshfeld surface analysis †

The conformationally congested species 1-(adamantane-1-carbonyl)-3-(2,4,6-trimethylphenyl)thiourea has been prepared and fully characterized by elemental analyses, FTIR, H NMR, C NMR and mass spectrometry. Its crystal structure was determined by single-crystal X-ray diffraction. The dihedral angle between the plane of the 2,4,6-trimethylphenyl group and the plane of the thiourea fragment was optimized by theoretical calculations applying the B3LYP/6-311++GIJd,p) level for the purpose of investigating the conformational effects on the stabilization of the crystal packing. A detailed analysis of the intermolecular interactions in a series of six closely related phenylthiourea species bearing the 1-(adamantane1-carbonyl) group has been performed based on the Hirshfeld surfaces and their associated twodimensional fingerprint plots. The relative contributions of the main intermolecular contacts as well as the enrichment ratios derived from the Hirshfeld surface analysis establish the 1-acyl thiourea synthon to be a widespread contributor.

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Although the π interactions have been widely investigated during the past two decades, 43 an increased number of theoretical and experimental studies have been recently carried out to understand the true nature of π· · ·π and C-H· · ·π interactions. [44][45][46] These non-covalent interactions could be used as tools in crystal engineering for the design of crystalline adamantane-based thioureas. To get a better understanding of the intermolecular interactions toward the crystal packing, the Hirshfeld surface analysis [47][48][49] for a series of six closely related 1-(adamantane-1carbonyl)-3-substituted-phenyl thioureas has been analyzed. Thus, the surfaces of all compounds are mapped by using of d norm , whereas shape-index and curvedness are properties mapped on the surfaces in order to facilitate a more detailed identification of the π-π interactions experienced by molecules in various studied compounds. 44 The present study allowed us to investigate the effect of molecular conformation adopted by the substituted-phenylthiourea group on the stabilization of crystal packing in these compounds, as well as to quantify the propensity of the intermolecular interactions to form the supramolecular assembly.

2.3-Quantum chemical calculations.
Optimization geometry was accomplished within the frame work of the density functional theory 50, 51 using the hybrid functional with non-local exchange due to Becke 52 and the correlation functional due to Lee, Yand and Parr, 53 (B3LYP)as implemented in the Gaussian 03 package. 54 Contracted gaussian basis sets of triple-zeta quality plus polarized and diffuse functions 6-311++G(d,p) for all atoms were used throughout the present work. 55 The corresponding vibrational analyses were performed for the optimized geometries to verify whether they are local minima or saddle points on the potential energy surface of the molecule. Calculated normal modes were also used as an aid in the assignment of experimental frequencies.
2.4-X-ray data collection and structure refinement. The crystal and refinement data for compound 1 are listed in Table 1. Data of compound (1) were collected at 173(2) K on a STOE IPDS II twocircle-diffractometer using MoKα radiation. The structure was solved by direct methods 56 and refined with full-matrix least-squares techniques on F 2 . All non-hydrogen atoms were refined anisotropically, and all H atoms bonded to C were placed in their calculated positions and then refined using the riding model. The H atoms bonded to N were freely refined. The geometry of the molecule was calculated using the WinGX 57 and PARST 58,59 software. XP in SHELXTL-Plus 56 , ORTEP-3 60 and Mercury 61 programs were used for molecular graphics.   The 2D fingerprint plots are displayed by using the translated 0.6-2.6 Å range, and including reciprocal contacts.

3.1-Conformational properties
Previous structural studies on 1-(adamantane-1-carbonyl)-3-mono substituted thioureas have shown that a local planar structure of the acyl-thiourea group is preferred, with opposite orientation between the C=O and C=S double bonds ("S-shape"). 41,42,70 In the present case, a similar conformational behaviour has been computationally determined for 1-(adamantane-1-carbonyl)-3-(2,4,6-tri-methylphenyl)thiourea, with the 1-acyl thiourea group adopting the S-shape and the substituted phenyl ring nearly perpendicular to the mean plane defined by the 1-acyl thiourea group.
It is worthy to notice that the molecule isolated in vacuum displays nearly-perfect C S symmetry.
For comparison purposes, similar calculations have been done for the related 1-(adamantane-1-carbonyl)-3-(phenyl)thiourea. For this species, the most stable form displays the same S-shape conformation, but on the contrary, the phenyl ring coplanar with the 1-acyl thiourea group. Thus, it becomes apparent that the conformation adopted by the 2,4,6-tri-methyl group is determined by strong steric impedance caused by the interaction between the C=S bond with the methyl groups occupying the 2,6-positions. The computed molecular structure is in very good agreement with the experimental one (see Section 3.3).

3.2-Vibrational properties
The determination of the vibrational properties of 1-acyl thioureas has showed to be a powerful tool for analyzing conformational and structural features in the solid state. 36 The FTIR spectrum of (1) have been measured and compared with the calculated [B3LYP/6-311++G(d,p)] harmonic frequencies. The experimental and simulated spectra are shown in Figure 1. Two welldefined absorptions are observed in the infrared spectrum at 3426 and 3231 cm -1 , the last one with higher intensity, which can be associated with the ν(N-H) stretching modes. 71 This spectral region is well reproduced by quantum chemical calculations with the corresponding harmonic frequencies computed at 3613 (56.6) and 3393 (366.5) cm -1 (computed intensities, in Km/mol, are given). The formation of the intramolecular N1-H···O1=C hydrogen bond is responsible for the impressive redshift and a strong intensification of the ν(N1-H) normal mode as compared with the second ν(N2-H) stretching, in agreement with previous data for related species. 72 This interaction also affect the force constant of the ν(C=O) stretching mode, 73 which is observed as an intense and symmetric band at 1674 cm -1 in the infrared spectrum in good agreement with the computed value (1707 cm -1 ).
The most intense absorption is observed as a rather broad band at 1511 cm -1 in the infrared spectrum, which can be assigned to the δ(N-H) deformation modes, in agreement with previous reported values for 1-acyl-3-mono-substituted thioureas. 74,75 The computed spectrum shows two intense absorptions at similar frequencies values [1567 (350.9 Km/mol) and 1546 (628.6 Km/mol) cm -1 ] that are associated with the δ(N1-H) and δ(N2-H) normal modes, respectively.
The medium intensity absorptions observed at 772 and 751 cm -1 are assigned to the characteristic "breathing mode" of the adamantane group 76 and to the ν(C=S) stretching mode, respectively. The last assignment is in agreement with previously studied thiourea derivatives 75,77 and suggest that the C=S group is acting as a H bond-acceptor . It is well-known that the formation of C=S···H-X intermolecular hydrogen bonds effect the frequency of the ν(C=S) mode. 78 Thus, based on the analysis of the main features of the infrared spectra it is concluded that compound (1) forms strong intra-and inter-molecular interactions in the solid, most probably due to the formation of hydrogen bonds involving the N1-H group as a donor and carbonyl and thiocarbonyl groups as acceptors.

3.4-Hirshfeld surface analysis
Hirshfeld surface analysis was carried out for the purpose to study the nature of intermolecular contacts and theirs quantitative contributions to the supramolecular assembly of 1, as well as on other five mono-substituted adamantyl phenylthiourea derivatives recently reported. 41,42,83 The selected structures are labelled here as 2: 1-(adamantane-1-carbonyl)-3-  (Table 2) forming dimers as described in Figure 3. The same type of interaction was only observed (labelled 1) for the structures 5 and 6. A pair of pale blue to white spots for structures 1 (labelled 6), 5 (labelled 4) and 6 (labelled 4) represent H···S contacts that indicate C· · ·H contacts associated to two T-shaped C-H· · ·π interactions as described in Table 3.
The distances between the involved H-atoms (H13 and H22A) and the nearest carbon atom in the corresponding benzene ring are in agreement with theoretical calculatons for related compounds. 84 For structures 2, 3 and 4 (labelled 1) this motif is combined with N-H···S hydrogen bonds forming typical centrosymmetric loops. It is worthwhile to highlight here that the dihedral angles of 65.22 (2)  bencene ring [centroid Cg(1); symmetry: 1-x,-y,1-z]. The shorter interaction 85 is found with H26B· · ·Cg(1) as described in Table 4. The distance of 2.820(1) Å between H26B atom and the nearest carbon atom in the benzene ring is in agreement with theoretical calculations. 84 Table 3. Geometrical parameters for the π-stacking moieties involved in the π· ··π interactions for Cg(1)· · ·Cg(2) 4.101(2) 3.371(2) 3.371 (2) 0.00 18.3 18.3 2-x, -y, 2-z a Cg(1) and Cg(2) are the centroids of the rings C102-C107 and C202-C207 for (2), respectively, and C1-C6 for (3) and (6). b Centroid distance between ring I and ring J. c Vertical distance from ring centroid I to ring J. d Vertical distance from ring centroid J to ring I. e Dihedral angle between mean planes I and J. f Angle between the centroid vector Cg(I)· · ·Cg(J) and the normal to the plane (I). g Angle between the centroid vector Cg(I)· · ·Cg(J) and the normal to the plane (J).   (2) 1-x,1-y,1-z * (H•••Cg1 < 3.0 Å, γ < 30.0 o ). a Centroid of benzene ring. b Perpendicular distance of H to ring plane J. c Angle between the Cg-H vector and ring J normal. d Distance between H-atom and the nearest carbon atom in the benzene ring. R1 denotes a puckered ring of adamantane group, and R2 of benzene ring.
The N-H·· ·S, C-H···S and C-H···O hydrogen bonds are present in the structures 2 and 3, and can be seen as deep-red spots labelled 1, 2 and 5, respectively, with similar values for the corresponding H···A distances (Table 2) The red to white areas marked as 6 and 7 for surface of 2, and 7 for surface of 6 are C· · ·C contacts representative of π· · ·π stacking interactions ( Table 3). The pattern of adjacent red and blue triangles that appears on the shape index surfaces of 2 and 6, as well as a relative large and flat green region at the same side of the molecule on the corresponding curvedness surfaces confirm the presence of π· · ·π interactions ( Figure 5). The largest region of flat curvedness appears for compound 2. This type of intermolecular contact is also evident by using of these properties mapped on the surface of 3 as showed in Figure 5, but its geometric parameters given in Table 3, particularly Rc, β and γ indicate a weaker interaction, in comparison with those on the surfaces 2 and 6. In addition, a relative smaller region of flat curvedness on the surface of 3 allows us estimate the existence of π· · ·π stacking with a minor overlapping of the adjacent molecules.  correspond to N-H· · ·O and C-H· · ·C hydrogen bonds, respectively. In addition, we observe S· · ·H contacts (labelled 4) with less sharper spikes centered around (d e + d i ) of 2.8 Å, attributed to C-H· · ·S hydrogen bonding ( Table 2). The H···H contacts are shortest for each of the compounds, and O· · · H, S· · · H and C· · · H intermolecular contacts are present in all the structures. In the case of structures 3 and 4, the distances of C· · ·H and O· · ·H contacts, respectively, are longer than the sum of van der Walls radii. Unlike the compound 1, there are O· · ·H reciprocal contacts with asymmetric pair of spikes for structure 2, indicating H· · ·O and O· · ·H contacts with significantly different (d e + d i ) distances, near of 2.3 and 2.5 Å, respectively. C· · ·C contacts (labelled 5) attributed to π· ··π interactions between phenyl rings were observed for the structures 2 and 6, with centroid-to-centroid distances of 3.656 (2)    In this study, we have calculated the enrichment ratios 86 of the main intermolecular contacts for compounds 1-6 in order to analyze the propensity of two chemical species (X,Y) to be in contact. The enrichment ratio E XY is a descriptor derived from the Hirshfeld surface analysis, and defined as the ratio between the proportion of actual contacts C XY in the crystal, and the theoretical proportion of random contacts R XY . The percentages of Hirshfeld surface contacts C XY are given by CrystalExplorer3.1. 66 The proportion S X of different chemical species on the molecular surface is obtained from C XX and C XY values. The random contacts R XY values are calculated from the corresponding S X and S Y proportions by using of probability products. The value of E XY is expected to be generally larger than unity for pairs of elements with high propensity to form contacts in crystals, while pairs that tend to avoid contacts are associated with E XY values lower than unity. Table 5 shows the enrichment ratios of the main intermolecular interactions for compounds 1-6 (the whole information is provided in Table S3). The H· ··H contacts can be considered as favoured in all structures due to enrichment ratios are very close to unity (E HH = 0.90-0.98), and constitute most of the interaction surface (33.9-72.0 %). The E SH values are larger than unity (1.12-1.49) for all the structures, indicating that S· ··H contacts have an increased likelihood to form in the crystal packing, with similar random contacts ranging from 8.1 to 9.4 %. The E CH ratios ranging from 1.10 to 1.37 (except structure 2) indicate that C· ··H contacts have a high propensity to form in crystal packing, as result of abundant S H proportion of hydrogen atoms (61.4-85.6%) at the molecular surfaces. The O· ··H contacts of all the structures are much enriched (except structure 3), with the highest propensity for structures 2 and 6. Despite the contribution of O· ··H contacts to the Hirshfeld surface (C OH = 11.9 %) for compound 6 is lower than that for structure 3 (C OH = 17.9 %), the proportion of oxygen atoms on the molecular surface of the former is significantly smaller (S O = 6.5%), decreasing the value of the random contacts (R OH = 8.7%). This allows to explain the higher propensity of the O· ··H contacts for structure 6 (E OH = 1.37) in comparison with that of the structure 3. value of E CC for structure 2 helps to explain the exceptional low propensity of the C· ··H contacts (E CH = 0.73) due to both C· ··C and C· ··H contacts are presumably in competition. In the case of structure 3 the high probability to form O· · ·O, C· · ·O and N· · ·O short contacts with enrichment ratios ranging from 1.20 to 2.72, is another reason to explain the reduced value of E OH (0.93), in comparison with the other structures. The X· · ·Y intermolecular contacts which are completely avoided with E XY = 0.00, are not included in Table 5.

4-Conclusions
The molecular structure of 1-(adamantane-1-carbonyl)-3-(2,4,6-trimethylphenyl)thiourea has been determined by single-crystal X-ray diffraction. The dihedral angle between the plane of 2,4,6-tri-methylphenyl fragment and the plane of thiourea moiety is 92.6º for the vacuum isolated molecule, a value very similar to that of 89.56(5) o obtained in the crystal structure determination.
All the cyclohexane rings in the adamantane group adopt a very slightly distorted chair conformation as reflected by q(3) value of 0.625Å. The Hirshfeld surfaces, fingerprint plots and enrichment ratios were found to be very useful in the study of the intermolecular interactions, and their quantitative contributions towards the crystal packing of a series of six 1-(adamantane-1carbonyl)-3-substituted-phenyl thioureas. The results revealed remarkable relative contributions in H· ··H interactions more than other contacts. There are structural similarities for the compounds 1, 5 and 6, such as the presence of N-H···O and C-H···S hydrogen bonds forming centrosymmetric and dimers, respectively, related with the nature of substituents on the trisubstituted-phenyl ring. According to the enrichment ratios the H· ··H contacts are favoured, and the S· ··H contacts have high propensity to form in crystals for all the structures. The O· ··H and C· ··H contacts displayed high propensity to occur in five structures. The presence of the less common C-H···F and C-H···Cl hydrogen bonds, as well as π· · ·π and C-H···π contacts, showed be as important as the conventional interactions to direct the packing of molecules. These results could be applied in crystal engineering for the design of supramolecular arrangements using the 1-(adamantane-1-carbonyl)-thiourea synton.

5-Acknowledgments
MFE is a member of the Carrera del Investigador of CONICET (República Argentina). The Argentinean author thanks to the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), the ANPCYT and to the Facultad de Ciencias Exactas, Universidad Nacional de La Plata for financial support.
The 1-acyl thiourea synton is characterized through a complete Hirshfeld surfaces analysis for a series of six closely related 1-(adamantane-1carbonyl) thioureas.