Article pubs.acs.org/crystal
Exploiting the Role of Molecular Electrostatic Potential, Deformation Density, Topology, and Energetics in the Characterization of S···N and Cl···N Supramolecular Motifs in Crystalline Triazolothiadiazoles Imtiaz Khan,† Piyush Panini,‡ Salah Ud-Din Khan,§ Usman Ali Rana,§ Hina Andleeb,† Deepak Chopra,*,‡ Shahid Hameed,*,† and Jim Simpson*,∥ †
Department of Chemistry, Quaid-i-Azam University, Islamabad-45320, Pakistan Crystallography and Crystal Chemistry Laboratory, Department of Chemistry, IISER, Bhopal 462066, India § Sustainable Energy Technologies (SET) Center, College of Engineering, King Saud University, P.O. Box 800, Riyadh 11421, Saudi Arabia ∥ Department of Chemistry, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand ‡
ABSTRACT: A detailed analysis of the molecular and crystal packing of a series of pharmaceutically active triazolothiadiazole derivatives is reported. The most notable feature from the analysis of the supramolecular motifs is the presence of inversion dimers due to the formation of strong S···N chalcogen bonds. This has been unequivocally established via inputs from energy calculations from PIXEL, the topological analysis using the approach of QTAIM from AIMALL, an analysis of the molecular electrostatic potentials plotted on Hirshfeld surfaces, and the analysis of the 3D-deformation densities obtained using Crystal Explorer. The total interaction energy for this contact is in the range of 28−33 kJ/mol in the molecules under investigation, and the electrostatic (Coulombic + polarization) contribution toward the total stabilization energy is more than 70%, indicating that such interactions are principally electrostatic in origin. The results from the analysis of the molecular ESP depict that this interaction exists between a strongly electropositive σ-hole on the sulfur atom and an electronegative region on the nitrogen. 3D-deformation density (DD) maps reveal the presence of a charge depletion (CD) region on the sulfur atom which is directed toward the charge concentration (CC) region on the nitrogen atom facilitating formation of such contacts in the crystal. These are further invesigated by QTAIM based calculations which establish the closed-shell nature of these contacts. The crystal packing is further stabilized by the presence of significantly important π···π stacking interactions, wherein the interaction energies, calculated by the PIXEL method, reveal that some of these interactions in crystals have significant contributions from electrostatic components, with a lesser contribution from dispersion forces that normally dominate such interactions. The existence of a contribution of ∼48% from electrostatics between stacked rings owing to their unique electrostatic complementarity is a rare supramolecular feature observed in crystal packing in these solids. In addition, the existence of C−H···O, C−H···N, C−H···F, and Cl···N interactions is also characterized by a significant electrostatic component in their formation in crystals of these compounds. areas, 7−11 and the nature and characteristics of such interactions is now very well understood.12,13 In recent years, attention has shifted toward the study of other classes of intermolecular interaction, such as π···π contacts,14 lp···π interactions,15−17 halogen bonds,18,19 chalcogen bonds,20−25 etc. π···π interactions were found to be important in biological molecules such as DNA, proteins, and other important functional materials of organic origin.14 A recently recognized class of interactions are those between the charge depleted (CD) region, known as a σ-hole,26−29 on an atom (mainly involving atoms of groups IV−VII in the periodic
1. INTRODUCTION Intermolecular interactions play a very essential role in many branches of science, including molecular recognition and aggregation, crystal engineering, and polymorphism. They also have great importance in biochemistry and structural biology.1−4 It is important to understand such interactions when designing a material with specific desirable properties.5,6 Hence, the study of different intermolecular interactions has always been a fascinating area of research in science. In general, the primary focus of the study of intermolecular interactions has been on the conventional hydrogen bond (e.g., NH···O and OH···O) and its utilization in the design of required supramolecular structures.6 Increasingly, however, the importance of the weak hydrogen bond, C−H···X (X= N, O, halogens, π electrons) has also been realized in different © 2016 American Chemical Society
Received: October 21, 2015 Revised: January 6, 2016 Published: January 12, 2016 1371
DOI: 10.1021/acs.cgd.5b01499 Cryst. Growth Des. 2016, 16, 1371−1386
Crystal Growth & Design
Article
spectra were recorded on a Bruker Avance (75 MHz) spectrometer using deuterated solvent as internal standard (DMSO-d6 at 39.52 ppm). The elemental analysis was performed on a Leco CHNS-932 Elemental Analyzer, Leco Corporation (USA). 2.2. Preparation of Triazolothiadiazoles. 2.2.1. General Procedure for the Synthesis of 4-Amino-1,2,4-triazole-3-thiols (3a−c). The appropriate carbohydrazide (1a−c) (1.0 mmol) was stirred with a solution of potassium hydroxide (1.5 mmol) dissolved in methanol (10 mL) at 0−5 °C. Carbon disulfide (1.5 mmol) was added slowly to this solution and the reaction mixture was left overnight at room temperature. The solid potassium dithiocarbazinate product (2a−c) was filtered, washed with chilled methanol and dried. It was used directly for the next step without further purification. To a solution of the corresponding potassium dithiocarbazinate (2a−c) in water (8 mL), hydrazine hydrate (2.0 mmol) was added and the reaction mixture was refluxed for 4−5 h. During progress of the reaction, the mixture turned green with the evolution of hydrogen sulfide and finally became homogeneous. It was then diluted with little cold water and acidified with conc. hydrochloric acid. The white precipitated solid was filtered, washed with cold water and recrystallized from aqueous ethanol to afford the compounds (3a−c). The physical and spectroscopic data obtained were found to be consistent with those observed in literature.48,50,51 2.2.2. General Procedure for the Synthesis of 1,2,4-triazolo[3,4b][1,3,4]thiadiazoles (4a−e). A mixture of the corresponding 4amino-1,2,4-triazole-3-thiol (3a−c) (1.0 mmol) and the substituted aromatic/heteroaromatic acids (1.1 mmol) in POCl3 (5 mL) was refluxed for 6 h. The reaction mixture was slowly poured into crushed ice with stirring and neutralized with sodium bicarbonate. The precipitated mass was filtered, washed with cold water, dried, and recrystallized (ethanol) to afford the 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles (4a−e).48,50,51 The synthesis of compound 4d has been reported by us previously,52 and the spectroscopic data obtained for 4a were found to be consistent with those observed in literature.48 2.2.1.1. 6-(2-Chloro-4,5-difluorophenyl)-3-(pyridin-3-yl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (4b). Off-white solid (79%): m.p 147−148 °C; Rf: 0.65 (10% MeOH/CHCl3); IR (ATR, cm−1): 3015 (Ar−H), 1593 (CN), 1572, 1499 (CC) 1168 (C−F), 1023 (C− Cl); 1H NMR (300 MHz, DMSO-d6): δ 9.39 (s, 1H, Ar−H), 8.74 (d, 1H, J = 6.9 Hz, Ar−H), 8.56−8.52 (m, 1H, Ar−H), 8.41−8.35 (m, 1H, Ar−H), 8.15−8.14 (m, 1H, Ar−H), 8.14−8.08 (m, 1H, Ar−H); 13C NMR (75 MHz, DMSO-d6): δ 170.89, 163.55, 159.74, 156.82, 151.26, 148.43, 147.54, 144.09, 137.39, 135.67, 132.63, 131.24, 126.89, 121.27, 120.99, 119.99. Analysis Calcd for C14H6ClF2N5S: C, 48.08; H, 1.73; N, 20.02; S, 9.17. Found: C, 47.96; H, 1.65; N, 19.92; S, 9.24. 2.2.1.2. 6-(4-Fluorobenzyl)-3-(pyridin-4-yl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (4c). Brown solid (75%): m.p 187−188 °C; Rf: 0.62 (10% MeOH/CHCl3); IR (ATR, cm−1): 3048 (Ar−H), 1602 (CN), 1569, 1506 (CC) 1218 (C−F); 1H NMR (300 MHz, DMSO-d6): δ 8.80 (bs, 2H, Ar−H), 8.14 (d, 2H, J = 5.7 Hz, Ar−H), 7.54−7.49 (m, 2H, Ar−H), 7.27−7.20 (m, 2H, Ar−H), 4.55 (s, 2H, CH2); 13C NMR (75 MHz, DMSO-d6): δ 171.86, 163.74, 160.51, 156.42, 151.16, 143.72, 132.87, 131.99, 131.94, 131.87, 131.76, 119.83, 116.36, 116.07, 36.74. Analysis Calcd for C15H10FN5S: C, 57.87; H, 3.24; N, 22.49; S, 11.30. Found: C, 57.68; H, 3.32; N, 22.31; S, 11.43. 2.2.1.3. 3-(Pyridin-4-yl)-6-(p-tolyloxymethyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (4e). Brown solid (78%): m.p 194−195 °C; Rf: 0.61 (10% MeOH/CHCl3); IR (ATR, cm−1): 3041 (Ar−H), 1605 (C N), 1546, 1528 (CC); 1H NMR (300 MHz, DMSO-d6): δ 8.82 (d, 2H, J = 6.0 Hz, Ar−H), 8.15−8.13 (m, 2H, Ar−H), 7.15 (d, 2H, J = 8.4 Hz, Ar−H), 7.03 (d, 2H, J = 8.7 Hz, Ar−H), 5.61 (s, 2H, OCH2), 2.25 (s, 3H, CH3); 13C NMR (75 MHz, DMSO-d6): δ 169.79, 156.02, 155.42, 151.21, 143.88, 132.77, 131.53, 130.55, 119.83, 115.46, 65.43, 20.55. Analysis Calcd for C16H13N5OS: C, 59.43; H, 4.05; N, 21.66; S, 9.92. Found: C, 59.56; H, 3.96; N, 21.58; S, 9.74. 2.3. Single Crystal Growth. The compounds 4a−e were dissolved in hot solution of ethanol. On slow evaporation of the solvent at room temperature (20−25 °C), good quality crystals suitable for X-ray diffraction were obtained.
table) with the charge concentrated (CC) region of an atom or part of a molecule, such as a π-ring. Among these, the most commonly investigated interaction is the “halogen bond”, which involves an interaction of the CD region on a halogen atom, opposite to a σ bond, with the other, non-hydrogen atoms in the molecule. According to the recent IUPAC definition,30 “A halogen bond occurs when there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity.” One of the characteristic features associated with this interaction, similar to that of the hydrogen bond, is that these are highly “directional” and the strength depends very much on the magnitude of the CD region on the halogen atom. Moreover, carbon bonds,31 pincogen bonds32,33 (Group V elements), and chalcogen bonds20−25 (Group VI elements) are similar interactions that also involve the presence of a σ-hole. These are currently a prime research focus so that such contacts can be used effectively to construct supramolecular assemblies. Furthermore, their importance has been widely recognized in different areas, including chemical biology, drug design, and functional organic materials research.18−33 Recognizing the importance of the above-mentioned interactions, in the present study, a series of five pharmaceutically active triazolothiadiazole derivatives have been synthesized and their crystal structures have been investigated by single crystal X-ray diffraction. The packing of molecules in the crystal involves important supramolecular interactions, and the nature and properties of these have been quantitatively investigated with contributions from different computational approaches. For the current study, the heterocycles and aromatic systems that make up the molecules were chosen because they occur in numerous structurally diverse bioactive natural products, synthetic drugs, and pharmaceuticals. Such drug candidates find widespread applications in medicinal chemistry, and they have gained eminence due to their substantial therapeutic potential for the effective treatment of various disorders.34,35 Among them, conjugated heterocycles derived from the 1,2,4triazole scaffold are particularly special heterocyclic ring systems featured in a large number of compounds with diverse and important biological activities. These hybrid structures have been observed in a wide variety of therapeutically important compounds demonstrating a broad spectrum of biological functions, including use as antitumor, antiviral, antihelmintic, antifungal, antibacterial, antitubercular, anti-inflammatory, or analgesic agents and as CNS-stimulants, PDE4 inhibitors, or hypoglycemic agents.36−45 In addition, triazolothiadiazoles have also been identified as selective inhibitors of the c-Met proteins46 and are used as molluscicidal agents,47 growth promoters,48 or as cholinesterase, monoamine oxidase, alkaline phosphatase, and urease inhibitors.49
2. EXPERIMENTAL SECTION 2.1. General. All commercially available reagents were used as received. Thin layer chromatography (TLC) was performed on Merck DF-Alufoilien 60F254 0.2 mm precoated plates. Product spots were visualized under UV light at 254 and 365 nm. Melting points were recorded on a Stuart melting point apparatus (SMP3) and are uncorrected. Infrared (IR) spectra were recorded on FTS 3000 MX, Bio-Rad Merlin (Excalibur model) spectrophotometer. 1H NMR spectra were recorded on a Bruker Avance (300 MHz) spectrometer. Chemical shifts (δ) are quoted in parts per million (ppm) downfield of tetramethylsilane, using residual protonated solvent as internal standard (DMSO-d6 at 2.50 ppm). Proton-decoupled 13C NMR 1372
DOI: 10.1021/acs.cgd.5b01499 Cryst. Growth Des. 2016, 16, 1371−1386
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Reflections collected Independent reflections Refinement method Data/restraints/ parameters Goodness-of-fit on F2 Final R indices [I > 2sigma(I)] R indices (all data) Largest diff. peak and hole
Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection Index ranges
Empirical formula CCDC No. Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions
320 1.967 to 34.104
2884.0(9) Å3 8 1.611 g cm−3 0.437 mm−1 1408 2.751 to 27.153°
1050.17(12) Å3 4 1.633 g cm−3
0.307 mm−1
528 0.50 × 0.21 × 0.05 mm3 3.804 to 33.336°
4c
R1 = 0.0722, wR2 = 0.1848 R1 = 0.0809, wR2 = 0.1891
R1 = 0.0437, wR2 = 0.1168
R1 = 0.0695, wR2 = 0.1313 0.632 and −0.722 eÅ−3
1.164
1.019
0.522 and −0.376 eÅ−3
1439/0/139
3792/0/162
0.504 and −0.255 eÅ−3
R1 = 0.0480, wR2 = 0.1021
R1 = 0.0382, wR2 = 0.0960
1.066
4652/0/199
Full-matrix least-squares on F2
0.225 and −0.309 eÅ−3
R1 = 0.0464, wR2 = 0.0969
R1 = 0.0352, wR2 = 0.0900
1.022
2639/0/190
Full-matrix least-squares on F2
0.220 and −0.267 eÅ−3
R1 = 0.0576, wR2 = 0.1146
R1 = 0.0418, wR2 = 0.1049
1.082
2591/0/266
Full-matrix least-squares on F2
Full-matrix least-squares on F2
Full-matrix least-squares on F2
2639 [R(int) = 0.0685]
2591 [R(int) = 0.0531]
4652 [Rint = 0.0349]
1439 [Rint = 0.0378]
3792 [Rint = 0.0608]
2.482 to 24.948°
672
−13 ≤ h ≤ 13; −10 ≤ k ≤ 10; −16 ≤ l ≤ 18 16051
1232 0.470 × 0.450 × 0.190 mm3 2.482 to 26.307°
0.263 mm−1
0.229 mm−1
1431645 323.37 90(2) K 0.71073 Å Monoclinic P21/c a = 11.3550(8) Å, b = 8.6409(7) Å, c = 15.7538(13) Å, β = 105.418(4)° 1490.1(2) Å3 4 1.441 g cm−3
990263 300.31 90(2) K 0.71073 Å Orthorhombic Pbcn a = 13.699(3) Å, b = 9.328(2) Å, c = 20.497(4) Å, α = β = γ = 90° 2619.3(10) Å3 8 1.523 g cm−3
C16H13N5OS
4e
C14H9FN4OS
4d
−16 ≤ h ≤ 15; −7 ≤ k ≤ 7; −29 ≤ l −15 = < h = < 16; 0 = < k = < 25; 0 −7 = < h = < 7; −15 = < k = < 16; −21 = < l = < 19 −17 ≤ h ≤ 14; −11 ≤ k ≤ 11; −25 ≤ l ≤ 25 =
