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Synthesis, crystal structure and theoretical analysis of intermolecular interactions in two biologically active derivatives of 1,2,4-triazoles
Accepted Manuscript Synthesis, crystal structure and theoretical analysis of intermolecular interactions in two biologically active derivatives of 1,2,4-triazoles Rahul Shukla, T.P. Mohan, B. Vishalakshi, Deepak Chopra PII:
S0022-2860(17)30011-X
DOI:
10.1016/j.molstruc.2017.01.011
Reference:
MOLSTR 23316
To appear in:
Journal of Molecular Structure
Received Date: 4 November 2016 Revised Date:
30 December 2016
Accepted Date: 2 January 2017
Please cite this article as: R. Shukla, T.P. Mohan, B. Vishalakshi, D. Chopra, Synthesis, crystal structure and theoretical analysis of intermolecular interactions in two biologically active derivatives of 1,2,4triazoles, Journal of Molecular Structure (2017), doi: 10.1016/j.molstruc.2017.01.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Synthesis, Crystal Structure and Theoretical Analysis of intermolecular interactions in two biologically active derivatives of 1,2,4-triazoles. a
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Rahul Shuklaa, T. P. Mohanb, B. Vishalakshi,c Deepak Chopra*a, Crystallography and Crystal Chemistry Laboratory, Department of Chemistry, Indian Institute of
Science Education and Research Bhopal, Bhopal 462066, Madhya Pradesh, India. c
Rallis India Ltd, Bangalore 560091, Karnataka, India.
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b
Department of Chemistry, Mangalore University, Bangalore 574199, Karnataka, India.
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Email: [email protected]. Fax: 91-755-6692392. Highlights
Synthesis of two biologicallyactive derivatives of 1,2,4-triazoles has been reported.
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Role in different intermolecular interaction in crystal packing.
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Quantitative investigation of the nature and strength of intermolecular interactions.
Abstract
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In the present study, we have synthesized and structurally characterized two biologically active derivatives of 1,2,4 triazoles, namely 3-(4-fluoro-3-phenoxyphenyl)-1-(piperidin-1-
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ylmethyl)-1H-1,2,4-triazole-5(4H)-thione (TR) and 1-((3-(4-fluoro-3-phenoxyphenyl)-5(methylthio)-1H-1,2,4-triazol-1-yl)methyl)piperidine(TR1)
via
single
crystal
X-ray
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diffraction. Both the structures show the presence of various intermolecular interactions in the crystalline solid such as C-H…F, C-H…S, C-H…N, C-H…O, C-H…π, and π…π intermolecular interactions. The role of these interactions in molecular packing was analyzed, and the nature of these interactions was evaluated through computational procedures using PIXEL. Hirshfeld analysis further reveals that the contribution of H…F interactions was more prominent towards packing as compared to H…N/O intermolecular interactions. Keywords 1,2,4-triazoles, crystal structure, intermolecular interactions, Hirshfeld analysis, PIXEL. 1
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1. Introduction Studying and analyzing intermolecular interactions plays a very pivotal role in the field of crystal engineering1-5. It facilitates the design of new materials with desirable properties and
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characteristics6-8. The presence of different kinds of intermolecular interactions in different crystal structures will lead to different chemical and biological activity, and this is of great importance to pharmaceutical industries9-10. The nature of intermolecular interactions in a crystal depends on the type of donor and acceptor atoms present in a particular molecule. In the presence of a strong acceptor and donor atom, the crystal packing will be predominantly
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controlled by thepresence of strong hydrogen bonds such as O/N-H…O/N11-12. However, the focus has now shifted to theinvestigation of weak intermolecular interactions such as C–
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H…O/N13-16, C–H…X (X = –F, –Cl, –Br, –I)17-22,C–H…π23and π…π24-25 and lp…π26-27 interactions present in the crystal structures. Weak intermolecular interactions involving organic fluorine have received special attention due to its small size, electronegativity, and lipophilic character28-31. Also, it has been observed that hybridization of the carbon atom participating in the formation of C-H…F-C interactions plays a significant role towards the strength of these interactions32. Due to these characteristics, organic fluorine has become an
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important component in many pharmaceutical drugs, and hence structural characterization of these compounds becomes very important33.
In the present study, we have synthesized two biologically active derivatives of 1, 2, 4triazoles, namely 3-(4-fluoro-3-phenoxyphenyl)-1-(piperidin-1-yl) methyl)-1H-1,2,4-triazole-
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5(4H)-thione (TR) and 1-((3-(4-fluoro-3-phenoxyphenyl)-5-(methylthio)-1H-1,2,4-triazol-1yl)methyl)piperidine (TR1) [Scheme 1]. These compounds were characterized via IR, 1H
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NMR spectroscopy and DSC (differential scanning calorimetry). 1, 2, 4-Triazoles have widespread recognition due to their biological activities (namely antihypertensive, antibacterial and antiviral)34. 1,2,4-triazoles have found its usefulness in industrial applications also35. Crystal structure analysis was performed on these two compounds by analyzing the nature of intermolecular interaction present in the molecule. The role of these weak interactions in crystal packing and a quantitative assessment of the nature of these interactions using PIXEL36-40 are of interest. Also, quantification of the intermolecular interactions present in the title compound using Hirshfeld surface analysis which is a
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graphical tool for visualization and understanding of intermolecular interactionconstitutes the main focus of this article.
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2. Theoretical Calculation The geometrical optimization of the molecule was performed at the B3LYP/6-311G** level of calculation using TURBOMOLE41-42. The crystallographic coordinates were used as the starting geometry for the optimization. The optimized structure thus obtained was used to compare the torsion angles of the isolated molecule with those obtained experimentally. The
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lattice energy of the crystalline solid and the nature and strength of different intermolecular interaction energies were calculated using the Coulomb-London-Pauli (CLP) computer
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program package43-45. The lattice energy obtained from this method was divided into coulombic, polarization, dispersion and repulsion contributions. The intermolecular interaction energy was evaluated using the PIXEL method available in CLP package. These interactions were further analyzed by Hirshfeld surfaces46 and 2D fingerprint47 plots using
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Crystal Explorer 3.048.
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3. Experimental
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3.1 Synthesis
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Scheme 1: Chemical scheme depicting the synthetic route for the formation of 1, 2, 4triazoles derivatives. To a solution of 4-fluoro-3-phenoxybenzohydrazide (I, 0.01 mol) in methanol (150 ml), a
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solution of potassium thiocyanate (0.03 mol) of hydrochloric acid (3 ml) was added with stirring. The reaction mixture was evaporated to dryness on a steam bath. The residue was heated for an additional one hour in methanol (50 ml). The resulting solid was filtered off, washed with water/ethanol, dried and crystallized from ethanol to afford 2-(4-fluoro-3phenoxybenzoyl)hydrazinecarbothioamide(II). In the next step, a mixture of II (0.01 mol) and sodium hydroxide solution (25ml, 8%) was refluxed for 3 hours, the resulting solution was acidified with cooling, the precipitate was then filtered and recrystallized from ethanol-water to give 5-(4-fluoro-3-phenoxyphenyl)-4H-1,2,4-triazole-3-thiol(III). In the next step, III was
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added to a mixture of ethanol (15ml), a solution of formaldehyde (40%, 1.5 ml) and a secondary amine (piperidine, 0.01 mol) and the reaction was stirred and refluxed for thirty minutes and was left overnight at room temperature. The resultant precipitate was filtered and recrystallized from aqueous dimethyformamide to obtain 3-(4-fluoro-3-phenoxyphenyl)-1-
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(piperidin-1-yl)methyl)-1H-1,2,4-triazole-5-thiol(TR). To a stirred solution of TR and sodium ethoxide (0.01 mol of sodium dissolved in 10ml of ethanol) the alkylating agent CH3Cl (0.01 mol) was added. The reaction mixture was stirred at room temperature for 12 hours and then poured into ice water. The crude product was filtered off, washed with water and recrystallized
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from ethanol to obtain 1-((3-(4-fluoro-3-phenoxyphenyl)-5-(methylthio)-1H-1,2,4-triazol-1-
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yl)methyl)piperidine(TR1).
The yields of the final product and the melting points of the compounds were recorded (from DSC @ 5°C/min) [Table TS1, ESI].All the synthesized compounds were characterized by FTIR[Figure-
S1 (a)–(b), ESI] and 1H-NMR [Figure S2-(a)–(b), ESI].
3.2 Crystal Growth
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Suitable crystals of TR and TR1 of appropriate quality and size for single-crystal X-ray diffraction were obtainedby slow evaporation method. Crystal of TRwas grown in 1:1 ratio of DCM:Hexane (10ml each) in a test tube at ~5°C. Crystal of TR1was obtained in 1:1 ratio of
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acetonitrile: hexane (1.5 ml each) in a beaker at ~5°C. 3.3 X-ray crystallography
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Single crystal X-ray diffraction data on these two crystals were collected on a Bruker APEXII diffractometer equipped with a CCD area detector using Mo-Kα radiation (λ = 0.70173 Å) in φ and ω scan modes at 100(2)K for TR and 298(2)K for TR1. The crystal structures were refined by least-squares methods on the basis of all observed reflections using SHELXL201349 present in WinGx (version 2013.3)50. Empirical absorption correction was applied using SADABS V2008/112 (Bruker AXS).All hydrogen atoms are fixed in geometrical positions. Non-hydrogen atoms are refined with anisotropic displacement parameters.The molecular connectivity was drawn using ORTEP3251and the crystal packing diagrams were generated using Mercury (CCDC) program52. Geometrical calculations were done using 5
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PARST53 and PLATON54. The details of the crystal data, data collection, and structure refinementsare shown in Table1.
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TR1 C21H23N4F1O1S1 398.49 0.71073 298(2) 992598 Monoclinic P21/c 10.1805(4) 11.3446(5) 17.4234(8) 90 91.532(3) 90 2011.57(15) 4 1.316 0.189 840 0.9455,0.9740 Fixed -12,12 / -13,13 / -20,20 15234 3524/2744 253 0.0541,0.0401 0.1042, 0.0970 -0.221, 0.161 1.036
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Table 1: Crystallographic and refinement data. Data TR C20H21N4F1O1S1 Formula 384.47 Formula Weight 0.71073 Wavelength 100(2) Temperature(K) 994822 CCDC no Monoclinic Crystal System P21/n Space Group 17.7481(6) a (Å) 5.42118(2) b(Å) 20.3343(7) c(Å) 90 α(˚) 109.230(2) β(˚) 90 γ(˚) 3 1844.12(11) V(cm ) 4 Z -3 1.385 Density(g cm ) µ(mm-1) 0.203 808 F (000) 2.43, 31.78 θ (min, max) Fixed Treatment of hydrogens -21, 21/-6, 5/ -20, 24 hmin,max / kmin,max / lmin,max 10899 No. of ref. 3251/2795 No. unique ref./ obs. ref. 244 No. of parameters 0.0390, 0.0319 R_all, R_obs 0.0891, 0.0847 wR2_all, wR2_obs -0.251, 0.285 ∆ρmin,max(eÅ-3) 1.054 G. o. F 4. Result and Discussion
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Figure 1: ORTEPdrawn with 50% ellipsoidal probability (a) TR with atom numbering scheme. The same has been followed for (b)TR1.
ORTEP of TR and TR1 has been shown in Figure 1. TR and TR1crystallize in the centrosymmetric P21/n and P21/c space groups respectively with one molecule in the asymmetric unit and with Z = 4. The molecule can be divided into three different parts. The
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1,2,4-triazole ring, the flexible fluorophenoxygroup, and the piperidine moiety. Figure 2: (a)(b) shows that the molecular conformation of TR and TR1 differs in their orientation of the fluorophenoxy as well as the piperidine ring in the solid state as well as in the gas phase. Figure 3 highlights the relevant torsions present in the molecule and the corresponding values
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are reported in Table 2. Torsion 1 suggests that the piperidine ring has similar torsion in TR and TR1 with differences in orientation only.The rotation along the C7-C9 bond causes the change in the orientation of the fluorophenoxy group (Torsion 3). Figure 2: (c)-(d) shows the
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overlay of TR and TR1 with their respective optimized structure and the difference occurs only in the fluorophenoxy part of the molecule (Torsion 4 and 5). Both the molecules contain multiple hydrogen bond donors, the hydrogen atom attached to sp2 and sp3 hybridized carbon can act as weak hydrogen bond donors. TR contains an additional N-H bond which can act as strong hydrogen bond donor. In term of the acceptor atoms, both the molecules contain anitrogen atom in different electronic environments in the molecule. Sulfur and oxygen atoms present in the molecule can also act as hydrogen bond acceptors. The presence of aromatic rings in the molecule can also act as weak hydrogen bond acceptors and can result in 7
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theformation of C-H…π interactions in addition to the formation of π…π interaction. A cooperative interplay amongst all these intermolecular interactions is essential for the
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formation of aperiodic arrangement of molecules inside the solid.
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Figure 2: (a) Overlay diagrams of TR (in yellow) and TR1 (in orange) in solid state geometry (b) for all the molecules in gas phase geometry. (c) The overlay diagram of the solid state geometry of TR (in
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yellow) with its corresponding optimized geometry (in red). (d) The overlay diagram of the solid state geometry of TR1(in orange) with its corresponding optimized geometry (in green).
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Figure 3: Torsion angles present in TR. Similar torsions were present in TR1. Table 2:List of important torsion angles (°) for TR, TR1.
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TR 60.9(2) Torsion-1 (C3-N1-C6-N2) 65.3* 98.9(2) Torsion-2 (C8-N2-C6-N1) 103.8* 10.7(2) Torsion-3 (N3-C7-C9-C10) 13.3* 122.3(2) Torsion-4 (C12-C11-O1-C15) 172.1* 165.3(2) Torsion-5 (C20-C15-O1-C11) 104.1* *: indicates values obtained from geometrical optimization.
TR1 65.9(2) 64.7* 98.8(2) 102.1* 175.2(2) 179.1* 99.7(2) 70.7* 179.9(2) 167.5*
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The lattice energy of the two crystalline solids was obtained using the CLP computer program package (Table 3). The energy values depict that the dispersion component has the highest contribution (58%) towards the total stabilization of the molecules in the crystal. Table 3:Lattice energy (in kcal/mol) of TR and TR1 Comp. Code TR TR1
ECoul -24.40 -8.46
EPol -15.03 -4.11
EDisp -53.37 -47.77
ERep 45.45 23.51
ETot -47.34 -36.83
Table 4:List of intermolecular interactions along with their interaction energies (kcal/mol) present in the two crystal structures. Cg1 (triazole): N2-N4-C7-N3-C8, Cg2 (piperidyl): N1-C39
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C2-C1-C5-C4, Cg3 (fluorophenoxy): C9-C10-C11-C12-C13-C14, Cg4 (phenyl): C15-C16-C17C18-C19-C20.
V VI I
II
III
IV V
VI
Epol kcal/mol
Edisp kcal/mol
Erep kcal/mol
Etot kcal/ mol
3.284(1) 3.694(2) 3.834(2) 3.703(2)
2.40 2.64 2.97 2.75
177 163 137 146
2-x, 2-y, 1-z
-25.78
-19.40
-18.32
33.24
-30.25
2-x, 1-y, 1-z
-6.35
-3.80
-15.89
12.93
-13.12
3.523(2)
2.56
147
x, -1+y, z
-3.70
-2.46
-15.27
10.82
-10.62
C4-H4A...F1 C4-H4B...F1 C1-H1A...F1 C14-H14...C13 (Cg3) C2-H2B...C18 (Cg4) C18-H18...C17 (Cg4) TR1 Cg1...Cg1 C21-H21B...N4 C16-H16...S1 C6-H6A...C14(Cg3) C14-H14...O1 C21-H21C...O1 C14-H14...C11(Cg3) C5-H5B...F1 C17-H17...S1 C17-H17...C8 (Cg1) C18-H18...C7 (Cg1) C2-H2A...F1 C3-H3A...C19 (Cg4) C4-H4B...F1
3.354(2) 3.564(2) 3.435(2) 3.883(3) 3.942(2) 3.854(2)
2.45 2.63 2.47 2.97 2.86 2.92
140 143 147 142 179 145
3/2-x, -1/2+y, 1/2-z
-2.41
-1.33
-10.87
6.95
-7.69
-1/2+x, 3/2-y,1/2+z 5/2-x, -1/2+y,1/2-z
-0.59 -0.26
-0.21 -0.23
-2.77 -2.24
1.31 1.19
-2.27 -1.15
3.578(3) 2.77 2.91 2.94 2.69 2.89 3.09 2.82 3.29 2.96 3.07 2.79 2.96 2.95
1-x,-y,1-z
-6.09
-2.39
-19.47
11.66
-16.30
3.696(3) 3.698(3) 3.720(2) 3.762(2) 3.791(3) 4.087(3) 3.524(3) 4.321(3) 3.888(2) 3.914(2) 3.815(2) 3.893(2) 3.982(2)
143 130 129 169 140 152 123 160 144 135 158 144 160
1-x, -1/2+y,3/2-z
-1.38
-0.64
-6.57
2.07
-6.52
-1+x,y,z
-0.74
-0.35
-5.04
1.86
-4.27
1+x, 1/2-y, -1/2+z
-0.71
-0.28
-4.06
1.55
-3.51
x,1/2-y, 1/2+z
-0.54
-0.50
-5.09
3.05
C19-H19...C12 (Cg3)
3.667(2)
2.72
146
-x, 1/2+y, 3/2-z
-0.59
-0.64
-5.23
3.51
-3.10 -2.96
TR N3-H3...S1 C10-H10...S1 C3-H3B...C17 (Cg4) C17-H17...N1 Molecular stack C20-H20...F1 Molecular stack
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Ecoul kcal/mol
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Symmetry code
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III
D-H...X Angle (°)
For a quantitative analysis of all the intermolecular interactions present in TR and TR1, the important
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II
X...A (Å)
molecular pairs were extracted from the crystal packing, and their intermolecular interaction energies were evaluated using PIXEL. Table 4 contains all the intermolecular interactions present in TR and TR1 along with the respective interaction energies in decreasing order. Figure 4:(a)-(f)represents the
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D...A (Å)
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D-H...X-A
molecular pairs of TRalong with their respectivednorm or shape-index plot and Figure 5:(a)-(b) depicts the crystal packing for TR utilizing different intermolecular interactions in the crystal. The crystal structure of TR involves the formation of a strong dimeric N-H…S interaction (involving H3 and S1) along with a weak C-H…S (involving H10 and S1) and C-H…π (involving H3B and C17 of Cg4 ring ) interaction (motif I). The red-spot in the dnorm plot confirms the presence of N-H…S and C-H…S interaction [Figure-4 (a)]. The intermolecular energy stabilization for Motif I is -30.25 kcal/mol, which is of considerably higher magnitude. The previous study on N-H...S interaction has reported the 10
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strength of this dimeric interaction to be -19.6 kcal/mol55.In our motif, the extra stabilization is because of the presence of other interactions in the molecular pair. It is also interesting to note that in motifI, the highest contribution towards stabilization was from coulombic energy (-25.78 kcal/mol) followed by acontribution from polarization (-19.40 kcal/mol) and dispersion components (-18.32
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kcal/mol). Motif IIis stabilized by the presence of a dimeric C-H…N interaction (involving H17 and N1) along with molecular stacking (involving the triazole ring) resulting in a total stabilization of 13.12 kcal/mol with dispersionmaking a significant contribution toward the stabilization (~61%). Previous studies have shown that π…π stacking interaction can contribute appreciably towards the
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stabilization of the molecular pair56-57. Motif I and Motif IIare then interconnectedvia multiple C(sp3)H…F-C(sp2) interaction (involving H1A, H4A, H4B and F1) [Motif IV] along with a C-H…π
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interaction (involving H14 and C13, respectively) resulting in the formation ofa molecular sheet down the ac-plane.[Figure-5 (a)]. The hydrogens involved in the interactions are of acidic nature because of thepresence of electronegative nitrogen atom in the close vicinity. Here also, the stability was largely governed by dispersive forces with ~75% contribution towards stabilization. The red spot in shapeindex plot [marked with anarrow in Figure 4(d)] shows the presence of C-H…F interactions.Also, thehydrogen attached to sp2 carbon atom is of acidic nature and hence actively participates in the
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formation of hydrogen bonds.TR is also involved in theformation of a C-H…F interaction (involving H20 and F1) along with molecular stacking (involving fluorophenoxy and phenyl rings), the total interaction energy being -10.62 kcal/mol [motif III].It is rather unusual to observe thehigh magnitude of coulombic energy in case of motif I & III (-6.35 and -3.70 kcal/mol, respectively) which have C-
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H…F interactions. However, this can be attributed to overall high interaction energies which result in asignificant contribution from all the energy components.Motif IIIis then connected to another similar
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motif via C-H…π interaction (involving H2B and C18) [motif V] with interaction energy of -2.27 kcal/mol resulting in the formation of a tetrameric motif[Figure-5(b)]. Perpendicular to b-axis, this tetramer is then connected to another similar tetramer via the formation of another C-H…π interaction (involving H18 and C17) [motif-VI] with interaction energy of -1.15 kcal/mol [Figure-5 (b)].
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Figure-4 (a)dnormplot of motif-I with red spot [marked with whitearrow] showing the presence of NH…S and C-H…S interaction. (b) Shape index plot for motif-II with the red spot [marked with white arrow] indicating the region of C-H…N interaction.(c) Shape-index plot for motif–III, the blue spot [marked withwhite arrow] showing C-H…F interaction. (d) The shape-index plot for motif-IV with small red spot [marked with whitearrow] showing the presence of C-H…F interaction.(e) The C-H…π interaction in motif-V with thered region around the benzene ring [marked with whitearrow] showing the presence of C-H…π interaction.(f) Similarly for motif-VI, the red region around the benzene ring [marked withwhite arrow] showing the presence of C-H…π interaction.
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Figure-5: (a)Crystal packing in TR utilizing the presence of C-H…S, C-H…F, C-H…N, C-H…π and molecular stacking down the ac-plane. I, II and IV depictthe molecular pairs in TR.
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Figure-5: (b) Formation of tetrameric motifs inTR by utilization of C-H…F, molecular stacking,and C-H…π interactions. Two such adjacent tetramers are connected via another C-H…π interaction. III, V, VI depicts the molecular pairs in TR. Black circle shows the C-H…π interaction in V and VI.
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Figure-6: (a) Shape-index plot of motif-I with red-blue triangle region [marked withwhite arrow] indicating the presence of π…π interaction. (b) Shape-index plot of motif-II with red region indicating the presence of C-H…O and C-H…π interaction[marked with white arrow]. (c)The red region around the sulfur atom in theshape-index plot of motif-III [marked withwhite arrow] indicating the presence of C-H…S interaction. (d) Red region in theshape-index plot of motif-III [marked withwhite arrow] indicating the presence of C-H…π interaction.(e) The blue region in theshape-index plot of motifV[marked withwhite arrow] indicating the presence of a C-H…F interaction. (f)A small red spot in the dnorm plot of motif-VI [marked withwhite arrow] showing the presence of C-H…π interaction.
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The relevant molecular pairs for TR1 along with respective interaction energy have been shown in Figure 6:(a)-(f) and the packing diagram has been shown in Figure 7:(a)-(c). Acceptor and
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donor atom in TR1 were similar to those observed inTR. In TR1, for all the molecular pairs the major contribution is from the dispersion interactions.The most stabilized molecular pair in TR1 is via π…π (involving triazole ring) interaction [Motif I]. The red-blue triangle in the shapeindex plot [marked with anarrow in Figure 6(a)] confirms the presence of this interaction. The molecular pair is further stabilized by the presence of C-H...N (involving H21B and N4), C-H...S (involving H16 and S1) and C-H...π (involving H6A and C14 of Cg3 ring) interactions resulting in overall interaction energy of -16.30 kcal/mol. The hydrogen atom involved in C-H…N interaction was of acidic nature due to its vicinity to an electronegative nitrogen atom. The CH…π interaction is represented by a red spot in theshape-index plot [marked with anarrow in 14
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Figure 6(a)].This motif I is then connected to another motif I via the formation of C-H…S interaction (involving H17 and S1) along with two C-H…π interaction (involving H17 and C8 of Cg1 ring and H18 and C7 of Cg1 ring) with interaction energy being -4.27 kcal/mol [motif III, Figure 6(c)] and resulting in formation of molecular chain down the bc-plane [Figure 7-(b)].The
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formation of second most stabilized molecular pair in TR1 take place via C-H…O interaction (involving H14, H21C and O1), C-H…F interaction (involving H5B and F1) and C-H…π interaction (involving H14 and C11) resulting in interaction energy of -6.52 kcal/mol [motif II, Figure 6(b)].Literature shows that C-H…O interactions play an important role in stabilization of
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protein structures58. The red-spot in shape-index plot clearly indicates the presence of C-H…O and C-H…π interaction [marked with anarrow in Figure 6(b)].This molecular pair [motif II] is
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then connected to another similar molecular pair via the presence of another C-H…F interactions (involving H2A and F1) resulting in the formation of 1D wave-like molecular assembly(motif IV) [Figure 7-(a)].Motif IVis further stabilized by the presence of C-H…π interaction (involving H3A and C19 of Cg4 ring). C-H…π interaction is clearly visible in the shape index plot [marked with anarrow in Figure 6(d)]. Motif Vconsists of a C-H…F interaction (involving H4B and F1) and has interaction energy of -3.10 kcal/mol [Figure 6(e)]. This molecular pair
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along with motif VI which consists of a C-H…π interaction (involving H19 and C12 of Cg3 ring) and hasan interaction energy of -2.96 kcal/mol forms a supramolecular assembly down the ac-plane [Figure 7(c)]. The presence of the C-H…π interaction is clearly visible from dnorm plot of motif-VI [Figure 6(f)].All molecular pairs in TR1 weredispersion dominant interactions with
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percentage contribution towards stabilization being more than 70% in all the cases.
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Figure 7: (a) Molecular packing of TR1 showing theutilization of C-H…F, C-H…O, C-H…π interaction in the formation of a 1D wake like molecular assembly.II, IV depicts the molecular pair in TR1. Black circle shows interactions involved in IV.
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Figure 7: (b) Molecular packing of TR1 showing theutilization of C-H…F, C-H…S, C-H…π, π…π interactions.I, IIIrepresents the molecular pair in TR1. Black circle shows interactions involved in III.
Figure 7: (c) Molecular packing of TR1 showing theutilization of C-H…F and C-H…π interactions in the formation of tetrameric supramolecular assembly down the ac-plane.V, VI depicts the molecular pair in TR1. Black circle shows interactions involved in Vand VI. 16
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Intermolecular interactions were further quantified by plotting Hirshfeld surfaces [Figure-S3, ESI] and 2D-Fingerprint plot [Figure-S4, ESI]. Figure-8 shows the percentage distribution of different intermolecular interaction present in crystal structure obtained through 2D-fingerprint analysis. Both TR and TR1 shows theidentical contribution of different kinds of interaction in crystal packing except
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in the case of H…S interaction where the contribution of H…S (8.8%)is more than double in TR as
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compared to that of TR1(3.7%).
Figure 8: Percentage distribution of the different intermolecular interactions present in the two crystal structures.
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5. Conclusion
In this study, two biologically active derivatives of 1,2,4-triazoles were synthesized, and crystal structure analysis has been performed to study the nature of intermolecular interactions present in these compounds. Molecular packing shows that weak intermolecular interactions such as C-H…F, C-
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H…π interaction also play a very important role in theformation of supramolecular assemblies in these molecules. Evaluated interaction energies also show that even in the presence of strong N-H…S
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interaction, weak interactions are also very much stabilized due to their dispersive nature. It is also interesting to note that the percentage contribution of different intermolecular interaction in both TR and TR1 are similar except for H…S interaction because of thedifferent electronic environment around the sulfur atom in both crystal structures.
Acknowledgements RS thanks DST-INSPIRE for Ph. D. scholarship. DC thanks, IISER Bhopal for infrastructure and research facilities and SERB for financial support. 17
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References 1. G. R. Desiraju, Cryst. Growth Des. 11 (2011) 896. 2. A. Mukherjee, S Tothadi, G. R. Desiraju, Acc. Chem. Res. 47 (2014) 2514.
4. G. R. Desiraju, J. Am. Chem. Soc. 135 (2013) 9952.
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3. C. B. Aakeröy, K. R. Seddan, Chem. Soc. Rev. 22 (1993) 397.
5. P. Panini, D. Chopra, Understanding of Noncovalent interactions involving Organic Fluorine in Z. –T. Li, L. –Z. Wu (Eds), Hydrogen bonded Supramolecular Structures, Springer, 2009, 37-
SC
67.
6. B. Kupcewicz, M. Malecka, Cryst. Growth Des. 15 (2015) 3893.
M AN U
7. C. Sutton, C. Risko, J. –L. Brédas, Chem. Mater 28 (2016) 3.
8. R. M. Ongungal, A. P. Sivadas, N. S. S. Kumar, S. Menon, S. Das, J. Mater. Chem. C 4 (2016) 9588.
9. C. Bissantz, B. Kuhn, M. Stahl, J. Med. Chem. 53 (2010) 5061. 10. R. Wilcken, M. O. Zimmermann, A. Lange, A. C. Joerger, F. M. Boeckler, J. Med. Chem. 56 (2013) 1363
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11. P. Panini, D. Chopra, CrystEngComm 14 (2012) 1972.
12. P. Panini, D. Chopra, CrystEngComm 15 (2013) 3711. 13. S. P. Thomas, M. S. Pavan, T. N. Guru Row, Cryst. Growth Des. 12 (2012) 6083. 14. M. Mazdik, D. Bläser, R. Boese, Tetrahedron 57 (2001) 5791.
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15. G. R. Desiraju, Chem. Commun. (2005) 2995. 16. E. Bosch, Cryst. Growth Des. 10 (2010) 3808.
AC C
17. G. Kaur, P. Panini, D. Chopra, A. R. Choudhury, Cryst. Growth Des. 12 (2012) 5096 18. M. Karanam, A. R. Choudhury, Cryst. Growth Des. 13 (2013) 4803. 19. D. Trybiński, A. Sikorski, CrystEngComm 15 (2013) 6808. 20. D. Dey, S. Bhandary, S. P. Thomas, M. A. Spackman, D. Chopra, Phys. Chem. Chem. Phys. (2016) DOI: 10.1039/C6CP05917A
21. P. Mondal, D. Chopra, CrystEngComm 18 (2016) 48. 22. P. Panini, D. Chopra, Cryst. Growth Des. 14 (2014) 3155. 23. M. Nishio, Phys. Chem. Chem. Phys. 12 (2011) 13873. 24. C. R. Martinez, B. L. Iverson, Chem. Sci. 3 (2012) 18
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25. J. F. Gonthier, S. N. Steinmann, L. Roch, A. Ruggi, N. Luisier, K. Severin, C. Corminboeuf, Chem. Commun. 48 (2012) 9239. 26. A. Robertazzi, F. Krull, W. Knapp, P. Gamez, CrystEngComm 13 (2011) 3293. 27. R. Shukla, T. P. Mohan, B. Vishalakshi, D. Chopra, CrystEngComm 16 (2014) 1702.
29. P. Panini, D. Chopra, New J. Chem. 39 (2015) 8720. 30. D. Chopra, Cryst. Growth Des. 12 (2012) 541.
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28. P. Panini, R. G. Gonnade, D. Chopra, New J. Chem. 40 (2016) 4981.
31. D. Chopra, T. N. Guru Row, CrystEngComm 13 (2011) 2175.
SC
32. R. Shukla, D. Chopra, CrystEngComm 17 (2015) 3596.
33. J. Wang, M. S. Roselló, J. L. Aceña, C. Pozo, A. E. Sorochinsky, S. Fustero, V. A. Solosonok,
M AN U
H. Liu, Chem. Rev. (2014) 2432.
34. A. M. Isloor, B. Kallurava, P. Shetty, Eur. J. Med. Chem. 44 (2009) 3784. 35. N. Singhal, P. K. Sharma, R. Dudhe, N. Kumar, Chem. Phar Res. 3 (2011) 126. 36. J. D. Dunitz, A. Gavezzotti, Cryst. Growth Des. 12 (2012) 5873. 37. L. Maschio, B. Civalleri, P. Ugliengo, A. Gavezzotti, J. Phys. Chem. A 115 (2011) 11179. 38. J. Dunitz, A. Gavezzotti, Chem. Soc. Rev. 38 (2009) 2622.
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39. A. Gavezzotti, CrystEngComm 5 (2003) 429.
40. A. Gavezzotti, CrystEngComm 5 (2003) 439. 41. R. Ahlrichs, M. Bär, M. Häser, H. Horn, C. Kölmel, Chem. Phys. Lett. 162 (1989) 165. 42. 33. TURBOMOLE V6.3 2011, a development of University of Karlsruhe and
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Forschungszentrum Karlsruhe GmbH, 1989–2007, TURBOMOLE GmbH, since 2007, available from http://www.turbomole.com.
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43. A. Gavezzotti, New J. Chem. 35 (2011) 1360. 44. A. Gavezzotti, J. Phys. Chem. B 107 (2003) 2344. 45. A. Gavezzotti, J. Phys. Chem. B 106 (2002) 4145. 46. M. A. Spackman, D. Jayatilaka, CrystEngComm 11 (2009) 19. 47. J. J. McKinnon, D. Jayatilaka, M. A. Spackman, Chem. Commun. (2007) 3814. 48. S. K. Wolff, D. J. Grimwood, J. J. McKinnon, M. J. Turner, D. Jayatilaka, M . A. Spackman, CrystalExplorer (Version 3.0), University of Western Australia, 2012. 49. G. M. Sheldrick, Acta Crystallogr. Sec. A: Found. Crystallogr. 64 (2007) 112. 50. L. J. Farrugia, J. Appl. Crystallogr. 45 (2012) 849. 19
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51. L. J. Farrugia, J. Appl. Crystallogr. 30 (1997) 565. 52. C. F. Macrae, I. J. Bruno, J. A. Chisholm, P. R. Edgington, P. McCabe, E. Pidcock, L. MongeRodriguez, R. Taylor, J. Streek, P. A. Wood, J. Appl. Crystallogr. 41 (2008) 466.
53. M. Nardelli, J. Appl. Crystallogr. 28 (1995) 659.
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www.ccdc.cam.ac.uk/mercury.
54. A. L. Spek, Acta Crystallogr. Sect. D: Biol. Crystallogr. 65 (2009) 148. 55. D. Dey, D. Chopra, Cryst. Growth Des. 14 (2014) 5881.
56. G. B. McGaughey, M. Gagné, A. K. Rappé, J. Biol. Chem. 273 (1998) 15458.
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57. M. P. Waller, A. Robertazzi, J. A. Platis, D. E. Hibbs, P. A. Williams, J. Comput. Chem. 27 (2006) 49.
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EP
TE D
M AN U
58. K. Ramanathan, V. Shanthi, R. Sethumadhavan, Int. J. Pharm. Pharm. Sci. 3 (2011) 324.
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ACCEPTED MANUSCRIPT Highlights Synthesis of two biologicallyactive derivatives of 1,2,4-triazoles has been reported.
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Role in different intermolecular interaction in crystal packing.
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Quantitative investigation of the nature and strength of intermolecular interactions.
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S0022-2860(17)30011-X
DOI:
10.1016/j.molstruc.2017.01.011
Reference:
MOLSTR 23316
To appear in:
Journal of Molecular Structure
Received Date: 4 November 2016 Revised Date:
30 December 2016
Accepted Date: 2 January 2017
Please cite this article as: R. Shukla, T.P. Mohan, B. Vishalakshi, D. Chopra, Synthesis, crystal structure and theoretical analysis of intermolecular interactions in two biologically active derivatives of 1,2,4triazoles, Journal of Molecular Structure (2017), doi: 10.1016/j.molstruc.2017.01.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Synthesis, Crystal Structure and Theoretical Analysis of intermolecular interactions in two biologically active derivatives of 1,2,4-triazoles. a
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Rahul Shuklaa, T. P. Mohanb, B. Vishalakshi,c Deepak Chopra*a, Crystallography and Crystal Chemistry Laboratory, Department of Chemistry, Indian Institute of
Science Education and Research Bhopal, Bhopal 462066, Madhya Pradesh, India. c
Rallis India Ltd, Bangalore 560091, Karnataka, India.
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b
Department of Chemistry, Mangalore University, Bangalore 574199, Karnataka, India.
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Email: [email protected]. Fax: 91-755-6692392. Highlights
Synthesis of two biologicallyactive derivatives of 1,2,4-triazoles has been reported.
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Role in different intermolecular interaction in crystal packing.
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Quantitative investigation of the nature and strength of intermolecular interactions.
Abstract
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In the present study, we have synthesized and structurally characterized two biologically active derivatives of 1,2,4 triazoles, namely 3-(4-fluoro-3-phenoxyphenyl)-1-(piperidin-1-
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ylmethyl)-1H-1,2,4-triazole-5(4H)-thione (TR) and 1-((3-(4-fluoro-3-phenoxyphenyl)-5(methylthio)-1H-1,2,4-triazol-1-yl)methyl)piperidine(TR1)
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single
crystal
X-ray
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diffraction. Both the structures show the presence of various intermolecular interactions in the crystalline solid such as C-H…F, C-H…S, C-H…N, C-H…O, C-H…π, and π…π intermolecular interactions. The role of these interactions in molecular packing was analyzed, and the nature of these interactions was evaluated through computational procedures using PIXEL. Hirshfeld analysis further reveals that the contribution of H…F interactions was more prominent towards packing as compared to H…N/O intermolecular interactions. Keywords 1,2,4-triazoles, crystal structure, intermolecular interactions, Hirshfeld analysis, PIXEL. 1
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1. Introduction Studying and analyzing intermolecular interactions plays a very pivotal role in the field of crystal engineering1-5. It facilitates the design of new materials with desirable properties and
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characteristics6-8. The presence of different kinds of intermolecular interactions in different crystal structures will lead to different chemical and biological activity, and this is of great importance to pharmaceutical industries9-10. The nature of intermolecular interactions in a crystal depends on the type of donor and acceptor atoms present in a particular molecule. In the presence of a strong acceptor and donor atom, the crystal packing will be predominantly
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controlled by thepresence of strong hydrogen bonds such as O/N-H…O/N11-12. However, the focus has now shifted to theinvestigation of weak intermolecular interactions such as C–
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H…O/N13-16, C–H…X (X = –F, –Cl, –Br, –I)17-22,C–H…π23and π…π24-25 and lp…π26-27 interactions present in the crystal structures. Weak intermolecular interactions involving organic fluorine have received special attention due to its small size, electronegativity, and lipophilic character28-31. Also, it has been observed that hybridization of the carbon atom participating in the formation of C-H…F-C interactions plays a significant role towards the strength of these interactions32. Due to these characteristics, organic fluorine has become an
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important component in many pharmaceutical drugs, and hence structural characterization of these compounds becomes very important33.
In the present study, we have synthesized two biologically active derivatives of 1, 2, 4triazoles, namely 3-(4-fluoro-3-phenoxyphenyl)-1-(piperidin-1-yl) methyl)-1H-1,2,4-triazole-
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5(4H)-thione (TR) and 1-((3-(4-fluoro-3-phenoxyphenyl)-5-(methylthio)-1H-1,2,4-triazol-1yl)methyl)piperidine (TR1) [Scheme 1]. These compounds were characterized via IR, 1H
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NMR spectroscopy and DSC (differential scanning calorimetry). 1, 2, 4-Triazoles have widespread recognition due to their biological activities (namely antihypertensive, antibacterial and antiviral)34. 1,2,4-triazoles have found its usefulness in industrial applications also35. Crystal structure analysis was performed on these two compounds by analyzing the nature of intermolecular interaction present in the molecule. The role of these weak interactions in crystal packing and a quantitative assessment of the nature of these interactions using PIXEL36-40 are of interest. Also, quantification of the intermolecular interactions present in the title compound using Hirshfeld surface analysis which is a
2
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graphical tool for visualization and understanding of intermolecular interactionconstitutes the main focus of this article.
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2. Theoretical Calculation The geometrical optimization of the molecule was performed at the B3LYP/6-311G** level of calculation using TURBOMOLE41-42. The crystallographic coordinates were used as the starting geometry for the optimization. The optimized structure thus obtained was used to compare the torsion angles of the isolated molecule with those obtained experimentally. The
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lattice energy of the crystalline solid and the nature and strength of different intermolecular interaction energies were calculated using the Coulomb-London-Pauli (CLP) computer
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program package43-45. The lattice energy obtained from this method was divided into coulombic, polarization, dispersion and repulsion contributions. The intermolecular interaction energy was evaluated using the PIXEL method available in CLP package. These interactions were further analyzed by Hirshfeld surfaces46 and 2D fingerprint47 plots using
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Crystal Explorer 3.048.
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3. Experimental
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3.1 Synthesis
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Scheme 1: Chemical scheme depicting the synthetic route for the formation of 1, 2, 4triazoles derivatives. To a solution of 4-fluoro-3-phenoxybenzohydrazide (I, 0.01 mol) in methanol (150 ml), a
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solution of potassium thiocyanate (0.03 mol) of hydrochloric acid (3 ml) was added with stirring. The reaction mixture was evaporated to dryness on a steam bath. The residue was heated for an additional one hour in methanol (50 ml). The resulting solid was filtered off, washed with water/ethanol, dried and crystallized from ethanol to afford 2-(4-fluoro-3phenoxybenzoyl)hydrazinecarbothioamide(II). In the next step, a mixture of II (0.01 mol) and sodium hydroxide solution (25ml, 8%) was refluxed for 3 hours, the resulting solution was acidified with cooling, the precipitate was then filtered and recrystallized from ethanol-water to give 5-(4-fluoro-3-phenoxyphenyl)-4H-1,2,4-triazole-3-thiol(III). In the next step, III was
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added to a mixture of ethanol (15ml), a solution of formaldehyde (40%, 1.5 ml) and a secondary amine (piperidine, 0.01 mol) and the reaction was stirred and refluxed for thirty minutes and was left overnight at room temperature. The resultant precipitate was filtered and recrystallized from aqueous dimethyformamide to obtain 3-(4-fluoro-3-phenoxyphenyl)-1-
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(piperidin-1-yl)methyl)-1H-1,2,4-triazole-5-thiol(TR). To a stirred solution of TR and sodium ethoxide (0.01 mol of sodium dissolved in 10ml of ethanol) the alkylating agent CH3Cl (0.01 mol) was added. The reaction mixture was stirred at room temperature for 12 hours and then poured into ice water. The crude product was filtered off, washed with water and recrystallized
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from ethanol to obtain 1-((3-(4-fluoro-3-phenoxyphenyl)-5-(methylthio)-1H-1,2,4-triazol-1-
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yl)methyl)piperidine(TR1).
The yields of the final product and the melting points of the compounds were recorded (from DSC @ 5°C/min) [Table TS1, ESI].All the synthesized compounds were characterized by FTIR[Figure-
S1 (a)–(b), ESI] and 1H-NMR [Figure S2-(a)–(b), ESI].
3.2 Crystal Growth
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Suitable crystals of TR and TR1 of appropriate quality and size for single-crystal X-ray diffraction were obtainedby slow evaporation method. Crystal of TRwas grown in 1:1 ratio of DCM:Hexane (10ml each) in a test tube at ~5°C. Crystal of TR1was obtained in 1:1 ratio of
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acetonitrile: hexane (1.5 ml each) in a beaker at ~5°C. 3.3 X-ray crystallography
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Single crystal X-ray diffraction data on these two crystals were collected on a Bruker APEXII diffractometer equipped with a CCD area detector using Mo-Kα radiation (λ = 0.70173 Å) in φ and ω scan modes at 100(2)K for TR and 298(2)K for TR1. The crystal structures were refined by least-squares methods on the basis of all observed reflections using SHELXL201349 present in WinGx (version 2013.3)50. Empirical absorption correction was applied using SADABS V2008/112 (Bruker AXS).All hydrogen atoms are fixed in geometrical positions. Non-hydrogen atoms are refined with anisotropic displacement parameters.The molecular connectivity was drawn using ORTEP3251and the crystal packing diagrams were generated using Mercury (CCDC) program52. Geometrical calculations were done using 5
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PARST53 and PLATON54. The details of the crystal data, data collection, and structure refinementsare shown in Table1.
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TR1 C21H23N4F1O1S1 398.49 0.71073 298(2) 992598 Monoclinic P21/c 10.1805(4) 11.3446(5) 17.4234(8) 90 91.532(3) 90 2011.57(15) 4 1.316 0.189 840 0.9455,0.9740 Fixed -12,12 / -13,13 / -20,20 15234 3524/2744 253 0.0541,0.0401 0.1042, 0.0970 -0.221, 0.161 1.036
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Table 1: Crystallographic and refinement data. Data TR C20H21N4F1O1S1 Formula 384.47 Formula Weight 0.71073 Wavelength 100(2) Temperature(K) 994822 CCDC no Monoclinic Crystal System P21/n Space Group 17.7481(6) a (Å) 5.42118(2) b(Å) 20.3343(7) c(Å) 90 α(˚) 109.230(2) β(˚) 90 γ(˚) 3 1844.12(11) V(cm ) 4 Z -3 1.385 Density(g cm ) µ(mm-1) 0.203 808 F (000) 2.43, 31.78 θ (min, max) Fixed Treatment of hydrogens -21, 21/-6, 5/ -20, 24 hmin,max / kmin,max / lmin,max 10899 No. of ref. 3251/2795 No. unique ref./ obs. ref. 244 No. of parameters 0.0390, 0.0319 R_all, R_obs 0.0891, 0.0847 wR2_all, wR2_obs -0.251, 0.285 ∆ρmin,max(eÅ-3) 1.054 G. o. F 4. Result and Discussion
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Figure 1: ORTEPdrawn with 50% ellipsoidal probability (a) TR with atom numbering scheme. The same has been followed for (b)TR1.
ORTEP of TR and TR1 has been shown in Figure 1. TR and TR1crystallize in the centrosymmetric P21/n and P21/c space groups respectively with one molecule in the asymmetric unit and with Z = 4. The molecule can be divided into three different parts. The
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1,2,4-triazole ring, the flexible fluorophenoxygroup, and the piperidine moiety. Figure 2: (a)(b) shows that the molecular conformation of TR and TR1 differs in their orientation of the fluorophenoxy as well as the piperidine ring in the solid state as well as in the gas phase. Figure 3 highlights the relevant torsions present in the molecule and the corresponding values
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are reported in Table 2. Torsion 1 suggests that the piperidine ring has similar torsion in TR and TR1 with differences in orientation only.The rotation along the C7-C9 bond causes the change in the orientation of the fluorophenoxy group (Torsion 3). Figure 2: (c)-(d) shows the
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overlay of TR and TR1 with their respective optimized structure and the difference occurs only in the fluorophenoxy part of the molecule (Torsion 4 and 5). Both the molecules contain multiple hydrogen bond donors, the hydrogen atom attached to sp2 and sp3 hybridized carbon can act as weak hydrogen bond donors. TR contains an additional N-H bond which can act as strong hydrogen bond donor. In term of the acceptor atoms, both the molecules contain anitrogen atom in different electronic environments in the molecule. Sulfur and oxygen atoms present in the molecule can also act as hydrogen bond acceptors. The presence of aromatic rings in the molecule can also act as weak hydrogen bond acceptors and can result in 7
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theformation of C-H…π interactions in addition to the formation of π…π interaction. A cooperative interplay amongst all these intermolecular interactions is essential for the
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formation of aperiodic arrangement of molecules inside the solid.
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Figure 2: (a) Overlay diagrams of TR (in yellow) and TR1 (in orange) in solid state geometry (b) for all the molecules in gas phase geometry. (c) The overlay diagram of the solid state geometry of TR (in
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yellow) with its corresponding optimized geometry (in red). (d) The overlay diagram of the solid state geometry of TR1(in orange) with its corresponding optimized geometry (in green).
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Figure 3: Torsion angles present in TR. Similar torsions were present in TR1. Table 2:List of important torsion angles (°) for TR, TR1.
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TR 60.9(2) Torsion-1 (C3-N1-C6-N2) 65.3* 98.9(2) Torsion-2 (C8-N2-C6-N1) 103.8* 10.7(2) Torsion-3 (N3-C7-C9-C10) 13.3* 122.3(2) Torsion-4 (C12-C11-O1-C15) 172.1* 165.3(2) Torsion-5 (C20-C15-O1-C11) 104.1* *: indicates values obtained from geometrical optimization.
TR1 65.9(2) 64.7* 98.8(2) 102.1* 175.2(2) 179.1* 99.7(2) 70.7* 179.9(2) 167.5*
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The lattice energy of the two crystalline solids was obtained using the CLP computer program package (Table 3). The energy values depict that the dispersion component has the highest contribution (58%) towards the total stabilization of the molecules in the crystal. Table 3:Lattice energy (in kcal/mol) of TR and TR1 Comp. Code TR TR1
ECoul -24.40 -8.46
EPol -15.03 -4.11
EDisp -53.37 -47.77
ERep 45.45 23.51
ETot -47.34 -36.83
Table 4:List of intermolecular interactions along with their interaction energies (kcal/mol) present in the two crystal structures. Cg1 (triazole): N2-N4-C7-N3-C8, Cg2 (piperidyl): N1-C39
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C2-C1-C5-C4, Cg3 (fluorophenoxy): C9-C10-C11-C12-C13-C14, Cg4 (phenyl): C15-C16-C17C18-C19-C20.
V VI I
II
III
IV V
VI
Epol kcal/mol
Edisp kcal/mol
Erep kcal/mol
Etot kcal/ mol
3.284(1) 3.694(2) 3.834(2) 3.703(2)
2.40 2.64 2.97 2.75
177 163 137 146
2-x, 2-y, 1-z
-25.78
-19.40
-18.32
33.24
-30.25
2-x, 1-y, 1-z
-6.35
-3.80
-15.89
12.93
-13.12
3.523(2)
2.56
147
x, -1+y, z
-3.70
-2.46
-15.27
10.82
-10.62
C4-H4A...F1 C4-H4B...F1 C1-H1A...F1 C14-H14...C13 (Cg3) C2-H2B...C18 (Cg4) C18-H18...C17 (Cg4) TR1 Cg1...Cg1 C21-H21B...N4 C16-H16...S1 C6-H6A...C14(Cg3) C14-H14...O1 C21-H21C...O1 C14-H14...C11(Cg3) C5-H5B...F1 C17-H17...S1 C17-H17...C8 (Cg1) C18-H18...C7 (Cg1) C2-H2A...F1 C3-H3A...C19 (Cg4) C4-H4B...F1
3.354(2) 3.564(2) 3.435(2) 3.883(3) 3.942(2) 3.854(2)
2.45 2.63 2.47 2.97 2.86 2.92
140 143 147 142 179 145
3/2-x, -1/2+y, 1/2-z
-2.41
-1.33
-10.87
6.95
-7.69
-1/2+x, 3/2-y,1/2+z 5/2-x, -1/2+y,1/2-z
-0.59 -0.26
-0.21 -0.23
-2.77 -2.24
1.31 1.19
-2.27 -1.15
3.578(3) 2.77 2.91 2.94 2.69 2.89 3.09 2.82 3.29 2.96 3.07 2.79 2.96 2.95
1-x,-y,1-z
-6.09
-2.39
-19.47
11.66
-16.30
3.696(3) 3.698(3) 3.720(2) 3.762(2) 3.791(3) 4.087(3) 3.524(3) 4.321(3) 3.888(2) 3.914(2) 3.815(2) 3.893(2) 3.982(2)
143 130 129 169 140 152 123 160 144 135 158 144 160
1-x, -1/2+y,3/2-z
-1.38
-0.64
-6.57
2.07
-6.52
-1+x,y,z
-0.74
-0.35
-5.04
1.86
-4.27
1+x, 1/2-y, -1/2+z
-0.71
-0.28
-4.06
1.55
-3.51
x,1/2-y, 1/2+z
-0.54
-0.50
-5.09
3.05
C19-H19...C12 (Cg3)
3.667(2)
2.72
146
-x, 1/2+y, 3/2-z
-0.59
-0.64
-5.23
3.51
-3.10 -2.96
TR N3-H3...S1 C10-H10...S1 C3-H3B...C17 (Cg4) C17-H17...N1 Molecular stack C20-H20...F1 Molecular stack
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Ecoul kcal/mol
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Symmetry code
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III
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For a quantitative analysis of all the intermolecular interactions present in TR and TR1, the important
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II
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molecular pairs were extracted from the crystal packing, and their intermolecular interaction energies were evaluated using PIXEL. Table 4 contains all the intermolecular interactions present in TR and TR1 along with the respective interaction energies in decreasing order. Figure 4:(a)-(f)represents the
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molecular pairs of TRalong with their respectivednorm or shape-index plot and Figure 5:(a)-(b) depicts the crystal packing for TR utilizing different intermolecular interactions in the crystal. The crystal structure of TR involves the formation of a strong dimeric N-H…S interaction (involving H3 and S1) along with a weak C-H…S (involving H10 and S1) and C-H…π (involving H3B and C17 of Cg4 ring ) interaction (motif I). The red-spot in the dnorm plot confirms the presence of N-H…S and C-H…S interaction [Figure-4 (a)]. The intermolecular energy stabilization for Motif I is -30.25 kcal/mol, which is of considerably higher magnitude. The previous study on N-H...S interaction has reported the 10
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strength of this dimeric interaction to be -19.6 kcal/mol55.In our motif, the extra stabilization is because of the presence of other interactions in the molecular pair. It is also interesting to note that in motifI, the highest contribution towards stabilization was from coulombic energy (-25.78 kcal/mol) followed by acontribution from polarization (-19.40 kcal/mol) and dispersion components (-18.32
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kcal/mol). Motif IIis stabilized by the presence of a dimeric C-H…N interaction (involving H17 and N1) along with molecular stacking (involving the triazole ring) resulting in a total stabilization of 13.12 kcal/mol with dispersionmaking a significant contribution toward the stabilization (~61%). Previous studies have shown that π…π stacking interaction can contribute appreciably towards the
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stabilization of the molecular pair56-57. Motif I and Motif IIare then interconnectedvia multiple C(sp3)H…F-C(sp2) interaction (involving H1A, H4A, H4B and F1) [Motif IV] along with a C-H…π
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interaction (involving H14 and C13, respectively) resulting in the formation ofa molecular sheet down the ac-plane.[Figure-5 (a)]. The hydrogens involved in the interactions are of acidic nature because of thepresence of electronegative nitrogen atom in the close vicinity. Here also, the stability was largely governed by dispersive forces with ~75% contribution towards stabilization. The red spot in shapeindex plot [marked with anarrow in Figure 4(d)] shows the presence of C-H…F interactions.Also, thehydrogen attached to sp2 carbon atom is of acidic nature and hence actively participates in the
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formation of hydrogen bonds.TR is also involved in theformation of a C-H…F interaction (involving H20 and F1) along with molecular stacking (involving fluorophenoxy and phenyl rings), the total interaction energy being -10.62 kcal/mol [motif III].It is rather unusual to observe thehigh magnitude of coulombic energy in case of motif I & III (-6.35 and -3.70 kcal/mol, respectively) which have C-
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H…F interactions. However, this can be attributed to overall high interaction energies which result in asignificant contribution from all the energy components.Motif IIIis then connected to another similar
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motif via C-H…π interaction (involving H2B and C18) [motif V] with interaction energy of -2.27 kcal/mol resulting in the formation of a tetrameric motif[Figure-5(b)]. Perpendicular to b-axis, this tetramer is then connected to another similar tetramer via the formation of another C-H…π interaction (involving H18 and C17) [motif-VI] with interaction energy of -1.15 kcal/mol [Figure-5 (b)].
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Figure-4 (a)dnormplot of motif-I with red spot [marked with whitearrow] showing the presence of NH…S and C-H…S interaction. (b) Shape index plot for motif-II with the red spot [marked with white arrow] indicating the region of C-H…N interaction.(c) Shape-index plot for motif–III, the blue spot [marked withwhite arrow] showing C-H…F interaction. (d) The shape-index plot for motif-IV with small red spot [marked with whitearrow] showing the presence of C-H…F interaction.(e) The C-H…π interaction in motif-V with thered region around the benzene ring [marked with whitearrow] showing the presence of C-H…π interaction.(f) Similarly for motif-VI, the red region around the benzene ring [marked withwhite arrow] showing the presence of C-H…π interaction.
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Figure-5: (a)Crystal packing in TR utilizing the presence of C-H…S, C-H…F, C-H…N, C-H…π and molecular stacking down the ac-plane. I, II and IV depictthe molecular pairs in TR.
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Figure-5: (b) Formation of tetrameric motifs inTR by utilization of C-H…F, molecular stacking,and C-H…π interactions. Two such adjacent tetramers are connected via another C-H…π interaction. III, V, VI depicts the molecular pairs in TR. Black circle shows the C-H…π interaction in V and VI.
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Figure-6: (a) Shape-index plot of motif-I with red-blue triangle region [marked withwhite arrow] indicating the presence of π…π interaction. (b) Shape-index plot of motif-II with red region indicating the presence of C-H…O and C-H…π interaction[marked with white arrow]. (c)The red region around the sulfur atom in theshape-index plot of motif-III [marked withwhite arrow] indicating the presence of C-H…S interaction. (d) Red region in theshape-index plot of motif-III [marked withwhite arrow] indicating the presence of C-H…π interaction.(e) The blue region in theshape-index plot of motifV[marked withwhite arrow] indicating the presence of a C-H…F interaction. (f)A small red spot in the dnorm plot of motif-VI [marked withwhite arrow] showing the presence of C-H…π interaction.
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The relevant molecular pairs for TR1 along with respective interaction energy have been shown in Figure 6:(a)-(f) and the packing diagram has been shown in Figure 7:(a)-(c). Acceptor and
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donor atom in TR1 were similar to those observed inTR. In TR1, for all the molecular pairs the major contribution is from the dispersion interactions.The most stabilized molecular pair in TR1 is via π…π (involving triazole ring) interaction [Motif I]. The red-blue triangle in the shapeindex plot [marked with anarrow in Figure 6(a)] confirms the presence of this interaction. The molecular pair is further stabilized by the presence of C-H...N (involving H21B and N4), C-H...S (involving H16 and S1) and C-H...π (involving H6A and C14 of Cg3 ring) interactions resulting in overall interaction energy of -16.30 kcal/mol. The hydrogen atom involved in C-H…N interaction was of acidic nature due to its vicinity to an electronegative nitrogen atom. The CH…π interaction is represented by a red spot in theshape-index plot [marked with anarrow in 14
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Figure 6(a)].This motif I is then connected to another motif I via the formation of C-H…S interaction (involving H17 and S1) along with two C-H…π interaction (involving H17 and C8 of Cg1 ring and H18 and C7 of Cg1 ring) with interaction energy being -4.27 kcal/mol [motif III, Figure 6(c)] and resulting in formation of molecular chain down the bc-plane [Figure 7-(b)].The
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formation of second most stabilized molecular pair in TR1 take place via C-H…O interaction (involving H14, H21C and O1), C-H…F interaction (involving H5B and F1) and C-H…π interaction (involving H14 and C11) resulting in interaction energy of -6.52 kcal/mol [motif II, Figure 6(b)].Literature shows that C-H…O interactions play an important role in stabilization of
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protein structures58. The red-spot in shape-index plot clearly indicates the presence of C-H…O and C-H…π interaction [marked with anarrow in Figure 6(b)].This molecular pair [motif II] is
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then connected to another similar molecular pair via the presence of another C-H…F interactions (involving H2A and F1) resulting in the formation of 1D wave-like molecular assembly(motif IV) [Figure 7-(a)].Motif IVis further stabilized by the presence of C-H…π interaction (involving H3A and C19 of Cg4 ring). C-H…π interaction is clearly visible in the shape index plot [marked with anarrow in Figure 6(d)]. Motif Vconsists of a C-H…F interaction (involving H4B and F1) and has interaction energy of -3.10 kcal/mol [Figure 6(e)]. This molecular pair
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along with motif VI which consists of a C-H…π interaction (involving H19 and C12 of Cg3 ring) and hasan interaction energy of -2.96 kcal/mol forms a supramolecular assembly down the ac-plane [Figure 7(c)]. The presence of the C-H…π interaction is clearly visible from dnorm plot of motif-VI [Figure 6(f)].All molecular pairs in TR1 weredispersion dominant interactions with
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percentage contribution towards stabilization being more than 70% in all the cases.
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Figure 7: (a) Molecular packing of TR1 showing theutilization of C-H…F, C-H…O, C-H…π interaction in the formation of a 1D wake like molecular assembly.II, IV depicts the molecular pair in TR1. Black circle shows interactions involved in IV.
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Figure 7: (b) Molecular packing of TR1 showing theutilization of C-H…F, C-H…S, C-H…π, π…π interactions.I, IIIrepresents the molecular pair in TR1. Black circle shows interactions involved in III.
Figure 7: (c) Molecular packing of TR1 showing theutilization of C-H…F and C-H…π interactions in the formation of tetrameric supramolecular assembly down the ac-plane.V, VI depicts the molecular pair in TR1. Black circle shows interactions involved in Vand VI. 16
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Intermolecular interactions were further quantified by plotting Hirshfeld surfaces [Figure-S3, ESI] and 2D-Fingerprint plot [Figure-S4, ESI]. Figure-8 shows the percentage distribution of different intermolecular interaction present in crystal structure obtained through 2D-fingerprint analysis. Both TR and TR1 shows theidentical contribution of different kinds of interaction in crystal packing except
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in the case of H…S interaction where the contribution of H…S (8.8%)is more than double in TR as
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compared to that of TR1(3.7%).
Figure 8: Percentage distribution of the different intermolecular interactions present in the two crystal structures.
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5. Conclusion
In this study, two biologically active derivatives of 1,2,4-triazoles were synthesized, and crystal structure analysis has been performed to study the nature of intermolecular interactions present in these compounds. Molecular packing shows that weak intermolecular interactions such as C-H…F, C-
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H…π interaction also play a very important role in theformation of supramolecular assemblies in these molecules. Evaluated interaction energies also show that even in the presence of strong N-H…S
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interaction, weak interactions are also very much stabilized due to their dispersive nature. It is also interesting to note that the percentage contribution of different intermolecular interaction in both TR and TR1 are similar except for H…S interaction because of thedifferent electronic environment around the sulfur atom in both crystal structures.
Acknowledgements RS thanks DST-INSPIRE for Ph. D. scholarship. DC thanks, IISER Bhopal for infrastructure and research facilities and SERB for financial support. 17
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References 1. G. R. Desiraju, Cryst. Growth Des. 11 (2011) 896. 2. A. Mukherjee, S Tothadi, G. R. Desiraju, Acc. Chem. Res. 47 (2014) 2514.
4. G. R. Desiraju, J. Am. Chem. Soc. 135 (2013) 9952.
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3. C. B. Aakeröy, K. R. Seddan, Chem. Soc. Rev. 22 (1993) 397.
5. P. Panini, D. Chopra, Understanding of Noncovalent interactions involving Organic Fluorine in Z. –T. Li, L. –Z. Wu (Eds), Hydrogen bonded Supramolecular Structures, Springer, 2009, 37-
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67.
6. B. Kupcewicz, M. Malecka, Cryst. Growth Des. 15 (2015) 3893.
M AN U
7. C. Sutton, C. Risko, J. –L. Brédas, Chem. Mater 28 (2016) 3.
8. R. M. Ongungal, A. P. Sivadas, N. S. S. Kumar, S. Menon, S. Das, J. Mater. Chem. C 4 (2016) 9588.
9. C. Bissantz, B. Kuhn, M. Stahl, J. Med. Chem. 53 (2010) 5061. 10. R. Wilcken, M. O. Zimmermann, A. Lange, A. C. Joerger, F. M. Boeckler, J. Med. Chem. 56 (2013) 1363
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11. P. Panini, D. Chopra, CrystEngComm 14 (2012) 1972.
12. P. Panini, D. Chopra, CrystEngComm 15 (2013) 3711. 13. S. P. Thomas, M. S. Pavan, T. N. Guru Row, Cryst. Growth Des. 12 (2012) 6083. 14. M. Mazdik, D. Bläser, R. Boese, Tetrahedron 57 (2001) 5791.
EP
15. G. R. Desiraju, Chem. Commun. (2005) 2995. 16. E. Bosch, Cryst. Growth Des. 10 (2010) 3808.
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17. G. Kaur, P. Panini, D. Chopra, A. R. Choudhury, Cryst. Growth Des. 12 (2012) 5096 18. M. Karanam, A. R. Choudhury, Cryst. Growth Des. 13 (2013) 4803. 19. D. Trybiński, A. Sikorski, CrystEngComm 15 (2013) 6808. 20. D. Dey, S. Bhandary, S. P. Thomas, M. A. Spackman, D. Chopra, Phys. Chem. Chem. Phys. (2016) DOI: 10.1039/C6CP05917A
21. P. Mondal, D. Chopra, CrystEngComm 18 (2016) 48. 22. P. Panini, D. Chopra, Cryst. Growth Des. 14 (2014) 3155. 23. M. Nishio, Phys. Chem. Chem. Phys. 12 (2011) 13873. 24. C. R. Martinez, B. L. Iverson, Chem. Sci. 3 (2012) 18
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25. J. F. Gonthier, S. N. Steinmann, L. Roch, A. Ruggi, N. Luisier, K. Severin, C. Corminboeuf, Chem. Commun. 48 (2012) 9239. 26. A. Robertazzi, F. Krull, W. Knapp, P. Gamez, CrystEngComm 13 (2011) 3293. 27. R. Shukla, T. P. Mohan, B. Vishalakshi, D. Chopra, CrystEngComm 16 (2014) 1702.
29. P. Panini, D. Chopra, New J. Chem. 39 (2015) 8720. 30. D. Chopra, Cryst. Growth Des. 12 (2012) 541.
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28. P. Panini, R. G. Gonnade, D. Chopra, New J. Chem. 40 (2016) 4981.
31. D. Chopra, T. N. Guru Row, CrystEngComm 13 (2011) 2175.
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32. R. Shukla, D. Chopra, CrystEngComm 17 (2015) 3596.
33. J. Wang, M. S. Roselló, J. L. Aceña, C. Pozo, A. E. Sorochinsky, S. Fustero, V. A. Solosonok,
M AN U
H. Liu, Chem. Rev. (2014) 2432.
34. A. M. Isloor, B. Kallurava, P. Shetty, Eur. J. Med. Chem. 44 (2009) 3784. 35. N. Singhal, P. K. Sharma, R. Dudhe, N. Kumar, Chem. Phar Res. 3 (2011) 126. 36. J. D. Dunitz, A. Gavezzotti, Cryst. Growth Des. 12 (2012) 5873. 37. L. Maschio, B. Civalleri, P. Ugliengo, A. Gavezzotti, J. Phys. Chem. A 115 (2011) 11179. 38. J. Dunitz, A. Gavezzotti, Chem. Soc. Rev. 38 (2009) 2622.
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39. A. Gavezzotti, CrystEngComm 5 (2003) 429.
40. A. Gavezzotti, CrystEngComm 5 (2003) 439. 41. R. Ahlrichs, M. Bär, M. Häser, H. Horn, C. Kölmel, Chem. Phys. Lett. 162 (1989) 165. 42. 33. TURBOMOLE V6.3 2011, a development of University of Karlsruhe and
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Forschungszentrum Karlsruhe GmbH, 1989–2007, TURBOMOLE GmbH, since 2007, available from http://www.turbomole.com.
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43. A. Gavezzotti, New J. Chem. 35 (2011) 1360. 44. A. Gavezzotti, J. Phys. Chem. B 107 (2003) 2344. 45. A. Gavezzotti, J. Phys. Chem. B 106 (2002) 4145. 46. M. A. Spackman, D. Jayatilaka, CrystEngComm 11 (2009) 19. 47. J. J. McKinnon, D. Jayatilaka, M. A. Spackman, Chem. Commun. (2007) 3814. 48. S. K. Wolff, D. J. Grimwood, J. J. McKinnon, M. J. Turner, D. Jayatilaka, M . A. Spackman, CrystalExplorer (Version 3.0), University of Western Australia, 2012. 49. G. M. Sheldrick, Acta Crystallogr. Sec. A: Found. Crystallogr. 64 (2007) 112. 50. L. J. Farrugia, J. Appl. Crystallogr. 45 (2012) 849. 19
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51. L. J. Farrugia, J. Appl. Crystallogr. 30 (1997) 565. 52. C. F. Macrae, I. J. Bruno, J. A. Chisholm, P. R. Edgington, P. McCabe, E. Pidcock, L. MongeRodriguez, R. Taylor, J. Streek, P. A. Wood, J. Appl. Crystallogr. 41 (2008) 466.
53. M. Nardelli, J. Appl. Crystallogr. 28 (1995) 659.
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www.ccdc.cam.ac.uk/mercury.
54. A. L. Spek, Acta Crystallogr. Sect. D: Biol. Crystallogr. 65 (2009) 148. 55. D. Dey, D. Chopra, Cryst. Growth Des. 14 (2014) 5881.
56. G. B. McGaughey, M. Gagné, A. K. Rappé, J. Biol. Chem. 273 (1998) 15458.
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57. M. P. Waller, A. Robertazzi, J. A. Platis, D. E. Hibbs, P. A. Williams, J. Comput. Chem. 27 (2006) 49.
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58. K. Ramanathan, V. Shanthi, R. Sethumadhavan, Int. J. Pharm. Pharm. Sci. 3 (2011) 324.
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Role in different intermolecular interaction in crystal packing.
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Quantitative investigation of the nature and strength of intermolecular interactions.
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