Structural characterization and crystal packing of the isoquinoline derivative European Journal of Chemistry 9 (3) (2018) 189-193 European Journal of Chemistry View Journal Online View Article Online Structural characterization and crystal packing of the isoquinoline derivative Viktor Vrábel 1, Ľubomír Švorc 1,*, Július Sivý 2, Štefan Marchalín 3 and Peter Šafař 3 1 Institute of Analytical Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, SK-812 37 Bratislava, Slovak Republic viktor.vrabel@stuba.sk (V.V.), lubomir.svorc@stuba.sk (Ľ.Š.) 2 Institute of Mathematics and Physics, Faculty of Mechanical Engineering, Slovak University of Technology in Bratislava, Námestie slobody 17, SK-812 31 Bratislava, Slovak Republic julius.sivy@stuba.sk (J.S.) 3 Institute of Organic Chemistry, Catalysis and Petrochemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, SK-812 37 Bratislava, Slovak Republic stefan.marchalin@stuba.sk (Š.M.), peter.safar@stuba.sk (P.Š.) * Corresponding author at: Institute of Analytical Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, SK-812 37 Bratislava, Slovak Republic. Tel: +421.2.59325302 Fax: +421.2.59325590 e-mail: lubomir.svorc@stuba.sk (Ľ. Švorc). 10.5155/eurjchem.9.3.189-193.1758 Received: 07 June 2018 Received in revised form: 30 June 2018 Accepted: 08 July 2018 Published online: 30 September 2018 Printed: 30 September 2018 We report the crystal and molecular structure of a new isoquinoline-derivative, namely methyl O-[(11R, 11aS)-4-oxo-1, 3, 4, 6, 11, 11a-hexahydro-2H-pyrido[1, 2-b]isoquinolin-11- yl]carbonodithioate (I), C15H17NO2S2, which crystallizes in the non-centrosymmetric space group P212121 and its absolute structure was confirmed by anomalous dispersion effects in diffraction measurements on the crystals. Two central six-membered heterocyclic rings adopt a distorted half-chair conformation. The molecules are linked by a combination of weak C—H∙∙∙O, C—H∙∙∙S, C—H∙∙∙π inter- and intra-molecular interactions resulting in a three- dimensional network in the crystal structure. Crystal Data for C15H17NO2S2 (M =307.41 g/mol): orthorhombic, space group P212121 (no. 19), a = 5.2804(5) Å, b = 8.1347(17) Å, c = 35.015(4) Å, V = 1504.1(4) Å3, Z = 4, T = 298(2) K, μ(MoKα) = 0.354 mm-1, Dcalc =1.358 g/cm3, 20270 reflections measured (5.522° ≤ 2Θ ≤ 50.69°), 2757 unique (Rint = 0.0346, Rsigma = 0.0203) which were used in all calculations. The final R1 was 0.0389 (I > 2σ(I)) and wR2 was 0.0965 (all data). Interaction Isoquinoline Conformation Hydrogen bond X-ray diffraction Crystal structure Cite this: Eur. J. Chem. 2018, 9(3), 189-193 Journal website: www.eurjchem.com 1. Introduction The isoquinoline alkaloids and their synthetic derivatives represent a large class of medicinally active compounds with potentially attractive properties, including antispasmodic, antimicrobial, antitumor, antifungal, anti-inflammatory, antiviral, amoebicidal, antioxidant and enzyme-inhibiting acti- vities. The increasing microbial resistance to primary active structures remains alarming and the effort to search for new antibacterial active structures is still of great scientific interest. One of the attractive ways how to find novel active structures consist in derivatization of well-known natural compounds. Quinoline and isoquinoline derivatives are considered as a useful structural motif for displaying chemical functionality in biologically active molecules. Some of these derivatives have appeared to exhibit potent biological activities as antibacterial against some gram-positive and gram-negative bacteria [1,2]. Amino-quinoline derivatives have also been used as inhibitors of human immuno deficiency virus (HIV) [3]. For example, 4- aminoquinoline was applied in treatment of erythrocytic plasmodial infections [4]. Pyrrolizidinylalkyl derivatives of 4- amino-7-chloroquinoline exhibited excellent antimalarial activity [5], through the accumulation in the acidic digestive vacuoles of the malaria parasite. Hence, it inhibits conversion of toxic haematin to b-haematin. Likewise, 8-aminoquinoline constitutes a family of drugs, namely, primaquine, tafenoquine and pamaquine [6] which has been used in the treatment of malaria. Some isoquinolines rendered other activities such as anti-neoplastic [7] and/or have been utilized as cardiovascular agents [8]. Quinolines and their isomers isoquinolines are also found in various natural products, such as quinine (anti-malarial) and quinidine (anti-arrhythmic). Furthermore, many isoquino- line alkaloids, including cepharanthine, berberine and tetran- dine, have shown anti-inflammatory effect [9-11]. The binding affinity and the solubility in physiological conditions can be considerably affected by the position of the nitrogen bearing a side chain on the isoquinoline skeleton [12]. Therefore, an ABSTRACT RESEARCH ARTICLE KEYWORDS European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2018 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. http://dx.doi.org/10.5155/eurjchem.9.3.189-193.1758 http://dx.doi.org/10.5155/eurjchem.9.3.189-193.1758 https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.9.3.189-193.1758&domain=pdf&date_stamp=2018-09-30 http://www.eurjchem.com/ http://dx.doi.org/10.5155/eurjchem.9.3.189-193.1758 mailto:viktor.vrabel@stuba.sk mailto:lubomir.svorc@stuba.sk mailto:julius.sivy@stuba.sk mailto:stefan.marchalin@stuba.sk mailto:peter.safar@stuba.sk mailto:lubomir.svorc@stuba.sk http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.9.3.189-193.1758&domain=pdf&date_stamp=2018-09-30� 190 Vrábel et al. / European Journal of Chemistry 9 (3) (2018) 189-193 Table 1. Crystal data and details of the structure refinement for compound I. Parameters Compound I Empirical formula C15H17NO2S2 Formula weight 307.41 Temperature (K) 298 Crystal system Orthorhombic Space group P212121 a, (Å) 5.2804(5) b, (Å) 8.1347(2) c, (Å) 35.015(4) Volume (Å3) 1504.1(4) Z 4 ρcalc (g/cm3) 1.358 μ (mm-1) 0.354 F(000) 648.0 Crystal size (mm3) 0.15 × 0.20 × 0.45 Radiation MoKα (λ = 0.71073) 2Θ range for data collection (°) 5.522 to 50.690 Index ranges -6 ≤ h ≤ 6, -9 ≤ k ≤ 9, -42 ≤ l ≤ 42 Reflections collected 20270 Independent reflections 2757 [Rint = 0.1724, Rsigma = 0.1163] Data/restraints/parameters 2757/0/182 Goodness-of-fit on F2 1.062 Final R indexes [I≥2σ (I)] R1 = 0.0389, wR2 = 0.0937 Final R indexes [all data] R1 = 0.0442, wR2 = 0.0965 Largest diff. peak/hole (e Å-3) 0.16/-0.19 Flack parameter -0.01(3) N O H H S O N HO H H O 1, NaH, CS2 SH3C 2, CH3I, THF Figure 1. Synthesis of the compound 1. enormous effort has been spent in developing novel and effective isoquinoline derivatives. 2. Experimental 2.1. Synthesis The compound I (Figure 1), methyl O-[(11R,11aS)-4-oxo-1, 3, 4, 6, 11, 11a-hexahydro-2H-pyrido[1, 2-b]isoquinolin-11-yl] carbonodithioate was prepared by the reaction of freshly crystallized (11R,11aS)-11-hydroxy-1,2,3,6,11,11a-hexahydro- 4H-pyrido[1,2-b]-isoquinolin-4-one with sodium hydride, then carbon disulfide and methyl iodide in dry THF at 60 °C. The recrystallization from n-heptane gave colourless crystals (81 %) as described in literature [13]. 2.2. Refinement Refinement of F2 against all reflections: the weighted R- factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > 2σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on all data will be even larger. All H atoms were placed in geometrically optimized positions and constrained to ride on their parent atoms, with C—H distances in the range of 0.93-0.98 Å. The Uiso(H) values were set at 1.2 Ueq(C-aromatic) and 1.5 Ueq(methyl). 2.3. Data collection Crystal data and conditions of data collection and refinement are reported in Table 1. CrysAlis CCD [14]; cell refinement: CrysAlis RED [14]; data reduction: CrysAlis RED [14]; program(s) used to solve structure: SHELXS97 [15]; program(s) used to refine structure: SHELXL97 [15]; molecular graphics: DIAMOND [16]; software used to prepare material for publication: enCIFer [17], PLATON [18] and WinGX [19]. 2.4. Instrument X-ray single crystal diffraction was carried out on a four- circle diffractometer, device type Xcalibur, Ruby, Gemini, enhance (Mo) X-ray source, radiation monochromator type graphite, CCD plate detector type Ruby, detector area resolution 5.2170 pixels/mm, analytical numeric absorption correction using a multifaceted crystal model based on expressions derived by R.C. Clark & J.S. Reid [20], empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. 3. Results and discussion The molecular geometry and the atom numbering scheme of the compound I is shown in Figure 2. The crystal packing of compound I is depicted in Figure 3. The geometric parameters are listed in Tables 2 and 3. 2018 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.9.3.189-193.1758 Vrábel et al. / European Journal of Chemistry 9 (3) (2018) 189-193 191 Table 2. Bond lengths for compound I. Atoms Length [Å] Atoms Length [Å] C1—C2 1.511 (5) C7—C12 1.394 (4) C1—C5 1.512 (4) C8—C9 1.372 (5) C2—C3 1.510 (5) C9—C10 1.365 (5) C3—C4 1.500 (5) C10—C13 1.385 (5) C4—O1 1.229 (4) C11—N1 1.451 (4) C4—N1 1.353 (4) C11—C13 1.497 (5) C5—N1 1.465 (4) C12—C13 1.392 (4) C5—C6 1.531 (4) C14—O2 1.337 (4) C6—O2 1.460 (3) C14—S1 1.617 (4) C6—C12 1.506 (4) C14—S2 1.742 (3) C7—C8 1.381 (5) C15—S2 1.786 (5) Table 3. Bond angles for compound I. Atoms Angle [°] Atoms Angle [°] C2—C1—C5 111.1 (3) N1—C11—C13 111.6 (3) C3—C2—C1 108.8 (3) C13—C12—C7 118.8 (3) C4—C3—C2 115.6 (3) C13—C12—C6 121.1 (3) O1—C4—N1 121.0 (3) C7—C12—C6 120.0 (3) O1—C4—C3 120.7 (3) C10—C13—C12 119.8 (3) N1—C4—C3 118.3 (3) C10—C13—C11 119.6 (3) N1—C5—C1 112.3 (3) C12—C13—C11 120.6 (3) N1—C5—C6 106.7 (2) O2—C14—S1 127.7 (3) C1—C5—C6 113.8 (3) O2—C14—S2 104.7 (2) O2—C6—C12 107.5 (2) S1—C14—S2 127.5 (2) O2—C6—C5 107.2 (2) C4—N1—C11 120.9 (3) C12—C6—C5 112.6 (2) C4—N1—C5 125.5 (3) C8—C7—C12 120.1 (3) C11—N1—C5 113.4 (2) C9—C8—C7 120.6 (3) C14—O2—C6 121.2 (2) C10—C9—C8 119.8 (3) C14—S2—C15 102.7 (2) Figure 2. Molecular structure of the compound I showing the atom labelling scheme. Displacement ellipsoids are drawn at the 50% probability level. The intramolecular hydrogen interaction is shown as a green dashed line. Figure 3. Stereo view of part crystal structure of the compound I, showing the formation of a hydrogen bonded C(8) chain parallel to [010]. Green dashed lines indicate hydrogen bonds. 2018 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.9.3.189-193.1758 192 Vrábel et al. / European Journal of Chemistry 9 (3) (2018) 189-193 Table 4. Hydrogen-bond geometry (Å, °). D—H∙∙∙A D—H H∙∙∙A D∙∙∙A D—H∙∙∙A C6—H6A∙∙∙S1 0.98(3) 2.576(1) 3.083(3) 112.3(2) C11—H11A∙∙∙O1 0.97(3) 2.311(3) 2.739(4) 105.7(2) C3—H3B∙∙∙O1i 0.97(3) 2.527(3) 3.483(5) 168.3(2) C5—H5A∙∙∙Cg1ii 0.97(3) 2.620 3.583 168.0 Symmetry codes: (i) – x −2, y −1/2, − z −1/2; (ii) 1+ x, y, z. The absolute configuration was unambiguously establis- hed by the structure determination. The expected stereo- chemistry of atoms C5, C6 was confirmed to be S, R. The results indicated that two six-membered rings in the quinolizine moiety of the structure are not planar and yield a half-chair conformation with atoms C2 and C5 above the plane [0.624 (4) and 0.667 (3) Å, respectively] formed by the remaining five atoms N1, C5, C1, C3 and C4 (second ring: C6, C12, C13, C11 and N1,), as approved by the ring-packering parameters [21]: Q = 0.479 (4) Å, θ = 132.9 (5)o and ϕ = 33.1 (4)o (Cremer-Pople puckering amplitude for second ring: Q = 0.509 (3) Å, θ = 48.6 (3)o and ϕ = 31.3 (5)o, respectively). Dihedral angle between the two six-membered rings in the quinolizine moiety is 44.7 (1)°. Atom N1 is sp2-hybridized, as shown by the sum of the valence angles around it (359.8°). These data are consistent with the conjugation of the lone-pair electrons on N1 with an adjacent carbonyl. Additionally, there is a number of weak intra and inter- molecular hydrogen bonds, together with C—H∙∙∙π contacts, within the crystal structure of (I) (geometric parameters are given in Table 4). Two intramolecular hydrogen bonds with graph-set motif S(5) [21], are generated by C6—H6A∙∙∙S1 and C11—H11A∙∙∙O1 contacts. Intermolecular C3—H3B∙∙∙O1 hydrogen bonds, involving O atoms of the carbonyl group link the molecules into infinite C(8) [22] zigzag chains of molecules along the b axis (Figure 3). Finally, there are further inter- molecular C5—H5A∙∙∙Cg1 (Cg1 is the centroid of the C7 – C12 benzene ring) hydrogen bonds in compound I. The molecules are linked into an extensive network in which every molecule acts as both a hydrogen-bond donor and acceptor, and the supramolecular assembly takes the form of infinite three- dimensional network. Bond length of the carbonyl group C4=O1 is 1.229 (4) Å which somewhat longer than typical carbonyl bonds. This may be due to atom O1 participating in intra- and intermolecular hydrogen interactions. 4. Conclusion The isoquinoline-derivatives are a large class of medicinally active compounds with potentially attractive properties, including antispasmodic, antimicrobial, anti- tumour, antifungal and anti-inflammatory activities. In this study, a new isoquinoline-derivative namely, methyl O-[(11R, 11aS)-4-oxo-1, 3, 4, 6, 11, 11a-hexahydro-2H-pyrido[1, 2-b] isoquinolin-11-yl] carbonodithioate (I), was synthesized and structurally characterized by single-crystal X-ray diffraction technique. The crystal structure allowed elucidating the absolute configuration of two stereo centers. According to the results of determination by single crystal X-ray diffraction it was established that the crystal structure of compound 1 is stabilized by intramolecular hydrogen bonds of the C—H∙∙∙O, C—H∙∙∙S, C-H···S type. In addition, C-H···O and C—H∙∙∙π inter- molecular interactions play a crucial role for the formation of supramolecular architectures in the structure of the studied compound. Acknowledgements This work was supported by the Slovak Research and Development Agency (APVV 0204-10) and the Grant Agency of the Slovak Republic (VEGA 1/0873/15, VEGA 1/0371/16 and KEGA 035STU-4/2017). This contribution is also the result of the project: Research Center for Industrial Synthesis of Drugs, ITMS 26240220061, supported by the Research & Development Operational Programme funded by the ERDF. The authors thank the Structural Funds, Interreg IIIA, for financial support in purchasing the diffractometer. Supporting information CCDC-1815853 contains the supplementary crystal- lographic data for this paper. These data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/, or by e-mailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033. Disclosure statement Conflict of interests: The authors declare that they have no conflict of interest. Author contributions: All authors contributed equally to this work. Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compounds are available from the author. ORCID Viktor Vrábel http://orcid.org/0000-0001-9455-8459 Ľubomír Švorc http://orcid.org/0000-0002-9588-8609 Július Sivý http://orcid.org/0000-0003-2932-2604 Štefan Marchalín http://orcid.org/0000-0003-0680-3771 Peter Šafař http://orcid.org/0000-0002-9502-3365 References [1]. Mansour, A. M.; Hassaneen, H. M.; Mohammed, Y. Sh.; Abdel-Ghani, N. T. J. Mol. Struct. 2013, 1045, 180-190. [2]. Kidwai, M.; Bhushan, K. 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Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). 2018 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.9.3.189-193.1758 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Experimental 2.1. Synthesis 2.2. Refinement 2.3. Data collection 2.4. Instrument 3. Results and discussion 4. Conclusion Acknowledgements Supporting information Disclosure statement ORCID References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: