Synthesis and description of intermolecular interactions in new sulfonamide derivatives of tranexamic acid

Journal of Molecular Structure 1103 (2016) 271e280

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Synthesis and description of intermolecular interactions in new sulfonamide derivatives of tranexamic acid Muhammad Ashfaq a, Muhammad Nadeem Arshad b, c, *, Muhammad Danish a, Abdullah M. Asiri b, c, Sadia Khatoon a, Ghulam Mustafa a, Pavel N. Zolotarev d, e, Rabia Ayub Butt a, Onur S¸ahin f a

Department of Chemistry, University of Gujrat, Gujrat 50700, Pakistan Chemistry Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia Centre of Excellence for Advanced Materials Research (CEAMR), King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia d Samara Center for Theoretical Materials Science (SCTMS), Samara State University, Ac. Pavlov St. 1, Samara 443011, Russian Federation e Samara State Aerospace University (National Research University), SSAU, 34, Moskovskoe Shosse Str., Samara 443086, Russian Federation f Scientific and Technological Research Application and Research Center, Sinop University, 57010 Sinop, Turkey b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 23 March 2015 Received in revised form 1 September 2015 Accepted 29 September 2015 Available online 3 October 2015

Tranexamic acid (4-aminomethyl-cyclohexanecarboxylic acid) was reacted with sulfonyl chlorides to produce structurally related four sulfonamide derivatives using simple and environmental friendly method to check out their three-dimensional behavior and van der Walls interactions. The molecules were crystallized in different possibilities, as it is/after alkylation at its O and N atoms/along with a comolecule. All molecules were crystallized in monoclinic crystal system with space group P21/n, P21/c and P21/a. X-ray studies reveal that the molecules stabilized themselves by different kinds of hydrogen bonding interactions. The molecules are getting connected through OeH/O hydrogen bonds to form inversion dimers which are further connected through NeH/O interactions. The molecules in which N and O atoms were alkylated showed non-classical interaction and generated centro-symmetric R2 2 ð24Þ ring motif. The co-crystallized host and guest molecules are connected to each other via OeH/O interactions to generate different ring motifs. By means of the ToposPro software an analysis of the topologies of underlying nets that correspond to molecular packings and hydrogen-bonded networks in structures under consideration was carried out. © 2015 Elsevier B.V. All rights reserved.

Keywords: Tranexamic acid Sulfonamide Crystallization Topological aspects of structure

1. Introduction Plasminogen is a plasma protein which is present in an inactive form. Because of an activator, it is transformed into plasmin, which originates from tissues in case of injuries or damage to the body. Plasmin is an enzyme that breaks down proteins (fibrin and several different proteins) through its proteolytic activity [1]. Tranexamic acid performs its antifibrinolytic activity as it blocks competitively those sites of protein plasmin, plasminogen and plasminogen activator that bind lysine hence their interaction with fibrin is prevented. So plasminogen cannot be converted into plasmin and in this way proteolytic activity is prohibited [2]. It is a synthetic drug

* Corresponding author. Chemistry Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia. E-mail address: [email protected] (M.N. Arshad). http://dx.doi.org/10.1016/j.molstruc.2015.09.022 0022-2860/© 2015 Elsevier B.V. All rights reserved.

that causes antifibrinolytic activity by inhibiting the breakdown of protein fibrin hence leads towards the stabilization of blood clots [3]. Gastrointestinal tract is the place where its absorption takes place and after almost 3 h peak plasma concentration occurs. The drug has a bioavailability around 30e50% and is excreted from the body mostly in an unchanged form [4]. Almost 95% drug is removed through kidneys in unaltered form. Its half-life is approximately 3 h [5]. Owing to its antifibrinolytic nature, the drug is being given to “Coronary Artery Bypass Graft” (CABG) patients on a regular basis [6]. It is an adjuvant drug that enhances the efficacy of other medicines when administered together with them so it is being used for site specific laser therapy. It also prevents menstrual loss of blood and is substitute for operation in menorrhagia. Hemophilic patients also require this drug during extraction of tooth and blood loss disorders [7]. Tranexamic acid is applied on the knee joint during knee arthroplasty so as to reduce bleeding after operation and it has also been used for spine, cardiac and dental procedures [8].

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Tranexamic acid does not have any p-electrons so it cannot act as fluorophore or chromophore and hence cannot be measured through UV spectroscopy. It is therefore imperative to derivatize this compound so as to quantify its UV-active derivative though HPLC-UV. A review of the literature resulted into many papers describing derivatization of this drug with different reagents followed by their HPLC determinations. Some of these methods utilized methanolic ninhydrin [9], phenylisothiocyanate [10], 2hydroxynaphthaldehyde in aqueous ethanol [11] and sodium picrylsulfonate [12] followed by their determination through HPLCUV. In addition to these, LC-fluorescence method utilizing naphthalene-2,3-dicarboxaldehyde plus cyanide [13], o-phthalaldehyde [14], an electrochemical method [15], a LC-MS method [16] and UPLC-MS/MS [17] has also been established for the determination of tranexamic acid. An RP-HPLC method for the determination of tranexamic acid along with its related substances and a GC method are also reported in the literature [18,19]. A number of scientists derivatized this drug, evaluated the activity and found that most derivatives were superior to the parent drug [20e24]. The present study is also in extension to our program for the synthesis and crystallographic studies of tranexamic acid [25,26]. Topological studies are also one of the area to explain the networks formed by the hydrogen bonds and other intermolecular interactions [27,28]. With the aim to study the structures of tranexamic acid sulfonamides, we reacted it with suitable sulfonyl chlorides to get these (Scheme 1), which further were crystalized as such, after alkylation or co-crystallized along with another guest molecule.

acetate and n-hexane was used as a solvent in TLC. Reactions were monitored using Merck patented aluminum-backed TLC plates coated with silica gel 60 or alumina (0.2 mm) containing a fluorescent indicator active at 254 nm. The chromatograms were visualized under UV light (254 nm and higher wavelength). Melting points were recorded using Stuart SMP 10 melting point apparatus and are reported as uncorrected. The experimental and theoretically calculated values of 1H NMR are provided in Supplementary material. 2.1. Synthesis of 4-[(toluene-4-sulfonylamino)-methyl]cyclohexanecarboxylic acid (VI) Tranxemic acid (4 g, 25.4 mmol) was dissolved in water (50 mL). p-Toluenesulfonyl chloride (4.85 g, 25.4 mmol) was added to it under stirring at room temperature keeping the pH of a mixture about 8e9 using 1 M sodium carbonate solution until the completion of reaction. The dissolution of suspended sulfonyl chloride to clear solution indicates the progress of reaction. On completion the pH of solution was decreased to 2e3 by adding 1 M HCl. The precipitates produced were filtered, washed by distilled water and recrystallized from methanol [20] (Yield: 84%) mp 192e194  C. 2.2. Synthesis of 4-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl) cyclohexanecarboxylic acid (VII) Tranxemic acid (2 g, 12.7 mmol) was dissolved in water (50 mL). 2,5-Dichlorobenzenesulfonyl chloride (3.11 g, 12.7 mmol) was added to it under stirring at room temperature keeping the pH of a mixture about 8e9 using 1 M sodium carbonate solution until the completion of reaction. The dissolution of suspended sulfonyl chloride to clear solution indicates the progress of reaction. On

2. Experimental The sulfonamide syntheses (Scheme 1) were carried out at room temperature using distilled water as a media. Mixture of ethyl

N H XI

HO

O O S

O N H

O H N OH

O

Cl S O O

Cl Cl S O O IV Cl

Cl

II HN S O O

Br

cocrystalization

OH

N H

HO

O O S N H . O OH Cl X

H3C

Cl S O O V

Cl

O

Cl S O O

I

O

Cl

VIII

OH

CH3

HO

VII

HO

O III NH2

HN S O O

O

O

VI

O O S Br

O N

O O S CH3

O O

Scheme 1. Synthesis of sulfonamide derivatives of tranexamic acid.

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completion the pH of solution was decreased to 2e3 by adding 1 M HCl. The precipitates produced were filtered, washed by distilled water and recrystallized from methanol (Yield: 94%) mp 180  C. 2.3. Synthesis of 4-[(4-bromo-benzenesulfonylamino)-methyl]cyclohexanecarboxylic acid (VIII) Tranxemic acid (2 g, 12.7 mmol) was dissolved in water (50 mL). 4-Bromobenzenesulfonyl chloride (3.24 g, 12.7 mmol) was added to it under stirring at room temperature keeping the pH of a mixture about 8e9 using 1 M sodium carbonate solution until the completion of reaction. The dissolution of suspended sulfonyl chloride to clear solution indicates the progress of reaction. On completion the pH of solution was decreased to 2e3 by adding 1 M HCl. The precipitates produced were filtered, washed by distilled water and recrystallized from methanol (Yield: 91%) mp 199  C. 2.4. Synthesis of 4-{[ethyl-(toluene-4-sulfonyl)-amino]-methyl}cyclohexanecarboxylic acid ethyl ester (IX) 4-[(Toluene-4-sulfonylamino)-methyl]-cyclohexanecarboxylic acid (VI) (0.183 g, 0.5 mmol) and sodium hydride (0.024 g, 1 mmol) was added in 15e20 mL dimethyl formamide (DMF). The mixture was stirred for half an hour. Then ethyl iodide (80 mL, 1 mmol) was added in the reaction mixture and stirred for 3e4 h. The progress of reaction was checked continuously by TLC. After the completion of reaction the mixture was poured into ice and precipitates were allowed to settle for some time and then filtered, washed with cold water and recrystallized from methanol (Yield: 88%) mp 134e136  C. 2.5. Synthesis of 4-[(2,5-dichloro-benzenesulfonylamino)-methyl]cyclohexanecarboxylic acid-benzoic acid (1:1) (X) The equimolar amount of 4-[(2,5-dichloro-benzenesulfonylamino)-methyl]-cyclohexane- carboxylic acid and benzoic acid were dissolved in methanol to get suitable crystals of (X) (Yield: 96%) mp 121  C.

273

2.6. Synthesis of 4-[(4-acetylamino-benzenesulfonylamino)methyl]-cyclohexane carboxylic acid (XI) Tranxemic acid (2 g, 12.7 mmol) was dissolved in water (50 mL). 4-Acetylamino benzenesulfonyl chloride (2.96 g, 12.7 mmol) was added to it under stirring at room temperature keeping the pH of mixture about 8e9 using 1 M sodium carbonate solution until the completion of reaction. The dissolution of suspended sulfonyl chloride to clear solution indicates the progress of reaction. On completion the pH of solution was decreased to 2e3 by adding 1 M HCl. The precipitates produced were filtered, washed by distilled water and recrystallized from methanol (Yield: 87%) mp 208e210  C. 3. Crystal structure determination Suitable crystals of VIII-X were selected and mounted on Bruker KAPA APEX II CCD diffractometer equipped with a graphite-monochromatic Mo-Ka radiation for data collection at 296 K. The data collection for molecule XI was completed on Agilent SuperNova (Dual source) Agilent Technologies Diffractometer, equipped with a microfocus Mo/Cu X-ray tube, using CrysAlisPro software at 296 K. The structures were solved by direct-methods using SHELXS-97 [29] and refined by full-matrix least-squares methods on F2 using SHELXL-97 [29] from within the WINGX [30,31] suite of software. All non-hydrogen atoms were refined with anisotropic parameters. The water hydrogen atoms were located in difference maps and refined freely. Hydrogen atoms bonded to carbon were placed in the calculated positions (CeH ¼ 0.93e0.97 Å) and treated using a riding model with U ¼ 1.2 times the U value of the parent atom for CH, CH2 and CH3. The hydroxyl and amino hydrogen atoms were positioned with idealized geometry with NeH ¼ 0.86 Å and OeH ¼ 0.82 Å with U ¼ 1.2 times the U value of the parent atoms. Molecular diagrams were produced using ORTEP-III [32] and MERCURY [33]. Geometric calculations were performed with PLATON [34]. The parameters for data collection and structure refinement of VIII-XI are listed in Table 1.

Table 1 Parameters for data collection and structure refinement of VIII-XI.

Empirical formula Formula weight (g/mol) Crystal size (mm) Crystal system Space group a(Å) b(Å) c(Å) b( ) V(Å3) Z Calculated density (g/cm3) l (Å) m(MoKa) (mm1) F(000) qmax ( ) Reflections measured Independent reflections Observed reflection (I > 2s(I)) Rint R, wR (I > 2s(I)) Goodness-of-fit (D/s)max Max./min. Dr (e/Å3)

VIII

IX

X

XI

C14H18BrNO4S 376.26 0.29  0.21  0.17 Monoclinic P21/n 12.2026(10) 5.8947(4) 22.4872(19) 100.917(3) 1588.3(2) 4 1.574 MoKa, 0.71073 2.733 768 28.27 15,139 3912 2218 0.0416 0.050, 0.1809 1.004 0.000 0.5641 and 0.491

C19H29NO4S 367.50 0.35  0.16  0.07 Monoclinic P21/n 6.3084(2) 8.3629(4) 37.7573(15) 93.420(2) 1988.40(14) 4 1.228 MoKa, 0.71073 0.185 792 28.33 4887 4887 3286 0.026 0.064, 0.184 1.04 0.001 0.296 and 0.269

C21H23Cl2NO6S 488.36 0.21  0.19  0.07 Monoclinic P21/c 19.6869(7) 11.4876(4) 10.1996(4) 97.976(2) 2284.38(3) 4 1.420 MoKa, 0.71073 0.413 1016 28.3 21,002 5622 3714 0.036 0.047, 0.135 1.00 0.001 0.41 and 0.37

C16H24N2O6S 372.44 0.45  0.39  0.08 Monoclinic P21/a 10.5144(3) 9.8046(2) 18.3571(4) 106.21(3) 1846.88(3) 4 1.339 CuKa, 1.54184 1.861 792 28.3 23,514 3862 3401 0.077 0.046, 0.1298 1.05 0.002 0.26 and 0.57

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4. Computational studies Lattice energies were calculated by means of the PIXEL method implemented in the CLP package [35]. Procedure requires the normalization of the distances of bonds involving H atom to typical values obtained from neutron diffraction experiments, i.e. CeH to 1.08 Å, OeH and NeH to 1.00 Å. Electron densities required for calculations were calculated by means of ab initio methods implemented in Gaussian09 [36] package at MP2/6-31G(d,p) level of theory. The output yields the total lattice energy, partitioned in electrostatic, polarization, dispersion and repulsion terms. Structures with normalized XeH distances were used for subsequent topological analysis. 5. Multilevel topological description of molecular packing The topological analysis of the crystal structure comprises several steps. At first, we have to determine all intermolecular interactions from the crystallographic data using the method of molecular Voronoi polyhedra [37]. Molecular Voronoi polyhedra are composed of the Voronoi polyhedra of all atoms [38] of the molecule and their external faces correspond to intermolecular interactions (Fig. 1). If the faces are direct, i.e. the line connecting the atoms in contact crosses the Voronoi polyhedron face, and the solid angle corresponding to that face is larger than 1.5% of 4p steradian, the contact is considered as an interaction. Among intermolecular interactions, we identify the hydrogen bonds in a fragment A-H … B in accordance with the following geometrical criteria: d(H … B)  2.5 Å; d(A … B) 3.5 Å;
performed by means of the program package ToposPro [40]. The resulting underlying net describes the method of connection of the molecules in the whole crystal. Having obtained the underlying net, we determine its topological type by comparing sets of topological indices that unambiguously determine the net. In this work, we use three-letter symbols of the Reticular Chemistry Structure Resource (RCSR) notation [41] or Fischer and Koch's symbols for 1- or 2-periodic sphere packings [42]. Those nets that are absent in the RCSR are designated with the TOPOS NDn nomenclature [43], where N is a sequence of coordination numbers of all non-equivalent nodes of the net, D is periodicity of the net (D ¼ M, C, L, T for 0-,1-,2-,3-periodic nets), and n is the ordinal number of the net in the set of all non-isomorphic nets with the given ND sequence. In order to conduct the multilevel topological description [28] of the crystal structure we need to select a criterion, which will serve as a weight factor. The value of molecular solid angle can be used as such a factor. The molecular solid angle of the contact of a given molecule with an ith neighbor is calculated using the next formula:

U Umol ðiÞ ¼ P i  100; i Ui where Ui is the sum of solid angles of the Voronoi polyhedra faces corresponding to all contacts between the two molecules; the corresponding Voronoi polyhedra faces form a surface that separates the interacting molecules (Fig. 1). Using the subroutine Copy Representation implemented in ToposPro, different subnets can be obtained that contain the edges of a weight no less than a specified value. An example of such a structure representation is shown in Fig. 2 and Table 2. Each subnet corresponds to a particular molecular packing representation. Thus, the total scheme of the topological analysis includes the following steps: (i) Determining all intra- and intermolecular interactions; ignoring all contacts with solid angles of less than 1.5%. (ii) Building underlying nets, by simplification procedure, taking into account all intermolecular contacts. (iii) Generating all representations of the molecular packings that correspond to different levels of the molecular solid angle value. To describe the local mutual arrangement of molecules in the structures with hydrogen bonds we used the notation that was proposed for description of hydrogen-bonded molecules [28]. Each molecule (L) is designated by letters M, B, T, K, P, G, H, O, N, D depending on the number n ¼ 1e10 of its atoms (both donors and acceptors) involved in the formation of intermolecular bonds (we call them active centers). The total number of molecules connected to a given one is listed as the upper index in the form mbtkpghond … where each integer m, b, t, k, … is equal to the number of molecules connected by one, two, three, four, … bonds. The molecular connection type symbol (MCTS) is written as Lmbktpghond. For example, MCTS notation K21 for molecule VIII (Fig. 3) means that the molecule has four active centers (L ¼ K): two H-bond donors (atoms H1 and H2) and two H-bond acceptors (atoms O1 and O2), and it is bonded to one neighbor molecules by two H-bonds (b ¼ 1) and to two other molecules by one H-bond (m ¼ 2).

6. Results and discussion Fig. 1. Top: molecular Voronoi polyhedra for molecule in the structure IX as a sum of faces of atomic polyhedra that correspond to intermolecular contact. Bottom: faces of molecular Voronoi polyhedra that correspond to intermolecular contact with neighbor molecules. Molecular solid angles for contact with molecule 1 and 2 are 12.2% and 5.7%, respectively.

6.1. Analysis of intermolecular contacts and interactions The ORTEP diagrams of molecules under consideration are

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275

Fig. 2. Subnets of the initial net corresponding to the molecular packing in structure 8 represent: (a) 2C1 chain; (b) chain with 36(1,2) topology; (c) hxl net, which correspond to a close packed layer; (d) vnf net; (e) fcu net, which correspond to face-centered close packing; (f) 14T3 net, which correspond to the molecular packing in the structure. Molecules in different layers are colored in yellow and green. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Table 2 Representation of molecular packings in structure VIII at different levels of contacts. Structure VIII No. of molecule 1, 2 3, 4 5, 6 7 8, 9 10, 11 12 13, 14

Ui, % 13.1 12.3 11.8 6.2 4.2 3.3 2.1 0.4

Topology 2C1 36(1,2) hxl ose vnf elc fcu 14T3

shown on Fig. 4. Selected bond lengths and angles are given in Table 3. All four molecules comprise of chair shaped cyclohexane and an aromatic ring which are connected through the sulfonamide functionality. The bond lengths and bond angles observed in (VIIIXI) have normal values, and are comparable to related structures [25,26]. The plane produced from the atoms of cyclohexane ring in

molecule VIII shows relative mean square (r.m.s.) deviation of 0.2307 Å with maximum displacement from the atoms C(13) and C(11) of about 0.2379 (2) Ǻ and 0.2414 (2) Ǻ. Similarly, r.m.s. deviation values for cyclohexane rings in molecules (IX, X and XI) are 0.251(2) Ǻ, 0.2297 (2) Ǻ and 0.2336 (2) Ǻ with maximum displacement from the atoms C(13) ¼ 0.2433 (2) Ǻ and C(14) ¼ 0.2426 (2) Ǻ for 9, C(3) ¼ 0.2378 (2) Ǻ and C(4) ¼ 0.2358 (2) Ǻ for X and C(10) ¼ 0.2359 (2) Ǻ and C(13) ¼ 0.2443 (2) Ǻ for XI. The puckering parameters [44] for the planes defined by atoms of cyclohexane are Q ¼ 0.5650 (2) Å, q ¼ 177.96(2)º and 4 ¼ 11.97(3)º for VIII, Q ¼ 0.5780 (2) Å, q ¼ 1.72(2)º and 4 ¼ 151.14 (3)º for IX, Q ¼ 0.563 (3) Ǻ, q ¼ 1.01(3)º and 4 ¼ 148(11)º for X and Q ¼ 0.5721 (2) Å, q ¼ 178.13(2)º and 4 ¼ 252.88(4)º for XI, respectively. The carboxylic groups and phenyl rings are planar, these are oriented with dihedral angles of 30.03 (4)º and 55.69(2)º for VIII, 65.41(2)º and 40.50(2)º for IX, 42.50(3)º and 77.39(8) for X and 52.06 (11)º and 64.74(6)º for XI with cyclohexane ring in each molecule, respectively. The S atom adopted the distorted tetrahedral geometry where the O(1)-S(1)-O(2) angles amount 119.69 for

Fig. 3. Molecule with MCTS K21. Independent active centers are designated H1, H2 and O1, O2.

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Fig. 4. ORTEP diagrams of molecules a-VIII, b-IX, c-X, d-Ⅺ.

Table 3 Selected bond lengths (Å) and bond angles ( ) for VIII-XI.

Bond Br(1)-C(4) S(1)-O(1) S(1)-O(2) S(1)-N(1) N(1)-C(X) C(X)-O(4) C(X)-O(3) Angle O(1)-S(1)-O(2) N(1)-S(1)-C(X) N(1)-S(1)-O(1) N(1)-S(1)-O(2) O(4)-C(X)-O(3) C(Y)-C(X)-O(4) C(Y)-C(X)-O(3)

VIII

IX

X

XI

1.893(4) 1.430(3) 1.426(3) 1.622(3) 1.476(4) X ¼ 7 1.305(4) X ¼ 14 1.211(4) X ¼ 14

e 1.423(2) 1.431(2) 1.623(2) 1.473(3) X ¼ 10 1.309(3) X ¼ 17 1.187(3) X ¼ 17

e 1.424(2) 1.429(2) 1.595(2) 1.466(3) X ¼ 13 1.273(3) X ¼ 20 1.243(3) X ¼ 20

e 1.432(1) 1.433(1) 1.592(2) 1.465(2) X ¼ 9 1.319 (3) X ¼ 16 1.208(3) X ¼ 16

119.63(2) 106.72(2) X ¼ 1 105.72(2) 107.76(2) 122.6(3) X ¼ 14 113.9(3) X ¼ 14, Y ¼ 11 123.6(3) X ¼ 14, Y ¼ 11

119.67(16) 108.61(11) X ¼ 1 107.49(13) 107.36(12) 121.7(3) X ¼ 17 112.1(2) X ¼ 17, Y ¼ 14 126.1(3) X ¼ 17, Y ¼ 14

119.37(11) 108.83(11) X ¼ 7 107.25(1) 108.21(1) 121.3(3) X ¼ 20 116.0(2) X ¼ 20, Y ¼ 4 122.7(2) X ¼ 20, Y ¼ 4

119.17(8) 109.07(9) X ¼ 1 107.97(8) 107.24(9) 121.9(2) X ¼ 16 112.96(2) X ¼ 16, Y ¼ 13 125.1(2) X ¼ 16, Y ¼ 13

VIII, 119.69 for IX, 119.36 for X and 119.17 for XI. The shortest angles observed around S atoms are N(1)-S(1)-O(1) ¼ 105.74 for VIII, N(1)-S(1)-O(1) ¼ 103.63 for IX, C(7)-S(1)-O(2) ¼ 104.86 for X and C(1)-S(1)-O(2) ¼ 105.52 for XI. 6.1.1. Compound VIII 4-[(4-Bromo-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic acid (VIII) crystallizes in the space group P21/n, the carboxylic group in the molecules are involved in typical inversion dimerization and generate centro-symmetric R2 2 ð8Þ ring motif through OeH/O hydrogen bonds. Atom N(1) in the reference molecule at (x, y, z) acts as a hydrogen bond donor via H(1), to atom O(1) in the molecule at (x  1/2, y  1/2, z þ 1/2), so connects the dimers to form a zig-zag fashion to generate C(4) chain along [010] direction. The combination of OeH/O and NeH/O hydrogen bonds produce edge-fused R2 2 ð8ÞR6 6 ð48Þ motifs (Table 4) (Fig. 5).

6.1.2. Compound IX 4-{[Ethyl-(toluene-4-sulfonyl)-amino]-methyl}-cyclohexanecarboxylic acid ethyl ester (IX), the second molecule, which differs from VIII in substitution at aromatic ring, a methyl group instead of bromine atom at para-position. It was synthesized by ethyl substitution at nitrogen and oxygen atoms of 4-[(toluene-4sulfonylamino)-methyl]-cyclohexanecarboxylic acid [20] and crystallizes in the space group P21/n. Molecules are linked through a non-classical weak CeH/O hydrogen bonds (Table 4). The CeH/O hydrogen bonds produce centro-symmetric R2 2 ð24Þ ring centered at (1, 0, 0) (Fig. 6). 6.1.3. Compound X The molecule of X was cocrystalized with benzoic acid which results in molecular complex 4-[(2,5-Dichloro-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic acid-benzoic acid (1:1) in P21/c space group. The two host-guest moieties join each other

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Table 4 Hydrogen bond lengths (Å) and bond angles ( ) for VIII-XI. DH$$$A VIII O(4)-H(4)/O(3)i N(1)-H(1)/O(1)ii IX C(18)-H(18B)/O(2)i X N(1)-H(1A)/O(2)i O(4)-H(4A)/O(6)ii O(5)-H(5)/O(3)iii XI N(1)-H(1N)/O(2)i N(1)-H(1N)/O(1)ii O(6W)-H(1W)/O(5)ii N(2)-H(2N)/O(6W) O(6W)-H(2W)/O(3)i O(4)-H(4O)/O(6W)iii C(6)-H(6)/O(2)iv C(5)-H(5)/O(5)

d(DH)

d(H$$$A)

d(D$$$A)

<(DHA)

0.82 0.86

1.834 2.514

2.652(3) 2.950(3)

176 112

0.97

2.56

3.459(2)

155(3)

0.86 0.82 0.82

2.16 1.79 1.813

2.949(3) 2.604(2) 2.623(3)

153 168 169

0.86 0.86 0.82(3) 0.82(3) 0.93 0.86(4) 0.92(3) 0.93

2.19 2.52 1.91(3) 2.35(3) 2.26 1.98(4) 1.79(3) 2.42

2.975(2) 3.044(2 3.044(2 3.159(3) 2.856(3) 2.819(3) 2.684(2) 3.314(2)

151 120 163(3) 173(3) 121 167(3) 164(3) 161

Symmetry codes: (i) x þ 1, y þ 1, z þ 1; (ii) x  1/2, y  1/2, zþ1/2 for 8; (i) 2  x, y, z for 9; (i) x, y þ 1/2, z  1/2; (ii) x, y  1/2, z  1/2; (iii) x, y þ 1/ 2, z  1/2 for 10; (i) 1  x, 1  y, 1  z; (ii) 1/2 þ x, 1/2  y, z; (iii) 1/2 þ x, 1/2  y, z þ 1; (iv) 1/2  x, y  1/2, 1  z for 11.

with their carboxylic groups through OeH/O hydrogen bonding and generates centro-symmetric R2 2 ð8Þ motif (Fig. 6). This is in difference to VIII, where the molecules form dimers (Fig. 5). The N(1) atom at (x, y, z) behaves as hydrogen-bond donor via H(1A), to O(2)i of SO2 to join the molecules in a one-dimensional C(4) chain along [001] direction (Table 4) (Fig. 7).

6.1.4. Compound Ⅺ 4-[(Toluene-4-sulfonylamino)-methyl]-cyclohexanecarboxylic acid (XI) was crystallized along with a water molecule in P21/a space group. The water molecule helps in formation of supramolecular structure. The sulfonamide functionality eSO2eNHe forms dimers through N(1)-H(1N)/O(2)i R2 2 ð8Þ motif. The N(1)eH(1N)/ O(1)ii hydrogen bond connects the molecules along a axis. The combination of OeH/O and NeH/O hydrogen bonds produce edge-fused R3 3 ð20ÞR5 4 ð28Þ motif (Table 4) (Fig. 8). The water molecule connects four molecules through OeH/O type intermolecular hydrogen bonding to form three-dimensional networks

Fig. 6. Crystal structure of IX, showing the formation of R2 2(24) ring (Symmetry code as in Table 4).

(Table 3) (Fig. 9). The water molecules form tetrahedral geometry via OeH/O and NeH/O hydrogen bonds. In addition to these, there are two non-classical, CeH/O type hydrogen bonding interactions, which stabilize the structure. As is seen from Table 5 structure IX is a dispersion-dominated crystalline; there are only weak CH … O hydrogen bonds and other non-specific interactions. In contrast, structures VIII, X and XI have a higher coulomb-polarization part in total lattice energy due to presence of strong hydrogen bonds, though it is paid by much higher repulsion terms. As a result, we observe the following order of the lattice energies. 6.2. Molecular packings in structures VIII-XI Structures VIII and IX are monomolecular, i.e. consist of one kind of molecule, while structures X and XI contain additional molecules e benzoic acid and water, respectively. Molecular coordination numbers are presented in Table 6. For two monomolecular structures MCN ¼ 14 is in agreement with the results of the MCN survey in organic crystals [37]. Small size of water molecule leads to the absence of waterewater contacts. Representations of molecular packings in structures IX-XI are presented in Table 7. The paths of assembling of molecules in 3D crystals are similar to the ones observed in 1,2-benzothiazines [28] with typical patterns such as 2C1 chains and 1M2-1 dimers correspond to largest contacts. The benzoic acid and water molecules slightly influence the packing of the sulfonamide molecules and result in 11-coordinated subnets of close-packed

Fig. 5. Crystal structure of VIII, showing the formation of R2 2 ð8Þ and R6 6 ð48Þ rings (Symmetry codes as in Table 4).

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Fig. 7. Crystal structure of X, showing the formation of a chain along [001] generated by NeH$$$O hydrogen bonds.

Fig. 8. Crystal structure of XI, showing the formation of edge-fused R3 3 ð20ÞR5 4 ð28Þ motif.

Table 5 Total lattice energies with partition in coulombic, polarization, dispersion and repulsion terms. Structure

Ec, kJ/mol

Ep, kJ/mol

Ed, kJ/mol

Er, kJ/mol

Elatt, kJ/mol

VIII IX X XI

105.3 48 120.8 129.4

56.9 23.1 60.2 58

165.3 172.1 127.9 106.4

159.2 88 162.2 147.3

168.3 155.2 146.7 146.6

Table 6 Molecular coordination numbers of molecules in structures VIII-XI. TXA e tranexamic acid derivative; BzA e benzoic acid. Structure

Molecule

MCN

VIII IX X

TXA TXA TXA BzA TXA water

14 14 11 TXA þ 7 BzA 2 BzA þ 7 TAD 11 TXA þ 7 water 7 TXA

XI

Fig. 9. Underlying net that represent three-dimensional hydrogen-bonded network in XI.

fcu (face-centered cubic) and hcp (hexagonal close packing) nets. In structure X one cannot observe close-packed layers (hxl) due to a stronger distortion from a large sized molecule i.e. benzoic acid.

6.3. Hydrogen-bonded networks in structures VIII, X and XI A hydrogen-bonded network with ubiquitous hcb (honeycomb) topology [45] and the MCTS K21 is observed in structure VIII. Structure X contains hydrogen-bonded 2C1 chains with the MCTS K21 and B01 for TXA and benzoic acid molecule, respectively, as shown in Fig. 10(a). Structure XI possesses a 3D system of hydrogen bonds with a tcj-4,5-P21/c topology (Fig. 9), which has never been

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279

Table 7 Representation of molecular packings in structures XI-XI at different levels of intermolecular contacts. In structures X and XI only TXA molecules are taken into account. Structure IX

Structure X

Structure XI

No. of molecule

Ui, %

Topology

No. of molecule

Ui, %

Topology

No. of molecule

Ui , %

Topology

1, 2 3 4 5 6 7,8 9, 10 11, 12 13, 14

12.1 11.5 11.3 10.7 10.2 7.4 5.7 1.8 0.9

2C1 44(0,2) sql cem hxl ecu bct fcu bcu-x

1,2 3 4 5,6 7,8 9 10,11

11.1 8.8 5 4.2 3.2 3 2.1

2C1 hcb dia vme vcs bct-9-Cmce fcu-11-C2/c

1 2,3 4 5,6 7,8 9,10 11

14.7 13.4 11 10.9 2.8 2 1.6

1M2-1 hcb sql hxl hex bct hcp-11-P21/c

in the structures under consideration are similar to the ones obtained previously from studies of 1,2-benzothiazines derivatives. The hydrogen-bonded patterns observed in structures VIII (hcb) and X (2C1) are frequent for 2-periodic and 1-periodic H-bonded networks, respectively. On the contrary, the three-dimensional net with a tcj-4,5-P21/c topology found in structure XI has never been observed in the hydrogen-bonded crystals, though the other description of the structure with a rtl topology of the net of the TXA dimers and water molecules is more typical for MOF's [43]. Acknowledgements M.A and M.D. acknowledge to HEC Pakistan for providing grant under the project no. 2549. P.N.Z. thanks Russian government (grant No. 14.B25.31.0005) and Russian Foundation for Basic Research (grant No. 13-07-00001) for support as well as Prof. Vladislav A. Blatov, Prof. Davide and M. Proserpio for fruitful discussion of the work. The authors acknowledge GC University, Lahore, Pakistan for data collection. This work was also funded by the Deanship of Scientific Research (DSR), King Abdulaziz University, under Research Group Track of Grant No. (3-102/428). The authors, therefore, acknowledge technical and financial support of KAU. Fig. 10. (a) Fragment of structure X with active centers of each molecule; (b) Fragment of structure XI. A molecule XI is shown with all its six active centers that participate in hydrogen bonding.

observed in the hydrogen-bonded organic structures. Each water molecule is hydrogen-bonded to four molecules of Ⅺ, therefore its MCTS is T4 as shown in Fig. 10(b). Each molecule of compound XI is bonded to four water molecules by means of one hydrogen bond and to another molecule XI through two hydrogen bonds that leads to MCTS G41. Considering hydrogen-bonded dimers in structures VIII and XI as distinct building units of the crystal instead of separate molecules, we can obtain an alternative description of the structures as nets of dimers [40]. This results in a 4-с sql net in VIII and a binodal 3,6-c rtl net in XI. 7. Conclusion Tranexamic acid helps in blood clotting and is widely used for treatment prevention of bleeding problems. Here we derivatized it into sulfonamides and crystallized itself, after alkylation and in the presence of another molecule. Tranexamic acid was reacted with sulfonyl chlorides to produce V, VI, VIII and IX. The molecule (V) was alkylated and (VI) was co-crystallized along with benzoic acid. The present study describes the simple synthesis as well as the conformations, bond angles, bond lengths of synthesized molecules and topological studies of the molecular packing in their crystals. Results of a multilevel topological study of the molecular packings

Appendix A. Supplementary material Supplementary material related to this article can be found at http://dx.doi.org/10.1016/j.molstruc.2015.09.022. References [1] Y. Sasaki, Rhinology 39 (2001) 220e225. [2] S.T. Hiippala, L.J. Strid, M.I. Wennerstrand, J.V.V. Arvela, H.M. Niemela, S.K. Mantyla, R.P. Kuisma, J.E. Ylinen, Anesth. Analg. 84 (1997) 839e844. [3] J. Wong, H.E. Beheiry, Y.R. Rampersaud, S. Lewis, H. Ahn, Y.D. Silva, A. Abrishami, N. Baig, R.J. McBroom, F. Chusng, Anesth. Analg. 107 (5) (2008) 1479e1486. [4] G.M. Hadad, A. El-Gindy, W.M.M. Mahmoud, Chromatographia 66 (2007) 311e317. [5] J. Makwana, S. Paranjape, J. Goswami, Indian J. Anesth. 54 (2010) 489e495. [6] V. Casati, C. Gerli, A. Franco, G. Torri, A.D. Angelo, S. Benussi, O. Alfieri, Ann. Thorac. Surg. 72 (2001) 470e475. [7] S. Natesan, D. Thanasekaran, V. Krishnaswami, C. Ponnusamy, Pharm. Anal. Acta. 2 (1) (2011) 1e6. [8] J. Wong, A. Abrishami, H.E. Beheiry, N.N. Mahomed, J.R. Davey, R. Gandhi, K.A. Syed, S.M.O. Hasan, Y.D. Silva, F. Chung, J. Bone Jt. Surg. 92A (2010) 2503e2513. [9] S. Natesan, D. Thanasekaran, V. Krishnaswami, C. Ponnusamy, Pharm. Anal. Acta 2 (2011), 115e115. [10] G.M. Hadad, A. El-Gindy, W.M.M. Mahmoud, Chromatographia 66 (2007) 311e317. [11] M.Y. Khuhawar, F.M.A. Rind, Chromatographia 53 (2001) 709e711. [12] S. Nojiri, S. Uehara, T. Hagiwara, M. Nishijima, Tokyo-toritsu Eisei Kenkyusho Kenkyu Nenpo 46 (1995) 58e61. [13] J.F. Huertas-Perez, M. Heger, H. Dekker, H. Krabbe, J. Lankelma, F. Ariese, J. Chromatogr. A 1157 (2007) 142e150. [14] P.M. Elworthy, S.A. Tsementzis, D. Westhead, E.R. Hitchcock, J. Chromatogr. B 343 (1985) 109e117.

280

M. Ashfaq et al. / Journal of Molecular Structure 1103 (2016) 271e280

[15] Y. Shih, K. Wu, J. Sue, A.S. Kumar, J. Zen, J. Pharm. Biomed. Anal. 48 (2008) 1446e1450. [16] Q. Chang, O.Q.P. Yin, M.S.S. Chow, J. Chromatogr. B 805 (2004) 275e280. [17] C. Abou-Diwan, R.M. Sniecinski, F. Szlam, J.C. Ritchie, J.M. Rhea, K.A. Tanaka, R.J. Molinaro, J. Chromatogr. B 879 (2011) 553e556. [18] K.U. Abbasi, M.Y. Khuhawar, M.I. Bhanger, Chromatographia 70 (2009) 1749e1754. [19] N. Du, Y. Wang, M.-M. Cai, B. Di, Chin. Pharm. J. 45 (2010) 144e147. [20] C.M. Svahn, F. Merenyi, L. Karlson, L. Widlund, M. Gralls, J. Med. Chem. 29 (1986) 448e453. [21] M.F. Khan, M.F. Khan, M. Ashfaq, G.M. Khan, Pak. J. Pharm. Sci. 15 (2002) 55e62. [22] K. Vavrova, A. Hrabalek, P. Dolezal, T. Holas, J. Klimentova, J. Control. Release 104 (2005) 41e49. [23] S. Shahzadi, S. Ali, M. Parvez, A. Badshah, E. Ahmed, A. Malik, Russ. J. Inorg. Chem. 52 (2007) 386e393. [24] F.A. Shah, S. Ali, S. Shahzadi, J. Iran. Chem. Soc. 7 (2010) 59e68. [25] M. Ashfaq, S. Iram, M. Akkurt, I.U. Khan, G. Mustafa, S. Sharif, Acta Crystallogr. E67 (2011) o1563. [26] M. Ashfaq, S. Iram, M. Akkurt, I.U. Khan, G. Mustafa, M. Danish, Acta Crystallogr. E67 (2011) o2248e2249. [27] O. Delgado-Friedrichs, M.D. Foster, M. O'Keeffe, D.M. Proserpio, M.M.J. Treacy, O.M. Yaghi, J. Solid State Chem. 178 (2005) 2533e2554. [28] F. Aman, A.M. Asiri, W.A. Siddiqui, M.N. Arshad, A. Ashraf, N.S. Zakharov, V.A. Blatov, CrystEngComm 16 (2014) 1963e1970. [29] G.M. Sheldrick, Acta Crystallogr. A64 (2008) 112e122. [30] L.J. Farrugia, WINGX, A Windows Program for Crystal Structure Analysis, University of Glasgow, Great Britain, 1998. [31] L.J. Farrugia, J. Appl. Crystallogr. 32 (1999) 837e838. [32] L.J. Farrugia, J. Appl. Crystallogr. 30 (1997) 565. [33] Mercury, version 3.0; CCDC, available online via ccdc.cam.ac.uk/products/ mercury.

[34] A.L. Spek, PLATON e A Multipurpose Crystallographic Tool, Utrecht University, Utrecht, The Netherlands, 2005. [35] A. Gavezzotti, J. Phys. Chem. B 107 (2003) 2344e2353. [36] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G.A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H.P. Hratchian, A.F. Izmaylov, J. Bloino, G. Zheng, J.L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J.A. Montgomery Jr., J.E. Peralta, F. Ogliaro, M. Bearpark, J.J. Heyd, E. Brothers, K.N. Kudin, V.N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.C. Burant, S.S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J.M. Millam, M. Klene, J.E. Knox, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, R.L. Martin, K. Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador, € Farkas, J.B. Foresman, J.V. Ortiz, J.J. Dannenberg, S. Dapprich, A.D. Daniels, O. J. Cioslowski, D.J. Fox, Gaussian 09, Revision C.01, Gaussian, Inc., Wallingford CT, 2010, p. 31. D. Roy, K. Todd, M. John, Semichem, Inc., Shawnee Mission, KS, 2009. Gauss View, Version 5. [37] E.V. Peresypkina, V.A. Blatov, Acta Crystallogr. B56 (2000) 1035e1045. [38] V.A. Blatov, Crystallogr. Rev. 10 (2004) 249e318. [39] I.A. Baburin, V.A. Blatov, Acta Crystallogr. B63 (2007) 791e802. [40] V.A. Blatov, A.P. Shevchenko, D.M. Proserpio, Cryst. Growth Des. 14 (2014) 3576e3586. [41] M. O'Keeffe, M.A. Peskov, S.J. Ramsden, O.M. Yaghi, Acc. Chem. Res. 41 (2008) 1782e1789. [42] E. Koch, W.Z. Fischer, Kristallogr 148 (1978) 107e152. [43] E.V. Alexandrov, V.A. Blatov, A.V. Kochetkov, D.M. Proserpio, CrystEngComm 13 (2011) 3947e3958. [44] D. Cremer, J.A. Pople, J. Am. Chem. Soc. 97 (1975) 1354e1358. [45] P.N. Zolotarev, M.N. Arshad, A.M. Asiri, Z.M. Al-amshany, V.A. Blatov, Cryst. Growth Des 14 (2014) 1938e1949.