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

Article abstract of DOI:10.1016/j.molstruc.2015.09.022

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 va

Full text of DOI:10.1016/j.molstruc.2015.09.022

Accepted Manuscript
Synthesis and description of intermolecular interactions in new sulfonamide
derivatives of tranexamic acid
Muhammad Ashfaq, Muhammad Nadeem Arshad, Muhammad Danish, Abdullah M.
Asiri, Sadia Khatoon, Ghulam Mustafa, Pavel N. Zolotarev, Rabia Ayub Butt, Onur
Şahin
PII:
S0022-2860(15)30285-4
10.1016/j.molstruc.2015.09.022
MOLSTR 21828
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 23 March 2015
Revised Date: 1 September 2015
Accepted Date: 29 September 2015
Please cite this article as: M. Ashfaq, M.N. Arshad, M. Danish, A.M. Asiri, S. Khatoon, G. Mustafa,
P.N. Zolotarev, R.A. Butt, O. Şahin, Synthesis and description of intermolecular interactions in new
sulfonamide derivatives of tranexamic acid, Journal of Molecular Structure (2015), doi: 10.1016/
j.molstruc.2015.09.022.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Synthesis and Description of Intermolecular Interactions in New
Sulfonamide Derivatives of Tranexamic Acid
a
b,c
a
Muhammad Ashfaq , Muhammad Nadeem Arshad* , Muhammad Danish ,
b,c
a
a
d
Abdullah M. Asiri , Sadia Khatoon , Ghulam Mustafa , Pavel N. Zolotarev ,
a
e
Rabia Ayub Butt , Onur Şahin
a
Department of Chemistry, University of Gujrat, Gujrat 50700, Pakistan
b
Chemistry Department, Faculty of Science, King Abdulaziz University P. O. Box 80203, Jeddah
2
1589, Saudi Arabia.
c
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
Scientific and Technological Research Application and Research Center, Sinop University,
5
*
7010 Sinop, Turkey.
Corresponding email: mnachemist@hotmail.com
Abstract
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 co-molecule. All molecules were crystallized in monoclinic
crystal system with space group P2 /n, P2 /c and P2 /a. X-ray studies reveal that the molecules
1
1
1
stabilized themselves by different kinds of hydrogen bonding interactions. The molecules are
1

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getting connected through O-HꢀꢀꢀO hydrogen bonds to form inversion dimers which are further
connected through N-HꢀꢀꢀO interactions. The molecules in which N and O atoms were alkylated
2
showed non-classical interaction and generated centro-symmetric R (24) ring motif. The co-
2
crystallized host and guest molecules are connected to each other via O-HꢀꢀꢀO 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.
Keywords: Tranexamic acid, sulfonamide, crystallization, topological aspects of
structure
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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
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 hours peak plasma concentration occurs. The drug has a
bioavailability around 30–50% 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
hours. [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].
Tranexamic acid does not have any π-electrons so it cannot act as fluorophore or chromophore
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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], phenylisothiocynate [10], 2-hydroxynaphthaldehyde in aqueous ethanol [11] and sodium
picrylsulfonate [12] followed by their determination through HPLC-UV. 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 [20-24]. 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.
Experimental
The sulfonamide syntheses (Scheme 1) were carried out at room temperature using distilled
water as a media. Mixture of ethyl acetate and n-hexane was used as a solvent in TLC. Reactions
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were monitored by using Merck patented aluminium-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
1
and theoretically calculated values of H-NMR are provided in supplementary material.
Synthesis of 4-[(Toluene-4-sulfonylamino)-methyl]-cyclohexanecarboxylic acid (VI)
Tranxemic acid (4g, 25.4 mmol) was dissolved in water (50 mL). p-Toluenesulphonyl
chloride (4.85g, 25.4 mmol) was added to it under stirring at room temperature keeping the pH
of a mixture about 8-9 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 2-3 by adding 1 M HCl. The precipitates
produced were filtered, washed by distilled water and recrystallized from methanol [20]. (Yield:
8
4%) mp 192-194°C
Synthesis of 4-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)cyclohexanecarboxylic
acid (VII)
Tranxemic acid (2g, 12.7 mmol) was dissolved in water (50 mL). 2,5-
Dichlorobenzenesulfonyl chloride (3.11g, 12.7 mmol) was added to it under stirring at room
temperature keeping the pH of a mixture about 8-9 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 2-3 by
adding 1 M HCl. The precipitates produced were filtered, washed by distilled water and
recrystallized from methanol. (Yield: 94%) mp 180°C
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Synthesis of 4-[(4-Bromo-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic acid
(VIII)
Tranxemic acid (2g, 12.7 mmol) was dissolved in water (50 mL). 4-Bromobenzenesulfonyl
chloride (3.24g, 12.7 mmol) was added to it under stirring at room temperature keeping the pH
of a mixture about 8-9 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 2-3 by adding 1 M HCl. The precipitates
produced were filtered, washed by distilled water and recrystallized from methanol. (Yield: 91%)
mp 199°C
Synthesis of 4-{[Ethyl-(toluene-4-sulfonyl)-amino]-methyl}-cyclohexanecarboxylic acid
ethyl ester (IX)
4
-[(Toluene-4-sulfonylamino)-methyl]-cyclohexanecarboxylic acid (VI) (0.183g, 0.5 mmol)
and sodium hydride (0.024g, 1 mmol) was added in 15-20mL dimethyl formamide (DMF). The
mixture was stirred for half an hour. Then ethyl iodide (80 ꢁL, 1 mmol) was added in the
reaction mixture and stirred for 3 to 4 hours. 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 134-136°C
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).
6

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(
Yield: 96%) mp 121°C.
Synthesis of 4-[(4-Acetylamino-benzenesulfonylamino)-methyl]-cyclohexane carboxylic
acid (XI)
Tranxemic acid (2g, 12.7 mmol) was dissolved in water (50 mL). 4-Acetylamino
benzenesulfonyl chloride (2.96g, 12.7 mmol) was added to it under stirring at room temperature
keeping the pH of mixture about 8-9 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 2-3 by adding 1 M HCl.
The precipitates produced were filtered, washed by distilled water and recrystallized from
methanol. (Yield: 87%) mp 208-210°C
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-K radiation for data collection at
α
2
96 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
2
[
29] and refined by full-matrix least-squares methods on F 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 (C–H = 0.93～0.97Å)
and treated using a riding model with U = 1.2 times the U value of the parent atom for CH, CH2
and CH . The hydroxyl and amino hydrogen atoms were positioned with idealized geometry
3
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with N-H = 0.86 Å and O-H = 0.82 Å with U = 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.
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. C-H to 1.08Å, O-H and N-H
to 1.00Å. 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 X–H distances were used for subsequent topological
analysis.
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
4
π steradian, the contact is considered as an interaction. Among intermolecular interactions, we
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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; ∠A-H…B ≥ 120⁰ (A=N, O; B= N, O, F, S, Cl) [39].
In the next step of topological analysis, we obtain with an appropriate simplification
procedure the underlying net, i.e. representation of the molecular network in terms of a graph-
theory approach. The simplification procedure consists of representing the molecule by its center
of mass, keeping the connectivity of the molecule with its neighbors; all intermolecular contacts
between a given pair of molecules transform to the same edge between the molecular centers of
mass in the simplified net. These simplification procedures as well as all topological analyses in
this study were 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=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 neighbour is calculated using the next formula:
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ꢇꢈ
ꢀꢁ
ꢂꢃꢄꢅꢆ = ∑ꢈ × 100,
ꢇꢈ
where ꢂ is the sum of solid angles of the Voronoi polyhedra faces corresponding to all contacts
i
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=1-10 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
1
0

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mbktpghond
molecular connection type symbol (MCTS) is written as L
. For example, MCTS
2
1
notation K for molecule VIII (Fig. 3) means that the molecule has four active centers (L=K):
two H-bond donors (atoms H1 and H2) and two H-bond acceptors (atoms O1 and O2), and it is
bonded to one neighbour molecules by two H-bonds (b=1) and to two other molecules by one H-
bond (m=2).
Results and discussion
Analysis of intermolecular contacts and interactions
The ORTEP diagrams of molecules under consideration are 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 (VIII-XI) 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 Ǻ 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) = 0.2433
(2) Ǻ and C(14) = -0.2426 (2) Ǻ for 9, C(3) = 0.2378 (2) Ǻ and C(4) = -0.2358 (2) Ǻ for X and
C(10) = 0.2359 (2) Ǻ and C(13) = -0.2443 (2) Ǻ for XI. The puckering parameters [44] for the
planes defined by atoms of cyclohexane are Q = 0.5650 (2) Å, θ = 177.96(2)º and φ = 11.97(3)º
for VIII, Q = 0.5780 (2) Å, θ = 1.72(2)º and φ = 151.14 (3)º for IX, Q = 0.563 (3) Ǻ, θ =
1
.01(3)º and φ = 148(11)º for X and Q = 0.5721 (2) Å, θ = 178.13(2)º and φ = 252.88(4)º for XI,
11

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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
7
7.39(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 119.69º for VIII, 119.69º for IX, 119.36º for X and 119.17º for XI. The shortest
angles observed around S atoms are N(1)-S(1)-O(1) = 105.74º for VIII, N(1)-S(1)-O(1) =
1
03.63º for IX, C(7)-S(1)-O(2) = 104.86º for X and C(1)-S(1)-O(2) = 105.52º for XI.
Compound VIII
-[(4-Bromo-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic
4
acid
(VIII)
crystallizes in the space group P2 /n, the carboxylic group in the molecules are involved in
1
2
typical inversion dimerization and generate centro-symmetric R (8) ring motif through O-HꢀꢀꢀO
2
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+1/2), so connects the dimers to form
a zig-zag fashion to generate C(4) chain along [010] direction. The combination of O-HꢀꢀꢀO and
2
6
N-HꢀꢀꢀO hydrogen bonds produce edge-fused R (8) R (48) motifs (Table 4) (Fig. 5).
2
6
Compound IX
-{[Ethyl-(toluene-4-sulfonyl)-amino]-methyl}-cyclohexanecarboxylic acid ethyl ester (IX),
4
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-4-sulfonylamino)-methyl]-cyclohexanecarboxylic acid [20] and
crystallizes in the space group P2 /n. Molecules are linked through a non-classical weak C-HꢀꢀꢀO
1
1
2

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2
hydrogen bonds (Table 4). The C-HꢀꢀꢀO hydrogen bonds produce centro-symmetric R (24) ring
2
centred at (1, 0, 0) (Fig. 6).
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 P2 /c space group. The two host-guest moieties join each other with their carboxylic groups
1
2
through O-HꢀꢀꢀO hydrogen bonding and generates centro-symmetric R (8) motif (Fig. 6). This is
2
in difference to VIII, where the molecules form dimers (Fig. 5). The N(1) atom at (x, y, z)
i
behaves as hydrogen-bond donor via H(1A), to O(2) of SO to join the molecules in an one-
2
dimensional C(4) chain along [001] direction (Table 4) (Fig. 7).
Compound Ⅺ
4
-[(Toluene-4-sulfonylamino)-methyl]-cyclohexanecarboxylic acid (XI) was crystallized
along with a water molecule in P2 /a space group. The water molecule helps in formation of
1
supramolecular structure. The sulfonamide functionality -SO -NH- forms dimers through N(1)-
2
i
2
ii
H(1N)ꢀꢀꢀO(2) R (8) motif. The N(1)-H(1N)ꢀꢀꢀO(1) hydrogen bond connects the molecules
2
along a axis. The combination of O-HꢀꢀꢀO and N-HꢀꢀꢀO hydrogen bonds produce edge-fused
3
3
4
5
R (20)R (28) motif (Table 4) (Fig. 8). The water molecule connects four molecules through O-
HꢀꢀꢀO type intermolecular hydrogen bonding to form three-dimensional networks (Table 3) (Fig.
). The water molecules form tetrahedral geometry via O-HꢀꢀꢀO and N-HꢀꢀꢀO hydrogen bonds. In
9
addition to these, there are two non-classical, C-HꢀꢀꢀO type hydrogen bonding interactions, which
stabilize the structure.
1
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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.
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 – benzoic acid and water, respectively.
Molecular coordination numbers are presented in table 6. For two monomolecular structures
MCN=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 water-water 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 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.
Hydrogen-bonded networks in structures VIII, X and XI
2
1
A hydrogen-bonded network with ubiquitous hcb (honeycomb) topology and the MCTS K is
observed in structure VIII. Structure X contains hydrogen-bonded 2C1 chains with the MCTS
1
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2
1
01
K and B 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-P2 /c topology (Fig. 9), which has
1
never been observed in the hydrogen-bonded organic structures. Each water molecule is
4
hydrogen-bonded to four molecules of Ⅺ, therefore its MCTS is T as shown in Fig. 10(b). Each
molecule of compound XI is bonded to four water molecules by means of one hydrogen bond
41
and to another molecule XI through two hydrogen bonds that leads to MCTS G . 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.
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 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-P2 /c topology found in structure XI has never
1
been observed in the hydrogen-bonded crystals, though the other description of the structure with
1
5

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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 and Centre of Excellence for Advanced Materials
Research (CEAMR), King Abdulaziz University, Jeddah, Saudi Arabia for structure solutions
and further refinement.
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O
O
S
O
N
H
N
HO
H
XI
O
H
N
Cl
O
OH
S
OH
O
Cl
Cl
O
O
O
III
CH
3
Cl
Cl
S
NH
S
O
O
IV
2
O
O
II
HO
I
HN
S
HN
Cl
O
S
O
O
O
O
Br
VII
Cl
O
3
H C
Cl
S
V
VI
O
O
O
OH
O
S
N
H
Br
HO
VIII
O
S
O
O
O
S
Cl
O
N
H
HO
N
.
Cl
CH
3
O
O
OH
O
X
O
IX
Scheme 1. Synthesis of sulfonamide derivatives of tranexamic acid
2
0

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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 neighbour molecules. Molecular solid
angles for contact with molecule 1 and 2 are 12.2% and 5.7%, respectively.
2
1

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Fig. 2. Subnets of the initial net corresponding to the molecular packing in structure 8
6
represent: (a) 2C1 chain; (b) chain with 3 (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
coloured in yellow and green.
2
2

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21
Fig. 3. Molecule with MCTS K . Independent active centres are designated H1, H2 and O1,
O2 .
2
3

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Fig. 4. ORTEP diagrams of molecules a-VIII, b-IX, c-X, d-Ⅺ.
2
4

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2
6
Fig. 5. Crystal structure of VIII, showing the formation of R (8) and R (48) rings
2
6
(Symmetry codes as in Table 4)
2
5

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

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Fig. 7. Crystal structure of X, showing the formation of a chain along [001] generated by N-
H···O hydrogen bonds
2
7

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3
4
Fig. 8. Crystal structure of XI, showing the formation of edge-fused R (20)R (28) motif
3
5
2
8