pubs.acs.org/crystal Published on Web 06/24/2010 r 2010 American Chemical Society

DOI: 10.1021/cg1003319

2010, Vol. 103480–3488

Solvatomorphism of 2-(4-Fluorophenylamino)-5-(2,4-dihydroxybenzeno)-1,3,4-thiadiazole Chloride

Daniel M. Kami�nski,*,† Anna A. Hoser,‡ Mariusz Gago�s,§ Arkadiusz Matwijczuk,§

Marta Arczewska,§ Andrzej Niewiadomy,† and Krzysztof Wo�zniak‡

†Department of Chemistry, University of Life Sciences in Lublin, Akademicka 15, 20-950 Lublin,Poland, ‡Department of Chemistry, Warsaw University, 02-093 Warszawa, Pasteura 1, Poland, and§Department of Biophysics, University of Life Sciences in Lublin, Akademicka 13, 20-950 Lublin, Poland

Received March 12, 2010; Revised Manuscript Received May 29, 2010

ABSTRACT: 2-(4-Fluorophenylamino)-5-(2,4-dihydroxybenzeno)-1,3,4-thiadiazole (FABT) is a biologically active com-pound. It forms planar molecules and cations. Single crystals of the FABTHþ chloride grown from water solutions of differentalcohols, such as methanol, propan-2-ol, and butanol, show structural changes induced mostly by hydrogen bond interactionswith chloride anions and solvent molecules. For structures with the alcohol molecules built in the crystal lattice, the FABTHþ

moiety takes the conformation with the o-OH (ortho position) group from the resorcin ring on the same side of the molecule asthe sulfur atom in the thiadiazole ring, whereas, in the alcohol free crystals growth from a butanol-water mixture, this group issituated on the other side of the thiadiazole ring. The incorporation of the alcoholmolecules into the crystal structures formed byFABTHþ cations strongly depends on their size, and it influences the properties of crystal lattices. In the case of theFABTHþCl-

crystallized from butanol, the crystal structure consists of columns of FABTHþ cations forming intermolecular channelscontaining two water molecules and two chloride anions related by centers of symmetry. The crystal structure of FABTHþCl-

crystallized from methanol is built of two separate layers consisting of FABTHþ cations and methanol and chloride anionsrepeating periodically. FABTHþCl- crystallized from propan-2-ol forms a 3D structure with separate water and propan-2-olmolecules glued by chloride anions and layers of the FABTHþ cations. The Hirshfeld surface analysis is a very useful tool inidentifying subtle differences between the solvates. The DFT computations allow us to estimate the energy difference betweenthe two conformers to be 3.2 kcal/mol and the rotational barrier to be 12.6 kcal/mol.

Introduction

Polymorphism, i.e. the existence of a substance in structurescharacterized by different unit cells, where each of the formsconsists of exactly the same elemental composition, and solvato-morphism, when crystal structures of a substance are definedby different unit cells differing in their elemental compositionthrough the inclusion of one or more molecules of a solvent,are two phenomena of paramount importance, particularlyfor the pharmaceutical industry.1,2 Solvatomorphism is anespecially important phenomenon because the active ingre-dients are delivered mostly as a solid phase. The propertiesof new solvates, new crystal phases, can vary markedly fromthose of the primary one.1 Understanding and controlling thesolid state properties of pharmaceuticals helps to improve theirbioavailability, purification process, stability, and other para-meters of drugs.

In this study, we present structures of different solvates ofbiologically active 2-(4-fluorophenylamino)-5-(2,4-dihydroxy-benzeno)-1,3,4-thiadiazole chloride (hereafter abbreviatedFABTHþCl-) obtained by single crystal X-ray diffraction(see Figure 1). The FABTmolecule belongs to a large class ofbiologically active components, exhibiting antiproliferativeand anticancer activities.3,4 Different structural and, as aconsequence, electronic effects in the FABT structures canalso influence the equilibrium of the keto/enol tautomerism5

possible in this molecule. The tautomerism is important in thefluidity of biological membranes.6

In this work, we want to study intermolecular interac-tions in FABTHþCl- alcohol free crystals (crystallized frombutanol), containing water molecules incorporated into a cry-stal lattice (and hereafter denoted as FABTHþCl-w) and sol-vated crystals of FABTHþCl- crystallized from methanoland propan-2-ol (hereafter abbreviated FABTHþ

Cl-m and

FABTHþCl-pw, respectively). Our aim is to rationalize thephysicochemical properties of FABTHþCl-, in particular, tolook for factors controlling the conformation of theFABTHþ

cation. We will present details of the crystal structures of thesolvates and expect that intermolecular interactions modifiedby different solventmolecules should also influence the arran-gement of molecules in 3D crystal lattices.

Because the studied compounds are very similar,wewant touse theHirshfeld surfaces7-9 to compare intermolecular inter-actions in the crystal lattices. The Hirshfeld surface analysisshould be very helpful in finding small differences between thesolvates,10 and to our knowledge, this is one of the very firstapplications of Hirshfeld analysis in such studies.

Materials and Methods

Materials. 2-(4-Fluorophenylamino)-5-(2,4-dihydroxybenzeno)-1,3,4-thiadiazole chloride (FABTHþCl-)11,12 (empirical formulaC14N3O2FSH10Cl, weight 309 g/mol, and melting temperature of279-280 �C) consists of three parts: resorcin, thiadiazole, andfluorobenzene rings (see Figure 1). Details of the synthetic proce-dures are described elsewhere.13 Compounds were purified bymeans of HPLC (YMC C-30 column with a length of 250 mm andinternal diameter 4.6 mm). The solvent mixture of acetonitrile/CH3OH/H2O (72:8:3 by volume) was applied as a moving phase.Then, FABTHþCl- was recrystallized from 96% methanol.

*Towhomcorrespondence shouldbe addressed.E-mail: daniel_kaminski3@wp.pl.

Article Crystal Growth & Design, Vol. 10, No. 8, 2010 3481

In order to remove residuals of the solvents (after evaporation in anN2 atmosphere), samples were placed in a vacuum for 1.5 h. Thesolvents used were purchased from Sigma-Aldrich Co.

All measured FABTHþCl- crystals were obtained from a mix-ture of different alcohols, such as methanol, propan-2-ol, or buta-nol, with 2MHCl as the protonating agent in the ratio of 4:1. Then,FABT was dissolved in such a prepared mixture at 35 �C. Crystalswere grown at room temperature for 3weeks. The ratio of alcohol towater in the crystallization mixture (during alcohol evaporation)was no lower than 1:1. Too low a concentration of alcohol leads tocrystallization of alcohol free crystals. A small amount of alcoholfreeFABTHþ

Cl-w crystals with the characteristic dark yellow color

also for crystallization from methanol and propan-2-ol mixtureswas observed on the bottomof a crystallization flask (effect of waterabsorption from the atmosphere). The solvates with methanol andpropan-2-ol have a light yellow color. In the crystals grown from thebutanol/water mixture (even in the ratio 6:1), still only watermolecules enter the crystal net. We attempted several times to cry-stallize the bare salt single crystals, unfortunately obtaining in eachcase a powder of FABTHþCl-. The same result was observed whenFABTHþCl-mcrystals were taken out from the crystallizationmix-ture and left under air.

X-rayDiffraction.Datacollection for singlecrystalsofFABTHþCl-mand FABTHþCl-pw (T=100 K) was carried out on a Bruker AXSKAPPA APEX II ULTRA diffractometer with a TXS rotating moly-bdenum anode and multilayer optics. Data sets were collected using theomega scan method, with an angular scan width of 0.5� for FABTHþ-Cl-m and 0.3� forFABTHþCl-pw. In both cases the exposure time was20 s per frame. The data were corrected for Lorentz and polarizationeffects. Indexing, integration, and scaling were performed with theoriginal Bruker Apex II software.14,15 Multiscan absorption correctionwas applied using SADABS.16

Data collection for a single crystal ofFABTHþCl

-w (T=100K)

was carried out on a single crystal X-ray κ-axis KM4CCD dif-fractometer17 with Mo KR radiation monochromated by graphitewith the use of the omega scan technique. The crystal was positioned65 mm from a CCD 1024�1024 pixel camera. The 2θ angle rangewas extended from ca. 2� up to 57�. Each frame was measured at an

0.8� angle interval and a counting time of 40 s. A multiscanabsorption correction was applied.18 Data reduction and analysiswere carried out with CRYSALIS RED.17

All structures were solved by direct methods19 and refined usingSHELXL.20 The refinement was based on squared structure factors(F2) for all reflections except thosewith very negativeF2.Most of thehydrogen atoms were located in idealized averaged geometricalpositions (those at the thiadiazole ring); however, the other hydro-gens were found from difference electron density maps. Scatteringfactors were taken from Tables 6.1.1.4 and 4.2.4.2 in ref 21. Table 1includes experimental details for all measured crystals.

Entries 768785-768787 of the CCDC contain the supplementarycrystallographic data for FABTH

þCl

-w, FABTHþ

Cl-m, and

FABTHþCl

-pw crystals. These data can be obtained free of charge

from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Hirshfeld Surfaces. To compare intermolecular interactions ininvestigated solvates, we used fingerprint plots generated fromHirshfeld surfaces.22 A weighing function is used to define theHirshfeld surface:

wAðrÞ ¼

P

i∈moleculeA

Fiðr- riÞP

i∈crystalFkðr- rkÞ

where Fi is the spherically averaged atomic electron density of thei-th atom in the molecule (centered at point ri) and Fk is the electrondensity of the k-th atom surrounding a particular molecule in thecrystal. This weighing function defines the so-called Hirshfeld sur-face for molecule A when wA(r) = 0.5 for every point r at the sur-face. Within the Hirshfeld surface, the promolecule electron densitydominates over the procrystal electron density. It is possible to mapdifferent properties on Hirshfeld surfaces: properties related to theshape of the surface (e.g., curvedness) and also those connected withdistances: de, external distance from the Hirshfeld surface to anatom belonging to the closest molecules outside the surface; di,internal distance from the surface to an atom inside the surface; and

Figure 1. Atom labeling and ORTEP representation of the anisotropic displacement parameters at the 50% probability level for(a) FABTHþCl-w, (b) FABTHþCl-m, and (c) FABTHþCl-pw.

3482 Crystal Growth & Design, Vol. 10, No. 8, 2010 Kami�nski et al.

dnorm, which combines both de and di, each normalized by the vander Waals (vdW) radius for the particular atoms involved in closeproximity to the surface. When de and di are calculated for eachpoint of theHirshfeld surface, a 2D (de vs di) plot called a fingerprintis created.22 As on Hirshfeld surfaces, the closest contacts from apoint belonging to the surfaces to a particular atom, both inside andoutside the surface, can be illustrated, and one can easily computerelative contributions to the Hirshfeld surface area for the variousclose intermolecular interactions. All the interactions sum up to100%, so a percentage of interaction can be estimated.23

The presented figures of Hirshfeld surface and fingerprint plotswere prepared in the CrystalExplorer program24, which is usingstandardized hydrogen atom positions.

Computational Details. To check the stability of the observedFABTHþ conformations and the rotational barrier between them,we performed the density functional calculations of the total energyfor the isolated molecule of FABTHþ in a vacuum. All geometryand energy calculations were carried out using the Gaussian03program.25 As the first step, the geometry optimization was doneby applying the AM1 semiempirical method. The second optimiza-tion step was performed at the B3LYP level of theory with the6-31þþG (2d, 2p) basis set and standard convergence criteria.

Results and Discussion

Geometry of FABTHþ. The bond lengths and valenceangles are very similar in all FABTHþ cations crystallized

from different solvents (see Table 2). In fact, the most specta-cular difference in the geometric parameters of the FABTHþ

cations regards its conformation. It appears that in the

FABTHþCl-w hydrate the resorcin ring is rotated in the

opposite direction with respect to the thiadiazole ring com-

pared to the other solvates. The S1C8C9C14 torsion is equal to

176.4� in FABTHþCl

-w and -3.7� and -1.7� in FABTH

þ-Cl-m and FABTHþCl-pw, respectively. This is caused by

hydrogen interactions of the o-OH group with the surround-

ing solvent molecules. Additionally, the fluorobenzene ring

is slightly rotatedwith respect to the thiadiazole ring with the

dihedral angle C7-N1-C4-C3 of 2.5� in FABTHþCl-wand -1.6 and -9.9� in FABTH

þCl

-m and FABTH

þCl

-pw,

respectively. The larger value of this torsion angle inFABTHþ-Cl-m could be due to asymmetric interactions in the stacks.

The N2-N3 bond length (on average 1.374 A) in thethiadiazole ring cation confirms the single character of thisbond, with a similar bond length as that of the singularN-Nbond in pyrazole (1.366 A26). The C-S bonds are in therange from 1.713 A to 1.757 A, as can be expected for singlebonds of this type (ref 1.751 A in ref 26);they are asym-metric, as can be seen in the values included in Table 2. Theprimary reason for this asymmetry in the C-S bond lengthsof the thiadiazole ring is the localization of charge resultingfrom protonation of the ring nitrogen atom. This protona-tion is a cause of the redistribution of electron density in thering. This effect is smaller in the case of the FABTHþCl-mdue to larger errors of structural parameters;in this case it iswithin the level of errors.

The aromatic C-C bond lengths are typical (in the rangefrom 1.36 A to 1.41 A), although on average, they are slightlyshorter in the fluorobenzene ring than in the resorcin frag-ment. The full table of the valence angles is attached in theSupporting Information (Table S1).

Packing and Intermolecular Interactions. FABTHþCl

-w.

Packing of molecules and their weak interactions in thecrystal structure FABTHþCl-w are illustrated in Figures 2and 3. The crystal lattice of this compound consists of theFABTHþ cations arranged in separate columns (see Figure 2).

Table 1. Data Collection and Refinement Details for the Measured Structures

FABTHþCl

-w FABTH

þCl

-m FABTH

þCl

-pw

formula C14H11N3F1S1O3þ3Cl

-3H2O C14H11N3F1S1O3

þ3Cl

-3CH3OH C14H11N3F1S1O3

þ3Cl

-3H2O 3C3H7OH

system monoclinic monoclinic monoclinicspace group P21/c P21/n P21/cunit cell dimensionsa/A 9.0617(9) 7.8639(7) 10.1887(6)b/A 12.8358(7) 13.2352(11) 6.4533(4)c/A 13.1915(10) 19.5416(17) 29.2134(19)R/deg 90.00 90.00 90.00β/deg 103.558(9) 92.082(5) 91.939(4)γ/deg 90.00 90.00 90.00volume/A3 1491.6(2) 2032.6(3) 1919.7(2)density 1.593 1.424 1.446absorption coefficient 0.426 0.333 0.346crystal size 0.25 � 0.12 � 0.10 0.31 � 0.15 � 0.12 0.22 � 0.14 � 0.11theta range 2.94-28.34 1.86-25.05 2.14-27.32no. of reflections 10919 19930 10302no. of independent refls/parameters 3446/232 3609/287 4316/328goodness-of-fit S 0.731 1.062 1.038R (all data)/R [F2

o>4σ(F2o)] 0.0992/0.0363 0.0935/0.0644 0.0764/0.0493

wR2 (all data)/wR2 [F2o>4σ(F2

o)] 0.0575/0.0514 0.1880/0.1724 0.1081/0.0993largest diff. peak and hole 0.32; -0.26 0.79; -0.40 0.56; -0.30

Table 2. Bond Distances and Angles for FABTHþ Cations in

Different Crystals

FABT crystallized from

methanol propanol butanol

S1-C8 1.738(4) 1.718(2) 1.713(2)S1-C7 1.749(4) 1.757(2) 1.751(2)F1-C1 1.368(5) 1.359(3) 1.359(2)O1-C12 1.341(5) 1.355(3) 1.343(3)O2-C14 1.351(5) 1.345(3) 1.341(3)N1-C7 1.347(5) 1.353(3) 1.340(3)N1-C4 1.403(5) 1.403(3) 1.398(3)N2-C7 1.312(5) 1.300(3) 1.297(3)N2-N3 1.372(5) 1.371(3) 1.379(2)N3-C8 1.314(5) 1.318(3) 1.307(3)C1-C2 1.362(6) 1.369(4) 1.356(3)C1-C6 1.377(6) 1.377(4) 1.374(3)C3-C2 1.381(6) 1.389(4) 1.383(3)C4-C3 1.386(6) 1.390(3) 1.379(3)C4-C5 1.398(6) 1.399(3) 1.386(3)C6-C5 1.383(6) 1.381(4) 1.374(3)C8-C9 1.438(6) 1.442(3) 1.425(3)C9-C14 1.404(6) 1.401(3) 1.408(3)C9-C10 1.405(6) 1.406(3) 1.407(3)C10-C11 1.360(6) 1.366(3) 1.360(3)C11-C12 1.402(6) 1.396(4) 1.397(3)C12-C13 1.380(6) 1.384(3) 1.367(3)C13-C14 1.378(6) 1.384(3) 1.373(3)

Article Crystal Growth & Design, Vol. 10, No. 8, 2010 3483

Two types ofFABTHþ columns parallel to the adirection arepresent in the crystal lattice, with molecules from each ofthem oriented perpendicularly to each other. They are relatedby the glide c planes. The columns are arranged in such a waythat they form channels going through the crystal latticefilled with water molecules and with chloride anions locatedaround the centers of symmetry. The FABTHþ cations in asingle column have sandwich-like packing with the oppositeorientation of the neighboring molecules, as is the commoncase for the molecules carrying a nonzero dipole moment.They are located in a given column in a slightly asymmetricmanner (see Figure 3), with the interplanar distances betweenthe neighboring molecules equal to 3.2 A and 3.3 A. Theshortest intermolecular distance between the atoms belong-ing to the different neighboring molecules is 3.240 A (theN2 3 3 3C13 close contact). The FABTHþ cations are alsoshifted along the longest molecular axis in such a mannerthat the π-electrons from the resorcin rings interact with theπ-electrons from the thiadiazole fragment. The oxygen O1atom from the resorcin ring is hydrogen bonded with theH3N hydrogen from the thiadiazole ring (1.99 A; seeFigure 2). The details of all hydrogen bonds and other closecontacts present in this crystal structure are shown in Table3. The hydrogen atom from the o-OH group in the resorcinring forms a hydrogen bond with the oxygen O1S atom fromthe water molecule (2.57 A; see Figure 2a). The hydrogenatom from the thiadiazole ring and the oxygen atom from theo-OH group form a weak H-bond with the F atom from the

next nearest column of the FABTHþ cations (H3N 3 3 3F12.19 A). The hydrogen from the p-OH group, the H1O in theresorcin ring, and the hydrogen H1N from the amine groupform bonds with two chloride anions Cl1 (2.24 A and 2.30 A,respectively). Additionally, the chloride anion Cl1 interactswith two surrounding water molecules O1S and O1S, form-ing H1OS 3 3 3Cl1 and H2OS 3 3 3Cl1 H-bonds (2.41 A and2.24 A, respectively). The structure is mainly stabilized byionic interactions between the chloride anions and FABTH

þ

cations and, additionally, fine-tuned by a network of hydro-gen bonds.

FABTm.The crystal structure of FABTHþCl

-m is built of

the FABTHþ cations arranged in layers and separated bymethanol and chloride anions (see Figure 4). The FABTHþ

cations in a given layer have the opposite tilt compared to theneighboring FABTH

þ layers. The neighboring FABTHþ

cations in each layer are oppositely oriented in such amannerthat the resorcin ring is over the fluorobenzene ring from theprevious molecule. Each FABTHþ cation in such a layer isshifted with respect to the previous one by ∼1.5 A. TheFABTHþ cations in a column interact via π 3 3 3π interactionsbetween the aromatic parts with an interplanar spacing of∼3.42 A and 3.38 A (see Figure 5b). The H1O atom from thep-OHgroup in the resorcin ring forms a hydrogen bond (1.77A) with a methanol molecule through the O2S atom (seeTable 4). Similarly, H2O from the o-OH group is H-bondedto the methanol O3S atom (1.53 A). The H3N from thethiadiazole fragment forms anH-bond to the thirdmethanol

Figure 2. Packing of molecules in the FABTHþCl-w crystal lattice: projection (a) along the a axis or (b) along the c axis. Bigger green dotsdenote chloride anions, and smaller red ones denote water molecules in the channels.

Figure 3. FABTHþCl-w crystal structure: (a) short intermolecular contacts and HBs in the FABTHþ plane; (b) stacking interactions inFABTHþ columns.

3484 Crystal Growth & Design, Vol. 10, No. 8, 2010 Kami�nski et al.

moiety (O1S; 1.84 A; see Figure 5). This hydrogen bond isaccompanied by weaker H10 3 3 3O1S interactions (2.55 A).All hydrogen atoms from the hydroxyl groups in the metha-nol moieties are interacting with the chloride anions withdistances of H1SO 3 3 3Cl1=2.29 A, H2SO 3 3 3Cl1= 2.34 A,and H3SO 3 3 3Cl1=2.13 A. Similarly to the previous struc-tures, the chloride anion interacts with the H1N hydrogen(2.32 A). All these interactions are illustrated in Figure 5a.

FABTHþCl-pw. The asymmetric part of the unit cell ofthe FABTHþCl-pw crystals contains one independentFABTHþ cation (Figure 1), one chloride anion, and one

water molecule, all in general positions. The 3D crystalstructure of this solvate consists of layers of the FABTHþ

cations accompanied by chloride anions (see Figure 6) loc-ated between the cations. The FABTHþ layers are arrangedin such amanner that the hydrophobic groups (fluorobenzenefragments) are pointing toward the layer of propan-2-olmolecules, whereas the resorcin rings of theFABTHþmoietiesare interactingwith the layer ofwatermolecules. This structureis an interesting example of segregationof twodifferent solventmoieties into their separate layers in a 3D crystal structure.All important hydrogen bonds and weak interactions in this

Table 3. Details of H-Bonding and Other Intermolecular Interactions in the FABTHþCl-w Crystal Lattice

D-H 3 3 3A symm d(D-H) [A] d(H 3 3 3A) [A] d(D 3 3 3A) [A] —DHA [deg]

N3-H3N 3 3 3O1 x, y, z 0.86(2) 2.00(2) 2.575(2) 123(2)N3-H3N 3 3 3F1 -x þ 1, y - 1/2, -z þ 3/2 0.86(2) 2.19(2) 2.999(2) 156(2)N1-H1N 3 3 3Cl1 x, y, z þ 1 0.86(2) 2.30(2) 3.152(2) 170(2)O1-H1O 3 3 3Cl1 -x, y - 1/2, -z þ 3/2 0.87(2) 2.24(2) 3.079(2) 163(2)O2-H2O 3 3 3O1S x, y, z 0.75(3) 1.83(3) 2.568(3) 168(2)O1S-H1OS 3 3 3Cl1 x, y - 1, z þ 1 0.74(3) 2.41(3) 3.116(2) 159(2)O1S-H2OS 3 3 3Cl1 -x, -y, -z þ 1 0.89(3) 2.24(3) 3.129(3) 172(2)

Weak Hydrogen BondsC11-H11 3 3 3O1S -x, y þ 1/2,

3/2 - z 0.93 2.69 3.606(3) 166C13-H13 3 3 3O1S x, y, z 0.93 2.55 3.203(3) 127

Distances in Face-to-Face StackingC8 3 3 3C14 -x, -y, 2 - z 3.363(3)C7 3 3 3C13 -x, -y, 2 - z 3.328(3)C13 3 3 3S1 -x, -y, 2 - z 3.484(2)

Figure 4. Crystal packing of FABTHþCl

-m: (a) view along the a axis; (b) projection along the c axis.

Figure 5. FABTHþCl-m crystal structure: (a) short contacts and HBs in the FABTHþ plane and (b) the stacking interactions in FABTHþ

columns.

Article Crystal Growth & Design, Vol. 10, No. 8, 2010 3485

Table 4. Details of H-Bonding and Other Intermolecular Interactions in the FABTHþCl-m Crystal Structure

D-H 3 3 3A symm d(D-H) [A] d(H 3 3 3A) [A] d(D 3 3 3A) [A] —DHA [deg]

N1-H1N 3 3 3Cl1 x, y, z 0.88 2.32 3.173(4) 163N3-H3N 3 3 3O1S -x þ 1, -y þ 2, -z þ 2 0.88 1.85 2.695(4) 161O1S-H1SO 3 3 3Cl1 x, y, z 0.83(6) 2.29(6) 3.111(4) 174(6)O1-H1O 3 3 3O2S -x þ 2, y þ 1/2, -z þ 3/2 0.89(6) 1.77(6) 2.638(4) 166(5)O2S-H2SO 3 3 3Cl1 x, y, z 0.77(5) 2.34(5) 3.101(4) 176(5)O2-H2O 3 3 3O3S x, y, z 1.06(7) 1.53(7) 2.565(4) 164(5)O3S-H3SO 3 3 3Cl1 -x þ 2, y þ 1/2, -z þ 3/2 0.97(6) 2.13(7) 3.075(4) 163(6)

Weak Hydrogen BondsC6-H6 3 3 3O1 x- 1, y - 1, z 0.95 2.6 3.467(5) 152.7C10-H10 3 3 3O1S -x þ 1, -y þ 2, -z þ 2 0.95 2.6 3.458(5) 160.4

Distances in Face-to-Face StackingC3 3 3 3C13 -x þ 2, -y þ 2, -z þ 2 3.345(5)C6 3 3 3C10 -x þ 1, -y þ 2, -z þ 2 3.312(5)

Figure 6. Packing of FABTHþCl

-pw: (a) view along the a axis (H-atoms omitted for clarity, the red dots denote water molecules, whereas the

green ones denote the chloride anions); (b) view along the b axis.

Figure 7. FABTHþCl-pw: (a) short contacts and HBs in the FABTHþ plane and (b) stacking interactions in FABTHþ columns.

Table 5. Details of H-Bonding and Other Intermolecular Interactions for FABTHþCl

-pw

D-H 3 3 3A symm d(D-H) [A] d(H 3 3 3A) [A] d(D 3 3 3A) [A] —DHA [deg]

O1-H1O 3 3 3Cl1 x, y þ 1, z 0.78(4) 2.322(4) 3.099(2) 172(3)N3-H3N 3 3 3O1S x, y, z 0.90(4) 1.854(4) 2.755(3) 176(3)O2-H2O 3 3 3O2S x, y þ 1, z - 1 0.82(3) 1.796(3) 2.597(3) 164(2)N1-H1N 3 3 3Cl1 x þ 1, y, z 0.80(3) 2.367(4) 3.158(2) 171(3)O1S-H1OS 3 3 3Cl1 x, y, z 0.77(4) 2.416(4) 3.160(2) 163(2)O2S-H1SO 3 3 3Cl1 -x þ 1, -y þ 1, -z þ 1 0.76(4) 2.409(4) 3.162(2) 169(3)O2S-H2SO 3 3 3Cl1 x þ 1, y, z þ 1 0.85(4) 2.525(4) 3.335(3) 159(3)

Weak Hydrogen BondsC13-H13 3 3 3O1 1 - x, 3 - y, -z 0.91(3) 2.63(3) 3.437(3) 148(2)C10-H10 3 3 3O1S x, y, z 0.92(3) 2.40(3) 3.298(3) 167(2)C11-H11 3 3 3Cl1 x, y þ 1, z 0.96(3) 2.81(3) 3.527(3) 133(2)

Distances in Stacking Face-to-FaceC13 3 3 3C13 1 - x, 2 - y, -z 3.387(5)C12 3 3 3C14 1 - x, 2 - y, -z 3.159(3)C1 3 3 3C7 x, y - 1, z 3.345(3)

3486 Crystal Growth & Design, Vol. 10, No. 8, 2010 Kami�nski et al.

structure are illustrated in Figure 7. Again, the FABTHþ

cations in a column interact via π 3 3 3π interactions betweenthe aromatic fragments with a symmetric spacing of∼3.32 A(see Figure 7b). All FABTHþ cations in a given column havethe same orientation (fluorobenzene rings are pointing in thesame direction). Each moiety in a column is shifted withrespect to the neighboring one along the longest molecularaxis by about∼5.5 A and along the shorter by∼1 A. For thisreason, the fluorobenzene ring from the first consideredmolecule is only partly overlapping with the thiadiazole ringfrom the nearest one.

The H-bonds and other closest contacts for this structureare summarized in Table 5 and Figure 6. Two neighboringcations of FABTHþ interact via C13-H13 3 3 3O1 H-bondsand formdimers relatedby the centerof symmetry (seeFigure7).The H1N hydrogen from the FABTmolecule interacts with theCl1 (2.37 A), andH1O from the p-OHgroup in the resorcin ringreacts with the other chloride anion (2.33 A). The molecularinteractions are strengthened by a dense network of hydrogenbonds introduced by water molecules located close to thechloride anions. The H3N hydrogen atom forms a strongH-bond with the O1S oxygen atom from propan-2-ol(1.86 A). Also, H1SO from the water molecule interacts withCl1 (2.41 A). The hydrophobic part of propan-2-ol is locatedclose to the hydrophobic part of the FABTHþ cations withits H1OS hydrogen atom from the hydroxyl group pointingtoward the chloride anion (2.42 A).

Hirshfeld Surfaces.TheHirshfeld surfaces were calculatedfor theFABTHþ cations in each structure.Although in generalthese surfaces are quite similar, they also exhibit some specificdifferences induced by interactions with different solventmoieties (see Figure 8). Closer inspection of the Hirshfeld

surfaces also reveals small differences resulting from diffe-rent conformations of the resorcin ring. The analysis of curved-ness mapped on the Hirshfeld surface shows the followingdifferences (Figure 8d-f): the largest region of the flatcurvedness appears for FABTHþCl-m. This is due to acomplementary overlap of the FABTH

þ cations arrangedin stacks. From analysis of dnorm mapped on a Hirshfeldsurface, one can find that the FABTHþ cation interacts withmolecules of different solvents via the same active groups:two OH and two NH groups. One can observe the followingsimilarities for the three studied compounds: first, the o-OHforms hydrogen bonds with the oxygen atoms from sur-rounding water or methanol molecules, and second, thelinking amine NH (N1) always interacts with the chlorideanions. However, there are also some differences: the p-OHgroup of FABTHþCl-pw and FABTHþCl-w interacts withthe chloride anion while, in the case of the FABTHþCl-mcrystallized from methanol, the O-H 3 3 3O H-bond isformed to the solvent molecule. In crystals grown frombutanol, the N3 nitrogen from the thiadiazole ring interactswith the F atom from the other FABTHþ cation, whereas,for both other solvates, it forms the N-H 3 3 3O hydrogenbond (with oxygen from methanol or propan-2-ol). Due tothese differences, the fingerprint plots for FABTHþ from theabove three structures also differ quite significantly (seeFigure 9). The 1 in this figure denotes those interactionsfor which the hydrogen atom is inside the surfaces and theoxygen atoms outside. For FABTHþCl-w, only one hydro-gen bond between the o-OHgroup from the resorcin ring anda water molecule contributes only about 5% to the totalamount of interactions in this structure (see Figure 10). Forthe FABTH

þCl

-m and FABTH

þCl

-pw crystals, addition-

ally, the N-H 3 3 3O interactions are present, and this is whythey together constitute ca. 9.5% and 8% of the totalinteractions, respectively. Number 2 on the fingerprint plots(see Figure 9) points to the H 3 3 3Cl interactions (H1N insidetheHirshfeld surface).ForFABTHþCl-wandFABTHþCl-pw,additional O-H 3 3 3Cl interactions have to be taken into ac-count. As a consequence, the H 3 3 3Cl interactions constitute ca.6% and 5% FABTHþCl-w and FABTHþCl-pw, and only 3%for FABTHþCl-m, respectively. Number 3 corresponds to theO 3 3 3H interactions (O inside the Hirshfeld surface). Number 4appears for FABTHþCl-w and denotes the F 3 3 3H interac-tions between the H3N and fluoride atom from the nextneighboringFABTHþ cation.Number 5 appears only for theFABTHþCl-pw, and it indicates the C-H 3 3 3C interactionsbetween the solvent and the C6 atom. In general, the H 3 3 3Hinteractions dominate in all structures, with their contribu-tions ranging from 30% to 35% of the total amount.

Figure 8. dnorm (a-c) and curvedness (d-f) mapped on a Hirshfeldsurface for the FABTHþ cations in (a and d) FABTHþ

Cl-w, (b and

e) FABTHþCl-pw, and (c and f) FABTHþCl-pw.

Figure 9. Fingerprint plots for (a) FABTHþCl-w, (b) FABTHþCl-m, and (c) FABTHþCl-pw.

Article Crystal Growth & Design, Vol. 10, No. 8, 2010 3487

Computational Confirmation.Themain results of this workare confirmed by DFT calculations for the protonatedFABTHþ cation in the vacuum. It appears that the conforma-tion with the o-OH group located on the nitrogen side of thethiadiazole fragment is more stable than the other conformer(with the o-OHgroup on the sulfur side of the thiadiazole ring;see Table 2S in the Supporting Information). The energydifference between both conformations is equal to 3.2 kcal/mol. The small energy difference between the two conformerscan be easily overcome by strong hydrogen bonds. However,the rotational barrier between the two conformers around thesingle C8-C9 bond amounts to 12.5 kcal/mol, which is asignificantly greater amount. This means that solid staterotational transformation around this bond is very unlikely.

Conclusions

In this work we present details of three different X-raystructures of solvates of biologically active 2-(4-fluorophenyl-amino)-5-(2,4-dihydroxybenzeno)-1,3,4-thiadiazole (FABT)chloride (FABTHþCl-) crystallized from butanol, metanol, andpropan-2-ol (FABTHþCl-w, FABTHþCl-m, and FABTHþ-Cl-pw, respectively). The main structural difference betweenthe alcohol free structure (FABTHþCl-w) compared to thestructures with methanol or propan-2-ol is the orientation ofthe resorcin ring with respect to the thiadiazole molecularfragment. For crystals with methanol and propan-2-ol, theo-OH group is located on the same side of the molecule as theS1 atom. This conformation seems to be promoted by inter-actions of the o-OH group with the nearest solvent moieties.However, both conformations are stable and dependent onthe presence of hydrogen bonds between the hydroxyl groups,the N-H dipoles, and surrounding chloride anions andmethanol and water moieties.

In the case of the FABTHþCl-w, the crystal structureconsists of columns of FABTHþ cations forming intermole-cular channels containing two water molecules and two chlo-ride anions related by the centers of symmetry. TheFABTHþ-Cl-m crystal structure is built of two separate layers consistingof the FABTH

þ cations (the first layer) and methanol andchloride anions (the second layer). The third crystal structure,FABTHþCl-pw, forms a quite unusual 3D structure with theseparate layers of water and propan-2-ol molecules glued bychloride anions. TheFABTHþ cations in all structures tend toform stacks.

TheHirshfeld surfaces appear to be a very useful tool in theanalysis of similar structures. The curvedness mapped on theHirshfeld surface shows that the largest regionof flat curvedness

appears for the FABTHþCl-m. This analysis allows us toestimate the percentage of specific interactions: It appears thatin all structures the H 3 3 3H interactions constitute ca. 30% ofall interactions. In the case of the FABTw, the other types ofinteractions constitute ca. 5-6% of the total amount each—these are H 3 3 3O, H 3 3 3Cl, F 3 3 3H, and C 3 3 3C interactions.For FABTm, these proportions are different: 11.6% ofC 3 3 3C, 9.5% of H 3 3 3O, and 6% of O 3 3 3H, 6% of C 3 3 3H,and only 3% of H 3 3 3Cl interactions. In the third structure,FABTpw, one can find 9%of C 3 3 3H, 8%ofH 3 3 3O, 6.6% ofC 3 3 3C, 5% of H 3 3 3Cl, and 3.5% of O 3 3 3H interactions.

DFT calculations confirm experimental results, enablingestimation of the energy difference between the conformers ofthe FABTHþ cation (3.2 kcal/mol) and of the rotationalenergy barrier (12.6 kcal/mol).

Acknowledgment. X-ray single crystal measurements wereaccomplished at the Structural Research Laboratory of theChemistry Department, Warsaw University, Poland, estab-lished with financial support from the European RegionalDevelopment Foundation in the Sectoral Operational Pro-gramme ‘‘Improvement of the Competitiveness of Enter-prises, years 2004-2006’’, project no. WKP_1/1.4.3./1/2004/72/72/165/2005/U. Support from the Foundation for PolishScience for K.W. and A.H. (Mistrz professorship) is greatlyacknowledged.

Supporting Information Available: Table 1S, showing valenceangles in FABTHþCl- solvates; Table 2S, showing results of theo-retical calculations for the FABTHþ cation; and submission detailsto the Cambridge Crystallographic Data Centre. This informationis available free of charge via the Internet at http://pubs.acs.org/.

References

(1) Brittain, H. G. Polymorphism and solvatomorphism. J. Pharm.Sci. 2009, 98 (5), 1617–1642.

(2) Byrn, S. R.; Pfeiffer, R. R.; Stowell, J. G., Solid-State Chemistry ofDrugs; SSCI: West Lafayette, IN, 1999.

(3) Palekar, V. S.; Damle, A. J.; Shukla, S. R. Synthesis and anti-bacterial activity of some novel bis-1,2,4-triazolo[3,4-b]-1,3,4-thia-diazoles and bis-4-thiazolidinone derivatives from terephthalicdihydrazide. Eur. J. Med. Chem. 2009, 44 (12), 5112-6.

(4) Rajak, H.; Deshmukh, R.; Aggarwal, N.; Kashaw, S.; Kharya,M. D.; Mishra, P. Synthesis of novel 2,5-disubstituted 1,3,4-thiadiazoles for their potential anticonvulsant activity: pharmaco-phoricmodel studies.Arch.Pharm. (Weinheim) 2009, 342 (8), 453–61.

(5) Gago�s, M.; Matwijczuk, A.; Kami�nski, D.; Niewiadomy, A.;Karwasz, G. P. Spectroscopic studies of 1,3,4-thiadiazoles: intra-molecular proton transfer induced by solvent polarizability.J. Phosphoresc., accepted.

(6) Rog, T.; Stimson, L. M.; Pasenkiewicz-Gierula, M.; Vattulainen,I.; Karttunen, M. Replacing the cholesterol hydroxyl group withthe ketone group facilitates sterol flip-flop and promotes mem-brane fluidity. J. Phys. Chem. B 2008, 112 (7), 1946–52.

(7) Spackman,M.A.; Byrom, P. G. A novel definition of amolecule ina crystal. Chem. Phys. Lett. 1997, 267 (3-4), 215–220.

(8) McKinnon, J. J.; Spackman,M. A.; Mitchell, A. S. Novel tools forvisualizing and exploring intermolecular interactions in molecularcrystals. Acta Crystallogr., B 2004, B60, 627–668.

(9) McKinnon, J. J.; Fabbiani, F. P.A.; Spackman,M.A.Comparisonof Polymorphic Molecular Crystal Structures through HirshfeldSurface Analysis. Cryst. Growth Des. 2007, 7 (4), 755–769.

(10) Spackman, M. A.; Jayatilaka, D. Hirshfeld surface analysis. Crys-tEngComm 2009, No. 11, 19–32.

(11) Rzeski, W.; Matysiak, J.; Kandefer-Szerszen, M. Anticancer,neuroprotective activities and computational studies of 2-amino-1,3,4-thiadiazole based compound. Bioorg. Med. Chem. 2007, 15(9), 3201–7.

(12) Matysiak, J.; Opolski, A. Synthesis and antiproliferative activityof N-substituted 2-amino-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazolesBioorg. Med. Chem. 2006, 14 (13), 4483–9.

Figure 10. Relative contributions of chosen intermolecular inter-actions to the Hirshfeld surface area for three solvates of FABTHþ.

3488 Crystal Growth & Design, Vol. 10, No. 8, 2010 Kami�nski et al.

(13) Niewiadomy, A.; Matysiak, J. The method of synthesis of 2-aryl-(alkyl, alkenyl)amino-5-(2,4-dihydroxybenzene)-1,3,4-thiadiazoles;Patent pending P362805; Poland, 2003.

(14) Bruker Nonius (2007). APEXII-2008v1.0.(15) Bruker Nonius (2007). SAINT V7.34A.(16) Sheldrick, G. M. SADABS; University of G€ottingen, Germany,

1996.(17) Oxford Diffraction. CrysAlis CCD and CrysAlis RED; Oxford

Diffraction Poland: Wroczaw, Poland, 2001.(18) CrysAlis RED, Version 1.171.33.41 (release 06-05-2009 CrysA-

lis171 .NET) (compiled May 6 2009,17:20:42) Empirical absorp-tion correction using spherical harmonics, implemented in SCALE3ABSPACK scaling algorithm; Oxford Diffraction Ltd.

(19) Sheldrick, G. M. Phase annealing in SHELX-90: direct methodsfor larger structures. Acta Crystallogr., A 1990, A46 (6), 473–478.

(20) Sheldrick, G. M. SHELXL93, Program for the Refinement ofCrystal Structures; University of G€ottingen: Germany, 2003.

(21) International Tables for Crystallography; Wilson, A. J. C., Ed.;Kluwer: Dordrecht, 1992; Vol. C.

(22) Spackman, M. A.; McKinnon, J. J. Fingerprinting intermole-cular interactions in molecular crystals. CrystEngComm. 2002, 4,378–392.

(23) McKinnon, J. J.; Jayatilaka, D.; Spackman, M. A. Towardsquantitative analysis of intermolecular interactions with Hirshfeldsurfaces. Chem. Commun. 2007, 3814–3816.

(24) Wolff, S. K.; Grimwood, D. J.; McKinnon, J. J.; Jayatilaka, D.;Spackman, M. A. Crystal Explorer, 2.0 ed.; University of WesternAustralia: Perth, 2005-2007 (http://hirshfeldsurface.net/Crystal-Explorer).

(25) Frisch,M. J.; Trucks,G.W.; Schlegel,H. B.; Scuseria,G. E.; Robb,M.A.;Cheeseman, J.R.;Montgomery, J.A.; Vreven, J., T.;Kudin,K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;Petersson, G. A.; Nakatsuji, H.; Hada,M.; Ehara,M.; Toyota, K.;Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian,H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;Gomperts, R.; Stratmann,R. E.; Yazyev,O.; Austin,A. J.; Cammi,R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.;Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick,D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz,J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov,B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin,R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.;Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,Revision C.02; Wallingford, CT, 2004.

(26) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen,A. G.; Taylor, R. J. Chem. Soc., Perkin Trans. 2 1987, S1–S19.