x-ray, 1h nmr and dft study on 5-para-x-benzylidene-thiazolidine derivatives with x = br, f

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Journal of Molecular Structure: THEOCHEM 851 (2008) 63–74

X-ray, 1H NMR and DFT study on5-para-X-benzylidene-thiazolidine derivatives with X = Br, F

Vasile Chis� a,*, Adrian Pırnau a,1, Mihai Vasilescu a, Richard A. Varga b, Ovidiu Oniga c

a Babes�-Bolyai University, Faculty of Physics, Kogalniceanu 1, RO-400084 Cluj-Napoca, Romaniab Babes�-Bolyai University, Faculty of Chemistry and Chemical Engineering, Arany Janos 11, RO-400028 Cluj-Napoca, Romania

c Iuliu Hat�ieganu University of Medicine and Pharmacy, Department of Pharmaceutical Chemistry, Emil Isac 13, RO-400023 Cluj Napoca, Romania

Received 3 October 2007; received in revised form 29 October 2007; accepted 30 October 2007Available online 7 November 2007

Abstract

Experimental methods (NMR spectroscopy and X-ray diffraction) and quantum chemical calculations based on density functionaltheory (DFT) were used for structural and electronic characterization of two thiazolidine-2-thione-4-one derivatives with antimicrobialactivity, namely 5-para-bromo-benzylidene-thiazolidine-2-thione-4-one (5pBr-BTT) and 5-para-fluoro-benzylidene-thiazolidine-2-thi-one-4-one (5pF-BTT). X-ray diffraction technique indicates that 5pBr-BTT crystallizes with one DMSO solvent molecule, forming a1:1 5pBr-BTTÆDMSO complex, in the triclinic space group P�1, with Z = 2 and cell parameters a = 4.4597(7) A, b = 12.5508(19) A,c = 13.7270(2) A, a = 90.75(2)�, b = 96.23(2)� and c = 97.86(3)�. The linear conformation adopted in the crystalline state is establishedby intermolecular hydrogen bonds formed between oxygen atoms from DMSO and the thione group. 5pF-BTT crystallizes in the mono-clinic space group P21/c with Z = 4 and cell parameters a = 4.9161(4) A, b = 19.9008(17) A, c = 10.4934(9) A and b = 92.90(2)�; thesemolecules form a wave-like arrangement along the c axis, with direct intermolecular hydrogen bonds (HBs).

The lowest energy optimized geometries of the investigated compounds in gas-phase correspond to thionic tautomers and they areconsistent with those obtained by X-ray technique. Tautomeric equilibrium between the thione, thiol and enol forms of the two com-pounds have been considered and analyzed by theoretical methods. While crystal structures correspond to the thione forms, the inves-tigated compounds show thione–thiol tautomerism in DMSO solution, this conclusion being supported by theoretical results obtained byusing the PCM solvation model. On the other hand, the continuum PCM solvation model fails to describe the experimental chemicalshift associated with the NH proton in the thione form of the two compounds, but a very good correlation between experiment and the-ory was obtained by taking into account the specific solute–solvent interactions.� 2007 Elsevier B.V. All rights reserved.

Keywords: Thiazolidine-2-thione-4-one; X-ray diffraction; NMR; DFT calculations; Tautomers

1. Introduction

Oxazolidinones have attracted great attention as a newclass of active synthetic antibiotics with a unique mecha-nism of bacterial protein synthesis inhibition [1,2]. Linezo-lid is one compound from this class that exhibits a broadspectrum of antibacterial activity but it exhibits also

0166-1280/$ - see front matter � 2007 Elsevier B.V. All rights reserved.

doi:10.1016/j.theochem.2007.10.041

* Corresponding author. Tel.: +40 264 405300; fax: +40 264 591906.E-mail address: [email protected] (V. Chis�).

1 Present address: National Institute for Research and Development ofIsotopic and Molecular Technologies, 71-103 Donath Str., P.O. Box 700,RO-400293 Cluj-Napoca, Romania.

adverse effects as the inhibition of monoamine oxidaseand myelosuppression. For this reason, and in the develop-ment’s context of the bacterial resistance’s phenomenonagainst the frequently used antibiotics, new heterocyclecompounds which contain in their structure a series ofstructural units similar to those of Linezolid are proposedand used to discover new antimicrobial leads. In this con-nection, thiazolidines derivatives have been obtained byreplacing the oxygen atom of the oxazolidinone ring witha bulkier sulfur atom [3,4]. Antimicrobial data of thiazoli-dine-4-ones against some mycotoxigenic and bacterial iso-lates indicate a moderate to strong inhibitory activitycompared to streptomicin and nystatin [5].

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Table 1Crystal data and structure refinement for 5pBr-BTTÆDMSO and 5pF-BTT

5pBr-BTTÆDMSO 5pF-BTT

Empirical formula C12H12BrNO2S3 C10H6FNOS2

Formula weight 378.32 239.28Temperature (K) 297(2) 297(2)Wavelength (A) 0.71073 0.71073Crystal system Triclinic MonoclinicSpace group P�1 P21/ca (A) 4.4597(7) 4.9161(4)b (A) 12.5508(19) 19.9008(17)c (A) 13.727(2) 10.4934(9)a (deg) 90.751(2) 90.0b (deg) 96.230(2) 92.901(2)c (deg) 97.865(3) 90.0Volume (A3) 756.3(2) 1025.30(15)Z 2 4Calculated density (g/cm3) 1.661 1.550Absorption coefficient (mm�1) 3.127 0.502F(000) 380 488Crystal size (mm) 0.26 · 0.24 · 0.20 0.32 · 0.11 · 0.06h range for data collection (deg) 1.49–26.37 2.05–26.37Limiting indices �5 6 h 6 5 �6 6 h 6 6

�15 6 k 6 15 �24 6 k624�17 6 l 6 17 �13 6 l 6 12

Reflection collected/unique 8161/3077 8112/2091[R(int) = 0.0322] [R(int) = 0.0398]

Completeness to h 99.3 100.0Refinement method Full-matrix least-squares on F2

Data/restrains/parameters 3077/1/178 2091/1/140Goodness-of-fit on F2 1.058 1.195Final R indices [I > 2r(I)] R1 = 0.0448, R1 = 0.0581,

wR2 = 0.1143 wR2 = 0.1175R indices (all data) R1 = 0.0526, R1 = 0.0666,

wR2 = 0.1190 wR2 = 0.1213Largest diff. peak and hole (e A�3) 1.244 and �0.535 0.355 and �0.272

64 V. Chis� et al. / Journal of Molecular Structure: THEOCHEM 851 (2008) 63–74

X-ray diffraction technique is widely applied to provideinformation in the structure-based drug design approachesduring drug discovery stages [6], thus helping in the designof physically and biopharmaceutically relevant crystallinematerials. However, in order to maximize its potential forsuccess, it is very important to couple this technique withquantum chemical calculations [7].

The two thiazolidine-2-thione-4-one derivatives, 5-para-bromo-benzylidene-thiazolidine-2-thione-4-one (5pBr-BTT)and 5-para-fluoro-benzylidene-thiazolidine-2-thione-4-one(5pF-BTT) have been synthesized according to Scheme 1and were then tested against the b-hemolytic streptococcusby minimum inhibitory concentration (MIC) determina-tion, being shown as having a superior activity than amp-icilin used as a reference standard, against this bacteria(MIC < 50 lg/ml) [8]. For these reasons, we become inter-ested in the molecular and electronic structure of thiazoli-dine-4-ones derivatives as potent antimicrobial agents.For this purpose we used X-ray diffraction and NMR tech-niques coupled with quantum chemical calculations per-formed in the framework of DFT approach by using thehybrid B3LYP exchange-correlation functional [9,10]. Thisfunctional in combination with the Pople’s group splitvalence basis sets [11] has been previously shown [12–20]to provide an excellent compromise between accuracyand computational efficiency of molecular structures andvibrational and NMR spectra, for large and medium-sizemolecules.

The experimental and theoretical vibrational spectra ofthe two compounds have been previously reported [8],but for a better understanding of different binding modesof these compounds, their preferred conformations in solidand liquid-phase have to be known [21].

2. Experimental

X-ray diffraction measurements were performed on aBruker Smart Apex CCD diffractometer at 297 K. Theintensity data were collected using graphite monochromat-ed Mo-Ka radiation (k = 0.71073 A). The structures weresolved by direct methods using the SHELX-97 softwarepackage [22] and refined by full-matrix least-squares proce-dures on F2. All non-hydrogen atoms were refined withanisotropic thermal parameters. All C-bound H atoms wereplaced in calculated positions (CAH = 0.93–0.97 A) andtreated using a riding model with Uiso = 1.5 Ueq (C) for

Scheme 1.

methyl (from DMSO) and Uiso = 1.2 Ueq (C) for aryl Hatoms; the methyl groups were allowed to rotate but notto tip. Hydrogen atom bonded to nitrogen was calculatedand fixed at the standard NAH distance of 0.85(2) A, bothfor 5pBr-BTTÆDMSO and 5pF-BTT. The drawings werecreated using the Diamond program by Crystal ImpactGbR [23]. The crystal data, further details of the experimen-tal conditions and the structure refinement parameters for5pBr-BTTÆDMSO and 5pF-BTT are given in Table 1.

Crystallographic data for the structures reported in thispaper have been deposited with the Cambridge Crystallo-graphic Data Centre as Supplementary Publication CCDCNos. 635824 and 635825.

The 1H NMR spectra were recorded at room tempera-ture on a Bruker Avance NMR spectrometer operating at400.13 MHz and tetramethylsilane (TMS) was used asinternal standard. The samples were prepared by dissolvingthe synthesized powder of the two derivatives in DMSO-d6

(dH = 2.51 ppm).

3. Computational details

The molecular geometry optimizations and NMR spec-tra calculations were performed with the Gaussian 98W

V. Chis� et al. / Journal of Molecular Structure: THEOCHEM 851 (2008) 63–74 65

software package [24] by using DFT methods with B3LYPhybrid exchange-correlation functional [9,10], which havebeen previously shown to perform very well both for geom-etry optimizations and NMR spectra calculations [12–14,25–27]. The 6-31+G(d,p) basis set was used for calcula-tions on the gas-phase tautomers of the two BTT deriva-tives. The relative energies were calculated from absoluteenergies corrected to the zero-point vibrational energies(ZPVE).

Two models have been used for assessing the influenceof the solvent on the molecular and electronic structureof the two investigated compounds. The first is the polariz-able continuum model (PCM) [28,29], with water andDMSO as solvents (UAHF radii were used to obtainmolecular cavity, as implemented in the Gaussian 98Wpackage). Due to the large amount of CPU time requiredfor these calculations, the 6-31G(d) basis set was used forthis purpose. Molecular clusters, as microscopic modelfor the environment, have also been used by placing oneor two DMSO molecules near the NH group of the twocompounds or by calculations performed on 5pF-BTTdimer, the calculations being performed at B3LYP/6-31+G(d,p) level of theory. The starting geometries werethose found by X-ray technique.

Partial atomic charges were calculated at B3LYP/6-31G(d) level of theory, based on Natural Population Anal-ysis scheme.

Shielding tensors of the two derivatives were evaluatedby using the GIAO (Gauge-Including Atomic Orbitals)formalism [30,31], implemented in the Gaussian package,with the B3LYP functional, in conjunction with the basisset given above. In order to express the chemical shifts inppm, the geometry of the tetramethylsilane (TMS) mole-cule had been optimized and then its NMR spectrum wascalculated by using the same method and basis set as inthe case of the calculations on thiazolidine derivatives.The calculated isotropic shielding constants ri were thentransformed to chemical shifts relative to TMS bydi = rTMS � ri.

Fig. 1. ORTEP diagrams of 5pBr-BTTÆDMSO (a) and 5pF-B

4. Results and discussions

4.1. Solid-state structures

The crystal and molecular structures of 5pBr-BTTÆDMSO and 5pF-BTT (see Fig. 1 for ORTEP dia-grams and atom numbering schemes), were determinedby single-crystal X-ray diffraction technique. Suitable crys-tals for X-ray diffraction analysis were grown by recrystal-lization from hot DMSO-d6 for both compounds. 5pBr-BTT crystallizes with one DMSO solvent molecule in thetriclinic space group P�1 with Z = 2 and cell parametersa = 4.4597 A, b = 12.5508 A, c = 13.7270 A, a = 90.75�,b = 96.23� and c = 97.86�. 5pF-BTT crystallizes in themonoclinic space group P21/c with Z = 4 and cell parame-ters a = 4.9161 A, b = 19.9008 A, c = 10.4934 A andb = 92.90�.

In solid state, two 5pBr-BTT molecules together withtwo solvent molecules form dimers through H-bondingbetween the oxygen atoms from DMSO molecules andthe thione group from 5pBr-BTT (Fig. 2a); these dimersare stacked along the crystallographic a axis (Fig. 2b). Inthis case, hydrogen bond lengths O(25)ÆÆÆH(7) andO(8)ÆÆÆH(23A) are 1.962 A and 2.524 A, respectively.5pF-BTT molecules form dimers through double directO(8)ÆÆÆH(7) 0 hydrogen bonds whose lengths are 1.994 A(Fig. 31). The dimers are stacked along a axis andthey form a wave-like arrangement along the c axis (seeFig. 3b).

Experimental bond lengths and angles of the two com-pounds are given in Table 2 along with their theoreticalcounterparts obtained by geometry optimizations atB3LYP/6-31+G(d,p) level of theory. Molecular structuresof the compounds with the atom numbering schemes areshown in Fig. 1.

The starting geometries for DFT calculations were con-structed based on crystallographic data and the obtainedoptimized geometries were checked as minima on thepotential energy surfaces by frequency calculations.

TT (b) with thermal ellipsoids at 50% probability level.

Fig. 2. (a) Hydrogen bonding pattern of 5pBr-BTTÆDMSO; (b) crystal packing of 5pBr-BTTÆDMSO.

Fig. 3. (a) Hydrogen bonding pattern of 5pF-BTT; (b) crystal packing of 5pF-BTT.


In solid state, benzilidene ring with its substituents (Brand F) and thiazolidine ring posses an extended configura-

tion with the dihedral angle between the two ring planes of4.0� and 3.8�, for 5pBr-BTT and 5pF-BTT, respectively.

Table 2Experimental and B3LYP/6-31+G(d,p) calculated geometrical parameters of 5pBr-BTTÆDMSO complex and 5pF-BTT (see Fig. 1 for atom numberingschemes)

X-ray Calculated

5pBr-BTTÆDMSO 5pF-BTT 5pBr-BTTÆ2DMSO 5pF-BTT dimer

Bond lengths (A)

S(1)AC(2) 1.747(3) 1.748(3) 1.788 1.783S(1)AC(5) 1.741(3) 1.755(3) 1.767 1.771C(2)AN(3) 1.351(4) 1.366(4) 1.364 1.372C(2)AS(6) 1.628(3) 1.626(3) 1.646 1.641N(3)AC(4) 1.378(4) 1.374(4) 1.389 1.383C(4)AC(5) 1.487(4) 1.482(4) 1.493 1.484C(4)AO(8) 1.209(4) 1.221(3) 1.225 1.231C(5)AC(9) 1.342(5) 1.336(4) 1.354 1.356C(9)AC(11) 1.455(5) 1.452(4) 1.454 1.453C(11)AC(12) 1.398(5) 1.396(4) 1.412 1.414C(11)AC(16) 1.382(5) 1.395(4) 1.411 1.413C(12)AC(13) 1.368(5) 1.381(4) 1.391 1.391C(13)AC(14) 1.376(5) 1.364(5) 1.396 1.391C(14)AC(15) 1.369(5) 1.364(5) 1.396 1.392C(14)AX(21) 1.896(3) 1.356(3) 1.904 1.354C(15)AC(16) 1.388(5) 1.376(4) 1.392 1.392N(3)AH(7) 0.853(2) 0.853(2) 1.047 1.032C(9)AH(10) 0.930 0.930 1.089 1.089C(12)AH(17) 0.930 0.930 1.086 1.086C(13)AH(18) 0.930 0.930 1.084 1.084C(15)AH(19) 0.930 0.930 1.084 1.084C(16)AH(20) 0.930 0.930 1.083 1.083

Bond angles (�)

C(2)AS(1)AC(5) 92.5(2) 92.9(1) 92.4 92.5S(1)AC(2)AN(3) 110.6(2) 109.8(2) 109.5 109.0N(3)AC(2)AS(6) 127.0(3) 126.2(2) 127.4 126.8C(2)AN(3)AC(4) 117.6(3) 117.9(2) 118.5 118.7N(3)AC(4)AC(5) 109.9(3) 110.6(2) 110.3 110.5N(3)AC(4)AO(8) 124.5(3) 123.6(3) 123.8 123.7S(1)AC(5)AC(4) 109.4(2) 108.8(2) 109.3 109.3S(1)AC(5)AC(9) 130.5(3) 130.0(2) 130.7 130.7C(5)AC(9)AC(11) 131.1(3) 130.5(3) 131.7 131.7C(9)AC(11)AC(12) 118.0(3) 118.4(3) 117.6 117.4C(9)AC(11)AC(16) 124.2(3) 124.1(3) 124.7 124.7C(11)AC(12)AC(13) 121.9(3) 121.3(3) 121.7 121.7C(12)AC(13)AC(14) 118.8(3) 118.5(3) 119.0 118.2C(13)AC(14)AC(15) 121.3(3) 122.5(3) 121.0 122.4C(13)AC(14)AX(21) 119.6(3) 118.9(3) 119.5 118.8C(14)AC(15)AC(16) 119.3(3) 118.8(3) 119.5 118.7C(11)AC(16)AC(15) 121.0(3) 121.3(3) 121.2 121.1C(2)AN(3)AH(7) 119.0(3) 118.0(2) 122.3 121.7C(5)AC(9)AH(10) 114.4 114.8 112.9 112.9C(11)AC(12)AH(17) 119.1 119.3 119.2 119.1C(12)AC(13)AH(18) 120.6 120.8 120.5 121.8C(14)AC(15)AH(19) 120.4 120.6 120.3 119.8C(11)AC(16)AH(20) 119.5 119.4 120.8 120.8

Dihedral angles (�)

S(1)AC(2)AN(3)AC(4) 0.0(4) �2.5(3) 0.1 0.0S(6)AC(2)AN(3)AC(4) 179.1(3) 178.1(2) 180.0 180.0C(2)AN(3)AC(4)AC(5) 1.2(4) 2.1(4) 0.0 0.0C(2)AN(3)AC(4)AO(8) �179.0(4) �177.2(3) -180.0 �179.9C(2)AS(1)AC(5)AC(4) 1.5(3) �0.5(2) 0.1 �0.1C(2)AS(1)AC(5)AC(9) �177.1(4) �178.5(3) �180.0 �180.0N(3)AC(4)AC(5)AS(1) �1.8(4) �0.7(3) 0.0 0.0O(8)AC(4)AC(5)AS(1) 178.4(3) 178.6(2) 180.0 180.0C(5)AS(1)AC(2)AN(3) �0.9(3) 1.6(2) �0.1 0.1S(1)AC(5)AC(9)AC(11) 1.1(6) 0.8(5) 0.0 0.0C(5)AC(9)AC(11)AC(12) 177.1(4) �179.6(3) 180.0 �180.0

(continued on next page)


Table 2 (continued)

X-ray Calculated

5pBr-BTTÆDMSO 5pF-BTT 5pBr-BTTÆ2DMSO 5pF-BTT dimer

C(9)AC(11)AC(12)AC(13) �179.2(4) �178.9(3) �180.0 �180.0C(11)AC(12)AC(13)AC(14) �0.4(6) 0.0(5) 0.0 0.0C(12)AC(13)AC(14)AC(15) �0.2(6) �0.3(6) 0.0 0.0C(12)AC(13)AC(14)AX(21) �179.9(3) �179.7(3) �180.0 �180.0C(13)AC(14)AC(15)AC(16) 0.8(6) 0.0(5) 0.0 0.0C(12)AC(11)AC(16)AC(15) 0.1(6) �0.8(5) 0.0 0.0C(14)AC(15)AC(16)AC(11) �0.7(6) 0.5(5) 0.0 0.0X(21)AC(14)AC(15)AC(16) �179.6(6) 179.4(3) �180.0 180.0S(1)AC(2)AN(3)AH(7) �179.7 178.0 179.0 179.9S(1)AC(5)AC(9)AH(10) �178.9 �179.2 �179.9 �180.0C(16)AC(11)AC(12)AH(17) �179.6 �179.4 �179.9 �180.0C(11)AC(12)AC(13)AH(18) 179.5 �179.9 180.0 �180.0C(13)AC(14)AC(15)AH(19) �179.2 �179.9 �179.9 �180.0C(14)AC(15)AC(16)AH(20) 179.3 �179.4 179.9 �180.0

X = Br, F, respectively.


DFT calculations predict a perfect planar arrangement ofthe two individual gas-phase molecules. However, whenPCM model was used to account for solvation effects, thedihedral angle between the two rings in the case of thionetautomers in DMSO bulk solution was 5.9� and 3.2�, for5pBr-BTT and 5pF-BTT, respectively. As seen in Table2, almost all the calculated bond lengths are longer thantheir experimental counterparts, especially the XAHbonds, where X = C,N. The disagreement observed forthe XAH distances is obviously due to well-known inherentlimitations of the X-ray technique in predicting the hydro-genic positions. On the other hand, these XAH bondlengths fall in the range calculated for other organic com-pounds [32–34]. Thus, for 5pBr-BTT, only theC(9)AC(11) bond length is predicted nearly identical toits value in solid state, while for 5pF-BTT, C(9)AC(11)and C(14)AF(21) bond lengths are almost perfect predictedby calculations. Since the two investigated compoundshave been optimized in gas-phase, the observed discrepan-cies can easily be attributed to the crystal packing effects. Itis worth mentioning that carbon–halogen bond lengths arevery well reproduced by theoretical calculations. Thus,these experimental/theoretical values are 1.896/1.904 Aand 1.356/1.354 A for 5pBr-BTT and 5pF-BTT,respectively.

The medium CC distances in the benzilidene rings of thetwo investigated compounds are almost identical: 1.380 Afor 5pBr-BTT and 1.379 A for 5pF-BTT. For the first com-pound, an alternation of CC bond lengths is observed,while in the case of 5pF-BTT the benzilidene ring has analmost C2 symmetry axis due to very similar values of thebond lengths pairs C(12)AC(11)AC(16) andC(13)AC(14)AC(15). In the thiazolidine rings, the experi-mental bond lengths have similar values for the two com-pounds excepting the C(2)AN(3), S(1)AC(5) andC(4)AO(8) bonds, all of them being shorter in 5pBr-BTT.

To account for intermolecular interactions, 5pBr-BTThas been optimized by placing two DMSO molecules

around its thiazolidine ring, as revealed by X-ray diffrac-tion data. For 5pF-BTT, two models had been consideredfor this purpose: the first is the dimer model, used todescribe the hydrogen bonding in solid state, as indicatedby X-ray diffraction data. The second one is the 5pF-BTTÆ2DMSO complex, used to describe the hydrogenbonding in liquid state because by dissolving this com-pound in DMSO solvent it is likely that dimer interactionspresent in solid state will be replaced by 5pF-BTT–DMSOintermolecular interactions. Since diffuse functions onheavy atoms and polarization functions on hydrogenatoms play a key role when modeling weak interactions likeintermolecular HBs [27,35,36], the 6-31+G(d,p) basis setwas used for these calculations.

As seen in Table 3, excepting the dihedral angles, hydro-gen bonding parameters (DÆÆÆA distance and DHA angle,where D and A are the hydrogen bond donor and acceptoratom, respectively) are very well reproduced by calcula-tions for the two compounds. For 5pF-BTT, theoreticalparameters suggest weaker HBs in the case of dimer thanfor the complex formed with two DMSO molecules. Onthe other hand, H-bonding parameters calculated for5pF-BTT dimer, particularly the OÆÆÆH distance andNAHÆÆÆO angle, are in better agreement with solid-statedata than those provided by 5pF-BTTÆ2DMSO complex.

According to the classification criteria for the strengthof the hydrogen bonds as a function of geometrical param-eters [37,38], our structural data coupled with the H(7)downfield chemical shift (see NMR results) suggest a mod-erate to strong intermolecular hydrogen bonds in thesecompounds. Moreover, both experimental and theoreticaldata suggest slightly stronger HBs for 5pBr-BTT. Besidesthe SAOÆÆÆHAN hydrogen bond, 5pBr-BTT participatesin another non-classical hydrogen interaction of theCAHÆÆÆO type through O(8) atom and one of the methylgroup of DMSO molecule, with hydrogen bonding param-eters also given in Table 2. This kind of HBs has beenrecently investigated in detail by Jensen et al. [35] and its

Table 3Experimental and B3LYP/6-31+G(d,p) calculated hydrogen bondingparameters for 5pBr-BTTÆDMSO and 5pF-BTT (see Fig. 2a and Fig. 3afor atom numbering schemes)

5pBr-BTTÆDMSO X-ray Calculated (5pBr-BTTÆ2DMSOcomplex)

Bond lengths (A)

N(3)AH(7) 0.853 1.047N(3)ÆÆÆO(25) 2.792 2.758O(25)ÆÆÆH(7) 1.962 1.716C(23)ÆÆÆO(8) 3.396 3.360O(8)ÆÆÆH(23A) 2.524 2.376

Bond angles (�)

N(3)AH(7)AO(25) 163.8 173.1C(23)AH(23A)AO(8) 151.0 149.1

Dihedral angles (�)

C(2)AN(3)AH(7)AO(25) �139.6 �164.2N(3)AH(7)AO(25)AS(24) �97.0 �40.4S(24)AC(23)AH(23A)AO(8) 38.7 14.7C(4)AO(8)AH(23A)AC(23) �24.8 43.1

5pF-BTT X-ray Calculated (5pF-BTT dimer)

Bond lengths (A)

N(3)AH(7) 0.853 1.032N(3)ÆÆÆO(8)0 2.831 2.859O(8)0ÆÆÆH(7) 1.994 1.845

Bond angles (�)

N(3)AH(7)AO(8)0 167.3 166.9C(4)AN(3)AH(7) 123.1 119.5

Torsion angles (�)

N(3)AH(7)AO(8)0AC(4) 0 10.6 7.8


geometrical parameters suggest that it is significantlyweaker than SAOÆÆÆHAN hydrogen bond. As seen in Table3, the AÆÆÆD and AÆÆÆH distances are indeed larger forCAHÆÆÆO HB than for NAHÆÆÆO HB in 5pBr-BTT.

Mulliken charges are strongly basis set dependent[69,70]. They can give reasonable results only if well-bal-anced basis sets like 6-31G(d) is used but may lead to com-pletely bad results for basis sets including diffuse functions[71]. Thus, in order to obtain reliable atomic charges, theNatural Population Analysis (NPA) scheme [72] was usedat B3LYP/6-31G(d) level of theory.

Partial atomic charges have been obtained for the twoindividual molecules as well as for the two 5pX-BTTÆ2DMSO complexes (X = Br, F) and for 5pF-BTTdimer. These quantities are useful in deriving or refiningnew force fields [39,40], in the development of inductivereactivity indices as a novel and effective class of QSARdescriptors [41] or as local molecular parameters used forthe site reactivity analysis [42]. Moreover, it is acceptedthat these formal charges and the electron density distribu-tion in different functional groups of a given compoundgreatly influences its biological activity [43–46].

Comparing the two compounds, a change in sign of par-tial atomic charge is noted for C(14) atom, its chargechanging from negative (�0.101e) in the 5pBr-BTT com-pound to positive (+0.443e) in 5pF-BTT, due to a charge

re-equilibration as a result of the substituent electronega-tivity. The greater electronegativity of the F atom is alsoreflected in its negative partial charge of �0.324e, whilethe Br atom in 5pBr-BTT has a positive partial charge of+0.082e. Other less significant changes in partial chargesare noted for C(13) and C(15) atoms whose values arechanging from �0.246e and �0.240e to �0.301e to�0.296e, respectively, when going from Br to F substitutedbenzilidene ring. It is worth mentioning that all the atomsin the thiazolidine rings of the two compounds are practi-cally not affected by Br fi F substitution. Moreover, theC@O, NAH and C@S groups have very similar chargesin the two compounds, their values for 5pBr-BTT/5pF-BTT being +0.112e/+0.107e, �0.166e/�0.168e and�0.197e/�0.199e, respectively, leading to the conclusionthat the influence exerted by the halogen substituent isrestricted to the benzilidene rings.

According to calculations, no important variations inpartial charges are observed when going from the individ-ual 5pX-BTT (X = Br, F) molecules to their H-bondedcomplexes with 2DMSO molecules. In addition, the influ-ence of the solvent molecules is only restricted to the thia-zolidine rings. Thus, S(1) and O(8) atoms become morenegative by 0.018e and 0.04e, respectively, in complexes,while C(2), and H(7) become more positive by 0.02e, forboth compounds. Again, very similar partial atomiccharges are obtained for 5pF-BTTÆ2DMSO complex and5pF-BTT dimer. The only notable difference is seen forS(6) atom whose charge is calculated �0.061e in complexand �0.022e in dimer.

4.2. Relative stability of the three tautomers

First, we will discuss the relative stability of the threepossible tautomeric forms (thione, thiol and enol) in vacuoand in water and DMSO solution. For this purpose theyhave been optimized without any constraint at B3LYPlevel of theory with 6-31G(d) basis set in gas-phase andby using the SCRF-PCM solvation model. No imaginaryfrequencies were obtained for optimized geometries andthus, all structures represent true minima on the potentialenergy surface. According to calculations, in gas-phase,but also in the two solutions, the lowest energy tautomeris in thionic form for both compounds (see Table 4). Thetwo possible thiolic tautomers that differ in the relative ori-entation of SH bond are less stable in gas-phase by about15.0 kcal/mol and the two enolic forms are less stable byabout 15.8 kcal/mol (ZPVE correction included). However,the 6-31+G(d,p) basis set predicts the gas-phase enol tau-tomers slightly more stable than thiolic forms by 0.5 and0.7 kcal/mol, respectively, for the two compounds. The thi-olic tautomers are predicted only 0.35 kcal/mol more stableby this basis set with respect to 6-31G(d). Despite therather large energy difference between the thione and thiolforms, as also reported in other studies [47–51], contribu-tions from thiolic tautomers can not be excluded inliquid-phase [52–56] and this was indeed observed in our

Table 4Relative energies including ZPVE correction (in kcal/mol, first row) anddipole moments (in Debye, second row), calculated at B3LYP/6-31G(d)level of theory for the three tautomers of 5pX-BTT (X-Br, F) in vacuo,water and DMSO solution

Solvent Thione Thiol Enol

5pBr-BTT Vacuo 0.00 14.96 15.802.63 2.41 5.39

Water �17.61 18.29 6.492.81 3.25 9.07

DMSO �4.27 3.13 11.633.36 3.54 7.81

5pF-BTT Vacuo 0.00 15.07 15.802.56 2.69 5.78

Water �12.73 9.92 �0.795.22 3.94 10.51

DMSO �3.72 3.37 11.304.09 4.01 8.37


NMR spectra of the two compounds (see bellow). How-ever, no experimental evidence for enol tautomers exists,even if in gas-phase they are comparable in energy withthe thiolic ones [57,58].

The thione–thiol tautomeric equilibrium has a signifi-cant importance in biochemistry and it has attracted both,experimental and theoretical interest, different tautomers insolid and liquid-phase being commonly reported [18,49–60]. For our compounds, the presence of thiol tautomersin both syn and anti conformers can be supposed becausethe barrier to rotation amounts to 0.96 kcal/mol atB3LYP/6-31G(d) level of theory, both for 5pBr-BTT and5pF-BTT in gas-phase.

PCM model has been used to analyze the non-specificsolvent effects on the geometric and energetic parametersfor the three tautomers and their calculated relative ener-gies in vacuo and in water and DMSO bulk solutions aregiven in Table 4. The energies in this table are given relativeto the gas-phase thione tautomers’ energies.

In liquid-phase, the two tautomeric forms (thione andthiol) can convert into each other by a direct proton trans-fer mechanism, a similar case with that reported by Delaereand coworkers [59]. However, a solvent assisted protontransfer reaction [61] is also plausible due to the fact thatNH donor and C@S acceptor H-bonding sites are availablefor stable complexes formation which are predicted togreatly decrease the energy barrier height [51].

For 5pBr-BTT, the C(2)AN(3) bond length decreasesfrom 1.370 to 1.285 A, while the N(3)AC(4) andC(2)AS(6) distances increases from 1.398 and 1.642 A to1.414 and 1.753 A, respectively, in going from thione tothiol form. For thione–enol proton transfer, the mostimportant changes are noted for N(3)AC(4) andC(4)AO(8) bonds which are becoming 0.097 A shorterand 0.118 A longer, respectively, for the enol tautomer.

The S(1)C(2)N(3) and C(2)N(3)C(4) bond angles arechanged from 108.7� and 119.6� to 118.5� and 111.8�,respectively, when going from thione to thiol tautomer,while for thione–enol tautomerism the most important

changes in bond angles are noted for C(2)N(3)C(4) andN(3)C(4)C(5), from 119.6� and 109.1� to 112.4� and119.6�, respectively. Very similar structural changes arenoted also for 5pF-BTT.

As seen in Table 4, thione–thiol tautomeric equilibriumstrongly depends on the investigated system and its envi-ronment. Thus, the dipole moments of the thione and thiolforms for 5pBr-BTT are similar in vacuo and remain com-parable in water and DMSO (see Table 3). However, whilesmaller in gas-phase, the dipole moment of thiol tautomerbecomes greater by 0.44 D in water solution and furtherincreases in DMSO, remaining 0.18 D greater than thatcorresponding to thione form. On the other hand, thedipole moment of the enol form increases from 5.39 D to9.07 D when going from vacuo to water solution and thendecreases to 7.81 D in DMSO.

Quite similar, for 5pF-BTT, the dipole moment of theenol form increases from 5.78 D in vacuo to 10.51 D inwater and then decreases to 8.37 D in DMSO. However,contrary to 5pBr-BTT, the thione tautomer has largerdipole moment in water than the thiol form (5.22 D com-pared to 3.94 D).

As seen in Table 4, the water and DMSO bulk solutionsstabilize the thione tautomers for both compounds, the sta-bilization energy being however much less important inDMSO. It is evident that DMSO bulk solution stronglystabilizes the thiol tautomer relative to the thione form.Thus, for 5pBr-BTT, the thiol tautomer is less stable thanthione tautomer by only 7.4 kcal/mol, while in water, thecorresponding energetic difference is 35.9 kcal/mol. Con-versely, with respect to thione tautomer, the enol form isless stable by 24.1 kcal/mol in water and by 15.9 kcal/molin DMSO. Moreover, the reduction in the relative energiesof thiolic forms of the two compounds is due to a dramaticincrease of the energy of thione tautomers in DMSO, withrespect to water, accompanied by a significant reduction ofthe thiol energy.

This energetic overall picture is also valid for 5pF-BTTcompound. In this case, the thiol and enol tautomers areless stable than thione form by 7.09 kcal/mol and15.02 kcal/mol in DMSO and by 22.65 and 11.94 kcal/mol in water bulk solution. These theoretical results leadto the conclusion that in DMSO solution, thiazolidine ringexists in thione–thiol equilibrium due to the mobility of theNH proton and they are in perfect agreement with the fol-lowing NMR results. Similar effects were observed forsome oxadiazole, triazole and triazine derivatives [48,50].

4.3. 1H NMR spectra

Besides X-ray crystallography, NMR spectroscopy canprovide the required structural data for the investigatedcompounds [62–64]. Particularly, by NMR dilution studiesone can identify multiple conformations and tautomersand investigate the intermolecular hydrogen bonding.

The 1H NMR measurements on the two investigatedcompounds were made on liquid-state samples, using

Fig. 4. 1H NMR spectra of 5pBr-BTT (top) and 5pF-BTT (bottom); inset: 1H NMR spectrum of DMSO solvent.


DMSO-d6 as deuterated solvent and the correspondingexperimental spectra are given in Fig. 4. It is worth men-tioning that liquid samples were prepared starting fromthe powders obtained from synthesis and not from singlecrystals that, for 5pBr-BTT already contain the crystalliza-tion DMSO molecules. Also, for the following discussion itis important to note that the water contaminant in this sol-vent gives a residual peak at about 3.30 ppm [65]; this peakis clearly observed in our NMR spectra of the pure solvent(see inset of Fig. 4).

The benzilidene ring protons (H(17), H(18), H(19) andH(20)) (see Fig. 1 for atom numbering schemes) areexpected to give rise to NMR signals in the 7–8 ppm range.For 5pBr-BTT, their peaks appear clearly resolved inFig. 4; thus, the peak at 7.61 ppm is assigned to theH(10) proton, while the two doublets centered at 7.73and 7.53 ppm are assigned to the two pairs of protonsH(18)AH(19) and H(17)AH(20), respectively, the values

of peak integrals nicely reproducing the number of protonsin each group. The calculated chemical shifts for the threetautomers of 5pBr-BTT are given in Table 5, along withtheir experimental counterparts.

The proton bonded to nitrogen atom in the thione con-former usually gives signals in 7–8 ppm range. When such aproton migrates to the nearby sulfur atom via an intramo-lecular transfer, it becomes much more shielded and itschemical shift falls in a significantly lower range [66]. Onthe other hand, when hydrogen atoms are involved inhydrogen bonds, depending on the particular type of inter-actions, their protons are significantly more deshielded[61,67,68]. Thus, in order to make a reliable assignmentfor H(7) proton, we shall consider the coexistence of twotautomers, the thione tautomer with the proton bondedto nitrogen N(3) atom and involved in a hydrogen bondwith the oxygen atom from a DMSO solvent molecule,and the thiol tautomer.

Table 51H experimental and theoretical chemical shifts of 5pBr-BTT (ppm)

Nucleus Calculated (B3LYP/6-31+G(d,p)) Experimental

Thione isolatedmolecule

Thione in water/DMSO solvent

Thiol isolatedmolecule

Enol isolatedmolecule

5pBr-BTTÆ2DMSO

H7 8.08 8.53/8.69 4.02 6.48 14.14 3.38; 13.86H10 7.55 7.59/7.57 7.91 7.34 7.37 7.61H17, H20 7.46 7.50/7.52 7.48 7.44 7.38 7.53H18, H19 7.73 7.90/7.81 7.72 7.73 7.69 7.73

Table 61H experimental and theoretical chemical shifts of 5pF-BTT (ppm)

Nucleus Calculated (B3LYP/6-31+G(d,p)) Experimental

Thione isolatedmolecule

Thione in water/DMSO solvent

Thiol isolatedmolecule

Enol isolatedmolecule

5pF-BTTÆ2DMSO

5pF-BTT dimer

H7 7.98 8.67/8.66 4.05 6.43 13.94 12.47 3.37; 13.88H10 7.71 7.53/7.53 7.93 7.34 7.45 7.36 7.67H17,H20 7.62 7.67/7.66 7.57 7.59 7.56 7.67 7.69H18,H19 7.32 7.47/7.48 7.35 7.33 7.34 7.35 7.40


Besides the discrete models used to account for the inter-action with solvent molecules, the continuum solventSCRF-PCM solvation model was also tested in order todescribe the influence exerted by solvent on the 1H NMRspectra of the two compounds. As seen in Tables 5 and6, excepting the H7 proton, the SCRF-PCM model withwater or DMSO solvents give the chemical shifts in verygood agreement with the experiment, with minor differ-ences relative to the isolated thione conformer. On theother hand, this model, irrespective of the solvent used,gives larger chemical shifts for H7 protons than in the caseof isolated molecules, for both compounds. However, thetheoretical chemical shift associated with the H(7) protonstill remain unacceptable apart from the experimental val-ues, being obviously that chemical shifts associated withthis proton are not correctly described by continuummodel. Thus, it is clear that continuum model fails inreproducing the experimental findings for the hydrogen-bonded H(7) proton and specific solute–solvent interac-tions are expected to completely explain the NMR spectraof the two compounds. For this purpose, we optimized andthen calculated the NMR spectrum of the 5pBr-BTT mol-ecule with two DMSO molecules, the starting geometry ofthe complex being obtained from X-ray diffraction data. Asseen in Table 5, the chemical shift at 13.86 ppm in the 1HNMR spectrum of 5pBr-BTT is assigned to the hydro-gen-bonded proton of the thione conformer, while the sig-nal at 3.38 ppm is assigned to the proton bound to S(6)atom in the thiol conformer [66] (superimposed on the peakdue to the residual water from solvent). Theoretical spec-trum is in very good agreement with experimental data:thus, the thione tautomers having the lowest energy havethe closest chemical shifts to the experimental ones. Theo-retical chemical shift for hydrogen-bonded H(7) proton is14.14 ppm, in very good agreement with experiment. On

the other hand, the SH proton in the thiolic tautomer hasa calculated chemical shift of 4.02 ppm, in good agreementwith the experimental value of 3.38 ppm. It is worth men-tioning that the 6-31G(d) gives a value of 3.50 ppm forthe chemical shift associated with this proton, in perfectagreement with experiment and most probably, the bettermatch in the case of this less flexible basis set is due to afortuitous cancellation of errors.

1H NMR spectrum of 5pF-BTT (Fig. 4 bottom) can besafely assigned by a similar analysis. For this compound,the H(18) and H(19) protons are more shielded than inthe case of 5pBr-BTT (see Fig. 4 and Table 6). Their peakappears as a triplet with the intensities ratio 1:2:1 at7.40 ppm, while the peak assigned to H(10) proton is super-imposed on the doublets at lower field, attributed to theH(17)AH(20) pair of protons centered at 7.69 ppm.

NMR spectra of 5pF-BTT were calculated on the gas-phase optimized geometries of the individual tautomersand also, by using the dimer and 5pF-BTTÆ2DMSO com-plex models, the results being collected in Table 6. Asrevealed by the chemical shift associated to H(7) proton,hydrogen bonding interaction of this compound, is betterreproduced by the second model and this fact suggest thatin liquid state, dimer interactions are replaced by 5pF-BTT–DMSO interactions.

The broad signal at 13.88 ppm is assigned to the hydro-gen-bonded H(7) proton in the thione conformer, while thecontribution to the signal at 3.37 ppm is again assigned tothe thiol tautomer [66]. These experimental values are verywell reproduced by theory which gives 13.94 ppm for thechemical shift corresponding to H7 proton in the hydro-gen-bonded thione conformer of 5pF-BTTÆ2DMSO com-plex and 4.05 ppm for the chemical shift associated to theproton in the thiol group. Again, the 6-31G(d) basis setpredicts a lower chemical shift (3.39 ppm) associated with


this proton, in much better agreement with the experimen-tal value. Thus, the discrete model is very useful forexplaining the chemical shifts related to the protoninvolved in intermolecular hydrogen bond interactions.

As shown in Table 4, the energetic difference betweenthe thionic and thiolic tautomers is reduced from14.96 kcal/mol in gas-phase to only 7.40 kcal/mol inDMSO.

The calculated relative energies of the three gas-phasetautomers are slightly depending on the basis set used.Thus, they varies less than 2 kcal/mol between the 6-31G(d) and 6-31+G(d,p) basis sets. However, other studiesreported large variations in the relative energies of differenttautomers, depending on the method and basis set used incalculations [49,56,73–75].

Similar relative energies were obtained by Cramer andTruhlar who studied the tautomeric equilibrium betweenthe hydroxy and oxo forms of 5-hydroxyisoxazoles [73].As reported by these authors, including both bulk electricpolarization and first-hydration effects is expected to givemore accurate relative energies of the tautomers. Contrerasand Alderete reported also tautomeric thione–thiol conver-sion between solid and gas-phase states for 2-thiopyrimi-dine [74] with similar (5.81 kcal/mol) relative energybetween the two tautomers, in favor of the thiolic one.

Tautomeric forms of 2-thiouracil in gas-phase and indifferent solvents were studied by Yekeler [75] and again,similar calculated relative energies between tautomers werereported.

5. Conclusions

Crystal structures of the 5pBr-BTTÆDMSO and 5pF-BTT have been determined by X-ray diffraction technique.Molecular structures and relative energies of the three pos-sible tautomers of the two compounds have been investi-gated in detail by DFT calculations and for bothmolecules, we found that the thione tautomer is the moststable in gas-phase, but also in water and DMSO solution.However, as revealed by NMR experiments coupled withtheoretical calculations, in deuterated DMSO-d6 solutionboth, the thionic and thiolic tautomers coexist; in this apro-tic solvent, the energetic difference between thionic and thi-olic forms is reduced to 7.4 kcal/mol, from 14.9 kcal/mol invacuo and 35.9 kcal/mol in water.

The influence exerted by the halogen substituents (Br orF atoms) on the partial atomic charges is restricted to thebenzilidene rings, the most affected being the C(14) atomsin these rings. The hydrogen-bonded solvent DMSO mole-cules exert a very minor influence on the thiazolidine rings.

As the chemical shift assigned to H(7) proton of 5pF-BTT are better reproduced in the case of its DMSO com-plex than for its dimer, theoretical calculations suggest thatdimer type interactions of 5pF-BTT in solid state arereplaced by direct solute–solvent interactions in liquid-phase. In addition, the specific solute–solvent interactionsmust be considered for a proper and reliable description

of the influence of solvent on the chemical shifts associatedwith hydrogen-bonded systems.

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x-ray, 1h nmr and dft study on 5-para-x-benzylidene-thiazolidine derivatives with x = br, f

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