Mol DiversDOI 10.1007/s11030-009-9202-4

FULL-LENGTH PAPER

Structural relationships in the solid state of the anti-chagas agent(E)-phenylethenylbenzofuroxan

Felipe Terra Martins · Alejandro Pedro Ayala ·Williams Porcal · Hugo Cerecetto ·Mercedes González · Javier Ellena

Received: 30 March 2009 / Accepted: 19 October 2009© Springer Science+Business Media B.V. 2009

Abstract The crystal structure and the vibrationalspectrum of a potential drug for Chagas‘s disease treatment,the (E)-isomer of phenylethenylbenzofuroxan 1 (5(6)(E)-[(2-phenylethenyl)]benzo[1,2-c]1,2,5-oxadiazole N -oxide),are reported. In order to provide insights into structural rela-tionships, quantum mechanical calculations were employedstarting from crystal structure. These results have given the-oretical support to state interesting structural features, suchas the effect of some intermolecular contacts on the moleculeconformation and the electronic delocalization decreas-ing through atoms of the benzofuroxan moiety. Further-more, the MOGUL comparative analysis in the CambridgeStructural Database provided additional evidences on thesestructural behaviors of compound 1. Intermolecular contactsinterfere on the intramolecular geometry, as, for instance, onthe phenyl group orientation, which is twisted by 12.32(6)◦from the ethenylbenzofuroxan plane. The experimental Ra-man spectrum of compound 1 presents unexpected frequencyshift and also anomalous Raman activities. At last, the mol-ecule skeleton deformation and the characteristic vibrationalmodes were correlated by matching the experimental Ramanspectrum to the calculated one.

F. T. Martins · J. Ellena (B)Instituto de Física de São Carlos, Universidade de São Paulo, CP 369,Sao Carlos, 13560-970 SP, Brazile-mail: javiere@ifsc.usp.br

A. P. AyalaDepartamento de Física, Universidade Federal do Ceará, CP 6030,Fortaleza, 60455-760 CE, Brazil

W. Porcal · H. Cerecetto · M. GonzálezDepartamento de Química Orgânica, Facultad de Ciencias-Facultad deQuímica, Universidad de la República, Iguá 4225, 11400 Montevideo,Uruguay

Keywords Benzofuroxan derivative · Crystal structure ·FT-Raman · Geometry optimization · Mesomeric effect ·Antichagasic drug

Introduction

Chagas’s disease was described for the first time in 1909by a Brazilian physician, the infectologist Carlos Chagas.This parasitic disease, also known as American trypano-somiasis, is caused by a protozoan of the Trypanosomat-idae family, the Trypanosoma cruzi, which was named inhonor to Oswaldo Cruz, a noted Brazilian epidemiologist(http://www.who.int/ctd/chagas). Recent data of WorldHealth Organization (WHO) show that 16–18 million per-sons are infected by T. cruzi and 100 million are at regionsof risk, mainly in tropical countries. In Brazil, 6 million indi-viduals are sickened with Chagas’ disease (http://www.who.int/ctd/chagas). This parasitosis presents two main phases, ararely symptomatic acute one and another chronic stage thatalters the life course of the patients [1].

Although the American trypanosomiasis was reported atthe beginning of twentieth century, significant advances forits treatment have occurred recently. For instance, benzof-uroxan (benzo[1,2-c]-1,2,5-oxadiazole N -oxide) derivativeshave emerged as promising chemotherapeutic agents againstT. cruzi [2]. These compounds are less cytotoxic to humanmacrophages than other drugs clinically used in antichagasictherapy, such as Nifurtimox and Benznidazole. These activepharmaceutical ingredients manifest undesirable side effectsdue to their unspecific activities on human cells resultingfrom the oxidative or reductive attack to the host’s tissues.The anti-parasitic action is also based on electron transfermechanisms [3]. Moreover, the developed benzofuroxanshave shown to be more selective and active against all T. cruzi

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strains than old drugs [3]. Such features increase the likeli-hood of clinical safety and effectiveness of the benzo[1,2-c]-1,2,5-oxadiazole N -oxide class when compared to othertrypanocidal drugs. Because of their improved toxicologicaland pharmacological profiles, these new antitrypanosomalagents are currently in clinical trials.

With regard to the molecular mode of action, benzofurox-ans have a bioreductive N -oxide group able to produce cyto-toxic free radical species, which can be selectively formedby enzymes from T. cruzi [4]. Structure–activity relation-ship studies have pointed out that benzofuroxan derivativespossessing a phenylethenyl moiety were some of the mostactiveanti-Chagascompoundsof theseriesbecause theyshowinhibiting effect on parasite respiration in association withreactive oxygen species release [5]. Furthermore, the amphi-pathic attribute of these compounds is an important pharma-cokinetic requirement for the in vivo effectiveness [6,7].

In this article, we present the crystal structure andthe vibrational analysis of the (E)-isomer of 5(6)-phen-ylethenylbenzofuroxan (1, 5(6)(E)-[(2-phenylethenyl)]benzo1,2,5-oxadiazole N -oxide), a potential drug for Chagas’ dis-ease treatment. The structural features of 1 were comparedto those from related compounds. For these comparisons,the stereochemistry of the ethenyl group and the tautomericequilibrium at the benzofuroxan core were considered. Like-wise, theoretical calculations were performed to approachthe structural relationships in the solid state.

Experimental method

Synthesis and purification

Compound 1 was prepared, in good global yield, using aWittig–Boden process [8]. It was prepurified by columnchromatography (SiO2 flash, petroleum ether/EtOAc (90:10to 80:20) followed by successive crystallizations from hotpetroleum ether:EtOAc (85:15) giving 1 as orange needles,m.p. (uncorrected) 143.8–145.5 ◦C [7,8].

Single crystal X-ray diffraction experiment

After recrystallizations from hot petroleum ether:EtOAc(85:15), a well-shaped clear single crystal was selected forthe X-ray diffraction experiment. Intensity data were col-lected at room temperature (293 K) using a graphite mono-chromated MoKα radiation (λ = 0.71073 Å) from an Enraf-Nonius Kappa-CCD diffractometer. The cell refinementswere performed using the software packages Collect andScalepack [9,10], and the final cell parameters were obtainedon all reflections. Data for 1 were measured up to 26.07◦ inθ , including 13334 Bragg reflections. Data reduction wascarried out using the software packages Denzo-SMN and

Scalepack, while the XdisplayF computational interface wasused for visual representation of data [10]. No significantabsorption coefficient of 0.092 mm−1 was observed. Thus,absorption correction was not necessary.

The structure was solved using the software SHELXS-97 [11], and refined using the software SHELXL-97 [12],wherein the C, N, and O atoms were clearly solved. Full-matrix least-squares refinement of these atoms with aniso-tropic thermalparameterswascarriedon.Thehydrogenatomswere positioned stereochemically and were refined with fixedindividual displacement parameters [Uiso(H)= 1.2Ueq] us-ing a riding model with C–H bond lengths of 0.93 Å.

Table 1, where the details concerning the data collectionand structure refinement are displayed, was prepared usingWinGX (version 1.70.01) [13]. ORTEP-3 [14] and MER-CURY [15] were also used in order to publish the crystaldata. The MOGUL [16] program was useful to evaluate themolecular conformation and geometry of compound 1. Thislast tool searches substructures deposited at Cambridge Crys-tallographic Data Centre (CCDC) that are similar to those ofa compound submitted either manually or by another com-puter software via an instruction-file interface for, typically,all its bonds, angles, and torsional angles [17].

Even though compound 1 has crystallized in a non-centrosymmetric space group, the Flack parameter was notrefined during X-ray crystallographic analysis. Since themost electron-rich atom is oxygen, which does not have ananomalous scattering large enough (using MoKα radiation)to allow determination of the absolute structure, Friedel pairswere averaged before refinement.

The crystallographic information file (abbreviated CIF)loading the data sets (excluding the structure factors) forbenzofuroxan 1 form has been deposited with the CambridgeStructural Data Base under deposit code CCDC 697835 (cop-ies of these data may be obtained free of charge from TheDirector, CCDC, 12 Union Road, Cambridge, CB2 1EZ,UK, fax: +44123-336-033; e-mail: deposit@ccdc.cam.ac.ukor http://www.ccdc.cam.ac.uk).

Vibrational analysis

FT-Raman spectra were recorded from the original sam-ples on a Bruker VERTEX 70 FTIR/FT-Raman spectrometerequipped with a Nd:YAG laser (1,064 nm excitation line) anda liquid-nitrogen cooled Ge detector. FT-Raman spectra wereacquired by accumulating 1024 scans with a spectral resolu-tion of 4 cm−1.

Molecular calculations of compound 1

The optimized geometry and electronic structure of 1 werecomputed within density functional theory using Gaussian

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Table 1 Crystal data and structure refinement for phenylethenylben-zofuroxan (1)

Empirical formula C14H10N2O2

Formula weight 238.24

Temperature [K] 293(2)

Wavelength [Å] 0.71073

Crystal system Orthorhombic

Space group P212121

Unit cell dimensions a = 7.2368(6) Å

b = 12.613(1) Å

c = 12.884(1) Å

Volume [Å3] 1176.1

Z 4

Density (calculated) [mg/m3] 1.346

Absorption coefficient [mm−1] 0.092

F (000) 496

Crystal size [mm] 0.1 × 0.1 × 0.3

θ-Range for data acquisition (◦) 3.16–26.07

Index ranges −7 ≤ h ≤ 8, −14 ≤ k ≤ 15,−15 ≤ l ≤ 15

Reflections collected 13334

Independent reflections 2257 [R(int) = 0.0849]

Completeness to θ = 26.07◦ 98.1%

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 2257 / 0 / 165

Goodness-of-fit on F2 1.007

Final R for I > 2σ(I ) R1 = 0.0459

R for all data wR2 = 0.1178

Largest diff. peak and hole [e.Å−3] 0.120 and −0.113

03 [18], employing the hybrid of Becke’s nonlocal threeparameter exchange functional and Lee–Yang–Parr corre-lation functional (B3LYP) [19–21]. The 6-31G++(d,p) splitvalence-shell basis set augmented by d polarization functionson heavy atoms and p polarization functions on hydrogenatoms as well as diffuse functions for both hydrogen andheavy atoms was used [22,23]. In vacuo full geometry opti-mizations were carried out without symmetry constraints.The vibrational frequencies and absolute intensities were cal-culated within the harmonic approximation at the same levelof theory used for the optimized geometries. Local minimawere verified by establishing that the matrix of energy sec-ond derivatives (Hessian) has only positive eigenvalues. Thenormal coordinate analysis was performed and the potentialenergy distributions (PED) was calculated among symmetrycoordinates for the molecule [24,25]. The vibrational assign-ments of the normal modes were provided on the basis of thecalculated PED by using the program GAR2PED [26]. Vibra-tional modes of six-membered rings are described in termsof Wilson’s notation [27].

The Raman scattering cross section, ∂σ j /∂�, which isproportional to the Raman intensity, was calculated follow-ing the procedure described by Guirgis et al. [28,29] usingthe relationship:

∂σ j

∂�=

(24π4

45

) ⎛⎝

(ν̃0 − ν̃ j

)4

1 − exp[−hcν̃ j

kT

]⎞⎠ (

h

8π2cν̃ j

)S j (1)

where S j and ν̃ j are, respectively, the scattering activitiesand the predicted wavenumbers (in cm−1) of the j th nor-mal mode, ν̃0 is the exciting frequency (in cm−1), and h, cand k are universal constants. The calculated Raman scatter-ing cross section was used to convolve each predicted vibra-tional mode with a lorentzian lineshape (FWHM = 8 cm−1)

to produce the simulated spectrum. A linear scaling proce-

dure(ν̃′

j = 0.9694 · ν̃ j + 7.80)

was applied to optimize the

comparison between the experimental and calculated vibra-tional frequencies below 1,800 cm−1 [30].

Results and discussion

As it can be seen in Fig. 1, an ORTEP-3 [14] representation ofthe asymmetric unit determined by X-ray diffraction analysisof benzofuroxan 1, the stereochemistry of the double bond isunambiguously described as an (E)-configuration. In solu-tion, benzofuroxan derivatives are a mixture of tautomers atroom temperature [2,31–33], as it is illustrated in Fig. 2 forcompound 1 (tautomers 1A and 1B). The X-ray diffractionanalysis allowed us to conclude that the tautomer 1A is thepredominant tautomeric form in the crystalline state of thecharacterized benzofuroxan.

Benzofuroxan 1 is almost completely planar, with excep-tion of a rotation on the C(1)–C(9) (according to ORTEPlabels, always we will use the ORTEP label nomenclaturegiven in Fig. 1) bond axis that deviates the phenyl headfrom the molecule plane. The benzofuroxan moiety is planarbecause the highest deviation from the least-squares plane

Fig. 1 The ORTEP [14] view of benzofuroxan 1. Ellipsoids represent50% probability level and an arbitrary labeling of the atoms, rings andethenyl group is given. The hydrogen atoms are shown as spheres ofarbitrary radii

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Fig. 2 Tautomers of compound1 in solution. The XRDstructural determination hasproved to be the tautomericform 1A present in the crystalstructure

passing through these two fused rings formed by atoms C(3)–C(4)–C(5)–N(1)–O(1)–N(2)–C(6)–C(7)–C(8) and the exo-cyclic O(2) oxygen atom of the N -oxide group is 0.009(2)Å for C(7) (RMSD of the fitted atoms is 0.0060 Å). Further-more, if the exocyclic doubly bonded C(1) and C(2) atomsare also taken to calculate a plane going through them and the10 aforementioned atoms, a least-square ethenylbenzofuro-xan plane is less fitted than that crossing through the benzof-uroxan framework, although there is a remarkable planaritybetween the double bond carbons and the benzoxadiazoleN -oxide core. The negligible bend (2.8(1)◦) between thesestructural motifs confirms this previous observation. In thesame way, the largest deviation from the least-squares planethrough the 12 non-hydrogen atoms of the ethenylbenzofuro-xan moiety is 0.042(2) Å for C(1) (RMSD of the fitted atomsis 0.0167 Å).

On the other hand, the phenyl group is slightly twisted by12.32(6)◦ from the least-square ethenylbenzofuroxan plane,which can be also noted looking at the results of the MOGULintramolecular matching in Cambridge Structural Database(CSD) [17]. The determined torsional angle between thephenyl and ethenyl groups was found to be 167.8(2)◦ forC(2)–C(1)–C(9)–C(14). This value is significantly lowerthan the expected average for a perfectly conjugated π -system, about 180◦. The histogram displayed in Fig. 3 exhib-its the distribution of 9213 hits containing structures similarto compound 1 for the C(2)–C(1)–C(9)–C(14) dihedral angle,which were found by the MOGUL searches in the CambridgeStructural Database (CSD) [17]. In Fig. 3, it is observed thatsuch torsion is approximately 180◦ (or 0◦) for the most ofselected entries (hits). The corresponding value of benzof-uroxan 1 can also be graphically observed in Fig. 3.

The optimization of the molecular conformation of thefree molecule using, as starting geometry, the crystallinestructure shows a completely planar structure, in agreementwith the MOGUL assessments. Furthermore, the geome-try optimization has produced a structure which is remark-ably similar to that of the crystallographic asymmetric unit.The optimized and experimental structures were compared

by superimposing the benzofuroxan moiety using a least-squares algorithm that minimizes the distances among thenon-hydrogen atoms (Fig. 4). The main differences betweenthe calculated and experimental conformations are indeedrelated to the orientation of the phenyl ring. So, the inter-molecular interaction pattern should rationalize the abovediscussed conformational changes occurred on the benzof-uroxan 1 solid state structure. In accordance with this obser-vation, there is a weak non-classical C(13)–H(13)· · ·O(2)hydrogen bonding that slightly pulls the phenyl group in thedirection to the N -oxide O(2) oxygen atom from a neighbor-ing molecule in the lattice, in order to favor geometrically thishydrogen bonding. The solid-state packing representationsof compound 1 were generated via ORTEP-3 [14] and theyare depicted in Figs. 5 and 6. The non-classical hydrogenbonds C(13)–H(13)· · ·O(2) and C(8)–H(8)· · ·O(1) connectthe molecules along the [001] direction. Indeed, there aretwo hydrogen-bonded infinite one-dimensional chains paral-lel to the [001] direction and they are related by a 21 screwaxis symmetry along the c axis with a 3.6 Å distance betweeneach individual chain (Fig. 5). In Table 2, the details of twohydrogen bonding contacts in the network of 1 are presented.

The determined intramolecular geometry and conforma-tion of compound 1 were analyzed by two ways: usingMOGUL [16], a crystallographic tool that is very useful tounderstand structural relationships in chemical compounds,and by matching the experimental measurements to the corre-sponding parameters resulting from the computational opti-mization. Interesting geometrical features have been pointedout as consequences of the mesomeric effect crossing themolecular backbone of 1. In the determined structure, the aro-matic double bonds C(3)=C(4), C(7)=C(8), and N(1)=C(5)have distances of 1.355(3), 1.348(3), and 1.326(3) Å, respec-tively. These measurements are shorter than those in the opti-mized structure, 1.385, 1.365, and 1.342 Å, respectively. Onthe other hand, the C(3)–C(8) single bond distance is 1.430(3)Å in the crystal structure. This value is longer than thataveraged on 10,000 like-1 compounds returned by MOGULsurveys in the Cambridge Structural Database (CSD) [17],

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Fig. 3 Histogram comparingthe C(2)–C(1)–C(9)–C(14)dihedral angle of compound 1 toequivalent torsions of resembledcompounds found in CSD

Fig. 4 Comparison of the optimized (planar) and experimental(twisted) structures of benzofuroxan 1

1.39(2) Å. In Fig. 7, a MOGUL histogram illustrates a com-parison among the C(3)=C(4) bond length and equivalentC–C bond distances from related compounds that are depos-ited in CSD. These deviations from the most common bonddistance values and from the calculated ones have beenunderstood as results of an electronic mesomerism decreas-ing through the atoms of benzofuroxan heterocycle, becausethe aforementioned double bonds are less delocalized thanthose of an ideally conjugated π -ring due to the low aroma-ticity of the carbocyclic ring [34]. The previous observationwas stated on the basis of the increased double bond char-acter of the shortened C(3)=C(4), C(7)=C(8) and N(1)=C(5)bonds and also based on the decreased double bond characterof the enlarged C(3)–C(8) bond that possess a greater singlebond feature.

Both the molecular conformation and intermolecularinteractions due to the crystal packing are usually reflectedin the vibrational spectrum. Based on that, the Raman spec-

trum of benzofuroxan 1 was calculated and compared withexperimental data (Fig. 8). Raman spectroscopy is especiallyuseful in this particular case, since the main changes in-duced by the crystalline structure are related to the molecularskeleton whose characteristic vibrational modes are expectedto be observed at low wavenumbers (below 400 cm−1). Po-tential energy distribution (PED) calculations have allowedus to describe the vibrational modes in terms of the inter-nal coordinates of the molecule. The internal modes areclassified according to the main molecular groups as indi-cated in Fig. 8. Table 3 reports the normal modes of ben-zofuroxan 1 in the fingerprint and low-energy regions to-gether with their PED distribution. In general, there is agood agreement between the scaled wavenumbers and therelative intensities with the corresponding experimental data.For example, we may cite some of the most intense Ramanband located at 1630, 1623, 1594, and 1463 cm−1, whichare associated to the stretching of the double bonds of thephenyl, ethenyl, and benzofuroxan moieties (see the insetin Fig. 8). The set of bands around 600 cm−1 (637, 619,and 571 cm−1) are also well described by the calculationsand corresponds to the in-plane deformation of the rings. Asimilar behavior is observed in the bands related to the tor-sional deformations of the benzofuroxan moiety (312, 204,and 185 cm−1).

Despite the good correlation between the experimentaland calculated spectra, some vibrational modes exhibit ananomalous behavior. That is the case of the bands around1,000 cm−1, which are mostly related to in-plane and out-of-plane deformations of the phenyl ring (Modes 5, 12, 17, and18). A similar behavior is observed around 400 cm−1 where

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a

o b

c3.6 A

o

I__

Fig. 5 Crystal structure of benzofuroxan 1 projected onto the ab plane (110) showing the infinite one-dimensional dimeric chains connected byweak hydrogen bonds

a

o

c

b

C13

H13

O2 i

C8H8

O1ii

O1

O2

H13j

H8m

H8 jj

O1j

C13j

C8m

Fig. 6 Crystal packing of benzofuroxan 1 along the [001] direction.Double dotted lines represent the intermolecular hydrogen bonds. TheH-atoms involved in the hydrogen bonds are shown as spheres of

arbitrary radii. Symmetry codes: (i) x ; y; z − 1; (ii) −x + 1/2; −y;z − 1/2; ( j) x ; y; z + 1; (jj) −x + 1/2; −y; z + 1/2; (m) −x + 1/2;−y; z + 3/2

the C–C–C out-of-plane deformations (16a and 16b) are ex-pected. Finally, Raman bands associated to lattice vibrations[35] are usually observed below 200 cm−1. In this way, twolow energy bands (132 and 110 cm−1) cannot be directly cor-related with the calculated ones and were associated to latticemodes.

Notice that as a rule, the vibrational modes classifiedas anomalous always exhibit relevant contributions of thetorsion around the C(1)–C(9) bond (Fig. 1), which char-acterize the departing of the planar configuration in orderto favor geometrically the C(13)–H(13)· · ·O(2) hydrogenbonding. On the other hand, the absence of strong hydrogenbonds leaves the molecule in a conformation which can bedirectly compared with the calculated one producing an over-all good agreement between the experimental and theoretical

Raman spectra. Thus, the small deformations of the molecu-lar skeleton play an important role in determining the Ra-man polarizability and energy of some particular vibra-tional modes allowing us to establish a direct correlationbetween the X-ray diffraction and Raman spectroscopyobservations.

Conclusions

The crystal structure of benzofuroxan 1 was established forthe fist time in this article, resulting in an entire character-ization of their intra and inter-molecular geometries. The(E)-stereochemistry of the ethenyl bridge and the majortautomer where the phenylethenyl substituent is located in

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Table 2 Hydrogen-bonding geometry (Å, ◦) for benzofuroxan 1

D–H· · · Aa D–H H· · ·A D· · ·A D–H· · ·A

C(13)–H(13)· · ·O(2)b 0.93 2.64 3.488(4) 151

C(8)–H(8)· · ·O(1)c 0.93 2.71 3.393(3) 131

a The symbols ‘D’ and ‘A’ mean hydrogen donor and acceptor, respectively. b Symmetry: x ; y; z − 1. c Symmetry: −x + 1/2; −y; z − 1/2

Fig. 7 Histogram comparingthe C(3)–C(4) bond length ofcompound 1 to equivalentdistances of resembledcompounds found in CSD

Fig. 8 Experimental andcalculated Raman spectra ofbenzofuroxan 1

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Table 3 Selected scaled DFTand experimental Ramanfundamental vibrational modes(in cm−1) of benzofuroxan 1

DFT (scaled) Experimental PEDa,b(%)

1644 1630 Rb[8a](11) + V[ν(CC)](56) + Rc[ν(CN)](14)

1630 1623 Rb[8a](35) + V[ν(CC)](17) + Rc[ν(CN)](32)

1604 1595 Ra[8a](78)

1595 1594 Rb[8a](47) + Rc[ν(NO)](38)

1579 1578 Ra[8b](92)

1534 1538 Rb[8b](77) + Rc[ν(NC)](18)

1504 1496 Ra[19a](11) + Rb[19a](41) + Rc[ν(NC)](36)

1492 1486 Ra[19a](74)

1468 1463 Rb[19b](90)

1448 1450 Ra[19b](85)

1394 1403 Rb[δ(CH)](55) +V[δ(CH)](15)

1379 1373 Rb[δ(CH)](57) +Rc[ν(NC)](36)

1334 1334 Ra[3](63) + V[δ(CH)](20)

1331 1325 Ra[14](84) + V[δ(CH)](10)

1317 1315 Ra[3](17) + V[δ(CH)](66)

1281 1284 V[δ(CH)](23) + Rb[3](35) + Rc[ν(CN)](16)

1265 1265 RbV[ν(CC)](41) + RaV[ν(CC)](44)

1227 1226 Rb[δ(CH)](45) + V[δ(CH)](21)

1203 1207 Ra[δ(CH)](32) + ν[Ra-V](19) + Rb[δ(CH)](21)

1180 1181 Ra[9a](93)

1158 1164 Rb[18b](64) +Ra[δ(CH)](19)

1157 1164 Rb[18b](14) +Ra[δ(CH)](81)

1119 1120 Rb[9b](44) + ν[Rb-V](15) +Rc[ν(CN)](29)

1082 1076 Ra[18b](89)

1032 1044 Rb[δ(CH)](13) + Rc[ν(NO)](80)

1028 1026 Rb[18a](13) + Rc[ν(NO)](80)

988 1014 Ra[12](100)

984 996 Ra[5](85) + V[o(CH)](12)

972 973 Ra[5](32) + Rb[5](24) + V[o(CH)](40)

961 965 Ra[17a](99)

959 965 Rb[17a](82) + V[o(CH)](14)

930 939 Rb[1](73)

911 918 Ra[17b](75) + V[o(CH)](15)

879 879 Ra[17b](10) + V[δ(CH)](48) + Rb[17b](30)

858 858 Rb[18b](11) + Rc[δ(NO)](72)

849 847 Ra[1](28) + δ[V](41)+ Rb[15](11)

840 838 Ra[10a](14) + Rb[o(CH)](53) + V[o(CH)](25)

830 830 Ra[10a](76) + V[o(CH)](12)

801 808 Rb[10a](83)

784 785 Rb[1](33) + Rc[δ(NO)](38)

761 761 Rb[1](54) + Rc[δ(NO)](35)

752 757 Ra[11](87)

706 737 τ [Rb](89)

687 696 τ [Ra](89)

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Table 3 continued

Types of vibration: ν, stretching;δ, deformation; τ , torsion; o, outof plane bending. a Proposedassignment based on thePotential Energy Distribution(PED) for vibrational normalmodes. b The functional groupsare labeled according to Fig. 1and the six-member aromaticrings modes are labeledfollowing the Wilson’s notation[29]

DFT (scaled) Experimental PEDa,b(%)

668 668 δ[Rb](25) + δ[Rc](65)

636 637 Ra[6a](32) + δ[V](16) + Rb[6a](17) + δ[Rc](16)

621 619 Ra[6b](93)

607 610 τ [Rb](53) + τ [Rc](28)

573 571 Ra[6a](16) + Rb[6a] (31) + δ[Rc](33)

529 524 τ [Rc](84)

506 504 Ra[6a](21) + Rb[6a](43) + δ[Rc](21)

500 502 Ra[6a](21) + Rb[6a](43) + Rc[ν(NO)](21)

481 477 Rb[6a](20) + Rc[ν(NO)](57)

459 456 δ[Ra-V](22) + V[δ](29) + δ[Rb-V](32)

436 436 Rb[16b](70) + τ [Rb-Rc](13)

411 407 Ra[16a](96)

392 400 Rb[16b](30) + τ [Rb-Rc](47)

316 313 δ[Ra-V](19) + Rb[15](37) + Rc[δ(NO)](21)

313 312 τ [V](14) + τ [Rb](47) + τ [Rc](23)

257 275 Ra[10b](49) + τ [V](25)

208 204 δ[V](78) + Rc[δ(NO)](22)

191 185 τ [Rb-Rc](35) + τ [V](11) + τ [Rb-V](38)

189 180 δ[Ra-V](26) + δ[V](24) + δ[Rb-V](38)

162 143 τ [Rb](61) + τ [Rc](23)

132 Lattice

110 Lattice

91 87 τ [V](94)

69 68 δ[V](84)

52 τ [V](81)

32 τ [V](87)

position 6 respect to N -oxide group were unambiguouslydescribed for the crystalline state of the benzofuroxan 1.Furthermore, some deviations for bond angles and lengthsand torsions from expected values were reported as con-sequences of intermolecular contacts and electronic delo-calization decreasing through atoms of the benzofuroxanmoiety. Quantum mechanical calculations have confirmedthe anomalous deviation of the reported parameters, sincethe geometrical optimization produces a molecular confor-mation slightly different than that of the determined crystalstructure. These features are also evidenced by comparingthe experimental Raman and calculated spectra of the ben-zofuroxan 1, which exhibit not only unexpected frequencyshift but also anomalous Raman activities.

Acknowledgments We thank the FAPESP (Fundação de Amparoà Pesquisa do Estado de São Paulo) and CNPq (Conselho Nacionalde Desenvolvimento Científico e Tecnológico) for research fellowship(FTM, FAPESP; APA and JE, CNPq), CAPES (Coordenação de Aper-feiçoamento de Pessoal de Nível Superior), CNPq-PROSUL (Conselho

Nacional de Desenvolvimento Científico e Tecnológico-Programa Sul-Americano) and DNDi (Drugs for Neglected Disease Initiative).

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