3 Bromo β lapachone

organic papers

o296

Structure Reports

Online

ISSN 1600-5368

3-Bromo-

b

-lapachone

C. A. De Simone,a_{* V. R. S.} Malta,a_{M. A. Pereira,}a_{J. R. S.} Bispo,a_{A. V. Pinto}b _and M. C. F. R. Pintob

a_{Departamento de QuõÂmica, Universidade} Federal de Alagoas, 57072-970 MaceioÂ, AL, Brazil, andb_{NuÂcleo de Pesquisas de Produtos} Naturais, Universidade Federal do Rio de Janeiro, 21941-970 Rio de Janeiro, RJ, Brazil

Correspondence e-mail: [email protected]

Key indicators Single-crystal X-ray study T= 120 K

Mean(C±C) = 0.003 AÊ Rfactor = 0.038 wRfactor = 0.114

Data-to-parameter ratio = 17.0

For details of how these key indicators were automatically derived from the article, see http://journals.iucr.org/e.

#2002 International Union of Crystallography Printed in Great Britain ± all rights reserved

In the title compound, C15H13BrO3, the benzo and quinone

rings are planar, while the heterocycle is in a distorted half-chair conformation.

Comment

Naphthoquinone compounds are often found in nature and their biological activity has been associated with various medicinal applications. Their action ranges from antibiotic to antineoplastic activity, although some of them do not presently have a de®ned function (Pintoet al., 1980). Among the naphthoquinone compounds, lapachol, lapachones and their derivatives have been of interest to the scienti®c communities of several countries for more than 100 years because of the large range of biological activities found for these compounds (Subramanian, 1996). Among these activ-ities are: antiviral (Pinto, Pinto et al., 1987), antimalarial (Fieser et al., 1967), antitumor (Li et al., 1999), and activity against trypanosoma cruzi, the protozoan of Chagas disease (GoncËalveset al., 1980; Pinto, Ferreiraet al., 1987). As part of a search for compounds with therapeutic activity against a number of parasitic diseases endemic to Brazil, a series of derivatives has been prepared from lapachol (Cruz et al., 1977).

The title compound, (I), is a derivative of lapachol. It was tested in two biological assays, against trypanosoma cruzi (Lopeset al., 1978), and as a protection against the penetration of Schistosomiasis mansoni cercariae in tails of mice (Pintoet al., 1977), and showed, in both tests, discrete biological activity.

The crystal structure of (I) (Fig. 1) shows that the atoms comprising ringsAandBand the adjacent C and O atoms are essentially coplanar, with an r.m.s. deviation of 0.039 AÊ for the 14 atoms. Atoms C2 and C3 are 0.256 (2) and 0.519 (3) AÊ out of this plane, respectively. Therefore, the C ring assumes a

distorted half-chair conformation, the Cremer & Pople (1975)

ring-puckering parameters being q2 = 0.407 (2), q3 =

0.314 (2) AÊ,Q= 0.514 (2) AÊ,= 52.4 (2)_{and'= 160.8 (3).}

The overall geometry of both the B andC rings is in good

agreement with that found for this moiety in a similar compound (Pereira, 1989).

Experimental

The title compound, (I), was synthesized for the ®rst time by Paterno (1882). However, the method used here was that of Hooker (1892). This substance is easily prepared, in chloroform solvent, by reaction of lapachol with bromine, followed by evaporation and crystallization from ethanol. It was recrystallized from acetone at room tempera-ture.

Crystal data C15H13BrO3

Mr= 321.16

Monoclinic,P21=c

a= 11.823 (2) AÊ

b= 8.191 (2) AÊ

c= 13.894 (3) AÊ

= 106.05 (1)

V= 1293.1 (5) AÊ3

Z= 4

Dx= 1.650 Mg mÿ3

MoKradiation Cell parameters from 3176

re¯ections

= 1.0±27.5

= 3.18 mmÿ1

T= 120 (2) K Prism, orange 0.220.150.12 mm Data collection

Nonius KappaCCD diffractometer

'scans, and!scans withoffsets Absorption correction: multi-scan

(Blessing, 1995)

Tmin= 0.541,Tmax= 0.702

5298 measured re¯ections 2971 independent re¯ections

2601 re¯ections withI> 2(I)

Rint= 0.016

max= 27.5

h= 0!15

k= 0!10

l=ÿ18!17

Re®nement Re®nement onF2

R[F2_{> 2(F}2_{)] = 0.039}

wR(F2_{) = 0.114}

S= 1.09 2971 re¯ections 175 parameters

H-atom parameters constrained

w= 1/[2_(F

o2) + (0.069P)2

+ 0.7539P]

whereP= (Fo2+ 2Fc2)/3

(/)max< 0.001

max= 1.05 e AÊÿ3

min=ÿ0.80 e AÊÿ3

Table 1

Selected geometric parameters (AÊ,_).

BrÐC3 1.958 (2) O1ÐC1 1.351 (3) O1ÐC2 1.473 (3) C4AÐC1 1.363 (3)

C4AÐC4 1.505 (3) C3ÐC4 1.513 (3) C3ÐC2 1.536 (4)

C1ÐO1ÐC2 119.39 (18) C4ÐC3ÐC2 112.2 (2) C2ÐC3ÐBr 111.39 (16)

O1ÐC2ÐC3 105.23 (18) C4AÐC4ÐC3 107.7 (2)

H atoms were positioned geometrically and re®ned with a riding model, with isotropic displacement parameters equal to 1.5 (for methyl H atoms) or 1.2 timesUeqof the parent atom.

Data collection:COLLECT(Nonius, 1999); cell re®nement:HKL SCALEPACK(Otwinowski & Minor, 1997); data reduction:HKL DENZO (Otwinowski & Minor, 1997); program(s) used to solve structure:SHELXS97 (Sheldrick, 1997); program(s) used to re®ne structure: SHELXL97 (Sheldrick, 1997); molecular graphics:

ORTEP-3 for Windows (Farrugia, 1997); software used to prepare

The authors thank Dr Javier A. Ellena for his help in collecting the diffraction data and Dr Julio Zukerman-Schpector for his help with the CIF. This work has received partial support from CNPq, CAPES, FAPEAL and FINEP.

References

Blessing, R. H. (1995).Acta Cryst.A51, 33±38.

Cremer, D. & Pople, J. A. (1975).J. Am. Chem. Soc.97, 1354±1358. Cruz, F. S., Gilbert, B., Lopes, J. N., Pinchin, R. & Pinto, A. V. (1977).Rev.

Latinoam. Quim.8, 138±140.

Farrugia, L. J. (1997).ORTEP-3. University of Glasgow, Scotland. Farrugia, L. J. (1999).WinGX. University of Glasgow, Scotland.

Fieser, L. F., Schirmer, J. P., Archer, S., Lorenz, R. R. & Pfaffenbach, P. I. (1967).J. Med. Chem.10, 513±517.

GoncËalves, A. M., Vasconcellos, M. E., Do Campo, R., de Cruz, F. S., de Souza, W. & Leon, W. (1980).Biochem. Parasit.1, 167±176.

Hooker, S. C. (1892).J. Chem. Soc, pp. 611±651.

Li, C. J., Li, Y. Z., Pinto, A. V. & Pardee, A. B. (1999).Proc. Natl Acad. Sci. USA,96, 13369±13374.

Lopes, J. B., Cruz, F. S., Do Campo, R., Vasconcellos, M. E., Sampaio, M. C. R., Pinto, A. V. & Gilbert, B. (1978).Ann. Trop. Med. Parasit.72, 9±17. Nonius (1999).COLLECT. Version 5.0. Nonius BV, Delft, The Netherlands. Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276,

Macromolecular Crystallography, Part A, edited by C. W. Carter and R. M. Sweet, pp. 307±326. London: Academic Press.

PaternoÂ, E. (1882).Gazz. Chim. Ital.12, 337±350.

Pereira, M. A. (1989). Doctoral Thesis. Universidade de Sao Paulo, Brazil. Pinto, A. V., Ferreira, V. F., Capella, R. S., Gilbert, B., Pinto, M. do C. & da

Silva, J. S. (1987).Trans. R. Soc. Trop. Med. Hyg.81, 609±10.

Pinto, A. V., Ferreira, V. F. & Coutada, L. C. M. (1980).Acad. Bras. Cienc.52, 477±479.

Pinto, A. V., Pinto, M. C. F. R., Gilbert, B., Pellegrino, J. & Mello, R. T. (1977).

Trans. R. Soc. Trop. Med. Hyg.71, 133±135.

Pinto, A. V., Pinto, M. do C., Lagrota, M. H., Wigg, M. D. & Aguiar, M. A. (1987).An. Rev. Latinoam. Microbiol.29, 15±20.

Sheldrick, G. M. (1997). SHELXS97 and SHELXL97. University of

Figure 1

supporting information

sup-1

supporting information

Acta Cryst. (2002). E58, o296–o297 [doi:10.1107/S1600536802001265]

3-Bromo-

β

-lapachone

C. A. De Simone, V. R. S. Malta, M. A. Pereira, J. R. S. Bispo, A. V. Pinto and M. C. F. R. Pinto

S1. Comment

Naphthoquinonic compounds are often found in nature and their biological activity has been associated with various

medicinal applications. Their action ranges from antibiotic to antineoplastic activity, although some of them do not

presently have a defined function (Pinto et al., 1980). Among the naphthoquinonic compounds, lapachol, lapachones and their derivatives have been of interest to the scientific communities of several countries for more than 100 years because

of the large range of biological activities found for these compounds (Subramanian, 1996). Among these activities are:

antiviral (Pinto, Pinto et al., 1987), antimalarial (Fieser et al., 1967), antitumor (Li et al., 1999), and activity against trypanosoma cruzi, the protozoan of Chagas disease (Gonçalves et al., 1980; Pinto, Ferreira et al., 1987). As part of a search for compounds with therapeutic activity against a number of parasitic diseases endemic to Brazil, a series of

derivatives has been prepared from lapachol (Cruz et al., 1977).

The title compound, (I), is a derivative of lapachol. It was tested in two biological assays, against trypanosoma cruzi

(Lopes et al., 1978), and as a protection against the penetration of Schistosomiasis mansoni cercariae in tails of mice (Pinto et al., 1977), and showed, in both tests, discrete biological activity.

The crystal structure of (I) (Fig. 1) shows that the atoms comprising rings A and B and the adjacent C and O atoms are

essentially coplanar, with an r.m.s. deviation of 0.039 Å for the 14 atoms. Atoms C2 and C3 are 0.256 (2) and 0.519 (3) Å

out of this plane, respectively. Therefore, the C ring assumes a distorted half-chair conformation, the Cremer & Pople

(1975) ring-puckering parameters being q2 = 0.407 (2), q3 = 0.314 (2) Å, Q = 0.514 (2) Å, θ = 52.4 (2)° and φ = 160.8 (3)°. The overall geometry of both B and C rings is in good agreement with that found for this moiety in a similar

compound (Pereira, 1989).

S2. Experimental

The title compound, (I), was synthesized for the first time by Paternó (1882). However, the method used here was that of

Hooker (1892). This substance is easily prepared, in chloroform solvent, by reaction of lapachol with bromine, followed

by evaporation and crystallization from ethanol. It was recrystallized from acetone at room temperature.

S3. Refinement

H atoms were positioned geometrically and refined with a riding model, with isotropic displacement parameters equal to

Figure 1

The molecular structure of (I), showing the atom labelling and 50% probability displacement ellipsoids.

(I)

Crystal data

C15H13BrO3

Mr = 321.16

Monoclinic, P21/c a = 11.823 (2) Å

b = 8.191 (2) Å

c = 13.894 (3) Å

β = 106.05 (1)°

V = 1293.1 (5) Å3

Z = 4

F(000) = 648

Dx = 1.650 Mg m−3

Mo Kα radiation, λ = 0.71070 Å Cell parameters from 3176 reflections

θ = 1.0–27.5°

µ = 3.18 mm−1

T = 120 K Prism, orange

0.22 × 0.15 × 0.12 mm

Data collection

Nonius KappaCCD diffractometer

Radiation source: fine-focus sealed tube Graphite monochromator

Detector resolution: 9 pixels mm-1

φ scans, and ω scans with κ offsets

Absorption correction: multi-scan (Blessing, 1995)

Tmin = 0.541, Tmax = 0.702 5298 measured reflections 2971 independent reflections 2601 reflections with I > 2σ(I)

supporting information

sup-3

θmax = 27.5°, θmin = 1.8°

h = 0→15

k = 0→10

l = −18→17

Refinement

Refinement on F2 Least-squares matrix: full

R[F2 _{> 2σ(F}2_{)] = 0.039}

wR(F2_{) = 0.114}

S = 1.09 2971 reflections 175 parameters 0 restraints

Primary atom site location: structure-invariant direct methods

Secondary atom site location: difference Fourier map

Hydrogen site location: inferred from neighbouring sites

H-atom parameters constrained

w = 1/[σ2_(F

o2) + (0.069P)2 + 0.7539P] where P = (Fo2 + 2Fc2)/3

(Δ/σ)max < 0.001 Δρmax = 1.05 e Å−3 Δρmin = −0.80 e Å−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes)

are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F2 _{against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F}2_, conventional R-factors R are based

on F, with F set to zero for negative F2_{. The threshold expression of}

F2 _{> σ(F}2_{) is used only for calculating R-factors(gt) etc. and}

is not relevant to the choice of reflections for refinement. R-factors based on F2 _{are statistically about twice as large as} those based on F, and

R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2₎

x y z Uiso*/Ueq

Br 0.02654 (2) 0.10427 (4) 0.17914 (2) 0.03901 (13) C10 0.5407 (2) 0.3889 (3) 0.10681 (18) 0.0239 (5)

H10 0.4857 0.4731 0.1075 0.029*

C7 0.7053 (2) 0.1448 (3) 0.10824 (17) 0.0255 (5)

H7 0.7617 0.0616 0.1097 0.031*

O1 0.32160 (15) 0.31129 (19) 0.11720 (13) 0.0253 (3) C6A 0.5942 (2) 0.1036 (3) 0.11613 (17) 0.0225 (5) C4A 0.3568 (2) 0.0233 (3) 0.12886 (17) 0.0247 (5) O3 0.41395 (17) −0.2531 (2) 0.14410 (13) 0.0316 (4) O2 0.63408 (16) −0.1795 (2) 0.12945 (14) 0.0319 (4) C11 0.1356 (2) 0.2586 (3) −0.00585 (19) 0.0320 (5)

H11A 0.1774 0.1724 −0.0310 0.048*

H11B 0.1376 0.3598 −0.0430 0.048*

H11C 0.0536 0.2255 −0.0149 0.048*

C3 0.1879 (2) 0.1403 (3) 0.17233 (19) 0.0273 (5)

H3 0.2373 0.1660 0.2416 0.033*

H4A 0.2404 −0.1021 0.1886 0.033*

H4B 0.1839 −0.0510 0.0736 0.033*

C10A 0.5101 (2) 0.2262 (3) 0.11514 (16) 0.0218 (4) C6 0.5640 (2) −0.0693 (3) 0.12655 (17) 0.0247 (5) C1 0.3918 (2) 0.1800 (3) 0.12090 (16) 0.0229 (4) C8 0.7343 (2) 0.3067 (3) 0.09834 (18) 0.0279 (5)

H8 0.8100 0.3345 0.0922 0.034*

C12 0.1566 (2) 0.4462 (3) 0.1419 (2) 0.0329 (5)

H12A 0.1842 0.5377 0.1089 0.049*

H12C 0.1904 0.4549 0.2145 0.049*

H12B 0.0706 0.4491 0.1259 0.049*

C9 0.6517 (2) 0.4282 (3) 0.09743 (18) 0.0269 (5)

H9 0.6713 0.5392 0.0903 0.032*

Atomic displacement parameters (Å2₎

U11 _U22 _U33 _U12 _U13 _U23

Br 0.02618 (18) 0.0457 (2) 0.0482 (2) −0.00395 (10) 0.01535 (13) −0.00299 (11) C10 0.0260 (11) 0.0201 (11) 0.0240 (11) 0.0046 (8) 0.0042 (9) 0.0000 (8) C7 0.0252 (11) 0.0262 (11) 0.0236 (11) 0.0053 (9) 0.0046 (9) −0.0011 (9) O1 0.0233 (8) 0.0197 (8) 0.0337 (8) 0.0046 (6) 0.0092 (7) −0.0006 (6) C6A 0.0253 (11) 0.0218 (11) 0.0187 (10) 0.0048 (8) 0.0031 (8) −0.0009 (8) C4A 0.0277 (11) 0.0225 (11) 0.0234 (10) 0.0014 (9) 0.0065 (9) −0.0001 (8) O3 0.0406 (10) 0.0203 (8) 0.0341 (9) 0.0003 (7) 0.0106 (8) 0.0012 (7) O2 0.0319 (9) 0.0231 (8) 0.0378 (9) 0.0088 (7) 0.0048 (8) −0.0012 (7) C11 0.0305 (12) 0.0333 (13) 0.0301 (12) 0.0033 (11) 0.0050 (10) −0.0014 (10) C3 0.0210 (11) 0.0330 (12) 0.0282 (11) −0.0003 (9) 0.0074 (9) −0.0032 (9) C5 0.0325 (13) 0.0203 (11) 0.0204 (10) 0.0018 (9) 0.0057 (9) −0.0002 (8) C2 0.0205 (11) 0.0286 (12) 0.0293 (11) 0.0016 (9) 0.0068 (9) −0.0022 (9) C4 0.0277 (12) 0.0255 (11) 0.0292 (11) −0.0017 (9) 0.0089 (9) −0.0009 (9) C10A 0.0227 (11) 0.0216 (10) 0.0203 (10) 0.0040 (8) 0.0048 (8) −0.0006 (8) C6 0.0282 (12) 0.0221 (10) 0.0216 (10) 0.0059 (9) 0.0030 (9) 0.0002 (8) C1 0.0262 (11) 0.0208 (11) 0.0209 (10) 0.0042 (9) 0.0048 (8) −0.0008 (8) C8 0.0238 (11) 0.0308 (13) 0.0292 (11) 0.0018 (9) 0.0072 (9) 0.0006 (9) C12 0.0266 (12) 0.0318 (13) 0.0401 (14) 0.0060 (10) 0.0090 (10) −0.0053 (11) C9 0.0284 (12) 0.0236 (11) 0.0270 (11) −0.0008 (9) 0.0052 (9) 0.0000 (9)

Geometric parameters (Å, º)

Br—C3 1.958 (2) C11—H11A 0.980

C10—C9 1.393 (4) C11—H11B 0.980

C10—C10A 1.394 (3) C11—H11C 0.980

C10—H10 0.950 C3—C4 1.513 (3)

C7—C8 1.385 (3) C3—C2 1.536 (4)

C7—C6A 1.390 (4) C3—H3 1.000

C7—H7 0.950 C5—C6 1.545 (4)

O1—C1 1.351 (3) C2—C12 1.515 (3)

supporting information

sup-5

C6A—C10A 1.411 (3) C4—H4B 0.990

C6A—C6 1.478 (3) C10A—C1 1.472 (3)

C4A—C1 1.363 (3) C8—C9 1.392 (3)

C4A—C5 1.449 (3) C8—H8 0.950

C4A—C4 1.505 (3) C12—H12A 0.980

O3—C5 1.229 (3) C12—H12C 0.980

O2—C6 1.219 (3) C12—H12B 0.980

C11—C2 1.527 (3) C9—H9 0.950

C9—C10—C10A 120.1 (2) O1—C2—C3 105.23 (18)

C9—C10—H10 119.9 C12—C2—C3 113.5 (2)

C10A—C10—H10 119.9 C11—C2—C3 114.1 (2)

C8—C7—C6A 120.3 (2) C4A—C4—C3 107.7 (2)

C8—C7—H7 119.8 C4A—C4—H4A 110.2

C6A—C7—H7 119.8 C3—C4—H4A 110.2

C1—O1—C2 119.39 (18) C4A—C4—H4B 110.2

C7—C6A—C10A 120.4 (2) C3—C4—H4B 110.2

C7—C6A—C6 120.0 (2) H4A—C4—H4B 108.5

C10A—C6A—C6 119.6 (2) C10—C10A—C6A 118.9 (2)

C1—C4A—C5 119.8 (2) C10—C10A—C1 121.5 (2)

C1—C4A—C4 121.2 (2) C6A—C10A—C1 119.6 (2)

C5—C4A—C4 118.9 (2) O2—C6—C6A 122.2 (2)

C2—C11—H11A 109.5 O2—C6—C5 119.5 (2)

C2—C11—H11B 109.5 C6A—C6—C5 118.3 (2)

H11A—C11—H11B 109.5 O1—C1—C4A 123.8 (2)

C2—C11—H11C 109.5 O1—C1—C10A 112.1 (2)

H11A—C11—H11C 109.5 C4A—C1—C10A 124.2 (2)

H11B—C11—H11C 109.5 C7—C8—C9 119.6 (2)

C4—C3—C2 112.2 (2) C7—C8—H8 120.2

C4—C3—Br 110.05 (17) C9—C8—H8 120.2

C2—C3—Br 111.39 (16) C2—C12—H12A 109.5

C4—C3—H3 107.6 C2—C12—H12C 109.5

C2—C3—H3 107.6 H12A—C12—H12C 109.5

Br—C3—H3 107.6 C2—C12—H12B 109.5

O3—C5—C4A 123.0 (2) H12A—C12—H12B 109.5

O3—C5—C6 118.6 (2) H12C—C12—H12B 109.5

C4A—C5—C6 118.5 (2) C8—C9—C10 120.7 (2)

O1—C2—C12 103.55 (19) C8—C9—H9 119.6

O1—C2—C11 107.63 (19) C10—C9—H9 119.6

C12—C2—C11 111.9 (2)