2-Hydroxy-4,6-dimethoxyacetophenone from leaves of Peperomia glabella

ARTICLE

2-Hydroxy-4,6-dimethoxyacetophenone from leaves of Peperomia glabella

Marisi G. Soares^I; Ana P. V. de Felippe^I; Elsie F. Guimarães^I; Massuo J. Kato^I; Javier Ellena^II; Antonio C. Doriguetto^{*, III}

^IInstituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, 05508-900 São Paulo-SP, Brazil

^IIInstituto de Física de São Carlos, Universidade de São Paulo, CP 369, 13560-970 São Carlos-SP, Brazil

^IIIDepartamento de Ciências Exatas, Universidade Federal de Alfenas, 37130-000 Alfenas-MG, Brazil

ABSTRACT

The 2-hydroxy-4,6-dimethoxyacetophenone was isolated from the leaves of the Peperomia glabella (Piperaceae family). The molecule crystallizes in the space group P¹ with two independent molecules in the asymmetric unit. The structural analysis reveals an infinite two-dimensional network in the (011) plane, stabilized by intermolecular hydrogen bonds along [100] and van der Waals interactions along [011]. The molecules present strong intra-molecular hydrogen bonds [O1-HO1...O4 = 1.53(2) Å and O5-HO5...O8 = 1.38(2) Å]. The molecular conformation was analyzed using the MOGUL, a knowledge base of molecular geometry derived from the CSD (Cambridge Structural Database).

Keywords:Peperomia glabella, 2-hydroxy-4,6-dimethoxyacetophenone, X-ray diffraction

RESUMO

A 2-hidroxi-4,6-dimetoxiacetofenona foi isolada de folhas de Peperomia glabella (família Piperaceae). A substância cristaliza no grupo espacial P¹ com duas moléculas na unidade assimétrica. A análise estrutural revela uma rede bidimensional infinita no plano (011), estabilizada por ligações de hidrogênio inter-moleculares ao longo da direção [100] e interações de van der Waals ao longo da direção [011]. As moléculas apresentam fortes ligações de hidrogênio intra-moleculares [O1-HO1...O4 = 1,53(2) Å e O5-HO5...O8 = 1,38(2) Å]. A conformação molecular foi analisada usando o MOGUL, uma base de dados de geometria molecular derivada do CSD (Cambridge Structural Database).

Introduction

Peperomia glabella (Piperaceae) is an epiphyte used in Venezuelan folk medicine as an antiasthmatic.¹ Piperaceae family comprises 14 genera and 1950 species.² Among these, Piper and Peperomia are the most abundant with approximately 700 and 600 species, respectively.³ Phytochemical profile from genus Piper is characterized by occurrence of lignans and neolignans,^4,5 chromenes,^6-8 amides,^9,10 alkaloids,¹¹ Phenylpropanoids,¹² and cyclopentenedione derivatives.¹³ Comparative study showed divergence of secondary metabolism in cell suspension cultures and differentiated plants of P. cernuum and P.crassinervium.¹⁴ Compared with the genus Piper, few chemical investigations reported so far for Peperomia species have shown their common constituents as phenylpropanoids, benzopyrans, chromenes, and prenylated hydroquinones.^15-17 Additionally there are several nor/seco-compounds, e.g., the cyclobutane compound from Peperomia pellucida that seems to be produced by dimerisation of styryl phenol (a nor-phenylpropanoid).¹⁸P. glabella has been shown to contain one secolignan of butenolide skeleton.¹⁹ In this work we wish to report the structure of the 2-hydroxy-4,6-dimethoxy-acetophenone, (1), extracted from leaves of Peperomia glabella. Acetophenone derivatives have shown many interesting biological properties such as antinflammatory,^20,21 cytotoxic,²² and choleretic²³ activities. This compound was previously isolated from Artemisia maritima,²⁴Artemisia gypsaceae,²⁵ and Plagiochila fasciculata showing antifungal activities against Trichophyton mentagrophytes²⁶ from strain of Trichoderma pseudokoningii Rifai.²⁷ It is important to emphasize that (1) can be also obtained by synthetic route, from different starting compound, such as 1-hydroxy-3,5-dimethoxybenzene,^{28, 29} 2,4,6-trihydroxiacetophenone,³⁰ and 1,3,5-trihydroxybenzene.³¹

The aim of the present work is to determine unambiguously the molecular structure of (1) by X-ray diffraction (XRD) and its intra and inter-molecular geometry as well. To the best of our knowledge, this is the first occurrence of this class of compound in Peperomia species.

Experimental

General Considerations

The compound was isolated from leaves of samples of Peperomia glabella. All chemicals used during the extraction, purification and crystallization were of analytical or chromatography grade.

¹H and ¹³C NMR spectra (4.9 T) were recorded on a Bruker AC-200 spectrometer operating at room temperature, using tetramethylsilane as an internal reference.

Plant material, extraction and isolation of 2-hydroxy-4,6-dimethoxyacetophenone

Peperomia glabella samples were collected at Lençóis (12º 45' 19.5" S 41º 30' 34.1" W) Bahia, Brazil. The leaves (8.20 g) were extracted four times with methanol (300 mL each time) at room temperature. This extract (2.07 g) was submitted to normal-phase silica gel column chromatography using increasing proportions of hexane:CH₂Cl₂. 2-hydroxy-4,6-dimethoxyacetophenone was obtained as solid white, 172 mg, crystallized from CH₃OH:CH₂Cl₂.

Identification of 2-hydroxy-4,6-dimethoxyacetophenone

The ¹H NMR spectrum of (1) showed two aromatic meta hydrogens at d 6.05 and 5.93 (d, J 2.2 Hz). In addition, the acetophenone group was inferred from the methyl group at d 2.60 and confirmed by ¹³C NMR spectrum at d 32.7 and by acetophenone carbonyl at d 203.5. The additional substituents of the aromatic ring were defined as one quelated hydroxyl at d 11.20 and two methoxyls observed at d 3.85 (d 55.4) and d 3.81 (d 55.4). The ¹³C NMR spectrum (4.9 T) showed signals corresponding to four aromatic carbon quaternary atoms (d 105.8; 167.5; 166.0; and 162.7); and two aromatic methyne (d 90.6 and 93.0). Thus, compound (1) was identified as 2-hydroxy-4,6-dimethoxyacetophenone.²⁴

X-ray Structure analysis of 2-hydroxy-4,6-dimethoxyacetophenone

A well-shaped single crystal of (1) was selected for the XRD experiments. The intensity data were collected at 150 K on an Enraf-Nonius Kappa-CCD diffractometer (95 mm CCD camera on k-goniostat) with graphite monochromated Mo Ka (l = 0.71073 Å) radiation. The temperature was controlled using an Oxford Cryosystem low temperature device. Data collection (j scans and w scans with k offsets) was made using the COLLECT;³² integration and scaling of the reflections were performed with the HKL Denzo-Scalepack system of programs.³³ The final unit cell parameters were based on all reflections using HKL Scalepack.³³ The structure was solved using Direct Methods with SHELXS-97.³⁴ The model was refined by full-matrix least-squares procedures on F² using SHELXL-97.³⁴ H atoms of the phenyl and methyl groups were positioned stereochemically and were refined with fixed individual displacement parameters [U_iso(H) = 1.2U_eq(C_aromatic) or 1.5U_eq(C_methoxy)] using a riding model, with aromatic C-H distances of 0.95 Å and methyl C-H distances of 0.98 Å. The two hydroxyl H atoms were located by difference Fourier synthesis and were set as isotropic.

Data collections and experimental details for (1) are summarized in Table 1. The programs SHELXL-97, SHELXS-97, and ORTEP-3³⁵ were used within WinGX³⁶ to prepare materials for publication. The programs Mercury³⁷ and ORTEP-3 were used to prepare the molecular graphics.

Results and Discussion

Figure 1 shows an ORTEP-3³⁵ view of (1) with the atom numbering scheme. The structure crystallizes in P with two independent molecules in the asymmetric unit (labelled as A and B in Figure 1). Comparison of these molecules by the method of Kabsch³⁸ showed them to be very similar with a root mean square deviation between homologous atoms of 0.024 Å. This fact suggested that the crystal could belong to a higher symmetric space group with just one molecule per asymmetric unit. Closer scrutiny, however, showed this is not the case because the affin transformation relating the two moieties did not coincide with any of those belonging to other space group. This symmetry was also carefully examined using PLATON,³⁹ and it was concluded that P is in fact the correct space group.

The main geometric parameters are given in Table 2. The molecular conformation was analyzed using the MOGUL,⁴⁰ a knowledge base of molecular geometry derived from the Cambridge Structural Database (CSD)⁴¹ that provides rapid access to information on the preferred values of bond lengths, valence angles and acyclic torsion angles. The Figure 2 shows an example of the graphical result of the query molecule studied here (molecule A). The resulting histogram is the C1-O1 bond length comparing with the C-O bond lengths in CSD entries containing similar structures. As emphasized by Bruno et al.,⁴⁰ comparison of the dimensions of a newly determined small-molecule crystal structure with bond lengths and angles of similar structures in the CSD is useful as a check against refinement errors and to highlight unusual geometrical features. This study showed that all bond lengths and bond angles are in agreement with the expected values for a good X-ray diffraction structure refinement. However, the MOGUL analysis has pointed out two interesting geometrical features due to resonance involving the moiety O3-C5-C6-C7-O4 (see Figure 1 and Table 2). It was observed that C5-O3 and C6-C7 is shorter than the average query values whereas the C5-C6 and C7-O4 is longer than the expected ones. It is important to emphasize that the same behaviour (not shown in Table 2) was observed to the molecule B present in the asymmetric unit.

Both molecules in the asymmetric unit are almost flat. The largest deviations from the least squares plane through the aromatic ring system A are -0.176(4) and 0.112(4) Å for C8 and C9 atoms, respectively. Similar results were observed to the molecule B: the largest deviations were observed to the C18 (-0.173(4) Å) and C19 (0.120(4) Å) atoms. The least squares planes of the A and B molecules form an angle of 0.8(1)º. This result shows that the two moieties are in the same plane, which is also illustrated in Figures 3 and 4.

The molecules A and B exhibited strong intra-molecular hydrogen bonds involving O1-HO1...O4 and O5-HO5...O8, respectively (Table 3 and Figure 1). The weak inter-molecular hydrogen bond between the aromatic hydrogen linked to C4 (molecule A) and the adjacent carboxyl oxygen O1 at x+1, y, z stabilizes the packing of the molecule A and gives rise to an infinite one dimensional chain parallel to the [100] direction (Table 3, Figures 1 and 3). The same interaction occur to the molecule B involving the aromatic hydrogen linked to C14 (molecule B) and the adjacent carboxyl oxygen O5 at x+1, y, z. The chains form a planar structure, connected by van der Waals interactions along the [011] direction. Therefore, the chains are linked themselves, forming an infinite two-dimensional network parallel to the (011) plane. The stacking of these two-dimensional networks is shown in the Figure 4. It is also observed that double chains, which are related by the inversion symmetry, are formed along [100] direction either to molecule A or B. The distance between parallels two-dimensional networks is about 3.4 Å.

Acknowledgments

The authors are grateful to CNPq and FAPESP for financial support. One of us, MGS, thanks FAPESP for the postdoctoral fellowship.

Supplementary Information

¹H and ¹³C NMR data for 1 are avaliable free of charge at http://jbcs.sbq.org.br, as PDF file.

Supplementary crystallographic data sets for (1) is available through the Cambridge Structural Data Base, deposition number CCDC 296321. Copies of this information may be obtained free of charge from The Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: [phone]; e-mail: [e-mail] or http:www.ccdc.ac.uk

Received: January 31, 2006

Published on the web: July 20, 2006

FAPESP helped in meeting the publication costs of this article.

Supplementary Information

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Publication Dates

• Publication in this collection
  29 Jan 2007
• Date of issue
  Dec 2006

History

• Accepted
  20 July 2006
• Received
  31 Jan 2006