Molecular and Crystal Structures of Three Berberine Derivatives
1
Department of Organic Chemistry, Faculty of Science, Masaryk University, Kotlářská 2, CZ-611 37 Brno, Czech Republic
2
Department of Inorganic Chemistry, Faculty of Science, Masaryk University, Kotlářská 2, CZ-611 37 Brno, Czech Republic
3
Department of Biochemistry, Faculty of Medicine, Masaryk University, Komenského nám. 2, CZ-662 43 Brno, Czech Republic
*
Author to whom correspondence should be addressed.
Molecules 2001, 6(5), 433-441; https://doi.org/10.3390/60500433
Submission received: 23 February 2001
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Revised: 9 April 2001
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Accepted: 10 April 2001
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Published: 30 April 2001
Abstract
:Berberine azide, berberine thiocyanate, and 8-cyano-8H-berberine were prepared from berberine chloride, a quaternary protoberberine alkaloid. The molecular and crystal structures of all compounds are reported and discussed.
Introduction
Berberine (1) is a yellow quaternary protoberberine alkaloid occuring in many plant species of the Berberidaceae and other families. Berberine is known as an antimicrobial agent for the treatment of eye infections, gastrointestinal disorders, and other diseases [1,2]. The chemistry of berberine and related alkaloids may deal either with side chains alterations to form structural analogs [3] or with nucleophile attack on the iminium C=N+ bond [4,5]. Continuing our research on the conversions of isoquinoline alkaloids with nucleophiles we investigated the reactions of berberine chloride with azide, thiocyanate, and cyanide ions.
Results and Discussion
The protoberberine skeleton is derived from 5,6-dihydrodibenzo[a,g]quinolizinium. Berberine (1) is a tetrasubstituted alkaloid with a methylenedioxy group at C2 and C3, and two methoxy groups at C9 and C10. The susceptibility of berberine to nucleophilic attack at carbon C8 is known and several adducts are described in literature, especially those with oxygen- and carbon-nucleophiles [4,5]. An early example is the reaction with cyanide which provides 8-cyano-8H-berberine (2) (8-cyanodihydroberberine, berberine pseudocyanide) [6]. Little is known about reactions of berberine with nitrogen- and sulfur-nucleophiles.
We tried to prepare berberine adducts by rection with azide and thiocyanate ions. Under the described experimental conditions, berberine chloride (1a) did not give expected adducts. An excess of sodium azide led to a mere exchange of counter-anions so that we isolated berberine azide (1b) as a principal product. The IR spectrum of 1b indicated an intensive band of the antisymmetric valence vibration of azide ion [N=N=N]- at 2035 cm−1. The reaction of 1a with sodium thiocyanate proceeded similarly to yield berberine thiocyanate (1c). On the other hand, the reaction of berberine chloride with NaCN, performed according to literature [7], gave 8-cyano-8H-berberine (2). After slow recrystallizations, all the three products afforded crystals suitable for X-ray data collection.
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Crystal data and selected geometric parameters of the compounds 1b, 1c, 2 are summarized in Table 1, Table 2. All bond lengths and angles are within normal range. The quaternary cations in 1b and 1c are relatively planar species (Fig. 1, Fig. 2). Planarity is disturbed only in a partially saturated ring B. The ring B adopts a twisted half-chair conformation with the atoms C5 and C6 significantly deviated from the best plane of the aromatic rings A and C. The shortest bond length, 1.334(3) Å (1b), 1.332(4) Å (1c), is for the iminium N7-C8 bond in the ring C. The longest bonds are C4a-C5 (sp2-sp3) and C5-C6 (sp3-sp3) (Table 2). Similar findings were made in other berberine salts (chloride, bromide, iodide, sulfate, hydrogen sulfate) [8,9] and jatrorrhizine chloride, a protoberberine alkaloid with a different substitution pattern [10]. In the molecule of berberine, two aromatic parts can be distinguished, the ring A and the fused rings C,D. The least-squared planes calculated for these two parts are twisted by 10° (1b) and 15° (1c), respectively. The azide ion is linear with the angle N21-N22-N23 178.9(3)° and quite symmetrical with both the bond lengths of 1.179(3) Å. Berberine azide crystallized with one molecule of acetonitrile. The thiocyanate ion in 1c is also nearly linear, the N21-C22-S23 angle is 176.9(4)°. The bond lengths are 1.186(6) Å (C22-N21) and 1.625(6) Å (S23-C22).
Figure 1.
A perspective view of berberine azide (1b)
Figure 2.
A perspective view of berberine thiocyanate (1c)
| Parameter | 1b | 1c | 2 |
|---|---|---|---|
| Empirical formula | C20H18N4O4 ⋅ CH3CN | C21H18N2O4S | C21H18N2O4 |
| Formula weight | 419.44 | 394.43 | 362.37 |
| Temperature (K) | 150(2) | 293(2) | 150(2) |
| Crystal system | Triclinic | Triclinic | Monoclinic |
| Space group | P-1 | P-1 | P2(1)/c |
| a (Å) | 8.571(2) | 7.037(1) | 10.634(1) |
| b (Å) | 9.367(2) | 10.613(2) | 18.328(1) |
| c (Å) | 13.003(3) | 12.344(2) | 9.789(1) |
| α (°) | 88.21(3) | 101.18(3) | 90 |
| β (°) | 75.94(3) | 94.37(3) | 116.30(1) |
| γ (°) | 81.25(3) | 97.69(3) | 90 |
| Volume (Å−3) | 1000.9(4) | 895.1(3) | 1710.4 (3) |
| Z | 2 | 2 | 4 |
| Calc. density (Mg/m−3) | 1.392 | 1.463 | 1.407 |
| Crystal size (mm) | 0.4 × 0.1 × 0.1 | 0.2 × 0.1 × 0.1 | 0.5 × 0.5 × 0.3 |
| Crystal colour | Yellow | Yellow | Orange-red |
| θ range (°) | 3.57 - 25.00 | 3.22 - 28.46 | 2.57 - 25.00 |
| Index ranges | h -5 → 10 | h -6 → 9 | h -12 → 8 |
| k -11 → 11 | k -13 → 13 | k -21 → 21 | |
| l -15 → 15 | l -16 → 15 | l -11 → 11 | |
| Reflections collected / Unique | 6219 / 3353 | 6394 / 3808 | 16293 / 3008 |
| Data / Restraints / Parameters | 3353 / 0 / 281 | 3808 / 0 / 254 | 3008 / 0 / 245 |
| Final R indices [I>2σ (I)] | 0.0629 / 0.1618 | 0.0829 / 0.2195 | 0.0436 / 0.0984 |
| R indices (all data) | 0.0835 / 0.1961 | 0.1149 / 0.2790 | 0.0494 / 0.1050 |
| Hydrogen atoms treatment | Constrained | Constrained | Constrained |
| Largest diff. peak and hole (e.Å−3) | 0.432 and -0.348 | 0.620 and -0.675 | 0.222 and -0.230 |
| Bond / Angle | 1b | 1c | 2 |
|---|---|---|---|
| C4a-C13b | 1.400(3) | 1.402(5) | 1.400(2) |
| C4a-C5 | 1.504(4) | 1.506(5) | 1.505(2) |
| C5-C6 | 1.509(4) | 1.500(5) | 1.515(2) |
| C6-N7 | 1.492(3) | 1.484(4) | 1.462(2) |
| N7-C13a | 1.391(3) | 1.390(4) | 1.416(2) |
| C13a-C13b | 1.464(3) | 1.469(5) | 1.474(2) |
| N7-C8 | 1.334(3) | 1.332(4) | 1.451(2) |
| C8-C8a | 1.398(3) | 1.400(4) | 1.515(2) |
| C8a-C12a | 1.423(3) | 1.410(4) | 1.401(2) |
| C12a-C13 | 1.404(3) | 1.406(4) | 1.445(2) |
| C2-O17 | 1.380(3) | 1.366(4) | 1.379(2) |
| O17-C14 | 1.433(3) | 1.433(5) | 1.441(2) |
| C14-O18 | 1.442(3) | 1.430(5) | 1.433(2) |
| O18-C3 | 1.379(3) | 1.366(4) | 1.372(2) |
| C9-O19 | 1.376(3) | 1.364(4) | 1.3854(19) |
| O19-C15 | 1.443(3) | 1.427(5) | 1.441(2) |
| C10-O20 | 1.358(3) | 1.350(4) | 1.3699(19) |
| O20-C16 | 1.431(3) | 1.436(4) | 1.428(2) |
| C8-N7-C6 | 117.5(2) | 118.6(3) | 114.12(13) |
| C8-N7-C13a | 122.3(2) | 122.4(3) | 115.94(13) |
| C13a-N7-C6 | 120.1(2) | 118.9(3) | 118.55(13) |
| C8a-C9-O19 | 118.8(2) | 119.7(3) | 119.63(14) |
| C9-O19-C15 | 113.3(2) | 115.0(3) | 112.75(13) |
| C10-C9-O19 | 121.2(2) | 121.1(3) | 120.64(14) |
| C9-C10-O20 | 116.7(2) | 116.7(3) | 115.61(14) |
| C10-O20-C16 | 118.0(2) | 117.5(3) | 117.09(13) |
| C11-C10-O20 | 123.6(2) | 124.3(3) | 124.86(14) |
8-Cyano-8H-berberine (2) is an adduct of berberine with CN- ion. The nucleophilic attack altered the nature of the ring C so that it is partially saturated. The nitrogen aton N7 is trivalent and the C8 atom has the sp3 hybridization. The shortest bond length is in the cyano group C21-N22 1.145(2) Å, the longest bonds are C5-C6 in ring B and C8-C8a in ring C, both 1.515(2) Å. The ring C is in a half-chair conformation with atom C8 deviated from the mean plane of the ring. The ring B conformation resembles those in berberine azide and thiocyanate (Fig. 3). The puckering parameters of the six-membered heterocyclic rings in all three derivatives were calculated [12] and the values are listed in Table 3.
Figure 3.
A perspective view of 8-cyano-8H-berberine (2)
| Compound / Ring | Q [Å] | θ [°] | φ [°] |
|---|---|---|---|
| 1b / B (N7 to C13a) | 0.428(3) | 117.3(4) | 269.8(4) |
| 1b / C (N7 to C13a) | τ = 0.8 ° | ||
| 1c / B (N7 to C13a) | 0.504(4) | 65.8(5) | 83.9(4) |
| 1c / C (N7 to C13a) | τ = 2.0 ° | ||
| 2 / B (N7 to C13a) | 0.523(2) | 115.9(2) | 265.7(2) |
| 2 / C (N7 to C13a) | 0.411(2) | 67.1(3) | 30.2(3) |
In all three compounds, the dioxolane ring C2-O17-C14-O18-C3 is reasonably planar, the methoxy group at C10 (O20-C16) more or less in-plane, and the methoxy group at C9 almost perpendicular to the D-ring plane (Table 4).
| Torsion angle | 1b | 1c | 2 |
|---|---|---|---|
| C8a-C9-O19-C15 | 96.8(3) | -97.1(4) | -103.08 (17) |
| C10-C9-O19-C15 | -86.3(3) | 84.1(4) | 78.90(18) |
| C9-C10-O20-C16 | -179.0(2) | 167.1(3) | 168.27(14) |
| C11-C10-O20-C16 | 0.9(4) | -12.1(5) | -13.00(14) |
In both ionic structures of 1b and 1c, the organic cations pack in centrosymmetric pairs which in turn form columns, mutully parallel. Similar arrangement has been reported for other berberine salts [9]. The spaces between columns are occupied by anions (1b, 1c) and solvent molecules (1b). On the other hand, no similar pairing can be observed in the spatial arrangement of neutral 8-cyano-8H-berberine (2).
Experimental
General
Melting points were determined on a Kofler hot-plate Rapido 792106 and are uncorrected. Infrared spectra were measured on a ATI Mattson Genesis FT IR spectrometer in KBr pellets (wavenumbers in cm−1). 1H- and 13C-NMR spectra (δ, ppm; J, Hz) were recorded on a Bruker Avance DRX 500 spectrometer in DMSO-d6 with TMS as an internal standard. 1H and 13C assignments were based on H,H-COSY, NOESY, and HBMC experiments. Mass spectra were determined on a Finnigan MAT TSQ 700 instrument in electron impact mode (70 eV). Berberine chloride (1a), m.p. 200-206 °C, isolated from Berberis vulgaris L., was obtained from the Department of Biochemistry, Faculty of Medicine, Masaryk University Brno.
X-ray diffraction analysis
Diffraction data were collected on a KUMA KM-4 κ-axis diffractomer using either ω-2θ (1b, 1c) or ω scan mode (area detector, 2). Both structures were solved by direct methods and refined by full-matrix least-squares methods using SHELXTL program package [11].
Syntheses
Berberine azide (1b).- Berberine chloride (100 mg, 0.23 mmol) was suspended in water and sodium azide (500 mg, 7.7 mmol) was added. The mixture was refluxed for 1 h. After cooling to room temperature a yellow precipitate was collected, washed with water and dried. Yield: 76 mg (74 %). M.p. 196-201 °C. IR (KBr) 3007, 2945, 2945, 2920, 2847, 2035 (s, N3-), 1600, 1506, 1388, 1362, 1331, 1272, 1235, 1102, 1037 cm−1. 1H-NMR spectrum (DMSO-d6) was in agreement with that of berberine chloride [13]. Slow evaporation of saturated acetonitrile solution afforded a single crystal for X-ray diffraction analysis.
Berberine thiocyanate (1c).- Berberine chloride (100 mg, 0.23 mmol) was suspended in water and sodium thiocyanate (500 mg, 6 mmol) was added. The mixture was refluxed for 2 h. After cooling to room temperature a yellow precipitate was collected, washed with water and dried. Yield: 81 mg (76%). M.p. 224-227 °C. IR (KBr) 3052, 2989, 2943, 2912, 2845, 2051 (s, SCN-), 1600, 1504, 1388, 1362, 1337, 1274, 1231, 1102, 1034 cm−1. 1H-NMR spectrum (DMSO-d6) was in agreement with that of berberine chloride [13]. Slow evaporation of saturated aqueous solution afforded a single crystal for X-ray diffraction analysis.
8-Cyano-8H-berberine (2).- Sodium cyanide (160 mg, 2.5 mmol) dissolved in water was added to a solution of berberine chloride (100 mg, 0.23 mmol) in methanol. The mixture was refluxed for 15 min. After slow cooling to 5 °C a brown precipitate was separated and recrystallized from diethyl ether. Yield: 13 mg (13 %) of red- orange crystals. M.p. 163-172 °C. IR (KBr) 3056, 2938, 2911, 2845, 2224 (w, C≡N), 1603, 1502, 1389, 1363, 1338, 1276, 1233, 1168, 1092, 1038 cm−1. 1H-NMR (DMSO-d6): 2.75-2.90 (m, 2H, H5); 3.10-3.18 + 3.47-3.52 (m, 2H, H6); 3.83 (s, 3H, 10-OMe); 3.87 (s, 3H, 9-OMe); 5.97 (s, 1H, H8); 6.02 + 6.03 (2× s, 2H, OCH2O); 6.35 (s, 1H, H13); 6.79 (s, 1H, H4); 6.89 (d, 8.4 Hz, 1H, H12); 7.05 (d, 8.4 Hz, 1H, H11); 7.35 (s, 1H, H1). 13C-NMR (DMSO-d6): 29.1 (C5), 47.3 (C6), 49.5 (C8), 56.4 (10-OMe), 61.0 (9-OMe), 98.1 (C13), 101.5 (OCH2O), 104.2 (C1), 108.3 (C4), 114.7 (C11), 117.0 (C8a), 117.3 (CN), 119.9 (C12), 123.9 (C13b), 127. 1 (C12a), 129.1 (C4a), 138.5 (C13a), 144.4 (C9), 147.1 (C2), 147.8 (C3), 150.7 (C10). EIMS m/z (%): 362 (M+, 63), 347 (18), 320 (52), 306 (27), 292 (28), 278 (47).
Acknowledgements
This research project was supported by the Ministry of Education of the Czech Republic (FRVŠ 403/99 and CEZ:J07/98:143100011), and by the Grant Agency of the Czech Republic (203/99/0067).
References
- Schmeller, T.; Wink, M. Alkaloids: Biochemistry, Ecology, and Medicinal Applications; Roberts, M. F., Wink, M., Eds.; Plenum Press: New York, 1998; Chapter 18; p. 438. [Google Scholar]
- Simeon, S.; Rios, J. L.; Villar, A. Pharmacological activities of protoberberine alkaloids. Plant. Med. Phytother. 1989, 23, 202–250. [Google Scholar]
- Iwasa, K.; Kim, H. S.; Wataya, Y.; Lee, D. U. Antimalarial activity and structure-activity relationships of protoberberine alkaloids. Eur. J. Med. Chem. 1998, 33, 65–69. [Google Scholar] [CrossRef]
- Bentley, K. W. The Isoquinoline Alkaloids; Harwood Academic Publishers: Amsterdam, 1998; pp. 219–264. [Google Scholar]
- Bhakuni, D. S.; Jain, S. The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1986; vol. 28, Chapter 2; pp. 95–181. [Google Scholar]
- Robinson, G. M.; Robinson, R. Researches on pseudo-bases. Part II. Note on some berberine derivatives and remarks on the mechanism of the condensation reactions of pseudo-bases. J. Chem. Soc. 1917, 111, 958–969. [Google Scholar] [CrossRef]
- Vennerstrom, J. L.; Klayman, D. L. Protoberberine alkaloids as antimalarials. J. Med. Chem. 1988, 31, 1084–1087. [Google Scholar] [CrossRef] [PubMed]
- Abadi, B. E. A.; Moss, D. S.; Palmer, R. A. Molecular structure of an ancient folk medicine: berberine hydrogen sulfate. J. Crystalogr. Spectrosc. Res. 1984, 14, 269–281. [Google Scholar] [CrossRef]
- Kariuki, B. M.; Jones, W. Five salts of berberine. Acta Cryst. C 1995, 51, 1234–1240. [Google Scholar] [CrossRef]
- Ghosh, R.; Mukherjee, K.; Roychowdhury, P.; Klayman, D. L. Structure of an antimalarial alkaloid, jatrorrhizine. Acta Cryst. C 1993, 49, 1665–1667. [Google Scholar] [CrossRef]
- SHELXTL Version 5.1. Bruker AXS, GmbH: Karlsruhe, Germany, 1998.
- Spek, A. L. PLATON, A Multipurpose Crystallographic Tool. Utrecht University: Utrecht, The Netherlands, 2000. [Google Scholar]
- Blasko, G.; Cordell, G. A.; Bhamarapravati, S.; Beecher, C. W. W. Carbon-13 NMR assignments of berberine and sanguinarine. Heterocycles 1988, 27, 911–916. [Google Scholar]
- Sample Availability: Samples may be synthesized by the authors on request.
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MDPI and ACS Style
Man, S.; Potáček, M.; Nečas, M.; Žák, Z.; Dostál, J. Molecular and Crystal Structures of Three Berberine Derivatives. Molecules 2001, 6, 433-441. https://doi.org/10.3390/60500433
AMA Style
Man S, Potáček M, Nečas M, Žák Z, Dostál J. Molecular and Crystal Structures of Three Berberine Derivatives. Molecules. 2001; 6(5):433-441. https://doi.org/10.3390/60500433
Chicago/Turabian StyleMan, Stanislav, Milan Potáček, Marek Nečas, Zdirad Žák, and Jiří Dostál. 2001. "Molecular and Crystal Structures of Three Berberine Derivatives" Molecules 6, no. 5: 433-441. https://doi.org/10.3390/60500433
