Crystal structure of bergapten: a photomutagenic and photobiologically active furan­ocoumarin

The title mol­ecule, bergapten, a psoralen/furan­ocoumarin derivative, possesses photocarcinogenic and photomutagenic activity. In the crystal, mol­ecules are linked via C—H⋯O hydrogen bonds, forming a three-dimensional framework.

Abstract

The title compound, C₁₂H₈O₄, is a furan­ocoumarin [systematic name: 4-meth­oxy-7H-furo[3,2-g]chromen-7-one], which was isolated from the Indian herb T. stictocarpum. The mol­ecule is almost planar with an r.m.s. deviation of 0.024 Å for the hetero atoms of the fused-ring system. In the crystal, mol­ecules are linked by C—H⋯O hydrogen bonds, forming a three-dimensional framework. There are offset π–π inter­actions present involving the coumarin moieties stacking along the a-axis direction [shortest inter-centroid distance = 3.717 (3) Å].

Chemical context  

The title mol­ecule, bergapten, is a linear furan­ocoumarin having a meth­oxy group in the benzene ring at position C5. This class of furano coumarins have absorption bands in the near UV region due to the presence of conjugated double bonds, and exhibit photomutagenic (Appendino, et al., 2004 ▸) and photocarcinogenic properties, binding with purine bases of DNA in living cells to yield photoadducts (Filomena et al., 2009 ▸). Based on this property, they are employed to treat numerous inflammatory skin diseases, such as atopic dermatitis, and pigment disorders like vitiligo and psoriasis by UV photodynamic therapy. In addition, due to their strong ability to absorb UV radiation, this class of mol­ecules are utilized as photoprotective agents, to prevent the absorption of harmful UV radiation by the skin. A variety of sun-screen lotions are widely used in dermatological applications in the cosmetic and pharmaceutical industries (Chen et al., 2007 ▸, 2009 ▸). In addition, the in vitro anti­proliferation activity and in vivo photoxicity of the title mol­ecule has been reported against epithelial cancer cell lines, including HL60, A431 (Conconi et al., 1998 ▸). Bergapten (5-meth­oxy psoralen/methoxsalen) has been used successfully in combination with UV photodynamic therapy to mange psoriasis and vitiligo; it inhibits proliferation in human hepatocellular carcinoma cell line (March et al., 1993 ▸). Experimental results revealed that its phototoxicity and photomutagenicity is exerted via a Diels–Alder reaction binding the double bond of a purine base of DNA in a living cell with the double bonds of bergapten to yield mono- and di-adducts (Conforti et al., 2009 ▸).

While this is the first report of the crystal structure of the title compound, its chemical structure was determined by spectrometric and spectroscopic analysis many years ago (Howell & Robertson, 1937 ▸; Ray et al., 1937 ▸; Lin et al., 1979 ▸; Confalone & Confalone, 1983 ▸).

Structural commentary  

The title compound (Fig. 1 ▸), belongs to the psoralen class of compounds and is composed of three fused rings viz. furan, benzene and pyrone. It is an almost planar mol­ecule with an r.m.s. deviation of 0.024 Å for the atoms of the fused ring system, O1–O2/C1–C11. The meth­oxy C atom, C12, is displaced from this mean plane by 0.925 (5) Å, while atoms O3 and O4 are displaced from the mean plane by 0.069 (3) and 0.035 (3) Å, respectively.

Figure 1.

A view of the mol­ecular structure of the title compound, with the atom labelling. Displacement ellipsoids are drawn at the 50% probability level.

Supra­molecular features  

In the crystal, mol­ecules are linked by a series of C—H⋯O hydrogen bonds, which are illustrated in Fig. 2 ▸ (see also Table 1 ▸). They form a three-dimensional network (Table 1 ▸ and Fig. 3 ▸). There are offset π–π inter­actions present involving the coumarin moieties stacking along the a-axis direction [shortest inter-centroid distance Cg2⋯Cg3ⁱ = 3.717 (3) Å, inter­planar distance = 3.425 (2) Å, slippage = 1.356 Å, Cg2 and Cg3 are the centroids of rings O2/C6/C7/C9–C11 and C1/C4–C8, respectively, symmetry code: (i) x − 1, y, z].

Figure 2.

A view of the various C—H⋯O hydrogen bonds (dashed lines; see Table 1 ▸ for details) in the crystal of the title compound.

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C2—H2⋯O3i	0.93	2.49	3.406 (5)	170
C3—H3⋯O4ii	0.93	2.57	3.484 (6)	170
C10—H10⋯O4iii	0.93	2.51	3.387 (5)	158
C12—H12A⋯O4ii	0.96	2.44	3.376 (5)	165

Symmetry codes: (i) ; (ii) ; (iii) .

Figure 3.

A view along the a axis of the crystal packing of the title compound. Hydrogen bonds are drawn as dashed lines (see Table 1 ▸) and H atoms not involved in these inter­actions have been omitted for clarity.

Database survey  

A search of the Cambridge Structural Database (CSD, Version 5.37, last update May 2016; Groom et al., 2016 ▸) gave 16 hits for the furan­ocoumarin skeleton with an O atom substituent in position 5, similar to the title compound. Two compounds closely resemble the title compound, viz. 5-hy­droxy­psolalen [JIXBOH; Ginderow, 1991 ▸] isolated from the bark of Citrus bergamia, and 5,8-di­meth­oxy­psoralen [ISIMP (293 K); Gopalakrishna et al., 1977 ▸] and [ISIMP01 (120 K); Napolitano et al., 2003 ▸]. The latter was isolated from the roots and leaves of Adiscanthus fusciflorus (Rutaceae).

Synthesis and crystallization  

The title compound was isolated as a colourless solid from the methanol extract of T. stictocarpum by means of column chromatography over silica gel by gradient elution with a mixture of binary solvents system hexane and ethyl acetate. It was purified by reverse phase high-pressure liquid chromatography. Colourless rod-like crystals, suitable crystals for X ray diffraction analysis, were obtained after the title compound was recrystallized three times from ethyl acetate:hexane (1:4) mixed solvents at room temperature by slow evaporation of the solvents (m.p. 469 K).

¹H NMR data (CHCl₃, 200 MHz) 8.13 (d, 1H, J = 9.8 Hz, H-9), 7.57 (d, 1H, J = 2.2 Hz, H-2), 7.11 (s, 1H, H-8), 7.05 (d, 1H, J = 2.2 Hz, H-3), 6.25 (d, 1H, J = 9.8 Hz, H-10), 4.26 (s, 3H, OCH₃). EIMS (70 ev) data: m/z (%) 216 (100; base peak/mol­ecular ion peak) [M ⁺], 201 (25.2%) [M ⁺−CH₃), 188 (25.7) [M ⁺−OCH₃], 173 (25.6) [M ⁺−(CH₃–CO)], 145 (33.8) [M ⁺−(OCH₃–CO₂)], 89(17.0).

Refinement  

Crystal data, data collection and structure refinement details are summarized in Table 2 ▸. The C-bound H atoms were included in calculated positions and treated as riding atoms: C—H = 0.93–0.96 Å with U _iso(H) = 1.5U _eq(C-meth­yl) and 1.2Ueq(C) for other H atoms. The structure was refined as a two-component twin [180° rotation about the a* axis; BASF = 0.3955 (2)].

Table 2. Experimental details.

Crystal data
Chemical formula	C12H8O4
M r	216.18
Crystal system, space group	Monoclinic, P21/c
Temperature (K)	299
a, b, c (Å)	3.8486 (8), 14.676 (2), 16.866 (3)
β (°)	92.12 (2)
V (Å3)	952.0 (3)
Z	4
Radiation type	Mo Kα
μ (mm−1)	0.12
Crystal size (mm)	0.44 × 0.08 × 0.02
Data collection
Diffractometer	Oxford Diffraction Xcalibur with a Sapphire CCD detector
Absorption correction	Multi-scan (CrysAlis RED; Oxford Diffraction, 2009 ▸)’
T min, T max	0.951, 0.998
No. of measured, independent and observed [I > 2σ(I)] reflections	7096, 7096, 3811
R int	0.08
(sin θ/λ)max (Å−1)	0.602
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.055, 0.138, 0.86
No. of reflections	7096
No. of parameters	147
H-atom treatment	H-atom parameters constrained
Δρmax, Δρmin (e Å−3)	0.19, −0.22

Computer programs: CrysAlis CCD and CrysAlis RED (Oxford Diffraction, 2009 ▸), SHELXS2014 (Sheldrick, 2008 ▸), SHELXL2014 (Sheldrick, 2015 ▸) and PLATON (Spek, 2009 ▸).

Supplementary Material

CCDC reference: 1491854

Additional supporting information: crystallographic information; 3D view; checkCIF report

supplementary crystallographic information

Crystal data

C12H8O4	Dx = 1.508 Mg m−3
Mr = 216.18	Melting point: 469 K
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 3.8486 (8) Å	Cell parameters from 870 reflections
b = 14.676 (2) Å	θ = 2.8–27.9°
c = 16.866 (3) Å	µ = 0.12 mm−1
β = 92.12 (2)°	T = 299 K
V = 952.0 (3) Å3	Needle, colourless
Z = 4	0.44 × 0.08 × 0.02 mm
F(000) = 448

Data collection

Oxford Diffraction Xcalibur with a Sapphire CCD detector diffractometer	7096 independent reflections
Radiation source: fine-focus sealed tube	3811 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.08
Rotation method data acquisition using ω and phi scans.	θmax = 25.4°, θmin = 2.8°
Absorption correction: multi-scan (CrysAlis RED; Oxford Diffraction, 2009)'	h = −4→4
Tmin = 0.951, Tmax = 0.998	k = −17→17
7096 measured reflections	l = −20→20

Refinement

Refinement on F2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.055	Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.138	H-atom parameters constrained
S = 0.86	w = 1/[σ2(Fo2) + (0.0738P)2] where P = (Fo2 + 2Fc2)/3
7096 reflections	(Δ/σ)max = 0.002
147 parameters	Δρmax = 0.19 e Å−3
0 restraints	Δρmin = −0.22 e Å−3

Special details

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

Refinement. Refined as a 2-component twin.

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

	x	y	z	Uiso*/Ueq
O1	0.7447 (9)	0.00489 (18)	0.37565 (18)	0.0525 (10)
O2	0.3156 (8)	0.26727 (18)	0.50579 (14)	0.0399 (9)
O3	0.7860 (9)	0.28906 (17)	0.24893 (16)	0.0510 (10)
O4	0.1046 (9)	0.3863 (2)	0.56614 (18)	0.0617 (11)
C1	0.6682 (13)	0.0956 (3)	0.3822 (3)	0.0392 (13)
C2	0.8854 (13)	−0.0043 (3)	0.3016 (3)	0.0534 (15)
H2	0.9619	−0.0595	0.2814	0.064*
C3	0.8989 (13)	0.0740 (3)	0.2626 (3)	0.0477 (14)
H3	0.9832	0.0833	0.2123	0.057*
C4	0.7573 (13)	0.1417 (3)	0.3137 (2)	0.0369 (12)
C5	0.6975 (12)	0.2354 (3)	0.3111 (2)	0.0344 (12)
C6	0.5523 (11)	0.2781 (3)	0.3757 (2)	0.0304 (11)
C7	0.4677 (11)	0.2262 (3)	0.4418 (2)	0.0348 (12)
C8	0.5234 (12)	0.1339 (3)	0.4477 (3)	0.0397 (13)
H8	0.4679	0.1003	0.4922	0.048*
C9	0.4692 (12)	0.3738 (3)	0.3771 (3)	0.0373 (13)
H9	0.5221	0.4101	0.3339	0.045*
C10	0.3191 (12)	0.4114 (3)	0.4385 (2)	0.0431 (13)
H10	0.2654	0.4732	0.4371	0.052*
C11	0.2370 (13)	0.3592 (3)	0.5074 (3)	0.0433 (13)
C12	0.6549 (14)	0.2653 (3)	0.1726 (2)	0.0652 (17)
H12A	0.7936	0.2173	0.1516	0.098*
H12B	0.6630	0.3175	0.1384	0.098*
H12C	0.4187	0.2450	0.1758	0.098*

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
O1	0.075 (3)	0.0265 (17)	0.056 (2)	0.0074 (19)	0.006 (2)	−0.0024 (16)
O2	0.054 (2)	0.0343 (18)	0.0321 (16)	0.0034 (18)	0.0073 (19)	0.0003 (14)
O3	0.081 (3)	0.0419 (18)	0.0300 (17)	−0.0206 (19)	0.005 (2)	0.0006 (15)
O4	0.089 (3)	0.052 (2)	0.045 (2)	0.018 (2)	0.025 (2)	−0.0027 (18)
C1	0.045 (4)	0.029 (3)	0.043 (3)	0.000 (3)	−0.007 (3)	0.000 (2)
C2	0.063 (4)	0.040 (3)	0.058 (3)	0.009 (3)	0.010 (3)	−0.013 (3)
C3	0.054 (4)	0.041 (3)	0.048 (3)	−0.001 (3)	0.007 (3)	−0.006 (2)
C4	0.040 (3)	0.032 (3)	0.039 (3)	−0.002 (3)	−0.001 (3)	−0.0073 (19)
C5	0.036 (3)	0.037 (3)	0.030 (2)	−0.006 (3)	0.001 (3)	0.001 (2)
C6	0.029 (3)	0.029 (2)	0.033 (2)	−0.002 (2)	−0.002 (2)	−0.001 (2)
C7	0.041 (3)	0.033 (3)	0.031 (2)	−0.002 (3)	0.005 (2)	−0.002 (2)
C8	0.049 (4)	0.033 (3)	0.038 (3)	−0.002 (3)	0.004 (3)	0.008 (2)
C9	0.047 (3)	0.030 (3)	0.035 (3)	−0.004 (2)	0.002 (3)	0.005 (2)
C10	0.056 (4)	0.029 (2)	0.044 (3)	0.004 (3)	0.001 (3)	0.003 (2)
C11	0.046 (4)	0.036 (3)	0.048 (3)	0.007 (3)	0.006 (3)	−0.001 (2)
C12	0.099 (5)	0.060 (3)	0.037 (3)	−0.013 (4)	0.001 (3)	−0.003 (2)

Geometric parameters (Å, º)

O1—C1	1.369 (5)	C4—C5	1.394 (6)
O1—C2	1.386 (5)	C5—C6	1.391 (5)
O2—C7	1.385 (4)	C6—C7	1.398 (5)
O2—C11	1.383 (5)	C6—C9	1.442 (5)
O3—C5	1.365 (4)	C7—C8	1.374 (5)
O3—C12	1.409 (4)	C8—H8	0.9300
O4—C11	1.200 (5)	C9—C10	1.325 (5)
C1—C8	1.376 (5)	C9—H9	0.9300
C1—C4	1.393 (6)	C10—C11	1.435 (5)
C2—C3	1.327 (6)	C10—H10	0.9300
C2—H2	0.9300	C12—H12A	0.9600
C3—C4	1.435 (6)	C12—H12B	0.9600
C3—H3	0.9300	C12—H12C	0.9600
C1—O1—C2	105.1 (3)	C8—C7—O2	116.2 (4)
C7—O2—C11	122.6 (3)	C8—C7—C6	123.7 (4)
C5—O3—C12	117.9 (3)	O2—C7—C6	120.1 (4)
O1—C1—C8	123.8 (4)	C1—C8—C7	114.2 (4)
O1—C1—C4	110.2 (4)	C1—C8—H8	122.9
C8—C1—C4	126.0 (4)	C7—C8—H8	122.9
C3—C2—O1	112.7 (4)	C10—C9—C6	121.4 (4)
C3—C2—H2	123.7	C10—C9—H9	119.3
O1—C2—H2	123.7	C6—C9—H9	119.3
C2—C3—C4	106.2 (4)	C9—C10—C11	121.7 (4)
C2—C3—H3	126.9	C9—C10—H10	119.1
C4—C3—H3	126.9	C11—C10—H10	119.1
C5—C4—C1	117.3 (4)	O4—C11—O2	116.1 (4)
C5—C4—C3	136.9 (4)	O4—C11—C10	127.2 (4)
C1—C4—C3	105.8 (4)	O2—C11—C10	116.8 (4)
O3—C5—C6	117.4 (4)	O3—C12—H12A	109.5
O3—C5—C4	123.2 (4)	O3—C12—H12B	109.5
C6—C5—C4	119.4 (4)	H12A—C12—H12B	109.5
C5—C6—C7	119.4 (4)	O3—C12—H12C	109.5
C5—C6—C9	123.2 (4)	H12A—C12—H12C	109.5
C7—C6—C9	117.4 (4)	H12B—C12—H12C	109.5
C2—O1—C1—C8	−179.8 (5)	C4—C5—C6—C9	−177.6 (4)
C2—O1—C1—C4	0.3 (5)	C11—O2—C7—C8	−178.5 (4)
C1—O1—C2—C3	−0.2 (6)	C11—O2—C7—C6	0.9 (6)
O1—C2—C3—C4	0.0 (6)	C5—C6—C7—C8	0.8 (6)
O1—C1—C4—C5	−179.6 (4)	C9—C6—C7—C8	178.3 (4)
C8—C1—C4—C5	0.5 (7)	C5—C6—C7—O2	−178.5 (4)
O1—C1—C4—C3	−0.3 (5)	C9—C6—C7—O2	−1.1 (6)
C8—C1—C4—C3	179.8 (5)	O1—C1—C8—C7	−179.9 (5)
C2—C3—C4—C5	179.2 (6)	C4—C1—C8—C7	−0.1 (7)
C2—C3—C4—C1	0.2 (6)	O2—C7—C8—C1	178.7 (4)
C12—O3—C5—C6	−126.8 (4)	C6—C7—C8—C1	−0.6 (7)
C12—O3—C5—C4	55.5 (6)	C5—C6—C9—C10	177.4 (5)
C1—C4—C5—O3	177.3 (4)	C7—C6—C9—C10	0.1 (7)
C3—C4—C5—O3	−1.7 (9)	C6—C9—C10—C11	1.1 (7)
C1—C4—C5—C6	−0.3 (7)	C7—O2—C11—O4	179.7 (4)
C3—C4—C5—C6	−179.3 (5)	C7—O2—C11—C10	0.3 (6)
O3—C5—C6—C7	−178.0 (4)	C9—C10—C11—O4	179.3 (5)
C4—C5—C6—C7	−0.3 (6)	C9—C10—C11—O2	−1.3 (7)
O3—C5—C6—C9	4.7 (6)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C2—H2···O3i	0.93	2.49	3.406 (5)	170
C3—H3···O4ii	0.93	2.57	3.484 (6)	170
C10—H10···O4iii	0.93	2.51	3.387 (5)	158
C12—H12A···O4ii	0.96	2.44	3.376 (5)	165

Symmetry codes: (i) −x+2, y−1/2, −z+1/2; (ii) x+1, −y+1/2, z−1/2; (iii) −x, −y+1, −z+1.