Crystal structure of the ethyl 2,4-dihy­droxy-6-methyl­benzoate from Illicium difengpi K.I.B et K.I.M.

Xiong, H.; Mao, S.; Lv, Q.; Zhang, N.

doi:10.1107/S2414314618017765

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 3| Part 12| December 2018| x181776

https://doi.org/10.1107/S2414314618017765

Open

access

Crystal structure of the ethyl 2,4-dihydroxy-6-methylbenzoate from Illicium difengpi K.I.B et K.I.M.

Huiping Xiong,^a Shilong Mao,^b Qianzhou Lv ^b and Ning Zhang ^b ^*

^aSchool of Mathematics and Physics, Shanghai University of Electric Power, Shanghai, 200090, People's Republic of China, and ^bDepartment of Pharmacy, Xuhui District Central Hospital, Shanghai, 200031, People's Republic of China
^*Correspondence e-mail: zhangningpharm@163.com

Edited by M. Zeller, Purdue University, USA (Received 29 November 2018; accepted 15 December 2018; online 21 December 2018)

The title compound, C₁₀H₁₂O₄, was isolated from Illicium difengpi K.I.B et K.I.M. An intramolecular O—H⋯O hydrogen bond stabilizes the molecular conformation. In the crystal, the compound forms offset slanted stacks of alternating inversion-related molecules along the a axis direction. Intermolecular O—H⋯O hydrogen bonds link the molecules into double strands parallel to the [101] direction.

Keywords: crystal structure; phenolic acid; 2,4-dihydroxy-6-methylbenzoic acid ethyl ester.

CCDC reference: 1885274

Structure description

Illicium difengpi is a small shrub growing in Guangxi province of China, belonging to the family Illiciaceae (He et al., 2014 ). The stem bark of I. difengpi is listed in the Chinese Pharmacopoeia (Pharmacopeia Committee of P. R. of China, 2010 ). It is an important traditional Chinese medicine and is mainly used as a treatment for rheumatic arthritics (Huang et al., 1996 ). The alcoholature of the stem bark of I. difengpi showed outstanding clinical efficacy and pharmacodynamics potency. Previous studies led to the isolation of phenylpropanoids, lignans, neolignans and triterpenoids from an extract of I. difengpi (Kouno et al., 1992 ,1993 ; Wang et al., 1994 ; Huang et al., 1997 ; Fang et al., 2010 , 2011 ; Chu et al., 2011 ; Li et al., 2013 , 2015a ,b ; Pan et al., 2016 ). An ongoing search for bioactive natural products from folk medicine resulted in the isolation of the title compound, which was previously obtained from Umbilicaria esculenta (Miyoshi) Minks (Qiu & Ding, 2001 ). The isolation of the title compound from the stem bark of I. difengpi and its crystal structure are reported here.

The molecular structure of the title compound is shown in Fig. 1. The molecular structure contains a methyl group, two hydroxyl groups, and a carboethoxy group, which are attached to C2, C4, C6 and C7 of the central benzene ring, respectively. An intramolecular O3—H3⋯O1 hydrogen bond (Table 1) stabilizes the molecular conformation.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O3—H3⋯O1	0.89 (2)	1.72 (3)	2.4868 (18)	143 (3)
O4—H4⋯O3ⁱ	0.96 (3)	1.91 (3)	2.853 (2)	169 (3)
C3—H3A⋯O4ⁱⁱ	0.93	2.54	3.290 (2)	138
Symmetry codes: (i) $[x+{\script{1\over 2}}, -y+{\script{1\over 2}}, z+{\script{1\over 2}}]$ ; (ii) $[x-{\script{1\over 2}}, -y+{\script{1\over 2}}, z-{\script{1\over 2}}]$ .

Figure 1
The molecular structure. Displacement ellipsoids are shown at the 50% probability level.

In the crystal, O4—H4⋯O3ⁱ and C3—H3A⋯O4ⁱⁱ hydrogen bonds link the molecules into double strands parallel to the [101] direction. (Fig. 2, Table 2). In the solid state, the compound also forms offset slanted stacks of alternating inversion-related molecules along the a-axis direction. (Fig. 3)

Table 2
Experimental details

Crystal data
Chemical formula	C₁₀H₁₂O₄
M_r	196.20
Crystal system, space group	Monoclinic, P2₁/n
Temperature (K)	293
a, b, c (Å)	7.818 (3), 17.017 (6), 8.189 (3)
β (°)	117.459 (4)
V (Å³)	966.7 (6)
Z	4
Radiation type	Mo Kα
μ (mm⁻¹)	0.10
Crystal size (mm)	0.15 × 0.13 × 0.08

Data collection
Diffractometer	Bruker SMART APEX CCD area-detector
Absorption correction	Multi-scan (SAINT-Plus; Bruker, 1999 )
T_min, T_max	0.405, 0.968
No. of measured, independent and observed [I > 2σ(I)] reflections	4542, 2097, 1390
R_int	0.037
(sin θ/λ)_max (Å⁻¹)	0.649

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.057, 0.172, 1.02
No. of reflections	2097
No. of parameters	135
No. of restraints	2
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.45, −0.23
Computer programs: SMART (Bruker, 1997 ), SAINT-Plus (Bruker, 1999), SHELXS97 and SHELXTL (Sheldrick, 2008 ), SHELXL2016 (Sheldrick, 2015 ) and publCIF (Westrip, 2010 ).

Figure 2
The packing of the title compound viewed along the a-axis direction. Dashed lines indicate hydrogen bonds.

Figure 3
One of the slanted stacks of inversion-related molecules along the a-axis direction.

A search of the Cambridge Crystallographic Database (version 5.39 with updates up to May 2018; Groom et al., 2016 ) indicated that no 2,4-dihydroxy-6-methylbenzoic acid ethyl ester has been structurally characterized. Four structurally similar 2,4-dihydroxy-6-methylbenzoic acid derivatives have been reported, namely (2-ethoxycarbonyl-3,5-dihydroxyphenyl)acetic acid monohydrate (Luck & Mendenhall, 2002 ), phomozin monohydrate (Mazars et al.,1990 ), 2,3-dimethyl-3-(O-orsellinoyl)lactic acid monohydrate (Declercq et al.,1991 ) and 2,3,4,5-tetrahydroxypentyl 4,6-dihydroxy-2,3-dimethylbenzoate (Talontsi et al., 2012 ).

Synthesis and crystallization

The stem bark of Illicium difengpi (5.0 kg), which was purchased from Caitongde Pharmacy, Shanghai, China, was powdered and extracted three times with aqueous ethanol (ethanol/water 8:2) under reflux. The solvent was then evaporated under reduced pressure to obtain a dry residue (150 g). The residue was suspended in water (2 L) and extracted successively with petroleum ether (3 × 2 L), EtOAc (3 × 2 L) and BuOH (3 × 2 L), affording 5 g, 70 g, and 40 g, respectively, of each dried fraction. The EtOAc fraction was subjected to silica gel column chromatography using gradient elution (CH₂Cl₂/CH₃OH, 200:1 to 2:1, v/v) to give four main fractions (Fr.1-1–Fr.1-4), of which Fr.1-2 was purified by successive silica gel column chromatography (CH₂Cl₂/CH₃OH, 100:1→20:1); 2,4-dihydroxy-6-methylbenzoic acid ethyl ester (30 mg) was obtained from the fraction eluted by CH₂Cl₂/CH₃OH (40:1). Single crystals suitable for X-ray diffraction analysis were obtained by slow evaporation from acetone solution after two weeks at room temperature.

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2.

Structural data

CCDC reference: 1885274

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2414314618017765/zl4028sup1.cif

Supporting information file. DOI: https://doi.org/10.1107/S2414314618017765/zl4028Isup2.cml

checkCIF report

Computing details top

Data collection: SMART (Bruker, 1997); cell refinement: SMART (Bruker, 1997); data reduction: SAINT-Plus (Bruker, 1999); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2016 (Sheldrick, 2015); molecular graphics: SHELXTL (Sheldrick, 2008) and publCIF (Westrip, 2010); software used to prepare material for publication: SHELXTL (Sheldrick, 2008) and publCIF (Westrip, 2010).

Ethyl 2,4-dihydroxy-6-methylbenzoate top

Crystal data top

C₁₀H₁₂O₄	F(000) = 416
M_r = 196.20	D_x = 1.348 Mg m⁻³
Monoclinic, P2₁/n	Mo Kα radiation, λ = 0.71073 Å
a = 7.818 (3) Å	Cell parameters from 878 reflections
b = 17.017 (6) Å	θ = 2.4–26.4°
c = 8.189 (3) Å	µ = 0.10 mm⁻¹
β = 117.459 (4)°	T = 293 K
V = 966.7 (6) Å³	Sheet, colorless
Z = 4	0.15 × 0.13 × 0.08 mm

Data collection top

Bruker SMART APEX CCD area-detector diffractometer	1390 reflections with I > 2σ(I)
phi and ω scans	R_int = 0.037
Absorption correction: multi-scan (SAINT-Plus; Bruker, 1999)	θ_max = 27.5°, θ_min = 2.4°
T_min = 0.405, T_max = 0.968	h = −5→10
4542 measured reflections	k = −21→22
2097 independent reflections	l = −10→8

Refinement top

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)] = 0.057	Hydrogen site location: mixed
wR(F²) = 0.172	H atoms treated by a mixture of independent and constrained refinement
S = 1.02	w = 1/[σ²(F_o²) + (0.1019P)²] where P = (F_o² + 2F_c²)/3
2097 reflections	(Δ/σ)_max < 0.001
135 parameters	Δρ_max = 0.45 e Å⁻³
2 restraints	Δρ_min = −0.23 e Å⁻³

Special details top

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. The positions of hydroxyl H atoms attached to O3 and O4 were refined. All other H atoms were positioned geometrically and treated as riding atoms: C—H = 0.93–0.97 Å. U_iso(H) were set to 1.5U_eq(C/O) for CH₃ and OH, and to 1.2U_eq(C) for CH₂ and aromatic C—H.

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

	x	y	z	U_iso*/U_eq
O1	−0.0021 (2)	0.46363 (7)	−0.27773 (18)	0.0663 (5)
O2	0.11562 (18)	0.57656 (6)	−0.13811 (16)	0.0529 (4)
O3	0.1367 (2)	0.33529 (7)	−0.13142 (19)	0.0679 (5)
H3	0.050 (4)	0.3664 (16)	−0.216 (3)	0.102*
O4	0.6778 (2)	0.32885 (8)	0.44828 (18)	0.0718 (5)
H4	0.648 (4)	0.2753 (16)	0.410 (4)	0.108*
C1	0.2660 (2)	0.45967 (8)	0.0181 (2)	0.0420 (4)
C2	0.2682 (2)	0.37634 (9)	0.0131 (2)	0.0484 (4)
C3	0.4047 (3)	0.33288 (9)	0.1552 (3)	0.0551 (5)
H3A	0.403637	0.278312	0.148712	0.066*
C4	0.5412 (3)	0.37051 (10)	0.3052 (2)	0.0524 (5)
C5	0.5453 (3)	0.45134 (10)	0.3168 (2)	0.0525 (5)
H5	0.640522	0.475644	0.420632	0.063*
C6	0.4098 (2)	0.49723 (9)	0.1763 (2)	0.0450 (4)
C7	0.1165 (2)	0.49885 (9)	−0.1435 (2)	0.0450 (4)
C8	−0.0274 (3)	0.61634 (11)	−0.3005 (3)	0.0612 (5)
H8A	−0.156271	0.600967	−0.324130	0.073*
H8B	−0.010341	0.602890	−0.407205	0.073*
C9	0.0009 (4)	0.70282 (12)	−0.2630 (3)	0.0802 (7)
H9A	−0.015784	0.715282	−0.156911	0.120*
H9B	−0.091898	0.731300	−0.367576	0.120*
H9C	0.128638	0.717279	−0.240524	0.120*
C10	0.4251 (3)	0.58478 (9)	0.2029 (3)	0.0592 (5)
H10A	0.535726	0.597063	0.317280	0.089*
H10B	0.310970	0.604287	0.205170	0.089*
H10C	0.438365	0.608915	0.103419	0.089*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0702 (9)	0.0471 (7)	0.0545 (8)	−0.0021 (6)	0.0056 (7)	−0.0024 (5)
O2	0.0591 (8)	0.0349 (6)	0.0567 (8)	0.0057 (5)	0.0198 (6)	0.0033 (5)
O3	0.0783 (10)	0.0327 (6)	0.0659 (9)	−0.0050 (6)	0.0105 (7)	−0.0064 (5)
O4	0.0743 (10)	0.0545 (8)	0.0646 (9)	0.0156 (7)	0.0131 (8)	0.0103 (6)
C1	0.0470 (9)	0.0329 (8)	0.0473 (9)	−0.0001 (6)	0.0228 (8)	−0.0009 (6)
C2	0.0547 (10)	0.0351 (8)	0.0517 (10)	−0.0036 (7)	0.0214 (8)	−0.0036 (7)
C3	0.0657 (12)	0.0326 (8)	0.0659 (11)	0.0043 (8)	0.0294 (10)	0.0027 (8)
C4	0.0542 (10)	0.0455 (9)	0.0558 (10)	0.0095 (8)	0.0238 (9)	0.0080 (8)
C5	0.0501 (10)	0.0517 (10)	0.0479 (10)	−0.0036 (7)	0.0159 (8)	−0.0053 (7)
C6	0.0497 (9)	0.0377 (8)	0.0484 (9)	−0.0032 (7)	0.0234 (8)	−0.0029 (7)
C7	0.0496 (9)	0.0357 (8)	0.0485 (9)	−0.0018 (7)	0.0217 (8)	−0.0015 (7)
C8	0.0674 (12)	0.0505 (10)	0.0580 (11)	0.0125 (9)	0.0223 (10)	0.0125 (8)
C9	0.0965 (17)	0.0464 (11)	0.0998 (17)	0.0137 (10)	0.0471 (14)	0.0177 (10)
C10	0.0657 (12)	0.0390 (9)	0.0612 (11)	−0.0087 (8)	0.0192 (10)	−0.0093 (8)

Geometric parameters (Å, º) top

O1—C7	1.220 (2)	C4—C5	1.378 (3)
O2—C7	1.323 (2)	C5—C6	1.390 (2)
O2—C8	1.451 (2)	C5—H5	0.9300
O3—C2	1.3502 (19)	C6—C10	1.502 (2)
O3—H3	0.89 (2)	C8—C9	1.499 (3)
O4—C4	1.365 (2)	C8—H8A	0.9700
O4—H4	0.96 (3)	C8—H8B	0.9700
C1—C6	1.417 (2)	C9—H9A	0.9600
C1—C2	1.419 (2)	C9—H9B	0.9600
C1—C7	1.461 (2)	C9—H9C	0.9600
C2—C3	1.377 (2)	C10—H10A	0.9600
C3—C4	1.359 (2)	C10—H10B	0.9600
C3—H3A	0.9300	C10—H10C	0.9600

C7—O2—C8	116.70 (13)	O1—C7—O2	120.51 (15)
C2—O3—H3	112.1 (18)	O1—C7—C1	123.39 (15)
C4—O4—H4	103.7 (17)	O2—C7—C1	116.10 (13)
C6—C1—C2	117.54 (14)	O2—C8—C9	106.95 (15)
C6—C1—C7	126.02 (14)	O2—C8—H8A	110.3
C2—C1—C7	116.42 (14)	C9—C8—H8A	110.3
O3—C2—C3	116.31 (14)	O2—C8—H8B	110.3
O3—C2—C1	121.87 (14)	C9—C8—H8B	110.3
C3—C2—C1	121.82 (15)	H8A—C8—H8B	108.6
C4—C3—C2	119.36 (15)	C8—C9—H9A	109.5
C4—C3—H3A	120.3	C8—C9—H9B	109.5
C2—C3—H3A	120.3	H9A—C9—H9B	109.5
C3—C4—O4	120.56 (15)	C8—C9—H9C	109.5
C3—C4—C5	121.07 (15)	H9A—C9—H9C	109.5
O4—C4—C5	118.36 (16)	H9B—C9—H9C	109.5
C4—C5—C6	121.27 (16)	C6—C10—H10A	109.5
C4—C5—H5	119.4	C6—C10—H10B	109.5
C6—C5—H5	119.4	H10A—C10—H10B	109.5
C5—C6—C1	118.93 (15)	C6—C10—H10C	109.5
C5—C6—C10	117.23 (15)	H10A—C10—H10C	109.5
C1—C6—C10	123.84 (14)	H10B—C10—H10C	109.5

C6—C1—C2—O3	179.79 (15)	C2—C1—C6—C5	0.4 (2)
C7—C1—C2—O3	−1.4 (2)	C7—C1—C6—C5	−178.29 (16)
C6—C1—C2—C3	−0.3 (2)	C2—C1—C6—C10	−179.25 (15)
C7—C1—C2—C3	178.47 (16)	C7—C1—C6—C10	2.1 (3)
O3—C2—C3—C4	−179.87 (17)	C8—O2—C7—O1	−2.1 (2)
C1—C2—C3—C4	0.3 (3)	C8—O2—C7—C1	177.74 (14)
C2—C3—C4—O4	179.75 (17)	C6—C1—C7—O1	178.68 (16)
C2—C3—C4—C5	−0.2 (3)	C2—C1—C7—O1	0.0 (2)
C3—C4—C5—C6	0.3 (3)	C6—C1—C7—O2	−1.1 (2)
O4—C4—C5—C6	−179.68 (16)	C2—C1—C7—O2	−179.83 (14)
C4—C5—C6—C1	−0.4 (2)	C7—O2—C8—C9	−179.38 (14)
C4—C5—C6—C10	179.29 (16)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O1	0.89 (2)	1.72 (3)	2.4868 (18)	143 (3)
O4—H4···O3ⁱ	0.96 (3)	1.91 (3)	2.853 (2)	169 (3)
C3—H3A···O4ⁱⁱ	0.93	2.54	3.290 (2)	138

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

Acknowledgements

The authors thank Professor Zhenxia Chen (Department of Chemistry, Fudan University, Shanghai) for the structure analysis.

Funding information

Funding for this research was provided by: Research Project of Xuhui District Central Hospital (award No. 201706).

References

Bruker (1997). SMART. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Bruker (1999). SAINT-Plus. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Chu, S.-S., Wang, C.-F., Du, S.-S., Liu, S.-L. & Liu, Z.-L. (2011). J. Insect Sci. 11, 152. Google Scholar
Declercq, J.-P., Klaebe, A., Rossignol, M. & Mazars, C. (1991). Acta Cryst. C47, 470–472. CrossRef IUCr Journals Google Scholar
Fang, L., Du, D., Ding, G.-Z., Si, Y.-K., Yu, S.-S., Liu, Y., Wang, W.-J., Ma, S.-G., Xu, S., Qu, J., Wang, J. M. & Liu, Y. X. (2010). J. Nat. Prod. 73, 818–824. CrossRef Google Scholar
Fang, L., Wang, X.-J., Ma, S.-G. & Yu, S.-S. (2011). Acta Pharm. Sin. B, 1, 178–183. CrossRef Google Scholar
Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. Web of Science CrossRef IUCr Journals Google Scholar
He, Y.-Z., Osoro, E. K., Palmer, S. I., Wang, L.-N. & Aboud, N. S. (2014). Chinese Herbal Medicines, 6, 76–79. CrossRef Google Scholar
Huang, P., Nishi, M., Zheng, X.-Z., Lai, M.-X. & Naknishi, T. (1997). Acta Pharm. Sin, 32, 704–707. Google Scholar
Huang, P., Xi, Z.-M., Zheng, X.-Z., Lai, M.-X. & Zhong, X.-Q. (1996). Acta Pharm. Sin, 31, 278–281. Google Scholar
Kouno, I., Yanagida, Y., Shimono, S., Shintomi, M., Ito, Y. & Chun-Shu, Y. (1993). Phytochemistry, 32, 1573–1577. CrossRef Google Scholar
Kouno, I., Yanagida, Y., Shimono, S., Shintomi, M. & Yang, C.-S. (1992). Chem. Pharm. Bull. 40, 2461–2464. CrossRef Google Scholar
Li, C.-T., Wu, Z.-J. & Chen, W.-S. (2013). Evid-Based Compl. Alt, 2013, 942541. Google Scholar
Li, C.-T., Wu, Z.-J. & Chen, W.-S. (2015a). Nat. Prod. Res. 29, 1793–1797. CrossRef Google Scholar
Li, C.-T., Wu, Z.-J. & Chen, W.-S. (2015b). Rec. Nat. Prod, 9, 251–261. Google Scholar
Luck, R. L. & Mendenhall, G. D. (2002). Acta Cryst. E58, o1387–o1388. CrossRef IUCr Journals Google Scholar
Mazars, C., Rossignol, M. P., Auriol, P. & Klaebe, A. (1990). Phytochemistry, 29, 3441–3444. CrossRef Google Scholar
Pan, Z.-H., Ning, D.-S., Huang, S.-S., Cheng, L., Xia, M.-W., Peng, L.-Y. & Li, D.-P. (2016). Molecules, 21, 607. CrossRef Google Scholar
Pharmacopeia Committee of P. R. of China (2010). Pharmacopoeia of People's Republic of China. Beijing: Medical Science and Technology Press. Google Scholar
Qiu, C. & Ding, Y. (2001). China J. Chin. Mater. Med, 26, 608–610. Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Sheldrick, G. M. (2015). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Talontsi, F. M., Nwemeguela Kenla, T. J., Dittrich, B., Douanla-Meli, C. & Laatsch, H. (2012). Planta Med. 78, 1020–1023. Google Scholar
Wang, J.-L., Yang, C.-S. & Da, W.-R. (1994). China J. Chin. Mater. Med, 19, 422–423. Google Scholar
Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925. Web of Science CrossRef CAS IUCr Journals Google Scholar

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.