Crystal structure and Hirshfeld surface analysis of a third polymorph of 2,6-di­meth­oxy­benzoic acid

Portalone, G.

doi:10.1107/S2056989020014553

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Volume 76| Part 12| December 2020| Pages 1823-1826

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Crystal structure and Hirshfeld surface analysis of a third polymorph of 2,6-dimethoxybenzoic acid

Gustavo Portalone ^a ^*

^aChemistry Department, "Sapienza" University of Rome, P. le A. Moro 5, I-00185 Rome, Italy
^*Correspondence e-mail: gustavo.portalone@uniroma1.it

Edited by H. Ishida, Okayama University, Japan (Received 7 July 2020; accepted 3 November 2020; online 6 November 2020)

A third crystalline form of the title compound, C₉H₁₀O₄, crystallizing in the centrosymmetric monoclinic space group P2₁/c, has been identified during screening for co-crystals. The asymmetric unit comprises a non-planar independent molecule with a synplanar conformation of the OH group. The sterically bulky o-methoxy substituents force the carboxy group to be twisted away from the plane of the benzene ring by 74.10 (6)°. The carboxy group exhibits the acidic H atom disordered over two sites between two O atoms. A similar situation has been found for the second tetragonal polymorph reported [Portalone (2011 ). Acta Cryst. E67, o3394–o3395], in which molecules with the OH group in a synplanar conformation form dimeric units via strong O—H⋯O hydrogen bonds. In contrast, in the first orthorhombic form reported [Swaminathan et al. (1976 ). Acta Cryst. B32, 1897–1900; Bryan & White (1982 ). Acta Cryst. B38, 1014–1016; Portalone (2009 ). Acta Cryst. E65, o327–o328], the molecular components do not form conventional dimeric units, as an antiplanar conformation adopted by the OH group favors the association of molecules in chains stabilized by linear O—H⋯O hydrogen bonds.

Keywords: crystal structure; benzoic acids; polymorphism; hydrogen bond; 2,6-dimethoxybenzoic acid.

CCDC reference: 2042162

1. Chemical context

Until now, two polymorphs are known for 2,6-dimethoxybenzoic acid. Polymorph (Iα) crystallizes in the orthorhombic space group P2₁2₁2₁ with one molecule in the asymmetric unit (Swaminathan et al., 1976; Bryan & White, 1982; Portalone, 2009). As a result of the antiplanar conformation adopted by the OH group, the molecular components are associated in the crystal in chains stabilized by linear O—H⋯O hydrogen bonds. Polymorph (Iβ) crystallizes in the tetragonal space group P4₁2₁2 with one molecule in the asymmetric unit (Portalone, 2011). In the crystal of the second polymorph, the synplanar conformation of the OH group favours the formation of dimers through O—H⋯O hydrogen bonds. In this article, it is reported the crystal structure of a third polymorph, (Iγ), of 2,6-dimethoxybenzoic acid produced unexpectedly during an attempt to synthesize co-crystals of 5-fluorouracil with the title compound.

2. Structural commentary

The title compound (Iγ) crystallizes in the monoclinic centrosymmetric space group P2₁/c, and the asymmetric unit comprises a non-planar independent molecule. The carboxy group is twisted away from the plane of the benzene ring by 74.10 (6)° because of a significant steric hindrance of the two o-methoxy substituents (Fig. 1). The above angle between the planes is comparable with that found for the orthorhombic form, 56.12 (9)°, and for the tetragonal form, 65.72 (15)°. The carboxy group, in which OH adopts a synplanar conformation similar to that observed for the tetragonal form, exhibits the carboxy H atom disordered over two sites between two O atoms. The pattern of bond lengths and bond angles of the phenyl ring is consistent with that reported in the structure determination of the two previously determined polymorphs, and a comparison of the present results with those obtained for similar benzene derivatives (Colapietro et al., 1984 ; Irrera et al., 2012 ; Portalone, 2012 ) shows no appreciable effects of the crystal environment on the ring deformation induced by substituents.

Figure 1
The molecular structure of (Iγ), showing the atom-labeling scheme. Displacement ellipsoids are at the 50% probability level.

3. Supramolecular features

Analysis of the crystal packing of (Iγ), (Fig. 2), shows that the molecular components form the conventional dimeric units observed in benzoic acids (Leiserowitz, 1976 ; Kanters et al., 1991 ; Moorthy et al., 2002 ). Indeed, the crystal structure is stabilized by strong intermolecular O—H⋯O hydrogen bonds, which link inversion-related molecules into homodimers (Table 1). These homodimers are then joined by weak C—H⋯O intermolecular interactions of graph-set motif R₂²(6) between the methoxy and the carboxy groups of adjacent molecules to form a two-dimensional network parallel to the bc plane.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1⋯O2ⁱ	0.86 (6)	1.79 (6)	2.6411 (15)	174 (4)
O2—H2⋯O1ⁱ	0.81 (6)	1.84 (6)	2.6411 (15)	167 (5)
C9—H9A⋯O2ⁱⁱ	0.97	2.60	3.571 (3)	178
Symmetry codes: (i) ; (ii) $[-x+1, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ .

Figure 2
Crystal packing diagram for (Iγ) viewed approximately down the a axis. All atoms are shown as small spheres of arbitrary radii. Hydrogen bonding is indicated by red dashed lines.

The Hirshfeld surface analysis (Spackman & Jayatilaka, 2009 ) was carried out using CrystalExplorer (Turner et al., 2017 ). The surface enables the visualization of intermolecular contacts over the surface by different colors and color intensity, and shorter and longer contacts are indicated as red and blue spots, respectively. In Fig. 3 are shown the 3D Hirshfeld surface, modeled by choosing one of the two equally disordered components and mapped over d_norm, and the two-dimensional fingerprint plots, which give the contribution of the interatomic contacts to the Hirshfeld surface. The most prominent interactions, due to strong O—H⋯O hydrogen bonds, are shown by large and deep red spots on the surface. Small red spots on the surface indicate the areas where close-contact interactions due to weak C—H⋯O hydrogen bonds take place. The H⋯H contacts, representing van der Waals interactions, and the O⋯H/H⋯O contacts, representing intermolecular hydrogen bonds, are the most populated contacts and contribute 39.2 and 39.1% of the total intermolecular contacts, respectively. Other important contacts, such as C⋯H/H⋯C (19.1%), also supplement the overall crystal packing. The contributions of the O⋯C/C⋯O (2.5%) contacts are less significant.

Figure 3
(a) A view of the three-dimensional Hirshfeld surface of the title compound mapped over d_norm with a fixed color scale of −0.742 (red) to 1.283 (blue) a.u. (b), (c), (d), (e) and (f): decomposed two-dimensional fingerprint plots for the title compound showing various close contacts and their proportional contributions.

4. Database survey

A search of crystal structure of 2,6-dimethoxy benzoic acid alone in the Cambridge Crystallographic Database (CSD version 5.41, May 2020 update; Groom et al., 2016 ) yielded four hits as crystalline polymorphs. Three were for the orthorhombic polymorph: DMOXBA (Swaminathan et al., 1976), DMOXBA01 (Bryan & White, 1982) and DMOXBA02 (Portalone, 2009); the fourth one was for the tetragonal polymorph: DMOXBA03 (Portalone, 2011).

5. Synthesis and crystallization

Polymorph (Iγ) was formed from an unsuccessful co-crystallization between 2,6-dimethoxybenzoic acid and 5-fluorouracil. Colorless plate-like crystals were formed by the slow evaporation of an aqueous solution of 2,6-dimethoxybenzoic acid (1 mmol, Sigma Aldrich at 99% purity) and 5-fluorouracil (1 mmol, Sigma Aldrich at 99% purity) in a 1:1 molar ratio.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. All H atoms were identified in difference-Fourier maps, but in the refinement all C-bound H atoms were placed in calculated positions, with C—H = 0.97 Å, and refined as riding on their carrier atoms, with U_iso(H) = 1.2U_eq(C_phenyl) or 1.5U_eq(C_methyl). A rotating group model was applied to the methyl groups. The remaining two halves of the disordered O-bound H atom, H1 and H2, were refined freely and their U_iso values were kept equal to 1.2U_eq(O). Site-occupation factors of H1 and H2 refined to 0.53 (3) and 0.47 (3), respectively.

Table 2
Experimental details

Crystal data
Chemical formula	C₉H₁₀O₄
M_r	182.17
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	298
a, b, c (Å)	7.7574 (10), 8.4763 (10), 14.3322 (19)
β (°)	97.526 (12)
V (Å³)	934.3 (2)
Z	4
Radiation type	Mo Kα
μ (mm⁻¹)	0.10
Crystal size (mm)	0.20 × 0.14 × 0.11

Data collection
Diffractometer	Oxford Diffraction Xcalibur S CCD
Absorption correction	Multi-scan (CrysAlis RED; Rigaku OD, 2018 $[Rigaku OD (2018). CrysAlis PRO and CrysAlis RED. Rigaku Oxford Diffraction, Yarnton, England.]$ )
T_min, T_max	0.970, 0.999
No. of measured, independent and observed [I > 2σ(I)] reflections	9067, 2708, 1420
R_int	0.040
(sin θ/λ)_max (Å⁻¹)	0.704

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.049, 0.132, 1.02
No. of reflections	2708
No. of parameters	134
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.14, −0.12
Computer programs: CrysAlis PRO (Rigaku OD, 2018 $[Rigaku OD (2018). CrysAlis PRO and CrysAlis RED. Rigaku Oxford Diffraction, Yarnton, England.]$ ), SIR2004 (Burla et al., 2005 ), SHELXL2014/7 (Sheldrick, 2015 ) and WinGX (Farrugia, 2012 ).

Supporting information

CCDC reference: 2042162

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2056989020014553/is5548sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989020014553/is5548Isup2.hkl

checkCIF report

Computing details top

Data collection: CrysAlis PRO (Rigaku OD, 2018); cell refinement: CrysAlis PRO (Rigaku OD, 2018); data reduction: CrysAlis PRO (Rigaku OD, 2018); program(s) used to solve structure: SIR2004 (Burla et al., 2005); program(s) used to refine structure: SHELXL2014/7 (Sheldrick, 2015); molecular graphics: WinGX (Farrugia, 2012); software used to prepare material for publication: WinGX (Farrugia, 2012).

2,6-Dimethoxybenzic acid. top

Crystal data top

C₉H₁₀O₄	F(000) = 384
M_r = 182.17	D_x = 1.295 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.710689 Å
a = 7.7574 (10) Å	Cell parameters from 1806 reflections
b = 8.4763 (10) Å	θ = 2.9–32.6°
c = 14.3322 (19) Å	µ = 0.10 mm⁻¹
β = 97.526 (12)°	T = 298 K
V = 934.3 (2) Å³	Tablets, colourless
Z = 4	0.20 × 0.14 × 0.11 mm

Data collection top

Oxford Diffraction Xcalibur S CCD diffractometer	2708 independent reflections
Radiation source: Enhance (Mo) X-ray source	1420 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.040
Detector resolution: 16.0696 pixels mm^-1	θ_max = 30.0°, θ_min = 2.9°
ω and φ scans	h = −10→10
Absorption correction: multi-scan (CrysAlis RED; Rigaku OD, 2018)	k = −11→6
T_min = 0.970, T_max = 0.999	l = −19→20
9067 measured reflections

Refinement top

Refinement on F²	Hydrogen site location: mixed
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F² > 2σ(F²)] = 0.049	w = 1/[σ²(F_o²) + (0.0439P)² + 0.0492P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.132	(Δ/σ)_max < 0.001
S = 1.02	Δρ_max = 0.14 e Å⁻³
2708 reflections	Δρ_min = −0.12 e Å⁻³
134 parameters	Extinction correction: SHELXL-2014/7 (Sheldrick 2015\bbr000), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
0 restraints	Extinction coefficient: 0.031 (4)

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.

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

	x	y	z	U_iso*/U_eq	Occ. (<1)
O1	0.50254 (16)	0.32576 (15)	0.56267 (9)	0.0726 (4)
H1	0.446 (6)	0.372 (5)	0.515 (3)	0.087*	0.53 (3)
O2	0.68711 (16)	0.52450 (15)	0.57631 (9)	0.0776 (5)
H2	0.643 (7)	0.571 (6)	0.530 (4)	0.093*	0.47 (3)
O3	0.94633 (16)	0.24939 (16)	0.59823 (10)	0.0827 (4)
O4	0.50328 (18)	0.39851 (17)	0.76761 (9)	0.0900 (5)
C1	0.73003 (19)	0.31878 (17)	0.68819 (11)	0.0531 (4)
C2	0.8886 (2)	0.24603 (19)	0.68370 (13)	0.0622 (5)
C3	0.9743 (2)	0.1717 (2)	0.76309 (15)	0.0767 (6)
H3	1.0852	0.1199	0.7610	0.092*
C4	0.8991 (3)	0.1731 (2)	0.84415 (15)	0.0836 (7)
H4	0.9582	0.1201	0.8992	0.100*
C5	0.7430 (3)	0.2467 (2)	0.85095 (13)	0.0782 (6)
H5	0.6940	0.2474	0.9099	0.094*
C6	0.6574 (2)	0.3199 (2)	0.77134 (12)	0.0648 (5)
C7	0.63417 (19)	0.39559 (18)	0.60344 (10)	0.0508 (4)
C8	1.1123 (3)	0.1829 (4)	0.5897 (2)	0.1261 (10)
H8A	1.2012	0.2385	0.6310	0.158 (12)*
H8B	1.1358	0.1925	0.5251	0.152 (12)*
H8C	1.1129	0.0723	0.6072	0.169 (13)*
C9	0.4198 (3)	0.4098 (3)	0.84841 (17)	0.0986 (7)
H9A	0.3944	0.3048	0.8698	0.139 (10)*
H9B	0.3122	0.4684	0.8337	0.129 (9)*
H9C	0.4950	0.4641	0.8976	0.155 (12)*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0660 (8)	0.0702 (8)	0.0718 (8)	−0.0169 (6)	−0.0278 (6)	0.0167 (6)
O2	0.0747 (8)	0.0651 (8)	0.0823 (9)	−0.0180 (6)	−0.0302 (7)	0.0257 (7)
O3	0.0585 (8)	0.1008 (10)	0.0873 (10)	0.0180 (7)	0.0041 (6)	0.0170 (8)
O4	0.0984 (10)	0.1059 (11)	0.0659 (9)	0.0408 (8)	0.0118 (7)	0.0165 (7)
C1	0.0513 (8)	0.0503 (8)	0.0525 (9)	0.0003 (7)	−0.0128 (7)	0.0062 (7)
C2	0.0512 (9)	0.0611 (10)	0.0693 (12)	−0.0009 (7)	−0.0108 (8)	0.0098 (8)
C3	0.0579 (10)	0.0739 (12)	0.0904 (14)	0.0082 (9)	−0.0199 (10)	0.0192 (10)
C4	0.0835 (14)	0.0788 (13)	0.0775 (14)	0.0018 (11)	−0.0309 (11)	0.0234 (10)
C5	0.0925 (15)	0.0788 (12)	0.0580 (11)	0.0040 (11)	−0.0103 (9)	0.0152 (9)
C6	0.0712 (11)	0.0584 (10)	0.0599 (11)	0.0086 (8)	−0.0104 (9)	0.0068 (8)
C7	0.0461 (8)	0.0509 (8)	0.0522 (9)	0.0012 (7)	−0.0057 (6)	0.0047 (7)
C8	0.0704 (16)	0.173 (3)	0.138 (3)	0.0443 (17)	0.0250 (17)	0.037 (2)
C9	0.1151 (19)	0.0953 (17)	0.0891 (16)	0.0249 (15)	0.0273 (15)	0.0135 (14)

Geometric parameters (Å, º) top

O1—C7	1.2563 (17)	C3—C4	1.367 (3)
O1—H1	0.86 (6)	C3—H3	0.9700
O2—C7	1.2472 (18)	C4—C5	1.377 (3)
O2—H2	0.81 (6)	C4—H4	0.9700
O3—C2	1.359 (2)	C5—C6	1.389 (2)
O3—C8	1.425 (2)	C5—H5	0.9700
O4—C6	1.363 (2)	C8—H8A	0.9701
O4—C9	1.402 (2)	C8—H8B	0.9701
C1—C6	1.383 (2)	C8—H8C	0.9701
C1—C2	1.385 (2)	C9—H9A	0.9701
C1—C7	1.4885 (19)	C9—H9B	0.9701
C2—C3	1.391 (2)	C9—H9C	0.9701

C7—O1—H1	117 (3)	O4—C6—C1	115.07 (14)
C7—O2—H2	124 (3)	O4—C6—C5	124.95 (19)
C2—O3—C8	118.50 (17)	C1—C6—C5	119.97 (17)
C6—O4—C9	119.91 (16)	O2—C7—O1	123.27 (13)
C6—C1—C2	120.51 (14)	O2—C7—C1	119.20 (13)
C6—C1—C7	118.92 (14)	O1—C7—C1	117.53 (14)
C2—C1—C7	120.57 (16)	O3—C8—H8A	109.5
O3—C2—C1	115.62 (14)	O3—C8—H8B	109.5
O3—C2—C3	124.61 (17)	H8A—C8—H8B	109.5
C1—C2—C3	119.74 (18)	O3—C8—H8C	109.5
C4—C3—C2	118.64 (18)	H8A—C8—H8C	109.5
C4—C3—H3	120.7	H8B—C8—H8C	109.5
C2—C3—H3	120.7	O4—C9—H9A	109.5
C3—C4—C5	122.81 (16)	O4—C9—H9B	109.5
C3—C4—H4	118.6	H9A—C9—H9B	109.5
C5—C4—H4	118.6	O4—C9—H9C	109.5
C4—C5—C6	118.33 (19)	H9A—C9—H9C	109.5
C4—C5—H5	120.8	H9B—C9—H9C	109.5
C6—C5—H5	120.8

C8—O3—C2—C1	177.2 (2)	C9—O4—C6—C5	0.1 (3)
C8—O3—C2—C3	−4.9 (3)	C2—C1—C6—O4	178.43 (14)
C6—C1—C2—O3	178.84 (15)	C7—C1—C6—O4	−2.2 (2)
C7—C1—C2—O3	−0.5 (2)	C2—C1—C6—C5	−0.5 (3)
C6—C1—C2—C3	0.9 (2)	C7—C1—C6—C5	178.92 (15)
C7—C1—C2—C3	−178.51 (14)	C4—C5—C6—O4	−179.32 (17)
O3—C2—C3—C4	−178.01 (17)	C4—C5—C6—C1	−0.5 (3)
C1—C2—C3—C4	−0.2 (3)	C6—C1—C7—O2	106.30 (19)
C2—C3—C4—C5	−0.8 (3)	C2—C1—C7—O2	−74.3 (2)
C3—C4—C5—C6	1.2 (3)	C6—C1—C7—O1	−73.7 (2)
C9—O4—C6—C1	−178.74 (18)	C2—C1—C7—O1	105.66 (18)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···O2ⁱ	0.86 (6)	1.79 (6)	2.6411 (15)	174 (4)
O2—H2···O1ⁱ	0.81 (6)	1.84 (6)	2.6411 (15)	167 (5)
C9—H9A···O2ⁱⁱ	0.97	2.60	3.571 (3)	178

Symmetry codes: (i) −x+1, −y+1, −z+1; (ii) −x+1, y−1/2, −z+3/2.

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