(±)-2,2-Dimethyl-5-oxotetra­hydro­furan-3-carb­oxy­lic acid (terebic acid): a racemic layered structure

A racemic crystalline form of terebic acid, C₇H₁₀O₄, which is an important industrial chemical compound, is reported for the first time. The crystal structure is stabilized by O-H...O and C-H...O hydrogen bonds which form racemic double layers parallel to (001).

S1. Comment

Terebic acid, (I), belongs to the γ-lactone family (five-membered cyclic ester). Lactones are generally formed by an intramolecular dehydration reaction (cyclocondensation) of hydroxy acid or by an intermolecular dehydration followed by a cyclization involving an alcohol and a carboxylic acid (Yoshida et al., 2011; Eckert et al., 2011).

Terebic acid and its derivatives, as well as substances in which (I) participates as a precursor, have been reported as having anti-inflammatory, antibiotic (Fisnerova et al., 1982), antithrombotic (Franciskovich et al., 2006) and antitumoral (Gielen et al., 1998) properties. (I) derivatives are also present in pharmaceutical formulations with dermatological (Malle, 2009) and capillary (Kang & Lim, 2004) applications and have been shown to be useful as a prophylaxis agent for physiological disorders (Ikeura et al., 2009). Although the first synthesis of terebic acid dates from the end of the 19th century and despite its industrial importance, its crystal structure remains unknown. In the present study, the first racemic crystalline form of (I) (Fig. 1) is reported.

The intramolecular geometry of (I) was analyzed using Mogul (Bruno et al., 2004), a knowledge base of molecular geometry derived from the Cambridge Structural Database (CSD; Version ???; Allen, 2002). This study shows that all bond lengths and bond angles are in agreement with the expected values for a good X-ray diffraction structure refinement. As expected in the case of γ-lactones, differences in the two C—O3 bond distances are observed. The O3—C4 bond [1.4718 (16) Å; Mogul average query = 1.48 (2) Å] is longer than the O3—C3 bond [1.3262 (17) Å; Mogul average query = 1.35 (2) Å].

In (I), the lactone ring adopts an envelope conformation with atom C1 at the flap position. The puckering parameters of Cremer & Pople (1975) [q₂ = 0.282 (2) Å and ϕ₂ = 114.0 (3)°] confirm the envelope on C1 for the five-membered ring. Atoms O1 and C1 deviate by -0.076 (6) and 0.446 (2) Å, respectively, from the least-squares plane through the C2—C3—O3—C4 moiety [r.m.s. deviation = 0.0153 Å and largest deviation = 0.019 (1) Å for O3]. The previous calculated plane forms an angle of 28.1 (1)° with that through the C2—C1—C4 moiety. An intramolecular nonclassical hydrogen bond is observed, in which C2 acts as hydrogen-bond donor to the carboxyl O4 atoms. The hydrogen-bond geometry is given in Table 1.

The supramolecular analysis of (I) shows that there are O—H···O and C—H···O hydrogen bonds involving the ketone and carboxyl groups and the lactone ring, contributing to the stabilization of the crystal packing (Figs. 2 and 3, Table 1). In the solid state, carboxylic acids generally form supramolecular dimers with R₂²(8) assemblies [see Bernstein et al. (1995) for nomenclature of hydrogen-bond motifs] as observed, for example, for the three polymorphs of 4-(dimethylamino)benzoic acid (Aakeröy et al., 2005). However, when there are other hydrogen-bond donating or accepting functional group(s) in the same molecule, a successful rate of carboxylic dimer motif is smaller (Beyer & Price, 2000), as observed for (I). The strongest intermolecular force is a classical hydrogen bond having the carboxylic atom O2 as hydrogen-bonding donor to the ketone atom O1ⁱ [symmetry code: (i) x-1, y-1, z], giving rise to a translation-related pure-enantiomer chain along the [110] direction, as shown in Fig. 2. An extended racemic double chain is formed in the same direction since a nonclassical hydrogen bond gives rise to a related racemic dimer R₂²(8) having C2 as the hydrogen-bonding donor to the ketone atom O1ⁱⁱ [symmetry code: (ii) -x+1, -y+2, -z]. The aggregation in [110] includes R₄²(14) and R₂²(8) assemblies (Fig. 2). Each chain shown in Fig. 2 is itself connected along the [110] direction by weak intermolecular interactions involving the H atoms of the asymmetric C atom and the O atoms of an adjacent lactone carbonyl group, C1—H1···O1ⁱⁱⁱ [symmetry code: (iii) x-1, y, z], which contribute to an R₄⁴(20) assembly (Fig. 3). The chains which form the layers are separated by 3.908 Å, considering a least-squares plane through the adjacent lactonic rings. Fig. 3 shows the layer formed by the S enantiomers, which contain translation-related molecules along the a and b axes considering the asymmetric unit. Finally, a racemic double layer parallel to (001) is completed by a layer consisting of the R enantiomer at (-x, -y, -z) and its translations along the a and b axes. Because of the space-group symmetry, another racemic double layer also occurs at the middle of the c axis defined by translation along the a and b axes of molecules generated by the 2₁ screw axis and the c-glide plane (Fig. 4). The difference is that chains grow along [110] and they are themselves stacked along [110]. Considering the three intermolecular hydrogen bonds, it is noted that atom O1 acts as a trifurcated hydrogen-bond acceptor (Figs. 2 and 3).

Related literature

For related literature, see: Aakeröy et al. (2005); Allen (2002); Bernstein et al. (1995); Beyer & Price (2000); Bruno et al. (2004); Cremer & Pople (1975); Eckert et al. (2011); Fisnerova et al. (1982); Franciskovich et al. (2006); Gielen et al. (1998); Ikeura et al. (2009); Kang & Lim (2004); Malle (2009); Yoshida et al. (2011).

S2. Experimental

Commercial racemic terebic acid (Sigma–Aldrich) was used. Colourless prismatic crystals of (I) were obtained from an isopropyl alcohol solution by slow evaporation at room temperature.

S3. Refinement

H atoms on C atoms were positioned stereochemically and were refined with fixed individual displacement parameters [U_iso(H) = 1.5U_eq(C) for methyl groups or 1.2U_eq(C) for methine and methylene groups], using a riding model and rotating group model (for methyl group), with C—H bond lengths of 0.96, 0.97 and 0.98 Å for methyl, methine and methylene groups, respectively. The hydroxy H atom was located by difference Fourier synthesis and refined with free coordinates and with U_iso(H) = 1.5U_eq(O).

Computing details

Data collection: COLLECT (Nonius, 1999); cell refinement: SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO and SCALEPACK (Otwinowski & Minor, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997) and Mercury (Macrae et al., 2006); software used to prepare material for publication: WinGX (Farrugia, 1999) and publCIF (Westrip, 2010).

Figures

	Fig. 1. The molecular structure of (I) (S enantiomer), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radii. The intramolecular interaction is shown as a dashed line.
	Fig. 2. A partial packing diagram for (I), showing the racemic double chain formed along [110]. The R and S enantiomers are identified as R and S. Hydrogen bonds are shown as dashed lines. [Symmetry codes: (i) x-1, y-1, z; (ii) -x+1, -y+2, -z; (iv) x+1, y+1, z.]
	Fig. 3. A section of the supramolecular bidimensional (two-dimensional) assembly of (I) (S enantiomer), projected onto (201). The chain separation along [110] is schematically shown. Hydrogen bonds are shown as dashed lines. [Symmetry codes: (i) x-1, y-1, z; (iii) x-1, y, z; (iv) x-2, y-2, z; (v) x+1, y, z.]
	Fig. 4. The packing of (I), projected onto (101). Ribbons in dark and light grey representing, respectively, the layers formed by the S and R enantiomers of (I) are included. Hydrogen bonds are shown as dashed lines.

(±)-2,2-Dimethyl-5-oxotetrahydrofuran-3-carboxylic acid

Crystal data

C7H10O4	F(000) = 336
Mr = 158.15	Dx = 1.401 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 2814 reflections
a = 5.989 (1) Å	θ = 2.9–25.7°
b = 5.663 (1) Å	µ = 0.12 mm^−1
c = 22.282 (1) Å	T = 293 K
β = 97.07 (1)°	Prism, colourless
V = 750.0 (2) Å^3	0.09 × 0.06 × 0.03 mm
Z = 4

Data collection

KappaCCD diffractometer	1130 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.034
Detector resolution: 9 pixels mm^-1	θmax = 26.4°, θmin = 3.4°
CCD scans	h = −7→7
2864 measured reflections	k = −7→6
1516 independent reflections	l = −27→27

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.042	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.115	H atoms treated by a mixture of independent and constrained refinement
S = 1.04	w = 1/[σ^2(Fo^2) + (0.061P)^2 + 0.0594P] where P = (Fo^2 + 2Fc^2)/3
1516 reflections	(Δ/σ)max < 0.001
105 parameters	Δρmax = 0.17 e Å^−3
0 restraints	Δρmin = −0.13 e Å^−3

Special details

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

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

	x	y	z	Uiso*/Ueq
C1	0.1384 (2)	0.7159 (2)	0.09276 (6)	0.0421 (4)
H1	0.0216	0.8344	0.0813	0.051*
C2	0.3341 (2)	0.7630 (3)	0.05786 (6)	0.0497 (4)
H2A	0.4144	0.6183	0.0514	0.06*
H2B	0.2838	0.8347	0.019	0.06*
C3	0.4780 (2)	0.9284 (3)	0.09742 (7)	0.0461 (4)
C4	0.2389 (2)	0.7599 (2)	0.15913 (6)	0.0435 (4)
C5	0.0359 (2)	0.4746 (3)	0.08306 (7)	0.0459 (4)
C6	0.0779 (3)	0.8764 (3)	0.19646 (7)	0.0587 (5)
H6A	0.0288	1.0241	0.1782	0.088*
H6B	0.1519	0.9041	0.2366	0.088*
H6C	−0.0498	0.7755	0.1984	0.088*
C7	0.3506 (3)	0.5455 (3)	0.19020 (7)	0.0566 (4)
H7A	0.4523	0.477	0.165	0.085*
H7B	0.2379	0.4317	0.1972	0.085*
H7C	0.4325	0.5918	0.2281	0.085*
O1	0.63122 (18)	1.0478 (2)	0.08425 (5)	0.0612 (4)
O2	−0.15315 (18)	0.4562 (2)	0.10829 (6)	0.0639 (4)
H2	−0.219 (3)	0.308 (4)	0.0998 (9)	0.096*
O3	0.41873 (16)	0.93195 (19)	0.15283 (4)	0.0507 (3)
O4	0.11153 (18)	0.3154 (2)	0.05664 (5)	0.0626 (4)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0389 (7)	0.0393 (8)	0.0478 (8)	−0.0059 (6)	0.0032 (6)	0.0004 (6)
C2	0.0526 (9)	0.0519 (10)	0.0453 (8)	−0.0129 (7)	0.0087 (6)	−0.0011 (7)
C3	0.0426 (8)	0.0454 (9)	0.0503 (9)	−0.0076 (7)	0.0063 (6)	0.0033 (7)
C4	0.0445 (8)	0.0411 (9)	0.0455 (8)	−0.0082 (6)	0.0082 (6)	0.0000 (6)
C5	0.0423 (8)	0.0443 (9)	0.0505 (8)	−0.0057 (7)	0.0029 (6)	0.0007 (7)
C6	0.0634 (10)	0.0574 (10)	0.0574 (9)	−0.0036 (8)	0.0162 (8)	−0.0086 (8)
C7	0.0612 (10)	0.0534 (10)	0.0538 (9)	−0.0022 (8)	0.0013 (7)	0.0054 (8)
O1	0.0539 (6)	0.0612 (8)	0.0691 (8)	−0.0224 (6)	0.0104 (5)	0.0028 (6)
O2	0.0529 (7)	0.0536 (7)	0.0888 (9)	−0.0180 (6)	0.0231 (6)	−0.0115 (6)
O3	0.0526 (6)	0.0502 (7)	0.0488 (6)	−0.0173 (5)	0.0043 (4)	−0.0033 (5)
O4	0.0618 (7)	0.0473 (7)	0.0804 (8)	−0.0077 (6)	0.0154 (6)	−0.0135 (6)

Geometric parameters (Å, º)

C1—C5	1.503 (2)	C4—C7	1.512 (2)
C1—C2	1.5080 (19)	C5—O4	1.1958 (18)
C1—C4	1.5468 (19)	C5—O2	1.3285 (18)
C1—H1	0.98	C6—H6A	0.96
C2—C3	1.487 (2)	C6—H6B	0.96
C2—H2A	0.97	C6—H6C	0.96
C2—H2B	0.97	C7—H7A	0.96
C3—O1	1.2049 (17)	C7—H7B	0.96
C3—O3	1.3262 (17)	C7—H7C	0.96
C4—O3	1.4718 (16)	O2—H2	0.94 (2)
C4—C6	1.501 (2)
C5—C1—C2	114.61 (12)	C6—C4—C1	113.54 (12)
C5—C1—C4	112.84 (11)	C7—C4—C1	114.00 (12)
C2—C1—C4	103.22 (11)	O4—C5—O2	122.91 (14)
C5—C1—H1	108.6	O4—C5—C1	125.68 (14)
C2—C1—H1	108.6	O2—C5—C1	111.40 (13)
C4—C1—H1	108.6	C4—C6—H6A	109.5
C3—C2—C1	103.68 (12)	C4—C6—H6B	109.5
C3—C2—H2A	111	H6A—C6—H6B	109.5
C1—C2—H2A	111	C4—C6—H6C	109.5
C3—C2—H2B	111	H6A—C6—H6C	109.5
C1—C2—H2B	111	H6B—C6—H6C	109.5
H2A—C2—H2B	109	C4—C7—H7A	109.5
O1—C3—O3	121.16 (13)	C4—C7—H7B	109.5
O1—C3—C2	127.77 (13)	H7A—C7—H7B	109.5
O3—C3—C2	111.07 (12)	C4—C7—H7C	109.5
O3—C4—C6	106.80 (12)	H7A—C7—H7C	109.5
O3—C4—C7	106.71 (11)	H7B—C7—H7C	109.5
C6—C4—C7	112.17 (13)	C5—O2—H2	110.1 (12)
O3—C4—C1	102.64 (10)	C3—O3—C4	111.19 (11)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C2—H2A···O4	0.97	2.51	2.863 (2)	101
O2—H2···O1^i	0.91 (2)	1.77 (2)	2.673 (2)	174 (2)
C2—H2B···O1^ii	0.97	2.51	3.373 (2)	149
C1—H1···O1^iii	0.98	2.64	3.557 (2)	156

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