Polymorphism in 3-acetyl-4-hydroxy-2H-chromen-2-one

A new polymorph (denoted polymorph II) of 3-acetyl-4-hydroxy-2H-chromen-2-one, C₁₁H₈O₄, was obtained unexpectedly during an attempt to recrystallize the compound from salt–melted ice, and the structure is compared with that of the original polymorph (denoted polymorph I) [Lyssenko & Antipin (2001). Russ. Chem. Bull. 50, 418–431]. Strong intra­molecular O—H...O hydrogen bonds are observed equally in the two polymorphs [O...O = 2.4263 (13) Å in polymorph II and 2.442 (1) Å in polymorph I], with a slight delocalization of the hydroxy H atom towards the ketonic O atom in polymorph II [H...O = 1.32 (2) Å in polymorph II and 1.45 (3) Å in polymorph I]. In both crystal structures, the packing of the mol­ecules is dominated and stabilized by weak inter­molecular C—H...O hydrogen bonds. Additional π–π stacking inter­actions between the keto–enol hydrogen-bonded rings stabilize polymorph I [the centres are separated by 3.28 (1) Å], while polymorph II is stabilized by inter­actions between α-pyrone rings, which are parallel to one another and separated by 3.670 (5) Å.

S1. Introduction

Coumarin (2H-1-benzo­pyran-2-one, cis-o-coumarinic acid lactone or coumarinic anhydride) consists of an aromatic ring fused to a condensed lactone ring. Because of its biochemical properties, coumarin has been used in clinical medicine (Egan et al., 1990; Thornes et al., 1989; Cox et al., 1989; Dexeus et al., 1990; Marshall et al., 1994).

Coumarin is a naturally occurring compound, being present in a wide variety of plants and microorganisms and in some animal species. The metabolism, toxicity and results of tests for carcinogenicity have recently been reviewed with respect to the safety for humans of coumarin present in foodstuffs and for fragrances used in cosmetic products (Lake, 1999). In many studies, coumarin has been reported to reduce the incidence of tumours produced by genotoxic carcinogens (Tseng, 1991).

In general, active pharmaceutical ingredients (APIs) are capable of existing in polymorphic forms and hence may show distinguishable physicochemical properties, bioavailabilities and therapeutic effects due to the different arrangement of the molecules in the crystal structure. Therefore, identifying and controlling the polymorphic properties of this class of compound are of crucial importance in medicinal chemistry (Arshad et al., 2014). In fact, slight variations in the crystallization process, such as changes in temperature, solvent, additives and concentration, can lead to different packings and the formation of different crystal structures or polymorphs (Munshi et al., 2004). Thus, the identification of new polymorphs of coumarin derivatives, like 3-acetyl-4-hy­droxy­coumarin, is an inter­esting target for organic chemists. Various strategies for manipulating their synthesis through changes in acyl­ation, bromination, metallation or Claisen–Schmidt condensation could result in more polymorphs (Abdou, 2014).

The present investigation is a continuation of our broad focus on the synthesis, biological evaluation and structural study of coumarin derivatives as Schiff bases (Rohlíček et al., 2013), amino­coumarins (Brahmia et al., 2013) or chalcones (Mechi et al., 2009; Afef et al., 2011) in order to understand the geometric features and underlying inter­molecular inter­actions which govern the assembly of the molecules in the crystalline lattice. In this paper, we report the crystal structure of a new polymorph, hereafter polymorph II, of 3-acetyl-4-hy­droxy­coumarin, (I) (see Scheme 1), and compare it with the structure of the originally reported polymorph, hereafter polymorph I (Lyssenko & Anti­pin, 2001).

S2. Synthesis and crystallization

All the chemicals were available commercially and used without further purification. All the solvents were dried using standard methods before use. Phospho­rus oxychloride (5.6 ml) was added to a solution of 4-hy­droxy­chromen-2-one (3 g, 1.86 mmol) in acetic acid (16 ml). The mixture was heated under reflux for 30 min. After cooling, the precipitate was collected and recrystallized from ethanol at low temperature in a salt–melted ice bath to give 3-acetyl-4-hy­droxy­chromen-2-one, (I), as light-yellow prism crystals (yield 2.7 g, 90%; m.p. 408-410 K). It should be noted that the recrystallization of 3-acetyl-4-hy­droxy­coumarin at room temperature led systematically to polymorph I as yellow needle-shaped crystals (m.p. 405–407 K). The synthetic procedure used to prepare polymorph II of (I) is shown in Scheme 1.

S3. Refinement details

Crystal data, data collection and structure refinement details (for model 1a) are summarized in Table 1. First, the O4—H hydrogen atom was located in a difference map and refined isotropically with full occupancy and no restraints. When the H atom was removed, two distinct peaks were evident in the electron-density difference map. Two other models with a split H atom were investigated (see Fig. 1). In the first split model, denoted model 2b, two hy­droxy H atoms were allowed to refine with an occupancy of 0.5, using a rotating-group refinement. In the second split model, denoted model 2c, these hy­droxy H atoms were refined with restraints on the O—H bond lengths (O—H = 0.82 Å for O3—H93 and O4—H94) and with occupancies of 0.4 and 0.6. Refinement assuming split model 2b yielded residuals of wR(F²) = 0.1971 and R(F) = 0.0555; for split model 2c, the residuals were wR(F²) = 0.1955 and R(F) = 0.0554. Split-model 2c seems to be the more reliable. The remaining H atoms were placed at idealized positions and allowed to ride on their parent atoms, with C—H = 0.93 (aromatic) or 0.96 Å (CH₃), and with U_iso(H) = 1.2U_eq(C). We refer to both model 1a and split-model 2c in the discussion that follows.

S4. Results and discussion

An attempt to recrystallize freshly synthesized 3-acetyl-4-hy­droxy­coumarin, (I), from ethanol in an ice–salt bath unexpectedly produced light-yellow prism-shaped crystals suitable for X-ray diffraction. Fig. 2 shows two models of the crystal structure of this new polymorph, hereafter polymorph II, i.e. with the H atom located in difference maps and refined isotropically with no restraints (model 1a) or the more reliable split-atom model (model 2c).

A detailed discussion of the geometric analysis of polymorph I from X-ray single-crystal diffraction data collected at room temperature and at different temperatures has already been reported in the literature (Lyssenko & Anti­pin, 2001; Traven et al., 2000). Both polymorphs crystallize in the monoclinic system with different unit-cell parameters, i.e. a = 10.3193 (9) Å, b = 5.1605 (5) Å, c = 17.071 (1)Å and β = 99.337 (2)° for polymorph I; see Table 1 for the corresponding parameters for polymorph II. In all discussions herein, we refer to the room-temperature structure determination of polymorph I at 300 K (Lyssenko & Anti­pin, 2001).

In polymorphs I and II, the molecules have very similar geometries and exhibit strong intra­molecular hydrogen bonding of the O—H···O type between the hy­droxy group and the ketonic O atom [O···O = 2.4263 (13) Å in polymorph II and 2.442 (1) Å in polymorph I; Tables 2 and 3]. The H···O3 distance of 1.32 (2) Å, considering model 1a for polymorph II, is decreased compared with its value in polymorph I [1.45 (3) Å]. In fact, the O—H distance [1.02 (3) Å] in polymorph I is shorter than that in model 1a of polymorph II [1.11 (2) Å], owing to a shift of the hy­droxy H atom towards the ketonic O atom. The O4—H···O3 angle of 169 (2)° in polymorph II is larger than that found for polymorph I [161 (2)°]. It should be noted that the C10—O3, C10—C8, C8—C7 and C7—O4 bond lengths [1.2534 (15), 1.4459 (17), 1.3995 (15) and 1.2957 (13) Å, respectively, for split-model 2c of polymorph II; Table 2] are only slightly different compared with the corresponding values observed for polymorph I [1.255 (1), 1.449 (2), 1.396 (2) and 1.304 (2) Å, respectively]; the C9—O2 bond length of 1.2019 (15) Å for split-model 2c of polymorph II is similar to, and possibly shorter than, that found in polymorph I at room temperature [1.203 (2) Å; Lyssenko & Anti­pin, 2001]. The bond lengths within the O4—C7═ C8—C10═O3 keto–enol fragment in polymorph II are indicative of substantial electron-density stabilization, which is manifested in the elongation of the formal C7═C8 and C10═O3 double bonds and the shortening of the C7—O4 and C8—C10 single bonds, compared with the `ideal' values for C—O, C═ O, C—C and C═C bonds (Gilli et al., 1989). Broadly speaking, the increase in π-delocalization of the O—C═C—C═OH fragment appears to be linearly related to the decrease in the O···O contact distance (intra­molecular hydrogen bond).

In polymorph II using split-model 2c, the acetyl group is nearly coplanar with the fused ring plane, with torsion angles C7—C8—C10—C11 = -177.38 (11)°, C9—C8—C10—C11 = 0.94 (19)°, O2—-C9—-C8—C10 = -1.4 (2)° and C7—C8—C9—O2 = 179.74 (13)°. The C8—C7 bond length of 1.3995 (15) Å is representative of sp² C═C double-bond character and is slightly elongated from the C═C double bond found at the same position in other compounds, for example, 1.375 (8) Å for the coumarin derivative 3-(2,2-di­bromo­acetyl)-4-hy­droxy-2H-chromen-2-one (Brahmia et al., 2015), and slightly shorter than the corresponding distance found in the structure of polymorph I, i.e. 1.4035 (15) Å. The O2═ C9 bond length of 1.2019 (15) Å and the bond angles of 114.81 (11), 127.59 (13) and 117.60 (10)° at the C9 atom (Table 2) confirm the C═O bond character. The shorter O2═C9 bond length is probably due to the delocalized electrons in the lactone system. Table 2 recapitulates and summarizes the principal bond lengths and angles in polymorphs I and II (model 1a and split-model 2c) according to X-ray diffraction data at room temperature.

Fig. 3 shows that the packing in the crystalline lattice of polymorph II is mainly through C—H···O inter­actions, which link molecules into zigzag chains extended in the [100] direction, and a π–π inter­action, with an acceptable separation distance, providing additional stability to the dimers and holding the chains in the crystallographic [010] direction. Lyssenko & Anti­pin (2001) have shown that, in the crystal packing of polymorph I, the molecules are linked into dimers through bifurcated C—H···O contacts, viz. C4—H4···O1' and C4—H4···O2' [C4···O1' = 3.523 (1) Å, H4···O1' = 2.51 Å and C4—H4··· O1' = 157°; C4···O2' = 3.404 (1) Å, H4···O2' = 2.44 Å and C4—H4···O2' = 149°; The prime denotes which symmetry operation?]. The dimers, in turn, are linked into layers through analogous contacts between the H atoms of the methyl group and the O3 atom of the keto–enol fragment [C11—-H11···O3''; C11···O3'' = 3.535 (1) Å, H11···O3'' = 2.47 Å and C11—H11···O3'' = 177°; The double prime denotes which symmetry operation?]. However, in polymorph II, we found that the molecules are linked into layers through analogous contacts between the H atoms of the methyl group and the O4 atom of the hy­droxy group, viz. C11—H11···O4ⁱⁱ and C4—H4···O2ⁱ (Table 3). In addition to the above-mentioned contacts, the dimers in polymorph I are linked by π–π inter­actions between the keto–enol hydrogen-bonded rings parallel to one another, with a separation of 3.280 Å between their centres (Lyssenko & Anti­pin, 2001), while in polymorph II, π–π inter­actions are observed between the lactone rings (α-pyrone rings), with a Cg1···Cg1ⁱ separation of 3.670 (5) Å [Cg1 is the centroid of the O1/C5–C9 ring [OK?]; symmetry code: (i) -x + 1, -y - 1, -z + 1]. The observed stacking arrangement can be considered as a balance between van der Waals dispersion and repulsion inter­actions, and electrostatic inter­actions between the two α-pyrone rings of opposed polarity resulting from the opposed orientation. It can be said that the subsequent verification of subtle differences in the inter­molecular inter­actions is due to delocalization of the hy­droxy H atom between the hy­droxy O atom and the ketone O atom in polymorph II. This result also correlates with the difference in the melting points of the two crystals, viz. 408–410 K for polymorph I and 405–407 K for polymorph II.

S5. Conclusions

We have compared the crystal structures of two polymorphs of 3-acetyl-4-hy­droxy-2H-chromen-2-one which pack differently in their crystal structures. In addition, there is more delocalization in polymorph II versus polymorph I, leading to almost identical C—O bond lengths for formally C—OH and C═O bonds, resulting in a molecule with an H atom shared between two O-atom centres.

Computing details

Data collection: SMART (Bruker, 2001); cell refinement: SMART (Bruker, 2001); data reduction: SAINT (Bruker, 2001); 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, 2012); software used to prepare material for publication: WinGX (Farrugia, 2012).

Figures

	Fig. 1. The central ring in polymorph II for (a) model 1a, (b) split-model 2b and (c) split-model 2c. The dashed line denotes a hydrogen bond. [Updated caption OK?]
	Fig. 2. The molecular structures of (a) model 1a and (b) model 2c of polymorph II, showing 50% probability displacement ellipsoids and the atomic numbering. The dashed line denotes a hydrogen bond.
	Fig. 3. A packing diagram showing the π–π interactions (between α-pyrone rings; dashed line) in polymorph II, along the b axis.

3-Acetyl-4-hydroxy-2H-chromen-2-one

Crystal data

C11H8O4	Z = 4
Mr = 204.17	F(000) = 424
Monoclinic, P21/n	Dx = 1.481 Mg m^−3
Hall symbol: -P 2 y n	Mo Kα radiation, λ = 0.71073 Å
a = 7.3340 (1) Å	µ = 0.11 mm^−1
b = 9.9110 (1) Å	T = 298 K
c = 12.6800 (2) Å	Prism, yellow
β = 96.649 (1)°	0.40 × 0.30 × 0.20 mm
V = 915.48 (2) Å^3

Data collection

Bruker SMART?? CCD area-detector diffractometer	2153 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.021
Graphite monochromator	θmax = 35.5°, θmin = 2.6°
φ and ω scans	h = −11→10
12216 measured reflections	k = −16→15
4084 independent reflections	l = −18→20

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)] = 0.056	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.199	H atoms treated by a mixture of independent and constrained refinement
S = 1.05	w = 1/[σ^2(Fo^2) + (0.1018P)^2 + 0.041P] where P = (Fo^2 + 2Fc^2)/3
4084 reflections	(Δ/σ)max < 0.001
140 parameters	Δρmax = 0.33 e Å^−3
0 restraints	Δρmin = −0.24 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. 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 > 2sigma(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
O4	0.79610 (14)	−0.14012 (9)	0.64919 (6)	0.0553 (3)
C8	0.69322 (14)	−0.13504 (11)	0.46616 (8)	0.0385 (2)
O3	0.68053 (16)	−0.34053 (10)	0.55390 (8)	0.0632 (3)
C7	0.76572 (15)	−0.07321 (11)	0.56104 (8)	0.0385 (2)
C6	0.81042 (14)	0.06839 (11)	0.56420 (8)	0.0387 (2)
C5	0.78099 (16)	0.14036 (12)	0.47033 (9)	0.0434 (3)
C9	0.66511 (17)	−0.05560 (13)	0.36977 (9)	0.0473 (3)
C1	0.88262 (18)	0.13521 (13)	0.65727 (10)	0.0502 (3)
H1	0.9035	0.0881	0.7209	0.060*
C4	0.8210 (2)	0.27721 (15)	0.46668 (12)	0.0602 (4)
H4	0.8010	0.3251	0.4033	0.072*
O2	0.60509 (16)	−0.09320 (12)	0.28242 (7)	0.0740 (3)
C11	0.5836 (2)	−0.35630 (15)	0.37174 (12)	0.0647 (4)
H11A	0.5672	−0.4488	0.3910	0.097*
H11B	0.6703	−0.3513	0.3207	0.097*
H11C	0.4681	−0.3196	0.3415	0.097*
C10	0.65335 (17)	−0.27786 (13)	0.46759 (10)	0.0482 (3)
C3	0.8913 (2)	0.34009 (14)	0.55981 (14)	0.0647 (4)
H3	0.9183	0.4317	0.5588	0.078*
C2	0.9223 (2)	0.27032 (15)	0.65409 (12)	0.0595 (4)
H2	0.9702	0.3148	0.7157	0.071*
O1	0.71054 (13)	0.08011 (10)	0.37678 (7)	0.0543 (3)
H	0.754 (3)	−0.238 (2)	0.6105 (17)	0.114 (7)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O4	0.0777 (6)	0.0544 (5)	0.0325 (4)	−0.0051 (4)	0.0006 (4)	0.0086 (3)
C8	0.0379 (5)	0.0443 (6)	0.0329 (5)	0.0010 (4)	0.0025 (4)	0.0021 (4)
O3	0.0820 (7)	0.0478 (5)	0.0587 (6)	−0.0102 (5)	0.0027 (5)	0.0094 (4)
C7	0.0400 (5)	0.0448 (6)	0.0311 (4)	0.0026 (4)	0.0054 (4)	0.0041 (4)
C6	0.0383 (5)	0.0412 (5)	0.0375 (5)	0.0027 (4)	0.0083 (4)	−0.0003 (4)
C5	0.0434 (6)	0.0449 (6)	0.0428 (5)	0.0053 (4)	0.0081 (4)	0.0051 (4)
C9	0.0490 (6)	0.0568 (7)	0.0349 (5)	0.0032 (5)	0.0003 (4)	0.0037 (5)
C1	0.0530 (7)	0.0563 (7)	0.0423 (6)	−0.0017 (5)	0.0095 (5)	−0.0069 (5)
C4	0.0672 (8)	0.0480 (7)	0.0675 (8)	0.0062 (6)	0.0175 (7)	0.0138 (6)
O2	0.0970 (8)	0.0855 (8)	0.0348 (5)	−0.0016 (6)	−0.0123 (5)	0.0001 (4)
C11	0.0671 (9)	0.0618 (9)	0.0633 (9)	−0.0132 (7)	−0.0001 (7)	−0.0146 (7)
C10	0.0437 (6)	0.0510 (7)	0.0495 (6)	−0.0018 (5)	0.0038 (5)	−0.0034 (5)
C3	0.0677 (9)	0.0410 (6)	0.0898 (11)	−0.0035 (6)	0.0282 (8)	−0.0072 (7)
C2	0.0608 (8)	0.0560 (7)	0.0648 (8)	−0.0071 (6)	0.0201 (6)	−0.0187 (6)
O1	0.0671 (6)	0.0552 (5)	0.0391 (4)	0.0030 (4)	−0.0001 (4)	0.0127 (4)

Geometric parameters (Å, º)

O4—C7	1.2965 (13)	C9—O1	1.3861 (16)
O4—H	1.11 (2)	C1—C2	1.3719 (19)
C8—C7	1.3992 (15)	C1—H1	0.9300
C8—C10	1.4460 (17)	C4—C3	1.381 (2)
C8—C9	1.4483 (15)	C4—H4	0.9300
O3—C10	1.2540 (15)	C11—C10	1.4830 (18)
O3—H	1.32 (2)	C11—H11A	0.9600
C7—C6	1.4407 (16)	C11—H11B	0.9600
C6—C5	1.3830 (15)	C11—H11C	0.9600
C6—C1	1.4025 (16)	C3—C2	1.377 (2)
C5—O1	1.3743 (14)	C3—H3	0.9300
C5—C4	1.3895 (19)	C2—H2	0.9300
C9—O2	1.2028 (14)
C7—O4—H	93.1 (11)	C3—C4—C5	118.12 (13)
C7—C8—C10	118.37 (10)	C3—C4—H4	120.9
C7—C8—C9	119.36 (10)	C5—C4—H4	120.9
C10—C8—C9	122.25 (10)	C10—C11—H11A	109.5
C10—O3—H	96.1 (9)	C10—C11—H11B	109.5
O4—C7—C8	121.84 (10)	H11A—C11—H11B	109.5
O4—C7—C6	117.29 (10)	C10—C11—H11C	109.5
C8—C7—C6	120.87 (9)	H11A—C11—H11C	109.5
C5—C6—C1	119.12 (11)	H11B—C11—H11C	109.5
C5—C6—C7	117.79 (10)	O3—C10—C8	118.94 (11)
C1—C6—C7	123.08 (10)	O3—C10—C11	117.42 (12)
O1—C5—C6	121.62 (11)	C8—C10—C11	123.64 (11)
O1—C5—C4	117.07 (11)	C2—C3—C4	121.56 (13)
C6—C5—C4	121.31 (12)	C2—C3—H3	119.2
O2—C9—O1	114.79 (11)	C4—C3—H3	119.2
O2—C9—C8	127.58 (13)	C1—C2—C3	120.10 (13)
O1—C9—C8	117.63 (10)	C1—C2—H2	120.0
C2—C1—C6	119.79 (13)	C3—C2—H2	120.0
C2—C1—H1	120.1	C5—O1—C9	122.72 (9)
C6—C1—H1	120.1
C10—C8—C7—O4	−0.56 (17)	C5—C6—C1—C2	0.21 (18)
C9—C8—C7—O4	−178.97 (10)	C7—C6—C1—C2	179.84 (11)
C10—C8—C7—C6	179.18 (10)	O1—C5—C4—C3	179.76 (11)
C9—C8—C7—C6	0.77 (16)	C6—C5—C4—C3	−0.05 (19)
O4—C7—C6—C5	179.11 (10)	C7—C8—C10—O3	1.79 (17)
C8—C7—C6—C5	−0.64 (15)	C9—C8—C10—O3	−179.85 (11)
O4—C7—C6—C1	−0.52 (17)	C7—C8—C10—C11	−177.38 (11)
C8—C7—C6—C1	179.73 (10)	C9—C8—C10—C11	0.97 (19)
C1—C6—C5—O1	−179.99 (10)	C5—C4—C3—C2	0.3 (2)
C7—C6—C5—O1	0.37 (16)	C6—C1—C2—C3	0.01 (19)
C1—C6—C5—C4	−0.19 (17)	C4—C3—C2—C1	−0.3 (2)
C7—C6—C5—C4	−179.84 (11)	C6—C5—O1—C9	−0.25 (17)
C7—C8—C9—O2	179.77 (12)	C4—C5—O1—C9	179.95 (11)
C10—C8—C9—O2	1.4 (2)	O2—C9—O1—C5	−179.98 (11)
C7—C8—C9—O1	−0.62 (16)	C8—C9—O1—C5	0.37 (17)
C10—C8—C9—O1	−178.96 (10)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O4—H···O3	1.11 (2)	1.32 (2)	2.4263 (13)	169 (2)
C4—H4···O2^i	0.93	2.65	3.510 (2)	153
C11—H11C···O4^ii	0.96	2.64	3.320 (2)	128

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