γ-Indomethacin at 120 K

Cox, P.J.; Manson, P.L.

doi:10.1107/S160053680301290X

γ-Indomethacin at 120 K

P. J. Cox and P. L. Manson

The crystal structure of γ-indomethacin, C₁₉H₁₆ClNO₄, is supported, not only by O—H

O interactions, but also by C—H

π and π–π interactions.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S160053680301290X/cf6262sup1.cif Contains datablocks global, I
	Structure factor file (CIF format) https://doi.org/10.1107/S160053680301290X/cf6262Isup2.hkl Contains datablock I

CCDC reference: 217467

checkCIF report

Key indicators

Single-crystal X-ray study
T = 120 K
Mean (C-C) = 0.003 Å
R factor = 0.044
wR factor = 0.105
Data-to-parameter ratio = 16.4

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry

Comment top

Room-temperature crystal structures of γ-indomethacin, (I), have been reported previously (Kistenmacher & Marsh, 1972; Galdecki & Glowka, 1976) and the crystal structure of the metastable α form at 203 K is also known (Chen et al., 2002). The compound presents an unusual case in which the more stable γ form is reported to have the lower density. Also, the known dimer formation between the carboxylic acid groups would be difficult to predict in the presence of other donors and acceptors. Only in the metastable α form does the carbonyl atom O1 act as an acceptor, whereby trimers are formed in the space group P2₁ with Z = 6.

Apart from the previously reported O—H···O interactions, we have now examined other non-covalent interactions between γ-indomethacin molecules. Both crystal structures of γ-indomethacin reported previously used different cell settings, so to avoid confusion, we have used reduced cell dimensions throughout our study.

The molecular structure of (I) is shown in Fig. 1. The dihedral angle between the mean planes of the indole ring system and the chlorophenyl ring is 66.51 (5)°. The geometry of the R²₂(8) hydrogen bonding between centrosymmetrically related carboxylic acid groups is given in Table 2 and the interaction is shown in Fig. 2.

As well as the classical hydrogen bonding involved in dimer formation, the supramolecular structure is also supported by edge-to-face C—H···π interactions, as listed in Table 3 and shown in Fig. 3. Here the methylene H atoms on C18 and methyl atom H20A interact with the π systems of the indole rings.

Completing the molecular attractions is a π–π interaction between centrosymmetrically related chlorophenyl rings, as shown in Fig. 4 and detailed in Table 4.

Morphological evaluation of γ-indomethacin has also been performed (Slavin et al., 2002).

Experimental top

Indomethacin was purchased from Sigma and was recrystallized from 4-methylpentan-2-one, to produce the γ-polymorph.

Computing details top

Data collection: DENZO (Otwinowski & Minor, 1997) and COLLECT (Hooft, 1998); cell refinement: DENZO and COLLECT; data reduction: DENZO and COLLECT; program(s) used to solve structure: SIR97 (Altomare et al., 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: WinGX (Farrugia, 1999).

Figures top

	Fig. 1. The molecular structure of (I). Displacement ellipsoids are drawn at the 50% probability level.
	Fig. 2. Dimer formation between carboxylic acid groups. Atoms marked with an asterisk (*) are at the symmetry position (−1 − x, 1 − y, −z).
	Fig. 3. The C—H···π hydrogen bonding, shown as double-dashed lines, between molecules related by a centre of symmetry.
	Fig. 4. A crystal packing diagram showing the π–π interactions, as a dashed line, between chlorophenyl rings stacked across a centre of symmetry. The ring centre is indicated by a dot. Dimer formation is also shown.

(I) top

Crystal data top

C₁₉H₁₆ClNO₄	Z = 2
M_r = 357.78	F(000) = 372
Triclinic, P1	D_x = 1.401 Mg m⁻³
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71073 Å
a = 9.236 (5) Å	Cell parameters from 4841 reflections
b = 9.620 (5) Å	θ = 2.9–27.5°
c = 10.887 (5) Å	µ = 0.25 mm⁻¹
α = 69.897 (5)°	T = 120 K
β = 87.328 (5)°	Plate, colourless
γ = 69.501 (5)°	0.23 × 0.2 × 0.02 mm
V = 847.9 (7) Å³

Data collection top

Nonius KappaCCD area-detector diffractometer	2586 reflections with I > 2σ(I)
ϕ and ω scans	R_int = 0.056
Absorption correction: multi-scan (SORTAV; Blessing, 1995, 1997)	θ_max = 27.5°, θ_min = 3.0°
T_min = 0.956, T_max = 0.992	h = −11→11
10585 measured reflections	k = −11→12
3800 independent reflections	l = −14→14

Refinement top

Refinement on F²	H atoms treated by a mixture of independent and constrained refinement
Least-squares matrix: full	w = 1/[σ²(F_o²) + (0.0439P)² + 0.0875P] where P = (F_o² + 2F_c²)/3
R[F² > 2σ(F²)] = 0.044	(Δ/σ)_max < 0.001
wR(F²) = 0.105	Δρ_max = 0.27 e Å⁻³
S = 1.01	Δρ_min = −0.26 e Å⁻³
3800 reflections	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
232 parameters	Extinction coefficient: 0.012 (2)
0 restraints

Crystal data top

C₁₉H₁₆ClNO₄	γ = 69.501 (5)°
M_r = 357.78	V = 847.9 (7) Å³
Triclinic, P1	Z = 2
a = 9.236 (5) Å	Mo Kα radiation
b = 9.620 (5) Å	µ = 0.25 mm⁻¹
c = 10.887 (5) Å	T = 120 K
α = 69.897 (5)°	0.23 × 0.2 × 0.02 mm
β = 87.328 (5)°

Data collection top

Nonius KappaCCD area-detector diffractometer	3800 independent reflections
Absorption correction: multi-scan (SORTAV; Blessing, 1995, 1997)	2586 reflections with I > 2σ(I)
T_min = 0.956, T_max = 0.992	R_int = 0.056
10585 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.044	0 restraints
wR(F²) = 0.105	H atoms treated by a mixture of independent and constrained refinement
S = 1.01	Δρ_max = 0.27 e Å⁻³
3800 reflections	Δρ_min = −0.26 e Å⁻³
232 parameters

Special details top

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

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

	x	y	z	U_iso*/U_eq
Cl1	0.80746 (6)	−0.45402 (6)	0.57008 (5)	0.03666 (18)
O1	0.03608 (16)	−0.17070 (16)	0.50769 (12)	0.0279 (3)
O2	0.22313 (17)	0.42194 (16)	−0.09306 (13)	0.0322 (4)
O3	−0.41729 (18)	0.39171 (18)	−0.11120 (13)	0.0349 (4)
H3	−0.490 (3)	0.481 (3)	−0.105 (2)	0.042*
O4	−0.38537 (15)	0.33417 (15)	0.10489 (12)	0.0257 (3)
N1	0.06753 (17)	−0.04055 (17)	0.29426 (14)	0.0195 (4)
C2	−0.0734 (2)	−0.0227 (2)	0.23317 (18)	0.0198 (4)
C3	−0.0977 (2)	0.0896 (2)	0.11135 (17)	0.0187 (4)
C4	0.0257 (2)	0.1515 (2)	0.09355 (17)	0.0181 (4)
C5	0.0524 (2)	0.2719 (2)	−0.01188 (18)	0.0200 (4)
H5	−0.0166	0.3268	−0.0892	0.024*
C6	0.1818 (2)	0.3074 (2)	0.00067 (18)	0.0228 (4)
C7	0.2815 (2)	0.2272 (2)	0.11648 (19)	0.0268 (5)
H7	0.3695	0.2545	0.1232	0.032*
C8	0.2551 (2)	0.1095 (2)	0.22104 (19)	0.0245 (4)
H8	0.3224	0.0573	0.2994	0.029*
C9	0.1272 (2)	0.0705 (2)	0.20744 (17)	0.0184 (4)
C10	0.1238 (2)	−0.1381 (2)	0.42508 (18)	0.0206 (4)
C11	0.2954 (2)	−0.2061 (2)	0.45484 (17)	0.0194 (4)
C12	0.3937 (2)	−0.2635 (2)	0.36842 (18)	0.0227 (4)
H12	0.352	−0.2502	0.2853	0.027*
C13	0.5518 (2)	−0.3399 (2)	0.40265 (18)	0.0252 (5)
H13	0.6188	−0.3811	0.3447	0.03*
C14	0.6100 (2)	−0.3547 (2)	0.52357 (19)	0.0239 (4)
C15	0.5142 (2)	−0.2964 (2)	0.60978 (18)	0.0246 (4)
H15	0.5565	−0.3061	0.6914	0.03*
C16	0.3566 (2)	−0.2242 (2)	0.57606 (18)	0.0231 (4)
H16	0.2896	−0.1866	0.6358	0.028*
C17	−0.1655 (2)	−0.1244 (2)	0.29603 (19)	0.0273 (5)
H17A	−0.2408	−0.1145	0.2301	0.035*
H17B	−0.2205	−0.0907	0.3659	0.035*
H17C	−0.0958	−0.2351	0.3335	0.035*
C18	−0.2287 (2)	0.1459 (2)	0.01031 (18)	0.0212 (4)
H18A	−0.2769	0.0643	0.029	0.025*
H18B	−0.1878	0.1595	−0.077	0.025*
C19	−0.3506 (2)	0.3000 (2)	0.00690 (18)	0.0200 (4)
C20	0.1179 (2)	0.5202 (2)	−0.20739 (18)	0.0282 (5)
H20A	0.015	0.5686	−0.1808	0.037*
H20B	0.1112	0.4557	−0.2582	0.037*
H20C	0.1554	0.6035	−0.2614	0.037*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Cl1	0.0219 (3)	0.0375 (3)	0.0394 (3)	−0.0077 (2)	−0.0060 (2)	−0.0018 (2)
O1	0.0272 (8)	0.0292 (8)	0.0209 (7)	−0.0083 (7)	0.0048 (6)	−0.0034 (6)
O2	0.0329 (8)	0.0307 (8)	0.0275 (8)	−0.0181 (7)	−0.0013 (6)	0.0036 (6)
O3	0.0355 (9)	0.0301 (8)	0.0200 (7)	0.0117 (7)	−0.0045 (6)	−0.0091 (7)
O4	0.0257 (8)	0.0253 (7)	0.0195 (7)	−0.0005 (6)	0.0007 (6)	−0.0087 (6)
N1	0.0187 (8)	0.0185 (8)	0.0168 (8)	−0.0053 (7)	−0.0013 (6)	−0.0018 (6)
C2	0.0168 (10)	0.0191 (10)	0.0227 (10)	−0.0038 (8)	0.0019 (8)	−0.0090 (8)
C3	0.0164 (9)	0.0172 (9)	0.0203 (10)	−0.0023 (8)	0.0003 (8)	−0.0077 (8)
C4	0.0186 (10)	0.0168 (9)	0.0176 (9)	−0.0031 (8)	0.0010 (8)	−0.0079 (8)
C5	0.0211 (10)	0.0172 (9)	0.0169 (9)	−0.0022 (8)	−0.0011 (8)	−0.0045 (8)
C6	0.0261 (11)	0.0192 (10)	0.0208 (10)	−0.0090 (9)	0.0032 (8)	−0.0035 (8)
C7	0.0226 (11)	0.0312 (11)	0.0293 (11)	−0.0143 (9)	0.0000 (9)	−0.0088 (9)
C8	0.0230 (11)	0.0230 (10)	0.0226 (10)	−0.0059 (9)	−0.0047 (8)	−0.0038 (9)
C9	0.0189 (10)	0.0152 (9)	0.0184 (9)	−0.0040 (8)	0.0024 (8)	−0.0047 (8)
C10	0.0249 (11)	0.0156 (9)	0.0192 (10)	−0.0052 (8)	−0.0015 (8)	−0.0052 (8)
C11	0.0235 (10)	0.0149 (9)	0.0164 (9)	−0.0057 (8)	0.0004 (8)	−0.0023 (7)
C12	0.0267 (11)	0.0221 (10)	0.0153 (9)	−0.0050 (9)	−0.0028 (8)	−0.0051 (8)
C13	0.0256 (11)	0.0247 (11)	0.0218 (10)	−0.0061 (9)	0.0013 (9)	−0.0067 (9)
C14	0.0187 (10)	0.0192 (10)	0.0270 (11)	−0.0066 (8)	−0.0036 (8)	0.0005 (8)
C15	0.0289 (11)	0.0274 (11)	0.0171 (10)	−0.0128 (9)	−0.0034 (8)	−0.0036 (8)
C16	0.0293 (11)	0.0207 (10)	0.0177 (10)	−0.0088 (9)	0.0027 (8)	−0.0052 (8)
C17	0.0266 (11)	0.0269 (11)	0.0281 (11)	−0.0118 (9)	0.0025 (9)	−0.0070 (9)
C18	0.0196 (10)	0.0192 (10)	0.0224 (10)	−0.0042 (8)	−0.0012 (8)	−0.0069 (8)
C19	0.0168 (10)	0.0229 (10)	0.0190 (10)	−0.0063 (8)	−0.0003 (8)	−0.0063 (8)
C20	0.0338 (12)	0.0255 (11)	0.0222 (10)	−0.0122 (9)	0.0030 (9)	−0.0034 (9)

Geometric parameters (Å, º) top

Cl1—C14	1.740 (2)	C8—H8	0.95
O1—C10	1.216 (2)	C10—C11	1.490 (3)
O2—C6	1.373 (2)	C11—C16	1.391 (3)
O2—C20	1.431 (2)	C11—C12	1.393 (3)
O3—C19	1.313 (2)	C12—C13	1.386 (3)
O3—H3	0.91 (2)	C12—H12	0.95
O4—C19	1.218 (2)	C13—C14	1.388 (3)
N1—C10	1.410 (2)	C13—H13	0.95
N1—C9	1.417 (2)	C14—C15	1.384 (3)
N1—C2	1.418 (2)	C15—C16	1.379 (3)
C2—C3	1.360 (3)	C15—H15	0.95
C2—C17	1.489 (3)	C16—H16	0.95
C3—C4	1.437 (3)	C17—H17A	0.98
C3—C18	1.491 (3)	C17—H17B	0.98
C4—C9	1.399 (3)	C17—H17C	0.98
C4—C5	1.407 (3)	C18—C19	1.505 (3)
C5—C6	1.378 (3)	C18—H18A	0.99
C5—H5	0.95	C18—H18B	0.99
C6—C7	1.405 (3)	C20—H20A	0.98
C7—C8	1.385 (3)	C20—H20B	0.98
C7—H7	0.95	C20—H20C	0.98
C8—C9	1.387 (3)

C6—O2—C20	117.68 (16)	C13—C12—H12	119.7
C19—O3—H3	108.1 (13)	C11—C12—H12	119.7
C10—N1—C9	127.18 (16)	C12—C13—C14	118.46 (18)
C10—N1—C2	124.39 (15)	C12—C13—H13	120.8
C9—N1—C2	107.94 (14)	C14—C13—H13	120.8
C3—C2—N1	108.62 (16)	C15—C14—C13	121.63 (18)
C3—C2—C17	128.94 (17)	C15—C14—Cl1	119.12 (15)
N1—C2—C17	122.28 (16)	C13—C14—Cl1	119.22 (16)
C2—C3—C4	108.40 (16)	C16—C15—C14	119.40 (18)
C2—C3—C18	127.92 (17)	C16—C15—H15	120.3
C4—C3—C18	123.67 (16)	C14—C15—H15	120.3
C9—C4—C5	121.07 (17)	C15—C16—C11	120.15 (18)
C9—C4—C3	107.74 (16)	C15—C16—H16	119.9
C5—C4—C3	131.18 (17)	C11—C16—H16	119.9
C6—C5—C4	117.85 (17)	C2—C17—H17A	109.5
C6—C5—H5	121.1	C2—C17—H17B	109.5
C4—C5—H5	121.1	H17A—C17—H17B	109.5
O2—C6—C5	124.72 (17)	C2—C17—H17C	109.5
O2—C6—C7	114.70 (17)	H17A—C17—H17C	109.5
C5—C6—C7	120.57 (17)	H17B—C17—H17C	109.5
C8—C7—C6	121.85 (18)	C3—C18—C19	112.44 (15)
C8—C7—H7	119.1	C3—C18—H18A	109.1
C6—C7—H7	119.1	C19—C18—H18A	109.1
C7—C8—C9	117.74 (18)	C3—C18—H18B	109.1
C7—C8—H8	121.1	C19—C18—H18B	109.1
C9—C8—H8	121.1	H18A—C18—H18B	107.8
C8—C9—C4	120.89 (17)	O4—C19—O3	123.67 (17)
C8—C9—N1	131.83 (17)	O4—C19—C18	122.95 (17)
C4—C9—N1	107.23 (16)	O3—C19—C18	113.37 (16)
O1—C10—N1	121.16 (18)	O2—C20—H20A	109.5
O1—C10—C11	121.94 (17)	O2—C20—H20B	109.5
N1—C10—C11	116.81 (16)	H20A—C20—H20B	109.5
C16—C11—C12	119.72 (18)	O2—C20—H20C	109.5
C16—C11—C10	118.87 (17)	H20A—C20—H20C	109.5
C12—C11—C10	121.19 (16)	H20B—C20—H20C	109.5
C13—C12—C11	120.61 (17)

C10—N1—C2—C3	175.00 (16)	C10—N1—C9—C8	3.4 (3)
C9—N1—C2—C3	2.49 (19)	C2—N1—C9—C8	175.65 (19)
C10—N1—C2—C17	−9.2 (3)	C10—N1—C9—C4	−173.88 (16)
C9—N1—C2—C17	178.34 (16)	C2—N1—C9—C4	−1.65 (19)
N1—C2—C3—C4	−2.3 (2)	C9—N1—C10—O1	145.19 (18)
C17—C2—C3—C4	−177.82 (18)	C2—N1—C10—O1	−25.9 (3)
N1—C2—C3—C18	178.70 (16)	C9—N1—C10—C11	−38.2 (2)
C17—C2—C3—C18	3.2 (3)	C2—N1—C10—C11	150.80 (16)
C2—C3—C4—C9	1.3 (2)	O1—C10—C11—C16	−38.7 (3)
C18—C3—C4—C9	−179.67 (16)	N1—C10—C11—C16	144.67 (17)
C2—C3—C4—C5	−177.67 (18)	O1—C10—C11—C12	135.90 (19)
C18—C3—C4—C5	1.4 (3)	N1—C10—C11—C12	−40.7 (2)
C9—C4—C5—C6	0.0 (3)	C16—C11—C12—C13	0.6 (3)
C3—C4—C5—C6	178.87 (18)	C10—C11—C12—C13	−173.92 (17)
C20—O2—C6—C5	5.4 (3)	C11—C12—C13—C14	−1.3 (3)
C20—O2—C6—C7	−173.24 (17)	C12—C13—C14—C15	0.5 (3)
C4—C5—C6—O2	−179.68 (17)	C12—C13—C14—Cl1	178.57 (15)
C4—C5—C6—C7	−1.1 (3)	C13—C14—C15—C16	1.1 (3)
O2—C6—C7—C8	179.31 (18)	Cl1—C14—C15—C16	−176.97 (14)
C5—C6—C7—C8	0.6 (3)	C14—C15—C16—C11	−1.9 (3)
C6—C7—C8—C9	1.0 (3)	C12—C11—C16—C15	1.0 (3)
C7—C8—C9—C4	−2.2 (3)	C10—C11—C16—C15	175.67 (17)
C7—C8—C9—N1	−179.16 (18)	C2—C3—C18—C19	100.1 (2)
C5—C4—C9—C8	1.7 (3)	C4—C3—C18—C19	−78.7 (2)
C3—C4—C9—C8	−177.40 (17)	C3—C18—C19—O4	−35.0 (3)
C5—C4—C9—N1	179.35 (16)	C3—C18—C19—O3	146.26 (17)
C3—C4—C9—N1	0.25 (19)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O4ⁱ	0.91 (3)	1.75 (3)	2.651 (3)	173 (3)

Symmetry code: (i) −x−1, −y+1, −z.

Experimental details

Crystal data
Chemical formula	C₁₉H₁₆ClNO₄
M_r	357.78
Crystal system, space group	Triclinic, P1
Temperature (K)	120
a, b, c (Å)	9.236 (5), 9.620 (5), 10.887 (5)
α, β, γ (°)	69.897 (5), 87.328 (5), 69.501 (5)
V (Å³)	847.9 (7)
Z	2
Radiation type	Mo Kα
µ (mm⁻¹)	0.25
Crystal size (mm)	0.23 × 0.2 × 0.02

Data collection
Diffractometer	Nonius KappaCCD area-detector diffractometer
Absorption correction	Multi-scan (SORTAV; Blessing, 1995, 1997)
T_min, T_max	0.956, 0.992
No. of measured, independent and observed [I > 2σ(I)] reflections	10585, 3800, 2586
R_int	0.056
(sin θ/λ)_max (Å⁻¹)	0.650

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.044, 0.105, 1.01
No. of reflections	3800
No. of parameters	232
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.27, −0.26

Computer programs: DENZO (Otwinowski & Minor, 1997) and COLLECT (Hooft, 1998), DENZO and COLLECT, SIR97 (Altomare et al., 1997), SHELXL97 (Sheldrick, 1997), ORTEP-3 for Windows (Farrugia, 1997), WinGX (Farrugia, 1999).

Selected geometric parameters (Å, º) top

Cl1—C14	1.740 (2)	O4—C19	1.218 (2)
O1—C10	1.216 (2)	C18—C19	1.505 (3)
O3—C19	1.313 (2)

C9—C4—C3	107.74 (16)	C8—C9—N1	131.83 (17)
C5—C4—C3	131.18 (17)	C4—C9—N1	107.23 (16)

C10—N1—C2—C17	−9.2 (3)	C2—N1—C10—O1	−25.9 (3)
C17—C2—C3—C18	3.2 (3)	O1—C10—C11—C12	135.90 (19)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O4ⁱ	0.91 (3)	1.75 (3)	2.651 (3)	173 (3)

Symmetry code: (i) −x−1, −y+1, −z.

C—H···π interactions (Å, °) top

C—H	CgI	Symmetry code	H···CgI	C—H···CgI	C···CgI
C18—H18A	2	-x, −y, −z	3.12	118	3.687 (3)
C18—H18B	1	-x, −y, −z	2.72	166	3.692 (3)
C20—H20A	2	-x, 1 − y, −z	2.68	142	3.511 (3)

Cg is the centre of gravity of rings in the indole system: Cg1 five-membered ring and Cg2 six-membered ring. The symmetry applies to the CgI position.

π–π interactions (Å, °) top

CgI	CgJ	Symmetry code	Cg···Cg	dihedral_angle	interplanar	offset
3	3	1 − x, −1 − y, 1 − z	3.922 (2)	0.0	3.411 (2)	1.942

Cg3 is the centre of gravity of the chlorophenyl ring. The symmetry applies to the CgJ position.

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