Low-temperature determination of theophylline dimethyl sulfoxide solvate

The title solvate, C₇H₈N₄O₂·C₂H₆OS, was obtained unintentionally from a cocrystal screen involving theophylline and isophthalic acid. One mol­ecule each of theophylline and dimethyl sulfoxide is present in the asymmetric unit. The packing consists of mol­ecular sheets lying parallel to the (040) series of lattice planes, in which each theophylline mol­ecule is hydrogen bonded to one dimethyl sulfoxide mol­ecule through an N—H...O [2.7658 (15) Å] hydrogen bond. This particular hydrogen-bond donor was found to be used in this type of inter­action in a variety of other crystal structures of theophylline.

Key indicators

• Single-crystal X-ray study
• T = 150 K
• Mean [sigma](C-C) = 0.002 Å
• R factor = 0.039
• wR factor = 0.103
• Data-to-parameter ratio = 16.1

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S1. Comment

Theophylline is a pharmaceutically active compound for the treatment of asthma, and is currently known to have two anhydrous and one monohydrate crystal modifications (Sun et al., 2002; Sutor, 1958; Ebisuzaki et al., 1997). A variety of molecular complexes of theophylline have been determined, including with urea (Wiedenfeld & Knoch, 1986), and phenobarbital (Nakao et al., 1977). In addition, a recent co-crystal study on theophylline has also been performed (Trask et al., 2006). In this paper we report the dimethyl sulfoxide solvate of theophylline (I).

(I) has one molecule each of theophylline and dimethyl sulfoxide in the asymmetric unit, with the C—N and C—C bond lengths in (I) ranging from 1.3470 (17) to 1.4702 (16) Å, and 1.3720 (16) to 1.4251 (17) Å, respectively. The packing consists of molecular sheets (Fig 2), lying parallel to the (040) series of lattice planes. Within the molecular sheets each theophylline molecule is hydrogen bonded to one dimethyl sulfoxide molecule through a N—H···O -(2.7658 (15) Å) hydrogen bond (Fig 1). This particular hydrogen bond donor (N7—H1) was found to undergo hydrogen bonding within a variety of theophylline crystal structures, including the anhydrous (Sutor, 1958; Ebisuzaki et al., 1997) and monohydrate (Sun et al., 2002) forms, and in a variety of theophylline cocrystals (Trask et al., 2006).

Related literature

For related literature, see: Ebisuzaki et al. (1997); Sun et al. (2002); Sutor (1958); Trask et al. (2006); Wiedenfeld & Knoch (1986); Nakao et al. (1977); Spek (2004).

S2. Experimental

As part of a cocrystal study on theophylline, (I) was obtained from a solution of theophylline in dimethyl sulfoxide to which an equimolar amount of isophthalic acid was added. The solution was allowed to evaporate at room temperature, forming long plate-like crystals.

S3. Refinement

All non-hydrogen atoms were refined with anisotropic displacement parameters, while the hydrogen atoms were freely refined with an isotropic model.

Computing details

Data collection: CrysAlis CCD (Oxford Diffraction, 2005); cell refinement: CrysAlis RED (Oxford Diffraction, 2005); data reduction: CrysAlis RED; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPIII (Burnett & Johnson, 1996) and Mercury (Bruno et al., 2002); software used to prepare material for publication: SHELXL97.

Figures

	Fig. 1. View of (I) showing the atom labelling scheme. Displacement ellipsoids are drawn at 50% level. The N7—H1···O01 hydrogen bond is also shown.
	Fig. 2. The crystal packing in (I) showing the molecular sheets parallel to the (040) series of lattice planes.

Theophylline dimethyl sulfoxide solvate

Crystal data

C7H8N4O2·C2H6OS	F(000) = 544
Mr = 258.30	Dx = 1.469 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 10.1078 (4) Å	Cell parameters from 7829 reflections
b = 6.6686 (2) Å	θ = 3.0–30.1°
c = 17.3716 (6) Å	µ = 0.28 mm^−1
β = 94.000 (3)°	T = 150 K
V = 1168.08 (7) Å^3	Plate, colourless
Z = 4	0.30 × 0.20 × 0.10 mm

Data collection

Oxford Diffaction Xcalibur System diffractometer	3389 independent reflections
Radiation source: Enhance (Mo) X-ray Source	2954 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.018
Detector resolution: 16.2086 pixels mm^-1	θmax = 30.1°, θmin = 3.0°
321 frames, counting time 10 s. scans	h = −14→13
Absorption correction: multi-scan (ABSPACK; Oxford Diffraction, 2005)	k = −9→4
Tmin = 0.909, Tmax = 1.000	l = −24→23
7829 measured reflections

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)] = 0.039	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.103	All H-atom parameters refined
S = 1.14	w = 1/[σ^2(Fo^2) + (0.0448P)^2 + 0.4489P] where P = (Fo^2 + 2Fc^2)/3
3389 reflections	(Δ/σ)max = 0.001
210 parameters	Δρmax = 0.48 e Å^−3
0 restraints	Δρmin = −0.32 e Å^−3

Special details

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.

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
S01	0.99246 (3)	0.27513 (6)	0.39406 (2)	0.02725 (10)
O01	0.86611 (10)	0.21464 (19)	0.43009 (6)	0.0339 (3)
O13	0.80020 (10)	0.20643 (18)	0.22207 (6)	0.0324 (2)
C12	0.25006 (13)	0.2289 (3)	0.17748 (8)	0.0280 (3)
N3	0.39458 (10)	0.21980 (16)	0.18986 (6)	0.0185 (2)
O11	0.41996 (10)	0.22404 (15)	0.06081 (5)	0.0259 (2)
N7	0.61561 (11)	0.21610 (16)	0.35505 (6)	0.0196 (2)
N1	0.60823 (11)	0.21461 (16)	0.14185 (6)	0.0197 (2)
N9	0.39424 (11)	0.21847 (17)	0.33061 (6)	0.0210 (2)
C10	0.68505 (15)	0.2138 (2)	0.07304 (8)	0.0285 (3)
C02	1.04433 (15)	0.0636 (3)	0.34142 (9)	0.0341 (3)
C4	0.45550 (12)	0.21723 (17)	0.26335 (7)	0.0165 (2)
C8	0.49588 (13)	0.21820 (19)	0.38458 (7)	0.0208 (2)
C6	0.67877 (13)	0.21158 (19)	0.21484 (7)	0.0206 (2)
C5	0.59106 (12)	0.21525 (17)	0.27559 (6)	0.0171 (2)
C2	0.47051 (12)	0.21983 (18)	0.12719 (7)	0.0186 (2)
C01	1.12025 (16)	0.2617 (3)	0.47024 (10)	0.0364 (4)
H2	0.4860 (17)	0.220 (2)	0.4387 (10)	0.024 (4)*
H6	0.6500 (17)	0.105 (3)	0.0372 (10)	0.033 (4)*
H1	0.694 (2)	0.220 (3)	0.3829 (12)	0.038 (5)*
H7	0.7726 (19)	0.191 (3)	0.0903 (11)	0.033 (5)*
H11	1.1159 (19)	0.130 (3)	0.4954 (11)	0.043 (5)*
H8	0.6760 (18)	0.344 (3)	0.0467 (11)	0.038 (5)*
H13	1.039 (2)	−0.057 (3)	0.3756 (12)	0.050 (6)*
H5	0.222 (2)	0.309 (4)	0.1328 (14)	0.056 (6)*
H12	1.134 (2)	0.086 (3)	0.3285 (11)	0.044 (5)*
H14	0.986 (2)	0.051 (3)	0.2967 (12)	0.049 (6)*
H3	0.220 (2)	0.294 (3)	0.2224 (14)	0.054 (6)*
H9	1.106 (2)	0.364 (3)	0.5073 (12)	0.046 (5)*
H4	0.215 (2)	0.103 (4)	0.1702 (14)	0.065 (7)*
H10	1.204 (3)	0.280 (3)	0.4482 (16)	0.064 (7)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S01	0.01938 (16)	0.03553 (19)	0.02636 (17)	0.00271 (12)	−0.00191 (12)	0.00318 (13)
O01	0.0160 (4)	0.0631 (7)	0.0226 (5)	0.0054 (4)	0.0019 (3)	−0.0009 (5)
O13	0.0174 (5)	0.0550 (7)	0.0245 (5)	−0.0004 (4)	0.0007 (4)	0.0054 (4)
C12	0.0171 (6)	0.0443 (8)	0.0218 (6)	−0.0008 (5)	−0.0038 (5)	0.0000 (6)
N3	0.0163 (5)	0.0248 (5)	0.0141 (4)	−0.0004 (4)	−0.0021 (3)	−0.0002 (4)
O11	0.0256 (5)	0.0369 (5)	0.0145 (4)	−0.0007 (4)	−0.0025 (3)	−0.0007 (4)
N7	0.0196 (5)	0.0238 (5)	0.0149 (4)	−0.0004 (4)	−0.0027 (4)	0.0005 (4)
N1	0.0196 (5)	0.0253 (5)	0.0143 (4)	−0.0003 (4)	0.0015 (4)	0.0001 (4)
N9	0.0197 (5)	0.0278 (5)	0.0154 (4)	0.0001 (4)	0.0011 (4)	−0.0003 (4)
C10	0.0245 (7)	0.0431 (8)	0.0185 (6)	−0.0004 (6)	0.0062 (5)	−0.0018 (5)
C02	0.0215 (7)	0.0530 (10)	0.0281 (7)	0.0041 (6)	0.0030 (5)	−0.0064 (7)
C4	0.0183 (5)	0.0163 (5)	0.0146 (5)	−0.0004 (4)	−0.0013 (4)	−0.0001 (4)
C8	0.0229 (6)	0.0245 (6)	0.0149 (5)	0.0005 (5)	0.0000 (4)	0.0000 (4)
C6	0.0193 (6)	0.0241 (6)	0.0180 (5)	−0.0009 (4)	−0.0010 (4)	0.0017 (4)
C5	0.0177 (5)	0.0191 (5)	0.0143 (5)	−0.0004 (4)	−0.0016 (4)	0.0008 (4)
C2	0.0214 (6)	0.0184 (5)	0.0156 (5)	−0.0004 (4)	−0.0007 (4)	−0.0005 (4)
C01	0.0254 (7)	0.0438 (9)	0.0382 (8)	0.0013 (6)	−0.0106 (6)	−0.0062 (7)

Geometric parameters (Å, º)

S01—O01	1.5156 (11)	N1—C10	1.4702 (16)
S01—C02	1.7797 (17)	N9—C8	1.3417 (16)
S01—C01	1.7859 (16)	N9—C4	1.3601 (15)
O13—C6	1.2256 (16)	C10—H6	1.003 (18)
C12—N3	1.4628 (16)	C10—H7	0.927 (19)
C12—H5	0.97 (2)	C10—H8	0.98 (2)
C12—H3	0.96 (2)	C02—H13	1.01 (2)
C12—H4	0.91 (3)	C02—H12	0.96 (2)
N3—C2	1.3751 (16)	C02—H14	0.94 (2)
N3—C4	1.3781 (14)	C4—C5	1.3720 (16)
O11—C2	1.2286 (15)	C8—H2	0.952 (17)
N7—C8	1.3470 (17)	C6—C5	1.4251 (17)
N7—C5	1.3854 (15)	C01—H11	0.98 (2)
N7—H1	0.90 (2)	C01—H9	0.96 (2)
N1—C2	1.3980 (16)	C01—H10	0.96 (3)
N1—C6	1.4108 (15)
O01—S01—C02	106.75 (7)	S01—C02—H12	108.2 (12)
O01—S01—C01	105.50 (8)	H13—C02—H12	110.5 (17)
C02—S01—C01	96.73 (8)	S01—C02—H14	107.5 (13)
N3—C12—H5	112.3 (13)	H13—C02—H14	111.2 (17)
N3—C12—H3	105.7 (14)	H12—C02—H14	111.4 (17)
H5—C12—H3	107.8 (19)	N9—C4—C5	112.12 (10)
N3—C12—H4	110.7 (15)	N9—C4—N3	126.50 (11)
H5—C12—H4	107.8 (19)	C5—C4—N3	121.37 (11)
H3—C12—H4	112.6 (19)	N9—C8—N7	113.49 (11)
C2—N3—C4	119.69 (10)	N9—C8—H2	124.2 (11)
C2—N3—C12	119.36 (10)	N7—C8—H2	122.3 (11)
C4—N3—C12	120.92 (11)	O13—C6—N1	122.16 (12)
C8—N7—C5	106.03 (10)	O13—C6—C5	126.50 (12)
C8—N7—H1	125.1 (13)	N1—C6—C5	111.33 (11)
C5—N7—H1	128.8 (13)	C4—C5—N7	105.19 (10)
C2—N1—C6	126.76 (10)	C4—C5—C6	123.47 (11)
C2—N1—C10	115.32 (10)	N7—C5—C6	131.34 (11)
C6—N1—C10	117.92 (11)	O11—C2—N3	121.64 (12)
C8—N9—C4	103.18 (10)	O11—C2—N1	121.01 (11)
N1—C10—H6	108.9 (10)	N3—C2—N1	117.35 (10)
N1—C10—H7	106.5 (12)	S01—C01—H11	108.8 (12)
H6—C10—H7	111.7 (15)	S01—C01—H9	109.1 (12)
N1—C10—H8	109.7 (11)	H11—C01—H9	108.9 (18)
H6—C10—H8	109.4 (15)	S01—C01—H10	108.1 (16)
H7—C10—H8	110.6 (16)	H11—C01—H10	111.0 (18)
S01—C02—H13	107.8 (12)	H9—C01—H10	110.9 (19)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N7—H1···O01	0.90 (2)	1.87 (2)	2.7658 (15)	172.8 (19)