The 1:1 hydrate of diflunisal

2',4'-Di­fluoro-4-hydroxy­bi­phenyl-3-carboxyl­ic acid (diflunisal) hydrate, C₁₃H₈F₂O₃·H₂O, forms a monoclinic crystal lattice with special channels parallel to the twofold screw axes along the b direction. These channels are occupied by disordered water mol­ecules. The crystal lattice consists of dimers of diflunisal, in which two mol­ecules are linked together by a pair of hydrogen bonds between their respective carboxyl groups.

Key indicators

• Single-crystal X-ray study
• T = 298 K
• Mean [sigma](C-C) = 0.004 Å
• H-atom completeness 91%
• Disorder in main residue
• R factor = 0.050
• wR factor = 0.178
• Data-to-parameter ratio = 9.9

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry


 Alert Level B:



PLAT_030  Alert B Refined Extinction parameter within range ....       1.90 Sigma


 Alert Level C:



SHFSU_01  Alert C The absolute value of parameter shift to su ratio > 0.05
          Absolute value of the parameter shift to su ratio given   0.072
          Additional refinement cycles may be required.

PLAT_301  Alert C Main Residue Disorder ........................       5.00 Perc.

PLAT_302  Alert C Anion/Solvent Disorder .......................      50.00 Perc.

PLAT_722  Alert C Angle   Calc      110.75, Rep      109.40, Dev.      1.35 Deg.
                     O1W  -O2W  -H12W    4.545   1.555   1.555

General Notes



FORMU_01  There is a discrepancy between the atom counts in the
          _chemical_formula_sum and the formula from the _atom_site* data.
          Atom count from _chemical_formula_sum:C13 H10 F2 O4
          Atom count from the _atom_site data:  C13 H9 F2 O4

CELLZ_01
         From the CIF: _cell_formula_units_Z    8
         From the CIF: _chemical_formula_sum  C13 H10 F2 O4
         TEST: Compare cell contents of formula and atom_site data

         atom    Z*formula  cif sites diff
         C        104.00    104.00    0.00
         H         80.00     72.00    8.00
         F         16.00     16.00    0.00
         O         32.00     32.00    0.00
          Difference between formula and atom_site contents detected.
          WARNING: H atoms missing from atom site list. Is this intentional?


 0 Alert Level A = Potentially serious problem

 1 Alert Level B = Potential problem

 4 Alert Level C = Please check

---

S1. Comment

Diflunisal is a difluorphenyl derivative of acetyl salicylic acid (aspirin), which is used therapeutically as an anti-inflammatory drug similar to aspirin. The structure of unsolvated diflunisal was described earlier (Kim & Park, 1996). However, this new investigation displays properties of clathrate materials and includes in the crystal lattice solvent molecules. Here, the structure of its hydrate, (I), is reported. The investigated structure is characterized as a packing of the diflunisal dimers, which is obtained by energetic equivalent hydrogen bonds between two adjacent molecules (Table 1). Probably, atom O2 takes part in forming not only the intermolecular bonds but also the intramolecular ones O1—H10···O2.

The conformation state of a diflunisal molecule may be characterized as follows: the phenyl planes are tilted round the C1—C8 bond by a dihedral angle of 43.9 (1)°. Similar values of angles have been reported for π-stacking interactions in nucleic acids (Langlet et al., 1981; Rein, 1978; Claverie, 1978). For comparison, the planes of benzene molecules in an orthorhombic crystal, which are situated 5.81 Å apart, form a dihedral angle of 29° (Bacon at al., 1964). It should be noted that theoretical analysis of the structure of benzene clusters (Sun & Bernstein, 1996) derives dihedral angles between planes of benzene molecules corresponding to approximately 40°, where the molecules are packed in a herring-bone fashion.

In diflunisal, the hydroxyl group is tilted against the phenyl group: the torsion angle C3—C4—O1—H1O is 3(3)°. The geometry of carboxyl group slightly differs from a planar arrangement [torsion angle O2—C7—O3—H2O is 2(2)°] and is approximately coplanar with the phenyl fragment [torsion angle O3—C7—C3—C2 is 0.7 (4)°]. The F atoms in positions 2'- and 6'- are disordered. This means that the peaks found for F21 and F22 are a combination of a half-hydrogen peak with a half-fluorine peak even though the bond lengths found for the C—F bonds are normal. This may be explained by the fact that fluorine is a much heavier element compared to hydrogen (19:1), so the influence of hydrogen on the C—F bond will be negligible. The phenyl groups of neighbouring parallel molecules are stacked face-to-face and shifted by R_shift = 1.6 Å. The distance between these planes of the phenyl rings is R_b = 3.73 Å. These parameters are in good agreement with the values for the local energetic minimum calculated for benzene dimers: R_shift* = 1.6 Å and R_b* = 3.85 Å (Hobza at al., 1993, 1994), and the relative orientation and packing of phenyl rings in diflunisal follow in general the rules of packing of benzene dimers. Out of four energetic minima calculated for benzene arrangement (parallel staggered PS; parallel displaced, PD; herring-bone, H; T-shape, T), in the present case, two such local energetic minima are realised (PD and H).

The characteristic (specific) property of the crystal lattice of diflunisal is the existence of channels along the twofold screw axes and parallel to the b direction. The geometry of these channels allows accommodation of solvent molecules of appropriate sizes. In the present case, the channels are filled by water molecules, which are situated in a disordered state. It should be noted the investigated solvate is stable at room conditions. In order to check the stoichiometry of the solvate DSC and TG measurements were carried out at various heating rates (v = 1–20 K min^-1). The heat effect occurring during desolvation at v = 10 K min^-1 and temperature interval from 353 to 383 K is 16 J mol^-1. The average mass losses achieved 7.1% and it corresponded to a stoichiometry of diflunisal:water as 1:1. This result is in a good agreement with the X-ray experiment. Considering the possible orientations of the water molecule in the two sites, a calculation has been carried out by using the HYDROGEN program (Nardelli, 1999). These results lead to conclude that the water molecules in the channels form hydrogen bonds between themselves. However, these molecules (guests) are located at relatively long distances from host(diflunisal)-molecules and do not take part in specific host–guest interactions.

S2. Experimental

The solvate was grown by crystallization of a saturated solution of diflunisal and acetone by vapour diffusion of H₂O (Guillory, 1999). All programs used in the solution (Sheldrick, 1997a), refinement (Sheldrick, 1997b) and display (Burnett & Johnson, 1996) of the structures are included in the OSCAIL program package (McArdle, 1993).

Computing details

Data collection: CAD-4 Software (Enraf-Nonius, 1989); cell refinement: CAD-4 Software; data reduction: CAD-4 Software; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPIII (Burnett & Johnson, 1996); software used to prepare material for publication: OSCAIL (McArdle, 1993).

Figures

	Fig. 1. A view of diflunisal with the atomic numbering scheme. Displacement ellipsoids are drawn at the 20% probability level.
	Fig. 2. Fragment of the crystal packing looking down the b axis.

2',4'-Difluoro-4-hydroxybiphenyl-3-carboxylic acid hydrate

Crystal data

C13H8F2O3·H2O	F(000) = 1024
Mr = 268.21	Dx = 1.417 Mg m^−3
Monoclinic, C2/c	Mo Kα radiation, λ = 0.71069 Å
a = 34.650 (2) Å	Cell parameters from 25 reflections
b = 3.730 (2) Å	θ = 12–16°
c = 20.760 (2) Å	µ = 0.12 mm^−1
β = 110.47 (6)°	T = 298 K
V = 2513.7 (14) Å^3	Needle, white
Z = 8	0.30 × 0.20 × 0.15 mm

Data collection

Enraf-Nonius CAD-4 diffractometer	Rint = 0.014
Radiation source: fine-focus sealed tube	θmax = 25.0°, θmin = 1.3°
Graphite monochromator	h = −1→40
ω–2θ scans	k = 0→4
2306 measured reflections	l = −24→23
2221 independent reflections	3 standard reflections every 120 min
1127 reflections with I > 2σ(I)	intensity decay: 1%

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.050	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.178	w = 1/[σ^2(Fo^2) + (0.1388P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 0.83	(Δ/σ)max = 0.072
2221 reflections	Δρmax = 0.26 e Å^−3
225 parameters	Δρmin = −0.16 e Å^−3
12 restraints	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0019 (10)

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	Occ. (<1)
O2	0.21016 (6)	0.4183 (7)	0.51319 (10)	0.0799 (7)
O1	0.14124 (7)	0.6837 (7)	0.51807 (10)	0.0803 (7)
F1	0.04258 (6)	0.7662 (6)	0.01551 (9)	0.1004 (8)
O3	0.21697 (6)	0.3433 (6)	0.41116 (10)	0.0744 (7)
F22	0.14811 (9)	0.9780 (9)	0.22339 (15)	0.0729 (9)	0.50
F21	0.02001 (9)	0.4863 (9)	0.21767 (16)	0.0710 (9)	0.50
O1W	0.2503 (14)	0.30 (2)	0.2028 (17)	0.61 (4)	0.35
H11W	0.2347	0.1304	0.1861	0.22 (7)*	0.50
H21W	0.2221	0.4924	0.1899	0.10 (2)*	0.50
O2W	0.2684 (12)	0.03 (2)	0.284 (2)	0.81 (6)	0.65
H12W	0.2842	−0.0501	0.2660	0.21 (6)*	0.50
H22W	0.2717	0.2020	0.3112	0.14 (4)*	0.50
H2O	0.2441 (11)	0.247 (9)	0.4415 (16)	0.090 (10)*
H1O	0.1735 (17)	0.594 (18)	0.545 (3)	0.20 (2)*
H12	0.0012 (9)	0.565 (8)	0.0892 (14)	0.078 (8)*
H6	0.0475 (9)	0.933 (8)	0.3163 (13)	0.070 (8)*
H2	0.1563 (7)	0.512 (7)	0.3167 (12)	0.054 (7)*
H10	0.1109 (9)	0.940 (8)	0.0936 (14)	0.072 (8)*
H5	0.0757 (8)	0.897 (8)	0.4393 (14)	0.073 (8)*
C1	0.10061 (7)	0.7280 (6)	0.30416 (13)	0.0523 (7)
C2	0.13952 (8)	0.6003 (7)	0.34099 (13)	0.0531 (7)
C3	0.15455 (7)	0.5818 (7)	0.41225 (13)	0.0544 (7)
C4	0.12911 (8)	0.6963 (7)	0.44856 (14)	0.0583 (7)
C5	0.09024 (8)	0.8234 (8)	0.41219 (15)	0.0603 (7)
C6	0.07633 (8)	0.8403 (7)	0.34188 (14)	0.0570 (7)
C7	0.19583 (8)	0.4423 (8)	0.44992 (14)	0.0604 (7)
C8	0.08514 (8)	0.7419 (6)	0.22797 (13)	0.0523 (7)
C9	0.10952 (8)	0.8607 (8)	0.19111 (14)	0.0594 (7)
C10	0.09597 (9)	0.8707 (9)	0.12048 (15)	0.0675 (8)
C11	0.05671 (10)	0.7592 (8)	0.08547 (14)	0.0697 (8)
C12	0.03057 (9)	0.6409 (9)	0.11752 (15)	0.0668 (8)
C13	0.04560 (8)	0.6320 (8)	0.18820 (13)	0.0581 (7)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O2	0.0695 (13)	0.1062 (18)	0.0642 (13)	0.0226 (13)	0.0238 (10)	0.0031 (12)
O1	0.0802 (14)	0.1068 (17)	0.0590 (12)	0.0176 (13)	0.0309 (10)	−0.0026 (11)
F1	0.1103 (15)	0.1289 (19)	0.0616 (11)	−0.0115 (13)	0.0294 (10)	0.0072 (10)
O3	0.0604 (12)	0.0973 (16)	0.0683 (13)	0.0203 (12)	0.0259 (10)	0.0016 (11)
F22	0.0619 (18)	0.090 (2)	0.0715 (19)	−0.0175 (17)	0.0293 (15)	0.0015 (18)
F21	0.0579 (16)	0.084 (2)	0.0758 (18)	−0.0040 (16)	0.0291 (15)	−0.0006 (17)
O1W	0.91 (8)	0.72 (8)	0.41 (4)	0.44 (7)	0.49 (5)	0.22 (4)
O2W	0.74 (7)	1.09 (12)	0.86 (9)	−0.04 (7)	0.60 (7)	0.19 (7)
C1	0.0554 (15)	0.0419 (15)	0.0622 (16)	0.0010 (11)	0.0238 (12)	−0.0001 (11)
C2	0.0585 (16)	0.0454 (15)	0.0621 (16)	0.0026 (12)	0.0293 (13)	−0.0006 (12)
C3	0.0551 (15)	0.0474 (15)	0.0644 (16)	0.0018 (12)	0.0256 (12)	−0.0015 (12)
C4	0.0614 (16)	0.0546 (16)	0.0633 (17)	0.0024 (13)	0.0273 (13)	−0.0041 (13)
C5	0.0620 (17)	0.0585 (17)	0.0689 (18)	0.0033 (14)	0.0335 (15)	−0.0042 (14)
C6	0.0537 (15)	0.0495 (15)	0.0713 (18)	0.0052 (14)	0.0262 (13)	0.0004 (14)
C7	0.0591 (15)	0.0597 (17)	0.0657 (18)	0.0031 (14)	0.0261 (14)	0.0002 (13)
C8	0.0555 (15)	0.0408 (15)	0.0638 (16)	0.0029 (11)	0.0249 (12)	0.0002 (11)
C9	0.0631 (16)	0.0510 (15)	0.0678 (17)	−0.0015 (13)	0.0277 (13)	0.0009 (13)
C10	0.0754 (19)	0.0673 (19)	0.0697 (19)	−0.0049 (16)	0.0376 (16)	0.0022 (16)
C11	0.085 (2)	0.070 (2)	0.0562 (17)	0.0017 (16)	0.0264 (15)	0.0061 (14)
C12	0.0597 (17)	0.0722 (19)	0.0656 (18)	0.0014 (15)	0.0182 (14)	0.0003 (15)
C13	0.0538 (15)	0.0548 (16)	0.0717 (18)	0.0005 (13)	0.0293 (13)	0.0023 (13)

Geometric parameters (Å, º)

O2—C7	1.234 (3)	C2—C3	1.388 (4)
O1—C4	1.355 (3)	C2—H2	0.95 (2)
O1—H1O	1.11 (6)	C3—C4	1.411 (3)
F1—C11	1.361 (3)	C3—C7	1.465 (4)
O3—C7	1.316 (3)	C4—C5	1.378 (4)
O3—H2O	1.00 (3)	C5—C6	1.369 (4)
F22—C9	1.343 (4)	C5—H5	0.92 (3)
F21—C13	1.355 (4)	C6—H6	1.02 (3)
O1W—O2W^i	1.18 (4)	C8—C13	1.391 (4)
O1W—H11W	0.8200	C8—C9	1.395 (4)
O1W—H21W	1.1686	C9—C10	1.375 (4)
O2W—O1W^ii	1.18 (4)	C10—C11	1.364 (4)
O2W—H12W	0.8200	C10—H10	0.92 (3)
O2W—H22W	0.8297	C11—C12	1.371 (4)
C1—C2	1.381 (4)	C12—C13	1.375 (4)
C1—C6	1.399 (3)	C12—H12	1.02 (3)
C1—C8	1.483 (4)
C4—O1—H1O	116 (3)	C5—C6—H6	119.2 (14)
C7—O3—H2O	108.5 (17)	C1—C6—H6	119.0 (15)
O2W^i—O1W—H11W	109.6	O2—C7—O3	121.8 (3)
O2W^i—O1W—H21W	27.1	O2—C7—C3	123.2 (2)
H11W—O1W—H21W	90.3	O3—C7—C3	114.9 (2)
O1W^ii—O2W—H12W	109.4	C13—C8—C9	115.3 (2)
O1W^ii—O2W—H22W	110.9	C13—C8—C1	122.4 (2)
H12W—O2W—H22W	130.2	C9—C8—C1	122.3 (2)
C2—C1—C6	117.1 (2)	F22—C9—C10	115.6 (3)
C2—C1—C8	121.4 (2)	F22—C9—C8	121.2 (3)
C6—C1—C8	121.5 (2)	C10—C9—C8	123.2 (3)
C1—C2—C3	122.5 (2)	C11—C10—C9	117.7 (3)
C1—C2—H2	118.9 (14)	C11—C10—H10	115.5 (17)
C3—C2—H2	118.5 (14)	C9—C10—H10	126.8 (18)
C2—C3—C4	118.9 (2)	F1—C11—C10	118.8 (3)
C2—C3—C7	121.3 (2)	F1—C11—C12	118.2 (3)
C4—C3—C7	119.9 (2)	C10—C11—C12	123.0 (3)
O1—C4—C5	118.4 (2)	C11—C12—C13	117.3 (3)
O1—C4—C3	122.6 (2)	C11—C12—H12	120.3 (16)
C5—C4—C3	119.0 (3)	C13—C12—H12	122.4 (16)
C6—C5—C4	120.8 (3)	F21—C13—C12	115.4 (3)
C6—C5—H5	125.1 (17)	F21—C13—C8	121.0 (3)
C4—C5—H5	114.1 (17)	C12—C13—C8	123.6 (2)
C5—C6—C1	121.8 (3)
C6—C1—C2—C3	0.0 (4)	C2—C1—C8—C9	−43.2 (3)
C8—C1—C2—C3	−179.5 (2)	C6—C1—C8—C9	137.4 (3)
C1—C2—C3—C4	0.3 (4)	C13—C8—C9—F22	179.2 (3)
C1—C2—C3—C7	179.5 (2)	C1—C8—C9—F22	−1.9 (4)
C2—C3—C4—O1	179.3 (3)	C13—C8—C9—C10	0.1 (4)
C7—C3—C4—O1	0.1 (4)	C1—C8—C9—C10	179.0 (3)
C2—C3—C4—C5	−0.2 (4)	F22—C9—C10—C11	−179.0 (3)
C7—C3—C4—C5	−179.4 (3)	C8—C9—C10—C11	0.2 (5)
O1—C4—C5—C6	−179.7 (3)	C9—C10—C11—F1	−179.9 (3)
C3—C4—C5—C6	−0.2 (4)	C9—C10—C11—C12	0.3 (5)
C4—C5—C6—C1	0.5 (4)	F1—C11—C12—C13	179.3 (3)
C2—C1—C6—C5	−0.3 (4)	C10—C11—C12—C13	−1.0 (5)
C8—C1—C6—C5	179.1 (2)	C11—C12—C13—F21	−174.8 (3)
C2—C3—C7—O2	−179.3 (3)	C11—C12—C13—C8	1.2 (5)
C4—C3—C7—O2	−0.1 (4)	C9—C8—C13—F21	175.1 (3)
C2—C3—C7—O3	0.9 (4)	C1—C8—C13—F21	−3.9 (4)
C4—C3—C7—O3	−180.0 (2)	C9—C8—C13—C12	−0.8 (4)
C2—C1—C8—C13	135.7 (3)	C1—C8—C13—C12	−179.7 (3)
C6—C1—C8—C13	−43.7 (3)

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

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O3—H2O···O2^iii	1.00 (4)	1.65 (4)	2.650 (3)	176 (4)
O1—H1O···O2	1.11 (6)	1.75 (6)	2.620 (4)	131 (4)

Symmetry code: (iii) −x+1/2, −y+1/2, −z+1.