2',4'-Difluoro-4-hydroxybiphenyl-3-carboxylic acid (diflunisal, C13H8F2O3) 0.25-hexane solvate forms a monoclinic crystal lattice with special channels parallel to the twofold screw axes along the b direction. These channels are occupied by disordered hexane molecules. The crystal lattice consists of the dimers of diflunisal, in which two molecules are linked together by a pair of hydrogen bonds between their respective carboxyl groups.
Supporting information
CCDC reference: 170768
Key indicators
- Single-crystal X-ray study
- T = 298 K
- Mean (C-C) = 0.008 Å
- Disorder in main residue
- R factor = 0.066
- wR factor = 0.200
- Data-to-parameter ratio = 9.8
checkCIF results
No syntax errors found
ADDSYM reports no extra symmetry
Alert Level B:
SHFSU_01 Alert B The absolute value of parameter shift to su ratio > 0.10
Absolute value of the parameter shift to su ratio given 0.183
Additional refinement cycles may be required.
Alert Level C:
PLAT_301 Alert C Main Residue Disorder ........................ 5.00 Perc.
PLAT_302 Alert C Anion/Solvent Disorder ....................... 50.00 Perc.
0 Alert Level A = Potentially serious problem
1 Alert Level B = Potential problem
2 Alert Level C = Please check
The solvate was grown by crystallization saturated solution of (diflunisal +
acetone) by vapour diffusion of hexane (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).
Program(s) used to solve structure: SHELXS97 (Sheldrick, 1997a); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997b); molecular graphics: ORTEPIII (Burnett & Johnson, 1996); software used to prepare material for publication: OSCAIL (McArdle, 1993).
Crystal data top
C14.5H7F2O3 | F(000) = 1024 |
Mr = 267.21 | Dx = 1.410 Mg m−3 |
Monoclinic, C2/c | Mo Kα radiation, λ = 0.71069 Å |
a = 34.826 (17) Å | Cell parameters from 26 reflections |
b = 3.7296 (16) Å | θ = 12–16° |
c = 20.703 (10) Å | µ = 0.12 mm−1 |
β = 110.63 (5)° | T = 298 K |
V = 2517 (2) Å3 | Needle, white |
Z = 8 | 0.30 × 0.20 × 0.10 mm |
Data collection top
Enraf-Nonius CAD4 diffractometer | Rint = 0.045 |
Radiation source: fine-focus sealed tube | θmax = 25.0°, θmin = 1.3° |
Graphite monochromator | h = −40→38 |
ω–2θ scans | k = −1→4 |
2312 measured reflections | l = −1→24 |
2220 independent reflections | 3 standard reflections every 120 min |
715 reflections with I > 2σ(I) | intensity decay: 2% |
Refinement top
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.066 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.200 | All H-atom parameters refined |
S = 1.04 | w = 1/[σ2(Fo2) + (0.0837P)2P] where P = (Fo2 + 2Fc2)/3 |
2220 reflections | (Δ/σ)max = 0.183 |
227 parameters | Δρmax = 0.27 e Å−3 |
18 restraints | Δρmin = −0.27 e Å−3 |
Crystal data top
C14.5H7F2O3 | V = 2517 (2) Å3 |
Mr = 267.21 | Z = 8 |
Monoclinic, C2/c | Mo Kα radiation |
a = 34.826 (17) Å | µ = 0.12 mm−1 |
b = 3.7296 (16) Å | T = 298 K |
c = 20.703 (10) Å | 0.30 × 0.20 × 0.10 mm |
β = 110.63 (5)° | |
Data collection top
Enraf-Nonius CAD4 diffractometer | Rint = 0.045 |
2312 measured reflections | 3 standard reflections every 120 min |
2220 independent reflections | intensity decay: 2% |
715 reflections with I > 2σ(I) | |
Refinement top
R[F2 > 2σ(F2)] = 0.066 | 18 restraints |
wR(F2) = 0.200 | All H-atom parameters refined |
S = 1.04 | (Δ/σ)max = 0.183 |
2220 reflections | Δρmax = 0.27 e Å−3 |
227 parameters | Δρmin = −0.27 e Å−3 |
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. |
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 (Å2) top | x | y | z | Uiso*/Ueq | Occ. (<1) |
F1 | 0.04231 (9) | 0.7722 (11) | 0.01519 (15) | 0.0962 (13) | |
O1 | 0.14128 (12) | 0.6827 (11) | 0.5178 (2) | 0.0726 (13) | |
O2 | 0.21030 (10) | 0.4171 (12) | 0.51349 (18) | 0.0725 (12) | |
F21 | 0.02012 (14) | 0.4877 (16) | 0.2175 (3) | 0.0622 (16) | 0.50 |
F22 | 0.14783 (15) | 0.9826 (17) | 0.2244 (2) | 0.0649 (17) | 0.50 |
O3 | 0.21634 (12) | 0.3412 (11) | 0.41045 (18) | 0.0694 (12) | |
C1W | 0.2401 (19) | 0.23 (3) | 0.201 (3) | 0.36 (4) | 0.50 |
C2W | 0.2292 (16) | 0.22 (3) | 0.247 (3) | 0.39 (3) | 0.50 |
C3W | 0.2728 (14) | 0.16 (3) | 0.299 (3) | 0.34 (2) | 0.50 |
H12 | −0.0001 (16) | 0.568 (16) | 0.083 (2) | 0.096 (18)* | |
H10 | 0.1131 (16) | 0.955 (17) | 0.101 (3) | 0.09 (2)* | |
H2 | 0.1572 (12) | 0.540 (11) | 0.3175 (17) | 0.040 (12)* | |
H3O | 0.2455 (16) | 0.300 (15) | 0.444 (2) | 0.083 (18)* | |
H5 | 0.0755 (11) | 0.929 (11) | 0.4364 (19) | 0.041 (12)* | |
H1O | 0.1673 (16) | 0.624 (17) | 0.547 (2) | 0.09 (2)* | |
H6 | 0.0501 (12) | 0.939 (11) | 0.3152 (19) | 0.040 (12)* | |
C1 | 0.10098 (14) | 0.7291 (13) | 0.3045 (2) | 0.0472 (13) | |
C2 | 0.13974 (14) | 0.6010 (14) | 0.3417 (3) | 0.0491 (14) | |
C3 | 0.15445 (13) | 0.5821 (14) | 0.4122 (2) | 0.0449 (13) | |
C4 | 0.12957 (16) | 0.6939 (15) | 0.4488 (3) | 0.0551 (15) | |
C5 | 0.09050 (16) | 0.8217 (16) | 0.4131 (3) | 0.0553 (15) | |
C6 | 0.07678 (16) | 0.8422 (14) | 0.3435 (3) | 0.0528 (15) | |
C7 | 0.19622 (15) | 0.4421 (15) | 0.4507 (3) | 0.0561 (14) | |
C8 | 0.08548 (14) | 0.7435 (14) | 0.2291 (3) | 0.0502 (14) | |
C9 | 0.10978 (15) | 0.8645 (15) | 0.1916 (3) | 0.0510 (14) | |
C10 | 0.09574 (19) | 0.8762 (18) | 0.1204 (3) | 0.0671 (17) | |
C11 | 0.05600 (18) | 0.7618 (16) | 0.0859 (3) | 0.0664 (17) | |
C12 | 0.03015 (17) | 0.6434 (17) | 0.1178 (3) | 0.0619 (16) | |
C13 | 0.04555 (15) | 0.6336 (15) | 0.1883 (3) | 0.0557 (15) | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
F1 | 0.095 (3) | 0.121 (3) | 0.073 (2) | −0.015 (2) | 0.0307 (19) | 0.006 (2) |
O1 | 0.057 (2) | 0.101 (4) | 0.064 (3) | 0.019 (2) | 0.026 (2) | 0.003 (2) |
O2 | 0.056 (2) | 0.101 (3) | 0.060 (2) | 0.027 (2) | 0.0201 (18) | 0.007 (2) |
F21 | 0.045 (3) | 0.076 (4) | 0.072 (3) | −0.012 (3) | 0.028 (3) | −0.006 (4) |
F22 | 0.050 (3) | 0.079 (5) | 0.069 (4) | −0.015 (3) | 0.024 (3) | −0.006 (4) |
O3 | 0.053 (2) | 0.094 (3) | 0.068 (2) | 0.019 (2) | 0.030 (2) | −0.001 (2) |
C1W | 0.40 (6) | 0.50 (8) | 0.29 (5) | 0.12 (6) | 0.25 (5) | −0.04 (5) |
C2W | 0.32 (5) | 0.53 (9) | 0.23 (4) | 0.01 (7) | −0.01 (4) | −0.14 (5) |
C3W | 0.26 (4) | 0.49 (7) | 0.32 (5) | −0.05 (5) | 0.18 (4) | −0.01 (6) |
C1 | 0.047 (3) | 0.043 (3) | 0.055 (3) | 0.002 (3) | 0.022 (3) | 0.000 (3) |
C2 | 0.038 (3) | 0.050 (4) | 0.064 (4) | 0.007 (3) | 0.023 (3) | 0.000 (3) |
C3 | 0.041 (3) | 0.048 (3) | 0.044 (3) | 0.005 (3) | 0.012 (2) | −0.003 (3) |
C4 | 0.062 (3) | 0.057 (4) | 0.049 (3) | 0.003 (3) | 0.023 (3) | 0.001 (3) |
C5 | 0.045 (3) | 0.070 (4) | 0.057 (4) | 0.008 (3) | 0.024 (3) | −0.008 (3) |
C6 | 0.049 (3) | 0.044 (4) | 0.068 (4) | 0.005 (3) | 0.024 (3) | −0.001 (3) |
C7 | 0.050 (3) | 0.052 (4) | 0.065 (4) | −0.001 (3) | 0.019 (3) | 0.002 (3) |
C8 | 0.042 (3) | 0.049 (4) | 0.059 (3) | 0.005 (3) | 0.017 (3) | 0.006 (3) |
C9 | 0.045 (3) | 0.054 (4) | 0.055 (3) | −0.005 (3) | 0.020 (3) | −0.002 (3) |
C10 | 0.068 (4) | 0.072 (5) | 0.069 (4) | −0.003 (4) | 0.033 (4) | 0.012 (4) |
C11 | 0.079 (4) | 0.070 (4) | 0.052 (4) | 0.013 (4) | 0.025 (3) | 0.009 (3) |
C12 | 0.055 (3) | 0.069 (4) | 0.062 (4) | −0.002 (3) | 0.020 (3) | 0.008 (3) |
C13 | 0.049 (3) | 0.057 (4) | 0.065 (4) | 0.012 (3) | 0.026 (3) | 0.021 (3) |
Geometric parameters (Å, º) top
F1—C11 | 1.370 (5) | C1—C6 | 1.422 (6) |
O1—C4 | 1.341 (5) | C1—C8 | 1.461 (6) |
O2—C7 | 1.221 (5) | C2—C3 | 1.369 (6) |
F21—C13 | 1.351 (6) | C3—C4 | 1.401 (6) |
F22—C9 | 1.333 (6) | C3—C7 | 1.486 (6) |
O3—C7 | 1.318 (5) | C4—C5 | 1.384 (6) |
C1W—C2W | 1.15 (7) | C5—C6 | 1.350 (6) |
C1W—C3Wi | 1.66 (8) | C8—C9 | 1.410 (6) |
C1W—C3W | 1.97 (5) | C8—C13 | 1.410 (6) |
C2W—C3W | 1.54 (7) | C9—C10 | 1.381 (7) |
C2W—C3Wi | 1.88 (12) | C10—C11 | 1.382 (7) |
C3W—C1Wii | 1.66 (8) | C11—C12 | 1.365 (7) |
C3W—C2Wii | 1.88 (12) | C12—C13 | 1.366 (7) |
C1—C2 | 1.382 (6) | | |
| | | |
C2W—C1W—C3Wi | 82 (6) | C5—C4—C3 | 119.5 (5) |
C2W—C1W—C3W | 51 (4) | C6—C5—C4 | 120.1 (5) |
C3Wi—C1W—C3W | 101 (4) | C5—C6—C1 | 122.1 (5) |
C1W—C2W—C3W | 93 (5) | O2—C7—O3 | 123.2 (5) |
C1W—C2W—C3Wi | 61 (6) | O2—C7—C3 | 123.2 (5) |
C3W—C2W—C3Wi | 110 (7) | O3—C7—C3 | 113.5 (5) |
C2W—C3W—C1Wii | 87 (5) | C9—C8—C13 | 114.8 (5) |
C2W—C3W—C2Wii | 86 (4) | C9—C8—C1 | 122.2 (4) |
C1Wii—C3W—C2Wii | 37 (2) | C13—C8—C1 | 123.0 (5) |
C2W—C3W—C1W | 36 (3) | F22—C9—C10 | 116.6 (5) |
C1Wii—C3W—C1W | 94 (5) | F22—C9—C8 | 120.4 (5) |
C2Wii—C3W—C1W | 72 (4) | C10—C9—C8 | 122.9 (5) |
C2—C1—C6 | 116.4 (5) | C9—C10—C11 | 117.1 (6) |
C2—C1—C8 | 121.9 (4) | C12—C11—F1 | 119.1 (6) |
C6—C1—C8 | 121.7 (5) | C12—C11—C10 | 124.1 (5) |
C3—C2—C1 | 122.5 (5) | F1—C11—C10 | 116.8 (5) |
C2—C3—C4 | 119.5 (5) | C11—C12—C13 | 116.7 (6) |
C2—C3—C7 | 121.2 (5) | F21—C13—C12 | 114.6 (5) |
C4—C3—C7 | 119.4 (4) | F21—C13—C8 | 120.8 (5) |
O1—C4—C5 | 116.9 (5) | C12—C13—C8 | 124.5 (5) |
O1—C4—C3 | 123.6 (5) | | |
| | | |
C3Wi—C1W—C2W—C3W | −111 (8) | C2—C3—C7—O2 | −179.1 (5) |
C3W—C1W—C2W—C3Wi | 111 (7) | C4—C3—C7—O2 | 0.3 (8) |
C1W—C2W—C3W—C1Wii | −102 (11) | C2—C3—C7—O3 | −0.3 (7) |
C3Wi—C2W—C3W—C1Wii | −162 (7) | C4—C3—C7—O3 | 179.1 (5) |
C1W—C2W—C3W—C2Wii | −65 (10) | C2—C1—C8—C9 | −43.4 (8) |
C3Wi—C2W—C3W—C2Wii | −125 (8) | C6—C1—C8—C9 | 137.3 (5) |
C3Wi—C2W—C3W—C1W | −60 (6) | C2—C1—C8—C13 | 135.6 (5) |
C3Wi—C1W—C3W—C2W | 70 (9) | C6—C1—C8—C13 | −43.6 (8) |
C2W—C1W—C3W—C1Wii | 78 (11) | C13—C8—C9—F22 | 178.6 (5) |
C3Wi—C1W—C3W—C1Wii | 149 (5) | C1—C8—C9—F22 | −2.3 (8) |
C2W—C1W—C3W—C2Wii | 109 (11) | C13—C8—C9—C10 | 0.2 (8) |
C3Wi—C1W—C3W—C2Wii | 179 (5) | C1—C8—C9—C10 | 179.3 (6) |
C6—C1—C2—C3 | 0.0 (8) | F22—C9—C10—C11 | −178.6 (5) |
C8—C1—C2—C3 | −179.2 (5) | C8—C9—C10—C11 | −0.1 (9) |
C1—C2—C3—C4 | 0.4 (8) | C9—C10—C11—C12 | 0.7 (10) |
C1—C2—C3—C7 | 179.8 (5) | C9—C10—C11—F1 | −179.7 (5) |
C2—C3—C4—O1 | 179.5 (5) | F1—C11—C12—C13 | 179.1 (5) |
C7—C3—C4—O1 | 0.1 (8) | C10—C11—C12—C13 | −1.3 (9) |
C2—C3—C4—C5 | 0.0 (8) | C11—C12—C13—F21 | −174.9 (5) |
C7—C3—C4—C5 | −179.5 (5) | C11—C12—C13—C8 | 1.4 (9) |
O1—C4—C5—C6 | 179.6 (5) | C9—C8—C13—F21 | 175.2 (5) |
C3—C4—C5—C6 | −0.8 (8) | C1—C8—C13—F21 | −3.9 (8) |
C4—C5—C6—C1 | 1.3 (9) | C9—C8—C13—C12 | −0.8 (8) |
C2—C1—C6—C5 | −0.9 (8) | C1—C8—C13—C12 | −179.9 (5) |
C8—C1—C6—C5 | 178.4 (5) | | |
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) top
D—H···A | D—H | H···A | D···A | D—H···A |
O3—H3O···O2iii | 1.02 (5) | 1.69 (5) | 2.665 (6) | 159 (3) |
O1—H1O···O2 | 0.92 (5) | 2.01 (6) | 2.630 (6) | 123 (3) |
Symmetry code: (iii) −x+1/2, −y+1/2, −z+1. |
Experimental details
Crystal data |
Chemical formula | C14.5H7F2O3 |
Mr | 267.21 |
Crystal system, space group | Monoclinic, C2/c |
Temperature (K) | 298 |
a, b, c (Å) | 34.826 (17), 3.7296 (16), 20.703 (10) |
β (°) | 110.63 (5) |
V (Å3) | 2517 (2) |
Z | 8 |
Radiation type | Mo Kα |
µ (mm−1) | 0.12 |
Crystal size (mm) | 0.30 × 0.20 × 0.10 |
|
Data collection |
Diffractometer | Enraf-Nonius CAD4 diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 2312, 2220, 715 |
Rint | 0.045 |
(sin θ/λ)max (Å−1) | 0.594 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.066, 0.200, 1.04 |
No. of reflections | 2220 |
No. of parameters | 227 |
No. of restraints | 18 |
H-atom treatment | All H-atom parameters refined |
(Δ/σ)max | 0.183 |
Δρmax, Δρmin (e Å−3) | 0.27, −0.27 |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
O3—H3O···O2i | 1.02 (5) | 1.69 (5) | 2.665 (6) | 159 (3) |
O1—H1O···O2 | 0.92 (5) | 2.01 (6) | 2.630 (6) | 123 (3) |
Symmetry code: (i) −x+1/2, −y+1/2, −z+1. |
Diflunisal is a difluorphenyl-derivative of acetyl salicylic acid (aspirin), which is used therapeutically as an antiinflammatory drug similarly to aspirin·The structure of unsolvated diflunisal was described earlier (Yang Bae Kim & Il Yeong Park, 1996). However, this new investigation displays properties of clathrate materials and includes in the crystal lattice solvent molecules. Here, the structure of its hexane solvate, (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, the 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 43.4 (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 from each other, 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 like herringbone.
In diflunisal, the hydroxyl group is tilted against the phenyl group: the torsion angle C3—C4—O1—H1O is 7(3)°. The geometry of carboxyl group slightly differs from a planar arrangement [torsion angle O2—C7—O3—H3O is 12 (2)]° and is approximately coplanar to the phenyl fragment [torsion angle O3—C7—C3—C2 is 0(2)°]. Fluorine atoms in positions 2'- and 6'- are disordered.
The phenyl groups of neighbouring parallel molecules are stacked face-to-face and shifted by Rshift=1.6 Å. The distance between these planes of the phenyl rings is Rb=3.73 Å. These parameters are in good agreement with the values for the local energetic minimum calculated for benzene dimers: Rshift*=1.6 Å and Rb*=3.85 Å (Hobza et al., 1993; Hobza et al., 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; herringbone, 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 hexane molecules, which are situated in a disordered state.
Our suppositions about the existence of a hexane solvate and not an acetone molecule, are based on the following. The results of TG-measurements show that the stoichiometry acetone solvate have to be 3 diflunisal and 1 acetone. The absorption band C=O stretching-vibrations for acetone has the value 1725 cm-1 (+ 5 cm-1). The position of the peak is sufficiently distinguished from the absorption peak of the diflunisal C=O stretching-vibrations (1671 cm-1). If taking into account the assumed stoichiometry (diflunisal: acetone), we have to observe an additional band in the region of 1725 cm-1 with intensity three times less than the diflunisal C=O stretching-vibrations. But experiments show no any peaks in the noted region. It gives us the basis to conclude that the described solvate contains hexane molecules. Furthermore, difference Fourier maps show three peaks about the same size around a twofold screw axis, generating a full hexane molecule over this symmetry element.
The diflunisal hydrate was described by us earler (Hansen et al., 2001). As it follows from the data the hexane molecule may occupy two different sites. It should be noted that 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 365 to 389 K is 10 J g-1. The average mass losses achieved 7.3% and it corresponded to stoichiometry diflunisal:hexane as 1:4. This result is in a good agreement with the X-ray experiment.