Anti-inflammatory drugs. X. Hydrated pyrrolidinium {2-[(2,6-di­chloro­phenyl)­amino]­phenyl}acetate (HP·D·H₂O)

In the solid-state structure of the title compound, C₄H₁₀N⁺·C₁₄H₁₀Cl₂NO₂^-·H₂O, the asymmetric unit contains one cation, one anion and a water mol­ecule. There is a network of hydrogen bonds which is similar to that found in the hydrated diethyl­ammonium diclofenac salt. A comparison is made of the molecular conformation of the anions in the two related structures.

S1. Comment

The systematic structural work being carried out on diclofenac salts, a type of non-steroidal anti-inflammatory drug (Castellari & Sabatino, 1994, 1996; Castellari & Ottani, 1995, 1996, 1997a,b, 1998; Castellari, Feroci & Ottani, 1999; Castellari, Comelli & Ottani, 1999; Castellari et al., 2001) has important pharmaceutical implications, since the presence of polymorphic forms and/or hydrates influences the bioavailability of the drug.

As shown in Fig. 1, the asymmetric unit of the title compound, (I), contains one cation, one anion and a water molecule. The bond lenghts and angles of the anion are in good agreement with the corresponding values found in previous works. In particular, the carboxylate group shows a marked π delocalization. The diclofenac anion is stabilized, as usual, by two intramolecular hydrogen bonds between the amino group and atoms O1 and Cl1. In the pyrrolidinium cation, the N atom is shifted out of the plane of the four C atoms by 0.308 (5) Å, and C17 and C18 are out of the C₄ plane by -0.101 (3) and 0.102 (3) Å, respectively

The C—N distances are normal, but the C—C bond lengths are shorter than expected. For the pyrrolidinium cation, a similar behaviour in the C—C distances was reported (Teske et al., 1996). Since, in both structures, the displacement parameters of the C atoms opposite the N atom are larger than those of the adjacent C atoms, the apparent contraction of the –C–C distances could be attributed to the average displacement parameters. Actually, the distances involving C18, the atom affected by the largest thermal motion, are the shortest; C15—C18 = 1.458 (4) Å and C17—C18 = 1.453 (4) Å.

The intermolecular hydrogen-bond network is similar to that recently reported for the hydrated diethylammonium diclofenac salt (HDEA·D·H₂O) (Castellari et al., 2001). In both salts, anions, cations and water molecules are linked into two-dimensional networks lying in a plane, i.e. [001] and [100] for HDEA·D·H₂O and HP·D·H₂O, respectively. The intermolecular hydrogen-bond scheme involves four normal hydrogen bonds, one charge-assisted between the anion and the cation and three involving the water molecule, where the O1W atom acts as a donor towards the two carboxylate O atoms and as an acceptor towards the pyrrolidinium N atom.

A comparison of the molecular conformation of D in the two structures is of some interest. The degrees of freedom of the diclofenac anion can be described by the following dihedral angles between planes, the values being quoted for HDEA·D·H₂O and HP·D·H₂O, respectively: C1–C6/C1—N1—C7 = 16.5 (1) and 18.2 (3)°, C7–C12/C1—N1—C7 = 61.6 (1) and 49.5 (2)°, C1—C2–C6/C2—C13—C14 = 77.5 (1) and 79.0 (2)° and O1—C14—O2/C2—C13—C14 = 56.3 (2) and 52.6 (2)°. Inspection of these values shows that the largest difference in the molecular conformation of the anions occurs in the dihedral angle between the dichlorophenyl ring (C7–C12) and the C1/N1/C7 plane [the difference in torsion angles C1—N1—C7—C12 = 11.0 (2)°]. However, we note that the smaller steric hindrance of the pyrrolidinium cation, compared with that of diethylammonium, influences the crystal packing.

In HP·D·H₂O, the average H···A distance is 1.84 (1) Å and the density is 1.389 Mg m^-3. In contrast, the average H···A distance in HDEA·D·H₂O is 1.90 (1) Å and the density is 1.280 Mg m ^-3. The higher packing efficiency in HP·D·H₂O compared with HDEA·D·H₂O most likely results in lower stresses to accomodate the anions in the crystals. This may consequently lead to the smaller twist angle between the two phenyl rings, viz. 60.68 (8) versus 72.4 (2)°.

S2. Experimental

Crystalline HP·D·H₂O was prepared by mixing equivalent molar amounts of diclofenac acid and pyrrolidine. Crystals were obtained from a water solution.

S3. Refinement

The H1 atom and the H atom bonded to the N2 and O3W atoms were located from a difference synthesis and were refined isotropically. The remaining H atoms were placed in calculated positions and refined riding on their parent atoms.

Computing details

Data collection: SMART (Bruker, 1998); cell refinement: SMART; data reduction: SAINT-Plus (Bruker, 1999); program(s) used to solve structure: SHELXS86 (Sheldrick, 1990); program(s) used to refine structure: SHELXL93 (Sheldrick, 1993); molecular graphics: ORTEPII (Johnson, 1976).

Figures

Fig. 1. ORTEPII (Johnson, 1976) diagram of HP·D·H2O. Non-H atoms are represented by displacement ellipsoids of 50% probability and H atoms by spheres of arbitrary size.

(I)

Crystal data

C4H10N^+·C14H10Cl2NO2^−·H2O	F(000) = 808
Mr = 385.28	Dx = 1.389 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 18.9631 (7) Å	Cell parameters from 5166 reflections
b = 9.6845 (3) Å	θ = 2.5–26.1°
c = 10.0505 (4) Å	µ = 0.37 mm^−1
β = 93.134 (1)°	T = 293 K
V = 1842.99 (12) Å^3	Blocks, colourless
Z = 4	0.5 × 0.5 × 0.4 mm

Data collection

Bruker SMART 2000 CDD diffractometer	2046 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.087
Graphite monochromator	θmax = 25.0°, θmin = 1.1°
/w scans	h = −22→22
17027 measured reflections	k = −11→11
3244 independent reflections	l = −11→11

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)] = 0.041	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.105	Weighting scheme based on measured s.u.'s w = 1/[σ^2(Fo^2) + (0.0776P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 0.89	(Δ/σ)max = 0.037
3244 reflections	Δρmax = 0.29 e Å^−3
247 parameters	Δρmin = −0.30 e Å^−3
32 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: 0.0047 (10)

Special details

Experimental. Data collection was performed by an area detector over the whole reflection sphere, but data reduction was performed up to 25 degs to preserve as many informations as possible. However, on data merging, several observations (>30%) have been assigned a null value (17027 measured reflections, 3244 are independent, but, out of these, only 2046 have intensities > 2 sigma).

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 on F² for ALL reflections except for 0 with very negative F² or flagged by the user for potential systematic errors. Weighted R-factors wR and all goodnesses of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The observed criterion of F² > σ(F²) is used only for calculating _R_factor_obs 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
Cl1	0.25198 (4)	0.69551 (7)	1.01753 (8)	0.0610 (3)
Cl2	0.04070 (4)	0.45113 (7)	0.71787 (7)	0.0515 (2)
O1	0.34634 (9)	0.45728 (19)	0.81873 (19)	0.0555 (5)
O2	0.40697 (9)	0.36771 (19)	0.65867 (19)	0.0535 (5)
N1	0.19438 (11)	0.4871 (2)	0.8218 (2)	0.0429 (6)
H1	0.2406 (10)	0.516 (3)	0.835 (3)	0.061 (9)*
C1	0.19075 (12)	0.3413 (2)	0.8098 (2)	0.0357 (6)
C2	0.23255 (12)	0.2770 (2)	0.7167 (2)	0.0374 (6)
C3	0.22812 (14)	0.1350 (3)	0.7035 (3)	0.0471 (7)
H2	0.2554	0.0911	0.6421	0.057*
C4	0.18420 (15)	0.0564 (3)	0.7793 (3)	0.0539 (8)
H3	0.1815	−0.0388	0.7676	0.065*
C5	0.14485 (14)	0.1205 (3)	0.8715 (3)	0.0477 (7)
H4	0.1160	0.0684	0.9240	0.057*
C6	0.14786 (13)	0.2615 (3)	0.8868 (3)	0.0422 (7)
H5	0.1208	0.3039	0.9495	0.051*
C7	0.14377 (13)	0.5670 (2)	0.8811 (2)	0.0362 (6)
C8	0.16313 (13)	0.6694 (2)	0.9756 (3)	0.0398 (6)
C9	0.11463 (15)	0.7520 (3)	1.0338 (3)	0.0468 (7)
H6	0.1296	0.8196	1.0946	0.056*
C10	0.04396 (15)	0.7343 (3)	1.0017 (3)	0.0499 (7)
H7	0.0108	0.7861	1.0447	0.060*
C11	0.02229 (14)	0.6398 (3)	0.9060 (3)	0.0465 (7)
H8	−0.0255	0.6299	0.8821	0.056*
C12	0.07158 (13)	0.5594 (2)	0.8453 (3)	0.0382 (6)
C13	0.28123 (13)	0.3583 (3)	0.6333 (3)	0.0417 (6)
H9	0.2573	0.4418	0.6021	0.050*
H10	0.2920	0.3041	0.5558	0.050*
C14	0.35001 (13)	0.3975 (2)	0.7094 (3)	0.0386 (6)
N2	0.46860 (12)	−0.0400 (2)	0.7225 (2)	0.0427 (6)
H11	0.5147 (9)	−0.061 (3)	0.748 (3)	0.081 (11)*
H12	0.4678 (15)	0.019 (2)	0.651 (2)	0.068 (10)*
C15	0.42941 (15)	−0.1684 (3)	0.6865 (3)	0.0599 (8)
H13	0.3949	−0.1519	0.6135	0.072*
H14	0.4615	−0.2405	0.6608	0.072*
C16	0.43093 (15)	0.0260 (3)	0.8332 (3)	0.0523 (7)
H15	0.4644	0.0558	0.9038	0.063*
H16	0.4041	0.1055	0.8006	0.063*
C17	0.38306 (19)	−0.0818 (3)	0.8827 (4)	0.0765 (10)
H17	0.3934	−0.0980	0.9770	0.092*
H18	0.3342	−0.0525	0.8698	0.092*
C18	0.3948 (2)	−0.2069 (3)	0.8072 (4)	0.0963 (14)
H19	0.3501	−0.2520	0.7841	0.116*
H20	0.4244	−0.2704	0.8599	0.116*
O1W	0.43925 (11)	0.1397 (2)	0.5139 (2)	0.0588 (6)
H1W	0.420 (2)	0.213 (3)	0.559 (4)	0.129 (16)*
H2W	0.4037 (16)	0.103 (3)	0.455 (3)	0.088 (12)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.0400 (4)	0.0557 (5)	0.0869 (6)	−0.0110 (3)	−0.0001 (4)	−0.0104 (4)
Cl2	0.0463 (4)	0.0494 (4)	0.0577 (5)	−0.0002 (3)	−0.0069 (3)	−0.0046 (3)
O1	0.0388 (11)	0.0678 (13)	0.0599 (14)	−0.0002 (9)	0.0013 (9)	−0.0248 (11)
O2	0.0279 (11)	0.0727 (13)	0.0604 (13)	0.0006 (9)	0.0057 (9)	−0.0145 (10)
N1	0.0315 (13)	0.0347 (12)	0.0639 (16)	−0.0024 (10)	0.0137 (11)	−0.0058 (11)
C1	0.0267 (14)	0.0337 (14)	0.0466 (16)	−0.0006 (11)	0.0000 (12)	0.0009 (12)
C2	0.0274 (14)	0.0404 (15)	0.0439 (16)	−0.0019 (11)	−0.0028 (12)	−0.0035 (12)
C3	0.0420 (17)	0.0459 (17)	0.0532 (18)	0.0015 (13)	0.0013 (14)	−0.0100 (14)
C4	0.0532 (19)	0.0350 (15)	0.073 (2)	−0.0016 (14)	−0.0033 (16)	−0.0029 (15)
C5	0.0410 (17)	0.0400 (16)	0.061 (2)	−0.0046 (13)	−0.0045 (14)	0.0089 (14)
C6	0.0336 (15)	0.0426 (16)	0.0507 (17)	0.0013 (12)	0.0041 (13)	0.0012 (13)
C7	0.0339 (15)	0.0311 (13)	0.0443 (16)	0.0013 (11)	0.0085 (12)	0.0073 (12)
C8	0.0328 (15)	0.0340 (14)	0.0528 (17)	−0.0039 (11)	0.0061 (12)	0.0035 (12)
C9	0.0521 (19)	0.0366 (14)	0.0520 (18)	−0.0009 (13)	0.0069 (14)	−0.0034 (13)
C10	0.0460 (18)	0.0452 (17)	0.060 (2)	0.0126 (13)	0.0125 (15)	0.0005 (15)
C11	0.0362 (16)	0.0435 (16)	0.0601 (19)	0.0051 (13)	0.0049 (14)	0.0047 (14)
C12	0.0374 (15)	0.0330 (14)	0.0444 (16)	0.0005 (11)	0.0045 (12)	0.0016 (12)
C13	0.0308 (14)	0.0509 (16)	0.0438 (16)	0.0020 (12)	0.0042 (12)	−0.0009 (13)
C14	0.0317 (15)	0.0355 (14)	0.0484 (17)	0.0016 (11)	0.0017 (12)	0.0028 (13)
N2	0.0350 (14)	0.0495 (14)	0.0436 (14)	−0.0021 (11)	0.0026 (11)	0.0035 (12)
C15	0.0507 (19)	0.0571 (18)	0.072 (2)	−0.0047 (15)	0.0051 (16)	−0.0194 (16)
C16	0.062 (2)	0.0486 (17)	0.0474 (17)	−0.0001 (14)	0.0073 (15)	−0.0053 (14)
C17	0.080 (3)	0.067 (2)	0.087 (3)	−0.0143 (18)	0.039 (2)	−0.0117 (19)
C18	0.134 (4)	0.067 (2)	0.092 (3)	−0.047 (2)	0.051 (3)	−0.017 (2)
O1W	0.0595 (15)	0.0687 (15)	0.0479 (13)	0.0180 (12)	0.0003 (11)	0.0010 (11)

Geometric parameters (Å, º)

Cl1—C8	1.733 (3)	C10—H7	0.9300
Cl2—C12	1.732 (3)	C11—C12	1.384 (3)
O1—C14	1.248 (3)	C11—H8	0.9300
O2—C14	1.253 (3)	C13—C14	1.523 (3)
N1—C7	1.391 (3)	C13—H9	0.9700
N1—C1	1.419 (3)	C13—H10	0.9700
N1—H1	0.922 (17)	N2—C15	1.483 (3)
C1—C6	1.388 (3)	N2—C16	1.498 (3)
C1—C2	1.405 (3)	N2—H11	0.921 (14)
C2—C3	1.383 (3)	N2—H12	0.919 (13)
C2—C13	1.504 (3)	C15—C18	1.458 (4)
C3—C4	1.387 (4)	C15—H13	0.9700
C3—H2	0.9300	C15—H14	0.9700
C4—C5	1.370 (4)	C16—C17	1.487 (4)
C4—H3	0.9300	C16—H15	0.9700
C5—C6	1.375 (3)	C16—H16	0.9700
C5—H4	0.9300	C17—C18	1.453 (4)
C6—H5	0.9300	C17—H17	0.9700
C7—C12	1.398 (3)	C17—H18	0.9700
C7—C8	1.408 (3)	C18—H19	0.9700
C8—C9	1.374 (3)	C18—H20	0.9700
C9—C10	1.372 (4)	O1W—H1W	0.93 (2)
C9—H6	0.9300	O1W—H2W	0.94 (2)
C10—C11	1.374 (4)
C7—N1—C1	123.9 (2)	C2—C13—H9	109.1
C7—N1—H1	116.4 (17)	C14—C13—H9	109.1
C1—N1—H1	110.5 (17)	C2—C13—H10	109.1
C6—C1—C2	119.5 (2)	C14—C13—H10	109.1
C6—C1—N1	122.3 (2)	H9—C13—H10	107.8
C2—C1—N1	118.1 (2)	O1—C14—O2	123.8 (2)
C3—C2—C1	118.1 (2)	O1—C14—C13	118.1 (2)
C3—C2—C13	120.2 (2)	O2—C14—C13	118.2 (2)
C1—C2—C13	121.7 (2)	C15—N2—C16	106.6 (2)
C2—C3—C4	121.9 (3)	C15—N2—H11	109.8 (18)
C2—C3—H2	119.0	C16—N2—H11	112 (2)
C4—C3—H2	119.0	C15—N2—H12	110.3 (18)
C5—C4—C3	119.2 (3)	C16—N2—H12	109.0 (18)
C5—C4—H3	120.4	H11—N2—H12	109 (3)
C3—C4—H3	120.4	C18—C15—N2	104.7 (2)
C4—C5—C6	120.3 (3)	C18—C15—H13	110.8
C4—C5—H4	119.8	N2—C15—H13	110.8
C6—C5—H4	119.8	C18—C15—H14	110.8
C5—C6—C1	120.9 (3)	N2—C15—H14	110.8
C5—C6—H5	119.6	H13—C15—H14	108.9
C1—C6—H5	119.6	C17—C16—N2	105.9 (2)
N1—C7—C12	123.3 (2)	C17—C16—H15	110.6
N1—C7—C8	121.3 (2)	N2—C16—H15	110.6
C12—C7—C8	115.2 (2)	C17—C16—H16	110.6
C9—C8—C7	122.8 (2)	N2—C16—H16	110.6
C9—C8—Cl1	118.4 (2)	H15—C16—H16	108.7
C7—C8—Cl1	118.76 (19)	C18—C17—C16	107.3 (3)
C10—C9—C8	119.7 (3)	C18—C17—H17	110.3
C10—C9—H6	120.2	C16—C17—H17	110.3
C8—C9—H6	120.2	C18—C17—H18	110.3
C9—C10—C11	119.9 (3)	C16—C17—H18	110.3
C9—C10—H7	120.0	H17—C17—H18	108.5
C11—C10—H7	120.0	C17—C18—C15	108.0 (3)
C10—C11—C12	120.0 (3)	C17—C18—H19	110.1
C10—C11—H8	120.0	C15—C18—H19	110.1
C12—C11—H8	120.0	C17—C18—H20	110.1
C11—C12—C7	122.2 (2)	C15—C18—H20	110.1
C11—C12—Cl2	117.2 (2)	H19—C18—H20	108.4
C7—C12—Cl2	120.55 (19)	H1W—O1W—H2W	108 (3)
C2—C13—C14	112.7 (2)
C7—N1—C1—C6	−18.2 (4)	C7—C8—C9—C10	1.2 (4)
C7—N1—C1—C2	162.0 (2)	Cl1—C8—C9—C10	179.5 (2)
C6—C1—C2—C3	1.3 (3)	C8—C9—C10—C11	−3.8 (4)
N1—C1—C2—C3	−179.0 (2)	C9—C10—C11—C12	2.2 (4)
C6—C1—C2—C13	−178.5 (2)	C10—C11—C12—C7	2.3 (4)
N1—C1—C2—C13	1.3 (3)	C10—C11—C12—Cl2	−175.8 (2)
C1—C2—C3—C4	−0.2 (4)	N1—C7—C12—C11	179.9 (2)
C13—C2—C3—C4	179.6 (2)	C8—C7—C12—C11	−4.7 (4)
C2—C3—C4—C5	−1.1 (4)	N1—C7—C12—Cl2	−2.2 (3)
C3—C4—C5—C6	1.3 (4)	C8—C7—C12—Cl2	173.28 (17)
C4—C5—C6—C1	−0.2 (4)	C3—C2—C13—C14	−100.6 (3)
C2—C1—C6—C5	−1.1 (4)	C1—C2—C13—C14	79.1 (3)
N1—C1—C6—C5	179.1 (2)	C2—C13—C14—O1	−52.6 (3)
C1—N1—C7—C12	−52.4 (4)	C2—C13—C14—O2	127.4 (2)
C1—N1—C7—C8	132.4 (3)	C16—N2—C15—C18	−25.6 (3)
N1—C7—C8—C9	178.5 (2)	C15—N2—C16—C17	14.5 (3)
C12—C7—C8—C9	3.0 (3)	N2—C16—C17—C18	2.2 (4)
N1—C7—C8—Cl1	0.2 (3)	C16—C17—C18—C15	−18.6 (5)
C12—C7—C8—Cl1	−175.39 (18)	N2—C15—C18—C17	27.5 (4)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···Cl1	0.92 (2)	2.53 (3)	2.983 (2)	110 (2)
N1—H1···O1	0.92 (2)	2.09 (3)	2.898 (3)	144 (2)
O1W—H1W···O2	0.93 (2)	1.83 (2)	2.733 (3)	164 (4)
O1W—H2W···O1^i	0.94 (2)	1.80 (2)	2.730 (3)	170 (3)
N2—H11···O2^ii	0.92 (1)	1.85 (1)	2.736 (3)	162 (3)
N2—H12···O1W	0.92 (1)	1.86 (2)	2.758 (2)	164 (3)

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