7,8-Dihydr­oxy-4-propyl-1,2,3,4,4a,5,6,10b-octa­hydro­benzo[f]quinolinium bromide monohydrate, a dopamine agonist

In the crystal structure of the title dopamine­rgic compound, C₁₆H₂₄NO₂⁺·Br⁻·H₂O, protonation occurs at the piperidine N atom. The piperidine ring adopts a chair conformation and the cyclo­hexene ring adopts a half-chair conformation; together with the planar benzene ring, this results in a relatively planar shape for the whole mol­ecule. Classical hydrogen bonds (N—H...Br, O—H...Br and O—H...O) produce an infinite three-dimensional network. Hydrogen bonds between water ­mol­ecules and Br⁻ anions create centrosymmetric rings throughout the crystal structure. Structural comparison of the mol­ecule with the ergoline dopamine agonist pergolide shows that it is the hydrogen-bond-forming hydr­oxy or imino group that is necessary for dopamine­rgic activity, rather than the presence of a phenyl or a pyrrole ring per se.

S1. Comment

TL140, (I) (Fig. 1), was synthesized and shown to be a potent dopamine agonist (Cannon et al., 1979). Bond distances and angles are within the normal ranges. Protonation of the molecule occurs at atom N1 of the piperidine ring and the sum of the angles at this atom is 335°. The piperidine ring adopts a chair conformation, with puckering parameters (Cremer & Pople, 1975) of Q = 0.558 (4) Å, Θ = 175.4 (4)° and Φ = 129 (5)°. The cyclohexene ring adopts a half-chair conformation, with puckering parameters of Q = 0.537 (4) Å, Θ = 49.1 (4)° and Φ= 213.3 (5)°. The benzene ring, with its hydroxy atoms O18 and O19, is planar. Despite the saturated and partly saturated nature of two of the rings, the whole molecule displays a high degree of planarity. The r.m.s. deviation from the plane through all non-H atoms of the molecule is 0.2378 Å and the largest deviation is −0.541 (4) Å for atom C8. Classical hydrogen bonds (N—H···Br, O—H···Br and O—H···O) produce an infinite three-dimensional network (Table 1, and Fig. 2). Layers of a hydrophobic character (cyclohexene and benzene rings) are interspersed with hydrophilic layers (water molecules, Br⁻ anions and hydroxy groups) running parallel to the bc plane. The significant difference in the C11—O18—H18 (108.9°) and C12—O19—H19 (121.5°) angles can be explained considering the hydrogen bonding involved. The intramolecular O18—H18···O19 hydrogen bond forces H18 towards O19, thus decreasing the angle, and the intermolecular O19—H19···O20 hydrogen bond to the water molecule forces H19 towards O20 due to the position of the water in the crystal lattice, thus increasing the angle. Hydrogen bonding of the water molecules and Br⁻ anions creates centrosymmetric rings throughout the crystal structure; van der Waals interactions also contribute to the crystal packing.

The identification of the dopamine pharmacophore in ergoline compounds such as pergolide, (II), was questioned when dopaminergic analogues lacking the phenyl A ring were synthesized. This led to suggestions (Bach et al., 1980; Nordmann & Petcher, 1985) that the pyrrolethylamine moiety, rather than the dopamine-like phenylethylamine, was the ergoline dopaminergic entity. However, if the electronegative meta-O atom of dopamine and the pyrrole N atom of pergolide are necessary for dopamine activity, rather than a particular ring structure (Camerman & Camerman, 1981), the distinction is academic. TL140 presents a means of testing the pharmacophore models as it resembles the overall ring structure of pergolide but lacks a pyrrole ring. Fig. 3 is a stereoscopic superposition of TL140 with pergolide (Ma et al., 1987); the atoms of the three six-membered rings in each molecule were used in the least-squares fitting procedure. The structures of the two molecules overlap closely at all atoms in common, including the propyl groups. The functional groups superpose well, viz. the two piperidine N atoms, and the meta-hydroxy O atom of TL140 with the pyrrole N atom of pergolide. Thus, as suggested previously, the ring phenyl and/or pyrrole structures in these compounds likely serve to position the functional electronegative atoms properly for acceptor interaction in these rigid dopamine agonists, and the nature of the ring itself, apart from planarity, is not critical.

S2. Experimental

The crystal chosen for data collection was obtained by slow evaporation (over a period of 25 d) from a 10:1:1 (v/v/v) methanol–water–propanol solution at 294 K.

S3. Refinement

The final difference map revealed the positions of all H atoms; however, due to the limited intensity data, all H atoms, except for those of the water molecule and the two hydroxy groups, were placed in calculated positions and allowed for as riding. One overall isotropic displacement parameter was refined for the methyl H atoms [U_iso(H) = 0.183 (19) Ų] and another for the remaining H atoms [U_iso(H) = 0.068 (3) Ų]. The positions of the H atoms of the water molecule and the two hydroxy groups were taken from the final difference map. The positional parameters were not refined and the isotropic displacement parameters were fixed at U_iso(H) = 0.14 and 0.06 Ų for the water and hydroxy H atoms, respectively. The range of C—H distances is 0.92–0.98 Å and the N—H distance is 0.91 Å.

Computing details

Data collection: Picker Operating Manual (Picker, 1967); cell refinement: Picker Operating Manual; data reduction: DATRDN: The X-ray System, (Stewart, 1976); program(s) used to solve structure: SHELXS97 (Sheldrick, 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: SHELXL97.

Figures

	Fig. 1. The molecular structure of the title compound, showing 50% probability displacement elipsoids. H atoms are drawn as small circles of arbitrary radii.
	Fig. 2. Stereodiagram of the molecular packing and hydrogen-bond scheme. Atoms are drawn as circles of arbitrary radii. For clarity, only H atoms involved in hydrogen bonding are shown.
	Fig. 3. Stereodiagram of the superposition of the title compound and pergolide (filled bonds and small circles).

7,8-Dihydroxy-4-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolinium bromide monohydrate

Crystal data

C16H24NO2^+·Br^−·H2O	F(000) = 752
Mr = 360.29	Dx = 1.429 Mg m^−3
Monoclinic, P21/c	Cu Kα radiation, λ = 1.54178 Å
a = 13.907 (3) Å	Cell parameters from 32 reflections
b = 7.856 (2) Å	θ = 26–53°
c = 15.357 (3) Å	µ = 3.42 mm^−1
β = 93.21 (2)°	T = 294 K
V = 1675.2 (6) Å^3	Prism, colorless
Z = 4	0.43 × 0.28 × 0.25 mm

Data collection

Picker FACS-1 four-circle diffractometer	1439 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.017
Ni filtered radiation monochromator	θmax = 65.0°, θmin = 3.2°
θ/2θ scans	h = 0→16
Absorption correction: ψ scan (North et al., 1968)	k = 0→9
Tmin = 0.361, Tmax = 0.423	l = −18→18
2858 measured reflections	3 standard reflections every 100 reflections
2854 independent reflections	intensity decay: 2.1%

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)] = 0.033	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.085	H-atom parameters constrained
S = 0.70	w = 1/[σ^2(Fo^2)] where P = (Fo^2 + 2Fc^2)/3
2854 reflections	(Δ/σ)max < 0.001
193 parameters	Δρmax = 0.49 e Å^−3
0 restraints	Δρmin = −0.45 e Å^−3

Special details

Experimental. PICKER FACS-1 mechanical limit does not allow for data collection above θ = 65°

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
Br	0.14741 (3)	0.50323 (7)	0.11638 (3)	0.05494 (14)
O20	0.9105 (2)	0.5955 (8)	0.0834 (3)	0.146 (2)
N1	0.22651 (18)	0.8880 (4)	0.08390 (19)	0.0421 (7)
H1	0.2069	0.7793	0.0929	0.068 (3)*
C2	0.2097 (3)	0.9238 (6)	−0.0115 (2)	0.0533 (10)
H2A	0.1415	0.9124	−0.0276	0.068 (3)*
H2B	0.2283	1.0402	−0.0232	0.068 (3)*
C3	0.2652 (3)	0.8062 (6)	−0.0661 (2)	0.0560 (11)
H3A	0.2564	0.8407	−0.1267	0.068 (3)*
H3B	0.2394	0.6921	−0.0613	0.068 (3)*
C4	0.3724 (3)	0.8026 (6)	−0.0403 (2)	0.0515 (10)
H4A	0.4033	0.7137	−0.0725	0.068 (3)*
H4B	0.4012	0.9106	−0.0549	0.068 (3)*
C5	0.4950 (2)	0.7647 (5)	0.0883 (2)	0.0392 (8)
C6	0.5267 (2)	0.8236 (5)	0.1703 (2)	0.0384 (8)
C7	0.4592 (3)	0.8993 (6)	0.2327 (2)	0.0528 (10)
H7A	0.4676	1.0219	0.2339	0.068 (3)*
H7B	0.4755	0.8563	0.2908	0.068 (3)*
C8	0.3533 (2)	0.8586 (6)	0.2081 (2)	0.0479 (10)
H8A	0.3403	0.7398	0.2199	0.068 (3)*
H8B	0.3118	0.9278	0.2424	0.068 (3)*
C9	0.3887 (2)	0.7699 (5)	0.0575 (2)	0.0375 (8)
H9	0.3622	0.6569	0.0688	0.068 (3)*
C10	0.3336 (2)	0.8959 (4)	0.1110 (2)	0.0359 (8)
H10	0.3570	1.0108	0.0990	0.068 (3)*
C11	0.6249 (2)	0.8180 (5)	0.1967 (2)	0.0456 (9)
C12	0.6906 (2)	0.7460 (5)	0.1440 (3)	0.0440 (9)
C13	0.6613 (2)	0.6835 (5)	0.0629 (2)	0.0433 (9)
H13	0.7058	0.6346	0.0275	0.068 (3)*
C14	0.5636 (2)	0.6940 (5)	0.0342 (3)	0.0437 (9)
H14	0.5440	0.6540	−0.0209	0.068 (3)*
C15	0.1673 (2)	1.0014 (7)	0.1384 (3)	0.0589 (10)
H15A	0.1804	0.9710	0.1992	0.068 (3)*
H15B	0.1890	1.1177	0.1313	0.068 (3)*
C16	0.0628 (3)	0.9972 (9)	0.1199 (3)	0.0823 (14)
H16A	0.0420	0.8794	0.1164	0.068 (3)*
H16B	0.0481	1.0489	0.0634	0.068 (3)*
C17	0.0064 (3)	1.0875 (8)	0.1868 (3)	0.0803 (16)
H17A	0.0227	1.0409	0.2435	0.183 (19)*
H17B	−0.0613	1.0725	0.1729	0.183 (19)*
H17C	0.0217	1.2066	0.1866	0.183 (19)*
O18	0.65033 (18)	0.8797 (5)	0.27776 (18)	0.0638 (9)
O19	0.78395 (17)	0.7455 (4)	0.17753 (19)	0.0636 (8)
H18	0.7163	0.8789	0.2856	0.060*
H19	0.8360	0.7368	0.1413	0.060*
H20A	0.9679	0.5431	0.0998	0.140*
H20B	0.8989	0.6219	0.0251	0.140*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Br	0.03647 (17)	0.0587 (2)	0.0693 (2)	−0.0038 (3)	−0.00059 (14)	0.0096 (3)
O20	0.0484 (18)	0.284 (6)	0.103 (3)	0.052 (3)	−0.0202 (18)	−0.098 (4)
N1	0.0247 (13)	0.0482 (19)	0.0533 (18)	0.0005 (14)	0.0012 (12)	−0.0009 (16)
C2	0.041 (2)	0.067 (3)	0.051 (2)	−0.003 (2)	−0.0030 (17)	0.011 (2)
C3	0.047 (2)	0.081 (3)	0.040 (2)	0.004 (2)	0.0053 (18)	−0.005 (2)
C4	0.0361 (19)	0.069 (3)	0.050 (2)	−0.003 (2)	0.0034 (17)	0.005 (2)
C5	0.0357 (18)	0.038 (2)	0.044 (2)	0.0008 (17)	0.0084 (15)	0.0024 (17)
C6	0.0328 (17)	0.045 (2)	0.038 (2)	0.0025 (16)	0.0059 (15)	0.0051 (17)
C7	0.042 (2)	0.072 (3)	0.045 (2)	0.002 (2)	0.0048 (17)	−0.005 (2)
C8	0.0338 (18)	0.061 (3)	0.049 (2)	0.0087 (18)	0.0062 (16)	−0.003 (2)
C9	0.0257 (16)	0.042 (2)	0.045 (2)	−0.0026 (16)	0.0044 (14)	0.0065 (17)
C10	0.0262 (16)	0.037 (2)	0.045 (2)	−0.0064 (16)	0.0027 (14)	0.0038 (17)
C11	0.0328 (18)	0.054 (2)	0.050 (2)	0.0040 (18)	−0.0014 (16)	0.0059 (19)
C12	0.0366 (19)	0.040 (2)	0.056 (2)	0.0052 (17)	0.0052 (17)	0.0060 (19)
C13	0.0362 (19)	0.042 (2)	0.052 (2)	0.0074 (18)	0.0083 (17)	−0.0080 (18)
C14	0.0389 (19)	0.044 (2)	0.048 (2)	−0.0069 (18)	0.0050 (16)	−0.0013 (18)
C15	0.0457 (19)	0.059 (2)	0.071 (3)	0.002 (3)	−0.0023 (17)	−0.030 (3)
C16	0.046 (2)	0.105 (4)	0.095 (3)	0.002 (4)	−0.001 (2)	−0.022 (4)
C17	0.048 (2)	0.128 (5)	0.067 (3)	0.013 (3)	0.015 (2)	−0.014 (3)
O18	0.0382 (14)	0.101 (3)	0.0512 (17)	0.0037 (16)	−0.0081 (12)	−0.0178 (17)
O19	0.0288 (12)	0.093 (2)	0.0680 (18)	0.0058 (15)	−0.0038 (12)	−0.0036 (17)

Geometric parameters (Å, º)

O20—H20A	0.920	C8—H8A	0.9700
O20—H20B	0.924	C8—H8B	0.9700
N1—C2	1.498 (5)	C9—C10	1.521 (5)
N1—C15	1.500 (5)	C9—H9	0.9800
N1—C10	1.525 (4)	C10—H10	0.9800
N1—H1	0.9100	C11—O18	1.364 (5)
C2—C3	1.492 (6)	C11—C12	1.376 (5)
C2—H2A	0.9700	C12—O19	1.370 (4)
C2—H2B	0.9700	C12—C13	1.378 (5)
C3—C4	1.522 (5)	C13—C14	1.407 (5)
C3—H3A	0.9700	C13—H13	0.9300
C3—H3B	0.9700	C14—H14	0.9300
C4—C9	1.528 (5)	C15—C16	1.465 (5)
C4—H4A	0.9700	C15—H15A	0.9700
C4—H4B	0.9700	C15—H15B	0.9700
C5—C6	1.391 (5)	C16—C17	1.505 (6)
C5—C14	1.413 (5)	C16—H16A	0.9700
C5—C9	1.527 (4)	C16—H16B	0.9700
C6—C11	1.402 (5)	C17—H17A	0.9600
C6—C7	1.502 (5)	C17—H17B	0.9600
C7—C8	1.532 (5)	C17—H17C	0.9600
C7—H7A	0.9700	O18—H18	0.919
C7—H7B	0.9700	O19—H19	0.940
C8—C10	1.529 (5)
H20A—O20—H20B	117.9	C10—C9—C4	111.7 (3)
C2—N1—C15	112.0 (3)	C5—C9—C4	113.3 (3)
C2—N1—C10	110.9 (3)	C10—C9—H9	106.8
C15—N1—C10	112.4 (3)	C5—C9—H9	106.8
C2—N1—H1	107.1	C4—C9—H9	106.8
C15—N1—H1	107.1	C9—C10—N1	109.9 (3)
C10—N1—H1	107.1	C9—C10—C8	109.4 (3)
C3—C2—N1	112.1 (3)	N1—C10—C8	112.2 (3)
C3—C2—H2A	109.2	C9—C10—H10	108.4
N1—C2—H2A	109.2	N1—C10—H10	108.4
C3—C2—H2B	109.2	C8—C10—H10	108.4
N1—C2—H2B	109.2	O18—C11—C12	122.4 (3)
H2A—C2—H2B	107.9	O18—C11—C6	116.8 (3)
C2—C3—C4	113.3 (4)	C12—C11—C6	120.7 (4)
C2—C3—H3A	108.9	C11—C12—O19	115.2 (3)
C4—C3—H3A	108.9	C11—C12—C13	120.4 (3)
C2—C3—H3B	108.9	O19—C12—C13	124.4 (3)
C4—C3—H3B	108.9	C12—C13—C14	119.6 (3)
H3A—C3—H3B	107.7	C12—C13—H13	120.2
C9—C4—C3	110.4 (3)	C14—C13—H13	120.2
C9—C4—H4A	109.6	C13—C14—C5	120.7 (3)
C3—C4—H4A	109.6	C13—C14—H14	119.6
C9—C4—H4B	109.6	C5—C14—H14	119.6
C3—C4—H4B	109.6	C16—C15—N1	116.6 (4)
H4A—C4—H4B	108.1	C16—C15—H15A	108.1
C6—C5—C14	118.2 (3)	N1—C15—H15A	108.1
C6—C5—C9	121.6 (3)	C16—C15—H15B	108.1
C14—C5—C9	120.2 (3)	N1—C15—H15B	108.1
C5—C6—C11	120.4 (3)	H15A—C15—H15B	107.3
C5—C6—C7	122.1 (3)	C15—C16—C17	114.0 (4)
C11—C6—C7	117.5 (3)	C15—C16—H16A	108.8
C6—C7—C8	112.7 (3)	C17—C16—H16A	108.8
C6—C7—H7A	109.0	C15—C16—H16B	108.8
C8—C7—H7A	109.0	C17—C16—H16B	108.8
C6—C7—H7B	109.0	H16A—C16—H16B	107.7
C8—C7—H7B	109.0	C16—C17—H17A	109.5
H7A—C7—H7B	107.8	C16—C17—H17B	109.5
C10—C8—C7	108.6 (3)	H17A—C17—H17B	109.5
C10—C8—H8A	110.0	C16—C17—H17C	109.5
C7—C8—H8A	110.0	H17A—C17—H17C	109.5
C10—C8—H8B	110.0	H17B—C17—H17C	109.5
C7—C8—H8B	110.0	C11—O18—H18	108.9
H8A—C8—H8B	108.4	C12—O19—H19	121.5
C10—C9—C5	111.0 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···Br	0.91	2.36	3.265 (3)	177
O18—H18···O19	0.92	2.22	2.694 (4)	112
O18—H18···Br^i	0.919	2.55	3.314 (3)	141.22 (18)
O19—H19···O20	0.94	1.79	2.620 (5)	146
O20—H20A···Br^ii	0.920	2.52	3.384 (3)	157.5 (4)
O20—H20B···Br^iii	0.924	2.44	3.222 (4)	142.8 (4)

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