The antiestrogen [2-(4-benzyl­phenoxy)­ethyl]­diethyl­ammonium chloride

The crystal structure of the title compound, C₁₉H₂₆NO⁺·Cl⁻ (common name: N,N-diethyl-2-[(4-phenyl­methyl)phenoxy]-ethan­amine hydro­chloride), contains one mol­ecule in the asymmetric unit. The planes through the two phenyl rings are roughly perpendicular. Protonation occurs at the N atom, to which the Cl⁻ ion is linked via an N—H...Cl hydrogen bond. The mol­ecule adopts an eclipsed rather than extended conformation.

S1. Comment

[2-(4-Benzylphenoxy)ethyl]diethylammonium chloride, (I), is a diphenylmethane analogue of the antioestrogen tamoxifen which antagonizes the binding of histamine to intracellular growth-regulatory sites associated with antioestrogen-binding sites in microsomes and nuclei. It has been found that (I) increases the therapeutic index of some chemotherapy drugs, with the added benefit of lower toxicity to normal tissue like bone marrow, gut and hair, and the compound has been studied as a treatment for metastatic prostate cancer (Brandes et al., 1994, 1995). A chemopotentiating effect of the drug in patients with early metastatic breast cancer has also been observed (Brandes & Bracken, 1998), and growth-inhibitory effects on human ovarian cancer cells when combined with cisplatin have been reported by Hiramatsu et al. (1997). Since knowledge of the stereochemistry is useful in the rational design of drugs with enhanced chemotherapeutic effects and lower toxicities, we now report on the three-dimensional structure of (I). \scheme

The molecular conformation in the crystal (Fig. 1) consists of two phenyl rings and an N,N-diethyl side chain in an eclipsed conformation. The best planes through the phenyl rings intersect at an angle of 79.12 (12)°. In the closely related compounds clomiphene hydrochloride (Ernst & Hite, 1976), and tamoxifen (Precigoux et al., 1979), the angles are 78 and 87° respectively. Protonation occurs in (I) at nitrogen atom N17, as the reduction of the values of the angles at N17 [110.4 (2), 111.0 (2), 110.5 (2) and 108.3°] confirm.

The only hydrogen bond in (I) is between N17 (D) and Cl1 (A): H···A 2.208 (4) and D···A 3.116 (2) Å, and DHA 174.9 (2)°. The molecular bond distances and angles are consistent with the normal values. The C12—C11—O14—C15, C11—O14—C15—C16, O14—C15—C16—N17 and C15—C16—N17—C20 torsion angles are 178.2 (3), 169.7 (2), 73.9 (3) and -80.3 (3)°, respectively. Similar values were found in clomiphene (Ernst & Hite, 1976). In the crystal structure of (I) the molecules lie virtually parallel to the b axis, with only van der Waals contacts between them.

Fig. 2 shows the crystal structure conformation of (I) superimposed with that of clomiphene. The corresponding parts of the two molecules overlap closely; only small rotations about single bonds would be required for total overlap. The same situation holds for (I) and tamoxifen, as tamoxifen and clomiphene have been shown to share conformational and stereochemical features (Camerman et al., 1980). It may be that this part of the molecular structure is responsible for the common antioestrogen properties of these molecules and the third phenyl ring, absent in (I), may be involved in other antiproliferative actions of three-ring antioestrogens on cancer cells (Lavie et al., 1998) independent of oestrogen receptors.

S2. Experimental

Crystals of (I) were obtained as very small needles by solvent evaporation from an ethanol/ethyl acetate mixture. Due to the small size of the available crystals, data were collected on the synchrotron at NSLS (Brookhaven).

S3. Refinement

The SHELX97 (Sheldrick, 1997) instructions TWIN and BASF were included; the Flack parameter is the volume fraction of one of the individuals of the racemic twin.

Computing details

Data collection: DENZO-SMN (Otwinowski & Minor,1997); cell refinement: DENZO-SMN; data reduction: DENZO-SMN; program(s) used to solve structure: SHELX97; program(s) used to refine structure: SHELX97; molecular graphics: ORTEP-3 for Windows (Farrugia, 1998); software used to prepare material for publication: SHELX97.

Figures

	Fig. 1. ORTEP-3 (Farrugia, 1997) view of (I), showing 50% probability displacement ellipsoids. H atoms are drawn as small circles of arbitrary radii.
	Fig. 2. Superposition of the crystal structures of (I) (solid lines) and clomiphene (open lines).

[2-(4-benzylphenoxy)ethyl]diethylammonium chloride

Crystal data

C19H26NO^+·Cl^−	Dx = 1.183 Mg m^−3
Mr = 319.86	Synchrotron radiation radiation, λ = 0.9200 (1) Å
Orthorhombic, Pca21	Cell parameters from all reflections
a = 16.427 (2) Å	θ = 2.4–30.7°
b = 15.195 (2) Å	µ = 0.44 mm^−1
c = 7.194 (1) Å	T = 293 K
V = 1795.7 (5) Å^3	Needle, colourless
Z = 4	0.13 × 0.01 × 0.01 mm
F(000) = 688

Data collection

ADSC Quantum-4 CCD detector diffractometer	2237 reflections with I > 2σ(I)
Radiation source: X9B beamline at NSLS (Brookhaven)	Rint = 0.051
Double Si111 monochromator	θmax = 30.7°, θmin = 2.4°
single axis rotation method scans	h = −18→18
7875 measured reflections	k = −16→16
2438 independent reflections	l = −7→7

Refinement

Refinement on F^2	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F^2 > 2σ(F^2)] = 0.036	w = 1/[σ^2(Fo^2) + (0.0618P)^2 + 0.388P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.105	(Δ/σ)max < 0.001
S = 1.00	Δρmax = 0.14 e Å^−3
2438 reflections	Δρmin = −0.19 e Å^−3
208 parameters	Extinction correction: SHELX97 (Sheldrick, 1997), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
1 restraint	Extinction coefficient: 0.0153 (18)
Primary atom site location: structure-invariant direct methods	Absolute structure: Flack (1983)
Secondary atom site location: difference Fourier map	Absolute structure parameter: 0.58 (5)

Special details

Experimental. Completeness of only 98.2% resulted from the fact that we used the synchrotron beamline X9B at Brookhaven, which is designed and set up primarily for macromolecular experiments. We used the shortest wavelength permitted by the monochromator setup (0.92 Å) and shortest possible crystal-to-detector distance (50 mm), which gives the resolution of 0.90 Å (sin(Θ)/Λ=0.555) at the edge of the ADSC Quantum-4 CCD detector (the hardware limitation which could not have been overcome).

A crystal of dimensions 0.130 × 0.010 × 0.008 mm was used for X-ray data collection. The crystal was too small for data collection on a conventional diffractometer, so data were collected at NSLS (Brookhaven) using synchrotron radiation and an ADSC Quantum-4 CCD detector using single axis rotation method with the crystal in arbitrary orientation. Crystal to detector distance was 50 mm, exposure time per image 10sec, rotation per image 3.0° and the number of images 51. The values of the unit-cell parameters and their accuracy were estimated in the postrefinement procedure during data merging after integration. The cell angles were fixed at 90°. The estimation of the accuracy of the cell dimensions was based on the statistical analysis (observed standard deviations) of the spread of cell dimension values obtained for individual images.

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 > 2σ(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.

A total of 7875 reflections were measured and 2438 unique reflections including Friedel pairs were used in the structure analysis and refinement. Completeness was 98.2%. All H atoms were calculated in their geometrical positions and introduced into the refinement process using a riding model. C—H distances in the methyl groups (two parameters) and H-atom U_iso values (three parameters) were varied.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
Cl1	0.11651 (4)	0.37167 (5)	−0.11216 (12)	0.0589 (3)
C1	0.0698 (3)	1.0333 (4)	−0.3818 (7)	0.0997 (16)
H1	0.0439	1.0585	−0.4836	0.075 (4)*
C2	0.1128 (3)	1.0843 (3)	−0.2636 (8)	0.0947 (16)
H2	0.1162	1.1446	−0.2842	0.075 (4)*
C3	0.1514 (2)	1.0481 (2)	−0.1145 (6)	0.0663 (9)
H3	0.1807	1.0841	−0.0343	0.075 (4)*
C4	0.14756 (16)	0.95850 (18)	−0.0804 (4)	0.0450 (7)
C5	0.10378 (18)	0.9069 (2)	−0.2001 (5)	0.0550 (8)
H5	0.1005	0.8466	−0.1798	0.075 (4)*
C6	0.0643 (2)	0.9438 (3)	−0.3514 (5)	0.0785 (12)
H6	0.0343	0.9086	−0.4318	0.075 (4)*
C7	0.1935 (2)	0.9229 (2)	0.0859 (5)	0.0609 (9)
H7A	0.2513	0.9295	0.0623	0.063 (3)*
H7B	0.1803	0.9591	0.1929	0.063 (3)*
C8	0.17716 (18)	0.82813 (19)	0.1356 (4)	0.0482 (7)
C9	0.23448 (18)	0.76344 (19)	0.1009 (4)	0.0479 (8)
H9	0.2828	0.7784	0.0413	0.075 (4)*
C10	0.22130 (16)	0.67623 (18)	0.1533 (4)	0.0430 (7)
H10	0.2603	0.6335	0.1286	0.075 (4)*
C11	0.15009 (16)	0.65414 (18)	0.2418 (4)	0.0405 (6)
C12	0.09005 (16)	0.71713 (19)	0.2721 (4)	0.0458 (7)
H12	0.0409	0.7016	0.3273	0.075 (4)*
C13	0.10439 (18)	0.8027 (2)	0.2193 (4)	0.0495 (7)
H13	0.0644	0.8449	0.2401	0.075 (4)*
O14	0.13224 (11)	0.57160 (12)	0.3101 (3)	0.0491 (5)
C15	0.19018 (15)	0.50310 (16)	0.2790 (4)	0.0421 (7)
H15A	0.2441	0.5232	0.3142	0.063 (3)*
H15B	0.1912	0.4879	0.1481	0.063 (3)*
C16	0.16762 (15)	0.42385 (17)	0.3917 (4)	0.0423 (6)
H16A	0.1558	0.4426	0.5177	0.063 (3)*
H16B	0.2141	0.3846	0.3968	0.063 (3)*
N17	0.09552 (14)	0.37339 (14)	0.3183 (3)	0.0395 (5)
H17	0.0982	0.3732	0.1919	0.063 (3)*
C18	0.09807 (19)	0.28006 (18)	0.3844 (6)	0.0565 (8)
H18A	0.0465	0.2520	0.3564	0.063 (3)*
H18B	0.1050	0.2796	0.5183	0.063 (3)*
C19	0.1658 (3)	0.2277 (2)	0.2967 (7)	0.0833 (12)
H19A	0.1620 (10)	0.2320 (15)	0.164 (3)	0.111 (7)*
H19B	0.1612 (11)	0.1674 (16)	0.333 (3)	0.111 (7)*
H19C	0.2171 (13)	0.2505 (13)	0.337 (3)	0.111 (7)*
C20	0.01646 (14)	0.41786 (19)	0.3756 (5)	0.0459 (7)
H20A	0.0088	0.4103	0.5084	0.063 (3)*
H20B	0.0207	0.4805	0.3510	0.063 (3)*
C21	−0.05657 (19)	0.3821 (2)	0.2758 (5)	0.0628 (9)
H21A	−0.0466 (7)	0.3841 (17)	0.136 (3)	0.111 (7)*
H21B	−0.1064 (13)	0.4193 (14)	0.308 (3)	0.111 (7)*
H21C	−0.0664 (10)	0.3186 (16)	0.316 (3)	0.111 (7)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.0488 (4)	0.0938 (6)	0.0341 (4)	−0.0102 (3)	−0.0008 (4)	0.0000 (4)
C1	0.084 (3)	0.149 (5)	0.066 (3)	0.045 (3)	−0.004 (3)	0.047 (3)
C2	0.103 (3)	0.086 (3)	0.095 (4)	0.033 (2)	0.004 (3)	0.047 (3)
C3	0.074 (2)	0.0546 (19)	0.070 (2)	0.0102 (15)	0.010 (2)	0.021 (2)
C4	0.0444 (14)	0.0489 (17)	0.0417 (18)	0.0032 (12)	0.0016 (13)	0.0070 (14)
C5	0.0514 (17)	0.066 (2)	0.0474 (17)	0.0008 (14)	−0.0015 (15)	0.0009 (17)
C6	0.056 (2)	0.131 (4)	0.048 (2)	0.010 (2)	−0.0056 (17)	0.001 (2)
C7	0.080 (2)	0.0446 (17)	0.058 (2)	−0.0118 (15)	−0.0209 (17)	0.0123 (16)
C8	0.0553 (18)	0.0519 (16)	0.0374 (16)	−0.0074 (14)	−0.0080 (14)	0.0083 (13)
C9	0.0500 (19)	0.0593 (18)	0.0343 (18)	−0.0138 (14)	0.0009 (13)	0.0077 (13)
C10	0.0427 (15)	0.0497 (16)	0.0367 (16)	−0.0020 (11)	0.0046 (13)	0.0007 (12)
C11	0.0432 (15)	0.0452 (16)	0.0333 (14)	−0.0054 (12)	0.0015 (12)	0.0059 (12)
C12	0.0373 (14)	0.0586 (18)	0.0416 (18)	0.0037 (12)	0.0029 (13)	0.0076 (14)
C13	0.0524 (17)	0.0483 (18)	0.0479 (18)	0.0080 (13)	−0.0029 (14)	0.0052 (14)
O14	0.0445 (10)	0.0449 (11)	0.0579 (12)	−0.0003 (8)	0.0137 (9)	0.0064 (9)
C15	0.0358 (13)	0.0485 (15)	0.0420 (16)	0.0009 (11)	0.0036 (12)	0.0011 (12)
C16	0.0381 (13)	0.0512 (16)	0.0377 (14)	−0.0036 (11)	−0.0036 (14)	0.0038 (14)
N17	0.0430 (12)	0.0428 (13)	0.0328 (13)	−0.0018 (9)	0.0015 (9)	0.0045 (9)
C18	0.0711 (19)	0.0434 (17)	0.0552 (18)	−0.0019 (13)	−0.0009 (19)	0.0091 (17)
C19	0.111 (3)	0.0557 (19)	0.083 (3)	0.019 (2)	0.016 (3)	0.001 (2)
C20	0.0406 (14)	0.0517 (17)	0.0454 (16)	−0.0039 (11)	0.0045 (15)	−0.0019 (14)
C21	0.0449 (17)	0.083 (2)	0.061 (2)	−0.0118 (15)	−0.0046 (16)	0.0022 (18)

Geometric parameters (Å, º)

C1—C2	1.349 (8)	C12—H12	0.9300
C1—C6	1.381 (7)	C13—H13	0.9300
C1—H1	0.9300	O14—C15	1.428 (3)
C2—C3	1.361 (6)	C15—C16	1.498 (4)
C2—H2	0.9300	C15—H15A	0.9700
C3—C4	1.384 (4)	C15—H15B	0.9700
C3—H3	0.9300	C16—N17	1.506 (3)
C4—C5	1.369 (5)	C16—H16A	0.9700
C4—C7	1.514 (4)	C16—H16B	0.9700
C5—C6	1.385 (5)	N17—C18	1.496 (3)
C5—H5	0.9300	N17—C20	1.521 (3)
C6—H6	0.9300	N17—H17	0.9100
C7—C8	1.508 (4)	C18—C19	1.506 (5)
C7—H7A	0.9700	C18—H18A	0.9700
C7—H7B	0.9700	C18—H18B	0.9700
C8—C9	1.384 (4)	C19—H19A	0.9561
C8—C13	1.393 (4)	C19—H19B	0.9561
C9—C10	1.395 (4)	C19—H19C	0.9561
C9—H9	0.9300	C20—C21	1.500 (4)
C10—C11	1.373 (4)	C20—H20A	0.9700
C10—H10	0.9300	C20—H20B	0.9700
C11—O14	1.378 (3)	C21—H21A	1.0207
C11—C12	1.392 (4)	C21—H21B	1.0207
C12—C13	1.376 (4)	C21—H21C	1.0207
C2—C1—C6	120.0 (4)	O14—C15—C16	109.6 (2)
C2—C1—H1	120.0	O14—C15—H15A	109.7
C6—C1—H1	120.0	C16—C15—H15A	109.7
C1—C2—C3	120.5 (4)	O14—C15—H15B	109.7
C1—C2—H2	119.7	C16—C15—H15B	109.7
C3—C2—H2	119.7	H15A—C15—H15B	108.2
C2—C3—C4	121.1 (4)	C15—C16—N17	114.5 (2)
C2—C3—H3	119.5	C15—C16—H16A	108.6
C4—C3—H3	119.5	N17—C16—H16A	108.6
C5—C4—C3	118.4 (3)	C15—C16—H16B	108.6
C5—C4—C7	123.7 (3)	N17—C16—H16B	108.6
C3—C4—C7	117.9 (3)	H16A—C16—H16B	107.6
C4—C5—C6	120.6 (3)	C18—N17—C16	110.4 (2)
C4—C5—H5	119.7	C18—N17—C20	111.0 (2)
C6—C5—H5	119.7	C16—N17—C20	110.5 (2)
C1—C6—C5	119.5 (4)	C18—N17—H17	108.3
C1—C6—H6	120.3	C16—N17—H17	108.3
C5—C6—H6	120.3	C20—N17—H17	108.3
C8—C7—C4	116.1 (3)	N17—C18—C19	112.8 (3)
C8—C7—H7A	108.3	N17—C18—H18A	109.0
C4—C7—H7A	108.3	C19—C18—H18A	109.0
C8—C7—H7B	108.3	N17—C18—H18B	109.0
C4—C7—H7B	108.3	C19—C18—H18B	109.0
H7A—C7—H7B	107.4	H18A—C18—H18B	107.8
C9—C8—C13	117.7 (3)	C18—C19—H19A	109.5
C9—C8—C7	121.0 (3)	C18—C19—H19B	109.5
C13—C8—C7	121.3 (3)	H19A—C19—H19B	109.5
C8—C9—C10	121.4 (3)	C18—C19—H19C	109.5
C8—C9—H9	119.3	H19A—C19—H19C	109.5
C10—C9—H9	119.3	H19B—C19—H19C	109.5
C11—C10—C9	119.3 (3)	C21—C20—N17	113.1 (3)
C11—C10—H10	120.3	C21—C20—H20A	109.0
C9—C10—H10	120.3	N17—C20—H20A	109.0
O14—C11—C10	124.7 (2)	C21—C20—H20B	109.0
O14—C11—C12	114.8 (2)	N17—C20—H20B	109.0
C10—C11—C12	120.5 (3)	H20A—C20—H20B	107.8
C13—C12—C11	119.1 (3)	C20—C21—H21A	109.5
C13—C12—H12	120.5	C20—C21—H21B	109.5
C11—C12—H12	120.5	H21A—C21—H21B	109.5
C12—C13—C8	121.9 (3)	C20—C21—H21C	109.5
C12—C13—H13	119.1	H21A—C21—H21C	109.5
C8—C13—H13	119.1	H21B—C21—H21C	109.5
C11—O14—C15	117.7 (2)
C6—C1—C2—C3	0.3 (7)	C9—C10—C11—C12	2.7 (4)
C1—C2—C3—C4	0.1 (6)	O14—C11—C12—C13	176.0 (3)
C2—C3—C4—C5	−0.2 (5)	C10—C11—C12—C13	−2.8 (4)
C2—C3—C4—C7	178.7 (3)	C11—C12—C13—C8	0.3 (5)
C3—C4—C5—C6	−0.1 (5)	C9—C8—C13—C12	2.1 (4)
C7—C4—C5—C6	−178.9 (3)	C7—C8—C13—C12	−177.4 (3)
C2—C1—C6—C5	−0.6 (6)	C10—C11—O14—C15	−3.1 (4)
C4—C5—C6—C1	0.5 (5)	C12—C11—O14—C15	178.2 (3)
C5—C4—C7—C8	−10.5 (5)	C11—O14—C15—C16	169.7 (2)
C3—C4—C7—C8	170.7 (3)	O14—C15—C16—N17	73.9 (3)
C4—C7—C8—C9	106.9 (3)	C15—C16—N17—C18	156.5 (2)
C4—C7—C8—C13	−73.7 (4)	C15—C16—N17—C20	−80.3 (3)
C13—C8—C9—C10	−2.1 (4)	C16—N17—C18—C19	−69.7 (4)
C7—C8—C9—C10	177.3 (3)	C20—N17—C18—C19	167.4 (3)
C8—C9—C10—C11	−0.2 (4)	C18—N17—C20—C21	−68.9 (3)
C9—C10—C11—O14	−175.9 (3)	C16—N17—C20—C21	168.2 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N17—H17···Cl1	0.91 (1)	2.21 (1)	3.116 (2)	175 (1)