(R,R)-Disynephrine ether bis­(hydrogen sulfate)

William Arbuckle; Alan R Kennedy; Catriona A Morrison

doi:10.1107/S1600536809025288

. 2009 Jul 4;65(Pt 8):o1768–o1769. doi: 10.1107/S1600536809025288

(R,R)-Disynephrine ether bis(hydrogen sulfate)

William Arbuckle ^a, Alan R Kennedy ^b,^*, Catriona A Morrison ^b

PMCID: PMC2977255 PMID: 21583478

Abstract

The asymmetric unit of the title compound [systematic name: (R,R)-2,4-bis(4-hydroxyphenyl)-N,N′-dimethyl-3-oxapentane-1,5-diammonium bis(hydrogen sulfate)], C₁₈H₂₆N₂O₃ ²⁺·2HSO₄ ⁻, contains one half-cation and one hydrogen sulfate anion. The cation has crystallographically imposed twofold symmetry with the rotation axis passing through the central ether O atom. Hydrogen bonds between the hydroxy group and amine H atoms of the cation to two hydrogen sulfate anions link the three ions in a ring motif. A three-dimensional network is accomplished by additional O—H⋯O hydrogen bonds between the anions and by N—H⋯O hydrogen bonds between the cations. Disorder with equally occupied sites affects the H-atom position in the anion.

Related literature

For the preparation and structure of the equivalent bromide salt, see: Mukhopadhyay & Dattagupta (1984 ▶, 1988 ▶). For recent examples of synephrine use, see: Blanck et al. (2007 ▶): Haller et al. (2008 ▶). For general background, see: Bruice (2007 ▶); Jacques et al. (1981 ▶).

Experimental

Crystal data

C₁₈H₂₆N₂O₃ ²⁺·2HSO₄ ⁻
M _r = 512.54
Monoclinic,
a = 13.7204 (9) Å
b = 11.5853 (5) Å
c = 7.6579 (5) Å
β = 116.413 (8)°
V = 1090.19 (13) Å³
Z = 2
Mo Kα radiation
μ = 0.31 mm⁻¹
T = 123 K
0.23 × 0.15 × 0.11 mm

Data collection

Oxford Diffraction Gemini S CCD diffractometer
Absorption correction: multi-scan (ABSPACK; Oxford Diffraction, 2007 ▶) T _min = 0.974, T _max = 1.000 (expected range = 0.942–0.967)
5888 measured reflections
2401 independent reflections
2034 reflections with I > 2σ(I)
R _int = 0.027

Refinement

R[F ² > 2σ(F ²)] = 0.043
wR(F ²) = 0.111
S = 1.03
2401 reflections
161 parameters
1 restraint
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.57 e Å⁻³
Δρ_min = −0.43 e Å⁻³
Absolute structure: Flack (1983 ▶), 1032 Friedel pairs
Flack parameter: 0.08 (11)

Data collection: CrysAlis CCD (Oxford Diffraction, 2007 ▶); cell refinement: CrysAlis CCD; data reduction: CrysAlis RED (Oxford Diffraction, 2007 ▶); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 (Farrugia, 1997 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536809025288/wm2243sup1.cif

e-65-o1768-sup1.cif^{(16.8KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809025288/wm2243Isup2.hkl

e-65-o1768-Isup2.hkl^{(115.6KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1⋯O3ⁱ	0.84	1.95	2.739 (3)	155
N1—H1N⋯O4ⁱⁱ	0.83 (3)	1.93 (3)	2.700 (4)	153 (3)
N1—H2N⋯O1ⁱⁱⁱ	0.82 (3)	2.27 (3)	2.999 (3)	149 (3)
O5—H1S⋯O5^iv	0.91	1.65	2.502 (6)	155
O6—H2S⋯O6ⁱ	1.05	1.60	2.493 (5)	139

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) .

Acknowledgments

The authors thank Schering-Plough for funding towards a studentship (CAM).

supplementary crystallographic information

Comment

Synephrine (systematic name 2-hydroxy-2-(4-hydroxyphenyl)-N-methylethanamine) is a member of the phenylethylamine drug family and it is often found in products marketed as "traditional medicines" or "weight-loss" pills (Blanck et al., 2007; Haller et al., 2008). An attempt to prepare the sulfate salt of a racemic sample gave instead only the title compound, di-synephrine ether di-hydrogen sulfate, presumably via a variation of the well known S_N² condensation reaction (Mukhopadhyay & Dattagupta, 1988; Bruice, 2007).

The salt crystallizes in space group C2, with half a cation and one hydrogen sulfate anion in the asymmetric unit. The twofold rotation axis passes through O2, the etheric O atom (Fig. 1). The (R,R) conformation was assigned after refinement of the Flack parameter (0.08 (11)). The bulk sample is presumably thus a conglomerate (Jacques et al., 1981). Similar symmetry is seen in the molecular structure of the analogous bromide salt (Mukhopadhyay & Dattagupta, 1988). Despite the gross structural similarities imposed by the identical symmetries, the two salts do have somewhat different conformations. This is best illustrated by the C8—C7—C7*—C8* torsion angle (-28.7 (3) ° here and -11.3 ° in the Br salt). Disorder effects the H atom position in the [HSO₄] anion, with equally occupied proton sites (50:50) associated with both O5 and O6.

Hydrogen bonds (Table 1) from the cation's hydroxy and amine H atoms to two [HSO₄] anions link the three ions (one cation and two anions) in a ring motif (Fig. 2). Further anion to anion hydrogen bonded interactions give columns of [HSO₄] lying along the c direction and complete a hydrogen bonded network in the ac plane (Fig. 3). A final, weaker cation to cation interaction between the NH₂ and –OH links these planes in the b direction.

Experimental

The title compound was obtained on treating an aqueous solution of (+/-)synephrine with dilute sulfuric acid. Single-crystals were obtained by allowing the solvent of the reaction mixture to evaporate at 295 K. ¹H NMR (DMSO-d6) 9.67 (2H, s br, OH); 8.40 (4H, s br, NH₂); 7.07 (4H, d, sp² CH); 6.80 (4H, d, sp² CH); 4.20 (2H, dd, OCH); 3.32 (2H, m, CH₂); 2.99 (2H, m, CH₂); 2.57 (6H, t, Me).