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Acta Crystallogr Sect E Struct Rep Online. 2009 August 1; 65(Pt 8): o1768–o1769.
Published online 2009 July 4. doi:  10.1107/S1600536809025288
PMCID: PMC2977255

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

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 [triangle], 1988 [triangle]). For recent examples of synephrine use, see: Blanck et al. (2007 [triangle]): Haller et al. (2008 [triangle]). For general background, see: Bruice (2007 [triangle]); Jacques et al. (1981 [triangle]).

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Object name is e-65-o1768-scheme1.jpg

Experimental

Crystal data

  • C18H26N2O3 2+·2HSO4
  • M r = 512.54
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-65-o1768-efi1.jpg
  • 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 [triangle]) 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
  • Δρmax = 0.57 e Å−3
  • Δρmin = −0.43 e Å−3
  • Absolute structure: Flack (1983 [triangle]), 1032 Friedel pairs
  • Flack parameter: 0.08 (11)

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

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

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

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

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

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 SN2 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).

Refinement

Amine H atomes were found by difference synthesis and refined isotropically. All other H atoms of the cation were positioned geometrically at distances of 0.95, 1.00, 0.99, 0.98 and 0.84 Å from the parent atoms for CH(ar), CH(sp3), CH2, CH3 and ROH groups respectively. For these groups a riding model was used with Uiso(H) values constrained to be 1.2 times Ueq of the parent atom for CH and CH2 groups and 1.5 times Ueq of the parent atom for OH and CH3 groups. The anion's proton was found by difference synthesis to be disordered over two equally occupied sites. These were placed as found and constrained to ride on the parent O atoms with Uiso(H) equal to 1.5 times Ueq of the parent atom.

Figures

Fig. 1.
The molecular structure and atomic labelling of the cation, showing 50% probability displacement ellipsoids. H atoms are shown as spheres of arbitrary radius.
Fig. 2.
The hydrogen-bonded ring motif between one cation and two anions in the structure of [C18H26N2O3][SO4H]2.
Fig. 3.
Packed structure viewed down the c-axis. S-atoms are pink and O-atoms are red. Hydrogen-bonding is shown as dashed lines.

Crystal data

C18H26N2O32+·2HSO4F(000) = 540
Mr = 512.54Dx = 1.561 Mg m3
Monoclinic, C2Mo Kα radiation, λ = 0.71073 Å
Hall symbol: C 2yCell parameters from 3122 reflections
a = 13.7204 (9) Åθ = 2.4–29.1°
b = 11.5853 (5) ŵ = 0.31 mm1
c = 7.6579 (5) ÅT = 123 K
β = 116.413 (8)°Prism, colourless
V = 1090.19 (13) Å30.23 × 0.15 × 0.11 mm
Z = 2

Data collection

Oxford Diffraction Gemini S CCD diffractometer2401 independent reflections
Radiation source: fine-focus sealed tube2034 reflections with I > 2σ(I)
graphiteRint = 0.027
ω scansθmax = 28.0°, θmin = 2.4°
Absorption correction: multi-scan (ABSPACK; Oxford Diffraction, 2007)h = −17→16
Tmin = 0.974, Tmax = 1.000k = −14→14
5888 measured reflectionsl = −10→10

Refinement

Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.043H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.111w = 1/[σ2(Fo2) + (0.071P)2] where P = (Fo2 + 2Fc2)/3
S = 1.03(Δ/σ)max < 0.001
2401 reflectionsΔρmax = 0.57 e Å3
161 parametersΔρmin = −0.43 e Å3
1 restraintAbsolute structure: Flack (1983), 1032 Friedel pairs
Primary atom site location: structure-invariant direct methodsFlack parameter: 0.08 (11)

Special details

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)

xyzUiso*/UeqOcc. (<1)
S10.08291 (6)0.20896 (7)0.33257 (10)0.0289 (2)
O10.17446 (14)0.40319 (17)−0.2357 (3)0.0181 (4)
H10.11850.3616−0.27960.027*
O20.50000.1062 (2)0.50000.0128 (5)
O30.02688 (19)0.31541 (19)0.3192 (4)0.0304 (6)
O40.19286 (16)0.2108 (3)0.4864 (3)0.0395 (6)
O50.0193 (2)0.1104 (2)0.3550 (4)0.0456 (7)
H1S0.02040.12550.47240.068*0.50
O60.0896 (2)0.1834 (3)0.1477 (4)0.0519 (8)
H2S0.02950.21600.01490.078*0.50
N10.6712 (2)0.0279 (2)0.4186 (4)0.0191 (5)
C10.4315 (2)0.2368 (2)0.2158 (3)0.0135 (6)
C20.3329 (2)0.1795 (2)0.1126 (4)0.0156 (6)
H20.32470.10250.14700.019*
C30.2473 (2)0.2329 (2)−0.0382 (4)0.0166 (6)
H30.18070.1927−0.10780.020*
C40.2581 (2)0.3458 (2)−0.0891 (4)0.0139 (5)
C50.3554 (2)0.4041 (3)0.0124 (4)0.0182 (6)
H50.36330.4812−0.02170.022*
C60.4414 (2)0.3491 (2)0.1646 (4)0.0173 (6)
H60.50790.38930.23460.021*
C70.5277 (2)0.1742 (2)0.3714 (4)0.0136 (5)
H70.58510.23150.44950.016*
C80.5734 (2)0.0900 (3)0.2748 (4)0.0172 (6)
H8A0.51650.03290.19890.021*
H8B0.59280.13260.18270.021*
C90.7267 (3)−0.0381 (3)0.3240 (5)0.0302 (7)
H9A0.7837−0.08640.42120.045*
H9B0.75950.01550.26620.045*
H9C0.6738−0.08730.22160.045*
H1N0.711 (2)0.082 (3)0.482 (4)0.013 (8)*
H2N0.648 (3)−0.011 (3)0.480 (4)0.012 (8)*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
S10.0228 (4)0.0289 (4)0.0312 (4)0.0004 (4)0.0086 (3)−0.0031 (4)
O10.0142 (9)0.0149 (9)0.0191 (10)0.0002 (8)0.0019 (8)0.0039 (8)
O20.0139 (12)0.0143 (13)0.0101 (11)0.0000.0053 (10)0.000
O30.0196 (11)0.0272 (12)0.0420 (13)0.0024 (9)0.0117 (10)−0.0016 (10)
O40.0275 (11)0.0363 (12)0.0388 (12)0.0082 (14)0.0005 (9)0.0003 (14)
O50.0485 (16)0.0330 (14)0.0552 (17)−0.0104 (13)0.0231 (14)−0.0060 (13)
O60.0427 (15)0.072 (2)0.0398 (14)0.0081 (15)0.0172 (13)−0.0090 (13)
N10.0160 (12)0.0187 (13)0.0244 (12)0.0036 (10)0.0106 (11)0.0065 (11)
C10.0139 (13)0.0157 (15)0.0108 (11)0.0032 (9)0.0054 (10)0.0027 (9)
C20.0190 (13)0.0106 (13)0.0178 (12)−0.0004 (10)0.0088 (11)0.0009 (9)
C30.0134 (13)0.0172 (16)0.0178 (12)−0.0026 (10)0.0057 (10)−0.0019 (10)
C40.0164 (13)0.0118 (12)0.0125 (12)0.0040 (10)0.0055 (11)0.0010 (10)
C50.0184 (14)0.0138 (12)0.0217 (14)0.0003 (12)0.0082 (12)0.0044 (11)
C60.0135 (13)0.0140 (13)0.0224 (13)−0.0030 (11)0.0063 (11)−0.0010 (11)
C70.0143 (12)0.0120 (12)0.0133 (12)−0.0016 (9)0.0053 (10)0.0011 (9)
C80.0145 (13)0.0239 (15)0.0148 (12)0.0049 (11)0.0079 (10)0.0031 (11)
C90.0292 (18)0.0236 (17)0.047 (2)0.0087 (13)0.0251 (16)0.0051 (14)

Geometric parameters (Å, °)

S1—O31.433 (2)C1—C71.513 (3)
S1—O41.443 (2)C2—C31.375 (4)
S1—O61.488 (3)C2—H20.9500
S1—O51.492 (3)C3—C41.392 (4)
O1—C41.368 (3)C3—H30.9500
O1—H10.8400C4—C51.386 (4)
O2—C71.438 (3)C5—C61.390 (4)
O2—C7i1.438 (3)C5—H50.9500
O5—H1S0.9095C6—H60.9500
O6—H2S1.0540C7—C81.517 (4)
N1—C91.477 (4)C7—H71.0000
N1—C81.489 (3)C8—H8A0.9900
N1—H1N0.83 (3)C8—H8B0.9900
N1—H2N0.82 (3)C9—H9A0.9800
C1—C61.383 (4)C9—H9B0.9800
C1—C21.395 (4)C9—H9C0.9800
O3—S1—O4112.25 (15)O1—C4—C3122.1 (2)
O3—S1—O6111.20 (16)C5—C4—C3119.8 (2)
O4—S1—O6107.16 (15)C4—C5—C6119.6 (3)
O3—S1—O5110.11 (14)C4—C5—H5120.2
O4—S1—O5111.70 (16)C6—C5—H5120.2
O6—S1—O5104.10 (17)C1—C6—C5121.0 (2)
C4—O1—H1109.5C1—C6—H6119.5
C7—O2—C7i113.6 (3)C5—C6—H6119.5
S1—O5—H1S102.3O2—C7—C1113.45 (19)
S1—O6—H2S119.6O2—C7—C8105.9 (2)
C9—N1—C8112.3 (2)C1—C7—C8109.2 (2)
C9—N1—H1N109 (2)O2—C7—H7109.4
C8—N1—H1N102 (2)C1—C7—H7109.4
C9—N1—H2N114 (2)C8—C7—H7109.4
C8—N1—H2N104 (2)N1—C8—C7112.5 (2)
H1N—N1—H2N114 (3)N1—C8—H8A109.1
C6—C1—C2118.7 (2)C7—C8—H8A109.1
C6—C1—C7120.9 (2)N1—C8—H8B109.1
C2—C1—C7120.3 (2)C7—C8—H8B109.1
C3—C2—C1120.8 (2)H8A—C8—H8B107.8
C3—C2—H2119.6N1—C9—H9A109.5
C1—C2—H2119.6N1—C9—H9B109.5
C2—C3—C4120.1 (2)H9A—C9—H9B109.5
C2—C3—H3120.0N1—C9—H9C109.5
C4—C3—H3120.0H9A—C9—H9C109.5
O1—C4—C5118.1 (2)H9B—C9—H9C109.5
C6—C1—C2—C30.6 (4)C7i—O2—C7—C1−70.07 (17)
C7—C1—C2—C3−175.4 (2)C7i—O2—C7—C8170.1 (2)
C1—C2—C3—C4−0.4 (4)C6—C1—C7—O2139.0 (2)
C2—C3—C4—O1−178.7 (2)C2—C1—C7—O2−45.1 (3)
C2—C3—C4—C50.2 (4)C6—C1—C7—C8−103.1 (3)
O1—C4—C5—C6178.8 (2)C2—C1—C7—C872.8 (3)
C3—C4—C5—C6−0.1 (4)C9—N1—C8—C7−169.9 (2)
C2—C1—C6—C5−0.5 (4)O2—C7—C8—N1−59.6 (3)
C7—C1—C6—C5175.4 (2)C1—C7—C8—N1177.9 (2)
C4—C5—C6—C10.3 (4)

Symmetry codes: (i) −x+1, y, −z+1.

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
O1—H1···O3ii0.841.952.739 (3)155
N1—H1N···O4i0.83 (3)1.93 (3)2.700 (4)153 (3)
N1—H2N···O1iii0.82 (3)2.27 (3)2.999 (3)149 (3)
O5—H1S···O5iv0.911.652.502 (6)155
O6—H2S···O6ii1.051.602.493 (5)139

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

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: WM2243).

References

  • Blanck, H. M., Serdula, M. K., Gillespie, C., Galuska, D. A., Sharpe, P. A., Conway, J. M., Kettel, L. & Ainsworth, B. E. (2007). J. Am. Dietetic Assoc.107, 441–447. [PubMed]
  • Bruice, P. Y. (2007). Organic Chemistry, 5th ed., pp. 441–442. New Jersey: Pearson Prentice Hall.
  • Farrugia, L. J. (1997). J. Appl. Cryst.30, 565.
  • Flack, H. D. (1983). Acta Cryst. A39, 876–881.
  • Haller, C. A., Duan, M. J., Jacob, P. & Benowitz, I. (2008). Br. J. Clin. Pharm.65, 833–840. [PMC free article] [PubMed]
  • Jacques, J., Collet, A. & Wilen, S. H. (1981). Enantiomers, Racemates and Resolutions New York: Wiley,.
  • Mukhopadhyay, B. P. & Dattagupta, J. K. (1984). Acta Cryst. A40, C283.
  • Mukhopadhyay, B. P. & Dattagupta, J. K. (1988). J. Crystallogr. Spectrosc. Res.18, 509–516.
  • Oxford Diffraction (2007). CrysAlis CCD, CrysAlis RED and ABSPACK Oxford Diffraction Ltd, Abingdon, England.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]

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