rac-6-Hy­droxy-2,5,7,8-tetra­methyl­chroman-2-carboxamide from synchrotron data

Krzysztof Brzezinski; Zbigniew Dauter; Aneta Baj; Piotr Wałejko; Stanisław Witkowski

doi:10.1107/S1600536811002807

. 2011 Jan 29;67(Pt 2):o503–o504. doi: 10.1107/S1600536811002807

rac-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide from synchrotron data

Krzysztof Brzezinski ^a,^*, Zbigniew Dauter ^a, Aneta Baj ^b, Piotr Wałejko ^b, Stanisław Witkowski ^b

PMCID: PMC3051603 PMID: 21523156

Abstract

The crystal structure of the title water-soluble analogue of vitamin E, trolox amide, C₁₄H₁₉NO₃, solved and refined against synchrotron diffraction data, contains two molecules in the asymmetric unit. In both molecules, the heterocyclic ring is in a half-chair conformation. The crystal packing features a herring-bone pattern generated by N—H⋯O hydrogen bonds between the hydroxy and amide groups. O—H⋯O hydrogen bonds also occur.

Related literature

For background to the chemistry of trolox, its substituted amides and their applications as antioxidants and anti-inflamatory agents, see: Ross et al. (1995 ▶); Scott et al. (1974 ▶); Cort et al. (1975 ▶); Cohen et al. (1981 ▶); Walther et al. (1991 ▶); Silver et al. (1992 ▶); Netscher & Gautschi (1992 ▶); Van Ginkel et al. (1992) ▶; Moulin et al. (1998 ▶); Vajragupta et al. (2000 ▶); Koufaki et al. (2010 ▶). For the use of trolox as an intermediate for the synthesis of natural tocols such as vitamin E and α-tocotrienol, see: Cohen et al. (1979 ▶); Hyatt & Skelton (1997 ▶); Sakito & Suzokamo (1982 ▶); Sugai et al. (1991 ▶).

Experimental

Crystal data

C₁₄H₁₉NO₃
M _r = 249.31
Monoclinic,
a = 9.11 (1) Å
b = 17.92 (2) Å
c = 15.95 (1) Å
β = 100.43 (1)°
V = 2561 (4) Å³
Z = 8
Synchrotron radiation
λ = 0.59040 Å
μ = 0.06 mm⁻¹
T = 100 K
0.2 × 0.05 × 0.04 mm

Data collection

MAR315 CCD diffractometer
Absorption correction: multi-scan (SCALEPACK; Otwinowski & Minor, 2003 ▶) T _min = 0.988, T _max = 0.997
14016 measured reflections
6360 independent reflections
5153 reflections with I > 2σ(I)
R _int = 0.030

Refinement

R[F ² > 2σ(F ²)] = 0.050
wR(F ²) = 0.147
S = 1.08
6360 reflections
327 parameters
H-atom parameters constrained
Δρ_max = 0.41 e Å⁻³
Δρ_min = −0.25 e Å⁻³

Data collection: NECAT APS beamline software; cell refinement: HKL-2000 (Otwinowski & Minor, 1997 ▶); data reduction: HKL-2000; program(s) used to solve structure: SHELXD (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 (Farrugia, 1997 ▶) and pyMOL (DeLano, 2002 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536811002807/kp2304sup1.cif

e-67-0o503-sup1.cif^{(27.1KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536811002807/kp2304Isup2.hkl

e-67-0o503-Isup2.hkl^{(311.3KB, 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
N13—H13A⋯O16ⁱ	0.88	2.13	2.971 (2)	160
N13—H13B⋯O32ⁱⁱ	0.88	2.49	2.896 (3)	109
O16—H16A⋯O32ⁱⁱⁱ	0.84	1.91	2.631 (2)	143
N33—H33B⋯O12	0.88	2.29	2.861 (3)	123
N33—H33A⋯O36ⁱ	0.88	2.53	3.281 (3)	143
O36—H36A⋯O12^iv	0.84	1.91	2.727 (2)	165

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

Acknowledgments

Financial support from the Polish Ministry of Science and Higher Education (grant No. N N204 177639) is gratefully acknowledged. This work was in part supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. X-ray data were collected at the NECAT 24ID-C beamline of the Advanced Photon Source, Argonne National Laboratory. Use of the APS was supported by the US Department of Energy under contract No. W-31–109-Eng-38.

supplementary crystallographic information

Comment

Trolox is a water-soluble analog of α-tocopherol (vitamin E), in which lipophilic side chain was replaced with carboxylic group (Ross et al., 1995). Owing to its high radical scavenging activity it is often used as a model compound for investigation of some aspects of vitamin E biological activity as well as for structural studies. It is commercially available in both enantiomerically pure forms, and is an important intermediate for the synthesis of natural tocols such as vitamin E and α-tocotrienol (Cohen et al., 1979; Sakito et al., 1982; Sugai et al., 1991); Hyatt & Skelton, 1997).

The asymmetric unit contains two molecules differing in chirality of C2 (C22) atoms and in conformation of dihydropyranyl ring of chroman system. In both molecules the heterocyclic ring is in a half-chair conformation but the two out of plane atoms (C2 and C3 or C22 and C23) have the inverted configuration (Fig. 2). In one molecule the methyl group is axial and amide group is equatorial, whereas in the second molecule this arrangement is opposite. The average planes of the two unique molecules are highly parallel, but their aromatic rings are shifted and do not participate in effective π-stacking interactions. Together with their centrosymmetric mates they form columns of molecules extending along the b axis. The presence of the neighbouring columns related by the 2₁ axes or c-glide planes results in the overall herring-bone type arrangement of molecules in the crystal (Fig. 2). Each molecule participates in three intermolecular hydrogen bonds engaging both amide oxygen and nitrogen atoms and the hydroxy group. The hydrogen bond network connects molecules of the adjacent columns (Table 1 and Fig. 2).

Experimental

The title compound was obtained from RS-trolox in two-step synthesis via acyl chloride (SOCl₂, DMF) followed by aminolysis (NH₃ in CHCl₃). After purification by column-flush chromatography pure crystalline compound was obtained (80% yield); mp 491–493 K; 1H NMR (MeOH-d4): δ 2.65–2.56 (m, 2H), 2.34–2.28 (m, 1H), 2.17 (s, 6H), 2.09 (s, 3H), 1.88–1.81 (m, 1H), 1.50 (s, 3H) p.p.m.; 13 C NMR (MeOH-d4) 178.6, 145.7, 144.3, 123.4, 121.4, 120.8, 117.1, 72.6, 29.4, 23.3, 20.1, 11.3, 10.7, 10.4 p.p.m.; IR (KBr): 3493; 3372; 2927; 1647; 1578 cm_-1; ESI – MS: 272 (M⁺Na⁺). The crystallization was carried out at room temperature by slow evaporation of acetone solution of 6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxamide.