N-Hexyl-3-(4-hy­droxy-3,5-dimeth­oxy­phen­yl)propanamide

L C R Andrade; J A Paixão; M J M de Almeida; E J Tavares da Silva; F M Fernandes Roleira

doi:10.1107/S1600536812019022

. 2012 May 2;68(Pt 6):o1603–o1604. doi: 10.1107/S1600536812019022

N-Hexyl-3-(4-hydroxy-3,5-dimethoxyphenyl)propanamide

L C R Andrade ^a, J A Paixão ^a,^*, M J M de Almeida ^a, E J Tavares da Silva ^b, F M Fernandes Roleira ^b

PMCID: PMC3379212 PMID: 22719410

Abstract

In the title compound, C₁₇H₂₇NO₄, which is an hydrosinapic acid derivative with increased lipophilicity conferred by an additional alkyl chain, the central and the hexyl linear chains contain slightly shorter bond lengths [C—N = 1.316 (2) Å; average linear chain C—C = 1.487 (6) Å] than reported average values [Csp ²—N = 1.334, C—C for CH₂—CH₂ = 1.524 and 1.513 Å for CH₂—CH₃]. The 4-hydroxy-3,5-dimethoxyphenyl plane [r.m.s. deviation 0.055 (12) Å] makes an angle of 59.89 (5)° with the central plane of the molecule (composed of the N atom, the carbonyl group and the two methylene C atoms linking the carbonyl group and the ring, [r.m.s. deviation 0.0026 (10) Å], which, in turn, makes an angle of 64.24 (13)° with the essentially planar hexyl chain [r.m.s. deviation 0.035 (18) Å]. The N—H group of the amide group is involved in a bifurcated hydrogen bond towards the hydroxy and one of the methoxy O atoms of the 4-hydroxy-3,5-dimethoxyphenyl substituent of a neighbouring molecule, forming a two-dimensional network in the (100) plane. In addition, the same hydroxy group acts as a donor towards the carbonyl O atom of another neighbouring molecule, forming chains running along the b axis.

Related literature

For the dependence on their structural characteristics of the anticancer activity of phenolic acids and their derivatives, see: Gomes et al. (2003 ▶). For restrictions on protection of lipophilic systems due to the hydrophilic nature of molecules in aqueous media, see: Gao & Hu (2010 ▶). For the synthesis, see: Roleira et al. (2010 ▶). For reference bond lengths, see: Allen et al. (1987 ▶). graphic file with name e-68-o1603-scheme1.jpg

Experimental

Crystal data

C₁₇H₂₇NO₄
M _r = 309.40
Monoclinic,
a = 19.1126 (5) Å
b = 8.4086 (2) Å
c = 11.0715 (3) Å
β = 91.5691 (15)°
V = 1778.64 (8) Å³
Z = 4
Mo Kα radiation
μ = 0.08 mm⁻¹
T = 293 K
0.34 × 0.26 × 0.19 mm

Data collection

Bruker APEX CCD diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 2000 ▶) T _min = 0.856, T _max = 0.865
34604 measured reflections
4259 independent reflections
2478 reflections with I > 2σ(I)
R _int = 0.038

Refinement

R[F ² > 2σ(F ²)] = 0.048
wR(F ²) = 0.172
S = 0.99
4255 reflections
204 parameters
H-atom parameters constrained
Δρ_max = 0.19 e Å⁻³
Δρ_min = −0.15 e Å⁻³

Data collection: SMART (Bruker, 2006 ▶); cell refinement: SAINT (Bruker, 2006 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: PLATON (Spek, 2009) ▶; software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536812019022/bt5889sup1.cif

e-68-o1603-sup1.cif^{(27.1KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812019022/bt5889Isup2.hkl

e-68-o1603-Isup2.hkl^{(208.5KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536812019022/bt5889Isup3.cml

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
N—H10⋯O4ⁱ	0.86	2.16	2.9655 (19)	155
N—H10⋯O5ⁱ	0.86	2.55	3.244 (2)	138
O4—H4⋯O9ⁱⁱ	0.82	1.84	2.6216 (17)	158

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

Acknowledgments

This work was supported by funds from FEDER via the COMPETE (Programa Operacional Factores de Competitividade) programme and by the FCT (Fundação para a Ciência e a Tecnologia; project PEst-C/FIS/UI0036/2011).

supplementary crystallographic information

Comment

Hydroxycinnamic acids and derivatives are known to display relevant antioxidant properties as well as biological activity towards several tumor cells, with their growth-inhibitory potency being strongly dependent on their structural characteristics (Gomes et al., 2003). Despite all the interesting biological effects of hydroxycinnamic acids and despite being dietary components, their bioavailability presents some limitations: although working well in aqueous media, their hydrophilic nature is usually a restriction for lipophilic systems protection (Gao & Hu, 2010). In order to develop new and more effective phenolic agents suitable for chemopreventive and/or chemotherapeutic purposes, hydrosinapic acid derivatives with increased lipophilicity conferred by an additional alkyl chain, were developed. For this, N-hexyl-3-(4-hydroxy-3,5-dimethoxyphenyl)propanamide was synthesized by reaction of the corresponding acid with hexylamine, in the presence of the coupling agent (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (Roleira et al., 2010). Single crystal X-ray measurements evidence normal bond length values for the phenyl ring and its substituents. However the C_sp²–N bond length in the molecule's central chain [1.316 (2) Å] is shorter than the reported average value of 1.334 Å (Allen et al., 1987). Furthermore the average value of the five measured C_sp³–C_sp³ bond lengths of the hexyl chain [1.487 (6) Å] is also significantly shorter then the average reported values (1.524 for CH₂–CH₂ and 1.513 for CH₂–CH₃, Allen et al., 1987). The molecule is characterized by an intramolecular C11–H11A···O9 pseudo-hydrogen bond within the central chain plane (deviation 0.0026 Å). The dihedral angle between this plane and the phenyl one (deviation 0.0545 Å) is 59.89 (5)°, being 64.24 (13)° the corresponding value between the central plane and the one of the hexyl chain (deviation 0.0349 Å). Cohesion of the structure is obtained through an extended newtork of H-bonds. The H atom of the amide group is involved in a bifurcated H-bond towards the hydroxy and one of the methoxy O atoms of the 4-hydroxy-3,5-dimethoxyphenyl substituent of a neignhbour molecule, forming a two dimensional network in the (100) plane. In addition, the same hydroxy group acts as a donnor towards the carbonyl O atom of another neighbour molecule forming chains running along the b axis.

Experimental

The title amide was prepared from the 3-(4-hydroxy-3,5-dimethoxyphenyl)propanoic acid by dissolution of 5 mmol of the acid in 10 ml of DMF followed by the addition of triethylamine (0.7 ml, 5 mmol). The solution was cooled in an ice-water bath and 0.657 ml (5 mmol) of N-hexylamine were added followed by a solution of 2.21 g (5 mmol) of BOP in 10 ml of methylene chloride. The mixture was stirred at 273 K for 30 min and then at room temperature for 30 min. Methylene chloride was removed under reduced pressure and the solution was diluted with 150 ml of water and extracted with ethyl acetate (150 ml). The organic phase was washed successively with 1 N hydrochloride acid (3x100 ml), water (150 ml), 1M NaHCO₃ (3x100 ml), and water (2x100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated, affording a crude material which was purified by crystallization yielding the desired amide. Suitable crystals for X-ray analysis were grown from slow evaporation of ethyl acetate. Mp(ethyl acetate): 366–367 K; IR (ATR) υ_max cm^-1: 3319 (N—H stretch), 1643 (C═O), 1125 (C–O).