ANALYTICAL SCIENCES 2006, VOL. 22 2006 © The Japan Society for Analytical Chemistry
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Synthesis and Crystal Structure of 5-Ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine S. NAVEEN,* Santhosh L. GAONKAR,** BASAPPA,** S. Nanjunda SWAMY,** Sridhar M. ANANDALWAR,*† J. Shashidhara PRASAD,* Kanchugarakoppal S. RANGAPPA** *Department of Studies in Physics, University of Mysore, Mysore 570 006, India **Department of Studies in Chemistry, University of Mysore, Mysore 570 006, India The title compound, C15H16N2O3, was synthesized and the structure was investigated by X-ray crystallography. The compound crystallizes in the orthorhombic space group Pbca with cell parameters a = 17.3530(6)Å, b = 8.158(3)Å, c = 20.482(3)Å, Z = 8. The structure exhibits intermolecular hydrogen bonds of the type C–H·N. (Received June 26, 2006; Accepted September 13, 2006; Published on web November 16, 2006) Pioglitazone, [5-[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]2,4]thiazolidine-dione monohydrochloride, belongs to the class of compounds known as thiazolidinediones, and is used to treat type 2 diabetes mellitus.1 Pioglitazone belongs to a different chemical class and has a different pharmacological action than the sulfonyl ureas, metformin, or the α-glucosidase inhibitors. The compound 5-ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine is the key intermediate for the synthesis of antidiabetic drug pioglitazone, and it is also an intermediate for the synthesis of other biologically active heterocycles. In order to study the structural conformation details, we report herein the synthesis and crystal structure of the title compound. An equimolar mixture of 2-(5-ethylpyridin-2-yl)ethanol (1.5 g, 10 mmol), sodium hydride (0.29 g, 12 mmol) and 1-fluoro-4nitrobenzene (1.41 g, 10 mmol) was stirred at room temperature in dimethylformamide for 10 h to obtain the title compound, which was then crystallized from ethylacetate. M. P. 53˚C. A schematic diagram of the molecule is shown in Fig. 1. A single crystal of the title compound with dimensions 0.3 × 0.27 × 0.25 mm was chosen for an X-ray diffraction study. The data were collected on a DIPLabo Image Plate system equipped with a normal-focus, 3 kW sealed X-ray source (graphite monochromated Mo Kα). The crystal-to-detector distance is fixed at 120 mm with a detector area of 441 × 240 mm2. Thirty six frames of data were collected at room temperature by the oscillation method. Each exposure of the image plate was set to a period of 400 s. Successive frames were scanned in steps of 5˚ per min with an oscillation range of 5˚. Image processing and data reduction were performed using Denzo. The reflections were merged with Scalepack.2 All of the frames could be indexed using a primitive monoclinic lattice. The structure was solved by direct methods using SHELXS-97.3 All the non-hydrogen atoms were revealed in the first Fourier map, itself. A least-squares refinement using SHELXL-973 with
Fig. 1 †
Schematic diagram.
To whom correspondence should be addressed. E-mail:
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isotropic temperature factors for all the non-hydrogen atoms converged the residual R1 to 0.1657. Subsequent refinements were carried out with anisotropic thermal parameters for nonhydrogen atoms. After eight cycles of refinement the residuals converged to 0.0725. The hydrogen atoms were fixed at chemically acceptable positions and were allowed to ride on their parent atoms. The details of the crystal data and refinement are given in Table 1. The final atomic coordinates and the equivalent thermal parameters for all non-hydrogen atoms are given in Table 2.
Table 1
Crystal data and structure refinement table
Empirical formula Formula weight Temperature Wavelength Crystal system Space group Cell dimensions
Volume Z Dc Absorption coefficient F000 θ max Reflections collected Independent reflections Absorption correction Refinement method Data/restraints/parameters Goodness-of-fit on F2 Final R indices [I > 2σ (I)] R indices (all data) (∆/σ )max (∆ρ )max (∆ρ )min Refinement method Measurement Program system Structure determination Refinement CCDC 611372
C15H16N2O3 272.30 293(2)K 0.71073 Å orthorhombic Pbca a = 17.3530(6)Å b = 8.158(3)Å c = 20.482(3)Å 2899.6(11)Å3 8 1.248 Mg/m3 0.088 mm–1 1152 25.02˚ 4056 2280 [R(int) = 0.0214] none full-matrix least-squares on F2 2280/0/183 1.063 R1 = 0.0725, wR2 = 0.2234 R1 = 0.1049, wR2 = 0.2666 0.000 0.418 e.Å–3 –0.225 e.Å–3 full-matrix least-squares on F2 DIPLabo Denzo SHELXS-97 full-matrix: SHELXL-97
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Table 2 Atomic coordinates and parameters of the non-hydrogen atoms Atom
x
equivalent
y
thermal
z
Ueq
Fig. 2
ORTEP diagram of the molecule at 30% probability.
Ueq = (1/3)ΣiΣjUij(ai*aj*)(ai·aj).
Table 3 Atoms
Selected bond lengths (Å) and bond angles (˚) Length
Atoms
Length
Fig. 3 Packing diagram of the molecules when viewed down the b axis. The dotted lines represent intermolecular hydrogen bonds.
C12–O11–C10–C9 and O11–C10–C9–C6, respectively. The O11–C10 bond is nearly coplanar with the benzene ring, whereas the C9–C10 bond deviates markedly from the plane of the pyridine ring, as indicated by the torsion angle values of –6.21(49)˚ and 66.87˚ respectively for C13–C12–O11–C10 and These values are comparable with the N5–C6–C9–C10. corresponding values reported earlier.4 The intermolecular C–H·N contact is found between the nitrophenyl ring and the pyridyl ring. The molecules form hydrogen bonded dimers [Fig. 3]. The intermolecular hydrogen bond between the pyridine ring and the nitrophenyl moiety has a length of 3.471(5)Å and an angle of 167˚ with symmetry code –x, –1/2 + y, 1/2 – z.
Acknowledgements The bond lengths and angles of all the non-hydrogen atoms are given in Table 3, which are in good agreement with the standard values. Due to the large thermal motion of the ethyl group, the bond distances (C3–C7 (1.62 Å) and C7–C8 (1.31 Å)) are not normal for a single bond. Figure 2 represents an ORTEP diagram of the molecule with thermal ellipsoids drawn at 30% probability. The dihedral angle between the phenyl ring and the pyridine ring is 83.2(2)˚. This value is large when compared with the corresponding value of 74.80(5)˚ reported for 4-[2-(5The ethyl ethylpyridin-2-yl)ethoxy]benzaldehyde oxime.4 group is orthogonal to the pyridine ring, as indicated by the torsion angle of 95.11(10)˚ for C2–C3–C7–C8. The nitro group appears to be coplanar with the benzene ring plane as indicated by the torsion angle values of –2.87(55)˚ and 0.13(52)˚ for C14–C15–N18–O20 and C16–C15–N18–O19, respectively. The O11–C10 bond is in an synclinal conformation, while the C9–C10 bond is in an antiperiplanar conformation, as indicated by the torsion angle values of 58.97(41)˚ and 177.38(30)˚ for
We are grateful to CSIR, New Delhi for the financial support under the project 01(1904)/03/EMRII and DST, Government of India for the financial assiatance under the project SP/I2/FOO/93.
References 1. W. Z. Zhong and D. B. Lakings, J. Chromatogr., 1990, 490, 377. 2. S. Mackay, C. J. Gilmore, C. Edwards, N. Stewart, and K. Shankland, 1999, maXus Computer Program for the Solution and Refinement of Crystal Structures., Bruker Nonius, The Netherlands, MacScience, Japan and The University of Glasgow. 3. G. M. Sheldrick, (SHELXS-97, SHELXL-97), 1997, University of Göttingen, Germany. 4. S. L. Gaonkar, H. S. Yathirajan, K. M. Lokanatharai, B. Nagaraj, and M. Bolte, Acta Cryst., 2005, E61, o751.
