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Volume 70 
Part 2 
Pages 236-240  
February 2014  

Received 4 October 2013
Accepted 6 January 2014
Online 31 January 2014

C-H...O and C-H...N inter­actions in three hexa­hydro­cyclo­octa­[b]pyridine-3-carbo­nitriles

aDepartment of Physics, Madura College, Madurai 625 011, India, and bDepartment of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
Correspondence e-mail: ambujasureshj@yahoo.com

The structures of three new pyridine derivatives, 2-meth­oxy-4-(4-meth­oxy­phenyl)-5,6,7,8,9,10-hexa­hydro­cyclo­octa­[b]pyridine-3-carbo­nitrile, C20H22N2O2, (I), 2-eth­oxy-4-(3-nitrophenyl)-5,6,7,8,9,10-hexa­hydro­cyclo­octa­[b]pyridine-3-carbonitrile, C20H21N3O3, (II), and 2-eth­oxy-4-(4-meth­oxy­phenyl)-5,6,7,8,9,10-hexa­hydro­cyclo­octa­[b]pyridine-3-carbo­nitrile, C21H24N2O2, (III), differ in the nature of the substituents either at the 2-position of the central pyridine ring or on the pendent aryl ring. This simple change in the structure substantially alters the inter­molecular inter­action patterns. The substituted phenyl group adopts a synclinal geometry with respect to the plane of the pyridine ring in all three compounds. In (I), a C-H...N inter­action results in a one-dimensional chain parallel to the b axis. In (II), there are two C-H...N(nitrile) inter­actions from different symmetry-related mol­ecules, resulting in a two-dimensional network parallel to the bc plane. There is also a weak C-H...O inter­action from the eth­oxy group to an adjacent nitro O atom. The present work is an example of how the simple replacement of a substituent in the main mol­ecular scaffold may transform the structure type, paving the way for a variety of supra­molecular motifs and consequently altering the complexity of the inter­molecular inter­action patterns.

1. Introduction

The title compounds, (I)[link]-(III)[link], belong to the cyclo­alkeno­pyridine class of compounds. It has been observed that many naturally occurring biologically active compounds feature a cyclo­alkeno­pyridine fragment as the basic skeleton. This observation prompted the development of a range of synthetic methods to prepare pharmaceuticals and agrochemicals containing the cyclo­alkeno­pyridine unit as an important building block (Thummel, 2008[Thummel, R. P. (2008). Carbocyclic Annelated Pyridines. In Chemistry of Heterocyclic Compounds: Pyridine and its Derivatives, edited by G. R. Newkome, Part 5, Vol. 14. Hoboken, New Jersey: John Wiley & Sons Inc.]). The synthesis of hydrogenated compounds has been extensively studied due to their inter­esting biological properties. For example, derivatives of 1,4-di­hydro­pyridine exhibit high biological activities as calcium channel blockers (Bossert et al., 1981[Bossert, F., Meyer, H. & Wehinger, E. (1981). Angew. Chem. Int. Ed. Engl. 20, 762-764.]) and as calcium agonists or antagonists (Triggle et al., 1980[Triggle, A. M., Shefter, E. & Triggle, D. G. (1980). J. Med. Chem. 23, 1442-1445.]; Kokubun & Reuter, 1984[Kokubun, S. & Reuter, H. (1984). Proc. Natl Acad. Sci. USA, 81, 4824-4827.]; Bossert & Vater, 1989[Bossert, F. & Vater, W. (1989). Med. Res. Rev. 9, 291-324.]; Wang et al., 1989[Wang, S. D., Herbette, L. G. & Rhodes, D. G. (1989). Acta Cryst. C45, 1748-1751.]; Alajarin et al., 1995[Alajarin, R., Vaquero, J. J., Alvarez-Builla, J., Pastor, M., Sunkel, C., de Casa- Juana, M. F., Priego, J., Statkow, P. R., Sanz-Aparicio, J. & Fonseca, I. (1995). J. Med. Chem. 38, 2830-2841.]). Cyclo­octane compounds exhibit moderate to high anti­bacterial and anti­fungal effects against pathogenic microorganisms. For example, 2-[(4-sulfonamido­phenyl)methyl­idene]cyclo­octanone has excellent activity against Listeria monocytogenes (Korany et al., 2012[Korany, A. A., Hanaa, M. H., Eman, A. R. & Sherein, I. A. (2012). Arch. Pharm. Chem. Life Sci. 345, 231-239.]). The above observations prompted us to synthesize the title compounds containing cyclo­alkeno­pyridine carbo­nitrile groups and substituted pyridine scaffolds and to determine their crystal structures.

[Scheme 1]
[Figure 1]
Figure 1
The mol­ecular structure of (I)[link], showing 30% probability displacement ellipsoids and the atom-numbering scheme.
[Figure 2]
Figure 2
The mol­ecular structure of (II)[link], showing 30% probability displacement ellipsoids and the atom-numbering scheme.
[Figure 3]
Figure 3
The mol­ecular structure of (III)[link], showing 30% probability displacement ellipsoids and the atom-numbering scheme. The minor disorder components of atoms C4 (C4') and C5 (C5') are indicated by dashed lines.
[Figure 4]
Figure 4
A partial packing view of (I)[link]. A pair of mol­ecules are inter­connected through a [pi]-[pi] stacking inter­action (dotted lines) and further linked through a C-H...N inter­action (dashed lines), generating C(7) chain motifs. [Symmetry codes: (i) x + 1, y, z; (ii) -x, -y, -z + 1.]
[Figure 5]
Figure 5
A partial packing view of (II)[link]. Two C-H...N inter­actions are shown, one forming an inversion-related dimer generating an R22(18) motif [symmetry code: (ii) -x, -y + 1, -z] and the other linked by a C(7) motif [symmetry code: (i) -x, y - [{1\over 2}], -z + [{1\over 2}]]. A C14-H14B...O2 inter­action forms a C(12) motif that lies along the c axis of the unit cell [symmetry code: (iii) x, y, z + 1].
[Figure 6]
Figure 6
A partial packing view of (III)[link]. A C97-H97A...O2ii inter­action (dashed lines) generates an R22(6) ring motif [symmetry code: (ii) -x - 1, -y + 1, -z + 1]. A C92-H92...O1i inter­action (dashed lines) forms a C(7) motif that lies along the a axis of the unit cell [symmetry code: (i) x - 1, y, z].

2. Experimental

2.1. Synthesis and crystallization

The solvent used in the reaction is incorporated in the product at position 2 of the pyridine ring. In (I)[link], methanol was used, whereas in (II)[link] and (III)[link], ethanol was the solvent.

The general reaction procedure is as follows. A mixture of cyclo­octanone (1 mmol), 4-meth­oxy­benzaldehyde or 3-nitro­benzaldehyde (1 mmol), malono­nitrile (1 mmol) and lithium ethoxide (1 equivalent) was heated under reflux in methanol or ethanol (10 ml) for 2-3 h. After completion of the reaction, as evidenced by thin-layer chromatography, the reaction mixture was poured into crushed ice and the resultant precipitate was extracted with ethyl acetate. The excess solvent was removed under vacuum and the residue was subjected to column chromatography using a petroleum ether-ethyl acetate mixture (95:5 v/v) as eluent to obtain the pure products. For (I)[link], yield 74%, m.p. 460-461 K; for (II)[link], yield 64%, m.p. 394-396 K; for (III)[link], yield 65%, m.p. 399-400 K.

2.2. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 1[link]. H atoms were placed at calculated positions and allowed to ride on their carrier atoms, with C-H = 0.93-0.98 Å, and with Uiso = 1.5Ueq(C) for methyl H atoms or 1.2Ueq(C) otherwise. In (III)[link], atoms C4 and C5 of the cyclo­octane ring are each disordered over two sites and were refined with site-occupancy factors of 0.652 (9) and 0.348 (9) for the major and minor components, respectively.

3. Results and discussion

In the mol­ecular structures of (I)[link] (Fig. 1[link]), (II)[link] (Fig. 2[link]) and (III)[link] (Fig. 3[link]), the cyclo­octane rings adopt a twist-boat-chair conformation, as found in related structures (Xiong et al., 2007[Xiong, Y., Gao, W.-Y., Deng, K.-Z., Chen, H.-X. & Wang, S.-J. (2007). Acta Cryst. E63, o333-o334.]; Fun et al., 2010[Fun, H.-K., Yeap, C. S., Ragavan, R. V., Vijayakumar, V. & Sarveswari, S. (2010). Acta Cryst. E66, o3019.]; Suresh et al., 2007[Suresh, J., Suresh Kumar, R., Perumal, S. & Natarajan, S. (2007). Acta Cryst. C63, o538-o542.]).

The bond lengths and angles of the phenyl rings of (I)[link]-(III)[link] are consistent with those observed in similar structures (Patel et al., 2002a[Patel, U. H., Dave, C. G., Jotani, M. M. & Shah, H. C. (2002a). Acta Cryst. C58, o191-o192.],b[Patel, U. H., Dave, C. G., Jotani, M. M. & Shah, H. C. (2002b). Z. Kristallogr. New Cryst. Struct. 217, 29-31.],c[Patel, U. H., Dave, C. G., Jotani, M. M. & Shah, H. C. (2002c). Z. Kristallogr. New Cryst. Struct. 217, 32-34.]; Black et al., 1992[Black, S. N., Davey, R. J., Slawin, A. M. Z. & Williams, D. J. (1992). Acta Cryst. C48, 323-325.]; Hussain et al., 1996[Hussain, Z., Fleming, F. F., Norman, R. E. & Chang, S.-C. (1996). Acta Cryst. C52, 1010-1012.]). The deviations of the nitrile atoms (C12 and N2) from the mean plane of the pyridine ring system (N1/C1/C8-C11) are -0.0422 (1) and -0.0896 (5) Å, respectively, in (I)[link], -0.0081 (5) and -0.0416 (2) Å, respectively, in (II)[link], and -0.0624 (4) and -0.1038 (1) Å, respectively, in (III)[link], indicative of coplanarity.

The phenyl substituent at C9 of the pyridine ring has a (+)synclinal conformation in (I)[link], a (+)anticlinal conformation in (II)[link] and a (-)synclinal conformation in (III)[link], which is evidenced by the C96-C91-C9-C10 torsion angles (see Tables 2[link], 3[link] and 4[link]). The C10-C12 (Csp2-Csp) bonds in (I)[link]-(III)[link] tend towards aromatic bond lengths (see Table 1[link]) rather than a [sigma] bond length (~1.50 Å), presumably due to conjugation. However, the C12[triple bond]N2 bond lengths in (I)[link]-(III)[link] are apparently normal. The meth­oxy group in (I)[link] and the eth­oxy groups in (II)[link] and (III)[link] are coplanar with the plane of the attached pyridine ring, as can be seen from the values of the C10-C11-O1-C13 and N1-C11-O1-C13 torsion angles. These torsion angles are similar to those in related structures (Ramesh, Subbiahpandi et al., 2009[Ramesh, P., Subbiahpandi, A., Thirumurugan, P., Perumal, P. T. & Ponnuswamy, M. N. (2009). Acta Cryst. E65, o450.]; Ramesh, Sundaresan et al., 2009[Ramesh, P., Sundaresan, S. S., Thirumurugan, P., Perumal, P. T. & Ponnuswamy, M. N. (2009). Acta Cryst. E65, o996-o997.]).

There are phenyl-nitrile C-H...N inter­actions within the extended structures of (I)[link] and (II)[link] that are not present in (III)[link]. This inter­action results in a chain with a graph-set motif of C(7) (Bernstein et al., 1995[Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555-1573.]) (Figs. 4[link] and 5[link]). The C92...N2i distance in (II)[link] is noticeably lengthened compared with the analogous contact in (I)[link] [see Tables 5[link], 6[link] and 7[link]; symmetry code: (i) -x, y - [{1\over 2}], -z + [{1\over 2}]]. The C-N contact in (II)[link] is considered as a hydrogen bond despite the long donor-acceptor distance, because the interaction is nearly linear.

The hydrogen-bonded chains in (I)[link] are crosslinked through a [pi]-[pi] stacking interaction, Cg1...Cg1ii (Cg1 is the centroid of the pyridine ring) (Fig. 4[link]), with a centroid-centroid separation of 3.7526 (2) Å [symmetry code: (ii) -x, -y, -z + 1].

In the crystal structure of (II)[link] (Fig. 5[link]), atom C94 of the nitro­phenyl ring is involved in a weak inter­molecular C94...H94...N2ii inter­action with cyano atom N2 of an inversion-related mol­ecule, forming a hydrogen-bonded dimer and generating an R22(18) graph-set motif; these motifs are in turn linked through a C92-H92...N2i inter­action [symmetry codes: (i) -x, y - [{1\over 2}], -z + [{1\over 2}]; (ii) -x, -y + 1, -z]. Meth­oxy atom C14 is involved in a C14-H14...O2iii inter­action with nitro atom O2 of a symmetry-related mol­ecule, generating a continuous parallel double chain with graph-set motif C(12) [symmetry code: (iii) x, y, z + 1].

The crystal structure of (III)[link] (Fig. 6[link]) has intra­molecular C-H...O inter­actions. An inter­molecular C97-H97A...O2ii inter­action links inversion-related mol­ecules into an aggregate, forming an R22(6) ring motif [symmetry code: (ii) -x - 1, -y + 1, -z + 1]. An inter­molecular C92-H92...O1i inter­action forms a chain pattern running along the a axis generating a C(7) graph-set motif [symmetry code: (i) x - 1, y, z].

Table 1
Experimental details

  (I) (II) (III)
Crystal data
Chemical formula C20H22N2O2 C20H21N3O3 C21H24N2O2
Mr 322.40 351.40 336.42
Crystal system, space group Monoclinic, P21/n Monoclinic, P21/c Monoclinic, P21/c
Temperature (K) 293 293 293
a, b, c (Å) 9.1018 (3), 13.6319 (4), 13.5920 (4) 13.2948 (6), 11.0251 (4), 14.0788 (5) 6.9763 (4), 17.8163 (8), 14.9545 (8)
[beta] (°) 93.545 (2) 117.566 (2) 96.751 (2)
V3) 1683.20 (9) 1829.36 (12) 1845.83 (17)
Z 4 4 4
Radiation type Mo K[alpha] Mo K[alpha] Mo K[alpha]
[mu] (mm-1) 0.08 0.09 0.08
Crystal size (mm) 0.24 × 0.22 × 0.20 0.21 × 0.20 × 0.19 0.23 × 0.21 × 0.18
 
Data collection
Diffractometer Bruker Kappa APEXII area-detector diffractometer Bruker Kappa APEXII area-detector diffractometer Bruker Kappa APEXII are-detector diffractometer
Absorption correction Multi-scan (SADABS; Sheldrick, 1996[Sheldrick, G. M. (1996). SADABS. University of Göttingen, Germany.]) Multi-scan (SADABS; Sheldrick, 1996[Sheldrick, G. M. (1996). SADABS. University of Göttingen, Germany.]) Multi-scan (SADABS; Sheldrick, 1996[Sheldrick, G. M. (1996). SADABS. University of Göttingen, Germany.])
Tmin, Tmax 0.983, 0.984 0.980, 0.984 0.982, 0.986
No. of measured, independent and observed [I > 2[sigma](I)] reflections 14067, 3312, 2605 16156, 3399, 2571 17391, 3433, 2330
Rint 0.028 0.030 0.034
(sin [theta]/[lambda])max-1) 0.617 0.606 0.606
 
Refinement
R[F2 > 2[sigma](F2)], wR(F2), S 0.036, 0.106, 1.04 0.043, 0.130, 1.07 0.044, 0.124, 1.01
No. of reflections 3312 3399 3432
No. of parameters 220 236 247
H-atom treatment H-atom parameters constrained H-atom parameters constrained H atoms treated by a mixture of independent and constrained refinement
[Delta][rho]max, [Delta][rho]min (e Å-3) 0.17, -0.13 0.30, -0.23 0.16, -0.14
Computer programs: APEX2 (Bruker, 2004[Bruker (2004). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]), SAINT (Bruker, 2004[Bruker (2004). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]), SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]), SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]) and PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]).

Table 2
Selected geometric parameters (Å, °) for (I)[link]

C10-C12 1.4306 (18) C12-N2 1.1441 (17)
       
C10-C9-C91-C96 66.95 (16) C10-C11-O1-C13 178.97 (12)
N1-C11-O1-C13 -1.54 (18)    

Table 3
Selected geometric parameters (Å, °) for (II)[link]

C10-C12 1.434 (2) C12-N2 1.135 (2)
       
C96-C91-C9-C10 92.78 (18) C10-C11-O1-C13 174.34 (17)
N1-C11-O1-C13 -5.4 (3)    

Table 4
Selected geometric parameters (Å, °) for (III)[link]

C10-C12 1.428 (2) C12-N2 1.139 (2)
       
C96-C91-C9-C10 -76.2 (2) C13-O1-C11-C10 174.85 (15)
C13-O1-C11-N1 -3.9 (2)    

Table 5
Hydrogen-bond geometry (Å, °) for (I)[link]

D-H...A D-H H...A D...A D-H...A
C92-H92...N2i 0.93 2.75 3.490 (2) 138
Symmetry code: (i) [-x+{\script{1\over 2}}, y+{\script{1\over 2}}, -z+{\script{1\over 2}}].

Table 6
Hydrogen-bond geometry (Å, °) for (II)[link]

D-H...A D-H H...A D...A D-H...A
C92-H92...N2i 0.93 2.72 3.644 (2) 172
C94-H94...N2ii 0.93 2.68 3.508 (2) 148
C14-H14B...O2iii 0.96 2.57 3.468 (3) 155
Symmetry codes: (i) [-x, y-{\script{1\over 2}}, -z+{\script{1\over 2}}]; (ii) -x, -y+1, -z; (iii) x, y, z+1.

Table 7
Hydrogen-bond geometry (Å, °) for (III)[link]

D-H...A D-H H...A D...A D-H...A
C92-H92...O1i 0.93 2.72 3.559 (2) 150
C97-H97A...O2ii 0.96 2.76 3.324 (2) 118
Symmetry codes: (i) x-1, y, z; (ii) -x-1, -y+1, -z+1.

Supporting information for this paper is available from the IUCr electronic archives (Reference: OV3043 ).


Acknowledgements

JS and RV thank the management of Madura College for their encouragement and support. RRK thanks DST, New Delhi, for funds under the Fast Track Scheme (No. SR/FT/CS-073/2009).

References

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Acta Cryst (2014). C70, 236-240   [ doi:10.1107/S2053229614000291 ]