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Acta Crystallogr C. 2009 April 15; 65(Pt 4): o155–o159.
Published online 2009 March 18. doi:  10.1107/S0108270109008336
PMCID: PMC2665971

From small structural modifications to adjustment of structurally dependent properties: 1-methyl-3,5-bis­[(E)-2-thienyl­idene]-4-piperidone and 3,5-bis­[(E)-5-bromo-2-thienyl­idene]-1-methyl-4-piperidone

Abstract

The mol­ecules of the title compounds, C16H15NOS2, (I), and C16H13Br2NOS2, (II), are E,E-isomers and consist of an extensive conjugated system, which determines their mol­ecular geometries. Compound (I) crystallizes in the monoclinic space group P21/c. It has one thio­phene ring disordered over two positions, with a minor component contribution of 0.100 (3). Compound (II) crystallizes in the noncentrosymmetric ortho­rhom­bic space group Pca21 with two independent mol­ecules in the unit cell. These mol­ecules are related by a noncrystallographic pseudo-inversion center and possess very similar geometries. The crystal packings of (I) and (II) have a topologically common structural motif, viz. stacks along the b axis, in which the mol­ecules are bound by weak C—H(...)O hydrogen bonds. The noncentrosymmetric packing of (II) is governed by attractive inter­molecular Br(...)Br and Br(...)N inter­actions, which are also responsible for the very high density of (II) (1.861 Mg m−3).

Comment

Cross-conjugated dienones of the bis-aryl­idenecyclo­alkanone series and related piperidones have recently attracted considerable attention. These compounds are used in the construction of different polymers (Yakimansky et al., 2002 [triangle]; Aly et al., 2003 [triangle]), and in the design of crystals with nonlinear optical (Kishore & Kishore, 1993 [triangle]; Kawamata et al., 1995 [triangle], 1996 [triangle]; Sarkisov et al., 2005 [triangle]) and fluorescent (Nesterov et al., 2003 [triangle], 2008 [triangle]) properties. Furthermore, it is well known that they possess a variety of biological activities, such as anti­viral (El-Subbagh et al., 2000 [triangle]), anti­bacterial (Lyrand et al., 1999 [triangle]; Amal Raj et al., 2003 [triangle]) and anti­phlogistic activity (Rovnyak et al., 1982 [triangle]).

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Object name is c-65-0o155-scheme1.jpg

Recently, instead of aryl substituents, the use of heterocyclic ligands was suggested, as these are able to bind important metal cations to form diverse coordination associates (Vatsadze et al., 2006 [triangle]). However, to our knowledge, there are very few structurally characterized compounds of this type in the literature (Vatsadze et al., 2006 [triangle]). In this paper, we describe two new cross-conjugated piperidones with thienyl­idene substituents in the side chains, namely 1-methyl-3,5-bis­[(E)-2-thienyl­idene]-4-piperidone, (I), and 3,5-bis­[(E)-5-bromo-2-thienyl­idene]-1-methyl-4-piperidone, (II), which represent modified analogs of the recently reported compounds 2,6-bis­[(2-thienyl)methyl­idene]cyclo­hexa­none, (III) (Vatsadze et al., 2006 [triangle]), and 2,6-bis­[(5-methyl­thio­phene-2-yl)methyl­ene]­cyclo­hexa­none, (IV) (Liang et al., 2007 [triangle]) (see scheme above). One purpose of our investigation was to analyze the influence of small structural modifications of the mol­ecules on their structurally dependent properties. It should be noted that these compounds are potential anti­tumor (anti­cancer) agents (Dimmock et al., 1992 [triangle], 1994 [triangle], 2001 [triangle]), and even small differences in the structures may cause significant changes in their biological activity.

Compound (I) crystallizes in the monoclinic space group P21/c. One thio­phene ring is disordered over two positions related by a 180° rotation about the C6—C7 bond. The minor component contribution refined to 0.100 (3) (Fig. 1 [triangle]).

Figure 1
The mol­ecular structure of (I), showing the atom-numbering scheme. The alternative position of the disordered thio­phene ring is drawn with open lines. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown ...

In general, the linear structure of conjugated bonds is the more favorable, and deviations from this rule are usually a result of specific reasons such as steric factors, hydrogen bonds and different attractive inter­actions. Quantum-chemical calculations using the density functional theory method of the GAUSSIAN03 program, B3LYP functional, 6-31G* basis set (Frisch et al., 2003 [triangle]), also show that the minimum of the potential energy surface corresponds to the major conformer (conformer A) found experimentally in the crystal structure of (I) (see Fig. 3 [triangle]). Although the energy differences between the three conformers, denoted A, B and C, are not large, there is a clear trend for compounds with larger deviations of the conjugated bonds from the linear structure to be less stable. In the crystal structure of (I), the presence of the minor conformer B may be explained by the weak inter­molecular C6—H6A(...)S1′(1 − x, −y, −z) hydrogen bond [C6(...)S1′ = 3.487 (2) Å, H6A(...)S1′ = 2.78 Å and C6—H6A(...)S1′ = 132°].

Figure 3
The minimum potential energies found experimentally for conformers A (top; ΔE = 0 kcal mol−1; 1 kcal mol−1 = 4.184 kJ mol−1), B (middle; ΔE = 0.68 kcal mol ...

Compound (II) crystallizes in the noncentrosymmetric ortho­rhom­bic space group Pca21, with two independent mol­ecules, A and B, in the unit cell (Fig. 2 [triangle]). However, in the crystal structure, mol­ecules A and B are related by a noncrystallographic pseudo-inversion center with coordinates [0.3045 (2), 0.7536 (6), 0.5553 (2)]. Consequently, mol­ecules A and B possess very similar geometries (Fig. 4 [triangle]), and only the average values of the geometric parameters of (II) are discussed below.

Figure 2
The mol­ecular structure of (II), showing the atom-numbering scheme. The two independent mol­ecules, A and B, related by a noncrystallographic pseudo-inversion center, are depicted. Displacement ellipsoids are drawn at the 50% probability ...
Figure 4
A comparison of the conformations of mol­ecules A (solid lines) and B (dashed lines) in (II).

In the mol­ecules of both compounds, the central piperidone ring adopts a flattened boat conformation; atoms N1 and C1 lie 0.702 (1) and 0.242 (1) Å in (I), and 0.699 (3) and 0.158 (3) Å in (II), respectively, out of the C2/C3/C4/C5 plane. Atom N1 of the heterocycle has pyramidal coordination, as revealed by the sums of the bond angles about this atom of 332.6 (2)° in (I) and 330.2 (3)° in (II). The methyl group occupies the more sterically favored equatorial position.

Both (I) and (II) contain three planar fragments. The first of these includes the plane of the piperidone ring (atoms C1–C5; PA), while the planar fragments PB [S1/C6–C10 in (I) and Br1/S1/C6–C10 in (II)] and PC [S2/C11–C15 in (I) and Br2/S2/C11–C15 in (II)] include a thio­phene ring and adjacent atoms. The dihedral angles PA/PB, PA/PC and PB/PC between these fragments are 13.2 (1), 17.0 (1) and 27.4 (1)°, respectively, in (I), and 10.9 (3), 13.9 (3) and 23.4 (3)° in (II).

The mol­ecules of (I) and (II) can exist as E,E-, Z,E- and Z,Z-isomers (see scheme below; Th denotes thiophene). Evidently, the E,E-isomers observed for (I) and (II), both in the solid state and in solution (see 1H NMR data in Experimental), are preferred because of steric reasons. Nevertheless, they may undergo isomerization into the Z,E- and Z,Z-isomers in solution upon irradiation with visible light (Vatsadze et al., 2006 [triangle]).

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Object name is c-65-0o155-scheme2.jpg

Inter­estingly, the introduction of the Br atoms in the thio­phene rings of (II) does not give rise to significant changes to its mol­ecular geometry compared with that of (I). Moreover, their structural features are similar to those of compounds (III) and (IV). It is surprising that, despite the presence of a bulkier N—CH3 fragment on the central piperidone ring compared with a CH2 fragment, compounds (I) and (III) are isostructural. These findings allow us to propose that the mol­ecular structures of compounds (I)–(IV), as well as the crystal structures of compounds (I) and (III), are defined by similar effects.

The mol­ecular geometries of compounds (I)–(IV) are determined by an extensive conjugated system that is quite stable to the influence of substituents of different types. For this reason, neither the introduction of simple substituents (methyl and halide) to peripheral parts, nor the replacement of one fragment on the saturated part of the central piperidone cycle by another of comparable dimensions, can alter its structure substanti­ally. Thus, any small modifications of compounds containing analogous systems will mainly affect their mol­ecular arrangement (or their crystal packing in the case of the solid state), and, consequently, their chemical properties as a whole.

In the case of dibenzyl­idene­cyclo­alkanones, it has previously been established that inter­molecular C—H(...)O hydrogen bonds between the carbonyl O atom and a H atom of the methyl­ene groups of the central ring are an important factor in the design of crystals with nonlinear optical properties (Kawamata et al., 1998 [triangle]). These hydrogen-bonding interactions possibly contribute to the isostructurality of (I) and (III). The topologically common structural motif (stacks along the b axis, in which the mol­ecules are bound by C—H(...)O hydrogen bonds) is also maintained in the crystal structures of (II) and (IV) (Table 1). However, in the crystal structure of (IV), the stacks are shifted relative to each other compared with the crystal structures of (I) and (III), due to the presence of additional peripheral methyl groups, resulting in the space group P21/n.

It is very important to note that the crystal packing of the mol­ecules of (I), (III) and (IV) is centrosymmetric. However, in order for any compound to display nonlinear optical properties, its crystal packing should be noncentrosymmetric. To this end, we decided to use the well known attractive inter­molecular halogen–halogen (Desiraju & Parthasarathy, 1989 [triangle]; Price et al., 1994 [triangle]; Saha et al., 2006 [triangle]) and halogen–nitro­gen inter­actions (Desiraju & Harlow, 1989 [triangle]; Lucassen et al., 2007 [triangle]). It was suggested that, owing to these inter­actions, the introduction of Br atoms at the peripheral positions of the thio­phene rings of (III) does not destroy its common structural motif, but results in a shift of the stacks in such a manner that the crystal packing of the compound loses the crystallographic inversion center. Indeed, compound (II) has a noncentrosymmetric crystal structure (see above), while the common structural motif is preserved.

The inter­molecular Br(...)Br [Br1A(...)Br2B(An external file that holds a picture, illustration, etc.
Object name is c-65-0o155-efi1.jpg − x, 1 + y, An external file that holds a picture, illustration, etc.
Object name is c-65-0o155-efi1.jpg + z) = 3.591 (2) Å] and Br(...)N [Br1A(...)N1B(1 − x, 2 − y, An external file that holds a picture, illustration, etc.
Object name is c-65-0o155-efi1.jpg + z) = 3.168 (4) Å] inter­actions result in a very high density for (II) (1.861 Mg m−3), even among bromine-containing compounds. The average crystal density of bromine-containing organic compounds with short Br(...)Br contacts is 1.75 (2) Mg m−3 [184 hits; Cambridge Structural Database (Allen, 2002 [triangle]), 2009 release], but without such contacts the density is lower, at 1.619 (6) Mg m−3 (1137 hits). The crystal packing of (II) is presented in Fig. 5 [triangle].

Figure 5
A packing diagram of (II), viewed along the b axis. Dashed lines indicate inter­molecular attractive Br(...)Br and Br(...)N inter­actions. H atoms have been omitted for clarity.

Comparison of the structures of (I) and (II) with analogous compounds has shown that their mol­ecules are similar to piperidones used as anti­cancer agents (Das et al., 2007 [triangle]). Their combination of remarkable features suggests potential application of these compounds as agents for cancer treatment.

Experimental

For the preparation of (I), a mixture of 1-methyl-4-piperidone (1.13 g, 0.01 mol) and thio­phene-2-carbaldehyde (2.24 g, 0.02 mol) was treated with alcoholic NaOH (50 ml, 10%) and stirred at room temperature for 30 min. The crude product was filtered and recrystallized from ethanol to give yellow plate-like crystals of (I) (yield 2.41 g, 80%; m.p. 385–387 K). 1H NMR (CDCl3, 300 MHz): δ 7.89 [s, 2H, CH (vinyl)], 7.11–7.52 [m, 6H, CH (thio­phene)], 3.76 (s, 4H, CH2), 2.55 (s, 3H, CH3).

For the preparation of (II), a mixture of 1-methyl-4-piperidone (1.13 g, 0.01 mol) and 5-bromothio­phene-2-carbaldehyde (3.82 g, 0.02 mol) was treated with alcoholic NaOH (50 ml, 10%) and stirred at room temperature for 30 min. The crude product was filtered and recrystallized from methanol to give pink needle-like crystals of (II) (yield 4.32 g, 94%; m.p. 422–423 K). 1H NMR (300 MHz, CDCl3): δ 7.74 [s, 2H, CH (vinyl)], 7.04–7.09 [m, 4H, CH (thio­phene)], 3.67 (s, 4H, CH2), 2.56 (s, 3H, CH3).

Compound (I)

Crystal data

  • C16H15NOS2
  • M r = 301.41
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is c-65-0o155-efi4.jpg
  • a = 15.108 (5) Å
  • b = 12.609 (4) Å
  • c = 7.523 (2) Å
  • β = 93.962 (4)°
  • V = 1429.8 (8) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 0.37 mm−1
  • T = 100 K
  • 0.55 × 0.24 × 0.12 mm

Data collection

  • Bruker APEXII CCD diffractometer
  • Absorption correction: multi-scan (SADABS; Sheldrick, 2003 [triangle]) T min = 0.824, T max = 0.957
  • 14615 measured reflections
  • 3779 independent reflections
  • 2841 reflections with I > 2σ(I)
  • R int = 0.057

Refinement

  • R[F 2 > 2σ(F 2)] = 0.049
  • wR(F 2) = 0.121
  • S = 1.01
  • 3779 reflections
  • 188 parameters
  • 24 restraints
  • H-atom parameters constrained
  • Δρmax = 0.51 e Å−3
  • Δρmin = −0.49 e Å−3

Compound (II)

Crystal data

  • C16H13Br2NOS2
  • M r = 459.21
  • Orthorhombic, An external file that holds a picture, illustration, etc.
Object name is c-65-0o155-efi5.jpg
  • a = 23.222 (3) Å
  • b = 5.8840 (7) Å
  • c = 23.994 (3) Å
  • V = 3278.6 (7) Å3
  • Z = 8
  • Mo Kα radiation
  • μ = 5.20 mm−1
  • T = 100 K
  • 0.50 × 0.30 × 0.20 mm

Data collection

  • Bruker APEXII CCD diffractometer
  • Absorption correction: multi-scan (SADABS; Sheldrick, 2003 [triangle]) T min = 0.111, T max = 0.353
  • 49136 measured reflections
  • 10192 independent reflections
  • 7285 reflections with I > 2σ(I)
  • R int = 0.099

Refinement

  • R[F 2 > 2σ(F 2)] = 0.054
  • wR(F 2) = 0.122
  • S = 1.02
  • 10192 reflections
  • 400 parameters
  • 1 restraint
  • H-atom parameters constrained
  • Δρmax = 1.48 e Å−3
  • Δρmin = −1.20 e Å−3
  • Absolute structure: Flack (1983 [triangle]), with 4954 Friedel pairs
  • Flack parameter: 0.347 (7)

H atoms were placed in calculated positions and refined in the riding model, with C—H = 0.95–0.99 Å and U iso(H) = 1.5U eq(C) for CH3 groups or 1.2U eq(C) for other groups.

20 distance restraints were used to fit the ideal conformations for both orientations of the disordered thio­phene ring in compound (I). The S—C distances were fixed at 1.740 (2) (S1—C7 and S1′—C7) and 1.710 (2) Å (S1—C10 and S1′—C10′) (four restraints). Single-bond C—C distances were fixed at 1.420 (2) Å (two restraints), and double-bond C=C distances were fixed at 1.400 (2) (C7=C8 and C7=C8′) and 1.360 (2) Å (C9=C10 and C9′=C10′) (four restraints). S(...)C distances were fixed at 2.570 (2) (S1(...)C9 and S1′(...)C9′) and 2.550 (2) Å (S1(...)C8 and S1′(...)C8′) (four restraints). C(...)C distances were fixed at 2.490 (2) (C7(...)C10 and C7(...)C10′), 2.340 (2) (C7(...)C9 and C7(...)C9′) and 2.320 (2) Å (C8(...)C10 and C8(...)C10′) (six restraints). Moreover, it was taken into account that the thio­phene ring is flat (two restraints), and the anisotropic displacement parameters for both the S atoms and the corresponding C atoms of the thio­phene ring are equal (three restraints). 21 reflections, with experimentally observed F 2 deviating significantly from the theoretically calculated F 2 were omitted from the refinement.

For both compounds, data collection: APEX2 (Bruker, 2005 [triangle]); cell refinement: SAINT-Plus (Bruker, 2001 [triangle]); data reduction: SAINT-Plus; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Table 1
Intermolecular C—H(...)O hydrogen bonds (Å, °) in compounds (I)–(IV)

Supplementary Material

Crystal structure: contains datablocks global, I, II. DOI: 10.1107/S0108270109008336/gz3158sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S0108270109008336/gz3158Isup2.hkl

Structure factors: contains datablocks II. DOI: 10.1107/S0108270109008336/gz3158IIsup3.hkl

Acknowledgments

The authors are grateful to the NIH for support via the RIMI program (grant No. P20MD001104-01), and to the NSF for acquisition of the single-crystal X-ray diffractometer (grant No. DMR-0420863). We thank A. A. Yakovenko for assistance with the X-ray diffraction analysis of compound (II).

Footnotes

Supplementary data for this paper are available from the IUCr electronic archives (Reference: GZ3158). Services for accessing these data are described at the back of the journal.

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