Structural Chemistry & Crystallography Communication

Keywords

Single-crystal X-ray study; Tetrahydropyrimidine; Weak interaction; R factor

Introduction

In recent years, the interest in Dihydropyrimidines (DHPMs) has increased rapidly because of the structural resemblance of DHPM with clinically important Hantzsch pyridines [1,2]. The biologically active dihydropyridine molecules contain the substituent 4-phenyl ring positioned above and in the vertical plane of 1, 4-dihydropyridine ring, which itself is a flattened boat conformation [3]. Pyrimidine derivatives comprise a diverse and interesting group of drugs which are extremely important for their biological activities. Dihydropyrimidines and their derivatives have attracted increasing interest owing to their therapeutic and pharmaceutical properties, such as antiviral, antitubercular, [4,5] antimicrobial agent [6-10], antagonists of the human adenosine A2A receptor [11], cyclooxygenase-2 inhibitory activity [12,13], tyrosine kinase inhibitors [14], Antiamoebic activity [15], and cytotoxicity [16,17]. The chemical structure of sulphanilamide provides a most valuable molecular template for the development of agents able to interact with a wide variety of biological activities [18]. The tetrahydropyrimidines is structurally similar to Dihydropyrimidines. Hence, it was thought worthwhile to synthesize new congeners by incorporating chlorophenyl and carboxylate with 1,2,3,4-tetrahydropyrimidinones moieties in a single molecular framework.

Experimental

A mixture of ethyl-4-chloroacetoacetate (4.1 mL, 0.025 mol), 3-chlorobenzaldehyde (3.6 gm, 0.025 mol), and urea (4.5 g, 0.075 mol) in ethanol (5 ml) was heated under reflux in the presence of concentrated HCl (1 mL) for 8 h (monitored by TLC). The reaction mixture, after being cooled to room temperature, was poured onto crushed ice and stirred for 5-10 min. The precipitate was washed with sodium bicarbonate solution, filtered, dried and again washed with petroleum ether (40-60%) and dried over in a vacuum. The compound was recrystallized from absolute ethanol with melting point 151-153≡ C and yield 72% (Scheme 1).

Scheme 1:

X-ray structure determination

Single crystal X-ray diffraction data for the compound at room temperature was collected by Bruker Kappa diffractometer with Mo Kα radiation using ω/2θ scan mode. SMART APEX2 CCD area detector with Mo Kα radiation and ω scan mode was applied to obtain an accurate unit cell parameters and orientation matrix within the least-square fit of several high angle reflections in the ranges 2.3 ≡<θ<19.20 ≡. Cell refinement and data reduction were carried out using SAINT. A total of 4647 reflections were collected, resulting in 1230 independent reflections of which 905 had I>2σ(I). The intensities for Lorentz and polarization effects and absorption corrections were corrected by using SADABS [19]. The structure of compound was solved by direct method procedure as implemented in SHELXS97 [20] program. The full matrix least square refinement using SHELXL97 program was used to include the position of all non hydrogen atoms. The thermal parameters for each atom were assigned a value of 0.05 (U’s) in the initial stage and refinement was followed. The initial scale factor was pegged at 1.0. Thereafter the anisotropic refinement for a few cycles of full matrix least square was continued. At this stage the positions of all hydrogen’s were geometrically fixed at calculated positions and they were allowed to ride on the corresponding non hydrogen atoms. The minimum and maximum value of residual electron density was -0.39, 0.38 e. Å-3 and the final R-factor were 0.061. Crystallographic data of the compound is summarized in Table 1.

Table 1 Crystal data, data collection and structure refinement.

Results and Discussion

Figure 1 shows the ORTEP plot of the molecule drawn at 30% probability ellipsoid level with atom numbering scheme. Figure 2 shows the packing of compound viewed down ‘a’ axis. The geometric parameters of the title molecule (Figure 1) agree well with reported similar structure [21-23]. The chlorophenyl ring makes a dihedral angles of 86.25(4)° with the tetrahydropyrimidine ring. Table 2 summarizes the selected geometrical parameters of the compound. The molecular structure is stabilized by weak intra-molecular C-H···O interaction. The atom O2 is acting as potent acceptor for C₁₁-H₁₁B…O₂ hydrogen bond in which atom C₁₁ donates a proton. The interaction C₁₁-H₁₁B...O₂ generates a sixmembered ring with S(6) graph set motif [24]. The crystal packing of the molecule is controlled by weak N-H…O interactions. All non-hydrogen atoms were refined anisotrophically and hydrogen atoms are fixed using riding modal. Two NH with oxygen atoms and one CH with oxygen atom are involved in non bonded interactions and possible hydrogen bonds are given in Table 3. In the crystal structure of molecule is interlinked via C₁₁-H₁₁B… Crystallographic data (excluding structure factors) for the structural analysis has been deposited with the Cambridge Crystallographic Data Centre, No. CCDC-848738. Copies of this information may be obtained free of charge from: The Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK. Fax: +44(1223)336-033, E-mail: deposit@ccdc.cam.ac.uk or web: www.ccdc.cam.ac.uk.

Table 2 Selected geometrical parameters (Å, ≡) with su’s in parentheses

Table 3 Non-Bonded interactions and possible hydrogen bonds ( Å, ≡).

Figure 1: ORTEP plot of the compound drawn at 30% probability.

Figure 2: Packing of the compound viewed down ‘a’ axis. Hydrogen bonds are shown as dashed lines.

O₂, N₁-H₁...O₂ ⁱ and N₂-H₂...O₁ ⁱⁱ hydrogen bonds to form R₁₂ (6) ring motifs [17] which play a role in stabilizing the crystal structure. These sets of ring motifs are then linked into intermolecular hydrogen bonds.

Conclusion

Derivatives of Dihydropyrimidines exhibit a variety of medicinal properties by serving as antiviral, antitubercular, antimicrobial agents. The molecular structure of the compound is stabilized by weak intra-molecular C-H...O type of hydrogen bond. The crystal packing is controlled by weak inter-molecular N-H...O, interactions. Presence of inter and intra molecular hydrogen bonds in the title compound shows that, the derivative exhbit wide range of biological activities.

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