Structural Chemistry & Crystallography Communication

Keywords

β-lactams; Antibiotics; Crystal structure

Introduction

The four membered β-lactam ring constitutes an important class of heterocyclic compounds as it is a key pharmacophoric feature of the several antibiotic families such as penicillins, cephalosporins, carbapenems and monobactams (Figure 1) [1]. Apart from its wide therapeutic potential, β-lactam core is well explored as a versatile synthon for the preparation of a variety of natural products such as α, β- amino acids, amino sugars, alkaloids and toxoids [2]. In view of the large potential applications of β-lactam derivatives and in extension to our efforts to develop diverse biologically active scaffolds [3-5], crystal structure studies of two monocyclic β-lactam derivatives (I and II) are elaborated.

Figure 1: Structure of commonly used ß-lactam antibiotics.

Experimental

General procedure for the synthesis of β-lactams (I and II)

Initially, Imines were synthesized using the previously reported method [3] by the condensation of aryl aldehyde (1.0 mmol) and substituted benzylamine (1.0 mmol) in anhydrous ethanol. These imines (1.0 mmol) were then treated with phenylacetic acid (1.5 mmol), triethylamine (4.0 mmol) and phosphorous oxychloride (1.1 mmol) in toluene (10 ml) at 110°C under inert atmosphere. After overnight refluxing, it was cooled to room temperature and neutralized with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulphate. After evaporation of the solvent, the residue was purified by column chromatography using silica gel (230-400 mesh) eluted with 30-40% ethyl acetate in hexane. The title compounds were obtained in low to good yield [3]. The structures of the synthesized compounds are given in Figure 6.

X-ray structural study of compounds I and II

The structures of β-lactams I and II were unambiguously established by X-ray crystallographic studies. Single crystals of I and II were obtained through the slow evaporation of ethyl acetate: hexane solution. Data sets for compound I (C₂₄H₂₃NO₃) were collected with D8 Venture Dual Source 100 CMOS diffractometer at 100K using ϕ and ω scans methods. No significant loss in intensities was observed during data collection. A total of 2184 frames were collected within the exposure time of 18.90 hours. The frames were integrated with the Bruker SAINT software package using a wide-frame algorithm resulting in to a total of 27702 reflections. Data were corrected for absorption effects using the multi-scan method (SADABS) [6]. Data collection, reduction and refinement were performed using APEX2 V2014.5- 0 and SAINT V8.34A software [7]. The structure was solved and refined using the Bruker SHELXTL Software Package [8]. The data sets for compound II (C₃₂H₂₆N₂O₂) were collected with a Nonius Kappa CCD diffractometer. A total of 22382 reflections were collected. Data collection, data reduction, absorption correction, structure solution and refinement were performed using COLLECT [9], Denzo-SMN [10], Denzo [11], SHELXS-97 and SHELXL-97 [12] programs, respectively. The molecular graphics were prepared using XP [13].

Results and Discussion

X-ray structural study of compounds I and II

The single X-ray crystallographic study of compounds I and II exhibited the presence of various non-covalent (C-H...O, C-H...π, C-O...π and π-π) interactions which play important roles in molecular recognition, crystal engineering, foldamers and drug development [14]. Diffraction quality crystals of the compounds I and II were obtained from the ethyl acetate: hexane mixture of compounds by slow evaporation at room temperature. Total 27702 and 22382 reflections were collected for compounds I and II, out of which 3566 and 5921 reflections were independent with Rint values of 4.65 and 5.70%, respectively. Crystal structure analysis revealed that both compounds I and II crystallize in monoclinic crystal system with space group P21/c. The final R-factors for model structures were converged to 3.79 and 5.72%, respectively. The data collection and structure refinement details are provided in Table 1. The bond lengths and bond angles of I and II are listed in Tables 2, 3, 5 and 6. The relevant hydrogen bond details of I and II are given in Tables 4 and 7. ORTEP diagrams of the compounds I and II with ellipsoids drawn at 30% probability level along with their atomic numbering schemes are shown in Figures 2 and 4, respectively. Crystal structure analysis of compound I showed that the aromatic rings attached to the β-lactam rings are planer while the four membered β-lactam rings is nearly planer. The absence of puckering of the rings is also indicated through Cremer and Pople analysis [15]. The unit cell of compound II contains four molecules of similar conformations connected through multiple weak intermolecular non-covalent C-H…O interactions, two molecules of which form molecular dimers through C₂₆−H₂₆...O₁ interactions (symmetry position 1-X, -Y, -Z) (Figure 3). Various C-H...π (C₁₄-H₁₄...Cg(4), C₁₆-H₁₆...Cg(1), C₂₂-H₂₂...Cg(4), C₂₆-H₂₆...Cg(₁), C₂₇-H₂₇B...Cg(3), C₂₈-H₂₈...Cg(3)) and C-O...π (C1-O1...Cg(1)) interactions [16] are also observed in the packing, with the neighboring molecules at different symmetric positions. Here Cg(1), Cg(2), Cg(3) and Cg(4) represent the centroids of the rings N₁-C₁-C₂-C₃, C₁₁-C₁₂-C₁₃-C₁₄-C₁₅-C₁₆, C₂₁-C₂₂- C₂₃-C₂₄-C₂₅-C₂₆ and C₃₁-C₃₂-C₃₃-C₃₄-C₃₅-C₃₆ respectively. The crystal structure analysis of compound II showed that all the benzene rings are planar; four membered β-lactam ring is almost planar, while nine membered indole ring shows deviations from the planarity. It has been observed that the indole ring is puckered to form a twisted boat like structure [17]. Crystal packing of compound II also exhibits the presence of four molecules in unit cell, having similar conformations forming two pairs. The molecules of each pair are connected through bifurcated C-H...O hydrogen bonding interactions (Figure 5), The pairs of molecules are flanked through π...π and C-H...π interactions to form sheet like structure.

Figure 2: ORTEP diagram of compound I with atomic numbering scheme (30% probability level of thermal ellipsoids).

Figure 3: Crystal packing diagram of compound Figure 3 I (Hydrogen bonding is shown by dotted lines).

Figure 4: ORTEP diagram of compound II with atomic numbering scheme (30% probability level of thermal ellipsoids).

Figure 5: Crystal packing diagram of compound II (Hydrogen bonding is shown by dotted lines).

Figure 6: The structures of the synthesized ß-lactams.

Table 1: Crystal data and structure refinement details for I and II.

Table 2: Bond lengths (Å) for compound I.

Table 4: Stability data of dry suspension and Reconstituting medium.

Table 4: Hydrogen bond distances (Å) and angles (°) of compound II.

Table 5: Bond lengths (Å) of compound II.

Table 6: Bond angles (°) of compound II.

Table 7: Hydrogen coordinates (x 10⁴) isotropic displacement parameters (Å2 x 10³) of compound II.

Acknowledgements

Mohammad Abid gratefully acknowledges the funding support in the form of Young Scientist from Science and Engineering Research Board (Grant No. SR/FT/LS-03/2011), Government of India, New Delhi, India. SA is thankful to UGC for the financial assistance (F. No. 41-277/2012) and BA would like to acknowledge UGC, India for BSR fellowship.

Additional Information

Crystallographic data for the compounds I and II with CCDC1059749, 1059750 have been reported in this article. This data can be obtained free of charge from the Cambridge Crystallographic Data Centre via https://summary.ccdc.cam. ac.uk/structure-summary-form.

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