J Chem Crystallogr (2007) 37:727–731 DOI 10.1007/s10870-007-9240-7
ORIGINAL PAPER
Synthesis and Crystal Structure Studies of a Novel Bioactive Heterocycle: 1-Benzhydryl-4-phenylmethane Sulfonyl Piperazine C. S. Ananda Kumar Æ S. Naveen Æ S. B. Benaka Prasad Æ N. R. Thimme Gowda Æ N. S. Linge Gowda Æ M. A. Sridhar Æ J. Shashidhara Prasad Æ K. S. Rangappa
Received: 9 November 2006 / Accepted: 10 August 2007 / Published online: 14 September 2007 Springer Science+Business Media, LLC 2007
Abstract 1-Benzhydryl-4-phenylmethane sulfonyl piperazine was synthesized from 1-benzhydryl piperazine with phenylmethane sulfonyl chloride. The product obtained was characterized by 1H NMR, MS and IR techniques and finally confirmed by X-ray crystallography. The title compound C24H26N2O2S, Mr = 406.53, crystallizes in the orthorhombic crystal class in the space group Pbca with unit ˚ , b = 9.4940(15)A ˚, cell parameters a = 11.1240(10)A 3 ˚ ˚ c = 40.239(4)A, Z = 8 and V = 4249.7(9)A . The structure was solved by direct methods and refined to R1=0.0561 for 2,445 reflections with [I [ 2 r(I)]. The piperazine ring adopts a chair conformation. The sulfonyl moiety is in a distorted tetrahedral configuration. Keywords Benzhydrylpiperazine Sulfonyl chloride Crystal structure Tetrahedral configuration
Piperazine and its analogues are important pharmacores that can be found in biologically active compounds across a number of different therapeutic areas [1], such as antifungal [2], anti-bacterial, anti-malarial, anti-psychotic agents [3], HIV protease inhibitor [4–6], anti-depressant [7] and anti-tumour activity against colon, prostate, breast, C. S. Ananda Kumar S. B. Benaka Prasad N. R. Thimme Gowda N. S. Linge Gowda K. S. Rangappa (&) Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India e-mails:
[email protected];
[email protected] S. Naveen M. A. Sridhar J. Shashidhara Prasad Department of Studies in Physics, University of Mysore, Manasagangotri, Mysore 570 006, India
lung and leukemia tumors[8]. The benzhydryl piperazine is a fundamental component present in the anti-histamine drugs such as Cyclizine, Cinnarazine and Oxatomide. By changing the substitutions at nitrogen of piperazine in the basic moiety of benzhydryl piperazine, the resultant derivatives possess broad pharmacological action on central nervous system [9]. They are also reported to be potent enterovirus inhibitors [10]. Sulfonamides are among the most widely used anti-bacterial agents in the world, chiefly because of their low cost, low toxicity and excellent activity against common bacterial disease. Piperazine sulfonamides exhibit diverse pharmacological activities such as MMP-3 inhibition, anti-bacterial activity and carbonic anhydrase inhibition [11]. Literature survey revealed that no efforts were directed towards the study of crystal structure of 1-benzhydrylpiperazine with phenylmethyl sulfonyl chloride. As a part of our ongoing research on novel heterocycles and their crystal structures, we have synthesized the title compound using the procedure reported previously [10]. The reaction of 1-benzhydryl-piperazine with phenylmethyl sulfonyl chloride was carried out in the presence of triethylamine and dichloromethane as a solvent. The structure of the compound was established on the basis of FTIR absorption spectroscopy, 1H NMR and elemental analysis and finally confirmed by X-ray crystallography.
Experimental Preparation of 1-Benzhydryl-4-phenylmethane Sulfonyl-piperazine 6 A solution of 1-benzhydryl-piperazine 5 (0.5 g, 1.98 mmol) in dichloromethane (10 mL) was taken and
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cooled to 0–5 C in an ice bath. Then, triethylamine (0.601 g, 5.94 mmol) was added to the cold reaction mixture. This mixture was stirred for 10 min. Then phenylmethyl sulfonyl chloride (0.377 g, 1.98 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 5 h. The reaction was monitored by TLC. On completion of the reaction, the solvent was removed under reduced pressure and the residue was taken in water and extracted with ethyl acetate. Finally the organic layer was washed with water and dried with anhydrous sodium sulphate. The solvent was evaporated to get a crude product which was purified by column chromatography over silica gel using hexane:ethyl acetate (8:2) as an eluent. The pure product obtained was dissolved in ethyl acetate. The yield was 80% with M.P. 169–171 C. Due to the slow evaporation of the solvent, white crystals developed after 3 days. The procedure employed for synthesis is shown in Scheme 1. The melting points were determined using Veego model VMP-III melting point apparatus and are uncorrected. The IR spectra were recorded using a Jasco FTIR-4100 series. 1 H NMR spectra were recorded on a Bruker AM-400, and chemical shifts (ppm, for d) are relative to TMS as an internal standard. Spin multiplets are given as s (singlet), d Scheme 1 Reaction scheme
(doublet), t (triplet) and m (multiplet). Mass spectra were recorded on a Trio 1000 Thermo Quest spectrometer. Elemental analyses (CHNS) were done on a Vario EL III Elementar. Silica gel column chromatography was performed using Merck 7734 silica gel (60–120 mesh) and Merck made TLC plates. 1 H NMR (DMSO, 400 MHz): d 7.35 (d, 4H, Ar–H), 7.24 (t, 4H, Ar–H), 7.15 (t, 2H, Ar–H), 7.45–7.50 (b, 5H, Ar–H), 4.24 (t, 2H, –CH2–), 2.9 (t, 4H, –CH2–), 2.35 (t, 4H, –CH2–), 4.4 (s, 1H, –CH–). MS (ESI + ion): m/z = 407.58 IR (KBr, cm–1): 1,158 (symmetric str of -SO2), 1,323 (asymmetric str of –SO2), 3,065, 3,025 (Aromatic –C–H– str), 2,949 (–C–H str of –CH2–). Anal. Calcd. for C24H26N2O2S (in %): C-70.91, H-6.45, N-6.89, S-7.89. Found C-70.88, H-6.42, N-6.87, S-7.86.
Crystal Structure Determination A single crystal of the title compound with dimensions 0.3 · 0.27 · 0.25 mm was chosen for X-ray diffraction study. The data were collected on a DIPLabo Image Plate system equipped with a normal focus, 3 kW sealed X-ray O MgBr
H
H SO Cl 2
dry THF
+
OH
MDC 0−5oC, 2hrs
r. t. 2 hrs 1
2 3
H
H Cl
Piperazine
N
N
DM F, 80 oC
SO 2Cl
5
4
Triethylamine Dichloromethane
O
H N
N
S O
6
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CH 2
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Table 1 Crystal data and structure refinement table
˚ ) and bond angles () Table 2 Bond lengths (A
CCDC deposition number
CCDC 619337
Atoms
Length
Atoms
Length
Empirical formula
C24 H26 N2 O2 S
Formula weight
406.53
N1–C6
1.465(5)
C14–C15
1.360(7)
Temperature
293(2) K
N1–C2
1.469(4)
C15–C16
1.387(5)
Wavelength
˚ 0.71073 A
N1–S7
1.638(3)
C17–C18
1.515(5)
Crystal system
Orthorhombic
Space group
Pbca
Cell dimensions
˚ a = 11.124(10) A ˚ b = 9.4940(15) A
Volume
˚ c = 40.239(4) A 3 ˚ 4249.7(9) A
Z
8
Density (calculated)
1.271 mg/m3
Absorption coefficient
0.175 mm–1
F000 Crystal size
1,728 0.3 · 0.27 · 0.25 mm
Theta range for data collection
2.09 to 25.03
Index ranges
–11 £ h £ 11 –10 £ k £ 10 –47 £ l £ 47
Reflections collected
3,747
Independent reflections
2,445 [R(int) = 0.0211]
Refinement method
Full-matrix least-squares on F
Data/restraints/parameters
2,445/0/263
Goodness-of-fit on F2
1.086
Final R indices [I [ 2 r(I)]
R1 = 0.0561, wR2 = 0.1662
R indices (all data)
R1 = 0.0771, wR2 = 0.1994
Extinction coefficient
0.0065(13)
Largest diff. peak and hole
˚ –3 0.335 and –0.253 eA
2
source [graphite monochromated MoKa]. 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 minute with an oscillation range of 5. Image processing and data reduction were done using Denzo [12]. The reflections were merged with Scalepack [13]. All of the frames could be indexed using a primitive orthorhombic lattice. The structure was solved by direct methods using SHELXS-97 [14]. All the non-hydrogen atoms were revealed in the first Fourier map itself. Full-matrix least squares refinement using SHELXL-97 [15] with isotropic temperature factors for all the atoms converged the residuals to R1 = 0.1345. Refinement of non-hydrogen atoms with anisotropic parameters was started at this stage. The hydrogen atoms were placed at chemically acceptable positions and were allowed to ride on the parent atoms. About 263 parameters were refined with 2,445 unique reflections which saturated
C2–C3
1.518(5)
C17–C24
1.516(5)
C3–N4
1.458(5)
C18–C23
1.384(5)
N4–C5
1.465(4)
C18–C19
1.386(5)
N4–C17
1.475(4)
C19–C20
1.386(5)
C5–C6
1.501(5)
C20–C21
1.375(5)
S7–O8 S7–O9
1.428(3) 1.432(3)
C21–C22 C22–C23
1.373(6) 1.381(6)
S7–C10
1.779(4)
C24–C29
1.374(6)
C10–C11
1.498(5)
C24–C25
1.386(5)
C11–C16
1.369(5)
C25–C26
1.372(6)
C11–C12
1.384(6)
C26–C27
1.366(6)
C12–C13
1.381(5)
C27–C28
1.381(6)
C13–C14
1.353(6)
C28–C29
1.376(6)
Atoms
Angle
Atoms
Angle
C6–N1–C2
111.5(3)
C13–C14–C15
120.1(4)
C6–N1–S7
119.0(2)
C14–C15–C16
120.5(4)
C2–N1–S7
118.8(2)
C11–C16–C15
120.0(4)
N1–C2–C3
108.0(3)
N4–C17–C18
111.1(3)
N4–C3–C2
111.1(3)
N4–C17–C24
112.8(3)
C3–N4–C5
108.7(3)
C18–C17–C24
108.5(3)
C3–N4–C17
110.4(3)
C23–C18–C19
117.6(3)
C5–N4–C17 N4–C5–C6
114.1(3) 110.3(3)
C23–C18–C17 C19–C18–C17
120.4(3) 121.8(3)
N1–C6–C5
109.2(3)
C20–C19–C18
121.4(3)
O8–S7–O9
119.00(17)
C21–C20–C19
119.9(4)
O8–S7–N1
107.36(15)
C22–C21–C20
119.4(4)
O9–S7–N1
106.33(16)
C21–C22–C23
120.4(3)
O8–S7–C10
107.98(18)
C22–C23–C18
121.2(4)
O9–S7–C10
108.79(19)
C29–C24–C25
118.4(4)
N1–S7–C10
106.76(17)
C29–C24–C17
120.4(4)
C11–C10–S7
111.8(3)
C25–C24–C17
121.2(4)
C16–C11–C12
118.8(3)
C26–C25–C24
120.5(4)
C16–C11–C10
121.2(4)
C27–C26–C25
120.8(4)
C12–C11–C10
120.0(3)
C26–C27–C28
119.3(4)
C13–C12–C11
120.4(4)
C29–C28–C27
119.9(5)
C14–C13–C12
120.1(4)
C24–C29–C28
121.1(4)
the residuals to R1 = 0.0561. The details of the crystal data and refinement are given in Table 1.1 1
CCDC 619337 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033. email:
[email protected]
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Fig. 1 ORTEP of the molecule with thermal ellipsoids drawn at 50% probability
Results and Discussion The bond lengths and angles of all the non-hydrogen atoms, given in Table 2, are in good agreement with standard values. Figure 1 represents the ORTEP[16] of the molecule with thermal ellipsoids drawn at 50% probability. A study of the torsion angles, asymmetric parameters and least-squares plane calculations reveals that the piperazine ring in the structure adopts a chair conformation with the atoms N1 and N4 lying –0.235(3) and ˚ from the Cremer and Pople [17] plane defined 0.250(3) A by the atoms N1/C2/C3/N4/C5/C6. This is confirmed by ˚, h = the puckering parameters Q = 0.5934(39) A 178.55(35) and / = 5(19). The ring puckering analysis revealed that the piperazine ring has a weighted average ˚ and a weighted ring bond distance of 1.4796(21,102) A average absolute torsion angle of 59.17(16, 40). The bonds N1–S7 and N4–C17 make an angle of 85.85(17) and 76.0(2) respectively from the Cremer and Pople plane of the piperazine ring and thus lie in the equatorial plane of the piperazine ring. The dihedral angle between the least-squares plane of the piprazine ring and the phenyl ring bridged by the methylsulfonyl group is 5.6(2) indicating that the phenyl ring is nearly coplanar with the piperazine ring. The dihedral angle between the least squares planes of the piperazine ring and the phenyl rings
(C18–C23) and (C24–C29) are 63.7(2) and 74.71(19) respectively. This value is very much low when compared to the corresponding values of 86.32(10) and 88.27(15) reported for 1-benzhydrylpiperazine [18]. This is due to the steric hindrance caused by the bulky sulfonyl group at the first position of the piperazine ring. The dihedral angle between the least squares planes of the two phenyl rings bridged by the carbon atom is 84.4(2). The angular disposition of the bonds about the S atom shows significant deviation from that of a regular tetrahedron with the largest deviations being seen for the O–S–O [O8–S7–O9 = 119.00(17)] and O–S–N [O9–S7–N1 = 106.33(16)]. This widening of the angles is due to the repulsive interactions between the S=O bonds. The S–N distances [S7– ˚ ] lie within the expected range of 1.63– N1 = 1.638(3) A ˚ 1.69 A [19]. The narrowing of the N1–S7–C10 to 106.76(17) from the ideal tetrahedral value is attributed to the Thorpe–Ingold effect [20]. The structure exhibits both inter and intramolecuar hydrogen bonds of the type C– HO and C–HN respectively. The stability of the crystal structure can be accounted by these hydrogen bonds. The five observed hydrogen bonds are listed in Table 3. The packing of the molecules when viewed down the c axis reveal that the molecules are interlinked by intermolecular hydrogen bonds and they form a one-dimensional chain (Fig. 2).
˚ ) Table 3 Hydrogen-bonding geometry (A D–HA
D–H*
H–A*
D–A
D–H...A
C2–H2BO8
0.9700
2.6000
3.007(5)
106
C6–H6AO9
0.9700
2.4400
2.884(5)
108
C12–H12O9 C16–H16O8
0.9300 0.9300
2.5100 2.5100
3.422(6) 3.322(6)
165 146
C19–H19N4
0.9300
2.4800
2.825(5)
102
* The D–H and H–A distances are essentially standard values and are not derived from the experiment
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Symmetry codes
1/2–x,1/2 + y, z 1/2 + x,y, 1/2–z
J Chem Crystallogr (2007) 37:727–731
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Fig. 2 Packing of the molecules when viewed down the c axis. The dashed lines represent the intermolecular hydrogen bonds
Acknowledgements The authors are grateful to DST/DST-FIST and Government of India for financial assistance under the projects SP/I2/ FOO/93 and UGC-SAP(Phase-I)No.F.540/10/DRS/2004(SAP-I).
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