X-ray crystal structure and conformational flexibility study of a N-substituted 2,6-diphenylpiperidine derivative

Article abstract of DOI:10.1134/S0022476617040230

Piperidine is one of the basic skeletons in many of pharmacological active compounds derived from natural or synthetic medicaments. Substitution of various groups in the piperidine ring regulates conformational flexibility due to the nature of the substituent on the nitrogen atom. One of the N-substituted piperidine derivatives, PMDPM, phenyl(3-methyl-2,6-diphenylpiperidin-1-yl)methanone, was crystallized and analysed by X-ray crystallography. The crystallographic data are: C₂₃H₂₅NO, M = 355.46, triclinic, space group P1?, a = 8.2543(7), b = 10.5543(8), c = 12.6184(6) ?, α = 77.901(7), β = 71.270(2)°, γ = 70.390(5)°; V = 974.3(1) ?³, Z = 2, d_cal = 1.212 Mg/m³, λ(MoK_α) = 0.71073 ?. The core piperidine ring of PMDPM shows a positional disorder and adopts dual conformations as chair and twisted boat. The phenyl rings are oriented axially to the piperidine ring with the dihedral angle of 22.0(1)° between them. The packing is stabilized by C–H?O intra molecular interactions including few C–H?π and weak interactions.

Full text of DOI:10.1134/S0022476617040230

Journal of Structural Chemistry. Vol. 58, No. 4, pp. 804-808, 2017.
Original Russian Text © 2017 N. Sampath.
X-RAY CRYSTAL STRUCTURE AND
CONFORMATIONAL FLEXIBILITY STUDY
OF A N-SUBSTITUTED 2,6-DIPHENYLPIPERIDINE
DERIVATIVE
N. Sampath
UDC 548.73:548.737
Piperidine is one of the basic skeletons in many of pharmacological active compounds derived from natural
or synthetic medicaments. Substitution of various groups in the piperidine ring regulates conformational
flexibility due to the nature of the substituent on the nitrogen atom. One of the N-substituted piperidine
derivatives, PMDPM, phenyl(3-methyl-2,6-diphenylpiperidin-1-yl)methanone, was crystallized and
analysed by X-ray crystallography. The crystallographic data are: C23H25NO, M = 355.46, triclinic, space
group Pī, a = 8.2543(7), b = 10.5543(8), c = 12.6184(6) Å, α = 77.901(7), β = 71.270(2)°, γ = 70.390(5)°;
3
3
V = 974.3(1) Å , Z = 2, dcal = 1.212 Mg/m , λ(MoKα) = 0.71073 Å. The core piperidine ring of PMDPM
shows a positional disorder and adopts dual conformations as chair and twisted boat. The phenyl rings are
oriented axially to the piperidine ring with the dihedral angle of 22.0(1)° between them. The packing is
stabilized by C–H⋯O intra molecular interactions including few C–H⋯π and π⋯π weak interactions.
DOI: 10.1134/S0022476617040230
Keywords: piperidine, conformation, crystallography, chair, twisted boat, dihedral angle, PMDPM, phenyl
ring.
INTRODUCTION
Piperidine is one of the N-containing heterocyclic rings, which is observed in many synthetic and natural
medicaments [1-3]. Piperidine derivatives are synthetic intermediates in various alkaloids and pharmaceutical products [4, 5].
Various piperidine derivatives possess pharmacological activities and form an essential moiety in the molecular structure of
important drugs. For example, the piperidine ring is a characteristic feature of antihistaminic agents [6], oral anaesthetics,
narcotic analgesic [7, 8] and postganglionic parasympathetic agonists [9]. Clebopride, a 1,4-disubstituted piperidine, is used
clinically to prevent post-operative vomiting, to speed up gastric emptying before giving anaesthesia, to facilitate radiological
evaluation and to correct a variety of disturbances of gastrointestinal function [10]. Several 2,6-disubstituted piperidine
derivatives are found to be very useful as tranquillisers [11], hypotensive drugs [12]. Bacterial, fungicidal and herbicidal
activities have been also reported [13]. Many piperidine derivatives form the skeleton of several alkaloids [14, 15].
School of Chemical and Biotechnology, SASTRA University, Thirumalaisamudram, Thanjavur, Tamil nadu-
613401, India; sams76@gmail.com. The text was submitted by the authors in English. Zhurnal Strukturnoi Khimii, Vol. 58,
No. 4, pp. 834-838, July-August, 2017. Original article submitted February 7, 2015; revised March 6, 2016.
804
0022-4766/17/5804-0804 © 2017 by Pleiades Publishing, Ltd.

The importance of these piperidine derivatives lies in the clinical use of suitably substituted groups and the different
ways available for making modifications in the anticipated structure of the pharmacologically active compounds. Substitution
of electron withdrawing groups (CHO, COCH2CH3, COPh, NO, etc.) at the nitrogen atom of piperidine ring causes major
changes in the ring conformations [16]. In the title compound, phenyl(3-methyl-2,6-diphenylpiperidin-1-yl)methanone
(PMDPM), the benzoyl group at the nitrogen atom shows electron delocalization through the atoms N1, C20 and O1 (Fig. 1)
which causes conformationally flexible piperidine ring to adopt dual conformations as chair and twisted boat. By contrary,
the compound with the COOCH2CH3 substituent at nitrogen showed only twisted boat conformation [16].
EXPERIMENTAL
The starting compound, 3-methyl-2,6-diphenylpiperidin-4-one (3) was obtained by adopting an earlier method [17],
and it was reduced with amalgamated zinc in aqueous methanol solution in presence of small amount of HCl into 3-methyl-
2,6-diphenylpiperidine (4). To a well stirred solution of 4 (2 mM) and triethylamine (4 mM) in freshly distilled benzene
(50 ml), a little excess of benzoylchloride (2.2 mM) was added dropwise and the stirring was continued until the reaction was
over. The reaction mixture was then poured into water and the final compound (5), phenyl(3-methyl-2,6-diphenylpiperidin-1-
yl)methanone (PMDPM, scheme 1), was extracted with dichloromethane. Pale yellow PMDPM X-ray quality crystals of 5
were obtained by slow evaporation from ethanol.
Scheme 1. Synthetic root of the compound, PMDPM
Crystal data collection and reduction. A suitable-size PMDPM crystal was mounted on a glass fibre and used for
data collection. Cell parameters and an orientation matrix for data collection were obtained by least-squares refinement of the
diffraction data from 25 reflections in an ENRAF–NONIUS CAD4 automatic diffractometer [18]. Data were collected at
293(2) K using MoKα radiation (λ = 0.71073 Å) with ω scan technique. The minimum and maximum of 2θ angle data
collected for this structure are 2.722° and 33.221°, respectively. The data reduction was carried out by XCAD4 [19] program.
Out of 8836 reflections collected, 6597 reflections with I ≥ 2σ(I) were used for structure solution and refinement. The
intensity data were corrected for Lorentz and polarization effects.
Structure determination. The structure of PMDPM was solved by direct-methods by using SHELXS97 [20]
program, which results the position of non-hydrogen atoms, and refined the structure with F2 full-matrix least squares
procedure using SHELXL97 [20] program. All non-hydrogen atoms were refined anisotropically and the hydrogen atoms
were fixed geometrically and allowed to ride over their respective parent atoms. The final refinement of PMDPM structure
was analysed and the structural formula consists the atoms C23H25NO with the molecular weight of 355.46. The structure was
solved with triclinic system using the space group Pī, which contains the cell parameters a = 8.2543(7), b = 10.5543(8),
3
c = 12.6184(6) Å, α = 77.901(7), β = 71.270(2), γ = 70.390(5)°. The crystal volume was found to be 74.3(1) Å with the
3
calculated crystal density of 1.212 Mg/m . The final cycle of the refinement was converged to R1 = 0.0873 and wR2 = 0.2067
805

Fig. 1. ORTEP diagram of the molecule PMDPM with the atom
numbering scheme. Displacement ellipsoid is drawn at 30%
probability level. Dashed lines represent the connection between
the disordered atoms. Hydrogen atoms were removed for clarity.
for the observed reflections. The maximum and minimum heights in the final difference Fourier map were found to be
3
3
0.490 e/Å and –0.330 e/Å , respectively. The final refinement of the structure PMDPM was done using two restraints
{isotropic Uij restraint ISOR (C3A & C3B) and bond distance restraint DFIX (H3B & H8)} to converge the structure in
appropriate conformation due to the presence of disordered atoms. The final goodness-of-fit of this structure was found to be
1.021, which indicates that the structure is fully converged to form stable conformation. Least-squares planes and asymmetry
calculations were done using the program PARST97 [21]. The thermal ellipsoid plot was done using ORTEP [22] and
PLATON [23] programs.
Selected bond distances, bond angles and torsion angles are given in Table 1. The atomic coordinates of the non-
hydrogen atoms with their equivalent thermal displacement parameters are included in the deposited material CCDC 1050050
as a complete list of bond distances and angles. The data can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif or from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk.
TABLE 1. Selected Torsion Angles (deg.), Bond Angles (deg.) and Bond Lengths (Å) for Molecule PMDPM
Atoms
Angle
Atoms
Angle
Atoms
Bond lengths
C3A–C4A–C5–C6
C6–N1–C2–C3A
C4A–C3A–C2–N1
C2–C3A–C4A–C5
C4A–C5–C6–N1
C2–N1–C6–C5
–57.6(4)
57.2(3)
–53.2(5)
55.6(5)
55.9(3)
–57.9(2)
38.8(8)
33.5(4)
26.0(8)
–64.7(9)
21.1(4)
87.7(5)
C4B–C3B–C2–C7
C4A–C5–C6–C13
C4B–C5–C6–C13
C2–N1–C6–C13
C6–N1–C2–C7
149.6(6)
–70.8(3)
–105.6(4)
71.6(2)
C3A–C4A
C3A–C2
C3A–C19
C4A–C5
C3B–C4B
C3B–C2
C3B–C19
C4B–C5
O1–C20
1.599(6)
1.549(6)
1.479(7)
1.578(5)
1.358(1)
1.597(6)
1.590(7)
1.427(9)
1.231(2)
–89.7(2)
C3B–C4B–C5–C6
C6–N1–C2–C3B
C4B–C3B–C2–N1
C2–C3B–C4B–C5
C4B–C5–C6–N1
C4A–C3A–C2–C7
C6–N1–C2
C20–N1–C2
C20–N1–C6
O1–C20–N1
O1–C20–C21
N1–C20–C21
118.0(2)
118.0(2)
123.8(2)
122.4(2)
118.4(2)
119.3(2)
806

RESULTS AND DISCUSSION
The compound 5, PMDPM, was crystallized in triclinic system (Pī space group) using ethanol as solvent by slow
evaporation method. The perspective view of ORTEP diagram of PMDPM is shown in Fig. 1. The central piperidine ring
atoms, C3 and C4, show positional disorder which results from two ring conformations, a chair (N1, C2, C3A, C4A, C5 &
C6; QT = 0.581(2) Å) and a twisted boat (N1, C2, C3B, C4B C5 & C6). The disordered atoms of C3A and C4A showed the
occupancies 48% and 64%, respectively, to form chair conformation. Similarly, the other two atoms, C3B and C4B, had the
occupancies 52% and 36%, respectively, to form a twisted boat conformation.
In the chair conformation, the atoms N1 and C4A deviate by –0.611(1) Å and 0.738(1) Å, respectively, from the
plane atoms (C2, C3A, C5 and C6) with the phase angle of 175.6(7)°. Similarly, the twisted boat conformation shows
puckering amplitude QT = 0.662(1) Å with the phase angle of 89.5(1)° [21, 24]. Conformational flexibility of this piperidine
ring (chair and twisted boat) is also evidenced from the respective torsion angles which are shown in Fig. 2. A reported
structure almost similar to PMDPM, but with of an ethyl acetate group at the nitrogen atom adopts perfect twisted boat
conformation, and the phenyl rings at C2 and C6 occupy axial and equatorial positions [16]. Instead, the PMDPM structure
shows conformational flexibility, adopting both chair and twisted boat conformations due to positional disorder of C3 and C4
atoms. The disorder might be caused by the presence of bulky benzoyl substituents on N1 atom, forcing both phenyl rings
into the axial positions at C2 and C6 atoms to avoid the steric hindrance.
Axially substituted phenyl rings at C2 and C6 position of PMDPM are also confirmed by the torsion angles {C2–
N1–C6–C13 = 71.6(2) & C6–N1–C2–C7 = –89.7(2)}, and the dihedral angle between these phenyl rings is 21.6(1)°. The
dihedral angles between the phenyl rings and piperidine ring (chair) are 88.8(1)° (C7 through C12) and 74.1(1)° (C13
through C18). Similarly, the dihedral angles between the phenyl rings and piperidine ring (twisted boat) are 80.2(1)° (C7
through C12) and 82.9(1)° (C13 through C18). The methyl group substituted in the disordered C3 atom is oriented in
equatorial position. All these substitutions are confirmed by the respective torsion angles (Table 1).
The benzoyl group at N1 atom is coplanar to the piperidine ring, and the respective atoms {C2, N1, C6, C20, O1,
and C21} are positioned in the same plane. The co-planarity conformation is due to the existence of electron delocalization
between the atoms of nitrogen from piperidine ring and carbonyl atoms from benzoyl moiety. This co-planarity is also
expressed in the respective torsion angles {[C2–N1–C20–O1 = ] –7.8(3)°; [C2–N1–C20–C21 = ] 172.0(2)°; [C6–N1–C20–
C21 = ] –3.3(3)°; and [C6–N1–C20–O1 = ] 176.9(2)°}. The dihedral angles between the benzoyl group and piperidine ring of
chair and twisted boat are 37.7(1)° and 35.5(1)°, respectively [21, 24]. The molecule does not form classical hydrogen bonds.
1
1
3
In addition to the van-der-Waals forces, four C–H⋯π {C24–H24⋯Cg , Cg (C7 through C12) and C17–H17⋯Cg , C19–
3
3
3
1
2
2
H19F…Cg & C19–H19B…Cg ; Cg (C21 through C26)} and an intra π⋯π {[Cg ⋯Cg = ] 4.04 Å; Cg (C13 through
C18)} weak interactions help to control the molecules in the crystal packing. The detailed geometry of the non-bonded
interactions is presented in Table 2.
Fig. 2. Dual conformations and their respective torsion angels (°) of
piperidine ring of PMDPM: twisted boat conformation (a), chair
conformation (b).
807

TABLE 2. Possible Non-Bonded Interactions in the Molecule of PMDPM
D–H⋯A
D–H
H⋯A
D⋯A
D–H⋯A
0.93
0.93
0.93
0.96
0.96
2.50
2.93
2.81
2.84
2.99
3.180(1)
3.661
131
136
144
158
137
C12–H12…O1
i
1
C24–H24⋯Cg
ii
3
C17–H17⋯Cg
3.607
iii
iii
3
3
3.752
C19–H19F…Cg
3.752
C19–H19B…Cg
ii
iii
Symmetry codes: i x+1, y–1, z; 1–x, –y, –z; –x, –y, 1–z.
CONCLUSIONS
A new piperidine derivative, PMDPM, was synthesised and its X-ray crystal structure was determined to understand
the structural features and its property. The piperidine ring adopts both chair and twisted boat conformations. Most of the early
reported N-substituted (with electron withdrawing groups) piperidine rings showed twisted boat conformations with phenyl
rings substituted in C2 and C6 positions occupying axial and equatorial positions. In the PMDPM structure both phenyl rings
occupy only axial positions in the piperidine ring. This structural feature might be adopted in order to avoid the steric hindrance.
The author NS thanks the management, SASTRA University, Thanjavur, Tamil Nadu, for providing facilities and
for the Prof. T. R. Rajagopalan funding.
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