Synthesis and conformational studies on 1-aryl-cis-2,6-diphenylpiperidines

Article abstract of DOI:10.1016/j.molstruc.2021.130065

A facile and convenient synthesis of N-aryl-cis-2,6-diphenylpiperidines was achieved via reductive amination of 1,5-diphenyl-1,5-pentanedione with aryl ammonium formate under metal-free and microwave mediated Leuckrdt Wallach reaction conditions. The gas-

Full text of DOI:10.1016/j.molstruc.2021.130065

Journal of Molecular Structure 1232 (2021) 130065
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis and conformational studies on
1-aryl-cis-2,6-diphenylpiperidines
H. Surya Prakash Raoa,b,∗, E. Poonguzhalib,c, Jayaraman Muthukumarand
a Department of Chemistry and Biochemistry, School of Basic Sciences and Research, Sharda University, Greater Noida 201306, India
b Department of Chemistry, Pondicherry University, Puducherry 605 014, India
c Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, Tamil Nadu, India
d Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201306, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and convenient synthesis of N-aryl-cis-2,6-diphenylpiperidines was achieved via reductive ami-
nation of 1,5-diphenyl-1,5-pentanedione with aryl ammonium formate under metal-free and microwave
mediated Leuckrdt Wallach reaction conditions. The gas-phase (by Density Functional Theory studies),
Liquid phase (by Nuclear Magnetic Resonance spectral analysis) and solid-phase (by X-ray crystallogra-
phy along with Hirshfeld and Fingerprint plot analysis) structural studies on the title compound showed
that the N-aryl, C(2) and C(6) phenyl rings were preferentially oriented equatorially and piperidine ring
flattened-chair conformation. Besides, the DFT calculation showed a face-to-face arrangement of N-aryl
ring with adjacent phenyl rings, and they were orthogonal to mean plane of the piperidine ring. The
single-crystal structure (CCDC 1415313) analysis showed that the title compound crystallized in the mon-
oclinic crystal system with P2(1)/C space group. The crystal packing was stabilized by intermolecular
C-H…π interactions. Overall, the orientation of aryl rings looks like that of elephant ears flanking the
snout.
Received 25 October 2020
Revised 31 January 2021
Accepted 1 February 2021
Available online 4 February 2021
Keywords:
N-aryl-cis-2,6-diphenylpiperidines
Density Functional Theory
X-ray Crystallography
Hirshfeld analysis
Fingerprint plot analysis
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
ing the stable conformation of the ring [7]. To attain stable confor-
mation for the ring, the substituents occupy pseudo-equatorial or
In addition to the Lipinski’s drug-like and ADMET (Absorption,
Distribution, Metabolism, Excretion and Toxicity) properties, the
conformational structures of medicinally important non-aromatic
heterocyclic compounds are extremely important as they play a
vital role in the SARs (structure-activity relationships) [1]. This is
particularly true for nitrogen incorporated drug candidates as their
conformational structure determines the availability of the nitro-
gen lone pair for hydrogen bonding acceptor properties and for ba-
sicity. [2]. Piperidine and its derivatives are among the most impor-
tant nitrogen incorporated non-aromatic heterocyclic compounds.
Many bioactive natural products (e.g. anabasine, a tobacco alka-
loid) [3] and non-natural product drug candidates (e.g. nojirimycin,
an anti-diabetic drug) [4] have piperidine core [5]. Like cyclohex-
ane, the stable conformation of the piperidine ring is a chair, but
unlike cyclohexane its conversion from one chair into another pri-
marily goes through inversion at nitrogen [6]. In the case of N-
substituted piperidines, substituents play crucial role in determin-
pseudo-axial position resulting in interplay between stable confor-
mation of the ring and that of the substituent. Our previous stud-
ies have revealed that in the case of 1-alkyl-2,6-diaryl substituted
piperidines, the piperidine ring stabilizes in flattened chair confor-
mation and the N-alkyl group adopts an equatorial orientation [8].
Since many bioactive piperidines, including anticancer drug Gilteri-
tinib (1) [9], anti-tuberculosis drug Delamanid (2) [10], antidiabetic
drug Repaglinide (3) [11] (Fig. 1.) are N-aryl piperidines, we be-
came interested in the synthesis and study of the conformational
structures of 1,2,6-triaryl piperidines. Herein, we describe a facile
synthesis and solution (by NMR), solid (by single crystal XRD, Hir-
shfeld Surface and Fingerprint Plot Analysis) and gas phase (by DFT
calculations) structural properties of a set of 1-aryl-2,6-diphenyl
piperidines.
Several methods exist for the construction of N-substituted
piperidines. They include Leuckart reductive amination [12], palla-
dium catalyzed Buchwald-Hartwig amination [13] and copper cat-
alyzed Ullmann reaction [14]. By considering environmental as-
pects, we explored the synthesis of N-arylpiperidines by Leuckart
reductive amination, which works under metal-free conditions
[15]. We have previously reported a method for the Leuckart re-
ductive amination towards the construction of piperidine ring from
Abbreviations: DFT, Density Functional Theory; XRD, X-ray Diffraction; GOOF,
Goodness of Fit; NMR, Nuclear Magnetic Resonance.
∗
Corresponding author.
E-mail address: profhspr@gmail.com (H.S.P. Rao).
https://doi.org/10.1016/j.molstruc.2021.130065
0022-2860/© 2021 Elsevier B.V. All rights reserved.

H.S.P. Rao, E. Poonguzhali and J. Muthukumaran
Journal of Molecular Structure 1232 (2021) 130065
Fig. 1. Structures of Gilteritinib (1), Delamanid (2), and Repaglinide (3).
Scheme 1. Microwave mediated synthesis of 1,2,6-triarylpiperidines.
oven kept at 120°C for 4 min for complete consumption of the
diketone. Workup and chromatographic purification furnished the
triphenyl piperidine 4a in 66% yield (Scheme 1). Reduction of
reaction temperature (e.g. 100°C) or reduction in time (e.g. 2 min)
led to incomplete conversion. Increasing the reaction temperature
open chain 1,5-diketones under conventional thermal conditions
[16]. For the present study, we have explored microwave heating
as an alternative [17], and found that the reactions were fast, clean,
and high yielding [18].
to 140°C led to decomposition of the reactants/product; as
a
2. Materials and Methods
result, there was a lowering of the yield (54%). We varied the
solvent from PEG-200 to ethylene glycol (42%), triethylene glycol
(61%) and tetraethylene glycol (53%), PEG-400 (51%) and PEG-600
(47%) and found that PEG-200 is the most suitable medium for
the reaction. PEG-200 is an inexpensive, food compatible, readily
available, water-soluble, and high boiling liquid [19]. Unlike PEG-
400 or PEG-600, it is not highly viscous and like them absorbs
microwaves efficiently. The 13C NMR spectrum of 4a displayed
11 signals which confirmed that the C(2) and C(6) phenyl groups
are cis. If they were trans, due to lack of symmetry, the spectrum
would have displayed 17 signals.
The materials and methodology section of the current work is
given in the supplementary information.
3. Results and discussion
3.1. Synthesis and characterization
Synthesis
of
1,2,6-triphenylpiperidine
4a
from
1,5-
diphenylpentane-1,5-dione
5
and phenylammoniunmformate
6a was selected as the test case to develop optimal conditions
for the Leuckart reaction (Scheme 1). We conducted each run at
1 mmol scale of the dione 5. In the beginning, we prepared 2
mmol of phenylammonium formate by slow addition of aniline
(2 equiv) to formic acid (2 equiv, 85% aqueous solution) taken in
3 equiv of polyethylene glycol-200 (PEG-200; average molecular
weight of glycols is 200) at 0°C. To the resulting turbid viscous
liquid, 1,5-diphenylpentane-1,5-dione 5 (1 mmol) in 3 equivalent
of PEG-200 was added, and the resulting viscous liquid was ex-
posed to microwaves (MW) generated in a mono-mode microwave
The MW mediated Leuckart reaction of the 1,5-diketone 5 with
phenylammonium formate 6a to form 1,2,6-triphenylpiperidine 4a
under optimized conditions proved to be general. By following this
ꢀ
ꢀ
method, we prepared N-4 -tolyl, N-anisyl, and N-2 -tolyl substi-
tuted cis-2,6-diphenylpiperidines 4b-d in good yield (Scheme 1)
[20]. In each case, a single diastereomer resulted in the reac-
tion. We confirmed the structures of 4b-d based on their 1H and
ꢀ
13C NMR spectra. Facile synthesis of N-2 -tolyl substituted cis-2,6-
ꢀ
diphenylpiperidines 4d, which has a sterically demanding N-2 -
2

H.S.P. Rao, E. Poonguzhali and J. Muthukumaran
Journal of Molecular Structure 1232 (2021) 130065
Fig. 2. Structure and 1H NMR spectral data of N-phenylpiperidine 8, 1,2-diphenylpiperidine 9 and 1,2,6-triphenylpiperidine 4a.
Fig. 3. Minimum energy conformation of N-aryl-cis-2,6-diphenylpiperidines 4a-d generated by DFT calculations.
tolyl substitution, indicated robust nature of the microwave me-
rings located on consecutive carbon/nitrogen atoms of the ring. In
order to attain stability, and to avoid steric repulsion between the
aryl rings, the piperidine ring may deviate from the stable chair
conformation to boat or twisted boat conformation. Alternatively,
the ring may adopt chair conformation and the N-aryl group may
adopt axial orientation.
diated method for the Leuckart’s reductive amination.
3.2. Stereochemical Analysis
Conformational analysis of the N-aryl-2,6-diphenylpiperidines
4a-d was taken-up to understand the orientation of the three aryl
3

H.S.P. Rao, E. Poonguzhali and J. Muthukumaran
Journal of Molecular Structure 1232 (2021) 130065
Table 1
Conformational study of minimum energy compounds 4a-d derived from DFT calculations.
Entry
4a(N-Ph)
4b(N-4ꢀ-CH3Ph)
4c(N-4ꢀ-OCH3Ph)
4d(N-2ꢀ-CH3Ph)
Observations
Torsional angle
1
C15-C4-N1-C2 = 64o
C11-C4-N1-C2 = -115o
C15-C4-N1-C8 = -64o
C11-C4-N1-C8 = 115o
H3-C2-C22-H23 = 173o
H3-C2-C22-H24 = 57o
H9-C8-C25-H27= -173o
H9-C8-C25-H26 = -57o
H3-C2-N1-C8 = -65o
C15-C4-N1-C2 = -63o
C11-C4-N1-C2 = 117o
C15-C4-N1-C8 = -65o
C11-C4-N1-C8 = 114o
H3-C2-C22-H23=-173o
H3-C2-C22-H24=-58o
H9-C8-C25-H27 = 173o
H9-C8-C25-H26 = 57o
H3-C2-N1-C8 = -64o
C15-C4-N1-C2 = -64o
C11-C4-N1-C2 = 115o
C15-C4-N1-C8 = -63o
C11-C4-N1-C8 = 116o
H3-C2-C22-H23 = -173o
H3-C2-C22-H24 = -57o
H9-C8-C25-H27 = 173o
H9-C8-C25-H26 = 57o
H3-C2-N1-C8 = -65o
C15-C4-N1-C2 = -63o
C11-C4-N1-C2 = 116o
C15-C4-N1-C8 = 63o
C11-C4-N1-C8 = -116o
H3-C2-C22-H23 = -175o
H3-C2-C22-H24 = -59o
H9-C8-C25-H27 = 175o
H9-C8-C25-H26 = 59o
H3-C2-N1-C8 = -61o
Perpendicular to the piperidine
Nearly Chair conformation
2
3
4
5
Axial hydrogen on C2 and C6 of
piperidine
H9-C8-N1-C2 = 65o
C5-C2-N1-C8 = -175o
H9-C8-N1-C2 = 64o
C5-C2-N1-C8 = 176o
H9-C8-N1-C2 = 65o
C5-C2-N1-C8 = 175o
H9-C8-N1-C2 = 61o
C5-C2-N1-C8 = 179o
Equatorial phenyl ring on C2
and C6 of piperidine
C17-C8-N1-C2 = 175o
C17-C8-N1-C2 = -175o
C22-C2-N1-C4 = 179o
C25-C8-N1-C4 = -179o
C17-C8-N1-C2 = -175o
C22-C2-N1-C4 = -179o
C25-C8-N1-C4 = 179o
C17-C8-N1-C2 = -179o
C22-C2-N1-C4 = -178o
C25-C8-N1-C4 = 177o
C22-C2-N1-C4 = -179.8o
C25-C8-N1-C4 = -179.99o
Equatorial N-Phenyl ring
6
7
H3-C2-C5-C32 = -9o
H3-C2-C5-C18 = 173o
H9-C8-C17-C34 = -173o
H9-C8-C17-C20 = 9o
C-N-C Angle
H3-C2-C5-C32 = 10o
H3-C2-C5-C18 = -173o
H9-C8-C17-C34 = 174o
H9-C8-C17-C20 = -9o
H3-C2-C5-C32 = 9o
H3-C2-C5-C32 = 0.5o
H3-C2-C5-C18 = 177o
H9-C8-C17-C34 = -177o
H9-C8-C17-C20 = -0.3o
Nearly orthogonal to the
piperidine ring
H3-C2-C5-C18 = 174o
H9-C8-C17-C34 = 173o
H9-C8-C17-C20 = -9o
8
9
C2-N1-C8 = 113.90o
C2-N1-C4 = 111.30o
C8-N1-C4 = 111.32o
Grand total = 336.5o
Degree of Pyramidalization
360 - 337 = 23o
C2-N1-C8 = 113.69o
C2-N1-C4 = 111.57o
C8-N1-C4 = 111.48o
Grand total = 336.7o
C2-N1-C8 = 113.91o
C2-N1-C4 = 111.45o
C8-N1-C4 = 111.53o
Grand total = 336.8o
C2-N1-C6 = 112.28o
C2-N1-C19 = 111.47o
C8-N1-C4 = 111.53o
Grand total = 335.2o
sp3 - hybridization
360 - 337 = 23o
360 - 337 = 23o
360 - 335 = 25o
Flattened chair conformation
Fig. 4. The molecular structure of the 4b with the atom-numbering scheme and displacement ellipsoids drawn at the 50% probability level
ring is in classical chair form, the dihedral angles would be 180°
and 60°. Observed dihedral angles indicated that to avoid steric in-
teractions between three phenyl rings, the molecule adopts a flat-
tened chair conformation in its most stable form. The signals at
δ 6.59 (br m, 1H), 6.73-6.78 (m, 4H), 6.95-6.97 (m, 2H), 7.01-7.05
(m, 4H), 7.16-7.19 (m, 4H) ppm were assigned to aromatic hydrogen
atoms. This data matched well with the data of N-phenylpiperidine
8 (δ 6.88 (tt, J = 7.2, 1.0 Hz, 1H), 6.95-7.04 (m, 2H), 7.26-7.35 (m,
2H)) [21] and 1,2-diphenylpiperidine 9 (6.7-7.3 m, 10H) [21]. Fur-
Our first attempt was to understand stable conformation of
4a in solution phase. The 400 MHz 1H NMR spectrum of 1,2,6-
triphenylpiperidine 4a recorded as a dilute solution (1% w/v) in
CDCl3 displayed a double doublet (dd) at δ 3.95 ppm (J = 6.77 Hz,
6.49 Hz) assignable to C(2)H and C(6)H. The central peaks in the
dd almost merged, giving it a triplet like an appearance. The cou-
pling constants, when fitted into the Karplus equation gave dihe-
dral angles of 149° and 27° between H-C(2)-C(3)-Hax and H-C(2)-
C(3)-Heq. If the C(2)Ph and C(6)Ph were equatorial and piperidine
4

H.S.P. Rao, E. Poonguzhali and J. Muthukumaran
Journal of Molecular Structure 1232 (2021) 130065
Fig. 5. View of the three-dimensional Hirshfeld surface of the 4b. Interacting portions were also highlighted as red in color.
Fig. 6. The two-dimensional Fingerprint plots of the 4b, showing CꢀH interactions [de and di represent the distances from a point on the Hirshfeld Surface to the nearest
atoms outside (external) and inside (internal) the surface, respectively.
thermore, the data indicated that there is the near absence of the
anisotropic influence by neighboring C(2) and C(6) phenyl rings on
the central N-phenyl ring.
values further confirmed that the ortho-hydrogen atoms of the N-
aryl ring come within the shielding zone of the adjacent C(2) and
C(6)phenyl rings.
The ortho and meta hydrogen atoms of the N-4-methylphenyl
of 4b appeared as two doublets at δ 6.66 and 6.53 ppm. When
compared with the reported values of 4-methylphenylpiperidine
[22], which displayed two doublets at δ 6.86 and 7.05 ppm cor-
responding signals for 4b shifted up-field by δ 0.39 and 0.33
ppm indicating their presence in the shielded environment. Sim-
ilarly, for 4c, the ortho and meta hydrogen atoms of the N-4-
methoxyphenyl group appeared as two doublets located at δ 6.33
and 6.76 ppm. These values, when compared with the reported
values of 4-methoxyphenylpiperidine [23] (δ 6.82 and 6.91 ppm)
were shifted up-field by δ 0.49 and 0.15 ppm, respectively. These
We prepared 1-(2-methylphenyl)-2,6-diphenylpiperidine 4d to
study conformational preferences of the piperidine and the aro-
matic rings upon increasing steric crowding in the N-aryl ring due
to the presence of C(2’)Me group. Unlike 4a-c, the 1H NMR spec-
trum of 4d displayed a doublet at δ 3.95 (d, J = 10.8 Hz, 2H).
The large coupling constant value shows that C(2)H and C(6)H
were of axial orientation. The chemical shift of C(2’)Me was δ 1.8
ppm which when matched with an aromatic methyl group in 4-
methyl-orthotolylpiperidine (δ 2.28 ppm) [24] was shifted up-field
by about 0.48 ppm. Similarly, the aromatic C(6’)H was up-field
shifted by about 0.43 ppm (δ 6.48 ppm for 4d and (δ 6.91 ppm
5

H.S.P. Rao, E. Poonguzhali and J. Muthukumaran
Journal of Molecular Structure 1232 (2021) 130065
Fig. 7. Crystal packing of 4b showing weak intermolecular C-H…π interactions.
for 4-methyl-orthotolylpiperidine). The up-field shift indicates that
N-aryl ring in 4d experiences shielding effect from the C(2) and
C(6) phenyl rings.
C2-N1-C19 elucidated the equatorial orientation of phenyl ring on
C(2) / C(6) and N-aryl on piperidine (Table 1, entry 4 & 5). The tor-
sional angle between H25-C2-C13-C14 / H25-C2-C13-C18 and H32-
C6-C7-C8 / H32-C6-C7-C12 showing the orthogonal orientation of
C(2) and C(6)-phenyl ring to piperidine (Table 1, entry 6 & 7). The
sum of the angle around ꢀCNC piperidine (C2-N1-C6, C2-N1-C19
and C19-N1-C6) showing the sp3 hybridization of nitrogen (Table 1,
entry 8) and the value of 360°-ꢀCNC illuminate the flattened chair
Observed up-field shift of N-aryl C(2)H signals in the NMR spec-
tra of 4a-d owing to the influence of C(2) and C(6) phenyl rings
prompted us to study the conformational structures using Den-
sity Functional Theory (DFT). The DFT calculations provided gas-
phase conformational structures, whereas the NMR spectra pro-
vided solution-phase structural information. Computations were
carried out using the B3LYP method and 6-31G(d,p) basis set in
Gaussian 03 suite of programs [25] for the calculation of geome-
try optimization, vibration frequencies and NMR spectroscopy. All
the optimized structures of the compounds 4a-d yielded real vi-
brational frequencies which ensured that they were minima on
the potential surface as shown in Fig. 3. The NMR chemical shift
calculations were obtained using the GIAO method [26] at the
same level of theory for the synthesized compounds 4a-d and TMS
(tetramethylsilane) the reference compound to scale the absolute
shielding value. Minimum energy conformation for the other com-
pounds 4b-d was also calculated and shown in Fig. 3.
ꢀ
conformation (Table 1, entry 9). The N-2 -tolyl methyl group is syn
to the nitrogen lone pair to avoid C2-C6-diaxial hydrogen repul-
sion (A1,5 strain) in compound 4d. The degree of pyramidalization
at the nitrogen of the piperidine ring is an indicator for chair flat-
tening (Table 1, entry 9) [27]. The degree of pyramidalization at ni-
trogen in 4a-d was about 23° which when compared to the corre-
sponding values observed for trimethyl amine (27.3°) and ammonia
(38.4°) indicated relative flattening at nitrogen atom in the piperi-
dine ring.
Further, we utilized the minimum energy conformation of 4a-
d to generate theoretical NMR spectra. The comparison of NMR
spectral data in liquid and gas phase showed that the chemical
shift values corroborate with each other. Both liquid and gas phase
study explained the up-field shift of the hydrogen atoms in the N-
aryl ring is due to the influence of ring flattening and substitution
of phenyl on piperidine nitrogen.
The minimum energy structural data were displayed in Table 1.
The derived torsional angle of C20-C19-N1-C2, C24-C19-N1-C2,
C20-C19-N1-C6 and C24-C19-N1-C6 explained perpendicular ori-
entation of N-aryl to the piperidine (Table 1, entry 1). The tor-
sional angle of H25-C2-C3-H27(ax), H25-C2-C3-H26(eq), H32-C6-C5-
H31(ax) and H32-C6-C5-H30(eq) shown the presence of nearly chair
conformation (Table 1, entry 2). The observed torsional angle of
H25-C2-N1-C6 and H32-C6-N1-C2 clarified the axially oriented hy-
drogen atoms on C(2) and C(6) of piperidine (Table 1, entry 3). Tor-
sional angle of C13-C2-N1-C6, C7-C6-N1-C2, C5-C6-N1-C19 and C3-
The results obtained from NMR spectral data analysis (liquid-
phase) and DFT calculations (gas-phase) espoused the study of
conformational structures in the solid phase by analysis of single-
crystal XRD data followed by Hirshfeld Surface and Fingerprint Plot
Analysis. We were able to obtain the single crystal XRD worthy
crystals of 4b by slow evaporation at room temperature of its so-
6

H.S.P. Rao, E. Poonguzhali and J. Muthukumaran
Journal of Molecular Structure 1232 (2021) 130065
Table 2
Comparison of 4b using XRD and DFT derived structure in solid and gas phases.
4b (N-4ꢀ-CH3Ph)Single
4b (N-4ꢀ-CH3Ph)DFT
Entry
crystal XRD
Observations
derived structure
Observations
Torsional angle
1
C15-C4-N1-C2 = -49o
C11-C4-N1-C2 = 134o
C15-C4-N1-C8 = -75o
C11-C4-N1-C8 = 100o
H3-C2-C22-H23 = -176o
H3-C2-C22-H24 = -59o
H9-C8-C25-H27 = 177o
H9-C8-C25-H26 = 59o
H3-C2-N1-C8 = -62o
H9-C8-N1-C2 = 61o
C5-C2-N1-C8 = 178o
C17-C8-N1-C2 = 178o
C22-C2-N1-C4 = -179o
C25-C8-N1-C4 = 178o
H3-C2-C5-C32 = 11o
H3-C2-C5-C18 = -172o
H9-C8-C17-C34 = -175o
H9-C8-C17-C20 = 6o
C-N-C Angle
Perpendicular to the piperidine
C15-C4-N1-C2 = -63o
Perpendicular to the piperidine
Eclipsed conformation with
nitrogen lone pair electrons
Nearly eclipsed conformation with C11-C4-N1-C2 = 117o
nitrogen lone pair of electrons
C15-C4-N1-C8 = -65o
C11-C4-N1-C8 = 114o
H3-C2-C22-H23 = -173o
H3-C2-C22-H24 = -58o
H9-C8-C25-H27 = 173o
H9-C8-C25-H26 = 57o
H3-C2-N1-C8 = -64o
H9-C8-N1-C2 = 64o
2
Nearly Chair conformation
nearly chair conformation
3
4
5
6
7
Axial hydrogen on C2 and C6 of
piperidine
Axial hydrogen on C2 and C6 of
piperidine
Equatorial phenyl ring on C2 and
C6 of piperidine
C5-C2-N1-C8 = 176o
C17-C8-N1-C2 = -175o
C22-C2-N1-C4 = 179o
C25-C8-N1-C4 = -179o
H3-C2-C5-C32 = 10o
H3-C2-C5-C18 = -173o
H9-C8-C17-C34 = 174o
H9-C8-C17-C20 = -9o
Equatorial phenyl ring on C2 and
C6 of piperidine
Equatorial N-Phenyl ring
equatorial N-Phenyl ring
Nearly phenyl on C2 and C8 are
orthogonal to the piperidine ring
Nearly phenyl on C2 and C8 are
orthogonal to the piperidine ring
8
9
C2-N1-C8 = 112.04o
C2-N1-C4 = 112.00o
C4-N1-C8 = 109.99o
Grand total = 334.03o
Degree of Pyramidalization
360 - 334 = 26o
sp3 - hybridization
C2-N1-C8 = 113.69o
C2-N1-C4 = 111.57o
C4-N1-C8 = 111.48o
Grand total = 336.7o
sp3 - hybridization
nearly chair conformation
360 - 337 = 23o
Flattened chair conformation
Table 3
Crystal data summary of 6b.
Empirical formula
C24 H25
327.45
N
Formula weight
Temperature
298(2) K
˚
Wavelength
0.71073 A
Crystal system, space group
Unit cell dimensions
Monoclinic, P2(1)/c
˚
a = 13.8737(9)A alpha = 90°
˚
b = 6.1658(4)A beta = 93.397(3)°
˚
c = 22.5571(15) A gamma = 90°
3
˚
Volume
1926.2(2) A
Z, Calculated density
Absorption coefficient
F(000)
4, 1.129 Mg/m3
0.065 mm−1
704
Crystal size
0.25 × 0.20 × 0.15 mm
1.81 to 28.35°
Theta range for data collection
Limiting indices
-18<=h<=14, -6<=k<=7, -25<=l<=22
10123 / 3675 [R(int) = 0.0284]
88.3 %
Reflections collected / unique
Completeness to theta = 25.00
Absorption correction
Max. and min. transmission
Refinement method
None
0.9904 and 0.9840
Full-matrix least-squares on F2
3675 / 0 / 227
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2sigma(I)]
R indices (all data)
1.007
R1 = 0.0513, wR2 = 0.1398
R1 = 0.1110, wR2 = 0.1752
0.185 and -0.219 e.A−3
Largest diff. peak and hole
lution in the mixture of ethyl acetate and hexanes (1:2). Collected
data at 298 K showed that 4b crystallized in monoclinic crystal
system with P2(1)/C space group and with unit cell parameters of
chair conformation with the puckering parameters of Q (Pucker-
˚
ing Amplitude): 0.5703 A, θ: 0.88° and ϕ: 201.5172°. To under-
stand the presence and role of intra and intermolecular interac-
tion in the crystal structure of 4b, we have additionally performed
Hirshfeld Surface and Fingerprint Plot analysis [28,29]. These anal-
yses are mainly used to find out the interacting atoms and ex-
plore the contribution of each atom in the 4b for the forma-
tion of intra and intermolecular interactions [30]. From the results,
it became clear that weak intermolecular C-H -π (C14-H14…Cg;
˚
˚
˚
a = 13.8737 A, b = 6.1658 A, c = 22.5571 A and cell angles of
α = 90o, β = 93.397o, γ = 90o and R-factors of the crystal were
R1 = 0.0513, wR2 = 0.1398. The crystal structure of 4b was de-
posited into CCDC with the accession number of 1415313. The crys-
tal data summary of 4b was presented in Table 3. The Goodness
of Fit (Goof) of 4b was observed to be 1.007. The solid state struc-
ture shows that the piperidine ring (N1/C1/C2/C3/C4/C5) makes di-
hedral angles of 112.04°, 126.95° and 94.75 (4)° to three aromatic
rings (Ring1: C6-C11/Ring2: C12-C17/Ring 3: C18-C24). The Cremer-
Pople puckering analysis suggested that the piperidine ring adopts
˚
H14…Cg = 2.99 A) interaction stabilize the crystal packing (Figs.
5-7). The observed distance in C-H -π interaction agree with those
described by Nishio 2011 [31]. However, there were no signifi-
cant intramolecular interactions between the aryl rings. The ta-
7

H.S.P. Rao, E. Poonguzhali and J. Muthukumaran
Journal of Molecular Structure 1232 (2021) 130065
bles related to the crystal structure of 4b was presented in Sup-
plementary Data. The percentage contributions from the different
interatomic contacts to the Hirshfeld Surfaces are as follows: HꢀH
(77.7%), CꢀH/HꢀC (22.2%), HꢀO/OꢀH (19.2%), CꢀC (0%), NꢀH (0%),
CꢀN (0%) and NꢀN (0%) as shown in the two-dimensional Finger-
print Plot (Fig. 6).
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4. Conclusion
We developed
a facile MW mediated synthesis of N-aryl-
cis-2,6-diphenylpiperidines using arylamine, formic acid, and 1,5-
diphenylpentane-1,5-dione through the novel application of mi-
crowaves to the classical Leuckart reaction. Detailed structural
studies using NMR (liquid phase), DFT (gas-phase) and single-
crystal XRD (solid phase) revealed that all the three aryl groups
on piperidine ring in N-aryl-cis-2,6-diphenylpiperidines are equa-
torially oriented to minimize unfavorable steric interactions and
maximize favorable C-H-π interactions. As a result, the piperi-
dine ring gets flattened. To us, the structure of N-aryl-2,6-
diphenylpiperidines looked like the head of an elephant. The C(2)
and C(6) phenyl rings resemble its ears and central N-aryl ring its
snout.
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H. Surya Prakash Rao: Conceptualization, supervision, literature
survey, analysis, writing, review, and editing. E. Poonguzhali: Ex-
perimental work, literature survey, spectral data collection, compi-
lation, and report. Jayaraman Muthukumaran: XRD data analysis,
writing at draft stage, review, and editing.
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
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Acknowledgements
Authors thank to Department of Chemistry, Pondicherry Central
University, Puducherry for facilities. EP thanks to DST-FIST for XRD
single crystal facility at Department of Chemistry, Indian Institute
of Technology Madras (IITM), Council for Science and Technology
(CSIR) and Department of Science Technology (DST), New Delhi for
financial support. JM thanks Sharda University, Greater Noida for
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9