Spectral assignments and structural studies of a warfarin derivative stereoselectively formed by tandem cyclization

Article abstract of DOI:10.1016/j.molstruc.2015.07.058

Abstract The structural elucidation of a Mannich condensation product of rac-Warfarin with benzaldehyde and methyl amine was carried out using IR, Mass, ¹H NMR, ¹³C NMR, ¹H-¹H COSY, ¹H-¹³C COSY, DEPT-135, HMBC, NOESY spectra and single crystal X-ray diffraction. Formation of a new pyran ring via a tandem cyclization in the presence of methyl amine was observed. The optimized geometry and HOMO-LUMO energy gap along with other important physical parameters were found by Gaussian 09 program using HF 6-31G (d, p) and B3YLP/DFT 6-31G (d, p) level of theory. The preferred conformation of the piperidine ring in solution state was found to be chair from the NMR spectra. Single crystal X-ray diffraction and optimized geometry (by theoretical study) also confirms the chair conformation in the solid state.

Full text of DOI:10.1016/j.molstruc.2015.07.058

Journal of Molecular Structure 1100 (2015) 447e454
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Spectral assignments and structural studies of a warfarin derivative
stereoselectively formed by tandem cyclization
M. Velayutham Pillai, K. Rajeswari, T. Vidhyasagar*
Department of Chemistry, Annamalai University, Annamalai Nagar, 608 002 Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The structural elucidation of a Mannich condensation product of raceWarfarin with benzaldehyde and
methyl amine was carried out using IR, Mass, 1H NMR, 13C NMR, 1He1H COSY, 1He13C COSY, DEPTe135,
HMBC, NOESY spectra and single crystal X-ray diffraction. Formation of a new pyran ring via a tandem
cyclization in the presence of methyl amine was observed. The optimized geometry and HOMOeLUMO
energy gap along with other important physical parameters were found by Gaussian 09 program using
HF 6e31G (d, p) and B3YLP/DFT 6e31G (d, p) level of theory. The preferred conformation of the
piperidine ring in solution state was found to be chair from the NMR spectra. Single crystal X-ray
diffraction and optimized geometry (by theoretical study) also confirms the chair conformation in the
solid state.
Received 23 February 2015
Received in revised form
12 July 2015
Accepted 27 July 2015
Available online 30 July 2015
Keywords:
Tandem cyclization
Warfarin derivative
1D and 2D NMR
© 2015 Elsevier B.V. All rights reserved.
Single crystal X-ray diffraction
Theoretical studies
1. Introduction
we have tried to synthesize a molecular hybrid (5) containing both
coumarin and substituted piperidine moiety through a oneestep
2,6eDisubstitutede4epiperidines [1] are being constituents of
a number of alkaloids which have broad spectrum of biological
activities. Bicyclic systems with Nemethyl piperidine and pyran
units [2] together showed a distinct potential pattern of selectivity
towards antitumor activity. Aza spirosystems [3] containing
substituted piperidinyl rings exhibit antibacterial and antifungal
activities. Antimycobacterial evaluation carried out to explore the
biological efficacy of pyran derivatives [4,5] of Nemethyl piper-
idone is also known. 4eHydroxycoumarin derivatives such as
Warfarin, Acenocoumarol [6e9] possess anticoagulant and roden-
ticidal properties. Warfarin is being studied extensively due to its
pharmacological properties. Racemic sodium warfarin is the most
widely used antithrombotic drug in USA and Canada.
Mannich reaction. The reaction proceeded one step further to form
a cyclized product (4) containing an additional pyran ring with the
expected piperidine and coumarin rings. The structure and ste-
reochemistry of the newly synthesized product is established
through IR, Mass, 1H NMR, 13C NMR, 1He1H COSY,1He13C COSY,
DEPTe135, HMBC, NOESY spectra and through single crystal X-ray
diffraction analysis. Theoretical studies have also been carried out
using HF/6e31G (d, p) and B3YLP/DFT 6e31G (d, p) methods to
deduce optimized geometry, HOMOeLUMO energy gap, NLO
properties and Mulliken charge distribution etc.
2. Experimental
Multicomponent reactions involving three or more different
substrates reacting in a welledefined manner to form a single
compound has emerged as a powerful tool for synthesizing bio-
logically potent molecules [10]. Tandem reactions often afford
stereoselectivity [11e17] of medicinally important structural moi-
eties in a facile manner. It is noteworthy that hybrid molecules play
an important role in biological activity. Prompted by these reports,
2.1. Synthesis of compound 4
The parent compound racewarfarin (3) was prepared from
4ehydroxycoumarin (1) and benzylidene acetone (2) by the
Michael addition reaction as reported in the literature [6]. The title
compound 4 was prepared from racewarfarin as follows: A mixture
of 1 mmol (0.31 g) of racewarfarin, 2 equivalents (0.21 mL) of
benzaldehyde and 2 equivalents (0.17 mL) of methyl amine solution
(40% in water) in ethanol was heated to boiling on a hot plate.
Colourless crystals thus precipitated on cooling were recrystallized
from ethanol to get the product in pure form. Single crystal suitable
* Corresponding author.
E-mail address: tvschemau@gmail.com (T. Vidhyasagar).
http://dx.doi.org/10.1016/j.molstruc.2015.07.058
0022-2860/© 2015 Elsevier B.V. All rights reserved.

448
M. Velayutham Pillai et al. / Journal of Molecular Structure 1100 (2015) 447e454
for X-ray diffraction analysis was obtained by slow evaporation of a
solution of compound 4 in ethanol.
spectrum with number of scans ¼ 2000, acquisition time ¼ 1.36 s,
relaxation time ¼ 2 s, 90ꢀ pulse width (P1) ¼ 8.25
ms, spectral
width ¼ 24,038.461 Hz, line broadening ¼ 1.00 Hz, and FT
size ¼ 32,768. 1He1H COSY, 1He13C COSY, HMBC, DEPTe135 and
NOESY spectra were measured with the pulse sequence gcosy,
ghsqc, ghmbc, deptsp 135 and noesy respectively.
Single crystal X-ray diffraction analysis was carried out at 298 K
using a three circle Bruker SMARTeAPEX CCD area detector system
2.2. Spectral measurements and X-ray diffraction
FTeIR spectrum was recorded on a NICOLET AVATAR 360 FTeIR
spectrometer and the pellet technique (KBr) was adopted to record
the spectrum. LCeMass spectrum was recorded on
madzueLCMS 2010A mass spectrometer.
a Shi-
under Mo K
a
(
l
¼ 0.71073 Å) graphite monochromated X-ray beam
with a crystal to detector distance of 60 mm and a collimator of
0.5 mm. The total number of reflections was equal to 5582. The
structural refinement was done using SHELXL 97 by fullematrix
leastesquares method with anisotropic temperature parameter for
all non-hydrogen atoms.
NMR spectra were recorded on a Bruker ULTRASHILED 400 PLUS
spectrometer (Bruker Biospin gmBH, Rheinstetten, Germany) at
around 294 K. Deuterated chloroform was used as a solvent to
dissolve the compound 4. The quantity of sample (compound 4)
taken for 1H NMR and 1H decoupled 13C NMR were 10 mg and
50 mg respectively in 0.5 mL of CDCl3. Chemical shifts (
d) are
quoted in parts per million (ppm) and are referenced to the TMS,
2.3. Theoretical calculations
d
¼ 0 ppm. Spin multiplicities are expressed as singlet (s), doublet
(d), triplet (t), doublet of doublets (dd) and multiplet (m). Coupling
constants (J) are given in Hz. The 1H NMR data were acquired at
400 MHz frequency with number of scans ¼ 16, acquisition
Theoretical calculations were done by considering the crystal
structure of compound 4 as the initial structure using HF and
B3YLP/DFT methods using 6e31G (d, p) as the basis set in Gaussian
09 package [18] to optimize the structure. The lowest unoccupied
molecular orbital (LUMO) and highest occupied molecular orbital
(HOMO) energy differences for the molecule were calculated by
time ¼ 3.98 s, relaxation time ¼ 1 s, 90ꢀ pulse width (P1) ¼ 13.50
ms,
spectral width ¼ 8223.685 Hz, line broadening ¼ 0.30 Hz, and FT
size ¼ 65,536. A frequency at 100 MHz was observable for 13C NMR
Scheme 1. Synthetic scheme of compound 4.

M. Velayutham Pillai et al. / Journal of Molecular Structure 1100 (2015) 447e454
449
Table 1
1H (400 MHz) and 13C NMR (100 MHz) spectroscopic data of compound 4 (in CDCl3).
Atom
dH (ppm)
dC (ppm)
number
1
2
8.07 (d, 1H, J ¼ 7.6 Hz, H1)
122.8 (C1)
124.0 (C2)
7.36 (t, 3H, AreH)(H2 and H4 e merged with phenyl ring proton signal)
3
4
7.64 (t, 1H, J ¼ 8 Hz, H3)
132.0 (C3)
116.9 (C4)
7.36 (t, 3H, AreH) (H2 and H4 e merged with phenyl ring proton signal)
4a
6
e
153.2 (C4a)
162.3 (C6)
e
6a
7
e
92.9 (C6a)
36.1 (C7)
3.97 (s, 1H, H7)
7a
8
9
10
11
11a
12a
13
2.89 (d, 1H, J ¼ 10.8 Hz, H7a)
50.3 (C7a)
71.3 (C8)
42.0 (NCH3)
65.5 (C10)
43.0 (C11)
26.4 (NHCH3) 99.6 (C11a)
159.3 (C12a)
115.9 (C13)
2.95 (d, 1H, J ¼ 10.8 Hz, H8)
1.68 (s, 3H,N9eCH3)
3.35 (d,1H, J ¼ 9.6 Hz, H10)
2.05 (t, 1H, J ¼ 13.6 Hz, H11ax) 2.63 (dd,1H, J ¼ 14.4 Hz, 2.4 Hz, H11eq)
2.17 (s,3H, NHeCH3) 3.48 (s,1H, NHeCH3)
e
e
Phenyl 6.85 (d, 2H, J ¼ 7.6 Hz, AreH) 7.11 (t, 1H, J ¼ 7.6 Hz, AreH) 7.19 (t, 2H, J ¼ 7.6 Hz, AreH) 7.30 (t, 2H, J ¼ 7.2 H, AreH) 142.2, 142.5, 144.0 (ipso carbons) 126.3,
rings 7.36 (t, 3H, AreH)(H2 and H4 e merged with phenyl ring proton signal) 7.43 (t, 3H, J ¼ 8.4 Hz, AreH) 7.89 (bs, 1H, 126.7, 127.1, 127.4, 128.1, 128.7, 128.9, 129.1,
AreH)
129.6, 131.1 (Others)
these methods. The other properties like bond lengths, bond an-
gles, dihedral angles, dipole moment, polarizability, hyper-
polarizability and Mulliken charge distribution pattern and some
other important molecular properties are also calculated using the
same package. Gauss View program is used to visualize the results
obtained from calculations, which were made by Gaussian 09
program.
3. Results and discussion
3.1. General
The reaction between 1 mmol of racewarfarin (3), 2 eq. benz-
aldehyde and 2 eq. methyl amine (40% in water) in ethanol at
boiling condition has resulted the precipitation of the crystalline
Fig. 1. 1H NMR spectrum of compound 4.

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M. Velayutham Pillai et al. / Journal of Molecular Structure 1100 (2015) 447e454
product:
9emethyle11ae(methylamino)e7,8,10etriphenyle7a,
3.2.2. 1H NMR spectrum
8,9,10,11,11aehexahydrochromeno
[30,40:5,6]pyrano[3,2ec]
The 1H and 13C chemical shift values are furnished in Table 1. The
signals in the 1H (Fig.1) and 13C NMR spectra (Fig. 2) of compound 4
were assigned based on their chemical shift, splitting pattern,
coupling constant values, correlations in the 2D NMR spectra and
comparison with the 1H and 13C NMR spectral data of
4ehydroxycoumarin available from spectral database for organic
compounds (SDBS) [19]. Selected 1He1H COSY, 1He13C COSY, HMBC
and NOE correlations of compound 4 (Table 2) are illustrated
through Fig. 3. The methyl protons of NCH3 and NHCH3 group are
resonating at 1.68 ppm and 2.16 ppm respectively as readily
recognizable signals in the 1H NMR spectrum. In the 1He1H COSY
spectrum (Fig. S1 in supplementary files), three signals respectively
at 3.35 ppm, 2.63 ppm and 2.05 ppm correlated among themselves
represent H10, H11eq and H11ax protons forming an AMX spin
system of coupling. This assignment is confirmed by their coupling
pyridine6(7H)eone (4). The synthetic scheme of compound 4 is
shown in Scheme 1. Recrystallization of the crude product from
ethanol gave the pure product (yield 68%).
The Michael addition of 4ehydroxycoumarin (1) with benzyli-
dene acetone (2) in water heated to reflux condition gives
4ehydroxye3e(3eoxoe1ephenylbutyl)e2Hechromene2eone
which is also known as racewarfarin (3). Warfarin undergoes
Mannich condensation with 2 equivalents of benzaldehyde and 1
equivalent
oxoe2Hechromene3eyl)
of
methylamine
forms
3e[(4ehydroxye2e
(phenyl)methyl]e1emethyle2,6e
diphenylpiperidine4eone (5) which on enamination at the ketonic
carbonyl group of piperidine ring by means of methylamine fol-
lowed by cyclization with the enolic group of the coumarin moiety
to give the title compound 4 stereoselectively in such a way that the
cyclization resulted in the formation of a pyran ring and a new
stereogenic centre.
constant values observed [3J(H10ax,
¼
9.6 Hz,
H11ax)
2J(H11eq,H11ax) ¼ 14.4 Hz, and J(H11eq,H10ax) ¼ 2.4 Hz]. A one proton
singlet at 3.97 ppm correlated to one of the protons of the AB spin
system at 2.89 ppm with a coupling constant of 10.8 Hz represents
H7 and H7a protons which are characteristic of vicinal protons
orienting trans axially to each other. Further, the correlation be-
tween one of the proton signal of AB spin system at 2.95 ppm
(J ¼ 10.8 Hz) with the carbon signal at 71.3 ppm in the 1He13C COSY
spectrum (Fig. S2 in supplementary file) indicates the former as H8.
The one proton signal at 3.48 ppm assigned to amino proton (NH) is
substantiated by D2O exchange process (Spectrum shown in the
supplementary file).
3
3.2. Spectral assignments
3.2.1. FTeIR and LCeMASS spectra
FTeIR spectrum of compound 4 (Fig. S6 in the supplementary
file) showed peaks at 3389 (NeH stretching), 1705 (C]O stretch-
ing), 1619 (C]C stretching), 1199 (CeO stretching) and others
which confirmed the product formation. Further, LCeMass spec-
trum (Fig. S7 given in the supplementary data) also displayed base
peak at m/z ¼ 529 representing (M þ H)þ ion thereby substantiated
the product formation.
Fig. 2. 13C NMR spectrum of compound 4.

M. Velayutham Pillai et al. / Journal of Molecular Structure 1100 (2015) 447e454
451
Table 2
Selected 1He1H COSY, 1He13C COSY, HMBC and NOESY spectral correlations of compound 4.
1H chemical shifts (in ppm)
1He1H COSY correlations
1He13C COSY correlations
13C chemical shifts in ppm)
HMBC correlations
13C chemical shifts in ppm)
NOESY correlations
(1H chemical shifts in ppm)
(
(
(1H chemical shifts in ppm)
8.07e6.84 (Aromatic Hydrogens) 8.07e6.84
132.0e116.9
36.1
Aromatic carbons
50.3,71.3,92.8, 99.6, 126.3, 142.2,
Aromatic protons
2.89,6.85
3.97(H7)
2.89
142.4, 159.3, 162.3
3.48(NH)
e
e
e
e
3.35(H10)
2.95(H8)
2.63,2.16,2.05
e
65.5
e
1.68, 2.05, 2.63, 2.95
71.3, 50.3
71.3, 50.3
42.9
26.4
42.9
42.0, 50.3, 126.3, 132.0, 142.2, 142.4 1.68, 3.35, 3.97, 6.85, 7.11, 7.89
36.1,71.3,99.6, 142.2, 142.4
50.3,92.8
92.8
65.5, 144.0
2.89(H7a)
2.63(11Heq)
2.16(NHCH3)
2.05(11Hax)
1.68(NCH3)
3.97
3.35, 2.05
3.35
3.35, 2.63
e
1.68, 2.05, 3.35, 3.97,6.85, 7.11, 7.89
2.05, 2.16, 3.35
2.63, 3.35
2.63, 2.89, 3.35
2.95, 3.35
42.0
65.5, 71.3
3.2.3. 13C NMR spectrum
DEPTe135 spectrum characteristic of methylene carbon and also
has significant 1He1H COSY, 1He13C COSY and HMBC spectral cor-
relations with respective protons. The latter signal is ascribable to
NeCH3 carbon as supported by its 1He13C COSY and HMBC spectral
correlations. Finally, the upfield signals at 36.1 and 26.4 ppm are
perceived as the signals of C7 and NHeCH3 from their correlations
in the 1He1H COSY, 1He13C COSY and HMBC spectra.
The less intense signals at 162.3, 159.3, 144.0, 142.5 and
142.2 ppm in the 13C NMR spectrum are assigned to C6, C12a and
ipso carbons of the phenyl rings respectively based on their corre-
lations in the HMBC spectrum (Fig. S3 in supplementary file), while
the signal of C4a carbon is found at 153.2 ppm. The signal of C13
carbon at 115.9 ppm is ascertained by its absence in the DEPTe135
spectrum (Fig. S4 in supplementary file), as it is a quaternary aro-
matic carbon. Similarly, other two quaternary carbons present in
the molecule viz. C11a & C6a are not observed in the DEPTe135
spectrum and the 13C NMR signals at 99.6 and 92.9 ppm are
assigned to them respectively based on the correlations of C11a
with H7 & H7a and the correlations of C6a with H7, H11eq &
C11aeNHCH3 in the HMBC spectrum. The signals pertaining to C8
and C10 carbons are assigned based on their correlations in the
1He13C COSY, DEPTe135 and HMBC spectra as 71.3 and 65.5 ppm
respectively. The piperidine ring carbon C7a which has significant
correlations with H7, H8 and H11eq protons in the HMBC spectrum
and shown correlation with H7a in the 1He13C COSY spectrum
showed its resonance at 50.3 ppm.
3.2.4. Stereochemistry
From the 1H NMR spectrum, the coupling constants between H7a
3
3
& H8 and H10 & H11 are extracted as J(H8,H7a) ¼ 10.8 Hz, J(H10ax,
2
3
¼ 9.6 Hz, J(H11eq,H11ax) ¼ 14.4 Hz, and J(H11eq,H10ax) ¼ 2.4 Hz
H11ax)
respectively. The large coupling (>10 Hz) experienced by the coupled
protons reveals their trans axial disposition and consequently sup-
ports the equatorial orientation of the substituents present in the
piperidine ring. This configuration leads to a stable chair conforma-
tion for the piperidine ring. Further, the coupling between H7 & H7a
amounts to 0 Hz as the former is observed as a singlet which is
supportive of the orientation of H7 and H7a protons 90ꢀ to each
other. From the NOESY spectrum (Fig. S5 in supplementary file), the
equatorial orientation of the NHCH3 group is confirmed by the cor-
relation between the methyl protons of it with the H11eq proton. The
Of the two adjacent signals at 43.0 and 42.0 ppm, the former one
is assigned to C11 carbon as it has shown negative peak in the
Fig. 3. (a) Selected 1He1H COSY and 1He13C COSY correlations (b) Selected HMBC spectral correlations and (c) Selected NOE correlations of compound 4.

452
M. Velayutham Pillai et al. / Journal of Molecular Structure 1100 (2015) 447e454
Fig. 4. ORTEP of compound 4 drawn at 50% probability level.
conformational preference of the pyran ring present in the molecule
is deducible as halfechair from X-ray crystallography.
shown in Fig. 4. The crystal belongs to triclinic system with the
ꢀ
space group Pı. In this molecule, piperidine ring adopts a chair
conformation with equatorial orientation of substituents while the
pyran ring exists in a half chair conformation. The torsion angle
O3eC13eC12eC11 ¼ 60.0ꢀ suggests that in the piperidine ring,
C13eO3 bond is axially oriented which resulted in the equatorial
3.2.5. Single crystal X-ray diffraction analysis
The single crystal X-ray diffraction analysis [20] of compound 4
was carried out to find the solid state geometry. A summary of data
obtained from the analysis is illustrated through Table S1 (in the
supplementary file). The ORTEP drawn at 50% probability level is
orientation
of
the
C13eN1
bond
(torsion
angle
N1eC13eC12eC22 ¼ 173.5ꢀ).
Fig. 5. Optimized structure of compound 4 by HF 6e31G (d, p) and DFT 6e31G (d, p).

M. Velayutham Pillai et al. / Journal of Molecular Structure 1100 (2015) 447e454
453
3.3. Theoretical study
3.3.1. Molecular geometry
Theoretical study has been carried out using HF/6e31G (d, p)
and B3YLP/DFT 6e31G (d, p) methods in Gaussian 09 program. The
full geometry optimization was carried out using 6e31G (d, p) basis
set both by HF and DFT methods. The optimized geometry for the
molecule predicted in the gas phase is shown in Fig. 5 and the
optimization parameters such as bond lengths, bond angles and
dihedral angles along with the experimental data obtained from X-
ray diffraction are given in the Table S2 (in supplementary file) for
comparative purpose. From the table, it is noticeable that there is
considerable agreement between theoretical and experimental
values of parameters such as bond lengths, bond angles. Despite
some deviations in bond angles and dihedral angles, the stereo-
chemical orientations of the substituents are not changed much.
The variations observed between theoretical and experimental
parameters could be understandable form the fact that in the solid
state, intra as well as intermolecular interactions (such as hydrogen
bonding and van der Waal's forces of attraction) play an important
role in the molecular packing and stability of the molecule. More-
over, in the theoretical study an isolated molecule in the gaseous
state is considered for calculations.
3.3.2. HOMOeLUMO energies
The HOMO and LUMO energies calculated by HF 6e31G (d, p)
are ꢁ8.7890 eV and ꢁ5.4422 eV respectively while that by DFT
6e31G (d, p) are ꢁ8.7639 eV and ꢁ5.4776 eV respectively. The
LUMO and HOMO are being measures of electron affinity (A) and
ionization energy (I) as - ELUMO ¼ A and -EHOMO ¼ I respectively. The
energy gap between the LUMO and HOMO is also indicative of the
global hardness (
the stability of the system while the term chemical potential (
given by ½[ELUMO þ EHOMO]. Further, the global electrophilicity in-
dex ( ) is derived from the relation . The above molecular
2/2
h
¼ ½[ELUMOꢁEHOMO]) which is associated with
m) is
u
u
¼
m
h
properties calculated are depicted in Table S3 (in the
supplementary file). The energy gap between the HOMO and the
LUMO as calculated by HF and DFT methods are 3.3468 eV and
3.2863 eV respectively which suggests that the molecule is soft,
more polarizable, associated with appreciable chemical reactivity.
Moreover, the HOMO and LUMO energy gap explains the eventual
charge transfer interactions that take place within the molecule
which are responsible for the bioactivity of the molecule.
The HOMO and LUMO diagrams of compound 4 as predicted by
HF and DFT methods are shown in Fig. 6. It is observed from the
HOMO and LUMO orbital diagrams [HF 6e31G (d, p)] that in the
HOMO, the electron density is localized mainly over the piperidine
ring only while in the LUMO; the electron density is distributed
mainly over the coumarin ring only and this also indicates that the
Fig. 6. HOMO and LUMO diagrams of compound 4.
hyperpolarizability calculated by theoretical study are shown in
Table S4 (in supplementary file). The dipole moment value equal to
4.2929 D (HF) and/or 3.9144 D (DFT) indicates the polar nature of
the molecule. The highest value of dipole moment is observed for
the component my equal to 2.7613 (HF) and/or 1.9532 (DFT) in the
molecule. The calculated polarizability is higher for the component
ayy ¼ ꢁ203.757 (HF) and/or ꢁ205.343 (DFT) and the hyper-
polarizability is higher for the bxxz component [75.9377 (HF) and/or
66.0241 (DFT)]. It is interesting to note that the calculated polar-
HOMO is made up of setype and LUMO is mostly petype orbitals.
The HOMOeLUMO diagram as per the DFT method reveals that the
electron density in HOMO is concentrated mainly in the piperidine
ring and there is only a partial distribution of electrons over phenyl
and coumarin rings. However, the LUMO has the electron density in
the coumarin and piperidine part but the phenyl rings attached to
the piperidine ring don't contribute to the LUMO and the phenyl
ring attached to the pyran ring is having a partial electron delo-
calization over it. It is notable that, when electronic transitions
occur from HOMO to LUMO in the molecule, electron density
significantly increases in the coumarin ring which thereby behaves
as an electron acceptor in the molecule and the remaining part of
the molecule act as the electron donor.
izability (
a
) value for compound 4 is equal to 62.209 ꢂ 10ꢁ24 e.s.u.
(HF) and/or 61.119 ꢂ 10ꢁ24 e.s.u. (DFT) which is almost 2½ times
greater than that of penitroaniline, a typical NLO material [21,22].
Also the comparison of hyperpolarizability [
b
, 0.98719 ꢂ 10ꢁ30
e.s.u. (HF) and/or 0.82098 ꢂ 10ꢁ30 e.s.u. (DFT)] of compound 4
(which is greater than that of the standard NLO material urea [23],
3.3.3. NLO properties
b
¼ 0.72137 ꢂ 10ꢁ30 e.s.u.) reveals that the former could be used as
The NLO properties such as dipole moment, polarizabilty and

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M. Velayutham Pillai et al. / Journal of Molecular Structure 1100 (2015) 447e454
Synthetic Applications of Piperidine and its Derivatives, Elsevier, Amsterdam,
an effective NLO material.
1991;
b) M.W. Edwards, H.M. Garraffo, J.W. Daly, Synthesis 11 (1994) 1167e1170.
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org. Med. Chem. Lett. 17 (2007) 6459e6462.
[5] R. Ranjith Kumar, S. Perumal, J. Carlos Menendez, P. Yogeeswari, D. Sriram,
Bioorg. Med. Chem. Lett. 19 (2011) 3444e3450.
3.3.4. Atomic charge distribution
The charge distribution on a molecule has a significant influence
on dipole moment, molecular polarizability, electronic structure,
vibrational spectra and other properties of molecular systems.
Mulliken atomic charge distribution is calculated for compound 4
and the table summarizing the charge distribution is given along
with the graph explaining the same pictorially in the
supplementary file (Table S5 and Fig. S8). It is seen from the graph
that the heteroatoms O1, N2, O3, N64 and O69 (atom numbering is
as per the theoretical study) are accumulated with negative charges
as a result of molecular relaxation and these atoms behave as
electron acceptors. There is a large accumulation of positive charge
on C21 and a large negative charge on O69 atoms. It is also notable
that both oxygen and nitrogen atoms are having equal negative
charges. The excess is taken from the nearby carbon and hydrogen
atoms and as a result of this they are found with positive sign in the
graph. Further, most of the carbon atoms are negatively charged
indicating the charge transfers that occur from hydrogen atoms to
carbon atoms in the molecule.
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4. Conclusion
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[20] Crystallographic data of compound 4 have been deposited with the Cam-
bridge Crystallographic Data Centre as publication number CCDC 995847.
Copy of the data can be obtained free of charge from CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [Fax: þ44(0) 1223 336033 or through eemail:
deposit@ccdc.cam.ac.uk].
A novel heteroaromatic product formed stereoselectively by
tandem sequence of reactions between rac-wararin, benzaldehyde
and methylamine was characterized through IR, Mass, 1H and 13C
NMR, 1He1H COSY, 1He13C COSY, DEPT-135, HMBC,NOESY spectra
and single crystal X-Ray diffraction. The conformation in the solu-
tion state of the piperidine ring is found to be chair and that of
pyran ring is half chair as per the NMR and single crystal data. The
optimized geometry of the molecule was found from theoretical
calculation using HF 6-31G (d, p) and B3YLP/DFT 6-31G (d, p) level
of theory in Gaussian 09 program and compared with the experi-
mental results.
Appendix A. Supplementary data
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b) P. Pulay, J. Chem. Phys. 78 (1983) 5043e5051;
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.molstruc.2015.07.058.
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