Crystal Structure Theory and Applications, 2012, 1, 74-78
http://dx.doi.org/10.4236/csta.2012.13014 Published Online December 2012 (http://www.SciRP.org/journal/csta)
Spectral Analysis and Crystal Structure of Spiro[2.2”]
Acenaphthene-1”-One-Spiro[3.3’]-5’-(2,3-Dichlorophenyl
Methylidene)-1’-Methylpiperidin-4’-One-4-
(2,3-Dichlorophenyl) Octahydroindolizine
Rakkappan Vishnu Priya1, Janakiraman Suresh1*, Sathiyamoorthi Sivakumar2, Raju Ranjith Kumar2
1Department of Physics, The Madura College (Autonomous), Madurai, India
2Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai, India
Received October 13, 2012; revised November 20, 2012; accepted November 27, 2012
ABSTRACT
The crystal structure of spiro[2.2”]acenaphthene-1”-onespiro[3.3’]-5’-(2,3-dichlorophenylmethylidene)-1’-methylpipe-
ridin-4’-one-4-(2,3-dich orophenyl) octahydroindolizine was elucidated by single crystal X-ray diffraction. The title
compound C37H30Cl4N2O2, crystallizes in the orthorhombic system, space group P212121 with a = 8.4610(4) Å, b =
16.0926(6) Å, c = 23.8997(11) Å and Z = 4. The central piperidine ring adopts twisted conformation, the piperidine of
octahydroindolizine ring is in chair conformation and the pyrrole ring is in slightly twisted envelope conformation. De-
tails of the synthesis, NMR, crystal structure determination and intra- and intermolecular interactions of the compound
are given.
Keywords: Single Crystal Structure; Conformation; Hydrogen Bond; NMR Spectra
1. Introduction
Tuberculosis (TB) is an infectious disease caused by the
bacterium Mycobacterium tuberculosis (MTB), which
usually infects the lungs but may also affect the other
parts of the body. This is one of the most prevalent dis-
eases responsible for the death of approximately one bil-
lion people during the last two centuries. TB remains a
severe public health problem in India accounting for
nearly one-third of the global burden, and it has been
estimated that 3.5 million of the population are infected
with TB [1]. In the past years, only a few drugs have
been approved by the Food and Drug Administration
(FDA) to treat TB, which reflects the inherent difficulties
in the discovery and clinical testing of new agents [2].
Hence, the discovery of fast-acting new drugs to effec-
tively combat TB is imperative.
In general, spiro compounds [3,4] and nitrogen het-
erocycles display good antimycobacterial activities [5-7].
Recently, Perumal et al. reported an atom economic syn-
thesis and evaluation of antimycobacterial activities of
spiro pyrido-pyrrolizines and pyrrolidines, [8,9] which
inhibited in vitro MTB and multi-drug resistant Myco-
bacterium tuberculosis (MDR-TB). In the course of
screening to discover new compounds that could be use-
ful for the treatment of TB, we herein report the synthe-
sis, NMR spectra and single crystal X-ray studies of the
title spiro compound.
Further it is also pertinent to note that the synthesis of
biologically active indolizine derivatives continues to
attract the attention of organic chemists, because of their
wide spectrum of biological activity. Indolizine deriva-
tives have been found to possess a variety of biological
activities such as anti-inflammatory [10], antiviral [11],
aromatase inhibitory [12], analgesic and antitumor [13]
activities. A brief survey of the Cambridge Structural
Database (Version 5.33; [14]) revealed a scarcity of pre-
cise crystallographic data on octahydroindolizine ring
systems. Hence, this structure is presumed to be very
interesting and rarely studied moieties. The chemical
diagram of the title compound is shown in Figure 1.
2. Experimental
2.1. Synthesis of the Title Compound
1,3-Dipolar cycloaddition of azomethine ylides to exo-
cyclic olefins constitutes a versatile protocol for the con-
struction of poly functionalized spiro-heterocycles. In
this context, we have synthesized 1-methyl-3,5-bis[(E)-
*Corresponding author.
C
opyright © 2012 SciRes. CSTA

R. V. PRIYA ET AL. 75
Figure 1. Chemical diagram of the molecule.
2,3-dichlorophenylmethylidene]tetrahydro-4(1H)-pyridi
none, an exocyclic dipolarophile, from the reaction of
1-methyl-4-piperidone and 2,3-dichlorobenzaldehyde in
ethanol in the presence of NaOH. The cycloaddition of
the above dipolarophile with azomethine ylide generated
in situ from the decarboxylative condensation of ace-
naphthenequinone and piperidine-2-carboxylic acid led
to the formation of the title compound in excellent yield.
A mixture of 1-methyl-3,5-bis[(E)-2,3-dichlorophenyl-
methylidene]tetrahydro-4(1H)-pyridinone (1 mmol), acena-
phthenequinone (1 mmol) and piperidine-2-carboxylic acid
(1 mmol) was dissolved in isopropyl alcohol (15 mL) and
heated to reflux for 60 min. After completion of the reac-
tion as evident from TLC, the mixture was poured into
water (50 mL), the precipitated solid was filtered and
washed with water (100 mL) to obtain the product as
pure yellow solid. The product was recrystallized from
ethyl acetate to obtain suitable crystals for the X-ray ana-
lysis. Melting point: 494 (2) K, Yield: 94%.
2.2. Structure Determination and Refinement
For the crystal structure determination, the intensity data
of the single-crystal of the compound C37H30Cl4N2O2 was
collected using a Bruker AXS Kappa APEX II single
crystal CCD Diffractometer equipped with graphite-
monochromated MoKα radiation (λ = 0.71073 Å) at room
temperature with a crystal dimension of 0.35 × 0.25 × 0.20
mm3. Accurate unit cell parameters were determined
from the reflections of 36 frames measured in three dif-
ferent crystallographic zones. The data collection, data
reduction and absorption correction were performed by
APEX2, SAINT-plus and SADABS program [15]. The
structure was solved by the direct method procedure and
the non-hydrogen atoms were subjected to anisotropic
refinement by full-matrix least squares on F2 using
SHELXL-97 program [16]. The positions of all the hy-
drogen atoms were identified from difference electron
density map, and they were constrained to ride on the
corresponding non-hydrogen atoms. Molecular graphics
were drawn using PLATON [17]. The crystal data, ex-
perimental conditions and structure refinement parame-
ters for the title compound are presented in Table 1.
Table 1. The crystal data, experimental conditions and stru-
cture refinement parameters of the title compound.
Empirical formula C37H30Cl4N2O2
Formula weight 676.43
Temperature 293(2) K
Wavelength 0.71073 Å
Crystal system, space group P212121, orthorhombic
Unit cell dimensions
a = 8.4610(4) Å
b = 16.0926(6) Å
c = 23.8997(11) Å
Volume 3254.2(2) Å3
Z, Calculated density 4, 1.38 mg/m3
Absorption coefficient 0.401 mm–1
F(000) 1400
Crystal size 0.23 × 0.21 × 0.19 mm3
Theta range for data collection2.12 to 24.91 deg
Limiting indices –8< = h < = 10, –18, = k < = 19
–22< = l < = 28
Reflections collected/unique 16629/5642 [R(int) = 0.032]
Completeness to theta 99.6%
Absorption correction ω-scan
Refinement method Full-matrix least-squares on F2
Data/restraints/parameters 5642/0/407
Goodness-of-fit on F2 1.024
Final R indices [I > 2sigma(I)]R1 = 0.038, wR2 = 0.077
R indices (all data) R1 = 0.058, wR2 = 0.085
Largest diff. peak and hole 0.194 and −0.203 e·A–3
3. Results and Discussion
3.1. Spectral Data
The structure of title compound has been elucidated with
the help of 1H, 13C and two dimensional NMR spectro-
scopic studies. The H,H-COSY spectrum of the com-
pound assigns a doublet and multiplet at 4.81 ppm (J =
9.9 Hz) and 4.00 ppm to H-4 and H-4a respectively.
Further, H-4 shows HMBC correlations with C-4’, C-3,
C-4a and C-5 at 195.7, 64.4, 64.5 and 25.5 ppm respec-
tively. The signals of 5, 6, 7 and 8-CH2 protons overlap
and appear as a multiplets from 1.26 to 2.15 ppm
whereas the carbon signals appear at 25.5, 24.1, 30.8 and
45.6 respectively. The multiplet in a range 1.26 - 1.30
ppm and the doublet at 2.95 ppm (J = 12.6 Hz) are as-
signed to 2’-CH2 protons. The 6’-CH2 protons appears as
doublets at 2.71 and 2.48 ppm (J = 15.3 Hz). The C,H-
COSY correlations assign the carbon signals at 56.9 and
55.3 to C-2’ and C-6’ carbons respectively. The singlet at

R. V. PRIYA ET AL.
76
1.69 ppm is due to the N-CH3 protons. The aromatic
protons appear as a multiplet in a range 6.58 - 7.97 ppm.
The 1H and 13C NMR chemical shifts of the title com-
pound are shown in Figure 2.
It is pertinent to observe that the chemical shifts of
2’-CH2 of the compound (2.95 ppm ~1.30 ppm) differ
very much by 1.65 ppm. This suggests that probably the
H-2eq is spatially proximate to the carbonyl of ace-
naphthylen-1 (2H)-one shifting it downfield, while H-2ax
lies in the shielding zone of the acenaphthylen-1(2H)-
one ring shifting it downfield suggesting relative con-
figuration at C-2 for the compound. The alternative ste-
reochemistry with inversion of configuration at C-2 rela-
tive to that shown on the compound bringing both the
carbonyls of the piperidone and acenapthene rings to-
wards each other in spatial proximity, probably renders
the transition state of the cycloaddition unstable by elec-
trostatic repulsion. This could raise the free energy of
activation (transition state B in Figure 3), relative to the
transition state leading to the formation of the compound
with both carbonyls placed far off (transition state A in
Figure 3).
Figure 2. 1H and 13C NMR chemical shifts of the com-
pound.
Figure 3. Stereochemistry of formation of cycloadducts dif-
fering in their configurations at C-2.
3.2. Crystal Structure
Figure 4 shows the ORTEP plot drawn at 50% probabi-
lity displacement ellipsoids of title compound and the
atom-numbering scheme. The six membered piperidine
ring in the title compound adopts the half chair confor-
mation as evident from puckering parameters Q = 0.561
(3) Å, θ = 136.9(3)˚ and Φ = 140.6(4)˚ [18]. The olefinic
double bond in the structure has an E configuration. The
piperidine of octahydroindolizine ring is in the chair con-
formation as evident from the puckering parameters Q =
0.574(2) Å, θ = 180(3)˚ and Φ = 69(11)˚ [18]. The
pyrrole ring is in the twisted envelope conformation with
atom N2 at the flap as the puckering parameters are, Q =
0.424(3) Å, and Φ = 12.2(4)˚ [18,19].
The dihedral angles between the mean plane of the
piperidone ring and the aryl rings are 38.69(1)˚, 82.28(1)˚
which indicate that the aryl rings in the structure are not
coplanar with the mean plane of the piperidone ring.
As a result, the torsion angle C3C31C32C33 is
41.24(3)˚. This lack of coplanarity is caused by non-
bonded interactions between one of the ortho H atoms in
the aryl ring and the equatorial H atoms at the 2-position
of the piperidone ring (H33/H2A or H2B). As a result of
these steric repulsions, the bond angle C3C31C32
expands to 128.69 (19)˚ instead of 120˚. The dichloro-
phenyl rings are planar as confirmed by the values of the
r.m.s. deviations 0.0186 and 0.0127 Å. The dihedral an-
gle between the dichlorophenyl rings is 74.22 (1)˚. The
di- hedral angles of these dichlorophenyl rings with ace-
naphthene group are 30.84 (1)˚ and 78.99 (1)˚.
The Csp2-Csp2 distances in the acenaphthene group
range from 1.346(3) (C19-C20) to 1.574(2) Å (C13-C14)
and the C-C-C bond angles from 101.54(16)˚ (C12-C11-
Figure 4. The molecular structure of the tittle compound
showing the atom numbering scheme. Displacement ellip-
soids are drawn at 50% probability level, using ORTEP 3.
Hydrogen atoms are omitted for clarity.

R. V. PRIYA ET AL. 77
C19) to 123.32(2)˚ (C16-C17-C21). These values are in
agreement with related structures [20-24]. The C8-N2
bond distance being 1.450 (3) Å is comparable to the
Csp2-Nsp2 distances found in similar structures [25,26]. In
the crystal structure some weak C—H···O intramolecular
interactions have been observed (Table 2). A C---H...π
interaction (Ta bl e 2) C10---H10B…Cg1, (Cg1 is the
centroid of the ring C32-C37) forms, a two dimensional
linear zig zag chain running parallel to the b-axis as
shown in Figure 5.
4. Conclusion
Spiro[2.2”]acenaphthene-1”-onespiro[3.3’]-5’-(2,3-dich-
lorophenylmethylidene)-1’-methylpiperidin-4’-
one-4-(2,3-dichlorophenyl) octahydroindolizine was syn-
thesized through 1,3-dipolar cycloaddition reaction. The
single crystal of the title compound is obtained by slow
evaporation method (solvent: 1:1 ethyl acetate-ethanol).
The conformational features of the compound are deter-
mined in the solid phase by X-ray method and in liquid
phase by NMR method. The replacements of the equato-
rial H atoms at the 2- and 6-positions, and the attachment
of different atoms to one or two of the atoms C33, C37,
C72 and C76, are likely to alter the C3-C31-C32 and
C8-C7-C71 bond angles. Correlations have been established
Table 2. Hydrogen bonds [Å and ] of the compound.
D-H...A d(D-H)d(H...A) d(D...A)DHA
C(6)-H(6A)...O(2) 0.97 2.37 3.003(3)122
C(7)-H(7)...Cl1(1) 0.98 2.53 3.062(3)114
C(8)-H(8)...O(2) 0.98 2.45 3.091(3)123
C(18)-H(18)...O(1) 0.93 2.55 3.192(4)126
C(7)-H(7)...O(1) 0.98 2.23 2.774(3)113
C(10)-H(10B)...Cg1 (i) 0.93 2.88 3.675(4)140
Symmetry transformations used to generate equivalent atoms: (i) 1 – x, 1/2 + y,
1/2 – z.
Figure 5. Partial packing diagram showing the C---H…π
interaction along “b” axis.
between the bond angle values and bio-activity [27]. In
addition, the orientation of aryl rings will affect the
alignment of these rings at a binding site and hence in-
fluence bioactivity [28]. Further studies on structure-
bioactivity relationship of this compound are in progress
in our research group.
5. Acknowledgements
JS thanks the UGC for the FIST support. JS and RV
thank the management of Madura College for their en-
couragement and support. RRK thanks DST, New Delhi
for funds under fast track scheme (No.SR/FT/CS-073/
2009).
REFERENCES
[1] R. Granich, F. Wares, S. Suvanand and L. S. Chauhan,
“Lancet Infectious Disease,” Tuberculosis Control in In-
dia, Vol. 3, No. 9, 2003, p. 535.
doi:10.1016/S1473-309 9(03)00744-8
[2] R. J. O’Brien and P. P. Nunn, “The Need for New Drugs
against Tuberculosis. Obstacles, Opportunities, and Next
Steps,” American Journal of Respiratory and Critical
Care Medicine, Vol. 163, No. 5, 2001, pp. 1055-1058.
[3] M. S. Chande, R. S. Verma, P. A. Barve, R. R. Khanwel-
kar, R. B. Vaidya and K. B. Ajaikumar, “Facile Synthesis
of Active Antitubercular, Cytotoxic and Antibacterial
Agents: A Michael Addition Approach,” Journal of Me-
dicinal Chemistry, Vol. 40, No. 11, 2005, p. 1143.
[4] A. Dandia, M. Sati, K. Arya, R. Sharma and A. Loupy,
“Facile One Pot Microwave Induced Solvent-Free Syn-
thesis and Antifungal, Antitubercular Screening of Spiro
[1,5]-Benzothiazepin-2,3’[3’H]indol-2[1’H]-ones,” Che-
mical & Pharmaceutical Bulletin, Vol. 51, No. 10, 2003,
p. 1137.
[5] D. Sriram, P. Yogeeswari and K. Madhu, “Synthesis and
in Vitro Antitubercular Activity of Some 1-[(4-sub)
Phenyl]-3-(4-{1-[(Pyridine-4-Carbonyl)Hydrazono]Ethyl}
Phenyl)Thiourea,” Bioorganic & Medicinal Chemistry
Letters, Vol. 16, No. 4, 2006, pp. 876-878.
doi:10.1016/j.bmcl.2005.11.004
[6] M. Biava, G. C. Porretta, G. Poc, S. Supino, D. Deidda, R.
Pompei, P. Molicotti, F. Manetti and M. J. Botta, “Anti-
mycobacterial Agents. Novel Diarylpyrrole Derivatives of
BM212 Endowed with High Activity toward Myco-
bacterium Tuberculosis and Low Cytotoxicity,” Journal
of Medicinal Chemistry, Vol. 49, No. 16, 2006, pp. 4946-
4952. doi:10.1021/jm0602662
[7] M. Shaharyar, A. A. Siddiqui, M. A. Ali, D. Sriram and P.
Yogeeswari, “Synthesis and in Vitro Antimycobacterial
Activity of N1-Nicotinoyl-3-(4’-Hydroxy-3’-Methyl Phenyl)-
5-[(sub)Phenyl]-2-Pyrazolines,” Bioorganic & Medicinal
Chemistry Letters, Vol. 16, No. 15, 2006, pp. 3947-3949.
doi:10.1016/j.bmcl.2006.05.024
[8] R. R. Kumar, S. Perumal, P. Senthilkumar, P. Yogeeswari
and D. Sriram, “A Highly Atom Economic, Chemo-,
Regio- and Stereoselective Synthesis, and Discovery of

R. V. PRIYA ET AL.
78
Spiro-Pyrido-Pyrrolizines and Pyrrolidines as Antimyco-
bacterial Agents,” Tetrahedron, Vol. 64, No. 13, 2008, pp.
2962-2971. doi:10.1016/j.tet.2008.01.072
[9] R. R. Kumar, S. Perumal, P. Senthilkumar, P. Yogeeswari
and D. Sriram, “Discovery of Antimycobacterial Spiro-
piperidin-4-Ones: An Atom Economic, Stereoselective Syn-
thesis, and Biological Intervention,” Journal of Medicinal
Chemistry, Vol. 51, No. 18, 2008, pp. 5731-5735.
doi:10.1021/jm800545k
[10] H. Malonne, J. Hanuise and J. Fontaine, “Topical Anti-
Inflammatory Activity of New 2-(1-Indolizinyl)Propionic
Acid Derivatives in mice,” Pharmacy and Pharmacology
Communications, Vol. 4, No. 5, 1998, pp. 241-243.
[11] S. Medda, P. Jaisankar, R. K. Manna, B. Pal, V. S. Giri
and M. K. Basu, “Phospholipid Microspheres: A Novel
Delivery Mode for Targeting Antileishmanial Agent in
Experimental Leishmaniasis,” Journal of Drug Targeting,
Vol. 11, No. 2, 2003, pp. 123-128.
doi:10.1080/1061186031000119101
[12] P. Sonnet, P. Dallemagne, J. Guillom, C. Engueard, S.
Stiebing, J. Tangue, B. Bureau, S. Rault, P. Auvray, S.
Moslemi, P. Sourdaine and G. E. Seralini, “New Aro-
matase Inhibitors. Synthesis and Biological Activity of
Aryl-Substituted Pyrrolizine and Indolizine Derivatives,”
Bioorganic & Medicinal Chemistry, Vol. 8, No. 5, 2000,
pp. 945-955. doi:10.1016/S0968-0896(00)00024-9
[13] W. H. Pearson and L. Guo, “Synthesis and Mannosidase
Inhibitory Activity of 3-Benzyloxymethyl Analogs of
Swainsonine,” Tetrahedron Letters, Vol. 42, No. 47, 2001,
pp. 8267-8271. doi:10.1016/S0040-4039(01)01777-4
[14] F. H. Allen, “The Cambridge Structural Database: A Quar-
ter of a Million Crystal Structures and Rising,” Acta Cry-
stallographica, Vol. B58, No. 1, 2002, pp. 380-388.
[15] Bruker, “APEX2, SAINT-Plus and XPREP,” Bruker
AXS Inc., Madison, 2004.
[16] G. M. Sheldrick, “A Short History of SHELX,” Acta Cry-
stallographica, Vol. A64, Part 1, 2008, pp. 112-122.
[17] A. L. Spek, “Structure Validation in Chemical Crystallo-
graphy,” Acta Crystallographica, Vol. D65, Part 2, 2009,
pp. 148-155.
[18] D. Cremer and A. J. Pople, “General Definition of Ring
Puckering Coordinates,” Journal of the American Che-
mical Society, Vol. 97, No. 6, 1975, pp. 1354-1358.
doi:10.1021/ja00839a011
[19] M. Nardelli, “Ring Asymmetry Parameters from Out-of-
Plane Atomic Displacements,” Acta Crystallographica,
Vol. C39, Part 8, 1983, pp. 1141-1142.
[20] A. C. Hazell, “The Crystal Structure of 6b,8a-Dihydro-
cyclobut[a]Acenaphthylene, C14H10,” Acta Crystallo-
graphica, Vol. B32, Part 7, 1976, pp. 2010-2013.
[21] A. C. Hazell and R. G. Hazell, “The Crystal Structure of 6b,
10b-Dihydrobenzo[j]Cyclobut[a]Acenaphthylene, C18H12,”
Acta Crystallographica, Vol. B33, Part 2, 1977, pp. 360-
365.
[22] A. C. Hazell and Weigelt, “6b,12b-Dihydronaphtho[2,3-
j]Cyclobut[a]Acenaphthylene,” Acta Crystallographica,
Vol. B32, Part 1, 1976, pp. 306-308.
[23] P. G. Jones, P. Bubenitschek, G. M. Sheldrick and G.
Dyker, “Acenaphtho[1,2a]acenaphthylene at 178 K,” Acta
Crystallographica, Vol. C48, Part 9, 1992, pp. 1633-1635.
[24] T. V. Sundar, V. Parthasarathi, A’lvarez-Ruá, C. S. Gar-
cıá-Granda, A. Saxena, P. Pardasani and R. T. Par- dasani,
“(rac-5RS,7RS,8SR)-Spiro[7-Methoxycar-bonyl-1-
aza-3-tHiabicyclo[3.3.0]octane-8,1’-acenaphthylen]-2’-one,”
Acta Crystallographica, Vol. E58, Part 12, 2002, pp.
o1405-o1407.
[25] J. L. Sussman and S. J. Wodak, “The Crystal Structure of
Fulvine: A Pyrrolizidine Alkaloid,” Acta Crystallogra-
phica, Vol. B29, Part 12, 1973, pp. 2918-2926.
[26] S. J. Wodak, “The Crystal Structure of Heliotrine: A Pyr-
Rolizidine Alkaloid Monoester,” Acta Crystallographica,
Vol. B31, Part 2, 1975, pp. 569-573.
[27] S. N. Pandeya and J. R. Dimmock, “An Introduction to
Drug Design,” New Age International Publishers, New
Delhi, 1997.
[28] J. W. Quail, A. Doroud, H. N. Pati, U. Das and J. R. Dim-
mock, “(E,E)-2-(4-Fluorophenylmethylene)-6-(4-Nitrophen-
ylmeThylene)Cyclohexanone,” Acta Crystallographica,
Vol. E61, Part 6, 2005, pp. o1774-o1776.