Unique trifurcated hydrogen bonding in a pseudopolymorph of tricyclohexane triperoxide (TCTP) and its thermal studies

Article abstract of DOI:10.1016/j.tetlet.2012.08.134

Tricyclohexane triperoxide (TCTP) was synthesized as a main by-product of tetraoxane synthesis and was characterized by spectroscopic techniques viz. ¹H NMR, ¹³C NMR, FT-IR and Raman. The single crystal X-ray structure revealed the inclusion of solvent in 1:1 stoichiometric ratio involving a unique trifurcated C(sp³)-H...O hydrogen bonding imparting remarkable symmetry to the molecule. The thermal stability of single crystal was determined by TG-DTA and DSC.

Full text of DOI:10.1016/j.tetlet.2012.08.134

Tetrahedron Letters 53 (2012) 6067–6070
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unique trifurcated hydrogen bonding in a pseudopolymorph of tricyclohexane
triperoxide (TCTP) and its thermal studies
⇑
Chiranjeev Sharma Neupane, Satish Kumar Awasthi
Chemical Biology Laboratory, Department of Chemistry, University of Delhi, New Delhi 110007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2012
Revised 27 August 2012
Accepted 28 August 2012
Available online 6 September 2012
Tricyclohexane triperoxide (TCTP) was synthesized as a main by-product of tetraoxane synthesis and was
characterized by spectroscopic techniques viz. 1H NMR, 13C NMR, FT-IR and Raman. The single crystal X-
ray structure revealed the inclusion of solvent in 1:1 stoichiometric ratio involving a unique trifurcated
C(sp3)–HÁ Á ÁO hydrogen bonding imparting remarkable symmetry to the molecule. The thermal stability
of single crystal was determined by TG-DTA and DSC.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Hydrogen bonding
Pseudopolymorphism
Tricyclohexane triperoxide
Single crystal XRD
Thermal stability
Cyclic peroxides are of interest because of their many potential
applications. Their derivatives have been studied as radical initia-
tors,1 cetane number improvers,2 improvised explosives3 and anti-
malarials.4 They are also interesting from the conformational point
of view since their large rings can be stabilized in different confor-
mations.5 As a part of continuing research work in our laboratory
on design, synthesis and characterization of new drug molecules6
and X-ray crystal studies7 of small organic molecules, we are
extending our work to the design and synthesis of new cyclic per-
oxides to evaluate their antimalarial activity against drug resistant
forms of malaria such as Plasmodium falciparum and also crystalliz-
ing them to study their crystal structure.
tored by 13C NMR. The crude obtained after conventional work-
up with CHCl3 was a pale yellow viscous oil which solidified into
an off white solid within two days. The solid was removed by sim-
ple filtration from the remaining yellow syrup and characterized
by spectroscopic techniques viz. 1H NMR, 13C NMR, FT-IR and Ra-
man (see Supplementary data). However, spectroscopic studies re-
vealed the formation of
a peroxide trimer, tricyclohexane
triperoxide (TCTP) 4, which is a main by-product of tetraoxane
synthesis.12 Raman spectrum recorded for TCTP (Fig. 1) shows
A naturally occurring sesquiterpene endoperoxide artemisinin
has established the cyclic peroxides as potential antimalarial
agents.8 An exhaustive literature survey led us to speculate that
by incorporating nitrogen9 within the cyclohexyl ring, we could
generate a new series of cyclic peroxides with improved antimalar-
ial activity. We initially started with 4-piperidone monohydrate
hydrochloride, which was alkylated with methyl bromoacetate in
the presence of K2CO3 mixed in 1:2:2 ratios in acetone. The reac-
tion mixture was refluxed for 15 h to yield methyl 2-(4-oxopiperi-
din-1-yl)acetate 1. We followed previously reported procedures2,10
with slight modifications11 to synthesize piperidine-1,2,4,5-tetra-
oxane 3 for the first time. The progress of the reaction was moni-
⇑
Corresponding author. Tel.: +91 11 27666646x121/134, mobile: +91
9582087608.
E-mail addresses: awasthisatish@yahoo.com, skawasthi@chemistry.du.ac.in (S.K.
Awasthi).
Figure 1. Raman spectrum of TCTP (200–600 cmÀ1).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.134

6068
C. S. Neupane, S. K. Awasthi / Tetrahedron Letters 53 (2012) 6067–6070
Scheme 1. Attempted tetraoxane synthesis.
peaks in the range of 800–1000 cmÀ1 corresponding to the combi-
nation of O–O and C–O stretching modes of hexaoxonane ring.
Peaks at 1446 cmÀ1 and between 1200–1300 cmÀ1 can be attrib-
uted to C–C stretching mode and peroxide ring C–O stretching,
respectively, which are well in agreement with the theoretically
calculated spectrum reported by Oxley et al.13 A schematic dia-
gram depicting the above observation is shown in Scheme 1.14
Several attempts in our laboratory to isolate compound 3 in
workable amounts from the reaction mixture were unsuccessful.
Meanwhile, motivated by rich polymorphism shown by triacetone
triperoxide (TATP), we started investigating the crystal structure of
4. Herein, we report several interesting observations made from
the crystal structure analysis of TCTP single crystal grown in
chloroform.
For the present study X-ray quality single crystals were grown
in a thin tube of 5 mm diameter by the slow evaporation solution
growth technique at room temperature. X-ray structure revealed
solvated chloroform in 1:1 stoichiometric ratio in the crystal lattice
of TCTP resulting in a pseudopolymorph of TCTP, which is the first
example of solvated TCTP (sTCTP).15 The sTCTP crystallized in a tri-
gonal cell and R3c space group with the following lattice parame-
the crystal lattice of sTCTP, although C–H group of C(sp3)–H is a
reluctant hydrogen bond donor. However, three chlorine atoms
activate ‘C–H’ of CHCl3 for hydrogen bonding.16 A rare trifurcated
hydrogen bond17 C(sp3)–HÁ Á ÁO (dH–O = 2.661 Å) was observed be-
tween the hydrogen atom (H19) of chloroform and three oxygen
atoms (O2, O4 and O6) of the nine-membered hexaoxonane ring
contributing to the symmetry of the complex, imparting C3-sym-
metry. The oxygen atoms in hexaoxonane ring are arranged in
two parallel planes separated by a distance of 1.076 Å (Fig. 2a).
As a consequence of hydrogen bonding the three oxygen atoms
(O2, O4 and O6) converge18 towards H19. The packing diagram
shows an intricately stacked picturesque floral pattern along the
crystallographic C-axis and molecules appeared to be arranged in
parallel layers along the B-axis (Fig. 2).
The thermal stability19 of single crystal was determined by TG-
DTA and DSC (Fig. 3). TG-DTA measurements were performed in an
open ceramic pan in flowing nitrogen on 4.79 mg of sample and
DSC was done in a sealed aluminium pan. DTA and DSC measure-
ments gave consistent results. An endothermic peak occured at
92.24 °C corresponding to the melting point5b of sTCTP and the
exothermic peak at 193.27 °C corresponding to sharp weight loss
in the DTA curve that can be attributed to the decomposition pro-
cess. However, we could not ascertain the thermolysis products in
DTA curve and another endothermic peak at 378.81 °C. Neverthe-
less, thermal studies clearly indicate the stability of the compound
till its meting point at 92.24 °C after which it decomposes above
120 °C.
Following these observations, sTCTP can be tried for peroxide
based explosives20 or as a propellant.21 Crystallization of new poly-
morphs or pseudopolymorphs of TCTP and analogues (TATP) may
be attempted in future using different solvents and mixture of sol-
vents, which will enable us to evaluate the inclusion property of
the crystal lattice of TCTP for discriminative selectivity22 towards
the solvent (CHCl3) inclusion which till date is shown only by
cyclodextrin and large ring (30-membered) hexalactam hosts.23
In conclusion, the reaction procedure needs further optimiza-
tion to synthesize compound 3 in good yield which was formed
in traces. Compound 3 can be a precursor for the synthesis of diver-
sified tetraoxane libraries, which can be screened for antimalarial
and anticancer activities. Nevertheless, the synthesis of compound
1 offers a convenient synthetic entry to a variety of intermediates
used in the synthetic medicinal chemistry. TCTP, a main by-prod-
uct of tetraoxane synthesis was synthesized and its crystals were
grown in chloroform resulting in inclusion of chloroform in a
pseudopolymorph (sTCTP). H-atom of CHCl3 projects into the cen-
tre of the molecular cavity formed by hexaoxonane ring and re-
ter: a = 14.3252(3) Å, b = 14.3252(3) Å, c = 18.4732(5) Å,
a
= 90°,
b = 90°,
c q
= 120°, V = 3283.02(13) Å3 and = 1.4015 gcmÀ3. Com-
parison of geometrical parameters between TCTP and sTCTP5b (Ta-
ble 1) showed no significant difference, which is consistent with
the earlier reported observations.5a,15
Six different polymorphic crystals of TATP were reported by
Reany et al.5a and TCTP is also known to possess two separable
conformers at room temperature,5b however without any solvent
inclusion in any of the polymorphs. Thus, sTCTP is the only known
example of a solvated cyclic triperoxide.15
Crystal packing suggests a dominant role of C–HÁ Á ÁO interac-
tions in determining molecular conformation and stability of sol-
vated crystal as there were no other intermolecular contacts in
Table 1
Comparison of geometric parameters between TCTP and sTCTP
Geometric parameter
C–O
sTCTP [°/Å]
TCTPa [°/Å]
1.417 (2)
1.4176 (18), 1.418 (2),
1.4271 (19)
O–C
1.419 (2)
1.473 (2)
111.96 (1)
135.75
1.4284 (18), 1.431 (2),
1.4187 (18)
1.4747 (14), 1.475 (2),
1.4678 (15)
112.76 (12), 112.76 (12),
112.05 (11)
135.0, 136.2, 134.2
O–O
O–C–O
C–O–O–C
sulted in
a rare trifurcated hydrogen bond imparting C3
a
As reported by Denekamp et al. Org. Lett. 2005.
symmetry to the molecule and stabilizing the resultant sTCTP.

C. S. Neupane, S. K. Awasthi / Tetrahedron Letters 53 (2012) 6067–6070
6069
Figure 3. TG-DTA and DSC curve of sTCTP.
Supplementary data
Supplementary data(crystallographic data (excluding structure
factors) for the structure in this Letter have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication nos. 875952. Copy of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.-
cam.ac.Uk) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.134.
References and notes
1. Cerna, J. R.; Morales, G.; Eyler, G. N.; Cañizo, A. I. J. Appl. Polym. Sci. 2002, 83, 1–
11.
2. Rode, A. B.; Chung, K.; Kim, Y. W.; Hong, I. S. Energy Fuels 2010, 24, 1636–1639.
3. Evans, H. K.; Tulleners, F. A. J.; Sanchez, B. L.; Rasmussen, C. A. J. Foren. Sci. 1986,
31, 1119–1125.
4. Slack, R. D.; Jacobine, A. M.; Posner, G. H. Med. Chem. Commun. 2012, 3, 281–
297.
5. (a) Reany, O.; Kapon, M.; Botoshansky, M.; Keinan, E. Cryst. Growth Des. 2009, 9,
3661–3670; (b) Denekamp, C.; Gottlieb, L.; Tamiri, T.; Tsoglin, A.; Shilav, R.;
Kapon, M. Org. lett. 2005, 7, 2461–2464.
6. (a) Yadav, N.; Dixit, S. K.; Bhattacharya, A.; Mishra, L. C.; Sharma, M.; Awasthi, S.
K.; Bhasin, V. K. Chem. Boil. Drug Des. 2012, 80, 340–347; (b) Dixit, S. K.; Mishra,
N.; Sharma, M.; Singh, S.; Agarwal, A.; Awasthi, S. K.; Bhasin, V. K. Eur. J Med.
Chem. 2012, 51, 52–59; (c) Awasthi, S. K.; Mishra, N.; Dixit, S. K.; Singh, A.;
Yadav, M.; Yadav, S. S.; Rathur, S. Am. J Trop. Med. Hyg. 2009, 80, 764–7668.
7. (a) Singh, S.; Singh, M.; Agarwal, A.; Awasthi, S. K. Acta Cryst. E. 2011, E67,
o3163; (b) Singh, S.; Singh, M.; Hussain, F.; Agarwal, A.; Awasthi, S. K. Acta
Cryst. E. 2011, E67, o1616–o1617.
8. Jefford, C. W. Drug Discov. Today. 2007, 12, 487–495.
9. (a) Vennerstrom, J. L.; Tang, Y.; Dong, Y.; Chollet, J.; Matile, H.; Padmanilayam,
M.; Charman, W. N.; U. S. Patent, 6825230, 2004.; (b) Padmanilayam, M.;
Scorneaux, B.; Dong, Y.; Chollet, J.; Matile, H.; Charman, S. A.; Creek, D. J.;
Charman, W. N.; Tomas, J. S.; Scheurer, C.; Wittlin, S.; Brun, R.; Vennerstrom, J.
L. Bioorg. Med. Chem. Lett. 2006, 16, 5542–5545; (c) Sabbani, S.; Stocks, P. A.;
Ellis, G. L.; Davies, J.; Hedenstrom, E.; Ward, S. A.; O’Neill, P. M. Bioorg. Med.
Chem. Lett. 2008, 18, 5804–5808.
Figure 2. (a) Relevant lengths and angles: Trifurcated hydrogen bonding in ball and
stick model, (b) Crystal packing along the B-axis (nine-membered hexaoxonane ring
in Spacefill and CHCl3 in ball and stick model) and (c) along C-axis in capped stick
model. [(cyclohexyl ring removed in a and b and H atoms of cyclohexane removed
in
c for clarity), C-grey, H-white, O-red, Cl-green and dotted line represents
10. Amewu, R.; O’Neill, P. M.; Stachulski, A.; Ellis, G.; Ward, A. S. International
patent, 038030, 2008.
hydrogen bonding].
11. Although we tried various combinations, the results which we report here was
obtained when we took 3 mmol of compound 1 and 6 mmol of compound 2 for
tetraoxane synthesis. However, Rode et al. synthesized the tetraoxanes and
hexaoxonanes using ketone (1.2 mmol) and dihydroperoxide (1 mmol).
Further, they quenched the reaction after 25–50 min of additional stirring
upon addition of H2SO4/CH3CN mixture and we stirred our reaction at room
temperature for 24 h. Detailed procedure for the synthesis of compounds 1–4
is given in Supplementary data.
Finally, thermal stability was revealed by TG-DTA and DSC exper-
iments. The crystal of sTCTP was found stable up to its melting
point and decomposed after 120 °C.
Acknowledgments
12. Opsenica, D. M.; Solaja, B. A. J. Serb. Chem. Soc. 2009, 74, 1155–1193.
13. Oxley, J.; Smith, J.; Brady, J.; Dubnikova, R. K.; Zeiri, L.; Zeiri, Y. Appl. Spectrosc.
2008, 62, 906–915.
14. The yield of compound 3 is not preparative, see Supplementary data for more.
15. Terent’ev, A. O.; Platonov, M. M.; Sonneveld, E. J.; Peschar, R.; Chernyshev, V. V.;
Starikova, Z. A.; Nikishin, G. I. J. Org. Chem. 2007, 72, 7237–7243.
16. Steiner, T. Chem. Commun. 1997, 727–734.
S.K.A. acknowledges the financial assistance from University of
Delhi and University Scientific Instrumentation Center (USIC), Uni-
versity of Delhi, Delhi-110007, India for analytical data. Authors
are thankful to Dr. R. Nagarajan for discussion and CSN is thankful
to UGC for providing JRF.

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C. S. Neupane, S. K. Awasthi / Tetrahedron Letters 53 (2012) 6067–6070
17. (a) Steiner, T. Angew. Chem., Int. Ed. 2002, 41, 48–76; (b) Renaud, F.; Piguet, C.;
Bernardinelli, G.; Hopfgartner, G.; Bünzli, J. G. Chem. Commun. 1999, 457–458.
18. H19 sits at 2.149 Å and 3.225 Å above the centroids of both pairs of oxygen
atoms O2,O4,O6 and O1,O3,O5, respectively, lying in two parallel planes (see
Supplementary data). However, the O–O distance between a former set of
oxygen atoms is 2.718 Å and 2.751 Å for latter. Thus, we can say that oxygen
involved in hydrogen bonding (O2,O4,O6) converge towards H19.
carried out with extreme care in small quantity using nonmetallic vessel and
small amount of compound was taken for thermal studies.
20. Dubnikova, F.; Kosloff, R.; Almong, J.; Zeiri, Y.; Boese, R.; Itzhaky, H.; Alt, A.;
Keinan, E. J. Am. Chem. Soc. 2005, 127, 1146–1159.
21. Fitchett, C. M. Chem. N.Z. 2009, 156–160.
22. Weber, E.; Csoregh, I.; Stensland, B.; Czugler, M. J. Am. Chem. Soc. 1984, 106,
3297–3306.
19. Caution. Peroxides are believed to be chemically and thermally unstable, shock
sensitive compounds, which undergo spontaneous explosion. Synthesis was
23. Vögtle, F.; Puff, H.; Friedrichs, E.; Müller, W. M. J. Chem. Soc. Chem. Commun.
1982, 1398–1400.