Synthesis of norbornahemicucurbiturils

Article abstract of DOI:10.1055/s-0033-1339850

Ethyleneurea fused with a norbornane ring was prepared. Acid-catalyzed polycondensation of the urea with paraformaldehyde yielded a new six-membered hemicucurbituril derivative. The presence of hemicucurbiturils containing from four to eight monomer units were also detected. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339850

LETTER
▌2443
lSetyternthesis of Norbornahemicucurbiturils
Norbornahemicucurbiturils
Tomas Fiala, Vladimir Sindelar*
Department of Chemistry and Centre for Toxic Compounds in the Environment, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
Fax +420(549)492443; E-mail: sindelar@chemi.muni.cz
Received: 25.07.2013; Accepted after revision: 27.08.2013
Abstract: Ethyleneurea fused with a norbornane ring was prepared.
Acid-catalyzed polycondensation of the urea with paraformalde-
hyde yielded a new six-membered hemicucurbituril derivative. The
presence of hemicucurbiturils containing from four to eight mono-
mer units were also detected.
Key words: hemicucurbiturils, cucurbiturils, macrocycles, poly-
condensation, supramolecular chemistry
Hemicucurbit[n]urils (HmCB[n]) are macrocyclic com-
pounds consisting of n ethyleneurea units linked together
Vladimir Sindelar (left) was born in Pelhrimov, Czech Republic, in
with n methylene bridges1 (Figure 1). The name of
1975. He received his Ph.D. in polymer chemistry from the Institute
HmCB[n]s was chosen because of their structural resem-
blance to cucurbit[n]urils (CB[n]s)2,3 that have been di-
vided in half along the equator. HmCB[n]s were
introduced in 2004 by Miyahara et al., who prepared six-
and twelve-membered rings, HmCB[6] and HmCB[12].
These compounds were synthesized by a Mannich-type4
polycondenzation reaction of ethyleneurea with formalde-
hyde in aqueous HCl. The size of the prepared hemicucur-
bituril macrocycle can be controlled by the concentration
of the acid, reaction time, and temperature. HmCB[6] was
obtained in an excellent yield of 94% as a precipitate from
4 M HCl after stirring at room temperature for
30 minutes. Chloride anions act as a template and the re-
sulting HmCB[6] is the kinetic product of the reaction.
HmCB[12] requires 1 M HCl, a temperature of 55 °C, and
is formed as a gel after three hours. The conformation of
ethyleneurea units within HmCB[n] differs significantly
from that of glycoluril in CB[n]s (Figure 1). Glycoluril
units of CB[n]s are linked together with a pair of methy-
lene bridges, resulting in a very rigid structure with only
little conformational variability. On the other hand, only
one row of CH2 bridges connect the ethyleneurea units of
HmCB[n]s, allowing rotations of the individual units with
respect to each other. With this freedom, ethyleneurea
units adopt an alternate conformation in which the carbon-
yl groups of adjacent urea units are directed towards op-
posite sides of the macrocycle plane. A similar
conformation was previously described in a related family
of macrocyclic compounds – bambus[n]urils (Figure 1).5
of Chemical Technology, Prague, in 2002 under the supervision of
Petr Sysel. After a period of postdoctoral research at the Heriot-Watt
University with Graeme Cooke, and the University of Miami with
Angel E. Kaifer, he joined Masaryk University, where he is now As-
sociate Professor of Organic Chemistry. His research focuses on the
synthesis of supramolecular host molecules including cucurbiturils
and bambusurils and the investigation of their self-sorting processes.
Tomas Fiala (right) was born in Brno, Czech Republic, in 1990. He
obtained his bachelor’s degree from Masaryk University in 2013. He
is currently pursuing his M.Sc. degree with Vladimir Sindelar at the
same university.
and elevated temperature was required for the formation
of the macrocyclic product. The resulting macrocycles
contained six ethyleneurea units fused with cyclohexane
rings.
Figure
1
(a) Cucurbit[n]uril CB[6], (b) Hemicucurbit[n]uril
HmCB[6], and (c) Me12BU[6]
HmCB[n]s have been investigated for their ability to bind
anions and cations,7–9 and they have also been used in
crystal engineering and catalysis.6,10 The introduction of
new substituents on the hemicucurbituril framework
could modify their binding affinity as well as catalytic
properties and could also tune their packing in the crystal
structure. Therefore, we decided to investigate the prepa-
ration of a new HmCB[n] derivative.
Until today, only two derivatives of HmCB[n]s have been
reported.6,7 The syntheses were performed according to
the protocol for HmCB[n]s but cis- and trans-octahydro-
2H-benzimidazol-2-one instead of ethyleneurea was used,
SYNLETT 2013, 24, 2443–2445
Advanced online publication: 13.09.2013
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DOI: 10.1055/s-0033-1339850; Art ID: ST-2013-B0699-L
© Georg Thieme Verlag Stuttgart · New York

2444
T. Fiala, V. Sindelar
LETTER
hexameric hemicucurbituril (Figure 2), NMR spectra
were more complex. This indicates the presence of low
molecular weight oligomers that were not detected by
MALDI-TOF mass spectrometry. The pure hexamer was
obtained after silica gel column chromatography by using
acetone–CHCl3 (1:4 v/v) as the mobile phase. In accor-
dance with the nomenclature used in cucurbituril chemis-
try, we named the new macrocycle norborna-
hemicucurbit[6]uril (NorHmCB[6]).
O
O
H2, 10% Pd/C
HN
NH
HN
NH
MeOH–CH2Cl2 (4:1 v/v)
r.t., 22 h
2
1
Scheme 1 Reduction of endo-3,5-diazatricyclo[5.2.1.02,6]dec-8-ene-
4-one (2) to endo-3,5-diazatricyclo[5.2.1.02,6]decane-4-one (1)
We selected endo-3,5-diazatricyclo[5.2.1.02,6]decane-4-
one (1) as a basic building block for the synthesis. This
modified ethyleneurea is more spacious and rigid com-
pared with those previously used. It was prepared by the
reduction of endo-3,5-diazatricyclo[5.2.1.02,6]dec-8-ene-
4-one (2) under hydrogen gas (1 atm) in the presence of
10% Pd/C (Scheme 1).11 The starting material 2 was syn-
thesized in several steps through the preparation of 2,3-di-
hydro-1H-imidazol-2-one, its conversion into the
corresponding diacetyl, followed by Diels–Alder cyclo-
addition with cyclopentadiene and final deacetylation. All
these methods, which were described in literature,12–14
were optimized to increase the reaction yields (see the
Supporting Information). Macrocyclization of ethylene-
urea 1 with paraformaldehyde was performed in 4 M HCl
at 70 °C for four hours (Scheme 2).15 Hydrochloric acid
was chosen because it proved to be most efficient for the
preparation of this class of macrocyclic compounds.7 Af-
ter investigating various acid concentrations and tempera-
tures, the given conditions were found to be optimal
regarding the yield and purity of the product. The forma-
tion of macrocycles did not take place when an HCl con-
centration of less than 3 M was used. Higher reaction
temperatures resulted in the formation of an impurity that
was difficult to separate from the product.
Figure 2 MALDI-TOF MS analysis (HCCA, positive mode) of the
crude white precipitate after macrocyclization of 1
Being inspired by the preparation of benzyl groups con-
taining bambusurils,16 we also attempted to prepare the
target macrocycle in chloroform by using p-toluenesul-
fonic acid and trifluoroacetic acid. However, all attempts
to prepare the products in organic solvent, both in the
presence and in the absence of tetrabutylammonium io-
dide as a template, failed to give the desired macrocyclic
product.
Figure 3 1H NMR (300 MHz, CDCl3, 30 °C) spectrum of NorHm-
CB[6]
Ethyleneurea units within the macrocycle are relatively
large, which prevents their free rotation. Among others,
two probable arrangements of the units – alternate and
cone – are possible. The 1H NMR spectrum of the macro-
cycle showed a singlet at δ = 4.59 ppm corresponding to
two chemically equivalent hydrogen atoms of the methy-
lene bridges C(11)-H2 (Figure 3). This signal is character-
istic for the alternate arrangement of the ethyleneurea
units, as known for all hemicucurbiturils and bambusu-
rils.1,5,6 Unique singlets of methanetriyl hydrogen signals
from C(2,6)-H and C(1,7)-H prove that the orientation of
all ethyleneurea units within the macrocycle are identical.
The endo- configuration of the monomer units in NorHm-
CB[6] together with steric effects of the spacious norbor-
nane rings ensure that the C(2,6)-H hydrogen atoms point
O
O
O
N
N
HN
NH
4 M aq HCl
70 °C, 4 h
+
6
H
H
1
NorHmCB[6]
Scheme 2 Macrocyclization of 1; synthesis of norbornahemicucur-
bit[6]uril (NorHmCB[6])
The macrocyclization in aqueous HCl provided a white
precipitate that was collected by filtration and analyzed by
1
MALDI-TOF MS and H NMR spectroscopy. Although
MS analysis revealed only signals corresponding to the
Synlett 2013, 24, 2443–2445
© Georg Thieme Verlag Stuttgart · New York

LETTER
Norbornahemicucurbiturils
2445
(5) Svec, J.; Necas, M.; Sindelar, V. Angew. Chem. Int. Ed.
2010, 49, 2378.
(6) Li, Y.; Li, L.; Zhu, Y.; Meng, X.; Wu, A. Cryst. Growth Des.
2009, 9, 4255.
(7) Aav, R.; Shmatova, E.; Reile, I.; Borissova, M.; Topić, F.;
Rissanen, K. Org. Lett. 2013, 15, 3786.
(8) Buschmann, H.-J.; Cleve, E.; Schollmeyer, E. Inorg. Chem.
Commun. 2005, 8, 125.
(9) Buschmann, H.-J.; Zielesny, A.; Schollmeyer, E. J. Incl.
Phenom. Macrocycl. Chem. 2006, 54, 181.
(10) Cong, H.; Yamato, T.; Feng, X.; Tao, Z. J. Mol. Catal.
Chem. 2012, 365, 181.
to the center of the macrocycle cavity whereas the norbor-
bornane groups are reversed out.
The filtrate that was left after collecting the precipitate
from the reaction mixture was analyzed by MALDI-TOF
MS. Surprisingly, not only the six-membered macrocycle
was found but also macrocycles with 4, 5, 7, and 8 ethyl-
eneurea units were detected in the spectrum (Figure 4).
Until now, only six- and twelve-membered hemicucurbi-
turils have been reported. This unexpected result is cur-
rently under investigation.
(11) endo-3,5-Diazatricyclo[5.2.1.02,6]decane-4-one (1): A
solution of 2 (0.27 g, 1.8 mmol) in MeOH–CH2Cl2 (12 mL,
4:1 v/v) was stirred under an atmospheric pressure of H2 in
the presence of 10% Pd/C (0.12 g) for 22 h. The resulting
mixture was filtered through Celite, washed with MeOH (15
mL) and the combined filtrates were concentrated in vacuo
to give 1 (0.26 g, 1.7 mmol, 95%) as a white solid; mp
235.7–236.1 °C (dec.). IR (KBr): 710 (m), 774 (m), 1131
(m), 1252 (m), 1351 (m), 1466 (m), 1690 (s), 2871 (m), 2949
(s), 3067 (br. m), 3218 (br. s) cm–1. 1H NMR (300 MHz,
CDCl3, 30 °C): δ = 1.36 (d, J = 8 Hz, 2 H, C(8,9)-HA), 1.39
(d, J = 11 Hz, 1 H, C(10)-HA), 1.48 (d, J = 11 Hz, 1 H,
C(10)-HB), 1.71 (d, J = 8 Hz, 2 H, C(8,9)-HB), 2.32 (s, 2 H,
C(1,7)-H), 3.96 (s, 2 H, C(2,6)-H), 4.75 (br s, 2 H, NH); 13
C
NMR (125 MHz, CDCl3, 30 °C): δ = 21.7 (C(8,9)-H2), 36.4
(C(10)-H2), 40.8 (C(1,7)-H), 57.7 (C(2,6)-H), 163.6 (C=O).
HRMS: m/z calcd. for [C8H12N2O+H]+: 153.1022; found:
153.1022.
Figure 4 MALDI-TOF MS (HCCA, positive mode) of the filtrate
after the macrocyclization of 1 (M[n] = NorHmCB[n])
In conclusion, a new hexameric derivative of hemicucur-
bituril has been isolated and fully characterized. endo-3,5-
Diazatricyclo[5.2.1.02,6]]decane-4-one was used as an eth-
ylene urea derivative for the macrocyclization. Hemicu-
curbiturils differing in the number of glycoluril units are
side products of this reaction.
(12) Groaz, E.; Banti, D.; North, M. Tetrahedron 2008, 64, 204.
(13) Hossain, D.; Lavoie, G. G. Synth. Commun. 2012, 42, 1200.
(14) Eissenstat, M. A.; Weaver, J. D. J. Org. Chem. 1993, 58,
3387.
(15) Norbornahemicucurbit[6]uril (NorHmCB[6]):
Compound 1 (0.25 g, 1.6 mmol) was dissolved in 4 M aq
HCl (20 mL) at 70 °C. Paraformaldehyde (0.054 g, 1.8 mmol
of CH2O) was added and the resulting mixture was heated at
70 °C for 4 h (during this period a white precipitate formed).
The solid material was collected by filtration, washed with
H2O (10 mL), and dried in vacuo. The desired macrocyclic
product was separated from the crude mixture by silica gel
column chromatography (acetone–CHCl3, 1:4 v/v). Yield:
0.024 g (0.024 mmol, 8.9%); mp >250 °C. IR (KBr): 614
(m), 760 (m), 813 (w), 1216 (s), 1372 (s), 1441 (s), 1699 (s),
2871 (m), 2961 (m), 3437 (br m) cm–1. 1H NMR (300 MHz,
CDCl3, 30 °C): δ = 1.28 (d, J = 13 Hz, 6 H, C(10)-HA), 1.34
(d, J = 11 Hz, 12 H, C(8,9)-HA), 1.40 (d, J = 11 Hz, 12 H,
C(8,9)-HB), 1.57 (d, J = 13 Hz, 6 H, C(10)-HB), 2.63 (s,
12 H, C(1,7)-H), 3.50 (s, 12 H, C(2,6)-H), 4.59 (s, 12 H,
C(11)-H2). 13C NMR (125 MHz, CDCl3, 30 °C): δ = 21.9
(C(8,9)-H2), 36.4 (C(10)-H2), 39.4 (C(1,7)-H), 49.1 (C(11)-
H2), 57.0 (C(2,6)-H), 160.4 (C=O). HRMS: m/z calcd for
[C54H72N12O6+H]+: 985.5771; found: 985.5777. Anal. Calcd
for C54H72N12O6·2 H2O: C, 63.51; H, 7.50; N, 16.46. Found:
C, 63.55; H, 7.55; N, 15.75.
Acknowledgment
Support for this work was provided by the Czech Science Founda-
tion (P207/10/0695) and the project CETOCOEN (no.
CZ.1.05/2.1.00/01.0001) from the European Regional Develop-
ment Fund.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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References and Notes
(1) Miyahara, Y.; Goto, K.; Oka, M.; Inazu, T. Angew. Chem.
Int. Ed. 2004, 43, 5019.
(2) Lagona, J.; Mukhopadhyay, P.; Chakrabarti, S.; Isaacs, L.
Angew. Chem. Int. Ed. 2005, 44, 4844.
(3) Masson, E.; Ling, X.; Joseph, R.; Kyeremeh-Mensah, L.; Lu,
X. RSC Adv. 2012, 2, 1213.
(4) Mannich, C.; Krösche, W. Arch. Pharm. (Weinheim) 1912,
250, 647.
(16) Havel, V.; Svec, J.; Wimmerova, M.; Dusek, M.; Pojarova,
M.; Sindelar, V. Org. Lett. 2011, 13, 4000.
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