Cucurbit[6]uril as a potential catalyst for the acidic decomposition of azidoaminoalkanes

Article abstract of DOI:10.1016/j.tetlet.2012.06.016

Five azidoalkyl-1-amines and p-azidoaniline have been synthesized and complexed with cucurbit[6]uril in acidic solutions. Isothermal titration calorimetry has been employed to determine the association constant K and the enthalpy of complex formation ΔH of the azidoalkyl- and azidoarylamines. 4-Azidobutyl-1-amine forms by far the most stable complex. Cucurbit[6]uril significantly catalyzes the decomposition of the azidoalkyl- and azidoarylamines studied.

Full text of DOI:10.1016/j.tetlet.2012.06.016

Tetrahedron Letters 53 (2012) 4351–4353
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cucurbit[6]uril as a potential catalyst for the acidic decomposition
of azidoaminoalkanes
⇑
Marcel Wieland, Jean-Luc Mieusset, Udo H. Brinker
Institut für Organische Chemie, Universität Wien, Währinger Straße 38, A-1090 Wien, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
Five azidoalkyl-1-amines and p-azidoaniline have been synthesized and complexed with cucurbit[6]uril
Received 27 April 2012
Revised 3 June 2012
Accepted 5 June 2012
Available online 12 June 2012
in acidic solutions. Isothermal titration calorimetry has been employed to determine the association con-
stant K and the enthalpy of complex formation
DH of the azidoalkyl- and azidoarylamines. 4-Azidobutyl-
1-amine forms by far the most stable complex. Cucurbit[6]uril significantly catalyzes the decomposition
of the azidoalkyl- and azidoarylamines studied.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Supramolecular catalysis
Cucurbiturils
Azides
Association constants
Host–guest chemistry
Supramolecular catalysis is a promising field. Indeed, it has al-
ready produced very attractive results for easy syntheses of com-
pounds that otherwise would be difficult to obtain under mild
conditions and with satisfactory regioselectivity.1 In order to
achieve this goal, in general a host molecule is used to mediate
the reaction. Much work has already been done on the basis of
self-assembled capsules,2 calixarenes,3 hemicarcerands,4 and
cyclodextrins5 the latter host molecules being especially useful be-
cause of their intrinsic aptitude to transfer chirality to entrapped
guest molecules.5a,6 Since the discovery7 and the rediscovery of
cucurbit[n]urils (n = 5, 6, 7, 8, and 10) and their complexing abil-
ity,8 this family of host molecules is gaining ever more significance
for applications in slightly acidic aqueous media. This is due to
their high affinity for positively charged organic molecules such
as ammonium compounds, combined with a relatively high speci-
ficity owing to their rigidity.9 With cucurbit[6]uril (CB[6]), Mock
has shown their ability to catalyze the 1,3-dipolar cycloaddition
of azidoalkylamines to aminoalkynes, leading to the exclusive for-
mation of only one triazole regioisomer.10 Since then, this ap-
proach has been used for the preparation of a self-threading
polyrotaxane11 and for the synthesis of oligotriazoles.12 Further
examples were reported with the highly stereoselective photodi-
merization of diaminostilbenes13 and stilbazoles14 in the larger
cavity of cucurbit[8]uril. In contrast, cucurbit[7]uril has been uti-
lized to mediate the dimerization of aminopyridine to a tricyclic
compound,15 producing exclusively the anti-trans isomer and
being able to stabilize it with respect to decomposition. All these
synthetic applications have in common that they are employing
protonated nitrogen compounds as a substrate. The presence of
this functional group greatly enhances complex formation, and as
a consequence, the catalytic efficiency of the system.
In the course of our efforts to investigate the possibilities to im-
prove the synthetic utility of azides and nitrenes, we recently could
demonstrate the remarkable regioselectivity of the monofunction-
alization of a resorcinarene cavitand using an encapsulated phenyl
azide.3b Therefore, we now have prepared inclusion complexes of
azidoalkyl- and azidoarylamines in cucurbit[6]uril to investigate
scope and limitations of this approach. In this Letter, we report
about the preparation and the stability of these complexes.
Azidoalkylamines 3–7 were synthesized from dibromoalkanes 1
in analogy to a known literature procedure (Scheme 1).16,17 The
first step corresponds to the preparation of diazides 2 by thermal
treatment of the corresponding dibromides with NaN3 in DMF
(80 °C, 20 h) followed by reduction of one azido group with PPh3
using a slightly modified Staudinger reaction.18 The reduction of
Br
N3
NH2
(CH2)n
N3
n = 1
n = 2
n = 3
n = 4
n = 6
3
4
5
6
7
PPh
NaN3
DMF
3
(CH2)n
(CH2)n
5% HCl
Br
N3
⇑
2
Corresponding author. Tel.: +43 1 4277 52121.
E-mail addresses: ubrinker@binghamton.edu, udo.brinker@univie.ac.at (U.H.
1
Brinker).
Scheme 1. Synthesis of azidoalkylamines 3–7.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.016

4352
M. Wieland et al. / Tetrahedron Letters 53 (2012) 4351–4353
9
8
7
6
5
4
3
2
1
0
0
0.2
0.4
0.6
0.8
1
xG
Figure 1. Job plot of 4+@CB[6].
Table 1
Association constants of cucurbit[6]uril complexes 4+ and 5+ in 7.6 M DCl
4+
5+
K (MÀ1
)
676
108
the second azido group is avoided by use of cold temperatures and
a two-phase system: the freshly generated azidoalkylamine is pro-
tonated and extracted into the acidic aqueous phase and therefore
not available for a second reduction. The hydrochloride salts were
obtained by bubbling dry hydrogen chloride into an ethereal solu-
tion of azidoalkylamines 3–7 in their free base form. For all reac-
tions the yields were uniformly high (85–90%).
Figure 2. ITC titration curves of 6+ and 8+ with CB[6] in 50% formic acid.
The complexes were prepared by dissolution of azidoalkylamine
hydrochloride in water followed by addition of cucurbit[6]uril.19
A
putative complex of 4-azidobutyl-1-ammonium 4+ in cucur-
bit[6]uril is represented in the graphical abstract.20 The stoichiom-
etry of the complexes 3+@CB[6], 4+@CB[6], and 5+@CB[6] was
determined by 1H NMR spectroscopy in 7.6 M DCl using the method
of continuous variation (Job plot, Fig. 1). A 1:1 stoichiometry was
found for all complexes. The association constants were determined
by titration to give 676 MÀ1 for 4+@CB[6],21 and 108 MÀ1 for
5+@CB[6]22 (Table 1). Some unsuccessful attempts were made to
obtain single crystals of the complexes.23
Table 2
Energetic parameters and association constants of the CB[6] complexes in 50% formic
acid
4+ Butyl
6+ Pentyl
7+ Hexyl
8+ Aniline
K (MÀ1
H (KJ/mol)
)
5500 50
À22.8
514
5
713
5
655
5
D
À24.1
À26.3
À9.6
We also employed isothermal titration calorimetry (ITC) with 1/
1 (v/v) HCO2H/H2O as the solvent to determine the binding
constants of azidoalkylamines in CB[6] (Fig. 2). This choice of sol-
vent combination was partly dictated by the poor solubility of
cucurbit[6]uril in pure water and in common solvents and by the
technical requirements of the ITC apparatus used. The binding
properties of the four azidoamines 4, 6, 7, and 8 are shown in Ta-
ble 2. Due to the larger benzene ring, p-azidophenylammonium
8+ (K = 655 MÀ1) is bound about eight times weaker than 4-azido-
butylammonium 4+ (K = 5500 MÀ1) which seems to be a perfect fit
for the cavity of cucurbit[6]uril. Chain lengths longer than four
carbon atoms led to a much weaker bonding (K = 514 MÀ1 for 6-
azidopentylammonium 6+ and K = 713 MÀ1 for 8-azidohexylam-
monium 7+). This preferential binding for the butyl group can be
found again in previous works,24 where it has been shown that
complexation of butylammonium in cucurbit[6]uril leads to a
highly negative value for the reaction enthalpy combined with an
almost maximal entropic gain among all linear alkylammoniums.
However, in comparison to other complexes of alkylammoniums
in cucurbit[6]uril,24 the association constants are relatively low,
indicating that the azido group has a negative effect on the stability
of the complex, which is probably due to the presence of an elec-
tron lone-pair on its nitrogen atoms generating a repulsive interac-
tion with a rim of the host. A second reason for the low measured
affinity is the choice of solvent, for example, a strongly acidic solu-
tion, which leads to a competition for binding with protons and
formic acid.24 The binding constants of comparable amines are
known to be much larger in water25 or even in 0.05 M NaCl.24
Whereas azidoammoniums 4+–8+ are stable in acidic solution at
room temperature, they decompose completely within a week in
the dark, when cucurbit[6]uril is added. Considering that pKa shifts
in the magnitude of 4–5 units have already been reported upon
complexation,25,26 a plausible explanation is that protonation of
the azido group is facilitated by complex formation, generating a
dication, which can be efficiently stabilized by the CO groups at
the rims of the host. The decay has been observed by 1H NMR spec-
troscopy showing the disappearance of azidoammonium X+ after
only a few hours. However, in the liquid phase, no products of
low molecular weight could be detected. Similar results showing
the efficacy of cucurbiturils as supramolecular acid catalysts have
already been published.27 Our experiments also have shown that
the decomposition of an azidoalkylamine in cucurbituril cannot
proceed through a catalytic cycle. In fact, stoichiometric amounts
of cucurbit[6]uril are required because the major products, the cor-

M. Wieland et al. / Tetrahedron Letters 53 (2012) 4351–4353
4353
responding diamines, have a much higher affinity to the host24,28
than the starting compounds, thereby forming a poorly soluble
complex.
In conclusion, azidoalkylamines 3–7 and azidoarylamine 8 form
complexes with cucurbit[6]uril in acidic aqueous solution. Among
these compounds, the best fit is provided by butyl derivative 4 for
which an association constant of 5500 MÀ1 has been determined.
The solutions of 3–8@CB[6] in 7.6 M DCl have proven to be chem-
ically unstable. Although the studied azidoalkyl- and azidoarylam-
ines can be kept in this solvent at room temperature, they do
decompose rapidly in the presence of cucurbit[6]uril.
were washed several times with water and finally with brine to remove DMF.
The solvent was removed under reduced pressure at room temperature to
obtain the diazide as a colorless liquid. Warning! Care should be taken during
evaporation of the solvent due the explosive nature of the diazides! Also,
exposure to sunlight and other light sources should be minimized to prevent
decomposition! The liquid residue was dissolved in a 1:1 mixture of ether and
hexane (100 mL) and poured into 200 mL of 5% HCl. The mixture was rapidly
stirred to ensure proper emulsification and cooled to 0 °C. Then a solution of
triphenylphosphine (2.62 g, 10 mmol) in 50 mL of ether was added slowly over
30 min, keeping the temperature at 0 °C. The mixture was stirred overnight.
The organic phase was discarded and the aqueous phase was washed several
times to remove the majority of triphenylphosphine oxide. The aqueous phase
was brought to pH 11, whereby the solution turned turbid. The amine-free
base was extracted three times with ether (50 mL), dried over anhydrous
MgSO4 and the solvent was evaporated under reduced pressure at room
temperature (Do not heat!). 1H and 13C NMR spectroscopy confirm the absence
of traces of the corresponding diamine. Finally, the obtained free base was
dissolved in 50 mL of anhydrous ether and dry HCl was bubbled into the
solution to obtain the corresponding HCl salt. This was suction-filtered, dried
at room temperature in vacuo and stored in the dark at 2 °C. Care should be
taken because of the hygroscopic nature of the HCl salts.
Acknowledgments
We gratefully thank Dr. Jürgen Seidel and co-workers from the
Institute of Physical Chemistry of the Freiberg University of Mining
and Technology, Germany, for ITC measurements and Susanne Fel-
singer of the Institute of Organic Chemistry, University of Vienna,
for the recording of NMR spectra.
18. (a) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635–646; (b) Tian, W. Q.;
Wang, Y. A. J. Org. Chem. 2004, 69, 4299–4308.
19. Preparation of the complexes: Azidoalkylamine hydrochloride (100 mg) was
dissolved in 20 mL of distilled water. Then 3 equiv. of cucurbit[6]uril were
added at 45 °C and the resulting suspension was stirred for 4 h at this
temperature. Undissolved material was removed by filtration. Subsequently,
from the vial with the obtained solution placed in a desiccator over ca. 100 mL
of acetone, a white precipitate was produced by vapor diffusion of acetone at
room temperature. The crystals were suction-filtered, washed with a small
amount of cold acetone and dried in vacuo.
20. Graphical abstract: The Figure in the graphical abstract was obtained by
drawing a putative complex of 4-azidobutyl-1-ammonium in cucurbit[6]uril
and minimizing the energy of the structure with Spartan 04. The resulting
structure was then displayed with Mercury 2.0 and GIMP 2 to obtain the final
image.
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1:1 stoichiometry. The association constant K was determined as 676 MÀ1
.
22. Titration experiments with azidopentylamine (5)ÁHCl and CB[6]: Two stock
solutions were prepared: azidopentylamine (5)ÁHCl (0.02 M in 7.6 M DCl) and
cucurbit[6]uril (0.02 M in 7.6 M DCl). Under the acidic conditions (7.6 M DCl),
for azidopentylamine (5)ÁHCl the spectra clearly indicate a kinetically stable
complex between the amine and CB[6]. K = 108 MÀ1
.
23. Attempts at crystallization: A 1:1 mixture of the amine hydrochloride and
CB[6] in water was carefully heated up to 40 °C for 5 min under exclusion of
light, cooled to room temperature and filtered off after 2 h of stirring. The
obtained clear colorless filtrate was stored in an open vial in the dark at room
temperature (26 °C). After two weeks the solution had turned into a syrupy
yellowish liquid and small colorless crystals were formed. These were checked
by X-ray analysis. The result clearly showed that the azidoalkylamine was
converted into the corresponding diamine and fully included within the cavity
of CB[6]. The diamine was highly disordered, so a further refinement failed.
Azidobutylamine hydrochloride (4)ÁHCl, azidopentylamine hydrochloride
(5)ÁHCl, and azidohexylamine hydrochloride (6)ÁHCl also showed the same
behavior.
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in portions to a stirred solution of the dibromoalkanes (10 mmol) and a
catalytic amount of KI (20 mg) in 50 mL of DMF over a period of 30 min. The
flask was then covered with aluminum foil to exclude light and the mixture
was heated to 80–85 °C for 20 h. The yellowish liquid was poured on ice/water
(250 mL) and extracted three times with hexane. The combined organic phases
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