Nitric oxide release mediated by calix[4]hydroquinones

Article abstract of DOI:10.1021/ol800156m

Calix[4]monohydroquinone has been used as a supramolecular system for the generation of NO gas. In a one-electron reduction scheme Involving NO ⁺ ?calix[4]monohydroquinone complex, NO is released without the presence of an external reducing agent. Free calix[4]monoqulnone, thus obtained, can be reused for a new NO-releasing cycle after NaBH₄-reductlon to calix[4]monohydroquinone.

Full text of DOI:10.1021/ol800156m

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1263-1266
Nitric Oxide Release Mediated by
Calix[4]hydroquinones
Eranda Wanigasekara,† Carmine Gaeta,‡ Placido Neri,*,‡ and
Dmitry M. Rudkevich*,†,§
Dipartimento di Chimica, UniVersita` di Salerno, Via Ponte don Melillo,
I-84084 Fisciano (Salerno), Italy, and Department of Chemistry and Biochemistry,
UniVersity of Texas at Arlington, Arlington, Texas 76019-005
neri@unisa.it
Received January 22, 2008
ABSTRACT
Calix[4]monohydroquinone has been used as a supramolecular system for the generation of NO gas. In a one-electron reduction scheme
+
involving NO
⊂
calix[4]monohydroquinone complex, NO is released without the presence of an external reducing agent. Free calix[4]monoquinone,
thus obtained, can be reused for a new NO-releasing cycle after NaBH4-reduction to calix[4]monohydroquinone.
Nitric oxide (NO) is a colorless odorless gas, which plays
important roles in several biological functions.1 In particular,
in the human body nitric oxide is involved in the regulation
of cardiovascular, respiratory, and nervous systems. The
development of therapeutic agents designed to release NO
is an intensively active area of research, since NO gas has
shown beneficial effects against several types of disease
states. Thus, NO-releasing organic nitrates, as glyceryltri-
nitrate, are used as antianginal drugs2 thanks to the vasodi-
latator properties of NO gas, whereas the antiinflammatory
properties of NO gas have been used in NO-NSAIDS,3 a
class of nonsteroidal antiinflammatory drugs able to release
NO. In addition, NO gas has shown antibacterial4 and
antitumoral5 activity, and consequently, there is a strong
(2) (a) Murrell, W. Lancet 1879, 1, 80. (b) Parker, J. O.; Farrell, B.;
Lahey, K. A.; Moe, G. N. Engl. J. Med. 1987, 316, 1635.
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cited therein.
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2001, 123, 9712.
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M. A. Cancer Res. 1995, 55, 727. (b) Jenkins, D. C.; Charles, I. G.;
Thomsen, L. L.; Moss, D. W.; Holmes, L. S.; Baylis, S. A.; Rhodes, P.;
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L. G.; Knowles, R. G.; Moncada, S. Br. J. Cancer 1995, 72, 41.
† Universita` di Salerno.
‡ University of Texas at Arlington.
§ Sadly deceased on August 04, 2007.
(1) (a) Marletta, M. A.; Tayeh, M. A.; Hevel, J. M. BioFactors 1990, 2,
219. (b) Moncada, S.; Higgs, A. N. Engl. J. Med. 1993, 30, 2002. (c) Pfeiffer,
S.; Mayer, B.; Hemmens, B. Angew. Chem., Int. Ed. 1999, 38, 1714. c)
Fleming, I.; Busse, R. Angew. Chem., Int. Ed. 1999, 31, 5. (d) Ignarro, L.
J. Nitric Oxide: Biology and Pathobiology; Academic Press: San Diego,
CA, 2000. (e) Butler, A. R.; Nicholson, R. Life, Death and Nitric Oxide;
Royal Society of Chemistry: Cambridge, 2003.
10.1021/ol800156m CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/28/2008

interest in the search of synthetic compounds that chemically
store and release NO in a controlled fashion.6
The designed compound, p-tert-butylcalix[4]mono-
hydroquinone 3, was obtained by NaBH4 reduction of the
corresponding tripropoxycalix[4]monoquinone 2,17 which in
turn was prepared by Tl(CF3COO)3-mediated oxidation18 of
tripropoxy-p-tert-butylcalix[4]arene 1 (Scheme 1).19,20
Thus, Schoenfisch and co-workers have reported the
synthesis and characterization of NO-releasing systems based
on diazeniumdiolate7 NO-donors.8 The diazeniumdiolate
groups, covalently bound to dendrimer or silica nanoparticles,
were able to dissociate spontaneously under physiological
conditions to give NO gas.
Scheme 1
At the same time, there has been a growing interest in
supramolecular systems that have the capability to reversibly
trap, store, and release NO.9,10 Among them, increasing
attention has been devoted to the development of calixarene-
based11 materials able to store NO in the form of entrapped
nitrosonium (NO+) ion.12 Thus, Rathore and Rudkevich have
described stable complexes between calixarene derivatives
and NO+ ion,12 with this ion strongly bound within the
calixarene aromatic cavity by means of cation-π interac-
tions.13 This work was also extended to the storage of NO+
ion into the cavity of synthetic calixarene-based nano-
tubes.14,15
We have shown that nitric oxide (NO) can be smoothly
released from the calixarene cavity after a one-electron
reduction scheme involving NO+⊂calixarene complexes and
an external reducing agent such as hydroquinone molecule.16
After releasing NO, the starting calixarene was regenerated
in 95% yield and was reused for a new NO-releasing cycle.
In this paper, we wish to report a new calixarene-based
supramolecular system endowed with an internal hydro-
quinone reducing moiety and therefore able to release NO
without the addition of external agents.
1
Examination of its H and 13C NMR spectra20 indicated
that calix[4]monohydroquinone 3 adopts a cone conforma-
tion.21 In fact, two AX systems relative to ArCH2Ar groups
[4.32/3.17 ppm (J ) 12.5 Hz), 4.36/3.16 ppm (J ) 13.2 Hz)]
were present in the 1H NMR spectrum (Figure 1a), whereas
the 13C NMR spectrum displayed two ArCH2Ar resonances
at 31.2 and 31.4 ppm.21c,d,22
(6) (a) Wang, P. G.; Xian, M.; Tang, X.; Wu, X.; Wen, Z.; Cai, T.;
Janczuk, A. J. Chem. ReV. 2002, 102, 1091. (b) Burgaud, J.-L.; Onigini,
E.; Del Soldato, P. Ann. N. Y. Acad. Sci. 2002, 962, 360. (c) Low, S. Y.
Mol. Aspects Med. 2005, 26, 97. (d) Wang, P. G.; Cai, T. B.; Taniguchi,
N. Nitric Oxide Donors: For Pharmaceutical and Biological Applications;
Wiley-VCH: Weinheim, Germany, 2005.
Tripropoxycalix[4]monoquinone 2 shows the presence of
a broad singlet (or a very tight AB system) at 3.51 ppm
relative to ArCH2Quin protons adjacent to quinone ring and
an AX system [4.14/3.10 ppm (J ) 12.5 Hz), 4H] relative
to ArCH2Ar protons (see for comparison its spectrum in the
presence of TFA reported in Figure 1d). This is indicative
of a fixed syn orientation of ArOPr rings associated to a fast
through-the-annulus rotation of the quinone ring. This
behavior was confirmed by the presence of two resonances
at 35.5 and 31.0 ppm relative to ArCH2Quin and ArCH2Ar
carbon, respectively, in the 13C NMR spectrum of 2.20,21c-d,22
When tert-butylnitrite (2 equiv) was added to a mixture
of calix[4]monohydroquinone 3 and TFA in CDCl3, a deep-
(7) Hrabie, J. A.; Keefer, L. K. Chem. ReV. 2002, 102, 1135.
(8) (a) Stasko, N. A.; Schoenfisch, M. H. J. Am. Chem. Soc. 2006, 128,
8265. (b) Shin, J. H.; Metzger, S. K.; Schoenfisch, M. H. J. Am. Chem.
Soc. 2007, 129, 4612.
(9) (a) Ding, X. D.; Weichsel, A.; Andersen, J. F.; Shokhireva, T. K.;
Balfour, C.; Pierik, A. J.; Averill, B. A.; Montfort, W. R.; Walker, F. A. J.
Am. Chem. Soc. 1999, 121, 128. (b) Padden, K. M.; Krebs, J. F.; MacBeth,
C. E.; Scarrow, R. C.; Borovik, A. S. J. Am. Chem. Soc. 2001, 123, 1072.
(c) Mitchell-Koch, J. T.; Reed, T. M. A.; Borovik, S. Angew. Chem., Int.
Ed. 2004, 43, 2806.
(10) For a more general review on the supramolecular chemistry of gases,
see: Rudkevich, D. M. Angew. Chem., Int. Ed. 2004, 43, 558.
(11) For general reviews on calixarenes, see: (a) Bo¨hmer, V. Angew.
Chem., Int. Ed. 1995, 34, 713. (b) Ikeda, A.; Shinkai, S. Chem. ReV. 1997,
97, 1713. (c) Gutsche, C. D. Calixarenes ReVisited; Royal Society of
Chemistry: Cambridge, 1998. (d) Calixarenes 2001; Asfari, Z., Bo¨hmer,
V., Harrowfield, J., Vicens, J., Eds.; Kluwer: Dordrecht, 2001. (e) Bo¨hmer,
V. In The Chemistry of Phenols; Rappoport, Z., Ed.; Wiley: Chichester,
UK, 2003; Chapter 19. (f) Calixarenes in the Nanoworld; Vicens, J.,
Harrowfield, J., Eds.; Springer: Dordrecht, 2006.
(12) (a) Rathore, R.; Lindeman, S. V.; Rao, K. S. S. P.; Sun, D.; Kochi,
J. K. Angew. Chem., Int. Ed. 2000, 39, 2123. (b) Zyryanov, G. V.; Kang,
Y.; Rudkevich, D. M. J. Am. Chem. Soc. 2003, 125, 2997. (c) Kang, Y.;
Zyryanov, G. V.; Rudkevich, D. M. Chem.-Eur. J. 2005, 11, 1924.
(13) For a recent example of NO+⊂resorc[4]arene complexes, see: Botta,
B.; D’Acquarica, I.; Delle Monache, G.; Nevola, L.; Tullo, D.; Ugozzoli,
F.; Pierini, M. J. Am. Chem. Soc. 2007, 129, 11202.
(17) Lu, L.-G.; Li, G.-K.; Peng, X.-X.; Chen, C.-F.; Huang, Z.-T.
Tetrahedron Lett. 2006, 47, 6021.
(18) Reddy, P. A.; Kashyap, R. P.; Watson, W. H.; Gutsche, C. D. Isr.
J. Chem. 1992, 32, 89.
(19) Iwamoto, K.; Araki, K.; Shinkai, S. J. Org. Chem. 1991, 56, 4955.
(20) See the Supporting Information for additional details.
(21) (a) Gutsche, C. D. Calixarenes; Royal Society of Chemistry:
Cambridge, 1989, pp. 110-111. (b) Kanamathareddy, S.; Gutsche, C. D.
J. Org. Chem. 1992, 57, 3160. (c) Bifulco, G.; Gomez-Paloma, L.; Riccio,
R.; Gaeta, C.; Troisi, F.; Neri, P. Org. Lett. 2005, 7, 5757. (d) Bifulco, G.;
Riccio, R.; Gaeta, C.; Neri, P. Chem.-Eur. J. 2007, 13, 7185.
(22) (a) Jaime, C.; de Mendoza, J.; Prados, P.; Nieto, P. M.; Sanchez,
C. J. Org. Chem. 1991, 56, 3372. (b) Magrans, J. O.; de Mendoza, J.; Pons,
M.; Prados, P. J. Org. Chem. 1997, 62, 4518.
(14) Organo, V. G.; Leontiev, A. V.; Sgarlata, V.; Dias, H. V. R.;
Rudkevich, D. M. Angew. Chem., Int. Ed. 2005, 44, 3043.
(15) For a review on the host-guest chemistry of synthetic nanotubes,
see: Organo, V. G.; Rudkevich, D. M. Chem. Commun. 2007, 3891.
(16) Wanigasekara, E.; Leontiev, A. V.; Organo, V. G.; Rudkevich, D.
M. Eur. J. Org. Chem. 2007, 2254.
1264
Org. Lett., Vol. 10, No. 6, 2008

situated inside the calix[4]monohydroquinone cavity, whereas
the second postulates an external π-complex, with NO+
situated outside the calixarene cavity. Energetically, the
encapsulated π-complex seems much more favorable; in fact,
it is well known that NO+ is easily encapsulated into the
π-electron rich calix cavity and generally shows Kassoc
.
106 M-1.12b The deep-purple color initially developed is an
additional proof of the formation of NO+⊂3 complex. In
fact, as shown in previous works,12,16 this deep-purple color
is caused by the strong charge transfer interaction between
NO+ and the electron rich π-surface of aromatic rings present
in 3.13 This was corroborated by a broad charge-transfer band
at λmax ) 545 nm in CHCl3, typical for these systems.20,24
1H NMR analysis confirmed the above conclusions. In fact,
1
the H NMR spectrum of the mixture of p-tert butylcalix-
[4]monohydroquinone 3 and TFA (Figure 1b) changed
substantially after the addition of tert-butylnitrite.
In particular, a new set of resonances relative to NO+⊂3
complex (Figure 1c) appeared, whose aromatic protons were
shifted downfield with respect to calix[4]monohydroquinone
3, in accordance with our previous results.14,16 In addition,
the 1H NMR spectrum (Figure 1c) displayed also the
resonances relative to tripropoxycalix[4]monoquinone 2
(marked signals). After that the reduction had taken place
completely and neutral NO molecule was released, calix[4]-
monoquinone 2 was obtained in quantitative yield, as
confirmed by NMR analysis (Figure 1d) and by the transpar-
ent pale-yellow color of solution. Calix[4]monoquinone 2
thus obtained was sufficiently pure (Figure 1d) and, after
NaBH4-reduction to 3, can be reused for a new NO-releasing
cycle (Scheme 2).
Figure 1. 1H NMR spectra (300 MHz, CDCl3, 295 K) of: (a)
p-tert-butylcalix[4]monohydroquinone 3; (b) monohydroquinone 3
in the presence of TFA; (c) formation of NO+⊂3 complex upon
addition of t-BuONO to solution “b”; (d) Solution “c” after 5 min
from the addition of t-BuONO, corresponding to monoquinone 2
in the presence of TFA. Relevant signals of monoquinone 2 are
marked with asterisks in “c” and “d”.
Scheme 2
purple color initially appeared.20 Subsequently, NO gas was
released out from the system, and within 5 min, the solution
turned to a transparent pale-yellow color.23
These results are consistent with an initially formed NO+
ion encapsulated into the calixarene cavity and then quickly
reduced to NO by means of a one-electron reduction scheme
by the hydroquinone moiety of calix[4]monohydroquinone
3, which was oxidized to calix[4]monoquinone 2. Clearly,
there are two possibilities for the reduction of NO+ ion to
NO: the first is an encapsulated π-complex, with NO+
The headspace NO gas generated by the reaction between
3 and tert-butylnitrite in TFA was analyzed using UV
spectrophotometry, and three characteristic peaks were
obtained at λmax ) 206, 214, and 226 nm (Figure 2). These
UV data are in agreement with previously published UV
absorption data for identification of NO.25
(23) In a preparative procedure, tert-butylnitrite (0.70 mmol) was reacted
with trifluoroacetic acid (3.5 mmol) in presence of p-tert-butyl-calix[4]-
mono-hydroquinone 3 (0.25 g, 0.35 mmol) in dry chloroform (1.5 mL) under
vigorous stream of N2. The evolved NO gas (ca. 7.6 mL, 0.34 mmol) was
collected by a syringe or over cold water and identified by UV spectroscopy
(yield 97%). Three characteristic peaks were observed at λmax 206, 214,
226 nm, which confirmed the evolution of pure NO gas. The tripropoxycalix-
[4]monoquinone 2 was quantitatively (>95%) produced and identified by
1H NMR spectroscopy.
In contrast to the NO-releasing experiment reported in
Scheme 2, if 4 equiv of tert-butylnitrite were added to a
(24) (a) Borodkin, G. I.; Shubin, V. G. Russ. Chem. ReV. 2001, 70, 211.
(b) Zyryanov, G. V.; Rudkevich, D. M. J. Am. Chem. Soc. 2004, 126, 4264.
(25) (a) Marmo, F. F. J. Opt. Soc. Am. 1953, 43, 1186. (b) Bosch, E.;
Rathore, R.; Kochi, J. K. J. Org. Chem. 1994, 59, 2229.
Org. Lett., Vol. 10, No. 6, 2008
1265

spectrum. In fact, a singlet was present at 8.07 ppm relative
to protons in ortho to nitro group, whereas an AB system
relative to the remaining aromatic protons was present at
6.54 and 6.89 ppm (J ) 2.1 Hz, 4 H). In addition, a
resonance was present at 6.74 ppm (2H) relative to the
protons of the quinone moiety. Also in this case, the presence
of a broad singlet at 3.56 ppm and of an AX system at 4.22/
3.27 ppm (J ) 13.0 Hz) relative to ArCH2Quin and ArCH2Ar
protons, respectively, were indicative of a fast through-
the-annulus rotation of the quinone ring of 4, which was
confirmed by the pertinent 13C NMR signals.
The regiochemical outcome of the nitrosation can be
explained by considering that very likely the excess NO+
ion is complexed by quinone 2, as indicated by the deep-
purple color of the solution. In this complex, the nitrosonium
cation should be sandwiched between the two distal Ar-
OPr rings, which would be parallel to one another. In this
way, the NO+ ion is perfectly oriented to give the ipso-
nitrosation onto the central Ar-OPr ring opposite to quinone
system, with high regioselectivity.27 This reaction can be
considered as an interesting example of supramolecular
control of a reaction outcome,28 which could be probably
exploited in a larger context.
In conclusion, we have shown that p-tert-butylcalix[4]-
monohydroquinone 3 can be used for the generation of NO
gas. In a one-electron reduction scheme involving NO+⊂3
complex, NO is released without the presence of an external
reducing agent. Free tripropoxycalix[4]monoquinone 2, thus
obtained, can be reused for a new NO-releasing cycle after
NaBH4-reduction to 3.
Figure 2. UV spectrum of the head space gas generated from the
NO+⊂3 complex.
mixture of 3 and TFA (10 equiv) in dry chloroform, the
excess nitrosonium ion reacted further with calix[4]-
monoquinone 2 and allowed the selective ipso-nitration of
2 at the distal aromatic ring with respect to the quinone
moiety, yielding 4 in 60% yield (Scheme 3). The reaction
Scheme 3
Acknowledgment. Financial support is gratefully ac-
knowledged from the National Science Foundation (NSF)
(CHE-0350958), the Alfred P. Sloan Foundation, and the
Italian MUR.
Supporting Information Available: Experimental and
outcome is likely to be the result of an initial ipso-nitrosation
of 2, followed by an oxidation of the nitroso intermediate to
nitroderivative 4 by oxygen.26 The structure of 4 was assigned
by spectral analysis. In particular, the presence of a pseudo-
molecular ion peak at m/z 723 in the ESI(+) mass spectrum
confirmed the molecular formula. The molecular structure
of 4 was confirmed by the pertinent signals in the 1H NMR
1
synthetic details and H/13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL800156M
(27) A comparable selectivity was observed in the nitrosation of
secondary amides by nitrosonium⊂calixarene camplexes (see ref 12c and
Zyryanov, G. V.; Rudkevich, D. M. Org. Lett. 2003, 5, 1253).
(28) For other examples of supramolecular control of a reaction outcome,
see: (a) Maia, A.; Landini, D.; Penso, M.; Brandt, K.; Siwy, M.; Schroeder,
G.; Gierczyk, B. New J. Chem. 2001, 25, 1078. (b) Chen, J.; Rebek, J., Jr.
Org. Lett. 2002, 4, 327. (c) Iwasawa, T.; Mann, E.; Rebek, J., Jr. J. Am.
Chem. Soc. 2006, 128, 9308.
(26) For spontaneous oxidation of p-nitroso phenol to p-nitro derivative
in presence of oxygen see: The Chemistry of Phenols; Rappoport, Z., Ed.;
Wiley: Chichester, UK, 2003; Chapter 9, p 639, and references therein.
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