J. Am. Chem. Soc. 2001, 123, 4853-4854
Scheme 1
4853
Decomposition of S-Nitrosothiols: Unimolecular
versus Autocatalytic Mechanism
Loris Grossi,* Pier Carlo Montevecchi,* and
Samantha Strazzari
Dipartimento di Chimica Organica “A. Mangini”
UniVersit a` di Bologna, Viale Risorgimento 4,
I-40136 Bologna, Italy
ReceiVed NoVember 7, 2000
We report herein that nitrosothiols (RSNOs) undergo thermal
decomposition at a rate independent of the bulkiness of the alkyl
group. The disappearance of RSNO is inhibited if nitric oxide,
produced by reversible homolytic S-N bond scission, is not
removed from the reaction mixture. When the decomposition is
carried out in aerated solution, the disappearance of RSNO is
faster and occurs through an autocatalytic mechanism induced
by N
2
O
3
, which is produced by dioxygen oxidation of the
the anti conformation, green. Bulky nitrosothiols are believed to
be more stable, but a reliable explanation is still unknown.
To achieve a more confident picture of the chemical behavior
of RSNOs we have undertaken a kinetic study of the decomposi-
tion of a number of simple S-nitrosothiols under different reaction
conditions.
endogenous nitric oxide. The chain-decomposition reaction rate
is dependent on the bulkiness of the alkyl group, this suggesting
that steric factors play an important role in the propagation step.
In the past decade a large number of biological roles have been
1
ascribed to S-nitrosothiols; in particular, it has been postulated
that nitrosothiol derivatives of biological molecules, for instance
cysteine and glutathione, can act as in vivo carriers of nitric oxide.
For this preliminary work, benzylnitrosothiol (1a) and n-
hexylnitrosothiol (1b), both red, and tert-butylnitrosothiol (1c),
green, have been considered9 and the effect of the presence of
nitric oxide, dioxygen, and antioxidants on their decomposition
mechanism has been investigated.
2
,10
Despite the present great interest of chemists and biochemists
toward these compounds, a concrete picture of the mechanism
of the decomposition leading to nitric oxide under thermal
conditions is still lacking, since the data available in the literature
are often contradictory.
The thermal decomposition was monitored spectrophotometri-
cally at λ ) 550 nm for 1a11 and 1b and λ ) 605 nm for 1c
11a
11b
3
in 12 mM n-pentane (or n-octane) solution under various reaction
conditions.
Since early experiments, it is generally assumed that RSNOs
decompose through a unimolecular mechanism by homolytic
When the experiments were conducted at 0 °C in n-octane
deareated solutions under bubbling of argon, nitrosothiols 1a,c
decomposed within a few days at the same rate following a first-
cleavage of the labile S-N bond, even if it has been reported
that the half-life time (t1/2) of RSNO is dependent on its
concentration4 and the presence of air.5 In addition to the
-
4
-1
order kinetic law (k ) 2.8 × 10 min ) (Figure 1, curve a).
For both substrates, GC-MS analysis of the resulting reaction
mixture showed the exclusive presence of the corresponding
disulfide 2a,c. But, we found that complete decomposition of
nitrosothiols 1a-c occurred after several weeks (more than 5-6)
when a dearerated n-pentane solution was kept in a sealed tube
under argon atmosphere at both 0 and 25 °C. These results led
us to infer that nitrosothiols undergo unimolecular homolytic
scission of the S-N bond at a rate independent of the bulkiness
of the alkyl group. In principle, the resulting sulfanyl radicals
can dimerize to disulfide 2 or undergo a competing out of cage
recombination to RSNO. The former was the exclusive reaction
allowed when nitric oxide was removed through bubbling of
argon. When the decomposition was carried out in a sealed tube,
the reversible coupling of sulfanyl radicals with nitric oxide might
efficiently compete with the dimerization, and that can account
for the slower rate of disappearance of RSNOs observed (Scheme
1).
homolytic cleavage mechanism, the involvement of heterolytic
6
pathways also has been hypothesized. The thermal stability of
S-nitrosothiols has been reported to be affected by steric factors.7
,8
RSNOs exist as two geometrical syn and anti isomers, due to
some S-N double bond character.7 Primary and secondary
S-nitrosothiols seem to adopt the syn conformation, red color,
whereas tertiary nitrosothiols, owing to steric factors, would prefer
(
1) (a) Oae, S.; Shinhama, K. Thionitrites and Related Substances. Org.
Prep. Proc. Int. 1983, 15, 165-198. (b) Williams, D. H. L. Chem. Soc. ReV.
1
983, 14, 171-196. (c) Stamler, J. S. Curr. Top. Microbiol. Immun. 1995,
96, 19-36. (d) Williams, D. H. L. Acc. Chem. Res. 1999, 32, 869-876.
1
(
2) (a) Ignarro, L. J. In Nitric Oxide: Biology and Pathobiology; Ignarro,
L. J., Ed.; Academic Press: San Diego, 2000; Chapter 1. (b) Singh, R. J.;
Hogg, N.; Joseph, J.; Kalyanaraman, B. J. Biol. Chem. 1996, 271, 18596-
1
1
8603. (c) Mathews, W. R.; Kerr, S. W. J. Pharmacol. Exp. Ther. 1993, 267,
529. (d) Gaston, B.; Reilly, J.; Drazen, J. M.; Fackler, J.; Ramdev, P.; Arnelle,
D.; Mullins, M. E.; Sugarbaker, D. J.; Chee, C.; Singel, D. J.; Loscalzo, D.;
Stamler, J. S. Proc. Natl. Acad. Sci. 1993, 90, 10957-10961.
(
3) Rao, P. M.; Copeck, J. A.; Knight, A. R. Can. J. Chem. 1967, 45, 1369-
1
1
374. Josephy, P. D.; Rehorek, D.; Janzen, E. G. Tetrahedron Lett. 1984, 25,
685-1688.
In air-saturated n-pentane solution, nitrosothiols 1a-c decom-
posed at 0 °C at a rate that was found to be dependent on the
nature of the alkyl group and not to follow a simple first-order
(
4) Oae, S.; Fukushima, D.; Kim, Y. H. J. Chem. Soc., Chem. Commun.
1
977, 407-408.
(
5) Ignarro, L. J.; Lippton, H.; Edwards, J. C.; Baricos, W. H.; Hymann,
A. L.; Kadowitz, P. J.; Gruetter, C. A. J. Pharmacol. Exp. Ther. 1981, 218,
39-749.
6) (a) Field, L.; Dilts, R. V.; Ravichandran, R.; Lenhert, P. G.; Carnahan,
7
(9) As we have recently reported (see ref 10), S-nitrosothiols 1a,b (80%)
and 1c (62%) were obtained by reacting the corresponding thiol (1 mmol)
with aqueous (pH 13.5) 0.40 M peroxynitrite (5 mL) and 12 M hydrochloric
acid (0.45 mL) in acetonitrile solution (10 mL).
(10) Grossi, L.; Montevecchi, P. C.; Strazzari, S. Eur. J. Org. Chem. 2001,
131-135.
(11) (a) Barret, J.; Fitzgibbons, L. J.; Glauser, J.; Still, R. H.; Young, P.
N. W. Nature 1966, 211, 848. (b) Oae, S.; Kim, Y. H.; Fukushima, D.;
Shinhama, K. J. Chem. Soc., Perkin Trans. 1 1978, 913-917.
(
G. E. J. Chem. Soc., Chem. Commun. 1978, 249-250. (b) Lipton, S. A.; Choi,
Y. B.; Pan, Z. H.; Lei, S. Z.; Vincent Chen, H. S.; Sucher, N. J.; Loscalzo, J.;
Singel, D. J.; Stamler, J. S. Nature 1993, 364, 626-632.
(7) Bartberger, M. D.; Houk, K. N.; Powell, S. C.; Mannion, J. D.; Lo, K.
Y.; Stamler, J. S.; Toone, E. J. J. Am. Chem. Soc. 2000, 122, 5889-5890.
8) Oae, S.; Shinhama, K.; Fujimori, K.; Kim, Y. H. Bull. Chem. Soc. Jpn.
980, 53, 775-784.
(
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0.1021/ja005761g CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/28/2001