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Chem. Res. Toxicol. 1998, 11, 710-711
Forum: Reactive Species of Peroxynitrite Mechanisms of Peroxynitrite Oxidations and Rearrangements: The Theoretical Perspective Michael D. Bartberger, Leif P. Olson,† and K. N. Houk* Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569 Received March 24, 1998
Introduction. The mechanisms of peroxynitrite reactions such as conversion to nitrate, oxidation, and nitration are controversial. Of particular interest has been the involvement of the hydroxyl radical or other radical species (1). Modern theory can provide reliable activation energies and thermodynamics; here we summarize theoretical predictions regarding the reaction mechanisms of peroxynitrite and its derivatives. Two-Electron Oxidations. B3LYP/6-31G* calculations predict that amines, sulfides, and alkenes can be readily oxidized by peroxynitrous acid in a concerted process (2). The activation energies (∆Eq ) 13-18 kcal/ mol) are in line with the experimentally observed oxidations of sulfides. The transition structure for the oxidation of ammonia is shown as 1. The epoxidation of alkenes by peroxynitrous acid has an activation barrier of 13 kcal/mol, 2 kcal/mol less than epoxidation of ethylene by peroxyformic acid (3). The relative ease by which oxidation is predicted to occur is thwarted by the short lifetime of HOONO in solution; however, nucleophilic oxygen transfer to ethylene (or carbonyls; see below) by the more stable ONOO- is also predicted to occur readily (∆Eq ) 12 kcal/mol) (2). Mechanism of Peroxynitrous Acid Conversion to Nitric Acid. Both theory and experiment show that a variety of Brønsted and Lewis acids catalyze the rearrangements of peroxynitrite to nitrate. For peroxynitrous acid an experimental free energy of activation of 17 ( 1 kcal/mol has been measured (1). However, the mechanism of this transformation has been heavily debated. Arguments against free hydroxyl radical participation have led to the proposal of a concerted mechanism, whereby either an activated complex on the reaction pathway, a vibrationally excited form of trans-peroxynitrous acid (HOONO*) (1), or simply the trans form itself (4) is responsible for rearrangement and the high oxidative reactivity of HOONO. The enthalpy of O-O bond dissociation in HOONO to •ONO and •OH has been calculated as 22.5 kcal/mol at the B3LYP/6-31G* level of theory. The free energy for this homolysis is only 9.0 kcal/mol (2). The Complete Basis Set (CBS-Q) methodology, known to provide thermochemical estimates to within experimental accuracy, predicts ∆Hq and ∆Gq values of 20.3 and 9.3 kcal/mol, respectively. Transition structures corresponding to unimolecular rearrangement have also been characterized at the MP4SDQ (5), B3LYP (6), and (8,8) CASSCF † Current address: Eastman Kodak Co., 1999 Lake Ave., Rochester, NY 14650-2102.
Figure 1. B3LYP-optimized bond lengths (Å) and angles (degrees) of structures discussed in the text.
(7) levels, with the inclusion of both SCRF (5) and explicit (6) aqueous solvation (2, B3LYP/6-311++G** geometric parameters shown) (7). An even “looser” diradicaloid structure is found with the multireference CASSCF method. All of these calculations predict that the concerted mechanism has an activation energy of 47-60 kcal/mol. This cannot be a contributing pathway in the HOONO-HNO3 conversion. The O-O bond homolysis in HOONO leads to either of two structurally similar hydrogen-bonded radical pairs, 3 and 4. The hydrogen bonds in these “endo” and “exo” intermediates are stabilizing by about 2 kcal/mol, respectively, relative to free •ONO and •OH, and are slightly stronger than the calculated energy of a hydrogen bond from water to •ONO. The free energies of hydrogenbonded species 3 and 4 are 15.6 and 15.0 kcal/mol, respectively, above that of peroxynitrous acid. Recombination of these “caged” diradicals is barrierless, except for the 2 kcal/mol necessary to break the hydrogen bonds. While we do not expect a solvated form of this species to have an identical structure as in the gas phase, homolysis energetics should not change significantly (6). Solvated
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Forum: Reactive Species of Peroxynitrite
3 and 4 or related species would possess reactivity characteristic of the hydroxyl radical, though diffusion out of an aqueous solvation cage might be retarded. The activation energy for the formation of 3 or 4 matches the experimental energetics and is, therefore, an alternative to the previously proposed activated HOONO* (1, 4). Kinetics of oxidation involving 3 or 4 may be either firstor second-order, depending on the relative ease of attack on substrate versus radical recombination to HOONO or HNO3. Reactions of Peroxynitrite with CO2 and Other Carbonyl Compounds: Nitration and the Mechanism of Nitrate Formation. Conversion of peroxynitrite to peroxynitrous acid gives a peroxide, a labile radical precursor. Lewis acids can also have a similar activating effect. If the Lewis acid is capable of stabilizing a negative charge, such species may also serve as a NO2+ donor and thus a potent nitrating agent. For example, the oxidizing and nitrating ability of peroxynitrite is modulated by carbon dioxide; inhibition of hydroxylation and an increase in the nitration of aromatics and other organic substrates are observed in the presence of CO2 or added carbonate (8). Peroxynitrite reacts readily with carbon dioxide in an exothermic fashion (-25.7 kcal/mol, B3LYP/6-31G*) to yield nitrosoperoxycarbonate anion 5 (ONOO-CO2-). Rearrangement of such an adduct to nitrocarbonate anion (O2N-OCO2-) has been proposed (9). However, this species is not a minimum; instead, it collapses to •ONO and •CO3- via spontaneous N-O homolysis (2). These products can also be formed directly by the facile cleavage of 5, with an energy of only 8.7 kcal/mol. •ONO and •CO3- may undergo oxygen transfer, predicted to occur without barrier to form NO3-. Thus, the CO2-catalyzed rearrangement of ONOO- to NO3- is even more facile than Brønsted acid-promoted decomposition. Alternatively, protonation of •CO3- (pKa ) 6.8) yields the bicarbonate radical; one-electron oxidation [E°(phenoxyl/phenol) ) 0.8 V, E°(HCO3•-/HCO3-) ) 1.5 V] followed by subsequent entrapment by •ONO is postulated in phenol nitration (10). Free NO2+ from solvolysis of 5 is estimated to be slightly endothermic to thermoneutral in aqueous solution (2), but NO2+ transfer to a nucleophile could be facile. Free NO2+ should be readily captured by water, yielding nitrate (k ) 5 × 108 s-1) (9). The reaction of peroxynitrite with aldehydes (10) and ketones constitutes another set of (seemingly) similar pathways for the catalytic formation of nitrate from ONOO-. However, unlike the CO2-catalyzed conversion, aromatic nitration is inhibited in the presence of added aldehyde (10). A mechanism analogous to the addition of ONOO- to CO2 was proposed by Uppu et al., involving facile homolysis of RCH(OH)OONO, followed by recombination with N-O bond formation and subsequent dissociation to yield free nitrate and regenerated aldehyde (10). Our theoretical studies have uncovered an alternate mechanism, whereby concerted reaction occurs without a barrier to ketones, e.g., acetone, to yield dimethyldioxirane (DMDO) and nitrite ion. This reaction involves nucleophilic addition via the species 6, which may be an intermediate in solution. In the gas phase, it collapses to DMDO and nitrite. Oxygen transfer occurs in a second, spontaneous step after dioxirane formation. Such a mechanism is consistent with both the efficient conversion of peroxynitrate to nitrate (occurring without barrier), the absence of an effective nitrating agent in the
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presence of added carbonyl compounds, and the absence of free nitrite in such reactions (10). The difference between CO2 and simple aldehydes and ketones seems to be that CO2 forms an adduct with ONOO- which undergoes homolytic and heterolytic processes, while less electrophilic carbonyls form dioxirane intermediates which rapidly oxidize nitrite to nitrate. Conclusions. Peroxynitrous acid is predicted to readily oxidize organic substrates. The HOONO-HNO3 conversion occurs via a dissociative mechanism, involving hydrogen-bound radical pairs. Other Lewis acids can effect isomerization by similar homolytic pathways. Addition of peroxynitrite to CO2 followed by homolysis, heterolysis, or oxygen transfer (all of which are very facile processes) gives rise to the catalytic activity of CO2. Activation of peroxynitrite by ketones occurs via the rapid formation of a dioxirane intermediate followed by spontaneous oxygen transfer. Thus theory can aid experiment by uncovering previously unpostulated mechanistic pathways and by testing mechanistic ideas proposed by experimentalists.
Acknowledgment. Support of this work by the National Institutes of Health and the National Science Foundation is gratefully acknowledged.
References (1) Pryor, W. A., and Squadrito, G. L. (1995) The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide. Am. J. Physiol. 268 (Lung Cell. Mol. Physiol. 12), L699-L722. (2) Houk, K. N., Condroski, K. R., and Pryor, W. A. (1996) Radical and concerted mechanisms in oxidations of amines, sulfides, and alkenes by peroxynitrite, peroxynitrous acid, and the peroxynitrite-CO2 adduct: density functional theory transition structures and energetics. J. Am. Chem. Soc. 118, 13002-13006 and references therein. (3) Houk, K. N., Liu, J., DeMello, N. C., and Condroski, K. R. (1997) Transition states of epoxidations: diradical character, spiro geometries, transition state flexibility, and the origins of stereoselectivity. J. Am. Chem. Soc. 119, 10147-10152. (4) Koppenol, W. H., Moreno, J. J., Pryor, W. A., Ischiropoulos, H., and Beckman, J. S. (1992) Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide. Chem. Res. Toxicol. 5, 834-842. (5) Cameron, D. R., Borrajo, A. M. P., Bennett, B. M., and Thatcher, G. R. J. (1995) Organic nitrates, thionitrates, peroxynitrites, and nitric oxide: a molecular orbital study of the RXNO2 - RXONO (X ) O, S) rearrangement, a reaction of potential biological significance. Can. J. Chem. 73, 1627-1638. (6) Jursic, B. S., Klasinc, L., Pecur, S., and Pryor, W. A. (1997) On the mechanism of HOONO to HONO2 conversion. Nitric Oxide: Biol. Chem. 1, 494-501. (7) Sumathi, R., and Peyerimhoff, S. D. (1997) An ab initio molecular orbital study of the potential energy surface of the HO2+NO reaction. J. Chem. Phys. 107, 1872-1880. (8) Lemercier, J.-N., Padmaja, S., Cueto, R., Squadrito, G. L., Uppu, R. M., and Pryor, W. A. (1997) Carbon dioxide modulation of hydroxylation and nitration of phenol by peroxynitrite. Arch. Biochem. Biosphys. 345, 160-170. (9) Uppu, R. M., Squadrito, G. L., and Pryor, W. A. (1996) Acceleration of peroxynitrite oxidations by carbon dioxide. Arch. Biochem. Biophys. 327, 335-343. (10) Uppu, R. M., Winston, G. W., and Pryor, W. A. (1997) Reactions of peroxynitrite with aldehydes as probes for the reactive intermediates responsible for biological nitration. Chem. Res. Toxicol. 10, 1331-1337.
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