Reaction of CO2 with ONOOâ: One Molecule of CO2 Is Not Enough

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The Reaction of CO with ONOO. One Molecule of CO is not Enough Sandra Serrano-Luginbuehl, Reinhard Kissner, and Willem Hendrik Koppenol Chem. Res. Toxicol., Just Accepted Manuscript • DOI: 10.1021/acs.chemrestox.8b00068 • Publication Date (Web): 24 Jul 2018 Downloaded from http://pubs.acs.org on July 30, 2018

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Chemical Research in Toxicology

The Reaction of CO2 with ONOO−. One molecule of CO2 is not Enough

Sandra Serrano-Luginbuehl, Reinhard Kissner, and Willem H. Koppenol* Institute of Inorganic Chemistry, Department of Chemistry and Applied Biosciences Swiss Federal Institute of Technology 8093 Zürich, Switzerland

1 ACS Paragon Plus Environment


For TOC only.

/%

3

Relative yield of CO3• ̶

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2

1 Physiological [CO2] 0 0

2

4 6 [CO2] / mM

8

Legend, if required: Yield of CO3•− is below 1% relative to ONOO−


10

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ABSTRACT: With CO2 present in excess, ONOO− reacts to form an adduct in solution and in the solid state, most likely ONOOCO2−. In solution, the adduct appears within 2 ms and absorbs at 300 with an extinction coefficient which is either 50% or 100% (preferred) of that of ONOO−, 1.70 • 103 M−1cm−1, and at 685 nm with an extinction coefficient of 85 M−1cm−1. When solid [(CH3)4N][ONOO] is treated with CO2, these two maxima are red-shifted by 30 − 50 nm. The equilibrium constant for adduct formation in solution is (4.5 ± 0.5) • 103 M. The adduct reacts further with another CO2 at a rate of (2.6 ± 0.8) • 104 M−1s−1 and produces 2 CO2 and NO3−.Thermochemical calculations show that ΟΝΟΟCO2− is a strong two-electron oxidizing agent, E°(ONOOCO2−, H+/NO2−, HCO3−) = +1.28 V at pH 7, and an even stronger one-electron oxidizing agent E°'(ONOOCO2−, H+/NO2•, HCO3−) = +1.51 V at pH 7. The extent of homolysis, that is formation of NO2• and CO3•−, is small, slightly less than 1% relative to ONOO− at the physiological concentration of CO2 of 1.3 mM in plasma. Thus, ONOOCO2− is more relevant than CO3•− under in vivo conditions.


Chemical Research in Toxicology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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INTRODUCTION O2•− reacts at a diffusion-controlled rate with NO• to form ONOO−, k = 1.6•1010 M−1s−1.1 In water, the protonated form, ONOOH, isomerizes to NO3− and H+ with a rate of 1.11 s−1.2 ONOOH, pKa = 6.7 at I = 0.20 M

2

is much more damaging than its progenitors in that it can

oxidize and nitrate biomolecules.3;4 Widespread in the literature is the notion that ONOOH undergoes homolysis to HO• and NO2•, to an extent of ca. 30%,5 a reaction that is thought to contribute to its toxicity. However, an extensive review of the literature has shown that the extent of that reaction is at most 5%.6 In vivo, ONOO− reacts with CO2 before homolysis could occur. This reaction is more likely to account for the toxicity of ONOO−, as the adduct, ONOOCO2−, is thought to be a strong oxidant itself, or to homolyze, in part, into NO2• and CO3•−. Evidence for the latter was reported in 1999.7;8 In 1929, Gleu and Roell found that addition of HCO3− to an alkaline solution of ONOO− led to its rapid conversion to NO3−.9 The effect of HCO3− was rediscovered in 1993,10 and in 1995, Lymar and Hurst reported that ONOO– reacts with CO2 with a rate constant of 3•104 M−1s−1.11 In addition, these authors postulated that ONOO– and CO2 react to form a short-lived intermediate, ONOOCO2–, which then decays rapidly, reactions 1 and 2).

ONOO– + CO2

⇌ ONOOCO2–

k1, k-1,

(1)

ONOOCO2–

→ Products

k2

(2)

Since then, the reaction of ONOO– with CO2 has been studied further, especially with regard to the oxidative properties of its intermediates. The products of the reaction of ONOO– with CO2


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oxidize tyrosine, I–, [Fe(CN)6]4–, [Mo(CN)8]4– as well as [Fe(bpy)3]2+, [Ru(bpy)3]2+ and [Os(bpy)3]2+,12;13 among others. Two different explanations for the oxidative behavior have been put forth: the first states that ONOOCO2– is an oxidant.12-14 The second,15 which is favored by a majority of researchers, and supported by theoretical studies,16;17 states that ONOOCO2− first undergoes homolysis to form CO3•– and NO2• to an extent of 30%; these radicals then oxidize the substrates by one-electron processes (reaction 3) and are responsible for a typical 60% total products yield.

ONOOCO2– + 2 Xn– → CO3•– + NO2• + 2 Xn–

→ CO32– + NO2– + 2 X(n-1)–

(3)

It has also been postulated that ONOOCO2− does not exist at all, but that instead, CO3•− and NO2• form a caged radical pair;18;19 in other cases, ONOOCO2– is not even mentioned at all.20 However, there have been reports which ascribe a transient absorption with a maximum at 650 nm to ONOOCO2−.7;14 In the solid state, the blue color associated with this Lewis acid-base adduct is stable for a few minutes.14 An interpretation of this observation is complicated because CO3•− has an absorption maximum at 600 nm,21 and any absorption in that region could be mimicked by higher-order light: ONOO– absorbs maximally at 300 nm, and that absorption will also be “reported” by the grating monochromator at 600 nm. If ONOOCO2– is formed in the absence of a reducing species, it can either undergo homolysis to form CO3•– and NO2•, which then react further to form the final reaction products, CO2 and NO3− (reactions 4 & 5). Alternatively, ONOOCO2– decays directly to the final products, CO2 and NO3− (reaction 6). Crystalline [(CH3)4N][ONOO]22 is present in the cis-conformation,23 in agreement with ab inito studies.24;25 In another theoretical study,26 it has been suggested CO2 acts a catalyst, in that it, 5 ACS Paragon Plus Environment


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when bound, reduces the activation energy for the cis to trans transition of peroxynitrite that is necessary for isomerization.

ONOOCO2−

→ CO3•− + NO2•

(4)

CO3•− + NO2•

→ CO2 + NO3−

(5)

ONOOCO2−

→ CO2 + NO3−

(6)

Scheme 1 shows the reactions discussed above and also highlights the catalytic role of carbon dioxide: −

ONOO + CO2

k1

ONOOCO2−

k-1

CO3•− + NO2• CO2 + NO3−

Scheme 1. Catalytic role of CO2 in the isomerization of ONOO−.

None of the hypotheses mentioned above accounts for two observations. First, when ONOO− and CO2 are mixed in a stopped-flow apparatus, the initial absorption does not reflect the ONOO− concentration at t = 0 at 302 nm. In fact, the absorption corresponds to half or less of what one would expect, remains constant more or less for 2-3 ms and then decreases.14;18 Second, when exposed to CO2, solid orange [(CH3)4N][ONOO] turns green, stays that way for a few minutes, and turns slowly to white. The green color stems from a mixture of the orange peroxynitrite and a blue compound. If, as purported, the blue color indicates the presence of CO3•−, then one would not expect the green color to persist that long. We show here evidence for the existence of 6 ACS Paragon Plus Environment

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ONOOCO2–, and that it has absorption maxima at both 302 nm and 650 nm. By measuring kinetics traces of the 650 nm band, and by varying [CO2] under CO2 excess conditions, we are able to determine the second-order rate constant of the reaction of ONOOCO2− with CO2, as well as the equilibrium constant of the reaction of ONOO– with CO2. Under conditions of CO2 excess, the CO3•– yield with respect to the initial ONOO– concentration is only a few percent and depends on the CO2 concentration.



METHODS

General. All reagents, except for [(CH3)4N][ONOO] and CO2, were purchased from Merck, Fluka or Siegfried and were of analytical grade or better. [(CH3)4N][ONOO] was synthesized according to Bohle et al.27 and 1 ml aliquots of ca. 10 mM were kept in a freezer at −70 °C. Upon removal from the freezer, the still–frozen pellets were dissolved in a 0.010 M NaOH solution on ice to yield the desired concentration. A solution containing CO2 was made by saturating a 0.10 M NaHCO3 solution with CO2 evaporated from dry ice. This method is different from the usual one, by which CO2 is supplied indirectly by the use of a high concentration of NaHCO3 and variation of the pH to obtain the desired CO2 concentration. The latter method has two drawbacks: the conversion of HCO3– to CO2 is slow in comparison to the other reactions, and the reactivity of ONOOH, due to its pKa of 6.8 at 25°C,28 is pH-dependent, making the interpretation of kinetics results more difficult. NaHCO3/CO2 was used as buffer because it does not introduce any new species; it eliminates additional competitive reactions which, for example, would be introduced by a phosphate or an acetate buffer. In order to make dilutions, and to supply the solutions to the stopped flow spectrophotometer, gastight syringes were used.

Concentration Determination of ONOO– and CO2. [ONOO–] was measured for each solution with a spectrophotometer (Analytik Jena, Specord 200) from 250 nm to 500 nm in a quartz cuvette. The absorption maximum at 300 nm and ε300 nm = 1.70 × 103 cm−1M−1 22 were used to calculate the concentration. [CO2] was determined for the saturated solution 0.10 M NaHCO3 by titration with 1.00 M NaOH Merck Titrisol in a Metrohm 665 Dosimat.

Stopped-flow Spectrophotometry. For all the stopped–flow data shown, an Applied Photophysics SX17MV stopped-flow spectrophotometer was used. Solutions of ONOO− in NaOH, and of CO2 in NaHCO3 were combined in the mixing cell. For experiments with CO2 in


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excess, [ONOO–] was kept constant (approximately 0.25 mM) and [CO2] was decreased stepwise from 10 mM until 0.5 mM by diluting the CO2-saturated buffer with 0.10 M NaHCO3. We also kept [CO2] constant and in excess, and decreased [ONOO–] stepwise by diluting the stock ONOO– solution with 0.010 M NaOH. The Applied Photophysics Spectrophotometer was determined to have a mixing time of smaller than 2 ms. Therefore, all of the kinetic traces were fitted and extrapolated to 0 s, which introduces a source of uncertainty. Furthermore, the monochromator of the spectrophotometer transmits both first- and second-order light. For this reason we used a 550 nm edge filter to block second-order light while recording the absorption spectrum of ONOOCO2− from 640 to 750 nm and a 320 nm edge filter for all other measurements above 450 nm. We estimate that the maximal error in the absorbance introduced by second–order light above 640 nm is about 10 %.

Solid State Spectra. We placed dry solid fresh [(CH3)4N][ONOO] on white paper and used an Analytik Jena Specord 250 spectrophotometer equipped with an integrating sphere to record its diffuse absorption spectrum. Afterwards, CO2 was streamed over the solid [(CH3)4N][ONOO] and the spectrum was measured again.

Anion Chromatography. To study the products of experiments with CO2 in excess, solutions of ONOO− with [ONOO–] = 0.53 mM in 0.010 M NaOH and of 20 mM CO2 in deionized H2O were prepared. The CO2-containing solutions were not buffered with NaHCO3. The two solutions were mixed 1:1 in an OLIS RSM stopped-flow device set to flush mode in order to ensure optimal mixing. The resulting solution was degassed and then diluted 10-fold before chromatography. For calibration, solutions of NaNO2 and NaNO3 in H2O with concentrations of 20, 50 and 100 µM were prepared. They were saturated with CO2 as described above and



subsequently degassed. A Metrohm anion chromatograph with conductometric detection was used; the eluent was OH– in H2O, generated by a Dionex Reagent-Free Controller.

Flow Reactor. For the flow reactor experiments we filled one gas-tight syringe with 1 mM ONOO− in 0.010 M NaOH and another with 20 mM CO2 in 0.10 M NaHCO3. Both syringes were connected to a HPLC gradient mixer attached to a calibrated HPLC tube. Solutions were mixed at a ratio of 1:1. The flow rate was set in such a way that the reaction was quenched after 2 ms by directing the reaction mixture into a rapidly stirred 1.0 M NaOH solution of a much larger volume which both stabilized ONOO− and removed all CO2 (Figure 1). The concentration of ONOO− was measured before and after mixing.

[(CH3)4N][ONOO] solution HPLC gradient mixer

Syringe pump

Volume-calibrated PEEK capillary CO2 solution

1 M NaOH

Magnetic stirrer 5 4

6 7 8

3

9

2

1

11 10

Figure 1: Sketch of the flow reactor.


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RESULTS

Absorption Spectrum of ONOOCO2−. In order to construct the spectrum of ONOOCO2−, kinetics traces were recorded from 450 nm to 750 nm at 5-10 nm intervals. The concentrations of CO2 and ONOO– in the mixing cell of the stopped-flow were always 10 mM and 0.26 mM, respectively. The traces were all fitted to first–order kinetics and extrapolated to t = 0 s. The extrapolated initial absorbances were then plotted against the wavelength, see the diamonds in Figure 2a. In the same Figure, this spectrum is compared to the solution spectrum of ONOO− at a concentration of 0.34 mM. In the “initial absorbance” spectrum two maxima can be seen, at 600 nm and at 650 nm. In the same spectral range, ONOO– has an absorbance close to zero. The peak at 600 nm can be assigned to CO3•−, which has an absorbance maximum at 600 nm with ε = (1.86 ± 0.16)•103 M cm-1.21 We assign the broad band centered at 650 nm to ONOOCO2–. In order to eliminate spectral contributions from CO3•− to the constructed spectrum of ONOOCO2, the absorption spectrum of CO3•−

21

was overlaid with and subtracted from that shown in Figure

2a (diamonds) to yield the difference spectrum shown in Figure 2b (circles) . This difference spectrum was fitted with 3 Gaussian curves (Figure 2b, dashed line). This strongly indicates that the band at 650 nm does indeed stem from ONOOCO2–.



0.0100

1200

a

b

1000

0.0075

a. u.

800 Abs

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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0.0050

600 400

0.0025 200 0

0.0000 400

500

600

700

800

500

550

600

650

λ / nm

λ / nm

Figure 2. a: Extrapolated initial absorbance values of the kinetic traces from the stopped–flow (diamonds), in comparison with the solution spectrum of ONOO– taken with a spectrophotometer (line). The points of the constructed spectrum from 750 nm to 640 nm were measured with a filter that blocks light with wavelengths below 550 nm. b: The absorption spectrum of CO3•− 21 was overlaid with and subtracted from that in figure 2a to yield the difference spectrum shown here (circles). The difference spectrum was fitted with the sum of 3 Gaussian curves (dashed line). The vertical axis is scaled arbitrarily.

Figure 3 shows traces at 300 nm, 585 nm and 685 nm which were all recorded by using the same solutions. The initial absorbance is normalized to the same values for comparison. The traces of 300 nm and 685 nm are fairly congruent, whereas the trace at 585 nm is clearly different. Because the absorptions at 585 and 685 nm decay with different rate constants, we conclude that they belong to two different species. Consequently, the trace at 685 nm can only originate from ONOOCO2–, and is not merely a tail of the CO3•– peak. Thus, the maximum at 650 nm in Figures 2a and 2b is caused by ONOOCO2– and not by CO3•–. Furthermore, the


700

750

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congruency of the traces at 300 nm and 685 nm indicates that they stem from the same species, ONOOCO2–. We thus propose that ONOOCO2–, like ONOO–, has a strong absorption at 300 nm.

0.012

0.008 Abs

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0.004

0.000 0.00

0.02

0.04

0.06

t/s

Figure 3: Normalized kinetics traces at 300 nm (dashed), 585 nm (dotted) and 685 nm (solid line), with [CO2]0 = 10 mM and [ONOO–]0 = 0.27 mM. The traces at 585 nm and 685 nm were both taken with a 320 nm edge filter in front of the detector.

Further evidence for the above assignments stems from diffuse surface absorbance spectroscopy. In Figure 4, the spectrum of solid, fresh ONOO− and that of solid ONOO− after exposure to CO2 are shown. The spectra of both samples show a maximum of similar intensity at approximately 350 nm. The spectrum of ONOO– which had been exposed to CO2 has a second maximum at about 680 nm and a very broad third maximum at 640 nm and was green, in contrast to fresh ONOO− which is orange. The spectrum of fresh ONOO– also has a second maximum at 680 nm, but with a lower intensity than ONOO− that had been exposed to a high



concentration of CO2. In solution, ONOO− absorbs maximally at 300 nm, whereas as a solid it absorbs at 350 nm. Consequently, the peak at 650 nm in solution could shift to 680 nm in the reflectance spectrum, a shift of 30 nm, and the peak at 640 nm in the reflectance spectrum corresponds to the 600 nm peak in the absorption spectrum, a 40 nm shift.

1.2

refeflected intensity

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

550

650

750

0.8

0.4

0.0 250

350

450

550

650

750

λ /nm Figure 4: Surface absorbance of solid, orange [(CH3)4N][ONOO] (dotted line) and solid, green [(CH3)4N][ONOO] formed by exposition to CO2 (solid line). The inset shows the spectra of both species between 550 nm and 750 nm. The small peak at 680 nm in the spectrum of fresh [(CH3)4N][ONOO] is due to the unavoidable reaction of ONOO– with trace levels of CO2 when [(CH3)4N][ONOO] is exposed to air upon removal from the storage tube.

All these results clearly show that ONOOCO2– has an absorption maximum at 650 nm in solution, as we reported before.7 In addition, it also absorbs at 300 nm, and somewhat surprisingly, with a similar extinction coefficient as ONOO–. Based on these results, we decided to study the variation in time of the CO3•− concentration at 585 nm and that of ONOOCO2− at 14 ACS Paragon Plus Environment

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685 nm and 300 nm. The absorptions at 585 nm and 685 nm are sufficiently separated to minimize interferences, but still close enough to the maxima of the two species to assure enough intensity for accurate analysis.

Bimolecular Rate Constant of ONOOCO2− Decay. The decay of ONOOCO2− was measured at variable CO2 concentrations and a constant ONOO– concentration of 0.26 mM. An example of a kinetic trace at 685 nm, along with the exponential fit, can be seen in Figure 5. kobs for this particular record is 273 s-1. A plateau in absorption lasting for the first 2-3 ms is visible.

0.025

0.020

0.015 Abs

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0.010

0.005

0.000 0

0.01

0.02

0.03

t/s Figure 5: Kinetic trace at 685 nm (line) fitted with an exponential function (dotted). [CO2] = 10 mM, and [ONOO–] = 0.26 mM. The plateau, that is, the constant absorption which deviates from the exponential fit, is present for the first 3 ms.

All kinetic traces obtained at 300 nm and 685 nm were fitted as shown above to yield kobs values, which were plotted against the CO2 concentration (Figure 6). These kobs values are linearly 15 ACS Paragon Plus Environment


dependent on [CO2]. When CO2 is present in excess, kobs is independent of [ONOO−] (not shown). From this, the bimolecular rate constant of ONOO– or ONOOCO2– decay was calculated as k2 = (2.6 ± 0.8)•104 M−1 s−1.

300

200 kobs / s-1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

100

0 0

2

4

6

8

10

[CO2] / mM Figure 6: The averaged kobs at 685 and 300 nm are plotted as a function of [CO2], with a linear fit that yields k2 = (2.6 ± 0.8)•104 M-1 s-1.

The Reaction of CO2 with ONOO− is an Equilibrium. It cannot be easily determined which species contribute to what extent to the absorption at 300 nm: ONOO−, ONOOCO2−, or both. It may be possible to partially solve this problem by estimating the equilibrium constant of the reaction of ONOO− with CO2, Reaction 1, and by the use of the 685 nm band which contains no contribution from ONOO−. With the assumption that the equilibrium establishes itself much faster than ONOOCO2− decays, the equilibrium constant K1 can be expressed as: 16 ACS Paragon Plus Environment

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[ONOOCO-2 ]t = 0 [ONOOCO-2 ]t =0 K1 = = [CO 2 ][ONOO- ] ([CO 2 ]0 − [ONOOCO-2 ]t = 0 )([ONOO- ]0 − [ONOOCO-2 ]t =0 )

(7)

By rearranging equation 7 and substituting c0 = [CO2 ]0 , p0 = [ONOO − ]0 , we obtain 1 [ONOOCO-2 ]t2=0 − [ONOOCO-2 ]t =0 (c0 + p0 + ) + c0 p0 = 0 K1

(8)

This quadratic equation can be solved for [ONOOCO2−]t=0, which is related to initial absorbance by

A0 = ε 685 d [ONOOCO-2 ]t =0 (c0 + p0 + A0 = ε 685 d

(9)

1 1 ) − (c0 + p0 + ) 2 − 4c0 p0 K1 K1 2

(10)

in which d is the optical path length. To solve equation 10, kinetics traces at 685 nm were measured at different initial concentrations of CO2 and ONOO–. They were fitted based on firstorder kinetics and extrapolated back to t = 0 s. These initial absorbance values were then plotted against [CO2]0 and [ONOO–]0. As shown in Figure 7, A0 increases asymptotically at higher [CO2] when [ONOO–] is kept constant, while in Figure 8, one sees that when [CO2] is kept constant and [ONOO–] is increased, A0 increases linearly. We fitted the data points in both Figures to equation 10 by optimizing K1 and ε685, and find that K1 = (4.5 ± 0.5)•103 and ε685 ≈ 85 M-1 cm-1. If the extrapolation to t = 0 in Figures 3 and 5, which gives absorbances expected for ONOO− at that time, is warranted, and given the value of K1 and the saturation observed in Figure 7, we conclude that, at sufficiently high concentrations of CO2, the traces at 300 nm do not stem from ONOO−, but from ONOOCO2−. We conclude that the extinction coefficients of ONOO− and ONOOCO2− at 300 nm are very similar. 17 ACS Paragon Plus Environment


0.03

0.02 A0

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

0.01

0.00 0.0

2.5

5.0

7.5

10.0

c0 (CO2) / mM Figure 7: Initial absorbance at 685 nm at constant [ONOO–], 0.25 mM as a function of [CO2]. The dashed line represents the solution to equation 10 with optimized K1 and εAdduct values.


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0.03

0.02 A0

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0.01

0.00 0.0

0.1 c0

(ONOO-)

0.2

0.3

/ mM

Figure 8: Initial absorbance at 685 nm at constant [CO2], 0.010 M as a function of [ONOO–]. The dashed line represents the solution to equation 10 with optimized K1 and εAdduct values.

In order to further confirm that reaction 1 is an equilibrium, we set up a flow reactor experiment as set up as described under Experimental Procedures. Of the original ONOO− concentration, 57 ± 7 % was retrieved upon rapid removal of CO2 from the reacting mixture at t = t1/2.

Product Analysis with CO2 in Excess. The concentration of ONOO− in the stopped-flow mixing cell was 266 µM. The resulting NO3− and NO2− concentrations were 305 µM and 45 µM, respectively. This suggests a contamination of the original ONOO− pellets with 15% NO3– and 17% NO2– as a result of a slow decomposition at pH 12 which involves complex reactions which are not entirely understood.29



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CO3•−Reactions and Yield. After having confirmed that ONOOCO2− is formed and having determined the equilibrium constant K2, we now turn our attention to the products that can be formed after ONOOCO2− homolysis. The radical products can undergo several reactions. In addition to reactions 4−5, CO3•− also participates in reactions 11–13.30 NO2• reacts with itself to form N2O4, reaction 14. To complicate matters further, reaction 12 and 13 may take place to a considerable extent, especially in the presence of a high concentration of ONOO– that is contaminated by a substantial percentage of NO2–.

CO3•– + CO3•−

→ CO32− + CO2

(11)

CO3•− + NO2–

→ NO2• + CO32 –

(12)

CO3•− + ONOO–

→ CO32− + NO• + O2

(13)

NO2• + NO2•

→ N2O4

(14)

The high reactivity of CO3•− makes it difficult to simulate its kinetics trace in order to correctly calculate its relative yield. However, because CO3•−participates in a number of reactions, its kinetics trace converges toward a pseudo−first−order decay curve, as the combined concentration of reactants is in excess of that of CO3•−. We took advantage of this behavior by fitting the kinetics traces, taken at 585 nm, of CO3•− with CO2 present in excess with a simple exponential function using a least-squares analysis. An example of this fit can be seen in Figure 9, for [CO2] = 10 mM, [ONOO–] = 0.27 mM and λ = 585 nm. This Figure is a supplement to Figure 3 that shows that the signals at 685 nm and 585 nm follow different kinetics, while the traces at 685 nm and 300 nm are congruent. The attempt to fit a first-order rate constant to the 585 nm trace is


Page 21 of 41

shown in here. The exponential function was fitted by the least-squares method, starting at 4 ms in order to bypass the initial plateau. Weighting of values was uniform. If we attempt to diminish the curvature of the exponential to better account for the lesser fit between 0.02 and 0.05 s, the discrepancy between the initial steep part and the fit becomes extreme, and the least-squares sum increases far over that of the best first-order rate constant. While the processes observed at 300 nm and 685 nm are clearly first-order or pseudo-first-order, the 585 nm trace has a significant hyperbolic contribution between 0.02 s and 0.05 s that points at the influence of a bimolecular reaction between identical molecules, presumably CO3•− given its absorption maximum at 600 nm. Even though this fit is not perfect and may not represent a global minimum, it is a useful and simple strategy for estimating the initial absorbance, A0, which for Figure 9 is 0.0106 ± 0.004.

0.012

0.008 Abs

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0.004

0.000 0.00

0.02

0.04

0.06

0.08

t/s Figure 9: Kinetics trace at 585 nm with [CO2] = 10 mM and [ONOO–] = 0.27 mM. The dashed line is a simple exponential fit of the trace. The fit deviates from the measured curve most noticeably between 0.02 s and 0.05 s. The initial extrapolated absorbance is 0.0116 ± 0.0004.



A0 was converted to [CO3•−] as follows: ε600nm = (1.86 ± 0.16)•103 M−1 cm−1 21 was multiplied with the ratio A 585nm/A 600 nm deduced from the spectrum in Figure 2 to result in ε585nm = (1.7 ± 0.2)•103 M-1 cm-1. This value represents a maximum, because the spectral absorption of ONOOCO2− is most likely not negligible at 585 nm, given the result shown in Figure 2b. We use ε585nm = (1.7 ± 0.2)•103 M-1 cm-1 to estimate the maximal possible concentration of this radical.

A0 was divided by ε585nm to obtain the initial concentration of CO3•−, which, for the case shown in Figure 9, resulted in 6.3 ± 0.7 µM of CO3•− at the beginning, a yield of 2.6 ± 0.2 % with respect to the initial ONOO− concentration. Since we can assume that the fraction of CO3•− released is always proportional to [ONOOCO2−], its percentage also represents the total yield under the condition of CO2 excess. The same calculation was carried out for different concentrations of CO2 and yielded the surprising result that the relative CO3•− yield decreases with decreasing [CO2], as shown in Figure 10.


Page 22 of 41

Page 23 of 41

3.0

yield / % based on c0(ONOO-)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2.5 2.0 1.5 1.0 Physiological [CO2]

0.5 0.0 0

2

4

6

8

10

[CO2] / mM Figure 10: Yield of CO3•− with respect to [ONOO−]0, plotted against [CO2]. The maximum yield is 2.6 % and decreases to 0.53 % at [CO2] = 0.59 mM.



DISCUSSION

ONOOCO2–, Spectrum and Reactivity. The reaction of ONOO− with CO2, reaction 1, leads to an intermediate, most likely ONOOCO2−. It can be unambiguously identified and discriminated from CO3•− by UV-Vis spectroscopy. The spectral contributions of ONOOCO2− are present in both the absorption spectra in solution and the reflection spectra of the solid (Figures 1, 2 and 4). It shows two maxima, at 300 nm and at 650 nm in aqueous solution, and at 350 nm and at 680 nm for crystals of [(CH3)4N][ONOO] exposed to CO2. While the band at 650 nm in solution is unique, the one at 300 nm could be attributed to unreacted ONOO–, under the assumption that ONOOCO2– is a minor component in equilibrium. We showed, however, that the 650 nm band absorbance approaches saturation with increasing CO2 excess (see Figure 4), which implies that, under that condition, almost all ONOO– must be trapped in the adduct. However, the 300 nm band still persists. Thus ONOOCO2− also absorbs at 300 nm. This conclusion is further supported by the identical decay kinetics observed at 300 nm and at 685 nm, to the right of the 650 nm band to minimize overlap with the absorption of CO3•– at 600 nm. As a consequence, the equilibrium constant of ONOOCO2– formation must be moderately high, larger than 1000 M-1, as we have demonstrated here: K1 = (4.5 ± 0.5)•103. Our conclusion that the extinction coefficients of ONOO− and ONOOCO2− are very similar hinges on two assumptions: (1) the saturation (Figure 7) is real, and (2) the extrapolation to t = 0 in Figures 3 and 5, which gives absorbances expected for ONOO− at t = 0, is warranted. Regarding point 1, we observe at higher concentrations of CO2 over ONOO−, that the absorptions, at which the plateaus are observed, and the extrapolated values of the absorptions at t = 0 become constant. These observations are compatible with reaching saturation. Additional experiments would require


Page 24 of 41

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higher CO2 concentrations which, given its solubility, are not possible. As to point 2, we extrapolated the kinetics curves back to t = 0, but do not have a definitive explanation for the plateaus during the first 2-3 ms (see below). If the plateau at about half the extrapolated absorption is caused by physical effects during mixing, the curve should be extrapolated to t = 0. The plateau may also be caused by a short-lived pseudo-steady-state, in which case the initial absorption would be more representative of ONOOCO2−. Furthermore, given the value of equilibrium constant K1, all ONOO− should be present as ONOOCO2− when CO2 is present in excess. Thus, the extinction coefficient of ONOOCO2− is close to that of ONOO−, 1.7•103 M−1cm−1, or possibly half as much, 0.8•103 M−1cm−1. We prefer the former value, also because both ONOO– and ONOOCO2– have similar chromophores. It follows that the decomposition of ONOO– is distinctly accelerated even by small CO2 concentrations, which confirms the observations made for accelerated decay of ONOO– in presence of HCO3–.10 The kinetics trace of ONOOCO2– decomposition at 300 nm and 685 nm, see Figures 3 and 5, shows a reproducible initial plateau followed by decay. This observation indicates that [ONOOCO2–] is only stationary during 2-4 ms directly after mixing, and then goes to 0, i.e. the system described with reactions (1) and (2) cannot be described with steady-state approximations, because in that case, one would assume that k1 ≤ k2 . Given the shape of the trace, formation of ONOOCO2– must be extremely fast. We thus conclude that k1 > k2 and that the decay of ONOOCO2– must be the rate-liming reaction. In addition, it can be seen in Figure 5 that the absorbance plateau lasts up to 3 ms. It is not clear what the reason for this plateau is; it could either stem from turbulent mixing, or from a outgassing and bubble formation of the reaction mixture due to cavitation in the mixer, because homogenization is complete in 1.5 – 2



Page 26 of 41

ms. Formation of ONOOCO2– must take place within the mixing time of the stopped-flow apparatus, which requires k1 ≥ 107 M−1s−1. The large value of k1 is an additional confirmation that, with CO2 in excess, the traces at 300 nm do indeed stem from ONOOCO2– and not from ONOO–. In a flow reactor experiment, we were able to show reaction 1 is a true equilibrium because otherwise, ONOO– would not have been recovered upon rapid removal of CO2. The recovered [ONOO–], 57 ± 7 %, is in very good agreement with our calculations based on the measured and estimated rate constants: under the assumption that k1 ≈ 107 M−1s−1 and with measured k2 = (2.6 ± 0.8)•104 M−1s−1, 58 % of the original ONOOCO2− concentration would remain after 2 ms. For the equilibrium constant of reaction 1 we find K1 = (4.0 ± 0.5)•103M−1. Since k1 ≥ 107 M−1s−1 and K1= k1/k−1, k−1 is on the order of 2.5•103s−1. Very surprising is the finding that k2,obs, the apparent first-order decay reaction constant of ONOOCO2–, is also dependent on the concentration of CO2 (Figure 6). The associated bimolecular rate constant k2 is (2.6±0.8)•104 M−1s−1. This value is identical to that conventionally assigned to the bimolecular reaction constant for the reaction of CO2 with ONOO−.11;31. However, with CO2 in excess we showed, based on the kinetics at 300 nm, that the decrease in absorption is related to the decay of ONOOCO2– and not that of ONOO–. The discovery that ONOOCO2– undergoes a bimolecular reaction with CO2 is not accounted for by the reactions shown in equation 2 and scheme 1, which predicts a true first–order decay of ONOOCO2−, independent of [CO2]. We postulate that ONOOCO2– reacts with an additional CO2 molecule in a second−order reaction, reaction 15:

ONOOCO2– + CO2

→ NO3− + 2 CO2 26 ACS Paragon Plus Environment

(15)

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Apparently, ONOOCO2– is not inherently unstable. This explains why it was possible to record its reflectance spectrum under ambient conditions, which took about 2 minutes. If the atmospheric CO2 concentration is on the order of 400 ppm, the reaction of ONOOCO2− with CO2 would proceed slowly, rendering ONOOCO2– stable enough to be detected. The reactivity of ONOOCO2– towards CO2 is further confirmed by the observation that the blue color bleaches quickly when the CO2 stream over the solid peroxynitrite is kept going after its formation.

Revised Reaction Scheme. The reaction of ONOOCO2– with CO2 and that with a reducing agent would be competing pathways for ONOOCO2– decay. Thus, if ONOOCO2– reacts directly with a reducing agent, this compound will be oxidized; however, if ONOOCO2– reacts with CO2, it will be neutralized, save for the small amounts of NO2• and CO3•– that are formed. These considerations lead to Scheme 2:



Page 28 of 41

≤ 5%

−

ONOO + CO2

k1 ≅ 107 M-1s-1 3

-1

k-1 ≅ 2.5x10 s

ONOOCO2−

X

n+2

CO2 k2 ≅ 2.5x104 M-1s-1

ion petit m o C

Xn + CO2 + NO2

CO3•− + NO2• + CO2

≥ 95%

2CO2 + NO3−

−

Scheme 2. Mechanism for the interactions of CO2 with ONOO−. An alternative reaction mechanism with the same set of rate constants is shown in scheme 3: ONOO− + CO2

Xn

ONOOCO2− ≤ 5% 4

-1 -1

k2 ≅ 2.5x10 M s

≥ 95%

Xn+2 + CO2 + NO2−

CO3•− + NO2• CO2 + NO3−

Scheme 3. Alternative, but less likely, mechanism for the interactions of CO2 with ONOO−

Scheme 2 satisfies the requirement that two CO2 molecules are needed to complete the degradation of ONOO–. Scheme 3 also describes a CO2-dependent direct decay of ONOO− with ONOOCO2− as an oxidizing byproduct. Scheme 2 explains more convincingly why ONOOCO2− persists for minutes when formed in the solid state, because, according to scheme 3, the products of a dissociating ONOOCO2− molecule could immediately undergo in situ rapid decay to NO3− and CO2, while according to scheme 2, ONOOCO2− has to encounter another CO2 molecule to complete decay. The latter process is slowed down by the hindered diffusion in a solid and by a


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low CO2 partial pressure. There is another major reservation against scheme 3: it is rather unlikely that ONOO− and CO2 would react through two different pathways with distinctly different rate constants k1 and k2. We thus favor Scheme 2.

Reaction Mechanism. We assume that the first CO2 binds to the terminal peroxide oxygen, although the nitrogen-bound oxygen has only a slightly smaller negative charge, −0.63 vs. −0.57.32 This intermediate would be the relatively stable blue species, which is directly observed when solid [(CH3)4N][ONOO] is exposed to a small amount of CO2. We speculate that the second CO2 binds to the carboxylate end of ONOOCO2−, reaction 16.

ONOOCO2− + CO2 → ONOOCO2CO2−

(16)

An analogous, short-lived species, CO2CO32−, has been proposed to be formed when CO2 reacts with CO32−,33 to account for the rapid scrambling of 18O when 13C-enriched CO2 is mixed with C18O32−.34 ONOOCO2− is analogous to O2COOCO22−, synthesized for the first time35;36 in 1896, and of which the potassium and rubidium salts have been characterized more recently.37;38 Already in 1896, the color of O2COOCO22− was given as sky blue. Withdrawal of electron density in the O−O bond in ONOOCO2CO2− may facilitate isomerization of ONOO− to NO3− as well as homolysis. The mechanism is shown in Figure 11.



Page 30 of 41

O O

O−

+

N

O O

O−

O

O

N

O

O

O

N

O

N

O

O

O−

O

oxygen scrambling in ONOOCO2−

O

O−

O

O

isomerization

O O

O

O

N

O

O O−

O

O O

homolysis

O

Figure 11. Binding of one CO2 can account for the scrambling observed,19 while binding of a second CO2 would lead to isomerisation, and, to a lesser extent, homolysis.

The stability constant of 4•103 M−1 for formation of ONOOCO2− results in a ∆rxn1G° of −21 kJ mol−1. Given the standard Gibbs energies of reaction 17 and 18, calculated from literature data,6;39-41 formation of radicals, reaction 16, is slightly endergonic whereas formation of CO2 and NO3− is very exergonic.

ONOO– + CO2

→ CO3•– + NO2•

∆G160 = +7 ± 3 kJ/ mol

(17)

ONOO– + CO2

→ CO2 + NO3−

∆G170 = −179 ± 1 kJ/ mol

(18)


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Homolysis of ONOOCO2− costs 28 kJ mol−1, Figure 12, which translates into 0.35% formation of NO2• and CO3•− at equilibrium. Direct formation of NO2• and CO3•− from CO2 and ONOO−, reaction 17, is energetically less uphill and would result in 24% homolysis. Even if the error in the Gibbs energies of formation of the radicals is taken into account, there would be at least 14% homolysis. These thermodynamic values, although not directly comparable, are much smaller than the energies found in theoretical studies,16;17 which emphasizes the need to “tether” such studies to experimental data.42

CO2 + ONOO−

CO3•− + NO2• −21 ONOOCO2−

+28

−158

CO2 + NO3−

Figure 12. Standard Gibbs energy diagram (kJ mol−1) of the reaction of CO2 with ONOO−.

Yield of CO3•−. We found that the highest possible CO3•− yield with respect to ONOO– is approximately 5%, see Figure 10. This result is in agreement with earlier work reporting very low yields of CO3•− and NO2•,7;14 and it is supported by thermochemical calculations discussed above. Thus, the oxidative behavior of the CO2/ONOO– system is not primarily governed by the formation of free radicals. In addition, because the CO3•– yield decreases with decreasing [CO2], radical-induced oxidations are practically irrelevant at lower CO2 concentrations, as under 31 ACS Paragon Plus Environment


physiological conditions. For instance, in plasma pCO2 values average near 40 mm Hg (5.3 kPa) which correspond to [CO2] = 1.3 mM;43 under those conditions, the yield of CO3•− relative to ONOO− is 0.9%, see Figure 10. Thus, the toxicity of ONOOCO2− may be best ascribed to its high one- and two-electron electrode potentials. Overall we may conclude that CO2 in excess over ONOO− is protective in that it accelerates the isomerisation of the latter to NO3−.


Page 32 of 41

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AUTHOR INFORMATION

Corresponding Author *E-mail: [email protected] Retired. ORCID: 0000-0002-1620-6594

Present addresses: (S.S.-L.) Biotronik AG, Ackerstrasse 6, CH-8180 Bülach, Switzerland. (W.H.K) Schwändibergstrasse 25, CH-8784 Braunwald, Switzerland.

Funding This research was supported by the Schweizerische Nationalfonds (SNF) and the Swiss Federal Institute of Technology (ETH).

Notes The authors declare no competing financial interest.



NOMENCLATURE Venerable names in italics. O2•−, dioxide(•1−), dioxidanidyl or superoxide; NO•, oxidonitrogen(•) or nitrogen monoxide: ONOO− (dioxido)oxidonitrate(1−), or peroxynitrite; ONOOH, (hydridodioxido)oxidonitrogen or peroxynitrous acid; HO•, hydridooxygen(•), oxidanyl or

hydroxyl; NO2•, dioxidonitrogen(•) or nitrogen dioxide. CO3•−, trioxidocarbonate(•1−); ONOOCO2−, (nitrosodioxido)dioxidocarbonate(−) or nitrosoperoxocarbonate.44;45 The names “nitric oxide” and “carbonate radical”, although widespread, are not systematic and to be avoided. Names for common chemicals are found in Connelly et al. 45


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