NITRIC OXIDE: Biology and Chemistry

Vol. 3, No. 3, pp. 191–198 (1999)

Article ID niox.1999.0232, available online at http://www.idealibrary.com on

BRIEF REVIEW
Gas-Phase Oxidation of Nitric Oxide: Chemical Kinetics
and Rate Constant

Hirokazu Tsukahara,* ,1 Takanobu Ishida,† and Mitsufumi Mayumi*

*Department of Pediatrics, Faculty of Medicine, Fukui Medical University, Fukui 910-1193, Japan; and †Department of
Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794-3400

Received January 25, 1999, and in revised form April 21, 1999

Nitric oxide (NO) is an endothelium-derived relax-

Inhaled nitric oxide (NO) is gaining popularity as
a selective pulmonary vasodilator. Because of the
potential toxicity of NO and its oxidizing product
nitrogen dioxide (NO 2), any system for the delivery
of inhaled NO must aim at predictable and repro-
ducible levels of NO and at as low concentrations of
NO 2 as possible. This review describes the chemical
kinetics and rate constant values k for the reaction
2NO 1 O 2 5 2NO 2. This reaction has been well es-
tablished as a third-order homogeneous reaction.
Published data support two equally plausible two-
step mechanisms for the reaction between NO and
O 2 over a wide range of temperature and pressure.
The Arrhenius equation k (L 2 z mol 22 z s 21) 5 1.2 3 10 3
e 530/T (51.2 3 10 3 3 10 230/T) gives the best fit to the
experimental values of the rate constant thus far
reported in a temperature range of 273 to 600 K.
Using the reaction mechanism and the rate con-
stant k, one can make reliable predictions about
NO 2 formation in any set of NO inhalation therapy
conditions. It is also pointed out that NO 3, the inter-
mediate of one of the two mechanisms, deserves
serious attention in NO inhalation therapy. © 1999
Academic Press
Key Words: chemical kinetics; nitric oxide; nitro-
gen dioxide; nitrogen trioxide; oxidation; peroxyni-
trite radical; rate constant.
1
To whom correspondence should be addressed. Fax: 81-776-
61-8129. E-mail: htsuka@fmsrsa.fukui-med.ac.jp.
ing factor (1, 2), which when inhaled may act as a
selective pulmonary vasodilator (3, 4). Inhalation of
low doses of NO (less than 1 to 80 ppm) is increas-
ingly used in the treatment of pulmonary hyperten-
sion and hypoxemia in children and adults. How-
ever, NO is a potentially toxic molecule, the
biochemistry of which is not fully understood (2).
Toxicity caused by inhalation of NO may be pro-
duced by either NO itself or its reactive metabolite,
notably, nitrogen dioxide (NO 2) (2– 4). NO 2 has sev-
eral times greater pulmonary toxicity than NO and
is corrosive because of the formation of nitrous and
nitric acids from NO 2 and water. These acids can
alter alveolar permeability and cause lung injury
with pulmonary edema and death. Nitric acid irre-
versibly oxidizes all organic substances, including
proteins. Therefore, accurate and extensive informa-
tion on the formation of NO 2 from NO is crucial for
the development of guidelines for effective and safe
administration of inhaled NO. However, recent clin-
ical and biological reports have not detailed the
chemical kinetics of the gas-phase oxidation of NO to
NO 2.
In this paper, we will review basic chemical
aspects of the oxidation of NO by O 2 in the gas
phase and will focus on the evaluation of the re-
action mechanism and the rate constant for this
reaction. However, the review will exclude the

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All rights of reproduction in any form reserved.
192 TSUKAHARA, ISHIDA, AND MAYUMI

reactions involving water as well as photochemi-
cal reactions.
CHEMICAL KINETICS OF THE REACTION OF NO
WITH O 2
In the oxygenated gaseous environments the re-
action of NO with O 2
2NO 1 O2 5 2NO2
proceeds as a third-order reaction 2 (5):
2d@NO#/dt 5 1d@NO2 #/dt 5 2k z @NO# 2 z @O2 #.
Since the first chemical kinetic study of this reac-
tion by Bodenstein and Wackenheim (6) 80 years
ago, an overwhelming majority of published experi-
mental results (7–27) support the differential rate
law [2] and the view that Reaction [1] is a homoge-
neous gas-phase reaction and does not require the
participation of solid surfaces. These results include
the older data obtained with the NO pressures rang-
ing from few torrs to a few hundred torrs and the
more recent data involving low NO concentrations
down to the ppm level. The revived interest in NO
that predates the discovery of the physiological NO
has been in the fields of atmospheric pollution and
ozone layer depletion (15–18, 20, 24, 28). One dis-
tinct characteristic of the rate of this reaction is its
slightly negative temperature coefficient in a wide
temperature range from the cryogenic as low as
;140 K to as high as ;650 K (5).
Studies of effects of various substances and solid
surfaces on the rate of this reaction that have led to
the conclusions stated above will be discussed in the
following section. In this section, we will review the
reaction mechanisms that have been proposed to
explain the rate law [2] and the negative tempera-
ture coefficients and then will point out important
implications of these mechanisms.
Three mechanisms have been proposed.
2
It should be noted that there are two quantitatively different
definitions of k in use in the literature; quite a few authors (12,
14 –20, 22–24) defined their k’s without the factor 2 of the last
expression of Eq. [2]. We have divided these k values by 2 to make
them consistent with Eq. [2].
(i) Termolecular reaction: According to this view,
two molecules of NO and one O 2 molecule simulta-
neously collide and form a transient complex, which
then takes a single step to form two molecules of
NO 2. Kassel (29) calculated the frequencies of three-
body collisions for this reaction and concluded that,
although the frequency is not high, it is sufficiently
high to explain the observed rates of the reaction
and that the rate via the termolecular collisions
could decrease with increasing temperature.
[1]
Through a parameter-fitting process using Eyring’s
transition state theory and reasonable molecular
properties, Gershinowitz and Eyring (30) justified a
transition state in which each O atom of an O 2
@2#
molecule is partially bonded to the N atom of each of
the two NO molecules. If, instead, two of the three
molecules first form a complex which then reacts
with the third molecule, Reaction [1] would not be
termed truly termolecular.
Although this reaction has long served as a clas-
sical example of termolecular reaction in chemistry
textbooks, a majority of researchers in recent years
prefer the two-step mechanisms, as described below.
Persuasiveness of a two-step mechanism hinges
on the demonstration of the existence of an inter-
mediate.
(ii) Preequilibrium mechanism with dimer of NO
as an intermediate:
NO 1 NO 7 ~NO! 2 @fast# [3a]
~NO! 2 1 O2 3 2NO2 @slow and rate determining#
[3b]
2d@NO#/dt 5 k 1 z k 2 z @NO# 2 z @O2 #/$k 21 1 k 2 z @O2 #%
[3c]
Equation [3c] results from the assumption that the
rate constants k 1 and k 21 for the forward and re-
verse reactions of [3a] are significantly greater than
that (k 2 ) of the second step, [3b]. Since [O 2] is only
0.041 mol z L 21 even in pure O 2 gas at 1 atm and 298
K, the relation k 21 @ k 2 z [O 2] is assumed valid, thus
making Eq. [3c] take the form of Eq. [2]. Several
authors proposed this mechanism (8, 19). In the
solid and liquid, NO exists as (NO) 2. At cryogenic
temperatures the dimer is also present in low con-
centrations in the gas phase (31, 32). For the gas-

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 GAS-PHASE OXIDATION OF NITRIC OXIDE
phase equilibrium, 2NO 5 (NO) 2; DS°298 5 228.0
cal z K 21, DH°298 5 22.62 kcal, and ln K (atm 21) 5
11320/T (K) 2 14.05 (33). Accordingly, the tem-
perature coefficient of the equilibrium constant K,
i.e., d(ln K)/dT 5 DH°/RT 2 , is negative, thus low-
ering the equilibrium concentration of (NO) 2 with
increasing temperature. This accounts for the ob-
served negative activation energies of Reaction [1].
At 298 K, K (3a) 5 6.6 3 10 25 atm 21, and 0.0065% of
gaseous NO is in the dimerized form.
(iii) Preequilibrium mechanism with NO 3 as an
intermediate:
NO 1 O2 7 NO3 @fast#
NO3 1 NO 3 2NO2 @slow and rate determining#
2d@NO#/dt 5 k 3 z k 4 z @NO# 2 z @O2 #/$k 23 1 k 4 z @NO#%
In Eq. [4c], k 3 and k 23 are, respectively, the rate
constants of the forward and reverse directions of
[4a] and k 4 the constant for Reaction [4b]. The molar
concentration of NO is especially low in NO inhala-
tion therapy (3, 4), and the expression [4c] converges
to the form of Eq. [2]. Many authors proposed this
mechanism (9, 12–15, 18, 20).
NO 3 is a well-known intermediate in the decom-
position of dinitrogen pentoxide to NO 2 and O 2 (34,
35). Two structures for NO 3 are in the literature: (a)
nitrogen trioxide, a nitrate-like planar trigonal
structure, in which the N atom is surrounded by
three equivalent O atoms (36, 37); and (b) a bent-
chain structure with an atomic sequence
OOOONOO (32, 38, 39), which has been called by
various names, including peroxynitrite radical and
nitrosyldioxyl. We will use peroxynitrite radical for
the chain structure and NO 3 to refer to both nitrogen
trioxide and peroxynitrite radical. Although per-
oxynitrite radical is more persuasive than nitrogen
trioxide as an intermediate of Mechanism (iii), there
is insufficient evidence to definitely favor one over
the other. The steady-state concentration of the in-
termediate of Mechanism (iii) is small; e.g., in case
the intermediate is nitrogen trioxide, we have for
Reaction [4a] DH°298 5 24.58 kcal, DS°298 5 238.95
cal z K 21, DG°298 5 1 7.03 kcal, and K (4a) 5 6.8 3 10 26
Copyright © 1999 by Academic Press. All rights of reproduction in any form reserved.
193
atm 21 at 298 K from the thermodynamic tables (37).
This gives the steady state concentration of NO 3 as
0.00068% of that of NO at 298 K.
Bodenstein considered both Mechanisms (ii) and
(iii) as possible explanations of his experimental re-
sults (6, 7). More recently, Heicklen and Cohen (40)
compared the two mechanisms and concluded that
both have equal merits. Hisatsune and Zafonte (22),
Baulch et al. (5), and Olbregts (25) also reached the
same conclusion on the relative merits of the two
mechanisms.
Let us now briefly discuss implications of Mecha-
nisms (ii) and (iii). In both, the existence of their
[4a] respective intermediates has been demonstrated.
Both mechanisms are compatible with the experi-
mental fact that the rate of Reaction [1] decreases
[4b] with increasing temperature (5). Both pathways are
more probable than the termolecular reaction,
which requires three-body collisions. In (ii), NO is an
[4c] odd-electron molecule, i.e., a free radical, but (NO) 2
is not. In Mechanism (iii), the formal oxidation state
of the N atom in the intermediate is 16. At 298 K
the standard reduction potential E° for ONOO • 1
e 2 3 ONOO 2 is 0.4 V (37, 41, 42); that is, peroxynitrite
radical is more oxidative than peroxynitrite anion
(ONOO 2), which itself is a strong oxidant: E°9 for
ONOO 2 1 2H 1 1 e 2 3 NO 2 1 H 2O is 1.4 V at pH
7 (41, 42). However, reactivity and toxicity studies of
peroxynitrite radical have largely escaped experi-
mentalists’ attention. For nitrogen trioxide, various
estimates for E° of NO 3 1 e 2 3 NO 32 fall within a
limit of 2.5 6 0.2 V (43, 44), again indicating a highly
oxidative nature of the intermediate of Mechanism
(iii). A careful molecular orbital study (45) has noted
that peroxynitrite radical is less stable than nitro-
gen trioxide in the gas phase. Thus, the intermedi-
ate of the pathway (iii) could be biologically at least
as damaging as ONOO 2 and more damaging than
NO 2.
Furthermore, at such low NO concentrations as
those used in the NO inhalation therapy (3, 4), the
collision frequency for the formation of NO 3 from NO
and O 2 by Reaction [4a] is expected to be higher than
the collision frequency between two molecules of NO
in Reaction [3a] under comparable experimental
conditions. Then, if Mechanism (iii) does in fact play
a significant role in the NO inhalation environment,
NO 3 would be a target of two competitive reaction
194 TSUKAHARA, ISHIDA, AND MAYUMI
paths, one leading to NO 2 by Reaction [4b] and the
other the oxidations of biological surroundings. The
fact that the steady-state concentration of NO 3 in
Mechanism (iii) is low is immaterial, because NO 3 is
rapidly and steadily supplied by the forward reac-
tion of [4a]. As far as we are aware, however, no
study on the biological effects of NO 3 has been made,
and no safety regulations specific to NO 3 currently
exist. Further studies of the reaction intermediates,
especially with regard to NO 3, and their biological
effects appear to be in order.
It is worth noting that, in a sense, Mechanisms (i)
and (ii) are similar. The best accepted structure of
(NO) 2 is a planar chain of the sequence,
OON . . . NOO, with the two O atoms in a cis con-
formation and with the OONON angle ranging
from 90° to 110° (31, 46). In Step [3b] of Mechanism
(ii), O 2 is thought to descend upon the N . . . N bond
of (NO) 2 with the OOO axis parallel to the N . . . N
bond. The transition state obtained by Gershinowitz
and Eyring for Mechanism (i) (30) has a chain struc-
ture with the atomic sequence OON . . . OOO . . .
NOO, with the OOO bond parallel to the N 3 N
direction and the NOOOO bond angle of about 90°.
Then, the only essential difference between Mecha-
nisms (i) and (ii) seems to be the timing of approach
of the O 2 molecule to the ONNO moiety.
RATE CONSTANT FOR OXIDATION OF NO TO NO 2
Table I summarizes prime examples of the exist-
ing data on the rate constant k for the oxidation of
NO in static and nominally water-free systems. The
k value has been reported in various units, including
L 2 z mol 22 z s 21, mL 2 z mol 22 z s 21, mL 2 z molecule 22 z
s 21, torr 22 z s 21, and ppm 22 z min 21. These k values
shown in Table I have been recalculated in units of
L 2 z mol 22 z s 21. Equation [2] defines the rate constant
k for Reaction [1], which will be used in this review.
The progress of Reaction [1] was followed by a
variety of analytical methods: manometric measure-
ments of the rate of fall of the total pressure (6 – 8,
11, 13, 14, 19, 21, 23, 25), photometry and colorim-
etry of the rate of production of NO 2 (10, 12, 14 –17,
20 –22, 25), chemiluminescence for NO (24, 27), and
other techniques (9, 18, 26). In these investigations,
the concentration of NO ranged over five orders of
magnitude from 8.2 3 10 28 to 1.8 3 10 22 mol z L 21
Copyright © 1999 by Academic Press. All rights of reproduction in any form reserved.
and the temperature from 225 to 843 K. Further-
more, in many recent studies, N 2 gas was used as a
diluent (11, 13–18, 20 –24, 26, 27).
Although there have been almost as many differ-
ent experimental conditions and equipment for de-
termination of the rate constant as there have been
publications on this subject, it can be seen that a
fairly good agreement exists between various deter-
minations. Most of the kinetic studies agree that the
rate constant k is independent of variations in the
total pressure (from less than 20 torr to atmospheric
pressure) and the absolute NO concentration or the
NO:O 2 ratio (up to a thousandfold variation) (6, 7,
9 –11, 14, 15, 18, 20 –25, 27) and that the logarithm
of the rate constant is inversely proportional to the
absolute temperature (6 – 8, 13, 14, 20, 22, 23, 25,
27). Except for a few (12, 19), most authors also
agree on the orders of the reaction, namely, 2 for NO
and 1 for O 2 (6 –11, 13–18, 20 –27).
Temperature dependence of the rate constant is
one of the peculiar features of this reaction. Al-
though the best accepted negative temperature de-
pendence of k in T 5 273 to 600 K is represented by
an Arrhenius-type equation (47),
k ~L 2 z mol 22 z s 21 ! 5 1.2 3 10 3 e 530/T
5 1.2 3 10 3 3 10 230/T , [5]
the activation energy contains a large uncertainty.
The number, 530, in Eq. [5] is equal to the negative
of the activation energy, 2E act, divided by the ideal
gas constant R, and the best estimate of the uncer-
tainty on 2E act/R is 6400 K (47). E act/R 5 2530 K
is small as an activation energy. The large uncer-
tainty on the small activation energy has always
caused a controversy among investigators over
whether the activation energy is positive or nega-
tive. The following has now been accepted. As we
have noted in the preceding section, the activation
energy is slightly negative; i.e., the rate decreases
with increasing temperature at ambient and sub-
zero temperatures, slowly becomes less negative as
the temperature increases, goes through E act 5 0,
and becomes positive above T ;650 K.
In summary, k 5 7.0 3 10 3 L 2 z mol 22 z s 21 near
the ambient temperature (;300 K) and decreases by
only 0.04 3 10 3 L 2 z mol 22 z s 21 per degree of rise in
 GAS-PHASE OXIDATION OF NITRIC OXIDE 195

TABLE I
Rate Constants for the Reaction 2NO 1 O 2 5 2NO 2

Temperature
Reference Rate constant k (L 2 z mol 22 z s 21) [NO] 0 (mol z L 21) [O 2] 0 (mol z L 21) (K)

Bodenstein and Wachenheim (6)
Bodenstein and Lindner (7)
Hasche and Patrick (8)
Brown and Crist (9)
Smith (10)
Johnston and Slentz (11)
Treacy and Daniels (12)
Tipper and Williams (13)
Ashmore et al. (14)
Glasson and Tuesday (15)
Bufalini and Stephens (16)
Greig and Hall (17)
Morrison et al. (18)
Solc (19)
Greig and Hall (20)
Morecroft and Thomas (21)
Hisatsune and Zafonte (22)
Mahenc et al. (23)
Stedman and Niki (24)
Olbregts (25)
Cueto and Pryor (26)
Aida et al. (27)
4.5 3 10 3–8.9 3 10 3 (6.5 3 10 3) 4.5 3 10 24–8.0 3 10 24 1.4 3 10 24–7.3 3 10 24 273–363
2.5 3 10 3–4.0 3 10 3 (3.1 3 10 3) 3.2 3 10 24–7.2 3 10 24 5.4 3 10 25–4.7 3 10 24 413–667
8.0 3 10 3–1.1 3 10 4 (9.6 3 10 3) 8.3 3 10 24–1.5 3 10 23 1.1 3 10 23–1.4 3 10 23 273–303
6.8 3 10 3–7.8 3 10 3 (7.5 3 10 3) 1.1 3 10 26–6.8 3 10 26 4.2 3 10 24–1.2 3 10 23 298
4.9 3 10 3–7.4 3 10 3 (6.0 3 10 3) 5.9 3 10 25–2.7 3 10 23 1.7 3 10 24–1.4 3 10 23 298
7.0 3 10 3–7.4 3 10 3 (7.1 3 10 3) 4.4 3 10 24–1.8 3 10 22 5.7 3 10 25–2.3 3 10 22 298
(3.8 3 10 3) 5.4 3 10 24 2.7 3 10 24–1.1 3 10 23 298
1.6 3 10 3–7.8 3 10 3 (4.3 3 10 3) 5.5 3 10 24–5.5 3 10 23 1.0 3 10 24–4.9 3 10 23 293–843
2.9 3 10 3–5.0 3 10 3 (3.3 3 10 3) 6.8 3 10 25–2.5 3 10 23 3.4 3 10 24–2.0 3 10 22 377–779
6.0 3 10 3–8.5 3 10 3 (7.7 3 10 3) 8.2 3 10 28–2.1 3 10 26 8.2 3 10 24–2.5 3 10 22 296
(9.0 3 10 3) 1.3 3 10 27–8.1 3 10 27 8.6 3 10 23 299
9.6 3 10 3–1.1 3 10 4 (1.0 3 10 4) 6.9 3 10 27–3.1 3 10 26 7.4 3 10 23 293
4.5 3 10 3–1.1 3 10 4 (6.5 3 10 3) 9.0 3 10 28–3.1 3 10 26 1.3 3 10 23–1.0 3 10 22 290–311
4.0 3 10 3–7.4 3 10 3 (5.7 3 10 3) 5.4 3 10 25–2.7 3 10 23 5.4 3 10 25–2.7 3 10 23 298
6.8 3 10 3–1.1 3 10 4 (9.2 3 10 3) 1.1 3 10 26–2.2 3 10 26 2.7 3 10 25–1.3 3 10 22 293–372
3.0 3 10 3–3.2 3 10 3 (3.1 3 10 3) 6.7 3 10 24–8.4 3 10 24 3.4 3 10 24–9.2 3 10 24 478
[3.8 3 10 3 3 10 81/T ] 3.1 3 10 24–1.4 3 10 22 1.2 3 10 24–2.8 3 10 22 277–329
5.4 3 10 3–8.9 3 10 3 (7.1 3 10 3) 4.0 3 10 24–1.0 3 10 23 8.9 3 10 25–4.7 3 10 24 274–333
[5.0 3 10 2 3 10 339/T]
(7.2 3 10 3) 2.0 3 10 27–4.1 3 10 25 2.7 3 10 23–3.5 3 10 22 298
3.0 3 10 3–2.1 3 10 4 (6.2 3 10 3) 9.0 3 10 25–1.2 3 10 23 1.2 3 10 25–1.4 3 10 23 225–760
[10 (25.1812.70log(T)1700/T) ]
(6.7 3 10 3) 3.9 3 10 25 8.6 3 10 23 296
7.3 3 10 3–8.4 3 10 3 (7.9 3 10 )
3
4.1 3 10 27–6.5 3 10 26 8.3 3 10 23–4.0 3 10 22 298–310

Note. [NO] 0, initial NO concentration; [O 2] 0, initial O 2 concentration. These values were obtained in static water-free systems where NO
and O 2 were mixed in the presence or absence of N 2 (6 –27). The atmospheric pressure was assumed to be 760 torr, except for the work
by Greig and Hall (17, 20) where the pressure of 630 torr was mentioned. A range of observed k values is presented, whenever available.
The values in the parentheses are the mean values. In some, experimental data are expressed as equations. When the concentrations of
NO and NO 2 are expressed in ppm, i.e., 1 ppm 5 (n/V) 3 10 26 5 (P/RT) 3 10 26 mol z L 21, cf. Ref. 15, the rate constant k of Eq. [2] is
no longer independent of pressure and even small changes in temperature. When ppm is used for NO or NO 2 in Eq. [2] while [O 2] can be
considered constant, the corresponding value of k z [O 2 ] in ppm 21 z s 21 is equal to the k values listed in the table multiplied by (P/RT) 3
10 26, where R is the ideal gas constant, 0.0821 L z atm z mol 21 z K 21 and P the total pressure or pressure of O 2 in atm. If ppm is used for
all gases, the corresponding k is (P/RT) 2 3 10 212 times the values in the table.

the temperature, which is well within the limits of
uncertainty of the absolute value of k.
There remain other features of the reaction that
are still a subject of disagreement, particularly the
effects of the surface of the reaction vessel and the
presence of other gasses and humidity. Some au-
thors found the reaction rate to depend on the
surface/volume ratio (8), but many other workers (6,
12, 17, 18) have failed to observe such effects. The
surface effects were observed in the experiments
that used insufficient evacuation and degassing of
the reaction vessel. Morrison et al. (18) reported that
the rate was increased by the addition of NO 2, thus
claiming the reaction to be autocatalytic. On the
other hand, Treacy and Daniels (12) found NO 2 to
have a small retarding effect. Other workers (15, 22,
23), however, were unable to detect such effects. The
addition of N 2, CO 2, methane, and olefins has no
apparent effect on the order and rate constant for
the reaction of NO and O 2 (12, 14, 15, 20 –23). The
influence of humidity has also been examined. Most
workers found that the rate constant is not influ-
enced by moisture (up to 90% relative humidity) (6,
17, 24, 27), with the exception of Treacy and Daniels
(12), who reported an increase in the rate constant
with water vapor. Since water reacts with NO 2 but
not with NO in the absence of dissolved O 2, we
expect that the presence of water in the NO/O 2 re-
action systems will shift the final equilibrium to-
ward the products, i.e., the products that include

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196 TSUKAHARA, ISHIDA, AND MAYUMI
oxyacids of nitrogen and their anions, but it will not
change the rate with which NO is oxidized.
Despite the conflicting results on some aspects of
oxidation of NO, most evidence suggests that the
reaction is essentially homogeneous in nature over a
wide range of temperature and pressures of NO
and O 2.
The values of the rate constant described above
were determined under static dry conditions and
might differ in such dynamic systems as mechanical
ventilation. Nishimura et al. (48) reported the rate
constant for the oxidation of NO to NO 2, k 5 7.3 3
10 3 L 2 z mol 22 z s 21 in the mechanical ventilation
setting. The rate constant in their study is similar to
the aforementioned values. In contrast, Lindberg
and Rydgren (49) found an initial buildup of NO 2,
which seemed to appear immediately after mixing
NO and O 2, in their NO delivery system. It has been
well known among the nitrogen chemists that under
elevated pressure, disproportionation of NO occurs
to form nitrous oxide (N 2O) and NO 2 by the reaction
3NO 3 N 2O 1 NO 2. Thus, freshly purified NO,
stored in a cylinder at room temperature under pres-
sures of 50 –100 atm shows an increase of N 2O and
NO 2 content at the rate of 2–3% per month (50). It
seems plausible that a buildup of NO 2 had occurred
in the commercial cylinders that they used. Regard-
less of the system used to deliver NO, it is manda-
tory to monitor the delivered dose of NO 2 as well as
NO and to purify NO against the other nitrogen
oxides, if necessary.
PREDICTION OF NO 2 FORMATION USING THE
RATE CONSTANT k
Since O 2 concentration is markedly higher than
that of NO in the typical NO inhalation therapy (3,
4), it can be assumed that [O 2] remains unchanged.
Thus, a pseudo-second-order kinetics can be applied
to Reaction [1]. Integration of Eq. [2] yields
1/@NO# t 2 1/@NO# o 5 2k z @O2 # z t,
where [NO] t represents NO concentration after a
residence time t and [NO] o is the initial NO concen-
tration. Since the difference between [NO] o and
[NO] t is [NO 2],
Copyright © 1999 by Academic Press. All rights of reproduction in any form reserved.
t 5 $1/~2k z @O2 # z @NO# o!% z @NO2 #/~@NO# o 2 @NO2 #!
[7]
t 5 $1/~2k z @O2 # z @NO# o!% z f /~1 2 f !, [8]
where f is the fraction of NO that has become NO 2 in
time t (i.e., [NO 2]/[NO] o). It is evident from Eq. [8]
that the time required for the conversion of a certain
fraction of NO to NO 2 is inversely proportional to the
initial NO concentration and the rate constant k.
The time t required to achieve a given f value is
independent of the presence of N 2 gas that is most
commonly used as the carrier of NO for the inhala-
tion therapy. Equation [8] can be used to calculate
the time to reach a certain concentration of NO 2 for
any concentration of initial NO in O 2 (48).
During NO inhalation therapy, the inhaled NO 2
as well as NO levels should be maintained as low as
possible (3, 4). Threshold limit values for workers
have been set by the United States Occupational
Safety and Health Administration (OSHA) (4). The
OSHA has set the permissible limits for NO at a
value not to exceed 25 ppm for an 8-h time-weighted
average period and NO 2 not to exceed 5 ppm during
any part of the working day. On the other hand, the
United States National Institute for Occupational
Safety and Health has set the recommended expo-
sure limit for NO 2 at a value not to exceed 1 ppm for
a 15-min exposure and a maximum inhaled NO 2
level of 5 ppm. The UK standard set by the Health
and Safety Executive is 3 ppm NO 2, and in France
the standard is 2 ppm for nitrogen oxides. However,
these recommendations are intended for healthy
workers and not for patients (especially neonates)
with pulmonary diseases, although some guidelines
regarding the use of NO in neonates have been
based on these recommendations (51, 52). In addi-
tion, inhaled NO therapy must frequently be contin-
ued for prolonged periods ranging from several
hours to several weeks (3, 4). The national ambient
air quality standard for the annual NO 2 level in the
United States is 0.05 ppm (28), and it is 0.04 to 0.06
[6] ppm in Japan. The adverse effects of low-dose NO 2,
even at 1 ppm or less, have been demonstrated (28,
53, 54).
The initial rate of production of NO 2 is propor-
tional to the square of the initial concentration of
NO, so that a small error in the initial timing of NO
 GAS-PHASE OXIDATION OF NITRIC OXIDE
inhalation therapy could lead to a larger error in the
exposure to the undesirable NO 2. Thus, under a
condition of inspired O 2 fraction 5 1.0, T 5 300 K,
and k 5 7.0 3 1.0 3 L 2 z mol 22 z s 21, the concentration
of NO 2 reaches 52, 8.8, 2.3, 0.57, and 0.023 ppm in
the first 10 s of inhalation of 500, 200, 100, 50, and
10 ppm NO, respectively. At high NO concentra-
tions, even a 1-s error in the timing could cause
serious consequences.
CONCLUDING REMARKS
We reviewed the chemical kinetics, its possible
implications, and rate constant values k for the re-
action 2NO 1 O 2 5 2NO 2. We believe that this
information is helpful in handling NO/N 2 and O 2
mixtures and in developing guidelines that are more
specific and appropriate for the administration of
inhaled NO to patients. The existing guidelines have
been developed by borrowing the standards for gen-
eral air pollution, and such standards continue to
change from year to year.
ACKNOWLEDGMENT
This work was supported by a Grant for Pediatric Research
from the Ministry of Health and Welfare, Japan.
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