Photogeneration and reactivity of acyl nitroso compounds

Article abstract of DOI:10.1139/V10-101

Acyl nitroso compounds have been generated by photolysis of several different classes of precursors including 9,10-dimethylanthracene adducts, nitrodiazo compounds, and 1,2,4-oxadiazole-4-oxides. Consideration of the nitronate-like resonance structure of nitrodiazo compounds led to an examination of the photochemistry of nitronates with -leaving groups. Photolysis of such nitronates has been shown to generate an acyl nitroso species along with a carbene intermediate. Nanosecond time-resolved infrared (TRIR) spectroscopy has been used to detect photogenerated acyl nitroso compounds directly and to examine their reaction kinetics with amines and thiols. The mechanism of acyl nitroso aminolysis by primary amines involves general base catalysis, while the mechanism of aminolysis by secondary amines is strictly bimolecular. Thiols do not seem to be reactive with acyl nitroso compounds on the microsecond time scale, but thiolates are quite reactive. The reaction between benzoyl nitroside and an organic-soluble thiolate, tetrabutylammonium dodecanethiolate, proceeds via a proposed tetrahedral intermediate, which is observable by TRIR spectroscopy.

Full text of DOI:10.1139/V10-101

130
Photogeneration and reactivity of acyl nitroso
compounds
Anthony S. Evans, Andrew D. Cohen, Zachary A. Gurard-Levin, Naod Kebede,
Tevye C. Celius, Alexander P. Miceli, and John P. Toscano
Abstract: Acyl nitroso compounds have been generated by photolysis of several different classes of precursors including
9,10-dimethylanthracene adducts, nitrodiazo compounds, and 1,2,4-oxadiazole-4-oxides. Consideration of the nitronate-like
resonance structure of nitrodiazo compounds led to an examination of the photochemistry of nitronates with a-leaving
groups. Photolysis of such nitronates has been shown to generate an acyl nitroso species along with a carbene intermedi-
ate. Nanosecond time-resolved infrared (TRIR) spectroscopy has been used to detect photogenerated acyl nitroso com-
pounds directly and to examine their reaction kinetics with amines and thiols. The mechanism of acyl nitroso aminolysis
by primary amines involves general base catalysis, while the mechanism of aminolysis by secondary amines is strictly bi-
molecular. Thiols do not seem to be reactive with acyl nitroso compounds on the microsecond time scale, but thiolates are
quite reactive. The reaction between benzoyl nitroside and an organic-soluble thiolate, tetrabutylammonium dodecanethio-
late, proceeds via a proposed tetrahedral intermediate, which is observable by TRIR spectroscopy.
Key words: acyl nitroso, nitrodiazo, nitronate photochemistry, 1,2,4-oxadiazole-4-oxides, time-resolved IR spectroscopy.
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Resume : On a genere des composes acylnitroso par photolyse des plusieurs classes differentes de precurseurs, y compris
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des adduits du 9,10-dimethylanthracene, des composes nitrodiazo et des 4-oxydes de 1,2,4-oxadiazoles. Une consideration
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de la structure des composes nitrodiazo qui est similaire a la structure de resonance des nitronates a conduit a un examen
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de la photochimie des nitronates possedant un groupe partant en position a. On a montre que la photolyse de tels nitrona-
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tes conduit a la formation d’especes acylnitroso aux cotes d’un intermediaire carbene. On a fait appel a la spectroscopie
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infrarouge resolue en fonction du temps (IR-RT) pour detecter directement les composes acylnitroso photogeneres et pour
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determiner la cinetique de leurs reactions avec des amines et des thiols. Le mecanisme de l’aminolyse d’un acylnitroso par
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les amines primaires implique une catalyse basique generale alors que le mecanisme de l’aminolyse d’un acylnitroso par
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les amines secondaires est strictement bimoleculaire. Les thiols ne semblent pas etre reactifs vis-a-vis des composes acylni-
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troso a l’echelle de temps de la microseconde, mais les thiolates sont tres reactifs. La reaction entre le nitroside de ben-
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zoyle et le thiolate organique soluble, decanethiolate de tetrabutylammonium, se fait par le biais d’une intermediaire
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tetraedrique que l’on peut observer par spectroscopie IR-RT.
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Mots-cles : acylnitroso, nitrodiazo, photochimie du nitronate, 4-oxydes de 1,2,4-oxadiazoles, spectroscopie infrarouge reso-
lue en fonction du temps (IR-RT).
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[Traduit par la Redaction]
electron-withdrawing character of the carbonyl functionality
ought to render acyl nitroso species reactive in [4 + 2] cy-
cloadditions as well. Indeed, the mild periodate oxidation of
aceto- and benzohydroxamic acid in the presence of a vari-
ety of conjugated dienes such as 9,10-dimethylanthracene
(DMA) yields the Diels–Alder product 2 in high yield
(Scheme 1). Further studies with these Diels–Alder adducts
revealed that they can undergo a retro-Diels–Alder reaction
at elevated temperatures and that the generated acyl nitroso
intermediate could be trapped by a different diene.7
Introduction
Acyl nitroso (C-nitrosocarbonyl) compounds (1) are tran-
sient electrophiles that were originally proposed as inter-
mediates in the pyrolysis of alkyl nitrites in the presence of
aldehydes1 as well as in the oxidation of hydroxamic
acids.2–4 Seminal work strongly suggesting the intermediacy
of acyl nitroso compounds in the oxidation of hydroxamic
acids was reported in a series of papers by Kirby5 and Kirby
and Sweeney.6,7 Building on previous studies of the dieno-
philic character of nitrosyl cyanide, it was reasoned that the
Received 1 June 2010. Accepted 17 June 2010. Published on the NRC Research Press Web site at canjchem.nrc.ca on 5 January 2011.
This article is part of a Special Issue dedicated to Professor J. C. Scaiano in appreciation of his contributions to photochemistry and
organic reaction mechanisms.
A.S. Evans, A.D. Cohen, Z.A. Gurard-Levin, N. Kebede,1 T.C. Celius,2 A.P. Miceli, and J.P. Toscano.3 Department of Chemistry,
Johns Hopkins University, Baltimore, MD 21218, USA.
1Present address: Department of Chemistry, Edinboro University of Pennsylvania, Edinboro, PA 16444, USA.
2Present address: Department of Chemistry and Biochemistry, Ohio Northern University, Ada, OH 45810, USA.
3Corresponding author (e-mail: jtoscano@jhu.edu).
Can. J. Chem. 89: 130–138 (2011)
doi:10.1139/V10-101
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Evans et al.
131
Scheme 1. The oxidative generation of acyl nitroso compounds (1)
and subsequent reaction with DMA to form Diels–Alder adducts
Scheme 4. The generation of acyl nitroso compounds (1) from
1,2,4-oxadiazole-4-oxide derivatives (4).
(2).
Fig. 1. TRIR difference spectra averaged over the time frames in-
dicated following laser photolysis (266 nm, 5 ns, 3 mJ) of a
5 mmol L–1 solution of 2 (R = Ph) in dichloromethane.
Scheme 2. The reaction of acyl nitroso compounds (1) with
nucleophiles to generate HNO.
Scheme 3. The generation of acyl nitroso compounds (1) from
nitrodiazo precursors (3).
Reactions of acyl nitroso species with nucleophiles had
been suggested by initial observations but were more care-
fully examined by Corrie et al.8 Periodate oxidation of ben-
zohydroxamic acid in aqueous media yields predominantly
benzoic acid, while tetraalkyl-ammonium periodate oxida-
tion in dichloromethane yields O-benzoylbenzohydroxamic
acid. Atkinson et al.9 studied the reaction of acyl nitroso
compounds with amines to give amides in reasonable yields.
Clearly, 1 is able to acylate nucleophiles such as water, hy-
droxamic acids, and amines, presumably with concomitant
generation of nitroxyl (HNO) (Scheme 2). The detection of
nitrous oxide (N2O), the product of HNO dimerization and
subsequent dehydration, in the reaction of 1 with amines is
consistent with HNO formation.9
In this manuscript, we are pleased to extend our original
TRIR studies of acyl nitroso compounds generated from 4
and also to report on the photochemistry of DMA adducts
(2), nitrodiazo compounds (3), and related nitronate deriva-
tives.
Results and discussion
Photogeneration of acyl nitroso compounds from DMA
adducts
Acyl nitroso species have also been proposed as inter-
mediates in the decomposition of nitrodiazo compounds (3).
Although nitrocarbene intermediates can be trapped follow-
ing rhodium-catalyzed decomposition,10–14 thermolysis or
photolysis leads only to acyl nitroso-derived products
(Scheme 3).15,16 Calculations predict that singlet nitrocar-
bene has little to no barrier to rearrangement to nitrosofor-
maldehyde.17
Quadrelli et al. have developed 1,2,4-oxadiazole-4-oxide
derivatives (4) as efficient photochemical18 and thermal19
precursors to acyl nitroso compounds (Scheme 4), and
Quadrelli and Caramella20 have made use of these precur-
sors in a wide variety of synthetic applications. We have re-
cently utilized 3,5-diphenyl-1,2,4-oxadiazole-4-oxide (4, R =
Ph) in the first direct observation of an acyl nitroso species
in solution by nanosecond time-resolved infrared (TRIR)
spectroscopy.21 In this study, the strongest diagnostic signal
for benzoyl nitroside (1, R = Ph) appeared at 1735 cm–1; it
was produced faster than the time resolution of our spec-
trometer (kobs > 2.0 Â 107 s–1) and was stable for at least
1 ms in the absence of nucleophiles.
Following our initial TRIR studies of benzoyl nitroside
generated from a 1,2,4-oxadiazole-4-oxide,21 we have per-
formed analogous studies on its DMA adduct (2, R = Ph).
Laser photolysis (266 nm, 5 ns, 3 mJ) of a 5 mmol L–1 sol-
ution of 2 (R = Ph) in dichloromethane produces the TRIR
difference spectrum shown in Fig. 1. Interestingly, in addi-
tion to the diagnostic acyl nitroso band at 1735 cm–1, an-
other prominent band is observed at 1820 cm–1. The
1820 cm–1 band is formed faster than the time resolution of
our spectrometer (kobs > 2.0 Â 107 s–1) and decays on the
microsecond time scale with concomitant additional growth
of the 1735 cm–1 acyl nitroso band.
IR absorbances above 1800 cm–1 are relatively rare for
organic species and are typically observed only for highly
strained carbonyls, carbonyls substituted with strongly electron-
withdrawing groups, and acyl radicals. Acyl radicals have
been extensively studied in hydrocarbon solvent by TRIR
spectroscopy.22,23 Benzoyl radical is reported to absorb at
1828 cm–1, consistent with our 1820 cm–1 signal in dichloro-
methane. We envision two potential pathways consistent
with the TRIR data of Fig. 1: (i) simple secondary photoly-
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Can. J. Chem. Vol. 89, 2011
Scheme 5. Two potential photochemical pathways for the DMA
adduct (2, R = Ph).
arose from consideration of their nitronate-like resonance
structure (3-N). Alkyl nitronates (6) have been shown to
undergo a photoinduced rearrangment to hydroxamic acids
(Scheme 7a).27–31 An analogous reaction from a nitrodiazo
compound leads to the N-oxirane intermediate 7, which
could undergo further rearrangement, via two potential path-
ways, to the acyl nitroso product (Scheme 7b).
Photogeneration of acyl nitroso compounds from
nitronates with a-leaving groups
To test the reaction scheme shown in Scheme 7b we have
examined the photochemistry of nitronates with a-leaving
groups. Our initial studies have focused on phenylcyano-
nitromethane nitronate (8); results similar to those reported
below have also been observed in preliminary experiments
with the 4-chloro and 4-methoxy analogues.
Nitronate 8 is stable in sodium hydroxide or methanol sol-
utions. As shown in Scheme 8, photolysis (Rayonet,
254 nm) of 8 in methanol cleanly provides two products,
methyl benzoate (10) and methoxyphenylacetonitrile (12).
HPLC and GC–MS analysis reveal a 29% 5% yield of 10
and a 63% 7% yield of 12 (values are means SD). The
production of methyl benzoate was confirmed by compari-
son with an authentic sample; the GC–MS data for nitrile
12 match well with its reported mass spectrum.32 N2O quan-
tification following photolysis of nitronate 8 in methanol in-
dicates that HNO is formed in a 26% 5% yield, consistent
with the yield of methyl benzoate.
To explain the formation of nitrile 12, we propose that N-
oxirane intermediate 9 partitions between the anticipated
loss of cyanide ion and the loss of nitrite ion to form phe-
nylcyano carbene (11), which is trapped by methanol to
form nitrile 12, as has been previously observed.33,34
Although we have not yet conducted experiments that indi-
cate whether carbene 11 is formed thermally or photochemi-
cally (analogous to epoxide photochemistry34–36) from N-
oxirane 9, this hypothesis is consistent with earlier studies
of nitronate photochemistry where carbene intermediates
were proposed.30
Further experimental evidence for the formation of car-
bene 11 is provided by additional trapping experiments.
GC–MS analysis following photolysis of nitronate 8 in ace-
tonitrile containing either cyclohexene or 2,3-dimethyl-2-
butene reveals carbene–alkene adducts (both C–H and C=C
insertion products).36 Moreover, the addition of increasing
concentrations of alkene to a methanol-containing acetoni-
trile solution of nitronate 8 results in a decrease of the
carbene–methanol adduct 12 accompanied by a concomitant
increase in carbene–alkene derived products. Finally, photol-
ysis of nitronate 8 in THF results in products (14 and 15,
Scheme 8) consistent with the rearrangement of carbene-
derived ylide 13. Analogous THF–ylide rearrangement prod-
ucts have been observed in the study of 2-naphthyl(carbo-
methoxy)carbene.37
sis of benzoyl nitroside within the 266 nm laser pulse to
form nitric oxide (NO) and benzoyl radical, which subse-
quently recombine (Scheme 5, path 1), or (ii) Norrish type I
cleavage of precursor 2 to form benzoyl radical and NO/
DMA adduct (5), which rapidly dissociates to NO and
DMA, followed by NO–benzoyl radical recombination
(Scheme 5, path 2). Similar photochemistry has very re-
cently been proposed for other acyl nitroso Diels–Alder cy-
cloadducts.24
Analogous TRIR experiments on the acetyl nitroside/
DMA adduct (2, R = Me) reveal only the characteristic acyl
nitroso band, in this case observed at 1780 cm–1 (consistent
with B3LYP/6-31G* calculations), with no evidence for the
acetyl radical (Supplementary data). Since acetyl nitroside is
not expected to absorb at 266 nm, whereas benzoyl nitroside
should, these experiments suggest that the secondary photol-
ysis pathway (Scheme 5, path 1) is operative.
Photogeneration of acyl nitroso compounds from
nitrodiazo compounds
We have also examined the photogeneration of acyl ni-
troso compounds from nitrodiazo precursors by TRIR spec-
troscopy. Ethyl nitrodiazoacetate (3, R = CO2Et) and
nitrodiazomethyl tert-butyl ketone (3, R = C(O)-t-Bu) both
provide the characteristic acyl nitroso TRIR signal at 1788
and 1756 cm–1, respectively, consistent with B3LYP/6-
31G* calculations (Supplementary data). Each of these
bands was produced faster than the time resolution of our
spectrometer (kobs > 2.0 Â 107 s–1) and was stable for at
least 1 ms in dichloromethane. In the spectral region be-
tween 2200 and 2000 cm–1, we also observe diazo depletion
bands with no TRIR evidence for the formation of ke-
tene,25,26 which could potentially be formed via Wolff rear-
rangement from either of these precursors (Supplementary
data). Consistent with the lack of Wolff rearrangement,
nearly quantitative yields of N2O (formed via acyl nitroso-
produced HNO) are observed following the photolysis of
Reactivity of acyl nitroso compounds with amines
ethyl nitrodiazoacetate
(Scheme 6).
Given the above results and previous observations that
photogenerated nitrocarbenes are not trappable,15,16 we have
begun to explore an alternative photochemical pathway to
acyl nitroso compounds from nitrodiazo precursors that
in 75:25 acetonitrile/water
We have examined the reactivity of three acyl nitroso
compounds (1, R = Ph, Me, and 4-Cl-Ph) with a variety of
amines in dichloromethane. Acyl nitroso compounds (1, R =
Ph and 4-Cl-Ph) were generated from 1,2,4-oxadiazole-4-
oxides (4), and acyl nitroso 1 (R = Me) was generated from
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Evans et al.
133
Scheme 6. The photodecomposition of ethyl nitrodiazoacetate in 75:25 acetonitrile/water.
Scheme 7. (a) The photochemistry of alkyl nitronates. (b) The ana-
logous photochemistry of nitrodiazo precursors to produce acyl ni-
troso compounds.
of esters by primary and secondary amines in organic sol-
vent.38–40 Our results indicate that the mechanism of acyl ni-
troso aminolysis by primary amines involves general base
catalysis, while the mechanism of aminolysis by secondary
amines is strictly bimolecular.
For a given amine, the rate of aminolysis is also depend-
ent on the structure of the acyl nitroso compound. Consis-
tent with expected electronic effects, 1 (R = 4-Cl-Ph) reacts
2 to 3 times more rapidly than 1 (R = Ph) with DEA and
NBA, respectively. Also, aliphatic acyl nitroso (1, R = Me)
reacts 2.5 to 10 times more rapidly than aromatic acyl ni-
troso (1, R = Ph) with NBA and PIP, respectively.
Reactivity of acyl nitroso compounds with thiols
We have also examined the kinetics and mechanism of
the reaction of 1 (R = Ph) with thiols. Initial experiments
surprisingly revealed no observed increase in the acyl ni-
troso decay rate upon the addition of up to 100 mmol L–1
N-acetylcysteine methyl ester (NAC). However, in the pres-
ence of 3.4 mmol L–1 NAC and 48 mmol L–1 DEA, the de-
cay of 1 was observable and faster than that in the presence
of 48 mmol L–1 DEA alone. We postulate that although the
thiol itself is not reactive (on the microsecond time scale),
the in situ generated diethylammonium thiolate is. We
examined thiolate reactivity directly using organic-soluble
tetrabutylammonium dodecanethiolate (TBA-D). The de-
pendence of the acyl nitroso decay rate fit well to the
pseudo-first-order rate equation kobs = ko + kTBA-D[TBA-D]
and a value of kTBA-D = 4.2 ( 0.6) Â 107 L mol–1 s–1 was
determined (Supplementary data).
For all amines examined, acyl nitroso decay is accompa-
nied by concomitant growth of the corresponding amide
product (*1660 cm–1). In the case of the reaction of TBA-
D with 1 (R = Ph), however, the acyl nitroso (1735 cm–1)
decays over the microsecond time scale to a strongly absorb-
ing intermediate that is observed at 1615 cm–1 (Fig. 4). This
intermediate subsequently decays on the millisecond time
scale to the product thiobenzoate (17), observed at
1706 cm–1, consistent with the reported carbonyl stretching
frequency of ethylthiobenzoate.41 We have tentatively as-
signed this 1615 cm–1 band to tetrahedral intermediate 16
(Scheme 9), which is calculated (Supplementary data) to
have a very intense N=O stretch at 1597 cm–1, reasonably
consistent with the observed TRIR band.
its DMA adduct (2). The decay kinetics of the characteristic
acyl nitroso TRIR signals were monitored as a function of
varying concentrations of added amine to derive reaction
rate constants.
For the secondary amines, diethylamine (DEA) and piper-
idine (PIP), plots of observed decay rates (kobs) versus amine
concentration are linear and fit well to the pseudo-first-order
rate equation kobs = ko + kamine[amine] (Fig. 2 and Supple-
mentary data). Derived second-order rate constants are
shown in Table 1. (Note that the reaction of benzoyl nitro-
side (1, R = Ph) with DEA has been refined slightly from
that originally reported (kDEA = 1.3 Â 105 0.5 Â 105 L
mol–1 s–1).21) The twofold faster rate constant for the reac-
tion of 1 (R = Ph) with PIP versus DEA is consistent with
the decreased steric bulk of the ring-constrained PIP.
For the primary amines, n-butylamine (NBA) and benzyl-
amine (BA), in contrast to the above secondary amines,
plots of kobs versus amine concentration are not linear, but
rather fit to the rate equation kobs = ko + kamine[amine]2
(Fig. 3 and Supplementary data), indicating that the reaction
of acyl nitroso species with primary amines is a third-order
reaction, requiring two molecules of the primary amine. Rel-
ative rate constants derived for NBA and BA (Table 1) are
again consistent with expected reactivity. No reactivity was
observed with tert-butylamine (TBA), even at concentrations
approaching 2 mol L–1, owing to the steric bulk of this
poorly nucleophilic amine.
The rate of decay of the intermediate 1615 cm–1 band and
the rate of growth of the 1706 cm–1 product band are both
independent of the concentration of TBA-D, consistent with
a unimolecular reaction of 16. A similar tetrahedral inter-
mediate has been proposed in the alkaline hydrolysis of thi-
obenzoates.42
The dependence of the reaction order of the aminolysis of
acyl nitroso species on amine structure (i.e., primary vs. sec-
ondary) is consistent with previous reports of the aminolysis
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134
Can. J. Chem. Vol. 89, 2011
Scheme 8. The photochemistry of phenylcyanonitromethane nitronate (8).
Table 1. Rate constants for the reaction of acyl nitroso compounds with amines.
k  10–5 (L mol–1 s–1)
k  10–4 (L–1 mol–2 s–1)
Acyl nitroso 1, R =
DEA
PIP
NBA
BA
TBA
Ph
Me
4-Cl-Ph
1.2 0.1
ND
2.3 0.1
2.0 0.1
22 1
ND
2.8 0.1
7.1 0.1
10.1 0.1
0.36 0.9
ND
ND
No rxn
No rxn
No rxn
Note: DEA, diethylamine; PIP, piperidine; NBA, n-butylamine; BA, benzylamine; TBA, tert-butylamine;
ND, not determined; no rxn, no reaction observed on the microsecond time scale.
Fig. 2. Plots of observed rate of decay of 1 (R = Ph) in dichloro-
Fig. 3. Plots of observed rate of decay of 1 (R = Ph) in dichloro-
methane monitored at 1735 cm–1 as a function of benzylamine
(squares) or n-butylamine (circles) concentration. The dotted lines
are the least-squares fit to a polynomial function.
methane monitored at 1735 cm–1 as a function of diethylamine
(squares) or piperidine (circles) concentration. The dotted lines are
the least-squares fit to a linear function.
Nanosecond TRIR spectroscopy has been used to detect
photogenerated acyl nitroso compounds directly and to ex-
amine their reaction kinetics with amines and thiols. The
mechanism of acyl nitroso aminolysis by primary amines in-
volves general base catalysis, while the mechanism of ami-
nolysis by secondary amines is strictly bimolecular. Thiols
do not seem to be reactive with acyl nitroso compounds on
the microsecond time scale, but thiolates are quite reactive.
The reaction between benzoyl nitroside (1, R = Ph) and the
organic-soluble thiolate TBA-D proceeds via a proposed tet-
Conclusions
Acyl nitroso compounds have been generated by photoly-
sis of several different classes of precursors including DMA
adducts (2), nitrodiazo compounds (3), and 1,2,4-oxadiazole-
4-oxides (4). Consideration of the nitronate-like resonance
structure of nitrodiazo compounds led to an examination of
the photochemistry of nitronates with a-leaving groups (e.g.,
8). Photolysis of nitronate 8 has been shown to generate an
acyl nitroso species along with a carbene intermediate.
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Evans et al.
135
Fig. 4. (a) TRIR difference spectra averaged over the time frames indicated and (b and c) kinetic traces observed following laser photolysis
(355 nm, 5 ns, 4 mJ) of a 1 mmol L–1 solution of 4 (R = Ph) containing 10 mmol L–1 TBA-D in dichloromethane.
Scheme 9. The postulated mechanism for the thiolysis of benzoyl
nitroside illustrating the intermediacy of 16.
amines were redistilled prior to use and stored over potas-
sium hydroxide.
1H NMR spectra were recorded on a Bruker Avance
400 MHz FT NMR operating at 400 MHz; 13C NMR spectra
were recorded on a Bruker Avance 300 MHz FT NMR oper-
1
ating at 75 MHz. All H resonances are reported in parts per
million, and are referenced to solvent (1H NMR (chloroform-
d) d: 7.26, (methanol-d4) d: 3.3). Melting points were re-
corded on a Mel-Temp apparatus and are uncorrected. High
resolution mass spectra were obtained on a VG70SE double
focusing magnetic sector mass spectrometer operating in fast
atom bombardment ionization mode. Reported masses were
referenced to a doubly potassiated PEGMME mass calibrant.
Ultraviolet–visible (UV–vis) absorption spectra were ob-
tained using a Hewlett Packard 8453 diode array spectrome-
ter. Infrared (IR) absorption spectra were obtained using a
Bruker IFS 55 Fourier transform infrared spectrometer. All
density functional theory (DFT) calculations were performed
using Spartan ‘04 (Wavefunction, Inc.) for Macintosh or
rahedral intermediate, which is observable by TRIR spectro-
scopy.
Experimental section
General methods
Unless otherwise noted, materials were obtained from the
Sigma-Aldrich Chemical Company, Fisher Scientific, or
Cambridge Isotope Laboratories. All solvents were purified
with a PureSolv MD 5 solvent purification system. All
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136
Can. J. Chem. Vol. 89, 2011
Spartan ‘08 (Wavefunction, Inc.) for Windows using the
B3LYP/6-31G* method and basis set.
HPLC methods
HPLC data were collected on a Waters Delta 600 system
equipped with a Model 6000A pump and a Model 2487 dual
wavelength UV detector monitoring at 230 nm equipped
with a Waters C-18 symmetry column. All HPLC eluents
contained 0.1% trifluoroacetic acid. Nitronate samples were
prepared in methanol, sparged with argon, and then photo-
lyzed (Rayonet, 254 nm). HPLC analysis was then per-
formed with a flow rate of 1 mL min–1 with 35:65
acetonitrile/water. Yields are reported as an average of four
individual experiments.
Time-resolved IR methods
TRIR experiments were conducted following the method
of Iwata and Hamaguchi43 as described previously.25
Briefly, the broadband output of a MoSi2 IR source
(JASCO) is crossed with excitation pulses from a Contin-
uum Minilite II Nd:YAG laser (266 nm or 355 nm) operat-
ing at 15 Hz. Changes in IR intensity are monitored using
an AC-coupled mercury/cadmium/tellurium (MCT) photo-
voltaic IR detector (Kolmar Technologies, KMPV11-J1/
AC), amplified, digitized with a Tektronix TDS520A oscil-
loscope, and collected on a Macintosh with IGOR for data
processing. The experiment is conducted in dispersive mode
with a JASCO TRIR 1000 spectrometer.
General procedure for the synthesis of DMA
cycloadducts (2)
The synthesis of DMA cycloadducts (2) was carried out
in accordance with a literature procedure, using tetrabutyl-
ammonium periodate instead of tetraethyl-ammonium peri-
odate.7 Benzoyl nitroside/DMA cycloadduct (2, R = Ph):
mp 126–128 8C (lit. value7 mp 127–128 8C). Acetyl nitro-
side/DMA cycloadduct (2, R = Me): mp 133–136 8C (lit.
value7 mp 133–136 8C).
N2O quantification via GC headspace analysis
GC headspace analysis was performed on a Varian CP-
3800 instrument equipped with a Restek ShinCarbon ST 80/
100 molecular sieve-packed column and an electron capture
detector.
General procedure for the synthesis of
Photolysis of Angeli’s salt (a classic HNO donor under
physiologically relevant conditions44) has been shown to
produce HNO/NO–, which subsequently yields N2O.45 To
quantify the amount of N2O produced following photolysis
of Angeli’s salt, a 1 mmol L–1 solution in 0.01 mol L–1
NaOH was prepared and 1 mL of this solution was placed
in series of 1 cm quartz cuvettes. The cuvettes were sealed
with rubber septa and sparged with argon for 20 min. Sam-
ples were then photolyzed (Rayonet, 254 nm) until comple-
tion as indicated by the disappearance of the characteristic
Angeli’s salt UV absorbance at 254 nm. Samples were al-
lowed to equilibrate at 37 8C for 1 h and then 100 mL of
headspace was analyzed for N2O. N2O yields are taken as
an average of five injections. The theoretical yield of An-
geli’s salt-derived N2O was calculated for the NaOH solu-
tion using Henry’s law and was found to be quantitative
versus authentic samples. N2O yields were determined anal-
ogously for ethyl nitrodiazoacetate (3, R = CO2Et) in 75:25
acetonitrile/water and phenylcyano-nitromethane nitronate
(8) in methanol and compared with that found for Angeli’s
salt (assumed to be 100%) in 75:25 acetonitrile/water and
methanol, respectively.
nitrodiazocarbonyl compounds (3)
Ethylnitrodiazoacetate and nitrodiazomethyl tert-butyl ke-
tone were synthesized by the method reported by Charette et
al.46 Ethylnitrodiazoacetate (3, R = CO2Et): IR (film, cm–1)
1
nmax: 2148, 1750, 1693. H NMR (CDCl3) d: 4.42 (2H, q),
1.38 (3H, t). Nitrodiazomethyl tert-butyl ketone (3, R =
C(O)-t-Bu): IR (film, cm–1) nmax: 2142, 2180, 1690, 1650.
1H NMR (CDCl3) d: 1.35 (s, 9 H).
General procedure for the synthesis of 1,2,4-oxadiazole-
4-oxides (4)
The synthesis of 1,2,4-oxadiazole-4-oxides was performed
using a slight modification of a literature procedure.47 The
synthesis of 3,5-diphenyl-1,2,4-oxadiazole-4-oxide is shown
below as a general procedure.
3,5-Diphenyl-1,2,4-oxadiazole-4-oxide (4, R = Ph)
Benzohydroximoyl chloride was prepared from benzalde-
hyde oxime in accordance with literature procedures and
used directly for the next step.48 Dehydrohalogenation was
performed in ethanol using triethanolamine to yield benzoni-
trile oxide. The nitrile oxide dimerization was accomplished
in situ with triethanolamine, yielding a mixture of three di-
meric species. The desired dimer was initially purified by
silica gel column chromatography (10%–30% ethyl
acetate / hexanes). The column-purified product was further
purified by recrystallization from methanol/water, yielding
white needles; mp 132–133 8C (lit. value49 mp 134 8C).
GC–MS methods
GC–MS analysis was performed on a Shimadzu GC17A/
QP5050A instrument equipped with electron ionization. Ni-
tronate samples were prepared in methanol, THF, or acetoni-
trile, sparged with argon, photolyzed (Rayonet, 254 nm),
concentrated under vacuum, reconstituted in 1 mL of metha-
nol, and then analyzed by GC–MS. Carbene trapping by al-
kenes (cyclohexene and 2,3-dimethyl-2-butene) was
analyzed analogously in acetonitrile solutions. Competitive
carbene trapping by methanol versus alkene (cyclohexene
or 2,3-dimethyl-2-butene) was also performed in acetonitrile
with 10 mmol L–1 methanol and 0–50 mmol L–1 alkene.
Yields are reported as an average of four individual experi-
ments.
3,5-Bis(4-chlorophenyl)-1,2,4-oxadiazole-4-oxide (4, R =
4-Cl-Ph)
Prepared from 4-chlorobenzaldehyde oxime using the
general procedure; mp 189–190 8C (lit. value49 mp 189–
190 8C).
General procedure for the synthesis of
arylcyanonitromethane potassium nitronates
Arylcyanonitromethane potassium nitronate derivatives
Published by NRC Research Press

Evans et al.
137
were prepared via modification of a literature procedure.50
Synthesis of phenylcyanonitromethane potassium nitronate
is shown below as a general procedure.
(3) Moffatt, J. G.; Lerch, U. J. Org. Chem. 1971, 36 (22), 3391.
doi:10.1021/jo00821a027.
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2761.
(5) Kirby, G. W. Chem. Soc. Rev. 1977, 6 (1), 1. doi:10.1039/
cs9770600001.
(6) Kirby, G. W.; Sweeny, J. G. J. Chem. Soc., Chem. Commun.
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(7) Kirby, G. W.; Sweeny, J. G. J. Chem. Soc., Perkin Trans. 1
1981, 3250. doi:10.1039/p19810003250.
Phenylcyanonitromethane potassium nitronate (8)
Benzyl cyanide (2.93 g, 0.025 mol) was added to a solu-
tion of potassium tert-butoxide (9.25 g, 0.0825 mol) in
90 mL of THF at –50 8C in a dry ice / acetone bath. Isoamyl
nitrate (7.3 g, 0.55 mol) was added dropwise, maintaining
the temperature at –45 to –50 8C. The cooling bath was re-
moved and the reaction mixture allowed to warm to room
temperature. The precipitate that formed was filtered and
washed with THF and then ether. The residue was recrystal-
lized from ethanol/hexanes (2.25 g, 45%). IR (mineral oil,
cm–1) nmax: 2201, 1495, 1455, 1417, 1366, 1339, 1310,
(8) Corrie, J. E. T.; Kirby, G. W.; Mackinnon, J. W. M. J.
Chem. Soc., Perkin Trans.
1 1985, 883. doi:10.1039/
p19850000883.
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82943-7.
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3096. doi:10.1021/jo00274a027.
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(32), 4197. doi:10.1016/S0040-4039(01)80688-2.
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7341. doi:10.1016/S0040-4020(01)89052-9.
1
1284, 1264, 1190, 1167, 1034, 1005, 989, 762. H NMR
(methanol-d4) d: 7.15 (1H, t), 7.32 (2H, d), 7.90 (2H, d).
13C NMR (D2O) d: 129.40, 128.52, 127.68, 125.87, 117.88,
102.10. HR-FAB-MS m/z: 238.9629 [M + 2K]+. Calcd. for
C8H5K2N2O2: 238.9625.
(13) O’Bannon, P. E.; Dailey, W. P. J. Org. Chem. 1991, 56 (6),
2258. doi:10.1021/jo00006a058.
(14) Charette, A. B.; Wurz, R. P.; Ollevier, T. Helv. Chim. Acta
4-Chloro-phenylcyanonitromethane potassium nitronate
Prepared from 4-chlorobenzyl cyanide using the general
procedure. IR (mineral oil, cm–1) nmax: 2200, 1497, 1397,
1303, 1279, 1248, 1115, 1098, 996, 824. 1H NMR
(methanol-d4) d: 7.32 (2H, d), 7.90 (2H, d). 13C NMR
(D2O) d: 132.14, 128.31, 128.05, 126.89, 117.48, 101.49.
HR-FAB-MS m/z: 272.9232 [M + 2K, 35Cl]+, 274.9210
[M + 2K, 37Cl]+. Calcd. for C8H4ClK2N2O2: 272.9235.
2002, 85 (12), 4468. doi:10.1002/hlca.200290023.
¨
(15) Schollkopf, U.; Markusch, P. Justus Liebigs Ann. Chem.
1971, 753, 143. doi:10.1002/jlac.19717530113.
(16) O’Bannon, P. E.; Dailey, W. P. Tetrahedron Lett. 1988, 29
(45), 5719. doi:10.1016/S0040-4039(00)82171-1.
(17) O’Bannon, P. E.; Dailey, W. P. Tetrahedron Lett. 1988, 29
(9), 987. doi:10.1016/0040-4039(88)85315-2.
(18) Quadrelli, P.; Mella, M.; Caramella, P. Tetrahedron Lett.
1999, 40 (4), 797. doi:10.1016/S0040-4039(98)02416-2.
(19) Quadrelli, P.; Campari, G.; Mella, M.; Caramella, P. Tetra-
hedron Lett. 2000, 41 (12), 2019. doi:10.1016/S0040-
4039(00)00093-9.
(20) Quadrelli, P.; Caramella, P. Curr. Org. Chem. 2007, 11 (11),
959. doi:10.2174/138527207781058745.
(21) Cohen, A. D.; Zeng, B.-B.; King, S. B.; Toscano, J. P. J.
Am. Chem. Soc. 2003, 125 (6), 1444. doi:10.1021/
ja028978e. PMID:12568581.
4-Methoxy-phenylcyanonitromethane potassium
nitronate
Prepared from 4-methoxybenzyl cyanide using the general
procedure. IR (mineral oil, cm–1) nmax: 2205, 1600, 1514,
1412, 1351, 1310, 1290, 1241, 1189, 1151, 1028, 991, 828.
1H NMR (methanol-d4) d: 3.79 (3H, s), 6.90 (2H, d), 7.80
(2H, d). 13C NMR (D2O) d: 158.07, 127.60, 122.14, 117.60,
113.87, 101.80, 55.28. HR-FAB-MS m/z: 268.9726 [M +
2K]+. Calcd. for C9H7K2N2O3: 268.9731.
(22) Neville, A. G.; Brown, C. E.; Rayner, D. M.; Lusztyk, J.; In-
gold, K. U. J. Am. Chem. Soc. 1991, 113 (5), 1869. doi:10.
1021/ja00005a082.
Synthesis of tetrabutylammonium dodecanethiolate
(TBA-D)
The synthesis was carried out in accordance with the pub-
(23) Brown, C. E.; Neville, A. G.; Rayner, D. M.; Ingold, K. U.;
lished procedure.51,52
Lusztyk, J. Aust. J. Chem. 1995, 48 (2), 363.
(24) Matsuo, K.; Nakagawa, H.; Adachi, Y.; Kameda, E.; Tsu-
moto, H.; Suzuki, T.; Miyata, N. Chem. Commun. (Camb.)
2010, 46 (21), 3788. doi:10.1039/c001502d. PMID:
20393655.
(25) Wang, Y.; Yuzawa, T.; Hamaguchi, H.; Toscano, J. P. J.
Am. Chem. Soc. 1999, 121 (12), 2875. doi:10.1021/
ja983278o.
Supplementary data
Supplementary data (additional TRIR data, kinetic analy-
ses, and computational results) for this article are available
on the journal Web site (canjchem.nrc.ca).
Acknowledgment
(26) Wang, Y.; Toscano, J. P. J. Am. Chem. Soc. 2000, 122 (18),
4512. doi:10.1021/ja9937775.
J.P.T. thanks the U.S. National Science Foundation (CHE-
0911305) for generous support of this research.
(27) Imam, S. H.; Marples, B. A. Tetrahedron Lett. 1977, 18
(30), 2613. doi:10.1016/S0040-4039(01)83834-X.
(28) Yamada, K.; Kanekiyo, T.; Tanaka, S.; Naruchi, K.; Yama-
moto, M. J. Am. Chem. Soc. 1981, 103 (23), 7003. doi:10.
1021/ja00413a056.
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