Reaction of nitric oxide with benzyl cyanide to yield a bis-diazeniumdiolated imidate

Article abstract of DOI:10.1016/S0040-4039(00)01535-5

The reaction of nitric oxide with benzyl cyanide in the presence of sodium methoxide forms the bis-diazeniumdiolated imidate, PhC[C(OMe)=NH][N(O)NO^-Na⁺]₂. This compound decomposes in acidic media to yield nitric oxide, nitrous oxide and 2-oximino-2-phenylacetic acid methyl ester. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01535-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8421–8424
Reaction of nitric oxide with benzyl cyanide to yield a
bis-diazeniumdiolated imidate
a
a
b,
Ernst V. Arnold, Larry K. Keefer and Joseph A. Hrabie *
a
Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute,
Frederick Cancer Research and Development Center, Frederick, MD 21702, USA
b
SAIC Frederick, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick,
MD 21702, USA
Received 24 August 2000; revised 7 September 2000; accepted 11 September 2000
Abstract
The reaction of nitric oxide with benzyl cyanide in the presence of sodium methoxide forms the
−
+
bis-diazeniumdiolated imidate, PhC[C(OMe)ꢀNH][N(O)NO Na ] . This compound decomposes in acidic
2
media to yield nitric oxide, nitrous oxide and 2-oximino-2-phenylacetic acid methyl ester. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: nitrogen oxides; nitriles; imidic acids and derivatives; diazenes.
−
Despite the widely growing use of diazeniumdiolates (compounds containing the ꢁ[N(O)NO]
1–4
functional group) as selective nitric oxide donor compounds for biological research,
the
fundamental chemistry of this functional group is not as yet fully understood. Recently, several
reports on the decomposition of mono substituted carbon-bound diazeniumdiolates have
demonstrated the contradictory behavior of these compounds. On the one hand, the 2-
adamantyl derivative was shown to decompose in a stepwise manner to liberate nitrous oxide as
5
,6
the sole nitrogenous gas. On the other hand, the acidic decomposition of N-nitrosohydroxy-
guanidines produces both nitric oxide (NO) and nitrous oxide (N O) in a ratio which is pH
2
7
8
dependent and certain enamine diazeniumdiolates produce only NO on decomposition. The
factors which control the ratio of NO to N O are of great interest for the design and synthesis
2
of novel NO donor carbon based diazeniumdiolates.
The pioneering work of Wilhelm Traube demonstrated that nitroalkanes, alcohols, ketones,
certain esters and benzyl cyanide react with NO in the presence of strong base to form
compounds in which either one or two of the acidic protons have been replaced by a
9
diazeniumdiolate group. As an extension to the simple hydrogen replacement reaction, we
*
Corresponding author. Tel: 301 846 7184; fax: 301 846 6037; e-mail: hrabie@mail.ncifcrf.gov
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01535-5

8422
would like to report our observation that the reaction of nitric oxide with benzyl cyanide in a
solution of methanolic sodium methoxide yields the bis-diazeniumdiolated imidate, which
decomposes in acidic media to produce NO, N O and 2-oximino-2-phenylacetic acid methyl
2
ester, as illustrated in Fig. 1.
Figure 1. Synthesis of 2 and its decomposition to yield nitric oxide and nitrous oxide
In a typical procedure, benzyl cyanide (Compound 1; 5 mL; 0.043 mol) was dissolved in 50
mL methanol in a pressure bottle and 2 equivalents of sodium methoxide (0.086 mol) were
slowly added. After 10 cycles of nitrogen/vacuum degassing, the solution was exposed to 40 psi
NO for 24 h with stirring at room temperature. During this time, copious amounts of a cream
colored precipitate formed. After removing the excess nitric oxide gas, the precipitate was
filtered, dissolved in a minimum of water and immediately precipitated with an excess of
methanol. The resulting snow white material was the bis-diazeniumdiolated imidate, compound
−
1
−1
1
2
: 35% yield, umax=264 nm, m=14.0 mM cm (0.1 M NaOH); chars above 250°C; H NMR
(
300 MHz, D O) 3.8 ppm (s, 3H), 7.2–7.6 ppm (m, 5H). Anal. calcd for C H N O Na ·2H O:
2
9
9
5
5
2
2
C, 30.95; H, 3.75; N, 20.05. Found: C, 30.65; H, 3.85; N, 19.79. There is no nitrile absorption
−
1
in the infrared spectrum but rather a strong absorption at 1665 cm corresponding to the
1
0
CꢀN(H) stretch of the imidate.
Although stable in 0.01 M NaOH solution, compound 2 decomposes vigorously in acidic
media to produce NO and N O. The amount of N O generated as detected by gas chromato-
2
2
graphy was independent of pH. Whether in 1.0 M HCl or in pH 7.4 phosphate buffer, 1.5
molecules of N O were evolved for each molecule of diazeniumdiolated imidate that decom-
2
posed. The amount of NO produced, as detected by chemiluminescence and confirmed by the
1
1
Griess assay, varied slightly from a maximum of 0.5 molecules in 10% H SO to a minimum
2
4
of 0.3 molecules in pH 7.4 buffer per molecule of compound 2. The rate of decomposition of
compound 2, followed spectrophotometrically by the decay of the peak at 264 nm, shows linear
dependence upon pH in the range 4.0–7.4. The pseudo first-order rate constant at 37°C and pH
−
3
−1
7
.4, 0.1 M phosphate buffer, was found to be 3.35±0.27×10
s
(t =3.4 minutes).
1
/2
The organic product, isolated from the acidic decomposition of 2 as fine colorless needles, is
1
2
compound 3: mp=146–147°C (lit. 145–148°C with 142–143°C reported for the purified
1
3
1
(
E)-configured oxime ); H NMR (300 MHz, CDCl ) 3.81 ppm (s, 3H), 7.2–7.6 ppm (m, 5H).
3
Anal. calcd for C H NO : C, 60.33; H, 5.06; N, 7.82. Found: C, 60.20; H, 5.10; N, 7.80. In the
9
9
3
−
1
infrared spectrum, the carbonyl appears as a strong, sharp absorption at 1725 cm . While
formation of the ester is not surprising since imidates are known to undergo hydrolysis in dilute
acid, isolation and characterization of 3 represents an important confirmation of Traube’s
1
4
9
speculation that bis-diazeniumdiolates might release NO via decomposition to oximes.
It is worthwhile to note that the diazeniumdiolated imidate has been isolated from the
reaction under a variety of conditions. These include the use of sodium hydroxide as the base,
as well as using only 1 atmosphere of nitric oxide in the headspace. Interruption of the reaction

8423
in NaOH after only 2 h yielded a product with an infrared spectrum identical to that obtained
from the methoxide method. This was somewhat surprising since it is known that the conversion
of benzyl cyanide to the imidate proceeds only to the extent of 12% in 24 h at room
1
5
temperature. However, the presence of a strongly electron withdrawing group would be
expected to facilitate this conversion, and the diazeniumdiolate group is capable of activating by
1
6
electron withdrawal. Therefore, in the case presented here, we speculate that the bis-diazenium-
diolated nitrile is transiently formed but rapidly undergoes conversion to the imidate under these
reaction conditions (Fig. 2).
Figure 2. Intermediate in the proposed stepwise reaction pathway
An alert reader might then ask if acetonitrile would react with NO in the presence of base
since acetonitrile has been shown to be an excellent solvent for the synthesis of various
1
7
polyamine diazeniumdiolates. Apparently, the polyamines lack the basicity to abstract protons
from acetonitrile and in those reaction mixtures only the polyamines combine with NO in the
above syntheses. However, we have found that in the presence of the stronger base sodium
methoxide, acetonitrile does react with NO to produce a fine, light yellow precipitate. This
material not only produces gases upon acidification but also turns blue, suggesting the
formation of a C-nitroso compound. Further investigations into the reaction chemistry of NO
and nitriles are underway.
Traube reacted benzyl cyanide with nitric oxide in EtOH/EtONa solution under seemingly
similar conditions but obtained the nitrile instead of the imidate as the ultimate product. Our
results represent yet another manifestation of the relatively great solvent sensitivity noted in
1
7
previous diazeniumdiolation reactions. Acetonitrile has emerged as a popular solvent for these
reactions and this report also represents an important cautionary note concerning its use under
highly basic conditions. Finally, the demonstration of nitric oxide release from this type of
C-diazeniumdiolate may also be of significance in the realm of drug discovery since it serves to
8
further clarify the structural requirements for NO release from this type of compound.
Acknowledgements
We thank Mr. Michael Citro for the nitric oxide analysis, Mr. Stephen Fox for the nitrous
oxide analysis and Mr. John Klose for the NMR data. This project was funded in part by the
National Cancer Institute under Contract NO1-CO-56000.
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