A new synthesis of alkyl nitrites: The reaction of alkyl alcohols with nitric oxide in organic solvents

Article abstract of DOI:10.1021/jo982341p

In a nonaqueous solvent, alkyl nitrites can be easily achieved through the reaction of alkyl alcohols and gaseous NO. In the presence of air, the nitric oxide can in fact be oxidized to nitrous anhydride, which acts as a nitrosating agent. A quantitative

Full text of DOI:10.1021/jo982341p

8076
J . Org. Chem. 1999, 64, 8076-8079
A New Syn th esis of Alk yl Nitr ites: Th e Rea ction of Alk yl Alcoh ols
w ith Nitr ic Oxid e in Or ga n ic Solven ts
Loris Grossi* and Samantha Strazzari1
Dipartimento di Chimica Organica “A.Mangini”, Universita` di Bologna, Viale Risorgimento 4,
I-40136 Bologna, Italy
Received November 30, 1998
In a nonaqueous solvent, alkyl nitrites can be easily achieved through the reaction of alkyl alcohols
and gaseous NO. In the presence of air, the nitric oxide can in fact be oxidized to nitrous anhydride,
which acts as a nitrosating agent. A quantitative study conducted on cycloalkyl alcohols has shown
conversion yields to nitrites within the range 65-90%. This result has been validated by ESR
spectroscopy experiments on several alkyl alcohols/NO mixtures, which lead to the detection of
the same radical species detectable when a solution of the corresponding nitrites is photolyzed.
Sch em e 1
In tr od u ction
Several methods are available for the preparation of
alkyl nitrites, the most important of which is the reaction
between the corresponding alcohol and nitrous acid under
acidic conditions.2 We used this method for preparing
most of the cyclopentyl-type nitrites previously investi-
gated,3 whose photolysis leads to the detection of the
corresponding δ-valerolactam-1-oxyl-type radicals formed
via a ring-expansion process (Scheme 1), but the method
fails, for example, in the synthesis of the 3-nitrite-
tetrahydrofuran because of the rapid cleavage of the
parent alcohol.
Sch em e 2
An interesting alternative method of synthesis of
nitrites is the rapid nitrosyl exchange between an alcohol
and tert-butyl nitrite:4 the transfer from the t-BuONO
to the alcohol takes place very easily at room temperature
and leads to a complete nitrosyl exchange within a few
minutes. Following this method, the 3-nitrite-tetrahy-
drofuran was then successfully synthesized.
From our previous study5 conducted on the photo-
induced oxidation of alcohols by lanthanide ions (CAN),
we were able to hypothesize a further alternative mech-
anism for the formation of alkyl nitrites starting from
the parent alcohol. In particular, the NO itself, or one of
its oxidized products, could act directly as the nytrosating
agent as suggested for low-molecular-weight alcohols.6
In this paper we report on the preparation of cycloalkyl
nitrites starting from the corresponding cycloalkyl alcohol
and nitric oxide, in a solution of acetonitrile and in
aerobic conditions.
the possibility to detect by ESR spectroscopy radical
species that suggested, by their formation, the presence
of free NO/NOx in the medium. For instance, when
cyclohexanol was investigated, this led to the detection
of two isomer radicals:7 the 2-oxocyclohexane-1-iminoxyl
radical cis, (3a ) [a(N) ) 2.675 mT, a(2Hâ) ) 0.150 mT; g
) 2.0049], and trans, (3b) [a(N) ) 3.275 mT, a(2Hꢀ) )
0.257 mT, a(2Hδ) ) 0.150 mT; g ) 2.0049]. These radical
species are the same that were detectable8 when the
photolysis of an acetonitrile solution of cyclohexanone
with NO, in aerobic conditions, was performed directly
in the cavity of an ESR spectrometer, Scheme 2. In fact,
it is well-known9 that the cyclohexanone is the main
product of the photoinduced oxidation of 2 by CAN, and
it could also be anticipated that NOx would be produced
Resu lts a n d Discu ssion
The photooxidation of cyclopentanol (1) and cyclohex-
anol (2) by CAN (cerium ammonium nitrate)5 had shown
(7) In relative amounts 3a :3b ) 88:12.
(8) (a) Fox, W. M.; McRae, J . A.; Symons, M. C. R. J . Chem. Soc. A
1967, 1773. (b) Hudson, A. Austral. J . Chem. 1966, 19, 1807.
(9) Ho, T. L. In Organic Syntheses by Oxidation with Metal
Compounds; Mijs, W. J ., De J onge, C. R. H. I., Eds.; Plenum Press:
New York, 1986; Chapter 11, p 603.
* Phone: +39-051-2093627. Fax: +39-051-2093654. E-mail: grossi@
ms.fci.unibo.it.
(1) In partial fulfilment of the requirements for the Ph.D. degree in
Chemical Sciences, University of Bologna.
(2) Noyes, W. A. Organic Syntheses; J ohn Wiley: New York, 1943;
vol. III, pp 108-109.
(3) Grossi, L. Tetrahedron 1997, 53, 3205 and references therein.
(4) Doyle, M. P.; Terpstra, J . W.; Pickering, R. A.; Le Poire, D. M.
J . Org. Chem. 1983, 48, 3379.
(10) Martin, T. W.; Henshall, A.; Gross, R. C. J . Am. Chem. Soc.
1963, 85, 113.
(11) (a) Baciocchi, E.; Del Giacco, T.; Rol, C.; Sebastiani, G. V
Tetrahedron Lett. 1985, 26, 541. (b) Baciocchi, E.; Del Giacco, T.; Rol,
C.; Sebastiani, G. V Tetrahedron Lett. 1985, 26, 3353. (c) Baciocchi,
E.; Del Giacco, T.; Murgia, M. S.; Sebastiani, G. V Tetrahedron 1988,
44, 6651. (d) Del Giacco, T.; Baciocchi, E.; Steenken, S. J . Phys. Chem.
1993, 97, 5451.
(5) Grossi, L. Res. Chem. Intermed. 1996, 22, 315.
(6) Nelson, J . R. Eur. Pat. Appl. EP 301, 191 (CA 111: 80345q).
10.1021/jo982341p CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/08/1999

New Synthesis of Alkyl Nitrites
J . Org. Chem., Vol. 64, No. 22, 1999 8077
Ta ble 1. ESR Hyp er fin e Sp littin g Con sta n ts (a , m T)a of
Nitr oxid e Ra d ica ls Gen er a ted by P h otolysis of
Aceton itr ile Solu tion s of Alk yl Alcoh ols a n d NO
substrate
radical
a
gb
1
4
a(N) ) 0.760
a(2Hꢀ) ) 1.160c
a(2Hâ) ) 0.180
a(N) ) 1.500
a(4H) ) 1.000
2.0064
5
8
2.0054
2.0064
6
a(N) ) 0.650
a(Hꢀ) ) 0.710
a(2Hâ) ) 0.125
a(N) ) 1.450
a(2H) ) 0.912
a(H) ) 0.575
9d
2.0053
2.0064
7
10
a(N) ) 0.737
a(Hꢀ) ) 1.238
a(Hâ′) ) 0.212
a(Hâ) ) 0.150
a(N) ) 1.475
a(2H) ) 0.375
11d
2.0054
a
b
Typically at -30 °C. Values are ( 0.0002; the g factors have
been determined by comparison with the g factor of the DPPH
(2.0037 ( 0.0001). c The numbering starts from the carbonyl group
d
next to the nitrogen atom. At 0 °C.
Sch em e 3
F igu r e 1. ESR spectrum obtained in the photolysis of an
acetonitrile solution of 6 (10-3 M), into which gaseous NO has
been bubbled for 2 min, showing radical 8 at -30 °C.
conducted. For instance, the cyclopentanol/NO mixture
led to the detection of the hypothesized radicals 4 and
5,3,13 Scheme 3.
All of the analyzed alcohols led to the detection of the
forecasted radical species, i.e., those observed when the
corresponding nitrites3,12,14 are photolyzed. Unexpectedly,
the 1,4-anhydroerithritol (tetrahydro-3,4-furandiol) (6)
and the 2-methylcyclopentanol (7) enabled us to detect15
(see Table 1) the corresponding δ-valerolactam-1-oxyl-
type radicals, respectively 8 (see Figure 1) and 10 (see
Figure 2). Detection had failed when the pure nitrites
were investigated. Most likely, this alternative pathway
established more favorable conditions for the formation
of the 5-nitroso-pentanal-type (12) intermediate, precur-
sor of the δ-valerolactam-1-oxyl-type radical (see Scheme
4).
in this reaction because the primary photochemical
process which is believed10,11 to occur during the pho-
tolysis of CAN is the transfer of an electron from one
nitrate ligand to the central Ce(IV) atom to yield the
nitrate radical:
Hence, the interaction between an alkyl alcohol and
NO to form the corresponding alkyl nitrite seemed likely,
even though no direct evidence or information on its
nature has been reported. The UV spectroscopy could in
principle fulfill this request. Thus, the UV-visible ab-
sorption spectra of an acetonitrile solution of cyclopen-
tanol/NO and of pure cyclopentyl nitrite were compared.
The two solutions showed an identical spectrum, with
Ce(IV)NO3- 9hν8 Ce(III) + NO3
•
Even more remarkable was the result achieved when
cyclopentanol (1) was investigated: the δ-valerolactam-
1-oxyl radical (4) and the dialkyl nitroxide (5), i.e., the
same radical species resulting in the photolysis of the
cyclopentyl nitrite,3 Table 1, were detected (see Scheme
3). To account for these findings, the interaction between
unreacted alcohol and free NO/NOx yielding to the
corresponding nitrite had to be invoked. Thus, in prin-
ciple, the photolysis of a solution of an alkyl alcohol and
NO could lead to the detection, by ESR spectroscopy, of
the same radical species obtained from the corresponding
nitrite. At this point, experiments on acetonitrile solu-
tions of alcohols/NOx, whose behavior of the correspond-
ing nitrites toward photolysis is well known,3,12 were then
(12) Grossi, L. Tetrahedron 1997, 53, 6401.
(13) Suginome, H.; Mizuguchi, T.; Masamune, T. Tetrahedron Lett.
1971, 49, 4723.
(14) Kabasakalian, P.; Townley, E. R.; Yudis, M. D. J . Am. Chem.
Soc. 1962, 84, 2718.
(15) Besides radicals 8 and 10, it was possible to identify, at higher
temperature (0 °C) and higher flow rates (0.8 mL/min) the nitroxides
9
and 11, respectively, deriving from the competitive â-scission
processes.

8078 J . Org. Chem., Vol. 64, No. 22, 1999
Grossi and Strazzari
Ta ble 2. P r od u ct Distr ibu tion fr om Rea ction s of
Ga seou s NO a n d Sever a l Cycloa lk yl Alcoh ols in th e
P r esen ce of Oxygen in CH3CN a t 0 °C
recovered
substrate
nitrite (%)a
alcohol (%)a
1
2
89.1
82.2
87.6
64.3
10.9
17.8
12.4
35.7
13
14b
a
Values calculated by GC-MS analysis using an internal
b
standard. If the cyclooctyl nitrite is not recovered rapidly from
the solution, in the presence of an excess of NO the yield in the
product becomes lower and correspondingly the formation of a
byproduct, the 4-nitrosocyclooctanol, is observed as a result of the
occurrence of a 1,5-H shift process.
oxygen the nitric oxide is readily oxidized to NO2 and
then converted to N2O3 (eqs 1 and 2),6,17,18 which is
2 NO + O2 f 2 NO2
(1)
claimed to be an active nitrosating species18,19 even in
organic solvent solutions.20,21
NO2 + NO h N2O3
(2)
F igu r e 2. ESR spectrum obtained in the photolysis of an
acetonitrile solution of 7 (10-3 M), into which gaseous NO has
been bubbled for 2 min, showing radical 10 at -30 °C.
In particular, at 0 °C in the presence of air and with an
excess of NO, the equilibrium in reaction 2 is shifted6
toward the formation of N2O3, as confirmed by the
appearance of a pale blue color due to the solvation of
the N2O3.17 To discriminate between NO and N2O3 as the
actual nitrosating agent, two experiments, one with and
one without the presence of air, were performed. The
experiment conducted in anaerobic condition showed the
formation of only traces of cyclopentyl nitrite, thus
suggesting N2O3 as the real active species in the nitro-
sating process.18
Sch em e 4
Con clu sion s
Cycloalkyl alcohols combine with oxides of nitrogen to
form the corresponding nitrites. NO does not react
directly with alcohols, but must undergo oxidation to form
N2O3, a likely candidate as nitrosating species19-21 in this
reaction sequence:6,18
absorption bands in the region between 320 and 410 nm
(see the Experimental Section), i.e., those characteristic
of the cyclopentyl nitrite.16
2 NO + O2 f 2 NO2
NO + NO2 h N2O3
Although these results support the formation of the
nitrite, they do not give any information about the yield
of the reaction. In fact, because ESR spectroscopy is a
very sensitive technique of investigation, detecting ca.
10-4/10-5 M, the yield could be very low, and thus the
process may be not suitable for synthetic purposes.
A quantitative product analysis of the reactions be-
tween 1, 2, cycloheptanol (13), and cyclooctanol (14) and
NO in acetonitrile was then conducted (see the Experi-
mental Section). The yield of conversion into the corre-
sponding nitrites was, in each case, very high, which
validated this new method of synthesis of alkyl nitrites
(see Table 2).
ROH + N2O3 f RONO + HNO2
This method of synthesis seems to be very promising for
preparing directly, in organic solvent, alkyl nitrites in
very good yields, thus avoiding many restrictions caused
by the low solubility of organic compounds in aqueous
medium, as well as damage caused by the acidic medium.
Even more interesting seems the possibility, shown by
preliminary results obtained by ESR experiments, to
consider this procedure a very promising method for
converting polyalcohols, such as ribose or glucose, or
other substrates of biological interest, such as testoster-
one, into the corresponding nitrites.
The reaction mechanism, however, was still completely
unknown. The real nitrosating agent could be either NO
or a product of its oxidation. In fact, in the presence of
(16) Calvert, J . G.; Pitts, J . N., J r. In Photochemistry; J ohn Wiley
and Sons: New York, 1966; p 450.
(17) Greenwood, N. N.; Earnshaw, A. In Chemistry of the Elements;
Pergamon Press: Oxford, 1990; Chapter 11, p 508.
(18) Upchurch, G. R.; Welch, G. N.; Loscalzo, J . Adv. Pharmacol.
1995, 34, 343 and references therein.
(19) Crow, J . P.; Beckman, J . S. Adv. Pharmacol. (San Diego) 1995,
6, 17.
(20) William, D. L. H. Adv. Phys. Org. Chem. 1983, 19, 381.
(21) Pryor, W. A.; Castle, L.; Church, D. F. J . Am. Chem. Soc. 1985,
107, 211.

New Synthesis of Alkyl Nitrites
J . Org. Chem., Vol. 64, No. 22, 1999 8079
Cycloh ep tyl n itr ite: bp 74 °C at 23 mbar; 1H NMR
(CDCl3, 200 MHz) δ 1.42-1.93 (10H, m), 1.92-2.17 (2H, m),
5.54 (1H, m, CH); 13C NMR (CDCl3, 50.3 MHz) δ 23.6 (CH2),
29.1 (CH2), 35.1 (CH2), 81.4 (CH). Anal. Calcd for C7H13NO2:
C, 58.72; H, 9.15; N, 9.78. Found: C, 58.65; H, 9.22; N, 9.70.
Cyclooctyl n itr ite: bp 86-87 °C at 23 mbar; 1H NMR
(CDCl3, 200 MHz) δ 1.43-1.80 (10H, m), 1.77-2.04 (4H, m),
5.51 (1H, m, CH); 13C NMR (CDCl3, 50.3 MHz) δ 23.6 (CH2),
26.0 (CH2), 27.7 (CH2), 32.6 (CH2), 81.2 (CH). Anal. Calcd for
C8H15NO2: C, 61.12; H, 9.62; N, 8.91. Found: C, 61.15; H, 9.56;
N, 8.84.
2-Meth ylcyclop en tyl n itr ite: 1.53 g, 79.3%, bp 118-120
°C; 1H NMR (CDCl3, 200 MHz) δ 1.06 (3H, d, CH3), 1.19-1.42
(2H, m), 1.67-1.82 (2H, m), 1.87-2.36 (3H, m), 5.29 (1H, m,
CH); 13C NMR (CDCl3, 50.3 MHz) δ 18.8 (CH3), 23.3 (CH2),
32.1 (CH2), 32.8 (CH2), 40.6 (CH), 88.2 (CH). Anal. Calcd for
C6H11NO2: C, 55.80; H, 8.58; N, 10.84. Found: C, 55.76; H,
8.63; N, 10.80.
4-Hyd r oxytetr a h yd r o-3-fu r a n yl n itr ite: 1.91 g, 95.6%;
1H NMR (CDCl3, 200 MHz) δ 3.24 (1H, bs, OH), 3.73 (2H, m),
3.92 (2H, m), 4.29 (1H, bs, CH-OH), 6.14 (1H, bs, CH-ONO);
13C NMR (CDCl3, 50.3 MHz) δ 71.9 (2CH2), 72.4 (CH-OH),
73.5 (CH-ONO). Anal. Calcd for C4H7NO4: C, 36.09; H, 5.30;
N, 10.52. Found: C, 36.04; H, 5.36; N, 10.49.
GC-MS Stu d ies. Quantitative GC-MS analyses were
performed using as internal standards 1,4-dioxane for the
cyclohexanol and n-butyl ether for the other alcohols, with a
gas chromatograph equipped with a methyl silicone plus 5%
phenyl silicone capillary column and fid integration. All
compounds were identified by comparison of their retention
times with those of authentic samples and by their mass
spectra.
UV-Visible Exp er im en ts. The UV-vis absorption spec-
trum of an acetonitrile solution of the pure cyclopentyl nitrite
was recorded in the range between 300 and 440 nm and
compared to that obtained from an acetonitrile solution of
cyclopentanol into which gaseous NO had been bubbled for 1
h at 0 °C. The two solutions showed identical spectra with clear
absorption bands at λmax ) 338.1, 349.0, 360.3, and 373.3 nm.
ESR Exp er im en ts. Acetonitrile solutions of the alkyl
alcohol (10-3 M), in which pure gaseous NO was bubbled for
1-2 min, were prepared.26 The solutions were then continu-
ously flowed by a syringe pump (at flow rates in the range
0.1-0.6 mL/min) through a flat cell arrangement (0.3 mm
optical path length) and directly photolyzed in the cavity of a
Varian E-104 ESR spectrometer equipped with a variable
temperature control system. The irradiation was performed
with a 500 W high-pressure mercury lamp. The acetonitrile
was deoxygenated before being used, by purging with N2 gas
for 50-60 min.
Nitrous anhydride, produced from the reaction of NO
with molecular oxygen, is likely to be a potent nitrosating
agent in vivo at physiological pH.22,23 In fact, N2O3 may
damage DNA directly through nitrosation of primary
amines on DNA bases or indirectly via nitrosation of
various secondary amines to form N-nitrosamines, which
can then be metabolized to strongly alkylating electro-
philes capable of reacting with DNA.22,23 N2O3 may also
react with the sulfhydryl groups of various proteins.18,23,24
On the basis of our findings, it can be suggested that this
nitrosating agent could also be capable of damaging DNA
through direct interaction with the hydroxyl functions
of the sugar framework.
Exp er im en ta l Section
Ma ter ia ls. All alcohols were commercial products and used
as received unless the purity was less than 98%, in which case
they were distilled. The alkyl nitrites were prepared through
the standard procedure2 or by bubbling of gaseous NO in the
solution of the corresponding alcohols.
R ea ct ion of Cycloa lk yl Alcoh ols w it h Ga seou s NO.
Approximately 0.015 mol of the appropriate cycloalkyl alcohol
was dissolved in 20 mL of CH3CN. The solution was then kept
at 0 °C, and gaseous NO was bubbled gently for 1 h in the
presence of a stream of air. Once quantitative GC-MS
analyses were performed on the solutions, the solvent was
removed under reduced pressure, and the nitrites were
obtained by distillation under vacuum. All products gave
analytical and spectral data in agreement with literature
values and with the structural assignment.3,12,25
Cyclop en tyl n itr ite: bp 102-103 °C; 1H NMR (CDCl3, 200
MHz) δ 1.54-1.91 (6H, m), 1.87-2.22 (2H, m), 5.78 (1H, m,
CH); 13C NMR (CDCl3, 50.3 MHz) δ 24.0 (CH2), 33.1 (CH2),
81.9 (CH). Anal. Calcd for C5H9NO2: C, 52.16; H, 7.88; N,
12.17. Found: C, 52.09; H, 7.93; N, 12.11.
Cycloh exyl n itr ite: bp 40 °C at 23 mbar; 1H NMR (CDCl3,
200 MHz) δ 1.14-1.73 (6H, m), 1.68-1.88 (2H, m), 1.86-2.08
(2H, m), 5.35, (1H, m, CH); 13C NMR (CDCl3, 50.3 MHz) δ 24.7
(CH2), 26.0 (CH2), 33.1 (CH2), 79.0 (CH). Anal. Calcd for C6H11
-
NO2: C, 55.80; H, 8.58; N, 10.84. Found: C, 55.84; H, 8.66; N,
10.75.
(22) Lewis, R. S.; Tannenbaum, S. R.; Deen, W. M. J . Am. Chem.
Soc. 1995, 117, 3933.
(23) Pfeiffer, S.; Mayer, B.; Hemmens, B. Angew. Chem., Int. Ed.
1999, 38, 1714.
(24) Stamler, J . S.; Simon, D. I.; Osborne, J . A.; Mullins, M. E.;
J araki, D.; Michel, T.; Singel, D. J .; Loscalzo, J . Proc. Natl. Acad. Sci.
U.S.A. 1992, 89, 444.
(25) (a) Hunter, L.; Marriott, J . A. J . Chem. Soc. 1936, 285. (b) Gray,
P.; Rathbone, P.; Williams, A. J . Chem. Soc. 1961, 2620. (c) Kornblum,
N.; Teitelbam, C. J . Am. Chem. Soc. 1952, 74, 3076. (d) Kabasakalian,
P.; Townley, E. R. J . Org. Chem. 1962, 27, 2918.
(26) Because of the high sensitivity of the ESR spectroscopy, the
samples were prepared by bubbling NO into an acetonitrile solution
of the appropriate alcohol for only a short lapse of time. In these
conditions, a small amount of the nitrite is formed, which is enough
to allow the detection of the related radical species.
Ack n ow led gm en t. This work was carried out with
the financial support of Ministry of the University and
Scientific and Technological Research (MURST), Rome.
J O982341P