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Improved chemoselective, ecofriendly conditions for the conversion of
primary alkyl halides into nitroalkanes under PEG400
Roberto Ballini,* Luciano Barboni and Alessandro Palmieri
Published on 11 August 2008. Downloaded by University of Prince Edward Island on 29/10/2014 15:24:44.
Received 8th April 2008, Accepted 18th June 2008
First published as an Advance Article on the web 11th August 2008
DOI: 10.1039/b805985c
Treatment of primary alkyl bromides or iodides with 1.5–3 equivalents of sodium nitrite, at room
temperature, in PEG400 as solvent, allows the chemoselective formation of primary nitroalkanes
in satisfactory to good yields, under ecofriendly reaction conditions.
It is widely acknowledged that there is a growing need for more
environmentally acceptable processes in the chemical industry.
This trend towards what has become known as “sustainable
technology” necessitates a paradigm shift from traditional
concepts of processes efficiency, that focus largely on chemical
yield, to one that assigns economic value to eliminating waste
at source and avoiding the use of toxic and/or hazardous
substances.
In this context, an important aspect which is receiving
increasing attention is the use of alternative reaction media that
circumvent the problems associated with many of the traditional
volatile organic solvents (VOCs). It has been estimated that ca.
85% of the total mass of chemicals involved in pharmaceutical
manufacture comprises solvents,1 and from the green chemistry
point of view there are several issues which influence the
choice of solvent. It should be relatively nontoxic and relatively
nonhazardous, not inflammable (such as volatile solvents, e.g.
pentane or diethyl ether) or corrosive.
A number of companies have published solvent selection
guides,2,3 and more recently other authors4,5 published a detailed
and comprehensive approach to the environmental selection of
solvents.
Removal of residual solvent from products is usually achieved
by evaporation or distillation and most popular solvents are,
therefore, highly volatile. Spillage and evaporation inevitably
leads to atmospheric pollution. Moreover, worker exposure to
volatile organic compounds is a serious health issue.6 Another
class of solvents which presents environmental problems com-
prises the polar aprotic solvents, such as dimethylformamide
and dimethyl sulfoxide, that are the solvent of choice for many
nucleophilic substitutions. They have high boiling points and not
easily removed by distillation, in addition, they are also water-
miscible which enables their separation by washing with water.
Unfortunately, this inevitably leads to contaminated aqueous
effluent.
Nitroalkanes are one of the main classes of compounds in or-
ganic chemistry due to their high chemical versatility7 and their
importance as key building blocks for the synthesis of a variety
of fine chemicals.8 Thus, the availability of nitroalkanes appears
Dipartimento di Scienze Chimiche dell’Università di Camerino, Via S.
Agostino 1, 62032, Camerino, Italy. E-mail: roberto.ballini@unicam.it;
Fax: +39 0737 402297; Tel: +39 0737 402270
1004 | Green Chem., 2008, 10, 1004–1006
crucial and the development of new ecofriendly procedures for
their preparation remains an important goal.
Nitroalkanes can be obtained from many sources, however,
the conversion of alklyl halides into nitro compounds, by
using metal nitrite, is one of the most used strategies.7,9 For
these procedures silver nitrite in diethyl ether, potassium nitrite
or sodium nitrite in N,N-dimethylformamide (DMF) or in
dimethyl sulfoxide (DMSO) have been proposed.9,10
In order to improve the ecofriendly reaction conditions for
the above method, recently we reported11 the first conversion
of primary alkyl halides into nitroalkanes under aqueous
medium. The method has been realized by reaction of primary
alkyl halides with 4 equivalents of silver nitrite; however, the
drawbacks of this procedure consist of the need of a large
excess of expensive reagents, such as silver nitrite, and the
formation, as side products, of the corresponding alcohol due
to the competitive nucleophilic action of water vs. nitrite.
With the aim of improving the ecosustainability of this
fundamental method for the preparation of nitroalkanes, we
wish here to propose the conversion of alklyl halides into
nitro compounds by using sodium nitrite in polyethylene glycol
(PEG400) as green reaction media.
In fact, recently PEG has attracted great interest as novel
solvent for catalytic processes since it is relatively inexpensive,
essentially nontoxic, readily available and biodegradable mate-
rial (PEG is approved for use in beverages).5,12
Thus, treatment of primary alkyl halides 1 with 1.5–3
equivalents of sodium nitrite, at room temperature, in PEG400
as solvent, allows the chemoselective formation of primary
nitroalkanes in satisfactory to good yields (Scheme 1).
Scheme 1 Conversion of primary alkyl halides into nitroalkanes.
In order to verify the potential of the procedure, we tested
a variety of primary alkyl halides and only alkyl iodides
and bromides were converted into the corresponding nitro
derivatives, while chloro derivatives were inactive. However,
this result can be considered as a chemoselective procedure
for the survival of the chloro atom during the nitration of
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Table 1 Nitroalkanes 2 prepared and reaction conditions
R X
a n-C7 H15 I 1.5
b n-C11 H23 I 1.5
c n-C10 H21 Br
d CH2 =CH(CH2 )8 Br
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e HO(CH2 )8 Br
f Ph(CH2 )2 Br
f Ph(CH2 )2 I 1.5
g AcO(CH2 )3 I 1.5
h Cl(CH2 )3 I 1.5
i Br
j CH2 =CHCH2 OCO(CH2 )7 Br
a
Yield of pure isolated product. b With this nitroalkane, a better yield is obtained by extraction with Et2 O due to its low solubility in cyclohexane.
iodides or bromides (1h to 2h, Table 1). Moreover, due to the
mildness of the procedure other functionalities such as esters,
hydroxyl, carbon–carbon double bonds, ethers, aromatics and
amides can be preserved (Table 1). It should be noted that only
traces of alkylnitrite could be observed (2–6%, detected as the
corresponding alcohol13 by GC-MS).
Although the procedure works well with both alkyl iodides
and bromides, the latter need a larger amount of sodium nitrite
(3 equiv. vs 1.5) and a longer reaction time.
It is important to note that PEG400, after the extraction with
cyclohexane, can be recycled at least twice for the same reaction
before its disposal as waste. In addition, cyclohexane can be
recovered by distillation and reused for further extractions.
Moreover, the procedure offers the opportunity to convert,
in a one-pot process, a,x-diodo structures, such as 3 into
the corresponding 1,8-dinitrooctane 4 in 54% overall yield
(Scheme 2).
Scheme 2 Conversion of 1,8-diiodooctane into 1,8-dinitrooctane.
The conversion of secondary halo derivatives fails by our
method, and this result can be applied for the chemoselective
nitration of primary iodides or bromides in the presence of a
secondary one. In fact treatment of 1,5-dibromohexane 5 with
four equivalents of sodium nitrite, in PEG400, produces 1-nitro-
4-bromohexane 6 as the exclusive nitroderivative (42% yield,
Scheme 3).
Scheme 3 Chemoselective nitration of 1,5-dibromohexane.
Thus, the reported method represents an improved, chemos-
elective, ecosustainable procedure for the synthesis of primary
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equivalents of NaNO2 Reaction times/h Yield (%)a of 2
2.5 70
4 76
3 24 54
3 20 72
3 5 73b
1.5 4.5 71
1.5 74
2 68
3 70
3 22 63
3 20 71
nitroalkanes from the corresponding halo derivatives since it
can be realized avoiding both volatile and toxic organic solvents
during the process. In addition, PEG400 can be reused twice for
the same reaction (with comparable yields) before its disposal as
waste. In fact, the conversion of 1a into 2a, gives the following
results: (i) 1st recycle 70%, 2nd recycle 67%, 3rd recycle 41%.
Experimental
Typical procedure
A mixture of PEG400 (2 mL) and NaNO2 (1.5–3 mmol, Table 1)
was stirred for 3 h at room temperature, then the halide 1
(1 mmol) was added and the reaction was stirred for the
appropriate time (Table 1). Finally, the solution was treated
with 2 mL of cyclohexane and stirred for additional 5 min, then
the stirring was stopped and the upper layer was transferred
into another flask; the same procedure was repeated another
3 times (4 × 2 mL). Most of the cyclohexane is, then, removed
by distillation (and reused), while the residue is directly charged
on a chromatographic column (EtOAc/cyclohexane) giving the
pure product 2.†
PEG400, after the extraction with cyclohexane, can be reused
at least twice for the same reaction, simply by adding one more
mmol of NaNO2 .
9-Nitrononan-1-ol (2e). Waxy white solid, IR (nujol) m: 1376,
1560, 3401 cm−1 . 1 H NMR (CDCl3 , 400 MHz) d (ppm) 1.20–
1.66 (m, 13H), 1.89–2.10 (m, 2H), 3.63 (t, 2H, J = 6.6 Hz), 4.38
(t, 2H, J = 7.1 Hz). 13 C NMR (CDCl3 , 100 MHz) d (ppm) 25.9,
26.4, 27.6, 29.0, 29.4, 32.9, 63.2, 75.9. GC-MS (m/z): 124, 95,
81, 69, 55 (100), 41, 30. Elemental analysis for C9 H19 NO3 Calcd:
C, 57.12; H, 10.12, N, 7.40. Found: C, 57.69; H, 10.88; N, 7.19.
5-Bromo-1-nitrohexane (6). Oil, IR (neat) m: 1378, 1552, 2926
cm−1 . 1 H NMR (CDCl3 , 400 MHz) d (ppm) 1.46–1.56 (m, 1H),
1.57–1.68 (m, 1H), 1.70 (d, 3H, J = 6.9 Hz), 1.77–1.88 (m, 2H),
† The syntheses of the nitrocompounds 2, except for 2e and 6, have
already been reported in the literature and all our spectral data are in
agreement with those published.11,14–17
Green Chem., 2008, 10, 1004–1006 | 1005

1.94–2.11 (m, 2H), 4.05–4.16 (m, 1H), 4.40 (t, 2H, J = 7.0 Hz).
13
C NMR (CDCl3 , 100 MHz) d (ppm) 24.7, 26.6, 26.8, 40.3, 50.8,
75.5. GC-MS (m/z): 130, 83, 55 (100), 41, 29. Elemental analysis
for C6 H12 BrNO2 Calcd: C, 34.31; H, 5.76, N, 6.67. Found: C,
34.75; H, 5.98; N, 6.38.
Published on 11 August 2008. Downloaded by University of Prince Edward Island on 29/10/2014 15:24:44.
Acknowledgements
Financial support from the University of Camerino and MUR-
Italy (National Project “Sintesi organiche ecosostenibili mediate
da nuovi sistemi catalitici”) is gratefully acknowledged.
Notes and references
1 D. J. C. Constable, A. D. Curzons and V. L. Cunningham, Green
Chem., 2002, 4, 521.
2 A. D. Curzons, D. C. Constable and V. L. Cunningham, Clean Prod.
Process., 1999, 1, 82.
3 C. Jimenez-Gonzales, A. D. Curzons, D. J. C. Constable and V. L.
Cunningham, Clean Technol. Environ. Pollut., 2005, 7, 42.
4 C. Capello, U. Fisher and K. Hungerbuhler, Green Chem., 2007, 9,
917.
5 R. A. Sheldon, Green Chem., 2005, 7, 267.
6 K. Alfonsi, J. Colberg, P. J. Dunn, T. Fevig, S. Jennings, T. A. Johnson,
H. P. Kleine, C. Knight, M. A. Nagy, D. A. Perry and M. Stefaniak,
Green Chem., 2008, 10, 31.
7 G. Rosini and R. Ballini, Synthesis, 1988, 833; R. Ballini, G. Bosica,
D. Fiorini, A. Palmieri and M. Petrini, Chem. Rev., 2005, 105, 933;
1006 | Green Chem., 2008, 10, 1004–1006
View Article Online
R. Ballini and M. Petrini, Tetrahedron, 2004, 60, 1017; R. Ballini,
G. Bosica, D. Fiorini and A. Palmieri, Tetrahedron, 2005, 61, 8971;
R. Ballini, L. Barboni, F. Fringuelli, A. Palmieri, F. Pizzo and L.
Vaccaro, Green Chem., 2007, 9, 823.
8 R. Ballini, in Studies in Natural Products Chemistry, ed. Atta-ur-
Rahman, Elsevier, Amsterdam, 1997, vol. 19, p. 117; R. Ballini, A.
Palmieri and P. Righi, Tetrahedron, 2007, 63, 12099.
9 N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH, New
York, 2001; D. Seebach, E. W. Colvin, F. Lehr and T. Weller, Chimia,
1979, 33, 1.
10 N. Kornblum, Org. React., 1962, 12, 101; H. Feuer and G. Leston,
Organic Synthesis, Wiley, New York, 1963; N. Kornblum, H. O.
Larson, R. K. Blackwood, D. D. Mooberry, E. P. Oliveto and G.
E. Graham, J. Am. Chem. Soc., 1956, 78, 1497; T. A. Ainscow,
M. R. Belmont, J. L. Henshall, R. M. Hooper and D. J. Simmons,
Tetrahedron Lett., 1987, 43, 115; J. K. Addo, P. Teesdale-Spittle and
J. O. Hoberg, Synthesis, 2005, 1923; C. J. Easton, L. Xia, M. J. Pitt,
A. Ferrante, A. Poulos and D. A. Rathjen, Synthesis, 2001, 451.
11 R. Ballini, L. Barboni and G. Giarlo, J. Org. Chem., 2004, 69, 6907.
12 J. Chen, S. K. Spear, J. G. Huddleston and R. D. Rogers, Green
Chem., 2005, 7, 64.
13 N. Kornblum, R. K. Blackwood and D. D. Mooberry, J. Am. Chem.
Soc., 1956, 78, 1501; M. P. Doyle, J. W. Terpstra, R. A. Pickering and
D. M. LePoire, J. Org. Chem., 1983, 48, 3379.
14 J. Mc Nulty, J. J. Nair, S. Cheekoori, V. Larichev, A. Capretta and
Al. J. Robertson, Chem.–Eur. J., 2006, 12, 9314.
15 V. Gil and A. J. MacLeod, Tetrahedron, 1980, 36, 779.
16 A. Goti, A. Brandi, G. Danza, A. Guarna, D. Donati and F. De
Sarlo, J. Chem. Soc., Perkin Trans. 1, 1989, 1253.
17 S. R. Woodcock, A. J. V. Marwitz, P. Bruno and B. P. Branchand,
Org. Lett., 2006, 8, 3931.
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