Aromatic nitration in liquid Ag0.51K0.42Na 0.07NO3

Article abstract of DOI:10.1021/jo800839f

(Figure Presented) Aromatic molecules have a strong affinity for silver(I) and dissolve to a limited extent in Ag_0.51K_0.42Na _0.07NO₃, a low-melting eutectic mixture of silver, potassium, and sodium nitrates. Aromatic nitration in this inorganic ionic liquid leads to products which arise from nonelectrophilic substitution pathways.

Full text of DOI:10.1021/jo800839f

Aromatic Nitration in Liquid Ag0.51K0.42Na0.07NO3
Mark Mascal,*,† Lunxiang Yin,† Ross Edwards,‡ and Michael Jarosh†
Department of Chemistry, UniVersity of California DaVis, 1 Shields AVenue, DaVis, California 95616, and
Department of Chemistry, UniVersity of Nottingham, Nottingham NG7 2RD, U.K.
mascal@chem.ucdaVis.edu
ReceiVed April 16, 2008
Aromatic molecules have a strong affinity for silver(I) and dissolve to a limited extent in
Ag0.51K0.42Na0.07NO3, a low-melting eutectic mixture of silver, potassium, and sodium nitrates. Aromatic
nitration in this inorganic ionic liquid leads to products which arise from nonelectrophilic substitution
pathways.
Introduction
Recognizing the affinity of AgI for organic π electron donors,
we wondered how molecules with a substantial π bond content
might interact with an inorganic ionic liquid containing silver.
The advantages of such a medium might be similar to those of
organic ionic liquids, i.e., promotion of reactivity, involatility,
nonflammability, phase separation, and recyclability. Common
silver salts are less expensive than typical ethylmethylimida-
zolium-based ionic liquids, relatively nontoxic to humans,3 and
known to participate in low-melting (80-120 °C) eutectics.4
They may also be considered “green” in the sense that they are
not petroleum-derived.
A literature search for applications of inorganic ionic liquids
in organic reactions turns up a trail of scattered reports from
the 1960s onward. In a 1965 review, molten salts are described
being used as catalysts in the chlorination, nitration, and cracking
of hydrocarbons at high temperatures.5 Later reviews discuss
inorganic eutectics and early uses of organic ionic liquids side
by side.6 The types of reactions promoted by fused salts are
Organic reactions have been carried out in diverse phases.
Thus, chemistry may occur at the solid-solid interface by
grinding reactants together, the solid-liquid and solid-gas
interfaces by allowing mobile phases to permeate solids, at the
liquid-liquid and liquid-gas (e.g., aerosol) interfaces, in the
vapor phase, neat liquids, crystals (topochemically), structured
micromedia (e.g., gels, liquid crystals, micelles, emulsions,
monolayers), and in solution with water, supercritical solvents,
fluorous phases, and, of course, organic solvents. In recent years,
ionic liquids have emerged as yet another medium for perform-
ing organic reactions.1 Based mainly on imidazolium and
pyridinium cations with noncoordinating counterions, these low-
melting salts have become a popular choice for a number of
applications due to their solvent characteristics across a range
of polarities, low volatility/flammability, enhancement of various
kinds of reactivity, and phase behavior which allows for efficient
partitioning. They are, however, essentially organic solvents,
and their often-cited green nature has been called into question
due to their common derivation from petroleum and toxicity
concerns.2
(2) (a) Zhao, D.; Liao, Y.; Zhang, Z. Clean: Soil, Air, Water 2007, 35, 42.
(b) Pretti, C.; Chiappe, C.; Pieraccini, D.; Gregori, M.; Abramo, F.; Monni, G.;
Intorre, L. Green Chem. 2006, 8, 238.
(3) (a) Lansdown, A. B. G. Crit. ReV. Toxicol. 2007, 37, 237. (b) Lansdown,
A. B. Curr. Probl. Dermatol. 2006, 33, 17.
† University of California Davis.
‡ University of Nottingham.
(4) (a) Janz, G. J. Molten Salts Handbook; Academic Press: New York, 1967.
(b) Grimes, W. R.; Cuneo, D. R. In Reactor Handbook; Tipton, C. R., Jr., Ed.;
Wiley Interscience: New York, 1960; Vol. 1. (c) Janz, G. J.; Allen, C. B.;
Downey, J. R., Jr.; Tomkins, R. P. T. Eutectic Data: Safety Hazards, Corrosion,
Melting Points, Compositions and Biography; Molten Salts Data Center,
Renassler Polytechnic University: Troy, NY, 1976.
(1) Reviews: (a) Heintz, A.; Wertz, C. Pure Appl. Chem. 2006, 78, 1587.
(b) Jain, N.; Kumar, A.; Chauhan, S.; Chauhan, S. M. S. Tetrahedron 2005, 61,
1015. (c) Forsyth, S. A.; Pringle, J. M.; Mac Farlane, D. R. Aust. J. Chem. 2004,
57, 113. (d) Seddon, K. R. Nat. Mater. 2003, 2, 363. (e) Earle, M. J.; Seddon,
K. R. Pure Appl. Chem. 2000, 72, 1391. (f) Welton, T. Chem. ReV. 1999, 99,
2071.
(5) Sundermeyer, W. Angew. Chem., Int. Ed. Engl. 1965, 4, 222.
6148 J. Org. Chem. 2008, 73, 6148–6151
10.1021/jo800839f CCC: $40.75 2008 American Chemical Society
Published on Web 07/11/2008

Aromatic Nitration in Liquid Ag0.51K0.42Na0.07NO3
SCHEME 1
TABLE 1. Molar Equivalents of K3Fe(CN)6, Reaction Time, and
Isolated Percent Yields of Recovered 1, 2 (2a:2b Ratio), and 3
(3a:3b:3c:3d:3e Ratio) in the Nitration of 2 mmol of Naphthalene
with 10 g of the Ag0.51K0.42Na0.07NO3 Eutectica
remarkably varied and include hydrocarbon C-H bond activa-
tion, various aromatic substitution reactions, aryl couplings,
alkali fusion, fragmentations, and rearrangements, among others.
In the bulk of this work, the inorganic liquid appears to be acting
as a heterogeneous catalyst, since the reaction temperature is
often above the boiling point of the organic compound and/or
solubility in the medium would be expected to be very limited.
Subsequent research in this area seems to have declined in the
tide of interest in the aforementioned organic ionic liquids.
Of the types of reactivity mentioned above, we were
particularly interested in nitration. The nitration of aromatic
molecules is an industrial process which is central to the
preparation of numerous synthetic intermediates and end
products. Of all reactions done in the practice of organic
chemistry, nitration remains one of the most intensively studied.7
With the above background material in mind, the question
became this: Could we exploit the affinity of silver(I) for
aromatic molecules to develop an efficient, green, acid-free
method for aromatic nitration in an inorganic medium?
entry K3Fe(CN)6 (equiv) time (h)
1
2
3
1
2
3
4
5
6
0.25
0.5
1.0
2.0
0.5
0.5
1
1
1
1
0.5
2
27 37 (6:1) 14 (30:4:15:15:35)
17 57 (6:1) 13 (33:8:11:11:36)
16 54 (5:1) 15 (24:12:10:39:15)
15 50 (5:1) 16 (23:13:10:42:13)
26 47 (6:1) 17 (33:9:18:16:24)
11 43 (5:1) 15 (35:5:15:20:25)
a The reaction temperature was 160 °C in each case. Entries in bold
denote key variables.
N2O5,9–11 and potassium ferricyanide was found to dissolve in
the liquid eutectic to give an orange solution. When naphthalene
was added, nitration was observed (Scheme 1). As can be seen
in Table 1, the yield of nitration products reaches a maximum
in the presence of 0.5 equiv of FeIII and a reaction time of 1 h
(entry 2). Longer reaction times lead to mechanical losses due
to the tendency of naphthalene and its simple derivatives to
sublime.
Results and Discussion
The reaction gives the two mononitro isomers in an R/ꢀ ratio
lower than would be expected under conditions where NO2+ is
the nitrating agent (i.e., >10:1).12,13 The most striking feature,
however, of this reaction is the formation of the 1,3- and 2,3-
dinitronaphthalenes 3a and 3e, which is unprecedented in
nitrations carried out under ionic conditions. There are two
literature accounts of the observation of the 1,3- and 2,3-isomers,
both of which employed nitrogen dioxide as the nitrating agent,
either with14 or without15 irradiation. Iron(III) is capable of
decomposing nitrate into NO2 and Fe2O3,16 and the above
reaction is accompanied by traces of a red-brown gas and the
gradual accumulation of a brown solid, so the participation of
NO2 in some form is evident.17 The nature of the ligands on
the iron was not crucial, since the reaction also worked with
FeCl3, although the yields were somewhat lower. While the de
facto nature of the nitrating agent in this reaction is not certain,
the participation of AgI is essential, since use of the K-Na-Li
The eutectic we chose for this study was a mixture of AgNO3,
KNO3, and NaNO3 in a 51:42:7 mol % ratio, respectively, which
is a free-flowing liquid above 116 °C. The aromatic substrate
was naphthalene, the boiling point of which (218 °C) would be
well above the fusion point of the eutectic. Mixtures of the
eutectic components and naphthalene formed two phases when
heated above the melting point. Interestingly, however, naph-
thalene was found to possess a solubility of 1.9 mg mL-1 in
this medium.8 The naphthalene could be quantitatively recovered
by dissolving the cooled mixture in water and extracting with
dichloromethane.
Turning to nitration, it was supposed that the disproportion-
ation of nitrate into nitronium and oxide ions would be promoted
by the addition of a Lewis acid. We were aware that iron(III)
catalyzed the nitration of arenes with either NO2-O2 or
(6) (a) Pagni, R. M. In AdVances in Molten Salt Chemistry; Mamantov, G.,
Manantov, C. B., Braunstein, J., Eds.; Elsevier: Amsterdam, 1987; Vol. 6, pp
211-346. (b) Gordon, J. E. In Techniques and Methods of Organic and
Organometallic Chemistry; Denny, D. B., Ed.; Marcel Dekker: New York, 1969;
Vol. 1, pp 51-188.
(9) Nose, M.; Suzuki, H.; Suzuki, H. J. Org. Chem. 2001, 66, 4356.
(10) Bak, R. R.; Smallridge, A. J. Tetrahedron Lett. 2001, 42, 6767.
(11) Suzuki, H.; Yonezawa, S.; Nonoyama, N.; Mori, T. J. Chem. Soc., Perkin
Trans. 1 1996, 2385.
(7) A Chemical Abstracts search of the of the term “nitration” produces over
40000 hits.
(12) Olah, G. A.; Fung, A. P.; Narang, S. C.; Olah, J. A. Proc. Natl. Acad.
Sci. U.S.A. 1981, 78, 3298.
(8) Solubilities were determined by vigorously stirring 500 mg of aromatic
compound and 10 g of the eutectic together in a test tube at 160 °C for 30 min
and then allowing the mixture to stand undisturbed for 10 min before cooling to
rt. The resulting hard pellet was divided approximately in two, and the top half
of which (including the solidified organic layer) was discarded. The remainder
was weighed and then dissolved in water and extracted with dichloromethane.
The solvent was dried (MgSO4) and evaporated and the mass of the aromatic
compound determined.
(13) Suzuki, H.; Mori, T. J. Chem. Soc., Perkin Trans. 2 1996, 677.
(14) Barlas, H.; Parlar, H.; Kotzias, D.; Korte, F. Chem. Zeit. 1982, 106,
293.
(15) Squadrito, G. L.; Fronczek, F. R.; Church, D. F.; Pryor, W. A. J. Org.
Chem. 1989, 54, 548.
(16) 4 Fe3+ + 12 NO3- f 2 Fe2O3 + 12 NO2 + 3 O2. See: Hill, W. D., Jr.
Inorg. Chim. Acta 1986, 121, L33.
J. Org. Chem. Vol. 73, No. 16, 2008 6149

Mascal et al.
TABLE 3. Molar Equivalents of K3Fe(CN)6 and Isolated % Yields
of Products for the Nitration of 2 mmol of Hydroquinone Dimethyl
Ether (4) with 10 g of the Ag0.51K0.42Na0.07NO3 Eutectic at 160 °Ca
SCHEME 2
entry
K3Fe(CN)6 (equiv)
5a
5b
5c
1
2
3
4
0
0
53
88
75
36
16
18
13
0
2
3
0
0
0
0.25
0.5
1.0
2.0
2.0
4.0
4.0
9
6
TABLE 2. Nitrate Eutectic, Additive, Temperature, Reaction
Time, and Isolated % Yields of Products in the Nitration of 2 mmol
of Hydroquinone Dimethyl Ether (4) with 10 g of Eutectic in the
Presence of 0.5 molar equiv of Additivea
5
24
29
32
35
19
28
44
42
6b
7
8b
entry nitrate eutectic
additive
T (°C) time (h) 5a 5b
a The reaction time was 1 h unless otherwise noted. b Reaction time
6 h.
1
2
3
4
5
6
7
8
K-Na-Li
Ag-Na-NH4
Ag-K-Na
Ag-K-Na
Ag-K-Na
Ag-K-Na
Ag-K-Na
Ag-K-Na
Ag-K-Na
Ag-K-Na
Ag-K-Na
Ag-K-Na
Ag-K-Na
K3Fe(CN)6
K3Fe(CN)6
K3Fe(CN)6
FeCl3
AlCl3
K2S2O7
160
160
160
160
160
160
160
120
140
180
160
160
160
1
1
1
1
1
1
1
1
1
1
0.25
0.5
2
0
77
88
64
58
25
12
75
86
87
82
86
87
0
2
3
0
0
0
0
3
3
2
2
2
3
additive of choice in early work in this area,20 gave low yields
of nitro products, and zinc chloride was even less effective.
Raising the temperature beyond 140 °C had no effect on yield.
Interestingly, the reaction was shown to be essentially complete
within 15 min.
ZnCl2
K3Fe(CN)6
K3Fe(CN)6
K3Fe(CN)6
K3Fe(CN)6
K3Fe(CN)6
K3Fe(CN)6
9
10
11
12
13
While negligible amounts of dinitration products were
observed when the molar ratio of additive to substrate was 1:2,
raising the amount of ferricyanide increased the degree of
nitration of 4. As shown in Table 3, the reaction could be
controlled to give >75% dinitration, as a mixture of 2,3- (5b)
and 2,5- (5c) dinitro products. As with naphthalene, the product
distribution in this reaction is also unusual. Dinitration of 4 with
aqueous HNO3 typically gives 5b to 5c ratios of about 8:1,
respectively,21 whereas we observe a less than 1:1 ratio.
a Entries in bold denote key variables.
nitrate eutectic (mp 120 °C) resulted in no product under
otherwise identical conditions. Interestingly, silver nitrate has
been previously used for the nitration of aromatic compounds,18
including naphthalene,12 but in acetonitrile solution and in the
presence of boron trifluoride. The products of such reactions
are similar to those observed in normal acid-catalyzed nitration.
Attempting the nitration of naphthalene with potassium ferri-
cyanide and silver nitrate in acetonitrile returned only unchanged
starting material, even after 6 h reflux. Grinding the components
of the reaction together or wet milling them as an aqueous paste
also gave no product.
Finally, we submitted related molecules to the silver eutectic
nitration conditions to probe the generality of the reaction. Thus,
1-methylnaphthalene (6), 1-methoxynaphthalene (8), 2-meth-
oxynaphthalene (11), and biphenyl (15) gave the respective nitro
products indicated in Scheme 3. The optimal parameters for
the mononitration of 4 were used in each case, and no attempt
was made to tune the reactivity to the individual substrates.
Phenol and imidazole conflagrated to ash under the same
conditions, and the method appears to be generally unsuitable
for highly oxidizable aromatics.
While the study of naphthalene provided useful insights into
the reactivity of the silver(I)-based medium, its high vapor
pressure did not enable us to follow the reaction to 100%
conversion.19 Further study of this chemistry took the form of
the nitration of hydroquinone dimethyl ether 4 (Scheme 2).
Compound 4, in contact with the liquid nitrate eutectic described
In conclusion, we have demonstrated that the silver-potas-
sium-sodium nitrate eutectic is an effective medium for
nitrating aromatic molecules. Naphthalene (1) and hydroquinone
dimethyl ether (4) are nitrated with unusual regioselectivities
indicative of free radical processes. In the case of 4, the reaction
can be controlled to give either mono- or predominantly
disubstitution products in high yields. We suggest here that any
number of aromatic systems may be amenable to this method
of nitration, giving access in some cases to substitution patterns
which are not normally available by acid-catalyzed nitration.
Beyond this, we have established in a more general sense that
the silver-potassium-sodium nitrate eutectic can act as a
solvent for molecules like 1 and 4, which possess solubilities
between ca. 1-2 g L-1 in this medium. This raises the question
as to whether other aspects of the chemistry of π-rich systems
might be probed in low-melting, silver(I)-containing inorganic
liquids, such as radical reactions, substitution, or aryl coupling,
and whether these will likewise demonstrate unusual reactivity.
above, showed no tendency to sublime from the reaction vessel.
8
Its solubility in the medium was determined to be 1.2 mg mL-1
,
which was somewhat lower than that of 1.
The results of the systematic evaluation of four variables
(eutectic composition, promoter, reaction temperature, and
reaction time) in the nitration of 4 are shown in Table 2. As
with naphthalene, eutectics containing no silver gave no
evidence of nitration. The promoter used in the nitration of
naphthalene, K3Fe(CN)6, proved also to work best here, with
FeCl3 and AlCl3 giving less satisfactory results. Pyrosulfate, the
(17) A reviewer brought up the question of whether the eutectic could be
regenerated after the reaction and reused. Since the reaction consumes NO3
-
and produces Fe2O3, titration of the aqueous phase (see workup procedure in
the Experimental Section) with nitric acid followed by drying could, in principle,
regenerate a reactive eutectic, although we have not yet attempted this.
(18) Olah, G. A.; Fung, A. P.; Narang, S. C.; Olah, J. A. J. Org. Chem.
1981, 46, 3533.
(20) Temple, R. B.; Fay, C.; Williamson, J. J. Chem. Soc., Chem. Commun
(19) It might be supposed this problem could simply be surmounted by
performing the reaction in a sealed vessel. However, doing so led on one occasion
to a detonation, possibly due to the buildup of higher concentrations of polynitro
species.
1967, 966.
(21) (a) Fisher, G. H.; Moreno, H. R.; Oatis, J. E., Jr.; Schultz, H. P. J. Med.
Chem. 1975, 18, 746. (b) Flader, C.; Liu, J.; Borch, R. F. J. Med. Chem. 2000,
43, 3157.
6150 J. Org. Chem. Vol. 73, No. 16, 2008

Aromatic Nitration in Liquid Ag0.51K0.42Na0.07NO3
SCHEME 3
(b) 1- and 2-nitronaphthalenes (by mass of the mixture and 1H NMR
integration); and (c) dinitronaphthalenes (by mass of the mixture
and 1H NMR integration). In all other cases, the individual products
themselves were isolated. The nitro compounds described in this
work were all identified by comparison with published NMR data.
Cautionary Note. Polynitroaromatics are high energy materials
and present an explosion hazard. Due care must be taken when
preparing and handling such compounds.
Experimental Section
General Procedure for Nitration of Aromatics. A flask was
charged with an intimate mixture of silver nitrate, potassium nitrate,
and sodium nitrate in a molar ratio of 51:42:7, respectively, and
placed under vacuum. The mixture was immersed in a heating bath
at 160 °C, resulting in the fusion of the components to a free-
flowing liquid. The vacuum was broken by backfilling with argon.
Potassium hexacyanoferrate (or other additive from Table 2) was
then added, and the mixture was vigorously stirred for 30 s, at which
point the aromatic was introduced. Stirring was continued for the
required time (see Tables 1–3), after which the reaction mixture
was removed from the heating bath. The resulting solid residue
was dissolved in water and extracted at least three times with
dichloromethane. The combined organic fractions were dried and
evaporated to give the crude product, which was chromatographed
on silica gel using a hexane/ethyl acetate gradient. In the case of
naphthalene, the yields were determined by quantification of the
following isolated fractions: (a) recovered naphthalene (by mass);
Acknowledgment. This work was supported by a Short Term
Innovative Research (STIR) grant from the Army Research
Office.
1
Supporting Information Available: H NMR spectra of
compounds 5a-c, 7, 9, 10, 12-14, 16, and 17. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO800839F
J. Org. Chem. Vol. 73, No. 16, 2008 6151