Improved synthesis of 3-nitrosalicylic acid

Article abstract of DOI:10.1080/00397910903419852

Nitration of salicylic acid using 2-propyl nitrate/sulfuric acid/tetrabutylammonium hydrogensulfate/dichloromethane/water yielded a mixture of 3-nitro and 5-nitrosalicylic acids in the ratio 56:44. Pure potassium 3-nitrosalicylate was crystallized and converted to 3-nitrosalicylic acid in 30% overall yield. Copyright

Full text of DOI:10.1080/00397910903419852

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Improved Synthesis of 3-Nitrosalicylic
Acid
Michael Hummel a , Gerhard Laus a , Sven Nerdinger b & Herwig
Schottenberger a
a Faculty of Chemistry and Pharmacy, University of Innsbruck,
Innsbruck, Austria
b Sandoz GmbH, Kundl, Austria
Version of record first published: 15 Oct 2010
To cite this article: Michael Hummel, Gerhard Laus, Sven Nerdinger & Herwig Schottenberger (2010):
Improved Synthesis of 3-Nitrosalicylic Acid, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 40:22, 3353-3357
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Synthetic Communications1, 40: 3353–3357, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903419852
IMPROVED SYNTHESIS OF 3-NITROSALICYLIC ACID
Michael Hummel,1 Gerhard Laus,1 Sven Nerdinger,2 and
Herwig Schottenberger1
1Faculty of Chemistry and Pharmacy, University of Innsbruck, Innsbruck,
Austria
2Sandoz GmbH, Kundl, Austria
Nitration of salicylic acid using 2-propyl nitrate / sulfuric acid / tetrabutylammonium
hydrogensulfate / dichloromethane / water yielded a mixture of 3-nitro and 5-nitrosalicylic
acids in the ratio 56:44. Pure potassium 3-nitrosalicylate was crystallized and converted
to 3-nitrosalicylic acid in 30% overall yield.
Keywords: 3-Nitrosalicylic acid; potassium 3-nitrosalicylate; 2-propyl nitrate
INTRODUCTION
3-Nitrosalicylic acid is a very useful synthetic intermediate for 3-aminosalicylates
or 3-aminosalicylamides, which are of wide interest and relevance for pharmaceutical
and agrochemical products, as reflected in the literature.[1] The compound has been
prepared from salicylic acid by various nitration methods. Typical procedures involve
dilute nitric acid,[2] nitric acid=acetic acid mixtures,[3] sodium nitrite=hot sulfuric acid
in an extremely violent reaction,[4] and toxic or expensive reagents such as
transition-metal nitrates, like zinc nitrate=dinitrogen tetroxide[5] or cerium ammo-
nium nitrate.[6] All the known methods suffer from a lack of regioselectivity. The
undesired 5-nitro isomer is preferentially formed, accompanied by decarboxylation
and dinitration products, as detailed studies have shown.[3] However, no protocols
allowing for a reliable isolation of a pure product have been disclosed in all these
published methods. In addition, violent runaway reactions have been observed.
No matter how the nitration is performed, the subsequent separation of the
isomers is obviously necessary to obtain pure 3-nitrosalicylic acid. Meldrum’s classic
method via the monopotassium salts is well suited for this purpose.[2] Unfortunately,
in Meldrum’s original publication, no experimental details of the crystallization are
given.
3-Nitrosalicylic acid is now commercially available, but the price is relatively
high. Also no satisfactory process has been published. For these reasons, we assessed
a new method of nitration and optimized the separation of the isomers.
Received August 30, 2009.
Address correspondence to Gerhard Laus, Faculty of Chemistry and Pharmacy, University of
Innsbruck, Innsbruck, Austria. E-mail: gerhard.laus@uibk.ac.at
3353

3354
M. HUMMEL ET AL.
RESULTS AND DISCUSSION
Several known methods of nitration were checked. In an attempt to reproduce
Meldrum’s original nitration=workup recipe, we were not able to reach the reported
yield (25% given). The procedure described used dilute nitric acid and gave a viscous
paste that was difficult to stir. The reaction was very slow when cooling was applied,
and without cooling a runaway reaction occurred. The use of more acid facilitated
stirring and temperature control (20 ꢀC). Nevertheless, in our hands only 12% of
the pure 3-nitro product was obtained.
In another attempt by microwave-assisted nitration of salicylic acid using
cerium ammonium nitrate (in analogy to a published method),[7] a violent explosion
occurred and completely wrecked our microwave equipment.
Several known methods for ortho-nitration of phenolic compounds fail in the
presence of electron-withdrawing groups such as a carboxylic acid. A new method
that favors the desired ortho-nitration has recently been described in a patent.[8] It
involves phase-transfer catalysis and the use of 2-propyl nitrate=sulfuric acid in
dichloromethane, where the 3-nitro isomer is claimed to precipitate exclusively
from the reaction mixture. However, in our hands no pure product was obtained
following the instructions. On the other hand, isopropyl nitrate is indeed a safe[9]
and inexpensive nitration agent that is easy to handle and gives preferentially the
3-nitro isomer. Therefore, a more detailed investigation was undertaken. We found
that the use of less than 2.5 equivalents of nitration reagent led to incomplete con-
version, whereas prolongation of the reaction time did not increase the yield. NMR
spectra revealed that the crude product was a mixture of 3- and 5-nitrosalicylic
acid in the ratio of 56:44 (mean value of 10 runs). After addition of potassium car-
bonate, pure potassium 3-nitrosalicylate precipitates, but the solution of the salts
must not be cooled below 20 ꢀC. Cooling by means of an ice bath, as one might
be tempted to do, provokes precipitation of unwanted potassium 5-nitrosalicylate.
Liberation of the acid and subsequent crystallization is straightforward. As
previously reported, the colorless primary product is a hydrate, whereas the
anhydrous acid is yellow.[2] Finally, it should be noted that this optimized nitration
Scheme 1. Synthesis of 3-nitrosalicylic acid.

IMPROVED SYNTHESIS OF 3-NITROSALICYLIC ACID
3355
procedure has also been carried out on double the scale specified, with similar yield
and without any problem.
This procedure represents a combination of the most ortho-selective nitration
method of salicylic acid with the optimized classic separation of the isomers by
crystallization of the monopotassium salts.[2] The described three-step synthesis
(Scheme 1) is superior to all previous ones with respect to safety, yield, convenience,
and overall costs.
EXPERIMENTAL
Chemicals were obtained from commercial sources (Sigma-Aldrich) and were
used as received. NMR spectra were recorded using a Bruker AC 300 spectrometer.
Infrared (IR) spectra were obtained with a Nicolet 5700 FT spectrometer in
attenuated total reflection (ATR) mode.
Preparation of a Mixture of 3-Nitrosalicylic Acid (2) and
5-Nitrosalicylic Acid (3)
A 500-mL, two-necked, round-bottomed flask equipped with a 50-mL
pressure-equalizing addition funnel, a thermometer, and a magnetic stirrer is charged
with salicylic acid (1; 20.7 g, 0.150 mol) and 300 mL of dichloromethane. The suspen-
sion is cooled by means of an ice bath. Subsequently, tetrabutylammonium hydro-
gensulfate (2.55 g, 7.5 mmol, 0.05 equivalents) and 2-propyl nitrate (38 mL,
0.38 mol, 2.5 equivalents) are added. Then, concentrated sulfuric acid (21 mL) is
added dropwise from the funnel over a period of 40 min (the temperature does not
exceed 10 ꢀC). In the course of addition, a yellow precipitate is formed. After the
addition is completed, the reaction mixture is stirred for an additional 10 min with
cooling and then for another hour without cooling (the temperature rises to
35 ꢀC). The suspension is poured into a 3-L beaker filled with 1500 mL of distilled
water and stirred rapidly by means of a magnetic stirrer. After 10 min, the precipitate
is filtered through a Buechner funnel, washed with water (3 ꢁ 100 mL), and predried
by suction. The crude product is finally dried in a vacuum desiccator over phos-
phorus pentoxide (P2O5) to yield 17.7 g (64% of theory) of a mixture of 3- and
5-nitrosalicylic acid in the ratio of 56:44 (mean value of 10 runs).
Purification of Potassium 3-Nitrosalicylate (4)
The mixture of isomeric 3- and 5-nitrosalicylic acid (17.7 g, 0.097 mol) is placed
in a 1000-mL round-bottomed flask equipped with a magnetic stirring bar, and a
1.45 M solution of potassium carbonate (270 mL) is added carefully under vigorous
stirring, followed by 180 mL of distilled water. The flask is fitted with a reflux con-
denser, and the dark-orange suspension is heated by means of an oil bath (110 ꢀC).
After complete dissolution, the solution is allowed to cool to 20 ꢀC. The yellow pre-
cipitate is filtered through a glass frit (porosity 3), washed with ice-cold water
(2 ꢁ 50 mL), and predried by suction. The solid is finally dried in a vacuum desic-
cator over phosphorus pentoxide (P2O5) to yield 10.2 g of potassium 3-nitrosalicylate
(4) as fine yellow needles (31% overall yield). NMR spectra show less than 1% of

3356
M. HUMMEL ET AL.
potassium 5-nitrosalicylate. An even purer product can be obtained by a second
recrystallization. Mp 296 ꢀC (dec); 1H NMR (300 MHz, DMSO-d6): d 6.52 (t,
J ¼ 7.7 Hz, 1H), 7.86 (dd, J ¼ 8.1, 1.9 Hz, 1H), 7.95 (dd, J ¼ 7.5, 1.9 Hz, 1H) ppm;
13C NMR (75.5 MHz, DMSO-d6): d 112.0, 122.2, 129.0, 135.6, 138.1, 162.6,
169.6 ppm; IR (neat): 1578, 1522, 1451, 1401, 1346, 1281, 1073, 912, 854, 778, 739,
600, 456 cmꢂ1
.
3-Nitrosalicylic Acid (5)
A 500-mL, two-necked, round-bottomed flask equipped with a magnetic stir-
ring bar, an addition funnel, and a reflux condenser is charged with the purified pot-
assium 3-nitrosalicylate (4; 10.0 g, 0.045 mol) and deionized water (240 mL). The
mixture is heated to boiling (bath temperature 115 ꢀC) under vigorous stirring until
a clear solution is obtained. Concentrated hydrochloric acid (37%, 3.8 mL) is added
dropwise from the funnel. A precipitate forms, which dissolves again on stirring and
heating for another 5 to 10 min. The hot solution is allowed to cool with stirring to
room temperature and then is refrigerated at 5 ꢀC. After standing for 30 min, the pre-
cipitated 3-nitrosalicylic acid is filtered with suction and washed with ice-cold water
until it is free of chloride. The off-white product is dried in a vacuum desiccator over
phosphorus pentoxide (P2O5) and then at 60 ꢀC in high vacuum to a constant weight
to yield 8.1 g (30% overall yield) of yellow, anhydrous 3-nitrosalicylic acid (5). Mp
148 ꢀC; 1H NMR (300 MHz, DMSO-d6): d ¼ 7.05 (t, J ¼ 8.0 Hz, 1H), 8.11 (dd,
J ¼ 8.0, 1.7 Hz, 1H), 8.15 (dd, J ¼ 8.0, 1.7 Hz, 1H) ppm; 13C NMR (75.5 MHz,
DMSO-d6): d ¼ 116.3, 118.4, 130.8, 135.6, 138.2, 155.1, 171.2 ppm; IR (neat):
3096, 2824, 2548, 1667, 1596, 1519, 1441, 1357, 1251, 1130, 1097, 900, 848, 771,
743, 693, 597 cmꢂ1; HRMS (EIþ) m=z calcd. for C7H5NO5: 183.0162, found
183.0175 (Mþ.).
Spectral Data of Potassium 5-Nitrosalicylate
1H NMR (300 MHz, DMSO-d6): d ¼ 6.64 (d, J ¼ 9.2 Hz, 1H), 8.01 (dd, J ¼ 9.2,
3.1 Hz, 1H), 8.49 (d, J ¼ 3.1 Hz, 1H) ppm.
Spectral Data of 5-Nitrosalicylic Acid
1H NMR (300 MHz, DMSO-d6): d ¼ 7.12 (d, J ¼ 9.2 Hz, 1H), 8.30 (dd, J ¼ 9.2,
2.9 Hz, 1H), 8.53 (d, J ¼ 2.9 Hz, 1H) ppm.
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