Improved Protocol for Mononitration of Phenols with Bismuth(III) and Iron(III) Nitrates

Article abstract of DOI:10.1080/00397911.2014.954730

A simple and efficient multigram procedure was developed for the selective mononitration of various activated phenols. The reaction proceeded smoothly with 0.5 equivalents of Bi(NO₃)₃ · 5H₂O or Fe(NO₃)₃ · 9H₂O in acetone at ambient temperature or at reflux. The desired products were isolated in 62-93% total yield and essentially no overnitrated compounds were detected.

Full text of DOI:10.1080/00397911.2014.954730

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Improved Protocol for Mononitration of
Phenols with Bismuth(III) and Iron(III)
Nitrates
Małgorzata Wąsińska a , Anna Korczewska a , Mirosław Giurg a &
Jacek Skarżewski a
a Department of Organic Chemistry, Faculty of Chemistry , Wrocław
University of Technology , Wrocław , Poland
Accepted author version posted online: 25 Sep 2014.Published
online: 19 Nov 2014.
To cite this article: Małgorzata Wąsińska , Anna Korczewska , Mirosław Giurg & Jacek Skarżewski
(2015) Improved Protocol for Mononitration of Phenols with Bismuth(III) and Iron(III) Nitrates,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 45:1, 143-150, DOI: 10.1080/00397911.2014.954730
To link to this article: http://dx.doi.org/10.1080/00397911.2014.954730
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Synthetic Communications1, 45: 143–150, 2015
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.954730
IMPROVED PROTOCOL FOR MONONITRATION OF
PHENOLS WITH BISMUTH(III) AND IRON(III) NITRATES
´
Małgorzata Wa˛sinska, Anna Korczewska, Mirosław Giurg,
and Jacek Skarz˙ewski
Department of Organic Chemistry, Faculty of Chemistry, Wrocław
University of Technology, Wrocław, Poland
GRAPHICAL ABSTRACT
Abstract A simple and efficient multigram procedure was developed for the selective
mononitration of various activated phenols. The reaction proceeded smoothly with 0.5
equivalents of Bi(NO3)3 ꢀ 5H2O or Fe(NO3)3 ꢀ 9H2O in acetone at ambient temperature
or at reflux. The desired products were isolated in 62–93% total yield and essentially no
overnitrated compounds were detected.
Keywords Bismuth(III) nitrate; iron(III) nitrate; mono-nitration; phenols
INTRODUCTION
Electrophilic aromatic nitration is one of the most widely used reactions[1] for
the synthesis of important intermediates for drugs and fine chemicals.[2] The nitra-
tions of less reactive aromatic compounds are usually carried out with an excess
of concentrated nitric acid or its mixture with sulfuric acid.[1,2] However, highly
reactive, electron-rich aromatic systems such as aniline and phenols require much
milder nitration conditions. Otherwise, the unwanted oxidized products and
multi-nitro compounds are formed.[3] Numerous useful reagents for the preparation
of nitrophenols that are substituted have already been developed, for example,
AgNO3=I2=Ph2PCl,[4] NaNO3=Mg(HSO4)2 or NaNO3=NaHSO4,[5] Ca(NO3)2,[6]
NaNO3,[7] or PEG-N2O4.[8] The nitration procedures often require special media
or additional activators.[9] Moreover, many of these methods still suffer from
Received June 3, 2014.
Address correspondence to Jacek Skarzewski, Department of Organic Chemistry, Faculty of
˙
Chemistry, Wrocław University of Technology, Wyb. Wyspianskiego 27, 50-370 Wrocław, Poland.
E-mail: jacek.skarzewski@pwr.wroc.pl
143

´
M. WA˛ SINSKA ET AL.
144
drawbacks, including tedious workup, poor selectivity, poor yields, overnitration,
and overoxidation, wasting valuable starting materials.
In the past decade, metal salts including (NH4)2Ce(NO3)6,[10] ZrO(NO3)2 ꢀ
xH2O,[11] Fe(NO3)3 ꢀ 9H2O,[12] and Bi(NO3)3 ꢀ 5H2O[13,14] have been introduced as
advantageous nitrating agents. In particular, the two last nitrates are cheap, easily
available, and nontoxic reagents with LD50 of ca. 3–4 g=kg. The use of high-valent
metal nitrates exclude a need for strong acids or external promoters. However, even
these mild reagents, targeted at the mononitration of phenolic substrates, often gave
also the unwanted dinitro derivatives.[13a]
For our ongoing project we needed a series of nitrophenols substituted with
electron-donating groups. To choose the most suitable mononitration procedure,
we decided to additionally examine the nitrating properties of the metallic nitrates.
RESULTS AND DISCUSSION
Looking for the appropriate mononitration method we tested the reaction of
4-phenylphenol (1a) with iron(III) nitrate and bismuth(III) nitrate. The previously
reported procedures[12a,12c,14] were used, applying equimolar amounts of the substi-
tuted phenol and the corresponding nitrates, and the desired product was obtained in
excellent yield (Table 1, entry 1). Further experiments demonstrated that practically
the same yields of 4-phenyl-2-nitrophenol (2a) were obtained using only half the
amount of nitrates (Table 1, entries 2 and 5). In this manner the yield based on
the nitrate was doubled (cf. entries 1 and 2). When we applied 0.33 equivalent of
the nitrates, similarly about two thirds of the anions were consumed in the reaction,
leaving one third of the substrate 1a unreacted (entry 3). Even more nitrate from the
ferric salt was introduced into 2a and less of the phenol remained (entry 4).
Table 1. Bismuth(III) and iron(III) nitrates reaction with 4-phenylphenol (1a)a
Ratio
1a=M(NO3)3
Conversion of
1a (yield of 2a) (%)b
Based on
M(NO3)3
c
Entry
Nitrate
Time (h)
1
2
3
4
5
1:1
Bi(NO3)3 ꢀ 5H2O
Bi(NO3)3 ꢀ 5H2O
Bi(NO3)3 ꢀ 5H2O
Fe(NO3)3 ꢀ 9H2O
Fe(NO3)3 ꢀ 9H2O
2
2
6
6
2
100 (92)
97 (92)
66 (64)
82 (75)
100 (93)
31
62
64
75
62
1:0.5
1:0.33
1:0.33
1:0.5
aThe reaction was carried out using 10 mmol of the nitrate salt and 10, 20, or 30 mmol of 1a in 100 mL of
acetone at 20 ꢁC.
bIsolated yield of 2a in parentheses.
cBased on the consumed nitrate.

MONONITRATION OF PHENOLS BY Bi(NO3)3 AND Fe(NO3)3
145
Based on these observations, the stoichiometry of nitration for entries 1–3
leads us to believe that the inorganic product is the well-known bismuth oxynitrate
[(Eq. (1)]:
It seems that the formation of the exceptionally stable oxo-bismuth species (BiOþ) is
responsible for this outcome. Interestingly, bismuth oxynitrate has been used for
nitration of phenols, but this compound needed additional activation by thionyl
chloride[9e] or trichloroisocyanuric acid.[9f]
Thus we have found that the nitration of 4-phenylphenol (1a) with 0.5 equiva-
lent of Bi(NO3)3 ꢀ 5H2O or Fe(NO3)3 ꢀ 9H2O in acetone at room temperature gave the
2-nitro-4-phenylphenol (2a) in excellent yield. It is noteworthy that the method[14]
recommended for the nitration of electron-rich phenols with equimolar amount of
Bi(NO3)3 ꢀ 5H2O was developed for a small laboratory scale only. The authors were
aware that extra care would be needed when the procedure was performed on a mul-
tigram scale, because the reaction was exothermic. Hence, in the scaled-up pro-
cedure, only half of the amounts of the previously used nitrating agents were
used, and we smoothly obtained the desired mononitrated product, avoiding the
reported difficulties.[14] Moreover, grinding 4-phenylphenol (1a) with 0.5 equivalent
of bismuth(III) nitrate in the absence of solvent did not yield any product.
It has been reported that the selective nitration of phenols with cerium(IV)
ammonium nitrate (CAN) in the presence NaHCO3 afforded o-nitrophenols in
good yields.[10] Among them 3-methoxyphenol (1e) was reportedly converted to
3-methoxy-6-nitrophenol (2e) in 90% yield.[10a] In our hands this reaction resulted
in the formation of isomeric mononitrates: 2e (18%), 3e (9%), and 4e (7%). Also,
the attempted nitration of 2-benzylphenol (1d) with CAN=NaHCO3 gave 4.5% of
6-benzyl-2-nitrophenol (4d) only.
To compare the reactivity of Bi(NO3)3 ꢀ 5H2O and Fe(NO3)3 ꢀ 9H2O as the
mononitrating agents we ran the reactions with four additional phenols (Scheme 1).
The obtained results demonstrated that both salts performed similarly well,
with somewhat greater yields obtained for bismuth nitrate. One can relate this differ-
ence to the respective oxidizing abilities (Eꢁ for Bi3þ=Bi0, Fe3þ=Fe2þ, and Ce4þ=Ce3þ
are þ0.317,[15a] þ0.771,[15b] and þ1.61[15c] V, respectively). Thus CAN is known as a
strong outer-sphere oxidant, easily generating radical cations, highly reactive
intermediates, leading to many different products. The reaction with ferric nitrate
supposedly forms ArO-Fe(NO3)2 species, where an internal electron transfer may
take place, forming a phenoxyl radical and iron(II) salt. In consequence, the
obtained phenoxyl radical could reduce nitric acid to (NO2), initiating a radical
nitration pathway.[12d] However, the observed resemblance of the nitration product
distribution for bismuth and ferric nitrates (Scheme 1) suggests that a similar
mechanism is operating in both cases. When we attempted to react 1-methoxy-2,4-
dimethylbenzene (7k) with bismuth nitrate, no nitration product could be detected.
This supports the formation of ArO-Bi(NO3)2 as the first intermediate on the

´
M. WA˛ SINSKA ET AL.
146
Scheme 1. Nitration of 1b–d with 0.5 equiv. and 1e with 0.33 equiv. of Bi(NO3)3 ꢀ 5H2O or Fe(NO3)3 ꢀ
9H2O in acetone.[19]
reaction route, as depicted in Scheme 2. It is also consistent with the known large
oxophilicity of bismuth(III). On the other hand, the less-oxidizing character of
Bi3þ than Fe3þ is reflected in slightly greater selectivity toward ortho-nitration and
the products observed when the bismuth salt is used are in strict compliance with
the stoichiometric equation [Eq. (1)] (Table 1, entries 3 and 4).
Moreover, in the reaction of 2,6-dimethylphenol (1c) with both nitrates, along
with the expected mononitration product 4c, we also obtained the respective

MONONITRATION OF PHENOLS BY Bi(NO3)3 AND Fe(NO3)3
147
Scheme 2. Nitration mechanism.
oxidation product 5c (Scheme 1). As has already been noted, the observed
carbon–carbon coupling is related to the presence of two methyl substituents in both
ortho-positions of the phenolic ring.[3a]
Additionally, we examined the nitration of further phenolic compounds 1f–l
with Bi(NO3)3 ꢀ 5H2O. The reaction was performed under heterogeneous conditions
at room temperature or at solvent boiling point, to give the mononitration products
2–4 in good to excellent yields (Table 2).[16]
Accordingly, scope of the reaction is illustrated by 12 examples of the mono-
nitrated phenols 1a–l (Tables 1 and 2, Scheme 1). In all cases, the conversion of
the substrates was complete. On the other hand, phenols with electron-withdrawing
substituents, such as 3-trifluoromethylphenol, 2-methyl-6-nitrophenol, and both 2-
and 4-carboxymethylphenols remained resistant toward nitration. This outcome dif-
fers from the reported effective corresponding nitration using 1 equivalent of
Bi(NO3)3.[14] We also examined competitive reactions of the equimolar mixture of
2,4-dimethylphenol (1k) and its O-methyl derivative with bismuth(III) and ferric(III)
nitrating salts. It was observed that the nitration of 1k took place exclusively,
whereas 1-methoxy-2,4-dimethylbenzene remained intact in the reaction mixture.
These results also suggest that the radical nitration pathway plays for both nitrates
a marginal role only.
CONCLUSIONS
In conclusion, we have developed simple multigram protocols for the selective
mono-nitration of various activated phenols. Based on the observed stoichiometry,
the reaction was carried out with 0.5 equivalents of Bi(NO3)3 ꢀ 5H2O or Fe(NO3)3 ꢀ
9H2O in acetone at ambient temperature or at reflux. The desired mono-
nitrophenols were isolated in 62–93% total yield and essentially no overnitrated com-
pounds were detected. The reaction, under the applied conditions, is highly specific
for the activated phenols. The readily available, inexpensive, and environmentally
acceptable nitrating salts and the simple procedure offer an attractive alternative
to the classical nitration methods for the electron-rich phenols.
EXPERIMENTAL
Acetone (100 ml) was added to a solid mixture of the phenol (10.0, 20.0,
or 30.0 mmol) and Bi(NO3)3 ꢀ 5H2O (10.0 mmol). The resulting mixture was mag-
netically stirred at room temperature or at reflux for 2–24 h (Tables 1 and 2).

´
M. WA˛ SINSKA ET AL.
148
Table 2. Mononitration of phenolic compounds 1f–l with 0.5 equiv of Bi(NO3)3 ꢀ 5H2Oa
Phenolic
compound
Entry
1
T (ꢁC) Time (h)
Nitrated compound (% isolated yields)b
20
56
20
(80)
2
3
6
(87)
(45)
0
20
(42)
4
20
6
(52)c
(28)c
5
56
6
(80)
6
20
6
(87)
(Continued )

MONONITRATION OF PHENOLS BY Bi(NO3)3 AND Fe(NO3)3
149
Table 2. Continued
Phenolic
compound
Entry
T (ꢁC) Time (h)
Nitrated compound (% isolated yields)b
7
20
2
(52)
aReaction conditions: Phenolic compound (20 mmol), Bi(NO3)3 ꢀ 5H2O (10 mmol), and acetone (0.1 L)
were stirred at 0–56 ꢁC for 6–20 h.
bIsolated yield based on the amount of phenol used.
cDistribution of isomer determined by 1H NMR.
The progress of the reaction was monitored by thin-layer chromatography (TLC)
using silica-coated plates. After the reaction had finished the insoluble materials were
filtered off using a Celite pad, which was then additionally washed with acetone
(50 ml). The filtrate was treated with solid NaHCO3. The insoluble material was
filtered off again, and the solvent was removed under vacuum in a water bath at
25–35 ꢁC. The products were separated and purified by column chromatography
using silica gel. All the isolated products are known compounds characterized by
1H and 13C NMR and IR spectroscopy, and were identified by comparison of the
spectral data and melting points with those reported in the literature. For the
analytical details, see the Supporting Information.
FUNDING
The work was financed by a statutory activity subsidy from the Polish Ministry
of Science and Higher Education for the Faculty of Chemistry of Wroclaw
University of Technology.
SUPPLEMENTAL MATERIAL
Supplemental date for this article can be accessed on the publisher’s website.
REFERENCES
1. (a) Smith, M. B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanisms,
and Structure, 6th ed.; Wiley: New York, 2007; chap. 11–2; (b) Olah, G. A.; Malhorta, R.;
Narang, S. C. Nitration Methods and Mechanisms; VCH: New York, 1989; (c) for a recent
review, see Guobing, Y.; Minghua, Y. Org. Biomol. Chem. 2013, 11, 2554–2566.
2. (a) Ullmann’s Encyclopedia of Industrial Chemistry, 6th ed.; Wiley-VCH: Weinheim, 2003;
(b) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York, 2001.
3. (a) Crivello, J. V. J. Org. Chem. 1981, 46, 3056–3060; (b) Freer, A. A.; Kirby, G. W.; Rao,
G. V.; Cain, R. B. J. Chem. Soc., Perkin Trans. 1996, 2111–2116.

´
M. WA˛ SINSKA ET AL.
150
4. Nowrouzi, N.; Jonaghani, M. Z. Tetraherdron Lett. 2011, 52, 5081–5082.
5. Zolfigol, M. A.; Ghaemi, A.; Madrakian, E. Molecules 2001, 6, 614–620.
6. (a) Bisarya, S. C.; Joshi, S. K.; Holkar, A. G. Synth. Commun. 1993, 23, 1125–1137; (b)
Bose, A. K.; Ganguly, S. N.; Manhas, M. S.; Rao, S.; Speck, J.; Pekelnya, U.;
Pombo-Villars, E. Tetrahedron Lett. 2006, 47, 1885–1888.
7. (a) Zolfigol, M. A.; Ghaemi, E.; Madrakian, E. Molecules 2001, 6, 614–620; (b) Zolfigol,
M. A.; Ghaemi, E.; Madrakian, E. Synlett 2003, 191–194; (c) Zolfigol, M. A.; Madrakian,
E.; Ghaemi, E. Molecules 2002, 7, 734–741; (d) Beheshti, S.; Kianmehr, E.; Yahyaee, M.;
Tabatabai, K. Bull. Korean Chem. Soc. 2006, 27, 1056–1058.
8. Zolfigol, M. A.; Madrakian, E.; Ghaemi, E., Nikman, K. Synth. Commun. 2008, 38, 3366–
3374.
9. (a) Laszlo, P. Acc. Chem. Res. 1986, 19, 121–127; (b) Chatre, A. S.; Joshi, R. A.; Kulkarni,
B. D. J. Colloid Interface Sci. 1993, 158, 183–187; (c) Currie, F.; Holmberg, K.; Westman,
G. Colloids Surf. 2001, 182, 321–327; (d) Laali, K. K.; Gettwert, V. J. J. Org. Chem. 2001,
66, 35–40; (e) Muathen, H. A. Molecules 2003, 8, 593–598; (f) Pourali, A. R.; Fatemi, F.
Chin. Chem. Lett. 2010, 21, 1283–1286; (g) for a recent review, see Vekariya, R. H.; Patel,
H. D. Synth. Commun. 2014, 44, 2313–2335.
10. (a) Sathunuru, R.; Rao, U. N.; Biehl, E. Arkivoc 2003, 124–133; (b) Sathunuru, R.; Biehl,
E. Arkivoc 2004, 89–95; (c) Perez, C.; Perez-Gutierrez, S.; Gomez, S. A.; Fuentes, G. A.;
Zavala, M. A.; Perez. Org. Prep. Proc. Int. 2005, 37, 387–396; (d) Yang, X.; Xi, C.;
Jiang, Y. Tetrahedron Lett. 2005, 46, 8781–8783.
11. Selvam, J. J. P.; Suresh, V.; Rajesh, K.; Reddy, S. R.; Venkateswarlu, Y. Tetrahedron Lett.
2006, 47, 2507–2509.
12. (a) Cornelis, A.; Laszlo, P. Synthesis 1985, 909–918; (b) Poirier, J.-M.; Vottero, C.
Tetrahedron 1989, 45, 1415–1422; (c) Rajagopal, R.; Srinivisan, K. V. Synth. Commun.
2003, 33, 961–966; (d) Liu, Y.; Zu, M.; Zou, X.; Zheng, Q.; Li, X.; Zhou, X.; Tang, Q.;
Zhang, S.; Zhang, L.; Li, Y. Asian J. Chem. 2014, 26A, 241–246.
13. (a) Cornelis, A.; Delaude, L.; Gerstmans, A.; Laszlo, P. Tetrahedron Lett. 1988, 29, 5909–
5912; (b) Samajdar, S.; Becker, F. F.; Banik, B. K. Tetrahedron Lett. 2000, 41, 8017–8020;
(c) Samajdar, S.; Becker, F. F.; Banik, B. K. Arkivoc 2001, 27–33; (d) Shi, M.; Cui, S.-C.
Adv. Synth. Catal. 2003, 345, 1197–1202; (e) Banik, B. K.; Samajdar, S.; Banik, I.; Ng, S. S.;
Hann, J. Heterocycles 2003, 61, 97–100; (f) Bose, A.; Sanjoto, W. P.; Villarreal, S.;
Aguilar, H.; Banik, B. K. Tetrahedron Lett. 2007, 48, 3945–3947; (g) Jacoway, J.; Kumar,
G. G. K. S. N.; Laali, K. K. Tetrahedron Lett. 2012, 53, 6782–6785; (h) Canales, L.;
Bandyopadhyay, D.; Banik, B. K. Org. Med. Chem. Lett. 2011, 1, 9; For reviews, see
(i) Leonard, N. M.; Wieland, L. C.; Mohan, R. S. Tetrahedron 2002, 58, 8373–8397; (j)
Bothwell, J. M.; Krabbez, S. W.; Mohan, R. S. Chem. Soc. Rev. 2011, 40, 4649–4707.
14. Sun, H.-B.; Hua, R.; Yin, Y. J. Org. Chem. 2005, 70, 9071–9073.
15. (a) Jung, H.; Rheem, Y.; Chartuprayoon, N.; Lim, J.-H.; Lee, K.-H.; Yoo, B.; Lee, K.-J.;
Choa, Y.-H.; Wei, P.; Shi, J.; Myung, N. V. J. Mater. Chem. 2010, 20, 9982–9987; (b) Li,
R.; Chen, W.; Kobayashi, H.; Ma, C. Green Chem. 2010, 12, 212–215; (c) Nair, V.;
Deepthi, A. Chem. Rev. 2007, 107, 1862–1891.