p-Toluenesulfonic acid catalyzed regiospecific nitration of phenols with metal nitrates

Article abstract of DOI:10.1016/j.tetlet.2006.05.017

Highly regiospecific mononitration of phenols and substituted phenols is accomplished employing a metal nitrate and a catalytic amount of p-toluenesulfonic acid in acetone. An exclusive ortho-selectivity was observed with excellent yields. A variety of metal nitrates were used to obtain o-nitrophenols exclusively in good to excellent yields. The use of p-toluenesulfonic acid is key for the selectivity observed.

Full text of DOI:10.1016/j.tetlet.2006.05.017

Tetrahedron Letters 47 (2006) 4933–4935
p-Toluenesulfonic acid catalyzed regiospecific nitration
I
of phenols with metal nitrates
V. Anuradha, P. V. Srinivas, P. Aparna and J. Madhusudana Rao*
Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 8 March 2006; revised 24 April 2006; accepted 4 May 2006
Available online 24 May 2006
Abstract—Highly regiospecific mononitration of phenols and substituted phenols is accomplished employing a metal nitrate and a
catalytic amount of p-toluenesulfonic acid in acetone. An exclusive ortho-selectivity was observed with excellent yields. A variety of
metal nitrates were used to obtain o-nitrophenols exclusively in good to excellent yields. The use of p-toluenesulfonic acid is key for
the selectivity observed.
Ó 2006 Elsevier Ltd. All rights reserved.
Nitration of aromatic compounds is an industrially
important reaction as the nitrated products are
are concerns regarding achieving efficient regioselectiv-
ity. All these methods also suffer from other drawbacks,
for example some of the nitrates must be prepared from
dinitrogen pentoxide, or they must either be clay sup-
ported or absorbed on silica gel prior to their use as
nitrating agents. Some even employ the use of expensive
1
intermediates for fine chemicals and pharmaceuticals.
Usually, nitration reactions are not selective and are
the cause of environmental concerns regarding the
disposal of large excesses of mixed acids employed in
these processes. Thus, the utility of the existing pro-
9
ionic liquids as solvents.
2
,3
cesses are generally low. The nitration of phenol is a
fundamental process and there is a need for a regiospec-
ific pollution-free method. A variety of nitrating agents,
Herein, we report our results on the regiospecific nitra-
tion of phenols and their derivatives using a metal
nitrate and a catalytic amount of p-toluenesulfonic acid
including concentrated nitric acid, Yb(OTf) , and
3
4
10
Hf(OTf)4 in conjunction with HNO , peroxynitrite
in acetone. Although nitration of phenols has been
3
À
5
6
7
(
ONOO ), nitrogen oxides, and several metal nitrates
reported with several metal nitrates, the observation of
8
b
have been employed.
regiospecificity is rare. Very recently a report appeared
describing the use of Bi(NO ) Æ5H O as a nitrating agent
3
3
2
1
1
With regard to the nitration of phenols, the use of con-
centrated nitric acid or mixed acids has been associated
with the formation of dinitro compounds, oxidized
products, and unspecified resinous tarry materials
resulting from the over-oxidation of the substrates.
for phenols, albeit with no regiospecificity. This report
also described the use of other metal nitrates, which did
not show any reactivity, for example Ni(NO ) Æ9H O,
3
3
2
Ba(NO ) , Ca(NO ) Æ4H O, and Cu(NO ) Æ3H O.
3
2
3 2
2
3 2
2
Table 1. Nitration of p-cresol with different metal nitrates and p-TSA
to give an o-nitro compound
The typical yields of direct nitration never exceed
2
6
0% because of the above mentioned side reactions in
most cases, making these processes uneconomical. On
the other hand, the use of metal nitrates like ferric
nitrate, ceric ammonium nitrate, copper nitrate, and
Entry
M(NO
3
)
n
ÆxH
2
O
Reaction
conditions
o-Nitro
compound
isolated yield (%)
a
8
(
min)
vanadium nitrate have contributed significantly, enhan-
cing the scope of the nitration process, however, there
1
2
3
4
5
6
Ni(NO ) Æ6H O
1
2
15
2
3
3
85
75
50
75
60
60
3
2
2
Co(NO
Fe(NO
Bi(NO
Mn(NO
Cu(NO
3
)
2
Æ6H
Æ9H
Æ5H
Æ2H
Æ3H
2
O
O
2
O
3
)
3
2
3
)
3
3
)
2
2
O
Keywords: Nitration; Nickel nitrate; Regiospecific; p-TSA.
q
IICT Communication No. 060416.
3
)
2
2
O
a
*
Corresponding author. Tel.: +91 40 27193434; fax: +91 40
7160512; e-mail: janaswamy@iict.res.in
1 mmol p-cresol, 1 mmol metal nitrate and 0.012 mmol of p-TSA in
15 ml acetone at 25 °C.
2
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.017

4934
V. Anuradha et al. / Tetrahedron Letters 47 (2006) 4933–4935
OH
OH
A variety of metal nitrates were screened and the results
M(NO3)n.xH2O, PTSA
acetone, RT / reflux
NO2
are summarized in Table 1. The use of a catalytic
amount of p-toluenesulfonic acid (p-TSA) is key for
the reaction to proceed with high regiospecificity and
each of the metal nitrates used afforded o-nitrophenols
as a single regioisomer in good to excellent yields.
R
R
R = H, Me, OMe, Br, CHO
M = Ni, Co, Fe, Bi, Mn, Cu
Even though the reaction proceeds with various metal
nitrates, the time required for completion of the reaction
Scheme 1.
Table 2. Nitration of phenol with nickel(II) nitrate and p-TSA
b
c
Entry
Phenol
Time (min)
30
Product
Yield (%)
OH
OH
1
NO2
OH
85
80
OH
2
3
30
NO2
NO2
OH
OH
5
1
97
CH3
CH3
H C
OH
3
4
5
H C
OH
OH
98
75
3
NO2
OH
HO
HO
a
30
O N
2
Br
OH
6
7
Br
OH
60
60
78
72
NO2
OHC
OH
OHC
OH
NO2
OCH3
OCH3
OH
8
9
70
OHC
OH
71
86
OHC
NO2
OH
OH
NO2
a
30
Br
Br
OH
OH
NO2
a
10
30
85
OMe
OH
OMe
1
1
1
2
30
5
85
97
HO
HO
NO2
OH
NO2
H C
H C
3
3
COOH
a
1
3
4
720
No reaction
No reaction
HO
HO
OMe
OMe
COOMe
a
1
720
a
b
c
Reaction carried out at 50 °C.
All the products were characterized by H NMR and mass spectroscopy.
Isolated yields after column chromatography.
1

V. Anuradha et al. / Tetrahedron Letters 47 (2006) 4933–4935
4935
was found to be less with Ni(NO ) Æ6H O. Moreover,
the use of nickel(II) nitrate as a nitrating agent for phe-
nols is unprecedented.
2. Vogel’s Text Book of Practical Organic Chemistry,
th ed.; Longman Group UK Harlow, UK, 1989.
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2
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Org. Proc. Res. Dev. 2003, 7, 95–97; (e) Kamal, A.;
Kumar, A. B.; Arifudin, M.; Patrick, M. Ultrason.
Sonochem. 2004, 11, 455–457.
The use of a sulfonic acid is precedented in the form of
trifluoromethanesulfonic acid and its derivatives1 but
the use of p-toluenesulfonic acid in the nitration of
phenols has not been reported previously. p-Toluene-
sulfonic acid enjoys other advantages over triflic acid
because it is non-corrosive and much cheaper.
2
5
6
7
. (a) Geletii, Y. V.; Bailey, A. J.; Cowan, J. J.; Weinstock, I.
A.; Hill, C. L. Can. J. Chem. 2001, 79, 792–794; (b)
Nonoyama, N.; Chiba, K.; Hisatome, K.; Suzuki, H.;
Shintani, F. Tetrahedron Lett. 1999, 40, 6933–6937; (c)
Ramezanian, M. S.; Padmaja, S.; Koppenol, W. H. Chem.
Res. Toxicol. 1996, 9, 232–240.
. (a) Zolfigol, M. A.; Bagherzadeh, M.; Madrakian, E.;
Ghaemi, E.; Taqian-Nasab, A. J. Chem. Res. (S) 2001, 4,
140–142; (b) Iranpoor, N.; Firouzabadi, H.; Heydari, R.
Synth. Commun. 1999, 29, 3295–3302; (c) Suzuki, H.;
Yonezawa, S.; Nonoyama, N.; Mori, T. J. Chem. Soc.,
Perkin. Trans. 1 1996, 2385–2389.
Phenol was treated with a metal nitrate and p-TSA in
acetone either at room temperature or at reflux to afford
o-nitrophenol as the exclusive product in satisfactory to
good yields (Scheme 1).
The scope and generality of the method is illustrated
with several examples in Table 2. A variety of phenols
were subjected to the standardized conditions of Scheme
1
and all of them yielded the o-nitro product exclusively
in good to excellent yields.
. (a) Dove, M. F. A.; Manz, B.; Montgomery, J.; Pattenden,
G.; Wood, S. A. J. Chem. Soc., Perkin Trans. 1 1998,
Phenols with electron donating groups (entries 3, 4, 5,
and 10, Table 2) behaved very well to afford the o-nitro-
phenols as the exclusive products in excellent isolated
yields. Phenols with moderately deactivating groups (en-
tries 6, 7, and 9) also yielded the o-nitrophenols in good
yields. A phenol with both an activating and a deactivat-
ing group (entry 8) also reacted to afford the desired
product in good yield.
1
589–1590; (b) Firouzabadi, H.; Iranpoor, N.; Zolfigol,
M. A. Synth. Commun. 1997, 27, 3301–3311; (c)
Iranpoor, N.; Firouzabadi, H.; Zolfigol, M. A. Synth.
Commun. 1998, 28, 2773–2781; (d) Gu, S.; Jing, H.;
Wu, J.; Liang, Y. Synth. Commun. 1997, 27, 2793–
2797; (e) Rajagopal, R.; Srinivasan, K. V. Synth. Commun.
2003, 33, 961–966; (f) Zolfigol, M. A.; Ghaemi, E.;
Madrakian, E. Molecules 2001, 6, 614–620; (g) Gigante,
B.; Prazeres, A. O.; Marcelo-Curto, M. J.; Cornelis, A.;
Laszlo, P. J. Org. Chem. 1995, 60, 3445–3447, and
references cited therein; (h) Cornelis, A.; Laszlo, P.;
Pennetreau, P. J. Org. Chem. 1983, 48, 4771–4772; (i)
Samajdar, S.; Becker, F. F.; Banik, B. K. Tetrahedron
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Marcos, C. F.; Tojo, G. Synth. Commun. 1995, 25, 1717–
Bakuchiol (entry 11), a phenolic natural product also
yielded the o-nitrophenol as the exclusive product in
excellent isolated yield. Phenols with strong deactiving
groups failed to react under the given protocol.
In conclusion, the mono-nitration of phenols with a
metal nitrate and p-TSA has been achieved with high
regiospecificity and with excellent isolated yields. In
general, exclusive ortho-selectivity was observed for all
the phenols subjected to this protocol.
1
727.
8. (a) Grenier, J. L.; Catteau, J. P.; Cottelle, P. Synth.
Commun. 1999, 29, 1201–1208; (b) Sathunuru, R.; Rao, U.
N.; Biehl, E. ARKIVOC 2003, 124–133.
9
. Kenneth, K. L.; Volker, J. G. J. Org. Chem. 2001, 66, 35–
0.
4
The high regiospecificity, with excellent isolated yields
and the use of inexpensive and easily accessible p-TSA
as the catalyst makes this methodology of wide synthetic
and commercial utility.
1
0. Typical Experimental Procedure: To a stirred solution of
the phenol (1 mmol) in acetone (15 ml) was added
nickel(II) nitrate (1 mmol) followed by a catalytic amount
of p-TSA (0.012 mmol) and the reaction mixture was
either refluxed or stirred at room temperature until all the
phenol was consumed. Acetone was removed under
vacuum and the crude mass was partitioned between
dichloromethane and water. The combined organic layers
were dried over anhydrous sodium sulfate and concen-
trated under vacuum. The crude product was purified by
silica gel column chromatography using hexane and ethyl
acetate (98:2) as eluent.
Acknowledgments
V.A. thanks Dr. J. S. Yadav, Director, IICT Hyderabad
for providing financial support and encouragement.
References and notes
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