A novel one pot synthesis of o-nitrophenylacetic acid and unexpected p-nitrobenzoic acid by HNO3-mediated CH2 extrusion reaction of phenylacetic acid

Article abstract of DOI:10.1002/cjoc.201180458

The HNO₃-mediated CH₂ extrusion reactions of phenylacetic acid lead to one pot synthesis of unexpected commercially important product 4-nitrobenzoic acid through the formation of 4-nitrophenylacetic acid and 2-nitrophenylacetic acid. Copyright

Full text of DOI:10.1002/cjoc.201180458

FULL PAPER
DOI: 10.1002/cjoc.201180458
A Novel One Pot Synthesis of o-Nitrophenylacetic Acid and
Unexpected p-Nitrobenzoic Acid by HNO3-Mediated CH2
Extrusion Reaction of Phenylacetic Acid
Sohail, Muhammad*,a,b
Raza, Abdul Raufa
a Ibn-e-Sina Block, Department of Chemistry, University of Sargodha, Sargodha 40100, Pakistan
b Department of Applied Chemistry, School of Chemical Engineering and Environment, Beijing Institute of
Technology, 5 South Zhongguancun Street, Haidian District, Beijing 100081, China
The HNO3-mediated CH2 extrusion reactions of phenylacetic acid lead to one pot synthesis of unexpected
commercially important product 4-nitrobenzoic acid through the formation of 4-nitrophenylacetic acid and
2-nitrophenylacetic acid.
Keywords synthetic methods, regioselectivity, carboxylic acid, aromatic substitution, industrial chemistry
Introduction
Results and Discussion
The extrusion reactions involving the removal of sta-
ble entities, such as N2,[1] CO2,[2] CO,[3] SO2,[4] SO,[5]
S,[6] Se,[7] Me2SiO,[8] etc., are already reported. No re-
port is available that describes the one step synthesis of
4-nitrobenzoic acid by a possible extrusion of an unsta-
ble entity like :CH2 and commercially expensive ortho-
nitrophenylacetic acid which is difficult with respect to
its regioselectivity. The former itself has a wide indus-
trial applications on commercial scale in azodyes, drug
intermediates,[9] p-aminobenzoic acid,[10] follic acid[11]
etc.
Selectivity regarding the ortho nitration of
phenylacetic acid (PAA) on commercial scale is still
demanding leading towards the asymmetric synthesis of
isocoumarins involving the coupling of substituted ho-
mophthalic acid 2 with N-protected-(S)-amino acid
chlorides 3 and 3,4-dihydroisocoumarins, which at-
tracted us due to wide range of biological applications
like anti-malarial[12] anti-cancer[13] and anti-HIV[14]
agents (Scheme 1). Both 4-nitrobenzoic acid and
2-nitroPAA are used on commercial scale.
The o-regioselectivity in the nitration of PAA 1 im-
proves by decrease in temperature.[15] The nitration of
PAA below 60 ℃ with HNO3 and H2SO4 normally
yields dinitroPAA.[16] A mixture of products (ortho,
meta and para) with poor yield was obtained by the ni-
tration of PAA with HNO3 and catalytic amount of
H2SO4 at low temperature conditions. In order to im-
prove the selectivity the nitration of PAA with same
equivalents of HNO3 and H2SO4 at elevated temperature
(90 ℃ ) afforded very interesting results. The
o-nitroPAA 5 and p-nitrobenzoic acid 6a were obtained
in high yields upon treatment with nitrating mixture
followed by at 90 ℃ (Scheme 2). According to our
finding the 5∶6a depends upon the number of equiva-
lents of HNO3. The yield of 6a increases by the increase
in equivalents of HNO3 (Table 1).
These results clearly suggest that it is the first nitra-
tion that takes place followed by extrusion; when less
equivalents of HNO3 are used it causes stabilization of
＋NO2 by coordination with COOH group leading to the
o-nitration of 1a[17] hence, more cations are trapped and
less are available for p-nitration resulting in regioselec-
tivity of 5 (Scheme 3 & Figure 2).[18] By increasing
Scheme 1
Scheme 2
*
E-mail: binnawaz@hotmail.com, binnawaz@gmail.com; Tel.: 0086-18910628797
Received May 3, 2011; accepted August 23, 2011; published online January 19, 2012.
Chin. J. Chem. 2012, 30, 353—356
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
353

Sohail & Raza
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Table 1 Dependence of CH2 extrusion on equivalents of HNO3
The absence of CH2 signal both in H & 13C NMR
(broad band and dept-45/135 assignments) indicates the
removal of CH2 from 7 to afford 6a. Similarly, the sin-
gle crystal XRD data of 6a also confirm the removal of
CH2 entity (Figure 2).[20] The same behavior was ob-
served when the nitration of homophthalic acid 1b was
carried out leading to the formation of phthallic acid 6b.
1
Equivalents to 1a
Yield/%
Entry
HNO3
2.26
3.39
4.52
5.65
6.78
H2SO4
5
6a
40
51
55
63
73
1
2
3
4
5
0.96
1.14
1.92
2.4
55
44
40
30
7.7
2.88
Scheme 3
more equivalents of HNO3 the regioselectivity reverses
because more free ＋NO2 ions are available. These
conditions may be exploited for one step synthesis of
commercially important regioisomers 5 and 6a.
Upon quenching the reaction after 20 min o-nitroPAA
5 and p-nitroPAA 7 were produced in 7∶3 ratio[19] while
using nitrating mixture in 2.35∶1 (HNO3∶H2SO4). The
formation of 7 and 6a in contrast to meta directing ben-
zoic acid reveals that the p-nitration takes place first prior
1
to the :CH2 extrusion. The presence of H signals of 2H
integration (singlet) at δ 3.76 and two sets of doublets of
same integration at δ 8.08 and 7.51 (J＝8.2 Hz) con-
firmed the formation of 7 (Figure 1).
Figure 2 Single crystal-XRD structures of 5 and 6a.
All these spectroscopic evidence confirms the extru-
sion of CH2. There are two possible mechanisms that
may be the reason of this extrusion. First, the p-nitration
of 1a to 7 followed by the interaction of —COOH
group with excess of ＋ NO2 ion, since over two
equivalents of HNO3 were used in all reactions, results
in the formation of 7a. This intermediate, rather
o-nitration, releases ＋NO2 ion and CH2 to afford 6a
(Scheme 4). Second, the interaction of enol form of 7
with ＋NO2 ion results in the formation of 7b that leads
to the formation of 1,3,2-dioxazolidine 7c upon rear-
rangement. The decarboxylation from this heterocyclic
intermediate 7c at high temperature (90 ℃) yields an
intermediate 7d that upon addition of H2O followed by
oxidation of C and removal of hydroxylamine results in
the formation of 6a (Scheme 5). While strong hydrogen
bonding between NO2 and OH of COOH in ortho-
nitroPAA 5 stablizes its hypothetical enol form.
Scheme 4
Figure 1 1H NMR (500 MHz, CD3OD) of a mixture of 5 and 7.
The integration of signals reveals the yield (7∶3 respectively).
354
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 353—356

A Novel One Pot Synthesis of o-Nitrophenylacetic Acid and Unexpected p-Nitrobenzoic Acid
Scheme 5
has been developed for the synthesis of ortho-nitroPAA
which was previously difficult to synthesize with re-
spect to its selectivity and separation of regioisomers.
This is first report according to our knowledge for the
direct synthesis of para-nirtobenzoic acid.
Experimental Section
General experimental methods
All solids used during research were re-crystallized
while liquid reagents and solvents were distilled prior to
use. Reaction monitoring and determination of the pu-
rity of the products must be carried out by TLC (thin
layer chromatography) which can be visualized under
UV lamp. For column chromatography, flash silica
(mesh size＝0.063—0.200 mm) was used as solid sup-
port.
The EIMS of derivatives of PAA showed very inter-
esting results as well. Since highly accelerated electrons
with 70 eV energy are bombarded in EIMS, therefore, it
makes conditions very harsh that probably causes extru-
sion of CH2. The EIMS of derivatives of PAA (8—9)
showed molecular ions and an additional daughter ion
[M－14] showing the CH2 loss, whereas, 5 showed no
molecular ion but showed [M－14] CH2 loss. Neither
ions were detected in 10. The harsh conditions and the
presence of electron withdrawing groups, it means, ac-
celerate the CH2 extrusion but the reason of no extru-
sion in 6a is still unclear and under investigation.
This mystery can be solved to confirm the mecha-
nism, whether CH2 or CO2 leaves, by carrying out the
nitration of isotopic (13C) labeled PAA 1a and ho-
mophthalic acid 1b. The allylic bromination of toluene
followed by substitution with isotopic labeled CN anion
and acid hydrolysis will afford isotopic labeled PAA 13.
According to other scheme, the allylic bromination of
o-toluic acid followed by same sequence will afford the
isotopic labeled homophthallic acid 16 (Scheme 6). If
the CH2 extrusion takes place upon nitration of 13 or 16
then only isotopic labeled products 17a—17b will be
formed (Scheme 4), whereas, decarboxylation will af-
ford normal 3a—3b products (Scheme 5). These studies
are still in progress.
The melting points were recorded on a Gallenkamp
melting point apparatus Cat No. MFB595010M and are
reported uncorrected. Infra red spectra were recorded on
Perkin Elmer Nicolet 510P FT-IR spectrometer and
were run as a neat thin film of liquid compounds be-
tween KBr discs. UV spectra were recorded on Thermo
Spectronic UV-300 spectrometer using quartz cell in
MeOH. Low-resolution mass spectra (LREIMS) were
recorded on a Fisons Instrument VG Autospec mass
1
spectrometer using electron impact at 70 eV. H NMR
spectra were recorded on 300 MHz Bruker Avance
AC-300, 400 or 500 MHz Bruker AMX 500 instruments.
The 13C NMR were recorded on a Bruker Avance
AC-300 instrument at 75 MHz or Bruker AMX 500 in-
strument at 100 MHz.
2-(2-Nitrophenyl)acetic acid 5 The H2SO4 (9.01 g,
92 mmol) was added as drops to stirred HNO3 (13.65 g,
0.22 mol) at room temperature. Solid phenylacetic acid
1 (13 g, 96 mmol) was added slowly to the nitrating
mixture and the temperature was controlled to 90 ℃.
The reaction mixture was heated for 5 h at 90 ℃. The
residue was filtered and washed with H2O (30 mL). The
solid was dissolved in CHCl3 (30 mL), filtered, dried
over anhydrous Na2SO4, concentrated under reduced
pressure and crystallization from CHCl3 afforded
Conclusions
An efficient, novel and economically cheap method
Scheme 6
Chin. J. Chem. 2012, 30, 353—356
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
355

Sohail & Raza
FULL PAPER
pale-yellow crystals of 2-(2-nitrophenyl)acetic acid 5
(7.0 g, 40%); m.p. 141 ℃ (from CHCl3); Rf 0.65
ernment of Pakistan for a research project grant
(HEC-20-809) and generous studentship to our research
group students. We also thank Dr. Muhammad Nawaz
Tahir (Department of Physics, University of Sargodha,
Sargodha, Pakistan) for his support in analyzing the
compound by XRD and Dr. Muhammad Danish (De-
partment of Chemistry, University of Gujrat, Gujrat,
Pakistan) for useful discussion.
(EtOAc); IR (KBr) υmax: 1698 (C＝O), 1523 (N＝O)
－
1
1
cm ; H NMR (CDCl3, 400 MHz) δ: 8.12 (d, J＝7.6
Hz, 1H, 3'-H), 7.60 (ddd, J＝7.6, 7.6, 0.8 Hz, 1H, 5'-H),
7.48 (ddd, J＝8.0, 8.0, 0.8 Hz, 1H, 4'-H), 7.35 (d, J＝
7.6 Hz, 1H, 6'-H), 4.0 (s, 2H, CH2); 13C NMR (CDCl3,
100.6 MHz) δ: 175.4 (s, COOH), 148.6 (s, C-2'), 133.7,
133.4, (d, C-3' & C-5') 129.1 (s, C-1'), 128.8, 125.4 (d,
C-4' & C-6'), 39.5 (t, CH2); MS(EI) m/z (%): 167 (M＋
•
References and Note
＋
•
－CH2, X, 20), 120 (X－HNO2, 85), 135 (M －NO2,
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100).
p-Nitrobenzoic acid 6a The residue of above pro-
cedure was dissolved in MeOH, dried over anhydrous
Na2SO4, concentrated under reduced pressure and left
for crystallization that afforded the pure p-nitrobenzoic
acid 6a (9.6 g, 60%) as crystalline solid. m.p. 242 ℃
(from MeOH); Rf 0.302 (EtOAc); IR (KBr) υmax: 1710
－
1
1
(C＝O), 1554 (N＝O) cm ; H NMR (CD3OD, 300
MHz) δ: 8.30 (d, J＝8.9 Hz, 2H, 3'-H), 8.21 (d, J＝8.9
Hz, 2H, 2'-H); 13C NMR (CD3OD, 75.5 MHz) δ: 167.6
(s, COOH), 152.0 (s, C-4'), 137.6, (s, C-1'), 132.0 (d,
＋
•
2C-3'), 124.5 (d, 2C-2'); MS(EI) m/z (%): 167 (M ,
＋
＋
•
•
100), 150 (M －•OH, X, 8), 122 (X－CO, 7), 121 (M
－NO2, Y, 73), 104 (Y－•OH, Z, 12), 76 (Z－CO, 18).
Phthalic acid 6b The H2SO4 (4.71 g, 48 mmol)
was added slowly to the stirred HNO3 (7.11 g, 0.113
mol) at room temperature. The solid homophtalic acid
1b (3 g, 16.6 mmol) was added in portions to the nitrat-
ing mixture and the temperature was controlled to 90 ℃.
The reaction mixture was heated for 5 h at 90 ℃ and
left overnight for stirring. The residue was filtered,
washed with H2O (30 mL), dissolved in MeOH, dried
over anhydrous Na2SO4, concentrated in vacuo and
crystallized at 7 ℃ to afford colorless crystals of
phthalic acid 6b (1.39 g, 51%). m.p. 214 ℃ (from
MeOH); Rf: 0.35 (MeCN); IR (KBr) υmax: 3050 (OH),
－
＋
•
1
1690 (C＝O) cm ; MS (EI) m/z (%): 166 (M , 3), 149
＋
＋
•
(M －•OH, A, 13), 148 (M －H2O, Y, 19), 105 (X－
•
[18] Tonogaki, M.; Kawata, T.; Ohba, S.; Iwata, Y.; Shibuya, I. Acta
Cryst. 1993, B27, 1031.
＋
CO2, 100), 104 (Y－CO2, 95), 122 (M• －CO2, 90).
1
[19] The ratio is calculated by integrating the CH2 signals in H NMR of
reaction mixture of 5 and 7.
[20] Wardell, J. L.; Low, J. N.; Glidewell, C. Acta Cryst. 2006, E62,
Acknowledgement
We thank the Higher Education Commission, Gov-
o1915.
(E1105035 Cheng F.)
356
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 353—356