Ozone-mediated nitration of phenylalkyl ethers, phenylacetic esters, and related compounds with nitrogen dioxide. the highest ortho substitution observed in the electrophilic nitration of arenes

Article abstract of DOI:10.1021/jo9606867

By the combined action of ozonized oxygen and nitrogen dioxide (the kyodai-nitration), the title compounds were smoothly nitrated in dichloromethane at subzero degrees with hiigh ortho positional selectivity. Although the conventional nitration of phenylacetic acid and esters mainly produces m- and p-nitro derivatives, the present nitration offers a simple high-yield synthesis of o-nitro derivatives which are important as precursor in organic synthesis. The proportions of the ortho isomer in the nitration products from methyl 2-phenylethyl ether and methyl phenylacetate were 71 and 88%, respectively, the latter value being the highest ortho isomer proportion so far observed in the electrophilic aromatic nitration. The observed high ortho selectivity has been rationalized in terms of radical cation intermediate and six-membered cyclic transition state.

Full text of DOI:10.1021/jo9606867

5944
J . Org. Chem. 1996, 61, 5944-5947
Ozon e-Med ia ted Nitr a tion of P h en yla lk yl Eth er s, P h en yla cetic
Ester s, a n d Rela ted Com p ou n d s w ith Nitr ogen Dioxid e. Th e
High est Or th o Su bstitu tion Obser ved in th e Electr op h ilic
Nitr a tion of Ar en es
Hitomi Suzuki,*,† Toyomi Takeuchi, and Tadashi Mori
Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa, Sakyo-ku,
Kyoto, 606-01, J apan
Received April 15, 1996X
By the combined action of ozonized oxygen and nitrogen dioxide (the kyodai-nitration), the title
compounds were smoothly nitrated in dichloromethane at subzero degrees with high ortho positional
selectivity. Although the conventional nitration of phenylacetic acid and esters mainly produces
m- and p-nitro derivatives, the present nitration offers a simple high-yield synthesis of o-nitro
derivatives which are important as precursor in organic synthesis. The proportions of the ortho
isomer in the nitration products from methyl 2-phenylethyl ether and methyl phenylacetate were
71 and 88%, respectively, the latter value being the highest ortho isomer proportion so far observed
in the electrophilic aromatic nitration. The observed high ortho selectivity has been rationalized
in terms of radical cation intermediate and six-membered cyclic transition state.
In tr od u ction
ity in the nitration of acetanilides.2 The recently reported
nitration of phenylacetic esters with nitric acid in dichlo-
romethane has shown that the high ortho selectivity can
be realized under appropriate substrate/reagent ratios.
This finding was interpreted in terms of the precomplex
formation between nitric acid and solvent employed.3
We report herein the ozone-mediated nitration of
phenylalkyl ethers, phenylacetic esters, and some related
compounds with nitrogen dioxide (the kyodai-nitration4),
proposing an alternative mechanistic view based on
radical cation intermediates for the observed high ortho
selectivity. The classical nitration of phenylacetic acid
and esters mainly produces m- and p-nitro derivatives,
while our nitration offers a unique, simple high-yield
synthesis of o-nitro derivatives which are important as
precursors to oxindoles and derivatives.5
The control of ortho-para isomer ratio in electrophilic
aromatic substitution is an everlasting challenge to
organic chemists. Low positional selectivity means the
formation of large amounts of unwanted product or
products, the disposal of which would often be problem-
atic, bringing on economical loss or environmental con-
cern. Steric bulkiness of reagent and/or substrate usually
provides one solution for para-selective aromatic substi-
tution. Thus the attachment of a bulky group such as
tert-butyl onto aromatic substrate directs the entering
electrophile to an unhindered site, favoring the substitu-
tion para to the blocking group. Some supported re-
agents and catalysts are also known to favor the para
substitution.1 However, is there any sort of promising
means available to us when we need the ortho substitu-
tion products?
Resu lts a n d Discu ssion
The nitration of benzylic ethers and phenylacetic esters
has been studied in some detail because of the synthetic
utilities of the products as well as mechanistic interest.
A high proportion of the o-nitro derivatives observed in
the nitration of these compounds with acetyl nitrate
stands in marked contrast to the results obtained from
the conventional nitration based on the use of nitric acid
alone or nitric acid-sulfuric acid (mixed acid). This
interesting phenonmenon has been explained in terms
of an SN2-type displacement reaction involving dinitrogen
pentaoxide as the actual nitrating species.2 The conven-
tional nitration of these compounds proceeds in strong
acid medium through a protonated or solvated species
rather than a neutral one, while a special mechanism
operates in the nitration with acetyl nitrate where the
nitronium ion, generated in situ from dinitrogen pen-
taoxide, coordinates toward the oxygen function of side
chain prior to the nuclear attack. A similar mechanism
has also been proposed to explain the high ortho selectiv-
Th e Kyod a i-Nit r a t ion of E t h er s. Methyl phenyl-
alkyl ethers 1 were smoothly nitrated by the kyodai
method to give an isomeric mixture of nitro compounds
in excellent yields (Table 1). The examination of meth-
oxyalkyl groups of different chain length has revealed
that the relative distance between the aromatic nucleus
and the oxygen atom has a profound influence over the
isomer composition of the products. Thus, when methyl
2-phenylethyl ether 1b was subjected to this reaction at
0 °C, the o-nitro ether 2b was obtained in a yield above
70%, the o/p isomer ratio being 2.73. A similar high ortho
selectivity was reported for the nitration with acetyl
nitrate in acetic anhydride (o/p ) 1.84).6 These results
contrast to the nitration with mixed acid, where the
major product is p-nitro derivative (o/p ) 0.3-0.5).7
When our reaction was carried out under much milder
conditions, the ortho selectivity was further improved;
(3) Strazzolini, P.; Verardo, G.; Gorassini, F.; Giumanini, A. G. Bull.
Chem. Soc. J pn. 1995, 68, 1155.
† E-mail: suzuki@kuchem.kyoto-u.ac.jp
X Abstract published in Advance ACS Abstracts, August 1, 1996.
(1) (a) Delaude, L.; Laszlo, P.; Smith, K. Acc. Chem. Res. 1993, 26,
607. (b) Malyshera, L. V.; Paukshtis, E. A.; Ione, K. G. Catal. Rev.
Sci. Eng. 1995, 37, 179. (c) Smith, K.; Musson, A.; DeBoos, G. A. J .
Chem. Soc., Chem. Commun. 1996, 469.
(4) For a survey, see: Mori, T.; Suzuki, H. Synlett 1995, 383.
(5) (a) Cooper, K. E.; Ingold, C. K. J . Chem. Soc. 1927, 836. (b)
Yabroff, D. L.; Porter, C. W. J . Am. Chem. Soc. 1932, 54, 1199.
(6) Knowles, J . R.; Norman, R. O. C. J . Chem. Soc. 1961, 3888.
(7) Hartshorn, S. R.; Moodie, R. B.; Schofield, K. J . Chem. Soc. (B)
1971, 2454.
(2) Norman, R. O. C.; Radda, G. K. J . Chem. Soc. 1961, 3030.
S0022-3263(96)00686-X CCC: $12.00 © 1996 American Chemical Society

Ozone-Mediated Nitration of Arenes with Nitrogen Dioxide
J . Org. Chem., Vol. 61, No. 17, 1996 5945
Ta ble 1. Th e Kyod a i-Nitr a tion s of Meth yl P h en yla lk yl
Eth er s 1a -d a n d P h en yla cetic Ester s 3a -ca
isomer
proportions
Ep yield (%)c o:m:p (%)
b
substrate
benzyl methyl ether
methyl 2-phenylethyl ether
1a 2.76 >99
69:4:27
71:3:26
79:2:19
81:6:13
38:3:59
54:3:43
70:4:26
88:4:8
1b 2.65 >99 (77)
98d
58e
methyl 3-phenylpropyl ether
methyl 4-phenylbutyl ether
tert-butyl 2-phenylethyl etherf
methyl phenylacetate
ethyl phenylacetate
1c 2.64 >99
1d 2.70 >99 (74)
2.63
3a 2.70
3b 2.79
3c 2.96
96 (77)
85 (84)
78
87:5:8
88:4:8
55:1:44
isobutyl phenylacetate
n-butylbenzene
50
2.66 >99
a
All reactions were carried out for a substrate (5 mmol) in
dichloromethane (20 mL) and nitrogen dioxide (1.0 mL) at 0 °C
b
for 1 h, unless otherwise indicated. V vs NHE. c GC yield.
d
Isolated yields after purification on silica gel are given in
parentheses. At -20 °C. e At -78 °C. f Reaction was carried out
using a double amount of nitrogen dioxide.
d
F igu r e 1. Frontier electron densities for the radical reaction,
calculated by the PM3 method, of the radical cations derived
from methyl 2-phenylethyl ether 6 and related compounds.
Sch em e 1
Sch em e 2
the reaction performed at -78 °C revealed as high as 81%
of the ortho product. The kyodai-nitration of n-butyl-
benzene carried out under the same conditions showed
the o/p isomer ratio of 1.25, demonstrating an important
role of the ether function in the enhancement of the ortho
substitution (Scheme 1).
The ortho selective substitution may be rationalized
on a similar basis as has been discussed in a previous
paper.8 For example, the SET reaction between nitrogen
trioxide and ether 1b generates the radical cation 6
through a radical cation-nitrate anion pair 5 (Scheme
2).9,10 Semiempirical MO calculation11 for radical cation
6 revealed its radical susceptibility to be highest on the
oxygen atom (Figure 1). Nitrogen dioxide combines with
the oxygen atom of the radical cation to form the
intermediate ion 7, which then rearranges through an
energetically favored, six-membered cyclic transition
state to yield the o-nitro isomer 2b.
A similar ortho enhancement was observed in 1,2-
dichloroethane, but in more polar solvents such as
nitromethane and acetonitrile, or in the presence of a
protic acid, the ortho selectivity decreased (Table 2). In
order to see if the coordination of an acid molecule to the
radical cation may lower the ortho selectivity, the semiem-
pirical MO calculation was carried out for a model species
8 in which one molecule of nitric acid is associated to the
radical cation 6 at the ether function (Figure 1). In this
Ta ble 2. Com p a r ison of th e Nitr a tion s of Meth yl
2-P h en yleth yl Eth er 1b u n d er Va r iou s Con d ition sa
isomer
conversion proportions
reagent
NO2-O3
solvent
CH2Cl2
additive
(%)
o:m:p (%)
-
34
26
79:4:17
70:2:28
MeSO3H
(1 equiv)
fum-HNO3
41
64:1:35
(1 equiv)
MeNO2
MeCN
CHCl3
-
-
-
37
38
14
45
-
66:3:31
65:4:31
76:4:20
81:2:17
29:9:62b
66:4:30b
ClCH2CH2Cl -
HNO3-H2SO4
AcONO2-MeCN
-
a
All reactions were carried out for the substrate (5 mmol) in
dichloromethane (20 mL) containing nitrogen dioxide (1.0 mL) at
b
0 °C for 10 min. At 0 °C. See ref 2.
simple model, the radical susceptibility of the oxygen
atom is lowered while that of the ring carbon atom at
para position is slightly increased as compared with the
noncoordinated species 6. The ratios of the coxygen/cp-carbon
coefficients are 2.35 and 2.15 for the relevant species 6
and 8, respectively, which correspond to ca. 10% increase
of the p-carbon selectivity. Association of multiple acid
and/or solvent molecules to the radical cation would lead
to much lower spin density on the oxygen atom, resulting
in further decrease in ortho orientation.
(8) Suzuki, H.; Tatsumi, A.; Ishibashi, T.; Mori, T. J . Chem. Soc.,
Perkin Trans. 1 1995, 339.
(9) (a) Suzuki, H.; Mori, T. J . Chem. Soc., Perkin Trans. 2 1996,
677. (b) Suzuki, H.; Mori, T. J . Chem. Soc., Perkin Trans. 2 1994,
479. (c) Suzuki, H.; Murashima, T.; Kozai, I.; Mori, T. J . Chem. Soc.,
Perkin Trans. 1 1993, 1591. (d) Suzuki, H.; Murashima, T.; Mori, T.
J . Chem. Soc., Chem. Commun. 1994, 1443.
(10) Suzuki, H.; Mori, T. J . Chem. Soc., Perkin Trans. 2 1995, 41.
(11) For calculation methods, see: (a) Stewart, J . J . P. J . Comput.
Chem. 1989, 10, 209. (b) Stewart, J . J . P. J . Comput. Chem. 1989, 10,
221. (c) Dewar, M. J . S.; Zoebish, E. G.; Healy, E. F.; Stewart, J . J . P.
J . Am. Chem. Soc. 1985, 107, 3902.

5946 J . Org. Chem., Vol. 61, No. 17, 1996
Suzuki et al.
Ta ble 3. Rela tive Ra tes a n d P a r tia l Ra te F a ctor s for th e
Kyod a i-Nitr a tion of Som e Selected Ar en es Bea r in g th e
Meth oxya lk yl or Alk oxyca r bon ylm eth yl Su bstitu en tsa
Sch em e 3
a
substrate
conditions
kPhR/kPhH
fo
fm fp reference
3
39 this workb
1b
NO2-O3
30
17
1.8
31
29
4
68
-
HNO3-Ac2O
HNO3-H2SO4
NO2-O3
-
-
3
-
7
7
-
-
1c
56
-
71 this workb
HNO3-Ac2O
HNO3-H2SO4
NO2-O3
-
-
3
-
-
8
7
7
Sch em e 4
-
3a
3b
15
3.7
37
this workb
HNO3-Ac2O
4.6 1.2 10 13
a
Relative rate to benzene. b Determined at around 15% conver-
sion in dichloromethane at 0 °C.
1b is slightly lower than that of toluene (ktoluene/kbenzene
)
329c), probably due to the electron-withdrawing nature
of the oxygen function on the side chain. Noticeable rate
enhancement is observed with those substrates which can
take a six-membered cyclic transition state, i.e., 1b and
3a . The nitration with mixed acid is slower, since the
substrates are protonated to a considerable extent in a
strong acid such as sulfuric acid.7
Con clu sion
Methyl 2-phenylethyl ether and phenylacetic esters
undergo the kyodai-nitration smoothly in dichloromethane
at subzero degrees to produce a high proportion of the
corresponding ortho isomers. The high ortho selectivity
may be rationalized by the initial attachment of nitrogen
dioxide to the oxygen atom of the substrate radical cation,
followed by a rearrangement of the resulting oxonium
ion intermediate through a six-membered cyclic transi-
tion state.
The kyodai-nitration in chloroform was found to be
somewhat sluggish as compared with those carried out
in the other solvents (Table 2). A similar anomaly
observed in the kyodai-nitration of benzene in chloro-
form10 was attributed to the fact that chloroform is 10
times more reactive toward nitrogen trioxide than dichlo-
romethane.12
Th e Kyod a i-Nitr a tion of Ester s. Under similar
conditions, alkyl esters of phenylacetic acid 3 were also
easily nitrated to give a high proportion of the ortho
isomers 4 in good yields (Scheme 3; Table 1). The
reactions proceeded more slowly as compared to the
nitration of phenylalkyl ethers, and nitrophenylacetic
acid 12 was obtained as a minor byproduct.
Exp er im en ta l Section
General experimental details were given in previous
papers.8-10 All reagents and solvents used were reagent-grade
commercial products. Dichloromethane was dried by distil-
lation from calcium hydride. Nitrogen dioxide (99% pure) was
obtained in a cylinder from Sumitomo Seika Co. Ltd. and used
after transfer distillation. An apparatus (Nippon Ozone Co.
Ltd., type ON-1-2) was used for the generation of ozone. The
machine produced ozone at a rate of 0.6 mmol min-1 with an
oxygen flow of 10 L h-1 under an applied voltage of 80 V. Its
efficiency was calibrated by iodometric titration. Methyl
2-phenylethyl ether and homologous ethers were prepared
from the corresponding alcohols by standard methods.2 tert-
Butyl 2-phenylethyl ether was prepared according to the
literature procedure.14 Methyl, ethyl, and sec-butyl phenylac-
etates were used as obtained. All products were known and
The high ortho orientation may be explained in a way
similar to that made for the nitration of phenylethyl ether
(Scheme 4). The oxonium ion intermediates 10 and/or
11 derived from the reaction of nitrogen dioxide and
radical cation 9 undergo rearrangement through a six-
membered cyclic transition state to afford the ortho nitro
products 4. The semiempirical MO calculation performed
for the radical cation 9a revealed the high radical
susceptibility of both the alcoholic and carbonyl oxygen
atoms (Figure 1). The value at the ipso position is also
high, but the attachment of a nitrogen dioxide molecule
to this carbon atom would be less favored by steric
hindrance of the side chain. The side product 12 can be
derived from the nitrogen dioxide adduct 10 by a loss of
alkyl moiety. Diminished yield of the mononitration
products according to the increase of steric bulk of alkyl
groups may be a reflection of easier loss of the alkyl
moiety as a cation (Table 1).
1
identified by H-NMR, IR, GC-MS spectroscopies or by direct
comparison with the authentic samples. Cyclic voltammetry
was performed on a BAS-CV-50W electrochemical analyzer.
Anodic peak potentials in the irreversible cyclic voltammo-
grams were measured using a platinum electrode in dichlo-
-
romethane containing 0.1 M nBu4N+PF6 at a sweep rate of
100 mV s-1. The Ag/AgNO3 reference electrode was used and
converted to the V vs NHE values by the relationship: E(NHE)
) E(Ag/AgNO3) + 0.49 V.
Th e Kyod a i-Nitr a tion of Meth yl P h en yla lk yl Eth er s
(1) a n d P h en yla cetic Ester s (3): Typ ica l P r oced u r e.
Methyl 2-phenylethyl ether (1b) (0.68 g, 5 mmol) was dissolved
in a freshly distilled dichloromethane (20 mL) containing
nitrogen dioxide (1.0 mL), and the solution was placed in a
three-necked flask fitted with a gas inlet tube and a vent which
permitted waste gas to escape. The third neck was used for
withdrawing an aliquot for monitoring. The mixture was
P a r tia l Ra te F a ctor s. Relative rates and partial rate
factors of the nitration are given for some selected
substrates in Table 3. Partial rate factors for the ortho
substitution of the compounds 1b and 3a are higher than
those of toluene or compound 1c.7,13 The relative rate of
(12) Boyd, A. A.; Canosa-Mas, C. E.; King, A. D.; Wayne, R. P.;
Wilson, M. R. J . Chem. Soc., Faraday Trans. 1991, 87, 2913.
(13) Ingold, C. K.; Shaw, F. R. J . Chem. Soc. 1949, 575.
(14) Holcombe, J . L.; Livinghouse, T. J . Org. Chem. 1986, 51, 111.

Ozone-Mediated Nitration of Arenes with Nitrogen Dioxide
J . Org. Chem., Vol. 61, No. 17, 1996 5947
cooled to 0 °C externally with a cooling bath (EYELA COOL
ECS-1 with two thermocontrollers THS-40 and THD-50), while
a stream of ozonized oxygen was introduced under vigorous
magnetic stirring from the gas inlet tube, which should dip
just below the surface of the liquid in the flask. Throughout
the reaction, ozonized oxygen was fed continuously at a low
flow rate. Under these reaction conditions, the loss of nitrogen
dioxide was not so significant. After 1 h the reaction was
quenched by the addition of iced water, and excess nitrogen
dioxide was expelled by blowing argon into the solution. The
resulting mixture was neutralized with saturated aqueous
sodium hydrogen carbonate (30 mL), and the organic phase
was separated, washed successively with water (30 mL) and
brine (30 mL), and dried over sodium sulfate. Removal of the
solvent under reduced pressure left a mixture of unreacted
substrate and isomeric nitro ethers as an oily residue. The
isomer composition was determined by GLC using cyclodode-
cane as an internal standard on a Shimadzu gas chromato-
graph instrument GC-14A, fitted with a fused silica capillary
column (J &W Scientific, DB-5-30N-STD, 30 m × 0.25 mm i.d.,
5% phenyl-methylsilicone, df ) 0.25 mm) and a flame ioniza-
tion detector. Peak areas were determined using a Shimadzu
C-R5A Chromatopac computing integrator.
Molecu la r Or bita l Ca lcu la tion s. All semiempirical cal-
culations were carried out with the MOPAC11 program using
the PM3 Hamiltonian implemented on a Sony Tektronix
CAChe system (versions 3.7 and 3.8). Unrestricted Hartree-
Fock wave functions were employed, and the calculations were
carried out by full optimization using an extra keyword
PRECISE. The frontier electron densities for radical reactions
were defined by Fukui et al. as a sum of the HOMO and SOMO
coefficients.15
Ack n ow led gm en t. Financial support of this work
from the Grant-in-Aid for Scientific Research (No.
05554023) of the Ministry of Education, Science, Sports
and Culture of J apan is gratefully acknowledged. T.M.
thanks the J apan Society for the Promotion of Science
for the Fellowship (No. 5026).
J O9606867
(15) (a) Fukui, K.; Yonezawa, T.; Nagata, V.; Shingu, H. J . Chem.
Phys. 1954, 22, 1433. (b) Fukui, K.; Yonezawa, T.; Shingu, H. J . Chem.
Phys. 1952, 20, 722.