Regioselectivity in the nitration of dialkoxybenzenes

Article abstract of DOI:10.1021/jo102113t

Dinitrodialkoxybenzene derivatives are important precursors for Schiff base macrocycles and a variety of other molecules. During our investigations, we have found that the dinitration reaction of 1,2-dialkoxybenzenes proceeds with unusual regioselectivity

Full text of DOI:10.1021/jo102113t

pubs.acs.org/joc
Regioselectivity in the Nitration of Dialkoxybenzenes
Kevin Shopsowitz,† Francesco Lelj,*,‡ and Mark J. MacLachlan*,†
†Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1,
Canada, and La.M.I. and LaSCAMM INSTM Sezione Basilicata, Dipartimento di Chimica,
ꢀ
Universita della Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy
‡
francesco.lelj@unibas.it; mmaclach@chem.ubc.ca
Received October 25, 2010
Dinitrodialkoxybenzene derivatives are important precursors for Schiff base macrocycles and a
variety of other molecules. During our investigations, we have found that the dinitration reaction of
1,2-dialkoxybenzenes proceeds with unusual regioselectivity, giving exclusively the desired 1,2-
dialkoxy-4,5-dinitrobenzene product, but we have been unable to find a good explanation for this
result. The dinitration of 1,4-dialkoxybenzene derivatives also exhibits surprising regioselecti-
vity that has hitherto been left unexplained. Herein, we report a detailed DFT analysis of the
regioselective dinitration of both 1,2- and 1,4-dimethoxybenzene. These results show that the
reaction mechanism likely involves a single electron transfer (SET) process. In the case of the former
isomer, the regioselectivity is mainly determined by the symmetry of the HOMO of the aromatic
moiety that defines the structure of the SHOMO of the aromatic radical cation formed by the SET
process. In the case of the latter isomer, the selectivity is due mainly to solvation effects and may thus
be altered depending on the solvent environment. Synthetic studies of the nitration of 1,4-
dialkoxybenzene derivatives using different solvent conditions support this conclusion and provide
practical information for tuning the regioselectivity of the reaction.
Introduction
(e.g., 2a-d) with dialdehyde 3, Scheme 1.4 These macrocycles
with peripheral alkoxy chains exhibit interesting coordination
and supramolecular chemistry.5,6
The preparation of macrocycles 4 requires diamines 2,
which are easily synthesized by the reduction of dinitroaryl
compounds 1 (Scheme 1). In addition to their application in
Schiff base macrocycle synthesis, 1,2-dialkoxy-4,5-dinitro-
benzene compounds (e.g., 1a-d) and their reduced diamine
derivatives (e.g., 2a-d) are useful precursors for many
compounds, including liquid crystals,7 optical materials,8
Schiff base condensation is a convenient method for the
construction of macrocycles1,2 and complex structures.3 We
have been investigating macrocycles 4a-d, which are prepared
by the condensation of 1,2-dialkoxy-4,5-diaminobenzenes
(1) (a) Borisova, N. E.; Reshetova, M. D.; Ustynyuk, Y. A. Chem. Rev.
2007, 107, 46–79. (b) Vigato, P. A.; Tamburini, S.; Bertolo, L. Coord. Chem.
Rev. 2007, 251, 1311–1492. (c) MacLachlan, M. J. Pure Appl. Chem. 2006, 78,
873–888.
DOI: 10.1021/jo102113t
r
Published on Web 01/31/2011
J. Org. Chem. 2011, 76, 1285–1294 1285
2011 American Chemical Society

Shopsowitz et al.
JOCArticle
SCHEME 1. Synthesis of Macrocycles 4
and pharmaceuticals.9 Typically, the dinitroaryl compounds
1 are readily prepared by the nitration of 1,2-dialkoxyben-
zene derivatives in concentrated nitric acid, which almost
exclusively yields the desired 4,5-dinitro product.10 While
this has been extremely beneficial to our study of Schiff base
macrocycles, we have previously been unable to find an
adequate explanation for this surprising regioselectivity.
Like their 1,2-dialkoxy counterparts, 1,4-dialkoxy-2,3-
dinitrobenzene derivatives 5 are another class of compounds
that are useful precursors for many different molecules,
potentially including new Schiff base macrocycles. From
the basic rules for electrophilic aromatic substitution, one
would predict that the dinitration of 1,4-dimethoxybenzene
(8a) would give primarily the 2,6-dinitro isomer 9 (favorable
from the o,p-directing methoxy groups and the m-directing
ability of the nitro group), with the 2,3-dinitro isomer being
the least favored due to sterics; Scheme 3 shows the possible
dinitration products. To our surprise, we found in the litera-
ture that nitration of 1,4-dimethoxybenzene yields only the
2,3-dinitro and 2,5-dinitro isomers 5a and 10a. Furthermore
the relative amounts of 5a and 10a reported vary significantly
from study to study depending on the conditions used.11 Others
have also expressed surprise at the regioselectivity of this
reaction,12 but we have been unable to find a good explanation
for this result.
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SCHEME 2. Proposed Synthesis of Macrocycles 7
was based on more solid grounds,16 though some doubts were
cast on this pathway in the case of aromatic compounds with
lower ionization potentials.17 According to this mechanism, it
was suggested that the early stages of the nitration reaction
could be related to an electron transfer process between the
SCHEME 3. Possible Nitration Products from the
Nitration of 8a
þ
aromatic molecule and the NO2 cation. Figure 1 shows the
two different mechanisms.
The two-electron process assumes that the main process is
related to the formation of an intermediate nitrated cationic
species. In the single electron transfer (SET) model, the
nitraþtion reaction is a two-step redox process in which the
NO2 ion is first reduced by the aromatic molecule. The
intimate complex of the two radicals then evolves into a
cationic transition state that further yields the Wheland
intermediate cationic species, which, after exchanging a
proton by either an intra- or intermolecular (solvent) pro-
cess, yields the nitroaromatic derivative.
In this paper, we provide a detailed computational ex-
planation for the regioselective dinitration of both 1,2- and
1,4-dimethoxybenzene. We also discuss the synthesis of some
new 1,4-dialkoxydinitrobenzene derivatives and provide ex-
perimental observations on the effects of alkoxy chain length
and solvent on the selectivity of the reaction.
Results and Discussion
The two possible mechanisms have been investigated by
several computational approaches. Some early investiga-
tions, based on a single-determinant approach, mainly at-
tempted to describe the transition states and intermediates
for the Wheland mechanism,18 while other authors have
investigated the one-electron process in a multideterminan-
tal framework.19
The dinitration of 1,2-dialkoxybenzenes yields the 4,5-
dinitro isomer as the only product regardless of which alkoxy
chains are present. In contrast, the nitration of 1,4-dimethoxy-
benzene in concentrated nitric acid yields the 2,3-dinitro
isomer as the major product and the 2,5-dinitro isomer as a
minor product (∼9:1). The introduction of different alkoxy
chains and/or solvent conditions results in a change in the
relative amounts of the 2,3- and 2,5-dinitro isomers formed
from the reaction (Scheme 4, Table 7). In the following
sections we provide a detailed computational and theoretical
explanation for these unexpected regioselectivies and experi-
mental observations that examine factors influencing the
selectivity of the nitration of 1,4-dialkoxybenzenes.
Computational Studies of the Nitration of 1,2-Dialkoxy-
benzenes. Electrophilic aromatic substitution reactions have
been thoroughly and intensively studied and debated for
many years. Among these, nitration reactions have been
assumed to proceed according to the same mechanism as
other electrophilic reagents. In particular, it was thought that
in the early stage of the reaction it proceeds according to the
same mechanism as the class of reactions giving rise to a high-
energy intermediate, the so-called Wheland adduct.13 Besides
the polar electrophilic reaction mechanism, a one-electron
pathway was also proposed.14,15 After 1977, this hypothesis
More recent computational investigations20 have been
undertaken at the DFT level and have discussed the first
step in the nitration process. Upon changing the substituent
on a monosubstituted benzene ring, the reaction can trans-
form from a one-electron to a two-electron process.21 An
accurate multideterminantal investigation22 compared the
NOþ and NO2þ electrophilic processes and concluded that in
(16) Perrin, C. L. J. Am. Chem. Soc. 1977, 99, 5516–5518.
€
(17) (a) Eberson, L.; Jonsson, L.; Radner, F. Acta Chem. Scand. B 1978,
32, 749–753. (b) Eberson, L.; Radner, F. Acta Chem. Scand. B 1980, 34, 739.
(c) Eberson, L.; Radner, F. Acc. Chem. Res. 1987, 20, 53–59.
(18) Chen, L.; Xiao, H.; Xiao, J.; Gong, X. J. Phys. Chem. A 2003, 107,
11440–11444.
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(b) Albunia, A. R.; Borrelli, R.; Peluso, A. Theor. Chem. Acc. 2000, 104, 218–
222.
(20) Esteves, P. M.; Carneiro, J. W. D.; Cardoso, S. P.; Barbosa, A. G. H.;
Laali, K. K.; Rasul, G.; Prakash, G. K. S.; Olah, G. A. J. Am. Chem. Soc.
2003, 125, 4836–4849.
(21) de Queiroz, J. F.; Carneiro, J. W. D..; Sabino, A. A.; Sparrapan, R.;
Eberlin, M. N.; Esteves, P. M. J. Org. Chem. 2006, 71, 6192–6203.
(22) (a) Gwaltney, S. R.; Rosokha, S. V.; Head-Gordon, M.; Kochi, J. K.
J. Am. Chem. Soc. 2003, 125, 3273–3283. (b) Rosokha, S. V.; Kochi, J. K.
Charge-Transfer Effects on Arene Structure and Reactivity. In Modern
Arene Chemistry; Astruc, D., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA:
Weinheim, 2002; pp 435-478.
(13) (a) Wheland, G. W. J. Am. Chem. Soc. 1942, 64, 900–908. (b) Wheland,
G. W. The Theory of Resonance; Wiley: New York, 1944. (c) Olah, G. A. Acc.
Chem. Res. 1971, 4, 240–248.
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(15) Weiss, J. Trans. Faraday Soc. 1946, 42, 116–121.
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FIGURE 1. Two possible mechanisms proposed for the nitration of benzene. Adapted from ref 21.
SCHEME 4. Nitration of 1,4-Dialkoxybenzene Derivatives 8a-d
the case of the benzene molecule they can both be described
as single electron transfer processes. According to this view,
which is the intermediate in the double nitration of vera-
trole. For 1,2-DMNB, the interaction energy surface with
a NO2 ion has been computed as a function of two
þ
þ
the NO2 cation is first π-coordinated to the benzene
molecule (the precursor complex, PC). Further electron
spherical angular variables, as defined in Figure 2. Thþe
aromatic moiety has been assumed rigid, and the NO2
ion’s geometrical parameters, the separation between the
center ofþthe aromatic ring and the nitrogen atom, and
the NO2 moiety’s orientation relative to the aromatic
molecule have been fully optimized. Starting from the
geometry of the most stable structures, whose angular
(θ, φ) parameters are close to the 3, 4, and 5 unsubstituted
positions, the molecular energy has been further mini-
mized in the space of the whole set of molecular geometric
parameters.
A plot of the energy as a function of the θ,φ angular
parameters is shown in Figure 3. Energies corresponding to
the same φ angle are connected. Superimposed on this plot is
the aromatic molecule. It can easily be seen that the most
stable adduct is the one on the rim of the aromatic ring close
to the C2 position (see blue and indigo lines). This adduct is
characterized by a zenith angle in the range of 20-30°, hence
close to the perpendicular of the aromatic molecule, suggest-
ing that the most stable adduct should be the ipso one on the
C2 π system. In fact, in the case of a monosubstituted
benzene ring, the possibility of an ipso adduct has also been
reported23 along with the formation of adducts on the
carbons bearing hydrogen atoms.24 This has been discussed
3
transfer generates the NO2 radical π-coordinated to the
rim of the benzene radical cation at a distance of 2.175 A. In
the case of benzene as the substrate, the rate-determining
step appears to be the transformation of the PC to the σ
complex (successor complex, SC). The last step is the
scission of the C-H bond in the σ complex, which is fast
and, in the case of the benzene molecule, shows no deuter-
ium isotope effect. This process can be intra- or intermolec-
ular if an opportune Lewis base accepts the proton from
the protonated aromatic molecule. A further process in-
volves the 1,2 migration of the NO2 moiety between adja-
cent carbon atoms. For the benzene molecule, this has a
very low activation barrier comparable to the PC-SC
energy barrier.20
þ
The potential energy surface for the interaction of NO2
and benzene is very complex, and many intermediates and
side products have been documented.20 On the other hand no
previous studies have been performed on multisubstituted
benzene rings. Last, but not least, the contribution of solva-
tion effects cannot be underestimated due to the different
polarization induced by and on the solvent in the case of
different isomers. It has been shown that this can be very
relevant in the case of nitration processes on benzene
molecules.18
(23) Perrin, C. L.; Skinner, G. A. J. Am. Chem. Soc. 1971, 93, 3389–3394.
(24) De Queiroz, J. F.; Carneiro, J. W. D.; Sabino, A. A.; Sparrapan, R.;
Eberlin, M. N.; Esteves, P. M. J. Org. Chem. 2006, 71, 6192–6203.
For purposes of computation, we examined the mechanism
of nitration of 1,2-dimethoxy-4-nitrobenzene (1,2-DMNB),
1288 J. Org. Chem. Vol. 76, No. 5, 2011

Shopsowitz et al.
JOCArticle
C6 show an increase in energy going from 5° to 45°, the
former showing the largest gradient.
The energies of the different Wheland intermediates have
been computed with full geometry optimization starting
from the most stable structures that were previously located.
From Table 1 it can be seen that the adduct stability order is
C5 ≈ C1-C2 (π) . C6 ≈ C3. Indeed the last structure can be
obtained only by an NO2þ migration from the π adduct on
the rim between the C1 and C2 carbon atoms with a transition
state (C1-C2)fC3. In fact the lowest energy structure obtained
from the previous map always ended with a π adduct on the
molecular rim between C1 and C2. This pattern suggests that
substitution in position 5 should be the most easily reached,
and it could be directly obtained in the case of an approach
from the top of the molecule (φ close to the vertical to the
molecular plane and θ values in the range 140-160°). We
have performed different searches starting from several
starting positions of the NO2þ cation on top of 1,2-DMNB.
It appears that two different products are always obtained.
The C2 adduct is obtained if the starting position of the
NO2þ cation is far from the benzene ring (4.5 A) irrespective
of whether it is closer to the C3 or C5 atoms. Conversely, the
FIGURE 2. Angular parameters φ (zenith) and θ (azimuth) are
defined as used in the potential energy map.
þ
process always ends on the C5 atom if the NO2 is closer
(3.5 A) to the 1,2-DMNB molecule and at the same distance
from C3 and C5. This reaction pathway is followed without
any activation energy and proceeds smoothly with the
bending of the NO2þ from 180° to the final angle of ∼134°.
Other substitutions require larger modifications of the elec-
tronic structure and proceed through multiple steps around
the rim of the aromatic molecule. This pathway has already
been pointed out in the case of the benzene molecule.
The (C1-C2)fC3 pathway has been further checked by
computing the intrinsic reaction coordinate (IRC)27 in both
directions along the transition vector corresponding to the
negative Hessian eigenvalue starting from the found transi-
tion state.
The study of the different pathways suggests that the NO2
moiety can move around the ring starting from the π-bonded
adduct near C2 or C4 toward different carbon atoms gen-
erating the Wheland adducts. These processes go through
transition states, whose energies are reported in Table 2.
Figure 4 reports the trend of the electrostatic potential
evaluated at a van der Waals distance from each atom in the
case of the neutral molecule. The trend of the electrostatic
potential is well synthesized by the net atomic charges
computed according to the Merz-Kollman approach
(Table 3).28
FIGURE 3. Energy as a function of angular parameters for the
approach of NO2þ to 1,2-dimethoxy-4-nitrobenzene (1,2-DMNB).
In each colored trace, the energy (kcal/mol) is radially plotted for
the same φ-value (5-45°) as a function of the in-plane angle θ
(0-360°). Thus, points corresponding to lower energy are closer to
the center. For each point, the distance of the nitrogen atom of the
NO2 moiety from the center of the aromatic ring was optimized for
minimum energy, but this distance is not represented on the graph.
and taken into account in order to explain in general the ipso
substitution products23,25 that are obtained in the case of
good leaving groups such as tert-butyl and trimethylsilyl on
the benzene ring26 (different products are formed in the
reaction due to the nature of the group present in the ipso
position; see ref 23) and to explain the composition of the ions
found in MS studies.24
A value for φ around 45° shows low energy values in the
plot region around θ = 120°. This is reminiscent of a
geometry akin to the Wheland intermediate. It is worth
noting that this position is the only one in which the energy
decreases when going from φ = 5° to 45°. Positions C3 and
As a general observation, all methods for computing
charge distribution both in the neutral molecule and in the
corresponding radical cation (Tables 3 and 4) are unable to
pinpoint the complexity and the essential physics of the
þ
interaction process between NO2 and the aromatic mole-
cule. To some extent only NBO charges suggest that the
þ
interaction of the NO2 ion should prefer the interaction
with C5 rather than C3 but fail completely to predict the
good π interaction with C2. On the other hand, spin density
(see Figure 5) suggests that among the substituted carbon
atoms C2 should be the most reactive, whereas C5 should be
(25) (a) Olah, G. A.; Malhotra, R.; Narang, S. C. Nitration Methods and
Mechanism; VCH: New York, 1989. (b) Nightingale, D. V. Chem. Rev. 1947,
40, 117–140. (c) Moodie, R. B.; Schofield, K. Acc. Chem. Res. 1976, 9, 287–
292. (d) Attina, M.; Cacace, F.; Ricci, A. J. Phys. Chem. 1996, 100, 4424–
4429.
(27) (a) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154–2161.
(b) Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523–5527.
(28) Besler, B. H.; Merz, K. M., Jr.; Kollman, P. A. J. Comput. Chem.
1990, 11, 431–439.
(26) Eaborn, C. Organosilicon Compounds; Academic Press: New York,
1960.
J. Org. Chem. Vol. 76, No. 5, 2011 1289

Shopsowitz et al.
JOCArticle
TABLE 1. Energies and Relevant Parameters for the NO2þ Adducts of 1,2-DMNB
adduct
molecular energya (hartree) relative energy (kcal/mol) ZPE (hartree) molecular energya þ ZPE (hartree) relative energy (kcal/mol)
π C1-C2
σ C3
π C4
σ C5
σ C6
-870.286 777
-870.281 342
-870.282 138
-870.288 289
-870.280 377
0.9
4.4
3.9
0.0
5.0
0.179 442
0.180 684
0.180 013
0.180 586
0.180 577
-870.107 335
-870.100 656
-870.102 125
-870.107 220
-870.099 820
0.0
4.2
3.3
0.1
4.7
aNuclear þ electronic contributions.
TABLE 2. Transition-State Energies and Imaginary Frequencies of 1,2-DMNB
molecular energya
(hartree)
imaginary
frequency (cm-1
ZPE
(hartree)
molecular
relative energy
(kcal/mol)
TS
)
energya þ ZPEc (hartree)
(C1-C2)fC6
(C1-C2)f C3
C4f C3
-870.273 998
-870.278 265
-870.262 062
-870.281 176
147
118
391
72
0.179 174
0.179 585
0.178 110
0.179 418
-870.094 824
-870.098 680
-870.083 952
-870.101 758
4.5
1.8
12.0
0.0
C4f C5
aNuclear þ electronic contributions.
FIGURE 5. (A) 1,2-DMNB cation spin density (blue = spin
density increase; red = spin density depletion). (B) 1,2-DMNB
cation SHOMO (red and blue refer to the sign of the wave function).
substitution turns the 1,2-DMNB into a good reducing agent
toward NO2þ irrespective of the presence of the nitro group.
This is confirmed by the comparison of the relaxed ionization
FIGURE 4. Electrostatic potential computed at van der Waals
distance (red: negatively charged; blue: positively charged).
TABLE 3. 1,2-DMNB Net Atomic Charges According to Different
Approaches for the Neutral Molecule (atomic units)
þ
potential of 1,2-DMNB and the electron affinity of NO2
,
computed using the energies of the cation and the neutral
molecules at the same level of approximation, which are 8.03
and -8.32 eV (experimental = -9.586 ( 0.002 eV),21 respec-
tively. These results lead to an exothermic reaction energy of
0.29 eV or 6.69 kcal/mol (1.55 eV or 31.8 kcal/mol if using the
experimental value). With this large reaction energy the SET
intermediate cannot be trapped and the process directly affords
the Wheland σ adduct.16
atom
Mulliken
NBO29,a
ESPb
C1
C2
C3
C4
C5
C6
-0.339
-0.095
þ0.489
-1.071
-0.044
þ0.642
þ0.326
þ0.296
-0.301
þ0.051
-0.215
-0.217
þ0.265
þ0.294
-0.213
þ0.044
-0.289
-0.186
aNBO: natural bond orbital. bESP: electrostatic potential.
The high selectivity for position 5 is easily understood by
looking at the plot of the spin density.16 From Figure 5 it is
evident that the molecule is split into two different basins: one
related to the two OMe groups and the other containing the C4
and C5 atoms. Carbons C3 and C6 have reduced spin densities
due to the nodal structure of the SHOMO, which shows a nodal
plane perpendicular to the average molecular plane and passing
through C3-C6 atoms. The origin of the SHOMO can be
easily understood by taking into account the interaction be-
tween the two OMe groups and the benzene doubly degenerate
highest occupied orbital. The NO2 fragment orbitals are very
low in energy due to the large electronegativity of all constituent
atoms and give a negligible contribution to the resulting MOs,
even if it is enough to remove the equivalence of the C1 and C2
atoms as far as the spin density is concerned.
TABLE 4. 1,2-DMNB Radical Cation Net Atomic Charges and Spin
Densities on the Aromatic Carbon Atoms (atomic units)
atom
Mulliken
NBOa
ESPb
spin
C1
C2
C3
C4
C5
C6
þ0.124
þ0.105
-0.138
-0.005
-0.136
-0.134
þ0.358
þ0.392
-0.289
þ0.106
-0.141
-0.216
-0.304
-0.010
þ0.236
-0.915
þ0.205
þ0.613
þ0.210
þ0.225
-0.030
þ0.157
þ0.131
-0.052
aNBO: natural bond orbital. bESP: electrostatic potential.
the one where the most stable Wheland adduct should be formed
after reduction of the NO2þ and oxidation of the aromatic mole-
cule. This behavior strongly hints that in this case the nitration
process should be related to a SET process and that dimethoxy
1290 J. Org. Chem. Vol. 76, No. 5, 2011

Shopsowitz et al.
JOCArticle
molecular energy the trend is modified and the relative
stability order of the adducts becomes C3 > C5 > C6.
The difference in energy of 2.48 millihartree corresponds to
1.50 kcal mol-1, which at 27 °C gives a Keq that corresponds
to a C3:C5 substitution ratio of ∼10:1.
Besides the direct addition to the carbon atoms that gives
rise directly to the substitution products, we also investigated
the possibility of NO2 moiety migration between adjacent
carbon atoms. In this case the transition-state energy for the
migration C4fC5 is also lower than that for C4fC3 in the
gas phase, and the introduction of a solvation contribution
results in the C4fC3 transition-state energy becoming lower
(see Table 6). These data suggest that the C5 adduct could be
the most stable in nonpolar solvents or in the gas phase,
whereas the C3 adduct is favored in polar environments such
as concentrated nitric acid. Furthermore, in polar environ-
ments, the C3 isomer is the most abundant product both in
the case of a direct addition to the hydrogen-bearing carbon
atom or when the first adduct is on the carbon atom bearinþg
the more electron-donating alkoxy group. Because the NO2
ion adds from “above” the aromatic ring and the linear
aliphatic substituents are always far apart from the reactive
centers, an increase in the bulkiness of substituents on the C1
and C4 atoms should not be able to reverse the relative
abundance of the C3/C5 products. However, more specific
solvent distribution around the aromatic molecule modu-
lated by the different bulkiness or hydrophobicity of the
aliphatic substituent can modify the relative contribution of
the solvation energy and modify to some extent the actual
ratio of the two isomers formed. Moreover, in the case of
very bulky substituents whose structure can influence the
ipso position (e.g., OtBu), the stability of the π ipso adduct
can be affected, and this can potentially influence the C3/C5
adducts ratio.
Synthetic Studies of the Nitration of 1,4-Dialkoxybenzenes
Supporting Computational Studies. We undertook a series of
experiments to support the computational results for the
nitration of 1,4-dialkoxybenzenes (Scheme 4). From the
calculations, in nonpolar environments the 2,5-dinitro iso-
mer should be favored, whereas in strongly polar solvent
environments the opposite is expected. Indeed, we found that
the nitration of dialkoxy benzenes 8a-d in concentrated
nitric acid all result in the 2,3-dinitro isomer being formed as
the major product. However, the ratio of 2,3-dinitro isomer
relative to 2,5-dinitro isomer obtained from the nitration of
8b-d is considerably less compared to that obtained from the
nitration of 8a (Table 7). Although it seemed plausible that
the increased steric bulk in 8b-d may have been responsible
for the shift in selectivity, our computational studies sug-
gested that steric effects should be insignificant and that
solvation is the dominant factor influencing selectivity. To
further test this, we isolated the mixed-alkoxy-mononitro
compounds 11a and 11b and subjected them to a second
nitration reaction (Scheme 5). If steric effects were signifi-
cant, we would expect different selectivities for the two
mononitro compounds. Instead we found that the same ratio
of dinitration products is obtained from the nitration of 11a
and 11b, indicating that steric effects do not play a major
role.
FIGURE 6. Schematic orbital interaction diagram between the
benzene MOs (left) and the symmetry-adapted π orbitals of the
two OMe fragments (right). The occupied orbitals are shown in
the red box. The two arrows depict the electrons in the HOMO.
The two OMe oxygen atoms give rise to an almost degene-
rate set of bonding-antibonding orbitals. Indeed the small
distance between the two oxygen atoms and the resulting
nonzero overlap between the π orbitals removes the degene-
racy between the couple.
Owing to the symmetry of benzene’s MO characterized by
the nodal plane perpendicular to the average molecular plane
and passing through the C3-C6 atoms, the interaction with
the bonding combination of the two OMe fragment orbitals
generates a bonding and an antibonding orbital (Figure 6).
The resulting orbitals are both occupied, and the one reported
in Figure 5B is the HOMO. This MO gives rise to the spin
density reported in Figure 5A when one electron is removed.
Computational Studies of the Nitration of 1,4-Dialkoxy-
benzenes. In the case of 1,4-OR substitution, the distance
between the two oxygen atoms is very large and the couple is
degenerate. In this case, the interaction is with the other e1g
benzene orbital and the resulting MOs (bonding and anti-
bonding combination) preserve the nodal plane perpendicu-
lar to the C2-C3 and C5-C6 bonds. In this way the incipient
NO2 radical does not have any definite preferred interaction
site with developing spin density on the incipient aromatic
radical cation (if not for the small perturbation due to
inductive effects through the σ skeleton).
Table 5 reports the results for the complexes in the case of
1,4-DMNB. As with 1,2-DMNB, the most stable π-adducts
are the ipso ones, in this case on C1 and C4, whose stability
order is C1 > C4, in agreement with the spin densities of the
radical cation of 1,4-DMNB. As for the σ adducts at posi-
tions 3, 5, and 6, in spite of the fact that the spin densities on
these carbon atoms are in the order C5 > C6 > C3, the
interaction energy under vacuum indicates that the adduct
stability order is C5 > C3 > C6 and the C5 adduct is the
most stable isomer. On the other hand it can be seen that
after we introduce the solvation contribution of water to the
In previous studies, the nitration of 1,4-dimethoxybenzene
(8a) has been carried out using different solvent systems
and has led to variable proportions of 2,3-dinitro:2,5-dinitro
(29) Carpenter, J. E.; Weinhold, F. J. Mol. Struct. (THEOCHEM) 1988,
169, 41–62.
J. Org. Chem. Vol. 76, No. 5, 2011 1291

Shopsowitz et al.
JOCArticle
TABLE 5. Spin Densities of Radical Cation, Energies (hartree), and Relative Energies for Different Adducts of 1,4-DMNB
spin density
(radical cation)
molecular energy (ΔE)
rel. energy
(kcal/mol)
rel. energy
(kcal/mol)
atom/isomer
[DMNB-NO2]þ
ZPE
ΔE þ ZPE
ΔEsol þ ZPE
C1 (π)
C2
C3
C4 (π)
C5
C6
0.223
0.019
0.038
0.221
0.082
0.059
-870.282 466
0.179 655
-870.102 811
0.00
-870.187 517
2.53
-870.278 850
-870.282 082
-870.280 345
-870.268 875
0.180 241
0.179 636
0.180 162
0.180 176
-870.098 609
-870.102 446
-870.100 183
-870.088 700
2.64
0.23
1.65
8.85
-870.191 542
-870.189 133
-870.189 141
0.00
1.51
1.50
TABLE 6. [1,4-DMNB-NO2]þ Transition-State Energies (hartree) for the Indicated Processes
TS
molecular energy
ZPE
ΔEsol
ΔEsol þ ZPE
-870.186 72
-870.184 10
ΔE‡sol þ ZPE
3.03
4.67
imaginary frequency (cm-1
)
C4fC3
C4fC5
-870.278 146
-870.278 754
0.17948
0.17920
-870.366 198
-870.363 305
54.6
62.7
TABLE 7. Relative Amountof Regioisomers Formed from the Nitration
of 8a-d in Concentrated Nitric Acida
precursor
alkoxy chains
% 2,3-isomer % 2,5-isomer
8a
8b
8c
8d
R = R0 = OMe
88
60
59
66
12
40
41
34
R = R0 = OBu-n
R = R0 = OHex-n
R = OMe, R0 = OHex-n
a[8a-d] = 0.72 M.
isomers depending on the conditions that were employed.11
We decided to use acetic anhydride combined with concen-
trated nitric acid as a system to study the influence of
solvent polarity on the selectivity of the dinitration reac-
tion. Overall we studied the nitration of 8a using four
different conditions ranging in solvent polarity with the
most polar condition being concentrated nitric acid (Figure 7).
Two nitration conditions of intermediate solvent polarity
were examined by mixing acetic anhydride and concen-
trated nitric acid in different ratios prior to the addition of
8a. For the least polar nitration condition, 8a was first
dissolved in acetic anhydride and concentrated nitric acid
was then slowly added to the solution. In agreement with
the theoretical prediction, a clear increase in the formation
of the 2,5-dinitro isomer is observed with decreasing solvent
polarity. In the case of the least polar nitration condition,
the 2,5-dinitro isomer is favored over the 2,3-dinitro isomer
by a 2:1 ratio, which to the best of our knowledge is the
highest regioselectivity for 1,4-dimethoxy-2,5-dinitroben-
zene that has been reported. This is compared to an 8:1 ratio
favoring the 2,3-dinitro isomer when the nitration is per-
formed in concentrated nitric acid. Mixed dialkoxyaryl
compound 8d was also nitrated using this latter condition
(8b and 8c could not be studied due to poor solubility in
acetic anhydride at 0 °C); in contrast to the results for
concentrated nitric acid, the ratios of 2,3-dinitro and 2,5-
dinitro isomers for the nitrations of 8a and 8d are virtually
identical. We believe that this is further evidence that the
solvent environment determines the regioselectivity consid-
ering that both 8a and 8d were completely dissolved prior to
the addition of nitric acid. These results lead us to postulate
that the different selectivities observed for the double
nitration of 8b-d compared with 1,4-dimethoxybenzene
(8a) in concentrated nitric acid are simply due to shielding
from the polar solvent environment by the hydrophobic
alkoxy chains.
FIGURE 7. 1H NMR spectra (CDCl3) of the aromatic regions for
the nitration of 8a using different solvent conditions: (a) concen-
trated nitric acid; (b) AcOAc/HNO3 (0.54:1 v/v); (c) AcOAc/HNO3
(0.14:1 v/v); (d) AcOAc followed by the slow addition of HNO3.
Spectra are offset and the residual solvent peaks (7.27 ppm) were
removed for clarity.
SCHEME 5. Nitration of Mononitrodialkoxybenzenes 11a and
11b
version of 11b (15N-11b) was synthesized by mononitrating
8d using K15NO3. 15N-11b was subjected to concentrated
nitric acid at 80 °C, conditions that readily lead to the doubly
nitrated products shown in Scheme 6. After 1 h at 80 °C the
crude product was isolated and consisted of the 2,3-dinitro
and 2,5-dinitro isomers. EI-MS revealed the presence of
15N/14N dinitro products, while only trace amounts of
14N/14N products were detected. This indicates that the
second nitration step is essentially irreversible, and therefore
no intermolecular scrambling occurs.
To further understand the mechanism of the dinitration,
we undertook 15N-labeling experiments. The 15N-labeled
1292 J. Org. Chem. Vol. 76, No. 5, 2011

Shopsowitz et al.
JOCArticle
SCHEME 6. Products Obtained from the Nitration of 15N-11b
in Concentrated Nitric Acid (80 °C, 1 h)
Synthesis. Compounds 8b,35 8c,36 and 8d37 were prepared by
literature methods. The ratios of 2,3-dinitro:2,5-dinitro regio-
isomers were calculated by integrating the peaks assigned to the
1
aromatic C-H groups in the H NMR spectra. All reactions
were carried out under air unless otherwise noted.
Procedure for the Nitration of 8 in Concentrated Nitric Acid
(8a as an example). 1,4-Dimethoxybenzene (1.0 g, 7.2 mmol) was
slowly added to 10 mL of concentrated nitric acid chilled on an
ice/water bath. The reaction mixture was stirred at 0 °C for 1 h,
then stirred at room temperature for 1 h, and finally heated to
80 °C for 1 h. The dark orange reaction mixture was then poured
into ∼30 mL of ice water, resulting in the formation of a yellow
precipitate. This was then filtered and washed with a large
amount of water, giving the crude product (1.4 g, 85%) as a
mixture of 2,3- and 2,5-dinitro-1,4-dimethoxybenzene (5a and
10a, respectively). 1H NMR spectroscopy was conducted on the
crude isolated product in order to determine the relative
amounts of 5a and 10a formed.
General Procedure for the Isolation of 5b-d and 10b-d (5b and
10b as examples). The crude product (2.5 g) from the nitration of
1,4-dibutyloxybenzene (8b) was separated by column chroma-
tography (silica gel, petroleum ether/ethyl acetate = 4:1). 1,4-
Dibutyloxy-2,5-dinitrobenzene (10b, 0.79 g, 2.5 mmol, 32%)
was isolated as the faster moving band. After all of the 2,5-
dinitro isomer had been collected (as monitored by TLC), the
second fraction was eluted with toluene, giving 1,4-dibutyloxy-
2,3-dinitrobenzene (5b, 1.0 g, 3.2 mmol, 40%).
Conclusions
Detailed calculations were carried out to better under-
stand the unexpected selectivity observed for the dinitration
of 1,2-dialkoxy- and 1,4-dialkoxybenzenes. In the case of the
nitration of 1,2-dialkoxybenzenes, the exclusive formation
of the 4,5-dinitro-substituted product can be explained on
the basis of the single electron transfer mechanism and
simple molecular orbital arguments. For the dinitration of
1,4-dialkoxybenzenes, DFT calculations indicated that the
2,3-dinitro and 2,5-dinitro products should both be formed
and that the relative amounts should mostly be influenced by
the solvent environment as opposed to steric and inductive
electronic influences. Nitration experiments carried out on a
variety of 1,4-dialkoxybenzene derivatives support these
conclusions, confirming that the steric environment of the
benzene ring in 1,4-dialkoxybenzenes appears to have no
influence on selectivity, whereas the choice of solvent
system has a large effect. Finally we show that this informa-
tion may be used to rationally tune the regioselectivity of the
reaction.
1,4-Dibutyloxy-2,3-dinitrobenzene (5b). 1H NMR (CDCl3,
400 MHz): δ 0.96 (t, J = 7.5 Hz, 6H), 1.42-1.52 (h, J = 7.5
Hz, 4H), 1.73-1.80 (p, J = 7.5 Hz, 4H), 4.07 (t, J = 7.5 Hz, 4H),
7.16 (s, 2H). 13C{1H} NMR (CDCl3, 100 MHz): δ 13.6, 18.9,
30.9, 70.8, 117.8, 134.7, 144.8. MS (EI): m/z 312 (Mþ). IR ν
(neat): 2956, 2873, 1536, 1490, 1351, 1274, 1153, 1051, 1029, 936,
807, 755, 623, 538 cm-1. Mp = 66-68 °C. Anal. Calcd for
C14H20N2O6: C, 53.84, H, 6.45, N, 8.97. Found: C, 53.90, H,
6.53, N, 9.04.
Experimental Section
1,4-Dihexyloxy-2,3-dinitrobenzene (5c). 1H NMR (CDCl3,
400 MHz): δ 0.91 (t, J = 7.0 Hz, 6H), 1.30-1.36 (m, 8H),
1.43 (p, J = 7.2 Hz, 4H), 1.78 (p, 7.2 Hz, 4H), 4.06 (t, 6.5 Hz,
4H), 7.16 (s, 2H). 13C{1H} NMR (CDCl3, 100 MHz): δ 13.9,
22.5, 25.3, 28.8, 31.4, 71.1, 117.8, 134.7, 144.8. MS (EI): m/z 368
(Mþ). IR ν (neat): 2952, 2929, 2870, 1545, 1496, 1465, 1359,
1272, 1156, 1042, 802, 725, 626, 544 cm-1. Mp = 48-50 °C.
Anal. Calcd for C18H28N2O6: C, 58.68, H, 7.66, N, 7.60. Found:
C, 58.81, H, 7.42, N, 7.75.
Calculations. Gaussian03 (revision D.02)30 has been used for
all the computations. Density functional theory (DFT) has been
applied by using the Schmider and Becke hybrid xc functionals31
and 6-31þþG(d,p)32 basis set. All of the stationary structures
found have been verified to be minima by computing the
Hessian matrix. All energies are corrected by the zero point
energy (ZPE) contribution. Solvation effects have been taken
into account by the IEPCM33 without further geometry opti-
mization. Molecular structures have been drawn with the pro-
grams GaussView3.0 and Molekel4.3.34 All computations have
been mainly performed using model compounds 1,2-dimethoxy-
4-nitrobenzene (1,2-DMNB) and 1,4-dimethoxy-2-nitroben-
zene (1,4-DMNB).
1-Hexyloxy-4-methoxy-2,3-dinitrobenzene (5d). 1H NMR
(CDCl3, 400 MHz): δ 0.90 (t, J = 7.0 Hz, 3H), 1.31-1.36 (m,
4H), 1.43 (p, J = 7.0 Hz, 2H), 1.77 (p, J = 7.5 Hz, 2H), 3.93 (s,
3H), 4.07 (t, J = 6.5 Hz, 2H), 7.19 (s, 2H). 13C{1H} NMR
(CDCl3, 100 MHz): δ 14.2, 22.8, 25.7, 29.1, 31.6, 57.9, 71.4,
117.0, 118.2, 134.7, 135.0, 145.3, 145.5. IR ν (neat): 2932, 2844,
1533, 1491, 1441, 1349, 1273, 1154, 1061, 1015, 924, 789, 733,
606 cm-1. Mp = 82-84 °C. HRMS: calcd for C13H18N2O6
[M]þ 298.11649, found 298.11664.
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Spitznagel, G. W.; Schleyer, P. v. R. J. Comput. Chem. 1983, 4, 294–301.
(33) (a) Cammi, R.; Mennucci, B.; Tomasi, J. J. Phys. Chem. A 2000, 104,
5631–5637. (b) Cammi, R.; Mennucci, B.; Tomasi, J. J. Phys. Chem. A 1999,
1,4-Dibutyloxy-2,5-dinitrobenzene (10b). 1H NMR (CDCl3,
300 MHz): δ 0.98 (t, J = 7.5 Hz, 6H), 1.46-1.58 (h, J = 7.5 Hz,
4H), 1.78-1.87 (p, J = 7.5 Hz, 4H), 4.11 (t, J = 7.5 Hz, 4H),
7.52 (s, 2H). 13C{1H} NMR (CDCl3, 100 MHz): δ 13.7, 19.0,
30.8, 70.6, 111.9, 142.0, 145.5. MS (EI): m/z 312 (Mþ). IR ν
(neat): 2959, 2933, 2873, 1536, 1462, 1391, 1344, 1276, 1220,
1064, 985, 877, 789, 757, 628, 539 cm-1. Mp = 132-135 °C.
Anal. Calcd for C14H20N2O6: C, 53.84, H, 6.45, N, 8.97. Found:
C, 53.39, H, 6.38, N, 9.19.
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(37) Altman, R. A.; Shafir, A.; Choi, A.; Lichtor, P. A.; Buchwald, S. L.
J. Org. Chem. 2008, 73, 284–286.
400 MHz): δ 0.92 (t, J = 6.7 Hz, 6H), 1.32-1.37 (m, 8H), 1.48
(p, J = 7.5 Hz, 4H), 1.83 (p, J = 7.5 Hz, 4H), 4.10 (t, J = 6.5 Hz,
4H), 7.51 (s, 2H). 13C{1H} NMR (CDCl3, 100 MHz): δ 13.9,
22.5, 25.4, 28.7, 31.3, 70.9, 111.9, 142.0, 145.5. MS (EI): m/z 368
J. Org. Chem. Vol. 76, No. 5, 2011 1293

Shopsowitz et al.
JOCArticle
(Mþ). IR ν (neat): 2957, 2930, 2859, 1534, 1392, 1270, 1224, 996,
877, 794, 759 cm-1. Mp = 111-113 °C. Anal. Calcd for
C18H28N2O6: C, 58.68, H, 7.66, N, 7.60. Found: C, 58.68, H,
7.59, N, 7.75.
MS (EI): m/z 253 (Mþ). IR ν (neat): 2930, 2858, 1526, 1498, 1466,
1349, 1277, 1219, 1150, 1037, 913, 855, 808, 778, 747, 562 cm-1
.
Anal. Calcd for C13H19NO4: C, 61.64, H, 7.56, N, 5.53. Found: C,
61.74, H, 7.50, N, 5.68.
1-Hexyloxy-4-methoxy-2,5-dinitrobenzene (10d). 1H NMR
(CDCl3, 300 MHz): δ 0.91 (t, J = 7.0 Hz, 3H), 1.32-1.37 (m,
4H), 1.48 (p, J = 7.0 Hz, 2H), 1.84 (p, J = 7.5 Hz, 2H), 3.98 (s,
3H), 4.11 (t, J = 6.4 Hz, 2H), 7.54 (s, 2H). 13C{1H} NMR
(CDCl3, 100 MHz): δ 14.2, 22.8, 25.7, 29.0, 31.6, 57.7, 71.2,
111.3, 112.4, 142.0, 142.3, 146.0, 146.2. MS (EI): m/z 298 (Mþ).
IR ν (neat): 2933, 2858, 1547, 1519, 1473, 1351, 1278, 1226, 1004,
882, 787, 593, 555 cm-1. Mp = 93-96 °C. Anal. Calcd for
C13H18N2O6: C, 52.34, H, 6.08, N, 9.39. Found: C, 52.31, H,
6.06, N, 9.52.
Preparation of 1-Hexyloxy-4-methoxy-3-nitrobenzene (11a).
1-Hexyloxy-4-methoxybenzene (0.50 g, 2.4 mmol) was added to
a solution of 1.5 mL of concentrated nitric acid dissolved in
10 mL of ethyl acetate at room temperature. After stirring the
reaction mixture at room temperature for 18 h, 40 mL of ethyl
acetate and 50 mL of water were added. The organic phase was
isolated, then washed with 2 ꢀ 30 mL of water, dried over
MgSO4, and filtered. Removal of the solvent under vacuum gave
a dark orange oil (340 mg, 1.34 mmol, 56%) consisting of the
two mononitro isomers. Column chromatography (silica gel,
hexanes/ethyl acetate = 9:1) was used to isolate 12a as the
slower moving fraction (orange oil, 100 mg, 0.39 mmol, 17%).
1-Hexyloxy-4-methoxy-3-nitrobenzene (11a). 1H NMR (CDCl3,
400 MHz): δ 0.92 (t, J = 7.5 Hz, 3H), 1.32-1.38 (m, 4H),
1.44-1.48 (m, 2H), 1.78 (p, J = 7.5 Hz, 2H), 3.92 (s, 3H), 3.95
(t, J = 7.5 Hz, 2H), 7.02 (d, J = 10 Hz, 1H), 7.09-7.12 (m, 1H),
7.39 (d, J = 4.5 Hz, 1H). 13C{1H} NMR (CDCl3, 100 MHz): δ
14.0, 22.5, 25.6, 29.1, 31.5, 57.1, 69.1, 110.7, 115.1, 121.4, 139.6,
147.2, 152.5. IR ν (neat): 2930, 2858, 1526, 1466, 1350, 1272, 1218,
1019, 812, 771, 743, 547 cm-1. HRMS: calcd for C13H19NO4 [M]þ
253.13141, found 253.13130.
Preparation of 1-Hexyloxy-4-methoxy-2-nitrobenzene (11b).
Potassium carbonate (1.64 g, 21.8 mmol), 1-bromohexane (1.66
mL, 11.8 mmol), and sodium iodide (100 mg, 0.67 mmol) were
added to a solution of 4-methoxy-2-nitrophenol (2.0 g, 11.8
mmol) dissolved in 40 mL of acetone. The reaction mixture was
then heated to reflux for 16 h. The cloudy red reaction mixture
was filtered, and then the solvent was removed under vacuum.
Water (100 mL) was added to the oily red residue, and the
product was then extracted with 3 ꢀ 50 mL of dichloromethane.
The combined organic fractions were washed with 2 ꢀ 50 mL of
5% NaOH solution and 50 mL of water, dried over MgSO4, and
then filtered. An orange oil was obtained after the solvent was
removed under vacuum. The oil was filtered through a short
silica plug with 20:1 petroleum ether/ethyl acetate, resulting in a
pale yellow solution. The solvent was removed under vacuum,
yielding 12b as a yellow oil (1.73 g, 6.8 mmol, 57%).
Preparation of 15N-1-Hexyloxy-4-methoxy-2-nitrobenzene
(15N-11b). 1-Hexyloxy-4-methoxybenzene (8d, 0.50 g, 2.4 mmol)
was slowly added to a solution of K15NO3 (0.26 g, 2.6 mmol) and
p-toluenesulfonic acid (0.57 g, 3.0 mmol) in 7.5 mL of acetic
anhydride chilled on an ice/water bath. Following the addition,
the reaction mixture was allowed to stir at RT for 18 h. After the
addition of 30 mL of water, the organic phase was extracted with
3 ꢀ 20 mL of DCM. The organic fractions were combined,
washed with water (3 ꢀ 30 mL), and dried over MgSO4. The
solvent was removed under vacuum, leaving behind a dark
yellow oil consisting of the two mononitro isomers. 15N-11b
was isolated by column chromatography (silica gel, hexanes/
ethyl acetate = 9:1) as the faster moving fraction (160 mg, 0.63
1
mmol, 26%). The product was confirmed by H NMR spec-
troscopy and EI-MS (m/z 254 (Mþ)).
Nitration Study of 1,4-Dimethoxybenzene (8a) in Acetic Anhy-
dride and Nitric Acid. Three different solvent conditions were
used and are labeled according to the scheme given in the
caption for Figure 7. b: 1,4-Dimethoxybenzene (8a, 0.50 g, 3.6
mmol) was slowly added to a mixture of 7.4 mL of acetic
anhydride and 4 mL of concentrated nitric acid chilled to 0 °C
in an ice/water bath. This mixture was stirred on ice for 1 h, then
at room temperature for 1 h, and finally heated to 80 °C for 1 h.
The reaction mixture was poured into ∼30 mL of ice/water,
resulting in the formation of a yellow precipitate. This was then
isolated on a Buchner funnel, rinsed with water, and then air-
dried to give a mixture of 2,3- and 2,5-dinitro-1,4-dimethox-
ybenzene (715 mg, 3.1 mmol, 87%). 1H NMR spectroscopy was
used to determine the ratio of 2,3-dinitro and 2,5-dinitro isomers
formed. c: The same procedure was employed except that the
volumes of acetic anhydride and concentrated nitric acid used
were 10 and 1.4 mL, respectively. d: Compound 8a was dissolved
in 10 mL of acetic anhydride and chilled in an ice/water bath.
Then 1.4 mL of concentrated nitric acid was added dropwise
with vigorous stirring. The reaction mixture was allowed to stir
on ice for 1 h, then at RT for 1 h, and finally for 1 h at 80 °C. The
reaction mixture was poured into ∼30 mL of ice/water, resulting
in the formation of a yellow precipitate, which was isolated by
vacuum filtration, rinsed with water, and air-dried to give a
mixture of 2,3- and 2,5-dinitro-1,4-dimethoxybenzene (740 mg,
3.2 mmol, 90%). Procedure d was also used for the nitration
of 8d.
Acknowledgment. We thank UBC and NSERC (Discovery
Grant) for funding. K.E.S. thanks NSERC for a postgraduate
fellowship. F.L. is grateful to INSTM and the Project “Call for
ꢀ
Ideas” of Universita della Basilicata for the year 2010 for
financial support.
1-Hexyloxy-4-methoxy-2-nitrobenzene (11b). 1H NMR (CDCl3,
300 MHz): δ 0.91 (t, J = 7.5 Hz, 3H), 1.31-1.38 (m, 4H),
1.45-1.53 (m, 2H), 1.82 (p, J = 7.5 Hz, 2H), 3.82 (s, 3H), 4.05
(t, J = 7.5 Hz, 2H), 7.02 (d, J = 10 Hz, 1H), 7.07-7.11 (m, 1H),
7.38 (d, J = 4.5 Hz, 1H). 13C{1H} (CDCl3, 100 MHz): δ 13.9, 22.5,
25.5, 29.1, 31.4, 56.0, 70.5, 109.7, 116.4, 120.7, 140.0, 146.8, 152.8.
Supporting Information Available: Text and figures giving
details of computation coordinates and characterization data
(1H NMR, 13C NMR, MS). This material is available free of
charge via the Internet at http://pubs.acs.org.
1294 J. Org. Chem. Vol. 76, No. 5, 2011