The regiochemistry of the NO3-promoted gas phase nitration of toluene and phenol with NO2

Article abstract of DOI:10.1002/poc.1060

Product studies, kinetic isotope effect measurements, linear free energy relationships and calculations have been used to study the NO ₃-promoted nitration of toluene and phenol in presence of NO ₂. The competition between of a rate-

Full text of DOI:10.1002/poc.1060

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2006; 19: 570–578
Published online 17 July 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.1060
The regiochemistry of the NO3-promoted ygas phase
nitration of toluene and phenol with NO2
Ezio Bolzacchini,1 Maurizio Bruschi,1 Guido Galliani,1 Jens Hjorth,2 Marco Orlandi1 and Bruno
Rindone1
*
1Dipartimento di Scienze dell’Ambiente e del Territorio, Universita’ di Milano-Bicocca, Piazza della Scienza, 1, I-20126 Milano, Italy
2Joint Research Center, Ispra, Italy
Received 10 October 2005; revised 26 February 2006; accepted 3 March 2006
ABSTRACT: Product studies, kinetic isotope effect measurements, linear free energy relationships and calculations
have been used to study the NO3-promoted nitration of toluene and phenol in presence of NO2. The competition
between of a rate-determining hydrogen abstraction of NO3 to give the benzyl radical and HNO3 and of a rate-
determining addition-elimination pathway has been evaluated. The preference for the nitration in ortho and para
position of toluene and for the ortho position of phenol is suggested to derive from the concerted loss of nitric acid
from an intermediate cyclohexadiene.A kinetic analysis suggests reasons for the dependence of the ratio ortho:para-
nitration from the initial concentration of reactants. Copyright # 2006 John Wiley & Sons, Ltd.
Supplementary electronic material for this paper is available in Wiley Interscience at http://www.interscience.
wiley.com/jpages/0894-3230/suppmat/
KEYWORDS: gas phase; nitration; nitrate radical; toluene; phenol; density functional theory
INTRODUCTION
1. A hydrogen abstraction reaction (H-ABS) forming a
benzyl radical 6 (X ¼ CH2) or a phenoxy radical
6 (X ¼ O). Addition of NO2 will form ortho- and
para-nitration products exclusively.
2. An electron transfer reaction (ET) to give a cation
radical 7. This is generally not occurring in gas phase
chemistry.
3. An addition reaction (ADD) to give four isomeric
adducts 2–5 in an equilibrium reaction. Addition of
NO2 gives seven isomeric cyclohexadienes 8–14.
These intermediates have generally two stereogenic
carbons. Hence, a total of 24 isomers may be formed.
These undergo elimination of HOY to give the three
nitroderivatives 15–17. Here, the nature of the cyclo-
hexadiene intermediate controls the nitroderivative
formed. Alternatively, loss of HOY from adducts 2–5
gives a benzyl radical 6 (X ¼ CH2) or a phenoxy radical
6 (X ¼ O) with subsequent formation of ortho- and
para-nitration products exclusively.
Aromatic hydrocarbons such as benzene and toluene are
one of the most important classes of primary pollutants
emitted into the atmosphere from fuels and exhaust gases.
This accounts for about 10% of all of the organic com-
pounds in air. Functionalized aromatic compounds such as
phenol can also be formed in the atmosphere by the OH-
initiated atmospheric oxidation of these primary pollutants
and their yields can be relatively high.1,2 These aromatic
compounds can subsequently be transformed into the
corresponding nitroderivatives by reaction with NO2 pro-
moted by hydroxyl (OH) or nitrate (NO3) radicals. These
radicals are important oxidizing agents in the troposphere;
the former during the day, the latter during the night.
The regiochemistry of the gas phase nitration of electron-
rich aromatic compounds is often different from that in
solution. Interestingly, there are also differences in OH- and
NO3-promoted nitrations, suggesting that different reaction
pathways are involved in these two cases. Schemes 1 and 2
show three possible pathways in this reaction. They are:
The gas phase OH-initiated nitration of toluene 1 (X ¼
CH2) with NO2 has been extensively investigated both
experimentally and theoretically. The rate of decay of OH
with toluene shows an unusual dependence with the
temperature.3,4 At room temperature the OH decay is
exponential and the rate constant decreases slightly with
increasing the temperature giving a positive slope of the
Arrhenius plot. In the range 325–380 K, the rate constant
increases as a function of the temperature and the OH
decay is no longer exponential. Finally, for temperatures
above 380 K the rate constant increases as a function of
*Correspondence to: B. Rindone, Dipartimento di Scienze dell’
Ambiente e del Territorio, Universita’ di Milano-Bicocca, Piazza della
Scienza, 1, I-20126 Milano, Italy.
E-mail: Bruno.Rindone@unimib.it
ySelected paper presented at the 10th European Symposium on Organic
Reactivity, 25–30 July 2005, Rome, Italy.
Contract/grant sponsor: EC; contract/grant number: ENV4-CT97-
0411.
Copyright # 2006 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2006; 19: 570–578

REGIOCHEMISTRY
571
Scheme 1
the temperature but the OH decay is still exponential. The
different behavior as a function of the temperature has
been explained with the competition of the ADD and H-
ABS mechanisms, which should be differently favored
with the temperature. The negative activation energy
observed at the room temperature (positive slope of the
Arrhenius plot) has been explained with the formation of
a OH-toluene pre-reactive complex with a (negative)
binding energy larger than the subsequent (positive)
activation energy to give the reaction products.3–6
This pre-reactive complex has been characterized by
Vivier-Bunge et al.6
In the OH-promoted nitration of toluene at room
temperature, nitrotoluenes are formed in the ratio:
meta:para:ortho ¼ 70:25:5.7,8 This ratio is very different
from that observed in the electrophilic nitration of toluene
in solution9.
equilibrium the predominant formation of the ortho-
hydroxycyclohexadienyl radical adduct 4 (X ¼ CH2)10
and 10% via a hydrogen abstraction reaction (H-ABS)
which forms a benzyl radical 6 (X ¼ CH2). Accordingly,
values of kinetic isotope effect (kH/kD) in the range
0.98–1.13 were found11 and a Linear Free Energy
Relationship (LFER) study12 gave r ¼ ꢀ2.3 ꢁ 0.2; r2 ¼
0.96.
The H-ABS mechanism with toluene is reported to
have higher kH/kD and lower r, for example, the
bromination reaction (kH/kD ¼ 4.86 ꢀ 4.59)13, the chlori-
nation with chlorine (kH/kD ¼ 3.6–4.01,14r ¼ ꢀ1.515) or
with hypochlorite (kH/kD ¼ 3.616; r ¼ ꢀ1.7 against sþ14),
the microsomal oxidation (kH/kD ¼ 2.13;17r ¼ ꢀ0.86
against sþ18).
The radical adducts reacts with O2 in an equilibrium
reaction19 to give a peroxy radical and this is the reason for
the predominant formation of ortho-cresol20 together with
other ring-retaining compounds21 and ring fragmentation
The reaction, at room temperature, is suggested to
occur 90% via a rate-determining ADD giving at the
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572
E. BOLZACCHINI ET AL.
EXPERIMENTAL AND COMPUTATIONAL
DETAILS
The reaction was studied in purified air at 760 Torr in a
480 L Teflon-coated 60 cm diameter cylindrical chamber
equipped with an 81.2 m total beam path length White
type mirror system coupled to a Bruker IFS 113V FT
spectrometer for on-line Infrared Spectroscopy.
Concentrations of reactants and reaction products were
monitored in situ by long path infrared spectroscopy.
Experiments were performed at ambient pressure and
temperature. Calibrations of the IR measurements were
performed either by introducing known volumes of vapor
at known pressures into the chamber or by evaporating
known quantities of the compounds and transferring them
with a stream of air into the chamber. Calibrated gas phase
spectra of nitrotoluenes and nitrophenols were obtained.
NO3 generated by reacting NO2 with O3 may be used as
the promoter in gas phase nitration reactions.24 The
organic substrate is then admitted in the reactor and the
nitration is due to the presence of NO2 in the system.
Moreover, the NO3-initiated nitration of phenol with NO2
in gas phase gives a ratio ortho:para which depends on the
concentration of NO2.25
In the experiments to study yields of nitrophenols, N2O5
was synthesized in the chamber by mixing O3 with an
excess of NO2. Subsequently phenol was added and the
reaction was allowed to proceed until only insignificant
amounts (<100 ppb) of N2O5 remained. Initial concen-
trations were 10–25 ppmV N2O5, 3–55 ppmV NO2, and
15–30 ppmV of the organic compound. In some exper-
iments, phenol and NO2 were added first to the chamber,
then ozone. The initial concentrations in this case were
11–51 ppmV NO2, 22–31 ppmV phenol and 16–70 ppmV
ozone.
The rate constant of the reaction of NO3 with phenols
was determined relative to that of its reaction with
2-methyl-2-butene. In these experiments phenol and
2-methyl-2-butene were added first to the chamber, then
N2O5 was introduced by evaporating solid N2O5, prepared
by the method of Schott and Davidson,26 and bringing it
into the chamber with a stream of air. In this case, the initial
concentrations were 15–18 ppmV of 2-methyl-2-butene
and 5–10 ppmV phenol. N2O5 was in most experiments
added several times during the experimental run in portions
of a few ppmV. Initial NO2 concentrations were 1–3 ppmV
in these experiments. In other experiments, NO2 was added
to provide initial concentrations of 29–59 ppmV in order to
test the influence of the concentration of NO2 on the
observed rate constant.
Structural parameters and energies of the reactants,
intermediates and products along the H-ABS and ADD
pathways of the NO3-promoted nitration of toluene and
phenol in their stable geometries and at transition states
were computed in the framework of the density functional
theory (DFT)27 with the hybrid three parameter
B3LYP28,29 exchange-correlation functional and the split
Scheme 2
products.22 If NO2 is present, in a competitive pathway the
hydroxycyclohexadienyl radical adduct 4 (X¼ CH2)
will react with NO2 to give cyclohexadienes 12–13
(X¼ CH2)23 A 1,2-elimination reaction of H2O will form
mainly 3-nitrotoluene 17 (X¼ CH2).
The gas phase NO3-initiated nitration of toluene and
phenol has been less extensively investigated and the
regiochemistry of the reaction is still far from being
rationalized.
Prompted by these considerations we present in this work
an experimental and computational study on the NO3-
initiated nitration of toluene and phenol. The H-ABS and
ADD pathways will be investigated both theoretically and
experimentally and correlated to the well-studied OH-
promoted reaction of toluene. The results will allow to shed
some light on the origin of the different regiochemistry in
the NO3-promoted nitration of these two aromatic
compounds.
Copyright # 2006 John Wiley & Sons, Ltd.
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REGIOCHEMISTRY
Table 1. Distribution of nitration products from toluene and phenol in different conditions
Toluene 1 (X ¼ CH2)
573
Phenol 1 (X ¼ H)
NO3-promoted
nitration with
NO2
Electrophilic44
NO3-promoted
nitration with
NO2
Electrophilic45
33
25
Ortho-nitration
Meta-nitration
Para-nitration
55
14
31
57
2
41
69–29
40–17
28
4
58
valence basis set including a full set of polarization
functions, 6-31G(d,p).30 Minima and saddle-points (TS)
of the potential energy were determined by gradient-
based algorithms and by Synchronous Transit Guided
Quasi-Newton (STQN) method.31 The exact nature of
each null-gradient point was checked by vibrational
analysis. Free energy (G) values were calculated from the
values. In fact, a r value of ꢀ0.72 was obtained39 in the
ozone-promoted nitration of phenols with NO2 (the
Kyodai nitration) occurring through a concerted addition-
elimination pathway.
In order to settle the discrepancy between kinetic
isotope effect and the LFER data the H-ABS and ADD
reaction pathways were investigated theoretically and
compared with the values calculated for the OH-initiated
nitration of toluene. A detailed analysis of the theoretical
results is presented elsewhere.40 Here, we report only the
values of the reaction (DGr) and transition state (DG#) free
energy for the ADD and the H-ABS mechanism (Table 2).
total partition function (Q), in which the terms qtranslational
,
q
rotational, qvibrational, are considered under the assumption
that Q may be written as their product.32 In order to
evaluate enthalpy and entropy contributions, the value for
temperature, and pressure was set to 298.15 K, and 1 Atm,
respectively. Translations and rotations were treated
classically and vibrational modes described according to
the harmonic approximation.
Table 2. Reaction Gibbs free energy (DGr; in kcal molꢀ1
)
and corresponding transition state Gibbs free energy (DG#;
in kcal molꢀ1) computed at B3LYP/6-31G(d,p) level of theory
for the OH- and NO3-promoted nitration of toluene and
NO3-promoted nitration of phenol
RESULTS AND DISCUSSION
The NO3-promoted nitration of toluene
In the NO3-initiated gas phase nitration of toluene with
NO2 the distribution of reaction products is very similar to
that occurring in the electrophilic nitration as shown in
Table 1.33 Again, ADD and H-ABS could occur, the former
giving adducts 2–5 (X¼ CH2; Y ¼ NO2) and consequently
nitrotoluenes 15–17 (X ¼ CH2) via cyclohexadienes 8–14
(X¼ CH2), the latter giving the benzyl radical 6 (X¼ CH2)
and then 4-nitrotoluene 15 (X ¼ CH2) and 2-nitrotoluene
16 (X¼ CH2) (Schemes 1 and 2).
Toluene
Phenol
OH-
promoted
nitration
NO3-
promoted
nitration
NO3-
promoted
nitration
DGr
DGr
DGr
1 þ OY!1-OY
1-OY!6 þ HOY
(H-ABS)
ꢀ5.69
ꢀ5.76
ꢀ6.97
ꢀ3.52
ꢀ24.02
ꢀ18.00
A kinetic isotope effect kH/kD ¼ 2.0–2.334 was found
and is close to the value of 1.5–1.8 found with p-xylene.35
These values are borderline between being secondary and
primary. A similar value (kH/kD ¼ 1.6) was found for the
reaction of toluene in acetonitrile with photochemically
produced NO3 and was attributed to an ET mechanism
concerted with carbon–hydrogen bond cleavage to give a
benzyl radical and a proton.36
1-OY!2
ꢀ8.94
ꢀ13.04
ꢀ11.67
ꢀ13.72
7.20
5.07
6.04
5.13
5.58
1.65
6.00
4.43
(ADD ipso)
1-OY!4
(ADD ortho)
1-OY!3
(ADD meta)
1-OY!5
(ADD para)
DG#
DG#
4.14
DG#
n.d.
1-OY!6-TS
(H-ABS)
0.15
In a LFER study the plot of log k for ten para-
substituted toluenes versus Hammett’s s of the sub-
stituents gave r ¼ ꢀ4.3 ꢁ 0.6; r2 ¼ 0.87.37 This r value is
more negative than that found in the reaction of OH with
toluene (r ¼ ꢀ2.3 ꢁ 0.2; r2 ¼ 0.96) and of that (r ¼ ꢀ3.2)
found in the reaction of toluenes substituted with
electron-withdrawing groups with NO3 in solution.38 In
both cases a rate-determining ADD mechanism was
suggested. The H-ABS mechanism gives much lower r
1-OY!2-TS
(ADD ipso)
1-OY!4-TS
(ADD ortho)
1-OY!3-TS
(ADD meta)
1-OY!5-TS
(ADD para)
2.63
0.99
1.96
1.63
10.72
8.83
9.91
8.74
11.21
8.18
11.72
8.79
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574
E. BOLZACCHINI ET AL.
A pre-reactive complex between NO3 and toluene
(1-NO3), corresponding to that reported by Vivier-Bunge
et al.6 for OH and toluene (1-OH), has been characterized
endoergonic by 5–7 kcal molꢀ1, while the corresponding
addition of OH to form cyclohexadienes 2–5 (X ¼ OH) is
significantly exoergonic (Table 2). In particular, in the
case of the NO3 þ toluene reaction, the DGr of the ADD
pathways is within ꢁ1 kcal molꢀ1 with respect to the
separate reactants, while for the OH þ toluene reaction, if
the separate reactants are taken as reference, the addition
pathway is still more exoergonic. The energy barriers
(DG#) for the addition of OH to the aromatic ring are
positive and very low (within 1–3 kcal molꢀ1; Table 2) if
compared to the pre-reactive complex and negative if
compared to the separate reactants. As discussed above
this accounts for the positive slope of the Arrhenius plot
observed for the rate of the OH decay at room
temperature. On the other hand, DG# calculated for
the NO3 addition are still larger with respect to the
separate reactants by 3–5 kcal molꢀ1. The results pre-
sented above suggest that in the case of OH radical
the pre-reactive complex evolves completely to give the
by our calculations with
a Gibbs free energy
5.76 kcal molꢀ1 lower than the separate reactants. This
value is very similar (ꢀ5.69 kcal molꢀ1) to that calculated
for the OH-toluene complex at the same level of theory
(Table 2).
The values of DGr and DG# reported in Table 2 are
referred to these pre-reactive complexes. In the NO3-
toluene complex the NO3 radical is oriented perpendicu-
lar to the aromatic ring with two oxygen atoms pointing
toward the ipso and para carbon atoms of toluene at a
˚
distance of 2.84 and 2.92 A, respectively (Fig. 1). This
NO3-toluene pre-reactive complex can evolve to cyclo-
hexadienes 2–5 (X ¼ CH2) through the ADD mechanism.
It is interesting to note that addition of NO3 to the four
positions of the aromatic ring from the pre-reactive
complex to form cyclohexadienes 2–5 (X ¼ CH2) is
Figure 1. Selected geometry parameters of 1-NO3 and 1-OH complexes and of the corresponding transition states (6-TS) in
the H-ABS mechanism computed at B3LYP/6-31G(d,p) level of theory
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REGIOCHEMISTRY
575
addition products, whereas in the case of NO3
significant amount of pre-reactive complex is present at
the equilibrium.
a
Table 3. Transition state energies (kcal molꢀ1) of the 1,2-
elimination of HNO3 to give nitrotoluenes computed at
B3LYP/6-31G(d,p) level of theory
As shown in Table 2, the H-ABS mechanism for the
reactions of toluene with both OH and NO3 is
significantly more exoergonic than the corresponding
ADD reaction. Furthermore, for the reaction of toluene
with OH the DG# value of H-ABS is very similar to that of
the ADD reaction, whereas for the NO3 reaction the DG#
value of H-ABS is significantly lower than that of the
ADD reaction (Table 2). The geometry of the transition
states (6-TS) (Fig. 1) is characterized by the NO3 group
far from the aromatic ring and with an oxygen atom in the
C–H axis. The hydrogen atom to be transferred is at 1.223
By 1,2-elimination of
HNO3 gives
Cyclohexadiene Configuration
DE#
(X ¼ CH2;
Y ¼ NO2)
8
8
trans
cis
1,4-elimination
1,4-elimination
9
9
1S,2R
1R,2R
2R,3R
2S,3R
2S,5R
2R,5R
2R,3R
2S,3R
3R,4R
3S,4R
3S,4R
3R,4R
16, ortho-nitrotoluene 60.49
16, ortho-nitrotoluene 16.34
17, meta-nitrotoluene 22.72
17, meta-nitrotoluene 60.58
1,4-elimination
12
12
13
13
10
10
11
11
14
14
1,4-elimination
˚
and 1.408 A from the carbon and oxygen atoms,
16, ortho-nitrotoluene 23.43
16, ortho-nitrotoluene 62.63
15, para-nitrotoluene 20.75
15, para-nitrotoluene 61.29
17, meta-nitrotoluene 61.95
17, meta-nitrotoluene 21.90
respectively. An intrinsic reaction coordinate analysis
(IRC) confirmed that 6-TS is on the reaction coordinate
which connects the pre-reactive complex to the reaction
products. In the interpretation of the DG# values it should
be noted that the B3LYP functional is well known to
underestimate the energy barriers of hydrogen-transfer
reactions by a few kcal mol .
ꢀ1 41 Furthermore, in the case
of the ADD mechanism there are six different addition
products which render this pathway statistically pre-
ferred. These considerations explain the great preference
for the ADD pathway observed experimentally in the case
of the addition of OH to toluene. In the case of NO3 the
reaction should proceed by a reversible ADD to give a
mixture of cyclohexadienyl adduct and pre-reactive
complex followed by the irreversible H-ABS step to
give the benzyl radical final product. This mechanism is
in line with the values of the Hammett’s s which refers
to the reversible ring addition step and the kinetic isotope
effect data which is related to the irreversible H-ABS
step which leads to the final benzyl radical and HNO3.
Clearly, even if this latter mechanism is preferred, a
fraction of the addition adducts (2–5) could react with
NO2 giving cyclohexadienes and consequently the final
nitrotoluenes.
In order to further explore the regiochemistry of the
NO3-initiated nitration of toluene, we also investigated
the final loss of nitric acid from the adducts 8–14. In fact,
even if the H-ABS pathway should be preferred to the
ADD one, this latter mechanism can significantly
contribute to the nitration reaction. Transition state
energies for the elimination of HNO3 from the
cyclohexadienes 8–14 are collected in Table 3. All
the cyclohexadienes having a cis arrangement of the
groups to be eliminated (H and ONO2) (e.g., in the R,R or
S,S configuration) show transition state energies far lower
than the corresponding trans isomers) (e.g., those in the
R,S or S,R configuration). The transition state with cis
intermediates shows early cleavage of the carbon–oxygen
bond between the nitrate group and the ring carbon, thus
suggesting that the loss of nitric acid from these
intermediates is a concerted process42 having a chair-
like six-membered transition state.
The intermediates showing the lowest transition state
energy for the loss of nitric acid (16.34 and
20.75 kcal molꢀ1) predict for the formation of 2-
nitrotoluene 16 (X ¼ CH2) and 4-nitrotoluene 15
(X ¼ CH2), which were the most abundant nitration
products experimentally observed.
The NO3-promoted nitration of phenol
In the NO3-initiated gas phase nitration of phenol 1
(X ¼ O) with NO2 high yields of 2-nitrophenol 16
(X ¼ O) are found. Also small amounts of 4-nitrophenol
15 (X ¼ O) are formed and the ratio 16:15 (X ¼ O) varies
upon changing reaction conditions.
Concerning the reaction mechanism, phenol 1 (X ¼ O)
could undergo the ADD mechanism to give adducts 2–5
(X ¼ O; Y ¼ NO2). Here, all isomeric nitrophenols should
be formed. The isomerization of the ipso adduct 2 to
intermediate 18 and then to 2-nitrophenol 16 (X ¼ O) is
also possible.
Alternatively, H-ABS to the phenoxy radical 6 (X ¼ O)
should give 4-nitrophenol 15 (X ¼ O) and 2-nitrophenol
16 (X ¼ O) exclusively.
The plot of log k for four para-substituted phenols
versus Hammett’s s for the reaction with NO3 gave
r ¼ ꢀ1.48 ꢁ 0.89; r2 ¼ 0.79, a value similar to that
(r ¼ ꢀ1.0) obtained in the reaction of the carbonate
radical anion with phenol in solution to give phenoxy
radicals via H-ABS.43 However, H-ABS is unable to
explain the predominant formation of the ortho-nitration
product.
The experiments show that the ratio 2-nitrophenol
16 (X ¼ O)/4-nitrophenol 15 (X ¼ O) depends in this
reaction from the initial ratio [NO2]/[phenol] (Figs. 2 and
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576
E. BOLZACCHINI ET AL.
Figure 2. The dependence of the ratio 2-nitrophenol 16
(X ¼ O)/4-nitrophenol 15 (X ¼ O) from the ratio NO2/phenol
for b ¼ 0.23
3, solid squares). To understand this fact, a kinetic
analysis was performed.
The ipso radical adduct 2 and the meta radical adduct 3
(X ¼ O) formed via kadd generate the final nitrophenols
via three different pathways:
1. Slow addition of NO2 via k1 to give cyclohexadiene 9
(X ¼ O) (from 2 X ¼ O), or cyclohexadienes 10 and 11
(X ¼ O) (from 3 X ¼ O) followed by a fast irreversible
elimination of nitric acid (kelim). The formation of
2-nitrophenol 16 (X ¼ O) from 9 (X ¼ O) and of both
2–16 and 4-nitrophenol 15 (X ¼ O) (from 10 and 11
(X ¼ O) is expected.
Scheme 3
determining the content of 2-nitrophenol 16 (X ¼ O) and
4-nitrophenol 15 (X ¼ O) of the reaction mixture are
initial rates, (vortho)0 and (vpara)0. The initial rates are
correlated to the initial values of partial pressures of
reactants, [phenol]0 and [NO2]0, respectively. In this case
the ratio between 2-nitrophenol 16 and 4-nitrophenol 15
can be estimated as the ratio between (vortho)0 and (vpara)0.
This ratio is a linear function of [NO2]0. It may be shown
that:
2. Loss of nitric acid via k2 to form a phenoxy radical 6
(X ¼ O) followed by reaction with NO2 to give both
2-nitrophenol 16 (X ¼ O) and 4-nitrophenol 15
(X ¼ O) via kortho and kpara
.
3. Isomerization of the ipso radical adduct 2 via k3 with
formation of intermediate 18 and then of 2-nitrophenol
16 (X ¼ O) exclusively.
½2 ꢀ nitrophenol 16ꢂ=½4 ꢀ nitrophenol 15ꢂ
¼ ðnorthoÞ0=ðnparaÞ0 ¼ a½NO2ꢂ0 þ b
where a and b are complex combinations of the rate
The steady state hypothesis was applied to intermedi-
ates 2, 3, 6, 9, 10, and 11 according to Scheme 3. Since
initial values of [phenol] and [NO2] are much higher than
the partial pressures of the products found at the end of the
experiment, they can be considered as constant. In other
words, the values vortho and vpara actually measured by
constant involved (see supplementary material).
Five values of the ratio 2-nitrophenol 16 (X ¼ O)/4-
nitrophenol 15 (X ¼ O) shown in Figs. 2 and 3 give
a ¼ 2.06 and b ¼ 0.23. Hence, the increase in the ratio 2-
nitrophenol 16 (X ¼ O)/4-nitrophenol 15 (X ¼ O) reflects
the increased importance of pathway 2 (reaction via a
phenoxy radical 6 (X ¼ O) with consequent loss of
regiochemistry) over pathway 1 (reaction via a cyclohex-
adiene with consequent control of the stereochemistry).
The ratio [NO2]/[phenol] controls the slow step in
pathway 1 but not the loss of nitric acid in pathway 2.
Increasing this ratio from 0.67 to 1.46 results in a higher
amount of NO2 available for the bimolecular process
constituting the slow step in pathway 1, thus allowing this
pathway to compete with pathway 2.
A different situation occurs when the ratio [NO2]/
[phenol] is as low as 0.14. Here, ortho-nitration sharply
predominates, indicating that the ADD pathway is
Figure 3. Simulated dependence of the ratio 2-nitrophenol
16 (X ¼ O)/4-nitrophenol 15 (X ¼ O) from the ratio NO2/
phenol for a0 ¼ 2.05
Copyright # 2006 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2006; 19: 570–578

REGIOCHEMISTRY
577
preferred to H-ABS. The low concentration of NO3 in
these conditions could switch part of the ipso adduct 2 to
isomerization to 18 and consequently to the formation of
the ortho nitration product. In other words k3 (Scheme 3)
could compete with k2 in these conditions.
Table 4. Transition state energies (kcal molꢀ1) of the 1,2-
elimination of HNO3 to give nitrophenols computed at
B3LYP/6-31G(d,p) level of theory
By 1,2-elimination of
HNO3 gives
Cyclohexadiene Configuration
DE#
The H-ABS and ADD pathways of the NO3-initiated
nitration of phenol were also investigated theoretically
and correlated to the experimental data. A pre-reactive
NO3-phenol complex, similar to that described above for
toluene has been found with a Gibbs free energy about
3.5 kcal molꢀ1 lower than the separate reactants (Table 2).
As noted for toluene, the NO3-phenol pre-reactive
complex can evolve to the cyclohexadienes 2–5 (X ¼ OH)
through the ADD mechanism. This process is endoergo-
nic by about 2 kcal molꢀ1 with respect to the separate
reactants for the ipso, meta, and para addition. For the
ortho addition the process is exoergonic by about
2 kcal molꢀ1. The larger stability of the ortho- with
respect to the ipso, meta, and para adducts is due to the
formation of a hydrogen bond between an oxygen atom of
the NO3 group and the hydrogen atom of the hydroxyl
group. DG# are similar to those calculated for the ADD
mechanism of toluene. In this case, due to the lower DGr
of the pre-reactive complex, DG# are about 5–
7 kcal molꢀ1 larger than the separate reactants, values
slightly larger than that calculated for the NO3-toluene
system. These results suggest that at the equilibrium the
yield of pre-reactive complex is significantly larger than
that of the adducts. On the other hand, the H-ABS
mechanism is significantly exoergonic (Table 2)
suggesting a preferred and irreversible formation of the
phenoxy radical. However, we were not able to locate a
TS along the reaction coordinate connecting the pre-
reactive complex and the H-ABS products. This should be
explained by considering the great distance between the
hydrogen atom of the OH group, which, in the pre-
reactive complex, is in the plane of the aromatic ring, and
the oxygen atom of the NO3 radical. In fact, differently
from toluene, at the transition state 6-TS bond formation
should involve a significant rotation of the C—OH bond.
Therefore, the formation of the pre-reactive complex
should selectively drive the reaction toward the ADD
mechanism. On the other hand, the H-ABS process
should involve a less probable mechanism in which the
reaction coordinate start from the two separate reactants.
In summary, the comparison between these two pathways
suggest that the ADD mechanism is preferred over H-
ABS. Based on the results considered above the
regiochemistry of the NO3-initiated nitration of phenol
should be explained by considering the irreversible
elimination of HNO3 from the 8–14 adducts.
(X ¼ CH2;
Y ¼ NO2)
8
8
trans
cis
1,4-elimination
1,4-elimination
9
9
1R,2R
1S,2R
2S,3R
2R,3R
2R,4R
2S,4R
2S,3R
2R,3R
3S,4R
3R,4R
3S,4R
3R,4R
16, ortho-nitrophenol 12.40
16, ortho-nitrophenol 54.47
17, meta-nitrophenol 23.20
17, meta-nitrophenol 65.30
1,4-elimination
12
12
13
13
10
10
11
11
14
14
1,4-elimination
16, ortho-nitrophenol 18.19
16, ortho-nitrophenol 56.14
15, para-nitrophenol 61.36
15, para-nitrophenol 17.40
17, meta-nitrophenol 63.30
17, meta-nitrophenol 24.81
energies far lower than the corresponding trans isomers)
(e.g., those in the R,S or S,R configuration). Again, the
transition state with cis intermediates shows early
cleavage of the carbon–oxygen bond between the nitrate
group and the ring carbon, thus suggesting that the loss of
nitric acid is a concerted process25 having a chair-like six-
membered transition state. Cyclohexadiene 9, (X ¼ O;
Y ¼ NO2, 1R,2R), shows the lowest transition state
energy for the loss of nitric acid (12.40 kcal molꢀ1) and
predicts the preferential formation of 2-nitrophenol 16
(X ¼ O).
CONCLUSIONS
In conclusion the NO3-promoted nitration of toluene in
presence of NO2 occurs mostly via a rate-determining H-
ABS process. The H-ABS step is preceded by an
equilibrium between the pre-reactive complex and the
addition adducts, therefore accounting for the values of
the Hammett’s s which appear to indicate an ADD
mechanism. The ADD mechanism should also be
operative to a lesser extent and the preference for the
nitration in ortho and para position, in this case, should
depend from the concerted loss of nitric acid from the
intermediate cyclohexadienes. The NO3-promoted
nitration of phenol in presence of NO2 occurs mostly
via a rate-determining ADD mechanism and the
stereocontrolled elimination of nitric acid has an
important role in driving the reaction toward the ortho-
nitration. The reasons for the dependence of the ratio
ortho:para-nitration from the initial concentration of
reactants are understood. These observations may be
useful for modeling the chemistry in the tropospheric gas
phase.
Activation energy values of this latter process are
reported in Table 4. The transition state energy from the
elimination of nitric acid from these was calculated as
above. Again, all the cyclohexadienes having a cis
arrangement of the groups to be eliminated (H and ONO2)
(e.g., in the R,R or S,S configuration) show transition state
Copyright # 2006 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2006; 19: 570–578

578
E. BOLZACCHINI ET AL.
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