HNO3/HFIP: A Nitrating System for Arenes with Direct Observation of π-Complex Intermediates

Article abstract of DOI:10.1021/acs.orglett.8b01028

This report describes an efficient nitrating system for the nitration of arenes at room temperature by using an equivalent of nitric acid in HFIP (1,1,1,3,3,3-hexafluoroisopropanol). The π-complex intermediate of an arene with a nitronium ion stabilized by HFIP can be directly observed by UV-vis spectra and is supported by theoretical calculations.

Full text of DOI:10.1021/acs.orglett.8b01028

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
HNO3/HFIP: A Nitrating System for Arenes with Direct Observation of
π‑Complex Intermediates
Le Lu, Huixin Liu, and Ruimao Hua*
Department of Chemistry, Key Laboratory of Organic Optoelectronics & Molecular Engineering of Ministry of Education, Tsinghua
University, Beijing 100084, China
S
* Supporting Information
ABSTRACT: This report describes an efficient nitrating system for the
nitration of arenes at room temperature by using an equivalent of nitric acid
in HFIP (1,1,1,3,3,3-hexafluoroisopropanol). The π-complex intermediate of
an arene with a nitronium ion stabilized by HFIP can be directly observed by
UV−vis spectra and is supported by theoretical calculations.
experimental and computational UV−vis spectra. In this paper,
we report the detailed results of our investigation.
he nitration of arenes is one of the most important and
fundamental electrophilic aromatic substitutions (SEAr). It
T
We first have to examine the stability of HFIP in the
presence of HNO3, although the oxidation reaction of benzyl
alcohols in HFIP using 68% HNO3 as the oxidant,3j and the
formation of hexafluoroisopropyl nitrate under very harsh
conditions from the reaction of HFIP with the excess amount
of concentrated HNO3 (>90%) and oleum6 were known.
The computational studies (see the Supporting Information
(SI)) reveal that the dehydrating energy of protonated HFIP
(78.8 kcal/mol) is about three times as high as that of 2-
propanol (25.2 kcal/mol), which mostly prevents its conversion
into carbocation and further transformation. In addition, HFIP
lacks β-H, which makes it impossible to produce alkenes via the
second-order elimination. Moreover, no considerable amount
of nitrated HFIP can be observed in a solution of concentrated
HNO3 in HFIP (1.0 M) at 25 °C for 1 h, which is confirmed by
1H NMR spectra (see SI). From the computational studies and
experimental results, it has also been confirmed that HFIP is
stable in the presence of concentrated HNO3. Then, we
performed the nitration of arenes in HFIP at room temper-
ature.
usually requires an excess amount of the mixed acid of nitric
acid with concentrated sulfuric acid, resulting in a significant
problem on workup by water washing before isolation of the
product to produce a large amount of acidic wastewater.
Therefore, a wide variety of catalytic systems have been
developed with the use of 1 equiv of nitric acid to provide
efficient and green nitration procedures.1
On the other hand, the solvent effect is somewhat observed
in most organic synthetic reactions to affect the rate and
outcomes of transformation.2 In particular, HFIP (1,1,1,3,3,3-
hexafluoroisopropanol) has been well applied and investigated
as a unique solvent in organic synthesis,3 owing to its extreme
properties, including strong hydrogen-bond donating ability,
high ionizing and stabilizing ability, low viscosity, low boiling
point, and recyclability. In addition, a combined computational
and experimental analysis has revealed that the aggregation
effect of HFIP is one of the critical factors to promote the
reactions.4 Recently, the properties and applications of HFIP
have been summarized in detail in a review paper.3l
It would be apparently advantageous to develop the nitration
system under mild conditions with the use of 1 equiv of HNO3
and without the use of catalysts or other promoters with simple
workup from the point of view of economy and green
chemistry. Therefore, in continuation of our interest in the
development of a nitration reaction of arenes,5 and due to the
extreme advantages of HFIP, we have investigated the nitration
reaction of arenes in HFIP at room temperature using 1 equiv
of HNO3 and have disclosed some interesting features: (1) the
nitration process occurs smoothly with high efficiency of
HNO3; (2) the π-complex intermediates of arenes with a
nitronium ion can be stabilized by HFIP and confirmed by
The results of the nitration reaction of electron-rich and
electron-deficient arenes at 25 °C with an equivalent of 68%
HNO3 or concentrated HNO3 in HFIP (1.0 M) are
summarized in Table 1. After 1 h, the mononitrated products
were isolated in good to high yields, and the use of
concentrated HNO3 resulted in a considerable increase of
yields with almost the same ratios of the nitrated isomers. One
of the most advantageous features of an HNO3/HFIP system is
the fact that both benzene, electron-rich arenes (toluene, p-
Received: March 31, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01028
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Letter
indicate the reaction occurring rapidly, which was further
supported by the GC−MS analysis of reaction mixture.
In addition, as other advantages of the present nitration
system, the solvent of HFIP (ca. 90%) can be recovered by
simple distillation under reduced pressure after the nitration
reactions with a 10 mL scale, and the mononitrated products
were obtained by silica gel column chromatographic separation
and were characterized by GC−MS and NMR spectra (see the
SI).
It is worth noting that the mentioned phenomena of color
change of the nitration reaction could not be observed either
when 68% HNO3 was used as a nitrating reagent or when other
solvents, such as sulfolane, acetic acid, nitromethane, dichloro-
methane (DCM), or even trifluoroethanol (TFE), were
employed with the use of 1 equiv of concentrated HNO3.
Very recently, Galabov and Schaefer have investigated the
formation of a π-complex intermediate between benzene and a
nitronium ion in a mixed acid solution of nitric and sulfuric acid
by theoretical calculations and UV−vis spectra of the reaction.8
On the basis of the reported results, one important piece of
evidence to support the formation of a π-complex intermediate
is to directly observe a broad band absorption at around 400
nm resulting from the electron excitation from the HOMO of
arenes to the LUMO of nitronium cation by theoretical
calculations without considering the interaction of a sulfuric
acid molecule in a vacuum. The theoretical modeling concludes
that the nitration reaction favors a stepwise mechanism with
intermediate formation of the π- and σ-complexes.
Table 1. Yield and Selectivity of Nitration in HFIP
b
yield (%)
a
entry
arene
68% HNO3
90% HNO3
1
2
3
4
5
6
7
8
9
benzene
toluene
80
90
75 (o/m/p = 48:3:49)
85
99 (o/m/p = 48:2:50)
96
p-xylene
mesitylene
88
92
c
durene
90
95
c
anisole
82 (o/p = 40:60)
56 (o/p = 18:82)
81 (o/p = 28:72)
86 (o/p = 30:70)
90 (o:p = 40:60)
85 (o/p = 20:80)
88 (o/p = 32:68)
93 (o/p = 36:64)
PhF
PhCl
PhBr
a
Reactions were performed using 1.0 mmol of arenes and 1 equiv of
b
c
nitric acid in 1.0 mL of HFIP at 25 °C for 1 h. Isolated yield. The
reaction was performed at 0 °C within 5 min.
xylene, mesitylene, durene, anisole), and electron-deficient
arenes (PhF, PhCl)7 undergo the nitration reaction with
concentrated HNO3 smoothly with high efficiency of HNO3 to
give the nitrated products in high yields (85−99%). Although
the isolated yields summarized in Table 1 were obtained after a
1 h reaction at 25 °C, one of the other features is an estimation
method for the reaction progress, which can be visually
appreciated by the color change of the reaction solution. As
shown in Figure 1, the progress of the formation and
Since intense change in color of the solution indicates the
formation and conversion of π-conjugated intermediates with
strong UV−vis absorption, we propose that the formation and
disappearance of the brown solution in the nitration of arenes
with the use of an HNO3/HFIP system results from the
formation of a π-complex and its further transformation.
Therefore, we next attempted to verify the formation of a π-
complex intermediate by experimental and computational
studies of UV−vis spectra in HFIP.
Although there are several variations of the mechanism for
the nitration of arenes, the commonly proposed mechanism
involves the formation of a π-complex via the interaction of a
+
nitronium cation (NO2 ) species with the π-system of arene
and then the formation of a σ-complex intermediate; finally, the
nitrated product is obtained via removal of the ipso-proton, as
shown in Scheme 1.9 In the present HNO3/HFIP system,
without use of other acids, nitronium cation is considered to
result from the autoprotolysis of nitric acid.
Figure 1. Color change of reaction mixture. The left of each picture
shows the appearance of 1.0 mL of 1.0 M HFIP/HNO3 (90% HNO3)
with a stir bar, and t = 0 min shows the initial state of reaction mixtures
after arenes are added. In the case where durene was used, the
colorless solution of the first photo is a solution of predissolved durene
in HFIP, and then HNO3 is added in the second photo since durene
cannot be dissolved immediately when it is added to HFIP.
Scheme 1. General Proposed Mechanism of Nitration of
Arenes
disappearance of the brown colored solution after the addition
of arenes was observed differently for each reaction bottle from
minutes to hours, depending on the arenes used. The kinetic
experiments of were also studied by using time-resolved UV−
vis absorption spectroscopy, and the krel (kobs./ kobs.(benzene))
values of intermediate decay are consistent with the observed
color-fading rate (see SI).
In addition, an alternative experimental result has disclosed
that durene also undergoes the nitration reaction with 1 equiv
of concentrated HNO3 at 0 °C in HFIP, and the complete
conversion can be confirmed by the color change of the
solution from deep brown to light yellow within 1 min to
It has been found that the UV−vis absorption spectrum of
the reaction mixture of benzene in HNO3/HFIP at 25 °C
shows a broad shoulder at 427 nm (<1 min. Figure 2), which
partially absorbs blue and green light to result in a brownish
solution, and the color fades to a light yellow after 50 min, as
shown in Figure 1. On the basis of the results reported by
Galabov and Schaefer,7 we consider that the broad absorption
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6-311+G(2d, 2p) basis set to compare with the observed
spectrum of nitrobenzene in HFIP, as shown in Figure 3, there
is a broad absorption at 271 nm observed in the UV−vis
absorption spectrum of nitrobenzene/HFIP solution, and the
theoretical predicted maximum absorption wavelength, using
TD-DFT with M06-2X/6-311+G(2d, 2p), is located at 243 nm,
which gives a systematic error around −28 nm and shows a
small overestimation of the excitation energy. The predicted
absorption spectra of possible intermediates and products are
shown in Figure 3. All σ-complexes of a nitronium ion with
benzene, including the structures of σ-1-, σ-2-, σ-3-, and σ-4-
protonated nitrobenzene (PhNO2H+), and nitrobenzene
contributed shorter wavelength of absorption between 190
and 325 nm. However, the computationally predicted
absorption spectrum of a π-complex of a nitronium ion with
benzene showed an intense and broad absorption band at about
400 nm, which is far from the predicted absorption band of
PhNO2H+, σ-complexes as well as nitrobenzene (product).
Therefore, the predicted UV−vis absorption spectrum at about
400 nm supports that the experimental spectrum at 427 nm is
caused by π-1, π-2, and π-3 intermediates.
In the predicted π-complexes, π-2 and π-3 are much more
stable structures than π-1. The solvation model of π-2 is also
treated by using two explicit HFIP molecules and is embedded
in a IEFPCM solvation model, which gives a similar result in
the prediction of UV−vis absorption spectrum (see SI) as the
use of a solvation model of dichloromethane. On the basis of
these results, the UV−vis spectra of other arenes have been
studied with an explicit solvation model by using both DCM
and HFIPs. The difference between the maximum absorption
wavelength between DCM and HFIPs model is not significant;
it shows that the effect of a dielectric constant on the predicted
absorption spectrum can be ignored.
Figure 2. Observed UV−vis absorption spectrum (black) of 1.0 mmol
of benzene in 1.0 M HNO3/HFIP solution at the initial state with 271
nm (blue) and 427 nm (pink) fitting curves.
of UV−vis at 427 nm corresponds to the formation of a π-
complex intermediate of benzene with a nitronium ion, which is
somewhat stabilized by an HFIP solvent.
To provide the results from the theoretical calculations10 to
clarify the observed UV−vis absorption spectrum at 427 nm in
an HNO3/HFIP system being really resulted from the
formation of a π-complex intermediate, we have also
theoretically calculated the absorption spectra of the other
possible σ-complex generated via the reported proton trans-
fer,11 or the σ-complex from the ipso-addition of methyl
arenes12 in the nitration reaction, as shown in Figure 3.
With the use of nitrobenzene as a reference to examine the
accuracy of the combination of using M06-2X functional with a
It is commonly known that the formation of π-complexes of
arenes with a nitronium is a fast process, and the conversion of
π-complexes to σ-complexes is considered to be the rate-
determining step in a nitration reaction of arenes. To confirm if
the conversion of π-complexes to σ-complexes is also the rate-
determining step in HNO3/HFIP system, a kinetic isotope
effect (KIE) experiment has been performed (see the SI). The
observed KIE value of a nitration of C6H6/C6D6 (1:1 in molar
ratio) is 0.82, indicating the conversion of sp2 hybrid carbon to
sp3, an inverse second-degree KIE, is the rate-determining step
in the pathway of a nitration reaction to support the stepwise
mechanism of nitration.13
As mentioned above, the electron-rich arenes, such as
toluene, xylene, mesitylene, and durene, show extremely strong
light absorption and form a dark solution when they are added
to HNO3/HFIP, whereas halobenzenes show only light brown
solution under the same conditions and similar operation.
These observed phenomena can be explained by the
experimental results of UV−vis absorption spectra of the
reaction solution, as shown in the upper in Figure 4. We
observed the broad absorption bands in HNO3/HFIP between
430 and 700 nm. Xylene and mesitylene show a very broad
absorption band shoulder at 500 nm with an approximate 200
nm full width at half-maximum, which absorbs most of the
visible light and results in a dark solution. The reaction of
durene and nitric acid in HFIP is too fast to determine its UV−
vis absorption spectrum at room temperature.
To confirm that the observed color change phenomena
corresponds to the formation of π-complexes of NO2 with
arenes, with the computational methods, as shown in the lower
Figure 3. Normalized predicted UV−vis absorption spectra of possible
intermediates and the observed spectrum of the reacting mixture of
benzene with HNO3/HFIP solution.
+
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01028.
Experimental procedures, preparation of anhydrous nitric
acid, and UV−vis spectrum and molecular structures
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ruimao@mail.tsinghua.edu.cn.
ORCID
Ruimao Hua: 0000-0003-2545-807X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the “Tsinghua Xuetang Talents Program” for support
of computational resources.
■
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