Jian-Wei Wu, P. Zhang and Zhi-Xin Guo
Tetrahedron Letters 72 (2021) 153087
corresponding diacylfuroxan was obtained as the major product as
we reported before [42], ketone without alfa-H such as pivalophe-
none (Table 2, entry 6) resulted in the expected nitrated product.
The o-, m-, and p-nitropivalophenones were obtained in the per-
centage ratio of 30.0:43.3:26.7, which is quite comparable to the
classical nitration as well as the nitration reaction by taking NO2-
BF4 as nitration reagent [56]. The nitration of benzonitrile (Table 2,
entry 7) in the HSBM reaction condition resulted in a nitration mix-
ture with m-/o-/p- ratio as 18.3:72.0:9.7, in agreement with the
nitration results obtained by employing nitric acid/trifluoroacetic
anhydride/zeolite Hb as nitration system [10]. Compared with
the traditional nitration reaction [53], a slightly higher proportion
of the p-isomer is generated.
While all of the deactivated arenes mentioned above could be
nitrated to their expecting mono nitrated products under the stan-
dard HSBM reaction condition, nitrobenzene and methyl benzene-
sulfonate could not be nitrated, only unreacted starting materials
were recovered. In order to make nitrobenzene nitrated, the ration
of P2O5 was raised to 10 equivalent compared with that of
nitrobenzene while keeping the ratio of Fe(NO3)3Á9H2O unchanged.
The nitration reaction was performed very well, dinitrobenzene
was obtained in 98% yield with o-/m-/p- ratio as 9.2:87.7:3.1
(Table 2, entry 8), in agreement with the classical nitration result
[57]. To our surprise, 15 equivalent of P2O5 was a necessary to
nitrate the methyl benzenesulfonate (Table 2, entry 9), resulting
in a mixture with 90.7% of m-nitro methyl benzenesulfonate as
well as 9.3% of p-nitro methyl benzenesulfonate. These results
imply that the benzenesulfonate is more difficult to be nitrated
than nitrobenzene under the mechanochemical reaction conduc-
tion. Meanwhile, more P2O5 can enhance the reactivity of the
HSBM nitration.
In order to investigate the applicability of the HSBM nitration
protocol on a larger scale, the mechanochemical reaction of large
quantity of benzoic acid (0.2442 g, 2 mmol) was performed in a
big stainless milling beaker (25 mL), along with one big stainless
milling ball (ø = 15.4 mm) under the standard HSBM reaction con-
dition. The nitrobenzoic acid was obtained in 94% yield with the o-/
m-/p- proportional ratio as 8.0:86.7:5.3, indicating the possibility
for applying this reaction in larger scale.
In the next phase of the study, a survey of nitration of disubsti-
tuted arenes was conducted, the results are summarized in Table 3.
It’s not surprising that dinitro compounds were the domain prod-
ucts for those disubstituted arenes with two activated groups
(Table 3, entries 1–3). For those arenes with one deactivated sub-
stituent (Table 3, entries 4–11), the single nitrated products were
the major products. As for 4-methylbenzonic acid as well as 4-
nitrotoluene, only one product was obtained in excellent yield
due to the regioselectivity.
which is generated by the thermal decomposition of iron(III)
nitrate was proposed to response for the nitration reaction
[59,60,62,63]. It was also proposed by Hajipour et al. [33] that in
their solid phase grinding reaction of arenes with 65% nitric acid
in the presence of P2O5 supported on silica gel, N2O5 is the key spe-
cies, which was generated from nitric acid and P2O5. N2O5 decom-
posed to give nitronium ion, being responsible for the nitration
reaction. However, they did not give any explanation. During our
experiments, we have noticed that P2O5 played the key role in
the nitration reaction. If no P2O5 or less equivalent of P2O5 pre-
sented in the reaction mixture, the nitration did not occur (Table 1,
entries 1–2) or the conversion of arene was less (Table 1, entry 3).
However, if adequate equivalent of P2O5 existed, the nitration reac-
tion occurred smoothly. The nitration reactivity was even
enhanced when P2O5 was overloading (Table 2, entries 8 and 9).
We have also observed the release of a pungent smell gas with
brown color when the HSBM reaction was failed to give any
nitrated product. Normally, this gas should be N2O4 or NO2. Based
on the above experimental phenomena and literatures, we pro-
posed that in the HSBM nitration reaction, the Fe(NO3)3Á9H2O
was reacted with P2O5 to generate nitric acid. The in situ produced
nitric acid could be decomposed to generate N2O4/NO2 under the
mechanical force provided by the ball milling. The in situ produced
N2O4/NO2 should be responsible for the nitration, most probably,
following a radical-type mechanism reported by Kaupp et al. [64].
In summery, we have reported here a new method for nitration
of deactivated arenes under HSBM reaction condition by the com-
bination of Fe(NO3)3Á9H2O and P2O5 as nitrating reagent. Deacti-
vated aromatics could be nitrated with excellent yields.
Compared with traditional methods for nitrating deactivated are-
nes, this method is eco-friendly, effective, and exhibits advantages
in terms of safety and easier operation. We propose HNO3 gener-
ated in situ from the reaction of Fe(NO3)3Á9H2O with P2O5 could
be decomposed to give N2O4/NO2, which play a major role for
the aromatic nitration via a radical mechanism.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
Acknowledgment
We thank Ms. Li-Yu Lu for experimental assistance.
Appendix A. Supplementary data
It was reported that arenes could be nitrated by taking Fe
(NO3)3Á9H2O as nitrating reagent in solution chemistry [58-63].
For example. The mono nitration of phenols with Fe(NO3)3ÁÁ9H2O
was achieved in high para-nitrated regioselectivities using certain
ionic liquid as the solvent [58]. Acyl protected anilines could also
be ortho-nitrated in moderate to good yields via Fe(NO3)3ÁÁ9H2O
catalyzed by NHPI [62]. An efficient ipso-nitration of arylboronic
acids with Fe(NO3)3ÁÁ9H2O was also developed [59]. 8-Amino-
quinoline amides could be regioselectively nitrated in C(5) position
by taking Fe(NO3)3ÁÁ9H2O as promotor as well as nitro source [61].
Compared with these publications, the mechanical nitration reac-
tion developed in this letter is simple,straight-forward, effective,
and more powerful. However, the regioselectivity of this mechan-
ical nitration is more likely following the classical nitration reac-
tion, which may be improved in the future work.
Supplementary data to this article can be found online at
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Currently, it is not easy to monitor the mechanism of a organic
mechanochemical reaction. For Fe(NO3)3Á9H2O involved nitration
reaction in solution, a nitrogen dioxide radical (NO2Á) intermediate,
4