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reduced to the corresponding hydroxylamine (Table 2, entries 6–8). times and produced more unidentified side products. In a similar
This is possible because the formed product resulted in the change manner to previous reports, azoxybenzene formation was observed to
of electronic density of another nitro-group and therefore another be a spontaneous condensation process.10 In nitroarenes bearing an
nitro-group could not be further reduced by BaNTR1. Similar electron-withdrawing group, the N–O bond of arylhydroxyamine
results have been reported in the previous literature.7b,9e The best was strengthened and relatively stable,11 with only trace amounts of
result was observed at the para-position, with excellent (>99%) the side product azoxybenzene being formed in the crude product.
selectivity and 100% conversion being observed within 1 h However, in nitroarenes bearing no electron-withdrawing or electron-
(Table 2, entry 8). In the case of the ortho-nitro group, the donating group, the corresponding hydroxylamine was more
reduction process occurred at a slower rate because of steric unstable, and formed azoxybenzene rapidly.
hindrance, with a lower conversion of 90.5% being achieved
In summary, we have developed a controllable reduction
from a larger catalyst charge after 4 h, although the selectivity method for the synthesis of arylhydroxylamines using a highly
was still high (>99%) (Table 2, entry 6). For the meta-position selective nitroreductase as a biocatalyst. In the reduction of
dinitrobenzene, however, the BaNTR1 charge had to be nitroarenes bearing an electron-withdrawing group, this process
increased 2-fold to allow the conversion to reach 100% in 1 h, allowed for the formation of high purity arylhydroxylamines in
and trace amounts of side products and amine (1.4%) were excellent yield and therefore represents a green, simple and
detected in the reaction mixture (Table 2, entry 7).
highly efficient process.
We also investigated the reduction of nitrobenzenes bearing
We are grateful for financial support from the National
electron-donating groups, including p-nitrotoluene and p-nitro- Natural Science Foundation of China (No. 31200050), Ministry
anisole. The results revealed that these substrates did not perform as of Science and Technology, P.R. China (No. 2011AA02A210 &
well as those bearing electron-withdrawing groups. In the 2011CB710800), and the Fundamental Research Funds for the
absence of any other substituent, the reduction of nitrobenzene Central Universities, Ministry of Education, P.R. China.
required the catalyst charge to be increased 4-fold to give a
conversion of 100% and a selectivity of 98.3% in 1 h (Table 2,
Notes and references
entry 9). Under the same conditions, p-nitrotoluene and
1 (a) Y. Z. Wang, L. W. Ye and L. M. Zhang, Chem. Commun., 2011, 47,
p-nitroanisole provided conversion levels of 99% and 96.7%,
7815–7817; (b) G. L. Zhao and A. Cordova, Tetrahedron Lett., 2006,
respectively (Table 2, entries 10 and 11), although large
amounts of corresponding azoxybenzene as well as trace
amounts of the amine were detected in the reaction mixture,
suggesting that the hydroxylamine products of these reactions
were further reduced to the amines and that the remaining
hydroxylamines were rapidly and spontaneously condensed
to azoxybenzene (ESI†). This suggestion would explain why the
corresponding hydroxylamine was not detected after evaporation.
Based on our observations, we have proposed a mechanism for
the reaction, as shown in Scheme 1. In contrast to other reported
NTRs that are capable of further reducing arylhydroxylamines to
arylamines, it was assumed that BaNTR1 continuously reduces
nitroarenes to arylhydroxylamines in two steps via the transfer of
four electrons. The controllable reduction of nitroarenes bearing
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more challenging because the formation of the corresponding
amines was also observed. These results showed that nitroarenes
bearing a strong electron-donating group required longer reaction
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Scheme 1 Proposed bioreaction pathways for the controllable reduction
of nitroarene compounds to the corresponding N-aryl hydroxylamines
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