130 Synthetic Routes to AromaticC-Nitro Compounds
Nitrating agent, solvent, temperature, concentration and the ratio of substrate to nitrating
agent must all be considered when an aromatic substrate is to be nitrated. Substituents which
withdraw electron density from the aromatic ring make nitration more difficult, whereas those
that release electron density through either inductive or resonance effects make nitration easier.
Reaction rates between substrates can be several orders of magnitude different. Reactive sub-
strates can be nitrated with mixed acid containing relatively large amounts of water, whereas
less reactive substrates and substrates that require polynitration need treatment with more con-
centrated acids and usually at higher temperatures. Nitrations with mixed acid vary from the
use of concentrated nitric acid or even dilute nitric acid in sulfuric acid to the use of oleum and
fuming nitric acid at elevated temperatures. Commercial ‘concentrated’ nitric acid contains
70 % acid, whereas fuming nitric acid contains 90 %+acid, but both are commonly used in
nitrations. Pure nitric acid containing 98–99 % nitric acid is more expensive, less widely avail-
able and has a limited shelf-life. Anhydrous mixed acid is often prepared from fuming nitric
acid and oleum. Oleum, or ‘fuming sulfuric acid’ as it is sometimes known, is sulfuric acid
containing dissolved sulfur trioxide and the latter reacts with water formed during nitration to
generate more sulfuric acid.
The rate of a nitration is fastest at the start of a reaction when a large excess of nitric acid
is present. As the reaction progresses the water formed during nitration dilutes the mixed acid
and slows the rate of reaction, and as such, it is common towards the end of a nitration, when
most of the substrate has reacted, to heat the reaction to completion. This dilution of the acid
with water is an important point and the amount of sulfuric acid used should be enough to take
up all the water formed during the reaction; otherwise, nitration may be incomplete and result
in an unfavourable mixture of product and starting material. Increased amounts of water in
mixed acid rapidly reduce the concentration of nitronium ions.^17 –^19 When concentrated nitric
acid is used for the nitration of some of the more reactive substrates a large excess of sulfuric
is often used to compensate for the water present.
It is common practice during the mono- or di-nitration of a substrate, dependent on its
reactivity, to use a small excess of nitric acid (1–5 %) in the mixed acid. The further nitration
and polynitration of substrates often requires more vigorous conditions and a greater excess
of nitric acid (5–100 %) is used in order to ensure complete nitration.
During most nitrations on both a laboratory and industrial scale the aromatic substrate is
added slowly and in portions/aliquots to the mixed acid. This is desirable on safety grounds
but has the problem that the first aliquots of substrate are in the presence of a large excess
of nitric acid and this may lead to overnitration. In contrast, the last portions of substrate to
be added may remain unreacted, although the presence of a small excess of nitric acid in the
mixed acid often accounts for this problem. Adding the mixed acid to the substrate would
avoid these problems but must be considered a more dangerous process and is rarely practical.
A more suitable method involves the slow and simultaneous addition of both mixed acid and
organic substrate to the reaction vessel. The advent of continuous flow reactors allows this on
an industrial scale and increases safety. Studies show that optimum nitrating conditions are
achieved when a constant ratio of water to sulfuric acid is maintained throughout a nitration.^20
Nitrations with mixed acid are exothermic reactions. The polynitration of aromatic sub-
strates frequently involves strong mixed acid and high temperatures. Heating organic sub-
stances with solutions containing strong oxidants like nitric acid always involve some danger
and so it is customary that the temperature is kept as low as possible during the initial stages of
nitration and raised later on when most of the substrate has reacted. More than often, substrate
addition is regulated so that a stable temperature is maintained without the need for external