Organic Process Research & Development 2009, 13, 999–1002
Continuous Flow Nitration of Benzaldehyde
Amol A. Kulkarni,*,† Vishwanath S. Kalyani,† Ramesh A. Joshi,‡ and Rohini R. Joshi‡
Chemical Engineering DiVision (CEPD), National Chemical Laboratory, Pune - 411 008, India, and DiVision of Organic
Chemistry, National Chemical Laboratory, Pune - 411 008, India
Abstract:
is feasible in devices where the characteristic flow dimensions
offer significantly fewer transport limitations. This indicates that
it is not always necessary to carry out the flow synthesis in
devices with very small channel sizes (<100 µm), and channel
sizes slightly greater than a millimeter may also be feasible.
Here we illustrate one such example of aromatic nitration, where
the process intensification can be achieved using a micromixer
followed by reaction channel size slightly greater than 1 mm.
The nitro derivatives of aromatic compounds6 find applica-
tions in a variety of fields and are synthesized in quantities
ranging from bulk chemicals to fine chemicals to drug inter-
mediates. The nitro derivatives of benzaldehyde find applica-
tions in dyes, pesticides, pharmaceutical drugs, and nonlinear
optical materials. Nitrobenzaldehyde also serves as a raw
material for the preparation of benzodiazepines and other
cardiovascular drugs of the dihyropyridine group. Specifically,
o-nitro derivative has explicit applications and is usually desired
in good yield and high purity. However, in most of the
conventional synthesis routes of direct nitration of benzaldehyde,
the meta isomer is obtained in large quantities, and the usual
mole ratio of the products is o:m ) 1:4. This ratio can be varied
by changing the w/w amount of the nitrating mixture with
respect to the substrate (benzaldehyde) or even by varying the
internal composition of the nitrating mixture (HNO3:H2SO4,
mol/mol). The condensation of 2-nitrotoluene followed by
hypochlorite oxidation yields only a trace amount of nitroben-
zaldehyde.8 For a brief review of the other methods used for
direct synthesis of the ortho derivative, the reader may refer to
Sainz-Diaz.7 In the typical batch reaction of direct nitration of
benzaldehyde, the mixing of the nitrating mixture and the
substrate is done very slowly by adding either the substrate to
the nitrating agent or vice versa. The reaction is usually carried
out in the temperature range of -5 to 15 °C, and depending
upon the composition of the nitrating agent and the mole ratio
of reacting species, the reaction time reported in the literature
falls in the range of 2.3-6 h. These issues stress adoption of
new synthesis methods that help to achieve a better control on
the product composition, safe handling of hazardous materials,
and reduced release of the toxic materials in the environment.
In the case of direct nitration of benzaldehyde, as per the
reaction mechanism itself, the nitration in the ortho position is
very unlikely due to steric hindrance and low nucleophilic
character of this position. This is mainly due to the solvation
of the aldehyde group in the strongly protic system of the
nitrating mixture containing higher proportions of H2SO4.
The nitration of benzaldehyde can be carried out in a safe manner
in continuous mode using a microreactor system. Choice of a
micromixer was seen to affect the performance of this two-phase
reaction significantly. The reaction time could be brought down
to 2 min by increasing the reaction temperature and thereby taking
advantage of higher heat transfer area. The simple T-micromixer
is seen to be inefficient for two-phase reactions. Further scope of
process intensification is also discussed.
Introduction
Microreactors are being used for several fast and exothermic
reactions, and a vast amount of information on the feasibility
of many homonegeous and heterogeneous reactions in miniatur-
ized devices is reported in the literature.1-4 A few of the
important advantages of microreactors are: (i) very high heat
transfer area, which helps carry out exothermic reactions, (ii)
smaller residence time, which helps carry out fast reactions at
true kinetic rates, (iii) better control of the overall reaction rates,
which helps achieve the desired selectivity by providing the
possibility of introducing the reactant(s) at different spatial
locations, (iv) the need for very much smaller amounts of
chemicals to obtain the necessary kinetic information, (v) safe
operation, (vi) the ability to withstand extreme conditions
because of smaller reaction volumes, etc. Nitration of aromatic
substrates is one such class of reactions, where the above-
mentioned advantages are useful for achieving better yield and
selectivity when the reactions are done in microreactors. Since
the channel dimensions are small, the diffusion time scales are
much smaller than in conventional batch operations. This results
in rapid mixing, which subsequently reduces the possibility of
byproduct formation in fast reactions, and it also yields higher
mass transfer rates in case of two-phase flows. A detailed
discussion of the advantages of continuous flow synthesis and
a list of different classes of reactions that can be carried out in
continuous flow mode can be seen in a recent review by Wiles
and Watts.5 In reality, the concept of continuous flow synthesis
* Corresponding author. Telephone: +91-20-25902153. Fax: 91-20-25902621.
E-mail: aa.kulkarni@ncl.res.in.
† Chemical Engineering Division (CEPD).
‡ Division of Organic Chemistry.
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(2) Ehrfeld, W.; Hessel, V.; Lo¨we, H. Microreactors. Wiley-VCH: Wein-
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(3) Ja¨hnisch, K.; Hessel, V.; Lo¨we, H.; Baerns, M. Angew. Chem., Int. Ed.
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(7) Sainz-Diaz, C. I. Monatsh. Chem. 2002, 133, 9–22.
(4) Pennemann, H.; Watts, P.; Haswell, S. J.; Hessel, V.; Lowe, H. Org.
Process Res. DeV. 2004, 8, 422–439.
(5) Wiles, C.; Watts, P. Eur. J. Org. Chem. 2008, 10, 1655–1671.
(8) Meyer, H. Chem. Abstr. 1976, 84, 16962. DE Patent 2 415 062, 1975.
10.1021/op900129w CCC: $40.75 2009 American Chemical Society
Published on Web 08/26/2009
Vol. 13, No. 5, 2009 / Organic Process Research & Development
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