Simple, Fast, and Safe Continuous Flow Nitrations with the IceCubeTM Flow Reactor

IceCubeTM Flow Reactor Application Note


Nitration of aromatics is one of the oldest and industrially most important reactions. A reaction between an organic compound and a nitrating agent leads to the introduction of a nitro group onto a carbon, nitrogen, or oxygen atom of that organic compound.

Nitro derivatives of aromatic compounds are used in a variety of basic and specialty chemicals that are employed in dyes, perfumes, pharmaceuticals, explosives, intermediates, colorants, and pesticides.

Almost 65% of APIs require at least one nitration step in the whole process.


In general, several types of nitrating agents are used for nitration. One-third of the published literature from the last 50 years report on nitrations of organic substrates with sulfuric acid and nitric acid as the nitrating agents1.

Other types of nitration methods may also employ highly corrosive agents that together with the exothermic nature of such reactions require special instrumentations that can prevent both corrosion and enable ideal reaction conditions.

Continuous flow nitration using miniaturized devices is an excellent approach to avoid issues related to corrosion, heat transfer, mass transfer, homogeneity inside the reactor and mixing.

In this application note, we share details of two nitration examples demonstrating the versatility of the IceCube flow reactor, dedicated to the safe running of exothermic reactions. The first reaction is the nitration of phenol, which was carried out at 10 °C providing 2-nitrophenol as the main product. In the second example, when toluene was nitrated with fuming nitric acid at -20 °C, precooling of the starting material was required before mixing and reacting them to form 2-nitrotoluene.

Ref: 1. Beilstein J. Org. Chem. 2014, 10, 405–424.


The IceCube™ reactor is made up of 4 modules: the Ozone ModuleTM, Pump Module, Reactor Module, and the Control Unit. The modules can be configured separately to match the application you wish to perform.


The Reactor Module is a highly versatile reactor capable of controlling even extremely exothermic reactions safely and simply. Composed of two reactor zones with Peltier heating/cooling, and a reaction line made of Teflon for wide chemical compatibility. Difficult or dangerous reactions such as nitration, lithiation, azide generation or ozonolysis may now be performed and quenched immediately without the need for isolation of dangerous intermediates.

Main reactor zone temperature range: -70-80 °C,

secondary reactor zone temperature range: -30-80 °C.


The Pump Module is made up of 2 rotary piston pumps, which have good chemical compatibility. The pumps are connected to two pressure sensors and 3-way valves, which control the path of reactant or solvent through the reactor.

Flow rate: 0.2-4 mL/min.

Max pressure: 6 bar


The Ozone ModuleTM gives you a safe and efficient way of generating ozone from oxygen. The ozone/oxygen amount is precisely controlled through the built-in mass flow controller. The system can also be used as a powerful and compact stand-alone ozonizer.

Oxygen flow rate: 10-100 mL/min.

O3/O2 v/v%: 14% at 20 mL/min oxygen flow rate.

Maximum reaction pressure: 3 bar.


The Control Module is a small touch screen, which provides full control over all the attached modules. Reaction parameters can be easily set and monitored over time. The provided software has predefined processes for different applications, such as for ozonolysis, and it is also possible to design your own configuration.


General Experimental Protocol

The nitrating mixture and the sulfuric acid solution of the phenol (1 M) were pumped into a PTFE T-piece by the system’s inert rotary piston pumps. The combined reagent and reactant streamlines were then introduced into the IceCube flow reactor’s first reactor zone, where the reactor plate was filled with a 2 mL 1/8” PTFE tube. As a last step, the nitrated compounds were collected onto ice. Scheme 1. represents the IceCube as it was set up for the nitration reaction, and Table 1 summarizes the reaction conditions with the results included.


The excellent chemical resistivity of the IceCube flow reactor system allowed the nitration of phenol in a continuous manner in minutes that together with the reactor’s automated Peltier cooling unit made sure that the heat generated was adequately dissipated during the course of such a highly exothermic reaction. The temperature of the reaction was kept to a constant of 10 °C. The integrated 3-way valves in each of the pumps enabled both safe and quick methods to flush out the residual acidic mixture from the system with water that made the system available for other types of exothermic flow reactions in minutes.

Reaction 1. Nitration of phenol in the IceCube flow reactor.

Scheme 1. Reaction setup of the IceCube flow reactor for the nitration of phenol.

EntryFlow Rate (mL/min)ReactorConversion (%)Selectivity (%)
Pump #1Pump #2VolumeResidence timeTemperature2-NP4-NP2,4-NP2,6-NP
10.20.22 mL (1=8")5 min10 °C8459.626.28.33.6
2112 mL (1=8")1 min10 °C8460.723.810.74.8

Table 1. Experimental reaction conditions and results.


General Experimental Protocol

Fuming nitric acid and toluene were delivered into the first reaction zone of the IceCube flow reactor by the system’s inert rotary piston pumps. Both materials were pumped through 2 ml precooling sections before they were combined by a PTFE T-piece. The combined reaction streams passed through a 4 mL PTFE reactor loop, in which the nitration was conducted at a constant -20 °C. Finally, the nitrated compounds were collected into water. Scheme 2 represents the IceCube as it was set up for the reaction, and Table 2 summarizes the reaction conditions with the results included.


Just as in the previous nitration example, the IceCubeTM Flow Reactor enabled safe and facile nitration of the toluene with fuming nitric acid. The automatic cooling system of the unit kept the reactor at the set -20 °C constantly, despite the several hundred kcal/mol reaction heat that was released during the course of the reaction.

Reaction 2. Nitration of toluene in the the IceCube Flow Reactor.

Scheme 2. Reaction setup of the IceCube flow reactor for the nitration of toluene.

EntryFlow Rate (mL/min)Acid equivalencyPrecoolingReactorSelectivity (%)
Pump #1Pump #2TouleneNitric AcidVolumeResidence timeTemperature2-NP3-NP4-NP2,6-NP2,4-NP
1211.2622-20 °C4 mL80 sec-20 °C41,71.834.33.618.5
22.810.9224 mL-20 °C63 sec-20 °CGC-MS results did not indicate differences between Entry 1. and 2. results

Table 2. Experimental reaction conditions and results.