What is nitration?
Nitration is the introduction of a nitro group (NO2) into an organic compound. Since its discovery in 1834, the nitration of benzene has become a stalwart of chemical synthesis [1]. However, the requirement of both fuming nitric and concentrated sulfuric acid or glacial acetic acid (and sometimes acetic anhydride), and the strong exotherm generated during the reaction, mean that safety considerations are paramount [2]. For example, within the Handbook of Reactive Chemical Hazards [3] there is extensive discussion of the incompatibilities of nitric acid with over 80 classes of reagents, and the following cautionary statement is provided:
‘If anywhere near stoichiometric composition, an homogeneous mixture of nitric acid and virtually any organic is a sensitive high explosive.’
This is where continuous flow processing can provide a valuable alternative to batch chemistry, due to the ability to control reaction rate and temperature by changing the rate that materials flow through the system [4].
Scheme 1: General overview of the utility of nitration reactions.
In its simplest form, nitration is the addition of a nitro group to a benzene ring, and provides a handle to installation of further functionality. For example, the nitro group itself reduces the reactivity of a benzene ring towards electrophiles by virtue of its electronics, directs electrophilic species to specific position of substitution in SEAr reactions, and enables nucleophilic aromatic substitution (SNAr) if a suitable leaving group is present. Alongside this, it is relatively unreactive within most common organic transformations, therefore within pharmaceutical and pesticide chemistry it is often used as a ‘masked’, or protected, aniline. The aniline can be readily accessed through reduction, providing access to a broad range of amine-based chemistry, as well as diazo couplings, metal-mediated cross-couplings and heterocycle formation, allowing rapid functionalisation, Scheme 1.
Key considerations
One of the main drawbacks of nitration is the reagents required. In most circumstances fuming nitric acid is used, which is a strongly corrosive and oxidising material. In addition, another strong acid is usually required to allow for preparation of the nitronium ion, the key nitrating reagent. Often this is sulfuric acid, but other materials such as glacial acetic acid can also be used.
As well as the latent safety issues associated with the use of strong acids, the solution itself must be heated, often to 100 °C or more, with the chance of an adverse event due to thermal run-away increasing as the scale of reaction increases. Completing nitration reactions on large scale requires extensive safety assessments and in some cases scale-up is simply not possible, which therefore limits the quantity of product that can be formed. In addition, an excess of nitrating agent can lead to polynitration, with separation of the desired product adding purification operations and costs to a synthesis, as well as the risk of explosive byproducts.
Benefits of continuous flow for nitration
In the case of nitration, continuous flow offers significant advantage because the temperature and stoichiometries can be accurately controlled by varying the flow rates of nitrating agent and substrate, as well as using efficient cooling systems [5]. However, the use of acid-resistant pumps and parts is of paramount importance to avoid equipment failure.
One of the first adopters to use flow chemistry for nitration of aromatic materials was Novartis [5]. With careful optimisation of the flow conditions, reactions that led to multiple products or decomposition in batch mode gave excellent yields, with fewer impurities and on significantly shorter time-scales, Scheme 2.
The authors stated: “Not only were the screening experiments complete within a matter of hours, but we were also able to produce the required 250 g of material in just one day’s work (including workup) using the Vapourtec setup. The flow reaction shows a considerable time saving compared to the batch experiment, which required two months of safety evaluation and a subsequent week to safely perform the chemistry in a 2.5-L reactor using a trifluoroacetic/nitric acid alternative as the nitrating mixture”.
Scheme 2: Comparison of nitration in (a) batch and, (b) flow.
In another example, Kyprianou and co-workers used flow chemistry to nitrate 2,4-dinitrotoluene (DNT) to give 2,4,6-trinitrotoluene (TNT) through use of concentrated nitric acid and concentrated sulfuric acid [6]. During this process clogging of the reactor by the TNT product was an issue, therefore chloroform was added in the outlet flow stream to improve product solubility. Upon comparison with batch mode, the yield was better (58% in 1 hour in batch, 99% in 20 mins in flow), less concentrated acids could be used, and the reaction was faster. In addition, reproducibility was improved, and the risk of run-away reactions was minimized. In this case, adaptation to flow did not require significant re-optimisation of the conditions and resulted in a much higher quality product.
In summary, the use of flow chemistry for nitration of aromatic rings can provide significant advantages over batch chemistry due to an improved safety profile by virtue of the more precise temperature control and the possibility for use of less concentrated acids, and improved selectivity, opening the possibility of more simple purification procedures saving time and money.
References
[1] Nitroaromatic Compounds, from Synthesis to Biodegradation (K.-S. Ju, R. E. Parales, Microbiol. Mol. Biol. Rev., 2010, 74, 2, 250 – 272) https://doi.org/10.1128/mmbr.00006-10
[2] Hazard Evaluation and Safety Considerations for Scale-Up of a Fuming Nitric Acid Mediated Nitration of Aryl Boronic Acids (J. I. Murray, D. B. Brown, M. V. Silva Elipe and S. Caille, Org. Proc. Res. Dev., 2022, 26, 3, 657 – 660) https://doi.org/10.1021/acs.oprd.1c00131
[3] Bretherick’s Handbook of Reactive Chemical Hazards (Urben, P. G., 2019, 6th ed.; Butterworth-Heinemann: Oxford, U.K.)
[4] Continuous flow nitration in miniaturized devices (A. A. Kulkarni, Belstein J. Org. Chem., 2014, 10, 405 – 424) https://doi.org/10.3762/bjoc.10.38
[5] Nitration Chemistry in Continuous Flow using Fuming Nitric Acid in a Commercially Available Flow Reactor (C. E. Brocklehurst, H.Lehmann and L. La Vecchia, Org. Process. Res. Dev., 2011, 15, 1447 – 1453) https://doi.org/10.1021/op200055r
[6] Synthesis of 2,4,6-Trinitrotoluene (TNT) Using Flow Chemistry (D. Kyprianou, M. Berglund, G. Emma, G. Rarata, D. Anderson, G. Diaconu and V. Exarchou, Molecules, 2020, 25, 3586 – 3601) https://doi.org/10.3390/molecules25163586
