Continuous flow nitration in miniaturized devices

Abstract

SummaryThis review highlights the state of the art in the field of continuous flow nitration with miniaturized devices. Although nitration has been one of the oldest and most important unit reactions, the advent of miniaturized devices has paved the way for new opportunities to reconsider the conventional approach for exothermic and selectivity sensitive nitration reactions. Four different approaches to flow nitration with microreactors are presented herein and discussed in view of their advantages, limitations and applicability of the information towards scale-up. Selected recent patents that disclose scale-up methodologies for continuous flow nitration are also briefly reviewed.

A Pioneering Early Microreactor Concept for Ultrafast Nitration Reactions — Placing the Seminal Brennecke and Kobe 1956 Contribution into Perspective

“…Levy and coworkers described the nitration of benzene using a small scale stirred-tank reactor [14]. It is not, however, until the beginning of the 21st century when miniaturized reactors (microreactors) have been perceived to have made their entry into the development of continuous-flow arene nitrations [6], with important contributions to the field from the groups of Loebbecke [15] or Roberge [7, 16], among others.Within this context, we believe that the pioneering research by Brennecke and Kobe [17] has received too little or no attention in the recent flow literature. In 1956, these authors reported the mixed acid nitration of toluene in a miniature continuous-flow reactor from which useful kinetic data could be obtained for this very fast transformation.…”

“…Levy and coworkers described the nitration of benzene using a small scale stirred-tank reactor [14]. It is not, however, until the beginning of the 21st century when miniaturized reactors (microreactors) have been perceived to have made their entry into the development of continuous-flow arene nitrations [6], with important contributions to the field from the groups of Loebbecke [15] or Roberge [7, 16], among others.…”

“…Nitration processes under very drastic conditions can also be performed in a safe and controllable manner [8]. There are a considerable number of continuous nitrations (especially for the preparation of nitroarenes) reported in the literature, as well as commercial scale plants in operation [3,6]. Impressive production scale examples include a microreactor system for the continuous production of around 10 kg/h of nitroglycerin [9], or the formation of a nitrate-building block in the synthesis of naproxcinod, an anti-inflammatory drug with a total capacity of approximately 100 kg/h, by DSM [10].…”

“…Nitrations are typically very exothermic and difficult to control on a large scale, and moreover, nitration products are often temperature-and friction-sensitive explosive compounds [5]. It is therefore not surprising that nitration reactions have benefited tremendously from the advantages provided by microreactor technology [6]. In 2005, Ducry and Roberge demonstrated that using microreactor technology dramatically enhances the selectivity and process safety, even during autocatalytic nitrations such as the nitration of phenols [7].…”

Prospects for Flow Chemistry

“…Invited presentations discussed (1) photochemical transformations by T. Noël [4], S. Fuse [5], M. Oelgemöller [6], and A. Beeler [7]; (2) generation and safe usage of hazardous species by K. Hirose [8], C. O. Kappe [9,10], and T. Wirth [11]; (3) carbonylation reactions by I. Ryu [12]; (4) catalysis by N. Kumagai [13] and R. Souza [14]; (5) multistep synthetic transformations by T. Jamison [15,16] and A. Kulkarni [17]; (6) polymer construction by C. Serra [18]; and finally, (7) general advances in flow chemistry by M. Organ [19], D. Kim [20,21], and E. Kumacheva [22]. The popularity of these transformations is driven by the need to overcome the limitations of conventional batch reactions such as mixing, thermal control, safety metrics, and scale-up issues.…”