The Concept of Chemical Generators: On-Site On-Demand Production of Hazardous Reagents in Continuous Flow

Abstract

In recent years, a steadily growing number of chemists, from both academia and industry, have dedicated their research to the development of continuous flow processes performed in milli- or microreactors. The common availability of continuous flow equipment at virtually all scales and affordable cost has additionally impacted this trend. Furthermore, regulatory agencies such as the United States Food and Drug Administration actively encourage continuous manufacturing of active pharmaceutical ingredients (APIs) with the vision of quality and productivity improvements. That is why the pharmaceutical industry is progressively implementing continuous flow technologies. As a result of the exceptional characteristics of continuous flow reactors such as small reactor volumes and remarkably fast heat and mass transfer, process conditions which need to be avoided in conventional batch syntheses can be safely employed. Thus, continuous operation is particularly advantageous for reactions at high temperatures/pressures (novel process windows) and for ultrafast, exothermic reactions (flash chemistry).In addition to conditions that are outside of the operation range of conventional stirred tank reactors, reagents possessing a high hazard potential and therefore not amenable to batch processing can be safely utilized (forbidden chemistry). Because of the small reactor volumes, risks in case of a failure are minimized. Such hazardous reagents often are low molecular weight compounds, leading generally to the most atom-, time-, and cost-efficient route toward the desired product. Ideally, they are generated from benign, readily available and cheap precursors within the closed environment of the flow reactor on-site on-demand. By doing so, the transport, storage, and handling of those compounds, which impose a certain safety risk especially on a large scale, are circumvented. This strategy also positively impacts the global supply chain dependency, which can be a severe issue, particularly in times of stricter safety regulations or an epidemic. The concept of the in situ production of a hazardous material is generally referred to as the "generator" of the material. Importantly, in an integrated flow process, multiple modules can be assembled consecutively, allowing not only an in-line purification/separation and quenching of the reagent, but also its downstream conversion to a nonhazardous product.For the past decade, research in our group has focused on the continuous generation of hazardous reagents using a range of reactor designs and experimental techniques, particularly toward the synthesis of APIs. In this Account, we therefore introduce chemical generator concepts that have been developed in our laboratories for the production of toxic, explosive, and short-lived reagents. We have defined three different classes of generators depending on the reactivity/stability of the reagents, featuring reagents such as Br₂, HCN, peracids, diazomethane (CH₂N₂), or hydrazoic acid (HN₃). The various reactor designs, including in-line membrane separation techniques and real-time process analytical technologies for the generation, purification, and monitoring of those hazardous reagents, and also their downstream transformations are presented. This Account should serve as food for thought to extend the scope of chemical generators for accomplishing more efficient and more economic processes.

Figure 1

Concept of a chemical generator with subsequent consumption of the hazardous reagent to the desired product. PAT: process analytical technology.

Figure 2

Classification of hazardous reagents according to their stability.

Figure 3

Overview of used continuous flow icons.

Scheme 1. Br₂ and BrCN Generators Connected in Series for the Synthesis of Cyclic Guanidines

Scheme 2. Br₂ Generator and Its Use in Photochemical Benzylic Brominations

Scheme 3. Cl₂ Generator and Its Use in the Selective Oxidation of Secondary Alcohols

Scheme 4. NOCl Generator and Its Use in the Photochemical Oximation of Cyclohexane

Scheme 5. Anhydrous HCN Generator (HCN on Tap) and Its Use in the Asymmetric Strecker Reaction (a) and Synthesis of Diaminomaleonitrile (b)

Scheme 6. CMME Generator and Its Use in Alkoxyalkylation Reactions (MOM Protection)

Scheme 7. SO₂ Generator and Its Use for the Synthesis of Sulfonamides

Scheme 8. HCO₃H Generator and Its Use in the C14 Hydroxylation of Oripavine toward a Telescoped Synthesis of 1,3-Oxazolidine 4

Scheme 9. LDA Generator with Integrated Enolate Formation and Electrophilic Addition toward α-Functionalized Esters

Scheme 10. Anhydrous Diazomethane Generator (Tube-in-Tube Reactor) and Its Use in Various Downstream Transformations

Scheme 11. Anhydrous Diazomethane Generator (Tube-in-CSTR) in a CSTR Cascade for the Synthesis of α-Chloroketone 7

Figure 4

Tube-in-flask setup with the AF-2400 membrane coiled inside a standard flask.

Scheme 12. Anhydrous Trifluoromethyl Diazomethane Generator (Tube-in-Tube Reactor) and Its Use in Aldol-type Condensation with Aldehydes

Scheme 13. BrN₃ Generator with an Integrated Tubular Photochemical Reactor for the Synthesis of 1,2-Bromine Azides

Scheme 14. HN₃ Generator and Its Use in the Synthesis of 5-Substituted 1H-Tetrazoles