Continuous Processing of Concentrated Organolithiums in Flow Using Static and Dynamic Spinning Disc Reactor Technologies

Abstract

Organometallic reactions involving highly reactive organolithium reagents are widely used in organic synthesis. However, the use of such organometallics in batch mode on a pilot and industrial scale is challenging for safety reasons and frequently requires expensive cryogenic process conditions. A change to continuous processing in flow mode can provide major advantages for process safety and economics. In this study, we compare static and dynamic flow reactor technologies for two important organolithium (butyllithium and hexyllithium)-enabled transformations: deprotonations and bromine/lithium exchange reactions. Using higher concentrated (≥3 M) butyllithium (BuLi) solutions, that is, reaction mixtures with reduced hydrocarbon content, decreases the risk of reactor fouling and allows for increased space/time yields. In the flow mode, the observed reactions could be carried out under more convenient conditions, that is, at higher temperatures compared to the batch mode, and the deprotonation reaction even at ambient temperature instead of −78 °C. The formation of precipitates with the risk of clogging can be further reduced by changing from static flow to dynamic spinning disc reactor technology. The SpinPro reactor system from Flowid has been identified to ensure robust performance, as it tolerates salt precipitations and can provide excellent mass transfer conditions. Flow process technology using concentrated organolithium products can provide unique benefits for the manufacturing of pharmaceutical intermediates, agrochemical products, and specialty chemicals.

NMR detection of the strained metallacycles in organolithiums: theoretical study

“…6,7 Recent advances allowed the application of flow processes for more effective industrial usage of organolithium. [8][9][10][11] This diversity originates in low cost, simplicity of handling and tuneable reactivity. The latter is arguably the most fascinating feature of organolithiums: the implementation of additives, such as ligands or metal-containing species, or the simple act of changing the solvent allows to enhance the reaction rate, control regioselectivity and open up new reaction pathways.…”

Thermal characterization of highly exothermic flash chemistry in a continuous flow calorimeter

“…In batch reactors, these flash reactions are typically carried out at cryogenic temperatures (typically between −100 and 0 °C) with one reagent slowly feeding into another, to avoid side reactions and decomposition of reagents. 2 Nevertheless, safety is still a major concern due to the limited heat dissipation rate of batch reactors, especially at large scales. [3][4][5] The long processing time combined with the requirement of cryogenic conditions also makes it an onerous task to scale-up these reactions.…”

Minimizing Material Consumption in Flow Process Research and Development: A Novel Approach Toward Robust and Controlled Mixing of Reactants

“…As such, establishing an active mixing component, i.e., a mixer that introduces energy via a different pathway than just by flow and pressure drop, is key. Such an approach has been recently published by Wietelmann et al, 12 who successfully applied a spinning disc reactor to carry out organolithium chemistry. After the first attempts using ultrasound as the active mixing device were unsuccessful, it was decided to invest in the development of a novel approach: to use a microannular gear pump HNPM (mzr-2521X1 by HNP Mikrosysteme GmbH) as the active mixer.…”