Fouling of Flow Reactors in Organolithium Mediated Transformations: Experience on Scale-up and Proposed Solution

Abstract

Continuous processing has been demonstrated to be a superior approach when applied to fast and energetic chemical transformations. Indeed, whereas classical batch or semi-batch methods require cryogenic conditions and slow addition rates of reactive species, flow technologies enable rapid mixing of synthetic partners in a highly controlled environment. As a result, low yielding and dangerous processes in batch can be performed at scale in a cost competitive and safer continuous manner. Despite the advantages of higher quality and safety, the perennial problems of solids build-up and pipe fouling threaten the robustness and reliability of flow processes. In this contribution, a new methodology to prevent reactor fouling is reported and discussed. The implementation of this methodology has been decisive in solving fouling issues encountered during the piloting of an organolithium based flow process.

Reaction Calorimetry in Continuous Flow Mode: A New Approach for the Thermal Characterization of High Energetic and Fast Reactions

“…Beyond other side reactions whose relevance is substrate specific, common byproducts derive from the proton−lithium exchange promoted by the presence of any protic sources and from the coupling with the alkyl halide generated from the halogen−lithium exchange (Scheme 2). While the proton quench can be effectively suppressed by removing any traces of water in the initial substrate solution, 14 the second side reaction can be limited only by the fast generation and electrophilic quench of the lithiated intermediate. Indeed, in this pathway the second halide substitution is considered the rate-limiting step (Scheme 2 C).…”

“…In order to minimize the energetic contribution of the undesired proton quench and by following the procedure we recently published, 14 the aryl bromide 1 feed was treated with an appropriate amount of iPrMgCl to chemically deactivate any acidic protons already present either in the solvent or in the starting material. To control the reaction performance and quality, the product solution was quenched with iodine to selectively derivatize the lithiated intermediate into a more stable species that can be then easily analyzed by quantitative HPLC.…”

Flash chemistry enables high productivity metalation-substitution of 5-alkyltetrazoles

“…97 Precipitation resulting in blockage of continuous flow systems is occasionally observed over extended reaction times. 98 In our case, careful inspection of the flow system and collection vessel revealed no evidence of precipitate after the large scale experiment. We note that in our experience, precipitates from organolithium reactions are often soluble in THF, and should other researchers encounter this problem, a periodic valve-controlled automated flush of the flow system with dry THF may provide a resolution.…”

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

“…As an alternative, a recently published chemical drying method using calculated amounts of iPrMgCl allows quick and complete drying but still needs a membrane filtration step to remove insoluble Mg salts formed upon the hydrolysis reaction. 13 Another source for undesired precipitation is presented by lithiated organic intermediates, might it be alkoxides, halides, or compounds with direct C−Li bonds, which exhibit low solubility in the hydrocarbon-containing solvent blends applied.…”