Automated Serendipity with Self‐Optimizing Continuous‐Flow Reactors

Abstract

A self‐optimizing approach is used as a tool for targeting known and unknown materials in the continuous reaction of aniline, dimethyl carbonate (DMC) and tetrahydrofuran (THF) in supercritical CO2 on γ‐Al2O3. The study led to the formation of methylated anilines or carbamate derivatives and unusual addition products with THF including pyrrolidines and N‐alkylated anilines. The identification of these products leads to the development of a plausible mechanism for the reactions. The system not only demonstrates a high flexibility that the self‐optimization approach provides, including the ability to optimize for a variety of products by using a single catalyst, but also the ability to discover unexpected and original synthetic reactions.

Enhanced process development using automated continuous reactors by self-optimisation algorithms and statistical empirical modelling

“…Self-optimising reactors have been designed using a variety of analytical techniques including IR [14][15][16] and NMR spectroscopy 17 , mass spectrometry 16,18 , gas [19][20][21][22] and liquid 23,24 chromatography. In this paper, a feedback-controlled flow reactor, equipped with an at-line HPLC system, is used to provide fast separation and quantification of the desired compounds.…”

“…The concentration of any compound can later be increased with the corresponding yield optimisation. 22 The existing responses can be used as a starting point to limit the number of experiments required for completion, but additional optimisations ultimately result in an increase of time and resource. A better methodology could be to predict where unknown compounds have the highest yields and then carry out yield optimisations in a smaller operating window around that point.…”

Continuous niobium phosphate catalysed Skraup reaction for quinoline synthesis from solketal

“…We have reported in previous work that aniline reacts with polar solvents, such as small alcohols, in presence of NbP resulting in alkylation reactions. 30 Since glycerol is only soluble in water or very polar protic solvents, we decided to switch to an alternative reagent, solketal 1b, which is the isopropylidene acetal-protected form of glycerol. It is produced by the condensation of acetone with glycerol.…”

“…Several heterogeneous catalytic systems have already shown to be active in the dehydration of glycerol to acrolein; these include zeolites, 22,23 heteropolyacids, 24,25,26,27 and metal oxides. 28,29 In this report we use niobium phosphate (NbP) as a heterogeneous acid catalyst that exhibits strong surface acidity and has been successfully used in the past to catalyse several reactions, 30 including the dehydration of several bio-derived compounds such as xylose, 31 fructose, 32 cellulose 33 and glycerol. 28,34 NbP has acidic catalytic properties similar to niobium oxide.…”

Engineering chemistry for the future of chemical synthesis

“…Much more recently, an autonomous control system was used to explore new reaction space that had not been reported previously. [25] This study began by attempt to prevent precipitations blocking reactor tubing during a specific reaction of aniline with dimethyl carbonate over an alumina catalyst. Tetrahydrofuran (THF) was added as a co-solvent in an attempt to act as solvent for the formed reaction solids.…”