Fast Scale-Up Using Microreactors: Pyrrole Synthesis from Micro to Production Scale

Nieuwland, Pieter J.; Segers, R. P. A. M.; Koch, Karl‐Heinz; Hest, Jan C. M. van; Rutjes, Floris P. J. T.

doi:10.1021/op100338z

Cited by 51 publications

(35 citation statements)

References 19 publications

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“…30 Previous mechanistic studies have shown the rate determining step to be the cyclization step and for that reason the reaction was assumed to follow a single step mechanism with an unknown pre-exponential parameter (A), temperature dependence term ('activation energy') (E) and reaction orders (m,n).…”

Section: Analysis Proceduresmentioning

confidence: 99%

“…[6][7][8][9][10][11] Continuous flow systems have been used for complex chemical synthesis, [12][13][14][15] gas-phase reactions, [16][17][18][19] photochemistry, [20][21][22][23] electrochemistry, 24,25 and reaction optimization [26][27][28] but their robustness for reaction kinetics is hindered by the need to take steady state measurements. [29][30][31][32] Recent studies have shown that transient flow data could be used to quickly generate kinetic data. [33][34][35][36] Mozharov used the transient data generated from a step change in flow to scan different reaction times and fit kinetic data collected with inline Raman spectroscopy.…”

Section: Introductionmentioning

confidence: 99%

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Efficient kinetic experiments in continuous flow microreactors

Aroh

Jensen

2018

React. Chem. Eng.

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Flow chemistry is an enabling technology that can offer an automated and robust approach for the generation of reaction kinetics data. Recent studies have taken advantage of transient flows to quickly generate concentration profiles with various online analytical tools. In this work, we demonstrate an improved method where temperature and flow are transient throughout the reaction. It was observed that only two orthogonal temperature ramp experiments under the same transient flow condition were sufficient to characterize a Paal-Knorr (one step bimolecular) reaction within our chosen reaction space. This method further shortens the time and decreases the materials needed to collect sufficient kinetic data and provides a framework with which more complex kinetic studies could be performed.

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Section: Analysis Proceduresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Efficient kinetic experiments in continuous flow microreactors

Aroh

Jensen

2018

React. Chem. Eng.

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“…The gram-scale flow synthesis of 2,5-dimethyl-pyrroles (35) from 2,5-hexanedione (36) was achieved by D-optimal algorithms aimed at defining the best set for temperature, stoichiometry of amine-diketone, and reaction time (Scheme 10) [28]. Two solutions of 36 and ethanolamine (37)-ethylamine (38) in MeOH were used as feedstock, and 2-bromotoluene was added as internal standard to follow the conversion of both the substrate and yield by quantitative GC-flame ionization detection (FID) analysis.…”

Section: Central Composite Designmentioning

confidence: 99%

Concepts and Optimization Strategies of Experimental Design in Continuous-Flow Processing

Gioiello¹,

Filipponi²,

Mostarda³

et al. 2016

J Flow Chem

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The integration of flow systems with statistical design of experiments is emerging as a valuable strategy to develop new synthetic routes towards relevant building blocks, chemical probes, and drug compounds. Optimization by experimental design incorporates statistical algorithms, mathematical models and equations, predicting tools, feedback control, and validation to generate new optimal conditions. Continuous-flow chemistry is ideally suited for this scope, as the integration of in-line analysis is simple; experimental parameters such as temperature, pressure, and flow rate can be easily controlled and fine-regulated; and automation of reaction screening can be accomplished with software assistance. This review article aims to illustrate how the combination of flow synthesizers and design of experiments can be profitable to speed up the development and optimization of more efficient, safer, and reproducible protocols for modern synthetic methods and manufacturing processes.

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“…We conducted the synthesis of pyrrole by reacting 2,5-hexanedione (Sigma) with ethanolamine (Sigma) in microdroplets on the chip (see Figure 6) [72]. We generated droplets from a compound stream formed by two incoming solutions of the substrates delivered directly into a FF-junction (SI, Figure S3).…”

Section: Chemical Reactions In Dropletsmentioning

confidence: 99%

Scaling up the Throughput of Synthesis and Extraction in Droplet Microfluidic Reactors

et al. 2015

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Conducting reactions in droplets in microfluidic chips offers several highly attractive characteristics, among others, increased yield and selectivity of chemical syntheses. The use of droplet microfluidic systems in synthetic chemistry is, however, hampered by the intrinsically small throughput of micrometric channels. Here, we verify experimentally the potential to increase throughput via an increase of the scale of the channels. We use the results of these experiments characterizing the processes of (1) generation of droplets, (2) mixing in droplets, (3) inter-phase extraction, and (4) the yield of synthesis of pyrrole, to postulate a number of guidelines for scaling up the throughput of microfluidic droplet systems. In particular, we suggest the rules for maximizing the throughput via an increase of the size of the channels and via parallelization to optimize the throughput of synthesis against the cost of fabrication of the chips and against the kinetic requirements of specific reactions.

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Fast Scale-Up Using Microreactors: Pyrrole Synthesis from Micro to Production Scale

Cited by 51 publications

References 19 publications

Efficient kinetic experiments in continuous flow microreactors

Efficient kinetic experiments in continuous flow microreactors

Concepts and Optimization Strategies of Experimental Design in Continuous-Flow Processing

Scaling up the Throughput of Synthesis and Extraction in Droplet Microfluidic Reactors

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