Synthesis and analysis of combinatorial libraries performed in an automated micro reactor system

García‐Egido, Eduardo; Spikmans, Val; Wong, Stephanie Y. F.; Warrington, Brian H.

doi:10.1039/b302381h

Cited by 115 publications

(81 citation statements)

References 6 publications

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“…We are interested in derivatives of ouabain (OUA) because it is a poisonous cardiac glycoside and is extensively used in studies of neurons 17 to block the sodium pump (Na-K-ATPase). Selective deacetylation of Ac 6 -OUA has been reported only to the ouabain triacetate (Ac 3 -OUA) in 22% yield. 18 We envisioned that screening for optimal conditions would consist of two steps-screening a large number of reagents to evaluate reactivity rapidly, and then repeating the screening with a narrower set of reagents while varying reaction conditions (time, solvents, and concentrations).…”

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confidence: 99%

Microgram-Scale Testing of Reaction Conditions in Solution Using Nanoliter Plugs in Microfluidics with Detection by MALDI-MS

2006

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This paper describes a microfluidic system to screen and optimize organic reaction conditions on a submicrogram scale. Optimization of reaction conditions is required to achieve high efficiency and selectivity in organic reactions. Combinatorial methods 1 and high-throughput screening 2 are powerful tools for optimization. To perform solution-phase synthesis, typical microtiter plates or reaction blocks for parallel synthesis run reactions on the scale of mL/ reaction 1 and are less applicable to precious substrates (e.g., products of long synthetic sequences and natural products that can be isolated only in small quantities). To address this problem, one approach used arrayed micro-wells in combination with a robotic liquid sampler on the scale of ~125 nL per reaction. 3 To reduce the use of robotics and to minimize evaporation, others used microchannels 4-6 to perform reactions, including synthesis of pyrazoles with UV detection (5 μL per reaction) 6 and optimization of glycosylation conditions 5 (~2 mg reagent per reaction).Here, we report a screening method that consumes substrates on the scale of less than 1 μg per reaction. The system uses discrete droplets (plugs) 7 as microreactors 8 separated and transported by a continuous phase of a fluorinated carrier fluid. Such approach is not limited to microfluidics-fluorinated fluids were used previously to segment samples in NMR 9 and PCR 10 in tubes to prevent dispersion of sample solutions. Previously, we demonstrated the use of a microfabricated PDMS plug-based microfluidic system to perform assays and crystallization experiments in aqueous solutions with optical detection. 11 Here, we developed an approach that does not require microfabrication of microfluidic devices, 12 is applicable to synthetic reactions in organic solvents, and uses detection by MALDI-MS.The system consisted of three components: preformed cartridge 11,13 of reagent plugs, a PEEK Tee, and a receiving tubing (Figure 1). A cartridge is an array of discrete plugs surrounded by fluorinated carrier fluid; each plug is composed of a solution of a different reagent. The cartridge was prepared by serially aspirating the reagents into a piece of Teflon tubing prefilled with carrier fluid. A commercially available PEEK Tee connected the cartridge and the inlet tubing, containing as little as a submicroliter volume of a solution of the substrate. Fluorinated carrier fluid (FC-70) was used to fill the two syringes ( Figure 1) and the connecting tubing, enabling no-loss manipulation of submicroliter volumes of solutions. FC-70 has low miscibility with organic reagents and reasonably low viscosity (Supporting Information). To perform the reactions, the flow was induced with the two syringes, and the reagent plugs were sequentially merged with the substrate solution. After all resulting plugs flowed out of the Tee into the receiving tubing, the flow was stopped, and the receiving tubing was sealed. After incubation, E-mail: r-ismagilov@uchicago.edu. Supporting Information Available: Materials and meth...

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confidence: 99%

Microgram-Scale Testing of Reaction Conditions in Solution Using Nanoliter Plugs in Microfluidics with Detection by MALDI-MS

2006

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“…Most synthesis reactions that have been performed within droplets are single-step synthesis reactions [61][62][63][64][65]. One major issue in complex synthesis is that multiple reaction steps are involved.…”

Section: Droplet-based Chemical Synthesismentioning

confidence: 99%

Droplet microfluidics: A tool for biology, chemistry and nanotechnology

Mashaghi

Abbaspourrad

Weitz

et al. 2016

TrAC Trends in Analytical Chemistry

309

188

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The ability to perform laboratory operations on small scales using miniaturized devices provides numerous benefits, including reduced quantities of reagents and waste as well as increased portability and controllability of assays. These operations can involve reaction components in the solution phase and as a result, their miniaturization can be accomplished through microfluidic approaches. One such approach, droplet microfluidics, provides a high-throughput platform for a wide range of assays and approaches in chemistry, biology and nanotechnology. We highlight recent advances in the application of droplet microfluidics in chipbased technologies, such as single-cell analysis tools, small-scale cell cultures, in-droplet chemical synthesis, high-throughput drug screening, and nanodevice fabrication.

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“…Using a chip reactor, Fernandez-Saurez et al [67] developed, at GlaxoSmithKline (GSK), a 2 × 2 library for a domino reaction, composing of Knoevenagel condensation that gave an intermediate that immediately underwent an intramolecular hetero-Diels-Alder reaction with inverse electron demand. For the drug application, Garcia-Egido et al [68] synthesized a 3 × 7 library using the Knorr reaction of 1,3-dicarbonyl compounds and hydrazincs under ring closure to pyrazoles. Similar size libraries were used for kinetic data extraction for the asymmetric syntheses and screening of homogeneous catalysts under multiphase conditions.…”

Section: Microreactor Technologymentioning

confidence: 99%

Process intensification in green synthesis

Kumar

Nigam

2012

Green Processing and Synthesis

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In the past few decades there has been an extensive increase in the research for green synthesis processes due to environmental concerns, industrial safety and sustainable development, which makes it an attractive alternative to the conventional synthesis processes. The interest of researchers in the green synthesis processes highlights the importance of understanding the mechanism and the fundamental differences between the different processes. The number of publications in the fi eld of " Green Synthesis " in journals, proceedings, patents, etc. has increased by almost 20 times from 2001 to 2010. The published reports are mainly concerned with green synthesis with catalytic processes, less harmful solvents and process intensifi ed techniques. In the present article, the technological development efforts in the area of green synthesis are summarized. Various techniques for green synthesis process intensifi cation are discussed, e.g., mixers, microreactors, spin disc reactor, oscillated fl ow reactors, microwave irradiation, ultrasonication, multifunctional membranes and coiled fl ow inverter. The applications of green synthesis processes for biofuel, nanoparticle, ionic liquids and pharmaceutical production are also discussed.

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Synthesis and analysis of combinatorial libraries performed in an automated micro reactor system

Cited by 115 publications

References 6 publications

Microgram-Scale Testing of Reaction Conditions in Solution Using Nanoliter Plugs in Microfluidics with Detection by MALDI-MS

Microgram-Scale Testing of Reaction Conditions in Solution Using Nanoliter Plugs in Microfluidics with Detection by MALDI-MS

Droplet microfluidics: A tool for biology, chemistry and nanotechnology

Process intensification in green synthesis

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