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Special Issue "Recent Advances in Flow Chemistry"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Synthesis".

Deadline for manuscript submissions: closed (15 August 2016)

Special Issue Editor

Guest Editor
Dr. Kerry Gilmore

Max Planck Institute of Colloids and Interfaces, Department of Biomolecular Systems, Potsdam-Golm Science Park, D-14424 Potsdam, Germany
Website | E-Mail
Interests: Development of chemical assembly systems for the production of small molecules and pharmaceuticals, mechanistic investigations, development of new flow techniques/technologies

Special Issue Information

Dear Colleagues,

Over the past 20 years, continuous chemistry has emerged as an effective means to conduct chemical syntheses, both at the micro- and meso-scale, providing an improved product quality and safety as well as being accompanied by a lowered environmental impact when compared to traditional batch syntheses. Flow chemistry offers two distinct advantages over the respective batch processes: control and connectivity. Precise control over reaction conditions, in particular reaction time, mixing, heat transfer, and irradiation window, has allowed for a wide range of chemistries either not possible or extremely inefficient in batch. With the ability to connect several flow reactors in series, elegant multi-step syntheses have been accomplished, producing high value compounds and active pharmaceutical ingredients. Due to large increases in surface area, biphasic reactions are significantly accelerated within the confines of a flow system. While not all encompassing, flow chemistry has proven to be facilitating in the studying and performing a wide range of chemical reactions encompassing biochemistry, materials, polymers, mechanistic studies, and elegant multistep organic syntheses. This Special Issue of Molecules welcomes submissions of research articles covering both micro- and mesoflow reactions dealing with selectivity, catalysis, photochemistry, multi-step synthesis, the development of new reactions, and other related subjects.

Dr. Kerry Gilmore
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.


Keywords

  • Photochemistry in flow
  • Packed-bed reactors
  • Continuous, multi-step synthesis
  • Flash chemistry
  • Biphasic transformations

Published Papers (7 papers)

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Research

Open AccessArticle Kinetic Spectrophotometric Method for the 1,4-Diionic Organophosphorus Formation in the Presence of Meldrum′s Acid: Stopped-Flow Approach
Molecules 2016, 21(11), 1514; doi:10.3390/molecules21111514
Received: 6 August 2016 / Revised: 1 November 2016 / Accepted: 2 November 2016 / Published: 11 November 2016
Cited by 2 | PDF Full-text (2920 KB) | HTML Full-text | XML Full-text
Abstract
The kinetics of the reaction between triphenylphosphine (TPP) and dimethyl acetylenedicarboxylate (DMAD) in the presence of Meldrum’s acid (MA) for the generation of the 1,4-diionic organophosphorus compound has been investigated using the stopped-flow and UV-VIS spectrophotometry techniques. The first step of the reaction
[...] Read more.
The kinetics of the reaction between triphenylphosphine (TPP) and dimethyl acetylenedicarboxylate (DMAD) in the presence of Meldrum’s acid (MA) for the generation of the 1,4-diionic organophosphorus compound has been investigated using the stopped-flow and UV-VIS spectrophotometry techniques. The first step of the reaction between TPP and DMAD for the generation of (I1) in ethanol was followed by the stopped-flow apparatus. This step was recognized as a fast step. The reaction between the intermediate (I1) and MA showed first-order kinetics, and it was followed by the UV-VIS spectrophotometry technique. The activation parameters for the slow step of the proposed mechanism were determined using two linearized forms of the Eyring equation. From the temperature, concentration and solvent studies, the activation energy (Ea = 20.16 kJ·mol−1) and the related activation parameters (ΔG = 71.17 ± 0.015 kJ·mol−1, ΔS = −185.49 ± 0.026 J·mol−1 and ΔH =17.72 ± 0.007 kJ·mol−1) were calculated. The experimental data indicated that the reaction was zero-order in MA and second-order overall. The proposed mechanism was confirmed with the observed kinetic data obtained from the UV-VIS and stopped-flow techniques. Full article
(This article belongs to the Special Issue Recent Advances in Flow Chemistry)
Figures

Figure 1

Open AccessArticle Towards a Rational Design of a Continuous-Flow Method for the Acetalization of Crude Glycerol: Scope and Limitations of Commercial Amberlyst 36 and AlF3·3H2O as Model Catalysts
Molecules 2016, 21(5), 657; doi:10.3390/molecules21050657
Received: 15 April 2016 / Revised: 3 May 2016 / Accepted: 12 May 2016 / Published: 18 May 2016
Cited by 1 | PDF Full-text (1984 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The acetalization of six different types of glycerol including pure, wet, and crude-like grade compounds of compositions simulating those of crude glycerols produced by the biodiesel manufacture, was carried out with two model ketones such as acetone and 2-butanone. The reaction was investigated
[...] Read more.
The acetalization of six different types of glycerol including pure, wet, and crude-like grade compounds of compositions simulating those of crude glycerols produced by the biodiesel manufacture, was carried out with two model ketones such as acetone and 2-butanone. The reaction was investigated under continuous-flow (CF) conditions through a comparative analysis of an already known acetalization catalyst such as Amberlyst 36 (A36), and aluminum fluoride three hydrate (AlF3·3H2O, AF) whose use was never previously reported for the synthesis of acetals. At 10 bar and 25 °C, A36 was a highly active catalyst allowing good-to-excellent conversion (85%–97%) and selectivity (99%) when either pure or wet glycerol was used as a reagent. This catalyst however, proved unsuitable for the CF acetalization of crude-like glycerol (CG) since it severely and irreversibly deactivated in a few hours by the presence of low amounts of NaCl (2.5 wt %) which is a typical inorganic impurity of raw glycerol from the biorefinery. Higher temperature and pressure (up to 100 °C and 30 bar) were not successful to improve the outcome. By contrast, at 10 bar and 100 °C, AF catalyzed the acetalization of CG with both acetone and 2-butanone, yielding stable conversion and productivity up to 78% and 5.6 h−1, respectively. A XRD analysis of fresh and used catalysts proved that the active phase was a solid solution (SS) of formula Al2[F1-x(OH)x]6(H2O)y present as a component of the investigated commercial AF sample. A hypothesis to explain the role of such SS phase was then formulated based on the Brønsted acidity of OH groups of the solid framework. Overall, the AF catalyst allowed not only a straightforward upgrading of CG to acetals, but also a more cost-efficient protocol avoiding the expensive refining of raw glycerol itself. Full article
(This article belongs to the Special Issue Recent Advances in Flow Chemistry)
Figures

Open AccessArticle Continuous-Flow Synthesis of Deuterium-Labeled Antidiabetic Chalcones: Studies towards the Selective Deuteration of the Alkynone Core
Molecules 2016, 21(3), 318; doi:10.3390/molecules21030318
Received: 9 February 2016 / Accepted: 24 February 2016 / Published: 7 March 2016
Cited by 3 | PDF Full-text (1518 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Flow chemistry-based syntheses of deuterium-labeled analogs of important antidiabetic chalcones were achieved via highly controlled partial C≡C bond deuteration of the corresponding 1,3-diphenylalkynones. The benefits of a scalable continuous process in combination with on-demand electrolytic D2 gas generation were exploited to suppress
[...] Read more.
Flow chemistry-based syntheses of deuterium-labeled analogs of important antidiabetic chalcones were achieved via highly controlled partial C≡C bond deuteration of the corresponding 1,3-diphenylalkynones. The benefits of a scalable continuous process in combination with on-demand electrolytic D2 gas generation were exploited to suppress undesired over-reactions and to maximize reaction rates simultaneously. The novel deuterium-containing chalcone derivatives may have interesting biological effects and improved metabolic properties as compared with the parent compounds. Full article
(This article belongs to the Special Issue Recent Advances in Flow Chemistry)
Open AccessArticle Microreactors—A Powerful Tool to Synthesize Peroxycarboxylic Esters
Molecules 2016, 21(1), 5; doi:10.3390/molecules21010005
Received: 20 October 2015 / Revised: 30 November 2015 / Accepted: 15 December 2015 / Published: 22 December 2015
PDF Full-text (2569 KB) | HTML Full-text | XML Full-text
Abstract
The synthesis of peroxycarboxylic esters, as one subgroup of organic peroxides, is characterized by a high thermal hazard potential regarding process safety. In case of failure in the production process, e.g., if the heat of reaction cannot be removed sufficiently fast, decomposition reactions
[...] Read more.
The synthesis of peroxycarboxylic esters, as one subgroup of organic peroxides, is characterized by a high thermal hazard potential regarding process safety. In case of failure in the production process, e.g., if the heat of reaction cannot be removed sufficiently fast, decomposition reactions can be triggered, and as a result, remarkable amounts of heat and gas can be released and can cause a high extent of damage. Multifarious technical and organizational measures are necessary to ensure the safe industrial production of peroxides. With the introduction of microreaction technology plenty of possibilities have been opened to carry out highly exothermic reactions in smaller volumes and with more efficient heat removal. In this paper we report the application of three different microstructured reactors, representing different mixing strategies, to synthesize two peroxymonocarboxylic esters, namely tert-butyl peroxypivalate and tert-butyl peroxy-2-ethylhexanoate. The following reactor types were considered: an orifice microreactor, a split and recombine microreactor and a capillary tube reactor in combination with ultrasonication. The efficiency of the two phase liquid/liquid reaction is expressed in comparison of conversion and selectivity. With microreaction technology a remarkable increase in space-time-yield, ranging from 12,500 kg·m−3·h−1 to 414,000 kg·m−3·h−1, is achieved. Full article
(This article belongs to the Special Issue Recent Advances in Flow Chemistry)
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Open AccessArticle Amination of Aryl Halides and Esters Using Intensified Continuous Flow Processing
Molecules 2015, 20(10), 17860-17871; doi:10.3390/molecules201017860
Received: 25 August 2015 / Revised: 17 September 2015 / Accepted: 22 September 2015 / Published: 25 September 2015
Cited by 1 | PDF Full-text (1035 KB) | HTML Full-text | XML Full-text
Abstract
Significant process intensification of the amination reactions of aryl halides and esters has been demonstrated using continuous flow processing. Using this technology traditionally difficult amination reactions have been performed safely at elevated temperatures. These reactions were successfully conducted on laboratory scale coil reactor
[...] Read more.
Significant process intensification of the amination reactions of aryl halides and esters has been demonstrated using continuous flow processing. Using this technology traditionally difficult amination reactions have been performed safely at elevated temperatures. These reactions were successfully conducted on laboratory scale coil reactor modules with 1 mm internal diameter (ID) and on a preparatory scale tubular reactor with 6 mm ID containing static mixers. Full article
(This article belongs to the Special Issue Recent Advances in Flow Chemistry)
Figures

Open AccessCommunication Flow Synthesis of 2-Methylpyridines via α-Methylation
Molecules 2015, 20(9), 15797-15806; doi:10.3390/molecules200915797
Received: 12 August 2015 / Revised: 20 August 2015 / Accepted: 21 August 2015 / Published: 31 August 2015
Cited by 2 | PDF Full-text (765 KB) | HTML Full-text | XML Full-text
Abstract
A series of simple 2-methylpyridines were synthesized in an expedited and convenient manner using a simplified bench-top continuous flow setup. The reactions proceeded with a high degree of selectivity, producing α-methylated pyridines in a much greener fashion than is possible using conventional batch
[...] Read more.
A series of simple 2-methylpyridines were synthesized in an expedited and convenient manner using a simplified bench-top continuous flow setup. The reactions proceeded with a high degree of selectivity, producing α-methylated pyridines in a much greener fashion than is possible using conventional batch reaction protocols. Eight 2-methylated pyridines were produced by progressing starting material through a column packed with Raney® nickel using a low boiling point alcohol (1-propanol) at high temperature. Simple collection and removal of the solvent gave products in very good yields that were suitable for further use without additional work-up or purification. Overall, this continuous flow method represents a synthetically useful protocol that is superior to batch processes in terms of shorter reaction times, increased safety, avoidance of work-up procedures, and reduced waste. A brief discussion of the possible mechanism(s) of the reaction is also presented which involves heterogeneous catalysis and/or a Ladenberg rearrangement, with the proposed methyl source as C1 of the primary alcohol. Full article
(This article belongs to the Special Issue Recent Advances in Flow Chemistry)
Figures

Open AccessArticle Continuous Polyol Synthesis of Metal and Metal Oxide Nanoparticles Using a Segmented Flow Tubular Reactor (SFTR)
Molecules 2015, 20(6), 10566-10581; doi:10.3390/molecules200610566
Received: 12 May 2015 / Revised: 22 May 2015 / Accepted: 26 May 2015 / Published: 8 June 2015
Cited by 5 | PDF Full-text (4824 KB) | HTML Full-text | XML Full-text
Abstract
Over the last years a new type of tubular plug flow reactor, the segmented flow tubular reactor (SFTR), has proven its versatility and robustness through the water-based synthesis of precipitates as varied as CaCO3, BaTiO3, Mn(1−x)Nix
[...] Read more.
Over the last years a new type of tubular plug flow reactor, the segmented flow tubular reactor (SFTR), has proven its versatility and robustness through the water-based synthesis of precipitates as varied as CaCO3, BaTiO3, Mn(1−x)NixC2O4·2H2O, YBa oxalates, copper oxalate, ZnS, ZnO, iron oxides, and TiO2 produced with a high powder quality (phase composition, particle size, and shape) and high reproducibility. The SFTR has been developed to overcome the classical problems of powder production scale-up from batch processes, which are mainly linked with mass and heat transfer. Recently, the SFTR concept has been further developed and applied for the synthesis of metals, metal oxides, and salts in form of nano- or micro-particles in organic solvents. This has been done by increasing the working temperature and modifying the particle carrying solvent. In this paper we summarize the experimental results for four materials prepared according to the polyol synthesis route combined with the SFTR. CeO2, Ni, Ag, and Ca3(PO4)2 nanoparticles (NPs) can be obtained with a production rate of about 1–10 g per h. The production was carried out for several hours with constant product quality. These findings further corroborate the reliability and versatility of the SFTR for high throughput powder production. Full article
(This article belongs to the Special Issue Recent Advances in Flow Chemistry)

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Microreactors – A Powerful Tool to Synthesize Peroxycarboxylic Esters
Authors: Tobias Illg 1,*, Annett Knorr 2,† and Lutz Fritzsche 2,†
Affiliation: 1 Fraunhofer ICT‐IMM, 55129 Mainz, Carl‐Zeiss‐Straße 18‐20, Germany; E‐Mail:tobias.illg@imm.fraunhofer.de
2 BAM Federal Institute for Materials Research and Testing , 12205 Berlin, Unter den Eichen 87,
Germany; E‐Mails: annett.knorr@bam.de (A.K.); lutz.fritzsche@bam.de (L.F.)
These authors contributed equally to this work.
Author to whom correspondence should be addressed; E‐Mail: tobias.illg@imm.fraunhofer.de;Tel.: +49‐6131‐990‐335; Fax: +49‐6131‐990‐205.
Abstract: The synthesis of peroxycarboxylic esters, as one subgroup of organic peroxides, is characterized by a high thermal hazard potential regarding process safety. In case of failure in the production process, e.g., if the heat of reaction cannot be removed sufficiently fast, the decomposition reaction can be triggered. In consequence remarkable amounts of heat and gas can be released and can cause a high extent of damage. Multifarious technical and organizational measures are necessary to organize the industrial production of peroxides safely. With the introduction of micro reaction technology plenty of possibilities have been opened to carry out highly exothermic reactions in smaller volumes and with more efficient heat removal. In this paper we report the application of three different microstructured reactors, representing different mixing strategies, to synthesize two peroxymonocarboxylic esters, namely tert‐Butyl peroxypivalate and tert‐Butyl peroxy‐2‐ethylhexanoate. The following reactor types were considered: an orifice microreactor, a split and recombine microreactor and a capillary tube reactor in combination with ultrasonication. The efficiency of the two phase liquid/liquid reaction is expressed in comparison of conversion and selectivity. With micro reaction technology a remarkable increase in space‐time‐yield, ranging from 6,200 kgm‐3 h‐1 to 414.000 kgm‐3 h‐1, is achieved.
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