In the past few years, continuous‐flow reactors with channel dimensions in the micro‐ or millimeter region have found widespread application in organic synthesis. The characteristic properties of ...these reactors are their exceptionally fast heat and mass transfer. In microstructured devices of this type, virtually instantaneous mixing can be achieved for all but the fastest reactions. Similarly, the accumulation of heat, formation of hot spots, and dangers of thermal runaways can be prevented. As a result of the small reactor volumes, the overall safety of the process is significantly improved, even when harsh reaction conditions are used. Thus, microreactor technology offers a unique way to perform ultrafast, exothermic reactions, and allows the execution of reactions which proceed via highly unstable or even explosive intermediates. This Review discusses recent literature examples of continuous‐flow organic synthesis where hazardous reactions or extreme process windows have been employed, with a focus on applications of relevance to the preparation of pharmaceuticals.
Go with the flow: Continuous‐flow processing is becoming increasingly important in synthetic organic chemistry. The high heat and mass transfer, very fast mixing, and small reactor volumes allow reactions to be run safely under very harsh conditions also when hazardous intermediates are involved, as shown here with selected examples.
A mild, catalyst‐free electrochemical oxytrifluoromethylation of alkenes has been developed. The procedure is based on the paired electrolysis of sodium triflinate and water in an undivided cell. ...Anodic oxidation of the triflinate anion generates trifluoromethyl radicals that react with the alkene. Water plays a dual role as oxidant for the cathode and nucleophile. The method has been utilized to prepare a diverse set of 1‐hydroxy‐2‐trifluoromethyl compounds in moderate to excellent yields (27–94 %). Alcohols have also been tested as nucleophiles for this versatile method with moderate yields. Facile recycling of the electrolyte has been demonstrated, and application of electricity avoids the use of stoichiometric amounts of oxidizers in a safe and environmentally benign reaction.
Electricity and water are key ingredients in this alkene difunctionalization method. Paired electrolysis of sodium trifluoromethanesulfinate and water in an undivided cell enables a mild, catalyst‐free oxytrifluoromethylation of styrenes. Trapping experiments provide evidence of a mechanism involving three radical intermediates.
It's not magic! The effects observed in microwave‐irradiated chemical transformations can in most cases be rationalized by purely bulk thermal phenomena associated with rapid heating to elevated ...temperatures. As discussed in this Essay, the existence of so‐called nonthermal or specific microwave effects is highly doubtful.
This Personal Account describes the author's involvement in the field of microwave‐assisted organic synthesis (MAOS) from the late 1990’s starting out with kitchen microwave ovens right through to ...the development of a reactor in 2016 that – although not using microwave technology – in many ways mimics the performance of a modern laboratory microwave. The reader is taken along a journey that has spanned two decades of intense research on various aspects of microwave chemistry, and, at the same time, was intimately linked to key innovations regarding equipment design and development. A “behind the scenes” approach is taken in this article to share – from a very personal point of view – how specific projects and research ideas were conceived and developed in my research group, and how in general the field of microwave chemistry has progressed in the last two decades.
Microwave chemistry has turned from laboratory curiosity to an accepted technology in the past three decades. While dedicated instrumentation was rather expensive in the early days, current equipment runs at significantly below 10.000 €. This account details advancements in equipment design and development and describes the author's involvement in the field of microwave‐assisted organic synthesis since 1998.
Running oil‐bath chemistry in a microwave! Using reaction vials made out of strongly microwave‐absorbing silicon carbide (SiC) in a microwave reactor simulates experiments conducted in an autoclave ...with conductive heating because of the efficient shielding of the electromagnetic field by the SiC vial. This technology makes it possible to study the significance of microwave effects.
Although fire is now rarely used in synthetic chemistry, it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied to a reaction vessel in a ...focused manner. The Bunsen burner was later superseded by the isomantle, oil bath, or hot plate as a source for applying heat to a chemical reaction. In the past few years, heating and driving chemical reactions by microwave energy has been an increasingly popular theme in the scientific community. This nonclassical heating technique is slowly moving from a laboratory curiosity to an established technique that is heavily used in both academia and industry. The efficiency of “microwave flash heating” in dramatically reducing reaction times (from days and hours to minutes and seconds) is just one of the many advantages. This Review highlights recent applications of controlled microwave heating in modern organic synthesis, and discusses some of the underlying phenomena and issues involved.
Out of the kitchen into the laboratory: Direct heating by microwave irradiation (see picture) in many cases enables synthesis to be carried out in a fraction of the time required with conventional heating techniques. The use of microwave heating in organic synthesis is growing rapidly and the advantages not only include faster reaction times, but also higher product yields, cleaner reactions, better controllability, and reproducibility.
New kid on the block: The cross-coupling of thioorganic compounds with boronic acids under neutral conditions in the presence of catalytic palladium(0) and a stoichiometric amount of a copper(I) ...oxygenate has emerged as a very useful method for the construction of C---C bonds (see scheme). This intriguing and mechanistically unprecedented base-free coupling has distinct advantages, in particular when traditional Pd⁰-catalyzed cross-coupling is not possible.Although a plethora of highly selective and reliable methods for the construction of C---C bonds are known to organic chemists, there is growing interest in the development of new protocols that offer different or orthogonal reactivity to that of existing methods. In 2000, Liebeskind and Srogl described a mechanistically unprecedented transition-metal-catalyzed cross-coupling of thioesters with boronic acids to produce ketones under neutral conditions. This desulfitative cross-coupling process is catalytic in palladium(0), stoichiometric in copper(I), and applicable to a range of organosulfur derivatives and nucleophilic organometallic reagents. In this Minireview, we highlight recent applications of this intriguing cross-coupling reaction in modern organic synthesis, with an emphasis on cases in which traditional methods for C---C bond formation have failed.
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