Closing the radical gap in chemical synthesis

doi:10.1126/science.abc2985

GSTDTAP > 气候变化

DOI	10.1126/science.abc2985
	Closing the radical gap in chemical synthesis
	Jian-Quan Liu; Andrey Shatskiy; Markus D. Kärkäs
	2020-06-19
发表期刊	Science
出版年	2020
英文摘要	Chemists now face the daunting task of identifying synthetic methods that are more practical, scalable, and sustainable. Approaches include the development of safer, more readily available reactants and reagents as well as discoveries in method development that provide more effective and selective synthetic transformations ([ 1 ][1], [ 2 ][2]). Conventionally, organic synthesis has been conducted through batch processes, but the use of continuous-flow technologies can allow straightforward scale-up, facilitate operational simplicity, and reduce occupational hazards and industrial waste streams ([ 3 ][3]). On page 1352 of this issue, Mo et al. ([ 4 ][4]) demonstrate that microfluidic electrochemical technologies can be applied to single-electron transfer (SET) redox-neutral reactions. Their strategy enables the efficient formation and utilization of free-radical intermediates by placing the anode and cathode in close proximity to overcome radical instability. These versatile intermediates were leveraged in Minisci-type reactions of electron-deficient heterocyclic compounds, as well as radical-radical and nickel-catalyzed sp2 carbon–oxygen cross-couplings. Students of organic chemistry are mainly taught the idea of assembling organic compounds by reacting a pair of oppositely charged species, such as electrophiles with nucleophiles ([ 5 ][5]). However, these ionic transformations often have considerable activation barriers that must be overcome thermally. Alternatively, lower-energy pathways can be accessed through the use of catalysis or additives. By contrast, many emerging approaches rely on free-radical chemistry. In organic synthesis, radical reactions historically have been perceived as uncontrollable and impractical, but this perception has gradually shifted, mainly because of the conceptual advances in the areas of photoredox catalysis ([ 6 ][6], [ 7 ][7]) and electrosynthesis ([ 8 ][8], [ 9 ][9]). Redox-modulating techniques allow chemists to target functional groups in a molecule on the basis of their different redox potentials, thereby enabling the mild and selective generation of radicals. Compared to conventional two-electron chemistry, using radicals opens up alternative reactivity and selectivity profiles and can greatly simplify synthesis through nontraditional bond construction. The revitalized interest in radicals has propelled their incorporation in contemporary chemical synthesis ([ 10 ][10], [ 11 ][11]). ![Figure][12] Approaches to redox-neutral radical-radical coupling Photoredox and electrosynthetic approaches to radical-radical coupling reactions differ in fundamental ways. Both generate radicals through single-electron transfers that can undergo otherwise difficult coupling reactions. GRAPHIC: C. BICKEL/ SCIENCE Reactions that proceed through radical intermediates can be classified as net oxidations, net reductions, or redox neutral. In the first two cases, stoichiometric reagents must be used as electron donors or acceptors. In redox-neutral reactions, the balance of electron-transfer steps between the reacting molecular partners allows construction of complex molecules in a more atom-economical fashion ([ 12 ][13]). In one of the redox-neutral approaches, both reactive partners are transformed into free-radical intermediates, and bond formation proceeds through radical-radical coupling. The activation barrier in such reactions predominantly stems from the oxidation and reduction steps and can be surmounted with the aid of photoredox catalysis or electrosynthesis. Either the energy of photons in photoredox setups or the potential energy between the electrodes in an electrosynthetic cell can drive the formation of radical intermediates. An important distinction between the two approaches is the spatial separation between the oxidation and reduction reaction sites (see the figure). In photoredox catalysis, the molecular photocatalyst acts as both the oxidizing and reducing agent and is freely diffusing in solution. In an electrosynthetic cell, the oxidation and reduction reactions are confined to the surface of the cell electrodes. This distinction leads to profound differences in reactivity patterns and intrinsic limitations observed in both systems. For example, back-electron transfer can compete with the productive reaction pathways in photocatalytic systems, and the short half-life of certain free-radical species can restrict product formation in electrosynthetic cells. The latter challenge has been successfully addressed in the work by Mo et al. by introduction of a microfluidic redox-neutral electrochemistry (µRN-eChem) platform inspired by the previous developments in continuous-flow electrosynthesis ([ 13 ][14], [ 14 ][15]). The disclosed approach relies on an extremely small interelectrode gap (down to 25 µm) in the electrosynthetic cell that substantially decreases the diffusion time between electrodes and intensifies the mass transport of unstable free-radical coupling partners generated on the electrodes. The decreased interelectrode gap also eliminates the need for a supporting electrolyte and redox mediators, commonly used to facilitate charge transfer between the electrodes and the species in solution. These improvements allowed Mo et al. to use the µRN-eChem platform with reactions in which the free-radical intermediates are too unstable to allow their efficient coupling in conventional electrosynthetic cells or in photoredox systems. They executed redox-neutral coupling reactions with unstable carbon- and nitrogen-based radical intermediates, illustrating that the immense potential of radical-chemistry manifolds can be harnessed with an appropriate electrosynthetic cell design. To date, complex radical-based transformations were mainly demonstrated in photoredox settings, and far fewer synthetically challenging reactions were executed with electrosynthesis ([ 15 ][16]). The current work strives to eliminate this difference and provides synthetic chemists with a powerful tool for expanding the scope of redox-neutral free-radical reaction manifolds in electrochemical settings. 1. [↵][17]1. A. M. Armaly, 2. Y. C. DePorre, 3. E. J. Groso, 4. P. S. Riehl, 5. C. S. Schindler , Chem. Rev. 115, 9232 (2015). [OpenUrl][18] 2. [↵][19]1. L. A. Morrill, 2. R. B. Susick, 3. J. V. Chari, 4. N. K. Garg , J. Am. Chem. Soc. 141, 12423 (2019). [OpenUrl][20] 3. [↵][21]1. M. B. Plutschack, 2. B. Pieber, 3. K. Gilmore, 4. P. H. Seeberger , Chem. Rev. 117, 11796 (2017). [OpenUrl][22][CrossRef][23][PubMed][24] 4. [↵][25]1. Y. Mo et al ., Science 368, 1352 (2020). [OpenUrl][26][Abstract/FREE Full Text][27] 5. [↵][28]1. E. J. Corey, 2. X.-M. 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领域	气候变化 ; 资源环境
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引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/276685
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Jian-Quan Liu,Andrey Shatskiy,Markus D. Kärkäs. Closing the radical gap in chemical synthesis[J]. Science,2020.
APA	Jian-Quan Liu,Andrey Shatskiy,&Markus D. Kärkäs.(2020).Closing the radical gap in chemical synthesis.Science.
MLA	Jian-Quan Liu,et al."Closing the radical gap in chemical synthesis".Science (2020).