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In an electrophilic aromatic substitution reaction, an electrophile substitutes for a hydrogen of an aromatic compound.
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Simple aryl halides do not react with nucleophiles. However, nucleophilic aromatic substitutions can be forced under certain conditions, such as high temperatures or strong bases. The mechanism of substitution under such conditions involves the highly unstable and reactive benzyne intermediate. Benzyne contains equivalent carbon centers at both ends of the triple bond, each of which is equally susceptible to nucleophilic attack. This 50–50 distribution of products is...
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Friedel–Crafts reactions were developed in 1877 by the French chemist Charles Friedel and the American chemist James Crafts. Friedel–Crafts alkylation refers to the replacement of an aromatic proton with an alkyl group via electrophilic aromatic substitution. A Lewis acid catalyst such as aluminum chloride reacts with an alkyl halide to form a carbocation. The resulting carbocation then reacts with the aromatic ring and undergoes a series of electron rearrangements before giving the final...
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All ortho–para directors, excluding halogens, are activating groups. These groups donate electrons to the ring, making the ring carbons electron-rich. Consequently, the reactivity of the aromatic ring towards electrophilic substitution increases. For instance, the nitration of anisole is about 10,000 times faster than the nitration of benzene. The electron-donating effect of the methoxy group in anisole activates the ortho and para positions on the ring and stabilizes the corresponding...
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Benzaldehyde, like formaldehyde, lacks an α hydrogen and cannot enolize to form an enolate. Hence, the reaction of benzaldehyde with a ketone in the presence of an aqueous base forms a single crossed product. This reaction is referred to as Claisen–Schmidt condensation.
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Heteroaromatic swapping in aromatic ketones.

Hikaru Nakahara1, Ryotaro Shirai1, Yoshio Nishimoto2

  • 1Department of Applied Chemistry, Waseda University, 513 Wasedatsurumakicho, Shinjuku, Tokyo, 162-0041, Japan.

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|October 9, 2025
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Summary
This summary is machine-generated.

Medicinal chemists can now efficiently swap aromatic rings for heteroaromatic rings in one step. This novel Claisen/retro-Claisen strategy broadens access to diverse bioactive compounds with improved properties.

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Area of Science:

  • Medicinal Chemistry
  • Organic Synthesis

Background:

  • Modifying aromatic rings to heteroaromatic rings is key in medicinal chemistry for tuning lipophilicity and metabolic stability.
  • Current methods for aromatic ring transformation to heteroaromatic rings (heteroaromatic swapping) lack generality and efficiency.

Purpose of the Study:

  • To develop a generalizable, one-step method for heteroaromatic swapping.
  • To overcome limitations of existing skeletal editing and transition-metal-catalyzed methods.

Main Methods:

  • A novel strategy employing a Claisen/retro-Claisen mechanism.
  • Utilizing heteroaryl esters and aromatic ketones as key reagents.

Main Results:

  • Selective exchange of aromatic rings with diverse heteroaromatic rings across a broad substrate scope.
  • High-yield conversion of bioactive aromatic ketones into their heteroaromatic analogs.
  • Demonstrated efficiency and broad applicability, surpassing existing techniques.

Conclusions:

  • The developed method provides an efficient and versatile platform for synthesizing bioactive compounds.
  • Expands the molecular editing toolkit for medicinal chemists.
  • Enables the creation of compounds with enhanced physicochemical properties.