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Unlike aldehydes and ketones, carboxylic acids do not readily participate in α halogenation reactions via enols or enolate intermediates. However, α-halogenated acids are obtained through other methods. One of the approaches is the Hell–Volhard–Zelinsky (HVZ) reaction, wherein the carboxylic acid is treated with halogen in the presence of PBr3. It involves the conversion of acid to acid halide, which exists in equilibrium with its enol form. The enol attacks the...
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Hydrolysis of acid halides is a nucleophilic acyl substitution reaction in which acid halides react with water to give carboxylic acids. The reaction occurs readily and does not require acid or a base catalyst.
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By replacing an α-hydrogen with a halogen, acid-catalyzed α-halogenation of aldehydes or ketones yields a monohalogenated product
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α-Halogenation of aldehydes and ketones is a reaction involving the substitution of α hydrogens with halogens in the presence of a base.  The reaction begins with the abstraction of  α hydrogen by the base to produce a nucleophilic enolate ion. This intermediate undergoes a subsequent nucleophilic substitution with the halogen to produce a monohalogenated carbonyl compound. If the starting substrate has more than one α hydrogen, it is difficult to stop the reaction...
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Nucleophilic substitution in α-halocarbonyl compounds can be achieved via an SN2 pathway. The reaction in α-haloketones is generally carried out with less basic nucleophiles. The use of strong basic nucleophiles leads to the generation of α-haloenolate ions, which often participate in other side reactions.
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A method involving the transformation of methyl ketones to carboxylic acids using excess base and halogen is called the haloform reaction. It begins with the deprotonation of α hydrogen to form an enolate ion which reacts with the electrophilic halogen to give an α-halo ketone. The step continues until all the α protons are substituted to form a trihalomethyl ketone. The resulting molecule is unstable, and in the presence of a hydroxide base, it readily undergoes nucleophilic...
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Aryl Halide Carboxylation via Decarboxylative Metal-Halogen Exchange.

Daniel J Ryder-Mahoney1, Ken Yamazaki2, Gregory J P Perry1

  • 1School of Chemistry and Chemical Engineering, University of Southampton, Southampton SO17 1BJ, U.K.

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|February 27, 2026
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Summary

A novel method uses carboxylic acid salts for metal-halogen exchange and carboxylation of aromatic halides. This approach avoids hazardous organometallics, offering a safer and simpler alternative for chemical synthesis and isotope labeling.

Keywords:
CO2 TransferCarbon Isotope LabelingCarboxylationDual-Function ReagentMetal−Halogen Exchange

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Area of Science:

  • Organic Chemistry
  • Synthetic Methodology

Background:

  • Metal-halogen exchange is crucial for functionalizing aromatic halides.
  • Traditional methods often rely on hazardous and sensitive organometallic reagents.
  • There is a need for safer, more accessible reagents for carboxylation reactions.

Purpose of the Study:

  • To report a unique mode of metal-halogen exchange for aromatic halide carboxylation.
  • To demonstrate the use of bench-stable carboxylic acid salts as precursors for metalating agents.
  • To develop a mild, broadly applicable carboxylation procedure avoiding hazardous reagents and specialized equipment.

Main Methods:

  • Utilizing potassium salts of carboxylic acids as both CO2 source and metalating agent.
  • Performing metal-halogen exchange and subsequent carboxylation under mild conditions.
  • Employing experimental and computational studies to elucidate the reaction mechanism.

Main Results:

  • A novel decarboxylative metal-halogen exchange mechanism was proposed and supported by evidence.
  • The method successfully carboxylated a range of aromatic halides using readily available carboxylic acid salts.
  • The procedure was applied to carbon isotope labeling of biologically relevant molecules, including late-stage labeling.

Conclusions:

  • Carboxylic acid salts offer a safe and convenient alternative to traditional organometallic reagents for metal-halogen exchange.
  • This method provides a versatile and mild route for the carboxylation of aromatic halides.
  • The developed protocol facilitates carbon isotope labeling for applications in chemical biology and medicinal chemistry.