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Acid-Catalyzed α-Halogenation of Aldehydes and Ketones01:21

Acid-Catalyzed α-Halogenation of Aldehydes and Ketones

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By replacing an α-hydrogen with a halogen, acid-catalyzed α-halogenation of aldehydes or ketones yields a monohalogenated product
In the first step of the mechanism, the acid protonates the carbonyl oxygen resulting in a resonance-stabilized cation, which subsequently loses an α-hydrogen to form an enol tautomer. The C=C bond in an enol is highly nucleophilic because of the electron-donating nature of the –OH group. Consequently, the double bond attacks an electrophilic halogen to form a...
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Halogenation of Alkenes02:46

Halogenation of Alkenes

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Halogenation is the addition of chlorine or bromine across the double bond in an alkene to yield a vicinal dihalide. The reaction occurs in the presence of inert and non-nucleophilic solvents, such as methylene chloride, chloroform, or carbon tetrachloride.
Consider the bromination of cyclopentene. Molecular bromine is polarized in the proximity of the π electrons of cyclopentene. An electrophilic bromine atom adds across the double bond, forming a cyclic bromonium ion intermediate.
15.3K
Base-Promoted α-Halogenation of Aldehydes and Ketones00:51

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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...
3.4K
Reactions at the Benzylic Position: Halogenation01:11

Reactions at the Benzylic Position: Halogenation

2.4K
Benzylic halogenation takes place under conditions that favor radical reactions such as heat, light, or a free radical initiator like peroxide.
2.4K
Electrophilic Addition to Alkynes: Hydrohalogenation02:35

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Electrophilic addition of hydrogen halides, HX (X = Cl, Br or I) to alkenes forms alkyl halides as per Markovnikov's rule, where the hydrogen gets added to the less substituted carbon of the double bond. Hydrohalogenation of alkynes takes place in a similar manner, with the first addition of HX forming a vinyl halide and the second giving a geminal dihalide.
9.8K
Radical Substitution: Hydrogenolysis of Alkyl Halides with Tributyltin Hydride01:26

Radical Substitution: Hydrogenolysis of Alkyl Halides with Tributyltin Hydride

1.8K
Radical substitution reactions can be used to remove functional groups from molecules. The hydrogenolysis of alkyl halides is one such reaction, where the weak Sn–H bond in tributyltin hydride reacts with alkyl halides to form alkanes. Here, the reagent Bu3SnH yields tributyltin halide as a byproduct.
The bonds formed in this reaction are stronger than the bonds broken, making it energetically favorable. The reaction follows a radical chain mechanism similar to radical halogenation...
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[DPEPhosbcpCu]PF6: A General and Broadly Applicable Copper-Based Photoredox Catalyst
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Copper-dependent halogenase catalyses unactivated C-H bond functionalization.

Chen-Yu Chiang1, Masao Ohashi2, Jessie Le3

  • 1Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA.

Nature
|January 29, 2025
PubMed
Summary
This summary is machine-generated.

A new copper-dependent enzyme, ApnU, enables novel halogenation and pseudohalogenation of carbon-hydrogen bonds. This discovery expands enzymatic capabilities for C-H bond functionalization and offers insights into binuclear copper oxidative enzymes.

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Area of Science:

  • Biochemistry
  • Enzymology
  • Organic Chemistry

Background:

  • Carbon-hydrogen (C-H) bonds are fundamental to organic molecules, presenting ideal targets for chemical synthesis.
  • Selective functionalization of C(sp³)-H bonds remains a significant challenge in synthetic chemistry.
  • Metalloenzymes have emerged as powerful tools for C(sp³)-H bond functionalization, though enzymatic halogenation is limited.

Purpose of the Study:

  • To discover and characterize novel enzymes capable of halogenating and pseudohalogenating unactivated C(sp³)-H bonds.
  • To expand the scope of enzymatic C(sp³)-H bond functionalization beyond existing limitations.
  • To elucidate the structural and mechanistic basis of a new class of oxidative enzymes.

Main Methods:

  • Discovery and characterization of the ApnU enzyme from the DUF3328 protein family.
  • Biochemical assays to determine enzymatic activity and substrate scope.
  • Electron paramagnetic resonance (EPR) spectroscopy to analyze the active site's copper centers.
  • Proteomics analysis to identify the enzyme's oligomeric state and disulfide bond linkages.

Main Results:

  • Identification of ApnU, a novel copper-dependent halogenase capable of iterative C(sp³)-H chlorination.
  • Demonstration of ApnU's ability to perform unprecedented C(sp³)-H iodination and thiocyanation using its copper active site.
  • Characterization of ApnU as a covalently linked homodimer with essential disulfide bonds.
  • Determination of a binuclear type II copper active site in ApnU via EPR spectroscopy.

Conclusions:

  • ApnU represents a significant expansion of enzymatic C(sp³)-H halogenase capabilities.
  • The enzyme's unique binuclear copper active site enables novel halogenation and pseudohalogenation reactions.
  • This work provides foundational understanding of DUF3328 family enzymes as binuclear copper-dependent oxidative catalysts.