22.4 Alpha Bromination of Carboxylic Acids

The HVZ reaction is a game-changer for carboxylic acids, letting us add bromine right next to the carbonyl group. It's super picky about where it puts that bromine, which is pretty cool when you're trying to make specific molecules.

This reaction is part of a bigger picture of how we can change carboxylic acids. It's not just about adding bromine - we can use this as a stepping stone to make all sorts of other compounds. It's like giving carboxylic acids a makeover.

Alpha Bromination of Carboxylic Acids

Mechanism of HVZ reaction

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• HVZ reaction selectively brominates alpha position of carboxylic acids ($RCOOH$)
• Carboxylic acid treated with phosphorus tribromide ($PBr_3$) converts to acyl bromide intermediate ($RCOBr$)
  • Red phosphorus can also be used as an alternative to $PBr_3$
• Acyl bromide undergoes alpha bromination via enol intermediate
  • Bromine ($Br_2$) acts as electrophile attacking alpha carbon of enol
  • Enol forms by deprotonation of alpha carbon and formation of carbon-carbon double bond
  • This process involves keto-enol tautomerism
• Hydrolysis of alpha-brominated acyl bromide with water ($H_2O$) yields alpha-brominated carboxylic acid product ($RCHBrCOOH$)
• Mechanism proceeds through electrophilic addition of bromine to enol followed by hydrolysis

Reagent effects in HVZ reaction

• Final step of HVZ reaction involves hydrolysis of alpha-brominated acyl bromide intermediate
• Using water ($H_2O$) in final step yields alpha-brominated carboxylic acid ($RCHBrCOOH$)
• Using alcohol ($ROH$) like methanol ($CH_3OH$) or ethanol ($C_2H_5OH$) in final step yields alpha-brominated ester ($RCHBrCOOR$)
• Using primary amine ($R_1NH_2$) or secondary amine ($R_1R_2NH$) in final step yields alpha-brominated amide ($RCHBrCONR_2$)
• Choice of final reagent allows synthesis of various alpha-brominated carbonyl compounds (acids, esters, amides) from same acyl bromide intermediate

HVZ vs other carbonyl brominations

• HVZ reaction more selective for alpha bromination of carboxylic acids vs ketones ($RCOR$) and aldehydes ($RCHO$)
  • Ketones and aldehydes can brominate at any alpha position, carboxylic acids selectively brominate at alpha carbon adjacent to carbonyl ($C=O$)
• Other carbonyl compounds typically brominated using molecular bromine ($Br_2$) and protic solvent like water ($H_2O$) or Lewis acid catalyst like aluminum bromide ($AlBr_3$)
  • Lower selectivity compared to HVZ reaction for carboxylic acids
• Alpha-brominated products of carboxylic acids more stable than those of ketones and aldehydes
  • Alpha-brominated ketones ($RCHBrCOR$) and aldehydes ($RCHBrCHO$) prone to elimination reactions forming alpha,beta-unsaturated carbonyl compounds
  • Alpha-brominated carboxylic acids, esters, and amides more resistant to elimination due to electron-withdrawing effect of carbonyl group

Mechanistic Considerations and Stereochemistry

• The HVZ reaction proceeds through a radical mechanism
• The stereochemistry of the alpha-brominated product depends on the specific substrate and reaction conditions
• Nucleophilic substitution can occur in subsequent reactions of alpha-brominated carboxylic acids, allowing for further functionalization