What Is Hell-Volhard-Zelinsky Reaction?
Hell-Volhard-Zelinsky reaction (HVZ reaction): a carboxylic acid/halogen reaction in which catalytic amount of phosphorus tribromide, phosphorus trichloride (also phosphorus + halogen), replaces α-hydrogen with halogen to give α-halogenated carboxylic acid. Monobasic or polybasic halogenated acids are obtained by controlling the halogen amount. Various chloroacetic acids in industry are prepared through this reaction. The reaction is named after chemists Carl Magnus Von Hell, Jacob Volhard and Nikolay Zelinsky.
It is worth mentioning that this reaction cannot be used for α-iodination and fluorination. If the Hell Volhard Zelinsky reaction is carried out at extremely high temperatures, hydrogen halide may be eliminated from the product, resulting in the formation of β-unsaturated carboxylic acids.
- Reaction conditions: The reaction conditions of the Hell-Volhard-Zelinsky reaction are very stringent - involving reaction temperatures exceeding 373 K and increased reaction times. The reaction generally requires less than one equivalent of phosphorus (or a phosphorus trihalide). Some carboxylic acids and acid derivatives, such as acyl halides or anhydrides, can be halogenated in the absence of a catalyst.
- Reagents: Phosphorus tribromide (PBr3) or phosphorus trichloride (PCl3) (catalyst), bromine (Br2) or chlorine (Cl2) (halogenating agent).
- Reactants: Carboxylic acid.
- Products: α-Halo carboxylic acid.
- Reaction type: Formation of C-X bonds (X=Cl, Br).
- Related reactions: Reformatsky reaction.
Fig 1. Hell-Volhard-Zelinsky reaction and its mechanism. [1]
Mechanism of Hell-Volhard-Zelinsky Reaction
The bromine reacts with the phosphorus to form phosphorus tribromide, which is then converted to the acyl bromide. The acyl bromide can exist in the enol form, and this tautomer can be rapidly brominated at the α-position. The resulting monobrominated product is very low in nucleophilicity, and all brominations remain at the monosubstituted stage. The resulting bromoacyl bromide undergoes bromine exchange with the unreacted carboxylic acid by forming anhydride, completing the catalytic cycle.
Application Examples of Hell-Volhard-Zelinsky Reaction
- Example 1: A large number of α-xanthogenic carboxylic acids can be prepared using the Hell−Volhard−Zelinsky reaction and other processes such as the free radical addition of xanthogenic esters to acrylic acid. For example, in the synthesis of N-protected β2-amino acids, 2-phthalimidopropionic acid 13 can be used to obtain bromide 14 through the classic Hell−Volhard−Zelinsky reaction, which can be further used to synthesize the free carboxylic acid 15. [2]
- Example 2: Anton A. Homon et al. designed a technique to effectively synthesise different substituted 3-azabicyclo[3.2.0]heptane-derived structural units from [3+2] cycloaddition of cyclobut-1-eneraboxylic acid ester and in-situ made methenyl ylides and used it on multigram scale. One of these was cylobut-1-enecarboxylic acid ester 1, an intermediate used to make 3-azabicyclo[3.2.0]-heptane derivatives, which was obtained through the Hell-Volhard-Zelinsky reaction of cyclobutanecarboxylic acid (2) and the dehydrobromination of the resulting -bromoester 3. [3]
Fig 2. Synthetic examples via Hell-Volhard-Zelinsky.
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References
- Jie Jack Li. Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications Fifth Edition, 2014: 310-311.
- Chen X, et al. Organic letters, 2020, 22(9), 3628-3632.
- Homon A A, et al. European Journal of Organic Chemistry, 2018, 2018(40), 5596-5604.
