What Is Hunsdiecker Reaction?
In 1939, chemist H. Hunsdiecker reported that dry silver salts of fatty acids reacted with elemental bromine to obtain the corresponding bromoalkanes with one less carbon. This decarboxylation bromination reaction is called Hunsdiecker reaction.
Further research found that in addition to elemental bromine, chlorine and elemental iodine can also react to produce corresponding chloroalkanes and iodoalkanes. Carboxylates are not limited to silver salts. More stable and easier to crystallize monovalent thallium salts and mercury salts are also conducive to improving the yield. In addition to fatty acids, aromatic acids with electron-withdrawing groups can also be used as reaction substrates. Of course, the Hunsdiecker reaction also has disadvantages, such as poor functional group compatibility. When the α-position of the carboxylic acid is an optically active carbon, the reaction has a large degree of racemization.
Since this reaction can convert carboxylic acid into a bromoalkane with one less carbon, the obvious difference from the general decarboxylation reaction is that the functional group in the product is not reduced. Therefore, it has very important application value in organic synthesis, which has attracted widespread attention from chemists.
- Reagents: Halogen (usually bromine, chlorine, and iodine).
- Reactants: Carboxylates, fatty acids, aromatic acids.
- Products: Alkyl halides.
- Reaction type: Formation of C-X bonds (X=Cl, Br, I).
- Related reaction: Barton Decarboxylation.
Fig 1. Hunsdiecker reaction and its mechanism. [1]
Mechanism of Hunsdiecker Reaction
First, the carboxylic acid anion attacks the elemental bromine to form an O-Br bond. Since the bond energy of the O-Br bond is relatively low, it is easy to undergo homolysis. The generated acyloxy radical removes a molecule of CO2, and the generated alkyl radical is then coupled with the bromine radical or attacks the elemental bromine to obtain the product bromoalkane.
Improvement of Hunsdiecker Reaction
The efforts of many researchers have greatly improved and developed this reaction. There are two types of relatively important improvements.
Suarez and Kochi improvement
The first type is the Suarez improvement and the Kochi improvement. The Suarez improvement is to react carboxylic acid with diacetate iodobenzene (DIB) and elemental iodine, and react under ultraviolet light to prepare the corresponding iodide. The Kochi modification method uses Pb(OAc)4 as an oxidant and carboxylic acid as a raw material to react with elemental iodine or lithium halide under ultraviolet light to obtain the corresponding alkyl halide. This type of modification directly uses acid as a raw material, eliminating the preparation of carboxylate, so it is more convenient to use.
Barton improvement method
The second improvement is the famous Barton improvement method. First, the carboxylic acid is condensed with 2-mercaptopyridine N-oxide to form the corresponding O-carbonylthiohydroxamate (also known as Barton ester or PTOC ester). Then, benzene or cyclohexane is used as a solvent, and it reacts with carbon tetrachloride or monobromotrichloride or iodoform under heating, light or free radical initiator to obtain the corresponding alkyl halide. The advantage of this modification method is that the functional group compatibility is particularly good, especially when AIBN is used as an initiator, basically all aromatic acids can obtain decarboxylation halogenated products in high yield. In addition, this modification method avoids the preparation of anhydrous metal salts and is simpler to operate.
Application Examples of Hunsdiecker Reaction
- Example 1: In the total synthetic strategy of bastine and 3-dehydroxybastine, aryl vinyl halides were obtained by Hunsdieckere-Borodin type decarboxylation/halogenation of aryl acrylic acid. Treatment of acid 5a with N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS) gave the corresponding aryl vinyl bromide 6 and -iodide 7a in 83% and 80% yields, respectively. [2]
- Example 2: Gregory J. P. Perry et al. reported transition metal-free decarboxylative iodination, an aromatic Hunsdiecker reaction. In this method, decarboxylative iodination of (hetero)aromatic acids using only readily available I2 can avoid the use of stoichiometric amounts of transition metals, and generally less reactive benzoic acids (e.g., electron-rich and non-ortho-substituted acids) can be efficiently coupled. [3]
Fig 2. Synthetic examples via Hunsdiecker reaction.
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References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 272-274.
- Lorentzen, Marianne, et al. Tetrahedron, 2015, 71(43), 8278-8284.
- Perry, Gregory JP, et al. Journal of the American Chemical Society, 2017, 139(33), 11527-11536.
