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Cannizzaro Reaction
Introduction of Cannizzaro Reaction
Cannizzaro reaction is non-enolizable aldehydes of hydrogen undergo intermolecular oxidation-reduction reactions under the action of strong bases, resulting in an organic disproportionation reaction of one molecule of carboxylic acid and one molecule of alcohol.1,2?When Italian chemist Stanislau Cannizzaro used plant ash to treat benzaldehyde, he obtained benzoic acid and benzyl alcohol at the same time, and found this reaction for the first time, hence the name of the reaction. 3
Fig. 1. Canizaro reaction
The aldehydes applicable in the Cannizzaro reaction are generally aromatic aldehydes (e.g. benzaldehyde) and formaldehyde. If the aldehyde contains α-active hydrogen, the base will take away its α-active hydrogen, which in turn leads to hydroxyl aldol condensation reaction, resulting in a lower yield of the Cannizzaro reaction. 4
The Cannizzaro reaction can also occur intramolecularly, and in some cases the product hydroxy acids are further cyclized by water loss to form lactones.
Mechanism of Cannizzaro Reaction
Fig 2. Mechanism of Cannizzaro Reaction
The reaction starts from the attack of nucleophilic reagent (such as hydroxyl ion) on carbonyl carbon, which triggers disproportionation reaction and deprotonation to produce two negative charged divalent anions.
The intermediate manifestation of the generation can act as a hydride reducing agent. Due to its unstable nature, a hydride anion is released from the intermediate. This hydride anion continues to attack another aldehyde molecule. During this process, divalent anions are converted into carboxylate anions, and aldehydes are converted into alkoxide anions.
In the final step, water provides protons to the alkoxide anion, resulting in the final alcohol product. Due to the stronger alkalinity of alkoxides compared to water, the reaction can proceed. When acid post-treatment is used, carboxylic acid ions produce the final carboxylic acid product (acid post-treatment is required because the alkalinity of carboxylic acid ions is weaker than that of water, so protons cannot be obtained from water).
Crossed Cannizzaro Reaction
Cross Cannizzaro reaction is a type of Cannizzaro reaction: mixing two different types without α - The aldehyde with active hydrogen as the substrate undergoes a cross oxidation reduction reaction under alkaline conditions, which is called a cross Cannizzaro reaction.4?This reaction often produces multiple products and has no preparation value. But it is possible to sacrifice aldehydes to combine with more valuable chemicals. If one of the aldehydes is formaldehyde, it always oxidizes itself to formic acid (because formaldehyde has the strongest reducibility), while alcohols are obtained from the reduction of another aldehyde chemical, which has preparation value. Due to the complete conversion of two different aldehydes into their respective desired products, the yield of valuable target products has also greatly increased. For example, this method is adopted for the industrial preparation of pentaerythritol.
Fig 3. Industrial preparation of pentaerythritol
In summary, the Cannizzaro reaction can be used to control the disproportionation of non enolated aldehydes. The cross Cannizzaro reaction can be used to increase the production of the valuable?chemicals.
Research progress in Cannizzaro reaction
Lithium bromide, as a mild and recyclable reagent, can interact with triethylamine in the room temperature solvent-free Cannizzaro reaction.5
Under the catalysis of TOX ligand and Cu(II), the asymmetric intramolecular Cannizzaro reaction of aryl and alkylglyoxal with alcohols exhibits unprecedented high enantioselectivity. The preliminary results indicate that in addition to the dynamic kinetic resolution of acetal intermediates, the enantioselective addition of alcohols and glyoxal contributes the most to stereoselectivity.6
Using a series of simple 2-acylbenzaldehyde as the reaction substrate, 2-formylarylene ketones in marine natural product pestalone derivatives can be conveniently converted (isomerization) into 3-substituted phthalates under nucleophilic catalysis (NaCN) in the Cannizaro reaction or under photochemical conditions (DMSO, 350 nm).7
?Reference
1.?Cannizzaro, S. Ueber den der Benzo?s?ure entsprechenden Alkohol. Liebigs Annalen. 1853, 88: 129–130. https://doi.org/10.1002/jlac.18530880114
2.?2. List, K.; Limpricht, H. Ueber das sogenannte Benzo?oxyd und einige andere gepaarte Verbindungen. Liebigs Annalen. 1854, 90: 190–210. https://doi.org/10.1002/jlac.18540900211
3.?Geissman, T. A. "The Cannizzaro Reaction" Org. React. 1944, 2, 94. https://doi.org/10.1002/0471264180
4.??Kürti, L., Czakó, B. (2005).?Strategic Applications of Named Reactions in Organic Synthesis; Background and Detailed Mechanisms. Burlington, MA: Elsevier Academic Press.
5.?Mohammad M. Mojtahedi,Elahe Akbarzadeh,Roholah Sharifi and,M. Saeed Abaee. Lithium Bromide as a Flexible, Mild, and Recyclable Reagent for Solvent-Free Cannizzaro, Tishchenko, and Meerwein?Ponndorf?Verley Reactions[J]. Org. Lett.,2007,9(15).?https://doi.org/10.1021/ol070894t
6.?Wang Pan,Tao Wen-Jie,Sun Xiu-Li,Liao Saihu,Tang Yong. A highly efficient and enantioselective intramolecular Cannizzaro reaction under TOX/Cu(II) catalysis.[J]. Journal of the American Chemical Society,2013,135(45).?https://doi.org/10.1021/ja409859x
7.?Gerbino Dario C,Augner Daniel,Slavov Nikolay,Schmalz Hans-Günther. Nucleophile- or light-induced synthesis of 3-substituted phthalides from 2-formylarylketones.[J]. Organic letters,2012,14(9). https://doi.org/10.1021/ol300757m
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