Organocatalysis

Article

October 20, 2021

In organic chemistry, the term organocatalysis means the catalysis of reactions where the catalyst used to accelerate the reaction is a small organic molecule, devoid of inorganic elements such as metals and containing carbon, hydrogen, sulfur. The term was coined in 1935 by German chemist Wolfgang Langenbeck. On 6 October 2021, chemists David MacMillan and Benjamin List were awarded the Nobel Prize in Chemistry for their studies on organocatalysis.

Historical notes

The first use of an organic molecule as a catalyst is attributed to Justus von Liebig, who in 1859 discovered the transformation of cyanogen into oxamide catalyzed by acetaldehyde. Liebig identified acetaldehyde as the catalyst of the reaction and recognized in its effects an analogy with ferments (enzymes). The first asymmetric organocatalysis reaction was published by Breding and Fiske in 1912. In this reaction a cyanhydrin was formed from benzaldehyde using alkaloids as catalysts. These studies were considered very innovative, even if the enantiomeric excess achieved was less than 10%. Decades later, significant stereoselectivity was achieved for the first time in an organocatalysis reaction. The (S) or (R) -proline amino acid in a Robinson ringing was used as catalyst to obtain the Wieland-Miescher ketone. This reaction is now called the Hajos-Parrish-Eder-Sauer-Wiechert reaction from the name of the discoverers, and is of considerable importance for the total synthesis of steroids. Zimmerman-Traxler, for the aldol reaction of metal-free enamines. Cross aldol direct reactions were independently developed by List, Barbas, Shibasaki and Trost. The first enantioselective cross aldol organocatalytic reaction of aldehydes was developed in 2002 by MacMillan.

Reaction mechanism

During the catalytic cycle the catalyst can be covalently bonded to the substrate molecule; in this case a relatively high concentration of organic catalyst is required. Even through non-covalent bonds such as hydrogen bonds, catalytic interactions can occur, and in this case only small amounts of catalyst are required.

Covalent mechanism

The principle of most organocatalytic processes is that the catalyst is first reacted with a reactant to form (reversibly) a covalent bond. In the proline-catalyzed aldol reaction, proline initially gives a condensation reaction with the ketone used. The resulting iminium cation then tautomerizes to enamine, which in the next step gives a nucleophilic attack on the aldehyde. By subsequent hydrolysis the product is released and the proline is reformed. In the reaction, the stereochemical information is determined by the chiral proline. The carboxyl group of proline also activates the aldehyde by forming a hydrogen bond. The reaction proceeds through a six-membered, chair-shaped transition state similar to the Zimmerman-Traxler model for lithium enolates. The substituent of the aldehyde lies in the pseudo-equatorial plane. The course of the reaction through a chair transition state was first postulated by Houk based on quantum mechanical calculations, and then experimentally demonstrated by List using labeled oxygen.

Non-covalent mechanism

In this mechanism the catalyst does not form covalent bonds. There are weak directional interactions between the substrate to be activated and the organic catalyst. This is the principle by which many enzymes also react, which are also used as a model for the development of non-covalent organic catalysts. In this field, neutral species are used that can give hydrogen bonds, such as urea or t derivatives

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