Organocatalysis

Under organocatalysis is understood in organic chemistry, the catalysis of organic reactions by means of small metal- free organic molecules, which are composed of the elements carbon, hydrogen, oxygen, nitrogen, sulfur and phosphorus. The term was coined by the German chemist Wolfgang Langenbeck.

  • 3.1 Derived from Natural Products catalysts

History

The beginning of organocatalysis applies in 1832, discovered by Justus von Liebig and Friedrich Wöhler benzoin addition with cyanide catalysis to aromatic α - hydroxy ketones ( benzoin ).

In 1859, Justus von Liebig discovered the oxamide synthesis of cyanogen and water in the presence of acetaldehyde. Arbitrarily identified acetaldehyde as a catalyst for the reaction and the effect realized in parallel with the enzymes ( enzymes ).

The first asymmetric organocatalytic reaction was published in 1912 by Bredig and Fiske. Thus, the cyanohydrin reaction with benzaldehyde was catalyzed to Mandelsäurenitrilen with alkaloids. The enantiomeric excesses were achieved by 10%.

Decades later, were the first to be obtained in an organocatalytic reaction remarkable stereoselectivity. As a catalyst, the amino acid proline [(S) - or (R )-proline ] used in a Robinson annulation, which leads to the Wieland - Miescher ketone. This reaction is now named after their discoverers Hajos- Parrish -Eder -Sauer- Wiechert reaction and possessed for the total synthesis of steroids importance.

Was first proposed a coherent mechanism for the metal-free enamine aldol reaction analogous to the Zimmerman -Traxler model by Houk model. Crossed direct aldol reactions have been developed independently by List, Barbas, Shibasaki and Trost. The first organocatalytic cross-aldol reaction of aldehydes was developed in 2002 by MacMillan.

Reaction mechanism

The catalyst may be covalently bound to the substrate molecule in the catalytic cycle; In this case, relatively high concentrations of are necessary organocatalyst. , Catalytic, non-covalent interactions such as hydrogen- bonding is possible, that only require small amounts of catalyst.

Covalent mechanism

The principle of most of organocatalytic method is that the catalyst is first reacted with a reactant to form a ( reversible ) covalent bond. In the aldol reaction prolinkatalytischen proline first condensed to the ketone. The resulting iminium tautomerization to the enamine then that nucleophilic attack on the aldehyde used in the next step. Subsequent hydrolysis of the product is released and re-formed proline.

In the reaction, the stereo information is transmitted by the chiral proline. The carboxyl group of proline activated by formation of a hydrogen bond and the aldehyde. The reaction is similar to the Zimmerman -Traxler model for lithium enolates via a six- membered chair -like transition state. The substituent of the aldehyde in this field is the pseudo- equatorial plane.

The course of the reaction via a chair -like transition state was first postulated by quantum-chemical calculations by Houk and later proven experimentally by oxygen List of marking.

Non-covalent organocatalysis

Wherein non-covalent organocatalysis no covalent bonds are formed to the catalyst. It is based on weak directional interactions between an organic catalyst and the substrate to be activated. According to this principle also react many enzymes, which also serve as a model for the development of non -covalent organocatalysts. As a neutral hydrogen- for example, derivatives of urea or thiourea can be used. Be favorable here catalysts have proven that are electron and of rigid structure and possess a phenyl ring which bear electron-withdrawing, non-coordinating substituents in the 3,4 and / or 5-position.

Benefits of thiourea derivatives (especially compared to traditional metal - containing Lewis acid catalysts):

  • Non-covalent binding to the substrate, thus small product inhibition
  • Low catalyst loading (up to 0.001 mol % ), high TOF values
  • Simple and convenient synthesis and structural modification
  • Connection to the solid phase; thus recovery possible
  • Not air-or water -sensitive, no inert gas atmosphere necessary unproblematic handling
  • Allow catalysis under almost neutral conditions, tolerance of acid-labile substrates
  • Metal -free, non-toxic, such as many metal-containing Lewis acid catalysts
  • Environmentally friendly ("green chemistry")

Reactions

For the following reactions, there is already effective organocatalysts:

  • Aldol reactions
  • Michael additions
  • Mannich reactions
  • α - amination
  • Diels -Alder and hetero-Diels -Alder reactions
  • Knoevenagel condensations
  • Wittig rearrangements
  • Fluorination
  • Reductions
  • Asymmetric Stetter reactions
  • Nitroaldol
  • Shi epoxidation
  • Baylis -Hillman reaction
  • Reduction of Ketones

Derived from Natural Products catalysts

Are common and are the amino acids ( S)-proline used derived catalysts. Also derived from (S) -phenylalanine, catalysts are often used.

Of the Cinchona (China) alkaloids, some catalysts used in organocatalytic reactions derived:

Also derived from tartaric acid catalysts, for example TADDOLs be used in organocatalytic reactions:

The first catalysts for enantioselective organocatalytic Diels -Alder reactions have been developed by MacMillan:

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