Organocatalysis

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In organic chemistry, the term Organocatalysis (a concatenation of the terms "organic" and "catalyst") refers to a form of catalysis, whereby the rate of a chemical reaction is increased by an organic catalyst referred to as an "organocatalyst" consiting of carbon, hydrogen, sulfur and other nonmetal elements found in organic compounds ^{[1] [1] [1] [1]}. Because of their similarity in composition and description, they are often mistaken as a misnomer for enzymes due to their comparable effects on reaction rates and forms of catalysis involved.

The term "organocatalysis" was created by David MacMillan in 2000 from the old and well known concept of "organic catalysis" introduced by the German chemist Wolfgang Langenbeck; "organocatalysis" is nothing more than a new name for an old methodology, but thus gives fresh impulses for intensive research in the following years.

Organocatalysts which display secondary amine functionality can be described as performing either enamine catalysis (by forming catalytic quantities of an active enamine nucleophile) or iminium catalysis (by forming catalytic quantities of an activated iminium electrophile). This mechanism is typical for covalent organocatalysis. Covalent binding of substrate normally requires high catalyst loading (for proline-catalysis typically 20-30 mol%). Noncovalent interactions such as hydrogen-bonding facilitates low catalyst loadings (down to 0.001 mol%).

Two main advantages of organocatalysis are:

• there is no need for metal-based catalysis thus making a contribution to green chemistry
• when the organocatalyst is chiral an avenue is opened to asymmetric catalysis, for example the use of proline in aldol reactions,

Imidazolidinone organocatalysis

A certain class of imidazolidinone compounds (also called McMillan catalysts) are suitable catalysts for asymmetric Diels-Alder reactions. The original such compound was derived from the biomolecule phenylalanine in two chemical steps (amidation with methylamine followed by condensation reaction with acetone) which leave the chirality intact ^[1]:

Image:McMillanCatalystSynthesis.png

For an example of its use: see Asymmetric DA reactions

Thiourea organocatalysis

In nature noncovalent interactions such as hydrogen bonding ("partial protonation") play a crucial role in enzyme catalysis that is characterized by selective substrate recognition (molecular recognition), substrate activation, and enormous acceleration of organic tranformations. Based on the pioneering exmaninations by Kelly, Etter, Jorgensen, Hine, Curran, Göbel, and De Mendoza (see review articles cited below) on hydrogen bonding interactions of small, metal-free compounds with electron-rich binding sites Schreiner and co-workers peformed series of theoretical and experimental systematic investigations towards the hydrogen-bonding ability of various thiourea derivatives ^{[1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1] [1]}. This purely organic compounds revealed effective acceleration of simple Diels-Alder reaction, act like weak Lewis acid catalyst, but act through explicit double hydrogen bonding instead of covalent binding known from traditional metal-ion mediated catalysis. Schreiner and co-workers identified and indroduced electron-poor thiourea derivatives as hydrogen-bonding organocatalysts. N,N'-bis[[3,5-bis(trifluormethyl)phenyl thiourea is to date the most effective achiral thiourea derivative and combines all typical structural features for double H-bonding mediated organocatalysis:

• electron-poor
• rigid structure
• non-coordinating, electron withdrawing substituents in 3,4, and/or 5 position of a phenyl ring
• the trifluoromethyl-group is the preferred substituent

Advantages of thiourea derivatives:

• no product inhibition due to weak enthalpic binding, but specific binding-“recognition“
• low catalyst-loading (down to 0.001 mol%)^{[citation needed]}
• high TOF values (up to 2,000 h^–1)^{[citation needed]}
• simple and inexpensive synthesis
• easily to modulate and to handle, no inert atmosphere necessary
• immobilization on solid phase (polymer-bound organocatalysts), catalyst recovery and reusability
• catalysis under almost neutral conditions (pk_a thiourea 21.0), acid-sensitive substrates are tolerated
• metal-free, not toxic (compare traditional metal-containing Lewis-acid catalysts
• water-tolerant, even catalytically effective in water or aqueous media
• environmentally benign ("Green Chemistry")

To date various organic transformations are organocatalyzed through hydrogen-bonding N,N'-bis[[3,5-bis(trifluormethyl)phenyl thiourea at low catalyst loadings and in good to excellent product yields. This electron-poor thiourea derivative has proven to be the benchmark for noncovalent organocatalysis utilizing explicit hydrogen-bonding as well as to be the basis for development of a wide range of catalytically active derivatives.

Thiourea functionalized organocatalysts

Since 2001 research groups world-wide (e.g., Berkessel, Connon, Jacobsen, Nagaswa, Takemoto) have realized the potential of thiourea derivatives and developed various achiral/chiral mono- and bifunctional derivatives incorporating the electron-poor 3,5-bis(trifluoromethyl)phenyl substrate-"anchor" functionality. Meanwhile a broad spectrum of organic transformations are performed through hydrogen-bonding organocatalysis and the research ist still in the focus of interest.

References