Organocatalysts

Organocatalysts are small organic molecules that accelerate chemical reactions without the need for metals. They enable a range of transformations under mild conditions and often provide enantioselectivity. Organocatalysis can rely on covalent mechanisms, noncovalent interactions, or a combination of both, and is compatible with air and moisture in many cases. The approach is complementary to metal catalysis and biocatalysis, and many organocatalysts are readily prepared from inexpensive starting materials.

The dominant modes of organocatalysis include covalent and noncovalent pathways. Covalent organocatalysis comprises enamine catalysis, in which a secondary amine forms an enamine with aldehydes or ketones to activate them toward nucleophilic attack, and iminium catalysis, where an amine activates electrophiles such as α,β-unsaturated carbonyl compounds by forming an iminium ion. N-heterocyclic carbene (NHC) catalysis uses Breslow-type intermediates to invert the polarity of aldehydes, enabling umpolung reactivity. Noncovalent organocatalysis relies on hydrogen bonding, often with thiourea or related catalysts, to activate electrophiles, as well as ion-pair or charge-transfer interactions to organize transition states.

Representative organocatalysts include proline and its derivatives for enantioselective aldol and Michael reactions; MacMillan’s imidazolidinone catalysts for enantioselective Diels–Alder and related reactions; Jørgensen–Hayashi catalysts; and cinchona alkaloid derivatives used across various enantioselective transformations. The field, which gained prominence in the early 2000s, has expanded to organocascade catalysis and organocatalytic polymerization.

Applications span natural product and pharmaceutical intermediate synthesis, as well as environmentally friendlier processes. Advantages of organocatalysis include metal-free conditions, operational simplicity, broad functional-group tolerance, and high selectivity, while limitations may include variable catalyst activity, synthesis complexity, and substrate scope constraints in some reactions.