Hydrogen-bond catalysis is a type of organocatalysis that relies on use of hydrogen bonding interactions to accelerate and control organic reactions. In biological systems, hydrogen bonding plays a key role in many enzymatic reactions, both in orienting the substrate molecules and lowering barriers to reaction. However, chemists have only recently attempted to harness the power of using hydrogen bonds to perform catalysis, and the field is relatively undeveloped compared to research in Lewis acid catalysis.
Catalytic amounts of hydrogen-bond donors can promote reactions through a variety of different mechanisms. During the course of a reaction, hydrogen bonding can be used to stabilize anionic intermediates and transition states. Alternatively, some catalysts can bind small anions, enabling the formation of reactive electrophilic cations. More acidic donors can act as general or specific acids, which activate electrophiles by protonation. A powerful approach is the simultaneous activation of both partners in a reaction, e.g. nucleophile and electrophile, termed "bifunctional catalysis". In all cases, the close association of the catalyst molecule to substrate also makes hydrogen-bond catalysis a powerful method of inducing enantioselectivity.
Hydrogen-bonding catalysts are often simple to make, relatively robust, and can be synthesized in high enantiomeric purity. New reactions catalyzed by hydrogen-bond donors are being discovered at an increasing pace, including asymmetric variants of common organic reactions useful for synthesis, such as aldol additions, Diels-Alder cycloadditions and Mannich reactions.
However, there are several challenges that must be overcome before hydrogen-bond catalysis can achieve its full potential in terms of synthetic utility. Current known reactions are very substrate specific and generally exhibit low rate acceleration and turnover, thus requiring high catalyst loading. Catalysts are often discovered and optimized by trial and error, and chemists have a poor understanding of the relationship between catalyst structure and reactivity. Additionally, the field suffers from a lack of general mechanistic understanding, which has been greatly outpaced by the discovery of new reactions. With more detailed studies of structure and mechanism in the future, hydrogen-bond catalysis has great potential for enabling new, efficient, selective reactions and promising applications in asymmetric synthesis.