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= Bifunctional catalysis =

Introduction
Catalysis, first introduced by Jöns Jakob Berzelius in 1835, has attracted unceasing attention throughout the development of new chemical reactivities. Traditionally, catalytic pathways generally rely on a mono-activation model, in which a unique catalyst would interact with one single substrate, thereby lowering the energetic barrier of the reaction. While this mono-catalysis concept dominating the world of catalysis over the years, multi-catalysis concepts, including synergistic catalysis, relay catalysis, sequential catalysis, double activation catalysis and so on, have recently begun to emerge and have been used to access many difficult or unattainable transformations. Among all the multi-catalysis models, Bifunctional catalysis features a single catalyst that can activate both the electrophile and nucleophile synchronously with discrete functional groups.

The most prominent advantage of bifunctional catalysis among all multi-catalysis systems stands as its built-in compatibility of the two catalytic sites. For example, the self-quenching of a Lewis basic amine and a Lewis acidic transition-metal may cause catalyst deactivation. However, by incorporating both activation modes into one catalyst through covalent bonds could potentially solve this problem.

Enzyme Catalysis
The idea of bifunctional catalysis has its origin partially from enzyme catalysis, where multiple catalytic sites are incorporated in one single enzyme. For example, in the enzymatic hydrolysis reaction, the collaborative function of the whole enzyme pocket increased the nucleophilicity of water as well as the electrophilicity of the amide, which allows for the rapid hydrolysis.

Metal-Organo Catalysis
Another origin of the idea of bifunctional catalysis comes from the study of noncovalent interaction between catalyst and substrate, which in most case can be classified in the ‘lock and key model’. The interactions studied most are steric effects, dispersion interactions , π-π stacking and so on. Deriving from this, stronger interactions were introduced into the catalytic system, including hydrogen bonding, ion pair interaction and Lewis acid/ base interactions. Furthermore, organo catalysis, particularly enamine catalysis was also studied as an even stronger form of interaction. Most of the time, the function of the secondary interaction is simply locking the substrate in a specific configuration. In other words, this interaction works as an external directing group.

Hydrogen bonding interaction
Hydrogen-bond catalysis describes an organo catalysis typically with hydrogen bond donor as organo catalyst and hydrogen bond acceptor on substrate. Examples of these catalysts include urea, thiourea, square acid, square amide, phosphoric acid, guanidine and so on. 2015, Kanai and co-workers reported the iridium catalyzed meta C-H activation reaction using a bipyridine-urea bifunctional catalyst. Careful tuning of the linker length allows predominantly meta functionalization. It is worth mentioning that when thiourea was used as the organo catalyst instead of urea, no conversion was detected, presumably because of the strong self-quenching of the sulfur atom and Iridium catalyst, showcasing the importance of compatibility between the organo and transition metal catalytic sites.

Lewis acid/ base interaction
Similar to the enzyme catalysis system, 1999, Kanai and Shibasaki group published a aldehyde cynation reaction using TMSCN as the cyanide source. The interaction between the Lewis basic phosphine oxide and TMS group increases the nucleophilicity of CN, while the Lewis acid Aluminum activates aldehyde. By having both Lewis acid and base on the same catalyst, the two reactants were able to approach and react in an intramolecular fashion.

Ion pair interaction
Ion pair interaction is commonly seen in phase transfer catalysis. Here, the Zhang group utilized the interaction between thiourea and iminium salt to bring close the rhodium catalyst, thus realized the asymmetric hydrogenation reaction to get the chiral amine product.

Enamine catalysis
Enamine chemistry has been used in selective ketone α-functionalization throughout the decades. 2009, Zhang and co-workers developed a pyridine diamide- pyrrolidine catalyst that allows for the asymmetric aldol reaction. chiral induction model of the reaction comes from the amino acid side arm.

Heterobimetallic Catalysis
Rare earth metal and alkali metal can form bimetallic complexes which the catalysts exhibit both Lewis acidity and Brønsted basicity. In particular, heterobimetallic rare earth-alkali metal-BINOL (REMB) complexes can enable various reactions including Michael reactions, Aldol reactions, Mannich reactions and so on. By using a dinucleating Schiff base ligand, transition metal can form a bimetallic system with alkali metal which exhibit similar reactivity.

Summary
Through all the examples mentioned above, most of them includes a secondary interaction on either the metal site or the organo catalyst site, which indicates that the reaction is still on a preliminary stage. Complex reactivities have not yet been developed. In many cases, transition/ main group metal is acting as a Lewis acid. The combination of the two catalytic system is supposed to merge the various reactivity of transition metal catalysis and the easier chiral induction of organo catalysis. However, this goal is still under development for the moment.