Despite the widespread interest in organocatalysis and the large number of new catalytic systems that are continuously being discovered, progress in the understanding of mechanism and catalyst design in the field of hydrogen-bond catalysis is extremely limited. Compared to a more developed field like palladium-catalyzed coupling reactions, hydrogen-bond catalysis presents many challenges that have not yet been successfully tackled.
*Turnover: While palladium-catalyzed reactions can often be effective with catalyst loading of less than 0.1 mol%, hydrogen-bond catalysts are often added in more than 10 mol%. Poor rate acceleration is a general trend that will have to be overcome in order for hydrogen-bond catalysis to be a practical synthetic strategy.
*Mechanism: In the future, further investigation of the precise steps involved in the mechanism of hydrogen-bond catalysis will be required that will enable chemists to rationally design catalytic strategies for more complex or more useful transformations. For comparison, the basic steps of palladium-catalyzed cross coupling have been systematically and thoroughly studied over the last few decades and have led to dramatic advances in catalytic scope, control and reaction design principles. For example, improved understanding of oxidative addition has led to aryl chlorides becoming practical coupling partners, while improved understanding of reductive elimination has led to the development of new reactions involving sp centers. Knowing these fundamental catalytic steps, the ability to rationally plan new reactions and cascades has been extremely useful in the field of total synthesis. In contrast, we lack a general, systematic mechanistic understanding of the steps of hydrogen-bond catalysis and how to influence them. Detailed mechanistic studies have so far been limited to individual systems, and their findings have not been of demonstrable predictive use.
*Catalyst: A related challenge is the investigation of how changes in catalyst, structural, conformational, and electronic can be used to rationally influence the reaction. The goal would be to fully understand how to use multiple co-operative interactions to best accelerate a reaction and impart selectivity. Ideally, rational catalyst design will eventually replace screening of families of catalysts and the choice of building blocks will become more systematic.
*Scope: While new reactions are constantly being discovered, most reactions have extremely narrow substrate scope and the reason for such narrow scope is often not understood. In the field of palladium catalysis, after the foundations of mechanistic understanding were established, the scope of reactions saw rapid growth. Knowing the factors that affected each step of catalysis allowed for the chemists to envision and pursue new reactions of high synthetic utility, such as C-H bond activation reactions. In the field hydrogen-bond catalysis, chemists have not yet reached a stage where new types of reactivity can be easily and systematically targeted. At this point, reaction discovery is useful, but more detailed mechanistic study is required to realize the full potential of hydrogen-bond catalysis.