Modern mechanistic studies for rational catalyst design
Final Report Summary - MOMES (Modern mechanistic studies for rational catalyst design)
Catalysis plays a central role in chemistry because it allows more sustainable and environmentally friendly chemical processes. Historically, chemists have used metal-based compounds as reaction promoters. However, in the last fifteen years, the use of pure organic molecules as catalysts has been established as a successful alternative approach, overcoming some of the common disadvantages found in organometallic catalysis, such as cost, toxicity, and catalysts’ instability. For these reasons, organocatalysis, and in particular, aminocatalysis, has experienced an impressive growth since its advent. Although a large number of new methodologies have been discovered using this strategy, the vast majority of them have used an empirical approach based on large screenings, and the accurate understanding of the reaction mechanisms have been neglected and usually misunderstood.
Therefore, the general aim of this project has been the rational improvement and design of aminocatalytic processes based on the accurate study of the reaction mechanisms. Prior to the beginning of the project, aminocatalytic downstream intermediates were identified as key elements that control the selectivity outcome in these kinds of transformations. The present two-years project has gained insights into the kinetic and thermodynamic properties of these systems, leading to three new works with high potential at both academic and industrial level.
1. Deciphering the role of multiple additives in organocatalyzed Michael addition.
Primary amine-thioureas (PAT) catalysts are widely used to activate ketones as nucleophiles in the Michael addition to electron-poor olefins, because of their easy preparation, versatility and effectiveness. Besides the catalytic bifunctional scaffold, the role of water and acid additives have a fundamental impact in the reactivity and selectivity, but remained unclear.
We have demonstrated that acid provides turnover to the PAT catalysts, promoting the hydrolysis of the product imine (A). If not present, the product imine (A) attacks another molecule of nitroalkene, generating the double addition product imine (B). Therefore, acid also prevents the formation of the undesired double addition side product. On the other hand, water prevents catalyst deactivation by polymerization of the catalytic intermediates (A or B) with the nitroalkene, and stabilize the productive reaction pathway. Therefore, although water slows down the reaction, it allows a final higher product conversion.