Linear Free Energy Relationships in the Rational Design of Novel Chiral Catalysts in Catalysis via Dioxiranes and Primary Amines

• Grant number: 25/19628-7
• Support Opportunities: Scholarships in Brazil - Master
• Start date: October 01, 2025
• End date: September 30, 2027
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Bruno Matos Paz
• Grantee: Álvaro Tobias Gonçalves de Almeida e Silva
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 22/14310-0 - Linear Free Energy Relationships in Asymmetric Catalysis, AP.JP

Abstract

This master's project aims at the rational design of new chiral organocatalysts and the detailed understanding of their mechanisms of action, integrating three complementary fronts: aminocatalysis, dioxirane-based catalysis, and kinetic monitoring by ¹¿F NMR. The proposal relies on the application of linear free energy relationships (LFERs) to correlate electronic and structural effects of the catalysts with catalytic performance parameters, moving toward the predictive design of more selective and efficient systems.In the first approach, primary amine-type catalysts inspired by privileged structures will be studied, including derivatives of ¿,¿-diaryl-¿-siloxy diamines and functional heterocycles. Structural modifications in both the backbone and side chains will allow the exploration of steric, electronic, and acid-base (pKaH) effects on reactivity and stereoselectivity. The goal is to overcome known limitations of traditional aminocatalysts toward ¿-branched aldehydes and ketones, establishing Hammett correlations between substituents and performance metrics such as turnover number (TON), turnover frequency (TOF), and enantio- and diastereoselectivity.In the second approach, chiral ketones for asymmetric epoxidation via dioxiranes will be developed, starting from fructose-derived scaffolds and benzophenones bearing electron-donating or electron-withdrawing substituents. The systematic introduction of these groups will enable the construction of LFERs, correlating electronic properties with the reactivity and selectivity of the epoxidation step. This study aims to enhance the applicability of the Shi catalyst and its analogues, expanding their efficiency in challenging olefins and providing general principles for the design of new dioxirane-based catalytic systems.In the third approach, ¹¿F NMR spectroscopy will be applied as a kinetic tool to monitor in real time the consumption of substrates and the formation of intermediates and fluorinated products in model reactions. The high sensitivity and selectivity of the technique will allow the identification of transient species, elucidation of rate-determining steps, and experimental validation of correlations proposed in Hammett studies. Thus, ¹¿F NMR will provide direct support for mechanistic understanding and contribute to the consolidation of more robust structure-reactivity models in organocatalysis.Taken together, this project seeks to overcome the problem of high catalyst loadings (10-20%) still required in organocatalysis, moving toward more selective, efficient, and applicable systems. Beyond the scientific contribution to the understanding of fundamental mechanisms, the results are expected to have a significant impact on the synthesis of bioactive molecules, consolidating the proposal as a rational foundation for the development of broadly applicable enantioselective methodologies.