The present thesis work is mainly focused on the study of the influence of the Brønsted acid-base interaction on different chemical systems. In the first chapter an overview of chiral Brønsted catalysis is provided. Due to the recent publication of exhaustive reviews,1-3 this introductory chapter assumes a conceptual role, avoiding the listing of the numerous published papers on the topic. Indeed, after an overview on the synthesis of the most common acidic catalysts, only the most significant examples of their application are reported, which represent the most known modes of activation involved in this kind of catalysis. In particular, few examples of mono, dual and bifunctional activation of imines by chiral phosphoric acids are presented. The reasons for the development of other acidic functional groups are then illustrated, and an overview on the activation of other electrophiles is reported. As last part of this first chapter, the few published chemico-physical works on the topic are summarized, introducing the reader to the state of the art about: (i) the establishment of pKa scales of acidic catalysts in organic solvents; (ii) the study of the acid-base interaction through NMR techniques; (iii) the study of the nature of the interactions responsible for the stereoselectivity in chiral Brønsted acid catalysis. In chapter 2, several chemico-physical studies performed in our laboratories are presented. The exploration of the use of the NMR as an easily available and suitable tool for the assessment of pKa scales of Brønsted acids is presented. Low temperature NMR studies on acid-base pairs are then reported, which allowed to provide new insight in the understanding of the mechanism involved in the Brønsted acid activation of imines (typical substrates for chiral Brønsted acid catalysis). In the second part of chapter 2, investigations about the Brønsted catalysis law via kinetic experiments are reported. Specifically, the importance of the influence of steric effects on the catalytic activity of Brønsted acids is proved by taking into account the Friedel-Craft alkylation of N-tosylimines, a classical reaction where we have found a counterintuitive violation of the Brønsted catalysis law. Chapter 3 is centered on the synthesis of new chiral phosphoric acids. Since the development of chiral Brønsted acid catalysis, the most existing catalysts rely on the BINOL or SPINOL scaffolds. Despite their huge use and high efficiency, these catalysts are expensive and, sometimes, difficult to synthesize. On the basis of a geometry analysis, new compounds supposed to be similarly hindered to BINOL and SPINOL catalysts have been designed, and seven derivatives of a new (R,R)-diaminocyclohexane-based class of compounds have been synthesized. The obtained catalysts have been tested in two typical reactions providing promising results. On the basis of the reaction outcome, a structural analysis of the tested compounds was performed. In chapters 4 and 5 two projects that lie outside the field of Brønsted acid catalysis are presented. In the first a computational study of the proline-catalyzed aldol reaction is reported. Since the computational rationalization of this important reaction has not provided yet any good prediction of the experimentally obtained results, we introduced a new theoretical approach which allowed us to take into account not only the kinetic of the process, but also the thermodynamic properties of the catalytic system. This is particularly important in the light of several experiments that we have performed, which highlighted the thermodynamic nature of this reaction especially when electronrich ketols are formed. Indeed, this kind of compounds have shown to easily give retro-aldol reaction in the presence of proline. Thus, the inclusion of such effects in the computational model allowed us to predict, for the first time, realistic conversions and stereoselectivity. In the second side project that we have included in this thesis (chapter 5), new mechanistic studies performed on the trichlorosilane-mediated reduction of nitro groups are reported. This reaction, that we have recently published, represents the first example of metal-free reduction of nitrocompounds performed under mild conditions, and was found to be highly efficient and selective. On the basis of several experiments, we hypothesized that the evanescent species SiCl2, known to be generated under our reaction conditions, may be the actual reducing agent (especially when stabilized by a tertiary amine). Some competition experiments highlighted the nucleophilic nature of the reductant, and computational studies confirmed that the most probable reduction pathway involves the R3N-SiCl2 species. Finally, in chapter 6, the experimental details regarding all the studies reported from chapters 2 to 5 are provided.

DESIGN OF NEW CHIRAL BRØNSTED ACID CATALYSTS AND RATIONALIZATION OF H-BOND MEDIATED REACTIONS / M. Orlandi ; tutor: F. Cozzi ; cotutor: M. Ceotto ; coordinatrice: E. Licandro. - : . DIPARTIMENTO DI CHIMICA, 2015 Nov 24. ((28. ciclo, Anno Accademico 2015. [10.13130/orlandi-manuel_phd2015-11-24].

DESIGN OF NEW CHIRAL BRØNSTED ACID CATALYSTS AND RATIONALIZATION OF H-BOND MEDIATED REACTIONS

M. Orlandi
2015-11-24

Abstract

The present thesis work is mainly focused on the study of the influence of the Brønsted acid-base interaction on different chemical systems. In the first chapter an overview of chiral Brønsted catalysis is provided. Due to the recent publication of exhaustive reviews,1-3 this introductory chapter assumes a conceptual role, avoiding the listing of the numerous published papers on the topic. Indeed, after an overview on the synthesis of the most common acidic catalysts, only the most significant examples of their application are reported, which represent the most known modes of activation involved in this kind of catalysis. In particular, few examples of mono, dual and bifunctional activation of imines by chiral phosphoric acids are presented. The reasons for the development of other acidic functional groups are then illustrated, and an overview on the activation of other electrophiles is reported. As last part of this first chapter, the few published chemico-physical works on the topic are summarized, introducing the reader to the state of the art about: (i) the establishment of pKa scales of acidic catalysts in organic solvents; (ii) the study of the acid-base interaction through NMR techniques; (iii) the study of the nature of the interactions responsible for the stereoselectivity in chiral Brønsted acid catalysis. In chapter 2, several chemico-physical studies performed in our laboratories are presented. The exploration of the use of the NMR as an easily available and suitable tool for the assessment of pKa scales of Brønsted acids is presented. Low temperature NMR studies on acid-base pairs are then reported, which allowed to provide new insight in the understanding of the mechanism involved in the Brønsted acid activation of imines (typical substrates for chiral Brønsted acid catalysis). In the second part of chapter 2, investigations about the Brønsted catalysis law via kinetic experiments are reported. Specifically, the importance of the influence of steric effects on the catalytic activity of Brønsted acids is proved by taking into account the Friedel-Craft alkylation of N-tosylimines, a classical reaction where we have found a counterintuitive violation of the Brønsted catalysis law. Chapter 3 is centered on the synthesis of new chiral phosphoric acids. Since the development of chiral Brønsted acid catalysis, the most existing catalysts rely on the BINOL or SPINOL scaffolds. Despite their huge use and high efficiency, these catalysts are expensive and, sometimes, difficult to synthesize. On the basis of a geometry analysis, new compounds supposed to be similarly hindered to BINOL and SPINOL catalysts have been designed, and seven derivatives of a new (R,R)-diaminocyclohexane-based class of compounds have been synthesized. The obtained catalysts have been tested in two typical reactions providing promising results. On the basis of the reaction outcome, a structural analysis of the tested compounds was performed. In chapters 4 and 5 two projects that lie outside the field of Brønsted acid catalysis are presented. In the first a computational study of the proline-catalyzed aldol reaction is reported. Since the computational rationalization of this important reaction has not provided yet any good prediction of the experimentally obtained results, we introduced a new theoretical approach which allowed us to take into account not only the kinetic of the process, but also the thermodynamic properties of the catalytic system. This is particularly important in the light of several experiments that we have performed, which highlighted the thermodynamic nature of this reaction especially when electronrich ketols are formed. Indeed, this kind of compounds have shown to easily give retro-aldol reaction in the presence of proline. Thus, the inclusion of such effects in the computational model allowed us to predict, for the first time, realistic conversions and stereoselectivity. In the second side project that we have included in this thesis (chapter 5), new mechanistic studies performed on the trichlorosilane-mediated reduction of nitro groups are reported. This reaction, that we have recently published, represents the first example of metal-free reduction of nitrocompounds performed under mild conditions, and was found to be highly efficient and selective. On the basis of several experiments, we hypothesized that the evanescent species SiCl2, known to be generated under our reaction conditions, may be the actual reducing agent (especially when stabilized by a tertiary amine). Some competition experiments highlighted the nucleophilic nature of the reductant, and computational studies confirmed that the most probable reduction pathway involves the R3N-SiCl2 species. Finally, in chapter 6, the experimental details regarding all the studies reported from chapters 2 to 5 are provided.
COZZI, FRANCO
LICANDRO, EMANUELA
Organocatalysis; Bronsted acids; trichlorosilane; computational studies; proline catalyzed aldol reaction; nitro groups reduction
Settore CHIM/06 - Chimica Organica
CENTRO INTERDIPARTIMENTALE GRANDI APPARECCHIATURE CIGA
DESIGN OF NEW CHIRAL BRØNSTED ACID CATALYSTS AND RATIONALIZATION OF H-BOND MEDIATED REACTIONS / M. Orlandi ; tutor: F. Cozzi ; cotutor: M. Ceotto ; coordinatrice: E. Licandro. - : . DIPARTIMENTO DI CHIMICA, 2015 Nov 24. ((28. ciclo, Anno Accademico 2015. [10.13130/orlandi-manuel_phd2015-11-24].
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/330245
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