In Situ Kinetic Studies of Reactions Involving Dirhodium(II) Donor/Acceptor Carbenes Pubblico

Abstract

The exceptional reactivity of dirhodium(II) donor/acceptor carbenes has made them key intermediates in organic synthesis. The breadth of transformations that can be conducted include C-H functionalization, ylide formation, cyclopropanation, N-H, O-H and Si-H insertion. Moreover, the advent of chiral catalysts has rendered many of these transformations asymmetric. These catalysts are extremely active and in special cases are capable of very high turnover numbers. However, the high turnover capability is very dependent on the substrates used, and a general problem is the occurrence of a major drop in the levels of enantioselectivity when low catalyst loadings are used. Research to date has not pinpointed the cause of the catalyst failure, and this seriously limits the practical utility of such an expensive catalyst and its application as an immobilized catalyst or in flow chemistry. The purpose of the work described in this thesis is to gain a better understanding of the factors that govern catalysts activity and stability, especially under high turnover conditions.The two major goals of the thesis are to (1) explore modes of catalyst deactivation/ decomposition via kinetic analysis and (2) demonstrate how kinetic understanding can aid in natural product synthesis. These goals have been undertaken through detailed kinetic analysis for three classic dirhodium(II) carbenoid reactions and application of the kinetic knowledge gained to a synthetic approach for a complex natural product. Particular interest has focused on cyclopropanation of styrene. The selectivity of this standard reaction and ability for the catalyst to achieve high turnover numbers under solvent-free conditions has been extensively studied; however, the stability of the catalyst is not well understood. A more challenging reaction, C-H insertion into activated and unactivated C-H bonds was explored because high TONs have yet to be achieved for these reactions. Si-H insertion is a reaction that has shown to be very robust for dirhodium(II) carbenoid catalysis. Therefore, understanding factors attributing the high activity of the catalyst is integral. Finally, application of the kinetic analysis to address relative rate challenges in a project directed towards the synthesis of phorbol was undertaken.

Table of Contents

TABLE OF CONTENTS

CHAPTER 1: Introduction to Dirhodium(II) Carbene Chemistry...1

1.1 Description of Chapter...1

1.2 Classes of Metallocarbenoids...2

1.3 Dirhodium (II) Catalysts...4

1.4 Reactivity of Dirhodium(II) Carbenoids...6

1.5 Site- and Chemo-selectivity of Dirhodium Donor/Acceptor Carbenoids for C-H Functionalization...8

1.6 Mechanistic Studies of Dirhodium(II) Carbenoid Carbenes...11

1.6.1 Proposed Mechanism...11

1.6.2 Isolation of the Dirhodium(II) Carbene...12

1.6.3 KIE Analysis...13

1.6.4 Hammett Analysis...15

1.6.5 Computational Analysis...17

1.6.6 Michealis-Menten Kinetics...18

1.7 Coordination to the Dirhodium Core and Catalyst Decomposition...20

1.8 Technique: Reaction Progress Kinetic Analysis...21

1.9 Description of Thesis...32

CHAPTER 2: Kinetic Studies on the Donor/Acceptor Dirhodium(II) Carbene Cyclopropanation of Styrene...42

2.1 Background...42

2.1.1 Dirhodium Catalysts High TON...43

2.2 Results...45

2.2.1 Dirhodium(II) Catalyst Screening...47

2.2.2 RPKA Studies...56

2.2.3 Mechanism and Rate Law...64

2.2.4 Reaction Calorimetry...69

2.2.5 Addition Experiments...74

2.2.6 Unusual Kinetics for methyl p-methoxy-phenyldiazoaceate...82

2.3 Discussion and Conclusions...88

2.4 Experimental...94

CHAPTER 3: Kinetic Studies on Donor/Acceptor Dirhodium(II) Carbene C-H Functionalization...112

3.1 Background...112

3.2 Results...113

3.2.1 RPKA for C-H insertion into 1,4-Cyclohexadiene...113

3.2.2 High TON for C-H Insertion into 1,4-Cyclohexadiene...122

3.2.3. Reaction Calorimetry...124

3.2.4 Bridging vs. Non Bridging Catalysts...125

3.2.5 Exploration of MK-1-235...129

3.2.6 C-H insertion into Cyclohexane...131

3.3 Discussion and Conclusions...133

3.4 Experimental...135

CHAPTER 4: Kinetic Studies on Donor/Acceptor Dirhodium(II) Carbene Si-H Insertion...144

4.1 Background...144

4.2 Project Logic...146

4.3 Results...147

4.3.1. Si-H Kinetic Studies...147

4.3.2 Reaction Calorimetry...151

4.3.3 Further Kinetic Screening for Si-H Insertion...158

4.4 Discussion and Conclusions...165

4.5 Experimental...166

CHAPTER 5: Kinetic Studies for the Dirhodium(II) Mediated Reactions of a Chemically Non-equivalent Bis-Diazo Compound...171

5.1 Background...171

5.1.1 Bis-Diazo Compounds...172

5.2 Dr. Guzman's Results...176

5.3 Goals of This Work...179

5.4 Results...180

5.4.1 Kinetic Experiments of Diazo Compounds 31, 32, 33...180

5.4.2 Competition Studies...184

5.4.3 Kinetic Studies of the Bis-Diazo Compounds...192

5.5 Discussion and Conclusions...197

5.6 Experimental...199

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School	Laney Graduate School
Department	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Parola chiave	C-H functionalization dirhodium kinetics
Committee Chair / Thesis Advisor	Davies, Huw, Emory University
Committee Members	McDonald, Frank, Emory University Blakey, Simon, Emory University

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