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Full Thesis Corrections V3 REGIOSELECTIVE RHODIUM-CATALYZED ALKYNE HYDROTHIOLATION WITH ALKANE THIOLS: SUBSTRATE SCOPE AND MECHANISTIC INVESTIGATIONS by SHIVA SHOAI B.Sc. (Hon), The University of British Columbia, 2002 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) July 2010 © Shiva Shoai, 2010 Abstract The optimization and substrate scope of ClRh(PPh3)3-catalyzed alkyne hydrothiolation with alkane thiols producing E-linear vinyl sulfides is presented. The reactions generally proceed in good yields with good selectivities for a variety of alkane thiols and alkynes. Bulky aliphatic alkynes result in the best selectivity, while aryl alkynes with para-substituted electron donating groups give the best yields. The presence of coordinating functional groups in either the substrate or solvent negatively affects the reaction both in yield and selectivity. Deuterium-labeling studies indicate that the reaction proceeds via thiol oxidative addition, migratory alkyne insertion into the Rh-H bond, followed by reductive elimination. Investigations into the mechanism of Tp*Rh(PPh3)2-catalyzed alkyne hydrothiolation are discussed. Five mechanisms are identified as being the most likely for this process; experiments were designed to support or refute each of these possibilities. Two mechanisms are definitively dismissed and another is dismissed as highly unlikely. The results cannot distinguish between the remaining two. The product distribution of hydrothiolation is analyzed and compared to other precatalysts. Stoichiometric reactivity of Tp*Rh(PPh3)2 with benzyl thiol is presented. Two new complexes, proposed to be Tp*Rh(PPh3)2(HSBn) and Tp*Rh(H)(SBn)(PPh3), are generated. Presumed Tp*Rh(H)(SBn)(PPh3), prepared in situ, does not catalyze alkyne hydrothiolation. Kinetic analysis was complicated by reaction inhibition at high thiol concentrations and competing side-reactions at high alkyne concentrations. Kinetic isotope effect experiments indicate that the alkyne is not involved in the rate-determining step; however, differences in the reactivity of several para-substituted phenyl acetylenes suggest that the rate-determining step is influenced by alkyne electronics. Overall, the reaction appears to obey the following rate law under normal catalytic reaction conditions 1 1 0 rate = k[Tp*Rh(PPh3)2] [thiol] [alkyne] . The reaction is hypothesized to proceed by thiol oxidative addition, migratory alkyne insertion into the Rh-S bond, followed by reductive elimination. ii Table of Contents Abstract ..........................................................................................................................ii Table of Contents...........................................................................................................iii List of Tables..................................................................................................................v List of Figures................................................................................................................vi List of Abbreviations.....................................................................................................vii Acknowledgements........................................................................................................xi 1 Chapter 1: Introduction ...................................................................................................1 1.1 Importance of Sulfur Containing Molecules........................................................1 1.1.1 Vinyl Sulfides..........................................................................................3 1.2 Hydrothiolation ..................................................................................................5 1.2.1 Nucleophilic Hydrothiolation...................................................................5 1.2.2 Radical Hydrothiolation ...........................................................................6 1.3 Transition-Metal-Catalyzed Hydrothiolation.......................................................8 1.3.1 Early Work ..............................................................................................9 1.3.2 Linear Vinyl Sulfides............................................................................. 12 1.3.3 Branched Vinyl Sulfides ........................................................................ 14 1.3.4 Intramolecular Alkyne Hydrothiolation.................................................. 19 1.3.5 Alkene Hydrothiolation.......................................................................... 20 1.3.6 RS-G Additions ..................................................................................... 21 1.3.7 Summary of Successes and Failures of Alkyne Hydrothiolation............. 23 1.4 Hydrothiolation Mechanisms............................................................................ 24 1.5 Scope of Thesis ................................................................................................ 31 2 Chapter 2: ClRh(PPh3)3-Catalyzed Alkyne Hydrothiolation with Alkane Thiols............ 32 2.1 Introduction...................................................................................................... 32 2.2 Results and Discussion ..................................................................................... 34 2.2.1 Optimization .......................................................................................... 36 2.2.2 Substrate Scope...................................................................................... 39 2.2.3 Mechanistic Studies ............................................................................... 51 2.3 Conclusions...................................................................................................... 56 2.4 Experimental .................................................................................................... 57 2.4.1 General Procedures ................................................................................ 57 2.4.2 Materials and Methods........................................................................... 57 2.4.3 General Experimental Procedure for Hydrothiolation............................. 58 2.4.4 Analytical data for hydrothiolation products........................................... 59 iii 3 Chapter 3: Mechanism of Tp*Rh(PPh3)2-Catalyzed Alkyne Hydrothiolation................. 65 3.1 Introduction...................................................................................................... 65 3.1.1 S-H Activation Followed by Alkyne Insertion into the Rh-H Bond ........ 69 3.1.2 S-H Activation Followed by Alkyne Insertion into the Rh-S Bond......... 71 3.1.3 Disulfide Intermediate............................................................................ 73 3.1.4 C-H Activation....................................................................................... 75 3.1.5 Transition-Metal-Assisted Nucleophilic Attack...................................... 76 3.1.6 Summation of Mechanistic Possibilites .................................................. 77 3.2 Results and Discussion ..................................................................................... 78 3.2.1 Product Analysis.................................................................................... 78 3.2.1.1 Syn vs Anti Addition.......................................................................... 80 3.2.1.2 Minor Products................................................................................... 81 3.2.1.3 Diene Byproduct ................................................................................ 85 3.2.1.4 Vinyl Disulfides................................................................................. 89 3.2.1.5 Summary of Product Analysis............................................................ 91 3.2.2 Stoichiometric Reactions........................................................................ 92 3.2.3 Kinetic Analysis................................................................................... 108 3.2.4 Substrate Scope Analysis ..................................................................... 115 3.2.4.1 Substrate Compatibility.................................................................... 115 3.2.4.2 Arene Thiols .................................................................................... 117 3.3 Conclusions.................................................................................................... 119 3.4 Experimental .................................................................................................. 121 3.4.1 General Procedures .............................................................................. 121 3.4.2 Materials and Methods......................................................................... 121 3.4.3 General Experimental Procedures for Hydrothiolation and Stoichiometric Reactions .......................................................................... 122 3.4.4 General Experimental Procedures for Kinetic Studies .......................... 128 4 Chapter 4: Conclusions and Future Work.................................................................... 131 4.1 Conclusions.................................................................................................... 131 4.2 Future Work ................................................................................................... 133 5 References .................................................................................................................
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