“ON WATER” WITTIG REACTION LABORATORY EXPERIMENT AND THE DEVELOPMENT OF AN “ON WATER” CATALYTIC WITTIG REACTION _______________ A Thesis Presented to the Faculty of San Diego State University _______________ In Partial Fulfillment of the Requirements for the Degree Master of Science in Chemistry _______________ by Lucas Brett Fallot Spring 2014 iii Copyright © 2014 by Lucas Brett Fallot All Rights Reserved iv DEDICATION This thesis is dedicated to my beloved family; Laura, Autumn and Preston. You follow me to the ends of the earth and unconditionally support me through whatever I do. Thank you for believing in me. v ABSTRACT OF THE THESIS “On Water” Wittig Reaction Laboratory Experiment and the Development of an “On Water” Catalytic Wittig Reaction by Lucas Brett Fallot Master of Science in Chemistry San Diego State University, 2014 I. “On Water” Wittig Reaction Laboratory Experiment The aqueous Wittig reaction is a suitable undergraduate experiment which allows for instructors to effectively and very quickly demonstrate and promote a greener alternative of an alkene synthesis in the organic chemistry teaching laboratory. There is an opportunity for students to compare previously reported Wittig reaction approaches and evaluate those with the green “on water” type Wittig reaction methodology. II. Development of an “On Water” Catalytic Wittig Reaction The achievement of an “on water” catalytic Wittig reaction is the next big step in making the Wittig reaction greener. Employing the normal phosphine oxide by-product of the Wittig reaction as the catalyst will improve the reactions overall atom economy. The development of an “on water” catalytic Wittig reaction using triphenylphosphine oxide and 3-methyl-1-phenylphospholane oxide is reported. 3-Methyl-1-phenylphospholane oxide compared to triphenylphosphine oxide is a more promising catalyst to achieve an “on water” catalytic Wittig reaction because it reduces more easily. vi TABLE OF CONTENTS PAGE ABSTRACT ...............................................................................................................................v LIST OF TABLES ................................................................................................................... ix LIST OF FIGURES ...................................................................................................................x LIST OF ABBREVIATIONS ................................................................................................ xiii ACKNOWLEDGMENTS ..................................................................................................... xiv CHAPTER 1 “ON WATER” WITTIG REACTION LABORATORY EXPERIMENT ....................1 1.1 Introduction ........................................................................................................1 1.2 Previous Wittig Reaction Protocols ...................................................................3 1.2.1 Hazardous Reagent Wittig Reaction Protocols .........................................3 1.2.2 Phase Transfer Catalysis ...........................................................................5 1.2.3 “Instant Ylid” ............................................................................................5 1.2.4 Solvent-Free Wittig Reactions ..................................................................6 1.2.4.1 Ball Milling ......................................................................................6 1.2.4.2 Mortar and Pestle .............................................................................8 1.2.5 Microwave Assisted Experiments .............................................................9 1.2.5.1 Household Microwave .....................................................................9 1.2.5.2 Laboratory Grade Microwave Reactor ..........................................10 1.2.6 Stabilized Ylide Wittig Reaction ............................................................11 1.3 “On Water” Wittig Reaction Laboratory Experiment .....................................11 1.3.1 Experimental Procedure ..........................................................................12 1.3.2 Results and Discussion ...........................................................................15 1.3.3 Hazards of the Experiment ......................................................................18 1.4 Laboratory Experiment Comparison ................................................................18 1.5 Conclusion .......................................................................................................20 2 THE ATTEMPTED DEVELOPMENT OF AN “ON WATER” CATALYTIC WITTIG REACTION ..................................................................................................21 vii 2.1 Introduction ......................................................................................................21 2.2 Use of Triphenylphosphine Oxide ...................................................................21 2.2.1 Standard Wittig Reaction Using Ph3P in Organic Solvent .....................23 2.2.2 Reduction Protocols for Ph3PO ...............................................................24 2.2.2.1 Metal Hydrides...............................................................................24 2.2.2.2 Hydrosilanes and a Titanium Catalyst ...........................................24 2.2.2.3 Phosphoric Acid Derivative with a Silane .....................................25 2.2.2.4 Benzoic Acid Derivative with a Silane ..........................................26 2.2.3 Work Towards a Catalytic Wittig Reaction in Organic Solvent .............29 2.2.3.1 Wittig Reaction and Beller Reduction Protocol .............................29 2.2.3.2 O’Brien Catalytic Wittig Reaction in Organic Solvents ................32 2.2.3.3 Catalytic Wittig Reaction Attempt Using O’Brien’s Protocol with Diphenylsilane and Sodium Carbonate ...................33 2.2.4 “On Water” Reduction Protocols for Ph3PO ..........................................34 2.2.5 “On Water” Catalytic Wittig Reaction Attempt Using Ph3PO ...............37 2.3 Use of 3-methyl-1-phenylphospholane Oxide .................................................38 2.3.1 Standard “On Water” Wittig Reaction Using 3-methyl-1- phenylphospholane .................................................................................39 2.3.2 “On Water” Reduction of 3-methyl-1-phenylphospholane oxide with Ph2SiH2 ...........................................................................................39 2.3.3 “On Water” Catalytic Wittig Reaction Attempts Using 3-methyl- 1-phenylphospholane oxide ....................................................................40 2.4 Future Work for the Development of an “On Water” Catalytic Wittig Reaction ...........................................................................................................43 2.5 Conclusion .......................................................................................................46 3 THE EXPERIMENTAL PART ...................................................................................47 3.1 General .............................................................................................................47 3.2 “On Water” Wittig Reaction Experiment ........................................................47 3.3 Attempted Catalytic Wittig Reaction Experiments Using Ph3P and Ph3PO ...............................................................................................................48 3.3.1 Standard Wittig Reaction Using Ph3P in Organic Solvent .....................48 3.3.2 Reduction of Ph3PO in Organic Solvent .................................................48 3.3.3 Compatibility Test of Standard Wittig Reaction and Beller Reduction Protocol ..................................................................................49 viii 3.3.4 Experiments to Develop a Catalytic Wittig Reaction in Organic Solvent ....................................................................................................49 3.3.5 Attempted Catalytic Wittig Reaction Experiment Using Ph3PO in Organic Solvents Without NEt3 ..............................................................50 3.3.6 Standard Wittig Reaction Experiment Using Diethoxymethylsilane and Ph3P ..............................................................50 3.3.7 Attempted Catalytic Wittig Reaction Using O’Brien’s Protocol, Sodium Carbonate, and Ph3PO ...............................................................51 3.3.8 “On Water” Reduction of Ph3PO ............................................................51 3.3.9 Reduction of Ph3PO in 15% DMSO and Water ......................................52 3.3.10 Attempted Catalytic Wittig Reaction in Water Using 5% DMSO, NaCO3, Ph3PO, and Ph2SiH2 .....................................................52 3.4 Experimental Work Towards an “On Water” Catalytic Wittig Reaction Using 3-methyl-1-phenylphospholane oxide ...................................................53 3.4.1 Optimized O’Brien Catalytic Wittig Reaction in Toluene .....................53 3.4.2 “On Water” Wittig Reaction Using 3-methyl-1- phenylphospholane .................................................................................53 3.4.3 “On Water” Reduction of 3-methyl-1-phenylphospholane oxide ..........54 3.4.4 Attempted “On Water” Catalytic Wittig Reaction using Optimized O’Brien Catalytic Wittig Reaction Protocol .........................54 3.4.5 Attempted “On Water” Catalytic Wittig Reactions Using 3- methyl-1-phenylphospholane oxide