“on water” wittig reaction laboratory experiment

“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.

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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 and Na2CO3/NaHCO3 ....................55

3.4.6 Attempted “On Water” Catalytic Wittig Reactions Using O’Brien’s Protocol and Tertiary Nitrogen Bases ....................................55

3.4.7 Initial Optimization Attempts of Experiment 2.31 .................................56

3.4.8 Optimization Attempts of Experiment 2.31 with Greater Equivalents of Methyl Bromoacetate ......................................................56

REFERENCES ........................................................................................................................58

APPENDIX

A JOURNAL OF CHEMICAL EDUCATION “ON WATER” WITTIG REACTION LABORATORY EXPERIMENT SUBMISSION .................................62

B 1H NMR, AND 31P NMR OF REACTIONS ...............................................................68

ix

LIST OF TABLES

PAGE

Table 1.1. Ball-Milling Wittig Reactions ..................................................................................7

Table 1.2. Equipment for “On Water” Wittig Reaction Experiment .......................................13

Table 1.3. Cost, Yield and Reaction Time Comparison of Wittig Reaction Experiments .................................................................................................................19

Table 2.1. Reduction of Ph3PO with TMDS and Ti(OiPr)4 .....................................................25

Table 2.2. Beller Reduction Protocol .......................................................................................26

Table 2.3. O’Brien Reduction Protocol ...................................................................................28

Table 2.4. O’Brien’s Catalytic Wittig Reactions in Organic Solvents ....................................33

Table 2.5. Silane in the Presence of Water ..............................................................................35

Table 2.6. Microwave Reduction of Ph3PO in Water ..............................................................36

x

LIST OF FIGURES

PAGE

Figure 1.1. Twelve principles of green chemistry. ....................................................................2

Figure 1.2. Wittig reaction using a lachrymator and a pyrophoric base. ...................................3

Figure 1.3. Wittig reaction using a pyrophoric starting material. ..............................................4

Figure 1.4. Wittig reaction using sodium hydride. ....................................................................4

Figure 1.5. Phase transfer catalysis using a 50% sodium hydroxide solution. ..........................5

Figure 1.6. “Instant Ylid” Wittig reaction. ................................................................................6

Figure 1.7. Ball-milling Wittig reactions. ..................................................................................7

Figure 1.8. Ball-milling one-pot Wittig reaction. ......................................................................7

Figure 1.9. Mortar and pestle Wittig reaction. ...........................................................................8

Figure 1.10. Domestic household microwave Wittig reaction. .................................................9

Figure 1.11. Microwave reactor Wittig reaction. .....................................................................10

Figure 1.12. Stabilized ylide Wittig reaction. ..........................................................................11

Figure 1.13. “On water” Wittig reaction experiment. ..............................................................11

Figure 1.14. Experiment set-up. ...............................................................................................14

Figure 1.15. Product 1H NMR of (E/Z)-ethyl cinnamate. ........................................................16

Figure 1.16. Starting material 1H NMR of triphenylphosphine. ..............................................17

Figure 1.17. Starting material 1H NMR of ethyl bromoacetate. ..............................................17

Figure 1.18. Starting material 1H NMR of benzaldehyde. .......................................................17

Figure 2.1. Four steps of a catalytic Wittig reaction. ...............................................................22

Figure 2.2. Catalytic Wittig reaction with tributylarsenic. ......................................................22

Figure 2.3. Catalytic Wittig reaction using a tellurium compound. .........................................23

Figure 2.4. Standard Wittig using Ph3P in organic solvent. .....................................................23

Figure 2.5. Reduction of Ph3PO with TMDS and Ti(OiPr)4. ...................................................24

Figure 2.6. Beller reduction protocol. ......................................................................................26

Figure 2.7. Proposed Beller reduction mechanism of Ph3PO. .................................................27

Figure 2.8. O’Brien reduction protocol ....................................................................................27

Figure 2.9. Reduction study of Ph3PO using Ph2SiH2 and 4-nitrobenzoic acid. .....................29

xi

Figure 2.10. Compatibility test of standard Wittig reaction and Beller reduction protocol. ..............................................................................................................30

Figure 2.11. Catalytic Wittig reaction using Ph3PO in toluene. ..............................................30

Figure 2.12. Catalytic Wittig using diphenylsilane and diphenylphosphate. ..........................31

Figure 2.13. Catalytic Wittig reaction using 50 mol % of diphenylphosphate. .......................31

Figure 2.14. Catalytic Wittig reaction without the use of NEt3. ..............................................31

Figure 2.15. Standard Wittig reaction with Ph3P and (EtO)2MeSiH. ......................................32

Figure 2.16. O’Brien’s catalytic Wittig reactions in organic solvents. ....................................33

Figure 2.17. Catalytic Wittig reaction with Ph3PO in toluene. ................................................34

Figure 2.18. Greaney’s one-pot silyl-Reformatsky olefination. ..............................................35

Figure 2.19. Microwave reduction of Ph3PO in water. ............................................................36

Figure 2.20. Ph3PO reduction in 15% DMSO and water. ........................................................37

Figure 2.21. Attempted “on water” catalytic Wittig reaction with DMSO. ............................37

Figure 2.22. O’Brien et al. catalytic Wittig reaction in toluene. ..............................................38

Figure 2.23. Optimized O’Brien catalytic Wittig reaction in toluene. .....................................39

Figure 2.24. “On water” Wittig reaction using 3-methyl-1-phenylphospholane. ....................39

Figure 2.25. “On water” reduction of 3-methyl-1-phenylphospholane oxide. ........................40

Figure 2.26. Catalytic “on-water” Wittig with 3-methyl-1-phenylphospholane oxide. ..........40

Figure 2.27. Attempted “on water” catalytic Wittig experiments with Na2CO3 and NaHCO3. .............................................................................................................41

Figure 2.28. Attempted “on water” catalytic Wittig reactions with tertiary nitrogen bases. ...................................................................................................................42

Figure 2.29. Initial optimization attempts of reaction 2.31. .....................................................42

Figure 2.30. Reaction 2.31 with greater equivalents of methyl bromoacetate. .......................43

Figure 2.31. Side reaction of methyl bromoacetate with base and water. ...............................44

Figure 2.32. Reduction side reaction of methyl bromoacetate with diphenylsilane and water. ...................................................................................................................45

Figure B.1. 1H NMR of reaction 1.1. .......................................................................................69


Figure B.3. 31P NMR of reaction 2.5. ......................................................................................71




xii



Figure B.9. 1H NMR of reaction 2.10. .....................................................................................77

Figure B.10. 1H NMR of reaction 2.11. ...................................................................................78


Figure B.12. 31P NMR of reaction 2.21. ..................................................................................80





Figure B.17. 31P NMR of 3-methyl-1-phenylphospholane oxide. ...........................................85

Figure B.18. 31P NMR of reaction 2.25. ..................................................................................86











xiii

LIST OF ABBREVIATIONS

DCM Dichloromethane

DIPEA Diisopropylethylamine

DMAP Dimethylaminopyridine

DMF Dimethylformamide

DMSO Dimethylsulfoxide

NMR Nuclear Magnetic Resonance

PMHS Polymethylhydrosiloxane

RT Room Temperature

THF Tetrahydrofuran

TMDS Tetramethyldisiloxane

xiv

ACKNOWLEDGMENTS

First and foremost, I would like to thank God for giving my family and I the strength

to endure all of the obstacles we had to face during our time in San Diego. I would like to say

thank you to Dr. Bergdahl for the opportunity to work in his lab and for providing me with an

exceptional research idea for my thesis. I am very proud to say I received my practical

experience of working in an organic chemistry lab from the Bergdahl group! Thank you to all

of the members of the Bergdahl crowd; your patience, wisdom and kindness never ceased to

amaze me. You all contributed greatly to my education and I am forever grateful to have

worked with you and more importantly, call you friends. I would also like to thank all of the

chemistry department staff and faculty at San Diego State University for providing a top-

notch chemistry curriculum. I feel as though I am leaving school with a well-rounded

knowledge of chemistry that will help me to instruct cadets at my following assignment at

West Point. Thank you to Dr. LeRoy Lafferty for teaching me how to operate the NMR

equipment, for aiding me when I needed help and for his countless efforts to maintain the

NMR equipment. Lastly, I would like to make a special thank you to Michael Kelly for

taking me under his wing and helping me every step of the way; even to the emergency

room. His selflessness and goodwill to all whom he encounters is unparalleled. I am forever

grateful for the time and effort he dedicated to help me in the lab.

1

CHAPTER 1

“ON WATER” WITTIG REACTION

LABORATORY EXPERIMENT

1.1 INTRODUCTION

There is ample evidence that the scale and very nature of industrial activity has

permanently changed the chemical dynamics of “stable” systems in nature.1 Environmental

issues that arise due to industrial activity include climate change, stratospheric ozone

depletion, photochemical ozone formation, acidification, and eutrophication.2 Population

growth along with an increased demand of industrial materials has led to an increase of

requirements for natural and synthetic materials. The scale and accelerating rate of change

results in activity and waste streams that disrupt and degrade natural systems worldwide—the

very systems that provide critical services on which society and the economy depend on like

healthy air, clean energy, productive soil and safe food.1

Sustainability is a global concept to achieve a balance between environmental,

economic and social realms of society in order to ensure the development of the present does

not impede the development of future generations.2 Though there are many ways to prevent

pollution, green chemistry is an approach that chemists can take to change chemical

processes so they are of less risk to human health and to improve the balance of

environmental sustainability.3 The concepts of sustainability and green chemistry must be

heavily integrated into the scientific community so that there may be a paradigm shift in

industry to move away from dangerous pollute-then-clean up practices.4

Although, sustainability and environmental protection are two critical issues in our

society, greener practices have only been slowly adopted in the organic chemistry teaching

laboratory. Often, especially at the undergraduate level, many laboratory procedures have

minor changes from those of fifty years ago. In order to increase awareness and adoption of

practical greener chemistry in the future, it is essential to positively inform students early in

their education about the alternatives possible for more environmentally-friendly chemistry.4

2

Educators can use the Wittig reaction along with the Twelve Principles of Green Chemistry

as a way to simplify the concept of green chemistry and use it as a model to practically

demonstrate it (Figure 1.13).

Figure 1.1. Twelve principles of green chemistry. Source: Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New York, 1998; p 30.

The Wittig reaction is a fundamental introductory organic chemistry reaction used to

produce an alkene from the reaction of a phosphonium ylide with a carbonyl compound.5 The

Wittig reaction can be used to promote practical greener chemistry by way of replacing

organic solvents with water. Water is by its very nature nontoxic, cost-effective and less-

harmful to the environment than the organic solvents traditionally used when conducting the

Wittig reaction. It also represents the outside-the-box thinking that will be necessary for a

more-sustainable approach to common chemical problems without diminishing the larger

lesson: the fundamental utility of the Witting reaction. The positive influence of the Twelve

3

Principles of Green Chemistry along with the Wittig reaction will help convince students

early-on in their education to buy-in to green chemistry, and later in their professional

careers, to help positively influence industry to achieve green sustainability goals and in turn,

protect our world’s natural systems for future generations.

1.2 PREVIOUS WITTIG REACTION PROTOCOLS

In order to best demonstrate the necessary thinking for the implementation of greener

solutions to common chemical problems, it is helpful to first examine and compare some

traditional Wittig reaction protocols from literature. Variations of the Wittig reaction can be

found in many laboratory textbooks as well as in the Journal of Chemical Education.

Among these sources, none demonstrate that a simple Wittig reaction can be done in water in

a way that can be easily and practically conducted by undergraduate students in an organic

chemistry teaching laboratory.

1.2.1 Hazardous Reagent Wittig Reaction Protocols

In some of these early reported experiments, pyrophoric reagents like butyllithium

(Figure 1.2), acutely toxic and flammable reagents like triethylphosphite (Figure 1.3) and

lacrymators, for instance benzyl chloride, are used in order to make an unstable ylide.6,7 One

case in particular reports the use of sodium hydride (Figure 1.4), which appears unsuitable as

a reagent in an undergraduate teaching laboratory because of its pyrophoric properties.8 Even

more startling, in a commonly used textbook today, one Wittig reaction protocol calls for the

use of sodium metal to make the strong base sodium ethoxide.9

Figure 1.2. Wittig reaction using a lachrymator and a pyrophoric base.

4

Figure 1.3. Wittig reaction using a pyrophoric starting material.

Figure 1.4. Wittig reaction using sodium hydride.

In accordance with The Twelve Principles of Green Chemistry, the use of harmful

substances like toxic solvents, pyrophoric reagents and lachrymators should be minimized or

replaced where possible and practical. In addition, for obvious safety concerns, the use of

many of these reagents is wholly unnecessary, and requires laboratories to be equipped with

inert gas support and special waste bins, both factors which can increase the cost and reduce

the practicality of the execution of the experiments in a teaching laboratory. The use of

dangerous substances can require precious lab time for special student training. For example,

in using these harmful reagents, more work is placed on the undergraduate students to rinse

the syringe with concentrated ammonium hydroxide after using a lachrymator and rinse the

syringe with hexanes after using a pyrophoric base. In terms of special training, students have

to be instructed the importance of setting up a reaction vessel that eliminates moisture from

the reaction. Avoiding such reagents will simplify the reaction procedure for students. Lastly,

in terms of energy efficiency, these reactions utilize organic solvents refluxing at elevated

temperatures of around 100 oC. It is greener for teaching laboratories to use protocols carried

out at ambient temperature.

5

1.2.2 Phase Transfer Catalysis

The use of phase transfer catalysis is another common protocol for conducting Wittig

chemistry.10-16 These reactions are also carried out in two steps—first, in-situ preparation of

the ylide followed by the Wittig reaction itself. These reactions take advantage of

lachrymators in the first step in the formation of the phosphonium salt. The phosphonium salt

is the catalyst that brings the hydroxide ion across into the organic phase to remove a proton

from the phosphonium salt to produce the phosphorous ylide. In contrast to the previous

example using a pyrophoric base, a 50% aqueous sodium hydroxide solution is used to make

the ylide, which is a step forward towards a greener and safer approach in organic chemistry

(Figure 1.5).

Figure 1.5. Phase transfer catalysis using a 50% sodium hydroxide solution.

The phase transfer catalysis reactions are also beneficial to conduct in an organic

chemistry teaching laboratory because they are done at ambient temperature. Despite the

ambient temperature, 50% aqueous sodium hydroxide might prove to be dangerous to

students because of the severe burns it can cause upon exposure to skin.

An additional J. Chem. Ed. paper17 illustrates the one phase transfer catalysis Wittig

experiment, using a 50-fold excess of formaldehyde. This protocol would not be good to use

in an undergraduate teaching laboratory since formaldehyde is a well known carcinogen.

1.2.3 “Instant Ylid”

Taking advantage of an “instant ylid” is an example of a protocol that greatly

simplifies the Wittig reaction,18 but it is unfortunately potentially harmful in a teaching

6

laboratory setting for undergraduates because of the use of alkyl triphenylphosphonium

bromide and sodium amide in anhydrous THF (Figure 1.6).

Figure 1.6. “Instant Ylid” Wittig reaction.

The reaction calls for the protective use of a calcium chloride drying agent in addition

to freshly distilled THF. These precautions must be made because the reactive properties of

sodium amide against water. Although this experiment is seemingly simple to conduct, it

should be avoided in the undergraduate organic chemistry teaching lab because of the

potential for a severe accident occurring if water accidently is added to the sodium amide. In

addition to this, the reaction also calls for the use of ligroin, a flammable petroleum fraction,

which is also a suspected human carcinogen. It is also a skin absorbent and should not be

used around any materials that build up static electricity.

1.2.4 Solvent-Free Wittig Reactions

There are also published experiments which describe more safer and greener

strategies in performing Wittig reactions in the undergraduate teaching laboratory.19,20

Examples of these include solvent-free reaction that takes advantage of either a ball-milling

apparatus or a mortar and pestle to replace the use of organic solvents during the reaction.

1.2.4.1 BALL MILLING

The ball-milling protocol (Figure 1.7, Table 1.1) involves innovative Wittig reactions

with potassium carbonate as the base, but unfortunately, these reactions take an extensive

amount of time (7 to 14 hours) to conduct.

7

Figure 1.7. Ball-milling Wittig reactions.

Table 1.1. Ball-Milling Wittig Reactions

Compound Milling Time, hr Yield, % E/Z Ratio

3a 7 85 1.6:1

3b 8 92 2:1

3c 14 70 3.4:1

3d 12 73 -

Reactions conducted in an undergraduate organic teaching laboratory need to be done

in a reasonable time frame so students can be able to conduct necessary workups after the

reaction is complete. In addition, the reaction uses a ball-milling apparatus, a piece of

laboratory equipment not typically found in undergraduate organic teaching laboratories. It

would be a costly expenditure for a chemistry department to purchase ball-milling

apparatus’.

The ball-milling experiments are greener than previously discussed Wittig reaction

experiments because they do not use an organic solvent and they use a safer base compared

to previously mentioned Wittig protocols. This is one of the few undergraduate organic

chemistry teaching Wittig reactions that describes a one-pot reaction with the generation of

an in-situ ylide at ambient temperature (Figure 1.8).

Figure 1.8. Ball-milling one-pot Wittig reaction.

8

As green as this reaction is, the reaction time is quite long (8 hours). Therefore, it

might not be as suitable for undergraduates to conduct as a laboratory experiment. Typical

undergraduate laboratory experiments at San Diego State University are conducted for 3

hours, hence the reaction time needs to be shorter so students can have enough time to set-up

the reaction, conduct the experiment, perform work-up procedures and then isolate the

product.

1.2.4.2 MORTAR AND PESTLE

The use of a mortar and pestle is a wonderful example of a green Wittig reaction

experiment (Figure 1.9).

Figure 1.9. Mortar and pestle Wittig reaction.

This reaction consists of a commercially purchased phosphonium salt, benzyl

triphenylphosphonium chloride, 4-bromobenzaldehyde, and potassium phosphate to make

(E)-and (Z)-1-(4-bromophenyl)-2-phenylethene. This reaction is very green and needs no

solvent system. The reaction is conducted at ambient temperature and there is no use of

highly toxic chemicals. The most attractive point with this experiment is the actual isolation

of the E-isomer product—the initial crude is washed with water, followed by recrystallization

in ethanol. Similar to the ball-milling solvent-free Wittig reaction, this reaction uses a solid

base, potassium phosphate to generate the ylide during the reaction. In addition to the energy

efficiency of this reaction being done at ambient temperature, all is done by mechanical

movements of a student grinding all the reaction components together with a mortar and

pestle. This is an attractive alternative in a teaching laboratory since the mortar and pestle are

common and very inexpensive laboratory equipment.

Despite the green advantages, there are two issues with this reaction. The first issue is

reproducibility becomes a real problem because of the variables involved in physically

grinding the reactants for 20 minutes. Students not only move the pestle within the mortar

differently, but they also differ with how long they can physically grind the reaction. The

9

variable nature of the students’ grinding motion and endurance might provide different yields

for all the reactions done in the lab.

The second issue with this experiment is that it calls for an already premade

phosphonium salt. The goal for a greener Wittig reaction is for it to be one-pot so that in the

future it may be a catalytic reaction with the regeneration of the phosphine used in the

reaction. In addition to this, because the reaction requires no solvent system, the likelihood of

the development of a catalytic Wittig reaction using a solvent-free reaction methodology is

less likely to occur than a Wittig reaction using a solvent system. It is for these reasons that

even though the mortar and pestle reaction is greener than most Wittig reactions, educators

need to utilize a Wittig reaction that uses reagents that can be a one-pot Wittig reaction with

future potential towards being a catalytic Wittig reaction.

1.2.5 Microwave Assisted Experiments

The microwave accelerated Wittig reaction is another alternative way to introduce

greener chemistry into the teaching laboratory.21,22 One procedure utilizes the common

household microwave, and the other reports the use of a microwave reactor specifically

designed for organic reactions.

1.2.5.1 HOUSEHOLD MICROWAVE

The reported common household microwave experiment does not take the use of a

solvent system—it utilizes potassium carbonate to generate the specific ylide, which is an

attractive opportunity to introduce greener chemistry in the teaching laboratory (Figure 1.10).

Figure 1.10. Domestic household microwave Wittig reaction.

In addition to the benefit of not using a solvent system, the reaction takes around 10

minutes to conduct, adding to the amount of time students have to do any workup procedures

and analysis of results. Another advantage of this procedure is that the common household

microwave is relatively inexpensive. A fourth advantage of this reaction is that it uses

10

common lab equipment found in the organic chemistry teaching laboratory, so there are no

costly expenditures for educators to conduct this experiment.

Although the common household microwave is a relatively inexpensive instrument to

use in a teaching laboratory, it might pose as a potential danger and possibly a liability. It

does not have the built-in safety features found in microwave reactors specifically made for

conducting organic reactions; for example, a reinforced steel reaction chamber, a special

door-locking mechanism in the event of a reaction vessel rupture, fiber-optic thermocouple

temperature monitoring and an automatic temperature and pressure shutoff capability. Thus,

due to the possibility of an accidental overheating and explosion of a reaction, the use of a

household type microwave is not recommended in the undergraduate teaching laboratory.

Though they can be used in a teaching laboratory for the quick and routine heating of non-

harmful aqueous solutions, they are unsafe for complicated synthetic procedures.23

1.2.5.2 LABORATORY GRADE MICROWAVE

REACTOR

In regards to the laboratory experiment utilizing a reactor specifically designed for

organic reactions, the Wittig reaction is conducted in three separate phases and the laboratory

grade type microwave reactor is used only in the first phase to produce high yields of the

phosphonium salt in 6.5 minutes (Figure 1.11).

Figure 1.11. Microwave reactor Wittig reaction.

Although the reaction time, safety features of the microwave reactor, and increased

phosphonium salt yield utilizing the reactor make this reaction appealing, the experiment

calls for the use of xylenes, a chemical that permeates the skin and is potentially unsafe to

use in an undergraduate teaching laboratory. Moreover, the microwave reactor is very

expensive, so to make use of this technology with a great number of laboratory students, the

laboratory would require at least three microwave reactors. This could potentially be a very

costly purchase because a typical teaching laboratory microwave instrument costs between

11

twenty and thirty thousand dollars.23 Lastly, the life cycle replacement of the reaction vessels

and probes used in the reactor would also be expensive to maintain.

1.2.6 Stabilized Ylide Wittig Reaction

The stabilized ylide Wittig reaction is a very simple reaction of a premade stabilized

ylide, (carbethoxymethylene)triphenylphosphorane, with benzaldehyde in an organic solvent

of DCM (Figure 1.12).24

Figure 1.12. Stabilized ylide Wittig reaction.

The experiment is well suited for the teaching laboratory and offers several important

advantages. The synthesis, workup and characterization of the product may be accomplished

in a single laboratory session with commonly available laboratory equipment and glassware.

Furthermore, the product is obtained at high yield and excellent purity, and the reaction does

not require special precautions of pre-dried glassware, solvents, and reagents. This reaction is

an improvement to other Wittig reactions like the ones that use pyrophoric bases, but it uses

dichloromethane as the solvent, a known carcinogen. Although the reaction is very simple, it

can be improved upon by using water as the reaction medium. The reaction can also be made

simpler if the one-pot reaction creates the in-situ ylide rather than employing the pre-made

ylide.

1.3 “ON WATER” WITTIG REACTION LABORATORY EXPERIMENT

A water based Wittig reaction is a complement to the previous protocols mentioned in

that it maximize the exposure of greener chemistry and at the same time, maintains a high

level of safety in the organic chemistry teaching laboratory (Figure 1.13).

Figure 1.13. “On water” Wittig reaction experiment.

12

The adaptation of a simple Wittig reaction can be conducted in aqueous sodium

bicarbonate media—an experiment suitable for the organic teaching laboratory. The reaction

is conducted for 2 hours at ambient temperature and is a “one-pot” Wittig reaction of

triphenylphosphine, benzaldehyde and ethyl bromoacetate with aqueous saturated sodium

bicarbonate as the base. This organic reaction allows educators to provide students with a

safer, simpler, less expensive and more effective means to conduct a greener Wittig reaction

in an undergraduate organic chemistry laboratory setting (Appendix A). Water is not

considered a “solvent” in this reaction, but rather a “medium” since the reagents are quite

hydrophobic and appear insoluble. Aqueous diluted sodium bicarbonate is a very weak

suitable base for a teaching laboratory, used here to generate the in-situ stabilized ylide

needed for the Wittig reaction to produce the alkene product. Though ethyl bromoacetate is

classified as a lachrymator, it is used in small quantities within a ventilated setting. Adding to

the simplicity of the experiment, the reaction is done at ambient temperature utilizing all

common laboratory equipment (Table 1.2).

In consideration of cost, water is obviously much less costly than organic solvents.

Water is also environmentally benign and should always be considered as the medium in

future organic reactions. Also, the proposed experiment does not use any pyrophoric reagents

requiring an inert atmosphere. Not only does that make this experiment much safer, but it

reduces the cost to carry the experiment as well. Rather than purchasing the ylide, it is

proposed herein to be generated in-situ using inexpensive starting materials.

Water is a remarkably efficient medium for the Wittig reaction and can be used with a

wide range of stabilized ylides and aldehydes. Even more astonishing is that that reaction rate

for the Wittig reaction is faster in water than in organic solvents even though the reactions

seem heterogeneous in water.25 Wittig reactions in water work best when large hydrophobic

entities like aromatic functional groups are present. Despite the reactants’ poor solubility,

aqueous Wittig reactions have very high yields with high precedence for trans-(E)-

selectivities.26

1.3.1 Experimental Procedure

The “on water” Wittig lab experiment can be done in one 3 hour lab setting and

utilizes common, inexpensive lab equipment. The procedure is very simple and it can be

13

Tab

le 1

.2. E

qu

ipm

ent

for

“On

Wat

er”

Wit

tig

Rea

ctio

n E

xper

imen

t

Mat

eria

l Q

uan

tity

C

AS

(if

ap

pli

cab

le)

Mat

eria

l Q

uan

tity

C

AS

(if

ap

pli

cab

le)

trip

heny

lpho

sphi

ne

0.36

7 g

603-

35-0

se

para

tion

funn

el, 1

25 m

L

1 -

sodi

um b

icar

bona

te (

aq)

5 m

L

144-

55-8

er

lenm

eyer

fla

sk, 2

50 m

L

2 -

ethy

l bro

moa

ceta

te

0.2

mL

10

5-36

-2

erle

nmey

er f

lask

, 100

mL

1

-

benz

alde

hyde

0.

102

mL

10

0-52

-7

Buc

hner

fun

nel

2 -

ethy

l ace

tate

25

mL

14

1-78

-6

vacu

um f

lask

, 250

mL

1

-

sodi

um c

hlor

ide

(aq)

5

mL

76

47-1

4-5

roun

d bo

ttom

fla

sk, 2

50 m

L

1 -

hexa

ne

95 m

L

110-

54-3

gr

adua

ted

cylin

der,

20

mL

1

-

sodi

um b

isul

fite

(aq

) 10

mL

76

31-9

0-5

reag

ent d

igge

r sp

atul

a 1

-

anhy

drou

s so

dium

sul

fate

2

g 77

57-8

2-6

spat

ula

1 -

silic

a 20

0 m

L

7631

-86-

9 sy

ring

e, 1

mL

2

-

20 m

L s

cint

illat

ion

vial

2

- sy

ring

e, 2

0 m

L

1 -

flat

mag

netic

stir

bar

, 10

mm

1

- va

cuum

hos

e 1

-

mag

netic

stir

rer,

20

mm

1

- ex

tra

long

sta

inle

ss s

teel

luer

lo

ck s

yrin

ge n

eedl

es

2 -

14

conducted individually by all students. In general, this experiment can be recommended as an

initial laboratory procedure to be conducted by unfamiliar undergraduate students enrolled in

an organic chemistry laboratory course. Students are to write down observations from

beginning to end during the experiment in order for them to fully understand the reaction

takes place despite the hydrophobic entities present in the water.

To carry out the reaction, students are to add 0.367 g of triphenylphosphine to a 20

mL scintillation vial with a flat magnetic stir bar (Figure 1.14).

Figure 1.14. Experiment set-up.

The use of a flat magnetic stir bar on a flat vial surface ensures all reagents properly

mix in the reaction vessel. Students are to add the remaining reagents in the following order:

5 mL of aqueous sodium bicarbonate, 0.2 mL of ethyl bromoacetate, and 0.102 mL of

benzaldehyde. It is important for students to stir the heterogeneous reaction mixture

vigorously for two hours at room temperature.

Because the reaction time is quite long (2 hours) for a 3 hour laboratory period, it is

necessary for students to also use the two hour reaction time to prepare their workspace to

conduct the following work-up and purification processes. After the reaction stirs for two

hours the students will add 5 mL of ethyl acetate to the reaction vessel. This will separate the

organic phase from the aqueous phase in preparation for the work-up procedures. During the

work-up, students will separate the organic phase from the aqueous phase using a small 125

mL separation funnel. They will then wash the aqueous phase with small portions of ethyl

acetate (2 x 5 mL) to extract any remaining product from the aqueous phase. The organic

phases will then be combined and subsequently washed with 10% aqueous sodium bisulfite

15

(1 x 10 mL). The organic phase is then washed with saturated sodium chloride (1 x 5 mL)

and dried over anhydrous sodium sulfate. After filtering the dried organic phase under

vacuum using a Buchner funnel, the ethyl acetate was removed under vacuum and the crude

organic residue was the left to air dry.

After the residue is air dried, students will then perform the purification of their crude

product. The pure product has an Rf value of 0.5 using 10% ethyl acetate/hexane as an eluent.

Dissolve the residue in minimum 10% ethyl acetate and hexane and purify on a short silica

plug (5 x 2 cm). After removal of the organic solvent the students then determine their yields

(%) of the product after letting it air dry.

1.3.2 Results and Discussion

The product composition can then be analyzed by 1H NMR spectroscopy

(Figure B.1 in Appendix B). Here the students are able to compare their product 1H NMR

(Figure 1.15) spectrum with 1H NMR (Figures 1.16, 1.17, and 1.18) spectra of the starting

materials. 27-29 Simplicity of the 1H NMRs of the starting materials and the product is an

additional reason this experiment is beneficial to students in an undergraduate organic

chemistry teaching laboratory. The knowledge of the mechanism of the Wittig reaction in

conjunction with the starting material 1H NMRs will help them to conceptually predict what

their product 1H NMRs will look like.

The students will also be able to determine the trans/cis (E/Z) ratio of their alkene

products in their 1H NMR spectrum. In the event of unreacted aldehyde present after the

reaction is complete, it is removed by washing with sodium bisulfite. The triphenylphosphine

oxide formed during the Wittig reaction is removed on a short silica plug. Unreacted

triphenylphosphine remains when diluting the organic phase in 10% ethyl acetate and hexane

because triphenylphosphine is insoluble in hexane. Triphenylphosphine, if remaining, will

make up very little (<1%) of the product mass and has a distinguishable 1H NMR signal just

downfield from the chloroform signal. Unreacted ethyl bromoacetate may make up 6% of the

product mass. A typical student product yield was found to be on average 93% with an E/Z

ratio of circa 92/8.

16

Figure 1.15. Product 1H NMR of (E/Z)-ethyl cinnamate.

17

Figure 1.16. Starting material 1H NMR of triphenylphosphine.

Figure 1.17. Starting material 1H NMR of ethyl bromoacetate.

Figure 1.18. Starting material 1H NMR of benzaldehyde.

18

1.3.3 Hazards of the Experiment

Before students carry out the laboratory experiment, educators are to brief the hazards

of the reaction to the students. Even though the reaction is greener, all reactions still have

their inherent dangers, for instance, ethyl bromoacetate is a lachrymator and should be used

with caution in a ventilated hood. Even though it is employed herein, it is used in a quite

small quantity. Benzaldehyde, and triphenylphosphine are both irritants and should be used

with caution—they are also used in small quantities. Silica gel in its dust form is probably

one of the more hazardous of materials in this experiment. Long time exposure and

inhalation can cause silicosis. This is a form of occupational lung disease caused by

inhalation of crystalline silica dust, and is marked by inflammation and scarring in the form

of nodular lesions in the upper lobes of the lungs.30 Inhalation of silica dust can be mitigated

easily by students working with it in a well ventilated fume hood. Lastly, the prepared

product ethyl cinnamate is a known irritant and is hazardous only if swallowed.

1.4 LABORATORY EXPERIMENT COMPARISON

It is in every educator’s goal to be able to demonstrate valuable lessons through lab

experiments using the most effective and less costly means possible. The “on water” Wittig

reaction is the least expensive reaction to carry out when comparing the starting materials

used from all of the previous lab experiments discussed (Table 1.3). It costs only $0.23 per

student to carry out. For instance the mortar and pestle and phase transfer catalysis reaction,

previously mentioned herein, are fairly close in cost, $0.29 and $0.37 per student,

respectively. The low cost of this experiment is very attractive, especially when

undergraduate laboratory sizes generally range from 24 to 30 students, and not uncommon,

chemistry departments have multiple laboratory sections to conduct organic chemistry

experiments.

Of the green reactions, the “on water” Wittig reaction is the most well rounded when

looking at the evaluation criteria of cost, yield, and time to carry out the reaction. The green

mortar and pestle reaction is just as inexpensive and takes less time to carry out, but it only

has a yield of 70% compared to the 93% yield of the “on water” reaction. The ball-milling

one-pot also has a high yield, but is quite expensive and takes much longer to carry out

compared to the “on water” Wittig reaction. Comparing the stabilized ylide reaction with the

19

Tab

le 1

.3. C

ost,

Yie

ld a

nd

Rea

ctio

n T

ime

Com

par

ison

of

Wit

tig

Rea

ctio

n E

xper

imen

ts

$/g

Am

ount

Use

d (g

) $/

stud

ent

Pro

duct

T

otal

$/s

tude

nt

Yie

ld

Rea

ctio

n T

ime

$0.6

5 0.

2 $0

.13

tran

s-9-

(2-p

heny

leth

enyl

)ant

hrac

ene

$0.3

7 50

-70%

30

min

$2

.06

0.11

5 $0

.24

$19.

74

0.75

$1

4.81

1,

2-m

ethy

lene

diox

y-4-

(2-m

ethy

lpro

peny

l)-b

enze

ne

$14.

85

60%

30

min

$0.3

0 0.

15

$0.0

5

$0.6

5 0.

9 $0

.59

1-(p

heny

l)-2

-(2-

naph

thyl

)eth

ylen

e $0

.59

85%

7

hr

$0.8

4 3

$2.5

2 1-

(4-b

rom

ophe

nyl)

-2-p

heny

leth

ylen

e $2

.52

92%

8

hr

$2.7

6 0.

7 $1

.93

1-(4

-bro

mop

heny

l)-1

-met

hyl-

2-ph

enyl

ethy

lene

$1

.93

70%

14

hr

$0.6

3 0.

9 $0

.57

2-et

heny

lnap

htha

lene

$0

.57

73%

20

hr

$4.1

6 0.

42

$1.7

5

(E)-

and

(Z

)-1-

(4-b

rom

ophe

nyl)

-2-(

2-na

phth

yl)-

ethy

lene

s $2

.60

93%

8

hr

$1.7

1 0.

36

$0.6

2

$0.4

8 0.

5 $0

.24

$0.6

5 0.

2 $0

.13

(E)-

1-(4

-bro

mop

heny

l)-2

-phe

nyle

then

e $0

.29

70%

20

min

$1

.71

0.09

5 $0

.16

$0.7

0 6.

69

$4.6

8 4-

met

hoxy

-1-(

1-pr

open

yl)b

enze

ne

$5.5

5 42

%

11 m

in

$0.4

0 2.

17

$0.8

7

$0.4

8 2.

2 $1

.06

(E)-

and

(Z

)-1,

4-di

phen

yl-1

,3-b

utad

iene

$1

.27

a 91%

1

hr

$0.1

1 1.

65

$0.1

8

$0.0

7 0.

42

$0.0

3

$2.2

7 2

$4.5

4 (E

)-et

hyl c

inna

mat

e $4

.57

b high

yie

ld

30 m

in

$0.0

5 0.

5 $0

.03

$0.4

8 0.

367

$0.1

7

(E)-

and

(Z

)-et

hyl c

inna

mat

e $0

.23

93%

2

hr

$0.0

5 0.

106

$0.0

1

$0.1

8 0.

3 $0

.05

Not

e: a

) 91

% is

onl

y th

e pe

rcen

t yie

ld o

f th

e ph

osph

oniu

m s

alt f

rom

the

mic

row

ave

reac

tor

reac

tion

. N

o yi

eld

of f

inal

pro

duct

pro

vide

d. b

) no

num

eria

l yie

ld is

pro

vide

d, ju

st "

high

yie

ld".

20

“on water” reaction, even though it reports a “high yield”, and only a 1 hour reaction time, it

is too expensive compared to the “on water” Wittig reaction. If an undergraduate program

has 6 lab sections and 21 students per lab section, the stabilized Wittig reaction would cost

$576 compared to the cost of the “on water” Wittig reaction, $29. Not only is there a

significant difference in cost to conduct an experiment where the same lessons can be

achieved and learned, but the “on water” Wittig reaction is significantly safer as well. The

“on water” Wittig reaction substantially complements all of the prior Wittig reactions.

1.5 CONCLUSION

Water is herein illustrated as a very safe and efficient medium for the Wittig

olefination reaction employing an in-situ prepared stabilized ylide and benzaldehyde in the

teaching laboratory. The separation of triphenylphosphine oxide from the alkene product

without using an organic solvent work-up, however, remains a classic problem. Regardless,

this experiment demonstrates that solubility of the reagents and substrates is not of a

paramount nature in the Wittig reaction, even though pronounced hydrophobic entities are

present.

At the end of this laboratory experiment, with the knowledge of previous Wittig

reaction protocols along with the awareness of the “on water" Wittig reaction and the Twelve

Principles of Green Chemistry, organic chemistry students will have a good initial

understanding of how they can better design green chemistry experiments and hopefully

influence industry practices throughout their future careers.

21

CHAPTER 2

THE ATTEMPTED DEVELOPMENT OF AN “ON

WATER” CATALYTIC WITTIG REACTION

2.1 INTRODUCTION

Switching the solvent from an organic solvent to a water media was an exceptional

leap for making the Wittig reaction a greener alternative. The ultimate goal for making the

Wittig reaction greener is for it to take advantage of a catalytic amount of triphenylphosphine

in water media. During the Wittig reaction, a great deal of phosphine oxide by-product is

formed affecting the Wittig reaction to have poor atom economy; once the phosphine oxide is

produced from a stoichiometric Wittig reaction, it remains a useless by-product in the

reaction.31 In accordance with the Twelve Principles of Green Chemistry, a catalytic Wittig

reaction will make it greener because the use of a catalytic amount of one reagent is far

superior than the use of a stoichiometric amount of the same reagent. Also, the atom

economy will improve because the by-product made in the reaction will be used to continue

the reaction. A catalytic Wittig reaction is illustrated in Figure 2.1.32

There are four steps in a catalytic Wittig reaction. The first step is to form the

phosphonium salt with a phosphine and an alkyl halide. The second step is to generate the in-

situ ylide with a base by removing the α-hydrogen from the phosphonium salt. The third step

in the catalytic Wittig reaction is the actual Wittig transformation and the creation of the

olefin and the phosphine oxide by-product. The fourth–and most critical step–in making the

catalytic Wittig reaction occur is the reduction of the phosphine oxide back to the phosphine

employing a suitable reducing agent compatible with rest of the reagents in this reaction.32

This chapter discusses a study conducted to develop an “on-water” catalytic Wittig reaction.

2.2 USE OF TRIPHENYLPHOSPHINE OXIDE

The development of the catalytic Wittig reaction relies on the reduction of the

phosphine oxide by-product to the phosphine. The P=O bond strength of Ph3PO is 544

kJ/mol, and because of its relative stability, one would expect this reduction to be relatively

22

Figure 2.1. Four steps of a catalytic Wittig reaction.

slow in a catalytic Wittig reaction.32 In comparison to the bond strength of P=O, As=O has a

bond strength much less, 389 kJ/mol. The first catalytic Wittig-type reaction was reported

with the use of tributylarsenic as the catalyst and triphenylphosphite as the reducing agent

(Figure 2.2).33

Figure 2.2. Catalytic Wittig reaction with tributylarsenic.

There is also a report of the use of a tellurium oxide compound as a catalyst34 because

of the Te-O bond strength32 of 376 kJ/mol, a bond strength significantly less than the P=O

bond strength (Figure 2.3).

23

Figure 2.3. Catalytic Wittig reaction using a tellurium compound.

Despite the advantage of arsenic and tellurium oxide compounds being easily reduced

compared to the phosphine oxide, it is important to note that a phosphine oxide compound is

environmentally more complimentary to use for a catalytic olefination reaction. The

corresponding arsenic and tellurium oxides are more toxic and obviously less greener. If

catalytic Wittig reactions are to be conducted in industry at a large scale, Wittig reactions

catalyzed by greener phosphine oxides should be more accepted and employed.35

2.2.1 Standard Wittig Reaction Using Ph3P in Organic Solvent

The development of an “on-water” catalytic Wittig reaction started with the

determination of a successful one-pot Wittig reaction in an organic solvent. The results of

this reaction will be used to compare the catalytic Wittig reactions using triphenylphosphine

oxide hereafter. The standard Wittig reaction consisted of o-anisaldehyde,

triphenylphosphine and methyl bromoacetate in toluene refluxing under argon for 24 hours

(Figure 2.4).

Figure 2.4. Standard Wittig using Ph3P in organic solvent.

The reaction was refluxed for 24 hours in toluene. The reaction condition is similar to

the condition reported for where triphenylphosphine oxide is reduced to triphenylphosphine

in toluene.36 A tertiary amine will be a suitable base since they do not provide the

corresponding imines or enamines with aldehydes. The standard reaction protocol provided a

67% yield with an E/Z ratio of 96/4 (Figure B.2 in Appendix B).

24

2.2.2 Reduction Protocols for Ph3PO

In order to create a catalytic Wittig reaction, it will be important to use a reduction

protocol that selectively reduces the phosphine oxide over other reducible functional groups

like double bonds, carbonyls and halogens. To that end, protocols were sought from multiple

sources for the reduction of phosphine oxides in organic solvents and in aqueous media.

2.2.2.1 METAL HYDRIDES

There have been many reported reduction protocols of phosphine oxides using metal

hydrides like lithium aluminum hydride, diisobutylaluminum hydride, and sodium

borohydride.37-42 Lithium aluminum hydride and diisobutylaluminum hydride would not be

considered as reducing agents for the “on water” catalytic Wittig reaction because they are

too pyrophoric. Sodium borohydride, however, can be used in water, but was not considered

in this study because it will reduce the aldehyde function needed for the Wittig reaction,

which is also the case for lithium aluminum hydride and diisobutylaluminum hydride. In

accordance with the Twelve Principles of Green Chemistry, less toxic and less hazardous

compounds should be used to reduce phosphine oxides.

2.2.2.2 HYDROSILANES AND A TITANIUM CATALYST

There are also phosphine oxide reduction protocols utilizing a combination of

titanium tetraisopropoxide (Ti(OiPr)4) and hydrosilanes.43-46 One in particular uses TMDS

and 10 mol % of Ti(OiPr)4 to reduce triphenylphosphine oxide to triphenylphosphine

(Figure 2.5 and Table 2.1).44

Figure 2.5. Reduction of Ph3PO with TMDS and Ti(OiPr)4.

25

Table 2.1. Reduction of Ph3PO with TMDS and Ti(OiPr)4

Entry Si-H/P=O Molar Ratio Temp (oC) Drying Agent Conversion (%)

1 1.2 100 - 86

2 1.2 100 Na2SO4 100

3 1.2 60 Na2SO4 100

4 1.2 60 K2CO3 100

5 1.2 60 MgSO4 100

6 1.2 60 MS 4 A 83

As reported in the mechanism of this reaction, an equimolar amount of water is

produced. Because of the release of water during the reaction, Petit et al. studied the effects

of introducing a drying agent during the catalytic reaction. Comparing entries 2 and 3 from

Table 2.1, there is a notable difference in the conversion of triphenylphosphine oxide. When

anhydrous sodium sulfate is added to the reaction, the conversion is 100%, compared to 86%

in the absence of drying agent. It is suspected that the water byproduct produced from the

reaction reacts with some of the Ti(iOPr)4 in the catalytic system, thus reducing the yield of

the product,44 hence the reason for not employing the Ti(iOPr)4 in this study. The ultimate

goal of this research is to create a catalytic Wittig reaction in water. Therefore, the Ti(iOPr)4

will be unsuitable as a reagent in the aqueous system. In addition, the reduction of the

triphenylphosphine oxide using an additive drying agent violates one of the principles of the

Twelve Principles of Green Chemistry—the goal of a green reaction is to eliminate the usage

of any other extra additives during the reaction.

2.2.2.3 PHOSPHORIC ACID DERIVATIVE

WITH A SILANE

Beller created a protocol reducing triphenylphosphine oxide using a silane activated

by applying a metal free Lewis acid; specifically, phosphoric acid derivatives

(Figure 2.6 and Table 2.2).36

Beller’s study showed that because of the high bond energy between the phosphorous

and oxygen atoms, a silane cannot reduce triphenylphosphine oxide alone,

(entry 1, Table 2.2). It was proposed that the reduction occurs with the facilitation of a Lewis

26

Figure 2.6. Beller reduction protocol.

Table 2.2. Beller Reduction Protocol

Entry Catalyst Silane (equiv.) T (oC) Yield (%)

1 - (EtO)2MeSiH (3) 100 <1

2 3a (EtO)2MeSiH (4) 110 90

3 3b (EtO)2MeSiH (4) 110 >99

4 3a PhSiH3 (3) 110 91

5 3a Ph2SiH2 (3) 110 56

acid, a concerted activation of both the Lewis acidic silane and the Lewis basic phosphine

oxide by the bifunctional phosphoric silyl ester in an intramolecular deoxygenation sequence

to form the phosphine product, disiloxane and H2 (Figure 2.7).36

Adopted from this study, we confirmed the use of bis(4-nitrophenyl) phosphate as the

phosphoric acid derivative and diethoxymethylsilane as the reducing agent (entry 3). We also

corroborated the reduction of triphenylphosphine oxide to triphenylphosphine using

diphenylphosphate and diphenylsilane (entry 5). The Beller protocol was determined to be a

viable reduction method to combine with the earlier reported standard Wittig reaction using

triphenylphosphine.

2.2.2.4 BENZOIC ACID DERIVATIVE WITH A

SILANE

O’Brien reported a reduction protocol of phosphine oxides using silanes and benzoic

acid derivatives (Figure 2.8, Table 2.3).47 The majority of O’Brien’s study focused on the

reduction of cyclic phosphine oxides because of the ability to reduce them more easily than

acyclic phosphine oxides like triphenylphosphine oxide. Similar to the work conducted by

Beller, this study reduced phosphine oxides with a silane, but instead of activating it with a

phosphoric acid derivative, O’Brien used a benzoic acid derivative, primarily 4-nitrobenzoic

27

Figure 2.7. Proposed Beller reduction mechanism of Ph3PO.

Figure 2.8. O’Brien reduction protocol

acid. In response to Beller’s reduction protocol of phosphine oxides using phosphoric acid

derivatives,36 O’Brien conducted two catalytic Wittig reactions to prove 4-nitrobenzoic acid

is more effective in activating phosphine oxides than bis(4-nitrophenyl)phosphate. The

catalytic Wittig reaction using 4-nitrobenzoic acid achieved a 76% yield compared to the

34% yield of the catalytic Wittig reaction using bis(4-nitrophenyl)phosphate.

28

Table 2.3. O’Brien Reduction Protocol

Entry R3PO Silane Solvent R1 T (oC) t (min) Yield (%)

1 1 PhSiH3 THF H RT 60 94

2 1 Ph2SiH2 THF NO2 RT 60 61

3 1 PhSiH3 THF NO2 RT 2 74

4 2 PhSiH3 Toluene NO2 100 10 50

5 2 4-CF3PhSiH3 Toluene NO2 100 10 81

In their study above, O’Brien found the use of phenylsilane with benzoic acid gave

the best results when reducing the cyclic phosphine oxide (entry 1). Referencing entries 4

and 5 (Table 2.3), phenylsilane and 4-(trifluoromethyl)-phenylsilane used with 4-

nitrobenzoic acid reduced triphenylphosphine oxide in toluene. The results were more than

impressive—most notably 81% when using 4-(trifluoromethyl)-phenylsilane. Considering

the reaction conditions of the study herein, both phenylsilane and 4-(trifluoromethyl)-

phenylsilane react violently with water. For this obvious reason the specific reagent

combinations were not considered (Table 2.3), but instead, slightly altered using other

reagent combinations favoring known reduction reaction conditions of Ph3PO. More

specifically, diphenylsilane was used as the reducing agent, 4-nitrobenzoic acid as the Lewis

acid, and the reactions reacted at room temperature or refluxed in THF or in toluene

(Figure 2.9).

The above study was initiated by employing the reaction conditions from entry 2

(Table 2.3) by changing the phosphine oxide from a cyclic analog to triphenylphosphine

oxide. According to O’Brien’s study, DIPEA was also present in the reaction in order to test

compatibility of the base with the silane. All the reactions were conducted under argon. No

product was observed from reaction 2.2 when all components reacted in THF for 60 minutes

at room temperature. The same results were seen in reaction 2.3 when the reaction time was

altered to 24 hours. The same result was obtained for reaction 2.4 when the reaction was

refluxed in THF at 110 oC for 24 hours. Reaction 2.5 displayed somewhat more positive

results when the solvent was changed from THF to toluene, the same solvent used in the

prior reduction protocol using the phosphoric acid derivative. The conversion of

triphenylphosphine oxide to triphenylphosphine was confirmed by 31P NMR showing a

single peak at -7.293 ppm (Figure B.3 in Appendix B). Unfortunately, it was impossible to

determine the yield to the generated triphenylphosphine because of the presence of

29

Ph3P O Ph3POH

OO2N

Ph3P O Ph3POH

OO2N

Ph3P O Ph3POH

OO2N

Ph3P O Ph3POH

OO2N

THF, 110oC, 24 hr

1 equiv.14 equiv. of iPr2NEt

14 equiv. Ph2SiH2

No product formed

1 equiv.

toluene, 110oC, 24 hr


14 equiv. Ph2SiH2

Little product formed

1 equiv.

THF, RT, 24 hr


14 equiv. Ph2SiH2

No product formed

1 equiv.

THF, RT, 60 min


14 equiv. Ph2SiH2

No product formed

1 equiv.

a.

b.

c.

d.

2.2

2.3

2.4

2.5

Figure 2.9. Reduction study of Ph3PO using Ph2SiH2 and 4-nitrobenzoic acid.

by-products in the crude, possibly the presence of hydroxydiphenylsilanes seen in the 1H

NMR (Figure B.4 in Appendix B) spectrum. Moreover, the crude mass was too small and the

triphenylphosphine present would have been little compared to the expected yield.

2.2.3 Work Towards a Catalytic Wittig Reaction in Organic Solvent

This phase of the research sought to develop a catalytic Wittig reaction using Ph3PO

in organic solvents by combining the standard Wittig reaction and the Lewis acid and silane

reduction protocols.

2.2.3.1 WITTIG REACTION AND BELLER

REDUCTION PROTOCOL

This portion of the research started out to test the compatibility of the standard Wittig

reaction using triphenylphosphine and the phosphoric acid derivative protocol in toluene

(Figure 2.10).

30

Figure 2.10. Compatibility test of standard Wittig reaction and Beller reduction protocol.

Supported by the results of reaction 2.6, the two protocols are possibly compatible

with each other because a 66% yield of product was attained (Figure B.5 in Appendix B), a

yield close to the 67% yield of the standard Witting reaction. Following this lead, a similar

reaction was conducted, but instead of using triphenylphosphine, triphenylphosphine oxide

was used as a proof of concept to prove the reduction of triphenylphosphine oxide worked if

now the product was derived from the generation of an in-situ ylide (Figure 2.11).

Figure 2.11. Catalytic Wittig reaction using Ph3PO in toluene.

Unfortunately, the product yield of reaction 2.7 was 6% (Figure B.6 in Appendix B).

This result concludes the reduction of the phosphine oxide occurred (or at least partly

occurred) because of the generation of some product, but it is unknown the exact reason of

the observed low yield. It is difficult to ascertain a specific reason because of the many

reagents involved in this one-pot catalytic Wittig reaction. Despite this result, the study was

continued to find a one-pot catalytic Wittig reaction in toluene by changing reaction

conditions. This was done by first replacing the bis(4-nitrophenyl) phosphate to

diphenylphosphate in reaction 2.8 (Figure 2.12), but no product formation was observed.

There was only aldehyde present according to the 1H NMR spectrum

(Figure B.7 in Appendix B).

31

Figure 2.12. Catalytic Wittig using diphenylsilane and diphenylphosphate.

In the original reduction protocol, 15 mol % of the phosphoric acid derivative was

employed. The next change in the portion of this study was to increase the amount of

phosphoric acid derivative used to 50 mol % (Figure 2.13).

Figure 2.13. Catalytic Wittig reaction using 50 mol % of diphenylphosphate.

The increase of the phosphoric acid derivative did not yield any product, only the

aldehyde was present in the 1H NMR (Figure B.8 in Appendix B). Attention was then turned

to the use of triethylamine as the base and thus a reaction was conducted in the absence of

triethylamine (Figure 2.14). This was conducted in order to determine if the base was needed

in the first place and secondly if it was negatively interfering with the reaction.

Figure 2.14. Catalytic Wittig reaction without the use of NEt3.

In the absence of triethylamine of reaction 2.10 there was mostly unreacted aldehyde

according to the 1H NMR spectrum (Figure B.9 in Appendix B). The result obtained from the

reaction in the absence of base seems similar to the result of the reaction in the presence of

triethylamine. Thus, it appears that the presence of a tertiary amine is unneccesary.

Interesting is also which base in reaction 2.14 is responsible for creating the crucial ylide to

32

be formed in order for the Wittig reaction to occur. The assumption is that not only does the

diethoxymethylsilane take part in the reduction of triphenylphosphine oxide, but it also

appears to remove the acidic proton from the phosphonium salt to produce the in-situ ylide.

With this assumption in mind, the standard one-pot Wittig reaction was conducted with

triphenylphosphine, but instead of using triethylamine as the base, the impact of

diethoxymethylsilane was studied (Figure 2.15).

Figure 2.15. Standard Wittig reaction with Ph3P and (EtO)2MeSiH.

Even though only 16% of product was produced from this experiment, it is still

enough generated product to assume that diethoxymethylsilane can play a role in removing

the acidic proton from the phosphonium salt in order to produce the in-situ ylide. There was

mostly unreacted aldehyde. The absence of any methyl bromoacetate according to the 1H

NMR spectrum shows that most likely the ester has reacted with the silane


2.2.3.2 O’BRIEN CATALYTIC WITTIG

REACTION IN ORGANIC SOLVENTS

Following the start of this research, O’Brien published two articles illustrating his

accomplishment of a one-pot catalytic Wittig reaction in organic solvents

(Figure 2.16, Table 2.4).47,48

O’Brien reported successful catalytic Wittig reactions employing both cyclic and

acyclic phosphine oxides in organic solvents. In this study, more focus was placed on

developing a catalytic Wittig reaction in water media using triphenylphosphine oxide.

Although O’Brien’s group successfully accomplished a catalytic Wittig reaction using

triphenylphosphine oxide as their catalyst, they reported the successful use with the 4-

(trifluoromethyl)-phenylsilane as the alternative reducing agent. However, this specific silane

reacts violently with water; hence it is not useful for a one-pot catalytic Wittig reaction

33

Figure 2.16. O’Brien’s catalytic Wittig reactions in organic solvents.

Table 2.4. O’Brien’s Catalytic Wittig Reactions in Organic Solvents

Entry R3PO Silane Solvent T (oC) Conversion % E/Z

1 1 PhSiH3 THF RT 91 75/25

2 2 4-(trifluoromethyl)-phenylsilane Toluene 100 89 90/10

3 3 Ph3SiH Toluene 100 trace n.d.

4 3 Ph2SiH2 Toluene 100 75 >95/5

5 3 PhSiH3 Toluene 100 46 >95/5

6 3 (MeO)3SiH Toluene 100 61 70/30

in water, which is also the case for phenylsilane. Since O’Brien’s group did not have success

with triphenylsilane, it was also not considered as a silane suitable for aqueous Wittig

chemistry. Although O’Brien was successful in employing trimethoxysilane, this silane was

not considered for this study because of its hazardous nature. In addition, it could very likely

lose its hydride in water like diethoxymethylsilane. Despite O’Brien’s successes for

generating a catalytic Wittig reaction using triphenylphosphine oxide in organic solvents, a

study was still conducted to develop an “on water” catalytic Wittig reaction.

2.2.3.3 CATALYTIC WITTIG REACTION

ATTEMPT USING O’BRIEN’S PROTOCOL

WITH DIPHENYLSILANE AND SODIUM

CARBONATE

Due to the success reported by O’Brien and the goal to find a successful catalytic

one-pot reaction in organic solvent with the potential to be transferred to water, a catalytic

34

one-pot Wittig reaction in toluene was conducted using diphenylsilane, sodium carbonate and

triphenylphosphine oxide. It was determined from O’Brien’s work that sodium carbonate was

an acceptable alternative to DIPEA. This tertiary amine was replaced with sodium carbonate

in this study because of its better solubility in water. Rather than employing o-anisaldehyde

as the standard aldehyde, benzaldehyde was used since it was the preferred aldehyde used in

the work published by O’Brien (Figure 2.17).

Figure 2.17. Catalytic Wittig reaction with Ph3PO in toluene.

O’Brien’s group did most of their work with a cyclic phospholane oxide because of

the ease of reduction of the cyclic phospholane oxide compared to the reduction of

triphenylphosphine oxide, probably due to relieving of the ring strain of the cyclic

phospholane oxides.35 A key catalytic Wittig reaction criteria for the O’Brien group was that

it would be done in 24 hours. In order for this to occur, the pre-catalyst loading of 10 mol %

would have to cycle every 2.4 hours. They felt that triphenylphosphine oxide would not

fulfill this requirement. In light of this information, reaction 2.12 had to be conducted for 96

hours in order for the triphenylphosphine oxide catalyst to be reduced.

The 96 hour reaction time did not matter for the reduction of the triphenylphosphine

oxide–only trace amounts of the product were formed. A greater amount of unreacted

benzaldehyde remained in the reaction crude compared to the product from the results of the 1H NMR (Figure B.11 in Appendix B). The results of this reaction leave us very uncertain as

to why this reaction is not working. The stability of the triphenylphosphine oxide is the most

logical reason as to why this reaction is not functioning catalytically and producing a high

yield of the product.

2.2.4 “On Water” Reduction Protocols for Ph3PO

Reduction protocols “on water” media have been reported, but most are for

hydrogenation, dehalogenation and reduction of carbonyl compounds with water soluble

35

metal catalysts that would not be compatible with the rest of the functional groups from the

catalytic Wittig reaction components.49 Therefore, this study continued to use silanes as the

reducing agent. Before “on water” reduction experiments of triphenylphosphine oxide were

conducted, experiments were first conducted to determine which silane compounds did not

readily lose their hydrides when mixed with water at room temperature for an hour

(Table 2.5).

Table 2.5. Silane in the Presence of Water

Silane In Presence of Water

diphenylsilane Retains hydride

polymethylhydrosiloxane Retains hydride

tetramethyldisiloxane Retains hydride

triisopropylsilane Retains hydride

diethoxymethylsilane Loses hydride

trichlorosilane Reacts violently with water

phenylsilane Reacts violently with water

4-(trifluoromethyl)-phenylsilane Reacts violently with water

Diphenylsilane, PMHS, TMDS, and triisopropylsilane all retain their hydride(s) and

overall structure in the presence of water. Surprisingly, diethoxymethylsilane, the silane with

the best reduction results of triphenylphosphine oxide, does not retain its hydride when

mixed with water. O’Brien reported catalytic Wittig reactions using phenylsilane and 4-

(trifluoromethyl)-phenylsilane, but those silanes react violently with water. Likewise,

trichlorosilane, a silane used by Greaney50 in a catalytic one-pot silyl-Reformatsky

olefination reaction using triphenylphosphine oxide, and triethylamine in a DCM solvent,

also reacts violently in water (Figure 2.18). Therefore these reagents cannot be used in this

study to achieve an aqueous one-pot catalytic Wittig reaction.

Figure 2.18. Greaney’s one-pot silyl-Reformatsky olefination.

36

There is another reduction protocol reported for the reduction of acyclic phosphine

oxides to phosphines using hexachlorodisilane in chloroform at room temperature or

refluxing in benzene.51 Unfortunately, similar to trichlorosilane, the hexachlorodisilane also

reacts violently with water and cannot be employed in this aqueous study.

Following the experiments to determine what silane compounds can be used in water,

”on water” reduction experiments were conducted utilizing the known reduction protocols to

reduce triphenylphosphine oxide in organic solvents. To expedite this process, a laboratory

grade microwave was used to mimic the reaction conditions needed to carry out the

following protocols. To ensure this would work, triphenylphosphine oxide was reduced using

diethoxymethylsilane, and bis(4-nitrophenyl)phosphoric acid in toluene. The reaction yield

was greater than 99%. Multiple “on water” reductions of triphenylphosphine oxide were

attempted using different combinations of silanes and either a phosphoric acid derivative or a

benzoic acid derivative (Figure 2.19 and Table 2.6).

Figure 2.19. Microwave reduction of Ph3PO in water.

Table 2.6. Microwave Reduction of Ph3PO in Water

Silane

Phosphoric or Carboxylic Acid Derivative

Diphenylphosphate bis(4-nitrophenyl) phosphate 4-nitrobenzoic acid

diphenylsilane No Reduction No Reduction No Reduction

triisopropylsilane No Reduction No Reduction No Reduction

PMHS No Reduction - -

TMDS No Reduction - -

No reaction combinations of any silane and Lewis acid resulted in the reduction of

triphenylphosphine oxide. This was confirmed by 1H NMR and especially by 31P NMR

spectroscopy. Despite these results, an effort was made to make the triphenylphosphine oxide

more soluble in water in order to have better reaction results. This was achieved by solvating

37

the triphenylphosphine oxide in DMSO before introducing it to the reaction vessel filled with

water, silane and Lewis acid, in this case diphenylphosphate (Figure 2.20).

Figure 2.20. Ph3PO reduction in 15% DMSO and water.

In reaction 2.21, solvating the triphenylphosphine oxide in 15% DMSO in water

proved to help produce triphenylphosphine, verified by 31P NMR and 1H NMR

(Figure B.12 and B.13 in Appendix B). The triphenylphosphine produced was not able to be

isolated in order to accurately determine the yield for the reaction.

2.2.5 “On Water” Catalytic Wittig Reaction Attempt Using Ph3PO

Due to the earlier mentioned reports of O’Brien developing a catalytic Wittig reaction

in organic solvents, this study continued to work towards an “on water” catalytic Wittig

reaction. Sodium carbonate was first used as the base because it is highly soluble in water

(Figure 2.21). Also, O’Brien estimated the pKa value of the ylide-forming proton of the

phosphonium salt to be approximately 9, hence the pKa of the conjugate acid of the base

needs to be between 9 and 12.48 The pKa of the conjugate acid of sodium carbonate is 10.33.

DMSO was used to better solvate the triphenylphosphine oxide so it is more dispersed

throughout the water media.

H

O

BrO

O

1.5 eq. Na2CO3(aq), 100 oC, 96 hr

5% DMSO

O

O

1 equiv. 1.2 equiv.

O=PPh3 - 10 mol %Ph2SiH2 - 1.1 equiv.

No product formed

2.22

Figure 2.21. Attempted “on water” catalytic Wittig reaction with DMSO.

Unlike the catalytic Wittig reaction 2.12 in toluene, no product was formed in

reaction 2.22, which was confirmed from the 1H NMR spectrum obtained of the crude

product mixture (Figure B.14 in Appendix B); the aldehyde was present and appears not to

react with the other reagents present. However, quite puzzling, there was no methyl

38

bromoacetate remaining according to the 1H NMR spectrum. Due to the uncertainty of the

root cause of the catalytic Wittig reaction not occurring when employing triphenylphosphine

oxide, the focus of this study was turned to the use of 3-methyl-1-phenylphospholane as the

active phosphine with hopes of removing the hardships of reducing the phosphine oxide

during the catalytic process.

2.3 USE OF 3-METHYL-1-PHENYLPHOSPHOLANE OXIDE

Due to the unsuccessful results from the use of triphenylphosphine oxide as the

catalyst in this study and the success reported by O’Brien when developing a catalytic Wittig

reaction in organic solvents with 3-methyl-1-phenylphospholane oxide, this study was

continued with 3-methyl-1-phenylphospholane oxide as the catalyst. O’Brien reported the

cyclic phospholane oxides in his experiments because of the ease of reduction compared to

the reduction of triphenylphosphine oxide. This is most likely due to the need of relieving the

ring strain of the cyclic phospholane oxide.35 Decreasing the hardship of reducing the

phosphine oxide will further aid in the discovery of an “on water” catalytic Wittig reaction.

In addition to this change, instead of using o-anisaldehyde as the aldehyde, this study

changed to the use of benzaldehyde to best mimic the successful work reported by O’Brien.

Below is yet another successful catalytic Wittig reaction reported by O’Brien. In this

example they used the cyclic phospholane oxide, diphenylsilane, benzaldehyde, methyl

bromoacetate, and DIPEA as the base (Figure 2.22).48

Figure 2.22. O’Brien et al. catalytic Wittig reaction in toluene.

In an attempt to recreate and verify this experiment, only a 38% yield of product was

obtained. This is much less than the yield reported by O’Brien (80%). A similar reaction was

conducted, but stoichiometric amounts of the silane and the base were increased as well as

the catalytic amount of the cyclic phospholane oxide (Figure 2.23).

39

Figure 2.23. Optimized O’Brien catalytic Wittig reaction in toluene.

The yield in reaction 2.23 was significantly greater (Figure B.15 in Appendix B)

compared to the yield of the reaction to verify O’Brien catalytic protocol. The protocol used

in Figure 2.23 was used to conduct similar “on water” experiments; though, before

conducting “on water” catalytic experiments, this study first set out to achieve a standard “on

water” Wittig reaction using 3-methyl-1-phenylphospholane and reduce 3-methyl-1-

phenylphospholane oxide “on water”.

2.3.1 Standard “On Water” Wittig Reaction Using 3-methyl-1-phenylphospholane

The standard Wittig reaction in aqueous media consisted of benzaldehyde, 3-methyl-

1-phenylphospholane, methyl bromoacetate and DIPEA refluxing “on water” for 24 hours

(Figure 2.24).

Figure 2.24. “On water” Wittig reaction using 3-methyl-1-phenylphospholane.

Reaction 2.24 provided a 54% product yield with an E/Z ratio of 70/30


2.3.2 “On Water” Reduction of 3-methyl-1-phenylphospholane oxide with Ph2SiH2

3-Methyl-1-phenylphospholane oxide was reduced “on water” using diphenylsilane

as the reducing agent and refluxing at 100 oC for 24 hours (Figure 2.25).

40

Figure 2.25. “On water” reduction of 3-methyl-1-phenylphospholane oxide.

Reaction 2.25 provided a product yield of 93%. The formation of 3-methyl-1-

phenylphospholane was verified using 31P NMR. The cyclic phosphine oxide has a 95:5

mixture of diastereomers at 59.80 ppm and 59.43 ppm (Figure B.17 in Appendix B) and the

product 31P NMR of reaction 2.25 showed peaks at -13.44 ppm and -13.88 ppm

(Figure B.18 in Appendix B). The reduction of the cyclic phosphine oxide “on water” and the

“on water” Wittig reaction using the cyclic phospholane were great steps forward in

developing an “on water” catalytic Wittig reaction.

2.3.3 “On Water” Catalytic Wittig Reaction Attempts Using 3-methyl-1-phenylphospholane oxide

Due to the promising results from reactions 2.23, 2.24 and 2.25, it was then decided

to combine the “on water” one-pot Wittig reaction protocol using 3-methyl-1-

phenylphospholane and the “on water” reduction protocol (Figure 2.26).

Figure 2.26. Catalytic “on-water” Wittig with 3-methyl-1-phenylphospholane oxide.

The 1H NMR spectrum of this crude reaction showed no product, mostly aldehyde

(Figure B.19 in Appendix B). It is quite surprising that this reaction did not show any product

formation because of the success conducting the same reaction in toluene with 68% yield.

This information gives question to whether or not the water plays a role in hampering this

reaction through a side reaction with another component of the Wittig reaction, like the

methyl bromoacetate.

41

In light of this result, other bases were used with this protocol (Figure 2.27). In

O’Brien’s work,48 they describe the use of sodium carbonate as the base comparable to the

use of DIPEA. They switched from sodium carbonate to DIPEA because it was more soluble

in organic solvents than sodium carbonate. Similar experiments to reaction 2.26 were

conducted, but with the use of sodium carbonate or sodium bicarbonate as the bases. These

two bases are ideal to use to develop an “on water” catalytic Wittig reaction because they are

very green and non-toxic bases.

Figure 2.27. Attempted “on water” catalytic Wittig experiments with Na2CO3 and NaHCO3.

The crude 1H NMR spectra of both reactions, 2.27 and 2.28, showed little olefin

peaks for the product compared to the chemical shift peaks of impurities and the aldehyde

(Figures B.20 and B.21 in Appendix B). The products from both reactions were too small to

be isolated. The purification however was quite difficult to conduct due to the white solid by-

product formed. These experiments were repeated, but in the presence of tertiary nitrogen

bases: DMAP, triethylamine and N,N-dimethylaniline (Figure 2.28). The use of sodium

carbonate and sodium bicarbonate are much greener options compared to the use of DMAP,

triethylamine and N,N-dimethylaniline, but isolating the product proved to be troublesome.

In reaction 2.29, no product was formed when DMAP was used

(Figure B.22 in Appendix B), the same with reaction 2.30 with triethylamine as the base

(Figure B.23 in Appendix B), but there was a less than 1% product yield in reaction 2.31

when N,N-dimethylaniline was used as the base (Figure B.24 in Appendix B). The reaction

work-up and isolation was much easier for reaction 2.31 compared to the work-up and

42

Figure 2.28. Attempted “on water” catalytic Wittig reactions with tertiary nitrogen bases.

isolation attempts when sodium carbonate and sodium bicarbonate were used as the bases.

After achieving a product yield when using N,N-dimethylaniline as the base, optimization

attempts were conducted by changing different variables (Figure 2.29).

Figure 2.29. Initial optimization attempts of reaction 2.31.

Unfortunately, the reactions to optimize the less than 1% yield of reaction 2.31 were

not successful in producing better product yields. No product was produced when a greater

equivalent of methyl bromoacetate was used in reaction 2.32. Reaction 2.33 also had a less

43

than 1% yield of product. Evident in all of the 1H NMR spectra for these reactions is the fact

that there is no methyl bromoacetate left in the reactions (Figures B.25 and B.26 in

Appendix B). Because of this, two more experiments were conducted where the equivalents

of methyl bromoacetate were drastically increased to see if the same results can be achieved

(Figure 2.30).

PPh O

H

O

BrO

O

1 equiv. 3 equiv.

+ +

20 mol %

O

O3 equiv. N,N-dimethylaniline3 equiv. Ph2SiH2

PPh O

H

O

BrO

O

1 equiv. 5 equiv.

+ +

20 mol %

O

O

< 1 % product yield

3 equiv. N,N-dimethylaniline3 equiv. Ph2SiH2

2.34

2.35

3 mL H2O, 100 oC, 24 hr

3 mL H2O, 100 oC, 24 hr

< 1 % product yield

Figure 2.30. Reaction 2.31 with greater equivalents of methyl bromoacetate.

Both reactions 2.34 and 2.35 had less than 1% product yield. Though again, very little

product was formed, aldehyde remained and there was no methyl bromoacetate left

remaining according to the crude reaction NMR spectra (Figures B.27 and B.28 in

Appendix B). It is believed methyl bromoacetate must be consumed via a side reaction and

therefore, is not available long enough to be able to form the in-situ ylides with the reduced

cyclic phospholane oxide.

2.4 FUTURE WORK FOR THE DEVELOPMENT OF AN “ON

WATER” CATALYTIC WITTIG REACTION

Future work to develop an “on water” catalytic Wittig reaction should continue with

the use of 3-methyl-1-phenylphospholane oxide as the catalyst because of the reported

successes of an “on water” Wittig reaction with 3-methyl-1-phenylphospholane and an “on

water” reduction of 3-methyl-1-phenylphospholane oxide.

Due to the possibility of methyl bromoacetate undergoing side reactions quickly and

not being present for further Wittig reaction cycles in the previously attempted “on water”

catalytic Wittig reactions, future work can be done to conduct experiments that incrementally

44

add the methyl bromoacetate to the reaction vessel over the 24 hour reaction period.

Figure 2.31 is a possible side reaction where N,N-dimethylaniline and water react with

methyl bromoacetate and convert it to methyl hydroxyacetate, thus removing methyl

bromoacetate from reacting with more cycles of the reduced cyclic phospholane oxide.

Figure 2.31. Side reaction of methyl bromoacetate with base and water.

Future work can be done using a different α-halo ester like methyl chloroacetate.

Chlorine is a more electronegative atom compared to bromine, so it is more strongly bonded

to the α-carbon of the α-halo ester. Also, a chlorine atom is smaller than a bromine atom, so

its bond overlap with the α-carbon of the methyl acetate will be stronger. Due to these two

physical properties of the chlorine atom, chlorine is a worse leaving group compared to

bromine and the methyl chloroacetate would possibly not undergo side reactions before

reacting with the phosphine to make the phosphonium salt. Along with the same idea of

changing the bromine atom to a chlorine atom of the α-halo ester, a tosylate leaving group

can be used instead of a halide. The steric bulk of that group might help deter side reactions

from occurring.

In organic non-polar solvents like toluene, O’Brien was successful in achieving a

catalytic Wittig reaction using methyl bromoacetate in the presence of diphenylsilane. Due to

the success of these reactions, methyl bromoacetate was not reduced by the diphenylsilane.

Although there are reports of esters undergoing reduction by transition metal catalysts and

hydrosilanes like diphenylsilane,52 the methyl bromoacetate in O’Brien’s work did not go

through a reduction side reaction; their product yields are too high to suggest a side reaction

occurred. This is not the case for the attempted “on water” catalytic Wittig reaction

45

experiments in this study. Figure 2.32 is a possible reduction side reaction of the methyl

bromoacetate with diphenylsilane and water.

Figure 2.32. Reduction side reaction of methyl bromoacetate with diphenylsilane and water.

The hydrogen bonding provided by the protic water media in these reactions help

remove the methoxy group from the ester, furthering the ability for the intramolecular

hydride transfer from the pentavalent silicon to the carbonyl carbocation. In addition to the

influence of the hydrogen bonding of the water media, this side reaction is more probable “on

water” than in toluene because all of the reactants are closely pushed together and more able

to react with one another due to their hydrophobic properties.

Future work to terminate this possible side reaction of the α-halo ester with

diphenylsilane and water is to replace the methyl group of the α-halo ester with a t-butyl

group and for instance use a different α-halo ester like t-butyl chloroacetate. Along with the

steric hindrance provided by the t-butyl group, a t-butoxy group is more basic than a methoxy

group, so it will better resist removal by a hydride and the hydrogen bonding of water.

Lastly, learned from reactions 2.10 and 2.11, a silane can quite possibly act as a

reducing agent and a base in order to make a catalytic Wittig reaction work. This dual action

by the silane might help remove another side reaction variable from the reaction vessel.

46

Future work can be done to see if an “on water” catalytic Wittig reaction using 3-methyl-1-

phenyl-phospholane oxide can be achieved with just a silane and no other base present.

2.5 CONCLUSION

Standard “on water” Wittig reactions can be achieved using triphenylphosphine and

3-methyl-1-phenylphospolane; though, only 3-methyl-1-phenylphospholane oxide can easily

be reduced “on water”. The cyclic phospholane oxide is a much more feasible catalyst for the

discovery of an “on water” catalytic Wittig reaction compared to the use of

triphenylphosphine oxide. Though there was little success in producing product when N,N-

dimethylaniline was used as the base for the “on water” catalytic Wittig reaction, it is less

favored to use than greener bases like sodium carbonate and sodium bicarbonate.

47

CHAPTER 3

THE EXPERIMENTAL PART

3.1 GENERAL

All reagents used were commercially purchased. Flash chromatography was

conducted using silica gel (60 Å, 230-400 mesh). Flash chromatography was performed on

Biotage SP1 using 25 mL columns. 1H NMR and 31P NMR spectra were recorded on a 400-

MHz instrument at 25 oC, with chemical shift values reported in ppm relative to TMS as an

internal standard (δ=ppm). Coupling patterns are abbreviated as: s (singlet), d (doublet), t

(triplet), q (quartet), and m (multiplet). Reactions done using a microwave reactor were done in

2 mL capped vials using a Biotage Initiator Classic 2.0.

3.2 “ON WATER” WITTIG REACTION EXPERIMENT

(E,Z)-Ethyl cinnamate (1.1). Add 0.367 g of triphenylphosphine to a 20 mL

scintillation vial with a flat magnetic stir bar. The use of a flat magnetic stir bar on a flat vial

surface ensures all reagents properly mix in the reaction vessel. Next, add 5 mL of saturated

aqueous sodium bicarbonate, 0.2 mL of ethyl bromoacetate and 0.102 mL of benzaldehyde to

the reaction vessel. Stir the heterogeneous reaction mixture vigorously for 2 hours at RT and

then add 5 mL of ethyl acetate to the reaction vessel. Separate the organic phase using a

small separation funnel. Wash the aqueous phase with small portions of ethyl acetate (2 x 5

mL). Combine and wash the organic phases once with 10% aqueous sodium bisulfite (1 x 10

mL). Wash the organic phase with saturated sodium chloride (1 x 5 mL). Dry the organic

phase over anhydrous sodium sulfate. Filter the dry organic phase under vacuum using a

Buchner funnel. Evaporate the ethyl acetate and let the crude organic residue air dry. The

pure product has an Rf value of 0.5 using 10% ethyl acetate/hexane as an eluent. Dissolve the

residue in minimum 10% ethyl acetate and hexane and purify on a short silica plug (5 x 2

cm). After evaporating the organic solvent determine the yield (%) of the product after letting

it air dry. 1H NMR (400 MHz, CDCl3): δ 1.24 (t, 3H), 1.34 (t, 3H), 4.17 (q, 2H), 4.27 (q,

2H), 5.95 (d, 1H), 6.44 (d, 1H), 6.94 (d, 1H), 7.3-7.6 (m, 8H), 7.7 (d, 1H).

48

3.3 ATTEMPTED CATALYTIC WITTIG REACTION

EXPERIMENTS USING PH3P AND PH3PO

The following experiments are those done using Ph3P and Ph3PO in development

towards an “on water” catalytic Wittig reaction.

3.3.1 Standard Wittig Reaction Using Ph3P in Organic Solvent

3-(2'-Methoxyphenyl)- (E,Z)-propenoic acid methyl ester (2.1). The reaction was

done in a 50 mL round bottom with magnetic stir bar, refluxing in toluene at 110 oC, under

argon for 24 hours. Add 0.290 g of triphenylphosphine (1.1 mmol), and then 5 mL of

toluene. Put reaction vessel under argon. Add the remaining reagents in the following order:

0.11 mL (0.9 mmol) of o-anisaldehyde, 0.11 mL (1.1 mmol) of methyl bromoacetate, and

0.56 mL (4 mmol) of triethylamine. After the reaction runs for 24 hours, let cool to RT and

then add 5 mL of 1M HCl to quench the triethylamine. Add 5 mL of DCM to the reaction

vessel and then wash the aqueous phase once with DCM. Combine organic phases and dry

over anhydrous MgSO4. Product separated using flash column with 20% ethyl acetate in

hexanes as the eluent. 1H NMR (400 MHz, CDCl3): δ 3.66 (s, 3H), 3.80 (s, 3H), 3.83 (s, 3H),

3.89 (s, 3H), 5.98 (d, 1H), 6.53 (d, 1H), 7.18 (d, 1H), 7.3-7.85 (m, 6H), 7.993 (d, 1H).

3.3.2 Reduction of Ph3PO in Organic Solvent

Triphenylphosphine (2.2 thru 2.5). Reactions 2.2 and 2.3 were done at RT, under

argon, with THF as the solvent in a 20 mL scintillation vial with a flat magnetic stir bar.

Reaction 2.2 reacted for 60 minutes and then reaction 2.3 reacted for 24 hours. Reactions 2.4

and 2.5 were done in a 25 mL bulb with stir bar, under argon, 2.4 in THF and 2.5 in toluene,

under argon refluxing for 24 hours. Add 0.0278 g (0.1 mmol) of triphenylphosphine oxide

and charge reaction vessel with argon. Add the remainder reagents in the following order: 3

mL of solvent, 0.017 g (0.1 mmol) of 4-nitrobenzoic acid, 0.26 mL (1.4 mmol) of

diphenylsilane, and then 0.24 mL (1.4 mmol) of DIPEA. Crude products dried under vacuum

and analyzed using 1H NMR and 31P NMR. 1H NMR (400 MHz, CDCl3): δ 7.33 (m, 15H). 31P NMR (400 MHz, CDCl3): δ -7.29 (s, 1P).

49

3.3.3 Compatibility Test of Standard Wittig Reaction and Beller Reduction Protocol

3-(2'-Methoxyphenyl)-(E,Z)-propenoic acid methyl ester (2.6). Reaction done in a 25

mL round bottom with stir bar, under argon, refluxing in toluene for 24 hours. Add 0.289 g

(1.1 mmol) of triphenylphosphine and 0.056 g (15 mol %) of bis(4-nitrophenyl)phosphate to

the reaction vessel and then charge it with argon. Add remaining reagents in the following

order: 10 mL of toluene, 0.109 mL (0.9 mmol) of o-anisaldehyde, 0.104 mL of methyl

bromoacetate (1.1 mmol), 0.66 mL (4 mmol) of diethoxymethylsilane and 0.56 mL (4 mmol)

of triethylamine. After reacting for 24 hours, cool to 0 oC and then add 5 mL of 1M KOH in

methanol. After 3 hours of mixing, add 3 mL of H2O. Extract organic layer with ethyl acetate

(3 x 20 mL). Wash organic phase with 1 M HCl (3 x 5 mL) and wash the organic layer with

1M NaHCO3 (3 x 5 mL). Dry organic layer with anhydrous NaSO4 and purify with a silica

plug using 20% ethyl acetate in hexanes. 1H NMR (400 MHz, CDCl3): δ 3.66 (s, 3H), 3.80

(s, 3H), 3.83 (s, 3H), 3.89 (s, 3H), 5.98 (d, 1H), 6.53 (d, 1H), 7.18 (d, 1H), 7.3-7.85 (m, 6H),

7.993 (d, 1H).

3.3.4 Experiments to Develop a Catalytic Wittig Reaction in Organic Solvent

3-(2'-Methoxyphenyl)-(E,Z)-propenoic acid methyl ester (2.7 thru 2.9). All reactions

were done in a 50 mL round bottom flask with stir bar, in toluene, refluxing for 24 hours

under argon. Add 0.306 g (1.1 mmol) of triphenylphophine oxide to reaction 2.7 and add

0.145 (0.5 mmol) to reactions 2.8 and 2.9. Add 0.151 g of bis(4-nitrophenyl)phosphate (15

mol % of Ph3PO) to 2.7, add 0.02 g (15 mol % of Ph3PO) of diphenylphosphate to 2.8 and

0.07 g of diphenylphosphate (50 mol % of Ph3PO) to 2.9. Charge reaction vessels with argon

and add the following remaining reagents to the reaction vessels: Add 10 mL of toluene to

each reaction vessel; add 0.109 mL (0.9 mmol) of o-anisaldehyde to 2.7, 0.063 mL (0.5

mmol) of o-anisaldehyde to 2.8 and 2.9; add 0.104 mL (1.1 mmol) of methyl bromoacetate to

2.7 and add 0.05 mL (0.5 mmol) of methyl bromo acetate to 2.8 and 2.9.; add 0.64 mL (4

mmol) of diethoxymethylsilane to 2.7 and add 0.33 mL (2 mmol) of diethoxymethylsilane to

2.8 and 2.9; add 0.56 mL (4 mmol) triethylamine to 2.7 and add 0.3 mL (2 mmol) of

triethylamine to 2.8 and 2.9. After reacting for 24 hours, cool to 0 oC and then add 5 mL of

1M KOH in methanol. After 3 hours of mixing, add 3 mL of H2O. Extract organic layer with

50

ethyl acetate (3 x 20 mL). Wash organic phase with 1M HCl (3 x 5 mL) and wash the organic

layer with 1M NaHCO3 (3 x 5 mL). Dry organic layer with anhydrous NaSO4 and purify with

a silica plug using 20% ethyl acetate in hexanes. 1H NMR (400 MHz, CDCl3): δ 3.66 (s, 3H),

3.80 (s, 3H), 3.83 (s, 3H), 3.89 (s, 3H), 5.98 (d, 1H), 6.53 (d, 1H), 7.18 (d, 1H), 7.3-7.85 (m,

6H), 7.993 (d, 1H).

3.3.5 Attempted Catalytic Wittig Reaction Experiment Using Ph3PO in Organic

Solvents Without NEt3

3-(2'-Methoxyphenyl)-(E,Z)-propenoic acid methyl ester (2.10). The reaction was

done in a 50 mL round bottom flask with stir bar, in toluene, refluxing for 24 hours under

argon. Add 0.145 (0.5 mmol) triphenylphosphine oxide and 0.07 g (50 mol % of Ph3PO) to

the reaction vessel and then charge it with argon. Add the remaining reagents in the

following order: 10 mL of tolune, 0.06 mL (0.5 mmol) of o-anisaldehyde, 0.05 mL (0.5

mmol) of methyl bromoacetate, and 0.33 mL (2 mmol) of diethoxymethylsilane. After

reacting for 24 hours, cool to 0 oC and then add 5 mL of 1M KOH in methanol. After 3 hours

of mixing, add 3 mL of H2O. Extract organic layer with ethyl acetate (3 x 20 mL). Wash

organic phase with 1M HCl (3 x 5 mL) and wash the organic layer with 1M NaHCO3 (3 x 5

mL). Dry organic layer with anhydrous NaSO4 and purify with a silica plug using 20% ethyl

acetate in hexanes. 1H NMR (400 MHz, CDCl3) δ: 3.66 (s, 3H), 3.80 (s, 3H), 3.83 (s, 3H),

3.89 (s, 3H), 5.98 (d, 1H), 6.53 (d, 1H), 7.18 (d, 1H), 7.3-7.85 (m, 6H), 7.993 (d, 1H).

3.3.6 Standard Wittig Reaction Experiment Using Diethoxymethylsilane and Ph3P

3-(2'-Methoxyphenyl)-(E,Z)-propenoic acid methyl ester (2.11). This reaction was

carried out in a 25 mL round bottom with stir bar, under argon, and refluxing in toluene for

24 hours. Add 0.306 g (1.1 mmol) of triphenylphosphine, and charge reaction vessel with

argon. Add the following remaining reagents in the following order: 10 mL of toluene, 0.121

mL (1 mmol) of o-anisaldehyde, 0.104 mL (1.1 mmol) methyl bromoacetate, and 0.50 mL (3

mmol) of diethoxymethylsilane. After the reaction goes for 24 hours, let cool to RT and add

5 mL of 1M HCl. Add 3 mL of DCM to reaction vessel and separate organic phase using

DCM. Wash the aqueous layer with DCM (3 x 5 mL). Dry the combined layers using

51

anhydrous MgSO4. Run crude through a dry silica plug using 20% ethyl acetate in hexanes. 1H NMR (400 MHz, CDCl3): δ 3.66 (s, 3H), 3.80 (s, 3H), 3.83 (s, 3H), 3.89 (s, 3H), 5.98 (d,

1H), 6.53 (d, 1H), 7.18 (d, 1H), 7.3-7.85 (m, 6H), 7.993 (d, 1H).

3.3.7 Attempted Catalytic Wittig Reaction Using O’Brien’s Protocol, Sodium Carbonate, and Ph3PO

(E,Z)-Methyl cinnamate (2.12). The reaction was conducted in a 50 mL round bottom

flask with stir bar, under argon and refluxing in toluene for 96 hours. First add 0.160 g (1.5

mmol) of sodium carbonate and 28 mg (10 mol %) of triphenylphosphine oxide to the

reaction vessel and put the reaction vessel under argon. Add the remaining reagents in the

following order: 10 mL of toluene, 0.102 mL (1 mmol) of benzaldehyde, 0.123 mL (1.3

mmol) methyl bromoacetate, and 0.21 mL (1.1 mmol) of diphenylsilane. Let the reaction

cool to RT after the 96 hour reaction time. Add 5 mL of ethyl acetate to the reaction vessel.

Wash the organic phase with H2O (3 x 10 mL). Wash the aqueous phase with ethyl acetate (1

x 10 mL). Dry organic layer with anhydrous NaSO4 and purify with a silica plug using 20%

ethyl acetate in hexanes. 1H NMR (400 MHz, CDCl3): δ 3.71 (s, 3H), 3.809 (s, 3H), 5.95 (d,

1H), 6.44 (d, 1H), 6.98 (d, 1H), 7.4-7.6 (m, 8H), 7.69 (d, 1H).

3.3.8 “On Water” Reduction of Ph3PO

Triphenylphosphine (2.13 thru 2.20). Reactions 2.13 thru 2.25 were done using a

microwave reactor. Reaction conditions were determined based off of a conversion chart. To

simulate water refluxing at 100 oC for 24 hours, the reactions ran for 13 minutes at 160 oC in

the microwave reactor. All the reactions were done in a 10 mL vial with a v-stir bar and stop

cap filled with 2 mL of H2O. For reactions 2.13 to 2.15, diphenylsilane is used as the silane.

For reactions 2.16 to 2.18, triisopropylsilane is used as the silane. For reaction 2.19, PMHS

was used and for reaction 2.20, TMDS was used. For reaction 2.13, add 0.07 (0.25 mmol) of

triphenylphosphine oxide, 0.19 mL (1 mmol) of diphenylsilane and 0.009 g (15 mol %) of

diphenylsilane. For reaction 2.14, add 0.07 g (0.25 mmol) of triphenylphosphine oxide, 0.19

mL (1 mmol) of diphenylsilane and 0.013 g (15 mol %) of bis(4-nitrophenyl)phosphate. For

reaction 2.15, add 0.021 g of triphenylphosphine oxide (0.075 mmol), 0.013 g (0.075 mmol)

of 4-nitrobenzoic acid, 0.18 mL (1.05 mmol) of DIPEA, and 0.020 mL (1.05 mmol) of

diphenylsilane. For reaction 2.16, add 0.07 g (0.25 mmol) of triphenylphosphine oxide, 0.013

52

g (15 mol %) of bis(4-nitrophenyl)phosphate, and 0.205 mL (1 mmol) of triisopropylsilane).

For reaction 2.17, add 0.07 g (0.25 mmol) of triphenylphosphine oxide, 0.009 g (15 mol %)

of diphenylphosphate, and 0.205 mL (1 mmol) of triisopropylsilane). For reaction 2.18, add

0.021 g (0.075 mmol) of triphenylphosphine oxide, 0.013 g (0.075 mmol) of 4-nitrobenzoic

acid, 0.22mL (1.05 mmol) of triisopropylsilane, and 0.18 mL (1.05 mmol) of DIPEA. For

reaction 2.19, add 0.13 mL (0.052 mmol) of PMHS, 0.0145 g (0.052mmol) of

triphenylphosphine oxide, and 0.002 g (15mol %) of diphenylphosphate. For reaction 2.20,

add 0.03 g (0.1 mmol) of triphenylphosphine oxide, 0.05 mL (0.1 mmol) of TMDS, and

0.004 g (15 mol %) of diphenylphosphate. Separate organic phase with DCM. Wash aqueous

phase with DCM (1 x 5 mL). Dry combined organic phases with anhydrous NaSO4. 1H NMR

(400 MHz, CDCl3): δ 7.33 (m, 15H). 31P NMR (400 MHz, CDCl3): δ -7.29 (s, 1P).

3.3.9 Reduction of Ph3PO in 15% DMSO and Water

Triphenylphosphine (2.21). Reaction was conducted in a 50 mL round bottom with

stir bar refluxing at 100 oC for 24 hours. First, add 0.07 g (0.025 mmol) of

triphenylphosphine oxide and then dilute in 0.7 mL (15% of 4.7 mL) of DMSO. Add stir bar

and then add the remaining reagents in the following order: 4 mL of H2O, 0.14 mL (0.75

mmol) of diphenylsilane, and 0.009 g (15 mol %) of diphenylsilane. Reaction cooled to RT

after 24 hours. Organic separated with 5 mL of ethyl acetate. Aqueous layer washed with

ethyl acetate (1 x 5 mL). Organic layers combined and dried using anhydrous NaSO4. 1H

NMR (400 MHz, CDCl3): δ 7.33 (m, 15H). 31P NMR (400 MHz, CDCl3): δ -7.29 (s, 1P).

3.3.10 Attempted Catalytic Wittig Reaction in Water Using 5% DMSO, NaCO3, Ph3PO, and Ph2SiH2

(E,Z)-Methyl cinnamate (2.22). This reaction was done in a 50 mL round bottom with

stir bar in 10 mL of H2O for 96 hours. First, add 0.028 (10 mol %) triphenylphosphine oxide

and then add 0.5 mL (5% of 10.5 mL) DMSO. Stir until triphenylphosphine oxide is

homogenous throughout mixture. Add remaining reagents in the following order: 0.102 mL

(1 mmol) of benzaldehyde, 0.123 mL (1.3 mmol) of methyl bromoacetate, 0.123 mL (1.1

mmol) of diphenylsilane and 0.160 g (1.5 mmol) of sodium carbonate. Let reaction run for 96

hours and then let cool to RT. Add 5 mL of ethyl acetate and separate organic phase from

aqueous phase. Wash aqueous phase once with ethyl acetate (1 x 5 mL). Dry combined

53

organic phases with anhydrous NaSO4. Dry organic layer with NaSO4 and purify with a silica

plug using 10% ethyl acetate in hexanes. 1H NMR (400 MHz, CDCl3): δ 3.71 (s, 3H), 3.809

(s, 3H), 5.95 (d, 1H), 6.44 (d, 1H), 6.98 (d, 1H), 7.4-7.6 (m, 8H), 7.69 (d, 1H).

3.4 EXPERIMENTAL WORK TOWARDS AN “ON WATER”

CATALYTIC WITTIG REACTION USING 3-METHYL-1-PHENYLPHOSPHOLANE OXIDE

The following experiments are those done with 3-methyl-1-phenylphospholane and 3-

methyl-1-phenylphospholane oxide in development of an “on water” catalytic Wittig

reaction.

3.4.1 Optimized O’Brien Catalytic Wittig Reaction in Toluene

(E,Z)-Methyl cinnamate (2.23). This reaction took place in a 50 mL round bottom

with magnetic stir bar refluxing in H2O for 24 hours. Add the reagents in the following order:

19 mg (20 mol %) 3-methyl-1-phenylphospholane oxide, 0.051 mL (0.5 mmol)

benzaldehyde, 0.051 mL methyl bromoacetate (0.55 mmol), 0.28 mL (1.5 mmol)

diphenylsilane, and 0.26 (1.5 mmol) DIPEA. Add 10 mL of ethyl acetate to reaction after

cooling reaction to RT. Separate the organic phase from aqueous phase using ethyl acetate.

Wash organic phase with 1 M HCl (2 x 10 mL). Wash combined organic phases with 10%

NaOH (aq) (2 x 10 mL). Use brine when needed. Dry combined organic phase with

anhydrous NaSO4. Run a flash column using 10% ethyl acetate in hexanes. Product has an Rf

value of 0.5 in 10% ethyl acetate in hexanes. Next, run a second column using DCM as the

solvent. The isolated product has an Rf value of 0.8 in DCM. 1H NMR (400 MHz, CDCl3): δ

3.71 (s, 3H), 3.809 (s, 3H), 5.95 (d, 1H), 6.44 (d, 1H), 6.98 (d, 1H), 7.4-7.6 (m, 8H), 7.69 (d,

1H).

3.4.2 “On Water” Wittig Reaction Using 3-methyl-1-phenylphospholane

(E,Z)-Methyl cinnamate (2.24). The reaction was done in a 50 mL round bottom with

magnetic stir bar refluxing for 24 hours. The reagents were added in the following order:

0.05 mL (0.5 mmol) benzaldehyde, 0.05 mL (0.55 mmol) methyl bromoacetate, 0.26 mL (1.5

mmol) DIPEA, and 0.098 g (0.55 mmol) of 3-methyl-1-phenylphospholane. After 24 hours,

54

reaction was cooled to RT. Add 5 mL of 1M HCl. Add 5 mL of ethyl acetate and separate

organic phase using ethyl acetate. Wash aqueous phase once with 5 mL ethyl acetate. Dry

combined organic phases using anhydrous NaSO4 and purify with a silica plug using 10%

ethyl acetate in hexanes. 1H NMR (400 MHz, CDCl3): δ 3.71 (s, 3H), 3.809 (s, 3H), 5.95 (d,

1H), 6.44 (d, 1H), 6.98 (d, 1H), 7.4-7.6 (m, 8H), 7.69 (d, 1H).

3.4.3 “On Water” Reduction of 3-methyl-1-phenylphospholane oxide

3-Methyl-1-phenylphospholane (2.25). Reaction was done in a 25 mL round bottom

with a stir bar in water refluxing for 24 hours. The reagents were added in the following

order: 0.097 g (0.5 mmol) 3-methyl-1-phenylphospholane oxide, and 0.28 mL (1.5 mmol) of

diphenylsilane. Cool reaction to RT. Separate organic phase from the aqueous phase using

ethyl acetate. Wash aqueous phase once with ethyl acetate. Dry combined organic phase

under anhydrous NaSO4. Wash organic phase multiple times with hexanes to further purify

and separate from white solid. Analyze using 31P NMR. 31P NMR (500 MHz, CDCl3): δ -

13.58 (s, 1P), -13.98 (s, 1P).

3.4.4 Attempted “On Water” Catalytic Wittig Reaction using Optimized O’Brien Catalytic

Wittig Reaction Protocol

(E,Z)-Methyl cinnamate (2.26). This reaction took place in a 50 mL round bottom

with magnetic stir bar refluxing in H2O for 24 hours. Add the reagents in the following order:

19 mg (20 mol %) 3-methyl-1-phenylphospholane oxide, 0.051 mL (0.5 mmol)

benzaldehyde, 0.051 mL methyl bromoacetate (0.55 mmol), 0.28 mL (1.5 mmol)

diphenylsilane, and 0.26 (1.5 mmol) DIPEA. Cool reaction to RT after running for 24 hours.

Adjust the pH to 5.5 using 1M H2SO4. Add 5 mL of ethyl acetate to the reaction and separate

the organic phase from the aqueous phase using ethyl acetate. Wash the aqueous phase once

with ethyl acetate. Dry combined organic phase with anhydrous NaSO4. 1H NMR (400 MHz,

CDCl3): δ 3.71 (s, 3H), 3.809 (s, 3H), 5.95 (d, 1H), 6.44 (d, 1H), 6.98 (d, 1H), 7.4-7.6 (m,

8H), 7.69 (d, 1H).

55

3.4.5 Attempted “On Water” Catalytic Wittig Reactions Using 3-methyl-1-phenylphospholane oxide

and Na2CO3/NaHCO3

(E,Z)-Methyl cinnamate (2.27 and 2.28). These reactions took place in a 50 mL

round bottom with magnetic stir bar refluxing in H2O for 24 hours. For reaction 2.27, add the

reagents in the following order: 19 mg (20 mol %) 3-methyl-1-phenylphospholane oxide,

0.051 mL (0.5 mmol) benzaldehyde, 0.051 mL methyl bromoacetate (0.55 mmol), 0.28 mL

(1.5 mmol) diphenylsilane, and 0.158 g (1.5 mmol) sodium carbonate. For reaction 2.28, add

the reagents in the following order: 19 mg (20 mol %) 3-methyl-1-phenylphospholane oxide,


(1.5 mmol) diphenylsilane, and 0.126 g (1.5 mmol) sodium bicarbonate. Add 5 mL of ethyl

acetate to the reaction and separate the organic phase from the aqueous phase using ethyl

acetate. Wash the aqueous phase once with ethyl acetate. Dry combined organic phase with

anhydrous NaSO4. Run crude through a silica plug using 10% ethyl acetate in hexanes. Wash

organic phase multiple times with hexanes to remove a white solid. 1H NMR (400 MHz,

CDCl3): δ 3.71 (s, 3H), 3.809 (s, 3H), 5.95 (d, 1H), 6.44 (d, 1H), 6.98 (d, 1H), 7.4-7.6 (m,

8H), 7.69 (d, 1H).

3.4.6 Attempted “On Water” Catalytic Wittig Reactions Using O’Brien’s Protocol and Tertiary

Nitrogen Bases

(E,Z)-Methyl cinnamate (2.29 to 2.31). These reactions took place in a 50 mL round

bottom with magnetic stir bar refluxing in H2O for 24 hours. For reaction 2.29, add the



(1.5 mmol) diphenylsilane, and 0.29 g (1.5 mmol) DMAP. For reaction 2.30, add the



(1.5 mmol) diphenylsilane, and 0.21 mL (1.5 mmol) triethylamine. For reaction 2.31, add the



(1.5 mmol) diphenylsilane, and 0.19 mL (1.5 mmol) N,N-dimethylaniline. Add 5 mL of ethyl

56



anhydrous NaSO4. Run crude through a flash column using 10% ethyl acetate in hexanes.

Next, run a second column using DCM as the solvent. The isolated product has an Rf value of

0.8 in DCM. Analyze using 1H NMR. 1H NMR (400 MHz, CDCl3): δ 3.71 (s, 3H), 3.809 (s,

3H), 5.95 (d, 1H), 6.44 (d, 1H), 6.98 (d, 1H), 7.4-7.6 (m, 8H), 7.69 (d, 1H).

3.4.7 Initial Optimization Attempts of Experiment 2.31




0.051 mL (0.5 mmol) benzaldehyde, 0.09 mL methyl bromoacetate (0.9 mmol), 0.28 mL (1.5

mmol) diphenylsilane, and 0.19 mL (1.5 mmol) N,N-dimethylaniline. For reaction 2.33, add

the reagents in the following order: 19 mg (20 mol %) 3-methyl-1-phenylphospholane oxide,

0.051 mL (0.5 mmol) benzaldehyde, 0.09 mL methyl bromoacetate (0.9 mmol), 0.28 mL (1.5

mmol) diphenylsilane, and 0.152 mL (0.6 mmol) N,N-dimethylaniline. Add 5 mL of ethyl



anhydrous NaSO4. Run crude through a flash column using 10% ethyl acetate in hexanes.

Next, run a second column using DCM as the solvent. The isolated product has an Rf value of

0.8 in DCM. 1H NMR (400 MHz, CDCl3): δ 3.71 (s, 3H), 3.809 (s, 3H), 5.95 (d, 1H), 6.44

(d, 1H), 6.98 (d, 1H), 7.4-7.6 (m, 8H), 7.69 (d, 1H).

3.4.8 Optimization Attempts of Experiment 2.31 with Greater Equivalents of Methyl Bromoacetate





(1.5 mmol) diphenylsilane, and 0.19 mL (1.5 mmol) N,N-dimethylaniline. For reaction 2.34,

add the reagents in the following order: 19 mg (20 mol %) 3-methyl-1-phenylphospholane

57

oxide, 0.051 mL (0.5 mmol) benzaldehyde, 0.24 mL methyl bromoacetate (2.5 mmol), 0.28

mL (1.5 mmol) diphenylsilane, and 0.152 mL (0.6 mmol) N,N-dimethylaniline. Add 5 mL of

ethyl acetate to the reaction and separate the organic phase from the aqueous phase using

ethyl acetate. Wash the aqueous phase once with ethyl acetate. Dry combined organic phase

with anhydrous NaSO4. Run crude through a flash column using 10% ethyl acetate in

hexanes. Next, run a second column using DCM as the solvent. The isolated product has an

Rf value of 0.8 in DCM. 1H NMR (400 MHz, CDCl3): δ 3.71 (s, 3H), 3.809 (s, 3H), 5.95 (d,

1H), 6.44 (d, 1H), 6.98 (d, 1H), 7.4-7.6 (m, 8H), 7.69 (d, 1H).

58

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9. Pavia, D.; Lampman, G.; Kriz, G.; Engel, R. Introduction to Organic Laboratory Techniques A Small Scale Approach, 2nd ed.; Thompson Brooks Cole: Belmont, CA, 2005; pp 341-347.

10. Lampman, G. M.; Koops, R. W.; Olden, C. C. Phosphorus and sulfur ylide formation: Preparation of 1-benzoyl-2-phenylcyclopropane and 1,4-diphenyl-1,3-butadiene by phase transfer catalysis. J. Chem. Educ. 1985, 62, 267-268.

11. Gillois, J.; Guillerm, G.; Savignac, M.; Stephan, E.; Vo-Quanq, L. Diphenylbutadienes syntheses by means of the Wittig reaction: Experimental introduction to the use of phase transfer catalysis. J. Chem. Educ. 1980, 57, 161-162.

12. Warner, J. C.; Anastas, P.T.; Anselme, J.-P. The Wittig Reaction in the Undergraduate Organic Laboratory. J. Chem. Educ. 1985, 62, 346.

13. Silversmith, E. F. A Wittig reaction that gives only one stereoisomer. J. Chem. Educ. 1986, 63, 645.

14. Breuer, S. W. The Wittig synthesis of alkenes by phase-transfer catalysis: The syntheses of 4,4'-dichlorostilbenes and of E, E-1,4 –diphenylbutadiene. J. Chem. Educ. 1991, 68, A58-A60.

59

15. Wilcox, C. F.; Wilcox, M. F. Experimental Organic Chemistry: A Small-Scale Approach, 2nd ed.; Prentice Hall: Upper Saddle River, NJ, 1995; pp 369-370.

16. Jaworek, C.; Iacobucci, S. Wittig Reaction: The Synthesis of trans-9-(2-Phenylethenyl)anthracene Revisited. J. Chem. Educ. 2002, 79, 111.

17. Broos, R.; Tavernier, D.; Anteunis, M. p-Carboxystyrene. A Wittig procedure in aqueous medium. J. Chem. Educ. 1978, 55, 813.

18. Pike, R. M.; Mayo, D. W.; Butcher, S. S.; Butcher, D. J.; Hinkle, R. J. Microscale organic laboratory: IV: A simple and rapid procedure for carrying out Wittig reactions. J. Chem. Educ. 1986, 63, 917-918.

19. Balema, V. P.; Wiench, J. W.; Pruski, M.; Pecharsky, V. K. Mechanically Induced Solid-State Generation of Phosphorus Ylides and the Solvent-Free Wittig Reaction. J. Am. Chem. Soc. 2002, 124, 6244-6245.

20. Leung, S. H.; Angel, S. A. Solvent-Free Wittig Reaction: A Green Organic Chemistry Laboratory Experiment. J. Chem. Educ. 2004, 81, 1492-1493.

21. Martin, E.; Kellen-Yuen, C. Microwave-Assisted Organic Synthesis in the Organic Teaching Lab: A Simple, Greener Wittig Reaction. J. Chem. Educ. 2007, 84, 2004-2006.

22. Baar, M.; Falcone, D.; Gordon, C. Microwave-Enhanced Organic Syntheses for the Undergraduate Laboratory: Diels−Alder Cycloaddition, Wittig Reaction, and Williamson Ether Synthesis. J. Chem. Educ. 2010, 87, 84-86.

23. Zovinka, E.; Stock, A. Microwave Instruments: Green Machines for Green Chemistry? J. Chem. Educ. 2010, 87, 350-352.

24. Speed, Traci J.; McIntyre, Jean P.; Thamattoor, Dasan M. Wittig Reaction Using a Stabilized Phosphorus Ylid: An Efficient and Stereoselective Synthesis of Ethyl trans-Cinnamate. J. Chem. Educ. 2004, 81, 1355-1356.

25. Narayan, S.; Muldoon, J.; Finn, M.; Fokin, V.; Kolb, H.; Sharpless, B. “On Water”: Unique Reactivity of Organic Compounds in Aqueous Suspension. Angew. Chem. Int. Ed. 2005, 44, 3275-3279.

26. El-Batta, A.; Jiang, C.; Zhao, W.; Anness, R.; Cooksy, A. L.; Bergdahl, M. Wittig Reactions in Water Media Employing Stabilized Ylides with Aldehydes. Synthesis of α,β-Unsaturated Esters from Mixing Aldehydes, α-Bromoesters, and Ph3P in Aqueous NaHCO3. J. Org. Chem. 2007, 72, 5244-5259.

27. Sigma Aldrich. Proton NMR of triphenylphosphine. http://www.sigmaaldrich.com/ catalog/product/fluka/93090?lang=en&region=US (accessed Jan 2014).

28. Sigma Aldrich. Proton NMR of ethyl bromoacetate. http://www.sigmaaldrich.com/ catalog/product/aldrich/133973?lang=en&region=US (accessed Jan 2014).

29. Sigma Aldrich. Proton NMR of benzaldehyde. http://www.sigmaaldrich.com/ catalog/product/aldrich/418099?lang=en&region=US (accessed Jan 2014).

30. R. W. Sidley. Silica Dust Material Safety Data Sheet. http://www.rwsidley .com/MSDS/manley.pdf (accessed Jan 2014).

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31. Van Kalkeren, H.; Blom, A.; Rutjes, F.; Huijbregts, M. On the usefulness of life cycle assessment in early chemical methodology development: the case of organophosphorus-catalyzed Appel and Wittig reactions. Green Chem. 2013, 15, 1255-1263.

32. Fairlamb, Ian. J. S. The Phosphine-Catalyzed Wittig Reaction: A New Vista for Olefin Synthesis? ChemSusChem. 2009, 2, 1021-1024.

33. Shi, L.; Wang, W.; Wang, Y.; Huang, Y. –Z. The first example of a catalytic Wittig-type reaction. Tri-n-butylarsine-catalyzed olefination in the presence of triphenyl phosphite. J. Org. Chem. 1989, 54, 2027-2028.

34. Huang, Z. –Z.; Tong, Y. Unexpected Catalyst for Wittig-Type and Dehalogenation Reactions. J. Org. Chem. 2002, 67, 5320-5326.

35. O’Brien, C. J.; Tellez, J.; Nixon, Z.; Kang, L.; Carter, A.; Kunkel, S.; Przeworski, K.; Chass, G. Recycling the Waste: The Development of a Catalytic Wittig Reaction. Angew. Chem. Int. Ed. 2009, 48, 6836-6839.

36. Li, Y.; Lu, L. –Q.; Das, S. Pisiewicz, S. Junge, K.; Beller, M. Highly Chemoselective Metal-Free Reduction of Phosphine Oxides to Phosphines. J. Am. Chem. Soc. 2012, 134, 18325-18329.

37. Henson, P.; Naumann, K.; Mislow, K. Stereomutation of phosphine oxides by lithium aluminum hydride. J. Am. Chem. Soc. 1969, 91, 5645.

38. Kobayashi, S.; Suzuki, M; Saegusa, T. A New Reduction Method of Poly(phosphine oxide) to Polyphosphine. Preparation of Poly[(P-phenyl)trimethylenephosphine]. Polym. Bull. 1982, 8, 417.

39. Imamoto, T.; Takeyama, T.; Kusumoto, T. Facile Reduction of Organic Halides and Phosphine Oxides with LiAlH4–CeCl3.Chem. Lett. 1985, 10, 1491.

40. Imamoto, T.; Kikuchi, S.; Miura,T.; Wada, Y. Stereospecific Reduction of Phosphine Oxides to Phosphines by the Use of a Methylation Reagent and Lithium Aluminum Hydride. Org. Lett. 2001, 3, 87.

41. Busacca, C.; Raju, R.; Grinberg, N.; Haddad, N.; James-Jones, P. Lee, H.; Lorenz, J.; Saha, A; Senanayake, C. Reduction of Tertiary Phosphine Oxides with DIBAL-H. J. Org. Chem. 2008, 73, 1524.

42. Rajendran, K.; Gilheany, D. Simple unprecedented conversion of phosphine oxides and sulfides to phosphine boranes using sodium borohydride. Chem. Comm. 2012, 48, 817.

43. Bethod, M.; Favre-Reguillon, A.; Mohamad, J.; Mignani, G.; Docherty, G.; Lemaire, M. A Catalytic Method for the Reduction of Secondary and Tertiary Phosphine Oxides. Synlett 2007, 10, 1545.

44. Petit, C.; Favre-Reguillon, A.; Albela, B.; Bonneviot, L.; Mignani, G.; Lemaire, M. Mechanistic Insight into the Reduction of Tertiary Phosphine Oxides by Ti(OiPr)4/TMDS. Organometallics 2009, 28, 6379.

61

45. Petit, C.; Favre-Reguillon, A.; Mignani, G.; Lemaire, M. A straightforward synthesis of unsymmetrical secondary phosphine boranes. Green Chem. 2010, 12, 326.

46. Coumbe, T. Lawrence, N.; Muhammad, F. Titanium (IV) catalysis in the reduction of phosphine oxides. Tetrahedron Lett. 1994, 35, 625–628.

47. O’Brien, C. J.; Lavigne, F.; Coyle, E. E.; Holohan, A. J.; Doonan, B. Breaking the Ring through a Room Temperature Catalytic Wittig Reaction. Chem. Eur. J. 2013, 19, 5854-5858.

48. O’Brien, C. J.; Nixon, Z.; Holohan, A.; Kunkel, S.; Tellez, J.; Doonan, B.; Coyle, E.; Lavigne, F.; Kang, L.; Przeworski, K. Part I: The Development of the Catalytic Wittig Reaction. Chem. Eur. J. 2013, 19, 15281-15289.

49. Fringuelli, F.; Piermatti, O.; Pizzo, F. Oxidation and Reductions in Water. In Organic Synthesis in Water, Grieco, P., Ed.; Springer: Netherlands, 1997; pp. 236-246.

50. Greaney, M.; Smith, J. A one-pot silyl-Reformatsky olefination. Tetrahedron Lett. 2007, 48, 8687-8690.

51. Naumann, K.; Zon, G.; Mislow, K. Use of hexachlorodisilane as a reducing agent. Stereospecific deoxygenation of acyclic phosphine oxides. J. Am. Chem. Soc. 1969, 91, 7012-7023.

52. Addis, D.; Das, S.; Junge, K.; Beller, M. Selective Reduction of Carboxylic Acid Derivatives by Catalytic Hydrosilylation. Angew. Chem. Int. Ed. 2011, 50, 6004-6011.

62

APPENDIX A

JOURNAL OF CHEMICAL EDUCATION “ON

WATER” WITTIG REACTION LABORATORY

EXPERIMENT SUBMISSION

63

The “On Water” type Wittig Reaction as an Essential Experiment in the Undergraduate Organic Chemistry Teaching Laboratory Lucas B. Fallot, Michael Kelly, and B. Mikael Bergdahl* Department of Chemistry and Biochemistry, San Diego State University, San Diego, California 92182-1030, United States

ABSTRACT 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 this proposed greener “on-water” type Wittig reaction methodology.

KEYWORDS Green Chemistry, Aqueous, Wittig Reaction, Organic Chemistry, Alkene, Synthesis

Sustainability and environmental protection are two increasingly critical issues in our society, but in many cases greener practices have been only slowly adopted in the chemistry laboratory. Often, especially at the undergraduate level, many laboratory procedures are little changed from those of fifty years ago. In order to increase awareness and adoption of practical greener chemistry in the future, it is essential to positively inform students early in their education about the alternatives possible for more environmentally-friendly chemistry.1 The Wittig reaction is a fundamental introductory organic chemistry reaction that can be used to promote practical greener chemistry by way of replacing organic solvents with water. Water is by its very nature nontoxic, cost-effective and less-harmful to the environment than the organic solvents traditionally used for the Wittig reaction, and it represents the outside-the-box thinking that will be necessary for a more-sustainable approach to common chemical problems without diminishing the larger lesson: the fundamental utility of the Witting reaction.

In order to best demonstrate the thinking necessary for the implementation of greener solutions to common chemical problems, it is helpful to first examine and compare some traditional Wittig reaction protocols from literature. The Wittig reaction is a fundamental method for the synthesis of alkenes and variations of it can be found in many laboratory textbooks as well as in the Journal of Chemical Education, as the samples below show. Among these sources, none discuss green chemistry or demonstrate that a simple Wittig reaction can be done in water in a way that can be easily and practically conducted by undergraduate students in a teaching laboratory.

In accordance with The Twelve Principles of Green Chemistry,2 harmful substances like toxic solvents, pyrophoric reagents and lachrymators should be minimized or replaced where possible and practical. Yet in some of these published protocols intended for undergraduate laboratories, pyrophoric reagents like butyllithium and lachrymators, like benzyl chloride, are used in order to make an unstable ylide.3,4 One case calls for the use of sodium hydride, which would seem unsuitable as a reagent in an undergraduate teaching laboratory.5a Another Wittig protocol in one of the textbooks still commonly used calls for

64

the use of sodium metal to make the strong base sodium ethoxide.5b In addition to obvious safety concerns, the use of many of these reagents is wholly unnecessary, and requires laboratories to be equipped with inert gas support and special waste bins, both factors which can increase the cost and reduce the practicality of the execution of the experiments in a teaching laboratory, and which can require precious lab time for special student training.

The use of phase transfer catalysis is another common protocol for conducting Wittig chemistry.6-12 These reactions are also carried out in two steps: the in situ preparation of the ylide followed by the Wittig reaction itself. These reactions also commonly use lachrymators in the first step to form the phosphonium salt. However, in contrast to the previous examples which used pyrophoric or air-sensitive bases, a 50% aqueous sodium hydroxide solution is used to produce the ylide, which is a step toward a greener and safer approach to the chemistry, yet still holds more hazards than other options. An additional J. Chem. Ed. paper13 illustrates a one-phase transfer catalysis Wittig experiment using a 50-fold excess of formaldehyde, a well-known carcinogen.

In another Wittig protocol, the use of an “instant ylid” greatly simplifies the reaction,14 but is unfortunately potentially harmful in a teaching laboratory setting because of the use of an alkyl triphenylphosphonium bromide and sodium amide, an unnecessarily strong, toxic base, in anhydrous THF. It also reduces the practicality of the experiment because of its water sensitivity.

There are published experiments which describe much safer and greener strategies in performing Wittig reactions in the undergraduate teaching laboratory.15,16 Examples of these include solvent-free Wittig reactions that use either a ball milling apparatus or a mortar and pestle to replace the use of organic solvents during the reaction. The ball milling protocol involves an innovative one-pot Wittig reaction with very safe and inexpensive potassium carbonate as the base, but unfortunately this reaction takes 8 hours to conduct. The use of a mortar and pestle in a solvent-free reaction is another wonderful example of a green innovation in Wittig chemistry, but reproducibility becomes a real problem because of the variables involved in physically grinding the reactants.

The microwave accelerated Wittig reaction is another alternative way to introduce greener chemistry into the teaching laboratory.17,18 One procedure utilizes a common household microwave, and the other reports the use of a microwave reactor specifically designed for organic reactions. The reported common household microwave experiment does not require the use of a solvent, and it utilizes potassium carbonate to generate the ylide, which seems like an attractive greener alternative. Although the common household microwave is a relatively inexpensive instrument to use in a teaching laboratory, it might become a liability. It does not have the built-in safety features found in microwave reactors specifically made for conducting organic reactions; for example, a reinforced steel reaction chamber and a special door-locking mechanism in the event of a reaction vessel rupture. Thus, with the potential for overheating and explosions, the use of a household type microwave is not recommended in the undergraduate teaching laboratory. In regard to the laboratory experiment utilizing a microwave reactor specifically designed for organic reactions, the Wittig reaction is conducted in 3 separate phases and the reactor is used only in the first phase to produce high yields of the phosphonium salt in 6.5 minutes. Although the reaction time, safety features of the microwave reactor, and increased phosphonium salt yield utilizing the reactor make this reaction appealing, the experiment calls for the use of xylenes, a chemical that permeates the skin and is not safe to use with undergraduate students, and the cost of maintaining such a piece of equipment makes this approach less practical.

In order to emphasize the importance and methods of practical environmentally-friendly chemistry and at the same time maintain a high level of safety in the organic chemistry teaching laboratory, we hereby propose the introduction of a water-based Wittig reaction as a complement to previously reported methods.

65

We recommend the adaptation of a simple Wittig reaction protocol that can be conducted in aqueous saturated sodium bicarbonate media using safer reagents where possible – an experiment suitable for the organic teaching laboratory (Scheme 1). This organic reaction allows educators to provide students with a safer, fast, simpler, less expensive and more effective means to conduct a greener Wittig reaction. Water is not considered a “solvent” in this reaction but rather a “medium” since the reagents are quite hydrophobic and appear insoluble. Aqueous sodium bicarbonate is a relatively weak and safe base for students, used here to generate in-situ the stabilized ylide needed for the Wittig reaction to produce the alkene product. Though ethyl bromoacetate is classified as a lachrymator, its use is minimized. The proposed experiment does not use pyrophoric reagents requiring an inert atmosphere or any special training. Adding to the simplicity of the experiment, the reaction is done at ambient temperature utilizing common laboratory equipment. In consideration of cost, water is obviously much less costly than organic solvents. Water is also environmentally benign and has been shown to be effective as a medium in many organic reactions, and therefore can be considered as an option to replace harmful solvents in other organic reactions. Rather than purchasing the ylide, here it is generated in-situ using inexpensive starting materials. The proposed reaction and work-up can be conducted during a three hour organic laboratory period. Students without the experience of conducting the purification on a silica-plug need an additional laboratory period of circa three hours.

Water is a remarkably efficient medium for the Wittig reaction and can be used with a wide range of stabilized ylides and aldehydes. Even more astonishing is the increase in reaction rate that is evident in water as compared to common organic solvents even though the reaction seems heterogeneous in water.19 We have also reported that Wittig reactions in water work best when large hydrophobic entities like aromatic functional groups are present.20 Despite the reactants’ poor solubility, aqueous Wittig reactions have very high yields with high precedence for trans (E)-selectivities.

EXPERIMENTAL PROCEDURE

Add 0.367 g (1.40 mmol) of triphenylphosphine to a 20 mL scintillation vial with a flat magnetic stir bar (Figure 1). The use of a flat magnetic stir bar on a flat vial surface ensures all reagents properly mix in the reaction vessel. Next, add 5 mL of aqueous saturated sodium bicarbonate, 0.20 mL (1.80 mmol) of ethyl bromoacetate and 0.102 mL (1.00 mmol) of benzaldehyde to the reaction vessel. Stir the heterogeneous reaction mixture vigorously for 2 hours at room temperature and then add 5 mL of ethyl acetate to the reaction vessel. Separate the organic phase using a small separation funnel. Wash the aqueous phase with small portions of ethyl acetate (2 x 5 mL). Combine the organic phases and wash once with 10% aqueous sodium bisulfite (10 mL). Following this, wash once with saturated sodium chloride (5 mL). Dry the organic phase over anhydrous sodium sulfate. Filter the dry organic phase under vacuum on a Buchner funnel and evaporate the ethyl acetate. The pure product has an Rf of circa 0.5 using 10% ethyl acetate/hexane as an eluent. Dissolve the residue in minimum 10% ethyl acetate and hexane and purify on a short silica plug (5 x 2 cm). After evaporating the organic solvent determine the yield (%) and analyze the product using 1H-NMR (Figure 2).

66

RESULTS AND DISCUSSION The product composition can be analyzed by 1H-NMR spectroscopy. The students are

able to compare their product 1H-NMR data with 1H-NMR data of the starting material and reagents. The students will also be able to determine the trans/cis (E/Z) ratio of their alkene products in their NMR spectrum. By washing the organic phase with sodium bisulfite it is possible to remove unreacted aldehyde in the crude reaction mixture. The triphenylphosphine oxide formed during the Wittig reaction is removed on a short silica plug. Most of the unreacted triphenylphosphine remains as a residue when dissolving the crude residue in 10% ethyl acetate in hexane. The triphenylphosphine, which remains will make up very little (~<1%) of the product mass has quite a distinguishable 1H-NMR signal just downfield from the chloroform signal. A typical student product yield was found to be on average 93% with an E/Z ratio of circa 92/8.

Water is shown to be a safe and efficient medium for the Wittig olefination reaction employing an in-situ prepared stabilized ylide and benzaldehyde in a teaching laboratory, despite the heterogeneous appearance of the reaction mixture. The separation of the organic materials from the water still requires the use of a small amount of organic solvent, but benign solvents can be used, and their use can be minimized.

HAZARDS

Ethyl bromoacetate is a lachrymator and should be used with caution in a ventilated hood. Benzaldehyde, and triphenylphosphine are irritants and should be used with caution. Do not inhale silica dust, carefully use in a ventilated hood. Consult safety data sheets for all reagents prior to conducting the laboratory experiment.

ASSOCIATED CONTENT

Supporting Information

Laboratory materials, teacher preparation instructions, student handout, and 1H-NMR data are included. This material is available via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author *E-mail: [[email protected]]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT The authors wish to thank San Diego State University for the “University Grant

Program” in support for the development of this experiment. We also would like to thank the faculty and students at SDSU for their effort in incorporating this laboratory experiment into the undergraduate organic laboratory curriculum.

REFERENCES 1. Hjeresen, D. L.; Schutt, D. L.; Boese, J. M. J. Chem. Educ. 2000, 77, 1543-1547. 2. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New

York, 1998; p 30. 3. Roberts, M. R.; Gilbert, J. C.; Rodewald, L. B.; Wingrove, A. S. An Introduction to Modern

Experimental Organic Chemistry; Holt, Rinehart and Winston, Inc.: New York, 1974; pp 271-279. 4. Garner, C. M. Techniques and Experiments For Advanced Organic Laboratory; John Wiley & Sons,

Inc.: New York, 1997; pp 97-100. 5. a) Breton, G. W. J. Chem. Educ. 1997, 74, 114-115.; b) Pavia, D.; Lampman, G.; Kriz, G.; Engel, R.

Introduction to Organic Laboratory Techniques A Small Scale Approach, 2nd ed., Thompson Brooks Cole: Belmont, CA, 2005; pp 341-347.

6. Lampman, G. M.; Koops, R. W.; Olden, C. C. J. Chem. Educ. 1985, 62, 267-268.

67

7. Gillois, J.; Guillerm, G.; Savignac, M.; Stephan, E.; Vo-Quanq, L. J. Chem. Educ. 1980, 57, 161-162.

8. Warner, J. C.; Anastas, P.T.; Anselme, J.-P. J. Chem. Educ. 1985, 62, 346. 9. Silversmith, E. F. J. Chem. Educ. 1986, 63, 645. 10. Breuer, S. W. J. Chem. Educ. 1991, 68, A58-A60. 11. Wilcox, C. F.; Wilcox, M. F. Experimental Organic Chemistry: A Small-Scale Approach, 2nd ed.;

Prentice Hall: Upper Saddle River, NJ, 1995; pp 369-370. 12. Jaworek, C.; Iacobucci, S. J. Chem. Educ. 2002, 79, 111. 13. Broos, R.; Tavernier, D.; Anteunis, M. J. Chem. Educ. 1978, 55, 813. 14. Pike, R. M.; Mayo, D. W.; Butcher, S. S.; Butcher, D. J.; Hinkle, R. J. J. Chem. Educ. 1986, 63,

917-918. 15. Balema, V. P.; Wiench, J. W.; Pruski, M.; Pecharsky, V. K. J. Am. Chem. Soc. 2002, 124, 6244-

6245. 16. Leung, S. H.; Angel, S. A. J. Chem. Educ. 2004, 81, 1492-1493. 17. Martin, E.; Kellen-Yuen, C. J. Chem. Educ. 2007, 84, 2004-2006. 18. Baar, M.; Falcone, D.; Gordon, C. J. Chem. Educ. 2010, 87, 84-86. 19. Narayan, S.; Muldoon, J.; Finn, M.; Fokin, V.; Kolb, H.; Sharpless, B. Angew. Chem. Int. Ed.

2005, 44, 3275-3279. 20. El-Batta, A.; Jiang, C.; Zhao, W.; Anness, R.; Cooksy, A. L.; Bergdahl, M. J. Org. Chem. 2007, 72,

5244-5259.

68

APPENDIX B

1H NMR, AND 31P NMR OF REACTIONS

69

F

igu

re B

.1. 1 H

NM

R o

f re

acti

on 1

.1.

70

F

igu

re B

.2. 1 H

NM

R o

f re

acti

on 2

.1.

71

F

igu

re B

.3. 31

P N

MR

of

reac

tion

2.5

.

72

F

igu

re B

.4. 1 H

NM

R o

f re

acti

on 2

.5.

73

F

igu

re B

.5. 1 H

NM

R o

f re

acti

on 2

.6.

74

F

igu

re B

.6. 1 H

NM

R o

f re

acti

on 2

.7.

75

F

igu

re B

.7. 1 H

NM

R o

f re

acti

on 2

.8.

76

F

igu

re B

.8. 1 H

NM

R o

f re

acti

on 2

.9.

77

F

igu

re B

.9. 1 H

NM

R o

f re

acti

on 2

.10.

78

F

igu

re B

.10.

1 H N

MR

of

reac

tion

2.1

1.

79

F

igu

re B

.11.

1 H N

MR

of

reac

tion

2.1

2.

80

F

igu

re B

.12.

31P

NM

R o

f re

acti

on 2

.21.

81

F

igu

re B

.13.

1 H N

MR

of

reac

tion

2.2

1.

82

F

igu

re B

.14.

1 H N

MR

of

reac

tion

2.2

2.

83

F

igu

re B

.15.

1 H N

MR

of

reac

tion

2.2

3.

84

F

igu

re B

.16.

1 H N

MR

of

reac

tion

2.2

4.

85

F

igu

re B

.17.

31P

NM

R o

f 3-

met

hyl

-1-p

hen

ylp

hos

ph

olan

e ox

ide.

86

F

igu

re B

.18.

31P

NM

R o

f re

acti

on 2

.25.

87

F

igu

re B

.19.

1 H N

MR

of

reac

tion

2.2

6.

88

F

igu

re B

.20.

1 H N

MR

of

reac

tion

2.2

7.

89

F

igu

re B

.21.

1 H N

MR

of

reac

tion

2.2

8.

90

F

igu

re B

.22.

1 H N

MR

of

reac

tion

2.2

9.

No

prod

uct g

ener

ated

91

F

igu

re B

.23.

1 H N

MR

of

reac

tion

2.3

0.

92

F

igu

re B

.24.

1 H N

MR

of

reac

tion

2.3

1.

93

F

igu

re B

.25.

1 H N

MR

of

reac

tion

2.3

2.

94

F

igu

re B

.26.

1 H N

MR

of

reac

tion

2.3

3.

95

F

igu

re B

.27.

1 H N

MR

of

reac

tion

2.3

4.

96

F

igu

re B

.28.

1 H N

MR

of

reac

tion

2.3

5.

“on water” wittig reaction laboratory experiment

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