Investigating Benign Syntheses Via Mechanochemistry

Investigating benign syntheses via mechanochemistry

A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of

DOCTOR OF PHILOSOPHY (Ph.D.)

in the Department of Chemistry of the College of Arts and Sciences

2020

Lianna N Ortiz-Trankina B.S., Shawnee State University, 2015

Committee Chair: James Mack, Ph.D.

Abstract

In the last few decades, a larger effort has been given toward the development of more environmentally benign and human friendly processes and environments. This dissertation focuses on the use of a high-speed ball mill as a technique for solvent-free and benign mechanochemical synthesis. In order to minimize solvent waste production and the use of hazardous reagents, my research focused on developing safer synthetic routes with the use of benign reagents. There is also a large focus on the interaction and coordination of ions in solid state synthesis and how the lack of solvent can aid with the chemo- and stereoselectivity of these reactions. This work also demonstrates how the mechanochemical nature of these reactions can aid in the overcoming of the activation barrier in specific reactions. This approach is believed to be an environmentally friendly technique to understanding the foundations of many organic synthetic reactions.

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Acknowledgements

There are many people who deserve to be recognized in this section, but first I would like to thank my best friend and partner in life Jared. Thank you for supporting me and pushing me to continue through graduate school when I had doubted myself so many times. Thanks for heeding (take heed of?) my rants, soaking up all the tears, and listening to all my talks. Your endless love, support and encouragement have made this journey endurable.

I would also like to thank Audrey, Jared, and Sean for their hospitality, friendship, and encouragement to go to graduate school. Along with them, I would like to thank the rest of my former SSC family, especially Deanna, Michelle, Amanda, and Debbie, for their help and support. I honestly believe I would not be where I am today without all their generosity. I would like to thank my chemistry professors at Shawnee State, especially Dr. Derek Jones for giving me the opportunity to perform undergraduate research and encouraging me to go to graduate school.

The friends I have made in Cincinnati also deserve recognition. I especially would like to thank Gurdat. Our taco and margarita dates were a constant highlight through this adventure, and I will never forget San Diego. I would also love to thank Melissa. You have been an amazing friend and our Starbucks coffee runs were always the perfect break. I would like to thank the members of the Mack group for all their help, advice, and encouragement. Thank you, Dr.

Mack, for supporting my endeavors and for your mentorship. Your guidance has shaped the way I approach problem solving and mentoring. Heather, Kendra and Becca, thank you for being great friends and mentors even post-graduation. Thank you, Joel and Cong, for all your help, conversations and expertise. Thank you also to the members I am leaving behind:

Jazmine, Niza, Menna, and Rohesh. While I am excited for the future, I will miss our daily (pre-

COVID-19) conversations and laughs. Also, thank you to Jessie. I am so glad you came with us to the Green Chemistry Conference and winning our first The Office trivia with you and Becca is still one of the biggest highlights of my life.

I would also like to thank my e-friends Jamie, Mark, and Nicole. Our daily random conversations are always a highlight. I want to thank you guys for your openness and acceptance. We are all different types of people, yet we click so well as friends and I appreciate your love and encouragement.

Lastly, I would like to thank my parents. I hope someday you stumble upon this and know that I appreciate all that you have done for me. My work ethic, critical thinking, and communication skills all stem from the lessons you taught me throughout the years. I still have that torn piece of notebook paper where “Dr. Lianna Nina Ortiz-Trankina, MD or PhD” was written out. You knew what I was capable of and you encouraged me to always work hard so I could reach my fullest potential.

Thank you to those who provided funding in support of my research, education, and salary during my time in graduate school; namely, the National Science Foundation, the

American Chemical Society and the University of Cincinnati Department of Chemistry.

Table of Contents Abstract ...... ii Acknowledgments ...... iv Table of Contents ...... vi List of Figures ...... viii

List of Symbols ...... xiii Chapter 1. Introduction ...... 1 Mechanochemistry ...... 2

Ball milling ...... 3 Ions and solvent ...... 6 Hard-soft acid-base theory ...... 8 References ...... 12 Chapter 2.Ion Pair Roles in Acid/Base and Nucleophilic Substitution Reactions ...... 14 Introduction ...... 14 Results and Discussion ...... 19 Phenol Williamson Ether Synthesis ...... 19 Electrophilic aromatic substitution production ...... 22 Benzyl alcohol Williamson Ether Synthesis ...... 25

4-bromobenzyl iodide degradation ...... 29 EcoScale ...... 32 Conclusions ...... 35 Experimental ...... 37 References ...... 40 Chapter 3. Ion Pair Regioselectivity and Stereoselectivity ...... 41 Introduction ...... 41 Results and Discussion ...... 42 Ion pair regioselectivity ...... 42

Ion pair stereoselectivity ...... 47 Conclusions ...... 51 Experimental ...... 52 References ...... 54 Chapter 4. Benign Alkyne Chemistry ...... 56 Introduction ...... 56 Results and Discussion ...... 58 Nucleophilic Substitution ...... 58

Nucleophilic Addition ...... 62 Enyne Formation ...... 65 Hydrations ...... 66 Conclusions ...... 72 Experimental ...... 73 References ...... 76 Chapter 5. Calcium Carbide as an Alkyne Source ...... 79 Introduction ...... 79 Results and Discussion ...... 83 A3 Reaction ...... 83

Nucleophilic Additions ...... 85 Nucleophilic Substitutions ...... 87 Conclusions ...... 88 Experimental ...... 90 References ...... 91 Appendix: Spectra ...... 92

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List of Figures

Chapter 1:

Figure 1: Toxic Release Index data for hazardous chemical waste generated in 2017

Figure 2: Different types of ball mills: Wig-L-Bug grinder/mixer, Retsch Mixer Mill MM 400, the

Fritsch Pulverisette 6, and the SPEX SamplePrep 8000 M Mixer/mill

Figure 3: SpexCertiprep mixer mill, reaction vials and ball bearings

Figure 4: The motion of the ball bearing inside a mixer/mill

Figure 5: Types of milling technologies available and the milling motion varying from small scale

(A) SPEX mixer/mill, to medium scale (B) planetary mill, (C) attritor, to production scale (D) rolling ball mill

Figure 6: Polar protic and aprotic solvent shells surrounding NaBr

Figure 7: Crystal lattice structure showing the proposed formation of ion pairs in solventless conditions

Figure 8: Several ions and their characterization as hard or soft

Figure 9: Structural parameters, enthalpy of formation and lattice enthalpies for alkali halides

………......

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Chapter 2:

Figure 1: Proposed stepwise concerted mechanism for mechanochemical acid-base reactions and nucleophilic substitution reactions

Figures 2a & 2b: . Percent conversion and percent yields for different alkali metal phenoxides reacted with different benzyl halides

Figure 3: Proposed Zimmerman-Traxler reaction mechanism for the solventless Williamson Ether synthesis

Figure 4: Percent conversions of the other: para electrophilic aromatic substitution products

Figures 5a &5b: Proposed reaction transition states for the ortho and para-substituted products

Figure 6: Percent conversion of Williamson Ether Synthesis with 1 mmol and 2 mmol of different alkali metal carbonates

Figure 7: Percent yield of 4-bromobenzyl ether using 2 mmol of several alkali metal carbonates

Figure 8: Percent conversion and percent yield of 4-bromobenzyl ether using different alkali metal hydroxides

Figure 9: Comparison of percent conversion to 4-bromobenzyl ether using 1 mmol and 2 mmol carbonates and hydroxides

Figure 10. Thin Layer Chromatography and photos of change in 4-bromobenzyl iodide in acetone over 2 days

Figure 11. 1HNMR of 4-bromobenzyl iodide after 2 days in acetone

.………………………………………………………………………………………………………………………………………………….

Chapter 3

Figure 1: The regioselectivity of different metal thiocyanate and hydroxides on a benzyl bromide and chloride

Figure 2: Reaction scheme for regioselective reactions

Figure 3: Reaction scheme for the regioselective reaction of different metal thiocyanates with an α-bromo ketone

Figure 4: Reaction scheme of a potentially better method to test ion pairing regioselectivity on an α-bromo ketone

Figure 5: Mechanism for backside (SN2-b) and frontside (SN2-f) nucleophilic substitution

Figure 6: Proposed reaction scheme for nucleophilic substitution reactions on a chiral molecule with varying metal cation and halide sizes

Figure 7: Bromination of chiral alcohols to create chiral halides

…………………………………………………………………………………………………………………………………………………….

Chapter 4

Figure 1: Reaction scheme for the hydration of alkynes with PTSA and AcOH

Figure 2: Reaction scheme with Cs2CO3 as the base

Figure 3: Reaction scheme with CsOH as the base

Figure 4: Reaction scheme to determine the percent deprotonation

Figure 5: Reaction scheme for attempted nucleophilic substitutions with phenylacetylide and benzyl bromides

Figure 6: Proposed reaction mechanism scheme of nucleophilic substitution reaction with 18- crown-6

Figure 7: Proposed Zimmerman-Traxler six-membered transition state for nucleophilic additions with phenylacetylide

Figure 8: Proposed mechanism for the mechanochemical enyne formation

Figure 9. Reaction mechanism for alkyne hydration via TsOH in acidic conditions

Figure 10: Reaction of phenylacetylene with PTSA and acetic acid for 16 hours

Figure 11: Proposed retrosynthetic mechanism

Figure 12: Proposed mechanism for alkyne hydration with polymer bound PTSA

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Chapter 5

Figures 1a-1d: Reaction schemes of calcium carbide with different functional groups

Figure 2: Quadraphasic phase-vanishing system for direct application of acetylene gas applied in situ

3 Figure 3: Mechanochemical copper-catalyzed A couplings with CaC2 as the acetylene source

Figure 4: Proposed nucleophilic substitution reaction scheme using CaC2 and alkyl halides as the building blocks for alkynes

Figure 5: Reaction scheme of A3 reaction under HSBM conditions

Figure 6: Optimized reaction scheme of nucleophilic addition with calcium carbide

Figure 7: Favorskii alkynylation-type reaction scheme with benzophenone and calcium carbide in basic conditions

Figure 8: Reaction scheme for CaC2/KF reagent produced from a K2CO3/KOH/DMSO system

Figure 9: Reaction scheme for nucleophilic substitution by creating acetylene in situ

Figure 10. Crystal structure of tetragonal calcium carbide

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LIST OF SYMBOLS COVID-19: Coronavirus disease 2019 EPA: Environmental Protection Agency HSBM: High speed ball milling 17 hours: indicates one entire run of the ball mill (technically 999.9 minutes) NaBr: Sodium bromide HSAB: Hard-Soft Acid-Base LiCl: Lithium chloride

LiBr: Lithium bromide LiI: Lithium iodide NaF: Sodium fluoride KF: Potassium fluoride RbF: Rubidium fluoride CsF: Cesium fluoride DMSO: Dimethyl sulfoxide pKa: Negative base-10 logarithm of the acid dissociation constant (Ka)

CDCl3: Deuterated chloroform

M2CO3: Metal carbonate

Li2CO3: Lithium carbonate

Na2CO3: Sodium carbonate

K2CO3: Potassium carbonate

Cs2CO3: Cesium carbonate MOH: Metal hydroxide LiOH: Lithium hydroxide NaOH: Sodium hydroxide KOH: Potassium hydroxide CsOH: Cesium hydroxide

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MX: alkali metal halide

H2O: Water EAS: Electrophilic Aromatic Substitution DMF: Dimethylformamide THF: Tetrahydrofuran HPLC: High Pressure Liquid Chromatography

MgSO4: Magnesium sulfate TLC: Thin Layer Chromatography

NMR: Nuclear Magnetic Resonance Spectroscopy s.s.: Stainless steel (refers to stainless steel ball bearings) GC-MS: Gas chromatography- Mass Spectrometry MSCN: Metal thiocyanate NaSCN: Sodium thiocyanate KSCN: Potassium thiocyanate

NH4SCN: Ammonium thiocyanate PTSA: p-toluenesulfonic acid

D2O: Deuterated water

CaC2: Calcium carbide

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Chapter 1 Introduction

For centuries, chemical reactions have been performed in solution. This is due to influential philosophers believing dissolution of reactants in solvent was the only way to produce chemical change. This is described in Aristotle’s words “corpora non agunt nisi fluida seu solute” which translates into English as “compounds do not react unless fluid or dissolved”.1 Chemical companies at the early history of modern chemistry were not always honest about the shortcomings of their manufactured goods and procedures.2 These philosophies and practices have shaped the nature of chemical transformations to this day. While this has brought numerous benefits of chemistry to society, there are always significant developments to improving industrial, chemical, and pharmaceutical processes that use solvents.

The practice of creating products and processes as environmentally benign as possible describes the principle of green chemistry. There has been a slow increase in chemists’ interests to consider the negative impact of their work on the environment and human health. Because of this, there is a growing field of study for greening chemistry. A set of 12 principles have been created by Paul Anastas and John Warner where practices that would make a greener process or product are outlined.3 Some of the more important principles for organic synthesis are preventing waste, using less hazardous chemicals, and using safer solvents and auxiliaries. These are important because of the desire to prevent environmental incidents such as the Love Canal tragedy where the Hooker Chemical Company used an abandoned canal pit to dump chemical waste, which later made many residents ill.4

Since a large portion of chemical waste generated is due to organic solvents, they are a good starting point for improving the waste generation problem. 5 For over a decade, more modern approaches to selecting solvent for reactions, as well as, analysis have been implemented. These have led to a continuous improvement in the development of solvent selection where attributes such as toxicity, corrosiveness, flammability, etc. are addressed. 6–9 Recycling solvent and using water as a solvent has also gained popularity in creating more

environmentally benign processes.10 The greenest solvent, though, would be no solvent at all. The oldest form of this type of chemistry would be the grinding process of using a mortar and pestle. While this practice can be a bit of a grind, the concept of using that kind of energy for chemical processes is a growing field via mechanochemistry.

Figure 1. Toxic Release Index data for hazardous chemical waste generated in 2017

Hazardous Chemical Waste Generate 2017

Organic Others, Solvents, 52% 48%

Mechanochemistry can be described as the application of mechanical force to perform chemical processes. While solvent can be used in these systems, a growing amount of solid- state chemical methods have been developed.11 These are attractive not only because of their environmentally friendly processes but also because of the economics and higher reaction rates. Solid state reactions can consist of experimental tools with motions like shaking or grinding, heating, microwave or ultrasound, and heating. One tool that can incorporate one or more of these motions are mechanical mills where there is grinding, shaking, and heating.

These tools are not as well known to the general chemistry community but it is important to understand the fundamentals of them, so the field can continue to grow.

One popular form of mechanical milling is using a ball mill, which can be thought of as a mechanical mortar and pestle. They are generally used for crushing and grinding materials into an exceedingly fine state. Instead of human energy, electrical and mechanical energy are exerted to aid the chemical process. While there are different types of ball mills (Figure 2), all function very similarly. Reactants are placed in a vessel which is then placed in the mill where mechanical energy will be wielded to transform the reagents. The degree of the milling is influenced by a number of factors including12:

• Time material is spent in the mill

• The hardness of the ball bearings and/or grinding material

• The size and/or number of ball bearings

• The frequency or speed rate of the vessel

• The temperature at which the materials are reacting

Figure 2. Different types of ball mills: (A) Wig-L-Bug grinder/mixer (back and forth motion), (B)

Retsch Mixer Mill MM 400 (side to side motion), (C) Fritsch Pulverisette 6 (rotational motion), and (D) SPEX SamplePrep 8000M Mixer/mill (figure-eight motion)

One mill growing in popularity is the high-speed ball mill (HSBM). With this mill, reactants can be placed in a vial with a ball bearing and place it in the mill where mechanical energy allows for efficient mixing thereby driving the reaction (Figure 3). This process will grind the reagents to small particle sizes where there will be more surface area. It creates a phase similar to traditional solvent chemistry where the reagents can easily react. The motion of the ball bearing inside a reaction vial has been studied and mapped (Figure 4) to show the motion is random and the ball has a possibility to hit all areas inside the vial.13

Figure 3. SpexCertiprep mixer mill, reaction vials and ball bearings

Figure 4. The motion of the ball bearing inside a mixer/mill determined by simulated trajectory of sphere centre during first milling seconds

While different ball mills have different motions (Figure 5), they all have the same concept: using mechanical energy to facilitate mixing in order to drive reactions. Of all these types of mills, the Mack Group has focused on the high-speed ball mill due to the easy controllability of frequency, time, and temperature. While these features can be used to create more benign experiments, much research needs to be investigated to develop the methods.

Figure 5. Types of milling technologies available and the milling motion varying from small scale

(A) SPEX mixer/mill, to medium scale (B) planetary mill, (C) attritor, to production scale (D) rolling ball mill14

As particular reactions in mechanochemical conditions are optimized, the rules that govern these environments also need to be investigated. For now, the Mack Group has discovered reaction conditions such as the ball bearing material and size that produces efficient results, but individual organic synthetic reactions still need to be probed. This is especially necessary due to the non-traditional solventless environments. Since not much research has been done in these reaction conditions, guidelines to help facilitate them need to be created.

One area that has needed investigation is the role of ion pair coordination in solventless mechanochemical conditions. In traditional organic synthesis, ions are solvated and surrounded by solvent shells (Figure 6). Depending on the nature of the solvent (protic or aprotic), the ions will align with their respectively charged pair. In mechanochemical environments, there is a

6 void of solvent, thus giving a lack of solvent shells. Because of this, there could be more reactivity, but investigation of the coordination of the ions is essential.

Figure 6. Polar protic and aprotic solvent shells surrounding NaBr

Since there is no solvent in the reaction setup, it is believed the ion pairs are coordinated in a crystal lattice type structure as shown in Figure 7. The theory is when one ionic bond is broken a new bond needs to form since there is no solvent to stabilize the charge.

Because of this, there can be no free charges floating in the system, therefore these bonds behave as covalent bonds. The next step would be to investigate the interactions and determine if there are bonds that are more favorable than others using that to a mechanistic advantage.

Figure 7. Crystal lattice structure showing the proposed formation of ion pairs in solventless conditions

Fortunately, since there are some guidelines that govern these interactions in solution, there is a starting point to test them in mechanochemical conditions. One of these principles is

Pearson’s Hard-Soft Acid-Base (HSAB) theory which was developed to explain a trend in bonding between ions (Figure 8).15 Hard ions are considered small and not easily polarizable while soft ions are considered large and easily polarizable. The general trend for these ions is

“hard likes hard” and “soft likes soft”. For example, the smaller ion of Li+ would better pair with

F- than with a larger ion like I-. It can be assumed this trend would be similar in solventless conditions but perhaps bond strengths would differ.

While ion pairing is being investigated, reactions that typically rely on the charge and/or strength of the ion, such as bases and nucleophiles, can also be observed. Acid-base reactions are one of the most basic concepts in chemistry. One of the most critical features of this type of chemistry is the reactivity of the base. There are several theories that describe different aspects of acid-base reactions such as Brønsted–Lowry and Arrhenius. These theories are closely associated with solvation, particularly in water. Since HSBM conditions usually are solventless, base strength can likely deviate from what is traditionally observed. The ion-dipole interaction is easier to break between a weak base and solvent than between a strong base and solvent.16

An advantage of solid-state chemistry is higher reaction rates due to more reactant availability, therefore more benign reagents can be employed to replace harsher ones that are traditionally used.

Figure 8. Several ions and their characterization as hard or soft.

Another aspect that can be observed is the trend for alkali metal halides (MX) and if it can be altered to change the efficiency of reactions. Fortunately, there are experimental and calculated values for this type of ion pairing in solid state as shown in Figure 9.17 Most alkali metal halides, besides cesium salts, crystalize with face centered cubic lattices where each ion has a coordination number of six. Cesium salts crystalize in a body-centered cubic lattice where each ion has eight. Regardless of the coordination number, these ions interact similarly to the principles of the HSAB theory and it is believed it can assist governing mechanochemical solid state reactions. For example, the enthalpy of formation for LiF is more stable than LiCl, LiBr, and

LiI. When compared to the other metal alkali ions, it is also more stable than NaF, KF, RbF, and

CsF. This quantitatively shows the “hard likes hard” concept of the HSAB theory.

Figure 9. Structural parameters, enthalpy of formation and lattice enthalpies for alkali halides.

Finally, the impact of lack of solvent shells on nucleophilicity can be observed.

Traditionally polar protic solvents solvate cations and anions through hydrogen bonding. With aprotic solvents, there are no hydrogens to form ion-dipole interactions therefore the partial charges on their surface are what solvate the cations.16 Interestingly, in aprotic solvents cations are solvated better than anions, which will usually be stronger nucleophiles. For example, fluorine would be a better nucleophile in DMSO than in water. For a nucleophile to participate in SN2 reactions, one of the ion-dipole interactions needs to break because of the solvent shielding the nucleophile. When polar protic solvents are used, the hydrogens solvate the nucleophile thus reducing their nucleophilicity. As the size of the nucleophilic atom increases, the nucleophilicity increases. Therefore, a lack of solvent and increase in atom size should increase the nucleophilicity in mechanochemical conditions.

Conclusions

There is a large area of exploration when it comes to solid state ion interactions. This dissertation explores the varying routes solid state ion pairing can travel. We will look at the role in acid/base interactions and demonstrate potential benign design by using safer bases for reactions that traditionally require harsher ones. We will look at the role of ion pairs in alkyne chemistry as well as with competition reactions where nucleophiles rival for chemo- and stereoselectivity. Finally, we will look a little past the role of ion pairs and into creating alternate routes for the fundamental reactions of acetylene and chemistry with alkynes.

References

(1) Aristotle: On Coming-to-Be and Passing-Away The Works of Aristotle: Translated into English Meteorologica. Nature 1923, 112 (2816), 584–585. https://doi.org/10.1038/112584a0. (2) Markowitz, G.; Rosner, D. Deceit and Denial; University of California Press, 2003. (3) Warner, J.; Anastas, P. Green Chemistry: Theory and Practice; Oxford University Press Inc.: New York, 1998. (4) Beck, E. C. The Love Canal Tragedy. EPA.gov 1979. (5) EPA. Toxic Release Index. EPA.gov 2017. (6) Gottlieb, H. E.; Graczyk-Millbrandt, G.; Inglis, G. G. A.; Nudelman, A.; Perez, D.; Qian, Y.; Shuster, L. E.; Sneddon, H. F.; Upton, R. J. Development of GSK’s NMR Guides – a Tool to Encourage the Use of More Sustainable Solvents. Green Chemistry 2016, 18 (13), 3867–3878. https://doi.org/10.1039/C6GC00446F. (7) Henderson, R. K.; Jiménez-González, C.; Constable, D. J. C.; Alston, S. R.; Inglis, G. G. A.; Fisher, G.; Sherwood, J.; Binks, S. P.; Curzons, A. D. Expanding GSK’s Solvent Selection Guide – Embedding Sustainability into Solvent Selection Starting at Medicinal Chemistry. Green Chemistry 2011, 13 (4), 854. https://doi.org/10.1039/c0gc00918k. (8) Babi, D. K.; Kulajanpeng, K.; Tongrod, A.; Kammafoo, A.; Lourvanij, K.; Gani, R. A Systematic Approach to Green Solvent Selection, Design, and Verification. In The Application of Green Solvents in Separation Processes; 2017; pp 57–90. https://doi.org/10.1016/B978-0-12-805297- 6.00003-6. (9) Byrne, F. P.; Jin, S.; Paggiola, G.; Petchey, T. H. M.; Clark, J. H.; Farmer, T. J.; Hunt, A. J.; Robert McElroy, C.; Sherwood, J. Tools and Techniques for Solvent Selection: Green Solvent Selection Guides. Sustainable Chemical Processes 2016, 4 (1), 7. https://doi.org/10.1186/s40508-016- 0051-z. (10) Sheldon, R. A. Green Solvents for Sustainable Organic Synthesis: State of the Art. Green Chemistry 2005, 7 (5), 267. https://doi.org/10.1039/b418069k.

(11) James, S. L.; Friščić, T. Mechanochemistry. Chemical Society Reviews 2013, 42 (18), 7494. https://doi.org/10.1039/c3cs90058d. (12) Ranu, B.; Stolle, A. Ball Milling Towards Green Synthesis Applications, Projects, Challenges; The Royal Society of Chemistry, 2015. (13) Concas, A.; Lai, N.; Pisu, M.; Cao, G. Modelling of Comminution Processes in Spex Mixer/Mill. Chemical Engineering Science 2006, 61 (11), 3746–3760. https://doi.org/10.1016/j.ces.2006.01.007.

(14) Blair, R. G.; Chagoya, K.; Biltek, S.; Jackson, S.; Sinclair, A.; Taraboletti, A.; Restrepo, D. T. The Scalability in the Mechanochemical Syntheses of Edge Functionalized Graphene Materials and Biomass-Derived Chemicals. Faraday Discussions. 2014, 170, 223–233. https://doi.org/10.1039/C4FD00007B. (15) Pearson, R. G. Hard and Soft Acids and Bases. Journal of the American Chemical Society 1963, 85 (22), 3533–3539. https://doi.org/10.1021/ja00905a001. (16) Bach, R. D.; Winter, J. E.; McDouall, J. J. W. Relative Nucleophilicity: The Role of Solvation and Thermodynamics. Journal of the American Chemical Society 1995, 117 (33), 8586–8593. https://doi.org/10.1021/ja00138a014. (17) Gopikrishnan, C. R.; Jose, D.; Datta, A. Electronic Structure, Lattice Energies and Born Exponents for Alkali Halides from First Principles. AIP Advances 2012, 2 (1), 012131. https://doi.org/10.1063/1.3684608.

Chapter 2 Ion Pair Roles in Acid/Base and Nucleophilic Substitution Reactions

Introduction Some of the most fundamental reactions in organic chemistry have a foundation of acid- base and nucleophilic substitution type mechanisms. These reactions are reliable in many aspects of organic synthesis, but they often use reagents and conditions that can be hazardous to humans and the environment. There was an opportunity to use solvent-free mechanochemistry to replace any unsafe conditions and substitute them for more benign reagents and environments. High speed ball milling is a unique, solvent free technique that has principles that are not fully understood. This project was set out to investigate acid-base and nucleophilic substitution reactions in solvent free conditions. Due to the lack of solvent in these conditions, the absence of solvent shells needs to be considered and the roles of ion-pairs investigated.

The concept of pKa is commonly used as a quantitative measure of the strength of an acid in solution. This can be calculated using the equation: where HA is an acid that dissociates into the conjugate base (A-) and a hydrogen ion (H+). The pKa values that are traditionally used are those of acids that are dissociated in water, as shown in Table 1. These values can change depending on the solvent in which the acid dissociates.

Theoretical calculations can also be used via the Gibbs Free equation where pKa =

1 ΔGaq/RTln(10) and Δ Gaq = ΔGgas + ΔΔGsol. These calculations still rely on aqueous and solution conditions. Since there is no solution for acids to dissociate into in solvent-free conditions, there are no known ways of calculating solventless pKa values. Because of this, the strengths of

14 acids and bases in solventless conditions are not well known, but qualitative data can be used to get a general idea of these values.

Table 1. Table of pKa values for various functional groups.

The lack of solvent shells surrounding molecules or ions also needs to be considered.

This lack of solvent shell can leave ions freer to react under solvent free conditions which can lead to increased reactivity. Due to this, it is believed most HSBM reactions are concerted and there are no free-flowing ions since there is no solvent to stabilize them. Along with determining basicity strength, the interactions of ions were studied, and it was observed if different ion pairs lead to different outcomes. The principles of Pearson’s Hard Soft Acid Base

(HSAB) theory2 and the Jones-Dole B coefficient3 can be used to justify the findings qualitatively and quantitatively, respectively. The HSAB categorizes acids and bases as either hard or soft based off their characteristics such as size and polarizability. Table 2 shows alkali metal and halide ions in their respective hard and soft categories. The principle is hard acids prefer hard bases and soft acids prefer soft bases. For example, lithium and fluoride would be a better ion pair than lithium and iodide. The Jones-Dole B coefficient is a quantitative approach to predicting the ion pairings. These coefficients are calculated using the relationship between values of solution viscosity and solute concentration. The closer the values are to each other, the better the pair. For example, the coefficient for the lithium ion is 0.150 which is closer to the value of the fluoride ion (0.100) than the iodide ion (-0.068), thus leading to Li—F being a better pair.

Table 2. Pearson hardness rating and Jones-Dole Viscosity B coefficient2,3.

The study of these ion interactions began due to a trend that was noticed in a solvent- free mechanochemical Wittig reaction.4 A benzyl bromide and benzyl chloride were used as the alkyl halide and Li2CO3, Na2CO3, K2CO3, Rb2CO3, and Cs2CO3 were used as the bases that assist with creating the ylide. It was noticed there were higher percent yields with benzyl bromide and Cs2CO3 and no yields when Li2CO3 was used, thus leading to believe ions play a crucial role in solventless reactions. The thought was larger ion pairs, such as Cs—Br, were more favorable while small-large ion pairs were not.

It was envisioned using solvent-free mechanochemistry to restrain the use of dangerous chemicals and substitute them for safer reagents for a more benign synthesis, while incorporating ion-pairs to drive the reaction more efficiently. This was studied by performing a

17 solvent-free mechanochemical Williamson Ether synthesis where phenol and a benzyl alcohol were used as the acids and different alkali metal carbonates and hydroxides for the bases.

Several different benzyl halides were used as the electrophile for a substitution reaction done with metal alkoxides as the nucleophile. Since it is believed these solid state mechanochemical reactions are concerted, the proposed mechanism would show each atom in the reaction play a significant role as shown in Figure 1. The crucial elements that drive these reactions are the strength of the bases and the interactions of the ion. These ion interactions are important in both the acid-base step and the alkali metal—halide interaction in the nucleophilic substitution step.

Figure 1. Proposed stepwise concerted mechanism for mechanochemical acid-base reactions and nucleophilic substitution reactions.

Results and Discussion Phenol Williamson Ether Synthesis

When phenol was used as the acid, the mechanochemical Williamson Ether reaction showed a distinct trend with the alkali metals and halogens pairing. The trend for both percent conversion and percent yield tends to increase as the alkali metal of the carbonate and halogen became larger in size (Figure 2a & 2b). Percent conversion was determined via 1H NMR to establish how much starting material was converted to product. The Cs–I pair gave the highest percent yield while the Cs—Br pair followed right behind. For the smaller ions, there was little to none of the desired product. The percent conversion and yield had an increasing trend as the ion sizes of the alkali metals increased. Since these reactions are believed to be concerted, it is believed the one-pot Williamson Ether reactions have a Zimmerman-Traxler5 reaction mechanism where a six-membered transition state can be formed as shown in Figure 3. The efficiency of the reaction is based on the strength of the base and the interactions of the ion pairs. The alkali metal—oxygen ion pair of the base is the first step to determine the efficiency.

If the alkali metal and oxygen are a strong pair, they will likely stay ionically bonded together and not participate as effectively in the acid-base step.

Figure 2a. Percent conversion for different alkali metal phenoxides reacted with different benzyl halides.

Figure 2b. Percent yield for different alkali metal phenoxides reacted with different benzyl halides.

Figure 3. Our proposed Zimmerman-Traxler reaction mechanism for the solventless

Williamson Ether synthesis.

What were seen instead were the electrophilic aromatic substitution (EAS) products of the phenol and benzyl halides. A control study was ran with phenol and bromobenzyl bromide without the presence of base and noticed similar results to when Li2CO3 was used. The percent conversion of phenol into the ortho and para substituted products was calculated and a slight trend with the alkali metals was noticed (Figure 4). It was observed the smaller the alkali metal ion in the base, the more conversion to the EAS products. It is also noted the ortho: para ratio always favored the ortho substituted product. In Figures 5a and 5b, a different Zimmerman-

Traxler reaction mechanism was predicted for these reactions that involve electron movement within the aromatic ring of the phenol. The six-membered transition state of the ortho substitution seemed more favorable than the para substitution.

Figure 4. Percent conversions of the ortho: para electrophilic aromatic substitution products.

Figure 5a. Proposed 6-membered reaction mechanism for the ortho-substituted product before tautomerization to the enol.

Figure 5b. Proposed 6-membered reaction mechanism for the para-substituted product before tautomerization to the enol

If the ion pair of the base is not as strong, then the strength will be the next factor. If the base can deprotonate the acid, it will then create a nucleophile that can substitution into the benzyl halide. The proficiency of this step is relied on the ion interactions of the alkali metal of the base and the halide of the electrophile. If these ion pairs are favorable, a higher conversion and yield will be observed.

Benzyl Alcohol Williamson Ether Synthesis

A similar trend was seen when 4-bromobenzyl alcohol was used as the acid. Since alcohols are less acidic than phenol, they would traditionally need a slightly stronger base than carbonates to deprotonate them. Because of this, these reactions were performed with both carbonates and hydroxides. These results are shown in Figures 6-8. For these reactions, only used 4-bromobenzyl bromide was used as the electrophile to determine if the trend is comparable to the phenol reactions.

The results for the experiments with 1 mmol of carbonates were not nearly as efficient with the benzyl alcohol as it was with the phenol experiments. This was to be expected if comparing to solution acid-base reactions. As a proof of principle, 2 mmol of carbonates were added to these reactions with the idea that it would increase the chances of the base to meet the alcohol with the grinding of the ball bearing. This theory proved correct as an increase in percent conversion and yield in all the alkali metal carbonates was observed, although the percent increase for lithium and sodium carbonates was very small as shown in Figures 6 and 7.

The alkali metal—halide trend remained similar to what was observed with the phenol experiments with the Cs—Br ion pair being the most efficient.

Several different alkali metal hydroxides were also used to observe if there were any differentiations compared to the carbonates. While the increasing trend remained the same, a higher percent conversion and yield was noticed with LiOH and NaOH than with Li2CO3 and

Na2CO3 (Figure 8). This further confirmed the suspicions of a significance in the alkali metal— oxygen ionic bond strength of the base. The comparison of percent conversions among the hydroxides, 1 mmol carbonates, and 2 mmol carbonate reactions is shown in Figure 9. It is

25 suspected the Li—O ionic bond in hydroxide is not as strong as the Li—O ionic bond in carbonate, therefore the hydroxide is more available for the acid base step.

Figure 6. Comparison of percent conversion to 4-bromobenzyl ether using 1 mmol vs 2 mmol of different alkali metal carbonates.

Figure 7. Percent yield of 4-bromobenzyl ether using 2 mmol of several alkali metal carbonates.

Figure 8. Percent conversion and percent yield of 4-bromobenzyl ether using different alkali metal hydroxides.

Figure 9. Comparison of percent conversion to 4-bromobenzyl ether using 1 mmol and 2 mmol carbonates and hydroxides.

4-Bromobenzyl iodide One occurrence that should be noted is where the produced 4-bromobenzyl iodide would degrade over time. When performing the nucleophilic substitution reactions with this benzyl iodide, it is important to use it within a few days of production. It is believed there was possibly a radical reaction where the iodide was leaving, and a new product was forming. To test if this were happening in the nucleophilic substitution reaction, a radical trap with TEMPO was set up to see if it would stop the reaction. This reaction, though, produced the desired ether product. To determine if a radical reaction was happening within the reactant, samples of

4-bromobenzyl iodide were taken, solvated them in acetone wrapped one in foil and the other left exposed to light (Figure 10). After 2 days, it was noticed regardless of the condition, both samples became orange in color and showed a new spot on the TLC plate. Proton NMR showed a new aldehyde peak, which it is believed could be the result of a radical reaction (Figure 11).

Because of these results, it is believed the stability of the benzyl iodide is not long lasting and these reactions should be performed with fresh material each time.

Figure 10. Thin Layer Chromatography and photos of change in 4-bromobenzyl iodide in acetone over 2 days

Figure 11. 1HNMR of 4-bromobenzyl iodide after 2 days in acetone

EcoScale One method that can be used to quantitatively evaluate synthetic strategies is with the green metric of EcoScale.6 This approach is desirable for comparing the benign reactions to traditional solution-based chemistry. It considers many factors such as reagent price, safety, reaction setup, and purification techniques. Penalty points are assigned to each parameter and in the end are deducted from 100 to give an EcoScale score. The score then categorizes the reaction as inadequate, acceptable, or excellent. The EcoScale parameters and corresponding penalty points are shown in Table 3.

Table 3. The penalty points to calculate EcoScale.

Table 4 shows the comparison for two Williamson Ether synthesis methodologies with phenol. When compared to solution7, the mechanochemical method had a higher EcoScale rating. While the solution-based method had an acceptable rating, it had a few extra penalty

33 points due to the safety of DMF and the use of column chromatography. Since the yield was higher and chromatography was not needed, there was a higher score that was excellent.

Table 4. EcoScale calculations for Williamson Ether synthesis with phenol.

Table 5 shows the comparison for two Williamson Ether synthesis methodologies with

4-bromobenzyl alcohol as the acid. The solution-based reaction8 had an acceptable rating but had penalty points due to the safety of sodium hydride and THF, and the experimental setup.

When the solventless mechanochemical method was used, an acceptable rating of 62 was calculated which was lower that the solution-based acceptable rating of 70. This score was lower due to the low percent yield. When the equivalents of the carbonates were changed to 2 mmol from 1 mmol it was noticed a much higher percent yield thus increasing the over

EcoScale rating to be higher than that done in solution.

Table 5. EcoScale calculations for Williamson Ether synthesis with 4-bromobenzyl alcohol with 1 mmol and 2 mmol carbonates as the bases.

Conclusions In conclusion, we have determined the lack of solvent stabilization provides the opportunity to use safer reagents that would not typically be used in solution. This creates the chance to recreate some organic syntheses to have a more benign pathway. We also discovered acidity and basicity are different in solventless mechanochemical conditions. While we do not currently have the means to give these quantitative values that can be used for comparison, we can observe trends that can likely be applied to a broad range. The more reactive bases were those with less bond strength between the ions which follow the ideologies of Pearson and

Jones-Dole. Bases with cesium as its alkali metal tended to be more reactive due to the weaker

Cs—O interaction of the base. We also determined ion pairs can influence a nucleophilic substitution reaction between the alkali metal ionically bonded to the nucleophile and the

35 halide. The ion sizes and polarizability were a large influence in this as we saw the Cs—I interaction was the most efficient for these pairings, followed by Cs—Br and Cs—Cl. Because of these mechanochemical conditions, we were able to create more environmentally benign conditions.

EXPERIMENTAL (MATERIALS AND METHODS)

General Remarks SN2 reactions were carried out by mechanochemical milling in a SPEX8000M

Mixer Mill at a frequency of 18 Hz using a stainless steel vial with a 3/16” stainless steel ball bearing 1H and 13C {1H}NMR spectra were obtained on a Bruker Avance 400 MHz spectrometer, and all chemical shift values are reported in ppm on the δ scale. GC-MS data were obtained with a Hewlett-Packard 6890 series GC-MS with a Zebron ZB-5, 15 mm x 0.25 mm x 0.25 mm column.

Mass spectral determinations were carried out using ESI as the ionization method. Flash column chromatography was performed using a Combiflash® Automated Flash Column Chromatography system with RediSep Rf Gold® high performance flash columns (fine spherical silica gel 20-40 µm).

Deuterated chloroform was obtained from Cambridge Isotope Laboratories, Inc., Andover, MA, and used without further purification.

Rubidium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, 4-chlorobenzyl chloride, and 4-bromobenzyl bromide were purchased from Acros Organics. Phenol, lithium carbonate, sodium carbonate, and potassium carbonate were purchased from Fischer Scientific; all were used without further purification.

Typical procedure for preparing 4-bromobenzylphenyl ether To a custom-made 2.0 x 0.5 inch stainless steel screw capped vial was added phenol (1.00 mmol, 0.0941 g), 4-bromobenzyl halide

(1.00 mmol), a metal carbonate (1.00 mmol), and a 3/16” stainless steel ball bearing. A Teflon gasket was added, and the vial sealed and placed in a Spex 8000 mixer mill. The reaction was shaken for 16 hours at 18 hertz. The crude reaction mixture was extracted with approximately

25 mL of ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and solvent evaporated under reduced pressure to afford a mixture of products. The O-alkylated

37 product was separated from the C-alkylated products by flash column chromatography on silica gel using heptane/ethyl acetate as the eluent. 1H-NMR and GC-MS were used to assess the purity of the target molecule. Percent conversion was determined by 1H-NMR integration.

Typical procedure for preparing 4-chlorobenzylphenyl ether 4-chlorobenzyl chloride (mp 27-29

°C) was slightly heated and added dropwise (1.00 mmol, 0.161 g) to a custom-made 2.0 x 0.5 inch stainless steel screw capped vial followed by phenol (1.00 mmol, 0.0941 g), a metal carbonate

(1.00 mmol), and a 3/16” stainless steel ball bearing. A Teflon gasket was added, and the vial sealed and placed in a Spex 8000 mixer mill. The reaction was shaken for 16 hours at 18 hertz.

The crude reaction mixture was extracted with approximately 25 mL of ethyl acetate and water.

The organic layer was dried over anhydrous magnesium sulfate and solvent evaporated under reduced pressure to afford a mixture of products. The O-alkylated product was separated from the C-alkylated products by flash column chromatography on silica gel using heptane/ethyl acetate as the eluent. 1H-NMR and GC-MS were used to assess the purity of the target molecule.

Percent conversion was determined by 1H-NMR integration.

Typical procedure for preparing 4-bromobenzyl iodide

To a custom-made 2.0 x 0.5 inch stainless steel screw capped vial was added 4-bromobenzyl bromide (1.00 mmol, 0.250 g), sodium iodide (5.00 mmol, 0.750 g), 2 mL acetone, and three

3/16”stainless steel ball bearings. A Teflon gasket was added and the vial sealed and placed in a

Spex 8000 mixer mill. The reaction was shaken for 5 hours at 18 hertz. The crude reaction mixture was gravity filtered and the solvent evaporated under reduced pressure. The organic product was then extracted with approximately 25 mL of ethyl acetate and water. The product was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford a quantitative

38 amount of product. It should be noted the 4-bromobenzyl iodide should be used for these reactions within 24 hours of synthesis since it will begin to decompose in the presence of light.

References

(1) Raamat, E.; Kaupmees, K.; Ovsjannikov, G.; Trummal, A.; Kütt, A.; Saame, J.; Koppel, I.; Kaljurand, I.; Lipping, L.; Rodima, T.; Pihl, V.; Koppel, I. A.; Leito, I. Acidities of Strong Neutral Brønsted Acids in Different Media. Journal of Physical Organic Chemistry 2013, 26 (2), 162–170. https://doi.org/10.1002/poc.2946.

(2) Pearson, R. G.; Songstad, Jon. Application of the Principle of Hard and Soft Acids and Bases to Organic Chemistry. Journal of the American Chemical Society 1967, 89 (8), 1827–1836. https://doi.org/10.1021/ja00984a014.

(3) Robinson, J. B.; Strottmann, J. M.; Stellwagen, E. Prediction of Neutral Salt Elution Profiles for Affinity Chromatography. Proceedings of the National Academy of Sciences 1981, 78 (4), 2287. https://doi.org/10.1073/pnas.78.4.2287.

(4) Denlinger, K. L.; Ortiz-Trankina, L.; Carr, P.; Benson, K.; Waddell, D. C.; Mack, J. Liquid-Assisted Grinding and Ion Pairing Regulates Percentage Conversion and Diastereoselectivity of the Wittig Reaction under Mechanochemical Conditions. Beilstein Journal of Organic Chemistry 2018, 14, 688–696.

(5) Zimmerman, H. E.; Traxler, M. D. The Stereochemistry of the Ivanov and Reformatsky Reactions. I. Journal of the American Chemical Society 1957, 79 (8), 1920–1923. https://doi.org/10.1021/ja01565a041.

(6) Chakraborti, A. K.; Chankeshwara, S. v. Counterattack Mode Differential Acetylative Deprotection of Phenylmethyl Ethers: Applications to Solid Phase Organic Reactions. The Journal of Organic Chemistry 2009, 74 (3), 1367–1370. https://doi.org/10.1021/jo801659g.

(7) Diparjun, D.; Tridib, C.; Lalthazuala, R. Application of “Click” Chemistry in Solid Phase Synthesis of Alkyl Halides. Acta Chimica Slovenica 2015, 62 (4), 775–783. https://doi.org/10.17344/acsi.2015.1478.

(8) Thangaraj, M.; Bhojgude, S. S.; Mane, M. v; Biju, A. T. From Insertion to Multicomponent Coupling: Temperature Dependent Reactions of Arynes with Aliphatic Alcohols. Chemical Communications 2016, 52 (8), 1665–1668. https://doi.org/10.1039/C5CC08307A.

Chapter 3 Ion Pair Regioselectivity and Stereoselectivity

Introduction

It has been shown ions can influence chemo- and stereoselectivity of products. This has been shown with the halogenation of alkenes being controlled by the ion pair driving force where the probability of syn and anti additions rely on the bond energy of the counterions.1 Ion pair-directed regiocontrol for Iridium catalysts via borylation used a cationic ammonium substrate and anionic ligand.2 Ion pairing has also been shown to influence N-alkylation.3 Most of these experimental probes of ion interactions for regio- and stereoselectivity consist of metal-catalysts and are influenced by solvent environments. Ion-pair SN2 reactions are mostly studied via computational methods due to the variable trends of nucleophile basicity, electrophilicity, solvent, and leaving group. Computational studies can assist with the understanding of the rate and mechanistic course for these nucleophilic reactions and demonstrate the ionic coordination that influences them.

It is well known the bimolecular nucleophilic substitution reaction consists of a transition state where the nucleophile attacks and forces the leaving group off to form an inversion product while the unimolecular nucleophilic substitution reaction racemizes. What if there was a way to select the inversion or the retention product for a nucleophilic substitution reaction on a chiral molecule? Reaction pathways for SN2 reactions have been computationally studied over the years. Gas phase SN2 pathways have been studied with different mechanisms

4 (n-1) + + + + 5 such as LiNCO + CH3X (X = F, Cl, Br, and I) , MnNH2 + CH3Cl (M = Li , Na , K , and MgCl ) , LiY

6 + NH2X ((Y, X ) = F, Cl, Br, or I) where the favorable pathway (backside or frontside attack) is

41 determined by the energy barriers manipulated by the different variables (environmental phase, metal cation, nucleophile). Laloo, et. Al, computationally studied the substitution

(n-1) + + + + reaction of MnOH + CH3Cl (M = Li , Na , K , and MgCl ) where they discovered SN2 reactions are affected by counterions and solvation with how inversion overcomes for heavier alkali cations Na+ and K+.7

While there are many other computational studies of the influence of ion pairs on SN2 reactions8–10 there are little to no computational or experimental studies of the influence of ion pairs for these reactions on a chiral molecule in a solventless environment. Since it has been observed that ions have an influence in mechanochemical reactions, it is believed that the ion pair can be used to influence the stereoselectivity of the product based on the size of the metal alkali cation and its counterion. Ebraihimi, et al. theoretically demonstrated this concept on different methyl halides where the energy barriers for the backside attack were higher for small metals while the barrier for the frontside attack was higher for the bigger metal. The most favorable ion pairing for the retention pathway was Li—F while K—Cl and K—Br were the most favorable for the inversion pathway.11 It is believed this concept can be used on a chiral molecule.

Results and Discussion Ion Pair Regioselectivity

Since ion pairing influences solventless mechanochemical reactions, the application of the same concepts to control regioselectivity were studied. This was done by combining 4- bromobenzyl bromide and 4-chlorobenzyl chloride with different metal nucleophiles to

42 determine if the metal ion had an influence on the leaving group. Several metal phenoxides were used to begin since they worked well as nucleophiles in the substitution reactions in

Chapter 2. Unfortunately, the presence of electrophilic aromatic substitution products was once again noticed and believed there would continue to be these competitions if phenoxides were continued. Metal alkoxides and acetylide were then tried, but there was still competition between the nucleophile and the hydroxide of the starting base. To avoid any further competition, the metal salts of MOH and MSCN were used as the nucleophiles since they are already in a nucleophilic state. 1H NMR was used to determine the selectivity of each of the nucleophiles and to observe if the metal cation has an influence as seen in Figure 1.

Figure 1. The regioselectivity of different metal thiocyanate and hydroxides on a benzyl bromide and chloride

M+ Nu- Product(s) % Conversion

Na+ -SCN 19:0

+ - NH4 SCN 91:0

K+ -SCN 100:0

Li+ -OH 0:0

Na+ -OH 12:0

K+ -OH 31:0

Cs+ -OH 60:0

The regioselectivity of different metal nucleophiles on dihalides was also attempted as shown in Figure 2. Unfortunately, when nucleophilic substitution reactions were performed

44 with metal phenoxides, hydroxides, and thiocyanates mostly starting material was recovered.

Since hydroxides and thiocyanates were efficient nucleophiles, it is believed the dihalide is the issue. In the future, metal cyanides could be tried possibly along with the use of a phase transfer catalyst such as 18-crown-6 to facilitate the reaction. Phenols with electron withdrawing groups on the benzene ring could also be tried since this should slow down the attack on the aromatic ring.

Figure 2. Reaction scheme for regioselective reactions

Since both nucleophilic additions and substitutions were observed, the controlling of one pathway over the other via ion pairing was observed next. It was figured the best way to test this is with reacting a nucleophile with an α-bromoketone. Phenoxides and hydroxides were ruled out as potential nucleophiles since they are not preferable for nucleophilic additions, therefore it was planned to use acetylides and thiocyanates. These reactions began with 2-bromoacetophenone and phenylacetylene but quickly saw the competition reaction between the phenylacetylide and hydroxide where the hydroxide would substitute.

Thiocyanates were used next and only the substitution product was observed as shown in

Figure 3.

Figure 3. Reaction scheme for the regioselective reaction of different metal thiocyanates with an α-bromo ketone

Nucleophilic substitutions are likely to be the most favorable pathway for these reactions. Further investigation can include reacting several nucleophiles with an α- bromoketone. Figure 4 shows an example of a reaction scheme with 2-bromopinacolone and different nucleophiles. It is believed this α-bromoketone is more ideal for this type of reaction setup since there will not be any interference between acetylide nucleophiles and benzyl halides like previously seen. There are only two options for attack on this ketone, therefore if 2 different nucleophiles are placed, it can be observed how or if a certain nucleophile will go a specific pathway.

Figure 4. Reaction scheme of a potentially better method to test ion pairing regioselectivity on an α-bromo ketone

Ion Pair Stereoselectivity

Similar to how Savoo et al. analyzed the effect of counterions and solvent for the SN2 ion pair reaction (Figure 5)5, it was desired to experimentally perform a similar concept on a chiral molecule. The theory is when a large metal cation (large M) and large halide (large X) are paired there is enough bond distance that the inversion product will easily be produced. When the metal cation and halide are small (small M and X), it is believed there will either be less inversion product and/or more of the retention product. These proposed reaction schemes are shown in Figure 6.

Figure 5. Mechanism for backside (SN2-b) and frontside (SN2-f) nucleophilic substitution

Figure 6. Proposed reaction scheme for nucleophilic substitution reactions on a chiral molecule with varying metal cation and halide sizes

The first task was to choose a chiral halide that could be commercially obtained with a specific enantiomer to study the stereoselectivity. While there are not easily commercially available stereospecific chiral halides, both enantiomers of the chiral alcohol 1-phenylethanol were successfully brominated as shown in Figure 7. The stereochemistry of the chiral bromide could not be determined via HPLC with the chiral columns owned. The nucleophilic substitution reactions were still continued, but the enantiomeric excess of the starting material was never established, thus the results displayed may not tell the complete story.

Figure 7. Bromination of chiral alcohols to create chiral halides

To begin the analysis, MSCN (M = NH4, Na) were used as the nucleophiles and reacted it with racemic (1-bromoethyl)benzene to determine where the two enantiomers appear on the

HPLC chromatogram. This was followed by repeating the reaction using synthesized R-(1- bromoethyl)benzene to determine which peak represents the S enantiomer of the product. The time, environment, and metal cations were then varied. The preliminary results of these reactions are shown in Table 1.

Table 1. Preliminary date for thiocyanate reactions

a. Reaction was done in solution b. Reactions were first ran at 16 hours and then decreased in to determine the length required There are many more experiments necessary to fully understand the mechanistic pathways for this project but what can be gathered from these results are the following:

• The nucleophilic substitution is successful after at least 5 hours

• Aprotic solution increases the %ee of the inversion product

• The %ee of the inversion product decreases the longer the reaction runs, possibly

The last of these results could possibly imply the thiocyanate may act as a leaving group and the bromide acts as a nucleophile. Further tests will need to be done to confirm, but a better nucleophile might need to be chosen in the future, such as cyanide.

Conclusions

Mechanochemically controlling ion interactions shows potential in influencing the regio- and stereoselectivity for products of addition and nucleophilic substitution reactions. These reactions may open avenues for greener and safer conditions by omitting hazardous environments and reagents. They could also potentially open new synthetic routes.

EXPERIMENTAL (MATERIALS AND METHODS)

General Remarks SN2 reactions were carried out by mechanochemical milling in a SPEX8000M

Deuterated chloroform was obtained from Cambridge Isotope Laboratories, Inc., Andover, MA, and used without further purification.

All thiocyanates, phosphorus tribromide, 1-bromoethyl benzene, 1-phenylethanol, 2- bromoacetophenone, 1-bromo-4-chlorobutane, 4-chlorobenzyl chloride, and 4-bromobenzyl bromide were purchased from Acros Organics. (S)-(-)-1-Phenylethanol and (R)-(+)-1-

Phenylethanol were purchased from Millipore Sigma; all were used without further purification.

Typical procedure for preparing R/S-1-bromoethylbenzene To a stirred solution of (S)-1- phenylethanol or (R)-1-phenylethanol (1.0 g, 8.2 mmol) in anhydrous diethyl ether (30 mL) at

0°C was added dropwise PBr3 (0.75 equiv). The reaction was monitored by TLC analysis. After reaction for approximately 15 min, the reaction mixture was slowly poured into 50 mL of ice– water. The organic phase was washed with saturated NaHCO3 solution (30 mL × 2) and brine

1 (30 mL × 3), respectively, dried with anhydrous MgSO4, and concentrated by evaporation. H-

NMR and GC-MS were used to assess the purity of the target molecule. Percent conversion was determined by 1H-NMR integration. HPLC was used to assess stereochemistry via Daicel

Chiralpak OJ-H, heptane/i-PrOH = 98:2, flow rate 0.8 mL/min, tR = 9.108 min and tS = 9.815 min,

210 nm detection.

Typical procedure for regioselective SN2 reactions To a custom-made 2.0 x 0.5 inch stainless steel screw capped vial was added 4-bromobenzyl bromide (1.00 mmol, 0.250 g), 4- chlorobenzyl chloride (1.00 mmol, 0.161 g), a metal thiocyanate (1.00 mmol), and a 3/16” stainless steel ball bearing. A Teflon gasket was added, and the vial sealed and placed in a Spex

8000 mixer mill. The reaction was shaken for 16 hours at 18 hertz. The crude reaction mixture was extracted with approximately 25 mL of ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and solvent evaporated under reduced pressure to afford a mixture of products 1H-NMR was used to assess the stereochemistry of the reaction.

Percent conversion was determined by 1H-NMR integration.

References

(1) Gevorkyan, A. A.; Arakelyan, A. S.; Petrosyan, K. A. Ion-Pair Version of the Chemo- and Regioselectivity of Halogen Addition to Double Bond. Russian Journal of General Chemistry 2002, 72 (5), 767–773. https://doi.org/10.1023/A:1019568504571. (2) Davis, H. J.; Mihai, M. T.; Phipps, R. J. Ion Pair-Directed Regiocontrol in Transition-Metal Catalysis: A Meta-Selective C–H Borylation of Aromatic Quaternary Ammonium Salts. Journal of the American Chemical Society 2016, 138 (39), 12759–12762. https://doi.org/10.1021/jacs.6b08164. (3) Dale, H. J. A.; Hodges, G. R.; Lloyd-Jones, G. C. Taming Ambident Triazole Anions: Regioselective Ion Pairing Catalyzes Direct N-Alkylation with Atypical Regioselectivity. Journal of the American Chemical Society 2019, 141 (17), 7181–7193. https://doi.org/10.1021/jacs.9b02786. (4) Sun, Y.-X.; Ren, Y.; Wong, N.-B.; Chu, S.-Y.; Xue, Y. Comprehensive Mechanistic Study of Ion Pair S N 2 Reactions of Lithium Isocyanate and Methyl Halides. International Journal of Quantum Chemistry 2006, 106 (7), 1653–1663. https://doi.org/10.1002/qua.20914. (5) Savoo, N.; Laloo, J. Z. A.; Rhyman, L.; Ramasami, P.; Bickelhaupt, F. M.; Poater, J. Activation Strain Analyses of Counterion and Solvent Effects on the Ion‐Pair S N 2 Reaction of and CH 3 Cl. Journal of Computational Chemistry 2020, 41 (4), 317–327. https://doi.org/10.1002/jcc.26104.

(6) Ren, Y.; Chu, S.-Y. Ion Pair S N 2 Reactions at Nitrogen: A High-Level G2M(+) Computational Study. The Journal of Physical Chemistry A 2004, 108 (34), 7079–7086. https://doi.org/10.1021/jp048345h. (7) Laloo, J. Z. A.; Rhyman, L.; Larrañaga, O.; Ramasami, P.; Bickelhaupt, F. M.; de Cózar, A. Ion-Pair − S N 2 Reaction of OH and CH 3 Cl: Activation Strain Analyses of Counterion and Solvent Effects. Chemistry - An Asian Journal 2018, 13 (9), 1138–1147. https://doi.org/10.1002/asia.201800082. (8) Li, Q.-G.; Xu, K.; Ren, Y. Origin of Enhanced Reactivity of a Microsolvated Nucleophile in Ion Pair S N 2 Reactions: The Cases of Sodium p -Nitrophenoxide with Halomethanes in Acetone. The Journal of Physical Chemistry A 2015, 119 (17), 3878–3886. https://doi.org/10.1021/acs.jpca.5b01045.

(9) Ren, Y.; Gai, J.-G.; Xiong, Y.; Lee, K.-H.; Chu, S.-Y. Theoretical Study on the Identity Ion Pair S N 2 Reactions of LiX with CH 3 SX (X = Cl, Br, and I): Structure, Mechanism, and Potential Energy Surface †. The Journal of Physical Chemistry A 2007, 111 (29), 6615–6621. https://doi.org/10.1021/jp067495k.

(10) Kim, J.-Y.; Kim, D. W.; Song, C. E.; Chi, D. Y.; Lee, S. Nucleophilic Substitution Reactions Promoted by Oligoethylene Glycols: A Mechanistic Study of Ion-Pair S N 2 Processes Facilitated by Lewis Base. Journal of Physical Organic Chemistry 2013, 26 (1), 9–14. https://doi.org/10.1002/poc.3010.

(11) Ebrahimi, A.; Habibi, M.; Amirmijani, A. The Study of Counterion Effect on the Reactivity of Nucleophiles in Some S N2 Reactions in Gas Phase and Solvent Media; 2007; Vol. 809. https://doi.org/10.1016/j.theochem.2007.01.037.

Chapter 4 Benign Alkyne Chemistry

Introduction Alkynes are part of a large group of organic precursors for chemical and pharmaceutical industrial compounds. Acetylenes are the building blocks for many common products such as polyethylene plastics and polymers that form the material for polyvinylchloride (PVC).1 Vinyl chloride for example is the alkyne used for polymer synthesis of PVC. The carbon-carbon triple bond is present in many marketed drugs that range from antiretrovirals2 and antifungals3. Many alkynes are also used to make organic solvents and common organic compounds such as ethanol, ethanoic acid, and acrylic acid. Because of their properties, alkynes are desirable compounds for many different types of organic reactions.

A common acetylene reaction is an alkyne chain elongation where a terminal alkyne is deprotonated and transformed into a nucleophile where it can then substitute or add into an electrophile. Because terminal alkynes are not very acidic, they typically require a strong base for deprotonation such as n-butyl lithium4 or sodium hydride. This causes a disadvantage since these stronger bases are water-reactive and flammable, leading to the need for extra safety precautions and special equipment. Since the focus for these projects was to recreate organic synthesis to be more benign using benign reagents in a solventless environment, benign alkyne deprotonations were desired and further use them as a nucleophile.

Additionally, benign transformations of internal and external acetylenes to ketones were also desired. Specifically, it was desired to create a more benign synthesis for the oxymercuration of alkynes to form the Markovnikov product, which usually requires a strong

56 acid as well as a mercury catalyst such HgSO4.This reaction produces an enol which tautomerizes into a ketone. Due to the fatal nature of mercury, a more benign approach would be more desirable. The use of Bronsted acids have shown many benefits compared to transition metal catalysts due to their benign nature, cost efficiency, and ease of use. Hammond, Xu, and coworkers developed an effective alkyne hydration using a combined acid catalyst system with

5 Ga(OTf)3/AcOH. Inspired by this concept, Haixuan Liu and coworkers developed a system consisting of p-toluenesulfonic acid (PTSA) and acetic acid to efficiently hydrate alkynes to

Markonikov ketones as shown in Figure 1.6 This is a much more desirable system due to its practical use, safety, and low cost. They were able to perform clean and efficient hydrations using this method for both internal and external alkynes with varying times and temperatures.

These reactions were performed via traditional solvent synthesis using CH2Cl2. Since this solvent is a suspected carcinogen, the solvent-free mechanochemical conditions could be used to try to achieve successful hydrations as well. Furthermore, polymer bound PTSA was incorporated to decrease the amount of solvent needed for work up and be able to perform a simple gravity filtration to obtain our products.

Figure 1. Reaction scheme for the hydration of alkynes with PTSA and AcOH.

Results and Discussion Terminal Alkyne Nucleophilic Substitution Similar to the reaction conditions for the Williamson Ether experiments, it was desired to determine if there is a benign base strong enough to deprotonate a terminal alkyne and if there is significance in ion pairs. Phenylacetylene is a weaker acid than phenol and alcohols and traditionally requires a much stronger and usually harsher base than carbonate and hydroxide for deprotonation. The goal was to determine if these safer bases could be used in solventless

HSBM conditions to facilitate the reaction as efficiently as when they are in solution with stronger bases.

These reactions began by using 4-bromobenzyl bromide and Cs2CO3 with the phenylacetylene for 16 hours since these conditions proved efficient for the other reactions.

Starting material was mostly recovered while there was a small amount of Bis(4-bromobenzyl) carbonate which is a result from the carbonate acting as a nucleophile with the 4-bromobenzyl bromide7 as seen in Figure 2. This was assumed to mean carbonates were not strong enough to deprotonate alkynes. Hydroxides were used next where it was noticed a similar mechanism of the hydroxide acting as a nucleophile with the 4-bromobenzyl bromide rather than a base with the phenylacetylene. This would produce a dibromobenzyl ether from the substitution of the hydroxide on the bromide creating 4-bromobenzyl alcohol which then would be deprotonated and substitute into another equivalent of the halide (Figure 3).

To attempt to avoid further competition, this reaction was ran stepwise. The first step would be the acid-base interaction with the phenylacetylene and hydroxide, followed by the addition of the 4-bromobenzyl bromide. For the initial stepwise reaction, both steps were ran

58 for 16 hours. Again, no desired product was noticed, but the appearance of the base-made substitution products had diminished along with the appearance of starting material. Instead it was noticed an increase appearance of peaks in the alkene range of the NMR. Through further investigation, it was discovered these peaks belonged to cis and trans-enynes which will be discussed later in this chapter. The takeaway from these results is there is a certain length of time the phenylacetylene can react with the hydroxide before it is too long, and undesired products are formed. Again, there was no desired substitution product. Instead only starting material, the ether biproduct, and enyne formations were noticed.

Figure 2. Reaction scheme with Cs2CO3 as the base.

Figure 3. Reaction scheme with CsOH as the base.

Since no desired product was formed, the next step was to determine if it was the halide or the properties of the benzyl halide that prevented this. When these reactions were ran with

4-chlorobenzyl chloride it still produced the same types of results. To determine if it was the halide or terminal alkyne that was the limiting factor, D2O studies were performed for the first

59 deprotonation step between the base and phenylacetylene (Figure 4). This was optimized through time studies by performing the first acid-base step, working up with D2O and calculating the percent deprotonation from the proton integration on the NMR (Figure 4). It was discovered phenylacetylene is approximately 95% deprotonated by KOH and CsOH in approximately 90 minutes. If these two react longer than that specific time, the presence of enynes will increase.

Figure 4. Reaction scheme to determine the percent deprotonation.

Since it was confirmed the terminal alkyne was being deprotonated, it was considered the benzyl halides as the limiting factor in these reactions. Perhaps there was some interaction with the benzene ring that prevented the substitution. To explore this theory, substitution reactions with chain alkyl halides were used, starting with 1-bromopentane. It was discovered the substitution reaction was successful with 1-bromopentane, where there was quantitative conversion to the substitution product. Although the conversion of the starting material to product was high, the percent yields were lower ranging from 49-58% yield from LiOH to CsOH.

This is believed to possibly be due to the solubility and volatility of the starting material and product.

To fully determine if the aromatic ring of the benzyl halide is what is hindering the nucleophilic substitution, the reaction was ran with (2-bromoethyl)benzene and 1-bromo-3- phenylpropane with the idea that the distance of the halide from the aromatic ring would be significant (Figure 5). Once again, mostly starting material was covered. Next,

(bromomethyl)cylcohexane was used as the halide since lacks the aromatic ring. It was discovered substitution does occurs when a primary alkyl bromide is off a cyclohexane ring, but there is still competition with the enyne metathesis reaction.

Figure 5. Reaction scheme for attempted nucleophilic substitutions with phenylacetylide and benzyl bromides.

It has been seen in the past alkali metal cyanides did not work either for substitution with 4-bromobenzyl bromide without the presence of a phase transfer catalyst8, yet there has seen successful substitution with chain alkyl halides such as 1-bromopentane. It is believed there is an interaction with acetylide nucleophiles and the benzene ring on the benzyl halides that prevents the two from successfully reacting with each other.

Dong et al. were the first to use 18-crown-6 in solvent-free ball-milling conditions for the nucleophilic addition reactions of terminal alkynes to carbonyl compounds9. Previous work in the Mack group showed the addition of 18-crown-6 influences the basicity and nucleophilicity

61 of metal salts7,8. Since the oxygens of crown ethers act as donor atoms, this molecule can bind a variety of small cations. To determine if a nucleophilic reaction could be performed with a crown ether, we started with the addition of 18-crown-6 since it is known to bind with a potassium cation (Figure 6). Instead of the desired product, it was observed nucleophilic substitution with the hydroxide more efficient with a quantitative conversion to the benzyl alcohol product.

Figure 6. Proposed reaction mechanism scheme of nucleophilic substitution reaction with 18- crown-6.

Nucleophilic Additions

Since the D2O studies showed the terminal alkyne is indeed being deprotonated but would not easily react with the benzyl bromides, exploration of the phenylacetylide as a

62 nucleophile for addition reactions was desired. The reaction scheme was identical to the nucleophilic substitution reactions but with ketones replacing the halides. With methyl ethyl ketone, there was quantitative conversion to the desired product when KOH was used as the base. The CsOH did not produce as good of results, but this is likely due to its hygroscopicity and additional water in the starting material. To avoid this, CsOH was attempted to be made in situ using ion pair switching with CsF and LiOH. Using the principle of the HSAB Theory, it is believed the lithium and fluorine ions are favorable to create a hard-hard bond, leaving the cesium and hydroxide to bond and create the base. CsF and LiOH would be milled for 30 minutes before adding the phenylacetylene to react for the 90-minute first step. It was noticed an improvement in yield; therefore, this method was continued. It was also preferred to determine if steric hindrance possibly played a part in the unsuccessful nucleophilic substitutions, so additions with benzophenone were performed. Once again, the trend of increasing yield as the metal cation size increased was observed as seen in Table 1. A

Zimmerman-Traxler reaction mechanism where a six-membered transition state was proposed in Figure 7 where it is believed the completion of the addition reaction is reliant mostly on the interaction of the metal cation with the oxygen of both the hydroxide and the ketone.

Table 1. Percent yields of nucleophilic additions with phenylacetylide and the ketones methyl ethyl ketone and benzophenone.

Figure 7. Proposed Zimmerman-Traxler six-membered transition state for nucleophilic additions with phenylacetylide.

Ene-yne Formation

As previously mentioned, the formation of enynes in the phenylacetylene deprotonation step were noticed. This sparked interest due to the traditional enyne metathesis requiring a catalyst, typically metal salts consisting of ruthinium10,11, copper12–14, or palladium.15 The possibility of a metal from the stainless-steel vial being used as a catalyst was considered and the same reaction (phenylacetylene and base) was ran in a Teflon vial with a Teflon ball bearing, thus producing a metal free environment. After just 5 hours in the HSBM, all the starting material had converted into the E and Z enyne isomers (22:88) as well as the homo coupling product. The hypothesis of a transition state mechanism is in Figure 8 where it is believed one equivalent of acetylide is added into phenylacetylene and is further protonated by another molecule of phenylacetylene to create the enyne and recreate the acetylide.

Figure 8. Proposed mechanism for the mechanochemical enyne formation

A theory the KOH was responsible for the enyne metathesis was tested by recreating the experiment with deuterated potassium hydroxide (KOD). When KOD was used as the base, though, the same enyne product was shown in the GCMS. To confirm the hydrogen in the base was not involved the mechanism, potassium methoxide was used in place of the hydroxide.

Once again, the enyne product was shown. Further studies will need to be done to confirm if

Figure 8 is correct mechanism. This could possibly be done with deuterated or 13C-labeled phenylacetylene.

Alkyne Hydration One of the most beneficial techniques to create ketone substrates is with the hydration of alkynes. This transformation, traditionally known as Kucherov’s reaction, typically combines an alkyne with water in the presence of an acid and mercury (II) salts. With this method the alkyne is converted into an enol which tautomerizes to a ketone with Markonikov selectivity. For modern sustainable synthesis, though, the toxicity of mercury compounds and their handling and disposal make it an unappealing route. A continual development of alkyne hydration catalysts over the past few decades has been in effect with the desire to replace mercury (II) salts with less toxic and more active catalysts. Non-mercurial metal catalysts for

66 efficient alkyne hydration include ruthenium, rhodium, iridium, palladium, platinum, copper, and gold.16 Several solvent free systems have been developed as a green and sustainable approach with the use of gold nanoparticles17 and Hβ zeolite18 to create catalytic systems with solvent-free alkyne hydration. While these may work efficient, there is still the negative consequence of the expense, high acid concentration, and high catalyst loadings of these precious metals.

Another thoroughly investigated system includes Brønsted acid and base catalysts. With this route, pure water at elevated temperatures, diluted sulfuric acid, and microwave irradiation have assisted with the hydration of acetylene and terminal alkynes to Markonikov products.19–21 It has also been discovered that p-Toluenesulfonic acid (PTSA) can readily hydrate substituted alkynes in alcohol at reflux as well as with microwave heating.22,23 Many alkyne hydration systems with PTSA include transition metals catalysts such as platinum and

Indium24,25 but the Mack Group is more interested in more sustainable and metal-free hydrations. Hammond, Xu, and coworkers developed an effective alkyne hydration using a

5 combined acid catalyst system with Ga(OTf)3/AcOH. Inspired by this concept, Haixuan Liu and coworkers developed a system consisting of p-Toluenesulfonic acid (PTSA) and acetic acid to efficiently hydrate alkynes. This is a much desirable system due to its practical use, safety, and low cost. They were able to perform clean and efficient hydrations using this method for both internal and external alkynes with varying times and temperatures. These reactions were performed via traditional solvent synthesis using CH2Cl2. Since this solvent is a suspected carcinogen, the solvent-free mechanochemical conditions were desired to try to achieve successful hydrations as well. Furthermore, it was sought to determine if polymer bound PTSA

67 could be incorporated to decrease the amount of solvent needed for work up and be able to perform a simple gravity filtration to obtain the products.

To begin the benign alkyne hydrations, phenylacetylene was reacted with TsOH•H2O and acetic acid in the high speed ball mill for 16 hours. The proposed mechanism for this reaction in solution is shown in Figure 9 where the acetic acid renders the TsOH more reactive for the alkyne to take the proton and the OTs group add in (addition), followed by the production of an enol after the addition of water (hydrolysis).6 This enol would then tautomerize to the desired ketone.

Figure 9. Reaction mechanism for alkyne hydration via TsOH in acidic conditions

For the mechanochemical reaction, instead of producing the desired ketone, an enone was obtained as shown in Figure 10. This is believed to be due to the combination of acid and the amount of time it reacted as shown in the proposed mechanism in Figure 11 where desired acetophenone was created but then underwent an aldol condensation.

Figure 10. Reaction of phenylacetylene with PTSA and acetic acid for 16 hours.

Figure 11. Proposed retrosynthetic mechanism.

To attempt to stop the reaction at the ketone, the amount of time and amount of acetic acid were decreased. Even with a time decrease and elimination of AcOH, the enone was still formed. While trying to optimize this reaction, hydrations were also performed using a polymer bound PTSA with the idea of a similar to mechanism of the polymer bound Wittig reaction26 where the substrate on the polymer would perform the proper chemistry and the side product could easily be separated. With this method, column chromatography could be avoided by using simple gravity filtration. The polymer bound PTSA would stay in the filter paper and green solvents could be used to extract the product in the round bottom. If the theory is correct, the polymer bound PTSA would be regenerated and possibly recycled (Figure 12).

Figure 12. Proposed mechanism for alkyne hydration with polymer bound PTSA

To begin, phenylacetylene and the polymer bound PTSA were reacted for 1 hour. The

NMR showed quantitative conversion and there was an 83% yield. This led to a substrate scope with different terminal alkynes as well as internal alkynes as shown in Table 1.

Table 1. Substrate scope of alkyne hydration reactions with polymer bound PTSA

Alkynes (1) Ketones (2) Temp (˚C) Time (h) Yield of 2 (%)

52 1 83

1a 2a

90 0.5 88

1b 2b

90 3 83

1c 2c

120 3 82

1d 2d

90 0.5 95

1e 2e

120 3 94

1f 2f

It was discovered for these reactions to fully hydrate to the ketone, the small addition of

H2O (~1 mL) is necessary. This is believed to aid with the tautomerization of the enol to the enone and with the regeneration of the polymer bound PTSA. For terminal alkynes that are in liquid form (1a, 1c), the temperature the HSBM naturally gets to (~52oC) was sufficient for

71 hydration. When solid terminal alkynes (1b, 1e) were used, the addition of heat was necessary.

It was found that 90oC to be efficient enough for quantitative conversion to the ketone. For internal alkynes, higher heat and longer reaction times were necessary. It was found that 120oC for 3 hours to work for 1d and it was used as the starting point for the rest of the internal alkynes.

One of the more interesting results was the hydration of 1e where it was predicted only one of the terminal alkynes would be hydrated, but instead saw both be reacted. This led to believe the polymer bound PTSA was catalytic and could potentially be recycled and reused after a reaction. To test this theory, the polymer left in the filter paper for a terminal alkyne reaction was reused (1a). It was discovered quantitative conversion to the ketone product, thus confirming the hypothesis of the mechanism and the recyclability of the polymer.

Conclusions

Alkyne chemistry is the foundation of many reactions and we have developed several benign methods of synthesis using them. A mechanochemical acid/base chemistry method has been developed in which the benign base of hydroxide can replace stronger harsher bases. We believe we have developed a safer route to synthesizing enynes without the need of expensive metal catalysts. Finally, we were able to develop a method to safely hydrate terminal and internal alkynes without the need of toxic mercury or expensive metal catalysts.

EXPERIMENTAL (MATERIALS AND METHODS)

General Remarks All alkyne reactions were carried out by mechanochemical milling in a

SPEX8000M Mixer Mill at a frequency of 18 Hz using a 15 mL stainless steel SmartSnapTM grinding jar from Form-Tech Scientific. 1H and 13C {1H}NMR spectra were obtained on a Bruker Advance

400 MHz spectrometer, and all chemical shift values are reported in ppm on the δ scale. GC-MS data were obtained with a Hewlett-Packard 6890 series GC-MS with a Zebron ZB-5, 15 mm x 0.25 mm x 0.25 mm column. Mass spectral determinations were carried out using ESI as the ionization method. Deuterated chloroform was obtained from Cambridge Isotope Laboratories, Inc.,

Andover, MA, and used without further purification.

Phenylacetylene, 2-bromoethylbenzene, 1-bromo-3-phenylpropyne,

(bromomethyl)cyclohexane, 18-crown-6, deuterium oxide, p-toluenesulfonic acid, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, 4-chlorobenzyl chloride, and 4-bromobenzyl bromide were purchased from Acros Organics. Phenol, lithium carbonate, sodium carbonate, potassium carbonate, and all ketones were purchased from Fischer

Scientific; all were used without further purification. p-Toluenesulfonic acid, polymer bound; 4- phenyl-butyne, 1-phenyl-1-hexyne, diphenylacetylene, and 1,4-diethynylbenzene were obtained from Sigma-Aldrich and used without further purification.

Typical procedure for mechanochemical nucleophilic reactions

To a custom-made 2.0 x 0.5 inch stainless steel screw capped vial was added a terminal alkyne

(2.00 mmol), potassium hydroxide (2.00 mmol, 0.112 g), and a 3/16” stainless steel ball bearing.

A Teflon gasket was added and the vial sealed and placed in a Spex 8000 mixer mill. The reaction was shaken for 90 minutes at 18 hertz. The crude reaction mixture was extracted with

73 approximately 25 mL of ethyl acetate and D2O. The organic layer was dried over anhydrous magnesium sulfate and solvent evaporated under reduced pressure to afford a mixture of products. 1H-NMR and GC-MS were used to assess the purity of the target molecule. Percent conversion was determined by 1H-NMR integration.

Typical procedure for mechanochemical nucleophilic reactions

To a custom-made 2.0 x 0.5 inch stainless steel screw capped vial was added a terminal alkyne

(2.00 mmol), potassium hydroxide (2.00 mmol, 0.112 g), and a 3/16” stainless steel ball bearing.

A Teflon gasket was added, and the vial sealed and placed in a Spex 8000 mixer mill. The reaction was shaken for 90 minutes at 18 hertz. To the crude reaction mixture an alkyl halide (2.00 mmol) or ketone (2.00 mmol) was added and the reaction was shaken for 16 hours at 18 hertz. The crude reaction mixture was extracted with approximately 25 mL of ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and solvent evaporated under reduced pressure to afford a mixture of products. 1H-NMR and GC-MS were used to assess the purity of the target molecule. Percent conversion was determined by 1H-NMR integration.

Typical procedure for mechanochemical enyne formation

To a 15 mL stainless steel SmartSnapTM grinding jar from Form-Tech Scientific was added an alkyne (1.00 mmol), a hydroxide (1.00 mmol) and a3/16” stainless steel ball bearing. The vial was sealed and placed in a Spex 8000 mixer mill and were ball milled for 5 hours at 18 hertz. The crude reaction mixture was extracted with approximately 25 mL of ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and solvent evaporated under reduced pressure to afford a mixture of products. 1H-NMR and GC-MS were used to assess the purity of the target molecule. Percent conversion was determined by 1H-NMR integration.

Typical procedure for mechanochemical alkyne hydration

To a 15 mL stainless steel SmartSnapTM grinding jar from Form-Tech Scientific was added an alkyne (1.00 mmol), polymer bound p-Toluenesulfonic acid (0.800 mmol, 0.400 g), and 2 – 3/16” stainless steel ball bearings. The vial was sealed and placed in a Spex 8000 mixer mill and were ball milled at various times and temperatures (0.5-3hr, 52-120oC) at 18 hertz. The crude reaction mixture was extracted with approximately 50 mL of acetone and 1 mL of water and gravity filtered. The organic layer was dried over anhydrous magnesium sulfate and solvent evaporated under reduced pressure to afford a mixture of products. 1H-NMR and GC-MS were used to assess the purity of the target molecule.

References

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Chapter 5 Calcium Carbide as an Alkyne Source

Introduction Many essentially important processes and technologies are sourced from the chemistry of carbon-carbon triple bonds. These compounds are the building blocks for many synthetic and industrials syntheses. Many important industrial compounds that contain this chemical characteristic are derivatives of acetylene.

Unfortunately, acetylene has several drawbacks due to its gaseous form as well as its synthesis originating from oil and natural gas. Since it needs complicated high-pressure equipment for storage, it also adds an extra risk for transportation and laboratory use. Calcium carbide (CaC2) has been recently increasingly studied as an efficient alternative and source for in situ acetylene chemical revolutions. It is a stable and inexpensive alternative that is a precursor of acetylene that is readily available and easy to use.

The application of calcium carbide in organic synthesis can bring a new aspect to acetylene chemistry. The use of water-containing solvents can generate acetylene from CaC2 in situ for alkyne chemistry from the combination of CaC2. Since some of the few key reactions of acetylene in industry such as dimerization, vinylation, ethynylation, and carbonylation are essential for industrial synthesis, several studies have been done using CaC2 as a replacement in different conditions. Several vinyl ethers were obtained from an autoclave reaction with

2 alcohols and calcium carbide (Figure 1a). When CaC2 was reacted with acetone in benzene under basic conditions, the ynediol 2,5-dimethylhex-3-yne-2,5-diol was created (Figure 1b). By creating in situ acetylene with CaC2 and water, several propargyl alcohols were synthesized by

79 the interaction with aliphatic aldehydes and ketones (Figure 1c).3 Sonogashira couplings have also been done with CaC2 using aryl- and heteroaryl halides with palladium and copper cocatalysts in the presence of wet solvents (Figure 1d).4

Figure 1a. Reaction scheme of calcium carbide with alcohols.

Figure 1b. Reaction scheme of calcium carbide with acetone.

Figure 1c. Reaction scheme of calcium carbide with aldehydes and ketones to create propargyl alcohols containing a terminal alkyne group.

Figure 1d. Reaction scheme of alkynylation reaction of aryl bromides and calcium carbide as an acetylene source.

5 A disadvantage to CaC2 is its extremely low solubility in organic solvents. Because of this, there are special procedures for easier and safer methods of the chemical processes.6 For example, a one-pot multiphase system was created for reactions such as Sonogashira and the

“click” reaction that contained a layer of a fluorous solvent between the CaC2 and water layers

(Figure 2).1 This fluorous solvent acts as a membrane and regulates water and heat transport from the acetylene gas passing through to the organic solvent layer containing the remaining reagents. Other in situ reactions have taken place in two vessels without direct contact of the mixture7 and via solid state mechanochemical activation.8 The latter is a solvent free approach much like the work of the Mack lab.

Figure 2. Quadraphasic phase-vanishing system for direct application of acetylene gas applied in situ.

Propargylamines have previously been reported as the major product when CaC2 was used as an acetylene surrogate in solution-based copper-catalyzed A3 reactions.9 Hernández and co‐workers developed a mechanochemical route to incorporate the C≡C bond of calcium carbide without additional water under solventless conditions.1 They studied the production of propargylamine-type products from aldehyde/alkyne/amine coupling by running their reactions in a planetary ball mill. The milling process changes the crystal structure and surface area of the

CaC2 as well as the other reagents thus facilitating the process without the need to be in a solvent environment. Unlike the solvent-based approach, 1,4-diamino-2-butynes were the major product for these mechanochemical couplings (Figure 3).

3 Figure 3. Mechanochemical copper-catalyzed A couplings with CaC2 as the acetylene source.

Since CaC2 is known to perform relatively well under solvent-free conditions, it was chosen to investigate its role in nucleophilic addition and substitution reactions. It is believed, under the right conditions, calcium carbide can be used as an important building block for complex reactions. The goal was to develop a method for solvent-free and benign internal alkyne synthesis using CaC2 and different alkyl halides as shown in Figure 4. The hope was to be able to use these alkyne products for further multistep synthesis, with one possibly being the mechanochemical hydrations discussed in Chapter 4.

Figure 4. Proposed nucleophilic substitution reaction scheme using CaC2 and alkyl halides as the building blocks for alkynes.

Results and Discussion

Before the nucleophilic reactions began, the reactivity of the calcium carbide was tested by recreating the A3 reaction done by Hernandez and coworkers in the high speed ball mill

(Figure 5). As a proof of concept, only the NMR was looked at to see the percent conversion and it was noticed new product peaks and lack of starting material. Thus, it was concluded that the purchased CaC2 was sufficient to continue with the planned experiments.

Figure 5. Reaction scheme of A3 reaction under HSBM conditions.

Since it was discovered that acetylide nucleophiles can perform additions with ketones, the next step was to begin these calcium carbide studies with this type of reaction. After optimization, it was found that addition reactions with CaC2 happen relatively fast in basic conditions (Figure 6). When methyl ethyl ketone was used as the electrophile, a 63% yield was obtained. It was also discovered that the CaC2 favors a double addition to make a propargylic diol over a propargyl alcohol. The lower yield was suspectedly due to the loss of remaining ketone into the water layer after liquid-liquid extraction and the lack of accessibility to all CaC2 in the starting material. The impurities contained in the commercially available calcium carbide such as metals, sulfides and/or phosphines also need to be considered. Since the purity of the

CaC2 is only 75-80% it is nearly impossible to determine if the impurities are responsible for any mediation of the reactions. Thus, high yields for these kinds of reactions are not expected.

Figure 6. Optimized reaction scheme of nucleophilic addition with calcium carbide.

As we began to optimize the nucleophilic addition with CaC2 and benzophenone to determine the effect of a solid ketone, we discovered Hernandez and coworkers had published work with similar mechanochemical reactions, particularly the nucleophilic addition with benzophenone (Figure 7).1 With this reaction they produced a propargylic diol as well as a propargyl alcohol. One interesting thing to note is their use of KOH as an additive to assist with the facilitation of CaC2, very similar to the method. Fortunately, these reactions began with

KOH because of abundance of starting material. Hernandez and coworkers had also tested a series of additives including LiOH, NaOH, and Ca(OH)2 which they discovered all led to a drop in the reactivity of CaC2. This showed the basicity was not the main contributor of these additives, but likely ionic formations and lattice energies were responsible. This discovery runs parallel with the ion pair driven reactions discussed in Chapter 1.

Figure 7. Favorskii alkynylation-type reaction scheme with benzophenone and calcium carbide in basic conditions.

Since at around the same time it had been discovered phenylacetylide can perform nucleophilic substitution with alkyl halides, we decided to alter the synthetic plans and determine if CaC2 behaves in a similar way with SN2 reactions. Unfortunately, among several different alkyl halides, mostly starting material was recovered with very little substitution products. The purchased calcium carbide came in the form of rocks which then had to be milled down to smaller particle sizes to be able to perform millimole scale reactions. During this process, there is a high possibility the hygroscopic CaC2 reacted with atmospheric water and created calcium hydroxide, which is not beneficial to the specific reaction. There were attempts to mill and store the calcium carbide in inert conditions, but there was not a change in reactivity.

Direct vinylations of alcohols and phenols had been previously done using a CaC2/KF

10 reagent produced from a K2CO3/KOH/DMSO system. This process provides an atom- economical addition reaction that produces acetylene in situ which further reacts with a fluoride-activated alcohol (Figure 8). This fluoride activation is produced from the CaC2/KF reagent, where the carbide is displaced with fluoride to produce CaF2 when the water protonates the carbide to form acetylene. The concept of fluoride activation was used to attempt nucleophilic substitution reactions. The theory is the fluoride will displace the carbide leaving it to react with an electrophile rather than the water. Unfortunately, with this method, it was noticed more of the fluoride substituted SN2 product than the carbide substitution.

10 Figure 8. Reaction scheme for CaC2/KF reagent produced from a K2CO3/KOH/DMSO system

To attempt to solve hydration problem, freshly milled CaC2 was used to create fresh reactive surface area. This was achieved by milling small rocks of CaC2 for an hour, removing any large particles, and then adding the other reagents. It is believed this method will prevent the formation of calcium hydroxide because of the surface areas limited interaction with water.

With this method, acetylene was created in situ and use a base to deprotonate and then substitute an alkyl halide (Figure 9).

Figure 9. Reaction scheme for nucleophilic substitution by creating acetylene in situ

There was finally confirmed proof from GCMS of the creation of the nucleophilic substitution products. While there were multiple other products in the GCMS, this shows there is potential in creating terminal and internal alkyne products with calcium carbide as the foundation. Reactions, such as these nucleophilic substitutions, might be a challenge in solventless systems because of the ion structure of the calcium carbide. It might not be as simple as having one calcium connect to the same carbide. Instead, it may have a crystal lattice type structure as shown in Figure 10 where the carbide is bonded to two different calcium ions which ate bonded to two different carbide ions. This lattice structure might be more difficult to break, therefore perhaps more energy can be put in the system in the future to break these bonds.

Figure 10. Crystal structure of tetragonal calcium carbide11

Conclusions In conclusion, we have determined calcium carbide has much potential as a foundation for solventless acetylene chemistry in the high speed ball mill. CaC2 is efficient in solventless nucleophilic additions with both solid and liquid ketones. Nucleophilic substitutions have a lot of potential under freshly milled conditions. The addition of water and a base shows promise of successful substitutions with further optimization. Future work could potentially include using pre-milled CaC2 in excess amounts and reacting with different alkyl halides.

EXPERIMENTAL (MATERIALS AND METHODS)

General Remarks All calcium carbide reactions were carried out by mechanochemical milling in a SPEX8000M Mixer Mill at a frequency of 18 Hz using a 15 mL stainless steel SmartSnapTM grinding jar from Form-Tech Scientific. 1H and 13C {1H}NMR spectra were obtained on a Bruker

Advance 400 MHz spectrometer, and all chemical shift values are reported in ppm on the δ scale.

GC-MS data were obtained with a Hewlett-Packard 6890 series GC-MS with a Zebron ZB-5, 15 mm x 0.25 mm x 0.25 mm column. Mass spectral determinations were carried out using ESI as the ionization method. Deuterated chloroform was obtained from Cambridge Isotope

Laboratories, Inc., Andover, MA, and used without further purification.

Calcium carbide, sodium hydroxide, potassium hydroxide, cesium hydroxide, and bromomethylcyclohexane were purchased from Acros Organics. METHYL ETHYL KETONE,

Typical procedure for mechanochemical calcium carbide nucleophilic reactions

To a 15 mL stainless steel SmartSnapTM grinding jar from Form-Tech Scientific was added an excess of calcium carbide and two 3/16” stainless steel ball bearings. The vial was sealed and placed in a Spex 8000 mixer mill and was ball milled for 1 hour and 18 hertz. Unground pieces of calcium carbide were then removed and a 2:1 equivalent of calcium carbide: electrophile was added. The vial was sealed and placed in a Spex 8000 mixer mill and were ball milled for varying times at 18 hertz. The crude reaction mixture was extracted with approximately 25 mL of ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and solvent evaporated under reduced pressure to afford a mixture of products. 1H-NMR and GC-MS were used to assess the purity of the target molecule. Percent conversion was determined by 1H-NMR integration.

References

(1) Zhang, W.; Wu, H.; Liu, Z.; Zhong, P.; Zhang, L.; Huang, X.; Cheng, J. The Use of Calcium Carbide in One-Pot Synthesis of Symmetric Diaryl Ethynes. Chem. Commun. 2006, No. 46, 4826–4828. https://doi.org/10.1039/B607809E.

(2) Barber, W. A.; Sloan, C. L. SOLUBILITY OF CALCIUM CARBIDE IN FUSED SALT SYSTEMS. The Journal of Physical Chemistry 1961, 65 (11), 2026–2028. https://doi.org/10.1021/j100828a025.

(3) Hamberger, M.; Liebig, S.; Friedrich, U.; Korber, N.; Ruschewitz, U. Evidence of Solubility of the Acetylide Ion C22−: Syntheses and Crystal Structures of K2C2⋅2 NH3, Rb2C2⋅2 NH3, and Cs2C2⋅7 NH3. Angewandte Chemie International Edition 2012, 51 (52), 13006–13010. https://doi.org/10.1002/anie.201206349.

(4) Matake, R.; Niwa, Y.; Matsubara, H. Phase-Vanishing Method with Acetylene Evolution and Its Utilization in Several Organic Syntheses. Organic Letters 2015, 17 (10), 2354–2357. https://doi.org/10.1021/acs.orglett.5b00827.(5) Voronin, V. v.; Ledovskaya, M. S.; Bogachenkov, A. S.; Rodygin, K. S.; Ananikov, V. P. Acetylene in Organic Synthesis: Recent Progress and New Uses. Molecules 2018, 23 (10), 2442. https://doi.org/10.3390/molecules23102442.

(6) Ardila‐Fierro, K. J.; Bolm, C.; Hernández, J. G. Mechanosynthesis of Odd‐Numbered Tetraaryl[n]Cumulenes. Angewandte Chemie International Edition 2019, 58 (37), 12945–12949. https://doi.org/10.1002/anie.201905670.

(7) Lin, Z.; Yu, D.; Sum, Y. N.; Zhang, Y. Synthesis of Functional Acetylene Derivatives from Calcium Carbide. ChemSusChem 2012, 5 (4), 625–628. https://doi.org/10.1002/cssc.201100649.

(8) Turberg, M.; Ardila‐Fierro, K. J.; Bolm, C.; Hernández, J. G. Altering Copper‐Catalyzed A 3 Couplings by Mechanochemistry: One‐Pot Synthesis of 1,4‐Diamino‐2‐butynes from Aldehydes, Amines, and Calcium Carbide. Angewandte Chemie International Edition 2018, 57 (33), 10718–10722. https://doi.org/10.1002/anie.201805505.

(9) Rodygin, K. S.; Vikenteva, Y. A.; Ananikov, V. P. Calcium‐Based Sustainable Chemical Technologies for Total Carbon Recycling. ChemSusChem 2019, 12 (8), 1483–1516. https://doi.org/10.1002/cssc.201802412.

(10) Werner, G.; Rodygin, K. S.; Kostin, A. A.; Gordeev, E. G.; Kashin, A. S.; Ananikov, V. P. A Solid Acetylene Reagent with Enhanced Reactivity: Fluoride-Mediated Functionalization of Alcohols and Phenols. Green Chemistry 2017, 19 (13), 3032–3041. https://doi.org/10.1039/C7GC00724H.

(11) Ruiz, E.; Alemany, P. Electronic Structure and Bonding in CaC2. The Journal of Physical Chemistry 1995, 99 (10), 3114–3119. https://doi.org/10.1021/j100010a022.

Characterization Data

Helpful spectra for identifying some compounds have been noted under the appropriate spectrum. Chapter 2 4-Bromobenzyl iodide ...... 88

1-Bromo-4-(phenoxymethyl)benzene ...... 90 1-Chloro-4-(phenoxymethyl)benzene ...... 92 Bis(4-bromobenzyl ether ...... 94 Chapter 3 4-Bromobenzyl thiocyanate ...... 96 2-oxo-2-phenlethylthiocyanate ...... 97 1-(bromoethyl)benzene ...... 98 1-phenylethyl thiocyanate...... 99 Chapter 4 3-methyl-1-phenyl-1-pentyn-3-ol ...... 100

1,1,3-triphenylprop-2-yn-1-ol ...... 101 (E/Z)-1,4-diphenylbut-3-en-1-yne ...... 103 Dypnone ...... 104 Acetophenone ...... 105 4-Bromoacetophenone ...... 106

4-phenyl-2-butanone ...... 107 Caprophenone ...... 109 1,4-diacetylbenzene ...... 111 Chapter 5 1,4-bis(4-bromophenyl)-1,4-di(pyrrolidine-1-yl)but-2-yne ...... 113

3,6-dimethyl-oct-4-yne-3,6-diol ...... 114 prop-2-ynylcyclohexane and 4-cyclohexylbut-2-ynylcyclohexane ...... 116

Characterization data for 4-bromobenzyl iodide:

Characterization data for 1-Bromo-4-(phenoxymethyl)benzene:

Characterization data for 1-Chloro-4-(phenoxymethyl)benzene

Characterization data for Bis (4-bromobenzyl ether):

100

Characterization data for 4-bromobenzyl thiocyanate and 4-bromobenzyl isothiocyanate (2:1):

101

Characterization data for 2-oxo-2-phenylethylthiocyanate

102

Characterization data for 1-bromoethylbenzene

103

Characterization data for 1-phenylethyl thiocyanate

104

Characterization data for 3-methyl-1-phenyl-1-pentyn-3-ol

105

Characterization data for 1,1,3-triphenylprop-2-yn-1-ol

106

107

Characterization data for (E/Z)-1,4-diphenylbut-3-en-1-yne

108

Characterization data for Dypnone

109

Characterization data for acetophenone

110

Characterization data for 4-bromoacetophenone

111

Characterization data for 4-phenyl-2-butanone

112

113

Characterization data for caprophenone

114

115

Characterization data for 1,4-diacetylbenzene

116

117

Characterization data for 1,4-bis(4-bromophenyl)-1,4-di(pyrrolidine-1-yl)but-2-yne

118

Characterization data for 3,6-dimethyl-oct-4-yne-3,6-diol

119

120

Characterization data for prop-2-ynylcyclohexane and 4- cyclohexylbut-2-ynylcyclohexane

121