Understanding the Solvent-Free Nucleophilic Substitution Reaction

Home , Alpha effect, Benzyl iodide, Finkelstein reaction, Rate equation

Understanding the Solvent-free Nucleophilic Substitution Reaction Performed in the High Speed Ball Mill (HSBM): Reactions of Secondary Alkyl Halides and Alkali Metal-Halogen Salts

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

Master of Science

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

Sarah B. Machover

B.A. Chemistry Washington University in St. Louis May 2006

Committee Chair: James Mack, Ph.D. April 2011

An Abstract of a Thesis

Understanding the Solvent-free Nucleophilic Substitution Reaction Performed in the High Speed Ball Mill (HSBM): Reactions of Secondary Alkyl Halides and Alkali Metal-Halogen Salts

Sarah B. Machover

Governments around the world continue put forth new regulations to reduce the amount of solvent emissions into the environment.a R&D chemists must take on this challenge in order to make safer solvent choices and solvent reduction priorities in the beginning stages of product development. As the scientific community embraces the ideals of Green chemistry and moves towards more environmentally responsible research, it is necessary to understand the capacity of these new techniques on well- established reactions, e.g. SN1 and SN2 reactions. It has been proven that the nucleophilic substitution product of an SN2 reaction on a primary alkyl-halogen substrate can be formed in a High Speed Ball Mill (HSBM) under solvent-free conditions.1 The results of a nucleophilic substitution reaction performed on a secondary alkyl halide substrate in an HSBM under solvent-free conditions were previously uncharted. The mechanism of the reaction between a secondary alkyl-halogen can be considered SN1 or 2 SN2 depending on a variety of factors. The success of the SN1 reaction, a first-order nucleophilic substitution, is largely dependent on the solvent used. This is because of the charged species formed in the first step of the reaction: bond heterolysis. By using the HSBM under solvent-free conditions, the medium which stabilizes the intermediate and transition states of the SN1 reaction mechanism is removed. This investigation looks at the results from the reaction of a hindered secondary alkyl halide and an alkali metal-halogen salt in a solvent-free environment in order to answer the questions: What, if any, products are formed? and How does this compare to the predicted products as seen in classic SN1 reactions?

a Governmental regulations on solvent emissions can be found at the websites: epa.gov, legislation.gov.uk, and Canada.gc.ca.

Acknowledgements

To those for whom I may have been out of sight, but was never out of mind…Thank You.

“With the power of conviction there is no sacrifice.” - Pat Benetar, “Invincible”

Special thanks go to my family, Givaudan Flavors, and Dr. Mack for their endless enthusiasm and support.

iii

Table of Contents

Chapter Page

1. Introduction and Background……………………………………………………1-24

Green Chemistry………………………………………………………...... 1

Solvent…………………………………………………………………………...4

Grinding…………………………………………………………………...... 5

Nucleophilic Substitution Reaction………………………………………..7-19

The SN2 Reaction……………………………………………………...8

Solvent Effects…………………………………………………....11-14

Solvation……………………………………………………...11

Solvolysis……………………………………………………..12

Hydrogen Bonding………………………………………...... 12

Dielectric Constant…………………………………………..13

Ion Effects…………………………………………………………15-16

Common-Ion Effect………………………………………….15

“Special” Salt Effect………………………………………….15

The SN1 Reaction……………………………………….….…...... 16

Hard-Soft Acid-Base (HSAB) Principle…………………………………...... 19

Kornblum’s Rule……………………………………………………………….21

Swain-Scott Nucleophilicity………………………………………………..…23

Conclusion……………………………………………………………….….…24

2. Rationale and Design…………………………………………………………..25-66

The Finkelstein Reaction……………………………………………………..25

Nucleophilic Displacement of a Secondary Carbon: Benzhydryl

iv Substrates…………………………………………………………………………..26-30

Mechanism Overview…………………………………………..…....28

Ball-Milled Reactions…………………………………………………...... 30-65

Bromodiphenylmethane (6).………………………………….….30-42

HSAB Principle and Altering the Nucleophile…………….33

Results of Reactions with Different Alkali Metal-Halogen

Salts……………………………………………………………………35

Chlorodiphenylmethane (7)…………..…………………………...... 42

bis(Diphenylmethyl)ether (5) and other Oxygenated Products....47

Hetero-coupling Reactions………………………………….…...50-61

Mixing Studies………………………………………………..55

Reactions with Benzyl iodide (15)………………………….57

Mechanism Summation……………………………………………...60

Reactions in Vials of Alternative Materials: Copper, Teflon®,

and Nickel…………………...………………………………..…...62-65

Copper and Teflon® Vial Reactions………………………..62

Nickel Vial Reactions……………………………….…….....64

Conclusion……………………………………………………………………..65

3. Experimental Methods……………………………………………………………..67

4. References………………………………………………………………..……….105

Appendix: Spectra and X-ray Chrystallography…………………………………………..110

v List of Tables and Figures

Figure Page

1.1 – The four main classes of nucleophilic substitution reactions…………………………8

1.2 – Kinetic Energy Diagram of the SN2 Reaction………………………………………....10

1.3 – Solvation of a sodium cation by water…………………………………………………12

1.4 – Kinetic Energy Diagram of the SN1 Reaction…………………………………………17

2.1 – Mechanism of a 4-member transition state for neutral nucleophilic substitution………………………………………………………………………..26

2.2 – Concerted transition state for the solvent-free nucleophilic substitution of benzhydryl halides (A) ………………………..……………………………………………….28

2.3 – Concerted transition state for the solvent-free alkali metal-carbon bond formation mechanism……………………………………………………………………29

2.4 – Iododiphenylmethane (3), 1,1,2,2-tetraphenylethane (4), and bis(diphenylmethyl)ether (5), respectively……………...……………………………………29

2.5 – X-ray crystallographic image of bis(dipenymethyl)ether (5) ….…………………….30

2.6 – Six-member transition state leading to the homo-coupling with the assistance of the nucleophilic salt……………………………………………………………….……………51

2.7 – Four-member transition state leading to the homo-coupling without the participation of the nucleophilic salt…………………………………………………………….……………51

2.8 – Reaction of the diphenylmethide (C) and the benzhydryl substrate (A) to synthesize the homo-coupled product (4)………………………..……………………….53

2.9 – 1,2-dibenzylbenzene (11), 1,4-dibenzylbenzene (12), and ethane-1,1,2-triyltribenzene (13), respectively...... 58

2.10 – Resonance structures of diphenylmethide (C) leading to the synthesis

vi of the aromatic substitution products (8, 11, 12)……………………………………………59

A.1 – GC-MS of bromodiphenylmethane (6) ……………………………………………...110

A.2 – GC-MS of chlorodiphenylmethane (7) ……………………………………………....111

A.3 – GC-MS of iododiphenylmethane (3) ………………………………………….……..112

A.4 – GC-MS of fluorodiphenylmethane (14) …………………………………………..…113

A.5 – GC-MS of 1,1,2,2-tetraphenylethane (4) …………………………………………...114

A.6 – 1H NMR of 1,1,2,2-tetraphenylethane (4) ………………………………………..…115

A.7 – Close-up of the 1H NMR of 1,1,2,2-tetraphenylethane (4) ….………………….…116

A.8 – 13C NMR of 1,1,2,2-tetraphenylethane (4) ……………………………………….....117

A.9 – X-ray crystallographic image of bis(diphenylmethyl)ether (5) …………….…..….118

A.10 – GC-MS of bis(diphenylmethyl)ether (5) …………………………………………...119

A.11 – 1H NMR of bis(diphenylmethyl)ether (5) ……………………………………..……120

A.12 – Close-up of the 1H NMR of bis(diphenylmethyl)ether (5) ………………………..121

A.13 – 13C NMR of bis(diphenylmethyl)ether (5) ………………………………………….122

A.14 – GC-MS of diphenylmethane (9) ……………………………………….……………123

A.15 – 1H NMR of diphenylmethane (9) ……………………………………….…..………124

A.16 – Close-up of the 1H NMR of diphenylmethane (9) ……………………………...…125

A.17 – 13C NMR of diphenylmethane (9) ……………………………………….………….126

A.18 – GC-MS of p-benzyltriphenylmethane (8) …………………………….……………127

A.19 – 1H NMR of p-benzyltriphenylmethane (8) ………………………………………....128

A.20 – 13C NMR of p-benzyltriphenylmethane (8) ………………………………………..129

A.21 – Close-up of the 13C NMR of p-benzyltriphenylmethane (9) …………...………...130

A.22 – GC-MS of 1,2- or 1,4-dibenzylbenzene (11 and 12) ……………………….…….131

A.23 – GC-MS of 1,2- or 1,4-dibenzylbenzene (11 and 12) ……………………….…….132

A.24 – 1H NMR of 1,2- and 1,4-dibenzylbenzene (11 and 12) …………….……….…...133

A.25 – Close-up of the 1H NMR of 1,2- and 1,4-dibenzylbenzene (11 and 12) ……….134

vii A.26 – 13C NMR of 1,2- and 1,4-dibenzylbenzene (11 and 12) ………….……………...135

A.27 – Close-up of the 13C NMR of 1,2- and 1,4-dibenzylbenzene (11 and 12) ……....136

A.28 – GC-MS of benzyl iodide (15)….……………..……………………………………...137

A.29 – 1H NMR of benzyl iodide (15) …………………………………..…………………..138

A.30 – Close-up of the 1H NMR of benzyl iodide (15) ……………………………….…...139

A.31 – 13C NMR of benzyl iodide (15) …………………………………...…………………140

A.32 – GC-MS of dibenzyl ether (16) …………………………………...………………….141

A.33 – 1H NMR of dibenzyl ether (16) …………………………………...…………………142

A.34 – Close-up of the 1H NMR of dibenzyl ether (16) ………………...………………...143

A.35 – 13C NMR of dibenzyl ether (16) …………………………………..………………...144

Scheme

1.1 – Reaction rate equation of the SN2 Reaction……………………………………………9

1.2 – Nucleophilic substitution of tert-butyl bromide by methanol to afford 2-methoxy-2- methylpropane and hydrogen bromide………………………………………………………12

1.3 – Reaction rate equation of the SN1 Reaction…………………………………………..17

1.4 – Pearson’s equilibrium reaction used to make hard and soft determinations………19

1.5 – Acid-Base exchange equation………………………………………………………….20

1.6 – The reaction of silver nitrite with an alkyl bromide affords the nitrite ester, while a reaction of sodium nitrite with the same alkyl bromide affords the nitroparaffin…………22

2.1 – Finkelstein Reaction of alkyl chloride and sodium iodide in acetone………………25

2.2 – Solvent-free nucleophilic substitution reaction of p-bromobenzyl bromide (1) and potassium iodide………………………………………………………………………..…26

2.3 – Reaction of bromodiphenylmethane (6) and sodium or lithium iodide, under standard conditions, to form p-benzyltriphenylmethane (8) and

viii diphenylmethane (9)……………………………………………………………………………38

2.4 – The reaction of bromodiphenylmethane (6) and p-bromobenzyl bromide (1) failed to synthesize the heterocoupled product (10) ………………………………..…………….54

Table

1.1 – Physical properties of a variety of solvents…………………………………………...13

1.2 – Hard, Soft, and Borderline acid and base classifications……………………………21

2.1 – Comparison of the percent of reaction products in the crude product mixture of bromodiphenylmethane and potassium iodide using 5, 1, and 10 mol% equivalents of the nucleophilic salt…………………………………………………………………………….32

2.2 – Alkali metal-halogen interactions in reference to their status as hard or soft...... 34

2.3 – Results of the reactions between bromodiphenylmethane (6) and alkali metal- chloride salts under standard conditions…………………………………………………….36

2.4 – Percent of bromodiphenylmethane (6) present in the crude product mixture of reactions with various nucleophilic salts under standard conditions……………………...41

2.5 – Results of the reactions between chlorodiphenylmethane (7) and alkali metal-bromide salts under standard conditions………………………………………44

2.6 – Results of the reactions between chlorodiphenylmethane (7) and sodium-halogen salts under standard conditions……………………………………………………………….46

2.7 – Percent chlorodiphenylmethane (7) present in the crude product mixture of reactions with various nucleophilic salts under standard conditions………………...……47

ix Chapter 1

Introduction and Background

Green Chemistry

The term “green” is defined by the Merriam-Webster dictionary as: green (adj.): often capitalized: concerned with or supporting the environment; tending to preserve environmental quality (as by being recyclable, biodegradable, or non-polluting). green (n.): often capitalized: Environmentalist; especially: a member of an activist political party focusing on environmental and social issues.

The term “green,” as it is defined above, entered our vernacular in the 1990’s and has become a standard term used for describing everything from advertising campaigns, e.g.

“greenwashing,” to chemistry.

Green chemistry, also known as sustainable chemistry, is described by the United

States Environmental Protection Agency as the “design of chemical products and processes that reduce or eliminate the use or generation of hazardous substances.”a

Green chemistry can be part or all of the process of creating a chemical product; from conception to use.

The 12 principles of Green Chemistry are a guideline for chemists to follow in order to reduce the negative environmental impact of their experimentation. This can include

a The description of Green chemistry by the U.S. government can be found at epa.gov/greenchemistry/.

1 preventing hazards by thoroughly designing reaction schemes before they are implemented and increasing reaction efficiency by using catalysts. The principles were originally presented in Green Chemistry; Theory and Practice in1998 by Paul Anastas,

Director of the Center for Green Chemistry and Green Engineering at Yale University, and John Warner, of the Warner Babcock Institute for Green Chemistry. They are as follows:3

1. Prevention It is better to prevent waste than to treat or clean up waste after it has been created.

2. Atom Economy Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product.

3. Less Hazardous Chemical Syntheses Wherever practicable, synthetic methods should be designed to use and generate substances that possess little or no toxicity to human health and the environment.

4. Designing Safer Chemicals Chemical products should be designed to affect their desired function while minimizing their toxicity.

5. Safer Solvents and Auxiliaries The use of auxiliary substances (e.g., solvents, separation agents, etc.) should be made unnecessary wherever possible and innocuous when used.

6. Design for Energy Efficiency Energy requirements of chemical processes should be recognized for their environmental and economic impacts and should be minimized. If possible, synthetic methods should be conducted at ambient temperature and pressure.

2 7. Use of Renewable Feedstocks A raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable.

8. Reduce Derivatives Unnecessary derivatization (use of blocking groups, protection/deprotection, temporary modification of physical/chemical processes) should be minimized or avoided if possible, because such steps require additional reagents and can generate waste.

9. Catalysis Catalytic reagents (as selective as possible) are superior to stoichiometric reagents.

10. Design for Degradation Chemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment.

11. Real-time Analysis for Pollution Prevention Analytical methodologies need to be further developed to allow for real-time, in-process monitoring and control prior to the formation of hazardous substances.

12. Inherently Safer Chemistry for Accident Prevention Substances and the form of a substance used in a chemical process should be chosen to minimize the potential for chemical accidents, including releases, explosions, and fires.

In recent decades the Green chemistry movement has gained momentum, becoming a part of the chemistry language. Soon after the 12 Principles were published, the scientific journal, Green Chemistry, published by the Royal Society of Chemistry, was founded by Professor James Clark. As well, Green Chemistry Letters + Reviews, published by Taylor + Francis, founded by John Warner, has also been established.

Awards such as the 2005 Nobel Prize in Chemistry, for metathesis reactions, and Green

Chemistry Challenge Awards issued by the governments of several countries emphasize

3 the importance in finding “greener” solutions to our chemistry and global challenges. The chemistry community showed collective support of this idea in the theme of the 2010

Spring Meeting of the ACS, “Chemistry for a Sustainable World,” which showcased a variety of environmental impact seminars mingled with chemistry and engineering contributions toward reducing that impact.a

The government has long been involved in creating standards for air and water quality.b

Updated versions of the Clean Air Act and the Clean Water Act were first established in

1970 and 1972, respectively. These acts allow the EPA to create standards for air and water quality, and regulate discharge of emissions and pollutants into the air and water.

In 1990, the Pollution Prevention Act was created to enforce source reduction of pollution, as opposed to waste clean-up processes; since “source reduction is fundamentally different and more desirable than waste management or pollution control.”c This sentiment is reflected in the first principle of Green Chemistry: Prevention.

When discussing the impact of chemistry on the environment, the subject of solvent, both volume and type, cannot be overlooked.

Solvent

In a reaction, the solvent is used to dissolve reactants and reagents. When the reactants are uniformly distributed in the same phase, such as an aqueous solution, the individual molecules are able to collide to form a product. Solvents can also be used to transfer a Information on the 2010 Spring Meeting of the ACS can be found in the 239th ACS National Meeting and Exposition On-Site Program. b Information about these standards of air and water quality can be found at epa.gov. c A summary of the Pollution and Prevention Act can be found at epa.gov.

4 heat to or from a reaction and distribute any change in temperature evenly throughout the reaction mixture.4 In some cases, solvents can render a reactant more reactive such as the SN2 reaction of small negatively charged nucleophiles towards alkyl halides in polar aprotic solvent.5 Though it is typically desirable to use a solvent that is inert to the reaction taking place, solvents can often facilitate reactions4 or take part in reactions: esterifications6 and solvolytic reactions7-9 are some examples.

Solvent use is the largest contributor to batch process mass utilization and toxicity concerns.10 R&D chemists’ and engineers’ main goal is the synthesis of a molecule or development of a process; most often the solvent choice reflects this concern rather than that of environmental and health risks associated with the solvent.10, 11 Solvent can account for up to 80-90% of the overall mass utilization in pharmaceutical and fine chemical scale-up operations and because of this, is the major contributor to the toxicity of the process.10 Finding alternative solvent choices to N,N-dimethylformamide and dichloromethane is not apparent. Programs, guides, and ratings systems have been developed to highlight the positive and negative characteristics of widely used solvents in order to aid the R&D chemist and engineer in making an informed solvent choice.11

Modification of solvent choice based on this information does not always produce a more efficient route, but benefits the reduction of hazardous chemicals used in large-scale production. Solvent-free conditions can also be a viable option for complete elimination of solvent from a reaction or process.

Grinding

When solvent is removed from a reaction, the reaction can still take place, but will occur only at the reactants’ interface; where the reactants are in contact. Solids cannot

5 efficiently react in this manner. The reactants must be divided to a smaller particle size so that all of the reactant material may have a chance to collide and form product.

Grinding can facilitate this by decreasing particle size, increasing surface area per unit volume, and by providing the means and energy for collision. An increase in surface area increases reaction rate. Grinding reactions under solvent-free conditions do not have the temperature-regulation and dilution factors of reactions in solution. An increase in temperature and pressure (similar to increased concentration) inside the vessel can also increase reaction rate by improving the likelihood of collisions between reactants.12

The mortar and pestle has been used for grinding materials for over a half-million years.13 The same tools employed for food preparation, grinding herbs and grains, have also been used for chemical reactions. The use of the mortar and pestle in solid-state chemistry has been reported on for more than a century.14 Even with modern advancements and machinery, this rudimentary equipment is still used in kitchens and laboratories today.15-17 A type of alternative machinery is the ball mill, which shakes a vessel containing a ball-bearing at high speeds. Reactants are ground and mixed, allowing for chemical reactions to take place.18 Though ball mills are typically used for sample preparation, they have well-established use in inorganic chemistry and materials science.19 Ball mills are more efficient than previous methods because they require less energy exertion and work by the scientist.20 There are many types of ball mills: horizontal rotary ball mills, vibration ball mills, planetary ball mills, bead-mills, and jet-mills. The difference between each machine will depend on the amount of rotations per minute

(RPM) and the type of motion employed for mixing. For example, the High Speed Ball

Mill (HSBM), or vibration ball mill, operates at a frequency of 18 Hz. The vessel containing the reactants and reagents is moved in the shape of a 3-dimensional figure eight. The reaction vessels and balls can be made out of inert materials such as steel

6 and Teflon®, or metals such as nickel, copper, and iron, which can be used as reaction catalysts. Varying amounts of ball-bearings can also be used. The ball mill has been applied to several important organic chemistry reactions such as the aldol condensation, the Wittig reaction, and the Suzuki reaction. Certain reactions under solvent-free conditions in the ball mill have been shown to go to completion more quickly and with improved yields compared to the same reactions in solution.19, 21

Defying the chemistry adage, “like dissolves like,” can make reactions between ionic/polar and non-polar materials difficult due to issues of solubility. Phase transfer catalysts such as crown ethers and polyethylene glycols can be used to transport reactants with different solubility properties between phases so that the reactants may come in contact with one another. No solvent is required in ball milling reactions.

Besides reducing solvent waste, which adheres to the ideals of Green Chemistry, the ball mill has the advantage of directly mixing polar and non-polar materials. An example is the Knoevenagel condensation in the vibration ball mill where the ionic salts CaCO3

22 and CaF2 can be employed as catalysts. This reaction would normally have been performed in an organic solvent into which the salts would not have dissolved. As well, reactions such as the Michael addition, which requires the use of strong bases when in solution, has been successfully performed using a catalytic amount of weak base in the ball mill.23, 24

Nucleophilic Substitution Reactions

It has been noted that “in the whole of Organic Chemistry there is no reaction more important than the replacement by a nucleophile of a leaving group attached to an aliphatic carbon atom.”25 A nucleophilic substitution reaction is one that “involves the

7 replacement of one functional group, X, by another, N, in such a way that N supplies a pair of electrons to form the new bond and X departs with the pair of electrons from the old bond.”26 The basis for the understanding of nucleophilic substitution reactions was first developed by Edward Hughes and C.K. Ingold in the 1930’s. Accumulated data made the mechanistic patterns of these reactions apparent, and from this was developed the unimolecular “ionization mechanism” or SN1 and the bimolecular “direct

27 displacement mechanism” or SN2. Though these mechanisms, especially the SN1 mechanism, were only simply understood, Hughes and Ingold put forth the idea that not all nucleophilic substitution reactions followed the same mechanism. Four main classes of nucleophilic substitution reactions are listed below (Figure 1.1):28

N- + RX Æ R—N + X- (1) N + RX Æ R—N+ + X- (2) N- + RX+ Æ R—N + X (3) N + RX+ Æ R—N+ + X (4) Figure 1.1 – The four main classes of nucleophilic substitution reactions.

This work will be concerned with reaction (1).

SN2 Reaction

The bimolecular nucleophilic substitution reaction, or SN2 reaction, occurs when a nucleophile attacks an electrophilic carbon from the backside. The substrate has an unhindered primary (RCH2X) or, occasionally, secondary (R2CHX) central carbon, where

R is an alkyl group or a hydrogen and X is a halogen. SN2 reaction rates decrease with additionally bulkier R groups on the central carbon atom.29 Large R groups, such as a t- butyl or a phenyl ring, will prevent a backside attack while small R groups, such as

8 methyl or hydrogen, will allow for the nucleophile to attack at a 180° angle from the leaving group. This forms a bond with the opposite lobe of the same p-orbital from which the leaving group is bonded. In a single step, the nucleophile forms a bond with the

nd carbon, as the carbon’s bond with the leaving group is broken. This SN2 reaction is 2 order; the rate equation is first order in terms of both the nucleophile and the substrate, meaning that the rate of the reaction is dependent on the concentrations of both the substrate and the nucleophile (Scheme 1.1).

R= k[Substrate][Nucleophile] Rate=k[RX][N]

Scheme 1.1 – Reaction rate equation of the SN2 Reaction.

The SN2 reaction mechanism goes through a neutral, polar transition state which resembles the reactants.30 It occurs at the highest point of the free-energy of activation curve in the kinetic energy diagram (Figure 1.2); the leaving group and the nucleophile are both partially connected to the central carbon. The transition state cannot be isolated as it is unstable for the measure of a few vibrational frequencies and has no barriers preventing its collapse.30 If the central carbon is chiral, the product will form with inversion of stereochemistry.

a Figure 1.2 – Kinetic Energy Diagram of the SN2 Reaction.

The role of solvent in a SN2 reaction can be 2-fold. A neutral aprotic solvent does not contain any hydrogen atoms bonded to nitrogen or oxygen. These types of solvents, such as N,N-dimethylformamide (DMF), acetone, and acetonitrile (ACN), can have trouble solvating small, negatively charged nucleophiles such as chloride ions, because they are unable to participate in hydrogen-bonding with the nucleophile’s lone pair of electrons. This causes the nucleophile to be less stable and more reactive. Unless the nucleophile is the same molecule as the leaving group, the transition state will be polar.

A polar solvent will stabilize the transition state through solvation. Though polar aprotic solvents are preferred for use in SN2 reactions, they are not imperative to the success of

a Image of the kinetic energy diagram of an SN2 reaction from chemwiki.ucdavis.edu/.../149/=Haloalkanes_10.bmp.

10 31-33 the reaction. The SN2 reaction can still occur without stabilization from solvent because it is not necessary to form charged species in the transition state.1

Solvent Effects

Solvent effects are critical to the mechanism of the SN1 reaction. Solvent interactions with the reactants, transition state, intermediate species, and products can affect the free energy of each state which, in turn, affects the ease at which the reaction goes to completion. Solvent-free reactions avoid negative solvent effects at the cost of those positive effects.

Solvation

Solvation is the “process of attraction and association of molecules of a solvent with molecules or ions of a solute” which can involve electrostatic forces, van der Waals forces, and hydrogen-bonding.a Solvation of particles in polar solvents occur when the solvent molecules dissolve ions by aligning their dipoles with the ions’ charges; weakly bonding with them and thus dissolving them into solution. One such interaction is the solvation of the sodium cation, Na+, in water where the partial negative charges of the oxygen atom interact with the positively charged sodium (Figure 1.3). The solvation over the course of the reaction can differ depending on the amount and dispersal of charge of the current state in comparison to the ground state.5 Solvation is known to have implications, such as inversion of the order of nucleophilic reactivity of anionic nucleophiles, depending on the nature of the reaction solvent.34-38

a Definition of solvation from en.wikipedia.org/wiki/solvation and goldbook.iupac.org/S05747.html.

Figure 1.3 – Solvation of a sodium cation by water.a

Solvolysis

Water and alcohols, such as methanol, are weak nucleophiles. Nucleophilic substitution reactions in which the nucleophile and the solvent are one in the same are known as solvolytic reactions (Scheme 1.2).

(CH3)3C—Br + CH3—OH Æ (CH3)3C—OCH3 + HBr Scheme 1.2 – Nucleophilic substitution of tert-butyl bromide by methanol to afford 2- methoxy-2-methylpropane and hydrogen bromide.

Hydrogen Bonding

Protic solvents contain hydrogen atoms bonded to oxygen or nitrogen. This enables the solvent molecules to be hydrogen-bond donors. The use of protic solvents such as methanol, water, and ammonia can increase the reaction rate of SN1 reactions through

a Image of a sodium cation being solvated by water from course2.winona.edu/sberg/Free.htm images.

12 electrophilic assistance in bond heterolysis: anions such as chlorides and bromides are solvated through hydrogen-bonding with the anions’ lone pairs of electrons.39 The use of protic versus aprotic solvents has been shown to alter the configuration of the nucleophilic substitution product, since different solvents can promote different reaction pathways.40

Dielectric Constant

The dielectric constant denotes a solvent’s ability to insulate ions by reducing the strength of the electric field surrounding the charged particle. Effectively, in an SN1 reaction, a solvent with a high dielectric constant, represented as ε, would separate intimately associated ions, preventing re-formation of starting material. Water, with ε =

80.1, has the highest dielectric constant.

Table 1.1 – Physical properties of a variety of solvents.a

20 2O Solvent b.p. ε ρ RD nD μ (°C) Polar Protic Solvent

Water 100 80.1 0.998 3.7 1.333 1.85 Formic acid 101 58 1.22 1.3714 1.41 Trifluoroacetic acid 72 8.55 1.489 13.7 1.285 2.26 Methanol 65 32.7 0.791 8.2 1.3284 1.70 Ethanol 79 24.5 0.789 12.8 1.3614 1.69 Isopropanol 82 17.9 0.786 17.5 1.3772 1.66 Acetic acid 118 6.15 1.049 12.9 1.3716 1.74

a Physical properties of solvents compiled based on information from http://depts.washington.edu/eooptic/linkfiles/dielectric_chart%5B1%5D.pdf and macro.lsu.edu/HowTo/solvents/dielectric%20constant%20.htm. The physical properties represented in the table are boiling point (b.p.), dielectric constant (ε), density at 20°C (ρ20), molar 2O refraction (RD), refractive index at 20°C (nD ), and dipole moment (μ).

13 Polar Aprotic Solvent Dimethyl sulfoxide 189 46.7 1.096 20.1 1.4783 3.96 Pyridine 115 12.4 0.983 24.1 1.5102 2.37 N,N-Dimethylformamide 153 36.7 0.945 19.9 1.4305 3.82 Hexamethylphosphoramide 235 30 1.027 47.7 1.4588 5.54 (HMPA) N,N-Dimethylacetamide 166 37.8 0.937 24.2 1.4384 3.72 Acetone 56 20.7 0.788 16.2 1.3587 2.88 Ethyl Acetate 77 6.02 0.901 22.3 1.3724 1.88 Dichloromethane 40 8.93 1.326 16 1.4241 1.60 Nitrobenzene 211 34.82 1.204 32.7 1.5562 4.02 Nitromethane 101 35.87 1.137 12.5 1.3817 3.54 Tetrahydrofuran 66 7.5 0.888 19.9 1.4072 1.75 Acetonitrile 82 4.33 0.782 11.1 1.3441 3.92 Bromobenzene 156 5.17 1.495 33.7 1.558 1.55 Chlorobenzene 132 5.62 1.106 31.2 1.5248 1.54 Non-Polar Solvent Diethyl ether 35 4.3 0.713 22.1 1.3524 1.3 Dibutyl ether 142 3.1 0.769 40.8 1.3992 1.18 Toluene 111 2.38 0.867 31.1 1.4969 0.43 Chloroform 61 4.81 1.489 21 1.489 1.15 Benzene 80 2.27 0.879 26.2 1.5011 0 Cyclohexane 81 2.02 0.778 27.7 1.4262 0 Pentane 36 1.84 0.626 1.3575 0 Triethylamine 90 2.42 0.726 33 1.401 0.87 Carbon disulfide 46 2.6 1.274 21.3 1.6295 0 Carbon tetrachloride 77 2.24 1.594 25.8 1.4601 0 1,4-Dioxane 101 2.25 1.034 21.6 1.4224 0.45

14 Ion effects

Common-Ion Effect

The first and rate-determining step of the SN1 reaction mechanism is bond heterolysis.

The anionic leaving group, commonly a halide ion, is generally a better nucleophile than the reaction solvent. Solvolysis can occur mainly because of the abundance of solvent molecules versus halide ions.41 By adding to the reaction the same kind of ions as the leaving group, the reaction rate is decreased. This occurs according to LeChatellier’s principle; because of the increase in the amount of product present, the equilibrium shifts towards reactant formation. As the starting material is re-formed, there are fewer cations available to attack. The common-ion addition effect occurs when the cation is stabilized by its structure, making it less susceptible to solvolysis, and more likely to succumb to a more nucleophilic halide.41

“Special” Salt Effect

First observed by Winstein and co-workers in 1954, the addition of non-common ion salts to the reaction can increase the rate of solvolysis by a larger factor than is expected from an increase in ionic strength of the system.39 This effect helped to support

42-44 Winstein’s model of the SN1 reaction mechanism for solvolysis. After bond heterolysis occurs in the first step of the SN1 reaction, the formation of the contact ion pair (CIP) is followed by that of the solvent-separated ion pair (SSIP), followed by further

+ - separation to free ions (FI). Salts such as LiClO4 dissociate to Li and ClO4 . The perchlorate ion is basic and non-nucleophilic. It is able to associate with the cation, displacing the anion from the SSIP. This reduces the likelihood of attack on the cation by the leaving group which would result in re-forming the reactant, also known as “internal

15 return”. The solvent is then able to more easily attack the cation to form the solvolytic product.

The SN1 Reaction

The SN1 reaction is a unimolecular nucleophilic substitution reaction. The rate of the reaction is first order for the substrate, meaning that only the concentration of the substrate directly affects the reaction rate (Scheme 1.3). The reaction consists of multiple steps which are all dependent on the rate limiting step (Figure 1.4); the dissociation of the leaving group. The transition state of the SN1 reaction mechanism resembles an ion-pair, much like the intermediate, as opposed to resembling the

30 reactants, as seen in the SN2 transition state.

first TS

second TS

=/ ΔG Δ =/ Energy 1 G2 intermediate

reactants 0 ΔG

products

Reaction Progress

a Figure 1.4 – Kinetic Energy Diagram of the SN1 Reaction.

Reaction Rate= k[Substrate] Rate= k[RX]

Scheme 1.3 – Reaction rate equation of the SN1 Reaction.

The substrate is a hindered secondary or tertiary carbon. Whether a secondary substrate goes through the SN1 or SN2 mechanism can often be affected by the strength of the nucleophile and the type of solvent used.45 Bulky groups prevent the backside attack seen to occur in the SN2 reaction. This means that the bond between the carbon and the leaving group must first be broken, leaving a vacant bonding orbital, before the nucleophile will be able to attack the carbon. The dissociation of the leaving group,

a Image of the kinetic energy diagram of an SN1 reaction from http://www.cwu.edu/~fabryl/Chem362DEWinter09Fabry/Chem362s3w09FabryExam1AnswerKey. htm.

17 known as bond heterolysis, is the rate determining step in the reaction and can be encouraged by factors such as the type of reactant structure, leaving group, and solvent.2 Tertiary carbons undergo bond heterolysis more quickly than primary carbons because tertiary carbons can better stabilize the positive charge through inductive effects. A good leaving group, in this case, is electronegative and capable of stabilizing the electrons gained from the broken covalent bond. Groups such as tosylate, triflate, and mesylate can delocalize the acquired negative charge and are thus considered non- nucleophilic; they will not compete with the nucleophilic reaction by attempting to re-form the starting material. These are the conjugate bases of strong acids. Protic solvents promote leaving group dissociation by stabilizing the leaving group, while polar solvents promote bond heterolysis by stabilizing the carbocation intermediate relative to the covalently bonded starting material.46 If the starting material is chiral, the product will be a racemic mixture, or at least less optically pure than the starting material. An effective nucleophile for the SN1 reaction is a weak Lewis base. This is in contrast with the SN2 reaction. Examples of weak nucleophiles are water, methanol, and hydrogen sulfide. As well, the nucleophilicity of the solvent affects the rate at which solvolysis occurs.9

After the leaving group has dissociated, the carbocation and the leaving group are in a contact ion pair (CIP) which is then converted to the solvent-separated ion pair (SSIP), which is further converted to free ions (FI). The solvated ion pairs are held together by coulombic forces which, in this case, are the electrostatic forces between the charges of the two ions.43 Theoretical and experimental data confirm these interconversions, showing distinct energy differences between each ion pair configuration.47, 48 The dielectric constant of the solvent is important during the transformation of CIP to SSIP.43

A solvent with a higher dielectric constant will be more capable of separating the carbocation from the anionic leaving group, which prevents internal return. This will

18 increase the rate of the reaction by allowing for nucleophilic attack, often times by the solvent.

Hard-Soft Acid-Base (HSAB) Principle

Ralph Pearson and John Edwards studied the factors determining nucleophilic reactivity: basicity, polarizability, and the alpha effect.34 With this, the foundation was laid for

Pearson to introduce the principles of hard and soft acids and bases (HSAB) in 1963 to connect organic and inorganic chemistry, as well as explain chemical interactions and reactivities unexplained by the kinetic and thermodynamic properties of a reaction.35, 36

The use of HSAB principles remains largely qualitative. Referring to an acid or a base as

“hard” or “soft” does not have the same meaning as “strong” or “weak”.36 An overriding quantitative scale for assessing an atom’s “hardness” or “softness” has yet to be found.49

Hard and soft are denoted in addition to acid or base strength.

The reaction performed by Pearson is represented in Scheme 1.4. The equilibrium of the reaction determines the labeling of acids and bases as hard or soft.

N (base) + S-X (acid-base complex) S-N (acid-base complex) + X (base) Scheme 1.4 – Pearson’s equilibrium reaction used to make hard and soft determinations.

N is the electron donor, also referred to as a Lewis base and a nucleophile. S is the electron acceptor, also known as a Lewis acid and an electrophile. X, the replaceable group, is kept constant throughout the series of reactions. N can be a base which binds strongly to protons, in which case it would be denoted as hard, or a base that has high

19 polarizability and negligible proton basicity, referred to as soft. If the equilibrium of the reaction favors the formation of S-N, then they are considered reactive with one another and S is either hard or soft depending upon the categorization of N. Under the same principle which measures the stability of acid-base complexes, the rates of nucleophilic and electrophilic substitution reactions for a given substrate can also be a measure of nucleophilic reactivity.34, 36 Electrophilic cations with small atomic radii are considered hard acids. Electronegative anions with small atomic radii and high-energy empty orbitals are known as hard bases. Hard-hard interactions are considered ionic in nature.

Soft acids and soft bases contain atoms with larger atomic radii causing them to have high polarizability. Soft bases have low electronegativity. Because of these soft characteristics, repulsion between the acid and base is decreased and greater overlap of wave functions is achieved. This forms a covalent bond. Pearson’s general principle becomes: “hard acids prefer to coordinate to hard bases and soft acids prefer to coordinate to soft bases.”36 Yet, the order of decreasing or increasing softness or hardness is fickle and ultimately determined by the acid in the acid-base exchange equation:36

Scheme 1.5 – Acid-Base exchange equation.

Where A and A’ represent two different acids, and B and B’ represent two different bases (Scheme 1.5). Below find an abbreviated table of hard, soft, and borderline acids and bases (Table 1.2).35, 36

20 Table 1.2 – Hard, Soft, and Borderline acid and base classifications. Hard Borderline Soft Acids Bases Acids Bases Acids Bases + + + - - +2 +2 - - + + - - - - Na , K , H , F , NH3, OH , Fe , Cu , Cl , NO2 , Cs , Hg , Br , I , H , R , + + +2 + -2 - +2 +2 - Li , R3C , H2O, Zn , C6H5 , SO3 , N3 , Pd , Pt , CO, RS , - + + 0 HX (H- CH3COO , NO , SO2 C6H5NH2 Cu , M C6H6, RNC, - - bonding NO3 , ROH (metal CH3 , PR3 molecules), atoms), +4 +6 + SN , Cr , CH3 , BH3 Mn+2, Fe+3, Ca+2, Al+3, RCO+

Solvents can also be considered hard or soft since solute-solvent interactions can be viewed as acid-base interactions.35 Hard solvents are protic solvents: water, hydrogen fluoride, and alkoxides which will strongly solvate small hard bases by hydrogen bonding with the bases’ lone pair of electrons or hydrogen bond acceptors. This lowers the base’s ability to abstract a proton. Soft solvents, such as N,N-dimethylformamide, dimethylsulfoxide, and acetone prefer to solvate large soft bases. Soft solvents are aprotic and cannot hydrogen bond. Because of this, strong bases such as OH- and OR- will be highly reactive in soft solvents. Interactions with cations are also affected by a solvent’s hard or soft classification. In general, soft solvents prefer to solvate soft solutes and hard solvents prefer to solvate hard solutes.35

Kornblum’s Rule

Kornblum’s Rule was introduced in 1955,50 before Pearson’s paper describing the Hard-

Soft Acid-Base principles. In his paper, Kornblum speaks about ambident nucleophiles;

21 molecules that have two sites capable of nucleophilic attack. Examples of ambident nucleophiles are cyanides, nitrites, and amides. Kornblum’s rule states that “the greater the SN1 character of the transition state the greater is the preference for covalency formation with the atom of higher electronegativity and, conversely, the greater the SN2 contribution to the transition state the greater the preference for bond formation to the

50 atom of lower electronegativity.” Bond formation is of primary concern during the SN2 transition state, and so bonding is preferred with atoms of lower electronegativity because of these atoms’ willingness to share electrons. The transition state is directed

50 toward either SN1 or SN2 character depending upon the nucleophile’s counterion. An example of this occurrence is the reaction of silver nitrite and sodium nitrite with an alkyl bromide in N,N-dimethylformamide (Scheme 1.6).

+ - + - Ag NO2 + BrR Æ R-ONO + Ag Br + - + - Na NO2 + BrR Æ R-NO2 + Na Br Scheme 1.6 – The reaction of silver nitrite with an alkyl bromide affords the nitrite ester, while a reaction of sodium nitrite with the same alkyl bromide affords the nitroparaffin.

Silver promotes the formation of the nitrite ester; oxygen being more electronegative than nitrogen. The sodium cation promotes the formation of the nitro compound. The nitrite ester product is formed in majority when the silver cation is present because the silver polarizes the carbon halogen bond causing the transition state to have greater

50 carbocation, or SN1, character. The sodium cation does not cause this polarization and the transition state is likened more to the reactants.

Kornblum’s paper also highlights the importance of the interaction between the nucleophile’s counterion and the leaving group. In the example of silver nitrite, the

22 “formation of the silver-halogen bond furnishes an important part of the driving force for the reaction with alkyl halides” since the reaction of silver nitrite and sulfonate esters yields only starting material.50 This observation touches upon the HSAB principle, in that silver is a soft acid, while the sulfonyl sulfur is a borderline/hard base. The interaction between them is not preferred. Yet, bromide and iodide anions are borderline/soft and soft bases, respectively, and therefore have a favorable interaction with the silver cation.

A variation on this idea is also mentioned by Pearson and Songstad36 as the symbiotic effect. The aspect overlooked is the interaction of the nucleophile and its counterion as it is viewed to be of “secondary importance” relative to that of the counterion and alkyl halide substrate.50

Swain-Scott Nucleophilicity

There are several equations developed to place relative value on a nucleophile’s ability to successfully donate its electrons to form a chemical bond. The Swain-Scott equation:

log10 (k/k0) = sn

measures nucleophilic strength based on the log of the pseudo first-order reaction rate, k, divided by the standard rate constant in water, k0. The answer is represented as the product of s; a relative term “characteristic of only the substrate” and n; a relative term

“characteristic of only the nucleophilic reagent.”51 Quantitative values are measured against water for which n=0.00. The Swain-Scott equation has only two parameters. This is reflected in the tables prescribing nucleophilic and substrate constants, provided in the initial paper. The equation does not account for any interactions of the nucleophile’s counterion with the substrate, leaving group, or the nucleophile. This is not uncommon

23 when nucleophilic strengths are being assessed experimentally and theoretically.2, 28, 39,

52 - - - The Swain-Scott nucleophilicity order in water is given as S2O3 > I > SCN > C6H5NH2

- - - - - 51 > OH > N3 > Br > Cl > CH3COO > H2O. This ranking is similar to that given by

------Pearson and Edwards: RS > ArS > I > CN > OH > N3 > Br > ArO > Cl > pyridine >

- 34 AcO > H2O. Yet Katritsky, speaking about the controversial aspects of nucleophilic substitution reaction mechanisms, calls attention to the need to apply corrections for salt effects when anionic nucleophiles are being employed.28

Conclusion

Green chemistry can be an important step toward lessening the burden which chemical experimentation places on the environment. Reduction or even elimination of solvent would fulfill several principles toward this end. Yet, altering experiments to fall within the definition of Green chemistry can affect many aspects of the reaction and may necessitate reformulation based on the requirements for product formation. In the case of the nucleophilic substitution reaction, removal of solvent comes with the loss of control afforded by solvation, energy dispersion, hydrogen bonding, etc. Though several SN2 reactions have been proven viable in solvent-free HSBM experiments,1 many of the factors affecting the success of the SN1 reaction are due to the presence of the solvent.

By removing solvent from the reaction, soft chemistry principles such as Pearson’s principles of Hard Soft Acid Base chemistry and Kornblum’s rule may exert an increased influence on the reaction. These influences must be understood in order to design reaction schemes which take advantage of these new reaction kinetics. The topics discussed are important in informing the decisions made in the creation of experiments toward understanding the effect of a solvent-free environment on SN1 reactions using the

HSBM.

24 Chapter 2

Rationale and Design

The Finkelstein Reaction

The inspiration for this research came from the Finkelstein reaction53 (Scheme 2.1); a classic example of an SN2 reaction involving halogen exchange. The first experiments began by carrying out this type of nucleophilic substitution reaction in the HSBM without the use of solvent.1

In the Finkelstein reaction the nucleophile, I-, is in the form of a salt, NaI. The halogen ion attacks the primary alkyl group, R. The carbon-chloride bond breaks and the chloride anion can ionically bond with the sodium cation to form NaCl. Because acetone cannot solvate NaCl, the salt precipitates out of solution (Scheme 2.1). Based on LeChatellier’s principle, this occurrence drives the reaction toward product formation.

NaI RCl RI + NaCl (s) Acetone

Scheme 2.1 – Finkelstein Reaction of alkyl chloride and sodium iodide in acetone.

Using this concept of ion exchange, p-bromobenzyl bromide (1) was reacted with nucleophilic salts in a stainless steel vial with a 1/8” stainless steel ball bearing and without solvent. By combining the p-bromobenzyl bromide (1) with nucleophilic salts, the reaction is, theoretically, able to remain neutral throughout the substitution. The nucleophile, existing as an ion pair, does a backside attack on the substrate whose leaving group is then able to attack the nucleophile’s counter ion. The nucleophilic

25 substitution was successfully performed in the HSBM using several different nucleophilic salts.1 An example using potassium iodide is featured below (Scheme 2.2).

Scheme 2.2 – Solvent-free nucleophilic substitution reaction of p-bromobenzyl bromide (1) and potassium iodide.1

We currently propose that the mechanism is proceeding through a concerted transition state, but there are studies being done in order to confirm this hypothesis.

Figure 2.1 – Mechanism of a 4-member transition state for neutral nucleophilic substitution.

The reaction of p-bromobenzyl bromide (1) and potassium iodide was replicated and shown to have a great deal of selectivity. After milling for 16 hours, only the starting material (1) (53%) and the product (2) (40%) could be seen by gas chromatography analysis of the crude product mixture.

Nucleophilic Displacement of a Secondary Carbon: Benzhydryl Substrates

The mechanism of nucleophilic substitution reactions of benzhydryl substrates, such as chlorodiphenylmethane (7) and bromodiphenylmethane (6), has been studied

26 extensively in solvent.9, 39, 54 The substrate is known to react in solvolytic and non- solvolytic substitution reactions, in solvent, beginning with bond heterolysis; the first step of the SN1 mechanism. As well, benzhydryl halides (A) are known to undergo a halogen exchange with metal-halogen salts in solution.55 It is unknown whether the circumstances of the solvent-free reaction will allow for the creation of free ions, in

+ particular the carbocation, R3C . For these reasons, bromodiphenylmethane (6) was chosen as the substrate. The carbon center of bromodiphenylmethane (6) is substituted with a halogen leaving group and two bulky phenyl rings (R groups). This hinders the substrate towards a nucleophilic attack relative to the sp-hybridized carbon of p- bromobenzyl bromide (1) used in previous solvent-free experiments.1 Yet, the benzhydryl hybridization does not preclude these substrates from reacting through the

SN2 mechanism, seeing as the carbon is not fully saturated with R groups.

Examples of solid-state and solvent-free benzhydryl substitution reactions have been previously reported.56, 57 Substitutions of diphenylmethanol with gaseous hydrochloric acid were performed in the presence of para-toluenesulfonic acid (TsOH).56 TsOH is a hydrate and the water present very likely aided in the intermediate step of any SN1 reaction that took place. This experimentation does not prove whether a nucleophilic substitution can occur in an environment devoid of any stabilization imparted by solvent.

Another reported example converts benzhydryl alcohols to the corresponding halides in the absence of solvent using tin(IV) chloride and boron tribromide. As well, these Lewis acids are used to transhalogenate the bromo and chloro halides.57 Though solvent-free, the reaction uses Lewis acids instead of nucleophilic salts to halogenate the substrate.

The mechanism of this type of reaction in solvent follows a halogen abstraction from the substrate by the Lewis acid followed by a halogenation of the resulting carbocation

27 intermediate.58 Though hypothesized to occur in this solvent-free reaction, the formation of the carbocation is not certain in the ball-milled reactions since there is not a Lewis acid present to abstract the halogen leaving group.

Mechanism Overview

From the beginning, there were two working hypotheses to describe the mechanism of the nucleophilic substitution reaction of the benzhydryl halide (A) and the alkali metal- halogen salt in the HSBM. Both contain a 4-membered transition state. First is the nucleophilic substitution mechanism, described for the solvent-free SN2 reactions (Figure

2.2). The Finkelstein reaction of benzhydryl halides (A) in acetone are reported to follow through an SN2 mechanism; effects on the reaction rate and product formation are

59, 60 unseen by addition of LiClO4 and carbanion traps.

6 5 M 4 X X Y1 Y +M-Y 2 + M-X 3

A B Figure 2.2 – Concerted transition state for the solvent-free nucleophilic substitution of benzhydryl halides (A).

The second hypothesis is the alkali metal-carbon bond formation mechanism. The nucleophile abstracts the substrate’s leaving group while the carbon center forms a bond with the alkali metal (Figure 2.3). The carbon center can then attack either X, Y, or the benzhydryl halide (A) starting material.

Figure 2.3 – Concerted transition state for the solvent-free alkali metal- carbon bond formation mechanism.

Bromodiphenylmethane (6) was reacted with sodium iodide in dry acetone in the fashion of the Finkelstein reaction53 so as to have a background with which to compare the results of the solvent-free reactions. After 24 hours, the starting material was completely converted to product (Figure 2.4) being approximately a 1:1 ratio of iododiphenylmethane (3), the nucleophilic substitution product, and 1,1,2,2- tetraphenylethane (4), the dimer. The formation of the dimer has been reported by

Finkelstein where homocoupling of dichlorodiphenylmethane gives the 1,2- dichlorotetraphenylethane followed by a loss of chlorine to yield tetraphenylethylene.61

Less than 5% of oxygenated side product was present, which was later identified as bis(diphenylmethyl)ether (5) by X-ray crystallography (Figure 2.5 and Appendix; Figure

A.9).

Figure 2.4 – Iododiphenylmethane (3), 1,1,2,2-tetraphenylethane (4), and bis(diphenylmethyl)ether (5), respectively.

Figure 2.5 – X-ray crystallographic image of bis(dipenylmethyl)ether (5).

The Finkelstein reaction of bromodiphenylmethane (6) was also performed using potassium iodide. The results were similar to those of the reaction with sodium iodide.

After 20 hours stirred at room temperature the reaction mixture contained 6% bromodiphenylmethane (6), 30% iododiphenylmethane (3), and 45% 1,1,2,2- tetraphenylethane (4). Small amounts of oxygenated products, diphenylmethanol and bis(diphenylmethyl)ether (5) were also formed.

Ball-Milled Reactions

Bromodiphenylmethane (6)

The reaction of bromodiphenylmethane (6) and 5 equivalents of potassium iodide in a stainless steel vial with 1/8” stainless steel ball was milled for 16 hours. The resulting crude mixture contained almost equal amounts of iododiphenylmethane (3) and 1,1,2,2- tetraphenylethane (4). Other compounds, such as bis(diphenylmethyl)ether (5), diphenylmethanol, and benzophenone, were also present as a smaller percent of the crude mixture. These results are very similar to those achieved with the same reaction in solvent and show that the reaction was not specifically selective towards nucleophilic

30 1 substitution. This is in sharp contrast to the results of the SN2 reactions in the ball mill in which the crude product mixture contains only the remaining starting material and the substituted product. The formation of the iododiphenylmethane (3) was not indicative of either the SN1 or SN2 reaction pathway, yet there are clearly other reactions occurring concurrently.

For the purpose of atom economy, the results from using one molar equivalent of potassium iodide were compared to those using 5 molar equivalents when reacted with bromodiphenylmethane (6). The same ratio, 1:1, of iododiphenylmethane (3) and

1,1,2,2-tetraphenylethane (4) were seen in both reactions. The reduction in the amount of salt improved starting material conversion, probably due to the vial being less full, allowing for more efficient mixing to take place.

A catalytic amount, 10 mol%, of potassium iodide, was also tried in order to see if the reaction occurred catalytically. Bromodiphenylmethane (6) made up almost 70% of the crude product mixture. The ratio of iododiphenylmethane (3) to 1,1,2,2- tetraphenylethane (4) remained consistent, but was only 10% of the percent of the substitution product (B) and dimer (4) in the crude product mixture from the reaction that used 1 molar equivalent. This indicated that the nucleophilic salt is not a catalyst. The standard reaction was thus changed to 1 molar equivalent of both benzhydryl halide (A) and nucleophilic salt.

31 Table 2.1 – Comparison of the percent of reaction products in the crude product mixture of bromodiphenylmethane (6) and potassium iodide using 5, 1, and 10 mol% equivalents of the nucleophilic salt. Equivalents Time (hrs) % Compound in Crude Product Mixture of KI

Br Other

6 1. 5 16 12.4 38.6 36.4 12 2. 1 16 2.4 38 37 15 3. 10 mol % 16 68.4 3.4 3.5 18

Time studies were done on reactions of potassium iodide and potassium chloride with bromodiphenylmethane (6) in order to determine if the maximum starting material conversion occurred before 16 hours. Reducing the reaction time would not only increase turn-around, but would also decrease energy consumption.

At 16 hours, the percent of bromodiphenylmethane (6) remaining in the crude product mixture was 2.4%. After only 1 hour of milling, the crude product mixture contained 7.6% substrate (6). The percentage decreased at 3 and 5 hours, yet did not reach the minimum percent concentration seen until 16 hours. The reaction with potassium chloride was run for 1, 3, 5, and 16 hours as well. The minimum concentration of the substrate (6) in the crude product mixture was observed at 16 hours. All subsequent reactions were run between 14 and 16 hours to afford the maximum starting material conversion. Further experimentation milling reactions more than 5 hours and less than

32 16 hours may reveal a shorter reaction time needed to reach the maximum starting material conversion. The product ratios were generally unaltered by the reaction time.

Standard reaction conditions were set as one molar equivalent each of benzhydryl halide

(A) and nucleophilic salt placed in a stainless steel vial with 1/8” stainless steel ball and mixed on the HSBM between 14 and 16 hours.

HSAB Principle and Altering the Nucleophile

Well-established studies of nucleophilicity and reactivity in organic chemistry compare the strengths of different nucleophiles with the exclusion of any counterions51, 52 though corrections, due to salt effects, should be made to those reactions involving anionic nucleophiles.28 This discrepancy does not typically pose a problem in solvent as long as the nucleophile easily dissociates from any counterion. The solvent-free reactions lack dissociation and stabilization of the nucleophile provided by the solvent. Therefore, it may not be possible to rely on the Swain-Scott Nucleophilicity charts51 to determine how the nucleophile will perform according to its previously determined nucleophilic strength in solvent systems.

For the purposes of these experiments, Pearson’s borderline hard and soft classifications35, 36 are abandoned and the chloride anion is considered to be hard.

A driving force behind both the Finkelstein and the solvent-free SN2 reactions may be

HSAB affinities. In both cases, the soft iodide preferred to bond with the soft saturated carbon in lieu of the hard alkali metal ion. The leaving groups; chloride being a hard base and bromide being a less soft base than iodide, were displaced. Based on the

33 HSAB principle,36 the alkali metals’ interactions with bromide, of the solvent-free reaction, and chloride, of the Finkelstein reaction, are more favorable than their interactions with iodide. Kornblum’s Rule pulls from the same qualitative observation to account for the effect of the counterion on the nucleophile’s interaction with the substrate.50 As well, in the Finkelstein reaction, acetone plays a role in the hard-hard interaction of sodium and chloride, which precipitates because it cannot be solvated by acetone, a soft solvent.

The alkali metal cation’s affinities may be crucial to the leaving group’s dissociation from and the nucleophile’s attack of the electrophilic carbon center. To prove this point, different nucleophilic salts containing hard-hard, hard-soft, soft-hard, and soft-soft alkali metal-halogen combinations were reacted with the benzhydryl halide (A) under the standard reaction conditionsa (Table 2.2). The compilation of results showing different formation patterns of products could show how HSAB principles are affecting the nucleophile-substrate interaction.

Table 2.2 – Alkali metal-halogen interactions in reference to their status as hard or soft. F (Hard) Cl (Hard) Br (Soft) I (Soft) Li (Hard) Hard-Hard Hard-Hard Hard-Soft Hard-Soft Na (Hard) Hard-Hard Hard-Hard Hard-Soft Hard-Soft K (Hard) Hard-Hard Hard-Hard Hard-Soft Hard-Soft Cs (Soft) Soft-Hard Soft-Hard Soft-Soft Soft-Soft

a Standard reaction conditions were set as one molar equivalent each of benzhydryl substrate and nucleophilic salt placed in a stainless steel vial with 1/8” stainless steel ball and mixed on the HSBM between 14 and 16 hours.

34 In addition, the carbon center is substituted with 2 phenyl rings, which are soft, making the center more easily substituted with other soft atoms, according to the symbiotic effect.36 If two hard atoms or two soft atoms come together there is an added stabilization for that molecule.

Results of Reactions with Different Alkali Metal-Halogen Salts

The general understanding of nucleophilic reactivity is: I- > Br- > Cl- > F- in a protic solvent. The order is based on a protic solvent’s ability to solvate small, hard ions. In an aprotic solvent, the order reverses and ranking occurs according to the strongest carbon-halogen bond formed; in this case being C-F.34-37 Iodide is considered to be more nucleophilic than the rest of the featured halide ions. Therefore, one might assume that the largest conversion to the nucleophilic substitution product (B) would occur when iodide is the nucleophile.

A sp2-hybridized carbon substrate, the benzhydryl halide (A), was reacted with different combinations of alkali metal-halogen salts. The halogen was to act as the nucleophile.

When the halogen is kept constant and the alkali metal is varied, the nucleophile does not show consistent strength. One example is the reaction set of bromodiphenylmethane

(6) with potassium chloride, sodium chloride, and lithium chloride. The nucleophilic strength of the chloride seems to increase from lithium to potassium; down Column I of the periodic table (Table 2.3).

35 Table 2.3 – Results of the reactions between bromodiphenylmethane (6) and alkali metal-chloride salts under standard conditions.a M-Cl % Compounds in Crude Mixture

1. Li 87.8 7.6 1.5 2. Na 80.4 12.9 2.5 3. K 29.8 62.3 4.6

The reaction between bromodiphenylmethane (6) and potassium chloride shows the largest quantity of the nucleophilic substitution product (B); around 60% of the crude product mixture, as observed by GC and GC-MS. Around 30% of the starting material

(6) is still contained in the crude product mixture with only small amounts of 1,1,2,2- tetraphenylethane (4) and other side-products observed. The starting material conversion decreases significantly in the reaction using sodium chloride. When lithium is substituted for sodium, the conversion of starting material decreases once again.

Chlorodiphenylmethane (7) continues to be the major product throughout, with negligible amounts of dimer (4) formation occurring. A reaction with sodium chloride also produced

1,1,2,2-tetraphenylethane (4) at close to 20% of the crude product mixture, yet these results were not reproducible.

36 HSAB principles only partially account for this inconsistency of nucleophilic strength.

Chloride is hard, as are all of the alkali metals used. Bromide and the saturated carbon are soft. Regardless of the mechanism chosen to be followed, when chloro nucleophilic salts are used, the substrate (6) should always be present in higher amounts than the nucleophilic substitution product (B). This is true for lithium and sodium, yet not for potassium. In the case of potassium chloride, both mechanisms would result in the formation of potassium bromide salt. The affinity of potassium for bromide is present throughout the results of this research.

When reacted with bromodiphenylmethane (6) under standard conditions,a potassium iodide produces equal amounts of iododiphenylmethane (3) and 1,1,2,2- tetraphenylethane (4); similar to the ratios of the Finkelstein reaction carried out in acetone. The reactions using sodium iodide and lithium iodide resulted in a completely different product profile than those seen previously. When these reactions were prepared in an inert or dry atmosphere, the starting material was completely converted to p-benzyltriphenylmethane (8) and diphenylmethane (9), rather than the iodo- substitution product (3) and the dimer (4) (Scheme 2.3). The reactions with sodium iodide and lithium iodide are of high energy; tending to produce heat, smoke, and strong odors. This is in contrast to the solvent-free potassium iodide reactions in the stainless steel vial, which do not produce smoke or fumes.

Scheme 2.3 – Reaction of bromodiphenylmethane (6) and sodium or lithium iodide, under standard conditions,a to form p-benzyltriphenylmethane (8) and diphenylmethane (9).

Limited reports are available for the synthesis of p-benzyltriphenylmethane (8); one of which describes a radical reaction involving the phosphochlorination of diphenylmethane

(9).62 The only proof of a radical reaction comes from a reaction which combined bromodiphenylmethane (6) and tri(trimethylsilyl)silane, a hydrogen donator.63 The only product observed from this reaction was diphenylmethane (9), formed by hydrogen abstraction. Nucleophilic salt, usually necessary to produce p-benzyltriphenylmethane

(8) and diphenylmethane (9), was not present in the tri(trimethylsilyl)silane reaction. After some experimentation, to be mentioned, the hydrogen source for the reaction products of bromodiphenylmethane (6) and sodium or lithium iodide is still unknown.

Trace amounts of diphenylmethane (9) and p-benzyltriphenylmethane (8) are seen in the solvent-free potassium iodide reactions in the stainless steel vial, but not seen at all in the reaction in acetone. As well, these products are not formed in the reaction with sodium iodide in acetone.

38 An inert or dry atmosphere is necessary for the synthesis of p-benzyltriphenylmethane

(8) using sodium iodide. Moisture in the air resulted in a crude product mixture that resembled those of the solvent-free potassium iodide reactions and the Finkelstein reactions in acetone. The water may have absorbed some of the energy of the reaction, detracting from the amount necessary to produce the aromatic substitution. Preparing other reactions such as potassium iodide and potassium chloride with bromodiphenylmethane (6) in the glove box did not affect their outcome.

The reaction of potassium fluoride and bromodiphenylmethane (6) under standard conditionsa shows the greatest conversion of starting material of the fluoride reactions.

Only 52% substrate remained while more than 25% fluorodiphenylmethane (14) and

18% ether (5) were formed with negligible amounts of 1,1,2,2-tetraphenylethane (4).

This is followed by the reaction with cesium fluoride in which the crude product mixture was composed of 70.9% substrate (6) along with close to 19% fluorodiphenylmethane

(14). Results seen with sodium fluoride and lithium fluoride salts are similar to one another, with almost 90% of bromodiphenylmethane (6) remaining after 16 hours of mixing. Only very small amounts of products were seen to form. The results of the sodium and lithium fluoride reactions are consistent with HSAB principles. Sodium and lithium are hard acids and fluoride is a hard base. These salt combinations are less likely to dissociate to participate in a reaction because of the added stability of their hard-hard interactions. Once again, the potassium bromide formation is favored over all others, including cesium bromide. Other unidentified interactions may override the HSAB affinities, accounting for this discrepancy.

39 A control experiment was performed in order to state with certainty that the salts were affecting the outcome of the reaction. Bromodiphenylmethane (6) was milled in a stainless steel vial with a 1/8” stainless steel ball for 16 hours without a nucleophilic salt.

The crude product mixture was composed of 92% bromodiphenylmethane (6) and 4.6%

1,1,2,2-tetraphenylethane (4). Less than 1% p-benzyltriphenylmethane (8) was observed. The nucleophilic substitution product (B) is clearly not present because the reaction lacks a nucleophile. The results show that the synthesis of 1,1,2,2- tetraphenylethane (4) and p-benzyltriphenylmethane (8) does not require the use of a nucleophilic salt, yet their formation is clearly increased by the presence of certain alkali metal-halogen combinations.

Grouping salts based on a common alkali metal in the reactions with bromodiphenylmethane (6) reveals that the alkali metal-iodide combinations are the most reactive, although the nucleophilic substitution product (B) may not be the major product of those reactions. Starting material conversion is significantly greater for potassium, sodium, and lithium iodide when compared to their chloride and fluoride counterparts. Supplemental reaction products such as 1,1,2,2-tetraphenylethane (4) and p-benzyltriphenylmethane (8) occur in significantly higher amounts in the presence of iodide salts.

According to the experimental data, the chloride and fluoride salts do not show such a distinct pattern as the iodide salts. It would be expected that the fluoride salts would be least effective at synthesizing the nucleophilic substitution product (14) because fluorine is the most electronegative element. It has a Pauling scale value of 3.98 meaning that its non-bonding electron pair is held tightly and therefore does not readily participate in

40 electron donation. This characteristic diminishes fluorine’s ability to be a strong nucleophile as compared to the other halogens.

Based on experimentation, the alkali metals clearly have an affect on the nucleophile’s strength in the solvent-free experiment since the starting material conversion values cannot be predicted based solely on the type of nucleophile used (Table 2.4). Nor are the conversion values equal for any one nucleophile.

Table 2.4 – Percent of bromodiphenylmethane (6) present in the crude product mixture of reactions with various nucleophilic salts under standard conditions.a Nucleophilic Equivalents Time % Bromodiphenylmethane (6) in Salt (M-Y) of M-Y (hrs) Crude Product Mixture 1. NaI 1 16 0 2. LiI 1 16 0.8 3. KI 1 16 2.4 4. KCl 1 16 29.8 5. KF 1 16 52.8 6. CsF 1 16 70.9 7. NaCl 1 16 80.4 8. LiCl 1 16 87.8 9. NaF 1 16 88.9 10. LiF 1 16 89.7 11. No Salt 16 92.2

The greatest percent of the nucleophilic substitution product (B) observed in the crude product mixture does not arise from an iodide salt. This is contrary to assumptions made based on the order of nucleophilic strength in a protic solvent: I->Cl->F-. The greatest

41 amount of nucleophilic substitution product (7) occurs for potassium-halide salts with an order of: KCl > KI > KF, yet fifteen times as much starting material (6) remains in potassium chloride reactions as compared to those with potassium iodide and bromodiphenylmethane (6) under standard conditions.a Iodide may well be the strongest nucleophile in the ball mill; iododiphenylmethane (3) is known to dimerize60 and this discrepancy in the observation of the nucleophilic substitution product (3) possibly occurs due to this dimerization to form the subsequent reaction product (4).

Chlorodiphenylmethane (7)

We decided to investigate the effect of the leaving group on the reaction.

Chlorodiphenylmethane (7) was reacted in the same manner as bromodiphenylmethane

(6) had been. Alkali metal-bromide salts were used in lieu of alkali metal-chloride salts so that the nucleophilic substitution product (B) and the starting material (7) could be distinguished from one another.

Chlorodiphenylmethane (7) was first reacted with sodium iodide, since it had proven to be the most reactive nucleophilic salt in the previous solvent-free reactions. The result of the reaction under standard conditionsa was different from that obtained when using bromodiphenylmethane (6). The crude product mixture contained 37% iododiphenylmethane (3) and 48% 1,1,2,2-tetraphenylethane (4). All of the starting material (7) had been consumed. Minimal amounts of oxygenated products were also present. These results more closely resembled those from the reactions of

42 bromodiphenylmethane (6) with sodium iodide of the Finkelstein reaction in acetone or those prepared in a humid atmosphere.

When the alkali metal was changed, iodide showed inconsistent reactivity toward the substrate (7). Potassium iodide results in a nearly 1:1 ratio of iododiphenylmethane (3) to dimer (4). The crude product mixture contains 5.5% chlorodiphenylmethane (7). The product ratio for lithium iodide is similar to that of potassium iodide, though the crude product mixture contains 10% chlorodiphenylmethane (7). In all three cases, the crude product mixture is composed of between 5-7% bis(diphenylmethyl)ether (5). The high reactivity, resulting in the presence of 10% or less starting material (7) in the crude product mixture supports the HSAB principles. All three of the alkali metals are hard, while iodide is soft. The iodide would prefer to bond with the soft carbon center, and the alkali metals with the hard chloride leaving group.

When the nucleophile is bromide, changing the alkali metal results in dramatic changes to the percent of starting material conversion. Consistently, the major product is the nucleophilic substitution product: bromodiphenylmethane (6). The percent of the product

(6) and the percent of remaining starting material (7) are widely varied. Sodium bromide is the most reactive, followed by lithium bromide, and finally potassium bromide (Table

2.5).

43 Table 2.5 – Results of the reactions between chlorodiphenylmethane (7) and alkali metal-bromide salts under standard conditions.a M-Br % Compounds in Crude Mixture

6 1. Li 28.2 47 14.1 2. Na 15.8 64.6 7.6 3. K 57.5 31 5.7

The potassium bromide salt is the least reactive, reinforcing the trend of affinity between potassium and bromide. There is the potential to say that, like potassium and bromide, sodium and chloride have a greater affinity towards one another. Sodium bromide was the most reactive bromide salt and sodium chloride would be the resulting salt accompanying the nucleophilic substitution product (6) from this reaction, based on the proposed mechanisms.

Fluoride is the weakest nucleophile in reactions with chlorodiphenylmethane (7). Based on consumption of starting material, lithium fluoride was the most reactive, followed by potassium fluoride, then cesium fluoride, and finally sodium fluoride. The major product in each case was not the nucleophilic substitution product (14), but rather the dimer (4);

12.5% with lithium fluoride, 8.7% with potassium fluoride, 6% with cesium fluoride, and

1.8% with sodium fluoride. The iodide and bromide nucleophiles trended toward the sodium salt being most reactive with chlorodiphenylmethane (7), yet in the reaction of a Standard reaction conditions were set as one molar equivalent each of benzhydryl substrate and nucleophilic salt placed in a stainless steel vial with 1/8” stainless steel ball and mixed on the HSBM between 14 and 16 hours.

44 chlorodiphenylmethane (7) and alkali metal-fluoride salts the sodium salt is the least reactive of the four.

Results from the chlorodiphenylmethane (7) reactions with sodium fluoride, sodium bromide, and sodium iodide were similar to those of bromodiphenylmethane (6) reactions with potassium-halogen salts. As with the potassium iodide reactions, sodium iodide and chlorodiphenylmethane (7) produced almost equal amounts of iododiphenylmethane (3) and 1,1,2,2-tetraphenylethane (4). No substrate (7) remained in the crude product mixture. Sodium bromide was slightly less reactive, with 16% chlorodiphenylmethane (7) present in the crude product mixture. Bromodiphenylmethane

(6), the nucleophilic substitution product, was the major product composing 64% of the crude product mixture, while less than 15% of the mixture included the dimer (4) and oxygenated products. This is similar to the results of the reaction of potassium chloride and bromodiphenylmethane (6) where chlorodiphenylmethane (7) is major product by a significant margin. Finally, sodium fluoride is once again the least reactive of the sodium salts. The crude product mixture is composed almost completely of chlorodiphenylmethane (7), mirroring the reaction of bromodiphenylmethane (6) and potassium fluoride (Table 2.6).

45 Table 2.6 – Results of the reactions between chlorodiphenylmethane (7) and sodium- halogen salts under standard conditions.a Na-Y % Compounds in Crude Mixture

1. F 90.9 0.2 1.8 2. Br 15.8 64.6 7.6 3. I 0 37.1 47.8

Potassium and lithium salt reactions with chlorodiphenylmethane (7) showed the same reactivity order of the nucleophiles as the sodium salts using comparisons based on the identity of the alkali metal. The iodide salts converted the largest percent of starting material to product, followed by bromide, and then fluoride.

A control reaction was performed on chlorodiphenylmethane (7) where the reactant was mixed in a stainless steel vial with a stainless steel ball on the HSBM for 16 hours. As no salt was present, no nucleophilic substitution product (B) was observed. All of the chlorodiphenylmethane (7) remained save 1% each of 1,1,2,2-tetraphenylethane (4) and p-benzyltriphenylmethane (8). The results show that the alkali metal-halogen salts play a crucial role in the large conversion of starting material to the reaction products present in the product mixture.

46 Table 2.7 – Percent chlorodiphenylmethane (7) present in the crude product mixture of reactions with various nucleophilic salts under standard conditions.a Nucleophilic Equivalents % Chlorodiphenylmethane (7) Salt (M-Y) of M-Y Time (hrs) in Crude Product Mixture 1. NaI 1 16 0 2. KI 1 16 5.55 3. LiI 1 16 10.3 4. NaBr 1 16 15.8 5. LiBr 1 16 28.2 6. KBr 1 16 57.5 7. LiF 1 16 65 8. KF 1 16 79 9. CsF 1 16 85.3 10. NaF 1 16 90.9 11. No Salt 15 96.4

The reactions of chlorodiphenylmethane (7) show a more distinct trend in nucleophilic reactivity when compared to the reactions of the same salts with bromodiphenylmethane

(6) (Table 2.7 and Table 2.4). In the case of chlorodiphenylmethane (7), though the order of the alkali metals is not consistent, the halogens follow the same pattern as seen in protic solvent: I- > Br- > F-.

Bis(diphenylmethyl)ether (5) and other Oxygenated Products

The oxygenated products such as bis(diphenylmethyl)ether (5), diphenylmethanol, and benzophenone, were observed throughout the experimental research. Ether formation

47 occurs in solvent-free reactions where alcohols are used as reactants56, 64 or bases such as KOH18 are used as reagents. Yet, the oxygenated compounds mentioned above were formed even though the starting materials contained no oxygen atoms. This made the presence of oxygen in the reaction products puzzling.

At first it was assumed that the reaction’s workup and purification were causing the formation of the oxygenated products. In several reactions where the ether was not detected in the first sample of the pre-workup crude product mixture, it appeared as the major product in the post-workup crude product mixture. A specific example is a reaction between bromodiphenylmethane (6) and potassium chloride, milled for 5 hours in the stainless steel vial. Bromodiphenylmethane (6) and chlorodiphenylmethane (7) composed 78% of the pre-workup crude product mixture. No oxygenated products were observed by GC-MS analysis, yet bis(diphenylmethyl)ether (5) was obtained in 22.8% yield after attempts to recrystallize 1,1,2,2-tetraphenylethane (4) in methanol. Sources of this occurrence are the aqueous washes during workup and the recrystallization in short- chain alcohols. Water, methanol, and ethanol can perform solvolytic reactions on halogenated benzhydryl substrates (A). 9, 39, 54 Though this was seen to occur in several cases, solvolysis was not always the cause of oxygenated product synthesis. The crude product mixture of a reaction of bromodiphenylmethane (6) and potassium iodide contained 10.8% bis(diphenylmethyl)ether (5) even though a dry workup was performed; proving that the oxygenated products are being formed during the milling process.

Water is known to act as a nucleophile in solvolytic reactions9, 42, 54 as well as to stabilize ion formation in “solvent-free” reactions.56, 65 Therefore, moisture in the atmosphere was considered a potential cause of the occurrence of oxygenated side product formation.

Most of the reactions were prepared open to air in the lab, the environment of which was

48 not held constant. It was observed that the percent of oxygenated products in crude product mixtures was inconsistent between identical reactions. To test whether the oxygen was coming from the atmosphere we conducted the reaction of potassium iodide and bromodiphenylmethane (6) in an argon atmosphere. To our surprise, even in an argon atmosphere, the ether product (5) was present as 16% of the crude product mixture. The moisture could have been present in the salts as water can also be absorbed from the atmosphere by hygroscopic salts such as NaCl, LiCl, and LiBr, 66, 67

Yet, oven-drying the salts and vials did not always prevent the formation of oxygenated side products either.

Deuterium oxide, D2O, was added to a reaction of sodium iodide and bromodiphenylmethane (6) to see if heavy water would act as a nucleophile. This particular reaction was chosen because it had produced significant amounts of bis(dipenylmethyl)ether (5) and diphenylmethanol when prepared in a humid environment. Deuterium oxide was used to pre-wash the stainless steel vial and used as the aqueous phase of the reaction workup. If the heavy water performed a nucleophilic substitution on the substrate, then one would see the mass of D-diphenylmethanol distinctly by GC-MS. Deuterated diphenylmethanol was not found in the crude product

68 mixture using GC-MS. Water is more nucleophilic than D2O and diphenylmethanol was seen by GC-MS analysis. Water may have been present either in the D2O or in another context in the reaction. We concluded from this experiment that the oxygenated products were not coming from water.

The hydroxide ion, because of its negative charge, is a stronger nucleophile and base than water. Potassium hydroxide, acting as both a base and a nucleophile, has been used to form enolates from p-bromobenzyl bromide (1) and cyclohexanone. The desired

49 product was synthesized in a 3:1 ratio with di-p-bromobenzyl ether.18 Following this example, benzyl bromide was milled with 2 equivalents of sodium hydroxide in a stainless steel vial for 16 hours. The major product of the reaction, at 92.8% of the crude product mixture, was dibenzylether (16), as opposed to benzyl alcohol. These experiments indicated that using hydroxide as a nucleophile led to varying amounts of ether formation. Following this reaction, sodium hydroxide was milled with bromodiphenylmethane (6). The hydroxide anion was not very reactive, and after 16 hours of milling, bromodiphenylmethane (6) composed 66% of the crude product mixture. Diphenylmethanol was not observed, but benzophenone and bis(diphenylmethyl)ether (5) were present as 11.4% and 10.8% of the crude product mixture, respectively. This did not exceed the percent of oxygenated products in the crude mixture observed in reactions with alkali metal-halogen salts, yet they were, for the first time, the major products of the reaction in the pre-workup crude product mixture.

Hetero-coupling Reactions

The homo carbon-carbon bond formation of the dimer, 1,1,2,2-tetraphenylethane (4), sparked the idea of focusing efforts on the creation of carbon-carbon bonds. A 6- membered transition state, a combination of the two bond formation hypotheses, may account for the formation of the 1,1,2,2-tetraphenylethane (4) (Figure 2.6).

Figure 2.6 – Six-member transition state leading to the homo-coupling with the assistance of the nucleophilic salt.

A four-member transition state is also possible; the starting material (A), nucleophilic substitution product (B), or a combination of the two may react with one another (Figure

2.7).

Figure 2.7 – Four-member transition state leading to the homo-coupling without the participation of the nucleophilic salt.

A similar idea proposes the SN2 formation of the iododiphenylmethane (3) in a

Finkelstein reaction in acetone. This is followed by dissociation to create free radicals which couple to form 1,1,2,2-tetraphenylethane (4); the decomposition and dimerization has been followed by proton NMR.60 This is a plausible scenario considering that the formation of the dimer (4) is significantly increased when certain alkali metal iodide salts

51 are reacted with bromodiphenylmethane (6) and chlorodiphenylmethane (7). In lieu of a radical reaction, which would require further experimentation to prove its viability in the ball mill, the iododiphenylmethane (3) may simply go through the proposed four- membered transition state.

The third possible mechanism is shown in several literature examples. Coupled compounds of this kind tend to begin with the creation of an activated benzhydryl substrate (A) which can be reacted with primary and secondary alkyl halides.69-72

Typically, the activation of a benzhydryl is done by forming a diphenylmethide (C) prepared from an alkali metal in ammonia. Yet, this activation can also be done using metals such as magnesium or any number of transition metal catalysts70-74 with mechanisms varying from reductive dimerization, to radical mechanisms, to anion formation.

The use of sodium or potassium diphenylmethide (C) to form a carbon-carbon bond is applicable to this research. The proposed alkali metal-carbon bond formation mechanism applies as it would occur when the leaving group is attacked by the nucleophile and the activated carbon is stabilized by the alkali metal. This diphenylmethide (C) can then attack the electrophilic carbon of an alkyl halide; either itself or a different molecule (Figure 2.8). The differences seen in product distribution between reactions using different salts and benzhydryl halides (A) may then relate to

Hard-Soft Acid Base principles; affinities between the halides and alkali metals.

Figure 2.8 – Reaction of the diphenylmethide (C) and the benzhydryl substrate (A) to synthesize the homo-coupled product (4).

Literature examples of 1,1,2,2-tetraphenylethane (4) synthesis typically include the use of a transition metal. 73-77 The stainless steel vial consists of transition metals: iron and greater than 10% chromium, by weight. Other metals, such as nickel, can also be incorporated.78 The possible effect of the stainless steel on the reaction is not dismissed and investigation into the contribution of the vial material was later undertaken

(Reactions in Vials of Alternative Materials: Copper, Teflon®, and Nickel).

The incorporation of a second reactant could take advantage of these proposed mechanisms to form a carbon-carbon bond between two different molecules. The sodium iodide and chlorodiphenylmethane (7) reactions gave some of the highest conversion to 1,1,2,2-tetraphenylethane (4). As well, the sodium iodide reaction with bromodiphenylmethane (6) had the highest energy. It was decided to add p- bromobenzyl bromide (1), benzyl chloride, benzyl iodide (15), n-chlorobutane, and n- bromobutane into these reactions; without concern for the combinations of the different halogens.

Bromodiphenylmethane (6) and one equivalent of p-bromobenzyl bromide (1) were reacted under standard conditionsa in the presence of sodium iodide. p-Bromobenzyl bromide (1) composed 30% of the crude product mixture, with 17% a Standard reaction conditions were set as one molar equivalent each of benzhydryl substrate and nucleophilic salt placed in a stainless steel vial with 1/8” stainless steel ball and mixed on the HSBM between 14 and 16 hours.

53 iododiphenylmethane (3) and 10% p-bromobenzyl iodide (2). 1,1,2,2-Tetraphenylethane

(4) made up 22% of the mixture. No hetero carbon-carbon bond formation (10) was observed (Scheme 2.4).

Scheme 2.4 – The reaction of bromodiphenylmethane (4) and p-bromobenzyl bromide (1) failed to synthesize the heterocoupled product (10).

When this reaction was performed in the absence of any salt, only neglible amounts of

1,1,2,2-tetraphenylethane (4), bis(diphenylmethyl)ether (5), and p- benzyltriphenylmethane (8) were seen among large amounts of unreacted starting material (6).

The reaction of bromodiphenylmethane (6) with n-chlorobutane and sodium iodide was run twice under standard conditions.a The first reaction contained one equivalent of n- chlorobutane and resulted in the dimer (4) and iodo-substituted product (3), in-line with those sodium iodide reactions prepared in a humid environment. The second reaction used two equivalents of n-chlorobutane. The products were similar to those sodium iodide reactions prepared in a dry environment. The same reaction was performed with one equivalent of n-chlorobutane and potassium fluoride as the nucleophilic salt. The starting material (6) made up the majority of the crude product mixture with just above

54 20% 1,1,2,2-tetraphenylethane (4) and bis(diphenylmethyl)ether (5) combined. There was no hetero-coupled product detected.

Mixing Studies

When all of the reactants and reagents were placed in the stainless steel vial at once and in no particular order, no hetero carbon-carbon bond formation was seen. This was perhaps due to inadequate mixing of the starting material leading to an uneven mixture.

Mixing studies were done in order to understand how combining the molecules under specific circumstances to make a more uniform mixture could alter the outcome of the reactions.

The first technique tested involved milling the reactants in the HSBM for 15 minutes prior to the addition of the nucleophilic salt. The milling was meant to evenly distribute the reactants and increase their surface area. This method was tried on reactions of bromodiphenylmethane (6) with benzyl chloride, p-bromobenzyl bromide (1), and n- chlorobutane, and chlorodiphenylmethane (7) with benzyl chloride, and n-bromobutane, all in the presence of sodium iodide. The only significant difference seen between these

a reactions and those under standard conditions was an increase in the SN2 product, benzyl iodide (15), in reactions with benzyl chloride as a reactant. Still, none of the desired product was observed.

In another method, the nucleophilic salt was milled for 15 minutes in the HSBM prior to the addition of the reactants. The reaction of chlorodiphenylmethane (7), benzyl chloride,

55 and sodium iodide was performed in this way. No difference in reaction results was observed compared to results under standard conditions.a

Homogeneous mixing was promoted by the addition of 2 drops of dichloromethane to the reaction vessel in the reaction of chlorodiphenylmethane (7), benzyl chloride, and sodium iodide. The small amount of solvent would dissolve a small amount of the reactants and make easier the mixing of the materials in the vial. The only changes observed, relative to the reaction under standard conditions,a were a slight increase in benzyl iodide (15) formation and a slight decrease in iododiphenylmethane (3) formation.

Lastly, bromodiphenylmethane (6) and p-bromobenzyl bromide (1) were dissolved in dichloromethane. The solvent was removed in vacuo in order to co-crystallize the reactants. The co-crystallisation was done to create uniformity and to increase contact between the two molecules in order to promote their reaction with one another. The co- crystallization resulted in a slush containing the reactants and a small amount of 1,1,2,2- tetraphenylethane (4). The mixture was added to the steel vial with sodium iodide and mixed for 14 hours on the HSBM. The crude product mixture of the reaction under standard conditionsa was composed of 6.5% bromodiphenylmethane (6) and 29.5% p- bromobenzyl bromide (1) while the co-crystallized starting material was reacted completely. The most significant change in product formation for the reaction with co- crystallized reactants was a 3-fold increase in the SN2 product, p-bromobenzyl iodide (2).

56 None of the mixing techniques resulted in the synthesis of the desired products. The most significant change in product distribution was the increased formation of the nucleophilic substituted products in some of the reactions. Therefore, the inability to form the hetero carbon-carbon bonded product was not due to a lack of homogeneity in the reaction mixture.

Reactions with Benzyl Iodide (15)

The bromo and chloro-leaving groups on the primary carbon substrates were not reacting to form the hetero carbon-carbon bond. A molecule with an iodo-leaving group, which is more polarizable, can increase the reaction rate by lowering the energy of the transition-state through stabilization.

Benzyl iodide (15), synthesized by a Finkelstein reaction of benzyl bromide and sodium iodide in anhydrous acetone, was first reacted with bromodiphenylmethane (6) without the addition of a nucleophilic salt. Close to a 1:1 ratio of the starting materials as well as

9% dimer (4) and 3% diphenylmethane (9) were present in the crude reaction mixture.

Two other products observed were the iododiphenylmethane (3) (5.2%) and the benzyl bromide (6.6%). It seems that a small amount of the starting materials underwent a halogen-transfer with one another.

When a salt was incorporated, sodium iodide was chosen for its high reactivity in reactions with bromodiphenylmethane (6). When the salt was added to the reaction, two new products, 1,2-dibenzylbenzene (11) (15%) and 1,4-dibenzylbenzene (12) (12%), were detected by GC-MS. Their structures were further verified by NMR. The expected heterocoupled product, ethane-1,1,2-triyltribenzene (13), was not present (Figure 2.9).

Figure 2.9 – 1,2-dibenzylbenzene (11), 1,4-dibenzylbenzene (12), and ethane-1,1,2-triyltribenzene (13), respectively.

The synthesis of the ortho (1,2) and para (1,4) dibenzylbenzenes (11 and 12) was similar to that of the p-benzyltriphenylmethane (8): a high energy reaction resulting in a high percentage of diphenylmethane (9) and aromatic substitution. The majority of reactions used to synthesize the dibenzylbenzenes (11 and 12) employ Lewis acids to promote aromatic substitution by halogenated carbons.79-82 In the ball-milled reactions, not only were there no Lewis acids present, but the halogen substituted carbon of bromodiphenylmethane (6) was not the carbon upon which a reaction took place.

The mechanism of the diphenylmethide (C) is a plausible explanation and a working hypothesis for the synthesis of the aromatic substitution products; 1,2-dibenzylbenzene

(11), 1,4-dibenzylbenzene (12), and p-benzyltriphenylmethane (8). As the carbon holds the negative charge, it is stabilized by the alkali metal cation. The diphenylmethide (C) can have resonance structures where the ortho and para positions of the aromatic ring are capable of attacking an electrophilic carbon center (Figure 2.10).

Figure 2.10 – Resonance structures of diphenylmethide (C) leading to the synthesis of the aromatic substitution products (8, 11, 12).

In the case of p-benzyltriphenylmethane (8) synthesis, o-benzyltriphenylmethane is not observed indicating that the size and bulk of the phenyl rings prevent the reaction from occurring at the ortho position of the aromatic ring. This is consistent with results seen in published dimerization reactions of diphenylmethane (9).62 Following the bond formation, a hydrogen abstraction from the ortho or para position can occur to re-establish aromaticity.

Chlorodiphenylmethane (7) was also reacted with benzyl iodide (15) in the presence of sodium iodide. The 1,2- and 1,4-dibenzylbenzenes (11 and 12) were present in the crude product mixture at 10% each, along with 21% p-benzyltriphenylmethane (8) and

17% diphenylmethane (9).

Lithium iodide was also tried because p-benzyltriphenylmethane (8) and diphenylmethane (9) were the major products of its reaction with bromodiphenylmethane

(6) under standard conditions.a When bromodiphenylmethane (6) and benzyl iodide (15) were combined with the salt, the mixture began to crackle and create a purple smoke.

The crude product mixture consisted of 40% unreacted benzyl iodide (15) with the major a Standard reaction conditions were set as one molar equivalent each of benzhydryl substrate and nucleophilic salt placed in a stainless steel vial with 1/8” stainless steel ball and mixed on the HSBM between 14 and 16 hours.

59 product of the reaction being 1,1,2,2-tetraphenylethane (4). None of the desired product was synthesized possibly due to the premature energy release.

When potassium iodide was used in lieu of sodium iodide for the reaction of bromodiphenylmethane (6) and benzyl iodide (15), almost equal amounts of p- benzyltriphenylmethane (8) and diphenylmethane (9 accompanied the remaining benzyl iodide (15). This is a departure from the expected products. As well, the reaction of potassium iodide with chlorodiphenylmethane (7) and benzyl iodide (15) did not synthesize 1,2- and 1,4-dibenzylbenzene (11 and 12). Instead, benzyl iodide (15) composed almost half of the crude product mixture; the other half being the expected products iododiphenylmethane (3) and 1,1,2,2-tetraphenylethane (4).

Mechanism Summation

At this point in the research, the mechanism or mechanisms of these reactions using stainless steel vials and ball bearings on the HSBM are unresolved. Although the SN1 reaction mechanism has been studied for more than 70 years, it too leaves unanswered questions.46 The nucleophilic substitution mechanism and the alkali metal-carbon bond formation mechanism are both plausible for select reaction results.

The nucleophilic substitution mechanism can explain the synthesis of the nucleophilic substitution product (B). The benzhydryl halides (A) are sp2-hybridized and therefore the

SN2 mechanism is not dismissed. Subsequent reaction products may be formed by the decomposition of the nucleophilic substitution product (B) to radicals.60 Adding radical inhibitors, such as TEMPO or galvinoxyl, to the solvent-free milling reactions may shed light on the reaction mechanism.

The alkali metal-carbon bond formation mechanism gives the carbon center several choices: hydrogen extraction, re-formation of starting material (A), formation of the nucleophilic substitution product (B), and formation of carbon-carbon bonds (through possible rearrangement). It is established that a negatively charged carbon center can be stabilized by an alkali metal cation followed by the carbanion’s attack of halogenated carbons to form new carbon-carbon bonds.69-72 The diphenylmethide (C) can come about through the decomposition of the nucleophilic substitution product (B) or through the abstraction of the leaving group by the nucleophile. Regardless of how it is formed, the presence of the diphenylmethide (C) best explains the products formed in the ball milling reactions.

Though it is theoretically accounted for by the alkali metal-carbon bond formation mechanism, the quantities of diphenylmethane (9) are not easily explained. The location from which the hydrogen is abstracted remains undetermined. If the hydrogen abstraction occurred during the workup, quenching the reaction with deuterium oxide should have produced a deuterated-diphenylmethane. This product was not observed when D2O was used in the workup. Further experimentation, including reactions using deuterated benzhydryl halides and iododiphenylmethane (3) may help in understanding this situation.

61 Reactions in Vials of Alternative Materials: Copper, Teflon®, and Nickel

Copper and Teflon® vial reactions

The reaction of bromodiphenylmethane (6) and potassium iodide, a reaction that has shown consistent results, was performed in vials made of 3 different materials. Under standard conditions,a the major products of this reaction are iododiphenylmethane (3) and 1,1,2,2-tetraphenylethane (4); in a 1:1 ratio in the crude product mixture. The product mixture contains only a small percentage of starting material (6) and 11% bis(diphenylmethyl)ether (5). When the same reaction was performed in a copper vial with a copper ball, the crude product mixture contained 58% 1,1,2,2-tetraphenylethane

(4) and 34% bis(diphenylmethyl)ether (5). No starting material remained, nor was iododiphenylmethane (3) seen to form. Copper is a well-known coupling catalyst,83-85 which uses halides, especially iodide, to form carbon-carbon bonds. Copper powder is also used as an initiator in solvent-free radical reactions with alkyl iodides.86 To avoid traditional loose copper catalysts, copper vessels and balls can be employed to catalyze reactions.87 Copper could have changed the product distribution of the reaction of bromodiphenylmethane (6) and potassium iodide by initiating a radical reaction which caused dimerization of any iododiphenylmethane (3) that may have formed. Yet this mechanism most likely operates by metal insertion.

The reaction of potassium iodide and bromodiphenylmethane (6) performed in the

Teflon® vial was highly energetic; smoke and fumes were emitted when the reaction vial was unsealed. The starting material was completely consumed. The products present in significant amounts were diphenylmethane (9) and p-benzyltriphenylmethane (8); 35% a Standard reaction conditions were set as one molar equivalent each of benzhydryl substrate and nucleophilic salt placed in a stainless steel vial with 1/8” stainless steel ball and mixed on the HSBM between 14 and 16 hours.

62 and 51%, respectively, of the crude product mixture. These results resemble the reaction of sodium iodide and bromodiphenylmethane (6) under standard conditions.a Teflon® is generally considered inert because of its C-F bonds, and therefore most likely did not participate in the reaction. The higher energy may have been reached because this material has one of the lowest dynamic coefficients of friction88 which reduces the amount of energy of the reaction lost through friction.

Sodium iodide and bromodiphenylmethane (6) proved a highly energetic alkali metal- halogen combination, capable of synthesizing p-benzyltriphenylmethane (8) as a large percentage of the product mixture. The results from the reaction of bromodiphenylmethane (6) and potassium iodide in the Teflon® vial was equivalent to that of sodium iodide and bromodiphenylmethane (6) under standard conditionsa in an inert atmosphere. When benzyl iodide (15) was incorporated into the reaction of sodium iodide and bromodiphenylmethane (6) in the steel vial, the aromatic substitution products, 1,2-dibenzylbenzene (11) and 1,4-dibenzylbenzene (12), were formed in modest amounts. This prompted investigation into the synthesis of these products using potassium iodide with the Teflon® vial and Teflon® ball. Bromodiphenylmethane (6), benzyl iodide (15), and potassium iodide were reacted in the Teflon® vial. Though no bromodiphenylmethane (6) remained, benzyl iodide (15) composed 34% of the crude reaction mixture along with 20% diphenylmethane (9) and 22.7% p- benzyltriphenylmethane (8). Neither 1,2-diphenylbenzene (11) nor 1,4-diphenylbenzene

(12) was observed by GC-MS analysis. There is no explanation as to why p-

63 benzyltriphenylmethane (8) was seen, yet not the desired hetero-compound products

(11 and 12).

Nickel vial reactions

It is known that benzylic halides dimerize in reactions with transition metals such as vanadium, titanium, ruthenium, and iron.73-77 Metallic nickel, prepared by reducing a nickel halide with lithium aluminum hydride, has been reported to be an “alternative tool for the homocoupling of benzylic halides under mild conditions.”75 Research in solvent- free ball milling chemistry has shown that certain reactions requiring a metal catalyst can use a vial prepared from that same metal to facilitate the reaction, in lieu of adding the loose metal as a reagent.87 1,1,2,2-Tetraphenylethane (4) is formed during certain nucleophilic substitution reactions in the stainless steel vial with a stainless steel ball. A reaction was milled in the nickel vial with a nickel ball in order to test if the use of nickel would increase conversion to the dimer (4).

As a control reaction, bromodiphenylmethane (6) was milled without salt under standard conditions.a GC-analysis of the crude product mixture showed that it contained only

4.6% dimer (4). The same reaction was performed using a nickel vial and nickel ball in place of steel. GC-analysis showed that the crude product mixture consisted of 8%

1,1,2,2-tetraphenylethane (4) and 3.6% diphenylmethane (9), the reduction product. The highest yields reported by Inabab, Matsumoto, and Rieke were actually obtained when the metallic nickel was derived from the reduction of NiI2. It was hypothesized that the

64 iodide ions facilitate the homocoupling reaction through halogen exchange.75 To this end, in my research, a small iodine crystal was added to the nickel vial with bromodiphenylmethane (6). Conversion to the dimer (4) and diphenylmethane (9) increased to 31% and 33%, respectively, of the crude product mixture. The synthesis of diphenylmethane (9) was not surprising, as the reduction product was reported to accompany the homocoupled product in each case.75 Adding an iodine crystal to the reaction in a steel vial produced a crude product mixture containing 11.8% dimer (4), 8% iododiphenylmethane (3), and 1.5% diphenylmethane (9). From the data collected, it can be stated that, though less efficiently than the reported reactions in solvent, 75 the nickel vial and nickel ball facilitate the homocoupling and reduction reactions of bromodiphenylmethane (6) in the presence of iodine.

Conclusion

In conclusion, it would be false to assume that what is known for the classic nucleophilic substitution reactions consistently holds true under solvent-free conditions. Despite the

Finkelstein reaction’s basis in HSAB theory, the identity of the hard alkali metal does not seem as important as the fact that it is hard and that the nucleophile is soft. This is not consistent with the results seen from the reactions milled on the HSBM in a solvent-free environment, where the identity of the alkali metal can greatly alter the reaction products.

Yet, this is not the only factor which causes these differences. The simplest lesson that can be learned from the analysis of the laboratory research performed is that that there are many variables affecting the outcome of a nucleophilic substitution reaction on a secondary carbon in a ball mill under solvent-free conditions. This includes the substrate, the alkali metal, the anionic nucleophile, atmospheric conditions, and the reaction vessel material. Though the results of the chlorodiphenylmethane (7) reactions

65 resemble the nucleophilic strength trend in a protic solvent: I- > Br- > Cl- > F-, the results of the bromodiphenylmethane (6) reactions do not. The next logical step in this study would be to conduct reactions on the iododiphenylmethane (3) substrate.

In the words of Ralph Pearson, “Any solvent is much better than none as far as ions are concerned.”35 Without proving a mechanism, it is not possible to state with certainty whether ions are formed in a reaction lacking solvent. Currently the best hypothesis for the mechanism is the formation of the diphenylmethide (C) where the carbon center is stabilized by bonding with the alkali metal. More experiments must be performed in order to determine with greater certainty that this is the mechanism by which the variety of reaction products are formed.

66 Chapter 3

Experimental Methods

Instrumentation and Materials

All milling reactions were done on a Spex 8000M Mixer/Miller. All column separations used a Teledyne Isco Combiflash Companion Instrument. Gas Chromatography (GC) analysis was performed on an Agilent 6890N Network GC System. Gas

Chromatography-Mass Spectrometry (GC-MS) analysis was performed on an Agilent

5975 Inert XL Mass Selective Detector. The GC-MS run is 24.33 minutes long with a

100:1 split and a flow of 200 mL/min using He as the carrier gas. The temperature is increased over the course of the run from 100°C (held for 1 minute) to 300°C (held for 10 minutes) over a 15°/minute interval. Nuclear Magnetic Resonance (NMR) was performed on a 300 MHz Bruker Topspin. Bromodiphenylmethane (6) [776-74-9] was acquired from

MP Biomedicals. Chlorodiphenylmethane (7) 98% [90-99-3], 1-bromobutane 99% [109-

65-9], benzyl chloride 99% [100-44-7], and 4-bromobenzyl bromide (1) 98% [589-15-1] were acquired from Acros Organics. 1-Chlorobutane [109-69-3] was acquired from

Eastman Organic Chemicals.

Throughout the Experimental Methods these terms and abbreviations are used: HSBM

(high speed ball mill), Rt (GC-MS retention time), Rotovap (rotary evaporator), MTBE

(methyl tert-butyl ether), EtOAc (ethyl acetate), 1N HCl (1 normal solution of hydrochloric acid in water prepared by diluting 11 molar HCl purchased from Acros Organics with de- ionized water), and brine (a saturated solution of NaCl in de-ionized water).

67 Bromodiphenylmethane (6)

LiF

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.6 g, 2.4 mmol) and lithium fluoride (0.06 g, 2.4 mmol). The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a red liquid.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 89.7% bromodiphenylmethane (6) (Rt=7.9 min), 0.85% 1,1,2,2- tetraphenylethane (4) (Rt=13.0 min), 2.23% p-benzyltriphenylmethane (8) (Rt=14.3 min), and 3% diphenylmethane (9) (Rt=5.6 min).

The workup and purification of the reaction was abandoned at this point because of insufficient product formation.

LiCl

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.5 g, 2.0 mmol) and lithium chloride (0.09 g, 2.0 mmol).

The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a red liquid.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 87.7% bromodiphenylmethane (6) (Rt=7.9 min), 7.6% chlorodiphenylmethane

68 (7) (Rt=7.1 min), 1.3% 1,1,2,2-tetraphenylethane (4) (Rt=13.0), and 1.2% p- benzyltriphenylmethane (8) (Rt=14.3), and 1.4% diphenylmethane (9) (Rt=5.6 min).

The workup and purification of the reaction was abandoned at this point because of insufficient product formation.

LiI

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.5 g, 2.0 mmol) and lithium iodide (0.27 g, 2.0 mmol). The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a red liquid.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). The bi-phasic mixture was transferred to a separatory funnel. The organic phase was washed with 1N

HCl (1x) and brine (1x). The aqueous phases were back-extracted with MTBE (1x). The organic phases were then combined, dried over MgSO4, and filtered. The filtrate was concentrated by Rotovap to a thick yellow oil containing 40.9% diphenylmethane (9)

(Rt=5.6 min) and 45.9% p-benzyltriphenylmethane (8) (Rt=14.3 min) by GC-MS analysis; mass= 0.5 g.

The crude material was purified by flash chromatography: 40 g column. The diphenylmethane eluted at 5% EtOAc in hexanes and the p-benzyltriphenylmethane (8) eluted at 10% EtOAc in hexanes. Relevant fractions were combined and concentrated to a thick yellow oil; 82% pure, mass= 0.075 g. The major component of the thick yellow oil was identified as p-benzyltriphenylmethane (8) [54767-38-3] (yield= 9.2%) by GC-MS.

GC-MS: 334(M+), 257, 243, 178, 165, 152, 128, 91.

69 NaF

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.5 g, 2.0 mmol) and sodium fluoride (0.084 g, 2.0 mmol).

The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a grey solid.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 88.9% bromodiphenylmethane (6) (Rt=7.9 min), 3.3% 1,1,2,2- tetraphenylethane (4) (Rt=13.0 min), and 4.2% bis(diphenylmethyl)ether (5) (Rt=13.5 min).

The workup and purification of the reaction was abandoned at this point because of insufficient product formation.

NaCl

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.5 g, 2.0 mmol) and dry sodium chloride (0.084 g, 2.0 mmol). The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a red liquid.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 80.4% bromodiphenylmethane (6) (Rt=7.9 min), 12.9% chlorodiphenylmethane (7) (Rt=7.1 min), 2.5% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min), and 0.9% diphenylmethane (9) (Rt=5.6 min).

The workup and purification of the reaction was abandoned at this point because of insufficient product formation.

NaI: Preparation of p-benzyltriphenylmethane (8)

In a dry atmosphere, a clean, dry stainless steel vial fitted with a 1/8” steel ball was charged with bromodiphenylmethane (6) (0.5 g, 2.0 mmol) and sodium iodide (0.36 g,

2.0 mmol). The vial was sealed and placed on the HSBM for 14-16 hours. When the reaction was complete, the mixture was a smoking black tar.

The contents of the vial are diluted with MTBE and 10% Na2S2O3 (aq). The bi-phasic mixture was transferred to a separatory funnel. The organic phase was washed with 1N

HCl (1x) and brine (1x). The aqueous phases were back-extracted with MTBE (1x). The organic phases were then combined, dried over MgSO4, and filtered. The filtrate was concentrated by Rotovap to a red/brown liquid; mass= 1 g. Becoming a thick yellow liquid when diluted with a small amount of methanol.

The thick yellow oil is purified by column chromatography: 50 g column.

Diphenylmethane (9) eluted in 100% hexanes. The second product eluted at 10% EtOAc in hexanes. Relevant fractions containing the second product were combined and the solvent was removed by Rotovap to leave a thick yellow oil; 82% purity, mass=0.075 g.

The major component of the thick yellow oil was identified as p-benzyltriphenylmethane

(8) [54767-38-3] (yield= 9.2%) by GC-MS, 1H-NMR, 13C-NMR, DEPT, HMQC, and

1 13 COSY. H NMR (CDCl3) δ: 7.40-6.72 (m, 20H), 5.55-5.48 (s, 1H), 3.98-3.91 (s, 2H). C

NMR (CDCl3): 144.05, 129.48, 128.95, 128.92, 128.44, 128.42, 128.26, 126.05, 56.48,

41.55. GC-MS: 334(M+), 257, 243, 178, 165, 152, 128, 91.

NaI: Preparation of 1,1,2,2-tetraphenylethane (4)

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.6 g, 2.4 mmol) and sodium iodide (0.36 g, 2.4 mmol) in a moist atmosphere. The vial was sealed and placed on the HSBM for 14 hours. When the reaction was complete, the mixture was a smoking black tar.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). The bi-phasic mixture was transferred to a separatory funnel. The organic phase was washed with 1N

HCl (1x) and brine (1x). The aqueous phase was back extracted with MTBE (1x). The organic phases were combined, dried over Na2SO4, and filtered. The filtrate was concentrated by Rotovap to a red liquid which becomes a red soft solid when solvent is further removed by vacuum pump.

The soft solid was diluted with only enough ethanol to dissolve the solid completely upon heating. As the solution cooled to room temperature, white solid precipitated. The flask was stirred in an ice bath to cause further precipitation. The precipitate was collected using a glass filter frit attached to a vacuum and was washed with cold ethanol to remove the colored residue from the solid. The filtrate was concentrated to red oil with some precipitate. The recrystallization technique was repeated. A white solid: m.p. 205-

208°C, 100% purity, mass= 68.0 mg, was obtained and characterized as 1,1,2,2- tetraphenylethane (4) [632-50-8] (yield= 4.24%) by GC-MS, 1H-NMR, and 13C-NMR. 1H

13 NMR (CDCl3) δ: 7.21-7.05 (m, 16H), 7.03-6.93 (m, 4H), 4.79-4.72 (s, 2H). C NMR

+ (CDCl3): 143.45, 128.51, 128.13, 125.83, 56.33. GC-MS: 334 (M ), 167, 165, 152.

72 NaOH

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.6 g, 2.4 mmol) and sodium hydroxide (0.11 g, 2.4 mmol).

The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was an opaque white liquid.

The contents of the vial were diluted with MTBE and water. A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained

66% bromodiphenylmethane (6) (Rt=7.9 min), 5.5% 1,1,2,2-tetraphenylethane (4)

(Rt=13.0 min), and 10.8% bis(diphenylmethyl)ether (5) (Rt=13.5 min).

The workup and purification of the reaction was abandoned at this point because of insufficient product formation.

KF: Preparation of bis(diphenylmethyl)ether (5)

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.6 g, 2.4 mmol) and potassium fluoride (0.15 g, 2.4 mmol).

The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was an opaque lilac liquid.

The contents of the vial were diluted with MTBE and water. The biphasic mixture was transferred to a separatory funnel. The organic phase was washed with water (1x) and brine (1x). The aqueous phases were back-extracted with MTBE (1x). The organic phases were combined, dried over MgSO4, and filtered. The filtrate was concentrated by

Rotovap to a green/brown solid containing 52.8% bromodiphenylmethane (6) (Rt=7.9

73 min), 25.7% flourodiphenylmethane (14) (Rt=5.8 min), and 18.4% bis(diphenylmethyl)ether (5) (Rt=13.5 min). Crude mass= 0.41 g.

The solid was triturated with a small amount of methanol. The precipitate was collected using a glass filter frit attached to a vacuum. A white solid; m.p. 108-109.3°C, 98% purity, mass= 0.10 g, was characterized as bis(diphenylmethyl)ether (5) [574-42-5]

(yield= 11.9%) by GC-MS, X-ray chrystallography, 1H-NMR, and 13C-NMR. 1H NMR

13 (CDCl3) δ: 7.44-7.17 (m, 20H), 5.44-5.33 (s, 2H). C NMR (CDCl3): 142.20, 128.39,

127.45, 127.28, 79.98. GC-MS: 281, 183, 166, 17, 169, 152, 105, 77, 51.

CsF

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.6 g, 2.4 mmol) and cesium fluoride (0.37 g, 2.4 mmol).

The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was an opaque white liquid.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 70.9% bromodiphenylmethane (6) (Rt=7.9 min), 18.6% fluorodiphenylmethane (14) (Rt=5.8 min), 0.91% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min), and 5.2% bis(diphenylmethyl)ether (5) (Rt=13.5 min).

The workup and purification of the reaction was abandoned at this point because of insufficient product formation.

74 KCl

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.60 g, 2.4 mmol) and potassium chloride (0.18 g, 2.4 mmol). The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a green/yellow creamy liquid.

The contents of the vial were diluted with EtOAc and water. The biphasic mixture was transferred to a separatory funnel. The organic phase was washed with water (2x) and brine (1x). The aqueous layers were back extracted with EtOac (1x). The organic phases were combined, dried over MgSO4, and filtered. The filtrate was concentrated by

Rotovap to a yellow oil which contained 33.4% bromodiphenylmethane (6) (Rt=13.0 min), 59.6% chlorodiphenylmethane (7) (Rt=7.1 min), and 5% 1,1,2,2-tetraphenylethane

(4) (Rt=13.0 min).

Methanol was added to the oil to precipitate the 1,1,2,2-tetraphenylethane (4), which proved unsuccessful. The bromodiphenylmethane (6) and the chlorodiphenylmethane

(7) were too difficult to separate and thus purification efforts were discontinued.

KCl

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.5 g, 2.0 mmol) and potassium chloride (0.15 g, 2.0 mmol).

The vial was sealed and placed on the HSBM for 5 hours. When the reaction was complete, the mixture was a thick green/orange liquid.

The contents of the vial were diluted with MTBE and water. A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained

75 35.9% bromodiphenylmethane (6) (Rt=7.9 min), 42% chlorodiphenylmethane (7) (Rt=7.1 min), and 12% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min). The biphasic mixture was transferred to a separatory funnel. The organic phase was washed with water (2x). The aqueous layers were back extracted with MTBE (1x). The organic phases were combined, dried over MgSO4, and filtered. The filtrate was concentrated by Rotovap to a yellow oil. Over time, a solid precipitated out of solution.

The solid was triturated with a small amount of methanol. The precipitate was collected using a glass filter frit attached to a vacuum. A white solid; m.p. 108-109.3°C, 99.5% purity, mass= 0.16 g, was characterized as bis(diphenylmethyl)ether (5) [574-42-5]

1 13 1 (yield= 22.8%) by GC-MS, H-NMR, and C-NMR. H NMR (CDCl3) δ: 7.44-7.17 (m,

13 20H), 5.44-5.33 (s, 2H). C NMR (CDCl3): 142.20, 128.39, 127.45, 127.28, 79.98. GC-

MS: 281, 183, 166, 17, 169, 152, 105, 77, 51.

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.50 g, 2.0 mmol) and potassium iodide (0.33 g, 2.0 mmol).

The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a black liquid.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample from the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 2.4% bromodiphenylmethane (6) (Rt=7.9 min), 38% iododiphenylmethane (3)

(Rt=8.6 min), 37% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min), and 10.8% bis(diphenylmethyl)ether (5) (Rt=13.5 min).

76 Further workup was not undertaken. A general procedure can be followed if workup and purification is desired. Dilute the contents of the vial with MTBE and 10% Na2S2O3 (aq).

Transfer the bi-phasic mixture to a separatory funnel. Wash the organic phase with 1N

HCl (1x) and brine (1x). Back-extract the aqueous phases with MTBE (1x). Combine the organic phases, dry over MgSO4, and filter. Concentrate the filtrate by Rotovap.

If the crude product is a solid, purify by dissolving in hot ethanol. Allow the solution to cool and solid to precipitate. If the crude product is a liquid, allow to stand overnight for solid to precipitate. Filter off the precipitate using a glass filter frit connected to a vacuum. Wash the solid with cold ethanol to obtain 1,1,2,2-tetraphenylethane (4).

Reactions in Vials of Alternative Materials: Copper, Teflon, Nickel.

Nickel

A clean, dry nickel vial fitted with a nickel ball was charged with bromodiphenylmethane

(6) (0.6 g, 2.40 mmol). The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a red and silver liquid. The reaction caused pressure buildup in the vial.

The contents of the vial were diluted with MTBE and water. A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained

90% bromodiphenylmethane (6) (Rt=7.9 min) and 8% 1,1,2,2-tetraphenylethane (4)

(Rt=13.0 min).

The workup and purification of the reaction was abandoned at this point because of insufficient product formation.

Nickel (with I2)

A clean, dry nickel vial fitted with a nickel ball was charged with bromodiphenylmethane

(6) (0.3 g, 1.20 mmol) and a small crystal of iodine. The vial was sealed and placed on the HSBM for 14 hours. When the reaction was complete, the mixture was a red and silver liquid.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 21% bromodiphenylmethane (6) (Rt=7.9 min), 31% 1,1,2,2-tetraphenylethane

(4) (Rt=13.0 min), and 33% bis(diphenylmethyl)ether (5) (Rt=13.5 min).

Workup was not undertaken. A general procedure can be followed if workup and purification is desired. Dilute the contents of the vial with MTBE and 10% Na2S2O3 (aq).

Transfer the bi-phasic mixture to a separatory funnel. Wash the organic phase with 1N

HCl (1x) and brine (1x). Back-extract the aqueous phases with MTBE (1x). Combine the organic phases, dry over MgSO4, and filter. Concentrate the filtrate by Rotovap.

Copper

A clean, dry copper vial fitted with a copper ball was charged with bromodiphenylmethane (6) (0.5 g, 2.00 mmol) and potassium ioddide (0.34 g, 2.00

78 mmol). The vial was sealed and placed on the HSBM for 14 hours. When the reaction was complete, the mixture was a soft grey solid.

The contents of the vial were diluted with EtOAc and water. A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained

58% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min), 34% bis(diphenylmethyl)ether (5)

(Rt=13.5 min), and 6% p-benzyltriphenylmethane (8) (Rt=14.3 min). The bi-phasic mixture was transferred to a separatory funnel. The organic phase was washed with brine (1x). The aqueous phase was back extracted with EtOAc (1x). The organic phases were combined, dried over MgSO4, and filtered. The filtrate was concentrated by

Rotovap to a brown/orange solid.

The crude material was diluted with a minimal amount of ethanol. The mixture was heated to dissolve the solid. As the solution cooled to room temperature, white/grey solid precipitated. The precipitate was collected using a glass frit attached to a vacuum. A grey solid; 95% purity, mass= 0.06 g, was characterized as 1,1,2,2-tetraphenylethane (4)

1 13 1 [632-50-8] (corrected yield= 8.5%) by GC-MS, H-NMR, and C-NMR. H NMR (CDCl3)

13 δ: 7.21-7.05 (m, 16H), 7.03-6.93 (m, 4H), 4.79-4.72 (s, 2H). C NMR (CDCl3): 143.45,

128.51, 128.13, 125.83, 56.33. GC-MS: 334 (M+), 167, 165, 152.

Teflon®

A clean, dry Teflon® vial fitted with a Teflon® ball was charged with bromodiphenylmethane (6) (0.5 g, 2.00 mmol) and potassium idodide (0.33 g, 2.00 mmol). The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a black smoking liquid. The inside walls of the vial had become orange.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 35% diphenylmethane (9) (Rt=5.6 min), and 51% p-benzyltriphenylmethane

(8) (Rt=14.3 min). The bi-phasic mixture was transferred to a separatory funnel. The organic phase was washed with 1N HCl (1x) and brine (1x). The aqueous phase was back extracted with MTBE (1x). The organic phases were combined, dried over MgSO4, and filtered. The filtrate was concentrated by Rotovap to a thick yellow oil.

The crude material was purified by flash chromatography. Diphenylmethane (9) eluted at

100% hexanes. p-Benzyltriphenylmethane (8) eluted at 10% EtOAc in hexanes. A thick yellow oil; 80% purity, mass= 0.13 g, was characterized as p-benzyltriphenylmethane (8)

[54767-38-3] (corrected yield= 16.7%) by GC-MS, 1H-NMR, 13C-NMR, DEPT, HMQC,

1 and COSY. H NMR (CDCl3) δ: 7.40-6.72 (m, 20H), 5.55-5.48 (s, 1H), 3.98-3.91 (s, 2H).

13 C NMR (CDCl3): 144.05, 129.48, 128.95, 128.92, 128.44, 128.42, 128.26, 126.05,

56.48, 41.55. GC-MS: 334(M+), 257, 243, 178, 165, 152, 128, 91.

Chlorodiphenylmethane (7)

LiF

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with chlorodiphenylmethane (7) (0.5 g, 2.47 mmol) and lithium fluoride (0.07 g, 2.47 mmol).

The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a green liquid.

80 The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 65% chlorodiphenylmethane (7) (Rt=7.1 min), 7.8% diphenylmethane (9)

(Rt=5.6 min), 12.5% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min), and 7.3% p- benzyltriphenylmethane (8) (Rt=14.3 min).

The workup and purification of the reaction was abandoned at this point because of insufficient product formation.

LiBr

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with chlorodiphenylmethane (7) (0.5 g, 2.47 mmol) and lithium bromide (0.21 g, 2.47 mmol).

The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a red liquid.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 28% chlorodiphenylmethane (7) (Rt=7.1 min), 47% bromodiphenylmethane

(6) (Rt=7.9 min), and 14.1% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min).

An insufficient amount of 1,1,2,2-tetraphenylethane (4) was present to be precipitated from a crude solution. The bromodiphenylmethane (6) and the chlorodiphenylmethane

(7) were too difficult to separate and thus purification efforts were discontinued.

81 LiI

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with chlorodiphenylmethane (7) (0.5 g, 2.0 mmol) and lithium iodide (0.33 g, 2.0 mmol). The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a dark red resin.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 10.3% chlorodiphenylmethane (7) (Rt=7.1 min), 34.5% iododiphenylmethane

(3) (Rt=8.6 min), 31.2% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min), and 6% bis(diphenylmethyl)ether (5) (Rt=13.5 min).

Further workup was not undertaken. A general procedure can be followed if workup and purification is desired. Dilute the contents of the vial with MTBE and 10% Na2S2O3 (aq).

Transfer the bi-phasic mixture to a separatory funnel. Wash the organic phase with 1N

HCl (1x) and brine (1x). Back-extract the aqueous phases with MTBE (1x). Combine the organic phases, dry over MgSO4, and filter. Concentrate the filtrate by Rotovap.

NaF

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with chlorodiphenylmethane (7) (0.5 g, 2.47 mmol) and sodium fluoride (0.11 g, 2.47 mmol).

82 The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a white opaque suspension.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 90.9% chlorodiphenylmethane (7) (Rt=7.1 min), negligible fluorodiphenylmethane (14) formation (Rt=5.8 min), 1.8% 1,1,2,2-tetraphenylethane (4)

(Rt=13.0 min), and 2.2% bis(diphenylmethyl)ether (5) (Rt=13.5 min).

The workup and purification of the reaction was abandoned at this point because of insufficient product formation.

NaBr

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with chlorodiphenylmethane (7) (0.5 g, 2.47 mmol) and sodium bromide (0.29 g, 2.47 mmol).

The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a brown suspension.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 15.8% chlorodiphenylmethane (7) (Rt=7.1 min), 64.6% bromodiphenylmethane (6) (Rt=7.9 min), 7.6% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min), and 6.5% bis(diphenylmethyl)ether (5) (Rt=13.5 min).

83 An insufficient amount of 1,1,2,2-tetraphenylethane (4) was present to be precipitated from a crude solution. The bromodiphenylmethane (6) and the chlorodiphenylmethane

(7) were too difficult to separate and thus purification efforts were discontinued.

NaI

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with chlorodiphenylmethane (7) (0.6 g, 3.0 mmol) and sodium iodide (0.45 g, 3.0 mmol). The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a white opaque suspension.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained a negligible amount of chlorodiphenylmethane (7) (Rt=7.1 min), 34.8% iododiphenylmethane (3) (Rt=8.6 min), 48.2% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min), and 7.5% bis(diphenylmethyl)ether (5) (Rt=13.5 min).

Further workup was not undertaken. A general procedure can be followed if workup and purification is desired. Dilute the contents of the vial with MTBE and 10% Na2S2O3 (aq).

Transfer the bi-phasic mixture to a separatory funnel. Wash the organic phase with 1N

HCl (1x) and brine (1x). Back-extract the aqueous phases with MTBE (1x). Combine the organic phases, dry over MgSO4, and filter. Concentrate the filtrate by Rotovap.

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with chlorodiphenylmethane (7) (0.5 g, 2.47 mmol) and potassium fluoride (0.14 g, 2.47 mmol). The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a white opaque suspension.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 79% chlorodiphenylmethane (7) (Rt=7.1 min), 0.8% fluorodiphenylmethane

(14) (Rt=5.8 min), 8.7% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min), and 2.7% bis(diphenylmethyl)ether (5) (Rt=13.5 min).

The workup and purification of the reaction was abandoned at this point because of insufficient product formation.

KBr

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with chlorodiphenylmethane (7) (0.5 g, 2.47 mmol) and potassium bromide (0.29 g, 2.47 mmol). The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a brown suspension.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 57.5% chlorodiphenylmethane (7) (Rt=7.1 min), 31% bromodiphenylmethane

(6) (Rt=7.9 min), and 5.7% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min).

An insufficient amount of 1,1,2,2-tetraphenylethane (4) was present to be precipitated from a crude solution. The bromodiphenylmethane (6) and the chlorodiphenylmethane

(7) were too difficult to separate and thus purification efforts were discontinued.

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with chlorodiphenylmethane (7) (0.5 g, 2.0 mmol) and potassium iodide (0.33 g, 2.0 mmol).

The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a dark red resin.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 5.5% chlorodiphenylmethane (7) (Rt=7.1 min), 32% iododiphenylmethane (3)

(Rt=8.6 min), 34.5% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min), and 5.4% bis(diphenylmethyl)ether (5) (Rt=13.5 min).

Workup was not undertaken. A general procedure can be followed if workup and purification is desired. Dilute the contents of the vial with MTBE and 10% Na2S2O3 (aq).

Transfer the bi-phasic mixture to a separatory funnel. Wash the organic phase with 1N

HCl (1x) and brine (1x). Back-extract the aqueous phases with MTBE (1x). Combine the organic phases, dry over MgSO4, and filter. Concentrate the filtrate by Rotovap.

If the crude product is a solid, purify by dissolving in hot ethanol. Allow the solution to cool and solid to precipitate. If the crude product is a liquid, allow to stand overnight for

86 solid to precipitate. Filter off the precipitate using a glass filter frit connected to a vacuum. Wash the solid with cold ethanol to obtain 1,1,2,2-tetraphenylethane (4).

CsF

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with chlorodiphenylmethane (7) (0.5 g, 2.47 mmol) and cesium fluoride (0.14 g, 2.47 mmol).

The vial was sealed and placed on the HSBM for 16 hours. When the reaction was complete, the mixture was a white opaque suspension.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 85.3% chlorodiphenylmethane (7) (Rt=7.1 min), negligible fluorodiphenylmethane (14) formation (Rt=5.8 min), 6% 1,1,2,2-tetraphenylethane (4)

(Rt=13.0 min), and 1.7% bis(diphenylmethyl)ether (5) (Rt=13.5 min).

The workup and purification of the reaction was abandoned at this point because of insufficient product formation.

Heterogeneous Reactions

Bromodiphenylmethane (6) p-Bromobenzyl bromide (1)

No Salt

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.6 g, 2.4 mmol) and p-bromobenzyl bromide (1) (0.61 g,

87 2.4 mmol). The vial was sealed and placed on a HSBM for 15 hours. When the reaction was complete, the mixture was a red liquid.

The contents of the vial were diluted with MTBE. A sample was taken to be analyzed by

GC and GC-MS. The reaction mixture contained 50% bromodiphenylmethane (6)

(Rt=7.9 min) and 38% p-bromobenzyl bromide (1) (Rt=5.2 min).

The workup and purification of the reaction was abandoned at this point because of insufficient product formation.

NaI

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.6 g, 2.4 mmol), p-bromobenzyl bromide (1) (0.61 g, 2.4 mmol), and sodium iodide (0.37 g, 2.4 mmol). The vial was sealed and placed on a

HSBM for 14 hours. When the reaction was complete, the mixture was a green liquid.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 29% p-bromobenzyl bromide (1) (Rt=5.2 min), 6% bromodiphenylmethane (6)

(Rt=7.9 min), 10.5% p-bromobenzyl iodide (2) (Rt=6.1 min), 17% iododiphenylmethane

(3) (Rt=8.6 min), and 22% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min). The biphasic mixture is transferred to a separatory funnel and the organic phase is washed with 10%

Na2S2O3 (aq) (1x), 1N HCl (1x), and brine (1x). The aqueous phase is back extract with

MTBE (1x). The organic phases were combined, dried over MgSO4, and filtered. The filtrate was concentrated by Rotovap to a purple liquid containing long crystals.

88 Recrystallization proved ineffective because of the solubility of the crystals in organic solvent.

NaI (mixing study)

A 125 mL round-bottom flask was charged with bromodiphenylmethane (6) (0.8 g, 3.2 mmol) and p-bromobenzyl bromide (1) (0.81 g, 3.2 mmol) dissolved in 50 mL dichloromethane. The solvent is removed under reduced pressure to give a slushy off- white solid. Analysis by GC and GC-MS revealed the starting material in equal ratios as well as 2.3% 1,1,2,2-tetraphenylethane (4).

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with the mixture of bromodiphenylmethane (6) and p-bromobenzyl bromide (1), and sodium iodide (0.49 g, 3.2 mmol). The vial was sealed and placed on a HSBM for 14 hours.

When the reaction was complete, the mixture was a thick black liquid.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 18% iododiphenylmethane (3) (Rt=8.6 min), 38.7% p-bromobenzyl iodide (2)

(Rt=6.1 min), 24.7% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min), 7% diphenylmethane

(9) (Rt=5.6 min), and 7.8% bis(diphenylmethyl)ether (5) (Rt=13.5 min). The biphasic mixture is transferred to a separatory funnel and the organic phase is washed with saturated Na2S2O3 (aq) (2x). The aqueous phase is back extract with MTBE (1x).

The organic phases were combined, dried over MgSO4, and filtered. The filtrate was concentrated by Rotovap to a red liquid with solid precipitate.

89 The crude material was diluted with a minimal amount of methanol and cooled in an ice bath. The precipitate was collected using a glass frit attached to a vacuum. The precipitate is a slushy mixture. GC and GC-MS analysis show it to contain 60% p- bromobenzyl iodide (2) and varying amounts of 1,1,2,2-tetraphenylethane (4) and bis(diphenylmethyl)ether (5). No further separation was attempted.

Benzyl chloride

NaI

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.6 g, 2.4 mmol), benzyl chloride (0.31 g, 2.4 mmol), and sodium iodide (0.36 g, 2.4 mmol). The vial was sealed and placed on a HSBM for 13 hours. When the reaction was complete, the mixture was a brown liquid.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 38% benzyl chloride (Rt=2.2 min), 19.5% iododiphenylmethane (3) (Rt=8.6 min), 27.6% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min), and 6.2% bis(diphenylmethyl)ether (5) (Rt=13.5 min). The biphasic mixture is transferred to a separatory funnel and the organic phase is washed with saturated Na2S2O3 (aq) (2x).

The aqueous phase is back extracted with MTBE (1x). The organic phases were combined, dried over MgSO4, and filtered. The filtrate was concentrated by Rotovap to a yellow/orange oil.

The crude material was diluted with a minimal amount of methanol and cooled in an ice bath. The precipitate was collected using a glass frit attached to a vacuum. GC and GC-

90 MS analysis show it contains 1,1,2,2-tetraphenylethane (4) and bis(diphenylmethyl)ether

(5). No further separation was attempted.

NaI (mixing study)

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.6 g, 2.4 mmol) and benzyl chloride (0.62 g, 4.8 mmol).

The vial was sealed and placed on the HSBM for 15 minutes. The vial was removed from the machine and sodium iodide (0.36 g, 2.4 mmol) was added. The vial was sealed again and placed on a HSBM for 14 hours. When the reaction was complete, the mixture was a dark liquid.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 55% benzyl chloride (Rt=2.2 min), 7% benzyl iodide (15) (Rt=3.5 min), 10% iododiphenylmethane (3) (Rt=8.6 min), 17% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min),

5% bis(diphenylmethyl)ether (5) (Rt=13.5 min), and 5.2% diphenylmethane (9) (Rt=5.6 min). The biphasic mixture is transferred to a separatory funnel and the organic phase is washed with saturated Na2S2O3 (aq) (2x). The aqueous phase is back extracted with

MTBE (1x). The organic phases were combined, dried over MgSO4, and filtered. The filtrate was concentrated by Rotovap to a dark red oil.

Crystal generation was attempted by diluting the crude material with a small amount of ethanol. No precipitate formed.

91 Benzyl iodide (15)

LiI

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.5 g, 2.0 mmol), benzyl iodide (15) (0.44 g, 2.0 mmol), and lithium iodide (0.28 g, 2.0 mmol). Fizzing and cracking sounds, and bubbling were observed upon adding LiI to the contents of the vial. The vial was sealed and placed on a HSBM for 16 hours. When the reaction was complete, the mixture was a black liquid.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 40% benzyl iodide (15) (Rt=3.5 min), 6.7% diphenylmethane (9) (Rt=5.6 min),

11% iododiphenylmethane (3) (Rt=8.6 min), 22% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min), and 15% bis(diphenylmethyl)ether (5) (Rt=13.5 min). The biphasic mixture is transferred to a separatory funnel and the organic phase is washed with 10% Na2S2O3

(aq) (1x), 1N HCl (1x), and brine (1x). The aqueous phase is back extracted with MTBE

(1x). The organic phases were combined, dried over MgSO4, and filtered. The filtrate was concentrated by Rotovap to a red liquid.

Crystal generation was attempted by diluting the crude material with a small amount of ethanol. No precipitate formed.

NaI: Preparation of diphenylmethane (9), 1,2 dibenzylbenzene (11), and 1,4 dibenzylbenzene (12)

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.5 g, 2.0 mmol), benzyl iodide (15) (0.45 g, 2.0 mmol), and

92 sodium iodide (0.36 g, 2.0 mmol). The vial was sealed and placed on a HSBM for 16 hours. When the reaction was complete, the mixture was a black smoking liquid that smells of rotten eggs.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 43% diphenylmethane (9) (Rt=5.6 min), 12% (Rt=10.9 min) and 15% (Rt=11.3 min) unknown molecules both with mass of 258 m/z. The biphasic mixture is transferred to a separatory funnel and the organic phase is washed with 10% Na2S2O3 (aq) (1x).

The aqueous phase is back extracted with EtOAc (1x). The organic phases were combined, dried over MgSO4, and filtered. The filtrate was concentrated by Rotovap to an orange liquid.

The crude material was purified by flash chromatography. Diphenylmethane (9) elutes at

100% hexanes. Relevant fractions were combined and concentrated to a yellow oil;

100% purity, mass= 0.052 g, which was characterized as diphenylmethane (9) [101-81-

1 13 1 5] (yield= 15.5%) by GC-MS, H-NMR, C-NMR. H NMR (CDCl3) δ: 7.32-7.21 (m, 4H),

13 7.20-7.04 (m, 6H), 4.02-3.95 (s, 2H). C NMR (CDCl3): 141.91, 129.02, 128.54, 126.14,

42.02. GC-MS: 168 (M+), 167, 165, 153, 152, 115, 91, 65, 51, 39.

The unknown molecules eluted simultaneously at 5% MTBE in hexanes. Relevant fractions were combined and concentrated to a yellow oil; mass= 0.032 g, which was characterized as 1,2-dibenzylbenzene (11) [792-68-7] and 1,4-dibenzylbenzene (12)

1 13 1 [793-23-7] by GC-MS, H-NMR, C-NMR, DEPT, HMQC, and COSY. H NMR (CDCl3)

δ: 7.30-7.22 (m, 4H), 7.21-7.12 (m, 6H), 7.10-7.08 (s, 2H), 7.07-6.96 (t, 2H), 3.98-3.90

93 13 (s, 4H). C NMR (CDCl3): 141.28, 141.17, 138.88, 129.71, 129.02, 128.94, 128.60,

128.46, 126.77, 126.09, 41.93, 41.60. GC-MS: 258 (M+), 167, 152, 91.

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.5 g, 2.0 mmol), benzyl iodide (15) (0.45 g, 2.0 mmol), and potassium iodide (0.33 g, 2.0 mmol). The vial was sealed and placed on a HSBM for 16 hours. When the reaction was complete, the mixture was a black liquid with a piercing odor.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 34% benzyl iodide (15) (Rt=3.5 min), 20% diphenylmethane (9) (Rt=5.6 min), and 22.7% p-benzyltriphenylmethane (8) (Rt=14.3 min).

Workup was not undertaken. A general procedure can be followed if workup and purification is desired. Dilute the contents of the vial with MTBE and 10% Na2S2O3 (aq).

Transfer the bi-phasic mixture to a separatory funnel. Wash the organic phase with 1N

HCl (1x) and brine (1x). Back-extract the aqueous phases with MTBE (1x). Combine the organic phases, dry over MgSO4, and filter. Concentrate the filtrate by Rotovap.

Purify the crude material by column chromatography.

94 Chlorobutane

NaI

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.6 g, 2.4 mmol), n-chlorobutane (0.22 g, 2.4 mmol), and sodium iodide (0.36 g, 2.4 mmol). The vial was sealed and placed on a HSBM for 13 hours. When the reaction was complete, the mixture was a brown liquid.

The contents of the vial were diluted with EtOAc and sat. Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 34% iododiphenylmethane (3) (Rt=8.6 min), 49.6% 1,1,2,2-tetraphenylethane

(4) (Rt=13.0 min), and 7.9% bis(diphenylmethyl)ether (5) (Rt=13.5 min). The biphasic mixture is transferred to a separatory funnel and the organic phase is washed with sat.

Na2S2O3 (aq) (3x). The aqueous phase is back extracted with EtOAc (1x). The organic phases were combined, dried over MgSO4, and filtered. The filtrate was concentrated by

Rotovap to an orange liquid.

The crude material was diluted with a minimal amount of methanol and cooled in an ice bath. The precipitate was collected using a glass frit attached to a vacuum. The white solid; 98% purity, mass= 0.01 g, was characterized as 1,1,2,2-tetraphenylethane (4)

1 13 1 [632-50-8] (yield= 1.2%) by GC-MS, H-NMR, and C-NMR. H NMR (CDCl3) δ: 7.21-

13 7.05 (m, 16H), 7.03-6.93 (m, 4H), 4.79-4.72 (s, 2H). C NMR (CDCl3): 143.45, 128.51,

128.13, 125.83, 56.33. GC-MS: 334 (M+), 167, 165, 152.

95 NaI

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.6 g, 2.4 mmol), n-chlorobutane (0.44 g, 4.8 mmol), and sodium iodide (0.36 g, 2.4 mmol). The vial was sealed and placed on a HSBM for 16 hours. When the reaction was complete, the mixture was a black tar with a sharp odor.

The contents of the vial were diluted with MTBE and water. A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained

23.6% n-chlorobutane (Rt=1.2 min), 30.5% p-benzyltriphenylmethane (8) (Rt=14.3 min), and 24.4% diphenylmethane (9) (Rt=5.6 min).

Workup was not undertaken. A general procedure can be followed if workup and purification is desired. Dilute the contents of the vial with MTBE and 10% Na2S2O3 (aq).

Transfer the bi-phasic mixture to a separatory funnel. Wash the organic phase with 1N

HCl (1x) and brine (1x). Back-extract the aqueous phases with MTBE (1x). Combine the organic phases, dry over MgSO4, and filter. Concentrate the filtrate by Rotovap.

Purify the crude material by column chromatography.

NaI (mixing study)

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.6 g, 2.4 mmol) and n-chlorobutane (0.44 g, 4.8 mmol).

96 The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 28.5% iododiphenylmethane (3) (Rt=8.6 min), 50% 1,1,2,2-tetraphenylethane

(4) (Rt=13.0 min), 10.4% diphenylmethane (9) (Rt=5.6 min), and 8.3% bis(diphenylmethyl)ether (5) (Rt=13.5 min). The biphasic mixture is transferred to a separatory funnel and the organic phase is washed with saturated Na2S2O3 (aq) (2x).

The aqueous phase is back extracted with MTBE (1x). The organic phases were combined, dried over MgSO4, and filtered. The filtrate was concentrated by Rotovap to a dark red oil.

The crude material was diluted with a minimal amount of methanol and cooled in an ice bath. The precipitate was collected using a glass frit attached to a vacuum. GC and GC-

MS analysis show it contains 1,1,2,2-tetraphenylethane (4) and bis(diphenylmethyl)ether

(5). No further separation was attempted.

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with bromodiphenylmethane (6) (0.6 g, 2.4 mmol), n-chlorobutane (0.23 g, 2.4 mmol), and potassium fluoride (0.14 g, 2.4 mmol). The vial was sealed and placed on a HSBM for 14 hours. When the reaction was complete, the mixture was a opaque white liquid.

The contents of the vial were diluted with EtOAc and saturated Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 62% bromodiphenylmethane (6) (Rt=7.9 min), 14% 1,1,2,2-tetraphenylethane

(4) (Rt=13.0 min), 2.9% diphenylmethane (9) (Rt=5.6 min), and 9% bis(diphenylmethyl)ether (5) (Rt=13.5 min). The biphasic mixture is transferred to a

97 separatory funnel and the organic phase is washed with saturated Na2S2O3 (aq) (3x).

The aqueous phase is back extracted with EtOAc (1x). The organic phases were combined, dried over MgSO4, and filtered. The filtrate was concentrated by Rotovap to a thick yellow liquid.

Crystal generation was attempted by diluting the crude material with a small amount of methanol. No precipitate formed.

Chlorodiphenylmethane (7)

Benzyl chloride

No Salt

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with chlorodiphenylmethane (7) (0.6 g, 3.0 mmol) and benzyl chloride (0.38 g, 3.0 mmol). The vial was sealed and placed on a HSBM for 15 hours. When the reaction was complete, the mixture was an orange-red liquid.

The contents of the vial were diluted with MTBE and water. A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained

35% benzyl chloride (Rt=2.2 min), 59% chlorodiphenylmethane (7) (Rt=8.6 min), and

0.5% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min).

The workup and purification of the reaction was abandoned at this point because of insufficient product formation.

98 NaI

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with chlorodiphenylmethane (7) (0.6 g, 3.0 mmol), benzyl chloride (0.38 g, 3.0 mmol), and sodium iodide (0.45 g, 3.0 mmol). The vial was sealed and placed on a HSBM for 14 hours. When the reaction was complete, the mixture was a brown and grey liquid.

The contents of the vial were diluted with MTBE and 10% Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 35% benzyl chloride (Rt=2.2 min), 18.8% iododiphenylmethane (3) (Rt=8.6 min), 5.7% benzyl iodide (15) (Rt=3.5 min), 25.8% 1,1,2,2-tetraphenylethane (4)

(Rt=13.0 min), 6.6% bis(diphenylmethyl)ether (5) (Rt=13.5 min), and 5.2% diphenylmethane (9) (Rt=5.6 min). The biphasic mixture is transferred to a separatory funnel and the organic phase is washed with 10% Na2S2O3 (aq) (1x). The aqueous phase is back extracted with MTBE (1x). The organic phases were combined, dried over

MgSO4, and filtered. The filtrate was concentrated by Rotovap to a brown liquid.

The crude material was diluted with a minimal amount of methanol and cooled in an ice bath. The precipitate was collected using a glass frit attached to a vacuum. Less than 5 mg of yellow solid was collected. GC and GC-MS analysis show it is a mixture of 1,1,2,2- tetraphenylethane (4) and bis(diphenylmethyl)ether (5). No further separation was attempted.

NaI (mixing study)

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with chlorodiphenylmethane (7) (0.6 g, 3.0 mmol) and benzyl chloride (0.38 g, 3.0 mmol). The vial was sealed and placed on the HSBM for 15 minutes. The vial was removed from the

99 machine and sodium iodide (0.45 g, 3.0 mmol) was added. The vial was sealed again and placed on a HSBM for 16 hours. When the reaction was complete, the mixture was a milky green liquid.

The contents of the vial were diluted with MTBE and water. A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained

24% benzyl chloride (Rt=2.2 min), 16.6% iododiphenylmethane (3) (Rt=8.6 min), 15.5% benzyl iodide (15) (Rt=3.5 min), 24% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min), 9% bis(diphenylmethyl)ether (5) (Rt=13.5 min), and 8.5% diphenylmethane (9) (Rt=5.6 min).

Workup was not undertaken. A general procedure can be followed if workup and purification is desired. Dilute the contents of the vial with MTBE and 10% Na2S2O3 (aq).

Transfer the bi-phasic mixture to a separatory funnel. Wash the organic phase with 1N

HCl (1x) and brine (1x). Back-extract the aqueous phases with MTBE (1x). Combine the organic phases, dry over MgSO4, and filter. Concentrate the filtrate by Rotovap.

NaI (mixing study)

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with sodium iodide (0.46 g, 3.0 mmol). The vial was sealed and placed on the HSBM for 15 minutes. The vial was removed from the machine and chlorodiphenylmethane (7) (0.6 g,

3.0 mmol) and benzyl chloride (0.38 g, 3.0 mmol) were added. The vial was sealed

100 again and placed on a HSBM for 16 hours. When the reaction was complete, the mixture was a milky green liquid.

The contents of the vial were diluted with MTBE and water. A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained

30.6% benzyl chloride (Rt=2.2 min), 17.7% iododiphenylmethane (3) (Rt=8.6 min), 8.7% benzyl iodide (15) (Rt=3.5 min), 27% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min), 7% bis(diphenylmethyl)ether (5) (Rt=13.5 min), and 6.9% diphenylmethane (9) (Rt=5.6 min).

Workup was not undertaken. A general procedure can be followed if workup and purification is desired. Dilute the contents of the vial with MTBE and 10% Na2S2O3 (aq).

Transfer the bi-phasic mixture to a separatory funnel. Wash the organic phase with 1N

HCl (1x) and brine (1x). Back-extract the aqueous phases with MTBE (1x). Combine the organic phases, dry over MgSO4, and filter. Concentrate the filtrate by Rotovap.

NaI (mixing study)

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with chlorodiphenylmethane (7) (0.6 g, 3.0 mmol), benzyl chloride (0.39 g, 3.0 mmol), and sodium iodide (0.46 g, 3.0 mmol) along with one drop of dichloromethane. The vial was sealed and placed on a HSBM for 16 hours. When the reaction was complete, the mixture was a milky green liquid.

101

The contents of the vial were diluted with MTBE and water. A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained

29% benzyl chloride (Rt=2.2 min), 14.8% iododiphenylmethane (3) (Rt=8.6 min), 11.7% benzyl iodide (15) (Rt=3.5 min), 24.6% 1,1,2,2-tetraphenylethane (4) (Rt=13.0 min), 7% bis(diphenylmethyl)ether (5) (Rt=13.5 min), and 9% diphenylmethane (9) (Rt=5.6 min).

Workup was not undertaken. A general procedure can be followed if workup and purification is desired. Dilute the contents of the vial with MTBE and 10% Na2S2O3 (aq).

Transfer the bi-phasic mixture to a separatory funnel. Wash the organic phase with 1N

HCl (1x) and brine (1x). Back-extract the aqueous phases with MTBE (1x). Combine the organic phases, dry over MgSO4, and filter. Concentrate the filtrate by Rotovap.

Bromobutane

NaI

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with chlorodiphenylmethane (7) (0.6 g, 3.0 mmol) and n-bromobutane (0.66 g, 6.0 mmol).

The vial was removed from the machine and sodium iodide (0.37 g, 3.0 mmol) was added. The vial was sealed and placed on a HSBM for 14 hours. When the reaction was complete, the mixture was a dark liquid.

102

The contents of the vial were diluted with MTBE and saturated Na2S2O3 (aq). A sample of the organic phase was taken to be analyzed by GC and GC-MS. The reaction mixture contained 32.4% iododiphenylmethane (3) (Rt=8.6 min), 52% 1,1,2,2-tetraphenylethane

(4) (Rt=13.0 min), and 5.1% bis(diphenylmethyl)ether (5) (Rt=13.5 min). The biphasic mixture is transferred to a separatory funnel and the organic phase is washed with saturated Na2S2O3 (aq) (3x). The aqueous phase is back extracted with MTBE (1x). The organic phases were combined, dried over MgSO4, and filtered. The filtrate was concentrated by Rotovap to a dark red oil.

The crude material was diluted with a minimal amount of methanol and cooled in an ice bath. The precipitate was collected using a glass frit attached to a vacuum. The pink solid was identified as 1,1,2,2-tetraphenylethane (4). Attempts to remove the color by recrystallization were unsuccessful. No further purification was attempted.

Miscellaneous Reactions

Benzyl bromide and NaOH

A clean, dry stainless steel vial fitted with a 1/8” stainless steel ball was charged with benzyl bromide (0.61 g, 2.4 mmol) and sodium hydroxide (0.22 g, 2.4 mmol). The vial was sealed and placed on a HSBM for 16 hours. When the reaction was complete, the mixture was an opaque white semi-solid.

The contents of the vial were diluted with MTBE and water. The bi-phasic mixture was transferred to a separatory funnel. The organic phase was washed with brine (2x). The

103 aqueous phase was back extracted with MTBE (1x). The organic phases were combined, dried over MgSO4, and filtered. The filtrate was concentrated by Rotovap to a colorless oil.

The crude material was taken as is. A colorless oil; 92.8% purity, mass=0.15 g, was characterized as dibenzyl ether (16) [103-50-4] (yield= 29.4%) by GC-MS, 1H-NMR, and

13 1 13 C-NMR. H NMR (CDCl3) δ: 7.43-7.21 (m, 10H), 4.60-4,50 (s, 4H). C NMR (CDCl3):

138.35, 128.38, 127.75, 127.60, 72.09. GC-MS: 107, 92, 91, 79, 77, 65.

Finkelstein Reaction (SM-082):89

A 300 mL round-bottom flask is fitted with a magnetic stir bar and placed under N2 atmosphere. The flask is then charged with benzyl bromide (5.00 g, 29 mmol) and diluted with 80 mL of anhydrous acetone. The liquids are stirred to combine, after which time sodium iodide (6.59 g, 43.5 mmol) is added. The reaction flask is wrapped with paper-towel lined aluminum foil and stirred at room temperature for 24 hours. The reaction becomes yellow over time.

When the reaction is complete, the reaction solution is diluted with water and extracted with MTBE. The organic phase is washed with water (1x). The aqueous phase is back- extracted with MTBE (2x). The combined organic phases are dried over MgSO4, filtered, and the filtrate is concentrated by Rotovap to obtain an orange oil that solidifies under vacuum; 97% purity, mass= 5.85 g, which was characterized as benzyl iodide (15) [620-

1 13 1 05-3] (yield= 89.7%) by GC-MS, H-NMR, C-NMR. H NMR (CDCl3) δ: 7.41-7.31 (m,

13 2H), 7.30-7.18 (m, 3H), 4.49-4.41 (s, 2H). C NMR (CDCl3): 139.31, 128.85, 128.77,

127.92, 5.79. GC-MS: 218 (M+), 127, 91, 65, 39.

104 Chapter 4

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109 Appendix

Spectra and X-ray Chrystallography

Figure A.1 – GC-MS of bromodiphenylmethane (6).

110

Figure A.2 – GC-MS of chlorodiphenylmethane (7).

111 I

Figure A.3 – GC-MS of iododiphenylmethane (3).

112

Figure A.4 – GC-MS of fluorodiphenylmethane (14).

113

Figure A.5 – GC-MS of 1,1,2,2-tetraphenylethane (4).

114

Figure A.6 – 1H NMR of 1,1,2,2-tetraphenylethane (4).

115

Figure A.7 – Close-up of the 1H NMR of 1,1,2,2-tetraphenylethane (4).

116

Figure A.8 – 13C NMR of 1,1,2,2-tetraphenylethane (4).

117

Figure A.9 – X-Ray crystallographic image of bis(diphenylmethyl)ether (5).

118

Figure A.10 – GC-MS of bis(diphenylmethyl)ether (5).

119

Figure A.11 - 1H NMR of bis(diphenylmethyl)ether (5).

120

Figure A.12 – Close-up of the 1H NMR of bis(diphenylmethyl)ether (5).

121

Figure A.13 – 13C NMR of bis(diphenylmethyl)ether (5).

122

Figure A.14 – GC-MS of diphenylmethane (9).

123

Figure A.15 – 1H NMR of diphenylmethane (9).

124

Figure A.16 – Close-up of the 1H NMR of diphenylmethane (9).

125

Figure A.17 – 13C NMR of diphenylmethane (9).

126

Figure A.18 – GC-MS of p-benzyltriphenylmethane (8).

127

Figure A.19– 1H NMR of p-benzyltriphenylmethane (8).

128

Figure A.20– 13C NMR of p-benzyltriphenylmethane (8).

129

Figure A.21 – Close-up of 13C NMR of p-benzyltriphenylmethane (8).

130

Figure A.22 – GC-MS of 1,2- or 1,4-dibenzylbenze (11 and 12).

131

Figure A.23 – GC-MS of 1,2- or 1,4-dibenzylbenzene (11 and 12).

132

Figure A.24 – 1H NMR of 1,2-dibenzylbenzene and 1,4-dibenzylbenzene (11 and 12).

133

Figure A.25 – Close-up of the 1H NMR of 1,2-dibenzylbenzene and 1,4- dibenzylbenzene (11 and 12).

134

Figure A.26 – 13C NMR of 1,2-dibenzylbenzene and 1,4-dibenzylbenzene (11 and 12).

135

Figure A.27 – Close-up of the 13C NMR of 1,2-dibenzylbenzene and 1,4- dibenzylbenzene (11 and 12).

136 I

Figure A.28 – GC-MS of benzyl iodide (15).

137

Figure A.29 – 1H NMR of benzyl iodide (15).

138

Figure A.30 – Close-up of the 1H NMR of benzyl iodide (15).

139

Figure A.31 – 13C NMR of benzyl iodide (15).

140

Figure A.32 – GC-MS of dibenzyl ether (16).

141

Figure A.33 – 1H NMR of dibenzyl ether (16).

142

Figure A.34 – Close-up of the 1H NMR of dibenzyl ether (16).

143

Figure A.35 – 13C NMR of dibenzyl ether (16).

144