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 wellestablished 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
SN2 depending on a variety of factors.2 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.
i
ii
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-2methylpropane 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 metalchloride 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
and CaF2 can be employed as catalysts.22 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
displacement mechanism” or SN2.27 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 tbutyl 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
carbon, as the carbon’s bond with the leaving group is broken. This SN2 reaction is 2nd
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.
9
Figure 1.2 – Kinetic Energy Diagram of the SN2 Reaction. a
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
the reaction.31-33 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.
11
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 2methoxy-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.
Solvent
b.p.
ρ20
ε
a
RD
nD2O
μ
3.7
1.333
1.85
1.3714
1.41
(°C)
Polar Protic Solvent
Water
100
80.1
0.998
Formic acid
101
58
1.22
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
refraction (RD), refractive index at 20°C (nD2O), 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
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
(HMPA)
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
Winstein’s model of the SN1 reaction mechanism for solvolysis.42-44 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
reactants, as seen in the SN2 transition state.30
16
first TS
second TS
Energy
=/
ΔG1
=/
ΔG2
intermediate
reactants
ΔG0
products
Reaction Progress
Figure 1.4 – Kinetic Energy Diagram of the SN1 Reaction. a
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 nonnucleophilic; 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.
S-N (acid-base complex) + X (base)
N (base) + S-X (acid-base complex)
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
Acids
+
Borderline
Bases
+
+
-
Acids
-
+2
Bases
+2
Br-, I-, H-, R-,
Zn+2, C6H5+,
SO3-2, N3-,
Pd+2, Pt+2,
CO, RS-,
NO+, SO2
C6H5NH2
Cu+, M0
C6H6, RNC,
(metal
CH3-, PR3
Li+, R3C+,
H2O,
HX (H-
CH3COO-,
bonding
NO3-, ROH
-
+
Bases
Cs , Hg ,
F , NH3, OH , Fe , Cu ,
-
Acids
Cl , NO2 ,
Na , K , H ,
+
atoms),
molecules),
+4
Soft
+6
CH3+, BH3
SN , Cr ,
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 ORwill 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 HardSoft 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
atom of lower electronegativity.”50 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
toward either SN1 or SN2 character depending upon the nucleophile’s counterion.50 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+ BrNa+ NO2- + BrR Æ R-NO2 + Na+ BrScheme 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
carbocation, or SN1, character.50 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
> OH- > N3- > Br- > Cl- > CH3COO- > H2O.51 This ranking is similar to that given by
Pearson and Edwards: RS- > ArS- > I- > CN- > OH- > N3- > Br- > ArO- > Cl- > pyridine >
AcO- > H2O.34 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.
RCl
NaI
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 nonsolvolytic 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 pbromobenzyl 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 metalhalogen 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
unseen by addition of LiClO4 and carbanion traps.59, 60
6
M
Y1
5
4
X
+ M-Y
X
Y
2
+
3
A
M-X
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.
28
Figure 2.3 – Concerted transition state for the solvent-free alkali metalcarbon 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 1,1,2,2tetraphenylethane (4), the dimer. The formation of the dimer has been reported by
Finkelstein where homocoupling of dichlorodiphenylmethane gives the 1,2dichlorotetraphenylethane 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.
29
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% 1,1,2,2tetraphenylethane (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 1,1,2,2tetraphenylethane (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
substitution. This is in sharp contrast to the results of the SN2 reactions in the ball mill1 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 1,1,2,2tetraphenylethane (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
Other
Br
6
1.
5
16
12.4
38.6
36.4
12
2.
1
16
2.4
38
37
15
16
68.4
3.4
3.5
18
3.
10 mol %
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 conditions a (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 1,1,2,2tetraphenylethane (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.
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.
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 1,1,2,2tetraphenylethane (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 iodosubstitution 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.
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.
37
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.
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.
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
conditions a 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.
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.
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 1,1,2,2tetraphenylethane (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
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.
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 conditions a 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
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.
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
Br
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 sodiumhalogen 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.
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.
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
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.
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 shortchain 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
mixture using GC-MS. Water is more nucleophilic than D2O68 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 6membered 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).
50
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 fourmembered 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.
52
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 pbromobenzyl bromide (1), benzyl chloride, benzyl iodide (15), n-chlorobutane, and nbromobutane 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 conditions a 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 pbenzyltriphenylmethane (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 nchlorobutane 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
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.
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 nchlorobutane, and chlorodiphenylmethane (7) with benzyl chloride, and n-bromobutane,
all in the presence of sodium iodide. The only significant difference seen between these
reactions and those under standard conditions a 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,
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.
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 cocrystallization resulted in a slush containing the reactants and a small amount of 1,1,2,2tetraphenylethane (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% pbromobenzyl bromide (1) while the co-crystallized starting material was reacted
completely. The most significant change in product formation for the reaction with cocrystallized reactants was a 3-fold increase in the SN2 product, p-bromobenzyl iodide (2).
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.
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).
57
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).
58
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 pbenzyltriphenylmethane (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.
60
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 metalhalogen 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% pbenzyltriphenylmethane (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-
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.
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 solventfree 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
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.
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% [10965-9], 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 deionized 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% 1,1,2,2tetraphenylethane (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% pbenzyltriphenylmethane (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% 1,1,2,2tetraphenylethane (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).
70
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
COSY. 1H NMR (CDCl3) δ: 7.40-6.72 (m, 20H), 5.55-5.48 (s, 1H), 3.98-3.91 (s, 2H). 13C
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.
71
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. 205208°C, 100% purity, mass= 68.0 mg, was obtained and characterized as 1,1,2,2tetraphenylethane (4) [632-50-8] (yield= 4.24%) by GC-MS, 1H-NMR, and 13C-NMR. 1H
NMR (CDCl3) δ: 7.21-7.05 (m, 16H), 7.03-6.93 (m, 4H), 4.79-4.72 (s, 2H). 13C 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
(CDCl3) δ: 7.44-7.17 (m, 20H), 5.44-5.33 (s, 2H). 13C 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]
(yield= 22.8%) by GC-MS, 1H-NMR, and 13C-NMR. 1H NMR (CDCl3) δ: 7.44-7.17 (m,
20H), 5.44-5.33 (s, 2H). 13C NMR (CDCl3): 142.20, 128.39, 127.45, 127.28, 79.98. GCMS: 281, 183, 166, 17, 169, 152, 105, 77, 51.
KI
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.
77
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.
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).
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)
[632-50-8] (corrected yield= 8.5%) by GC-MS, 1H-NMR, and 13C-NMR. 1H NMR (CDCl3)
δ: 7.21-7.05 (m, 16H), 7.03-6.93 (m, 4H), 4.79-4.72 (s, 2H). 13C 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.
79
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,
and COSY. 1H 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% pbenzyltriphenylmethane (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.
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).
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.
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).
84
KF
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).
85
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.
KI
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 offwhite 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% pbromobenzyl 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) [101-815] (yield= 15.5%) by GC-MS, 1H-NMR, 13C-NMR. 1H NMR (CDCl3) δ: 7.32-7.21 (m, 4H),
7.20-7.04 (m, 6H), 4.02-3.95 (s, 2H). 13C 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)
[793-23-7] by GC-MS, 1H-NMR, 13C-NMR, DEPT, HMQC, and COSY. 1H 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
(s, 4H). 13C 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.
KI
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)
[632-50-8] (yield= 1.2%) by GC-MS, 1H-NMR, and 13C-NMR. 1H NMR (CDCl3) δ: 7.217.05 (m, 16H), 7.03-6.93 (m, 4H), 4.79-4.72 (s, 2H). 13C 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).
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.
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 GCMS analysis show it contains 1,1,2,2-tetraphenylethane (4) and bis(diphenylmethyl)ether
(5). No further separation was attempted.
KF
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 1,1,2,2tetraphenylethane (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.
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).
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.
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).
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.
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).
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
C-NMR. 1H NMR (CDCl3) δ: 7.43-7.21 (m, 10H), 4.60-4,50 (s, 4H). 13C 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 backextracted 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) [62005-3] (yield= 89.7%) by GC-MS, 1H-NMR, 13C-NMR. 1H NMR (CDCl3) δ: 7.41-7.31 (m,
2H), 7.30-7.18 (m, 3H), 4.49-4.41 (s, 2H). 13C 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 1,4dibenzylbenzene (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 1,4dibenzylbenzene (11 and 12).
136
I
Figure A.28 – GC-MS of benzyl iodide (15).
137
I
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