PHASE-VANISHING REACTIONS WITH PTFE (TEFLON) AS A PHASE SCREEN
by
Nathan J. Van Zee
A Thesis Submitted to the Faculty of
The Wilkes Honors College
in Partial Fulfillment of the Requirements for the Degree of
Bachelor of Arts in Liberal Arts and Sciences
with a Concentration in Chemistry
Wilkes Honors College of
Florida Atlantic University
Jupiter, FL
May, 2010
PHASE-VANISHING REACTIONS WITH PTFE (TEFLON) AS A PHASE SCREEN
by
Nathan J. Van Zee
This thesis was prepared under the direction of the candidate’s thesis advisor, Dr. Veljko
Dragojlovic, and has been approved by the members of his supervisory committee. It was
submitted to the faculty of The Honors College and was accepted in partial fulfillment of
the requirements for the degree of Bachelor of Arts in Liberal Arts and Sciences.
SUPERVISORY COMMITTEE:
____________________________ Dr. Veljko Dragojlovic
____________________________ Dr. Eugene Smith
____________________________ Dean, Wilkes Honors College
____________ Date
ii
ACKNOWLEDGEMENTS
I would like to thank the Department of Chemistry at Florida Atlantic University
for allowing us to use their 400 mHz NMR. I would also like to thank Salvatore Lepore,
Department of Chemistry, Florida Atlantic University, for helpful discussions and Nicole
Windmon from the Department of Chemistry, Florida Atlantic University, for recording
NMR spectra. Partial financial support from the Wilkes Honors College of Florida
Atlantic University is also gratefully acknowledged.
iii
ABSTRACT
Author:
Nathan J. Van Zee
Title:
Phase-Vanishing Reactions with PTFE (Teflon) as a Phase Screen
Institution:
Wilkes Honors College of Florida Atlantic University
Thesis Advisor:
Dr. Veljko Dragojlovic
Degree:
Bachelor of Arts in Liberal Arts and Sciences
Concentration:
Chemistry
Year:
2010
Phase-vanishing reactions are triphasic reactions that involve a reagent, a liquid
perfluoroalkane, and a substrate. In a phase-vanishing reaction with PTFE
(polytetrafluoroethylene) tape as the phase screen instead of a liquid perfluoroalkane,
there is no limitation related to the density of a phase, and the denser phase can be in the
top layer. Additionally, PTFE tape is inexpensive, easy to use, and reusable. In this work
we qualitatively described PTFE tape’s thickness, stretching characteristics, and
permeability. We investigated the phase-vanishing PTFE method’s usefulness both in
known transformations and also in a novel nucleophile-assisting leaving group (NALG)
reaction with menthol, thionyl bromide, and zirconium(IV) chloride. We successfully
used PTFE tape as a phase screen in bromination, bromolactonization, esterification,
chemiluminescence, and tandem bromination/esterification phase-vanishing reactions.
We found that the PTFE tape is an effective phase screen and useful in performing a slow
addition of a reagent.
iv
TABLE OF CONTENTS
LIST OF TABLES..............................................................................................................vi
LIST OF FIGURES...........................................................................................................vii
INTRODUCTION...............................................................................................................1
Fluorous Chemistry......................................................................................1
Phase-Vanishing Reactions..........................................................................2
Need for Phase-Vanishing Reactions with PTFE as a Phase Screen...........3
MATERIALS AND METHODS.........................................................................................5
Chemicals and Supplies...............................................................................5
Physical Characterization of PTFE Tape Setup...........................................6
Phase-Vanishing Reaction Setup.................................................................7
Experimental Procedures.............................................................................8
Instrumentation..........................................................................................13
RESULTS AND DISCUSSION........................................................................................13
Physical Characterization of PTFE Tape...................................................13
Application of the PV-PTFE Method to Known Transformations............15
Application of the PV-PTFE Method to a Novel NucleophileAssisting Leaving Group Reaction............................................................23
CONCLUSION..................................................................................................................26
REFERENCES..................................................................................................................28
APPENDIX........................................................................................................................30
v
LIST OF TABLES
Table 1. Yields and Mechanism of bromination and bromolactonization of 4-pentenoic
acid.........................................................................................................................16
Table 2. Bromination of cyclohexene to produce trans-1,2-dibromocyclohexane and 3bromocyclohexene.................................................................................................18
Table 3. NALG substitution of menthol to produce menthyl and neomenthyl chloride...25
vi
LIST OF FIGURES
Figure 1. Triphasic phase-vanishing reaction.....................................................................2
Figure 2. PTFE tape used in PV reactions..........................................................................5
Figure 3. a) Experimental design to measure thickness of PTFE tape. b) Expelling air
from between layers of PTFE..................................................................................6
Figure 4. a) Direction of PTFE tape definition. b) Experimental design to test stretching
of Taega Technologies PTFE tape...........................................................................7
Figure 5. a) Delivery tubes used in PV-PTFE reactions. b) PTFE tape can be secured
onto the delivery tube with an O-ring......................................................................8
Figure 6. Phase-vanishing reaction setups. a) Triphasic PV-PTFE bromination setup.
b) Tandem PV-PTFE bromination/transesterification setup. c) Tetraphasic
bromination of 4-pentenoic acid..............................................................................8
Figure 7. Stretching of PTFE tape a) lengthwise and b) widthwise................................14
Figure 8. Diffusion of a) titanium(IV) chloride, b) oxalyl chloride, c-d) bromine, and e)
phtalates through a single layer Taega Technologies PTFE tape..........................14
Figure 9. Mechanism and yields of bromination and bromolactonization of 3-butenoic
acid.........................................................................................................................17
Figure 10. Bromination of phenol to produce tribromophenol and 2,4-dibromophenol..19
Figure 11. Temperature change in the course of a bromination of phenol in water by a
direct addition, PV reaction with one (1) and two (2) layers of PTFE..................20
Figure 12. Tetraphasic bromination of phenol (bromine/PTFE/aqueous solution of
phenol/FC-72). The photograph depicts a completed reaction with the solid
product in the aqueous phase and impurities at the bottom...................................21
vii
Figure 13. Esterification of (-)-menthol with oxalyl chloride (top) and propionyl chloride
(bottom) to produce dimenthyl oxalate and menthyl propionate, respectively.....21
Figure 14. Photograph and scheme of the tandem bromination/esterification of 4pentenoic acid to produce ethyl 4,5-dibromopentanoate.......................................22
Figure 15. Starting and stopping of PV-PTFE chemiluminescence reaction...................23
Figure 16. NALG substiution of menthol with large sulfonyl leaving groups and
titanium(IV) chloride.............................................................................................24
Figure 17. Proposed mechanisms for the NALG substitution of menthol to produce
menthyl chloride....................................................................................................26
Figure 18. 1H NMR spectrum of 5-(bromomethyl)-dihydrofuran-2(3H)-one (2)............30
Figure 19. 13C NMR spectrum of 5-(bromomethyl)-dihydrofuran-2(3H)-one (2)...........30
Figure 20. MS of 5-(bromomethyl)-dihydrofuran-2(3H)-one (2).....................................31
Figure 21. 1H NMR spectrum of 4,5-dibromopentanoic acid (3).....................................31
Figure 22. MS of 4,5-dibromopentanoic acid (3).............................................................32
Figure 23. 1H NMR spectrum of 3,4-dibromobutanoic acid (5).......................................32
Figure 24. MS of 3,4-dibromobutanoic acid (5)...............................................................33
Figure 25. 1H NMR spectrum of 5-bromodihydrofuran-2(3H)-one (6)............................33
Figure 26. MS of 5-bromodihydrofuran-2(3H)-one (6)....................................................34
Figure 27. 1H NMR spectrum of trans-1,2-dibromocyclohexane (9)...............................34
Figure 28. MS of trans-1,2-dibromocyclohexane (9).......................................................35
Figure 29. 1H NMR spectra of 2,4,6-tribromophenol (12) and
2,4-dibromophenol (13).........................................................................................35
Figure 30. MS of 2,4,6-tribromophenol (12)....................................................................36
viii
Figure 31. MS of 2,4-dibromophenol (13)........................................................................36
Figure 32. 1H NMR spectrum of dimenthyl oxalate (15).................................................37
Figure 33. MS of dimenthyl oxalate (15)..........................................................................37
Figure 34. 1H NMR spectrum of menthyl propionate (16)...............................................38
Figure 35. 13C NMR spectrum of menthyl propionate (16)..............................................39
Figure 36. MS of menthyl propionate (16).......................................................................39
Figure 37. 1H NMR spectrum of ethyl 4,5-dibromopentanoate (17)................................39
Figure 38. 13C NMR spectrum of ethyl 4,5-dibromopentanoate (17)...............................40
Figure 39. MS of ethyl 4,5-dibromopentanoate (17)........................................................40
Figure 40. MS of menthyl chloride (17)...........................................................................41
Figure 41. MS of neomenthyl chloride (18).....................................................................42
ix
INTRODUCTION
Fluorous Chemistry
Phase-vanishing (PV) reactions that utilize fluorous phase screens have emerged
in the past ten years as an exciting new method in fluorous chemistry.1 Fluorous methods
take advantage of fluorous media’s inertness and nonpolar nature, which causes them to
be immiscible in organic solvents. Early research was dedicated to controlling the
solubility of compounds in fluorous solvents by taking advantage of the “like dissolves
like” principle. Phase-vanishing reactions do not operate on this principle. They instead
utilize fluorous solvents as a diffusion-controlled mechanism for the slow addition of a
reagent. The subject of this work – PV reactions with PTFE (polytetrafluoroethylene,
Tefon™) tape – does away with liquid fluorous media altogether.
Fluorous chemistry originates in Horváth and Rábai’s 1994 work on fluorous
biphasic systems.2 Their research began “heavy” fluorous chemistry; it involved
attaching fluorous “ponytails” (fluoroalkyl chains typically with 39 or more fluorines)3 to
substrates and catalysts to make them more soluble in fluorous solvents. In 2001,
Nakamura, Linclau, and Curran introduced a related heavy fluorous method called
fluorous triphasic reactions.4 The authors used a U-tube to hold a bottom fluorous phase.
On one side of the U-tube, they overlaid the fluorous phase with an organic reactant that
was tagged with a fluorous ponytail. On the other side, he overlaid the fluorous phase
with a product phase. Compounds with fluorous tags traveled from the reactant phase
through the fluorous phase to the product phase, where they were detagged. Residual
fluorous material in the product phase migrated to the fluorous phase, which resulted in
1
an auto-purifying process. Further developments of heavy fluorous chemistry include
liquid-liquid biphasic and triphasic extractions, thermomorphic reactions, and others.5
Phase-Vanishing Reactions
Phase-vanishing (PV) reactions, introduced by Ryu and Curran in 2002, are an
extension of Curran’s fluorous triphasic reactions.6 While fluorous triphasic reactions
were based on controlling the partition coefficient of a reagent based on its fluorine
content, PV reactions were designed to take advantage of fluorous media’s ability to act
as a “phase screen,” a liquid diffusion-controlled membrane. Because fluorous solvents
are more dense than most organic solvents and less dense than some common reagents,
fluorous media can be used as a convenient middle phase in a triphasic setup.
Figure 1. Triphasic phase-vanishing reaction.
In the PV bromination of an alkene, bromine is the bottom phase, a fluorous
solvent is the middle phase, and an alkene in an organic solvent is the top phase (Figure
1). The bromine diffuses slowly through the middle fluorous phase and reacts with the
top phase (Figure 1b), resulting in the bromine phase “vanishing” (Figure 1c). The
fluorous phase serves as a mechanism for the passive addition of a reagent.
2
The PV method has been applied to a range of different transformations. Iskra
reported the photochemical free-radical addition of bromine to neat alkenes and
aromatics.7,8 Dragojlovic has reported triphasic PV aromatization, isomerization,
halogenation, halolactonization, and tandem Diels-Alder/halogenation under solvent-free
conditions.9,10 Verkade reported a triphasic PV method to carry out the epoxidation of
alkenes with a solvent more dense than the fluorous phase.11 Interestingly, the top phase
in these reactions vanished. Curran demonstrated that Verkade’s method operates on an
extractive mechanism.12 Ryu introduced a tetraphasic design in which water was added as
a fourth “acid scavenger” phase to carry out the bromination of ketones.13 He also
devised a tetraphasic PV method to carry out water-sensitive reactions such as Grignard
reactions.14 Finally, Ryu reported an in situ addition of bromine to alkenes and alkanes in
a tetraphasic PV photochemical reaction.15
While most research groups have used either a vial or flask as a reaction vessel,
other groups have investigated the use of alternative reaction vessels in a variety of PV
reactions. With an experimental design similar to the one used in fluorous triphasic
reactions, Nakamura conducted PV reactions in a U-tube with reagents that were less
dense than the fluorous phase.16 Iskra described the use of a U-tube in a PV reaction with
a gas as the vanishing phase.17 Lastly, Weiss described the use of a “stacked reactor” (test
tube with a side arm) in a tetraphasic PV design. He utilized the compound
tridecylmethylphosphonium tribromide to sequentially add bromine to several alkenes.18
Need for Phase-Vanishing Reactions with PTFE as a Phase Screen
Phase-vanishing reactions with a liquid fluorous phase screen have a number of
advantages over conventional methods. The PV method allows for the slow and
3
controlled delivery of reagents. Thus, exothermic reactions that typically require low
temperatures (-78 to 0 °C) can be carried out both at room temperature and without an
expensive delivery system such as a syringe drive. The PV method also allows for neat
reagents to be used in reactions that would normally be too vigorous without a solvent.
While PV reactions with a liquid phase screen are simple and convenient, they
have a number of disadvantages. Common liquid fluorous solvents such as FC-72 are
expensive. Additionally, FC-72, has a high global warming potential (GWP ~10,000) and
a long atmospheric lifetime (3200 years).19 These PV reactions with liquid phase screens
also have limited applications because of their dependence on density. For example, one
cannot interchange the phases or carry out reactions under reflux.
In line with Ryu and Curran’s use of heavier perfluoro solvents13 and Gladysz’s
use of PTFE tape as a catalyst support,20 we have proposed that the conventional PV
method can be improved by using PTFE tape as a phase screen.21 In a typical setup, the
substrate in an organic solvent is placed in a small reaction vessel, such as a flask or test
tube. The reagent is placed in a delivery tube, such as an inverted pipet, which is sealed
on both ends with PTFE tape. This tube is then inserted into the reaction vessel so that
both reactants are in contact with the PTFE tape. The reaction proceeds as the reagent
slowly passes through the PTFE tape barrier.
PTFE tape presents a number of immediate advantages over liquid fluorous
solvents. PTFE tape is easier to obtain, less expensive, and simpler to use than liquid
fluorous media. PTFE tape is also more environmentally friendly, as it can be easily
recovered and reused. Furthermore, the use of PTFE tape allows for reagents to be easily
4
interchanged because there is no density dependence; the PTFE tape barrier allows for a
more dense phase to be the top phase. Reactions can also be carried out under reflux.
In this work we sought to meet three objectives. First, we wanted to qualitatively
describe the thickness, stretching characteristics, and permeability of PTFE tape. Second,
we wanted to evaluate the application of PTFE tape as a phase screen to established
transformations, such as bromination, lactonization, esterification, tandem bromination/
transesterification, and chemiluminescence. Third, we wanted to apply our PTFE method
to a new nucleophile-assisting leaving group (NALG) reaction utilizing thionyl bromide
as a leaving group and zironcium(IV) chloride as a Lewis acid.
MATERIALS AND METHODS
Chemicals and Supplies
Bromine, FC-72, cyclohexene, 4-pentenoic acid, 3-butenoic acid, phenol, (-)menthol, oxalyl chloride, propionyl chloride, aluminum chloride, zirconium(IV) chloride,
titanium(IV) chloride, benzene, sodium sulfate, sodium bicarbonate, sodium carbonate,
and magnesium sulfate were obtained from Sigma Aldrich. All solvents
(dichloromethane, ethyl acetate, n-hexane, acetonitrile, ethanol) were purchased through
either Sigma Aldrich or Fisher Scientific. Reagents and solvents were used as purchased.
Figure 2. PTFE tape used in PV reactions.
5
Several kinds of PTFE tape were purchased for this study (Figure 2). Some were
purchased from hardware stores. Their manufacturers did not provide thickness
measuremments. We purchased Taega Technologies’ High Density PTFE tape from
Fisher Scientific (catalog #14-610-121). It can be purchased in 1/2 and 1 inch widths.
According to Taega Technologies’ website, this tape is 0.08-0.09 mm thick.22
Physical Characterization of PTFE Tape Setup
Thickness
To measure the thickness of the PTFE tape purchased hardware stores, ten 3 cm
strips were cut (Figure 3a) and stacked. Air between the layers was expelled with a small
cylindrical weight (Figure 3b). We used calipers to take 6 measurements, three
lengthwise and three widthwise. The reported width is the mean of these measurements.
a)
b)
Figure 3. a) Experimental design to measure thickness of PTFE tape. b) Expelling air
from between layers of PTFE.
Stretching Characteristics
We qualitatively measured how the Taega PTFE tape stretches in the direction of
the tape (Figure 4a, direction A) and perpendicular to it (Figure 4a, direction B). A 1 cm
square was drawn in the center of a 2.5 cm square of the PTFE tape with a black
permanent marker. The top edge (either in the direction of A or B) of the square was
clipped to a metal rod. The bottom was clipped to a glass tube (Figure 4b). Small weights
6
were suspended from the tube. We observed the change in the dimensions of the black
square as weight was added (10 to 220 g).
a)
b)
Figure 4. a) Direction of PTFE tape definition. b) Experimental design to test stretching
of Taega Technologies PTFE tape.
Permeability
We qualitatively determined the permeability of PTFE tape towards several
solvents and reagents. In one experiment, 2 mL of either ethyl acetate, dichloromethane,
hexanes, tetraydrofuran, acetonitrile, or phthalates were placed in a vial, and a small
amount of bromine was placed in a delivery tube sealed with PTFE tape. In a second
experiment, 0.2 mL of either bromine, oxalyl chloride, or titanium(IV) chloride was
placed in a delivery tube sealed with PTFE tape. The tube was then placed above a flask.
PTFE Phase-Vanishing Reaction Setup
In a PV-PTFE reaction, the substrate in a solvent was placed in a reaction vessel
such as a vial, test tube, or flask. The reagent was placed in a delivery tube sealed on one
end with PTFE tape. A number of different delivery tubes were used (Figure 5a); we
found simple Pasteur pipets to be the easiest to work with. The other end of the tube was
sealed either with PTFE tape or a stopper. The PTFE tape can be secured with an O-ring
(Figure 5b). To start the reaction, one end of the delivery tube was immersed in the
reaction vessel. The substrate and reagent phases were in contact with the PTFE tape.
7
a)
b)
Figure 5. a) Delivery tubes used in PV-PTFE reactions. b) PTFE tape can be secured
onto the delivery tube with an O-ring.
The basic triphasic setup (Figure 6a) was modified to accommodate several
different kinds of reactions, including a tandem triphasic bromination/transesterification
reaction under reflux (Figure 6b) and a tetraphasic reaction (Figure 6c). This setup is also
suitable to carry out reactions with either an ice bath or an acetone/dry ice bath.
Figure 6. Phase-vanishing reaction setups. a) Triphasic PV-PTFE bromination setup. b)
Tandem PV-PTFE bromination/transesterification setup. c) Tetraphasic bromination of 4pentenoic acid.
Experimental Procedures
Bromination and Bromolactonization of 4-Pentenoic Acid
Four different kinds of reactions were performed with 4-pentenoic acid. In the
first, a tetraphasic reaction design was employed. A stirring bar, 4-pentenoic acid (2.0
mmol) and dichloromethane (2.0 mL) were placed into a 20 mL vial. A PTFE-sealed tube
8
with bromine (2.3 mmol) was inserted into the dichloromethane solution. The substrate
was overlaid with 1 mL of saturated aqueous sodium bicarbonate. The reaction time was
5 minutes. The layers were separated and the aqueous layer was extracted with
dichloromethane. Dichloromethane extracts were combined, extracted with saturated
aqueous sodium bicarbonate and dried with anhydrous magnesium sulfate.
In the second reaction type, 4-pentenoic acid (2.0 mmol) was added to a
suspension of sodium carbonate (0.120 g) in acetonitrile (2.0 mL) in a 10-mL round
bottom flask. The suspension was stirred for 15 minutes. A PTFE-sealed tube with
bromine (2.4 mmol) was then inserted into the solution. The reaction time was 1 hour.
The product was partitioned between water and dichloromethane. The aqueous layer was
extracted with dichloromethane. The extracts were combined, rinsed with aqueous
sodium bicarbonate, and dried.
The third type of reaction was carried out under reflux. A stirring bar, 4-pentenoic
acid (2.0 mmol) and ethyl acetate (5.0 mL) were placed in a two-neck 25-mL round
bottom flask. After heating the solution to reflux, a PTFE (2 layers)-sealed tube with
bromine (2.4 mmol) was inserted into the flask. The reaction time was 15 minutes. Ethyl
acetate was evaporated under a reduced pressure and the residue was purified by means
of preparative radial chromatography (4:1 hexanes/ethyl acetate).
In the fourth and final reaction setup, a basic triphasic reaction design was
employed. A stirring bar, 4-pentenoic acid (2.0 mmol) and dichloromethane (2.0 mL)
were placed into a 4-mL vial. A PTFE-sealed tube filled with 2.2 mmol of bromine was
inserted into the solution. The reaction time was 5 minutes.
9
Bromination and Bromolactonization of 3-Butenoic Acid
Two different types of reactions were performed on 3-butenoic acid. In the first, a
stirring bar, 3-butenoic acid (2.0 mmol) and dichloromethane (2.0 mL) were placed into a
4-mL vial. A PTFE-sealed tube with bromine (2.4 mmol) was inserted into the solution.
The reaction time was 5 minutes.
In the second reaction type, a tetraphasic reaction design was employed. A stirring
bar, 3-butenoic acid (2.0 mmol), and dichloromethane (2 mL) were placed into a 20-mL
vial. A PTFE-sealed tube with bromine (2.2 mmol) was inserted into the substrate. The
substrate was overlaid with 1.0 mL of a saturated sodium bicarbonate solution. The
reaction time was 5 minutes. The layers were separated and the aqueous layer was
extracted with dichloromethane. The dichloromethane extracts were combined, extracted
with saturated aqueous sodium bicarbonate, and dried with anhydrous magnesium sulfate.
Bromination of Cyclohexene
The bromination of cyclohexene was carried out with a basic triphasic reaction
setup with two different solvents. A stirring bar, cyclohexene (2.0 mmol) and either
dichloromethane or ethyl acetate (2.0 mL) were placed in a 4-mL brown vial. A PTFEsealed tube with bromine (2.2 mmol) was inserted into the solution. The reaction time
was 5 minutes with dichlormethane and 10 minutes with ethyl acetate.
Bromination of Phenol
Three different reaction types were performed on phenol. In the first, a stirring
bar, phenol (2.0 mmol) and water (2.0 mL) were placed into a 10-mL round bottom flask.
A PTFE-sealed tube with bromine (6.4 mmol) was inserted into the flask. Bromine was
10
consumed rapidly. The reaction time was 10 minutes. The solution was then stirred 20
minutes. The white solid precipitate was filtered and rinsed with a small amount of water.
In the second, a stirring bar, FC-72 (2.0 mL), and a solution of phenol (2.0 mmol)
in water (2.0 mL) were placed into a 10 mL test tube. A PTFE-sealed tube filled with 6.4
mmol of bromine was inserted into the aqueous layer. The reaction time was 3 hours. The
white precipitate was filtered and rinsed with a small amount of water.
In the third, a stirring bar, phenol (1.0 mmol) and dichloromethane (2.0 mL) were
placed in a 4-mL vial. A PTFE-sealed tube with bromine (3.0 mmol) was inserted into
the flask. The reaction time was 1 hour. The solution was rinsed with aqueous sodium
bisulfate. Dichloromethane was then removed under a reduced pressure. The residue was
purified by means of preparative radial chromatography (4:1 hexanes/ethyl acetate).
Esterification of Menthol
Two esterification reactions were performed with menthol, one with oxalyl
chloride and the other with propionyl chloride. In the first, a stirring bar, menthol (4.0
mmol) and dichloromethane (4.0 mL) were placed into a 10-mL round bottom flask. A
PTFE-sealed tube with a solution of oxalyl chloride (2.3 mmol) in dichloromethane (0.2
mL) was inserted into the flask. The reaction time was 10 minutes. The solution was
stirred for an additional hour. The solution was rinsed with a small amount of water and
then dried with anhydrous magnesium sulfate.
In the second reaction setup, a stirring bar, menthol (2.0 mmol), and
dichloromethane (2.0 mL) were placed in a 4-mL vial. A PTFE-sealed tube filled with
propionyl chloride (2.3 mmol) was inserted into the flask. The reaction time was about 10
minutes. The solution was then stirred for an additional 30 minutes.
11
Tandem Bromination/Esterification of 4-Pentenoic Acid
A stirring bar, 4-pentenoic acid (2.0 mmol), and ethanol (5.0 mL) were placed in a
two-neck 25-mL round bottom flask. After heating the solution to reflux, a PTFE (2
layers with an O-ring)-sealed tube with bromine (2.4 mmol) was inserted into the flask.
The reaction time was 15 minutes. After evaporating the solvent, the residue was
chromatographed (Harrison Chromatotron, eluting with 4:1 hexanes/ethyl acetate).
Chemiluminescence
One chemiluminescence reaction was performed. The hydrogen peroxide and
colored solutions of a yellow glow stick (Ozark TrailsTM) were separated into two amber
vials for storage. An 2 mL aliquot of the colored solution was placed in a 4-mL vial. A 1
mL aliquot of the hydrogen peroxide solution was placed in a PTFE-sealed tube and
inserted into the vial. We also performed the reaction with the phases interchanged.
Nucleophile-Assisting Leaving Group Reactions (NALG) with Menthol
In this reaction, a stir bar, menthol (2.0 mmol), zirconium(IV) chloride (2 mmol),
and either dichloromethane or a solution of 1:2 acetonitrile:dichloromethane (6 mL) were
placed in a 10-mL round bottom flask. The reaction was conducted at either room
temperature, 0 °C or -78 °C. A PTFE-sealed tube with thionyl bromide (2.2 mmol) was
inserted into the flask. The reaction was allowed to proceed until the solution obtained a
uniform color. The reaction time at room temperature and 0 °C was either 2 hours or
overnight. The reaction time at -78 °C was 4 hours. The solution was then quenched with
water and extracted with saturated sodium bicarbonate and brine. Extracts were passed
through florosil (2 g) and dried with anhydrous magnesium sulfate.
12
Instrumentation
The thickness of PTFE tape was measured with a Vernier caliper.
Chromatographic separations were performed by means of either column or preparative
radial thin layer chromatography (Harrison Chromatotron). GC/MS analyses were
conducted with an Agilent 6890N Gas Chromatograph equipped with an HP-5 MS 30 m
x 0.25 mm column and an Agilent 5973N MSD. 1H NMR spectra were recorded on a 400
MHz spectrometer in CDCl3. Temperature measurements were recorded using a Vernier
Stainless-Steel Temperature Probe and a Texas Instruments TI-83 calculator by means of
the Vernier LabProTM interface.
RESULTS AND DISCUSSION
Physical Characterization of PTFE tape
We determined the thickness of PTFE tape purchased from hardware stores to be
either 0.05 or 0.06 mm. The difference in their performance was significant. The thinner
tape (0.05 mm) was not suitable for any of the reactions we investigated, while the
slightly thicker tape (0.06 mm) could be used with less vigorous reagents, such as oxalyl
chloride in dichloromethane. We found the Taega PTFE tape to be the best suited for PVPTFE reactions. Our measurements indicated a thickness of 0.11 mm (compared to the
manufacturer’s specification of 0.08-0.09 mm).
13
a)
b)
Figure 7. Stretching of PTFE tape a) lengthwise and b) widthwise.
Since we used the Taega PTFE tape the most, we conducted an additional
experiment to determine its stretching capability. The tape demonstrated different
mechanical properties depending on which way it was stretched. When force was applied
lengthwise (Direction A, Figure 4a), the tape did not stretch appreciably even when
subjected to a considerable force (220 g, Figure 7a). However, when stretched widthwise
(Direction B, Figure 4b), the tape exhibited significant stretching when subjected to a
small force (10 g, Figure 7b).
a)
b)
c)
d)
e)
Figure 8. Diffusion of a) titanium(IV) chloride, b) oxalyl chloride, c-d) bromine, and e)
phtalates through a single layer Taega Technologies PTFE tape.
14
The permeability of the Taega PTFE tape depended on the solvent and the
reagent. Ethyl acetate, dichloromethane, acetonitrile, and tetrahydrofuran proved to be
very permeable. Water was only moderately permeable. Hexanes and phthalates were not
permeable.
As for reagents, PTFE tape did not present a barrier at all for titanium(IV)
chloride (Figure 8a). We also found that oxalyl chloride rapidly passed through the PTFE
screen; the color of the litmus paper in Figure 8b indicates the presence of HCl, which is
evolved when oxalyl chloride is hydrolyzed. Bromine, however, passed through the phase
screen at a moderate rate when suspended in an empty reaction vessel. The presence of
bromine could be observed immediately after setting the delivery tube in the vial (Figure
8c). It took some time for the level in the tube to drop (~30 minutes, Figure d). This
feature has been exploited in the development of solvent-free PV-PTFE reactions.23
Bromine diffused faster when the vapors were expelled with a stream of nitrogen. The
rate of diffusion was also increased when the phase screen was in contact with a solvent.
Application of the PV-PTFE Method to Known Transformations
The PV-PTFE reaction between 4-pentenoic acid (1) and bromine resulted in the
selective production of either the bromolactone (2, Table 1, entries 1-3) or the
dibromoacid (3, Table 1, entry 4). These results are significantly better than those
obtained by conventional methods (both with dichloromethane and solvent free) and
phase-vanishing methods with FC-72 as a phase screen.10
15
Table 1. Yields and Mechanism of bromination and bromolactonization of 4-pentenoic
acid. Note that cyclization could also occur during the bromonium intermediate.
Entry
Conditions
2(%)a
3(%)a
1
Br2/PTFE/CH2Cl2/NaHCO3 (aq.), rt, 5 min
82
4
2
Br2/PTFE/EtOAc, reflux, 15 min
72
9
3
Br2/PTFE/CH3CN/Na2CO3 (s), rt, 15 min
74
b
4
a
c
Br2/PTFE/CH2Cl2/ rt, 5 min
0
b
94
c
Isolated yields. Some 3 was observed but not isolated GC-MS analysis.
The best yield and highest purity of the bromolactone 2 (Table 1, entry 1) was
obtained when a delivery tube with bromine was inserted into a solution of 4-pentenoic
acid in dichloromethane, which was overlaid with aqueous sodium bicarbonate in a
modification of Ryu’s tetraphasic procedure (Figure 6c).13 Alternatively, a reaction in
ethyl acetate under reflux provided the bromolactone 2 in good yield (72%) with a small
amount of the dibromoacid 3 (9%, Table 1, entry 2). Finally, the bromolactone was also
produced in good yield in the PV-PTFE bromolactonization of sodium 4-pentenoate in
acetonitrile and sodium carbonate (Table 1, entry 3). Both 1H NMR and EI-MS
characterization of these compounds are provided in the appendix (Figures 18-24).
16
Br2/PTFE/CH2Cl2/ rt, 5 min
83%a
0%b
0%b
Br2/PTFE/CH2Cl2/
NaHCO3 (aq.)/ rt, 5 min
47%a
32%a
0%b
a
Isolated yields b GC-MS analysis.
Figure 9. Mechanism and yields of bromination and bromolactonization of 3-butenoic
acid.
The PV-PTFE reaction between 3-butenoic acid (4) and bromine yielded 3,4dibromobutanoic acid (5) as the major product (Figure 9). The reaction was completed in
5 minutes at room temperature in dichloromethane. The crude product gave a satisfactory
1
H NMR and MS (Figures 25 and 26). This result is a considerable improvement over the
previous method reported by Kasina et al.24 Their method consisted of slowly adding
bromine to 3-butenoic acid in carbon tetrachloride at 0 °C over 1 hour.
We discovered that the PV-PTFE bromination of 3-butenoic acid shows a
preference for dibromination as opposed to cyclization. This may in part be explained by
Baldwin’s rules for ring closure.25 These rules are based on the stereochemical
requirements for the entering group to displace the leaving group. In this case, both of the
carbons ! and " to the carboxylic group become tetrahedral. As in an SN2 reaction, the
hydroxyl group must approach the carbon at or close to 180° relative to the leaving
group. Thus, the 5-endo cyclization is a disfavored process. Interestingly, we did not
detect any 4-exo product 7, even though it is expected to be favored according to
Baldwin’s rules. The highest yield of the 5-endo product 6 was obtained by conducting a
17
tetraphasic PV-PTFE reaction in dichloromethane with an aqueous bicarbonate phase
(Figure 9).
Table 2. Bromination of cyclohexene to produce trans-1,2-dibromocyclohexane and 3bromocyclohexene.
a
Entry Conditions
9 (%)
10 (%)
1
2
3
70 a
85 a
0b
0b
10 b
0b
Br2/PTFE/CH2Cl2/ rt, 5 min.
Br2/PTFE/EtOAc/ rt, 15 min.
Br2/PTFE/hexanes/ rt, 12 h
Isolated yields b GC-MS analysis.
The bromination of cyclohexene 8 under PV-PTFE conditions worked very well
in dichloromethane to give rather pure trans-1,2-dibromocyclohexane 9 in good yield.
The reaction was completed in about 5 min. In ethyl acetate, the reaction was somewhat
slower, and formation of trans-1,2-dibromocyclohexane was accompanied by a small
amount of 3-bromocyclohexene 10 (<10% by GC/MS; Table 2, entry 2). The reaction
failed in hexanes (Table 2, entry 3). Both 1H NMR and MS spectra are provided in the
appendix (Figures 27 and 28). Please note that the bromination of cyclohexene has been
reported in good yields under traditional PV conditions.6,9,18
18
Br2/PTFE/H2O/FC-72/ rt, 3 h
Br2/PTFE/CH2Cl2/ rt, 1 h
a
12
13
87%a
0%b
0%b
74%a
Isolated yields b GC-MS analysis.
Figure 10. Bromination of phenol to produce tribromophenol and 2,4-dibromophenol.
The PV-PTFE bromination of phenol 11 in water produced the white solid 2,4,6tribromophenol 12. With this reaction, we investigated the effect of using multiple layers
of PTFE tape to the reaction temperature. The direct addition of bromine to a solution of
phenol in water was highly exothermic. A PV-PTFE reaction with a single layer of PTFE
tape as a phase screen was more moderate. When two layers of PTFE tape were used,
there was only a slight, gradual increase in the reaction temperature (Figure 11).
Although the reaction product was isolated in a high yield, it was not pure.
19
Figure 11. Temperature change in the course of a bromination of phenol in water by a
direct addition, PV reaction with one (1) and two (2) layers of PTFE.
We discovered an interesting extension to Curran’s original use of FC-72 in the
PV-PTFE bromination of phenol in water. Curran’s original application of FC-72 in
fluorous triphasic reactions involved the concomitant purification of the organic product
in the course of the reaction.4 We added a fourth FC-72 “purifying” phase to our typical
triphasic PV reaction setup (Figure 12, left). After 3 hours, solid 2,4,6-tribromophenol
formed a crust on the water/FC-72 interface, and additional product deposited on top of
it. At the same time, liquid impurities diffused through FC-72 and collected on the
bottom (Figure 12, right). Both 1H NMR and GC/MS analyses confirmed that the solid
product was pure (Figure 10). This tetraphasic PV-PTFE reaction is a useful alternative to
some recently published methods for bromination of phenols.26,27
20
Figure 12. Tetraphasic bromination of phenol (bromine/PTFE/aqueous solution of
phenol/FC-72). The photograph depicts a completed reaction with the solid product in the
aqueous phase and impurities at the bottom.
We found that the outcome of the PV-PTFE bromination of phenol (11) was
solvent-dependent. While reactions in water gave 2,4,6-tribromophenol, reactions in
dichloromethane gave 2,4-dibromophenol 13 as the major product (74%) even with an
excess (3 equivalents) of bromine (Figure 10). Both NMR and MS spectra are available
for these products in the appendix (Figures 29-31). Please note that the successful
bromination of phenol has been reported under conventional PV conditions.11
Figure 13. Esterification of (-)-menthol with oxalyl chloride (top) and propionyl chloride
(bottom) to produce dimenthyl oxalate and menthyl propionate, respectively.
21
Dimenthyl oxalate 15 and menthyl propionate 16 were prepared in good yields by
addition of the corresponding acyl chloride to a solution of menthol 14 in
dichloromethane (Figure 13). Because the permeability of PTFE tape towards oxalyl
chloride is high, a solution of oxalyl chloride in dichloromethane was placed in the
delivery tube. Upon completion of the addition, the reaction mixture was stirred for
approximately 1 hour at room temperature to ensure that the reaction was complete. Both
1
H NMR and MS spectra are provided in the appendix (Figures 32-36).
One of the major advantages of using PTFE tape instead of a liquid phase screen
is that it allows for a reaction to be carried out under reflux. We demonstrated this in the
PV-PTFE tandem bromination/esterification of 4-pentenoic acid (Figure 14). We
obtained 4,5-dibromopentanoate in 75% yield by GC/MS. Both NMR and MS spectra are
provided in the appendix (Figures 37-39). For comparison, Dragojlovic reported a
tandem PV bromination/transesterification reaction of 4-pentenoic acid in ethyl acetate
with FC-72 as a phase screen that yielded the dibromoester in 41% yield by GC/MS.10
Figure 14. Photograph and scheme of the tandem bromination/esterification of 4pentenoic acid to produce ethyl 4,5-dibromopentanoate.
22
We found that the PV-PTFE method can be utilized to start and stop a reaction at
will. This capability was demonstrated with a chemiluminescence reaction. The
oxalate/sensitizer solution was taken from a yellow glow stick and placed in a vial with
ethyl acetate. A delivery tube with hydrogen peroxide was inserted in the vial for 5
minutes. After the reaction had clearly begun, the tube was removed (Figure 15a). The
PTFE barrier glowed brightly, though the hydrogen peroxide solution in the tube did not
glow; the solution in the vial glowed moderately. After the tube had been removed from
the vial for 1.5 hours, the PTFE barrier had ceased to glow, and the solution in the vial
glowed faintly (Figure 15b). After the tube was reinserted for 5 minutes, the solution
glowed brightly, indicating that the reaction had resumed (Figure 15c). We believe this
phenomenon could be the basis for a new kind of glow stick that can be “turned off” by
means of a PTFE phase barrier.
a)
b)
c)
Figure 15. Starting and stopping of PV-PTFE chemiluminescence reaction.
Application of the PV-PTFE Method to a Novel Nucleophile-Assisting Leaving
Group (NALG) Reaction
Lepore et al. reported retention of stereochemistry in the substitution of alkyl
sulfonates with titanium(IV) chloride and bromide (Figure 16).28 Titanium complexes
23
were used as Lewis acids to decrease the partial negative charge in the leaving group.
They also facilitated the substitution of the leaving group with one of their nucleophilic
ligands. Lepore et al. proposed a concerted SNi mechanism with a six-member ring
intermediate (Figure 17, top). They produced menthyl chloride and bromide with several
menthyl sulfonates and TiCl4 or TiBr4 in dichloromethane at -78 °C.
Figure 16. NALG substiution of menthol with large sulfonyl leaving groups and
titanium(IV) chloride.
Braddock et al. reproduced these reactions with menthyl sulfonates and TiBr4, but
they suggested an alternative mechanism.29 They proposed that this reaction proceeds by
a TiBr4-induced carbocation or ion pair (Figure 17, bottom). They argued that the
conformation of the intermediate menthyl carbocation prevents a back-face attack,
leaving only a front-face, stereoretentive attack.
Both Lepore et al. and Braddock et al. reported good yields and high retention of
stereochemistry in producing menthyl chloride and menthyl bromide. However, their
methods involved the use of TiCl4 and TiBr4, both of which are unstable and
inconvenient to work with. Additionally, their reactions required very low temperatures
(-78 °C). We investigated the use of thionyl bromide as a NALG and zirconium(IV)
24
chloride as a Lewis acid to achieve the one-pot PV transformation of (-)-menthol to
menthyl chloride.
Table 3. NALG substitution of menthol to produce menthyl and neomenthyl chloride.
a
Entry
Conditions
17 (%)a
18 (%)a
1
-78 °C, 1:2 CH3CN:DCM, 4 hrs
NR
NR
2
-78 °C, DCM, 4 hrs
NR
NR
3
0 °C, 1:2 CH3CN:DCM, 2 hrs
5
13
4
0 °C, DCM, 2 hrs
41
27
5
r.t., MeCl2, 2 hrs
57
19
6
r.t., 1 mmol ZrCl4, CH3CN, overnight
3
23
7
r.t., CH3CN, overnight
9
16
GC-MS analysis.
We obtained three important results from these experiments. First, we did not
obtain any menthyl or neomenthyl bromide. Thionyl chloride is commonly used to
substitute hydroxyl groups with chlorides in alcohols. Our method prevented this reaction
from taking place.
Second, we observed the best stereoselectivity (3:1 menthyl chloride to
neomenthyl chloride) at room temperature in dichloromethane with a reaction time of 2
hours (Table 3, entry 5). At -78 °C, we did not observe any reaction, which is in stark
contrast to Lepore et al. and Braddock et al.’s results. We believe this is due to the
difference in reactivity between the Lewis acids. Zirconium(IV) chloride is much less
25
reactive than titanium(IV) chloride, so our reaction with zirconium required a higher
temperature than the titanium reactions to begin.
Figure 17. Proposed mechanisms for the NALG substitution of menthol to produce
menthyl chloride.
Third, we obtained both menthyl chloride 17 and neomenthyl chloride 18. The
MS spectra of each of these compounds is provided in the appendix (Figures 40 and 41).
The outcome of this reaction appeared to depend on the solvent. We obtained menthyl
chloride as the major product with dichloromethane (Table 3, entries 4 and 5) and
neomenthyl chloride with a 1:2 solution of acetonitrile and dichloromethane (Table 3,
entries 3, 6, and 7).
CONCLUSION
Our PV-PTFE method offers several advantages compared to the traditional PV
method. The PTFE phase screen is inexpensive, easy to use, and reusable. It also is
applicable to a wide range of known transformations, including brominations,
lactonizations, esterifications, and chemiluminescence. We think that it is an alternative
26
not only to traditional PV reactions but also to any reaction that involves a slow addition,
as demonstrated by our application to NALG reactions. Because there is no limitation
related to the densities of the reactants, one can conduct tandem or sequential reactions
with ease. One can also exploit this feature to essentially start and stop a reaction at will
by just inserting or removing the delivery tube from the reaction vessel. Finally, reactions
can be performed in the presence of an additional aqueous or fluorous phase to further
control selectivity and improve purity.
We believe that we have discovered only a fraction of PTFE tape’s usefulness as a
phase screen. Further research is necessary to uncover the physcio-chemical aspects of
PTFE tape that allow it to be such an effective phase screen. Future researchers should
also focus on investigating the use of PTFE tape in novel reactions. We believe that this
may be the next frontier for phase-vanishing reactions with PTFE tape as a phase screen.
27
REFERENCES
1.
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5.
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N. Windmon, V. Dragojlovic. Beilstein J. Org. Chem. 2008, 4, No. 29.
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H. Nakamura, T. Usui, H. Kuroda, I. Ryu, H. Matsubara, S. Yasuda, D. P. Curran.
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http://www.taegatech.com/techdata.htm. Accessed on May 24, 2009.
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29
APPENDIX
Figure 18. 1H NMR spectrum of 5-(bromomethyl)-dihydrofuran-2(3H)-one (2).
Figure 19. 13C NMR spectrum of 5-(bromomethyl)-dihydrofuran-2(3H)-one (2).
30
Figure 20. MS of 5-(bromomethyl)-dihydrofuran-2(3H)-one (2).
Figure 21. 1H NMR spectrum of 4,5-dibromopentanoic acid (3).
31
Figure 22. MS of 4,5-dibromopentanoic acid (3).
Figure 23. 1H NMR spectrum of 3,4-dibromobutanoic acid (5).
32
Figure 24. MS of 3,4-dibromobutanoic acid (5).
Figure 25. 1H NMR spectrum of 5-bromodihydrofuran-2(3H)-one (6).
33
Figure 26. MS of 5-bromodihydrofuran-2(3H)-one (6).
34
Figure 27. 1H NMR spectrum of trans-1,2-dibromocyclohexane (9).
Figure 28. MS of trans-1,2-dibromocyclohexane (9).
Figure 29. 1H NMR spectra of 2,4,6-tribromophenol (12) and 2,4-dibromophenol (13).
35
Figure 30. MS of 2,4,6-tribromophenol (12).
Figure 31. MS of 2,4-dibromophenol (13).
36
Figure 32. 1H NMR spectrum of dimenthyl oxalate (15).
37
Figure 33. MS of dimenthyl oxalate (15).
Figure 34. 1H NMR spectrum of menthyl propionate (16).
Figure 35. 13C NMR spectrum of menthyl propionate (16).
38
Figure 36. MS of menthyl propionate (16).
Figure 37. 1H NMR spectrum of ethyl 4,5-dibromopentanoate.
39
Figure 38. 13C NMR spectrum of ethyl 4,5-dibromopentanoate.
Figure 39. MS of ethyl 4,5-dibromopentanoate.
40
Figure 40. MS of menthyl chloride (17)
41
Figure 41. MS of neomenthyl chloride (18).
42