An optimised procedure for PTFE phase vanishing reactions: An improved reaction design and the use of reagents adsorbed on silica

Article abstract of DOI:10.3184/174751915X14416158938073

While the phase-vanishing (PV)-PTFE reaction design works well with a broad range of substrates and reaction conditions, there are occasional problems. A description of the problems and their importance, including their effects on the reaction outcome and ways to address them, are discussed. Details of an improved design, a hybrid of previously reported PV-PTFE and solvent-free PV-PTFE designs, is presented, as well as the use of silica-supported reagents.

Full text of DOI:10.3184/174751915X14416158938073

574 RESEARCH PAPER
VOL. 39 OCTOBER, 574–581
JOURNAL OF CHEMICAL RESEARCH 2015
An optimised procedure for PTFE phase vanishing reactions: an improved
reaction design and the use of reagents adsorbed on silica
Brendon A. Parsonsa,b, Olivia Lin Smitha and Veljko Dragojlovica*
aWilkes Honors College of Florida Atlantic University, 5353 Parkside Drive, Jupiter, FL 33458, USA
bPresent address address: Department of Chemistry, University of Washington, Box 351700, Seattle, WA 98195-1700, USA
While the phase-vanishing (PV)-PTFE reaction design works well with a broad range of substrates and reaction conditions, there are
occasional problems. A description of the problems and their importance, including their effects on the reaction outcome and ways to
address them, are discussed. Details of an improved design, a hybrid of previously reported PV-PTFE and solvent-free PV-PTFE designs,
is presented, as well as the use of silica-supported reagents.
Keywords: phase screen, PTFE, semipermeable membrane, synthesis design, bromination
The phase-vanishing (PV) reaction design is relatively new. It
replaces the reaction solvent with an inert perfluoroalkane as a
phase screen.1-16 The solvent provides a reaction medium for the
reactants and it also helps dissipate the heat of the reaction. The
role of the fluorous phase screen is to separate the reagent from
the substrate, which provides a way to carry out reactions under
ambient conditions on neat reactants. In the course of the reaction,
the reagent diffuses through the phase screen and the reagent
phase vanishes (Fig. 1a). The phase-vanishing method offers some
advantages compared to traditional methods. The experimental
design is simple and there is no need for a delivery system such as a
syringe drive. Diffusion through the phase screen enables the slow
and controlled delivery of reactants. Thus, exothermic reactions
normally carried out at low temperatures (typically –78 to 0 °C) can
both be conducted at an ambient temperature and the reactions that
otherwise would be too vigorous without a solvent can be carried
out on neat reagents.4,8,15,16
Bromination was one of the first reactions that was developed
as a phase-vanishing fluorous reaction.1,2 Other groups3-14 and
ourselves15,16 have made improvements to the original PV procedure
and applied it to various systems.
We introduced PTFE (polytetrafluoroethylene, Teflon) tape
as phase screen (Fig. 1b) in phase-vanishing PTFE (PV-PTFE)
reaction design.17-21 This experimental design also offers more
control of the reaction conditions and delivery of the reagent. The
original PV-PTFE design consisted of a PTFE-sealed reagent tube
immersed in a solution of the substrate in a suitable solvent.17 It has
been since modified to be carried out under solvent-free conditions18
and further developed to utilise PTFE-sealed vials for the delivery
of the reagent.20
The two methods, PV and PV-PTFE, are complementary. PV-
PTFE is inexpensive, more environmentally friendly and relies
on readily available laboratory materials. It works best with
highly reactive reagents whether they be liquids, or high vapour
pressure solids. However, it has some limitations. The reaction set-
up may be more time consuming and there are some limitations
as to suitable reagents and substrates. The more conventional
fluorous PV method requires the use of a costly fluorous solvent
and work up may be somewhat more involved owing to the need
to carefully separate the aqueous phase from the product phase,
and to appropriately handle the fluorous solvent to avoid loss. On
the other hand, this method can accommodate a greater variety of
reactants. Reviews of PV12,13 and both PV and PV-PTFE reactions19
have been published.
We now address the complications that we encountered in the
development and implementation of PV-PTFE reactions. As a
result, a new hybrid PV-PTFE reaction design and the use of silica-
supported reagents were introduced.
Results and discussion
While PV-PTFE reaction design generally performed very well,
we encountered some problems. These include the reaction
solvent being drawn or forced into the delivery tube, the surface
of the PTFE tape being clogged with the product, the reaction of
a volatile substrate with the reagent on the surface of the PTFE
tape, accumulation of solvent in the delivery tube when a hybrid
PV-PTFE reaction design was employed, excessive rate of reagent
delivery and local accumulation of the reagent.
The above problems do not appear in each trial and not all of
them appear regularly. Furthermore, most of them do not affect
the reaction outcome. However, they may make performing the
reaction and isolation of pure product more laborious and less
elegant. Therefore, we decided to address them and to further
optimise the reaction design.
Solvent being drawn or forced into the delivery tube
A draw of the solvent into the delivery tube is one of the most
consistent and reproducible problems we encountered (Fig. 2). We
explored the causes of it in our recent publication.21 While a draw of
the solvent into the delivery tube usually did not affect the reaction
outcome, it made the reaction conditions more difficult to control,
sometimes complicated the reaction work-up and, in general, made
the method less efficient and elegant.
The main problem with the solvent being drawn into the
delivery tube was that it dilutes the reagent and the reaction may
occur in the tube where the concentration of the reagent is high
(Figs 3a and 3b). There are several ways to avoid the solvent being
drawn into the delivery tube. First, one can select the solvents that
Fig. 1 (a) Phase-vanishing fluorous reaction. (b) PV-PTFE reaction set-up.
* Correspondent. E-mail: vdragojl@fau.edu

JOURNAL OF CHEMICAL RESEARCH 2015 575
Fig. 2 Draw of the solvent into the delivery tube. The initial solvent level is marked by a line. The solvents were acetone (with a blue ink added)
in the flask and water (with a red ink added) in the delivery tube. The total elapsed time was 25 min.
Fig. 3 (a) In a typical PV-PTFE reaction design delivery tube is immersed into the solvent. (b) Such a set-up allows solvent to be drawn into
the delivery tube. (c) A modified design in which the delivery tube just touches the surface of the solvent reduces solvent uptake.
(d) Solvent-free PV-PTFE design. (e) A hybrid reaction design.
Fig. 4 Bromination of trans-stilbene by means of a hybrid reaction design.
have low tendency to be drawn into the delivery tube.21 Another
Ph
H
H
Br
Br
Br2
involves a small change in the design, where the delivery tube is
not immersed into the reaction solution, but instead just touches
it (Fig. 3c). That way, as soon as some solvent is drawn into the
tube its level drops below the bottom of the delivery tube and the
uptake stops.21
Ph
1
2
Scheme 1
Finally, the most effective way to prevent solvent uptake is to
keep the delivery tube above the solvent level. That is a so-called
hybrid PV-PTFE reaction design (Fig. 3e) as it combines features
of the solvent-free17 (Fig. 3d) and PV-PTFE18 designs (Fig. 3a).
The hybrid reaction design enables clean and efficient delivery of
a volatile reagent to the reaction mixture. The reagent is delivered
into the gas phase above the reaction mixture and is then absorbed
by it. Such a design makes a draw of the solvent into the tube
impossible. However, it is restricted to the delivery of volatile
reagents such as bromine and iodine monochloride. Suitable
solvents included dichloromethane and, a more environmentally
friendly, ethyl acetate.
A suitable illustration of hybrid PV-PTFE reaction design is
bromination of trans-stilbene 3 in ethyl acetate (Fig. 4, Scheme 1).

576 JOURNAL OF CHEMICAL RESEARCH 2015
N
O2
N
O2
N
O2
O
H
O
O
(COCl)2
O
(1)
(2)
N
O
O2
N
O2
N
O2
3
4
N
O2
H
O
N
O2
O
N
O2
H
2O2
O
+
+
CO2
ligh
t
O
rubrene
N
O2
O
N
O2
N
O2
4
3
Scheme 2
Fig. 5 Reaction set-ups that prevent the solvent being forced into the delivery tube (a) A general set-up with a side arm on the left for pressure
equalization, the delivery tube in the middle and a flask for addition of solids attached to the right neck of the flask. (b) An example of a reaction set-
up to carry out the preparation of DNPO. (c) Chemiluminescence of DNPO prepared in the course of the PV-PTFE reaction.
meso-Dibromostilbene 2 precipitates out of the solution, while the
isomeric d,l-dibromostilbene 6 remains dissolved.
reaction. An example is the previously described bromination of
trans-stilbene 1. The product, meso-dibromostilbene 2, forms
an insoluble coat on the surface of the PTFE tape and further
reaction stops. Although carrying out the reaction with vigorous
stirring may help prevent clogging of the PTFE tape, the best
solution was the use of a hybrid PV-PTFE reaction design as
shown in Fig. 3e. Alternatively, bromination of trans-stilbene
can be carried out under solvent-free PV-PTFE conditions.18,20
In some cases the solvent was forced into the delivery tube.
Although the end result was the same as the solvent being
drawn into the delivery tube, the cause was different and was
easy to address. We encountered this problem when carrying
out the preparation of bis(2,4-dinitrophenyl) oxalate (DNPO)
4 from 2,4-dinitrophenol (2,4-DNP) 3 and oxalyl chloride in
dichloromethane [Scheme 2 (1)]. We avoided the use of a base,
such as triethylamine, as we wanted a pure product that did
not need any further purification. DNPO is highly moisture
sensitive and an attempt at further purification risks hydrolysis
of the product or, at best, considerably reduces the yield. In the
absence of a base, the reaction proceeds with the evolution of
gaseous hydrogen chloride. Thus, in a closed system there was a
pressure build-up and some solvent was forced into the delivery
tube. By simply placing a partially inflated nitrogen filled
balloon on one of the necks of the reaction flask, pressure build-
up was prevented and no solvent was drawn into the delivery
tube (Fig. 5a and b). The reaction proceeded smoothly to give
DNPO, which upon treatment with H2O2 mixture exhibited
intense and long lasting chemiluminescence (Fig. 5c) [Scheme
2 (2)].22-24
Reaction of a volatile substrate on the surface of the PTFE tape
In a solvent-free reaction, sometimes a substrate reacted with
the reagent on the surface of the PTFE tape coating it with the
product. That was the case when a volatile substrate was used
and the delivery tube was close to the surface of the substrate.
Sometimes, all that was necessary to avoid a reaction on the
PTFE surface was to find an optimum distance of the delivery
tube to the surface of the substrate. If the delivery tube was too
close, the reaction was rapid and occurred on the PTFE tape. If
the delivery tube was placed at a sufficient distance from the
substrate, the formation of the product on the surface of the
PTFE tape was reduced.
Thus, with a non-volatile cis-stilbene 5 as the substrate, there
was no observed reaction on the PTFE tape in repeated trials
(Fig. 6, Scheme 3). The solid product 6 was obtained in high
yield and purity, even when the delivery tube was placed close
to the surface of the substrate.
Surface of the PTFE tape being clogged with the product
In a conventional PV-PTFE reaction, the delivery tube was
immersed into the solution. Occasionally an insoluble product
formed on the surface of the PTFE tape and clogged it. That
prevented further delivery of the reagent and terminated the
A solvent-free reaction of volatile liquid 2,3-dimethyl-2-
butene 7 with bromine illustrates this problem (Fig. 7, Scheme
4). There was a rapid reaction on the surface of PTFE tape.

JOURNAL OF CHEMICAL RESEARCH 2015 577
Fig. 6 With a non-volatile substrate, such as cis-
stilbene, there was no reaction on the surface of
PTFE tape.
Fig. 7 A volatile substrate reacted with the reagent on the surface of PTFE tape coating it with the product.
Ph
r
B
r
B
H
Br2
r
B
2
H
Br
Ph
r
B
5
6
7
8
Scheme 4
Scheme 3
In this case, the product was scraped off the tape and left in a
fumehood until the excess of bromine evaporated. By-products,
apparently a result of allylic free radical substitution, were
observed by GC-MS analysis.
dimethylbutane 8 was pure, according to GC-MS analysis, and
was obtained in high yield.
Hybrid reaction design and accumulation of solvent in the
delivery tube
The problems involving volatility of some substrates can be
addressed by various measures. They include carrying out the
reaction in an ice bath, or by maintaining a sufficient distance
between the tube and the surface of the substrate. However,
as the use of an ice bath may not be sufficient and the size of
the apparatus may make it impossible to place the delivery
tube at an appropriate distance, an alternative is to dissolve
the substrate in a suitable solvent, a fool-proof method that
prevents this problem. While it does add the inconvenience of
dealing with a solvent with some very volatile substrates, such
as 2,3-dimethyl-2-butene, it is the best method. In addition
to addressing volatility issues, bromination of this particular
substrate should be carried out in the dark to avoid free radical
allylic substitution. When either dichloromethane or ethyl
acetate was used as the solvent, the resulting 2,3-dibromo-2,3-
As mentioned previously, to solve the above problems, we
developed a hybrid PV-PTFE reaction design. A typical hybrid
reaction set-up is shown in Fig. 8. Note that the bromine vapours
flow directly into the solution and none leave the flask. Thus,
the pressure-equalising arm can be left open. Alternatively, a
partially inflated balloon can be attached to it.
While the hybrid reaction design addressed solvent uptake
issues, occasionally the solvent vapours condensed and
accumulated in the delivery tube (Fig. 9). While this affected
neither the reaction outcome nor the yield, it required the use of
an additional small excess (10–20%) of the reagent.
Except for the obvious way to avoid the accumulation of a
solvent in the delivery tube, which is to carry out the reaction
under solvent-free conditions, there are two principal ways

578 JOURNAL OF CHEMICAL RESEARCH 2015
Fig. 8 Delivery of bromine to dicholormethane by means of
a hybrid PV-PTFE reaction design. While the flow of bromine
can be easily observed with a naked eye, it is difficult to see
bromine vapour on a photograph. The reaction apparatus
has been backlit and on the right the same photograph was
contrast-enhanced to show the flow of bromine vapour.
Fig. 9 Accumulation of the solvent in the delivery tube.
In this case, the reagent in the delivery tube was iodine
monochloride and the solvent was dichloromethane (two
different experiments shown).
to prevent this phenomenon. One is to utilise a less volatile
solvent and another is to utilise a solvent that does not dissolve
the reagent very well. For example, dichloromethane exhibited
a tendency to accumulate in the delivery tube. It is both
volatile and dissolves halogens efficiently. A change of solvent
to ethyl acetate addressed the problem.
to give a considerably less volatile solid 2,3-dibromo-2,3-
dimethylbutane 8.
The problem could be solved by various means of pressure
equalisation. One way is to place partially inflated balloons on
both the reaction flask and the top of the tube. A better way is to
equalise the pressure in the delivery tube and the reaction flask by
connecting the top of the delivery tube with a side arm of the flask
(Fig. 11). When a delivery vial is employed, the reagent adsorbed
on a solid carrier such as silica should be used (see below).
(b) Build-up of pressure in the delivery vessel occurred when
either a small vial or a glass tube inserted into a rubber septum
was used along with a volatile reagent, such as bromine. Vapour
accumulated in the upper part of the tube and exerted pressure
on the liquid below forcing it out at a fast rate. Interestingly,
when a stoppered delivery tube was used, no such fast delivery
of the reagent was observed (Fig. 12).18 It is possible that the
excess pressure was released by leaking at the stoppered joint.
(c) When a combination of both a drop in pressure in the
reaction vessel and an increase of the pressure in the delivery
tube occur, one can address them either by connecting the top
of the delivery tube to a side arm of the reaction flask (Fig. 11),
or by employing a reagent adsorbed on silica (see below).
Delivery of the reagent out of the delivery tube at a high rate
The purpose of both hybrid and PV-PTFE reaction designs was
to deliver either the neat reagent or the reagent in a solution at a
controlled rate. However, sometimes the reagent was delivered
at a rather fast rate and came out in droplets. Possible reasons
for that are: (a) a drop of pressure in the reaction flask, (b) a
build-up of pressure in the delivery tube, or (c) a combination
of the two factors. Interestingly, this problem was observed
only when the top of the delivery tube was completely sealed
such as use of an inverted vial as a delivery tube (Figs 10a and
b),20 or a glass tube inserted into a rubber septum (Fig. 10c).
(a) When carrying reaction on neat volatile substrates, the
formation of a non-volatile product lowers the pressure in the
reaction vessel. This occasionally resulted in the draw of the
reagent through the PTFE tape at a high rate. Instead of the
preferred thin stream of vapour, the reagent was delivered
dropwise (Fig. 10). Thus, the reagent was delivered at a faster
rate than intended. An example is a solvent-free reaction
of volatile liquid 2,3-dimethyl-2-butene 7 with bromine
Use of silica-adsorbed reagents
To make the reaction procedure safer and more environmentally
friendly, we adsorbed the reagent on silica (Fig. 13). Strictly

JOURNAL OF CHEMICAL RESEARCH 2015 579
(a)
(b)
(c)
Fig. 10 Sometimes the reagent was delivered dropwise due to (a) and (b) the increased pressure in the delivery vessel (a 2-mL vial) and
(c) the reduced pressure in the reaction flask. Bromination of (a) and (b) trans-stilbene and (c) 2,3-dimethyl-2-butene are shown.
Fig. 11 The best way to prevent the delivery of the reagent at a high
rate is to equalise pressure by connecting the top of the delivery tube
with the side arm of the reaction flask.
Fig. 12 Accumulated bromine vapour did not force bromine out of
a stoppered delivery tube.
Fig. 13 Use of silica-supported reagent in hybrid PV-PTFE reaction. A, Silica was placed in a 2-mL vial; B, bromine was added; C, the vial was
covered with PTFE tape and secured with an o-ring; D, the prepared vial can be capped and stored for future use; E, the vial was inserted into a
rubber septum; F and G, the septum with the vial was inserted into the flask which contains the substrate dissolved in a suitable solvent.
speaking, this is no longer a phase-vanishing design as, in the
course of the reaction, the silica phase does not vanish. Except
for slightly longer reaction times there were no other differences
in reaction outcomes compared to other PTFE reaction designs.
The rate of the delivery of the reagent can be manipulated by
altering the reagent/silica ratio. At a high reagent/silica ratio
(1:2), the reaction rate was very close to that of neat reagent.
As the amount of reagent relative to silica was reduced, the
rate of delivery was correspondingly slower. Upon completion
of the reaction, silica can be reused. Used silica was extracted

580 JOURNAL OF CHEMICAL RESEARCH 2015
Fig. 14 Examples of the use of silica-supported
reagents in hybrid PV-PTFE reactions.
Fig. 15 When a reaction was carried out without stirring, there was some local accumulation
of bromine. The white precipitate in the reaction on the left is meso-dibromostilbene.
Experimental
with dichloromethane and analysed by means of GC-MS. We
observed the presence of neither the substrate nor the reaction
product in the extract.
The use of silica-supported bromine along with the substrate
in a solution addressed all the problems associated with
bromination of 2,3-dimethyl-2-butene (formation of the product
on the surface of PTFE tape, fast dropwise draw of the reagent
out of the delivery tube, and accumulation of the solvent in the
delivery tube).
CAUTION: One must exercise care when handling bromine
or iodine monochloride. Bromine and iodine monochloride are
corrosive, cause skin burns, and their vapours are toxic. One should
work in a fume hood and wear eye protection and gloves.
PTFE tape was commercially available Teflon tape (High Density
PTFE tape, Mil. Spec. T-27730A) made by Taega Technologies
purchased from Fisher Scientific (cat. No. 14-610-120)). All of the
commercially available reagents (bromine, iodine monochloride,
2,3-dimethyl-2-butene, cis-stilbene, trans-stilbene, oxalyl chloride,
hydrogen peroxide, rubrene, dichloromethane and ethyl acetate) were
used as supplied without further purification. Dry dichloromethane
was obtained from Aldrich and used without further purification.
Commercially available 2,4-dinitrophenol was dissolved in
dichloromethane, the solution was separated from water, dried over
anhydrous MgSO4, filtered and dichloromethane was removed under
reduced pressure. The resulting 2,4-dinitrophenol was subjected one
more time to the same drying procedure. GC-MS analyses were
performed by means of an Agilent 6890N Gas Chromatograph
equipped with an HP-5MS 30 m x 0.25 mm column and an Agilent
5973N MSD. All reaction products were characterized with no further
purification, unless stated otherwise. Melting points were determined
with a MEL-TEMP Electrothermal heater equipped with an alcohol
thermometer and are uncorrected. Vials were National Scientific
C4000-1 (clear) and C4000-2W (amber) 2-mL vials obtained from
Fisher Scientific.
Preparation of halogen on silica reagent. In a 2-mL vial, silica
(230–400 mesh, 1.00 g) was mixed with bromine or iodine
monochloride (0.20 – 0.40 mL) of and left standing for 24 h before use.
meso-Dibromostilbene (2): A stir-bar, trans-stilbene 1 (0.450 g;
2.5 mmol) and ethyl acetate (15 mL) were placed into a 50-mL round
bottom flask. A PTFE vial containing bromine adsorbed on silica
was inserted (0.20 mL; 4.0 mmol of bromine; 1.0 g of silica) into the
vapour phase above the solution. After 20 min the solid product was
collected by vacuum filtration. meso-Dibromostilbene 2 (0.782 g) was
isolated in 92% yield. The melting point was 237–237.5 °C (dec.) (lit.25
237–239 °C).
Examples are shown in Fig. 14. Note that this reaction design
allows for a reaction to be carried out in a completely sealed
vessel without any need for a pressure equalisation.
Local accumulation of the reagent
When a reaction was carried out without stirring, a local
accumulation of the reagent was observed (Fig. 15). An obvious
solution was to use a stirrer. However, we were concerned that
the possible permeability of bulk PTFE coating and reaction of
the reagent with the iron core may affect the outcome of longer
experiments.21 Also, vigorous stirring sometimes resulted in the
splattering of the delivery tube with the reaction mixture.
Even though the accumulation of the reagent was noticeable,
there did not appear to be any effect on the reaction outcome in
terms of yield and purity of the product. However, we carried
out reactions on relatively simple systems where reactivity
was very good (fast reaction rate) with few possibilities for
competing side reactions and formation of by-products.
The use of a glass-coated stir-bar addressed the potential
problem of the local accumulation of the reagent. If a glass-
coated stir-bar is not available, one can be easily made from an
iron bar (e.g. a nail) and a glass pipette.4,19
Conclusion
We have examined potential complications and ways to address
them in order to make PV-PTFE reactions a convenient and
reproducible method. When designing a particular experiment
one can anticipate potential obstacles by taking into account
the nature of the reagent, the substrate and the solvent. A hybrid
PV-PTFE reaction design combined with a silica-supported
reagent successfully resolved most, if not all, of the problems we
encountered so far. The method is particularly suitable for reactions
involving volatile and highly reactive reagents. One also should
keep in mind that, in some cases, a more traditional fluorous PV
reaction, or simply a conventional reaction, may be more suitable.
Bis(2,4-dinitrophenyl) oxalate (4): A stir-bar, dry 2,4-dinitrophenol
3 (0.368 g, 2.0 mmol) and dry dichloromethane (4.0 mL) were placed
into a 10-mL round-bottom flask. The flask was cooled in an ice bath.
A PTFE sealed tube filled with a solution of oxalyl chloride (0.095 mL,
1.10 mmol) in dichloromethane (0.5 mL) was inserted into the flask.
The reaction was allowed to proceed until all of the oxalyl chloride
solution had diffused into the vial (~10 min). The ice bath was removed

JOURNAL OF CHEMICAL RESEARCH 2015 581
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Received 28 August 2015; accepted 4 September 2015
Paper 1503566 doi: 10.3184/174751915X14416158938073
Published online: 2 October 2015